ES2393215T3

ES2393215T3 - Morpholino pyrimidine derivatives useful in the treatment of proliferative disorders

Info

Publication number: ES2393215T3
Application number: ES07789273T
Authority: ES
Inventors: Maurice Raymond Verschoyle Finlay; Jeffrey Morris; Kurt Gordon Pike
Original assignee: AstraZeneca AB
Current assignee: AstraZeneca AB
Priority date: 2006-08-24
Filing date: 2007-08-21
Publication date: 2012-12-19
Anticipated expiration: 2027-08-21
Also published as: GB0616747D0; TW200817384A; CN101541781A; RU2440349C2; RU2009110255A; BRPI0715609A2; ZA200901015B; CN101541781B; CN101558046A

Abstract

Un compuesto de fórmula (I)fórmula (I)o una sal farmacéuticamente aceptable del mismo; en la quem es 0, 1, 2, 3 ó 4;1Y e Y2 son independientemente N o CR8 con la condición de que uno de 1Y e Y2 es N y el otro es CR8;X es un grupo enlazador seleccionado de -CR4>=CR5-, -CR4>=CR5CR6R7-, -CR6R7CR5>=CR4-, -C≡C-, -C≡CCR6R7-, -CR6R7C≡C-, -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S(O)CR6R7-, -S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R7-, -NR4C(O)NR5CR6R7-, -NR4S(O)2CR6R7-, -S(O)2NR4CR6R7-, -C(O)NR4-, -NR4C(O)-, -NR4C(O)NR5-, -S(O)2NR4- y -NR4S(O)2-;R1 es un grupo seleccionado de hidrógeno, alquilo de C1-6, alquenilo de C2-6, alquinilo de C2-6, carbociclilo, carbociclilalquilode C1-6, heterociclilo y heterociclil-alquilo de C1-6, estando dicho grupo opcionalmente sustituido con uno omás grupos sustituyentes seleccionados de halo, ciano, nitro, R9, -OR9, -SR9, -SOR9, -SO2R9, -COR9, -CO2R9, -CONR9R10, -NR9R10, -NR9COR10, -NR9CO2R10, -NR9CONR10R15, -NR9COCONR10R15 y -NR9SO2R10;R2 es un grupo seleccionado de alquilo de C1-6, carbociclilo y heterociclilo, estando dicho grupo sustituido con -NR17CONR18R19 y opcionalmente sustituido con uno o más grupos sustituyentes seleccionados independientementede halo, ciano, nitro, -R11, -OR11, -SR11, -SOR11, -SO2R11, -COR11, -CO2R11, -CONR11R12, -NR11R12, -NR11COR12, y -NR11COCONR12R16.A compound of formula (I) formula (I) or a pharmaceutically acceptable salt thereof; where it is 0, 1, 2, 3 or 4; 1Y and Y2 are independently N or CR8 with the proviso that one of 1Y and Y2 is N and the other is CR8; X is a linker group selected from -CR4> = CR5-, -CR4> = CR5CR6R7-, -CR6R7CR5> = CR4-, -C≡C-, -C≡CCR6R7-, -CR6R7C≡C-, -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S (O) CR6R7-, -S (O) 2CR6R7-, -C (O) NR4CR6R7-, -NR4C (O) CR6R7-, -NR4C (O) NR5CR6R7-, -NR4S (O) 2CR6R7-, -S (O ) 2NR4CR6R7-, -C (O) NR4-, -NR4C (O) -, -NR4C (O) NR5-, -S (O) 2NR4- and -NR4S (O) 2-; R1 is a selected group of hydrogen , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, C 1-6 carbocyclylalkyl, heterocyclyl and C 1-6 heterocyclyl-alkyl, said group being optionally substituted with one or more substituent groups selected from halo, cyano, nitro, R9, -OR9, -SR9, -SOR9, -SO2R9, -COR9, -CO2R9, -CONR9R10, -NR9R10, -NR9COR10, -NR9CO2R10, -NR9CONR10R15, -NR9COCONR10R2 and a selected group; of C1-6 alkyl, carbocyclyl and heterocyclyl, said group being substituted or with -NR17CONR18R19 and optionally substituted with one or more substituent groups independently selected from halo, cyano, nitro, -R11, -OR11, -SR11, -SOR11, -SO2R11, -COR11, -CO2R11, -CONR11R12, -NR11R12, -NR11COR12 , and -NR11COCONR12R16.

Description

Derivados de morfolino pirimidina útiles en el tratamiento de trastornos proliferativos Morpholino pyrimidine derivatives useful in the treatment of proliferative disorders

La presente invención se refiere a derivados de morfolino pirimidina, a procedimientos para su preparación, a composiciones farmacéuticas que los contienen, y a su uso en terapia, por ejemplo en el tratamiento de una enfermedad proliferativa tal como el cáncer, y particularmente en enfermedad mediada por una mTOR cinasa y/o una o más enzimas PI3K. The present invention relates to morpholino pyrimidine derivatives, methods for their preparation, pharmaceutical compositions containing them, and their use in therapy, for example in the treatment of a proliferative disease such as cancer, and particularly in disease mediated by an mTOR kinase and / or one or more PI3K enzymes.

Ahora se sabe con certeza que la desregulación de oncogenes y genes supresores de tumores contribuye a la formación de tumores malignos, por ejemplo por medio de una proliferación celular incrementada o supervivencia celular incrementada. También se sabe que las rutas de señalización mediadas por las familias PI3K/mTOR tienen un papel central en un número de procesos celulares, incluyendo la proliferación y la supervivencia, y la desregulación de estas rutas es un factor etiológico de un amplio espectro de cánceres humanos y otras enfermedades. It is now known with certainty that deregulation of tumor suppressor genes and oncogenes contributes to the formation of malignant tumors, for example by means of increased cell proliferation or increased cell survival. It is also known that signaling pathways mediated by PI3K / mTOR families play a central role in a number of cellular processes, including proliferation and survival, and deregulation of these routes is an etiological factor of a broad spectrum of human cancers. and other diseases.

La diana de mamífero del antibiótico macrólido Rapamicina (sirolimus) es la enzima mTOR. Esta enzima pertenece a la familia de proteínas cinasas de cinasas relacionadas con la fosfatidilinositol (PI) cinasa (PIKK), que también incluye ATM, ATR, DNA–PK y hSMG–1. La mTOR, como otros miembros de la familia PIKK, no posee actividad detectable de cinasa en lípidos, sino que funciona como una serina/treonina cinasa. Gran parte del conocimiento de la señalización de mTOR está basado en el uso de Rapamicina. La Rapamicina se une primero a la proteína de unión a la inmunofilina FK506 (FKBP12) de 12 kDa, y este complejo inhibe la señalización de mTOR (Tee y Blenis, Seminars in Cell and Developmental Biology, 2005, 16, 29–37). La proteína mTOR consiste en un dominio catalítico de cinasa, un dominio de unión de FKBP12–Rapamicina (FRB), un dominio represor putativo próximo al término C y hasta 20 motivos HEAT repetidos en tándem en el término N, así como el dominio del término C de FAT y FRAP– ATM–TRRAP (FAT) (Huang y Houghton, Current Opinion in Pharmacology, 2003, 3, 371–377). The mammalian target of the macrolide antibiotic Rapamycin (sirolimus) is the mTOR enzyme. This enzyme belongs to the family of kinase protein kinases related to phosphatidylinositol (PI) kinase (PIKK), which also includes ATM, ATR, DNA-PK and hSMG-1. MTOR, like other members of the PIKK family, has no detectable kinase activity in lipids, but works as a serine / threonine kinase. Much of the knowledge of mTOR signaling is based on the use of Rapamycin. Rapamycin first binds to the 12 kDa immunophilin binding protein FK506 (FKBP12), and this complex inhibits mTOR signaling (Tee and Blenis, Seminars in Cell and Developmental Biology, 2005, 16, 29–37). The mTOR protein consists of a kinase catalytic domain, a binding domain of FKBP12-Rapamycin (FRB), a putative repressor domain near term C and up to 20 HEAT motifs repeated in tandem at term N, as well as the domain of the term FAT and FRAP C – ATM – TRRAP (FAT) (Huang and Houghton, Current Opinion in Pharmacology, 2003, 3, 371–377).

La mTOR cinasa es un regulador clave del crecimiento celular y se ha demostrado que regula una gran variedad de funciones celulares, incluyendo traducción, transcripción, recambio del ARNm, estabilidad de la proteína, reorganización citoesquelética de la actina y autofagia (Jacinto y Hall, Nature Reviews Molecular and Cell Biology, 2005, 4, 117–126). La mTOR cinasa integra las señales de los factores de crecimiento (tales como el factor de crecimiento de tipo insulina o insulina) y nutrientes (tales como aminoácidos y glucosa) para regular el crecimiento celular. La mTOR cinasa es activada por factores de crecimiento a través de la ruta PI3K–Akt. La función mejor caracterizada de la mTOR cinasa en células de mamíferos es la regulación de la traducción a través de dos rutas, a saber, la activación de S6K1 ribosomal para mejorar la traducción de los ARNm que poseen un tracto de oligopirimidina 5’ terminal (TOP) y la supresión de 4E–BP1 para permitir la traducción del ARNm dependiente de CAP. MTOR kinase is a key regulator of cell growth and has been shown to regulate a wide variety of cellular functions, including translation, transcription, mRNA turnover, protein stability, cytoskeletal reorganization of actin and autophagy (Jacinto and Hall, Nature Reviews Molecular and Cell Biology, 2005, 4, 117-126). MTOR kinase integrates the signals of growth factors (such as insulin-like growth factor or insulin) and nutrients (such as amino acids and glucose) to regulate cell growth. MTOR kinase is activated by growth factors through the PI3K – Akt pathway. The best characterized function of mTOR kinase in mammalian cells is the regulation of translation through two routes, namely the activation of ribosomal S6K1 to improve the translation of mRNAs that possess a 5 'terminal oligopyrimidine tract (TOP ) and the suppression of 4E-BP1 to allow translation of the CAP-dependent mRNA.

Generalmente, los investigadores han explorado los papeles fisiológico y patológico de mTOR usando la inhibición con Rapamicina y análogos de Rapamicina relacionados basados en su especificidad para mTOR como una diana intracelular. Sin embargo, datos recientes sugieren que la Rapamicina exhibe acciones inhibidoras variables en las funciones de señalización de la mTOR, y sugieren que la inhibición directa del dominio de mTOR cinasa puede presentar actividades anticancerígenas sustancialmente más amplias que aquellas alcanzadas por la Rapamicina (Edinger et al., Cancer Research, 2003, 63, 8451–8460). Por esta razón, inhibidores potentes y selectivos de la actividad de mTOR cinasa serían útiles para permitir una comprensión más completa de la función de la mTOR cinasa y proporcionar agentes terapéuticos útiles. Generally, researchers have explored the physiological and pathological roles of mTOR using inhibition with Rapamycin and related Rapamycin analogs based on their specificity for mTOR as an intracellular target. However, recent data suggest that Rapamycin exhibits variable inhibitory actions on mTOR signaling functions, and suggests that direct inhibition of the mTOR kinase domain may present substantially broader anticancer activities than those achieved by Rapamycin (Edinger et al. ., Cancer Research, 2003, 63, 8451-8460). For this reason, potent and selective inhibitors of mTOR kinase activity would be useful to allow a more complete understanding of the function of mTOR kinase and to provide useful therapeutic agents.

Existen ahora considerables pruebas que indican que las rutas aguas arriba de mTOR, tales como la ruta de PI3K, son frecuentemente activadas en el cáncer (Vivanco y Sawyers, Nature Reviews Cancer, 2002, 2, 489–501; Bjomsti y Houghton, Nature Reviews Cancer, 2004, 4, 335–348; Inoki et al., Nature Genetics, 2005, 37, 19–24). Por ejemplo, los componentes de la ruta de PI3K, que están mutados en los diferentes tumores humanos, incluyen mutaciones activantes de los receptores de factores de crecimiento, y la amplificación y/o sobreexpresión de PI3K y Akt. There is now considerable evidence indicating that upstream routes of mTOR, such as the PI3K pathway, are frequently activated in cancer (Vivanco and Sawyers, Nature Reviews Cancer, 2002, 2, 489–501; Bjomsti and Houghton, Nature Reviews Cancer, 2004, 4, 335–348; Inoki et al., Nature Genetics, 2005, 37, 19–24). For example, the components of the PI3K pathway, which are mutated in different human tumors, include activating mutations of growth factor receptors, and amplification and / or overexpression of PI3K and Akt.

Además, existen pruebas de que la proliferación de células endoteliales puede también ser dependiente de la señalización de mTOR. La proliferación de células endoteliales es estimulada por la activación del factor de crecimiento celular endotelial vascular (VEGF) de la ruta de señalización de PI3K–Akt–mTOR (Dancey, Expert Opinion on Investigational Drugs, 2005, 14, 313–328). Además, se cree que la señalización de mTOR cinasa controla parcialmente la síntesis de VEGF a través de efectos sobre la expresión del factor 1! inducible por hipoxia (HIF–1!) (Hudson et al., Molecular and Cellular Biology, 2002, 22, 7004–7014). Por lo tanto, la angiogénesis tumoral puede depender de la señalización de mTOR cinasa de dos formas: a través de la síntesis de VEGF inducida por hipoxia por células estrómicas y tumorales, y a través de la estimulación mediante VEGF de la proliferación y supervivencia endotelial a través de la señalización de PI3K–Akt–mTOR. In addition, there is evidence that endothelial cell proliferation may also be dependent on mTOR signaling. Endothelial cell proliferation is stimulated by the activation of vascular endothelial cell growth factor (VEGF) of the PI3K – Akt – mTOR signaling pathway (Dancey, Expert Opinion on Investigational Drugs, 2005, 14, 313–328). Furthermore, it is believed that mTOR kinase signaling partially controls the synthesis of VEGF through effects on the expression of factor 1! hypoxia-inducible (HIF – 1!) (Hudson et al., Molecular and Cellular Biology, 2002, 22, 7004–7014). Therefore, tumor angiogenesis can depend on mTOR kinase signaling in two ways: through hypoxia-induced synthesis of VEGF by stromal and tumor cells, and through VEGF stimulation of endothelial proliferation and survival through of the signaling of PI3K – Akt – mTOR.

Estos descubrimientos sugieren que los inhibidores farmacológicos de mTOR cinasa deberían ser de valor terapéutico para el tratamiento de las diversas formas de cáncer, que comprenden tumores sólidos tales como carcinomas y sarcomas, y las leucemias y neoplasias linfoides. En particular, los inhibidores de mTOR cinasa deberían ser de valor terapéutico para el tratamiento de, por ejemplo, cáncer de mama, colorrectal, pulmón These findings suggest that mTOR kinase pharmacological inhibitors should be of therapeutic value for the treatment of various forms of cancer, which include solid tumors such as carcinomas and sarcomas, and lymphoid leukemias and neoplasms. In particular, mTOR kinase inhibitors should be of therapeutic value for the treatment of, for example, breast, colorectal, lung cancer.

(incluyendo cáncer de pulmón de células pequeñas, cáncer de pulmón de células no pequeñas y cáncer broncoalveolar) y próstata, y de cáncer del conducto biliar, hueso, vejiga, cabeza y cuello, riñón, hígado, tejido gastrointestinal, esófago, ovario, páncreas, piel, testículos, tiroides, útero, cérvix y vulva, y de leucemias (incluyendo ALL y CML), mieloma múltiple y linfoma. (including small cell lung cancer, non-small cell lung cancer and bronchoalveolar cancer) and prostate, and cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, esophagus, ovary, pancreas , skin, testicles, thyroid, uterus, cervix and vulva, and leukemia (including ALL and CML), multiple myeloma and lymphoma.

Además de la tumorigénesis, existen pruebas de que mTOR cinasa desempeña un papel en una serie de síndromes de hamartoma. Estudios recientes han mostrado que las proteínas supresoras de tumores, tales como TSC1, TSC2, PTEN y LKB1, controlan estrechamente la señalización de mTOR cinasa. La pérdida de estas proteínas supresoras de tumores conduce a una serie de hamartomas como resultado de la elevada señalización de mTOR cinasa (Tee y Blenis, Seminars in Cell and Developmental Biology, 2005, 16, 29–37). Los síndromes con una relación molecular establecida para la desregulación de mTOR cinasa incluyen el síndrome de Peutz–Jeghers (PJS), enfermedad de Cowden, síndrome de Bannayan–Riley–Ruvalcaba (BRRS), síndrome de Proteus, enfermedad de Lhermitte–Duclos y esclerosis tuberosa (TSC) (Inoki et al., Nature Genetics, 2005, 37, 19–24). Los pacientes con estos síndromes habitualmente desarrollan tumores hamartomatosos benignos en múltiples órganos. In addition to tumorigenesis, there is evidence that mTOR kinase plays a role in a series of hamartoma syndromes. Recent studies have shown that tumor suppressor proteins, such as TSC1, TSC2, PTEN and LKB1, closely control mTOR kinase signaling. Loss of these tumor suppressor proteins leads to a series of hamartomas as a result of the high mTOR kinase signaling (Tee and Blenis, Seminars in Cell and Developmental Biology, 2005, 16, 29–37). Syndromes with an established molecular relationship for the deregulation of mTOR kinase include Peutz-Jeghers syndrome (PJS), Cowden disease, Bannayan-Riley-Ruvalcaba syndrome (BRRS), Proteus syndrome, Lhermitte-Duclos disease and sclerosis tuberose (TSC) (Inoki et al., Nature Genetics, 2005, 37, 19–24). Patients with these syndromes usually develop benign hamartomatous tumors in multiple organs.

Estudios recientes han revelado un papel de mTOR cinasa en otras enfermedades (Easton y Houghton, Expert Opinion on Therapeutic Targets, 2004, 8, 551–564). La Rapamicina ha demostrado ser un potente inmunosupresor al inhibir la proliferación inducida por antígenos de células T, células B y la producción de anticuerpos (Sehgal, Transplantation Proceedings, 2003, 35, 7S–14S), y de esta forma los inhibidores de mTOR cinasa pueden ser también inmunosupresores útiles. La inhibición de la actividad de cinasa de mTOR también puede ser útil en la prevención de la restenosis, es decir, el control de la proliferación indeseada de células normales en la vasculatura en respuesta a la introducción de endoprótesis vasculares en el tratamiento de enfermedad de la vasculatura (Morice et al., New England Journal of Medicine, 2002, 346, 1773–1780). Además, el análogo de la Rapamicina, everolimus, puede reducir la gravedad e incidencia de la vasculopatía del aloinjerto cardíaco (Eisen et al., New England Journal of Medicine, 2003, 349, 847–858). La elevada actividad de mTOR cinasa se ha asociado con la hipertrofia cardiaca, la cual es de importancia clínica como un factor de riesgo importante para la insuficiencia cardiaca y es una consecuencia del tamaño celular incrementado de los cardiomiocitos (Tee y Blenis, Seminars in Cell and Developmental Biology, 2005, 16, 29–37). De esta forma, se espera que los inhibidores de mTOR cinasa sean útiles en la prevención y tratamiento de una gran variedad de enfermedades, además del cáncer. Recent studies have revealed a role of mTOR kinase in other diseases (Easton and Houghton, Expert Opinion on Therapeutic Targets, 2004, 8, 551-564). Rapamycin has been shown to be a potent immunosuppressant by inhibiting proliferation induced by T-cell, B-cell and antibody production (Sehgal, Transplantation Proceedings, 2003, 35, 7S-14S), and thus mTOR kinase inhibitors They can also be useful immunosuppressants. Inhibition of mTOR kinase activity may also be useful in the prevention of restenosis, that is, control of unwanted proliferation of normal cells in the vasculature in response to the introduction of vascular stents in the treatment of disease of the vasculature (Morice et al., New England Journal of Medicine, 2002, 346, 1773-1780). In addition, the Rapamycin analogue, everolimus, can reduce the severity and incidence of cardiac allograft vasculopathy (Eisen et al., New England Journal of Medicine, 2003, 349, 847-858). The high activity of mTOR kinase has been associated with cardiac hypertrophy, which is of clinical importance as an important risk factor for heart failure and is a consequence of the increased cell size of cardiomyocytes (Tee and Blenis, Seminars in Cell and Developmental Biology, 2005, 16, 29–37). In this way, mTOR kinase inhibitors are expected to be useful in the prevention and treatment of a wide variety of diseases, in addition to cancer.

También se cree que un número de estos derivados de morfolino pirimidina pueden tener actividad inhibidora contra la familia de cinasas de fosfatidilinositol (PI) 3–cinasas. It is also believed that a number of these morpholino pyrimidine derivatives may have inhibitory activity against the phosphatidylinositol (PI) 3-kinase kinase family.

Las fosfatidilinositol (PI) 3–cinasas (PI3K) son cinasas lipídicas ubicuas que funcionan tanto como transductores de la señal aguas abajo de los receptores de la superficie celular como en las rutas del tráfico de proteínas y la membrana intracelular constitutiva. Todas las PI3K son enzimas con especificidad dual, con una actividad de cinasa lipídica que fosforila las fosfoinositidas en la posición 3–hidroxi, y una actividad de proteína cinasa no tan bien caracterizada. Los productos lipídicos de las reacciones catalizadas por PI3K que comprenden 3,4,5–trisfosfato de fosfatidilinositol [PI(3,4,5)P3], 3,4–bifosfato de fosfatidilinositol [PI(3,4)P2] y 3–monofosfato de fosfatidilinositol [PI(3)P] constituyen los segundos mensajeros en una variedad de rutas de transducción de señales, incluyendo aquellas esenciales para la proliferación celular, adhesión, supervivencia, reorganización citoesquelética y tráfico vesicular. La PI(3)P está presente constitutivamente en todas las células, y sus niveles no cambian drasticamente tras la estimulación con agonista. Por el contrario, PI(3,4)P2 y PI(3,4,5)P3 están nominalmente ausentes en la mayoría de las células pero se acumulan rápidamente en la estimulación con agonista. Phosphatidylinositol (PI) 3-kinases (PI3K) are ubiquitous lipid kinases that function both as signal transducers downstream of cell surface receptors and in the protein trafficking pathways and the constitutive intracellular membrane. All PI3Ks are enzymes with dual specificity, with a lipid kinase activity that phosphorylates phosphoinositides in the 3-hydroxy position, and a not so well characterized protein kinase activity. The lipid products of the reactions catalyzed by PI3K comprising 3,4,5-phosphatidylinositol trisphosphate [PI (3,4,5) P3], 3,4-phosphatidylinositol bisphosphate [PI (3,4) P2] and 3 - Phosphatidylinositol monophosphate [PI (3) P] constitute the second messengers in a variety of signal transduction pathways, including those essential for cell proliferation, adhesion, survival, cytoskeletal reorganization and vesicular traffic. PI (3) P is constitutively present in all cells, and its levels do not change dramatically after agonist stimulation. In contrast, PI (3,4) P2 and PI (3,4,5) P3 are nominally absent in most cells but accumulate rapidly in agonist stimulation.

Los efectos aguas abajo de los segundos mensajeros de la 3–fosfoinositida producida por la PI3K están mediados por moléculas diana que contienen dominios de unión de 3–fosfoinositida tales como el dominio de homología de pleckstrina (PH) y los dominios recientemente identificados FYVE y fox. Las dianas proteicas bien caracterizadas para PI3K incluyen PDK1 y la proteína cinasa B (PKB). Además, las tirosina cinasas como Btk y Itk dependen de la actividad de la PI3K. The downstream effects of the second messengers of 3-phosphoinositide produced by PI3K are mediated by target molecules containing 3-phosphoinositide binding domains such as the pleckstrin homology domain (PH) and the newly identified domains FYVE and fox . Well characterized protein targets for PI3K include PDK1 and protein kinase B (PKB). In addition, tyrosine kinases such as Btk and Itk depend on the activity of PI3K.

La familia de la PI3K de las cinasas lipídicas se puede clasificar en tres grupos de acuerdo a su especificidad por el substrato fisiológico (Vanhaesebroeck et al., Trends in Biol. Sci., 1997, 22, 267). Las enzimas PI3K de la Clase III fosforilan la PI sola. Por el contrario, las enzimas PI3K de la Clase II fosforilan tanto la PI como la PI 4–fosfato [PI(4)P]. Las enzimas PI3K de la Clase I fosforilan la PI, PI(4)P y PI 4,5–bifosfato [PI(4,5)P2], aunque se cree que solamente la PI(4,5)P2 es el sustrato celular fisiológico. La fosforilación de la PI(4,5)P2 produce el segundo mensajero lipídico PI(3,4,5)P3. Miembros relacionados más distantes de la superfamilia de cinasas lipídicas son las cinasas de la Clase IV tales como mTOR (discutida anteriormente) y la cinasa dependiente del ADN que fosforila los restos de serina/treonina dentro de los sustratos de proteína. Las más estudiadas y comprendidas de las cinasas lipídicas PI3K son las enzimas PI3K de la Clase I. The PI3K family of lipid kinases can be classified into three groups according to their specificity by the physiological substrate (Vanhaesebroeck et al., Trends in Biol. Sci., 1997, 22, 267). Class III PI3K enzymes phosphorylate PI alone. In contrast, Class II PI3K enzymes phosphorylate both PI and PI 4-phosphate [PI (4) P]. Class I PI3K enzymes phosphorylate PI, PI (4) P and PI 4,5-bisphosphate [PI (4,5) P2], although only PI (4,5) P2 is believed to be the cellular substrate physiological. Phosphorylation of PI (4,5) P2 produces the second lipid messenger PI (3,4,5) P3. More distant related members of the lipid kinase superfamily are Class IV kinases such as mTOR (discussed above) and the DNA-dependent kinase that phosphorylates the serine / threonine residues within the protein substrates. The most studied and understood of the PI3K lipid kinases are the PI3K enzymes of Class I.

Las PI3K de la Clase I son heterodímeros que consisten en una subunidad catalítica p110 y una subunidad reguladora. La familia está dividida adicionalmente en enzimas de la Clase Ia y la Clase Ib sobre la base de los socios regulatorios y el mecanismo de regulación. Las enzimas de la Clase Ia consisten en tres subunidades catalíticas distintas (p110a, p110∀ y p110δ) que se dimerizan con cinco subunidades reguladoras distintas (p85!, p55!, p50!, p85∀ y p55#), siendo capaces todas las subunidades catalíticas de interactuar con todas las subunidades reguladoras para formar una variedad de heterodímeros. Las PI3K de la Clase Ia son generalmente Class I PI3Ks are heterodimers consisting of a p110 catalytic subunit and a regulatory subunit. The family is further divided into enzymes of Class Ia and Class Ib on the basis of regulatory partners and the regulatory mechanism. Class Ia enzymes consist of three different catalytic subunits (p110a, p110∀ and p110δ) that are dimerized with five different regulatory subunits (p85 !, p55 !, p50 !, p85∀ and p55 #), all subunits being capable catalytic to interact with all regulatory subunits to form a variety of heterodimers. Class I PI3Ks are generally

activadas en respuesta a la estimulación del factor de crecimiento del tirosina cinasas receptoras a través de la interacción de sus dominios de subunidad reguladora SH2 con restos de fosfo–tirosina específicos de proteínas receptoras o adaptadoras activadas, tales como IRS–1. Tanto p110a como p110∀ se expresan constitutivamente en todos los tipos de células, mientras que la expresión de p110δ está más restringida a las poblaciones de leucocitos y algunas células epiteliales. En contraste, la única enzima de la Clase Ib consiste en una subunidad catalítica p110# que interactúa con una subunidad reguladora p101. Además, la enzima de la Clase Ib es activada en respuesta a sistemas de receptores acoplados a proteína G (GPCR), y su expresión parece estar limitada a los leucocitos y cardiomiocitos. activated in response to the stimulation of the receptor tyrosine kinase growth factor through the interaction of its SH2 regulatory subunit domains with phospho-tyrosine residues specific for activated receptor or adaptive proteins, such as IRS-1. Both p110a and p110∀ are constitutively expressed in all cell types, while the expression of p110δ is more restricted to leukocyte populations and some epithelial cells. In contrast, the only enzyme in Class Ib consists of a p110 # catalytic subunit that interacts with a p101 regulatory subunit. In addition, the Class Ib enzyme is activated in response to G-protein coupled receptor systems (GPCR), and its expression appears to be limited to leukocytes and cardiomyocytes.

Existen ahora considerables pruebas que indican que las enzimas PI3K de la Clase Ia contribuyen a la tumorigénesis en una gran variedad de cánceres humanos, ya sea directa o indirectamente (Vivanco y Sawyers, Nature Reviews Cancer, 2002, 2, 489–501). Por ejemplo, la subunidad p110a es amplificada en algunos tumores tales como los de ovario (Shayesteh et al., Nature Genetics, 1999, 21, 99–102) y cuello uterino (Ma et al., Oncogene, 2000, 19, 2739–2744). Más recientemente, mutaciones activantes dentro del sitio catalítico de la subunidad catalítica p110! se han asociado con otros diversos tumores tales como los de la región colorrectal y de mama y pulmón (Samuels et al., Science, 2004, 304, 554). Las mutaciones relacionadas con tumores en la subunidad reguladora p85! también se han identificado en cánceres tales como los de ovario y colon (Philp et al., Cancer Research, 2001, 61, 7426–7429). Además de los efectos directos, se cree que la activación de las PI3K de la Clase Ia contribuye a los eventos tumorigénicos que ocurren aguas arriba en las rutas de señalización, por ejemplo por medio de la activación dependiente del ligando o independiente del ligando de tirosina cinasas receptoras, sistemas de GPCR o integrinas (Vara et al., Cancer Treatment Reviews, 2004, 30, 193–204). Ejemplos de tales rutas de señalización aguas arriba incluyen la sobreexpresión de la tirosina cinasa receptor erbB2 en una variedad de tumores que conducen a la activación de las rutas mediadas por la PI3K (Harari et al., Oncogene, 2000, 19, 6102–6114) y sobreexpresión del oncogén ras (Kauffmann–Zeh et al., Nature, 1997, 385, 544–548). Además, las PI3K de la Clase Ia pueden contribuir indirectamente a la tumorigénesis causada por varios eventos de señalización aguas abajo. Por ejemplo, la pérdida del efecto de la fosfatasa supresora de tumores PTEN que cataliza la conversión de PI(3,4,5)P3 nuevamente en PI(4,5)P2 está asociada con una gran variedad de tumores a través de la desregulación de la producción de PI(3,4,5)P3 mediada por PI3K (Simpson y Parsons, Exp. Cell Res., 2001, 264, 29–41). Además, se cree que el aumento de los efectos de otros eventos de señalización mediados por la PI3K contribuye a una variedad de cánceres, por ejemplo por activación de Akt (Nicholson y Anderson, Cellular Signalling, 2002, 14, 381– 395). There is now considerable evidence to indicate that Class III PI3K enzymes contribute to tumorigenesis in a wide variety of human cancers, either directly or indirectly (Vivanco and Sawyers, Nature Reviews Cancer, 2002, 2, 489–501). For example, the p110a subunit is amplified in some tumors such as ovarian (Shayesteh et al., Nature Genetics, 1999, 21, 99-102) and cervix (Ma et al., Oncogene, 2000, 19, 2739– 2744). More recently, activating mutations within the catalytic site of the p110 catalytic subunit! they have been associated with several other tumors such as those in the colorectal and breast and lung regions (Samuels et al., Science, 2004, 304, 554). Mutations related to tumors in the p85 regulatory subunit! They have also been identified in cancers such as ovarian and colon (Philp et al., Cancer Research, 2001, 61, 7426-7429). In addition to the direct effects, it is believed that the activation of Class III PI3Ks contributes to tumorigenic events that occur upstream in signaling pathways, for example by means of ligand-dependent or independent tyrosine kinase ligand activation. receptors, GPCR systems or integrins (Vara et al., Cancer Treatment Reviews, 2004, 30, 193-204). Examples of such upstream signaling pathways include overexpression of the erbB2 receptor tyrosine kinase in a variety of tumors that lead to activation of PI3K-mediated pathways (Harari et al., Oncogene, 2000, 19, 6102–6114) and overexpression of the ras oncogene (Kauffmann-Zeh et al., Nature, 1997, 385, 544-548). In addition, Class III PI3K can indirectly contribute to tumorigenesis caused by various downstream signaling events. For example, the loss of the effect of PTEN tumor suppressor phosphatase that catalyzes the conversion of PI (3,4,5) P3 back into PI (4,5) P2 is associated with a wide variety of tumors through deregulation of the production of PI (3,4,5) P3 mediated by PI3K (Simpson and Parsons, Exp. Cell Res., 2001, 264, 29–41). Furthermore, it is believed that the increased effects of other signaling events mediated by PI3K contribute to a variety of cancers, for example by activation of Akt (Nicholson and Anderson, Cellular Signaling, 2002, 14, 381-395).

Además de su papel en la mediación de la señalización proliferativa y la supervivencia en células tumorales, existen pruebas de que las enzimas PI3K de la Clase Ia contribuyen a la tumorigénesis en células estrómicas asociadas a tumores. Por ejemplo, se sabe que la señalización de la PI3K desempeña un papel importante en la mediación de eventos angiogénicos en células endoteliales en respuesta a factores proangiogénicos tales como VEGF (Abid et al., Arterioscler. Thromb. Vasc. Biol., 2004, 24, 294–300). Ya que las enzimas PI3K de la Clase I están también involucradas en la motilidad y migración (Sawyer, Expert Opinion Investig. Drugs, 2004, 13, 1–19), los inhibidores de la enzima PI3K deberían proporcionar beneficio terapéutico a través de la inhibición de la invasión de células tumorales y metástasis. Además, las enzimas PI3K de la Clase I desempeñan un papel importante en la regulación de células inmunes que contribuyen a los efectos protumorigénicos de las células inflamatorias (Coussens y Werb, Nature, 2002, 420, 860–867). In addition to their role in the mediation of proliferative signaling and survival in tumor cells, there is evidence that Class III PI3K enzymes contribute to tumorigenesis in tumor-associated stromal cells. For example, PI3K signaling is known to play an important role in mediating angiogenic events in endothelial cells in response to proangiogenic factors such as VEGF (Abid et al., Arterioscler. Thromb. Vasc. Biol., 2004, 24 , 294–300). Since Class I PI3K enzymes are also involved in motility and migration (Sawyer, Expert Opinion Investig. Drugs, 2004, 13, 1–19), PI3K enzyme inhibitors should provide therapeutic benefit through inhibition. of tumor cell invasion and metastasis. In addition, Class I PI3K enzymes play an important role in the regulation of immune cells that contribute to the protumorigenic effects of inflammatory cells (Coussens and Werb, Nature, 2002, 420, 860-867).

Estos hallazgos sugieren que los inhibidores farmacológicos de las enzimas PI3K de la Clase I serán de valor terapéutico para el tratamiento de diversas enfermedades, incluyendo diferentes formas de la enfermedad de cáncer que comprenden tumores sólidos tales como carcinomas y sarcomas y las leucemias y neoplasias linfoides. En particular, los inhibidores de las enzimas PI3K de la Clase I deberían ser de valor terapéutico para el tratamiento de, por ejemplo, cáncer de mama, colorrectal, pulmón (incluyendo cáncer de pulmón microcítico, cáncer de pulmón no microcítico y cáncer broncoalveolar) y próstata, y de cáncer del conducto biliar, hueso, vejiga, cabeza y cuello, riñón, hígado, tejido gastrointestinal, esófago, ovario, páncreas, piel, testículos, tiroides, útero, cérvix y vulva, y de leucemias (incluyendo ALL y CML), mieloma múltiple y linfoma. These findings suggest that pharmacological inhibitors of Class I PI3K enzymes will be of therapeutic value for the treatment of various diseases, including different forms of cancer disease comprising solid tumors such as carcinomas and sarcomas and lymphoid leukemias and neoplasms. In particular, inhibitors of Class I PI3K enzymes should be of therapeutic value for the treatment of, for example, breast, colorectal, lung cancer (including microcytic lung cancer, non-small cell lung cancer and bronchoalveolar cancer) and prostate, and cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, esophagus, ovary, pancreas, skin, testicles, thyroid, uterus, cervix and vulva, and leukemia (including ALL and CML ), multiple myeloma and lymphoma.

La PI3K#, la PI3K de la Clase Ib, es activada por los GPCR, como se demostró finalmente en ratones carentes de la enzima. De este modo, los neutrólifos y macrófagos derivados de los animales deficientes en PI3K# no produjeron PI(3,4,5)P3 en respuesta a la estimulación con diversas sustancias quimiotácticas (tales como IL–8, C5a, fMLP y MIP–1a), mientras que la señalización a través de los receptores acoplados a proteína tirosina cinasas para las PI3K de la Clase Ia se mantuvo intacta (Hirsch et al., Science, 2000, 287(5455), 1049–1053; Li et al., Science, 2002, 287(5455), 1046–1049; Sasaki et al., Science 2002, 287(5455), 1040–1046). Además, la fosforilación de PKB mediada por la PI(3,4,5)P3 no fue iniciada por estos ligandos de GPCR en células sin PI3K#. Tomados juntos, los resultados demostraron que, al menos en las células hematopoiéticas en reposo, la PI3K# es la única isoforma de PI3K que es activada por los GPCR in vivo. Cuando se ensayaron in vitro neutrólifos derivados de la médula ósea murina y macrófagos peritoneales procedentes de ratones PI3K#-/- y de tipo salvaje, se observó un comportamiento reducido, pero no completamente suprimido, en ensayos de quimiotaxia y adherencia. Sin embargo, esto se tradujo en un deterioro drástico de la infiltración de neutrófilos conducida por IL–8 en los tejidos (Hirsch et al., Science, 2000, 287(5455), 1049–1053). Datos recientes sugieren que la PI3K# está involucrada en el proceso de encontrar la ruta en lugar de en la generación de la fuerza mecánica para la motilidad, ya que la migración aleatoria no se vio PI3K #, the PI3K of Class Ib, is activated by GPCRs, as was finally demonstrated in mice lacking the enzyme. Thus, neutrophils and macrophages derived from PI3K # deficient animals did not produce PI (3,4,5) P3 in response to stimulation with various chemotactic substances (such as IL-8, C5a, fMLP and MIP-1a ), while signaling through protein tyrosine kinase-coupled receptors for Class III PI3Ks remained intact (Hirsch et al., Science, 2000, 287 (5455), 1049-1053; Li et al., Science, 2002, 287 (5455), 1046-1049; Sasaki et al., Science 2002, 287 (5455), 1040-1046). In addition, phosphorylation of PKB mediated by PI (3,4,5) P3 was not initiated by these GPCR ligands in cells without PI3K #. Taken together, the results showed that, at least in resting hematopoietic cells, PI3K # is the only PI3K isoform that is activated by GPCRs in vivo. When neutrophils derived from murine bone marrow and peritoneal macrophages from PI3K # - / - and wild-type mice were tested in vitro, reduced, but not completely suppressed, behavior was observed in chemotaxis and adhesion assays. However, this resulted in a drastic deterioration of IL-8-driven neutrophil infiltration in tissues (Hirsch et al., Science, 2000, 287 (5455), 1049-1053). Recent data suggest that the PI3K # is involved in the process of finding the route rather than in the generation of the mechanical force for motility, since random migration was not seen

afectada en células que carecían de PI3K# (Hannigan et al., Proc. Nat. Acad. of Sciences of U.S.A., 2002, 99(6), 3603–8). Los datos que vinculan a la PI3K# con la patología de la enfermedad respiratoria surgieron de la demostración que la PI3K# tiene un papel central en la regulación de la activación e infiltración pulmonar de neutrólifos inducida por endotoxinas que conducen a la lesión aguda del pulmón (Yum et al., J. Immunology, 2001, 167(11), 6601–8). El hecho de que, aunque la PI3K# está altamente expresada en los leucocitos, su pérdida parece no interferir con la hematopoyesis, y el hecho de que los ratones sin PI3K# son viables y fértiles, implica más a esta isoforma de la PI3K como una diana farmacéutica potencial. El trabajo con ratones sin el gen también estableció que la PI3K# es un amplificador esencial de la activación de mastocitos (Laffargue et al., Immunity, 2002, 16(3), 441– 451). affected in cells lacking PI3K # (Hannigan et al., Proc. Nat. Acad. of Sciences of U.S.A., 2002, 99 (6), 3603–8). The data linking PI3K # with the pathology of respiratory disease emerged from the demonstration that PI3K # plays a central role in regulating the activation and pulmonary infiltration of endotoxin-induced neutrophils that lead to acute lung injury ( Yum et al., J. Immunology, 2001, 167 (11), 6601-8). The fact that, although PI3K # is highly expressed in leukocytes, their loss seems not to interfere with hematopoiesis, and the fact that mice without PI3K # are viable and fertile, further implicates this isoform of PI3K as a potential pharmaceutical target. Work with mice without the gene also established that PI3K # is an essential amplifier of mast cell activation (Laffargue et al., Immunity, 2002, 16 (3), 441–451).

De este modo, además de la tumorigénesis, existen pruebas de que las enzimas PI3K de la Clase I desempeñan un papel en otras enfermedades (Wymann et al., Trends in Pharmacological Science, 2003, 24, 366–376). Tanto las enzimas PI3K de la Clase Ia como la única enzima de la Clase Ib tienen papeles importantes en las células del sistema inmunitario (Koyasu, Nature Immunology, 2003, 4, 313–319) y de este modo son dianas terapéuticas para las indicaciones inflamatorias y alérgicas. Informes recientes demuestran que los ratones deficientes en PI3K# y PI3Kδ son viables, pero tienen respuestas inflamatorias y alérgicas atenuadas (Ali et al., Nature, 2004, 431(7011), 1007–11). La inhibición de la PI3K es también útil para tratar la enfermedad cardiovascular a través de los efectos antiinflamatorios o directamente afectando los miocitos cardíacos (Prasad et al., Trends in Cardiovascular Medicine, 2003, 13, 206–212). De esta forma, se espera que los inhibidores de las enzimas PI3K de la Clase I sean útiles en la prevención y tratamiento de una gran variedad de enfermedades, además de cáncer. Thus, in addition to tumorigenesis, there is evidence that Class I PI3K enzymes play a role in other diseases (Wymann et al., Trends in Pharmacological Science, 2003, 24, 366–376). Both PI3K enzymes of Class Ia and the only enzyme of Class Ib have important roles in the cells of the immune system (Koyasu, Nature Immunology, 2003, 4, 313-319) and thus are therapeutic targets for inflammatory indications and allergic Recent reports show that mice deficient in PI3K # and PI3Kδ are viable, but have attenuated inflammatory and allergic responses (Ali et al., Nature, 2004, 431 (7011), 1007-11). Inhibition of PI3K is also useful for treating cardiovascular disease through anti-inflammatory effects or directly affecting cardiac myocytes (Prasad et al., Trends in Cardiovascular Medicine, 2003, 13, 206-212). Thus, inhibitors of Class I PI3K enzymes are expected to be useful in the prevention and treatment of a wide variety of diseases, in addition to cancer.

Se han identificado varios compuestos que inhiben las PI3K y las cinasas relacionadas con la fosfatidilinositol (PI) cinasa (PI3KK), incluyendo la wortmanina y el derivado de quercetina LY294002. Estos compuestos son inhibidores bastante específicos de las PI3K y PI3KK con respecto de otras cinasas, pero carecen de potencia y exhiben poca selectividad dentro de las familias de PI3K. Several compounds have been identified that inhibit PI3K and phosphatidylinositol (PI) kinase-related kinases (PI3KK), including wortmanin and the quercetin derivative LY294002. These compounds are quite specific inhibitors of PI3K and PI3KK with respect to other kinases, but they lack potency and exhibit little selectivity within the PI3K families.

Por consiguiente, sería deseable proporcionar inhibidores de mTOR y/o PI3K efectivos adicionales para uso en el tratamiento de cáncer, enfermedades inflamatorias u obstructivas de las vías respiratorias, enfermedades inmunes o cardiovasculares. Therefore, it would be desirable to provide additional effective mTOR and / or PI3K inhibitors for use in the treatment of cancer, inflammatory or obstructive airway diseases, immune or cardiovascular diseases.

Los derivados de la morfolino pirimidina y los inhibidores de la PI3K son conocidos en la técnica. Morpholino pyrimidine derivatives and PI3K inhibitors are known in the art.

La Solicitud Internacional de Patente WO 2004/048365 describe compuestos que poseen actividad inhibidora de la enzima PI3K y son útiles en el tratamiento de cáncer. Estos compuestos son pirimidinas sustituidas con arilamino y heteroarilamino las cuales difieren de los compuestos de la presente invención con respecto a sus sustituyentes arilamino y heteroarilamino. Estos sustituyentes no son equivalentes a los sustituyentes -XR1 de la presente invención. Los inhibidores de la actividad de PI3K útiles en el tratamiento de cáncer también se describen en la Solicitud de Patente Europea 1 277 738, la cual menciona los compuestos de heteroarilo bicíclicos sustituidos con 4–morfolino, tales como quinazolina y derivados de pirido[3,2–d]pirimidina, y los compuestos de heteroarilo tricíclicos sustituidos con 4–morfolino pero no derivados de pirimidina monocíclicos. International Patent Application WO 2004/048365 describes compounds that possess inhibitory activity of the PI3K enzyme and are useful in the treatment of cancer. These compounds are arylamino and heteroarylamino substituted pyrimidines which differ from the compounds of the present invention with respect to their arylamino and heteroarylamino substituents. These substituents are not equivalent to the -XR1 substituents of the present invention. Inhibitors of PI3K activity useful in the treatment of cancer are also described in European Patent Application 1,277,738, which mentions bicyclic heteroaryl compounds substituted with 4-morpholino, such as quinazoline and pyrido derivatives [3, 2-d] pyrimidine, and tricyclic heteroaryl compounds substituted with 4-morpholino but not monocyclic pyrimidine derivatives.

Un número de compuestos tales como 4–morfolin–4–il–6–(fenilsulfonilmetil)–2–piridin–4–il–pirimidina y 4–{6– [(fenilsulfonil)metil]–2–piridin–2–ilpirimidin–4–il}morfolina han sido registrados en la base de datos del Chemical Abstracts, pero no se ha indicado ninguna utilidad y no hay sugerencia de que estos compuestos tengan actividad inhibidora de mTOR y/o PI3K o propiedades terapéuticas útiles. A number of compounds such as 4-morpholin-4-yl-6- (phenylsulfonylmethyl) -2-pyridin-4-yl-pyrimidine and 4– {6– [(phenylsulfonyl) methyl] -2-pyridin-2-ylpyrimidin– 4-yl} morpholine have been registered in the Chemical Abstracts database, but no utility has been indicated and there is no suggestion that these compounds have mTOR and / or PI3K inhibitory activity or useful therapeutic properties.

Sorprendentemente, se ha descubierto que ciertos derivados de morfolino pirimidina poseen propiedades terapéuticas útiles. Sin querer ceñirnos a restricciones teóricas, se cree que la utilidad terapéutica de los derivados deriva de su actividad inhibidora contra mTOR cinasa y/o una o más enzimas PI3K (tales como la enzima de la Clase Ia y/o la enzima de la Clase Ib). Debido a que las rutas de señalización mediadas por las familias de PI3K/mTOR tienen un papel central en un número de procesos celulares, incluyendo la proliferación y supervivencia, y debido a que la desregulación de estas rutas es un factor etiológico en un amplio espectro de cánceres humanos y otras enfermedades, se espera que los derivados serán terapéuticamente útiles. En particular, se espera que los derivados tendrán propiedades antiproliferativas y/o apoptóticas, lo que significa que serán útiles en el tratamiento de una enfermedad proliferativa tal como cáncer. Los compuestos de la presente invención también pueden ser útiles inhibiendo la proliferación celular incontrolada que surge a partir de diversas enfermedades no malignas tales como enfermedades inflamatorias, enfermedades obstructivas de las vías respiratorias, enfermedades inmunitarias o enfermedades cardiovasculares. Surprisingly, it has been found that certain morpholino pyrimidine derivatives possess useful therapeutic properties. Without wishing to adhere to theoretical restrictions, it is believed that the therapeutic utility of the derivatives derives from their inhibitory activity against mTOR kinase and / or one or more PI3K enzymes (such as the Class Ia enzyme and / or the Class Ib enzyme ). Because signaling pathways mediated by PI3K / mTOR families play a central role in a number of cellular processes, including proliferation and survival, and because deregulation of these routes is an etiological factor in a broad spectrum of Human cancers and other diseases, derivatives are expected to be therapeutically useful. In particular, it is expected that derivatives will have antiproliferative and / or apoptotic properties, which means that they will be useful in the treatment of a proliferative disease such as cancer. The compounds of the present invention may also be useful by inhibiting uncontrolled cell proliferation that arises from various non-malignant diseases such as inflammatory diseases, obstructive diseases of the respiratory tract, immune diseases or cardiovascular diseases.

Generalmente, los compuestos de la presente invención poseen actividad inhibidora potente contra mTOR cinasa pero el compuesto también puede poseer actividad inhibidora potente contra una o más enzimas PI3K (tales como la enzima de la Clase Ia y/o la enzima de la Clase Ib). Generally, the compounds of the present invention possess potent inhibitory activity against mTOR kinase but the compound may also possess potent inhibitory activity against one or more PI3K enzymes (such as the Class Ia enzyme and / or the Class Ib enzyme).

De acuerdo con un aspecto de la presente invención, se proporciona un compuesto de fórmula (I) In accordance with one aspect of the present invention, a compound of formula (I) is provided

fórmula (I) formula (I)

o una sal farmacéuticamente aceptable del mismo; en la que or a pharmaceutically acceptable salt thereof; in which

m es 0, 1, 2, 3 ó 4; m is 0, 1, 2, 3 or 4;

1Y e Y2 son independientemente N o CR8 con la condición de que uno de 1Y e Y2 sea N y el otro sea CR8; 1Y and Y2 are independently N or CR8 with the proviso that one of 1Y and Y2 is N and the other is CR8;

X es un grupo enlazador seleccionado de –CR4=CR5–, –CR4=CR5CR6R7–, –CR6R7CR5=CR4–, –C∃C–, -C=CCR6R7–, –CR6R7C∃C–, –NR4CR6R7–, –OCR6R7–, –SCR6R7–, –S(O)CR6R7–, –S(O)2CR6R7–, -C(O)NR4CR6R7–, -NR4C(O)CR6R7–, –NR4C(O)NR5CR6R7–, -NR4S(O)2CR6R7–, –S(O)2NR4CR6R7–, –C(O)NR4–, –NR4C(O)–, -NR4C(O)NR5–, -S(O)2NR4– y –NR4S(O)2–; X is a linker group selected from –CR4 = CR5–, –CR4 = CR5CR6R7–, –CR6R7CR5 = CR4–, –C∃C–, -C = CCR6R7–, –CR6R7C∃C–, –NR4CR6R7–, –OCR6R7– , –SCR6R7–, –S (O) CR6R7–, –S (O) 2CR6R7–, -C (O) NR4CR6R7–, -NR4C (O) CR6R7–, –NR4C (O) NR5CR6R7–, -NR4S (O) 2CR6R7–, –S (O) 2NR4CR6R7–, –C (O) NR4–, –NR4C (O) -, -NR4C (O) NR5–, -S (O) 2NR4– and –NR4S (O) 2–;

R1 es un grupo seleccionado de hidrógeno, alquilo de C1-6, alquenilo de C2-6, alquinilo de C2-6, carbociclilo, carbociclilalquilo de C1-6, heterociclilo y heterociclil-alquilo de C1-6, grupo el cual está opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, R9, –OR9, -SR9, –SOR9, -SO2R9, –COR9, -CO2R9, – CONR9R10, –NR9R10, –NR9COR10, –NR9CO2R10, -NR9CONR10R15, -NR9COCONR10R15 y –NR9SO2R10; R1 is a group selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, carbocyclyl, C1-6 carbocyclyl alkyl, heterocyclyl and C1-6 heterocyclyl alkyl, which group is optionally substituted with one or more substituent groups selected from halo, cyano, nitro, R9, –OR9, -SR9, –SOR9, -SO2R9, –COR9, -CO2R9, - CONR9R10, –NR9R10, –NR9COR10, –NR9CO2R10, -NR9CONR10R15, - NR9COCONR10R15 and –NR9SO2R10;

R2 es un grupo seleccionado de alquilo de C1-6, carbociclilo y heterociclilo, grupo el cual está sustituido con -NR17CONR18R19 y opcionalmente sustituido con uno o más grupos sustituyentes seleccionados independientemente de halo, ciano, nitro, –R11, –OR11, –SR11, -SOR11, –SO2R11, –COR11, –CO2R11, –CONR11R12, -NR11R12, –NR11COR12, y -NR11COCONR12R16; R2 is a group selected from C1-6 alkyl, carbocyclyl and heterocyclyl, which group is substituted with -NR17CONR18R19 and optionally substituted with one or more substituent groups independently selected from halo, cyano, nitro, -R11, -OR11, -SR11 , -SOR11, –SO2R11, –COR11, –CO2R11, –CONR11R12, -NR11R12, –NR11COR12, and -NR11COCONR12R16;

cada R3, cuando está presente, se selecciona independientemente de halo, ciano, nitro, –R13, –OR13, –SR13, -SOR13, –SO2R13, –COR13, –CO2R13, –CONR13R14, –NR13R14, –NR13COR14, –NR13CO2R14 y –NR13SO2R14; each R3, when present, is independently selected from halo, cyano, nitro, –R13, –OR13, –SR13, -SOR13, –SO2R13, –COR13, –CO2R13, –CONR13R14, –NR13R14, –NR13COR14, –NR13CO2R14 and –NR13SO2R14;

R4 y R5 son independientemente hidrógeno o alquilo de C1-6; R4 and R5 are independently hydrogen or C1-6 alkyl;

o R1 y R4, junto con el átomo o átomos a los que están unidos, forman un anillo carbocíclico o heterocíclico de 4 a 10 miembros en el que 1, 2 ó 3 átomos de carbono anulares están opcionalmente reemplazados por N, O ó S, y estando dicho anillo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, hidroxi, oxo, alquilo de C1-6, alcoxi de C1-6, halo-alquilo de C1-6, halo-alcoxi de C1-6, hidroxi-alquilo de C1-6, hidroxi-alcoxi de C1-6, alcoxi C1-6-alquilo de C1-6, alcoxi C1-6-alcoxi de C1-6, amino, alquil C1-6-amino, bis(alquil C1-6)amino, amino-alquilo de C1-6, (alquil C1-6)-amino-alquilo de C1-6, bis(alquil C1-6)-amino-alquilo de C1-6, ciano-alquilo de C1-6, alquil C1-6-sulfonilo, alquil C1-6-sulfonilamino, alquil C1-6-sulfonil-(alquil C1-6)-amino, sulfamoilo, alquil C1-6sulfamoilo, bis(alquil C1-6)-sulfamoilo, alcanoil C1-6-amino, alcanoil C1-6-(alquil C1-6)-amino, carbamoilo, alquil C1-6carbamoilo y bis(alquil C1-6)-carbamoilo; or R1 and R4, together with the atom or atoms to which they are attached, form a 4- to 10-membered carbocyclic or heterocyclic ring in which 1, 2 or 3 annular carbon atoms are optionally replaced by N, O or S, and said ring being optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, C1-6 halo-alkyl, C1- halo-alkoxy 6, hydroxy-C 1-6 alkyl, hydroxy-C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkoxy, amino, C 1-6 alkyl, amino, bis (C1-6 alkyl) amino, C1-6 amino-alkyl, (C1-6 alkyl) -amino-C1-6 alkyl, bis (C1-6 alkyl) -amino-C1-6 alkyl, cyano-alkyl C 1-6, C 1-6 alkyl sulfonyl, C 1-6 alkyl sulfonylamino, C 1-6 alkyl sulfonyl- (C 1-6 alkyl) -amino, sulfamoyl, C 1-6 alkyl sulfamoyl, bis (C 1-6 alkyl) - sulfamoyl, C1-6 alkanoyl-amino, C1-6 alkanoyl- (C1-6 alkyl) -amino, carbamoyl, C1-6 alkylcarbamoyl and bis (C1-6 alkyl) -carbamoyl;

R6 y R7 se seleccionan independientemente de hidrógeno, halo, ciano, nitro y alquilo de C1-6; R6 and R7 are independently selected from hydrogen, halo, cyano, nitro and C1-6 alkyl;

R8 se selecciona de hidrógeno, halo, ciano y alquilo de C1-6; R8 is selected from hydrogen, halo, cyano and C1-6 alkyl;

R9 y R10 son independientemente hidrógeno o un grupo seleccionado de alquilo de C1-6, carbociclilo, carbociclilalquilo de C1-6, heterociclilo y heterociclil-alquilo de C1-6, estando dicho grupo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, hidroxi, oxo, alquilo de C1-6, alcoxi de C1-6, halo-alquilo de C1-6, halo-alcoxi de C1-6, hidroxi-alquilo de C1-6, hidroxi-alcoxi de C1-6, alcoxi C1-6-alquilo de C1-6, alcoxi C1-6-alcoxi de C1-6, amino, alquil C1-6-amino, bis(alquil C1-6)-amino, amino-alquilo de C1-6, (alquil C1-6)-amino-alquilo de C1-6, bis(alquil C1-6)-amino-alquilo de C1-6, ciano-alquilo de C1-6, alquil C1-6-sulfonilo, alquil C1-6-sulfonilamino, alquil C1-6sulfonil-(alquil C1-6)-amino, sulfamoilo, alquil C1-6-sulfamoilo, bis(alquil C1-6)-sulfamoilo, alcanoil C1-6-amino, alcanoil C1-6-(alquil C1-6)-amino, carbamoilo, alquil C1-6-carbamoilo y bis(alquil C1-6)-carbamoilo; R9 and R10 are independently hydrogen or a group selected from C1-6 alkyl, carbocyclyl, C1-6 carbocyclyl alkyl, heterocyclyl and C1-6 heterocyclyl alkyl, said group being optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, halo C1-6 alkyl, halo C1-6 alkoxy, hydroxy C1-6 alkyl, hydroxy C1- alkoxy 6, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkoxy, amino, C 1-6 alkyl, bis (C 1-6 alkyl) -amino, C 1-6 amino-alkyl , (C 1-6 alkyl) -Camino-C 1-6 alkyl, bis (C 1-6 alkyl) -amino-C 1-6 alkyl, cyano-C 1-6 alkyl, C 1-6 alkyl sulfonyl, C 1-6 alkyl 6-sulfonylamino, C1-6 alkyl sulfonyl- (C1-6 alkyl) -amino, sulfamoyl, C1-6 alkyl sulfamoyl, bis (C1-6 alkyl) -sulfamoyl, C1-6 alkanoyl-amino, C1-6 alkanoyl- ( C1-6 alkyl) -amino, carbamoyl, C1-6 alkylcarbamoyl and bis (C1-6 alkyl) -carbamoyl;

R11 R11

, R12 , R17 y R18 son independientemente hidrógeno o un grupo seleccionado de alquilo de C1-6, carbociclilo, carbociclil-alquilo de C1-6, heterociclilo y heterociclil-alquilo de C1-6, estando dicho grupo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, hidroxi, oxo, alquilo de C1-6, alcoxi de C1-6, haloalquilo de C1-6, halo-alcoxi de C1-6, hidroxi-alquilo de C1-6, hidroxi-alcoxi de C1-6, alcoxi C1-6-alquilo de C1-6, alcoxi C1-6alcoxi de C1-6, amino, alquil C1-6-amino, bis(alquil C1-6)-amino, amino-alquilo de C1-6, (alquil C1-6)-amino-alquilo de C1, R12, R17 and R18 are independently hydrogen or a group selected from C1-6 alkyl, carbocyclyl, C1-6 carbocyclyl alkyl, heterocyclyl and C1-6 heterocyclyl alkyl, said group being optionally substituted with one or more groups substituents selected from halo, cyano, nitro, hydroxy, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxy-alkyl, hydroxy-alkoxy C1-6, C1-6 alkoxy-C1-6 alkyl, C1-6 alkoxy C1-6 alkoxy, amino, C1-6-alkyl, bis (C1-6 alkyl) -amino, amino-C1- alkyl 6, (C1-6 alkyl) -amino-C1 alkyl

6, bis(alquil C1-6)-amino-alquilo de C1-6, ciano-alquilo de C1-6, alquil C1-6-sulfonilo, alcanoil C1-6-amino, alcanoil C1-6(alquil C1-6)-amino, carbamoilo, alquil C1-6-carbamoilo y bis(alquil C1-6)-carbamoilo; 6, bis (C 1-6 alkyl) -Camino-C 1-6 alkyl, cyano-C 1-6 alkyl, C 1-6 alkyl sulfonyl, C 1-6 alkanoyl, C 1-6 alkanoyl (C 1-6 alkyl) -amino, carbamoyl, C1-6 alkylcarbamoyl and bis (C1-6 alkyl) -carbamoyl;

R13, R14, R15, R16

y R19 son independientemente hidrógeno o un grupo seleccionado de alquilo de C1-6, carbociclilo, carbociclil-alquilo de C1-6, heterociclilo y heterociclil-alquilo de C1-6, estando dicho grupo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, hidroxi, oxo, alquilo de C1-6, alcoxi de C1-6, haloalquilo de C1-6, halo-alcoxi de C1-6, hidroxi-alquilo de C1-6, hidroxi-alcoxi de C1-6, alcoxi C1-6-alquilo de C1-6, alcoxi C1-6alcoxi de C1-6, amino, alquil C1-6-amino, bis(alquil C1-6)-amino, amino-alquilo de C1-6, (alquil C1-6)-amino-alquilo de C16, bis(alquil C1-6)-amino-alquilo de C1-6, ciano-alquilo de C1-6, alquil C1-6-sulfonilo, alquil C1-6-sulfonilamino, alquil C1-6sulfonil-(alquil C1-6)-amino, sulfamoilo, alquil C1-6-sulfamoilo, bis(alquil C1-6)-sulfamoilo, alcanoil C1-6-amino, alcanoil C1-6-(alquil C1-6)-amino, carbamoilo, alquil C1-6-carbamoilo y bis(alquil C1-6)-carbamoilo; and R19 are independently hydrogen or a group selected from C1-6 alkyl, carbocyclyl, carbocyclyl-C1-6 alkyl, heterocyclyl and heterocyclyl-C1-6 alkyl, said group being optionally substituted with one or more substituent groups selected from halo , cyano, nitro, hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 hydroxy-alkyl, C1-6 hydroxy-alkoxy , C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkoxy, amino, C 1-6 alkyl, bis (C 1-6 alkyl) -amino, C 1-6 amino-alkyl, (alkyl C1-6) -amino-C16 alkyl, bis (C1-6 alkyl) -amino-C1-6 alkyl, cyano-C1-6 alkyl, C1-6 alkyl sulfonyl, C1-6 alkyl sulfonylamino, alkyl C1-6sulfonyl- (C1-6 alkyl) -amino, sulfamoyl, C1-6 alkyl-sulfamoyl, bis (C1-6 alkyl) -sulfamoyl, C1-6-amino alkanoyl, C1-6 alkanoyl- (C1-6 alkyl) -amino, carbamoyl, C1-6 alkylcarbamoyl and bis (C1-6 alkyl) -carbamoyl;

o R18 y R19, junto con el átomo de nitrógeno al que están unidos, forman un anillo heterocíclico de 3 a 10 miembros en el que 1 ó 2 átomos de carbono anulares están opcionalmente reemplazados por N, O ó S, y estando dicho anillo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, hidroxi, oxo, alquilo de C1-6, alcoxi de C1-6, halo-alquilo de C1-6, halo-alcoxi de C1-6, hidroxi-alquilo de C1-6, hidroxi-alcoxi de C1-6, alcoxi C1-6-alquilo de C1-6, alcoxi C1-6-alcoxi de C1-6, amino, alquil C1-6-amino, bis(alquil C1-6)-amino, amino-alquilo de C1-6, (alquil C1-6)-amino-alquilo de C1-6, bis(alquil C1-6)-amino-alquilo de C1-6, ciano-alquilo de C1-6, alquil C1-6-sulfonilo, alquil C1-6-sulfonilamino, alquil C1-6-sulfonil-(alquil C1-6)-amino, sulfamoilo, alquil C1-6-sulfamoilo, bis(alquil C1-6)sulfamoilo, alcanoil C1-6-amino, alcanoil C1-6-(alquil C1-6)-amino, carbamoilo, alquil C1-6-carbamoilo y bis(alquil C16)carbamoilo or R18 and R19, together with the nitrogen atom to which they are attached, form a 3 to 10 membered heterocyclic ring in which 1 or 2 annular carbon atoms are optionally replaced by N, O or S, and said ring being optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, C1-6 halo-alkyl, C1-6 halo-alkoxy, hydroxy-alkyl C1-6, hydroxy-C1-6 alkoxy, C1-6 alkoxy-C1-6 alkyl, C1-6 alkoxy-C1-6 alkoxy, amino, C1-6-alkyl, bis (C1-6 alkyl ) -amino, C1-6 amino-alkyl, (C1-6 alkyl) -amino-C1-6 alkyl, bis (C1-6 alkyl) -amino-C1-6 alkyl, cyano-C1-6 alkyl , C1-6-sulfonyl alkyl, C1-6-sulfonylamino alkyl, C1-6-sulfonyl- (C1-6 alkyl) -amino, sulfamoyl, C1-6-sulfamoyl alkyl, bis (C1-6 alkyl) sulfamoyl, alkanoyl C1-6-amino, C1-6 alkanoyl- (C1-6 alkyl) -amino, carbamoyl, C1-6-carbamoyl alkyl and bis (C16 alkyl) carbamoyl

para uso como un medicamento en el tratamiento de una enfermedad proliferativa. for use as a medicine in the treatment of a proliferative disease.

De acuerdo con otro aspecto de la presente invención, se proporciona un compuesto de fórmula (I) In accordance with another aspect of the present invention, a compound of formula (I) is provided

fórmula (I) formula (I)

m es 0, 1, 2, 3 ó 4; m is 0, 1, 2, 3 or 4;

X es un grupo enlazador seleccionado de –CR4=CR5–, –CR4=CR5CR6R7–, –CR6R7CR5=CR4–, –C∃C–, -C∃CCR6R7–, –CR6R7C∃C–, –NR4CR6R7–, –OCR6R7–, –SCR6R7–, –S(O)CR6R7–, –S(O)2CR6R7–, -C(O)NR4CR6R7–, -NR4C(O)CR6R7–, –NR4C(O)NR5CR6R7–, -NR4S(O)2CR6R7–, –S(O)2NR4CR6R7–, –C(O)NR4–, –NR4C(O)–, -NR4C(O)NR5–, -S(O)2NR4– y –NR4S(O)2–; X is a linker group selected from –CR4 = CR5–, –CR4 = CR5CR6R7–, –CR6R7CR5 = CR4–, –C∃C–, -C∃CCR6R7–, –CR6R7C∃C–, –NR4CR6R7–, –OCR6R7– , –SCR6R7–, –S (O) CR6R7–, –S (O) 2CR6R7–, -C (O) NR4CR6R7–, -NR4C (O) CR6R7–, –NR4C (O) NR5CR6R7–, -NR4S (O) 2CR6R7–, –S (O) 2NR4CR6R7–, –C (O) NR4–, –NR4C (O) -, -NR4C (O) NR5–, -S (O) 2NR4– and –NR4S (O) 2–;

R1 es un grupo seleccionado de hidrógeno, alquilo de C1-6, alquenilo de C2-6, alquinilo de C2-6, carbociclilo, carbociclilalquilo de C1-6, heterociclilo y heterociclil-alquilo de C1-6, estando dicho grupo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, R9, –OR9, -SR9, –SOR9, -SO2R9, –COR9, -CO2R9, -CONR9R10, –NR9R10, –NR9COR10, –NR9CO2R10, -NR9CONR10R15, -NR9COCONR10R15 y –NR9SO2R10; R 1 is a group selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, C 1-6 carbocyclyl alkyl, heterocyclyl and C 1-6 heterocyclyl alkyl, said group being optionally substituted with one or more substituent groups selected from halo, cyano, nitro, R9, –OR9, -SR9, –SOR9, -SO2R9, –COR9, -CO2R9, -CONR9R10, –NR9R10, –NR9COR10, –NR9CO2R10, -NR9CONR10R15, -NR9CON15 and -NR9SO2R10;

R2 es un grupo seleccionado de alquilo de C1-6, carbociclilo y heterociclilo, estando dicho grupo sustituido con -NR17CONR18R19 y opcionalmente sustituido con uno o más grupos sustituyentes seleccionados independientemente de halo, ciano, nitro, –R11, –OR11, –SR11, -SOR11, –SO2R11, –COR11, –CO2R11, -CONR11R12, -NR11R12, –NR11COR12, y -NR11COCONR12R16; R2 is a group selected from C1-6 alkyl, carbocyclyl and heterocyclyl, said group being substituted with -NR17CONR18R19 and optionally substituted with one or more substituent groups independently selected from halo, cyano, nitro, -R11, -OR11, -SR11, -SOR11, –SO2R11, –COR11, –CO2R11, -CONR11R12, -NR11R12, –NR11COR12, and -NR11COCONR12R16;

cada R3, cuando está presente, se selecciona independientemente de halo, ciano, nitro, -R13, –OR13, –SR13, -SOR13, –SO2R13, –COR13, –CO2R13, –CONR13R14, –NR13R14, –NR13COR14,-NR13CO2R14 y –NR13SO2R14; each R3, when present, is independently selected from halo, cyano, nitro, -R13, –OR13, –SR13, -SOR13, –SO2R13, –COR13, –CO2R13, –CONR13R14, –NR13R14, –NR13COR14, -NR13CO2R14 and –NR13SO2R14;

o R1 y R4, junto con el átomo o átomos a los que están unidos, forman un anillo carbocíclico o heterocíclico de 4 a 10 miembros en el que 1, 2 ó 3 átomos de carbono anulares están opcionalmente reemplazados por N, O ó S, y or R1 and R4, together with the atom or atoms to which they are attached, form a 4- to 10-membered carbocyclic or heterocyclic ring in which 1, 2 or 3 annular carbon atoms are optionally replaced by N, O or S, Y

estando dicho anillo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, hidroxi, oxo, alquilo de C1-6, alcoxi de C1-6, halo-alquilo de C1-6, halo-alcoxi de C1-6, hidroxi-alquilo de C1-6, hidroxi-alcoxi de C1-6, alcoxi C1-6-alquilo de C1-6, alcoxi C1-6-alcoxi de C1-6, amino, alquil C1-6-amino, bis(alquil C1-6)amino, amino-alquilo de C1-6, (alquil C1-6)-amino-alquilo de C1-6, bis(alquil C1-6)-amino-alquilo de C1-6, ciano-alquilo de C1-6, alquil C1-6-sulfonilo, alquil C1-6-sulfonilamino, alquil C1-6-sulfonil-(alquil C1-6)-amino, sulfamoilo, alquil C1-6sulfamoilo, bis(alquil C1-6)-sulfamoilo, alcanoil C1-6-amino, alcanoil C1-6-(alquil C1-6)-amino, carbamoilo, alquil C1-6carbamoilo y bis(alquil C1-6)-carbamoilo; said ring being optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, C1-6 halo-alkyl, C1-6 halo-alkoxy , hydroxy-C 1-6 alkyl, hydroxy-C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkoxy, amino, C 1-6 alkyl-amino, bis ( C1-6 alkyl) amino, amino- C1-6 alkyl, (C1-6 alkyl) -amino-C1-6 alkyl, bis (C1-6 alkyl) -amino-C1-6 alkyl, cyano-alkyl C1-6, C1-6 alkyl sulfonyl, C1-6 alkyl sulfonylamino, C1-6 alkyl sulfonyl- (C1-6 alkyl) -amino, sulfamoyl, C1-6 sulfulfyl alkyl, bis (C1-6 alkyl) -sulfamoyl , C1-6 alkanoyl-amino, C1-6 alkanoyl- (C1-6 alkyl) -amino, carbamoyl, C1-6 alkylcarbamoyl and bis (C1-6 alkyl) -carbamoyl;

R9 y R10 son independientemente hidrógeno o un grupo seleccionado de alquilo de C1-6, carbociclilo, carbociclilalquilo de C1-6, heterociclilo y heterociclil-alquilo de C1-6, estando dicho grupo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, hidroxi, alquilo de C1-6, alcoxi de C1-6, halo-alquilo de C1-6, halo-alcoxi de C1-6, hidroxi-alquilo de C1-6, hidroxi-alcoxi de C1-6, alcoxi C1-6-alquilo de C1-6, alcoxi C1-6-alcoxi de C1-6, amino, alquil C1-6-amino, bis(alquil C1-6)-amino, amino-alquilo de C1-6, (alquil C1-6)-amino-alquilo de C1-6, bis(alquil C1-6)-amino-alquilo de C1-6, ciano-alquilo de C1-6, alquil C1-6-sulfonilo, alquil C1-6-sulfonilamino, alquil C1-6sulfonil-(alquil C1-6)-amino, sulfamoilo, alquil C1-6-sulfamoilo, bis(alquil C1-6)-sulfamoilo, alcanoil C1-6-amino, alcanoil C1-6-(alquil C1-6)-amino, carbamoilo, alquil C1-6-carbamoilo y bis(alquil C1-6)-carbamoilo; R9 and R10 are independently hydrogen or a group selected from C1-6 alkyl, carbocyclyl, C1-6 carbocyclyl alkyl, heterocyclyl and C1-6 heterocyclyl alkyl, said group being optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6 alkyl, C1-6 alkoxy, halo C1-6 alkyl, halo C1-6 alkoxy, hydroxy C1-6 alkyl, hydroxy C1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkoxy, amino, C 1-6 alkyl, bis (C 1-6 alkyl) -amino, C 1-6 amino-alkyl, ( C1-6 alkyl) -amino-C1-6 alkyl, bis (C1-6 alkyl) -amino-C1-6 alkyl, cyano-C1-6 alkyl, C1-6 alkyl sulfonyl, C1-6 alkyl sulfonylamino, C1-6 alkyl sulfonyl- (C1-6 alkyl) -amino, sulfamoyl, C1-6 alkyl sulfamoyl, bis (C1-6 alkyl) -sulfamoyl, C1-6-amino alkanoyl, C1-6 alkanoyl- (C1 alkyl -6) -amino, carbamoyl, C1-6 alkylcarbamoyl and bis (C1-6 alkyl) -carbamoyl;

R11 , R12 , R17R11, R12, R17

y R18 son independientemente hidrógeno o un grupo seleccionado de alquilo de C1-6, carbociclilo, carbociclil-alquilo de C1-6, heterociclilo y heterociclil-alquilo de C1-6, estando dicho grupo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, hidroxi, alquilo de C1-6, alcoxi de C1-6, haloalquilo de C1-6, halo-alcoxi de C1-6, hidroxi-alquilo de C1-6, hidroxi-alcoxi de C1-6, alcoxi C1-6-alquilo de C1-6, alcoxi C1-6alcoxi de C1-6, amino, alquil C1-6-amino, bis(alquil C1-6)-amino, amino-alquilo de C1-6, (alquil C1-6)-amino-alquilo de C16, bis(alquil C1-6)-amino-alquilo de C1-6, ciano-alquilo de C1-6, alquil C1-6-sulfonilo, alcanoil C1-6-amino, alcanoil C1-6(alquil C1-6)-amino, carbamoilo, alquil C1-6-carbamoilo y bis(alquil C1-6)-carbamoilo; and R18 are independently hydrogen or a group selected from C1-6 alkyl, carbocyclyl, carbocyclyl-C1-6 alkyl, heterocyclyl and heterocyclyl-C1-6 alkyl, said group being optionally substituted with one or more substituent groups selected from halo , cyano, nitro, hydroxy, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 hydroxy-alkyl, C1-6 hydroxy-alkoxy, alkoxy C1-6-C1-6 alkyl, C1-6 alkoxy C1-6 alkoxy, amino, C1-6-alkyl, bis (C1-6 alkyl) -amino, C1-6 amino-alkyl, (C1- alkyl 6) -amino-C16 alkyl, bis (C1-6 alkyl) -amino-C1-6 alkyl, cyano-C1-6 alkyl, C1-6 alkyl sulfonyl, C1-6-amino alkanoyl, C1- alkanoyl 6 (C1-6 alkyl) -amino, carbamoyl, C1-6 alkyl-carbamoyl and bis (C1-6 alkyl) -carbamoyl;

R13 R13

, R14 , R15 , R16 y R19 son independientemente hidrógeno o un grupo seleccionado de alquilo de C1-6, carbociclilo, carbociclil-alquilo de C1-6, heterociclilo y heterociclil-alquilo de C1-6, estando dicho grupo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, hidroxi, alquilo de C1-6, alcoxi de C1-6, haloalquilo de C1-6, halo-alcoxi de C1-6, hidroxi-alquilo de C1-6, hidroxi-alcoxi de C1-6, alcoxi C1-6-alquilo de C1-6, alcoxi C1-6alcoxi de C1-6, amino, alquil C1-6-amino, bis(alquil C1-6)-amino, amino-alquilo de C1-6, (alquil C1-6)-amino-alquilo de C16, bis(alquil C1-6)-amino-alquilo de C1-6, ciano-alquilo de C1-6, alquil C1-6-sulfonilo, alquil C1-6-sulfonilamino, alquil C1-6sulfonil-(alquil C1-6)-amino, sulfamoilo, alquil C1-6-sulfamoilo, bis(alquil C1-6)-sulfamoilo, alcanoil C1-6-amino, alcanoil C1-6-(alquil C1-6)-amino, carbamoilo, alquil C1-6-carbamoilo y bis(alquil C1-6)-carbamoilo; , R14, R15, R16 and R19 are independently hydrogen or a group selected from C1-6 alkyl, carbocyclyl, carbocyclyl-C1-6 alkyl, heterocyclyl and heterocyclyl-C1-6 alkyl, said group being optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 hydroxy-alkyl, hydroxy-alkoxy C1-6, C1-6 alkoxy-C1-6 alkyl, C1-6 alkoxy C1-6 alkoxy, amino, C1-6-alkyl, bis (C1-6 alkyl) -amino, amino-C1- alkyl 6, (C1-6 alkyl) -amino-C16 alkyl, bis (C1-6 alkyl) -amino-C1-6 alkyl, cyano-C1-6 alkyl, C1-6 alkyl sulfonyl, C1-6 alkyl -sulfonylamino, C1-6 alkyl sulfonyl- (C1-6 alkyl) -amino, sulfamoyl, C1-6 alkyl sulfamoyl, bis (C1-6 alkyl) -sulfamoyl, C1-6 alkanoyl-amino, C1-6 alkanoyl- (alkyl C1-6) -amino, carbamoyl, C1-6 alkylcarbamoyl and bis (C1-6 alkyl) -carbamoyl;

o R18 y R19, junto con el átomo de nitrógeno al que están unidos, forman un anillo heterocíclico de 3 a 10 miembros en el que 1 ó 2 átomos de carbono anulares están opcionalmente reemplazados por N, O ó S, y estando dicho anillo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, hidroxi, alquilo de C1-6, alcoxi de C1-6, halo-alquilo de C1-6, halo-alcoxi de C1-6, hidroxi-alquilo de C1-6, hidroxi-alcoxi de C1-6, alcoxi C1-6alquilo de C1-6, alcoxi C1-6-alcoxi de C1-6, amino, alquil C1-6-amino, bis(alquil C1-6)-amino, amino-alquilo de C1-6, (alquil C1-6)-amino-alquilo de C1-6, bis(alquil C1-6)-amino-alquilo de C1-6, ciano-alquilo de C1-6, alquil C1-6-sulfonilo, alquil C1-6sulfonilamino, alquil C1-6-sulfonil-(alquil C1-6)-amino, sulfamoilo, alquil C1-6-sulfamoilo, bis(alquil C1-6)-sulfamoilo, alcanoil C1-6-amino, alcanoil C1-6-(alquil C1-6)-amino, carbamoilo, alquil C1-6-carbamoilo y bis(alquil C1-6)carbamoilo or R18 and R19, together with the nitrogen atom to which they are attached, form a 3 to 10 membered heterocyclic ring in which 1 or 2 annular carbon atoms are optionally replaced by N, O or S, and said ring being optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6 alkyl, C1-6 alkoxy, halo C1-6 alkyl, halo C1-6 alkoxy, hydroxy C1 alkyl -6, C 1-6 hydroxy-alkoxy, C 1-6 alkoxyC 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkoxy, amino, C 1-6 alkyl-amino, bis (C 1-6 alkyl) -amino, C 1-6 amino-alkyl, (C 1-6 alkyl) -Camino-C 1-6 alkyl, bis (C 1-6 alkyl) -amino-C 1-6 alkyl, cyano-C 1-6 alkyl, C 1-6 alkyl 6-sulfonyl, C1-6 alkyl sulfonylamino, C1-6 alkyl-sulfonyl- (C1-6 alkyl) -amino, sulfamoyl, C1-6 alkyl sulfamoyl, bis (C1-6 alkyl) -sulfamoyl, C1-6-amino alkanoyl , C1-6 alkanoyl- (C1-6 alkyl) -amino, carbamoyl, C1-6 alkyl-carbamoyl and bis (C1-6 alkyl) carbamoyl

fórmula (I) formula (I)

o una sal farmacéuticamente aceptable del mismo; en la que 5 or a pharmaceutically acceptable salt thereof; in which 5

m es 0, 1, 2, 3 ó 4; m is 0, 1, 2, 3 or 4;

X es un grupo enlazador seleccionado de –CR4=CR5–, –CR4=CR5CR6R7–, –CR6R7CR5=CR4–, –C∃C–, -C∃CCR6R7–, –CR6R7C∃C–, –NR4CR6R7–, –OCR6R7–, –SCR6R7–, –S(O)CR6R7–, –S(O)2CR6R7–, -C(O)NR4CR6R7–, -NR4C(O)CR6R7–, –NR4C(O)NR5CR6R7–, –NR4S(O)2CR6R7–, –S(O)2NR4CR6R7–, –C(O)NR4–, –NR4C(O)–, -NR4C(O)NR5–, –S(O)2NR4– y –NR4S(O)2–; X is a linker group selected from –CR4 = CR5–, –CR4 = CR5CR6R7–, –CR6R7CR5 = CR4–, –C∃C–, -C∃CCR6R7–, –CR6R7C∃C–, –NR4CR6R7–, –OCR6R7– , –SCR6R7–, –S (O) CR6R7–, –S (O) 2CR6R7–, -C (O) NR4CR6R7–, -NR4C (O) CR6R7–, –NR4C (O) NR5CR6R7–, –NR4S (O) 2CR6R7–, –S (O) 2NR4CR6R7–, –C (O) NR4–, –NR4C (O) -, -NR4C (O) NR5–, –S (O) 2NR4– and –NR4S (O) 2–;

R1 es un grupo seleccionado de alquilo de C1-6, alquenilo de C2-6, alquinilo de C2-6, carbociclilo, carbociclil-alquilo de C1-6, heterociclilo y heterociclil-alquilo de C1-6, estando dicho grupo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, R9, –OR9, –SR9, –SOR9, –SO2R9, –COR9, -CO2R9, –CONR9R10, -NR9R10, –NR9COR10, –NR9CO2R10, –NR9CONR10R15, –NR9COCONR10R15 y –NR9SO2R10; R1 is a group selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, carbocyclyl, C1-6 carbocyclyl-alkyl, heterocyclyl and C1-6 heterocyclyl-alkyl, said group being optionally substituted with one or more substituent groups selected from halo, cyano, nitro, R9, –OR9, –SR9, –SOR9, –SO2R9, –COR9, -CO2R9, –CONR9R10, -NR9R10, –NR9COR10, –NR9CO2R10, –NR9CONR10R15, –NR9CON15 and -NR9SO2R10;

o X–R1 es –CR6R7OH; or X-R1 is -CR6R7OH;

R2 es un grupo seleccionado de alquilo de C1-6, carbociclilo y heterociclilo, estando dicho grupo sustituido con -NR17CONR18R19 y opcionalmente sustituido con uno o más grupos sustituyentes seleccionados independientemente de halo, ciano, nitro, –R11, –OR11, –SR11, –SOR11, –SO2R11, –COR11, –CO2R11, -CONR11R12, -NR11R12, –NR11COR12, y –NR11COCONR12R16; R2 is a group selected from C1-6 alkyl, carbocyclyl and heterocyclyl, said group being substituted with -NR17CONR18R19 and optionally substituted with one or more substituent groups independently selected from halo, cyano, nitro, -R11, -OR11, -SR11, –SOR11, –SO2R11, –COR11, –CO2R11, -CONR11R12, -NR11R12, –NR11COR12, and –NR11COCONR12R16;

R11 , R12 , R17R11, R12, R17

R13, R14, R15, R16

y R19 son independientemente hidrógeno o un grupo seleccionado de alquilo de C1-6, carbociclilo, carbociclil-alquilo de C1-6, heterociclilo y heterociclil-alquilo de C1-6, estando dicho grupo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, hidroxi, alquilo de C1-6, alcoxi de C1-6, haloalquilo de C1-6, halo-alcoxi de C1-6, hidroxi-alquilo de C1-6, hidroxi-alcoxi de C1-6, alcoxi C1-6-alquilo de C1-6, alcoxi C1-6alcoxi de C1-6, amino, alquil C1-6-amino, bis(alquil C1-6)-amino, amino-alquilo de C1-6, (alquil C1-6)-amino-alquilo de C16, bis(alquil C1-6)-amino-alquilo de C1-6, ciano-alquilo de C1-6, alquil C1-6-sulfonilo, alquil C1-6-sulfonilamino, alquil C1-6sulfonil-(alquil C1-6)-amino, sulfamoilo, alquil C1-6-sulfamoilo, bis(alquil C1-6)-sulfamoilo, alcanoil C1-6-amino, alcanoil C1-6-(alquil C1-6)-amino, carbamoilo, alquil C1-6-carbamoilo y bis(alquil C1-6)-carbamoilo; and R19 are independently hydrogen or a group selected from C1-6 alkyl, carbocyclyl, carbocyclyl-C1-6 alkyl, heterocyclyl and heterocyclyl-C1-6 alkyl, said group being optionally substituted with one or more substituent groups selected from halo , cyano, nitro, hydroxy, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 hydroxy-alkyl, C1-6 hydroxy-alkoxy, alkoxy C1-6-C1-6 alkyl, C1-6 alkoxy C1-6 alkoxy, amino, C1-6-alkyl, bis (C1-6 alkyl) -amino, C1-6 amino-alkyl, (C1- alkyl 6) -amino-C16 alkyl, bis (C1-6 alkyl) -amino-C1-6 alkyl, cyano-C1-6 alkyl, C1-6 alkyl sulfonyl, C1-6 alkyl sulfonylamino, C1- alkyl 6sulfonyl- (C1-6 alkyl) -amino, sulfamoyl, C1-6 alkyl-sulfamoyl, bis (C1-6 alkyl) -sulfamoyl, C1-6-alkanoyl, C1-6 alkanoyl- (C1-6 alkyl) -amino , carbamoyl, C 1-6 alkylcarbamoyl and bis (C 1-6 alkyl) carbamoyl;

o R18 y R19, junto con el átomo de nitrógeno al que están unidos, forman un anillo heterocíclico de 3 a 10 miembros en el que 1 ó 2 átomos de carbono anulares están opcionalmente reemplazados por N, O ó S, y estando dicho anillo or R18 and R19, together with the nitrogen atom to which they are attached, form a 3- to 10-membered heterocyclic ring in which 1 or 2 annular carbon atoms are optionally replaced by N, O or S, and said ring being

opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, hidroxi, alquilo de C1-6, alcoxi de C1-6, halo-alquilo de C1-6, halo-alcoxi de C1-6, hidroxi-alquilo de C1-6, hidroxi-alcoxi de C1-6, alcoxi C1-6alquilo de C1-6, alcoxi C1-6-alcoxi de C1-6, amino, alquil C1-6-amino, bis(alquil C1-6)-amino, amino-alquilo de C1-6, (alquil C1-6)-amino-alquilo de C1-6, bis(alquil C1-6)-amino-alquilo de C1-6, ciano-alquilo de C1-6, alquil C1-6-sulfonilo, alquil C1-6sulfonilamino, alquil C1-6-sulfonil-(alquil C1-6)-amino, sulfamoilo, alquil C1-6-sulfamoilo, bis(alquil C1-6)-sulfamoilo, alcanoil C1-6-amino, alcanoil C1-6-(alquil C1-6)-amino, carbamoilo, alquil C1-6-carbamoilo y bis(alquil C1-6)carbamoilo optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6 alkyl, C1-6 alkoxy, C1-6 halo-alkyl, C1-6 halo-alkoxy, hydroxy-alkyl C1-6, hydroxy-C1-6 alkoxy, C1-6 alkoxy C1-6 alkyl, C1-6 alkoxy-C1-6 alkoxy, amino, C1-6-alkyl, bis (C1-6 alkyl) -amino , C1-6 amino-alkyl, (C1-6 alkyl) -amino-C1-6 alkyl, bis (C1-6 alkyl) -amino-C1-6 alkyl, cyano-C1-6 alkyl, C1 alkyl -6-sulfonyl, C1-6 alkyl sulfonylamino, C1-6 alkyl-sulfonyl- (C1-6 alkyl) -amino, sulfamoyl, C1-6 alkyl sulfamoyl, bis (C1-6 alkyl) -sulfamoyl, C1-6 alkanoyl amino, C1-6 alkanoyl- (C1-6 alkyl) -amino, carbamoyl, C1-6 alkylcarbamoyl and bis (C1-6 alkyl) carbamoyl

fórmula (I) formula (I)

m es 0, 1, 2, 3 ó 4; m is 0, 1, 2, 3 or 4;

X es un grupo enlazador seleccionado de –CR4=CR5–, –CR4=CR5CR6R7–, –CR6R7CR5=CR4–, –C∃C–, -C∃CCR6R7–, –CR6R7C∃C–, –NR4CR6R7–, –OCR6R7–, –SCR6R7–, –S(O)CR6R7–, –S(O)2CR6R7–, -C(O)NR4CR6R7–, -NR4C(O)NR5CR6R7–, –S(O)2NR4CR6R7–, –C(O)NR4–, –NR4C(O)–, –NR4C(O)NR5–, -S(O)2NR4– y –NR4S(O)2–; X is a linker group selected from –CR4 = CR5–, –CR4 = CR5CR6R7–, –CR6R7CR5 = CR4–, –C∃C–, -C∃CCR6R7–, –CR6R7C∃C–, –NR4CR6R7–, –OCR6R7– , –SCR6R7–, –S (O) CR6R7–, –S (O) 2CR6R7–, -C (O) NR4CR6R7–, -NR4C (O) NR5CR6R7–, –S (O) 2NR4CR6R7–, –C (O) NR4–, –NR4C (O) -, –NR4C (O) NR5–, -S (O) 2NR4– and –NR4S (O) 2–;

R1 es un grupo seleccionado de alquilo de C1-6, alquenilo de C2-6, alquinilo de C2-6, carbociclilo, carbociclil-alquilo de C1-6, heterociclilo y heterociclil-alquilo de C1-6, estando dicho grupo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, R9, –OR9, -SR9, –SOR9, –SO2R9, –COR9, –CO2R9, -CONR9R10, -NR9R10, –NR9COR10, –NR9CO2R10, -NR9CONR10R15, –NR9COCONR10R15 y –NR9SO2R10; R1 is a group selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, carbocyclyl, C1-6 carbocyclyl-alkyl, heterocyclyl and C1-6 heterocyclyl-alkyl, said group being optionally substituted with one or more substituent groups selected from halo, cyano, nitro, R9, –OR9, -SR9, –SOR9, –SO2R9, –COR9, –CO2R9, -CONR9R10, -NR9R10, –NR9COR10, –NR9CO2R10, -NR9CONR10R15, –NR9CON15 and -NR9SO2R10;

o X–R1 es –CR6R7OH; or X-R1 is -CR6R7OH;

R2 es un grupo seleccionado de alquilo de C1-6, carbociclilo y heterociclilo, estando dicho grupo sustituido con -NR17CONR18R19 y opcionalmente sustituido con uno o más grupos sustituyentes seleccionados independientemente de halo, ciano, nitro, –R11, –OR11, –SR11, -SOR11, –SO2R11, –COR11, –CO2R11, -CONR11R12, -NR11R12, –NR11COR12,y -NR11COCONR12R16; R2 is a group selected from C1-6 alkyl, carbocyclyl and heterocyclyl, said group being substituted with -NR17CONR18R19 and optionally substituted with one or more substituent groups independently selected from halo, cyano, nitro, -R11, -OR11, -SR11, -SOR11, –SO2R11, –COR11, –CO2R11, -CONR11R12, -NR11R12, –NR11COR12, and -NR11COCONR12R16;

cada R3, cuando está presente, se selecciona independientemente de halo, ciano, nitro, -R13, –OR13, –SR13, -SOR13, –SO2R13, –COR13, –CO2R13, –CONR13R14, –NR13R14, –NR13COR14, -NR13CO2R14 y –NR13SO2R14; each R3, when present, is independently selected from halo, cyano, nitro, -R13, –OR13, –SR13, -SOR13, –SO2R13, –COR13, –CO2R13, –CONR13R14, –NR13R14, –NR13COR14, -NR13CO2R14 and –NR13SO2R14;

R9 y R10 son independientemente hidrógeno o un grupo seleccionado de alquilo de C1-6, carbociclilo, carbociclilalquilo de C1-6, heterociclilo y heterociclil-alquilo de C1-6, estando dicho grupo opcionalmente sustituido con uno o R9 and R10 are independently hydrogen or a group selected from C1-6 alkyl, carbocyclyl, C1-6 carbocyclyl alkyl, heterocyclyl and C1-6 heterocyclyl alkyl, said group being optionally substituted with one or

más grupos sustituyentes seleccionados de halo, ciano, nitro, hidroxi, alquilo de C1-6, alcoxi de C1-6, halo-alquilo de C1-6, halo-alcoxi de C1-6, hidroxi-alquilo de C1-6, hidroxi-alcoxi de C1-6, alcoxi C1-6-alquilo de C1-6, alcoxi C1-6-alcoxi de C1-6, amino, alquil C1-6-amino, bis(alquil C1-6)-amino, amino-alquilo de C1-6, (alquil C1-6)-amino-alquilo de C1-6, bis(alquil C1-6)-amino-alquilo de C1-6, ciano-alquilo de C1-6, alquil C1-6-sulfonilo, alquil C1-6-sulfonilamino, alquil C1-6sulfonil-(alquil C1-6)-amino, sulfamoilo, alquil C1-6-sulfamoilo, bis(alquil C1-6)-sulfamoilo, alcanoil C1-6-amino, alcanoil C1-6-(alquil C1-6)-amino, carbamoilo, alquil C1-6-carbamoilo y bis(alquil C1-6)-carbamoilo; more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6 alkyl, C1-6 alkoxy, C1-6 halo-alkyl, C1-6 halo-alkoxy, C1-6 hydroxy-alkyl, hydroxy -C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkoxy, amino, C 1-6 alkyl-amino, bis (C 1-6 alkyl) -amino, amino- C1-6 alkyl, (C1-6 alkyl) -amino-C1-6 alkyl, bis (C1-6 alkyl) -amino-C1-6 alkyl, cyano-C1-6 alkyl, C1-6 alkyl sulfonyl, C1-6 alkyl-sulfonylamino, C1-6 alkyl sulfonyl- (C1-6 alkyl) -amino, sulfamoyl, C1-6 alkyl-sulfamoyl, bis (C1-6 alkyl) -sulfamoyl, C1-6-amino alkanoyl, alkanoyl C1-6- (C1-6 alkyl) -amino, carbamoyl, C1-6 alkylcarbamoyl and bis (C1-6 alkyl) -carbamoyl;

R11, R12, R17 y R18 son independientemente hidrógeno o un grupo seleccionado de alquilo de C1-6, carbociclilo, carbociclil-alquilo de C1-6, heterociclilo y heterociclil-alquilo de C1-6, estando dicho grupo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, hidroxi, alquilo de C1-6, alcoxi de C1-6, haloalquilo de C1-6, halo-alcoxi de C1-6, hidroxi-alquilo de C1-6, hidroxi-alcoxi de C1-6, alcoxi C1-6-alquilo de C1-6, alcoxi C1-6alcoxi de C1-6, amino, alquil C1-6-amino, bis(alquil C1-6)-amino, amino-alquilo de C1-6, (alquil C1-6)-amino-alquilo de C16, bis(alquil C1-6)-amino-alquilo de C1-6, ciano-alquilo de C1-6, alquil C1-6-sulfonilo, alcanoil C1-6-amino, alcanoil C1-6(alquil C1-6)-amino, carbamoilo, alquil C1-6-carbamoilo y bis(alquil C1-6)-carbamoilo; R11, R12, R17 and R18 are independently hydrogen or a group selected from C1-6 alkyl, carbocyclyl, C1-6 carbocyclyl alkyl, heterocyclyl and C1-6 heterocyclyl alkyl, said group being optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 hydroxy-alkyl, hydroxy-alkoxy C1-6, C1-6 alkoxy-C1-6 alkyl, C1-6 alkoxy C1-6 alkoxy, amino, C1-6-alkyl, bis (C1-6 alkyl) -amino, amino- C1-6 alkyl , (C1-6 alkyl) -amino-C16 alkyl, bis (C1-6 alkyl) -amino-C1-6 alkyl, cyano-C1-6 alkyl, C1-6 alkyl sulfonyl, C1-6 alkanoyl- amino, C1-6 alkanoyl (C1-6 alkyl) -amino, carbamoyl, C1-6 alkylcarbamoyl and bis (C1-6 alkyl) -carbamoyl;

R13 R13

, R14 , R15, R16 y R19 son independientemente hidrógeno o un grupo seleccionado de alquilo de C1-6, carbociclilo, carbociclil-alquilo de C1-6, heterociclilo y heterociclil-alquilo de C1-6, estando dicho grupo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, hidroxi, alquilo de C1-6, alcoxi de C1-6, haloalquilo de C1-6, halo-alcoxi de C1-6, hidroxi-alquilo de C1-6, hidroxi-alcoxi de C1-6, alcoxi C1-6-alquilo de C1-6, alcoxi C1-6alcoxi de C1-6, amino, alquil C1-6-amino, bis(alquil C1-6)-amino, amino-alquilo de C1-6, (alquil C1-6)-amino-alquilo de C16, bis(alquil C1-6)-amino-alquilo de C1-6, ciano-alquilo de C1-6, alquil C1-6-sulfonilo, alquil C1-6-sulfonilamino, alquil C1-6sulfonil-(alquil C1-6)-amino, sulfamoilo, alquil C1-6-sulfamoilo, bis(alquil C1-6)-sulfamoilo, alcanoil C1-6-amino, alcanoil C1-6-(alquil C1-6)-amino, carbamoilo, alquil C1-6-carbamoilo y bis(alquil C1-6)-carbamoilo; , R14, R15, R16 and R19 are independently hydrogen or a group selected from C1-6 alkyl, carbocyclyl, carbocyclyl-C1-6 alkyl, heterocyclyl and heterocyclyl-C1-6 alkyl, said group being optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 hydroxy-alkyl, hydroxy-alkoxy C1-6, C1-6 alkoxy-C1-6 alkyl, C1-6 alkoxy C1-6 alkoxy, amino, C1-6-alkyl, bis (C1-6 alkyl) -amino, amino-C1- alkyl 6, (C1-6 alkyl) -amino-C16 alkyl, bis (C1-6 alkyl) -amino-C1-6 alkyl, cyano-C1-6 alkyl, C1-6 alkyl sulfonyl, C1-6 alkyl -sulfonylamino, C1-6 alkyl sulfonyl- (C1-6 alkyl) -amino, sulfamoyl, C1-6 alkyl sulfamoyl, bis (C1-6 alkyl) -sulfamoyl, C1-6 alkanoyl-amino, C1-6 alkanoyl- (alkyl C1-6) -amino, carbamoyl, C1-6 alkylcarbamoyl and bis (C1-6 alkyl) -carbamoyl;

De acuerdo con otro aspecto de la presente invención, se proporciona el uso de un compuesto de fórmula (I) In accordance with another aspect of the present invention, the use of a compound of formula (I) is provided

fórmula (I) formula (I)

o una sal farmacéuticamente aceptable del mismo; en la que m es 0, 1, 2, 3 ó 4; 1Y e Y2 son independientemente N o CR8 con la condición de que uno de 1Y e Y2 sea N y el otro sea CR8; or a pharmaceutically acceptable salt thereof; in which m is 0, 1, 2, 3 or 4; 1Y and Y2 are independently N or CR8 with the proviso that one of 1Y and Y2 is N and the other is CR8;

R1 es un grupo seleccionado de hidrógeno, alquilo de C1-6, alquenilo de C2-6, alquinilo de C2-6, carbociclilo, carbociclilalquilo de C1-6, heterociclilo y heterociclil-alquilo de C1-6, estando dicho grupo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, –R9, –OR9, –SR9, –SOR9, -SO2R9, –COR9, -CO2R9, – CONR9R10, –NR9R10, –NR9COR10, –NR9CO2R10, -NR9CONR10R15, -NR9COCONR10R15 y –NR9SO2R10; R 1 is a group selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, C 1-6 carbocyclyl alkyl, heterocyclyl and C 1-6 heterocyclyl alkyl, said group being optionally substituted with one or more substituent groups selected from halo, cyano, nitro, –R9, –OR9, –SR9, –SOR9, -SO2R9, –COR9, -CO2R9, - CONR9R10, –NR9R10, –NR9COR10, –NR9CO2R10, -NR9CONR10R15, - NR9COCONR10R15 and –NR9SO2R10;

R2 es un grupo seleccionado de alquilo de C1-6, carbociclilo y heterociclilo, estando dicho grupo sustituido con -NR17CONR18R19 y opcionalmente sustituido con uno o más grupos sustituyentes seleccionados independientemente de halo, ciano, nitro, –R11,–OR11, – SR11, -SOR11, –SO2R11, –COR11, –CO2R11, -CONR11R12, -NR11R12, –NR11COR12, y -NR11COCONR12R16; R2 is a group selected from C1-6 alkyl, carbocyclyl and heterocyclyl, said group being substituted with -NR17CONR18R19 and optionally substituted with one or more substituent groups independently selected from halo, cyano, nitro, -R11, -OR11, - SR11, -SOR11, –SO2R11, –COR11, –CO2R11, -CONR11R12, -NR11R12, –NR11COR12, and -NR11COCONR12R16;

cada R3, cuando está presente, se selecciona independientemente de halo, ciano, nitro, -R13, –OR13, –SR13, -SOR13, –SO2R13, –COR13, –CO2R13, –CONR13R14,–NR13R14, –NR13COR14, -NR13CO2R14 y –NR13SO2R14; each R3, when present, is independently selected from halo, cyano, nitro, -R13, –OR13, –SR13, -SOR13, –SO2R13, –COR13, –CO2R13, –CONR13R14, –NR13R14, –NR13COR14, -NR13CO2R14 and –NR13SO2R14;

R11, R12, R17 y R18 son independientemente hidrógeno o un grupo seleccionado de alquilo de C1-6, carbociclilo, carbociclil-alquilo de C1-6, heterociclilo y heterociclil-alquilo de C1-6, estando dicho grupo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, hidroxi, oxo, alquilo de C1-6, alcoxi de C1-6, haloalquilo de C1-6, halo-alcoxi de C1-6, hidroxi-alquilo de C1-6, hidroxi-alcoxi de C1-6, alcoxi C1-6-alquilo de C1-6, alcoxi C1-6alcoxi de C1-6, amino, alquil C1-6-amino, bis(alquil C1-6)-amino, amino-alquilo de C1-6, (alquil C1-6)-amino-alquilo de C16, bis(alquil C1-6)-amino-alquilo de C1-6, ciano-alquilo de C1-6, alquil C1-6-sulfonilo, alcanoil C1-6-amino, alcanoil C1-6(alquil C1-6)-amino, carbamoilo, alquil C1-6-carbamoilo y bis(alquil C1-6)-carbamoilo; R11, R12, R17 and R18 are independently hydrogen or a group selected from C1-6 alkyl, carbocyclyl, C1-6 carbocyclyl alkyl, heterocyclyl and C1-6 heterocyclyl alkyl, said group being optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 hydroxy-alkyl, hydroxy- C1-6 alkoxy, C1-6 alkoxy-C1-6 alkyl, C1-6 alkoxy C1-6 alkoxy, amino, C1-6-alkyl, bis (C1-6 alkyl) -amino, amino-C1-alkyl -6, (C1-6 alkyl) -amino-C16 alkyl, bis (C1-6 alkyl) -amino-C1-6 alkyl, cyano-C1-6 alkyl, C1-6 alkyl sulfonyl, C1-alkanoyl 6-amino, C 1-6 alkanoyl (C 1-6 alkyl) -amino, carbamoyl, C 1-6 alkyl-carbamoyl and bis (C 1-6 alkyl) -carbamoyl;

R13 R13

, R14 , R15, R16 y R19 son independientemente hidrógeno o un grupo seleccionado de alquilo de C1-6, carbociclilo, carbociclil-alquilo de C1-6, heterociclilo y heterociclil-alquilo de C1-6, estando dicho grupo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, hidroxi, oxo, alquilo de C1-6, alcoxi de C1-6, haloalquilo de C1-6, halo-alcoxi de C1-6, hidroxi-alquilo de C1-6, hidroxi-alcoxi de C1-6, alcoxi C1-6-alquilo de C1-6, alcoxi C1-6alcoxi de C1-6, amino, alquil C1-6-amino, bis(alquil C1-6)-amino, amino-alquilo de C1-6, (alquil C1-6)-amino-alquilo de C16, bis(alquil C1-6)-amino-alquilo de C1-6, ciano-alquilo de C1-6, alquil C1-6-sulfonilo, alquil C1-6-sulfonilamino, alquil C1-6sulfonil-(alquil C1-6)-amino, sulfamoilo, alquil C1-6-sulfamoilo, bis(alquil C1-6)-sulfamoilo, alcanoil C1-6-amino, alcanoil C1-6-(alquil C1-6)-amino, carbamoilo, alquil C1-6-carbamoilo y bis(alquil C1-6)-carbamoilo; , R14, R15, R16 and R19 are independently hydrogen or a group selected from C1-6 alkyl, carbocyclyl, carbocyclyl-C1-6 alkyl, heterocyclyl and heterocyclyl-C1-6 alkyl, said group being optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 hydroxy-alkyl, hydroxy -C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxyC 1-6 alkoxy, amino, C 1-6 alkyl-amino, bis (C 1-6 alkyl) -amino, amino-alkyl C1-6, (C1-6 alkyl) -amino-C16 alkyl, bis (C1-6 alkyl) -amino-C1-6 alkyl, cyano-C1-6 alkyl, C1-6 alkyl sulfonyl, C1 alkyl -6-sulfonylamino, C 1-6 alkyl sulfonyl- (C 1-6 alkyl) -amino, sulfamoyl, C 1-6 alkyl sulfamoyl, bis (C 1-6 alkyl) -sulfamoyl, C 1-6 alkanoyl, C 1-6 alkanoyl (C1-6 alkyl) -amino, carbamoyl, C1-6-alkylcarbamoyl and bis (C1-6 alkyl) -carbamoyl;

en la fabricación de un medicamento para el uso en el tratamiento de una enfermedad proliferativa. in the manufacture of a medicament for use in the treatment of a proliferative disease.

fórmula (I) formula (I)

m es 0, 1, 2, 3 ó 4; m is 0, 1, 2, 3 or 4;

R2 es un grupo seleccionado de alquilo de C1-6, carbociclilo y heterociclilo, estando dicho grupo sustituido con -NR17CONR18R19 y opcionalmente sustituido con uno o más grupos sustituyentes seleccionados independientemente de halo, ciano, nitro, –R11, –OR11, – SR11, -SOR11, –SO2R11, –COR11, –CO2R11, -CONR11R12, -NR11R12, –NR11COR12, y -NR11COCONR12R16; R2 is a group selected from C1-6 alkyl, carbocyclyl and heterocyclyl, said group being substituted with -NR17CONR18R19 and optionally substituted with one or more substituent groups independently selected from halo, cyano, nitro, -R11, -OR11, - SR11, -SOR11, –SO2R11, –COR11, –CO2R11, -CONR11R12, -NR11R12, –NR11COR12, and -NR11COCONR12R16;

R11, R12, R17 y R18 son independientemente hidrógeno o un grupo seleccionado de alquilo de C1-6, carbociclilo, carbociclil-alquilo de C1-6, heterociclilo y heterociclil-alquilo de C1-6, estando dicho grupo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, hidroxi, alquilo de C1-6, alcoxi de C1-6, haloalquilo de C1-6, halo-alcoxi de C1-6, hidroxi-alquilo de C1-6, hidroxi-alcoxi de C1-6, alcoxi C1-6-alquilo de C1-6, alcoxi C1-6alcoxi de C1-6, amino, alquil C1-6-amino, bis(alquil C1-6)-amino, amino-alquilo de C1-6, (alquil C1-6)-amino-alquilo de C1R11, R12, R17 and R18 are independently hydrogen or a group selected from C1-6 alkyl, carbocyclyl, C1-6 carbocyclyl alkyl, heterocyclyl and C1-6 heterocyclyl alkyl, said group being optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 hydroxy-alkyl, hydroxy-alkoxy C1-6, C1-6 alkoxy-C1-6 alkyl, C1-6 alkoxy C1-6 alkoxy, amino, C1-6-alkyl, bis (C1-6 alkyl) -amino, amino- C1-6 alkyl , (C1-6 alkyl) -amino-C1 alkyl

R13 R13

fórmula (I) formula (I)

m es 0, 1, 2, 3 ó 4; m is 0, 1, 2, 3 or 4;

R1 es un grupo seleccionado de alquilo de C1-6, alquenilo de C2-6, alquinilo de C2-6, carbociclilo, carbociclil-alquilo de C1-6, heterociclilo y heterociclil-alquilo de C1-6, estando dicho grupo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, –R9, –OR9, –SR9, –SOR9, –SO2R9, –COR9, –CO2R9, -CONR9R10, -NR9R10, –NR9COR10, –NR9CO2R10, -NR9CONR10R15, –NR9COCONR10R15 y –NR9SO2R10; R1 is a group selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, carbocyclyl, C1-6 carbocyclyl-alkyl, heterocyclyl and C1-6 heterocyclyl-alkyl, said group being optionally substituted with one or more substituent groups selected from halo, cyano, nitro, –R9, –OR9, –SR9, –SOR9, –SO2R9, –COR9, –CO2R9, -CONR9R10, -NR9R10, –NR9COR10, –NR9CO2R10, -NR9CONR10R15, - NR9COCONR10R15 and –NR9SO2R10;

o X–R1 es –CR6R7OH; or X-R1 is -CR6R7OH;

R13, R14

, R15, R16 y R19 son independientemente hidrógeno o un grupo seleccionado de alquilo de C1-6, carbociclilo, carbociclil-alquilo de C1-6, heterociclilo y heterociclil-alquilo de C1-6, estando dicho grupo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, hidroxi, alquilo de C1-6, alcoxi de C1-6, haloalquilo de C1-6, halo-alcoxi de C1-6, hidroxi-alquilo de C1-6, hidroxi-alcoxi de C1-6, alcoxi C1-6-alquilo de C1-6, alcoxi C1-6alcoxi de C1-6, amino, alquil C1-6-amino, bis(alquil C1-6)-amino, amino-alquilo de C1-6, (alquil C1-6)-amino-alquilo de C16, bis(alquil C1-6)-amino-alquilo de C1-6, ciano-alquilo de C1-6, alquil C1-6-sulfonilo, alquil C1-6-sulfonilamino, alquil C1-6sulfonil-(alquil C1-6)-amino, sulfamoilo, alquil C1-6-sulfamoilo, bis(alquil C1-6)-sulfamoilo, alcanoil C1-6-amino, alcanoil C1-6-(alquil C1-6)-amino, carbamoilo, alquil C1-6-carbamoilo y bis(alquil C1-6)-carbamoilo; , R15, R16 and R19 are independently hydrogen or a group selected from C1-6 alkyl, carbocyclyl, C1-6 carbocyclyl alkyl, heterocyclyl and C1-6 heterocyclyl alkyl, said group being optionally substituted with one or more groups substituents selected from halo, cyano, nitro, hydroxy, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 hydroxy-alkyl, C1-hydroxy-alkoxy -6, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkoxy, amino, C 1-6 alkyl, bis (C 1-6 alkyl) -amino, C 1-6 alkyl-amino, (C1-6 alkyl) -amino-C16 alkyl, bis (C1-6 alkyl) -amino-C1-6 alkyl, cyano-C1-6 alkyl, C1-6 alkyl sulfonyl, C1-6 alkyl sulfonylamino , C1-6 alkyl sulfonyl- (C1-6 alkyl) -amino, sulfamoyl, C1-6-sulfamoyl alkyl, bis (C1-6 alkyl) -sulfamoyl, C1-6-amino alkanoyl, C1-6 alkanoyl- (C1- alkyl 6) -amino, carbamoyl, C1-6 alkylcarbamoyl and bis (C1-6 alkyl) -carbamoyl;

fórmula (I) 5 formula (I) 5

o una sal farmacéuticamente aceptable; en la que or a pharmaceutically acceptable salt; in which

m es 0, 1, 2, 3 ó 4; m is 0, 1, 2, 3 or 4;

o X–R1 es –CR6R7OH or X – R1 is –CR6R7OH

cada R3, cuando está presente, se selecciona independientemente de halo, ciano, nitro, -R13, –OR13, –SR13, -SOR13, –SO2R13, –COR13, –CO2R13, –CONR13R14, –NR13R14, –NR13COR14, -R13CO2R14 y –NR13SO2R14; Each R3, when present, is independently selected from halo, cyano, nitro, -R13, –OR13, –SR13, -SOR13, –SO2R13, –COR13, –CO2R13, –CONR13R14, –NR13R14, –NR13COR14, -R13CO2R14 –NR13SO2R14;

R13, R14

De acuerdo con un aspecto adicional de la presente invención, también se proporciona un compuesto de fórmula (I) In accordance with a further aspect of the present invention, a compound of formula (I) is also provided

fórmula (I) formula (I)

m es 0, 1, 2, 3 ó 4; m is 0, 1, 2, 3 or 4;

X es un grupo enlazador seleccionado de –CR4=CR5–, –CR4=CR5CR6R7–, –CR6R7CR5=CR4–, –C∃C–, -C∃CCR6R7–, –CR6R7C∃C–, –NR4CR6R7–, –OCR6R7–, –SCR6R7–, –S(O)CR6R7–, –S(O)2CR6R7–, -C(O)NR4CR6R7–, -NR4C(O)CR6R7–, –NR4C(O)NR5CR6R7–, -NR4S(O)2CR6R7–, –S(O)2NR4CR6R7–, –C(O)NR4–, –NR4C(O)–, -NR4C(O)NR5–, -(O)2NR4– y –NR4S(O)2–; X is a linker group selected from –CR4 = CR5–, –CR4 = CR5CR6R7–, –CR6R7CR5 = CR4–, –C∃C–, -C∃CCR6R7–, –CR6R7C∃C–, –NR4CR6R7–, –OCR6R7– , –SCR6R7–, –S (O) CR6R7–, –S (O) 2CR6R7–, -C (O) NR4CR6R7–, -NR4C (O) CR6R7–, –NR4C (O) NR5CR6R7–, -NR4S (O) 2CR6R7–, –S (O) 2NR4CR6R7–, –C (O) NR4–, –NR4C (O) -, -NR4C (O) NR5–, - (O) 2NR4– and –NR4S (O) 2–;

R1 es un grupo seleccionado de hidrógeno, alquilo de C1-6, alquenilo de C2-6, alquinilo de C2-6, carbociclilo, carbociclilalquilo de C1-6, heterociclilo y heterociclil-alquilo de C1-6, estando dicho grupo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, –R9, –OR9, –SR9, –SOR9, -O2R9, –COR9, -CO2R9, – CONR9R10,–NR9R10, –NR9COR10, –NR9CO2R10, -NR9CONR10R15, –NR9COCONR10R15 y NR9SO2R10; R 1 is a group selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, C 1-6 carbocyclyl alkyl, heterocyclyl and C 1-6 heterocyclyl alkyl, said group being optionally substituted with one or more substituent groups selected from halo, cyano, nitro, –R9, –OR9, –SR9, –SOR9, -O2R9, –COR9, -CO2R9, - CONR9R10, –NR9R10, –NR9COR10, –NR9CO2R10, -NR9CONR10R15, - NR9COCONR10R15 and NR9SO2R10;

cada R3, cuando está presente, se selecciona independientemente de halo, ciano, nitro, -R13, –OR13, –R13, –SOR13, –SO2R13, –COR13, –CO2R13, –CONR13R14, –NR13R14, –NR13COR14, -NR13CO2R14 y –NR13SO2R14; Each R3, when present, is independently selected from halo, cyano, nitro, -R13, –OR13, –R13, –SOR13, –SO2R13, –COR13, –CO2R13, –CONR13R14, –NR13R14, –NR13COR14, -NR13CO2R14 –NR13SO2R14;

R13, R14

, R15, R16 y R19 son independientemente hidrógeno o un grupo seleccionado de alquilo de C1-6, carbociclilo, carbociclil-alquilo de C1-6, heterociclilo y heterociclil-alquilo de C1-6, estando dicho grupo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, hidroxi, oxo, alquilo de C1-6, alcoxi de C1-6, haloalquilo de C1-6, halo-alcoxi de C1-6, hidroxi-alquilo de C1-6, hidroxi-alcoxi de C1-6, alcoxi C1-6-alquilo de C1-6, alcoxi C1-6alcoxi de C1-6, amino, alquil C1-6-amino, bis(alquil C1-6)-amino, amino-alquilo de C1-6, (alquil C1-6)-amino-alquilo de C16, bis(alquil C1-6)-amino-alquilo de C1-6, ciano-alquilo de C1-6, alquil C1-6-sulfonilo, alquil C1-6-sulfonilamino, alquil C1-6sulfonil-(alquil C1-6)-amino, sulfamoilo, alquil C1-6-sulfamoilo, bis(alquil C1-6)-sulfamoilo, alcanoil C1-6-amino, alcanoil C1-6-(alquil C1-6)-amino, carbamoilo, alquil C1-6-carbamoilo y bis(alquil C1-6)-carbamoilo; , R15, R16 and R19 are independently hydrogen or a group selected from C1-6 alkyl, carbocyclyl, C1-6 carbocyclyl alkyl, heterocyclyl and C1-6 heterocyclyl alkyl, said group being optionally substituted with one or more groups substituents selected from halo, cyano, nitro, hydroxy, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxy-alkyl, hydroxy-alkoxy C1-6, C1-6 alkoxy-C1-6 alkyl, C1-6 alkoxy C1-6 alkoxy, amino, C1-6-alkyl, bis (C1-6 alkyl) -amino, amino-C1- alkyl 6, (C1-6 alkyl) -amino-C16 alkyl, bis (C1-6 alkyl) -amino-C1-6 alkyl, cyano-C1-6 alkyl, C1-6 alkyl sulfonyl, C1-6 alkyl -sulfonylamino, C1-6 alkyl sulfonyl- (C1-6 alkyl) -amino, sulfamoyl, C1-6 alkyl sulfamoyl, bis (C1-6 alkyl) -sulfamoyl, C1-6 alkanoyl-amino, C1-6 alkanoyl- (alkyl C1-6) -amino, carbamoyl, C1-6 alkylcarbamoyl and bis (C1-6 alkyl) -carbamoyl;

o R18 y R19, junto con el átomo de nitrógeno al que están unidos, forman un anillo heterocíclico de 3 a 10 miembros en el que 1 ó 2 átomos de carbono anulares están opcionalmente reemplazados por N, O ó S, y estando dicho anillo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, hidroxi, oxo, alquilo de C1-6, alcoxi de C1-6, halo-alquilo de C1-6, halo-alcoxi de C1-6, hidroxi-alquilo de C1-6, hidroxi-alcoxi de C1-6, alcoxi C1-6-alquilo de C1-6, alcoxi C1-6-alcoxi de C1-6, amino, alquil C1-6-amino, bis(alquil C1-6)-amino, amino-alquilo de C1-6, (alquil C1-6)-amino-alquilo de C1-6, bis(alquil C1-6)-amino-alquilo de C1-6, ciano-alquilo de C1-6, alquil C1-6-sulfonilo, alquil C1-6-sulfonilamino, alquil C1-6-sulfonil-(alquil C1-6)-amino, sulfamoilo, alquil C1-6-sulfamoilo, bis(alquil C1-6)sulfamoilo, alcanoil C1-6-amino, alcanoil C1-6-(alquil C1-6)-amino, carbamoilo, alquil C1-6-carbamoilo y bis(alquil C16)carbamoilo. or R18 and R19, together with the nitrogen atom to which they are attached, form a 3 to 10 membered heterocyclic ring in which 1 or 2 annular carbon atoms are optionally replaced by N, O or S, and said ring being optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, C1-6 halo-alkyl, C1-6 halo-alkoxy, hydroxy-alkyl C1-6, hydroxy-C1-6 alkoxy, C1-6 alkoxy-C1-6 alkyl, C1-6 alkoxy-C1-6 alkoxy, amino, C1-6-alkyl, bis (C1-6 alkyl ) -amino, C1-6 amino-alkyl, (C1-6 alkyl) -amino-C1-6 alkyl, bis (C1-6 alkyl) -amino-C1-6 alkyl, cyano-C1-6 alkyl , C1-6-sulfonyl alkyl, C1-6-sulfonylamino alkyl, C1-6-sulfonyl- (C1-6 alkyl) -amino, sulfamoyl, C1-6-sulfamoyl alkyl, bis (C1-6 alkyl) sulfamoyl, alkanoyl C1-6-amino, C1-6 alkanoyl- (C1-6 alkyl) -amino, carbamoyl, C1-6-carbamoyl alkyl and bis (C16 alkyl) carbamoyl.

fórmula (I) formula (I)

X es un grupo enlazador seleccionado de –CR4=CR5–, –CR4=CR5CR6R7–, –CR6R7CR5=CR4–, –C∃C–, –C∃CCR6R7-, –CR6R7C∃C–, –NR4CR6R7–, –OCR6R7–, –SCR6R7–, –S(O)CR6R7–, –S(O)2CR6R7–, –C(O)NR4CR6R7–, -NR4C(O)CR6R7–, –NR4C(O)NR5CR6R7–, -NR4S(O)2CR6R7–, –S(O)2NR4CR6R7–, –C(O)NR4–, –NR4C(O)–, -NR4C(O)NR5–, -(O)2NR4– y –NR4S(O)2–; X is a linker group selected from –CR4 = CR5–, –CR4 = CR5CR6R7–, –CR6R7CR5 = CR4–, –C∃C–, –C∃CCR6R7-, –CR6R7C∃C–, –NR4CR6R7–, –OCR6R7– , –SCR6R7–, –S (O) CR6R7–, –S (O) 2CR6R7–, –C (O) NR4CR6R7–, -NR4C (O) CR6R7–, –NR4C (O) NR5CR6R7–, -NR4S (O) 2CR6R7–, –S (O) 2NR4CR6R7–, –C (O) NR4–, –NR4C (O) -, -NR4C (O) NR5–, - (O) 2NR4– and –NR4S (O) 2–;

R1 es un grupo seleccionado de hidrógeno, alquilo de C1-6, alquenilo de C2-6, alquinilo de C2-6, carbociclilo, carbociclilalquilo de C1-6, heterociclilo y heterociclil-alquilo de C1-6, estando dicho grupo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, –R9, –OR9, –SR9, –SOR9, –O2R9, –COR9, -CO2R9, – CONR9R10, –NR9R10, –NR9COR10, –NR9CO2R10, -NR9CONR10R15, –NR9COCONR10R15 y NR9SO2R10; R 1 is a group selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, C 1-6 carbocyclyl alkyl, heterocyclyl and C 1-6 heterocyclyl alkyl, said group being optionally substituted with one or more substituent groups selected from halo, cyano, nitro, –R9, –OR9, –SR9, –SOR9, –O2R9, –COR9, -CO2R9, - CONR9R10, –NR9R10, –NR9COR10, –NR9CO2R10, -NR9CONR10R15, - NR9COCONR10R15 and NR9SO2R10;

R2 es un grupo seleccionado de alquilo de C1-6, carbociclilo y heterociclilo, estando dicho grupo sustituido con -NR17CONR18R19 y opcionalmente sustituido con uno o más grupos sustituyentes seleccionados independientemente de halo, ciano, nitro, –R11, –OR11, –SR11, -SOR11, –SO2R11, –COR11, –CO2R11, –CONR11R12, -NR11R12, –NR11COR12, y -NR11COCONR12R16; R2 is a group selected from C1-6 alkyl, carbocyclyl and heterocyclyl, said group being substituted with -NR17CONR18R19 and optionally substituted with one or more substituent groups independently selected from halo, cyano, nitro, -R11, -OR11, -SR11, -SOR11, –SO2R11, –COR11, –CO2R11, –CONR11R12, -NR11R12, –NR11COR12, and -NR11COCONR12R16;

cada R3, cuando está presente, se selecciona independientemente de halo, ciano, nitro, -R13, –OR13, –R13, –SOR13, –SO2R13, –COR13, –CO2R13, –CONR13R14, –NR13R14, –NR13COR14, -NR13CO2R14 y –NR13SO2R14; each R3, when present, is independently selected from halo, cyano, nitro, -R13, –OR13, –R13, –SOR13, –SO2R13, –COR13, –CO2R13, –CONR13R14, –NR13R14, –NR13COR14, -NR13CO2R14 and –NR13SO2R14;

R13 R13

o R18 y R19, junto con el átomo de nitrógeno al que están unidos, forman un anillo heterocíclico de 3 a 10 miembros en el que 1 ó 2 átomos de carbono anulares están opcionalmente reemplazados por N, O ó S, y estando dicho anillo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, hidroxi, alquilo de C1-6, alcoxi de C1-6, halo-alquilo de C1-6, halo-alcoxi de C1-6, hidroxi-alquilo de C1-6, hidroxi-alcoxi de C1-6, alcoxi C1-6alquilo de C1-6, alcoxi C1-6-alcoxi de C1-6, amino, alquil C1-6-amino, bis(alquil C1-6)-amino, amino-alquilo de C1-6, (alquil C1-6)-amino-alquilo de C1-6, bis(alquil C1-6)-amino-alquilo de C1-6, ciano-alquilo de C1-6, alquil C1-6-sulfonilo, alquil C1-6sulfonilamino, alquil C1-6-sulfonil-(alquil C1-6)-amino, sulfamoilo, alquil C1-6-sulfamoilo, bis(alquil C1-6)-sulfamoilo, alcanoil C1-6-amino, alcanoil C1-6-(alquil C1-6)-amino, carbamoilo, alquil C1-6-carbamoilo y bis(alquil C1-6)carbamoilo. or R18 and R19, together with the nitrogen atom to which they are attached, form a 3 to 10 membered heterocyclic ring in which 1 or 2 annular carbon atoms are optionally replaced by N, O or S, and said ring being optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6 alkyl, C1-6 alkoxy, halo C1-6 alkyl, halo C1-6 alkoxy, hydroxy C1 alkyl -6, C 1-6 hydroxy-alkoxy, C 1-6 alkoxyC 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkoxy, amino, C 1-6 alkyl-amino, bis (C 1-6 alkyl) -amino, C 1-6 amino-alkyl, (C 1-6 alkyl) -Camino-C 1-6 alkyl, bis (C 1-6 alkyl) -amino-C 1-6 alkyl, cyano-C 1-6 alkyl, C 1-6 alkyl 6-sulfonyl, C1-6 alkyl sulfonylamino, C1-6 alkyl-sulfonyl- (C1-6 alkyl) -amino, sulfamoyl, C1-6 alkyl sulfamoyl, bis (C1-6 alkyl) -sulfamoyl, C1-6-amino alkanoyl , C1-6 alkanoyl- (C1-6 alkyl) -amino, carbamoyl, C1-6 alkylcarbamoyl and bis (C1-6 alkyl) carbamoyl.

fórmula (I) formula (I)

m es 0, 1, 2, 3 ó 4; m is 0, 1, 2, 3 or 4;

R1 es un grupo seleccionado de alquilo de C1-6, alquenilo de C2-6, alquinilo de C2-6, carbociclilo, carbociclil-alquilo de C1-6, heterociclilo y heterociclil-alquilo de C1-6, estando dicho grupo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, –R9, –OR9, –SR9, –SOR9, –O2R9, –COR9, –CO2R9, –CONR9R10, -NR9R10, –NR9COR10,–NR9CO2R10, -NR9CONR10R15, –NR9COCONR10R15 y NR9SO2R10; R1 is a group selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, carbocyclyl, C1-6 carbocyclyl-alkyl, heterocyclyl and C1-6 heterocyclyl-alkyl, said group being optionally substituted with one or more substituent groups selected from halo, cyano, nitro, –R9, –OR9, –SR9, –SOR9, –O2R9, –COR9, –CO2R9, –CONR9R10, -NR9R10, –NR9COR10, –NR9CO2R10, -NR9CONR10R15, - NR9COCONR10R15 and NR9SO2R10;

o X–R1 es –CR6R7OH; or X-R1 is -CR6R7OH;

R11, R12, R17 y R18 son independientemente hidrógeno o un grupo seleccionado de alquilo de C1-6, carbociclilo, carbociclil-alquilo de C1-6, heterociclilo y heterociclil-alquilo de C1-6, estando dicho grupo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, hidroxi, alquilo de C1-6, alcoxi de C1-6, haloR11, R12, R17 and R18 are independently hydrogen or a group selected from C1-6 alkyl, carbocyclyl, C1-6 carbocyclyl alkyl, heterocyclyl and C1-6 heterocyclyl alkyl, said group being optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6 alkyl, C1-6 alkoxy, halo

alquilo de C1-6, halo-alcoxi de C1-6, hidroxi-alquilo de C1-6, hidroxi-alcoxi de C1-6, alcoxi C1-6-alquilo de C1-6, alcoxi C1-6alcoxi de C1-6, amino, alquil C1-6-amino, bis(alquil C1-6)-amino, amino-alquilo de C1-6, (alquil C1-6)-amino-alquilo de C16, bis(alquil C1-6)-amino-alquilo de C1-6, ciano-alquilo de C1-6, alquil C1-6-sulfonilo, alcanoil C1-6-amino, alcanoil C1-6(alquil C1-6)-amino, carbamoilo, alquil C1-6-carbamoilo y bis(alquil C1-6)-carbamoilo; C1-6 alkyl, halo C1-6 alkoxy, hydroxy C1-6 alkyl, hydroxy C1-6 alkoxy, C1-6 alkoxy C1-6 alkyl, C1-6 alkoxy C1-6 alkoxy, amino, C1-6 alkyl-amino, bis (C1-6 alkyl) -amino, amino C1-6 alkyl, (C1-6 alkyl) -amino-C16 alkyl, bis (C1-6 alkyl) -amino- C1-6 alkyl, cyano-C1-6 alkyl, C1-6 alkyl sulfonyl, C1-6 alkanoyl, C1-6 alkanoyl (C1-6 alkyl) -amino, carbamoyl, C1-6 alkylcarbamoyl and bis (C1-6 alkyl) -carbamoyl;

R13 R13

fórmula (I) formula (I)

m es 0, 1, 2, 3 ó 4; m is 0, 1, 2, 3 or 4;

X es un grupo enlazador seleccionado de –CR4=CR5–, –CR4=CR5CR6R7–, –CR6R7CR5=CR4–, –C∃C–, –C∃CCR6R7-, –CR6R7C∃C–, –NR4CR6R7–, –OCR6R7–, –SCR6R7–, –S(O)CR6R7–, –S(O)2CR6R7–, –C(O)NR4CR6R7–, -NR4C(O)NR5CR6R7–, –S(O)2NR4CR6R7–, –C(O)NR4–, –NR4C(O)–, -NR4C(O)NR5–, –S(O)2NR4– y –NR4S(O)2–; X is a linker group selected from –CR4 = CR5–, –CR4 = CR5CR6R7–, –CR6R7CR5 = CR4–, –C∃C–, –C∃CCR6R7-, –CR6R7C∃C–, –NR4CR6R7–, –OCR6R7– , –SCR6R7–, –S (O) CR6R7–, –S (O) 2CR6R7–, –C (O) NR4CR6R7–, -NR4C (O) NR5CR6R7–, –S (O) 2NR4CR6R7–, –C (O) NR4–, –NR4C (O) -, -NR4C (O) NR5–, –S (O) 2NR4– and –NR4S (O) 2–;

R1 es un grupo seleccionado de alquilo de C1-6, alquenilo de C2-6, alquinilo de C2-6, carbociclilo, carbociclil-alquilo de C1-6, heterociclilo y heterociclil-alquilo de C1-6, estando dicho grupo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, –R9, –OR9, –SR9, –SOR9, –O2R9, –COR9, –CO2R9, –CONR9R10, -NR9R10, –NR9COR10, –NR9CO2R10, -NR9CONR10R15, –NR9COCONR10R15 y NR9SO2R10; R1 is a group selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, carbocyclyl, C1-6 carbocyclyl-alkyl, heterocyclyl and C1-6 heterocyclyl-alkyl, said group being optionally substituted with one or more substituent groups selected from halo, cyano, nitro, –R9, –OR9, –SR9, –SOR9, –O2R9, –COR9, –CO2R9, –CONR9R10, -NR9R10, –NR9COR10, –NR9CO2R10, -NR9CONR10R15, - NR9COCONR10R15 and NR9SO2R10;

o X–R1 es –CR6R7OH; or X-R1 is -CR6R7OH;

R13, R14

Ciertos compuestos de fórmula (I) son capaces de existir en formas estereoisoméricas. Se entenderá que la invención abarca todos los isómeros geométricos y ópticos de los compuestos de fórmula (I) y las mezclas de los mismos, incluyendo los racematos. Los tautómeros y las mezclas de los mismos también forman un aspecto de la presente invención. Los solvatos y las mezclas de los mismos también forman un aspecto de la presente invención. Por ejemplo, un solvato adecuado de un compuesto de fórmula (I) es, por ejemplo, un hidrato tal como un hemihidrato, un monohidrato, un dihidrato o un trihidrato o una cantidad alternativa de los mismos. Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula (I) and mixtures thereof, including racemates. Tautomers and mixtures thereof also form an aspect of the present invention. Solvates and mixtures thereof also form an aspect of the present invention. For example, a suitable solvate of a compound of formula (I) is, for example, a hydrate such as a hemihydrate, a monohydrate, a dihydrate or a trihydrate or an alternative amount thereof.

La presente invención se refiere a los compuestos de fórmula (I) como se definió aquí, así como a las sales de los mismos. Las sales para uso en composiciones farmacéuticas serán sales farmacéuticamente aceptables, pero otras sales pueden ser útiles en la producción de los compuestos de fórmula (I) y sus sales farmacéuticamente aceptables. Las sales farmacéuticamente aceptables de la invención pueden, por ejemplo, incluir las sales de adición de ácidos de los compuestos de fórmula (I) como se define aquí, las cuales son lo suficientemente básicas para formar tales sales. Tales sales de adición de ácidos incluyen, pero no están limitadas a, las sales de fumarato, metanosulfonato, hidrocloruro, hidrobromuro, citrato y maleato y salse formas con ácido sulfúrico y fosfórico. Además, cuando los compuestos de fórmula (I) son suficientemente ácidos, las sales son sales de bases, y los ejemplos incluyen, pero no están limitados a, una sal de metal alcalino, por ejemplo sodio o potasio, una sal de metal alcalino-térreo, por ejemplo calcio o magnesio, o sal de amina orgánica, por ejemplo trietilamina, etanolamina, dietanolamina, trietanolamina, morfolina, N–metilpiperidina, N–etilpiperidina, dibencilamina, o aminoácidos tales como lisina. The present invention relates to the compounds of formula (I) as defined herein, as well as the salts thereof. The salts for use in pharmaceutical compositions will be pharmaceutically acceptable salts, but other salts may be useful in the production of the compounds of formula (I) and their pharmaceutically acceptable salts. The pharmaceutically acceptable salts of the invention can, for example, include the acid addition salts of the compounds of formula (I) as defined herein, which are basic enough to form such salts. Such acid addition salts include, but are not limited to, the salts of fumarate, methanesulfonate, hydrochloride, hydrobromide, citrate and maleate and salt forms with sulfuric and phosphoric acid. In addition, when the compounds of formula (I) are sufficiently acidic, the salts are base salts, and the examples include, but are not limited to, an alkali metal salt, for example sodium or potassium, an alkali metal salt. terrestrial, for example calcium or magnesium, or organic amine salt, for example triethylamine, ethanolamine, diethanolamine, triethanolamine, morpholine, N-methylpiperidine, N-ethylpiperidine, dibenzylamine, or amino acids such as lysine.

Los ésteres adecuados farmacéuticamente aceptables para carboxi incluyen ésteres alcoxi C1-6-metílicos, por ejemplo metoximetílico, ésteres alcanoil C1-6-oximetílicos, por ejemplo pivaloiloximetílico, ésteres ftalidílicos, ésteres cicloalcoxi C3-8-carboniloxialquílicos C1-6, por ejemplo 1-ciclohexilcarboniloxietílico, ésteres 1,3-dioxolen-2onilmetílicos, por ejemplo 5-metil-1,3-dioxolen-2-onilmetílico, y ésteres alcoxi C1-6-carboniloxietílicos, por ejemplo 1metoxicarboniloxietílico; y se pueden formar en cualquier grupo carboxi en los compuestos de esta invención. Suitable pharmaceutically acceptable esters for carboxy include C1-6-methyl alkoxy esters, for example methoxymethyl, C1-6-oxymethyl alkanoyl esters, for example pivaloyloxymethyl, phthalyl esters, C1-6 cycloalkoxy esters C1-6 alkyl, for example 1- cyclohexylcarbonyloxyethyl, 1,3-dioxolen-2-methylmethyl esters, for example 5-methyl-1,3-dioxolen-2-onylmethyl, and C1-6-alkoxycarbonyloxyethyl esters, for example 1-methoxycarbonyloxyethyl; and can be formed in any carboxy group in the compounds of this invention.

Ésteres adecuados farmacéuticamente aceptables para hidroxi incluyen ésteres inorgánicos tales como ésteres de fosfato (incluyendo ésteres cíclicos fosforamídicos) y éteres !-aciloxialquílicos y compuestos relacionados que, como resultado de la hidrólisis in vivo del éster, se rompen para dar el o los grupos hidroxi progenitores. Los ejemplos de éteres !-aciloxialquílicos incluyen acetoximetoxi y 2,2-dimetilpropioniloximetoxi. Una selección de grupos formadores de ésteres hidrolizables in vivo para hidroxi incluye alcanoilo de C1-C10, por ejemplo acetilo, benzoilo, fenilacetilo, benzoilo y fenilacetilo sustituidos; alcoxi C1-C10-carbonilo (para dar ésteres de carbonatos de alquilo), por ejemplo etoxicarbonilo; dialquil (C1-C4)-carbamoilo y N-(di-alquil (C1-C4)aminoetil)-N-alquil (C1C4)carbamoilo (para dar carbamatos); di-alquil (C1-C4)-aminoacetilo y carboxiacetilo. Los ejemplos de sustituyentes anulares en fenilacetilo y benzoilo incluyen aminometilo, alquil (C1-C4)aminometilo y di-(alquil (C1-C4))aminometilo, y morfolino o piperazino enlazados desde un átomo de nitrógeno anular, vía un grupo enlazante metilénico, a la posición 3 ó 4 del anillo benzoílico. Otros ésteres hidrolizables in vivo interesantes incluyen, por ejemplo, RAC(O)O-alquil(C1-C6)-CO-, en el que RA es, por ejemplo, benciloxi-alquilo (C1-C4), o fenilo. Los sustituyentes adecuados sobre un grupo fenilo en tales ésteres incluyen, por ejemplo, 4-(C1-C4)piperazino-alquilo (C1-C4), piperazino-alquilo (C1-C4) y morfolino-alquilo (C1-C4). Suitable pharmaceutically acceptable esters for hydroxy include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters) and γ-acyloxyalkyl ethers and related compounds which, as a result of in vivo hydrolysis of the ester, are broken to give the parent hydroxy group or groups . Examples of! -Acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. A selection of in vivo hydrolyzable ester forming groups for hydroxy includes C1-C10 alkanoyl, for example acetyl, benzoyl, phenylacetyl, benzoyl and substituted phenylacetyl; C1-C10-alkoxycarbonyl (to give alkyl carbonate esters), for example ethoxycarbonyl; dialkyl (C1-C4) -carbamoyl and N- (di-(C1-C4) aminoethyl) -N-(C1C4) carbamoyl (to give carbamates); di (C1-C4) alkyl amino amino and carboxy acetyl. Examples of ring substituents in phenylacetyl and benzoyl include aminomethyl, (C1-C4) alkyl aminomethyl and di- (C1-C4) alkyl aminomethyl, and morpholino or piperazino linked from an annular nitrogen atom, via a methylene linker group, to position 3 or 4 of the benzoyl ring. Other interesting in vivo hydrolysable esters include, for example, RAC (O) O-C 1 -C 6 alkyl -CO-, wherein RA is, for example, benzyloxy (C 1 -C 4) alkyl, or phenyl. Suitable substituents on a phenyl group in such esters include, for example, 4- (C1-C4) piperazino-C1-C4 alkyl, piperazino-C1-C4 alkyl and morpholino-C1-C4 alkyl.

En la técnica se conocen diversas formas de profármacos. Para ejemplos de tales derivados de profármacos, véase: Various forms of prodrugs are known in the art. For examples of such prodrug derivatives, see:

a) Design of Prodrugs, editado por H. Bundgaard, (Elsevier, 1985) y Methods in Enzymology, Vol. 42, p. 309–396, editado por K. Widder, et al. (Academic Press, 1985); a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309–396, edited by K. Widder, et al. (Academic Press, 1985);

b) A Textbook of Drug Design and Development, editado por Krogsgaard–Larsen y H. Bundgaard, Capítulo 5 “Design and Application of Prodrugs”, de H. Bundgaard p. 113–191 (1991); b) A Textbook of Drug Design and Development, edited by Krogsgaard – Larsen and H. Bundgaard, Chapter 5 “Design and Application of Prodrugs”, by H. Bundgaard p. 113-191 (1991);

c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1–38 (1992); c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1–38 (1992);

d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); y d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); Y

e) N. Kakeya, et al., Chem Pharm Bull, 32, 692 (1984). e) N. Kakeya, et al., Chem Pharm Bull, 32, 692 (1984).

En esta descripción el término genérico “alquilo de Cp–q” incluye tanto grupos alquilo de cadena lineal como de cadena ramificada. Sin embargo, las referencias a grupos alquilo individuales, tales como “propilo”, son específicas para la versión de cadena lineal solamente (es decir, n–propilo e isopropilo), y las referencias a grupos alquilo individuales de cadena ramificada, tales como “terc–butilo”, son específicas para la versión de cadena ramificada solamente. In this description the generic term "Cp-q alkyl" includes both straight chain and branched chain alkyl groups. However, references to individual alkyl groups, such as "propyl," are specific to the linear chain version only (ie, n-propyl and isopropyl), and references to individual branched chain alkyl groups, such as " tert-butyl ”, are specific to the branched chain version only.

El prefijo Cp–q en alquilo de Cp–q y otros términos (en los que p y q son números enteros) indica el intervalo de átomos de carbono que están presentes en el grupo, por ejemplo alquilo de C1-4 incluye alquilo de C1 (metilo), alquilo de C2 (etilo), alquilo de C3 (propilo como n–propilo e isopropilo) y alquilo de C4 (n–butilo, sec–butilo, isobutilo y terc– butil). The prefix Cp-q in Cp-q alkyl and other terms (in which p and q are whole numbers) indicates the range of carbon atoms that are present in the group, for example C1-4 alkyl includes C1 (methyl) alkyl , C2 alkyl (ethyl), C3 alkyl (propyl such as n-propyl and isopropyl) and C4 alkyl (n-butyl, sec-butyl, isobutyl and tert-butyl).

El término alcoxi de Cp–q comprende grupos –O–alquilo de Cp–q. The term Cp-q alkoxy comprises -O-Cp-q alkyl groups.

El término alcanoilo de Cp–q comprende grupos–C(O)-alquilo. The term Cp-q alkanoyl comprises -C (O) -alkyl groups.

El término halo incluye fluoro, cloro, bromo y yodo. The term halo includes fluoro, chloro, bromo and iodo.

“Carbociclilo” es un sistema de anillo monocíclico, bicíclico o tricíclico saturado, insaturado o parcialmente saturado que contiene de 3 a 14 átomos anulares, en el que un grupo CH2 del anillo puede ser reemplazado por un grupo C=O. “Carbociclilo” incluye “arilo”, “cicloalquilo de Cp–q” y “cicloalquenilo de Cp–q”. "Carbocyclyl" is a saturated, unsaturated or partially saturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 14 ring atoms, in which a CH2 group of the ring can be replaced by a group C = O. "Carbocyclyl" includes "aryl", "Cp-q cycloalkyl" and "Cp-q cycloalkenyl".

“Arilo” es un sistema anulares carbociclilo monocíclico, bicíclico o tricíclico, aromático. "Aryl" is a monocyclic, bicyclic or tricyclic, aromatic carbocyclyl ring system.

“Cicloalquenilo de Cp–q” es un sistema anulares carbociclilo monocíclico, bicíclico o tricíclico, insaturado o parcialmente saturado, que contiene al menos 1 enlace C=C, y en el que un grupo CH2 del anillo puede ser reemplazado por un grupo C=O. "Cp-q cycloalkenyl" is a monocyclic, bicyclic or tricyclic, unsaturated or partially saturated carbocyclyl ring system containing at least 1 C = C bond, and in which a CH2 group of the ring can be replaced by a group C = OR.

“Cicloalquilo de Cp–q” es un sistema anulares carbociclilo monocíclico, bicíclico o tricíclico, saturado, y en el que un grupo CH2 del anillo puede ser reemplazado por un grupo C=O. "Cp-q cycloalkyl" is a saturated monocyclic, bicyclic or tricyclic carbocyclyl ring system, and in which a ring CH2 group can be replaced by a C = O group.

“Heterociclilo” es un sistema anulares monocíclico, bicíclico o tricíclico, saturado, insaturado o parcialmente saturado, que contiene de 3 a 14 átomos en el , de los cuales 1, 2, 3 ó 4 átomos anulares se escogen de nitrógeno, azufre u oxígeno, anillo el cual puede estar enlazado mediante carbono o nitrógeno, y en el que un átomo de "Heterocyclyl" is a monocyclic, bicyclic or tricyclic ring system, saturated, unsaturated or partially saturated, containing from 3 to 14 atoms in which 1, 2, 3 or 4 ring atoms are chosen from nitrogen, sulfur or oxygen , ring which can be linked by carbon or nitrogen, and in which an atom of

nitrógeno o azufre del anillo puede estar oxidado, y en el que un grupo CH2 del anillo puede ser reemplazado por un grupo C=O. “Heterociclilo” incluye “heteroarilo”, “cicloheteroalquilo” y “cicloheteroalquenilo”. nitrogen or sulfur of the ring may be oxidized, and in which a group CH2 of the ring may be replaced by a group C = O. "Heterocyclyl" includes "heteroaryl", "cycloheteroalkyl" and "cycloheteroalkenyl".

“Heteroarilo” es un heterociclilo monocíclico, bicíclico o tricíclico, aromático, que tiene particularmente de 5 a 10 átomos anulares, de los cuales 1, 2, 3 ó 4 átomos anulares se escogen de nitrógeno, azufre u oxígeno, en el que un nitrógeno o azufre anular puede estar oxidado. "Heteroaryl" is a monocyclic, bicyclic or tricyclic, aromatic heterocyclyl, having in particular 5 to 10 ring atoms, of which 1, 2, 3 or 4 ring atoms are chosen from nitrogen, sulfur or oxygen, in which a nitrogen or ring sulfur may be oxidized.

“Cicloheteroalquenilo” es un sistema anular heterociclilo monocíclico, bicíclico o tricíclico, insaturado o parcialmente saturado, que tiene particularmente de 5 a 10 átomos anulares, de los cuales 1, 2, 3 ó 4 átomos anulares se escogen de nitrógeno, azufre u oxígeno, dicho anillo puede estar enlazado mediante carbono o nitrógeno, y en el que un átomo de nitrógeno o azufre anular puede estar oxidado, y en el que un grupo CH2 del anillo puede ser reemplazado por un grupo C=O. "Cycloheteroalkenyl" is a monocyclic, bicyclic or tricyclic, unsaturated or partially saturated heterocyclyl ring system, which in particular has 5 to 10 ring atoms, of which 1, 2, 3 or 4 ring atoms are chosen from nitrogen, sulfur or oxygen, said ring may be linked by carbon or nitrogen, and in which an annular nitrogen or sulfur atom may be oxidized, and in which a CH2 group of the ring may be replaced by a group C = O.

“Cicloheteroalquilo” es un sistema anular heterocíclico monocíclico, bicíclico o tricíclico, saturado, que tiene particularmente de 5 a 10 átomos anulares, de los cuales 1, 2, 3 ó 4 átomos del anillo se escogen de nitrógeno, azufre u oxígeno, dicho anillo puede estar enlazado mediante carbono o nitrógeno, y en el que un átomo de nitrógeno o azufre del anillo puede estar oxidado, y en el que un grupo CH2 del anillo puede ser reemplazado por un grupo C=O. "Cycloheteroalkyl" is a saturated monocyclic, bicyclic or tricyclic heterocyclic ring system, which has in particular 5 to 10 ring atoms, of which 1, 2, 3 or 4 ring atoms are chosen from nitrogen, sulfur or oxygen, said ring it can be linked by carbon or nitrogen, and in which a nitrogen or sulfur atom of the ring can be oxidized, and in which a CH2 group of the ring can be replaced by a group C = O.

Esta memoria descriptiva puede hacer uso de términos compuestos para describir grupos que comprenden más de una funcionalidad. Excepto que se describa de otro modo aquí, tales términos se han de interpretar como se entienden en la técnica. Por ejemplo, carbociclil-alquilo de Cp–q comprende alquilo de Cp–q sustituido con carbociclilo, heterociclil-alquilo de Cp–q comprende alquilo de Cp–q sustituido con heterociclilo, y bis(alquil Cp–q)amino comprende amino sustituido con 2 grupos alquilo de Cp–q los cuales pueden ser iguales o diferentes. This specification can make use of compound terms to describe groups that comprise more than one functionality. Except as otherwise described herein, such terms are to be interpreted as understood in the art. For example, Cp-q carbocyclyl-alkyl comprises Cp-q alkyl substituted with carbocyclyl, heterocyclyl-Cp-q alkyl comprises Cp-q alkyl substituted with heterocyclyl, and bis (Cp-q) alkyl amino comprises amino substituted with 2 Cp-q alkyl groups which may be the same or different.

Halo-alquilo de Cp–q es un grupo alquilo de Cp–q que está sustituido con 1 o más sustituyentes halo, y particularmente 1, 2 ó 3 sustituyentes halo. De manera similar, otros términos genéricos que contienen halo, tales como halo-alcoxi de Cp–q, pueden contener 1 o más sustituyentes halo, y particularmente 1, 2 ó 3 sustituyentes halo. Cp-q halo-alkyl is a Cp-q alkyl group that is substituted with 1 or more halo substituents, and particularly 1, 2 or 3 halo substituents. Similarly, other generic halo-containing terms, such as halo-Cp-q alkoxy, may contain 1 or more halo substituents, and particularly 1, 2 or 3 halo substituents.

Hidroxi-alquilo de Cp–q es un grupo alquilo de Cp–q que está sustituido con 1 o más sustituyentes hidroxilo, y particularmente por 1, 2 ó 3 sustituyentes hidroxi. De manera similar, otros términos genéricos que contienen hidroxi, tales como hidroxi-alcoxi de Cp–q, pueden contener 1 o más y está particularmente 1, 2 ó 3 sustituyentes hidroxi. Cp-q hydroxy-alkyl is a Cp-q alkyl group that is substituted with 1 or more hydroxyl substituents, and particularly with 1, 2 or 3 hydroxy substituents. Similarly, other generic hydroxy-containing terms, such as Cp-q hydroxy-alkoxy, may contain 1 or more and is particularly 1, 2 or 3 hydroxy substituents.

Alcoxi Cp–q-alquilo de Cp–q es un grupo alquilo de Cp–q que está sustituido con 1 o más sustituyentes alcoxi de Cp–q, y particularmente 1, 2 ó 3 sustituyentes alcoxi de Cp–q. De manera similar, otros términos genéricos que contienen alcoxi de Cp–q, tales como alcoxi Cp–q-alcoxi de Cp–q, pueden contener 1 o más sustituyentes alcoxi de Cp–q y particularmente 1, 2 ó 3 sustituyentes alcoxi de Cp–q. Cp-q-Cp-q alkoxy is a Cp-q alkyl group that is substituted with 1 or more Cp-q alkoxy substituents, and particularly 1, 2 or 3 Cp-q alkoxy substituents. Similarly, other generic terms containing Cp-q alkoxy, such as Cp-q-alkoxy of Cp-q, may contain 1 or more Cp-alkoxy substituents and particularly 1, 2 or 3 Cp alkoxy substituents q.

Cuando se escogen sustituyentes opcionales de “1 ó 2”, de “1, 2 ó 3” o de “1, 2, 3 ó 4” grupos o sustituyentes, se entiende que esta definición incluye todos los sustituyentes que se escogen de uno de los grupos especificados, es decir, todos los sustituyentes que son iguales o los sustituyentes que se escogen de dos o más de los grupos especificados, es decir, los sustituyentes que no son iguales. When optional substituents of "1 or 2", "1, 2 or 3" or "1, 2, 3 or 4" groups or substituents are chosen, it is understood that this definition includes all substituents chosen from one of the specified groups, that is, all the substituents that are the same or the substituents that are chosen from two or more of the specified groups, that is, the substituents that are not equal.

“Una enfermedad proliferativa” incluye enfermedades malignas tales como cáncer, así como enfermedades no maligna(s), tales como enfermedades inflamatorias, enfermedades obstructivas de las vías respiratorias, enfermedades inmunitarias o enfermedades cardiovasculares. "A proliferative disease" includes malignant diseases such as cancer, as well as non-malignant diseases (s), such as inflammatory diseases, obstructive diseases of the respiratory tract, immune diseases or cardiovascular diseases.

Los valores adecuados para cualquier grupo R o cualquier parte o sustituyente para tales grupos incluyen: Suitable values for any R group or any part or substituent for such groups include:

para alquilo de C1-4: metilo, etilo, propilo, butilo, 2–metilpropilo y terc–butilo; for C1-4 alkyl: methyl, ethyl, propyl, butyl, 2-methylpropyl and tert-butyl;

para alquilo de C1-6: alquilo de C1-4, pentilo, 2,2–dimetilpropilo, 3–metilbutilo y hexilo; for C1-6 alkyl: C1-4 alkyl, pentyl, 2,2-dimethylpropyl, 3-methylbutyl and hexyl;

para cicloalquilo de C3-6: for C3-6 cycloalkyl:: ciclopropilo, ciclobutilo, ciclopentilo y ciclohexilo; cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;

para cicloalquil C3-6-alquilo de C1-4: For C3-6 cycloalkyl-C1-4alkyl:: ciclopropilmetilo, ciclopropiletilo, ciclobutilmetilo, ciclopentilmetilo y cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl Y

ciclohexilmetilo; cyclohexylmethyl;

para arilo: for arilo:: fenilo y naftilo; phenyl and naphthyl;

para aril-alquilo de C1-4: for C1-4 aryl-alkyl:: bencilo, fenetilo, naftilmetilo y naftiletilo; benzyl, phenethyl, naphthylmethyl and naphthylethyl;

para carbocililo: for carbocyl:: arilo, ciclohexenilo y cicloalquilo de C3-6; C3-6 aryl, cyclohexenyl and cycloalkyl;

para halo: for halo:: fluoro, cloro, bromo y yodo; fluoro, chloro, bromo and iodo;

para alcoxi de C1-4: for C1-4 alkoxy:: metoxi, etoxi, propoxi e isopropoxi; methoxy, ethoxy, propoxy and isopropoxy;

para alcoxi de C1-6: for C1-6 alkoxy:: alcoxi de C1-4, pentiloxi, 1–etilpropoxi y hexiloxi; C1-4 alkoxy, pentyloxy, 1-ethylpropoxy and hexyloxy;

para alcanoilo de C1-6: acetilo, propanoilo y 2–metilpropanoilo; for C1-6 alkanoyl: acetyl, propanoyl and 2-methylpropanoyl;

para heteroarilo: piridilo, imidazolilo, quinolinilo, cinolilo, pirimidinilo, tienilo, pirrolilo, pirazolilo, tiazolilo, triazolilo, oxazolilo, isoxazolilo, furanilo, piridazinilo, pirazinilo, indolilo, benzofuranilo, dibenzofuranilo y benzotienilo; for heteroaryl: pyridyl, imidazolyl, quinolinyl, cinolyl, pyrimidinyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, triazolyl, oxazolyl, isoxazolyl, furanyl, pyridazinyl, pyrazinyl, indolyl, benzofuranyl, dibenzofuranyl and benzothienyl;

para heteroaril-alquilo de C1-4: pirrolilmetilo, pirroliletilo, imidazolinetilo, imidazoliletilo, pirazolilmetilo, pirazoliletilo, furanilmetilo, furaniletilo, tienilmetilo, tieniletilo, piridilmetilo, piridiletilo, pirazinilinetilo, piraziniletilo, pirimidinilmetilo, pirimidiniletilo, pirimidinilpropilo, pirimidinilbutilo, imidazolilpropilo, imidazolilbutilo, quinolinilpropilo, 1,3,4–triazolilpropilo y oxazolilmetilo; for heteroaryl- C1-4alkyl: pyrrolylmethyl, pyrrolylethyl, imidazolinetilo, imidazolylethyl, pyrazolylmethyl, pyrazolylethyl, furanylmethyl, furanylethyl, thienylmethyl, thienylethyl, pyridylmethyl, pyridylethyl, pirazinilinetilo, pyrazinylethyl, pyrimidinylmethyl, pyrimidinylethyl, pirimidinilpropilo, pirimidinilbutilo, imidazolylpropyl, imidazolylbutyl, quinolinylpropyl , 1,3,4-triazolylpropyl and oxazolylmethyl;

para heterociclilo: heteroarilo, pirrolidinilo, isoquinolinilo, quinoxalinilo, benzotiazolilo, benzoxazolilo, piperidinilo, piperazinilo, azetidinilo, morfolinilo, tetrahidroisoquinolinilo, tetrahidroquinolinilo, indolinilo, dihidro–2H–piranilo y tetrahidrofuranilo. for heterocyclyl: heteroaryl, pyrrolidinyl, isoquinolinyl, quinoxalinyl, benzothiazolyl, benzoxazolyl, piperidinyl, piperazinyl, azetidinyl, morpholinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, indolinyl, dihydro-2H-pyranyl and tetrahydrofuryl.

Se debe señalar que los ejemplos dados para los términos usados en la descripción no están limitados. It should be noted that the examples given for the terms used in the description are not limited.

Los valores particulares de m, X, 1Y e Y2, R1, R2 y R3 son los siguientes. Tales valores se pueden usar cuando sea apropiado, en relación con cualquier aspecto de la invención, o parte de la misma, y con cualquiera de las definiciones, reivindicaciones o realizaciones definidas aquí. The particular values of m, X, 1Y and Y2, R1, R2 and R3 are as follows. Such values may be used when appropriate, in relation to any aspect of the invention, or part thereof, and with any of the definitions, claims or embodiments defined herein.

m m

En un aspecto de la invención, m es 0, 1, 2 ó 3. En otro aspecto, m es 0, 1 ó 2. En un aspecto adicional, m es 0 ó 1. En aún otro aspecto, m es 0 de manera que R3 está ausente. En aún otro aspecto, m es 1 y R3 es metilo. In one aspect of the invention, m is 0, 1, 2 or 3. In another aspect, m is 0, 1 or 2. In a further aspect, m is 0 or 1. In yet another aspect, m is 0 so that R3 is absent. In yet another aspect, m is 1 and R3 is methyl.

1Y and Y2

En un aspecto de la invención, 1Y es N e Y2 es CR8. En otro aspecto, 1Y es N e Y2 es CH. En aún otro aspecto, 1Y es CR8 e Y2 es N. En un aspecto adicional, 1Y es CH o CF e Y2 es N. En aún un aspecto adicional, 1Y es CH e Y2 es N. In one aspect of the invention, 1Y is N and Y2 is CR8. In another aspect, 1Y is N and Y2 is CH. In yet another aspect, 1Y is CR8 and Y2 is N. In a further aspect, 1Y is CH or CF and Y2 is N. In still an additional aspect, 1Y is CH and Y2 is N.

X X

En un aspecto de la invención, X es un grupo enlazador seleccionado de –NR4CR6R7–, –OCR6R7–, –SCR6R7–, -S(O)CR6R7–, –S(O)2CR6R7–, –C(O)NR4CR6R7–, –NR4C(O)NR5CR6R7–, –S(O)2NR4CR6R7–, –NR4C(O)–, -C(O)NR4-, –S(O)2NR4– y -NR4S(O)2–. In one aspect of the invention, X is a linker group selected from –NR4CR6R7–, –OCR6R7–, –SCR6R7–, -S (O) CR6R7–, –S (O) 2CR6R7–, –C (O) NR4CR6R7–, –NR4C (O) NR5CR6R7–, –S (O) 2NR4CR6R7–, –NR4C (O) -, -C (O) NR4-, –S (O) 2NR4– and -NR4S (O) 2–.

En otro aspecto, X es un grupo enlazador seleccionado de –NR4CR6R7–, –OCR6R7–, -SCR6R7–, –S(O)CR6R7–, -S(O)2CR6R7–, –C(O)NR4CR6R7–, –NR4C(O)NR5CR6R7–, -S(O)2NR4CR6R7, –C(O)NR4– y –NR4C(O)–. In another aspect, X is a linker group selected from –NR4CR6R7–, –OCR6R7–, -SCR6R7–, –S (O) CR6R7–, -S (O) 2CR6R7–, –C (O) NR4CR6R7–, –NR4C ( O) NR5CR6R7–, -S (O) 2NR4CR6R7, –C (O) NR4– and –NR4C (O) -.

En un aspecto adicional, X es un grupo enlazador seleccionado de –NR4CR6R7–, -OCR6R7–, –SCR6R7–, -S(O)CR6R7–, –S(O)2CR6R7–, –C(O)NR4–, y –NR4C(O)–. In a further aspect, X is a linker group selected from –NR4CR6R7–, -OCR6R7–, –SCR6R7–, -S (O) CR6R7–, –S (O) 2CR6R7–, –C (O) NR4–, and - NR4C (O) -.

En un aspecto adicional, X es un grupo enlazador seleccionado de –NR4CR6R7–, -OCR6R7–, –SCR6R7–, -S(O)CR6R7– y –S(O)2CR6R7–. In a further aspect, X is a linker group selected from –NR4CR6R7–, -OCR6R7–, –SCR6R7–, -S (O) CR6R7– and –S (O) 2CR6R7–.

En aún otro aspecto, X es un grupo enlazador seleccionado de –SCR6R7–, -S(O)CR6R7– y –S(O)2CR6R7–. In yet another aspect, X is a linker group selected from –SCR6R7–, -S (O) CR6R7– and –S (O) 2CR6R7–.

En otro aspecto, X es un grupo enlazador seleccionado de –NR4CH2–, –OCH2–, -OCH(CH3)–, –OC(CH3)2–, –SCH2–, –SCH(CH3)–, –SC(CH3)2–, –S(O)CH2–, -S(O)CH(CH3)–, –S(O)C(CH3)2–, –S(O)2CH2–, –S(O)2CH(CH3)–, -S(O)2C(CH3)2–, -C(O)NR4–y –NR4C(O)–. In another aspect, X is a linker group selected from –NR4CH2–, –OCH2–, -OCH (CH3) -, –OC (CH3) 2–, –SCH2–, –SCH (CH3) -, –SC (CH3) 2–, –S (O) CH2–, -S (O) CH (CH3) -, –S (O) C (CH3) 2–, –S (O) 2CH2–, –S (O) 2CH (CH3 ) -, -S (O) 2C (CH3) 2–, -C (O) NR4 – and –NR4C (O) -.

En otro aspecto, X es un grupo enlazador seleccionado de –NR4CH2–, –OCH2–, -SCH2–, –S(O)CH2–, –S(O)2CH2–, -C(O)NR4–, y –NR4C(O)–. In another aspect, X is a linker group selected from –NR4CH2–, –OCH2–, -SCH2–, –S (O) CH2–, –S (O) 2CH2–, -C (O) NR4–, and –NR4C (OR)-.

En otro aspecto, X es un grupo enlazador seleccionado de –NR4CH2–, –OCH2–, -OCH(CH3)–, –OC(CH3)2–, –SCH2–, –SCH(CH3)–, –SC(CH3)2–, –S(O)CH2–, -S(O)CH(CH3)–, –S(O)C(CH3)2–, –S(O)2CH2–, –S(O)2CH(CH3)– y -S(O)2C(CH3)2–. In another aspect, X is a linker group selected from –NR4CH2–, –OCH2–, -OCH (CH3) -, –OC (CH3) 2–, –SCH2–, –SCH (CH3) -, –SC (CH3) 2–, –S (O) CH2–, -S (O) CH (CH3) -, –S (O) C (CH3) 2–, –S (O) 2CH2–, –S (O) 2CH (CH3 ) - and -S (O) 2C (CH3) 2–.

En otro aspecto, X es un grupo enlazador seleccionado de –NR4CH2–, –OCH2–, -SCH2–, –S(O)CH2– y –S(O)2CH2–. In another aspect, X is a linker group selected from –NR4CH2–, –OCH2–, -SCH2–, –S (O) CH2– and –S (O) 2CH2–.

En un aspecto adicional, X es un grupo enlazador seleccionado de –NHCH2–, -N(CH3)CH2–, –OCH2–, –OCH(CH3)–, –OC(CH3)2–, –SCH2–, –SCH(CH3)–, –SC(CH3)2–, -S(O)CH2–, –S(O)CH(CH3)–, –S(O)C(CH3)2–, –S(O)2CH2–, -S(O)2CH(CH3)–, -S(O)2C(CH3)2–, –C(O)NH–, –C(O)N(CH3)–, –NHC(O)– y –N(CH3)C(O)–. In a further aspect, X is a linker group selected from –NHCH2–, -N (CH3) CH2–, –OCH2–, –OCH (CH3) -, –OC (CH3) 2–, –SCH2–, –SCH ( CH3) -, –SC (CH3) 2–, -S (O) CH2–, –S (O) CH (CH3) -, –S (O) C (CH3) 2–, –S (O) 2CH2– , -S (O) 2CH (CH3) -, -S (O) 2C (CH3) 2–, –C (O) NH–, –C (O) N (CH3) -, –NHC (O) - and –N (CH3) C (O) -.

En un aspecto adicional, X es un grupo enlazador seleccionado de –NHCH2–, -N(CH3)CH2–, –OCH2–, –SCH2–, -S(O)CH2–, –S(O)2CH2–, –C(O)NH–, –C(O)N(CH3)–, -NHC(O)– y –N(CH3)C(O)–. In a further aspect, X is a linker group selected from –NHCH2–, -N (CH3) CH2–, –OCH2–, –SCH2–, -S (O) CH2–, –S (O) 2CH2–, –C (O) NH–, –C (O) N (CH3) -, -NHC (O) - and –N (CH3) C (O) -.

En aún un aspecto adicional, X es un grupo enlazador seleccionado de –NHCH2–, -N(CH3)CH2–, –OCH2–, -OCH(CH3)–, –OC(CH3)2–, –SCH2–, –SCH(CH3)–, –SC(CH3)2–, -S(O)CH2–, –S(O)CH(CH3)–, –S(O)C(CH3)2–, -S(O)2CH2–, –S(O)2CH(CH3)– y –S(O)2C(CH3)2–. In still a further aspect, X is a linker group selected from –NHCH2–, -N (CH3) CH2–, –OCH2–, -OCH (CH3) -, –OC (CH3) 2–, –SCH2–, –SCH (CH3) -, –SC (CH3) 2–, -S (O) CH2–, –S (O) CH (CH3) -, –S (O) C (CH3) 2–, -S (O) 2CH2 -, –S (O) 2CH (CH3) - and –S (O) 2C (CH3) 2–.

En aún un aspecto adicional, X es un grupo enlazador seleccionado de –NHCH2–, -N(CH3)CH2–, –OCH2–, –SCH2– y –S(O)2CH2–. In still a further aspect, X is a linker group selected from –NHCH2–, -N (CH3) CH2–, –OCH2–, –SCH2– and –S (O) 2CH2–.

En otro aspecto, X es –SCH2– o –S(O)2CH2–. In another aspect, X is –SCH2– or –S (O) 2CH2–.

En otro aspecto, X es –SCH2–, –SCH(CH3)– o –SC(CH3)2–. In another aspect, X is –SCH2–, –SCH (CH3) - or –SC (CH3) 2–.

En otro aspecto, X es –S(O)CH2–, –S(O)CH(CH3)– o –S(O)C(CH3)2–. In another aspect, X is –S (O) CH2–, –S (O) CH (CH3) - or –S (O) C (CH3) 2–.

En otro aspecto, X es –S(O)2CH2–, –S(O)2CH(CH3)– o –S(O)2C(CH3)2–. In another aspect, X is –S (O) 2CH2–, –S (O) 2CH (CH3) - or –S (O) 2C (CH3) 2–.

En otro aspecto, X es –S(O)2CH2–. In another aspect, X is –S (O) 2CH2–.

En otro aspecto, X es –S(O)2C(CH3)z–. In another aspect, X is –S (O) 2C (CH3) z–.

R1 R1

En un aspecto de la invención, R1 es un grupo seleccionado de alquilo de C1-4, cicloalquilo de C3–10, arilo, cicloalquil C3–10-alquilo de C1-4, aril-alquilo de C1-4, cicloheteroalquilo, heteroarilo, cicloheteroalquil-alquilo de C1-4, heteroarilalquilo de C1-4, estando dicho grupo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, R9, –OR9, -COR9, –CONR9R10, –NR9R10 y –NR9COR10. In one aspect of the invention, R 1 is a group selected from C 1-4 alkyl, C 3-10 cycloalkyl, aryl, C 3-10 cycloalkyl-C 1-4 alkyl, aryl-C 1-4 alkyl, cycloheteroalkyl, heteroaryl, C 1-4 cycloheteroalkyl-alkyl, C 1-4 heteroarylalkyl, said group being optionally substituted with one or more substituent groups selected from halo, cyano, nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R10 and -NR9COR10.

En otro aspecto, R1 es un grupo seleccionado de adamantilo, metilo, etilo, propilo, butilo, isobutilo, terc–butilo, ciclopentilo, ciclohexilo, fenilo, bencilo, oxetanilo, fenetilo, pirrolidinilo, pirrolilo, imidazolilo, pirazolilo, furanilo, tienilo, piridinilo, pirimidinilo, pirazinilo, pirrolidinilmetilo, pirrolidiniletilo, pirrolilmetilo, pirroliletilo, imidazolilmetilo, imidazoliletilo, pirazolilmetilo, pirazoliletilo, furanilmetilo, furaniletilo, tienilmetilo, tieniletilo, piridinilmetilo, piridiniletilo, pirimidinilmetilo, pirimidiniletilo, pirazinilmetilo y piraziniletilo, estando dicho grupo opcionalmente sustituido con 1, 2 ó 3 grupos sustituyentes seleccionados de halo, ciano, nitro, R9, –OR9, –COR9, –CONR9R10, –NR9R10 y –NR9COR10. In another aspect, R 1 is a group selected from adamantyl, methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, oxetanyl, phenethyl, pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolidinylmethyl, pyrrolidinylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, pyrazolylmethyl, pyrazolylethyl, furanylmethyl, furanylethyl, thienylmethyl, thienylethyl, pyridinylmethyl, pyridinyl ethyl, pyridinyl ethyl, pyridinyl ethyl group 2 or 3 substituent groups selected from halo, cyano, nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R10 and -NR9COR10.

En otro aspecto, R1 es un grupo seleccionado de adamantilo, metilo, etilo, propilo, butilo, isobutilo, terc–butilo, ciclopentilo, ciclohexilo, fenilo, bencilo, fenetilo, pirrolidinilo, pirrolilo, imidazolilo, pirazolilo, furanilo, tienilo, piridinilo, pirimidinilo, pirazinilo, pirrolidinilmetilo, pirrolidiniletilo, pirrolilmetilo, pirroliletilo, imidazolilmetilo, imidazoliletilo, pirazolilmetilo, pirazoliletilo, furanilmetilo, furaniletilo, tienilmetilo, tieniletilo, piridinilmetilo, piridiniletilo, pirimidinilmetilo, pirimidiniletilo, pirazinilmetilo y piraziniletilo, estando dicho grupo opcionalmente sustituido con 1, 2 ó 3 grupos sustituyentes seleccionados de halo, ciano, nitro, R9, –OR9, –COR9, -CONR9R10, –NR9R10 y –NR9COR10. In another aspect, R 1 is a group selected from adamantyl, methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, phenethyl, pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolidinylmethyl, pyrrolidinylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, pyrazolylmethyl, pyrazolylethyl, furanylmethyl, furanylethyl, thienylmethyl, thienylethyl, pyridinylmethyl, pyridinylmethyl, pyriminylmethyl, substituted 1-pyriminyl ethyl, pyriminylmethyl group 3 substituent groups selected from halo, cyano, nitro, R9, –OR9, –COR9, -CONR9R10, –NR9R10 and –NR9COR10.

En un aspecto adicional, R1 es un grupo seleccionado de metilo, etilo, propilo, butilo, isobutilo, terc–butilo, ciclopropilo, ciclopentilo, ciclohexilo, fenilo, bencilo, fenetilo, piridinilo, pirrolidinilo, pirazoliletilo, furanilmetilo, oxetanilo, imidazolilmetilo, tienilmetilo, tiazolilmetilo, tiadiazolilmetilo y piraziniletilo, estando dicho grupo opcionalmente sustituido con 1 ó 2 grupos sustituyentes seleccionados de amino, halo, ciano, metilo, metoxi, trifluorometilo, trifluorometoxi, –NMe2, –NHCOCH3, –CONH2 y –CONHCH3. In a further aspect, R 1 is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, benzyl, phenethyl, pyridinyl, pyrrolidinyl, pyrazolylethyl, furanylmethyl, oxetanyl, imidazolylmethyl, thienyl , thiazolylmethyl, thiadiazolylmethyl and pyrazinylethyl, said group being optionally substituted with 1 or 2 substituent groups selected from amino, halo, cyano, methyl, methoxy, trifluoromethyl, trifluoromethoxy, -NMe2, -NHCOCH3, -CONH2 and -CONHCH3.

En un aspecto adicional, R1 es un grupo seleccionado de metilo, etilo, propilo, butilo, isobutilo, terc–butilo, ciclopropilo, ciclopentilo, ciclohexilo, fenilo, bencilo, fenetilo, piridinilo, pirazoliletilo, furanilmetilo, tienilmetilo, tiazolilmetilo, tiadiazolilmetilo y piraziniletilo, estando dicho grupo opcionalmente sustituido con 1 ó 2 grupos sustituyentes seleccionados de amino, halo, ciano, metilo, metoxi, trifluorometilo, trifluorometoxi, –NHCOCH3, -CONH2 y –CONHCH3. In a further aspect, R 1 is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, benzyl, phenethyl, pyridinyl, pyrazolylethyl, furanylmethyl, thienylmethyl, thiazolylmethyl, thiadiazolylmethyl and pyrazylmethyl , said group being optionally substituted with 1 or 2 substituent groups selected from amino, halo, cyano, methyl, methoxy, trifluoromethyl, trifluoromethoxy, -NHCOCH3, -CONH2 and -CONHCH3.

En otro aspecto, R1 es un grupo seleccionado de metilo, etilo, isopropilo, ciclopropilo, ciclohexilo, –CH2CH2OH, -CH2CH2NC(O)CH3, fenilo, 4–fluorofenilo, 2–clorofenilo, 2–trifluorometilfenilo, 2–metoxifenilo, 2–metilfenilo, 4-acetamidofenilo, 4–aminofenilo, piridin–4–ilo, piridin–2–ilo, 2–oxopirolidin–3–ilo, tiazol–2–ilo, 4–metiltiazol–2–ilo, y 3–metil–1,3,4–tiadiazol–2–ilo. In another aspect, R1 is a group selected from methyl, ethyl, isopropyl, cyclopropyl, cyclohexyl, -CH2CH2OH, -CH2CH2NC (O) CH3, phenyl, 4-fluorophenyl, 2-chlorophenyl, 2-trifluoromethylphenyl, 2-methoxyphenyl, 2– methylphenyl, 4-acetamidophenyl, 4-aminophenyl, pyridin-4-yl, pyridin-2-yl, 2-oxopyrolidin-3-yl, thiazole-2-yl, 4-methylthiazole-2-yl, and 3-methyl-1 , 3,4-thiadiazol-2-yl.

En aún otro aspecto, R1 es un grupo seleccionado de metilo, isopropilo, ciclopropilo, ciclohexilo, –CH2CH2OH, -CH2CH2NC(O)CH3, –CH2CONH2, fenilo, 4–fluorofenilo, 2–clorofenilo, 2–trifluorometilfenilo, 2–metoxifenilo, 2-metilfenilo, 4–acetamidofenilo, 4–aminofenilo, piridin–4–ilo, piridin–2–ilo, 2–oxopirolidin–3–ilo, tiazol–2–ilo, 4-metiltiazol–2–ilo, y 3–metil–1,3,4–tiadiazol–2–ilo. In yet another aspect, R1 is a group selected from methyl, isopropyl, cyclopropyl, cyclohexyl, -CH2CH2OH, -CH2CH2NC (O) CH3, -CH2CONH2, phenyl, 4-fluorophenyl, 2-chlorophenyl, 2-trifluoromethylphenyl, 2-methoxyphenyl, 2-methylphenyl, 4-acetamidophenyl, 4-aminophenyl, pyridin-4-yl, pyridin-2-yl, 2-oxopyrolidin-3-yl, thiazole-2-yl, 4-methylthiazole-2-yl, and 3-methyl –1,3,4 – thiadiazole – 2 – yl.

En aún otro aspecto, R1 es un grupo seleccionado de metilo, etilo, isopropilo, terc–butilo, ciclopropilo, ciclopentilo, ciclohexilo, –CH2CH2OH, –CH2CH2OMe, –CH2CH2NMe2, –CH2CH2NC(O)CH3, –CH2CONH2, fenilo, 3,5-difluorofenilo, 4–fluorofenilo, 2–clorofenilo, 4–clorofenilo, 2–trifluorometilfenilo, 2–metoxifenilo, 2–metilfenilo, 4–acetamidofenilo, 4-aminofenilo, piridin–4–ilo, piridin–2–ilo, oxetan–3–ilo, 2–oxopirolidin–3–ilo, 1–metilimidazol–5–ilmetilo, 1-metilpirrolidin–3–ilo, tiazol–2–ilo, 4–metiltiazol–2–ilo, y 3–metil–1,3,4–tiadiazol–2–ilo. In yet another aspect, R1 is a group selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, -CH2CH2OH, -CH2CH2OMe, -CH2CH2NMe2, -CH2CH2NC (O) CH3, -CH2CONH2, phenyl, 3, 5-Difluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 4-chlorophenyl, 2-trifluoromethylphenyl, 2-methoxyphenyl, 2-methylphenyl, 4-acetamidophenyl, 4-aminophenyl, pyridin-4-yl, pyridin-2-yl, oxetan– 3-yl, 2-oxopyrolidin-3-yl, 1-methylimidazol-5-ylmethyl, 1-methylpyrrolidin-3-yl, thiazol-2-yl, 4-methylthiazole-2-yl, and 3-methyl-1,3 , 4-thiadiazol-2-yl.

En otro aspecto, R1 es metilo, etilo, isopropilo, terc–butilo, 4–fluorofenilo, 3,5–difluorofenilo, piridin–4–ilo o ciclopropilo. In another aspect, R1 is methyl, ethyl, isopropyl, tert-butyl, 4-fluorophenyl, 3,5-difluorophenyl, pyridin-4-yl or cyclopropyl.

En otro aspecto, R1 es metilo, etilo, isopropilo, terc–butilo, 4–fluorofenilo, piridin–4–ilo o ciclopropilo. In another aspect, R1 is methyl, ethyl, isopropyl, tert-butyl, 4-fluorophenyl, pyridin-4-yl or cyclopropyl.

En otro aspecto, R1 es metilo o ciclopropilo. In another aspect, R1 is methyl or cyclopropyl.

En otro aspecto, R1 es metilo. In another aspect, R1 is methyl.

X – R1

En una realización, X–R1 es –C(CH3)2OH o –CH2OH. In one embodiment, X-R1 is -C (CH3) 2OH or -CH2OH.

En una realización, X–R1 es –CH2OH. In one embodiment, X-R1 is -CH2OH.

R2 R2

En un aspecto de la invención, R2 se selecciona de carbociclilo o heterociclilo, estando dicho grupo sustituido con -NR17CONR18R19 y opcionalmente sustituido con uno o más grupos sustituyentes seleccionados independientemente de halo, ciano, nitro, –R11, –OR11, -COR11, –CONR11R12, –NR11R12 y –NR11COR12. In one aspect of the invention, R2 is selected from carbocyclyl or heterocyclyl, said group being substituted with -NR17CONR18R19 and optionally substituted with one or more substituent groups independently selected from halo, cyano, nitro, -R11, -OR11, -COR11, - CONR11R12, –NR11R12 and –NR11COR12.

En un aspecto de la invención, R2 se selecciona de carbociclilo o heterociclilo, estando dicho grupo sustituido con -NHCONR18R19 y opcionalmente sustituido con uno o más grupos sustituyentes seleccionados independientemente de halo, ciano, nitro, –R11, –OR11, –COR11, -CONR11R12, –NR11R12 y –NR11COR12. In one aspect of the invention, R2 is selected from carbocyclyl or heterocyclyl, said group being substituted with -NHCONR18R19 and optionally substituted with one or more substituent groups independently selected from halo, cyano, nitro, -R11, -OR11, -COR11, - CONR11R12, –NR11R12 and –NR11COR12.

En un aspecto de la invención, R2 se selecciona de carbociclilo o heterociclilo, estando dicho grupo sustituido con -NHCONHR19 y opcionalmente sustituido con uno o más grupos sustituyentes seleccionados independientemente de halo, ciano, nitro, –R11, –OR11, –COR11, -CONR11R12, –NR11R12 y –NR11COR12. In one aspect of the invention, R2 is selected from carbocyclyl or heterocyclyl, said group being substituted with -NHCONHR19 and optionally substituted with one or more substituent groups independently selected from halo, cyano, nitro, -R11, -OR11, -COR11, - CONR11R12, –NR11R12 and –NR11COR12.

En un aspecto de la invención, R2 se selecciona de carbociclilo o heterociclilo de 5 ó 6 miembros, estando dicho grupo sustituido con –NR17CONR18R19 y opcionalmente sustituido con uno o más grupos sustituyentes seleccionados independientemente de halo, ciano, nitro, -R11, –OR11, –COR11, –CONR11R12, –NR11R12 y – NR11COR12. In one aspect of the invention, R2 is selected from 5 or 6 membered carbocyclyl or heterocyclyl, said group being substituted with -NR17CONR18R19 and optionally substituted with one or more substituent groups independently selected from halo, cyano, nitro, -R11, -OR11 , –COR11, –CONR11R12, –NR11R12 and - NR11COR12.

En un aspecto de la invención, R2 se selecciona de carbociclilo o heterociclilo de 5 ó 6 miembros, estando dicho grupo sustituido con –NHCONR18R19 y opcionalmente sustituido con uno o más grupos sustituyentes seleccionados independientemente de halo, ciano, nitro, –R11, –OR11, –COR11, –CONR11R12, –NR11R12 y –NR11COR12. In one aspect of the invention, R2 is selected from 5 or 6 membered carbocyclyl or heterocyclyl, said group being substituted with -NHCONR18R19 and optionally substituted with one or more substituent groups independently selected from halo, cyano, nitro, -R11, -OR11 , –COR11, –CONR11R12, –NR11R12 and –NR11COR12.

En un aspecto de la invención, R2 se selecciona de carbociclilo o heterociclilo de 5 ó 6 miembros, estando dicho grupo sustituido con –NHCONHR19 y opcionalmente sustituido con uno o más grupos sustituyentes seleccionados independientemente de halo, ciano, nitro, –R11, –OR11, –COR11, –CONR11R12, –NR11R12 y –NR11COR12. In one aspect of the invention, R2 is selected from 5 or 6 membered carbocyclyl or heterocyclyl, said group being substituted with -NHCONHR19 and optionally substituted with one or more substituent groups independently selected from halo, cyano, nitro, -R11, -OR11 , –COR11, –CONR11R12, –NR11R12 and –NR11COR12.

En un aspecto de la invención, R2 se selecciona de un arilo de 6 miembros y heteroarilo de 5 ó 6 miembros, estando dicho grupo sustituido con –NR17CONR18R19 y opcionalmente sustituido con uno o más grupos sustituyentes seleccionados independientemente de halo, ciano, nitro, –R11, –OR11, –COR11, –CONR11R12, –NR11R12 y -NR11COR12. In one aspect of the invention, R2 is selected from a 6-membered aryl and 5 or 6-membered heteroaryl, said group being substituted with -NR17CONR18R19 and optionally substituted with one or more substituent groups independently selected from halo, cyano, nitro, - R11, –OR11, –COR11, –CONR11R12, –NR11R12 and -NR11COR12.

En un aspecto de la invención, R2 se selecciona de un arilo de 6 miembros y heteroarilo de 5 ó 6 miembros, estando dicho grupo sustituido con –NHCONR18R19 y opcionalmente sustituido con uno o más grupos sustituyentes seleccionados independientemente de halo, ciano, nitro, –R11, –OR11, –COR11, –CONR11R12, –NR11R12 y -NR11COR12. In one aspect of the invention, R2 is selected from a 6-membered aryl and 5 or 6-membered heteroaryl, said group being substituted with -NHCONR18R19 and optionally substituted with one or more substituent groups independently selected from halo, cyano, nitro, - R11, –OR11, –COR11, –CONR11R12, –NR11R12 and -NR11COR12.

En un aspecto de la invención, R2 se selecciona de un arilo de 6 miembros y heteroarilo de 5 ó 6 miembros, estando dicho grupo sustituido con –NHCONHR19 y opcionalmente sustituido con uno o más grupos sustituyentes seleccionados independientemente de halo, ciano, nitro, –R11, –OR11, –COR11, –CONR11R12, –NR11R12 y -NR11COR12. In one aspect of the invention, R2 is selected from a 6-membered aryl and 5- or 6-membered heteroaryl, said group being substituted with -NHCONHR19 and optionally substituted with one or more substituent groups independently selected from halo, cyano, nitro, - R11, –OR11, –COR11, –CONR11R12, –NR11R12 and -NR11COR12.

En otro aspecto, R2 se selecciona de fenilo, pirrolilo, imidazolilo, pirazolilo, furanilo, tienilo, piridinilo, pirimidinilo, piridazinilo y tiazolilo, estando dicho grupo sustituido con -NR17CONR18R19 y opcionalmente sustituido con uno o más grupos sustituyentes seleccionados independientemente de halo, ciano, nitro, –R11, –OR11, –COR11, – CONR11R12, -NR11R12 y –NR11COR12. In another aspect, R2 is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl and thiazolyl, said group being substituted with -NR17CONR18R19 and optionally substituted with one or more substituent groups independently selected from halo, cyano , nitro, –R11, –OR11, –COR11, - CONR11R12, -NR11R12 and –NR11COR12.

En otro aspecto, R2 se selecciona de fenilo, pirrolilo, imidazolilo, pirazolilo, furanilo, tienilo, piridinilo, pirimidinilo, piridazinilo y tiazolilo, estando dicho grupo sustituido con -NHCONR18R19 y opcionalmente sustituido con uno o más grupos sustituyentes seleccionados independientemente de halo, ciano, nitro, –R11, –OR11, –COR11, –CONR11R12, -NR11R12 y –NR11COR12. In another aspect, R2 is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl and thiazolyl, said group being substituted with -NHCONR18R19 and optionally substituted with one or more substituent groups independently selected from halo, cyano , nitro, –R11, –OR11, –COR11, –CONR11R12, -NR11R12 and –NR11COR12.

En otro aspecto, R2 se selecciona de fenilo, pirrolilo, imidazolilo, pirazolilo, furanilo, tienilo, piridinilo, pirimidinilo, piridazinilo y tiazolilo, estando dicho grupo sustituido con -NHCONHR19 y opcionalmente sustituido con uno o más grupos sustituyentes seleccionados independientemente de halo, ciano, nitro, –R11, –OR11, –COR11, –CONR11R12, -NR11R12 y –NR11COR12. In another aspect, R2 is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl and thiazolyl, said group being substituted with -NHCONHR19 and optionally substituted with one or more substituent groups independently selected from halo, cyano , nitro, –R11, –OR11, –COR11, –CONR11R12, -NR11R12 and –NR11COR12.

En otro aspecto, R2 se selecciona de fenilo, pirrolilo, imidazolilo, pirazolilo, furanilo, tienilo, piridinilo, pirimidinilo, piridazinilo y tiazolilo, estando dicho grupo sustituido con -NR17CONR18R19 y opcionalmente sustituido con uno o más grupos sustituyentes seleccionados independientemente de fluoro, metilo, metoxi, hidroximetilo, cianometilo, -CONH2, –CONHCH3 y –CON(CH3)2. In another aspect, R2 is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl and thiazolyl, said group being substituted with -NR17CONR18R19 and optionally substituted with one or more substituent groups independently selected from fluoro, methyl , methoxy, hydroxymethyl, cyanomethyl, -CONH2, -CONHCH3 and -CON (CH3) 2.

En otro aspecto, R2 se selecciona de fenilo, pirrolilo, imidazolilo, pirazolilo, furanilo, tienilo, piridinilo, pirimidinilo, piridazinilo y tiazolilo, estando dicho grupo sustituido con -NHCONR18R19 y opcionalmente sustituido con uno o más grupos sustituyentes seleccionados independientemente de fluoro, metilo, metoxi, hidroximetilo, cianometilo, -CONH2, –CONHCH3 y –CON(CH3)2. In another aspect, R2 is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl and thiazolyl, said group being substituted with -NHCONR18R19 and optionally substituted with one or more substituent groups independently selected from fluoro, methyl , methoxy, hydroxymethyl, cyanomethyl, -CONH2, -CONHCH3 and -CON (CH3) 2.

En otro aspecto, R2 se selecciona de fenilo, pirrolilo, imidazolilo, pirazolilo, furanilo, tienilo, piridinilo, pirimidinilo, piridazinilo y tiazolilo, estando dicho grupo sustituido con -NHCONHR19 y opcionalmente sustituido con uno o más grupos sustituyentes seleccionados independientemente de fluoro, metilo, metoxi, hidroximetilo, cianometilo, -CONH2, –CONHCH3 y –CON(CH3)2. In another aspect, R2 is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl and thiazolyl, said group being substituted with -NHCONHR19 and optionally substituted with one or more substituent groups independently selected from fluoro, methyl , methoxy, hydroxymethyl, cyanomethyl, -CONH2, -CONHCH3 and -CON (CH3) 2.

En otro aspecto, R2 es fenilo o piridilo sustituido con –NR17CONR18R19 y opcionalmente sustituido con uno o más grupos sustituyentes seleccionados independientemente de fluoro, metilo, metoxi, hidroximetilo, cianometilo, -CONH2, –CONHCH3 y –CON(CH3)2. In another aspect, R2 is phenyl or pyridyl substituted with -NR17CONR18R19 and optionally substituted with one or more substituent groups independently selected from fluoro, methyl, methoxy, hydroxymethyl, cyanomethyl, -CONH2, -CONHCH3 and -CON (CH3) 2.

En otro aspecto, R2 es fenilo o piridilo sustituido con –NHCONR18R19 y opcionalmente sustituido con uno o más grupos sustituyentes seleccionados independientemente de fluoro, metilo, metoxi, hidroximetilo, cianometilo, -CONH2, –CONHCH3 y –CON(CH3)2. In another aspect, R2 is phenyl or pyridyl substituted with -NHCONR18R19 and optionally substituted with one or more substituent groups independently selected from fluoro, methyl, methoxy, hydroxymethyl, cyanomethyl, -CONH2, -CONHCH3 and -CON (CH3) 2.

En otro aspecto, R2 es fenilo o piridilo sustituido con –NHCONHR19 y opcionalmente sustituido con uno o más grupos sustituyentes seleccionados independientemente de fluoro, metilo, metoxi, hidroximetilo, cianometilo, – CONH2, -CONHCH3 y –CON(CH3)2. In another aspect, R2 is phenyl or pyridyl substituted with -NHCONHR19 and optionally substituted with one or more substituent groups independently selected from fluoro, methyl, methoxy, hydroxymethyl, cyanomethyl, - CONH2, -CONHCH3 and -CON (CH3) 2.

En otro aspecto, R2 es fenilo o piridilo opcionalmente sustituido con –NR17CONR18R19. In another aspect, R2 is phenyl or pyridyl optionally substituted with -NR17CONR18R19.

En otro aspecto, R2 es fenilo o piridilo opcionalmente sustituido con –NHCONR18R19. In another aspect, R2 is phenyl or pyridyl optionally substituted with -NHCONR18R19.

En otro aspecto, R2 es fenilo o piridilo opcionalmente sustituido con –NHCONHR19. In another aspect, R2 is phenyl or pyridyl optionally substituted with -NHCONHR19.

En otro aspecto, R2 es In another aspect, R2 is

A1 A1

R17 R18 R17 R18

en la que A1 y A2 se seleccionan de CH o N, con la condición de que al menos uno de A1 o A2 sea CH. wherein A1 and A2 are selected from CH or N, with the proviso that at least one of A1 or A2 is CH.

En otro aspecto, R2 es In another aspect, R2 is

A1 A1

H R18

En otro aspecto, R2 es In another aspect, R2 is

A1 A1

R4 R4

En un aspecto de la invención, R4 es hidrógeno o metilo. In one aspect of the invention, R4 is hydrogen or methyl.

En otro aspecto, R4 es hidrógeno. In another aspect, R4 is hydrogen.

R4 y R1 R4 and R1

En otro aspecto de la invención, cuando X es –NR4CR6R7–, –NR4C(O)CR6R7–, -NR4C(O)NR5CR6R7–, -NR4S(O)2CR6R7–, –NR4C(O)–, –NR4C(O)NR5– o –NR4S(O)2–, R1 y R4, junto con el átomo o átomos a los que están unidos, forman un anillo heterocíclico de 4 a 10 miembros en el que 1, 2 ó 3 átomos de carbono anulares están opcionalmente reemplazados por N, O ó S, y estando dicho anillo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, hidroxi, oxo, alquilo de C1-6, alcoxi de C1-6, halo-alquilo de C1-6, halo-alcoxi de C1-6, hidroxi-alquilo de C1-6, hidroxi-alcoxi de C1-6, alcoxi C1-6-alquilo de C1-6, alcoxi C1-6-alcoxi de C1-6, amino, alquil C1-6-amino, bis(alquil C1-6)-amino, amino-alquilo de C1-6, (alquil C1-6)-amino-alquilo de C1-6, bis(alquil C16)-amino-alquilo de C1-6, ciano-alquilo de C1-6, alquil C1-6-sulfonilo, alquil C1–6-sulfonilamino, alquil C1-6-sulfonil(alquil C1–6)amino, sulfamoilo, alquil C1-6-sulfamoilo, bis(alquil C1-6)-sulfamoilo, alcanoil C1-6-amino, alcanoil C1-6-(alquil C1-6)amino, carbamoilo, alquil C1-6-carbamoilo y bis(alquil C1–6)carbamoilo. In another aspect of the invention, when X is –NR4CR6R7–, –NR4C (O) CR6R7–, -NR4C (O) NR5CR6R7–, -NR4S (O) 2CR6R7–, –NR4C (O) -, –NR4C (O) NR5– or –NR4S (O) 2–, R1 and R4, together with the atom or atoms to which they are attached, form a 4- to 10-membered heterocyclic ring in which 1, 2 or 3 annular carbon atoms are optionally replaced by N, O or S, and said ring being optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, halo- C1- alkyl 6, halo C1-6 alkoxy, hydroxy C1-6 alkyl, hydroxy C1-6 alkoxy, C1-6 alkoxy C1-6 alkyl, C1-6 alkoxy C1-6 alkoxy, amino, C1-6-amino alkyl, bis (C1-6 alkyl) -amino, amino-C1-6 alkyl, (C1-6 alkyl) -amino-C1-6 alkyl, bis (C16 alkyl) -amino-alkyl C 1-6, cyano-C 1-6 alkyl, C 1-6 alkyl sulfonyl, C 1-6 alkyl sulfonylamino, C 1-6 alkyl sulfonyl (C 1-6 alkyl) amino, sulfamoyl, C 1-6 alkyl sulfamoyl or, bis (C1-6 alkyl) -sulfamoyl, C1-6-amino alkanoyl, C1-6 alkanoyl- (C1-6 alkyl) amino, carbamoyl, C1-6 alkylcarbamoyl and bis (C1-6 alkyl) carbamoyl.

En otro aspecto de la invención, cuando X es –NR4CR6R7–, –NR4C(O)CR6R7–, -NR4C(O)NR5CR6R7–, -NR4S(O)2CR6R7–, –NR4C(O)–, –NR4C(O)NR5– o –NR4S(O)2–, R1 y R4, junto con el átomo o átomos a los que están unidos, forman un anillo heterocíclico de 4, 5, 6 ó 7 miembros en el que 1 átomo de carbono anular está opcionalmente reemplazado por N u O, y estando dicho anillo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, hidroxi, oxo, alquilo de C1-6, alcoxi de C1-6, halo-alquilo de C1-6, halo-alcoxi de C1-6, hidroxi-alquilo de C1-6, hidroxi-alcoxi de C1-6, alcoxi C1-6-alquilo de C1-6, alcoxi C1-6-alcoxi de C1-6, amino, alquil C1-6-amino, bis(alquil C1-6)-amino, amino-alquilo de C1-6, (alquil C1-6)-amino-alquilo de C1-6, bis(alquil C16)-amino-alquilo de C1-6, ciano-alquilo de C1-6, alquil C1-6-sulfonilo, alquil C1-6-sulfonilamino, alquil C1-6-sulfonil-(alquil C1-6)-amino, sulfamoilo, alquil C1-6-sulfamoilo, bis(alquil C1-6)-sulfamoilo, alcanoil C1-6-amino, alcanoil C1-6-(alquil C1-6)amino, carbamoilo, alquil C1-6-carbamoilo y bis(alquil C1-6)carbamoilo. In another aspect of the invention, when X is –NR4CR6R7–, –NR4C (O) CR6R7–, -NR4C (O) NR5CR6R7–, -NR4S (O) 2CR6R7–, –NR4C (O) -, –NR4C (O) NR5– or –NR4S (O) 2–, R1 and R4, together with the atom or atoms to which they are attached, form a 4, 5, 6 or 7-membered heterocyclic ring in which 1 annular carbon atom is optionally replaced by N or O, and said ring being optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, halo- C1-6 alkyl, C1-6 halo-alkoxy, C1-6 hydroxy-alkyl, C1-6 hydroxy-alkoxy, C1-6 alkoxy-C1-6 alkyl, C1-6 alkoxy-C1-6 alkoxy, amino, C1-alkyl -6-amino, bis (C1-6 alkyl) -amino, amino-C1-6 alkyl, (C1-6 alkyl) -amino-C1-6 alkyl, bis (C16 alkyl) -amino-C1- alkyl 6, cyano-C 1-6 alkyl, C 1-6 alkyl sulfonyl, C 1-6 alkyl sulfonylamino, C 1-6 alkyl sulfonyl- (C 1-6 alkyl) -amino, sulfamoyl, C 1-6 alkyl sulfamoyl, bis (rent C 1-6) -sulfamoyl, C 1-6 alkanoyl, C 1-6 alkanoyl- (C 1-6 alkyl) amino, carbamoyl, C 1-6 alkylcarbamoyl and bis (C 1-6 alkyl) carbamoyl.

En otro aspecto de la invención, cuando X es –NR4CR6R7–, –NR4C(O)CR6R7–, -NR4C(O)NR5CR6R7–, -NR4S(O)2CR6R7–, –NR4C(O)–, –NR4C(O)NR5– o –NR4S(O)2–, R1 y R4, junto con el átomo o átomos a los que están unidos, forman un anillo heterocíclico de 5 ó 6 miembros en el que 1 átomo de carbono anular está opcionalmente reemplazado por N u O, y estando dicho anillo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, hidroxi, oxo, alquilo de C1-6, alcoxi de C1-6, halo-alquilo de C1-6, halo-alcoxi de C16, hidroxi-alquilo de C1-6, hidroxi-alcoxi de C1-6, alcoxi C1-6-alquilo de C1-6, alcoxi C1-6-alcoxi de C1-6, amino, alquil C1-6amino, bis(alquil C1-6)-amino, amino-alquilo de C1-6, (alquil C1-6)-amino-alquilo de C1-6, bis(alquil C1-6)-amino-alquilo de C1-6, ciano-alquilo de C1-6, alquil C1-6-sulfonilo, alquil C1-6-sulfonilamino, alquil C1-6-sulfonil-(alquil C1-6)-amino, sulfamoilo, alquil C1-6-sulfamoilo, bis(alquil C1-6)-sulfamoilo, alcanoil C1-6-amino, alcanoil C1-6-(alquil C1-6)-amino, carbamoilo, alquil C1-6-carbamoilo y bis(alquil C1-6)carbamoilo. In another aspect of the invention, when X is –NR4CR6R7–, –NR4C (O) CR6R7–, -NR4C (O) NR5CR6R7–, -NR4S (O) 2CR6R7–, –NR4C (O) -, –NR4C (O) NR5– or –NR4S (O) 2–, R1 and R4, together with the atom or atoms to which they are attached, form a 5- or 6-membered heterocyclic ring in which 1 annular carbon atom is optionally replaced by N u Or, and said ring being optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, halo- C1-6 alkyl, halo-alkoxy of C16, hydroxy-C 1-6 alkyl, hydroxy-C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkoxy, amino, C 1-6 alkyl, bis (alkyl C1-6) -amino, C1-6 amino-alkyl, (C1-6 alkyl) -amino-C1-6 alkyl, bis (C1-6 alkyl) -amino-C1-6 alkyl, cyano-alkyl C1-6, C1-6-sulfonyl alkyl, C1-6-sulfonylamino alkyl, C1-6-sulfonyl- (C1-6 alkyl) -amino, sulfamoyl, C1-6-sulfamoyl alkyl, bis (C1-6 alkyl) - sulfamoyl, C1-6 alkanoyl-amino, C1-6 alkanoyl- (C1-6 alkyl) -amino, carbamoyl, C1-6 alkylcarbamoyl and bis (C1-6 alkyl) carbamoyl.

En otro aspecto de la invención, cuando X es –NR4CR6R7–, –NR4C(O)CR6R7–, -NR4C(O)NR5CR6R7–, -NR4S(O)2CR6R7–, –NR4C(O)–, –NR4C(O)NR5– o –NR4S(O)2–, R1 y R4, junto con el átomo o átomos a los que están unidos, forman un anillo heterocíclico de 6 ó 7 miembros en el que 1 átomo de carbono anular está opcionalmente reemplazado por N u O, y estando dicho anillo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, hidroxi, oxo, alquilo de C1-6, alcoxi de C1-6, halo-alquilo de C1-6, halo-alcoxi de C1-In another aspect of the invention, when X is –NR4CR6R7–, –NR4C (O) CR6R7–, -NR4C (O) NR5CR6R7–, -NR4S (O) 2CR6R7–, –NR4C (O) -, –NR4C (O) NR5– or –NR4S (O) 2–, R1 and R4, together with the atom or atoms to which they are attached, form a 6 or 7-membered heterocyclic ring in which 1 annular carbon atom is optionally replaced by N u Or, and said ring being optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, halo- C1-6 alkyl, halo-alkoxy of C1-

6, hidroxi-alquilo de C1-6, hidroxi-alcoxi de C1-6, alcoxi C1-6-alquilo de C1-6, alcoxi C1-6-alcoxi de C1-6, amino, alquil C1-6amino, bis(alquil C1-6)-amino, amino-alquilo de C1-6, (alquil C1-6)-amino-alquilo de C1-6, bis(alquil C1-6)-amino-alquilo de C1-6, ciano-alquilo de C1-6, alquil C1-6-sulfonilo, alquil C1-6-sulfonilamino, alquil C1-6-sulfonil-(alquil C1-6)-amino, sulfamoilo, alquil C1-6-sulfamoilo, bis(alquil C1-6)-sulfamoilo, alcanoil C1-6-amino, alcanoil C1-6-(alquil C1-6)-amino, carbamoilo, alquil C1-6-carbamoilo y bis(alquil C1-6)carbamoilo. 6, hydroxy-C 1-6 alkyl, hydroxy-C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkoxy, amino, C 1-6 alkyl, bis (alkyl C1-6) -amino, C1-6 amino-alkyl, (C1-6 alkyl) -amino-C1-6 alkyl, bis (C1-6 alkyl) -amino-C1-6 alkyl, cyano-alkyl C1-6, C1-6-sulfonyl alkyl, C1-6-sulfonylamino alkyl, C1-6-sulfonyl- (C1-6 alkyl) -amino, sulfamoyl, C1-6-sulfamoyl alkyl, bis (C1-6 alkyl) -sulfamoyl, C 1-6 alkanoyl-amino, C 1-6 alkanoyl- (C 1-6 alkyl) -amino, carbamoyl, C 1-6 alkyl-carbamoyl and bis (C 1-6 alkyl) carbamoyl.

En otro aspecto de la invención, cuando X es –NR4CR6R7–, –NR4C(O)CR6R7–, -NR4C(O)NR5CR6R7–, -NR4S(O)2CR6R7–, –NR4C(O)–, –NR4C(O)NR5– o –NR4S(O)2–, R1 y R4, junto con el átomo o átomos a los que están unidos, forman un anillo de piperidina, morfolina, azetidina, azepina, diazepano y tiomorfolina, estando dicho anillo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, hidroxi, oxo y alquilo de C1-6. In another aspect of the invention, when X is –NR4CR6R7–, –NR4C (O) CR6R7–, -NR4C (O) NR5CR6R7–, -NR4S (O) 2CR6R7–, –NR4C (O) -, –NR4C (O) NR5– or –NR4S (O) 2–, R1 and R4, together with the atom or atoms to which they are attached, form a piperidine, morpholine, azetidine, azepine, diazepane and thiomorpholine ring, said ring being optionally substituted with one or more substituent groups selected from halo, hydroxy, oxo and C1-6 alkyl.

En otro aspecto de la invención, cuando X es –NR4C(O)–, R1 y R4, junto con el átomo o átomos a los que están unidos, forman un anillo de piperidina, morfolina, azetidina, azepina, diazepano y tiomorfolina, estando dicho anillo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, hidroxi, oxo y alquilo de C1-6. In another aspect of the invention, when X is -NR4C (O) -, R1 and R4, together with the atom or atoms to which they are attached, form a piperidine, morpholine, azetidine, azepine, diazepane and thiomorpholine ring, being said ring optionally substituted with one or more substituent groups selected from halo, hydroxy, oxo and C1-6 alkyl.

En otro aspecto de la invención, cuando X es –NR4C(O)–, R1 y R4, junto con el átomo o átomos a los que están unidos, forman un anillo de 1–metil–piperidina, 4–hidroxi–piperidina, morfolina, 3–metilmorfolina, 3–hidroxiazetidina, azepina, 1,4–diazepán y 1,1–dióxido de tiomorfolina. In another aspect of the invention, when X is -NR4C (O) -, R1 and R4, together with the atom or atoms to which they are attached, form a ring of 1-methyl-piperidine, 4-hydroxy-piperidine, morpholine , 3-methylmorpholine, 3-hydroxyazetidine, azepine, 1,4-diazephan and 1,1-thiomorpholine dioxide.

R5 R5

En un aspecto de la invención, R5 es hidrógeno o metilo. En otro aspecto, R5 es hidrógeno. En otro aspecto, R5 es metilo. In one aspect of the invention, R5 is hydrogen or methyl. In another aspect, R5 is hydrogen. In another aspect, R5 is methyl.

R6 R6

En un aspecto de la invención, R6 es hidrógeno o metilo. En otro aspecto, R6 es hidrógeno. En otro aspecto, R6 es metilo. In one aspect of the invention, R6 is hydrogen or methyl. In another aspect, R6 is hydrogen. In another aspect, R6 is methyl.

R7 R7

En un aspecto de la invención, R7 es hidrógeno o metilo. En otro aspecto, R7 es hidrógeno. En otro aspecto, R7 es metilo. In one aspect of the invention, R7 is hydrogen or methyl. In another aspect, R7 is hydrogen. In another aspect, R7 is methyl.

R8 R8

En un aspecto de la invención, R8 es hidrógeno o halo. En otro aspecto, R8 es hidrógeno o fluoro. En un aspecto adicional, R8 es hidrógeno. In one aspect of the invention, R8 is hydrogen or halo. In another aspect, R8 is hydrogen or fluoro. In a further aspect, R8 is hydrogen.

R9 R9

En un aspecto de la invención, R9 es hidrógeno o alquilo de C1-4 opcionalmente sustituido con 1, 2 ó 3 grupos sustituyentes seleccionados de halo, ciano, nitro, hidroxi, alcoxi de C1-4, amino, alquil C1-4-amino y bis(alquil C1-4)amino. In one aspect of the invention, R9 is hydrogen or C1-4 alkyl optionally substituted with 1, 2 or 3 substituent groups selected from halo, cyano, nitro, hydroxy, C1-4 alkoxy, amino, C1-4 alkyl and bis (C1-4 alkyl) amino.

En otro aspecto, R9 es hidrógeno o alquilo de C1-4 opcionalmente sustituido con 1, 2 ó 3 sustituyentes halo. In another aspect, R9 is hydrogen or C1-4 alkyl optionally substituted with 1, 2 or 3 halo substituents.

En un aspecto adicional, R9 es hidrógeno, metilo o trifluorometilo. In a further aspect, R9 is hydrogen, methyl or trifluoromethyl.

R10 R10

En un aspecto de la invención, R10 es hidrógeno. In one aspect of the invention, R10 is hydrogen.

R11 R11

En un aspecto de la invención, R11 es hidrógeno o un grupo seleccionado de alquilo de C1-4, arilo y cicloheteroalquilo, estando dicho grupo opcionalmente sustituido con 1, 2 ó 3 grupos seleccionados de halo, hidroxi y ciano. In one aspect of the invention, R 11 is hydrogen or a group selected from C 1-4 alkyl, aryl and cycloheteroalkyl, said group being optionally substituted with 1, 2 or 3 groups selected from halo, hydroxy and cyano.

En otro aspecto, R11 es hidrógeno, metilo opcionalmente sustituido con hidroxi o ciano, fenilo o pirrolidinilo. In another aspect, R 11 is hydrogen, methyl optionally substituted with hydroxy or cyano, phenyl or pyrrolidinyl.

En otro aspecto, R11 es hidrógeno o metilo. In another aspect, R11 is hydrogen or methyl.

R12 R12

En un aspecto de la invención R12 es hidrógeno o metilo. In one aspect of the invention R12 is hydrogen or methyl.

R17 R17

En un aspecto de la invención, R17 es hidrógeno o un grupo seleccionado de alquilo de C1-4, arilo y cicloheteroalquilo, estando dicho grupo opcionalmente sustituido con 1, 2 ó 3 grupos seleccionados de halo, hidroxi y ciano. In one aspect of the invention, R17 is hydrogen or a group selected from C1-4alkyl, aryl and cycloheteroalkyl, said group being optionally substituted with 1, 2 or 3 groups selected from halo, hydroxy and cyano.

En otro aspecto, R17 es hidrógeno, metilo opcionalmente sustituido con hidroxi o ciano, fenilo o pirrolidinilo. In another aspect, R17 is hydrogen, methyl optionally substituted with hydroxy or cyano, phenyl or pyrrolidinyl.

En otro aspecto, R17 es hidrógeno o metilo. In another aspect, R17 is hydrogen or methyl.

En otro aspecto, R17 es hidrógeno. In another aspect, R17 is hydrogen.

R18 R18

En un aspecto de la invención, R18 es hidrógeno o metilo. In one aspect of the invention, R18 is hydrogen or methyl.

En un aspecto de la invención, R18 es hidrógeno. In one aspect of the invention, R18 is hydrogen.

R19 R19

En un aspecto de la invención, R19 es hidrógeno o un grupo seleccionado de alquilo de C1-6, cicloalquilo de C3-6, arilo, heteroarilo, aril-alquilo de C1-6 y heteroaril-alquilo de C1-6, estando dicho grupo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, hidroxi, oxo, alquilo de C1-6, alcoxi de C1-6, haloalquilo de C1-6, halo-alcoxi de C1-6, hidroxi-alquilo de C1-6, hidroxi-alcoxi de C1-6, alcoxi C1-6-alquilo de C1-6, alcoxi C1-6alcoxi de C1-6, amino, alquil C1-6-amino, bis(alquil C1-6)-amino, amino-alquilo de C1-6, (alquil C1-6)-amino-alquilo de C16, bis(alquil C1-6)-amino-alquilo de C1-6, ciano-alquilo de C1-6, alquil C1-6-sulfonilo, alquil C1-6-sulfonilamino, alquil C1-6sulfonil-(alquil C1-6)-amino, sulfamoilo, alquil C1-6-sulfamoilo, bis(alquil C1-6)-sulfamoilo, alcanoil C1-6-amino, alcanoil C1-6-(alquil C1-6)-amino, carbamoilo, alquil C1-6-carbamoilo y bis(alquil C1-6)carbamoilo. In one aspect of the invention, R19 is hydrogen or a group selected from C1-6 alkyl, C3-6 cycloalkyl, aryl, heteroaryl, aryl-C1-6 alkyl and heteroaryl-C1-6 alkyl, said group being optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, hydroxy-alkyl C1-6, hydroxy-C1-6 alkoxy, C1-6 alkoxy-C1-6 alkyl, C1-6 alkoxy C1-6 alkoxy, amino, C1-6 alkyl-amino, bis (C1-6 alkyl) -amino , C1-6 amino-alkyl, (C1-6 alkyl) -amino-C16 alkyl, bis (C1-6 alkyl) -amino-C1-6 alkyl, cyano-C1-6 alkyl, C1-6 alkyl -sulfonyl, C1-6 alkyl-sulfonylamino, C1-6 alkyl sulfonyl- (C1-6 alkyl) -amino, sulfamoyl, C1-6 alkyl-sulfamoyl, bis (C1-6 alkyl) -sulfamoyl, C1-6-amino alkanoyl, C 1-6 alkanoyl- (C 1-6 alkyl) -amino, carbamoyl, C 1-6 alkyl-carbamoyl and bis (C 1-6 alkyl) carbamoyl.

En un aspecto de la invención, R19 es hidrógeno o un grupo seleccionado de alquilo de C1-6, cicloalquilo de C3-6, arilo, heteroarilo, aril-alquilo de C1-6 y heteroaril-alquilo de C1-6, estando dicho grupo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, hidroxi, alquilo de C1-6, alcoxi de C1-6, haloalquilo de C1-6, halo-alcoxi de C1-6, hidroxi-alquilo de C1-6, hidroxi-alcoxi de C1-6, alcoxi C1-6-alquilo de C1-6, alcoxi C1-6alcoxi de C1-6, amino, alquil C1-6-amino, bis(alquil C1-6)-amino, amino-alquilo de C1-6, (alquil C1-6)-amino-alquilo de C16, bis(alquil C1-6)-amino-alquilo de C1-6, ciano-alquilo de C1-6, alquil C1-6-sulfonilo, alquil C1-6-sulfonilamino, alquil C1-6sulfonil-(alquil C1-6)-amino, sulfamoilo, alquil C1-6-sulfamoilo, bis(alquil C1-6)-sulfamoilo, alcanoil C1-6-amino, alcanoil C1-6-(alquil C1-6)-amino, carbamoilo, alquil C1-6-carbamoilo y bis(alquil C1-6)carbamoilo. In one aspect of the invention, R19 is hydrogen or a group selected from C1-6 alkyl, C3-6 cycloalkyl, aryl, heteroaryl, aryl-C1-6 alkyl and heteroaryl-C1-6 alkyl, said group being optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C1- hydroxy-alkyl 6, C 1-6 hydroxy-alkoxy, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxyC 1-6 alkoxy, amino, C 1-6 alkyl-amino, bis (C 1-6 alkyl) -amino, amino -C1-6 alkyl, (C1-6 alkyl) -amino-C16 alkyl, bis (C1-6 alkyl) -amino-C1-6 alkyl, cyano-C1-6 alkyl, C1-6 alkyl sulfonyl , C1-6 alkyl sulfonylamino, C1-6 alkyl sulfonyl- (C1-6 alkyl) -amino, sulfamoyl, C1-6 alkyl sulfamoyl, bis (C1-6 alkyl) sulfulfyl, C1-6 alkanoyl, C1 alkanoyl -6- (C 1-6 alkyl) -amino, carbamoyl, C 1-6 alkyl-carbamoyl and bis (C 1-6 alkyl) carbamoyl.

En un aspecto de la invención R19 es hidrógeno o un grupo seleccionado de alquilo de C1-6, cicloalquilo de C3-6, fenilo, naftilo, pirrolilo, imidazolilo, isoxazolilo, pirazolilo, furanilo, tienilo, piridinilo, pirimidinilo, piridazinilo, azaindolilo, indolilo, quinolinilo, bencimidazolilo, benzofuranilo, dibenzofuranilo, benzotienilo, fenil-alquilo de C1-6, naftil-alquilo de C1-6, pirrolil-alquilo de C1-6, imidazolil-alquilo de C1-6, isoxazolil-alquilo de C1-6, pirazolil-alquilo de C1-6, furanil-alquilo de C1-6, tienil-alquilo de C1-6, piridinil-alquilo de C1-6, pirimidinil-alquilo de C1-6, piridazinil-alquilo de C1-6, azaindolilalquilo de C1-6, indolil-alquilo de C1-6, quinolinil-alquilo de C1-6, bencimidazolil-alquilo de C1-6, benzofuranil-alquilo de C1-6, dibenzofuranil-alquilo de C1-6, benzotienil-alquilo de C1-6, estando dicho grupo opcionalmente sustituido con uno In one aspect of the invention R19 is hydrogen or a group selected from C1-6 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, pyrrolyl, imidazolyl, isoxazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl, azaindolyl, indolyl, quinolinyl, benzimidazolyl, benzofuranyl, dibenzofuranyl, benzothienyl, phenyl-C1-6 alkyl, naphthyl-C1-6 alkyl, pyrrolyl-C1-6 alkyl, imidazolyl-C1-6 alkyl, isoxazolyl-C1- alkyl 6, pyrazolyl-C 1-6 alkyl, furanyl-C 1-6 alkyl, thienyl-C 1-6 alkyl, pyridinyl-C 1-6 alkyl, pyrimidinyl-C 1-6 alkyl, pyridazinyl-C 1-6 alkyl, C1-6 azaindole alkyl, indolyl C1-6 alkyl, quinolinyl C1-6 alkyl, benzimidazolyl C1-6 alkyl, benzofuranyl C1-6 alkyl, dibenzofuranyl C1-6 alkyl, benzothienyl alkyl C1-6, said group being optionally substituted with one

: o más grupos sustituyentes seleccionados de halo, ciano, nitro, hidroxi, oxo, alquilo de C1-6, alcoxi de C1-6, haloalquilo de C1-6, halo-alcoxi de C1-6, hidroxi-alquilo de C1-6, hidroxi-alcoxi de C1-6, alcoxi C1-6-alquilo de C1-6, alcoxi C1-6alcoxi de C1-6, amino, alquil C1-6-amino, bis(alquil C1-6)-amino, amino-alquilo de C1-6, (alquil C1-6)-amino-alquilo de C16, bis(alquil C1-6)-amino-alquilo de C1-6, ciano-alquilo de C1-6, alquil C1-6-sulfonilo, alquil C1-6-sulfonilamino, alquil C1-6sulfonil-(alquil C1-6)-amino, sulfamoilo, alquil C1-6-sulfamoilo, bis(alquil C1-6)-sulfamoilo, alcanoil C1-6-amino, alcanoil C1-6-(alquil C1-6)-amino, carbamoilo, alquil C1-6-carbamoilo y bis(alquil C1-6)carbamoilo. or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 hydroxy-alkyl, C 1-6 hydroxy-alkoxy, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxyC 1-6 alkoxy, amino, C 1-6 alkyl-amino, bis (C 1-6 alkyl) -amino, amino-alkyl C1-6, (C1-6 alkyl) -amino-C16 alkyl, bis (C1-6 alkyl) -amino-C1-6 alkyl, cyano-C1-6 alkyl, C1-6 alkyl sulfonyl, alkyl C1-6-sulfonylamino, C1-6 alkyl sulfonyl- (C1-6 alkyl) -amino, sulfamoyl, C1-6 alkyl-sulfamoyl, bis (C1-6 alkyl) -sulfamoyl, C1-6-alkanoyl, C1-6 alkanoyl - (C1-6 alkyl) -amino, carbamoyl, C1-6 alkyl-carbamoyl and bis (C1-6 alkyl) carbamoyl.

En un aspecto de la invención, R19 es hidrógeno o un grupo seleccionado de alquilo de C1-6, cicloalquilo de C3-6, fenilo, naftilo, pirrolilo, imidazolilo, isoxazolilo, pirazolilo, furanilo, tienilo, piridinilo, pirimidinilo, piridazinilo, azaindolilo, indolilo, quinolinilo, bencimidazolilo, benzofuranilo, dibenzofuranilo, benzotienilo, fenil-alquilo de C1-6, naftil-alquilo de C1-6, pirrolil-alquilo de C1-6, imidazolil-alquilo de C1-6, isoxazolil-alquilo de C1-6, pirazolil-alquilo de C1-6, furanil-alquilo de C1-6, tienil-alquilo de C1-6, piridinil-alquilo de C1-6, pirimidinil-alquilo de C1-6, piridazinil-alquilo de C1-6, azaindolilalquilo de C1-6, indolil-alquilo de C1-6, quinolinil-alquilo de C1-6, bencimidazolil-alquilo de C1-6, benzofuranil-alquilo de C1-6, dibenzofuranil-alquilo de C1-6, benzotienil-alquilo de C1-6, estando dicho grupo opcionalmente sustituido con uno In one aspect of the invention, R19 is hydrogen or a group selected from C1-6 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, pyrrolyl, imidazolyl, isoxazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl, azaindolyl , indolyl, quinolinyl, benzimidazolyl, benzofuranyl, dibenzofuranyl, benzothienyl, phenyl-C1-6 alkyl, naphthyl-C1-6 alkyl, pyrrolyl-C1-6 alkyl, imidazolyl-C1-6 alkyl, isoxazolyl-C1 alkyl -6, pyrazolyl-C 1-6 alkyl, furanyl-C 1-6 alkyl, thienyl-C 1-6 alkyl, pyridinyl-C 1-6 alkyl, pyrimidinyl-C 1-6 alkyl, pyridazinyl-C 1-6 alkyl , C1-6 azaindole alkyl, indolyl C1-6 alkyl, quinolinyl C1-6 alkyl, benzimidazolyl C1-6 alkyl, benzofuranyl C1-6 alkyl, dibenzofuranyl C1-6 alkyl, benzothienyl alkyl C1-6, said group being optionally substituted with one

: o más grupos sustituyentes seleccionados de halo, ciano, nitro, hidroxi, alquilo de C1-6, alcoxi de C1-6, halo-alquilo de C1-6, halo-alcoxi de C1-6, hidroxi-alquilo de C1-6, hidroxi-alcoxi de C1-6, alcoxi C1-6-alquilo de C1-6, alcoxi C1-6-alcoxi de or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6 alkyl, C1-6 alkoxy, halo C1-6 alkyl, halo C1-6 alkoxy, hydroxy C1-6 alkyl, C 1-6 hydroxy-alkoxy, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy-alkoxy of

C1-6, amino, alquil C1-6-amino, bis(alquil C1-6)-amino, amino-alquilo de C1-6, (alquil C1-6)-amino-alquilo de C1-6, bis(alquil C1-6)-amino-alquilo de C1-6, ciano-alquilo de C1-6, alquil C1-6-sulfonilo, alquil C1-6-sulfonilamino, alquil C1-6sulfonil-(alquil C1-6)-amino, sulfamoilo, alquil C1-6-sulfamoilo, bis(alquil C1-6)-sulfamoilo, alcanoil C1-6-amino, alcanoil C1-6-(alquil C1-6)-amino, carbamoilo, alquil C1-6-carbamoilo y bis(alquil C1-6)carbamoilo. C1-6, amino, C1-6 alkyl-amino, bis (C1-6 alkyl) -amino, amino C1-6 alkyl, (C1-6 alkyl) -amino-C1-6 alkyl, bis (C1 alkyl -6) -Camino-C 1-6 alkyl, cyano-C 1-6 alkyl, C 1-6 alkyl sulfonyl, C 1-6 alkyl sulfonylamino, C 1-6 alkyl sulfonyl- (C 1-6 alkyl) -amino, sulfamoyl, C1-6-sulfamoyl alkyl, bis (C1-6 alkyl) -sulfamoyl, C1-6-amino alkanoyl, C1-6 alkanoyl- (C1-6 alkyl) -amino, carbamoyl, C1-6-carbamoyl alkyl and bis (alkyl C1-6) carbamoyl.

En un aspecto de la invención, R19 es hidrógeno o un grupo seleccionado de metilo, etilo, propilo, i–propilo, butilo, i– butilo, t–butilo, pentilo, ciclopropilo, ciclobutilo, ciclopentilo, ciclohexilo, fenilo, tienilo, imidazoilmetilo, isoxazolilo, pirazolilo, pirazolilmetilo, piridinilo y pirimidinilo, estando dicho grupo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, hidroxi, oxo, alquilo de C1-6, alcoxi de C1-6, halo-alquilo de C1-6, halo-alcoxi de C1-6, hidroxi-alquilo de C1-6, hidroxi-alcoxi de C1-6, alcoxi C1-6-alquilo de C1-6, alcoxi C1-6-alcoxi de C1-6, amino, alquil C1-6-amino, bis(alquil C1-6)-amino, amino-alquilo de C1-6, (alquil C1-6)-amino-alquilo de C1-6, bis(alquil C16)-amino-alquilo de C1-6, ciano-alquilo de C1-6, alquil C1-6-sulfonilo, alquil C1-6-sulfonilamino, alquil C1-6-sulfonil-(alquil C1-6)-amino, sulfamoilo, alquil C1-6-sulfamoilo, bis(alquil C1-6)-sulfamoilo, alcanoil C1-6-amino, alcanoil C1-6-(alquil C1-6)amino, carbamoilo, alquil C1-6-carbamoilo y bis(alquil C1-6)carbamoilo. In one aspect of the invention, R19 is hydrogen or a group selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, imidazoylmethyl , isoxazolyl, pyrazolyl, pyrazolylmethyl, pyridinyl and pyrimidinyl, said group being optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, halo-alkyl C1-6, halo- C1-6 alkoxy, hydroxy-C1-6 alkyl, hydroxy-C1-6 alkoxy, C1-6 alkoxy-C1-6 alkyl, C1-6 alkoxy-C1-6 alkoxy, amino, C1-6 alkyl-amino, bis (C1-6 alkyl) -amino, amino C1-6 alkyl, (C1-6 alkyl) -amino-C1-6 alkyl, bis (C16 alkyl) -amino- C1-6 alkyl, cyano-C1-6 alkyl, C1-6 alkyl sulfonyl, C1-6 alkyl sulfonylamino, C1-6 alkyl sulfonyl- (C1-6 alkyl) -amino, sulfamoyl, C1-6 alkyl -sulfamoyl, bis (C1-6 alkyl) -sulfamoyl, C1-6 alkanoyl, C1-6 alkanoyl- (C alkyl 1-6) amino, carbamoyl, C1-6 alkylcarbamoyl and bis (C1-6 alkyl) carbamoyl.

En un aspecto de la invención, R19 es hidrógeno o un grupo seleccionado de metilo, etilo, propilo, i–propilo, butilo, i– butilo, t–butilo, pentilo, ciclopropilo, ciclobutilo, ciclopentilo, ciclohexilo, fenilo, tienilo, imidazoilmetilo, isoxazolilo, pirazolilo, pirazolilmetilo, piridinilo y pirimidinilo, estando dicho grupo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, hidroxi, alquilo de C1-6, alcoxi de C1-6, halo-alquilo de C1-6, haloalcoxi de C1-6, hidroxi-alquilo de C1-6, hidroxi-alcoxi de C1-6, alcoxi C1-6-alquilo de C1-6, alcoxi C1-6-alcoxi de C1-6, amino, alquil C1-6-amino, bis(alquil C1-6)-amino, amino-alquilo de C1-6, (alquil C1-6)-amino-alquilo de C1-6, bis(alquil C16)-amino-alquilo de C1-6, ciano-alquilo de C1-6, alquil C1-6-sulfonilo, alquil C1-6-sulfonilamino, alquil C1-6-sulfonil-(alquil C1-6)-amino, sulfamoilo, alquil C1-6-sulfamoilo, bis(alquil C1-6)-sulfamoilo, alcanoil C1-6-amino, alcanoil C1-6-(alquil C1-6)amino, carbamoilo, alquil C1-6-carbamoilo y bis(alquil C1-6)carbamoilo. En un aspecto de la invención, R19 es hidrógeno o un grupo seleccionado de metilo, etilo, propilo, i-propilo, butilo, i-butilo, t-butilo, pentilo, ciclopropilo, ciclobutilo, ciclopentilo, ciclohexilo, -CH2(ciclopropilo), -CH2CH2NMe2, -CH(CH3)CH2OH, -C(CH3)2CH2OH, -CH2CH2OH, -CH2CH2CH2OH, 4-metilfenilo, 4-clorofenilo, 4-trifluorometilfenilo, 4-fluorofenilo, 4-metoxifenilo, 3,4difluorofenilo, tien-2-ilo, -CH2(imidazol-2-ilo), -CH2(imidazol-3-ilo), isoxazol-3-ilo, 6-oxo-1H-piridin-2-ilo, 5metilisoxazol-3-ilo, 1-metilpirazol-4-ilo, -CH2(1-metilpirazol-4-ilo), 6-metoxipiridin-3-ilo, 5-fluoropiridin-2-ilo, piridinil-2ilo, pirimidin-2-ilo, y 1H-pirazol-3-ilo. In one aspect of the invention, R19 is hydrogen or a group selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, imidazoylmethyl , isoxazolyl, pyrazolyl, pyrazolylmethyl, pyridinyl and pyrimidinyl, said group being optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6 alkyl, C1-6 alkoxy, C1- halo-alkyl 6, C1-6 haloalkoxy, C1-6 hydroxy-alkyl, C1-6 hydroxy-alkoxy, C1-6 alkoxy-C1-6 alkyl, C1-6 alkoxy-C1-6 alkoxy, amino, C1-alkyl -6-amino, bis (C1-6 alkyl) -amino, amino-C1-6 alkyl, (C1-6 alkyl) -amino-C1-6 alkyl, bis (C16 alkyl) -amino-C1- alkyl 6, cyano-C 1-6 alkyl, C 1-6 alkyl sulfonyl, C 1-6 alkyl sulfonylamino, C 1-6 alkyl sulfonyl- (C 1-6 alkyl) -amino, sulfamoyl, C 1-6 alkyl sulfamoyl, bis (C1-6 alkyl) -sulfamoyl, C1-6 alkanoyl-amino, C1-6 alkanoyl- (C1-6 alkyl) am ino, carbamoyl, C1-6 alkylcarbamoyl and bis (C1-6 alkyl) carbamoyl. In one aspect of the invention, R19 is hydrogen or a group selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2 (cyclopropyl) , -CH2CH2NMe2, -CH (CH3) CH2OH, -C (CH3) 2CH2OH, -CH2CH2OH, -CH2CH2CH2OH, 4-methylphenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, 4-fluorophenyl, 4-methoxyphenyl, 3,4-dipluorophenyl, thien 2-yl, -CH2 (imidazol-2-yl), -CH2 (imidazol-3-yl), isoxazol-3-yl, 6-oxo-1H-pyridin-2-yl, 5-methylisoxazol-3-yl, 1- methylpyrazol-4-yl, -CH2 (1-methylpyrazol-4-yl), 6-methoxypyridin-3-yl, 5-fluoropyridin-2-yl, pyridinyl-2yl, pyrimidin-2-yl, and 1H-pyrazole-3 -ilo.

En un aspecto de la invención, R19 es hidrógeno o un grupo seleccionado de metilo, etilo, propilo, i–propilo, butilo, i-butilo, t–butilo, pentilo, ciclopropilo, ciclobutilo, ciclopentilo, ciclohexilo, –CH2(ciclopropilo), –CH2CH2NMe2, -CH(CH3)CH2OH, –C(CH3)2CH2OH, –CH2CH2OH, -CH2CH2CH2OH, 4–metilfenilo, 4–clorofenilo, 4–trifluorometilfenilo, 4–fluorofenilo, 4–metoxifenilo, 3,4–difluorofenilo, tien–2–ilo, –CH2(imidazol–2–ilo), –CH2(imidazol–3–ilo), isoxazol–3– ilo, 6–oxo–1H–piridin–2–ilo, 5–metilisoxazol–3–ilo, 1–metilpirazol–4–ilo, –CH2(1–metilpirazol–4–ilo), 6–metoxipiridin– 3–ilo, 5–fluoropiridin–2–ilo, pirimidin–2–ilo, y 1H–pirazol–3–ilo. In one aspect of the invention, R19 is hydrogen or a group selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2 (cyclopropyl) , –CH2CH2NMe2, -CH (CH3) CH2OH, –C (CH3) 2CH2OH, –CH2CH2OH, -CH2CH2CH2OH, 4-methylphenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, 4-fluorophenyl, 4-methoxyphenyl, 3,4-difluorophenyl, tien – 2 – yl, –CH2 (imidazol – 2 – yl), –CH2 (imidazol – 3 – yl), isoxazol – 3– yl, 6 – oxo – 1H – pyridin – 2 – yl, 5 – methylisoxazole – 3– ilo, 1-methylpyrazole-4-yl, -CH2 (1-methylpyrazol-4-yl), 6-methoxypyridin-3-yl, 5-fluoropyridin-2-yl, pyrimidin-2-yl, and 1H-pyrazole-3 –Ilo.

En otro aspecto de la invención, R19 es un grupo seleccionado de metilo, etilo, propilo, ciclopropilo, ciclobutilo, -CH2CH2OH, –CH2CH2NMe2, –C(Me)2CH2OH y 1H–pirazol–3–ilo. In another aspect of the invention, R19 is a group selected from methyl, ethyl, propyl, cyclopropyl, cyclobutyl, -CH2CH2OH, -CH2CH2NMe2, -C (Me) 2CH2OH and 1H-pyrazole-3-yl.

R18 y R19 R18 and R19

En un aspecto de la invención, R18 y R19, junto con el átomo de nitrógeno al que están unidos, forman un anillo heterocíclico de 6 miembros en el que 1 átomo de carbono anular está opcionalmente reemplazado por N u O y, estando dicho anillo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, hidroxi, oxo, alquilo de C1-6, alcoxi de C1-6, halo-alquilo de C1-6, halo-alcoxi de C1-6, hidroxi-alquilo de C1-6, hidroxi-alcoxi de C1-6, alcoxi C1-6-alquilo de C1-6, alcoxi C1-6-alcoxi de C1-6, amino, alquil C1-6-amino, bis(alquil C1-6)amino, amino-alquilo de C1-6, (alquil C1-6)-amino-alquilo de C1-6, bis(alquil C1-6)-amino-alquilo de C1-6, ciano-alquilo de C1-6, alquil C1-6-sulfonilo, alquil C1-6-sulfonilamino, alquil C1-6-sulfonil-(alquil C1-6)-amino, sulfamoilo, alquil C1-6sulfamoilo, bis(alquil C1-6)-sulfamoilo, alcanoil C1-6-amino, alcanoil C1-6-(alquil C1-6)-amino, carbamoilo, alquil C1-6carbamoilo y bis(alquil C1-6)carbamoilo. In one aspect of the invention, R18 and R19, together with the nitrogen atom to which they are attached, form a 6-membered heterocyclic ring in which 1 annular carbon atom is optionally replaced by N or O and, said ring being optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, C1-6 halo-alkyl, C1-6 halo-alkoxy, hydroxy-alkyl C1-6, hydroxy-C1-6 alkoxy, C1-6 alkoxy-C1-6 alkyl, C1-6 alkoxy-C1-6 alkoxy, amino, C1-6-alkyl, bis (C1-6 alkyl ) amino, amino C1-6 alkyl, (C1-6 alkyl) -amino-C1-6 alkyl, bis (C1-6 alkyl) -amino-C1-6 alkyl, cyano-C1-6 alkyl, C1-6-sulfonyl alkyl, C1-6-sulfonylamino alkyl, C1-6-sulfonyl- (C1-6 alkyl) -amino, sulfamoyl, C1-6 alkyl sulfulfyl, bis (C1-6 alkyl) -sulfamoyl, C1- alkanoyl 6-amino, C 1-6 alkanoyl- (C 1-6 alkyl) -amino, carbamoyl, C 1-6 alkylcarbamoyl and bis (C 1-6 alkyl) carbamoyl.

En un aspecto de la invención, R18 y R19, junto con el átomo de nitrógeno al que están unidos, forman un anillo heterocíclico de 6 miembros en el que 1 átomo de carbono anular está opcionalmente reemplazado por N u O, y estando dicho anillo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, hidroxi, alquilo de C1-6, alcoxi de C1-6, halo-alquilo de C1-6, halo-alcoxi de C1-6, hidroxi-alquilo de C1-6, hidroxialcoxi de C1-6, alcoxi C1-6-alquilo de C1-6, alcoxi C1-6-alcoxi de C1-6, amino, alquil C1-6-amino, bis(alquil C1-6)-amino, amino-alquilo de C1-6, (alquil C1-6)-amino-alquilo de C1-6, bis(alquil C1-6)-amino-alquilo de C1-6, ciano-alquilo de C1-6, alquil C1-6-sulfonilo, alquil C1-6-sulfonilamino, alquil C1-6-sulfonil-(alquil C1-6)-amino, sulfamoilo, alquil C1-6-sulfamoilo, bis(alquil C1-6)-sulfamoilo, alcanoil C1-6-amino, alcanoil C1-6-(alquil C1-6)-amino, carbamoilo, alquil C1-6-carbamoilo y bis(alquil C1-6)carbamoilo. In one aspect of the invention, R18 and R19, together with the nitrogen atom to which they are attached, form a 6-membered heterocyclic ring in which 1 annular carbon atom is optionally replaced by N or O, and said ring being optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6 alkyl, C1-6 alkoxy, halo C1-6 alkyl, halo C1-6 alkoxy, hydroxy C1 alkyl -6, C 1-6 hydroxyalkoxy, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkoxy, amino, C 1-6 alkyl, bis (C 1-6 alkyl) -amino, C 1-6 amino-alkyl, (C 1-6 alkyl) -Camino-C 1-6 alkyl, bis (C 1-6 alkyl) -amino-C 1-6 alkyl, cyano-C 1-6 alkyl, C 1-6 alkyl 6-sulfonyl, C1-6 alkyl-sulfonylamino, C1-6 alkyl-sulfonyl- (C1-6 alkyl) -amino, sulfamoyl, C1-6 alkyl sulfamoyl, bis (C1-6 alkyl) -sulfamoyl, C1-6 alkanoyl -amino, C1-6 alkanoyl- (C1-6 alkyl) -amino, carbamoyl, C1-6-carbamoyl alkyl and bis (C1-6 alkyl) carbamoyl.

En un aspecto de la invención, R18 yR19, junto con el átomo de nitrógeno al que están unidos, forman un anillo de morfolina. In one aspect of the invention, R18 and R19, together with the nitrogen atom to which they are attached, form a morpholine ring.

En un aspecto de la invención, se proporciona un subconjunto de los compuestos de fórmula (I), o una sal farmacéuticamente aceptable de los mismos; In one aspect of the invention, a subset of the compounds of formula (I), or a pharmaceutically acceptable salt thereof, is provided;

m es 0, 1 ó 2; m is 0, 1 or 2;

X es un grupo enlazador seleccionado de –NR4CR6R7–, –OCR6R7–, –SCR6R7–, -S(O)CR6R7-, –S(O)2CR6R7–, -C(O)NR4CR6R7–, –NR4C(O)NR5CR6R7–, –S(O)2NR4CR6R7–, –NR4C(O)–, –S(O)2NR4– y –NR4S(O)2–; X is a linker group selected from –NR4CR6R7–, –OCR6R7–, –SCR6R7–, -S (O) CR6R7-, –S (O) 2CR6R7–, -C (O) NR4CR6R7–, –NR4C (O) NR5CR6R7– , –S (O) 2NR4CR6R7–, –NR4C (O) -, –S (O) 2NR4– and –NR4S (O) 2–;

R1 es un grupo seleccionado de alquilo de C1-6, carbociclilo, carbociclil-alquilo de C1-6, heterociclilo y heterociclilalquilo de C1-6, estando dicho grupo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, R9, –OR9, –COR9, –CONR9R10, –NR9R10 y –NR9COR10; R1 is a group selected from C1-6 alkyl, carbocyclyl, carbocyclyl-C1-6 alkyl, heterocyclyl and C1-6 heterocyclyl alkyl, said group being optionally substituted with one or more substituent groups selected from halo, cyano, nitro, R9 , –OR9, –COR9, –CONR9R10, –NR9R10 and –NR9COR10;

o X–R1 es –C(CH3)2OH o –CH2OH; or X-R1 is -C (CH3) 2OH or -CH2OH;

R2 se selecciona de arilo y heteroarilo estando dicho grupo sustituido con –NR17CONR18R19 y opcionalmente sustituido con uno o más grupos sustituyentes seleccionados independientemente de halo, ciano, nitro, –R11, –OR11, –COR11, –CONR11R12, –NR11R12 y –NR11COR12; R2 is selected from aryl and heteroaryl, said group being substituted with -NR17CONR18R19 and optionally substituted with one or more substituent groups independently selected from halo, cyano, nitro, -R11, -OR11, -COR11, -CONR11R12, -NR11R12 and -NR11COR12;

cada R3, cuando está presente, es metilo; each R3, when present, is methyl;

o, cuando X es –NR4CR6R7–, –NR4C(O)NR5CR6R7–, –NR4C(O)– o –NR4S(O)2–, R1 y R4, junto con el átomo o átomos a los que están unidos, forman un anillo heterocíclico de 4, 5, 6 ó 7 miembros en el que 1 átomo de carbono anular está opcionalmente reemplazado por N u O, y estando dicho anillo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, hidroxi, oxo, alquilo de C1-6, alcoxi de C1-6, halo-alquilo de C1-6, halo-alcoxi de C1-6, hidroxi-alquilo de C1-6, hidroxi-alcoxi de C1-6, alcoxi C1-6-alquilo de C1-6, alcoxi C1-6-alcoxi de C1-6, amino, alquil C1-6-amino, bis(alquil C1-6)-amino, amino-alquilo de C1-6, (alquil C1-6)-amino-alquilo de C1-6, bis(alquil C1-6)-amino-alquilo de C1-6, ciano-alquilo de C1-6, alquil C1-6-sulfonilo, alquil C1-6-sulfonilamino, alquil C1-6sulfonil-(alquil C1-6)-amino, sulfamoilo, alquil C1-6-sulfamoilo, bis(alquil C1-6)-sulfamoilo, alcanoil C1-6-amino, alcanoil C1-6-(alquil C1-6)-amino, carbamoilo, alquil C1-6-carbamoilo y bis(alquil C1-6)-carbamoilo; or, when X is –NR4CR6R7–, –NR4C (O) NR5CR6R7–, –NR4C (O) - or –NR4S (O) 2–, R1 and R4, together with the atom or atoms to which they are attached, form a 4, 5, 6 or 7-membered heterocyclic ring in which 1 ring carbon atom is optionally replaced by N or O, and said ring being optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo , C1-6 alkyl, C1-6 alkoxy, halo C1-6 alkyl, halo C1-6 alkoxy, hydroxy C1-6 alkyl, hydroxy C1-6 alkoxy, C1-6 alkoxy C1-6 alkyl, C1-6 alkoxy-C1-6 alkoxy, amino, C1-6-alkyl, bis (C1-6 alkyl) -amino, amino- C1-6 alkyl, (C1-6 alkyl) -amino-C1-6 alkyl, bis (C1-6 alkyl) -amino-C1-6 alkyl, cyano-C1-6 alkyl, C1-6 alkyl sulfonyl, C1-6 alkyl sulfonylamino, C1- alkyl 6sulfonyl- (C1-6 alkyl) -amino, sulfamoyl, C1-6 alkyl-sulfamoyl, bis (C1-6 alkyl) -sulfamoyl, C1-6-alkanoyl, C1-6 alkanoyl- (C1-6 alkyl) -amino carbamoyl C 1-6 alkylcarbamoyl and bis (C 1-6 alkyl) carbamoyl;

R9 y R10 son independientemente hidrógeno o un grupo seleccionado de alquilo de C1-6, carbociclilo y heterociclilo, estando dicho grupo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, hidroxi, oxo, alquilo de C1-6, alcoxi de C1-6, halo-alquilo de C1-6, halo-alcoxi de C1-6, hidroxi-alquilo de C1-6, hidroxi-alcoxi de C1-6, alcoxi C1-6-alquilo de C1-6, alcoxi C1-6-alcoxi de C1-6, amino, alquil C1-6-amino y bis(alquil C16)amino; R9 and R10 are independently hydrogen or a group selected from C1-6 alkyl, carbocyclyl and heterocyclyl, said group being optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, halo C1-6 alkyl, halo C1-6 alkoxy, hydroxy C1-6 alkyl, hydroxy C1-6 alkoxy, C1-6 alkoxy C1-6 alkyl, alkoxy C1-6-C1-6 alkoxy, amino, C1-6 alkyl, and bis (C16 alkyl) amino;

R11, R12, R17 y R18 son independientemente hidrógeno o un grupo seleccionado de alquilo de C1-6, carbociclilo y heterociclilo, estando dicho grupo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, hidroxi, oxo, alquilo de C1-6, alcoxi de C1-6, halo-alquilo de C1-6, halo-alcoxi de C1-6, hidroxi-alquilo de C1-6, hidroxi-alcoxi de C1-6, alcoxi C1-6-alquilo de C1-6, alcoxi C1-6-alcoxi de C1-6, amino, alquil C1-6-amino y bis(alquil C1-6)amino; y R11, R12, R17 and R18 are independently hydrogen or a group selected from C1-6 alkyl, carbocyclyl and heterocyclyl, said group being optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, alkyl C1-6, C1-6 alkoxy, halo C1-6 alkyl, halo C1-6 alkoxy, hydroxy C1-6 alkyl, hydroxy C1-6 alkoxy, C1-6 alkoxy C1 alkyl -6, C 1-6 alkoxy-C 1-6 alkoxy, amino, C 1-6 alkyl, and bis (C 1-6 alkyl) amino; Y

R19 es hidrógeno o un grupo seleccionado de alquilo de C1-6, cicloalquilo de C3-6, arilo, heteroarilo, aril-alquilo de C1-6 y heteroaril-alquilo de C1-6 estando dicho grupo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, hidroxi, oxo, alquilo de C1-6, alcoxi de C1-6, halo-alquilo de C1-6, halo-alcoxi de C16, hidroxi-alquilo de C1-6, hidroxi-alcoxi de C1-6, alcoxi C1-6-alquilo de C1-6, alcoxi C1-6-alcoxi de C1-6, amino, alquil C1-6amino, bis(alquil C1-6)-amino, amino-alquilo de C1-6, (alquil C1-6)-amino-alquilo de C1-6, bis(alquil C1-6)-amino-alquilo de C1-6, ciano-alquilo de C1-6, alquil C1-6-sulfonilo, alquil C1-6-sulfonilamino, alquil C1-6-sulfonil-(alquil C1-6)-amino, sulfamoilo, alquil C1-6-sulfamoilo, bis(alquil C1-6)-sulfamoilo, alcanoil C1-6-amino, alcanoil C1-6-(alquil C1-6)-amino, carbamoilo, alquil C1-6-carbamoilo y bis(alquil C1-6)-carbamoilo; R19 is hydrogen or a group selected from C1-6 alkyl, C3-6 cycloalkyl, aryl, heteroaryl, aryl-C1-6 alkyl and heteroaryl-C1-6 alkyl, said group being optionally substituted with one or more substituent groups Selected from halo, cyano, nitro, hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, C1-6 halo-alkyl, C16 halo-alkoxy, C1-6 hydroxy-alkyl, hydroxy-alkoxy C1-6, C1-6 alkoxy-C1-6 alkyl, C1-6 alkoxy-C1-6 alkoxy, amino, C1-6 alkyl, bis (C1-6 alkyl) -amino, amino- C1-6 alkyl , (C 1-6 alkyl) -Camino-C 1-6 alkyl, bis (C 1-6 alkyl) -amino-C 1-6 alkyl, cyano-C 1-6 alkyl, C 1-6 alkyl sulfonyl, C 1-6 alkyl 6-sulfonylamino, C1-6 alkyl-sulfonyl- (C1-6 alkyl) -amino, sulfamoyl, C1-6 alkyl sulfamoyl, bis (C1-6 alkyl) -sulfamoyl, C1-6 alkanoyl-amino, C1-6 alkanoyl - (C1-6 alkyl) -amino, carbamoyl, C1-6 alkylcarbamoyl and bis (C1-6 alkyl) -carbamoyl;

o R18 y R19, junto con el átomo de nitrógeno al que están unidos, forman un anillo heterocíclico de 6 miembros en el que 1 átomo de carbono anular está opcionalmente reemplazado por N u O, y estando dicho anillo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, hidroxi, oxo, alquilo de C1-6, alcoxi de C1-6, halo-alquilo de C1-6, halo-alcoxi de C1-6, hidroxi-alquilo de C1-6, hidroxi-alcoxi de C1-6, alcoxi C1-6-alquilo de C16, alcoxi C1-6-alcoxi de C1-6, amino, alquil C1-6-amino, bis(alquil C1-6)-amino, amino-alquilo de C1-6, (alquil C1-6)-aminoalquilo de C1-6, bis(alquil C1-6)-amino-alquilo de C1-6, ciano-alquilo de C1-6, alquil C1-6-sulfonilo, alquil C1-6sulfonilamino, alquil C1-6-sulfonil-(alquil C1-6)-amino, sulfamoilo, alquil C1-6-sulfamoilo, bis(alquil C1-6)-sulfamoilo, alcanoil C1-6-amino, alcanoil C1-6-(alquil C1-6)-amino, carbamoilo, alquil C1-6-carbamoilo y bis(alquil C1-6)carbamoilo. or R18 and R19, together with the nitrogen atom to which they are attached, form a 6-membered heterocyclic ring in which 1 annular carbon atom is optionally replaced by N or O, and said ring being optionally substituted with one or more groups substituents selected from halo, cyano, nitro, hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, halo C1-6 alkyl, halo C1-6 alkoxy, hydroxy C1-6 alkyl, hydroxy -C 1-6 alkoxy, C 1-6 alkoxy-C 16 alkyl, C 1-6 alkoxy-C 1-6 alkoxy, amino, C 1-6 alkyl, bis (C 1-6 alkyl) -amino, amino-alkyl C1-6, (C1-6 alkyl) -C 1-6 alkyl amino, bis (C1-6 alkyl) -C 1-6 alkyl, cyano-C1-6 alkyl, C1-6 alkyl sulfonyl, C1 alkyl -6sulfonylamino, C1-6 alkyl-sulfonyl- (C1-6 alkyl) -amino, sulfamoyl, C1-6 alkyl sulfamoyl, bis (C1-6 alkyl) -sulfamoyl, C1-6-alkanoyl-C1-6 alkanoyl (C1-6 alkyl) -amino, carbamoyl, C1-6 alkyl-carbamoyl and bis (C1-6 alkyl) carbamoyl.

En otro aspecto de la invención, se proporciona un subconjunto de los compuestos de fórmula (I), o una sal farmacéuticamente aceptable de los mismos; In another aspect of the invention, a subset of the compounds of formula (I), or a pharmaceutically acceptable salt thereof, is provided;

m es 0, 1 ó 2; m is 0, 1 or 2;

X es un grupo enlazador seleccionado de –NR4CR6R7–, –OCR6R7–, –SCR6R7–, –S(O)CR6R7–, –S(O)2CR6R7–, -C(O)NR4CR6R7–, –NR4C(O)NR5CR6R7–, –S(O)2NR4CR6R7–, –NR4C(O)–, –S(O)2NR4– y –NR4S(O)2–; X is a linker group selected from –NR4CR6R7–, –OCR6R7–, –SCR6R7–, –S (O) CR6R7–, –S (O) 2CR6R7–, -C (O) NR4CR6R7–, –NR4C (O) NR5CR6R7– , –S (O) 2NR4CR6R7–, –NR4C (O) -, –S (O) 2NR4– and –NR4S (O) 2–;

o X–R1 es –C(CH3)2OH o –CH2OH; or X-R1 is -C (CH3) 2OH or -CH2OH;

cada R3, cuando está presente, es metilo; each R3, when present, is methyl;

R9 y R10 son independientemente hidrógeno o un grupo seleccionado de alquilo de C1-6, carbociclilo y heterociclilo, estando dicho grupo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, hidroxi, alquilo de C1-6, alcoxi de C1-6, halo-alquilo de C1-6, halo-alcoxi de C1-6, hidroxi-alquilo de C1-6, hidroxialcoxi de C1-6, alcoxi C1-6-alquilo de C1-6, alcoxi C1-6-alcoxi de C1-6, amino, alquil C1-6-amino y bis(alquil C1-6)amino; R9 and R10 are independently hydrogen or a group selected from C1-6 alkyl, carbocyclyl and heterocyclyl, said group being optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6 alkyl, alkoxy C1-6, halo- C1-6 alkyl, halo- C1-6 alkoxy, hydroxy-C1-6 alkyl, hydroxy C1-6 alkoxy, C1-6 alkoxy-C1-6 alkyl, C1-6 alkoxy C 1-6 alkoxy, amino, C 1-6 alkyl, and bis (C 1-6 alkyl) amino;

R11, R12, R17 y R18 son independientemente hidrógeno o un grupo seleccionado de alquilo de C1-6, carbociclilo y heterociclilo, estando dicho grupo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, hidroxi, alquilo de C1-6, alcoxi de C1-6, halo-alquilo de C1-6, halo-alcoxi de C1-6, hidroxi-alquilo de C16, hidroxi-alcoxi de C1-6, alcoxi C1-6-alquilo de C1-6, alcoxi C1-6-alcoxi de C1-6, amino, alquil C1-6-amino y bis(alquil C16)amino; y R11, R12, R17 and R18 are independently hydrogen or a group selected from C1-6 alkyl, carbocyclyl and heterocyclyl, said group being optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1- alkyl 6, C1-6 alkoxy, C1-6 halo-alkyl, C1-6 halo-alkoxy, C16 hydroxy-alkyl, C1-6 hydroxy-alkoxy, C1-6 alkoxy-C1-6 alkyl, alkoxy C1-6-C1-6 alkoxy, amino, C1-6 alkyl, and bis (C16 alkyl) amino; Y

R19 es hidrógeno o un grupo seleccionado de alquilo de C1-6, cicloalquilo de C3-6, arilo, heteroarilo, aril-alquilo de C1-6 y heteroaril-alquilo de C1-6, estando dicho grupo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, hidroxi, alquilo de C1-6, alcoxi de C1-6, halo-alquilo de C1-6, halo-alcoxi de C1-6, hidroxi-alquilo de C1-6, hidroxi-alcoxi de C1-6, alcoxi C1-6-alquilo de C1-6, alcoxi C1-6-alcoxi de C1-6, amino, alquil C1-6amino, bis(alquil C1-6)-amino, amino-alquilo de C1-6, (alquil C1-6)-amino-alquilo de C1-6, bis(alquil C1-6)-amino-alquilo de C1-6, ciano-alquilo de C1-6, alquil C1-6-sulfonilo, alquil C1-6-sulfonilamino, alquil C1-6-sulfonil-(alquil C1-6)-amino, sulfamoilo, alquil C1-6-sulfamoilo, bis(alquil C1-6)-sulfamoilo, alcanoil C1-6-amino, alcanoil C1-6-(alquil C1-6)-amino, carbamoilo, alquil C1-6-carbamoilo y bis(alquil C1-6)-carbamoilo; R19 is hydrogen or a group selected from C1-6 alkyl, C3-6 cycloalkyl, aryl, heteroaryl, aryl-C1-6 alkyl and heteroaryl-C1-6 alkyl, said group being optionally substituted with one or more groups substituents selected from halo, cyano, nitro, hydroxy, C1-6 alkyl, C1-6 alkoxy, C1-6 halo-alkyl, C1-6 halo-alkoxy, C1-6 hydroxy-alkyl, hydroxy-alkoxy C 1-6, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkoxy, amino, C 1-6 alkyl, bis (C 1-6 alkyl) -amino, C 1-6 amino-alkyl 6, (C1-6 alkyl) -amino-C1-6 alkyl, bis (C1-6 alkyl) -amino-C1-6 alkyl, cyano-C1-6 alkyl, C1-6 alkyl sulfonyl, C1 alkyl -6-sulfonylamino, C1-6 alkyl-sulfonyl- (C1-6 alkyl) -amino, sulfamoyl, C1-6 alkyl sulfamoyl, bis (C1-6 alkyl) -sulfamoyl, C1-6-alkanoyl, C1- alkanoyl 6- (C1-6 alkyl) -amino, carbamoyl, C1-6 alkyl-carbamoyl and bis (C1-6 alkyl) -carbamoyl;

o R18 y R19, junto con el átomo de nitrógeno al que están unidos, forman un anillo heterocíclico de 6 miembros en el que 1 átomo de carbono anular está opcionalmente reemplazado por N u O, y estando dicho anillo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, hidroxi, alquilo de C1-6, alcoxi de C1-6, halo-alquilo de C1-6, halo-alcoxi de C1-6, hidroxi-alquilo de C1-6, hidroxi-alcoxi de C1-6, alcoxi C1-6-alquilo de C1-6, alcoxi C1-6-alcoxi de C1-6, amino, alquil C1-6-amino, bis(alquil C1-6)-amino, amino-alquilo de C1-6, (alquil C1-6)-aminoalquilo de C1-6, bis(alquil C1-6)-amino-alquilo de C1-6, ciano-alquilo de C1-6, alquil C1-6-sulfonilo, alquil C1-6sulfonilamino, alquil C1-6-sulfonil-(alquil C1-6)-amino, sulfamoilo, alquil C1-6-sulfamoilo, bis(alquil C1-6)-sulfamoilo, alcanoil C1-6-amino, alcanoil C1-6-(alquil C1-6)-amino, carbamoilo, alquil C1-6-carbamoilo y bis(alquil C1-6)carbamoilo. or R18 and R19, together with the nitrogen atom to which they are attached, form a 6-membered heterocyclic ring in which 1 annular carbon atom is optionally replaced by N or O, and said ring being optionally substituted with one or more groups substituents selected from halo, cyano, nitro, hydroxy, C1-6 alkyl, C1-6 alkoxy, C1-6 halo-alkyl, C1-6 halo-alkoxy, C1-6 hydroxy-alkyl, hydroxy-alkoxy C1-6, C1-6 alkoxy-C1-6 alkyl, C1-6 alkoxy-C1-6 alkoxy, amino, C1-6-alkyl, bis (C1-6 alkyl) -amino, amino-alkyl C1-6, (C1-6 alkyl) -C 1-6 alkyl amino, bis (C1-6 alkyl) -C 1-6 alkyl, cyano-C1-6 alkyl, C1-6 alkyl sulfonyl, C1 alkyl -6sulfonylamino, C1-6 alkyl-sulfonyl- (C1-6 alkyl) -amino, sulfamoyl, C1-6 alkyl sulfamoyl, bis (C1-6 alkyl) -sulfamoyl, C1-6-alkanoyl-C1-6 alkanoyl (C1-6 alkyl) -amino, carbamoyl, C1-6 alkyl-carbamoyl and bis (C1-6 alkyl) carbamoyl.

m es 0, 1 ó 2; m is 0, 1 or 2;

X es un grupo enlazador seleccionado de –NR4CH2–, –OCH2–, –OCH(CH3)–, –OC(CH3)2–, -SCH2–, –SCH(CH3)–, -SC(CH3)2–, –S(O)CH2–, –S(O)CH(CH3)–, –S(O)C(CH3)2–, -S(O)2CH2–, –S(O)2CH(CH3)–, –S(O)2C(CH3)2–, -C(O)NR4–y –NR4C(O)–; X is a linker group selected from –NR4CH2–, –OCH2–, –OCH (CH3) -, –OC (CH3) 2–, -SCH2–, –SCH (CH3) -, -SC (CH3) 2–, - S (O) CH2–, –S (O) CH (CH3) -, –S (O) C (CH3) 2–, -S (O) 2CH2–, –S (O) 2CH (CH3) -, - S (O) 2C (CH3) 2–, -C (O) NR4 – and –NR4C (O) -;

R1 es un grupo seleccionado de adamantilo, metilo, etilo, propilo, butilo, isobutilo, terc–butilo, ciclopentilo, ciclohexilo, fenilo, bencilo, fenetilo, pirrolidinilo, pirrolilo, imidazolilo, pirazolilo, furanilo, tienilo, piridinilo, pirimidinilo, pirazinilo, pirrolidinilinetilo, pirrolidiniletilo, pirrolilmetilo, pirroliletilo, imidazolilmetilo, imidazoliletilo, pirazolilmetilo, pirazoliletilo, furanilmetilo, furaniletilo, tienilmetilo, tieniletilo, piridinilinetilo, piridiniletilo, pirimidinilmetilo, pirimidiniletilo, pirazinilmetilo y piraziniletilo, estando dicho grupo opcionalmente sustituido con 1, 2 ó 3 grupos sustituyentes seleccionados de halo, ciano, nitro, R9, –OR9, –COR9, –CONR9R10, –NR9R10 y –NR9COR10; R1 is a group selected from adamantyl, methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, phenethyl, pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolidinylinethyl, pyrrolidinylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, pyrazolylmethyl, pyrazolylethyl, furanylmethyl, furanylethyl, thienylmethyl, thienylethyl, pyridinylinethyl, pyridinylethyl, pyrimidinylmethyl, pyrazinyl, 3-substituted groups, with 3-substituted groups of 3 halo, cyano, nitro, R9, –OR9, –COR9, –CONR9R10, –NR9R10 and –NR9COR10;

o X–R1 es –C(CH3)2OH o –CH2OH; or X-R1 is -C (CH3) 2OH or -CH2OH;

R2 se selecciona de arilo y heteroarilo de 5 ó 6 miembros, estando dicho grupo sustituido con -NHCONR18R19 y opcionalmente sustituido con uno o más grupos sustituyentes seleccionados independientemente de halo, ciano, nitro, –R11, –OR11, –COR11, –CONR11R12, –NR11R12 y –NR11COR12; R2 is selected from 5 or 6 membered aryl and heteroaryl, said group being substituted with -NHCONR18R19 and optionally substituted with one or more substituent groups independently selected from halo, cyano, nitro, -R11, -OR11, -COR11, -CONR11R12, –NR11R12 and –NR11COR12;

cada R3, cuando está presente, es metilo; each R3, when present, is methyl;

R4 es hidrógeno o alquilo de C1-6; R4 is hydrogen or C1-6 alkyl;

o, cuando X es –NR4CH2– o –NR4C(O)–, R1 y R4, junto con el átomo o átomos a los que están unidos, forman un anillo heterocíclico de 5 ó 6 miembros en el que 1 átomo de carbono anular está opcionalmente reemplazado por N u O, y estando dicho anillo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, hidroxi, alquilo de C1-6, alcoxi de C1-6, halo-alquilo de C1-6, halo-alcoxi de C1-6, hidroxi-alquilo de C1-6, hidroxi-alcoxi de C1-6, alcoxi C1-6-alquilo de C1-6, alcoxi C1-6-alcoxi de C1-6, amino, alquil C1-6-amino, bis(alquil C1-6)amino, amino-alquilo de C1-6, (alquil C1-6)-amino-alquilo de C1-6, bis(alquil C1-6)-amino-alquilo de C1-6, ciano-alquilo de C1-6, alquil C1-6-sulfonilo, alquil C1-6-sulfonilamino, alquil C1-6-sulfonil-(alquil C1-6)-amino, sulfamoilo, alquil C1-6sulfamoilo, bis(alquil C1-6)-sulfamoilo, alcanoil C1-6-amino, alcanoil C1-6-(alquil C1-6)-amino, carbamoilo, alquil C1-6carbamoilo y bis(alquil C1-6)-carbamoilo; or, when X is –NR4CH2– or –NR4C (O) -, R1 and R4, together with the atom or atoms to which they are attached, form a 5- or 6-membered heterocyclic ring in which 1 annular carbon atom is optionally replaced by N or O, and said ring being optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6 alkyl, C1-6 alkoxy, halo- C1-6 alkyl, halo C 1-6 alkoxy, C 1-6 hydroxy-alkyl, C 1-6 hydroxy-alkoxy, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkoxy, amino, C 1-6 alkyl 6-amino, bis (C1-6 alkyl) amino, amino-C1-6 alkyl, (C1-6 alkyl) -amino-C1-6 alkyl, bis (C1-6 alkyl) -amino-C1- alkyl 6, cyano-C 1-6 alkyl, C 1-6 alkyl sulfonyl, C 1-6 alkyl sulfonylamino, C 1-6 alkyl sulfonyl- (C 1-6 alkyl) -amino, sulfamoyl, C 1-6 alkyl sulfamoyl, bis (alkyl C1-6) -sulfamoyl, C1-6 alkanoyl-amino, C1-6 alkanoyl- (C1-6 alkyl) -amino, carbamoyl, C1-6 alkylcarbamoyl and bis (C1-6 alkyl) -carbamoyl;

R11, R12 y R18 son independientemente hidrógeno o un grupo seleccionado de alquilo de C1-6, carbociclilo y heterociclilo, estando dicho grupo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, hidroxi, alquilo de C1-6, alcoxi de C1-6, halo-alquilo de C1-6, halo-alcoxi de C1-6, hidroxi-alquilo de C16, hidroxi-alcoxi de C1-6, alcoxi C1-6-alquilo de C1-6, alcoxi C1-6-alcoxi de C1-6, amino, alquil C1-6-amino y bis(alquil C16)amino; y R11, R12 and R18 are independently hydrogen or a group selected from C1-6 alkyl, carbocyclyl and heterocyclyl, said group being optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6 alkyl, C1-6 alkoxy, halo C1-6 alkyl, halo C1-6 alkoxy, hydroxyC16 alkyl, hydroxy C1-6 alkoxy, C1-6 alkoxy C1-6 alkyl, C1- alkoxy C 1-6 alkoxy, amino, C 1-6 alkyl, and bis (C 16 alkyl) amino; Y

En otro aspecto particular del compuesto de fórmula (I), o una sal farmacéuticamente aceptable del mismo; In another particular aspect of the compound of formula (I), or a pharmaceutically acceptable salt thereof;

m es 0 ó 1; m is 0 or 1;

1Y es CH e Y2 es N; 1Y is CH and Y2 is N;

X es un grupo enlazador seleccionado de –S(O)2CH2–, –S(O)2CH(CH3)– y –S(O)2C(CH3)2–; X is a linker group selected from –S (O) 2CH2–, –S (O) 2CH (CH3) - and –S (O) 2C (CH3) 2–;

R1 es un grupo seleccionado de metilo, etilo, propilo, butilo, isobutilo, terc–butilo, ciclopropilo, ciclopentilo, ciclohexilo, fenilo, bencilo, fenetilo, piridinilo, pirrolidinilo, pirazoliletilo, furanilmetilo, oxetanilo, imidazolilmetilo, tienilmetilo, tiazolilmetilo, tiadiazolilmetilo y piraziniletilo, estando dicho grupo opcionalmente sustituido con 1 ó 2 grupos sustituyentes seleccionados de amino, halo, ciano, metilo, metoxi, trifluorometilo, trifluorometoxi, –NMe2, -NHCOCH3, –CONH2 y –CONHCH3; R1 is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, benzyl, phenethyl, pyridinyl, pyrrolidinyl, pyrazolylethyl, furanylmethyl, oxetanyl, imidazolylmethyl, thienylmethyl, thiazolethylmethyl, thiazolemethyl, methyl pyrazinylethyl, said group being optionally substituted with 1 or 2 substituent groups selected from amino, halo, cyano, methyl, methoxy, trifluoromethyl, trifluoromethoxy, -NMe2, -NHCOCH3, -CONH2 and -CONHCH3;

o –XR1 es –C(CH3)2OH o –CH2OH; or –XR1 is –C (CH3) 2OH or –CH2OH;

R2 se selecciona de fenilo, pirrolilo, imidazolilo, pirazolilo, furanilo, tienilo, piridinilo, pirimidinilo, piridazinilo y tiazolilo, estando dicho grupo sustituido con –NHCONHR19 y opcionalmente sustituido con uno o más grupos sustituyentes seleccionados independientemente de halo, ciano, nitro, –R11, –OR11, –COR11, –CONR11R12, –NR11R12 y -NR11COR12; R2 is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl and thiazolyl, said group being substituted with -NHCONHR19 and optionally substituted with one or more substituent groups independently selected from halo, cyano, nitro, - R11, –OR11, –COR11, –CONR11R12, –NR11R12 and -NR11COR12;

R3, cuando está presente, es metilo; R3, when present, is methyl;

R11, R12 y R18 son independientemente hidrógeno o un grupo seleccionado de alquilo de C1-6, carbociclilo y heterociclilo, estando dicho grupo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, hidroxi, oxo, alquilo de C1-6, alcoxi de C1-6, halo-alquilo de C1-6, halo-alcoxi de C1-6, hidroxi-alquilo de C1-6, hidroxi-alcoxi de C1-6, alcoxi C1-6-alquilo de C1-6, alcoxi C1-6-alcoxi de C1-6, amino, alquil C1-6-amino y bis(alquil C1-6)amino; y R11, R12 and R18 are independently hydrogen or a group selected from C1-6 alkyl, carbocyclyl and heterocyclyl, said group being optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, C1- alkyl 6, C1-6 alkoxy, halo C1-6 alkyl, halo C1-6 alkoxy, hydroxy C1-6 alkyl, hydroxy C1-6 alkoxy, C1-6 alkoxy C1-6 alkyl , C1-6 alkoxy-C1-6 alkoxy, amino, C1-6 alkyl, and bis (C1-6 alkyl) amino; Y

R19 es hidrógeno o un grupo seleccionado de alquilo de C1-6, cicloalquilo de C3-6, arilo, heteroarilo, aril-alquilo de C1-6 y heteroaril-alquilo de C1-6, estando dicho grupo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, hidroxi, oxo, alquilo de C1-6, alcoxi de C1-6, halo-alquilo de C1-6, halo-alcoxi de C16, hidroxi-alquilo de C1-6, hidroxi-alcoxi de C1-6, alcoxi C1-6-alquilo de C1-6, alcoxi C1-6-alcoxi de C1-6, amino, alquil C1-6amino, bis(alquil C1-6)-amino, amino-alquilo de C1-6, (alquil C1-6)-amino-alquilo de C1-6, bis(alquil C1-6)-amino-alquilo de C1-6, ciano-alquilo de C1-6, alquil C1-6-sulfonilo, alquil C1-6-sulfonilamino, alquil C1-6-sulfonil-(alquil C1-6)-amino, sulfamoilo, alquil C1-6-sulfamoilo, bis(alquil C1-6)-sulfamoilo, alcanoil C1-6-amino, alcanoil C1-6-(alquil C1-6)-amino, carbamoilo, alquil C1-6-carbamoilo y bis(alquil C1-6)carbamoilo. R19 is hydrogen or a group selected from C1-6 alkyl, C3-6 cycloalkyl, aryl, heteroaryl, aryl-C1-6 alkyl and heteroaryl-C1-6 alkyl, said group being optionally substituted with one or more groups substituents selected from halo, cyano, nitro, hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, C1-6 halo-alkyl, C16 halo-alkoxy, C1-6 hydroxy-alkyl, hydroxy-alkoxy C 1-6, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkoxy, amino, C 1-6 alkyl, bis (C 1-6 alkyl) -amino, C 1-6 amino-alkyl 6, (C1-6 alkyl) -amino-C1-6 alkyl, bis (C1-6 alkyl) -amino-C1-6 alkyl, cyano-C1-6 alkyl, C1-6 alkyl sulfonyl, C1 alkyl -6-sulfonylamino, C1-6 alkyl-sulfonyl- (C1-6 alkyl) -amino, sulfamoyl, C1-6 alkyl sulfamoyl, bis (C1-6 alkyl) -sulfamoyl, C1-6-alkanoyl, C1- alkanoyl 6- (C1-6 alkyl) -amino, carbamoyl, C1-6 alkyl-carbamoyl and bis (C1-6 alkyl) carbamoyl.

m es 0 ó 1; m is 0 or 1;

1Y es CH e Y2 es N; 1Y is CH and Y2 is N;

R1 es un grupo seleccionado de metilo, etilo, propilo, butilo, isobutilo, terc–butilo, ciclopropilo, ciclopentilo, ciclohexilo, fenilo, bencilo, fenetilo, piridinilo, pirazoliletilo, furanilmetilo, tienilmetilo, tiazolilmetilo, tiadiazolilmetilo y piraziniletilo, estando dicho grupo opcionalmente sustituido con 1 ó 2 grupos sustituyentes seleccionados de amino, halo, ciano, metilo, metoxi, trifluorometilo, trifluorometoxi, –NHCOCH3, –CONH2 y –CONHCH3; R1 is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, benzyl, phenethyl, pyridinyl, pyrazolylethyl, furanylmethyl, thienylmethyl, thiazolylmethyl, thiadiazolylmethyl and pyrazinylethyl group being optionally substituted with 1 or 2 substituent groups selected from amino, halo, cyano, methyl, methoxy, trifluoromethyl, trifluoromethoxy, -NHCOCH3, -CONH2 and -CONHCH3;

o –XR1 es –C(CH3)2OH o –CH2OH; or –XR1 is –C (CH3) 2OH or –CH2OH;

R3, cuando está presente, es metilo; R3, when present, is methyl;

R19 es hidrógeno o un grupo seleccionado de alquilo de C1-6, cicloalquilo de C3-6, arilo, heteroarilo, aril-alquilo de C1-6 y heteroaril-alquilo de C1-6, estando dicho grupo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, hidroxi, alquilo de C1-6, alcoxi de C1-6, halo-alquilo de C1-6, halo-alcoxi de C1-6, hidroxi-alquilo de C1-6, hidroxi-alcoxi de C1-6, alcoxi C1-6-alquilo de C1-6, alcoxi C1-6-alcoxi de C1-6, amino, alquil C1-6amino, bis(alquil C1-6)-amino, amino-alquilo de C1-6, (alquil C1-6)-amino-alquilo de C1-6, bis(alquil C1-6)-amino-alquilo de C1-6, ciano-alquilo de C1-6, alquil C1-6-sulfonilo, alquil C1-6-sulfonilamino, alquil C1-6-sulfonil-(alquil C1-6)-amino, R19 is hydrogen or a group selected from C1-6 alkyl, C3-6 cycloalkyl, aryl, heteroaryl, aryl-C1-6 alkyl and heteroaryl-C1-6 alkyl, said group being optionally substituted with one or more groups substituents selected from halo, cyano, nitro, hydroxy, C1-6 alkyl, C1-6 alkoxy, C1-6 halo-alkyl, C1-6 halo-alkoxy, C1-6 hydroxy-alkyl, hydroxy-alkoxy C 1-6, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkoxy, amino, C 1-6 alkyl, bis (C 1-6 alkyl) -amino, C 1-6 amino-alkyl 6, (C1-6 alkyl) -amino-C1-6 alkyl, bis (C1-6 alkyl) -amino-C1-6 alkyl, cyano-C1-6 alkyl, C1-6 alkyl sulfonyl, C1 alkyl -6-sulfonylamino, C1-6 alkyl-sulfonyl- (C1-6 alkyl) -amino,

sulfamoilo, alquil C1-6-sulfamoilo, bis(alquil C1-6)-sulfamoilo, alcanoil C1-6-amino, alcanoil C1-6-(alquil C1-6)-amino, carbamoilo, alquil C1-6-carbamoilo y bis(alquil C1-6)carbamoilo. En un aspecto particular adicional del compuesto de fórmula (I), o una sal farmacéuticamente aceptable del mismo; m es 1; X es un grupo enlazador seleccionado de –S(O)2CH2–, –S(O)2CH(CH3)– y –S(O)2C(CH3)2–; sulfamoyl, C1-6 alkyl-sulfamoyl, bis (C1-6 alkyl) -sulfamoyl, C1-6-alkanoyl, C1-6 alkanoyl- (C1-6 alkyl) -amino, carbamoyl, C1-6 alkylcarbamoyl and bis (C1-6 alkyl) carbamoyl. In a further particular aspect of the compound of formula (I), or a pharmaceutically acceptable salt thereof; m is 1; X is a linker group selected from –S (O) 2CH2–, –S (O) 2CH (CH3) - and –S (O) 2C (CH3) 2–;

1Y es CH e Y2 es N. R1 es un grupo seleccionado de metilo, etilo, propilo, butilo, isobutilo, terc–butilo, ciclopropilo, ciclopentilo, ciclohexilo, fenilo, bencilo, fenetilo, piridinilo, pirrolidinilo, pirazoliletilo, furanilmetilo, oxetanilo, imidazolilmetilo, tienilmetilo, tiazolilmetilo, tiadiazolilmetilo y piraziniletilo, estando dicho grupo opcionalmente sustituido con 1 ó 2 grupos sustituyentes seleccionados de amino, halo, ciano, metilo, metoxi, trifluorometilo, trifluorometoxi, –NMe2, -NHCOCH3, –CONH2 y –CONHCH3; 1Y is CH and Y2 is N. R1 is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, benzyl, phenethyl, pyridinyl, pyrrolidinyl, pyrazolylethyl, furanylmethyl, oxetanyl, imidazolylmethyl, thienylmethyl, thiazolylmethyl, thiadiazolylmethyl and pyrazinylethyl, said group being optionally substituted with 1 or 2 groups substituents selected from amino, halo, cyano, methyl, methoxy, trifluoromethyl, trifluoromethoxy, -NMe2, -NHCOCH3, –CONH2 and –CONHCH3;

R2 es fenilo o piridilo sustituido con –NHCONHR19 y opcionalmente sustituido con uno o más grupos sustituyentes seleccionados independientemente de fluoro, metilo, metoxi, hidroximetilo, cianometilo, –CONH2, –CONHCH3 y -CON(CH3)2; R2 is phenyl or pyridyl substituted with -NHCONHR19 and optionally substituted with one or more substituent groups independently selected from fluoro, methyl, methoxy, hydroxymethyl, cyanomethyl, -CONH2, -CONHCH3 and -CON (CH3) 2;

R3 es metilo; y R19R3 is methyl; and R19

es hidrógeno o un grupo seleccionado de metilo, etilo, propilo, i–propilo, butilo, i–butilo, t–butilo, pentilo, ciclopropilo, ciclobutilo, ciclopentilo, ciclohexilo, fenilo, tienilo, imidazoilmetilo, isoxazolilo, pirazolilo, pirazolilmetilo, piridinilo y pirimidinilo, estando dicho grupo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, hidroxi, oxo, alquilo de C1-6, alcoxi de C1-6, halo-alquilo de C1-6, halo-alcoxi de C16, hidroxi-alquilo de C1-6, hidroxi-alcoxi de C1-6, alcoxi C1-6-alquilo de C1-6, alcoxi C1-6-alcoxi de C1-6, amino, alquil C1-6amino, bis(alquil C1-6)-amino, amino-alquilo de C1-6, (alquil C1-6)-amino-alquilo de C1-6, bis(alquil C1-6)-amino-alquilo de C1-6, ciano-alquilo de C1-6, alquil C1-6-sulfonilo, alquil C1-6-sulfonilamino, alquil C1-6-sulfonil-(alquil C1-6)-amino, sulfamoilo, alquil C1-6-sulfamoilo, bis(alquil C1-6)-sulfamoilo, alcanoil C1-6-amino, alcanoil C1-6-(alquil C1-6)-amino, carbamoilo, alquil C1-6-carbamoilo y bis(alquil C1-6)carbamoilo. is hydrogen or a group selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, imidazoylmethyl, isoxazolyl, pyrazolyl, pyrazolylmethyl, pyridinyl and pyrimidinyl, said group being optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, halo- C1-6 alkyl, halo-alkoxy of C16, hydroxy-C 1-6 alkyl, hydroxy-C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkoxy, amino, C 1-6 alkyl, bis (alkyl C1-6) -amino, C1-6 amino-alkyl, (C1-6 alkyl) -amino-C1-6 alkyl, bis (C1-6 alkyl) -amino-C1-6 alkyl, cyano-alkyl C1-6, C1-6-sulfonyl alkyl, C1-6-sulfonylamino alkyl, C1-6-sulfonyl- (C1-6 alkyl) -amino, sulfamoyl, C1-6-sulfamoyl alkyl, bis (C1-6 alkyl) -sulfamoyl, C1-6 alkanoyl-amino, C1-6 alkanoyl- (C1-6 alkyl) -amino, carbamoyl, C1-6-ca alkyl rbamoyl and bis (C1-6 alkyl) carbamoyl.

En un aspecto particular adicional del compuesto de fórmula (I), o una sal farmacéuticamente aceptable del mismo; In a further particular aspect of the compound of formula (I), or a pharmaceutically acceptable salt thereof;

m es 1; m is 1;

1Y es CH e Y2 es N. 1Y is CH and Y2 is N.

R3 es metilo; y R3 is methyl; Y

R19R19

es hidrógeno o un grupo seleccionado de metilo, etilo, propilo, i–propilo, butilo, i–butilo, t–butilo, pentilo, ciclopropilo, ciclobutilo, ciclopentilo, ciclohexilo, fenilo, tienilo, imidazoilmetilo, isoxazolilo, pirazolilo, pirazolilmetilo, piridinilo y pirimidinilo, estando dicho grupo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, hidroxi, alquilo de C1-6, alcoxi de C1-6, halo-alquilo de C1-6, halo-alcoxi de C1-6, hidroxi-alquilo de C1-6, hidroxi-alcoxi de C1-6, alcoxi C1-6-alquilo de C1-6, alcoxi C1-6-alcoxi de C1-6, amino, alquil C1-6amino, bis(alquil C1-6)-amino, amino-alquilo de C1-6, (alquil C1-6)-amino-alquilo de C1-6, bis(alquil C1-6)-amino-alquilo de C1-6, ciano-alquilo de C1-6, alquil C1-6-sulfonilo, alquil C1-6-sulfonilamino, alquil C1-6-sulfonil-(alquil C1-6)-amino, sulfamoilo, alquil C1-6-sulfamoilo, bis(alquil C1-6)-sulfamoilo, alcanoil C1-6-amino, alcanoil C1-6-(alquil C1-6)-amino, carbamoilo, alquil C1-6-carbamoilo y bis(alquil C1-6)carbamoilo. is hydrogen or a group selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, imidazoylmethyl, isoxazolyl, pyrazolyl, pyrazolylmethyl, pyridinyl and pyrimidinyl, said group being optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6 alkyl, C1-6 alkoxy, halo- C1-6 alkyl, halo-C1- alkoxy 6, hydroxy-C 1-6 alkyl, hydroxy-C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkoxy, amino, C 1-6 alkyl, bis (alkyl C1-6) -amino, C1-6 amino-alkyl, (C1-6 alkyl) -amino-C1-6 alkyl, bis (C1-6 alkyl) -amino-C1-6 alkyl, cyano-alkyl C1-6, C1-6-sulfonyl alkyl, C1-6-sulfonylamino alkyl, C1-6-sulfonyl- (C1-6 alkyl) -amino, sulfamoyl, C1-6-sulfamoyl alkyl, bis (C1-6 alkyl) -sulfamoyl, C1-6 alkanoyl-amino, C1-6 alkanoyl- (C1-6 alkyl) -amino, carbamoyl, C1-6-carbamyl oyl and bis (C1-6 alkyl) carbamoyl.

m es 1; m is 1;

1Y es CH e Y2 es N. 1Y is CH and Y2 is N.

R1 es un grupo seleccionado de metilo, etilo, isopropilo, terc–butilo, ciclopropilo, ciclopentilo, ciclohexilo, -CH2CH2OH, –CH2CH2OMe, –CH2CH2NMe2, –CH2CH2NC(O)CH3, -CH2CONH2, fenilo, 3,5–difluorofenilo, 4-fluorofenilo, 2–clorofenilo, 4–clorofenilo, 2–trifluorometilfenilo, 2–metoxifenilo, 2–metilfenilo, 4–acetamidofenilo, 4-aminofenilo, piridin–4–ilo, piridin–2–ilo, oxetan–3–ilo, 2–oxopirolidin–3–ilo, 1–metilimidazol–5–ilmetilo, 1-metilpirrolidin–3–ilo, tiazol–2–ilo, 4–metiltiazol–2–ilo, y 3–metil–1,3,4–tiadiazol–2–ilo; R1 is a group selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, -CH2CH2OH, -CH2CH2OMe, -CH2CH2NMe2, -CH2CH2NC (O) CH3, -CH2CONH2, phenyl, 3,5-difluorophenyl, 4 -fluorophenyl, 2-chlorophenyl, 4-chlorophenyl, 2-trifluoromethylphenyl, 2-methoxyphenyl, 2-methylphenyl, 4-acetamidophenyl, 4-aminophenyl, pyridin-4-yl, pyridin-2-yl, oxetan-3-yl, 2 -Oxopyrolidin-3-yl, 1-methylimidazol-5-ylmethyl, 1-methylpyrrolidin-3-yl, thiazol-2-yl, 4-methylthiazole-2-yl, and 3-methyl-1,3,4-thiadiazole- 2-yl;

R2 es R2 is

A1 A1

en la que A1 y A2 se seleccionan de CH o N con la condición de que al menos uno de A1 o A2 es CH; R17 es hidrógeno; R18 es hidrógeno; in which A1 and A2 are selected from CH or N with the proviso that at least one of A1 or A2 is CH; R17 is hydrogen; R18 is hydrogen;

R19R19

es hidrógeno o un grupo seleccionado de metilo, etilo, propilo, i–propilo, butilo, i–butilo, t–butilo, pentilo, ciclopropilo, ciclobutilo, ciclopentilo, ciclohexilo, –CH2(ciclopropilo), –CH2CH2NMe2, –CH(CH3)CH2OH, -C(CH3)2CH2OH, –CH2CH2OH, –CH2CH2CH2OH, 4–metilfenilo, 4–clorofenilo, 4–trifluorometilfenilo, 4–fluorofenilo, 4-metoxifenilo, 3,4–difluorofenilo, tien–2–ilo, –CH2(imidazol–2–ilo), –CH2(imidazol–3–ilo), isoxazol–3–ilo, 6–oxo–1H– piridin–2–ilo, 5–metilisoxazol–3–ilo, 1–metilpirazol–4–ilo, –CH2(1–metilpirazol–4–ilo), 6–metoxipiridin–3–ilo, 5-fluoropiridin–2–ilo, piridinil–2–ilo, pirimidin–2–ilo, y 1H–pirazol–3–ilo; is hydrogen or a group selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, –CH2 (cyclopropyl), –CH2CH2NMe2, –CH (CH3 ) CH2OH, -C (CH3) 2CH2OH, –CH2CH2OH, –CH2CH2CH2OH, 4-methylphenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, 4-fluorophenyl, 4-methoxyphenyl, 3,4-difluorophenyl, thien-2-yl, –CH2 (imidazol-2-yl), -CH2 (imidazol-3-yl), isoxazol-3-yl, 6-oxo-1H- pyridin-2-yl, 5-methylisoxazole-3-yl, 1-methylpyrazole-4– ilo, -CH2 (1-methylpyrazol-4-yl), 6-methoxypyridin-3-yl, 5-fluoropyridin-2-yl, pyridinyl-2-yl, pyrimidin-2-yl, and 1H-pyrazole-3-yl ;

y, R3 es metilo. and, R3 is methyl.

m es 1; m is 1;

1Y es CH e Y2 es N. 1Y is CH and Y2 is N.

R1 es un grupo seleccionado de metilo, isopropilo, ciclopropilo, ciclohexilo, –CH2CH2OH, –CH2CH2NC(O)CH3, -CH2CONH2, fenilo, 4–fluorofenilo, 2–clorofenilo, 2–trifluorometilfenilo, 2–metoxifenilo, 2–metilfenilo, 4-acetamidofenilo, 4–aminofenilo, piridin–4–ilo, piridin–2–ilo, 2–oxopirolidin–3–ilo, tiazol–2–ilo, 4–metiltiazol–2–ilo, y 3–metil–1,3,4–tiadiazol–2–ilo; R1 is a group selected from methyl, isopropyl, cyclopropyl, cyclohexyl, -CH2CH2OH, -CH2CH2NC (O) CH3, -CH2CONH2, phenyl, 4-fluorophenyl, 2-chlorophenyl, 2-trifluoromethylphenyl, 2-methoxyphenyl, 2-methylphenyl, 4-methylphenyl, 4 -acetamidophenyl, 4-aminophenyl, pyridin-4-yl, pyridin-2-yl, 2-oxopyrolidin-3-yl, thiazol-2-yl, 4-methylthiazole-2-yl, and 3-methyl-1,3, 4-thiadiazol-2-yl;

R2 es R2 is

A1 A1

R17 R18 R17 R18

R19R19

es hidrógeno o un grupo seleccionado de metilo, etilo, propilo, i–propilo, butilo, i–butilo, t–butilo, pentilo, ciclopropilo, ciclobutilo, ciclopentilo, ciclohexilo, –CH2(ciclopropilo), –CH2CH2NMe2, –CH(CH3)CH2OH, -C(CH3)2CH2OH, –CH2CH2OH, –CH2CH2CH2OH, 4–metilfenilo, 4–clorofenilo, 4–trifluorometilfenilo, 4–fluorofenilo, 4-metoxifenilo, 3,4–difluorofenilo, tien–2–ilo, –CH2(imidazol–2–ilo), –CH2(imidazol–3–ilo), isoxazol–3–ilo, 6–oxo–1H– is hydrogen or a group selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, –CH2 (cyclopropyl), –CH2CH2NMe2, –CH (CH3 ) CH2OH, -C (CH3) 2CH2OH, –CH2CH2OH, –CH2CH2CH2OH, 4-methylphenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, 4-fluorophenyl, 4-methoxyphenyl, 3,4-difluorophenyl, thien-2-yl, –CH2 (imidazol-2-yl), -CH2 (imidazol-3-yl), isoxazol-3-yl, 6-oxo-1H-

piridin–2–ilo, 5–metilisoxazol–3–ilo, 1–metilpirazol–4–ilo, –CH2(1–metilpirazol–4–ilo), 6–metoxipiridin–3–ilo, 5-fluoropiridin–2–ilo, pirimidin–2–ilo, y 1H–pirazol–3–ilo; y, R3 es metilo. En un aspecto particular adicional del compuesto de fórmula (I), o una sal farmacéuticamente aceptable del mismo; m es 1; X es un grupo enlazador seleccionado de –S(O)2CH2–, –S(O)2CH(CH3)– y –S(O)2C(CH3)2–; 1Y es CH y Y2 es N. R1 es metilo o ciclopropilo; R2 es pyridin-2-yl, 5-methylisoxazol-3-yl, 1-methylpyrazole-4-yl, -CH2 (1-methylpyrazol-4-yl), 6-methoxypyridin-3-yl, 5-fluoropyridin-2-yl, pyrimidin-2-yl, and 1H-pyrazole-3-yl; and, R3 is methyl. In a further particular aspect of the compound of formula (I), or a pharmaceutically acceptable salt thereof; m is 1; X is a linker group selected from –S (O) 2CH2–, –S (O) 2CH (CH3) - and –S (O) 2C (CH3) 2–; 1Y is CH and Y2 is N. R1 is methyl or cyclopropyl; R2 is

10 en la que A1 y A2 se seleccionan de CH o N con la condición de que al menos uno de A1 o A2 es CH; R17 es hidrógeno; R18 es hidrógeno; 15 R19 es metilo, etilo, propilo, ciclopropilo, ciclobutilo, –CH2CH2OH, –CH2CH2NMe2, –C(Me)2CH2OH y 1H–pirazol–3– ilo; y, R3 es metilo. En un aspecto particular adicional del compuesto de fórmula (I), o una sal farmacéuticamente aceptable del mismo; m es 1; 20 X es un grupo enlazador seleccionado de–S(O)2C(CH3)2–; 1Y es CH y Y2 es N. R1 es etilo, isopropilo, terc–butilo, 4–fluorofenilo, piridin–4–ilo o ciclopropilo; R2 es A1 In which A1 and A2 are selected from CH or N with the proviso that at least one of A1 or A2 is CH; R17 is hydrogen; R18 is hydrogen; R19 is methyl, ethyl, propyl, cyclopropyl, cyclobutyl, -CH2CH2OH, -CH2CH2NMe2, -C (Me) 2CH2OH and 1H-pyrazole-3-yl; and, R3 is methyl. In a further particular aspect of the compound of formula (I), or a pharmaceutically acceptable salt thereof; m is 1; 20 X is a linker group selected from –S (O) 2C (CH3) 2–; 1Y is CH and Y2 is N. R1 is ethyl, isopropyl, tert-butyl, 4-fluorophenyl, pyridin-4-yl or cyclopropyl; R2 is A1

R17 R18 R17 R18

25 en la que A1 y A2 se seleccionan de CH o N con la condición de que al menos uno de A1 o A2 es CH; R17 es hidrógeno; R18 es hidrógeno; R19 es metilo, etilo, propilo, ciclopropilo, ciclobutilo, –CH2CH2OH, –CH2CH2NMe2, –C(Me)2CH2OH y 1H–pirazol–3– Wherein A1 and A2 are selected from CH or N with the proviso that at least one of A1 or A2 is CH; R17 is hydrogen; R18 is hydrogen; R19 is methyl, ethyl, propyl, cyclopropyl, cyclobutyl, -CH2CH2OH, -CH2CH2NMe2, -C (Me) 2CH2OH and 1H-pyrazole-3–

30 ilo; y, R3 es metilo. 30 yl; and, R3 is methyl.

En un aspecto de la invención, se proporciona un subconjunto de los compuestos de fórmula (I) en el que el compuesto de fórmula (I) es un compuesto de fórmula (Ia) o (Ib) In one aspect of the invention, a subset of the compounds of formula (I) in which the compound of formula (I) is a compound of formula (Ia) or (Ib) is provided

O OR

R3 R3

N N N N

1Y 1Y

Y2 1Y

Y2 Y2

X X

N N

X X

N N

(Ia) (Ib) (Ia) (Ib)

o una sal farmacéuticamente aceptable del mismo; or a pharmaceutically acceptable salt thereof;

o X–R1 es –C(CH3)2OH o –CH2OH; or X-R1 is -C (CH3) 2OH or -CH2OH;

R3 es metilo; R3 is methyl;

R19 es hidrógeno o un grupo seleccionado de alquilo de C1-6, cicloalquilo de C3-6, arilo, heteroarilo, aril-alquilo de C1-6 y heteroaril-alquilo de C1-6, estando dicho grupo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, hidroxi, oxo, alquilo de C1-6, alcoxi de C1-6, halo-alquilo de C1-6, halo-alcoxi de C16, hidroxi-alquilo de C1-6, hidroxi-alcoxi de C1-6, alcoxi C1-6-alquilo de C1-6, alcoxi C1-6-alcoxi de C1-6, amino, alquil C1-6R19 is hydrogen or a group selected from C1-6 alkyl, C3-6 cycloalkyl, aryl, heteroaryl, aryl-C1-6 alkyl and heteroaryl-C1-6 alkyl, said group being optionally substituted with one or more groups substituents selected from halo, cyano, nitro, hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, C1-6 halo-alkyl, C16 halo-alkoxy, C1-6 hydroxy-alkyl, hydroxy-alkoxy C1-6, C1-6 alkoxy-C1-6 alkyl, C1-6 alkoxy-C1-6 alkoxy, amino, C1-6 alkyl

amino, bis(alquil C1-6)-amino, amino-alquilo de C1-6, (alquil C1-6)-amino-alquilo de C1-6, bis(alquil C1-6)-amino-alquilo de C1-6, ciano-alquilo de C1-6, alquil C1-6-sulfonilo, alquil C1-6-sulfonilamino, alquil C1-6-sulfonil-(alquil C1-6)-amino, sulfamoilo, alquil C1-6-sulfamoilo, bis(alquil C1-6)-sulfamoilo, alcanoil C1-6-amino, alcanoil C1-6-(alquil C1-6)-amino, carbamoilo, alquil C1-6-carbamoilo y bis(alquil C1-6)-carbamoilo; amino, bis (C1-6 alkyl) -amino, amino-C1-6 alkyl, (C1-6 alkyl) -amino-C1-6 alkyl, bis (C1-6 alkyl) -amino-C1-6 alkyl , cyano-C 1-6 alkyl, C 1-6 alkyl sulfonyl, C 1-6 alkyl sulfonylamino, C 1-6 alkyl sulfonyl- (C 1-6 alkyl) -amino, sulfamoyl, C 1-6 alkyl sulfamoyl, bis ( C1-6 alkyl) -sulfamoyl, C1-6 alkanoyl-amino, C1-6 alkanoyl- (C1-6 alkyl) -amino, carbamoyl, C1-6 alkylcarbamoyl and bis (C1-6 alkyl) -carbamoyl;

En otro aspecto de la invención, se proporciona un subconjunto de los compuestos de fórmula (I) en el que el compuesto de fórmula (I) es un compuesto de fórmula (Ia) o (Ib) In another aspect of the invention, a subset of the compounds of formula (I) in which the compound of formula (I) is a compound of formula (Ia) or (Ib) is provided

O OR

R3 R3

N N N N

1Y 1Y

Y2 1Y Y2 1Y

Y2 Y2

X X

N N

X X

N N

(Ia) (Ib) (Ia) (Ib)

o X–R1 es –C(CH3)2OH o –CH2OH; or X-R1 is -C (CH3) 2OH or -CH2OH;

R2 se selecciona de arilo y heteroarilo, estando dicho grupo sustituido con –NR17CONR18R19 y opcionalmente sustituido con uno o más grupos sustituyentes seleccionados independientemente de halo, ciano, nitro, –R11, –OR11, –COR11, –CONR11R12, –NR11R12 y –NR11COR12; R2 is selected from aryl and heteroaryl, said group being substituted with -NR17CONR18R19 and optionally substituted with one or more substituent groups independently selected from halo, cyano, nitro, -R11, -OR11, -COR11, -CONR11R12, -NR11R12 and -NR11COR12 ;

R3 es metilo; R3 is methyl;

R9 y R10 son independientemente hidrógeno o un grupo seleccionado de alquilo de C1-6, carbociclilo y heterociclilo, estando dicho grupo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, R9 and R10 are independently hydrogen or a group selected from C1-6 alkyl, carbocyclyl and heterocyclyl, said group being optionally substituted with one or more substituent groups selected from halo, cyano,

nitro, hidroxi, alquilo de C1-6, alcoxi de C1-6, halo-alquilo de C1-6, halo-alcoxi de C1-6, hidroxi-alquilo de C1-6, hidroxialcoxi de C1-6, alcoxi C1-6-alquilo de C1-6, alcoxi C1-6-alcoxi de C1-6, amino, alquil C1-6-amino y bis(alquil C1-6)amino; nitro, hydroxy, C1-6 alkyl, C1-6 alkoxy, halo C1-6 alkyl, halo C1-6 alkoxy, hydroxy C1-6 alkyl, hydroxy C1-6 alkoxy, C1-6 alkoxy -C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkoxy, amino, C 1-6 alkyl-amino and bis (C 1-6 alkyl) amino;

O OR

R3 R3

N N N N

1Y 1Y

Y2 1Y Y2 1Y

Y2 Y2

X X

N N

X X

N N

(Ia) (Ib) (Ia) (Ib)

1Y e Y2 son independientemente N o CR8 con la condición de que uno de 1Y e Y2 es N y el otro es CR8; 1Y and Y2 are independently N or CR8 with the proviso that one of 1Y and Y2 is N and the other is CR8;

R1 es un grupo seleccionado de adamantilo, metilo, etilo, propilo, butilo, isobutilo, terc–butilo, ciclopentilo, ciclohexilo, fenilo, bencilo, fenetilo, pirrolidinilo, pirrolilo, imidazolilo, pirazolilo, furanilo, tienilo, piridinilo, pirimidinilo, pirazinilo, pirrolidinilmetilo, pirrolidiniletilo, pirrolilmetilo, pirroliletilo, imidazolilmetilo, imidazoliletilo, pirazolilmetilo, pirazoliletilo, furanilmetilo, furaniletilo, tienilmetilo, tieniletilo, piridinilmetilo, piridiniletilo, pirimidinilmetilo, pirimidiniletilo, pirazinilmetilo y piraziniletilo, estando dicho grupo opcionalmente sustituido con 1, 2 ó 3 grupos sustituyentes seleccionados de halo, ciano, nitro, R9, –OR9, –COR9, –CONR9R10, –NR9R10 y –NR9COR10; R1 is a group selected from adamantyl, methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, phenethyl, pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolidinylmethyl, pyrrolidinylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, pyrazolylmethyl, pyrazolylethyl, furanylmethyl, furanylethyl, thienylmethyl, thienylethyl, pyridinylmethyl, pyridinylethyl, pyrimidinylmethyl, pyrazidinyl group, 2-substituted groups being substituted with 1-group substituted substituently substituted groups halo, cyano, nitro, R9, –OR9, –COR9, –CONR9R10, –NR9R10 and –NR9COR10;

o X–R1 es –C(CH3)2OH o –CH2OH; or X-R1 is -C (CH3) 2OH or -CH2OH;

R2 se selecciona de arilo y heteroarilo de 5 ó 6 miembros, estando dicho grupo sustituido con –NHCONR18R19 y opcionalmente sustituido con uno o más grupos sustituyentes seleccionados independientemente de halo, ciano, nitro, –R11, –OR11, –COR11, –CONR11R12, –NR11R12 y –NR11COR12; R2 is selected from 5 or 6 membered aryl and heteroaryl, said group being substituted with -NHCONR18R19 and optionally substituted with one or more substituent groups independently selected from halo, cyano, nitro, -R11, -OR11, -COR11, -CONR11R12, –NR11R12 and –NR11COR12;

R3 es metilo; R4 es hidrógeno o alquilo de C1-6; R3 is methyl; R4 is hydrogen or C1-6 alkyl;

: o R18 y R19, junto con el átomo de nitrógeno al que están unidos, forman un anillo heterocíclico de 6 miembros en el que 1 átomo de carbono anular está opcionalmente reemplazado por N u O, y estando dicho anillo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, hidroxi, alquilo de C1-6, alcoxi de C1-6, halo-alquilo de C1-6, halo-alcoxi de C1-6, hidroxi-alquilo de C1-6, hidroxi-alcoxi de C1-6, alcoxi C1-6-alquilo de C1-6, alcoxi C1-6-alcoxi de C1-6, amino, alquil C1-6-amino, bis(alquil C1-6)-amino, amino-alquilo de C1-6, (alquil C1-6)-aminoalquilo de C1-6, bis(alquil C1-6)-amino-alquilo de C1-6, ciano-alquilo de C1-6, alquil C1-6-sulfonilo, alquil C1-6sulfonilamino, alquil C1-6-sulfonil-(alquil C1-6)-amino, sulfamoilo, alquil C1-6-sulfamoilo, bis(alquil C1-6)-sulfamoilo, alcanoil C1-6-amino, alcanoil C1-6-(alquil C1-6)-amino, carbamoilo, alquil C1-6-carbamoilo y bis(alquil C1-6)carbamoilo. or R18 and R19, together with the nitrogen atom to which they are attached, form a 6-membered heterocyclic ring in which 1 annular carbon atom is optionally replaced by N or O, and said ring being optionally substituted with one or more groups substituents selected from halo, cyano, nitro, hydroxy, C1-6 alkyl, C1-6 alkoxy, C1-6 halo-alkyl, C1-6 halo-alkoxy, C1-6 hydroxy-alkyl, hydroxy-alkoxy C1-6, C1-6 alkoxy-C1-6 alkyl, C1-6 alkoxy-C1-6 alkoxy, amino, C1-6-alkyl, bis (C1-6 alkyl) -amino, amino-alkyl C1-6, (C1-6 alkyl) -C 1-6 alkyl amino, bis (C1-6 alkyl) -C 1-6 alkyl, cyano-C1-6 alkyl, C1-6 alkyl sulfonyl, C1 alkyl -6sulfonylamino, C1-6 alkyl-sulfonyl- (C1-6 alkyl) -amino, sulfamoyl, C1-6 alkyl sulfamoyl, bis (C1-6 alkyl) -sulfamoyl, C1-6-alkanoyl-C1-6 alkanoyl (C1-6 alkyl) -amino, carbamoyl, C1-6 alkyl-carbamoyl and bis (C1-6 alkyl) carbamoyl.

En otro aspecto particular del compuesto de fórmula (I), el compuesto de fórmula (I) es un compuesto de fórmula (Ia) In another particular aspect of the compound of formula (I), the compound of formula (I) is a compound of formula (Ia)

: o (Ib), or (Ib),

O OR

R3 R3

N N N N

1Y 1Y

Y2 1Y Y2 1Y

Y2 Y2

X X

N N

X X

N N

(Ia) (Ib) (Ia) (Ib)

o una sal farmacéuticamente aceptable del mismo; 1Y es CH e Y2 es N; X es un grupo enlazador seleccionado de –S(O)2CH2–, –S(O)2CH(CH3)– y –S(O)2C(CH3)2–; R1 es un grupo seleccionado de metilo, etilo, propilo, butilo, isobutilo, terc–butilo, ciclopropilo, ciclopentilo, ciclohexilo, or a pharmaceutically acceptable salt thereof; 1Y is CH and Y2 is N; X is a linker group selected from –S (O) 2CH2–, –S (O) 2CH (CH3) - and –S (O) 2C (CH3) 2–; R1 is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl,

fenilo, bencilo, fenetilo, piridinilo, pirrolidinilo, pirazoliletilo, furanilmetilo, oxetanilo, imidazolilmetilo, tienilmetilo, tiazolilmetilo, tiadiazolilmetilo y piraziniletilo, estando dicho grupo opcionalmente sustituido con 1 ó 2 grupos phenyl, benzyl, phenethyl, pyridinyl, pyrrolidinyl, pyrazolylethyl, furanylmethyl, oxetanyl, imidazolylmethyl, thienylmethyl, thiazolylmethyl, thiadiazolylmethyl and pyrazinylethyl, said group being optionally substituted with 1 or 2 groups

sustituyentes seleccionados de amino, halo, ciano, metilo, metoxi, trifluorometilo, trifluorometoxi, –NMe2, -NHCOCH3, –CONH2 y -CONHCH3; substituents selected from amino, halo, cyano, methyl, methoxy, trifluoromethyl, trifluoromethoxy, -NMe2, -NHCOCH3, -CONH2 and -CONHCH3;

o –XR1 es –C(CH3)2OH o –CH2OH; or –XR1 is –C (CH3) 2OH or –CH2OH;

R3 es metilo; R3 is methyl;

o (Ib), or (Ib),

O OR

R3 R3

N N

1Y 1Y

Y2 1Y Y2 1Y

Y2 Y2

X X

N N

X X

N N

(Ia) (Ib) (Ia) (Ib)

1Y es CH e Y2 es N; 1Y is CH and Y2 is N;

o –XR1 es –C(CH3)2OH o –CH2OH; or –XR1 is –C (CH3) 2OH or –CH2OH;

R3 es metilo; R3 is methyl;

R11, R12 y R18 son independientemente hidrógeno o un grupo seleccionado de alquilo de C1-6, carbociclilo y heterociclilo, estando dicho grupo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, hidroxi, alquilo de C1-6, alcoxi de C1-6, halo-alquilo de C1-6, halo-alcoxi de C1-6, hidroxi-alquilo de C1R11, R12 and R18 are independently hydrogen or a group selected from C1-6 alkyl, carbocyclyl and heterocyclyl, said group being optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, C1-6 alkyl, C1-6 alkoxy, halo C1-6 alkyl, halo C1-6 alkoxy, hydroxy C1 alkyl

6, hidroxi-alcoxi de C1-6, alcoxi C1-6-alquilo de C1-6, alcoxi C1-6-alcoxi de C1-6, amino, alquil C1-6-amino y bis(alquil C16)amino; y 6, C 1-6 hydroxy-alkoxy, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkoxy, amino, C 1-6 alkyl, and bis (C 16 alkyl) amino; Y

R19 es hidrógeno o un grupo seleccionado de alquilo de C1-6, cicloalquilo de C3-6, arilo, heteroarilo, aril-alquilo de C1-6 y heteroaril-alquilo de C1-6, estando dicho grupo opcionalmente sustituido con uno o más grupos sustituyentes seleccionados de halo, ciano, nitro, hidroxi, alquilo de C1-6, alcoxi de C1-6, halo-alquilo de C1-6, halo-alcoxi de C1-6, hidroxi-alquilo de C1-6, hidroxi-alcoxi de C1-6, alcoxi C1-6-alquilo de C1-6, alcoxi C1-6-alcoxi de C1-6, amino, alquil C1-6amino, bis(alquil C1-6)-amino, amino-alquilo de C1-6, (alquil C1-6)-amino-alquilo de C1-6, bis(alquil C1-6)-amino-alquilo de C1-6, ciano-alquilo de C1-6, alquil C1-6-sulfonilo, alquil C1-6-sulfonilamino, alquil C1-6-sulfonil-(alquil C1-6)-amino, sulfamoilo, alquil C1-6-sulfamoilo, bis(alquil C1-6)-sulfamoilo, alcanoil C1-6-amino, alcanoil C1-6-(alquil C1-6)-amino, carbamoilo, alquil C1-6-carbamoilo y bis(alquil C1-6)carbamoilo. R19 is hydrogen or a group selected from C1-6 alkyl, C3-6 cycloalkyl, aryl, heteroaryl, aryl-C1-6 alkyl and heteroaryl-C1-6 alkyl, said group being optionally substituted with one or more groups substituents selected from halo, cyano, nitro, hydroxy, C1-6 alkyl, C1-6 alkoxy, C1-6 halo-alkyl, C1-6 halo-alkoxy, C1-6 hydroxy-alkyl, hydroxy-alkoxy C 1-6, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkoxy, amino, C 1-6 alkyl, bis (C 1-6 alkyl) -amino, C 1-6 amino-alkyl 6, (C1-6 alkyl) -amino-C1-6 alkyl, bis (C1-6 alkyl) -amino-C1-6 alkyl, cyano-C1-6 alkyl, C1-6 alkyl sulfonyl, C1 alkyl -6-sulfonylamino, C1-6 alkyl-sulfonyl- (C1-6 alkyl) -amino, sulfamoyl, C1-6 alkyl sulfamoyl, bis (C1-6 alkyl) -sulfamoyl, C1-6-alkanoyl, C1- alkanoyl 6- (C1-6 alkyl) -amino, carbamoyl, C1-6 alkyl-carbamoyl and bis (C1-6 alkyl) carbamoyl.

En un aspecto particular adicional del compuesto de fórmula (I), el compuesto de fórmula (I) es un compuesto de fórmula (Ia) o (Ib) In a further particular aspect of the compound of formula (I), the compound of formula (I) is a compound of formula (Ia) or (Ib)

O OR

R3 R3

N N N N

1Y 1Y

Y2 1Y Y2 1Y

Y2 Y2

X X

N N

X X

N N

(Ia) (Ib) (Ia) (Ib)

1Y es CH e Y2 es N. 1Y is CH and Y2 is N.

R3 es metilo; y R3 is methyl; Y

R19R19

O OR

R3 R3

N N

1Y 1Y

Y2 1Y Y2 1Y

Y2 Y2

X X

N N

X X

N N

(Ia) (Ib) (Ia) (Ib)

1Y es CH e Y2 es N. 1Y is CH and Y2 is N.

R3 es metilo; y R3 is methyl; Y

R19R19

O OR

R3 R3

N N

1Y 1Y

Y2 1Y Y2 1Y

Y2 Y2

X X

N N

X X

N N

(Ia) (Ib) (Ia) (Ib)

o una sal farmacéuticamente aceptable del mismo; m es 1; X es un grupo enlazador seleccionado de –S(O)2CH2–, –S(O)2CH(CH3)– y –S(O)2C(CH3)2–; 1Y es CH e Y2 es N. R1 es un grupo seleccionado de metilo, etilo, isopropilo, terc–butilo, ciclopropilo, ciclopentilo, ciclohexilo, or a pharmaceutically acceptable salt thereof; m is 1; X is a linker group selected from –S (O) 2CH2–, –S (O) 2CH (CH3) - and –S (O) 2C (CH3) 2–; 1Y is CH and Y2 is N. R1 is a group selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl,

--: CH2CH2OH, –CH2CH2OMe, –CH2CH2NMe2, –CH2CH2NC(O)CH3, –CH2CONH2, fenilo, 3,5–difluorofenilo, CH2CH2OH, –CH2CH2OMe, –CH2CH2NMe2, –CH2CH2NC (O) CH3, –CH2CONH2, phenyl, 3,5 – difluorophenyl,

4-fluorofenilo, 2–clorofenilo, 4–clorofenilo, 2–trifluorometilfenilo, 2–metoxifenilo, 2–metilfenilo, 4–acetamidofenilo, 4-aminofenilo, piridin–4–ilo, piridin–2–ilo, oxetan–3–ilo, 2–oxopirolidin–3–ilo, 1–metilimidazol–5–ilmetilo, 1-metilpirrolidin–3–ilo, tiazol–2–ilo, 4–metiltiazol–2–ilo, y 3–metil–1,3,4–tiadiazol–2–ilo; 4-fluorophenyl, 2-chlorophenyl, 4-chlorophenyl, 2-trifluoromethylphenyl, 2-methoxyphenyl, 2-methylphenyl, 4-acetamidophenyl, 4-aminophenyl, pyridin-4-yl, pyridin-2-yl, oxetan-3-yl, 2-oxopyrolidin-3-yl, 1-methylimidazol-5-ylmethyl, 1-methylpyrrolidin-3-yl, thiazol-2-yl, 4-methylthiazole-2-yl, and 3-methyl-1,3,4-thiadiazole –2 – ilo;

R2 es R2 is

A1 A1

R17 R18 5 R17 R18 5

en la que in which

A1 y A2 se seleccionan de CH o N con la condición de que al menos uno de A1 o A2 es CH; A1 and A2 are selected from CH or N with the proviso that at least one of A1 or A2 is CH;

R17 es hidrógeno; R17 is hydrogen;

R18 es hidrógeno; y R18 is hydrogen; Y

R19R19

10 es hidrógeno o un grupo seleccionado de metilo, etilo, propilo, i–propilo, butilo, i–butilo, t–butilo, pentilo, ciclopropilo, ciclobutilo, ciclopentilo, ciclohexilo, –CH2(ciclopropilo), –CH2CH2NMe2, –CH(CH3)CH2OH, -C(CH3)2CH2OH, –CH2CH2OH, –CH2CH2CH2OH, 4–metilfenilo, 4–clorofenilo, 4–trifluorometilfenilo, 4–fluorofenilo, 4-metoxifenilo, 3,4–difluorofenilo, tien–2–ilo, –CH2(imidazol–2–ilo), –CH2(imidazol–3–ilo), isoxazol–3–ilo, 6–oxo–1H– piridin–2–ilo, 5–metilisoxazol–3–ilo, 1–metilpirazol–4–ilo, –CH2(1–metilpirazol–4–ilo), 6–metoxipiridin–3–ilo, 10 is hydrogen or a group selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, –CH2 (cyclopropyl), –CH2CH2NMe2, –CH ( CH3) CH2OH, -C (CH3) 2CH2OH, -CH2CH2OH, -CH2CH2CH2OH, 4-methylphenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, 4-fluorophenyl, 4-methoxyphenyl, 3,4-difluorophenyl, thien-2-yl, - CH2 (imidazol-2-yl), -CH2 (imidazol-3-yl), isoxazol-3-yl, 6-oxo-1H- pyridin-2-yl, 5-methylisoxazol-3-yl, 1-methylpyrazole-4 –Ilo, –CH2 (1 – methylpyrazole – 4 – yl), 6 – methoxypyridin – 3 – yl,

15 5-fluoropiridin–2–ilo, piridinil–2–ilo, pirimidin–2–ilo, y 1H–pirazol–3–ilo; 15 5-fluoropyridin-2-yl, pyridinyl-2-yl, pyrimidin-2-yl, and 1H-pyrazole-3-yl;

y, R3 es metilo. and, R3 is methyl.

O OR

R3 R3

N N

1Y 1Y

Y2 1Y

Y2 Y2

X X

N N

X X

N N

20 (Ia) (Ib) 20 (Ia) (Ib)

o una sal farmacéuticamente aceptable del mismo; m es 1; X es un grupo enlazador seleccionado de –S(O)2CH2–, –S(O)2CH(CH3)– y –S(O)2C(CH3)2–; 1Y es CH e Y2 es N. or a pharmaceutically acceptable salt thereof; m is 1; X is a linker group selected from –S (O) 2CH2–, –S (O) 2CH (CH3) - and –S (O) 2C (CH3) 2–; 1Y is CH and Y2 is N.

25 R1 es un grupo seleccionado de metilo, isopropilo, ciclopropilo, ciclohexilo, –CH2CH2OH, –CH2CH2NC(O)CH3, -CH2CONH2, fenilo, 4–fluorofenilo, 2–clorofenilo, 2–trifluorometilfenilo, 2–metoxifenilo, 2–metilfenilo, 4-acetamidofenilo, 4–aminofenilo, piridin–4–ilo, piridin–2–ilo, 2–oxopirolidin–3–ilo, tiazol–2–ilo, 4–metiltiazol–2–ilo, y 3–metil–1,3,4–tiadiazol–2–ilo; R1 is a group selected from methyl, isopropyl, cyclopropyl, cyclohexyl, -CH2CH2OH, -CH2CH2NC (O) CH3, -CH2CONH2, phenyl, 4-fluorophenyl, 2-chlorophenyl, 2-trifluoromethylphenyl, 2-methoxyphenyl, 2-methylphenyl, 4-acetamidophenyl, 4-aminophenyl, pyridin-4-yl, pyridin-2-yl, 2-oxopyrolidin-3-yl, thiazol-2-yl, 4-methylthiazole-2-yl, and 3-methyl-1,3 , 4-thiadiazol-2-yl;

R2 es R2 is

A1 A1

R17 R18 R17 R18

en la que A1 y A2 se seleccionan de CH o N con la condición de que al menos uno de A1 o A2 es CH; R17 es hidrógeno; in which A1 and A2 are selected from CH or N with the proviso that at least one of A1 or A2 is CH; R17 is hydrogen;

5 R18 es hidrógeno; y R19 R18 is hydrogen; Y R19

10 piridin–2–ilo, 5–metilisoxazol–3–ilo, 1–metilpirazol–4–ilo, –CH2(1–metilpirazol–4–ilo), 6–metoxipiridin–3–ilo, 5-fluoropiridin–2–ilo, pirimidin–2–ilo, y 1H–pirazol–3–ilo; 10 pyridin-2-yl, 5-methylisoxazol-3-yl, 1-methylpyrazole-4-yl, -CH2 (1-methylpyrazol-4-yl), 6-methoxypyridin-3-yl, 5-fluoropyridin-2-yl , pyrimidin-2-yl, and 1H-pyrazole-3-yl;

y, R3 es metilo. and, R3 is methyl.

O O O o

: R3 R3

: R3R3

N N

1Y 1Y

Y2 1Y

Y2 Y2

X X

N N

X X

N N

15 (Ia) (Ib) 15 (Ia) (Ib)

o una sal farmacéuticamente aceptable del mismo; m es 1; X es un grupo enlazador seleccionado de –S(O)2CH2–, –S(O)2CH(CH3)– y –S(O)2C(CH3)2–; or a pharmaceutically acceptable salt thereof; m is 1; X is a linker group selected from –S (O) 2CH2–, –S (O) 2CH (CH3) - and –S (O) 2C (CH3) 2–;

20 1Y es CH e Y2 es N. R1 es metilo o ciclopropilo; R2 es 1Y is CH and Y2 is N. R1 is methyl or cyclopropyl; R2 is

A1 A1

R17 R18 R17 R18

en la que in which

25 A1 y A2 se seleccionan de CH o N con la condición de que al menos uno de A1 o A2 es CH; R17 es hidrógeno; A1 and A2 are selected from CH or N with the proviso that at least one of A1 or A2 is CH; R17 is hydrogen;

R18 es hidrógeno; y R19 R18 is hydrogen; Y R19

es hidrógeno o un grupo seleccionado de metilo, etilo, propilo, ciclopropilo, ciclobutilo, –CH2CH2OH, -CH2CH2NMe2, –C(Me)2CH2OH y 1H–pirazol–3–ilo; is hydrogen or a group selected from methyl, ethyl, propyl, cyclopropyl, cyclobutyl, -CH2CH2OH, -CH2CH2NMe2, -C (Me) 2CH2OH and 1H-pyrazole-3-yl;

y, R3 es metilo. and, R3 is methyl.

O OR

R3 R3

N N

1Y 1Y

Y2 1Y

Y2 Y2

X X

N N

X X

N N

(Ia) (Ib) (Ia) (Ib)

10 m es 1; X es un grupo enlazador –S(O)2C(CH3)2–; 1Y es CH e Y2 es N. R1 es metilo, etilo, isopropilo, terc–butilo, 4–fluorofenilo, piridin–4–ilo o ciclopropilo; R2 es 10 m is 1; X is a linking group –S (O) 2C (CH3) 2–; 1Y is CH and Y2 is N. R1 is methyl, ethyl, isopropyl, tert-butyl, 4-fluorophenyl, pyridin-4-yl or cyclopropyl; R2 is

A1 A1

R17 R18 15 en la que A1 y A2 se seleccionan de CH o N con la condición de que al menos uno de A1 o A2 es CH; R17 es hidrógeno; R18 es hidrógeno; y R19R17 R18 in which A1 and A2 are selected from CH or N with the proviso that at least one of A1 or A2 is CH; R17 is hydrogen; R18 is hydrogen; and R19

20 es hidrógeno o un grupo seleccionado de metilo, etilo, propilo, ciclopropilo, ciclobutilo, –CH2CH2OH, -CH2CH2NMe2, –C(Me)2CH2OH y 1H–pirazol–3–ilo; 20 is hydrogen or a group selected from methyl, ethyl, propyl, cyclopropyl, cyclobutyl, -CH2CH2OH, -CH2CH2NMe2, -C (Me) 2CH2OH and 1H-pyrazole-3-yl;

y, R3 es metilo. and, R3 is methyl.

Otro aspecto de la invención proporciona un compuesto, o una combinación de compuestos, seleccionado de uno cualquiera de los Ejemplos, o una sal farmacéuticamente aceptable del mismo. Another aspect of the invention provides a compound, or a combination of compounds, selected from any one of the Examples, or a pharmaceutically acceptable salt thereof.

25 La invención también proporciona procedimientos para la preparación de un compuesto de fórmula (I) o una sal farmacéuticamente aceptable del mismo. The invention also provides processes for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Un compuesto de fórmula (I), en el que X = –S(O)2CR6R7–, se puede preparar oxidando un compuesto de fórmula (I), en el que X = SCR6R7–, por ejemplo usando Oxone® a temperatura ambiente en un sistema de solvente mixto de agua y etanol. A compound of formula (I), in which X = –S (O) 2CR6R7–, can be prepared by oxidizing a compound of formula (I), in which X = SCR6R7–, for example using Oxone® at room temperature in a mixed solvent system of water and ethanol.

OO OO

(R3)m(R3)m (R3) m (R3) m

N R 8 N R 8

N N

R 8 N OO N R 8 N OO N

S S R2R1 S S R2R1

R2 R1 R2 R1

N R6R7 R6R7 N N R6R7 R6R7 N

(I) (I) (I) (I)

Un compuesto de fórmula (I), en el que R1X = R1OCR6R7–, se puede preparar mediante la reacción de un compuesto de fórmula (I), en el que R1X = HOCR6R7–, con un compuesto de fórmula (II), en el que L1 es un grupo saliente (tal como halo, tosilo, mesilo, etc.), opcionalmente en presencia de una base adecuada tal como trietilamina y un solvente tal como tetrahidrofurano o N,N–dimetilformamida. A compound of formula (I), in which R1X = R1OCR6R7–, can be prepared by reacting a compound of formula (I), in which R1X = HOCR6R7–, with a compound of formula (II), in which that L1 is a leaving group (such as halo, tosyl, mesyl, etc.), optionally in the presence of a suitable base such as triethylamine and a solvent such as tetrahydrofuran or N, N-dimethylformamide.

OO OO

(R3)m(R3)m (R3) m (R3) m

N R1L1 R 8 N R1L1 R 8

N N

R 8 N R 8 N

N N

(II) HO O R2R2 R1 (II) HO OR R2R2 R1

N R6R7 R6R7 N R6R7 R6R7

N N

(I) (I) (I) (I)

Un compuesto de fórmula (I), en el que R1X = R1R4NCR6R7–, se puede preparar mediante la reacción de un compuesto de fórmula (I), en el que R1X = HR4NCR6R7–, con un compuesto de fórmula (II), en el que L1 es un grupo saliente (tal como halo, tosilo, mesilo, etc.), opcionalmente en presencia de una base adecuada tal como trietilamina y un solvente tal como tetrahidrofurano o N,N–dimetilformamida; o mediante la reacción de un compuesto de fórmula (I), en el que R1X = HR4NCR6R7–, con un compuesto de fórmula (III) en presencia de un agente reductor adecuado tal como NaCNBH3. A compound of formula (I), in which R1X = R1R4NCR6R7–, can be prepared by reacting a compound of formula (I), in which R1X = HR4NCR6R7–, with a compound of formula (II), in which that L1 is a leaving group (such as halo, tosyl, mesyl, etc.), optionally in the presence of a suitable base such as triethylamine and a solvent such as tetrahydrofuran or N, N-dimethylformamide; or by reacting a compound of formula (I), wherein R1X = HR4NCR6R7–, with a compound of formula (III) in the presence of a suitable reducing agent such as NaCNBH3.

O R1 L1 O R1 L1

O OR

(R3)m (R3) m

(II) (II)

N R 8 N R 8

N N

R 8 O R 8 o

NN R4 H R1 NN R4 H R1

NN R2R4 R2 R1NNH NN R2R4 R2 R1NNH

R6R7 R6R7 R6R7 R6R7

(III) (I) (I) (III) (I) (I)

Un compuesto de fórmula (I), en el que X1 = –S(O)2CR6R7–, –SCR6R7–, –OCR6R7–, -R4NCR6R7–, –S(O)CR6R7–, se puede preparar mediante la reacción de un compuesto de fórmula (IV), en el que L1 es un grupo saliente (tal como halo, tosilo, mesilo, etc.), con un compuesto de fórmula (V), opcionalmente en presencia de una base adecuada tal como trietilamina y un solvente tal como tetrahidrofurano o N,N–dimetilformamida. A compound of formula (I), in which X1 = –S (O) 2CR6R7–, –SCR6R7–, –OCR6R7–, -R4NCR6R7–, –S (O) CR6R7–, can be prepared by reacting a compound of formula (IV), wherein L1 is a leaving group (such as halo, tosyl, mesyl, etc.), with a compound of formula (V), optionally in the presence of a suitable base such as triethylamine and a solvent such as tetrahydrofuran or N, N-dimethylformamide.

OO OO

(R3)m(R3)m (R3) m (R3) m

N R8 N R8

N N

R8 R1 X1 R8 R1 X1

N L1 N L1

NH X1 NH X1

R2 R6R7 R6R7 R2 R6R7 R6R7

(V) NR2 R1N (V) NR2 R1N

(IV) (I) (IV) (I)

Un compuesto de fórmula (I), en el que X = –SCR6R7–, se puede preparar mediante la reacción de un compuesto de fórmula (IV), en el que L1 es un grupo saliente (tal como halo, tosilo, mesilo, etc.), con tiourea en un solvente adecuado tal como etanol para generar un compuesto de fórmula (VI) el cual se hace reaccionar posteriormente con un compuesto de fórmula (II) en presencia de una base adecuada tal como hidróxido de sodio y un solvente tal como N,N–dimetilformamida. A compound of formula (I), in which X = –SCR6R7–, can be prepared by reacting a compound of formula (IV), in which L1 is a leaving group (such as halo, tosyl, mesyl, etc. .), with thiourea in a suitable solvent such as ethanol to generate a compound of formula (VI) which is subsequently reacted with a compound of formula (II) in the presence of a suitable base such as sodium hydroxide and a solvent such as N, N-dimethylformamide.

O OR

OO (R3)m R1 L1(R3)m N OO (R3) m R1 L1 (R3) m N

N R8 N R8

NSH NSH

R 8 R 8

R 8 H2N N R 8 H2N N

(R3)m (R3) m

N L1 NN L1 N

NH NH

S S

SH2N R2 R1 R2R2 N SH2N R2 R1 R2R2 N

N R6 R7 N R6 R7

N R6R7 R6R7 N R6R7 R6R7

(IV) NH (VI) (I) (IV) NH (VI) (I)

Un compuesto de fórmula (I), en el que X = –R4NC(O)–, se puede preparar mediante la reacción de un compuesto de fórmula (VII) con una amina de fórmula R1R4NH, seguido de la activación adecuada del ácido carboxílico por métodos conocidos en la bibliografía tales como el uso de un agente de acoplamiento tal como HATU o la conversión en un cloruro de acilo. A compound of formula (I), in which X = -R4NC (O) -, can be prepared by reacting a compound of formula (VII) with an amine of formula R1R4NH, followed by proper activation of the carboxylic acid by methods known in the literature such as the use of a coupling agent such as HATU or the conversion into an acyl chloride.

OO OO

(R3)m(R3)m (R3) m (R3) m

N R 8 N R 8

N N

R 8 N R4 R 8 N R4

N HO N HO

N R2N R2

R2 R1 R2 R1

N OO N OO

N N

(VII) (I) (VII) (I)

Un compuesto de fórmula (I), en el que X = –S(O)2CR6R7–, se puede preparar mediante la reacción secuencial de un compuesto de fórmula (I), en el que X = –S(O)2CH2–, con un compuesto de fórmula (VIII), seguido de la reacción con un compuesto de fórmula (IX), en el que L1 es un grupo saliente (tal como halo, tosilo, mesilo, etc.), en presencia de una base adecuada tal como hidruro de sodio o terc–butóxido de potasio en un solvente adecuado tal como tetrahidrofurano o N,N–dimetilformamida. A compound of formula (I), in which X = –S (O) 2CR6R7–, can be prepared by sequential reaction of a compound of formula (I), in which X = –S (O) 2CH2–, with a compound of formula (VIII), followed by reaction with a compound of formula (IX), wherein L1 is a leaving group (such as halo, tosyl, mesyl, etc.), in the presence of a suitable base such as sodium hydride or potassium tert-butoxide in a suitable solvent such as tetrahydrofuran or N, N-dimethylformamide.

OO OO

(R3)m (R3) m

(R3)m(R3) m

R6 L1 N R6 L1 N

N (VIII) N (VIII)

R 8 N R 8 N

R 8 R 8

N OO R7 L1 N OO R7 L1

O O SS R2R2 R1R1 NN OR O SS R2R2 R1R1 NN

(IX) R6 R7 (IX) R6 R7

(I) (I) (I) (I)

Un compuesto de fórmula (I), en el que R1X = HOCR6R7–, se puede preparar mediante la reacción de un compuesto de fórmula (X), con reactivos organometálicos adecuados de fórmula (XI) y fórmula (XII) tales como el reactivo de Grignard en un solvente adecuado. Cuando R6 y R7 son diferentes, entonces es posible usar técnicas conocidas en la bibliografía, tales como la conversión de un compuesto de fórmula (X) en la amida de Weinreb y la reacción con un reactivo organometálico de fórmula (XI) y luego la reacción con un reactivo organometálico de fórmula (XII) en una etapa posterior. A compound of formula (I), in which R1X = HOCR6R7–, can be prepared by reacting a compound of formula (X), with suitable organometallic reagents of formula (XI) and formula (XII) such as the reagent of Grignard in a suitable solvent. When R6 and R7 are different, then it is possible to use techniques known in the literature, such as the conversion of a compound of formula (X) into Weinreb amide and the reaction with an organometallic reagent of formula (XI) and then the reaction with an organometallic reagent of formula (XII) at a later stage.

OO OO

(R3)m (R3) m

(R3)m(R3) m

R6 M R6 M

N R 8N R 8

(XI) N (XI) N

R 8 N R 8 N

N R7 N R7

M O HO R2M O HO R2

R2R2

NNR(XII) NNR (XII)

R6 R7 O (X) (I) R6 R7 O (X) (I)

Un compuesto de fórmula (I) se puede preparar a partir de un compuesto de fórmula (XIII), en el que L2 es un grupo saliente (tal como halo, tosilo, mesilo, –SMe, –S(O)2Me, etc.), con un reactivo organometálico adecuado (tal como el ácido borónico R2B(OH)2 o el éster borónico R2B(OR)2, etc.) en presencia de un catalizador de metal adecuado (tal como paladio o cobre) en un solvente adecuado tal como 1,4–dioxano. Como alternativa, cuando R2 se conecta al anillo de pirimidina a través de un átomo de nitrógeno, oxígeno o azufre, un compuesto de fórmula (I) se puede preparar a partir de un compuesto de fórmula (XIII), en el que L2 es un grupo saliente (tal como halo, tosilo, mesilo, – SMe, –S(O)2Me, etc.), mediante reacción con la amina, alcohol o tiol requeridos en presencia de una base adecuada tal como carbonato de potasio en un solvente adecuado tal como N,N–dimetilformamida. A compound of formula (I) can be prepared from a compound of formula (XIII), in which L2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S (O) 2Me, etc. ), with a suitable organometallic reagent (such as boronic acid R2B (OH) 2 or boronic ester R2B (OR) 2, etc.) in the presence of a suitable metal catalyst (such as palladium or copper) in a suitable solvent such as 1,4-dioxane. Alternatively, when R2 is connected to the pyrimidine ring through a nitrogen, oxygen or sulfur atom, a compound of formula (I) can be prepared from a compound of formula (XIII), in which L2 is a leaving group (such as halo, tosyl, mesyl, - SMe, -S (O) 2Me, etc.), by reaction with the amine, alcohol or thiol required in the presence of a suitable base such as potassium carbonate in a suitable solvent such as N, N-dimethylformamide.

OO OO

(R3)m(R3)m (R3) m (R3) m

N R8 N R8

N N

R8 N R8 N

N R1 N R1

R1 R2L2 XNXN R1 R2L2 XNXN

(XIII) (I) (XIII) (I)

Será apreciará que un compuesto de fórmula (XIII) se puede transformar en otro compuesto de fórmula (XIII) mediante técnicas tales como oxidación, alquilación, aminación reductora, etc., enumeradas anteriormente o de otra forma conocida en la bibliografía. It will be appreciated that a compound of formula (XIII) can be transformed into another compound of formula (XIII) by techniques such as oxidation, alkylation, reductive amination, etc., listed above or otherwise known in the literature.

5 Un compuesto de fórmula (XIII), en el que X1 = –S(O)2CR6R7–, –SCR6R7–, –OCR6R7–, –R4NCR6R7–, –S(O)CR6R7–, se puede preparar mediante la reacción de un compuesto de fórmula (XIV), en el que L1 es un grupo saliente (tal como halo, tosilo, mesilo, etc.), con un compuesto de fórmula (V), opcionalmente en presencia de una base adecuada tal como trietilamina y un solvente tal como tetrahidrofurano o N,N–dimetilformamida. 5 A compound of formula (XIII), in which X1 = –S (O) 2CR6R7–, –SCR6R7–, –OCR6R7–, –R4NCR6R7–, –S (O) CR6R7–, can be prepared by reacting a compound of formula (XIV), wherein L1 is a leaving group (such as halo, tosyl, mesyl, etc.), with a compound of formula (V), optionally in the presence of a suitable base such as triethylamine and a solvent such as tetrahydrofuran or N, N-dimethylformamide.

OO OO

(R3)m (R3) m

N R8 N R8

N N

R8 R1 X1H R8 R1 X1H

N L1 N L1

N N

X1 X1

L2 R6R7 R6R7L2 R6R7 R6R7

(V) NL2 R1N (V) NL2 R1N

(XIV) (XIII) (XIV) (XIII)

10 Un compuesto de fórmula (XIII), en el que X = –SCR6R7–, se puede preparar mediante la reacción de un compuesto de fórmula (XIV), en el que L1 es un grupo saliente (tal como halo, tosilo, mesilo, etc.), con tiourea en un solvente adecuado tal como etanol para generar un compuesto de fórmula (XV) el cual se hacer reaccionar posteriormente con un compuesto de fórmula (II) en presencia de una base adecuada tal como hidróxido de sodio y un solvente tal como N,N–dimetilformamida. A compound of formula (XIII), in which X = -SCR6R7-, can be prepared by reacting a compound of formula (XIV), in which L1 is a leaving group (such as halo, tosyl, mesyl, etc.), with thiourea in a suitable solvent such as ethanol to generate a compound of formula (XV) which is subsequently reacted with a compound of formula (II) in the presence of a suitable base such as sodium hydroxide and a solvent such as N, N-dimethylformamide.

O OR

OO OO

(R3)m R1 L1 (R3) m R1 L1

(R3)m(R3)m NNSH (R3) m (R3) m NNSH

R 8 R 8

R 8 H2N R 8 H2N

N R8 N R8

N N

N L1 N L1

NNH S SNNH S S

H2N H2N

L2 R1 L2L2 N L2 R1 L2L2 N

N R6 R7 N R6 R7

N N

R6R7 R6R7 NH R6R7 R6R7 NH

(XIV) (XV) (XIII)(XIV) (XV) (XIII)

15 Un compuesto de fórmula (XIII), en el que X = –R4NC(O)–, se puede preparar mediante la reacción de un compuesto de fórmula (XVI) con una amina de fórmula R1R4NH, seguido de la activación adecuada del ácido carboxílico por métodos conocidos en la bibliografía tales como el uso de un agente de acoplamiento tal como HATU o la conversión a un cloruro de acilo. A compound of formula (XIII), in which X = –R4NC (O) -, can be prepared by reacting a compound of formula (XVI) with an amine of formula R1R4NH, followed by proper activation of the carboxylic acid by methods known in the literature such as the use of a coupling agent such as HATU or the conversion to an acyl chloride.

OO OO

(R3)m(R3)m (R3) m (R3) m

N R 8 N R 8

N N

R 8 N R4 R 8 N R4

N HO N HO

N L2N L2

L2 R1 L2 R1

N OO N OO

N N

(XVI) (XIII)(XVI) (XIII)

20 Un compuesto de fórmula (XIII), en el que X = –S(O)2CR6R7–, se puede preparar mediante la reacción secuencial de un compuesto de fórmula (XIII), en el que X = –S(O)2CH2–, con un compuesto de fórmula (VIII), seguido de la reacción con un compuesto de fórmula (IX), en el que L1 es un grupo saliente (tal como halo, tosilo, mesilo, etc.), en presencia de una base adecuada tal como hidruro de sodio o terc–butóxido de potasio en un solvente adecuado tal A compound of formula (XIII), in which X = –S (O) 2CR6R7–, can be prepared by sequential reaction of a compound of formula (XIII), in which X = –S (O) 2CH2– , with a compound of formula (VIII), followed by reaction with a compound of formula (IX), in which L1 is a leaving group (such as halo, tosyl, mesyl, etc.), in the presence of a suitable base such as sodium hydride or potassium tert-butoxide in a suitable solvent such

25 como tetrahidrofurano o N,N–dimetilformamida. 25 as tetrahydrofuran or N, N-dimethylformamide.

OO OO

(R3)m (R3) m

(R3)m(R3) m

R6 L1 N R6 L1 N

N(VIII) N (VIII)

R 8 NR 8 R 8 NR 8

N OO R7 L1 O O N OO R7 L1 O OR

SS L2L2 R1R1 NN SS L2L2 R1R1 NN

(IX) R6 R7 (IX) R6 R7

(XIII) (XIII) (XIII) (XIII)

Un compuesto de fórmula (XIII), en el que R1X = HOCR6R7–, se puede preparar mediante la reacción de un compuesto de fórmula (XVII) con un reactivo organometálico adecuado de fórmula (XI) y fórmula (XII), tal como el reactivo de Grignard, en un solvente adecuado. Cuando R6 y R7 son diferentes, entonces puede ser posible usar técnicas conocidas en la bibliografía tales como la conversión de un compuesto de fórmula (XVII) en la amida de Weinreb y la reacción con un reactivo organometálico de fórmula (XI) y luego la reacción con un reactivo organometálico de fórmula (XII) en una etapa posterior. A compound of formula (XIII), wherein R1X = HOCR6R7–, can be prepared by reacting a compound of formula (XVII) with a suitable organometallic reagent of formula (XI) and formula (XII), such as reagent from Grignard, in a suitable solvent. When R6 and R7 are different, then it may be possible to use techniques known in the literature such as the conversion of a compound of formula (XVII) into Weinreb amide and the reaction with an organometallic reagent of formula (XI) and then the reaction with an organometallic reagent of formula (XII) at a later stage.

OO OO

(R3)m (R3) m

(R3)m(R3) m

R6 R6

M N M N

N(XI) N (XI)

R 8 N R 8 N

R 8 R 8

N R7 N R7

M O HO L2M O HO L2

L2L2

NNR(XII) R6 R7 O (XVII) (XIII) NNR (XII) R6 R7 O (XVII) (XIII)

Un compuesto de fórmula (IV) se puede preparar a partir de un compuesto de fórmula (XIV), en el que L2 es un grupo saliente (tal como halo, tosilo, mesilo, –SMe, –S(O)2Me, etc.) y L1 es un grupo saliente (tal como halo, tosilo, mesilo, etc.), con un reactivo organometálico adecuado (tal como el ácido borónico R2B(OH)2 o el éster borónico R2B(OR)2 etc.) en presencia de un catalizador de metal adecuado (tal como paladio o cobre) en un solvente adecuado tal como 1,4–dioxano. Como alternativa, cuando R2 se conecta al anillo de pirimidina a través de un átomo de nitrógeno, oxígeno o azufre, un compuesto de fórmula (IV) se puede preparar a partir de un compuesto de fórmula (XIV), en el que L2 es un grupo saliente (tal como halo, tosilo, mesilo, –SMe, –S(O)2Me, etc.), mediante la reacción con la amina, alcohol o tiol requeridos en presencia de una base adecuada tal como carbonato de potasio en un solvente adecuado tal como N,N–dimetilformamida. A compound of formula (IV) can be prepared from a compound of formula (XIV), in which L2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S (O) 2Me, etc. ) and L1 is a leaving group (such as halo, tosyl, mesyl, etc.), with a suitable organometallic reagent (such as boronic acid R2B (OH) 2 or boronic ester R2B (OR) 2 etc.) in the presence of a suitable metal catalyst (such as palladium or copper) in a suitable solvent such as 1,4-dioxane. Alternatively, when R2 is connected to the pyrimidine ring through a nitrogen, oxygen or sulfur atom, a compound of formula (IV) can be prepared from a compound of formula (XIV), in which L2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S (O) 2Me, etc.), by reaction with the amine, alcohol or thiol required in the presence of a suitable base such as potassium carbonate in a solvent suitable such as N, N-dimethylformamide.

OO OO

(R3)m(R3)m (R3) m (R3) m

N R8 N R8

N N

R8 N R8 N

N L1 N L1

L1 R2L2L1 R2L2

NN R6R7 R6R7 NN R6R7 R6R7

(XIV) (IV) (XIV) (IV)

Un compuesto de fórmula (X) se puede preparar a partir de un compuesto de fórmula (XVII), en el que L2 es un grupo saliente (tal como halo, tosilo, mesilo, –SMe, –S(O)2Me, etc.) y R es un hidrógeno o grupo alquilo de C1-4, con un reactivo organometálico adecuado (tal como el ácido borónico R2B(OH)2 o el éster borónico R2B(OR)2, etc.) en presencia de un catalizador de metal adecuado (tal como paladio o cobre) en un solvente adecuado tal como 1,4– dioxano. Como alternativa, cuando R2 se conecta al anillo de pirimidina a través de un átomo de nitrógeno, oxígeno A compound of formula (X) can be prepared from a compound of formula (XVII), in which L2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S (O) 2Me, etc. ) and R is a hydrogen or C1-4 alkyl group, with a suitable organometallic reagent (such as boronic acid R2B (OH) 2 or boronic ester R2B (OR) 2, etc.) in the presence of a metal catalyst suitable (such as palladium or copper) in a suitable solvent such as 1,4-dioxane. Alternatively, when R2 is connected to the pyrimidine ring through a nitrogen atom, oxygen

o azufre, un compuesto de fórmula (X) se puede preparar a partir de un compuesto de fórmula (XVII), en el que L2 es un grupo saliente (tal como halo, tosilo, mesilo, –SMe, –S(O)2Me, etc.), mediante la reacción con la amina, alcohol o tiol requeridos en presencia de una base adecuada tal como carbonato de potasio en un solvente adecuado tal como N,N–dimetilformamida. or sulfur, a compound of formula (X) can be prepared from a compound of formula (XVII), in which L2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S (O) 2Me , etc.), by reaction with the amine, alcohol or thiol required in the presence of a suitable base such as potassium carbonate in a suitable solvent such as N, N-dimethylformamide.

OO OO

(R3)m(R3)m (R3) m (R3) m

N R 8 N R 8

N N

R 8 N R 8 N

N O NO

O R2L2 NR NR O R2L2 NR NR

O (XVII) O (X) O (XVII) O (X)

Un compuesto de fórmula (XVIII) se puede preparar a partir de un compuesto de fórmula (XIX), en el que L2 es un grupo saliente (tal como halo, tosilo, mesilo, –SMe, –S(O)2Me, etc.), con un reactivo organometálico adecuado (tal como el ácido borónico R2B(OH)2 o el éster borónico R2B(OR)2, etc.) en presencia de un catalizador de metal A compound of formula (XVIII) can be prepared from a compound of formula (XIX), in which L2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S (O) 2Me, etc. ), with a suitable organometallic reagent (such as boronic acid R2B (OH) 2 or boronic ester R2B (OR) 2, etc.) in the presence of a metal catalyst

adecuado (tal como paladio o cobre) en un solvente adecuado tal como 1,4–dioxano. Como alternativa, cuando R2 se conecta al anillo de pirimidina a través de un átomo de nitrógeno, oxígeno o azufre, un compuesto de fórmula suitable (such as palladium or copper) in a suitable solvent such as 1,4-dioxane. Alternatively, when R2 is connected to the pyrimidine ring through a nitrogen, oxygen or sulfur atom, a compound of formula

(XVIII) se puede preparar a partir de un compuesto de fórmula (XIX), en el que L2 es un grupo saliente (tal como halo, tosilo, mesilo, –SMe, –S(O)2Me, etc.), mediante la reacción con la amina, alcohol o tiol requeridos en presencia de una base adecuada tal como carbonato de potasio en un solvente adecuado tal como N,N–dimetilformamida. (XVIII) can be prepared from a compound of formula (XIX), in which L2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S (O) 2Me, etc.), by means of reaction with the amine, alcohol or thiol required in the presence of a suitable base such as potassium carbonate in a suitable solvent such as N, N-dimethylformamide.

OO OO

(R3)m(R3)m (R3) m (R3) m

N R8 N R8

N N

R8 N N R2NCN L2 NCN R8 N N R2NCN L2 NCN

(XIX) (XVIII) (XIX) (XVIII)

Un compuesto de fórmula (XX) se puede preparar a partir de un compuesto de fórmula (XXI), en el que L2 es un grupo saliente (tal como halo, tosilo, mesilo, –SMe, –S(O)2Me, etc.), con un reactivo organometálico adecuado (tal como el ácido borónico R2B(OH)2 o el éster borónico R2B(OR)2, etc.) en presencia de un catalizador de metal adecuado (tal como paladio o cobre) en un solvente adecuado tal como 1,4–dioxano. Como alternativa, cuando R2 se conecta al anillo de pirimidina a través de un átomo de nitrógeno, oxígeno o azufre, un compuesto de fórmula A compound of formula (XX) can be prepared from a compound of formula (XXI), in which L2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S (O) 2Me, etc. ), with a suitable organometallic reagent (such as boronic acid R2B (OH) 2 or boronic ester R2B (OR) 2, etc.) in the presence of a suitable metal catalyst (such as palladium or copper) in a suitable solvent such as 1,4-dioxane. Alternatively, when R2 is connected to the pyrimidine ring through a nitrogen, oxygen or sulfur atom, a compound of formula

(XX) se puede preparar a partir de un compuesto de fórmula (XXI), en el que L2 es un grupo saliente (tal como halo, tosilo, mesilo, –SMe, –S(O)2Me, etc.), mediante la reacción con la amina, alcohol o tiol requeridos en presencia de una base adecuada tal como carbonato de potasio en un solvente adecuado tal como N,N–dimetilformamida. (XX) can be prepared from a compound of formula (XXI), in which L2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S (O) 2Me, etc.), by means of reaction with the amine, alcohol or thiol required in the presence of a suitable base such as potassium carbonate in a suitable solvent such as N, N-dimethylformamide.

OO OO

(R3)m(R3)m (R3) m (R3) m

N R8 N R8

N N

R8 N R8 N

N R2N R2

L2 L2L2 L2

L2N N L2N N

(XXI) (XX) (XXI) (XX)

Un compuesto de fórmula (I), en el que L1 es un grupo saliente (tal como halo, tosilo, mesilo, etc.), se puede preparar mediante la reacción de un compuesto de fórmula (XXII) con un compuesto de fórmula (XXIII), opcionalmente en presencia de una base adecuada tal como trietilamina en un solvente adecuado tal como N,N–dimetilformamida. A compound of formula (I), in which L1 is a leaving group (such as halo, tosyl, mesyl, etc.), can be prepared by reacting a compound of formula (XXII) with a compound of formula (XXIII ), optionally in the presence of a suitable base such as triethylamine in a suitable solvent such as N, N-dimethylformamide.

O (R3)m L1 O (R3) m L1

NN

O OR

R8 (R3)m R8 (R3) m

R8 R8

N N N N

N N

R1R1 R2R1R1 R2

R2 R2

XNXNH XNXNH

(XXIII) (I)(XXIII) (I)

(XXII) (XXII)

Se apreciará que un compuesto de fórmula (XXII) se puede transformar en otro compuesto de fórmula (XXII) mediante técnicas tales como oxidación, alquilación, aminación reductora, etc., enumeradas anteriormente o de otra forma conocida en la bibliografía. It will be appreciated that a compound of formula (XXII) can be transformed into another compound of formula (XXII) by techniques such as oxidation, alkylation, reductive amination, etc., listed above or otherwise known in the literature.

Un compuesto de fórmula (IV), en el que L1 es un grupo saliente (tal como halo, tosilo, mesilo, etc.), se puede preparar mediante la reacción de un compuesto de fórmula (XXIV) con un compuesto de fórmula (XXIII), opcionalmente en presencia de una base adecuada tal como trietilamina en un solvente adecuado tal como N,N– dimetilformamida. A compound of formula (IV), in which L1 is a leaving group (such as halo, tosyl, mesyl, etc.), can be prepared by reacting a compound of formula (XXIV) with a compound of formula (XXIII ), optionally in the presence of a suitable base such as triethylamine in a suitable solvent such as N, N-dimethylformamide.

O (R3)m L1 O (R3) m L1

N O NO

R8 N R8 N

(R3)m L1 (R3) m L1

L1 N R2L1 N R2

R2R2

NNH R6R7 R6R7 NNH R6R7 R6R7

(XXIII) (XXIV) (IV) (XXIII) (XXIV) (IV)

Un compuesto de fórmula (X), en el que L1 es un grupo saliente (tal como halo, tosilo, mesilo, etc.) y R es un hidrógeno o un grupo alquilo de C1-4, se puede preparar mediante la reacción de un compuesto de fórmula (XXV) A compound of formula (X), in which L1 is a leaving group (such as halo, tosyl, mesyl, etc.) and R is a hydrogen or a C1-4 alkyl group, can be prepared by reacting a compound of formula (XXV)

con un compuesto de fórmula (XXIII), opcionalmente en presencia de una base adecuada tal como trietilamina en un solvente adecuado tal como N,N–dimetilformamida. with a compound of formula (XXIII), optionally in the presence of a suitable base such as triethylamine in a suitable solvent such as N, N-dimethylformamide.

O (R3)m L1 O (R3) m L1

NN

O OR

R 8 R 8

R 8 (R3)m R 8 (R3) m

N N N N

N N

: OOR

: O OR

R2 R2

R2R2

H NH N

N RR N RR

(XXIII) O (XXV) O (X) (XXIII) O (XXV) O (X)

Un compuesto de fórmula (XVIII), en el que L1 es un grupo saliente (tal como halo, tosilo, mesilo, etc.), se puede A compound of formula (XVIII), in which L1 is a leaving group (such as halo, tosyl, mesyl, etc.), can be

5 preparar mediante la reacción de un compuesto de fórmula (XXVI) con un compuesto de fórmula (XXIII), opcionalmente en presencia de una base adecuada tal como trietilamina en un solvente adecuado tal como N,N– dimetilformamida. 5 preparing by reacting a compound of formula (XXVI) with a compound of formula (XXIII), optionally in the presence of a suitable base such as triethylamine in a suitable solvent such as N, N-dimethylformamide.

O (R3)mO (R3) m

O OR

L1 L1

(R3)m R8 N (R3) m R8 N

R8 N R8 N

N H R2 N H R2

N N

NCNR2 NCN(XXIII) NCNR2 NCN (XXIII)

(XXVI) (XVIII) (XXVI) (XVIII)

Un compuesto de fórmula (XX), en el que L1 es un grupo saliente (tal como halo, tosilo, mesilo, etc.) y L2 es un grupo A compound of formula (XX), in which L1 is a leaving group (such as halo, tosyl, mesyl, etc.) and L2 is a group

10 saliente (tal como halo, tosilo, mesilo, –SMe, –S(O)2Me, etc.), se puede preparar mediante la reacción de un compuesto de fórmula (XXVII) con un compuesto de fórmula (XXIII), opcionalmente en presencia de una base adecuada tal como trietilamina en un solvente adecuado tal como N,N–dimetilformamida. Outgoing (such as halo, tosyl, mesyl, -SMe, -S (O) 2Me, etc.), can be prepared by reacting a compound of formula (XXVII) with a compound of formula (XXIII), optionally in presence of a suitable base such as triethylamine in a suitable solvent such as N, N-dimethylformamide.

O O O o

(R3)m (R3) m

(R3)m L1 N R8 (R3) m L1 N R8

R8 R8

N H N H

NN

N N

(XXIII) L2 R2(XXIII) L2 R2

L2NR2 N L2NR2 N

(XXVII) (XX) (XXVII) (XX)

Un compuesto de fórmula (XIII), en el que L1 es un grupo saliente (tal como halo, tosilo, mesilo, etc.) y L2 es un A compound of formula (XIII), wherein L1 is a leaving group (such as halo, tosyl, mesyl, etc.) and L2 is a

15 grupo saliente (tal como halo, tosilo, mesilo, –SMe, –S(O)2Me, etc.), se puede preparar mediante la reacción de un compuesto de fórmula (XXVIII) con un compuesto de fórmula (XXIII), opcionalmente en presencia de una base adecuada tal como trietilamina en un solvente adecuado tal como N,N–dimetilformamida. The leaving group (such as halo, tosyl, mesyl, -SMe, -S (O) 2Me, etc.), can be prepared by reacting a compound of formula (XXVIII) with a compound of formula (XXIII), optionally in the presence of a suitable base such as triethylamine in a suitable solvent such as N, N-dimethylformamide.

O (R3)m L1 O (R3) m L1

NN

O OR

R8 (R3)m R8 (R3) m

R8 R8

N N N N

N R1R1 L2N R1R1 L2

L2 L2

XNXNH XNXNH

(XXIII) (XXVIII) (XIII) (XXIII) (XXVIII) (XIII)

Se apreciará que un compuesto de fórmula (XIII) se puede transformar en otro compuesto de fórmula (XIII) mediante 20 técnicas tales como oxidación, alquilación, aminación reductora, etc., enumeradas anteriormente o de otra forma conocida en la bibliografía. It will be appreciated that a compound of formula (XIII) can be transformed into another compound of formula (XIII) by techniques such as oxidation, alkylation, reductive amination, etc., listed above or otherwise known in the literature.

Un compuesto de fórmula (XIV), en el que L1 es un grupo saliente (tal como halo, tosilo, mesilo, etc.) y L2 es un grupo saliente (tal como halo, tosilo, mesilo, –SMe, –S(O)2Me, etc.), se puede preparar mediante la reacción de un compuesto de fórmula (XXIX) con un compuesto de fórmula (XXIII), opcionalmente en presencia de una base A compound of formula (XIV), in which L1 is a leaving group (such as halo, tosyl, mesyl, etc.) and L2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S (O ) 2Me, etc.), can be prepared by reacting a compound of formula (XXIX) with a compound of formula (XXIII), optionally in the presence of a base

25 adecuada tal como trietilamina en un solvente adecuado tal como N,N–dimetilformamida. Suitable such as triethylamine in a suitable solvent such as N, N-dimethylformamide.

O OR

(R3)m L1 (R3) m L1

N O NO

R8 N R8 N

(R3)m L1 L1 N L2(R3) m L1 L1 N L2

L2L2

N NH NH

R6R7 R6R7 R6R7 R6R7

(XXIII) (XXIX) (XIV) (XXIII) (XXIX) (XIV)

Un compuesto de fórmula (XVII), en el que L1 es un grupo saliente (tal como halo, tosilo, mesilo, etc.) y L2 es un grupo saliente (tal como halo, tosilo, mesilo, –SMe, –S(O)2Me, etc.) y R es un hidrógeno o un grupo alquilo de C1-4, se puede preparar mediante la reacción de un compuesto de fórmula (XXX) con un compuesto de fórmula (XXIII), A compound of formula (XVII), in which L1 is a leaving group (such as halo, tosyl, mesyl, etc.) and L2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S (O ) 2Me, etc.) and R is a hydrogen or a C1-4 alkyl group, can be prepared by reacting a compound of formula (XXX) with a compound of formula (XXIII),

5 opcionalmente en presencia de una base adecuada tal como trietilamina en un solvente adecuado tal como N,N– dimetilformamida. 5 optionally in the presence of a suitable base such as triethylamine in a suitable solvent such as N, N-dimethylformamide.

O (R3)m L1 O (R3) m L1

NN

O OR

R 8 R 8

R 8 (R3)m R 8 (R3) m

N N N N

N N

: OOR

: O OR

L2 L2

L2L2

H NH N

N RR N RR

(XXIII) O O(XXIII) OR OR

(XXX) (XVII) (XXX) (XVII)

Un compuesto de fórmula (XIX), en el que L1 es un grupo saliente (tal como halo, tosilo, mesilo, etc.) y L2 es un grupo saliente (tal como halo, tosilo, mesilo, –SMe, –S(O)2Me, etc.), se puede preparar mediante la reacción de un 10 compuesto de fórmula (XXXI) con un compuesto de fórmula (XXIII), opcionalmente en presencia de una base adecuada tal como trietilamina en un solvente adecuado tal como N,N–dimetilformamida. A compound of formula (XIX), in which L1 is a leaving group (such as halo, tosyl, mesyl, etc.) and L2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S (O ) 2Me, etc.), can be prepared by reacting a compound of formula (XXXI) with a compound of formula (XXIII), optionally in the presence of a suitable base such as triethylamine in a suitable solvent such as N, N –Dimethylformamide.

O (R3)mO N(R3)m R8 L1 O (R3) mO N (R3) m R8 L1

R8 N R8 N

N H L2 N H L2

N N

NCNL2 NCN(XXIII) NCNL2 NCN (XXIII)

(XXXI) (XIX) (XXXI) (XIX)

Un compuesto de fórmula (XXI), en el que L1 es un grupo saliente (tal como halo, tosilo, mesilo, etc.) y L2 es un grupo saliente (tal como halo, tosilo, mesilo, –SMe, –S(O)2Me, etc.), se puede preparar mediante la reacción de un 15 compuesto de fórmula (XXXII) con un compuesto de fórmula (XXIII), opcionalmente en presencia de una base adecuada tal como trietilamina en un solvente adecuado tal como N,N–dimetilformamida. A compound of formula (XXI), in which L1 is a leaving group (such as halo, tosyl, mesyl, etc.) and L2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S (O ) 2Me, etc.), can be prepared by reacting a compound of formula (XXXII) with a compound of formula (XXIII), optionally in the presence of a suitable base such as triethylamine in a suitable solvent such as N, N –Dimethylformamide.

O O O o

(R3)m (R3)m L1 (R3) m (R3) m L1

N R8 N R8

R8 R8

N H N H

NN

N N

L2L2

L2 L2L2 L2

(XXIII) L2 N N (XXIII) L2 N N

(XXXII) (XXI) (XXXII) (XXI)

Un compuesto de fórmula (I), en el que R1X = H2NCH2–, se puede preparar a partir de un compuesto de fórmula A compound of formula (I), in which R1X = H2NCH2–, can be prepared from a compound of formula

(XVIII) mediante una reducción tal como hidrogenación con gas hidrógeno y un catalizador adecuado tal como 20 paladio sobre carbono en un solvente adecuado tal como etanol. (XVIII) by a reduction such as hydrogenation with hydrogen gas and a suitable catalyst such as 20 palladium on carbon in a suitable solvent such as ethanol.

O OR

O (R3)m O (R3) m

(R3)m NN (R3) m NN

R 8 R8 N R 8 R8 N

N H2N R2 N H2N R2

R2 NR2 N

NC N (I)(XVIII) NC N (I) (XVIII)

Un compuesto de fórmula (I), en el que R1X = H2NC(O)–, se puede preparar a partir de un compuesto de fórmula A compound of formula (I), in which R1X = H2NC (O) -, can be prepared from a compound of formula

(XVIII) mediante hidrólisis con, por ejemplo, hidróxido de sodio en un solvente adecuado tal como una mezcla de agua y etanol. (XVIII) by hydrolysis with, for example, sodium hydroxide in a suitable solvent such as a mixture of water and ethanol.

O OR

O (R3)m O (R3) m

(R3)m NN (R3) m NN

R 8 R8 N R 8 R8 N

N H2N R2NR2NC N N H2N R2NR2NC N

(XVIII) O (I) (XVIII) OR (I)

5 Un compuesto de fórmula (I), en el que R1X = H2NCR6R7–, se puede preparar a partir de un compuesto de fórmula A compound of formula (I), in which R1X = H2NCR6R7–, can be prepared from a compound of formula

(XVIII) mediante la reacción con reactivos organometálicos (XI) y (XII). (XVIII) by reaction with organometallic reagents (XI) and (XII).

O R6 O O R6 O

(R3)mM (R3) mM

(R3)m (R3) m

(XI) (XI)

N R8 N N R8 N

R 8 R7 N R 8 R7 N

NN

M H2N R2M H2N R2

(XII) NCNR2 N (XII) NCNR2 N

R6 R7 R6 R7

(XVIII) (I) (XVIII) (I)

Un compuesto de fórmula (XIII), en el que R1X = H2NCH2–, se puede preparar a partir de un compuesto de fórmula A compound of formula (XIII), in which R1X = H2NCH2–, can be prepared from a compound of formula

(XIX) mediante una reducción tal como hidrogenación con gas hidrógeno y un catalizador adecuado tal como paladio 10 sobre carbono en un solvente adecuado tal como etanol. (XIX) by a reduction such as hydrogenation with hydrogen gas and a suitable catalyst such as palladium 10 on carbon in a suitable solvent such as ethanol.

O OR

O (R3)m O (R3) m

(R3)m NN (R3) m NN

R 8 R8 N R 8 R8 N

N H2N L2 N H2N L2

L2 NL2 N

NC N (XIII)(XIX) NC N (XIII) (XIX)

Un compuesto de fórmula (XIII), en el que R1X = H2NC(O)–, se puede preparar a partir de un compuesto de fórmula A compound of formula (XIII), in which R1X = H2NC (O) -, can be prepared from a compound of formula

(XIX) mediante hidrólisis con, por ejemplo, hidróxido de sodio en un solvente adecuado tal como una mezcla de agua y etanol. (XIX) by hydrolysis with, for example, sodium hydroxide in a suitable solvent such as a mixture of water and ethanol.

O OR

O (R3)m O (R3) m

(R3)m NN (R3) m NN

R 8 R8 N R 8 R8 N

N H2N L2NL2N H2N L2NL2

NC N O NC N O

(XIX) (XIII) (XIX) (XIII)

15 Un compuesto de fórmula (XIII), en el que R1X = H2NCR6R7–, se puede preparar a partir de un compuesto de fórmula (XIX) mediante la reacción con reactivos organometálicos (XI) y (XII). A compound of formula (XIII), in which R1X = H2NCR6R7–, can be prepared from a compound of formula (XIX) by reaction with organometallic reagents (XI) and (XII).

O R6 O O R6 O

(R3)mM (R3) mM

(R3)m (R3) m

(XI) (XI)

N R8 N N R8 N

R 8 R7 N R 8 R7 N

NN

M H2N L2M H2N L2

(XII) NCN L2 N R6 R7 (XII) NCN L2 N R6 R7

(XIX) (XIII) (XIX) (XIII)

Se apreciará que el grupo R2 se puede introducir inicialmente en cualquier etapa como una amina carbocíclica o 20 heterocíclica (opcionalmente con el nitrógeno protegido; tales grupos protectores incluyen pero no están limitados a It will be appreciated that the R2 group may initially be introduced at any stage as a carbocyclic or heterocyclic amine (optionally with protected nitrogen; such protecting groups include but are not limited to

nitro, terc–butoxi carbamato, etc.) que se puede transformar en una etapa posterior en la síntesis (después de una desprotección apropiada) en una urea por la reacción directa con un isocianato (o un grupo activado de otra manera tal como un fenoxi carbamato, etc.) o por la activación de la amina (tal como con fosgeno o la formación de un fenoxi carbamato, etc.) y la reacción posterior con una amina apropiada, u otros métodos de formación de una urea conocidos en la bibliografía. nitro, tert-butoxy carbamate, etc.) which can be transformed at a later stage in the synthesis (after appropriate deprotection) into a urea by direct reaction with an isocyanate (or an otherwise activated group such as a phenoxy carbamate, etc.) or by the activation of the amine (such as with phosgene or the formation of a phenoxy carbamate, etc.) and subsequent reaction with an appropriate amine, or other urea formation methods known in the literature.

Se apreciará que algunos de los diversos sustituyentes anulares en los compuestos de la presente invención se pueden introducir mediante reacciones de sustitución aromática estándar, o se pueden generar mediante modificaciones de grupos funcionales convencionales antes de o inmediatamente a continuación de los procesos mencionados anteriormente, y como tal se incluyen en el aspecto del procedimiento de la invención. Por ejemplo, los compuestos de fórmula (I) se pueden convertir en compuestos adicionales de fórmula (I) mediante reacciones de sustitución aromática estándar, o mediante modificaciones de grupos funcionales convencionales. Tales reacciones y modificaciones incluyen, por ejemplo, la introducción de un sustituyente por medio de una reacción de sustitución aromática, reducción de sustituyentes, alquilación de sustituyentes y oxidación de sustituyentes. Los reactivos y las condiciones de reacción para tales procedimientos son bien conocidos en la técnica química. Ejemplos particulares de reacciones de sustitución aromática incluyen la introducción de un grupo nitro usando ácido nítrico concentrado, la introducción de un grupo acilo usando, por ejemplo, un haluro de acilo y ácido de Lewis (tal como tricloruro de aluminio) en condiciones de Friedel Crafts; la introducción de un grupo alquilo usando un haluro de alquilo y ácido de Lewis (tal como tricloruro de aluminio) en condiciones de Friedel Crafts; y la introducción de un grupo halógeno. Ejemplos particulares de modificaciones incluyen la reducción de un grupo nitro a un grupo amino mediante, por ejemplo, hidrogenación catalítica con un catalizador de níquel o tratamiento con hierro en presencia de ácido clorhídrico con calentamiento; oxidación de alquiltio a alquilsulfinilo o alquilsulfonilo. It will be appreciated that some of the various annular substituents in the compounds of the present invention may be introduced by standard aromatic substitution reactions, or they may be generated by modifications of conventional functional groups before or immediately following the processes mentioned above, and as such are included in the aspect of the process of the invention. For example, the compounds of formula (I) can be converted into additional compounds of formula (I) by standard aromatic substitution reactions, or by modifications of conventional functional groups. Such reactions and modifications include, for example, the introduction of a substituent by means of an aromatic substitution reaction, reduction of substituents, alkylation of substituents and oxidation of substituents. Reagents and reaction conditions for such procedures are well known in the chemical art. Particular examples of aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acyl halide and Lewis acid (such as aluminum trichloride) under Friedel Crafts conditions. ; introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminum trichloride) under Friedel Crafts conditions; and the introduction of a halogen group. Particular examples of modifications include the reduction of a nitro group to an amino group by, for example, catalytic hydrogenation with a nickel catalyst or iron treatment in the presence of heating hydrochloric acid; oxidation of alkylthio to alkylsulfinyl or alkylsulfonyl.

Se apreciará también que en algunas de las reacciones mencionadas aquí puede ser necesario/deseable proteger cualesquiera grupos sensibles en los compuestos. Los casos en los que la protección es necesaria o deseable y los métodos adecuados para la protección son conocidos por aquellos versados en la técnica. Los grupos protectores convencionales se pueden usar de acuerdo con la práctica estándar (para ejemplos, véase T.W. Green, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991). De este modo, si los reactivos incluyen grupos tales como amino, carboxi o hidroxi, puede ser deseable proteger el grupo en algunas de las reacciones mencionadas aquí. It will also be appreciated that in some of the reactions mentioned herein it may be necessary / desirable to protect any sensitive groups in the compounds. Cases in which protection is necessary or desirable and appropriate methods for protection are known to those skilled in the art. Conventional protecting groups can be used in accordance with standard practice (for examples, see T.W. Green, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991). Thus, if the reagents include groups such as amino, carboxy or hydroxy, it may be desirable to protect the group in some of the reactions mentioned herein.

Un grupo protector adecuado para un grupo amino o alquilamino es, por ejemplo, un grupo acilo, por ejemplo un grupo alcanoilo tal como acetilo, un grupo alcoxicarbonilo, por ejemplo un grupo metoxicarbonilo, etoxicarbonilo o terc–butoxicarbonilo, un grupo arilmetoxicarbonilo, por ejemplo benciloxicarbonilo, o un grupo aroilo, por ejemplo benzoilo. Las condiciones de desprotección para los grupos protectores anteriores varían necesariamente con la elección del grupo protector. De este modo, por ejemplo, un grupo acilo tal como un grupo alcanoilo o alcoxicarbonilo, o un grupo aroilo, se puede eliminar, por ejemplo, por hidrólisis con una base adecuada tal como un hidróxido de metal alcalino, por ejemplo hidróxido de litio o de sodio. Como alternativa, un grupo acilo, tal como un grupo terc–butoxicarbonilo, se puede eliminar, por ejemplo, por tratamiento con un ácido adecuado como ácido clorhídrico, sulfúrico o fosfórico, o ácido trifluoroacético, y un grupo arilmetoxicarbonilo, tal como un grupo benciloxicarbonilo, se puede eliminar, por ejemplo, por hidrogenación sobre un catalizador tal como paladio sobre carbono, o por tratamiento con un ácido de Lewis, por ejemplo tris(trifluoroacetato de boro. Un grupo protector alternativo adecuado para un grupo amino primario es, por ejemplo, un grupo ftaloilo el cual se puede eliminar por tratamiento con una alquilamina, por ejemplo dimetilaminopropilamina, o con hidrazina. A suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protective groups necessarily vary with the choice of the protective group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group, or an aroyl group, can be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium hydroxide or of sodium. Alternatively, an acyl group, such as a tert-butoxycarbonyl group, can be removed, for example, by treatment with a suitable acid such as hydrochloric, sulfuric or phosphoric acid, or trifluoroacetic acid, and an arylmethoxycarbonyl group, such as a benzyloxycarbonyl group. , it can be removed, for example, by hydrogenation on a catalyst such as palladium on carbon, or by treatment with a Lewis acid, for example tris (boron trifluoroacetate. An alternative protecting group suitable for a primary amino group is, for example , a phthaloyl group which can be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.

Un grupo protector adecuado para un grupo hidroxi es, por ejemplo, un grupo acilo, por ejemplo un grupo alcanoilo tal como acetilo, un grupo aroilo, por ejemplo benzoilo, o un grupo arilmetilo, por ejemplo bencilo. Las condiciones de desprotección para los grupos protectores anteriores variarán necesariamente con la elección del grupo protector. De este modo, por ejemplo, un grupo acilo, tal como un grupo alcanoilo o aroilo, se puede eliminar, por ejemplo, por hidrólisis con una base adecuada, tal como un hidróxido de metal alcalino, por ejemplo hidróxido de litio o de sodio. Como alternativa, un grupo arilmetilo, tal como un grupo bencilo, se puede eliminar, por ejemplo, por hidrogenación sobre un catalizador, tal como paladio sobre carbono. A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protective groups will necessarily vary with the choice of the protective group. Thus, for example, an acyl group, such as an alkanoyl or aroyl group, can be removed, for example, by hydrolysis with a suitable base, such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively, an arylmethyl group, such as a benzyl group, can be removed, for example, by hydrogenation on a catalyst, such as palladium on carbon.

Un grupo protector adecuado para un grupo carboxi es, por ejemplo, un grupo de esterificación, por ejemplo un grupo metilo o etilo, el cual se puede eliminar, por ejemplo, por hidrólisis con una base tal como hidróxido de sodio, o por ejemplo un grupo terc–butilo, el cual se puede eliminar, por ejemplo, por tratamiento con un ácido, por ejemplo un ácido orgánico tal como ácido trifluoroacético, o por ejemplo un grupo bencilo, el cual se puede eliminar, por ejemplo, por hidrogenación sobre un catalizador tal como paladio sobre carbón. A suitable protecting group for a carboxy group is, for example, an esterification group, for example a methyl or ethyl group, which can be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a tert-butyl group, which can be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group, which can be removed, for example, by hydrogenation on a catalyst such as palladium on carbon.

Los grupos protectores se pueden eliminar en cualquier etapa conveniente en la síntesis usando técnicas convencionales bien conocidas en la técnica química. The protecting groups can be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art.

Muchos de los productos intermedios definidos aquí son nuevos y se proporcionan como una característica adicional de la invención. Many of the intermediate products defined herein are new and are provided as an additional feature of the invention.

Ensayos biológicos Biological tests

Los siguientes ensayos se pueden usar para medir los efectos de los compuestos de la presente invención como inhibidores de mTOR cinasa, como inhibidores de PI3 cinasa, como inhibidores in vitro de la activación de las rutas de señalización de PI3 cinasa y como inhibidores in vitro de la proliferación de células humanas de adenocarcinoma de mama MDA–MB–468. The following tests can be used to measure the effects of the compounds of the present invention as mTOR kinase inhibitors, as PI3 kinase inhibitors, as in vitro inhibitors of the activation of PI3 kinase signaling pathways and as in vitro inhibitors of the proliferation of human breast adenocarcinoma cells MDA – MB – 468.

(a) Ensayo de mTOR cinasa in vitro (a) In vitro mTOR kinase assay

El ensayo usó la tecnología AlphaScreen (Gray et al., Analytical Biochemistry, 2003, 313: 234–245) para determinar la capacidad de los compuestos de ensayo para inhibir la fosforilación por mTOR recombinante. The assay used AlphaScreen technology (Gray et al., Analytical Biochemistry, 2003, 313: 234-245) to determine the ability of test compounds to inhibit phosphorylation by recombinant mTOR.

Un truncamiento C–terminal de mTOR que abarca los restos de aminoácidos 1362 al 2549 de mTOR (nº de acceso EMBL L34075) se expresó establemente como una fusión etiquetada con FLAG en células HEK293 como se describe por Vilella–Bach et al., Journal of Biochemistry, 1999, 274, 4266–4272. La línea celular estable HEK293 (1362–2549) de mTOR etiquetada con FLAG se mantuvo rutinariamente a 37ºC con 5% de CO2 hasta una confluencia de 70–90% en medio de crecimiento de Eagle modificado de Dulbecco (DMEM; Invitrogen Limited, Paisley, Reino Unido, nº de catálogo 41966–029) que contiene 10% de suero fetal de ternera inactivado por calor (FCS; Sigma, Poole, Dorset, Reino Unido, nº de catálogo F0392), 1% de L–glutamina (Gibco, nº de catálogo 25030– 024) y 2 mg/ml de Geneticina (sulfato de G418; Invitrogen Limited, Reino Unido, nº de catálogo 10131–027). Tras la expresión en la línea celular HEK293 de mamífero, la proteína expresada se purificó usando la etiqueta del epítopo FLAG usando técnicas de purificación estándar. A C-terminal truncation of mTOR spanning amino acid residues 1362 to 2549 of mTOR (EMBL accession No. L34075) was stably expressed as a FLAG-labeled fusion in HEK293 cells as described by Vilella-Bach et al., Journal of Biochemistry, 1999, 274, 4266-4272. The stable cell line HEK293 (1362-2549) of FLAG-labeled mTOR was routinely maintained at 37 ° C with 5% CO2 to a confluence of 70-90% in Dulbecco's modified Eagle growth medium (DMEM; Invitrogen Limited, Paisley, United Kingdom, catalog No. 41966–029) containing 10% heat-inactivated fetal calf serum (FCS; Sigma, Poole, Dorset, United Kingdom, catalog No. F0392), 1% L-glutamine (Gibco, no. Catalog 25030-024) and 2 mg / ml Geneticin (G418 Sulfate; Invitrogen Limited, United Kingdom, Catalog No. 10131-027). After expression in the mammalian HEK293 cell line, the expressed protein was purified using the FLAG epitope tag using standard purification techniques.

Los compuestos de ensayo se prepararon como disoluciones madre 10 mM en DMSO y se dilueyron en agua según se requirió para dar un intervalo de concentraciones finales del ensayo. Se colocaron alícuotas (2 %l) de cada dilución del compuesto en un pocillo de una placa Greiner de poliestireno blanco de bajo volumen (LV) de 384 pocillos (Greiner Bio–one). Se agitaron 30 %l de una mezcla de la enzima mTOR purificada recombinante, 1 %M de sustrato peptídico biotinilado (Biotin–Ahx–Lys–Lys–Ala–Asn–Gln–Val–Phe–Leu–Gly–Phe–Thr–Tyr–Val–Ala–Pro– Ser–Val–Leu–Glu–Ser–Val–Lys–Glu–NH2; Bachem Reino Unido Ltd), ATP (20 %M) y una disolución tampón [que comprende tampón Tris–HCl pH 7,4 (50 mM), EGTA (0,1 mM), seroalbúmina bovina (0,5 mg/ml), DTT (1,25 mM) y cloruro de manganeso (10 mM)] a temperatura ambiente durante 90 minutos. The test compounds were prepared as 10 mM stock solutions in DMSO and diluted in water as required to give a range of final test concentrations. Aliquots (2% 1) of each dilution of the compound were placed in a well of a low volume white polystyrene (LV) Greiner plate of 384 wells (Greiner Bio-one). 30% 1 of a mixture of the recombinant purified mTOR enzyme, 1% M of biotinylated peptide substrate (Biotin-Ahx-Lys-Lys-Ala-Asn-Gln-Val-Phe-Leu-Gly-Phe-Thhe-Tyr) was stirred –Val – Ala – Pro– Ser – Val – Leu – Glu – Ser – Val – Lys – Glu – NH2; Bachem United Kingdom Ltd), ATP (20% M) and a buffer solution [comprising Tris – HCl buffer pH 7 , 4 (50 mM), EGTA (0.1 mM), bovine serum albumin (0.5 mg / ml), DTT (1.25 mM) and manganese chloride (10 mM)] at room temperature for 90 minutes.

Los pocillos de control que produjeron una señal máxima que corresponde a la actividad máxima de la enzima se crearon usando 5% de DMSO en lugar del compuesto de ensayo. Los pocillos de control que produjeron una señal mínima que corresponde a la enzima completamente inhibida se crearon añadiendo EDTA (83 mM) en lugar del compuesto de ensayo. Estas disoluciones de ensayo se incubaron durante 2 horas a temperatura ambiente. Control wells that produced a maximum signal that corresponds to the maximum activity of the enzyme were created using 5% DMSO instead of the test compound. Control wells that produced a minimal signal corresponding to the completely inhibited enzyme were created by adding EDTA (83 mM) instead of the test compound. These test solutions were incubated for 2 hours at room temperature.

Cada reacción se detuvo por la adición de 10 %l de una mezcla de EDTA (50 mM), seroalbúmina bovina (BSA; 0,5 mg/ml) y tampón Tris–HCl pH7,4 (50 mM) que contiene Anticuerpo Monoclonal 1A5 p70 S6 Cinasa (T389) (Cell Signalling Technology, nº de catálogo 9206B), y se añadieron perlas donantes de Estreptavidina AlphaScreen y aceptoras de Proteína A (200 ng; Perkin Elmer, nº de catálogo 6760002B y 6760137R, respectivamente) y las placas de ensayo se dejaron durante alrededor de 20 horas a temperatura ambiente en la oscuridad. Las señales resultantes que derivan de la excitación con luz láser a 680 nm se leyeron usando un instrumento Packard Envision. Each reaction was stopped by the addition of 10% 1 of a mixture of EDTA (50 mM), bovine serum albumin (BSA; 0.5 mg / ml) and Tris-HCl buffer pH7.4 (50 mM) containing 1A5 Monoclonal Antibody p70 S6 Kinase (T389) (Cell Signaling Technology, catalog no. 9206B), and Streptavidin AlphaScreen donor beads and Protein A acceptors (200 ng; Perkin Elmer, catalog no. 6760002B and 6760137R, respectively) and the plates were added Assay were left for about 20 hours at room temperature in the dark. The resulting signals derived from excitation with laser light at 680 nm were read using a Packard Envision instrument.

El péptido biotinilado fosforilado se forma in situ como resultado de la fosforilación mediada por la mTOR. El péptido biotinilado fosforilado que está asociado con las perlas donantes de Estreptavidina AlphaScreen forma un complejo con el Anticuerpo Monoclonal 1A5 p70 S6 Cinasa (T389) que está asociado con las perlas aceptoras de Proteína A AlphaScreen. Con la excitación con luz láser a 680 nm, el complejo de perla donante : perla aceptora produce una señal que puede ser medida. Por consiguiente, la presencia de la actividad de la mTOR cinasa da como resultado una señal del ensayo. En presencia de un inhibidor de mTOR cinasa, la intensidad de la señal se reduce. The biotinylated phosphorylated peptide is formed in situ as a result of mTOR-mediated phosphorylation. The phosphorylated biotinylated peptide that is associated with the Streptavidin AlphaScreen donor beads forms a complex with the Monoclonal Antibody 1A5 p70 S6 Kinase (T389) that is associated with the AlphaScreen Protein A acceptor beads. With the excitation with laser light at 680 nm, the donor bead: acceptor bead complex produces a signal that can be measured. Therefore, the presence of mTOR kinase activity results in an assay signal. In the presence of an mTOR kinase inhibitor, the signal strength is reduced.

La inhibición de la enzima mTOR para un compuesto de ensayo dado se expresó como un valor IC50. Inhibition of the mTOR enzyme for a given test compound was expressed as an IC50 value.

(b) Ensayo de la enzima PI3K in vitro (b) PI3K enzyme assay in vitro

El ensayo usó la tecnología AlphaScreen (Gray et al., Analytical Biochemistry, 2003, 313: 234–245) para determinar la capacidad de los compuestos de ensayo para inhibir la fosforilación por las enzimas PI3K recombinantes Tipo I del lípido PI(4,5)P2. The assay used AlphaScreen technology (Gray et al., Analytical Biochemistry, 2003, 313: 234-245) to determine the ability of test compounds to inhibit phosphorylation by recombinant PI3K enzymes Type I lipid (4,5 ) P2.

Los fragmentos de ADN que codifican las subunidades reguladoras y catalíticas de la PI3K humana se aislaron de librerías de ADNc usando técnicas de clonación por PCR y de biología molecular estándares. Los fragmentos de ADN seleccionados se usaron para generar vectores de expresión de baculovirus. En particular, el ADN de longitud completa de cada una de las isoformas de p110 de la PI3K humana de Tipo Ia, p110!, p110∀ y p110δ (nº de acceso de EMBL HSU79143, S67334, Y10055 para p110!, p110∀ y p110δ respectivamente) se subclonó en un vector pDEST10 (Invitrogen Limited, Fountain Drive, Paisley, Reino Unido). El vector es una versión adaptada de Gateway de Fastbac1 que contiene una etiqueta del epítopo 6–His. Una forma truncada de la isoforma p110# de la PI3K humana de Tipo Ib que corresponde a los restos de aminoácidos 144–1102 (nº de acceso EMBL X8336A) y la subunidad reguladora de p85! humana de longitud completa (nº de acceso EMBL HSP13KIN) también se subclonaron en el vector pFastBac1 que contiene una etiqueta del epítopo 6–His. Los constructos de p110 de Tipo DNA fragments encoding the regulatory and catalytic subunits of human PI3K were isolated from cDNA libraries using standard PCR cloning and molecular biology techniques. Selected DNA fragments were used to generate baculovirus expression vectors. In particular, the full-length DNA of each of the isoforms of p110 of the human PI3K Type Ia, p110 !, p110∀ and p110δ (EMBL accession number HSU79143, S67334, Y10055 for p110 !, p110∀ and p110δ respectively) was subcloned into a pDEST10 vector (Invitrogen Limited, Fountain Drive, Paisley, United Kingdom). The vector is an adapted version of Fastbac1 Gateway that contains a 6-His epitope tag. A truncated form of the p110 # isoform of human Type Ib PI3K corresponding to amino acid residues 144–1102 (EMBL accession number X8336A) and the regulatory subunit of p85! Full length human (EMBL accession number HSP13KIN) were also subcloned into the pFastBac1 vector containing a 6-His epitope tag. Type p110 constructs

Ia se coexpresaron con la subunidad reguladora p85!. Tras la expresión en el sistema de baculovirus usando técnicas de expresión de baculovirus estándar, las proteínas expresadas se purificaron usando la etiqueta del epítopo His usando técnicas de purificación estándar. Ia were coexpressed with the regulatory subunit p85 !. After expression in the baculovirus system using standard baculovirus expression techniques, the expressed proteins were purified using the His epitope tag using standard purification techniques.

El ADN correspondiente a los aminoácidos 263 al 380 del receptor humano general para el dominio PH de fosfoinositidas (Grp1) se aisló de una librería de ADNc usando técnicas de clonación por PCR y de biología molecular estándar. El fragmento de ADN resultante se subclonó en un vector de expresión pGEX 4T1 de E. coli que contiene una etiqueta del epítopo GST (Amersham Pharmacia Biotech, Rainham, Essex, Reino Unido) como se describe por Gray et al., Analytical Biochemistry, 2003, 313: 234–245). El dominio PH Grp1 etiquetado con GST se expresó y purificó usando técnicas estándares. The DNA corresponding to amino acids 263 to 380 of the general human receptor for the PH domain of phosphoinositides (Grp1) was isolated from a cDNA library using PCR cloning techniques and standard molecular biology. The resulting DNA fragment was subcloned into an E. coli pGEX 4T1 expression vector containing a GST epitope tag (Amersham Pharmacia Biotech, Rainham, Essex, UK) as described by Gray et al., Analytical Biochemistry, 2003 , 313: 234-245). The PH Grp1 domain labeled with GST was expressed and purified using standard techniques.

Los compuestos de ensayo se prepararon como disoluciones madre 10 mM en DMSO y se diluyeron en agua según se requirió para dar un intervalo de concentraciones finales del ensayo. Se colocaron alícuotas (2 %l) de cada dilución del compuesto en un pocillo de una placa Greiner de poliestireno blanco de bajo volumen (LV) de 384 pocillos (Greiner Bio–one, Brunel Way, Stonehouse, Gloucestershire, Reino Unido, Nº de catálogo 784075). Una mezcla de cada uno de enzima PI3K purificada recombinante seleccionada (15 ng), sustrato DiC8–PI(4,5)P2 (40 %M; Cell Signals Inc., Kinnear Road, Columbus, USA, Nº de catálogo 901), trifosfato de adenosina (ATP; 4 %M) y una disolución tampón [que comprende tampón Tris–HCl pH7,6 (40 mM, 10 %l), 3–[(3–colamidopropil)dimetilamonio]–1– propanosulfonato (CHAPS; 0,04%), ditiotreitol (DTT; 2 mM) y cloruro de magnesio (10 mM)] se agitó a temperatura ambiente durante 20 minutos. The test compounds were prepared as 10 mM stock solutions in DMSO and diluted in water as required to give a range of final test concentrations. Aliquots (2% l) of each dilution of the compound were placed in a well of a 384-well white low-volume Greiner (LV) Greiner plate (Greiner Bio-one, Brunel Way, Stonehouse, Gloucestershire, UK, No. of catalog 784075). A mixture of each of the selected recombinant purified PI3K enzyme (15 ng), DiC8-PI substrate (4.5) P2 (40% M; Cell Signals Inc., Kinnear Road, Columbus, USA, Catalog No. 901), triphosphate of adenosine (ATP; 4% M) and a buffer solution [comprising Tris-HCl buffer pH7.6 (40 mM, 10% l), 3 - [(3-colamidopropyl) dimethylammonium] -1-propane sulfonate (CHAPS; 0 , 04%), dithiothreitol (DTT; 2 mM) and magnesium chloride (10 mM)] was stirred at room temperature for 20 minutes.

Los pocillos de control que produjeron una señal mínima que corresponde a la actividad máxima de la enzima se crearon usando 5% de DMSO en lugar del compuesto de ensayo. Los pocillos de control que produjeron una señal máxima que corresponde a la enzima completamente inhibida se crearon añadiendo wortmanina (6 %M; Calbiochem / Merck Bioscience, Padge Road, Beeston, Nottingham, Reino Unido, Nº de catálogo 681675) en lugar del compuesto de ensayo. Estas disoluciones de ensayo también se agitaron durante 20 minutos a temperatura ambiente. Control wells that produced a minimum signal that corresponds to the maximum activity of the enzyme were created using 5% DMSO instead of the test compound. Control wells that produced a maximum signal corresponding to the completely inhibited enzyme were created by adding wortmanin (6% M; Calbiochem / Merck Bioscience, Padge Road, Beeston, Nottingham, United Kingdom, Catalog No. 681675) instead of the compound of test. These test solutions were also stirred for 20 minutes at room temperature.

Cada reacción se detuvo por adición de 10 %l de una mezcla de EDTA (100 mM), seroalbúmina bovina (BSA, 0,045 %) y tampón Tris–HCl pH7,6 (40 mM). Each reaction was stopped by adding 10% 1 of a mixture of EDTA (100 mM), bovine serum albumin (BSA, 0.045%) and Tris-HCl buffer pH7.6 (40 mM).

Se añadieron DiC8–PI(3,4,5)P3 biotinilada (50 nM; Cell Signals Inc., Nº de catálogo 107), proteína PH GST–Grp1 purificada recombinante (2,5 nM) y perlas donantes y aceptoras Anti–GST de AlphaScreen (100 ng; Packard Bioscience Limited, Station Road, Pangboume, Berkshire, Reino Unido, Nº de catálogo 6760603M), y las placas de ensayo se dejaron durante alrededor de 5 a 20 horas a temperatura ambiente en la oscuridad. Las señales resultantes que derivan de la excitación con luz láser a 680 nm se leyeron usando un instrumento Packard AlphaQuest. Biotinylated DiC8-PI (3,4,5) P3 (50 nM; Cell Signals Inc., Catalog No. 107), recombinant purified GST-Grp1 PH protein (2.5 nM) and anti-GST donor and acceptor beads were added of AlphaScreen (100 ng; Packard Bioscience Limited, Station Road, Pangboume, Berkshire, United Kingdom, Catalog No. 6760603M), and the test plates were left for about 5 to 20 hours at room temperature in the dark. The resulting signals derived from the excitation with laser light at 680 nm were read using a Packard AlphaQuest instrument.

PI(3,4,5)P3 se forma in situ como resultado de la fosforilación de PI(4,5)P2 mediada por PI3K. La proteína del dominio PH GST–Grp1 que está asociada con las perlas donantes Anti–GST de AlphaScreen forma un complejo con la PI(3,4,5)P3 biotinilada que está asociada con las perlas aceptoras de Estreptavidina de AlphaScreen. La PI(3,4,5)P3 producida enzimáticamente compite con la PI(3,4,5)P3 biotinilada para unirse a la proteína del dominio PH. Tras la excitación con luz láser a 680 nm, el complejo perla donante : perla aceptora produce una señal que puede ser medida. Por consiguiente, la actividad de la enzima PI3K para formar la PI(3,4,5)P3 y la posterior competición con la PI(3,4,5)P3 biotinilada da como resultado una señal reducida. En presencia de un inhibidor de la enzima PI3K, se recupera la intensidad de la señal. PI (3,4,5) P3 is formed in situ as a result of the phosphorylation of PI (4,5) P2 mediated by PI3K. The PH GST-Grp1 domain protein that is associated with AlphaScreen Anti-GST donor beads forms a complex with biotinylated PI (3,4,5) P3 that is associated with AlphaScreen Streptavidin acceptor beads. The enzymatically produced PI (3,4,5) P3 competes with the biotinylated PI (3,4,5) P3 to bind to the PH domain protein. After excitation with laser light at 680 nm, the donor bead: acceptor bead complex produces a signal that can be measured. Therefore, the activity of the PI3K enzyme to form the PI (3,4,5) P3 and subsequent competition with the biotinylated PI (3,4,5) P3 results in a reduced signal. In the presence of a PI3K enzyme inhibitor, the signal strength is recovered.

La inhibición de la enzima PI3K para un compuesto de ensayo dado se expresó como un valor IC50. The inhibition of the PI3K enzyme for a given test compound was expressed as an IC50 value.

(c) Ensayo Akt de fosfo–Ser473 in vitro (c) Akt assay of phospho-Ser473 in vitro

Esto ensayo determina la capacidad de los compuestos de ensayo para inhibir la fosforilación de Serina 473 en Akt como se evaluó usando la tecnología Acumen Explorer (Acumen Bioscience Limited), un lector de placa que puede ser usado para cuantificar rápidamente características de imágenes generadas por barrido con láser. This assay determines the ability of the test compounds to inhibit phosphorylation of Serine 473 in Akt as evaluated using Acumen Explorer technology (Acumen Bioscience Limited), a plate reader that can be used to quickly quantify characteristics of scan-generated images. with laser

Una línea celular de adenocarcinoma de mama humana MDA–MB–468 (LGC Promochem, Teddington, Middlesex, Reino Unido, Nº de catálogo HTB–132) se mantuvo rutinariamente a 37ºC con 5% de CO2 hasta una confluencia de 70–90% en DMEM que contiene 10% de FCS inactivado por calor y 1% L–glutamina. A human breast adenocarcinoma cell line MDA-MB-468 (LGC Promochem, Teddington, Middlesex, UK, Catalog No. HTB-132) was routinely maintained at 37 ° C with 5% CO2 to a confluence of 70–90% in DMEM containing 10% heat-inactivated FCS and 1% L-glutamine.

Para el ensayo, las células se separaron del matraz de cultivo usando ‘Accutase’ (Innovative Cell Technologies Inc., San Diego, CA, USA; Nº de catálogo AT104) usando métodos de cultivo de tejidos estándar, y se resuspendieron en medios para dar 1,7x105 células por ml. Se sembraron alícuotas (90 %l) en cada uno de los 60 pocillos internos de una placa de 96 pocillos Packard negra (PerkinElmer, Boston, MA, USA; Nº de catálogo 6005182) para dar una densidad de ~15000 células por pocillo. Se colocaron alícuotas (90 %l) de los medios de cultivo en los pocillos externos para prevenir los efectos de borde. Las células se incubaron toda la noche a 37ºC con 5% de CO2 para permitirles adherirse. For the assay, cells were separated from the culture flask using 'Accutase' (Innovative Cell Technologies Inc., San Diego, CA, USA; Catalog No. AT104) using standard tissue culture methods, and resuspended in media to give 1.7x105 cells per ml. Aliquots (90% 1) were seeded in each of the 60 internal wells of a black Packard 96-well plate (PerkinElmer, Boston, MA, USA; Catalog No. 6005182) to give a density of ~ 15,000 cells per well. Aliquots (90% 1) of the culture media were placed in the external wells to prevent edge effects. The cells were incubated overnight at 37 ° C with 5% CO2 to allow them to adhere.

En el día 2, las células se trataron con compuestos de ensayo y se incubaron durante 2 horas a 37ºC con 5% de CO2. Los compuestos de ensayo se prepararon como disoluciones madre 10 mM en DMSO y se diluyeron de manera seriada según se requirió con medios de crecimiento para dar un intervalo de concentraciones que fueron 10 veces las concentraciones finales de ensayo requeridas. Se colocaron alícuotas (10 %l) de cada dilución del compuesto en un pocillo (por triplicado) para dar las concentraciones finales requeridas. Como un control de respuesta mínima, cada placa contenía pocillos con una concentración final de 100 %M de LY294002 (Calbiochem, Beeston, Reino Unido, Nº de catálogo 440202). Como un control de respuesta máxima, los pocillos contenían 1% DMSO en lugar del compuesto de ensayo. Tras la incubación, el contenido de las placas se fijó por tratamiento con 1,6% de una disolución de formaldehído acuosa (Sigma, Poole, Dorset, Reino Unido, Nº de catálogo F1635) a temperatura ambiente durante 1 hora. On day 2, the cells were treated with test compounds and incubated for 2 hours at 37 ° C with 5% CO2. The test compounds were prepared as 10 mM stock solutions in DMSO and serially diluted as required with growth media to give a range of concentrations that were 10 times the required final test concentrations. Aliquots (10% 1) of each dilution of the compound were placed in a well (in triplicate) to give the required final concentrations. As a minimum response control, each plate contained wells with a final concentration of 100% M of LY294002 (Calbiochem, Beeston, United Kingdom, Catalog No. 440202). As a maximum response control, the wells contained 1% DMSO instead of the test compound. After incubation, the contents of the plates were fixed by treatment with 1.6% of a solution of aqueous formaldehyde (Sigma, Poole, Dorset, United Kingdom, Catalog No. F1635) at room temperature for 1 hour.

Todas las etapas de aspiración y lavado posteriores se llevaron a cabo usando un lavador de placas de 96 pocillos Tecan (velocidad de aspiración 10 mm/s). La disolución de fijación se eliminó, y el contenido de las placas se lavó con disolución salina tamponada con fosfato (PBS; 50 %l; Gibco, Nº de catálogo 10010015). Los contenidos de las placas se trataron durante 10 minutos a temperatura ambiente con una alícuota (50 %l) de un tampón de permeabilización celular que consiste en una mezcla de PBS y 0,5% de Tween–20. El tampón de ‘permeabilización’ se eliminó, y los sitios de unión no específica se bloquearon por tratamiento durante 1 hora a temperatura ambiente de una alícuota (50 %l) de un tampón de bloqueo que consiste en 5% de leche desnatada seca [‘Marvel’ (marca registrada); Premier Beverages, Stafford, GB] en una mezcla de PBS y 0,05% de Tween–20. El tampón de ‘bloqueo’ se eliminó, y las células se incubaron durante 1 hora a temperatura ambiente con disolución de anticuerpo de conejo anti fosfo–Akt (Ser473) (50 %l por pocillo; Cell Signalling, Hitchin, Herts, Reino Unido, Nº de catálogo 9277) que se había diluido 1:500 en el tampón de “bloqueo”. Las células se lavaron tres veces en una mezcla de PBS y 0,05% de Tween–20. Posteriormente, las células se incubaron durante 1 hora a temperatura ambiente con anticuerpo antiIgG de conejo de cabra marcado Alexafluor488 (50 %l por pocillo; Molecular Probes, Invitrogen Limited, Paisley, Reino Unido, Nº de catálogo A11008) que se había diluido 1:500 en el tampón de “bloqueo”. Las células se lavaron 3 veces con una mezcla de PBS y 0,05% de Tween–20. Se añadió una alícuota de PBS (50 %l) a cada pocillo, y las placas se sellaron con selladores de placa negros y se detectó y analizó la señal de fluorescencia. All subsequent aspiration and washing steps were carried out using a Tecan 96-well plate washer (aspiration rate 10 mm / s). The fixation solution was removed, and the contents of the plates were washed with phosphate buffered saline (PBS; 50% l; Gibco, Catalog No. 10010015). The contents of the plates were treated for 10 minutes at room temperature with an aliquot (50% 1) of a cell permeabilization buffer consisting of a mixture of PBS and 0.5% Tween-20. The 'permeabilization' buffer was removed, and the non-specific binding sites were blocked by treatment for 1 hour at room temperature of an aliquot (50% l) of a blocking buffer consisting of 5% dried skim milk [' Marvel '(registered trademark); Premier Beverages, Stafford, GB] in a mixture of PBS and 0.05% Tween – 20. The 'blocking' buffer was removed, and the cells were incubated for 1 hour at room temperature with anti-phospho-Akt rabbit antibody solution (Ser473) (50% l per well; Cell Signaling, Hitchin, Herts, UK, Catalog No. 9277) that had been diluted 1: 500 in the "blocking" buffer. The cells were washed three times in a mixture of PBS and 0.05% Tween-20. Subsequently, the cells were incubated for 1 hour at room temperature with Alexafluor488 labeled goat rabbit antiIgG antibody (50% l per well; Molecular Probes, Invitrogen Limited, Paisley, United Kingdom, Catalog No. A11008) that had been diluted 1: 500 in the "block" buffer. The cells were washed 3 times with a mixture of PBS and 0.05% Tween-20. An aliquot of PBS (50% 1) was added to each well, and the plates were sealed with black plate sealants and the fluorescence signal was detected and analyzed.

Los datos de la respuesta a la dosis de fluorescencia obtenidos con cada compuesto se añalizaron, y el grado de inhibición de la Serina 473 en Akt se expresó como un valor IC50. The fluorescence dose response data obtained with each compound was added, and the degree of inhibition of Serine 473 in Akt was expressed as an IC50 value.

(d) Ensayo de proliferación de adenocarcinoma de mama humano MDA–MB–468 in vitro (d) MDA – MB – 468 human breast adenocarcinoma proliferation assay in vitro

Este ensayo determina la capacidad de los compuestos de ensayo para inhibir la proliferación celular como se evaluó usando la tecnología Cellomics Arrayscan. Una línea celular de adenocarcinoma de mama humano MDA– MB–468 (LGC Promochem, Nº de catálogo HTB–132) se mantuvo rutinariamente como se describió en el Ensayo Biológico (b) aquí. This assay determines the ability of test compounds to inhibit cell proliferation as evaluated using Cellomics Arrayscan technology. A human breast adenocarcinoma cell line MDA-MB-468 (LGC Promochem, Catalog No. HTB-132) was routinely maintained as described in the Biological Assay (b) here.

Para el ensayo de proliferación, las células se separaron del matraz de cultivo usando Accutase y se sembraron en 60 pocillos interiores de una placa de 96 pocillos Packard negra a una densidad de 8000 células por pocillo en 100 %l de medios de crecimiento completos. Los pocillos externos contenían 100 %l de PBS estéril. Las células se incubaron toda la noche a 37ºC con 5% de CO2 para permitirles adherirse. For the proliferation assay, cells were separated from the culture flask using Accutase and seeded in 60 inner wells of a black Packard 96-well plate at a density of 8000 cells per well in 100% 1 of complete growth media. The external wells contained 100% 1 sterile PBS. The cells were incubated overnight at 37 ° C with 5% CO2 to allow them to adhere.

En el día 2, las células se trataron con los compuestos de ensayo y se incubaron durante 48 horas a 37ºC con 5% de CO2. Los compuestos de ensayo se prepararon como disoluciones madre 10 mM en DMSO y se diluyeron de manera seriada saegún se requirió con los medios de crecimiento para dar un intervalo de concentraciones de prueba. Se colocaron alícuotas (50 %l) de cada dilución del compuesto en un pocillo, y las células se incubaron durante 2 días a 37ºC con 5% de CO2. Cada placa contenía pocillos de control sin compuesto de ensayo. On day 2, the cells were treated with the test compounds and incubated for 48 hours at 37 ° C with 5% CO2. The test compounds were prepared as 10 mM stock solutions in DMSO and diluted serially as required with the growth media to give a range of test concentrations. Aliquots (50% 1) of each dilution of the compound were placed in a well, and the cells were incubated for 2 days at 37 ° C with 5% CO2. Each plate contained control wells without test compound.

En el día 4, se añadió reactivo de marcado BrdU (Sigma, Nº de catálogo B9285) a una dilución final de 1:1000, y las células se incubaron durante 2 horas a 37ºC. El medio se eliminó, y las células en cada pocillo se fijaron por tratamiento con 100 %l de una mezcla de etanol y ácido acético glacial (90% de etanol, 5% de ácido acético glacial y 5% de agua) durante 30 minutos a temperatura ambiente. Las células en cada pocillo se lavaron dos veces con PBS (100 %l). Se añadió ácido clorhídrico acuoso (2M, 100 %l) a cada pocillo. Después de 20 minutos a temperatura ambiente, las células se lavaron dos veces con PBS. Se añadió peróxido de hidrógeno (3%, 50 %l; Sigma, Nº de catálogo H1009) a cada pocillo. Después de 10 minutos a temperatura ambiente, los pocillos se lavaron nuevamente con PBS. On day 4, BrdU labeling reagent (Sigma, Catalog No. B9285) was added at a final dilution of 1: 1000, and the cells were incubated for 2 hours at 37 ° C. The medium was removed, and the cells in each well were fixed by treatment with 100% l of a mixture of ethanol and glacial acetic acid (90% ethanol, 5% glacial acetic acid and 5% water) for 30 minutes at room temperature. The cells in each well were washed twice with PBS (100% l). Aqueous hydrochloric acid (2M, 100% L) was added to each well. After 20 minutes at room temperature, the cells were washed twice with PBS. Hydrogen peroxide (3%, 50% 1; Sigma, Catalog No. H1009) was added to each well. After 10 minutes at room temperature, the wells were washed again with PBS.

La incorporación de BrdU se detectó por incubación durante 1 hora a temperatura ambiente con anticuerpo anti– BrdU de ratón (50 %l; Caltag, Burlingame, CA, US; Nº de catálogo MD5200) que se diluyó 1:40 en PBS con 1% BSA y 0,05% de Tween–20. El anticuerpo no unido se eliminó con dos lavados de PBS. Para la visualización del BrdU incorporado, las células se trataron durante 1 hora a temperatura ambiente con PBS (50 %l) y 0,05% de tampón Tween–20 que contiene una dilución 1:1000 de antiIgG de ratón de cabra marcado con Alexa fluo 488. Para la visualización de los núcleos celulares, se añadió una dilución 1:1000 de tinte Hoechst (Molecular Probes, Nº de catálogo H3570). Cada placa se lavó a su vez con PBS. Posteriormente, se añadió PBS (100 %l) a cada pocillo y las placas se analizaron usando un ArrayScan de Cellomics para evaluar el número total de células y el número de células positivas BrdU. BrdU incorporation was detected by incubation for 1 hour at room temperature with mouse anti-BrdU antibody (50% l; Caltag, Burlingame, CA, US; Catalog No. MD5200) which was diluted 1:40 in PBS with 1% BSA and 0.05% Tween – 20. Unbound antibody was removed with two PBS washes. For visualization of the incorporated BrdU, the cells were treated for 1 hour at room temperature with PBS (50% 1) and 0.05% Tween-20 buffer containing a 1: 1000 dilution of goat mouse antiIgG labeled with Alexa 488. For visualization of cell nuclei, a 1: 1000 dilution of Hoechst dye (Molecular Probes, Catalog No. H3570) was added. Each plate was washed in turn with PBS. Subsequently, PBS (100% 1) was added to each well and the plates were analyzed using a Cellomics ArrayScan to evaluate the total number of cells and the number of BrdU positive cells.

Los datos de la respuesta a la dosis de fluorescencia obtenidos con cada compuesto se analizaron, y el grado de inhibición del crecimiento celular de MDA–MB–468 se expresó como un valor IC50. The fluorescence dose response data obtained with each compound was analyzed, and the degree of cell growth inhibition of MDA-MB-468 was expressed as an IC50 value.

Aunque las propiedades farmacológicas de los compuestos de fórmula (I) varían con el cambio estructural como se esperaba, en general se cree que la actividad que poseen los compuestos de fórmula (I) se puede demostrar a las siguientes concentraciones o dosis en uno o más de los siguientes ensayos (a) a (d) : Although the pharmacological properties of the compounds of formula (I) vary with the structural change as expected, it is generally believed that the activity possessed by the compounds of formula (I) can be demonstrated at the following concentrations or doses in one or more of the following tests (a) to (d):

Ensayo (a):– IC50 frente a mTOR cinasa de al menos 10 μM, en particular 0,001 – 0,5 μM para muchos Assay (a): - IC50 against mTOR kinase of at least 10 μM, in particular 0.001 - 0.5 μM for many

compuestos; por ejemplo 34b el IC50 fue medido en dos ocasiones, los valores fueron 0,155 y compounds; for example 34b the IC50 was measured twice, the values were 0.155 and

0,093 μM. 0.093 μM.

Ensayo (b):– IC50 frente a PI3K humana Tipo Ib p110# de al menos 10 μM, en particular 0,001 – 0,5 μM para muchos compuestos; e IC50 contra PI3K humana Tipo Ia p110! de al menos 10 μM, en particular 0,001 – 0,5 μM para muchos compuestos; para el ejemplo 34b, la IC50 se midió en dos ocasiones, los valores fueron 91,2 y 57,8 μM. Test (b): - IC50 against human PI3K Type Ib p110 # of at least 10 μM, in particular 0.001-0.5 μM for many compounds; and IC50 against human PI3K Type Ia p110! of at least 10 μM, in particular 0.001-0.5 μM for many compounds; For example 34b, the IC50 was measured twice, the values were 91.2 and 57.8 μM.

Ensayo (c):– IC50 frente a Serina 473 en Akt de al menos 10 μM, en particular 0,1 – 20 μM para muchos Test (c): - IC50 against Serina 473 in Akt of at least 10 μM, in particular 0.1 - 20 μM for many

compuestos); para el ejemplo 34b, la IC50 se midió en dos ocasiones, los valores fueron 1,361 y compounds); for example 34b, the IC50 was measured twice, the values were 1,361 and

0,654 μM. 0.654 μM.

Ensayo (d):– IC50 de al menos 20 μM; Test (d): - IC50 of at least 20 μM;

Los compuestos de la presente invención son ventajosos ya que poseen actividad farmacológica. En particular, los compuestos de la presente invención modulan (en particular, inhiben) las enzimas mTOR cinasa y/o fosfatidilinositol–3–cinasa (PI3K), tales como las enzimas PI3K de la Clase Ia (por ejemplo PI3Kalfa, PI3Kbeta y PI3Kdelta) y la enzima PI3K de la Clase Ib (PI3Kgamma). Más particularmente, los compuestos de la presente invención modulan (en particular, inhiben) la mTOR cinasa. Más particularmente, los compuestos de la presente invención modulan (en particular, inhiben) una o más enzimas PI3K. Las propiedades inhibidoras de los compuestos de fórmula (I) se pueden demostrar usando el procedimiento de ensayo expuesto aquí y en la sección experimental. Por consiguiente, los compuestos de fórmula (I) se pueden usar en el tratamiento (terapéutico o profiláctico) de afecciones/enfermedades en animales no humanos y humanos las cuales son mediadas por la mTOR cinasa y/o una o más enzima(s) PI3K, y en particular por la mTOR cinasa. The compounds of the present invention are advantageous since they possess pharmacological activity. In particular, the compounds of the present invention modulate (in particular, inhibit) the mTOR kinase and / or phosphatidylinositol-3-kinase (PI3K) enzymes, such as the PI3K enzymes of Class Ia (for example PI3Kalfa, PI3Kbeta and PI3Kdelta) and the PI3K enzyme of Class Ib (PI3Kgamma). More particularly, the compounds of the present invention modulate (in particular, inhibit) mTOR kinase. More particularly, the compounds of the present invention modulate (in particular, inhibit) one or more PI3K enzymes. The inhibitory properties of the compounds of formula (I) can be demonstrated using the test procedure set forth herein and in the experimental section. Accordingly, the compounds of formula (I) can be used in the treatment (therapeutic or prophylactic) of conditions / diseases in non-human and human animals which are mediated by mTOR kinase and / or one or more PI3K enzyme (s) , and in particular by mTOR kinase.

La invención también proporciona una composición farmacéutica que comprende un compuesto de fórmula (I), o una sal farmacéuticamente aceptable del mismo, como se define aquí, en asociación con un diluyente o vehículo farmacéuticamente aceptable. The invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein, in association with a pharmaceutically acceptable diluent or carrier.

Las composiciones de la invención pueden estar en una forma adecuada para uso oral (por ejemplo como comprimidos, pastillas, cápsulas duras o blandas, suspensiones aceitosas o acuosas, emulsiones, polvos o gránulos dispersables, siropes o elixires), para uso tópico (por ejemplo como cremas, ungüentos, geles, o disoluciones o suspensiones aceitosas o acuosas), para la administración por inhalación (por ejemplo como un polvo finamente dividido o un aerosol líquido), para la administración por insuflación (por ejemplo como un polvo finamente dividido) o para la administración parenteral (por ejemplo como una disolución aceitosa o acuosa estéril para dosificación intravenosa, subcutánea, intraperitoneal o intramuscular, o como un supositorio para dosificación rectal). The compositions of the invention may be in a form suitable for oral use (for example as tablets, pills, hard or soft capsules, oily or aqueous suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or oily or aqueous solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile oily or aqueous solution for intravenous, subcutaneous, intraperitoneal or intramuscular dosing, or as a suppository for rectal dosing).

Las composiciones de la invención se pueden obtener por procedimientos convencionales usando excipientes farmacéuticos convencionales, bien conocidos en la técnica. De este modo, las composiciones para uso oral pueden contener, por ejemplo, uno o más agentes de coloración, edulcorantes, saborizantes y/o conservantes. The compositions of the invention can be obtained by conventional methods using conventional pharmaceutical excipients, well known in the art. Thus, compositions for oral use may contain, for example, one or more coloring agents, sweeteners, flavorings and / or preservatives.

La cantidad de ingrediente activo que se combina con uno o más excipientes para producir una forma de dosificación única variará necesariamente dependiendo del hospedante tratado y la vía particular de administración. Por ejemplo, una formulación para administración oral a seres humanos generalmente contendrá, por ejemplo, de 1 mg a 1 g de agente activo (más adecuadamente de 1 a 250 mg, por ejemplo de 1 a 100 mg) formulado de una cantidad apropiada y conveniente de excipientes la cual puede variar de alrededor de 5 a alrededor de 98 por ciento por peso de la composición total. The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending on the host treated and the particular route of administration. For example, a formulation for oral administration to humans will generally contain, for example, from 1 mg to 1 g of active agent (more suitably from 1 to 250 mg, for example from 1 to 100 mg) formulated in an appropriate and convenient amount. of excipients which may vary from about 5 to about 98 percent by weight of the total composition.

El tamaño de la dosis para fines profilácticos o terapéuticos de un compuesto de fórmula I variará naturalmente de acuerdo con la naturaleza y gravedad del estado de la enfermedad, la edad y sexo del animal o paciente y la vía de administración, según principios de medicina bien conocidos. The dose size for prophylactic or therapeutic purposes of a compound of formula I will naturally vary according to the nature and severity of the disease state, the age and sex of the animal or patient and the route of administration, according to principles of medicine either. known.

Cuando se use un compuesto de fórmula (I) con fines profilácticos o terapéuticos, generalmente se administrará de manera que se reciba una dosis diaria en el intervalo de, por ejemplo, 1 mg/kg a 100 mg/kg de peso corporal, dada si es necesario en dosis divididas. En general, se administrarán dosis menores cuando se emplee una vía parenteral. De este modo, por ejemplo, para la administración intravenosa, generalmente se usará una dosis en el de intervalo de, por ejemplo, 1 mg/kg a 25 mg/kg de peso corporal. De manera similar, para administración por inhalación, se usará una dosis en el intervalo de, por ejemplo, 1 mg/kg a 25 mg/kg de peso corporal. Típicamente, las formas de dosificación unitaria contendrán alrededor de 10 mg a 0,5 g de un compuesto de esta invención. When a compound of formula (I) is used for prophylactic or therapeutic purposes, it will generally be administered so that a daily dose is received in the range of, for example, 1 mg / kg to 100 mg / kg body weight, given if It is necessary in divided doses. In general, lower doses will be administered when a parenteral route is used. Thus, for example, for intravenous administration, a dose in the range of, for example, 1 mg / kg to 25 mg / kg body weight will generally be used. Similarly, for administration by inhalation, a dose in the range of, for example, 1 mg / kg to 25 mg / kg body weight will be used. Typically, unit dosage forms will contain about 10 mg to 0.5 g of a compound of this invention.

Como se afirma aquí, se sabe que la mTOR cinasa y las enzimas PI3K tienen papeles tanto en la tumorigénesis así como en otras numerosas enfermedades. Se ha descubierto que los compuestos de fórmula (I) poseen actividad antitumoral potente, la cual se cree que se obtiene por medio de la inhibición de la mTOR cinasa y/o una o más de las enzimas PI3K. As stated here, it is known that mTOR kinase and PI3K enzymes have roles in both tumorigenesis as well as in numerous other diseases. It has been found that the compounds of formula (I) possess potent antitumor activity, which is believed to be obtained by inhibiting mTOR kinase and / or one or more of the PI3K enzymes.

Por consiguiente, los compuestos de la presente invención son útiles como agentes antitumorales. Particularmente, los compuestos de la presente invención son útiles como agentes antiproliferativos, apoptóticos y/o antiinvasivos en la contención y/o tratamiento de enfermedad de tumor sólido y/o líquido. Particularmente, se espera que los compuestos de la presente invención sean útiles en la prevención o el tratamiento de aquellos tumores que son sensibles a la inhibición de mTOR y/o una o más de las enzimas PI3K, tales como las enzimas PI3K de la Clase Ia y la enzima PI3K de la Clase Ib. Además, se espera que los compuestos de la presente invención sean útiles en la prevención o el tratamiento de aquellos tumores que están mediados solo o en parte por mTOR y/o una o más de las enzimas PI3K, tales como las enzimas PI3K de la Clase Ia y la enzima PI3K de la Clase Ib. Los compuestos se pueden usar de este modo para producir un efecto inhibidor de la enzima mTOR en un animal de sangre caliente necesitado de tal tratamiento. Ciertos compuestos se pueden usar para producir un efecto inhibidor de la enzima PI3K en un animal de sangre caliente necesitado de tal tratamiento. Accordingly, the compounds of the present invention are useful as antitumor agents. Particularly, the compounds of the present invention are useful as antiproliferative, apoptotic and / or anti-invasive agents in the containment and / or treatment of solid and / or liquid tumor disease. Particularly, it is expected that the compounds of the present invention will be useful in the prevention or treatment of those tumors that are sensitive to the inhibition of mTOR and / or one or more of the PI3K enzymes, such as the PI3K enzymes of Class Ia and the PI3K enzyme of Class Ib. In addition, the compounds of the present invention are expected to be useful in the prevention or treatment of those tumors that are mediated alone or in part by mTOR and / or one or more of the PI3K enzymes, such as the PI3K enzymes of the Class Ia and the PI3K enzyme of Class Ib. The compounds can be used in this way to produce an inhibitory effect of the mTOR enzyme in a warm-blooded animal in need of such treatment. Certain compounds can be used to produce an inhibitory effect of the PI3K enzyme in a warm-blooded animal in need of such treatment.

Como se afirma aquí, los inhibidores de la mTOR cinasa y/o una o más enzimas PI3K deberían ser de valor terapéutico para el tratamiento de una enfermedad proliferativa, tal como el cáncer, y en particular tumores sólidos tales como carcinomas y sarcomas, y las leucemias y malignidades linfoides, y en particular para el tratamiento de, por ejemplo, cáncer de mama, colorrectal, de pulmón (incluyendo cáncer de pulmón microcítico, cáncer de pulmón no microcítico y cáncer broncoalveolar) y de próstata, y de cáncer del conducto biliar, hueso, vejiga, cabeza y cuello, riñón, hígado, tejido gastrointestinal, esófago, ovario, páncreas, piel, testículos, tiroides, útero, cérvix y vulva, y de leucemias [incluyendo la leucemia linfocítica aguda (ALL) y leucemia mielógena crónica (CML)], mieloma múltiple y linfomas. As stated herein, mTOR kinase inhibitors and / or one or more PI3K enzymes should be of therapeutic value for the treatment of a proliferative disease, such as cancer, and in particular solid tumors such as carcinomas and sarcomas, and lymphoid leukemias and malignancies, and in particular for the treatment of, for example, breast, colorectal, lung cancer (including small cell lung cancer, non-small cell lung cancer and bronchoalveolar cancer) and prostate cancer, and bile duct cancer , bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, esophagus, ovary, pancreas, skin, testicles, thyroid, uterus, cervix and vulva, and leukemia [including acute lymphocytic leukemia (ALL) and chronic myelogenous leukemia (CML)], multiple myeloma and lymphomas.

De acuerdo con un aspecto adicional de la invención, se proporciona un compuesto de fórmula (I), o una sal farmacéuticamente aceptable del mismo, como se define aquí, para uso como un medicamento en un animal de sangre caliente tal como el hombre. According to a further aspect of the invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein, for use as a medicament in a warm-blooded animal such as man.

De acuerdo con un aspecto adicional de la invención, se proporciona un compuesto de fórmula (I), o una sal farmacéuticamente aceptable del mismo, como se define aquí, para uso en la producción de un efecto antiproliferativo en un animal de sangre caliente tal como el hombre. In accordance with a further aspect of the invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein, for use in the production of an antiproliferative effect in a warm-blooded animal such as the man.

De acuerdo con un aspecto adicional de la invención, se proporciona un compuesto de fórmula (I), o una sal farmacéuticamente aceptable del mismo, como se define aquí, para uso en la producción de un efecto apoptótico en un animal de sangre caliente tal como el hombre. In accordance with a further aspect of the invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein, for use in the production of an apoptotic effect in a warm-blooded animal such as the man.

De acuerdo con una característica adicional de la invención, se proporciona un compuesto de fórmula (I), o una sal farmacéuticamente aceptable del mismo, como se define aquí, para uso en un animal de sangre caliente, tal como el hombre, como un agente antiinvasivo en la contención y/o tratamiento de una enfermedad proliferativa tal como cáncer. According to a further feature of the invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein, for use in a warm-blooded animal, such as man, as an agent. anti-invasive containment and / or treatment of a proliferative disease such as cancer.

De acuerdo con una característica adicional de este aspecto de la invención, se proporciona el uso de un compuesto de fórmula (I), o una sal farmacéuticamente aceptable del mismo, como se define aquí, en la fabricación de un medicamento para uso en la producción de un efecto antiproliferativo en un animal de sangre caliente tal como el hombre. In accordance with a further feature of this aspect of the invention, the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein, in the manufacture of a medicament for production use is provided. of an antiproliferative effect on a warm-blooded animal such as man.

De acuerdo con una característica adicional de este aspecto de la invención, se proporciona el uso de un compuesto de fórmula (I), o una sal farmacéuticamente aceptable del mismo, como se define aquí, en la fabricación de un medicamento para uso en la producción de un efecto apoptótico en un animal de sangre caliente tal como el hombre. In accordance with a further feature of this aspect of the invention, the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein, in the manufacture of a medicament for production use is provided. of an apoptotic effect on a warm-blooded animal such as man.

De acuerdo con una característica adicional de la invención, se proporciona el uso de un compuesto de fórmula (I), o una sal farmacéuticamente aceptable del mismo, como se define aquí, en la fabricación de un medicamento para uso en un animal de sangre caliente, tal como el hombre, como un agente antiinvasivo en la contención y/o tratamiento de una enfermedad proliferativa tal como cáncer. In accordance with a further feature of the invention, the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein, is provided in the manufacture of a medicament for use in a warm-blooded animal. , such as man, as an anti-invasive agent in the containment and / or treatment of a proliferative disease such as cancer.

De acuerdo con un aspecto adicional de la invención, se proporciona el uso de un compuesto de fórmula (I), o una sal farmacéuticamente aceptable del mismo, como se define aquí, en la fabricación de un medicamento para uso en la prevención o el tratamiento de una enfermedad proliferativa, tal como cáncer, en un animal de sangre caliente tal como el hombre. In accordance with a further aspect of the invention, there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein, in the manufacture of a medicament for use in prevention or treatment. of a proliferative disease, such as cancer, in a warm-blooded animal such as man.

De acuerdo con un aspecto adicional de la invención, se proporciona un compuesto de fórmula (I), o una sal farmacéuticamente aceptable del mismo, como se define aquí, para uso en la prevención o el tratamiento de aquellos tumores que son sensibles a la inhibición de la mTOR cinasa y/o una o más enzimas PI3K (tales como las enzimas de la Clase Ia y/o la enzima PI3K de la Clase Ib) que están implicadas en las etapas de transducción de señales que conducen a la proliferación, supervivencia, invasividad y capacidad migratoria de las células tumorales. In accordance with a further aspect of the invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein, for use in the prevention or treatment of those tumors that are sensitive to inhibition. of mTOR kinase and / or one or more PI3K enzymes (such as Class Ia enzymes and / or Class Ib PI3K enzyme) that are involved in the signal transduction stages that lead to proliferation, survival, invasiveness and migratory capacity of tumor cells.

De acuerdo con una característica adicional de este aspecto de la invención, se proporciona el uso de un compuesto de fórmula (I), o una sal farmacéuticamente aceptable del mismo, como se define aquí, en la fabricación de un medicamento para uso en la prevención o el tratamiento de aquellos tumores que son sensibles a la inhibición de la mTOR cinasa y/o una o más enzimas PI3K (tales como las enzimas de la Clase Ia y/o la enzima PI3K de la Clase Ib) que están implicadas en las etapas de transducción de señales que conducen a la proliferación, supervivencia, invasividad y capacidad migratoria de las células tumorales. In accordance with a further feature of this aspect of the invention, the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein, in the manufacture of a medicament for use in prevention is provided. or the treatment of those tumors that are sensitive to the inhibition of mTOR kinase and / or one or more PI3K enzymes (such as Class Ia enzymes and / or Class Ib PI3K enzyme) that are involved in the stages of signal transduction that lead to proliferation, survival, invasiveness and migratory capacity of tumor cells.

De acuerdo con un aspecto adicional de la invención, se proporciona un compuesto de fórmula (I), o una sal farmacéuticamente aceptable del mismo, como se define aquí, para uso en la provisión de un efecto inhibidor de la mTOR cinasa y/o un efecto inhibidor de la enzima PI3K (tal como un efecto inhibidor de la enzima PI3K de la Clase Ia o la enzima PI3K de la Clase Ib). In accordance with a further aspect of the invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein, for use in the provision of an inhibitor effect of mTOR kinase and / or a inhibitory effect of the PI3K enzyme (such as an inhibitory effect of the PI3K enzyme of Class Ia or the PI3K enzyme of Class Ib).

De acuerdo con una característica adicional de este aspecto de la invención, se proporciona el uso de un compuesto de fórmula (I), o una sal farmacéuticamente aceptable del mismo, como se define aquí, en la fabricación de un medicamento para uso en la provisición de un efecto inhibidor de la mTOR cinasa y/o un efecto inhibidor de la enzima PI3K (tal como un efecto inhibidor de la enzima PI3K de la Clase Ia o la enzima PI3K de la Clase Ib). In accordance with a further feature of this aspect of the invention, the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein, in the manufacture of a medicament for use in the provision is provided. of an inhibitor effect of mTOR kinase and / or an inhibitory effect of the PI3K enzyme (such as an inhibitory effect of the PI3K enzyme of Class Ia or the PI3K enzyme of Class Ib).

De acuerdo con una característica adicional de la invención, se proporciona un compuesto de fórmula I, o una sal farmacéuticamente aceptable del mismo, como se define aquí, para uso en el tratamiento de cáncer, enfermedades inflamatorias, enfermedades obstructivas de las vías respiratorias, enfermedades inmunitarias o enfermedades cardiovasculares. In accordance with a further feature of the invention, a compound of formula I, or a pharmaceutically acceptable salt thereof, is provided, as defined herein, for use in the treatment of cancer, inflammatory diseases, obstructive airways diseases, diseases immune or cardiovascular diseases.

De acuerdo con una característica adicional de la invención, se proporciona un compuesto de fórmula I, o una sal farmacéuticamente aceptable del mismo, como se define aquí, para uso en el tratamiento de tumores sólidos tales como carcinomas y sarcomas y las leucemias y malignidades linfoides. In accordance with a further feature of the invention, a compound of formula I, or a pharmaceutically acceptable salt thereof, is provided, as defined herein, for use in the treatment of solid tumors such as carcinomas and sarcomas and lymphoid leukemias and malignancies. .

De acuerdo con una característica adicional de la invención, se proporciona un compuesto de fórmula I, o una sal farmacéuticamente aceptable del mismo, como se define aquí, para uso en el tratamiento de cáncer de mama, colorrectal, de pulmón (incluyendo cáncer de pulmón microcítico, cáncer de pulmón no microcítico y cáncer broncoalveolar) y próstata. In accordance with a further feature of the invention, a compound of formula I, or a pharmaceutically acceptable salt thereof, is provided, as defined herein, for use in the treatment of breast, colorectal, lung cancer (including lung cancer microcytic, non-small cell lung cancer and bronchoalveolar cancer) and prostate.

De acuerdo con una característica adicional de la invención, se proporciona un compuesto de fórmula (I), o una sal farmacéuticamente aceptable del mismo, como se define aquí, para uso en el tratamiento de cáncer del conducto biliar, hueso, vejiga, cabeza y cuello, riñón, hígado, tejido gastrointestinal, esófago, ovario, páncreas, piel, testículos, tiroides, útero, cérvix y vulva, y de leucemias (incluyendo ALL y CML), mieloma múltiple y linfomas. In accordance with a further feature of the invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein, for use in the treatment of cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, esophagus, ovary, pancreas, skin, testicles, thyroid, uterus, cervix and vulva, and leukemia (including ALL and CML), multiple myeloma and lymphomas.

De acuerdo con una característica adicional de la invención, se proporciona el uso de un compuesto de fórmula (I), o una sal farmacéuticamente aceptable del mismo, como se define aquí, en la fabricación de un medicamento para uso en el tratamiento de cáncer, enfermedades inflamatorias, enfermedades obstructivas de las vías respiratorias, enfermedades inmunitarias o enfermedades cardiovasculares. In accordance with a further feature of the invention, the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein, is provided in the manufacture of a medicament for use in the treatment of cancer, inflammatory diseases, obstructive diseases of the respiratory tract, immune diseases or cardiovascular diseases.

De acuerdo con una característica adicional de la invención, se proporciona el uso de un compuesto de fórmula (I), o una sal farmacéuticamente aceptable del mismo, como se define aquí, en la fabricación de un medicamento para uso en el tratamiento de tumores sólidos tales como carcinomas y sarcomas y las leucemias y malignidades linfoides. In accordance with a further feature of the invention, the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein, in the manufacture of a medicament for use in the treatment of solid tumors is provided. such as carcinomas and sarcomas and lymphoid leukemias and malignancies.

De acuerdo con una característica adicional de la invención, se proporciona el uso de un compuesto de fórmula (I), o una sal farmacéuticamente aceptable del mismo, como se define aquí, en la fabricación de un medicamento para uso en el tratamiento de cáncer de mama, colorrectal, pulmón (incluyendo cáncer de pulmón microcítico, cáncer de pulmón no microcítico y cáncer broncoalveolar) y próstata. In accordance with a further feature of the invention, the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein is provided in the manufacture of a medicament for use in the treatment of cancer of breast, colorectal, lung (including small cell lung cancer, non-small cell lung cancer and bronchoalveolar cancer) and prostate.

De acuerdo con una característica adicional de la invención, se proporciona el uso de un compuesto de fórmula (I), o una sal farmacéuticamente aceptable del mismo, como se define aquí, en la fabricación de un medicamento para uso en el tratamiento de cáncer del conducto biliar, hueso, vejiga, cabeza y cuello, riñón, hígado, tejido gastrointestinal, esófago, ovario, páncreas, piel, testículos, tiroides, útero, cérvix y vulva, y de leucemias (incluyendo ALL y CML), mieloma múltiple y linfoma. In accordance with a further feature of the invention, the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein, is provided in the manufacture of a medicament for use in the treatment of cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, esophagus, ovary, pancreas, skin, testicles, thyroid, uterus, cervix and vulva, and leukemia (including ALL and CML), multiple myeloma and lymphoma .

Como se afirma aquí, los efectos in vivo de un compuesto de fórmula (I) pueden ser ejercidos en parte por uno o más metabolitos que se forman en el cuerpo humano o animal después de la administración de un compuesto de fórmula (I). As stated herein, the in vivo effects of a compound of formula (I) may be exerted in part by one or more metabolites that are formed in the human or animal body after administration of a compound of formula (I).

En particular, el tratamiento definido aquí puede ser aplicado como una sola terapia o puede incluir, además de a los compuestos de la invención, cirugía convencional o radioterapia o quimioterapia. Por consiguiente, los compuestos de la invención también se pueden usar en combinación con agentes terapéuticos existentes para el tratamiento de cáncer. In particular, the treatment defined herein may be applied as a single therapy or may include, in addition to the compounds of the invention, conventional surgery or radiotherapy or chemotherapy. Accordingly, the compounds of the invention can also be used in combination with existing therapeutic agents for the treatment of cancer.

Los agentes adecuados para ser usados en combinación incluyen: Agents suitable for use in combination include:

(i)(i): fármacos antiproliferativos/antineoplásicos y combinaciones de los mismos, como se usan en oncología médica, tales como agentes alquilantes (por ejemplo, cis-platino, carboplatino, ciclofosfamida, mostaza de nitrógeno, melfalano, clorambucilo, busulfán y nitrosoureas); antimetabolitos (por ejemplo, antifolatos tales como fluoropirimidinas como 5-fluorouracilo y tegafur, raltitrexed, metotrexato, arabinósido de citosina, hidroxiurea y gemcitabina); antibióticos antitumorales (por ejemplo, antraciclinas como adriamicina, bleomicina, doxorrubicina, daunomicina, epirrubicina, idarrubicina, mitomicina-C, dactinomicina y mitramicina); agentes antimitóticos (por ejemplo, alcaloides de la vinca como vincristina, vinblastina, vindesina y vinorrelbina, y taxoides como taxol y taxotere); e inhibidores de topoisomerasa (por ejemplo epipodofilotoxinas como etopósido y tenipósido, amsacrina, topotecán y camptotecina); antiproliferative / antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example, cis-platinum, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan and nitrosoureas); antimetabolites (for example, antifolates such as fluoropyrimidines such as 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea and gemcitabine); antitumor antibiotics (for example, anthracyclines such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mitramycin); antimitotic agents (for example, vinca alkaloids such as vincristine, vinblastine, vindesine and vinorrelbine, and taxoids such as taxol and taxotere); and topoisomerase inhibitors (for example epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan and camptothecin);

(ii) (ii): agentes citostáticos tales como antiestrógenos (por ejemplo tamoxifeno, toremifeno, raloxifeno, droloxifeno y yodoxifeno), reductores de receptores de estrógenoes (por ejemplo fulvestrant), antiandrógenos (por ejemplo bicalutamida, flutamida, nilutamida y acetato de ciproterona), antagonistas de LHRH o agonistas de LHRH (por ejemplo goserelina, leuprorrelina y buserelina), progestágenos (por ejemplo acetato de megestrol), inhibidores de aromatasa (por ejemplo como anastrozol, letrozol, vorazol y exemestano) e inhibidores de 5!-reductasa tales como finasterida; cytostatic agents such as antiestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and iodoxifene), estrogen receptor reducers (for example fulvestrant), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate antagonists, or LH agonist antagonists) of LHRH (for example goserelin, leuprorrelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazol and exemestane) and 5! -reductase inhibitors such as finasteride;

(iii) agentes anti-invasión (por ejemplo, inhibidores de la familia de las cinasas c-Src como 4-(6-cloro-2,3metilendioxianilino)-7-[2-(4-metilpiperazin-1-il)etoxi]-5-tetrahidropiran-4-iloxiquinazolina (AZD0530; Solicitud de Patente Internacional WO 01/94341) y N-(2-cloro-6-metilfenil)-2-{6-[4-(2-hidroxietil)piperazin-1-il]-2-metilpirimidin-4ilamino}tiazol-5-carboxamida (dasatinib, BMS-354825; J. Med. Chem, 2,004, 47, 6658-6661), e inhibidores de metaloproteinasas como marimastat, inhibidores de la función del receptor de activador de plasminógeno urocinasa); (iii) anti-invasion agents (for example, c-Src family kinase inhibitors such as 4- (6-chloro-2,3-methylenedioxyanilino) -7- [2- (4-methylpiperazin-1-yl) ethoxy] -5-tetrahydropyran-4-yloxyquinazoline (AZD0530; International Patent Application WO 01/94341) and N- (2-chloro-6-methylphenyl) -2- {6- [4- (2-hydroxyethyl) piperazin-1- il] -2-methylpyrimidin-4-lamino} thiazol-5-carboxamide (dasatinib, BMS-354825; J. Med. Chem, 2,004, 47, 6658-6661), and metalloproteinase inhibitors such as marimastat, inhibitors of receptor function plasminogen urokinase activator);

(iv) (iv): inhibidores de la función del factor de crecimiento: por ejemplo, dichos inhibidores incluyen anticuerpos contra factores de crecimiento y anticuerpos contra receptores de factores de crecimiento (por ejemplo, el anticuerpo antierbB2 trastuzumab [Herceptin™], y el anticuerpo anti-erbB1 cetuximab [Erbitux, C225]); tales inhibidores también incluyen inhibidores de tirosina cinasa, por ejemplo inhibidores de la familia del factor de crecimiento epidérmico (por ejemplo, inhibidores de tirosina cinasa de la familia EGFR, tales como N-(3-cloro-4-fluorofenil)-7-metoxi-6-(3morfolinopropoxi)quinazolin-4-amina (gefitinib, ZD1839), N-(3-etinilfenil)-6,7-bis(2-metoxietoxi)quinazolin-4-amina (erlotinib, OSI-774) y 6-acrilamido-N-(3-cloro-4-fluorofenil)-7-(3-morfolinopropoxi)-quinazolin-4-amina (CI 1033), inhibidores de tirosina cinasa erbB2 tales como lapatinib), inhibidores de la familia de factores de crecimiento de hepatocitos, inhibidores de la familia de factores de crecimiento derivados de plaquetas tales como imatinib, inhibidores de serina/treonina cinasas (por ejemplo, inhibidores de la señalización Ras/Raf, tales como inhibidores de farnesil transferasa, por ejemplo sorafenib (BAY 43-9006)), e inhibidores de la señalización celular a través de MEK y/o AKT cinasas; growth factor function inhibitors: for example, such inhibitors include antibodies against growth factors and antibodies against growth factor receptors (for example, the antierbB2 antibody trastuzumab [Herceptin ™], and the anti-erbB1 cetuximab antibody [Erbitux , C225]); such inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example, tyrosine kinase inhibitors of the EGFR family, such as N- (3-chloro-4-fluorophenyl) -7-methoxy -6- (3morpholinopropoxy) quinazolin-4-amine (gefitinib, ZD1839), N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) quinazolin-4-amine (erlotinib, OSI-774) and 6- acrylamido-N- (3-chloro-4-fluorophenyl) -7- (3-morpholinopropoxy) -quinazolin-4-amine (CI 1033), tyrosine kinase inhibitors erbB2 such as lapatinib), growth factor family inhibitors of hepatocytes, inhibitors of the family of platelet-derived growth factors such as imatinib, serine / threonine kinase inhibitors (for example, Ras / Raf signaling inhibitors, such as farnesyl transferase inhibitors, for example sorafenib (BAY 43- 9006)), and cell signaling inhibitors through MEK and / or AKT kinases;

(v) (v): agentes antiangiogénicos tales como los que inhiben los efectos del factor de crecimiento endotelial vascular, [por ejemplo, el anticuerpo contra el factor de crecimiento de células endoteliales vasculares bevacizumab (Avastin™) e inhibidores de tirosina cinasa receptora VEGF, tales como 4-(4-bromo-2-fluoroanilino)-6-metoxi-7-(1metilpiperidin-4-ilmetoxi)quinazolina (ZD6474; Ejemplo 2 en el documento WO 01/32651), 4-(4-fluoro-2-metilindol-5iloxi)-6-metoxi-7-(3-pirrolidin-1-ilpropoxi)quinazolina (AZD2171; Ejemplo 240 en el documento WO 00/47212), vatalanib (PTK787; documento WO 98/35985) y SU11248 (sunitinib; documento WO 01/60814), y compuestos que actúan por otros mecanismos (por ejemplo linomida, inhibidores de la función de la integrina !&∀3 y angiostatina)]; antiangiogenic agents such as those that inhibit the effects of vascular endothelial growth factor, [eg, antibody against vascular endothelial growth factor bevacizumab (Avastin ™) and VEGF receptor tyrosine kinase inhibitors, such as 4- (4 -bromo-2-fluoroanilino) -6-methoxy-7- (1-methylpiperidin-4-ylmethoxy) quinazoline (ZD6474; Example 2 in WO 01/32651), 4- (4-fluoro-2-methylindole-5-yloxy) - 6-methoxy-7- (3-pyrrolidin-1-ylpropoxy) quinazoline (AZD2171; Example 240 in WO 00/47212), vatalanib (PTK787; WO 98/35985) and SU11248 (sunitinib; WO 01/60814 ), and compounds that act by other mechanisms (eg linomide, inhibitors of integrin function! & ∀3 and angiostatin)];

(vi)(saw): agentes de lesión vascular tales como Combretastatina A4 y compuestos descritos en las Solicitudes de Patente internacionales WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 y WO 02/08213; vascular lesion agents such as Combretastatin A4 and compounds described in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;

(vii) terapias antisentido, por ejemplo las que están dirigidas a las dianas indicadas anteriormente, tales como ISIS 2503, un agente antisentido anti-ras; (vii) antisense therapies, for example those directed at the targets indicated above, such as ISIS 2503, an anti-ras antisense agent;

(viii) estrategias de terapia génica, que incluyen estrategias para reemplazar genes anormales, tales como p53 anormal o BRCA1 o BRCA2 anormal, estrategias de GDEPT (terapia con profármacos enzimáticos dirigidos a genes), tales como las que usan citosina desaminasa, timidina cinasa o una enzima nitrorreductasa bacteriana, y estrategias para aumentar la tolerancia del paciente a la quimioterapia o radioterapia, tales como la terapia génica de resistencia a múltiples fármacos; y (viii) gene therapy strategies, which include strategies to replace abnormal genes, such as abnormal p53 or BRCA1 or abnormal BRCA2, GDEPT (gene targeted enzyme prodrug therapy) strategies, such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme, and strategies to increase the patient's tolerance to chemotherapy or radiotherapy, such as multiple drug resistance gene therapy; Y

(ix) estrategias de inmunoterapia, que incluyen estrategias ex vivo e in vivo para aumentar la inmunogenicidad de las células tumorales del paciente, tales como transfección con citocinas tales como interleucina 2, interleucina 4, o factor estimulante de colonias de granulocitos y macrófagos, estrategias para disminuir la anergia de células T, estrategias que emplean células inmunitarias transfectadas tales como las células dendríticas transfectadas con citocinas, estrategias que usan líneas celulares tumorales transfectadas con citocinas, y estrategias que usan anticuerpos antiidiotípicos. (ix) immunotherapy strategies, which include ex vivo and in vivo strategies to increase the immunogenicity of the patient's tumor cells, such as transfection with cytokines such as interleukin 2, interleukin 4, or granulocyte and macrophage colony stimulating factor, strategies to decrease the anergy of T cells, strategies that employ transfected immune cells such as dendritic cells transfected with cytokines, strategies that use tumor cell lines transfected with cytokines, and strategies that use anti-idiotypic antibodies.

La invención se explicará ahora adicionalmente con referencia a los siguientes ejemplos ilustrativos. The invention will now be explained further with reference to the following illustrative examples.

Excepto que se señale de ootro modo, los materiales de partida estaban comercialmente disponibles. Todos los disolventes y reactivos comerciales fueron de grado de laboratorio, y se usaron tal y como fueron recibidos. En los ejemplos, los espectros RMN 1H se registraron en un instrumento Bruker DPX 300 (300 MHz), Bruker DRX Except as otherwise noted, the starting materials were commercially available. All solvents and commercial reagents were laboratory grade, and were used as received. In the examples, 1H NMR spectra were recorded on a Bruker DPX 300 (300 MHz), Bruker DRX instrument

5 400 (400 MHz) o un instrumento Bruker DRX 500 (500 MHz). Los picos centrales de cloroformo–d (δH 7,27 ppm), dimetilsulfóxido–d6 (δH 2,50 ppm) o acetona–d6 (δH 2,05 ppm) se usaron como referencias internas. Se usaron las siguientes abreviaturas: s, singlete; d, doblete; t, triplete; q, cuartete; m, multiplete; br, amplio. 5 400 (400 MHz) or a Bruker DRX 500 instrument (500 MHz). The central peaks of chloroform-d (δH 7.27 ppm), dimethylsulfoxide-d6 (δH 2.50 ppm) or acetone-d6 (δH 2.05 ppm) were used as internal references. The following abbreviations were used: s, singlet; d, double up; t, triplet; q, quartete; m, multiplet; br, broad.

La cromatografía en columna se llevó a cabo usando gel de sílice (0,04–0,063 mm, Merck). En general, se usó una columna Kromasil KR–100–5–C18 de fase inversa (250 x 20 mm, Akzo Nobel) para la HPLC preparativa, con 10 mezclas de acetonitrilo y agua [que contiene 0,1% de ácido trifluoroacético (TFA)] usadas como eluente a un caudal de 10 ml/min. Los siguientes métodos se usaron para la cromatografía de líquidos (LC) / análisis espectral de masa (MS): HPLC: Agilent 1100 o Waters Alliance HT (2790 y 2795) Espectrómetro de Masa: Waters ZQ ESCi 15 Columna HPLC La columna de HPLC estándar usada es la Phemonenex Gemini C18 5μm, 50 x 2 mm. Métodos HPLC Ácida Column chromatography was carried out using silica gel (0.04-0.063 mm, Merck). In general, a Kromasil KR – 100–5 – C18 reverse phase column (250 x 20 mm, Akzo Nobel) was used for preparative HPLC, with 10 mixtures of acetonitrile and water [containing 0.1% trifluoroacetic acid ( TFA)] used as eluent at a flow rate of 10 ml / min. The following methods were used for liquid chromatography (LC) / mass spectral analysis (MS): HPLC: Agilent 1100 or Waters Alliance HT (2790 and 2795) Mass spectrometer: Waters ZQ ESCi 15 HPLC column The standard HPLC column used is the Phemonenex Gemini C18 5μm, 50 x 2 mm. Acid HPLC Methods

Las fases móviles usadas son: The mobile phases used are:: Fase móvil A: Agua Mobile phase A: Water

: Fase móvil B: Acetonitrilo Mobile phase B: Acetonitrile

: Fase móvil C: 1% de Ácido Fórmico en Agua:MeCN (v/v) C mobile phase: 1% Formic Acid in Water: MeCN (v / v)

A cada método le siguió un rápido equilibrado usando un caudal de 5 ml durante 0,45 min. Están disponibles cuatro métodos de HPLC genéricos: Método ácido Monitor 5 Minutos Each method was followed by a rapid equilibrium using a flow rate of 5 ml for 0.45 min. Four generic HPLC methods are available: Acid Method Monitor 5 Minutes

Tiempo /min Time / min: Fase móvil A: Fase móvil B: Fase móvil C: Curva Caudal /ml/min Mobile phase A: Mobile phase B: C mobile phase: Curve Flow rate / ml / min

0,00 0.00: 95 0 5 1 1,1 95 0 5 one 1.1

4 4: 0 95 5 6 1,1 0 95 5 6 1.1

4,5 4,5: 0 95 5 6 1,1 0 95 5 6 1.1

Método ácido temprano para los compuestos de elución temprana Early acid method for early elution compounds

0,00 0.00: 95 0 5 1 1,1 95 0 5 one 1.1

4 4: 57,5 37,5 5 6 1,1 57.5 37.5 5 6 1.1

4,5 4,5: 57,5 37,5 5 6 1,1 57.5 37.5 5 6 1.1

Método ácido medio para los compuestos de elución central Método ácido tardío para los compuestos de elución tardía Medium acid method for central elution compounds Late acid method for late elution compounds

0,00 0.00: 95 0 5 1 1,1 95 0 5 one 1.1

0,01 0.01: 67,5 27,5 5 6 1,1 67.5 27.5 5 6 1.1

4,5 4,5: 27,5 67,5 5 6 1,1 27.5 67.5 5 6 1.1

0,00 0.00: 95 0 5 1 1,1 95 0 5 one 1.1

0,01 0.01: 27,5 67,5 5 6 1,1 27.5 67.5 5 6 1.1

4,5 4,5: 5 95 5 6 1,1 5 95 5 6 1.1

Métodos de HPLC Básica Basic HPLC Methods

5 En algunos casos, los métodos ácidos estándares pueden ser inadecuados para la ionización del compuesto o la separación cromatográfica requerida. En tales casos, existen cuatro métodos HPLC Básica comparables. Las fases móviles usadas son: Fase móvil A: Agua Fase móvil B: Acetonitrilo 5 In some cases, standard acid methods may be unsuitable for the ionization of the compound or the required chromatographic separation. In such cases, there are four comparable Basic HPLC methods. The mobile phases used are: Mobile phase A: Water Mobile phase B: Acetonitrile

10 Fase móvil D: 0,1% de Amoniaco 880 en acetonitrilo A cada método le sigue un rápido equilibrado usando un caudal de 5 ml durante 0,45 min. Método Básico Monitor Minuto 10 Mobile phase D: 0.1% of Ammonia 880 in acetonitrile Each method is followed by a rapid equilibrium using a flow rate of 5 ml for 0.45 min. Basic Method Minute Monitor

Tiempo /min Time / min: Fase móvil A: Fase móvil B: Fase móvil D: Curva Caudal /ml/min Mobile phase A: Mobile phase B: Mobile phase D: Curve Flow rate / ml / min

0,00 0.00: 95 0 5 1 1,1 95 0 5 one 1.1

4 4: 0 95 5 6 1,1 0 95 5 6 1.1

4,5 4,5: 0 95 5 6 1,1 0 95 5 6 1.1

Método Básico temprano para los compuestos de elución temprana Early Basic Method for Early Elution Compounds

0,00 0.00: 95 0 5 1 1,1 95 0 5 one 1.1

4 4: 57,5 37,5 5 6 1,1 57.5 37.5 5 6 1.1

4,5 4,5: 57,5 37,5 5 6 1,1 57.5 37.5 5 6 1.1

Método Básico medio para los compuestos de elución central Medium Basic Method for Central Elution Compounds

0,00 0.00: 95 0 5 1 1,1 95 0 5 one 1.1

0,01 0.01: 67,5 27,5 5 6 1,1 67.5 27.5 5 6 1.1

4,5 4,5: 27,5 67,5 5 6 1,1 27.5 67.5 5 6 1.1

30 Método Básico tardío para los compuestos de elución tardía 30 Late Basic Method for late elution compounds

0,00 0.00: 95 0 5 1 1,1 95 0 5 one 1.1

0,01 0.01: 27,5 67,5 5 6 1,1 27.5 67.5 5 6 1.1

4,5 4,5: 5 95 5 6 1,1 5 95 5 6 1.1

Se usó el siguiente método para la cromatografía de líquidos (LC) / análisis espectral de masa (MS): The following method was used for liquid chromatography (LC) / mass spectral analysis (MS):

Instrumento: Agilent 1100; Columna: Waters ‘Symmetry’ 2,1 x 30 mm; análisis espectral de masa usando ionización química (APCI); Caudal: 0,7 ml/min; Longitud de Onda de Absorción: 254 nm; Disolvente A: agua + 0,1% de TFA; Disolvente B: acetonitrilo + 0,1% de TFA; Gradiente de Disolventes: 15–95% de Disolvente B durante 2,7 minutos seguido de 95% de Disolvente B durante 0,3 minutos. Instrument: Agilent 1100; Column: Waters ‘Symmetry’ 2.1 x 30 mm; mass spectral analysis using chemical ionization (APCI); Flow rate: 0.7 ml / min; Absorption Wavelength: 254 nm; Solvent A: water + 0.1% TFA; Solvent B: acetonitrile + 0.1% TFA; Solvent Gradient: 15–95% of Solvent B for 2.7 minutes followed by 95% of Solvent B for 0.3 minutes.

Se usaron los siguientes métodos para el análisis LC: The following methods were used for LC analysis:

Método A: Instrumento: Agilent 1100; Columna: sílice de fase inversa Kromasil C18, 100 x 3 mm, tamaño de partículas 5%m; Disolvente A: 0,1% de TFA/agua, Disolvente B: 0,08% de TFA/acetonitrilo; Caudal: 1 ml/min; Gradiente de disolventes: 10–100% de Disolvente B durante 20 minutos seguido de 100% de Disolvente B durante 1 minuto; Longitudes de Onda de Absorción: 220, 254 y 280 nm. En general, se anotó el tiempo de retención del producto. Method A: Instrument: Agilent 1100; Column: Kromasil C18 reverse phase silica, 100 x 3 mm, particle size 5% m; Solvent A: 0.1% TFA / water, Solvent B: 0.08% TFA / acetonitrile; Flow rate: 1 ml / min; Solvent gradient: 10–100% of Solvent B for 20 minutes followed by 100% of Solvent B for 1 minute; Absorption Wavelengths: 220, 254 and 280 nm. In general, the retention time of the product was noted.

Método B: Instrumento: Agilent 1100; Columna: sílice fase inversa Waters ‘Xterra’ C8, 100 x 3 mm, tamaño de partículas 5%m; Disolvente A: 0,015M de amoniaco en agua, Disolvente B: acetonitrilo; Caudal: 1 ml/min, Gradiente de Disolventes: 10–100% de Disolvente B durante 20 minutos seguido de 100% de Disolvente B durante 1 minuto; Longitud de Onda de Absorción: 220, 254 y 280 nm. En general, se anotó el tiempo de retención del producto. Method B: Instrument: Agilent 1100; Column: Waters ‘Xterra’ C8 reverse phase silica, 100 x 3 mm, particle size 5% m; Solvent A: 0.015M of ammonia in water, Solvent B: acetonitrile; Flow rate: 1 ml / min, Solvent Gradient: 10–100% of Solvent B for 20 minutes followed by 100% of Solvent B for 1 minute; Absorption Wavelength: 220, 254 and 280 nm. In general, the retention time of the product was noted.

Las siguientes abreviaturas se usan aquí o en los siguientes ejemplos ilustrativos: Los nombres químicos se generaron mediante un programa que usó Lexichem Toolkit (v. 1,40) de OpenEye Scientific Software (www.eyesopen.com) para generar nombres conforme a la IUPAC. The following abbreviations are used here or in the following illustrative examples: Chemical names were generated by a program used by Lexichem Toolkit (v. 1.40) of OpenEye Scientific Software (www.eyesopen.com) to generate names according to IUPAC .

HPLC HPLC: Cromatografía dxe Líquidos de Alto Rendimiento Chromatography dxe High Performance Liquids

HBTU HBTU: hexafluorofosfatode O–(benzotriazol–1–il)–N,N,N∋,N∋–tetrametiluronio; hexafluorophosphate O– (benzotriazol-1-yl) -N, N, N∋, N∋-tetramethyluronium;

HATU HEY YOU: hexafluorofosfato de O–(7–azabenzotriazol–1–il)–N,N,N∋,N∋–tetrametiluronio; O- (7-azabenzotriazol-1-yl) -N, N, N∋, N∋-tetramethyluronium hexafluorophosphate;

HOBT HOBT: 1–hidroxibenzotriazol; 1-hydroxybenzotriazole;

HOAT HOAT: 1–hidroxi–7–azabenzotriazol; 1-hydroxy-7-azabenzotriazole;

NMP NMP: N–metilpirrolidin–2–ona; N-methylpyrrolidin-2-one;

DMSO DMSO: dimetilsulfóxido; dimethylsulfoxide;

DMF DMF: N,N–dimetilformamida; N, N-dimethylformamide;

DMA Dma: N,N–dimetilacetamida; N, N-dimethylacetamide;

THF THF: tetrahidrofurano; tetrahydrofuran;

DME DME: 1,2–dimetoxietano; 1,2-dimethoxyethane;

DCCI DCCI: diciclohexilcarbodiimida; dicyclohexylcarbodiimide;

MeOH MeOH: metanol; methanol;

MeCN MeCN: acetonitrilo; acetonitrile;

DCM DCM: diclorometano; dichloromethane;

DIPEA DIPEA: N,N–diisopropiletilamina; N, N-diisopropylethylamine;

DBU DBU: 1,8–diazabiciclo[5,4,0]undec–7–eno; 1,8-diazabicyclo [5,4,0] undec-7-ene;

RT RT: temperatura ambiente (aproximadamente 17 a 25ºC); room temperature (approximately 17 to 25 ° C);

5 5: tR tiempo de retención; tR holding time;

m/z m / z: relación masa/carga. mass / load ratio.

Ejemplo 1: 1–Etil–3–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidin–2–il]fenil]urea Example 1: 1 – Ethyl – 3– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin – 2-yl] phenyl] urea

O OR

N NN N

OO S OO S

N N

O OR

N N

N HH N HH

Se disolvió 4–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidin–2–il]anilina (100 mg, 0,28 mmoles) en dioxano (4 ml). Se añadió isocianato de etilo (0,109 ml, 1,38 mmoles), y la reacción se calentó a 70ºC durante 4 horas. La reacción se terminó y se evaporó hasta sequedad. El aceite resultante se purificó mediante cromatografía, 4– [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidin-2-yl] aniline (100 mg, 0.28 mmol) was dissolved in dioxane (4 ml). Ethyl isocyanate (0.109 ml, 1.38 mmol) was added, and the reaction was heated at 70 ° C for 4 hours. The reaction was terminated and evaporated to dryness. The resulting oil was purified by chromatography,

15 eluyendo con 10–50% de acetato de etilo en isohexano, para dar 3–etil–1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6– (metilsulfonilmetil)pirimidin–2–il]fenil]urea como un aceite amarillo pálido (113 mg, 94%). 15 eluting with 10–50% ethyl acetate in isohexane, to give 3-ethyl-1– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin – 2 -Yl] phenyl] urea as a pale yellow oil (113 mg, 94%).

Espectro RMN: RMN 1H (399,9 MHz, DMSO–d6) δ 0,99 (t, 3H), 1,25 (d, 3H), 3,11 (q, 2H), 3,20 (s, 3H), 3,29 (m, 2H), 3,5 (m, 1H), 3,67 (m, 1H), 3,78 (m, 1H), 3,99 (m, 1H), 4,16 (m, 1H), 4,47 (s, 2H), 6,18 (t, 1H), 6,78 (s, 1H), 7,50 (d, 2H), 8,21 (d, 2H), 8,68 (s, 1H) NMR Spectrum: 1H NMR (399.9 MHz, DMSO-d6) δ 0.99 (t, 3H), 1.25 (d, 3H), 3.11 (q, 2H), 3.20 (s, 3H ), 3.29 (m, 2H), 3.5 (m, 1H), 3.67 (m, 1H), 3.78 (m, 1H), 3.99 (m, 1H), 4.16 (m, 1H), 4.47 (s, 2H), 6.18 (t, 1H), 6.78 (s, 1H), 7.50 (d, 2H), 8.21 (d, 2H) , 8.68 (s, 1 H)

20 Espectro LCMS: MH+ 434, tiempo de retención 1,37 min., Método Ácido 5 min. 20 LCMS spectrum: MH + 434, retention time 1.37 min., Acid Method 5 min.

Los compuestos mostrados en la tabla se prepararon de una manera análoga a la 3–etil–1–[4–[4–[(3S)–3– metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidin–2–il]fenil]urea haciendo reaccionar el isocianato apropiado con la anilina apropiada. The compounds shown in the table were prepared in a manner analogous to 3-ethyl-1– [4– [4 - [(3S) -3– methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin-2-yl ] phenyl] urea by reacting the appropriate isocyanate with the appropriate aniline.

Ejemplo Example: Estructura NOMBRE LCMS Tiempo de Notas Structure NAME LCMS Time of Notes

MH+ MH +: retención retention

(min.) (min.)

1a 1st: N N N O S O O N H NH O OMe 1–(4–metoxifenil)–3–[4–[4– [(3S)–3–metilmorfolin–4–il]–6– (metilsulfonilmetil)pirimidin–2– il]fenil]urea 512 2,19 Purificada mediante suspensión de acetato de etilo, después cromatografía N N N O S O O N H NH O OMe 1– (4 – methoxyphenyl) –3– [4– [4– [(3S) –3-methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin-2-yl] phenyl] urea 512 2.19 Purified by ethyl acetate suspension, then chromatography

1b 1 B: O 1–[4–[4–[(3S)–3–metilmorfolin– 482 2,26 Cromatografía OR 1– [4– [4 - [(3S) –3 – methylmorpholin– 482 2.26 Chromatography

: 4–il]–6–(metilsulfonilmetil) eluída con 0–8% 4-yl] –6– (methylsulfonylmethyl) eluted with 0–8%

N N N S O O N H NH O N N N S O O N H NH O: pirimidin–2–il]fenil]–3–fenil–urea MeOH/DCM pyrimidin – 2-yl] phenyl] –3-phenyl-urea MeOH / DCM

Ejemplo Example: Estructura NOMBRE LCMS MH+ Tiempo de retención (min.) Notas Structure NAME LCMS MH + Retention time (min.) Notes

1c 1 C: N N N O S O O N H NH O 3–[4–[4–[(3S)–3–metilmorfolin– 4–il]–6–(metilsulfonilmetil)pirimidin–2–il]fenil]–1–propan–2– il–urea 448 1,90 Cromatografía eluída con 0–8% MeOH/ DCM N N N O S O O N H NH O 3– [4– [4 - [(3S) –3 – methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin-2-yl] phenyl] –1 – propan – 2– il – urea 448 1.90 Chromatography eluted with 0–8% MeOH / DCM

1e 1e: N N N O S O O N H NH O 3–(4–fluorofenil)–1–[4–[4–[(3S)– 3–metilmorfolin–4–il]–6– (metilsulfonilmetil)pirimidin–2– il]fenil]urea 500 2,05 Triturada con acetato de etilo N N N O S O O N H NH O 3– (4 – fluorophenyl) –1– [4– [4 - [(3S) - 3-methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin – 2– yl] phenyl] urea 500 2.05 Crushed with ethyl acetate

F F

1f 1f: O 1–[2–fluoro–4–[4–[(3S)–3– 518 2,38 Purificada OR 1– [2 – fluoro – 4– [4 - [(3S) –3– 518 2.38 Purified

: metilmorfolin–4–il]–6– mediante methylmorpholin – 4 – il] –6– through

N N: (metilsulfonilmetil)pirimidin–2– cromatografía de (methylsulfonylmethyl) pyrimidin – 2– chromatography of

N N S O O N H NH O F N N S O O N H NH O F: il]fenil]–3–(4–fluorofenil)urea fase inversa il] phenyl] –3– (4-fluorophenyl) urea reverse phase

F F

1g 1g: O 1–[2–fluoro–4–[4–[(3S)–3– 500 2,36 Purificada OR 1– [2 – fluoro – 4– [4 - [(3S) –3– 500 2.36 Purified

N N S O O N H NH O F N N S O O N H NH O F: il]fenil]–3–fenil–urea fase inversa il] phenyl] –3 – phenyl-urea reverse phase

1h 1 hour: O 3–(4–fluorofenil)–1–[2–metoxi– 529 2,22 Cristalizada en OR 3– (4 – fluorophenyl) –1– [2 – methoxy– 529 2.22 Crystallized in

: 4–[4–[(3S)–3–metilmorfolin–4– NMP/agua, 4– [4 - [(3S) –3 – methylmorpholin – 4– NMP / water,

N N: il]–6–(metilsulfonilmetil)pirimidin– después triturada il] –6– (methylsulfonylmethyl) pyrimidin– then crushed

N N S O O N H NH O OMe N N S O O N H NH O OMe: 2–il]fenil]urea con EtOAc 2-yl] phenyl] urea with EtOAc

F F

1i 1i: O 3–[2–metoxi–4–[4–[(3S)–3– 542 2,06 Cristalizada en OR 3– [2 – methoxy – 4– [4 - [(3S) –3– 542 2.06 Crystallized in

: metilmorfolin–4–il]–6– NMP/agua, methylmorpholin – 4 – il] –6– NMP / water,

N N: (metilsulfonilmetil)pirimidin–2– después triturada (methylsulfonylmethyl) pyrimidin – 2– then crushed

N N S O O N H NH O OMe N N S O O N H NH O OMe: il]fenil]–1–(4–metoxifenil)urea con EtOAc il] phenyl] –1– (4-methoxyphenyl) urea with EtOAc

OMe OMe

1j 1j: O 3–(4–fluorofenil)–1–[5–[4–[(3S)– 501 2,26 Cristalizada en OR 3– (4 – fluorophenyl) –1– [5– [4 - [(3S) - 501 2.26 Crystallized in

N N: 3–metilmorfolin–4–il]–6– dimetilformamida/ 3 – methylmorpholin – 4 – il] –6– dimethylformamide /

NO O NO OR: (metilsulfonilmetil)pirimidin–2– agua (methylsulfonylmethyl) pyrimidin – 2– Water

NS N N H N H O F NS N N H N H O F: il]piridin–2–il]urea il] pyridin – 2 – il] urea

1k 1k: O 1–etil–3–[5–[4–[(3S)–3– 435 1,51 Purificada OR 1 – ethyl – 3– [5– [4 - [(3S) –3– 435 1.51 Purified

N N S O O N N H N H O N N S O O N N H N H O: il]piridin–2–il]urea fase inversa il] pyridin – 2 – il] urea reverse phase

Ejemplo 1a: RMN 1H (399,9 MHz, DMSO–d6) δ 1,28 (d, 3H), 3,21 (s, 3H), 3,4 (m, 2H), 3,5 (m, 1H), 3,65 (m, 1H), 3,71 (s, 3H), 3,8 (d, 1H), 3,99 (m, 1H), 4,2 (m, 1H), 4,50 (s, 2H), 6,79 (s, 1H), 6,89 (d, 2H), 7,38 (d, 2H), 7,55 (d, 2H), 8,25 (d, 2H), 8,50 (s, 1H), 8,83 (s, 1H) Example 1a: 1H NMR (399.9 MHz, DMSO-d6) δ 1.28 (d, 3H), 3.21 (s, 3H), 3.4 (m, 2H), 3.5 (m, 1H ), 3.65 (m, 1H), 3.71 (s, 3H), 3.8 (d, 1H), 3.99 (m, 1H), 4.2 (m, 1H), 4.50 (s, 2H), 6.79 (s, 1H), 6.89 (d, 2H), 7.38 (d, 2H), 7.55 (d, 2H), 8.25 (d, 2H) , 8.50 (s, 1H), 8.83 (s, 1H)

Ejemplo 1b: RMN 1H (399,9 MHz, DMSO–d6) δ 1,25 (d, 3H), 3,21 (s, 2H), 3,28–3,38 (m, 2H), 3,35 (t, 1H), 3,67 (d, 1H), 3,69 (d, 1H), 4,18–4,22 (m, 1H), 4,50 (s, 3H), 6,79 (s, 1H), 7,00 (m, 1H), 7,31 (m, 2H) 7,47 (d, 2H), 7,59 (d, 2H), 8,27 (d, 2H), 8,71 (s, 1H), 8,91 (s, 1H) Example 1b: 1H NMR (399.9 MHz, DMSO-d6) δ 1.25 (d, 3H), 3.21 (s, 2H), 3.28-3.38 (m, 2H), 3.35 (t, 1H), 3.67 (d, 1H), 3.69 (d, 1H), 4.18-4.22 (m, 1H), 4.50 (s, 3H), 6.79 ( s, 1H), 7.00 (m, 1H), 7.31 (m, 2H) 7.47 (d, 2H), 7.59 (d, 2H), 8.27 (d, 2H), 8 , 71 (s, 1H), 8.91 (s, 1H)

Ejemplo 1c: RMN 1H (399,9 MHz, DMSO–d6) δ 1,10 (d, 6H), 1,24 (d, 3H), 3,29 (s, 3H), 3,49 (m, 1H), 3,64–3,66 (m, 1H), 3,77 (m, 2H), 4,18–4,21 (m, 1H), 4,49 (s, 3H), 6,08 (d, 1H), 6,79, (s, 1H), 7,48 (d, 2H), 8,22 (d, 2H), 8,51 (s, 1H) Example 1c: 1H NMR (399.9 MHz, DMSO-d6) δ 1.10 (d, 6H), 1.24 (d, 3H), 3.29 (s, 3H), 3.49 (m, 1H ), 3.64-3.66 (m, 1H), 3.77 (m, 2H), 4.18-4.21 (m, 1H), 4.49 (s, 3H), 6.08 ( d, 1H), 6.79, (s, 1H), 7.48 (d, 2H), 8.22 (d, 2H), 8.51 (s, 1H)

Ejemplo 1d: RMN 1H (399,9 MHz, DMSO–d6) δ 1,25–1,27 (m, 3H), 3,22 (s, 3H), 3,35–3,36 (m, 1H), 3,41 (s, 1H), 3,51 (d, 2H), 3,65–3,68 (m, 1H), 3,79 (d, 1H), 3,98–4,02 (m, 1H), 4,18 (s, 1H), 4,50 (s, 2H), 6,80 (s, 1H), 7,12–7,16 (m, 2H), 7,47–7,50 (m, 2H), 7,57 (d, 2H), 8,27 (d, 2H), 8,75 (s, 1H), 8,92 (s, 1H) Example 1d: 1H NMR (399.9 MHz, DMSO-d6) δ 1.25-1.27 (m, 3H), 3.22 (s, 3H), 3.35–3.36 (m, 1H) , 3.41 (s, 1H), 3.51 (d, 2H), 3.65-3.68 (m, 1H), 3.79 (d, 1H), 3.98-4.02 (m , 1H), 4.18 (s, 1H), 4.50 (s, 2H), 6.80 (s, 1H), 7.12–7.16 (m, 2H), 7.47–7, 50 (m, 2H), 7.57 (d, 2H), 8.27 (d, 2H), 8.75 (s, 1H), 8.92 (s, 1H)

Ejemplo 1e: RMN 1H (399,9 MHz, DMSO–d6) δ 1,25–1,27 (m, 3H), 3,21 (s, 3H), 3,25 (t, 1H), 3,48–3,54 (m, 1H), 3,64–3,68 (m, 1H), 3,79 (d, 1H), 3,98–4,02 (m, 1H), 4,19 (s, 1H), 4,50 (m, 1H), 4,51 (s, 2H), 6,84 (s, 1H), 7,16 (d, 2H), 7,47–7,51 (m, 2H), 8,08–8,12 (m, 1H), 8,13–8,15 (m, 1H), 8,31 (t, 1H), 8,77 (d, 1H), 9,17 (s, 1H) Example 1e: 1H NMR (399.9 MHz, DMSO-d6) δ 1.25-1.27 (m, 3H), 3.21 (s, 3H), 3.25 (t, 1H), 3.48 –3.54 (m, 1H), 3.64–3.68 (m, 1H), 3.79 (d, 1H), 3.98–4.02 (m, 1H), 4.19 (s , 1H), 4.50 (m, 1H), 4.51 (s, 2H), 6.84 (s, 1H), 7.16 (d, 2H), 7.47–7.51 (m, 2H), 8.08–8.12 (m, 1H), 8.13–8.15 (m, 1H), 8.31 (t, 1H), 8.77 (d, 1H), 9.17 (s, 1H)

Ejemplo 1f: RMN 1H (399,9 MHz, DMSO–d6) δ 1,26 (d, 3H), 3,21 (s, 3H), 3,24–3,26 (m, 1H), 3,52 (t, 1H), 3,66 (t, 1H), 3,79 (d, 1H), 3,99–4,02 (m, 2H), 4,18 (m, 1H), 4,52 (s, 3H), 6,84 (s, 1H), 7,02 (t, 1H), 7,30–7,34 (m, 2H), 7,48 (d, 2H), 8,08–8,15 (m, 2H), 8,34 (t, 1H), 8,79 (d, 1H), 9,15 (s, 1H) Example 1f: 1H NMR (399.9 MHz, DMSO-d6) δ 1.26 (d, 3H), 3.21 (s, 3H), 3.24-3.26 (m, 1H), 3.52 (t, 1H), 3.66 (t, 1H), 3.79 (d, 1H), 3.99-4.02 (m, 2H), 4.18 (m, 1H), 4.52 ( s, 3H), 6.84 (s, 1H), 7.02 (t, 1H), 7.30–7.34 (m, 2H), 7.48 (d, 2H), 8.08–8 , 15 (m, 2H), 8.34 (t, 1H), 8.79 (d, 1H), 9.15 (s, 1H)

Ejemplo 1g: RMN 1H (399,9 MHz, DMSO–d6) δ 1,25–1,27 (m, 3H), 3,24 (s, 3H), 3,30 (m, 1H), 3,49–3,53 (m, 1H), 3,65–3,69 (m, 1H), 3,80 (d, 1H), 3,98 (s, 3H), 4,00 (m, 1H), 4,02 (m, 1H), 4,48 (m, 1H), 4,52 (s, 2H), 6,82 (s, 1H), 7,12–7,17 (m, 2H), 7,47–7,51 (m, 2H), 7,96 (s, 2H), 8,27 (s, 1H), 8,42 (s, 1H), 9,45 (d, 1H) Example 1g: 1H NMR (399.9 MHz, DMSO-d6) δ 1.25-1.27 (m, 3H), 3.24 (s, 3H), 3.30 (m, 1H), 3.49 –3.53 (m, 1H), 3.65-3.69 (m, 1H), 3.80 (d, 1H), 3.98 (s, 3H), 4.00 (m, 1H), 4.02 (m, 1H), 4.48 (m, 1H), 4.52 (s, 2H), 6.82 (s, 1H), 7.12–7.17 (m, 2H), 7 , 47–7.51 (m, 2H), 7.96 (s, 2H), 8.27 (s, 1H), 8.42 (s, 1H), 9.45 (d, 1H)

Ejemplo 1h: RMN 1H (399,9 MHz, DMSO–d6) δ 1,26 (d, 3H), 3,24 (s, 3H), 3,30 (m, 1H), 3,49–3,55 (m, 1H), 3,65– 3,69 (m, 1H), 3,74 (s, 3H), 3,80 (d, 1H), 3,97 (s, 3H), 4,00 (m, 1H), 4,02 (m, 1H), 4,18–4,22 (m, 1H), 4,47–4,49 (m, 1H), 4,52 (s, 2H), 6,81 (s, 1H), 6,88–6,91 (m, 2H, 7,36–7,40 (m, 2H), 7,95 (s, 2H), 8,28 (d, 1H), 8,36 (s, 1H), 9,23 (s, 1H) Example 1h: 1H NMR (399.9 MHz, DMSO-d6) δ 1.26 (d, 3H), 3.24 (s, 3H), 3.30 (m, 1H), 3.49-3.55 (m, 1H), 3.65– 3.69 (m, 1H), 3.74 (s, 3H), 3.80 (d, 1H), 3.97 (s, 3H), 4.00 ( m, 1H), 4.02 (m, 1H), 4.18-4.22 (m, 1H), 4.47-4.49 (m, 1H), 4.52 (s, 2H), 6 , 81 (s, 1H), 6.88-6.91 (m, 2H, 7.36-7.40 (m, 2H), 7.95 (s, 2H), 8.28 (d, 1H) , 8.36 (s, 1H), 9.23 (s, 1H)

Ejemplo 1i: RMN 1H (399,9 MHz, DMSO–d6) δ 1,27 (d, 3H), 3,21 (s, 3H), 3,25 (m, 1H), 3,48–3,55 (m, 1H), 3,65– 3,69 (m, 1H), 3,79 (d, 1H), 3,98–4,02 (m, 1H), 4,20 (s, 1H), 4,52 (s, 3H), 6,87 (s, 1H), 7,14–7,21 (m, 2H), 7,56–7,60 (m, 2H), 7,61–7,64 (m, 1H), 8,57–8,59 (m, 1H), 9,21–9,21 (m, 1H), 9,70 (s, 1H), 10,52 (s, 1H) Example 1i: 1H NMR (399.9 MHz, DMSO-d6) δ 1.27 (d, 3H), 3.21 (s, 3H), 3.25 (m, 1H), 3.48-3.55 (m, 1H), 3.65– 3.69 (m, 1H), 3.79 (d, 1H), 3.98-4.02 (m, 1H), 4.20 (s, 1H), 4.52 (s, 3H), 6.87 (s, 1H), 7.14–7.21 (m, 2H), 7.56–7.60 (m, 2H), 7.61–7, 64 (m, 1H), 8.57–8.59 (m, 1H), 9.21–9.21 (m, 1H), 9.70 (s, 1H), 10.52 (s, 1H)

Ejemplo 1j: RMN 1H (399,9 MHz, DMSO–d6) δ 1,12 (t, 3H), 1,25–1,26 (m, 3H), 3,20 (s, 3H), 3,22–3,24 (m, 2H), 3,26 (m, 1H), 3,47–3,54 (m, 1H), 3,64–3,67 (m, 1H), 3,78 (d, 1H), 3,97–4,01 (m, 1H), 4,18 (s, 1H), 4,50 (s, 3H), 6,84 (s, 1H), 7,48 (d, 1H), 8,10 (d, 1H), 8,48–8,51 (m, 1H), 9,11 (m, 1H), 9,41 (s, 1H) Example 1j: 1H NMR (399.9 MHz, DMSO-d6) δ 1.12 (t, 3H), 1.25-1.26 (m, 3H), 3.20 (s, 3H), 3.22 –3.24 (m, 2H), 3.26 (m, 1H), 3.47-3.54 (m, 1H), 3.64-3.67 (m, 1H), 3.78 (d , 1H), 3.97-4.01 (m, 1H), 4.18 (s, 1H), 4.50 (s, 3H), 6.84 (s, 1H), 7.48 (d, 1H), 8.10 (d, 1H), 8.48-8.51 (m, 1H), 9.11 (m, 1H), 9.41 (s, 1H)

Prueba (a): Ejemplo (1) 0,0062 μM; Ejemplo (1a) 0,062 μM; Ejemplo (1b) 0,013 μM; Ejemplo (1c) 0,078 μM; Ejemplo (1d) 0,042 μM; Ejemplo (1e) 0,32 μM; Ejemplo (1f) 0,36 μM; Ejemplo (1g) 0,96 μM; Ejemplo (lh) 1,2 μM; Ejemplo (li) 0,55 μM; Ejemplo (1j) 0,043 μM. Test (a): Example (1) 0.0062 μM; Example (1a) 0.062 μM; Example (1b) 0.013 μM; Example (1c) 0.078 μM; Example (1d) 0.042 μM; Example (1e) 0.32 μM; Example (1f) 0.36 μM; Example (1g) 0.96 μM; Example (lh) 1.2 μM; Example (li) 0.55 μM; Example (1j) 0.043 μM.

A continuación se describe la preparación de las anilinas 4–[4–[(3S)–3–metilmorfolin–4–il]–6– (metilsulfonilmetil)pirimidin–2–il]anilina y 2–fluoro–4–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidin–2– il]anilina. The following describes the preparation of anilines 4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin – 2-yl] aniline and 2-fluoro – 4– [4– [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidin-2-yl] aniline.

30 4–[4–[(3S)–3–Metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidin–2–il]anilina 30 4– [4 - [(3S) –3 – Methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin-2-yl] aniline

Se disolvió N–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidin–2–il]fenil]carbamato de terc–butilo (1,09 g, 2,35 mmoles) en metanol (5 ml), y se añadió cloruro de hidrógeno en dioxano 4M (5 ml). La disolución se agitó a temperatura ambiente toda la noche, después la mezcla se evaporó para obtener un aceite marrón oscuro y se disolvió en acetato de etilo (10 ml). Se añadió agua (5 ml) seguido por la adición de disolución de bicarbonato de sodio hasta que se logró un pH neutro (~2 ml). Las fases se separaron, y la fase orgánica se lavó con agua (10 ml). La capa orgánica se secó sobre sulfato de magnesio y se evaporó para obtener una espuma amarilla pálida (805 mg). N- [4– [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidin-2-yl] phenyl] tert-butyl carbamate (1.09 g, 2, 35 mmol) in methanol (5 ml), and hydrogen chloride in 4M dioxane (5 ml) was added. The solution was stirred at room temperature overnight, then the mixture was evaporated to obtain a dark brown oil and dissolved in ethyl acetate (10 ml). Water (5 ml) was added followed by the addition of sodium bicarbonate solution until a neutral pH (~ 2 ml) was achieved. The phases were separated, and the organic phase was washed with water (10 ml). The organic layer was dried over magnesium sulfate and evaporated to obtain a pale yellow foam (805 mg).

Espectro RMN: RMN 1H (399,9 MHz, DMSO–d6) δ 1,23 (3H, d), 3,31 (3H, s), 3,5 (1H, m), 3,64 (1H, m), 3,78 (1H, m), 4,13 (1H, m), 4,49 (2H, m), 5,57 (2H, s), 6,61 (2H, d), 6,68 (1H, s), 8,08 (1H, d) NMR Spectrum: 1H NMR (399.9 MHz, DMSO-d6) δ 1.23 (3H, d), 3.31 (3H, s), 3.5 (1H, m), 3.64 (1H, m ), 3.78 (1H, m), 4.13 (1H, m), 4.49 (2H, m), 5.57 (2H, s), 6.61 (2H, d), 6.68 (1H, s), 8.08 (1H, d)

Espectro LCMS: MH+ 363, tiempo de retención 1,02 min., Método Ácido 5 min. LCMS spectrum: MH + 363, retention time 1.02 min., Acid Method 5 min.

N–[4–[4–[(3S)–3–Metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidin–2–il]fenil]carbamato de terc–butilo N- [4– [4 - [(3S) –3 – Methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin-2-yl] phenyl] tert-butyl carbamate

O OR

Se disolvió 2–cloro–4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidina (1,0 g, 3,27 mmoles) en una disolución de 18% de DMF en una mezcla de DME:agua:etanol 7:3:2 (7 ml). Después se añadieron a la disolución ácido [4–[(2–metilpropan–2–il)oxicarbonilamino]fenil]borónico (1,165 g, 4,91 mmoles), disolución 2M de carbonato de sodio (4 ml) y catalizador de diclorobis(trifenilfosfina)paladio (115 mg, 0,16 mmoles) y se pusieron a reflujo a 90ºC durante 5 horas en una atmósfera de nitrógeno. La reacción se dejó enfriar hasta la temperatura ambiente, y después se repartió entre acetato de etilo y agua. Los productos orgánicos se secaron sobre sulfato de magnesio, se filtraron y se concentraron hasta sequedad. El aceite bruto se disolvió en diclorometano y se filtró para eliminar el material insoluble. Un sólido beige precipitó de los filtrados, y los filtrados se filtraron nuevamente. El sólido se analizó y se encontró que el ácido borónico en exceso y los filtrados contenían el producto y algunas impurezas. Los filtrados se purificaron mediante cromatografía en sílice, eluyendo con 0–40% de acetato de etilo en isohexano, para dar el compuesto deseado como un aceite naranja (530 mg). 2-Chloro-4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine (1.0 g, 3.27 mmol) was dissolved in an 18% solution of DMF in a mixture of DME: water: ethanol 7: 3: 2 (7 ml). Then [4 - [(2-methylpropan-2-yl) oxycarbonylamino] phenyl] boronic acid (1,165 g, 4.91 mmol), 2M solution of sodium carbonate (4 ml) and dichlorobis catalyst were added to the solution. triphenylphosphine) palladium (115 mg, 0.16 mmol) and refluxed at 90 ° C for 5 hours under a nitrogen atmosphere. The reaction was allowed to cool to room temperature, and then partitioned between ethyl acetate and water. The organic products were dried over magnesium sulfate, filtered and concentrated to dryness. The crude oil was dissolved in dichloromethane and filtered to remove insoluble material. A beige solid precipitated from the filtrates, and the filtrates were filtered again. The solid was analyzed and it was found that the excess boronic acid and the filtrates contained the product and some impurities. The filtrates were purified by silica chromatography, eluting with 0–40% ethyl acetate in isohexane, to give the desired compound as an orange oil (530 mg).

Espectro LCMS: MH+ 463, tiempo de retención 2,23 min., Método Ácido 5 min. LCMS spectrum: MH + 463, retention time 2.23 min., Acid Method 5 min.

2–Cloro–4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidina 2 – Chloro – 4 - [(3S) –3 – methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidine

Se disolvió 2,4–dicloro–6–(metilsulfonilmetil)pirimidina (30 g, 0,13 moles) en diclorometano y se agitó (en nitrógeno) a –5ºC. Se añadió trietilamina (17,4 ml, 0,13 moles) para dar una disolución marrón clara. Se disolvió (3S)–3– metilmorfolina en diclorometano, y se añadió gota a gota manteniendo la reacción por debajo de –5°C. Después el baño de enfriamiento se retiró, y la mezcla se agitó durante 1 hora. La mezcla de reacción se calentó a reflujo durante 2 horas, después la mezcla de reacción se lavó con agua, se secó y después se evaporó. El material bruto se purificó mediante HPLC preparativa para dar el material deseado como un sólido (19,3 g). 2,4-Dichloro-6– (methylsulfonylmethyl) pyrimidine (30 g, 0.13 mol) was dissolved in dichloromethane and stirred (in nitrogen) at –5 ° C. Triethylamine (17.4 ml, 0.13 mol) was added to give a light brown solution. (3S) -3- methylmorpholine was dissolved in dichloromethane, and added dropwise keeping the reaction below -5 ° C. Then the cooling bath was removed, and the mixture was stirred for 1 hour. The reaction mixture was heated at reflux for 2 hours, then the reaction mixture was washed with water, dried and then evaporated. The crude material was purified by preparative HPLC to give the desired material as a solid (19.3 g).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,21–1,23 (m, 3H), 3,11 (s, 3H), 3,19–3,26 (m, 1H), 3,42–3,49 (m, 1H), 3,58–3,62 (1H, m), 3,73 (d, 1H), 3,92–3,96 (m, 2H), 4,27–4,31 (m, 1H), 4,45 (s, 2H), 6,92 (s, 1H) Espectro LCMS: MH+ 306, tiempo de retención 1,42 min., Método Ácido 5 min. 2,4–Dicloro–6–(metilsulfonilmetil)pirimidina NMR Spectrum: 1H NMR (400.13 MHz, DMSO – d6) δ 1.21–1.23 (m, 3H), 3.11 (s, 3H), 3.19–3.26 (m, 1H) , 3.42–3.49 (m, 1H), 3.58–3.62 (1H, m), 3.73 (d, 1H), 3.92–3.96 (m, 2H), 4.27–4.31 (m , 1H), 4.45 (s, 2H), 6.92 (s, 1H) LCMS spectrum: MH + 306, retention time 1.42 min., Acid Method 5 min. 2,4-Dichloro-6– (methylsulfonylmethyl) pyrimidine

Cl Cl

Se añadió 6–(metilsulfonilmetil)–1H–pirimidin–2,4–diona (132 g, 0,65 moles) a oxicloruro de fósforo (1,2 l), y la mezcla se calentó a reflujo durante 16 horas, y después se enfrió hasta la temperatura ambiente. El exceso de oxicloruro de fósforo se eliminó a vacío, el residuo se disolvió azeotrópicamente con tolueno (2 x 500 ml) y se disolvió en diclorometano. Esta mezcla se vertió entonces lentamente en hielo (4 l) y se agitó durante 20 minutos, después se extrajo con diclorometano (3 x 1 l) (el material negro insoluble se filtró y se desechó) y acetato de etilo (2 x 1 l). Los extractos se combinaron, se secaron, y después se evaporaron para dejar el material deseado como un sólido marrón oscuro (51 g). El material se usó sin purificación adicional. 6– (Methylsulfonylmethyl) -1 H -pyrimidin-2,4-dione (132 g, 0.65 mol) was added to phosphorus oxychloride (1.2 L), and the mixture was heated at reflux for 16 hours, and then cooled to room temperature. The excess phosphorus oxychloride was removed in vacuo, the residue was azeotropically dissolved with toluene (2 x 500 ml) and dissolved in dichloromethane. This mixture was then slowly poured into ice (4 L) and stirred for 20 minutes, then extracted with dichloromethane (3 x 1 L) (the insoluble black material was filtered and discarded) and ethyl acetate (2 x 1 L ). The extracts were combined, dried, and then evaporated to leave the desired material as a dark brown solid (51 g). The material was used without further purification.

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 3,13 (s, 3H), 4,79 (s, 2H), 7,87 (s, 1H) NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 3.13 (s, 3H), 4.79 (s, 2H), 7.87 (s, 1H)

Espectro LCMS: MH+ 239, tiempo de retención 1,21 min., Método Ácido 5 min. LCMS spectrum: MH + 239, retention time 1.21 min., Acid Method 5 min.

6–(Metilsulfonilmetil)–1H–pirimidin–2,4–diona 6– (Methylsulfonylmethyl) –1H – pyrimidin – 2,4 – dione

O OR

Se disolvió 6–(clorometil)–1H–pirimidin–2,4–diona (175 g, 1,09 moles) en DMF (2 l), y se añadió sal sódica del ácido metanosulfínico (133,5 g, 1,31 moles). La reacción se calentó hasta 125ºC durante 2 horas, después se dejó enfriar, y la suspensión se filtró y se concentró a vacío para dar un sólido amarillo. El material bruto se lavó con agua, se filtró, y después se trituró con tolueno. El sólido se filtró, y después se trituró con isohexano para dejar el compuesto deseado como un sólido amarillo (250 g). El material se usó sin purificación adicional. 6– (Chloromethyl) -1H-pyrimidin-2,4-dione (175 g, 1.09 mol) was dissolved in DMF (2 L), and sodium salt of methanesulfinic acid (133.5 g, 1.31) was added moles) The reaction was heated to 125 ° C for 2 hours, then allowed to cool, and the suspension was filtered and concentrated in vacuo to give a yellow solid. The crude material was washed with water, filtered, and then triturated with toluene. The solid was filtered, and then triturated with isohexane to leave the desired compound as a yellow solid (250 g). The material was used without further purification.

La 6–(clorometil)–1H–pirimidin–2,4–diona es un material comercialmente disponible. 6– (chloromethyl) –1H – pyrimidin – 2,4 – dione is a commercially available material.

2–Fluoro–4–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidin–2–il]anilina 2 – Fluoro – 4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin – 2-yl] aniline

F F

Se disolvió 2–cloro–4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidina (860 mg) en 18% de DMF en DME:agua:etanol 7:3:2 (21 ml volumen total del disolvente). Después se añadieron a la disolución 4–pinacolato boro–2–fluoroanilina (1,005 g), carbonato de sodio 2M (4 ml) y diclorobis(trifenilfosfina)paladio (99 mg) y se calentaron a reflujo a 90ºC durante 5 horas en una atmósfera de nitrógeno. La reacción se repartió entre DCM (50 ml) y agua (50 ml). El extracto orgánico se secó sobre sulfato de magnesio, se filtró y se concentró a vacío. El aceite marrón se disolvió en diclorometano, se filtró para eliminar el material fino y se cargó en un Companion para la purificación, usando 0–50% de acetato de etilo en gradiente de isohexano durante 20 minutos. El producto purificado se obtuvo como un aceite amarillo pálido. 2-Chloro-4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine (860 mg) was dissolved in 18% DMF in DME: water: ethanol 7: 3: 2 (21 ml total volume of solvent). Then 4-pinacholate boron-2-fluoroaniline (1,005 g), 2M sodium carbonate (4 ml) and dichlorobis (triphenylphosphine) palladium (99 mg) were added to the solution and refluxed at 90 ° C for 5 hours in one atmosphere of nitrogen The reaction was partitioned between DCM (50 ml) and water (50 ml). The organic extract was dried over magnesium sulfate, filtered and concentrated in vacuo. The brown oil was dissolved in dichloromethane, filtered to remove the fine material and loaded into a Companion for purification, using 0–50% ethyl acetate in isohexane gradient for 20 minutes. The purified product was obtained as a pale yellow oil.

Espectro LCMS: MH+ 381, tiempo de retención 1,32 min., Método Ácido 5 min. LCMS spectrum: MH + 381, retention time 1.32 min., Acid Method 5 min.

5–[4–[(3S)–3–Metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidin–2–il]piridin–2–amina 5– [4 - [(3S) –3 – Methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin-2-yl] pyridin-2-amine

Se disolvió 2–cloro–4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidina (363 mg, 1,19 mmoles) en una disolución de 18% de DMF en una mezcla de DME:agua:etanol 7:3:2 (7 ml). Se añadieron 5–(4,4,5,5–tetrametil– 1,3,2–dioxaborolan–2–il)piridin–2–amina (496 mg, 2,25 mmoles), disolución de carbonato de sodio 2M (2 ml) y diclorobis(trifenilfosfina)paladio (42 mg) a la disolución, y ésta se calentó a reflujo a 90ºC durante 90 minutos en una atmósfera de nitrógeno. La reacción se repartió entre acetato de etilo (50 ml) y agua (50 ml), los productos orgánicos se secaron sobre sulfato de magnesio, se filtraron y se concentraron a vacío para dar el producto deseado como un aceite amarillo (410 mg) que se usó sin purificación adicional. 2-Chloro-4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine (363 mg, 1.19 mmol) was dissolved in an 18% solution of DMF in a mixture of DME : water: ethanol 7: 3: 2 (7 ml). 5– (4,4,5,5-tetramethyl– 1,3,2-dioxaborolan-2-yl) pyridin-2-amine (496 mg, 2.25 mmol), 2M sodium carbonate solution (2 ml) and dichlorobis (triphenylphosphine) palladium (42 mg) to the solution, and it was heated at reflux at 90 ° C for 90 minutes under a nitrogen atmosphere. The reaction was partitioned between ethyl acetate (50 ml) and water (50 ml), the organic products were dried over magnesium sulfate, filtered and concentrated in vacuo to give the desired product as a yellow oil (410 mg) which It was used without further purification.

Espectro LCMS: MH+ 364, tiempo de retención 0,89 min., Método Ácido 5 min. LCMS spectrum: MH + 364, retention time 0.89 min., Acid Method 5 min.

2–Metoxi–4–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidin–2–il]anilina 2 – Methoxy – 4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin – 2-yl] aniline

OMe OMe

Se disolvió 2–cloro–4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidina (700 mg, 2,29 mmoles) en una disolución de 18% de DMF en una mezcla de DME:agua:etanol 7:3:2 (7 ml). Después se añadieron a la disolución ácido (4–amino–3–metoxi–fenil)borónico (574 mg, 3,43 mmoles), disolución 2M de carbonato de sodio (4 ml) y diclorobis(trifenilfosfina)paladio (81 mg) y se pusieron a reflujo a 90ºC durante 1 hora. La reacción se dejó enfriar hasta la temperatura ambiente, después se repartió entre acetato de etilo (50 ml) y agua (50 ml), los productos orgánicos se secaron sobre sulfato de magnesio, se filtraron y se concentraron a vacío. El residuo se disolvió en diclorometano y se filtró para eliminar el material insoluble. Los filtrados se purificaron usando un Companion. 2-Chloro-4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine (700 mg, 2.29 mmol) was dissolved in an 18% solution of DMF in a mixture of DME : water: ethanol 7: 3: 2 (7 ml). Then (4-amino-3-methoxy-phenyl) boronic acid (574 mg, 3.43 mmol), 2M solution of sodium carbonate (4 ml) and dichlorobis (triphenylphosphine) palladium (81 mg) were added to the solution. they were refluxed at 90 ° C for 1 hour. The reaction was allowed to cool to room temperature, then partitioned between ethyl acetate (50 ml) and water (50 ml), the organic products were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was dissolved in dichloromethane and filtered to remove insoluble material. The filtrates were purified using a Companion.

Espectro RMN: RMN 1H (399,9 MHz, DMSO–d6) δ 1,24 (d, 3H), 3,17–3,21 (m, 1H), 3,23 (s, 3H), 3,47–3,54 (m, 1H), 3,64–3,67 (m, 1H), 3,78 (d, 1H), 3,83 (s, 3H), 3,97–4,01 (m, 1H), 4,16 (d, 1H), 4,46 (s, 3H), 5,23 (s, 2H), 6,68–6,70 (m, 1H), 6,69 (s, 1H), 7,77 (m, 1H), 7,97 (s, 1H) NMR Spectrum: 1H NMR (399.9 MHz, DMSO – d6) δ 1.24 (d, 3H), 3.17–3.21 (m, 1H), 3.23 (s, 3H), 3.47 –3.54 (m, 1H), 3.64–3.67 (m, 1H), 3.78 (d, 1H), 3.83 (s, 3H), 3.97–4.01 (m , 1H), 4.16 (d, 1H), 4.46 (s, 3H), 5.23 (s, 2H), 6.68-6.70 (m, 1H), 6.69 (s, 1H), 7.77 (m, 1H), 7.97 (s, 1H)

Espectro LCMS: MH+ 393, tiempo de retención 1,17min, método ácido 5 min. LCMS spectrum: MH + 393, retention time 1.17min, acid method 5 min.

Ejemplo 2: Example 2:

N–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidin–2–il]fenil]azetidin–1–carboxamida N– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin-2-yl] phenyl] azetidin-1-carboxamide

Se diluyó disolución de fosgeno al 20% en tolueno (0,245 ml, 0,50 mmoles) con diclorometano (0,5 ml). Se disolvió 4–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidin–2–il]anilina (150 mg, 0,41 mmoles) en diclorometano (2 ml) y piridina (0,5 ml). Esto se añadió a la disolución de fosgeno gota a gota durante 2 minutos. La reacción se agitó a temp. ambiente durante 1 hora. Después se añadió azetidina (0,034 ml, 0,50 mmoles), y la mezcla se agitó a temp. ambiente durante 1 hora. La reacción se repartió entre agua y acetato de etilo (25 ml de cada uno). La capa orgánica se secó sobre sulfato de magnesio y se evaporó hasta sequedad. El aceite amarillo se purificó mediante cromatografía, eluyendo con 10–70% de acetato de etilo en isohexano, para dar el material deseado como una espuma amarilla (50 mg, 25%). 20% phosgene solution in toluene (0.245 ml, 0.50 mmol) was diluted with dichloromethane (0.5 ml). 4– [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidin-2-yl] aniline (150 mg, 0.41 mmol) was dissolved in dichloromethane (2 ml) and pyridine (0.5 ml). This was added to the phosgene solution dropwise for 2 minutes. The reaction was stirred at temp. atmosphere for 1 hour. Then azetidine (0.034 ml, 0.50 mmol) was added, and the mixture was stirred at temp. atmosphere for 1 hour. The reaction was partitioned between water and ethyl acetate (25 ml of each). The organic layer was dried over magnesium sulfate and evaporated to dryness. The yellow oil was purified by chromatography, eluting with 10-70% ethyl acetate in isohexane, to give the desired material as a yellow foam (50 mg, 25%).

Espectro RMN: RMN 1H (399,9 MHz, DMSO–d6) δ 1,25 (d, 3H), 2,16–2,24 (m, 2H), 3,19–3,23 (m, 4H), 3,47–3,54 (m, 1H), 3,64–3,68 (m, 1H), 3,79 (d, 1H), 3,99 (t, 5H), 4,17 (s, 1H), 4,49 (s, 3H), 6,79 (s, 1H), 7,62–7,64 (m, 2H), 8,20– 8,23 (m, 2H), 8,57 (s, 1H) NMR Spectrum: 1H NMR (399.9 MHz, DMSO – d6) δ 1.25 (d, 3H), 2.16–2.24 (m, 2H), 3.19–3.23 (m, 4H) , 3.47-3.54 (m, 1H), 3.64-3.68 (m, 1H), 3.79 (d, 1H), 3.99 (t, 5H), 4.17 (s , 1H), 4.49 (s, 3H), 6.79 (s, 1H), 7.62–7.64 (m, 2H), 8.20– 8.23 (m, 2H), 8, 57 (s, 1 H)

Espectro LCMS: MH+ 446, tiempo de retención 1,37 min., Método Ácido 5 min. LCMS spectrum: MH + 446, retention time 1.37 min., Acid Method 5 min.

Los siguientes compuestos se prepararon de una manera análoga a N–[4–[4–[(3S)–3–metilmorfolin–4–il]–6– (metilsulfonilmetil)pirimidin–2–il]fenil]azetidin–1–carboxamida a partir de 4–[4–[(3S)–3–metilmorfolin–4–il]–6– (metilsulfonilmetil)pirimidin–2–il]anilina y la amina apropiada. The following compounds were prepared in a manner analogous to N– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin-2-yl] phenyl] azetidin-1-carboxamide from 4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin-2-yl] aniline and the appropriate amine.

2a 2nd: N N N O S O O N H N O OMe 1–(2–metoxietil)–1–metil–3–[4– [4–[(3S)–3–metilmorfolin–4–il]– 6–(metilsulfonilmetil)pirimidin–2– il]fenil]urea 478 1,46 N/a N N N O S O O N H N O OMe 1– (2 – methoxyethyl) –1 – methyl – 3– [4– [4 - [(3S) –3-methylmorpholin-4-yl] - 6– (methylsulfonylmethyl) pyrimidin-2-yl] phenyl] urea 478 1.46 N / a

2b 2b: N N N S O O O N H O N 1,1–dimetil–3–[4–[4–[(3S)–3– metilmorfolin–4–il]–6– (metilsulfonilmetil)pirimidin–2– il]fenil]urea 434 1,28 Purificada mediante cromatografía de fase inversa N N N S O O O N H O N 1,1 – dimethyl – 3– [4– [4 - [(3S) –3– methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin – 2– yl] phenyl] urea 434 1.28 Purified by reverse phase chromatography

2c 2 C: O 3–[2–metoxi–4–[4–[(3S)–3– 464 1,54 Purificada OR 3– [2 – methoxy – 4– [4 - [(3S) –3– 464 1.54 Purified

N N: (metilsulfonilmetil)pirimidin–2– cromatografía (methylsulfonylmethyl) pyrimidin – 2– chromatography

N N S O O N H O N O N N S O O N H O N O: il]fenil]–1,1–dimetil–urea de fase inversa il] phenyl] –1,1-dimethyl-urea reverse phase

2d 2d: N N N O S O O N H N H O 1–metil–3–[4–[4–[(3S)–3– metilmorfolin–4–il]–6– (metilsulfonilmetil)pirimidin–2– il]fenil]urea 420 1,19 Purificada mediante cromatografía de fase inversa N N N O S O O N H N H O 1 – methyl – 3– [4– [4 - [(3S) –3– methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin – 2– yl] phenyl] urea 420 1.19 Purified by reverse phase chromatography

2e 2e: O 3–[2–fluoro–4–[4–[(3S)–3– 438 1,44 Purificada OR 3– [2 – fluoro – 4– [4 - [(3S) –3– 438 1.44 Purified

N N S O O N H O N H F N N S O O N H O N H F: il]fenil]–1–metil–urea de fase inversa il] phenyl] –1 – methyl – urea reverse phase

2f 2f: O 3–[2–fluoro–4–[4–[(3S)–3– 452 1,55 Purificada OR 3– [2 – fluoro – 4– [4 - [(3S) –3– 452 1.55 Purified

N N S O O N H O N F N N S O O N H O N F: il]fenil]–1,1–dimetil–urea de fase inversa il] phenyl] –1,1-dimethyl-urea reverse phase

Ejemplo 2a: RMN 1H (399,9 MHz, DMSO–d6) δ 1,25 (d, 3H), 3,00 (s, 3H), 3,21 (s, 3H), 3,23–3,27 (m, 2H), 3,45 (m, 2H), 3,51 (s, 4H), 3,53 (m, 1H), 3,64–3,68 (m, 1H), 3,79 (d, 1H), 3,98–4,02 (m, 1H), 4,17–4,21 (m, 1H), 4,50 (s, 3H), 6,79 (s, 1H), 7,58 (s, 2H), 8,21–8,23 (m, 2H), 8,47 (s, 1H) Example 2a: 1H NMR (399.9 MHz, DMSO-d6) δ 1.25 (d, 3H), 3.00 (s, 3H), 3.21 (s, 3H), 3.23-3.27 (m, 2H), 3.45 (m, 2H), 3.51 (s, 4H), 3.53 (m, 1H), 3.64-3.68 (m, 1H), 3.79 ( d, 1H), 3.98-4.02 (m, 1H), 4.17-4.21 (m, 1H), 4.50 (s, 3H), 6.79 (s, 1H), 7 , 58 (s, 2H), 8.21–8.23 (m, 2H), 8.47 (s, 1H)

Ejemplo 2b: RMN 1H (399,9 MHz, DMSO–d6) δ 1,24–1,26 (m, 3H), 2,96 (s, 6H), 3,21 (s, 3H), 3,25 (d, 1H), 3,48– 3,54 (m, 1H), 3,64–3,68 (m, 1H), 3,79 (d, 1H), 3,98–4,02 (m, 1H), 4,19 (d, 1H), 4,49 (s, 3H), 6,79 (s, 1H), 7,58–7,62 (m, 2H), 8,20–8,23 (m, 2H), 8,50 (s, 1H) Example 2b: 1H NMR (399.9 MHz, DMSO-d6) δ 1.24-1.26 (m, 3H), 2.96 (s, 6H), 3.21 (s, 3H), 3.25 (d, 1H), 3.48– 3.54 (m, 1H), 3.64–3.68 (m, 1H), 3.79 (d, 1H), 3.98–4.02 (m , 1H), 4.19 (d, 1H), 4.49 (s, 3H), 6.79 (s, 1H), 7.58–7.62 (m, 2H), 8.20–8, 23 (m, 2H), 8.50 (s, 1H)

Ejemplo 2d: RMN 1H (399,9 MHz, DMSO–d6) δ 1,25 (d, 3H), 2,66–2,67 (d, 3H), 3,21 (s, 3H), 3,23 (d, 1H), 3,47–3,54 (m, 1H), 3,64–3,68 (m, 1H), 3,79 (d, 1H), 3,97–4,01 (m, 1H), 4,18 (d, 1H), 4,48 (m, 1H), 4,49 (s, 2H), 6,08 (q, 1H), 6,78 (s, 1H), 7,49–7,53 (m, 2H), 8,20–8,22 (m, 2H), 8,76 (s, 1H) Example 2d: 1H NMR (399.9 MHz, DMSO-d6) δ 1.25 (d, 3H), 2.66-2.67 (d, 3H), 3.21 (s, 3H), 3.23 (d, 1H), 3.47-3.54 (m, 1H), 3.64-3.68 (m, 1H), 3.79 (d, 1H), 3.97-4.01 (m , 1H), 4.18 (d, 1H), 4.48 (m, 1H), 4.49 (s, 2H), 6.08 (q, 1H), 6.78 (s, 1H), 7 , 49–7.53 (m, 2H), 8.20–8.22 (m, 2H), 8.76 (s, 1H)

10 Ejemplo 2e: RMN 1H (399,9 MHz, DMSO–d6) δ 1,24–1,26 (m, 3H), 2,69 (d, 3H), 3,23–3,24 (m, 1H), 3,26–3,27 (m, 1H), 3,20 (s, 3H), 3,47–3,54 (m, 1H), 3,64–3,67 (m, 1H), 3,79 (d, 1H), 3,97–4,01 (m, 1H), 4,16–4,20 (m, 1H), 4,50 (s, 2H), 6,57 (q, 1H), 6,82 (s, 1H), 8,02–8,09 (m, 1H), 8,05–8,07 (m, 1H), 8,29 (m, 1H), 8,55 (d, 1H) Example 2e: 1H NMR (399.9 MHz, DMSO-d6) δ 1.24-1.26 (m, 3H), 2.69 (d, 3H), 3.23-3.24 (m, 1H ), 3.26-3.27 (m, 1H), 3.20 (s, 3H), 3.47-3.54 (m, 1H), 3.64-3.67 (m, 1H), 3.79 (d, 1H), 3.97-4.01 (m, 1H), 4.16-4.20 (m, 1H), 4.50 (s, 2H), 6.57 (q, 1H), 6.82 (s, 1H), 8.02–8.09 (m, 1H), 8.05–8.07 (m, 1H), 8.29 (m, 1H), 8.55 (d, 1H)

Ejemplo 2f: RMN 1H (399,9 MHz, DMSO–d6) δ 1,25–1,27 (m, 3H), 2,96 (s, 6H), 3,20 (s, 3H), 3,48–3,55 (m, 1H), 3,64–3,68 (m, 1H), 3,79 (d, 1H), 3,98–4,02 (m, 1H), 4,21 (t, 1H), 4,40 (m, 1H), 4,51 (s, 2H), 6,85 (s, 1H), 7,68 (t, 1H), Example 2f: 1H NMR (399.9 MHz, DMSO-d6) δ 1.25-1.27 (m, 3H), 2.96 (s, 6H), 3.20 (s, 3H), 3.48 –3.55 (m, 1H), 3.64–3.68 (m, 1H), 3.79 (d, 1H), 3.98–4.02 (m, 1H), 4.21 (t , 1H), 4.40 (m, 1H), 4.51 (s, 2H), 6.85 (s, 1H), 7.68 (t, 1H),

15 8,02–8,11 (m, 2H), 8,15 (s, 1H) 15 8.02–8.11 (m, 2H), 8.15 (s, 1H)

Prueba (a): Ejemplo (2) 0,31 μM; Ejemplo (2a) 2,3 μM; Ejemplo (2b) 0,29 μM; Ejemplo (2c) 1,2 μM; Ejemplo (2d) 0,0068 μM; Ejemplo (2e) 0,035 μM; Ejemplo (2f) 1,7 μM. Test (a): Example (2) 0.31 μM; Example (2a) 2.3 μM; Example (2b) 0.29 μM; Example (2c) 1.2 μM; Example (2d) 0.0068 μM; Example (2e) 0.035 μM; Example (2f) 1.7 μM.

Ejemplo 3: Example 3:

1– [2 – Methyl – 4– [4 - [(3 S) –3 – methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin – 2-yl] phenyl] –3-phenyl-urea

O OR

N NN N

O OR

S S

N N

O OR

N N

N HH N HH

20 Se disolvió 2–metil–4–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidin–2–il]anilina (130 mg, 0,34 mmoles) en 1,4–dioxano (4 ml). Se añadió isocianato de fenilo (0,038 ml, 0,34 mmoles), y la reacción se calentó a 75ºC durante 3 horas. La mezcla de reacción se evaporó hasta sequedad, y el residuo resultante Triturada con acetato de etilo para dar el compuesto deseado como un sólido color crema (42 mg). 20 2-Methyl-4– [4 - [(3S) -3-Methylmorpholin-4-yl] -6– (Methylsulfonylmethyl) pyrimidin-2-yl] aniline (130 mg, 0.34 mmol) was dissolved in 1, 4-dioxane (4 ml). Phenyl isocyanate (0.038 ml, 0.34 mmol) was added, and the reaction was heated at 75 ° C for 3 hours. The reaction mixture was evaporated to dryness, and the resulting residue triturated with ethyl acetate to give the desired compound as a cream solid (42 mg).

25 Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,25 (s, 3H), 2,34 (s, 3H), 3,21 (s, 3H), 3,23–3,26 (m, 1H), 3,48– 3,55 (m, 1H), 3,64–3,68 (m, 1H), 3,79 (d, 1H), 4,00 (d, 1H), 4,20 (d, 1H), 4,50 (s, 3H), 6,79 (s, 1H), 6,97–7,01 (m, 1H), 7,31 (d, 2H), 7,47–7,50 (m, 2H), 8,08 (s, 2H), 8,13 (d, 2H), 9,13 (s, 1H) 25 NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.25 (s, 3H), 2.34 (s, 3H), 3.21 (s, 3H), 3.23-3, 26 (m, 1H), 3.48-3.55 (m, 1H), 3.64-3.68 (m, 1H), 3.79 (d, 1H), 4.00 (d, 1H) , 4.20 (d, 1H), 4.50 (s, 3H), 6.79 (s, 1H), 6.97–7.01 (m, 1H), 7.31 (d, 2H), 7.47–7.50 (m, 2H), 8.08 (s, 2H), 8.13 (d, 2H), 9.13 (s, 1H)

Espectro LCMS: MH+ 496, tiempo de retención 2,08 minutos, Método Ácido 5 min. LCMS spectrum: MH + 496, retention time 2.08 minutes, Acid Method 5 min.

El siguiente compuesto se preparó de manera análoga a partir de la anilina y el isocianato apropiados. The following compound was prepared analogously from the appropriate aniline and isocyanate.

MH+ MH +: retención retention

(min.) (min.)

3a 3rd: S O O N N N O N H O N H O 1–etil–3–[2–metoxi–4–[4–[(3S)– 3–metilmorfolin–4–il]–6– (metilsulfonilmetil)pirimidin–2– il]fenil]urea 464 1,54 Purificada mediante cromatografía de fase inversa, seguido de cromatografía de fase normal S O O N N N O N H O N H O 1-ethyl-3– [2-methoxy-4– [4 - [(3S) - 3-methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin-2-yl] phenyl] urea 464 1.54 Purified by reverse phase chromatography, followed by normal phase chromatography.

MH+ MH +: retención retention

(min.) (min.)

3b 3b: S O O N N N O N H N H OCl 1–[2–Cloro–4–[4–[(3S)–3– metilmorfolin–4–il]–6– (metilsulfonilmetil)pirimidin–2– il]fenil]–3–fenil–urea 515 2,51 Purificada sobre sílice eluyendo con 0-4% de metanol en DCM S O O N N N O N H N H OCl 1– [2 – Chloro – 4– [4 - [(3S) –3– methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin – 2– yl] phenyl] –3-phenyl-urea 515 2.51 Purified on silica eluting with 0-4% methanol in DCM

3c 3c: S O O N N N O N H N H O 1–[3–[4–[(3S)–3–Metilmorfolin– 4–il]–6–(metilsulfonilmetil)pirimidin–2–il]fenil]–3–fenil–urea 481 2,30 Purificada mediante recristalización en DMF/agua (dos veces), seguido de trituración con acetonitrilo S O O N N N O N H N H O 1– [3– [4 - [(3S) –3 – Methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin-2-yl] phenyl] –3-phenyl-urea 481 2.30 Purified by recrystallization from DMF / water (twice), followed by trituration with acetonitrile

3d 3d: S O O N N N O N N H O 1–Metil–1–[4–[4–[(3S)–3– metilmorfolin–4–il]–6– (metilsulfonilmetil)pirimidin–2– il]fenil]–3–fenil–urea 496 2,18 S O O N N N O N N H O 1 – Methyl – 1– [4– [4 - [(3S) –3– methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin – 2– yl] phenyl] –3-phenyl-urea 496 2.18

Ejemplo 3a: RMN 1H (400,13 MHz, DMSO–d6) δ 1,07 (t, 3H), 1,25 (d, 3H), 3,09–3,14 (m, 2H), 3,19–3,24 (m, 1H), 3,25 (s, 3H), 3,47–3,54 (m, 1H), 3,64–3,68 (m, 1H), 3,78 (d, 1H), 3,92 (s, 3H), 3,97–4,01 (m, H), 4,17–4,20 (m, 1H), 4,50 (s, 3H), 6,78 (s, 1H), 6,95 (t, 1H), 7,87–7,90 (m, 2H), 8,06 (s, 1H), 8,21–8,24 (m, 1H) Example 3a: 1H NMR (400.13 MHz, DMSO-d6) δ 1.07 (t, 3H), 1.25 (d, 3H), 3.09-3.14 (m, 2H), 3.19 –3.24 (m, 1H), 3.25 (s, 3H), 3.47-3.54 (m, 1H), 3.64-3.68 (m, 1H), 3.78 (d , 1H), 3.92 (s, 3H), 3.97-4.01 (m, H), 4.17-4.20 (m, 1H), 4.50 (s, 3H), 6, 78 (s, 1H), 6.95 (t, 1H), 7.87–7.90 (m, 2H), 8.06 (s, 1H), 8.21–8.24 (m, 1H)

5 Ejemplo 3b: RMN 1H (400,13 MHz, DMSO–d6) δ 1,26 (d, 3H), 3,20 (s, 3H), 3,25 (d, 1H), 3,48–3,54 (m, 1H), 3,64– 3,68 (m, 1H), 3,79 (d, 1H), 3,98–4,02 (m, 1H), 4,20 (d, 1H), 4,48 (m, 1H), 4,52 (s, 2H), 6,84 (s, 1H), 7,02 (t, 1H), 7,32 (d, 2H), 7,49 (d, 2H), 8,24–8,27 (m, 1H), 8,34 (d, 1H), 8,34–8,37 (m, 1H), 8,49 (s, 1H), 9,52 (s, 1H) 5 Example 3b: 1H NMR (400.13 MHz, DMSO-d6) δ 1.26 (d, 3H), 3.20 (s, 3H), 3.25 (d, 1H), 3.48-3, 54 (m, 1H), 3.64– 3.68 (m, 1H), 3.79 (d, 1H), 3.98–4.02 (m, 1H), 4.20 (d, 1H) , 4.48 (m, 1H), 4.52 (s, 2H), 6.84 (s, 1H), 7.02 (t, 1H), 7.32 (d, 2H), 7.49 ( d, 2H), 8.24–8.27 (m, 1H), 8.34 (d, 1H), 8.34–8.37 (m, 1H), 8.49 (s, 1H), 9 , 52 (s, 1H)

Ejemplo 3c: RMN 1H (400,13 MHz, DMSO–d6) δ 1,27 (d, 3H), 3,23 (s, 3H), 3,26 (m, 1H), 3,49–3,56 (m, 1H), 3,65– 3,69 (m, 1H), 3,80 (d, 1H), 3,99–4,03 (m, 1H), 4,20 (d, 1H), 4,53 (s, 3H), 6,87 (s, 1H), 6,98 (t, 1H), 7,29 (t, 2H), 7,40 Example 3c: 1H NMR (400.13 MHz, DMSO-d6) δ 1.27 (d, 3H), 3.23 (s, 3H), 3.26 (m, 1H), 3.49-3.56 (m, 1H), 3.65-3.69 (m, 1H), 3.80 (d, 1H), 3.99-4.03 (m, 1H), 4.20 (d, 1H), 4.53 (s, 3H), 6.87 (s, 1H), 6.98 (t, 1H), 7.29 (t, 2H), 7.40

10 (t, 1H), 7,47 (d, 2H), 7,71–7,74 (m, 1H), 7,95 (d, 1H), 8,31 (s, 1H), 8,65 (s, 1H), 8,82 (s, 1H) 10 (t, 1H), 7.47 (d, 2H), 7.71-7.74 (m, 1H), 7.95 (d, 1H), 8.31 (s, 1H), 8.65 (s, 1H), 8.82 (s, 1H)

Ejemplo 3d: RMN 1H (400,13 MHz, DMSO–d6) δ 1,25 (d, 3H), 3,21 (s, 3H), 3,34 (s, 3H), 3,39 (m, 1H), 3,50 (d, 1H), 3,66 (d, 1H), 3,79 (d, 1H), 4,00 (d, 1H), 4,17 (d, 1H), 4,52 (s, 3H), 6,85 (s, 1H), 6,96 (t, 1H), 7,24 (t, 2H), 7,44 (m, 4H), 8,33 (s, 1H), 8,35 (s, 2H) 3d example: 1H NMR (400.13 MHz, DMSO-d6) δ 1.25 (d, 3H), 3.21 (s, 3H), 3.34 (s, 3H), 3.39 (m, 1H ), 3.50 (d, 1H), 3.66 (d, 1H), 3.79 (d, 1H), 4.00 (d, 1H), 4.17 (d, 1H), 4.52 (s, 3H), 6.85 (s, 1H), 6.96 (t, 1H), 7.24 (t, 2H), 7.44 (m, 4H), 8.33 (s, 1H) , 8.35 (s, 2H)

Prueba (a): Ejemplo (3) 1,5 μM; Ejemplo (3a) 0,1 μM; Ejemplo (3b) 0,44 μM; Ejemplo (3c) 3,3 μM; Ejemplo (3d) 2,9 15 μM. Test (a): Example (3) 1.5 μM; Example (3a) 0.1 μM; Example (3b) 0.44 μM; Example (3c) 3.3 μM; Example (3d) 2.9 15 μM.

A continuación se describe la preparación de 2–metil–4–[4–[(3S)–3–metilmorfolin–4–il]–6– (metilsulfonilmetil)pirimidin–2–il]anilina. The preparation of 2-methyl-4– [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidin-2-yl] aniline is described below.

2–Metil–4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidin–2–il]anilina 2 – Methyl – 4 - [(3S) –3 – methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin – 2-yl] aniline

20 Se disolvieron 4–bromo–2–metilanilina (1,00 g, 5,37 mmoles), acetato de potasio (1,59 g, 16,1 mmoles) y 4,4,5,5– tetrametil–2–(4,4,5,5–tetrametil–1,3,2–dioxaborolan–2–il)–1,3,2–dioxaborolano (1,64 g, 6,45 mmoles) en 1,4– dioxano (20 ml), y la disolución se desgasificó durante 5 minutos. Se añadió diclorobis(trifenilfosfina)paladio (264 mg, 0,32 mmoles), y la reacción se agitó a 90ºC durante 4 horas. Se añadieron 2–cloro–4–[(3S)–3–metilmorfolin–4–il]–6– (metilsulfonilmetil)pirimidina (1,65 g, 5,37 mmoles), etanol (1,5 ml), disolución acuosa 2M de carbonato de sodio (3 20 4-Bromo-2-methylaniline (1.00 g, 5.37 mmol), potassium acetate (1.59 g, 16.1 mmol) and 4,4,5,5-tetramethyl-2– ( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,3,2-dioxaborolane (1.64 g, 6.45 mmol) in 1,4-dioxane (20 ml ), and the solution was degassed for 5 minutes. Dichlorobis (triphenylphosphine) palladium (264 mg, 0.32 mmol) was added, and the reaction was stirred at 90 ° C for 4 hours. 2-Chloro-4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine (1.65 g, 5.37 mmol), ethanol (1.5 ml), aqueous solution were added 2M sodium carbonate (3

25 ml) y diclorobis(trifenilfosfina)paladio (264 mg). La reacción se mantuvo a 90ºC durante 18 horas, y después se dejó 25 ml) and dichlorobis (triphenylphosphine) palladium (264 mg). The reaction was maintained at 90 ° C for 18 hours, and then left

enfriar hasta la temperatura ambiente. Se añadieron agua (15 ml) y acetato de etilo (15 ml), y la mezcla se filtró para eliminar las impurezas insolubles. Las fases se separaron, y la capa acuosa se extrajo con una segunda porción de acetato de etilo (15 ml). Los productos orgánicos combinados se secaron (MgSO4) y se concentraron a vacío. El residuo se cromatografió en sílice, eluyendo con 0–3% de metanol en DCM, para dar el compuesto deseado como una espuma beige (290 mg). cool to room temperature. Water (15 ml) and ethyl acetate (15 ml) were added, and the mixture was filtered to remove insoluble impurities. The phases were separated, and the aqueous layer was extracted with a second portion of ethyl acetate (15 ml). The combined organic products were dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on silica, eluting with 0-3% methanol in DCM, to give the desired compound as a beige foam (290 mg).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,22–1,24 (m, 3H), 3,16–3,19 (m, 1H), 3,20 (s, 3H), 3,46–3,52 (m, 1H), 3,62–3,66 (m, 1H), 3,77 (d, 1H), 3,90 (s, 1H), 3,96–4,00 (m, 1H), 4,14–4,18 (m, 1H), 4,43 (s, 2H), 4,45 (s, 1H), 5,32 (s, 2H), 6,63 (s, 1H), 6,66 (s, 1H), 7,91–7,94 (m, 2H) NMR Spectrum: 1H NMR (400.13 MHz, DMSO – d6) δ 1.22–1.24 (m, 3H), 3.16–3.19 (m, 1H), 3.20 (s, 3H) , 3.46-3.52 (m, 1H), 3.62-3.66 (m, 1H), 3.77 (d, 1H), 3.90 (s, 1H), 3.96-4 , 00 (m, 1H), 4.14-4.18 (m, 1H), 4.43 (s, 2H), 4.45 (s, 1H), 5.32 (s, 2H), 6, 63 (s, 1H), 6.66 (s, 1H), 7.91–7.94 (m, 2H)

Espectro LCMS: MH+ 377, tiempo de retención 1,21 min., Método Ácido 5 min. LCMS spectrum: MH + 377, retention time 1.21 min., Acid Method 5 min.

A continuación se describe la preparación de 2–cloro–4–[4–[(3S)–3–metilmorfolin–4–il]–6– (metilsulfonilmetil)pirimidin–2–il]anilina. The preparation of 2-chloro-4– [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidin-2-yl] aniline is described below.

2–Cloro–4–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidin–2–il]anilina 2 – Chloro – 4– [4 - [(3S) –3 – methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin – 2-yl] aniline

Se disolvieron 4–bromo–2–cloroanilina (1,00 g, 4,84 mmoles), acetato de potasio (1,58 g, 14,5 mmoles) y bis(pinacolato)diboro (1,64 g, 5,81 mmoles) en 1,4–dioxano (20 ml). La disolución se desgasificó en nitrógeno durante 5 min. Se añadió [1,1’–bis(difenilfosfino)ferroceno] (213 mg, 0,29 mmoles). La reacción se agitó a 90ºC durante 4 horas. Se añadieron etanol (1,5 ml), 2–cloro–4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidina (1,49 g, 4,84 mmoles), disolución 2M de carbonato de sodio (5,4 ml) y [1,1’–bis(difenilfosfino)ferroceno] (213 mg), y el calentamiento se continuó durante 18 horas. La reacción se evaporó hasta sequedad, y el residuo se repartió entre agua (15 ml) y acetato de etilo (15 ml). La mezcla se filtró para eliminar el material insoluble, las fases se separaron, y la capa acuosa se lavó con acetato de etilo (15 ml). Los productos orgánicos combinados se secaron sobre sulfato de magnesio y se evaporaron para obtener un aceite amarillo. El producto bruto se purificó mediante cromatografía en sílice, eluyendo con 0–4% de metanol en DCM, para dar el material deseado como una espuma de color crema (1,1 g). 4-Bromo-2-chloroaniline (1.00 g, 4.84 mmol), potassium acetate (1.58 g, 14.5 mmol) and bis (pinacolato) diboro (1.64 g, 5.81) were dissolved mmol) in 1,4-dioxane (20 ml). The solution was degassed under nitrogen for 5 min. [1,1’-bis (diphenylphosphino) ferrocene] (213 mg, 0.29 mmol) was added. The reaction was stirred at 90 ° C for 4 hours. Ethanol (1.5 ml), 2-chloro-4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine (1.49 g, 4.84 mmol), 2M solution were added of sodium carbonate (5.4 ml) and [1,1'-bis (diphenylphosphino) ferrocene] (213 mg), and heating was continued for 18 hours. The reaction was evaporated to dryness, and the residue was partitioned between water (15 ml) and ethyl acetate (15 ml). The mixture was filtered to remove insoluble material, the phases were separated, and the aqueous layer was washed with ethyl acetate (15 ml). The combined organic products were dried over magnesium sulfate and evaporated to obtain a yellow oil. The crude product was purified by silica chromatography, eluting with 0-4% methanol in DCM, to give the desired material as a cream-colored foam (1.1 g).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,22–1,24 (m, 3H), 3,18 (s, 3H), 3,19–3,21 (m, 1H), 3,45–3,52 (m, 1H), 3,62–3,65 (m, 1H), 3,77 (d, 1H), 3,96–4,00 (m, 1H), 4,13–4,17 (m, 1H), 4,46 (s, 3H), 5,82 (s, 2H), 6,72 (s, 1H), 6,85 (d, 1H), 8,00–8,03 (m, 1H), 8,14 (d, 1H) NMR Spectrum: 1H NMR (400.13 MHz, DMSO – d6) δ 1.22–1.24 (m, 3H), 3.18 (s, 3H), 3.19–3.21 (m, 1H) , 3.45-3.52 (m, 1H), 3.62-3.65 (m, 1H), 3.77 (d, 1H), 3.96-4.00 (m, 1H), 4 , 13–4.17 (m, 1H), 4.46 (s, 3H), 5.82 (s, 2H), 6.72 (s, 1H), 6.85 (d, 1H), 8, 00–8.03 (m, 1H), 8.14 (d, 1H)

Espectro LCMS: MH+397, tiempo de retención 1,64 min., Método Ácido 5 min. LCMS spectrum: MH + 397, retention time 1.64 min., Acid Method 5 min.

A continuación se describe la preparación de 3–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidin–2– il]anilina. The preparation of 3– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin-2-yl] aniline is described below.

3–[4–[(3S)–3–Metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidin–2–il]anilina 3– [4 - [(3S) –3 – Methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin-2-yl] aniline

Se disolvió 2–cloro–4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidina (1,50 g, 4,91 mmoles) en 18% de DMF en dimetoxietano:agua:etanol 7:3:2 (15 ml). Se añadieron a la disolución ácido (3–aminofenil)borónico (1,01 g, 7,36 mmoles), carbonato de sodio 2M (5 ml) y diclorobis(trifenilfosfina)paladio (173 mg, 0,25 mmoles). La reacción se puso a reflujo a 90ºC durante 18 horas en una atmósfera de nitrógeno, después la reacción se dejó enfriar y se repartió entre acetato de etilo (50 ml) y agua (50 ml). La capa orgánica se secó sobre sulfato de magnesio, se filtró y se sometió a vacío hasta sequedad. El aceite marrón resultante se disolvió en DCM y se filtró para eliminar el material insoluble, y después el filtrado se cromatografió en sílice, eluyendo con 0–4% de metanol en DCM, para dar el producto deseado como un aceite amarillo (1,61 g). 2-Chloro-4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine (1.50 g, 4.91 mmol) was dissolved in 18% DMF in dimethoxyethane: water: ethanol 7: 3: 2 (15 ml). To the solution (3-aminophenyl) boronic acid (1.01 g, 7.36 mmol), 2M sodium carbonate (5 ml) and dichlorobis (triphenylphosphine) palladium (173 mg, 0.25 mmol) were added. The reaction was refluxed at 90 ° C for 18 hours under a nitrogen atmosphere, then the reaction was allowed to cool and partitioned between ethyl acetate (50 ml) and water (50 ml). The organic layer was dried over magnesium sulfate, filtered and subjected to vacuum to dryness. The resulting brown oil was dissolved in DCM and filtered to remove insoluble material, and then the filtrate was chromatographed on silica, eluting with 0-4% methanol in DCM, to give the desired product as a yellow oil (1.61 g).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,24–1,26 (m, 3H), 2,90 (s, 3H), 3,19–3,26 (m, 1H), 3,47–3,54 (m, 1H), 3,64–3,68 (m, 1H), 3,77–3,80 (m, 1H), 3,99 (d, 1H), 4,17 (s, 1H), 4,49 (s, 3H), 6,67–6,70 (m, 1H), 6,81 (s, 1H), 7,11 (d, 1H), 7,50–7,52 (m, 1H), 7,57–7,58 (m, 1H), 7,96 (s, 1H) NMR Spectrum: 1H NMR (400.13 MHz, DMSO – d6) δ 1.24–1.26 (m, 3H), 2.90 (s, 3H), 3.19–3.26 (m, 1H) , 3.47-3.54 (m, 1H), 3.64-3.68 (m, 1H), 3.77-3.80 (m, 1H), 3.99 (d, 1H), 4 , 17 (s, 1H), 4.49 (s, 3H), 6.67-6.70 (m, 1H), 6.81 (s, 1H), 7.11 (d, 1H), 7, 50–7.52 (m, 1H), 7.57–7.58 (m, 1H), 7.96 (s, 1H)

Espectro LCMS: MH+364, tiempo de retención 0,93 min., Método Ácido 5 min. LCMS spectrum: MH + 364, retention time 0.93 min., Acid Method 5 min.

A continuación se describe la preparación de N–metil–4–[4–[(3S)–3–metilmorfolin–4–il]–6– (metilsulfonilmetil)pirimidin–2–il]anilina. The preparation of N-methyl-4– [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidin-2-yl] aniline is described below.

N–Metil–4–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidin–2–il]anilina N – Methyl – 4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin – 2-yl] aniline

Se disolvió 2–cloro–4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidina (1,01 g, 3,30 mmoles) en 18% de DMF en dimetoxietano:agua:etanol 7:3:2 (7 ml). Se añadieron a la disolución N–metil–4–(4,4,5,5–tetrametil–1,3,2– dioxaborolan–2–il)anilina (1,00 g, 4,29 mmoles), disolución 2M de carbonato de sodio (4 ml) y diclorobis(trifenilfosfina)paladio (116 mg, 0,16 mmoles). La reacción se puso a reflujo a 90ºC durante 3 horas en una atmósfera de nitrógeno, después la mezcla se dejó enfriar y se repartió entre acetato de etilo (30 ml) y agua (30 ml). La capa orgánica se secó sobre sulfato de magnesio, se filtró y se evaporó hasta sequedad. El aceite marrón se disolvió en DCM y se filtró para eliminar el material insoluble, y después el filtrado se cromatografió en sílice, eluyendo con 0–4% de metanol en DCM, para dar el producto deseado como una espuma amarilla (1,12 g, 90%). 2-Chloro-4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine (1.01 g, 3.30 mmol) was dissolved in 18% DMF in dimethoxyethane: water: ethanol 7: 3: 2 (7 ml). N-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (1.00 g, 4.29 mmol), 2M solution of sodium carbonate (4 ml) and dichlorobis (triphenylphosphine) palladium (116 mg, 0.16 mmol). The reaction was refluxed at 90 ° C for 3 hours under a nitrogen atmosphere, then the mixture was allowed to cool and partitioned between ethyl acetate (30 ml) and water (30 ml). The organic layer was dried over magnesium sulfate, filtered and evaporated to dryness. The brown oil was dissolved in DCM and filtered to remove insoluble material, and then the filtrate was chromatographed on silica, eluting with 0-4% methanol in DCM, to give the desired product as a yellow foam (1.12 g , 90%).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,23 (d, 3H), 2,74 (d, 3H), 3,06–3,17 (m, 1H), 3,21 (s, 3H), 3,46– 3,52 (m, 1H), 3,62–3,66 (m, 1H), 3,77 (d, 1H), 3,96–4,00 (m, 1H), 4,14 (d, 1H), 4,44 (s, 2H), 4,46 (s, 1H), 6,14 (q, 1H), 6,57–6,61 (m, 2H), 6,67 (s, 1H), 8,10–8,13 (m, 2H) NMR Spectrum: 1H NMR (400.13 MHz, DMSO – d6) δ 1.23 (d, 3H), 2.74 (d, 3H), 3.06–3.17 (m, 1H), 3.21 (s, 3H), 3.46-3.52 (m, 1H), 3.62-3.66 (m, 1H), 3.77 (d, 1H), 3.96-4.00 (m , 1H), 4.14 (d, 1H), 4.44 (s, 2H), 4.46 (s, 1H), 6.14 (q, 1H), 6.57-6.61 (m, 2H), 6.67 (s, 1H), 8.10–8.13 (m, 2H)

Espectro LCMS: MH+377, tiempo de retención 1,33 min., Método Ácido 5 min. LCMS spectrum: MH + 377, retention time 1.33 min., Acid Method 5 min.

Ejemplo 4: Example 4:

1–Etil–3–[2–fluoro–4–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidin–2–il]fenil]urea 1 – Ethyl – 3– [2 – fluoro – 4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin – 2-yl] phenyl] urea

O OR

N N

NO NO

O OR

S S

F F

N O NO

N N

HH H H

Se disolvió carbonato de bis(triclorometilo) (44 mg, 0,16 mmoles) en DCM (0,25 ml) para dar una disolución incolora. Se disolvió 2–fluoro–4–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidin–2–il]anilina (140 mg, 0,39 mmoles) en DCM (2,0 ml) y piridina (0,2 ml). La disolución resultante se añadió gota a gota a la disolución de carbonato de bis(triclorometilo) a 0ºC, y la mezcla se dejó calentar hasta la temperatura ambiente y después se agitó durante 10 minutos. Se añadió etilamina (2M en THF, 0,5 ml, 1,0 mmoles), y la mezcla se agitó a temperatura ambiente durante 1 hora. Se añadió agua (5 ml), y la capa acuosa se extrajo con DCM (5 ml). Las capas orgánicas combinadas se secaron (MgSO4) y se concentraron a vacío. El aceite bruto se purificó mediante HPLC prep. para dar el material deseado como un sólido blanco (149 mg, 84%). Bis (trichloromethyl) carbonate (44 mg, 0.16 mmol) was dissolved in DCM (0.25 ml) to give a colorless solution. 2-Fluoro-4– [4 - [(3S) -3-methylmorpholin-4-yl] -6– (methylsulfonylmethyl) pyrimidin-2-yl] aniline (140 mg, 0.39 mmol) was dissolved in DCM (2 , 0 ml) and pyridine (0.2 ml). The resulting solution was added dropwise to the bis (trichloromethyl) carbonate solution at 0 ° C, and the mixture was allowed to warm to room temperature and then stirred for 10 minutes. Ethylamine (2M in THF, 0.5 ml, 1.0 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Water (5 ml) was added, and the aqueous layer was extracted with DCM (5 ml). The combined organic layers were dried (MgSO4) and concentrated in vacuo. The crude oil was purified by prep HPLC. to give the desired material as a white solid (149 mg, 84%).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,08 (t, 3H), 1,25 (d, 3H), 3,13–3,18 (m, 2H), 3,20 (s, 3H), 3,22– 3,27 (m, 1H), 3,47–3,53 (m, 1H) 3,63–3,67 (m, 1H), 3,78 (d, 1H), 3,97–4,01 (m, 1H), 4,16–4,20 (m, 1H), 4,49 (m, 3H), 6,68 (t, 1H), 6,81 (s, 1H), 8,01–8,08 (m, 2H), 8,29 (t, 1H), 8,47 (d, 1H) NMR Spectrum: 1H NMR (400.13 MHz, DMSO – d6) δ 1.08 (t, 3H), 1.25 (d, 3H), 3.13–3.18 (m, 2H), 3.20 (s, 3H), 3.22-3.27 (m, 1H), 3.47-3.53 (m, 1H) 3.63-3.67 (m, 1H), 3.78 (d, 1H), 3.97-4.01 (m, 1H), 4.16-4.20 (m, 1H), 4.49 (m, 3H), 6.68 (t, 1H), 6.81 (s, 1H), 8.01–8.08 (m, 2H), 8.29 (t, 1H), 8.47 (d, 1H)

Espectro de masa: Mass spectrum:

Los siguientes compuestos se prepararon de manera análoga usando la anilina y las aminas apropiadas. The following compounds were prepared analogously using the appropriate aniline and amines.

Ejemplo Example: Estructura NOMBRE LCMS MH+ Tiempo de retención (min.) Structure NAME LCMS MH + Retention time (min.)

4a 4th: N N N N S O O O N H OF N–[2–Fluoro–4–[4–[(3S)–3– metilmorfolin–4–il]–6– (metilsulfonilmetil)pirimidin–2– il]fenil]azetidin–1–carboxamida 463 1,61 N N N N S O O O N H OF N– [2 – Fluoro – 4– [4 - [(3S) –3– methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin – 2– yl] phenyl] azetidin – 1-carboxamide 463 1.61

4b 4b: O 3–[2–fluoro–4–[4–[(3S)–3– 465 1,83 OR 3– [2 – fluoro – 4– [4 - [(3S) –3– 465 1.83

: metilmorfolin–4–il]–6– methylmorpholin – 4 – il] –6–

N N: (metilsulfonilmetil)pirimidin–2– (methylsulfonylmethyl) pyrimidin – 2–

N N S O O N H N H OF N N S O O N H N H OF: il]fenil]–1–propan–2–il–urea il] phenyl] –1 – propan – 2 – il – urea

4c 4c: O 3–[2–metoxi–4–[4–[(3S)–3– 450 1,36 OR 3– [2 – methoxy – 4– [4 - [(3S) –3– 450 1.36

: metilmorfolin–4–il]–6– methylmorpholin – 4 – il] –6–

N N: (metilsulfonilmetil)pirimidin–2–il]fenil]– (methylsulfonylmethyl) pyrimidin-2-yl] phenyl] -

N N S O O N H O N HO N N S O O N H O N HO: 1–metil–urea 1-methyl-urea

4d* 4d *: N N N S O O O N H O N H O 1–(2–metoxietil)–3–[4–[4–[(3S)–3– metilmorfolin–4–il]–6– (metilsulfonilmetil)pirimidin–2– il]fenil]urea 464 1,32 N N N S O O O N H O N H O 1– (2 – methoxyethyl) –3– [4– [4 - [(3S) –3– methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin – 2– yl] phenyl] urea 464 1.32

4e* 4e *: N N N S O O O N H O N H O O 1–(2–metoxietil)–3–[2–metoxi–4–[4– [(3S)–3–metilmorfolin–4–il]–6– (metilsulfonilmetil)pirimidin–2– il]fenil]urea 440 1,47 N N N S O O O N H O N H O O 1– (2-methoxyethyl) –3– [2-methoxy-4– [4– [(3S) –3-methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin-2-yl] phenyl] urea 440 1.47

4f* 4f *: O 3–[2–Fluoro–4–[4–[(3S)–3– 495 1,74 OR 3– [2 – Fluoro – 4– [4 - [(3S) –3– 495 1.74

: metilmorfolin–4–il]–6– methylmorpholin – 4 – il] –6–

N N S O O N H O N F O N N S O O N H O N F O: 1–(2–metoxietil)–1–metil–urea 1– (2 – methoxyethyl) –1 – methyl – urea

4g* 4g *: O 3–[2–fluoro–4–[4–[(3S)–3– 482 1,87 OR 3– [2 – fluoro – 4– [4 - [(3S) –3– 482 1.87

: metilmorfolin–4–il]–6– methylmorpholin – 4 – il] –6–

N N S O O N H O N H O F N N S O O N H O N H O F: 1–(2–metoxietil)urea 1– (2-methoxyethyl) urea

* Cromatografiado en sílice, eluyendo con 0–5% de metanol en DCM * Chromatographed on silica, eluting with 0–5% methanol in DCM

Ejemplo 4a: RMN 1H (400,13 MHz, DMSO–d6) δ 1,25 (d, 3H), 2,16–2,24 (m, 2H), 3,20 (s, 3H), 3,23–3,26 (m, 1H), 3,47–3,54 (m, 1H), 3,63–3,67 (m, 1H), 3,78 (d, 1H), 4,00 (t, 5H), 4,19 (d, 1H), 4,50 (s, 3H), 6,84 (s, 1H), 7,83–7,87 (m, 1H, 8,04 (d, 1H6), 8,08–8,10 (m, 1H), 8,18 (s, 1H) Example 4a: 1H NMR (400.13 MHz, DMSO-d6) δ 1.25 (d, 3H), 2.16-2.24 (m, 2H), 3.20 (s, 3H), 3.23 –3.26 (m, 1H), 3.47-3.54 (m, 1H), 3.63-3.67 (m, 1H), 3.78 (d, 1H), 4.00 (t , 5H), 4.19 (d, 1H), 4.50 (s, 3H), 6.84 (s, 1H), 7.83-7.87 (m, 1H, 8.04 (d, 1H6) ), 8.08–8.10 (m, 1H), 8.18 (s, 1H)

Ejemplo 4b: RMN 1H (400,13 MHz, DMSO–d6) δ 1,12 (d, 6H), 1,25 (d, 3H), 3,20 (s, 3H), 3,24 (d, 1H), 3,47–3,53 (m, 1H), 3,63–3,67 (m, 1H), 3,74–3,82 (m, 2H), 3,97–4,01 (m, 1H), 4,18 (d, 1H), 4,49 (s, 3H), 6,63 (d, 1H), 6,81 (s, 1H), 8,01–8,08 (m, 2H), 8,29 (t, 1H), 8,37 (d, 1H) Example 4b: 1H NMR (400.13 MHz, DMSO-d6) δ 1.12 (d, 6H), 1.25 (d, 3H), 3.20 (s, 3H), 3.24 (d, 1H ), 3.47-3.53 (m, 1H), 3.63-3.67 (m, 1H), 3.74-3.82 (m, 2H), 3.97-4.01 (m , 1H), 4.18 (d, 1H), 4.49 (s, 3H), 6.63 (d, 1H), 6.81 (s, 1H), 8.01–8.08 (m, 2H), 8.29 (t, 1H), 8.37 (d, 1H)

Ejemplo 4c: RMN 1H (399,9 MHz, DMSO–d6) δ 1,25–1,26 (m, 3H), 2,66–2,67 (m, 3H), 3,18 (d, 1H), 3,23 (s, 3H), 3,48–3,55 (m, 1H), 3,65–3,68 (m, 1H), 3,79 (d, 1H), 3,92 (s, 3H), 3,98–4,02 (m, 1H) 4,19 (s, 1H), 4,50 (s, 2H), 6,79 (s, H.), 6,85 (d, 1H), 7,90 (s, 1H), 8,11 (s, 1H), 8,22–8,24 (m, 1H) Example 4c: 1H NMR (399.9 MHz, DMSO-d6) δ 1.25-1.26 (m, 3H), 2.66-2.67 (m, 3H), 3.18 (d, 1H) , 3.23 (s, 3H), 3.48-3.55 (m, 1H), 3.65-3.68 (m, 1H), 3.79 (d, 1H), 3.92 (s , 3H), 3.98-4.02 (m, 1H) 4.19 (s, 1H), 4.50 (s, 2H), 6.79 (s, H.), 6.85 (d, 1H), 7.90 (s, 1H), 8.11 (s, 1H), 8.22–8.24 (m, 1H)

Ejemplo 4d: RMN 1H (400,13 MHz, DMSO–d6) δ 1,24 (d, 3H), 3,19–3,24 (m, 2H), 3,21 (s, 3H), 3,27 (s, 3H), 3,40 (t, 2H), 3,47–3,53 (m, 1H), 3,63–3,67 (m, 1H), 3,78 (d, 1H), 3,97–4,01 (m, 1H), 4,17 (s, 1H), 4,49 (s, 3H), 6,27 (t, 1H), 6,77 (s, 1H), 7,47–7,51 (m, 2H), 8,19–8,23 (m, 2H), 8,78 (s, 1H) Example 4d: 1H NMR (400.13 MHz, DMSO-d6) δ 1.24 (d, 3H), 3.19-3.24 (m, 2H), 3.21 (s, 3H), 3.27 (s, 3H), 3.40 (t, 2H), 3.47-3.53 (m, 1H), 3.63-3.67 (m, 1H), 3.78 (d, 1H), 3.97-4.01 (m, 1H), 4.17 (s, 1H), 4.49 (s, 3H), 6.27 (t, 1H), 6.77 (s, 1H), 7 , 47–7.51 (m, 2H), 8.19–8.23 (m, 2H), 8.78 (s, 1H)

Ejemplo 4e: RMN 1H (399,9 MHz, DMSO–d6) δ 1,25–1,26 (m, 3H), 3,23 (s, 3H), 3,27 (s, 1H), 3,28–3,21 (m, 2H), 3,38–3,40 (m, 2H), 3,51 (d, 1H), 3,66 (d, 1H), 3,77 (s, 1H), 3,92 (s, 3H), 4,00 (d, 1H), 4,17–4,21 (m, 1H), 4,50 (s, 3H), 6,79 (s, 1H), 7,12 (s, 1H), 7,88–7,90 (m, 2H), 8,22–8,24 (m, 1H), 8,26 (1s, H) Example 4e: 1H NMR (399.9 MHz, DMSO-d6) δ 1.25-1.26 (m, 3H), 3.23 (s, 3H), 3.27 (s, 1H), 3.28 –3.21 (m, 2H), 3.38-3.40 (m, 2H), 3.51 (d, 1H), 3.66 (d, 1H), 3.77 (s, 1H), 3.92 (s, 3H), 4.00 (d, 1H), 4.17-4.21 (m, 1H), 4.50 (s, 3H), 6.79 (s, 1H), 7 , 12 (s, 1H), 7.88–7.90 (m, 2H), 8.22–8.24 (m, 1H), 8.26 (1s, H)

Ejemplo 4f: RMN 1H (400,13 MHz, DMSO–d6) δ 1,24–1,26 (m, 3H.), 2,97 (s, 3H), 3,20 (s, 3H), 3,23–3,26 (m, 1H), 3,47–3,56 (m, 5H), 3,64–3,67 (m, 1H), 3,78 (d, 1H), 3,97–4,01 (m, 1H), 4,17–4,21 (m, 1H), 4,50 (s, 3H), 6,84 (s, 1H), 7,82 (t, 1H), 8,02–8,10 (m, 2H), 8,41 (s, 1H) Example 4f: 1H NMR (400.13 MHz, DMSO-d6) δ 1.24-1.26 (m, 3H.), 2.97 (s, 3H), 3.20 (s, 3H), 3, 23-3.26 (m, 1H), 3.47-3.56 (m, 5H), 3.64-3.67 (m, 1H), 3.78 (d, 1H), 3.97– 4.01 (m, 1H), 4.17-4.21 (m, 1H), 4.50 (s, 3H), 6.84 (s, 1H), 7.82 (t, 1H), 8 , 02–8.10 (m, 2H), 8.41 (s, 1H)

Ejemplo 4g: RMN 1H (399,9 MHz, DMSO–d6) δ 1,25 (d, 3H), 3,20 (s, 3H), 3,23 (m, 1H), 3,29 (m, 2H), 3,30 (s, 3H), 3,41 (t, 2H), 3,51 (d, 1H), 3,65 (d, 1H), 3,78 (d, 1H), 3,97–4,01 (m, 1H), 4,19 (d, 1H), 4,50 (s, 3H), 6,82 (s, 1H), 6,87 (t, 1H), 8,02–8,09 (m, 2H), 8,29 (t, 1H), 8,63 (d, 1H) Example 4g: 1H NMR (399.9 MHz, DMSO-d6) δ 1.25 (d, 3H), 3.20 (s, 3H), 3.23 (m, 1H), 3.29 (m, 2H ), 3.30 (s, 3H), 3.41 (t, 2H), 3.51 (d, 1H), 3.65 (d, 1H), 3.78 (d, 1H), 3.97 –4.01 (m, 1H), 4.19 (d, 1H), 4.50 (s, 3H), 6.82 (s, 1H), 6.87 (t, 1H), 8.02– 8.09 (m, 2H), 8.29 (t, 1H), 8.63 (d, 1H)

Prueba (a): Ejemplo (4) 0,031 μM; Ejemplo (4a) 1 μM; Ejemplo (4b) 0,14 μM; Ejemplo (4c) 0,8 μM; Ejemplo (4d) 0,17 μM; Ejemplo (4e) 0,6 μM; Ejemplo (4f) 0,68 μM; Ejemplo (4g) 0,83 μM. Test (a): Example (4) 0.031 μM; Example (4a) 1 μM; Example (4b) 0.14 μM; Example (4c) 0.8 μM; Example (4d) 0.17 μM; Example (4e) 0.6 μM; Example (4f) 0.68 μM; Example (4g) 0.83 μM.

Ejemplo 5: Example 5:

1–Etil–3–[4–[4–(Hidroximetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]urea 1 – Ethyl – 3– [4– [4– (Hydroxymethyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin – 2-yl] phenyl] urea

Se disolvió 1–[4–[4–[(dimetil–terc–butil–silil)oximetil]–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]–3–etil–urea (104 mg) en THF (10 ml), y se añadió TBAF (disolución 1,0 M, 0,22 ml). La reacción se dejó agitar durante 1 hora a temperatura ambiente y después se pasó por una columna SCX–2. La columna se lavó con metanol, y el material deseado se eluyó con amoniaco 7N en metanol. Las fracciones se concentraron a vacío para dar el compuesto deseado (76 mg) como un sólido blanco. 1– [4– [4 - [(dimethyl-tert-butyl-silyl) oxymethyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] -3-ethyl was dissolved -Urea (104 mg) in THF (10 ml), and TBAF (1.0 M solution, 0.22 ml) was added. The reaction was allowed to stir for 1 hour at room temperature and then passed through a SCX-2 column. The column was washed with methanol, and the desired material was eluted with 7N ammonia in methanol. The fractions were concentrated in vacuo to give the desired compound (76 mg) as a white solid.

Espectro RMN: RMN 1H (399,9 MHz, DMSO–d6) δ 1,07 (3H, t), 1,23 (3H, d), 3,11–3,16 (2H, m), 3,19–3,23 (1H, m), 3,49 (1H, d), 3,62–3,66 (1H, m), 3,77 (1H, d), 3,95–3,99 (1H, m), 4,16 (1H, d), 4,45 (2H, d), 4,48 (1H, s), 5,38 (1H, s), 6,14 (1H, t), 6,66 (1H, s), 7,46 (2H, d), 8,19 (2H, d), 8,62 (1H, s) NMR Spectrum: 1H NMR (399.9 MHz, DMSO-d6) δ 1.07 (3H, t), 1.23 (3H, d), 3.11-3.16 (2H, m), 3.19 –3.23 (1H, m), 3.49 (1H, d), 3.62-3.66 (1H, m), 3.77 (1H, d), 3.95–3.99 (1H , m), 4.16 (1H, d), 4.45 (2H, d), 4.48 (1H, s), 5.38 (1H, s), 6.14 (1H, t), 6 , 66 (1H, s), 7.46 (2H, d), 8.19 (2H, d), 8.62 (1H, s)

Espectro de masa: M+H+ 372. Mass spectrum: M + H + 372.

Prueba (a): 0,063 μM. Test (a): 0.063 μM.

A continuación se describe la preparación de 1–[4–[4–[(dimetil–terc–butil–silil)oximetil]–6–[(3S)–3–metilmorfolin–4– il]pirimidin–2–il]fenil]–3–etil–urea. The preparation of 1– [4– [4 - [(dimethyl-tert-butyl-silyl) oxymethyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl is described below. ] –3 – ethyl – urea.

1–[4–[4–[(Dimetil–terc–butil–silil)oximetil]–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]–3–etil–urea 1– [4– [4 - [(Dimethyl-tert-butyl-silyl) oxymethyl] –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] –3-ethyl-urea

O OR

N N

N O Si No Yes

O OR

N N

N HH N HH

N N

Se disolvió 4–[4–[(dimetil–terc–butil–silil)oximetil]–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]anilina (250 mg) en 1,4–dioxano (4 ml), y se añadió isocianato de etilo (0,144 ml). La reacción se calentó hasta 120ºC durante 1 hora en un reactor de microondas. La reacción se concentró a vacío, y después el residuo se cromatografió en sílice, eluyendo con 2,5% de metanol en DCM, para dar el compuesto deseado (106 mg) como un sólido blanco. 4– [4 - [(dimethyl-tert-butyl-silyl) oxymethyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-2-yl] aniline (250 mg) was dissolved in 1.4 -Dioxane (4 ml), and ethyl isocyanate (0.144 ml) was added. The reaction was heated to 120 ° C for 1 hour in a microwave reactor. The reaction was concentrated in vacuo, and then the residue was chromatographed on silica, eluting with 2.5% methanol in DCM, to give the desired compound (106 mg) as a white solid.

Espectro de masa: M+H+ 486. Mass spectrum: M + H + 486.

4–[4–[(Dimetil–terc–butil–silil)oximetil]–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]anilina 4– [4 - [(Dimethyl-tert-butyl-silyl) oxymethyl] –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin – 2-yl] aniline

Se disolvió [2–(4–aminofenil)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–4–il]metanol (1,54 g) en DCM (60 ml) y se [2– (4-Aminophenyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-4-yl] methanol (1.54 g) was dissolved in DCM (60 ml) and dissolved.

10 añadieron cloruro de terc–butildimetilsililo (928 mg) e imidazol. La mezcla se agitó a temperatura ambiente durante 0,5 horas antes de filtrarla, y se concentró a vacío. El residuo se cromatografió en sílice, eluyendo con 1% de metanol en DCM, para dar el compuesto deseado (1,61 g) como un sólido blanco. 10 added tert-butyldimethylsilyl chloride (928 mg) and imidazole. The mixture was stirred at room temperature for 0.5 hours before filtering, and concentrated in vacuo. The residue was chromatographed on silica, eluting with 1% methanol in DCM, to give the desired compound (1.61 g) as a white solid.

Espectro RMN: RMN 1H (399,9 MHz, DMSO–d6) δ 0,12–0,13 (6H, m), 0,94–0,95 (9H, m), 1,21 (3H, d), 3,13–3,20 (1H, m), 3,46–3,52 (1H, m), 3,62–3,66 (1H, m), 3,77 (1H, d), 3,96–3,99 (1H, m), 4,13 (1H, d), 4,37–4,39 (1H, m), NMR Spectrum: 1H NMR (399.9 MHz, DMSO – d6) δ 0.12–0.13 (6H, m), 0.94–0.95 (9H, m), 1.21 (3H, d) , 3.13-3.20 (1H, m), 3.46-3.52 (1H, m), 3.62-3.66 (1H, m), 3.77 (1H, d), 3 , 96–3.99 (1H, m), 4.13 (1H, d), 4.37–4.39 (1H, m),

15 4,60 (2H, s), 5,48 (2H, d), 6,50 (1H, s), 6,57–6,59 (2H, m), 8,02–8,04 (2H, m) 15 4.60 (2H, s), 5.48 (2H, d), 6.50 (1H, s), 6.57–6.59 (2H, m), 8.02–8.04 (2H m)

Espectro de masa: M+H+ 415. Mass spectrum: M + H + 415.

[2–(4–Aminofenil)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–4–il]metanol [2– (4 – Aminophenyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin – 4-yl] methanol

Se disolvió N–[4–[4–(hidroximetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]carbamato de terc–butilo (1,20 g) N- [4– [4– (hydroxymethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] tert-butyl carbamate (1.20 g) was dissolved

20 en cloruro de hidrógeno 4M en dioxano (5 ml) y dioxano (5 ml). La reacción se agitó durante 18 horas, y después se añadió DCM (10 ml) para ayudar a solubilizar el material. La reacción se agitó a 40ºC durante unas 18 horas adicionales, y después se evaporó hasta sequedad. El sólido se suspendió en DCM (20 ml), y se añadió una mezcla de una disolución acuosa saturada de hidrogenocarbonato de sodio (6 ml) y agua (4 ml). Los productos orgánicos se separaron, se secaron (MgSO4) y se concentraron a vacío para dar el compuesto deseado (648 mg) como un sólido 20 in 4M hydrogen chloride in dioxane (5 ml) and dioxane (5 ml). The reaction was stirred for 18 hours, and then DCM (10 ml) was added to help solubilize the material. The reaction was stirred at 40 ° C for an additional 18 hours, and then evaporated to dryness. The solid was suspended in DCM (20 ml), and a mixture of a saturated aqueous solution of sodium hydrogen carbonate (6 ml) and water (4 ml) was added. The organic products were separated, dried (MgSO4) and concentrated in vacuo to give the desired compound (648 mg) as a solid.

25 amarillo pálido. 25 pale yellow.

Espectro RMN: RMN 1H (399,9 MHz, DMSO–d6) δ 1,21 (3H, d), 3,16 (1H, d), 3,48 (1H, d), 3,61–3,65 (1H, m), 3,75 (1H, d), 3,95 (1H, d), 4,13 (1H, d), 4,41 (2H, d), 4,45 (1H, s), 5,32 (1H, t), 5,47 (2H, s), 6,57–6,59 (3H, m), 8,02–8,04 (2H, m) NMR Spectrum: 1H NMR (399.9 MHz, DMSO – d6) δ 1.21 (3H, d), 3.16 (1H, d), 3.48 (1H, d), 3.61–3.65 (1H, m), 3.75 (1H, d), 3.95 (1H, d), 4.13 (1H, d), 4.41 (2H, d), 4.45 (1H, s) , 5.32 (1H, t), 5.47 (2H, s), 6.57–6.59 (3H, m), 8.02–8.04 (2H, m)

Espectro de masa: M+H+ 301. Mass spectrum: M + H + 301.

30 N–[4–[4–(hidroximetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]carbamato de terc–butilo 30 N– [4– [4– (hydroxymethyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] tert-butyl carbamate

Se desgasificaron una mezcla de [2–cloro–6–[(3S)–3–metilmorfolin–4–il]pirimidin–4–il]metanol (2,44 g), ácido (4– Boc–aminofenil)borónico (4,76 g), disolución 2M de carbonato de sodio (10 ml) y una mezcla de disolventes (18% de DMF en DME:agua:etanol 7:3:2) (35 ml). Se añadió diclorobis(trifenilfosfina)paladio (300 mg), y la reacción se calentó a 80ºC durante 3 horas. La reacción se dejó enfriar y se concentró a vacío. El residuo se repartió entre acetato de etilo (200 ml) y agua (200 ml), los productos orgánicos se lavaron con salmuera (100 ml) y se secaron (MgSO4). El material bruto se cromatografió en sílice, eluyendo con 2,5% de metanol en DCM, para dar el compuesto deseado (4,00 g) como un sólido blanco. A mixture of [2-chloro-6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-4-yl] methanol (2.44 g), boronic acid (4-Boc-aminophenyl) (4) , 76 g), 2M solution of sodium carbonate (10 ml) and a mixture of solvents (18% DMF in DME: water: ethanol 7: 3: 2) (35 ml). Dichlorobis (triphenylphosphine) palladium (300 mg) was added, and the reaction was heated at 80 ° C for 3 hours. The reaction was allowed to cool and concentrated in vacuo. The residue was partitioned between ethyl acetate (200 ml) and water (200 ml), the organic products were washed with brine (100 ml) and dried (MgSO4). The crude material was chromatographed on silica, eluting with 2.5% methanol in DCM, to give the desired compound (4.00 g) as a white solid.

Espectro de masa: M+H+ 401. Mass spectrum: M + H + 401.

[2–Cloro–6–[(3S)–3–metilmorfolin–4–il]pirimidin–4–il]metanol [2 – Chloro – 6 - [(3S) –3 – methylmorpholin-4-yl] pyrimidin – 4-yl] methanol

Se disolvió 2–cloro–6–[(3S)–3–metilmorfolin–4–il]pirimidin–4–carboxilato de metilo (3,15 g) en THF seco (20 ml) y se enfrió hasta 0ºC en nitrógeno. A esto se añadió gota a gota una disolución de borohidruro de litio (2,0M en THF, 6,09 ml). La disolución se dejó calentar hasta la temperatura ambiente y se agitó durante 1 hora. La reacción se paralizó con agua (20 ml), y después se evaporó hasta sequedad. El residuo se disolvió en acetato de etilo (150 ml) y se lavó con agua (150 ml) seguido por salmuera (50 ml). Los productos orgánicos se concentraron a vacío para dar el compuesto deseado (2,44 g) como un sólido blanco. Methyl 2-chloro-6 - [(3S) -3-methylmorpholin-4-yl] methyl pyrimidin-4-carboxylate (3.15 g) was dissolved in dry THF (20 ml) and cooled to 0 ° C under nitrogen. To this was added dropwise a solution of lithium borohydride (2.0M in THF, 6.09 ml). The solution was allowed to warm to room temperature and stirred for 1 hour. The reaction was paralyzed with water (20 ml), and then evaporated to dryness. The residue was dissolved in ethyl acetate (150 ml) and washed with water (150 ml) followed by brine (50 ml). The organic products were concentrated in vacuo to give the desired compound (2.44 g) as a white solid.

Espectro RMN: RMN 1H (399,9 MHz, DMSO–d6) δ 1,20–1,21 (3H, m), 3,18–3,22 (1H, m), 3,40–3,47 (1H, m), 3,56– 3,60 (1H, m), 3,71 (1H, d), 3,91–3,94 (1H, m), 3,98 (1H, d), 4,35 (3H, d), 5,51 (1H, t), 6,74 (1H, s) NMR Spectrum: 1H NMR (399.9 MHz, DMSO – d6) δ 1.20–1.21 (3H, m), 3.18–3.22 (1H, m), 3.40–3.47 ( 1H, m), 3.56– 3.60 (1H, m), 3.71 (1H, d), 3.91–3.94 (1H, m), 3.98 (1H, d), 4 , 35 (3H, d), 5.51 (1H, t), 6.74 (1H, s)

Espectro de masa: M+H+ 244. Mass spectrum: M + H + 244.

2–Cloro–6–[(3S)–3–metilmorfolin–4–il]pirimidin–4–carboxilato de metilo 2-Chloro-6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-4-methyl carboxylate

O OR

Se disolvió 2,6–dicloropirimidin–4–carboxilato de metilo (5,00 g) en DCM (120 ml). Se disolvió (3S)–3–metilmorfolina (2,49 g) en trietilamina (3,70 ml), y se añadió gota a gota DCM (10 ml) a la disolución durante 10 minutos. La reacción se dejó agitar a temperatura ambiente durante 1 hora, después la mezcla se concentró a vacío y se disolvió en DCM (300 ml). Los productos orgánicos se lavaron con agua (150 ml) y se secaron (MgSO4). El material bruto se cromatografió en sílice, eluyendo con 2,5% de metanol en DCM, para dar el compuesto deseado (3,15 g) como un sólido blanco. Methyl 2,6-dichloropyrimidin-4-carboxylate (5.00 g) was dissolved in DCM (120 ml). (3 S) -3-methylmorpholine (2.49 g) was dissolved in triethylamine (3.70 ml), and DCM (10 ml) was added dropwise to the solution for 10 minutes. The reaction was allowed to stir at room temperature for 1 hour, then the mixture was concentrated in vacuo and dissolved in DCM (300 ml). The organic products were washed with water (150 ml) and dried (MgSO4). The crude material was chromatographed on silica, eluting with 2.5% methanol in DCM, to give the desired compound (3.15 g) as a white solid.

Espectro RMN: RMN 1H (399,9 MHz, DMSO–d6) δ 1,22–1,24 (3H, m), 3,25 (1H, d), 3,41–3,48 (1H, m), 3,57–3,61 (1H, m), 3,71 (1H, d), 3,87 (3H, s), 3,91–3,95 (1H, m), 4,25 (1H, s), 4,45 (1H, s), 7,29 (1H, s) NMR Spectrum: 1H NMR (399.9 MHz, DMSO – d6) δ 1.22–1.24 (3H, m), 3.25 (1H, d), 3.41–3.48 (1H, m) , 3.57-3.61 (1H, m), 3.71 (1H, d), 3.87 (3H, s), 3.91-3.95 (1H, m), 4.25 (1H , s), 4.45 (1H, s), 7.29 (1H, s)

Espectro de masa: M+H+ 272. Mass spectrum: M + H + 272.

Ejemplo 6: Example 6:

1– [4– [4– (Hydroxymethyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] –3-phenyl-urea

Se disolvieron 1–(4–bromo–fenil)–3–fenil–urea (960 mg), acetato de potasio (969 mg), bis(pinacolato)diboro (1,01 g) en 1,4 dioxano (50 ml). La disolución se desgasificó durante 5 minutos, después se añadió aducto de 1,1’– bis(difenilfosfino)ferrocenodicloropaladio(II) diclorometano (162 mg), y la reacción se calentó hasta 80ºC durante 3 5 horas. Se añadió Mmás aducto de 1,1’–bis(difenilfosfino)ferrocenodicloropaladio(II) diclorometano (162 mg), y la reacción se agitó a 80ºC durante otras 3 horas. Se añadieron [2–cloro–6–[(3S)–3–metilmorfolin–4–il]pirimidin–4– il]metanol (803 mg), etanol (3,75 ml), disolución 2M de carbonato de sodio (6,9 ml) y aducto 1,1’– bis(difenilfosfino)ferrocenodicloropaladio(II) diclorometano (162 mg), y el calentamiento se continuó durante 16 horas. Se añadieron más etanol (5 ml) y aducto de 1,1’–bis(difenilfosfino)ferrocenodicloropaladio(II) diclorometano 1– (4-Bromo-phenyl) -3-phenyl-urea (960 mg), potassium acetate (969 mg), bis (pinacolato) diboro (1.01 g) were dissolved in 1.4 dioxane (50 ml) . The solution was degassed for 5 minutes, then 1,1'-bis (diphenylphosphino) ferrocenodichloropaladium (II) dichloromethane adduct (162 mg) was added, and the reaction was heated to 80 ° C for 3-5 hours. Mmore adduct of 1,1'-bis (diphenylphosphino) ferrocenodichloropaladium (II) dichloromethane (162 mg) was added, and the reaction was stirred at 80 ° C for another 3 hours. [2-Chloro-6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-4-yl] methanol (803 mg), ethanol (3.75 ml), 2M solution of sodium carbonate (6 , 9 ml) and 1,1'– bis (diphenylphosphino) ferrocenodichloropaladium (II) dichloromethane (162 mg) adduct, and heating was continued for 16 hours. More ethanol (5 ml) and 1,1'-bis (diphenylphosphino) ferrocenodichloropaladium (II) dichloromethane adduct were added

10 (162 mg), y la reacción se dejó agitar durante otras 5 horas antes de dejarla enfriar y neutralizarla con ácido clorhídrico 2M. La mezcla de reacción se pasó a través de tres columnas SCX–2, cada vez cargando la muestra y lavando con metanol, y después eliminando el material deseado con amoniaco 7N en metanol. La disolución se concentró a vacío, y el residuo se cromatografió en sílice, eluyendo con 5% de metanol en DCM, para dar el material deseado (398 mg) como un sólido blanco. 10 (162 mg), and the reaction was allowed to stir for another 5 hours before allowing to cool and neutralize with 2M hydrochloric acid. The reaction mixture was passed through three SCX-2 columns, each time loading the sample and washing with methanol, and then removing the desired material with 7N ammonia in methanol. The solution was concentrated in vacuo, and the residue was chromatographed on silica, eluting with 5% methanol in DCM, to give the desired material (398 mg) as a white solid.

15 Espectro RMN: RMN 1H (DMSO–d6) δ 1,24 (3H, d), 3,20–3,24 (1H, m), 3,47–3,53 (1H, m), 3,63–3,67 (1H, m), 3,77 (1H, d), 3,96–4,00 (1H, m), 4,18 (1H, d), 4,47 (2H, d), 4,50 (1H, s), 5,39 (1H, t), 6,68 (1H, s), 6,97–7,01 (1H, m), 7,28–7,31 (1H, m), 7,30 (1H, s), 7,46–7,48 (2H, m), 7,52–7,56 (2H, m), 8,25–8,27 (2H, m), 8,68 (1H, s), 8,87 (1H, s) 15 NMR Spectrum: 1H NMR (DMSO – d6) δ 1.24 (3H, d), 3.20-3.24 (1H, m), 3.47-3.53 (1H, m), 3.63 –3.67 (1H, m), 3.77 (1H, d), 3.96-4.00 (1H, m), 4.18 (1H, d), 4.47 (2H, d), 4.50 (1H, s), 5.39 (1H, t), 6.68 (1H, s), 6.97–7.01 (1H, m), 7.28–7.31 (1H, m), 7.30 (1H, s), 7.46–7.48 (2H, m), 7.52–7.56 (2H, m), 8.25–8.27 (2H, m) , 8.68 (1H, s), 8.87 (1H, s)

Espectro de masa: M+H+ 419. Mass spectrum: M + H + 419.

Prueba (a): 0,56 μM. Test (a): 0.56 μM.

20 La preparación de [2–cloro–6–[(3S)–3–metilmorfolin–4–il]pirimidin–4–il]metanol se describió anteriormente. The preparation of [2-chloro-6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-4-yl] methanol was described above.

Ejemplo 7: Example 7:

3–[4–[4–(Metilsulfonilmetil)–6–morfolin–4–il–pirimidin–2–il]fenil]–1–propan–2–il–urea 3– [4– [4– (Methylsulfonylmethyl) –6-morpholin-4-yl-pyrimidin-2-yl] phenyl] –1-propan – 2-yl-urea

O OR

N N

N S N S

OO OO

N N

O OR

N N

N HH N HH

Se calentaron 4–[4–(metilsulfonilmetil)–6–morfolin–4–il–pirimidin–2–il]anilina (70 mg, 0,2 mmoles) e isocianato de 4– [4– (Methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] aniline (70 mg, 0.2 mmol) and isocyanate of

25 isopropilo (0,1 ml, 1 mmol) en dioxano (2 ml) a 70ºC durante 4 horas. La mezcla de reacción se evaporó, y el residuo Triturada con acetato de etilo. La suspensión se filtró, y el sólido blanco se lavó con acetato de etilo y éter dietílico, y después se secó a vacío a 60ºC toda la noche para producir el compuesto del título (38 mg). Isopropyl (0.1 ml, 1 mmol) in dioxane (2 ml) at 70 ° C for 4 hours. The reaction mixture was evaporated, and the residue triturated with ethyl acetate. The suspension was filtered, and the white solid was washed with ethyl acetate and diethyl ether, and then dried in vacuo at 60 ° C overnight to yield the title compound (38 mg).

Espectro LCMS: MH+ 434, Tiempo de retención 1,66 min., Método: Básico Monitor LCMS spectrum: MH + 434, Retention time 1.66 min., Method: Basic Monitor

Espectro RMN: RMN 1H (399,9 MHz, DMSO–d6) δ 1,11 (d, 6H), 3,2 (s, 3H), 3,7 (m, 8H), 3,76 (m, 1H), 4,48 (s, 2H), 30 6,05 (d, 1H), 6,8 (s, 1H), 7,48 (d, 2H), 8,2 (d, 2H), 8,54 (s, 1H) NMR Spectrum: 1H NMR (399.9 MHz, DMSO-d6) δ 1.11 (d, 6H), 3.2 (s, 3H), 3.7 (m, 8H), 3.76 (m, 1H ), 4.48 (s, 2H), 30 6.05 (d, 1H), 6.8 (s, 1H), 7.48 (d, 2H), 8.2 (d, 2H), 8, 54 (s, 1H)

Los siguientes compuestos se prepararon de manera análoga a partir de XXX usando el isocianato apropiado. The following compounds were prepared analogously from XXX using the appropriate isocyanate.

7a 7a: O 1–(4–metilfenil)–3–[4–[4– 482,03 2,15 OR 1– (4 – methylphenyl) –3– [4– [4– 482.03 2.15

N N N S O O N H N H O N N N S O O N H N H O: (metilsulfonilmetil)–6–morfolin–4–il– pirimidin–2–il]fenil]urea (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] phenyl] urea

7b 7b: O 3–(4–clorofenil)–1–[4–[4– 501,95 2,26 OR 3– (4 – chlorophenyl) –1– [4– [4– 501.95 2.26

N N N S O O N H N H O Cl N N N S O O N H N H O Cl: (metilsulfonilmetil)–6–morfolin–4–il– pirimidin–2–il]fenil]urea (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] phenyl] urea

7c 7c: O 1–[4–[4–(metilsulfonilmetil)–6– 536,00 2,39 OR 1– [4– [4– (methylsulfonylmethyl) –6– 536.00 2.39

N N N S O O N H N H O CF3 N N N S O O N H N H O CF3: morfolin–4–il–pirimidin–2–il]fenil]–3– [4–(trifluorometil)fenil]urea morpholin-4-yl-pyrimidin-2-yl] phenyl] –3– [4– (trifluoromethyl) phenyl] urea

7d 7d: O 1–(3,5–dimetilfenil)–3–[4–[4– 496,05 2,29 OR 1– (3,5 – dimethylphenyl) –3– [4– [4– 496.05 2.29

7e 7e: O 3–[2–(difluorometoxi)fenil]–1–[4–[4– 533,97 2,25 OR 3– [2– (difluoromethoxy) phenyl] –1– [4– [4– 533.97 2.25

: (metilsulfonilmetil)–6–morfolin–4–il– (methylsulfonylmethyl) –6 – morpholin-4-yl–

N N N S O O N H N H O O F F N N N S O O N H N H O O F F: pirimidin–2–il]fenil]urea pyrimidin – 2-yl] phenyl] urea

7f 7f: O 3–(4–fluorofenil)–1–[4–[4– 485,97 2,07 OR 3– (4 – fluorophenyl) –1– [4– [4– 485.97 2.07

N N N S O O N H N H O F N N N S O O N H N H O F: (metilsulfonilmetil)–6–morfolin–4–il– pirimidin–2–il]fenil]urea (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] phenyl] urea

7g 7g: O 3–(3–cloro–4–fluoro–fenil)–1–[4–[4– 519,96 2,29 OR 3– (3 – chloro – 4 – fluoro – phenyl) –1– [4– [4– 519.96 2.29

N N N S O O N H N H O F Cl N N N S O O N H N H O F Cl: (metilsulfonilmetil)–6–morfolin–4–il– pirimidin–2–il]fenil]urea (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] phenyl] urea

7h* 7h *: N N N O S O O N H N H O 1–[4–[4–(metilsulfonilmetil)–6– morfolin–4–il–pirimidin–2–il]fenil]–3– fenil–urea 468,56 3,00 N N N O S O O N H N H O 1– [4– [4– (methylsulfonylmethyl) –6– morpholin-4-yl-pyrimidin-2-yl] phenyl] –3– phenyl-urea 468.56 3.00

7i* 7i *: O 1–(4–metoxifenil)–3–[4–[4– 498,60 2,93 OR 1– (4 – methoxyphenyl) –3– [4– [4– 498.60 2.93

N N: (metilsulfonilmetil)–6–morfolin–4–il– (methylsulfonylmethyl) –6 – morpholin-4-yl–

N N S O O N H N H O OMe N N S O O N H N H O OMe: pirimidin–2–il]fenil]urea pyrimidin – 2-yl] phenyl] urea

7j* 7j *: N N N O S O O N H N H O 3–[4–[4–(metilsulfonilmetil)–6– morfolin–4–il–pirimidin–2–il]fenil]–1– pentil–urea 462,64 3,02 N N N O S O O N H N H O 3– [4– [4– (methylsulfonylmethyl) –6– morpholin-4-yl-pyrimidin-2-yl] phenyl] –1– pentyl-urea 462.64 3.02

7k* 7k *: O 3–(3,4–difluorofenil)–1–[4–[4– 504,59 OR 3– (3,4 – difluorophenyl) –1– [4– [4– 504.59

N N N S O O N H N H O F F N N N S O O N H N H O F F: (metilsulfonilmetil)–6–morfolin–4–il– pirimidin–2–il]fenil]urea (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] phenyl] urea

7l* 7l *: O 3–ciclohexil–1–[4–[4– 474,63 3,02 OR 3 – cyclohexyl – 1– [4– [4– 474.63 3.02

N N N S O O N H N H O N N N S O O N H N H O: pirimidin–2–il]fenil]urea pyrimidin – 2-yl] phenyl] urea

7m* 7m *: N N N O S O O N H N H O 1–etil–3–[4–[4–(metilsulfonilmetil)– 6–morfolin–4–il–pirimidin–2– il]fenil]urea 420,60 2,49 N N N O S O O N H N H O 1-ethyl-3– [4– [4– (methylsulfonylmethyl) - 6-morpholin-4-yl-pyrimidin-2-yl] phenyl] urea 420.60 2.49

7n* 7n *: N N N O S O O N H N H O 3–[4–[4–(metilsulfonilmetil)–6– morfolin–4–il–pirimidin–2–il]fenil]–1– propil–urea 434,61 2,66 N N N O S O O N H N H O 3– [4– [4– (methylsulfonylmethyl) –6– morpholin-4-yl-pyrimidin-2-yl] phenyl] –1– propyl-urea 434.61 2.66

7o* 7th *: O 1–(3–etilfenil)–3–[4–[4– 496,62 3,29 OR 1– (3 – ethylphenyl) –3– [4– [4– 496.62 3.29

7p* 7p *: O 3–(2–furilmetil)–1–[4–[4– 472,58 2,76 OR 3– (2 – furilmethyl) –1– [4– [4– 472.58 2.76

(metilsulfonilmetil)–6–morfolin–4–il– (methylsulfonylmethyl) –6 – morpholin-4-yl–

N N N S O O N H N H O O N N N S O O N H N H O O: pirimidin–2–il]fenil]urea pyrimidin – 2-yl] phenyl] urea

7q* 7q *: N N N O S O O N H N H O S 1–[4–[4–(metilsulfonilmetil)–6– morfolin–4–il–pirimidin–2–il]fenil]–3– (2–tiofen–2–iletil)urea 502,58 2,96 N N N O S O O N H N H O S 1– [4– [4– (methylsulfonylmethyl) –6– morpholin-4-yl-pyrimidin-2-yl] phenyl] –3– (2-thiophene-2-ileyl) urea 502.58 2.96

7r* 7r *: N N N O S O O N H N H O S 1–[4–[4–(metilsulfonilmetil)–6– morfolin–4–il–pirimidin–2–il]fenil]–3– tiofen–2–il–urea 474,54 2,92 N N N O S O O N H N H O S 1– [4– [4– (methylsulfonylmethyl) –6– morpholin-4-yl-pyrimidin-2-yl] phenyl] –3– thiophene – 2-il-urea 474.54 2.92

* Los compuestos se purificaron adicionalmente mediante HPLC prep. * The compounds were further purified by prep HPLC.

Ejemplo 7a: RMN 1H (400,13 MHz, DMSO–d6) δ 2,25 (s, 3H), 3,21 (s, 3H), 3,71 (s, 8H), 4,49 (s, 2H), 6,83 (s, 1H), 7,09 (d, 2H), 7,34 (d, 2H), 7,56 (d, 2H), 8,26 (d, 2H), 8,6 (s, 1H), 8,88 (s, 1H) Example 7a: 1H NMR (400.13 MHz, DMSO-d6) δ 2.25 (s, 3H), 3.21 (s, 3H), 3.71 (s, 8H), 4.49 (s, 2H ), 6.83 (s, 1H), 7.09 (d, 2H), 7.34 (d, 2H), 7.56 (d, 2H), 8.26 (d, 2H), 8.6 (s, 1H), 8.88 (s, 1H)

Ejemplo 7b: RMN 1H (400,13 MHz, DMSO–d6) δ 3,22 (s, 3H), 3,70 (s, 8H), 4,49 (s, 2H), 6,84 (s, 1H), 7,34 (d, 2H), 7,50 (d, 2H), 7,56 (d, 2H), 8,28 (d, 2H), 8,84 (s, 1H), 8,95 (s, 1H) Example 7b: 1H NMR (400.13 MHz, DMSO-d6) δ 3.22 (s, 3H), 3.70 (s, 8H), 4.49 (s, 2H), 6.84 (s, 1H ), 7.34 (d, 2H), 7.50 (d, 2H), 7.56 (d, 2H), 8.28 (d, 2H), 8.84 (s, 1H), 8.95 (s, 1H)

Ejemplo 7c: RMN 1H (400,13 MHz, DMSO–d6) δ 3,21 (s, 3H), 3,72 (s, 8H), 4,49 (s, 2H), 6,84 (s, 1H), 7,59 (d, 2H), 7,65 (m, 4H), 8,3 (d, 2H), 9,40 (s, 1H), 9,13 (s, 1H) Example 7c: 1H NMR (400.13 MHz, DMSO-d6) δ 3.21 (s, 3H), 3.72 (s, 8H), 4.49 (s, 2H), 6.84 (s, 1H ), 7.59 (d, 2H), 7.65 (m, 4H), 8.3 (d, 2H), 9.40 (s, 1H), 9.13 (s, 1H)

Ejemplo 7d: RMN 1H (400,13 MHz, DMSO–d6) δ 2,23 (s, 6H), 3,21 (s, 3H), 3,72 (bs, 8H), 4,49 (s, 2H), 6,64 (s, 1H), 6,85 (s, 1H), 7,08 (s, 2H), 7,55 (d, 2H), 8,28 (d, 2H), 8,58 (s, 1H), 8,92 (s, 1H) Example 7d: 1H NMR (400.13 MHz, DMSO-d6) δ 2.23 (s, 6H), 3.21 (s, 3H), 3.72 (bs, 8H), 4.49 (s, 2H ), 6.64 (s, 1H), 6.85 (s, 1H), 7.08 (s, 2H), 7.55 (d, 2H), 8.28 (d, 2H), 8.58 (s, 1H), 8.92 (s, 1H)

Ejemplo 7e: RMN 1H (400,13 MHz, DMSO–d6) δ 3,21 (s, 3H), 3,72 (s, 8H), 4,49 (s, 2H), 6,84 (s, 1H), 7,05 (m, 1H), 7,22 (m, 2H), 7,59 (d, 2H), 8,24 (d, 1H), 8,3 (d, 2H), 8,38 (s, 1H), 9,60 (s, 1H) Example 7e: 1H NMR (400.13 MHz, DMSO-d6) δ 3.21 (s, 3H), 3.72 (s, 8H), 4.49 (s, 2H), 6.84 (s, 1H ), 7.05 (m, 1H), 7.22 (m, 2H), 7.59 (d, 2H), 8.24 (d, 1H), 8.3 (d, 2H), 8.38 (s, 1H), 9.60 (s, 1H)

Ejemplo 7f: RMN 1H (400,13 MHz, DMSO–d6) δ 3,22 (s, 3H), 3,70 (bs, 8H), 4,49 (s, 2H), 6,84 (s, 1H), 7,12 (m, 2H), 7,48 (m, 2H), 7,55 (d, 2H), 8,26 (d, 2H), 8,73 (s, 1H), 8,90 (s, 1H) Example 7f: 1H NMR (400.13 MHz, DMSO-d6) δ 3.22 (s, 3H), 3.70 (bs, 8H), 4.49 (s, 2H), 6.84 (s, 1H ), 7.12 (m, 2H), 7.48 (m, 2H), 7.55 (d, 2H), 8.26 (d, 2H), 8.73 (s, 1H), 8.90 (s, 1H)

Ejemplo 7g: RMN 1H (400,13 MHz, DMSO–d6) δ 3,21 (s, 3H), 3,72 (s, 8H), 4,49 (s, 2H), 6,84 (s, 1H), 7,34 (m, 2H), 7,56 (m, 2H), 7,8 (m, 1H), 8,28 (m, 2H), 8,95 (s, 1H), 9,05 (s, 1H) Example 7g: 1H NMR (400.13 MHz, DMSO-d6) δ 3.21 (s, 3H), 3.72 (s, 8H), 4.49 (s, 2H), 6.84 (s, 1H ), 7.34 (m, 2H), 7.56 (m, 2H), 7.8 (m, 1H), 8.28 (m, 2H), 8.95 (s, 1H), 9.05 (s, 1H)

Ejemplo 7i: RMN 1H (400,13 MHz, DMSO–d6) δ 3,22 (s, 3H), 3,70 (bs, 8H), 4,49 (s, 2H), 6,84 (s, 1H), 7,34 (d, 2H), 7,50 (d, 2H), 7,56 (d, 2H), 8,28 (d, 2H), 8,84 (s, 1H), 8,95 (s, 1H) Example 7i: 1H NMR (400.13 MHz, DMSO-d6) δ 3.22 (s, 3H), 3.70 (bs, 8H), 4.49 (s, 2H), 6.84 (s, 1H ), 7.34 (d, 2H), 7.50 (d, 2H), 7.56 (d, 2H), 8.28 (d, 2H), 8.84 (s, 1H), 8.95 (s, 1H)

Ejemplo 7j: RMN 1H (400,13 MHz, DMSO–d6) δ 0,88 (m, 3H), 1,39 (m, 4H), 1,43 (m, 2H), 3,08 (m, 2H), 3,21 (s, 3H), 3,70 (bs, 8H), 4,47 (s, 2H), 6,2 (t, 1H), 6,81 (s, 1H), 7,49 (d, 2H), 8,20 (d, 2H), 8,66 (s, 1H) Example 7j: 1H NMR (400.13 MHz, DMSO-d6) δ 0.88 (m, 3H), 1.39 (m, 4H), 1.43 (m, 2H), 3.08 (m, 2H ), 3.21 (s, 3H), 3.70 (bs, 8H), 4.47 (s, 2H), 6.2 (t, 1H), 6.81 (s, 1H), 7.49 (d, 2H), 8.20 (d, 2H), 8.66 (s, 1H)

Ejemplo 7m: RMN 1H (400,13 MHz, DMSO–d6) δ 1,05 (t, 3H), 3,12 (q, 2H), 3,21 (s, 3H), 3,7 (bs, 8H), 4,46 (s, 2H), 6,19 (t, 1H), 6,8 (s, 1H), 7,50 (d, 2H), 8,21 (d, 2H), 8,69 (s, 1H) Example 7m: 1H NMR (400.13 MHz, DMSO-d6) δ 1.05 (t, 3H), 3.12 (q, 2H), 3.21 (s, 3H), 3.7 (bs, 8H ), 4.46 (s, 2H), 6.19 (t, 1H), 6.8 (s, 1H), 7.50 (d, 2H), 8.21 (d, 2H), 8.69 (s, 1H)

Ejemplo 7n: RMN 1H (400,13 MHz, DMSO–d6) δ 0,87 (m, 3H), 1,45 (m, 2H), 3,05 (m, 2H), 3,20 (s, 3H), 3,70 (bs, 8H), 4,45 (s, 2H), 6,14 (t, 1H), 6,81 (s, 1H), 7,49 (d, 2H), 8,20 (d, 2H), 8,69 (s, 1H) Example 7n: 1H NMR (400.13 MHz, DMSO-d6) δ 0.87 (m, 3H), 1.45 (m, 2H), 3.05 (m, 2H), 3.20 (s, 3H ), 3.70 (bs, 8H), 4.45 (s, 2H), 6.14 (t, 1H), 6.81 (s, 1H), 7.49 (d, 2H), 8.20 (d, 2H), 8.69 (s, 1H)

Ejemplo 7o: RMN 1H (400,13 MHz, DMSO–d6) δ 1,19 (t, 3H), 2,55 (q, 2H), 3,21 (s, 3H), 3,70 (bs, 8H), 4,49 (s, 2H), 6,85 (m, 2H), 7,19 (t, 2H), 7,27 (d, 1H), 7,33 (s, 1H), 7,56 (d, 2H), 8,26 (d, 2H), 8,68 (s, 1H), 8,92 (s, 1H) Example 7: 1H NMR (400.13 MHz, DMSO-d6) δ 1.19 (t, 3H), 2.55 (q, 2H), 3.21 (s, 3H), 3.70 (bs, 8H ), 4.49 (s, 2H), 6.85 (m, 2H), 7.19 (t, 2H), 7.27 (d, 1H), 7.33 (s, 1H), 7.56 (d, 2H), 8.26 (d, 2H), 8.68 (s, 1H), 8.92 (s, 1H)

Ejemplo 7p: RMN 1H (400,13 MHz, DMSO–d6) δ 3,20 (s, 3H), 3,70 (bs, 8H), 4,31 (d, 1H), 4,47 (s, 2H), 6,28 (d, 1h), 6,40 (d, 1H), 6,61 (t, 1H), 6,82 (s, 1H), 7,51 (d, 2H), 7,59 (s, 1H), 8,22 (d, 2H), 8,77 (s, 1H) Example 7p: 1H NMR (400.13 MHz, DMSO-d6) δ 3.20 (s, 3H), 3.70 (bs, 8H), 4.31 (d, 1H), 4.47 (s, 2H ), 6.28 (d, 1h), 6.40 (d, 1H), 6.61 (t, 1H), 6.82 (s, 1H), 7.51 (d, 2H), 7.59 (s, 1H), 8.22 (d, 2H), 8.77 (s, 1H)

Ejemplo 7q: RMN 1H (400,13 MHz, DMSO–d6) δ 2,98 (t, 2H), 3,21 (s, 3H), 3,38 (m, 2H), 3,70 (bs, 8H), 4,47 (s, 2H), 6,29 (t, 1H), 6,81 (s, 1H), 6,93 (d, 1H), 6,97 (m, 1H), 7,36 (m, 1H), 7,50 (d, 2H), 8,21 (d, 2H), 8,80 (s, 1H) Example 7q: 1H NMR (400.13 MHz, DMSO-d6) δ 2.98 (t, 2H), 3.21 (s, 3H), 3.38 (m, 2H), 3.70 (bs, 8H ), 4.47 (s, 2H), 6.29 (t, 1H), 6.81 (s, 1H), 6.93 (d, 1H), 6.97 (m, 1H), 7.36 (m, 1H), 7.50 (d, 2H), 8.21 (d, 2H), 8.80 (s, 1H)

Prueba (a): Ejemplo (7) 0,17 μM; Ejemplo (7a) 0,28 μM; Ejemplo (7b) 0,42 μM; Ejemplo (7c) 1,7 μM; Ejemplo (7d) 2,6 μM; Ejemplo (7e) 2,6 μM; Ejemplo (7f) 0,029 μM; Ejemplo (7g) 1,3 μM; Ejemplo (7h) 0,24 μM; Ejemplo (7i) 0,032 μM; Ejemplo (7j) 1,9 μM; Ejemplo (7k) 0,72 μM; Ejemplo (7l) 7 μM; Ejemplo (7m) 0,081 μM; Ejemplo (7n) 0,2 μM; Ejemplo (7o) 1,7 μM; Ejemplo (7p) 3,8 μM; Ejemplo (7q) 1,7 μM; Ejemplo (7r) 0,19 μM. Test (a): Example (7) 0.17 μM; Example (7a) 0.28 μM; Example (7b) 0.42 μM; Example (7c) 1.7 μM; Example (7d) 2.6 μM; Example (7e) 2.6 μM; Example (7f) 0.029 μM; Example (7g) 1.3 μM; Example (7h) 0.24 μM; Example (7i) 0.032 μM; Example (7j) 1.9 μM; Example (7k) 0.72 μM; Example (7l) 7 μM; Example (7m) 0.081 μM; Example (7n) 0.2 μM; Example (7o) 1.7 μM; Example (7p) 3.8 μM; Example (7q) 1.7 μM; Example (7r) 0.19 μM.

A continuación se describe la preparación de 4–[4–(metilsulfonilmetil)–6–morfolin–4–il–pirimidin–2–il]anilina: 4–[4–(Metilsulfonilmetil)–6–morfolin–4–il–pirimidin–2–il]anilina The preparation of 4– [4– (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] aniline is described below: 4– [4– (Methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin –2 – il] aniline

Se añadieron a una vasija de microondas 2–metilsulfanil–4–(metilsulfonilmetil)–6–morfolin–4–il–pirimidina (1,00 g, 3,3 mmoles), ácido 4–aminofenilborónico (904 mg, 6,60 mmoles), tiofeno–2–carboxilato de cobre(I) (1,64 g, 8,58 mmoles), Pd(PPh3)4 (153 mg, 0,04 equiv., 0,13 mmoles) y se añadió 1,4–dioxano (20 ml). El sistema se desgasificó con N2, se cerró herméticamente y se calentó en un reactor de microondas a 130ºC durante 1 hora. Después de enfriar la reacción se vertió en agua, y el precipitado resultante se recogió por filtración y se secó a vacío para proporcionar el compuesto del título como un sólido blancuzco (988 mg). 2-Methylsulfanyl-4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine (1.00 g, 3.3 mmol), 4-aminophenylboronic acid (904 mg, 6.60 mmol were added to a microwave vessel ), thiophene-2-carboxylate of copper (I) (1.64 g, 8.58 mmol), Pd (PPh3) 4 (153 mg, 0.04 equiv., 0.13 mmol) and 1.4 added –Dioxane (20 ml). The system was degassed with N2, sealed and heated in a microwave reactor at 130 ° C for 1 hour. After cooling the reaction was poured into water, and the resulting precipitate was collected by filtration and dried in vacuo to provide the title compound as an off-white solid (988 mg).

Espectro LCMS: MH+ 349,41, Tiempo de retención 1,43 Método: Ácido Monitor LCMS spectrum: MH + 349.41, Retention time 1.43 Method: Acid Monitor

Espectro RMN: RMN 1H (300,132 MHz, DMSO) δ 3,20 (3H, s), 3,61–3,83 (8H, m), 4,43 (2H, s), 5,57 (1H, s), 6,60 (2H, d), 6,70 (1H, s), 8,04 (2H, d) NMR Spectrum: 1H NMR (300.132 MHz, DMSO) δ 3.20 (3H, s), 3.61-3.83 (8H, m), 4.43 (2H, s), 5.57 (1H, s ), 6.60 (2H, d), 6.70 (1H, s), 8.04 (2H, d)

2–Metilsulfanil–4–(metilsulfonilmetil)–6–morfolin–4–il–pirimidina 2 – Methylsulfanyl – 4– (methylsulfonylmethyl) –6 – morpholin-4-yl-pyrimidine

Se calentó a reflujo 2–metilsulfanil–6–(metilsulfonilmetil)pirimidin–4–ol (15 g, 63,97 mmoles) en oxicloruro de fósforo (100 ml) durante aproximadamente 1 hora. El oxicloruro de fósforo se evaporó, y el residuo se neutralizó con disolución de hidróxido de sodio y se extrajo en acetato de etilo. Después la mezcla resultante se secó sobre sulfato de magnesio, se filtró y se evaporó hasta sequedad para proporcionar el producto de cloro bruto. Después esto se disolvió en DCM, se añadió morfolina (319 mmoles, 28 ml), y la reacción se agitó a temperatura ambiente. Después de terminar, el precipitado resultante se recogió como un sólido blanco. La concentración del filtrado proporcionó más sólido, dando un rendimiento combinado de 13,7 g. 2-Methylsulfanyl-6- (methylsulfonylmethyl) pyrimidin-4-ol (15 g, 63.97 mmol) in phosphorus oxychloride (100 ml) was heated at reflux for about 1 hour. The phosphorus oxychloride was evaporated, and the residue was neutralized with sodium hydroxide solution and extracted into ethyl acetate. The resulting mixture was then dried over magnesium sulfate, filtered and evaporated to dryness to provide the crude chlorine product. This was then dissolved in DCM, morpholine (319 mmol, 28 ml) was added, and the reaction was stirred at room temperature. After finishing, the resulting precipitate was collected as a white solid. The concentration of the filtrate provided more solid, giving a combined yield of 13.7 g.

Espectro RMN: RMN 1H (300,132 MHz, DMSO) δ 2,45 (s, 3H), 3,49–3,74 (m, 8H), 4,37 (s, 2H), 6,66 (s, 1H) ppm. NMR Spectrum: 1H NMR (300.132 MHz, DMSO) δ 2.45 (s, 3H), 3.49-3.74 (m, 8H), 4.37 (s, 2H), 6.66 (s, 1H ) ppm.

Espectro LCMS: MH+ 304,50, Tiempo de retención 1,49min, Método: Básico Monitor LCMS spectrum: MH + 304.50, Retention time 1.49min, Method: Basic Monitor

2–Metilsulfanil–6–(metilsulfonilmetil)pirimidin–4–ol 2 – Methylsulfanyl – 6– (methylsulfonylmethyl) pyrimidin – 4 – ol

OH OH

Se suspendió 6–(clorometil)–2–metilsulfanil–pirimidin–4–ol (19,07 g, 100 mmoles) en acetonitrilo (400 ml). A esta suspensión agitada se añadieron sal sódica del ácido metanosulfínico (12,255 g, 120 mmoles) y DMF (100 ml). La reacción se calentó después hasta 100ºC para dar una suspensión oscura y se monitorizó mediante LCMS. Una vez completada, los disolventes se eliminaron, y el producto resultante se añadió a MeOH:DCM 1:1 (200 ml) y se acidificó con ácido acético (10 ml). El precipitado resultante se recogió, se lavó con agua (200 ml) y MeOH (100 ml) y se secó toda la noche a vacío para proporcionar el compuesto del título como un sólido blanco, 16,45 g. 6– (chloromethyl) -2-methylsulfanyl-pyrimidin-4-ol (19.07 g, 100 mmol) was suspended in acetonitrile (400 ml). To this stirred suspension were added sodium salt of methanesulfinic acid (12,255 g, 120 mmol) and DMF (100 ml). The reaction was then heated to 100 ° C to give a dark suspension and monitored by LCMS. Once completed, the solvents were removed, and the resulting product was added to MeOH: DCM 1: 1 (200 ml) and acidified with acetic acid (10 ml). The resulting precipitate was collected, washed with water (200 ml) and MeOH (100 ml) and dried overnight in vacuo to give the title compound as a white solid, 16.45 g.

Espectro RMN: RMN 1H (300,132 MHz, DMSO) δ 2,50 (s, 3H), 3,12 (s, 3H), 4,39 (s, 2H), 6,25 (s, 1H), 13,09 (s, 1H) ppm. NMR Spectrum: 1H NMR (300.132 MHz, DMSO) δ 2.50 (s, 3H), 3.12 (s, 3H), 4.39 (s, 2H), 6.25 (s, 1H), 13, 09 (s, 1 H) ppm.

Espectro LCMS: MH+ 235,2, Tiempo de retención 0,5 minutos, Método: Básico Temprano 5min LCMS spectrum: MH + 235.2, Retention time 0.5 minutes, Method: Early Basic 5min

6–(Clorometil)–2–metilsulfanil–pirimidin–4–ol 6– (Chloromethyl) –2 – methylsulfanyl – pyrimidin – 4 – ol

OH OH

Se disolvieron sulfato de S–metil–2–tiopseudourea (20 g, 71,85 mmoles), 4–cloroacetoacetato de etilo (10,755 ml, 79,04 mmoles) y carbonato de sodio (13,925 g, 107,78 mmoles) en agua (100 ml) y se agitaron a temperatura ambiente toda la noche. La reacción se monitorizó mediante TLC, y una vez completada, el precipitado de la reacción se recogió y el sobrenadante se neutralizó con ácido clorhídrico 6N para producir más precipitado de la reacción el cual también se recogió. El precipitado acumulado se lavó después con agua (x3), y se obtuvo un sólido blancuzco. Éste se secó a vacío a 60(C durante 48 horas para producir el compuesto deseado como un sólido blanco/amarillo pálido, 43,2 g. S-methyl-2-thiopseudourea sulfate (20 g, 71.85 mmol), ethyl 4-chloroacetoacetate (10.755 ml, 79.04 mmol) and sodium carbonate (13.925 g, 107.78 mmol) were dissolved in water (100 ml) and stirred at room temperature overnight. The reaction was monitored by TLC, and once completed, the reaction precipitate was collected and the supernatant was neutralized with 6N hydrochloric acid to produce more reaction precipitate which was also collected. The accumulated precipitate was then washed with water (x3), and an off-white solid was obtained. This was dried under vacuum at 60 (C for 48 hours to produce the desired compound as a pale white / yellow solid, 43.2 g.

Espectro RMN: RMN 1H (300,132 MHz, CDCl3) δ 2,59 (s, 3H), 4,35 (s, 2H), 6,41 (s, 1H), 12,70 (s, 1H) ppm NMR Spectrum: 1H NMR (300.132 MHz, CDCl3) δ 2.59 (s, 3H), 4.35 (s, 2H), 6.41 (s, 1H), 12.70 (s, 1H) ppm

Espectro de masa: M+ 190 Mass spectrum: M + 190

También se puede preparar 4–[4–(metilsulfonilmetil)–6–morfolin–4–il–pirimidin–2–il]anilina a partir de 2,4–dicloro–6– (metilsulfonilmetil)pirimidina como se describe a continuación 4– [4– (Methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] aniline can also be prepared from 2,4-dichloro-6- (methylsulfonylmethyl) pyrimidine as described below.

4–(4–(Metilsulfonilmetil)–6–morfolin–4–il–pirimidin–2–il]anilina 4– (4– (Methylsulfonylmethyl) –6 – morpholin-4-yl-pyrimidin – 2-yl] aniline

Se disolvió 2–cloro–4–(metilsulfonilmetil)–6–morfolin–4–il–pirimidina (5 g, 17,1 mmoles), en una mezcla de DMF:DME:agua:etanol (16,5 ml:41 ml:18 ml:12 ml). se añadieron 4–(4,4,5,5–Tetrametil–1,3,2–dioxaborolan–2– il)anilina (5,62 g, 25,6 mmoles), una disolución acuosa 2M de carbonato de sodio (25 ml), y diclorobis(trifenilfosfina)paladio (600 mg), y la mezcla se puso a reflujo durante 5 horas en una atmósfera de nitrógeno. La mezcla se enfrió, se diluyó con agua y se extrajo en DCM. La capa orgánica se secó sobre Na2SO4, se filtró y se evaporó. El material bruto se disolvió en un mínimo de DCM caliente, después se añadió hexano, y el precipitado se filtró para dar el material deseado (1,6 g). 2-Chloro-4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine (5 g, 17.1 mmol) was dissolved in a mixture of DMF: DME: water: ethanol (16.5 ml: 41 ml : 18 ml: 12 ml). 4– (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (5.62 g, 25.6 mmol), a 2M aqueous solution of sodium carbonate (25 ml), and dichlorobis (triphenylphosphine) palladium (600 mg), and the mixture was refluxed for 5 hours under a nitrogen atmosphere. The mixture was cooled, diluted with water and extracted into DCM. The organic layer was dried over Na2SO4, filtered and evaporated. The crude material was dissolved in a minimum of hot DCM, then hexane was added, and the precipitate was filtered to give the desired material (1.6 g).

Espectro LCMS: MH+349, Tiempo de retención 1,48min, Método: Básico Monitor LCMS spectrum: MH + 349, Retention time 1.48min, Method: Basic Monitor

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 3,20 (3H, s), 3,67–3,72 (8H, m), 4,43 (2H, s), 5,55–5,56 (2H, m), 6,59 (2H, d), 6,70 (1H, s), 8,03 (2H, d) NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 3.20 (3H, s), 3.67-3.72 (8H, m), 4.43 (2H, s), 5.55 –5.56 (2H, m), 6.59 (2H, d), 6.70 (1H, s), 8.03 (2H, d)

2–Cloro–4–(metilsulfonilmetil)–6–morfolin–4–il–pirimidina 2 – Chloro – 4– (methylsulfonylmethyl) –6 – morpholin-4-yl-pyrimidine

Una suspensión de 2,4–dicloro–6–(metilsulfonilmetil)pirimidina (10,56 g) en DCM (230 ml) se agitó magnéticamente (en nitrógeno) y se enfrió hasta –5°C. Se añadió trietilamina (6,78 ml) seguido por la adición gota a gota de una disolución de morfolina (3,85 ml) en DCM (30 ml), manteniendo la temperatura de la reacción por debajo de –5°C. La reacción se agitó a temperatura ambiente durante 1 hora, y después la mezcla orgánica se lavó con agua (300 ml). La fase orgánica se secó (MgSO4), se filtró y se evaporó para obtener un sólido marrón el cual se cromatografió en sílice, eluyendo con 50% de acetato de etilo en DCM, para dar el material deseado (6,81 g) como un sólido blanco. A suspension of 2,4-dichloro-6- (methylsulfonylmethyl) pyrimidine (10.56 g) in DCM (230 ml) was magnetically stirred (in nitrogen) and cooled to -5 ° C. Triethylamine (6.78 ml) was added followed by the dropwise addition of a solution of morpholine (3.85 ml) in DCM (30 ml), keeping the reaction temperature below -5 ° C. The reaction was stirred at room temperature for 1 hour, and then the organic mixture was washed with water (300 ml). The organic phase was dried (MgSO4), filtered and evaporated to obtain a brown solid which was chromatographed on silica, eluting with 50% ethyl acetate in DCM, to give the desired material (6.81 g) as a white solid

Espectro RMN: RMN 1H (DMSO–d6) δ 3,12 (3H, s), 3,63 (4H, s), 3,68–3,70 (4H, m), 4,45 (2H, s), 6,96 (1H, s) NMR Spectrum: 1H NMR (DMSO – d6) δ 3.12 (3H, s), 3.63 (4H, s), 3.68–3.70 (4H, m), 4.45 (2H, s) , 6.96 (1H, s)

Espectro de masa: MH+ 292. Mass spectrum: MH + 292.

Ejemplo 8: Example 8:

3 – Cyclopropyl – 1– [4– [4– (methylsulfonylmethyl) –6-morpholin-4-yl-pyrimidin-2-yl] phenyl] urea

O OR

N N

N S OO N S OO

N N

N HH N HH

Una mezcla de N–[4–[4–(metilsulfonilmetil)–6–morfolin–4–il–pirimidin–2–il]fenil]carbamato de fenilo (94 mg, 0,2 mmoles), ciclopropilamina (0,069 ml, 1 mmol), y trietilamina (0,090 ml, 0,65 mmoles), en NMP (1–2 ml) se calentó a 50–70ºC durante 2 horas. Después la mezcla se purificó directamente usando HPLC prep. (método Monitor Básico) para dar el material deseado. A mixture of phenyl N- [4– [4– (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] phenyl] carbamate (94 mg, 0.2 mmol), cyclopropylamine (0.069 ml, 1 mmol), and triethylamine (0.090 ml, 0.65 mmol), in NMP (1-2 ml) was heated at 50-70 ° C for 2 hours. Then the mixture was purified directly using prep HPLC. (Basic Monitor method) to give the desired material.

Espectro LCMS : MH+432, Tiempo de retención 2,42 min., Método Básico LCMS spectrum: MH + 432, Retention time 2.42 min., Basic Method

Los siguientes compuestos se prepararon de manera análoga a partir del carbamato de fenilo requerido y la amina apropiada, usando NMP o DMF como el disolvente. The following compounds were prepared analogously from the required phenyl carbamate and the appropriate amine, using NMP or DMF as the solvent.

8a 8a: O 1–[4–[4–(metilsulfonilmetil)–6– 448 2,82 OR 1– [4– [4– (methylsulfonylmethyl) –6– 448 2.82

: morfolin–4–il–pirimidin–2–il]fenil]– morpholin-4-yl-pyrimidin-2-yl] phenyl] -

N N N S O O N H N H O N N N S O O N H N H O: 3–terc–butil–urea 3-tert-butyl-urea

8b 8b: N N N O S O O N H N H O NH O N–[2–[[4–[4–(metilsulfonilmetil)–6– morfolin–4–il–pirimidin–2– il]fenil]carbamoilamino]etil]acetami da 478 2,24 N N N O S O O N H N H O NH O N– [2 - [[4– [4– (methylsulfonylmethyl) –6– morpholin-4-yl-pyrimidin-2-yl] phenyl] carbamoylamino] ethyl] acetami da 478 2.24

8c 8c: N N N O S O O N H N O N 1–(2–dimetilaminoetil)–1–metil–3– [4–[4–(metilsulfonilmetil)–6– morfolin–4–il–pirimidin–2– il]fenil]urea 478 2,6 N N N O S O O N H N O N 1– (2-dimethylaminoethyl) –1 – methyl – 3– [4– [4– (methylsulfonylmethyl) –6– morpholin-4-yl-pyrimidin-2-yl] phenyl] urea 478 2.6

8d 8d: O 3–(1H–imidazol–2–ilmetil)–1–[4– 472 2,11 OR 3– (1H – imidazol – 2 – ilmethyl) –1– [4– 472 2.11

: [4–(metilsulfonilmetil)–6–morfolin– [4– (methylsulfonylmethyl) –6 – morpholin–

N N N S O O N H N H O N H N N N N S O O N H N H O N H N: 4–il–pirimidin–2–il]fenil]urea 4-yl-pyrimidin-2-yl] phenyl] urea

8c 8c: O 1–ciclopropil–1–metil–3–[4–[4– 446 2,45 OR 1 – cyclopropyl – 1 – methyl – 3– [4– [4– 446 2.45

: (metilsulfonilmetil)–6–morfolin–4– (methylsulfonylmethyl) –6 – morpholin-4–

N N N S O O N H N O N N N S O O N H N O: il–pirimidin–2–il]fenil]urea il-pyrimidin-2-yl] phenyl] urea

8f 8f: O 1–[4–[4–[(3S)–3–Metilmorfolin–4– 462 2,84 OR 1– [4– [4 - [(3S) –3 – Methylmorpholin – 4– 462 2.84

: il]–6–(metilsulfonilmetil)pirimidin– il] –6– (methylsulfonylmethyl) pyrimidin–

N N N S O O N H N H O N N N S O O N H N H O: 2–il]fenil]–3–(2–metilpropil)urea 2-yl] phenyl] –3– (2-methylpropyl) urea

8g 8g: O 1–[3–[4–[(3S)–3–Metilmorfolin–4– 448 1,71 Purificada OR 1– [3– [4 - [(3S) –3 – Methylmorpholin – 4– 448 1.71 Purified

: il]–6–(metilsulfonilmetil)pirimidin– mediante il] –6– (methylsulfonylmethyl) pyrimidin– through

N N N S O O N H N H O N N N S O O N H N H O: 2–il]fenil]–3–propan–2–il–urea trituración con metanol 2 – il] phenyl] –3 – propan – 2 – il – urea crushing with methanol

8h 8h: N N N O S O O N H N H O 3–Etil–1–[3–[4–[(3S)–3– metilmorfolin–4–il]–6– (metilsulfonilmetil)pirimidin–2– il]fenil]urea 434 1,71 Purificada mediante recristalización a partir de metanol N N N O S O O N H N H O 3 – Ethyl – 1– [3– [4 - [(3 S) –3– methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin – 2– yl] phenyl] urea 434 1.71 Purified by recrystallization from methanol

8i 8i: O 1–[2–Cloro–4–[4–[(3S)–3– 468 1,78 OR 1– [2 – Chlorine – 4– [4 - [(3S) –3– 468 1.78

: metilmorfolin–4–il]–6– methylmorpholin – 4 – il] –6–

N N S O O Cl N H N H O N N S O O Cl N H N H O: il]fenil]–3–etil–urea il] phenyl] –3-ethyl-urea

8j 8j: N N N O S O O N H N H O 3–Metil–1–[2–metil–4–[4–[(3S)–3– metilmorfolin–4–il]–6– (metilsulfonilmetil)pirimidin–2– il]fenil]urea 434 1,28 N N N O S O O N H N H O 3 – Methyl – 1– [2 – methyl – 4– [4 - [(3S) –3– methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin – 2– yl] phenyl] urea 434 1.28

Ejemplo 8g: RMN 1H (400,13 MHz, DMSO–d6) δ 1,11 (d, 6H), 1,26 (d, 3H), 3,23 (s, 3H), 3,25 (d, 1H), 3,48–3,55 (m, 1H), 3,65–3,68 (m, 1H), 3,76 (d, 1H), 3,80 (t, 1H), 3,98–4,02 (m, 1H), 4,18 (d, 1H), 4,48 (m, 1H), 4,52 (s, 2H), 5,98 (d, 1H), 6,85 (s, 1H), 7,32 (t, 1H), 7,65–7,68 (m, 1H), 7,86–7,88 (m, 1H), 8,20 (t, 1H), 8,43 (s, 1H) Example 8g: 1H NMR (400.13 MHz, DMSO-d6) δ 1.11 (d, 6H), 1.26 (d, 3H), 3.23 (s, 3H), 3.25 (d, 1H ), 3.48-3.55 (m, 1H), 3.65-3.68 (m, 1H), 3.76 (d, 1H), 3.80 (t, 1H), 3.98– 4.02 (m, 1H), 4.18 (d, 1H), 4.48 (m, 1H), 4.52 (s, 2H), 5.98 (d, 1H), 6.85 (s , 1H), 7.32 (t, 1H), 7.65-7.68 (m, 1H), 7.86-7.88 (m, 1H), 8.20 (t, 1H), 8, 43 (s, 1H)

5 Ejemplo 8h: RMN 1H (400,13 MHz, DMSO–d6) δ 1,07 (t, 3H), 1,26 (d, 3H), 3,09–3,14 (m, 2H), 3,22 (s, 3H), 3,24 (m, 1H), 3,48–3,55 (m, 1H), 3,65–3,68 (m, 1H), 3,79 (d, 1H), 3,98–4,02 (m, 1H), 4,18 (s, 1H), 4,51 (s, 3H), 6,08 (t, 1H), 6,85 (s, 1H), 7,32 (t, 1H), 7,64–7,67 (m, 1H), 7,86–7,88 (m, 1H), 8,23 (t, 1H), 8,55 (s, 1H) 5 Example 8h: 1H NMR (400.13 MHz, DMSO-d6) δ 1.07 (t, 3H), 1.26 (d, 3H), 3.09-3.14 (m, 2H), 3, 22 (s, 3H), 3.24 (m, 1H), 3.48-3.55 (m, 1H), 3.65-3.68 (m, 1H), 3.79 (d, 1H) , 3.98-4.02 (m, 1H), 4.18 (s, 1H), 4.51 (s, 3H), 6.08 (t, 1H), 6.85 (s, 1H), 7.32 (t, 1H), 7.64-7.67 (m, 1H), 7.86-7.88 (m, 1H), 8.23 (t, 1H), 8.55 (s, 1 HOUR)

Ejemplo 8i: RMN 1H (400,13 MHz, DMSO–d6) δ 1,09 (t, 3H), 1,25 (d, 3H), 3,15 (m, 2H), 3,19 (s, 3H), 3,20–3,26 (m, 1H), 3,47–3,53 (m, 1H), 3,63–3,67 (m, 1H), 3,78 (d, 1H), 3,97–4,01 (m, 1H), 4,18 (d, 1H), 4,46 (s, 1H), 4,50 (s, 2H), Example 8i: 1H NMR (400.13 MHz, DMSO-d6) δ 1.09 (t, 3H), 1.25 (d, 3H), 3.15 (m, 2H), 3.19 (s, 3H ), 3.20-3.26 (m, 1H), 3.47-3.53 (m, 1H), 3.63-3.67 (m, 1H), 3.78 (d, 1H), 3.97-4.01 (m, 1H), 4.18 (d, 1H), 4.46 (s, 1H), 4.50 (s, 2H),

10 6,82 (s, 1H), 7,13 (t, 1H), 8,14 (s, 1H), 8,17–8,20 (m, 1H), 8,28 (d, 1H), 8,33 (d, 1H) 10 6.82 (s, 1H), 7.13 (t, 1H), 8.14 (s, 1H), 8.17–8.20 (m, 1H), 8.28 (d, 1H), 8.33 (d, 1 H)

Ejemplo 8j: RMN 1H (400,13 MHz, DMSO–d6) δ 1,24 (d, 3H), 2,26 (s, 3H), 2,68 (d, 3H), 3,20 (s, 3H), 3,22–3,26 (m, 1H), 3,47–3,54 (m, 1H), 3,63–3,67 (m, 1H), 3,78 (d, 1H), 3,97–4,01 (m, 1H), 4,19 (d, 1H), 4,49 (s, 3H), 6,56 (q, 1H), 6,77 (s, 1H), 7,79 (s, 1H), 8,02 (s, 1H), 8,06–8,09 (m, 2H) Example 8j: 1H NMR (400.13 MHz, DMSO-d6) δ 1.24 (d, 3H), 2.26 (s, 3H), 2.68 (d, 3H), 3.20 (s, 3H ), 3.22-3.26 (m, 1H), 3.47-3.54 (m, 1H), 3.63-3.67 (m, 1H), 3.78 (d, 1H), 3.97-4.01 (m, 1H), 4.19 (d, 1H), 4.49 (s, 3H), 6.56 (q, 1H), 6.77 (s, 1H), 7 , 79 (s, 1H), 8.02 (s, 1H), 8.06–8.09 (m, 2H)

Prueba (a): Ejemplo (8) 0,031 μM; Ejemplo (8a) 0,47 μM; Ejemplo (8b) 0,42 μM; Ejemplo (8c) 2,2 μM; Ejemplo (8d) Test (a): Example (8) 0.031 μM; Example (8a) 0.47 μM; Example (8b) 0.42 μM; Example (8c) 2.2 μM; Example (8d)

15 0,57 μM; Ejemplo (8e) 0,28 μM; Ejemplo (8f) 0,3 μM; Ejemplo (8g) 0,96 μM; Ejemplo (8h) 0,92 μM; Ejemplo (8i) 1,4 μM; Ejemplo (8j) 0,16 μM. 15 0.57 μM; Example (8e) 0.28 μM; Example (8f) 0.3 μM; Example (8g) 0.96 μM; Example (8h) 0.92 μM; Example (8i) 1.4 μM; Example (8j) 0.16 μM.

A continuación se describe la preparación de N–[4–[4–(metilsulfonilmetil)–6–morfolin–4–il–pirimidin–2– il]fenil]carbamato de fenilo. The preparation of N- [4– [4– (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] phenyl] carbamate phenyl] is described below.

N–[4–[4–(Metilsulfonilmetil)–6–morfolin–4–il–pirimidin–2–il]fenil]carbamato de fenilo O N N– [4– [4– (Methylsulfonylmethyl) –6-morpholin-4-yl-pyrimidin-2-yl] phenyl] phenyl carbamate O N

N S OO N S OO

N N

O H Or h

Se añadió cloroformiato de fenilo (1,33 ml, 10,6 mmoles) a 0–5ºC a una mezcla de hidrogenocarbonato de sodio (1,34 g, 15,9 mmoles) y 4–[4–(metilsulfonilmetil)–6–morfolin–4–il–pirimidin–2–il]anilina (3,7 g, 10,6 mmoles) en Phenyl chloroformate (1.33 ml, 10.6 mmol) was added at 0-5 ° C to a mixture of sodium hydrogen carbonate (1.34 g, 15.9 mmol) and 4– [4– (methylsulfonylmethyl) –6– morpholin-4-yl-pyrimidin-2-yl] aniline (3.7 g, 10.6 mmol) in

5 dioxano (150 ml). La reacción se agitó a RT durante 3 horas, se evaporó, y después se diluyó en DCM. La mezcla orgánica se lavó con agua, se secó sobre Na2SO4, se filtró y se evaporó para obtener una espuma amarilla pálida la cual se trituró con hexano/éter, y después se filtró produciendo el material deseado como un sólido blanco (5,4 g). 5 dioxane (150 ml). The reaction was stirred at RT for 3 hours, evaporated, and then diluted in DCM. The organic mixture was washed with water, dried over Na2SO4, filtered and evaporated to obtain a pale yellow foam which was triturated with hexane / ether, and then filtered yielding the desired material as a white solid (5.4 g ).

Espectro LCMS MH+470, Tiempo de retención 2,18 Método: Básico Monitor LCMS Spectrum MH + 470, Retention Time 2.18 Method: Basic Monitor

Espectro RMN1H RMN (400,13 MHz, DMSO–d6) δ 3,22 (3H, s), 3,58 (4H, s), 3,73 (4H, s), 4,50 (2H, s), 6,88 (1H,s), 10 7,24–7,30 (3H, m), 7,43–7,47 (2H, m), 7,63 (2H, d), 8,30 (2H, d), 10,45 (1H,s). 1 H NMR spectrum NMR (400.13 MHz, DMSO-d6) δ 3.22 (3H, s), 3.58 (4H, s), 3.73 (4H, s), 4.50 (2H, s), 6.88 (1H, s), 10 7.24-7.30 (3H, m), 7.43-7.47 (2H, m), 7.63 (2H, d), 8.30 (2H , d), 10.45 (1H, s).

Los siguientes carbamatos de fenilo se prepararon de manera análoga a partir de la anilina apropiada. The following phenyl carbamates were prepared analogously from the appropriate aniline.

Estructura Structure: NOMBRE LCMS MH+ Tiempo de retención (min.) RMN RMN 1H (400,13 MHz, DMSO–d6) NAME LCMS MH + Retention time (min.) 1 H NMR (400.13 MHz, DMSO – d6)

N N N O S O O N H O O N N N O S O O N H O O: N–[4–[4–[(3S)–3– metilmorfolin–4–il]–6– (metilsulfonilmetil)pirimidin– 2–il]fenil]carbamato de fenilo 483 2,37 N– [4– [4 - [(3S) –3– methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin– 2-yl] phenyl] phenyl carbamate 483 2.37

O OR: N–[3–[4–[(3S)–3– 482 2,36 δ 1,26 (d, 3H), 3,23 (s, 3H), 3,21– N– [3– [4 - [(3S) –3– 482 2.36 δ 1.26 (d, 3H), 3.23 (s, 3H), 3.21–

: metilmorfolin–4–il]–6– 3,29 (m, 1H), 3,49–3,54 (m, 1H), methylmorpholin – 4 – il] –6– 3.29 (m, 1H), 3.49-3.54 (m, 1H),

N N: (metilsulfonilmetil)pirimidin– 3,58 (s, 1H), 3,64–3,68 (m, 1H), (methylsulfonylmethyl) pyrimidin– 3.58 (s, 1H), 3.64-3.68 (m, 1H),

NO O H NO OR H: 2–il]fenil]carbamato de fenilo 3,79 (d, 1H), 3,98–4,06 (m, 1H), 2-yl] phenyl] phenyl carbamate 3.79 (d, 1H), 3.98-4.06 (m, 1H),

NS N O NS N O: 4,19 (d, 1H), 4,53 (s, 2H), 6,87 (s, 4.19 (d, 1H), 4.53 (s, 2H), 6.87 (s,

O OR: 1H), 7,23–7,31 (m, 2H), 7,42 (d, 1H), 7.23-7.31 (m, 2H), 7.42 (d,

1H), 7,44–7,47 (m, 2H), 7,61–7,66 1H), 7.44-7.47 (m, 2H), 7.61-7.66

(m, 1H), 7,71 (d, 1H), 8,02–8,05 (m, (m, 1H), 7.71 (d, 1H), 8.02–8.05 (m,

1H), 8,50 (t, 1H), 10,36 (s, 1H) 1H), 8.50 (t, 1H), 10.36 (s, 1H)

N N N O S O O N H O OCl N N N O S O O N H O OCl: N–[2–cloro–4–[4–[(3S)–3– metilmorfolin–4–il]–6– (metilsulfonilmetil)pirimidin– 2–il]fenil]carbamato de fenilo 517 2,40 δ 1,26 (s, 3H), 3,20 (s, 3H), 3,24– 3,25 (m, 1H), 3,48–3,54 (m, 1H), 3,64–3,68 (m, 1H), 3,79 (d, 1H), 3,98–4,02 (m, 1H), 4,18–4,23 (m, 1H), 4,51 (m, 1H), 4,55 (s, 2H), 6,90 (s, 1H), 7,14–7,18 (m, 1H), 7,24–7,28 (m, 2H), 7,42–7,45 (m, 2H), 7,84 (d, 1H), 8,29–8,31 (m,1H), 8,39 (d, 1H), 9,83 (s, 1H) N- [2-chloro-4– [4 - [(3S) -3– methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin– 2-yl] phenyl] phenyl carbamate 517 2.40 δ 1.26 (s, 3H), 3.20 (s, 3H), 3.24-3.25 (m, 1H), 3.48-3.54 (m, 1H), 3.64-3 , 68 (m, 1H), 3.79 (d, 1H), 3.98-4.02 (m, 1H), 4.18-4.23 (m, 1H), 4.51 (m, 1H ), 4.55 (s, 2H), 6.90 (s, 1H), 7.14–7.18 (m, 1H), 7.24–7.28 (m, 2H), 7.42– 7.45 (m, 2H), 7.84 (d, 1H), 8.29–8.31 (m, 1H), 8.39 (d, 1H), 9.83 (s, 1H)

N N N O S O O N H O O N N N O S O O N H O O: N–[2–metil–4–[4–[(3S)–3– metilmorfolin–4–il]–6– (metilsulfonilmetil)pirimidin– 2–il]fenil]carbamato de fenilo 496 1,61 N- [2-methyl – 4– [4 - [(3S) –3– methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin– 2-yl] phenyl] phenyl carbamate 496 1.61

Las preparaciones de las anilinas requeridas arriba se describieron anteriormente. 92 The aniline preparations required above were described above. 92

Ejemplo 9: 1–[4–[4–[(3S)–3–Metilmorfolin–4–il]–6–(propan–2–ilsulfonilmetil)pirimidin–2–il]fenil]–3–fenil–urea Example 9: 1– [4– [4 - [(3S) –3 – Methylmorpholin-4-yl] –6– (propan – 2-ylsulfonylmethyl) pyrimidin – 2-yl] phenyl] –3-phenyl-urea

O OR

N N

N O S N O S

O OR

NN

O N O n

N HH N HH

Se disolvió 1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(propan–2–ilsulfanilmetil)pirimidin–2–il]fenil]–3–fenil–urea (78 mg) en 1,4–dioxano (6 ml) y agua (1 ml). La disolución se enfrió hasta 0ºC y se añadió ácido 3–cloroperoxibenzoico (75%) (34 mg) seguido inmediatamente por permanganato de sodio (40 mg). La reacción se dejó agitar a temperatura ambiente durante 2 horas. La reacción se cargó en una columna SCX–2, la columna se lavó con metanol y el material deseado se eluyó con amoniaco 7N en metanol. Las fracciones se concentraron a vacío para dar el compuesto deseado como un sólido amarillo pálido (77 mg). 1– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (propan – 2-ylsulfanylmethyl) pyrimidin – 2-yl] phenyl] –3-phenyl-urea (78 mg was dissolved ) in 1,4-dioxane (6 ml) and water (1 ml). The solution was cooled to 0 ° C and 3-chloroperoxybenzoic acid (75%) (34 mg) was added followed immediately by sodium permanganate (40 mg). The reaction was allowed to stir at room temperature for 2 hours. The reaction was loaded on an SCX-2 column, the column was washed with methanol and the desired material eluted with 7N ammonia in methanol. The fractions were concentrated in vacuo to give the desired compound as a pale yellow solid (77 mg).

Espectro RMN: RMN 1H (399,9 MHz, DMSO–d6) δ 1,25 (3H, d), 1,31–1,38 (6H, m), 3,18–3,24 (1H, m), 3,48–3,58 (2H, m), 3,64–3,68 (1H, m), 3,79 (1H, d), 3,98–4,01 (1H, m), 4,18 (1H, d), 4,48 (3H, s), 6,79 (1H, s), 6,97–7,01 (1H, m), 7,28–7,31 (1H, m), 7,31 (1H, d), 7,46–7,49 (2H, m), 7,56–7,58 (2H, m), 8,25 (2H, d), 8,73 (1H, s), 8,92 (1H, s) NMR Spectrum: 1H NMR (399.9 MHz, DMSO – d6) δ 1.25 (3H, d), 1.31–1.38 (6H, m), 3.18–3.24 (1H, m) , 3.48-3.58 (2H, m), 3.64-3.68 (1H, m), 3.79 (1H, d), 3.98-4.01 (1H, m), 4 , 18 (1H, d), 4.48 (3H, s), 6.79 (1H, s), 6.97–7.01 (1H, m), 7.28–7.31 (1H, m ), 7.31 (1H, d), 7.46–7.49 (2H, m), 7.56–7.58 (2H, m), 8.25 (2H, d), 8.73 ( 1H, s), 8.92 (1H, s)

Espectro de masa: M+H+ 510. Mass spectrum: M + H + 510.

Prueba (a): 0,59 μM. Test (a): 0.59 μM.

1–[4–[4–[(3S)–3–Metilmorfolin–4–il]–6–(propan–2–ilsulfanilmetil)pirimidin–2–il]fenil]–3–fenil–urea 1– [4– [4 - [(3S) –3 – Methylmorpholin-4-yl] –6– (propan – 2-ylsulfanylmethyl) pyrimidin – 2-yl] phenyl] –3-phenyl-urea

Se disolvió Isopropilmercaptano (0,075 ml) en acetonitrilo (5 ml) y 1,8–diazabiciclo[5,4,0]undec–7–eno (0,12 ml). La reacción se dejó agitar a temperatura ambiente durante 15 minutos, y después se añadió 1–[4–[4–[(3S)–3– metilmorfolin–4–il]–6–(metilsulfoniloximetil)pirimidin–2–il]fenil]–3–fenil–urea (228 mg) en acetonitrilo (5 ml). La reacción se agitó durante 30 minutos, y después se concentró a vacío. El residuo se cromatografió en sílice, eluyendo con 2,5% de metanol en DCM, para dar el compuesto deseado (78 mg) como una goma. Isopropylmercaptane (0.075 ml) was dissolved in acetonitrile (5 ml) and 1,8-diazabicyclo [5,4,0] undec-7-ene (0.12 ml). The reaction was allowed to stir at room temperature for 15 minutes, and then 1– [4– [4 - [(3S) –3– methylmorpholin-4-yl] –6– (methylsulfonyloxymethyl) pyrimidin-2-yl] phenyl was added ] –3-phenyl-urea (228 mg) in acetonitrile (5 ml). The reaction was stirred for 30 minutes, and then concentrated in vacuo. The residue was chromatographed on silica, eluting with 2.5% methanol in DCM, to give the desired compound (78 mg) as a gum.

Espectro de masa: M+H+ 478. Mass spectrum: M + H + 478.

1–[4–[4–[(3S)–3–Metilmorfolin–4–il]–6–(metilsulfoniloximetil)pirimidin–2–il]fenil]–3–fenil–urea 1– [4– [4 - [(3S) –3 – Methylmorpholin-4-yl] –6– (methylsulfonyloxymethyl) pyrimidin – 2-yl] phenyl] –3-phenyl-urea

O OR

N N

N O NO

O OR

S NO S NO

O N O n

N HH N HH

Se disolvió 1–[4–[4–(hidroximetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]–3–fenil–urea (388 mg) en DCM (15 ml) y trietilamina (0,194 ml), y la disolución se enfrió hasta 0ºC. se añadió cloruro de metanosulfonilo (0,108 ml), y la reacción se agitó durante 90 min. a 0ºC. La mezcla de reacción se concentró a vacío y se repartió entre DCM (20 ml) y agua (10 ml). La fase orgánica se lavó con salmuera (10 ml), se secó (MgSO4) y se concentró a vacío para dar el compuesto deseado (273 mg) como un sólido. 1– [4– [4– (hydroxymethyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] –3-phenyl-urea (388 mg) was dissolved in DCM ( 15 ml) and triethylamine (0.194 ml), and the solution was cooled to 0 ° C. methanesulfonyl chloride (0.108 ml) was added, and the reaction was stirred for 90 min. at 0 ° C. The reaction mixture was concentrated in vacuo and partitioned between DCM (20 ml) and water (10 ml). The organic phase was washed with brine (10 ml), dried (MgSO4) and concentrated in vacuo to give the desired compound (273 mg) as a solid.

La preparación de 1–[4–[4–(hidroximetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]–3–fenil–urea se describió anteriormente. The preparation of 1– [4– [4– (hydroxymethyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] –3-phenyl-urea was described above.

Ejemplo 10: 3–[4–[4–(Hidroximetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]–1,1–dimetil–urea Example 10: 3– [4– [4– (Hydroxymethyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] –1,1-dimethyl-urea

O OR

N N

N HO N HO

N N

O OR

N H 5 N H 5

N N

Se disolvieron 3–(4–bromofenil)–1,1–dimetil–urea (825 mg), acetato de potasio (998 mg), y bis(pinacolato)diboro (1,03 g) en 1,4 dioxano (45 ml). La disolución se desgasificó durante 5 minutos, después se añadió aducto de 1,1’– bis(difenilfosfino)ferrocenodicloropaladio(II) diclorometano (167 mg), y la reacción se calentó hasta 85ºC durante 3 horas. Se añadieron [2–cloro–6–[(3S)–3–metilmorfolin–4–il]pirimidin–4–il]metanol (828 mg), etanol (3,75 ml), 3– (4-Bromophenyl) -1,1-dimethyl-urea (825 mg), potassium acetate (998 mg), and bis (pinacolato) diboro (1.03 g) were dissolved in 1.4 dioxane (45 ml) ). The solution was degassed for 5 minutes, then 1,1'-bis (diphenylphosphino) ferrocenodichloropaladium (II) dichloromethane adduct (167 mg) was added, and the reaction was heated to 85 ° C for 3 hours. [2-Chloro-6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-4-yl] methanol (828 mg), ethanol (3.75 ml) were added,

10 disolución 2M de carbonato de sodio (8,53 ml) y aducto de 1,1’–bis(difenilfosfino)ferrocenodicloropaladio(II) diclorometano (167 mg), y el calentamiento se continuó durante 16 horas. La reacción se enfrió y se evaporó hasta sequedad, y el residuo se repartió entre acetato de etilo (125 ml) y agua (100 ml). Los productos orgánicos se secaron sobre sulfato de magnesio, se filtraron y se concentraron a vacío. El material bruto se cromatografió en sílice, eluyendo con 5% de metanol en DCM, para dar el material deseado (737 mg) como un sólido blanco. 10 2M solution of sodium carbonate (8.53 ml) and adduct of 1,1'-bis (diphenylphosphino) ferrocenodichloropaladium (II) dichloromethane (167 mg), and heating was continued for 16 hours. The reaction was cooled and evaporated to dryness, and the residue was partitioned between ethyl acetate (125 ml) and water (100 ml). The organic products were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was chromatographed on silica, eluting with 5% methanol in DCM, to give the desired material (737 mg) as a white solid.

15 Espectro RMN: RMN 1H (DMSO–d6) δ 1,22–1,24 (3H, m), 2,95 (6H, s), 3,16–3,23 (1H, m), 3,46–3,53 (1H, m), 3,62– 3,66 (1H, m), 3,77 (1H, d), 3,96–4,00 (1H, m), 4,18 (1H, d), 4,45–4,50 (3H, m), 5,38 (1H, t), 6,66 (1H, s), 7,55–7,59 (2H, m), 8,18–8,22 (2H, m), 8,45 (1H, s) 15 NMR Spectrum: 1H NMR (DMSO – d6) δ 1.22–1.24 (3H, m), 2.95 (6H, s), 3.16–3.23 (1H, m), 3.46 –3.53 (1H, m), 3.62– 3.66 (1H, m), 3.77 (1H, d), 3.96-4.00 (1H, m), 4.18 (1H , d), 4.45-4.50 (3H, m), 5.38 (1H, t), 6.66 (1H, s), 7.55–7.59 (2H, m), 8, 18–8.22 (2H, m), 8.45 (1H, s)

Espectro de masa: M+H+ 372. Mass spectrum: M + H + 372.

Prueba (a): 19 μM. Test (a): 19 μM.

20 A continuación se describe la preparación de 3–(4–bromofenil)–1,1–dimetil–urea. 20 The preparation of 3– (4-bromophenyl) -1,1-dimethyl-urea is described below.

3–(4–Bromofenil)–1,1–dimetil–urea 3– (4 – Bromophenyl) –1,1-dimethyl-urea

H H

Se disolvió isocianato de 4–bromofenilo (1,00 g) en THF (30 ml). Se añadió dimetilamina (2,0M en THF, 2,78 ml) a la disolución, y la reacción se agitó a RT durante 2 horas. La reacción se filtró, se concentró a vacío, y el residuo se 4-Bromophenyl isocyanate (1.00 g) was dissolved in THF (30 ml). Dimethylamine (2.0M in THF, 2.78 ml) was added to the solution, and the reaction was stirred at RT for 2 hours. The reaction was filtered, concentrated in vacuo, and the residue was

25 cromatografió en sílice, eluyendo con 5% de metanol en DCM, para dar el material deseado (830 mg) como un sólido blanco. Chromatographed on silica, eluting with 5% methanol in DCM, to give the desired material (830 mg) as a white solid.

Espectro RMN: RMN 1H (DMSO–d6) δ 2,90 (6H, s), 7,37–7,40 (2H, m), 7,45–7,47 (2H, m), 8,37 (1H, s) NMR Spectrum: 1H NMR (DMSO – d6) δ 2.90 (6H, s), 7.37–7.40 (2H, m), 7.45–7.47 (2H, m), 8.37 ( 1H, s)

Espectro de masa: M+H+ 244. Mass spectrum: M + H + 244.

Ejemplo 11: Example 11:

30 N–[2–[[6–[(3S)–3–metilmorfolin–4–il]–2–[4–(fenilcarbamoilamino)fenil]pirimidin–4– il]metilsulfonil]etil]acetamida 30 N– [2 - [[6 - [(3S) –3-methylmorpholin-4-yl] –2– [4– (phenylcarbamoylamino) phenyl] pyrimidin-4-yl] methylsulfonyl] ethyl] acetamide

O OR

N N

N S N S

NH O O N NH O O N

O OR

N N

N HH N HH

Se disolvió N–[2–[[6–[(3S)–3–metilmorfolin–4–il]–2–[4–(fenilcarbamoilamino)fenil]pirimidin–4–il]metilsulfanil]etil]acetamida (100 mg) en 1,4–dioxano (6 ml) y agua (1 ml). La disolución se enfrió hasta 0ºC y se añadió ácido 3– cloroperbenzoico (75%) (40 mg) seguido inmediatamente por permanganato de sodio (47 mg). La reacción se dejó agitar a RT durante 2 horas. Se añadieron ácido 3–cloroperbenzoico (4 mg) y permanganato de sodio (4 mg) adicionales, y la reacción se agitó durante una hora extra. La reacción se cargó en una columna SCX–2, se lavó con metanol, y el material deseado se eliminó con amoniaco 7N en metanol. El material deseado se aisló como un sólido blanco (102 mg). N– [2 - [[6 - [(3S) –3-methylmorpholin-4-yl] –2– [4– (phenylcarbamoylamino) phenyl] pyrimidin-4-yl] methylsulfanyl] ethyl] acetamide (100 mg) was dissolved in 1,4-dioxane (6 ml) and water (1 ml). The solution was cooled to 0 ° C and 3-chloroperbenzoic acid (75%) (40 mg) was added followed immediately by sodium permanganate (47 mg). The reaction was allowed to stir at RT for 2 hours. Additional 3-chloroperbenzoic acid (4 mg) and sodium permanganate (4 mg) were added, and the reaction was stirred for an extra hour. The reaction was loaded on an SCX-2 column, washed with methanol, and the desired material was removed with 7N ammonia in methanol. The desired material was isolated as a white solid (102 mg).

Espectro RMN: RMN 1H (DMSO–d6) δ 1,25 (3H, d), 1,84 (3H, s), 3,18–3,24 (1H, m), 3,48–3,54 (2H, m), 3,52 (1H, s), 3,58 (2H, q), 3,64–3,68 (1H, m), 3,79 (1H, d), 3,98–4,01 (1H, m), 4,18 (1H, d), 4,49 (1H, s), 4,53 (2H, s), 6,80 (1H, s), 6,99 (1H, t), 7,31 (2H, d), 7,46–7,49 (2H, m), 7,57 (2H, d), 8,16 (1H, t), 8,27 (2H, d), 8,70 (1H, s), 8,92 (1H, s) NMR Spectrum: 1H NMR (DMSO-d6) δ 1.25 (3H, d), 1.84 (3H, s), 3.18-3.24 (1H, m), 3.48-3.54 ( 2H, m), 3.52 (1H, s), 3.58 (2H, q), 3.64-3.68 (1H, m), 3.79 (1H, d), 3.98-4 , 01 (1H, m), 4.18 (1H, d), 4.49 (1H, s), 4.53 (2H, s), 6.80 (1H, s), 6.99 (1H, t), 7.31 (2H, d), 7.46-7.49 (2H, m), 7.57 (2H, d), 8.16 (1H, t), 8.27 (2H, d ), 8.70 (1H, s), 8.92 (1H, s)

Espectro de masa: M+H+ 553. Mass spectrum: M + H + 553.

Prueba (a): 0,14 μM. Test (a): 0.14 μM.

A continuación se describe la preparación de N–[2–[[6–[(3S)–3–metilmorfolin–4–il]–2–[4– (fenilcarbamoilamino)fenil]pirimidin–4–il]metilsulfanil]etil]acetamida. The preparation of N– [2 - [[6 - [(3S) –3-methylmorpholin-4-yl] –2– [4– (phenylcarbamoylamino) phenyl] pyrimidin-4-yl] methylsulfanyl] ethyl] is described below. acetamide

N–[2–[[6–[(3S)–3–Metilmorfolin–4–il]–2–[4–(fenilcarbamoilamino)fenil]pirimidin–4–il]metilsulfanil]etil]acetamida N– [2 - [[6 - [(3S) –3 – Methylmorpholin-4-yl] –2– [4– (phenylcarbamoylamino) phenyl] pyrimidin-4-yl] methylsulfanyl] ethyl] acetamide

OO NH N OO NH N

N S N S

N N

O OR

N N

N HH N HH

Se disolvió N–acetilcisteamina (0,086 ml) en acetonitrilo (5 ml). Después se añadió DBU (0,120 ml) a la disolución y se dejó agitar a RT durante 15 minutos. Se añadió 1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6– (metilsulfoniloximetil)pirimidin–2–il]fenil]–3–fenil–urea (228 mg) en acetonitrilo (5 ml) a la reacción y se agitó durante 30 minutos. La reacción se concentró a vacío, y el residuo bruto se purificó en sílice, eluyendo con 5% de metanol en DCM, para dar el compuesto deseado (100 mg) como un sólido blanco. N-acetylcysteamine (0.086 ml) was dissolved in acetonitrile (5 ml). Then DBU (0.120 ml) was added to the solution and allowed to stir at RT for 15 minutes. 1– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (methylsulfonyloxymethyl) pyrimidin-2-yl] phenyl] –3-phenyl-urea (228 mg) in acetonitrile ( 5 ml) to the reaction and stirred for 30 minutes. The reaction was concentrated in vacuo, and the crude residue was purified on silica, eluting with 5% methanol in DCM, to give the desired compound (100 mg) as a white solid.

Espectro de masa: M+H+ 521. Mass spectrum: M + H + 521.

La preparación de 1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfoniloximetil)pirimidin–2–il]fenil]–3–fenil–urea se describió anteriormente. The preparation of 1– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (methylsulfonyloxymethyl) pyrimidin-2-yl] phenyl] –3-phenyl-urea was described above.

Ejemplo 12: Example 12:

1–[4–[4–(Bencenosulfonilmetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]–3–fenil–urea 1– [4– [4– (Benzenesulfonylmethyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] –3-phenyl-urea

Se disolvió 1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(fenilsulfanilmetil)pirimidin–2–il]fenil]–3–fenil–urea (62 mg) en 1,4– dioxano (6 ml) y agua (1 ml). La disolución se enfrió hasta 0ºC y se añadió ácido 3–cloroperbenzoico (75%) (26 mg) seguido inmediatamente por permanganato de sodio (30 mg). La reacción se dejó agitar a RT durante 2 horas, y después se añadieron ácido 3–cloroperbenzoico (4 mg) y permanganato de sodio (4 mg) adicionales. La reacción se agitó durante 1 hora extra, después la reacción se cargó en una columna SCX–2, se lavó con metanol, y el material deseado se eliminó con amoniaco 7N en metanol. El material deseado se aisló como un sólido amarillo pálido (64 mg). 1– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (phenylsulfanylmethyl) pyrimidin – 2-yl] phenyl] –3-phenyl-urea (62 mg) was dissolved in 1, 4– dioxane (6 ml) and water (1 ml). The solution was cooled to 0 ° C and 3-chloroperbenzoic acid (75%) (26 mg) was added followed immediately by sodium permanganate (30 mg). The reaction was allowed to stir at RT for 2 hours, and then additional 3-chloroperbenzoic acid (4 mg) and sodium permanganate (4 mg) were added. The reaction was stirred for an extra 1 hour, then the reaction was loaded on an SCX-2 column, washed with methanol, and the desired material was removed with 7N ammonia in methanol. The desired material was isolated as a pale yellow solid (64 mg).

Espectro RMN: RMN 1H (DMSO–d6) δ 1,20 (3H, d), 3,14–3,21 (1H, m), 3,45–3,52 (1H, m), 3,61–3,65 (1H, m), 3,77 (1H, d), 3,96–3,99 (1H, m), 4,10 (1H, d), 4,38 (1H, s), 4,71 (2H, s), 6,63 (1H, s), 6,99 (1H, m), 7,31 (2H, d), 7,46 (4H, t), 7,63 (2H, t), 7,73–7,78 (1H, m), 7,82 (1H, d), 7,82–7,84 (1H, m), 7,87 (2H, d), 8,69 (1H, s), 8,87 (1H, s). NMR Spectrum: 1H NMR (DMSO – d6) δ 1.20 (3H, d), 3.14–3.21 (1H, m), 3.45–3.52 (1H, m), 3.61– 3.65 (1H, m), 3.77 (1H, d), 3.96-3.99 (1H, m), 4.10 (1H, d), 4.38 (1H, s), 4 , 71 (2H, s), 6.63 (1H, s), 6.99 (1H, m), 7.31 (2H, d), 7.46 (4H, t), 7.63 (2H, t), 7.73–7.78 (1H, m), 7.82 (1H, d), 7.82–7.84 (1H, m), 7.87 (2H, d), 8.69 (1H, s), 8.87 (1H, s).

Espectro de masa: M+H+ 544. Mass spectrum: M + H + 544.

Prueba (a): 0,23 μM. Test (a): 0.23 μM.

A continuación se describe la preparación de 1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(fenilsulfanilmetil)pirimidin–2– il]fenil]–3–fenil–urea. 1–[4–[4–[(3S)–3–Metilmorfolin–4–il]–6–(fenilsulfanilmetil)pirimidin–2–il]fenil]–3–fenil–urea The preparation of 1– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (phenylsulfanylmethyl) pyrimidin – 2– is described below il] phenyl] –3-phenyl-urea. 1– [4– [4 - [(3S) –3 – Methylmorpholin-4-yl] –6– (phenylsulfanylmethyl) pyrimidin-2-yl] phenyl] –3-phenyl-urea

HHH H

5 Se disolvió tiofenol (0,029 ml) en acetonitrilo (3 ml). Después se añadió DBU (0,043 ml) a la disolución y se dejó agitar a RT durante 15 minutos. Se añadió 1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfoniloximetil)pirimidin–2– il]fenil]–3–fenil–urea (80 mg) a la reacción y se agitó durante 30 minutos. La reacción se concentró a vacío, y el residuo se cromatografió en sílice, eluyendo con 5% de metanol en DCM, para dar el material deseado (62 mg) 5 Thiophenol (0.029 ml) was dissolved in acetonitrile (3 ml). Then DBU (0.043 ml) was added to the solution and allowed to stir at RT for 15 minutes. 1– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (methylsulfonyloxymethyl) pyrimidin-2-yl] phenyl] –3-phenyl-urea (80 mg) was added to the reaction and stirred for 30 minutes. The reaction was concentrated in vacuo, and the residue was chromatographed on silica, eluting with 5% methanol in DCM, to give the desired material (62 mg).

10 como un sólido blanco. 10 as a white solid.

Espectro de masa: M+H+ 512. Mass spectrum: M + H + 512.

Ejemplo 13: Example 13:

3–[4–[4–(Cianometilsulfonilmetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]–1,1–dimetil–urea 3– [4– [4– (Cyanomethylsulfonylmethyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] –1,1-dimethyl-urea

O OR

N N

N NC N NC

OO OO

S S

N N

O OR

N H N H

N N

15 Se disolvió 3–[4–[4–(cianometilsulfanilmetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]–1,1–dimetil–urea (162 mg) en 1,4–dioxano (6 ml) y agua (1 ml). La disolución se enfrió hasta 0ºC, y se añadió ácido 3–cloroperbenzoico (75%) (79 mg) seguido inmediatamente por permanganato de sodio (92 mg). La reacción se dejó agitar a RT durante 2 horas. Se añadieron ácido 3–cloroperbenzoico (40 mg) y permanganato de sodio (45 mg) adicionales, y la reacción se agitó durante 1 hora, después se añadieron ácido 3–cloroperbenzoico (40 mg) y permanganato de sodio 15 3– [4– [4– (cyanomethylsulfanylmethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] –1,1-dimethyl-urea (162 mg) was dissolved in 1,4-dioxane (6 ml) and water (1 ml). The solution was cooled to 0 ° C, and 3-chloroperbenzoic acid (75%) (79 mg) was added followed immediately by sodium permanganate (92 mg). The reaction was allowed to stir at RT for 2 hours. Additional 3-chloroperbenzoic acid (40 mg) and sodium permanganate (45 mg) were added, and the reaction was stirred for 1 hour, then 3-chloroperbenzoic acid (40 mg) and sodium permanganate were added

20 (45 mg) adicionales, y la reacción se agitó durante 1 hora. La reacción se cargó en una columna SCX–2, se lavó con metanol, y el material deseado se eliminó con amoniaco 7N en metanol. El material deseado se aisló como un sólido blanco (17 mg). An additional 20 (45 mg), and the reaction was stirred for 1 hour. The reaction was loaded on an SCX-2 column, washed with methanol, and the desired material was removed with 7N ammonia in methanol. The desired material was isolated as a white solid (17 mg).

Espectro RMN: RMN 1H (DMSO–d6) δ 1,25 (3H, d), 2,96 (6H, s), 3,18 (1H, d), 3,47–3,54 (1H, m), 3,64–3,67 (1H, m), 3,79 (1H, d), 3,98–4,01 (1H, m), 4,17 (1H, s), 4,46 (1H, d), 4,74 (2H, s), 5,10 (2H, d), 6,82 (1H, s), 7,59–7,61 (2H, m), NMR Spectrum: 1H NMR (DMSO-d6) δ 1.25 (3H, d), 2.96 (6H, s), 3.18 (1H, d), 3.47-3.54 (1H, m) , 3.64-3.67 (1H, m), 3.79 (1H, d), 3.98-4.01 (1H, m), 4.17 (1H, s), 4.46 (1H , d), 4.74 (2H, s), 5.10 (2H, d), 6.82 (1H, s), 7.59-7.61 (2H, m),

25 8,21–8,23 (2H, m), 8,49 (1H, s) 25 8.21–8.23 (2H, m), 8.49 (1H, s)

Espectro de masa: M+H+ 459. Mass spectrum: M + H + 459.

Prueba (a): 2,1 μM. Test (a): 2.1 μM.

A continuación se describe la preparación de 3–[4–[4–(cianometilsulfanilmetil)–6–[(3S)–3–metilmorfolin–4– il]pirimidin–2–il]fenil]–1,1–dimetil–urea. The preparation of 3– [4– [4– (cyanomethylsulfanylmethyl) –6 - [(3S) –3-methylmorpholin-4– yl] pyrimidin – 2-yl] phenyl] –1,1-dimethyl-urea is described below .

30 3–[4–[4–(Cianometilsulfanilmetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]–1,1–dimetil–urea 30 3– [4– [4– (Cyanomethylsulfanylmethyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] –1,1-dimethyl-urea

O OR

N NC N NC

N S N S

N N

O OR

N H N H

N N

Se disolvió 3–[4–[4–(carbamimidoilsulfanilmetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]–1,1–dimetil–urea (0,38 mmoles) en DMF (2 ml). Se trató con bromoacetonitrilo (0,030 ml) y después con hidróxido de sodio (61 mg) en agua (1 ml) y se agitó a RT durante 15 minutos. La mezcla de reacción se concentró a vacío, y el residuo se cargó en una columna SCX–2, se lavó con metanol y el material deseado se eliminó con amoniaco 7N en metanol. El material deseado se aisló y se usó sin cromatografía adicional. 3– [4– [4– (carbamimidoylsulfanylmethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] -1,1-dimethyl-urea (0.38 mmol) was dissolved ) in DMF (2 ml). It was treated with bromoacetonitrile (0.030 ml) and then with sodium hydroxide (61 mg) in water (1 ml) and stirred at RT for 15 minutes. The reaction mixture was concentrated in vacuo, and the residue was loaded on an SCX-2 column, washed with methanol and the desired material was removed with 7N ammonia in methanol. The desired material was isolated and used without additional chromatography.

Espectro de masa: M+H+ 427. Mass spectrum: M + H + 427.

3–[4–[4–(Carbamimidoilsulfanilmetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]–1,1–dimetil–urea 3– [4– [4– (Carbamimidoylsulfanylmethyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] –1,1-dimethyl-urea

O OR

N H2N NH N H2N NH

N S N S

N N

O OR

N H N H

N N

10 Se disolvió 3–[4–[4–(hidroximetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]–1,1–dimetil–urea (140 mg) en DCM (5 ml) y trietilamina (0,079 ml), y la disolución se enfrió hasta 0ºC. Se añadió cloruro de metanosulfonilo (0,044 ml), y la reacción se agitó durante 15 minutos a RT. El disolvente se eliminó a presión reducida y se reemplazó con etanol (5 ml), y después se añadió tiourea (32 mg). La reacción se calentó después hasta 70ºC durante 30 minutos, después se dejó enfriar y se concentró a vacío para dar el material deseado que se usó sin purificación adicional. 10 3– [4– [4– (hydroxymethyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] –1,1-dimethyl-urea (140 mg) was dissolved in DCM (5 ml) and triethylamine (0.079 ml), and the solution was cooled to 0 ° C. Methanesulfonyl chloride (0.044 ml) was added, and the reaction was stirred for 15 minutes at RT. The solvent was removed under reduced pressure and replaced with ethanol (5 ml), and then thiourea (32 mg) was added. The reaction was then heated to 70 ° C for 30 minutes, then allowed to cool and concentrated in vacuo to give the desired material that was used without further purification.

15 Espectro de masa: M+H+ 430. 15 Mass spectrum: M + H + 430.

Ejemplo 14: Example 14:

1,1–Dimetil–3–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(propan–2–ilsulfonilmetil)pirimidin–2–il]fenil]urea 1,1 – Dimethyl – 3– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (propan – 2-ylsulfonylmethyl) pyrimidin – 2-yl] phenyl] urea

O OR

N N

N S N S

OO OO

N N

O OR

N H N H

N N

Se disolvió 1,1–dimetil–3–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(propan–2–ilsulfanilmetil)pirimidin–2–il]fenil]urea (163 1,1-Dimethyl-3– [4– [4 - [(3S) -3-methylmorpholin-4-yl] –6– (propan-2-ylsulfanylmethyl) pyrimidin-2-yl] phenyl] urea (163) was dissolved

20 mg) en 1,4–dioxano (6 ml) y agua (1 ml). La disolución se enfrió hasta 0ºC, y se añadió ácido 3–cloroperbenzoico (75%) (79 mg) seguido inmediatamente por permanganato de sodio (92 mg). La reacción se dejó agitar a RT durante 2 horas, y después se añadieron ácido 3–cloroperbenzoico (20 mg) y permanganato de sodio (25 mg) adicionales. La reacción se dejó agitar durante 1 hora, después se cargó en una columna SCX–2, se lavó con metanol, y el material deseado se eliminó con amoniaco 7N en metanol. El material deseado (90 mg) se aisló como un sólido 20 mg) in 1,4-dioxane (6 ml) and water (1 ml). The solution was cooled to 0 ° C, and 3-chloroperbenzoic acid (75%) (79 mg) was added followed immediately by sodium permanganate (92 mg). The reaction was allowed to stir at RT for 2 hours, and then additional 3-chloroperbenzoic acid (20 mg) and sodium permanganate (25 mg) were added. The reaction was allowed to stir for 1 hour, then loaded on an SCX-2 column, washed with methanol, and the desired material was removed with 7N ammonia in methanol. The desired material (90 mg) was isolated as a solid

25 blanco. 25 white

Espectro RMN: RMN 1H (DMSO–d6) δ 1,25 (3H, d), 1,35–1,37 (6H, m), 2,95 (6H, s), 3,21–3,26 (2H, m), 3,47–3,54 (2H, m), 3,64–3,67 (1H, m), 3,78 (1H, d), 3,97–4,01 (1H, m), 4,24 (1H, m) 4,45–4,47 (2H, m), 6,78 (1H, s), 7,58–7,61 (2H, m), 8,17–8,20 (2H, m), 8,48 (1H, s) NMR Spectrum: 1H NMR (DMSO – d6) δ 1.25 (3H, d), 1.35-1.37 (6H, m), 2.95 (6H, s), 3.21–3.26 ( 2H, m), 3.47-3.54 (2H, m), 3.64-3.67 (1H, m), 3.78 (1H, d), 3.97-4.01 (1H, m), 4.24 (1H, m) 4.45-4.47 (2H, m), 6.78 (1H, s), 7.58-7.61 (2H, m), 8.17– 8.20 (2H, m), 8.48 (1H, s)

Espectro de masa: M+H+ 462. Mass spectrum: M + H + 462.

30 Prueba (a): 0,42 μM. 30 Test (a): 0.42 μM.

A continuación se describe la preparación de 1,1–dimetil–3–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(propan–2– ilsulfanilmetil)pirimidin–2–il]fenil]urea. 1,1–Dimetil–3–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(propan–2–ilsulfanilmetil)pirimidin–2–il]fenil]urea The preparation of 1,1-dimethyl-3– [4– [4 - [(3S) -3-methylmorpholin-4-yl] -6– (propan-2-ylsulfanylmethyl) pyrimidin-2-yl] is described below. phenyl] urea. 1,1 – Dimethyl – 3– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (propan – 2-ylsulfanylmethyl) pyrimidin – 2-yl] phenyl] urea

O OR

N N

N S N S

N N

O OR

N H N H

N N

5 Se disolvió 3–[4–[4–(hidroximetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]–1,1–dimetil–urea (140 mg) en DCM (5 ml) y trietilamina (0,079 ml), y la disolución se enfrió hasta 0ºC. Se añadió cloruro de metanosulfonilo (0,044 ml), y la reacción se agitó durante 15 minutos a RT antes de concentrarla a vacío para dar el mesilato, que se usó sin purificación adicional. Se disolvió isopropilmercaptano (0,062 ml) en acetonitrilo (5 ml). Después se añadió DBU (0,099 ml) a la disolución y se dejó agitar a RT durante 5 minutos. El mesilato bruto anterior se suspendió en 5 3– [4– [4– (hydroxymethyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] -1,1-dimethyl-urea (140 mg) was dissolved in DCM (5 ml) and triethylamine (0.079 ml), and the solution was cooled to 0 ° C. Methanesulfonyl chloride (0.044 ml) was added, and the reaction was stirred for 15 minutes at RT before concentrating in vacuo to give the mesylate, which was used without further purification. Isopropylmercaptane (0.062 ml) was dissolved in acetonitrile (5 ml). Then DBU (0.099 ml) was added to the solution and allowed to stir at RT for 5 minutes. The previous gross mesylate was suspended in

10 acetonitrilo (5 ml) y se añadió a la disolución de tiol. La reacción se dejó agitar a RT durante 1 hora, después se añadió DBU adicional (0,099 ml), y la reacción se agitó a RT durante 30 minutos. La mezcla de reacción se concentró a vacío para dar el material deseado que se usó sin purificación adicional. 10 acetonitrile (5 ml) and was added to the thiol solution. The reaction was allowed to stir at RT for 1 hour, then additional DBU (0.099 ml) was added, and the reaction was stirred at RT for 30 minutes. The reaction mixture was concentrated in vacuo to give the desired material that was used without further purification.

Espectro de masa: M+H+ 430. Mass spectrum: M + H + 430.

Ejemplo 15: Example 15:

15 3–[4–[4–(Bencenosulfonilmetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]–1,1–dimetil–urea 15 3– [4– [4– (Benzenesulfonylmethyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] –1,1-dimethyl-urea

O OR

N N

N S N S

OO OO

N N

O OR

N H N H

N N

Se disolvió 1,1–dimetil–3–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(fenilsulfanilmetil)pirimidin–2–il]fenil]urea (158 mg) en 1,4–dioxano (6 ml) y agua (1 ml). La disolución se enfrió hasta 0ºC, y se añadió ácido 3–cloroperbenzoico (75%) (89 mg) seguido inmediatamente por permanganato de sodio (96 mg). La reacción se dejó agitar a RT durante 16 horas, 1,1-Dimethyl-3– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (phenylsulfanylmethyl) pyrimidin – 2-yl] phenyl] urea (158 mg) was dissolved in 1 , 4-dioxane (6 ml) and water (1 ml). The solution was cooled to 0 ° C, and 3-chloroperbenzoic acid (75%) (89 mg) was added followed immediately by sodium permanganate (96 mg). The reaction was allowed to stir at RT for 16 hours,

20 y después se añadieron ácido 3–cloroperbenzoico (20 mg) y permanganato de sodio (25 mg) adicionales. La reacción se dejó agitar durante 1 hora, después se cargó en una columna SCX–2, se lavó con metanol, y el material deseado se eliminó con amoniaco 7N en metanol. El material deseado se aisló como un sólido blanco (90 mg). 20 and then additional 3-chloroperbenzoic acid (20 mg) and sodium permanganate (25 mg) were added. The reaction was allowed to stir for 1 hour, then loaded on an SCX-2 column, washed with methanol, and the desired material was removed with 7N ammonia in methanol. The desired material was isolated as a white solid (90 mg).

Espectro RMN: RMN 1H (DMSO–d6) δ 1,20 (3H, d), 2,95 (6H, s), 3,13–3,20 (1H, m), 3,44–3,51 (1H, m), 3,61–3,65 (1H, m), 3,76 (1H, d), 3,95–3,99 (1H, m), 4,07 (1H, t), 4,36 (1H, s), 4,70 (2H, s), 6,62 (1H, s), 7,47–7,49 (2H, m), 7,62 NMR Spectrum: 1H NMR (DMSO-d6) δ 1.20 (3H, d), 2.95 (6H, s), 3.13-3.20 (1H, m), 3.44-3.51 ( 1H, m), 3.61-3.65 (1H, m), 3.76 (1H, d), 3.95-3.99 (1H, m), 4.07 (1H, t), 4 , 36 (1H, s), 4.70 (2H, s), 6.62 (1H, s), 7.47-7.49 (2H, m), 7.62

25 (2H, t), 7,72–7,75 (1H, m), 7,79–7,84 (4H, m), 8,43 (1H, s) 25 (2H, t), 7.72–7.75 (1H, m), 7.79–7.84 (4H, m), 8.43 (1H, s)

Espectro de masa: M+H+ 496. Mass spectrum: M + H + 496.

Prueba (a): 1 μM. Test (a): 1 μM.

A continuación se describe la preparación de 1,1–dimetil–3–[4–[4–[(3S)–3–metilmorfolin–4–il]–6– (fenilsulfanilmetil)pirimidin–2–il]fenil]urea. The preparation of 1,1-dimethyl-3– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (phenylsulfanylmethyl) pyrimidin-2-yl] phenyl] urea is described below.

30 1,1–Dimetil–3–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(fenilsulfanilmetil)pirimidin–2–il]fenil]urea 30 1,1 – Dimethyl – 3– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (phenylsulfanylmethyl) pyrimidin – 2-yl] phenyl] urea

H H

Se disolvió tiofenol (0,062 ml) en acetonitrilo (5 ml). Después se añadió DBU (0,141 ml) a la disolución y se dejó agitar a RT durante 5 minutos. Se suspendió 1,1–dimetil–3–[4–[4–[(3S)–3–metilmorfolin–4–il]–6– (metilsulfoniloximetil)pirimidin–2–il]fenil]urea (154 mg) en acetonitrilo (5 ml) y se añadió al tiol. La reacción se dejó agitar a RT 1 hora, y después se concentró a vacío para dar el material deseado que se usó sin purificación adicional. Thiophenol (0.062 ml) was dissolved in acetonitrile (5 ml). DBU (0.141 ml) was then added to the solution and allowed to stir at RT for 5 minutes. 1,1-dimethyl-3– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (methylsulfonyloxymethyl) pyrimidin-2-yl] phenyl] urea (154 mg) was suspended in acetonitrile (5 ml) and added to the thiol. The reaction was allowed to stir at RT 1 hour, and then concentrated in vacuo to give the desired material that was used without further purification.

Espectro de masa: M+H+ 464. Mass spectrum: M + H + 464.

1,1–Dimetil–3–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfoniloximetil)pirimidin–2–il]fenil]urea 1,1 – Dimethyl – 3– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (methylsulfonyloxymethyl) pyrimidin – 2-yl] phenyl] urea

O OR

N O NO

SO SW

N O NO

N N

O OR

N H N H

N N

10 Se disolvió 3–[4–[4–(hidroximetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]–1,1–dimetil–urea (384 mg) en DCM (12 ml) y trietilamina (0,216 ml), y la disolución se enfrió hasta 0ºC. Se añadió cloruro de metanosulfonilo (0,121 ml), y la reacción se agitó durante 15 minutos a RT antes de concentrarla a vacío para dar el material deseado. 10 3– [4– [4– (hydroxymethyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] –1,1-dimethyl-urea (384 mg) was dissolved in DCM (12 ml) and triethylamine (0.216 ml), and the solution was cooled to 0 ° C. Methanesulfonyl chloride (0.121 ml) was added, and the reaction was stirred for 15 minutes at RT before concentrating in vacuo to give the desired material.

Espectro de masa: M+H+ 450. Mass spectrum: M + H + 450.

15 Ejemplo 16: 15 Example 16:

N–[2–[[2–[4–(Dimetilcarbamoilamino)fenil]–6–[(3S)–3–metilmorfolin–4–il]pirimidin–4–il]metilsulfonil]etil]acetamida N– [2 - [[2– [4– (Dimethylcarbamoylamino) phenyl] –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-4-yl] methylsulfonyl] ethyl] acetamide

O OR

N N

N S N S

NH O O NH O o

N N

O OR

N H N H

N N

Se disolvió N–[2–[[2–[4–(dimetilcarbamoilamino)fenil]–6–[(3S)–3–metilmorfolin–4–il]pirimidin–4–il]metilsulfanil]N– [2 - [[2– [4– (dimethylcarbamoylamino) phenyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-4-yl] methylsulfanyl] was dissolved.

20 etil]acetamida (158 mg) en 1,4–dioxano (6 ml) y agua (1 ml). La disolución se enfrió hasta 0ºC, y se añadió ácido 3– cloroperbenzoico (75%) (116 mg) seguido inmediatamente por permanganato de sodio (134 mg). La reacción se dejó agitar a RT durante 1 hora, después se cargó en una columna SCX–2, se lavó con metanol, y el material deseado se eliminó con amoniaco 7N en metanol. El material deseado (84 mg) se aisló como un sólido blanco. 20 ethyl] acetamide (158 mg) in 1,4-dioxane (6 ml) and water (1 ml). The solution was cooled to 0 ° C, and 3-chloroperbenzoic acid (75%) (116 mg) was added followed immediately by sodium permanganate (134 mg). The reaction was allowed to stir at RT for 1 hour, then loaded on an SCX-2 column, washed with methanol, and the desired material was removed with 7N ammonia in methanol. The desired material (84 mg) was isolated as a white solid.

Espectro RMN: RMN 1H (DMSO–d6) δ 1,25 (3H, d), 1,83 (3H, s), 2,96 (6H, s), 3,20–3,25 (1H, m), 3,47–3,50 (1H, m), NMR Spectrum: 1H NMR (DMSO – d6) δ 1.25 (3H, d), 1.83 (3H, s), 2.96 (6H, s), 3.20–3.25 (1H, m) , 3.47-3.50 (1H, m),

25 3,52 (2H, d), 3,57 (2H, q), 3,63–3,67 (1H, m), 3,78 (1H, d), 3,97–4,01 (1H, m), 4,18 (1H, d), 4,51 (3H, m), 6,78 (1H, s), 7,58–7,61 (2H, m), 8,16–8,19 (1H, m), 8,19–8,22 (2H, m), 8,49 (1H, s) 25 3.52 (2H, d), 3.57 (2H, q), 3.63-3.67 (1H, m), 3.78 (1H, d), 3.97-4.01 (1H , m), 4.18 (1H, d), 4.51 (3H, m), 6.78 (1H, s), 7.58-7.61 (2H, m), 8.16-8, 19 (1H, m), 8.19–8.22 (2H, m), 8.49 (1H, s)

Espectro de masa: M+H+ 505. Mass spectrum: M + H + 505.

Prueba (a): 4 μM. Test (a): 4 μM.

A continuación se describe la preparación de N–[2–[[2–[4–(Dimetilcarbamoilamino)fenil]–6–[(3S)–3–metilmorfolin–4– il]pirimidin–4–il]metilsulfanil]etil]acetamida. The preparation of N– [2 - [[2– [4– (Dimethylcarbamoylamino) phenyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-4-yl] methylsulfanyl] ethyl] is described below. acetamide

N–[2–[[2–[4–(Dimetilcarbamoilamino)fenil]–6–[(3S)–3–metilmorfolin–4–il]pirimidin–4–il]metilsulfanil]etil]acetamida N– [2 - [[2– [4– (Dimethylcarbamoylamino) phenyl] –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-4-yl] methylsulfanyl] ethyl] acetamide

O OR

O NH Or NH

N N

N S N S

N N

O N O n

N H N H

5 Se disolvió N–acetilcisteamina (0,064 ml) en acetonitrilo (5 ml). Después se añadió DBU (0,141 ml) a la disolución y se dejó agitar a RT durante 5 minutos. Se suspendió 1,1–dimetil–3–[4–[4–[(3S)–3–metilmorfolin–4–il]–6– (metilsulfoniloximetil)pirimidin–2–il]fenil]urea (154 mg) en acetonitrilo (5 ml) y se añadió al tiol. La reacción se dejó agitar a RT 1 hora, y después se concentró a vacío para dar el material deseado. 5 N-acetylcysteamine (0.064 ml) was dissolved in acetonitrile (5 ml). DBU (0.141 ml) was then added to the solution and allowed to stir at RT for 5 minutes. 1,1-dimethyl-3– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (methylsulfonyloxymethyl) pyrimidin-2-yl] phenyl] urea (154 mg) was suspended in acetonitrile (5 ml) and added to the thiol. The reaction was allowed to stir at RT 1 hour, and then concentrated in vacuo to give the desired material.

Espectro de masa: M+H+ 473. Mass spectrum: M + H + 473.

10 Ejemplo 17: 10 Example 17:

2–[[2–[4–(Dimetilcarbamoilamino)fenil]–6–[(3S)–3–metilmorfolin–4–il]pirimidin–4–il]metilsulfonil]acetamida 2 - [[2– [4– (Dimethylcarbamoylamino) phenyl] –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-4-yl] methylsulfonyl] acetamide

O OR

N N

N S N S

O OO O oo

N N

OH2N OH2N

N H N H

N N

Se disolvió 2–[[2–[4–(dimetilcarbamoilamino)fenil]–6–[(3S)–3–metilmorfolin–4–il]pirimidin–4–il]metilsulfanil]acetamida (158 mg) en 1,4–dioxano (6 ml) y agua (1 ml). La disolución se enfrió hasta 0ºC y se añadió ácido 3– 2 - [[2– [4– (dimethylcarbamoylamino) phenyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-4-yl] methylsulfanyl] acetamide (158 mg) was dissolved in 1.4– dioxane (6 ml) and water (1 ml). The solution was cooled to 0 ° C and 3– acid was added.

15 cloroperbenzoico (75%) (123 mg) seguido inmediatamente por permanganato de sodio (143 mg). La reacción se dejó agitar a RT durante 1 hora, después se cargó en una columna SCX–2, se lavó con metanol, y el material deseado se eliminó con amoniaco 7N en metanol. El material deseado (55 mg) se aisló como un sólido blanco. 15 chloroperbenzoic acid (75%) (123 mg) followed immediately by sodium permanganate (143 mg). The reaction was allowed to stir at RT for 1 hour, then loaded on an SCX-2 column, washed with methanol, and the desired material was removed with 7N ammonia in methanol. The desired material (55 mg) was isolated as a white solid.

Espectro RMN: RMN 1H (DMSO–d6) δ 1,25 (3H, d), 2,96 (6H, s), 3,22–3,26 (1H, m), 3,47–3,53 (1H, m), 3,63–3,67 (1H, m), 3,78 (1H, d), 3,97–4,01 (1H, m), 4,18 (1H, d), 4,27 (2H, s), 4,47 (1H, s), 4,67 (2H, s), 6,77 (1H, s), 7,53 (1H, NMR Spectrum: 1H NMR (DMSO-d6) δ 1.25 (3H, d), 2.96 (6H, s), 3.22-3.26 (1H, m), 3.47-3.53 ( 1H, m), 3.63-3.67 (1H, m), 3.78 (1H, d), 3.97-4.01 (1H, m), 4.18 (1H, d), 4 , 27 (2H, s), 4.47 (1H, s), 4.67 (2H, s), 6.77 (1H, s), 7.53 (1H,

20 s), 7,58–7,61 (2H, m), 7,79 (1H, s), 8,17–8,21 (2H, m), 8,49 (1H, s) 20 s), 7.58–7.61 (2H, m), 7.79 (1H, s), 8.17–8.21 (2H, m), 8.49 (1H, s)

Espectro de masa: M+H+ 477. Mass spectrum: M + H + 477.

Prueba (a): 1,1 μM. Test (a): 1.1 μM.

A continuación se describe la preparación de 2–[[2–[4–(dimetilcarbamoilamino)fenil]–6–[(3S)–3–metilmorfolin–4– il]pirimidin–4–il]metilsulfanil]acetamida. The preparation of 2 - [[2– [4– (dimethylcarbamoylamino) phenyl] –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-4-yl] methylsulfanyl] acetamide is described below.

25 2–[[2–[4–(Dimetilcarbamoilamino)fenil]–6–[(3S)–3–metilmorfolin–4–il]pirimidin–4–il]metilsulfanil]acetamida 25 2 - [[2– [4– (Dimethylcarbamoylamino) phenyl] –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-4-yl] methylsulfanyl] acetamide

O OR

NH2 NH2

N N

NN

O OR

S S

N N

O OR

N N

H H

Se disolvió dimetil–3–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfoniloximetil)pirimidin–2–il]fenil]urea (154 mg) en etanol (5 ml) y se añadió tiourea (29 mg). La reacción se calentó después hasta 70ºC durante 30 minutos antes de concentrarla a vacío. El residuo se disolvió en DMF (2 ml) y se trató con 2–bromoacetamida (52 mg) seguido por Dimethyl-3– [4– [4 - [(3S) -3-methylmorpholin-4-yl] -6– (methylsulfonyloxymethyl) pyrimidin-2-yl] phenyl] urea (154 mg) was dissolved in ethanol (5 ml) and thiourea (29 mg) was added. The reaction was then heated to 70 ° C for 30 minutes before concentrating in vacuo. The residue was dissolved in DMF (2 ml) and treated with 2-bromoacetamide (52 mg) followed by

hidróxido de sodio (55 mg) en agua (1 ml) y se agitó a RT durante 30 minutos. La mezcla de reacción se concentró a vacío, después se cargó en una columna SCX–2, se lavó con metanol, y el material deseado se eliminó con amoniaco 7N en metanol. El material deseado se usó sin purificación adicional. sodium hydroxide (55 mg) in water (1 ml) and stirred at RT for 30 minutes. The reaction mixture was concentrated in vacuo, then loaded on an SCX-2 column, washed with methanol, and the desired material was removed with 7N ammonia in methanol. The desired material was used without further purification.

Espectro de masa: M+H+ 445. Mass spectrum: M + H + 445.

Ejemplo 18: 1–[4–[4–(Hidroximetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]–3–metil–urea Example 18: 1– [4– [4– (Hydroxymethyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] –3-methyl-urea

Se disolvieron 1–(4–bromofenil)–3–metil–urea (2,50 g), acetato de potasio (3,21 g), y bis(pinacolato)diboro (3,33 g) en 1,4 dioxano (120 ml). La disolución se desgasificó durante 5 minutos, después se añadió aducto de 1,1’– bis(difenilfosfino)ferrocenodicloropaladio(II) diclorometano (535 mg), y la reacción se calentó hasta 90ºC durante 3 horas. Se añadió aducto de 1,1’–bis(difenilfosfino)ferrocenodicloropaladio(II) diclorometano (250 mg) adicional, y el calentamiento se continuó durante 1 hora. Se añadió aducto de 1,1’–bis(difenilfosfino) ferrocenodicloropaladio(II) diclorometano (250 mg) adicional, y el calentamiento se continuó durante 1 hora adicional. Se añadieron [2–cloro–6– [(3S)–3–metilmorfolin–4–il]pirimidin–4–il]metanol (2,66 mg), etanol (9,5 ml), disolución 2M de carbonato de sodio (27,3 ml) y aducto de 1,1’–bis(difenilfosfino)ferrocenodicloropaladio(II) diclorometano (535 mg), y el calentamiento se continuó durante 16 horas. La reacción se enfrió y se evaporó hasta sequedad, y después el residuo se repartió entre acetato de etilo (250 ml) y agua (100 ml). Los productos orgánicos se secaron sobre sulfato de magnesio, se filtraron y se concentraron a vacío. El material bruto se cromatografió en sílice, eluyendo con 5% de metanol en DCM, para dar el material deseado (1,25 g) como un sólido marrón. 1– (4-Bromophenyl) -3-methyl-urea (2.50 g), potassium acetate (3.21 g), and bis (pinacolato) diboro (3.33 g) were dissolved in 1.4 dioxane ( 120 ml) The solution was degassed for 5 minutes, then 1,1'-bis (diphenylphosphino) ferrocenodichloropaladium (II) dichloromethane (535 mg) adduct was added, and the reaction was heated to 90 ° C for 3 hours. Additional 1,1′-bis (diphenylphosphino) ferrocenodichloropaladium (II) dichloromethane (250 mg) adduct was added, and heating was continued for 1 hour. Additional 1,1′-bis (diphenylphosphino) ferrocenodichloropaladium (II) dichloromethane (250 mg) adduct was added, and heating was continued for an additional 1 hour. [2-Chloro-6– [(3S) -3-methylmorpholin-4-yl] pyrimidin-4-yl] methanol (2.66 mg), ethanol (9.5 ml), 2M sodium carbonate solution were added (27.3 ml) and 1,1'-bis (diphenylphosphino) ferrocenodichloropaladium (II) dichloromethane (535 mg) adduct, and heating was continued for 16 hours. The reaction was cooled and evaporated to dryness, and then the residue was partitioned between ethyl acetate (250 ml) and water (100 ml). The organic products were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was chromatographed on silica, eluting with 5% methanol in DCM, to give the desired material (1.25 g) as a brown solid.

Espectro RMN: RMN 1H (DMSO–d6) δ 1,23 (3H, d), 2,66 (3H, d), 3,18–3,23 (1H, m), 3,46–3,52 (1H, m), 3,62–3,66 (1H, m), 3,76 (1H, d), 3,96–3,99 (1H, m), 4,16 (1H, d), 4,45 (2H, d), 4,49 (1H, d), 5,38 (1H, t), 6,05 (1H, q), 6,66 (1H, s), 7,46–7,48 (2H, m), 8,18–8,21 (2H, m), 8,69 (1H, s) NMR Spectrum: 1H NMR (DMSO-d6) δ 1.23 (3H, d), 2.66 (3H, d), 3.18-3.23 (1H, m), 3.46-3.52 ( 1H, m), 3.62-3.66 (1H, m), 3.76 (1H, d), 3.96-3.99 (1H, m), 4.16 (1H, d), 4 , 45 (2H, d), 4.49 (1H, d), 5.38 (1H, t), 6.05 (1H, q), 6.66 (1H, s), 7.46–7, 48 (2H, m), 8.18–8.21 (2H, m), 8.69 (1H, s)

Espectro de masa: M+H+ 358. Mass spectrum: M + H + 358.

Prueba (a): 0,12 μM. Test (a): 0.12 μM.

A continuación se describe la preparación de 1–(4–bromofenil)–3–metil–urea. The preparation of 1– (4-bromophenyl) -3-methyl-urea is described below.

1–(4–Bromofenil)–3–metil–urea 1– (4 – Bromophenyl) –3 – methyl – urea

Se disolvió isocianato de 4–bromofenilo (2,50 g) en THF (75 ml). Se añadió metilamina (2,0M en THF, 75 ml) a la disolución y se agitó a RT durante 1 hora. La reacción se filtró y se sometió a vacío hasta sequedad. El material bruto se cromatografió en sílice, eluyendo con 5% de metanol en DCM, para dar el material deseado (2,65 g) como un sólido blanco. 4-Bromophenyl isocyanate (2.50 g) was dissolved in THF (75 ml). Methylamine (2.0M in THF, 75 ml) was added to the solution and stirred at RT for 1 hour. The reaction was filtered and subjected to vacuum to dryness. The crude material was chromatographed on silica, eluting with 5% methanol in DCM, to give the desired material (2.65 g) as a white solid.

Espectro RMN: RMN 1H (DMSO–d6) δ 2,64 (3H, d), 6,03 (1H, d), 7,37 (4H, s), 8,61 (1H, s) NMR Spectrum: 1H NMR (DMSO – d6) δ 2.64 (3H, d), 6.03 (1H, d), 7.37 (4H, s), 8.61 (1H, s)

Espectro de masa: M+H+ 229. Mass spectrum: M + H + 229.

Ejemplo 19: Example 19:

1– [4– [4– (Cyclohexylsulfonylmethyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] –3-methyl-urea

O OR

N N

OO OO

N N

O OR

N N

N HH N HH

Se disolvió 1–[4–[4–(ciclohexilsulfanilmetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]–3–metil–urea (0,35 mmoles) en 1,4–dioxano (5 ml) y agua (1 ml). Se añadió ácido 3–cloroperbenzoico (75%) (121 mg) a la disolución seguido inmediatamente por permanganato de sodio (140 mg), y las reacciones se agitaron a RT durante 1 hora. Se 5 añadieron ácido 3–cloroperbenzoico (75%) (121 mg) y permanganato de sodio (140 mg) adicionales, y las reacciones se dejaron agitar a RT durante 1 hora. Se añadieron ácido 3–cloroperbenzoico (75%) (121 mg) y permanganato de sodio (140 mg) adicionales, y las reacciones se dejaron agitar a RT durante otra hora, y después se cargaron en una columna SCX–3. La columna se lavó con metanol, y el material deseado se eliminó con amoniaco 7N en metanol. El material bruto se purificó mediante HPLC prep. (básica) para dar el material deseado 1– [4– [4– (cyclohexylsulfanylmethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] -3-methyl-urea (0.35 mmol) was dissolved in 1,4-dioxane (5 ml) and water (1 ml). 3-Chloroperbenzoic acid (75%) (121 mg) was added to the solution followed immediately by sodium permanganate (140 mg), and the reactions were stirred at RT for 1 hour. Additional 3-chloroperbenzoic acid (75%) (121 mg) and sodium permanganate (140 mg) were added, and the reactions were allowed to stir at RT for 1 hour. Additional 3-chloroperbenzoic acid (75%) (121 mg) and sodium permanganate (140 mg) were added, and the reactions were allowed to stir at RT for another hour, and then loaded onto a SCX-3 column. The column was washed with methanol, and the desired material was removed with 7N ammonia in methanol. The crude material was purified by prep HPLC. (basic) to give the desired material

10 (74 mg) como un sólido blanco. 10 (74 mg) as a white solid.

Espectro RMN: RMN 1H (DMSO–d6) δ 1,18–1,32 (7H, m), 1,42 (1H, d), 1,48 (1H, d), 1,68 (1H, d), 1,89 (2H, d), 2,25 (3H, d), 2,32–2,34 (1H, m), 2,66 (3H, d), 3,46–3,53 (1H, m), 3,63–3,67 (1H, m), 3,78 (1H, d), 3,97–4,01 (1H, m), 4,17 (1H, d), 4,43 (3H, s), 6,08 (1H, t), 6,77 (1H, s), 7,50–7,52 (2H, m), 8,19–8,21 (2H, m) NMR Spectrum: 1H NMR (DMSO-d6) δ 1.18-1.32 (7H, m), 1.42 (1H, d), 1.48 (1H, d), 1.68 (1H, d) , 1.89 (2H, d), 2.25 (3H, d), 2.32-2.34 (1H, m), 2.66 (3H, d), 3.46-3.53 (1H , m), 3.63-3.67 (1H, m), 3.78 (1H, d), 3.97-4.01 (1H, m), 4.17 (1H, d), 4, 43 (3H, s), 6.08 (1H, t), 6.77 (1H, s), 7.50–7.52 (2H, m), 8.19–8.21 (2H, m)

Espectro de masa: M+H+ 488. Mass spectrum: M + H + 488.

15 Los siguientes compuestos se prepararon de manera análoga a partir de los sulfuros apropiados. The following compounds were prepared analogously from the appropriate sulfides.

Ejemplo Example: Estructura NOMBRE LCMS MH+ Structure NAME LCMS MH +

19a 19th: N N N O S O O N H N H O 1–[4–[4–(bencenosulfonilmetil)–6–[(3S)–3– metilmorfolin–4–il]pirimidin–2–il]fenil]–3– metil–urea 482 N N N O S O O N H N H O 1– [4– [4– (benzenesulfonylmethyl) –6 - [(3S) –3– methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] –3– methyl-urea 482

19b 19b: O 1–[4–[4–[(4–fluorofenil)sulfonilmetil]–6– 500 OR 1– [4– [4 - [(4 – fluorophenyl) sulfonylmethyl] –6– 500

: [(3S)–3–metilmorfolin–4–il]pirimidin–2– [(3S) –3 – methylmorpholin-4-yl] pyrimidin – 2–

F F: N N N S O O N H N H O il]fenil]–3–metil–urea N N N S O O N H N H O il] phenyl] –3 – methyl – urea

19c 19c: N H O N N N O S O O N H N H O N–[4–[[2–[4–(metilcarbamoilamino)fenil]–6– [(3S)–3–metilmorfolin–4–il]pirimidin–4– il]metilsulfonil]fenil]acetamida 539 N H O N N N O S O O N H N H O N– [4 - [[2– [4– (methylcarbamoylamino) phenyl] –6– [(3S) –3-methylmorpholin-4-yl] pyrimidin-4-yl] methylsulfonyl] phenyl] acetamide 539

19d 19d: N N N O S O O N H N H O 3–metil–1–[4–[4–[(3S)–3–metilmorfolin–4– il]–6–(propan–2–ilsulfonilmetil)pirimidin–2– il]fenil]urea 448 N N N O S O O N H N H O 3 – methyl – 1– [4– [4 - [(3S) –3 – methylmorpholin-4– yl] –6– (propan – 2-ylsulfonylmethyl) pyrimidin – 2– yl] phenyl] urea 448

Ejemplo Example: Estructura NOMBRE LCMS MH+ Structure NAME LCMS MH +

19e 19e: N N N O S O O N H N H O OH 1–[4–[4–(2–hidroxietilsulfonilmetil)–6–[(3S)– 3–metilmorfolin–4–il]pirimidin–2–il]fenil]–3– metil–urea 450 N N N O S O O N H N H O OH 1– [4– [4– (2-hydroxyethylsulfonylmethyl) –6 - [(3S) - 3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] –3– methyl-urea 450

19f 19f: N N N O S O O N H N H O N 3–metil–1–[4–[4–[(3S)–3–metilmorfolin–4– il]–6–(piridin–4–ilsulfonilmetil)pirimidin–2– il]fenil]urea 483 N N N O S O O N H N H O N 3 – methyl – 1– [4– [4 - [(3S) –3 – methylmorpholin-4– yl] –6– (pyridin-4-ylsulfonylmethyl) pyrimidin – 2– yl] phenyl] urea 483

Ejemplo 19a: RMN 1H (DMSO–d6) δ 1,18 (3H, d), 2,66 (3H, q), 3,11–3,19 (1H, m), 3,43–3,50 (1H, m), 3,60–3,63 (1H, m), 3,75 (1H, d), 3,94–3,98 (1H, m), 4,08 (1H, d), 4,35 (1H, s), 4,69 (2H, s), 6,04 (1H, q), 6,59 (1H, s), 7,36–7,38 (2H, m), 7,61 (2H, t), 7,71–7,75 (1H, m), 7,79–7,81 (3H, m), 7,82 (1H, s), 8,69 (1H, s) Example 19a: 1H NMR (DMSO-d6) δ 1.18 (3H, d), 2.66 (3H, q), 3.11-3.19 (1H, m), 3.43-3.50 ( 1H, m), 3.60–3.63 (1H, m), 3.75 (1H, d), 3.94–3.98 (1H, m), 4.08 (1H, d), 4 , 35 (1H, s), 4.69 (2H, s), 6.04 (1H, q), 6.59 (1H, s), 7.36–7.38 (2H, m), 7, 61 (2H, t), 7.71–7.75 (1H, m), 7.79–7.81 (3H, m), 7.82 (1H, s), 8.69 (1H, s)

5 Ejemplo 19b: RMN 1H (DMSO–d6) δ 1,20 (3H, d), 2,66 (3H, d), 3,14–3,21 (1H, m), 3,45–3,51 (1H, m), 3,61–3,65 (1H, m), 3,76 (1H, d), 3,95–3,99 (1H, m), 4,11 (1H, d), 4,37 (1H, s), 4,71 (2H, s), 6,04 (1H, q), 6,64 (1H, s), 7,37–7,41 (2H, m), 7,43–7,48 (2H, m), 7,77–7,80 (2H, m), 7,85–7,89 (2H, m), 8,71 (1H, s) 5 Example 19b: 1H NMR (DMSO-d6) δ 1.20 (3H, d), 2.66 (3H, d), 3.14-3.21 (1H, m), 3.45-3.51 (1H, m), 3.61-3.65 (1H, m), 3.76 (1H, d), 3.95-3.99 (1H, m), 4.11 (1H, d), 4.37 (1H, s), 4.71 (2H, s), 6.04 (1H, q), 6.64 (1H, s), 7.37–7.41 (2H, m), 7 , 43–7.48 (2H, m), 7.77–7.80 (2H, m), 7.85–7.89 (2H, m), 8.71 (1H, s)

Ejemplo 19c: RMN 1H (DMSO–d6) δ 1,18 (3H, d), 2,13 (3H, s), 2,60–2,61 (3H, m), 2,67 (3H, q), 2,68 (1H, s), 3,44– 3,49 (1H, m), 4,08 (1H, d), 4,35 (1H, s), 4,60 (2H, s), 6,05 (1H, q), 6,54 (1H, s), 7,37–7,39 (2H, m), 7,70 (2H, d), 7,77 Example 19c: 1H NMR (DMSO-d6) δ 1.18 (3H, d), 2.13 (3H, s), 2.60-2.61 (3H, m), 2.67 (3H, q) , 2.68 (1H, s), 3.44– 3.49 (1H, m), 4.08 (1H, d), 4.35 (1H, s), 4.60 (2H, s), 6.05 (1H, q), 6.54 (1H, s), 7.37–7.39 (2H, m), 7.70 (2H, d), 7.77

10 (2H, d), 7,82 (2H, d), 8,68 (1H, s), 10,37 (1H, s) 10 (2H, d), 7.82 (2H, d), 8.68 (1H, s), 10.37 (1H, s)

Ejemplo 19d: RMN 1H (DMSO–d6) δ 1,24 (3H, d), 1,35–1,37 (7H, m), 2,66–2,69 (3H, m), 3,21–3,25 (1H, m), 3,47– 3,54 (2H, m), 3,63–3,67 (1H, m), 3,78 (1H, d), 3,97–4,01 (1H, m), 4,46 (3H, s), 6,08 (1H, q), 6,77 (1H, s), 7,49–7,51 (2H, m), 8,17–8,19 (2H, m), 8,73 (1H, s) Example 19d: 1H NMR (DMSO-d6) δ 1.24 (3H, d), 1.35-1.37 (7H, m), 2.66-2.69 (3H, m), 3.21– 3.25 (1H, m), 3.47-3.54 (2H, m), 3.63-3.67 (1H, m), 3.78 (1H, d), 3.97-4, 01 (1H, m), 4.46 (3H, s), 6.08 (1H, q), 6.77 (1H, s), 7.49-7.51 (2H, m), 8.17 –8.19 (2H, m), 8.73 (1H, s)

Ejemplo 19c: RMN 1H (DMSO–d6) δ 1,24 (3H, d), 2,66 (2H, s), 2,68 (2H, q), 3,21–3,26 (1H, m), 3,51 (3H, t), 3,63– Example 19c: 1H NMR (DMSO-d6) δ 1.24 (3H, d), 2.66 (2H, s), 2.68 (2H, q), 3.21-3.26 (1H, m) , 3.51 (3H, t), 3.63–

15 3,67 (1H, m), 3,78 (1H, d), 3,89–3,94 (2H, m), 3,97–4,01 (1H, m), 4,50 (3H, s), 5,18 (1H, t), 6,07 (1H, d), 6,76 (1H, s), 7,49–7,51 (2H, m), 8,20–8,22 (2H, m), 8,74 (1H, s) 15 3.67 (1H, m), 3.78 (1H, d), 3.89–3.94 (2H, m), 3.97–4.01 (1H, m), 4.50 (3H , s), 5.18 (1H, t), 6.07 (1H, d), 6.76 (1H, s), 7.49-7.51 (2H, m), 8.20–8, 22 (2H, m), 8.74 (1H, s)

Ejemplo 19f: RMN 1H (DMSO–d6) δ 1,20–1,25 (3H, m), 2,66 (3H, t), 3,15–3,21 (1H, m), 3,45–3,51 (1H, m), 3,61– 3,65 (1H, m), 3,77 (1H, t), 3,95–3,99 (1H, m), 4,11 (1H, d), 4,39 (1H, s), 4,87 (2H, s), 6,05 (1H, q), 6,71 (1H, s), 7,35– 7,37 (2H, m), 7,64–7,66 (2H, m), 7,81–7,82 (2H, m), 8,70 (1H, d), 8,90 (1H, d), 8,91 (1H, s) Example 19f: 1H NMR (DMSO-d6) δ 1.20–1.25 (3H, m), 2.66 (3H, t), 3.15–3.21 (1H, m), 3.45– 3.51 (1H, m), 3.61– 3.65 (1H, m), 3.77 (1H, t), 3.95–3.99 (1H, m), 4.11 (1H, d), 4.39 (1H, s), 4.87 (2H, s), 6.05 (1H, q), 6.71 (1H, s), 7.35–7.37 (2H, m ), 7.64–7.66 (2H, m), 7.81–7.82 (2H, m), 8.70 (1H, d), 8.90 (1H, d), 8.91 ( 1H, s)

20 Prueba (a): Ejemplo (19) 0,25 μM; Ejemplo (19a) 0,0047 μM; Ejemplo (19b) 0,033 μM; Ejemplo (19c) 0,022 μM; Ejemplo (19d) 0,066 μM; Ejemplo (19e) 0,011 μM; Ejemplo (19f) 0,027 μM. Test (a): Example (19) 0.25 μM; Example (19a) 0.0047 μM; Example (19b) 0.033 μM; Example (19c) 0.022 μM; Example (19d) 0.066 μM; Example (19e) 0.011 μM; Example (19f) 0.027 μM.

A continuación se describe la preparación de 1–[4–[4–(ciclohexilsulfanilmetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidin– 2–il]fenil]–3–metil–urea. The preparation of 1– [4– [4– (cyclohexylsulfanylmethyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin– 2-yl] phenyl] –3-methyl-urea is described below.

1–[4–[4–(Ciclohexilsulfanilmetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]–3–metil–urea 1– [4– [4– (Cyclohexylsulfanylmethyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] –3-methyl-urea

HHH H

25 Se disolvió ciclohexanotiol (0,61 mmoles) en acetonitrilo (4 ml). Después se añadió DBU (0,050 ml), y la disolución se dejó agitar a RT durante 5 minutos. Se disolvió 3–metil–1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6– (metilsulfoniloximetil)pirimidin–2–il]fenil]urea (151 mg) en acetonitrilo (2 ml) y se añadió DBU (0,054 ml), y las reacciones se agitaron a RT durante 2 horas. La mezcla de reacción se concentró a vacío para dar el material 25 Cyclohexanediol (0.61 mmol) was dissolved in acetonitrile (4 ml). Then DBU (0.050 ml) was added, and the solution was allowed to stir at RT for 5 minutes. 3-methyl-1– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (methylsulfonyloxymethyl) pyrimidin-2-yl] phenyl] urea (151 mg) was dissolved in acetonitrile (2 ml) and DBU (0.054 ml) was added, and the reactions were stirred at RT for 2 hours. The reaction mixture was concentrated in vacuo to give the material.

30 deseado que se usó sin purificación adicional. 30 that was used without further purification.

Los siguientes sulfuros se obtuvieron de una manera análoga a partir de 3–metil–1–[4–[4–[(3S)–3–metilmorfolin–4– il]–6–(metilsulfoniloximetil)pirimidin–2–il]fenil]urea y el tiol apropiado. The following sulfides were obtained in an analogous manner from 3-methyl-1– [4– [4 - [(3S) -3-methylmorpholin-4-yl] –6– (methylsulfonyloxymethyl) pyrimidin-2-yl] phenyl ] urea and the appropriate thiol.

Estructura Structure: NOMBRE NAME

: N N N O S N H N H O 3–metil–1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6– (fenilsulfanilmetil)pirimidin–2–il]fenil]urea N N N O S N H N H O 3 – methyl – 1– [4– [4 - [(3S) –3 – methylmorpholin-4-yl] –6– (phenylsulfanylmethyl) pyrimidin – 2-yl] phenyl] urea

F F: N N N O S N H N H O 1–[4–[4–[(4–fluorofenil)sulfanilmetil]–6–[(3S)–3– metilmorfolin–4–il]pirimidin–2–il]fenil]–3–metil–urea N N N O S N H N H O 1– [4– [4 - [(4 – fluorophenyl) sulfanylmethyl] –6 - [(3S) –3– methylmorpholin-4-yl] pyrimidin – 2-yl] phenyl] –3-methyl-urea

N H O N H O: N N N O S N H N H O N–[4–[[2–[4–(metilcarbamoilamino)fenil]–6–[(3S)–3– metilmorfolin–4–il]pirimidin–4– il]metilsulfanil]fenil]acetamida N N N O S N H N H O N– [4 - [[2– [4– (methylcarbamoylamino) phenyl] –6 - [(3S) –3– methylmorpholin-4-yl] pyrimidin-4– yl] methylsulfanyl] phenyl] acetamide

: N N N O S N H N H O 3–metil–1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6– (propan–2–ilsulfanilmetil)pirimidin–2–il]fenil]urea N N N O S N H N H O 3 – methyl – 1– [4– [4 - [(3S) –3 – methylmorpholin-4-yl] –6– (propan – 2-ylsulfanylmethyl) pyrimidin – 2-yl] phenyl] urea

OH OH: N N N O S N H N H O 1–[4–[4–(2–hidroxietilsulfanilmetil)–6–[(3S)–3– metilmorfolin–4–il]pirimidin–2–il]fenil]–3–metil–urea N N N O S N H N H O 1– [4– [4– (2-hydroxyethylsulfanylmethyl) –6 - [(3S) -3– methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] –3-methyl-urea

N N: N N N O S N H N H O 3–metil–1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6– (piridin–4–ilsulfanilmetil)pirimidin–2–il]fenil]urea N N N O S N H N H O 3-methyl – 1– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (pyridin-4-ylsulfanylmethyl) pyrimidin – 2-yl] phenyl] urea

A continuación se describe la preparación de 3–metil–1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6– (metilsulfoniloximetil)pirimidin–2–il]fenil]urea. The preparation of 3-methyl-1– [4– [4 - [(3S) -3-methylmorpholin-4-yl] -6– (methylsulfonyloxymethyl) pyrimidin-2-yl] phenyl] urea is described below.

3–Metil–1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfoniloximetil)pirimidin–2–il]fenil]urea 3 – Methyl – 1– [4– [4 - [(3 S) –3 – methylmorpholin-4-yl] –6– (methylsulfonyloxymethyl) pyrimidin – 2-yl] phenyl] urea

O OR

NN

O SO N O O SO N O

N N

O OR

N N

N HH N HH

Se disolvió parcialmente 1–[4–[4–(hidroximetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]–3–metil–urea (1,24 g) en DCM (30 ml) y trietilamina (0,724 ml), y la disolución se enfrió hasta 0ºC. Se añadió cloruro de metanosulfonilo (0,405 ml), y la reacción se agitó durante 15 minutos a RT, y después se concentró a vacío para dar el material deseado. 1– [4– [4– (hydroxymethyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] –3-methyl-urea (1.24 g) was partially dissolved in DCM (30 ml) and triethylamine (0.724 ml), and the solution was cooled to 0 ° C. Methanesulfonyl chloride (0.405 ml) was added, and the reaction was stirred for 15 minutes at RT, and then concentrated in vacuo to give the desired material.

Espectro de masa: M+H+ 436. Mass spectrum: M + H + 436.

Ejemplo 20: Example 20:

3–[4–[4–(Bencenosulfonilmetil)–6–morfolin–4–il–pirimidin–2–il]fenil]–1–metil–urea 3– [4– [4– (Benzenesulfonylmethyl) –6-morpholin-4-yl-pyrimidin-2-yl] phenyl] –1-methyl-urea

O OR

N N

N S N S

OO OO

N N

O OR

N N

N HH N HH

10 Se disolvió (4–{4–morfolin–4–il–6–[(fenilsulfonil)metil]pirimidin–2–il}fenil)carbamato de fenilo (250 mg, 0,45 mmoles) en DMF (5 ml). Se añadió trietilamina (0,188 ml, 1,35 mmoles) seguido por metilamina (2M en THF, 1,1 ml), y la disolución se calentó a 50ºC durante 1 hora. La reacción se enfrió hasta la temperatura ambiente y se concentró a vacío. El aceite resultante se purificó mediante cromatografía en sílice, eluyendo con 0–5% de metanol en DCM para dar el material deseado como un sólido blanco (120 mg). 10 Phenyl (4– {4-morpholin-4-yl-6 - [(phenylsulfonyl) methyl] pyrimidin-2-yl} phenyl) carbamate (250 mg, 0.45 mmol) was dissolved in DMF (5 ml). Triethylamine (0.188 ml, 1.35 mmol) was added followed by methylamine (2M in THF, 1.1 ml), and the solution was heated at 50 ° C for 1 hour. The reaction was cooled to room temperature and concentrated in vacuo. The resulting oil was purified by silica chromatography, eluting with 0-5% methanol in DCM to give the desired material as a white solid (120 mg).

15 Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 2,66 (d, 3H), 3,63 (m, 4H), 3,70 (m, 4H), 4,69 (s, 2H), 6,05 (m, 1H), 6,65 (s, 1H), 7,38 (d, 2H), 7,63 (t, 2H), 7,74 (d, 1H), 7,80 (m, 3H), 8,69 (s, 1H) 15 NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 2.66 (d, 3H), 3.63 (m, 4H), 3.70 (m, 4H), 4.69 (s, 2H), 6.05 (m, 1H), 6.65 (s, 1H), 7.38 (d, 2H), 7.63 (t, 2H), 7.74 (d, 1H), 7, 80 (m, 3H), 8.69 (s, 1H)

Espectro LCMS: MH+ 468, tiempo de retención 1,76 min., Método Básico 5 min. LCMS spectrum: MH + 468, retention time 1.76 min., Basic Method 5 min.

Los compuestos mostrados en la tabla se prepararon de una manera análoga a N’–(4–{4–morfolin–4–il–6– [(fenilsulfonil)metil]pirimidin–2–il}fenil)urea, haciendo reaccionar la amina apropiada con el carbamato de apropiado y The compounds shown in the table were prepared in a manner analogous to N '- (4– {4-morpholin-4-yl-6– [(phenylsulfonyl) methyl] pyrimidin-2-yl} phenyl) urea, reacting the amine appropriate with the appropriate carbamate and

20 mediante purificación mediante cromatografía en sílice o mediante HPLC preparativa. 20 by purification by silica chromatography or by preparative HPLC.

20a 20 a: N N N O S O O N H N H O 3–[4–[4–(bencenosulfonilmetil)–6– morfolin–4–il–pirimidin–2–il]fenil]– 1–etil–urea 482 1,98 N N N O S O O N H N H O 3– [4– [4– (benzenesulfonylmethyl) –6– morpholin-4-yl-pyrimidin-2-yl] phenyl] - 1-ethyl-urea 482 1.98

20b 20b: N N N O S O O N H N H O 1–[4–[4–(bencenosulfonilmetil)–6– morfolin–4–il–pirimidin–2–il]fenil]– 3–ciclopropil–urea 494 1,92 N N N O S O O N H N H O 1– [4– [4– (benzenesulfonylmethyl) –6– morpholin-4-yl-pyrimidin-2-yl] phenyl] - 3-cyclopropyl-urea 494 1.92

20c 20c: O 3–[4–[4–(bencenosulfonilmetil)–6– 525 1,98 OR 3– [4– [4– (benzenesulfonylmethyl) –6– 525 1.98

N N N S O O N H N H O N N N N S O O N H N H O N: 1–(2–dimetilaminoetil)urea 1– (2-dimethylaminoethyl) urea

20d 20d: O 3–[4–[4–(bencenosulfonilmetil)–6– 551 1,93 OR 3– [4– [4– (benzenesulfonylmethyl) –6– 551 1.93

morfolin–4–il–pirimidin–2–il]fenil]– morpholin-4-yl-pyrimidin-2-yl] phenyl] -

N N N S O O N H N H O N N N N S O O N H N H O N: 1–(1–metil–4–piperidil)urea 1– (1 – methyl – 4 – piperidyl) urea

20e 20e: O 3–[4–[4–(bencenosulfonilmetil)–6– 512 1,77 OR 3– [4– [4– (benzenesulfonylmethyl) –6– 512 1.77

N N N S O O N H N H O O N N N S O O N H N H O O: 1–(2–metoxietil)urea 1– (2-methoxyethyl) urea

20f 20f: O 3–[4–[4–(bencenosulfonilmetil)–6– 496 2,06 OR 3– [4– [4– (benzenesulfonylmethyl) –6– 496 2.06

: [(3S)–3–metilmorfolin–4– [(3S) –3 – methylmorpholin – 4–

N N N S O O N H N H O N N N S O O N H N H O: il]pirimidin–2–il]fenil]–1–etil–urea il] pyrimidin – 2-yl] phenyl] –1-ethyl-urea

20g 20g: N N N O S O O N H N H O 1–[4–[4–(bencenosulfonilmetil)–6– [(3S)–3–metilmorfolin–4– il]pirimidin–2–il]fenil]–3–ciclopropil– urea 508 2,08 N N N O S O O N H N H O 1– [4– [4– (benzenesulfonylmethyl) –6– [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] –3 – cyclopropyl– urea 508 2.08

20h 20h: N N N O S O O N H N H O N 1–[4–[4–(bencenosulfonilmetil)–6– [(3S)–3–metilmorfolin–4– il]pirimidin–2–il]fenil]–3–(2– dimetilaminoetil)urea 539 1,94 N N N O S O O N H N H O N 1– [4– [4– (benzenesulfonylmethyl) –6– [(3S) –3-methylmorpholin-4– yl] pyrimidin-2-yl] phenyl] –3– (2– dimethylaminoethyl) urea 539 1.94

20i 20i: N N N O S O O N H N H O N 1–[4–[4–(bencenosulfonilmetil)–6– [(3S)–3–metilmorfolin–4– il]pirimidin–2–il]fenil]–3–(1–metil–4– piperidil)urea 565 1,94 N N N O S O O N H N H O N 1– [4– [4– (benzenesulfonylmethyl) –6– [(3S) –3-methylmorpholin-4– yl] pyrimidin-2-yl] phenyl] –3– (1-methyl-4– piperidyl) urea 565 1.94

20j 20j: N N N O S O O N H N H O O 1–[4–[4–(bencenosulfonilmetil)–6– [(3S)–3–metilmorfolin–4– il]pirimidin–2–il]fenil]–3–(2– metoxietil)urea 526 1,98 N N N O S O O N H N H O O 1– [4– [4– (benzenesulfonylmethyl) –6– [(3S) –3-methylmorpholin-4– yl] pyrimidin-2-yl] phenyl] –3– (2– methoxyethyl) urea 526 1.98

20k 20k: O 3–metil–1–[4–[4–morfolin–4–il–6– 434 1,47 OR 3 – methyl – 1– [4– [4 – morpholin – 4 – il – 6– 434 1.47

: (propan–2–ilsulfonilmetil)pirimidin– (propan – 2-ylsulfonylmethyl) pyrimidin–

N N N S O O N H N H O N N N S O O N H N H O: 2–il]fenil]urea 2-yl] phenyl] urea

20l 20l: O 1–etil–3–[4–[4–morfolin–4–il–6– 448 1,61 OR 1 – ethyl – 3– [4– [4 – morpholin – 4 – il – 6– 448 1.61

20m 20m: N N N O S O O N H N H O 3–ciclopropil–1–[4–[4–morfolin–4– il–6–(propan–2– ilsulfonilmetil)pirimidin–2– il]fenil]urea 460 1,63 N N N O S O O N H N H O 3 – cyclopropyl – 1– [4– [4 – morpholin-4– il – 6– (propan – 2– ylsulfonylmethyl) pyrimidin – 2– yl] phenyl] urea 460 1.63

20n 20n: N N N O S O O N H N H O N 3–(2–dimetilaminoetil)–1–[4–[4– morfolin–4–il–6–(propan–2– ilsulfonilmetil)pirimidin–2– il]fenil]urea 491 1,59 N N N O S O O N H N H O N 3– (2-dimethylaminoethyl) –1– [4– [4– morpholin-4-yl – 6– (propan – 2– ylsulfonylmethyl) pyrimidin – 2– yl] phenyl] urea 491 1.59

20o 20th: N N N O S O O N H N H O N 3–(1–metil–4–piperidil)–1–[4–[4– morfolin–4–il–6–(propan–2– ilsulfonilmetil)pirimidin–2– il]fenil]urea 517 1,61 N N N O S O O N H N H O N 3– (1 – methyl – 4 – piperidil) –1– [4– [4– morpholin-4-yl – 6– (propan – 2– ylsulfonylmethyl) pyrimidin – 2– yl] phenyl] urea 517 1.61

20p 20p: N N N O S O O N H N H O O 3–(2–metoxietil)–1–[4–[4–morfolin– 4–il–6–(propan–2– ilsulfonilmetil)pirimidin–2– il]fenil]urea 478 1,53 N N N O S O O N H N H O O 3– (2-methoxyethyl) –1– [4– [4-morpholin-4-yl-6– (propan-2-ylsulfonylmethyl) pyrimidin-2-yl] phenyl] urea 478 1.53

20q 20q: N N N O S O O N H N H O 1–etil–3–[4–[4–[(3S)–3– metilmorfolin–4–il]–6–(propan–2– ilsulfonilmetil)pirimidin–2– il]fenil]urea 462 1,75 N N N O S O O N H N H O 1 – ethyl – 3– [4– [4 - [(3S) –3– methylmorpholin-4-yl] –6– (propan – 2– ylsulfonylmethyl) pyrimidin – 2– yl] phenyl] urea 462 1.75

20r 20r: N N N O S O O N H N H O 3–ciclopropil–1–[4–[4–[(3S)–3– metilmorfolin–4–il]–6–(propan–2– ilsulfonilmetil)pirimidin–2– il]fenil]urea 474 1,77 N N N O S O O N H N H O 3 – cyclopropyl – 1– [4– [4 - [(3S) –3– methylmorpholin-4-yl] –6– (propan – 2– ylsulfonylmethyl) pyrimidin – 2– yl] phenyl] urea 474 1.77

20s 20s: O 3–(2–dimetilaminoetil)–1–[4–[4– 505 1,76 OR 3– (2 – dimethylaminoethyl) –1– [4– [4– 505 1.76

: [(3S)–3–metilmorfolin–4–il]–6– [(3S) –3 – methylmorpholin – 4 – il] –6–

N N: (propan–2–ilsulfonilmetil)pirimidin– (propan – 2-ylsulfonylmethyl) pyrimidin–

N N S O O N H N H O N N N S O O N H N H O N: 2–il]fenil]urea 2-yl] phenyl] urea

20t 20t: O 1–[4–[4–[(3S)–3–metilmorfolin–4– 531 1,77 OR 1– [4– [4 - [(3S) –3 – methylmorpholin – 4– 531 1.77

: il]–6–(propan–2– il] –6– (propan – 2–

N N: ilsulfonilmetil)pirimidin–2–il]fenil]–3– ilsulfonylmethyl) pyrimidin – 2-yl] phenyl] –3–

N N S O O N H N H O N N N S O O N H N H O N: (1–metil–4–piperidil)urea (1 – methyl – 4 – piperidyl) urea

20u 20u: N N N O S O O N H N H O O 3–(2–metoxietil)–1–[4–[4–[(3S)–3– metilmorfolin–4–il]–6–(propan–2– ilsulfonilmetil)pirimidin–2– il]fenil]urea 492 1,67 N N N O S O O N H N H O O 3– (2 – methoxyethyl) –1– [4– [4 - [(3S) –3– methylmorpholin-4-yl] –6– (propan – 2– ylsulfonylmethyl) pyrimidin – 2– yl] phenyl] urea 492 1.67

Ejemplo 20a: RMN 1H (400,13 MHz, DMSO–d6) δ 1,00 (t, 3H), 3,05 (m, 2H), 3,56 (s, 4H), 3,63 (m, 4H), 4,62 (s, 2H), 6,07 (t, 1H), 6,59 (s, 1H), 7,30 (d, 2H), 7,55 (t, 2H), 7,71 (m, 5H), 8,54 (s, 1H) Example 20a: 1H NMR (400.13 MHz, DMSO-d6) δ 1.00 (t, 3H), 3.05 (m, 2H), 3.56 (s, 4H), 3.63 (m, 4H ), 4.62 (s, 2H), 6.07 (t, 1H), 6.59 (s, 1H), 7.30 (d, 2H), 7.55 (t, 2H), 7.71 (m, 5H), 8.54 (s, 1H)

Ejemplo 20b: RMN 1H (400,13 MHz, DMSO–d6) δ 0,42 (m, 2H), 0,65 (m, 2H), 2,55 (m, 1H), 3,64 (m, 4H), 3,71 (m, 5 4H), 4,69 (s, 2H), 6,41 (d, 1H), 6,66 (s, 1H), 7,38 (d, 2H), 7,63 (t, 2H), 7,75 (m, 1H), 7,81 (m, 4H), 8,49 (s, 1H) Example 20b: 1H NMR (400.13 MHz, DMSO-d6) δ 0.42 (m, 2H), 0.65 (m, 2H), 2.55 (m, 1H), 3.64 (m, 4H ), 3.71 (m, 5 4H), 4.69 (s, 2H), 6.41 (d, 1H), 6.66 (s, 1H), 7.38 (d, 2H), 7, 63 (t, 2H), 7.75 (m, 1H), 7.81 (m, 4H), 8.49 (s, 1H)

Ejemplo 20c: RMN 1H (400,13 MHz, DMSO–d6) δ 2,20 (s, 6H), 2,38 (t, 2H), 3,20 (m, 2H), 3,63 (s, 4H), 3,70 (s, 4H), 4,69 (s, 2H), 6,17 (s, 1H), 6,65 (s, 1H), 7,37 (d, 2H), 7,62 (t, 2H), 7,75 (t, 1H), 7,81 (t, 4H), 8,87 (s, 1H) Example 20c: 1H NMR (400.13 MHz, DMSO-d6) δ 2.20 (s, 6H), 2.38 (t, 2H), 3.20 (m, 2H), 3.63 (s, 4H ), 3.70 (s, 4H), 4.69 (s, 2H), 6.17 (s, 1H), 6.65 (s, 1H), 7.37 (d, 2H), 7.62 (t, 2H), 7.75 (t, 1H), 7.81 (t, 4H), 8.87 (s, 1H)

Ejemplo 20d: RMN 1H (400,13 MHz, DMSO–d6) δ 1,49 (m, 2H), 1,86 (m, 2H), 2,32 (s, 3H), 2,84 (m, 2H), 3,54 (m, 2H), 3,63 (s, 4H), 3,70 (m, 4H), 4,69 (s, 2H), 6,46 (d, 1H), 6,65 (s, 1H), 7,35 (d, 2H), 7,63 (t, 2H), 7,74 (t, 2H), 7,81 10 (m, 3H), 8,76 (s, 1H) Example 20d: 1H NMR (400.13 MHz, DMSO-d6) δ 1.49 (m, 2H), 1.86 (m, 2H), 2.32 (s, 3H), 2.84 (m, 2H ), 3.54 (m, 2H), 3.63 (s, 4H), 3.70 (m, 4H), 4.69 (s, 2H), 6.46 (d, 1H), 6.65 (s, 1H), 7.35 (d, 2H), 7.63 (t, 2H), 7.74 (t, 2H), 7.81 10 (m, 3H), 8.76 (s, 1H )

Ejemplo 20e: RMN 1H (400,13 MHz, DMSO–d6) δ 3,27 (m, 2H), 3,29 (s, 3H), 3,40 (t, 2H), 3,63 (s, 4H), 3,71 (m, 4H), 4,69 (s, 2H), 6,25 (t, 1H), 6,66 (s, 1H), 7,35 (d, 2H), 7,62 (t, 1H), 7,75 (m, 2H), 7,81 (m, 4H), 8,73 (s, 1H) Example 20e: 1H NMR (400.13 MHz, DMSO-d6) δ 3.27 (m, 2H), 3.29 (s, 3H), 3.40 (t, 2H), 3.63 (s, 4H ), 3.71 (m, 4H), 4.69 (s, 2H), 6.25 (t, 1H), 6.66 (s, 1H), 7.35 (d, 2H), 7.62 (t, 1H), 7.75 (m, 2H), 7.81 (m, 4H), 8.73 (s, 1H)

Ejemplo 20f: RMN 1H (400,13 MHz, DMSO–d6) δ 1,15 (t, 3H), 1,25 (d, 3H), 3,12 (m, 3H), 3,47 (t, 1H), 3,62 (d, 1H), 3,76 (d, 1H), 3,96 (d, 1H), 4,08 (d, 1H), 4,36 (s, 1H), 4,70 (s, 2H), 6,14 (t, 1H), 6,60 (s, 1H), 7,38 (d, 2H), 7,62 (t, 2H), 15 7,74 (t, 1H), 7,81 (m, 4H), 8,62 (s, 1H) Example 20f: 1H NMR (400.13 MHz, DMSO-d6) δ 1.15 (t, 3H), 1.25 (d, 3H), 3.12 (m, 3H), 3.47 (t, 1H ), 3.62 (d, 1H), 3.76 (d, 1H), 3.96 (d, 1H), 4.08 (d, 1H), 4.36 (s, 1H), 4.70 (s, 2H), 6.14 (t, 1H), 6.60 (s, 1H), 7.38 (d, 2H), 7.62 (t, 2H), 7.74 (t, 1H ), 7.81 (m, 4H), 8.62 (s, 1H)

Ejemplo 20g: RMN 1H (400,13 MHz, DMSO–d6) δ 0,42 (m, 2H), 0,65 (m, 2H), 1,20 (d, 3H), 2,55 (m, 1H), 3,16 (m, 1H), 3,47 (m, 1H), 3,62 (m, 1H), 3,75 (d, 1H), 3,97 (m, 1H), 4,09 (d, 1H), 4,36 (s, 1H), 4,70 (s, 2H), 6,42 (d, 1H), 6,60 (s, 1H), 7,39 (d, 2H), 7,63 (t, 2H), 7,75 (t, 1H), 7,82 (m, 4H), 8,49 (s, 1H) Example 20g: 1H NMR (400.13 MHz, DMSO-d6) δ 0.42 (m, 2H), 0.65 (m, 2H), 1.20 (d, 3H), 2.55 (m, 1H ), 3.16 (m, 1H), 3.47 (m, 1H), 3.62 (m, 1H), 3.75 (d, 1H), 3.97 (m, 1H), 4.09 (d, 1H), 4.36 (s, 1H), 4.70 (s, 2H), 6.42 (d, 1H), 6.60 (s, 1H), 7.39 (d, 2H) , 7.63 (t, 2H), 7.75 (t, 1H), 7.82 (m, 4H), 8.49 (s, 1H)

Ejemplo 20h: RMN 1H (400,13 MHz, DMSO–d6) δ 1,19 (d, 3H), 2,23 (s, 6H), 2,40 (t, 2H), 3,21 (m, 3H), 3,47 (m, 1H), 3,62 (m, 1H), 3,75 (d, 1H), 3,96 (m, 1H), 4,08 (d, 1H), 4,36 (s, 1H), 4,70 (s, 2H), 6,21 (t, 1H), 6,60 (s, 1H), 7,40 (d, 2H), 7,62 (t, 2H), 7,75 (t, 1H), 7,82 (m, 3H), 7,96 (s, 1H), 8,90 (s, 1H) Example 20h: 1H NMR (400.13 MHz, DMSO-d6) δ 1.19 (d, 3H), 2.23 (s, 6H), 2.40 (t, 2H), 3.21 (m, 3H ), 3.47 (m, 1H), 3.62 (m, 1H), 3.75 (d, 1H), 3.96 (m, 1H), 4.08 (d, 1H), 4.36 (s, 1H), 4.70 (s, 2H), 6.21 (t, 1H), 6.60 (s, 1H), 7.40 (d, 2H), 7.62 (t, 2H) , 7.75 (t, 1H), 7.82 (m, 3H), 7.96 (s, 1H), 8.90 (s, 1H)

Ejemplo 20i: RMN 1H (400,13 MHz, DMSO–d6) δ 1,19 (d, 3H), 1,40 (m, 2H), 1,79 (m, 2H), 2,02 (t, 2H), 2,16 (s, 3H), 2,64 (m, 2H), 3,16 (m, 1H), 3,47 (m, 2H), 3,62 (m, 1H), 3,75 (d, 1H), 3,96 (m, 1H), 4,08 (d, 1H), 4,35 (s, 1H), 4,69 (s, 2H), 6,16 (d, 1H), 6,60 (s, 1H), 7,35 (d, 2H), 7,65 (t, 2H), 7,74 (t, 1H), 7,81 (m, 4H), 8,52 (s, 1H) Example 20i: 1H NMR (400.13 MHz, DMSO-d6) δ 1.19 (d, 3H), 1.40 (m, 2H), 1.79 (m, 2H), 2.02 (t, 2H ), 2.16 (s, 3H), 2.64 (m, 2H), 3.16 (m, 1H), 3.47 (m, 2H), 3.62 (m, 1H), 3.75 (d, 1H), 3.96 (m, 1H), 4.08 (d, 1H), 4.35 (s, 1H), 4.69 (s, 2H), 6.16 (d, 1H) , 6.60 (s, 1H), 7.35 (d, 2H), 7.65 (t, 2H), 7.74 (t, 1H), 7.81 (m, 4H), 8.52 ( s, 1H)

Ejemplo 20j: RMN 1H (400,13 MHz, DMSO–d6) δ 1,20 (d, 3H), 3,15 (t, 1H), 3,29 (m, 5H), 3,40 (t, 2H), 3,47 (t, 1H), 3,62 (d, 1H), 3,75 (d, 1H), 3,96 (d, 1H), 4,08 (d, 1H), 4,36 (s, 1H), 4,70 (s, 2H), 6,25 (t, 1H), 6,60 (s, 1H), 7,37 (d, 2H), 7,62 (t, 2H), 7,74 (t, 1H), 7,82 (d, 4H), 8,73 (s, 1H) Example 20j: 1H NMR (400.13 MHz, DMSO-d6) δ 1.20 (d, 3H), 3.15 (t, 1H), 3.29 (m, 5H), 3.40 (t, 2H ), 3.47 (t, 1H), 3.62 (d, 1H), 3.75 (d, 1H), 3.96 (d, 1H), 4.08 (d, 1H), 4.36 (s, 1H), 4.70 (s, 2H), 6.25 (t, 1H), 6.60 (s, 1H), 7.37 (d, 2H), 7.62 (t, 2H) , 7.74 (t, 1H), 7.82 (d, 4H), 8.73 (s, 1H)

Ejemplo 20k: RMN 1H (400,13 MHz, DMSO–d6) δ 1,36 (d, 6H), 2,66 (s, 3H), 3,51 (m, 1H), 3,72 (s, 8H), 4,47 (s, 2H), 6,09 (s, 1H), 6,83 (s, 1H), 7,51 (d, 2H), 8,18 (d, 2H), 8,76 (s, 1H) Example 20k: 1H NMR (400.13 MHz, DMSO-d6) δ 1.36 (d, 6H), 2.66 (s, 3H), 3.51 (m, 1H), 3.72 (s, 8H ), 4.47 (s, 2H), 6.09 (s, 1H), 6.83 (s, 1H), 7.51 (d, 2H), 8.18 (d, 2H), 8.76 (s, 1H)

Ejemplo 20l: RMN 1H (400,13 MHz, DMSO–d6) δ 1,07 (t, 3H), 1,35 (d, 6H), 3,12 (m, 2H), 3,51 (m, 1H), 3,72 (s, 8H), 4,47 (s, 2H), 6,18 (s, 1H), 6,83 (s, 1H), 7,51 (d, 2H), 8,18 (d, 2H), 8,68 (s, 1H) Example 20l: 1H NMR (400.13 MHz, DMSO-d6) δ 1.07 (t, 3H), 1.35 (d, 6H), 3.12 (m, 2H), 3.51 (m, 1H ), 3.72 (s, 8H), 4.47 (s, 2H), 6.18 (s, 1H), 6.83 (s, 1H), 7.51 (d, 2H), 8.18 (d, 2H), 8.68 (s, 1H)

Ejemplo 20m: RMN 1H (400,13 MHz, DMSO–d6) δ 0,42 (m, 2H), 0,65 (m, 2H), 1,38 (d, 6H), 2,56 (m, 1H), 3,51 (m, 1H), 3,72 (s, 8H), 4,46 (s, 2H), 6,45 (s, 1H), 6,82 (s, 1H), 7,51 (d, 2H), 8,19 (d, 2H), 8,55 (s, 1H) Example 20m: 1H NMR (400.13 MHz, DMSO-d6) δ 0.42 (m, 2H), 0.65 (m, 2H), 1.38 (d, 6H), 2.56 (m, 1H ), 3.51 (m, 1H), 3.72 (s, 8H), 4.46 (s, 2H), 6.45 (s, 1H), 6.82 (s, 1H), 7.51 (d, 2H), 8.19 (d, 2H), 8.55 (s, 1H)

Ejemplo 20n: RMN 1H (400,13 MHz, DMSO–d6) δ 1,36 (d, 6H), 2,85 (d, 6H), 3,20 (m, 2H), 3,46 (m, 2H), 3,51 (m, 1H), 3,72 (s, 8H), 4,46 (s, 2H), 6,56 (t, 1H), 6,83 (s, 1H), 7,55 (d, 2H), 8,21 (d, 2H), 9,10 (s, 1H) Example 20n: 1H NMR (400.13 MHz, DMSO-d6) δ 1.36 (d, 6H), 2.85 (d, 6H), 3.20 (m, 2H), 3.46 (m, 2H ), 3.51 (m, 1H), 3.72 (s, 8H), 4.46 (s, 2H), 6.56 (t, 1H), 6.83 (s, 1H), 7.55 (d, 2H), 8.21 (d, 2H), 9.10 (s, 1H)

Ejemplo 20o: RMN 1H (400,13 MHz, DMSO–d6) δ 1,36 (d, 6H), 1,57 (m, 2H), 1,97 (d, 2H), 2,59 (s, 1H), 2,78 (s, 2H), 3,16 (d, 2H), 3,29 (s, 3H), 3,50 (m, 1H), 3,72 (s, 8H), 4,46 (s, 2H), 6,44 (d, 1H), 6,81 (s, 1H), 7,49 (d, 2H), 8,20 (d, 2H), 8,65 (s, 1H) Example 20o: 1H NMR (400.13 MHz, DMSO-d6) δ 1.36 (d, 6H), 1.57 (m, 2H), 1.97 (d, 2H), 2.59 (s, 1H ), 2.78 (s, 2H), 3.16 (d, 2H), 3.29 (s, 3H), 3.50 (m, 1H), 3.72 (s, 8H), 4.46 (s, 2H), 6.44 (d, 1H), 6.81 (s, 1H), 7.49 (d, 2H), 8.20 (d, 2H), 8.65 (s, 1H)

Ejemplo 20p: RMN 1H (400,13 MHz, DMSO–d6) δ 1,38 (d, 6H), 3,28 (m, 2H), 3,29 (s, 3H), 3,40 (t, 2H), 3,51 (m, 1H), 3,72 (s, 8H), 4,46 (s, 2H), 6,28 (t, 1H), 6,81 (s, 1H), 7,49 (d, 2H), 8,20 (d, 2H), 8,77 (s, 1H) Example 20p: 1H NMR (400.13 MHz, DMSO-d6) δ 1.38 (d, 6H), 3.28 (m, 2H), 3.29 (s, 3H), 3.40 (t, 2H ), 3.51 (m, 1H), 3.72 (s, 8H), 4.46 (s, 2H), 6.28 (t, 1H), 6.81 (s, 1H), 7.49 (d, 2H), 8.20 (d, 2H), 8.77 (s, 1H)

Ejemplo 20q: RMN 1H (400,13 MHz, DMSO–d6) δ 1,07 (t, 3H), 1,24 (d, 3H), 1,36 (m, 6H), 3,13 (m, 2H), 3,23 (m, 1H), 3,51 (m, 2H), 3,65 (m, 1H), 3,72 (d, 1H), 3,99 (m, 1H), 4,17 (d, 1H), 4,46 (s, 3H), 6,17 (t, 1H), 6,77 (s, 1H), 7,50 (d, 2H), 8,18 (d, 2H), 8,65 (s, 1H) Example 20q: 1H NMR (400.13 MHz, DMSO-d6) δ 1.07 (t, 3H), 1.24 (d, 3H), 1.36 (m, 6H), 3.13 (m, 2H ), 3.23 (m, 1H), 3.51 (m, 2H), 3.65 (m, 1H), 3.72 (d, 1H), 3.99 (m, 1H), 4.17 (d, 1H), 4.46 (s, 3H), 6.17 (t, 1H), 6.77 (s, 1H), 7.50 (d, 2H), 8.18 (d, 2H) , 8.65 (s, 1 H)

Ejemplo 20r: RMN 1H (400,13 MHz, DMSO–d6) δ 0,42 (m, 2H), 0,65 (m, 2H), 1,25 (d, 3H), 1,37 (d, 6H), 2,57 (m, 2H), 3,23 (m, 1H), 3,50 (m, 2H), 3,65 (m, 1H), 3,78 (d, 1H), 3,99 (m, 1H), 4,17 (d, 1H), 4,46 (s, 2H), 6,44 (d, 1H), 6,77 (s, 1H), 7,51 (d, 2H), 8,19 (d, 2H), 8,53 (s, 1H) Example 20r: 1H NMR (400.13 MHz, DMSO-d6) δ 0.42 (m, 2H), 0.65 (m, 2H), 1.25 (d, 3H), 1.37 (d, 6H ), 2.57 (m, 2H), 3.23 (m, 1H), 3.50 (m, 2H), 3.65 (m, 1H), 3.78 (d, 1H), 3.99 (m, 1H), 4.17 (d, 1H), 4.46 (s, 2H), 6.44 (d, 1H), 6.77 (s, 1H), 7.51 (d, 2H) , 8.19 (d, 2H), 8.53 (s, 1H)

Ejemplo 20s: RMN 1H (400,13 MHz, DMSO–d6) δ 1,22 (d, 3H), 1,36 (m, 6H), 2,18 (s, 6H), 2,34 (t, 2H), 3,21 (m, 2H), 3,50 (m, 2H), 3,65 (m, 1H), 3,76 (d, 1H), 3,99 (m, 1H), 4,06 (q, 2H), 4,17 (d, 1H), 4,46 (s, 2H), 6,17 (t, 1H), 6,77 (s, 1H), 7,49 (d, 2H), 8,18 (d, 2H), 8,89 (s, 1H) Example 20s: 1H NMR (400.13 MHz, DMSO-d6) δ 1.22 (d, 3H), 1.36 (m, 6H), 2.18 (s, 6H), 2.34 (t, 2H ), 3.21 (m, 2H), 3.50 (m, 2H), 3.65 (m, 1H), 3.76 (d, 1H), 3.99 (m, 1H), 4.06 (q, 2H), 4.17 (d, 1H), 4.46 (s, 2H), 6.17 (t, 1H), 6.77 (s, 1H), 7.49 (d, 2H) , 8.18 (d, 2H), 8.89 (s, 1H)

Ejemplo 20t: RMN 1H (400,13 MHz, DMSO–d6) δ 1,22 (d, 3H), 1,36 (m, 6H), 1,42 (m, 2H), 1,80 (m, 2H), 2,03 (t, 2H), 2,17 (s, 3H), 2,65 (d, 2H), 3,18 (d, 1H), 3,23 (m, 1H), 3,50 (m, 2H), 3,65 (m, 1H), 3,76 (d, 1H), 3,98 (m, 1H), 4,06 (m, 1H), 4,17 (d, 1H), 4,46 (s, 2H), 6,19 (d, 1H), 6,77 (s, 1H), 7,48 (d, 2H), 8,18 (d, 2H), 8,56 (s, 1H) Example 20t: 1H NMR (400.13 MHz, DMSO-d6) δ 1.22 (d, 3H), 1.36 (m, 6H), 1.42 (m, 2H), 1.80 (m, 2H ), 2.03 (t, 2H), 2.17 (s, 3H), 2.65 (d, 2H), 3.18 (d, 1H), 3.23 (m, 1H), 3.50 (m, 2H), 3.65 (m, 1H), 3.76 (d, 1H), 3.98 (m, 1H), 4.06 (m, 1H), 4.17 (d, 1H) , 4.46 (s, 2H), 6.19 (d, 1H), 6.77 (s, 1H), 7.48 (d, 2H), 8.18 (d, 2H), 8.56 ( s, 1H)

Ejemplo 20u: RMN 1H (400,13 MHz, DMSO–d6) δ 1,24 (d, 4H), 1,36 (m, 6H), 3,18 (d, 3H), 3,24 (m, 2H), 3,40 (t, 2H), 3,50 (m, 2H), 3,65 (m, 1H), 3,78 (d, 1H), 3,99 (m, 1H), 4,06 (m, 1H), 4,17 (d, 1H), 4,46 (s, 2H), 6,28 (t, 1H), 6,77 (s, 1H), 7,49 (d, 2H), 8,19 (d, 2H), 8,77 (s, 1H) Example 20u: 1H NMR (400.13 MHz, DMSO-d6) δ 1.24 (d, 4H), 1.36 (m, 6H), 3.18 (d, 3H), 3.24 (m, 2H ), 3.40 (t, 2H), 3.50 (m, 2H), 3.65 (m, 1H), 3.78 (d, 1H), 3.99 (m, 1H), 4.06 (m, 1H), 4.17 (d, 1H), 4.46 (s, 2H), 6.28 (t, 1H), 6.77 (s, 1H), 7.49 (d, 2H) , 8.19 (d, 2H), 8.77 (s, 1H)

Prueba (a): Ejemplo (20) 0,043 μM; Ejemplo (20a) 0,15 μM; Ejemplo (20b) 0,17 μM; Ejemplo (20c) 1 μM; Ejemplo (20d) 1,6 μM; Ejemplo (20e) 2,1 μM; Ejemplo (20f) 0,035 μM; Ejemplo (20g) 0,039 μM; Ejemplo (20h) 0,44 μM; Ejemplo (20i) 0,7 μM; Ejemplo (20j) 0,75 μM; Ejemplo (20k) 0,036 μM; Ejemplo (20l) 0,074 μM; Ejemplo (20m) 0,081 μM; Ejemplo (20n) 0,86 μM; Ejemplo (20o) 1,3 μM; Ejemplo (20p) 0,91 μM; Ejemplo (20q) 0,039 μM; Ejemplo (20r) 0,094 μM; Ejemplo (20s) 0,62 μM; Ejemplo (20t) 0,6 μM; Ejemplo (20u) 0,27 μM. Test (a): Example (20) 0.043 μM; Example (20a) 0.15 μM; Example (20b) 0.17 μM; Example (20c) 1 μM; Example (20d) 1.6 μM; Example (20e) 2.1 μM; Example (20f) 0.035 μM; Example (20g) 0.039 μM; Example (20h) 0.44 μM; Example (20i) 0.7 μM; Example (20j) 0.75 μM; Example (20k) 0.036 μM; Example (20l) 0.074 μM; Example (20m) 0.081 μM; Example (20n) 0.86 μM; Example (20o) 1.3 μM; Example (20p) 0.91 μM; Example (20q) 0.039 μM; Example (20r) 0.094 μM; Example (20s) 0.62 μM; Example (20t) 0.6 μM; Example (20u) 0.27 μM.

A continuación se describen las preparaciones de los carbamatos (4–{4–morfolin–4–il–6– [(fenilsulfonil)metil]pirimidin–2–il}fenil)carbamato de fenilo, (4–{4–[(3S)–3–metilmorfolin–4–il]–6– [(fenilsulfonil)metil]pirimidin–2–il}fenil)carbamato de fenilo, (4–{4–[(isopropilsulfonil)metil]–6–morfolin–4–ilpirimidin–2– il}fenil)carbamato de fenilo, (4–{4–[(isopropilsulfonil)metil]–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2– il}fenil)carbamato de fenilo. The preparations of the carbamates (4– {4-morpholin-4-yl-6– [(phenylsulfonyl) methyl] pyrimidin-2-yl} phenyl) phenyl carbamate, (4– {4 - [(3S ) –3 – methylmorpholin-4-yl] –6– [(phenylsulfonyl) methyl] pyrimidin-2-yl} phenyl) phenyl carbamate, (4– {4 - [(isopropylsulfonyl) methyl] –6 – morpholin-4– ilpirimidin – 2– yl} phenyl) phenyl carbamate, (4– {4 - [(isopropylsulfonyl) methyl] –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl} phenyl) carbamate phenyl.

(4–{4–Morfolin–4–il–6–[(fenilsulfonil)metil]pirimidin–2–il}fenil)carbamato de fenilo (4– {4 – Morpholin-4-yl – 6 - [(phenylsulfonyl) methyl] pyrimidin-2-yl} phenyl) phenyl carbamate

O OR

N N

N S OO N S OO

N N

O OR

N N

O H Or h

Se disolvió (4–{4–morfolin–4–il–6–[(fenilsulfonil)metil]pirimidin–2–il}fenil)amina (1 g, 2,44 mmoles) en dioxano (10 ml). Se añadió bicarbonato de sodio (307 mg, 3,65 mmoles), seguido por cloroformiato de fenilo (0,307 ml, 2,44 mmoles), y la reacción se agitó a temperatura ambiente durante 2 horas. El disolvente se eliminó a vacío, y el aceite resultante se repartió entre 10 ml de DCM y 10 ml de agua. La fase orgánica se secó sobre sulfato de magnesio, se filtró y se concentró a vacío. El sólido color crema obtenido se cromatografió en sílice, eluyendo con 0–50% de acetato de etilo en DCM, para dar el material deseado como un sólido blanco (790 mg). (4– {4-morpholin-4-yl-6 - [(phenylsulfonyl) methyl] pyrimidin-2-yl} phenyl) amine (1 g, 2.44 mmol) was dissolved in dioxane (10 ml). Sodium bicarbonate (307 mg, 3.65 mmol) was added, followed by phenyl chloroformate (0.307 ml, 2.44 mmol), and the reaction was stirred at room temperature for 2 hours. The solvent was removed in vacuo, and the resulting oil was partitioned between 10 ml of DCM and 10 ml of water. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The cream-colored solid obtained was chromatographed on silica, eluting with 0–50% ethyl acetate in DCM, to give the desired material as a white solid (790 mg).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 3,64 (s, 4H), 3,70 (m, 4H), 4,71 (s, 2H), 6,70 (s, 1H), 7,27 (m, 3H), 7,45 (t, 2H), 7,51 (d, 2H), 7,62 (t, 2H), 7,74 (m, 1H), 7,85 (m, 4H), 10,38 (s, 1H) NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 3.64 (s, 4H), 3.70 (m, 4H), 4.71 (s, 2H), 6.70 (s, 1H ), 7.27 (m, 3H), 7.45 (t, 2H), 7.51 (d, 2H), 7.62 (t, 2H), 7.74 (m, 1H), 7.85 (m, 4H), 10.38 (s, 1H)

Espectro LCMS: MH+ 531, tiempo de retención 2,61 min., Método Básico 5 min. LCMS spectrum: MH + 531, retention time 2.61 min., Basic Method 5 min.

(4–{4–Morfolin–4–il–6–[(fenilsulfonil)metil]pirimidin–2–il}fenil)amina (4– {4 – Morpholin-4-yl – 6 - [(phenylsulfonyl) methyl] pyrimidin-2-yl} phenyl) amine

Se disolvió 4–{2–cloro–6–[(fenilsulfonil)metil]pirimidin–4–il}morfolina (3,3 g, 9,33 mmoles) en una disolución de 18% de DMF en una mezcla de dimetoxietano:agua:etanol 7:3:2 (36 ml). Después se añadieron [4–(4,4,5,5–tetrametil– 1,3,2–dioxaborolan–2–il)fenil]amina (3,07 g, 13,99 mmoles), disolución 2M de carbonato de sodio (12 ml) y catalizador de diclorobis(trifenilfosfina)paladio (328 mg, 0,47 mmoles), y la reacción se puso a reflujo a 90ºC durante 2 horas en una atmósfera de nitrógeno. La reacción se dejó enfriar hasta la temperatura ambiente, y después se repartió entre acetato de etilo (20 ml) y agua (20 ml). Los productos orgánicos se secaron sobre sulfato de magnesio, se filtraron y se concentraron a vacío. El aceite bruto se disolvió en DCM y se filtró para eliminar el material insoluble. Un sólido beige precipitó de los filtrados, y los filtrados se filtraron nuevamente. El sólido se analizó y se encontró que era el material deseado (2,2 g). 4– {2-Chloro-6 - [(phenylsulfonyl) methyl] pyrimidin-4-yl} morpholine (3.3 g, 9.33 mmol) was dissolved in an 18% solution of DMF in a mixture of dimethoxyethane: water : 7: 3: 2 ethanol (36 ml). Then [4– (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] amine (3.07 g, 13.99 mmol), 2M solution of sodium carbonate were added (12 ml) and dichlorobis (triphenylphosphine) palladium catalyst (328 mg, 0.47 mmol), and the reaction was refluxed at 90 ° C for 2 hours under a nitrogen atmosphere. The reaction was allowed to cool to room temperature, and then partitioned between ethyl acetate (20 ml) and water (20 ml). The organic products were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude oil was dissolved in DCM and filtered to remove insoluble material. A beige solid precipitated from the filtrates, and the filtrates were filtered again. The solid was analyzed and found to be the desired material (2.2 g).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 3,60 (m, 4H), 3,69 (m, 4H), 4,64 (s, 2H), 5,50 (s, 2H), 6,48 (d, 2H), 6,54 (s, 1H), 7,63 (m, 4H), 7,74 (t, 1H), 7,82 (m, 2H) NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 3.60 (m, 4H), 3.69 (m, 4H), 4.64 (s, 2H), 5.50 (s, 2H ), 6.48 (d, 2H), 6.54 (s, 1H), 7.63 (m, 4H), 7.74 (t, 1H), 7.82 (m, 2H)

Espectro LCMS: MH+ 411, tiempo de retención 1,70 min., Método Básico 5 min. LCMS spectrum: MH + 411, retention time 1.70 min., Basic Method 5 min.

4–{2–Cloro–6–[(fenilsulfonil)metil]pirimidin–4–il}morfolina 4– {2 – Chloro – 6 - [(phenylsulfonyl) methyl] pyrimidin-4-yl} morpholine

Se disolvió 2,4–dicloro–6–[(fenilsulfonil)metil]pirimidina (6 g, 19,8 mmoles) en DCM (50 ml) y se agitó (en nitrógeno) a –5°C. Se añadió trietilamina (3,06 ml, 21,8 mmoles) para dar una disolución marrón clara. Se disolvió morfolina (1,65 ml, 19,8 mmoles) en DCM, y se añadió gota a gota manteniendo la reacción por debajo de –5°C. Después el baño de enfriamiento se retiró, y la mezcla de reacción se agitó a temperatura ambiente durante 1 hora. La mezcla de reacción se lavó después con agua (50 ml), se secó sobre sulfato de magnesio, se filtró y se concentró a vacío. El material bruto se cromatografió en sílice, eluyendo con 0–50% de acetato de etilo en DCM para dar el material deseado como un sólido blanco (4 g). 2,4-Dichloro-6 - [(phenylsulfonyl) methyl] pyrimidine (6 g, 19.8 mmol) was dissolved in DCM (50 ml) and stirred (in nitrogen) at -5 ° C. Triethylamine (3.06 ml, 21.8 mmol) was added to give a light brown solution. Morpholine (1.65 ml, 19.8 mmol) was dissolved in DCM, and added dropwise keeping the reaction below -5 ° C. Then the cooling bath was removed, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then washed with water (50 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was chromatographed on silica, eluting with 0–50% ethyl acetate in DCM to give the desired material as a white solid (4 g).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 3,53 (s, 4H), 3,65 (t, 4H), 4,61 (s, 2H), 6,71 (s, 1H), 7,64 (t, 2H), 7,77 (m, 3H) Espectro LCMS: MH+ 354, tiempo de retención 1,50 min., Método Básico 5 min. 2,4–dicloro–6–[(fenilsulfonil)metil]pirimidina NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 3.53 (s, 4H), 3.65 (t, 4H), 4.61 (s, 2H), 6.71 (s, 1H ), 7.64 (t, 2H), 7.77 (m, 3H) LCMS spectrum: MH + 354, retention time 1.50 min., Basic Method 5 min. 2,4-dichloro-6 - [(phenylsulfonyl) methyl] pyrimidine

Cl Cl

Se añadió 6–[(fenilsulfonil)metil]pirimidin–2,4 (1H,3H)–diona (13,3 g, 49 mmoles) a oxicloruro de fósforo (100 ml), y la mezcla se calentó a reflujo durante 16 horas. La reacción se enfrió después hasta la temperatura ambiente, y el exceso de oxicloruro de fósforo se eliminó a vacío. El residuo se destiló azeotrópicamente con tolueno (2 x 100 ml) y se disolvió en DCM. Esta mezcla se vertió entonces lentamente sobre hielo (1 l) y se agitó durante 20 minutos, y después se extrajo con DCM (3 x 500 ml). Los extractos se combinaron, se secaron sobre sulfato de magnesio, y después se concentraron a vacío para dar el material deseado como un sólido marrón (12 g). El material se usó sin purificación adicional. 6 - [(Phenylsulfonyl) methyl] pyrimidin-2,4 (1H, 3H) -dione (13.3 g, 49 mmol) was added to phosphorus oxychloride (100 ml), and the mixture was heated at reflux for 16 hours . The reaction was then cooled to room temperature, and the excess phosphorus oxychloride was removed in vacuo. The residue was azeotropically distilled with toluene (2 x 100 ml) and dissolved in DCM. This mixture was then slowly poured onto ice (1 L) and stirred for 20 minutes, and then extracted with DCM (3 x 500 ml). The extracts were combined, dried over magnesium sulfate, and then concentrated in vacuo to give the desired material as a brown solid (12 g). The material was used without further purification.

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 4,97 (s, 2H), 7,65 (t, 2H), 7,72 (s, 1H), 7,79 (m, 3H) NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 4.97 (s, 2H), 7.65 (t, 2H), 7.72 (s, 1H), 7.79 (m, 3H )

Espectro LCMS: M–H 301, tiempo de retención 2,08 min., Método Básico 5 min. LCMS spectrum: M – H 301, retention time 2.08 min., Basic Method 5 min.

6–[(Fenilsulfonil)metil]pirimidin–2,4 (1H,3H)–diona 6 - [(Phenylsulfonyl) methyl] pyrimidin-2,4 (1H, 3H) -dione

O OR

Se disolvió 6–(clorometil)–1H–pirimidin–2,4–diona (8 g, 50 mmoles) en DMF (200 ml), y se añadió sal sódica del ácido bencenosulfínico (9,8 g, 60 mmoles). La reacción se calentó hasta 125ºC durante 2 horas, después se dejó enfriar, y la suspensión se filtró y se concentró a vacío para dar un sólido amarillo. El material bruto se lavó con agua (100 ml), se filtró, y después se trituró con acetonitrilo para dar el material deseado como un sólido color crema (13,2 g). El material se usó sin purificación adicional. 6– (Chloromethyl) -1H-pyrimidin-2,4-dione (8 g, 50 mmol) was dissolved in DMF (200 ml), and sodium salt of benzenesulfinic acid (9.8 g, 60 mmol) was added. The reaction was heated to 125 ° C for 2 hours, then allowed to cool, and the suspension was filtered and concentrated in vacuo to give a yellow solid. The crude material was washed with water (100 ml), filtered, and then triturated with acetonitrile to give the desired material as a cream-colored solid (13.2 g). The material was used without further purification.

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 4,46 (s, 2H), 7,69 (t, 2H), 7,81 (m, 1H), 7,87 (m, 3H), 10,85 (s, 1H), 11,11 (s, 1H) NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 4.46 (s, 2H), 7.69 (t, 2H), 7.81 (m, 1H), 7.87 (m, 3H ), 10.85 (s, 1H), 11.11 (s, 1H)

(4–{4–[(3S)–3–Metilmorfolin–4–il]–6–[(fenilsulfonil)metil]pirimidin–2–il}fenil)carbamato de fenilo (4– {4 - [(3S) –3 – Methylmorpholin-4-yl] –6 - [(phenylsulfonyl) methyl] pyrimidin-2-yl} phenyl) phenyl carbamate

Se disolvió (4–{4–[(3S)–3–metilmorfolin–4–il]–6–[(fenilsulfonil)metil]pirimidin–2–il}fenil)amina (2 g, 4,71 mmoles) en dioxano (20 ml). Se añadió bicarbonato de sodio (594 mg, 7,07 mmoles), seguido por cloroformiato de fenilo (0,593 ml, 4,71 mmoles), y la reacción se agitó a temperatura ambiente durante 2 horas. El disolvente se eliminó a vacío, y el aceite resultante se repartió entre 20 ml de DCM y 20 ml de agua. La fase orgánica se secó sobre sulfato de magnesio, se filtró y se concentró a vacío. El sólido color crema obtenido se cromatografió en sílice, eluyendo con 0– 50% de acetato de etilo en DCM, para dar el material deseado como un sólido blanco (1,1 g). (4– {4 - [(3S) –3-methylmorpholin-4-yl] –6 - [(phenylsulfonyl) methyl] pyrimidin-2-yl} phenyl) amine (2 g, 4.71 mmol) was dissolved in dioxane (20 ml). Sodium bicarbonate (594 mg, 7.07 mmol) was added, followed by phenyl chloroformate (0.593 ml, 4.71 mmol), and the reaction was stirred at room temperature for 2 hours. The solvent was removed in vacuo, and the resulting oil was partitioned between 20 ml of DCM and 20 ml of water. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The cream-colored solid obtained was chromatographed on silica, eluting with 0-50% ethyl acetate in DCM, to give the desired material as a white solid (1.1 g).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,20 (d, 3H), 3,17 (m, 1H), 3,48 (m, 1H), 3,63 (m, 1H), 3,76 (d, 1H), 3,97 (m ,1H), 4,11 (d, 1H), 4,37 (s, 1H), 4,72 (s, 2H), 6,65 (s, 1H), 7,27 (m, 3H), 7,45 (t, 2H), 7,51 (d, 2H), 7,62 (t, 2H), 7,74 (t, 1H), 7,82 (d, 2H), 7,90 (d, 2H), 10,38 (s, 1H) NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.20 (d, 3H), 3.17 (m, 1H), 3.48 (m, 1H), 3.63 (m, 1H ), 3.76 (d, 1H), 3.97 (m, 1H), 4.11 (d, 1H), 4.37 (s, 1H), 4.72 (s, 2H), 6.65 (s, 1H), 7.27 (m, 3H), 7.45 (t, 2H), 7.51 (d, 2H), 7.62 (t, 2H), 7.74 (t, 1H) , 7.82 (d, 2H), 7.90 (d, 2H), 10.38 (s, 1H)

30 Espectro LCMS: MH+ 545, tiempo de retención 2,7 min., Método Básico 5 min. (4–{4–[(3S)–3–Metilmorfolin–4–il]–6–[(fenilsulfonil)metil]pirimidin–2–il}fenil)amina 30 LCMS spectrum: MH + 545, retention time 2.7 min., Basic Method 5 min. (4– {4 - [(3S) –3 – Methylmorpholin-4-yl] –6 - [(phenylsulfonyl) methyl] pyrimidin-2-yl} phenyl) amine

Se disolvió (4–{4–[(3S)–3–metilmorfolin–4–il]–6–[(fenilsulfonil)metil]pirimidin–2–il}fenil)carbamato de terc–butilo (3,1 g, 5,91 mmoles) en DCM (20 ml), y se añadió ácido trifluoroacético (10 ml). La mezcla de reacción se agitó a temperatura ambiente durante 2 horas, y después se diluyó con DCM (20 ml) y se lavó con bicarbonato de sodio saturado acuoso (20 ml). La fase orgánica se recogió, se secó sobre sulfato de magnesio, se filtró y se concentró a vacío para dar el material deseado como un sólido beige (2,5 g). Tert-Butyl (3.1g, 5) (4– {4 - [(3S) -3-methylmorpholin-4-yl] -6 - [(phenylsulfonyl) methyl] pyrimidin-2-yl} phenyl) carbamate was dissolved , 91 mmol) in DCM (20 ml), and trifluoroacetic acid (10 ml) was added. The reaction mixture was stirred at room temperature for 2 hours, and then diluted with DCM (20 ml) and washed with saturated aqueous sodium bicarbonate (20 ml). The organic phase was collected, dried over magnesium sulfate, filtered and concentrated in vacuo to give the desired material as a beige solid (2.5 g).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,22 (d, 3H), 3,24 (m, 1H), 3,47 (m, 1H), 3,62 (m, 1H), 3,78 (d, 1H), 3,98 (m, 1H), 4,14 (s, 1H), 4,37 (s, 1H), 4,75 (s, 2H), 6,56 (s, 1H), 6,67 (d, 3H), 7,65 (m, 2H), 7,78 (m, 3H), 7,84 (m, 3H) NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.22 (d, 3H), 3.24 (m, 1H), 3.47 (m, 1H), 3.62 (m, 1H ), 3.78 (d, 1H), 3.98 (m, 1H), 4.14 (s, 1H), 4.37 (s, 1H), 4.75 (s, 2H), 6.56 (s, 1H), 6.67 (d, 3H), 7.65 (m, 2H), 7.78 (m, 3H), 7.84 (m, 3H)

Espectro LCMS: MH+ 425, tiempo de retención 2,03 min., Método Básico 5 min. LCMS spectrum: MH + 425, retention time 2.03 min., Basic Method 5 min.

(4–{4–[(3S)–3–Metilmorfolin–4–il]–6–[(fenilsulfonil)metil]pirimidin–2–il}fenil)carbamato de terc–butilo (4– {4 - [(3S) –3 – Methylmorpholin-4-yl] –6 - [(phenylsulfonyl) methyl] pyrimidin-2-yl} phenyl) tert-butyl carbamate

O OR

Se disolvió (3S)–4–{2–cloro–6–[(fenilsulfonil)metil]pirimidin–4–il}–3–metilmorfolina (3,2 g, 8,70 mmoles) en una disolución de 18% de DMF en una mezcla de dimetoxietano:agua:etanol 7:3:2 (36 ml). Después se añadieron [4– (4,4,5,5–tetrametil–1,3,2–dioxaborolan–2–il)fenil]carbamato de terc–butilo (4,16 g, 13,05 mmoles), disolución 2M de carbonato de sodio (8 ml) y catalizador de diclorobis(trifenilfosfina)paladio (306 mg, 0,43 mmoles), y la reacción se puso a reflujo a 90ºC durante 2 horas en una atmósfera de nitrógeno. La reacción se dejó enfriar hasta la temperatura ambiente, y después se repartió entre acetato de etilo (20 ml) y agua (20 ml). Los productos orgánicos se secaron sobre sulfato de magnesio, se filtraron y se concentraron a vacío. El sólido bruto se cromatografió en sílice, eluyendo con 0–30% de acetato de etilo en DCM para dar el material deseado como un sólido beige (3,1 g). (3S) –4– {2-chloro-6 - [(phenylsulfonyl) methyl] pyrimidin-4-yl} -3-methylmorpholine (3.2 g, 8.70 mmol) was dissolved in a solution of 18% DMF in a mixture of dimethoxyethane: water: ethanol 7: 3: 2 (36 ml). Then [4– (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] tert-butyl carbamate (4.16 g, 13.05 mmol), 2M solution were added of sodium carbonate (8 ml) and dichlorobis (triphenylphosphine) palladium catalyst (306 mg, 0.43 mmol), and the reaction was refluxed at 90 ° C for 2 hours in a nitrogen atmosphere. The reaction was allowed to cool to room temperature, and then partitioned between ethyl acetate (20 ml) and water (20 ml). The organic products were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude solid was chromatographed on silica, eluting with 0-30% ethyl acetate in DCM to give the desired material as a beige solid (3.1 g).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,19 (d, 3H), 1,49 (s, 9H), 3,16 (m, 1H), 3,47 (m, 1H), 3,62 (m, 1H), 3,75 (d, 1H), 3,97 (m, 1H), 4,10 (d, 1H), 4,35 (s, 1H), 4,70 (s, 2H), 6,62 (s, 1H), 7,44 (d, 2H), 7,63 (d, 2H), 7,74 (m, 1H), 7,82 (m, 4H), 9,49 (s, 1H) NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.19 (d, 3H), 1.49 (s, 9H), 3.16 (m, 1H), 3.47 (m, 1H ), 3.62 (m, 1H), 3.75 (d, 1H), 3.97 (m, 1H), 4.10 (d, 1H), 4.35 (s, 1H), 4.70 (s, 2H), 6.62 (s, 1H), 7.44 (d, 2H), 7.63 (d, 2H), 7.74 (m, 1H), 7.82 (m, 4H) , 9.49 (s, 1 H)

Espectro LCMS: MH+ 525, tiempo de retención 2,80 min., Método Básico 5 min. LCMS spectrum: MH + 525, retention time 2.80 min., Basic Method 5 min.

(3S)–4–{2–cloro–6–[(fenilsulfonil)metil]pirimidin–4–il}–3–metilmorfolina (3S) –4– {2 – chloro – 6 - [(phenylsulfonyl) methyl] pyrimidin – 4-yl} –3-methylmorpholine

Se disolvió 2,4–dicloro–6–[(fenilsulfonil)metil]pirimidina (2,8 g, 9,24 mmoles) en DCM (20 ml) y se agitó (en nitrógeno) a –5ºC. Se añadió trietilamina (1,42 ml, 10,17 mmoles) para dar una disolución marrón clara. Se disolvió (3S)–3–metilmorfolina (935 mg, 9,24 mmoles) en DCM, y se añadió gota a gota manteniendo la reacción por debajo de –5ºC. Después el baño de enfriamiento se retiró, y la mezcla de reacción se agitó a temperatura ambiente 2,4-Dichloro-6 - [(phenylsulfonyl) methyl] pyrimidine (2.8 g, 9.24 mmol) was dissolved in DCM (20 ml) and stirred (under nitrogen) at -5 ° C. Triethylamine (1.42 ml, 10.17 mmol) was added to give a light brown solution. (3S) -3-methylmorpholine (935 mg, 9.24 mmol) was dissolved in DCM, and added dropwise keeping the reaction below -5 ° C. Then the cooling bath was removed, and the reaction mixture was stirred at room temperature.

durante 1 hora. La mezcla de reacción se lavó después con agua (50 ml), se secó sobre sulfato de magnesio, se filtró y se concentró a vacío. El material bruto se cromatografió en sílice, eluyendo con 0–50% de acetato de etilo en DCM para dar el material deseado como un sólido blanco (2,6 g). for 1 hour. The reaction mixture was then washed with water (50 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was chromatographed on silica, eluting with 0–50% ethyl acetate in DCM to give the desired material as a white solid (2.6 g).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,15 (d, 3H), 3,15 (m, 1H), 3,42 (m, 1H), 3,56 (m, 1H), 3,72 (d, 1H), 3,92 (m, 2H), 4,15 (s, 1H), 4,62 (s, 2H), 6,66 (s, 1H), 7,74 (t, 1H), 7,76 (t, 1H), 7,78 (d, 1H), 7,80 (m, 2H) NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.15 (d, 3H), 3.15 (m, 1H), 3.42 (m, 1H), 3.56 (m, 1H ), 3.72 (d, 1H), 3.92 (m, 2H), 4.15 (s, 1H), 4.62 (s, 2H), 6.66 (s, 1H), 7.74 (t, 1H), 7.76 (t, 1H), 7.78 (d, 1H), 7.80 (m, 2H)

Espectro LCMS: MH+ 368, tiempo de retención 1,95 min., Método Básico 5 min. LCMS spectrum: MH + 368, retention time 1.95 min., Basic Method 5 min.

(4–{4–[(Isopropilsulfonil)metil]–6–morfolin–4–ilpirimidin–2–il}fenil)carbamato de fenilo (4– {4 - [(Isopropylsulfonyl) methyl] –6-morpholin-4-ylpyrimidin-2-yl} phenyl) phenyl carbamate

O OR

N N

N S N S

OO OO

N N

O OR

N N

O H Or h

Se disolvió (4–{4–[(isopropilsulfonil)metil]–6–morfolin–4–ilpirimidin–2–il}fenil)amina (1,5 g, 3,98 mmoles) en dioxano (10 ml). Se añadió bicarbonato de sodio (503 mg, 5,98 mmoles), seguido por cloroformiato de fenilo (0,502 ml, 3,98 mmoles), y la reacción se agitó a temperatura ambiente durante 2 horas. El disolvente se eliminó a vacío, y el aceite resultante se repartió entre 10 ml de DCM y 10 ml de agua. La fase orgánica se secó sobre sulfato de magnesio, se filtró y se concentró a vacío. El sólido color crema obtenido se cromatografió en sílice, eluyendo con 0–50% de acetato de etilo en DCM, para dar el material deseado como un sólido blanco (1,5 g). (4– {4 - [(isopropylsulfonyl) methyl] -6-morpholin-4-ylpyrimidin-2-yl} phenyl) amine (1.5 g, 3.98 mmol) was dissolved in dioxane (10 ml). Sodium bicarbonate (503 mg, 5.98 mmol) was added, followed by phenyl chloroformate (0.502 ml, 3.98 mmol), and the reaction was stirred at room temperature for 2 hours. The solvent was removed in vacuo, and the resulting oil was partitioned between 10 ml of DCM and 10 ml of water. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The cream-colored solid obtained was chromatographed on silica, eluting with 0–50% ethyl acetate in DCM, to give the desired material as a white solid (1.5 g).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,30 (d, 6H), 3,45 (m, 1H), 3,65 (s, 8H), 4,40 (s, 2H), 6,78 (s, 1H), 7,20 (m, 3H), 7,38 (t, 2H), 7,56 (d, 2H), 8,22 (d, 2H), 10,37 (s, 1H) NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.30 (d, 6H), 3.45 (m, 1H), 3.65 (s, 8H), 4.40 (s, 2H ), 6.78 (s, 1H), 7.20 (m, 3H), 7.38 (t, 2H), 7.56 (d, 2H), 8.22 (d, 2H), 10.37 (s, 1H)

Espectro LCMS: MH+ 497, tiempo de retención 2,54 min., Método Básico 5 min. LCMS spectrum: MH + 497, retention time 2.54 min., Basic Method 5 min.

(4–{4–[(Isopropilsulfonil)metil]–6–morfolin–4–ilpirimidin–2–il}fenil)amina (4– {4 - [(Isopropylsulfonyl) methyl] –6-morpholin-4-ylpyrimidin-2-yl} phenyl) amine

Se disolvió (4–{4–[(isopropilsulfonil)metil]–6–morfolin–4–ilpirimidin–2–il}fenil)carbamato de terc–butilo (2,7 g, 5,67 mmoles) en DCM (20 ml), y se añadió ácido trifluoroacético (10 ml). La mezcla de reacción se agitó a temperatura ambiente durante 2 horas, después se diluyó con DCM (20 ml) y se lavó con bicarbonato de sodio saturado acuoso (20 ml). La fase orgánica se recogió, se secó sobre sulfato de magnesio, se filtró y se concentró a vacío para dar el material deseado como un sólido color crema (2,1 g). Tert-Butyl (4-{4 - [(isopropylsulfonyl) methyl] -6-morpholin-4-ylpyrimidin-2-yl} phenyl) carbamate (2.7 g, 5.67 mmol) was dissolved in DCM (20 ml ), and trifluoroacetic acid (10 ml) was added. The reaction mixture was stirred at room temperature for 2 hours, then diluted with DCM (20 ml) and washed with saturated aqueous sodium bicarbonate (20 ml). The organic phase was collected, dried over magnesium sulfate, filtered and concentrated in vacuo to give the desired material as a cream solid (2.1 g).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,35 (d, 6H), 3,50 (m, 1H), 3,67 (m, 4H), 3,72 (m, 4H), 4,41 (s, 2H), 5,57 (s, 2H), 6,60 (d, 2H), 6,70 (s, 1H), 8,03 (d, 2H) NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.35 (d, 6H), 3.50 (m, 1H), 3.67 (m, 4H), 3.72 (m, 4H ), 4.41 (s, 2H), 5.57 (s, 2H), 6.60 (d, 2H), 6.70 (s, 1H), 8.03 (d, 2H)

Espectro LCMS: MH+ 377, tiempo de retención 1,61 min., Método Básico 5 min. LCMS spectrum: MH + 377, retention time 1.61 min., Basic Method 5 min.

(4–{4–[(Isopropilsulfonil)metil]–6–morfolin–4–ilpirimidin–2–il}fenil)carbamato de terc–butilo (4– {4 - [(Isopropylsulfonyl) methyl] –6-morpholin-4-ylpyrimidin-2-yl} phenyl) tert-butyl carbamate

O OR

N N

N S N S

OO OO

N N

O OR

O H Or h

N N

Se disolvió 4–{2–cloro–6–[(isopropilsulfonil)metil]pirimidin–4–il}morfolina (1,5 g, 4,69 mmoles) en una disolución de 18% de DMF en una mezcla de dimetoxietano:agua:etanol 7:3:2 (36 ml). Después se añadieron ácido {4–[(terc– butoxicarbonil)amino]fenil}borónico (1,67 g, 7,04 mmoles), disolución 2M de carbonato de sodio (12 ml) y catalizador de diclorobis(trifenilfosfina)paladio (165 mg, 0,23 mmoles), y la reacción se puso a reflujo a 90ºC durante 2 horas en una atmósfera de nitrógeno. La reacción se dejó enfriar hasta la temperatura ambiente, y después se repartió entre acetato de etilo (20 ml) y agua (20 ml). Los productos orgánicos se secaron sobre sulfato de magnesio, se filtraron y se concentraron a vacío. El aceite bruto se disolvió en DCM y se filtró para eliminar el material insoluble. Un sólido marrón precipitó de los filtrados, y los filtrados se filtraron nuevamente. El sólido se analizó y se encontró que era el material deseado (1,9 g). 4– {2-Chloro-6 - [(isopropylsulfonyl) methyl] pyrimidin-4-yl} morpholine (1.5 g, 4.69 mmol) was dissolved in a solution of 18% DMF in a mixture of dimethoxyethane: water : 7: 3: 2 ethanol (36 ml). Then {4 - [(tert-butoxycarbonyl) amino] phenyl} boronic acid (1.67 g, 7.04 mmol), 2M solution of sodium carbonate (12 ml) and dichlorobis (triphenylphosphine) palladium (165) catalyst were added mg, 0.23 mmol), and the reaction was refluxed at 90 ° C for 2 hours under a nitrogen atmosphere. The reaction was allowed to cool to room temperature, and then partitioned between ethyl acetate (20 ml) and water (20 ml). The organic products were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude oil was dissolved in DCM and filtered to remove insoluble material. A brown solid precipitated from the filtrates, and the filtrates were filtered again. The solid was analyzed and found to be the desired material (1.9 g).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,36 (d, 6H), 1,50 (s, 9H), 3,52 (m, 1H), 3,72 (s, 8H), 4,46 (s, 2H), 6,83 (s, 1H), 7,57 (d, 2H), 8,22 (d, 2H), 9,56 (s, 1H) NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.36 (d, 6H), 1.50 (s, 9H), 3.52 (m, 1H), 3.72 (s, 8H ), 4.46 (s, 2H), 6.83 (s, 1H), 7.57 (d, 2H), 8.22 (d, 2H), 9.56 (s, 1H)

Espectro LCMS: MH+ 477, tiempo de retención 2,50 min., Método Básico 5 min. LCMS spectrum: MH + 477, retention time 2.50 min., Basic Method 5 min.

Se disolvió 2,4–dicloro–6–[(isopropilsulfonil)metil]pirimidina (2,65 g, 9,85 mmoles) en DCM (50 ml) y se agitó (en nitrógeno) a –5ºC. Se añadió trietilamina (1,5 ml, 10,84 mmoles) para dar una disolución marrón clara. Se disolvió morfolina (0,86 ml, 9,85 mmoles) en DCM, y se añadió gota a gota manteniendo la reacción por debajo de –5ºC. Después el baño de enfriamiento se retiró, y la mezcla de reacción se agitó a temperatura ambiente durante 1 hora. La mezcla de reacción se lavó después con agua (50 ml), se secó sobre sulfato de magnesio, se filtró y se concentró a vacío. El material bruto se cromatografió en sílice, eluyendo con 0–50% de acetato de etilo en DCM para dar el material deseado (2,5 g). 2,4-Dichloro-6 - [(isopropylsulfonyl) methyl] pyrimidine (2.65 g, 9.85 mmol) was dissolved in DCM (50 ml) and stirred (under nitrogen) at -5 ° C. Triethylamine (1.5 ml, 10.84 mmol) was added to give a light brown solution. Morpholine (0.86 ml, 9.85 mmol) was dissolved in DCM, and added dropwise keeping the reaction below -5 ° C. Then the cooling bath was removed, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then washed with water (50 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was chromatographed on silica, eluting with 0–50% ethyl acetate in DCM to give the desired material (2.5 g).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,30 (d, 6H), 3,42 (m, 1H), 3,62 (s, 4H), 3,68 (m, 4H), 4,42 (s, 2H), 6,95 (s, 1H) NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.30 (d, 6H), 3.42 (m, 1H), 3.62 (s, 4H), 3.68 (m, 4H ), 4.42 (s, 2H), 6.95 (s, 1H)

Espectro LCMS: MH+ 320, tiempo de retención 1,51 min., Método Básico 5 min. LCMS spectrum: MH + 320, retention time 1.51 min., Basic Method 5 min.

2,4–Dicloro–6–[(isopropilsulfonil)metil]pirimidina 2,4-Dichloro-6 - [(isopropylsulfonyl) methyl] pyrimidine

Cl Cl

Se disolvió 2,4–dicloro–6–[(isopropiltio)metil]pirimidina (6,2 g, 26,16 mmoles) en DCM (100 ml) y se añadió en porciones ácido 3,5–diclorobencenocarboperoxoico (13,5 g, 78,4 mmoles) durante 10 minutos. La reacción se agitó a temperatura ambiente durante 4 horas. La mezcla de reacción se lavó después con bicarbonato de sodio saturado acuoso (50 ml), se secó sobre sulfato de magnesio, se filtró y se concentró a vacío para dar un sólido color crema. La purificación mediante cromatografía en fase normal, eluyendo con 0–50% de acetato de etilo en iso–hexano dio el material deseado como un sólido color crema (5,3 g). 2,4-Dichloro-6 - [(isopropylthio) methyl] pyrimidine (6.2 g, 26.16 mmol) was dissolved in DCM (100 ml) and 3,5-dichlorobenzenecarboperoxoic acid (13.5 g) was added portionwise , 78.4 mmol) for 10 minutes. The reaction was stirred at room temperature for 4 hours. The reaction mixture was then washed with saturated aqueous sodium bicarbonate (50 ml), dried over magnesium sulfate, filtered and concentrated in vacuo to give a cream-colored solid. Purification by normal phase chromatography, eluting with 0–50% ethyl acetate in iso-hexane gave the desired material as a cream solid (5.3 g).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,25 (d, 6H), 3,43 (m, 1H), 4,77 (s, 2H), 7,87 (s, 1H) NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.25 (d, 6H), 3.43 (m, 1H), 4.77 (s, 2H), 7.87 (s, 1H )

Espectro LCMS: M–H 267, tiempo de retención 1,64 min., Método Básico 5 min. LCMS spectrum: M – H 267, retention time 1.64 min., Basic Method 5 min.

2,4–Dicloro–6–[(isopropiltio)metil]pirimidina 2,4-Dichloro-6 - [(isopropylthio) methyl] pyrimidine

Cl Cl

Se añadió 6–[(isopropiltio)metil]pirimidin–2,4 (1H,3H)–diona (8 g, 40 mmoles) a oxicloruro de fósforo (100 ml), y la mezcla se calentó a reflujo durante 16 horas. La reacción se enfrió después hasta la temperatura ambiente, y el 10 6 - [(Isopropylthio) methyl] pyrimidin-2,4 (1H, 3H) -dione (8 g, 40 mmol) was added to phosphorus oxychloride (100 ml), and the mixture was heated at reflux for 16 hours. The reaction was then cooled to room temperature, and

exceso de oxicloruro de fósforo se eliminó a vacío. El residuo se destiló azeotrópicamente con tolueno (2 x 100 ml) y se disolvió en DCM. Esta mezcla se vertió después lentamente sobre hielo (1 l) y se agitó durante 20 minutos, y después se extrajo con DCM (3 x 500 ml). Los extractos se combinaron, se secaron sobre sulfato de magnesio, y después se concentraron a vacío para dar el material deseado como un aceite marrón (6,5 g). El material se usó sin purificación adicional. Excess phosphorus oxychloride was removed in vacuo. The residue was azeotropically distilled with toluene (2 x 100 ml) and dissolved in DCM. This mixture was then slowly poured onto ice (1 L) and stirred for 20 minutes, and then extracted with DCM (3 x 500 ml). The extracts were combined, dried over magnesium sulfate, and then concentrated in vacuo to give the desired material as a brown oil (6.5 g). The material was used without further purification.

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,21 (d, 6H), 2,96 (m, 1H), 3,85 (s, 2H), 7,82 (s, 1H) NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.21 (d, 6H), 2.96 (m, 1H), 3.85 (s, 2H), 7.82 (s, 1H )

Espectro LCMS: Tiempo de retención 2,51 min., Método Básico 5 min. LCMS spectrum: Retention time 2.51 min., Basic Method 5 min.

6–[(Isopropiltio)metil]pirimidin–2,4 (1H,3H)–diona 6 - [(Isopropylthio) methyl] pyrimidin – 2,4 (1H, 3H) –dione

O OR

Se disolvió 6–(clorometil)–1H–pirimidin–2,4–diona (8 g, 50 mmoles) en acetonitrilo (200 ml), y se añadió 1,8– diazabiciclo[5,4,0]undec–7–eno (13 ml, 87,19 mmoles), y la reacción se agitó a temperatura ambiente durante 15 minutos. Después se añadió isopropilmercaptano (8,1 ml, 87,19 mmoles), y la reacción se agitó a temperatura ambiente durante unas 2 horas adicionales. El disolvente se eliminó a vacío, y el aceite marrón resultante se disolvió en DCM y se lavó con agua. La fase orgánica se secó sobre sulfato de magnesio, se filtró y se concentró a vacío. El aceite resultante se cromatografió en sílice, eluyendo con 0–10% de metanol en DCM para dar el material deseado como un sólido blanco (8 g). 6– (Chloromethyl) -1H-pyrimidin-2,4-dione (8 g, 50 mmol) was dissolved in acetonitrile (200 ml), and 1.8- diazabicyclo [5.4.0] undec-7– was added eno (13 ml, 87.19 mmol), and the reaction was stirred at room temperature for 15 minutes. Isopropylmercaptan (8.1 ml, 87.19 mmol) was then added, and the reaction was stirred at room temperature for an additional 2 hours. The solvent was removed in vacuo, and the resulting brown oil was dissolved in DCM and washed with water. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting oil was chromatographed on silica, eluting with 0-10% methanol in DCM to give the desired material as a white solid (8 g).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,21 (d, 6H), 2,90 (m, 1H), 3,42 (s, 2H), 5,49 (s, 1H), 10,82 (s, 1H), 10,94 (s, 1H) NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.21 (d, 6H), 2.90 (m, 1H), 3.42 (s, 2H), 5.49 (s, 1H ), 10.82 (s, 1H), 10.94 (s, 1H)

Espectro LCMS: M–H 199, tiempo de retención 0,63 min., Método Básico 5 min. LCMS spectrum: M – H 199, retention time 0.63 min., Basic Method 5 min.

(4–{4–[(Isopropilsulfonil)metil]–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il}fenil)carbamato de fenilo (4– {4 - [(Isopropylsulfonyl) methyl] –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl} phenyl) phenyl carbamate

Se disolvió (4–{4–[(isopropilsulfonil)metil]–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il}fenil)amina (1,5 g, 3,84 mmoles) en dioxano (10 ml). Se añadió bicarbonato de sodio (485 mg, 5,76 mmoles), seguido por cloroformiato de fenilo (0,484 ml, 3,84 mmoles), y la reacción se agitó a temperatura ambiente durante 2 horas. El disolvente se eliminó a vacío, y el aceite resultante se repartió entre 10 ml de DCM y 10 ml de agua. La fase orgánica se secó sobre sulfato de magnesio, se filtró y se concentró a vacío. El sólido color crema obtenido se cromatografió en sílice, eluyendo con 0–50% de acetato de etilo en DCM, para dar el material deseado como un sólido blanco (1,8 g). (4– {4 - [(isopropylsulfonyl) methyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-2-yl} phenyl) amine (1.5 g, 3.84 mmol) was dissolved in dioxane (10 ml). Sodium bicarbonate (485 mg, 5.76 mmol) was added, followed by phenyl chloroformate (0.484 ml, 3.84 mmol), and the reaction was stirred at room temperature for 2 hours. The solvent was removed in vacuo, and the resulting oil was partitioned between 10 ml of DCM and 10 ml of water. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The cream-colored solid obtained was chromatographed on silica, eluting with 0–50% ethyl acetate in DCM, to give the desired material as a white solid (1.8 g).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,18 (d, 3H), 1,30 (m, 6H), 3,17 (m, 2H), 3,44 (m, 2H), 3,58 (m, 1H), 3,70 (d, 1H), 3,92 (m, 1H), 4,12 (d, 1H), 4,41 (s, 2H), 6,74 (s, 1H), 7,20 (m, 3H), 7,38 (t, 2H), 7,56 (d, 2H), 8,22 (d, 2H), 10,37 (s, 1H) NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.18 (d, 3H), 1.30 (m, 6H), 3.17 (m, 2H), 3.44 (m, 2H ), 3.58 (m, 1H), 3.70 (d, 1H), 3.92 (m, 1H), 4.12 (d, 1H), 4.41 (s, 2H), 6.74 (s, 1H), 7.20 (m, 3H), 7.38 (t, 2H), 7.56 (d, 2H), 8.22 (d, 2H), 10.37 (s, 1H)

Espectro LCMS: MH+ 511, tiempo de retención 2,67 min., Método Básico 5 min. LCMS spectrum: MH + 511, retention time 2.67 min., Basic Method 5 min.

(4–{4–[(Isopropilsulfonil)metil]–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il}fenil)amina (4– {4 - [(Isopropylsulfonyl) methyl] –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl} phenyl) amine

Se disolvió (4–{4–[(isopropilsulfonil)metil]–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il}fenil)carbamato de terc–butilo (3,2 g, 6,52 mmoles) en DCM (20 ml), y se añadió ácido trifluoroacético (10 ml). La mezcla de reacción se agitó a temperatura ambiente durante 2 horas, después se diluyó con DCM (20 ml) y se lavó con bicarbonato de sodio saturado acuoso (20 ml). La fase orgánica se recogió, se secó sobre sulfato de magnesio, se filtró y se concentró a vacío para dar el material deseado como un sólido color crema (2,4 g). Tert-Butyl (4-{4 - [(isopropylsulfonyl) methyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-2-yl} phenyl) carbamate (3.2 g, 6 , 52 mmol) in DCM (20 ml), and trifluoroacetic acid (10 ml) was added. The reaction mixture was stirred at room temperature for 2 hours, then diluted with DCM (20 ml) and washed with saturated aqueous sodium bicarbonate (20 ml). The organic phase was collected, dried over magnesium sulfate, filtered and concentrated in vacuo to give the desired material as a cream solid (2.4 g).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,22 (d, 3H), 1,35 (m, 6H), 3,19 (m, 1H), 3,49 (m, 2H), 3,64 (m, 1H), 3,77 (d, 1H), 3,97 (m, 1H), 4,14 (d, 1H), 4,41 (s, 2H), 4,45 (m, 1H), 5,56 (s, 2H), 6,60 (d, 2H), 6,66 (s, 1H), 8,02 (d, 2H) NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.22 (d, 3H), 1.35 (m, 6H), 3.19 (m, 1H), 3.49 (m, 2H ), 3.64 (m, 1H), 3.77 (d, 1H), 3.97 (m, 1H), 4.14 (d, 1H), 4.41 (s, 2H), 4.45 (m, 1H), 5.56 (s, 2H), 6.60 (d, 2H), 6.66 (s, 1H), 8.02 (d, 2H)

Espectro LCMS: MH+ 391, tiempo de retención 1,84 min., Método Básico 5 min. LCMS spectrum: MH + 391, retention time 1.84 min., Basic Method 5 min.

(4–{4–[(Isopropilsulfonil)metil]–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il}fenil)carbamato de terc–butilo (4– {4 - [(Isopropylsulfonyl) methyl] –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl} phenyl) tert-butyl carbamate

O OR

Se disolvió (3S)–4–{2–cloro–6–[(isopropilsulfonil)metil]pirimidin–4–il}–3–metilmorfolina (2,0 g, 5,99 mmoles) en una disolución de 18% de DMF en una mezcla de dimetoxietano:agua:etanol 7:3:2 (16 ml). Después se añadieron ácido {4–[(terc–butoxicarbonil)amino]fenil}borónico (2,13 g, 8,99 mmoles), disolución 2M de carbonato de sodio (8 ml) y catalizador de diclorobis(trifenilfosfina)paladio (211 mg, 0,30 mmoles), y la reacción se puso a reflujo a 90ºC durante 2 horas en una atmósfera de nitrógeno. La reacción se dejó enfriar hasta la temperatura ambiente, y después se repartió entre acetato de etilo (20 ml) y agua (20 ml). Los productos orgánicos se secaron sobre sulfato de magnesio, se filtraron y se concentraron a vacío. El sólido color crema obtenido se cromatografió en sílice, eluyendo con 0–50% de acetato de etilo en DCM, para dar el material deseado como un sólido marrón (3,2 g). (3S) –4– {2-chloro-6 - [(isopropylsulfonyl) methyl] pyrimidin-4-yl} -3-methylmorpholine (2.0 g, 5.99 mmol) was dissolved in a solution of 18% DMF in a mixture of dimethoxyethane: water: ethanol 7: 3: 2 (16 ml). Then {4 - [(tert-butoxycarbonyl) amino] phenyl} boronic acid (2.13 g, 8.99 mmol), 2M solution of sodium carbonate (8 ml) and dichlorobis (triphenylphosphine) palladium catalyst (211 were added mg, 0.30 mmol), and the reaction was refluxed at 90 ° C for 2 hours under a nitrogen atmosphere. The reaction was allowed to cool to room temperature, and then partitioned between ethyl acetate (20 ml) and water (20 ml). The organic products were dried over magnesium sulfate, filtered and concentrated in vacuo. The cream solid obtained was chromatographed on silica, eluting with 0–50% ethyl acetate in DCM, to give the desired material as a brown solid (3.2 g).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,36 (m, 6H), 1,50 (s, 9H), 3,24 (m, 4H), 3,51 (m, 2H), 3,65 (m, 1H), 3,78 (d, 1H), 3,99 (m, 1H), 4,18 (d, 1H), 4,47 (s, 2H), 6,79 (s, 1H), 7,57 (d, 2H), 8,21 (d, 2H), 9,55 (s, 1H) NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.36 (m, 6H), 1.50 (s, 9H), 3.24 (m, 4H), 3.51 (m, 2H ), 3.65 (m, 1H), 3.78 (d, 1H), 3.99 (m, 1H), 4.18 (d, 1H), 4.47 (s, 2H), 6.79 (s, 1H), 7.57 (d, 2H), 8.21 (d, 2H), 9.55 (s, 1H)

Espectro LCMS: MH+ 491, tiempo de retención 2,67 min., Método Básico 5 min. LCMS spectrum: MH + 491, retention time 2.67 min., Basic Method 5 min.

(3S)–4–{2–Cloro–6–[(isopropilsulfonil)metilpirimidin–4–il}–3–metilmorfolina (3S) –4– {2 – Chloro – 6 - [(isopropylsulfonyl) methylpyrimidin-4-yl} -3-methylmorpholine

O OR

N N

NN

OO OO

S S

N Cl N Cl

Se disolvió 2,4–dicloro–6–[(isopropilsulfonil)metil]pirimidina (2,65 g, 9,85 mmoles) en DCM (50 ml) y se agitó (en nitrógeno) a –5°C. Se añadió trietilamina (1,5 ml, 10,84 mmoles) para dar una disolución marrón clara. Se disolvió 3S–3–metilmorfolina (997 mg, 9,85 mmoles) en DCM, y se añadió gota a gota manteniendo la reacción por debajo de –5ºC. Después el baño de enfriamiento se retiró, y la mezcla de reacción se agitó a temperatura ambiente durante 1 hora. La mezcla de reacción se lavó después con agua (50 ml), se secó sobre sulfato de magnesio, se filtró y se concentró a vacío. El material bruto se cromatografió en sílice, eluyendo con 0–50% de acetato de etilo en DCM para dar el material deseado como un sólido blanco (2 g). 2,4-Dichloro-6 - [(isopropylsulfonyl) methyl] pyrimidine (2.65 g, 9.85 mmol) was dissolved in DCM (50 ml) and stirred (under nitrogen) at -5 ° C. Triethylamine (1.5 ml, 10.84 mmol) was added to give a light brown solution. 3S-3-methylmorpholine (997 mg, 9.85 mmol) was dissolved in DCM, and added dropwise keeping the reaction below -5 ° C. Then the cooling bath was removed, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then washed with water (50 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was chromatographed on silica, eluting with 0–50% ethyl acetate in DCM to give the desired material as a white solid (2 g).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,22 (d, 3H), 1,31 (d, 6H), 3,22 (m, 1H), 3,43 (m, 2H), 3,60 (m, 1H), 3,74 (d, 1H), 3,98 (m, 1H), 4,30 (s, 1H), 4,43 (s, 2H), 6,91 (s, 1H) NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.22 (d, 3H), 1.31 (d, 6H), 3.22 (m, 1H), 3.43 (m, 2H ), 3.60 (m, 1H), 3.74 (d, 1H), 3.98 (m, 1H), 4.30 (s, 1H), 4.43 (s, 2H), 6.91 (s, 1H)

Espectro LCMS: MH+ 332, tiempo de retención 1,70 min., Método Básico 5 min. LCMS spectrum: MH + 332, retention time 1.70 min., Basic Method 5 min.

Ejemplo 21: Example 21:

3 – Methyl – 1– [4– [4– (2-methylsulfonylpropan-2-yl) –6-morpholin-4-yl-pyrimidin-2-yl] phenyl] urea

O OR

N N

N S OO N S OO

N N

O OR

N HH N HH

N N

Se disolvió (4–{4–[1–metil–1–(metilsulfonil)etil]–6–morfolin–4–ilpirimidin–2–il}fenil)carbamato de fenilo (116 mg, 0,22 mmoles) en DMF (3 ml). Se añadió trietilamina (0,098 ml, 0,7 mmoles) seguido por metilamina (2M en THF, 0,6 ml, 1,17 mmoles). La mezcla se agitó a 50ºC durante 1 hora. La reacción se concentró y se purificó mediante HPLC (4– {4– [1-methyl-1– (methylsulfonyl) ethyl] –6-morpholin-4-ylpyrimidin-2-yl} phenyl) phenyl carbamate (116 mg, 0.22 mmol) was dissolved in DMF ( 3 ml) Triethylamine (0.098 ml, 0.7 mmol) was added followed by methylamine (2M in THF, 0.6 ml, 1.17 mmol). The mixture was stirred at 50 ° C for 1 hour. The reaction was concentrated and purified by HPLC.

5 preparativa para dar el material deseado como un sólido blanco (54 mg). 5 preparative to give the desired material as a white solid (54 mg).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,77 (s, 6H), 2,66 (d, 3H), 3,04 (s, 3H), 3,73 (s, 8H), 6,06 (m, 1H), 6,79 (s, 1H), 7,51 (d, 2H), 8,24 (d, 2H), 8,74 (s, 1H) NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.77 (s, 6H), 2.66 (d, 3H), 3.04 (s, 3H), 3.73 (s, 8H ), 6.06 (m, 1H), 6.79 (s, 1H), 7.51 (d, 2H), 8.24 (d, 2H), 8.74 (s, 1H)

Espectro LCMS: MH+ 434, tiempo de retención 1,64 min., Método Básico 5 min. LCMS spectrum: MH + 434, retention time 1.64 min., Basic Method 5 min.

Los siguientes compuestos se prepararon de una manera análoga a partir de (4–{4–[1–metil–1–(metilsulfonil)etil]–6– The following compounds were prepared in an analogous manner from (4– {4– [1-methyl-1– (methylsulfonyl) ethyl] –6–

10 morfolin–4–ilpirimidin–2–il}fenil)carbamato de fenilo o (4–{4–[1–metil–1–(metilsulfonil)etil]–6–[(3S)–3–metilmorfolin– 4–il]pirimidin–2–il}fenil)carbamato de fenilo y la amina apropiada. 10 morpholin-4-ylpyrimidin-2-yl} phenyl) phenyl carbamate or (4– {4– [1-methyl-1– (methylsulfonyl) ethyl] –6 - [(3S) -3-methylmorpholin-4-yl ] Pyrimidin-2-yl} phenyl) phenyl carbamate and the appropriate amine.

21a 21st: S O O N N N O N H N H O 1–etil–3–[4–[4–(2– metilsulfonilpropan–2–il)–6– morfolin–4–il–pirimidin–2– il]fenil]urea 448 1,78 S O O N N N O N H N H O 1 – ethyl – 3– [4– [4– (2– methylsulfonylpropan – 2-yl) –6– morpholin-4-yl-pyrimidin – 2– yl] phenyl] urea 448 1.78

21b 21b: S O O N N N O N H N H O 3–ciclopropil–1–[4–[4–(2– metilsulfonilpropan–2–il)–6– morfolin–4–il–pirimidin–2– il]fenil]urea 460 1,91 S O O N N N O N H N H O 3 – cyclopropyl – 1– [4– [4– (2– methylsulfonylpropan – 2-yl) –6– morpholin-4-yl-pyrimidin – 2– il] phenyl] urea 460 1.91

21c 21c: S O O N N N O N H N H O N 3–(2–dimetilaminoetil)–1–[4–[4–(2– metilsulfonilpropan–2–il)–6– morfolin–4–il–pirimidin–2– il]fenil]urea 491 1,71 S O O N N N O N H N H O N 3– (2-dimethylaminoethyl) –1– [4– [4– (2– methylsulfonylpropan – 2-yl) –6– morpholin-4-yl-pyrimidin-2-yl] phenyl] urea 491 1.71

21d 21d: S O O N N N O N H N H O N 3–(1–metil–4–piperidil)–1–[4–[4– (2–metilsulfonilpropan–2–il)–6– morfolin–4–il–pirimidin–2– il]fenil]urea 517 1,75 S O O N N N O N H N H O N 3– (1 – methyl – 4 – piperidyl) –1– [4– [4– (2-methylsulfonylpropan – 2-yl) –6– morpholin-4-yl-pyrimidin – 2– yl] phenyl] urea 517 1.75

21e 21e: N N N O S O O N H N H O O 3–(2–metoxietil)–1–[4–[4–(2– metilsulfonilpropan–2–il)–6– morfolin–4–il–pirimidin–2– il]fenil]urea 478 1,72 N N N O S O O N H N H O O 3– (2 – methoxyethyl) –1– [4– [4– (2– methylsulfonylpropan – 2-yl) –6– morpholin-4-yl-pyrimidin-2-yl] phenyl] urea 478 1.72

21f 21f: O 3–metil–1–[4–[4–[(3S)–3– 448 1,76 OR 3 – methyl – 1– [4– [4 - [(3S) –3– 448 1.76

: metilmorfolin–4–il]–6–(2– methylmorpholin – 4 – il] –6– (2–

N N: metilsulfonilpropan–2–il)pirimidin– Methylsulfonylpropan – 2-yl) pyrimidin–

N N S O O N H N H O N N S O O N H N H O: 2–il]fenil]urea 2-yl] phenyl] urea

21g 21g: O 1–etil–3–[4–[4–[(3S)–3– 462 1,92 OR 1 – ethyl – 3– [4– [4 - [(3S) –3– 462 1.92

21h 9pm: O 3–ciclopropil–1–[4–[4–[(3S)–3– 474 1,93 OR 3 – cyclopropyl – 1– [4– [4 - [(3S) –3– 474 1.93

21i 21i: O 3–(2–dimetilaminoetil)–1–[4–[4– 505 1,83 OR 3– (2 – dimethylaminoethyl) –1– [4– [4– 505 1.83

: [(3S)–3–metilmorfolin–4–il]–6–(2– [(3S) –3 – methylmorpholin-4-yl] –6– (2–

21j 21j: N N N O S O O N H N H O N 1–[4–[4–[(3S)–3–metilmorfolin–4– il]–6–(2–metilsulfonilpropan–2– il)pirimidin–2–il]fenil]–3–(1–metil–4– piperidil)urea 531 1,86 N N N O S O O N H N H O N 1– [4– [4 - [(3S) –3 – methylmorpholin-4– yl] –6– (2-methylsulfonylpropan – 2– yl) pyrimidin – 2-yl] phenyl] –3– (1 – methyl – 4 - piperidyl) urea 531 1.86

21k 21k: O 3–(2–metoxietil)–1–[4–[4–[(3S)–3– 492 1,84 OR 3– (2 – methoxyethyl) –1– [4– [4 - [(3S) –3– 492 1.84

N N: metilsulfonilpropan–2–l)pirimidin– methylsulfonylpropan – 2 – l) pyrimidin–

N N S O O N H N H O O N N S O O N H N H O O: 2–il]fenil]urea 2-yl] phenyl] urea

Ejemplo 21a: RMN 1H (400,13 MHz, DMSO–d6) δ 1,07 (t, 3H), 1,77 (s, 6H), 3,04 (s, 3H), 3,13 (m, 2H), 3,73 (s, 8H), 6,15 (t, 1H), 6,79 (s, 1H), 7,50 (d, 2H), 8,24 (d, 2H), 8,66 (s, 1H) Example 21a: 1H NMR (400.13 MHz, DMSO-d6) δ 1.07 (t, 3H), 1.77 (s, 6H), 3.04 (s, 3H), 3.13 (m, 2H ), 3.73 (s, 8H), 6.15 (t, 1H), 6.79 (s, 1H), 7.50 (d, 2H), 8.24 (d, 2H), 8.66 (s, 1H)

Ejemplo 21b: RMN 1H (400,13 MHz, DMSO–d6) δ 0,42 (m, 2H), 0,65 (m, 2H), 1,77 (s, 6H), 2,57 (m, 1H), 3,04 (s, 3H), 3,73 (s, 8H), 6,43 (d, 1H), 6,79 (s, 1H), 7,51 (d, 2H), 8,24 (d, 2H), 8,54 (s, 1H) Example 21b: 1H NMR (400.13 MHz, DMSO-d6) δ 0.42 (m, 2H), 0.65 (m, 2H), 1.77 (s, 6H), 2.57 (m, 1H ), 3.04 (s, 3H), 3.73 (s, 8H), 6.43 (d, 1H), 6.79 (s, 1H), 7.51 (d, 2H), 8.24 (d, 2H), 8.54 (s, 1H)

Ejemplo 21c: RMN 1H (400,13 MHz, DMSO–d6) δ 1,77 (s, 6H), 2,18 (s, 6H), 2,34 (t, 2H), 3,04 (s, 3H), 3,19 (m, 2H), 3,73 (s, 8H), 6,15 (t, 1H), 6,79 (s, 1H), 7,49 (d, 2H), 8,24 (d, 2H), 8,90 (s, 1H) Example 21c: 1H NMR (400.13 MHz, DMSO-d6) δ 1.77 (s, 6H), 2.18 (s, 6H), 2.34 (t, 2H), 3.04 (s, 3H ), 3.19 (m, 2H), 3.73 (s, 8H), 6.15 (t, 1H), 6.79 (s, 1H), 7.49 (d, 2H), 8.24 (d, 2H), 8.90 (s, 1H)

Ejemplo 21d: RMN 1H (400,13 MHz, DMSO–d6) δ 1,40 (m, 2H), 1,77 (s, 6H), 2,03 (m, 2H), 2,17 (s, 3H), 2,45 (m, 2H), 2,67 (m, 2H), 3,04 (s, 3H), 3,47 (m, 1H), 3,73 (s, 8H), 6,18 (d, 1H), 6,79 (s, 1H), 7,48 (d, 2H), 8,24 (d, 2H), 8,57 (s, 1H) Example 21d: 1H NMR (400.13 MHz, DMSO-d6) δ 1.40 (m, 2H), 1.77 (s, 6H), 2.03 (m, 2H), 2.17 (s, 3H ), 2.45 (m, 2H), 2.67 (m, 2H), 3.04 (s, 3H), 3.47 (m, 1H), 3.73 (s, 8H), 6.18 (d, 1H), 6.79 (s, 1H), 7.48 (d, 2H), 8.24 (d, 2H), 8.57 (s, 1H)

Ejemplo 21e: RMN 1H (400,13 MHz, DMSO–d6) δ 1,77 (s, 6H), 3,04 (s, 3H), 3,27 (m, 2H), 3,29 (s, 3H), 3,40 (t, 2H), 3,73 (s, 8H), 6,26 (t, 1H), 6,79 (s, 1H), 7,49 (d, 2H), 8,24 (d, 2H), 8,79 (s, 1H) Example 21e: 1H NMR (400.13 MHz, DMSO-d6) δ 1.77 (s, 6H), 3.04 (s, 3H), 3.27 (m, 2H), 3.29 (s, 3H ), 3.40 (t, 2H), 3.73 (s, 8H), 6.26 (t, 1H), 6.79 (s, 1H), 7.49 (d, 2H), 8.24 (d, 2H), 8.79 (s, 1H)

Ejemplo 21f: RMN 1H (400,13 MHz, DMSO–d6) δ 1,16 (d, 3H), 1,70 (s, 6H), 2,59 (d, 3H), 2,96 (s, 3H), 3,16 (m, 1H), 3,43 (m, 1H), 3,58 (m, 1H), 3,70 (d, 1H), 3,91 (m, 1H), 4,16 (d, 1H), 4,53 (s, 1H), 5,99 (m, 1H), 6,66 (s, 1H), 7,44 (d, 2H), 8,16 (d, 2H), 8,67 (s, 1H) Example 21f: 1H NMR (400.13 MHz, DMSO-d6) δ 1.16 (d, 3H), 1.70 (s, 6H), 2.59 (d, 3H), 2.96 (s, 3H ), 3.16 (m, 1H), 3.43 (m, 1H), 3.58 (m, 1H), 3.70 (d, 1H), 3.91 (m, 1H), 4.16 (d, 1H), 4.53 (s, 1H), 5.99 (m, 1H), 6.66 (s, 1H), 7.44 (d, 2H), 8.16 (d, 2H) , 8.67 (s, 1 H)

Ejemplo 21g: RMN 1H (400,13 MHz, DMSO–d6) δ 1,00 (t, 3H), 1,16 (d, 3H), 1,70 (d, 6H), 2,96 (s, 3H), 3,06 (m, 2H), 3,16 (m, 1H), 3,43 (m, 1H), 3,58 (m, 1H), 3,70 (d, 1H), 3,91 (m, 1H), 4,16 (d, 1H), 4,52 (s, 1H), 6,09 (t, 1H), 6,67 (s, 1H), 7,43 (d, 2H), 8,16 (d, 2H), 8,59 (s, 1H) Example 21g: 1H NMR (400.13 MHz, DMSO-d6) δ 1.00 (t, 3H), 1.16 (d, 3H), 1.70 (d, 6H), 2.96 (s, 3H ), 3.06 (m, 2H), 3.16 (m, 1H), 3.43 (m, 1H), 3.58 (m, 1H), 3.70 (d, 1H), 3.91 (m, 1H), 4.16 (d, 1H), 4.52 (s, 1H), 6.09 (t, 1H), 6.67 (s, 1H), 7.43 (d, 2H) , 8.16 (d, 2H), 8.59 (s, 1H)

Ejemplo 21h: RMN 1H (400,13 MHz, DMSO–d6) δ 0,42 (m, 2H), 0,65 (m, 2H), 1,23 (d, 3H), 1,78 (d, 6H), 2,56 (m, 1H), 3,03 (s, 3H), 3,23 (m, 1H), 3,50 (m, 1H), 3,65 (m, 1H), 3,78 (d, 1H), 3,98 (m, 1H), 4,23 (d, 1H), 4,60 (s, 1H), 6,43 (d, 1H), 6,74 (s, 1H), 7,51 (d, 2H), 8,24 (d, 2H), 8,54 (s, 1H) Example 21h: 1H NMR (400.13 MHz, DMSO-d6) δ 0.42 (m, 2H), 0.65 (m, 2H), 1.23 (d, 3H), 1.78 (d, 6H ), 2.56 (m, 1H), 3.03 (s, 3H), 3.23 (m, 1H), 3.50 (m, 1H), 3.65 (m, 1H), 3.78 (d, 1H), 3.98 (m, 1H), 4.23 (d, 1H), 4.60 (s, 1H), 6.43 (d, 1H), 6.74 (s, 1H) , 7.51 (d, 2H), 8.24 (d, 2H), 8.54 (s, 1H)

Ejemplo 21i: RMN 1H (400,13 MHz, DMSO–d6) δ 1,23 (d, 3H), 1,77 (d, 6H), 2,18 (s, 6H), 2,34 (t, 2H), 3,03 (s, 3H), 3,19 (m, 3H), 3,49 (m, 1H), 3,65 (m, 1H), 3,77 (d, 1H), 3,98 (m, 1H), 4,23 (d, 1H), 4,59 (s, 1H), 6,16 (t, 1H), 6,73 (s, 1H), 7,49 (d, 2H), 8,23 (d, 2H), 8,90 (s, 1H) Example 21i: 1H NMR (400.13 MHz, DMSO-d6) δ 1.23 (d, 3H), 1.77 (d, 6H), 2.18 (s, 6H), 2.34 (t, 2H ), 3.03 (s, 3H), 3.19 (m, 3H), 3.49 (m, 1H), 3.65 (m, 1H), 3.77 (d, 1H), 3.98 (m, 1H), 4.23 (d, 1H), 4.59 (s, 1H), 6.16 (t, 1H), 6.73 (s, 1H), 7.49 (d, 2H) , 8.23 (d, 2H), 8.90 (s, 1H)

Ejemplo 21j: RMN 1H (400,13 MHz, DMSO–d6) δ 1,24 (s, 3H), 1,41 (m, 2H), 1,78 (d, 6H), 1,81 (m, 2H), 2,02 (t, 2H), 2,16 (s, 3H), 2,64 (m, 2H), 3,03 (s, 3H), 3,22 (m, 1H), 3,50 (m, 2H), 3,65 (m, 1H), 3,78 (d, 1H), 3,98 (m, 1H), 4,23 (d, 1H), 4,61 (s, 1H), 6,18 (d, 1H), 6,74 (s, 1H), 7,48 (d, 2H), 8,23 (d, 2H), 8,57 (s, 1H) Example 21j: 1H NMR (400.13 MHz, DMSO-d6) δ 1.24 (s, 3H), 1.41 (m, 2H), 1.78 (d, 6H), 1.81 (m, 2H ), 2.02 (t, 2H), 2.16 (s, 3H), 2.64 (m, 2H), 3.03 (s, 3H), 3.22 (m, 1H), 3.50 (m, 2H), 3.65 (m, 1H), 3.78 (d, 1H), 3.98 (m, 1H), 4.23 (d, 1H), 4.61 (s, 1H) , 6.18 (d, 1H), 6.74 (s, 1H), 7.48 (d, 2H), 8.23 (d, 2H), 8.57 (s, 1H)

Ejemplo 21k: RMN 1H (400,13 MHz, DMSO–d6) δ 1,23 (d, 3H), 1,77 (d, 6H), 3,03 (s, 3H), 3,21 (m, 2H), 3,27 (m, 1H), 3,40 (t, 2H), 3,48 (m, 2H), 3,65 (m, 1H), 3,72 (d, 1H), 3,97 (m, 1H), 4,23 (d, 1H), 4,60 (s, 1H), 6,26 (t, 1H), 6,74 (s, 1H), 6,86 (s, 1H), 7,49 (d, 2H), 8,24 (d, 2H), 8,78 (s, 1H) Example 21k: 1H NMR (400.13 MHz, DMSO-d6) δ 1.23 (d, 3H), 1.77 (d, 6H), 3.03 (s, 3H), 3.21 (m, 2H ), 3.27 (m, 1H), 3.40 (t, 2H), 3.48 (m, 2H), 3.65 (m, 1H), 3.72 (d, 1H), 3.97 (m, 1H), 4.23 (d, 1H), 4.60 (s, 1H), 6.26 (t, 1H), 6.74 (s, 1H), 6.86 (s, 1H) , 7.49 (d, 2H), 8.24 (d, 2H), 8.78 (s, 1H)

Prueba (a): Ejemplo (21) 0,05 μM; Ejemplo (21a) 0,73 μM; Ejemplo (21b) 0,36 μM; Ejemplo (21c) 0,48 μM; Ejemplo (21d) 0,27 μM; Ejemplo (21e) 1 μM; Ejemplo (21f) 0,017 μM; Ejemplo (21g) 0,02 μM; Ejemplo (21h) 0,028 μM; Ejemplo (21i) 0,076 μM; Ejemplo (21j) 0,51 μM; Ejemplo (21k) 0,31 μM. Test (a): Example (21) 0.05 μM; Example (21a) 0.73 μM; Example (21b) 0.36 μM; Example (21c) 0.48 μM; Example (21d) 0.27 μM; Example (21e) 1 μM; Example (21f) 0.017 μM; Example (21g) 0.02 μM; Example (21h) 0.028 μM; Example (21i) 0.076 μM; Example (21j) 0.51 μM; Example (21k) 0.31 μM.

A continuación se describen las preparaciones de (4–{4–[1–metil–1–(metilsulfonil)etil]–6–morfolin–4–ilpirimidin–2– il}fenil)carbamato de fenilo y (4–{4–[1–metil–1–(metilsulfonil)etil]–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2– il}fenil)carbamato de fenilo. The following describes the preparations of (4– {4– [1-methyl-1– (methylsulfonyl) ethyl] –6-morpholin-4-ylpyrimidin-2-yl} phenyl) phenyl carbamate and (4– {4– [1-methyl-1– (methylsulfonyl) ethyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-2-yl} phenyl) phenyl carbamate.

(4–{4–[1–metil–1–(metilsulfonil)etil]–6–morfolin–4–ilpirimidin–2–il}fenil)carbamato de fenilo (4– {4– [1-methyl-1– (methylsulfonyl) ethyl] –6-morpholin-4-ylpyrimidin-2-yl} phenyl) phenyl carbamate

Se disolvió (4–{4–[1–metil–1–(metilsulfonil)etil]–6–morfolin–4–ilpirimidin–2–il}fenil)amina (1,5 g, 3,98 mmoles) en dioxano (15 ml). Se añadió bicarbonato de sodio (503 mg, 5,98 mmoles), seguido por cloroformiato de fenilo (0,502 ml, 3,98 mmoles), y la reacción se agitó a temperatura ambiente durante 2 horas. El disolvente se eliminó a vacío, y el aceite resultante se repartió entre 20 ml de DCM y 20 ml de agua. La fase orgánica se secó sobre sulfato de magnesio, se filtró y se concentró a vacío. El sólido color crema obtenido se cromatografió en sílice, eluyendo con 0– 50% de acetato de etilo en DCM, para dar el material deseado como un sólido blanco (700 mg). (4– {4– [1-methyl-1– (methylsulfonyl) ethyl] –6-morpholin-4-ylpyrimidin-2-yl} phenyl) amine (1.5 g, 3.98 mmol) was dissolved in dioxane ( 15 ml) Sodium bicarbonate (503 mg, 5.98 mmol) was added, followed by phenyl chloroformate (0.502 ml, 3.98 mmol), and the reaction was stirred at room temperature for 2 hours. The solvent was removed in vacuo, and the resulting oil was partitioned between 20 ml of DCM and 20 ml of water. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The cream-colored solid obtained was chromatographed on silica, eluting with 0-50% ethyl acetate in DCM, to give the desired material as a white solid (700 mg).

Espectro LCMS: MH+ 545, tiempo de retención 2,7 min., Método Básico 5 min. LCMS spectrum: MH + 545, retention time 2.7 min., Basic Method 5 min.

(4–{4–[1–Metil–1–(metilsulfonil)etil]–6–morfolin–4–ilpirimidin–2–il}fenil)amina (4– {4– [1 – Methyl – 1– (methylsulfonyl) ethyl] –6 – morpholin-4-ylpyrimidin – 2-yl} phenyl) amine

Se disolvió (4–{4–[1–metil–1–(metilsulfonil)etil]–6–morfolin–4–ilpirimidin–2–il}fenil)carbamato de terc–butilo (2,6 g, 5,46 mmoles) en DCM (20 ml). y se añadió ácido trifluoroacético (10 ml). La mezcla de reacción se agitó a temperatura ambiente durante 2 horas, después se diluyó con DCM (20 ml) y se lavó con bicarbonato de sodio saturado acuoso (20 ml). La fase orgánica se recogió, se secó sobre sulfato de magnesio, se filtró y se concentró a vacío para dar el material deseado como un sólido color crema (2,1 g). (4– {4– [1-methyl-1– (methylsulfonyl) ethyl] –6-morpholin-4-ylpyrimidin-2-yl} phenyl) tert-butyl carbamate (2.6 g, 5.46 mmol) ) in DCM (20 ml). and trifluoroacetic acid (10 ml) was added. The reaction mixture was stirred at room temperature for 2 hours, then diluted with DCM (20 ml) and washed with saturated aqueous sodium bicarbonate (20 ml). The organic phase was collected, dried over magnesium sulfate, filtered and concentrated in vacuo to give the desired material as a cream solid (2.1 g).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,75 (s, 6H), 3,03 (s, 3H), 3,71 (s, 8H), 5,56 (s, 2H), 6,61 (d, 2H), 6,69 (s, 1H), 8,07 (d, 2H) NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.75 (s, 6H), 3.03 (s, 3H), 3.71 (s, 8H), 5.56 (s, 2H ), 6.61 (d, 2H), 6.69 (s, 1H), 8.07 (d, 2H)

Espectro LCMS: MH+ 377, tiempo de retención 1,84 min., Método Básico 5 min. LCMS spectrum: MH + 377, retention time 1.84 min., Basic Method 5 min.

(4–{4–[1–Metil–1–(metilsulfonil)etil]–6–morfolin–4–ilpirimidin–2–il}fenil)carbamato de terc–butilo (4– {4– [1-Methyl-1– (methylsulfonyl) ethyl] –6-morpholin-4-ylpyrimidin-2-yl} phenyl) tert-butyl carbamate

O OR

Se disolvió (3S)–4–{2–cloro–6–[1–metil–1–(metilsulfonil)etil]pirimidin–4–il}–3–metilmorfolina (1,75 g, 5,47 mmoles) en una disolución de 18% de DMF en una mezcla de dimetoxietano:agua:etanol 7:3:2 (18 ml). Después se añadieron [4–(4,4,5,5–tetrametil–1,3,2–dioxaborolan–2–il)fenil]carbamato de terc–butilo (2,62 g, 8,2 mmoles), disolución 2M de carbonato de sodio (8 ml) y catalizador de diclorobis(trifenilfosfina)paladio (192 mg, 0,27 mmoles), y la reacción se puso a reflujo a 90ºC durante 2 horas en una atmósfera de nitrógeno. La reacción se dejó enfriar hasta la temperatura ambiente, y después se repartió entre acetato de etilo (20 ml) y agua (20 ml). Los productos orgánicos se secaron sobre sulfato de magnesio, se filtraron y se concentraron a vacío. El sólido bruto se cromatografió en sílice, eluyendo con 0–30% de acetato de etilo en DCM para dar el material deseado como un sólido blanco (2,6 g). (3S) –4– {2-chloro-6– [1-methyl-1– (methylsulfonyl) ethyl] pyrimidin-4-yl} -3-methylmorpholine (1.75 g, 5.47 mmol) was dissolved in one 18% solution of DMF in a mixture of dimethoxyethane: water: ethanol 7: 3: 2 (18 ml). Then [4– (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] tert-butyl carbamate (2.62 g, 8.2 mmol), 2M solution were added of sodium carbonate (8 ml) and dichlorobis (triphenylphosphine) palladium (192 mg, 0.27 mmol) catalyst, and the reaction was refluxed at 90 ° C for 2 hours in a nitrogen atmosphere. The reaction was allowed to cool to room temperature, and then partitioned between ethyl acetate (20 ml) and water (20 ml). The organic products were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude solid was chromatographed on silica, eluting with 0-30% ethyl acetate in DCM to give the desired material as a white solid (2.6 g).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,50 (s, 9H), 1,77 (s, 6H), 3,04 (s, 3H), 3,73 (s, 8H), 6,80 (s, 1H), 7,57 (d, 2H), 8,26 (d, 2H), 9,54 (s, 1H) NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.50 (s, 9H), 1.77 (s, 6H), 3.04 (s, 3H), 3.73 (s, 8H ), 6.80 (s, 1H), 7.57 (d, 2H), 8.26 (d, 2H), 9.54 (s, 1H)

Espectro LCMS: MH+ 477, tiempo de retención 2,66 min., Método Básico 5 min. LCMS spectrum: MH + 477, retention time 2.66 min., Basic Method 5 min.

4–{2–Cloro–6–[1–metil–1–(metilsulfonil)etil]pirimidin–4–il}morfolina 4– {2 – Chloro – 6– [1-methyl-1– (methylsulfonyl) ethyl] pyrimidin-4-yl} morpholine

Se disolvió 4–{2–cloro–6–[(metilsulfonil)metil]pirimidin–4–il}morfolina (2,9 g, 9,94 mmoles) en DMF (20 ml), y la reacción se enfrió hasta –5ºC. Se añadió t–butóxido de sodio (956 mg, 9,94 mmoles) a la reacción, seguido por yodometano (0,6 ml, 9,94 mmoles), manteniendo la temperatura a –5ºC. Después se añadieron un segundo equivalente de t–butóxido de sodio (956 mg, 9,94 mmoles) y yodometano (0,6 ml, 9,94 mmoles), y la reacción se agitó a –5ºC durante 1 hora, y después a temperatura ambiente durante 4 horas. Se añadió DCM (20 ml), y la reacción se lavó con HCl acuoso 2M (20 ml). La fase orgánica se secó sobre sulfato de magnesio, se filtró y se concentró a vacío. El sólido bruto se cromatografió en sílice, eluyendo con 0–50% de acetato de etilo en DCM para dar el material deseado como un sólido blanco (1,7 g). 4– {2-Chloro-6 - [(methylsulfonyl) methyl] pyrimidin-4-yl} morpholine (2.9 g, 9.94 mmol) was dissolved in DMF (20 ml), and the reaction was cooled to –5 ° C . Sodium t-butoxide (956 mg, 9.94 mmol) was added to the reaction, followed by iodomethane (0.6 ml, 9.94 mmol), keeping the temperature at -5 ° C. Then a second equivalent of sodium t-butoxide (956 mg, 9.94 mmol) and iodomethane (0.6 ml, 9.94 mmol) was added, and the reaction was stirred at -5 ° C for 1 hour, and then at room temperature for 4 hours. DCM (20 ml) was added, and the reaction was washed with 2M aqueous HCl (20 ml). The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude solid was chromatographed on silica, eluting with 0–50% ethyl acetate in DCM to give the desired material as a white solid (1.7 g).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,68 (s, 6H), 2,99 (s, 3H), 3,67 (s, 8H), 6,91 (s, 1H) NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.68 (s, 6H), 2.99 (s, 3H), 3.67 (s, 8H), 6.91 (s, 1H )

Espectro LCMS: MH+ 320, tiempo de retención 1,67 min., Método Básico 5 min. (4–{4–[1–Metil–1–(metilsulfonil)etil]–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il}fenil)carbamato de fenilo LCMS spectrum: MH + 320, retention time 1.67 min., Basic Method 5 min. (4– {4– [1-Methyl-1– (methylsulfonyl) ethyl] –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl} phenyl) phenyl carbamate

Se disolvió (4–{4–[1–metil–1–(metilsulfonil)etil]–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il}fenil)amina (3,6 g, 8,77 mmoles) en dioxano (20 ml). Se añadió bicarbonato de sodio (1,1 g, 13,15 mmoles), seguido por cloroformiato de fenilo (1,1 ml, 8,77 mmoles), y la reacción se agitó a temperatura ambiente durante 2 horas. El disolvente se eliminó a vacío, y el aceite resultante se repartió entre 20 ml de DCM y 20 ml de agua. La fase orgánica se secó sobre sulfato de magnesio, se filtró y se concentró a vacío. El sólido color crema obtenido se cromatografió en sílice, eluyendo con 0–50% de acetato de etilo en DCM, para dar el material deseado como un sólido blanco (2 g). (4– {4– [1-methyl-1– (methylsulfonyl) ethyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-2-yl} phenyl) amine (3.6 g) , 8.77 mmol) in dioxane (20 ml). Sodium bicarbonate (1.1 g, 13.15 mmol) was added, followed by phenyl chloroformate (1.1 ml, 8.77 mmol), and the reaction was stirred at room temperature for 2 hours. The solvent was removed in vacuo, and the resulting oil was partitioned between 20 ml of DCM and 20 ml of water. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The cream-colored solid obtained was chromatographed on silica, eluting with 0–50% ethyl acetate in DCM, to give the desired material as a white solid (2 g).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,24 (d, 3H), 1,78 (d, 6H), 3,04 (s, 3H), 3,24 (m, 1H), 3,51 (m, 1H), 3,65 (m, 1H), 3,78 (d, 1H), 3,96 (m, 1H), 4,25 (d, 1H), 4,61 (s, 1H), 6,77 (s, 1H), 7,27 (m, 3H), 7,45 (m, 2H), 7,64 (d, 2H), 8,34 (d, 2H), 10,43 (s, 1H) NMR Spectrum: 1H NMR (400.13 MHz, DMSO – d6) δ 1.24 (d, 3H), 1.78 (d, 6H), 3.04 (s, 3H), 3.24 (m, 1H ), 3.51 (m, 1H), 3.65 (m, 1H), 3.78 (d, 1H), 3.96 (m, 1H), 4.25 (d, 1H), 4.61 (s, 1H), 6.77 (s, 1H), 7.27 (m, 3H), 7.45 (m, 2H), 7.64 (d, 2H), 8.34 (d, 2H) , 10.43 (s, 1 H)

Espectro LCMS: MH+ 511, tiempo de retención 2,7 min., Método Básico 5 min. LCMS spectrum: MH + 511, retention time 2.7 min., Basic Method 5 min.

(4–{4–[1–Metil–1–(metilsulfonil)etil]–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il}fenil)amina (4– {4– [1 – Methyl – 1– (methylsulfonyl) ethyl] –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin – 2-yl} phenyl) amine

Se disolvió (3S)–4–{2–cloro–6–[1–metil–1–(metilsulfonil)etil]pirimidin–4–il}–3–metilmorfolina (2,2 g, 6,59 mmoles) en una disolución de 18% de DMF en una mezcla de dimetoxietano:agua:etanol 7:3:2 (18 ml). Después se añadieron [4–(4,4,5,5–tetrametil–1,3,2–dioxaborolan–2–il)fenil]amina (2,17 g, 9,89 mmoles), disolución 2M de carbonato de sodio (8 ml) y catalizador de diclorobis(trifenilfosfina)paladio (232 mg, 0,33 mmoles), y la reacción se puso a reflujo a 90ºC durante 2 horas en una atmósfera de nitrógeno. La reacción se dejó enfriar hasta la temperatura ambiente, y después se repartió entre acetato de etilo (20 ml) y agua (20 ml). Los productos orgánicos se secaron sobre sulfato de magnesio, se filtraron y se concentraron a vacío. El sólido bruto se cromatografió en sílice, eluyendo con 0–10% de metanol en DCM para dar el material deseado como un aceite marrón (3,6 g). (3S) –4– {2-chloro-6– [1-methyl-1– (methylsulfonyl) ethyl] pyrimidin-4-yl} -3-methylmorpholine (2.2 g, 6.59 mmol) was dissolved in one 18% solution of DMF in a mixture of dimethoxyethane: water: ethanol 7: 3: 2 (18 ml). Then [4– (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] amine (2.17 g, 9.89 mmol), 2M solution of sodium carbonate were added (8 ml) and dichlorobis (triphenylphosphine) palladium catalyst (232 mg, 0.33 mmol), and the reaction was refluxed at 90 ° C for 2 hours under a nitrogen atmosphere. The reaction was allowed to cool to room temperature, and then partitioned between ethyl acetate (20 ml) and water (20 ml). The organic products were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude solid was chromatographed on silica, eluting with 0-10% methanol in DCM to give the desired material as a brown oil (3.6 g).

Espectro LCMS: MH+ 389, tiempo de retención 1,00 min., Método Básico 5 min. LCMS spectrum: MH + 389, retention time 1.00 min., Basic Method 5 min.

(3S)–4–{2–Cloro–6–[1–metil–1–(metilsulfonil)etil]pirimidin–4–il}–3–metilmorfolina (3S) –4– {2 – Chloro – 6– [1-methyl-1– (methylsulfonyl) ethyl] pyrimidin-4-yl} -3-methylmorpholine

Se disolvió (3S)–4–{2–cloro–6–[(metilsulfonil)metil]pirimidin–4–il}–3–metilmorfolina (2,1 g, 6,87 mmoles) en DMF (20 ml), y la reacción se enfrió hasta –5ºC. Se añadió t–butóxido de sodio (650 mg, 6,87 mmoles) a la reacción, seguido por yodometano (0,4 ml, 6,87 mmoles), manteniendo la temperatura a –5ºC. Después se añadieron un segundo equivalente de t–butóxido de sodio (650 mg, 6,87 mmoles) y yodometano (0,4 ml, 6,87 mmoles), y la reacción se agitó a –5ºC durante 1 hora, y después a temperatura ambiente durante 4 horas. Se añadió DCM (20 ml), y la reacción se lavó con ácido clorhídrico acuoso 2M (20 ml). La fase orgánica se secó sobre sulfato de magnesio, se filtró y se concentró a vacío. El sólido bruto se cromatografió en sílice, eluyendo con 0–50% de acetato de etilo en DCM para dar el material deseado (2,2 g). (3S) –4– {2-Chloro-6 - [(methylsulfonyl) methyl] pyrimidin-4-yl} -3-methylmorpholine (2.1 g, 6.87 mmol) was dissolved in DMF (20 ml), and The reaction was cooled to -5 ° C. Sodium t-butoxide (650 mg, 6.87 mmol) was added to the reaction, followed by iodomethane (0.4 ml, 6.87 mmol), keeping the temperature at -5 ° C. Then a second equivalent of sodium t-butoxide (650 mg, 6.87 mmol) and iodomethane (0.4 ml, 6.87 mmol) was added, and the reaction was stirred at -5 ° C for 1 hour, and then at room temperature for 4 hours. DCM (20 ml) was added, and the reaction was washed with 2M aqueous hydrochloric acid (20 ml). The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude solid was chromatographed on silica, eluting with 0–50% ethyl acetate in DCM to give the desired material (2.2 g).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,21 (d, 3H), 1,68 (s, 6H), 2,74 (s, 3H), 3,21 (m, 1H), 3,45 (m, 1H), 3,59 (m, 1H), 3,73 (d, 1H), 3,94 (m, 1H), 4,07 (d, 1H), 4,45 (s, 1H), 6,86 (s, 1H) NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.21 (d, 3H), 1.68 (s, 6H), 2.74 (s, 3H), 3.21 (m, 1H ), 3.45 (m, 1H), 3.59 (m, 1H), 3.73 (d, 1H), 3.94 (m, 1H), 4.07 (d, 1H), 4.45 (s, 1H), 6.86 (s, 1H)

Espectro LCMS: MH+ 334, tiempo de retención 1,85 min., Método Básico 5 min. LCMS spectrum: MH + 334, retention time 1.85 min., Basic Method 5 min.

Ejemplo 22: 1–[4–[4–[(3S)–3–Metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidin–2–il]fenil]–3–(1,2–oxazol–3–il)urea Example 22: 1– [4– [4 - [(3S) –3-Methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin-2-yl] phenyl] –3– (1,2-oxazol-3– il) urea

O OR

N N

N S OO N S OO

O OR

N N

O N O n

N HH N N HH N

Se disolvió N–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidin–2–il]fenil]carbamato de fenilo (170 mg, 0,35 mmoles) en DMF (1,5 ml). Se añadió trietilamina (0,147 ml, 1,06 mmoles). Se añadió 1,2–oxazol–3–amina (198 mg, 2,35 mmoles), y la reacción se agitó a 60ºC durante 2 horas. La reacción se evaporó hasta sequedad y se N- [4– [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidin-2-yl] phenyl] phenyl carbamate (170 mg, 0.35 mmol) was dissolved in DMF (1.5 ml). Triethylamine (0.147 ml, 1.06 mmol) was added. 1,2-oxazol-3-amine (198 mg, 2.35 mmol) was added, and the reaction was stirred at 60 ° C for 2 hours. The reaction was evaporated to dryness and was

10 purificó mediante cromatografía en fase inversa para dar el material deseado como un sólido blanco (81 mg). 10 purified by reverse phase chromatography to give the desired material as a white solid (81 mg).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,24–1,26 (3H, m), 3,21 (3H, s), 3,23–3,26 (1H, m), 3,47–3,54 (1H, m), 3,64–3,68 (1H, m), 3,79 (1H, d), 3,98–4,01 (1H, m), 4,17–4,20 (1H, m), 4,50 (3H, s), 6,81 (1H, s), 6,87 (1H, d), 7,58 (2H, d), 8,29 (2H, d), 8,75 (1H, d), 9,07 (1H, s), 9,62 (1H, s) NMR Spectrum: 1H NMR (400.13 MHz, DMSO – d6) δ 1.24–1.26 (3H, m), 3.21 (3H, s), 3.23–3.26 (1H, m) , 3.47-3.54 (1H, m), 3.64-3.68 (1H, m), 3.79 (1H, d), 3.98-4.01 (1H, m), 4 , 17-4.20 (1H, m), 4.50 (3H, s), 6.81 (1H, s), 6.87 (1H, d), 7.58 (2H, d), 8, 29 (2H, d), 8.75 (1H, d), 9.07 (1H, s), 9.62 (1H, s)

Espectro LCMS: MH+ 473, Tiempo de retención 1,63 min., Método Ácido Monitor LCMS spectrum: MH + 473, Retention time 1.63 min., Acid Monitor Method

15 Los siguientes compuestos se prepararon de una manera análoga a partir de N–[4–[4–[(3S)–3–metilmorfolin–4–il]– 6–(metilsulfonilmetil)pirimidin–2–il]fenil]carbamato de fenilo y la amina apropiada. The following compounds were prepared analogously from N– [4– [4 - [(3S) -3-methylmorpholin-4-yl] -6– (methylsulfonylmethyl) pyrimidin-2-yl] phenyl] carbamate phenyl and the appropriate amine.

22a 22nd: O 1–[4–[4–[(3S)–3–metilmorfolin–4–il]– 484 1,60 OR 1– [4– [4 - [(3S) –3 – methylmorpholin – 4 – il] - 484 1.60

: 6–(metilsulfonilmetil)pirimidin–2– 6– (methylsulfonylmethyl) pyrimidin – 2–

S O O S O O: N N N N H N H O N N il]fenil]–3–pirimidin–2–il–urea N N N N H N H O N N il] phenyl] –3 – pyrimidin – 2 – il – urea

22b 22b: S O O N N N O N H N H O 1–(2,6–dimetilfenil)–3–[4–[4–[(3S)– 3–metilmorfolin–4–il]–6– (metilsulfonilmetil)pirimidin–2– il]fenil]urea 510 1,98 S O O N N N O N H N H O 1– (2,6-dimethylphenyl) –3– [4– [4 - [(3S) - 3-methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin-2-yl] phenyl] urea 510 1.98

22c 22c: S O O N N N O N H N H O N H O 1–[4–[4–[(3S)–3–metilmorfolin–4–il]– 6–(metilsulfonilmetil)pirimidin–2– il]fenil]–3–(6–oxo–1H–piridin–2– il)urea 499 1,35 S O O N N N O N H N H O N H O 1– [4– [4 - [(3S) –3 – methylmorpholin-4-yl] - 6– (methylsulfonylmethyl) pyrimidin – 2– yl] phenyl] –3– (6 – oxo – 1H – pyridin – 2– il )urea 499 1.35

22d 22d: S O O N N N O N H N H O N O 3–[4–[4–[(3S)–3–metilmorfolin–4–il]– 6–(metilsulfonilmetil)pirimidin–2– il]fenil]–1–(5–metil–1,2–oxazol–3– il)urea 487 1,72 S O O N N N O N H N H O N O 3– [4– [4 - [(3S) –3-methylmorpholin-4-yl] - 6– (methylsulfonylmethyl) pyrimidin-2-yl] phenyl] –1– (5-methyl – 1,2-oxazol – 3 - il) urea 487 1.72

22e 22e: S O O N N N O N H N H O O N 3–[4–[4–[(3S)–3–metilmorfolin–4–il]– 6–(metilsulfonilmetil)pirimidin–2– il]fenil]–1–(5–metil–1,2–oxazol–4– il)urea 487 1,46 S O O N N N O N H N H O O N 3– [4– [4 - [(3S) –3-methylmorpholin-4-yl] - 6– (methylsulfonylmethyl) pyrimidin-2-yl] phenyl] –1– (5-methyl – 1,2-oxazol – 4 - il) urea 487 1.46

22f 22f: O 1–[4–[4–[(3S)–3–metilmorfolin–4–il]– 486 1,27 OR 1– [4– [4 - [(3S) –3 – methylmorpholin – 4 – il] - 486 1.27

S O O S O O: N N N N H N H O N N 6–(metilsulfonilmetil)pirimidin–2– il]fenil]–3–(1–metilpirazol–4–il)urea N N N N H N H O N N 6– (methylsulfonylmethyl) pyrimidin – 2– yl] phenyl] –3– (1-methylpyrazol-4-yl) urea

22g 22g: S O O N N N O N H N H O NH O 1–[4–[4–[(3S)–3–metilmorfolin–4–il]– 6–(metilsulfonilmetil)pirimidin–2– il]fenil]–3–(2–oxo–1H–piridin–4– il)urea 499 1,21 S O O N N N O N H N H O NH O 1– [4– [4 - [(3S) –3 – methylmorpholin-4-yl] - 6– (methylsulfonylmethyl) pyrimidin – 2– yl] phenyl] –3– (2 – oxo – 1H – pyridin – 4– il )urea 499 1.21

22h 22h: S O O N N N O N H N H O N N 3–[4–[4–[(3S)–3–metilmorfolin–4–il]– 6–(metilsulfonilmetil)pirimidin–2– il]fenil]–1–(1,3,5–trimetilpirazol–4– il)urea 514 1,29 S O O N N N O N H N H O N N 3– [4– [4 - [(3S) –3-methylmorpholin-4-yl] - 6– (methylsulfonylmethyl) pyrimidin-2-yl] phenyl] –1– (1,3,5-trimethylpyrazole-4– il )urea 514 1.29

22i 22i: S O O N N N O N H N H O NH N 1–(3,5–dimetil–1H–pirazol–4–il)–3– [4–[4–[(3S)–3–metilmorfolin–4–il]–6– (metilsulfonilmetil)pirimidin–2– il]fenil]urea 500 1,21 S O O N N N O N H N H O NH N 1– (3,5 – dimethyl – 1H – pyrazole – 4-yl) –3– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin – 2– il ] phenyl] urea 500 1.21

Ejemplo 22a: RMN 1H (400,13 MHz, DMSO-d6) δ 1,26 (3H, d), 3,22 (3H, s), 3,24–3,26 (1H, m), 3,48–3,55 (1H, m), 3,65–3,68 (1H, m), 3,79 (1H, d), 3,98–4,02 (1H, m), 4,20 (1H, d), 4,51 (3H, s), 6,82 (1H, s), 7,16 (1H, t), 7,71–7,73 (2H, m), 8,30–8,33 (2H, m), 8,70 (2H, d), 10,21 (1H, s), 11,63 (1H, s) Example 22a: 1H NMR (400.13 MHz, DMSO-d6) δ 1.26 (3H, d), 3.22 (3H, s), 3.24-3.26 (1H, m), 3.48 –3.55 (1H, m), 3.65–3.68 (1H, m), 3.79 (1H, d), 3.98–4.02 (1H, m), 4.20 (1H , d), 4.51 (3H, s), 6.82 (1H, s), 7.16 (1H, t), 7.71–7.73 (2H, m), 8.30–8, 33 (2H, m), 8.70 (2H, d), 10.21 (1H, s), 11.63 (1H, s)

5 Ejemplo 22b: RMN 1H (400,13 MHz, DMSO–d6) δ 1,24–1,26 (3H, m), 2,23 (6H, s), 3,21 (3H, s), 3,23 (1H, d), 3,47– 3,54 (1H, m), 3,64–3,67 (1H, m), 3,78 (1H, d), 3,97–4,01 (1H, m), 4,17–4,20 (1H, m), 4,49 (3H, s), 6,79 (1H, s), 7,08 (3H, d), 7,55–7,59 (2H, m), 7,78 (1H, s), 8,23–8,27 (2H, m), 9,00 (1H, s) 5 Example 22b: 1H NMR (400.13 MHz, DMSO-d6) δ 1.24-1.26 (3H, m), 2.23 (6H, s), 3.21 (3H, s), 3, 23 (1H, d), 3.47-3.54 (1H, m), 3.64-3.67 (1H, m), 3.78 (1H, d), 3.97-4.01 ( 1H, m), 4.17-4.20 (1H, m), 4.49 (3H, s), 6.79 (1H, s), 7.08 (3H, d), 7.55–7 , 59 (2H, m), 7.78 (1H, s), 8.23–8.27 (2H, m), 9.00 (1H, s)

Ejemplo 22c: RMN 1H (400,13 MHz, DMSO–d6) δ 1,26 (3H, d), 3,22 (3H, s), 3,24 (1H, d), 3,48–3,55 (1H, m), 3,64– 3,68 (1H, m), 3,79 (1H, d), 3,98–4,02 (1H, m), 4,19 (1H, d), 4,51 (3H, s), 6,24 (1H, d), 6,81 (1H, s), 7,56 (1H, t), 7,70 Example 22c: 1H NMR (400.13 MHz, DMSO-d6) δ 1.26 (3H, d), 3.22 (3H, s), 3.24 (1H, d), 3.48-3.55 (1H, m), 3.64– 3.68 (1H, m), 3.79 (1H, d), 3.98–4.02 (1H, m), 4.19 (1H, d), 4.51 (3H, s), 6.24 (1H, d), 6.81 (1H, s), 7.56 (1H, t), 7.70

10 (2H, d), 8,28–8,30 (2H, m), 9,28 (1H, s) 10 (2H, d), 8.28–8.30 (2H, m), 9.28 (1H, s)

Ejemplo 22d: RMN 1H (400,13 MHz, DMSO–d6) δ 1,25 (3H, d), 2,38 (3H, d), 3,21 (3H, s), 3,23 (1H, m), 3,47–3,54 (1H, m), 3,64–3,68 (1H, m), 3,79 (1H, d), 3,97–4,01 (1H, m), 4,18 (1H, d), 4,50 (3H, s), 6,57 (1H, d), 6,81 (1H, s), 7,56 (2H, d), 8,27–8,29 (2H, m), 9,05 (1H, d), 9,46 (1H, s) Example 22d: 1H NMR (400.13 MHz, DMSO-d6) δ 1.25 (3H, d), 2.38 (3H, d), 3.21 (3H, s), 3.23 (1H, m ), 3.47-3.54 (1H, m), 3.64-3.68 (1H, m), 3.79 (1H, d), 3.97-4.01 (1H, m), 4.18 (1H, d), 4.50 (3H, s), 6.57 (1H, d), 6.81 (1H, s), 7.56 (2H, d), 8.27–8 , 29 (2H, m), 9.05 (1H, d), 9.46 (1H, s)

Ejemplo 22e: RMN 1H (400,13 MHz, DMSO–d6) δ 1,25 (3H, d), 2,37 (3H, s), 3,21 (3H, s), 3,22–3,26 (1H, m), 3,47– Example 22e: 1H NMR (400.13 MHz, DMSO-d6) δ 1.25 (3H, d), 2.37 (3H, s), 3.21 (3H, s), 3.22–3.26 (1H, m), 3.47–

15 3,54 (1H, m), 3,64–3,67 (1H, m), 3,78 (1H, d), 3,97–4,01 (1H, m), 4,18 (1H, s), 4,49 (3H, s), 6,80 (1H, s), 7,55–7,58 (2H, m), 8,18 (1H, s), 8,25–8,27 (2H, m), 8,67 (1H, d), 8,99 (1H, s) 15 3.54 (1H, m), 3.64–3.67 (1H, m), 3.78 (1H, d), 3.97–4.01 (1H, m), 4.18 (1H , s), 4.49 (3H, s), 6.80 (1H, s), 7.55–7.58 (2H, m), 8.18 (1H, s), 8.25–8, 27 (2H, m), 8.67 (1H, d), 8.99 (1H, s)

Ejemplo 22f: RMN 1H (400,13 MHz, DMSO–d6) δ 1,25 (3H, d), 3,21 (3H, s), 3,22–3,26 (1H, m), 3,47–3,54 (1H, m), 3,64–3,67 (1H, m), 3,77–3,30 (1H, m) 3,79 (3H, s), 3,97–4,01 (1H, m), 4,18 (1H, s), 4,49 (3H, s), 6,79 (1H, s), 7,38 (1H, d), 7,53–7,57 (2H, m), 7,76 (1H, s), 8,23–8,26 (2H, m), 8,39 (1H, s), 8,84 (1H, s) Example 22f: 1H NMR (400.13 MHz, DMSO-d6) δ 1.25 (3H, d), 3.21 (3H, s), 3.22-3.26 (1H, m), 3.47 –3.54 (1H, m), 3.64–3.67 (1H, m), 3.77–3.30 (1H, m) 3.79 (3H, s), 3.97-4, 01 (1H, m), 4.18 (1H, s), 4.49 (3H, s), 6.79 (1H, s), 7.38 (1H, d), 7.53–7.57 (2H, m), 7.76 (1H, s), 8.23–8.26 (2H, m), 8.39 (1H, s), 8.84 (1H, s)

Ejemplo 22g: RMN 1H (400,13 MHz, DMSO–d6) δ 1,25 (3H, d), 3,21 (3H, s), 3,23–3,26 (1H, m), 3,47–3,54 (1H, m), 3,64–3,68 (1H, m), 3,78 (1H, d), 3,97–4,01 (1H, m), 4,18 (1H, d), 4,50 (3H, s), 6,25–6,27 (1H, m), 6,46 (1H, d), 6,81 (1H, s), 7,25 (1H, d), 7,55–7,57 (2H, m), 8,27–8,29 (2H, m), 8,92 (1H, s), 9,05 (1H, s), 11,04 (1H, s) Example 22g: 1H NMR (400.13 MHz, DMSO-d6) δ 1.25 (3H, d), 3.21 (3H, s), 3.23-3.26 (1H, m), 3.47 –3.54 (1H, m), 3.64–3.68 (1H, m), 3.78 (1H, d), 3.97–4.01 (1H, m), 4.18 (1H , d), 4.50 (3H, s), 6.25–6.27 (1H, m), 6.46 (1H, d), 6.81 (1H, s), 7.25 (1H, d), 7.55–7.57 (2H, m), 8.27–8.29 (2H, m), 8.92 (1H, s), 9.05 (1H, s), 11.04 (1H, s)

Ejemplo 22h: RMN 1H (400,13 MHz, DMSO–d6) δ 1,25 (3H, d), 2,01 (3H, s), 2,10 (3H, s), 3,21 (3H, s), 3,25 (1H, d), 3,47–3,54 (1H, m), 3,64 (3H, s), 3,66–3,70 (1H, m), 3,78 (1H, d), 3,97–4,01 (1H, m), 4,18 (1H, d), 4,49 (3H, s), 6,78 (1H, s), 7,48 (1H, s), 7,53–7,57 (2H, m), 8,22–8,24 (2H, m), 8,80 (1H, s) Example 22h: 1H NMR (400.13 MHz, DMSO-d6) δ 1.25 (3H, d), 2.01 (3H, s), 2.10 (3H, s), 3.21 (3H, s ), 3.25 (1H, d), 3.47-3.54 (1H, m), 3.64 (3H, s), 3.66-3.70 (1H, m), 3.78 ( 1H, d), 3.97-4.01 (1H, m), 4.18 (1H, d), 4.49 (3H, s), 6.78 (1H, s), 7.48 (1H , s), 7.53–7.57 (2H, m), 8.22–8.24 (2H, m), 8.80 (1H, s)

Ejemplo 22i: RMN 1H (400,13 MHz, DMSO–d6) δ 1,25 (3H, d), 2,03 (3H, s), 2,09 (3H, s), 3,21 (3H, s), 3,25 (1H, d), 3,47–3,54 (1H, m), 3,63–3,67 (1H, m), 3,78 (1H, d), 3,97–4,01 (1H, m), 4,18 (1H, d), 4,49 (3H, s), 6,78 (1H, s), 7,44 (1H, s), 7,55 (2H, d), 8,23 (2H, d), 8,81 (1H, s), 12,04 (1H, s) Example 22i: 1H NMR (400.13 MHz, DMSO-d6) δ 1.25 (3H, d), 2.03 (3H, s), 2.09 (3H, s), 3.21 (3H, s ), 3.25 (1H, d), 3.47-3.54 (1H, m), 3.63-3.67 (1H, m), 3.78 (1H, d), 3.97– 4.01 (1H, m), 4.18 (1H, d), 4.49 (3H, s), 6.78 (1H, s), 7.44 (1H, s), 7.55 (2H , d), 8.23 (2H, d), 8.81 (1H, s), 12.04 (1H, s)

Prueba (a): Ejemplo (22a) 0,06 μM; Ejemplo (22b) 1,6 μM; Ejemplo (22d) 0,0048 μM; Ejemplo (22e) 0,56 μM; Ejemplo (22f) 0,091 μM; Ejemplo (22g) 0,0045 μM; Ejemplo (22h) 1,5 μM; Ejemplo (22i) 4,3 μM. Test (a): Example (22a) 0.06 μM; Example (22b) 1.6 μM; Example (22d) 0.0048 μM; Example (22e) 0.56 μM; Example (22f) 0.091 μM; Example (22g) 0.0045 μM; Example (22h) 1.5 μM; Example (22i) 4.3 μM.

Prueba (c): Ejemplo (22c) 0,21 μM. Test (c): Example (22c) 0.21 μM.

La preparación de N–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidin–2–il]fenil]carbamato de fenilo se describió anteriormente. The preparation of phenyl N- [4– [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidin-2-yl] phenyl] carbamate was described above.

Ejemplo 23: Example 23:

3–Metil–1–[1–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidin–2–il]–4–piperidil]urea 3 – Methyl – 1– [1– [4 - [(3 S) –3-methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin – 2-yl] –4-piperidyl] urea

Se disolvió N–[1–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidin–2–il]–4–piperidil]carbamato de fenilo (220 mg, 0,45 mmoles) en DMF (3 ml). Se añadió trietilamina (0,188 ml, 1,35 mmoles), seguido por metilamina 2M en THF (1,2 ml, 2,25 mmoles). La mezcla se agitó a 50ºC durante 3 horas. La mezcla de reacción se evaporó hasta sequedad y se purificó mediante cromatografía en fase normal usando un gradiente de 0–6% de metanol en DCM para dar un aceite que, después de la trituración con éter dietílico, dio el material deseado como un sólido blanco (153 mg). N- [1– [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidin-2-yl] -4-piperidyl] phenyl carbamate (220 mg, 0.45) mmol) in DMF (3 ml). Triethylamine (0.188 ml, 1.35 mmol) was added, followed by 2M methylamine in THF (1.2 ml, 2.25 mmol). The mixture was stirred at 50 ° C for 3 hours. The reaction mixture was evaporated to dryness and purified by normal phase chromatography using a gradient of 0–6% methanol in DCM to give an oil which, after trituration with diethyl ether, gave the desired material as a white solid. (153 mg).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,17 (3H, d), 1,20–1,27 (2H, m), 1,77 (2H, d), 2,54 (3H, d), 2,99 (2H, d), 3,08 (1H, d), 3,12 (3H, s), 3,37–3,40 (1H, m), 3,43 (1H, d), 3,57 (1H, d), 3,71 (1H, d), 3,91 (1H, d), 3,94 (1H, d), 4,23 (2H, s), 4,26 (1H, d), 4,42 (2H, d), 5,57 (1H, q), 5,83 (1H, d), 6,14 (1H, s) NMR Spectrum: 1H NMR (400.13 MHz, DMSO – d6) δ 1.17 (3H, d), 1.20–1.27 (2H, m), 1.77 (2H, d), 2.54 (3H, d), 2.99 (2H, d), 3.08 (1H, d), 3.12 (3H, s), 3.37-3.40 (1H, m), 3.43 ( 1H, d), 3.57 (1H, d), 3.71 (1H, d), 3.91 (1H, d), 3.94 (1H, d), 4.23 (2H, s), 4.26 (1H, d), 4.42 (2H, d), 5.57 (1H, q), 5.83 (1H, d), 6.14 (1H, s)

Espectro LCMS: MH+ 427, Tiempo de retención 0,85 min., Método Ácido 5 Minutos LCMS spectrum: MH + 427, Retention time 0.85 min., Acid Method 5 Minutes

El siguiente compuesto se preparó de manera análoga a partir de N–[1–[4–[(3S)–3–metilmorfolin–4–il]–6– (metilsulfonilmetil)pirimidin–2–il]–4–piperidil]carbamato de fenilo y la amina apropiada. The following compound was prepared analogously from N– [1– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin-2-yl] –4-piperidyl] carbamate of phenyl and the appropriate amine.

23a 23rd: S O O N N N O N N H N H O 1–etil–3–[1–[4–[(3S)–3– metilmorfolin–4–il]–6– (metilsulfonilmetil)pirimidin– 2–il]–4–piperidil]urea 441 1,03 Purificada mediante cromatografía de fase inversa S O O N N N O N N H N H O 1 – ethyl – 3– [1– [4 - [(3S) –3– methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin– 2-yl] –4-piperidyl] urea 441 1.03 Purified by reverse phase chromatography

Ejemplo 23a: RMN 1H (400,13 MHz, DMSO–d6) δ 0,98 (3H, t), 1,13–1,18 (3H, m), 1,20–1,26 (2H, m), 1,77 (2H, d), 2,97–3,03 (4H, m), 3,05–3,10 (1H, m), 3,12 (3H, s), 3,38–3,45 (1H, m), 3,55–3,59 (1H, m), 3,63 (1H, t), 3,71 (1H, d), 3,92 (1H, d), 3,92 (1H, d), 4,23 (2H, s), 4,27 (1H, m), 4,41 (2H, d), 5,64 (1H, t), 5,77 (1H, d), 6,14 (1H, s) Example 23a: 1H NMR (400.13 MHz, DMSO-d6) δ 0.98 (3H, t), 1.13-1.18 (3H, m), 1.20-1.26 (2H, m) , 1.77 (2H, d), 2.97–3.03 (4H, m), 3.05–3.10 (1H, m), 3.12 (3H, s), 3.38–3 , 45 (1H, m), 3.55-3.59 (1H, m), 3.63 (1H, t), 3.71 (1H, d), 3.92 (1H, d), 3, 92 (1H, d), 4.23 (2H, s), 4.27 (1H, m), 4.41 (2H, d), 5.64 (1H, t), 5.77 (1H, d ), 6.14 (1H, s)

Prueba (a): Ejemplo (23) 5,6 μM; Ejemplo (23a) 3,7 μM. Test (a): Example (23) 5.6 μM; Example (23a) 3.7 μM.

A continuación se describe la preparación de N–[1–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidin–2– il]–4–piperidil]carbamato de fenilo. N–[1–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidin–2–il]–4–piperidil]carbamato de fenilo The preparation of N- [1– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin-2-yl] -4-piperidyl] phenyl carbamate is described below. N– [1– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin-2-yl] –4-piperidyl] phenyl carbamate

O OR

N N

N S OO N S OO

NN O NN O

N N

O H Or h

Se disolvió 1–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidin–2–il]piperidin–4–amina (500 mg, 1,35 mmoles) en dioxano (10 ml). Se añadió bicarbonato de sodio (171 mg, 1,50 mmoles). Después se añadió gota a gota durante 2 minutos cloroformiato de fenilo (0,171 ml, 1,35 mmoles). La suspensión se agitó a RT durante 3 horas. Se añadieron cloroformiato de fenilo (0,021 ml, 0,27 mmoles) y bicarbonato de sodio (21 mg, 0,12 mmoles). La agitación a temp. ambiente se continuó durante 1 hora, y la mezcla de reacción se evaporó hasta sequedad y se repartió entre agua (10 ml) y acetato de etilo (10 ml). El agua se extrajo con una segunda porción de acetato de etilo (10 ml). Los productos orgánicos combinados se secaron sobre sulfato de magnesio y se evaporaron para dar el material deseado como una espuma (701 mg). 1– [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidin-2-yl] piperidin-4-amine (500 mg, 1.35 mmol) was dissolved in dioxane (10 ml) Sodium bicarbonate (171 mg, 1.50 mmol) was added. Then phenyl chloroformate (0.171 ml, 1.35 mmol) was added dropwise over 2 minutes. The suspension was stirred at RT for 3 hours. Phenyl chloroformate (0.021 ml, 0.27 mmol) and sodium bicarbonate (21 mg, 0.12 mmol) were added. The stirring at temp. Ambient was continued for 1 hour, and the reaction mixture was evaporated to dryness and partitioned between water (10 ml) and ethyl acetate (10 ml). Water was extracted with a second portion of ethyl acetate (10 ml). The combined organic products were dried over magnesium sulfate and evaporated to give the desired material as a foam (701 mg).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,18 (3H, d), 1,34–1,44 (2H, m), 1,86 (2H, d), 2,99 (2H, d), 3,11 (1H, d), 3,13 (3H, s), 3,40–3,46 (1H, m), 3,60 (2H, d), 3,72 (2H, d), 3,91–3,96 (2H, m), 4,25 (2H, s), 4,28 (1H, m), 4,52 (2H, d), 6,16 (1H, s), 7,10 (2H, d), 7,20 (1H, t), 7,38 (2H, t), 7,76 (1H, d) NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.18 (3H, d), 1.34-1.44 (2H, m), 1.86 (2H, d), 2.99 (2H, d), 3.11 (1H, d), 3.13 (3H, s), 3.40-3.46 (1H, m), 3.60 (2H, d), 3.72 ( 2H, d), 3.91-3.96 (2H, m), 4.25 (2H, s), 4.28 (1H, m), 4.52 (2H, d), 6.16 (1H , s), 7.10 (2H, d), 7.20 (1H, t), 7.38 (2H, t), 7.76 (1H, d)

Espectro LCMS: MH+ 490, Tiempo de retención 1,58 min., Método Ácido Monitor LCMS spectrum: MH + 490, Retention time 1.58 min., Acid Monitor Method

1–[4–[(3S)–3–Metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidin–2–il]piperidin–4–amina 1– [4 - [(3S) –3 – Methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin-2-yl] piperidin-4-amine

Se disolvió N–[1–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidin–2–il]–4–piperidil]carbamato de terc– butilo (1,30 g, 2,77 mmoles) en metanol (10 ml). Se añadió ácido clorhídrico 4M en dioxano (10 ml). La reacción se agitó a RT durante 3 horas. Se añadió bicarbonato de sodio saturado acuoso hasta que se alcanzó pH 7, y los disolventes orgánicos se eliminaron a vacío. Se añadió agua (20 ml), y el producto se extrajo en acetato de etilo (50 ml). La capa acuosa se extrajo con una segunda porción de acetato de etilo (25 ml). Los productos orgánicos combinados se evaporaron para dar el material deseado como una espuma amarilla (1,05 g). N- [1– [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidin-2-yl] -4-piperidyl] tert-butyl carbamate (1.30 g) , 2.77 mmol) in methanol (10 ml). 4M hydrochloric acid in dioxane (10 ml) was added. The reaction was stirred at RT for 3 hours. Aqueous saturated sodium bicarbonate was added until pH 7 was reached, and the organic solvents were removed in vacuo. Water (20 ml) was added, and the product was extracted in ethyl acetate (50 ml). The aqueous layer was extracted with a second portion of ethyl acetate (25 ml). The combined organic products were evaporated to give the desired material as a yellow foam (1.05 g).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,17 (3H, d), 1,69–1,73 (2H, m), 2,75–2,80 (1H, m), 2,87–2,94 (2H, m), 3,07 (1H, d), 3,11 (1H, m), 3,12 (3H, s), 3,39–3,45 (1H, m), 3,55–3,62 (1H, m), 3,69–3,73 (1H, m), 3,90–3,94 (2H, m), 4,22 (2H, s), 4,26 (1H, s), 4,43 (1H, s), 4,46 (1H, d), 6,12 (1H, s) NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.17 (3H, d), 1.69-1.73 (2H, m), 2.75-2.80 (1H, m) , 2.87-2.94 (2H, m), 3.07 (1H, d), 3.11 (1H, m), 3.12 (3H, s), 3.39-3.45 (1H , m), 3.55-3.62 (1H, m), 3.69-3.73 (1H, m), 3.90-3.94 (2H, m), 4.22 (2H, s ), 4.26 (1H, s), 4.43 (1H, s), 4.46 (1H, d), 6.12 (1H, s)

Espectro LCMS: MH+ 370, Tiempo de retención 0,48 min., Método Ácido Monitor LCMS spectrum: MH + 370, Retention time 0.48 min., Acid Monitor Method

N–[1–[4–[(3S)–3–Metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidin–2–il]–4–piperidil]carbamato de terc–butilo N- [1– [4 - [(3S) -3-Methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidin-2-yl] -4-piperidyl] tert-butyl carbamate

O OR

N N

N S N S

OO OO

NN O NN O

O H Or h

N N

2–Cloro–4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidina (1,00 g, 3,27 mmoles), carbonato de potasio (498 mg, 3,60 mmoles) y N–(4–piperidil)carbamato de terc–butilo (721 mg, 3,60 mmoles). Se añadió acetonitrilo (10 ml), y la mezcla se calentó a reflujo durante 4 horas. El acetonitrilo se evaporó para dejar un sólido blanco que se repartió entre agua (40 ml) y acetato de etilo (60 ml). Las fases se separaron, y la capa acuosa se extrajo con una 2 – Chloro – 4 - [(3S) –3 – methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidine (1.00 g, 3.27 mmol), potassium carbonate (498 mg, 3.60 mmol) and tert-butyl N ((4-piperidyl) carbamate (721 mg, 3.60 mmol). Acetonitrile (10 ml) was added, and the mixture was heated at reflux for 4 hours. The acetonitrile was evaporated to leave a white solid that was partitioned between water (40 ml) and ethyl acetate (60 ml). The phases were separated, and the aqueous layer was extracted with a

5 segunda porción de acetato de etilo (40 ml). Los productos orgánicos combinados se evaporaron hasta sequedad para dar el material deseado como un sólido color crema (1,32 g). 5 second portion of ethyl acetate (40 ml). The combined organic products were evaporated to dryness to give the desired material as a cream solid (1.32 g).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,16–1,18 (3H, m), 1,23–1,31 (2H, m), 1,39 (9H, s), 1,74 (2H, d), 2,91 (2H, t), 3,06–3,09 (1H, m), 3,11 (3H, s), 3,39–3,44 (1H, m), 3,49 (1H, s), 3,55–3,59 (1H, m), 3,71 (1H, d), 3,90 (1H, d), 3,94 (1H, d), 4,23 (2H, s), 4,26 (1H, d), 4,50 (2H, d), 6,14 (1H, s), 6,78 (1H, d) NMR Spectrum: 1H NMR (400.13 MHz, DMSO – d6) δ 1.16–1.18 (3H, m), 1.23–1.31 (2H, m), 1.39 (9H, s) , 1.74 (2H, d), 2.91 (2H, t), 3.06-3.09 (1H, m), 3.11 (3H, s), 3.39-3.44 (1H , m), 3.49 (1H, s), 3.55-3.59 (1H, m), 3.71 (1H, d), 3.90 (1H, d), 3.94 (1H, d), 4.23 (2H, s), 4.26 (1H, d), 4.50 (2H, d), 6.14 (1H, s), 6.78 (1H, d)

10 Espectro LCMS: MH+ 470, Tiempo de retención 1,39 min., Método Ácido Monitor 10 LCMS spectrum: MH + 470, Retention time 1.39 min., Acid Monitor Method

La preparación de 2–cloro–4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidina se describió anteriormente. The preparation of 2-chloro-4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine was described above.

Ejemplo 24: Example 24:

1– [4– [4 - [(3S) –3 – Methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin-2-yl] phenyl] –3– (2-pyridin-2-ylethyl) urea

O OR

N N

N S N S

OO OO

N N

O OR

N N

N N HH N N HH

15 Se disolvió N–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidin–2–il]fenil]carbamato de fenilo (242 mg, 0,50 mmoles) en DMF (1,5 ml). Se añadió trietilamina (0,209 ml, 1,50 mmoles). Se añadió 2–piridin–2– iletanamina (306 mg, 2,50 mmoles). La reacción se agitó a 40ºC durante 2 horas. La mezcla de reacción se purificó mediante cromatografía en fase inversa para dar el material deseado como un sólido blanco (239 mg). 15 N– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin – 2-yl] phenyl] phenyl carbamate (242 mg, 0.50 mmol) was dissolved in DMF (1.5 ml). Triethylamine (0.209 ml, 1.50 mmol) was added. 2-Pyridin-2-iletanamine (306 mg, 2.50 mmol) was added. The reaction was stirred at 40 ° C for 2 hours. The reaction mixture was purified by reverse phase chromatography to give the desired material as a white solid (239 mg).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,24 (3H, d), 2,94 (2H, t), 3,21 (3H, s), 3,22–3,26 (1H, m), 3,48 NMR Spectrum: 1H NMR (400.13 MHz, DMSO – d6) δ 1.24 (3H, d), 2.94 (2H, t), 3.21 (3H, s), 3.22–3.26 (1H, m), 3.48

20 (1H, d), 3,50–3,54 (2H, m), 3,63–3,67 (1H, m), 3,78 (1H, d), 3,97–4,00 (1H, m), 4,17 (1H, d), 4,48 (3H, s), 6,26 (1H, t), 6,77 (1H, s), 7,22–7,26 (1H, m), 7,30 (1H, d), 7,47–7,51 (2H, m), 7,71–7,75 (1H, m), 8,19–8,22 (2H, m), 8,52–8,54 (1H, m), 8,77 (1H, s) 20 (1H, d), 3.50-3.54 (2H, m), 3.63-3.67 (1H, m), 3.78 (1H, d), 3.97-4.00 ( 1H, m), 4.17 (1H, d), 4.48 (3H, s), 6.26 (1H, t), 6.77 (1H, s), 7.22–7.26 (1H , m), 7.30 (1H, d), 7.47–7.51 (2H, m), 7.71–7.75 (1H, m), 8.19–8.22 (2H, m ), 8.52–8.54 (1H, m), 8.77 (1H, s)

Espectro LCMS: MH+ 511, Tiempo de retención 1,67 min., Método Básico 5 Minutos LCMS spectrum: MH + 511, Retention time 1.67 min., Basic Method 5 Minutes

Los siguientes compuestos se prepararon de una manera análoga a partir del carbamato apropiado y la amina 25 apropiada. The following compounds were prepared analogously from the appropriate carbamate and the appropriate amine.

Ejemplo Example: Estructura NOMBRE LCMS MH+ Tiempo de Structure NAME LCMS MH + Time of

retención retention

(min.) (min.)

24a 24th: O 1–[4–[4–[(3S)–3–metilmorfolin–4–il]– 497 1,56 OR 1– [4– [4 - [(3S) –3 – methylmorpholin – 4 – il] - 497 1.56

S O O S O O: N N N N H N H O N il]fenil]–3–(piridin–3–ilmetil)urea N N N N H N H O N il] phenyl] –3– (pyridin-3-ylmethyl) urea

24b 24b: S O O N N N O N H N H O NH N 3–[2–(1H–imidazol–4–il)etil]–1–[4– [4–[(3S)–3–metilmorfolin–4–il]–6– (metilsulfonilmetil)pirimidin–2– il]fenil]urea 500 1,42 S O O N N N O N H N H O NH N 3– [2– (1H – imidazol-4-yl) ethyl] –1– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin – 2– il] phenyl] urea 500 1.42

24c 24c: S O O N N N O N H N H O N N 3–[4–[4–[(3S)–3–metilmorfolin–4–il]– 6–(metilsulfonilmetil)pirimidin–2– il]fenil]–1–[(5–metilpirazin–2– il)metil]urea 512 1,52 S O O N N N O N H N H O N N 3– [4– [4 - [(3S) –3-methylmorpholin-4-yl] - 6– (methylsulfonylmethyl) pyrimidin-2-yl] phenyl] –1 - [(5-methylpyrazin-2-yl) methyl] urea 512 1.52

24d 24d: O 1–[4–[4–[(3S)–3–metilmorfolin–4–il]– 497 1,62 OR 1– [4– [4 - [(3S) –3 – methylmorpholin – 4 – il] - 497 1.62

S O O S O O: N N N N H N H O N il]fenil]–3–(piridin–2–ilmetil)urea N N N N H N H O N il] phenyl] –3– (pyridin – 2-ylmethyl) urea

24e 24e: O 1–[4–[4–[(3S)–3–metilmorfolin–4–il]– 497 1,55 OR 1– [4– [4 - [(3S) –3 – methylmorpholin – 4 – il] - 497 1.55

S O O S O O: N N N N H N H O N il]fenil]–3–(piridin–4–ilmetil)urea N N N N H N H O N il] phenyl] –3– (pyridin-4-ylmethyl) urea

24f 24f: S O O N N N O N H N H O O 3–[(4–metoxifenil)metil]–1–[4–[4– [(3S)–3–metilmorfolin–4–il]–6– (metilsulfonilmetil)pirimidin–2– il]fenil]urea 526 2,04 S O O N N N O N H N H O O 3 - [(4-methoxyphenyl) methyl] –1– [4– [4– [(3S) –3-methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin-2-yl] phenyl] urea 526 2.04

24g 24g: S O O N N N O N H N H O NN 1–[4–[4–[(3S)–3–metilmorfolin–4–il]– 6–(metilsulfonilmetil)pirimidin–2– il]fenil]–3–[(1–metilpirazol–4– il)metil]urea 500 1,50 S O O N N N O N H N H O NN 1– [4– [4 - [(3S) –3-methylmorpholin-4-yl] - 6– (methylsulfonylmethyl) pyrimidin-2-yl] phenyl] –3 - [(1-methylpyrazole-4-yl) methyl] urea 500 1.50

24h 24h: S O O N N N O N H N H O O N 3–[4–[4–[(3S)–3–metilmorfolin–4–il]– 6–(metilsulfonilmetil)pirimidin–2– il]fenil]–1–[(5–metil–1,2–oxazol–3– il)metil]urea 501 1,73 S O O N N N O N H N H O O N 3– [4– [4 - [(3S) –3-methylmorpholin-4-yl] - 6– (methylsulfonylmethyl) pyrimidin-2-yl] phenyl] –1 - [(5-methyl – 1,2-oxazole– 3– il) methyl] urea 501 1.73

24i 24i: S O O N N N O N H N H O N 3–[(3–dimetilaminofenil)metil]–1–[4– [4–[(3S)–3–metilmorfolin–4–il]–6– (metilsulfonilmetil)pirimidin–2– il]fenil]urea 539 2,15 S O O N N N O N H N H O N 3 - [(3-dimethylaminophenyl) methyl] –1– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin-2-yl] phenyl] urea 539 2.15

24j 24j: O 1–[4–[4–[(3S)–3–metilmorfolin–4–il]– 503 1,58 OR 1– [4– [4 - [(3S) –3 – methylmorpholin – 4 – il] - 503 1.58

N N N S O O N H N H O S N N N N S O O N H N H O S N: il]fenil]–3–(1,3–tiazol–5–ilmetil)urea il] phenyl] –3– (1,3-thiazol-5-ylmethyl) urea

24k 24k: O 3–metil–1–[1–[4–[(3S)–3– 410 2,18 OR 3 – methyl – 1– [1– [4 - [(3S) –3– 410 2.18

: metilmorfolin–4–il]–6– methylmorpholin – 4 – il] –6–

N N S O O N N N H N H O N N S O O N N N H N H O: il]pirazol–3–il]urea il] pyrazole – 3 – il] urea

24l 24l: O 1–etil–3–[1–[4–[(3S)–3– 424 2,29 OR 1 – ethyl – 3– [1– [4 - [(3S) –3– 424 2.29

: metilmorfolin–4–il]–6– methylmorpholin – 4 – il] –6–

24m 24m: O 3–ciclopropil–1–[1–[4–[(3S)–3– 436 2,30 OR 3 – cyclopropyl – 1– [1– [4 - [(3S) –3– 436 2.30

: metilmorfolin–4–il]–6– methylmorpholin – 4 – il] –6–

24n 24n: O 3–metil–1–[1–[4–[(3S)–3– 455 1,63 OR 3 – methyl – 1– [1– [4 - [(3S) –3– 455 1.63

N N: metilsulfonilpropan–2–il)pirimidin–2– methylsulfonylpropan – 2-yl) pyrimidin – 2–

N N S O O N N H N H O N N S O O N N H N H O: il]–4–piperidil]urea il] –4 – piperidil] urea

24o 24th: O 1–etil–3–[1–[4–[(3S)–3– 469 1,76 OR 1 – ethyl – 3– [1– [4 - [(3S) –3– 469 1.76

24p 24p: O 3–ciclopropil–1–[1–[4–[(3S)–3– 481 1,80 OR 3 – cyclopropyl – 1– [1– [4 - [(3S) –3– 481 1.80

24q 24q: O 1–[1–[4–[(3S)–3–metilmorfolin–4–il]– 535 1,69 OR 1– [1– [4 - [(3S) –3 – methylmorpholin – 4 – il] - 535 1.69

: 6–(2–metilsulfonilpropan–2– 6– (2 – methylsulfonylpropan – 2–

N N: il)pirimidin–2–il]–4–piperidil]–3–[(1– il) pyrimidin – 2 – il] –4 – piperidil] –3 - [(1–

N N S O O N N H N H O NN N N S O O N N H N H O NN: metilpirazol–4–il)metil]urea methylpyrazole-4-yl) methyl] urea

24r 24r: O 3–ciclopropil–1–[5–[4–[(3S)–3– 446 1,56 OR 3 – cyclopropyl – 1– [5– [4 - [(3S) –3– 446 1.56

: metilmorfolin–4–il]–6– methylmorpholin – 4 – il] –6–

N N S O O N N H N H O N N S O O N N H N H O: il]piridin–2–il]urea il] pyridin – 2 – il] urea

24s 24s: O 1–[4–[4–[(3S)–3–metilmorfolin–4–il]– 501 1,64 OR 1– [4– [4 - [(3S) –3 – methylmorpholin – 4 – il] - 501 1.64

N N: il)pirimidin–2–il]fenil]–3–(1,2–oxazol– il) pyrimidin – 2-yl] phenyl] –3– (1,2-oxazol–

N ON N S O O N H N H O N ON N S O O N H N H O: 3–il)urea 3 – il) urea

24t 24t: O 3–[4–[4–[(3S)–3–metilmorfolin–4–il]– 515 2,22 OR 3– [4– [4 - [(3S) –3 – methylmorpholin – 4 – il] - 515 2.22

N N: il)pirimidin–2–il]fenil]–1–(5–metil– il) pyrimidin – 2-yl] phenyl] –1– (5-methyl–

N ON N S O O N H N H O N ON N S O O N H N H O: 1,2–oxazol–3–il)urea 1,2-oxazol-3-yl) urea

24u 24u: N N N O S O O N H N H O N N 1–[4–[4–[(3S)–3–metilmorfolin–4–il]– 6–(2–metilsulfonilpropan–2– il)pirimidin–2–il]fenil]–3–pirimidin–2– il–urea 512 2,10 N N N O S O O N H N H O N N 1– [4– [4 - [(3S) –3 – methylmorpholin-4-yl] - 6– (2-methylsulfonylpropan – 2– yl) pyrimidin – 2-yl] phenyl] –3 – pyrimidin – 2– il– urea 512 2.10

24v 24v: O 1–[4–[4–[(3S)–3–metilmorfolin–4–il]– 500 2,05 OR 1– [4– [4 - [(3S) –3 – methylmorpholin – 4 – il] - 500 2.05

N N: il)pirimidin–2–il]fenil]–3–(1H–pirazol– il) pyrimidin – 2-yl] phenyl] –3– (1H – pyrazole–

N N S O O N H N H O N NH N N S O O N H N H O N NH: 3–il)urea 3 – il) urea

24w 24w: O 1–[4–[4–[(3S)–3–metilmorfolin–4–il]– 510 2,40 OR 1– [4– [4 - [(3S) –3 – methylmorpholin – 4 – il] - 510 2.40

N N N S O O N H N H O N N N S O O N H N H O: il)pirimidin–2–il]fenil]–3–fenil–urea il) pyrimidin – 2-yl] phenyl] –3-phenyl-urea

24x 24x: N N N O S O O N H N H O N O 3–(6–metoxipiridin–3–il)–1–[4–[4– [(3S)–3–metilmorfolin–4–il]–6–(2– metilsulfonilpropan–2–il)pirimidin–2– il]fenil]urea 541 2,14 N N N O S O O N H N H O N O 3– (6 – methoxypyridin – 3-yl) –1– [4– [4– [(3S) –3-methylmorpholin-4-yl] –6– (2– methylsulfonylpropan – 2-yl) pyrimidin – 2– il ] phenyl] urea 541 2.14

24y 24y: N N N O S O O N H N H O N F 3–(5–fluoropiridin–2–il)–1–[4–[4– [(3S)–3–metilmorfolin–4–il]–6–(2– metilsulfonilpropan–2–il)pirimidin–2– il]fenil]urea 529 2,39 N N N O S O O N H N H O N F 3– (5 – fluoropyridin – 2 – il) –1– [4– [4– [(3S) –3-methylmorpholin-4-yl] –6– (2– methylsulfonylpropan – 2-yl) pyrimidin – 2– il ] phenyl] urea 529 2.39

24z 24z: O 1–[5–[4–[(3S)–3–metilmorfolin–4–il]– 530 1,68 OR 1– [5– [4 - [(3S) –3 – methylmorpholin – 4 – il] - 530 1.68

N N: il)pirimidin–2–il]pirimidin–2–il]–3–[(1– il) pyrimidin – 2-yl] pyrimidin – 2-yl] –3 - [(1–

N N S O O N H N H O NN N N S O O N H N H O NN: metilpirazol–4–il)metil]urea methylpyrazole-4-yl) methyl] urea

24aa 24aa: N N N O S O O N H N H O 3–ciclopropil–1–[4–[4–[(3S)–3– metilmorfolin–4–il]–6– (metilsulfonilmetil)pirimidin–2– il]fenil]urea 446 1,38 N N N O S O O N H N H O 3 – cyclopropyl – 1– [4– [4 - [(3S) –3– methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin – 2– yl] phenyl] urea 446 1.38

24ab 24ab: O 1–[2,6–difluoro–4–[4–[(3S)–3– 484 2,44 OR 1– [2,6 – difluoro – 4– [4 - [(3S) –3– 484 2.44

N N S O O N H N H OF F N N S O O N H N H OF F: il]fenil]–3–metil–urea il] phenyl] –3 – methyl – urea

24ac 24ac: O 3–[2,6–difluoro–4–[4–[(3S)–3– 498 2,56 OR 3– [2,6 – difluoro – 4– [4 - [(3S) –3– 498 2.56

N N S O O N H N H OF F N N S O O N H N H OF F: il]fenil]–1–etil–urea il] phenyl] –1 – ethyl-urea

24ad 24ad: N N N O S O O N H N H OF F 3–ciclopropil–1–[2,6–difluoro–4–[4– [(3S)–3–metilmorfolin–4–il]–6–(2– metilsulfonilpropan–2–il)pirimidin–2– il]fenil]urea 510 2,58 N N N O S O O N H N H OF F 3 – cyclopropyl – 1– [2,6 – difluoro – 4– [4– [(3S) –3-methylmorpholin-4-yl] –6– (2– methylsulfonylpropan – 2-yl) pyrimidin – 2– yl] phenyl ]urea 510 2.58

24ae 24ae: N N N O S O O N H N H OF F NN 1–[2,6–difluoro–4–[4–[(3S)–3– metilmorfolin–4–il]–6–(2– metilsulfonilpropan–2–il)pirimidin–2– il]fenil]–3–[(1–metilpirazol–4– il)metil]urea 564 2,46 N N N O S O O N H N H OF F NN 1– [2,6 – difluoro – 4– [4 - [(3S) –3– methylmorpholin-4-yl] –6– (2– methylsulfonylpropan – 2-yl) pyrimidin – 2– yl] phenyl] –3– [(1-methylpyrazol-4-yl) methyl] urea 564 2.46

24af 24af: O 1–etil–3–[5–[4–[(3S)–3– 464 1,86 OR 1 – ethyl – 3– [5– [4 - [(3S) –3– 464 1.86

N N S O O N N N H N H O N N S O O N N N H N H O: il]pirimidin–2–il]urea il] pyrimidin – 2 – il] urea

24ag 24ag: O 3–ciclopropil–1–[5–[4–[(3S)–3– 476 1,88 OR 3 – cyclopropyl – 1– [5– [4 - [(3S) –3– 476 1.88

24ah 24ah: O 3–metil–1–[5–[4–[(3S)–3– 449 1,77 OR 3 – methyl – 1– [5– [4 - [(3S) –3– 449 1.77

24ai 24ai: O 1–etil–3–[5–[4–[(3S)–3– 463 1,92 OR 1 – ethyl – 3– [5– [4 - [(3S) –3– 463 1.92

24aj 24aj: O 3–ciclopropil–1–[5–[4–[(3S)–3– 475 1,95 OR 3 – cyclopropyl – 1– [5– [4 - [(3S) –3– 475 1.95

24ak 24ak: O 3–[4–[4–[(3S)–3–metilmorfolin–4–il]– OR 3– [4– [4 - [(3S) –3 – methylmorpholin – 4 – il] -

N N: il)pirimidin–2–il]fenil]–1–propil–urea il) pyrimidin – 2-yl] phenyl] –1-propyl-urea

N N S O O N H N H O N N S O O N H N H O: 476 1,92 476 1.92

24al 24al: N N N O S O O N H N H O 1–[4–[4–[(3S)–3–metilmorfolin–4–il]– 6–(2–metilsulfonilpropan–2– il)pirimidin–2–il]fenil]–3–propan–2–il– urea 476 2,08 N N N O S O O N H N H O 1– [4– [4 - [(3S) –3 – methylmorpholin-4-yl] - 6– (2-methylsulfonylpropan – 2– yl) pyrimidin – 2-yl] phenyl] –3 – propan – 2 – il– urea 476 2.08

24am 24am: N N N O S O O N H N H O 3–ciclobutil–1–[4–[4–[(3S)–3– metilmorfolin–4–il]–6–(2– metilsulfonilpropan–2–il)pirimidin–2– il]fenil]urea 488 2,15 N N N O S O O N H N H O 3 – cyclobutyl – 1– [4– [4 - [(3S) –3– methylmorpholin-4-yl] –6– (2– methylsulfonylpropan – 2-yl) pyrimidin – 2– yl] phenyl] urea 488 2.15

24an 24an: O 3–(1–hidroxi–2–metil–propan–2–il)– OR 3– (1 – hydroxy – 2 – methyl – propan – 2 – il) -

: 1–[4–[4–[(3S)–3–metilmorfolin–4–il]– 1– [4– [4 - [(3S) –3 – methylmorpholin – 4 – il] -

N N: 6–(2–metilsulfonilpropan–2– 6– (2 – methylsulfonylpropan – 2–

N N S O O N H N H O OH N N S O O N H N H O OH: il)pirimidin–2–il]fenil]urea 506 1,88 il) pyrimidin-2-yl] phenyl] urea 506 1.88

24ao 24th: N N N O S O O N H N H O N 1–[4–[4–[(3S)–3–metilmorfolin–4–il]– 6–(2–metilsulfonilpropan–2– il)pirimidin–2–il]fenil]–3–(piridin–3– ilmetil)urea 525 1,83 N N N O S O O N H N H O N 1– [4– [4 - [(3S) –3 – methylmorpholin-4-yl] - 6– (2-methylsulfonylpropan – 2– yl) pyrimidin – 2-yl] phenyl] –3– (pyridin-3– ilmethyl )urea 525 1.83

24ap 24ap: O 3–[(2R)–1–hidroxipropan–2–il]–1– OR 3 - [(2R) –1 – hydroxypropan – 2 – il] –1–

: [4–[4–[(3S)–3–metilmorfolin–4–il]–6– [4– [4 - [(3S) –3 – methylmorpholin – 4 – il] –6–

N N: (2–metilsulfonilpropan–2– (2 – Methylsulfonylpropan – 2–

N N S O O N H N H O OH N N S O O N H N H O OH: il)pirimidin–2–il]fenil]urea 492 1,71 il) pyrimidin-2-yl] phenyl] urea 492 1.71

24aq 24aq: N N N O S O O N H N H O 3–(ciclopropilmetil)–1–[4–[4–[(3S)– 3–metilmorfolin–4–il]–6–(2– metilsulfonilpropan–2–il)pirimidin–2– il]fenil]urea 488 2,14 N N N O S O O N H N H O 3– (cyclopropylmethyl) –1– [4– [4 - [(3S) - 3-methylmorpholin-4-yl] –6– (2– methylsulfonylpropan – 2-yl) pyrimidin-2-yl] phenyl] urea 488 2.14

24ar 24ar: N N N O S O O N H N H O N 1–[4–[4–[(3S)–3–metilmorfolin–4–il]– 6–(2–metilsulfonilpropan–2– il)pirimidin–2–il]fenil]–3–(piridin–4– ilmetil)urea 525 1,81 N N N O S O O N H N H O N 1– [4– [4 - [(3S) –3 – methylmorpholin-4-yl] - 6– (2-methylsulfonylpropan – 2– yl) pyrimidin – 2-yl] phenyl] –3– (pyridin-4– ilmethyl )urea 525 1.81

24as 24th: N N N O S O O N H N H O OH 3–(3–hidroxipropil)–1–[4–[4–[(3S)– 3–metilmorfolin–4–il]–6–(2– metilsulfonilpropan–2–il)pirimidin–2– il]fenil]urea 492 1,66 N N N O S O O N H N H O OH 3– (3 – hydroxypropyl) –1– [4– [4 - [(3S) - 3-methylmorpholin-4-yl] –6– (2– methylsulfonylpropan – 2-yl) pyrimidin – 2– yl] phenyl] urea 492 1.66

24at 24at: N N N O S O O N H N H O 1–[4–[4–[(3S)–3–metilmorfolin–4–il]– 6–(2–metilsulfonilpropan–2– il)pirimidin–2–il]fenil]–3–(2– metilpropil)urea 490 2,24 N N N O S O O N H N H O 1– [4– [4 - [(3S) –3 – methylmorpholin-4-yl] - 6– (2-methylsulfonylpropan – 2– yl) pyrimidin – 2-yl] phenyl] –3– (2– methylpropyl) urea 490 2.24

24au 24au: N N N O S O O N H N H O NHN 3–(1H–imidazol–2–ilmetil)–1–[4–[4– [(3S)–3–metilmorfolin–4–il]–6–(2– metilsulfonilpropan–2–il)pirimidin–2– il]fenil]urea 514 1,76 N N N O S O O N H N H O NHN 3– (1H – imidazol – 2-ylmethyl) –1– [4– [4– [(3S) –3-methylmorpholin-4-yl] –6– (2– methylsulfonylpropan – 2-yl) pyrimidin – 2– il ] phenyl] urea 514 1.76

24av 24av: O 1–[4–[4–[(3S)–3–metilmorfolin–4–il]– OR 1– [4– [4 - [(3S) –3 – methylmorpholin – 4 – il] -

N N: il)pirimidin–2–il]fenil]–3–[(1– il) pyrimidin – 2 – yl] phenyl] –3 - [(1–

N N S O O N H N H O NN N N S O O N H N H O NN: metilpirazol–4–il)metil]urea 528 1,93 methylpyrazole-4-yl) methyl] urea 528 1.93

24aw 24aw: O 3–[4–[4–[(3S)–3–metilmorfolin–4–il]– OR 3– [4– [4 - [(3S) –3 – methylmorpholin – 4 – il] -

N N: il)pirimidin–2–il]fenil]–1–[(5–metil– il) pyrimidin – 2-yl] phenyl] –1 - [(5-methyl–

N N S O O N H N H O O N N N S O O N H N H O O N: 1,2–oxazol–3–il)metil]urea 529 2,01 1,2-oxazol-3-yl) methyl] urea 529 2.01

24ax 24ax: N N N O S O O N H N H O N 1–[4–[4–[(3S)–3–metilmorfolin–4–il]– 6–(2–metilsulfonilpropan–2– il)pirimidin–2–il]fenil]–3–(1–piridin–3– iletil)urea 539 1,91 N N N O S O O N H N H O N 1– [4– [4 - [(3S) –3 – methylmorpholin-4-yl] - 6– (2-methylsulfonylpropan – 2– yl) pyrimidin – 2-yl] phenyl] –3– (1-pyridin – 3 - ileyl) urea 539 1.91

24ay 24ay: O 1–[4–[4–[(3S)–3–metilmorfolin–4–il]– OR 1– [4– [4 - [(3S) –3 – methylmorpholin – 4 – il] -

N N N S O O N H N H O N H N N N N S O O N H N H O N H N: il)pirimidin–2–il]fenil]–3–(1H–pirazol– 3–ilmetil)urea 514 1,75 il) pyrimidin – 2-yl] phenyl] –3– (1H – pyrazole– 3-ylmethyl) urea 514 1.75

24az 24az: O 1–[4–[4–[(3S)–3–metilmorfolin–4–il]– OR 1– [4– [4 - [(3S) –3 – methylmorpholin – 4 – il] -

N N S O O N H N H O N N N N S O O N H N H O N N: metilpirazol–3–il)metil]urea 528 1,84 methylpyrazole-3-yl) methyl] urea 528 1.84

retención retention

(min.) (min.)

24ba 24ba: S O O N N N O N H N O 1,1–dimetil–3–[4–[4–[(3S)–3– metilmorfolin–4–il]–6–(2– metilsulfonilpropan–2–il)pirimidin–2– il]fenil]urea 462 1,87 S O O N N N O N H N O 1,1 – dimethyl – 3– [4– [4 - [(3S) –3– methylmorpholin-4-yl] –6– (2– methylsulfonylpropan – 2-yl) pyrimidin – 2– yl] phenyl] urea 462 1.87

24bb 24bb: S O O N N N O N H O N O N–[4–[4–[(3S)–3–metilmorfolin–4– il]–6–(2–metilsulfonilpropan–2– il)pirimidin–2–il]fenil]morfolina–4– carboxamida 504 1,84 S O O N N N O N H O N O N– [4– [4 - [(3S) –3 – methylmorpholin-4– yl] –6– (2-methylsulfonylpropan – 2– yl) pyrimidin – 2-yl] phenyl] morpholine – 4– carboxamide 504 1.84

24bc 24bc: O 4–hidroxi–N–[4–[4–[(3S)–3– OR 4 – hydroxy – N– [4– [4 - [(3S) –3–

S O O S O O: N N N H O N OH il]fenil]piperidina–1–carboxamida 518 1,68 N N N H O N OH il] phenyl] piperidine-1-carboxamide 518 1.68

24bd 24bd: O 3–hidroxi–N–[4–[4–[(3S)–3– OR 3 – hydroxy – N– [4– [4 - [(3S) –3–

N N S O O N H O N OH N N S O O N H O N OH: il]fenil]piperidina–1–carboxamida 518 1,75 il] phenyl] piperidine-1-carboxamide 518 1.75

24be 24be: N N N O S O O N H O N N–[4–[4–[(3S)–3–metilmorfolin–4– il]–6–(2–metilsulfonilpropan–2– il)pirimidin–2–il]fenil]azetidina–1– carboxamida 474 1,91 N N N O S O O N H O N N– [4– [4 - [(3S) –3 – methylmorpholin-4– yl] –6– (2-methylsulfonylpropan – 2– yl) pyrimidin – 2-yl] phenyl] azetidine – 1– carboxamide 474 1.91

24bf 24bf: O 3–hidroxi–N–[4–[4–[(3S)–3– OR 3 – hydroxy – N– [4– [4 - [(3S) –3–

N N S O O N H O N OH N N S O O N H O N OH: il]fenil]azetidina–1–carboxamida 490 1,62 il] phenyl] azetidine-1-carboxamide 490 1.62

24bg 24bg: N N N O S O O N H O N 1–ciclopropil–1–metil–3–[4–[4– [(3S)–3–metilmorfolin–4–il]–6–(2– metilsulfonilpropan–2–il)pirimidin–2– il]fenil]urea 488 2,18 N N N O S O O N H O N 1 – cyclopropyl – 1 – methyl – 3– [4– [4– [(3S) –3-methylmorpholin-4-yl] –6– (2– methylsulfonylpropan – 2-yl) pyrimidin – 2– yl] phenyl] urea 488 2.18

24bh 24bh: O 3–metil–1–[5–[4–[(3S)–3– OR 3 – methyl – 1– [5– [4 - [(3S) –3–

N N S O O N N N H O N H N N S O O N N N H O N H: il]pirimidin–2–il]urea 450 1,70 il] pyrimidin – 2 – il] urea 450 1.70

24bi 24bi: O 1–[5–[4–[(3S)–3–metilmorfolin–4–il]– OR 1– [5– [4 - [(3S) –3 – methylmorpholin – 4 – il] -

N N: il)pirimidin–2–il]piridin–2–il]–3–[(1– il) pyrimidin – 2 – il] pyridin – 2 – il] –3 - [(1–

N N S O O N N H N H O NN N N S O O N N H N H O NN: metilpirazol–4–il)metil]urea 529 1,75 methylpyrazole-4-yl) methyl] urea 529 1.75

24bj 24bj: N N N O S O O N H N H O OH 3–(2–hidroxietil)–1–[4–[4–[(3S)–3– metilmorfolin–4–il]–6–(2– metilsulfonilpropan–2–il)pirimidin–2– il]fenil]urea 478 1,61 N N N O S O O N H N H O OH 3– (2 – hydroxyethyl) –1– [4– [4 - [(3S) –3– methylmorpholin-4-yl] –6– (2– methylsulfonylpropan – 2-yl) pyrimidin – 2– yl] phenyl] urea 478 1.61

Ejemplo 24a: RMN 1H (400,13 MHz, DMSO–d6) δ 1,24 (3H, d), 3,21 (3H, s), 3,22–3,26 (1H, m), 3,47–3,53 (1H, m), 3,63–3,67 (1H, m), 3,78 (1H, d), 3,97–4,01 (1H, m), 4,17 (1H, d), 4,35 (2H, d), 4,48 (3H, s), 6,77 (1H, t), 6,78 (1H, s), 7,35–7,38 (1H, m), 7,52 (2H, d), 7,71–7,74 (1H, m), 8,22 (2H, d), 8,46–8,47 (1H, m), 8,55 (1H, d), 8,88 (1H, s) Example 24a: 1H NMR (400.13 MHz, DMSO-d6) δ 1.24 (3H, d), 3.21 (3H, s), 3.22-3.26 (1H, m), 3.47 –3.53 (1H, m), 3.63–3.67 (1H, m), 3.78 (1H, d), 3.97–4.01 (1H, m), 4.17 (1H , d), 4.35 (2H, d), 4.48 (3H, s), 6.77 (1H, t), 6.78 (1H, s), 7.35–7.38 (1H, m), 7.52 (2H, d), 7.71–7.74 (1H, m), 8.22 (2H, d), 8.46–8.47 (1H, m), 8.55 (1H, d), 8.88 (1H, s)

Ejemplo 24b: RMN 1H (400,13 MHz, DMSO–d6) δ 1,24 (3H, d), 2,67 (2H, t), 3,21 (3H, s), 3,24 (1H, d), 3,34–3,39 (2H, m), 3,47–3,53 (1H, m), 3,63–3,67 (1H, m), 3,78 (1H, d), 3,97–4,00 (1H, m), 4,17 (1H, d), 4,48 (3H, s), 6,23 (1H, t), 6,77 (1H, s), 6,83 (1H, s), 7,49–7,51 (2H, m), 7,55 (1H, d), 8,21 (2H, s), 8,79 (1H, s), 11,81 (1H, s) Example 24b: 1H NMR (400.13 MHz, DMSO-d6) δ 1.24 (3H, d), 2.67 (2H, t), 3.21 (3H, s), 3.24 (1H, d ), 3.34-3.39 (2H, m), 3.47-3.53 (1H, m), 3.63-3.67 (1H, m), 3.78 (1H, d), 3.97-4.00 (1H, m), 4.17 (1H, d), 4.48 (3H, s), 6.23 (1H, t), 6.77 (1H, s), 6 , 83 (1H, s), 7.49–7.51 (2H, m), 7.55 (1H, d), 8.21 (2H, s), 8.79 (1H, s), 11, 81 (1H, s)

Ejemplo 24c: RMN 1H (400,13 MHz, DMSO–d6) δ 1,24 (3H, d), 2,48 (3H, s), 3,21 (3H, s), 3,22–3,26 (1H, m), 3,47– 3,53 (1H, m), 3,63–3,67 (1H, m), 3,78 (1H, d), 3,97–4,00 (1H, m), 4,17 (1H, d), 4,45 (2H, d), 4,49 (3H, s), 6,78 (1H, s), 6,85 (1H, t), 7,50–7,53 (2H, m), 8,21–8,23 (2H, m), 8,49–8,51 (2H, m), 9,01 (1H, s) Example 24c: 1H NMR (400.13 MHz, DMSO-d6) δ 1.24 (3H, d), 2.48 (3H, s), 3.21 (3H, s), 3.22-3.26 (1H, m), 3.47-3.53 (1H, m), 3.63-3.67 (1H, m), 3.78 (1H, d), 3.97-4.00 (1H , m), 4.17 (1H, d), 4.45 (2H, d), 4.49 (3H, s), 6.78 (1H, s), 6.85 (1H, t), 7 , 50–7.53 (2H, m), 8.21–8.23 (2H, m), 8.49–8.51 (2H, m), 9.01 (1H, s)

Ejemplo 24d: RMN 1H (400,13 MHz, DMSO–d6) δ 1,24 (3H, d), 3,21 (3H, s), 3,25 (1H, d), 3,47–3,53 (1H, m), 3,63– 3,67 (1H, m), 3,78 (1H, d), 3,97–4,01 (1H, m), 4,17 (1H, d), 4,44 (2H, d), 4,49 (3H, s), 6,78 (1H, s), 6,84 (1H, t), 7,27– 7,30 (1H, m), 7,37 (1H, d), 7,51–7,55 (2H, m), 7,76–7,80 (1H, m), 8,22 (2H, d), 8,53–8,55 (1H, m), 9,04 (1H, s) Example 24d: 1H NMR (400.13 MHz, DMSO-d6) δ 1.24 (3H, d), 3.21 (3H, s), 3.25 (1H, d), 3.47-3.53 (1H, m), 3.63– 3.67 (1H, m), 3.78 (1H, d), 3.97–4.01 (1H, m), 4.17 (1H, d), 4.44 (2H, d), 4.49 (3H, s), 6.78 (1H, s), 6.84 (1H, t), 7.27-7.30 (1H, m), 7 , 37 (1H, d), 7.51–7.55 (2H, m), 7.76–7.80 (1H, m), 8.22 (2H, d), 8.53–8.55 (1H, m), 9.04 (1H, s)

Ejemplo 24e: RMN 1H (400,13 MHz, DMSO–d6) δ 1,24 (3H, d), 3,21 (3H, s), 3,23–3,26 (1H, m), 3,50–3,53 (1H, m), 3,63–3,67 (1H, m), 3,78 (1H, d), 3,97 (1H, d), 4,00–4,19 (1H, m), 4,36 (2H, d), 4,48 (2H, s), 4,49 (1H, s), 6,78 (1H, s), 6,81 (1H, t), 7,30–7,31 (2H, m), 7,51–7,55 (2H, m), 8,21–8,24 (2H, m), 8,51–8,52 (2H, m), 8,96 (1H, s) Example 24e: 1H NMR (400.13 MHz, DMSO-d6) δ 1.24 (3H, d), 3.21 (3H, s), 3.23-3.26 (1H, m), 3.50 –3.53 (1H, m), 3.63–3.67 (1H, m), 3.78 (1H, d), 3.97 (1H, d), 4.00–4.19 (1H , m), 4.36 (2H, d), 4.48 (2H, s), 4.49 (1H, s), 6.78 (1H, s), 6.81 (1H, t), 7 , 30–7.31 (2H, m), 7.51–7.55 (2H, m), 8.21–8.24 (2H, m), 8.51–8.52 (2H, m) , 8.96 (1H, s)

Ejemplo 24f: RMN 1H (400,13 MHz, DMSO–d6) δ 1,24 (3H, d), 3,21 (3H, s), 3,24 (1H, d), 3,47–3,53 (1H, m), 3,63– 3,67 (1H, m), 3,74 (3H, s), 3,78 (1H, d), 3,97–4,01 (1H, m), 4,17 (1H, d), 4,25 (2H, d), 4,48–4,48 (2H, m), 6,59 (1H, t), 6,78 (1H, s), 6,89–6,92 (2H, m), 7,23–7,26 (2H, m), 7,50–7,52 (2H, m), 8,20–8,23 (2H, m), 8,76 (1H, s) Example 24f: 1H NMR (400.13 MHz, DMSO-d6) δ 1.24 (3H, d), 3.21 (3H, s), 3.24 (1H, d), 3.47-3.53 (1H, m), 3.63– 3.67 (1H, m), 3.74 (3H, s), 3.78 (1H, d), 3.97-4.01 (1H, m), 4.17 (1H, d), 4.25 (2H, d), 4.48-4.48 (2H, m), 6.59 (1H, t), 6.78 (1H, s), 6 , 89–6.92 (2H, m), 7.23–7.26 (2H, m), 7.50–7.52 (2H, m), 8.20–8.23 (2H, m) , 8.76 (1H, s)

Ejemplo 24g: RMN 1H (400,13 MHz, DMSO–d6) δ 1,24 (3H, d), 3,24 (1H, d), 3,47–3,53 (1H, m), 3,63–3,67 (1H, m), 3,76 (1H, s), 3,79 (3H, s), 3,97–4,01 (1H, m), 4,13 (2H, d), 4,19 (1H, s), 4,48 (2H, s), 4,49 (1H, s), 6,42 (1H, t), 6,77 (1H, s), 7,35 (1H, s), 7,49–7,51 (2H, m), 7,59 (1H, s), 8,20–8,22 (2H, m), 8,69 (1H, s) Example 24g: 1H NMR (400.13 MHz, DMSO-d6) δ 1.24 (3H, d), 3.24 (1H, d), 3.47-3.53 (1H, m), 3.63 –3.67 (1H, m), 3.76 (1H, s), 3.79 (3H, s), 3.97-4.01 (1H, m), 4.13 (2H, d), 4.19 (1H, s), 4.48 (2H, s), 4.49 (1H, s), 6.42 (1H, t), 6.77 (1H, s), 7.35 (1H , s), 7.49–7.51 (2H, m), 7.59 (1H, s), 8.20–8.22 (2H, m), 8.69 (1H, s)

Ejemplo 24h: RMN 1H (400,13 MHz, DMSO–d6) δ 1,24 (3H, d), 2,38 (3H, s), 3,25 (1H, d), 3,48–3,53 (1H, m), 3,63– 3,67 (1H, m), 3,78 (1H, d), 3,97–4,01 (1H, m), 4,17 (1H, d), 4,32 (2H, d), 4,48 (2H, s), 4,49 (1H, s), 6,16 (1H, d), 6,71 (1H, t), 6,78 (1H, s), 7,50–7,53 (2H, m), 8,21–8,24 (2H, m), 8,91 (1H, s) Example 24h: 1H NMR (400.13 MHz, DMSO-d6) δ 1.24 (3H, d), 2.38 (3H, s), 3.25 (1H, d), 3.48-3.53 (1H, m), 3.63– 3.67 (1H, m), 3.78 (1H, d), 3.97–4.01 (1H, m), 4.17 (1H, d), 4.32 (2H, d), 4.48 (2H, s), 4.49 (1H, s), 6.16 (1H, d), 6.71 (1H, t), 6.78 (1H , s), 7.50–7.53 (2H, m), 8.21–8.24 (2H, m), 8.91 (1H, s)

Ejemplo 24i: RMN 1H (400,13 MHz, DMSO–d6) δ 1,24 (3H, d), 2,88 (6H, s), 3,21 (3H, s), 3,25 (1H, d), 3,50–3,53 (1H, m), 3,63–3,67 (1H, m), 3,78 (1H, d), 3,97–4,01 (1H, m), 4,17 (1H, d), 4,25 (2H, d), 4,48 (1H, d), 4,49 (2H, s), 6,59 (2H, t), 6,63 (1H, d), 6,68 (1H, d), 6,78 (1H, s), 7,14 (1H, t), 7,51 (2H, d), 8,22 (2H, d), 8,77 (1H, s) Example 24i: 1H NMR (400.13 MHz, DMSO-d6) δ 1.24 (3H, d), 2.88 (6H, s), 3.21 (3H, s), 3.25 (1H, d ), 3.50–3.53 (1H, m), 3.63–3.67 (1H, m), 3.78 (1H, d), 3.97–4.01 (1H, m), 4.17 (1H, d), 4.25 (2H, d), 4.48 (1H, d), 4.49 (2H, s), 6.59 (2H, t), 6.63 (1H , d), 6.68 (1H, d), 6.78 (1H, s), 7.14 (1H, t), 7.51 (2H, d), 8.22 (2H, d), 8 , 77 (1H, s)

Ejemplo 24j: RMN 1H (400,13 MHz, DMSO–d6) δ 1,24 (3H, d), 3,21 (3H, d), 3,23–3,26 (1H, m), 3,47–3,53 (1H, m), 3,63–3,67 (1H, m), 3,78 (1H, d), 3,97–4,01 (1H, m), 4,17 (1H, s), 4,49 (1H, d), 4,49 (2H, s), 4,54 (2H, d), 6,78 (1H, s), 6,80 (1H, t), 7,50–7,54 (2H, m), 7,79 (1H, d), 8,21–8,24 (2H, m), 8,87 (1H, s), 8,97 (1H, d) Example 24j: 1H NMR (400.13 MHz, DMSO-d6) δ 1.24 (3H, d), 3.21 (3H, d), 3.23-3.26 (1H, m), 3.47 –3.53 (1H, m), 3.63–3.67 (1H, m), 3.78 (1H, d), 3.97–4.01 (1H, m), 4.17 (1H , s), 4.49 (1H, d), 4.49 (2H, s), 4.54 (2H, d), 6.78 (1H, s), 6.80 (1H, t), 7 , 50–7.54 (2H, m), 7.79 (1H, d), 8.21–8.24 (2H, m), 8.87 (1H, s), 8.97 (1H, d )

Ejemplo 24k: RMN 1H (400,13 MHz, DMSO–d6) δ 1,25 (3H, d), 2,69 (3H, d), 3,19 (1H, d), 3,25 (3H, s), 3,48 (1H, d), 3,63 (1H, d), 3,77 (1H, d), 3,96–3,99 (1H, m), 4,12 (1H, s), 4,44 (1H, m), 4,48 (2H, s), 6,49 (1H, d), 6,72 (1H, s), 6,78 (1H, s), 8,44 (1H, d), 9,30 (1H, s) Example 24k: 1H NMR (400.13 MHz, DMSO-d6) δ 1.25 (3H, d), 2.69 (3H, d), 3.19 (1H, d), 3.25 (3H, s ), 3.48 (1H, d), 3.63 (1H, d), 3.77 (1H, d), 3.96-3.99 (1H, m), 4.12 (1H, s) , 4.44 (1H, m), 4.48 (2H, s), 6.49 (1H, d), 6.72 (1H, s), 6.78 (1H, s), 8.44 ( 1H, d), 9.30 (1H, s)

Ejemplo 24l: RMN 1H (400,13 MHz, DMSO–d6) δ 1,08 (3H, t), 1,25 (3H, d), 3,12–3,19 (2H, m), 3,23 (3H, s), 3,24 (1H, m), 3,45–3,52 (1H, m), 3,62–3,65 (1H, m), 3,76 (1H, d), 3,95–3,99 (1H, m), 4,12 (1H, s), 4,45 (1H, m), 4,48 (2H, s), 6,46 (1H, d), 6,78 (1H, s), 6,89 (1H, s), 8,44 (1H, d), 9,22 (1H, s) Example 24l: 1H NMR (400.13 MHz, DMSO-d6) δ 1.08 (3H, t), 1.25 (3H, d), 3.12-3.19 (2H, m), 3.23 (3H, s), 3.24 (1H, m), 3.45-3.52 (1H, m), 3.62-3.65 (1H, m), 3.76 (1H, d), 3.95-3.99 (1H, m), 4.12 (1H, s), 4.45 (1H, m), 4.48 (2H, s), 6.46 (1H, d), 6 , 78 (1H, s), 6.89 (1H, s), 8.44 (1H, d), 9.22 (1H, s)

Ejemplo 24m: RMN 1H (400,13 MHz, DMSO–d6) δ 0,39–0,43 (2H, m), 0,64–0,69 (2H, m), 1,25 (3H, d), 2,56–2,60 (1H, m), 3,22 (3H, s), 3,25 (1H, m), 3,45–3,52 (1H, m), 3,62–3,66 (1H, m), 3,77 (1H, d), 3,95–3,99 (1H, m), 4,12 (1H, s), 4,45 (1H, s), 4,48 (2H, s), 6,47 (1H, d), 6,78 (1H, s), 7,09 (1H, s), 8,44 (1H, d), 9,16 (1H, s) Example 24m: 1H NMR (400.13 MHz, DMSO-d6) δ 0.39-0.43 (2H, m), 0.64-0.69 (2H, m), 1.25 (3H, d) , 2.56-2.60 (1H, m), 3.22 (3H, s), 3.25 (1H, m), 3.45-3.52 (1H, m), 3.62-3 , 66 (1H, m), 3.77 (1H, d), 3.95-3.99 (1H, m), 4.12 (1H, s), 4.45 (1H, s), 4, 48 (2H, s), 6.47 (1H, d), 6.78 (1H, s), 7.09 (1H, s), 8.44 (1H, d), 9.16 (1H, s )

Ejemplo 24n: RMN 1H (400,13 MHz, DMSO–d6) δ 1,16 (3H, d), 1,18–1,24 (2H, m), 1,64 (6H, s), 1,77 (2H, d), 2,54 (3H, d), 2,98 (3H, s), 3,02 (2H, t), 3,08–3,12 (1H, m), 3,39–3,45 (1H, m), 3,55–3,60 (1H, m), 3,62–3,66 (1H, m), 3,69– 3,74 (1H, m), 3,90–3,93 (1H, m), 3,98 (1H, d), 4,36 (1H, d), 4,42 (2H, d), 5,57 (1H, q), 5,82 (1H, s), 6,14 (1H, s) Example 24n: 1H NMR (400.13 MHz, DMSO-d6) δ 1.16 (3H, d), 1.18-1.24 (2H, m), 1.64 (6H, s), 1.77 (2H, d), 2.54 (3H, d), 2.98 (3H, s), 3.02 (2H, t), 3.08–3.12 (1H, m), 3.39– 3.45 (1H, m), 3.55-3.60 (1H, m), 3.62-3.66 (1H, m), 3.69-3.74 (1H, m), 3, 90–3.93 (1H, m), 3.98 (1H, d), 4.36 (1H, d), 4.42 (2H, d), 5.57 (1H, q), 5.82 (1H, s), 6.14 (1H, s)

Ejemplo 24o: RMN 1H (400,13 MHz, DMSO–d6) δ 0,98 (3H, t), 1,15 (3H, t), 1,20–1,27 (2H, m), 1,64 (6H, s), 1,77 (2H, d), 2,98 (4H, s), 3,00–3,02 (2H, m), 3,05 (1H, d), 3,08–3,12 (1H, m), 3,39–3,45 (1H, m), 3,55–3,60 (1H, m), 3,64 (1H, d), 3,71 (1H, d), 3,90–3,93 (1H, m), 3,99 (1H, d), 4,36 (1H, d), 4,42 (2H, d), 5,64 (1H, t), 5,76 (1H, d), 6,14 (1H, s) Example 24o: 1H NMR (400.13 MHz, DMSO-d6) δ 0.98 (3H, t), 1.15 (3H, t), 1.20-1.27 (2H, m), 1.64 (6H, s), 1.77 (2H, d), 2.98 (4H, s), 3.00–3.02 (2H, m), 3.05 (1H, d), 3.08– 3.12 (1H, m), 3.39-3.45 (1H, m), 3.55-3.60 (1H, m), 3.64 (1H, d), 3.71 (1H, d), 3.90–3.93 (1H, m), 3.99 (1H, d), 4.36 (1H, d), 4.42 (2H, d), 5.64 (1H, t ), 5.76 (1H, d), 6.14 (1H, s)

Ejemplo 24p: RMN 1H (400,13 MHz, DMSO–d6) δ 0,29–0,33 (2H, m), 0,53–0,57 (2H, m), 1,16 (3H, d), 1,31 (2H, m), 1,64 (6H, s), 1,76 (2H, d), 2,09 (3H, s), 2,37–2,43 (1H, m), 2,75 (1H, s), 2,98 (3H, s), 2,96–3,01 (1H, m), 3,05–3,12 (1H, m), 3,39–3,45 (1H, m), 3,55–3,59 (1H, m), 3,66 (1H, t), 3,71 (1H, d), 3,90–3,93 (1H, m), 3,99 (1H, d), 4,36 (1H, d), 4,44 (2H, d), 5,72 (1H, d), 5,97 (1H, d), 6,14 (1H, s) Example 24p: 1H NMR (400.13 MHz, DMSO-d6) δ 0.29-0.33 (2H, m), 0.53-0.57 (2H, m), 1.16 (3H, d) , 1.31 (2H, m), 1.64 (6H, s), 1.76 (2H, d), 2.09 (3H, s), 2.37-2.43 (1H, m), 2.75 (1H, s), 2.98 (3H, s), 2.96-3.01 (1H, m), 3.05-3.12 (1H, m), 3.39-3, 45 (1H, m), 3.55-3.59 (1H, m), 3.66 (1H, t), 3.71 (1H, d), 3.90-3.93 (1H, m) , 3.99 (1H, d), 4.36 (1H, d), 4.44 (2H, d), 5.72 (1H, d), 5.97 (1H, d), 6.14 ( 1H, s)

Ejemplo 24q: RMN 1H (400,13 MHz, DMSO–d6) δ 1,16 (3H, d), 1,18–1,27 (2H, m), 1,64 (6H, s), 1,78 (2H, d), 2,98 (3H, s), 3,00 (1H, s), 3,03 (1H, d), 3,08–3,12 (1H, m), 3,39–3,45 (1H, m), 3,58 (1H, d), 3,65 (1H, t), 3,71 (1H, t), 3,78 (3H, s), 3,89–3,93 (1H, m), 4,00 (3H, d), 4,35 (1H, s), 4,41 (2H, d), 5,82 (1H, d), 5,89 (1H, t), 6,14 (1H, s), 7,28 (1H, s), 7,51 (1H, s) Example 24q: 1H NMR (400.13 MHz, DMSO-d6) δ 1.16 (3H, d), 1.18-1.27 (2H, m), 1.64 (6H, s), 1.78 (2H, d), 2.98 (3H, s), 3.00 (1H, s), 3.03 (1H, d), 3.08–3.12 (1H, m), 3.39– 3.45 (1H, m), 3.58 (1H, d), 3.65 (1H, t), 3.71 (1H, t), 3.78 (3H, s), 3.89-3 , 93 (1H, m), 4.00 (3H, d), 4.35 (1H, s), 4.41 (2H, d), 5.82 (1H, d), 5.89 (1H, t), 6.14 (1H, s), 7.28 (1H, s), 7.51 (1H, s)

Ejemplo 24r: RMN 1H (400,13 MHz, DMSO–d6) δ 0,47–0,50 (2H, m), 0,66–0,71 (2H, m), 1,25 (3H, d), 2,61–2,67 (1H, m), 3,47–3,53 (1H, m), 3,63–3,67 (1H, m), 3,77 (1H, d), 3,96–4,00 (1H, m), 4,19 (1H, d), 4,49 (3H, d), 6,83 (1H, s), 7,54 (1H, d), 8,10 (1H, s), 8,48–8,51 (1H, m), 9,09 (1H, d), 9,32 (1H, s) Example 24r: 1H NMR (400.13 MHz, DMSO-d6) δ 0.47-0.50 (2H, m), 0.66-0.71 (2H, m), 1.25 (3H, d) , 2.61-2.67 (1H, m), 3.47-3.53 (1H, m), 3.63-3.67 (1H, m), 3.77 (1H, d), 3 , 96–4.00 (1H, m), 4.19 (1H, d), 4.49 (3H, d), 6.83 (1H, s), 7.54 (1H, d), 8, 10 (1H, s), 8.48-8.51 (1H, m), 9.09 (1H, d), 9.32 (1H, s)

Ejemplo 24s: RMN 1H (400,13 MHz, DMSO–d6) δ 1,24 (3H, d), 1,78 (6H, s), 3,04 (3H, s), 3,19–3,25 (1H, m), 3,47– 3,54 (1H, m), 3,64–3,67 (1H, m), 3,78 (1H, d), 3,97–4,01 (1H, m), 4,25 (1H, d), 4,61 (1H, s), 6,77 (1H, s), 6,87 (1H, d), 7,58 (2H, d), 8,31 (2H, d), 8,75 (1H, d), 9,07 (1H, s), 9,61 (1H, s) Example 24s: 1H NMR (400.13 MHz, DMSO-d6) δ 1.24 (3H, d), 1.78 (6H, s), 3.04 (3H, s), 3.19-3.25 (1H, m), 3.47-3.54 (1H, m), 3.64-3.67 (1H, m), 3.78 (1H, d), 3.97-4.01 (1H , m), 4.25 (1H, d), 4.61 (1H, s), 6.77 (1H, s), 6.87 (1H, d), 7.58 (2H, d), 8 , 31 (2H, d), 8.75 (1H, d), 9.07 (1H, s), 9.61 (1H, s)

Ejemplo 24t: RMN 1H (400,13 MHz, DMSO–d6) δ 1,24 (3H, d), 1,78 (6H, d), 2,38 (3H, d), 3,04 (3H, s), 3,19–3,25 (1H, m), 3,47–3,54 (1H, m), 3,64–3,67 (1H, m), 3,78 (1H, d), 3,97–4,01 (1H, m), 4,24 (1H, d), 4,61 (1H, d), 6,57 (1H, d), 6,77 (1H, s), 7,55–7,58 (2H, m), 8,31 (2H, d), 9,05 (1H, s), 9,46 (1H, s) Example 24t: 1H NMR (400.13 MHz, DMSO-d6) δ 1.24 (3H, d), 1.78 (6H, d), 2.38 (3H, d), 3.04 (3H, s ), 3.19-3.25 (1H, m), 3.47-3.54 (1H, m), 3.64-3.67 (1H, m), 3.78 (1H, d), 3.97-4.01 (1H, m), 4.24 (1H, d), 4.61 (1H, d), 6.57 (1H, d), 6.77 (1H, s), 7 , 55–7.58 (2H, m), 8.31 (2H, d), 9.05 (1H, s), 9.46 (1H, s)

Ejemplo 24u: RMN 1H (400,13 MHz, DMSO–d6) δ 1,24 (3H, d), 1,78 (6H, d), 3,04 (3H, s), 3,19–3,25 (1H, m), 3,47– 3,53 (1H, m), 3,64–3,67 (1H, m), 3,78 (1H, d), 3,83 (3H, s), 3,97–4,00 (1H, m), 4,24 (1H, d), 4,61 (1H, s), 6,76 (1H, s), 6,80 (1H, d), 7,57 (2H, d), 7,83–7,86 (1H, m), 8,21 (1H, d), 8,29 (2H, d), 8,62 (1H, s), 8,97 (1H, s) Example 24u: 1H NMR (400.13 MHz, DMSO-d6) δ 1.24 (3H, d), 1.78 (6H, d), 3.04 (3H, s), 3.19-3.25 (1H, m), 3.47-3.53 (1H, m), 3.64-3.67 (1H, m), 3.78 (1H, d), 3.83 (3H, s), 3.97-4.00 (1H, m), 4.24 (1H, d), 4.61 (1H, s), 6.76 (1H, s), 6.80 (1H, d), 7 , 57 (2H, d), 7.83–7.86 (1H, m), 8.21 (1H, d), 8.29 (2H, d), 8.62 (1H, s), 8, 97 (1H, s)

Ejemplo 24v: RMN 1H (400,13 MHz, DMSO–d6) δ 1,25 (3H, d), 1,79 (6H, d), 3,04 (3H, s), 3,19–3,26 (1H, m), 3,47– 3,54 (1H, m), 3,64–3,67 (1H, m), 3,78 (1H, d), 3,97–4,00 (1H, m), 4,25 (1H, d), 4,63 (1H, s), 5,42 (1H, s), 5,90 (1H, d), 6,78 (1H, s), 7,84 (2H, d), 8,06 (1H, d), 8,34 (2H, d), 9,84 (1H, s) Example 24v: 1H NMR (400.13 MHz, DMSO-d6) δ 1.25 (3H, d), 1.79 (6H, d), 3.04 (3H, s), 3.19–3.26 (1H, m), 3.47-3.54 (1H, m), 3.64-3.67 (1H, m), 3.78 (1H, d), 3.97-4.00 (1H , m), 4.25 (1H, d), 4.63 (1H, s), 5.42 (1H, s), 5.90 (1H, d), 6.78 (1H, s), 7 , 84 (2H, d), 8.06 (1H, d), 8.34 (2H, d), 9.84 (1H, s)

Ejemplo 24w: RMN 1H (400,13 MHz, DMSO–d6) δ 1,25 (3H, d), 1,78 (6H, d), 3,04 (3H, s), 3,20–3,25 (1H, m), 3,47– 3,54 (1H, m), 3,64–3,67 (1H, m), 3,78 (1H, d), 3,97–4,01 (1H, m), 4,24 (1H, d), 4,61 (1H, s), 6,76 (1H, s), 6,99 (1H, t), 7,30 (2H, d), 7,47 (2H, d), 7,57 (2H, d), 8,30 (2H, d), 8,71 (1H, s), 8,91 (1H, s) Example 24w: 1H NMR (400.13 MHz, DMSO-d6) δ 1.25 (3H, d), 1.78 (6H, d), 3.04 (3H, s), 3.20–3.25 (1H, m), 3.47-3.54 (1H, m), 3.64-3.67 (1H, m), 3.78 (1H, d), 3.97-4.01 (1H , m), 4.24 (1H, d), 4.61 (1H, s), 6.76 (1H, s), 6.99 (1H, t), 7.30 (2H, d), 7 , 47 (2H, d), 7.57 (2H, d), 8.30 (2H, d), 8.71 (1H, s), 8.91 (1H, s)

Ejemplo 24x: RMN 1H (400,13 MHz, DMSO–d6) δ 1,25 (3H, d), 1,78 (6H, d), 3,04 (3H, s), 3,20–3,25 (1H, m), 3,27 (3H, s), 3,47–3,54 (1H, m), 3,64–3,67 (1H, m), 3,78 (1H, d), 3,97–4,01 (1H, m), 4,24 (1H, d), 4,61 (1H, s), 6,76 (1H, s), 6,99 (1H, t), 7,30 (2H, d), 7,47 (2H, d), 7,57 (2H, d), 8,30 (2H, d), 8,71 (1H, s), 8,91 (1H, s) 24x Example: 1H NMR (400.13 MHz, DMSO – d6) δ 1.25 (3H, d), 1.78 (6H, d), 3.04 (3H, s), 3.20–3.25 (1H, m), 3.27 (3H, s), 3.47-3.54 (1H, m), 3.64-3.67 (1H, m), 3.78 (1H, d), 3.97-4.01 (1H, m), 4.24 (1H, d), 4.61 (1H, s), 6.76 (1H, s), 6.99 (1H, t), 7 , 30 (2H, d), 7.47 (2H, d), 7.57 (2H, d), 8.30 (2H, d), 8.71 (1H, s), 8.91 (1H, s)

Ejemplo 24y: RMN 1H (400,13 MHz, DMSO–d6) δ 1,25 (3H, d), 1,78 (6H, d), 3,04 (3H, s), 3,19–3,26 (1H, m), 3,48– 3,54 (1H, m), 3,64–3,68 (1H, m), 3,78 (1H, d), 3,97–4,01 (1H, m), 4,25 (1H, d), 4,62 (1H, s), 6,77 (1H, s), 7,61 (2H, d), 7,71–7,76 (1H, m), 7,78–7,82 (1H, m), 8,29 (1H, d), 8,32 (2H, d), 9,38 (1H, s), 9,87 (1H, s) Example 24y: 1H NMR (400.13 MHz, DMSO-d6) δ 1.25 (3H, d), 1.78 (6H, d), 3.04 (3H, s), 3.19-3.26 (1H, m), 3.48– 3.54 (1H, m), 3.64–3.68 (1H, m), 3.78 (1H, d), 3.97–4.01 (1H , m), 4.25 (1H, d), 4.62 (1H, s), 6.77 (1H, s), 7.61 (2H, d), 7.71–7.76 (1H, m), 7.78–7.82 (1H, m), 8.29 (1H, d), 8.32 (2H, d), 9.38 (1H, s), 9.87 (1H, s )

Ejemplo 24z: RMN 1H (400,13 MHz, DMSO–d6) δ 1,24 (3H, d), 1,77 (6H, s), 3,00 (3H, s), 3,02–3,23 (1H, m), 3,46– 3,51 (1H, m), 3,64 (1H, d), 3,76 (1H, d), 3,80 (3H, s), 3,95–3,98 (1H, m), 4,28 (1H, m), 4,29 (2H, d), 4,63 (1H, s), 6,83 (1H, s), 7,39 (1H, s), 7,63 (1H, s), 9,25 (1H, t), 9,36 (2H, s), 10,09 (1H, s) Example 24z: 1H NMR (400.13 MHz, DMSO-d6) δ 1.24 (3H, d), 1.77 (6H, s), 3.00 (3H, s), 3.02–3.23 (1H, m), 3.46– 3.51 (1H, m), 3.64 (1H, d), 3.76 (1H, d), 3.80 (3H, s), 3.95– 3.98 (1H, m), 4.28 (1H, m), 4.29 (2H, d), 4.63 (1H, s), 6.83 (1H, s), 7.39 (1H , s), 7.63 (1H, s), 9.25 (1H, t), 9.36 (2H, s), 10.09 (1H, s)

Ejemplo 24aa: RMN 1H (399,9 MHz, DMSO–d6) δ 0,41–0,45 (2H, m), 0,63–0,68 (2H, m), 1,25 (3H, d), 2,53–2,59 (1H, m), 3,21 (3H, s), 3,25 (1H, d), 3,47–3,54 (1H, m), 3,64–3,68 (1H, m), 3,78 (1H, d), 3,97–4,01 (1H, m), 4,18 (1H, d), 4,49 (3H, s), 6,44 (1H, d), 6,78 (1H, s), 7,52 (2H, d), 8,22 (2H, d), 8,55 (1H, s) Example 24aa: 1H NMR (399.9 MHz, DMSO-d6) δ 0.41-0.45 (2H, m), 0.63-0.68 (2H, m), 1.25 (3H, d) , 2.53–2.59 (1H, m), 3.21 (3H, s), 3.25 (1H, d), 3.47–3.54 (1H, m), 3.64–3 , 68 (1H, m), 3.78 (1H, d), 3.97-4.01 (1H, m), 4.18 (1H, d), 4.49 (3H, s), 6, 44 (1H, d), 6.78 (1H, s), 7.52 (2H, d), 8.22 (2H, d), 8.55 (1H, s)

Ejemplo 24ab: RMN 1H (399,9 MHz, DMSO–d6) δ 1,25 (3H, d), 1,79 (6H, d), 2,66 (3H, d), 3,02 (3H, s), 3,20–3,27 (1H, m), 3,47–3,54 (1H, m), 3,64–3,67 (1H, m), 3,78 (1H, d), 3,97–4,01 (1H, m), 4,27 (1H, d), 4,63 (1H, s), 6,27 (1H, q), 6,86 (1H, s), 7,95–8,01 (2H, m), 8,14 (1H, s) Example 24ab: 1H NMR (399.9 MHz, DMSO-d6) δ 1.25 (3H, d), 1.79 (6H, d), 2.66 (3H, d), 3.02 (3H, s ), 3.20-3.27 (1H, m), 3.47-3.54 (1H, m), 3.64-3.67 (1H, m), 3.78 (1H, d), 3.97-4.01 (1H, m), 4.27 (1H, d), 4.63 (1H, s), 6.27 (1H, q), 6.86 (1H, s), 7 , 95–8.01 (2H, m), 8.14 (1H, s)

Ejemplo 24ac: RMN 1H (399,9 MHz, DMSO–d6) δ 1,07 (3H, t), 1,25 (3H, d), 1,79 (6H, d), 3,01 (3H, s), 3,09–3,15 (2H, m), 3,20–3,27 (1H, m), 3,47–3,54 (1H, m), 3,64–3,67 (1H, m), 3,78 (1H, d), 3,97–4,01 (1H, m), 4,27 (1H, d), 4,63 (1H, s), 6,36 (1H, t), 6,85 (1H, s), 7,95–8,01 (2H, m), 8,05 (1H, s) Example 24ac: 1H NMR (399.9 MHz, DMSO-d6) δ 1.07 (3H, t), 1.25 (3H, d), 1.79 (6H, d), 3.01 (3H, s ), 3.09-3.15 (2H, m), 3.20-3.27 (1H, m), 3.47-3.54 (1H, m), 3.64-3.67 (1H , m), 3.78 (1H, d), 3.97-4.01 (1H, m), 4.27 (1H, d), 4.63 (1H, s), 6.36 (1H, t), 6.85 (1H, s), 7.95–8.01 (2H, m), 8.05 (1H, s)

Ejemplo 24ad: RMN 1H (399,9 MHz, DMSO–d6) δ 0,43–0,47 (2H, m), 0,63–0,67 (2H, m), 1,25 (3H, d), 1,79 (6H, d), 2,53–2,58 (1H, m), 3,02 (3H, s), 3,20–3,27 (1H, m), 3,47–3,54 (1H, m), 3,64–3,67 (1H, m), 3,78 (1H, d), 3,97–4,01 (1H, m), 4,27 (1H, d), 4,63 (1H, s), 6,66 (1H, d), 6,86 (1H, s), 7,97 (2H, d), 8,00 (1H, s) Example 24ad: 1H NMR (399.9 MHz, DMSO-d6) δ 0.43–0.47 (2H, m), 0.63–0.67 (2H, m), 1.25 (3H, d) , 1.79 (6H, d), 2.53–2.58 (1H, m), 3.02 (3H, s), 3.20–3.27 (1H, m), 3.47–3 , 54 (1H, m), 3.64–3.67 (1H, m), 3.78 (1H, d), 3.97–4.01 (1H, m), 4.27 (1H, d ), 4.63 (1H, s), 6.66 (1H, d), 6.86 (1H, s), 7.97 (2H, d), 8.00 (1H, s)

Ejemplo 24ae: RMN 1H (399,9 MHz, DMSO–d6) δ 1,25 (3H, d), 1,79 (6H, d), 3,02 (3H, s), 3,20–3,27 (1H, m), 3,47– 3,54 (1H, m), 3,64–3,67 (1H, m), 3,78 (1H, d), 3,81 (3H, s), 3,97–4,01 (1H, m), 4,12 (2H, d), 4,27 (1H, d), 4,63 (1H, s), 6,63 (1H, t), 6,86 (1H, s), 7,35 (1H, d), 7,58 (1H, s), 7,97–8,01 (2H, m), 8,09 (1H, s) Example 24ae: 1H NMR (399.9 MHz, DMSO-d6) δ 1.25 (3H, d), 1.79 (6H, d), 3.02 (3H, s), 3.20–3.27 (1H, m), 3.47-3.54 (1H, m), 3.64-3.67 (1H, m), 3.78 (1H, d), 3.81 (3H, s), 3.97-4.01 (1H, m), 4.12 (2H, d), 4.27 (1H, d), 4.63 (1H, s), 6.63 (1H, t), 6 , 86 (1H, s), 7.35 (1H, d), 7.58 (1H, s), 7.97–8.01 (2H, m), 8.09 (1H, s)

Ejemplo 24af: RMN 1H (399,9 MHz, DMSO–d6) δ 1,15 (3H, t), 1,25 (3H, d), 1,78 (6H, d), 3,02 (3H, s), 3,20–3,24 (1H, m), 3,27–3,29 (2H, m), 3,47–3,53 (1H, m), 3,63–3,67 (1H, m), 3,77 (1H, d), 3,96–4,00 (1H, m), 4,28 (1H, d), 4,64 (1H, s), 6,84 (1H, s), 9,06 (1H, t), 9,39 (2H, s), 10,01 (1H, s) Example 24af: 1H NMR (399.9 MHz, DMSO-d6) δ 1.15 (3H, t), 1.25 (3H, d), 1.78 (6H, d), 3.02 (3H, s ), 3.20–3.24 (1H, m), 3.27–3.29 (2H, m), 3.47–3.53 (1H, m), 3.63–3.67 (1H , m), 3.77 (1H, d), 3.96-4.00 (1H, m), 4.28 (1H, d), 4.64 (1H, s), 6.84 (1H, s), 9.06 (1H, t), 9.39 (2H, s), 10.01 (1H, s)

Ejemplo 24ag: RMN 1H (399,9 MHz, DMSO–d6) δ 0,54–0,57 (2H, m), 0,70–0,74 (2H, m), 1,25 (3H, d), 1,78 (3H, s), 1,78 (3H, s), 2,68–2,73 (1H, m), 3,02 (3H, s), 3,19–3,27 (1H, m), 3,46–3,53 (1H, m), 3,63–3,66 (1H, m), 3,77 (1H, d), 3,96–4,00 (1H, m), 4,28 (1H, d), 4,63 (1H, s), 6,84 (1H, s), 9,13 (1H, d), 9,38 (2H, s), 10,07 (1H, s) Example 24ag: 1H NMR (399.9 MHz, DMSO – d6) δ 0.54–0.57 (2H, m), 0.70–0.74 (2H, m), 1.25 (3H, d) , 1.78 (3H, s), 1.78 (3H, s), 2.68-2.73 (1H, m), 3.02 (3H, s), 3.19-3.27 (1H , m), 3.46-3.53 (1H, m), 3.63-3.66 (1H, m), 3.77 (1H, d), 3.96-4.00 (1H, m ), 4.28 (1H, d), 4.63 (1H, s), 6.84 (1H, s), 9.13 (1H, d), 9.38 (2H, s), 10.07 (1H, s)

Ejemplo 24ah: RMN 1H (399,9 MHz, DMSO–d6) δ 1,24 (3H, d), 1,78 (3H, s), 1,78 (3H, s), 2,76 (3H, d), 3,03 (3H, s), 3,20–3,26 (1H, m), 3,47–3,54 (1H, m), 3,63–3,67 (1H, m), 3,77 (1H, d), 3,96–4,00 (1H, m), 4,25 (1H, d), 4,62 (1H, s), 6,80 (1H, s), 7,42–7,45 (1H, m), 8,15 (1H, d), 8,52–8,55 (1H, m), 9,14 (1H, d), 9,48 (1H, s) Example 24ah: 1H NMR (399.9 MHz, DMSO-d6) δ 1.24 (3H, d), 1.78 (3H, s), 1.78 (3H, s), 2.76 (3H, d ), 3.03 (3H, s), 3.20-3.26 (1H, m), 3.47-3.54 (1H, m), 3.63-3.67 (1H, m), 3.77 (1H, d), 3.96-4.00 (1H, m), 4.25 (1H, d), 4.62 (1H, s), 6.80 (1H, s), 7 , 42–7.45 (1H, m), 8.15 (1H, d), 8.52–8.55 (1H, m), 9.14 (1H, d), 9.48 (1H, s )

Ejemplo 24ai: RMN 1H (399,9 MHz, DMSO–d6) δ 1,12 (3H, t), 1,24 (3H, d), 1,78 (3H, s), 1,78 (3H, s), 3,02 (3H, s), 3,19–3,23 (2H, m), 3,24–3,26 (1H, m), 3,47–3,54 (1H, m), 3,63–3,67 (1H, m), 3,77 (1H, d), 3,96–4,00 (1H, m), 4,25 (1H, d), 4,61 (1H, s), 6,80 (1H, s), 7,46–7,49 (1H, m), 8,17 (1H, t), 8,52–8,55 (1H, m), 9,14 (1H, d), 9,40 (1H, s) Example 24ai: 1H NMR (399.9 MHz, DMSO-d6) δ 1.12 (3H, t), 1.24 (3H, d), 1.78 (3H, s), 1.78 (3H, s ), 3.02 (3H, s), 3.19-3.23 (2H, m), 3.24-3.26 (1H, m), 3.47-3.54 (1H, m), 3.63-3.67 (1H, m), 3.77 (1H, d), 3.96-4.00 (1H, m), 4.25 (1H, d), 4.61 (1H, s), 6.80 (1H, s), 7.46–7.49 (1H, m), 8.17 (1H, t), 8.52–8.55 (1H, m), 9.14 (1H, d), 9.40 (1H, s)

Ejemplo 24aj: RMN 1H (399,9 MHz, DMSO–d6) δ 0,47–0,51 (2H, m), 0,67–0,71 (2H, m), 1,24 (3H, d), 1,78 (3H, s), 1,78 (3H, s), 2,61–2,67 (1H, m), 3,02 (3H, s), 3,19–3,26 (1H, m), 3,47–3,53 (1H, m), 3,63–3,67 (1H, m), 3,77 (1H, d), 3,96–4,00 (1H, m), 4,26 (1H, d), 4,62 (1H, s), 6,80 (1H, s), 7,53 (1H, d), 8,16 (1H, s), 8,53–8,56 (1H, m), 9,13 (1H, d), 9,33 (1H, s) Example 24aj: 1H NMR (399.9 MHz, DMSO – d6) δ 0.47–0.51 (2H, m), 0.67–0.71 (2H, m), 1.24 (3H, d) , 1.78 (3H, s), 1.78 (3H, s), 2.61-2.67 (1H, m), 3.02 (3H, s), 3.19-3.26 (1H , m), 3.47-3.53 (1H, m), 3.63-3.67 (1H, m), 3.77 (1H, d), 3.96-4.00 (1H, m ), 4.26 (1H, d), 4.62 (1H, s), 6.80 (1H, s), 7.53 (1H, d), 8.16 (1H, s), 8.53 –8.56 (1H, m), 9.13 (1H, d), 9.33 (1H, s)

Ejemplo 24ak: RMN 1H (399,9 MHz, DMSO–d6) δ 0,90 (3H, t), 1,24 (3H, d), 1,42–1,49 (2H, m), 1,78 (6H, d), 3,04 (3H, s), 3,18–3,25 (1H, m), 3,47–3,54 (1H, m), 3,63–3,67 (1H, m), 3,78 (1H, d), 3,97–4,00 (1H, m), 4,24 (1H, d), 4,61 (1H, d), 6,21 (1H, t), 6,74 (1H, s), 7,49–7,52 (2H, m), 8,23–8,25 (2H, m), 8,66 (1H, s) Example 24ak: 1H NMR (399.9 MHz, DMSO-d6) δ 0.90 (3H, t), 1.24 (3H, d), 1.42-1.49 (2H, m), 1.78 (6H, d), 3.04 (3H, s), 3.18-3.25 (1H, m), 3.47-3.54 (1H, m), 3.63-3.67 (1H , m), 3.78 (1H, d), 3.97-4.00 (1H, m), 4.24 (1H, d), 4.61 (1H, d), 6.21 (1H, t), 6.74 (1H, s), 7.49–7.52 (2H, m), 8.23–8.25 (2H, m), 8.66 (1H, s)

Ejemplo 24al: RMN 1H (399,9 MHz, DMSO–d6) δ 1,12 (6H, d), 1,24 (3H, d), 1,77 (3H, s), 1,78 (3H, s), 3,04 (3H, s), 3,21–3,24 (1H, m), 3,48–3,53 (1H, m), 3,63–3,67 (1H, m), 3,76–3,81 (2H, m), 3,97–4,00 (1H, m), 4,24 (1H, d), 4,60 (1H, d), 6,07 (1H, d), 6,74 (1H, s), 7,47–7,51 (2H, m), 8,23 (2H, d), 8,55 (1H, s) 24al Example: 1H NMR (399.9 MHz, DMSO-d6) δ 1.12 (6H, d), 1.24 (3H, d), 1.77 (3H, s), 1.78 (3H, s ), 3.04 (3H, s), 3.21-3.24 (1H, m), 3.48-3.53 (1H, m), 3.63-3.67 (1H, m), 3.76-3.81 (2H, m), 3.97-4.00 (1H, m), 4.24 (1H, d), 4.60 (1H, d), 6.07 (1H, d), 6.74 (1H, s), 7.47–7.51 (2H, m), 8.23 (2H, d), 8.55 (1H, s)

Ejemplo 24am: RMN 1H (399,9 MHz, DMSO–d6) δ 1,24 (3H, d), 1,59–1,66 (2H, m), 1,78 (6H, d), 1,84–1,89 (2H, m), 2,19–2,25 (2H, m), 3,04 (3H, s), 3,21–3,25 (1H, m), 3,48–3,53 (1H, m), 3,63–3,67 (1H, m), 3,78 (1H, d), 3,97–4,00 (1H, m), 4,15 (1H, q), 4,23 (1H, d), 4,60 (1H, d), 6,47 (1H, d), 6,74 (1H, s), 7,49 (2H, d), 8,24 (2H, d), 8,58 (1H, s) Example 24am: 1H NMR (399.9 MHz, DMSO-d6) δ 1.24 (3H, d), 1.59-1.66 (2H, m), 1.78 (6H, d), 1.84 –1.89 (2H, m), 2.19–2.25 (2H, m), 3.04 (3H, s), 3.21–3.25 (1H, m), 3.48–3 , 53 (1H, m), 3.63-3.67 (1H, m), 3.78 (1H, d), 3.97-4.00 (1H, m), 4.15 (1H, q ), 4.23 (1H, d), 4.60 (1H, d), 6.47 (1H, d), 6.74 (1H, s), 7.49 (2H, d), 8.24 (2H, d), 8.58 (1H, s)

Ejemplo 24an: RMN 1H (399,9 MHz, DMSO–d6) δ 1,24 (3H, d), 1,25–1,25 (5H, m), 1,78 (6H, s), 3,04 (3H, s), 3,19– 3,24 (1H, m), 3,40 (2H, d), 3,50 (1H, d), 3,63–3,67 (1H, m), 3,78 (1H, d), 3,97–4,01 (1H, m), 4,24 (1H, d), 4,59 (1H, s), 4,96 (1H, t), 6,01 (1H, s), 6,74 (1H, s), 7,46 (2H, d), 8,23 (2H, d), 8,74 (1H, s) Example 24an: 1H NMR (399.9 MHz, DMSO-d6) δ 1.24 (3H, d), 1.25-1.25 (5H, m), 1.78 (6H, s), 3.04 (3H, s), 3.19– 3.24 (1H, m), 3.40 (2H, d), 3.50 (1H, d), 3.63–3.67 (1H, m), 3.78 (1H, d), 3.97-4.01 (1H, m), 4.24 (1H, d), 4.59 (1H, s), 4.96 (1H, t), 6 , 01 (1H, s), 6.74 (1H, s), 7.46 (2H, d), 8.23 (2H, d), 8.74 (1H, s)

Ejemplo 24ao: RMN 1H (399,9 MHz, DMSO–d6) δ 1,24 (3H, d), 1,78 (6H, d), 3,04 (3H, s), 3,19–3,25 (1H, m), 3,47– 3,54 (1H, m), 3,63–3,67 (1H, m), 3,78 (1H, d), 3,97–4,00 (1H, m), 4,24 (1H, d), 4,36 (2H, d), 4,60 (1H, d), 6,75 (1H, s), 6,78 (1H, t), 7,36–7,39 (1H, m), 7,53 (2H, d), 7,72–7,75 (1H, m), 8,25 (2H, d), 8,46–8,48 (1H, m), 8,55 (1H, d), 8,88 (1H, s) Example 24ao: 1H NMR (399.9 MHz, DMSO-d6) δ 1.24 (3H, d), 1.78 (6H, d), 3.04 (3H, s), 3.19-3.25 (1H, m), 3.47-3.54 (1H, m), 3.63-3.67 (1H, m), 3.78 (1H, d), 3.97-4.00 (1H , m), 4.24 (1H, d), 4.36 (2H, d), 4.60 (1H, d), 6.75 (1H, s), 6.78 (1H, t), 7 , 36–7.39 (1H, m), 7.53 (2H, d), 7.72–7.75 (1H, m), 8.25 (2H, d), 8.46–8.48 (1H, m), 8.55 (1H, d), 8.88 (1H, s)

Ejemplo 24ap: RMN 1H (399,9 MHz, DMSO–d6) δ 1,09 (3H, d), 1,24 (3H, d), 1,77 (3H, s), 1,78 (3H, s), 3,04 (3H, s), 3,19–3,25 (1H, m), 3,34–3,42 (2H, m), 3,47–3,54 (1H, m), 3,65 (1H, d), 3,70–3,74 (1H, m), 3,78 (1H, d), 3,97–4,00 (1H, m), 4,24 (1H, d), 4,60 (1H, s), 4,79 (1H, t), 6,10 (1H, d), 6,74 (1H, s), 7,49 (2H, d), 8,24 (2H, d), 8,73 (1H, s) Example 24ap: 1H NMR (399.9 MHz, DMSO-d6) δ 1.09 (3H, d), 1.24 (3H, d), 1.77 (3H, s), 1.78 (3H, s ), 3.04 (3H, s), 3.19-3.25 (1H, m), 3.34-3.42 (2H, m), 3.47-3.54 (1H, m), 3.65 (1H, d), 3.70-3.74 (1H, m), 3.78 (1H, d), 3.97-4.00 (1H, m), 4.24 (1H, d), 4.60 (1H, s), 4.79 (1H, t), 6.10 (1H, d), 6.74 (1H, s), 7.49 (2H, d), 8, 24 (2H, d), 8.73 (1H, s)

Ejemplo 24aq: RMN 1H (399,9 MHz, DMSO–d6) δ 0,18–0,22 (2H, m), 0,42–0,47 (2H, m), 0,94–0,98 (1H, m), 1,24 (3H, d), 1,77 (3H, s), 1,78 (3H, s), 3,00 (2H, t), 3,04 (3H, s), 3,18–3,25 (1H, m), 3,47–3,54 (1H, m), 3,63–3,67 (1H, m), 3,78 (1H, d), 3,97–4,00 (1H, m), 4,24 (1H, d), 4,60 (1H, s), 6,27 (1H, t), 6,74 (1H, s), 7,50 (2H, d), 8,24 (2H, d), 8,70 (1H, s) Example 24aq: 1H NMR (399.9 MHz, DMSO – d6) δ 0.18–0.22 (2H, m), 0.42–0.47 (2H, m), 0.94–0.98 ( 1H, m), 1.24 (3H, d), 1.77 (3H, s), 1.78 (3H, s), 3.00 (2H, t), 3.04 (3H, s), 3.18-3.25 (1H, m), 3.47-3.54 (1H, m), 3.63-3.67 (1H, m), 3.78 (1H, d), 3, 97-4.00 (1H, m), 4.24 (1H, d), 4.60 (1H, s), 6.27 (1H, t), 6.74 (1H, s), 7.50 (2H, d), 8.24 (2H, d), 8.70 (1H, s)

Ejemplo 24ar: RMN 1H (400,13 MHz, DMSO–d6) δ 1,23 (3H, d), 1,76 (3H, s), 1,77 (3H, s), 3,04 (3H, s), 3,20–3,24 (1H, m), 3,46–3,52 (1H, m), 3,62–3,66 (1H, m), 3,77 (1H, d), 3,96–4,00 (1H, m), 4,24 (1H, d), 4,36 (2H, d), 4,60 (1H, s), 6,74 (1H, s), 6,83 (1H, t), 7,30–7,31 (2H, m), 7,51–7,55 (2H, m), 8,23–8,26 (2H, m), 8,51–8,52 (2H, m), 9,01 (1H, s) Example 24ar: 1H NMR (400.13 MHz, DMSO-d6) δ 1.23 (3H, d), 1.76 (3H, s), 1.77 (3H, s), 3.04 (3H, s ), 3.20-3.24 (1H, m), 3.46-3.52 (1H, m), 3.62-3.66 (1H, m), 3.77 (1H, d), 3.96-4.00 (1H, m), 4.24 (1H, d), 4.36 (2H, d), 4.60 (1H, s), 6.74 (1H, s), 6 , 83 (1H, t), 7.30–7.31 (2H, m), 7.51–7.55 (2H, m), 8.23–8.26 (2H, m), 8.51 –8.52 (2H, m), 9.01 (1H, s)

Ejemplo 24as: RMN 1H (400,13 MHz, DMSO–d6) δ 1,23 (3H, d), 1,56–1,62 (2H, m), 1,76 (3H, s), 1,77 (3H, s), 3,04 (3H, s), 3,14–3,19 (2H, m), 3,20–3,24 (1H, m), 3,44–3,47 (2H, m), 3,49–3,52 (1H, m), 3,62–3,66 (1H, m), 3,77 (1H, d), 3,96–4,00 (1H, m), 4,22 (1H, s), 4,52 (1H, t), 4,59 (1H, s), 6,22 (1H, t), 6,74 (1H, s), 7,48–7,51 (2H, m), 8,23 (2H, d), 8,75 (1H, s) Example 24as: 1H NMR (400.13 MHz, DMSO-d6) δ 1.23 (3H, d), 1.56-1.62 (2H, m), 1.76 (3H, s), 1.77 (3H, s), 3.04 (3H, s), 3.14–3.19 (2H, m), 3.20–3.24 (1H, m), 3.44–3.47 (2H , m), 3.49-3.52 (1H, m), 3.62-3.66 (1H, m), 3.77 (1H, d), 3.96-4.00 (1H, m ), 4.22 (1H, s), 4.52 (1H, t), 4.59 (1H, s), 6.22 (1H, t), 6.74 (1H, s), 7.48 –7.51 (2H, m), 8.23 (2H, d), 8.75 (1H, s)

Ejemplo 24at: RMN 1H (400,13 MHz, DMSO–d6) δ 0,88 (6H, d), 1,22 (3H, t), 1,66–1,73 (1H, m), 1,74–1,76 (3H, m), 1,77 (3H, s), 2,94 (2H, t), 3,04 (3H, s), 3,20–3,24 (1H, m), 3,46–3,53 (1H, m), 3,62–3,66 (1H, m), 3,77 (1H, d), 3,96– 4,00 (1H, m), 4,22 (1H, s), 4,60 (1H, s), 6,26 (1H, t), 6,74 (1H, s), 7,48–7,51 (2H, m), 8,23 (2H, d), 8,68 (1H, s) Example 24at: 1H NMR (400.13 MHz, DMSO-d6) δ 0.88 (6H, d), 1.22 (3H, t), 1.66-1.73 (1H, m), 1.74 –1.76 (3H, m), 1.77 (3H, s), 2.94 (2H, t), 3.04 (3H, s), 3.20–3.24 (1H, m), 3.46-3.53 (1H, m), 3.62-3.66 (1H, m), 3.77 (1H, d), 3.96-4.00 (1H, m), 4, 22 (1H, s), 4.60 (1H, s), 6.26 (1H, t), 6.74 (1H, s), 7.48-7.51 (2H, m), 8.23 (2H, d), 8.68 (1H, s)

Ejemplo 24au: RMN 1H (400,13 MHz, DMSO–d6) δ 1,23 (3H, d), 1,76 (3H, s), 1,77 (3H, s), 3,04 (3H, s), 3,17–3,24 (1H, m), 3,46–3,53 (1H, m), 3,62–3,66 (1H, m), 3,77 (1H, d), 3,96–4,00 (1H, m), 4,24 (1H, d), 4,32 (2H, d), 4,60 (1H, s), 6,64 (1H, t), 6,74 (1H, s), 6,83 (1H, s), 7,04 (1H, s), 7,50–7,53 (2H, m), 8,22–8,26 (2H, m), 8,96 (1H, s), 11,87 (1H, s) Example 24au: 1H NMR (400.13 MHz, DMSO-d6) δ 1.23 (3H, d), 1.76 (3H, s), 1.77 (3H, s), 3.04 (3H, s ), 3.17-3.24 (1H, m), 3.46-3.53 (1H, m), 3.62-3.66 (1H, m), 3.77 (1H, d), 3.96-4.00 (1H, m), 4.24 (1H, d), 4.32 (2H, d), 4.60 (1H, s), 6.64 (1H, t), 6 , 74 (1H, s), 6.83 (1H, s), 7.04 (1H, s), 7.50–7.53 (2H, m), 8.22–8.26 (2H, m ), 8.96 (1H, s), 11.87 (1H, s)

Ejemplo 24av: RMN 1H (400,13 MHz, DMSO–d6) δ 1,23 (3H, d), 1,76 (3H, s), 1,77 (3H, s), 3,04 (3H, s), 3,17–3,24 (1H, m), 3,46–3,53 (1H, m), 3,62–3,66 (1H, m), 3,76 (1H, s), 3,79 (3H, s), 3,96–4,00 (1H, m), 4,12 (2H, d), 4,23 (1H, s), 4,60 (1H, s), 6,44 (1H, t), 6,74 (1H, s), 7,35 (1H, s), 7,50 (2H, d), 7,60 (1H, s), 8,24 (2H, d), 8,74 (1H, s) Example 24av: 1H NMR (400.13 MHz, DMSO-d6) δ 1.23 (3H, d), 1.76 (3H, s), 1.77 (3H, s), 3.04 (3H, s ), 3.17-3.24 (1H, m), 3.46-3.53 (1H, m), 3.62-3.66 (1H, m), 3.76 (1H, s), 3.79 (3H, s), 3.96-4.00 (1H, m), 4.12 (2H, d), 4.23 (1H, s), 4.60 (1H, s), 6 , 44 (1H, t), 6.74 (1H, s), 7.35 (1H, s), 7.50 (2H, d), 7.60 (1H, s), 8.24 (2H, d), 8.74 (1H, s)

Ejemplo 24aw: RMN 1H (400,13 MHz, DMSO–d6) δ 1,23 (3H, d), 1,76 (3H, s), 1,77 (3H, s), 2,38 (3H, d), 3,04 (3H, s), 3,17–3,24 (1H, m), 3,46–3,53 (1H, m), 3,62–3,66 (1H, m), 3,77 (1H, d), 3,96–4,00 (1H, m), 4,24 (1H, d), 4,32 (2H, d), 4,60 (1H, s), 6,16 (1H, d), 6,71 (1H, s), 6,74 (1H, s), 7,52 (2H, d), 8,25 (2H, d), 8,96 (1H, s) Example 24aw: 1H NMR (400.13 MHz, DMSO-d6) δ 1.23 (3H, d), 1.76 (3H, s), 1.77 (3H, s), 2.38 (3H, d ), 3.04 (3H, s), 3.17-3.24 (1H, m), 3.46-3.53 (1H, m), 3.62-3.66 (1H, m), 3.77 (1H, d), 3.96-4.00 (1H, m), 4.24 (1H, d), 4.32 (2H, d), 4.60 (1H, s), 6 , 16 (1H, d), 6.71 (1H, s), 6.74 (1H, s), 7.52 (2H, d), 8.25 (2H, d), 8.96 (1H, s)

Ejemplo 24ax: RMN 1H (400,13 MHz, DMSO–d6) δ 1,22 (3H, d), 1,44 (3H, d), 1,76 (3H, s), 1,76 (3H, s), 3,03 (3H, s), 3,19–3,24 (1H, m), 3,45–3,52 (1H, m), 3,62–3,65 (1H, m), 3,77 (1H, d), 3,95–3,99 (1H, m), 4,23 (1H, d), 4,59 (1H, s), 4,88 (1H, t), 6,74 (1H, s), 6,81 (1H, d), 7,36–7,39 (1H, m), 7,48 (2H, d), 7,75–7,78 (1H, m), 8,23 (2H, d), 8,45–8,47 (1H, m), 8,59 (1H, d), 8,71 (1H, s) 24ax example: 1H NMR (400.13 MHz, DMSO-d6) δ 1.22 (3H, d), 1.44 (3H, d), 1.76 (3H, s), 1.76 (3H, s ), 3.03 (3H, s), 3.19-3.24 (1H, m), 3.45-3.52 (1H, m), 3.62-3.65 (1H, m), 3.77 (1H, d), 3.95–3.99 (1H, m), 4.23 (1H, d), 4.59 (1H, s), 4.88 (1H, t), 6 , 74 (1H, s), 6.81 (1H, d), 7.36–7.39 (1H, m), 7.48 (2H, d), 7.75–7.78 (1H, m ), 8.23 (2H, d), 8.45-8.47 (1H, m), 8.59 (1H, d), 8.71 (1H, s)

Ejemplo 24ay: RMN 1H (400,13 MHz, DMSO–d6) δ 1,23 (3H, d), 1,76 (3H, s), 1,77 (3H, s), 3,04 (3H, s), 3,17–3,24 (1H, m), 3,46–3,53 (1H, m), 3,62–3,66 (1H, m), 3,77 (1H, d), 3,96–4,00 (1H, m), 4,22–4,33 (1H, m), 4,28 (2H, d), 4,60 (1H, s), 6,18 (1H, s), 6,52 (1H, s), 6,74 (1H, s), 7,51 (2H, d), 7,67 (1H, s), 8,25 (2H, d), 8,84 (1H, s), 12,64 (1H, s) Example 24a: 1H NMR (400.13 MHz, DMSO-d6) δ 1.23 (3H, d), 1.76 (3H, s), 1.77 (3H, s), 3.04 (3H, s ), 3.17-3.24 (1H, m), 3.46-3.53 (1H, m), 3.62-3.66 (1H, m), 3.77 (1H, d), 3.96-4.00 (1H, m), 4.22-4.33 (1H, m), 4.28 (2H, d), 4.60 (1H, s), 6.18 (1H, s), 6.52 (1H, s), 6.74 (1H, s), 7.51 (2H, d), 7.67 (1H, s), 8.25 (2H, d), 8, 84 (1H, s), 12.64 (1H, s)

Ejemplo 24az: RMN 1H (400,13 MHz, DMSO–d6) δ 1,24–1,76 (5H, m), 1,77 (3H, s), 3,20 (1H, d), 3,47–3,53 (1H, m), 3,62–3,66 (1H, m), 3,76–3,80 (4H, m), 3,96–4,00 (1H, m), 4,23 (2H, d), 4,25 (1H, s), 4,60 (1H, s), 6,14 (1H, d), 6,52 (1H, t), 6,74 (1H, s), 7,51 (2H, d), 7,61 (1H, d), 8,24 (2H, d), 8,84 (1H, s) 24az Example: 1H NMR (400.13 MHz, DMSO-d6) δ 1.24-1.76 (5H, m), 1.77 (3H, s), 3.20 (1H, d), 3.47 –3.53 (1H, m), 3.62–3.66 (1H, m), 3.76–3.80 (4H, m), 3.96-4.00 (1H, m), 4 , 23 (2H, d), 4.25 (1H, s), 4.60 (1H, s), 6.14 (1H, d), 6.52 (1H, t), 6.74 (1H, s), 7.51 (2H, d), 7.61 (1H, d), 8.24 (2H, d), 8.84 (1H, s)

Ejemplo 24ba: RMN 1H (400,13 MHz, DMSO–d6) δ 1,23 (3H, d), 1,77 (3H, s), 1,77 (3H, s), 2,95 (6H, s), 3,04 (3H, s), 3,20–3,24 (1H, m), 3,49 (1H, d), 3,62–3,66 (1H, m), 3,77 (1H, d), 3,96–4,00 (1H, m), 4,23 (1H, s), 4,60 (1H, s), 6,75 (1H, s), 7,59 (2H, d), 8,23 (2H, d), 8,52 (1H, s) Example 24ba: 1H NMR (400.13 MHz, DMSO-d6) δ 1.23 (3H, d), 1.77 (3H, s), 1.77 (3H, s), 2.95 (6H, s ), 3.04 (3H, s), 3.20-3.24 (1H, m), 3.49 (1H, d), 3.62-3.66 (1H, m), 3.77 ( 1H, d), 3.96-4.00 (1H, m), 4.23 (1H, s), 4.60 (1H, s), 6.75 (1H, s), 7.59 (2H , d), 8.23 (2H, d), 8.52 (1H, s)

Ejemplo 24bb: RMN 1H (400,13 MHz, DMSO–d6) δ 1,23 (3H, d), 1,77 (3H, s), 1,77 (3H, s), 3,04 (3H, s), 3,17–3,24 (1H, m), 3,45 (4H, t), 3,49–3,52 (1H, m), 3,61–3,63 (4H, m), 3,65 (1H, s), 3,77 (1H, d), 3,96–4,00 (1H, m), 4,25 (1H, d), 4,60 (1H, s), 6,75 (1H, s), 7,59 (2H, d), 8,25 (2H, d), 8,77 (1H, s) Example 24bb: 1H NMR (400.13 MHz, DMSO-d6) δ 1.23 (3H, d), 1.77 (3H, s), 1.77 (3H, s), 3.04 (3H, s ), 3.17-3.24 (1H, m), 3.45 (4H, t), 3.49-3.52 (1H, m), 3.61-3.63 (4H, m), 3.65 (1H, s), 3.77 (1H, d), 3.96-4.00 (1H, m), 4.25 (1H, d), 4.60 (1H, s), 6 , 75 (1H, s), 7.59 (2H, d), 8.25 (2H, d), 8.77 (1H, s)

Ejemplo 24bc: RMN 1H (400,13 MHz, DMSO–d6) δ 1,23 (3H, d), 1,29–1,38 (2H, m), 1,75–1,77 (2H, m), 1,77 (3H, s), 1,77 (3H, s), 3,04 (4H, s), 3,07–3,11 (2H, m), 3,16–3,24 (1H, m), 3,46–3,53 (1H, m), 3,62–3,66 (1H, m), 3,67–3,70 (1H, m), 3,77 (1H, d), 3,85 (2H, q), 3,96–4,00 (1H, m), 4,24 (1H, d), 4,60 (1H, s), 4,74 (1H, d), 6,74 (1H, s), 7,58 (2H, d), 8,23 (2H, d), 8,72 (1H, s) Example 24bc: 1H NMR (400.13 MHz, DMSO-d6) δ 1.23 (3H, d), 1.29-1.38 (2H, m), 1.75-1.77 (2H, m) , 1.77 (3H, s), 1.77 (3H, s), 3.04 (4H, s), 3.07–3.11 (2H, m), 3.16–3.24 (1H , m), 3.46-3.53 (1H, m), 3.62-3.66 (1H, m), 3.67-3.70 (1H, m), 3.77 (1H, d ), 3.85 (2H, q), 3.96-4.00 (1H, m), 4.24 (1H, d), 4.60 (1H, s), 4.74 (1H, d) , 6.74 (1H, s), 7.58 (2H, d), 8.23 (2H, d), 8.72 (1H, s)

Ejemplo 24bd: RMN 1H (400,13 MHz, DMSO–d6) δ 1,23 (3H, d), 1,33–1,41 (2H, m), 1,69–1,73 (1H, m), 1,77 (3H, s), 1,77 (3H, s), 1,85–1,88 (1H, m), 2,74–2,79 (1H, m), 2,91–2,97 (1H, m), 3,04 (3H, s), 3,17–3,24 (1H, m), 3,45–3,53 (2H, m), 3,62–3,66 (1H, m), 3,76 (1H, s), 3,79 (1H, t), 3,93–4,00 (2H, m), 4,24 (1H, d), 4,60 (1H, s), 4,88 (1H, d), 6,74 (1H, s), 7,57–7,59 (2H, m), 8,21–8,24 (2H, m), 8,69 (1H, s) Example 24bd: 1H NMR (400.13 MHz, DMSO-d6) δ 1.23 (3H, d), 1.33-1.41 (2H, m), 1.69-1.73 (1H, m) , 1.77 (3H, s), 1.77 (3H, s), 1.85-1.88 (1H, m), 2.74-2.79 (1H, m), 2.91-2 , 97 (1H, m), 3.04 (3H, s), 3.17-3.24 (1H, m), 3.45-3.53 (2H, m), 3.62-3.66 (1H, m), 3.76 (1H, s), 3.79 (1H, t), 3.93-4.00 (2H, m), 4.24 (1H, d), 4.60 ( 1H, s), 4.88 (1H, d), 6.74 (1H, s), 7.57–7.59 (2H, m), 8.21–8.24 (2H, m), 8 , 69 (1H, s)

Ejemplo 24be: RMN 1H (400,13 MHz, DMSO–d6) δ 1,22 (3H, t), 1,76 (3H, s), 1,77 (3H, s), 2,15–2,23 (2H, m), 3,04 (3H, s), 3,18–3,24 (1H, m), 3,46–3,52 (1H, m), 3,62–3,66 (1H, m), 3,77 (1H, d), 3,98 (5H, t), 4,22 (1H, s), 4,60 (1H, s), 6,74 (1H, s), 7,62 (2H, d), 8,22–8,25 (2H, m), 8,59 (1H, s) Example 24be: 1H NMR (400.13 MHz, DMSO-d6) δ 1.22 (3H, t), 1.76 (3H, s), 1.77 (3H, s), 2.15-2.23 (2H, m), 3.04 (3H, s), 3.18-3.24 (1H, m), 3.46-3.52 (1H, m), 3.62-3.66 (1H , m), 3.77 (1H, d), 3.98 (5H, t), 4.22 (1H, s), 4.60 (1H, s), 6.74 (1H, s), 7 , 62 (2H, d), 8.22–8.25 (2H, m), 8.59 (1H, s)

Ejemplo 24bf: RMN 1H (400,13 MHz, DMSO–d6) δ 1,23 (3H, d), 1,76 (3H, s), 1,77 (3H, s), 3,04 (3H, s), 3,16–3,24 (1H, m), 3,46–3,53 (1H, m), 3,62–3,66 (1H, m), 3,71–3,75 (2H, m), 3,77 (1H, d), 3,96–4,00 (1H, m), 4,14–4,18 (2H, m), 4,24 (1H, d), 4,41–4,46 (1H, m), 4,60 (1H, s), 5,66 (1H, d), 6,74 (1H, s), 7,62 (2H, d), 8,22–8,25 (2H, m), 8,64 (1H, s) Example 24bf: 1H NMR (400.13 MHz, DMSO-d6) δ 1.23 (3H, d), 1.76 (3H, s), 1.77 (3H, s), 3.04 (3H, s ), 3.16-3.24 (1H, m), 3.46-3.53 (1H, m), 3.62-3.66 (1H, m), 3.71-3.75 (2H , m), 3.77 (1H, d), 3.96-4.00 (1H, m), 4.14-4.18 (2H, m), 4.24 (1H, d), 4, 41-4.46 (1H, m), 4.60 (1H, s), 5.66 (1H, d), 6.74 (1H, s), 7.62 (2H, d), 8.22 –8.25 (2H, m), 8.64 (1H, s)

Ejemplo 24bg: RMN 1H (400,13 MHz, DMSO–d6) δ 0,68–0,72 (2H, m), 0,90 (2H, d), 1,23 (3H, d), 1,77 (3H, s), 1,78 (3H, s), 2,70–2,74 (1H, m), 2,87 (3H, s), 3,04 (3H, d), 3,17–3,24 (1H, m), 3,46–3,53 (1H, m), 3,63–3,66 (1H, m), 3,77 (1H, d), 3,96–4,00 (1H, m), 4,25 (1H, d), 4,59 (1H, s), 6,75 (1H, s), 7,63–7,66 (2H, m), 8,24 (2H, d), 8,43 (1H, s) Example 24bg: 1H NMR (400.13 MHz, DMSO-d6) δ 0.68-0.72 (2H, m), 0.90 (2H, d), 1.23 (3H, d), 1.77 (3H, s), 1.78 (3H, s), 2.70-2.74 (1H, m), 2.87 (3H, s), 3.04 (3H, d), 3.17– 3.24 (1H, m), 3.46-3.53 (1H, m), 3.63-3.66 (1H, m), 3.77 (1H, d), 3.96-4, 00 (1H, m), 4.25 (1H, d), 4.59 (1H, s), 6.75 (1H, s), 7.63-7.66 (2H, m), 8.24 (2H, d), 8.43 (1H, s)

Ejemplo 24bh: RMN 1H (400,13 MHz, DMSO–d6) δ 1,23 (3H, d), 1,77 (3H, s), 1,77 (3H, s), 2,80 (3H, d), 3,02 (3H, s), 3,18–3,26 (1H, m), 3,46–3,52 (1H, m), 3,62–3,65 (1H, m), 3,77 (1H, d), 3,95–3,99 (1H, m), 4,27 (1H, d), 4,63 (1H, s), 6,84 (1H, s), 8,98 (1H, d), 9,37 (2H, s), 10,11 (1H, s) Example 24bh: 1H NMR (400.13 MHz, DMSO-d6) δ 1.23 (3H, d), 1.77 (3H, s), 1.77 (3H, s), 2.80 (3H, d ), 3.02 (3H, s), 3.18-3.26 (1H, m), 3.46-3.52 (1H, m), 3.62-3.65 (1H, m), 3.77 (1H, d), 3.95-3.99 (1H, m), 4.27 (1H, d), 4.63 (1H, s), 6.84 (1H, s), 8 , 98 (1H, d), 9.37 (2H, s), 10.11 (1H, s)

Ejemplo 24bi: RMN 1H (400,13 MHz, DMSO–d6) δ 1,24 (3H, d), 1,78 (6H, d), 3,02 (3H, s), 3,18–3,26 (1H, m), 3,46– 3,53 (1H, m), 3,63–3,66 (1H, m), 3,77 (1H, d), 3,80 (3H, s), 3,96–4,00 (1H, m), 4,24 (2H, d), 4,27 (1H, m), 4,61 (1H, s), 6,79 (1H, s), 7,38 (1H, s), 7,49–7,52 (1H, m), 7,62 (1H, s), 8,36 (1H, s), 8,53–8,56 (1H, m), 9,12 (1H, d), 9,45 (1H, s). Example 24bi: 1H NMR (400.13 MHz, DMSO-d6) δ 1.24 (3H, d), 1.78 (6H, d), 3.02 (3H, s), 3.18-3.26 (1H, m), 3.46-3.53 (1H, m), 3.63-3.66 (1H, m), 3.77 (1H, d), 3.80 (3H, s), 3.96-4.00 (1H, m), 4.24 (2H, d), 4.27 (1H, m), 4.61 (1H, s), 6.79 (1H, s), 7 , 38 (1H, s), 7.49–7.52 (1H, m), 7.62 (1H, s), 8.36 (1H, s), 8.53–8.56 (1H, m ), 9.12 (1H, d), 9.45 (1H, s).

Ejemplo 24bj: RMN 1H (400,13 MHz, DMSO–d6) δ 1,23 (3H, d), 1,77 (6H, d), 3,03 (3H, s), 3,17 (2H, q), 3,23 (1H, d), 3,46 (2H, q), 3,49–3,53 (1H, m), 3,63–3,66 (1H, m), 3,77 (1H, d), 3,96–4,00 (1H, m), 4,23 (1H, d), 4,60 (1H, d), 4,73 (1H, t), 6,25 (1H, t), 6,74 (1H, s), 7,50 (2H, d), 8,24 (2H, d), 8,81 (1H, s) Example 24bj: 1H NMR (400.13 MHz, DMSO-d6) δ 1.23 (3H, d), 1.77 (6H, d), 3.03 (3H, s), 3.17 (2H, q ), 3.23 (1H, d), 3.46 (2H, q), 3.49-3.53 (1H, m), 3.63-3.66 (1H, m), 3.77 ( 1H, d), 3.96-4.00 (1H, m), 4.23 (1H, d), 4.60 (1H, d), 4.73 (1H, t), 6.25 (1H , t), 6.74 (1H, s), 7.50 (2H, d), 8.24 (2H, d), 8.81 (1H, s)

Prueba (a): Ejemplo (24) 0,34 μM; Ejemplo (24a) 0,082 μM; Ejemplo (24b) 0,038 μM; Ejemplo (24c) 0,56 μM; Ejemplo (24d) 4,4 μM; Ejemplo (24e) 0,81 μM; Ejemplo 4,5 μM; Ejemplo (24g) 0,31 μM; Ejemplo (24h) 4,4 μM; Ejemplo (24i) 0,33 μM; Ejemplo (24j) 0,22 μM; Ejemplo (24k) 0,18 μM; Ejemplo (24l) 0,84 μM; Ejemplo (24m) 0,65 μM; Ejemplo (24n) 3,2 μM; Ejemplo (24o) 3,4 μM; Ejemplo (24p) 0,89 μM; Ejemplo (24q) 5,8 μM; Ejemplo (24r) 0,34 μM; Ejemplo (24s) 0,0047 μM; Ejemplo (24t) 0,012 μM; Ejemplo (24u) 0,12 μM; Ejemplo (24v) 0,055 μM; Ejemplo (24w) 0,034 μM; Ejemplo (24x) 0,1 μM; Ejemplo (24y) 2,2 μM; Ejemplo (24z) 0,37 μM; Ejemplo (24aa) 0,11 μM; Ejemplo (24ab) 0,042 μM; Ejemplo (24ac) 0,048 μM; Ejemplo (24ad) 0,51 μM; Ejemplo (24ae) 0,24 μM; Ejemplo (24bh) 0,012 μM; Ejemplo (24bi) 0,43 μM; Ejemplo (24bj) 0,051 μM. Test (a): Example (24) 0.34 μM; Example (24a) 0.082 μM; Example (24b) 0.038 μM; Example (24c) 0.56 μM; Example (24d) 4.4 μM; Example (24e) 0.81 μM; Example 4.5 μM; Example (24g) 0.31 μM; Example (24h) 4.4 μM; Example (24i) 0.33 μM; Example (24j) 0.22 μM; Example (24k) 0.18 μM; Example (24l) 0.84 μM; Example (24m) 0.65 μM; Example (24n) 3.2 μM; Example (24o) 3.4 μM; Example (24p) 0.89 μM; Example (24q) 5.8 μM; Example (24r) 0.34 μM; Example (24s) 0.0047 μM; Example (24t) 0.012 μM; Example (24u) 0.12 μM; Example (24v) 0.055 μM; Example (24w) 0.034 μM; Example (24x) 0.1 μM; Example (24y) 2.2 μM; Example (24z) 0.37 μM; Example (24aa) 0.11 μM; Example (24ab) 0.042 μM; Example (24ac) 0.048 μM; Example (24ad) 0.51 μM; Example (24ae) 0.24 μM; Example (24bh) 0.012 μM; Example (24bi) 0.43 μM; Example (24bj) 0.051 μM.

Prueba (c): Ejemplo (24af) 1,4 μM; Ejemplo (24ag) 0,32 μM; Ejemplo (24ah) 0,51 μM; Ejemplo (24ai) 0,26 μM; Ejemplo (24aj) 0,45 μM; Ejemplo (24ak) 0,21 μM; Ejemplo (24al) 0,038 μM; Ejemplo (24am) 0,21 μM; Ejemplo (24an) 1,8 μM; Ejemplo (24ao) 0,24 μM; Ejemplo (24ap) 0,077 μM; Ejemplo (24aq) 2 μM; Ejemplo (24ar) 0,049 μM; Ejemplo (24as) 0,22 μM; Ejemplo (24at) 0,089 μM; Ejemplo (24au) 2,4 μM; Ejemplo (24av) 4,9 μM; Ejemplo (24aw) 3,4 μM; Test (c): Example (24af) 1.4 μM; Example (24ag) 0.32 μM; Example (24ah) 0.51 μM; Example (24ai) 0.26 μM; Example (24aj) 0.45 μM; Example (24ak) 0.21 μM; Example (24al) 0.038 μM; Example (24am) 0.21 μM; Example (24an) 1.8 μM; Example (24ao) 0.24 μM; Example (24ap) 0.077 μM; Example (24aq) 2 μM; Example (24ar) 0.049 μM; Example (24as) 0.22 μM; Example (24at) 0.089 μM; Example (24au) 2.4 μM; Example (24av) 4.9 μM; Example (24aw) 3.4 μM;

5 Ejemplo (24ax) 0,64 μM; Ejemplo (24ay) 7,9 μM; Ejemplo (24az) 5,6 μM; Ejemplo (24ba) 5,1 μM; Ejemplo (24bb) 7,8 μM; Ejemplo (24bc) 0,69 μM; Ejemplo (24bd) 3,2 μM; Ejemplo (24be) 4,9 μM; Ejemplo (24bf) 6,7 μM; Ejemplo (24bg) 2,4 μM. 5 Example (24ax) 0.64 μM; Example (24a) 7.9 μM; Example (24az) 5.6 μM; Example (24ba) 5.1 μM; Example (24bb) 7.8 μM; Example (24bc) 0.69 μM; Example (24bd) 3.2 μM; Example (24be) 4.9 μM; Example (24bf) 6.7 μM; Example (24bg) 2.4 μM.

La preparación de N–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidin–2–il]fenil]carbamato de fenilo y (4–{4–[1–metil–1–(metilsulfonil)etil]–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il}fenil)carbamato de fenilo se describió The preparation of N– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin-2-yl] phenyl] phenyl carbamate and (4– {4– [1 -Methyl-1- (methylsulfonyl) ethyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-2-yl} phenyl) phenyl carbamate was described

10 anteriormente. 10 above.

Los siguientes carbamatos se prepararon a partir de la anilina o amina apropiadas, de manera análoga al N–[1–[4– [(3S)–3–metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidin–2–il]–4–piperidil]carbamato de fenilo descrito anteriormente. The following carbamates were prepared from the appropriate aniline or amine, analogously to N– [1– [4– [(3S) -3-methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin-2-yl ] -4-piperidyl] phenyl carbamate described above.

Estructura Structure: NOMBRE LCMS MH+ Tiempo de retención (min.) Notas NAME LCMS MH + Retention time (min.) Notes

S O O S O O: N N N O N N N H O O N–[1–[4–[(3S)–3–metilmorfolin– 4–il]–6– (metilsulfonilmetil)pirimidin–2– il]pirazol–3–il]carbamato de fenilo 495 2,09 Purificado mediante cromatografía usando 0–55% de acetato de etilo en isohexano N N N O N N N H O O N– [1– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin-2-yl] pyrazol-3-yl] phenyl carbamate 495 2.09 Purified by chromatography using 0–55% ethyl acetate in isohexane

S O O S O O: N N N O N N H O O N–[1–[4–[(3S)–3–metilmorfolin– 4–il]–6–(2–metilsulfonilpropan– 2–il)pirimidin–2–il]–4– piperidil]carbamato de fenilo 518 2,34 N N N O N N H O O N– [1– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (2-methylsulfonylpropan– 2-yl) pyrimidin-2-yl] –4– piperidyl] phenyl carbamate 518 2.34

S O O S O O: N N N O N N N H O O N–[5–[4–[(3S)–3–metilmorfolin– 4–il]–6–(2–metilsulfonilpropan– 2–il)pirimidin–2–il]pirimidin–2– il]carbamato de fenilo 513 2,21 Purificado mediante cromatografía usando 0–3% de metanol en DCM N N N O N N N H O O N– [5– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (2-methylsulfonylpropan– 2-yl) pyrimidin-2-yl] pyrimidin-2-yl] phenyl carbamate 513 2.21 Purified by chromatography using 0–3% methanol in DCM

S O O S O O: N N N O N N H O O N–[5–[4–[(3S)–3–metilmorfolin– 4–il]–6–(2–metilsulfonilpropan– 2–il)pirimidin–2–il]piridin–2– il]carbamato de fenilo 512 2,60 Purificado mediante cromatografía usando 0–3% de metanol en DCM N N N O N N H O O N– [5– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (2-methylsulfonylpropan– 2-yl) pyrimidin-2-yl] pyridin-2-yl] phenyl carbamate 512 2.60 Purified by chromatography using 0–3% methanol in DCM

S O O S O O: N N N O N H O O F F 2,6–difluoro–4–(4–(3– metilmorfolino)–6–(2– (metilsulfonil)propan–2– il)pirimidin–2–il)fenilcarbamato de (S)–fenilo 547 2,67 N N N O N H O O F F 2,6-Difluoro – 4– (4– (3– methylmorpholino) –6– (2– (methylsulfonyl) propan – 2– yl) pyrimidin – 2-yl) (S) -phenyl phenylcarbamate 547 2.67

15 2,6–difluoro–4–(4–(3–metilmorfolino)–6–(2–(metilsulfonil)propan–2–il)pirimidin–2–il)fenilcarbamato de (S)– Fenilo: RMN 1H (400,13 MHz, DMSO–d6) δ 1,25 (3H, d), 1,79 (6H, d), 3,00 (3H, s), 3,20–3,27 (1H, m), 3,47–3,55 (1H, m), 3,58 (15H, s), 3,65 (1H, d), 3,75 (1H, d), 3,97–4,01 (1H, m), 4,28 (1H, d), 4,63 (1H, s), 6,88 (1H, s), 7,21 (2H, d), 7,27 (1H, t), 7,44 (2H, t), 8,08 (2H, d), 9,96 (1H, s) 15 2,6 – Difluoro – 4– (4– (3-methylmorpholino) –6– (2– (methylsulfonyl) propan – 2-yl) pyrimidin – 2-yl) phenylcarbamate of (S) - Phenyl: 1 H NMR (400 , 13 MHz, DMSO – d6) δ 1.25 (3H, d), 1.79 (6H, d), 3.00 (3H, s), 3.20–3.27 (1H, m), 3 , 47–3.55 (1H, m), 3.58 (15H, s), 3.65 (1H, d), 3.75 (1H, d), 3.97–4.01 (1H, m ), 4.28 (1H, d), 4.63 (1H, s), 6.88 (1H, s), 7.21 (2H, d), 7.27 (1H, t), 7.44 (2H, t), 8.08 (2H, d), 9.96 (1H, s)

A continuación se describe la preparación de 1–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidin–2– il]pirazol–3–amina. The preparation of 1– [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidin-2-yl] pyrazole-3-amine is described below.

1–[4–[(3S)–3–Metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidin–2–il]pirazol–3–amina 1– [4 - [(3S) –3 – Methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin-2-yl] pyrazol-3-amine

5 Se disolvieron 2–cloro–4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidina (1,00 g), 1H–pirazol–3–amina (300 mg) y carbonato de potasio (498 mg) en butironitrilo (20 ml). La mezcla se calentó a reflujo durante 24 horas. La reacción se diluyó con acetato de etilo (20 ml) y se lavó con agua (20 ml). El agua se extrajo con acetato de etilo (20 ml). Los extractos orgánicos combinados se secaron sobre sulfato de magnesio y se evaporaron. El producto bruto se purificó mediante cromatografía en sílice, eluyendo con 0–5% de metanol en DCM para dar el material deseado 5 2-Chloro-4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine (1.00 g), 1H-pyrazole-3-amine (300 mg) and carbonate were dissolved. potassium (498 mg) in butyronitrile (20 ml). The mixture was heated at reflux for 24 hours. The reaction was diluted with ethyl acetate (20 ml) and washed with water (20 ml). Water was extracted with ethyl acetate (20 ml). The combined organic extracts were dried over magnesium sulfate and evaporated. The crude product was purified by silica chromatography, eluting with 0-5% methanol in DCM to give the desired material.

10 (635 mg). 10 (635 mg).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,23 (3H, d), 3,20 (3H, s), 3,24 (1H, m), 3,43–3,50 (1H, m), 3,60–3,64 (1H, m), 3,75 (1H, d), 3,94–3,98 (1H, m), 4,06–4,12 (1H, m), 4,43 (1H, s), 4,43 (2H, s), 5,25 (2H, s), 5,75 (1H, s), 5,80 (1H, d), 6,66 (1H, s), 8,26 (1H, d) NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.23 (3H, d), 3.20 (3H, s), 3.24 (1H, m), 3.43-3.50 (1H, m), 3.60–3.64 (1H, m), 3.75 (1H, d), 3.94–3.98 (1H, m), 4.06–4.12 (1H , m), 4.43 (1H, s), 4.43 (2H, s), 5.25 (2H, s), 5.75 (1H, s), 5.80 (1H, d), 6 , 66 (1H, s), 8.26 (1H, d)

15 Se preparó 1–[4–[(3S)–3–metilmorfolin–4–il]–6–(2–metilsulfonilpropan–2–il)pirimidin–2–il]piperidin–4–amina a partir de (3S)–4–{2–cloro–6–[1–metil–1–(metilsulfonil)etil]pirimidin–4–il}–3–metilmorfolina y N–(4–piperidil)carbamato de terc–butilo en un procedimiento de dos etapas análogo a 1–[4–[(3S)–3–metilmorfolin–4–il]–6– (metilsulfonilmetil)pirimidin–2–il]piperidin–4–amina. 15 1– [4 - [(3S) -3-methylmorpholin-4-yl] -6- (2-methylsulfonylpropan-2-yl) pyrimidin-2-yl] piperidin-4-amine was prepared from (3S) –4– {2 – chloro – 6– [1-methyl-1– (methylsulfonyl) ethyl] pyrimidin-4-yl} -3-methylmorpholine and N- (4-piperidyl) tert-butyl carbamate in a two-process 1– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin-2-yl] piperidin-4-amine analog steps.

Estructura Structure: NOMBRE LCMS MH+ Tiempo de retención (min.) NAME LCMS MH + Retention time (min.)

O OR: 1–[4–[(3S)–3–metilmorfolin–4–il]–6–(2– 398 0,94 1– [4 - [(3S) –3 – methylmorpholin – 4 – il] –6– (2– 398 0.94

: metilsulfonilpropan–2–il)pirimidin–2– methylsulfonylpropan – 2-yl) pyrimidin – 2–

N N N S O O N NH2 N N N S O O N NH2: il]piperidin–4–amina il] piperidin – 4 – amine

O OR: N–[1–[4–[(3S)–3–metilmorfolin–4–il]–6– 498 2,43 N– [1– [4 - [(3S) –3 – methylmorpholin-4-yl] –6– 498 2.43

: (2–metilsulfonilpropan–2–il)pirimidin–2– (2-Methylsulfonylpropan – 2-yl) pyrimidin – 2–

N N N S O O N N H O O N N N S O O N N H O O: il]–4–piperidil]carbamato de terc–butilo il] -4-piperidyl] tert-butyl carbamate

20 1–[4–[(3S)–3–metilmorfolin–4–il]–6–(2–metilsulfonilpropan–2–il)pirimidin–2–il]piperidin–4–amina: RMN 1H (400,13 MHz, DMSO–d6) δ 1,27 (3H, d), 1,75 (6H, s), 1,83–1,87 (2H, m), 2,88 (1H, d), 2,91 (5H, s), 2,94 (1H, d), 3,17–3,25 (1H, m), 3,50–3,57 (1H, m), 3,68 (1H, d), 3,70 (2H, s), 3,75–3,77 (1H, m), 3,92 (1H, s), 3,95–3,99 (2H, m), 4,30 (1H, d), 4,61 (2H, d), 6,06 (1H, s) 20 1– [4 - [(3S) –3 – methylmorpholin-4-yl] –6– (2-methylsulfonylpropan – 2-yl) pyrimidin – 2-yl] piperidin – 4-amine: 1H NMR (400.13 MHz , DMSO – d6) δ 1.27 (3H, d), 1.75 (6H, s), 1.83–1.87 (2H, m), 2.88 (1H, d), 2.91 ( 5H, s), 2.94 (1H, d), 3.17-3.25 (1H, m), 3.50-3.57 (1H, m), 3.68 (1H, d), 3 , 70 (2H, s), 3.75–3.77 (1H, m), 3.92 (1H, s), 3.95–3.99 (2H, m), 4.30 (1H, d ), 4.61 (2H, d), 6.06 (1H, s)

N– [1– [4 - [(3S) –3 – methylmorpholin-4-yl] –6– (2-methylsulfonylpropan – 2-yl) pyrimidin – 2-yl] –4-piperidyl] carbamate

25 terc–butilo: RMN 1H (400,13 MHz, DMSO–d6) δ 1,25 (5H, d), 1,27 (2H, d), 1,30–1,35 (2H, m), 1,45 (9H, s), 1,54 (6H, s), 1,98 (2H, d), 2,04 (4H, s), 2,90 (3H, s), 2,95–3,01 (2H, m), 3,17–3,24 (1H, m), 3,50–3,57 (1H, m), 3,66–3,70 (2H, m), 3,76 (1H, d), 3,95–3,99 (2H, m), 4,29 (1H, d), 4,56 (2H, d), 6,07 (1H, s) 25 tert-butyl: 1H NMR (400.13 MHz, DMSO-d6) δ 1.25 (5H, d), 1.27 (2H, d), 1.30–1.35 (2H, m), 1 , 45 (9H, s), 1.54 (6H, s), 1.98 (2H, d), 2.04 (4H, s), 2.90 (3H, s), 2.95–3, 01 (2H, m), 3.17-3.24 (1H, m), 3.50-3.57 (1H, m), 3.66-3.70 (2H, m), 3.76 ( 1H, d), 3.95–3.99 (2H, m), 4.29 (1H, d), 4.56 (2H, d), 6.07 (1H, s)

La preparación de (3S)–4–{2–cloro–6–[1–metil–1–(metilsulfonil)etil]pirimidin–4–il}–3–metilmorfolina se describió anteriormente. The preparation of (3S) –4– {2-chloro-6– [1-methyl-1– (methylsulfonyl) ethyl] pyrimidin-4-yl} -3-methylmorpholine was described above.

30 Se prepararon 5–[4–[(3S)–3–metilmorfolin–4–il]–6–(2–metilsulfonilpropan–2–il)pirimidin–2–il]pirimidin–2–amina y 5– [4–[(3S)–3–metilmorfolin–4–il]–6–(2–metilsulfonilpropan–2–il)pirimidin–2–il]piridin–2–amina a partir de (3S)–4–{2– cloro–6–[1–metil–1–(metilsulfonil)etil]pirimidin–4–il}–3–metilmorfolina de manera análoga a (4–{4–[1–metil–1– (metilsulfonil)etil]–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il}fenil)amina, descrita anteriormente. 30 5– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (2-methylsulfonylpropan-2-yl) pyrimidin-2-yl] pyrimidin-2-amine and 5– [4– [(3S) –3 – methylmorpholin-4-yl] –6– (2-methylsulfonylpropan-2-yl) pyrimidin-2-yl] pyridin-2-amine from (3S) –4– {2– chlorine– 6– [1-methyl-1– (methylsulfonyl) ethyl] pyrimidin-4-yl} -3-methylmorpholine analogously to (4– {4– [1-methyl-1– (methylsulfonyl) ethyl] –6– [ (3S) -3-methylmorpholin-4-yl] pyrimidin-2-yl} phenyl) amine, described above.

N N N O S O O N N NH2 N N N O S O O N N NH2: 5–[4–[(3S)–3–metilmorfolin–4–il]–6–(2– metilsulfonilpropan–2–il)pirimidin–2– il]pirimidin–2–amina 393 1,57 5– [4 - [(3S) –3 – methylmorpholin-4-yl] –6– (2– methylsulfonylpropan – 2-yl) pyrimidin – 2– yl] pyrimidin – 2-amine 393 1.57

N N N O S O O N NH2 N N N O S O O N NH2: 5–[4–[(3S)–3–metilmorfolin–4–il]–6–(2– metilsulfonilpropan–2–il)pirimidin–2– il]piridin–2–amina 392 1,16 5– [4 - [(3S) –3 – methylmorpholin-4-yl] –6– (2– methylsulfonylpropan – 2-yl) pyrimidin – 2– yl] pyridin – 2-amine 392 1.16

5–[4–[(3S)–3–metilmorfolin–4–il]–6–(2–metilsulfonilpropan–2–il)pirimidin–2–il]pirimidin–2–amina: RMN 1H 5 (400,13 MHz, DMSO–d6) δ 1,23 (3H, d), 1,75–1,76 (6H, m), 3,00 (3H, s), 3,16–3,23 (1H, m), 3,45–3,52 (1H, m), 3,61–3,65 (1H, m), 3,76 (1H, d), 3,95–3,99 (1H, m), 4,22 (1H, d), 4,57 (1H, s), 6,74 (1H, s), 7,11 (2H, s), 9,09 (2H, s) 5– [4 - [(3S) –3 – methylmorpholin-4-yl] –6– (2-methylsulfonylpropan – 2-yl) pyrimidin – 2-yl] pyrimidin – 2-amine: 1H 5 NMR (400.13 MHz , DMSO-d6) δ 1.23 (3H, d), 1.75-1.76 (6H, m), 3.00 (3H, s), 3.16-3.23 (1H, m), 3.45-3.52 (1H, m), 3.61-3.65 (1H, m), 3.76 (1H, d), 3.95-3.99 (1H, m), 4, 22 (1H, d), 4.57 (1H, s), 6.74 (1H, s), 7.11 (2H, s), 9.09 (2H, s)

5–[4–[(3S)–3–metilmorfolin–4–il]–6–(2–metilsulfonilpropan–2–il)pirimidin–2–il]piridin–2–amina: RMN 1H (400,13 MHz, CDCl3) δ 1,33 (3H, d), 1,86 (6H, s), 2,93 (3H, s), 3,31–3,35 (1H, m), 3,56–3,62 (1H, m), 3,72–3,75 (1H, m), 3,82 (1H, d), 4,02–4,05 (1H, m), 4,12 (1H, d), 4,48–4,50 (1H, m), 4,83 (2H, s), 6,52–6,55 (1H, m), 6,59 (1H, s), 5– [4 - [(3S) –3 – methylmorpholin-4-yl] –6– (2-methylsulfonylpropan – 2-yl) pyrimidin – 2-yl] pyridin – 2-amine: 1H NMR (400.13 MHz, CDCl3) δ 1.33 (3H, d), 1.86 (6H, s), 2.93 (3H, s), 3.31-3.35 (1H, m), 3.56-3.62 (1H, m), 3.72-3.75 (1H, m), 3.82 (1H, d), 4.02-4.05 (1H, m), 4.12 (1H, d), 4.48-4.50 (1H, m), 4.83 (2H, s), 6.52-6.55 (1H, m), 6.59 (1H, s),

10 8,35–8,38 (1H, m), 9,08–9,09 (1H, m) 10 8.35–8.38 (1H, m), 9.08–9.09 (1H, m)

A continuación se describe la preparación de 2,6–difluoro–4–[4–[(3S)–3–metilmorfolin–4–il]–6–(2– metilsulfonilpropan–2–il)pirimidin–2–il]anilina. The preparation of 2,6-difluoro-4– [4 - [(3S) -3-methylmorpholin-4-yl] -6- (2-methylsulfonylpropan-2-yl) pyrimidin-2-yl] aniline is described below. .

2,6–Difluoro–4–[4–[(3S)–3–metilmorfolin–4–il]–6–(2–metilsulfonilpropan–2–il)pirimidin–2–il]anilina 2,6 – Difluoro – 4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (2-methylsulfonylpropan – 2-yl) pyrimidin – 2-yl] aniline

F F

15 Se disolvieron 4–bromo–2,6–difluoro–anilina (400 mg, 1,92 mmoles), acetato de potasio (566 mg, 5,77 mmoles) y 4,4,5,5–tetrametil–2–(4,4,5,5–tetrametil–1,3,2–dioxaborolan–2–il)–1,3,2–dioxaborolano (587 mg, 2,31 mmoles) en 1,4 dioxano (5 ml). La disolución se desgasificó durante 10 minutos, después se añadió 1,1’– bis(difenilfosfino)ferrocenodicloropaladio (95 mg, 0,12 mmoles), y la reacción se agitó a 90ºC durante 3 horas. Se añadieron (3S)–4–{2–cloro–6–[1–metil–1–(metilsulfonil)etil]pirimidin–4–il}–3–metilmorfolina (450 mg, 1,35 mmoles), 15 4-Bromo-2,6-difluoro-aniline (400 mg, 1.92 mmol), potassium acetate (566 mg, 5.77 mmol) and 4,4,5,5-tetramethyl-2– ( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,3,2-dioxaborolane (587 mg, 2.31 mmol) in 1.4 dioxane (5 ml). The solution was degassed for 10 minutes, then 1,1'-bis (diphenylphosphino) ferrocenodichloropaladium (95 mg, 0.12 mmol) was added, and the reaction was stirred at 90 ° C for 3 hours. (3S) –4– {2-chloro-6– [1-methyl-1– (methylsulfonyl) ethyl] pyrimidin-4-yl} -3-methylmorpholine (450 mg, 1.35 mmol) were added,

20 etanol (1 ml), carbonato de sodio 2M (1 ml) y 1,1’–bis(difenilfosfino)ferrocenodicloropaladio (95 mg, 0,12 mmoles), y el calentamiento se continuó durante 18 horas. La reacción se dejó enfriar hasta RT, después se añadió agua (50 ml), seguido por acetato de etilo (50 ml). El sólido no disuelto se eliminó por filtración. Las fases se separaron, y la fase acuosa se extrajo con una segunda porción de acetato de etilo (30 ml). Los productos orgánicos combinados se secaron sobre sulfato de magnesio, se filtraron y se evaporaron hasta sequedad. El producto bruto se disolvió en 20 ethanol (1 ml), 2M sodium carbonate (1 ml) and 1,1'-bis (diphenylphosphino) ferrocenodichloropaladium (95 mg, 0.12 mmol), and heating was continued for 18 hours. The reaction was allowed to cool to RT, then water (50 ml) was added, followed by ethyl acetate (50 ml). The undissolved solid was removed by filtration. The phases were separated, and the aqueous phase was extracted with a second portion of ethyl acetate (30 ml). The combined organic products were dried over magnesium sulfate, filtered and evaporated to dryness. The crude product was dissolved in

25 DCM (25 ml), se filtró para eliminar el material insoluble, y el filtrado se purificó mediante cromatografía en sílice, eluyendo con 0–35% de acetato de etilo en isohexano, para dar el material deseado como un sólido blancuzco (402 mg). DCM (25 ml), was filtered to remove insoluble material, and the filtrate was purified by silica chromatography, eluting with 0-35% ethyl acetate in isohexane, to give the desired material as an off-white solid (402 mg ).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,23 (3H, d), 1,76 (6H, d), 3,00 (3H, s), 3,17–3,24 (1H, m), 3,45– 3,51 (1H, m), 3,62–3,65 (1H, m), 3,76 (1H, d), 3,95–3,99 (1H, m), 4,22 (1H, d), 4,57 (1H, s), 5,70 (2H, d), 6,73 (1H, NMR Spectrum: 1H NMR (400.13 MHz, DMSO – d6) δ 1.23 (3H, d), 1.76 (6H, d), 3.00 (3H, s), 3.17–3.24 (1H, m), 3.45-3.51 (1H, m), 3.62-3.65 (1H, m), 3.76 (1H, d), 3.95-3.99 (1H , m), 4.22 (1H, d), 4.57 (1H, s), 5.70 (2H, d), 6.73 (1H,

30 s), 7,83–7,85 (2H, m) 30 s), 7.83–7.85 (2H, m)

Espectro LCMS: MH+ 427, Tiempo de retención 2,35 min., Método Ácido Monitor A continuación se describe la preparación de N–[5–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidin–2– il]piridin–2–il]carbamato de fenilo. N–[5–[4–(3S)–3–Metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidin–2–il]piridin–2–il]carbamato de fenilo LCMS Spectrum: MH + 427, Retention Time 2.35 min., Acid Monitor Method The following describes the preparation of N– [5– [4 - [(3S) –3 – methylmorpholin – 4 – yl] –6– ( Methylsulfonylmethyl) pyrimidin-2-yl] pyridin-2-yl] phenyl carbamate. N– [5– [4– (3S) –3 – Methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin-2-yl] pyridin-2-yl] phenyl carbamate

O OR

N N

N S OO N S OO

N N

O NN OR NN

O H Or h

5 Se disolvió 5–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidin–2–il]piridin–2–amina (770 mg, 2,12 mmoles) en dioxano (10 ml) y se añadió bicarbonato de sodio (267 mg, 3,18 mmoles) para dar una suspensión amarilla fina. Se añadió gota a gota durante 10 minutos cloroformiato de fenilo (0,267 ml, 2,12 mmoles), controlando la exotermia usando un baño de agua, y la mezcla se agitó a RT durante 16 horas. Se añadieron bicarbonato de sodio (267 mg, 3,18 mmoles) y cloroformiato de fenilo (0,267 ml, 2,12 mmoles) adicionales, y la mezcla se agitó a 5 5– [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidin-2-yl] pyridin-2-amine (770 mg, 2.12 mmol) was dissolved in dioxane ( 10 ml) and sodium bicarbonate (267 mg, 3.18 mmol) was added to give a fine yellow suspension. Phenyl chloroformate (0.267 ml, 2.12 mmol) was added dropwise over 10 minutes, controlling the exotherm using a water bath, and the mixture was stirred at RT for 16 hours. Sodium bicarbonate (267 mg, 3.18 mmol) and phenyl chloroformate (0.267 ml, 2.12 mmol) were added, and the mixture was stirred at

10 RT durante 2 horas. Se añadió nuevamente cloroformiato de fenilo (0,267 ml, 2,12 mmoles), y la mezcla se agitó a RT durante 1 hora, y después se calentó hasta 35ºC durante 16 horas. La reacción se evaporó hasta sequedad, y el residuo se repartió entre agua (15 ml) y acetato de etilo (20 ml). El sólido blanco se filtró y se lavó con agua (5 ml), DCM (5 ml) y metanol (5 ml). El sólido se secó a vacío a 40ºC durante 5 horas para dar el producto como un sólido blanco (117 mg). 10 RT for 2 hours. Phenyl chloroformate (0.267 ml, 2.12 mmol) was added again, and the mixture was stirred at RT for 1 hour, and then heated to 35 ° C for 16 hours. The reaction was evaporated to dryness, and the residue was partitioned between water (15 ml) and ethyl acetate (20 ml). The white solid was filtered and washed with water (5 ml), DCM (5 ml) and methanol (5 ml). The solid was dried under vacuum at 40 ° C for 5 hours to give the product as a white solid (117 mg).

15 Espectro LCMS: MH+ 484, tiempo de retención 2,32 min., Método Ácido Monitor 15 LCMS Spectrum: MH + 484, retention time 2.32 min., Acid Monitor Method

La preparación de 5–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidin–2–il]piridin–2–amina se describió anteriormente. The preparation of 5– [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidin-2-yl] pyridin-2-amine was described above.

Ejemplo 25: Example 25:

1–[1–[4–[(3S)–3–Metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidin–2–il]pirazol–3–il]–3–fenil–urea 1– [1– [4 - [(3S) –3 – Methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin-2-yl] pyrazol-3-yl] –3-phenyl-urea

O OR

N N

N S N S

OO OO

N N H N N H

N N

NH N NH N

O OR

Se disolvió 1–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidin–2–il]pirazol–3–amina (90 mg, 0,26 mmoles) en dioxano (4 ml). Se añadió isocianato de fenilo (0,024 ml, 0,22 mmoles) a la disolución resultante. La mezcla se calentó a 80ºC durante 2 horas. El sólido se filtró y se lavó con éter dietílico (5 ml) para dar el material deseado como un sólido blanco (66 mg). 1– [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidin-2-yl] pyrazol-3-amine (90 mg, 0.26 mmol) was dissolved in dioxane (4 ml) Phenyl isocyanate (0.024 ml, 0.22 mmol) was added to the resulting solution. The mixture was heated at 80 ° C for 2 hours. The solid was filtered and washed with diethyl ether (5 ml) to give the desired material as a white solid (66 mg).

25 Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,26 (3H, d), 3,23 (3H, s), 3,40 (1H, m), 3,47–3,54 (1H, m), 3,63–3,67 (1H, m), 3,78 (1H, d), 3,98 (1H, d), 4,14 (1H, s), 4,47 (1H, m), 4,51 (2H, d), 6,60 (1H, d), 6,81 (1H, s), 7,01 (1H, t), 7,29–7,33 (2H, m), 7,47 (2H, d), 8,51 (1H, d), 9,18 (1H, s), 9,50 (1H, s) 25 NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.26 (3H, d), 3.23 (3H, s), 3.40 (1H, m), 3.47-3, 54 (1H, m), 3.63-3.67 (1H, m), 3.78 (1H, d), 3.98 (1H, d), 4.14 (1H, s), 4.47 (1H, m), 4.51 (2H, d), 6.60 (1H, d), 6.81 (1H, s), 7.01 (1H, t), 7.29–7.33 ( 2H, m), 7.47 (2H, d), 8.51 (1H, d), 9.18 (1H, s), 9.50 (1H, s)

Espectro LCMS: MH+ 472, Tiempo de retención 1,86 min., Método Ácido 5 min. LCMS spectrum: MH + 472, Retention time 1.86 min., Acid Method 5 min.

Los siguientes compuestos se prepararon de una manera análoga a partir de 1–[4–[(3S)–3–metilmorfolin–4–il]–6– 30 (metilsulfonilmetil)pirimidin–2–il]pirazol–3–amina y el isocianato apropiado. The following compounds were prepared in an analogous manner from 1– [4 - [(3S) -3-methylmorpholin-4-yl] -6-30 (methylsulfonylmethyl) pyrimidin-2-yl] pyrazole-3-amine and the appropriate isocyanate.

25a 25th: O 3–(4–metoxifenil)–1–[1–[4–[(3S)–3– 502 1,98 OR 3– (4 – methoxyphenyl) –1– [1– [4 - [(3S) –3– 502 1.98

: metilmorfolin–4–il]–6– methylmorpholin – 4 – il] –6–

N O NO: (metilsulfonilmetil)pirimidin–2– (methylsulfonylmethyl) pyrimidin – 2–

N N S O O N N N H N HO N N S O O N N N H N HO: il]pirazol–3–il]urea il] pyrazole – 3 – il] urea

25b 25b: O 3–(4–fluorofenil)–1–[1–[4–[(3S)–3– 512 2,06 OR 3– (4 – fluorophenyl) –1– [1– [4 - [(3S) –3– 512 2.06

: metilmorfolin–4–il]–6– methylmorpholin – 4 – il] –6–

N F N F: (metilsulfonilmetil)pirimidin–2– (methylsulfonylmethyl) pyrimidin – 2–

Ejemplo 25a: RMN 1H (400,13 MHz, DMSO–d6) δ 1,26 (3H, d), 3,47–3,53 (1H, m), 3,56 (1H, d), 3,63–3,67 (1H, m), 3,73 (3H, s), 3,78 (1H, d), 3,96–4,00 (1H, m), 4,14 (1H, s), 4,47 (1H, m), 4,50 (2H, s), 6,57 (1H, d), 6,81 (1H, s), 6,87–6,91 (2H, m), 7,35–7,39 (2H, m), 8,50 (1H, d), 9,04 (1H, s), 9,42 (1H, s) Example 25a: 1H NMR (400.13 MHz, DMSO-d6) δ 1.26 (3H, d), 3.47-3.53 (1H, m), 3.56 (1H, d), 3.63 –3.67 (1H, m), 3.73 (3H, s), 3.78 (1H, d), 3.96-4.00 (1H, m), 4.14 (1H, s), 4.47 (1H, m), 4.50 (2H, s), 6.57 (1H, d), 6.81 (1H, s), 6.87-6.91 (2H, m), 7 , 35–7.39 (2H, m), 8.50 (1H, d), 9.04 (1H, s), 9.42 (1H, s)

5 Ejemplo 25b: RMN 1H (400,13 MHz, DMSO–d6) δ 1,26 (3H, d), 3,26 (1H, m), 3,46–3,53 (1H, m), 3,58 (3H, s), 3,63– 3,67 (1H, m), 3,78 (1H, d), 3,96–4,00 (1H, m), 4,14 (1H, s), 4,46 (1H, m), 4,50 (2H, s), 6,59 (1H, d), 6,81 (1H, s), 7,13–7,18 (2H, m), 7,45–7,50 (2H, m), 8,51 (1H, d), 9,17 (1H, s), 9,51 (1H, s) 5 Example 25b: 1H NMR (400.13 MHz, DMSO-d6) δ 1.26 (3H, d), 3.26 (1H, m), 3.46-3.53 (1H, m), 3, 58 (3H, s), 3.63– 3.67 (1H, m), 3.78 (1H, d), 3.96-4.00 (1H, m), 4.14 (1H, s) , 4.46 (1H, m), 4.50 (2H, s), 6.59 (1H, d), 6.81 (1H, s), 7.13-7.18 (2H, m), 7.45–7.50 (2H, m), 8.51 (1H, d), 9.17 (1H, s), 9.51 (1H, s)

Prueba (a): Ejemplo (25) 1,9 μM; Ejemplo (25a) 4,4 μM; Ejemplo (25b) 4,4 μM. Test (a): Example (25) 1.9 μM; Example (25a) 4.4 μM; Example (25b) 4.4 μM.

Ejemplo 26: Example 26:

10 N-Methyl-2 - [[2– [4– (methylcarbamoylamino) phenyl] –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-4-yl] methylsulfonyl] acetamide

O OR

NH NH

N N

N O NO

O OR

S S

O OR

NN

O OR

N HH N HH

N N

Se disolvió N–metil–2–[[2–[4–(metilcarbamoilamino)fenil]–6–[(3S)–3–metilmorfolin–4–il]pirimidin–4– il]metilsulfanil]acetamida (0,35 mmoles) en 1,4–dioxano (5 ml) y agua (1 ml). Se añadieron a la disolución m–CPBA 15 (75%) (121 mg) seguido inmediatamente por permanganato de sodio (140 mg), y la reacción se agitó a RT durante 1 N-methyl-2 - [[2– [4– (methylcarbamoylamino) phenyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-4-yl] methylsulfanyl] acetamide (0.35 mmol) was dissolved ) in 1,4-dioxane (5 ml) and water (1 ml). M-CPBA 15 (75%) (121 mg) was immediately added to the solution followed immediately by sodium permanganate (140 mg), and the reaction was stirred at RT for 1

h. Se añadió m–CPBA (75%) adicional (121 mg) seguido inmediatamente por permanganato de sodio (140 mg) a la disolución, y ésta se agitó a RT durante 1 h. Se añadió nuevamente m–CPBA (75%) adicional (121 mg) seguido inmediatamente por permanganato de sodio (140 mg), y la reacción se agitó a RT durante 1 h. La reacción se cargó en una columna SCX–3 (10 g) que se lavó con metanol, y el producto se eluyó con amoniaco 7N en metanol. El h. An additional m-CPBA (75%) (121 mg) was added immediately followed by sodium permanganate (140 mg) to the solution, and it was stirred at RT for 1 h. An additional m-CPBA (75%) (121 mg) was immediately added followed immediately by sodium permanganate (140 mg), and the reaction was stirred at RT for 1 h. The reaction was loaded on an SCX-3 column (10 g) which was washed with methanol, and the product was eluted with 7N ammonia in methanol. He

20 material fue purificado adicionalmente mediante HPLC prep. (básica) para dar el material deseado (30 mg) como un sólido blanco. 20 material was further purified by prep HPLC. (basic) to give the desired material (30 mg) as a white solid.

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,23–1,25 (3H, m), 2,66–2,70 (3H, m), 2,68 (1H, d), 3,21–3,26 (1H, m), 3,46–3,53 (3H, m), 3,63–3,67 (1H, m), 3,78 (1H, d), 3,97–4,00 (1H, m), 4,17 (1H, d), 4,29 (2H, s), 4,47 (1H, s), 4,67 (2H, s), 6,07 (1H, q), 6,76 (1H, s), 7,48–7,52 (2H, m), 8,17–8,20 (2H, m), 8,31 (1H, t), 8,74 (1H, s) NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.23-1.25 (3H, m), 2.66-2.70 (3H, m), 2.68 (1H, d) , 3.21-3.26 (1H, m), 3.46-3.53 (3H, m), 3.63-3.67 (1H, m), 3.78 (1H, d), 3 , 97-4.00 (1H, m), 4.17 (1H, d), 4.29 (2H, s), 4.47 (1H, s), 4.67 (2H, s), 6, 07 (1H, q), 6.76 (1H, s), 7.48–7.52 (2H, m), 8.17–8.20 (2H, m), 8.31 (1H, t) , 8.74 (1H, s)

25 Espectro de masa: M+H+ 477. 25 Mass spectrum: M + H + 477.

Los siguientes compuestos se prepararon de manera análoga a partir de los sulfuros apropiados. The following compounds were prepared analogously from the appropriate sulfides.

Ejemplo Example: Estructura NOMBRE LCMS MH+ Structure NAME LCMS MH +

26a 26th: N N N O S N H N H OO O NH2 O 2–[[2–[4–(metilcarbamoilamino)fenil]–6–[(3S)– 3–metilmorfolin–4–il]pirimidin–4– il]metilsulfonil]acetamida 463 N N N O S N H N H OO O NH2 O 2 - [[2– [4– (methylcarbamoylamino) phenyl] –6 - [(3S) - 3-methylmorpholin-4-yl] pyrimidin-4-yl] methylsulfonyl] acetamide 463

26b 26b: N N N O S N H N H OO O NH O N–[2–[[2–[4–(metilcarbamoilamino)fenil]–6– [(3S)–3–metilmorfolin–4–il]pirimidin–4– il]metilsulfonil]etil]acetamida 491 N N N O S N H N H OO O NH O N– [2 - [[2– [4– (methylcarbamoylamino) phenyl] –6– [(3S) –3-methylmorpholin-4-yl] pyrimidin-4-yl] methylsulfonyl] ethyl] acetamide 491

Ejemplo 26a: RMN 1H (400,13 MHz, DMSO–d6) δ 1,24 (3H, d), 2,66 (3H, d), 3,18–3,26 (1H, m), 3,47–3,53 (1H, m), 3,63–3,67 (1H, m), 3,77 (1H, d), 3,97–4,00 (1H, m), 4,17 (1H, d), 4,27 (2H, s), 4,48 (1H, s), 4,66 (2H, s), 6,07 (1H, q), 6,76 (1H, s), 7,48–7,52 (3H, m), 7,79 (1H, s), 8,17–8,21 (2H, m), 8,74 (1H, s) Example 26a: 1H NMR (400.13 MHz, DMSO-d6) δ 1.24 (3H, d), 2.66 (3H, d), 3.18-3.26 (1H, m), 3.47 –3.53 (1H, m), 3.63–3.67 (1H, m), 3.77 (1H, d), 3.97-4.00 (1H, m), 4.17 (1H , d), 4.27 (2H, s), 4.48 (1H, s), 4.66 (2H, s), 6.07 (1H, q), 6.76 (1H, s), 7 , 48–7.52 (3H, m), 7.79 (1H, s), 8.17–8.21 (2H, m), 8.74 (1H, s)

5 Ejemplo 26b: RMN 1H (400,13 MHz, DMSO–d6) δ 1,24 (3H, d), 1,83 (3H, s), 2,66 (2H, s), 2,68 (2H, q), 3,21–3,26 (1H, m), 3,47–3,53 (2H, m), 3,52 (1H, s), 3,57 (2H, q), 3,63–3,67 (1H, m), 3,78 (1H, d), 3,97–4,01 (1H, m), 4,17 (1H, d), 4,51 (2H, s), 6,06 (1H, q), 6,77 (1H, s), 7,48–7,52 (2H, m), 8,14–8,21 (3H, m), 8,74 (1H, s) 5 Example 26b: 1H NMR (400.13 MHz, DMSO-d6) δ 1.24 (3H, d), 1.83 (3H, s), 2.66 (2H, s), 2.68 (2H, q), 3.21-3.26 (1H, m), 3.47-3.53 (2H, m), 3.52 (1H, s), 3.57 (2H, q), 3.63 –3.67 (1H, m), 3.78 (1H, d), 3.97-4.01 (1H, m), 4.17 (1H, d), 4.51 (2H, s), 6.06 (1H, q), 6.77 (1H, s), 7.48–7.52 (2H, m), 8.14–8.21 (3H, m), 8.74 (1H, s)

Prueba (a): Ejemplo (26) 0,029 μM; Ejemplo (26a) 0,037 μM; Ejemplo (26b) 0,041 μM. Test (a): Example (26) 0.029 μM; Example (26a) 0.037 μM; Example (26b) 0.041 μM.

A continuación se describe la preparación de N–metil–2–[[2–[4–(metilcarbamoilamino)fenil]–6–[(3S)–3– 10 metilmorfolin–4–il]pirimidin–4–il]metilsulfanil]acetamida. The preparation of N-methyl-2 - [[2– [4– (methylcarbamoylamino) phenyl] –6 - [(3S) –3– 10 methylmorpholin-4-yl] pyrimidin-4-yl] methylsulfanyl] is described below. acetamide

N–Metil–2–[[2–[4–(metilcarbamoilamino)fenil]–6–[(3S)–3–metilmorfolin–4–il]pirimidin–4–il]metilsulfanil]acetamida N – Methyl – 2 - [[2– [4– (methylcarbamoylamino) phenyl] –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-4-yl] methylsulfanyl] acetamide

O OR

NH NH

N N

N S N S

O OR

N N

N HH N HH

N N

Se disolvió N–metil–2–sulfanil–acetamida (0,61 mmoles) en acetonitrilo (4 ml). Después se añadió DBU (0,050 ml) a la disolución y ésta se agitó a RT durante 5 min. Se añadieron una disolución de 3–metil–1–[4–[4–[(3S)–3– metilmorfolin–4–il]–6–(metilsulfoniloximetil)pirimidin–2–il]fenil]urea (151 mg) en acetonitrilo (2 ml) y DBU (0,054 ml), y la reacción se agitó a RT durante 2 h antes de concentrarla a vacío, y se usó inmediatamente en la etapa subsiguiente. N-methyl-2-sulfanyl-acetamide (0.61 mmol) was dissolved in acetonitrile (4 ml). Then DBU (0.050 ml) was added to the solution and it was stirred at RT for 5 min. A solution of 3-methyl-1– [4– [4 - [(3S) -3– methylmorpholin-4-yl] –6– (methylsulfonyloxymethyl) pyrimidin-2-yl] phenyl] urea (151 mg) was added in acetonitrile (2 ml) and DBU (0.054 ml), and the reaction was stirred at RT for 2 h before concentrating in vacuo, and used immediately in the subsequent step.

Los siguientes sulfuros se obtuvieron de manera análoga. The following sulfides were obtained analogously.

Estructura Structure: NOMBRE NAME

S NH2 O S NH2 O: N N N O N H N H O 2–[[2–[4–(metilcarbamoilamino)fenil]–6– [(3S)–3–metilmorfolin–4–il]pirimidin–4– il]metilsulfanil]acetamida N N N O N H N H O 2 - [[2– [4– (methylcarbamoylamino) phenyl] –6– [(3S) –3-methylmorpholin-4-yl] pyrimidin-4-yl] methylsulfanyl] acetamide

S NH O S NH O: N N N O N H N H O N–[2–[[2–[4–(metilcarbamoilamino)fenil]–6– [(3S)–3–metilmorfolin–4–il]pirimidin–4– il]metilsulfanil]etil]acetamida N N N O N H N H O N– [2 - [[2– [4– (methylcarbamoylamino) phenyl] –6– [(3S) –3-methylmorpholin-4-yl] pyrimidin-4-yl] methylsulfanyl] ethyl] acetamide

La preparación de 3–metil–1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfoniloximetil)pirimidin–2–il]fenil]urea se describió anteriormente. The preparation of 3-methyl-1– [4– [4 - [(3S) -3-methylmorpholin-4-yl] –6– (methylsulfonyloxymethyl) pyrimidin-2-yl] phenyl] urea was described above.

Ejemplo 27: 1–[4–[4–[(3S)–3–Metilmorfolin–4–il]–6–(morfolin–4–ilmetil)pirimidin–2–il]fenil]–3–fenil–urea Example 27: 1– [4– [4 - [(3S) –3 – Methylmorpholin-4-yl] –6– (morpholin-4-ylmethyl) pyrimidin-2-yl] phenyl] –3-phenyl-urea

O OR

N N

O OR

N N N N

O OR

N N

N HH N HH

N N

Se disolvió 1–[4–[4–(hidroximetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]–3–fenil–urea (90 mg) en DCM (5 ml) y trietilamina (0,045 ml), y la disolución se enfrió hasta 0ºC. Se añadió cloruro de metanosulfonilo (0,026 ml), y la reacción se agitó durante 1 h a RT. Se añadió morfolina (0,2 ml), y la reacción se dejó a RT durante 72 horas antes 1– [4– [4– (hydroxymethyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] –3-phenyl-urea (90 mg) was dissolved in DCM ( 5 ml) and triethylamine (0.045 ml), and the solution was cooled to 0 ° C. Methanesulfonyl chloride (0.026 ml) was added, and the reaction was stirred for 1 h at RT. Morpholine (0.2 ml) was added, and the reaction was left at RT for 72 hours before

10 de concentrarla a vacío, y se purificó mediante HPLC prep. (básica) para dar el compuesto deseado (64 mg) como un sólido blanco. 10 to concentrate in vacuo, and was purified by prep HPLC. (basic) to give the desired compound (64 mg) as a white solid.

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,21 (3H, d), 3,17 (4H, t), 3,46–3,52 (4H, m), 3,63 (4H, d), 3,65 (1H, s), 3,76 (1H, d), 3,95–3,98 (1H, m), 4,14 (1H, d), 4,49 (1H, s), 6,64 (1H, s), 6,97 (1H, t), 7,29 (2H, d), 7,45 (2H, d), 7,53 (2H, d), 8,25 (2H, d), 8,68 (1H, s), 8,87 (1H, s). NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.21 (3H, d), 3.17 (4H, t), 3.46-3.52 (4H, m), 3.63 (4H, d), 3.65 (1H, s), 3.76 (1H, d), 3.95-3.98 (1H, m), 4.14 (1H, d), 4.49 ( 1H, s), 6.64 (1H, s), 6.97 (1H, t), 7.29 (2H, d), 7.45 (2H, d), 7.53 (2H, d), 8.25 (2H, d), 8.68 (1H, s), 8.87 (1H, s).

15 Espectro de masa: M+H+ 489. 15 Mass spectrum: M + H + 489.

Prueba (a): 0,19 μM. Test (a): 0.19 μM.

Ejemplo 28: Example 28:

20 1–[4–[4–[(3S)–3–Metilmorfolin–4–il]–6–(fenoximetil)pirimidin–2–il]fenil]–3–fenil–urea 20 1– [4– [4 - [(3S) –3 – Methylmorpholin-4-yl] –6– (phenoxymethyl) pyrimidin-2-yl] phenyl] –3-phenyl-urea

Se disolvió 1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfoniloximetil)pirimidin–2–il]fenil]–3–fenil–urea en DCM (5 ml), se añadió fenol (41 mg), y la reacción se dejó agitar a RT durante 1 h. Se añadió DBU (0,2 ml), y la mezcla se dejó agitar durante 18 horas antes de concentrarla a vacío, y se purificó mediante HPLC prep. (básica) para dar el material deseado (26 mg) como un sólido blanco. 1– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (methylsulfonyloxymethyl) pyrimidin – 2-yl] phenyl] –3-phenyl-urea was dissolved in DCM (5 ml), Phenol (41 mg) was added, and the reaction was allowed to stir at RT for 1 h. DBU (0.2 ml) was added, and the mixture was allowed to stir for 18 hours before concentrating in vacuo, and purified by prep HPLC. (basic) to give the desired material (26 mg) as a white solid.

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,19–1,21 (3H, m), 3,18 (1H, s), 3,47–3,52 (1H, m), 3,62–3,66 (1H, m), 3,76 (1H, d), 3,95–3,99 (1H, m), 4,16 (1H, s), 4,51 (1H, s), 5,08 (2H, s), 6,72 (1H, s), 6,96–7,01 (2H, m), 7,07–7,10 (2H, m), 7,28–7,35 (4H, m), 7,48 (2H, d), 7,57 (2H, d), 8,28 (2H, d), 8,75 (1H, s), 8,95 (1H, s) NMR Spectrum: 1H NMR (400.13 MHz, DMSO – d6) δ 1.19–1.21 (3H, m), 3.18 (1H, s), 3.47–3.52 (1H, m) , 3.62-3.66 (1H, m), 3.76 (1H, d), 3.95-3.99 (1H, m), 4.16 (1H, s), 4.51 (1H , s), 5.08 (2H, s), 6.72 (1H, s), 6.96–7.01 (2H, m), 7.07–7.10 (2H, m), 7, 28–7.35 (4H, m), 7.48 (2H, d), 7.57 (2H, d), 8.28 (2H, d), 8.75 (1H, s), 8.95 (1H, s)

Espectro de masa: M+H+ 496. Mass spectrum: M + H + 496.

Prueba (a): 4,7 μM. Test (a): 4.7 μM.

Ejemplo 29: 1–[4–[4–[(3S)–3–Metilmorfolin–4–il]–6–[(2–oxopirrolidin–3–il)sulfonilmetil]pirimidin–2–il]fenil]–3–fenil–urea Example 29: 1– [4– [4 - [(3S) –3 – Methylmorpholin-4-yl] –6 - [(2-oxopyrrolidin-3-yl) sulfonylmethyl] pyrimidin-2-yl] phenyl] –3– phenyl urea

O OR

N N

N S O OO N S O OO

N N

OHN N OHN N

N HH N HH

Se disolvió 1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–[(2–oxopirrolidin–3–il)sulfanilmetil]pirimidin–2–il]fenil]–3–fenil–urea (0,26 mmoles) en 1,4–dioxano (5 ml) y agua (1 ml). Se añadió a la disolución m–CPBA (75%) (113 mg) seguido inmediatamente por permanganato de sodio (125 mg) y se dejó agitar a RT durante 1 h. La reacción se cargó en una 1– [4– [4 - [(3S) -3-methylmorpholin-4-yl] -6 - [(2-oxopyrrolidin-3-yl) sulfanylmethyl] pyrimidin-2-yl] phenyl] -3-phenyl was dissolved –Urea (0.26 mmol) in 1,4-dioxane (5 ml) and water (1 ml). M-CPBA (75%) (113 mg) was immediately added to the solution followed immediately by sodium permanganate (125 mg) and allowed to stir at RT for 1 h. The reaction was loaded in a

10 columna SCX–2 (10 g) que se lavó con metanol, y el producto se eluyó con amoniaco 7N en metanol. El material se purificó adicionalmente mediante HPLC prep. (básica) para dar el material deseado (18 mg) como un sólido blanco. 10 SCX-2 column (10 g) which was washed with methanol, and the product was eluted with 7N ammonia in methanol. The material was further purified by prep HPLC. (basic) to give the desired material (18 mg) as a white solid.

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,25 (3H, d), 2,32–2,34 (1H, m), 2,47 (1H, d), 3,24 (2H, t), 3,34 (2H, d), 3,51 (1H, t), 3,66 (1H, d), 3,78 (1H, d), 3,97–4,01 (1H, m), 4,49 (1H, s), 4,58–4,63 (2H, m), 5,01 (1H, d), 6,79 (1H, s), 6,97–7,01 (1H, m), 7,28–7,32 (1H, m), 7,30 (1H, s), 7,46–7,48 (2H, m), 7,56–7,58 (2H, m), 8,24–8,27 (2H, NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.25 (3H, d), 2.32-2.34 (1H, m), 2.47 (1H, d), 3.24 (2H, t), 3.34 (2H, d), 3.51 (1H, t), 3.66 (1H, d), 3.78 (1H, d), 3.97-4.01 ( 1H, m), 4.49 (1H, s), 4.58-4.63 (2H, m), 5.01 (1H, d), 6.79 (1H, s), 6.97–7 , 01 (1H, m), 7.28–7.32 (1H, m), 7.30 (1H, s), 7.46–7.48 (2H, m), 7.56–7.58 (2H, m), 8.24–8.27 (2H,

15 m), 8,38 (1H, s), 8,72 (1H, s), 8,92 (1H, s) 15 m), 8.38 (1H, s), 8.72 (1H, s), 8.92 (1H, s)

Espectro de masa: M+H+ 551. Mass spectrum: M + H + 551.

Prueba (a): 0,56 μM. Test (a): 0.56 μM.

A continuación se describe la preparación de 1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–[(2–oxopirrolidin–3– il)sulfanilmetil]pirimidin–2–il]fenil]–3–fenil–urea. The preparation of 1– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6 - [(2-oxopyrrolidin-3-yl) sulfanylmethyl] pyrimidin-2-yl] phenyl is described below. ] –3 – phenyl-urea.

20 1–[4–[4–[(3S)–3–Metilmorfolin–4–il]–6–[(2–oxopirrolidin–3–il)sulfanilmetil]pirimidin–2–il]fenil]–3–fenil–urea 20 1– [4– [4 - [(3S) –3 – Methylmorpholin-4-yl] –6 - [(2-oxopyrrolidin-3-yl) sulfanylmethyl] pyrimidin-2-yl] phenyl] –3-phenyl– urea

O OR

N N

N S N S

O OR

NN

HN HN

N HH N HH

N N

Se disolvió 1–[4–[4–(carbamimidoilsulfanilmetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]–3–fenil–urea (125 mg) en DMF (3 ml). Después la disolución se trató con 3–bromo–pirrolidin–2–ona (48 mg) seguido por hidróxido de sodio (42 mg) en agua (1 ml), se calentó hasta 40ºC y se dejó agitar durante 24 h. La reacción se diluyó en un poco de metanol y se cargó en una columna SCX–2 (20 g) que se lavó con metanol, y el producto deseado se eluyó con amoniaco 7N en metanol para dar el material deseado que se usó sin caracterización adicional. 1– [4– [4– (carbamimidoylsulfanylmethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] –3-phenyl-urea (125 mg) was dissolved in DMF ( 3 ml) The solution was then treated with 3-bromo-pyrrolidin-2-one (48 mg) followed by sodium hydroxide (42 mg) in water (1 ml), heated to 40 ° C and allowed to stir for 24 h. The reaction was diluted in a little methanol and loaded onto an SCX-2 column (20 g) which was washed with methanol, and the desired product was eluted with 7N ammonia in methanol to give the desired material that was used without further characterization. .

1–[4–[4–(Carbamimidoilsulfanilmetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]–3–fenil–urea 1– [4– [4– (Carbamimidoylsulfanylmethyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] –3-phenyl-urea

O OR

N N

SH2N SH2N

O NH Or NH

N N

N HH N HH

N N

Se disolvió 1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfoniloximetil)pirimidin–2–il]fenil]–3–fenil–urea (865 mg) en etanol (30 ml), y se añadió tiourea (146 mg). La reacción se calentó después hasta 70ºC durante 30 min., después se dejó enfriar y se concentró a vacío para dar el material deseado que se usó sin caracterización adicional. 1– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (methylsulfonyloxymethyl) pyrimidin – 2-yl] phenyl] –3-phenyl-urea (865 mg) was dissolved in ethanol ( 30 ml), and thiourea (146 mg) was added. The reaction was then heated to 70 ° C for 30 min., Then allowed to cool and concentrated in vacuo to give the desired material that was used without further characterization.

Ejemplo 30: 1–[4–[4–(Anilinometil)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]–3–fenil–urea Example 30: 1– [4– [4– (Anilinomethyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] –3-phenyl-urea

Se añadió a anilina (0,097 ml, 1,06 mmoles) 1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfoniloximetil)pirimidin–2– Aniline (0.097 ml, 1.06 mmol) 1– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (methylsulfonyloxymethyl) pyrimidin-2– was added

10 il]fenil]–3–fenil–urea (105 mg, 0,21 mmoles) disuelta en una disolución de DCM (5 ml), y se agitó a RT durante 18 h. La mezcla se sometió a vacío hasta sequedad, y se purificó mediante HPLC prep. (básica) para dar el material deseado (41 mg) como un sólido blanco. 10 il] phenyl] -3-phenyl-urea (105 mg, 0.21 mmol) dissolved in a DCM solution (5 ml), and stirred at RT for 18 h. The mixture was subjected to vacuum to dryness, and purified by prep HPLC. (basic) to give the desired material (41 mg) as a white solid.

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,15 (3H, d), 3,12–3,18 (1H, m), 3,43–3,50 (1H, m), 3,59–3,63 (1H, m), 3,74 (1H, d), 3,93–3,97 (1H, m), 4,10 (1H, d), 4,24 (2H, d), 4,39 (1H, s), 6,20 (1H, t), 6,55 (1H, d), 6,60 (1H, NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.15 (3H, d), 3.12–3.18 (1H, m), 3.43-3.50 (1H, m) , 3.59-3.63 (1H, m), 3.74 (1H, d), 3.93-3.97 (1H, m), 4.10 (1H, d), 4.24 (2H , d), 4.39 (1H, s), 6.20 (1H, t), 6.55 (1H, d), 6.60 (1H,

15 s), 6,63 (1H, d), 6,65 (1H, s), 6,97–7,01 (1H, m), 7,06–7,10 (2H, m), 7,28–7,32 (1H, m), 7,30 (1H, s), 7,46–7,49 (2H, m), 7,55–7,57 (2H, m), 8,29–8,31 (2H, m), 8,69 (1H, s), 8,88 (1H, s). 15 s), 6.63 (1H, d), 6.65 (1H, s), 6.97–7.01 (1H, m), 7.06–7.10 (2H, m), 7, 28–7.32 (1H, m), 7.30 (1H, s), 7.46–7.49 (2H, m), 7.55–7.57 (2H, m), 8.29– 8.31 (2H, m), 8.69 (1H, s), 8.88 (1H, s).

Espectro de masa: M+H+ 495. Mass spectrum: M + H + 495.

Los siguientes compuestos se prepararon de manera análoga. The following compounds were prepared analogously.

Ejemplo Example: Estructura NOMBRE LCMS MH+ Structure NAME LCMS MH +

30a 30th: N N N N O N N H N H O 1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–[(4– metilpiperazin–1–il)metil]pirimidin–2–il]fenil]–3– fenil–urea 502 N N N N O N N H N H O 1– [4– [4 - [(3S) –3 – methylmorpholin-4-yl] –6 - [(4– methylpiperazin – 1-yl) methyl] pyrimidin – 2-yl] phenyl] –3– phenyl-urea 502

30b 30b: HN N N N O N H N H O 1–[4–[4–[(ciclopropilamino)metil]–6–[(3S)–3– metilmorfolin–4–il]pirimidin–2–il]fenil]–3–fenil– urea 459 HN N N N O N H N H O 1– [4– [4 - [(cyclopropylamino) methyl] –6 - [(3S) –3– methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] –3-phenyl- urea 459

30c 30c: O 1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–[[(1– 516 OR 1– [4– [4 - [(3S) –3 – methylmorpholin – 4 – il] –6 - [[(1– 516

HN N HN N: N N N N H N H O metil–4–piperidil)amino]metil]pirimidin–2– il]fenil]–3–fenil–urea N N N N H N H O methyl-4-piperidyl) amino] methyl] pyrimidin-2-yl] phenyl] –3-phenyl-urea

30d 30d: O 1–[4–[4–[(ciclopropil–metil–amino)metil]–6– 473 OR 1– [4– [4 - [(cyclopropyl-methyl-amino) methyl] –6– 473

: [(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]– [(3S) –3 – methylmorpholin-4-yl] pyrimidin – 2-yl] phenyl] -

N N: N N N N H N H O 3–fenil–urea N N N N H N H O 3-phenyl-urea

Ejemplo 30a: RMN 1H (400,13 MHz, DMSO–d6) δ 1,22 (3H, d), 2,22 (3H, s), 2,44 (2H, d), 2,53 (2H, d), 2,56 (2H, s), 2,60–2,61 (1H, m), 2,67–2,69 (1H, m), 3,15–3,23 (1H, m), 3,46–3,54 (3H, m), 3,63–3,67 (1H, m), 3,77 (1H, d), 3,96– 4,00 (1H, m), 4,15 (1H, d), 4,47–4,49 (1H, m), 6,63 (1H, s), 6,97–7,01 (1H, m), 7,28–7,32 (1H, m), 7,30 (1H, s), 7,46– 7,48 (2H, m), 7,53–7,56 (2H, m), 8,25–8,27 (2H, m), 8,69 (1H, s), 8,88 (1H, s) Example 30a: 1H NMR (400.13 MHz, DMSO-d6) δ 1.22 (3H, d), 2.22 (3H, s), 2.44 (2H, d), 2.53 (2H, d ), 2.56 (2H, s), 2.60-2.61 (1H, m), 2.67-2.69 (1H, m), 3.15-3.23 (1H, m), 3.46-3.54 (3H, m), 3.63-3.67 (1H, m), 3.77 (1H, d), 3.96-4.00 (1H, m), 4, 15 (1H, d), 4.47-4.49 (1H, m), 6.63 (1H, s), 6.97-7.01 (1H, m), 7.28-7.32 ( 1H, m), 7.30 (1H, s), 7.46-7.48 (2H, m), 7.53-7.56 (2H, m), 8.25-8.27 (2H, m), 8.69 (1H, s), 8.88 (1H, s)

Ejemplo 30b: RMN 1H (400,13 MHz, DMSO–d6) δ 0,30–0,31 (2H, m), 0,37–0,40 (2H, m), 1,23 (3H, d), 2,14–2,19 (1H, m), 3,15–3,23 (1H, m), 3,46–3,53 (1H, m), 3,63–3,66 (1H, m), 3,72 (2H, s), 3,77 (1H, d), 3,96–4,00 (1H, m), 4,17 (1H, d), 4,51 (1H, d), 6,67 (1H, s), 6,99–7,01 (1H, m), 7,28–7,32 (2H, m), 7,46–7,48 (2H, m), 7,53–7,56 (2H, m), 8,28 (2H, d), 8,69 (1H, s), 8,87 (1H, s) Example 30b: 1H NMR (400.13 MHz, DMSO-d6) δ 0.30–0.31 (2H, m), 0.37–0.40 (2H, m), 1.23 (3H, d) , 2.14-2.19 (1H, m), 3.15-3.23 (1H, m), 3.46-3.53 (1H, m), 3.63-3.66 (1H, m), 3.72 (2H, s), 3.77 (1H, d), 3.96-4.00 (1H, m), 4.17 (1H, d), 4.51 (1H, d ), 6.67 (1H, s), 6.99–7.01 (1H, m), 7.28–7.32 (2H, m), 7.46–7.48 (2H, m), 7.53–7.56 (2H, m), 8.28 (2H, d), 8.69 (1H, s), 8.87 (1H, s)

Ejemplo 30d: RMN 1H (400,13 MHz, DMSO–d6) δ 0,40– 0,41 (2H, t), 0,45–0,49 (2H, m), 1,21 (3H, d), 1,90–1,95 (1H, m), 2,34 (3H, s), 3,14–3,21 (1H, m), 3,46–3,53 (1H, m), 3,63 (3H, t), 3,76 (1H, d), 3,95–3,99 (1H, m), 4,13 (1H, d), 4,49 (1H, s), 6,54 (1H, s), 6,97–7,01 (1H, m), 7,28–7,32 (1H, m), 7,30 (1H, s), 7,46–7,48 (2H, m), 7,54–7,56 (2H, m), 8,26–8,28 (2H, m), 8,69 (1H, s), 8,87 (1H, s) Example 30d: 1H NMR (400.13 MHz, DMSO – d6) δ 0.40– 0.41 (2H, t), 0.45–0.49 (2H, m), 1.21 (3H, d) , 1.90-1.95 (1H, m), 2.34 (3H, s), 3.14-3.21 (1H, m), 3.46-3.53 (1H, m), 3 , 63 (3H, t), 3.76 (1H, d), 3.95-3.99 (1H, m), 4.13 (1H, d), 4.49 (1H, s), 6, 54 (1H, s), 6.97–7.01 (1H, m), 7.28–7.32 (1H, m), 7.30 (1H, s), 7.46–7.48 ( 2H, m), 7.54–7.56 (2H, m), 8.26–8.28 (2H, m), 8.69 (1H, s), 8.87 (1H, s)

Prueba (a): Ejemplo (30) 0,9 μM; Ejemplo (30a) 0,12 μM; Ejemplo (30b) 0,18 μM; Ejemplo (30c) 1,1 μM; Ejemplo (30d) 0,28 μM. Test (a): Example (30) 0.9 μM; Example (30a) 0.12 μM; Example (30b) 0.18 μM; Example (30c) 1.1 μM; Example (30d) 0.28 μM.

Ejemplo 31: Example 31:

1–[4–[4–[(3S)–3–Metilmorfolin–4–il]–6–[(1–metil–4–piperidil)oximetil]pirimidin–2–il]fenil]–3–fenil–urea 1– [4– [4 - [(3S) –3 – Methylmorpholin-4-yl] –6 - [(1-methyl-4-piperidyl) oxymethyl] pyrimidin – 2-yl] phenyl] –3-phenyl-urea

O HH Or hh

Se añadieron a 4–hidroxi–1–metilpiperidina (5 equivalentes) de 1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6– (metilsulfoniloximetil)pirimidin–2–il]fenil]–3–fenil–urea (105 mg) disuelta en una disolución de DCM (5 ml) y trietilamina (0,045 ml). Se añadió DBU (0,158 ml) y se agitó a RT durante 18 h. La mezcla se sometió a vacío hasta sequedad, y se purificó mediante HPLC prep. (básica) para dar el material deseado (64 mg) como un sólido blanco. To 4-hydroxy-1-methylpiperidine (5 equivalents) of 1– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (methylsulfonyloxymethyl) pyrimidin-2-yl] phenyl] were added -3-phenyl-urea (105 mg) dissolved in a solution of DCM (5 ml) and triethylamine (0.045 ml). DBU (0.158 ml) was added and stirred at RT for 18 h. The mixture was subjected to vacuum to dryness, and purified by prep HPLC. (basic) to give the desired material (64 mg) as a white solid.

Espectro de masa: M+H+ 517. Mass spectrum: M + H + 517.

Prueba (a): 0,35 μM. Test (a): 0.35 μM.

Ejemplo 32: 1–[4–[4–(Metoximetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]–3–fenil–urea Example 32: 1– [4– [4– (Methoxymethyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] –3-phenyl-urea

Se disolvió 1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfoniloximetil)pirimidin–2–il]fenil]–3–fenil–urea (90 mg) en una disolución de DCM (5 ml) y trietilamina (0,045 ml). Se añadió metóxido de sodio (33% en metanol) (0,073 ml) a la reacción, y la mezcla se agitó a RT durante 18 h antes paralizarla con agua, y se repartió. La fase orgánica se secó sobre sulfato de magnesio y se evaporó para dar una goma que se purificó mediante HPLC prep. (básica) para dar el compuesto deseado (32 mg) como un sólido blanco. 1– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (methylsulfonyloxymethyl) pyrimidin – 2-yl] phenyl] –3-phenyl-urea (90 mg) was dissolved in a solution of DCM (5 ml) and triethylamine (0.045 ml). Sodium methoxide (33% in methanol) (0.073 ml) was added to the reaction, and the mixture was stirred at RT for 18 h before being paralyzed with water, and partitioned. The organic phase was dried over magnesium sulfate and evaporated to give a gum that was purified by prep HPLC. (basic) to give the desired compound (32 mg) as a white solid.

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,23 (3H, d), 3,34 (1H, d), 3,43 (3H, s), 3,49 (1H, t), 3,63–3,66 (1H, m), 3,76 (1H, d), 3,97 (1H, d), 4,19 (1H, d), 4,41 (2H, s), 4,51 (1H, d), 6,59 (1H, s), 6,99 (1H, t), 7,30 (2H, t), 7,46–7,48 (2H, m), 7,55 (2H, d), 8,26 (2H, d), 8,69 (1H, s), 8,88 (1H, s) NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.23 (3H, d), 3.34 (1H, d), 3.43 (3H, s), 3.49 (1H, t ), 3.63-3.66 (1H, m), 3.76 (1H, d), 3.97 (1H, d), 4.19 (1H, d), 4.41 (2H, s) , 4.51 (1H, d), 6.59 (1H, s), 6.99 (1H, t), 7.30 (2H, t), 7.46-7.48 (2H, m), 7.55 (2H, d), 8.26 (2H, d), 8.69 (1H, s), 8.88 (1H, s)

Espectro de masa: M+H+ 434. Mass spectrum: M + H + 434.

Prueba (a): 0,0062 μM. Test (a): 0.0062 μM.

Ejemplo 33: 3–Metil–1–[4–[4–[(1–metilimidazol–2–il)sulfonilmetil]–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]urea Example 33: 3 – Methyl – 1– [4– [4 - [(1-methylimidazol-2-yl) sulfonylmethyl] –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl ]urea

O OR

N N

N N N N

N O NO

S S

N N

OO N OO N

N HH N HH

10 Se disolvió 3–metil–1–[4–[4–[(1–metilimidazol–2–il)sulfanilmetil]–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2– il]fenil]urea (0,23 mmoles) en 1,4–dioxano (4 ml) y agua (1 ml). Se añadió a la disolución m–CPBA (75%) (80 mg), seguido inmediatamente por permanganato de sodio (92 mg). La reacción se dejó agitar a RT durante 18 h, después se cargó en una columna SCX–2 (10 g) que se lavó con metanol, y el producto se eluyó con amoniaco 7N en 10 3-methyl-1– [4– [4 - [(1-methylimidazol-2-yl) sulfanylmethyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl was dissolved ] urea (0.23 mmol) in 1,4-dioxane (4 ml) and water (1 ml). M-CPBA (75%) (80 mg) was added to the solution, followed immediately by sodium permanganate (92 mg). The reaction was allowed to stir at RT for 18 h, then loaded on a SCX-2 column (10 g) which was washed with methanol, and the product was eluted with 7N ammonia in

15 metanol. La reacción se sometió a vacío hasta sequedad, y se purificó mediante HPLC prep. (básica) para dar el material deseado (37 mg) como un sólido blanco. 15 methanol The reaction was subjected to vacuum to dryness, and purified by prep HPLC. (basic) to give the desired material (37 mg) as a white solid.

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,17–1,22 (3H, m), 2,66 (3H, d), 2,68 (1H, t), 3,14–3,22 (1H, m), 3,45–3,49 (1H, m), 3,62 (3H, s), 3,77 (1H, d), 3,96–3,99 (1H, m), 4,09–4,12 (1H, m), 4,41 (1H, s), 4,75 (2H, s), 6,07 (1H, q), 6,61 (1H, s), 7,20 (1H, d), 7,43–7,47 (2H, m), 7,43–7,49 (1H, m), 7,95–7,97 (2H, m), 8,72 (1H, s) NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.17-1.22 (3H, m), 2.66 (3H, d), 2.68 (1H, t), 3.14 –3.22 (1H, m), 3.45-3.49 (1H, m), 3.62 (3H, s), 3.77 (1H, d), 3.96-3.99 (1H , m), 4.09-4.12 (1H, m), 4.41 (1H, s), 4.75 (2H, s), 6.07 (1H, q), 6.61 (1H, s), 7.20 (1H, d), 7.43-7.47 (2H, m), 7.43-7.49 (1H, m), 7.95-7.97 (2H, m) , 8.72 (1H, s)

20 Espectro de masa: M+H+ 486. 20 Mass spectrum: M + H + 486.

Ejemplo Example: Estructura NOMBRE LCMS MH+ Structure NAME LCMS MH +

33a 33rd: S O O Cl N N N O N H N H O 1–[4–[4–[(2–clorofenil)sulfonilmetil]–6–[(3S)–3– metilmorfolin–4–il]pirimidin–2–il]fenil]–3–metil– urea 516 S O O Cl N N N O N H N H O 1– [4– [4 - [(2-chlorophenyl) sulfonylmethyl] –6 - [(3S) -3– methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] –3-methyl-urea 516

33b 33b: S O O O N N N O N H N H O 1–[4–[4–[(2–metoxifenil)sulfonilmetil]–6–[(3S)– 3–metilmorfolin–4–il]pirimidin–2–il]fenil]–3– metil–urea 512 S O O O N N N O N H N H O 1– [4– [4 - [(2-methoxyphenyl) sulfonylmethyl] –6 - [(3S) - 3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] –3– methyl-urea 512

33c 33c: O 1–[4–[4–(1H–imidazol–2–ilsulfonilmetil)–6– 472 OR 1– [4– [4– (1H – imidazol – 2-ylsulfonylmethyl) –6– 472

S O O NHN S O O NHN: N N N N H N H O 3–metil–urea N N N N H N H O 3-methyl-urea

Ejemplo Example: Estructura NOMBRE LCMS MH+ Structure NAME LCMS MH +

33d 33d: N N N O S N H N H OO O NH2 1–[4–[4–[(4–aminofenil)sulfonilmetil]–6–[(3S)– 3–metilmorfolin–4–il]pirimidin–2–il]fenil]–3– metil–urea 497 N N N O S N H N H OO O NH2 1– [4– [4 - [(4 – aminophenyl) sulfonylmethyl] –6 - [(3S) - 3-methylmorpholin-4-yl] pyrimidin – 2-yl] phenyl] –3– methyl-urea 497

33e 33e: N N N O S N H N H OO O 3–metil–1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6– [(2–metilfenil)sulfonilmetil]pirimidin–2– il]fenil]urea 496 N N N O S N H N H OO O 3-methyl – 1– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– [(2-methylphenyl) sulfonylmethyl] pyrimidin – 2-yl] phenyl] urea 496

33f 33f: N N N O S N H N H OO O N 3–metil–1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6– (piridin–2–ilsulfonilmetil)pirimidin–2–il]fenil]urea 483 N N N O S N H N H OO O N 3 – methyl – 1– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (pyridin-2-ylsulfonylmethyl) pyrimidin – 2-yl] phenyl] urea 483

33g 33g: N N N O S N H N H OO O SN 3–metil–1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6– (1,3–tiazol–2–ilsulfonilmetil)pirimidin–2– il]fenil]urea 489 N N N O S N H N H OO O SN 3-methyl-1– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (1,3-thiazol-2-ylsulfonylmethyl) pyrimidin-2-yl] phenyl] urea 489

33h 33h: O 3–metil–1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6– 503 OR 3 – methyl – 1– [4– [4 - [(3S) –3 – methylmorpholin – 4 – il] –6– 503

: [(4–metil–1,3–tiazol–2–il)sulfonilmetil]pirimidin– [(4-methyl-1,3-thiazol-2-yl) sulfonylmethyl] pyrimidin–

N N N S N H N H OO O SN N N N S N H N H OO O SN: 2–il]fenil]urea 2-yl] phenyl] urea

Ejemplo 33a: RMN 1H (400,13 MHz, DMSO–d6) δ 1,22 (3H, q), 2,65–2,68 (3H, m), 2,68 (1H, d), 3,17 (1H, d), 3,44– 3,51 (1H, m), 3,61–3,65 (1H, m), 3,76 (1H, d), 3,95–3,99 (1H, m), 4,09 (1H, t), 4,88 (2H, s), 6,05 (1H, q), 6,71 (1H, s), 7,33–7,35 (2H, m), 7,44–7,48 (1H, m), 7,65–7,69 (1H, m), 7,67 (1H, s), 7,71–7,77 (2H, m), 7,83–7,85 (1H, m), 8,68 Example 33a: 1H NMR (400.13 MHz, DMSO-d6) δ 1.22 (3H, q), 2.65-2.68 (3H, m), 2.68 (1H, d), 3.17 (1H, d), 3.44-3.51 (1H, m), 3.61-3.65 (1H, m), 3.76 (1H, d), 3.95-3.99 (1H , m), 4.09 (1H, t), 4.88 (2H, s), 6.05 (1H, q), 6.71 (1H, s), 7.33-7.35 (2H, m), 7.44-7.48 (1H, m), 7.65-7.69 (1H, m), 7.67 (1H, s), 7.71-7.77 (2H, m) , 7.83–7.85 (1H, m), 8.68

5 (1H, s). 5 (1H, s).

Ejemplo 33b: RMN 1H (400,13 MHz, DMSO–d6) δ 1,18 (3H, d), 2,66–2,69 (3H, m), 3,12–3,21 (1H, m), 3,43–3,50 (1H, m), 3,59–3,63 (1H, m), 3,75 (1H, d), 3,94–3,98 (1H, m), 4,05 (4H, m), 4,37 (1H, s), 4,70–4,77 (2H, m), 6,04 (1H, q), 6,61 (1H, s), 7,01–7,05 (1H, m), 7,34–7,36 (2H, m), 7,39 (1H, d), 7,54–7,57 (1H, m), 7,67–7,74 (3H, m), 8,67 (1H, s). Example 33b: 1H NMR (400.13 MHz, DMSO-d6) δ 1.18 (3H, d), 2.66-2.69 (3H, m), 3.12–3.21 (1H, m) , 3.43-3.50 (1H, m), 3.59-3.63 (1H, m), 3.75 (1H, d), 3.94-3.98 (1H, m), 4 , 05 (4H, m), 4.37 (1H, s), 4.70-4.77 (2H, m), 6.04 (1H, q), 6.61 (1H, s), 7, 01–7.05 (1H, m), 7.34–7.36 (2H, m), 7.39 (1H, d), 7.54–7.57 (1H, m), 7.67– 7.74 (3H, m), 8.67 (1H, s).

10 Ejemplo 33c: RMN 1H (400,13 MHz, DMSO–d6) δ 1,20 (3H, d), 2,66 (3H, d), 3,12–3,20 (1H, m), 3,43–3,50 (1H, m), 3,60–3,63 (1H, m), 3,76 (1H, d), 3,95–3,99 (1H, m), 4,08 (1H, d), 4,36 (1H, s), 4,71 (2H, s), 6,06 (1H, q), 6,47 (1H, s), 7,34 (2H, s), 7,42–7,44 (2H, m), 7,95–7,97 (2H, m), 8,70 (1H, s), 13,52 (1H, s) Example 33c: 1H NMR (400.13 MHz, DMSO-d6) δ 1.20 (3H, d), 2.66 (3H, d), 3.12-3.20 (1H, m), 3, 43–3.50 (1H, m), 3.60–3.63 (1H, m), 3.76 (1H, d), 3.95–3.99 (1H, m), 4.08 ( 1H, d), 4.36 (1H, s), 4.71 (2H, s), 6.06 (1H, q), 6.47 (1H, s), 7.34 (2H, s), 7.42–7.44 (2H, m), 7.95–7.97 (2H, m), 8.70 (1H, s), 13.52 (1H, s)

Ejemplo 33d: RMN 1H (400,13 MHz, DMSO–d6) δ 1,19 (3H, d), 2,66–2,69 (3H, m), 3,12–3,21 (1H, m), 3,44–3,48 (1H, m), 3,60–3,64 (1H, m), 3,75 (1H, d), 3,94–3,98 (1H, m), 4,05 (1H, t), 4,33 (1H, s), 4,44 (2H, s), 6,06 (1H, t), 6,12 Example 33d: 1H NMR (400.13 MHz, DMSO-d6) δ 1.19 (3H, d), 2.66-2.69 (3H, m), 3.12–3.21 (1H, m) , 3.44-3.48 (1H, m), 3.60-3.64 (1H, m), 3.75 (1H, d), 3.94-3.98 (1H, m), 4 , 05 (1H, t), 4.33 (1H, s), 4.44 (2H, s), 6.06 (1H, t), 6.12

15 (2H, d), 6,41 (1H, s), 6,58–6,62 (2H, m), 7,34–7,38 (2H, m), 7,42–7,46 (2H, m), 7,99–8,01 (2H, m), 8,70 (1H, s) 15 (2H, d), 6.41 (1H, s), 6.58-6.62 (2H, m), 7.34-7.38 (2H, m), 7.42-7.46 ( 2H, m), 7.99–8.01 (2H, m), 8.70 (1H, s)

Ejemplo 33e: RMN 1H (400,13 MHz, DMSO–d6) δ 1,19 (3H, d), 2,67 (6H, m), 3,14–3,18 (1H, m), 3,44–3,50 (1H, m), 3,60–3,64 (1H, m), 3,76 (1H, d), 3,94–3,98 (1H, m), 4,06 (1H, q), 4,37 (1H, s), 4,66 (2H, s), 6,05 (1H, d), 6,60 (1H, s), 7,34 (1H, d), 7,36–7,38 (2H, m), 7,47 (1H, d), 7,56–7,60 (1H, m), 7,66–7,68 (1H, m), 7,77–7,80 (2H, m), 8,69 (1H, s) Example 33e: 1H NMR (400.13 MHz, DMSO-d6) δ 1.19 (3H, d), 2.67 (6H, m), 3.14-3.18 (1H, m), 3.44 –3.50 (1H, m), 3.60–3.64 (1H, m), 3.76 (1H, d), 3.94–3.98 (1H, m), 4.06 (1H , q), 4.37 (1H, s), 4.66 (2H, s), 6.05 (1H, d), 6.60 (1H, s), 7.34 (1H, d), 7 , 36–7.38 (2H, m), 7.47 (1H, d), 7.56–7.60 (1H, m), 7.66–7.68 (1H, m), 7.77 –7.80 (2H, m), 8.69 (1H, s)

Ejemplo 33f: RMN 1H (400,13 MHz, DMSO–d6) δ 1,20 (3H, d), 2,65–2,68 (3H, m), 3,16–3,21 (1H, m), 3,44–3,51 20 (1H, m), 3,60–3,64 (1H, m), 3,76 (1H, d), 3,95–3,99 (1H, m), 4,11 (1H, d), 4,38 (1H, s), 4,80–4,88 (2H, m), 6,04 (1H, q), 6,68 (1H, s), 7,34–7,36 (2H, m), 7,64–7,67 (2H, m), 7,78–7,81 (1H, m), 7,88–7,90 (1H, m), 8,07–8,12 (1H, m), 8,69 (1H, s), 8,92–8,94 (1H, m) Example 33f: 1H NMR (400.13 MHz, DMSO-d6) δ 1.20 (3H, d), 2.65-2.68 (3H, m), 3.16–3.21 (1H, m) , 3.44-3.51 20 (1H, m), 3.60-3.64 (1H, m), 3.76 (1H, d), 3.95-3.99 (1H, m), 4.11 (1H, d), 4.38 (1H, s), 4.80-4.88 (2H, m), 6.04 (1H, q), 6.68 (1H, s), 7 , 34–7.36 (2H, m), 7.64–7.67 (2H, m), 7.78–7.81 (1H, m), 7.88–7.90 (1H, m) , 8.07–8.12 (1H, m), 8.69 (1H, s), 8.92–8.94 (1H, m)

Ejemplo 33g: RMN 1H (400,13 MHz, DMSO–d6) δ 1,21 (3H, d), 2,67 (3H, q), 3,16–3,21 (1H, m), 3,45–3,52 (1H, m), 3,62–3,65 (1H, m), 3,77 (1H, d), 3,96–3,99 (1H, m), 4,40 (2H, s), 4,91 (2H, d), 6,06 (1H, d), 6,70 (1H, s), 7,40–7,42 5 (2H, m), 7,84 (2H, d), 8,27–8,29 (2H, m), 8,71 (1H, s). Example 33g: 1H NMR (400.13 MHz, DMSO-d6) δ 1.21 (3H, d), 2.67 (3H, q), 3.16-3.21 (1H, m), 3.45 –3.52 (1H, m), 3.62–3.65 (1H, m), 3.77 (1H, d), 3.96–3.99 (1H, m), 4.40 (2H , s), 4.91 (2H, d), 6.06 (1H, d), 6.70 (1H, s), 7.40–7.42 5 (2H, m), 7.84 (2H , d), 8.27–8.29 (2H, m), 8.71 (1H, s).

Ejemplo 33h: RMN 1H (400,13 MHz, DMSO–d6) δ 1,21–1,27 (3H, m), 2,52–2,61 (3H, m), 2,66–2,69 (3H, m), 3,15– 3,22 (1H, m), 3,45–3,52 (1H, m), 3,62–3,66 (1H, m), 3,77 (1H, d), 3,96–4,00 (1H, m), 4,13 (1H, d), 4,40 (1H, s), 4,87 (2H, d), 6,05 (1H, q), 6,70 (1H, s), 7,41–7,43 (2H, m), 7,82 (1H, S) Example 33h: 1H NMR (400.13 MHz, DMSO-d6) δ 1.21-1.27 (3H, m), 2.52-2.61 (3H, m), 2.66-2.69 ( 3H, m), 3.15-3.22 (1H, m), 3.45-3.52 (1H, m), 3.62-3.66 (1H, m), 3.77 (1H, d), 3.96-4.00 (1H, m), 4.13 (1H, d), 4.40 (1H, s), 4.87 (2H, d), 6.05 (1H, q ), 6.70 (1H, s), 7.41-7.43 (2H, m), 7.82 (1H, S)

Prueba (a): Ejemplo (33) 0,84 μM; Ejemplo (33a) 0,06 μM; Ejemplo (33b) 0,066 μM; Ejemplo (33c) 0,0014 μM; Test (a): Example (33) 0.84 μM; Example (33a) 0.06 μM; Example (33b) 0.066 μM; Example (33c) 0.0014 μM;

10 Ejemplo (33d) 0,00031 μM; Ejemplo (33e) 0,088 μM; Ejemplo (33f) 0,27 μM; Ejemplo (33g) 0,021 μM; Ejemplo (33h) 0,048 μM. 10 Example (33d) 0.00031 μM; Example (33e) 0.088 μM; Example (33f) 0.27 μM; Example (33g) 0.021 μM; Example (33h) 0.048 μM.

A continuación se describe la preparación de 3–metil–1–[4–[4–[(1–metilimidazol–2–il)sulfanilmetil]–6–[(3S)–3– metilmorfolin–4–il]pirimidin–2–il]fenil]urea. The preparation of 3-methyl-1– [4– [4 - [(1-methylimidazol-2-yl) sulfanylmethyl] –6 - [(3S) –3– methylmorpholin-4-yl] pyrimidin – 2 is described below. -Yl] phenyl] urea.

3–Metil–1–[4–[4–[(1–metilimidazol–2–il)sulfanilmetil]–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]urea 3 – Methyl – 1– [4– [4 - [(1-methylimidazol-2-yl) sulfanylmethyl] –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] urea

O OR

N N

N N N N

N S N S

OOR

N N

N HH N HH

N N

15 Se disolvió 1–metilimidazol–2–tiol (0,23 mmoles) en acetonitrilo (2 ml), se añadió DBU (0,035 ml), y la reacción se dejó agitar a RT durante 5 min. Se añadieron una disolución de 3–metil–1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6– (metilsulfoniloximetil)pirimidin–2–il]fenil]urea (100 mg) en acetonitrilo (2 ml) y DBU (0,034 ml), y la mezcla se dejó agitar a RT 18 h, antes de concentrarla a vacío para dar el material deseado. El material se usó sin purificación 1-Methylimidazole-2-thiol (0.23 mmol) was dissolved in acetonitrile (2 ml), DBU (0.035 ml) was added, and the reaction was allowed to stir at RT for 5 min. A solution of 3-methyl-1– [4– [4 - [(3S) -3-methylmorpholin-4-yl] -6– (methylsulfonyloxymethyl) pyrimidin-2-yl] phenyl] urea (100 mg) was added in 100 acetonitrile (2 ml) and DBU (0.034 ml), and the mixture was allowed to stir at RT 18 h, before concentrating in vacuo to give the desired material. The material was used without purification

20 adicional. 20 additional.

Los siguientes sulfuros se prepararon de manera análoga. The following sulfides were prepared analogously.

Estructura Structure: NOMBRE NAME

N N N O S N H N H O Cl N N N O S N H N H O Cl: 1–[4–[4–[(2–clorofenil)sulfanilmetil]–6–[(3S)–3– metilmorfolin–4–il]pirimidin–2–il]fenil]–3–metil–urea 1– [4– [4 - [(2-chlorophenyl) sulfanylmethyl] –6 - [(3S) –3– methylmorpholin-4-yl] pyrimidin – 2-yl] phenyl] –3-methyl-urea

N N N O S N H N H O O N N N O S N H N H O O: 1–[4–[4–[(2–metoxifenil)sulfanilmetil]–6–[(3S)–3– metilmorfolin–4–il]pirimidin–2–il]fenil]–3–metil–urea 1– [4– [4 - [(2-methoxyphenyl) sulfanylmethyl] –6 - [(3S) -3– methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] –3-methyl-urea

N N N O S N H N H O NHN N N N O S N H N H O NHN: 1–[4–[4–(1H–imidazol–2–ilsulfanilmetil)–6–[(3S)–3– metilmorfolin–4–il]pirimidin–2–il]fenil]–3–metil–urea 1– [4– [4– (1H – imidazol – 2-ylsulfanylmethyl) –6 - [(3S) –3– methylmorpholin-4-yl] pyrimidin – 2-yl] phenyl] –3-methyl-urea

Estructura Structure: NOMBRE NAME

S NH2 S NH2: N N N O N H N H O 1–[4–[4–[(4–aminofenil)sulfanilmetil]–6–[(3S)–3– metilmorfolin–4–il]pirimidin–2–il]fenil]–3–metil–urea N N N O N H N H O 1– [4– [4 - [(4 – aminophenyl) sulfanylmethyl] –6 - [(3S) –3– methylmorpholin-4-yl] pyrimidin – 2-yl] phenyl] –3-methyl-urea

S S: N N N O N H N H O 3–metil–1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–[(2– metilfenil)sulfanilmetil]pirimidin–2–il]fenil]urea N N N O N H N H O 3 – methyl – 1– [4– [4 - [(3S) –3 – methylmorpholin-4-yl] –6 - [(2– methylphenyl) sulfanylmethyl] pyrimidin – 2-yl] phenyl] urea

S N S N: N N N O N H N H O 3–metil–1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6– (piridin–2–ilsulfanilmetil)pirimidin–2–il]fenil]urea N N N O N H N H O 3 – methyl – 1– [4– [4 - [(3S) –3 – methylmorpholin-4-yl] –6– (pyridin-2-ylsulfanylmethyl) pyrimidin – 2-yl] phenyl] urea

S SN S SN: N N N O N H N H O 3–metil–1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(1,3– tiazol–2–ilsulfanilmetil)pirimidin–2–il]fenil]urea N N N O N H N H O 3 – methyl – 1– [4– [4 - [(3S) –3 – methylmorpholin-4-yl] –6– (1,3– thiazol-2-ylsulfanylmethyl) pyrimidin – 2-yl] phenyl] urea

S SN S SN: N N N O N H N H O 3–metil–1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–[(4– metil–1,3–tiazol–2–il)sulfanilmetil]pirimidin–2– il]fenil]urea N N N O N H N H O 3 – methyl – 1– [4– [4 - [(3S) –3 – methylmorpholin-4-yl] –6 - [(4– methyl – 1,3-thiazol-2-yl) sulfanylmethyl] pyrimidin – 2– il] phenyl] urea

Ejemplo 34: [4–[4–(Metilsulfonilmetil)–6–morfolin–4–il–pirimidin–2–il]fenil]urea
Example 34: [4– [4– (Methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] phenyl] urea

Se disolvió N–[4–[4–(metilsulfonilmetil)–6–morfolin–4–il–pirimidin–2–il]fenil]carbamato de fenilo (110 mg) en DMF (2 ml), y se añadió trietilamina (0,098 ml). Se añadió 2–aminopirimidina (108 mg), y la reacción se agitó a 40ºC durante 2 horas. La mezcla bruta se purificó mediante HPLC prep. (básica), sin embargo, solamente se aisló de la mezcla [4–[4–(metilsulfonilmetil)–6–morfolin–4–il–pirimidin–2–il]fenil]urea (8 mg). Phenyl N- [4– [4– (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] phenyl] carbamate (110 mg) was dissolved in DMF (2 ml), and triethylamine (0.098 ml) 2-Aminopyrimidine (108 mg) was added, and the reaction was stirred at 40 ° C for 2 hours. The crude mixture was purified by prep HPLC. (basic), however, only [4– [4– (methylsulfonylmethyl) –6-morpholin-4-yl-pyrimidin-2-yl] phenyl] urea (8 mg) was isolated from the mixture.

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 3,21 (3H, s), 3,71–3,72 (8H, m), 4,48 (2H, s), 5,91 (2H, s), 6,81 (1H, s), 7,49–7,51 (2H, m), 8,20–8,23 (2H, m), 8,76 (1H, s) NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 3.21 (3H, s), 3.71-3.72 (8H, m), 4.48 (2H, s), 5.91 (2H, s), 6.81 (1H, s), 7.49–7.51 (2H, m), 8.20–8.23 (2H, m), 8.76 (1H, s)

Espectro de masa: M+H+ 392. Los siguientes compuestos se prepararon en un procedimiento análogo. Mass spectrum: M + H + 392. The following compounds were prepared in an analogous procedure.

Ejemplo Example: Estructura NOMBRE LCMS MH+ Structure NAME LCMS MH +

34a 34th: S O O N N N O N H N H O N O 1–[4–[4–(metilsulfonilmetil)–6–morfolin–4–il– pirimidin–2–il]fenil]–3–(1,2–oxazol–3–il)urea 458 S O O N N N O N H N H O N O 1– [4– [4– (methylsulfonylmethyl) –6-morpholin-4-yl-pyrimidin-2-yl] phenyl] –3– (1,2-oxazol-3-yl) urea 458

34b 34b: O 1–(5–metil–1,2–oxazol–3–il)–3–[4–[4– 472 OR 1– (5 – methyl – 1,2 – oxazol – 3 – yl) –3– [4– [4– 472

(metilsulfonilmetil)–6–morfolin–4–il–pirimidin– (methylsulfonylmethyl) –6 – morpholin-4-yl-pyrimidin–

S O O S O O: N N N N H N H O N O 2–il]fenil]urea N N N N H N H O N O 2-yl] phenyl] urea

34c 34c: O 1–(1–metilpirazol–3–il)–3–[4–[4– 471 OR 1– (1 – methylpyrazole – 3 – il) –3– [4– [4– 471

S O O S O O: N N N N H N H O N N (metilsulfonilmetil)–6–morfolin–4–il–pirimidin– 2–il]fenil]urea N N N N H N H O N N (methylsulfonylmethyl) –6 – morpholin-4-yl-pyrimidin– 2-yl] phenyl] urea

Ejemplo 34a: RMN 1H (400,13 MHz, DMSO–d6) δ 3,21 (3H, s), 3,73 (8H, s), 4,50 (2H, s), 6,85–6,87 (2H, m), 7,56– 5 7,59 (2H, m), 8,28–8,31 (2H, m), 8,75 (1H, d), 9,07 (1H, s), 9,62 (1H, s) Example 34a: 1H NMR (400.13 MHz, DMSO-d6) δ 3.21 (3H, s), 3.73 (8H, s), 4.50 (2H, s), 6.85-6.87 (2H, m), 7.56-5.59 (2H, m), 8.28-8.31 (2H, m), 8.75 (1H, d), 9.07 (1H, s) , 9.62 (1H, s)

Ejemplo 34b: RMN 1H (400,13 MHz, DMSO–d6) δ 3,15–3,25 (3H, s), 3,21–3,26 (3H, S), 3,73 (8H, s), 4,49 (2H, s), 6,56 (1H, s), 6,85 (1H, s), 7,55–7,57 (2H, m), 8,28–8,30 (2H, m), 9,05 (1H, s), 9,47 (1H, s) Example 34b: 1H NMR (400.13 MHz, DMSO-d6) δ 3.15-3.25 (3H, s), 3.21-3.26 (3H, S), 3.73 (8H, s) , 4.49 (2H, s), 6.56 (1H, s), 6.85 (1H, s), 7.55–7.57 (2H, m), 8.28–8.30 (2H , m), 9.05 (1H, s), 9.47 (1H, s)

Ejemplo 34c: RMN 1H (400,13 MHz, DMSO–d6) δ 3,21 (3H, s), 3,72 (3H, s), 3,74 (8H, s), 4,49 (2H, s), 6,25 (1H, d), 6,84 (1H, s), 7,54–7,56 (2H, m), 7,57 (1H, d), 8,26–8,28 (2H, m), 8,93 (1H, s), 9,18 (1H, s). Example 34c: 1H NMR (400.13 MHz, DMSO-d6) δ 3.21 (3H, s), 3.72 (3H, s), 3.74 (8H, s), 4.49 (2H, s ), 6.25 (1H, d), 6.84 (1H, s), 7.54–7.56 (2H, m), 7.57 (1H, d), 8.26–8.28 ( 2H, m), 8.93 (1H, s), 9.18 (1H, s).

10 Prueba (a): Ejemplo (34) 0,21 μM; Ejemplo (34a) 0,042 μM; Ejemplo (34b) 0,12 μM; Ejemplo (34c) 0,72 μM. 10 Test (a): Example (34) 0.21 μM; Example (34a) 0.042 μM; Example (34b) 0.12 μM; Example (34c) 0.72 μM.

La preparación de N–[4–[4–(metilsulfonilmetil)–6–morfolin–4–il–pirimidin–2–il]fenil]carbamato de fenilo se describió anteriormente. The preparation of phenyl N- [4– [4– (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] phenyl] carbamate was described above.

Ejemplo 35: 3–(1–Hidroxipropan–2–il)–1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidin–2–il]fenil]urea Example 35: 3– (1 – Hydroxypropan – 2 – yl) –1– [4– [4 - [(3S) –3 – methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin – 2-yl] phenyl] urea

O OR

N N

N S N S

OO OO

OH OH

N N

O OR

N N

N HH N HH

15 Se añadieron a 2–aminopropan–1–ol (1,14 mmoles) una disolución de N–[4–[4–[(3S)–3–metilmorfolin–4–il]–6– (metilsulfonilmetil)pirimidin–2–il]fenil]carbamato de fenilo (110 mg, 0,23 mmoles) y trietilamina (0,079 ml, 0,68 mmoles) en DMF (2 ml). La reacción se agitó a 40ºC durante 2 horas y después se purificó mediante HPLC prep. (básica) para dar el material deseado como un sólido (22 mg). 15 A solution of N– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin – 2 was added to 2 – aminopropan – 1 – ol (1.14 mmol) -Yl] phenyl] phenyl carbamate (110 mg, 0.23 mmol) and triethylamine (0.079 ml, 0.68 mmol) in DMF (2 ml). The reaction was stirred at 40 ° C for 2 hours and then purified by prep HPLC. (basic) to give the desired material as a solid (22 mg).

20 Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,09 (3H, d), 1,24 (3H, d), 3,21 (3H, s), 3,37–3,43 (2H, m), 3,47– 3,53 (2H, m), 3,63–3,67 (1H, m), 3,72 (1H, d), 3,78 (1H, d), 3,97–4,01 (1H, m), 4,15–4,19 (1H, m), 4,48 (3H, s), 4,78 (1H, t), 6,09–6,11 (1H, m), 6,77 (1H, s), 7,47–7,49 (2H, m), 8,20–8,22 (2H, m), 8,71 (1H, s) 20 NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.09 (3H, d), 1.24 (3H, d), 3.21 (3H, s), 3.37-3, 43 (2H, m), 3.47-3.53 (2H, m), 3.63-3.67 (1H, m), 3.72 (1H, d), 3.78 (1H, d) , 3.97-4.01 (1H, m), 4.15-4.19 (1H, m), 4.48 (3H, s), 4.78 (1H, t), 6.09-6 , 11 (1H, m), 6.77 (1H, s), 7.47-7.49 (2H, m), 8.20-8.22 (2H, m), 8.71 (1H, s )

Espectro de masa: M+H+ 463. Los siguientes compuestos se prepararon de manera análoga Mass spectrum: M + H + 463. The following compounds were prepared analogously

Ejemplo Example: Estructura NOMBRE LCMS MH+ Structure NAME LCMS MH +

35a 35th: O 3–(3–dimetilaminopropil)–1–[4–[4–[(3S)–3– 491 OR 3– (3 – dimethylaminopropyl) –1– [4– [4 - [(3S) –3– 491

: metilmorfolin–4–il]–6– methylmorpholin – 4 – il] –6–

N N N S O O N H O N H N N N N S O O N H O N H N: (metilsulfonilmetil)pirimidin–2–il]fenil]urea (methylsulfonylmethyl) pyrimidin-2-yl] phenyl] urea

35b 35b: O 3–(3–metoxipropil)–1–[4–[4–[(3S)–3– 478 OR 3– (3 – methoxypropyl) –1– [4– [4 - [(3S) –3– 478

: metilmorfolin–4–il]–6– methylmorpholin – 4 – il] –6–

N N N S O O N H O N H O N N N S O O N H O N H O: (metilsulfonilmetil)pirimidin–2–il]fenil]urea (methylsulfonylmethyl) pyrimidin-2-yl] phenyl] urea

35c 35c: O N–[4–[4–[(3S)–3–metilmorfolin–4–il]–6– 460 OR N– [4– [4 - [(3S) –3 – methylmorpholin – 4 – il] –6– 460

: (metilsulfonilmetil)pirimidin–2–il]fenil]pirrolidina– (methylsulfonylmethyl) pyrimidin-2-yl] phenyl] pyrrolidine–

N N N S O O N H O N N N N S O O N H O N: 1–carboxamida 1-carboxamide

35d 35d: O N–[4–[4–[(3S)–3–metilmorfolin–4–il]–6– 476 OR N– [4– [4 - [(3S) –3 – methylmorpholin – 4 – il] –6– 476

: (metilsulfonilmetil)pirimidin–2–il]fenil]morfolina– (methylsulfonylmethyl) pyrimidin-2-yl] phenyl] morpholine–

N N N S O O N H O N O N N N S O O N H O N O: 4–carboxamida 4-carboxamide

35e 35e: O 4–hidroxi–N–[4–[4–[(3S)–3–metilmorfolin–4–il]– 490 OR 4 – hydroxy – N– [4– [4 - [(3S) –3 – methylmorpholin-4-yl] - 490

N N N S O O N H O N OH N N N S O O N H O N OH: il]fenil]piperidina–1–carboxamida il] phenyl] piperidine-1-carboxamide

35f 35f: N N N O S O O N H O N H 1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6– (metilsulfonilmetil)pirimidin–2–il]fenil]–3–terc– butil–urea 462 N N N O S O O N H O N H 1– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin-2-yl] phenyl] –3-tert-butyl-urea 462

35g 35g: O 3–(2–dimetilaminoetil)–1–[4–[4–[(3S)–3– 477 OR 3– (2 – dimethylaminoethyl) –1– [4– [4 - [(3S) –3– 477

: metilmorfolin–4–il]–6–(metilsulfonilmetil)- methylmorpholin-4-yl] –6– (methylsulfonylmethyl) -

N N N S O O N H O N H N N N N S O O N H O N H N: pirimidin–2–il]fenil]urea pyrimidin – 2-yl] phenyl] urea

Ejemplo Example: Estructura NOMBRE LCMS MH+ Structure NAME LCMS MH +

35h 35h: N N N O S O O N H O N H OH 3–(2–hidroxietil)–1–[4–[4–[(3S)–3–metilmorfolin– 4–il]–6–(metilsulfonilmetil)pirimidin–2–il]fenil]urea 450 N N N O S O O N H O N H OH 3– (2-hydroxyethyl) –1– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin – 2-yl] phenyl] urea 450

35i 35i: O 3–hidroxi–N–[4–[4–[(3S)–3–metilmorfolin–4–il]– 490 OR 3 – hydroxy – N– [4– [4 - [(3S) –3 – methylmorpholin-4-yl] - 490

35j 35j: O 1–(2–dimetilaminoetil)–1–metil–3–[4–[4–[(3S)–3– 491 OR 1– (2 – dimethylaminoethyl) –1 – methyl – 3– [4– [4 - [(3S) –3– 491

: metilmorfolin–4–il]–6– methylmorpholin – 4 – il] –6–

N N N S O O N H O N N N N N S O O N H O N N: (metilsulfonilmetil)pirimidin–2–il]fenil]urea (methylsulfonylmethyl) pyrimidin-2-yl] phenyl] urea

35k 35k: O 1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6– 486 OR 1– [4– [4 - [(3S) –3 – methylmorpholin – 4 – il] –6– 486

N N N S O O N H O N H N O N N N S O O N H O N H N O: (metilsulfonilmetil)pirimidin–2–il]fenil]–3–(2– morfolin–4–iletil)urea (methylsulfonylmethyl) pyrimidin – 2-yl] phenyl] –3– (2– morpholin-4-ylethyl) urea

35l 35l: O 3–(1H–imidazol–2–ilmetil)–1–[4–[4–[(3S)–3– 460 OR 3– (1H – imidazol – 2 – ilmethyl) –1– [4– [4 - [(3S) –3– 460

: metilmorfolin–4–il]–6– methylmorpholin – 4 – il] –6–

N N N S O O N H N H O NHN N N N S O O N H N H O NHN: (metilsulfonilmetil)pirimidin–2–il]fenil]urea (methylsulfonylmethyl) pyrimidin-2-yl] phenyl] urea

35m 35m: O 1–ciclopropil–1–metil–3–[4–[4–[(3S)–3– 460 OR 1 – cyclopropyl – 1 – methyl – 3– [4– [4 - [(3S) –3– 460

: metilmorfolin–4–il]–6– methylmorpholin – 4 – il] –6–

N N N S O O N H N O N N N S O O N H N O: (metilsulfonilmetil)pirimidin–2–il]fenil]urea (methylsulfonylmethyl) pyrimidin-2-yl] phenyl] urea

35n 35n: O (3S)–3–metil–N–[4–[4–[(3S)–3–metilmorfolin–4– 490 OR (3S) –3 – methyl – N– [4– [4 - [(3S) –3 – methylmorpholin – 4– 490

: il]–6–(metilsulfonilmetil)pirimidin–2– il] –6– (methylsulfonylmethyl) pyrimidin – 2–

N N N S O O N H O N O N N N S O O N H O N O: il]fenil]morfolina–4–carboxamida il] phenyl] morpholine-4-carboxamide

Ejemplo 35a: RMN 1H (400,13 MHz, DMSO–d6) δ 1,24 (3H, d), 1,54–1,62 (2H, m), 2,10–2,14 (6H, s), 2,23 (2H, d), 2,32–2,34 (1H, m), 2,44–2,47 (1H, m), 3,07–3,15 (2H, m), 3,21 (3H, s), 3,63–3,67 (1H, m), 3,78 (1H, d), 3,97–4,01 (1H, m), 4,17 (1H, d), 4,48 (3H, s), 6,32 (1H, t), 6,77 (1H, s), 7,48–7,52 (2H, m), 8,19–8,21 (2H, m), 8,79 (1H, s) Example 35a: 1H NMR (400.13 MHz, DMSO-d6) δ 1.24 (3H, d), 1.54–1.62 (2H, m), 2.10–2.14 (6H, s) , 2.23 (2H, d), 2.32–2.34 (1H, m), 2.44–2.47 (1H, m), 3.07–3.15 (2H, m), 3 , 21 (3H, s), 3.63-3.67 (1H, m), 3.78 (1H, d), 3.97-4.01 (1H, m), 4.17 (1H, d ), 4.48 (3H, s), 6.32 (1H, t), 6.77 (1H, s), 7.48–7.52 (2H, m), 8.19–8.21 ( 2H, m), 8.79 (1H, s)

Ejemplo 35b: RMN 1H (400,13 MHz, DMSO–d6) δ 1,24 (3H, d), 1,68 (2H, t), 3,15 (2H, d), 3,21 (3H, s), 3,25 (4H, s), 3,38 (2H, t), 3,50 (1H, d), 3,67 (1H, d), 3,76–3,79 (1H, m), 4,01 (1H, m), 4,17 (1H, d), 4,48 (3H, s), 6,21 (1H, s), 6,77 (1H, s), 7,48–7,51 (2H, m), 8,19–8,22 (2H, m), 8,70 (1H, s) Example 35b: 1H NMR (400.13 MHz, DMSO-d6) δ 1.24 (3H, d), 1.68 (2H, t), 3.15 (2H, d), 3.21 (3H, s ), 3.25 (4H, s), 3.38 (2H, t), 3.50 (1H, d), 3.67 (1H, d), 3.76-3.79 (1H, m) , 4.01 (1H, m), 4.17 (1H, d), 4.48 (3H, s), 6.21 (1H, s), 6.77 (1H, s), 7.48– 7.51 (2H, m), 8.19–8.22 (2H, m), 8.70 (1H, s)

Ejemplo 35c: RMN 1H (400,13 MHz, DMSO–d6) δ 1,25 (3H, d), 1,85–1,88 (4H, m), 3,21 (3H, s), 3,40 (5H, m), 3,47– 3,54 (1H, m), 3,64–3,67 (1H, m), 3,78 (1H, d), 3,97–4,01 (1H, m), 4,18 (1H, d), 4,48 (3H, s), 6,78 (1H, s), 7,63–7,66 (2H, m), 8,19–8,22 (2H, m), 8,31 (1H, s) Example 35c: 1H NMR (400.13 MHz, DMSO-d6) δ 1.25 (3H, d), 1.85-1.88 (4H, m), 3.21 (3H, s), 3.40 (5H, m), 3.47-3.54 (1H, m), 3.64-3.67 (1H, m), 3.78 (1H, d), 3.97-4.01 (1H , m), 4.18 (1H, d), 4.48 (3H, s), 6.78 (1H, s), 7.63-7.66 (2H, m), 8.19–8, 22 (2H, m), 8.31 (1H, s)

Ejemplo 35d: RMN 1H (400,13 MHz, DMSO–d6) δ 1,25 (3H, d), 3,21 (3H, s), 3,33–3,34 (1H, m), 3,46 (5H, t), 3,61– 3,63 (4H, m), 3,64–3,67 (1H, m), 3,78 (1H, d), 3,97–4,01 (1H, m), 4,19 (1H, d), 4,49 (3H, s), 6,79 (1H, s), 7,57–7,61 (2H, m), 8,21–8,23 (2H, m), 8,74 (1H, s) Example 35d: 1H NMR (400.13 MHz, DMSO-d6) δ 1.25 (3H, d), 3.21 (3H, s), 3.33-3.34 (1H, m), 3.46 (5H, t), 3.61– 3.63 (4H, m), 3.64–3.67 (1H, m), 3.78 (1H, d), 3.97–4.01 (1H , m), 4.19 (1H, d), 4.49 (3H, s), 6.79 (1H, s), 7.57-7.61 (2H, m), 8.21–8, 23 (2H, m), 8.74 (1H, s)

Ejemplo 35e: RMN 1H (400,13 MHz, DMSO–d6) δ 1,19–1,30 (4H, m), 1,31–1,39 (1H, m), 1,67 (2H, d), 1,71–1,72 (1H, m), 1,74–1,78 (2H, m), 3,09–3,12 (1H, m), 3,22 (3H, d), 3,48 (1H, d), 3,63–3,67 (1H, m), 3,78 (1H, d), 3,84 (1H, d), 3,83–3,88 (1H, m), 3,97–4,01 (1H, m), 4,19 (1H, d), 4,48–4,51 (3H, m), 4,69 (1H, s), 6,76 (1H, t), 7,57–7,59 (2H, m), 8,19–8,22 (2H, m), 8,69 (1H, s) Example 35e: 1H NMR (400.13 MHz, DMSO-d6) δ 1.19-1.30 (4H, m), 1.31-1.39 (1H, m), 1.67 (2H, d) , 1.71–1.72 (1H, m), 1.74–1.78 (2H, m), 3.09–3.12 (1H, m), 3.22 (3H, d), 3 , 48 (1H, d), 3.63-3.67 (1H, m), 3.78 (1H, d), 3.84 (1H, d), 3.83-3.88 (1H, m ), 3.97-4.01 (1H, m), 4.19 (1H, d), 4.48-4.51 (3H, m), 4.69 (1H, s), 6.76 ( 1H, t), 7.57–7.59 (2H, m), 8.19–8.22 (2H, m), 8.69 (1H, s)

Ejemplo 35f: RMN 1H (400,13 MHz, DMSO–d6) δ 1,24 (3H, d), 1,31 (9, s), 3,20 (3H, s), 3,22 (1H, d), 3,47–3,53 (1H, m), 3,63–3,67 (1H, m), 3,78 (1H, d), 3,97–4,01 (1H, m), 4,17 (1H, d), 4,48 (3H, s), 6,06 (1H, s), 6,77 (1H, s), 7,43– 7,47 (2H, m), 8,19–8,21 (2H, m), 8,48 (1H, s) Example 35f: 1H NMR (400.13 MHz, DMSO-d6) δ 1.24 (3H, d), 1.31 (9, s), 3.20 (3H, s), 3.22 (1H, d ), 3.47-3.53 (1H, m), 3.63-3.67 (1H, m), 3.78 (1H, d), 3.97-4.01 (1H, m), 4.17 (1H, d), 4.48 (3H, s), 6.06 (1H, s), 6.77 (1H, s), 7.43-7.47 (2H, m), 8 , 19–8.21 (2H, m), 8.48 (1H, s)

Ejemplo 35g: RMN 1H (400,13 MHz, DMSO–d6) δ 1,24 (3H, d), 2,18 (6H, s), 2,34 (2 h t), 3,17–3,25 (5H, m), 3,47– 3,53 (1H, m), 3,63–3,67 (1H, m), 3,78 (1H, d), 3,97–4,01 (1H, m), 4,17 (1H, d), 4,48 (3H, s), 6,16 (1H, t), 6,77 (1H, s), 7,47–7,51 (2H, m), 8,19–8,22 (2H, m), 8,89 (1H, s) Example 35g: 1H NMR (400.13 MHz, DMSO-d6) δ 1.24 (3H, d), 2.18 (6H, s), 2.34 (2 ht), 3.17-3.25 ( 5H, m), 3.47-3.53 (1H, m), 3.63-3.67 (1H, m), 3.78 (1H, d), 3.97-4.01 (1H, m), 4.17 (1H, d), 4.48 (3H, s), 6.16 (1H, t), 6.77 (1H, s), 7.47–7.51 (2H, m ), 8.19–8.22 (2H, m), 8.89 (1H, s)

Ejemplo 35h: RMN 1H (400,13 MHz, DMSO–d6) δ 1,24 (3H d), 3,21 (5H, t), 3,46 (3H, t), 3,52 (1H, d), 3,63–3,67 (1H, m), 3,78 (1H, d), 3,97–4,01 (1H, m), 4,15–4,19 (1H, m), 4,48 (3H, s), 4,73 (1H, s), 6,26 (1H, t), 6,77 (1H, s), 7,48– 7,50 (2H, m), 8,21 (2H, d), 8,82 (1H, s) Example 35h: 1H NMR (400.13 MHz, DMSO-d6) δ 1.24 (3H d), 3.21 (5H, t), 3.46 (3H, t), 3.52 (1H, d) , 3.63-3.67 (1H, m), 3.78 (1H, d), 3.97-4.01 (1H, m), 4.15-4.19 (1H, m), 4 , 48 (3H, s), 4.73 (1H, s), 6.26 (1H, t), 6.77 (1H, s), 7.48-7.50 (2H, m), 8, 21 (2H, d), 8.82 (1H, s)

Ejemplo 35i: RMN 1H (400,13 MHz, DMSO–d6) δ 1,25 (3H, d), 1,38 (2H, d), 1,70 (1H, d), 1,89 (1H, s), 2,74–2,78 (1H, m), 2,96 (1H, s), 3,20 (3H, s), 3,47–3,50 (1H, m), 3,51 (1H, s), 3,66–3,67 (1H, m), 3,77–3,80 (2H, m), 3,98 (2H, d), 4,17 (1H, d), 4,48 (3H, s), 4,83 (1H, d), 6,78 (1H, s), 7,57–7,59 (2H, m), 8,19–8,21 (2H, m), 8,66 (1H, s) Example 35i: 1H NMR (400.13 MHz, DMSO-d6) δ 1.25 (3H, d), 1.38 (2H, d), 1.70 (1H, d), 1.89 (1H, s ), 2.74-2.78 (1H, m), 2.96 (1H, s), 3.20 (3H, s), 3.47-3.50 (1H, m), 3.51 ( 1H, s), 3.66-3.67 (1H, m), 3.77-3.80 (2H, m), 3.98 (2H, d), 4.17 (1H, d), 4 , 48 (3H, s), 4.83 (1H, d), 6.78 (1H, s), 7.57–7.59 (2H, m), 8.19–8.21 (2H, m ), 8.66 (1H, s)

Ejemplo 35j: RMN 1H (400,13 MHz, DMSO–d6) δ 1,25 (3H, d), 2,26 (6H, s), 2,67–2,69 (2H, m), 2,95 (3H, s), 3,21 (3H, s), 3,40 (3H, t), 3,47–3,54 (1H, m), 3,64–3,67 (1H, m), 3,78 (1H, d), 3,97–4,01 (1H, m), 4,18 (1H, d), 4,49 (3H, s), 6,78 (1H, s), 7,50–7,53 (2H, m), 8,20–8,23 (2H, m), 9,51 (1H, s) Example 35j: 1H NMR (400.13 MHz, DMSO-d6) δ 1.25 (3H, d), 2.26 (6H, s), 2.67-2.69 (2H, m), 2.95 (3H, s), 3.21 (3H, s), 3.40 (3H, t), 3.47-3.54 (1H, m), 3.64-3.67 (1H, m), 3.78 (1H, d), 3.97-4.01 (1H, m), 4.18 (1H, d), 4.49 (3H, s), 6.78 (1H, s), 7 , 50–7.53 (2H, m), 8.20–8.23 (2H, m), 9.51 (1H, s)

Ejemplo 35k: RMN 1H (400,13 MHz, DMSO–d6) δ 1,24 (3H, d), 2,39 (2H, d), 2,41 (4H, d), 3,21 (3H, s), 3,24 (2H, t), 3,47–3,53 (1H, m), 3,58–3,63 (5H, m), 3,67 (1H, d), 3,78 (1H, d), 3,97–4,01 (1H, m), 4,17 (1H, d), 4,48 (3H, s), 6,17 (1H, t), 6,77 (1H, s), 7,49–7,51 (2H, m), 8,21 (2H, d), 8,88 (1H, s) Example 35k: 1H NMR (400.13 MHz, DMSO-d6) δ 1.24 (3H, d), 2.39 (2H, d), 2.41 (4H, d), 3.21 (3H, s ), 3.24 (2H, t), 3.47-3.53 (1H, m), 3.58-3.63 (5H, m), 3.67 (1H, d), 3.78 ( 1H, d), 3.97-4.01 (1H, m), 4.17 (1H, d), 4.48 (3H, s), 6.17 (1H, t), 6.77 (1H , s), 7.49–7.51 (2H, m), 8.21 (2H, d), 8.88 (1H, s)

Ejemplo 35l: RMN 1H (400,13 MHz, DMSO–d6) δ 1,25 (3H, d), 3,19–3,23 (3H, m), 3,26 (1H, s), 3,63–3,67 (1H, m), 3,78 (1H, d), 3,97–4,01 (1H, m), 4,16–4,19 (1H, m), 4,32 (2H, d), 4,48 (3H, s), 6,63 (1H, t), 6,78 (1H, s), 6,93 (2H, s), 7,51–7,53 (2H, m), 8,22 (2H, d), 8,93 (1H, s), 11,84 (1H, s) Example 351: 1H NMR (400.13 MHz, DMSO-d6) δ 1.25 (3H, d), 3.19-3.23 (3H, m), 3.26 (1H, s), 3.63 –3.67 (1H, m), 3.78 (1H, d), 3.97-4.01 (1H, m), 4.16-4.19 (1H, m), 4.32 (2H , d), 4.48 (3H, s), 6.63 (1H, t), 6.78 (1H, s), 6.93 (2H, s), 7.51–7.53 (2H, m), 8.22 (2H, d), 8.93 (1H, s), 11.84 (1H, s)

Ejemplo 35m: RMN 1H (400,13 MHz, DMSO–d6) δ 0,69–0,73 (2H, m), 0,88–0,93 (2H, m), 1,25 (3H, d), 2,70–2,76 (1H, m), 2,88 (3H, s), 3,21 (3H, s), 3,22–3,25 (1H, m), 3,47–3,54 (1H, m), 3,64–3,67 (1H, m), 3,78 (1H, d), 3,97–4,01 (1H, m), 4,19 (1H, d), 4,49 (3H, s), 6,79 (1H, s), 7,62–7,65 (2H, m), 8,21–8,23 (2H, m), 8,39 (1H, s) Example 35m: 1H NMR (400.13 MHz, DMSO-d6) δ 0.69-0.73 (2H, m), 0.88-0.93 (2H, m), 1.25 (3H, d) , 2.70–2.76 (1H, m), 2.88 (3H, s), 3.21 (3H, s), 3.22–3.25 (1H, m), 3.47–3 , 54 (1H, m), 3.64–3.67 (1H, m), 3.78 (1H, d), 3.97–4.01 (1H, m), 4.19 (1H, d ), 4.49 (3H, s), 6.79 (1H, s), 7.62–7.65 (2H, m), 8.21–8.23 (2H, m), 8.39 ( 1H, s)

Ejemplo 35n: RMN 1H (400,13 MHz, DMSO–d6) δ 1,21 (3H, d), 1,25 (3H, d), 3,15–3,23 (1H, m), 3,20 (3H, s), 3,36– 3,42 (2H, m), 3,50 (1H, d), 3,53–3,57 (1H, m), 3,64–3,68 (2H, m), 3,75 (1H, s), 3,78 (2H, d), 3,85–3,88 (1H, m), 3,97– 4,01 (1H, m), 4,20 (2H, d), 4,49 (3H, s), 6,79 (1H, s), 7,58–7,61 (2H, m), 8,21–8,23 (2H, m), 8,65 (1H, s). Example 35n: 1H NMR (400.13 MHz, DMSO-d6) δ 1.21 (3H, d), 1.25 (3H, d), 3.15-3.23 (1H, m), 3.20 (3H, s), 3.36-3.42 (2H, m), 3.50 (1H, d), 3.53-3.57 (1H, m), 3.64-3.68 (2H , m), 3.75 (1H, s), 3.78 (2H, d), 3.85-3.88 (1H, m), 3.97-4.01 (1H, m), 4, 20 (2H, d), 4.49 (3H, s), 6.79 (1H, s), 7.58–7.61 (2H, m), 8.21–8.23 (2H, m) , 8.65 (1H, s).

Prueba (a): Ejemplo (35) 0,064 μM; Ejemplo (35a) 6,4 μM; Ejemplo (35b) 0,42 μM; Ejemplo (35c) 3,4 μM; Ejemplo (35d) 3,2 μM; Ejemplo (35e) 2,5 μM; Ejemplo (35f) 0,82 μM; Ejemplo (35g) 0,66 μM; Ejemplo (35h) 0,024 μM; Ejemplo (35i) 0,77 μM; Ejemplo (35j) 3,6 μM; Ejemplo (35k) 1,2 μM; Ejemplo (35l) 0,47 μM; Ejemplo (35m) 2 μM; Ejemplo (35n)1,1 μM. Test (a): Example (35) 0.064 μM; Example (35a) 6.4 μM; Example (35b) 0.42 μM; Example (35c) 3.4 μM; Example (35d) 3.2 μM; Example (35e) 2.5 μM; Example (35f) 0.82 μM; Example (35g) 0.66 μM; Example (35h) 0.024 μM; Example (35i) 0.77 μM; Example (35j) 3.6 μM; Example (35k) 1.2 μM; Example (35l) 0.47 μM; Example (35m) 2 μM; Example (35n) 1.1 μM.

Ejemplo 36: Example 36:

3–Ciclopropil–1–[4–[4–[(3S)–3–metilmorfolina–4–carbonil]–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2– il]fenil]urea 3 – Cyclopropyl – 1– [4– [4 - [(3S) –3 – methylmorpholine – 4-carbonyl] –6 - [(3S) –3 – methylmorpholin – 4-yl] pyrimidin – 2– yl] phenyl] urea

O OR

N N

N N O N N O

N N

O O O o

N N

N HH N HH

Se disolvió ácido 2–[4–(ciclopropilcarbamoilamino)fenil]–6–[(3S)–3–metilmorfolin–4–il]pirimidin–4–carboxílico (95 mg) en DMF (3 ml), y se añadió (3S)–3–metilmorfolina. Se añadieron DIPEA (0,125 ml) y HATU (137 mg), y las reacciones se agitaron a RT durante 3 h antes de concentrarlas a vacío, y se repartieron entre DCM (25 ml) y agua 2– [4– (cyclopropylcarbamoylamino) phenyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-4-carboxylic acid (95 mg) was dissolved in DMF (3 ml), and added (3S ) –3 – methylmorpholine. DIPEA (0.125 ml) and HATU (137 mg) were added, and the reactions were stirred at RT for 3 h before concentrating in vacuo, and partitioned between DCM (25 ml) and water.

5 (25 ml). La capa orgánica se secó sobre sulfato de magnesio, se filtró y se evaporó hasta sequedad para dar el material deseado como un sólido (88 mg). 5 (25 ml). The organic layer was dried over magnesium sulfate, filtered and evaporated to dryness to give the desired material as a solid (88 mg).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 0,40–0,44 (2H, m), 0,63–0,67 (2H, m), 1,24 (6H, m), 2,52–2,61 (1H, m), 3,23–3,29 (2H, m) 3,41–3,42 (1H, m), 3,46–3,47 (1H, m), 3,50–3,55 (2H, m), 3,60 (2H, d), 3,70–3,81 (2H, m), 3,97 (2H, d), 4,17 (1H, s), 4,53 (1H, s), 6,43 (1H, s), 6,74 (1H, d), 7,51 (2H, d), 8,20 (2H, t), 8,54 (1H, s) NMR Spectrum: 1H NMR (400.13 MHz, DMSO – d6) δ 0.40–0.44 (2H, m), 0.63–0.67 (2H, m), 1.24 (6H, m) , 2.52–2.61 (1H, m), 3.23–3.29 (2H, m) 3.41–3.42 (1H, m), 3.46–3.47 (1H, m ), 3.50–3.55 (2H, m), 3.60 (2H, d), 3.70–3.81 (2H, m), 3.97 (2H, d), 4.17 ( 1H, s), 4.53 (1H, s), 6.43 (1H, s), 6.74 (1H, d), 7.51 (2H, d), 8.20 (2H, t), 8.54 (1H, s)

10 Espectro de masa: M+H+ 480. 10 Mass spectrum: M + H + 480.

Las siguientes muestras se prepararon de manera análoga The following samples were prepared analogously

Ejemplo Example: Estructura NOMBRE LCMS MH+ Structure NAME LCMS MH +

36a 36th: N N N O N H N H O N H O N–ciclopropil–2–[4–(ciclopropilcarbamoilamino)fenil]–6–[(3S)–3–metilmorfolin–4–il]pirimidin–4– carboxamida 436 N N N O N H N H O N H O N – cyclopropyl – 2– [4– (cyclopropylcarbamoylamino) phenyl] –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-4– carboxamide 436

36b 36b: N N N O N N H O N H O N 3–ciclopropil–1–[4–[4–[(3S)–3–metilmorfolin–4– il]–6–(4–metilpiperazina–1–carbonil)pirimidin–2– il]fenil]urea 479 N N N O N N H O N H O N 3 – cyclopropyl – 1– [4– [4 - [(3S) –3-methylmorpholin-4– yl] –6– (4-methylpiperazine – 1 – carbonyl) pyrimidin – 2– yl] phenyl] urea 479

Ejemplo 36a: RMN 1H (400,13 MHz, DMSO–d6) δ 0,39–0,44 (2H, m), 0,56–0,61 (2H, m), 0,65–0,68 (2H, m), 0,74– 0,76 (2H, m), 1,24 (3H, d), 2,52–2,59 (1H, m), 2,53–2,61 (1H, m), 3,25 (1H, s), 3,50 (1H, d), 3,63–3,67 (1H, m), 3,77 Example 36a: 1H NMR (400.13 MHz, DMSO-d6) δ 0.39-0.44 (2H, m), 0.56-0.61 (2H, m), 0.65-0.68 ( 2H, m), 0.74-2.76 (2H, m), 1.24 (3H, d), 2.52-2.59 (1H, m), 2.53-2.61 (1H, m), 3.25 (1H, s), 3.50 (1H, d), 3.63-3.67 (1H, m), 3.77

15 (1H, d), 3,96–4,00 (1H, m), 4,25 (1H, s), 4,53 (1H, s), 6,42–6,43 (1H, m), 7,12 (1H, d), 7,51 (2H, d), 8,38–8,41 (2H, m), 8,56 (1H, s), 8,69 (1H, d). 15 (1H, d), 3.96-4.00 (1H, m), 4.25 (1H, s), 4.53 (1H, s), 6.42-6.43 (1H, m) , 7.12 (1H, d), 7.51 (2H, d), 8.38-8.41 (2H, m), 8.56 (1H, s), 8.69 (1H, d).

Ejemplo 36b: RMN 1H (400,13 MHz, DMSO–d6) δ 0,40–0,44 (2H, m), 0,63–0,67 (2H, m), 1,24 (3H, d), 2,25–2,26 (3H, m), 2,40–2,48 (2H, m), 2,43–2,48 (2H, m), 2,52–2,61 (1H, m), 3,18–3,25 (1H, m), 3,46–3,52 (3H, m), 3,62–3,66 (3H, m), 3,76 (1H, d), 3,95–3,99 (1H, m), 4,22 (1H, d), 4,55 (1H, s), 6,44 (1H, d), 6,73 (1H, s), 7,50–7,52 (2H, m), Example 36b: 1H NMR (400.13 MHz, DMSO-d6) δ 0.40–0.44 (2H, m), 0.63–0.67 (2H, m), 1.24 (3H, d) , 2.25-2.26 (3H, m), 2.40-2.48 (2H, m), 2.43-2.48 (2H, m), 2.52-2.61 (1H, m), 3.18-3.25 (1H, m), 3.46-3.52 (3H, m), 3.62-3.66 (3H, m), 3.76 (1H, d) , 3.95-3.99 (1H, m), 4.22 (1H, d), 4.55 (1H, s), 6.44 (1H, d), 6.73 (1H, s), 7.50–7.52 (2H, m),

20 8,18–8,20 (2H, m), 8,54 (1H, s). 20 8.18-8.20 (2H, m), 8.54 (1H, s).

Prueba (a): Ejemplo (36) 0,062 μM; Ejemplo (36a) 2,9 μM; Ejemplo (36b) 0,18 μM. Test (a): Example (36) 0.062 μM; Example (36a) 2.9 μM; Example (36b) 0.18 μM.

A continuación se describe la preparación de ácido 2–[4–(ciclopropilcarbamoilamino)fenil]–6–[(3S)–3–metilmorfolin– 4–il]pirimidin–4–carboxílico. The preparation of 2– [4– (cyclopropylcarbamoylamino) phenyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-4-carboxylic acid is described below.

Ácido 2–[4–(ciclopropilcarbamoilamino)fenil]–6–[(3S)–3–metilmorfolin–4–il]pirimidin–4–carboxílico 2– [4– (cyclopropylcarbamoylamino) phenyl] –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-4-carboxylic acid

Se disolvió 2–[4–(ciclopropilcarbamoilamino)fenil]–6–[(3S)–3–metilmorfolin–4–il]pirimidin–4–carboxilato de metilo (350 mg) en agua (15 ml) que contiene hidróxido de sodio (67 mg), y la reacción se dejó agitar a RT durante 1 h. Se añadieron 2 equivalentes adicionales de hidróxido de sodio junto con THF (3 ml). La reacción se agitó durante 1 h más, y después el THF se eliminó a presión reducida, y la disolución acuosa se repartió con acetato de etilo (15 ml). La capa acuosa se acidificó con ácido clorhídrico concentrado, y el precipitado se filtró y se secó en un horno de vacío a 50ºC durante 18 h para dar el material deseado (350 mg) como un sólido blanco. 2– [4– (cyclopropylcarbamoylamino) phenyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-4-methyl carboxylate (350 mg) was dissolved in water (15 ml) containing sodium hydroxide (67 mg), and the reaction was allowed to stir at RT for 1 h. 2 additional equivalents of sodium hydroxide were added together with THF (3 ml). The reaction was stirred for a further 1 h, and then the THF was removed under reduced pressure, and the aqueous solution was partitioned with ethyl acetate (15 ml). The aqueous layer was acidified with concentrated hydrochloric acid, and the precipitate was filtered and dried in a vacuum oven at 50 ° C for 18 h to give the desired material (350 mg) as a white solid.

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 0,40–0,44 (2H, m), 0,60–0,64 (2H, m), 1,22 (3H, d), 2,52–2,58 (1H, m), 3,17–3,21 (1H, m), 3,46–3,53 (1H, m), 3,63–3,66 (1H, m), 3,75 (1H, d), 3,95–3,99 (1H, m), 4,14–4,17 (1H, m), 4,48 (1H, d), 6,92 (1H, s), 7,28 (1H, s), 7,56 (2H, d), 8,22 (2H, d), 9,41 (1H, s) NMR Spectrum: 1H NMR (400.13 MHz, DMSO – d6) δ 0.40–0.44 (2H, m), 0.60–0.64 (2H, m), 1.22 (3H, d) , 2.52-2.58 (1H, m), 3.17-3.21 (1H, m), 3.46-3.53 (1H, m), 3.63-3.66 (1H, m), 3.75 (1H, d), 3.95-3.99 (1H, m), 4.14-4.17 (1H, m), 4.48 (1H, d), 6.92 (1H, s), 7.28 (1H, s), 7.56 (2H, d), 8.22 (2H, d), 9.41 (1H, s)

Espectro de masa: M+H+ 398. Mass spectrum: M + H + 398.

2–[4–(Ciclopropilcarbamoilamino)fenil]–6–[(3S)–3–metilmorfolin–4–il]pirimidin–4–carboxilato de metilo 2– [4– (Cyclopropylcarbamoylamino) phenyl] –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-4-methyl carboxylate

Se disolvió 6–[(3S)–3–metilmorfolin–4–il]–2–[4–(fenoxicarbonilamino)fenil]pirimidin–4–carboxilato de metilo (547 mg) en DMF (8 ml) y trietilamina (0,59 ml) seguido de adición de ciclopropilamina (0,491 ml). La reacción se agitó a 40ºC durante 2 horas, después la mezcla se sometió a vacío hasta sequedad y se repartió entre DCM (50 ml) y agua (50 ml). La capa orgánica se secó sobre sulfato de magnesio y se sometió a vacío hasta sequedad, y después se cromatografió en sílice, eluyendo con 5% de metanol en DCM, para dar el material deseado (351 mg) como un sólido blanco. 6 - [(3S) –3-Methylmorpholin-4-yl] –2– [4– (phenoxycarbonylamino) phenyl] pyrimidin-4-carboxylate methyl (547 mg) was dissolved in DMF (8 ml) and triethylamine (0, 59 ml) followed by the addition of cyclopropylamine (0.491 ml). The reaction was stirred at 40 ° C for 2 hours, then the mixture was subjected to vacuum to dryness and partitioned between DCM (50 ml) and water (50 ml). The organic layer was dried over magnesium sulfate and subjected to vacuum to dryness, and then chromatographed on silica, eluting with 5% methanol in DCM, to give the desired material (351 mg) as a white solid.

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 0,41–0,44 (2H, m), 0,63–0,68 (2H, m), 1,25 (3H, d), 2,52–2,58 (1H, m), 2,67–2,69 (1H, m), 3,47–3,53 (1H, m), 3,63–3,67 (1H, m), 3,76 (1H, d), 3,91 (3H, s), 3,96–4,00 (1H, m), 4,23–4,27 (1H, m), 4,58 (1H, s), 6,43 (1H, d), 7,14 (1H, s), 7,51–7,53 (2H, m), 8,22–8,25 (2H, m), 8,56 (1H, s) NMR Spectrum: 1H NMR (400.13 MHz, DMSO – d6) δ 0.41–0.44 (2H, m), 0.63–0.68 (2H, m), 1.25 (3H, d) , 2.52-2.58 (1H, m), 2.67-2.69 (1H, m), 3.47-3.53 (1H, m), 3.63-3.67 (1H, m), 3.76 (1H, d), 3.91 (3H, s), 3.96-4.00 (1H, m), 4.23-4.27 (1H, m), 4.58 (1H, s), 6.43 (1H, d), 7.14 (1H, s), 7.51–7.53 (2H, m), 8.22–8.25 (2H, m), 8.56 (1H, s)

Espectro de masa: M+H+ 412. Mass spectrum: M + H + 412.

6–[(3S)–3–metilmorfolin–4–il]–2–[4–(fenoxicarbonilamino)fenil]pirimidin–4–carboxilato de metilo 6 - [(3S) –3 – methylmorpholin-4-yl] –2– [4– (phenoxycarbonylamino) phenyl] pyrimidin-4-methyl carboxylate

H H

Se disolvió 2–(4–aminofenil)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–4–carboxilato de metilo (400 mg) en dioxano (10 ml), y se añadieron gota a gota bicarbonato de sodio (154 mg) y cloroformiato de fenilo (0,154 ml). La mezcla se agitó a RT durante 16 horas, después el dioxano se eliminó a presión reducida, y el residuo se repartió entre agua (50 ml) y acetato de etilo (50 ml). La capa orgánica se secó sobre sulfato de magnesio, se filtró y se evaporó para dar el material deseado como una espuma marrón (624 mg). 2– (4-Aminophenyl) –6 - [(3S) –3-methylmorpholin-4-yl] methyl pyrimidin-4-carboxylate (400 mg) was dissolved in dioxane (10 ml), and bicarbonate was added dropwise sodium (154 mg) and phenyl chloroformate (0.154 ml). The mixture was stirred at RT for 16 hours, then the dioxane was removed under reduced pressure, and the residue was partitioned between water (50 ml) and ethyl acetate (50 ml). The organic layer was dried over magnesium sulfate, filtered and evaporated to give the desired material as a brown foam (624 mg).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,26 (3H, d), 3,11 (1H, s), 3,47–3,54 (1H, m), 3,58 (1H, s), 3,63– 3,67 (1H, m), 3,73 (1H, d), 3,91 (3H, s), 3,96–4,00 (1H, m), 4,27 (1H, s), 6,73–6,78 (1H, m), 7,14–7,20 (1H, m), 7,24– 7,30 (2H, m), 7,43–7,48 (2H, m), 7,64–7,66 (2H, m), 8,32–8,34 (2H, m), 10,46 (1H, s) NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.26 (3H, d), 3.11 (1H, s), 3.47-3.54 (1H, m), 3.58 (1H, s), 3.63– 3.67 (1H, m), 3.73 (1H, d), 3.91 (3H, s), 3.96-4.00 (1H, m), 4.27 (1H, s), 6.73-6.78 (1H, m), 7.14-7.20 (1H, m), 7.24- 7.30 (2H, m), 7, 43–7.48 (2H, m), 7.64–7.66 (2H, m), 8.32–8.34 (2H, m), 10.46 (1H, s)

Espectro de masa: M+H+ 449. Mass spectrum: M + H + 449.

2–(4–Aminofenil)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–4–carboxilato de metilo 2– (4 – Aminophenyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-4-methyl carboxylate

Se disolvió ácido 2–(4–aminofenil)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–4–carboxílico (1,15 g) en metanol (15 ml), se añadió ácido sulfúrico (0,01 ml), y la reacción se calentó a 80ºC durante 24 h. Se añadió una pequeña cantidad de tamiz molecular activado 4A a la reacción y se agitó durante 2 h. La reacción se filtró, se sometió a vacío hasta 2– (4-Aminophenyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-4-carboxylic acid (1.15 g) was dissolved in methanol (15 ml), sulfuric acid (0 , 01 ml), and the reaction was heated at 80 ° C for 24 h. A small amount of activated molecular sieve 4A was added to the reaction and stirred for 2 h. The reaction was filtered, subjected to vacuum until

10 sequedad, después se suspendió en acetato de etilo (250 ml) y se lavó una vez con una disolución saturada de bicarbonato de sodio (250 ml). La capa orgánica se filtró, se secó sobre sulfato de magnesio y se sometió a vacío hasta sequedad para dar el material deseado como un sólido marrón (405 mg). Dry, then suspended in ethyl acetate (250 ml) and washed once with a saturated solution of sodium bicarbonate (250 ml). The organic layer was filtered, dried over magnesium sulfate and subjected to vacuum to dryness to give the desired material as a brown solid (405 mg).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,23 (3H, d), 3,08 (1H, s), 3,45–3,52 (1H, m), 3,62–3,66 (1H, m), 3,75 (1H, d), 3,89 (3H, s), 3,97 (1H, d), 4,21 (1H, d), 4,55 (1H, s), 5,59 (2H, d), 6,59–6,63 (2H, m), 7,04 (1H, s), 8,06– NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.23 (3H, d), 3.08 (1H, s), 3.45-3.52 (1H, m), 3.62 –3.66 (1H, m), 3.75 (1H, d), 3.89 (3H, s), 3.97 (1H, d), 4.21 (1H, d), 4.55 ( 1H, s), 5.59 (2H, d), 6.59-6.63 (2H, m), 7.04 (1H, s), 8.06–

15 8,08 (2H, m) 15 8.08 (2H, m)

Espectro de masa: M+H+ 329. Mass spectrum: M + H + 329.

Ácido 2–(4–aminofenil)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–4–carboxílico 2– (4-Aminophenyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-4-carboxylic acid

Se disolvió 2–cloro–6–[(3S)–3–metilmorfolin–4–il]pirimidin–4–carboxilato de metilo (1,00 g) en 18% de DMF en una Methyl 2-chloro-6 - [(3S) -3-methylmorpholin-4-yl] methyl pyrimidin-4-carboxylate (1.00 g) was dissolved in 18% DMF in a

20 mezcla de DME:agua:etanol 7:3:2 (10 ml). Después se añadieron éster pinacólico del ácido (4–aminofenil)borónico (1,21 g) y carbonato de sodio 2M (5 ml), y la disolución se desgasificó durante 5 min. Se añadió catalizador de diclorobis(trifenilfosfina)paladio (130 mg), y la reacción se puso a reflujo a 90ºC durante 18 h en una atmósfera de nitrógeno. La reacción se dejó enfriar, se concentró a vacío, y el residuo se repartió entre acetato de etilo (100 ml) y agua (100 ml). La fase acuosa se filtró, y el volumen se redujo a vacío. La disolución resultante se acidificó con ácido 20 DME mixture: water: ethanol 7: 3: 2 (10 ml). Then (4-aminophenyl) boronic acid (1.21 g) and 2M sodium carbonate (5 ml) pinacolic ester were added, and the solution was degassed for 5 min. Dichlorobis (triphenylphosphine) palladium catalyst (130 mg) was added, and the reaction was refluxed at 90 ° C for 18 h under a nitrogen atmosphere. The reaction was allowed to cool, concentrated in vacuo, and the residue was partitioned between ethyl acetate (100 ml) and water (100 ml). The aqueous phase was filtered, and the volume was reduced in vacuo. The resulting solution was acidified with acid

25 clorhídrico concentrado y se sometió a vacío hasta sequedad para dar el material deseado. Concentrated hydrochloric and was subjected to vacuum to dryness to give the desired material.

Espectro de masa: M+H+ 315. Mass spectrum: M + H + 315.

La preparación de 2–cloro–6–[(3S)–3–metilmorfolin–4–il]pirimidin–4–carboxilato de metilo se describió anteriormente. The preparation of methyl 2-chloro-6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-4-carboxylate was described above.

Ejemplo 37: Example 37:

30 3 – Cyclopropyl – 1– [4– [4– (2 – Hydroxypropan – 2 – yl) –6 - [(3S) –3 – methylmorpholin-4-yl] pyrimidin – 2-yl] phenyl] urea

HH H H

Se disolvió 2–[2–cloro–6–[(3S)–3–metilmorfolin–4–il]pirimidin–4–il]propan–2–ol (70 mg) en 18% de DMF en una mezcla de DME:agua:etanol 7:3:2 (4 ml) y se añadieron ácido 4–(3–ciclopropilureido)fenilborónico (98 mg) y carbonato de sodio 2M (1 ml). Se añadió catalizador de diclorobis(trifenilfosfina)paladio (10 mg), y la disolución se calentó en un reactor de microondas a 100ºC durante 0,5 h. La mezcla se acidificó con ácido clorhídrico concentrado y se cargó directamente en una columna SCX–2 (10 g), la columna se lavó con metanol, y después el producto se eluyó con amoniaco 7N en metanol, para dar el material deseado (55 mg) como un sólido blanco. 2– [2-Chloro-6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-4-yl] propan-2-ol (70 mg) was dissolved in 18% DMF in a mixture of DME: water: 7: 3: 2 ethanol (4 ml) and 4– (3-cyclopropylureido) phenylboronic acid (98 mg) and 2M sodium carbonate (1 ml) were added. Dichlorobis (triphenylphosphine) palladium catalyst (10 mg) was added, and the solution was heated in a microwave reactor at 100 ° C for 0.5 h. The mixture was acidified with concentrated hydrochloric acid and loaded directly onto a SCX-2 column (10 g), the column was washed with methanol, and then the product was eluted with 7N ammonia in methanol, to give the desired material (55 mg ) as a white solid.

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 0,41–0,44 (2H, m), 0,62–0,67 (2H, m), 1,23 (3H, d), 1,45 (6H, s), 2,54 (1H, t), 3,19–3,23 (1H, m), 3,46–3,52 (1H, m), 3,62–3,66 (1H, m), 3,77 (1H, d), 3,96 (1H, d), 4,14–4,17 (1H, m), 4,50 (1H, s), 5,17 (1H, s), 6,41 (1H, d), 6,80 (1H, s), 7,48 (2H, d), 8,23 (2H, d), 8,50 (1H, s) NMR Spectrum: 1H NMR (400.13 MHz, DMSO – d6) δ 0.41–0.44 (2H, m), 0.62–0.67 (2H, m), 1.23 (3H, d) , 1.45 (6H, s), 2.54 (1H, t), 3.19-3.23 (1H, m), 3.46-3.52 (1H, m), 3.62-3 , 66 (1H, m), 3.77 (1H, d), 3.96 (1H, d), 4.14-4.17 (1H, m), 4.50 (1H, s), 5, 17 (1H, s), 6.41 (1H, d), 6.80 (1H, s), 7.48 (2H, d), 8.23 (2H, d), 8.50 (1H, s )

Espectro de masa: M+H+ 412. Mass spectrum: M + H + 412.

Prueba (a): 0,051 μM. Test (a): 0.051 μM.

A continuación se describe la preparación de 2–[2–cloro–6–[(3S)–3–metilmorfolin–4–il]pirimidin–4–il]propan–2–ol. The preparation of 2– [2-chloro-6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-4-yl] propan – 2 – ol is described below.

2–[2–Cloro–6–[(3S)–3–metilmorfolin–4–il]pirimidin–4–il]propan–2–ol 2– [2 – Chloro – 6 - [(3S) –3 – methylmorpholin-4-yl] pyrimidin – 4-yl] propan – 2 – ol

Se disolvió 2–cloro–6–[(3S)–3–metilmorfolin–4–il]pirimidin–4–carboxilato de metilo (300 mg) en THF seco y se enfrió hasta –78ºC. Se añadió gota a gota durante 2 min. bromuro de metilmagnesio (3,0 M en éter dietílico, 0,74 ml), y después la reacción se dejó agitar a –78ºC durante 20 min. antes de que se dejara calentar hasta RT. La reacción se agitó durante unos 20 min. adicionales y después se paralizó con agua (2 ml). La reacción se redujo hasta sequedad y se repartió entre acetato de etilo (50 ml) y agua (50 ml), y la capa orgánica se secó sobre sulfato de magnesio y se sometió a vacío hasta sequedad para dar el material deseado como un sólido blanco (291 mg). Methyl 2-chloro-6 - [(3S) -3-methylmorpholin-4-yl] methyl pyrimidin-4-carboxylate (300 mg) was dissolved in dry THF and cooled to -78 ° C. It was added dropwise for 2 min. methylmagnesium bromide (3.0 M in diethyl ether, 0.74 ml), and then the reaction was allowed to stir at -78 ° C for 20 min. before it was allowed to warm to RT. The reaction was stirred for about 20 min. additional and then paralyzed with water (2 ml). The reaction was reduced to dryness and partitioned between ethyl acetate (50 ml) and water (50 ml), and the organic layer was dried over magnesium sulfate and subjected to vacuum to dryness to give the desired material as a white solid. (291 mg).

Espectro RMN: (400,13 MHz, DMSO–d6) δ 1,16–1,23 (3H, m), 1,36 (6H, s), 3,15–3,23 (1H, m), 3,40–3,47 (1H, m), 3,56–3,60 (1H, m), 3,71 (1H, d), 3,91–3,94 (2H, m), 4,34 (1H, s), 5,28 (1H, s), 6,87 (1H, s). NMR Spectrum: (400.13 MHz, DMSO – d6) δ 1.16–1.23 (3H, m), 1.36 (6H, s), 3.15–3.23 (1H, m), 3 , 40–3.47 (1H, m), 3.56–3.60 (1H, m), 3.71 (1H, d), 3.91–3.94 (2H, m), 4.34 (1H, s), 5.28 (1H, s), 6.87 (1H, s).

Espectro de masa: M+H+ 272. Mass spectrum: M + H + 272.

Ejemplo 38: Example 38:

1–[4–[4–(2–Hidroxipropan–2–il)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]–3–[(1–metilpirazol–4– il)metil]urea 1– [4– [4– (2 – Hydroxypropan – 2-yl) –6 - [(3S) –3 – methylmorpholin-4-yl] pyrimidin – 2-yl] phenyl] –3 - [(1-methylpyrazole– 4– il) methyl] urea

Se disolvió 2–[2–cloro–6–[(3S)–3–metilmorfolin–4–il]pirimidin–4–il]propan–2–ol (70 mg) en 18% de DMF en una mezcla de DME:agua:etanol 7:3:2 (4 ml). Se añadieron 3–[(1–metilpirazol–4–il)metil]–1–[4–(4,4,5,5–tetrametil–1,3,2– dioxaborolan–2–il)fenil]urea (115 mg) y carbonato de sodio 2M (1 ml). Se añadió catalizador de diclorobis(trifenilfosfina)paladio (10 mg), y la disolución se calentó en un reactor de microondas a 100ºC durante 0,5 2– [2-Chloro-6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-4-yl] propan-2-ol (70 mg) was dissolved in 18% DMF in a mixture of DME: Water: 7: 3: 2 ethanol (4 ml). 3 - [(1-methylpyrazol-4-yl) methyl] -1- [4– (4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl) phenyl] urea (115) were added mg) and 2M sodium carbonate (1 ml). Dichlorobis (triphenylphosphine) palladium catalyst (10 mg) was added, and the solution was heated in a microwave reactor at 100 ° C for 0.5

h. La mezcla se acidificó con ácido clorhídrico concentrado y se cargó directamente en una columna SCX–2 (10 g), la columna se lavó con metanol, después el producto se eluyó con amoniaco 7N en metanol, para dar el material deseado (55 mg) como un sólido blanco. h. The mixture was acidified with concentrated hydrochloric acid and loaded directly onto a SCX-2 column (10 g), the column was washed with methanol, then the product was eluted with 7N ammonia in methanol, to give the desired material (55 mg) Like a white solid

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,23 (3H, d), 1,45 (6H, s), 3,16–3,23 (1H, m), 3,46–3,52 (1H, m), 3,62–3,66 (1H, m), 3,78–3,80 (1H, m), 3,75–3,81 (3H, s), 3,96–3,99 (1H, m), 4,13 (3H, d), 4,49–4,52 (1H, m), 5,17 (1H, s), 6,39 (1H, t), 6,80 (1H, s), 7,35 (1H, s), 7,47–7,49 (2H, m), 7,59 (1H, s), 8,22–8,24 (2H, m), 8,65 (1H, s) NMR Spectrum: 1H NMR (400.13 MHz, DMSO – d6) δ 1.23 (3H, d), 1.45 (6H, s), 3.16–3.23 (1H, m), 3.46 –3.52 (1H, m), 3.62–3.66 (1H, m), 3.78–3.80 (1H, m), 3.75–3.81 (3H, s), 3 , 96–3.99 (1H, m), 4.13 (3H, d), 4.49-4.52 (1H, m), 5.17 (1H, s), 6.39 (1H, t ), 6.80 (1H, s), 7.35 (1H, s), 7.47–7.49 (2H, m), 7.59 (1H, s), 8.22–8.24 ( 2H, m), 8.65 (1H, s)

Espectro de masa: M+H+ 466. Mass spectrum: M + H + 466.

Prueba (a): 1,3 μM. Test (a): 1.3 μM.

La preparación de 2–[2–cloro–6–[(3S)–3–metilmorfolin–4–il]pirimidin–4–il]propan–2–ol se describió anteriormente. The preparation of 2– [2-chloro-6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-4-yl] propan-2-ol was described above.

A continuación se describe la preparación de 3–[(1–metilpirazol–4–il)metil]–1–[4–(4,4,5,5–tetrametil–1,3,2– dioxaborolan–2–il)fenil]urea. The preparation of 3 - [(1-methylpyrazol-4-yl) methyl] –1– [4– (4,4,5,5-tetramethyl-1,3,2– dioxaborolan – 2-yl) is described below. phenyl] urea.

3–[(1–Metilpirazol–4–il)metil]–1–[4–(4,4,5,5–tetrametil–1,3,2–dioxaborolan–2–il)fenil]urea 3 - [(1-Methylpyrazol-4-yl) methyl] –1– [4– (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] urea

O B O Or B OR

O OR

N N

HH N HH N

Se disolvió éster pinacólico del ácido (4–aminofenil)borónico (200 mg) en THF seco (5 ml), y se añadió bicarbonato de sodio (116 mg) seguido por la adición gota a gota de cloroformiato de fenilo (0,115 ml). La mezcla se agitó a RT durante 1 hora. Se añadió (1–metilpirazol–4–il)metanamina (102 mg), y la reacción se dejó agitar a RT durante 2 h antes de calentarla hasta 40ºC durante 16 h. La mezcla se concentró a vacío, y el residuo se repartió entre DCM (25 ml) y agua (25 ml). Los productos orgánicos se secaron sobre sulfato de magnesio, se filtraron y se sometieron a vacío hasta sequedad. El material se cromatografió en sílice, eluyendo con acetato de etilo, para dar el material deseado (232 mg) como un sólido blanco. Pinacolic ester of (4-aminophenyl) boronic acid (200 mg) was dissolved in dry THF (5 ml), and sodium bicarbonate (116 mg) was added followed by the dropwise addition of phenyl chloroformate (0.115 ml). The mixture was stirred at RT for 1 hour. (1-Methylpyrazol-4-yl) methanamine (102 mg) was added, and the reaction was allowed to stir at RT for 2 h before heating to 40 ° C for 16 h. The mixture was concentrated in vacuo, and the residue was partitioned between DCM (25 ml) and water (25 ml). The organic products were dried over magnesium sulfate, filtered and subjected to vacuum to dryness. The material was chromatographed on silica, eluting with ethyl acetate, to give the desired material (232 mg) as a white solid.

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,28 (12 H, s), 3,79 (3H, s), 4,11 (2H, d), 6,39 (1H, t), 7,34 (1H, s), 7,39–7,41 (2H, m), 7,52–7,54 (2H, m), 7,59 (1H, s), 8,56 (1H, s) NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.28 (12 H, s), 3.79 (3H, s), 4.11 (2H, d), 6.39 (1H, t), 7.34 (1H, s), 7.39–7.41 (2H, m), 7.52–7.54 (2H, m), 7.59 (1H, s), 8.56 (1H, s)

Espectro de masa: M+H+ 357. Mass spectrum: M + H + 357.

Ejemplo 39: Example 39:

1–[4–[4–(Hidroximetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]–3–(1,2–oxazol–3–il)urea 1– [4– [4– (Hydroxymethyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] –3– (1,2-oxazol-3-yl) urea

Se disolvió [2–cloro–6–[(3S)–3–metilmorfolin–4–il]pirimidin–4–il]metanol (500 mg) en 18% de DMF en una mezcla de DME:agua:etanol 7:3:2 (10 ml). Después se añadieron a la disolución 3–(1,2–oxazol–3–il)–1–[4–(4,4,5,5–tetrametil– 1,3,2–dioxaborolan–2–il)fenil]urea (811 mg) y disolución acuosa 2M de carbonato de sodio (4 ml), y la mezcla resultante se desgasificó durante 5 min. Se añadió catalizador de diclorobis(trifenilfosfina)paladio (73 mg), y la disolución se puso a reflujo a 90ºC durante 7 h en una atmósfera de nitrógeno. La reacción se dejó enfriar, después se neutralizó con ácido clorhídrico concentrado y se cargó directamente en una columna SCX–2 (50 g), la columna se lavó con metanol, y el producto se eluyó con amoniaco 7N en metanol. El material se purificó adicionalmente mediante cromatografía en sílice, eluyendo con 5% de metanol en DCM, para dar el material deseado (318 mg) como un sólido blanco. [2-Chloro-6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-4-yl] methanol (500 mg) was dissolved in 18% DMF in a mixture of DME: water: ethanol 7: 3 : 2 (10 ml). Then 3– (1,2-oxazol-3-yl) -1- [4– (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl) phenyl] were added to the solution. urea (811 mg) and 2M aqueous solution of sodium carbonate (4 ml), and the resulting mixture was degassed for 5 min. Dichlorobis (triphenylphosphine) palladium catalyst (73 mg) was added, and the solution was refluxed at 90 ° C for 7 h under a nitrogen atmosphere. The reaction was allowed to cool, then neutralized with concentrated hydrochloric acid and loaded directly onto a SCX-2 column (50 g), the column was washed with methanol, and the product was eluted with 7N ammonia in methanol. The material was further purified by silica chromatography, eluting with 5% methanol in DCM, to give the desired material (318 mg) as a white solid.

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,24 (3H, d), 3,20–3,24 (1H, m), 3,47–3,53 (1H, m), 3,63–3,67 (1H, m), 3,77 (1H, d), 3,96–4,00 (1H, m), 4,16–4,19 (1H, m), 4,47 (2H, d), 4,50 (1H, s), 5,40 (1H, t), 6,69 (1H, s), 6,87 (1H, d), 7,53–7,56 (2H, m), 8,27–8,29 (2H, m), 8,75–8,75 (1H, m), 9,03 (1H, d), 9,60 (1H, s) NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.24 (3H, d), 3.20-3.24 (1H, m), 3.47-3.53 (1H, m) , 3.63–3.67 (1H, m), 3.77 (1H, d), 3.96-4.00 (1H, m), 4.16-4.19 (1H, m), 4 , 47 (2H, d), 4.50 (1H, s), 5.40 (1H, t), 6.69 (1H, s), 6.87 (1H, d), 7.53–7, 56 (2H, m), 8.27–8.29 (2H, m), 8.75–8.75 (1H, m), 9.03 (1H, d), 9.60 (1H, s)

Espectro de masa: M+H+ 411. Mass spectrum: M + H + 411.

Prueba (a): 0,075 μM. Test (a): 0.075 μM.

La preparación de [2–cloro–6–[(3S)–3–metilmorfolin–4–il]pirimidin–4–il]metanol se describió anteriormente. The preparation of [2-chloro-6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-4-yl] methanol was described above.

A continuación se describe la preparación de 3–(1,2–oxazol–3–il)–1–[4–(4,4,5,5–tetrametil–1,3,2–dioxaborolan–2– il)fenil]urea. The preparation of 3– (1,2-oxazol-3-yl) –1– [4– (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl is described below ]urea.

3–(1,2–Oxazol–3–il)–1–[4–(4,4,5,5–tetrametil–1,3,2–dioxaborolan–2–il)fenil]urea 3– (1,2 – Oxazol – 3-yl) –1– [4– (4,4,5,5-tetramethyl – 1,3,2-dioxaborolan – 2-yl) phenyl] urea

O B O Or B OR

O O N O O N

N N HH N N HH

Se disolvió éster pinacólico del ácido (4–aminofenil)borónico (1 g) en THF seco (30 ml), se añadió bicarbonato de sodio (576 mg) seguido por la adición gota a gota de cloroformiato de fenilo (0,575 ml). La mezcla se agitó a RT durante 1 hora, después se añadió 3–aminoisoxazol (0,506 ml), y la reacción se dejó agitar a 40ºC durante 16 h. Se añadieron más 3–aminoisoxazol (0,506 ml) y bicarbonato de sodio (576 mg), y la reacción se calentó hasta 75ºC durante 8 h. antes de que la mezcla se concentrara a vacío y se repartiera entre DCM (50 ml) y agua (50 ml). La capa orgánica se secó sobre sulfato de magnesio, se filtró y se sometió a vacío hasta sequedad. El residuo se cromatografió en sílice, eluyendo con acetato de etilo, para dar el compuesto deseado (1,05 g) como un sólido blanco. Pinacolic ester of (4-aminophenyl) boronic acid (1 g) was dissolved in dry THF (30 ml), sodium bicarbonate (576 mg) was added followed by the dropwise addition of phenyl chloroformate (0.575 ml). The mixture was stirred at RT for 1 hour, then 3-aminoisoxazole (0.506 ml) was added, and the reaction was allowed to stir at 40 ° C for 16 h. More 3-aminoisoxazole (0.506 ml) and sodium bicarbonate (576 mg) were added, and the reaction was heated to 75 ° C for 8 h. before the mixture was concentrated in vacuo and partitioned between DCM (50 ml) and water (50 ml). The organic layer was dried over magnesium sulfate, filtered and subjected to vacuum to dryness. The residue was chromatographed on silica, eluting with ethyl acetate, to give the desired compound (1.05 g) as a white solid.

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,29 (12 h, s), 5,89 (1H, d), 6,86 (1H, d), 7,47–7,49 (2H, m), 7,61–7,63 (2H, m), 8,32 (1H, t), 8,75 (1H, d) NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.29 (12 h, s), 5.89 (1H, d), 6.86 (1H, d), 7.47–7, 49 (2H, m), 7.61–7.63 (2H, m), 8.32 (1H, t), 8.75 (1H, d)

Espectro de masa: M+H+ 330. Mass spectrum: M + H + 330.

Ejemplo 40: Example 40:

N–[2–[[6–[(3S)–3–metilmorfolin–4–il]–2–[4–(1,2–oxazol–3–ilcarbamoilamino)fenil]pirimidin–4– il]metilsulfonil]etil]acetamida N– [2 - [[6 - [(3S) –3-methylmorpholin-4-yl] –2– [4– (1,2-oxazol-3-ylcarbamoylamino) phenyl] pyrimidin-4-yl] methylsulfonyl] ethyl ] acetamide

OO NH N OO NH N

N N

O OR

S S

N N

OO OO

O N O n

N N HH N N HH

Se disolvió parcialmente 1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfoniloximetil)pirimidin–2–il]fenil]–3–(1,2– oxazol–3–il)urea (89 mg, 0,18 mmoles) en acetonitrilo (4 ml) y se añadió N–(2–sulfaniletil)acetamida (0,034 ml, 0,32 mmoles). Se añadió DBU (0,055 ml, 0,36 mmoles), y la reacción se agitó a RT durante 6 h antes de someterla a vacío hasta sequedad. El material se disolvió en 1,4–dioxano (2 ml), y se añadió una disolución de m–CPBA (75%) (158 mg) en 1,4 dioxano (2 ml), seguido inmediatamente por una disolución de permanganato de sodio (175 mg) en agua (1 ml). La reacción se dejó agitar a RT durante 1 h, después se cargó en una columna SCX–2 (10 g), la columna se lavó con metanol, y el producto se eluyó con amoniaco 7N en metanol. El material se purificó adicionalmente mediante HPLC prep. (básica) para dar el material deseado como un sólido (13 mg). 1– [4– [4 - [(3S) –3-methylmorpholin-4-yl] -6– (methylsulfonyloxymethyl) pyrimidin-2-yl] phenyl] –3– (1,2– oxazole-3– il) urea (89 mg, 0.18 mmol) in acetonitrile (4 ml) and N- (2-sulfanylethyl) acetamide (0.034 ml, 0.32 mmol) was added. DBU (0.055 ml, 0.36 mmol) was added, and the reaction was stirred at RT for 6 h before being subjected to vacuum to dryness. The material was dissolved in 1,4-dioxane (2 ml), and a solution of m-CPBA (75%) (158 mg) in 1,4 dioxane (2 ml) was added, followed immediately by a solution of permanganate of sodium (175 mg) in water (1 ml). The reaction was allowed to stir at RT for 1 h, then loaded on an SCX-2 column (10 g), the column was washed with methanol, and the product was eluted with 7N ammonia in methanol. The material was further purified by prep HPLC. (basic) to give the desired material as a solid (13 mg).

Espectro RMN: RMN 1H (399,9 MHz, DMSO–d6) δ 1,26 (3H, d), 1,84 (3H, s), 3,24 (1H, d), 3,52 (2H, t), 3,54 (1H, s), 3,58 (2H, t), 3,65–3,68 (1H, m), 3,79 (1H, d), 3,98–4,02 (1H, m), 4,20 (1H, s), 4,54 (3H, m), 6,82 (1H, s), 6,88 (1H, d), 7,56–7,59 (2H, m), 8,16–8,17 (1H, m), 8,28–8,31 (2H, m), 8,76–8,77 (1H, m), 9,09 (1H, d), 9,62 (1H, s) NMR Spectrum: 1H NMR (399.9 MHz, DMSO-d6) δ 1.26 (3H, d), 1.84 (3H, s), 3.24 (1H, d), 3.52 (2H, t ), 3.54 (1H, s), 3.58 (2H, t), 3.65-3.68 (1H, m), 3.79 (1H, d), 3.98-4.02 ( 1H, m), 4.20 (1H, s), 4.54 (3H, m), 6.82 (1H, s), 6.88 (1H, d), 7.56–7.59 (2H , m), 8.16–8.17 (1H, m), 8.28–8.31 (2H, m), 8.76–8.77 (1H, m), 9.09 (1H, d ), 9.62 (1H, s)

Espectro de masa: M+H+ 544. Mass spectrum: M + H + 544.

Los siguientes compuestos se prepararon de manera análoga a partir de 1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6– (metilsulfoniloximetil)pirimidin–2–il]fenil]–3–(1,2–oxazol–3–il)urea y el tiol apropiado. The following compounds were prepared analogously from 1– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (methylsulfonyloxymethyl) pyrimidin-2-yl] phenyl] –3– ( 1,2-oxazol-3-yl) urea and the appropriate thiol.

Ejemplo Example: Estructura NOMBRE LCMS MH+ Structure NAME LCMS MH +

40a 40th: S O O OH N N N O N H O N H N O 1–[4–[4–(2–hidroxietilsulfonilmetil)–6–[(3S)–3– metilmorfolin–4–il]pirimidin–2–il]fenil]–3–(1,2– oxazol–3–il)urea 503 S O O OH N N N O N H O N H NO 1– [4– [4– (2-hydroxyethylsulfonylmethyl) –6 - [(3S) -3– methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] –3– (1,2– oxazol-3-yl )urea 503

Ejemplo 40a: RMN 1H (399,9 MHz, DMSO–d6) δ 1,26 (3H, d), 3,24 (1H, d), 3,53 (3H, t), 3,65–3,68 (1H, m), 3,79 (1H, d), 3,93 (2H, q), 3,98–4,02 (1H, m), 4,20 (1H, s), 4,51 (3H, d), 5,20 (1H, t), 6,80 (1H, s), 6,88–6,88 (1H, m), 7,58 (2H, d), 8,29–8,31 (2H, m), 8,76 (1H, s), 9,09 (1H, d), 9,64 (1H, s). Example 40a: 1H NMR (399.9 MHz, DMSO-d6) δ 1.26 (3H, d), 3.24 (1H, d), 3.53 (3H, t), 3.65-3.68 (1H, m), 3.79 (1H, d), 3.93 (2H, q), 3.98-4.02 (1H, m), 4.20 (1H, s), 4.51 ( 3H, d), 5.20 (1H, t), 6.80 (1H, s), 6.88-6.88 (1H, m), 7.58 (2H, d), 8.29–8 , 31 (2H, m), 8.76 (1H, s), 9.09 (1H, d), 9.64 (1H, s).

Prueba (c): Ejemplo (40) 0,1 μM; Ejemplo (40a) 0,055 μM. Test (c): Example (40) 0.1 μM; Example (40a) 0.055 μM.

A continuación se describe la preparación de 1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfoniloximetil)pirimidin– 2–il]fenil]–3–(1,2–oxazol–3–il)urea. The following describes the preparation of 1– [4– [4 - [(3 S) –3-methylmorpholin-4-yl] –6– (methylsulfonyloxymethyl) pyrimidin– 2-yl] phenyl] –3– (1,2– oxazol-3-yl) urea.

1–[4–[4–[(3S)–3–Metilmorfolin–4–il]–6–(metilsulfoniloximetil)pirimidin–2–il]fenil]–3–(1,2–oxazol–3–il)urea 1– [4– [4 - [(3S) –3 – Methylmorpholin-4-yl] –6– (methylsulfonyloxymethyl) pyrimidin – 2-yl] phenyl] –3– (1,2-oxazol-3-yl) urea

O OR

N N N N

O OR

N N

O O O o

S S

OO N OO N

N N HH N N HH

10 Se disolvió parcialmente 1–[4–[4–(hidroximetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]–3–(1,2–oxazol–3– il)urea (300 mg) en DCM (10 ml) y trietilamina (0,153 ml), y la disolución se enfrió hasta 0ºC. Se añadió cloruro de metanosulfonilo (0,086 ml), y la reacción se agitó durante 45 min. a RT. La reacción se lavó después con agua (2 ml) y se secó sobre sulfato de magnesio. La disolución se sometió a vacío hasta sequedad para dar el material deseado como un sólido amarillo. 10 Partially dissolved 1– [4– [4– (hydroxymethyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] –3– (1,2-oxazol-3 - il) urea (300 mg) in DCM (10 ml) and triethylamine (0.153 ml), and the solution was cooled to 0 ° C. Methanesulfonyl chloride (0.086 ml) was added, and the reaction was stirred for 45 min. art. The reaction was then washed with water (2 ml) and dried over magnesium sulfate. The solution was subjected to vacuum to dryness to give the desired material as a yellow solid.

15 Espectro de masa: M+H+ 489. 15 Mass spectrum: M + H + 489.

Ejemplo 41: Example 41:

1–[4–[4–(2–Hidroxipropan–2–il)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]–3–(1,2–oxazol–3–il)urea 1– [4– [4– (2 – Hydroxypropan – 2-yl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin – 2-yl] phenyl] –3– (1,2-oxazole –3 – il) urea

O OR

N N

N HO N HO

N N

O O N O O N

N N HH N N HH

Se añadió 2–[2–cloro–6–[(3S)–3–metilmorfolin–4–il]pirimidin–4–il]propan–2–ol (160 mg, 0,59 mmoles) a 3–(1,2– 2– [2-Chloro-6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-4-yl] propan-2-ol (160 mg, 0.59 mmol) was added to 3– (1, 2-

20 oxazol–3–il)–1–[4–(4,4,5,5–tetrametil–1,3,2–dioxaborolan–2–il)fenil]urea (242 mg) y catalizador de diclorobis(trifenilfosfina)paladio (21 mg) en 18% de DMF en una mezcla de DME:agua:etanol 7:3:2 (6 ml). La reacción se calentó hasta 100ºC durante 30 minutos en el reactor de microondas y se enfrió hasta RT. La mezcla de reacción se acidificó con ácido clorhídrico 2M, y el material bruto se cargó en una columna SCX (10 g), y el material deseado se eluyó con amoniaco 7N en metanol. El material se purificó adicionalmente mediante HPLC preparativa Oxazol-3-yl) -1– [4– (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] urea (242 mg) and dichlorobis (triphenylphosphine) catalyst Palladium (21 mg) in 18% DMF in a mixture of DME: water: ethanol 7: 3: 2 (6 ml). The reaction was heated to 100 ° C for 30 minutes in the microwave reactor and cooled to RT. The reaction mixture was acidified with 2M hydrochloric acid, and the crude material was loaded on an SCX column (10 g), and the desired material was eluted with 7N ammonia in methanol. The material was further purified by preparative HPLC

25 usando mezclas polares decrecientes de agua (que contiene 1% de NH3) y MeCN como eluyentes, para dar el material deseado (52 mg) como un sólido blanco. Using decreasing polar mixtures of water (containing 1% NH3) and MeCN as eluents, to give the desired material (52 mg) as a white solid.

Espectro RMN: RMN 1H (399,9 MHz, DMSO–d6) δ 1,24 (3H, d), 1,47 (6H, s), 3,18–3,25 (1H, m), 3,47–3,54 (1H, m), 3,64–3,67 (1H, m), 3,78 (1H, d), 3,97–4,01 (1H, m), 4,16–4,19 (1H, m), 4,51–4,53 (1H, m), 5,20 (1H, s), 6,84 (1H, s), 6,88 (1H, d), 7,55–7,57 (2H, m), 8,30–8,32 (2H, m), 8,76 (1H, d), 9,06 (1H, s), 9,61 (1H, s) NMR Spectrum: 1H NMR (399.9 MHz, DMSO-d6) δ 1.24 (3H, d), 1.47 (6H, s), 3.18-3.25 (1H, m), 3.47 –3.54 (1H, m), 3.64–3.67 (1H, m), 3.78 (1H, d), 3.97–4.01 (1H, m), 4.16–4 , 19 (1H, m), 4.51-4.53 (1H, m), 5.20 (1H, s), 6.84 (1H, s), 6.88 (1H, d), 7, 55–7.57 (2H, m), 8.30–8.32 (2H, m), 8.76 (1H, d), 9.06 (1H, s), 9.61 (1H, s)

30 Espectro de masa: M+H+ 439,4 30 Mass spectrum: M + H + 439.4

Prueba (c): 0,047 μM. Test (c): 0.047 μM.

La preparación de 2–[2–cloro–6–[(3S)–3–metilmorfolin–4–il]pirimidin–4–il]propan–2–ol y 3–(1,2–oxazol–3–il)–1–[4– (4,4,5,5–tetrametil–1,3,2–dioxaborolan–2–il)fenil]urea se describió anteriormente. The preparation of 2– [2 – chloro – 6 - [(3S) –3 – methylmorpholin-4-yl] pyrimidin – 4-yl] propan – 2 – ol and 3– (1,2-oxazol-3-yl) –1– [4– (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] urea was described above.

Ejemplo 42: 3–Ciclopropil–1–[4–[4–(Hidroximetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]urea Example 42: 3 – Cyclopropyl – 1– [4– [4– (Hydroxymethyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin – 2-yl] phenyl] urea

Se disolvió [2–cloro–6–[(3S)–3–metilmorfolin–4–il]pirimidin–4–il]metanol (3,30 g) en 18% de DMF en una mezcla de DME:agua:etanol 7:3:2 (50 ml). Después se añadieron ácido 4–(3–ciclopropilureido)fenilborónico (4,92 g) y carbonato de sodio 2M (5 ml), y la disolución se desgasificó durante 5 min. Después se añadió catalizador de diclorobis(trifenilfosfina)paladio (476 mg) a la disolución, y ésta se puso a reflujo a 90ºC durante 7h en una atmósfera de nitrógeno. La reacción se dejó enfriar, se evaporó, y el residuo se repartió entre DCM (200 ml) y agua (200 ml). La capa orgánica se secó sobre sulfato de magnesio, se evaporó, y se purificó mediante cromatografía en sílice, eluyendo con 5% de metanol en DCM, para dar el material deseado (4,33 g) como un sólido amarillo. [2-Chloro-6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-4-yl] methanol (3.30 g) was dissolved in 18% DMF in a mixture of DME: water: ethanol 7 : 3: 2 (50 ml). Then 4– (3-cyclopropylureido) phenylboronic acid (4.92 g) and 2M sodium carbonate (5 ml) were added, and the solution was degassed for 5 min. Then dichlorobis (triphenylphosphine) palladium catalyst (476 mg) was added to the solution, and it was refluxed at 90 ° C for 7 hours in a nitrogen atmosphere. The reaction was allowed to cool, evaporated, and the residue was partitioned between DCM (200 ml) and water (200 ml). The organic layer was dried over magnesium sulfate, evaporated, and purified by silica chromatography, eluting with 5% methanol in DCM, to give the desired material (4.33 g) as a yellow solid.

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 0,40–0,44 (2H, m), 0,62–0,67 (2H, m), 1,23 (3H, d), 2,54–2,58 (1H, m), 3,17–3,22 (1H, m), 3,46–3,52 (1H, m), 3,62–3,66 (1H, m), 3,77 (1H, d), 3,96–3,99 (1H, m), 4,15–4,18 (1H, m), 4,45 (2H, d), 4,49 (1H, d), 5,38 (1H, t), 6,41 (1H, d), 6,66 (1H, s), 7,46–7,50 (2H, m), 8,18–8,22 (2H, m), 8,49 (1H, s), NMR Spectrum: 1H NMR (400.13 MHz, DMSO – d6) δ 0.40–0.44 (2H, m), 0.62–0.67 (2H, m), 1.23 (3H, d) , 2.54-2.58 (1H, m), 3.17-3.22 (1H, m), 3.46-3.52 (1H, m), 3.62-3.66 (1H, m), 3.77 (1H, d), 3.96-3.99 (1H, m), 4.15-4.18 (1H, m), 4.45 (2H, d), 4.49 (1H, d), 5.38 (1H, t), 6.41 (1H, d), 6.66 (1H, s), 7.46-7.50 (2H, m), 8.18– 8.22 (2H, m), 8.49 (1H, s),

Espectro de masa: M+H+ 384. Mass spectrum: M + H + 384.

Prueba (a): 0,19 μM. Test (a): 0.19 μM.

Ejemplo 43: Example 43:

3–Ciclopropil–1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(piridin–4–ilsulfonilmetil)pirimidin–2–il]fenil]urea 3 – Cyclopropyl – 1– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (pyridin-4-ylsulfonylmethyl) pyrimidin – 2-yl] phenyl] urea

O OR

N N N N

N O NO

S N S N

O OR

O N O n

N HH N HH

Se disolvió parcialmente 3–ciclopropil–1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfoniloximetil)pirimidin–2– il]fenil]urea (100 mg, 0,24 mmoles) en acetonitrilo (4 ml), y se añadió piridina–4–tiol (0,38 mmoles). La reacción se agitó durante 1 h a RT, después se añadió DBU (0,065 ml, 0,43 mmoles), y la reacción se agitó a RT durante 18 h. La reacción se evaporó hasta sequedad y se disolvió en 1,4–dioxano (2 ml). Se añadió a la reacción una disolución de m–CPBA (75%) (94 mg) en 1,4 dioxano (2 ml), seguido inmediatamente por una disolución de permanganato de sodio (104 mg) en agua (1 ml), y se dejó agitar a RT durante 1 h. Se añadió una disolución adicional de m–CPBA (75%) (94 mg) en 1,4 dioxano (1 ml), seguido inmediatamente por una disolución de permanganato de sodio (104 mg) en agua (0,5 ml), y la reacción se agitó a RT durante 1 h. La mezcla de reacción se cargó en una columna SCX–2 (10 g), la columna se lavó con metanol, y el producto se eluyó con amoniaco 7N en metanol. El material se purificó adicionalmente mediante HPLC prep. (básica) para dar el material deseado como un sólido (10 mg). 3-Cyclopropyl-1– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (methylsulfonyloxymethyl) pyrimidin-2-yl] phenyl] urea (100 mg, 0.24) was partially dissolved mmol) in acetonitrile (4 ml), and pyridine-4-thiol (0.38 mmol) was added. The reaction was stirred for 1 h at RT, then DBU (0.065 ml, 0.43 mmol) was added, and the reaction was stirred at RT for 18 h. The reaction was evaporated to dryness and dissolved in 1,4-dioxane (2 ml). A solution of m-CPBA (75%) (94 mg) in 1.4 dioxane (2 ml) was added to the reaction, followed immediately by a solution of sodium permanganate (104 mg) in water (1 ml), and Stir at RT for 1 h. An additional solution of m-CPBA (75%) (94 mg) in 1.4 dioxane (1 ml) was added, followed immediately by a solution of sodium permanganate (104 mg) in water (0.5 ml), and The reaction was stirred at RT for 1 h. The reaction mixture was loaded on an SCX-2 column (10 g), the column was washed with methanol, and the product was eluted with 7N ammonia in methanol. The material was further purified by prep HPLC. (basic) to give the desired material as a solid (10 mg).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 0,40–0,44 (2H, m), 0,63–0,67 (2H, m), 1,21 (3H, d), 2,58–2,61 (1H, m), 3,15–3,25 (1H, m), 3,45–3,52 (1H, m), 3,61–3,65 (1H, m), 3,77 (1H, d), 3,96–3,99 (1H, m), 4,10–4,14 (1H, m), 4,38 (1H, s), 4,86 (2H, t), 6,41–6,42 (1H, m), 6,71 (1H, s), 7,37 (2H, d), 7,66 (2H, d), 7,81–7,82 (2H, m), 8,50 (1H, s), 8,90–8,91 (2H, m) NMR Spectrum: 1H NMR (400.13 MHz, DMSO – d6) δ 0.40–0.44 (2H, m), 0.63–0.67 (2H, m), 1.21 (3H, d) , 2.58-2.61 (1H, m), 3.15-3.25 (1H, m), 3.45-3.52 (1H, m), 3.61-3.65 (1H, m), 3.77 (1H, d), 3.96-3.99 (1H, m), 4.10-4.14 (1H, m), 4.38 (1H, s), 4.86 (2H, t), 6.41–6.42 (1H, m), 6.71 (1H, s), 7.37 (2H, d), 7.66 (2H, d), 7.81– 7.82 (2H, m), 8.50 (1H, s), 8.90–8.91 (2H, m)

Espectro de masa: M+H+ 509. Mass spectrum: M + H + 509.

Los siguientes compuestos se prepararon de manera análoga usando el tiol apropiado. 5 The following compounds were prepared analogously using the appropriate thiol. 5

Ejemplo Example: Estructura NOMBRE LCMS MH+ Structure NAME LCMS MH +

43a 43rd: S O O NH O N N N O N H O N H 2–[[2–[4–(ciclopropilcarbamoilamino)fenil]–6– [(3S)–3–metilmorfolin–4–il]pirimidin–4– il]metilsulfonil]–N–metil–acetamida 503 S O O NH O N N N O N H O N H 2 - [[2– [4– (cyclopropylcarbamoylamino) phenyl] –6– [(3S) –3-methylmorpholin-4-yl] pyrimidin-4-yl] methylsulfonyl] –N-methyl-acetamide 503

43b 43b: F O 3–ciclopropil–1–[4–[4–[(4– fluorofenil)sulfonilmetil]–6–[(3S)–3–metilmorfolin– 526 F OR 3 – cyclopropyl – 1– [4– [4 - [(4– fluorophenyl) sulfonylmethyl] –6 - [(3S) –3 – methylmorpholin– 526

S O O S O O: N N N N H O N H 4–il]pirimidin–2–il]fenil]urea N N N N H O N H 4-yl] pyrimidin-2-yl] phenyl] urea

43c 43c: S O O NH O N N N O N H O N H N–[4–[[2–[4–(ciclopropilcarbamoilamino)fenil]–6– [(3S)–3–metilmorfolin–4–il]pirimidin–4– il]metilsulfonil]fenil]acetamida 565 S O O NH O N N N O N H O N H N– [4 - [[2– [4– (cyclopropylcarbamoylamino) phenyl] –6– [(3S) –3-methylmorpholin-4-yl] pyrimidin-4-yl] methylsulfonyl] phenyl] acetamide 565

43d 43d: S O O OH N N N O N H O N H 3–ciclopropil–1–[4–[4–(2–hidroxietilsulfonilmetil)– 6–[(3S)–3–metilmorfolin–4–il]pirimidin–2– il]fenil]urea 476 S O O OH N N N O N H O N H 3 – cyclopropyl – 1– [4– [4– (2-hydroxyethylsulfonylmethyl) - 6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] urea 476

43e 43e: S O O SN N N N O N H O N H 3–ciclopropil–1–[4–[4–[(3S)–3–metilmorfolin–4– il]–6–(1,3–tiazol–2–ilsulfonilmetil)pirimidin–2– il]fenil]urea 515 S O O SN N N N O N H O N H 3 – cyclopropyl – 1– [4– [4 - [(3S) –3-methylmorpholin-4– yl] –6– (1,3-thiazol-2-ylsulfonylmethyl) pyrimidin-2-yl] phenyl] urea 515

43f 43f: O 3–ciclopropil–1–[4–[4–[(3S)–3–metilmorfolin–4– 576 OR 3 – cyclopropyl – 1– [4– [4 - [(3S) –3 – methylmorpholin – 4– 576

S O O F F F S O O F F F: N N N N H O N H il]–6–[[2–(trifluorometil)fenil]sulfonilmetil]pirimidin– 2–il]fenil]urea N N N N H O N H il] –6 - [[2– (trifluoromethyl) phenyl] sulfonylmethyl] pyrimidin– 2-yl] phenyl] urea

43g 43g: O 3–ciclopropil–1–[4–[4–[(3S)–3–metilmorfolin–4– 530 OR 3 – cyclopropyl – 1– [4– [4 - [(3S) –3 – methylmorpholin – 4– 530

: il]–6–[(5–metil–1,3,4–tiadiazol–2– il] –6 - [(5 – methyl – 1,3,4 – thiadiazole – 2–

S O O S N N S O O S N N: N N N N H O N H il)sulfonilmetil]pirimidin–2–il]fenil]urea N N N N H O N H il) sulfonylmethyl] pyrimidin-2-yl] phenyl] urea

43h 43h: S O O NH2 O N N N O N H O N H 2–[[2–[4–(ciclopropilcarbamoilamino)fenil]–6– [(3S)–3–metilmorfolin–4–il]pirimidin–4– il]metilsulfonil]acetamida 489 S O O NH2 O N N N O N H O N H 2 - [[2– [4– (cyclopropylcarbamoylamino) phenyl] –6– [(3S) –3-methylmorpholin-4-yl] pyrimidin-4-yl] methylsulfonyl] acetamide 489

Ejemplo Example: Estructura NOMBRE LCMS MH+ Structure NAME LCMS MH +

43i 43i: O 3–ciclopropil–1–[4–[4–[(3S)–3–metilmorfolin–4– 529 OR 3 – cyclopropyl – 1– [4– [4 - [(3S) –3 – methylmorpholin – 4– 529

: il]–6–[(4–metil–1,3–tiazol–2– il] –6 - [(4 – methyl – 1,3 – thiazole – 2–

N N N S N H O N H O O SN N N N S N H O N H O O SN: il)sulfonilmetil]pirimidin–2–il]fenil]urea il) sulfonylmethyl] pyrimidin-2-yl] phenyl] urea

43j 43j: N N N O S N H O N H O O NH O N–[2–[[2–[4–(ciclopropilcarbamoilamino)fenil]–6– [(3S)–3–metilmorfolin–4–il]pirimidin–4– il]metilsulfonil]etil]acetamida 517 N N N O S N H O N H O O NH O N– [2 - [[2– [4– (cyclopropylcarbamoylamino) phenyl] –6– [(3S) –3-methylmorpholin-4-yl] pyrimidin-4-yl] methylsulfonyl] ethyl] acetamide 517

43k 43k: N N N O S O O N H N H O 1–[4–[4–(1–adamantilsulfonilmetil)–6–[(3S)–3– metilmorfolin–4–il]pirimidin–2–il]fenil]–3– ciclopropil–urea 598 N N N O S O O N H N H O 1– [4– [4– (1 – adamantylsulfonylmethyl) –6 - [(3S) –3– methylmorpholin-4-yl] pyrimidin – 2-yl] phenyl] –3– cyclopropyl-urea 598

Ejemplo 43a: RMN 1H (400,13 MHz, DMSO–d6) δ 0,40–0,44 (2H, m), 0,63–0,67 (2H, m), 1,23–1,25 (3H, m), 2,57– 2,60 (1H, m), 2,67–2,70 (3H, m), 3,19–3,25 (1H, m), 3,47–3,53 (1H, m), 3,63–3,67 (1H, m), 3,78 (1H, d), 3,97–4,01 (1H, m), 4,15–4,19 (1H, m), 4,29 (2H, s), 4,48 (1H, s), 4,67 (2H, s), 6,43–6,44 (1H, m), 6,77 (1H, s), 7,50 (2H, d), 8,19 (2H, d), 8,31 (1H, t), 8,54 (1H, s) Example 43a: 1H NMR (400.13 MHz, DMSO-d6) δ 0.40–0.44 (2H, m), 0.63–0.67 (2H, m), 1.23–1.25 ( 3H, m), 2.57-2.60 (1H, m), 2.67-2.70 (3H, m), 3.19-3.25 (1H, m), 3.47-3, 53 (1H, m), 3.63-3.67 (1H, m), 3.78 (1H, d), 3.97-4.01 (1H, m), 4.15-4.19 ( 1H, m), 4.29 (2H, s), 4.48 (1H, s), 4.67 (2H, s), 6.43-6.44 (1H, m), 6.77 (1H , s), 7.50 (2H, d), 8.19 (2H, d), 8.31 (1H, t), 8.54 (1H, s)

Ejemplo 43b: RMN 1H (400,13 MHz, DMSO–d6) δ 0,40–0,44 (2H, m), 0,63–0,67 (2H, m), 1,20 (3H, d), 2,52–2,60 (1H, m), 3,15–3,20 (1H, m), 3,45–3,51 (1H, m), 3,61–3,65 (1H, m), 3,76 (1H, d), 3,95–3,99 (1H, m), 4,10–4,13 (1H, m), 4,38 (1H, s), 4,71 (2H, s), 6,40 (1H, d), 6,65 (1H, s), 7,38–7,41 (2H, m), 7,43–7,48 (2H, m), 7,79 (2H, d), 7,85– 7,89 (2H, m), 8,51 (1H, s) Example 43b: 1H NMR (400.13 MHz, DMSO – d6) δ 0.40–0.44 (2H, m), 0.63–0.67 (2H, m), 1.20 (3H, d) , 2.52-2.60 (1H, m), 3.15-3.20 (1H, m), 3.45-3.51 (1H, m), 3.61-3.65 (1H, m), 3.76 (1H, d), 3.95–3.99 (1H, m), 4.10-4.13 (1H, m), 4.38 (1H, s), 4.71 (2H, s), 6.40 (1H, d), 6.65 (1H, s), 7.38-7.41 (2H, m), 7.43-7.48 (2H, m), 7.79 (2H, d), 7.85– 7.89 (2H, m), 8.51 (1H, s)

Ejemplo 43c: RMN 1H (400,13 MHz, DMSO–d6) δ 0,40–0,44 (2H, m), 0,63–0,67 (2H, m), 1,19 (3H, d), 2,13 (3H, s), 2,53–2,61 (1H, m), 3,15–3,20 (1H, m), 3,43–3,50 (1H, m), 3,60–3,63 (1H, m), 3,75 (1H, d), 3,94–3,98 (1H, m), 4,09 (1H, s), 4,34 (1H, s), 4,60 (2H, s), 6,41–6,42 (1H, m), 6,55 (1H, s), 7,39 (2H, d), 7,70 (2H, d), 7,77 (2H, d), 7,83 (2H, d), 8,48 (1H, s), 10,37 (1H, s) Example 43c: 1H NMR (400.13 MHz, DMSO-d6) δ 0.40–0.44 (2H, m), 0.63–0.67 (2H, m), 1.19 (3H, d) , 2.13 (3H, s), 2.53-2.61 (1H, m), 3.15-3.20 (1H, m), 3.43-3.50 (1H, m), 3 , 60–3.63 (1H, m), 3.75 (1H, d), 3.94–3.98 (1H, m), 4.09 (1H, s), 4.34 (1H, s ), 4.60 (2H, s), 6.41–6.42 (1H, m), 6.55 (1H, s), 7.39 (2H, d), 7.70 (2H, d) , 7.77 (2H, d), 7.83 (2H, d), 8.48 (1H, s), 10.37 (1H, s)

Ejemplo 43d: RMN 1H (400,13 MHz, DMSO–d6) δ 0,40–0,44 (2H, m), 0,63–0,67 (2H, m), 1,24 (3H, d), 2,59–2,61 (1H, m), 3,15–3,20 (1H, m), 3,51 (3H, t), 3,63–3,67 (1H, m), 3,78 (1H, d), 3,92 (2H, q), 3,97–4,01 (1H, m), 4,16–4,19 (1H, m), 4,50 (3H, s), 5,18 (1H, t), 6,44 (1H, d), 6,76 (1H, s), 7,50–7,52 (2H, m), 8,21–8,23 (2H, m), 8,54 (1H, s) Example 43d: 1H NMR (400.13 MHz, DMSO-d6) δ 0.40–0.44 (2H, m), 0.63–0.67 (2H, m), 1.24 (3H, d) , 2.59-2.61 (1H, m), 3.15-3.20 (1H, m), 3.51 (3H, t), 3.63-3.67 (1H, m), 3 , 78 (1H, d), 3.92 (2H, q), 3.97-4.01 (1H, m), 4.16-4.19 (1H, m), 4.50 (3H, s ), 5.18 (1H, t), 6.44 (1H, d), 6.76 (1H, s), 7.50–7.52 (2H, m), 8.21–8.23 ( 2H, m), 8.54 (1H, s)

Ejemplo 43e: RMN 1H (400,13 MHz, DMSO–d6) δ 0,40–0,44 (2H, m), 0,63–0,67 (2H, m), 1,20 (3H, d), 2,52–2,61 (1H, m), 3,15–3,20 (1H, m), 3,45–3,52 (1H, m), 3,62–3,65 (1H, m), 3,77 (1H, d), 3,96–3,99 (1H, m), 4,12 (1H, d), 4,40 (2H, s), 4,90–4,91 (1H, m), 6,42 (1H, d), 6,71 (1H, s), 7,40–7,43 (2H, m), 7,84 (2H, d), 8,27–8,29 (2H, m), 8,50 (1H, s) Example 43e: 1H NMR (400.13 MHz, DMSO-d6) δ 0.40–0.44 (2H, m), 0.63–0.67 (2H, m), 1.20 (3H, d) , 2.52-2.61 (1H, m), 3.15-3.20 (1H, m), 3.45-3.52 (1H, m), 3.62-3.65 (1H, m), 3.77 (1H, d), 3.96-3.99 (1H, m), 4.12 (1H, d), 4.40 (2H, s), 4.90-4.91 (1H, m), 6.42 (1H, d), 6.71 (1H, s), 7.40-7.43 (2H, m), 7.84 (2H, d), 8.27– 8.29 (2H, m), 8.50 (1H, s)

Ejemplo 43f: RMN 1H (400,13 MHz, DMSO–d6) δ 0,40–0,44 (2H, m), 0,63–0,67 (2H, m), 1,20–1,22 (3H, m), 2,53 (1H, m), 3,17 (1H, d), 3,49 (1H, d), 3,62–3,66 (1H, m), 3,77 (1H, d), 3,95–3,99 (1H, m), 4,12 (1H, d), 4,40 (1H, s), 4,74–4,75 (2H, m), 6,42–6,42 (1H, m), 6,70 (1H, s), 7,37 (2H, d), 7,72 (2H, d), 7,80 (1H, d), 7,90 (2H, t), 8,08 (1H, d), 8,48 (1H, s) Example 43f: 1H NMR (400.13 MHz, DMSO-d6) δ 0.40–0.44 (2H, m), 0.63–0.67 (2H, m), 1.20–1.22 ( 3H, m), 2.53 (1H, m), 3.17 (1H, d), 3.49 (1H, d), 3.62-3.66 (1H, m), 3.77 (1H , d), 3.95–3.99 (1H, m), 4.12 (1H, d), 4.40 (1H, s), 4.74-4.75 (2H, m), 6, 42–6.42 (1H, m), 6.70 (1H, s), 7.37 (2H, d), 7.72 (2H, d), 7.80 (1H, d), 7.90 (2H, t), 8.08 (1H, d), 8.48 (1H, s)

Ejemplo 43g: RMN 1H (400,13 MHz, DMSO–d6) δ 0,42 (2H, d), 0,63–0,67 (2H, m), 1,23 (3H, d), 2,53 (1H, d), 2,80 (3H, s), 3,20 (1H, d), 3,48 (1H, d), 3,62–3,66 (1H, m), 3,77 (1H, d), 4,12 (1H, d), 4,40 (2H, s), 5,04 (2H, t), 6,44 (1H, s), 6,80 (1H, s), 7,43 (2H, d), 7,79 (2H, d), 8,53 (1H, s) Example 43g: 1H NMR (400.13 MHz, DMSO-d6) δ 0.42 (2H, d), 0.63-0.67 (2H, m), 1.23 (3H, d), 2.53 (1H, d), 2.80 (3H, s), 3.20 (1H, d), 3.48 (1H, d), 3.62-3.66 (1H, m), 3.77 ( 1H, d), 4.12 (1H, d), 4.40 (2H, s), 5.04 (2H, t), 6.44 (1H, s), 6.80 (1H, s), 7.43 (2H, d), 7.79 (2H, d), 8.53 (1H, s)

Ejemplo 43i: RMN 1H (400,13 MHz, DMSO–d6) δ 0,40–0,44 (2H, m), 0,63–0,67 (2H, m), 1,21 (3H, d), 2,60–2,61 (1H, m), 3,20 (1H, d), 3,34–3,39 (3H, s), 3,45–3,52 (1H, m), 3,62–3,66 (1H, m), 3,77 (1H, d), 3,96–4,00 (1H, m), 4,12 (1H, d), 4,41 (1H, s), 4,86–4,87 (2H, m), 6,41–6,42 (1H, m), 6,71 (1H, s), 7,41–7,44 (2H, m), 7,82 (1H, d), 7,87 (2H, d), 8,51 (1H, s) Example 43i: 1H NMR (400.13 MHz, DMSO-d6) δ 0.40–0.44 (2H, m), 0.63–0.67 (2H, m), 1.21 (3H, d) , 2.60–2.61 (1H, m), 3.20 (1H, d), 3.34–3.39 (3H, s), 3.45–3.52 (1H, m), 3 , 62–3.66 (1H, m), 3.77 (1H, d), 3.96-4.00 (1H, m), 4.12 (1H, d), 4.41 (1H, s ), 4.86–4.87 (2H, m), 6.41–6.42 (1H, m), 6.71 (1H, s), 7.41–7.44 (2H, m), 7.82 (1H, d), 7.87 (2H, d), 8.51 (1H, s)

Ejemplo 43j: RMN 1H (400,13 MHz, DMSO–d6) δ 0,40–0,44 (2H, m), 0,63–0,67 (2H, m), 1,24 (3H, t), 1,83 (3H, s), 2,52–2,60 (1H, m), 3,19–3,25 (1H, m), 3,47–3,50 (2H, m), 3,52 (2H, d), 3,56 (2H, d), 3,63–3,67 (1H, m), 3,78 (1H, d), Example 43j: 1H NMR (400.13 MHz, DMSO-d6) δ 0.40-0.44 (2H, m), 0.63-0.67 (2H, m), 1.24 (3H, t) , 1.83 (3H, s), 2.52–2.60 (1H, m), 3.19–3.25 (1H, m), 3.47–3.50 (2H, m), 3 , 52 (2H, d), 3.56 (2H, d), 3.63-3.67 (1H, m), 3.78 (1H, d),

3,97–4,01 (1H, m), 4,12 (1H, d), 4,50 (2H, d), 6,43 (1H, d), 6,78 (1H, s), 7,50 (2H, d), 8,19–8,22 (2H, m), 8,54 (1H, s), 9,00 (1H, s) 3.97-4.01 (1H, m), 4.12 (1H, d), 4.50 (2H, d), 6.43 (1H, d), 6.78 (1H, s), 7 , 50 (2H, d), 8.19–8.22 (2H, m), 8.54 (1H, s), 9.00 (1H, s)

Ejemplo 43k: RMN 1H (400,13 MHz, DMSO–d6) δ 0,40–0,44 (2H, m), 0,63–0,67 (2H, m), 1,24 (3H, d), 1,67 (6H, d), 2,03 (6H, s), 2,12 (3H, s), 2,53–2,60 (1H, m), 3,20–3,24 (1H, m), 3,47–3,51 (1H, m), 3,64–3,67 (1H, m), 3,78 (1H, d), 3,97–4,01 (1H, m), 4,12 (1H, d), 4,39–4,45 (3H, m), 6,43 (1H, d), 6,73 (1H, s), 7,49–7,51 (2H, m), 8,22 (2H, d), 8,53 (1H, s) Example 43k: 1H NMR (400.13 MHz, DMSO-d6) δ 0.40–0.44 (2H, m), 0.63–0.67 (2H, m), 1.24 (3H, d) , 1.67 (6H, d), 2.03 (6H, s), 2.12 (3H, s), 2.53–2.60 (1H, m), 3.20–3.24 (1H , m), 3.47-3.51 (1H, m), 3.64-3.67 (1H, m), 3.78 (1H, d), 3.97-4.01 (1H, m ), 4.12 (1H, d), 4.39-4.45 (3H, m), 6.43 (1H, d), 6.73 (1H, s), 7.49-7.51 ( 2H, m), 8.22 (2H, d), 8.53 (1H, s)

Prueba (a): Ejemplo (43) 0,076 μM; Ejemplo (43a) 0,087 μM; Ejemplo (43b) 0,15 μM; Ejemplo (43c) 0,013 μM; Ejemplo (43d) 0,011 μM; Ejemplo (43e) 0,13 μM; Ejemplo (43f) 0,11 μM; Ejemplo (43h) 0,0071 μM; Ejemplo (43i) 0,058 μM; Ejemplo (43j) 1,8 μM. Test (a): Example (43) 0.076 μM; Example (43a) 0.087 μM; Example (43b) 0.15 μM; Example (43c) 0.013 μM; Example (43d) 0.011 μM; Example (43e) 0.13 μM; Example (43f) 0.11 μM; Example (43h) 0.0071 μM; Example (43i) 0.058 μM; Example (43j) 1.8 μM.

Prueba (c): Ejemplo (43g) 1,9 μM; Ejemplo (43k) 2,9 μM Test (c): Example (43g) 1.9 μM; Example (43k) 2.9 μM

A continuación se describe la preparación de 3–ciclopropil–1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6– (metilsulfoniloximetil)pirimidin–2–il]fenil]urea. The preparation of 3-cyclopropyl-1– [4– [4 - [(3S) -3-methylmorpholin-4-yl] -6– (methylsulfonyloxymethyl) pyrimidin-2-yl] phenyl] urea is described below.

3–Ciclopropil–1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfoniloximetil)pirimidin–2–il]fenil]urea 3 – Cyclopropyl – 1– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (methylsulfonyloxymethyl) pyrimidin – 2-yl] phenyl] urea

O OR

N N

O N O n

O OR

OO N S OO N S

N HH N HH

Se disolvió parcialmente 3–ciclopropil–1–[4–[4–(hidroximetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]urea (1,83 g) en DCM (50 ml) y trietilamina (1 ml), y la disolución se enfrió hasta 0ºC. Se añadió cloruro de metanosulfonilo (0,56 ml), y la reacción se agitó durante 45 min. a RT. La reacción se lavó después con agua (10 ml), y los productos orgánicos se secaron sobre sulfato de magnesio. La disolución se sometió a vacío hasta sequedad para dar el material deseado como un sólido amarillo. 3-Cyclopropyl-1– [4– [4– (hydroxymethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] urea (1.83 g) was dissolved partially DCM (50 ml) and triethylamine (1 ml), and the solution was cooled to 0 ° C. Methanesulfonyl chloride (0.56 ml) was added, and the reaction was stirred for 45 min. art. The reaction was then washed with water (10 ml), and the organic products were dried over magnesium sulfate. The solution was subjected to vacuum to dryness to give the desired material as a yellow solid.

Espectro de masa: M+H+ 462. Mass spectrum: M + H + 462.

Ejemplo 44: Example 44:

3–Ciclopropil–1–[4–[4–(3–Hidroxipropilsulfonilmetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]urea 3 – Cyclopropyl – 1– [4– [4– (3 – Hydroxypropylsulfonylmethyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin – 2-yl] phenyl] urea

Se añadió de permanganato de sodio monohidratado (38 mg, 0,24 mmoles) a m–CPBA (33,2 mg, 0,19 mmoles) y 3– ciclopropil–1–[4–[4–(3–hidroxipropilsulfanilmetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]urea (44 mg, 0,10 mmoles) en dioxano (2 ml) y agua (1 ml) a 20ºC. La disolución resultante se agitó a 20ºC durante 45 minutos, y la mezcla se cargó en una columna SCX–3 (5 g), y el producto deseado se eluyó de la columna usando amoniaco 7M en metanol. El material se purificó adicionalmente mediante HPLC preparativa usando mezclas polares decrecientes de agua (que contiene 1% de NH3) y acetonitrilo como eluyentes, para dar el material deseado (19 mg) como un sólido blanco. Sodium permanganate monohydrate (38 mg, 0.24 mmol) am – CPBA (33.2 mg, 0.19 mmol) and 3– cyclopropyl – 1– [4– [4– (3-hydroxypropylsulfanylmethyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] urea (44 mg, 0.10 mmol) in dioxane (2 ml) and water (1 ml) at 20 ° C. The resulting solution was stirred at 20 ° C for 45 minutes, and the mixture was loaded on an SCX-3 column (5 g), and the desired product was eluted from the column using 7M ammonia in methanol. The material was further purified by preparative HPLC using decreasing polar mixtures of water (containing 1% NH3) and acetonitrile as eluents, to give the desired material (19 mg) as a white solid.

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 0,40–0,44 (2H, m), 0,63–0,67 (2H, m), 1,24 (3H, d), 1,92–1,99 (2H, m), 2,53–2,60 (1H, m), 3,18–3,26 (1H, m), 3,39 (2H, q), 3,47–3,50 (1H, m), 3,55 (2H, q), 3,63–3,67 (1H, m), 3,78 (1H, d), 3,97–4,01 (1H, m), 4,16–4,19 (1H, m), 4,46 (3H, s), 4,72 (1H, t), 6,43 (1H, d), 6,78 (1H, s), 7,49–7,51 (2H, m), 8,20–8,23 (2H, m), 8,53 (1H, s) NMR Spectrum: 1H NMR (400.13 MHz, DMSO – d6) δ 0.40–0.44 (2H, m), 0.63–0.67 (2H, m), 1.24 (3H, d) , 1.92–1.99 (2H, m), 2.53–2.60 (1H, m), 3.18–3.26 (1H, m), 3.39 (2H, q), 3 , 47–3.50 (1H, m), 3.55 (2H, q), 3.63–3.67 (1H, m), 3.78 (1H, d), 3.97–4.01 (1H, m), 4.16-4.19 (1H, m), 4.46 (3H, s), 4.72 (1H, t), 6.43 (1H, d), 6.78 ( 1H, s), 7.49–7.51 (2H, m), 8.20–8.23 (2H, m), 8.53 (1H, s)

Espectro de masa: M+H+ 490 Mass spectrum: M + H + 490

Prueba (a): 1,8 μM. Test (a): 1.8 μM.

A continuación se describe la preparación de 3–ciclopropil–1–[4–[4–(3–hidroxipropilsulfanilmetil)–6–[(3S)–3– metilmorfolin–4–il]pirimidin–2–il]fenil]urea. The preparation of 3-cyclopropyl-1– [4– [4– (3-hydroxypropylsulfanylmethyl) -6 - [(3S) -3– methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] urea is described below.

3–Ciclopropil–1–[4–[4–(3–hidroxipropilsulfanilmetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]urea 3 – Cyclopropyl – 1– [4– [4– (3-hydroxypropylsulfanylmethyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin – 2-yl] phenyl] urea

5 Se disolvió parcialmente 3–ciclopropil–1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfoniloximetil)pirimidin–2– il]fenil]urea (100 mg) en acetonitrilo (4 ml) y se añadió a 3–sulfanilpropan–1–ol (0,38 mmoles). La reacción se agitó durante 1 h a RT. Se añadió DBU (0,065 ul) a la reacción, y la mezcla se dejó agitar a RT durante 18 h. La mezcla se concentró a vacío y se purificó mediante HPLC prep. (básica) para dar el material deseado (44 mg) como un sólido blanco. 5 3-Cyclopropyl-1– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (methylsulfonyloxymethyl) pyrimidin-2-yl] phenyl] urea (100 mg) was dissolved in acetonitrile (4 ml) and added to 3-sulfanylpropan-1-ol (0.38 mmol). The reaction was stirred for 1 h at RT. DBU (0.065 ul) was added to the reaction, and the mixture was allowed to stir at RT for 18 h. The mixture was concentrated in vacuo and purified by prep HPLC. (basic) to give the desired material (44 mg) as a white solid.

10 Espectro de masa: M+H+ 458. 10 Mass spectrum: M + H + 458.

La preparación de 3–ciclopropil–1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfoniloximetil)pirimidin–2–il]fenil]urea se describió anteriormente. The preparation of 3-cyclopropyl-1– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (methylsulfonyloxymethyl) pyrimidin-2-yl] phenyl] urea was described above.

Ejemplo 45: Example 45:

1–(2–Hidroxietil)–1–metil–3–[4–[4–(metilsulfonilmetil)–6–morfolin–4–il–pirimidin–2–il]fenil]urea 1– (2 – Hydroxyethyl) –1 – methyl – 3– [4– [4– (methylsulfonylmethyl) –6 – morpholin-4-yl-pyrimidin – 2-yl] phenyl] urea

O OR

N N

N S N S

OO OO

N N

O OH Or oh

N H 15 N H 15

N N

Se añadió a 2–metilaminoetanol (10 mmoles) una disolución de N–[4–[4–(metilsulfonilmetil)–6–morfolin–4–il– pirimidin–2–il]fenil]carbamato de fenilo (94 mg, 2 mmoles) y trietilamina (0,09 ml, 9,2 mmoles) en NMP (1 ml). La mezcla se calentó a 70ºC durante 2 horas, y la reacción se purificó mediante HPLC prep., para dar el compuesto deseado. A solution of N- [4– [4– (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] phenyl] phenyl] carbamate (94 mg, 2 mmol) was added to 2-methylaminoethanol (10 mmol) ) and triethylamine (0.09 ml, 9.2 mmol) in NMP (1 ml). The mixture was heated at 70 ° C for 2 hours, and the reaction was purified by prep. HPLC, to give the desired compound.

20 Espectro LCMS: MH+ 450, Tiempo de retención 2,07 min. 20 LCMS spectrum: MH + 450, Retention time 2.07 min.

Los siguientes compuestos se obtuvieron de manera análoga a partir de N–[4–[4–(metilsulfonilmetil)–6–morfolin–4– il–pirimidin–2–il]fenil]carbamato de fenilo o N–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidin–2– il]fenil]carbamato de fenilo y la amina apropiada. The following compounds were obtained analogously from N- [4– [4– (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] phenyl] phenyl carbamate or N– [4– [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidin-2-yl] phenyl] phenyl carbamate and the appropriate amine.

45a 45th: S O O N N N O N H O N N–[4–[4–(metilsulfonilmetil)–6– morfolin–4–il–pirimidin–2– il]fenil]piperidina–1–carboxamida 460 2,74 S O O N N N O N H O N N– [4– [4– (methylsulfonylmethyl) –6– morpholin-4-yl-pyrimidin-2-yl] phenyl] piperidine – 1-carboxamide 460 2.74

45b 45b: O 1–(2–metilpropil)–3–[4–[4– 448 2,76 OR 1– (2 – methylpropyl) –3– [4– [4– 448 2.76

N N N S O O N H O N H N N N S O O N H O N H: pirimidin–2–il]fenil]urea pyrimidin – 2-yl] phenyl] urea

45c 45c: O 1–(3–metoxipropil)–3–[4–[4– 464 2,46 OR 1– (3 – methoxypropyl) –3– [4– [4– 464 2.46

N N N S O O N H O N H O N N N S O O N H O N H O: pirimidin–2–il]fenil]urea pyrimidin – 2-yl] phenyl] urea

45d 45d: O 1–(4–dimetilaminobutil)–3–[4–[4– 491 2,8 OR 1– (4 – dimethylaminobutyl) –3– [4– [4– 491 2.8

45e 45e: O 1–[4–[4–(metilsulfonilmetil)–6– 504 2,27 OR 1– [4– [4– (methylsulfonylmethyl) –6– 504 2.27

: morfolin–4–il–pirimidin–2–il]fenil]–3– morpholin-4-yl-pyrimidin-2-yl] phenyl] –3–

N N N S O O N H O N H N N HO N N N S O O N H O N H N N HO: [2–(2–oxoimidazolidin–1–il)etil]urea [2– (2 – oxoimidazolidin – 1-yl) ethyl] urea

45f 45f: O N–[4–[4–(metilsulfonilmetil)–6– 446 2,56 OR N– [4– [4– (methylsulfonylmethyl) –6– 446 2.56

morfolin–4–il–pirimidin–2– morpholin-4-yl-pyrimidin-2–

N N N S O O N H O N N N N S O O N H O N: il]fenil]pirrolidina–1–carboxamida il] phenyl] pyrrolidine-1-carboxamide

45g 45g: O N–[4–[4–(metilsulfonilmetil)–6– 462 2,4 OR N– [4– [4– (methylsulfonylmethyl) –6– 462 2.4

: morfolin–4–il–pirimidin–2– morpholin-4-yl-pyrimidin-2–

45h 45h: N N N O S O O N H O N OH 4–hidroxi–N–[4–[4– (metilsulfonilmetil)–6–morfolin–4–il– pirimidin–2–il]fenil]piperidina–1– carboxamida 476 2,28 N N N O S O O N H O N OH 4-hydroxy-N– [4– [4– (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] phenyl] piperidine – 1– carboxamide 476 2.28

45i 45i: O 1–(1–metoxipropan–2–il)–3–[4–[4– 464 2,51 OR 1– (1 – methoxypropan – 2 – il) –3– [4– [4– 464 2.51

N N N S O O N H O N O N N N S O O N H O N O: pirimidin–2–il]fenil]urea pyrimidin – 2-yl] phenyl] urea

45j 45j: O 1–(2–dimetilaminoetil)–3–[4–[4– 463 2,52 OR 1– (2 – dimethylaminoethyl) –3– [4– [4– 463 2.52

45k 45k: O 3–(2–hidroxietil)–1–[4–[4– 436 2,21 OR 3– (2 – hydroxyethyl) –1– [4– [4– 436 2.21

N N N S O O N H O N H OH N N N S O O N H O N H OH: pirimidin–2–il]fenil]urea pyrimidin – 2-yl] phenyl] urea

45l 45l: O 1–etil–1–metil–3–[4–[4– 434 2,54 OR 1 – ethyl – 1 – methyl – 3– [4– [4– 434 2.54

N N N S O O N H O N N N N S O O N H O N: pirimidin–2–il]fenil]urea pyrimidin – 2-yl] phenyl] urea

45m 45m: N N N O S O O N H O N OH 3–hidroxi–N–[4–[4– (metilsulfonilmetil)–6–morfolin–4–il– pirimidin–2–il]fenil]piperidina–1– carboxamida 476 2,35 N N N O S O O N H O N OH 3-hydroxy-N– [4– [4– (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] phenyl] piperidine – 1– carboxamide 476 2.35

45n 45n: N N N O S O O N H O N S O O 3–metilsulfonil–N–[4–[4– (metilsulfonilmetil)–6–morfolin–4–il– pirimidin–2–il]fenil]pirrolidina–1– carboxamida 524 2,34 N N N O S O O N H O N S O O 3-methylsulfonyl-N– [4– [4– (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] phenyl] pyrrolidine-1-carboxamide 524 2.34

45o 45o: O 1–[4–[4–(metilsulfonilmetil)–6– 505 2,14 OR 1– [4– [4– (methylsulfonylmethyl) –6– 505 2.14

N N N S O O N H O N H N O N N N S O O N H O N H N O: morfolin–4–il–pirimidin–2–il]fenil]–3– (2–morfolin–4–iletil)urea morpholin-4-yl-pyrimidin-2-yl] phenyl] -3- (2-morpholin-4-ileyl) urea

45p 45p: O 1–(2,2–dimetilpropil)–3–[4–[4– 462 2,68 OR 1– (2,2 – dimethylpropyl) –3– [4– [4– 462 2.68

45q 45q: O 3–(3–hidroxipropil)–1–[4–[4– 450 2,05 OR 3– (3 – hydroxypropyl) –1– [4– [4– 450 2.05

45r 45r: O 1–bencil–1–metil–3–[4–[4– 496 2,74 OR 1 – benzyl – 1 – methyl – 3– [4– [4– 496 2.74

45s 45s: O 1–(2–etoxietil)–3–[4–[4– 464 2,29 OR 1– (2 – ethoxyethyl) –3– [4– [4– 464 2.29

45t 45t: O 1–(1–hidroxipropan–2–il)–3–[4–[4– 450 2,09 OR 1– (1 – hydroxypropan – 2 – il) –3– [4– [4– 450 2.09

45u 45u: O 1–[4–[4–(metilsulfonilmetil)–6– 476 2,21 OR 1– [4– [4– (methylsulfonylmethyl) –6– 476 2.21

morfolin–4–il–pirimidin–2–il]fenil]–3– morpholin-4-yl-pyrimidin-2-yl] phenyl] –3–

N N N S O O N H O N H O N N N S O O N H O N H O: (oxan–4–il)urea (oxan – 4 – il) urea

45v 45v: O N–[4–[4–(metilsulfonilmetil)–6– 475 2,00 OR N– [4– [4– (methylsulfonylmethyl) –6– 475 2.00

N N N S O O N H O N NH O N N N S O O N H O N NH O: oxo–piperazina–1–carboxamida oxo – piperazine – 1 – carboxamide

45w 45w: O 1–[2–(4–metilpiperazin–1–il)etil]–3– 518 2,11 OR 1– [2– (4 – methylpiperazin – 1-yl) ethyl] –3– 518 2.11

N N: [4–[4–(metilsulfonilmetil)–6–morfolin– [4– [4– (methylsulfonylmethyl) –6 – morpholin–

N N S O O N H O N H N N N N S O O N H O N H N N: 4–il–pirimidin–2–il]fenil]urea 4-yl-pyrimidin-2-yl] phenyl] urea

45x 45x: O 1–metil–1–(2–metilsulfoniletil)–3–[4– 512 2,14 OR 1 – methyl – 1– (2 – methylsulfonylethyl) –3– [4– 512 2.14

[4–(metilsulfonilmetil)–6–morfolin–4– [4– (methylsulfonylmethyl) –6 – morpholin-4–

N N N S O O N H O N S O O N N N S O O N H O N S O O: il–pirimidin–2–il]fenil]urea il-pyrimidin-2-yl] phenyl] urea

45y 45y: O N’–metil–N–[4–[4–(metilsulfonilmetil)– 516 2,07 OR N’ – methyl – N– [4– [4– (methylsulfonylmethyl) - 516 2.07

N N N S O O N H O N O NH N N N S O O N H O N O NH: 6–morfolin–4–il–pirimidin–2– il]fenil]piperidina–1,4–dicarboxamida 6-morpholin-4-yl-pyrimidin-2-yl] phenyl] piperidine-1,4-dicarboxamide

45z 45z: N N N O S O O N H O N H NO N,N–dimetil–2–[[4–[4– (metilsulfonilmetil)–6–morfolin–4–il– pirimidin–2– il]fenil]carbamoilamino]acetamida 477 2,11 N N N O S O O N H O N H NO N, N-dimethyl-2 - [[4– [4– (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidin-2-yl] phenyl] carbamoylamino] acetamide 477 2.11

45aa 45aa: O 4–metil–N–[4–[4–[(3S)–3– 489 1,23 OR 4 – methyl – N– [4– [4 - [(3S) –3– 489 1.23

: metilmorfolin–4–il]–6– methylmorpholin – 4 – il] –6–

N N S O O N H O N N O N N S O O N H O N N O: 3–oxo–piperazina–1–carboxamida 3 – oxo – piperazine – 1 – carboxamide

45ab 45ab: O 4–dimetilamino–N–[4–[4–[(3S)–3– 518 1,6 OR 4 – dimethylamino – N– [4– [4 - [(3S) –3– 518 1.6

: metilmorfolin–4–il]–6– methylmorpholin – 4 – il] –6–

N N S O O N H O N N N N S O O N H O N N: il]fenil]piperidina–1–carboxamida il] phenyl] piperidine-1-carboxamide

Prueba (a): Ejemplo (45) 0,66 μM; Ejemplo (45a) 0,63 μM; Ejemplo (45b) 0,12 μM; Ejemplo (45c) 0,082 μM; Ejemplo (45d) 0,56 μM; Ejemplo (45e) 0,56 μM; Ejemplo (45f) 1,6 μM; Ejemplo (45g) 0,041 μM; Ejemplo (45h) 0,14 μM; Ejemplo (45i) 3 μM; Ejemplo (45j) 0,72 μM; Ejemplo (45k) 0,049 μM; Ejemplo (45l) 1,1 μM; Ejemplo (45m) 0,17 μM; Test (a): Example (45) 0.66 μM; Example (45a) 0.63 μM; Example (45b) 0.12 μM; Example (45c) 0.082 μM; Example (45d) 0.56 μM; Example (45e) 0.56 μM; Example (45f) 1.6 μM; Example (45g) 0.041 μM; Example (45h) 0.14 μM; Example (45i) 3 μM; Example (45j) 0.72 μM; Example (45k) 0.049 μM; Example (45l) 1.1 μM; Example (45m) 0.17 μM;

5 Ejemplo (45n) 0,63 μM; Ejemplo (45o) 0,9 μM; Ejemplo (45p) 0,92 μM; Ejemplo (45q) 0,032 μM; Ejemplo (45r) 0,41 μM; Ejemplo (45s) 0,3 μM; Ejemplo (45t) 0,082 μM; Ejemplo (45u) 0,42 μM; Ejemplo (45v) 1,2 μM; Ejemplo (45w) 0,74 μM; Ejemplo (45x) 1,1 μM; Ejemplo (45y) 1,2 μM; Ejemplo (45z) 1 μM; Ejemplo (45aa) 0,83 μM; Ejemplo (45ab) 0,39 μM. 5 Example (45n) 0.63 μM; Example (45o) 0.9 μM; Example (45p) 0.92 μM; Example (45q) 0.032 μM; Example (45r) 0.41 μM; Example (45s) 0.3 μM; Example (45t) 0.082 μM; Example (45u) 0.42 μM; Example (45v) 1.2 μM; Example (45w) 0.74 μM; Example (45x) 1.1 μM; Example (45y) 1.2 μM; Example (45z) 1 μM; Example (45aa) 0.83 μM; Example (45ab) 0.39 μM.

La preparación de N–[4–[4–(metilsulfonilmetil)–6–morfolin–4–il–pirimidin–2–il]fenil]carbamato de fenilo y N–[4–[4– 10 [(3S)–3–metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidin–2–il]fenil]carbamato de fenilo se describió anteriormente. The preparation of N– [4– [4– (methylsulfonylmethyl) –6-morpholin-4-yl-pyrimidin-2-yl] phenyl] phenyl carbamate and N– [4– [4– 10 [(3S) –3 Methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidin-2-yl] phenyl] phenyl carbamate was described above.

Ejemplo 46: Example 46:

3–Metil–1–[5–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidin–2–il]–1,3–tiazol–2–il]urea 3 – Methyl – 1– [5– [4 - [(3 S) –3 – methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin – 2-yl] –1,3-thiazol-2-yl] urea

O OR

N N

N S OO N S OO

SH SH

N N

N NN N NN

HO HO

Una mezcla de N–[5–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidin–2–il]–1,3–tiazol–2–il]carbamato de fenilo (100 mg, 0,2 mmoles), metilamina (1 mmoles), y trietilamina (0,085 ml, 0,6 mmoles) en NMP (2 ml) se calentó a 70ºC durante 2 horas. El material se purificó mediante HPLC prep. para dar el material deseado como un sólido blanco (27 mg). A mixture of N– [5– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin-2-yl] –1,3-thiazol-2-yl] phenyl carbamate (100 mg, 0.2 mmol), methylamine (1 mmol), and triethylamine (0.085 ml, 0.6 mmol) in NMP (2 ml) was heated at 70 ° C for 2 hours. The material was purified by prep HPLC. to give the desired material as a white solid (27 mg).

Espectro LCMS: MH+ 427, Tiempo de retención 1,44 min. LCMS spectrum: MH + 427, Retention time 1.44 min.

46a 46th: O 1–[5–[4–[(3S)–3–metilmorfolin–4–il]– 455 1,84 OR 1– [5– [4 - [(3S) –3 – methylmorpholin – 4 – il] - 455 1.84

: 6–(metilsulfonilmetil)pirimidin–2–il]– 6– (methylsulfonylmethyl) pyrimidin – 2-yl] -

N N N S O O N S N H N HO N N N S O O N S N H N HO: 1,3–tiazol–2–il]–3–propan–2–il–urea 1,3-thiazol-2-yl] -3-propan-2-yl-urea

46b 46b: O 1–etil–3–[5–[4–[(3S)–3–metilmorfolin– 441 1,48 OR 1 – ethyl – 3– [5– [4 - [(3S) –3 – methylmorpholin– 441 1.48

: 4–il]–6–(metilsulfonilmetil)pirimidin–2– 4-yl] –6– (methylsulfonylmethyl) pyrimidin – 2–

N N N S O O N S N H N HO N N N S O O N S N H N HO: il]–1,3–tiazol–2–il]urea il] –1,3 – thiazol – 2 – il] urea

46c 46c: O 1–[5–[4–[(3S)–3–metilmorfolin–4–il]– 489 1,86 OR 1– [5– [4 - [(3S) –3 – methylmorpholin – 4 – il] - 489 1.86

N N N S O O N S N H N HO N N N S O O N S N H N HO: 1,3–tiazol–2–il]–3–fenil–urea 1,3-thiazol-2-yl] -3-phenyl-urea

46d 46d: O 3–(4–fluorofenil)–1–[5–[4–[(3S)–3– 507 1,88 OR 3– (4 – fluorophenyl) –1– [5– [4 - [(3S) –3– 507 1.88

: metilmorfolin–4–il]–6– methylmorpholin – 4 – il] –6–

N F N F: (metilsulfonilmetil)pirimidin–2–il]–1,3– (methylsulfonylmethyl) pyrimidin – 2-yl] –1,3–

N N S O O N S N H N HO N N S O O N S N H N HO: tiazol–2–il]urea thiazol-2-yl] urea

46e 46e: O 1–ciclopropil–1–metil–3–[5–[4–[(3S)– 467 1,69 OR 1 – cyclopropyl – 1 – methyl – 3– [5– [4 - [(3S) - 467 1.69

: 3–metilmorfolin–4–il]–6– 3 – methylmorpholin – 4 – il] –6–

N N: (metilsulfonilmetil)pirimidin–2–il]–1,3– (methylsulfonylmethyl) pyrimidin – 2-yl] –1,3–

N N S O O N S N H N O N N S O O N S N H N O: tiazol–2–il]urea thiazol-2-yl] urea

46f 46f: O 3–(4–metoxifenil)–1–[5–[4–[(3S)–3– 519 1,82 OR 3– (4 – methoxyphenyl) –1– [5– [4 - [(3S) –3– 519 1.82

: metilmorfolin–4–il]–6– methylmorpholin – 4 – il] –6–

N O NO: (metilsulfonilmetil)pirimidin–2–il]–1,3– (methylsulfonylmethyl) pyrimidin – 2-yl] –1,3–

46g 46g: O 3–(2–dimetilaminoetil)–1–[5–[4–[(3S)– 484 1,39 OR 3– (2 – dimethylaminoethyl) –1– [5– [4 - [(3S) - 484 1.39

N N S O O N S N H N HO N N N S O O N S N H N HO N: tiazol–2–il]urea thiazol-2-yl] urea

46h 46h: N N N O S O O N S N H N HO N N 1–[5–[4–[(3S)–3–metilmorfolin–4–il]– 6–(metilsulfonilmetil)pirimidin–2–il]– 1,3–tiazol–2–il]–3–(1–metilpirazol–4– il)urea 493 1,25 N N N O S O O N S N H N HO N N 1– [5– [4 - [(3S) –3-methylmorpholin-4-yl] - 6– (methylsulfonylmethyl) pyrimidin-2-yl] - 1,3-thiazol-2-yl] –3– (1– methylpyrazole – 4– il) urea 493 1.25

46i 46i: O 3–ciclopropil–1–[5–[4–[(3S)–3– 453 1,59 OR 3 – cyclopropyl – 1– [5– [4 - [(3S) –3– 453 1.59

: metilmorfolin–4–il]–6– methylmorpholin – 4 – il] –6–

Prueba (a): Ejemplo (46) 0,14 μM; Ejemplo (46a) 0,35 μM; Ejemplo (46b) 0,0061 μM; Ejemplo (46c) 0,45 μM; Ejemplo (46d) 0,85 μM; Ejemplo (46e) 0,71 μM; Ejemplo (46f) 1,2 μM; Ejemplo (46g) 0,73 μM; Ejemplo (46h) 0,063 μM; Ejemplo (46i) 0,097 μM. Test (a): Example (46) 0.14 μM; Example (46a) 0.35 μM; Example (46b) 0.0061 μM; Example (46c) 0.45 μM; Example (46d) 0.85 μM; Example (46e) 0.71 μM; Example (46f) 1.2 μM; Example (46g) 0.73 μM; Example (46h) 0.063 μM; Example (46i) 0.097 μM.

A continuación se describe la preparación de N–[5–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidin–2– il]–1,3–tiazol–2–il]carbamato de fenilo. The following describes the preparation of N– [5– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin – 2– yl] –1,3-thiazol-2-yl ] phenyl carbamate.

N–[5–[4–[(3S)–3–Metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidin–2–il]–1,3–tiazol–2–il]carbamato de fenilo N– [5– [4 - [(3S) –3 – Methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin-2-yl] –1,3-thiazol-2-yl] phenyl carbamate

O OR

N N

O O O o: N N

S S: N S N H N S N H

N N: O OR

O OR

Una disolución de 5–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidin–2–il]–1,3–tiazol–2–amina (1 g, A solution of 5– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin-2-yl] –1,3-thiazole-2-amine (1 g,

10 2,71 mmoles), hidrogenocarbonato de sodio (342 mg), y cloroformiato de fenilo (0,511 ml) en dioxano se agitó a RT durante 2 horas y después se concentró a vacío. El residuo se repartió entre DCM y agua, y la capa orgánica se secó sobre sulfato de sodio y se evaporó para dar una espuma. La espuma se trituró con una mezcla de hexano y éter dietílico para dar el material deseado como un sólido blanco (1,1 g). 10 2.71 mmol), sodium hydrogen carbonate (342 mg), and phenyl chloroformate (0.511 ml) in dioxane was stirred at RT for 2 hours and then concentrated in vacuo. The residue was partitioned between DCM and water, and the organic layer was dried over sodium sulfate and evaporated to foam. The foam was triturated with a mixture of hexane and diethyl ether to give the desired material as a white solid (1.1 g).

Espectro LCMS: MH+490, tiempo de retención 2,17, Método Ácido Monitor. LCMS spectrum: MH + 490, retention time 2.17, Acid Monitor Method.

15 5–[4–[(3S)–3–Metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidin–2–il]–1,3–tiazol–2–amina 15 5– [4 - [(3S) –3 – Methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin-2-yl] –1,3-thiazole-2-amine

Una disolución de N–[5–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidin–2–il]–1,3–tiazol–2–il]–N–[(2– metilpropan–2–il)oxicarbonil]carbamato de terc–butilo (1,7 g, 2,9 mmoles) y TFA (8 ml) en DCM (15 ml) se agitó a RT durante 16 horas. El disolvente se eliminó a presión reducida, y el residuo se hizo básico con disolución de amoniaco acuosa. El producto se extrajo con acetato de etilo, los productos orgánicos se secaron sobre sulfato de sodio, se filtraron y se evaporaron para dar el material deseado como un sólido blanco (1 g). A solution of N– [5– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin-2-yl] –1,3-thiazol-2-yl] –N– [(2-methylpropan-2-yl) oxycarbonyl] tert-butyl carbamate (1.7 g, 2.9 mmol) and TFA (8 ml) in DCM (15 ml) was stirred at RT for 16 hours. The solvent was removed under reduced pressure, and the residue was made basic with aqueous ammonia solution. The product was extracted with ethyl acetate, the organic products were dried over sodium sulfate, filtered and evaporated to give the desired material as a white solid (1 g).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,16–1,22 (3H, m), 3,13–3,18 (1H, m), 3,19 (3H, s), 3,43–3,50 (1H, m), 3,60–3,63 (1H, m), 3,75 (1H, d), 3,94–3,97 (1H, dd), 4,04 (1H, d), 4,37 (1H, s), 4,40 (2H, s), 5,75 (1H, s), 6,64 (1H, s), 7,40 (2H, s), 7,73 (1H, s) NMR Spectrum: 1H NMR (400.13 MHz, DMSO – d6) δ 1.16–1.22 (3H, m), 3.13–3.18 (1H, m), 3.19 (3H, s) , 3.43-3.50 (1H, m), 3.60-3.63 (1H, m), 3.75 (1H, d), 3.94-3.97 (1H, dd), 4 , 04 (1H, d), 4.37 (1H, s), 4.40 (2H, s), 5.75 (1H, s), 6.64 (1H, s), 7.40 (2H, s), 7.73 (1H, s)

Espectro LCMS: MH+ 370, tiempo de retención 1,38 min. Método Básico Monitor. LCMS spectrum: MH + 370, retention time 1.38 min. Basic Method Monitor.

N–[5–[4–[(3S)–3–Metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidin–2–il]–1,3–tiazol–2–il]–N–[(2–metilpropan–2– il)oxicarbonil]carbamato de terc–butilo N– [5– [4 - [(3S) –3 – Methylmorpholin-4-yl] –6– (methylsulfonylmethyl) pyrimidin-2-yl] –1,3-thiazole-2-yl] –N - [(2 –Methylpropan – 2– yl) oxycarbonyl] tert-butyl carbamate

O OR

N N

NO O OO NO OR OO

S S

N N

N O NO

Una mezcla de N–[(2–metilpropan–2–il)oxicarbonil]–N–(5–tributilestannil–1,3–tiazol–2–il)carbamato de terc–butilo (3 g, 5,1 mmoles), 2–cloro–4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfonilmetil)pirimidina (1 g, 3,2 mmoles) y tetraquis(trifenilfosfina)paladio (50 mg) en tolueno (10 ml) se calentó a 105ºC durante 2 horas en nitrógeno. La mezcla se cromatografió en sílice para dar el material deseado (1,7 g). A mixture of tert-butyl N - [(2-methylpropan-2-yl) oxycarbonyl] -N- (5-tributylstannyl-1,3-thiazol-2-yl) carbamate (3 g, 5.1 mmol), 2-chloro-4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine (1 g, 3.2 mmol) and tetrakis (triphenylphosphine) palladium (50 mg) in toluene (10 ml ) was heated at 105 ° C for 2 hours under nitrogen. The mixture was chromatographed on silica to give the desired material (1.7 g).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,20 (3H, d), 1,53 (9H, s), 3,18 (3H, s), 3,55 (1H, t), 3,62 (1H, d), 3,75 (1H, d), 3,98 (1H, d), 4,10 (1H, s), 3,90 (1H, s), 3,98 (2H, s), 6,80 (1H, s), 8,18 (1H, s) NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.20 (3H, d), 1.53 (9H, s), 3.18 (3H, s), 3.55 (1H, t ), 3.62 (1H, d), 3.75 (1H, d), 3.98 (1H, d), 4.10 (1H, s), 3.90 (1H, s), 3.98 (2H, s), 6.80 (1H, s), 8.18 (1H, s)

Espectro LCMS: MH+ 570, tiempo de retención 2,89 min. Método Básico Monitor. LCMS spectrum: MH + 570, retention time 2.89 min. Basic Method Monitor.

N–[(2–Metilpropan–2–il)oxicarbonil]–N–(5–tributilestannil–1,3–tiazol–2–il)carbamato de terc–butilo N-[(2-Methylpropan-2-yl) oxycarbonyl] -N- (5-tributylstannil-1,3-thiazol-2-yl) tert-butyl carbamate

Se añadió n–butil-litio (1,6 M en hexanos, 30 ml, 0,48 moles) a diisopropilamina (6,7 ml, 0,48 moles) en THF (480 ml) a 0ºC. La mezcla se agitó a 0ºC durante 30 min. y después se enfrió hasta –78ºC. Se añadió N–[(2–metilpropan–2– il)oxicarbonil]–N–(1,3–tiazol–2–il)carbamato de terc–butilo (12 g, 0,05 moles), y la disolución se agitó durante 30 minutos. Se añadió cloruro de tributilestaño (16,3 ml), y la disolución se agitó durante 30 minutos antes de que se dejara calentar hasta RT. La reacción se paralizó con una disolución acuosa saturada de cloruro de amonio (20 ml), y el producto se extrajo con acetato de etilo. Los productos orgánicos se secaron sobre sulfato de sodio, se concentraron a vacío y se cromatografiaron en sílice, eluyendo con 5–15% de acetato de etilo en hexano, para dar el material deseado como un aceite claro (9 g). N-Butyllithium (1.6 M in hexanes, 30 ml, 0.48 mol) was added to diisopropylamine (6.7 ml, 0.48 mol) in THF (480 ml) at 0 ° C. The mixture was stirred at 0 ° C for 30 min. and then cooled to -78 ° C. Tert-Butyl N-[(2-methylpropan-2-yl) oxycarbonyl] -N- (1,3-thiazol-2-yl) carbamate (12 g, 0.05 mol) was added, and the solution was stirred for 30 minutes Tributyltin chloride (16.3 ml) was added, and the solution was stirred for 30 minutes before it was allowed to warm to RT. The reaction was stopped with a saturated aqueous solution of ammonium chloride (20 ml), and the product was extracted with ethyl acetate. The organic products were dried over sodium sulfate, concentrated in vacuo and chromatographed on silica, eluting with 5-15% ethyl acetate in hexane, to give the desired material as a clear oil (9 g).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,49 (18H, s), 7,50 (1H, d), 7,55 (1H, d) NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.49 (18H, s), 7.50 (1H, d), 7.55 (1H, d)

N–[(2–Metilpropan–2–il)oxicarbonil]–N–(1,3–tiazol–2–il)carbamato de terc–butilo N-[(2-Methylpropan-2-yl) oxycarbonyl] -N- (1,3-thiazol-2-yl) tert-butyl carbamate

Una disolución de 2–aminotiazol (5 g, 0,05 moles), de (2–metilpropan–2–il)oxicarbonil carbonato de terc–butilo (27,8 g, 0,15 moles) y DMAP (100 mg) en THF (100 ml) se agitó a reflujo toda la noche. La mezcla se dejó enfriar y se 5 concentró a vacío. El residuo se cromatografió en sílice, eluyendo con 8% de acetato de etilo en hexano, para dar el material deseado como un sólido blanco (12 g). A solution of 2-aminothiazole (5 g, 0.05 mol), of tert-butyl (2-methylpropan-2-yl) oxycarbonyl carbonate (27.8 g, 0.15 mol) and DMAP (100 mg) in THF (100 ml) was stirred at reflux overnight. The mixture was allowed to cool and concentrated in vacuo. The residue was chromatographed on silica, eluting with 8% ethyl acetate in hexane, to give the desired material as a white solid (12 g).

Espectro LCMS MH– 299, tiempo de retención 2,6 min. Método Básico Monitor LCMS spectrum MH– 299, retention time 2.6 min. Basic Method Monitor

Ejemplo 47: Example 47:

10 3 – Methyl – 1– [5– [4 - [(3 S) –3 – methylmorpholin-4-yl] –6– (2-methylsulfonylpropan – 2-yl) pyrimidin – 2-yl] –1,3-thiazole –2– il] urea

O OR

N N

N S OO N S OO

SH SH

N N

N H NN H N

N O NO

Una disolución de N–[5–[4–[(3S)–3–metilmorfolin–4–il]–6–(2–metilsulfonilpropan–2–il)pirimidin–2–il]–1,3–tiazol–2– il]carbamato de fenilo (200 mg, 0,39 mmoles), metilamina (1,5 mmoles) y trietilamina (0,163 ml, 1,16 mmoles) en 15 NMP (3 ml) se calentó a 70ºC durante 2 horas. La mezcla se cromatografió en sílice, eluyendo con 0–5% de metanol en acetato de etilo para dar el material deseado. A solution of N– [5– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (2-methylsulfonylpropan-2-yl) pyrimidin – 2-yl] –1,3-thiazole – 2 - il] phenyl carbamate (200 mg, 0.39 mmol), methylamine (1.5 mmol) and triethylamine (0.163 ml, 1.16 mmol) in 15 NMP (3 ml) was heated at 70 ° C for 2 hours. The mixture was chromatographed on silica, eluting with 0-5% methanol in ethyl acetate to give the desired material.

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,22 (3H, d), 1,70 (6H, s), 3,19 (3H, s), 3,20 (1H, dd), 3,45 (1H, dd), 3,62 (1H, d), 3,75 (1H, d), 3,96 (1H, d), 4,18 (1H, d), 4,52 (1H, s), 6,40 (1H, s), 6,65 (1H, s), 8,09 (1H, s), 10,70 (1H, s) NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.22 (3H, d), 1.70 (6H, s), 3.19 (3H, s), 3.20 (1H, dd ), 3.45 (1H, dd), 3.62 (1H, d), 3.75 (1H, d), 3.96 (1H, d), 4.18 (1H, d), 4.52 (1H, s), 6.40 (1H, s), 6.65 (1H, s), 8.09 (1H, s), 10.70 (1H, s)

20 Espectro LCMS: MH+ 455, tiempo de retención 1,78 min. 20 LCMS spectrum: MH + 455, retention time 1.78 min.

47a 47th: O 3–ciclopropil–1–[5–[4–[(3S)–3– 481 1,94 OR 3 – cyclopropyl – 1– [5– [4 - [(3S) –3– 481 1.94

N N S O O N S N H N HO N N S O O N S N H N HO: il]–1,3–tiazol–2–il]urea il] –1,3 – thiazol – 2 – il] urea

47b 47b: O 1–[5–[4–[(3S)–3–metilmorfolin–4–il]– 521 1,62 OR 1– [5– [4 - [(3S) –3 – methylmorpholin – 4 – il] - 521 1.62

N N: il)pirimidin–2–il]–1,3–tiazol–2–il]–3– il) pyrimidin – 2-yl] –1,3-thiazol-2-yl] –3–

N N S O O N S N H N HO N N N N S O O N S N H N HO N N: (1–metilpirazol–4–il)urea (1-methylpyrazol-4-yl) urea

Ejemplo Example: Estructura NOMBRE LCMS Tiempo de Structure NAME LCMS Time of

MH+ MH +: retención retention

(min.) (min.)

47c 47c: S O O N N N O N S N H N HO N N 1–[5–[4–[(3S)–3–metilmorfolin–4–il]– 6–(2–metilsulfonilpropan–2– il)pirimidin–2–il]–1,3–tiazol–2–il]–3– [(1–metilpirazol–4–il)metil]urea 535 1,81 S O O N N N O N S N H N HO N N 1– [5– [4 - [(3S) –3 – methylmorpholin-4-yl] - 6– (2-methylsulfonylpropan – 2– yl) pyrimidin – 2-yl] –1,3-thiazol-2-yl] –3– [(1 – methylpyrazole – 4-yl) methyl] urea 535 1.81

47d 47d: O 1–etil–3–[5–[4–[(3S)–3–metilmorfolin– 469 1,95 OR 1 – ethyl – 3– [5– [4 - [(3S) –3 – methylmorpholin– 469 1.95

: 4–il]–6–(2–metilsulfonilpropan–2– 4 – il] –6– (2 – methylsulfonylpropan – 2–

N N: il)pirimidin–2–il]–1,3–tiazol–2–il]urea il) pyrimidin-2-yl] –1,3-thiazol-2-yl] urea

O O O o: N N

S S: N S N H N Y N H

N N HO N N HO

Ejemplo 47a: RMN 1H (400,13 MHz, DMSO–d6) δ 0,45 (2H, q), 0,68 (2H, q), 1,20 (3H, d), 1,70 (6H, s), 3,05 (3H, s), 3,20 (1H, dd), 3,48 (1H, dd), 3,62 (1H, d), 3,75 (1H, d), 3,98 (1H, dd), 4,18 (1H, d), 4,55 (1H, s), 6,68 (1H, s), 6,75 (1H, s), 8,05 (1H, s), 11,0 (1H, s). Example 47a: 1H NMR (400.13 MHz, DMSO-d6) δ 0.45 (2H, q), 0.68 (2H, q), 1.20 (3H, d), 1.70 (6H, s ), 3.05 (3H, s), 3.20 (1H, dd), 3.48 (1H, dd), 3.62 (1H, d), 3.75 (1H, d), 3.98 (1H, dd), 4.18 (1H, d), 4.55 (1H, s), 6.68 (1H, s), 6.75 (1H, s), 8.05 (1H, s) , 11.0 (1H, s).

5 Ejemplo 47b: RMN 1H (400,13 MHz, DMSO–d6) δ 1,20 (3H, d), 1,70 (6H, s), 3,03 (3H, s), 3,20 (1H, dd), 3,48 (1H, dd), 3,65 (1H, d), 3,70–3,80 (4H, m), 3,99 (1H, dd), 4,15 (1H, d), 4,53 (1H, s), 6,70 (1H, s), 7,42 (1H, s), 7,82 (1H, s), 8,10 (1H, s), 8,72 (1H, s), 10,75 (1H, s) 5 Example 47b: 1H NMR (400.13 MHz, DMSO-d6) δ 1.20 (3H, d), 1.70 (6H, s), 3.03 (3H, s), 3.20 (1H, dd), 3.48 (1H, dd), 3.65 (1H, d), 3.70-3.80 (4H, m), 3.99 (1H, dd), 4.15 (1H, d ), 4.53 (1H, s), 6.70 (1H, s), 7.42 (1H, s), 7.82 (1H, s), 8.10 (1H, s), 8.72 (1H, s), 10.75 (1H, s)

Ejemplo 47c: RMN 1H (400,13 MHz, DMSO–d6) δ 1,20 (3H, d), 1,70 (6H, s), 2,68 (3H, s), 3,05 (3H, s), 3,18 (1H, dd), 3,48 (1H, dd), 3,62 (1H, d), 3,75 (1H, d), 3,98 (1H, d), 4,05 (1H, q), 4,18 (2H, s), 4,51 (1H, s), 6,68 (1H, s), 6,78 (1H, Example 47c: 1H NMR (400.13 MHz, DMSO-d6) δ 1.20 (3H, d), 1.70 (6H, s), 2.68 (3H, s), 3.05 (3H, s ), 3.18 (1H, dd), 3.48 (1H, dd), 3.62 (1H, d), 3.75 (1H, d), 3.98 (1H, d), 4.05 (1H, q), 4.18 (2H, s), 4.51 (1H, s), 6.68 (1H, s), 6.78 (1H,

10 s), 7,35 (1H, s), 7,62 (1H, s), 8,09 (1H, s), 10,60 (1H, s). 10 s), 7.35 (1H, s), 7.62 (1H, s), 8.09 (1H, s), 10.60 (1H, s).

Prueba (a): Ejemplo (47) 0,26 μM; Ejemplo (47a) 1,2 μM; Ejemplo (47b) 0,41 μM; Ejemplo (47c) 1,4 μM; Ejemplo (47d) 0,97 μM. Test (a): Example (47) 0.26 μM; Example (47a) 1.2 μM; Example (47b) 0.41 μM; Example (47c) 1.4 μM; Example (47d) 0.97 μM.

A continuación se describe la preparación de N–[5–[4–[(3S)–3–metilmorfolin–4–il]–6–(2–metilsulfonilpropan–2– il)pirimidin–2–il]–1,3–tiazol–2–il]carbamato de fenilo. The preparation of N– [5– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (2-methylsulfonylpropan – 2– yl) pyrimidin – 2-yl] –1,3 is described below. -Thiazol-2-yl] phenyl carbamate.

15 N–[5–[4–[(3S)–3–Metilmorfolin–4–il]–6–(2–metilsulfonilpropan–2–il)pirimidin–2–il]–1,3–tiazol–2–il]carbamato de fenilo 15 N– [5– [4 - [(3S) –3 – Methylmorpholin-4-yl] –6– (2-methylsulfonylpropan-2-yl) pyrimidin – 2-yl] –1,3-thiazole – 2 – il ] phenyl carbamate

O OR

N N

NN

OO OO

S S

SHSH

N N

OOR

N N

O OR

Una mezcla de 5–[4–[(3S)–3–metilmorfolin–4–il]–6–(2–metilsulfonilpropan–2–il)pirimidin–2–il]–1,3–tiazol–2–amina (1,05 g, 2,6 mmoles), cloroformiato de fenilo (618 mg, 3,9 mmoles) e hidrogenocarbonato de sodio (311 mg, 3,9 mmoles) en dioxano (10 ml) se agitó a RT durante 2 horas, después se diluyó con acetato de etilo y se lavó con agua (150 ml) y salmuera (100 ml). Los productos orgánicos se secaron sobre sulfato de magnesio y se concentraron a vacío. El residuo se recristalizó en éter dietílico y hexano para dar el producto deseado como un sólido beige (1 g). A mixture of 5– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (2-methylsulfonylpropan-2-yl) pyrimidin-2-yl] –1,3-thiazole-2-amine ( 1.05 g, 2.6 mmol), phenyl chloroformate (618 mg, 3.9 mmol) and sodium hydrogen carbonate (311 mg, 3.9 mmol) in dioxane (10 mL) was stirred at RT for 2 hours, It was then diluted with ethyl acetate and washed with water (150 ml) and brine (100 ml). The organic products were dried over magnesium sulfate and concentrated in vacuo. The residue was recrystallized from diethyl ether and hexane to give the desired product as a beige solid (1 g).

5– [4 - [(3S) –3 – Methylmorpholin-4-yl] –6– (2-methylsulfonylpropan-2-yl) pyrimidin-2-yl] –1,3-thiazole-2-amine

Una mezcla de 2–cloro–4–[(3S)–3–metilmorfolin–4–il]–6–(2–metilsulfonilpropan–2–il)pirimidina (1,2 g, 3,6 mmoles), N–[(2–metilpropan–2–il)oxicarbonil]–N–(5–tributilestannil–1,3–tiazol–2–il)carbamato de terc–butilo (3,1 g, 5,2 mmoles), y tetraquis(trifenilfosfina)paladio (200 mg) en tolueno (30 ml) se calentó a 110ºC en una atmósfera de nitrógeno toda la noche. La mezcla se diluyó con acetato de etilo y se lavó con agua. Los productos orgánicos se secaron sobre sulfato de magnesio, se filtraron y se evaporaron. El residuo se disolvió en DCM (50 ml), y se añadió ácido trifluroacético (15 ml). Después de dejar agitar durante 2 horas, la mezcla se evaporó y se añadió agua. La mezcla se hizo básica con disolución de amoniaco acuosa y se extrajo con acetato de etilo. Los productos orgánicos se secaron sobre sulfato de magnesio, se filtraron y se evaporaron hasta un sólido. El residuo se trituró con una mezcla de éter dietílico y hexano para dar el material deseado (1,05 g). A mixture of 2-chloro-4 - [(3S) -3-methylmorpholin-4-yl] -6- (2-methylsulfonylpropan-2-yl) pyrimidine (1.2 g, 3.6 mmol), N– [ (2-methylpropan-2-yl) oxycarbonyl] -N- (5-tributylstannyl-1,3-thiazol-2-yl) tert-butyl carbamate (3.1 g, 5.2 mmol), and tetrakis (triphenylphosphine ) Palladium (200 mg) in toluene (30 ml) was heated at 110 ° C under a nitrogen atmosphere overnight. The mixture was diluted with ethyl acetate and washed with water. The organic products were dried over magnesium sulfate, filtered and evaporated. The residue was dissolved in DCM (50 ml), and trifluroacetic acid (15 ml) was added. After stirring for 2 hours, the mixture was evaporated and water was added. The mixture was made basic with aqueous ammonia solution and extracted with ethyl acetate. The organic products were dried over magnesium sulfate, filtered and evaporated to a solid. The residue was triturated with a mixture of diethyl ether and hexane to give the desired material (1.05 g).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,18 (3H, d), 1,65 (6H, s), 3,0 (3H, s), 3,15 (3H, dd), 3,45 (1H, dd), 3,60 (1H, dd), 3,71 (1H, d), 3,95 (1H, dd), 4,10 (1H, d), 4,50 (1H, S), 6,60 (1H, s), 7,35 (2H, s), 7,75 (1H, s). NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.18 (3H, d), 1.65 (6H, s), 3.0 (3H, s), 3.15 (3H, dd ), 3.45 (1H, dd), 3.60 (1H, dd), 3.71 (1H, d), 3.95 (1H, dd), 4.10 (1H, d), 4.50 (1H, S), 6.60 (1H, s), 7.35 (2H, s), 7.75 (1H, s).

Espectro LCMS: MH+ 398 tiempo de retención 1,76 min. método básico monitor LCMS spectrum: MH + 398 retention time 1.76 min. basic method monitor

La preparación de 2–cloro–4–[(3S)–3–metilmorfolin–4–il]–6–(2–metilsulfonilpropan–2–il)pirimidina y N–[(2– metilpropan–2–il)oxicarbonil]–N–(5–tributilestannil–1,3–tiazol–2–il)carbamato de terc–butilo se describió anteriormente. The preparation of 2-chloro-4 - [(3S) -3-methylmorpholin-4-yl] -6- (2-methylsulfonylpropan-2-yl) pyrimidine and N - [(2-methylpropan-2-yl) oxycarbonyl] -N- (5-Tributyltanyl-1,3-thiazol-2-yl) tert-butyl carbamate was described above.

Ejemplo 48: Example 48:

3–Ciclobutil–1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(piridin–4–ilsulfonilmetil)pirimidin–2–il]fenil]urea 3 – Cyclobutyl – 1– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (pyridin-4-ylsulfonylmethyl) pyrimidin – 2-yl] phenyl] urea

Se añadió ciclobutilamina (0,074 ml, 0,87 mmoles) a una disolución de N–[4–[4–[(3S)–3–metilmorfolin–4–il]–6– (piridin–4–ilsulfonilmetil)pirimidin–2–il]fenil]carbamato de fenilo (0,095 g, 0,17 mmoles) y trietilamina (0,073 ml, 0,52 mmoles) en DMF (3 ml), y después se calentó hasta 50ºC en nitrógeno. La disolución resultante se agitó a 50ºC durante 2 horas. El disolvente se eliminó a vacío, y el producto bruto se purificó mediante HPLC prep. para dar el material deseado como un sólido blanco (0,089 g). Cyclobutylamine (0.074 ml, 0.87 mmol) was added to a solution of N– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (pyridin-4-ylsulfonylmethyl) pyrimidin – 2 -Yl] phenyl] phenyl carbamate (0.095 g, 0.17 mmol) and triethylamine (0.073 ml, 0.52 mmol) in DMF (3 ml), and then heated to 50 ° C under nitrogen. The resulting solution was stirred at 50 ° C for 2 hours. The solvent was removed in vacuo, and the crude product was purified by prep HPLC. to give the desired material as a white solid (0.089 g).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,20–1,22 (3H, d), 1,59–1,66 (2H, m), 1,82–1,92 (2H, m), 2,18– 2,25 (2H, m), 3,15–3,22 (1H, td), 3,45–3,52 (1H, td), 3,62–3,65 (1H, td), 3,75–3,78 (1H, d), 3,96–3,99 (1H, dd), 4,09– 4,17 (2H, m), 4,39 (1H, bs), 4,87 (2H, s), 6,52–6,54 (1H, d), 6,71 (1H, s), 7,33–7,35 (2H, d), 7,64–7,67 (2H, d), 7,80– 7,82 (2H, q), 8,61 (1H, s), 8,90–8,91 (2H, q). NMR Spectrum: 1H NMR (400.13 MHz, DMSO – d6) δ 1.20–1.22 (3H, d), 1.59–1.66 (2H, m), 1.82–1.92 ( 2H, m), 2.18-2.25 (2H, m), 3.15-3.22 (1H, td), 3.45-3.52 (1H, td), 3.62-3, 65 (1H, td), 3.75-3.78 (1H, d), 3.96-3.99 (1H, dd), 4.09-4.17 (2H, m), 4.39 ( 1H, bs), 4.87 (2H, s), 6.52–6.54 (1H, d), 6.71 (1H, s), 7.33–7.35 (2H, d), 7 , 64–7.67 (2H, d), 7.80–7.82 (2H, q), 8.61 (1H, s), 8.90–8.91 (2H, q).

Espectro LCMS: MH+ 523 tiempo de retención 1,96 min. LCMS spectrum: MH + 523 retention time 1.96 min.

Los siguientes compuestos se prepararon de manera análoga a partir de N–[4–[4–[(3S)–3–metilmorfolin–4–il]–6– (piridin–4–ilsulfonilmetil)pirimidin–2–il]fenil]carbamato de fenilo y la amina apropiada. The following compounds were prepared analogously from N– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (pyridin-4-ylsulfonylmethyl) pyrimidin-2-yl] phenyl] phenyl carbamate and the appropriate amine.

MH+ MH +: retención retention

(min.) (min.)

48a 48th: N N N N O S O O N H N H O 3–etil–1–[4–[4–[(3S)–3– metilmorfolin–4–il]–6–(piridin–4– ilsulfonilmetil)pirimidin–2– il]fenil]urea 497 1,74 N N N N O S O O N H N H O 3 – ethyl – 1– [4– [4 - [(3S) –3– methylmorpholin-4-yl] –6– (pyridin-4– ylsulfonylmethyl) pyrimidin – 2– yl] phenyl] urea 497 1.74

48b 48b: O 3–(2–dimetilaminoetil)–1–[4–[4– 540 1,83 OR 3– (2 – dimethylaminoethyl) –1– [4– [4– 540 1.83

N N: (piridin–4–ilsulfonilmetil)- (pyridin-4-ylsulfonylmethyl) -

N N: N N S O O N H N H O N pirimidin–2–il]fenil]urea N N S O O N H N H O N pyrimidin – 2-yl] phenyl] urea

Ejemplo 48a: RMN 1H (400,13 MHz, DMSO–d6) δ 1,05–1,09 (3H, t), 1,20–1,22 (3H, d), 3,09–3,16 (2H, m), 3,16– 3,22 (1H, td), 3,45–3,52 (1H, td), 3,62–3,65 (1H, dd), 3,75–3,78 (1H, d), 3,96–3,99 (1H, dd), 4,10–4,14 (1H, d), 4,39 (1H, bs), 4,88 (2H, s), 6,14–6,17 (1H, t), 6,71 (1H, s), 7,35–7,37 (2H, d), 7,65–7,67 (2H, d), 7,81–7,82 (2H, d), 8,64 Example 48a: 1H NMR (400.13 MHz, DMSO-d6) δ 1.05-1.09 (3H, t), 1.20-1.22 (3H, d), 3.09-3.16 ( 2H, m), 3.16-3.22 (1H, td), 3.45-3.52 (1H, td), 3.62-3.65 (1H, dd), 3.75-3, 78 (1H, d), 3.96-3.99 (1H, dd), 4.10-4.14 (1H, d), 4.39 (1H, bs), 4.88 (2H, s) , 6.14–6.17 (1H, t), 6.71 (1H, s), 7.35–7.37 (2H, d), 7.65–7.67 (2H, d), 7 , 81–7.82 (2H, d), 8.64

5 (1H, s), 8,90–8,91 (2H, d). 5 (1H, s), 8.90–8.91 (2H, d).

Ejemplo 48b: RMN 1H (400,13 MHz, DMSO–d6) δ 1,20–1,21 (3H, d), 2,41 (2H, bs), 2,74 (3H, s), 2,90 (3H, s), 3,15– 3,23 (1H, td), 3,2–3,4 (2H, m), 3,45–3,51 (1H, td), 3,61–3,65 (1H, dd), 3,75–3,78 (1H, d), 3,96–3,99 (1H, dd), 4,10– 4,13 (1H, d), 4,39 (1H, bs), 4,87 (2H, s), 6,25 (1H, t), 6,72 (1H, s), 7,35–7,37 (2H, d), 7,65–7,67 (2H, d), 7,81–7,82 (2H, q), 7,96 (1H, s), 8,89–8,91 (2H, d). Example 48b: 1H NMR (400.13 MHz, DMSO-d6) δ 1.20-1.21 (3H, d), 2.41 (2H, bs), 2.74 (3H, s), 2.90 (3H, s), 3.15– 3.23 (1H, td), 3.2–3.4 (2H, m), 3.45–3.51 (1H, td), 3.61–3 , 65 (1H, dd), 3.75–3.78 (1H, d), 3.96–3.99 (1H, dd), 4.10– 4.13 (1H, d), 4.39 (1H, bs), 4.87 (2H, s), 6.25 (1H, t), 6.72 (1H, s), 7.35–7.37 (2H, d), 7.65– 7.67 (2H, d), 7.81–7.82 (2H, q), 7.96 (1H, s), 8.89–8.91 (2H, d).

10 Prueba (c): Ejemplo (48) 0,038 μM; Ejemplo (48a) 0,25 μM. 10 Test (c): Example (48) 0.038 μM; Example (48a) 0.25 μM.

A continuación se describe la preparación de N–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(piridin–4– ilsulfonilmetil)pirimidin–2–il]fenil]carbamato de fenilo. The preparation of N- [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (pyridin-4-ylsulfonylmethyl) pyrimidin-2-yl] phenyl] carbamate phenyl is described below.

N–[4–[4–[(3S)–3–Metilmorfolin–4–il]–6–(piridin–4–ilsulfonilmetil)pirimidin–2–il]fenil]carbamato de fenilo N– [4– [4 - [(3S) –3 – Methylmorpholin-4-yl] –6– (pyridin-4-ylsulfonylmethyl) pyrimidin-2-yl] phenyl] phenyl carbamate

O OR

N N

N S N S

OO OO

O N O n

N N

O H Or h

N N

15 Se añadió cloroformiato de fenilo (0,029 ml, 0,23 mmoles) a una disolución de 4–[4–[(3S)–3–metilmorfolin–4–il]–6– (piridin–4–ilsulfonilmetil)pirimidin–2–il]anilina (0,097 g, 0,23 mmoles) y bicarbonato de sodio (0,029 g, 0,34 mmoles) en dioxano a RT. La suspensión resultante se agitó a RT durante 2 horas. Se añadió cloroformiato de fenilo adicional (2 x 0,005 ml) para terminar la reacción. Después se añadió agua a la reacción, y el sólido se filtró, y se secó en un horno de vacío para dar el material deseado como un sólido blancuzco (0,098 g). 15 Phenyl chloroformate (0.029 ml, 0.23 mmol) was added to a solution of 4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (pyridin-4-ylsulfonylmethyl) pyrimidin – 2 -Il] aniline (0.097 g, 0.23 mmol) and sodium bicarbonate (0.029 g, 0.34 mmol) in dioxane at RT. The resulting suspension was stirred at RT for 2 hours. Additional phenyl chloroformate (2 x 0.005 ml) was added to terminate the reaction. Water was then added to the reaction, and the solid was filtered, and dried in a vacuum oven to give the desired material as an off-white solid (0.098 g).

20 Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,21–1,23 (3H, d), 3,16–3,24 (1H, td), 3,46–3,52 (1H, td), 3,62– 3,66 (1H, dd), 3,76–3,79 (1H, d), 3,96–4,00 (1H, dd), 4,13–4,16 (1H, bd), 4,41 (1H, bs), 4,90 (2H, s), 6,76 (s, 1H), 7,23–7,31 (3H, m), 7,43–7,51 (4H, m), 7,74–7,77 (2H, m), 7,81–7,83 (2H, dd), 8,90–8,92 (2H, dd), 10,39 (1H, s). 20 NMR Spectrum: 1H NMR (400.13 MHz, DMSO – d6) δ 1.21–1.23 (3H, d), 3.16–3.24 (1H, td), 3.46–3.52 (1H, td), 3.62– 3.66 (1H, dd), 3.76–3.79 (1H, d), 3.96–4.00 (1H, dd), 4.13–4 , 16 (1H, bd), 4.41 (1H, bs), 4.90 (2H, s), 6.76 (s, 1H), 7.23-7.31 (3H, m), 7, 43–7.51 (4H, m), 7.74–7.77 (2H, m), 7.81–7.83 (2H, dd), 8.90–8.92 (2H, dd), 10.39 (1H, s).

Espectro LCMS: MH+ 546 tiempo de retención 2,35 min. LCMS spectrum: MH + 546 retention time 2.35 min.

4–[4–[(3S)–3–Metilmorfolin–4–il]–6–(piridin–4–ilsulfonilmetil)pirimidin–2–il]anilina 4– [4 - [(3S) –3 – Methylmorpholin-4-yl] –6– (pyridin-4-ylsulfonylmethyl) pyrimidin – 2-yl] aniline

Se añadió trans–diclorobis(trifenilfosfina)paladio (II) (0,039 g, 0,06 mmoles) a una mezcla de 2–cloro–4–[(3S)–3– metilmorfolin–4–il]–6–(piridin–4–ilsulfonilmetil)pirimidina (0,411 g, 1,11 mmoles), 4–(4,4,5,5–tetrametil–1,3,2– dioxaborolan–2–il)anilina (0,366 g, 1,67 mmoles) y carbonato de sodio (0,233 ml, 5,56 mmoles) en 18% de DMF en una mezcla de DME:agua:etanol 7:3:2 (100 ml) a RT en nitrógeno. La disolución resultante se agitó a 90ºC durante 5 horas. La reacción se enfrió y se diluyó con acetato de etilo y agua. La mezcla de reacción se extrajo con acetato de etilo, y los productos orgánicos combinados se secaron (MgSO4), se filtraron y se evaporaron. El producto bruto se cromatografió en sílice, eluyendo con 0–5% de metanol en DCM, para dar el material deseado como un sólido blanco (0,453 g). Trans-dichlorobis (triphenylphosphine) palladium (II) (0.039 g, 0.06 mmol) was added to a mixture of 2-chloro-4 - [(3S) –3– methylmorpholin-4-yl] –6– (pyridin– 4-ylsulfonylmethyl) pyrimidine (0.411 g, 1.11 mmol), 4– (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (0.366 g, 1.67 mmol) and sodium carbonate (0.233 ml, 5.56 mmol) in 18% DMF in a mixture of DME: water: ethanol 7: 3: 2 (100 ml) at RT in nitrogen. The resulting solution was stirred at 90 ° C for 5 hours. The reaction was cooled and diluted with ethyl acetate and water. The reaction mixture was extracted with ethyl acetate, and the combined organic products were dried (MgSO4), filtered and evaporated. The crude product was chromatographed on silica, eluting with 0-5% methanol in DCM, to give the desired material as a white solid (0.453 g).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,19–1,20 (3H, d), 3,12–3,19 (1H, td), 3,44–3,50 (1H, td), 3,61– 3,64 (1H, dd), 3,74–3,77 (1H, d), 3,95–3,98 (1H, dd), 4,07–4,11 (1H, d), 4,37 (1H, bs), 4,83 (2H, s), 5,50–5,52 (2H, d), 6,45–6,47 (2H, d), 6,60 (1H, s), 7,48–7,50 (2H, d), 7,80–7,81 (2H, q), 8,89–8,90 (2H, q). NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.19–1.20 (3H, d), 3.12–3.19 (1H, td), 3.44–3.50 ( 1H, td), 3.61-3.64 (1H, dd), 3.74-3.77 (1H, d), 3.95-3.98 (1H, dd), 4.07-4, 11 (1H, d), 4.37 (1H, bs), 4.83 (2H, s), 5.50-5.52 (2H, d), 6.45-6.47 (2H, d) , 6.60 (1H, s), 7.48-7.50 (2H, d), 7.80-7.81 (2H, q), 8.89-8.90 (2H, q).

Espectro LCMS: MH+ 426 tiempo de retención 1,80 min. LCMS spectrum: MH + 426 retention time 1.80 min.

2–Cloro–4–[(3S)–3–metilmorfolin–4–il]–6–(piridin–4–ilsulfonilmetil)pirimidina 2 – Chloro – 4 - [(3S) –3 – methylmorpholin-4-yl] –6– (pyridin-4-ylsulfonylmethyl) pyrimidine

Una disolución de peróxido de hidrógeno (1,799 ml, 58,19 mmoles) se añadió gota a gota a una disolución agitada de 2–cloro–4–[(3S)–3–metilmorfolin–4–il]–6–(piridin–4–ilsulfanilmetil)pirimidina (0,980 g, 2,91 mmoles), volframato de sodio dihidratado (0,005 ml, 0,06 mmoles) y ácido sulfúrico 2N (0,075 ml) en dioxano (200 ml) a 55ºC, durante un período de 5 minutos al aire. La disolución resultante se agitó a 55ºC durante 3 horas. Se añadió agua (200 ml), y la reacción se enfrió, los sólidos se filtraron, se lavaron con agua y se secaron en el horno de vacío a 50ºC toda la noche para dar el material deseado como un sólido blanco (0,580 g). Se obtuvo material adicional extrayendo la capa acuosa con DCM. Los extractos se secaron (MgSO4), se filtraron, se evaporaron y se cromatografiaron en sílice, eluyendo con 0–3% de metanol en DCM, para dar una porción adicional del material deseado (0,144 g). A solution of hydrogen peroxide (1,799 ml, 58.19 mmol) was added dropwise to a stirred solution of 2-chloro-4 - [(3S) -3-methylmorpholin-4-yl] -6- (pyridin- 4-ylsulfanylmethyl) pyrimidine (0.980 g, 2.91 mmol), sodium volframate dihydrate (0.005 ml, 0.06 mmol) and 2N sulfuric acid (0.075 ml) in dioxane (200 ml) at 55 ° C, over a period of 5 minutes on air The resulting solution was stirred at 55 ° C for 3 hours. Water (200 ml) was added, and the reaction was cooled, the solids filtered, washed with water and dried in the vacuum oven at 50 ° C overnight to give the desired material as a white solid (0.580 g). Additional material was obtained by extracting the aqueous layer with DCM. The extracts were dried (MgSO4), filtered, evaporated and chromatographed on silica, eluting with 0-3% methanol in DCM, to give an additional portion of the desired material (0.144 g).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,17–1,19 (3H, d), 3,14–3,22 (1H, td), 3,40–3,47 (1H, td), 3,56– 3,60 (1H, dd), 3,71–3,74 (1H, d), 3,90 (1H, bs), 3,91–3,95 (1H, dd), 4,20 (1H, bs), 4,79 (2H, s), 6,79 (1H, s), 7,77– 7,79 (2H, q), 8,92–8,93 (2H, q). NMR Spectrum: 1H NMR (400.13 MHz, DMSO – d6) δ 1.17–1.19 (3H, d), 3.14–3.22 (1H, td), 3.40–3.47 ( 1H, td), 3.56– 3.60 (1H, dd), 3.71–3.74 (1H, d), 3.90 (1H, bs), 3.91–3.95 (1H, dd), 4.20 (1H, bs), 4.79 (2H, s), 6.79 (1H, s), 7.77– 7.79 (2H, q), 8.92–8.93 (2H, q).

Espectro LCMS: MH+ 369 tiempo de retención 1,39 min. LCMS spectrum: MH + 369 retention time 1.39 min.

2–Cloro–4–[(3S)–3–metilmorfolin–4–il]–6–(piridin–4–ilsulfanilmetil)pirimidina 2 – Chloro – 4 - [(3S) –3 – methylmorpholin-4-yl] –6– (pyridin-4-ylsulfanylmethyl) pyrimidine

Se añadió 4–mercaptopiridina (0,752 g, 6,77 mmoles) a 2–cloro–4–(yodometil)–6–[(3S)–3–metilmorfolin–4– il]pirimidina (1,596 g, 4,51 mmoles) en acetonitrilo (100 ml) a RT al aire. Después se añadió DBU (0,3 ml, 2,01 mmoles), y la disolución resultante se agitó a RT durante 2 minutos. El disolvente se eliminó, y se añadió DCM. La mezcla de reacción se lavó secuencialmente con agua, la capa orgánica se secó (MgSO4), se filtró, y se evaporó. El producto bruto se cromatografió en sílice, eluyendo con 0–2% de metanol en DCM. Las fracciones impuras se 4-Mercaptopyridine (0.752 g, 6.77 mmol) was added to 2-chloro-4- (iodomethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine (1,596 g, 4.51 mmol) in acetonitrile (100 ml) at RT in air. Then DBU (0.3 ml, 2.01 mmol) was added, and the resulting solution was stirred at RT for 2 minutes. The solvent was removed, and DCM was added. The reaction mixture was washed sequentially with water, the organic layer was dried (MgSO4), filtered, and evaporated. The crude product was chromatographed on silica, eluting with 0-2% methanol in DCM. Impure fractions are

cromatografiaron adicionalmente en sílice, eluyendo con 0–4,5% de metanol en DCM y se combinaron con las fracciones puras iniciales para dar el material deseado como una goma amarilla (0,980 g). They were further chromatographed on silica, eluting with 0-4.5% methanol in DCM and combined with the initial pure fractions to give the desired material as a yellow gum (0.980 g).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,14–1,16 (3H, d), 3,11–3,18 (1H, td), 3,37–3,44 (1H, td), 3,53– 3,57 (1H, dd), 3,64–3,67 (1H, d), 3,86–3,90 (2H, dd), 4,01 (2H, s), 4,14 (1H, bs), 6,43 (1H, s), 7,04–7,06 (2H, d), 8,29–8,30 (2H, d). NMR Spectrum: 1H NMR (400.13 MHz, DMSO – d6) δ 1.14–1.16 (3H, d), 3.11–3.18 (1H, td), 3.37–3.44 ( 1H, td), 3.53-3.57 (1H, dd), 3.64-3.67 (1H, d), 3.86-3.90 (2H, dd), 4.01 (2H, s), 4.14 (1H, bs), 6.43 (1H, s), 7.04-7.06 (2H, d), 8.29-8.30 (2H, d).

Espectro LCMS: MH+ 337 tiempo de retención 1,62 min. LCMS spectrum: MH + 337 retention time 1.62 min.

2–Cloro–4–(yodometil)–6–[(3S)–3–metilmorfolin–4–il]pirimidina 2 – Chloro – 4– (iodomethyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidine

Se añadió yoduro de sodio (1,006 ml, 24,61 mmoles) a 2–cloro–4–[(3S)–3–metilmorfolin–4–il]–6– (metilsulfoniloximetil)pirimidina (1,584 g, 4,92 mmoles) en DCM a RT. La disolución resultante se puso a reflujo a 40ºC durante 18 horas. La mezcla de reacción se diluyó con DCM y se lavó con agua. La capa orgánica se secó (MgSO4), se filtró, y se evaporó para proporcionar el producto deseado (1,596 g). Sodium iodide (1.006 ml, 24.61 mmol) was added to 2-chloro-4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonyloxymethyl) pyrimidine (1,584 g, 4.92 mmol) in DCM to RT. The resulting solution was refluxed at 40 ° C for 18 hours. The reaction mixture was diluted with DCM and washed with water. The organic layer was dried (MgSO4), filtered, and evaporated to provide the desired product (1,596 g).

Espectro RMN: RMN 1H (400,13 MHz, CDCl3) δ 1,27–1,28 (3H, d), 3,20–3,27 (1H, td), 3,46–3,53 (1H, td), 3,62–3,65 (1H, dd), 3,72–3,75 (1H, d), 3,93–3,97 (2H, dd), 4,17 (2H, s), 4,26 (1H, bs), 6,41 (1H, s). NMR Spectrum: 1H NMR (400.13 MHz, CDCl3) δ 1.27-1.28 (3H, d), 3.20-3.27 (1H, td), 3.46-3.53 (1H, td), 3.62–3.65 (1H, dd), 3.72–3.75 (1H, d), 3.93–3.97 (2H, dd), 4.17 (2H, s) , 4.26 (1H, bs), 6.41 (1H, s).

Espectro LCMS: MH+ 354 tiempo de retención 1,85 min. LCMS spectrum: MH + 354 retention time 1.85 min.

2–Cloro–4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfoniloximetil)pirimidina 2 – Chloro – 4 - [(3S) –3 – methylmorpholin-4-yl] –6– (methylsulfonyloxymethyl) pyrimidine

Se añadió gota a gota cloruro de metanosulfonilo (0,488 ml, 6,31 mmoles) a [2–cloro–6–[(3S)–3–metilmorfolin–4– il]pirimidin–4–il]metanol (1,025 g, 4,21 mmoles), y trietilamina (0,880 ml, 6,31 mmoles) en DCM a 0ºC durante un período de 2 minutos. La disolución resultante se dejó calentar gradualmente hasta RT durante un período de 2 horas. La mezcla de reacción se diluyó con DCM (50 ml), y se lavó con agua. La capa orgánica se secó (MgSO4), se filtró y se evaporó para proporcionar el material deseado (1,584 g) que se usó sin purificación adicional. Methanesulfonyl chloride (0.488 ml, 6.31 mmol) was added dropwise to [2-chloro-6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-4-yl] methanol (1,025 g, 4 , 21 mmol), and triethylamine (0.880 ml, 6.31 mmol) in DCM at 0 ° C for a period of 2 minutes. The resulting solution was allowed to warm gradually to RT for a period of 2 hours. The reaction mixture was diluted with DCM (50 ml), and washed with water. The organic layer was dried (MgSO4), filtered and evaporated to provide the desired material (1,584 g) that was used without further purification.

Espectro LCMS: MH+ 322 tiempo de retención 1,60 min. LCMS spectrum: MH + 322 retention time 1.60 min.

Example 49: 3 – Cyclopropyl – 1– [4– [4 - [(cyclopropylamino) methyl] –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] urea

Se disolvió 3–ciclopropil–1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfoniloximetil)pirimidin–2–il]fenil]urea (107 mg, 0,23 mmoles) en DCM (5 ml) y se añadió a ciclopropilamina (1,16 mmoles). Se añadió trietilamina (0,162 ml, 1,16 mmoles) a la disolución y se agitó a RT durante 18 horas. La reacción se evaporó hasta sequedad, y se purificó mediante HPLC prep. (básica) para dar el material deseado como un sólido blanco (27 mg). 3-Cyclopropyl-1– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (methylsulfonyloxymethyl) pyrimidin-2-yl] phenyl] urea (107 mg, 0.23 mmol) ) in DCM (5 ml) and was added to cyclopropylamine (1.16 mmol). Triethylamine (0.162 ml, 1.16 mmol) was added to the solution and stirred at RT for 18 hours. The reaction was evaporated to dryness, and purified by prep HPLC. (basic) to give the desired material as a white solid (27 mg).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 0,29–0,31 (2H, m), 0,34–0,44 (4H, m), 0,62–0,67 (2H, m), 1,21– 1,27 (3H, m), 2,13–2,17 (1H, m), 2,53–2,58 (1H, m), 3,14–3,21 (1H, m), 3,45–3,52 (1H, m), 3,62–3,65 (1H, m), 3,71 (2H, d), 3,75 (1H, s), 3,95–3,99 (1H, m), 4,14–4,17 (1H, m), 4,49–4,51 (1H, m), 6,46 (1H, d), 6,65 (1H, s), 7,47–7,50 (2H, m), 8,21–8,23 (2H, m), 8,55 (1H, s). NMR Spectrum: 1H NMR (400.13 MHz, DMSO – d6) δ 0.29–0.31 (2H, m), 0.34–0.44 (4H, m), 0.62–0.67 ( 2H, m), 1.21– 1.27 (3H, m), 2.13–2.17 (1H, m), 2.53–2.58 (1H, m), 3.14–3, 21 (1H, m), 3.45-3.52 (1H, m), 3.62-3.65 (1H, m), 3.71 (2H, d), 3.75 (1H, s) , 3.95–3.99 (1H, m), 4.14–4.17 (1H, m), 4.49–4.51 (1H, m), 6.46 (1H, d), 6 , 65 (1H, s), 7.47-7.50 (2H, m), 8.21-8.23 (2H, m), 8.55 (1H, s).

Espectro de masa: M+H+ 423. Mass spectrum: M + H + 423.

Los siguientes compuestos se obtuvieron de manera análoga a partir de 3–ciclopropil–1–[4–[4–[(3S)–3– metilmorfolin–4–il]–6–(metilsulfoniloximetil)pirimidin–2–il]fenil]urea y la amina apropiada. The following compounds were obtained analogously from 3-cyclopropyl-1– [4– [4 - [(3S) -3– methylmorpholin-4-yl] –6– (methylsulfonyloxymethyl) pyrimidin-2-yl] phenyl] urea and the appropriate amine.

Ejemplo Example: Estructura NOMBRE LCMS MH+ Structure NAME LCMS MH +

49a 49th: O 3–ciclopropil–1–[4–[4–[(2–hidroxietil– 441 OR 3 – cyclopropyl – 1– [4– [4 - [(2 – hydroxyethyl– 441

: metil–amino)metil]–6–[(3S)–3– methyl-amino) methyl] –6 - [(3S) –3–

N N N N N H N H O OH N N N N N H N H O OH: metilmorfolin–4–il]pirimidin–2–il]fenil]urea methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] urea

49b 49b: O 3–ciclopropil–1–[4–[4–[(3S)–3– 466 OR 3 – cyclopropyl – 1– [4– [4 - [(3S) –3– 466

: metilmorfolin–4–il]–6–[(4–metilpiperazin– methylmorpholin – 4 – il] –6 - [(4 – methylpiperazin–

N N N N H N H ON N N N N N H N H ON N: 1–il)metil]pirimidin–2–il]fenil]urea 1-yl) methyl] pyrimidin-2-yl] phenyl] urea

49c 49c: O 3–ciclopropil–1–[4–[4–[(2– 441 OR 3 – cyclopropyl – 1– [4– [4 - [(2– 441

: metoxietilamino)metil]–6–[(3S)–3– methoxyethylamino) methyl] –6 - [(3S) –3–

N N N N H N H OHN O N N N N H N H OHN O: metilmorfolin–4–il]pirimidin–2–il]fenil]urea methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] urea

49d 49d: O 3–ciclopropil–1–[4–[4– 411 OR 3 – cyclopropyl – 1– [4– [4– 411

: (dimetilaminometil)–6–[(3S)–3– (dimethylaminomethyl) –6 - [(3S) –3–

N N N N H N H ON N N N N H N H ON: metilmorfolin–4–il]pirimidin–2–il]fenil]urea methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] urea

49e 49e: N N N O N H N H OHN N 3–ciclopropil–1–[4–[4–[(3– dimetilaminopropilamino)metil]–6–[(3S)– 3–metilmorfolin–4–il]pirimidin–2– il]fenil]urea 468 N N N O N H N H OHN N 3 – cyclopropyl – 1– [4– [4 - [(3– dimethylaminopropylamino) methyl] –6 - [(3S) - 3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] urea 468

49f 49f: O 3–ciclopropil–1–[4–[4–[(3S)–3– 453 OR 3 – cyclopropyl – 1– [4– [4 - [(3S) –3– 453

: metilmorfolin–4–il]–6–(morfolin–4– methylmorpholin – 4 – il] –6– (morpholin – 4–

N N N N H N H ON O N N N N H N H ON O: ilmetil)pirimidin–2–il]fenil]urea ilmethyl) pyrimidin – 2-yl] phenyl] urea

Ejemplo Example: Estructura NOMBRE LCMS MH+ Structure NAME LCMS MH +

49g 49g: O 3–ciclopropil–1–[4–[4–[(2– 454 OR 3 – cyclopropyl – 1– [4– [4 - [(2– 454

: dimetilaminoetilamino)metil]–6–[(3S)–3– dimethylaminoethylamino) methyl] –6 - [(3S) –3–

N N N HN N H N H O N N N N HN N H N H O N: metilmorfolin–4–il]pirimidin–2–il]fenil]urea methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] urea

49h 49h: O 3–ciclopropil–1–[4–[4–[(4–metil–1,4– 480 OR 3 – cyclopropyl – 1– [4– [4 - [(4 – methyl – 1,4– 480

: diazepan–1–il)metil]–6–[(3S)–3– diazepan – 1 – il) methyl] –6 - [(3S) –3–

N N N N H N H ON N N N N N H N H ON N: metilmorfolin–4–il]pirimidin–2–il]fenil]urea methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] urea

49i 49i: N N N O N H N H OHN OH 3–ciclopropil–1–[4–[4–[[(1–hidroxi–2– metil–propan–2–il)amino]metil]–6–[(3S)– 3–metilmorfolin–4–il]pirimidin–2– il]fenil]urea 455 N N N O N H N H OHN OH 3 – cyclopropyl – 1– [4– [4 - [[(1-hydroxy-2– methyl-propan – 2-yl) amino] methyl] –6 - [(3S) - 3-methylmorpholin-4-yl] pyrimidin –2– il] phenyl] urea 455

49j 49j: O 3–ciclopropil–1–[4–[4–[(3S)–3– 456 OR 3 – cyclopropyl – 1– [4– [4 - [(3S) –3– 456

: metilmorfolin–4–il]–6–[(3–oxopiperazin– methylmorpholin – 4 – il] –6 - [(3 – oxopiperazin–

N N N N H N H ON HN O N N N N H N H ON HN O: 1–il)metil]pirimidin–2–il]fenil]urea 1-yl) methyl] pyrimidin-2-yl] phenyl] urea

49k 49k: O 3–ciclopropil–1–[4–[4–[(3– 439 OR 3 – cyclopropyl – 1– [4– [4 - [(3– 439

: hidroxiazetidin–1–il)metil]–6–[(3S)–3– hydroxyazetidin – 1 – yl) methyl] –6 - [(3S) –3–

N N N N H N H ON HO N N N N H N H ON HO: metilmorfolin–4–il]pirimidin–2–il]fenil]urea methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] urea

49l 49l: N N N O N H N H ON O 3–ciclopropil–1–[4–[4–[(3S)–3– metilmorfolin–4–il]–6–[[(3S)–3– metilmorfolin–4–il]metil]pirimidin–2– il]fenil]urea 467 N N N O N H N H ON O 3 – cyclopropyl – 1– [4– [4 - [(3S) –3– methylmorpholin-4-yl] –6 - [[(3S) –3– methylmorpholin-4-yl] methyl] pyrimidin – 2– il] phenyl] urea 467

Ejemplo 49a: RMN 1H (400,13 MHz, DMSO–d6) δ 0,40–0,44 (2H, m), 0,62–0,67 (2H, m), 1,21–1,27 (3H, m), 2,30 (3H, s), 2,53–2,58 (1H, m), 3,14–3,21 (1H, m), 3,46–3,58 (7H, m), 3,62–3,66 (1H, m), 3,76 (1H, d), 3,95–3,99 (1H, m), 4,15–4,18 (1H, m), 4,45 (1H, t), 4,48 (1H, s), 6,42 (1H, d), 6,73 (1H, s), 7,47–7,49 (2H, m), 8,19–8,21 (2H, m), Example 49a: 1H NMR (400.13 MHz, DMSO-d6) δ 0.40–0.44 (2H, m), 0.62–0.67 (2H, m), 1.21–1.27 ( 3H, m), 2.30 (3H, s), 2.53-2.58 (1H, m), 3.14-3.21 (1H, m), 3.46-3.58 (7H, m), 3.62–3.66 (1H, m), 3.76 (1H, d), 3.95–3.99 (1H, m), 4.15-4.18 (1H, m) , 4.45 (1H, t), 4.48 (1H, s), 6.42 (1H, d), 6.73 (1H, s), 7.47-7.49 (2H, m), 8.19–8.21 (2H, m),

5 8,50 (1H, s). 5 8.50 (1H, s).

Ejemplo 49b: RMN 1H (400,13 MHz, DMSO–d6) δ 0,40–0,44 (2H, m), 0,62–0,67 (2H, m), 1,21 (3H, d), 2,17 (3H, s), 2,30–2,37 (8H, m), 2,53–2,58 (1H, m), 3,14–3,21 (1H, m), 3,47–3,50 (3H, m), 3,63–3,66 (1H, m), 3,76 (1H, d), 3,95– 3,99 (1H, m), 4,12–4,15 (1H, m), 4,45–4,47 (1H, m), 6,43 (1H, d), 6,61 (1H, s), 7,46–7,50 (2H, m), 8,19–8,21 (2H, m), 8,51 (1H, s). Example 49b: 1H NMR (400.13 MHz, DMSO-d6) δ 0.40–0.44 (2H, m), 0.62–0.67 (2H, m), 1.21 (3H, d) , 2.17 (3H, s), 2.30–2.37 (8H, m), 2.53–2.58 (1H, m), 3.14–3.21 (1H, m), 3 , 47–3.50 (3H, m), 3.63–3.66 (1H, m), 3.76 (1H, d), 3.95– 3.99 (1H, m), 4.12 –4.15 (1H, m), 4.45-4.47 (1H, m), 6.43 (1H, d), 6.61 (1H, s), 7.46–7.50 (2H , m), 8.19-8.21 (2H, m), 8.51 (1H, s).

10 Ejemplo 49c: RMN 1H (400,13 MHz, DMSO–d6) δ 0,40–0,44 (2H, m), 0,62–0,67 (2H, m), 1,21–1,26 (3H, m), 3,14– 3,22 (1H, m), 3,26 (3H, s), 3,39–3,49 (5H, m), 3,62–3,66 (2H, m), 3,67 (2H, s), 3,76 (1H, d), 3,95–3,99 (1H, m), 4,16 (1H, d), 4,48 (1H, s), 6,54 (1H, s), 6,66 (1H, s), 7,50 (2H, d), 8,19 (2H, q), 8,62 (1H, s). Example 49c: 1H NMR (400.13 MHz, DMSO-d6) δ 0.40–0.44 (2H, m), 0.62–0.67 (2H, m), 1.21–1.26 (3H, m), 3.14-3.22 (1H, m), 3.26 (3H, s), 3.39-3.49 (5H, m), 3.62-3.66 (2H , m), 3.67 (2H, s), 3.76 (1H, d), 3.95-3.99 (1H, m), 4.16 (1H, d), 4.48 (1H, s), 6.54 (1H, s), 6.66 (1H, s), 7.50 (2H, d), 8.19 (2H, q), 8.62 (1H, s).

Ejemplo 49d: RMN 1H (400,13 MHz, DMSO–d6) δ 0,40–0,44 (2H, m), 0,62–0,67 (2H, m), 1,21–1,22 (3H, m), 2,25 (6H, s), 2,52–2,57 (1H, m), 3,17 (1H, d), 3,42 (2H, s), 3,46–3,50 (1H, m), 3,62–3,66 (1H, m), 3,75 (1H, d), 3,95–3,98 (1H, m), 4,14–4,18 (1H, m), 4,46–4,48 (1H, m), 6,44 (1H, d), 6,61 (1H, s), 7,47–7,50 (2H, m), 8,19–8,22 (2H, m), 8,53 (1H, s). Example 49d: 1H NMR (400.13 MHz, DMSO-d6) δ 0.40–0.44 (2H, m), 0.62–0.67 (2H, m), 1.21–1.22 ( 3H, m), 2.25 (6H, s), 2.52-2.57 (1H, m), 3.17 (1H, d), 3.42 (2H, s), 3.46-3 , 50 (1H, m), 3.62–3.66 (1H, m), 3.75 (1H, d), 3.95–3.98 (1H, m), 4.14–4.18 (1H, m), 4.46-4.48 (1H, m), 6.44 (1H, d), 6.61 (1H, s), 7.47-7.50 (2H, m), 8.19–8.22 (2H, m), 8.53 (1H, s).

Ejemplo 49e: ningún espectro Example 49e: no spectrum

Ejemplo 49f: RMN 1H (400,13 MHz, DMSO–d6) δ 0,40–0,44 (2H, m), 0,62–0,67 (2H, m), 1,21 (3H, d), 2,52–2,57 (1H, m), 3,14–3,21 (1H, m), 3,49 (2H, s), 3,50 (2H, t), 3,63 (7H, m), 3,66 (1H, d), 3,76 (1H, d), 3,95–3,99 (1H, m), 4,13–4,16 (1H, m), 4,49 (1H, d), 6,42 (1H, d), 6,64 (1H, s), 7,47–7,49 (2H, m), 8,19–8,21 (2H, m), 8,51 (1H, s). Example 49f: 1H NMR (400.13 MHz, DMSO-d6) δ 0.40-0.44 (2H, m), 0.62-0.67 (2H, m), 1.21 (3H, d) , 2.52–2.57 (1H, m), 3.14–3.21 (1H, m), 3.49 (2H, s), 3.50 (2H, t), 3.63 (7H , m), 3.66 (1H, d), 3.76 (1H, d), 3.95–3.99 (1H, m), 4.13-4.16 (1H, m), 4, 49 (1H, d), 6.42 (1H, d), 6.64 (1H, s), 7.47-7.49 (2H, m), 8.19-8.21 (2H, m) , 8.51 (1H, s).

Ejemplo 49g: RMN 1H (400,13 MHz, DMSO–d6) δ 0,40–0,44 (2H, m), 0,62–0,67 (2H, m), 1,22 (3H, d), 2,13 (6H, s), 2,32–2,35 (2H, m), 2,52–2,57 (1H, m), 2,62 (2H, t), 3,14–3,22 (1H, m), 3,45–3,52 (1H, m), 3,62–3,66 (1H, m), 3,67 (3H, s), 3,76 (1H, d), 3,95–3,99 (1H, m), 4,14–4,18 (1H, m), 4,49 (1H, s), 6,42 (1H, d), 6,65 (1H, s), 7,48 (2H, d), 8,22 (2H, d), 8,50 (1H, s). Example 49g: 1H NMR (400.13 MHz, DMSO-d6) δ 0.40–0.44 (2H, m), 0.62–0.67 (2H, m), 1.22 (3H, d) , 2.13 (6H, s), 2.32–2.35 (2H, m), 2.52–2.57 (1H, m), 2.62 (2H, t), 3.14–3 , 22 (1H, m), 3.45-3.52 (1H, m), 3.62-3.66 (1H, m), 3.67 (3H, s), 3.76 (1H, d ), 3.95–3.99 (1H, m), 4.14–4.18 (1H, m), 4.49 (1H, s), 6.42 (1H, d), 6.65 ( 1H, s), 7.48 (2H, d), 8.22 (2H, d), 8.50 (1H, s).

Ejemplo 49h: RMN 1H (400,13 MHz, DMSO–d6) δ 0,40–0,44 (2H, m), 0,62–0,67 (2H, m), 1,24 (3H, d), 1,46 (1H, d), 1,73–1,77 (2H, m), 2,27 (4H, s), 2,37 (1H, d), 2,43 (1H, s), 2,56–2,61 (2H, m), 2,73–2,76 (3H, m), 3,14–3,21 (1H, m), 3,47–3,53 (1H, m), 3,59–3,68 (3H, m), 3,77 (1H, d), 3,96–4,00 (1H, m), 4,14–4,17 (1H, m), 4,45 (1H, s), 6,43 (1H, d), 6,65 (1H, s), 7,47–7,49 (2H, m), 8,19–8,21 (2H, m), 8,51 (1H, s) Example 49h: 1H NMR (400.13 MHz, DMSO-d6) δ 0.40–0.44 (2H, m), 0.62–0.67 (2H, m), 1.24 (3H, d) , 1.46 (1H, d), 1.73-1.77 (2H, m), 2.27 (4H, s), 2.37 (1H, d), 2.43 (1H, s), 2.56-2.61 (2H, m), 2.73-2.76 (3H, m), 3.14-3.21 (1H, m), 3.47-3.53 (1H, m ), 3.59-3.68 (3H, m), 3.77 (1H, d), 3.96-4.00 (1H, m), 4.14-4.17 (1H, m), 4.45 (1H, s), 6.43 (1H, d), 6.65 (1H, s), 7.47-7.49 (2H, m), 8.19–8.21 (2H, m), 8.51 (1H, s)

Ejemplo 49i: RMN 1H (400,13 MHz, DMSO–d6) δ 0,40–0,44 (2H, m), 0,62–0,67 (2H, m), 1,01 (6H, s), 1,21–1,27 (3H, m), 1,36 (1H, t), 2,07 (1H, t), 2,52–2,57 (1H, m), 3,15–3,21 (1H, m), 3,23 (2H, d), 3,45–3,52 (1H, m), 3,62–3,65 (3H, m), 3,76 (1H, d), 3,95–3,99 (1H, m), 4,12–4,16 (1H, m), 4,50–4,52 (1H, m), 6,49 (1H, s), 6,69 (1H, s), 7,47–7,50 (2H, m), 8,16–8,22 (2H, m), 8,56 (1H, s), Example 49i: 1H NMR (400.13 MHz, DMSO-d6) δ 0.40–0.44 (2H, m), 0.62–0.67 (2H, m), 1.01 (6H, s) , 1.21–1.27 (3H, m), 1.36 (1H, t), 2.07 (1H, t), 2.52–2.57 (1H, m), 3.15–3 , 21 (1H, m), 3.23 (2H, d), 3.45-3.52 (1H, m), 3.62-3.65 (3H, m), 3.76 (1H, d ), 3.95–3.99 (1H, m), 4.12–4.16 (1H, m), 4.50–4.52 (1H, m), 6.49 (1H, s), 6.69 (1H, s), 7.47–7.50 (2H, m), 8.16–8.22 (2H, m), 8.56 (1H, s),

Ejemplo 49j: RMN 1H (400,13 MHz, DMSO–d6) δ 0,40–0,44 (2H, m), 0,62–0,67 (2H, m), 1,21–1,27 (3H, m), 2,53– 2,58 (1H, m), 2,68 (2H, q), 3,09 (2H, s), 3,18 (1H, t), 3,20 (2H, t), 3,46–3,53 (1H, m), 3,57 (2H, s), 3,62–3,66 (1H, m), 3,75 (1H, d), 3,95–3,99 (1H, m), 4,15–4,18 (1H, m), 4,48–4,51 (1H, m), 6,44 (1H, d), 6,63 (1H, s), 7,48–7,50 (2H, m), 7,74 (1H, s), 8,19–8,22 (2H, m), 8,53 (1H, s), Example 49j: 1H NMR (400.13 MHz, DMSO-d6) δ 0.40–0.44 (2H, m), 0.62–0.67 (2H, m), 1.21–1.27 ( 3H, m), 2.53– 2.58 (1H, m), 2.68 (2H, q), 3.09 (2H, s), 3.18 (1H, t), 3.20 (2H , t), 3.46-3.53 (1H, m), 3.57 (2H, s), 3.62-3.66 (1H, m), 3.75 (1H, d), 3, 95–3.99 (1H, m), 4.15–4.18 (1H, m), 4.48–4.51 (1H, m), 6.44 (1H, d), 6.63 ( 1H, s), 7.48–7.50 (2H, m), 7.74 (1H, s), 8.19–8.22 (2H, m), 8.53 (1H, s),

Prueba (a): Ejemplo (49) 0,033 μM; Ejemplo (49a) 0,15 μM; Ejemplo (49b) 0,014 μM; Ejemplo (49c) 0,04 μM; Ejemplo (49e) 0,032 μM; Ejemplo (49f) 0,2 μM; Ejemplo (49g0 0,087 μM; Ejemplo (49h) 0,18 μM; Ejemplo (49i) 0,016 μM; Ejemplo (49k) 0,014 μM; Ejemplo (49l) 1,6 μM. Test (a): Example (49) 0.033 μM; Example (49a) 0.15 μM; Example (49b) 0.014 μM; Example (49c) 0.04 μM; Example (49e) 0.032 μM; Example (49f) 0.2 μM; Example (49g0 0.087 μM; Example (49h) 0.18 μM; Example (49i) 0.016 μM; Example (49k) 0.014 μM; Example (49l) 1.6 μM.

Prueba (c): Ejemplo (49d) 0,62 μM; Ejemplo (49j) 0,13 μM. Test (c): Example (49d) 0.62 μM; Example (49j) 0.13 μM.

Ejemplo 50: Example 50:

3–Ciclopropil–1–[4–[4–[(1,1–dioxo–1,4–tiazinan–4–il)metil]–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2– il]fenil]urea 3 – Cyclopropyl – 1– [4– [4 - [(1,1-dioxo-1,4-thiazinan-4-yl) methyl] –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin– 2– il] phenyl] urea

Se disolvió 3–ciclopropil–1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfoniloximetil)pirimidin–2–il]fenil]urea (107 mg, 0,23 mmoles) en DCM (5 ml) y se añadió a tiomorfolina (1,16 mmoles). Se añadió trietilamina (0,162 ml, 1,16 mmoles) a la disolución y se agitó a RT durante 18 horas. La reacción se evaporó hasta sequedad y se disolvió en una mezcla de 1,4–dioxano (4 ml) y agua (1 ml). Se añadieron en porciones simples ácido meta–cloroperbenzoico (100 mg, 0,58 mmoles) y permanganato de sodio (110 mg, 0,69 mmoles) a la disolución, y ésta se agitó a RT durante 1 hora. La disolución bruta se cargó en una columna SCX–2, se eliminó con amoniaco 7N en metanol y se evaporó hasta sequedad. El sólido se purificó mediante HPLC prep. (básica) para dar el material deseado como un sólido blanco (11 mg). 3-Cyclopropyl-1– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (methylsulfonyloxymethyl) pyrimidin-2-yl] phenyl] urea (107 mg, 0.23 mmol) ) in DCM (5 ml) and thiomorpholine (1.16 mmol) was added. Triethylamine (0.162 ml, 1.16 mmol) was added to the solution and stirred at RT for 18 hours. The reaction was evaporated to dryness and dissolved in a mixture of 1,4-dioxane (4 ml) and water (1 ml). Meta-chloroperbenzoic acid (100 mg, 0.58 mmol) and sodium permanganate (110 mg, 0.69 mmol) were added in single portions to the solution, and it was stirred at RT for 1 hour. The crude solution was loaded on an SCX-2 column, removed with 7N ammonia in methanol and evaporated to dryness. The solid was purified by prep HPLC. (basic) to give the desired material as a white solid (11 mg).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 0,40–0,44 (2H, m), 0,62–0,67 (2H, m), 1,22 (3H, d), 2,53–2,58 (1H, m), 3,00 (1H, s), 3,02 (3H, t), 3,15–3,22 (5H, m), 3,50 (1H, d), 3,63–3,67 (1H, m), 3,70 (2H, s), 3,77 (1H, d), 3,96–3,99 (1H, m), 4,18 (1H, s), 4,53 (1H, s), 6,42 (1H, d), 6,70 (1H, s), 7,47–7,50 (2H, m), 8,19–8,21 (2H, m), 8,50 (1H, s). NMR Spectrum: 1H NMR (400.13 MHz, DMSO – d6) δ 0.40–0.44 (2H, m), 0.62–0.67 (2H, m), 1.22 (3H, d) , 2.53–2.58 (1H, m), 3.00 (1H, s), 3.02 (3H, t), 3.15–3.22 (5H, m), 3.50 (1H , d), 3.63-3.67 (1H, m), 3.70 (2H, s), 3.77 (1H, d), 3.96-3.99 (1H, m), 4, 18 (1H, s), 4.53 (1H, s), 6.42 (1H, d), 6.70 (1H, s), 7.47-7.50 (2H, m), 8.19 –8.21 (2H, m), 8.50 (1H, s).

Espectro de masa: M+H+ 501. Mass spectrum: M + H + 501.

Prueba (a): 0,0016 μM. Test (a): 0.0016 μM.

Ejemplo 51: Example 51:

1–[4–[4–(Hidroximetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]–3–[(1–metilpirazol–4–il)metil]urea 1– [4– [4– (Hydroxymethyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] –3 - [(1-methylpyrazole-4-yl) methyl] urea

O N O n

N NN HO N NN HO

ON NN ON NN

HH H H

Se añadió [2–cloro–6–[(3S)–3–metilmorfolin–4–il]pirimidin–4–il]metanol (1,00 g, 4,10 mmoles) a 3–[(1–metilpirazol– 4–il)metil]–1–[4–(4,4,5,5–tetrametil–1,3,2–dioxaborolan–2–il)fenil]urea (2,193 g, 6,16 mmoles) y carbonato de sodio (8,21 ml, 16,41 mmoles) en 18% de DMF en DME:EtOH:agua 7:2:3 (18 ml), y la disolución se desgasificó durante 5 minutos. Se añadió diclorobis(trifenilfosfina)paladio(II) (0,144 g, 0,21 mmoles) a la mezcla. La disolución resultante se agitó a 85ºC durante 18 horas. La reacción se dejó enfriar y se neutralizó con ácido clorhídrico concentrado. El producto bruto se purificó mediante cromatografía de intercambio iónico, usando una columna SCX –2 (50 g), después se purificó adicionalmente mediante cromatografía ultrarrápida en sílice, gradiente de elución 0 a 7% de metanol en DCM, para dar el material deseado como un sólido blanco (963 mg). [2-Chloro-6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-4-yl] methanol (1.00 g, 4.10 mmol) was added to 3 - [(1-methylpyrazole– 4 –Il) methyl] –1– [4– (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] urea (2,193 g, 6.16 mmol) and sodium carbonate (8.21 ml, 16.41 mmol) in 18% DMF in DME: EtOH: water 7: 2: 3 (18 ml), and the solution was degassed for 5 minutes. Dichlorobis (triphenylphosphine) palladium (II) (0.144 g, 0.21 mmol) was added to the mixture. The resulting solution was stirred at 85 ° C for 18 hours. The reaction was allowed to cool and neutralized with concentrated hydrochloric acid. The crude product was purified by ion exchange chromatography, using a SCX-2 column (50 g), then further purified by flash chromatography on silica, gradient elution 0 to 7% methanol in DCM, to give the desired material as a white solid (963 mg).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,23 (3H, d), 3,19–3,23 (1H, m), 3,46–3,52 (1H, m), 3,62–3,66 (1H, m), 3,78 (1H, d), 3,79 (3H, s), 3,96–3,99 (1H, m), 4,13 (3H, d), 4,45–4,50 (3H, m), 5,38 (1H, t), 6,39 (1H, t), 6,66 (1H, s), 7,35 (1H, s), 7,45–7,49 (2H, m), 7,59 (1H, s), 8,19–8,21 (2H, m), 8,64 (1H, s), m/z NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.23 (3H, d), 3.19–3.23 (1H, m), 3.46-3.52 (1H, m) , 3.62-3.66 (1H, m), 3.78 (1H, d), 3.79 (3H, s), 3.96-3.99 (1H, m), 4.13 (3H , d), 4.45-4.50 (3H, m), 5.38 (1H, t), 6.39 (1H, t), 6.66 (1H, s), 7.35 (1H, s), 7.45–7.49 (2H, m), 7.59 (1H, s), 8.19–8.21 (2H, m), 8.64 (1H, s), m / z

Espectro LCMS: MH+ 438, tiempo de retención 1,37 minutos. LCMS spectrum: MH + 438, retention time 1.37 minutes.

Las preparaciones de [2–cloro–6–[(3S)–3–metilmorfolin–4–il]pirimidin–4–il]metanol (1,00 g, 4,10 mmoles) y 3–[(1– metilpirazol–4–il)metil]–1–[4–(4,4,5,5–tetrametil–1,3,2–dioxaborolan–2–il)fenil]urea se describieron anteriormente. Preparations of [2-chloro-6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-4-yl] methanol (1.00 g, 4.10 mmol) and 3 - [(1– methylpyrazole– 4-yl) methyl] –1– [4– (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] urea were described above.

Ejemplo 52: Example 52:

1–[4–[4–[(3S)–3–Metilmorfolin–4–il]–6–[(4–metilpiperazin–1–il)metil]pirimidin–2–il]fenil]–3–[(1–metilpirazol–4– il)metil]urea 1– [4– [4 - [(3S) –3 – Methylmorpholin-4-yl] –6 - [(4-methylpiperazin-1-yl) methyl] pyrimidin – 2-yl] phenyl] –3 - [(1 –Methylpyrazole – 4– il) methyl] urea

O OR

Se añadió 1–metilpiperazina (0,067 ml, 0,60 mmoles) a una disolución de trietilamina (0,084 ml, 0,60 mmoles) y 1– [4–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfoniloximetil)pirimidin–2–il]fenil]–3–[(1–metilpirazol–4–il)metil]urea (155 mg, 0,30 mmoles) en DCM (5 ml) a RT en nitrógeno. La disolución resultante se agitó a RT durante 18 horas. La mezcla de reacción se evaporó. El producto bruto se purificó mediante HPLC preparativa usando mezclas polares decrecientes de agua (que contiene 1% de NH3) y MeCN como eluyentes, para dar el material deseado como un sólido blanco (65 mg). 1-Methylpiperazine (0.067 ml, 0.60 mmol) was added to a solution of triethylamine (0.084 ml, 0.60 mmol) and 1– [4– [4 - [(3 S) –3-methylmorpholin-4-yl] –6– (methylsulfonyloxymethyl) pyrimidin-2-yl] phenyl] –3 - [(1-methylpyrazol-4-yl) methyl] urea (155 mg, 0.30 mmol) in DCM (5 ml) at RT in nitrogen. The resulting solution was stirred at RT for 18 hours. The reaction mixture was evaporated. The crude product was purified by preparative HPLC using decreasing polar mixtures of water (containing 1% NH3) and MeCN as eluents, to give the desired material as a white solid (65 mg).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,21 (3H, d), 2,17 (3H, s), 2,35 (8H, s), 3,14–3,21 (1H, m), 3,47– 3,50 (3H, m), 3,62–3,66 (1H, m), 3,77 (1H, s), 3,79 (3H, s), 3,95–3,99 (1H, m), 4,13 (3H, d), 4,46 (1H, d), 6,42 (1H, t), 6,61 (1H, s), 7,35 (1H, s), 7,47 (2H, d), 7,59 (1H, s), 8,20 (2H, d), 8,66 (1H, s). NMR Spectrum: 1H NMR (400.13 MHz, DMSO – d6) δ 1.21 (3H, d), 2.17 (3H, s), 2.35 (8H, s), 3.14–3.21 (1H, m), 3.47-3.50 (3H, m), 3.62-3.66 (1H, m), 3.77 (1H, s), 3.79 (3H, s), 3.95-3.99 (1H, m), 4.13 (3H, d), 4.46 (1H, d), 6.42 (1H, t), 6.61 (1H, s), 7 , 35 (1H, s), 7.47 (2H, d), 7.59 (1H, s), 8.20 (2H, d), 8.66 (1H, s).

Espectro LCMS: MH+ 520, tiempo de retención 1,49 minutos. LCMS spectrum: MH + 520, retention time 1.49 minutes.

Los siguientes compuestos se prepararon de manera análoga a partir de 1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6– (metilsulfoniloximetil)pirimidin–2–il]fenil]–3–[(1–metilpirazol–4–il)metil]urea y la amina apropiada. The following compounds were prepared analogously from 1– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (methylsulfonyloxymethyl) pyrimidin-2-yl] phenyl] –3– [ (1-methylpyrazol-4-yl) methyl] urea and the appropriate amine.

MH+ MH +: retención retention

(min.) (min.)

52a 52a: HN N N N O N H N H O NN 1–[4–[4–[(ciclopropilamino)metil]–6– [(3S)–3–metilmorfolin–4–il]pirimidin–2– il]fenil]–3–[(1–metilpirazol–4– il)metil]urea 477 1,66 HN N N N O N H N H O NN 1– [4– [4 - [(cyclopropylamino) methyl] –6– [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] –3 - [(1-methylpyrazole-4– il ) methyl] urea 477 1.66

52b 52b: O 1–[4–[4–[(ciclopropil–metil– 491 1,89 OR 1– [4– [4 - [(cyclopropyl-methyl– 491 1.89

: amino)metil]–6–[(3S)–3–metilmorfolin– amino) methyl] –6 - [(3S) –3 – methylmorpholin–

: N 4–il]pirimidin–2–il]fenil]–3–[(1– N 4 – il] pyrimidin – 2 – il] phenyl] –3 - [(1–

N N: N N N H N H O NN metilpirazol–4–il)metil]urea N N N H N H O NN methylpyrazole-4-yl) methyl] urea

Ejemplo 52a: RMN 1H (400,13 MHz, DMSO–d6) δ 0,28–0,33 (2H, m), 0,37–0,39 (1H, m), 1,21–1,26 (3H, m), 1,36 Example 52a: 1H NMR (400.13 MHz, DMSO-d6) δ 0.28–0.33 (2H, m), 0.37–0.39 (1H, m), 1.21–1.26 ( 3H, m), 1.36

5 (1H, t), 2,13–2,17 (1H, m), 2,82 (1H, s), 3,14–3,21 (1H, m), 3,43–3,51 (1H, m), 3,62–3,65 (1H, m), 3,71 (2H, d), 3,77– 3,79 (4H, m), 3,95–3,99 (1H, m), 4,12–4,17 (3H, m), 4,50 (1H, d), 6,55 (1H, s), 6,64 (1H, s), 7,35 (1H, s), 7,48 (2H, d), 7,59 (1H, s), 8,17–8,23 (2H, m), 8,79 (1H, s). 5 (1H, t), 2.13-2.17 (1H, m), 2.82 (1H, s), 3.14-3.21 (1H, m), 3.43-3.51 ( 1H, m), 3.62-3.65 (1H, m), 3.71 (2H, d), 3.77-3.79 (4H, m), 3.95-3.99 (1H, m), 4.12-4.17 (3H, m), 4.50 (1H, d), 6.55 (1H, s), 6.64 (1H, s), 7.35 (1H, s ), 7.48 (2H, d), 7.59 (1H, s), 8.17–8.23 (2H, m), 8.79 (1H, s).

Ejemplo 52b: RMN 1H (400,13 MHz, DMSO–d6) δ 0,40 (2H, t), 0,44–0,49 (2H, m), 1,20 (3H, d), 1,89–1,94 (1H, m), 2,33 (3H, s), 3,16–3,20 (2H, m), 3,45–3,52 (1H, m), 3,65 (3H, d), 3,79 (3H, s), 3,94–3,98 (1H, m), 4,13 (3H, d), 4,46 Example 52b: 1H NMR (400.13 MHz, DMSO-d6) δ 0.40 (2H, t), 0.44-0.49 (2H, m), 1.20 (3H, d), 1.89 –1.94 (1H, m), 2.33 (3H, s), 3.16-3.20 (2H, m), 3.45-3.52 (1H, m), 3.65 (3H , d), 3.79 (3H, s), 3.94-3.98 (1H, m), 4.13 (3H, d), 4.46

10 (1H, s), 6,40 (1H, t), 6,52 (1H, s), 7,35 (1H, s), 7,46–7,49 (2H, m), 7,59 (1H, s), 8,21 (2H, d), 8,64 (1H, s). 10 (1H, s), 6.40 (1H, t), 6.52 (1H, s), 7.35 (1H, s), 7.46-7.49 (2H, m), 7.59 (1H, s), 8.21 (2H, d), 8.64 (1H, s).

Prueba (a): Ejemplo (52) 1,4 μM; Ejemplo (52a) 0,33 μM; Ejemplo (52b) 0,57 μM. Test (a): Example (52) 1.4 μM; Example (52a) 0.33 μM; Example (52b) 0.57 μM.

A continuación se describe la preparación de 1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfoniloximetil)pirimidin– 2–il]fenil]–3–[(1–metilpirazol–4–il)metil]urea. The preparation of 1– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (methylsulfonyloxymethyl) pyrimidin– 2-yl] phenyl] –3 - [(1-methylpyrazole) –4 – il) methyl] urea.

1–[4–[4–[(3S)–3–Metilmorfolin–4–il]–6–(metilsulfoniloximetil)pirimidin–2–il]fenil]–3–[(1–metilpirazol–4–il)metil]urea 1– [4– [4 - [(3S) –3 – Methylmorpholin-4-yl] –6– (methylsulfonyloxymethyl) pyrimidin-2-yl] phenyl] –3 - [(1-methylpyrazole-4-yl) methyl] urea

O OR

N N N N

O OR

O O O N O o O n

S N S N

N N

HH NHH N

15 Se añadió gota a gota durante un período de 10 minutos cloruro de metanosulfonilo (0,246 ml, 3,15 mmoles) a una disolución de trietilamina (0,440 ml, 3,15 mmoles) y 1–[4–[4–(hidroximetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2– il]fenil]–3–[(1–metilpirazol–4–il)metil]urea (920 mg, 2,10 mmoles) en DCM (30 ml) a 0ºC en nitrógeno. La disolución resultante se agitó a 20ºC durante 45 minutos. La mezcla de reacción se lavó con agua (10 ml). La capa orgánica se 15 Methanesulfonyl chloride (0.246 ml, 3.15 mmol) was added dropwise over a period of 10 minutes to a solution of triethylamine (0.440 ml, 3.15 mmol) and 1– [4– [4– (hydroxymethyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] –3 - [(1-methylpyrazol-4-yl) methyl] urea (920 mg, 2.10 mmol) in DCM (30 ml) at 0 ° C in nitrogen. The resulting solution was stirred at 20 ° C for 45 minutes. The reaction mixture was washed with water (10 ml). The organic layer is

20 secó (MgSO4), se filtró y se evaporó para proporcionar el material deseado que se usó sin purificación adicional. 20 dried (MgSO4), filtered and evaporated to provide the desired material that was used without further purification.

Espectro LCMS: MH+ 516, tiempo de retención 1,72 min. LCMS spectrum: MH + 516, retention time 1.72 min.

La preparación de –[4–[4–(hidroximetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]–3–[(1–metilpirazol–4– il)metil]urea se describió anteriormente. The preparation of - [4– [4– (hydroxymethyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] –3 - [(1-methylpyrazole-4-yl) methyl] urea was described above.

Ejemplo 53: Example 53:

25 N– [2 - [[6 - [(3S) –3-methylmorpholin-4-yl] –2– [4 - [(1-methylpyrazol-4-yl) methylcarbamoylamino] phenyl] pyrimidin-4– yl] methylsulfonyl ] ethyl] acetamide

O OR

N N

N S O OO N S O oo

O H Or h

N N N N

N N

HH N HH N

Se añadieron gota a gota ácido meta–cloroperbenzoico (156 mg, 0,90 mmoles) disuelto en dioxano (2 ml), y monohidrato de permanganato de sodio (192 mg, 1,20 mmoles) disuelto en agua (1 ml) a N–[2–[[6–[(3S)–3– metilmorfolin–4–il]–2–[4–[(1–metilpirazol–4–il)metilcarbamoilamino]fenil]pirimidin–4–il]metilsulfanil]etil]acetamida Meta-chloroperbenzoic acid (156 mg, 0.90 mmol) dissolved in dioxane (2 ml), and sodium permanganate monohydrate (192 mg, 1.20 mmol) dissolved in water (1 ml) were added dropwise to N - [2 - [[6 - [(3S) –3– methylmorpholin-4-yl] –2– [4 - [(1-methylpyrazol-4-yl) methylcarbamoylamino] phenyl] pyrimidin-4-yl] methylsulfanyl] ethyl ] acetamide

5 (162 mg, 0,30 mmoles) en dioxano (6 ml) y agua (2 ml) a RT en nitrógeno. La disolución resultante se agitó a RT durante 1 hora. El producto bruto se purificó mediante cromatografía de intercambio iónico, usando una columna SCX. El producto deseado se eluyó de la columna usando amoniaco 7M en metanol, y las fracciones puras se evaporaron hasta sequedad. El producto bruto se purificó mediante HPLC preparativa usando mezclas polares decrecientes de agua (que contiene 1% de NH3) y MeCN como eluyentes, para dar el material deseado como un 5 (162 mg, 0.30 mmol) in dioxane (6 ml) and water (2 ml) at RT in nitrogen. The resulting solution was stirred at RT for 1 hour. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M ammonia in methanol, and the pure fractions evaporated to dryness. The crude product was purified by preparative HPLC using decreasing polar mixtures of water (containing 1% NH3) and MeCN as eluents, to give the desired material as a

10 sólido blanco (61 mg). 10 white solid (61 mg).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,24 (3H, d), 1,83 (3H, s), 3,18 (1H, m), 3,50–3,58 (6H, m), 3,66–3,67 (1H, m), 3,76 (1H, s), 3,80 (3H, s), 3,97 (1H, s), 4,13 (2H, d), 4,51 (3H, m), 6,40 (1H, d), 6,78 (1H, s), 7,35 (1H, s), 7,48–7,51 (2H, m), 7,59 (1H, s), 8,15 (1H, s), 8,21 (2H, d), 8,69 (1H, s). NMR Spectrum: 1H NMR (400.13 MHz, DMSO – d6) δ 1.24 (3H, d), 1.83 (3H, s), 3.18 (1H, m), 3.50–3.58 (6H, m), 3.66-3.67 (1H, m), 3.76 (1H, s), 3.80 (3H, s), 3.97 (1H, s), 4.13 ( 2H, d), 4.51 (3H, m), 6.40 (1H, d), 6.78 (1H, s), 7.35 (1H, s), 7.48–7.51 (2H , m), 7.59 (1H, s), 8.15 (1H, s), 8.21 (2H, d), 8.69 (1H, s).

Espectro LCMS: MH+ 571, tiempo de retención 1,42 min. LCMS spectrum: MH + 571, retention time 1.42 min.

53a 53a: S O O NH2 O N N N O N H N H O NN 2–[[6–[(3S)–3–metilmorfolin–4–il]–2–[4– [(1–metilpirazol–4– il)metilcarbamoilamino]fenil]pirimidin–4– il]metilsulfonil]acetamida 543 1,40 S O O NH2 O N N N O N H N H O NN 2 - [[6 - [(3S) –3 – methylmorpholin-4-yl] –2– [4– [(1-methylpyrazol-4-yl) methylcarbamoylamino] phenyl] pyrimidin-4-yl] methylsulfonyl] acetamide 543 1.40

53b 53b: S O O OH N N N O N H N H O NN 1–[4–[4–(2–hidroxietilsulfonilmetil)–6– [(3S)–3–metilmorfolin–4–il]pirimidin–2– il]fenil]–3–[(1–metilpirazol–4– il)metil]urea 530 1,43 S O O OH N N N O N H N H O NN 1– [4– [4– (2-hydroxyethylsulfonylmethyl) –6– [(3S) –3-methylmorpholin-4-yl] pyrimidin – 2– yl] phenyl] –3 - [(1-methylpyrazole-4-yl) methyl] urea 530 1.43

52c 52c: S O O N N N N O N H N H O NN 1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6– (piridin–4–ilsulfonilmetil)pirimidin–2– il]fenil]–3–[(1–metilpirazol–4– il)metil]urea 563 1,63 S O O N N N N O N H N H O NN 1– [4– [4 - [(3S) –3 – methylmorpholin-4-yl] –6– (pyridin-4-ylsulfonylmethyl) pyrimidin – 2– yl] phenyl] –3 - [(1-methylpyrazole-4– il) methyl] urea 563 1.63

Ejemplo 53a: RMN 1H (400,13 MHz, DMSO–d6) δ 1,24 (3H, d), 3,19–3,25 (1H, m), 3,47–3,53 (1H, m), 3,63–3,67 (1H, m), 3,76 (1H, s), 3,79 (3H, s), 3,97–4,00 (1H, m), 4,13 (3H, d), 4,27 (2H, s), 4,48 (1H, s), 4,67 (2H, s), 6,42 (1H, t), 6,76 (1H, s), 7,35 (1H, s), 7,48–7,52 (3H, m), 7,59 (1H, s), 7,79 (1H, s), 8,20 (2H, d), 8,69 (1H, s). Example 53a: 1H NMR (400.13 MHz, DMSO-d6) δ 1.24 (3H, d), 3.19-3.25 (1H, m), 3.47-3.53 (1H, m) , 3.63–3.67 (1H, m), 3.76 (1H, s), 3.79 (3H, s), 3.97-4.00 (1H, m), 4.13 (3H , d), 4.27 (2H, s), 4.48 (1H, s), 4.67 (2H, s), 6.42 (1H, t), 6.76 (1H, s), 7 , 35 (1H, s), 7.48–7.52 (3H, m), 7.59 (1H, s), 7.79 (1H, s), 8.20 (2H, d), 8, 69 (1H, s).

Ejemplo 53b: RMN 1H (400,13 MHz, DMSO–d6) δ 1,24 (3H, d), 3,22 (1H, d), 3,51 (3H, t), 3,63–3,67 (1H, m), 3,80 (4H, s), 3,92 (2H, q), 3,97–4,01 (1H, m), 4,13 (3H, d), 4,50 (3H, s), 5,18 (1H, t), 6,42 (1H, t), 6,76 (1H, s), 7,35 (1H, s), 7,49–7,51 (2H, m), 7,59 (1H, s), 8,22 (2H, d), 8,68 (1H, s). Example 53b: 1H NMR (400.13 MHz, DMSO-d6) δ 1.24 (3H, d), 3.22 (1H, d), 3.51 (3H, t), 3.63-3.67 (1H, m), 3.80 (4H, s), 3.92 (2H, q), 3.97-4.01 (1H, m), 4.13 (3H, d), 4.50 ( 3H, s), 5.18 (1H, t), 6.42 (1H, t), 6.76 (1H, s), 7.35 (1H, s), 7.49–7.51 (2H , m), 7.59 (1H, s), 8.22 (2H, d), 8.68 (1H, s).

Ejemplo 53c: RMN 1H (400,13 MHz, DMSO–d6) δ 1,20–1,26 (3H, m), 3,15–3,22 (1H, m), 3,45–3,52 (1H, m), 3,61– 3,65 (1H, m), 3,78 (1H, s), 3,80 (3H, s), 3,95–3,99 (1H, m), 4,12 (3H, d), 4,39 (1H, s), 4,87 (2H, s), 6,39 (1H, t), 6,71 (1H, s), 7,34–7,39 (3H, m), 7,59 (1H, s), 7,66 (2H, d), 7,81–7,82 (2H, m), 8,64 (1H, s), 8,90–8,91 (2H, m). Example 53c: 1H NMR (400.13 MHz, DMSO-d6) δ 1.20-1.26 (3H, m), 3.15-3.22 (1H, m), 3.45-3.52 ( 1H, m), 3.61– 3.65 (1H, m), 3.78 (1H, s), 3.80 (3H, s), 3.95–3.99 (1H, m), 4 , 12 (3H, d), 4.39 (1H, s), 4.87 (2H, s), 6.39 (1H, t), 6.71 (1H, s), 7.34–7, 39 (3H, m), 7.59 (1H, s), 7.66 (2H, d), 7.81-7.82 (2H, m), 8.64 (1H, s), 8.90 –8.91 (2H, m).

Prueba (a): Ejemplo (53) 0,64 μM; Ejemplo (53a) 0,6 μM; Ejemplo (53c) 0,03 μM. Test (a): Example (53) 0.64 μM; Example (53a) 0.6 μM; Example (53c) 0.03 μM.

Prueba (c): Ejemplo (53b) 3 μM. Test (c): Example (53b) 3 μM.

A continuación se describe la preparación de N–[2–[[6–[(3S)–3–metilmorfolin–4–il]–2–[4–[(1–metilpirazol–4– il)metilcarbamoilamino]fenil]pirimidin–4–il]metilsulfanil]etil]acetamida. The preparation of N– [2 - [[6 - [(3S) –3-methylmorpholin-4-yl] –2– [4 - [(1-methylpyrazol-4-yl) methylcarbamoylamino] phenyl] pyrimidine is described below. -4-yl] methylsulfanyl] ethyl] acetamide.

N–[2–[[6–[(3S)–3–Metilmorfolin–4–il]–2–[4–[(1–metilpirazol–4–il)metilcarbamoilamino]fenil]pirimidin–4– il]metilsulfanil]etil]acetamida N– [2 - [[6 - [(3S) –3 – Methylmorpholin-4-yl] –2– [4 - [(1-methylpyrazol-4-yl) methylcarbamoylamino] phenyl] pyrimidin-4-yl] methylsulfanyl] ethyl] acetamide

O OR

N N

O OR

N S N S

O H Or h

N N N N

N N

HH NHH N

10 Se añadió N–acetilcisteamina (0,056 ml, 0,53 mmoles) a DBU (0,091 ml, 0,60 mmoles) y 1–[4–[4–[(3S)–3– metilmorfolin–4–il]–6–(metilsulfoniloximetil)pirimidin–2–il]fenil]–3–[(1–metilpirazol–4–il)metil]urea (155 mg, 0,30 mmoles) en acetonitrilo (4 ml) en nitrógeno. La disolución resultante se agitó a RT durante 5 horas. La mezcla de reacción se evaporó para dar el material deseado que se usó sin purificación adicional. 10 N-acetylcysteamine (0.056 ml, 0.53 mmol) was added to DBU (0.091 ml, 0.60 mmol) and 1– [4– [4 - [(3S) –3– methylmorpholin-4-yl] –6 - (methylsulfonyloxymethyl) pyrimidin-2-yl] phenyl] -3 - [(1-methylpyrazol-4-yl) methyl] urea (155 mg, 0.30 mmol) in acetonitrile (4 ml) in nitrogen. The resulting solution was stirred at RT for 5 hours. The reaction mixture was evaporated to give the desired material that was used without further purification.

15 Espectro LCMS: MH+ 539, tiempo de retención 1,66 min. 15 LCMS spectrum: MH + 539, retention time 1.66 min.

Los siguientes sulfuros se prepararon de manera análoga a partir de 1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6– (metilsulfoniloximetil)pirimidin–2–il]fenil]–3–[(1–metilpirazol–4–il)metil]urea y el tiol apropiado. The following sulfides were prepared analogously from 1– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (methylsulfonyloxymethyl) pyrimidin – 2-yl] phenyl] –3– [ (1-methylpyrazol-4-yl) methyl] urea and the appropriate thiol.

Estructura Structure: NOMBRE NAME

O OR: 2–[[6–[(3S)–3–metilmorfolin–4–il]–2–[4–[(1– 2 - [[6 - [(3S) –3 – methylmorpholin-4-yl] –2– [4 - [(1–

: metilpirazol–4–il)metilcarbamoilamino]fenil]pirimidin– methylpyrazol-4-yl) methylcarbamoylamino] phenyl] pyrimidin–

S NH2 O S NH2 O: N N N N H N H O NN 4–il]metilsulfanil]acetamida N N N N H N H O NN 4-yl] methylsulfanyl] acetamide

O OR: 1–[4–[4–(2–hidroxietilsulfanilmetil)–6–[(3S)–3– 1– [4– [4– (2 – hydroxyethylsulfanylmethyl) –6 - [(3S) –3–

: metilmorfolin–4–il]pirimidin–2–il]fenil]–3–[(1– methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] –3 - [(1–

S OH S OH: N N N N H N H O NN metilpirazol–4–il)metil]urea N N N N H N H O NN methylpyrazole-4-yl) methyl] urea

O OR: 1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(piridin–4– 1– [4– [4 - [(3S) –3 – methylmorpholin-4-yl] –6– (pyridin – 4–

N N
N N: ilsulfanilmetil)pirimidin–2–il]fenil]–3–[(1–metilpirazol–4– il)metil]urea ilsulfanylmethyl) pyrimidin-2-yl] phenyl] –3 - [(1-methylpyrazol-4-yl) methyl] urea

: N NN N NN

S S: N O NO

N N N N

H H H H

Ejemplo 54: 3–Ciclopropil–1–[4–[4–(metoximetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]urea
Example 54: 3 – Cyclopropyl – 1– [4– [4– (methoxymethyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin – 2-yl] phenyl] urea

La preparación de 1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfoniloximetil)pirimidin–2–il]fenil]–3–[(1– metilpirazol–4–il)metil]urea se describió anteriormente. The preparation of 1– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (methylsulfonyloxymethyl) pyrimidin-2-yl] phenyl] –3 - [(1– methylpyrazole-4-yl ) methyl] urea was described above.

Se suspendieron 3–ciclopropil–1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(metilsulfoniloximetil)pirimidin–2–il]fenil]urea (75 mg, 0,16 mmoles) y carbonato de potasio (90 mg, 0,65 mmoles) en metanol (3 ml) y se cerraron herméticamente en un tubo de microondas. La reacción se calentó hasta 100ºC durante 10 minutos en el reactor de microondas y se enfrió hasta RT. El producto bruto se purificó mediante cromatografía de intercambio iónico, usando una columna SCX. El producto deseado se eluyó de la columna usando amoniaco 7M en metanol. El producto bruto se purificó adicionalmente mediante HPLC preparativa usando mezclas polares decrecientes de agua (que contiene 1% de NH3) y MeCN como eluyentes, para dar el material deseado como un sólido blanco (15 mg). 3-Cyclopropyl-1– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (methylsulfonyloxymethyl) pyrimidin – 2-yl] phenyl] urea (75 mg, 0.16 mmol were suspended ) and potassium carbonate (90 mg, 0.65 mmol) in methanol (3 ml) and sealed in a microwave tube. The reaction was heated to 100 ° C for 10 minutes in the microwave reactor and cooled to RT. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M ammonia in methanol. The crude product was further purified by preparative HPLC using decreasing polar mixtures of water (containing 1% NH3) and MeCN as eluents, to give the desired material as a white solid (15 mg).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 0,40–0,44 (2H, m), 0,62–0,67 (2H, m), 1,22 (3H, d), 2,54–2,58 (1H, m), 3,18–3,23 (1H, m), 3,40 (3H, s), 3,45–3,52 (1H, m), 3,62–3,66 (1H, m), 3,75 (1H, d), 3,95–3,98 (1H, m), 4,16–4,19 (1H, m), 4,39 (2H, s), 4,50 (1H, s), 6,42 (1H, d), 6,57 (1H, s), 7,47–7,50 (2H, m), 8,19–8,21 (2H, m), 8,51 (1H, s). NMR Spectrum: 1H NMR (400.13 MHz, DMSO – d6) δ 0.40–0.44 (2H, m), 0.62–0.67 (2H, m), 1.22 (3H, d) , 2.54–2.58 (1H, m), 3.18–3.23 (1H, m), 3.40 (3H, s), 3.45–3.52 (1H, m), 3 , 62–3.66 (1H, m), 3.75 (1H, d), 3.95–3.98 (1H, m), 4.16–4.19 (1H, m), 4.39 (2H, s), 4.50 (1H, s), 6.42 (1H, d), 6.57 (1H, s), 7.47-7.50 (2H, m), 8.19– 8.21 (2H, m), 8.51 (1H, s).

Espectro LCMS: MH+ 398, tiempo de retención 1,86 min. LCMS spectrum: MH + 398, retention time 1.86 min.

Prueba (c): 0,11 μM Test (c): 0.11 μM

Ejemplo 55: Example 55:

3–Ciclopropil–1–[4–[4–(ciclopropilsulfonilmetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]urea 3 – Cyclopropyl – 1– [4– [4– (cyclopropylsulfonylmethyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin – 2-yl] phenyl] urea

O OR

N N

N S N S

OO OO

N N

O OR

N N

N HH N HH

Se suspendieron éster pinacólico del ácido [4–(3–ciclopropilureido)fenil]borónico (80 mg, 0,26 mmoles), carbonato de sodio (1,055 ml, 2,11 mmoles), diclorobis(trifenilfosfina)paladio(II) (14,8 mg, 0,02 mmoles) y 2–cloro–4– (ciclopropilsulfonilmetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidina (70 mg, 0,21 mmoles) en 18% de DMF en una mezcla de DME:etanol:agua 7:2:3 (4 ml) y se cerraron herméticamente un tubo de microondas. La reacción se calentó hasta 100ºC durante 10 minutos en el reactor de microondas y se enfrió hasta RT. El producto bruto se purificó mediante cromatografía de intercambio iónico, usando una columna SCX. El producto deseado se eluyó de la columna usando amoniaco 7M en metanol. El producto bruto se purificó adicionalmente mediante HPLC preparativa usando mezclas polares decrecientes de agua (que contiene 1% de NH3) y MeCN como eluyentes, para dar el material deseado como una goma incolora (33,0 mg). [4– (3-Cyclopropylureido) phenyl] boronic acid (80 mg, 0.26 mmol), sodium carbonate (1.055 ml, 2.11 mmol), dichlorobis (triphenylphosphine) palladium (II) (14) suspensions were suspended , 8 mg, 0.02 mmol) and 2-chloro-4– (cyclopropylsulfonylmethyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidine (70 mg, 0.21 mmol) in 18% DMF in a mixture of DME: ethanol: water 7: 2: 3 (4 ml) and a microwave tube was sealed. The reaction was heated to 100 ° C for 10 minutes in the microwave reactor and cooled to RT. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M ammonia in methanol. The crude product was further purified by preparative HPLC using decreasing polar mixtures of water (containing 1% NH3) and MeCN as eluents, to give the desired material as a colorless gum (33.0 mg).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 0,41–0,43 (2H, m), 0,64–0,66 (2H, m), 0,98–1,01 (2H, m), 1,04– 1,08 (2H, m), 1,24 (3H, d), 2,56 (1H, s), 2,86 (1H, d), 3,18 (1H, d), 3,50 (1H, d), 3,67 (1H, d), 3,76–3,79 (1H, m), 4,50 (2H, s), 6,43 (1H, d), 6,77 (1H, s), 7,49–7,51 (2H, m), 7,55–7,57 (1H, m), 7,60–7,65 (2H, m), 8,21–8,23 (2H, m), 8,53 (1H, s). NMR Spectrum: 1H NMR (400.13 MHz, DMSO – d6) δ 0.41–0.43 (2H, m), 0.64–0.66 (2H, m), 0.98–1.01 ( 2H, m), 1.04– 1.08 (2H, m), 1.24 (3H, d), 2.56 (1H, s), 2.86 (1H, d), 3.18 (1H , d), 3.50 (1H, d), 3.67 (1H, d), 3.76-3.79 (1H, m), 4.50 (2H, s), 6.43 (1H, d), 6.77 (1H, s), 7.49–7.51 (2H, m), 7.55–7.57 (1H, m), 7.60–7.65 (2H, m) , 8.21–8.23 (2H, m), 8.53 (1H, s).

Espectro LCMS: MH+ 472, tiempo de retención 1,80 min. LCMS spectrum: MH + 472, retention time 1.80 min.

Prueba (a): 0,062 μM. Test (a): 0.062 μM.

A continuación se describe la preparación de 2–cloro–4–(ciclopropilsulfonilmetil)–6–[(3S)–3–metilmorfolin–4– il]pirimidina. The preparation of 2-chloro-4- (cyclopropylsulfonylmethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine is described below.

2–Cloro–4–(ciclopropilsulfonilmetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidina 2 – Chloro – 4– (cyclopropylsulfonylmethyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidine

Se añadió en una porción sal sódica del ácido ciclopropanosulfínico (381 mg, 2,97 mmoles) a 2–cloro–4– (yodometil)–6–[(3S)–3–metilmorfolin–4–il]pirimidina (700 mg, 1,98 mmoles) en acetonitrilo (20 ml) a RT. La suspensión resultante se agitó a 90ºC durante 3 horas. La mezcla de reacción se evaporó hasta sequedad y se volvió a disolver en DCM (50 ml), y se lavó con agua (50 ml). La capa orgánica se secó (MgSO4), se filtró y se evaporó para proporcionar el producto bruto. El producto bruto se purificó mediante cromatografía ultrarrápida en sílice, gradiente de elución 0 a 40% de acetato de etilo en DCM, para dar el material deseado como un sólido blanco (458 mg). Sodium salt of cyclopropanesulfinic acid (381 mg, 2.97 mmol) was added to 2-chloro-4- (iodomethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine (700 mg, 1.98 mmol) in acetonitrile (20 ml) at RT. The resulting suspension was stirred at 90 ° C for 3 hours. The reaction mixture was evaporated to dryness and re-dissolved in DCM (50 ml), and washed with water (50 ml). The organic layer was dried (MgSO4), filtered and evaporated to provide the crude product. The crude product was purified by flash chromatography on silica, gradient elution 0 to 40% ethyl acetate in DCM, to give the desired material as a white solid (458 mg).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 0,95–0,98 (2H, m), 1,02–1,06 (2H, m), 1,18–1,23 (3H, m), 2,77– 2,83 (1H, m), 3,19–3,25 (1H, m), 3,42–3,49 (1H, m), 3,58–3,62 (1H, m), 3,73 (1H, d), 3,92–3,96 (2H, m), 4,30 (1H, s), 4,48 (2H, s), 6,92 (1H, s). NMR Spectrum: 1H NMR (400.13 MHz, DMSO – d6) δ 0.95–0.98 (2H, m), 1.02–1.06 (2H, m), 1.18–1.23 ( 3H, m), 2.77-3.83 (1H, m), 3.19-3.25 (1H, m), 3.42-3.49 (1H, m), 3.58-3, 62 (1H, m), 3.73 (1H, d), 3.92-3.96 (2H, m), 4.30 (1H, s), 4.48 (2H, s), 6.92 (1H, s).

Espectro LCMS: MH+ 332, tiempo de retención 1,68 min. LCMS spectrum: MH + 332, retention time 1.68 min.

La preparación de 2–cloro–4–(yodometil)–6–[(3S)–3–metilmorfolin–4–il]pirimidina se describió anteriormente. The preparation of 2-chloro-4- (iodomethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine was described above.

Ejemplo 56: Example 56:

3–Ciclopropil–1–[4–[4–(2–ciclopropilsulfonilpropan–2–il)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2– il]fenil]urea 3 – Cyclopropyl – 1– [4– [4– (2-cyclopropylsulfonylpropan – 2-yl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] urea

Se suspendieron éster pinacólico del ácido [4–(3–ciclopropilureido)fenil]borónico (199 mg, 0,66 mmoles), 2–cloro–4– (2–ciclopropilsulfonilpropan–2–il)–6–[(3S)–3–metilmorfolin–4–il]pirimidina (190 mg, 0,53 mmoles), carbonato de sodio (1,320 ml, 2,64 mmoles) y diclorobis(trifenilfosfina)paladio(II) (37,1 mg, 0,05 mmoles) en 18% de DMF en una disolución de DME:agua:EtOH 7:3:2 (4 ml) y se cerraron herméticamente un tubo de microondas. La reacción se calentó hasta 100ºC durante 20 minutos en el reactor de microondas y se enfrió hasta RT. El producto bruto se purificó mediante cromatografía de intercambio iónico, usando una columna SCX. El producto deseado se eluyó de la columna usando amoniaco 7M en metanol, y las fracciones puras se evaporaron hasta sequedad. El producto bruto se purificó adicionalmente mediante HPLC preparativa usando mezclas polares decrecientes de agua (que contiene 1% de NH3) y MeCN como eluyentes, para dar el material deseado como un sólido blanco (85 mg). [4– (3-Cyclopropylureido) phenyl] boronic acid (199 mg, 0.66 mmol), 2-chloro-4– (2-cyclopropylsulfonylpropan-2-yl) -6 - [(3S) - were suspended 3-methylmorpholin-4-yl] pyrimidine (190 mg, 0.53 mmol), sodium carbonate (1,320 ml, 2.64 mmol) and dichlorobis (triphenylphosphine) palladium (II) (37.1 mg, 0.05 mmol ) in 18% DMF in a solution of DME: water: EtOH 7: 3: 2 (4 ml) and a microwave tube was sealed. The reaction was heated to 100 ° C for 20 minutes in the microwave reactor and cooled to RT. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M ammonia in methanol, and the pure fractions evaporated to dryness. The crude product was further purified by preparative HPLC using decreasing polar mixtures of water (containing 1% NH3) and MeCN as eluents, to give the desired material as a white solid (85 mg).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 0,40–0,44 (2H, m), 0,62–0,67 (2H, m), 0,78–0,83 (1H, m), 0,81 (1H, d), 0,95 (2H, d), 1,23 (3H, d), 1,81 (6H, d), 2,56 (1H, q), 2,73–2,77 (1H, m), 3,20–3,24 (1H, m), 3,48–3,53 (1H, m), 3,63–3,67 (1H, m), 3,77 (1H, d), 3,96–4,00 (1H, m), 4,20–4,23 (1H, m), 4,57–4,59 (1H, m), 6,42 (1H, d), 6,77 (1H, s), 7,49–7,51 (2H, m), 8,23–8,25 (2H, m), 8,52 (1H, s). NMR Spectrum: 1H NMR (400.13 MHz, DMSO – d6) δ 0.40–0.44 (2H, m), 0.62–0.67 (2H, m), 0.78–0.83 ( 1H, m), 0.81 (1H, d), 0.95 (2H, d), 1.23 (3H, d), 1.81 (6H, d), 2.56 (1H, q), 2.73-2.77 (1H, m), 3.20-3.24 (1H, m), 3.48-3.53 (1H, m), 3.63-3.67 (1H, m ), 3.77 (1H, d), 3.96-4.00 (1H, m), 4.20-4.23 (1H, m), 4.57-4.59 (1H, m), 6.42 (1H, d), 6.77 (1H, s), 7.49–7.51 (2H, m), 8.23–8.25 (2H, m), 8.52 (1H, s).

Espectro LCMS: MH+ 500, tiempo de retención 2,04 min. LCMS spectrum: MH + 500, retention time 2.04 min.

Prueba (a): 2,4 μM. Test (a): 2.4 μM.

A continuación se describe la preparación de 2–cloro–4–(2–ciclopropilsulfonilpropan–2–il)–6–[(3S)–3–metilmorfolin– 4–il]pirimidina. The preparation of 2-chloro-4- (2-cyclopropylsulfonylpropan-2-yl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine is described below.

2–Cloro–4–(2–ciclopropilsulfonilpropan–2–il)–6–[(3S)–3–metilmorfolin–4–il]pirimidina 2 – Chloro – 4– (2 – cyclopropylsulfonylpropan – 2 – yl) –6 - [(3S) –3 – methylmorpholin-4-yl] pyrimidine

Se añadió yodometano (0,033 ml, 0,53 mmoles) a terc–butóxido de sodio (50,7 mg, 0,53 mmoles) y 2–cloro–4– (ciclopropilsulfonilmetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidina (175 mg, 0,53 mmoles) en DMF (2 ml) a –10ºC. La suspensión espesa resultante se agitó a RT durante 15 minutos para facilitar la agitación. Nuevamente se añadieron a la reacción yodometano (0,033 ml, 0,53 mmoles) y terc–butóxido de sodio (50,7 mg, 0,53 mmoles), y la suspensión resultante se agitó a RT durante 15 minutos. La mezcla de reacción se diluyó con DCM (20 ml) y se lavó con agua (20 ml). La capa orgánica se secó (MgSO4), se filtró y se evaporó para proporcionar el material deseado (153 mg). Iodomethane (0.033 ml, 0.53 mmol) was added to sodium tert-butoxide (50.7 mg, 0.53 mmol) and 2-chloro-4- (cyclopropylsulfonylmethyl) -6 - [(3S) -3-methylmorpholin -4-yl] pyrimidine (175 mg, 0.53 mmol) in DMF (2 ml) at –10 ° C. The resulting thick suspension was stirred at RT for 15 minutes to facilitate stirring. Again, iodomethane (0.033 ml, 0.53 mmol) and sodium tert-butoxide (50.7 mg, 0.53 mmol) were added to the reaction, and the resulting suspension was stirred at RT for 15 minutes. The reaction mixture was diluted with DCM (20 ml) and washed with water (20 ml). The organic layer was dried (MgSO4), filtered and evaporated to provide the desired material (153 mg).

Espectro LCMS: MH+ 360, tiempo de retención 2,13 min. LCMS spectrum: MH + 360, retention time 2.13 min.

La preparación de 2–cloro–4–(ciclopropilsulfonilmetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidina se describió anteriormente. The preparation of 2-chloro-4- (cyclopropylsulfonylmethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine was described above.

Example 57:

1–[4–[4–(2–Ciclopropilsulfonilpropan–2–il)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]–3–metil–urea 1– [4– [4– (2 – Cyclopropylsulfonylpropan – 2-yl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin – 2-yl] phenyl] –3-methyl-urea

Se añadió metilamina (0,699 ml, 1,40 mmoles) a N–[4–[4–(2–ciclopropilsulfonilpropan–2–il)–6–[(3S)–3– metilmorfolin–4–il]pirimidin–2–il]fenil]carbamato de fenilo (150 mg, 0,28 mmoles) y trietilamina (0,117 ml, 0,84 mmoles) en DMF (2 ml). La disolución resultante se agitó a 40ºC durante 2 horas. El producto bruto se purificó mediante HPLC preparativa usando mezclas polares decrecientes de agua (que contiene 1% de NH3) y MeCN como eluyentes, para dar el material deseado como un sólido blanco (74,0 mg). Methylamine (0.699 ml, 1.40 mmol) was added to N– [4– [4– (2-cyclopropylsulfonylpropan-2-yl) –6 - [(3S) –3– methylmorpholin-4-yl] pyrimidin – 2– il] phenyl] phenyl carbamate (150 mg, 0.28 mmol) and triethylamine (0.117 ml, 0.84 mmol) in DMF (2 ml). The resulting solution was stirred at 40 ° C for 2 hours. The crude product was purified by preparative HPLC using decreasing polar mixtures of water (containing 1% NH3) and MeCN as eluents, to give the desired material as a white solid (74.0 mg).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 0,77–0,85 (2H, m), 0,91–0,98 (2H, m), 1,22–1,23 (3H, m), 1,81 (6H, d), 2,67 (3H, t), 2,72–2,78 (1H, m), 3,20–3,24 (1H, m), 3,47–3,54 (1H, m), 3,63–3,67 (1H, m), 3,77 (1H, d), 3,96–4,00 (1H, m), 4,20–4,23 (1H, m), 4,57–4,59 (1H, m), 6,06 (1H, q), 6,77 (1H, s), 7,48–7,52 (2H, m), 8,22–8,25 (2H, m), 8,72 (1H, s). NMR Spectrum: 1H NMR (400.13 MHz, DMSO – d6) δ 0.77–0.85 (2H, m), 0.91–0.98 (2H, m), 1.22–1.23 ( 3H, m), 1.81 (6H, d), 2.67 (3H, t), 2.72-2.78 (1H, m), 3.20-3.24 (1H, m), 3 , 47-3.54 (1H, m), 3.63-3.67 (1H, m), 3.77 (1H, d), 3.96-4.00 (1H, m), 4.20 –4.23 (1H, m), 4.57–4.59 (1H, m), 6.06 (1H, q), 6.77 (1H, s), 7.48–7.52 (2H , m), 8.22–8.25 (2H, m), 8.72 (1H, s).

Espectro LCMS: MH+ 474, tiempo de retención 1,92 min. LCMS spectrum: MH + 474, retention time 1.92 min.

Prueba (c): Ejemplo (57) 0,25 μM; Ejemplo (57a) 0,064 μM; Ejemplo (57b) 0,089 μM; Ejemplo (57c) 0,36 μM; Ejemplo (57d) 0,84 μM; Ejemplo (57e) 0,38 μM; Ejemplo (57f) 0,72 μM; Ejemplo (57g) 0,095 μM; Ejemplo (57h) 0,066 μM; Ejemplo (57i) 0,27 μM; Ejemplo (57j) 0,07 μM; Ejemplo (57k) 0,34 μM; Ejemplo (57l) 0,088 μM. Test (c): Example (57) 0.25 μM; Example (57a) 0.064 μM; Example (57b) 0.089 μM; Example (57c) 0.36 μM; Example (57d) 0.84 μM; Example (57e) 0.38 μM; Example (57f) 0.72 μM; Example (57g) 0.095 μM; Example (57h) 0.066 μM; Example (57i) 0.27 μM; Example (57j) 0.07 μM; Example (57k) 0.34 μM; Example (57l) 0.088 μM.

Los siguientes compuestos se obtuvieron de manera análoga a partir de N–[4–[4–(2–ciclopropilsulfonilpropan–2–il)– 6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]carbamato de fenilo o N–[4–[4–(ciclopropilsulfonilmetil)–6–[(3S)–3– metilmorfolin–4–il]pirimidin–2–il]fenil]carbamato de fenilo y la amina apropiada. The following compounds were obtained analogously from N– [4– [4– (2-cyclopropylsulfonylpropan-2-yl) - 6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] phenyl carbamate or N– [4– [4– (cyclopropylsulfonylmethyl) –6 - [(3S) –3– methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] phenyl carbamate and the appropriate amine.

57a 57th: S O O N N N O N H N H O OH 1–[4–[4–(2–ciclopropilsulfonilpropan–2– il)–6–[(3S)–3–metilmorfolin–4– il]pirimidin–2–il]fenil]–3–(1–hidroxi–2– metil–propan–2–il)urea 532 2,03 S O O N N N O N H N H O OH 1– [4– [4– (2 – cyclopropylsulfonylpropan – 2– yl) –6 - [(3S) –3 – methylmorpholin-4– yl] pyrimidin – 2-yl] phenyl] –3– (1 – hydroxy – 2 - methyl – propan – 2 – il) urea 532 2.03

57b 57b: N N N O S O O N H N H O N 1–[4–[4–(2–ciclopropilsulfonilpropan–2– il)–6–[(3S)–3–metilmorfolin–4– il]pirimidin–2–il]fenil]–3–(2– dimetilaminoetil)urea 531 2,00 N N N O S O O N H N H O N 1– [4– [4– (2 – cyclopropylsulfonylpropan – 2– yl) –6 - [(3S) –3 – methylmorpholin-4– yl] pyrimidin – 2-yl] phenyl] –3– (2– dimethylaminoethyl) urea 531 2.00

57c 57c: O 1–[4–[4–(2–ciclopropilsulfonilpropan–2– 540 1,93 OR 1– [4– [4– (2 – cyclopropylsulfonylpropan – 2– 540 1.93

: il)–6–[(3S)–3–metilmorfolin–4– il) –6 - [(3S) –3 – methylmorpholin – 4–

N N: il]pirimidin–2–il]fenil]–3–(1–metilpirazol– il] pyrimidin – 2-yl] phenyl] –3– (1-methylpyrazole–

N N S O O N H N H O N N N N S O O N H N H O N N: 4–il)urea 4 – il) urea

57d 57d: O 1–[4–[4–(ciclopropilsulfonilmetil)–6– 446 1,56 OR 1– [4– [4– (cyclopropylsulfonylmethyl) –6– 446 1.56

N N N S O O N H N H O N N N S O O N H N H O: il]fenil]–3–metil–urea il] phenyl] –3 – methyl – urea

57e 57e: O 1–[4–[4–(ciclopropilsulfonilmetil)–6– 504 1,70 OR 1– [4– [4– (cyclopropylsulfonylmethyl) –6– 504 1.70

N N: il]fenil]–3–(1–hidroxi–2–metil–propan– il] phenyl] –3– (1-hydroxy-2-methyl-propan–

N N S O O N H N H O OH N N S O O N H N H O OH: 2–il)urea 2 – il) urea

57f 57f: O 1–[4–[4–(ciclopropilsulfonilmetil)–6– 503 1,66 OR 1– [4– [4– (cyclopropylsulfonylmethyl) –6– 503 1.66

N N N S O O N H N H O N N N N S O O N H N H O N: il]fenil]–3–(2–dimetilaminoetil)urea il] phenyl] –3– (2-dimethylaminoethyl) urea

57g 57g: O 1–[4–[4–(ciclopropilsulfonilmetil)–6– 512 1,63 OR 1– [4– [4– (cyclopropylsulfonylmethyl) –6– 512 1.63

N N N S O O N H N H O N N N N N S O O N H N H O N N: il]fenil]–3–(1–metilpirazol–4–il)urea il] phenyl] –3– (1 – methylpyrazole – 4-yl) urea

57h 57h: N N N O S O O N H N H O 3–ciclobutil–1–[4–[4–(2– ciclopropilsulfonilpropan–2–il)–6–[(3S)– 3–metilmorfolin–4–il]pirimidin–2– il]fenil]urea 514 2,28 N N N O S O O N H N H O 3 – cyclobutyl – 1– [4– [4– (2– cyclopropylsulfonylpropan – 2-yl) –6 - [(3S) - 3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] urea 514 2.28

MH+ MH +: retención retention

(min.) (min.)

57i 57i: S O O N N N O N H N H O OH 1–[4–[4–(2–ciclopropilsulfonilpropan–2– il)–6–[(3S)–3–metilmorfolin–4– il]pirimidin–2–il]fenil]–3–(2– hidroxietil)urea 504 1,72 S O O N N N O N H N H O OH 1– [4– [4– (2 – cyclopropylsulfonylpropan – 2– yl) –6 - [(3S) –3 – methylmorpholin-4– yl] pyrimidin – 2-yl] phenyl] –3– (2– hydroxyethyl) urea 504 1.72

57j 57j: O 1–[4–[4–(ciclopropilsulfonilmetil)–6– 460 1,71 OR 1– [4– [4– (cyclopropylsulfonylmethyl) –6– 460 1.71

S O O S O O: N N N N H N H O il]fenil]–3–etil–urea N N N N H N H O il] phenyl] –3-ethyl-urea

57k 57k: O 1–[4–[4–(2–ciclopropilsulfonilpropan–2– 488 2,04 OR 1– [4– [4– (2 – cyclopropylsulfonylpropan – 2– 488 2.04

S O O S O O: N N N N H N H O il]pirimidin–2–il]fenil]–3–etil–urea N N N N H N H O il] pyrimidin – 2-yl] phenyl] –3-ethyl-urea

57l 57l: S O O N N N O N H N H O 3–ciclobutil–1–[4–[4– (ciclopropilsulfonilmetil)–6–[(3S)–3– metilmorfolin–4–il]pirimidin–2– il]fenil]urea 486 1,96 S O O N N N O N H N H O 3 – cyclobutyl – 1– [4– [4– (cyclopropylsulfonylmethyl) –6 - [(3S) –3– methylmorpholin-4-yl] pyrimidin – 2-yl] phenyl] urea 486 1.96

Ejemplo 57a: RMN 1H (400,13 MHz, DMSO–d6) δ 0,79–0,83 (2H, m), 0,94–0,97 (2H, m), 1,22 (3H, d), 1,24 (6H, s), 1,81 (6H, d), 2,74–2,78 (1H, m), 3,21 (1H, t), 3,39 (2H, d), 3,50 (1H, d), 3,63–3,67 (1H, m), 3,77 (1H, d), 3,96–4,00 (1H, m), 4,20–4,23 (1H, m), 4,56–4,59 (1H, m), 4,95 (1H, t), 6,00 (1H, s), 6,76 (1H, s), 7,44–7,46 (2H, m), 8,22 (2H, Example 57a: 1H NMR (400.13 MHz, DMSO-d6) δ 0.79-0.83 (2H, m), 0.94-0.97 (2H, m), 1.22 (3H, d) , 1.24 (6H, s), 1.81 (6H, d), 2.74-2.78 (1H, m), 3.21 (1H, t), 3.39 (2H, d), 3.50 (1H, d), 3.63–3.67 (1H, m), 3.77 (1H, d), 3.96-4.00 (1H, m), 4.20–4, 23 (1H, m), 4.56-4.59 (1H, m), 4.95 (1H, t), 6.00 (1H, s), 6.76 (1H, s), 7.44 –7.46 (2H, m), 8.22 (2H,

5 d), 8,72 (1H, s). 5 d), 8.72 (1H, s).

Ejemplo 57b: RMN 1H (400,13 MHz, DMSO–d6) δ 0,79–0,84 (2H, m), 0,95 (2H, d), 1,23 (3H, d), 1,81 (6H, d), 2,18 (6H, s), 2,34 (2H, t), 2,73–2,77 (1H, m), 3,17–3,23 (3H, m), 3,47–3,54 (1H, m), 3,63–3,67 (1H, m), 3,77 (1H, d), 3,96– 4,00 (1H, m), 4,19–4,23 (1H, m), 4,58 (1H, d), 6,15 (1H, t), 6,77 (1H, s), 7,47–7,50 (2H, m), 8,22–8,24 (2H, m), 8,88 (1H, s). Example 57b: 1H NMR (400.13 MHz, DMSO-d6) δ 0.79-0.84 (2H, m), 0.95 (2H, d), 1.23 (3H, d), 1.81 (6H, d), 2.18 (6H, s), 2.34 (2H, t), 2.73-2.77 (1H, m), 3.17-3.23 (3H, m), 3.47-3.54 (1H, m), 3.63-3.67 (1H, m), 3.77 (1H, d), 3.96-4.00 (1H, m), 4, 19–4.23 (1H, m), 4.58 (1H, d), 6.15 (1H, t), 6.77 (1H, s), 7.47–7.50 (2H, m) , 8.22–8.24 (2H, m), 8.88 (1H, s).

10 Ejemplo 57c: RMN 1H (400,13 MHz, DMSO–d6) δ 0,81–0,83 (2H, m), 0,96 (2H, d), 1,22–1,24 (3H, m), 1,82 (6H, d), 2,73–2,77 (1H, m), 3,21–3,25 (1H, m), 3,47–3,51 (1H, m), 3,64–3,68 (1H, m), 3,76 (1H, s), 3,79 (3H, s), 3,97–4,00 (1H, m), 4,22 (1H, d), 4,57–4,60 (1H, m), 6,78 (1H, s), 7,38 (1H, d), 7,53–7,56 (2H, m), 7,76 (1H, s), 8,27 (2H, d), 8,38 (1H, s), 8,82 (1H, s) Example 57c: 1H NMR (400.13 MHz, DMSO-d6) δ 0.81–0.83 (2H, m), 0.96 (2H, d), 1.22–1.24 (3H, m ), 1.82 (6H, d), 2.73-2.77 (1H, m), 3.21-3.25 (1H, m), 3.47-3.51 (1H, m), 3.64-3.68 (1H, m), 3.76 (1H, s), 3.79 (3H, s), 3.97-4.00 (1H, m), 4.22 (1H, d), 4.57-4.60 (1H, m), 6.78 (1H, s), 7.38 (1H, d), 7.53–7.56 (2H, m), 7.76 (1H, s), 8.27 (2H, d), 8.38 (1H, s), 8.82 (1H, s)

Ejemplo 57d: RMN 1H (400,13 MHz, DMSO–d6) δ 0,97–1,01 (2H, m), 1,03–1,09 (2H, m), 1,23–1,25 (3H, m), 2,67 Example 57d: 1H NMR (400.13 MHz, DMSO-d6) δ 0.97-1.01 (2H, m), 1.03-1.09 (2H, m), 1.23-1.25 ( 3H, m), 2.67

15 (3H, t), 2,83–2,90 (1H, m), 3,18 (1H, m), 3,47–3,54 (1H, m), 3,64–3,67 (1H, m), 3,78 (1H, d), 3,97–4,01 (1H, m), 4,20 (1H, d), 4,50 (3H, m), 6,06 (1H, q), 6,77 (1H, s), 7,48–7,51 (2H, m), 8,20–8,23 (2H, m), 8,72 (1H, s). 15 (3H, t), 2.83-2.90 (1H, m), 3.18 (1H, m), 3.47-3.54 (1H, m), 3.64-3.67 ( 1H, m), 3.78 (1H, d), 3.97-4.01 (1H, m), 4.20 (1H, d), 4.50 (3H, m), 6.06 (1H , q), 6.77 (1H, s), 7.48-7.51 (2H, m), 8.20-8.23 (2H, m), 8.72 (1H, s).

Ejemplo 57e: RMN 1H (400,13 MHz, DMSO–d6) δ 0,98–1,01 (2H, m), 1,05–1,09 (2H, m), 1,23 (3H, d), 1,25 (6H, s), 2,85–2,89 (1H, m), 3,18 (1H, d), 3,39 (2H, d), 3,47–3,51 (1H, m), 3,64–3,67 (1H, m), 3,78 (1H, d), 3,97–4,01 (1H, m), 4,15–4,18 (1H, m), 4,47 (1H, s), 4,50 (2H, s), 4,95 (1H, t), 6,00 (1H, s), 6,77 (1H, s), 7,43–7,47 (2H, m), 8,21 (2H, d), Example 57e: 1H NMR (400.13 MHz, DMSO-d6) δ 0.98-1.01 (2H, m), 1.05-1.09 (2H, m), 1.23 (3H, d) , 1.25 (6H, s), 2.85-2.89 (1H, m), 3.18 (1H, d), 3.39 (2H, d), 3.47-3.51 (1H , m), 3.64–3.67 (1H, m), 3.78 (1H, d), 3.97–4.01 (1H, m), 4.15-4.18 (1H, m ), 4.47 (1H, s), 4.50 (2H, s), 4.95 (1H, t), 6.00 (1H, s), 6.77 (1H, s), 7.43 –7.47 (2H, m), 8.21 (2H, d),

20 8,72 (1H, s). 20 8.72 (1H, s).

Ejemplo 57f: RMN 1H (400,13 MHz, DMSO–d6) δ 0,99–1,01 (2H, m), 1,05–1,08 (2H, m), 1,24 (3H, d), 2,18 (6H, s), 2,34 (2H, t), 2,86 (1H, d), 3,17 (1H, d), 3,20 (2H, m), 3,51 (1H, s), 3,66–3,67 (1H, m), 3,76–3,79 (1H, m), 4,02 (1H, d), 4,20 (1H, d), 4,50 (3H, m), 6,15 (1H, s), 6,77 (1H, s), 7,47–7,49 (2H, m), 8,20–8,23 (2H, m), 8,88 (1H, s). Example 57f: 1H NMR (400.13 MHz, DMSO-d6) δ 0.99-1.01 (2H, m), 1.05-1.08 (2H, m), 1.24 (3H, d) , 2.18 (6H, s), 2.34 (2H, t), 2.86 (1H, d), 3.17 (1H, d), 3.20 (2H, m), 3.51 ( 1H, s), 3.66-3.67 (1H, m), 3.76-3.79 (1H, m), 4.02 (1H, d), 4.20 (1H, d), 4 , 50 (3H, m), 6.15 (1H, s), 6.77 (1H, s), 7.47-7.49 (2H, m), 8.20–8.23 (2H, m ), 8.88 (1H, s).

Ejemplo 57g: RMN 1H (400,13 MHz, DMSO–d6) δ 0,99–1,02 (2H, m), 1,04–1,10 (2H, m), 1,25 (3H, d), 2,85–2,89 25 (1H, m), 3,18 (2H, m), 3,48–3,51 (1H, m), 3,64–3,68 (1H, m), 3,77 (1H, s), 3,79 (3H, s), 3,97–4,01 (1H, m), 4,48 (1H, Example 57g: 1H NMR (400.13 MHz, DMSO-d6) δ 0.99-1.02 (2H, m), 1.04-1.10 (2H, m), 1.25 (3H, d) , 2.85-2.89 25 (1H, m), 3.18 (2H, m), 3.48-3.51 (1H, m), 3.64-3.68 (1H, m), 3.77 (1H, s), 3.79 (3H, s), 3.97-4.01 (1H, m), 4.48 (1H,

s), 4,51 (2H, s), 6,78 (1H, d), 7,38–7,39 (1H, m), 7,53–7,55 (2H, m), 7,76 (1H, s), 8,24–8,27 (2H, m), 8,38 (1H, s), 8,82 (1H, s). s), 4.51 (2H, s), 6.78 (1H, d), 7.38–7.39 (1H, m), 7.53–7.55 (2H, m), 7.76 (1H, s), 8.24-8.27 (2H, m), 8.38 (1H, s), 8.82 (1H, s).

Ejemplo 57h: RMN 1H (400,13 MHz, DMSO–d6) δ 0,77–0,84 (2H, m), 0,91–0,96 (2H, m), 1,22–1,23 (3H, m), 1,59– 1,64 (2H, m), 1,80 (6H, s), 1,81–1,85 (2H, m), 2,17–2,25 (2H, m), 2,73–2,77 (1H, m), 3,16–3,24 (1H, m), 3,47–3,53 (1H, m), 3,63–3,67 (1H, m), 3,77 (1H, d), 3,96–4,00 (1H, m), 4,11 (1H, m), 4,19 (1H, m), 4,56–4,59 (1H, m), 6,46 (1H, d), 6,77 (1H, s), 7,46–7,49 (2H, m), 8,24 (2H, d), 8,55 (1H, s). Example 57h: 1H NMR (400.13 MHz, DMSO – d6) δ 0.77–0.84 (2H, m), 0.91–0.96 (2H, m), 1.22–1.23 ( 3H, m), 1.59– 1.64 (2H, m), 1.80 (6H, s), 1.81–1.85 (2H, m), 2.17–2.25 (2H, m), 2.73-2.77 (1H, m), 3.16-3.24 (1H, m), 3.47-3.53 (1H, m), 3.63-3.67 ( 1H, m), 3.77 (1H, d), 3.96-4.00 (1H, m), 4.11 (1H, m), 4.19 (1H, m), 4.56-4 , 59 (1H, m), 6.46 (1H, d), 6.77 (1H, s), 7.46-7.49 (2H, m), 8.24 (2H, d), 8, 55 (1H, s).

Ejemplo 57i: RMN 1H (400,13 MHz, DMSO–d6) δ 0,77–0,83 (2H, m), 0,94 (2H, t), 1,23 (3H, d), 1,81 (6H, d), 2,73– 2,77 (1H, m), 3,18 (2H, d), 3,20–3,24 (1H, m), 3,46 (2H, q), 3,48–3,53 (1H, m), 3,63–3,67 (1H, m), 3,77 (1H, d), 3,96–4,00 (1H, m), 4,21 (1H, d), 4,58 (1H, d), 4,72 (1H, t), 6,25 (1H, t), 6,75 (1H, d), 7,47–7,50 (2H, m), 8,23–8,25 (2H, m), 8,79 (1H, s). Example 57i: 1H NMR (400.13 MHz, DMSO-d6) δ 0.77-0.83 (2H, m), 0.94 (2H, t), 1.23 (3H, d), 1.81 (6H, d), 2.73-2.77 (1H, m), 3.18 (2H, d), 3.20-3.24 (1H, m), 3.46 (2H, q), 3.48-3.53 (1H, m), 3.63-3.67 (1H, m), 3.77 (1H, d), 3.96-4.00 (1H, m), 4, 21 (1H, d), 4.58 (1H, d), 4.72 (1H, t), 6.25 (1H, t), 6.75 (1H, d), 7.47-7.50 (2H, m), 8.23–8.25 (2H, m), 8.79 (1H, s).

Ejemplo 57j: RMN 1H (400,13 MHz, DMSO–d6) δ 0,97–1,01 (2H, m), 1,03–1,10 (2H, m), 1,04–1,09 (3H, m), 1,23– 1,25 (3H, m), 2,85–2,89 (1H, m), 3,09–3,16 (2H, m), 3,21–3,25 (1H, m), 3,47–3,54 (1H, m), 3,64–3,67 (1H, m), 3,78 (1H, d), 3,97–4,01 (1H, m), 4,15 (1H, d), 4,50 (3H, m), 6,16 (1H, t), 6,77 (1H, s), 7,47–7,50 (2H, m), 8,20–8,23 (2H, m), 8,65 (1H, s). Example 57j: 1H NMR (400.13 MHz, DMSO-d6) δ 0.97-1.01 (2H, m), 1.03-1.10 (2H, m), 1.04-1.09 ( 3H, m), 1.23– 1.25 (3H, m), 2.85–2.89 (1H, m), 3.09–3.16 (2H, m), 3.21–3, 25 (1H, m), 3.47-3.54 (1H, m), 3.64-3.67 (1H, m), 3.78 (1H, d), 3.97-4.01 ( 1H, m), 4.15 (1H, d), 4.50 (3H, m), 6.16 (1H, t), 6.77 (1H, s), 7.47-7.50 (2H , m), 8.20–8.23 (2H, m), 8.65 (1H, s).

Ejemplo 57k: RMN 1H (400,13 MHz, DMSO–d6) δ 0,78–0,83 (2H, m), 0,95 (2H, d), 1,07 (3H, t), 1,23 (3H, d), 1,81 (6H, d), 2,75 (1H, d), 3,15 (2H, d), 3,18 (1H, s), 3,50 (1H, d), 3,63–3,67 (1H, m), 3,77 (1H, d), 3,96–4,00 (1H, m), 4,19–4,23 (1H, m), 4,58 (1H, d), 6,16 (1H, t), 6,74–6,77 (1H, m), 7,48–7,50 (2H, m), 8,23 (2H, d), 8,65 (1H, s). Example 57k: 1H NMR (400.13 MHz, DMSO-d6) δ 0.78-0.83 (2H, m), 0.95 (2H, d), 1.07 (3H, t), 1.23 (3H, d), 1.81 (6H, d), 2.75 (1H, d), 3.15 (2H, d), 3.18 (1H, s), 3.50 (1H, d) , 3.63-3.67 (1H, m), 3.77 (1H, d), 3.96-4.00 (1H, m), 4.19-4.23 (1H, m), 4 , 58 (1H, d), 6.16 (1H, t), 6.74-6.77 (1H, m), 7.48-7.50 (2H, m), 8.23 (2H, d ), 8.65 (1H, s).

Ejemplo 57l: RMN 1H (400,13 MHz, DMSO–d6) δ 0,97–1,03 (2H, m), 1,03–1,09 (2H, m), 1,23–1,25 (3H, m), 1,57– 1,66 (2H, m), 1,83–1,88 (2H, m), 2,17–2,24 (2H, m), 2,83–2,88 (1H, m), 3,21–3,25 (1H, m), 3,47–3,54 (1H, m), 3,63– 3,67 (1H, m), 3,78 (1H, d), 3,97–4,00 (1H, m), 4,14 (2H, m), 4,50 (3H, m), 6,45 (1H, d), 6,77 (1H, s), 7,45–7,49 (2H, m), 8,20–8,23 (2H, m), 8,55 (1H, s). Example 571: 1H NMR (400.13 MHz, DMSO-d6) δ 0.97-1.03 (2H, m), 1.03-1.09 (2H, m), 1.23-1.25 ( 3H, m), 1.57-1.66 (2H, m), 1.83-1.88 (2H, m), 2.17-2.24 (2H, m), 2.83-2, 88 (1H, m), 3.21-3.25 (1H, m), 3.47-3.54 (1H, m), 3.63-3.67 (1H, m), 3.78 ( 1H, d), 3.97-4.00 (1H, m), 4.14 (2H, m), 4.50 (3H, m), 6.45 (1H, d), 6.77 (1H , s), 7.45-7.49 (2H, m), 8.20-8.23 (2H, m), 8.55 (1H, s).

A continuación se describe la preparación de N–[4–[4–(2–ciclopropilsulfonilpropan–2–il)–6–[(3S)–3–metilmorfolin–4– il]pirimidin–2–il]fenil]carbamato de fenilo. The preparation of N- [4– [4– (2-cyclopropylsulfonylpropan-2-yl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] carbamate is described below. phenyl.

N–[4–[4–(2–Ciclopropilsulfonilpropan–2–il)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]carbamato de fenilo N– [4– [4– (2 – Cyclopropylsulfonylpropan – 2-yl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] phenyl carbamate

O H Or h

Se añadió gota a gota cloroformiato de fenilo (0,215 ml, 1,71 mmoles) a 4–[4–(2–ciclopropilsulfonilpropan–2–il)–6– [(3S)–3–metilmorfolin–4–il]pirimidin–2–il]anilina (712 mg, 1,71 mmoles) y bicarbonato de sodio (215 mg, 2,56 mmoles) en dioxano (15 ml) en nitrógeno. La suspensión resultante se agitó a RT durante 2 horas. La mezcla de reacción se evaporó hasta sequedad y se volvió a disolver en acetato de etilo (100 ml) y se lavó con agua (100 ml). La capa orgánica se secó (MgSO4), se filtró y se evaporó para dar el material deseado (983 mg). Phenyl chloroformate (0.215 ml, 1.71 mmol) was added dropwise to 4– [4– (2-cyclopropylsulfonylpropan-2-yl) –6– [(3S) –3-methylmorpholin-4-yl] pyrimidin– 2-yl] aniline (712 mg, 1.71 mmol) and sodium bicarbonate (215 mg, 2.56 mmol) in dioxane (15 ml) in nitrogen. The resulting suspension was stirred at RT for 2 hours. The reaction mixture was evaporated to dryness and re-dissolved in ethyl acetate (100 ml) and washed with water (100 ml). The organic layer was dried (MgSO4), filtered and evaporated to give the desired material (983 mg).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 0,77–0,84 (2H, m), 0,95 (2H, t), 1,23 (3H, s), 1,82 (6H, d), 2,74– 2,78 (1H, m), 3,18–3,25 (1H, m), 3,47–3,54 (1H, m), 3,64–3,67 (1H, m), 3,77 (1H, d), 3,96–4,00 (1H, m), 4,23 (1H, d), 4,59 (1H, s), 6,80 (1H, s), 7,22–7,30 (3H, m), 7,40–7,48 (2H, m), 7,55–7,64 (2H, m), 8,35 (2H, d), 10,42 (1H, s). NMR Spectrum: 1H NMR (400.13 MHz, DMSO – d6) δ 0.77–0.84 (2H, m), 0.95 (2H, t), 1.23 (3H, s), 1.82 (6H, d), 2.74-2.78 (1H, m), 3.18-3.25 (1H, m), 3.47-3.54 (1H, m), 3.64-3 , 67 (1H, m), 3.77 (1H, d), 3.96-4.00 (1H, m), 4.23 (1H, d), 4.59 (1H, s), 6, 80 (1H, s), 7.22–7.30 (3H, m), 7.40–7.48 (2H, m), 7.55–7.64 (2H, m), 8.35 ( 2H, d), 10.42 (1H, s).

Espectro LCMS: MH+ 537, tiempo de retención 2,87 min. LCMS spectrum: MH + 537, retention time 2.87 min.

4–[4–(2–Ciclopropilsulfonilpropan–2–il)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]anilina 4– [4– (2 – Cyclopropylsulfonylpropan – 2-yl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin – 2-yl] aniline

Se añadió diclorobis(trifenilfosfina)paladio(II) (96 mg, 0,14 mmoles) a éster pinacólico del ácido (4– aminofenil)borónico (747 mg, 3,41 mmoles), 2–cloro–4–(2–ciclopropilsulfonilpropan–2–il)–6–[(3S)–3–metilmorfolin– 4–il]pirimidina (982 mg, 2,73 mmoles) y carbonato de sodio (6,82 ml, 13,64 mmoles) en 18% de DMF en Dichlorobis (triphenylphosphine) palladium (II) (96 mg, 0.14 mmol) was added to pinacolic acid (4-aminophenyl) boronic acid (747 mg, 3.41 mmol), 2-chloro-4– (2-cyclopropylsulfonylpropan –2 – il) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidine (982 mg, 2.73 mmol) and sodium carbonate (6.82 ml, 13.64 mmol) in 18% of DMF in

DME:agua:etanol 7:3:2 (20 ml). La disolución resultante se agitó a 80ºC durante 16 horas. El producto bruto se purificó mediante cromatografía de intercambio iónico, usando una columna SCX. El producto deseado se eluyó de la columna usando amoniaco 7M en metanol. El producto bruto se purificó adicionalmente mediante cromatografía ultrarrápida en sílice, gradiente de elución 0 a 2,5% de metanol en DCM, para dar el material deseado como un sólido cristalino amarillo (712 mg). DME: water: ethanol 7: 3: 2 (20 ml). The resulting solution was stirred at 80 ° C for 16 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M ammonia in methanol. The crude product was further purified by flash silica chromatography, gradient elution 0 to 2.5% methanol in DCM, to give the desired material as a yellow crystalline solid (712 mg).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 0,79–0,83 (2H, m), 0,94–0,96 (2H, s), 1,21 (3H, d), 1,79 (6H, d), 2,74 (1H, m), 3,17 (1H, d), 3,49 (1H, d), 3,62–3,66 (1H, m), 3,76 (1H, d), 3,95–3,99 (1H, m), 4,16–4,19 (1H, m), 4,54 (1H, d), 5,51–5,53 (2H, m), 6,59 (2H, t), 6,67 (1H, s), 8,07 (2H, d). NMR Spectrum: 1H NMR (400.13 MHz, DMSO – d6) δ 0.79–0.83 (2H, m), 0.94–0.96 (2H, s), 1.21 (3H, d) , 1.79 (6H, d), 2.74 (1H, m), 3.17 (1H, d), 3.49 (1H, d), 3.62-3.66 (1H, m), 3.76 (1H, d), 3.95–3.99 (1H, m), 4.16-4.19 (1H, m), 4.54 (1H, d), 5.51–5, 53 (2H, m), 6.59 (2H, t), 6.67 (1H, s), 8.07 (2H, d).

Espectro LCMS: MH+ 417, tiempo de retención 2,22 min. LCMS spectrum: MH + 417, retention time 2.22 min.

La preparación de 2–cloro–4–(2–ciclopropilsulfonilpropan–2–il)–6–[(3S)–3–metilmorfolin–4–il]pirimidina se describió anteriormente. The preparation of 2-chloro-4- (2-cyclopropylsulfonylpropan-2-yl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine was described above.

A continuación se describe la preparación de N–[4–[4–(ciclopropilsulfonilmetil)–6–[(3S)–3–metilmorfolin–4– il]pirimidin–2–il]fenil]carbamato de fenilo. The preparation of N- [4– [4– (cyclopropylsulfonylmethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] carbamate is described below.

N–[4–[4–(Ciclopropilsulfonilmetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]carbamato de fenilo N– [4– [4– (Cyclopropylsulfonylmethyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] phenyl carbamate

O H Or h

Se añadió gota a gota cloroformiato de fenilo (0,315 ml, 2,50 mmoles) a 4–[4–(ciclopropilsulfonilmetil)–6–[(3S)–3– metilmorfolin–4–il]pirimidin–2–il]anilina (972 mg, 2,50 mmoles) y bicarbonato de sodio (315 mg, 3,75 mmoles) en dioxano (20 ml). La suspensión resultante se agitó a RT durante 2 horas. La mezcla de reacción se evaporó hasta sequedad y se volvió a disolver en acetato de etilo (100 ml) y se lavó con agua (100 ml). La capa orgánica se secó (MgSO4), se filtró y se evaporó para proporcionar el material deseado (1,35 g). Phenyl chloroformate (0.315 ml, 2.50 mmol) was added dropwise to 4– [4– (cyclopropylsulfonylmethyl) -6 - [(3S) -3– methylmorpholin-4-yl] pyrimidin-2-yl] aniline ( 972 mg, 2.50 mmol) and sodium bicarbonate (315 mg, 3.75 mmol) in dioxane (20 ml). The resulting suspension was stirred at RT for 2 hours. The reaction mixture was evaporated to dryness and re-dissolved in ethyl acetate (100 ml) and washed with water (100 ml). The organic layer was dried (MgSO4), filtered and evaporated to provide the desired material (1.35 g).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 0,98–1,03 (2H, m), 1,06–1,10 (2H, m), 1,26 (3H, d), 2,86–2,93 (1H, m), 3,48–3,52 (1H, m), 3,58 (1H, s), 3,64–3,68 (1H, m), 3,77–3,80 (1H, m), 3,98–4,06 (1H, m), 4,17 (1H, d), 4,50 (1H, s), 4,56 (2H, s), 6,86 (1H, s), 7,24–7,29 (3H, m), 7,43–7,47 (2H, m), 7,65 (2H, d), 8,31 (2H, d), 10,47 (1H, s). NMR Spectrum: 1H NMR (400.13 MHz, DMSO – d6) δ 0.98-1.03 (2H, m), 1.06–1.10 (2H, m), 1.26 (3H, d) , 2.86–2.93 (1H, m), 3.48–3.52 (1H, m), 3.58 (1H, s), 3.64–3.68 (1H, m), 3 , 77–3.80 (1H, m), 3.98–4.06 (1H, m), 4.17 (1H, d), 4.50 (1H, s), 4.56 (2H, s ), 6.86 (1H, s), 7.24–7.29 (3H, m), 7.43–7.47 (2H, m), 7.65 (2H, d), 8.31 ( 2H, d), 10.47 (1H, s).

Espectro LCMS: MH+ 509, tiempo de retención 2,29 min. LCMS spectrum: MH + 509, retention time 2.29 min.

4–[4–(Ciclopropilsulfonilmetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]anilina 4– [4– (Cyclopropylsulfonylmethyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] aniline

Se añadió diclorobis(trifenilfosfina)paladio(II) (96 mg, 0,14 mmoles) a éster pinacólico del ácido (4– aminofenil)borónico (747 mg, 3,41 mmoles), 2–cloro–4–(ciclopropilsulfonilmetil)–6–[(3S)–3–metilmorfolin–4– il]pirimidina (905 mg, 2,73 mmoles) y carbonato de sodio (6,82 ml, 13,64 mmoles) en 18% de DMF en DME:agua:etanol 7:3:2 (20 ml). La disolución resultante se agitó a 80ºC durante 6 horas. La reacción bruta se purificó mediante cromatografía de intercambio iónico, usando una columna SCX. El producto deseado se eluyó de la columna usando amoniaco 7M en metanol. El producto bruto se purificó adicionalmente mediante cromatografía ultrarrápida en sílice, gradiente de elución 0 a 2,5% de metanol en DCM, para dar el material deseado como un sólido amarillo (972 mg). Dichlorobis (triphenylphosphine) palladium (II) (96 mg, 0.14 mmol) was added to pinacolic acid (4-aminophenyl) boronic acid (747 mg, 3.41 mmol), 2-chloro-4– (cyclopropylsulfonylmethyl) - 6 - [(3S) –3-methylmorpholin-4-yl] pyrimidine (905 mg, 2.73 mmol) and sodium carbonate (6.82 ml, 13.64 mmol) in 18% DMF in DME: water: 7: 3: 2 ethanol (20 ml). The resulting solution was stirred at 80 ° C for 6 hours. The crude reaction was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M ammonia in methanol. The crude product was further purified by flash chromatography on silica, gradient elution 0 to 2.5% methanol in DCM, to give the desired material as a yellow solid (972 mg).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 0,97–1,02 (2H, m), 1,03–1,10 (2H, m), 1,23 (3H, d), 2,81–2,87 (1H, m), 3,15–3,22 (1H, m), 3,46–3,52 (1H, m), 3,62–3,66 (1H, m), 3,77 (1H, d), 3,96–3,99 (1H, m), 4,12–4,15 (1H, m), 4,45 (3H, s), 5,53 (2H, d), 6,58–6,61 (2H, m), 6,66 (1H, s), 8,03–8,07 (2H, m). NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 0.97-1.02 (2H, m), 1.03–1.10 (2H, m), 1.23 (3H, d) , 2.81-2.87 (1H, m), 3.15-3.22 (1H, m), 3.46-3.52 (1H, m), 3.62-3.66 (1H, m), 3.77 (1H, d), 3.96-3.99 (1H, m), 4.12-4.15 (1H, m), 4.45 (3H, s), 5.53 (2H, d), 6.58-6.61 (2H, m), 6.66 (1H, s), 8.03-8.07 (2H, m).

Espectro LCMS: MH+ 389, tiempo de retención 1,82. LCMS spectrum: MH + 389, retention time 1.82.

Ejemplo 58: 3–Metil–1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(2–piridin–4–ilsulfonilpropan–2–il)pirimidin–2–il]fenil]urea Example 58: 3 – Methyl – 1– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (2-pyridin-4-ylsulfonylpropan – 2-yl) pyrimidin – 2-yl] phenyl] urea

O OR

N N

N S OO N S OO

O N O n

N N

N HH N HH

N N

5 Se añadió metilamina (disolución 2M en THF) (0,55 ml, 1,10 mmoles) a N–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(2– piridin–4–ilsulfonilpropan–2–il)pirimidin–2–il]fenil]carbamato de fenilo (125 mg, 0,22 mmoles) y trietilamina (0,092 ml, 0,66 mmoles) en DMF (4 ml). La disolución resultante se agitó a 50ºC toda la noche. El producto bruto se purificó mediante HPLC preparativa usando mezclas polares decrecientes de agua (que contiene 1% de NH3) y acetonitrilo 5 Methylamine (2M solution in THF) (0.55 ml, 1.10 mmol) was added to N– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (2– pyridin -4-ylsulfonylpropan-2-yl) pyrimidin-2-yl] phenyl] phenyl carbamate (125 mg, 0.22 mmol) and triethylamine (0.092 ml, 0.66 mmol) in DMF (4 ml). The resulting solution was stirred at 50 ° C overnight. The crude product was purified by preparative HPLC using decreasing polar mixtures of water (containing 1% NH3) and acetonitrile.

10 como eluyentes, para dar el material deseado como un sólido blanco (91 mg). 10 as eluents, to give the desired material as a white solid (91 mg).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,22–1,23 (3H, d), 1,82–1,83 (6H, d), 2,66–2,67 (3H, d), 3,15– 3,23 (1H, td), 3,47–3,53 (1H, td), 3,63–3,53 (1H, dd), 3,76–3,79 (1H, d), 3,96–4,00 (1H, dd), 4,18–4,21 (1H, d), 4,57 (1H, bs), 6,03-6,07 (1H, q), 6,71 (1H, s), 7,35–7,37 (2H, d), 7,47–7,48 (2H, q), 7,65–7,68 (2H, d), 8,70 (1H, s), 8,74– 8,75 (2H, q). NMR Spectrum: 1H NMR (400.13 MHz, DMSO – d6) δ 1.22–1.23 (3H, d), 1.82–1.83 (6H, d), 2.66–2.67 ( 3H, d), 3.15-3.23 (1H, td), 3.47-3.53 (1H, td), 3.63-3.53 (1H, dd), 3.76-3, 79 (1H, d), 3.96-4.00 (1H, dd), 4.18-4.21 (1H, d), 4.57 (1H, bs), 6.03-6.07 ( 1H, q), 6.71 (1H, s), 7.35–7.37 (2H, d), 7.47–7.48 (2H, q), 7.65–7.68 (2H, d), 8.70 (1H, s), 8.74-8.75 (2H, q).

15 Espectro LCMS: MH+ 511, tiempo de retención 2,03 min. 15 LCMS spectrum: MH + 511, retention time 2.03 min.

Los siguientes compuestos se obtuvieron de manera análoga a partir de N–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(2– piridin–4–ilsulfonilpropan–2–il)pirimidin–2–il]fenil]carbamato de fenilo y la amina apropiada. The following compounds were obtained analogously from N– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (2– pyridin-4-ylsulfonylpropan – 2-yl) pyrimidin– 2-yl] phenyl] phenyl carbamate and the appropriate amine.

MH+ MH +: retención retention

(min.) (min.)

58a 58th: O 3–etil–1–[4–[4–[(3S)–3–metilmorfolin– 525 2,17 OR 3 – ethyl – 1– [4– [4 - [(3S) –3 – methylmorpholin– 525 2.17

: 4–il]–6–(2–piridin–4–ilsulfonilpropan–2– 4 – il] –6– (2 – pyridin – 4 – ilsulfonylpropan – 2–

N N: N N N S O O N H N H O il)pirimidin–2–il]fenil]urea N N N S O O N H N H O il) pyrimidin-2-yl] phenyl] urea

58b 58b: N N N N O S O O N H N H O 3–ciclopropil–1–[4–[4–[(3S)–3– metilmorfolin–4–il]–6–(2–piridin–4– ilsulfonilpropan–2–il)pirimidin–2– il]fenil]urea 537 2,19 N N N N O S O O N H N H O 3 – cyclopropyl – 1– [4– [4 - [(3S) –3– methylmorpholin-4-yl] –6– (2-pyridin-4– ylsulfonylpropan – 2-yl) pyrimidin – 2– il] phenyl] urea 537 2.19

58c 58c: N N N N O S O O N H N H O 3–ciclobutil–1–[4–[4–[(3S)–3– metilmorfolin–4–il]–6–(2–piridin–4– ilsulfonilpropan–2–il)pirimidin–2– il]fenil]urea 551 2,39 N N N N O S O O N H N H O 3 – cyclobutyl – 1– [4– [4 - [(3S) –3– methylmorpholin-4-yl] –6– (2-pyridin-4– ylsulfonylpropan – 2-yl) pyrimidin – 2– yl] phenyl] urea 551 2.39

58d 58d: N N N N O S O O N H N H O OH 3–(2–hidroxietil)–1–[4–[4–[(3S)–3– metilmorfolin–4–il]–6–(2–piridin–4– ilsulfonilpropan–2–il)pirimidin–2– il]fenil]urea 541 1,90 N N N N O S O O N H N H O OH 3– (2 – hydroxyethyl) –1– [4– [4 - [(3S) –3– methylmorpholin-4-yl] –6– (2-pyridin – 4– ylsulfonylpropan – 2-yl) pyrimidin – 2– il ] phenyl] urea 541 1.90

58e 58e: N N N N O S O O N H N H O N 3–(2–dimetilaminoetil)–1–[4–[4–[(3S)– 3–metilmorfolin–4–il]–6–(2–piridin–4– ilsulfonilpropan–2–il)pirimidin–2– il]fenil]urea 568 2,36 N N N N O S O O N H N H O N 3– (2-dimethylaminoethyl) –1– [4– [4 - [(3S) - 3-methylmorpholin-4-yl] –6– (2-pyridin-4– ylsulfonylpropan – 2-yl) pyrimidin – 2– il ] phenyl] urea 568 2.36

Ejemplo 58a: RMN 1H (400,13 MHz, DMSO–d6) δ 1,05–1,09 (3H, t), 1,22–1,23 (3H, d), 1,82–1,83 (6H, d), 3,09–3,22 (3H, m), 3,47–3,53 (1H, td), 3,63–3,67 (1H, dd), 3,76–3,79 (1H, d), 3,96–3,99 (1H, dd), 4,18–4,22 (1H, d), 4,57 (1H, bs), 6,13-6,15 (1H, t), 6,71 (1H, s), 7,34–7,36 (2H, d), 7,47–7,48 (2H, q), 7,65–7,68 (2H, d), 8,62 (1H, s), 8,74–8,75 Example 58a: 1H NMR (400.13 MHz, DMSO-d6) δ 1.05-1.09 (3H, t), 1.22-1.23 (3H, d), 1.82-1.83 ( 6H, d), 3.09-3.22 (3H, m), 3.47-3.53 (1H, td), 3.63-3.67 (1H, dd), 3.76-3, 79 (1H, d), 3.96-3.99 (1H, dd), 4.18-4.22 (1H, d), 4.57 (1H, bs), 6.13-6.15 ( 1H, t), 6.71 (1H, s), 7.34-7.36 (2H, d), 7.47-7.48 (2H, q), 7.65-7.68 (2H, d), 8.62 (1H, s), 8.74–8.75

5 (2H, q). 5 (2H, q).

Ejemplo 58b: RMN 1H (400,13 MHz, DMSO–d6) δ 0,40–0,44 (2H, m), 0,63–0,68 (2H, m), 1,22–1,23 (3H, d), 1,82– 1,83 (6H, d), 2,54–2,59 (1H, m), 3,15–3,23 (1H, td), 3,47–3,53 (1H, td), 3,63–3,67 (1H, dd), 3,76–3,79 (1H, d), 3,96– 4,00 (1H, dd), 4,18–4,21 (1H, d), 4,57 (1H, bs), 6,41–6,42 (1H, d), 6,72 (1H, s), 7,35–7,38 (2H, d), 7,47–7,48 (2H, q), 7,66–7,68 (2H, d), 8,50 (1H, s), 8,74–8,75 (2H, q). Example 58b: 1 H NMR (400.13 MHz, DMSO-d6) δ 0.40–0.44 (2H, m), 0.63–0.68 (2H, m), 1.22–1.23 ( 3H, d), 1.82– 1.83 (6H, d), 2.54–2.59 (1H, m), 3.15–3.23 (1H, td), 3.47–3, 53 (1H, td), 3.63-3.67 (1H, dd), 3.76-3.79 (1H, d), 3.96-4.00 (1H, dd), 4.18– 4.21 (1H, d), 4.57 (1H, bs), 6.41–6.42 (1H, d), 6.72 (1H, s), 7.35–7.38 (2H, d), 7.47–7.48 (2H, q), 7.66–7.68 (2H, d), 8.50 (1H, s), 8.74–8.75 (2H, q) .

10 Ejemplo 58c: RMN 1H (400,13 MHz, DMSO–d6) δ 1,22–1,23 (3H,d), 1,58–1,66 (2H, m), 1,82–1,83 (6H, d), 1,83– 1,89 (2H, m), 2,18–2,25 (2H, m), 3,15–3,22 (1H, td), 3,47–3,53 (1H, td), 3,63–3,67 (1H, dd), 3,76–3,79 (1H, d), 3,96– 4,00 (1H, dd), 4,11–4,21 (2H, m), 4,57 (1H,bs), 6,43-6,45 (1H, d), 6,72 (1H, s), 7,32–7,34 (2H, d), 7,46–7,48 (2H, q), 7,65–7,68 (2H, d), 8,83 (1H, s), 8,74–8,75 (2H, q). Example 58c: 1H NMR (400.13 MHz, DMSO-d6) δ 1.22-1.23 (3H, d), 1.58-1.66 (2H, m), 1.82-1.83 (6H, d), 1.83– 1.89 (2H, m), 2.18–2.25 (2H, m), 3.15–3.22 (1H, td), 3.47–3 , 53 (1H, td), 3.63-3.67 (1H, dd), 3.76-3.79 (1H, d), 3.96-4.00 (1H, dd), 4.11 –4.21 (2H, m), 4.57 (1H, bs), 6.43-6.45 (1H, d), 6.72 (1H, s), 7.32–7.34 (2H , d), 7.46–7.48 (2H, q), 7.65–7.68 (2H, d), 8.83 (1H, s), 8.74–8.75 (2H, q ).

Ejemplo 58d: RMN 1H (400,13 MHz, DMSO–d6) δ 1,22–1,23 (3H, d), 1,82–1,83 (6H, d), 3,16–3,23 (3H, m), 3,44– Example 58d: 1H NMR (400.13 MHz, DMSO – d6) δ 1.22–1.23 (3H, d), 1.82–1.83 (6H, d), 3.16–3.23 ( 3H, m), 3.44–

15 3,48 (2H, q), 3,48–3,53 (1H, td), 3,63–3,67 (1H, dd), 3,76–3,79 (1H, d), 3,96–4,00 (1H, dd), 4,18–4,22 (1H, d), 4,56 (1H, bs), 4,71–4,74 (1H, t), 6,22–6,25 (1H, t), 6,72 (1H, s), 7,33–7,36 (2H, d), 7,47–7,48 (2H, q), 7,66–7,68 (2H, d), 8,74–8,75 (2H, q), 8,77 (1H, s). 15 3.48 (2H, q), 3.48-3.53 (1H, td), 3.63-3.67 (1H, dd), 3.76-3.79 (1H, d), 3 , 96-4.00 (1H, dd), 4.18-4.22 (1H, d), 4.56 (1H, bs), 4.71-4.74 (1H, t), 6.22 –6.25 (1H, t), 6.72 (1H, s), 7.33–7.36 (2H, d), 7.47–7.48 (2H, q), 7.66–7 , 68 (2H, d), 8.74-8.75 (2H, q), 8.77 (1H, s).

Ejemplo 58e: RMN 1H (400,13 MHz, DMSO–d6) δ 1,22–123 (3H, d), 1,82–1,83 (6H, d), 2,19 (6H, s), 2,32–2,36 (2H, t), 3,15–3,22 (3H, m), 3,47–3,53 (1H, td), 3,63–3,67 (1H, dd), 3,76–3,79 (1H, d), 3,96–4,00 (1H, dd), 4,18–4,21 (1H, Example 58e: 1H NMR (400.13 MHz, DMSO-d6) δ 1.22–123 (3H, d), 1.82–1.83 (6H, d), 2.19 (6H, s), 2 , 32–2.36 (2H, t), 3.15–3.22 (3H, m), 3.47–3.53 (1H, td), 3.63–3.67 (1H, dd) , 3.76-3.79 (1H, d), 3.96-4.00 (1H, dd), 4.18-4.21 (1H,

20 d), 4,56 (1H, bs), 6,13-6,15 (1H, t), 6,72 (1H, s), 7,33–7,35 (2H, d), 7,47–7,48 (2H, q), 7,66–7,68 (2H, d), 8,74–8,75 (2H, q), 8,85 (1H, s). 20 d), 4.56 (1H, bs), 6.13-6.15 (1H, t), 6.72 (1H, s), 7.33-7.35 (2H, d), 7, 47–7.48 (2H, q), 7.66–7.68 (2H, d), 8.74–8.75 (2H, q), 8.85 (1H, s).

A continuación se describe la preparación de N–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(2–piridin–4–ilsulfonilpropan– 2–il)pirimidin–2–il]fenil]carbamato de fenilo. The preparation of N– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (2-pyridin-4-ylsulfonylpropan– 2-yl) pyrimidin-2-yl] is described below. phenyl] phenyl carbamate.

N–[4–[4–[(3S)–3–Metilmorfolin–4–il]–6–(2–piridin–4–ilsulfonilpropan–2–il)pirimidin–2–il]fenil]carbamato de fenilo N– [4– [4 - [(3S) –3 – Methylmorpholin-4-yl] –6– (2-pyridin-4-ylsulfonylpropan-2-yl) pyrimidin-2-yl] phenyl] phenyl carbamate

O OR

N N

N S N S

OO OO

N N

O N O n

N N

O H Or h

25 Se añadió cloroformiato de fenilo (0,177 ml, 1,41 mmoles) a 4–[4–[(3S)–3–metilmorfolin–4–il]–6–(2–piridin–4– ilsulfonilpropan–2–il)pirimidin–2–il]anilina (0,640 g, 1,41 mmoles) y bicarbonato de sodio (0,178 g, 2,12 mmoles) en dioxano (175 ml) a RT al aire. La suspensión resultante se agitó a RT durante 2 horas. Se añadieron dos porciones más de cloroformiato de fenilo (2 x 0,005 ml), y la reacción se dejó agitar a RT. Después se añadió agua a la 25 Phenyl chloroformate (0.177 ml, 1.41 mmol) was added at 4– [4 - [(3S) -3-methylmorpholin-4-yl] -6– (2-pyridin-4-ylsulfonylpropan-2-yl) pyrimidin-2-yl] aniline (0.640 g, 1.41 mmol) and sodium bicarbonate (0.178 g, 2.12 mmol) in dioxane (175 ml) at RT in air. The resulting suspension was stirred at RT for 2 hours. Two more portions of phenyl chloroformate (2 x 0.005 ml) were added, and the reaction was allowed to stir at RT. Then water was added to the

30 reacción, y los sólidos se filtraron y se secaron en un horno de vacío a 55ºC toda la noche para dar el material deseado como un sólido color bonceado (0,758 g). 30 reaction, and the solids were filtered and dried in a vacuum oven at 55 ° C overnight to give the desired material as a bonded solid (0.758 g).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,23–1,24 (3H, d), 1,83–1,84 (6H, d), 3,17–3,24 (1H, td), 3,48– 3,53 (1H, td), 3,64–3,67 (1H, dd), 3,76–3,79 (1H, d), 3,97–4,00 (1H, dd), 4,21–4,24 (1H, d), 4,59 (1H, bs), 6,76 (1H, s), 7,24–7,31 (3H, m), 7,43–7,50 (6H, m), 7,75–7,78 (2H, d), 8,74–8,76 (2H, d), 10,39 (1H, s). NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.23-1.24 (3H, d), 1.83-1.84 (6H, d), 3.17-3.24 ( 1H, td), 3.48-3.53 (1H, td), 3.64-3.67 (1H, dd), 3.76-3.79 (1H, d), 3.97-4, 00 (1H, dd), 4.21-4.24 (1H, d), 4.59 (1H, bs), 6.76 (1H, s), 7.24–7.31 (3H, m) , 7.43-7.50 (6H, m), 7.75-7.78 (2H, d), 8.74-8.76 (2H, d), 10.39 (1H, s).

Espectro LCMS: MH+572, tiempo de retención 2,82 min. LCMS spectrum: MH + 572, retention time 2.82 min.

4–[4–[(3S)–3–Metilmorfolin–4–il]–6–(2–piridin–4–ilsulfonilpropan–2–il)pirimidin–2–il]anilina 4– [4 - [(3S) –3 – Methylmorpholin-4-yl] –6– (2-pyridin-4-ylsulfonylpropan – 2-yl) pyrimidin – 2-yl] aniline

Se añadió trans–diclorobis(trifenilfosfina)paladio(II) (0,050 g, 0,07 mmoles) a 2–cloro–4–[(3S)–3–metilmorfolin–4–il]– 6–(2–piridin–4–ilsulfonilpropan–2–il)pirimidina (0,560 g, 1,41 mmoles), 4–(4,4,5,5–tetrametil–1,3,2–dioxaborolan–2– il)anilina (0,464 g, 2,12 mmoles) y carbonato de sodio (3,53 ml, 7,05 mmoles) en 18% de DMF en una mezcla de DME:agua:etanol (7:3:2) (30 ml) a RT en nitrógeno. La disolución resultante se agitó a 80ºC durante 5 horas. La reacción se dejó enfriar y se repartió entre acetato de etilo y agua. La capa acuosa se extrajo con acetato de etilo dos veces, y los productos orgánicos combinados se secaron (MgSO4), se filtraron y se evaporaron para proporcionar el material deseado (0,640 g) que se usó sin purificación adicional. Trans-dichlorobis (triphenylphosphine) palladium (II) (0.050 g, 0.07 mmol) was added to 2-chloro-4 - [(3S) -3-methylmorpholin-4-yl] - 6– (2-pyridin-4 -Ylsulfonylpropan-2-yl) pyrimidine (0.560 g, 1.41 mmol), 4– (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (0.464 g, 2, 12 mmol) and sodium carbonate (3.53 ml, 7.05 mmol) in 18% DMF in a mixture of DME: water: ethanol (7: 3: 2) (30 ml) at RT in nitrogen. The resulting solution was stirred at 80 ° C for 5 hours. The reaction was allowed to cool and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate twice, and the combined organic products were dried (MgSO4), filtered and evaporated to provide the desired material (0.640 g) that was used without further purification.

Espectro LCMS: MH+454, tiempo de retención 2,18 min. LCMS spectrum: MH + 454, retention time 2.18 min.

2–Cloro–4–[(3S)–3–metilmorfolin–4–il]–6–(2–piridin–4–ilsulfonilpropan–2–il)pirimidina 2 – Chloro – 4 - [(3S) –3 – methylmorpholin-4-yl] –6– (2-pyridin-4-ylsulfonylpropan – 2-yl) pyrimidine

Se añadió yodometano (0,164 ml, 2,63 mmoles) a 2–cloro–4–[(3S)–3–metilmorfolin–4–il]–6–(piridin–4– ilsulfonilmetil)pirimidina (0,970 g, 2,63 mmoles) y terc–butóxido de sodio (0,253 g, 2,63 mmoles) en DMF (15 ml) a 0ºC al aire. Se añadieron terc–butóxido de sodio (0,253 g, 2,63 mmoles) y yodometano (0,164 ml, 2,63 mmoles) adicionales, y la disolución resultante se agitó a 0ºC durante 1 hora. La disolución se dejó calentar lentamente hasta RT. Se añadieron agua y acetato de etilo, y la disolución se separó. La capa acuosa se extrajo con acetato de etilo dos veces, y los productos orgánicos combinados se secaron (MgSO4), se filtraron y se evaporaron en sílice. El producto bruto se cromatografió en sílice, eluyendo con 0–60% de acetato de etilo en DCM, para dar el material deseado como un aceite amarillo el cual se solidificó al reposar (0,56 g). Iodomethane (0.164 ml, 2.63 mmol) was added to 2-chloro-4 - [(3S) -3-methylmorpholin-4-yl] -6- (pyridin-4-ylsulfonylmethyl) pyrimidine (0.970 g, 2.63 mmol) and sodium tert-butoxide (0.253 g, 2.63 mmol) in DMF (15 ml) at 0 ° C in air. Sodium tert-butoxide (0.253 g, 2.63 mmol) and iodomethane (0.164 ml, 2.63 mmol) were added, and the resulting solution was stirred at 0 ° C for 1 hour. The solution was allowed to warm slowly to RT. Water and ethyl acetate were added, and the solution was separated. The aqueous layer was extracted with ethyl acetate twice, and the combined organic products were dried (MgSO4), filtered and evaporated on silica. The crude product was chromatographed on silica, eluting with 0–60% ethyl acetate in DCM, to give the desired material as a yellow oil which solidified on standing (0.56 g).

Espectro RMN: RMN 1H (400,13 MHz, CDCl3) δ 1,27–1,29 (3H, d), 1,71–1,72 (6H, d), 3,22–3,29 (1H, td), 3,48–3,54 (1H, td), 3,64–3,67 (1H, dd), 3,73–3,76 (1H, d), 3,95–3,98 (2H, dd), 4,29 (1H, bs), 6,63 (1H, s), 7,39–7,41 (2H, dd), 8,78–8,79 (2H, dd). NMR Spectrum: 1H NMR (400.13 MHz, CDCl3) δ 1.27–1.29 (3H, d), 1.71–1.72 (6H, d), 3.22–3.29 (1H, td), 3.48-3.54 (1H, td), 3.64-3.67 (1H, dd), 3.73-3.76 (1H, d), 3.95-3.98 ( 2H, dd), 4.29 (1H, bs), 6.63 (1H, s), 7.39-7.41 (2H, dd), 8.78-8.79 (2H, dd).

Espectro LCMS: MH+ 397, tiempo de retención 1,73 min. LCMS spectrum: MH + 397, retention time 1.73 min.

La preparación de 2–cloro–4–[(3S)–3–metilmorfolin–4–il]–6–(piridin–4–ilsulfonilmetil)pirimidina se describió anteriormente. The preparation of 2-chloro-4 - [(3S) -3-methylmorpholin-4-yl] -6- (pyridin-4-ylsulfonylmethyl) pyrimidine was described above.

Ejemplo 59: Example 59:

3–Etil–1–[4–[4–(2–Hidroxietilsulfonilmetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]urea 3 – Ethyl – 1– [4– [4– (2 – Hydroxyethylsulfonylmethyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin – 2-yl] phenyl] urea

O OR

N N

N S OO N S OO

N N

OHO N OHO N

N HH N HH

Se combinaron y se calentaron a 50ºC en una atmósfera de aire toda la noche N–[4–[4–(2–hidroxietilsulfonilmetil)– 6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]carbamato de fenilo (0,073 g, 0,14 mmoles), etilamina (0,70 mmoles) y trietilamina (0,42 mmoles). El producto bruto se purificó mediante HPLC preparativa usando mezclas polares N– [4– [4– (2-hydroxyethylsulfonylmethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-2-yl] were combined and heated at 50 ° C overnight. phenyl] phenyl carbamate (0.073 g, 0.14 mmol), ethylamine (0.70 mmol) and triethylamine (0.42 mmol). The crude product was purified by preparative HPLC using polar mixtures.

5 decrecientes de agua (que contiene 1% de NH3) y MeCN como eluyentes para dar el material deseado como un sólido blanco (0,047 g). 5 decreases of water (containing 1% NH3) and MeCN as eluents to give the desired material as a white solid (0.047 g).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,06–1,09 (3H, t), 1,24–1,25 (3H, d), 3,10–3,17 (2H, m), 3,19– 3,26 (1H, td), 3,47–3,53 (3H, m), 3,64–3,67 (1H, dd), 3,77–3,80 (1H, d), 3,90–3,94 (2H, q), 3,97–4,01 (1H, dd), 4,15– 4,19 (1H, d), 4,48 (1H, bs), 4,50 (2H, s), 5,17–5,20 (1H, t), 6,15–6,18 (1H, t), 6,76 (1H, s), 7,49–7,51 (2H, d), 8,20– NMR Spectrum: 1H NMR (400.13 MHz, DMSO – d6) δ 1.06–1.09 (3H, t), 1.24–1.25 (3H, d), 3.10–3.17 ( 2H, m), 3.19-3.26 (1H, td), 3.47-3.53 (3H, m), 3.64-3.67 (1H, dd), 3.77-3, 80 (1H, d), 3.90–3.94 (2H, q), 3.97–4.01 (1H, dd), 4.15– 4.19 (1H, d), 4.48 ( 1H, bs), 4.50 (2H, s), 5.17-5.20 (1H, t), 6.15–6.18 (1H, t), 6.76 (1H, s), 7 , 49–7.51 (2H, d), 8.20–

10 8,23 (2H, d), 8,66 (1H, s). 10 8.23 (2H, d), 8.66 (1H, s).

Espectro LCMS: MH+ 464, tiempo de retención 1,62 min. LCMS spectrum: MH + 464, retention time 1.62 min.

Los siguientes compuestos se prepararon de manera análoga a partir de N–[4–[4–(2–hidroxietilsulfonilmetil)–6– [(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]carbamato de fenilo y la amina apropiada. The following compounds were prepared analogously from N- [4– [4– (2-hydroxyethylsulfonylmethyl) -6– [(3S) -3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] carbamate phenyl and the appropriate amine.

59a 59th: S OH O O N N N O N H N H O 3–ciclobutil–1–[4–[4–(2– hidroxietilsulfonilmetil)–6–[(3S)–3– metilmorfolin–4–il]pirimidin–2– il]fenil]urea 490 1,84 S OH O O N N N O N H N H O 3 – cyclobutyl – 1– [4– [4– (2– hydroxyethylsulfonylmethyl) –6 - [(3S) –3– methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] urea 490 1.84

59b 59b: S OH O O N N N O N H N H O N 3–(2–dimetilaminoetil)–1–[4–[4–(2– hidroxietilsulfonilmetil)–6–[(3S)–3– metilmorfolin–4–il]pirimidin–2– il]fenil]urea 507 1,61 S OH O O N N N O N H N H O N 3– (2-dimethylaminoethyl) –1– [4– [4– (2– hydroxyethylsulfonylmethyl) –6 - [(3S) –3– methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] urea 507 1.61

15 Ejemplo 59a: RMN 1H (400,13 MHz, DMSO–d6) δ 1,24–1,25 (3H, d), 1,57–1,69 (2H, m), 1,82–1,92 (2H, m), 2,18– 2,25 (2H, m), 3,18–3,27 (1H, td), 3,47–3,53 (3H, m), 3,64–3,67 (1H, dd), 3,77–3,79 (1H, d), 3,90–3,94 (2H, q), 3,97– 4,01 (1H, dd), 4,10–4,18 (2H, m), 4,47 (1H, bs), 4,50 (2H, s), 5,17–5,20 (1H, t), 6,46–6,48 (1H, d), 6,76 (1H, s), 7,47– 7,49 (2H, d), 8,20–8,22 (2H, d), 8,56 (1H, s). Example 59a: 1H NMR (400.13 MHz, DMSO-d6) δ 1.24-1.25 (3H, d), 1.57-1.69 (2H, m), 1.82-1.92 (2H, m), 2.18– 2.25 (2H, m), 3.18–3.27 (1H, td), 3.47–3.53 (3H, m), 3.64–3 , 67 (1H, dd), 3.77–3.79 (1H, d), 3.90–3.94 (2H, q), 3.97– 4.01 (1H, dd), 4.10 –4.18 (2H, m), 4.47 (1H, bs), 4.50 (2H, s), 5.17-5.20 (1H, t), 6.46-6.48 (1H , d), 6.76 (1H, s), 7.47-7.49 (2H, d), 8.20-8.22 (2H, d), 8.56 (1H, s).

Ejemplo 59b: RMN 1H (400,13 MHz, DMSO–d6) δ 1,35–1,37 (3H, d), 3,37 (6H, s), 2,56–2,59 (2H, t), 3,31–3,38 (5H, Example 59b: 1H NMR (400.13 MHz, DMSO-d6) δ 1.35-1.37 (3H, d), 3.37 (6H, s), 2.56-2.59 (2H, t) , 3.31-3.38 (5H,

20 m), 3,49 (2H, s), 3,56–3,63 (1H, td), 3,72–3,76 (1H, dd), 3,82–3,85 (1H, d), 4,03–4,07 (1H, dd), 4,14–4,17 (2H, t), 4,17–4,20 (1H, d), 4,42–4,43 (2H, d), 4,48 (1H, bs), 5,61 (1H, bs), 6,45 (1H, s), 7,46–7,48 (2H, d), 8,19–8,21 (2H, d). 20 m), 3.49 (2H, s), 3.56-3.63 (1H, td), 3.72-3.76 (1H, dd), 3.82-3.85 (1H, d ), 4.03-4.07 (1H, dd), 4.14-4.17 (2H, t), 4.17-4.20 (1H, d), 4.42-4.43 (2H , d), 4.48 (1H, bs), 5.61 (1H, bs), 6.45 (1H, s), 7.46–7.48 (2H, d), 8.19–8, 21 (2H, d).

Prueba (c): Ejemplo (59a) 0,037 μM; Ejemplo (57b) 0,043 μM. Test (c): Example (59a) 0.037 μM; Example (57b) 0.043 μM.

A continuación se describe la preparación de N–[4–[4–(2–hidroxietilsulfonilmetil)–6–[(3S)–3–metilmorfolin–4– il]pirimidin–2–il]fenil]carbamato de fenilo. The preparation of N- [4– [4– (2-hydroxyethylsulfonylmethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] carbamate phenyl is described below.

25 N–[4–[4–(2–Hidroxietilsulfonilmetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]carbamato de fenilo 25 N– [4– [4– (2 – Hydroxyethylsulfonylmethyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin – 2-yl] phenyl] phenyl carbamate

O OR

N N

N S OO N S OO

N N

OHO N OHO N

O H Or h

Se añadió cloroformiato de fenilo (0,046 ml, 0,36 mmoles) a 2–[[2–(4–aminofenil)–6–[(3S)–3–metilmorfolin–4– il]pirimidin–4–il]metilsulfonil]etanol (0,143 g, 0,36 mmoles) y bicarbonato de sodio (0,046 g, 0,55 mmoles) en dioxano (20 ml) a RT al aire. La suspensión resultante se agitó a RT durante 2 horas. Se añadió agua, y la mezcla se extrajo con DCM tres veces. Los productos orgánicos combinados se secaron (MgSO4), se filtraron y se concentraron a vacío para dar el material deseado como un sólido amarillo (0,228 g). Phenyl chloroformate (0.046 ml, 0.36 mmol) was added to 2 - [[2– (4-aminophenyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-4-yl] methylsulfonyl] ethanol (0.143 g, 0.36 mmol) and sodium bicarbonate (0.046 g, 0.55 mmol) in dioxane (20 ml) at RT in air. The resulting suspension was stirred at RT for 2 hours. Water was added, and the mixture was extracted with DCM three times. The combined organic products were dried (MgSO4), filtered and concentrated in vacuo to give the desired material as a yellow solid (0.228 g).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,24–1,26 (3H, d), 3,20–3,26 (1H, td), 3,51–3,54 (3H, m), 3,58 (1H, s), 3,64–3,68 (1H, dd), 3,77–3,80 (1H, d), 3,90–3,95 (2H, m), 3,97–4,01 (1H, dd), 4,18–4,21 (1H, d), 4,48 (1H, bs), 4,52 (2H, s), 5,18–5,20 (1H, t), 6,80 (1H, s), 7,25–7,30 (3H, m), 7,43–7,47 (2H, t), 7,63–7,65 (3H, d), 8,31–8,33 (2H, d), 10,44 (1H, s). NMR Spectrum: 1H NMR (400.13 MHz, DMSO – d6) δ 1.24–1.26 (3H, d), 3.20–3.26 (1H, td), 3.51–3.54 ( 3H, m), 3.58 (1H, s), 3.64-3.68 (1H, dd), 3.77-3.80 (1H, d), 3.90-3.95 (2H, m), 3.97-4.01 (1H, dd), 4.18-4.21 (1H, d), 4.48 (1H, bs), 4.52 (2H, s), 5.18 –5.20 (1H, t), 6.80 (1H, s), 7.25–7.30 (3H, m), 7.43–7.47 (2H, t), 7.63–7 , 65 (3H, d), 8.31-8.33 (2H, d), 10.44 (1H, s).

Espectro LCMS: MH+ 513, tiempo de retención 2,28 min. LCMS spectrum: MH + 513, retention time 2.28 min.

2–[[2–(4–Aminofenil)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–4–il]metilsulfonil]etanol 2 - [[2– (4 – Aminophenyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-4-yl] methylsulfonyl] ethanol

Se añadió trans–diclorobis(trifenilfosfina)paladio (II) (0,013 g, 0,02 mmoles) a 2–[[2–cloro–6–[(3S)–3–metilmorfolin– 4–il]pirimidin–4–il]metilsulfonil]etanol (0,122 g, 0,36 mmoles), 4–(4,4,5,5–tetrametil–1,3,2–dioxaborolan–2–il)anilina (0,119 g, 0,54 mmoles) y carbonato de sodio (0,908 ml, 1,82 mmoles) en 18% de DMF en una mezcla de DME:agua:etanol (7:3:2) (10 ml) a RT en nitrógeno. La disolución resultante se agitó a 80ºC durante 2 horas. La reacción se enfrió y se repartió entre acetato de etilo y agua. La mezcla de reacción se extrajo con acetato de etilo dos veces, y los productos orgánicos combinados se secaron (MgSO4), se filtraron y se concentraron a vacío para dar el producto deseado (0,143 g). Trans-dichlorobis (triphenylphosphine) palladium (II) (0.013 g, 0.02 mmol) was added to 2 - [[2-chloro-6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-4-yl ] methylsulfonyl] ethanol (0.122 g, 0.36 mmol), 4– (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (0.119 g, 0.54 mmol) and sodium carbonate (0.908 ml, 1.82 mmol) in 18% DMF in a mixture of DME: water: ethanol (7: 3: 2) (10 ml) at RT in nitrogen. The resulting solution was stirred at 80 ° C for 2 hours. The reaction was cooled and partitioned between ethyl acetate and water. The reaction mixture was extracted with ethyl acetate twice, and the combined organic products were dried (MgSO4), filtered and concentrated in vacuo to give the desired product (0.143 g).

Espectro LCMS: MH+ 393, tiempo de retención 1,30 min. LCMS spectrum: MH + 393, retention time 1.30 min.

2–[[2–Cloro–6–[(3S)–3–metilmorfolin–4–il]pirimidin–4–il]metilsulfonil]etanol 2 - [[2-Chloro-6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-4-yl] methylsulfonyl] ethanol

Una disolución acuosa al 30% de peróxido de hidrógeno (0,225 ml, 7,29 mmoles) se añadió a una disolución agitada de 2–cloro–4–[(3S)–3–metilmorfolin–4–il]–6–[2–(oxan–2–iloxi)etilsulfanilmetil]pirimidina (0,141 g, 0,36 mmoles), volframato de sodio dihidratado (2,4 mg, 0,0073 mmoles) en agua (0,2 ml) y ácido sulfúrico 2N (0,011 ml) en 1,4– dioxano (1,4 ml) y metanol (1,4 ml) y se calentó hasta 55ºC al aire. La disolución resultante se agitó a 55ºC durante 4 horas, después se añadió agua (50 ml), y la reacción se enfrió. Se añadió una disolución acuosa al 10% de metabisulfito de sodio y después la disolución entera se extrajo con DCM. Los productos orgánicos se secaron (MgSO4), se filtraron y se concentraron a vacío para dar el material deseado como un aceite opaco (0,198 g). A 30% aqueous solution of hydrogen peroxide (0.225 ml, 7.29 mmol) was added to a stirred solution of 2-chloro-4 - [(3S) -3-methylmorpholin-4-yl] -6– [2 - (oxan-2-yloxy) ethylsulfanylmethyl] pyrimidine (0.141 g, 0.36 mmol), sodium volframate dihydrate (2.4 mg, 0.0073 mmol) in water (0.2 ml) and 2N sulfuric acid (0.011 ml) in 1,4-dioxane (1.4 ml) and methanol (1.4 ml) and heated to 55 ° C in air. The resulting solution was stirred at 55 ° C for 4 hours, then water (50 ml) was added, and the reaction was cooled. A 10% aqueous solution of sodium metabisulfite was added and then the entire solution was extracted with DCM. The organic products were dried (MgSO4), filtered and concentrated in vacuo to give the desired material as an opaque oil (0.198 g).

Espectro LCMS: MH+ 336, tiempo de retención 1,18 min. LCMS spectrum: MH + 336, retention time 1.18 min.

2–Cloro–4–[(3S)–3–metilmorfolin–4–il]–6–[2–(oxan–2–iloxi)etilsulfanilmetil]pirimidina Se añadió gota a gota DIPEA (0,211 g, 1,63 mmoles) a 2–cloro–4–(yodometil)–6–[(3S)–3–metilmorfolin–4– il]pirimidina (0,231 g, 0,65 mmoles) y 2–(tetrahidro–2H–piran–2–iloxi)etanotiol (0,133 g, 0,82 mmoles) en acetonitrilo a RT al aire. La disolución resultante se agitó a RT durante 1 hora. El disolvente se eliminó, y la mezcla de reacción 2 – Chloro – 4 - [(3S) –3 – methylmorpholin-4-yl] –6– [2– (oxan – 2-yloxy) ethylsulfanylmethyl] pyrimidine DIPEA (0.211 g, 1.63 mmol) was added dropwise at 2-chloro-4– (iodomethyl) –6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine (0.231 g, 0.65 mmol) and 2– (tetrahydro-2H-pyran-2-yloxy) ethanothiol (0.133 g, 0.82 mmol) in acetonitrile at RT in air. The resulting solution was stirred at RT for 1 hour. The solvent was removed, and the reaction mixture

5 se diluyó con DCM y se lavó con agua. La capa orgánica se secó (MgSO4), se filtró y se evaporó para proporcionar el producto bruto. El producto bruto se purificó mediante cromatografía ultrarrápida en sílice, eluyendo con 0–2% de metanol en DCM, para dar el material deseado como un aceite incoloro (0,141 g). 5 was diluted with DCM and washed with water. The organic layer was dried (MgSO4), filtered and evaporated to provide the crude product. The crude product was purified by flash chromatography on silica, eluting with 0-2% methanol in DCM, to give the desired material as a colorless oil (0.141 g).

Espectro RMN: RMN 1H (400,13 MHz, CDCl3) δ 1,24–1,26 (3H, d), 1,40–1,55 (4H, m), 1,60–1,67 (1H, m), 1,69–1,77 (1H, m), 2,68–2,71 (2H, t), 3,17–3,24 (1H, td), 3,41–3,47 (2H, m), 3,50–3,58 (1H, m), 3,59 (2H, s), 3,62–3,63 (1H, d), NMR Spectrum: 1H NMR (400.13 MHz, CDCl3) δ 1.24-1.26 (3H, d), 1.40-1.55 (4H, m), 1.60-1.67 (1H, m), 1.69-1.77 (1H, m), 2.68-2.71 (2H, t), 3.17-3.24 (1H, td), 3.41-3.47 ( 2H, m), 3.50–3.58 (1H, m), 3.59 (2H, s), 3.62–3.63 (1H, d),

10 3,69–3,72 (1H, d), 3,76–3,86 (2H, m), 3,91–3,95 (1H, dd), 3,97 (1H, bs), 4,25 (1H, bs)< 4,52–4,54 (1H, t), 6,44 (1H, s). 10 3.69-3.72 (1H, d), 3.76-3.86 (2H, m), 3.91-3.95 (1H, dd), 3.97 (1H, bs), 4 , 25 (1H, bs) <4.52-4.54 (1H, t), 6.44 (1H, s).

Espectro LCMS: m/z (ES+) (M+H)+=386; HPLC tR=2,11 min. MH+ 386, tiempo de retención 2,11 min. LCMS spectrum: m / z (ES +) (M + H) + = 386; HPLC tR = 2.11 min. MH + 386, retention time 2.11 min.

Ejemplo 60: Example 60:

15 3–Ciclobutil–1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(propan–2–ilsulfonilmetil)pirimidin–2–il]fenil]urea 15 3 – Cyclobutyl – 1– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (propan – 2-ylsulfonylmethyl) pyrimidin – 2-yl] phenyl] urea

O OR

N N

N S N S

OO OO

N N

O OR

N N

N HH N HH

Se añadió ciclobutilamina (70 mg, 0,98 mmoles) a (4–{4–[(isopropilsulfonil)metil]–6–[(3S)–3–metilmorfolin–4– il]pirimidin–2–il}fenil)carbamato de fenilo (100 mg, 0,20 mmoles) y trietilamina (0,082 ml, 0,59 mmoles) en DMF (2 ml). La disolución resultante se agitó a 50ºC durante 2 horas. El producto bruto se purificó mediante HPLC Cyclobutylamine (70 mg, 0.98 mmol) was added to (4– {4 - [(isopropylsulfonyl) methyl] –6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-2-yl} phenyl) carbamate of phenyl (100 mg, 0.20 mmol) and triethylamine (0.082 ml, 0.59 mmol) in DMF (2 ml). The resulting solution was stirred at 50 ° C for 2 hours. The crude product was purified by HPLC

20 preparativa usando mezclas polares decrecientes de agua (que contiene 1% de NH3) y MeCN como eluyentes, para dar el material deseado como un sólido blanco (57 mg). Preparative using decreasing polar mixtures of water (containing 1% NH3) and MeCN as eluents, to give the desired material as a white solid (57 mg).

Espectro RMN: RMN 1H (400,132 MHz, DMSO–d6) δ 1,24 (3H, d), 1,35 (3H, d), 1,37 (3H, d), 1,57–1,68 (2H, m), 1,81–1,91 (2H, m), 2,18–2,25 (2H, m), 3,18–3,25 (1H, m), 3,25–3,27 (1H, m), 3,47–3,54 (2H, m), 3,65 (1H, dd), 3,78 (1H, d), 3,99 (1H, dd), 4,11–4,17 (2H, m), 4,46 (2H, s), 6,47 (1H, d), 6,77 (1H, s), 7,48 (2H, d), 8,18 (2H, d), 8,55 (1H, NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.24 (3H, d), 1.35 (3H, d), 1.37 (3H, d), 1.57–1.68 (2H , m), 1.81–1.91 (2H, m), 2.18–2.25 (2H, m), 3.18–3.25 (1H, m), 3.25–3.27 (1H, m), 3.47-3.54 (2H, m), 3.65 (1H, dd), 3.78 (1H, d), 3.99 (1H, dd), 4.11– 4.17 (2H, m), 4.46 (2H, s), 6.47 (1H, d), 6.77 (1H, s), 7.48 (2H, d), 8.18 (2H , d), 8.55 (1H,

25 s) 25 s)

Espectro LCMS: MH+ 488, tiempo de retención 1,99 min. LCMS spectrum: MH + 488, retention time 1.99 min.

Los siguientes compuestos se obtuvieron de manera análoga a partir de (4–{4–[(isopropilsulfonil)metil]–6–[(3S)–3– metilmorfolin–4–il]pirimidin–2–il}fenil)carbamato de fenilo o N–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(2–propan–2– ilsulfonilpropan–2–il)pirimidin–2–il]fenil]carbamato de fenilo y la amina apropiada. The following compounds were obtained analogously from (4– {4 - [(isopropylsulfonyl) methyl] –6 - [(3S) -3– methylmorpholin-4-yl] pyrimidin-2-yl} phenyl) phenyl carbamate or N– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (2-propan-2-ylsulfonylpropan-2-yl) pyrimidin-2-yl] phenyl] phenyl carbamate and the appropriate amine.

60a 60th: N N N O S O O N H N H O 3–[4–[4–[(3S)–3–metilmorfolin–4–il]–6– (propan–2–ilsulfonilmetil)pirimidin–2– il]fenil]–1–propil–urea 476 1,91 N N N O S O O N H N H O 3– [4– [4 - [(3S) –3 – methylmorpholin-4-yl] –6– (propan – 2-ylsulfonylmethyl) pyrimidin – 2– yl] phenyl] –1-propyl-urea 476 1.91

60b 60b: O 1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6– 490 2,10 OR 1– [4– [4 - [(3S) –3 – methylmorpholin – 4 – il] –6– 490 2.10

: (propan–2–ilsulfonilmetil)pirimidin–2– (propan – 2-ylsulfonylmethyl) pyrimidin – 2–

N N N S O O N H N H O N N N S O O N H N H O: il]fenil]–3–(2–metilpropil)urea il] phenyl] –3– (2-methylpropyl) urea

60c 60c: O 3–(3–hidroxipropil)–1–[4–[4–[(3S)–3– 492 1,45 OR 3– (3 – hydroxypropyl) –1– [4– [4 - [(3S) –3– 492 1.45

: metilmorfolin–4–il]–6–(propan–2– methylmorpholin – 4 – il] –6– (propan – 2–

N N N S O O N H N H O OH N N N S O O N H N H O OH: ilsulfonilmetil)pirimidin–2–il]fenil]urea ilsulfonylmethyl) pyrimidin-2-yl] phenyl] urea

60d 60d: O 1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6– 578 2,70 OR 1– [4– [4 - [(3S) –3 – methylmorpholin – 4 – il] –6– 578 2.70

N N N S O O N H N H O F F F N N N S O O N H N H O F F F: il]fenil]–3–[4–(trifluorometil)fenil]urea il] phenyl] –3– [4– (trifluoromethyl) phenyl] urea

60e 60e: O 1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6– 511 2,16 OR 1– [4– [4 - [(3S) –3 – methylmorpholin – 4 – il] –6– 511 2.16

N N N S O O N H N H O N N N N S O O N H N H O N: il]fenil]–3–piridin–2–il–urea il] phenyl] –3 – pyridin – 2 – il – urea

60f 60f: O 1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6– 476 2,00 OR 1– [4– [4 - [(3S) –3 – methylmorpholin – 4 – il] –6– 476 2.00

N N N S O O N H N H O N N N S O O N H N H O: il]fenil]–3–propan–2–il–urea il] phenyl] –3 – propan – 2 – il – urea

60g 60g: O 3–(1–hidroxi–2–metil–propan–2–il)–1–[4– 506 1,81 OR 3– (1 – hydroxy – 2 – methyl – propan – 2 – il) –1– [4– 506 1.81

: [4–[(3S)–3–metilmorfolin–4–il]–6–(propan– [4 - [(3S) –3 – methylmorpholin-4-yl] –6– (propan–

N N N S O O N H N H O OH N N N S O O N H N H O OH: 2–ilsulfonilmetil)pirimidin–2–il]fenil]urea 2-ylsulfonylmethyl) pyrimidin-2-yl] phenyl] urea

60h 60h: O 1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6– 514 1,71 OR 1– [4– [4 - [(3S) –3 – methylmorpholin – 4 – il] –6– 514 1.71

60i 60i: O 3–metil–1–[4–[4–[(3S)–3–metilmorfolin–4– OR 3 – methyl – 1– [4– [4 - [(3S) –3 – methylmorpholin – 4–

: il]–6–(2–propan–2–ilsulfonilpropan–2– il] –6– (2 – propan – 2 – ilsulfonylpropan – 2–

N N: il)pirimidin–2–il]fenil]urea il) pyrimidin-2-yl] phenyl] urea

N N S O O N H N H O N N S O O N H N H O: 476 1,96 476 1.96

60j 60j: O 1–etil–3–[4–[4–[(3S)–3–metilmorfolin–4– OR 1 – ethyl – 3– [4– [4 - [(3S) –3 – methylmorpholin – 4–

N N: il)pirimidin–2–il]fenil]urea il) pyrimidin-2-yl] phenyl] urea

N N S O O N H N H O N N S O O N H N H O: 490 2,14 490 2.14

60k 60k: O 1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(2– OR 1– [4– [4 - [(3S) –3 – methylmorpholin – 4 – il] –6– (2–

: propan–2–ilsulfonilpropan–2–il)pirimidin– propan – 2-ylsulfonylpropan – 2-yl) pyrimidin–

N N: 2–il]fenil]–3–propan–2–il–urea 2 – il] phenyl] –3 – propan – 2 – il – urea

N N S O O N H N H O N N S O O N H N H O: 504 2,29 504 2.29

60l 60l: N N N O S O O N H N H O 3–ciclopropil–1–[4–[4–[(3S)–3– metilmorfolin–4–il]–6–(2–propan–2– ilsulfonilpropan–2–il)pirimidin–2– il]fenil]urea 502 2,12 N N N O S O O N H N H O 3 – cyclopropyl – 1– [4– [4 - [(3S) –3– methylmorpholin-4-yl] –6– (2 – propan – 2– ylsulfonylpropan – 2-yl) pyrimidin – 2– yl] phenyl] urea 502 2.12

60m 60m: N N N O S O O N H N H O 3–ciclobutil–1–[4–[4–[(3S)–3– metilmorfolin–4–il]–6–(2–propan–2– ilsulfonilpropan–2–il)pirimidin–2– il]fenil]urea 516 2,34 N N N O S O O N H N H O 3 – cyclobutyl – 1– [4– [4 - [(3S) –3– methylmorpholin-4-yl] –6– (2 – propan – 2– ylsulfonylpropan – 2-yl) pyrimidin – 2– yl] phenyl] urea 516 2.34

60n 60n: N N N O S O O N H N H O OH 3–(2–hidroxietil)–1–[4–[4–[(3S)–3– metilmorfolin–4–il]–6–(2–propan–2– ilsulfonilpropan–2–il)pirimidin–2– il]fenil]urea 506 1,78 N N N O S O O N H N H O OH 3– (2 – hydroxyethyl) –1– [4– [4 - [(3S) –3– methylmorpholin-4-yl] –6– (2-propan – 2– ylsulfonylpropan – 2-yl) pyrimidin – 2– il ] phenyl] urea 506 1.78

60o 60o: O 3–(1–hidroxi–2–metil–propan–2–il)–1–[4– OR 3– (1 – hydroxy – 2 – methyl – propan – 2 – il) –1– [4–

: [4–[(3S)–3–metilmorfolin–4–il]–6–(2– [4 - [(3S) –3 – methylmorpholin-4-yl] –6– (2–

N N: propan–2–ilsulfonilpropan–2–il)pirimidin– propan – 2-ylsulfonylpropan – 2-yl) pyrimidin–

N N S O O N H N H O OH N N S O O N H N H O OH: 2–il]fenil]urea 534 2,07 2-yl] phenyl] urea 534 2.07

60p 60p: N N N O S O O N H N H O N 3–(2–dimetilaminoetil)–1–[4–[4–[(3S)–3– metilmorfolin–4–il]–6–(2–propan–2– ilsulfonilpropan–2–il)pirimidin–2– il]fenil]urea 533 2,07 N N N O S O O N H N H O N 3– (2 – dimethylaminoethyl) –1– [4– [4 - [(3S) –3– methylmorpholin-4-yl] –6– (2-propan – 2– ylsulfonylpropan – 2-yl) pyrimidin – 2– il ] phenyl] urea 533 2.07

60q 60q: O 3–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(2– OR 3– [4– [4 - [(3S) –3 – methylmorpholin – 4 – il] –6– (2–

N N: 2–il]fenil]–1–propil–urea 2-yl] phenyl] –1-propyl-urea

N N S O O N H N H O N N S O O N H N H O: 504 2,26 504 2.26

60r 60r: O 1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(2– OR 1– [4– [4 - [(3S) –3 – methylmorpholin – 4 – il] –6– (2–

N N: 2–il]fenil]–3–(2–metilpropil)urea 2-yl] phenyl] –3– (2-methylpropyl) urea

N N S O O N H N H O N N S O O N H N H O: 518 2,43 518 2.43

60s 60s: N N N O S O O N H N H O OH 3–(3–hidroxipropil)–1–[4–[4–[(3S)–3– metilmorfolin–4–il]–6–(2–propan–2– ilsulfonilpropan–2–il)pirimidin–2– il]fenil]urea 520 1,82 N N N O S O O N H N H O OH 3– (3 – hydroxypropyl) –1– [4– [4 - [(3S) –3– methylmorpholin-4-yl] –6– (2 – propan – 2– ylsulfonylpropan – 2 – yl) pyrimidin – 2– il ] phenyl] urea 520 1.82

60t 60t: O 1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(2– OR 1– [4– [4 - [(3S) –3 – methylmorpholin – 4 – il] –6– (2–

N N: 2–il]fenil]–3–[4–(trifluorometil)fenil]urea 2-yl] phenyl] –3– [4– (trifluoromethyl) phenyl] urea

N N S O O N H N H O F F F N N S O O N H N H O F F F: 606 2,95 606 2.95

60u 60u: O 1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(2– OR 1– [4– [4 - [(3S) –3 – methylmorpholin – 4 – il] –6– (2–

N N: 2–il]fenil]–3–piridin–2–il–urea 2-yl] phenyl] -3-pyridin-2-yl-urea

N N S O O N H N H O N N N S O O N H N H O N: 539 2,54 539 2.54

60v 60v: O 1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(2– OR 1– [4– [4 - [(3S) –3 – methylmorpholin – 4 – il] –6– (2–

N N: 2–il]fenil]–3–(1–metilpirazol–4–il)urea 2-yl] phenyl] –3– (1-methylpyrazole-4-yl) urea

N N S O O N H N H O N N N N S O O N H N H O N N: 542 1,97 542 1.97

Ejemplo 60a: RMN 1H (400,132 MHz, DMSO–d6) δ 0,89 (3H, t), 1,25 (3H, d), 1,35 (3H, d), 1,37 (3H, d), 1,43–1,49 (2H, m), 3,04–3,07 (1H, m), 3,21–3,26 (1H, m), 3,47–3,52 (2H, m), 3,64–3,67 (1H, m), 3,67–3,87 (3H, m), 3,98–4,00 (1H, m), 4,20 (1H, d), 4,47 (2H, s), 6,23 (1H, t), 6,79 (1H, s), 7,50 (2H, d), 8,18 (2H, d), 8,66 (1H, s) Example 60a: 1H NMR (400.132 MHz, DMSO-d6) δ 0.89 (3H, t), 1.25 (3H, d), 1.35 (3H, d), 1.37 (3H, d), 1.43-1.49 (2H, m), 3.04-3.07 (1H, m), 3.21-3.26 (1H, m), 3.47-3.52 (2H, m ), 3.64-3.67 (1H, m), 3.67-3.87 (3H, m), 3.98-4.00 (1H, m), 4.20 (1H, d), 4.47 (2H, s), 6.23 (1H, t), 6.79 (1H, s), 7.50 (2H, d), 8.18 (2H, d), 8.66 (1H , s)

Ejemplo 60b: RMN 1H (400,132 MHz, DMSO–d6) δ 0,89 (6H, d), 1,25 (3H, d), 1,35 (3H, d), 1,37 (3H, d), 1,71 (1H, quinteto), 2,95 (2H, t), 3,20–3,27 (1H, m), 3,47–3,54 (3H, m), 3,65 (1H, dd), 3,78 (1H, d), 3,99 (1H, dd), 4,19 (1H, d), 4,47 (2H, s), 6,27 (1H, t), 6,79 (1H, s), 7,50 (2H, d), 8,18 (2H, d), 8,66 (1H, s) Example 60b: 1H NMR (400.132 MHz, DMSO-d6) δ 0.89 (6H, d), 1.25 (3H, d), 1.35 (3H, d), 1.37 (3H, d), 1.71 (1H, quintet), 2.95 (2H, t), 3.20-3.27 (1H, m), 3.47-3.54 (3H, m), 3.65 (1H, dd), 3.78 (1H, d), 3.99 (1H, dd), 4.19 (1H, d), 4.47 (2H, s), 6.27 (1H, t), 6, 79 (1H, s), 7.50 (2H, d), 8.18 (2H, d), 8.66 (1H, s)

Ejemplo 60c: RMN 1H (400,132 MHz, DMSO–d6) δ 1,24 (3H, d), 1,35–1,37 (6H, m), 1,60 (2H, quinteto), 3,17 (2H, q), 3,21–3,25 (1H, m), 3,45–3,54 (4H, m), 3,63–3,67 (1H, m), 3,78 (1H, d), 3,97–4,00 (1H, m), 4,17 (1H, d), 4,46– 4,49 (3H, m), 6,21 (1H, t), 6,77 (1H, s), 7,49 (2H, d), 8,18 (2H, d), 8,70 (1H, s) Example 60c: 1H NMR (400.132 MHz, DMSO-d6) δ 1.24 (3H, d), 1.35-1.37 (6H, m), 1.60 (2H, quintet), 3.17 (2H , q), 3.21-3.25 (1H, m), 3.45-3.54 (4H, m), 3.63-3.67 (1H, m), 3.78 (1H, d ), 3.97-4.00 (1H, m), 4.17 (1H, d), 4.46-4.49 (3H, m), 6.21 (1H, t), 6.77 ( 1H, s), 7.49 (2H, d), 8.18 (2H, d), 8.70 (1H, s)

Ejemplo 60d: RMN 1H (400,132 MHz, DMSO–d6) δ 1,25 (3H, d), 1,36 (3H, d), 1,38 (3H, d), 3,20–3,27 (2H, m), 3,48– 3,55 (2H, m), 3,66 (1H, dd), 3,79 (1H, d), 4,00 (1H, dd), 4,19 (1H, d), 4,48 (2H, s), 6,80 (1H, s), 7,59 (2H, d), 7,64– 7,70 (4H, m), 8,27 (2H, d), 9,04 (1H, s), 9,15 (1H, s) Example 60d: 1H NMR (400.132 MHz, DMSO-d6) δ 1.25 (3H, d), 1.36 (3H, d), 1.38 (3H, d), 3.20-3.27 (2H , m), 3.48-3.55 (2H, m), 3.66 (1H, dd), 3.79 (1H, d), 4.00 (1H, dd), 4.19 (1H, d), 4.48 (2H, s), 6.80 (1H, s), 7.59 (2H, d), 7.64-7.70 (4H, m), 8.27 (2H, d ), 9.04 (1H, s), 9.15 (1H, s)

Ejemplo 60e: RMN 1H (400,132 MHz, DMSO–d6) δ 1,25 (3H, d), 1,37 (3H, d), 1,38 (3H, d), 3,20–3,24 (1H, m), 3,27 (1H, s), 3,48–3,56 (2H, m), 3,66 (1H, dd), 3,79 (1H, d), 4,00 (1H, dd), 4,19 (1H, d), 4,49 (2H, s), 6,81 (1H, s), 7,02– 7,05 (1H, m), 7,55 (1H, d), 7,65 (2H, d), 7,75–7,79 (1H, m), 8,27–8,31 (3H, m), 9,47 (1H, s), 10,63 (1H, s) Example 60e: 1H NMR (400.132 MHz, DMSO-d6) δ 1.25 (3H, d), 1.37 (3H, d), 1.38 (3H, d), 3.20-3.24 (1H , m), 3.27 (1H, s), 3.48-3.56 (2H, m), 3.66 (1H, dd), 3.79 (1H, d), 4.00 (1H, dd), 4.19 (1H, d), 4.49 (2H, s), 6.81 (1H, s), 7.02– 7.05 (1H, m), 7.55 (1H, d ), 7.65 (2H, d), 7.75–7.79 (1H, m), 8.27–8.31 (3H, m), 9.47 (1H, s), 10.63 ( 1H, s)

Ejemplo 60f: RMN 1H (400,132 MHz, DMSO–d6) δ 1,11 (6H, d), 1,24 (3H, d), 1,35 (3H, d), 1,37 (3H, d), 3,19–3,25 (2H, m), 3,47–3,54 (2H, m), 3,65 (1H, dd), 3,73–3,82 (2H, m), 3,99 (1H, dd), 4,17 (1H, d), 4,46 (2H, s), 6,07 (1H, d), 6,77 (1H, s), 7,48 (2H, d), 8,18 (2H, d), 8,52 (1H, s) Example 60f: 1H NMR (400.132 MHz, DMSO-d6) δ 1.11 (6H, d), 1.24 (3H, d), 1.35 (3H, d), 1.37 (3H, d), 3.19-3.25 (2H, m), 3.47-3.54 (2H, m), 3.65 (1H, dd), 3.73-3.82 (2H, m), 3, 99 (1H, dd), 4.17 (1H, d), 4.46 (2H, s), 6.07 (1H, d), 6.77 (1H, s), 7.48 (2H, d ), 8.18 (2H, d), 8.52 (1H, s)

Ejemplo 60g: RMN 1H (400,132 MHz, DMSO–d6) δ 1,24 (3H, d), 1,24 (6H, s), 1,35 (3H, d), 1,37 (3H, d), 3,18 (1H, d), 3,22–3,27 (1H, m), 3,39 (1H, d), 3,47–3,55 (2H, m), 3,64–3,66 (1H, m), 3,78 (1H, d), 3,98–4,00 (1H, m), 4,17 (1H, d), 4,46 (2H, s), 4,95 (1H, t), 6,01 (1H, s), 6,77 (1H, s), 7,46 (2H, d), 8,17 (2H, d), 8,73 (1H, s) Example 60g: 1H NMR (400.132 MHz, DMSO-d6) δ 1.24 (3H, d), 1.24 (6H, s), 1.35 (3H, d), 1.37 (3H, d), 3.18 (1H, d), 3.22-3.27 (1H, m), 3.39 (1H, d), 3.47-3.55 (2H, m), 3.64-3, 66 (1H, m), 3.78 (1H, d), 3.98-4.00 (1H, m), 4.17 (1H, d), 4.46 (2H, s), 4.95 (1H, t), 6.01 (1H, s), 6.77 (1H, s), 7.46 (2H, d), 8.17 (2H, d), 8.73 (1H, s)

Ejemplo 60h: RMN 1H (400,132 MHz, DMSO–d6) δ 1,25 (3H, d), 1,36 (3H, d), 1,38 (3H, d), 3,18–3,25 (2H, m), 3,48– 3,54 (2H, m), 3,66 (1H, dd), 3,78 (1H, d), 3,79 (3H, s), 3,99 (1H, dd), 4,18 (1H, d), 4,47 (2H, s), 6,78 (1H, s), 7,39 (1H, s), 7,55 (2H, d), 7,76 (1H, s), 8,22 (2H, d), 8,40 (1H, s), 8,83 (1H, s) Example 60h: 1H NMR (400.132 MHz, DMSO-d6) δ 1.25 (3H, d), 1.36 (3H, d), 1.38 (3H, d), 3.18-3.25 (2H , m), 3.48-3.54 (2H, m), 3.66 (1H, dd), 3.78 (1H, d), 3.79 (3H, s), 3.99 (1H, dd), 4.18 (1H, d), 4.47 (2H, s), 6.78 (1H, s), 7.39 (1H, s), 7.55 (2H, d), 7, 76 (1H, s), 8.22 (2H, d), 8.40 (1H, s), 8.83 (1H, s)

Ejemplo 60i: RMN 1H (400,132 MHz, DMSO–d6) δ 1,09 (3H, d), 1,12 (3H, d), 1,22 (3H, d), 1,79 (6H, d), 2,66 (3H, d), 3,16–3,24 (1H, m), 3,50 (1H, dt), 3,65 (1H, dd), 3,70–3,78 (2H, m), 3,98 (1H, dd), 4,22 (1H, d), 4,56 (1H, s), 6,06– 6,08 (1H, m), 6,78 (1H, s), 7,51 (2H, d), 8,23 (2H, d), 8,74 (1H, s) Example 60i: 1H NMR (400.132 MHz, DMSO-d6) δ 1.09 (3H, d), 1.12 (3H, d), 1.22 (3H, d), 1.79 (6H, d), 2.66 (3H, d), 3.16-3.24 (1H, m), 3.50 (1H, dt), 3.65 (1H, dd), 3.70-3.78 (2H, m), 3.98 (1H, dd), 4.22 (1H, d), 4.56 (1H, s), 6.06- 6.08 (1H, m), 6.78 (1H, s ), 7.51 (2H, d), 8.23 (2H, d), 8.74 (1H, s)

Ejemplo 60j: RMN 1H (400,132 MHz, DMSO–d6) δ 1,07 (3H, t), 1,09 (3H, d), 1,12 (3H, d), 1,22 (3H, d), 1,79 (6H, d), 3,10–3,15 (2H, m), 3,16–3,24 (1H, m), 3,50 (1H, dt), 3,65 (1H, dd), 3,70–3,78 (2H, m), 3,98 (1H, dd), 4,22 (1H, d), 4,56 (1H, s), 6,16 (1H, t), 6,78 (1H, s), 7,50 (2H, d), 8,23 (2H, d), 8,66 (1H, s) Example 60j: 1H NMR (400.132 MHz, DMSO-d6) δ 1.07 (3H, t), 1.09 (3H, d), 1.12 (3H, d), 1.22 (3H, d), 1.79 (6H, d), 3.10–3.15 (2H, m), 3.16–3.24 (1H, m), 3.50 (1H, dt), 3.65 (1H, dd), 3.70-3.78 (2H, m), 3.98 (1H, dd), 4.22 (1H, d), 4.56 (1H, s), 6.16 (1H, t ), 6.78 (1H, s), 7.50 (2H, d), 8.23 (2H, d), 8.66 (1H, s)

Ejemplo 60k: RMN 1H (400,132 MHz, DMSO–d6) δ 1,08–1,13 (12H, m), 1,22 (3H, d), 1,79 (6H, d), 3,18–3,24 (2H, m), 3,50 (1H, dt), 3,65 (1H, dd), 3,70–3,82 (2H, m), 3,98 (1H, dd), 4,22 (1H, d), 4,55 (1H, s), 6,06 (1H, d), 6,78 (1H, s), 7,49 (2H, d), 8,23 (2H, d), 8,53 (1H, s) Example 60k: 1H NMR (400.132 MHz, DMSO-d6) δ 1.08-1.13 (12H, m), 1.22 (3H, d), 1.79 (6H, d), 3.18-3 , 24 (2H, m), 3.50 (1H, dt), 3.65 (1H, dd), 3.70-3.82 (2H, m), 3.98 (1H, dd), 4, 22 (1H, d), 4.55 (1H, s), 6.06 (1H, d), 6.78 (1H, s), 7.49 (2H, d), 8.23 (2H, d ), 8.53 (1H, s)

Ejemplo 60l: RMN 1H (400,132 MHz, DMSO–d6) δ 0,33–0,37 (2H, m), 0,56–0,60 (2H, m), 1,02 (3H, d), 1,05 (3H, d), 1,15 (3H, d), 1,73 (6H, d), 2,47–2,52 (1H, m), 3,14 (1H, dt), 3,43 (1H, dt), 3,58 (1H, dd), 3,63–3,72 (2H, m), 3,89– 3,92 (1H, m), 4,16 (1H, d), 4,50 (1H, s), 6,36 (1H, d), 6,72 (1H, s), 7,44 (2H, d), 8,16 (2H, d), 8,46 (1H, s) Example 60l: 1H NMR (400.132 MHz, DMSO-d6) δ 0.33-0.37 (2H, m), 0.56-0.60 (2H, m), 1.02 (3H, d), 1 , 05 (3H, d), 1.15 (3H, d), 1.73 (6H, d), 2.47-2.52 (1H, m), 3.14 (1H, dt), 3, 43 (1H, dt), 3.58 (1H, dd), 3.63-3.72 (2H, m), 3.89- 3.92 (1H, m), 4.16 (1H, d) , 4.50 (1H, s), 6.36 (1H, d), 6.72 (1H, s), 7.44 (2H, d), 8.16 (2H, d), 8.46 ( 1H, s)

Ejemplo 60m: RMN 1H (400,132 MHz, DMSO–d6) δ 1,09 (3H, d), 1,12 (3H, d), 1,22 (3H, d), 1,57–1,66 (2H, m), 1,79 (6H, d), 1,83–1,90 (2H, m), 2,18–2,25 (2H, m), 3,20 (1H, dt), 3,50 (1H, dt), 3,65 (1H, dd), 3,70–3,78 (2H, m), 3,98 (1H, dd), 4,12–4,18 (1H, m), 4,22 (1H, d), 4,55 (1H, s), 6,46 (1H, d), 6,78 (1H, s), 7,48 (2H, d), 8,23 (2H, d), 8,56 (1H, s) Example 60m: 1H NMR (400.132 MHz, DMSO-d6) δ 1.09 (3H, d), 1.12 (3H, d), 1.22 (3H, d), 1.57-1.66 (2H , m), 1.79 (6H, d), 1.83-1.90 (2H, m), 2.18-2.25 (2H, m), 3.20 (1H, dt), 3, 50 (1H, dt), 3.65 (1H, dd), 3.70-3.78 (2H, m), 3.98 (1H, dd), 4.12-4.18 (1H, m) , 4.22 (1H, d), 4.55 (1H, s), 6.46 (1H, d), 6.78 (1H, s), 7.48 (2H, d), 8.23 ( 2H, d), 8.56 (1H, s)

Ejemplo 60n: RMN 1H (400,132 MHz, DMSO–d6) δ 1,09 (3H, d), 1,12 (3H, d), 1,22 (3H, d), 1,79 (6H, d), 3,16–3,24 (2H, m), 3,44–3,53 (3H, m), 3,65 (1H, dd), 3,70–3,78 (2H, m), 3,98 (1H, dd), 4,22 (1H, d), 4,55 (1H, s), 4,73 (1H, t), 6,26 (1H, t), 6,78 (1H, s), 7,50 (2H, d), 8,24 (2H, s), 8,80 (1H, s) Example 60n: 1H NMR (400.132 MHz, DMSO-d6) δ 1.09 (3H, d), 1.12 (3H, d), 1.22 (3H, d), 1.79 (6H, d), 3.16-3.24 (2H, m), 3.44-3.53 (3H, m), 3.65 (1H, dd), 3.70-3.78 (2H, m), 3, 98 (1H, dd), 4.22 (1H, d), 4.55 (1H, s), 4.73 (1H, t), 6.26 (1H, t), 6.78 (1H, s ), 7.50 (2H, d), 8.24 (2H, s), 8.80 (1H, s)

Ejemplo 60o: RMN 1H (400,132 MHz, DMSO–d6) δ 1,09 (3H, d), 1,13 (3H, d), 1,22 (3H, d), 1,24 (6H, s), 1,79 (6H, d), 3,17–3,24 (1H, m), 3,39 (2H, d), 3,50 (1H, dt), 3,65 (1H, dd), 3,71–3,78 (2H, m), 3,98 (1H, dd), 4,22 (1H, d), 4,56 (1H, s), 4,95 (1H, t), 6,01 (1H, s), 6,78 (1H, s), 7,46 (2H, d), 8,22 (2H, d), 8,73 (1H, s) Example 60o: 1H NMR (400.132 MHz, DMSO-d6) δ 1.09 (3H, d), 1.13 (3H, d), 1.22 (3H, d), 1.24 (6H, s), 1.79 (6H, d), 3.17-3.24 (1H, m), 3.39 (2H, d), 3.50 (1H, dt), 3.65 (1H, dd), 3 , 71–3.78 (2H, m), 3.98 (1H, dd), 4.22 (1H, d), 4.56 (1H, s), 4.95 (1H, t), 6, 01 (1H, s), 6.78 (1H, s), 7.46 (2H, d), 8.22 (2H, d), 8.73 (1H, s)

Ejemplo 60p: RMN 1H (400,132 MHz, DMSO–d6) δ 1,09 (3H, d), 1,12 (3H, d), 1,22 (3H, d), 1,79 (6H, d), 2,18 (6H, s), 2,32–2,35 (2H, m), 3,17–3,22 (3H, m), 3,50 (1H, dt), 3,66 (1H, dd), 3,70–3,78 (2H, m), 3,98 (1H, dd), 4,22 (1H, d), 4,57 (1H, s), 6,16 (1H, t), 6,78 (1H, s), 7,50 (2H, d), 8,23 (2H, d), 8,89 (1H, s) Example 60p: 1H NMR (400.132 MHz, DMSO-d6) δ 1.09 (3H, d), 1.12 (3H, d), 1.22 (3H, d), 1.79 (6H, d), 2.18 (6H, s), 2.32-2.35 (2H, m), 3.17-3.22 (3H, m), 3.50 (1H, dt), 3.66 (1H, dd), 3.70-3.78 (2H, m), 3.98 (1H, dd), 4.22 (1H, d), 4.57 (1H, s), 6.16 (1H, t ), 6.78 (1H, s), 7.50 (2H, d), 8.23 (2H, d), 8.89 (1H, s)

Ejemplo 60q: RMN 1H (400,132 MHz, DMSO–d6) δ 0,89 (3H, t), 1,09 (3H, d), 1,12 (3H, d), 1,22 (3H, d), 1,41–1,50 (2H, m), 1,79 (6H, d), 3,04–3,09 (2H, m), 3,18–3,24 (2H, m), 3,50 (1H, dt), 3,65 (1H, dd), 3,70–3,78 (1H, m), 3,98 (1H, dd), 4,22 (1H, d), 4,56 (1H, s), 6,21 (1H, t), 6,78 (1H, s), 7,50 (2H, d), 8,23 (2H, d), 8,65 (1H, s) Example 60q: 1H NMR (400.132 MHz, DMSO-d6) δ 0.89 (3H, t), 1.09 (3H, d), 1.12 (3H, d), 1.22 (3H, d), 1.41–1.50 (2H, m), 1.79 (6H, d), 3.04–3.09 (2H, m), 3.18–3.24 (2H, m), 3, 50 (1H, dt), 3.65 (1H, dd), 3.70-3.78 (1H, m), 3.98 (1H, dd), 4.22 (1H, d), 4.56 (1H, s), 6.21 (1H, t), 6.78 (1H, s), 7.50 (2H, d), 8.23 (2H, d), 8.65 (1H, s)

Ejemplo 60r: RMN 1H (400,132 MHz, DMSO–d6) δ 0,89 (6H, d), 1,09 (3H, d), 1,12 (3H, d), 1,22 (3H, d), 1,67–1,74 (1H, m), 1,79 (6H, d), 2,95 (2H, t), 3,22 (1H, dd), 3,50 (1H, dt), 3,65 (1H, dd), 3,70–3,79 (2H, m), 3,98 (1H, dd), 4,22 (1H, d), 4,55 (1H, s), 6,25 (1H, t), 6,78 (1H, s), 7,50 (2H, d), 8,23 (2H, d), 8,64 (1H, s) Example 60r: 1H NMR (400.132 MHz, DMSO-d6) δ 0.89 (6H, d), 1.09 (3H, d), 1.12 (3H, d), 1.22 (3H, d), 1.67-1.74 (1H, m), 1.79 (6H, d), 2.95 (2H, t), 3.22 (1H, dd), 3.50 (1H, dt), 3 , 65 (1H, dd), 3.70-3.79 (2H, m), 3.98 (1H, dd), 4.22 (1H, d), 4.55 (1H, s), 6, 25 (1H, t), 6.78 (1H, s), 7.50 (2H, d), 8.23 (2H, d), 8.64 (1H, s)

Ejemplo 60s: RMN 1H (400,132 MHz, DMSO–d6) δ 1,09 (3H, d), 1,12 (3H, d), 1,22 (3H, d), 1,60 (2H, quinteto), 1,79 (6H, d), 3,15–3,24 (3H, m), 3,45–3,53 (3H, m), 3,65 (1H, dd), 3,70–3,78 (2H, m), 3,98 (1H, dd), 4,22 (1H, d), 4,47 (1H, t), 4,55 (1H, s), 6,21 (1H, t), 6,78 (1H, s), 7,50 (2H, d), 8,23 (2H, d), 8,71 (1H, s) Example 60s: 1H NMR (400.132 MHz, DMSO-d6) δ 1.09 (3H, d), 1.12 (3H, d), 1.22 (3H, d), 1.60 (2H, quintet), 1.79 (6H, d), 3.15-3.24 (3H, m), 3.45-3.53 (3H, m), 3.65 (1H, dd), 3.70-3, 78 (2H, m), 3.98 (1H, dd), 4.22 (1H, d), 4.47 (1H, t), 4.55 (1H, s), 6.21 (1H, t ), 6.78 (1H, s), 7.50 (2H, d), 8.23 (2H, d), 8.71 (1H, s)

Ejemplo 60t: RMN 1H (400,132 MHz, DMSO–d6) δ 1,10 (3H, d), 1,13 (3H, d), 1,23 (3H, d), 1,81 (6H, d), 3,22–3,25 (1H, m), 3,66 (1H, dd), 3,71–3,79 (1H, m), 3,97–4,00 (2H, m), 4,04–4,08 (1H, m), 4,24 (1H, d), 4,57 (1H, s), 6,82 (1H, s), 7,59 (2H, d), 7,64–7,70 (4H, m), 8,31 (2H, d), 9,04 (1H, s), 9,14 (1H, s) Example 60t: 1H NMR (400.132 MHz, DMSO-d6) δ 1.10 (3H, d), 1.13 (3H, d), 1.23 (3H, d), 1.81 (6H, d), 3.22-3.25 (1H, m), 3.66 (1H, dd), 3.71-4.79 (1H, m), 3.97-4.00 (2H, m), 4, 04-4.08 (1H, m), 4.24 (1H, d), 4.57 (1H, s), 6.82 (1H, s), 7.59 (2H, d), 7.64 –7.70 (4H, m), 8.31 (2H, d), 9.04 (1H, s), 9.14 (1H, s)

Ejemplo 60u: RMN 1H (400,132 MHz, DMSO–d6) δ 1,10 (3H, d), 1,14 (3H, d), 1,24 (3H, d), 1,81 (6H, d), 3,18–3,27 (1H, m), 3,51 (1H, dt), 3,66 (1H, ddd), 3,73–3,80 (2H, m), 3,99 (1H, dd), 4,24 (1H, d), 4,57 (1H, s), 6,82 (1H, s), 7,02– 7,05 (1H, m), 7,57 (1H, t), 7,65 (2H, d), 7,74–7,79 (1H, m), 8,29–8,33 (3H, m), 9,45 (1H, s), 10,59 (1H, s) Example 60u: 1H NMR (400.132 MHz, DMSO-d6) δ 1.10 (3H, d), 1.14 (3H, d), 1.24 (3H, d), 1.81 (6H, d), 3.18-3.27 (1H, m), 3.51 (1H, dt), 3.66 (1H, ddd), 3.73-3.80 (2H, m), 3.99 (1H, dd), 4.24 (1H, d), 4.57 (1H, s), 6.82 (1H, s), 7.02–7.05 (1H, m), 7.57 (1H, t ), 7.65 (2H, d), 7.74–7.79 (1H, m), 8.29–8.33 (3H, m), 9.45 (1H, s), 10.59 ( 1H, s)

Ejemplo 60v: RMN 1H (400,132 MHz, DMSO–d6) δ 1,09 (3H, d), 1,13 (3H, d), 1,23 (3H, d), 1,80 (6H, d), 3,18–3,24 (2H, m), 3,51 (1H, dt), 3,64–3,68 (1H, m), 3,71–3,78 (1H, m), 3,79 (3H, s), 3,98 (1H, dd), 4,23 (1H, d), 4,56 (1H, s), 6,80 (1H, s), 7,39 (1H, s), 7,55 (2H, d), 7,76 (1H, s), 8,27 (2H, d), 8,39 (1H, s), 8,84 (1H, s) Example 60v: 1H NMR (400.132 MHz, DMSO-d6) δ 1.09 (3H, d), 1.13 (3H, d), 1.23 (3H, d), 1.80 (6H, d), 3.18-3.24 (2H, m), 3.51 (1H, dt), 3.64-3.68 (1H, m), 3.71-3.78 (1H, m), 3, 79 (3H, s), 3.98 (1H, dd), 4.23 (1H, d), 4.56 (1H, s), 6.80 (1H, s), 7.39 (1H, s ), 7.55 (2H, d), 7.76 (1H, s), 8.27 (2H, d), 8.39 (1H, s), 8.84 (1H, s)

Prueba (c): Ejemplo (60) 1,0 μM; Ejemplo (60a) 3,3 μM; Ejemplo (60b) 1,8 μM; Ejemplo (60b) 1,8 μM; Ejemplo (60c) 0,77 μM; Ejemplo (60d) 0,59 μM; Ejemplo (60e) 1,3 μM; Ejemplo (60f) 0,87 μM; Ejemplo (60g) 0,22 μM; Ejemplo (60h) 1,9 μM; Ejemplo (60i) 0,12 μM; Ejemplo (60j) 0,19 μM; Ejemplo (60k) 0,18 μM; Ejemplo (60l) 0,064 μM; Ejemplo (60m) 0,059 μM; Ejemplo (60n) 0,15 μM; Ejemplo (60o) 0,086 μM; Ejemplo (60p) 0,14 μM; Ejemplo (60q) 0,16 μM; Ejemplo (60r) 0,21 μM; Ejemplo (60s) 0,3 μM; Ejemplo (60t) 1,4 μM; Ejemplo (60u) 0,16 μM; Ejemplo (60v) 0,27μM. Test (c): Example (60) 1.0 μM; Example (60a) 3.3 μM; Example (60b) 1.8 μM; Example (60b) 1.8 μM; Example (60c) 0.77 μM; Example (60d) 0.59 μM; Example (60e) 1.3 μM; Example (60f) 0.87 μM; Example (60g) 0.22 μM; Example (60h) 1.9 μM; Example (60i) 0.12 μM; Example (60j) 0.19 μM; Example (60k) 0.18 μM; Example (60l) 0.064 μM; Example (60m) 0.059 μM; Example (60n) 0.15 μM; Example (60o) 0.086 μM; Example (60p) 0.14 μM; Example (60q) 0.16 μM; Example (60r) 0.21 μM; Example (60s) 0.3 μM; Example (60t) 1.4 μM; Example (60u) 0.16 μM; Example (60v) 0.27μM.

La preparación de (4–{4–[(isopropilsulfonil)metil]–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il}fenil)carbamato de fenilo se describió anteriormente. The preparation of phenyl (4– {4 - [(isopropylsulfonyl) methyl] –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl} phenyl) carbamate was described above.

A continuación se describe la preparación de N–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(2–propan–2–ilsulfonilpropan– 2–il)pirimidin–2–il]fenil]carbamato de fenilo. The preparation of N– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (2-propan-2-ylsulfonylpropan– 2-yl) pyrimidin-2-yl] is described below. phenyl] phenyl carbamate.

N–[4–[4–[(3S)–3–Metilmorfolin–4–il]–6–(2–propan–2–ilsulfonilpropan–2–il)pirimidin–2–il]fenil]carbamato de fenilo N– [4– [4 - [(3S) –3 – Methylmorpholin-4-yl] –6– (2-propan-2-ylsulfonylpropan-2-yl) pyrimidin-2-yl] phenyl] phenyl carbamate

Se añadió gota a gota cloroformiato de fenilo (0,42 ml, 3,34 mmoles) a 4–[4–[(3S)–3–metilmorfolin–4–il]–6–(2– propan–2–ilsulfonilpropan–2–il)pirimidin–2–il]anilina (1,4 g, 3,34 mmoles) y carbonato de sodio (0,421 g, 5,02 mmoles) en dioxano (20 ml) en nitrógeno. La suspensión resultante se agitó a RT durante 2 horas. La mezcla de reacción se evaporó hasta sequedad y se volvió a disolver en DCM (50 ml) y se lavó con agua (50 ml). La capa orgánica se secó (MgSO4), se filtró y se evaporó para dar el producto bruto el cual se trituró con éter dietílico para dar el producto deseado (1,57 g). Phenyl chloroformate (0.42 ml, 3.34 mmol) was added dropwise at 4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (2– propan – 2-ylsulfonylpropan– 2-yl) pyrimidin-2-yl] aniline (1.4 g, 3.34 mmol) and sodium carbonate (0.421 g, 5.02 mmol) in dioxane (20 ml) in nitrogen. The resulting suspension was stirred at RT for 2 hours. The reaction mixture was evaporated to dryness and re-dissolved in DCM (50 ml) and washed with water (50 ml). The organic layer was dried (MgSO4), filtered and evaporated to give the crude product which was triturated with diethyl ether to give the desired product (1.57 g).

Espectro RMN: RMN 1H (400,132 MHz, DMSO–d6) δ 1,09 (3H, d), 1,12 (3H, d), 1,23 (3H, d), 1,80 (6H, d), 3,17–3,25 (1H, m), 3,47–3,54 (1H, m), 3,66 (1H, dd), 3,72–3,79 (2H, m), 3,97–4,00 (1H, m), 4,24 (1H, d), 4,57 (1H, s), 6,82 (1H, s), 7,25 (3H, d), 7,45 (2H, t), 7,64 (2H, d), 8,34 (2H, d), 10,43 (1H, s) NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.09 (3H, d), 1.12 (3H, d), 1.23 (3H, d), 1.80 (6H, d), 3.17-3.25 (1H, m), 3.47-3.54 (1H, m), 3.66 (1H, dd), 3.72-3.79 (2H, m), 3, 97-4.00 (1H, m), 4.24 (1H, d), 4.57 (1H, s), 6.82 (1H, s), 7.25 (3H, d), 7.45 (2H, t), 7.64 (2H, d), 8.34 (2H, d), 10.43 (1H, s)

Espectro LCMS: MH+ 539, tiempo de retención 2,76 min. LCMS spectrum: MH + 539, retention time 2.76 min.

4–[4–[(3S)–3–Metilmorfolin–4–il]–6–(2–propan–2–ilsulfonilpropan–2–il)pirimidin–2–il]anilina 4– [4 - [(3S) –3 – Methylmorpholin-4-yl] –6– (2-propan – 2-ylsulfonylpropan – 2-yl) pyrimidin – 2-yl] aniline

Se añadió diclorobis(trifenilfosfina)paladio(II) (116 mg, 0,17 mmoles) a 2–cloro–4–[(3S)–3–metilmorfolin–4–il]–6–(2– propan–2–ilsulfonilpropan–2–il)pirimidina (1,2 g, 3,32 mmoles), y carbonato de sodio (5 ml, 10,00 mmoles) en 18% de DMF en una mezcla de DME:agua:etanol (7:3:2) (20 ml). La disolución resultante se agitó a 90ºC durante 4 Dichlorobis (triphenylphosphine) palladium (II) (116 mg, 0.17 mmol) was added to 2-chloro-4 - [(3S) -3-methylmorpholin-4-yl] -6- (2-propan-2-ylsulfonylpropan -2-yl) pyrimidine (1.2 g, 3.32 mmol), and sodium carbonate (5 ml, 10.00 mmol) in 18% DMF in a mixture of DME: water: ethanol (7: 3: 2) (20 ml). The resulting solution was stirred at 90 ° C for 4

horas. La mezcla de reacción se diluyó con acetato de etilo (20 ml), y se lavó con agua (2 x 20 ml). La capa orgánica se secó (MgSO4), se filtró y se evaporó para proporcionar el producto bruto. hours. The reaction mixture was diluted with ethyl acetate (20 ml), and washed with water (2 x 20 ml). The organic layer was dried (MgSO4), filtered and evaporated to provide the crude product.

El producto bruto se purificó mediante cromatografía ultrarrápida en sílice, gradiente de elución 5 a 60% de acetato de etilo en isohexano, para dar el material deseado como un sólido color crema (1,40 g). The crude product was purified by flash chromatography on silica, gradient elution 5 to 60% ethyl acetate in isohexane, to give the desired material as a cream-colored solid (1.40 g).

Espectro RMN: RMN 1H (400,132 MHz, DMSO–d6) δ 1,09 (3H, d), 1,12 (3H, d), 1,21 (3H, d), 1,77 (6H, d), 3,13–3,21 (1H, m), 3,46–3,52 (1H, m), 3,62–3,66 (1H, m), 3,69–3,77 (2H, m), 3,97 (1H, dd), 4,19 (1H, d), 4,53 (1H, d), 5,55 (2H, s), 6,61 (2H, d), 6,69 (1H, s), 8,06 (2H, d) NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.09 (3H, d), 1.12 (3H, d), 1.21 (3H, d), 1.77 (6H, d), 3.13-3.21 (1H, m), 3.46-3.52 (1H, m), 3.62-3.66 (1H, m), 3.69-3.77 (2H, m ), 3.97 (1H, dd), 4.19 (1H, d), 4.53 (1H, d), 5.55 (2H, s), 6.61 (2H, d), 6.69 (1H, s), 8.06 (2H, d)

Espectro LCMS: MH+ 419, tiempo de retención 2,11 min. LCMS spectrum: MH + 419, retention time 2.11 min.

2–Cloro–4–[(3S)–3–metilmorfolin–4–il]–6–(2–propan–2–ilsulfonilpropan–2–il)pirimidina 2 – Chloro – 4 - [(3S) –3 – methylmorpholin-4-yl] –6– (2-propan – 2-ylsulfonylpropan – 2-yl) pyrimidine

O OR

N N

NN

OO OO

S S

N Cl N Cl

Se añadió yodometano (0,23 ml, 3,75 mmoles) a terc–butóxido de sodio (360 mg, 3,75 mmoles) y (3S)–4–{2–cloro– 6–[(isopropilsulfonil)metil]pirimidin–4–il}–3–metilmorfolina (2,5 g, 7,49 mmoles) en DMF (2 ml) a –10ºC. La suspensión espesa resultante se agitó a RT durante 15 minutos para facilitar la agitación. Se añadieron nuevamente yodometano (0,23 ml, 3,75 mmoles) y terc–butóxido de sodio (360 mg, 3,75 mmoles) a la reacción, y la suspensión resultante se agitó a RT durante 15 minutos. La mezcla de reacción se diluyó con DCM (20 ml) y se lavó con agua (20 ml). La capa orgánica se secó (MgSO4), se filtró y se evaporó para proporcionar el producto bruto. El producto bruto se purificó mediante cromatografía ultrarrápida en sílice, gradiente de elución 0 a 50% de acetato de etilo en DCM, para dar el material deseado como un sólido beige (1,20 g). Iodomethane (0.23 ml, 3.75 mmol) was added to sodium tert-butoxide (360 mg, 3.75 mmol) and (3S) –4– {2-chloro– 6 - [(isopropylsulfonyl) methyl] pyrimidin –4 – il} –3 – methylmorpholine (2.5 g, 7.49 mmol) in DMF (2 ml) at –10ºC. The resulting thick suspension was stirred at RT for 15 minutes to facilitate stirring. Iodomethane (0.23 ml, 3.75 mmol) and sodium tert-butoxide (360 mg, 3.75 mmol) were added to the reaction again, and the resulting suspension was stirred at RT for 15 minutes. The reaction mixture was diluted with DCM (20 ml) and washed with water (20 ml). The organic layer was dried (MgSO4), filtered and evaporated to provide the crude product. The crude product was purified by flash chromatography on silica, gradient elution 0 to 50% ethyl acetate in DCM, to give the desired material as a beige solid (1.20 g).

Espectro RMN: RMN 1H (400,132 MHz, DMSO–d6) δ 1,11 (3H, d), 1,14 (3H, d), 1,20 (3H, d), 1,70 (6H, s), 3,16–3,24 (1H, m), 3,41–3,48 (1H, m), 3,59 (1H, dd), 3,67 (1H, q), 3,72 (1H, d), 3,94 (1H, dd), 4,06 (1H, d), 4,42 (1H, s), 6,91 (1H, s) NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.11 (3H, d), 1.14 (3H, d), 1.20 (3H, d), 1.70 (6H, s), 3.16-3.24 (1H, m), 3.41-3.48 (1H, m), 3.59 (1H, dd), 3.67 (1H, q), 3.72 (1H, d), 3.94 (1H, dd), 4.06 (1H, d), 4.42 (1H, s), 6.91 (1H, s)

Espectro LCMS: MH+ 362, tiempo de retención 2,08 min. LCMS spectrum: MH + 362, retention time 2.08 min.

La preparación de (3S)–4–{2–cloro–6–[(isopropilsulfonil)metil]pirimidin–4–il}–3–metilmorfolina se describió anteriormente. The preparation of (3S) –4– {2-chloro-6 - [(isopropylsulfonyl) methyl] pyrimidin-4-yl} -3-methylmorpholine was described above.

Example 61:

3–Ciclobutil–1–[4–[4–[(4–fluorofenil)sulfonilmetil]–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]urea 3 – Cyclobutyl – 1– [4– [4 - [(4-fluorophenyl) sulfonylmethyl] –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin – 2-yl] phenyl] urea

Se añadió ciclobutilamina (0,96 mmoles) a N–[4–[4–[(4–fluorofenil)sulfonilmetil]–6–[(3S)–3–metilmorfolin–4– il]pirimidin–2–il]fenil]carbamato de fenilo (120 mg, 0,21 mmoles) y trietilamina (0,090 ml, 0,59 mmoles) en DMF (2 ml). La disolución resultante se agitó a 50ºC durante 3 horas. El producto bruto se purificó mediante HPLC preparativa usando mezclas polares decrecientes de agua (que contiene 1% de NH3) y MeCN como eluyentes, para dar el material deseado como un sólido blanco (117 mg). Cyclobutylamine (0.96 mmol) was added to N– [4– [4 - [(4-fluorophenyl) sulfonylmethyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] phenyl carbamate (120 mg, 0.21 mmol) and triethylamine (0.090 ml, 0.59 mmol) in DMF (2 ml). The resulting solution was stirred at 50 ° C for 3 hours. The crude product was purified by preparative HPLC using decreasing polar mixtures of water (containing 1% NH3) and MeCN as eluents, to give the desired material as a white solid (117 mg).

Espectro RMN: RMN 1H (400,132 MHz, DMSO–d6) δ 1,20 (3H, d), 1,57–1,66 (2H, m), 1,81–1,91 (2H, m), 2,18–2,24 (2H, m), 3,17 (1H, dt), 3,47 (1H, dt), 3,63 (1H, dd), 3,76 (1H, d), 3,97 (1H, dd), 4,08–4,19 (2H, m), 4,38 (1H, s), 4,71 (2H, s), 6,42 (1H, d), 6,64 (1H, s), 7,36 (2H, d), 7,46 (2H, t), 7,78 (2H, d), 7,85–7,89 (2H, m), 8,53 (1H, s) NMR Spectrum: 1H NMR (400.132 MHz, DMSO – d6) δ 1.20 (3H, d), 1.57–1.66 (2H, m), 1.81–1.91 (2H, m), 2 , 18-2.24 (2H, m), 3.17 (1H, dt), 3.47 (1H, dt), 3.63 (1H, dd), 3.76 (1H, d), 3, 97 (1H, dd), 4.08-4.19 (2H, m), 4.38 (1H, s), 4.71 (2H, s), 6.42 (1H, d), 6.64 (1H, s), 7.36 (2H, d), 7.46 (2H, t), 7.78 (2H, d), 7.85–7.89 (2H, m), 8.53 ( 1H, s)

Espectro LCMS: MH+ 540, tiempo de retención 2,25 min. LCMS spectrum: MH + 540, retention time 2.25 min.

Los siguientes compuestos se obtuvieron de manera análoga a partir de N–[4–[4–[(4–fluorofenil)sulfonilmetil]–6– [(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]carbamato de fenilo o N–[4–[4–[2–(4–fluorofenil)sulfonilpropan–2–il]–6– [(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]carbamato de fenilo y la amina apropiada. The following compounds were obtained analogously from N– [4– [4 - [(4-fluorophenyl) sulfonylmethyl] –6– [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl ] phenyl carbamate or N– [4– [4– [2– (4-fluorophenyl) sulfonylpropan – 2-yl] –6– [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl ] phenyl carbamate and the appropriate amine.

61a 61a: S F O O N N N O N H N H O 1–etil–3–[4–[4–[(4– fluorofenil)sulfonilmetil]–6–[(3S)–3– metilmorfolin–4–il]pirimidin–2– il]fenil]urea 514 2,02 S F O O N N N O N H N H O 1 – ethyl – 3– [4– [4 - [(4– fluorophenyl) sulfonylmethyl] –6 - [(3S) –3– methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] urea 514 2.02

61b 61b: S F O O N N N O N H N H O 1–[4–[4–[(4–fluorofenil)sulfonilmetil]– 6–[(3S)–3–metilmorfolin–4– il]pirimidin–2–il]fenil]–3–propan–2–il– urea 528 2,17 S F O O N N N O N H N H O 1– [4– [4 - [(4-fluorophenyl) sulfonylmethyl] - 6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] –3-propan – 2-yl-urea 528 2.17

61c 61c: S F O O N N N O N H N H O OH 1–[4–[4–[(4–fluorofenil)sulfonilmetil]– 6–[(3S)–3–metilmorfolin–4– il]pirimidin–2–il]fenil]–3–(2– hidroxietil)urea 530 1,72 S F O O N N N O N H N H O OH 1– [4– [4 - [(4-fluorophenyl) sulfonylmethyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] –3– (2– hydroxyethyl) urea 530 1.72

61d 61d: F O 1–[4–[4–[(4–fluorofenil)sulfonilmetil]– 6–[(3S)–3–metilmorfolin–4– 558 1,99 F OR 1– [4– [4 - [(4 – fluorophenyl) sulfonylmethyl] - 6 - [(3S) –3 – methylmorpholin – 4– 558 1.99

: N il]pirimidin–2–il]fenil]–3–(1–hidroxi–2– N il] pyrimidin – 2-yl] phenyl] –3– (1-hydroxy – 2–

S O O S O O: N N N H N H O OH metil–propan–2–il)urea N N N H N H O OH methyl – propan – 2 – il) urea

61e 61e: S F O O N N N O N H N H O N 3–(2–dimetilaminoetil)–1–[4–[4–[(4– fluorofenil)sulfonilmetil]–6–[(3S)–3– metilmorfolin–4–il]pirimidin–2– il]fenil]urea 557 1,98 S F O O N N N O N H N H O N 3– (2-dimethylaminoethyl) –1– [4– [4 - [(4– fluorophenyl) sulfonylmethyl] –6 - [(3S) –3– methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] urea 557 1.98

61f 61f: F O 3–[4–[4–[(4–fluorofenil)sulfonilmetil]– 6–[(3S)–3–metilmorfolin–4– 528 2,18 F OR 3– [4– [4 - [(4 – fluorophenyl) sulfonylmethyl] - 6 - [(3S) –3 – methylmorpholin – 4– 528 2.18

S O O S O O: N N N N H N H O il]pirimidin–2–il]fenil]–1–propil–urea N N N N H N H O il] pyrimidin – 2-yl] phenyl] –1-propyl-urea

61g 61g: S F O O N N N O N H N H O 1–[4–[4–[(4–fluorofenil)sulfonilmetil]– 6–[(3S)–3–metilmorfolin–4– il]pirimidin–2–il]fenil]–3–(2– metilpropil)urea 542 2,34 S F O O N N N O N H N H O 1– [4– [4 - [(4-fluorophenyl) sulfonylmethyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] –3– (2– methylpropyl) urea 542 2.34

61h 61h: N N N O S N H N H O F O O OH 1–[4–[4–[(4–fluorofenil)sulfonilmetil]– 6–[(3S)–3–metilmorfolin–4– il]pirimidin–2–il]fenil]–3–(3– hidroxipropil)urea 544 1,76 N N N O S N H N H O F O O OH 1– [4– [4 - [(4-fluorophenyl) sulfonylmethyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] –3– (3– hydroxypropyl) urea 544 1.76

61i 61i: N N N O S N H N H O F O O F F F 1–[4–[4–[(4–fluorofenil)sulfonilmetil]– 6–[(3S)–3–metilmorfolin–4– il]pirimidin–2–il]fenil]–3–[4– (trifluorometil)fenil]urea 630 2,82 N N N O S N H N H O F O O F F F 1– [4– [4 - [(4-fluorophenyl) sulfonylmethyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] –3– [4– (trifluoromethyl) phenyl ]urea 630 2.82

61j 61j: N N N O S N H N H O F O O N 1–[4–[4–[(4–fluorofenil)sulfonilmetil]– 6–[(3S)–3–metilmorfolin–4– il]pirimidin–2–il]fenil]–3–piridin–2–il– urea 563 2,40 N N N O S N H N H O F O O N 1– [4– [4 - [(4-fluorophenyl) sulfonylmethyl] - 6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] –3-pyridin-2-yl-urea 563 2.40

61k 61k: O F 1–[4–[4–[2–(4– fluorofenil)sulfonilpropan–2–il]–6– 528 2,19 O F 1– [4– [4– [2– (4– fluorophenyl) sulfonylpropan – 2-yl] –6– 528 2.19

N N: [(3S)–3–metilmorfolin–4–il]pirimidin– [(3S) –3 – methylmorpholin-4-yl] pyrimidin–

N N S N H N H OO O N N S N H N H OO O: 2–il]fenil]–3–metil–urea 2-yl] phenyl] –3-methyl-urea

61l 61l: O F 1–etil–3–[4–[4–[2–(4– fluorofenil)sulfonilpropan–2–il]–6– 542 2,34 O F 1 – ethyl – 3– [4– [4– [2– (4– fluorophenyl) sulfonylpropan – 2-yl] –6– 542 2.34

N N S N H N H OO O N N S N H N H OO O: 2–il]fenil]urea 2-yl] phenyl] urea

61m 61m: O F 1–[4–[4–[2–(4– fluorofenil)sulfonilpropan–2–il]–6– 556 2,49 O F 1– [4– [4– [2– (4– fluorophenyl) sulfonylpropan – 2-yl] –6– 556 2.49

N N S N H N H OO O N N S N H N H OO O: 2–il]fenil]–3–propan–2–il–urea 2 – il] phenyl] –3 – propan – 2 – il – urea

61n 61n: O F 3–ciclobutil–1–[4–[4–[2–(4– fluorofenil)sulfonilpropan–2–il]–6– 568 2,57 O F 3 – cyclobutyl – 1– [4– [4– [2– (4– fluorophenyl) sulfonylpropan – 2-yl] –6– 568 2.57

N N S N H N H OO O N N S N H N H OO O: 2–il]fenil]urea 2-yl] phenyl] urea

61o 61o: O F 3–(2–dimetilaminoetil)–1–[4–[4–[2–(4– fluorofenil)sulfonilpropan–2–il]–6– 585 1,91 O F 3– (2-dimethylaminoethyl) –1– [4– [4– [2– (4– fluorophenyl) sulfonylpropan – 2-yl] –6– 585 1.91

N N S N H N H OO O N N N S N H N H OO O N: 2–il]fenil]urea 2-yl] phenyl] urea

61p 61p: O F 1–[4–[4–[2–(4– fluorofenil)sulfonilpropan–2–il]–6– 558 2,01 O F 1– [4– [4– [2– (4– fluorophenyl) sulfonylpropan – 2-yl] –6– 558 2.01

N N S N H N H OO O OH N N S N H N H OO O OH: 2–il]fenil]–3–(2–hidroxietil)urea 2-yl] phenyl] –3– (2-hydroxyethyl) urea

61q 61q: O F 3–ciclopropil–1–[4–[4–[2–(4– fluorofenil)sulfonilpropan–2–il]–6– 554 2,35 O F 3 – cyclopropyl – 1– [4– [4– [2– (4– fluorophenyl) sulfonylpropan – 2-yl] –6– 554 2.35

N N S N H N H OO O N N S N H N H OO O: 2–il]fenil]urea 2-yl] phenyl] urea

Ejemplo 61a: RMN 1H (400,132 MHz, DMSO–d6) δ 1,07 (3H, t), 1,20 (3H, d), 3,09–3,21 (3H, m), 3,49 (1H, dd), 3,63 (1H, dd), 3,76 (1H, d), 3,97 (1H, dd), 4,11 (1H, d), 4,37 (1H, s), 4,71 (2H, s), 6,13 (1H, t), 6,64 (1H, s), 7,38 (2H, d), 7,46 (2H, t), 7,78 (2H, d), 7,85–7,88 (2H, m), 8,64 (1H, s) Example 61a: 1H NMR (400.132 MHz, DMSO-d6) δ 1.07 (3H, t), 1.20 (3H, d), 3.09-3.21 (3H, m), 3.49 (1H , dd), 3.63 (1H, dd), 3.76 (1H, d), 3.97 (1H, dd), 4.11 (1H, d), 4.37 (1H, s), 4 , 71 (2H, s), 6.13 (1H, t), 6.64 (1H, s), 7.38 (2H, d), 7.46 (2H, t), 7.78 (2H, d), 7.85–7.88 (2H, m), 8.64 (1H, s)

5 Ejemplo 61b: RMN 1H (400,132 MHz, DMSO–d6) δ 1,11 (6H, d), 1,20 (3H, d), 3,18 (1H, dt), 3,48 (1H, dt), 3,63 (1H, dd), 3,73–3,81 (2H, m), 3,97 (1H, dd), 4,11 (1H, d), 4,38 (1H, s), 4,71 (2H, s), 6,03 (1H, d), 6,64 (1H, s), 7,36 (2H, d), 7,46 (2H, t), 7,79 (2H, d), 7,85–7,89 (2H, m), 8,51 (1H, s) 5 Example 61b: 1H NMR (400.132 MHz, DMSO-d6) δ 1.11 (6H, d), 1.20 (3H, d), 3.18 (1H, dt), 3.48 (1H, dt) , 3.63 (1H, dd), 3.73-3.81 (2H, m), 3.97 (1H, dd), 4.11 (1H, d), 4.38 (1H, s), 4.71 (2H, s), 6.03 (1H, d), 6.64 (1H, s), 7.36 (2H, d), 7.46 (2H, t), 7.79 (2H , d), 7.85–7.89 (2H, m), 8.51 (1H, s)

Ejemplo 61c: RMN 1H (400,132 MHz, DMSO–d6) δ 1,20 (3H, d), 3,13–3,21 (3H, m), 3,44–3,50 (3H, m), 3,63 (1H, dd), 3,76 (1H, d), 3,97 (1H, dd), 4,11 (1H, d), 4,37 (1H, s), 4,71–4,74 (3H, m), 6,22 (1H, t), 6,64 (1H, s), 7,38 (2H, d), Example 61c: 1H NMR (400.132 MHz, DMSO-d6) δ 1.20 (3H, d), 3.13-3.21 (3H, m), 3.44-3.50 (3H, m), 3 , 63 (1H, dd), 3.76 (1H, d), 3.97 (1H, dd), 4.11 (1H, d), 4.37 (1H, s), 4.71-4, 74 (3H, m), 6.22 (1H, t), 6.64 (1H, s), 7.38 (2H, d),

10 7,46 (2H, t), 7,79 (2H, d), 7,85–7,89 (2H, m), 8,78 (1H, s) 10 7.46 (2H, t), 7.79 (2H, d), 7.85–7.89 (2H, m), 8.78 (1H, s)

Ejemplo 61d: RMN 1H (400,132 MHz, DMSO–d6) δ 1,20 (3H, d), 1,24 (6H, s), 3,14–3,20 (2H, m), 3,39 (1H, d), 3,48 (1H, t), 3,63 (1H, d), 3,76 (1H, d), 3,97 (1H, d), 4,11 (1H, d), 4,37 (1H, s), 4,72 (2H, s), 4,95 (1H, s), 5,98 (1H, s), 6,64 (1H, s), 7,34 (2H, d), 7,46 (2H, t), 7,78 (2H, d), 7,86–7,89 (2H, m), 8,72 (1H, s) Example 61d: 1H NMR (400.132 MHz, DMSO-d6) δ 1.20 (3H, d), 1.24 (6H, s), 3.14-3.20 (2H, m), 3.39 (1H , d), 3.48 (1H, t), 3.63 (1H, d), 3.76 (1H, d), 3.97 (1H, d), 4.11 (1H, d), 4 , 37 (1H, s), 4.72 (2H, s), 4.95 (1H, s), 5.98 (1H, s), 6.64 (1H, s), 7.34 (2H, d), 7.46 (2H, t), 7.78 (2H, d), 7.86-7.89 (2H, m), 8.72 (1H, s)

Ejemplo 61e: RMN 1H (400,132 MHz, DMSO–d6) δ 1,20 (3H, d), 2,18 (6H, s), 2,34 (2H, t), 3,14–3,21 (3H, m), 3,48 Example 61e: 1H NMR (400.132 MHz, DMSO-d6) δ 1.20 (3H, d), 2.18 (6H, s), 2.34 (2H, t), 3.14–3.21 (3H , m), 3.48

15 (1H, dt), 3,63 (1H, d), 3,76 (1H, d), 3,97 (1H, d), 4,04–4,12 (1H, m), 4,37 (1H, s), 4,71 (2H, s), 6,13 (1H, t), 6,64 (1H, s), 7,37 (2H, d), 7,46 (2H, t), 7,78 (2H, d), 7,85–7,89 (2H, m), 8,86 (1H, s) 15 (1H, dt), 3.63 (1H, d), 3.76 (1H, d), 3.97 (1H, d), 4.04-4.12 (1H, m), 4.37 (1H, s), 4.71 (2H, s), 6.13 (1H, t), 6.64 (1H, s), 7.37 (2H, d), 7.46 (2H, t) , 7.78 (2H, d), 7.85–7.89 (2H, m), 8.86 (1H, s)

Ejemplo 61f: RMN 1H (400,132 MHz, DMSO–d6) δ 0,89 (3H, t), 1,20 (3H, d), 1,46 (2H, sexteto), 3,06 (2H, q), 3,17 (1H, dt), 3,48 (1H, dt), 3,63 (1H, dd), 3,76 (1H, d), 3,97 (1H, dd), 4,11 (1H, d), 4,37 (1H, s), 4,71 (2H, s), 6,17 (1H, t), 6,64 (1H, s), 7,38 (2H, d), 7,46 (2H, t), 7,79 (2H, d), 7,86–7,89 (2H, m), 8,62 (1H, s) Example 61f: 1H NMR (400.132 MHz, DMSO-d6) δ 0.89 (3H, t), 1.20 (3H, d), 1.46 (2H, sextet), 3.06 (2H, q), 3.17 (1H, dt), 3.48 (1H, dt), 3.63 (1H, dd), 3.76 (1H, d), 3.97 (1H, dd), 4.11 (1H , d), 4.37 (1H, s), 4.71 (2H, s), 6.17 (1H, t), 6.64 (1H, s), 7.38 (2H, d), 7 , 46 (2H, t), 7.79 (2H, d), 7.86-7.89 (2H, m), 8.62 (1H, s)

20 Ejemplo 61g: RMN 1H (400,132 MHz, DMSO–d6) δ 0,89 (6H, d), 1,20 (3H, d), 1,67–1,72 (1H, m), 2,94 (2H, t), 3,17 (1H, t), 3,48 (1H, t), 3,63 (1H, dd), 3,76 (1H, d), 3,97 (1H, dd), 4,11 (1H, d), 4,38 (1H, s), 4,72 (2H, s), 6,21 (1H, t), 6,65 (1H, s), 7,38 (2H, d), 7,46 (2H, t), 7,79 (2H, d), 7,85–7,89 (2H, m), 8,62 (1H, s) Example 61g: 1H NMR (400.132 MHz, DMSO-d6) δ 0.89 (6H, d), 1.20 (3H, d), 1.67-1.72 (1H, m), 2.94 ( 2H, t), 3.17 (1H, t), 3.48 (1H, t), 3.63 (1H, dd), 3.76 (1H, d), 3.97 (1H, dd), 4.11 (1H, d), 4.38 (1H, s), 4.72 (2H, s), 6.21 (1H, t), 6.65 (1H, s), 7.38 (2H , d), 7.46 (2H, t), 7.79 (2H, d), 7.85–7.89 (2H, m), 8.62 (1H, s)

Ejemplo 61h: RMN 1H (400,132 MHz, DMSO–d6) δ 1,20 (3H, d), 1,60 (2H, quinteto), 3,14–3,21 (3H, m), 3,45–3,51 (3H, m), 3,63 (1H, dd), 3,76 (1H, d), 3,97 (1H, dd), 4,11 (1H, d), 4,38 (1H, s), 4,47 (1H, t), 4,71 (2H, s), 6,17 (1H, t), Example 61h: 1H NMR (400.132 MHz, DMSO-d6) δ 1.20 (3H, d), 1.60 (2H, quintet), 3.14-3.21 (3H, m), 3.45-3 , 51 (3H, m), 3.63 (1H, dd), 3.76 (1H, d), 3.97 (1H, dd), 4.11 (1H, d), 4.38 (1H, s), 4.47 (1H, t), 4.71 (2H, s), 6.17 (1H, t),

25 6,64 (1H, s), 7,38 (2H, d), 7,46 (2H, t), 7,78 (2H, d), 7,85–7,89 (2H, m), 8,68 (1H, s) 25.64 (1H, s), 7.38 (2H, d), 7.46 (2H, t), 7.78 (2H, d), 7.85-7.89 (2H, m), 8.68 (1H, s)

Ejemplo 61i: RMN 1H (400,132 MHz, DMSO–d6) δ 9,10 (1H, s), 9,02 (1H, s), 7,86–7,89 (4H, m), 7,64–7,70 (4H, m), 7,45–7,49 (4H, m), 6,68 (1H, s), 4,73 (2H, s), 4,39 (1H, s), 4,13 (1H, d), 3,98 (1H, d), 3,77 (1H, d), 3,64 (1H, dd), 3,49 (1H, td), 3,19 (1H, td), 1,21 (3H, d) Example 61i: 1H NMR (400.132 MHz, DMSO-d6) δ 9.10 (1H, s), 9.02 (1H, s), 7.86–7.89 (4H, m), 7.64–7 , 70 (4H, m), 7.45-7.49 (4H, m), 6.68 (1H, s), 4.73 (2H, s), 4.39 (1H, s), 4, 13 (1H, d), 3.98 (1H, d), 3.77 (1H, d), 3.64 (1H, dd), 3.49 (1H, td), 3.19 (1H, td ), 1.21 (3H, d)

Ejemplo 61j: RMN 1H (400,132 MHz, DMSO–d6) δ 1,21 (3H, d), 3,19 (1H, dt), 3,50 (1H, dt), 3,64 (1H, d), 3,77 (1H, d), 3,98 (1H, d), 4,12 (1H, d), 4,39 (1H, s), 4,74 (2H, s), 6,68 (1H, s), 7,02–7,05 (1H, m), 7,45–7,59 (5H, m), 7,75– 7,79 (1H, m), 7,86–7,90 (4H, m), 8,30 (1H, d), 9,42 (1H, s), 10,52 (1H, s) Example 61j: 1H NMR (400.132 MHz, DMSO-d6) δ 1.21 (3H, d), 3.19 (1H, dt), 3.50 (1H, dt), 3.64 (1H, d), 3.77 (1H, d), 3.98 (1H, d), 4.12 (1H, d), 4.39 (1H, s), 4.74 (2H, s), 6.68 (1H , s), 7.02–7.05 (1H, m), 7.45–7.59 (5H, m), 7.75– 7.79 (1H, m), 7.86–7.90 (4H, m), 8.30 (1H, d), 9.42 (1H, s), 10.52 (1H, s)

Ejemplo 61k: RMN 1H (400,132 MHz, DMSO–d6) δ 1,27 (3H, d), 1,84 (6H, d), 2,71 (3H, d), 3,19–3,26 (1H, m), 3,52– 3,57 (1H, m), 3,70 (1H, dd), 3,82 (1H, d), 4,02 (1H, dd), 4,22 (1H, d), 4,59 (1H, s), 6,09–6,10 (1H, m), 6,73 (1H, s), 7,36 (2H, t), 7,44 (2H, d), 7,60–7,63 (2H, m), 7,83 (2H, d), 8,76 (1H, s) Example 61k: 1H NMR (400.132 MHz, DMSO-d6) δ 1.27 (3H, d), 1.84 (6H, d), 2.71 (3H, d), 3.19-3.26 (1H , m), 3.52– 3.57 (1H, m), 3.70 (1H, dd), 3.82 (1H, d), 4.02 (1H, dd), 4.22 (1H, d), 4.59 (1H, s), 6.09-6.10 (1H, m), 6.73 (1H, s), 7.36 (2H, t), 7.44 (2H, d ), 7.60–7.63 (2H, m), 7.83 (2H, d), 8.76 (1H, s)

Ejemplo 61l: RMN 1H (400,132 MHz, DMSO–d6) δ 1,07 (3H, t), 1,22 (3H, d), 1,79 (6H, d), 3,09–3,20 (3H, m), 3,50 (1H, t), 3,65 (1H, d), 3,77 (1H, d), 3,98 (1H, d), 4,17 (1H, d), 4,55 (1H, s), 6,13 (1H, t), 6,68 (1H, s), 7,31 (2H, t), 7,38 (2H, d), 7,54–7,58 (2H, m), 7,78 (2H, d), 8,62 (1H, s) Example 61l: 1H NMR (400.132 MHz, DMSO-d6) δ 1.07 (3H, t), 1.22 (3H, d), 1.79 (6H, d), 3.09-3.20 (3H , m), 3.50 (1H, t), 3.65 (1H, d), 3.77 (1H, d), 3.98 (1H, d), 4.17 (1H, d), 4 , 55 (1H, s), 6.13 (1H, t), 6.68 (1H, s), 7.31 (2H, t), 7.38 (2H, d), 7.54–7, 58 (2H, m), 7.78 (2H, d), 8.62 (1H, s)

Ejemplo 61m: RMN 1H (400,132 MHz, DMSO–d6) δ 1,11 (6H, d), 1,22 (3H, d), 1,79 (6H, d), 3,11–3,20 (1H, m), 3,50 (1H, t), 3,65 (1H, d), 3,75–3,80 (2H, m), 3,98 (1H, d), 4,17 (1H, d), 4,54 (1H, s), 6,03 (1H, d), 6,68 (1H, s), 7,31 (2H, t), 7,36 (2H, d), 7,54–7,58 (2H, m), 7,78 (2H, d), 8,50 (1H, s) Example 61m: 1H NMR (400.132 MHz, DMSO-d6) δ 1.11 (6H, d), 1.22 (3H, d), 1.79 (6H, d), 3.11-3.20 (1H , m), 3.50 (1H, t), 3.65 (1H, d), 3.75-3.80 (2H, m), 3.98 (1H, d), 4.17 (1H, d), 4.54 (1H, s), 6.03 (1H, d), 6.68 (1H, s), 7.31 (2H, t), 7.36 (2H, d), 7, 54–7.58 (2H, m), 7.78 (2H, d), 8.50 (1H, s)

Ejemplo 61n: RMN 1H (400,132 MHz, DMSO–d6) δ 1,21 (3H, d), 1,57–1,66 (2H, m), 1,78 (6H, d), 1,82–1,91 (2H, m), 2,14–2,25 (2H, m), 3,17 (1H, dt), 3,49 (1H, dt), 3,64 (1H, dd), 3,77 (1H, d), 3,97 (1H, dd), 4,09–4,18 (2H, m), 4,54 (1H, s), 6,43 (1H, d), 6,68 (1H, s), 7,31 (2H, t), 7,36 (2H, d), 7,54–7,58 (2H, m), 7,78 (2H, d), 8,53 (1H, s) Example 61n: 1H NMR (400.132 MHz, DMSO-d6) δ 1.21 (3H, d), 1.57-1.66 (2H, m), 1.78 (6H, d), 1.82-1 , 91 (2H, m), 2.14-2.25 (2H, m), 3.17 (1H, dt), 3.49 (1H, dt), 3.64 (1H, dd), 3, 77 (1H, d), 3.97 (1H, dd), 4.09-4.18 (2H, m), 4.54 (1H, s), 6.43 (1H, d), 6.68 (1H, s), 7.31 (2H, t), 7.36 (2H, d), 7.54–7.58 (2H, m), 7.78 (2H, d), 8.53 ( 1H, s)

Ejemplo 61o: RMN 1H (400,132 MHz, DMSO–d6) δ 1,22 (3H, d), 1,79 (6H, d), 2,18 (6H, s), 2,34 (2H, t), 3,13–3,21 (3H, m), 3,50 (1H, t), 3,64 (1H, d), 3,77 (1H, d), 3,98 (1H, d), 4,17 (1H, d), 4,55 (1H, s), 6,14 (1H, t), 6,67 (1H, s), 7,31 (2H, t), 7,37 (2H, d), 7,54–7,58 (2H, m), 7,78 (2H, d), 8,85 (1H, s) Example 61: 1 H NMR (400.132 MHz, DMSO-d 6) δ 1.22 (3H, d), 1.79 (6H, d), 2.18 (6H, s), 2.34 (2H, t), 3.13-3.21 (3H, m), 3.50 (1H, t), 3.64 (1H, d), 3.77 (1H, d), 3.98 (1H, d), 4 , 17 (1H, d), 4.55 (1H, s), 6.14 (1H, t), 6.67 (1H, s), 7.31 (2H, t), 7.37 (2H, d), 7.54–7.58 (2H, m), 7.78 (2H, d), 8.85 (1H, s)

Ejemplo 61p: RMN 1H (400,132 MHz, DMSO–d6) δ 1,22 (3H, d), 1,79 (6H, d), 3,14–3,21 (3H, m), 3,44–3,53 (3H, m), 3,65 (1H, dd), 3,77 (1H, d), 3,98 (1H, dd), 4,17 (1H, d), 4,55 (1H, s), 4,72 (1H, t), 6,23 (1H, t), 6,68 (1H, s), 7,31 (2H, t), 7,37 (2H, d), 7,54–7,58 (2H, m), 7,78 (2H, d), 8,77 (1H, s) Example 61p: 1H NMR (400.132 MHz, DMSO-d6) δ 1.22 (3H, d), 1.79 (6H, d), 3.14-3.21 (3H, m), 3.44-3 , 53 (3H, m), 3.65 (1H, dd), 3.77 (1H, d), 3.98 (1H, dd), 4.17 (1H, d), 4.55 (1H, s), 4.72 (1H, t), 6.23 (1H, t), 6.68 (1H, s), 7.31 (2H, t), 7.37 (2H, d), 7, 54–7.58 (2H, m), 7.78 (2H, d), 8.77 (1H, s)

Ejemplo 61q: RMN 1H (400,132 MHz, DMSO–d6) δ 0,40–0,44 (2H, m), 0,62–0,67 (2H, m), 1,22 (3H, d), 1,79 (6H, d), 2,54–2,58 (1H, m), 3,17 (1H, dt), 3,49 (1H, dt), 3,65 (1H, dd), 3,77 (1H, d), 3,97 (1H, dd), 4,17 (1H, d), 4,55 (1H, s), 6,40 (1H, d), 6,68 (1H, s), 7,31 (2H, t), 7,39 (2H, d), 7,54–7,58 (2H, m), 7,79 (2H, d), 8,50 (1H, s) Example 61q: 1H NMR (400.132 MHz, DMSO-d6) δ 0.40–0.44 (2H, m), 0.62–0.67 (2H, m), 1.22 (3H, d), 1 , 79 (6H, d), 2.54-2.58 (1H, m), 3.17 (1H, dt), 3.49 (1H, dt), 3.65 (1H, dd), 3, 77 (1H, d), 3.97 (1H, dd), 4.17 (1H, d), 4.55 (1H, s), 6.40 (1H, d), 6.68 (1H, s ), 7.31 (2H, t), 7.39 (2H, d), 7.54–7.58 (2H, m), 7.79 (2H, d), 8.50 (1H, s)

Prueba (c): Ejemplo (61) 0,33 μM; Ejemplo (61a) 0,75 μM; Ejemplo (61b) 0,038 μM; Ejemplo (61c) 0,41 μM; Ejemplo (61d) 0,18 μM; Ejemplo (61e) 0,12 μM; Ejemplo (61g) 0,45 μM; Ejemplo (61h) 0,79 μM; Ejemplo (61k) 0,12 μM; Ejemplo (61l) 0,099 μM; Ejemplo (61m) 0,03 μM; Ejemplo (61n) 0,038 μM; Ejemplo (61o) 0,045 μM; Ejemplo (61q) 0,077 μM; Test (c): Example (61) 0.33 μM; Example (61a) 0.75 μM; Example (61b) 0.038 μM; Example (61c) 0.41 μM; Example (61d) 0.18 μM; Example (61e) 0.12 μM; Example (61g) 0.45 μM; Example (61h) 0.79 μM; Example (61k) 0.12 μM; Example (61l) 0.099 μM; Example (61m) 0.03 μM; Example (61n) 0.038 μM; Example (61o) 0.045 μM; Example (61q) 0.077 μM;

A continuación se describe la preparación de N–[4–[4–[(4–fluorofenil)sulfonilmetil]–6–[(3S)–3–metilmorfolin–4– il]pirimidin–2–il]fenil]carbamato de fenilo. The preparation of N– [4– [4 - [(4-fluorophenyl) sulfonylmethyl] –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] phenyl carbamate is described below. .

N–[4–[4–[(4–Fluorofenil)sulfonilmetil]–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]carbamato de fenilo N– [4– [4 - [(4 – Fluorophenyl) sulfonylmethyl] –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin – 2-yl] phenyl] phenyl carbamate

Se añadió gota a gota cloroformiato de fenilo (0,474 ml, 3,77 mmoles) a 4–[4–[(4–fluorofenil)sulfonilmetil]–6–[(3S)– 3–metilmorfolin–4–il]pirimidin–2–il]anilina (1,67 g, 3,77 mmoles) y bicarbonato de sodio (476 mg, 5,66 mmoles) en dioxano (20 ml) en nitrógeno. La suspensión resultante se agitó a RT durante 2 horas. La mezcla de reacción se evaporó hasta sequedad y se volvió a disolver en DCM (50 ml) y se lavó con agua (50 ml). La capa orgánica se secó (MgSO4), se filtró y se evaporó para dar el producto bruto el cual se trituró con éter dietílico para dar el producto deseado (1,90 g). Phenyl chloroformate (0.474 ml, 3.77 mmol) was added dropwise to 4– [4 - [(4-fluorophenyl) sulfonylmethyl] –6 - [(3 S) - 3-methylmorpholin-4-yl] pyrimidin – 2 -Yl] aniline (1.67 g, 3.77 mmol) and sodium bicarbonate (476 mg, 5.66 mmol) in dioxane (20 ml) in nitrogen. The resulting suspension was stirred at RT for 2 hours. The reaction mixture was evaporated to dryness and re-dissolved in DCM (50 ml) and washed with water (50 ml). The organic layer was dried (MgSO4), filtered and evaporated to give the crude product which was triturated with diethyl ether to give the desired product (1.90 g).

Espectro RMN: RMN 1H (400,132 MHz, DMSO–d6) δ 1,21 (3H, d), 3,15–3,22 (1H, m), 3,35 (1H, s), 3,45–3,52 (1H, m), 3,63 (1H, dd), 3,77 (1H, d), 3,97 (1H, dd), 4,13 (1H, d), 4,39 (1H, s), 4,73 (2H, s), 6,69 (1H, s), 7,24–7,26 (2H, m), 7,43–7,48 (4H, m), 7,53 (2H, d), 7,86–7,90 (4H, m), 10,39 (1H, s) NMR Spectrum: 1H NMR (400.132 MHz, DMSO – d6) δ 1.21 (3H, d), 3.15–3.22 (1H, m), 3.35 (1H, s), 3.45–3 , 52 (1H, m), 3.63 (1H, dd), 3.77 (1H, d), 3.97 (1H, dd), 4.13 (1H, d), 4.39 (1H, s), 4.73 (2H, s), 6.69 (1H, s), 7.24–7.26 (2H, m), 7.43–7.48 (4H, m), 7.53 (2H, d), 7.86–7.90 (4H, m), 10.39 (1H, s)

Espectro LCMS: MH+ 563, tiempo de retención 2,65 min. LCMS spectrum: MH + 563, retention time 2.65 min.

4–[4–[(4–Fluorofenil)sulfonilmetil]–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]anilina 4– [4 - [(4 – Fluorophenyl) sulfonylmethyl] –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin – 2-yl] aniline

Se añadió diclorobis(trifenilfosfina)paladio(II) (136 mg, 0,19 mmoles) a 4–(4,4,5,5–tetrametil–1,3,2–dioxaborolan–2– il)anilina (1,107 g, 5,05 mmoles) y 2–cloro–4–[(4–fluorofenil)sulfonilmetil]–6–[(3S)–3–metilmorfolin–4–il]pirimidina (1,50 g, 3,89 mmoles) y carbonato de sodio (5 ml, 10,00 mmoles) en 18% de DMF en DME:agua:etanol (7:3:2) (20 ml). La disolución resultante se agitó a 90ºC durante 4 horas. La mezcla de reacción se diluyó con acetato de etilo (20 ml), y se lavó con agua (2 x 20 ml). La capa orgánica se secó (MgSO4), se filtró y se evaporó para proporcionar el producto bruto. El producto bruto se purificó mediante cromatografía ultrarrápida en sílice, gradiente de elución 5 a 60% de acetato de etilo en isohexano, para dar el material deseado como un sólido color crema (1,670 g). Dichlorobis (triphenylphosphine) palladium (II) (136 mg, 0.19 mmol) was added to 4– (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (1,107 g, 5.05 mmol) and 2-chloro-4 - [(4-fluorophenyl) sulfonylmethyl] –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidine (1.50 g, 3.89 mmol) and carbonate of sodium (5 ml, 10.00 mmol) in 18% DMF in DME: water: ethanol (7: 3: 2) (20 ml). The resulting solution was stirred at 90 ° C for 4 hours. The reaction mixture was diluted with ethyl acetate (20 ml), and washed with water (2 x 20 ml). The organic layer was dried (MgSO4), filtered and evaporated to provide the crude product. The crude product was purified by flash chromatography on silica, gradient elution 5 to 60% ethyl acetate in isohexane, to give the desired material as a cream solid (1,670 g).

Espectro RMN: RMN 1H (400,132 MHz, DMSO–d6) δ 1,18 (3H, d), 3,10–3,18 (1H, m), 3,44–3,50 (1H, m), 3,62 (1H, dd), 3,75 (1H, d), 3,96 (1H, dd), 4,07 (1H, d), 4,35 (1H, s), 4,67 (2H, s), 5,52 (2H, s), 6,49 (2H, d), 6,53 (1H, s), 7,45 (2H, t), 7,62 (2H, d), 7,84–7,88 (2H, m) NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.18 (3H, d), 3.10-3.18 (1H, m), 3.44-3.50 (1H, m), 3 , 62 (1H, dd), 3.75 (1H, d), 3.96 (1H, dd), 4.07 (1H, d), 4.35 (1H, s), 4.67 (2H, s), 5.52 (2H, s), 6.49 (2H, d), 6.53 (1H, s), 7.45 (2H, t), 7.62 (2H, d), 7, 84–7.88 (2H, m)

Espectro LCMS: MH+ 443, tiempo de retención 1,96 min. LCMS spectrum: MH + 443, retention time 1.96 min.

2–Cloro–4–[(4–fluorofenil)sulfonilmetil]–6–[(3S)–3–metilmorfolin–4–il]pirimidina 2 – Chloro – 4 - [(4 – fluorophenyl) sulfonylmethyl] –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidine

Se añadió trietilamina (1,117 ml, 8,01 mmoles) a 2,4–dicloro–6–[(4–fluorofenil)sulfonilmetil]pirimidina (2,34 g, 7,29 mmoles) en DCM (36,4 ml) a 0ºC seguido por (3S)–3–metilmorfolina (0,737 g, 7,29 mmoles) en DCM (20 ml) durante 15 minutos. La reacción se agitó después a RT durante 16 horas. La mezcla de reacción se lavó con agua (50 ml), la capa orgánica se secó (MgSO4), se filtró y se evaporó para proporcionar el producto bruto. El producto bruto se purificó mediante cromatografía ultrarrápida en sílice, gradiente de elución 0 a 50% de acetato de etilo en DCM, para dar el material deseado como un sólido beige (1,530 g). Triethylamine (1,117 ml, 8.01 mmol) was added to 2,4-dichloro-6 - [(4-fluorophenyl) sulfonylmethyl] pyrimidine (2.34 g, 7.29 mmol) in DCM (36.4 ml) at 0 ° C followed by (3S) -3-methylmorpholine (0.737 g, 7.29 mmol) in DCM (20 ml) for 15 minutes. The reaction was then stirred at RT for 16 hours. The reaction mixture was washed with water (50 ml), the organic layer was dried (MgSO4), filtered and evaporated to provide the crude product. The crude product was purified by flash chromatography on silica, gradient elution 0 to 50% ethyl acetate in DCM, to give the desired material as a beige solid (1,530 g).

Espectro RMN: RMN 1H (400,132 MHz, DMSO–d6) δ 1,17 (3H, d), 3,13–3,20 (1H, m), 3,27–3,28 (1H, m), 3,39–3,46 (1H, m), 3,57 (1H, dd), 3,72 (1H, d), 3,93 (1H, dd), 4,17 (1H, s), 4,65 (2H, s), 6,71 (1H, s), 7,48 (2H, t), 7,83–7,87 (2H, m) NMR Spectrum: 1H NMR (400.132 MHz, DMSO – d6) δ 1.17 (3H, d), 3.13–3.20 (1H, m), 3.27–3.28 (1H, m), 3 , 39–3.46 (1H, m), 3.57 (1H, dd), 3.72 (1H, d), 3.93 (1H, dd), 4.17 (1H, s), 4, 65 (2H, s), 6.71 (1H, s), 7.48 (2H, t), 7.83–7.87 (2H, m)

Espectro LCMS: MH+ 386, tiempo de retención 1,94 min. LCMS spectrum: MH + 386, retention time 1.94 min.

2,4–Dicloro–6–[(4–fluorofenil)sulfonilmetil]pirimidina 2,4-Dichloro-6 - [(4-fluorophenyl) sulfonylmethyl] pyrimidine

Cl Cl

Se añadió en porciones ácido 3–cloroperoxibenzoico (3,78 g, 21,89 mmoles) a 2,4–dicloro–6–[(4– fluorofenil)sulfanilmetil]pirimidina (2,11 g, 7,30 mmoles) en DCM (36,5 ml), y la reacción se agitó a RT durante 2 horas. La mezcla de reacción se lavó con una disolución saturada acuosa de hidrogenocarbonato de sodio (50 ml), y la capa orgánica se secó (MgSO4), se filtró y se evaporó para proporcionar el producto deseado (2,35 g). 3-Chloroperoxybenzoic acid (3.78 g, 21.89 mmol) was added portionwise to 2,4-dichloro-6 - [(4-fluorophenyl) sulfanylmethyl] pyrimidine (2.11 g, 7.30 mmol) in DCM (36.5 ml), and the reaction was stirred at RT for 2 hours. The reaction mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate (50 ml), and the organic layer was dried (MgSO4), filtered and evaporated to provide the desired product (2.35 g).

Espectro RMN: RMN 1H (400,132 MHz, DMSO–d6) δ 4,99 (2H, s), 7,48–7,52 (2H, m), 7,76 (1H, s), 7,85–7,88 (2H, m) NMR Spectrum: 1H NMR (400.132 MHz, DMSO – d6) δ 4.99 (2H, s), 7.48–7.52 (2H, m), 7.76 (1H, s), 7.85–7 , 88 (2H, m)

Espectro LCMS: MH+ 319, tiempo de retención 2,01 min. LCMS spectrum: MH + 319, retention time 2.01 min.

2,4–Dicloro–6–[(4–fluorofenil)sulfanilmetil]pirimidina 2,4-Dichloro-6 - [(4-fluorophenyl) sulfanylmethyl] pyrimidine

Cl Cl

Se añadió oxicloruro de fósforo (15,2 g, 99,1 mmoles) a 6–[(4–fluorofenil)sulfanilmetil]–1H–pirimidin–2,4–diona (2,5 g, 9,91 mmoles), y la disolución resultante se agitó a reflujo durante 7 horas. La reacción se dejó enfriar, y el oxicloruro de fósforo se eliminó a presión reducida para dar un aceite marrón. Esto se disolvió en DCM y se añadió agua con hielo (50 ml) seguido por bicarbonato de sodio sólido (hasta que se detuvo la efervescencia). La capa acuosa se extrajo con DCM (2 x 50 ml), y los productos orgánicos se secaron (MgSO4), se filtraron y se evaporaron para proporcionar el producto bruto. El producto bruto se purificó mediante cromatografía ultrarrápida en sílice, gradiente de elución 0 a 40% de acetato de etilo en isohexano, para dar el material deseado como una goma amarilla (2,11 g). Phosphorus oxychloride (15.2 g, 99.1 mmol) was added to 6 - [(4-fluorophenyl) sulfanylmethyl] -1 H -pyrimidin-2,4-dione (2.5 g, 9.91 mmol), and The resulting solution was stirred at reflux for 7 hours. The reaction was allowed to cool, and the phosphorus oxychloride was removed under reduced pressure to give a brown oil. This was dissolved in DCM and ice water (50 ml) was added followed by solid sodium bicarbonate (until the effervescence was stopped). The aqueous layer was extracted with DCM (2 x 50 ml), and the organic products were dried (MgSO4), filtered and evaporated to provide the crude product. The crude product was purified by flash chromatography on silica, gradient elution 0 to 40% ethyl acetate in isohexane, to give the desired material as a yellow gum (2.11 g).

Espectro RMN: RMN 1H (400,132 MHz, DMSO–d6) δ 4,21 (2H, s), 7,09–7,14 (2H, m), 7,34–7,38 (2H, m), 7,58 (1H, s) NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 4.21 (2H, s), 7.09–7.14 (2H, m), 7.34–7.38 (2H, m), 7 , 58 (1H, s)

Espectro LCMS: M–H+ 287, tiempo de retención 2,51 min. LCMS spectrum: M – H + 287, retention time 2.51 min.

6–[(4–Fluorofenil)sulfanilmetil]–1H–pirimidin–2,4–diona 6 - [(4 – Fluorophenyl) sulfanylmethyl] –1H – pyrimidin – 2,4 – dione

O OR

Se añadió DBU (4,02 ml, 26,91 mmoles) a 4–fluorobencenotiol (3,45 g, 26,91 mmoles), en DMF (90 ml) a RT. La disolución resultante se agitó a 20ºC durante 15 minutos. Después se añadió 6–(clorometil)–1H–pirimidin–2,4–diona (2,88 g, 17,94 mmoles), y la reacción se agitó durante 4 horas. La mezcla de reacción se concentró y se diluyó con DCM (100 ml), y se lavó con agua (100 ml). La capa acuosa se acidificó con ácido clorhídrico 2M para dar un sólido blanco que se filtró y se lavó con agua, y después se secó a vacío para dar el producto deseado (2,5 g). DBU (4.02 ml, 26.91 mmol) was added to 4-fluorobenzenethiol (3.45 g, 26.91 mmol), in DMF (90 ml) at RT. The resulting solution was stirred at 20 ° C for 15 minutes. Then 6– (chloromethyl) -1H-pyrimidin-2,4-dione (2.88 g, 17.94 mmol) was added, and the reaction was stirred for 4 hours. The reaction mixture was concentrated and diluted with DCM (100 ml), and washed with water (100 ml). The aqueous layer was acidified with 2M hydrochloric acid to give a white solid that was filtered and washed with water, and then dried under vacuum to give the desired product (2.5 g).

Espectro RMN: RMN 1H (400,132 MHz, DMSO–d6) δ 3,80 (2H, s), 5,20 (1H, s), 7,18–7,23 (2H, m), 7,45–7,49 (2H, m), 10,90 (1H, s), 10,93 (1H, s) NMR Spectrum: 1H NMR (400.132 MHz, DMSO – d6) δ 3.80 (2H, s), 5.20 (1H, s), 7.18–7.23 (2H, m), 7.45–7 , 49 (2H, m), 10.90 (1H, s), 10.93 (1H, s)

Espectro LCMS: M–H– 251, tiempo de retención 0,80 min. LCMS spectrum: M – H– 251, retention time 0.80 min.

A continuación se describe la preparación de N–[4–[4–[2–(4–fluorofenil)sulfonilpropan–2–il]–6–[(3S)–3– metilmorfolin–4–il]pirimidin–2–il]fenil]carbamato de fenilo. The preparation of N– [4– [4– [2– (4-fluorophenyl) sulfonylpropan-2-yl] –6 - [(3S) –3– methylmorpholin-4-yl] pyrimidin-2-yl is described below. ] phenyl] phenyl carbamate.

N–[4–[4–[2–(4–Fluorofenil)sulfonilpropan–2–il]–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]carbamato de fenilo N– [4– [4– [2– (4 – Fluorophenyl) sulfonylpropan – 2-yl] –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] phenyl carbamate

Se añadió gota a gota cloroformiato de fenilo (0,482 ml, 3,83 mmoles) a 4–[4–[2–(4–fluorofenil)sulfonilpropan–2–il]– 6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]anilina (1,8 g, 3,83 mmoles) y bicarbonato de sodio (0,482 g, 5,74 mmoles) en dioxano (20 ml) en nitrógeno. La suspensión resultante se agitó a RT durante 2 horas. La mezcla de reacción se evaporó hasta sequedad y se volvió a disolver en DCM (50 ml) y se lavó con agua (50 ml). La capa orgánica se secó (MgSO4), se filtró y se evaporó para dar el producto bruto el cual se trituró con éter dietílico para dar el material deseado como un sólido blanco (2,26 g). Phenyl chloroformate (0.482 ml, 3.83 mmol) was added dropwise to 4– [4– [2– (4-fluorophenyl) sulfonylpropan-2-yl] - 6 - [(3S) –3-methylmorpholin-4 -Yl] pyrimidin-2-yl] aniline (1.8 g, 3.83 mmol) and sodium bicarbonate (0.482 g, 5.74 mmol) in dioxane (20 ml) in nitrogen. The resulting suspension was stirred at RT for 2 hours. The reaction mixture was evaporated to dryness and re-dissolved in DCM (50 ml) and washed with water (50 ml). The organic layer was dried (MgSO4), filtered and evaporated to give the crude product which was triturated with diethyl ether to give the desired material as a white solid (2.26 g).

Espectro RMN: RMN 1H (400,132 MHz, DMSO–d6) δ 1,22 (3H, d), 1,80 (6H, d), 3,18 (1H, dt), 3,50 (1H, dt), 3,65 (1H, dd), 3,77 (1H, d), 3,98 (1H, dd), 4,19 (1H, d), 4,55 (1H, s), 6,72 (1H, s), 7,24–7,33 (5H, m), 7,45 (2H, t), 7,52 (2H, d), 7,55–7,58 (2H, m), 7,88 (2H, d), 10,39 (1H, s) NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.22 (3H, d), 1.80 (6H, d), 3.18 (1H, dt), 3.50 (1H, dt), 3.65 (1H, dd), 3.77 (1H, d), 3.98 (1H, dd), 4.19 (1H, d), 4.55 (1H, s), 6.72 (1H , s), 7.24-7.33 (5H, m), 7.45 (2H, t), 7.52 (2H, d), 7.55-7.58 (2H, m), 7, 88 (2H, d), 10.39 (1H, s)

Espectro LCMS: MH+ 591, tiempo de retención 3,10 min. LCMS spectrum: MH + 591, retention time 3.10 min.

30 4–[4–[2–(4–Fluorofenil)sulfonilpropan–2–il]–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]anilina 30 4– [4– [2– (4 – Fluorophenyl) sulfonylpropan – 2-yl] –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin – 2-yl] aniline

Se añadió diclorobis(trifenilfosfina)paladio(II) (170 mg, 0,24 mmoles) a 4–(4,4,5,5–tetrametil–1,3,2–dioxaborolan–2– il)anilina (1,376 g, 6,28 mmoles) y 2–cloro–4–[2–(4–fluorofenil)sulfonilpropan–2–il]–6–[(3S)–3–metilmorfolin–4– il]pirimidina (2 g, 4,83 mmoles), y carbonato de sodio (5 ml, 10,00 mmoles) en 18% de DMF en DME:agua:etanol Dichlorobis (triphenylphosphine) palladium (II) (170 mg, 0.24 mmol) was added to 4– (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (1,376 g, 6.28 mmol) and 2-chloro-4– [2– (4-fluorophenyl) sulfonylpropan-2-yl] –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidine (2 g, 4.83 mmol), and sodium carbonate (5 ml, 10.00 mmol) in 18% DMF in DME: water: ethanol

(7:3:2) (20 ml). La disolución resultante se agitó a 90ºC durante 4 horas. La mezcla de reacción se diluyó con acetato de etilo (20 ml), y se lavó con agua (2 x 20 ml). La capa orgánica se secó (MgSO4), se filtró y se evaporó para proporcionar el producto bruto. El producto bruto se purificó mediante cromatografía ultrarrápida en sílice, gradiente de elución 5 a 60% de acetato de etilo en isohexano, para dar el material deseado como un sólido color crema (1,80 g). (7: 3: 2) (20 ml). The resulting solution was stirred at 90 ° C for 4 hours. The reaction mixture was diluted with ethyl acetate (20 ml), and washed with water (2 x 20 ml). The organic layer was dried (MgSO4), filtered and evaporated to provide the crude product. The crude product was purified by flash chromatography on silica, gradient elution 5 to 60% ethyl acetate in isohexane, to give the desired material as a cream solid (1.80 g).

Espectro RMN: RMN 1H (400,132 MHz, DMSO–d6) δ 1,20 (3H, d), 1,76 (6H, d), 3,14 (1H, dt), 3,48 (1H, dt), 3,63 (1H, dd), 3,76 (1H, d), 3,96 (1H, dd), 4,13 (1H, d), 4,51 (1H, d), 5,50 (2H, s), 6,49 (2H, d), 6,58 (1H, s), 7,31 (2H, t), 7,54– 7,57 (2H, m), 7,62 (2H, d) NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.20 (3H, d), 1.76 (6H, d), 3.14 (1H, dt), 3.48 (1H, dt), 3.63 (1H, dd), 3.76 (1H, d), 3.96 (1H, dd), 4.13 (1H, d), 4.51 (1H, d), 5.50 (2H , s), 6.49 (2H, d), 6.58 (1H, s), 7.31 (2H, t), 7.54-7.57 (2H, m), 7.62 (2H, d)

Espectro LCMS: MH+ 471, tiempo de retención 2,57 min. LCMS spectrum: MH + 471, retention time 2.57 min.

2–Cloro–4–[2–(4–fluorofenil)sulfonilpropan–2–il]–6–[(3S)–3–metilmorfolin–4–il]pirimidina 2 – Chloro – 4– [2– (4 – fluorophenyl) sulfonylpropan – 2-yl] –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidine

Se añadió yodometano (0,32 ml, 5,20 mmoles) a terc–butóxido de sodio (498 mg, 5,20 mmoles) y 2–cloro–4–[(4– fluorofenil)sulfonilmetil]–6–[(3S)–3–metilmorfolin–4–il]pirimidina (2 g, 5,18 mmoles) en DMF (2 ml) a –10ºC. La suspensión espesa resultante se agitó a RT durante 15 minutos para facilitar la agitación. Se añadieron nuevamente yodometano (0,32 ml, 5,20 mmoles) y terc–butóxido de sodio (498 mg, 5,20 mmoles) a la reacción, y la suspensión resultante se agitó a RT durante 15 minutos. La mezcla de reacción se diluyó con DCM (20 ml) y se lavó con agua (20 ml). La capa orgánica se secó (MgSO4), se filtró y se evaporó para proporcionar el producto bruto. El producto bruto se purificó mediante cromatografía ultrarrápida en sílice, gradiente de elución 0 a 50% de acetato de etilo en DCM. Las fracciones puras se evaporaron hasta sequedad para dar el producto deseado como un sólido blanco (2,00 g). Iodomethane (0.32 ml, 5.20 mmol) was added to sodium tert-butoxide (498 mg, 5.20 mmol) and 2-chloro-4 - [(4– fluorophenyl) sulfonylmethyl] –6 - [(3S ) -3-methylmorpholin-4-yl] pyrimidine (2 g, 5.18 mmol) in DMF (2 ml) at -10 ° C. The resulting thick suspension was stirred at RT for 15 minutes to facilitate stirring. Iodomethane (0.32 ml, 5.20 mmol) and sodium tert-butoxide (498 mg, 5.20 mmol) were added to the reaction again, and the resulting suspension was stirred at RT for 15 minutes. The reaction mixture was diluted with DCM (20 ml) and washed with water (20 ml). The organic layer was dried (MgSO4), filtered and evaporated to provide the crude product. The crude product was purified by flash chromatography on silica, gradient elution 0 to 50% ethyl acetate in DCM. The pure fractions were evaporated to dryness to give the desired product as a white solid (2.00 g).

Espectro RMN: RMN 1H (400,132 MHz, DMSO–d6) δ 1,19 (3H, d), 1,67 (6H, d), 3,17 (1H, dt), 3,43 (1H, dt), 3,58 (1H, dd), 3,72 (1H, d), 3,93 (1H, dd), 4,01 (1H, d), 4,38 (1H, s), 6,75 (1H, s), 7,44 (2H, t), 7,58–7,61 (2H, m) NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.19 (3H, d), 1.67 (6H, d), 3.17 (1H, dt), 3.43 (1H, dt), 3.58 (1H, dd), 3.72 (1H, d), 3.93 (1H, dd), 4.01 (1H, d), 4.38 (1H, s), 6.75 (1H , s), 7.44 (2H, t), 7.58-7.61 (2H, m)

Espectro LCMS: MH+ 414, tiempo de retención 2,35 min. LCMS spectrum: MH + 414, retention time 2.35 min.

La preparación de 2–cloro–4–[(4–fluorofenil)sulfonilmetil]–6–[(3S)–3–metilmorfolin–4–il]pirimidina se describió anteriormente. The preparation of 2-chloro-4 - [(4-fluorophenyl) sulfonylmethyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine was described above.

Ejemplo 62: Example 62:

3 – Cyclopropyl – 1– [4– [4– (2-ethylsulfonylpropan – 2-yl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] urea

O OR

N N

N S OO N S OO

N N

N HH N HH

A una disolución de N–[4–[4–(2–etilsulfonilpropan–2–il)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]carbamato de fenilo (150 mg, 0,29 mmoles) en DMF (2 ml) se añadió trietilamina (0,120 ml, 0,86 mmoles) seguido por ciclopropilamina (0,100 ml, 1,44 mmoles), y la reacción se calentó a 50ºC durante 2 horas. El producto bruto se To a solution of N– [4– [4– (2-ethylsulfonylpropan-2-yl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] phenyl carbamate (150 mg, 0.29 mmol) in DMF (2 ml) triethylamine (0.115 ml, 0.86 mmol) was added followed by cyclopropylamine (0.100 ml, 1.44 mmol), and the reaction was heated at 50 ° C for 2 hours. The gross product is

5 purificó mediante HPLC preparativa usando mezclas polares decrecientes de agua (que contiene 1% de NH3) y acetonitrilo como eluyentes, para dar el material deseado como un sólido blanco (85 mg). 5 purified by preparative HPLC using decreasing polar mixtures of water (containing 1% NH3) and acetonitrile as eluents, to give the desired material as a white solid (85 mg).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 0,40–0,44 (2H, m), 0,63–0,67 (2H, m), 1,14 (3H, t), 1,23 (3H, d), 1,79 (6H, s), 2,55 (1H, m), 3,17–3,21 (1H, m), 3,23 (2H, d), 3,46–3,50 (1H, m), 3,63–3,67 (1H, m), 3,77 (1H, d), 3,96– 4,00 (1H, m), 4,23 (1H, d), 4,59 (1H, s), 6,43 (1H, d), 6,75 (1H, s), 7,51 (2H, d), 8,23 (2H, d), 8,54 (1H, s). NMR Spectrum: 1H NMR (400.13 MHz, DMSO – d6) δ 0.40–0.44 (2H, m), 0.63–0.67 (2H, m), 1.14 (3H, t) , 1.23 (3H, d), 1.79 (6H, s), 2.55 (1H, m), 3.17-3.21 (1H, m), 3.23 (2H, d), 3.46-3.50 (1H, m), 3.63-3.67 (1H, m), 3.77 (1H, d), 3.96-4.00 (1H, m), 4, 23 (1H, d), 4.59 (1H, s), 6.43 (1H, d), 6.75 (1H, s), 7.51 (2H, d), 8.23 (2H, d ), 8.54 (1H, s).

10 Espectro LCMS: MH+ 488, tiempo de retención 2,19 min. 10 LCMS spectrum: MH + 488, retention time 2.19 min.

Los siguientes compuestos se obtuvieron de manera análoga a partir de N–[4–[4–(2–etilsulfonilpropan–2–il)–6– [(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]carbamato de fenilo o N–[4–[4–(etilsulfonilmetil)–6–[(3S)–3– metilmorfolin–4–il]pirimidin–2–il]fenil]carbamato de fenilo y la amina apropiada. The following compounds were obtained analogously from N– [4– [4– (2-ethylsulfonylpropan-2-yl) –6– [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] phenyl carbamate or N– [4– [4– (ethylsulfonylmethyl) –6 - [(3S) –3– methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] phenyl carbamate and the appropriate amine.

MH+ MH +: retención retention

(min.) (min.)

62a 62a: O 1–[4–[4–(2–etilsulfonilpropan–2–il)–6– 502 2,42 OR 1– [4– [4– (2 – ethylsulfonylpropan – 2 – yl) –6– 502 2.42

62b 62b: O 1–etil–3–[4–[4–(2–etilsulfonilpropan–2– 476 2,16 OR 1 – ethyl – 3– [4– [4– (2 – ethylsulfonylpropan – 2– 476 2.16

N N N S O O N H N H O N N N S O O N H N H O: il]pirimidin–2–il]fenil]urea il] pyrimidin – 2-yl] phenyl] urea

62c 62c: N N N O S O O N H N H O N 3–(2–dimetilaminoetil)–1–[4–[4–(2– etilsulfonilpropan–2–il)–6–[(3S)–3– metilmorfolin–4–il]pirimidin–2– il]fenil]urea 519 2,10 N N N O S O O N H N H O N 3– (2-dimethylaminoethyl) –1– [4– [4– (2– ethylsulfonylpropan – 2-yl) –6 - [(3S) –3– methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] urea 519 2.10

62d 62d: O 1–[4–[4–(2–etilsulfonilpropan–2–il)–6– 492 1,83 OR 1– [4– [4– (2 – ethylsulfonylpropan – 2 – yl) –6– 492 1.83

N N N S O O N H N H O OH N N N S O O N H N H O OH: il]fenil]–3–(2–hidroxietil)urea il] phenyl] –3– (2-hydroxyethyl) urea

MH+ MH +: retención retention

(min.) (min.)

62e 62e: S O O N N N O N H N H O 3–ciclobutil–1–[4–[4–(2– etilsulfonilpropan–2–il)–6–[(3S)–3– metilmorfolin–4–il]pirimidin–2– il]fenil]urea 462 2,00 S O O N N N O N H N H O 3 – cyclobutyl – 1– [4– [4– (2– ethylsulfonylpropan – 2-yl) –6 - [(3S) –3– methylmorpholin-4-yl] pyrimidin – 2– yl] phenyl] urea 462 2.00

62f 62f: O 3–ciclobutil–1–[4–[4–(etilsulfonilmetil)– 474 2,14 OR 3 – cyclobutyl – 1– [4– [4– (ethylsulfonylmethyl) - 474 2.14

: 6–[(3S)–3–metilmorfolin–4–il]pirimidin– 6 - [(3S) –3 – methylmorpholin-4-yl] pyrimidin–

S O O S O O: N N N N H N H O 2–il]fenil]urea N N N N H N H O 2-yl] phenyl] urea

62g 62g: S O O N N N O N H N H O 1–etil–3–[4–[4–(etilsulfonilmetil)–6– [(3S)–3–metilmorfolin–4–il]pirimidin–2– il]fenil]urea 448 1,87 S O O N N N O N H N H O 1 – ethyl – 3– [4– [4– (ethylsulfonylmethyl) –6– [(3S) –3-methylmorpholin-4-yl] pyrimidin – 2– yl] phenyl] urea 448 1.87

62h 62h: S O O N N N O N H N H O N 3–(2–dimetilaminoetil)–1–[4–[4– (etilsulfonilmetil)–6–[(3S)–3– metilmorfolin–4–il]pirimidin–2– il]fenil]urea 491 1,83 S O O N N N O N H N H O N 3– (2-dimethylaminoethyl) –1– [4– [4– (ethylsulfonylmethyl) –6 - [(3S) –3– methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] urea 491 1.83

Ejemplo 62a: RMN 1H (400,13 MHz, DMSO–d6) δ 1,14 (3H, t), 1,23 (3H, d), 1,54–1,68 (2H, m), 1,78 (6H, s), 1,83 – 1,90 (2H, d), 2,18–2,25 (2H, m), 3,17–3,21 (1H, m), 3,23 (2H, q), 3,46–3,53 (1H, m), 3,63–3,66 (1H, m), 3,77 (1H, d), 3,96–4,00 (1H, m), 4,15 (1H, q), 4,22 (1H, d), 4,59 (1H, s), 6,46 (1H, d), 6,75 (1H, s), 7,48 (2H, d), 8,22 (2H, d), 8,56 Example 62a: 1H NMR (400.13 MHz, DMSO-d6) δ 1.14 (3H, t), 1.23 (3H, d), 1.54-1.68 (2H, m), 1.78 (6H, s), 1.83-1.90 (2H, d), 2.18-2.25 (2H, m), 3.17-3.21 (1H, m), 3.23 (2H , q), 3.46-3.53 (1H, m), 3.63-3.66 (1H, m), 3.77 (1H, d), 3.96-4.00 (1H, m ), 4.15 (1H, q), 4.22 (1H, d), 4.59 (1H, s), 6.46 (1H, d), 6.75 (1H, s), 7.48 (2H, d), 8.22 (2H, d), 8.56

5 (1H, s) 5 (1H, s)

Ejemplo 62b: RMN 1H (400,13 MHz, DMSO–d6) δ 1,07 (3H, t), 1,14 (3H, t), 1,23 (3H, d), 1,78 (6H, d), 3,09–3,16 (2H, m), 3,18 (1H, m), 3,22 (2H, t), 3,46–3,53 (1H, m), 3,63–3,67 (1H, m), 3,77 (1H, d), 3,96–4,00 (1H, m), 4,23 (1H, d), 4,58 (1H, s), 6,16 (1H, t), 6,75 (1H, d), 7,50 (2H, d), 8,22 (2H, d), 8,66 (1H, s) Example 62b: 1H NMR (400.13 MHz, DMSO-d6) δ 1.07 (3H, t), 1.14 (3H, t), 1.23 (3H, d), 1.78 (6H, d ), 3.09-3.16 (2H, m), 3.18 (1H, m), 3.22 (2H, t), 3.46-3.53 (1H, m), 3.63– 3.67 (1H, m), 3.77 (1H, d), 3.96-4.00 (1H, m), 4.23 (1H, d), 4.58 (1H, s), 6 , 16 (1H, t), 6.75 (1H, d), 7.50 (2H, d), 8.22 (2H, d), 8.66 (1H, s)

Ejemplo 62c: RMN 1H (400,13 MHz, DMSO–d6) δ 1,07 (3H, t), 1,14 (3H, t), 1,23 (3H, d), 1,78 (6H, d), 3,09–3,16 Example 62c: 1H NMR (400.13 MHz, DMSO-d6) δ 1.07 (3H, t), 1.14 (3H, t), 1.23 (3H, d), 1.78 (6H, d ), 3.09–3.16

10 (2H, m), 3,18 (1H, m), 3,22 (2H, t), 3,46–3,53 (1H, m), 3,63–3,67 (1H, m), 3,77 (1H, d), 3,96–4,00 (1H, m), 4,23 (1H, d), 4,58 (1H, s), 6,16 (1H, t), 6,75 (1H, d), 7,50 (2H, d), 8,22 (2H, d), 8,66 (1H, s) 10 (2H, m), 3.18 (1H, m), 3.22 (2H, t), 3.46-3.53 (1H, m), 3.63-3.67 (1H, m) , 3.77 (1H, d), 3.96-4.00 (1H, m), 4.23 (1H, d), 4.58 (1H, s), 6.16 (1H, t), 6.75 (1H, d), 7.50 (2H, d), 8.22 (2H, d), 8.66 (1H, s)

Ejemplo 62d: RMN 1H (400,13 MHz, DMSO–d6) δ 1,14 (3H, t), 1,22–1,24 (3H, m), 1,78 (6H, s), 3,17 (1H, t), 3,20– 3,22 (2H, s), 3,24 (2H, m), 3,46 (2H, q), 3,48 (1H, m), 3,63–3,66 (1H, m), 3,77 (1H, d), 3,96–4,00 (1H, m), 4,21–4,24 (1H, m), 4,57–4,60 (1H, m), 4,73 (1H, t), 6,25 (1H, t), 6,75 (1H, s), 7,48–7,51 (2H, m), 8,23 (2H, d), 8,80 (1H, s) Example 62d: 1H NMR (400.13 MHz, DMSO-d6) δ 1.14 (3H, t), 1.22-1.24 (3H, m), 1.78 (6H, s), 3.17 (1H, t), 3.20– 3.22 (2H, s), 3.24 (2H, m), 3.46 (2H, q), 3.48 (1H, m), 3.63– 3.66 (1H, m), 3.77 (1H, d), 3.96-4.00 (1H, m), 4.21-4.24 (1H, m), 4.57-4, 60 (1H, m), 4.73 (1H, t), 6.25 (1H, t), 6.75 (1H, s), 7.48-7.51 (2H, m), 8.23 (2H, d), 8.80 (1H, s)

15 Ejemplo 62e: RMN 1H (400,13 MHz, DMSO–d6) δ 1,14 (3H, t), 1,27 (3H, d), 1,78 (6H, m), 2,68 (3H, d), 3,18 (1H, m), 3,24 (2H, m), 3,46–3,53 (1H, m), 3,63–3,66 (1H, m), 3,77 (1H, d), 3,96–4,00 (1H, m), 4,23 (1H, d), 4,59 (1H, s), 6,07 (1H, t), 6,75 (1H, s), 7,51 (2H, d), 8,22 (2H, d), 8,74 (1H, s) Example 62e: 1H NMR (400.13 MHz, DMSO-d6) δ 1.14 (3H, t), 1.27 (3H, d), 1.78 (6H, m), 2.68 (3H, d), 3.18 (1H, m), 3.24 (2H, m), 3.46-3.53 (1H, m), 3.63-3.66 (1H, m), 3.77 (1H, d), 3.96-4.00 (1H, m), 4.23 (1H, d), 4.59 (1H, s), 6.07 (1H, t), 6.75 ( 1H, s), 7.51 (2H, d), 8.22 (2H, d), 8.74 (1H, s)

Ejemplo 62f: RMN 1H (400,13 MHz, DMSO–d6) δ 1,23–1,25 (3H, m), 1,35 (3H, t), 1,59–1,66 (2H, m), 1,83–1,86 (2H, m), 2,19–2,23 (2H, m), 3,18 (1H, m), 3,33 (2H, m), 3,47–3,50 (1H, m), 3,66 (1H, d), 3,76–3,79 (1H, m), 3,96 (1H, d), Example 62f: 1H NMR (400.13 MHz, DMSO-d6) δ 1.23-1.25 (3H, m), 1.35 (3H, t), 1.59-1.66 (2H, m) , 1.83–1.86 (2H, m), 2.19–2.23 (2H, m), 3.18 (1H, m), 3.33 (2H, m), 3.47–3 , 50 (1H, m), 3.66 (1H, d), 3.76-3.79 (1H, m), 3.96 (1H, d),

20 4,14 (2H, d), 4,45 (3H, m), 6,47 (1H, d), 6,78 (1H, s), 7,47–7,49 (2H, m), 8,18–8,20 (2H, m), 8,56 (1H, s) 20 4.14 (2H, d), 4.45 (3H, m), 6.47 (1H, d), 6.78 (1H, s), 7.47-7.49 (2H, m), 8.18–8.20 (2H, m), 8.56 (1H, s)

Ejemplo 62g: RMN 1H (400,13 MHz, DMSO–d6) δ 1,07 (3H, t), 1,24 (3H, d), 1,35 (3H, t), 3,09–3,16 (2H, m), 3,21– 3,26 (1H, m), 3,33 (2H, d), 3,47–3,53 (1H, m), 3,63–3,67 (1H, m), 3,78 (1H, d), 3,97–4,01 (1H, m), 4,14 (1H, d), 4,45 (3H, s), 6,17 (1H, t), 6,77 (1H, s), 7,48–7,51 (2H, m), 8,18–8,20 (2H, m), 8,66 (1H, s) Example 62g: 1H NMR (400.13 MHz, DMSO-d6) δ 1.07 (3H, t), 1.24 (3H, d), 1.35 (3H, t), 3.09-3.16 (2H, m), 3.21-3.26 (1H, m), 3.33 (2H, d), 3.47-3.53 (1H, m), 3.63-3.67 (1H , m), 3.78 (1H, d), 3.97-4.01 (1H, m), 4.14 (1H, d), 4.45 (3H, s), 6.17 (1H, t), 6.77 (1H, s), 7.48–7.51 (2H, m), 8.18–8.20 (2H, m), 8.66 (1H, s)

Ejemplo 62h: RMN 1H (400,13 MHz, DMSO–d6) δ 1,23–1,25 (3H, m), 1,35 (3H, t), 2,18 (6H, s), 2,34 (2H, t), 3,20 (3H, q), 3,33 (2H, d), 3,47–3,53 (1H, m), 3,63–3,67 (1H, m), 3,78 (1H, d), 3,97–4,01 (1H, m), 4,14 (1H, d), 4,45 (3H, s), 6,16 (1H, t), 6,77 (1H, s), 7,47–7,51 (2H, m), 8,18–8,20 (2H, m), 8,89 (1H, s) Example 62h: 1H NMR (400.13 MHz, DMSO-d6) δ 1.23-1.25 (3H, m), 1.35 (3H, t), 2.18 (6H, s), 2.34 (2H, t), 3.20 (3H, q), 3.33 (2H, d), 3.47-3.53 (1H, m), 3.63-3.67 (1H, m), 3.78 (1H, d), 3.97-4.01 (1H, m), 4.14 (1H, d), 4.45 (3H, s), 6.16 (1H, t), 6 , 77 (1H, s), 7.47–7.51 (2H, m), 8.18–8.20 (2H, m), 8.89 (1H, s)

A continuación se describe la preparación de N–[4–[4–(2–etilsulfonilpropan–2–il)–6–[(3S)–3–metilmorfolin–4– il]pirimidin–2–il]fenil]carbamato de fenilo. The preparation of N– [4– [4– (2-ethylsulfonylpropan – 2-yl) –6 - [(3S) –3-methylmorpholin-4– yl] pyrimidin-2-yl] phenyl] carbamate of phenyl.

N–[4–[4–(2–Etilsulfonilpropan–2–il)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]carbamato de fenilo N– [4– [4– (2-Ethylsulfonylpropan-2-yl) –6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] phenyl carbamate

Se añadió gota a gota cloroformiato de fenilo (0,373 ml, 2,97 mmoles) a 4–[4–(2–etilsulfonilpropan–2–il)–6–[(3S)–3– metilmorfolin–4–il]pirimidin–2–il]anilina (1,20 g, 2,97 mmoles) y bicarbonato de sodio (0,374 g, 4,45 mmoles) en dioxano (25 ml) en nitrógeno. La suspensión resultante se agitó a RT durante 2 horas. La mezcla de reacción se evaporó hasta sequedad y se repartió entre acetato de etilo (150 ml) y agua (150 ml). La capa orgánica se secó (MgSO4), se filtró y se evaporó para dar el material deseado como un sólido blanco (1,40 g). Phenyl chloroformate (0.373 ml, 2.97 mmol) was added dropwise to 4– [4– (2-ethylsulfonylpropan-2-yl) –6 - [(3S) –3– methylmorpholin-4-yl] pyrimidin– 2-yl] aniline (1.20 g, 2.97 mmol) and sodium bicarbonate (0.374 g, 4.45 mmol) in dioxane (25 ml) in nitrogen. The resulting suspension was stirred at RT for 2 hours. The reaction mixture was evaporated to dryness and partitioned between ethyl acetate (150 ml) and water (150 ml). The organic layer was dried (MgSO4), filtered and evaporated to give the desired material as a white solid (1.40 g).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,14 (3H, t), 1,24 (3H, d), 1,79 (6H, d), 3,24 (3H, q), 3,47–3,54 (1H, m), 3,63–3,67 (1H, m), 3,77 (1H, d), 3,96–4,00 (1H, m), 4,24 (1H, d), 4,60 (1H, s), 6,74–6,79 (2H, m), 7,24–7,27 (2H, m), 7,43–7,47 (2H, m), 7,61–7,64 (2H, m), 8,33 (2H, d), 10,43 (1H, s) NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.14 (3H, t), 1.24 (3H, d), 1.79 (6H, d), 3.24 (3H, q ), 3.47-3.54 (1H, m), 3.63-3.67 (1H, m), 3.77 (1H, d), 3.96-4.00 (1H, m), 4.24 (1H, d), 4.60 (1H, s), 6.74–6.79 (2H, m), 7.24–7.27 (2H, m), 7.43–7, 47 (2H, m), 7.61–7.64 (2H, m), 8.33 (2H, d), 10.43 (1H, s)

Espectro LCMS: MH+ 525, tiempo de retención 2,84 min. LCMS spectrum: MH + 525, retention time 2.84 min.

4–[4–(2–Etilsulfonilpropan–2–il)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]anilina 4– [4– (2 – Ethylsulfonylpropan – 2-yl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin – 2-yl] aniline

Se añadió diclorobis(trifenilfosfina)paladio(II) (0,360 g, 0,51 mmoles) a una disolución desgasificada de 2–cloro–4– (2–etilsulfonilpropan–2–il)–6–[(3S)–3–metilmorfolin–4–il]pirimidina (1,784 g, 5,13 mmoles), 4–(4,4,5,5–tetrametil– 1,3,2–dioxaborolan–2–il)anilina (1,404 g, 6,41 mmoles) y carbonato de sodio (12,82 ml, 25,64 mmoles) en una mezcla de 18% de DMF en DME:agua:etanol (7:3:2) (25 ml). La disolución resultante se agitó a 85ºC durante 2 horas. La mezcla de reacción se concentró y se repartió entre DCM (150 ml) y agua (100 ml), y los productos orgánicos se lavaron con salmuera (100 ml), se secaron (MgSO4), se filtraron y se evaporaron para proporcionar el producto bruto. El producto bruto se purificó mediante cromatografía ultrarrápida en sílice, gradiente de elución 0 a 2,5% de metanol en DCM, para dar el material deseado como un sólido marrón (1,20 g). Dichlorobis (triphenylphosphine) palladium (II) (0.360 g, 0.51 mmol) was added to a degassed solution of 2-chloro-4- (2-ethylsulfonylpropan-2-yl) -6 - [(3S) -3-methylmorpholin -4-yl] pyrimidine (1,784 g, 5.13 mmol), 4– (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl) aniline (1,404 g, 6.41 mmol ) and sodium carbonate (12.82 ml, 25.64 mmol) in a mixture of 18% DMF in DME: water: ethanol (7: 3: 2) (25 ml). The resulting solution was stirred at 85 ° C for 2 hours. The reaction mixture was concentrated and partitioned between DCM (150 ml) and water (100 ml), and the organic products were washed with brine (100 ml), dried (MgSO4), filtered and evaporated to provide the product. stupid. The crude product was purified by flash chromatography on silica, gradient elution 0 to 2.5% methanol in DCM, to give the desired material as a brown solid (1.20 g).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,13 (3H, t), 1,21 (3H, d), 1,76 (6H, d), 3,14–3,18 (1H, m), 3,23 (2H, q), 3,45–3,52 (1H, m), 3,62–3,65 (1H, m), 3,76 (1H, d), 3,95–3,99 (1H, m), 4,17–4,21 (1H, m), 4,54–4,56 (1H, m), 5,54 (2H, d), 6,61 (1H, d), 6,62 (2H, t), 8,06 (2H, d) NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.13 (3H, t), 1.21 (3H, d), 1.76 (6H, d), 3.14–3.18 (1H, m), 3.23 (2H, q), 3.45-3.52 (1H, m), 3.62-3.65 (1H, m), 3.76 (1H, d), 3.95-3.99 (1H, m), 4.17-4.21 (1H, m), 4.54-4.56 (1H, m), 5.54 (2H, d), 6, 61 (1H, d), 6.62 (2H, t), 8.06 (2H, d)

Espectro LCMS: MH+ 405, tiempo de retención 2,14 min. LCMS spectrum: MH + 405, retention time 2.14 min.

2–Cloro–4–(2–etilsulfonilpropan–2–il)–6–[(3S)–3–metilmorfolin–4–il]pirimidina 2 – Chloro – 4– (2 – ethylsulfonylpropan – 2 – yl) –6 - [(3S) –3 – methylmorpholin-4-yl] pyrimidine

Se añadió yodometano (0,321 ml, 5,13 mmoles) a terc–butóxido de sodio (0,493 g, 5,13 mmoles) y 2–cloro–4– (etilsulfonilmetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidina (1,64 g, 5,13 mmoles) en DMF (75 ml) a –5ºC. La disolución se agitó a –5ºC durante 15 minutos. Se añadieron yodometano (0,321 ml, 5,13 mmoles) y terc–butóxido de sodio (0,493 g, 5,13 mmoles) adicionales, y la reacción se agitó a –5ºC durante 15 minutos. La mezcla de reacción se diluyó con DCM (200 ml) y se lavó con agua (2 x 100 ml) y salmuera (100 ml). Los productos orgánicos se secaron (MgSO4), se filtraron y se evaporaron para dar el material deseado como un sólido marrón (1,784 g). Iodomethane (0.321 ml, 5.13 mmol) was added to sodium tert-butoxide (0.493 g, 5.13 mmol) and 2-chloro-4- (ethylsulfonylmethyl) -6 - [(3S) -3-methylmorpholin-4 -Yl] pyrimidine (1.64 g, 5.13 mmol) in DMF (75 ml) at -5 ° C. The solution was stirred at -5 ° C for 15 minutes. Additional iodomethane (0.321 ml, 5.13 mmol) and sodium tert-butoxide (0.493 g, 5.13 mmol) were added, and the reaction was stirred at -5 ° C for 15 minutes. The reaction mixture was diluted with DCM (200 ml) and washed with water (2 x 100 ml) and brine (100 ml). The organic products were dried (MgSO4), filtered and evaporated to give the desired material as a brown solid (1.784 g).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,16 (3H, t), 1,21 (3H, d), 1,69 (6H, s), 3,15–3,19 (2H, m), 3,14– 3,24 (1H, m), 3,41–3,48 (1H, m), 3,57–3,61 (1H, m), 3,72 (1H, d), 3,92–3,95 (1H, m), 4,05–4,44 (2H, m), 6,87 (1H, s) NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.16 (3H, t), 1.21 (3H, d), 1.69 (6H, s), 3.15–3.19 (2H, m), 3.14– 3.24 (1H, m), 3.41–3.48 (1H, m), 3.57–3.61 (1H, m), 3.72 (1H , d), 3.92–3.95 (1H, m), 4.05-4.44 (2H, m), 6.87 (1H, s)

Espectro LCMS: MH+ 348, tiempo de retención 1,79 min. LCMS spectrum: MH + 348, retention time 1.79 min.

2–Cloro–4–(etilsulfonilmetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidina 2 – Chloro – 4– (ethylsulfonylmethyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidine

Se añadió en una porción sal sódica del ácido etanosulfónico (3,94 g, 33,94 mmoles) a 2–cloro–4–(yodometil)–6– [(3S)–3–metilmorfolin–4–il]pirimidina (12,0 g, 33,94 mmoles) en acetonitrilo (250 ml) a RT. La suspensión resultante se agitó a 80ºC durante 16 horas. La mezcla de reacción se evaporó hasta sequedad, y el residuo se repartió entre DCM (250 ml) y agua (200 ml). La capa orgánica se secó (MgSO4), se filtró y se evaporó para proporcionar el producto bruto. El producto bruto se purificó mediante cromatografía ultrarrápida en sílice, gradiente de elución 0 a 40% de acetato de etilo en DCM, para dar el material deseado como un sólido amarillo (5,94 g). Sodium salt of ethanesulfonic acid (3.94 g, 33.94 mmol) was added in 2-chloro-4– (iodomethyl) -6– [(3S) -3-methylmorpholin-4-yl] pyrimidine (12 , 0 g, 33.94 mmol) in acetonitrile (250 ml) at RT. The resulting suspension was stirred at 80 ° C for 16 hours. The reaction mixture was evaporated to dryness, and the residue was partitioned between DCM (250 ml) and water (200 ml). The organic layer was dried (MgSO4), filtered and evaporated to provide the crude product. The crude product was purified by flash chromatography on silica, gradient elution 0 to 40% ethyl acetate in DCM, to give the desired material as a yellow solid (5.94 g).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,23 (3H, m), 1,28 (3H, t), 3,22 (2H, d), 3,32 (1H, s), 3,42–3,49 (1H, m), 3,58–3,62 (1H, m), 3,73 (1H, d), 3,92–3,96 (2H, m), 4,25–4,31 (1H, m), 4,43 (2H, s), 6,92 (1H, s) NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.23 (3H, m), 1.28 (3H, t), 3.22 (2H, d), 3.32 (1H, s ), 3.42-3.49 (1H, m), 3.58-3.62 (1H, m), 3.73 (1H, d), 3.92-3.96 (2H, m), 4.25-4.31 (1H, m), 4.43 (2H, s), 6.92 (1H, s)

Espectro LCMS: MH+ 320, tiempo de retención 1,46 min. LCMS spectrum: MH + 320, retention time 1.46 min.

A continuación se describe la preparación de N–[4–[4–(etilsulfonilmetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2– il]fenil]carbamato de fenilo. The preparation of N- [4– [4– (ethylsulfonylmethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] carbamate is described below.

N–[4–[4–(Etilsulfonilmetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]carbamato de fenilo N– [4– [4– (Ethylsulfonylmethyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] phenyl carbamate

O H Or h

Se añadió gota a gota cloroformiato de fenilo (0,207 ml, 1,65 mmoles) a 4–[4–(etilsulfonilmetil)–6–[(3S)–3– metilmorfolin–4–il]pirimidin–2–il]anilina (620 mg, 1,65 mmoles) y bicarbonato de sodio (208 mg, 2,47 mmoles) en dioxano (15 ml) en nitrógeno. La suspensión resultante se agitó a RT durante 2 horas. La mezcla de reacción se evaporó hasta sequedad, y el residuo se repartió entre acetato de etilo (200 ml) y agua (200 ml). La capa orgánica se secó (MgSO4), se filtró y se evaporó para dar el material deseado como un sólido blanco (885 mg). Phenyl chloroformate (0.207 ml, 1.65 mmol) was added dropwise to 4– [4– (ethylsulfonylmethyl) -6 - [(3S) -3– methylmorpholin-4-yl] pyrimidin-2-yl] aniline ( 620 mg, 1.65 mmol) and sodium bicarbonate (208 mg, 2.47 mmol) in dioxane (15 ml) in nitrogen. The resulting suspension was stirred at RT for 2 hours. The reaction mixture was evaporated to dryness, and the residue was partitioned between ethyl acetate (200 ml) and water (200 ml). The organic layer was dried (MgSO4), filtered and evaporated to give the desired material as a white solid (885 mg).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,21–1,29 (3H, m), 1,35 (3H, t), 3,20–3,28 (2H, m), 3,47–3,54 (2H, m), 3,64–3,68 (1H, m), 3,78 (1H, d), 3,97–4,01 (1H, m), 4,20 (1H, d), 4,48 (3H, s), 6,83 (1H, s), 7,24–7,30 (3H, m), 7,42–7,48 (2H, m), 7,64 (2H, d), 8,28–8,30 (2H, m), 10,45 (1H, s) NMR Spectrum: 1H NMR (400.13 MHz, DMSO – d6) δ 1.21–1.29 (3H, m), 1.35 (3H, t), 3.20–3.28 (2H, m) , 3.47-3.54 (2H, m), 3.64-3.68 (1H, m), 3.78 (1H, d), 3.97-4.01 (1H, m), 4 , 20 (1H, d), 4.48 (3H, s), 6.83 (1H, s), 7.24-7.30 (3H, m), 7.42-7.48 (2H, m ), 7.64 (2H, d), 8.28-8.30 (2H, m), 10.45 (1H, s)

Espectro LCMS: MH+ 497, tiempo de retención 2,57 min. LCMS spectrum: MH + 497, retention time 2.57 min.

4–[4–(Etilsulfonilmetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]anilina 4– [4– (Ethylsulfonylmethyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] aniline

Se añadió diclorobis(trifenilfosfina)paladio(II) (0,162 g, 0,23 mmoles) a una disolución desgasificada de 2–cloro–4– (etilsulfonilmetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidina (0,74 g, 2,31 mmoles), 4–(4,4,5,5–tetrametil–1,3,2– dioxaborolan–2–il)anilina (0,634 g, 2,89 mmoles) y carbonato de sodio (5,78 ml, 11,57 mmoles) en una mezcla de 5 18% de DMF en DME:agua:etanol (7:3:2) (20 ml). La disolución resultante se agitó a 85ºC durante 30 minutos. La mezcla de reacción se concentró y se diluyó con DCM (100 ml), y después se lavó con agua (100 ml). La capa orgánica se secó (MgSO4), se filtró y se evaporó para proporcionar el producto bruto. El producto bruto se purificó mediante cromatografía ultrarrápida en sílice, gradiente de elución 0 a 2,5% de metanol en DCM. El material obtenido se purificó adicionalmente usando una columna SCX, eluyendo con amoniaco 7M en metanol, para dar el Dichlorobis (triphenylphosphine) palladium (II) (0.162 g, 0.23 mmol) was added to a degassed solution of 2-chloro-4- (ethylsulfonylmethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine (0.74 g, 2.31 mmol), 4– (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (0.634 g, 2.89 mmol) and carbonate sodium (5.78 ml, 11.57 mmol) in a mixture of 5 18% DMF in DME: water: ethanol (7: 3: 2) (20 ml). The resulting solution was stirred at 85 ° C for 30 minutes. The reaction mixture was concentrated and diluted with DCM (100 ml), and then washed with water (100 ml). The organic layer was dried (MgSO4), filtered and evaporated to provide the crude product. The crude product was purified by flash chromatography on silica, gradient elution 0 to 2.5% methanol in DCM. The material obtained was further purified using an SCX column, eluting with 7M ammonia in methanol, to give the

10 material deseado como un sólido amarillo (0,62 g). 10 desired material as a yellow solid (0.62 g).

Espectro RMN: RMN 1H (400,13 MHz, DMSO–d6) δ 1,23 (3H, d), 1,34 (3H, t), 3,16–3,19 (1H, m), 3,32 (2H, m), 3,45– 3,52 (1H, m), 3,62–3,66 (1H, m), 3,77 (1H, d), 3,96–3,99 (1H, m), 4,12 (1H, s), 4,42 (3H, d), 5,56 (2H, s), 6,59–6,62 (2H, m), 6,67 (1H, s), 8,01–8,04 (2H, m) NMR Spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.23 (3H, d), 1.34 (3H, t), 3.16-3.19 (1H, m), 3.32 (2H, m), 3.45-3.52 (1H, m), 3.62-3.66 (1H, m), 3.77 (1H, d), 3.96-3.99 (1H , m), 4.12 (1H, s), 4.42 (3H, d), 5.56 (2H, s), 6.59-6.62 (2H, m), 6.67 (1H, s), 8.01–8.04 (2H, m)

Espectro LCMS: MH+ 377, tiempo de retención 1,83 min. LCMS spectrum: MH + 377, retention time 1.83 min.

15 La preparación de 2–cloro–4–(etilsulfonilmetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidina se describió anteriormente. The preparation of 2-chloro-4- (ethylsulfonylmethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine was described above.

Ejemplo 63: Example 63:

3–Ciclopropil–1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(morfolina–4–carbonil)pirimidin–2–il]fenil]urea 3 – Cyclopropyl – 1– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (morpholine-4-carbonyl) pyrimidin – 2-yl] phenyl] urea

O OR

N N

N N N N

O OR

O O O o

N N

N HH N HH

N N

Se añadió ácido 2–[4–(ciclopropilcarbamoilamino)fenil]–6–[(3S)–3–metilmorfolin–4–il]pirimidin–4–carboxílico (100 2– [4– (cyclopropylcarbamoylamino) phenyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-4-carboxylic acid (100

20 mg, 0,25 mmoles) a morfolina (0,066 ml, 0,75 mmoles), DIPEA (0,132 ml, 0,75 mmoles) y HATU (144 mg, 0,38 mmoles) en DMF seco (3 ml) a RT durante un período de 30 minutos en nitrógeno. La disolución resultante se agitó a RT durante 3 horas, y el producto bruto se purificó mediante HPLC preparativa usando mezclas polares decrecientes de agua (que contiene 1% de NH3) y acetonitrilo como eluyentes, para dar el material deseado como un sólido blanco (98 mg). 20 mg, 0.25 mmol) to morpholine (0.066 ml, 0.75 mmol), DIPEA (0.132 ml, 0.75 mmol) and HATU (144 mg, 0.38 mmol) in dry DMF (3 ml) at RT over a period of 30 minutes in nitrogen. The resulting solution was stirred at RT for 3 hours, and the crude product was purified by preparative HPLC using decreasing polar mixtures of water (containing 1% NH3) and acetonitrile as eluents, to give the desired material as a white solid (98 mg)

25 Espectro RMN: RMN 1H (400MHz, DMSO–d6) δ 0,40–0,44 (2H, m), 0,63–0,68 (2H, m), 1,23–1,25 (3H, d), 2,54–2,59 (1H, m), 3,18–3,27 (1H, m), 3,46–3,49 (3H, m), 3,60–3,69 (7H, m), 3,74–3,77 (1H, d), 3,95–3,99 (1H, dd), 4,21–4,24 (1H, d), 4,56 (1H, s), 6,43-6,44 (1H, d), 6,77 (1H, s), 7,50–7,52 (2H, d), 8,18–8,20 (2H, d), 8,54 (1H, s) 25 NMR Spectrum: 1H NMR (400MHz, DMSO – d6) δ 0.40–0.44 (2H, m), 0.63–0.68 (2H, m), 1.23–1.25 (3H, d), 2.54-2.59 (1H, m), 3.18-3.27 (1H, m), 3.46-3.49 (3H, m), 3.60-3.69 ( 7H, m), 3.74-3.77 (1H, d), 3.95-3.99 (1H, dd), 4.21-4.24 (1H, d), 4.56 (1H, s), 6.43-6.44 (1H, d), 6.77 (1H, s), 7.50–7.52 (2H, d), 8.18–8.20 (2H, d) , 8.54 (1H, s)

Espectro LCMS: MH+ 467, tiempo de retención 1,69 min. LCMS spectrum: MH + 467, retention time 1.69 min.

Los siguientes compuestos se prepararon de manera análoga a partir de ácido 2–[4– 30 (ciclopropilcarbamoilamino)fenil]–6–[(3S)–3–metilmorfolin–4–il]pirimidin–4–carboxílico usando la amina apropiada. The following compounds were prepared analogously from 2– [4-30 (cyclopropylcarbamoylamino) phenyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-4-carboxylic acid using the appropriate amine.

63a 63rd: N N N O N H N H O O N HN 3–ciclopropil–1–[4–[4–(1,4– diazepán–1–carbonil)–6–[(3S)–3– metilmorfolin–4–il]pirimidin–2– il]fenil]urea 479 1,6 N N N O N H N H O O N HN 3 – cyclopropyl – 1– [4– [4– (1,4– diazepan – 1-carbonyl) –6 - [(3S) –3– methylmorpholin-4-yl] pyrimidin – 2-yl] phenyl] urea 479 1.6

63b 63b: O 3–ciclopropil–1–[4–[4–(1,1– OR 3 – cyclopropyl – 1– [4– [4– (1,1–

: dioxo1,4–tiazinano–4–carbonil)–6– dioxo1,4 – thiazinan – 4 – carbonyl) –6–

NO NO: [(3S)–3–metilmorfolin–4–il]pirimidin– [(3S) –3 – methylmorpholin-4-yl] pyrimidin–

N N N H N H O O N SO N N N H N H O O N SO: 2–il]fenil]urea 514 1,74 2-yl] phenyl] urea 514 1.74

63c 63c: O 3–ciclopropil–1–[4–[4–[(2R,6S)–2,6– OR 3 – cyclopropyl – 1– [4– [4 - [(2R, 6S) –2.6–

: dimetilmorfolina–4–carbonil]–6– dimethylmorpholine – 4 – carbonyl] –6–

N N N H N H O O N O N N N H N H O O N O: 2–il]fenil]urea 494 1,93 2-yl] phenyl] urea 494 1.93

63d 63d: N N N O N H N H O O N 2–[4–(ciclopropilcarbamoilamino)fenil]–N,N–dimetil–6–[(3S)–3– metilmorfolin–4–il]pirimidin–4– carboxamida 424 1,69 N N N O N H N H O O N 2– [4– (cyclopropylcarbamoylamino) phenyl] –N, N-dimethyl-6 - [(3S) -3– methylmorpholin-4-yl] pyrimidin-4– carboxamide 424 1.69

63e 63e: O 2–[4–(ciclopropilcarbamoilamino) OR 2– [4– (cyclopropylcarbamoylamino)

: fenil]–N–(2–hidroxietil)–N–metil–6– phenyl] –N– (2-hydroxyethyl) –N – methyl – 6–

NOH NOH: [(3S)–3–metilmorfolin–4–il]pirimidin– [(3S) –3 – methylmorpholin-4-yl] pyrimidin–

N N N N H N H O O N N N N H N H O O: 4–carboxamida 455 1,53 4-carboxamide 455 1.53

63f 63f: N N N O HN N H N H O O O 2–[4–(ciclopropilcarbamoilamino)fenil]–N–(2–metoxietil)–6–[(3S)–3– metilmorfolin–4–il]pirimidin–4– carboxamida 455 1,92 N N N O HN N H N H O O O 2– [4– (cyclopropylcarbamoylamino) phenyl] –N– (2-methoxyethyl) –6 - [(3S) –3– methylmorpholin-4-yl] pyrimidin-4– carboxamide 455 1.92

63g 63g: N N N O N N H N H O O N 2–[4–(ciclopropilcarbamoilamino)fenil]–N–metil–6–[(3S)–3– metilmorfolin–4–il]–N–(1– metilpirrolidin–3–il)pirimidin–4– carboxamida 494 1,72 N N N O N N H N H O O N 2– [4– (cyclopropylcarbamoylamino) phenyl] –N – methyl – 6 - [(3S) –3– methylmorpholin-4-yl] –N– (1– methylpyrrolidin-3-yl) pyrimidin – 4– carboxamide 494 1.72

63h 63h: O 3–ciclopropil–1–[4–[4–(4– OR 3 – cyclopropyl – 1– [4– [4– (4–

: hidroxipiperidina–1–carbonil)–6– hydroxypiperidine – 1 – carbonyl) –6–

N N N N H N H O O N HO N N N N H N H O O N HO: [(3S)–3–metilmorfolin–4–il]pirimidin– 2–il]fenil]urea 481 1,54 [(3S) –3 – methylmorpholin-4-yl] pyrimidin– 2-yl] phenyl] urea 481 1.54

63i 63i: O 1–[4–[4–(azepano–1–carbonil)–6– OR 1– [4– [4– (azepane – 1 – carbonyl) –6–

: [(3S)–3–metilmorfolin–4–il]pirimidin– [(3S) –3 – methylmorpholin-4-yl] pyrimidin–

N N: 2–il]fenil]–3–ciclopropil–urea 2-yl] phenyl] –3 – cyclopropyl-urea

N N N H N H O O N N N N H N H O O N: 479 2,15 479 2.15

63j 63j: N N N O N H N H O O HN 2–[4– (ciclopropilcarbamoilamino)fenil]–N– etil–6–[(3S)–3–metilmorfolin–4– il]pirimidin–4–carboxamida 425 2,00 N N N O N H N H O O HN 2– [4– (cyclopropylcarbamoylamino) phenyl] -N- ethyl-6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-4-carboxamide 425 2.00

63k 63k: N N N O N H N H O O N N 2–[4– (ciclopropilcarbamoilamino)fenil]–N– (2–dimetilaminoetil)–N–metil–6– [(3S)–3–metilmorfolin–4–il]pirimidin– 4–carboxamida 482 1,68 N N N O N H N H O O N N 2– [4– (cyclopropylcarbamoylamino) phenyl] –N– (2-dimethylaminoethyl) -N-methyl-6– [(3S) –3-methylmorpholin-4-yl] pyrimidin– 4-carboxamide 482 1.68

63l 63l: N N N O N H N H O O N O 2–[4– (ciclopropilcarbamoilamino)fenil]–N– (2–metoxietil)–N–metil–6–[(3S)–3– metilmorfolin–4–il]pirimidin–4– carboxamida 469 1,77 N N N O N H N H O O N O 2– [4– (cyclopropylcarbamoylamino) phenyl] –N– (2-methoxyethyl) -N-methyl-6 - [(3S) -3– methylmorpholin-4-yl] pyrimidin-4– carboxamide 469 1.77

63m 63m: N N N O N H N H O O HN N 2–[4–(ciclopropilcarbamoilamino)fenil]–6–[(3S)–3–metilmorfolin–4–il]– N–(1–metil–4–piperidil)pirimidin–4– carboxamida 494 1,93 N N N O N H N H O O HN N 2– [4– (cyclopropylcarbamoylamino) phenyl] –6 - [(3S) –3-methylmorpholin-4-yl] - N– (1-methyl-4-piperidyl) pyrimidin – 4– carboxamide 494 1.93

63n 63n: O 3–ciclopropil–1–[4–[4–(3– OR 3 – cyclopropyl – 1– [4– [4– (3–

: hidroxiazetidina–1–carbonil)–6– hydroxyazetidine – 1 – carbonyl) –6–

N N N H N H O O N HO N N N H N H O O N HO: 2–il]fenil]urea 453 1,62 2-yl] phenyl] urea 453 1.62

63o 63rd: O 2–[4–(ciclopropilcarbamoilamino)- OR 2– [4– (cyclopropylcarbamoylamino) -

NN NN: fenil]–N–[(3–metilimidazol–4– il)metil]–6–[(3S)–3–metilmorfolin–4– phenyl] –N - [(3-methylimidazol – 4– yl) methyl] –6 - [(3S) –3 – methylmorpholin-4–

N N N H N H O O HN N N N N H N H O O HN N: il]pirimidin–4–carboxamida 491 1,79 il] pyrimidin-4-carboxamide 491 1.79

63p 63p: O 2–[4–(ciclopropilcarbamoilamino) OR 2– [4– (cyclopropylcarbamoylamino)

: fenil]–N–(dimetilcarbamoilmetil)–6– phenyl] –N– (dimethylcarbamoylmethyl) –6–

NN NN: [(3S)–3–metilmorfolin–4–il]pirimidin– [(3S) –3 – methylmorpholin-4-yl] pyrimidin–

N N N H N H O O HN O N N N H N H O O HN O: 4–carboxamida 482 1,80 4-carboxamide 482 1.80

63q 63q: O N–ciclopropil–2–[4–(ciclopropil OR N – cyclopropyl – 2– [4– (cyclopropyl

: carbamoilamino)fenil]–N–metil–6– carbamoylamino) phenyl] –N – methyl – 6–

N N N H N H O O N N N N H N H O O N: 4–carboxamida 451 1,85 4-carboxamide 451 1.85

63r 63r: N N N O N H N H O O N 2–[4–(ciclopropilcarbamoilamino)fenil]–N–(ciclopropilmetil)–N–metil– 6–[(3S)–3–metilmorfolin–4– il]pirimidin–4–carboxamida 465 2,02 N N N O N H N H O O N 2– [4– (cyclopropylcarbamoylamino) phenyl] –N– (cyclopropylmethyl) -N-methyl– 6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-4-carboxamide 465 2.02

63s 63s: N N N O N H N H O O HN O 2–[4–(ciclopropilcarbamoilamino)fenil]–6–[(3S)–3–metilmorfolin–4–il]– N–(oxetan–3–il)pirimidin–4– carboxamida 453 1,84 N N N O N H N H O O HN O 2– [4– (cyclopropylcarbamoylamino) phenyl] –6 - [(3S) –3-methylmorpholin-4-yl] - N– (oxetan – 3-yl) pyrimidin – 4– carboxamide 453 1.84

Ejemplo 63a: RMN 1H (400MHz, CDCl3) δ 0,68–0,68 (2H, d), 0,86–0,87 (2H, d), 1,34–1,35 (3H, d), 1,86–1,90 (1H, m), 1,94–2,02 (1H, m), 2,62–2,64 (1H, t), 2,99–3,04 (2H, m), 3,06–3,11 (2H, m), 3,30–3,37 (1H, td), 3,56–3,59 (1H, d), 3,63–3,68 (3H, m), 3,72–3,75 (1H, d), 3,78–3,84 (3H, m), 4,02–4,06 (1H, dd), 4,15–4,18 (1H, d), 4,49 (1H, s), Example 63a: 1H NMR (400MHz, CDCl3) δ 0.68-0.68 (2H, d), 0.86-0.87 (2H, d), 1.34-1.35 (3H, d), 1.86–1.90 (1H, m), 1.94–2.02 (1H, m), 2.62–2.64 (1H, t), 2.99–3.04 (2H, m ), 3.06-3.11 (2H, m), 3.30-3.37 (1H, td), 3.56-3.59 (1H, d), 3.63-3.68 (3H , m), 3.72–3.75 (1H, d), 3.78–3.84 (3H, m), 4.02–4.06 (1H, dd), 4.15–4.18 (1H, d), 4.49 (1H, s),

5 4,98–4,99 (1H, d), 6,62–6,64 (1H, d), 7,07–7,08 (1H, d), 7,48–7,50 (2H, d), 8,30–8,33 (2H, m) 5 4.98–4.99 (1H, d), 6.62–6.64 (1H, d), 7.07–7.08 (1H, d), 7.48–7.50 (2H, d), 8.30–8.33 (2H, m)

Ejemplo 63b: RMN 1H (400MHz, DMSO–d6) δ 0,40–0,44 (2H, m), 0,63–0,67 (2H, m), 1,23–1,24 (3H, d), 1,64–1,70 (2H, m), 1,75–1,80 (2H, m), 2,54–2,58 (1H, m), 3,2–3,21 (1H, d), 3,36–3,44 (2H, dt), 3,46–3,53 (1H, m), 3,57–3,60 (1H, q), 3,62–3,65 (2H, m), 3,74–3,77 (1H, d), 3,95–3,98 (1H, dd), 4,21–4,24 (1H, d), 4,54 (1H, s), 6,43-6,44 (1H, d), 6,70–6,71 (1H, d), 7,49–7,51 (2H, d), 8,18–8,20 (2H, d), 8,45 (1H, s) Example 63b: 1H NMR (400MHz, DMSO-d6) δ 0.40–0.44 (2H, m), 0.63–0.67 (2H, m), 1.23–1.24 (3H, d ), 1.64-1.70 (2H, m), 1.75-1.80 (2H, m), 2.54-2.58 (1H, m), 3.2–3.21 (1H , d), 3.36-3.44 (2H, dt), 3.46-3.53 (1H, m), 3.57-3.60 (1H, q), 3.62-3.65 (2H, m), 3.74-3.77 (1H, d), 3.95-3.98 (1H, dd), 4.21-4.24 (1H, d), 4.54 (1H , s), 6.43-6.44 (1H, d), 6.70–6.71 (1H, d), 7.49–7.51 (2H, d), 8.18–8.20 (2H, d), 8.45 (1H, s)

10 Ejemplo 63c: RMN 1H (400MHz, CDCl3) δ 0,68–0,72 (2H, m), 0,86–0,90 (2H, m), 1,13–1,15 (3H, dd), 1,27–1,29 (3H, d), 1,35–1,37 (3H, d), 2,54–2,61 (1H, t), 2,62–2,66 (1H, m), 2,82–2,91 (1H, m), 3,31–3,39 (1H, td), 3,57–3,63 (1H, td), 3,73–3,76 (3H, m), 3,82–3,85 (1H, d), 4,03–4,07 (1H, dd), 4,11–4,18 (2H, m), 4,51 (1H, s), 4,56–4,60 (1H, dd), 4,96 (1H, s), 6,69 (1H, s), 7,069 (1H, s), 7,51–7,53 (2H, d), 8,31–8,33 (2H, d), Example 63c: 1H NMR (400MHz, CDCl3) δ 0.68-0.72 (2H, m), 0.86-0.90 (2H, m), 1.13-1.15 (3H, dd) , 1.27-1.29 (3H, d), 1.35-1.37 (3H, d), 2.54-2.61 (1H, t), 2.62-2.66 (1H, m), 2.82–2.91 (1H, m), 3.31–3.39 (1H, td), 3.57–3.63 (1H, td), 3.73–3.76 ( 3H, m), 3.82–3.85 (1H, d), 4.03-4.07 (1H, dd), 4.11-4.18 (2H, m), 4.51 (1H, s), 4.56-4.60 (1H, dd), 4.96 (1H, s), 6.69 (1H, s), 7.069 (1H, s), 7.51-7.53 (2H , d), 8.31–8.33 (2H, d),

Ejemplo 63d: RMN 1H (400MHz, DMSO–d6) δ 0,42–0,44 (2H, m), 0,63–0,68 (2H, m), 1,23–1,25 (3H, d), 2,54–2,59 Example 63d: 1H NMR (400MHz, DMSO-d6) δ 0.42–0.44 (2H, m), 0.63–0.68 (2H, m), 1.23–1.25 (3H, d ), 2.54–2.59

15 (1H, m), 2,99–3,01 (6H, d), 3,46–3,53 (1H, td), 3,62–3,66 (1H, dd), 3,74–3,77 (1H, d), 3,95–3,99 (1H, dd), 4,21–4,24 (1H, d), 4,55 (1H, s), 6,43-6,44 (1H, d), 6,71 (1H, s), 7,49–7,51 (2H, d), 8,19–8,21 (2H, d), 8,54 (1H, s) 15 (1H, m), 2.99–3.01 (6H, d), 3.46–3.53 (1H, td), 3.62–3.66 (1H, dd), 3.74– 3.77 (1H, d), 3.95–3.99 (1H, dd), 4.21-4.24 (1H, d), 4.55 (1H, s), 6.43-6, 44 (1H, d), 6.71 (1H, s), 7.49–7.51 (2H, d), 8.19–8.21 (2H, d), 8.54 (1H, s)

Ejemplo 63e: RMN 1H (400MHz, DMSO–d6) δ 0,41–0,44 (2H, m), 0,63–0,67 (2H, m), 1,23–1,25 (3H, d), 2,32–2,34 (1H, m), 2,54–2,61 (1H, m), 3,03 (3H, s), 3,18–3,25 (1H, td), 3,36–3,41 (1H, q), 3,49–3,50 (1H, d), 3,52–3,54 (1H, d), 3,57 (1H, s), 3,63–3,66 (1H, dd), 3,74–3,77 (1H, d), 3,95–3,99 (1H, dd), 4,21–4,23 (1H, d), 4,52 (1H, s), 4,74 (1H, s), Example 63e: 1H NMR (400MHz, DMSO – d6) δ 0.41–0.44 (2H, m), 0.63–0.67 (2H, m), 1.23–1.25 (3H, d ), 2.32-2.34 (1H, m), 2.54-2.61 (1H, m), 3.03 (3H, s), 3.18-2.25 (1H, td), 3.36-3.41 (1H, q), 3.49-3.50 (1H, d), 3.52-3.54 (1H, d), 3.57 (1H, s), 3, 63–3.66 (1H, dd), 3.74–3.77 (1H, d), 3.95–3.99 (1H, dd), 4.21–4.23 (1H, d), 4.52 (1H, s), 4.74 (1H, s),

20 6,45–6,46 (1H, d), 6,70 (1H, s), 7,50–7,52 (2H, d), 8,17–8,20 (2H, m), 8,56 (1H, s) 20 6.45-6.46 (1H, d), 6.70 (1H, s), 7.50-7.52 (2H, d), 8.17-8.20 (2H, m), 8 , 56 (1H, s)

Ejemplo 63f: RMN 1H (400MHz, DMSO–d6) δ 0,41–0,45 (2H, m), 0,63–0,68 (2H, m), 1,24–1,26 (3H, d), 2,33–2,35 (1H, m), 2,67–2,69 (1H, m), 2,70 (1H, s), 2,74 (2H, s), 2,90 (3H, s), 3,49–3,53 (2H, m), 3,63–3,67 (1H, dd), 3,76–3,78 (1H, d), 3,96–4,00 (1H, dd), 4,35 (1H, s), 4,56–4,58 (1H, d), 6,43-6,44 (1H, d), 7,13 (1H, s), 7,52–7,54 (2H, d), 7,96 (1H, s), 8,38–8,40 (2H, d), 8,57 (1H, s) Example 63f: 1H NMR (400MHz, DMSO – d6) δ 0.41-0.45 (2H, m), 0.63-0.68 (2H, m), 1.24-1.26 (3H, d ), 2.33-2.35 (1H, m), 2.67-2.69 (1H, m), 2.70 (1H, s), 2.74 (2H, s), 2.90 ( 3H, s), 3.49-3.53 (2H, m), 3.63-3.67 (1H, dd), 3.76-3.78 (1H, d), 3.96-4, 00 (1H, dd), 4.35 (1H, s), 4.56-4.58 (1H, d), 6.43-6.44 (1H, d), 7.13 (1H, s) , 7.52–7.54 (2H, d), 7.96 (1H, s), 8.38–8.40 (2H, d), 8.57 (1H, s)

Ejemplo 63g: RMN 1H (400MHz, DMSO–d6) δ 0,41–0,44 (2H, m), 0,63–0,68 (2H, m), 1,23–1,25 (3H, d), 2,20 (2H, s), 2,27 (1H, s), 2,33–2,35 (2H, m), 2,67–2,69 (3H, m), 2,74 (1H, s), 2,90–2,91 (2H, d), 2,97 (2H, s), 3,17–3,21 (1H, m), 3,47–3,52 (1H, m), 3,63–3,66 (1H, dd), 3,74–3,77 (1H, d), 3,96–3,98 (1H, dd), 4,22–4,24 (1H, d), 4,32–4,34 (1H, d), 4,56 (1H, s), 6,43-6,45 (1H, m), 6,69–6,70 (1H, d), 7,49–7,53 (2H, dd), 8,19–8,21 (2H, dd), 8,54 (1H, s), Example 63g: 1H NMR (400MHz, DMSO – d6) δ 0.41-0.44 (2H, m), 0.63-0.68 (2H, m), 1.23-1.25 (3H, d ), 2.20 (2H, s), 2.27 (1H, s), 2.33-2.35 (2H, m), 2.67-2.69 (3H, m), 2.74 ( 1H, s), 2.90-2.91 (2H, d), 2.97 (2H, s), 3.17-3.21 (1H, m), 3.47-3.52 (1H, m), 3.63-3.66 (1H, dd), 3.74-3.77 (1H, d), 3.96-3.98 (1H, dd), 4.22-4.24 ( 1H, d), 4.32-4.34 (1H, d), 4.56 (1H, s), 6.43-6.45 (1H, m), 6.69-6.70 (1H, d), 7.49–7.53 (2H, dd), 8.19–8.21 (2H, dd), 8.54 (1H, s),

Ejemplo 63h: RMN 1H (400MHz, DMSO–d6) δ 0,40–0,44 (2H, m), 0,63–0,67 (2H, m), 1,23–1,24 (3H, d), 1,43 (2H, s), 1,74–1,84 (2H, d), 2,53–2,57 (1H, m), 3,14–3,18 (1H, m), 3,21–2,24 (2H, m), 3,46–3,52 (1H, td), 3,56 (1H, m), 3,62–3,66 (1H, dd), 3,74–3,77 (2H, d), 3,95–3,98 (1H, dd), 4,00–4,04 (1H, m), 4,21 (1H, d), 4,55 (1H, s), 4,77–4,78 (1H, d), 6,43-6,44 (1H, d), 6,71 (1H, s), 7,49–7,52 (2H, d), 8,18–8,20 (2H, d), 8,54 (1H, s) Example 63h: 1H NMR (400MHz, DMSO – d6) δ 0.40-0.44 (2H, m), 0.63-0.67 (2H, m), 1.23-1.24 (3H, d ), 1.43 (2H, s), 1.74–1.84 (2H, d), 2.53–2.57 (1H, m), 3.14–3.18 (1H, m), 3.21-2.24 (2H, m), 3.46-3.52 (1H, td), 3.56 (1H, m), 3.62-3.66 (1H, dd), 3, 74–3.77 (2H, d), 3.95–3.98 (1H, dd), 4.00–4.04 (1H, m), 4.21 (1H, d), 4.55 ( 1H, s), 4.77-4.78 (1H, d), 6.43-6.44 (1H, d), 6.71 (1H, s), 7.49-7.52 (2H, d), 8.18–8.20 (2H, d), 8.54 (1H, s)

Ejemplo 63i: RMN 1H (400MHz, DMSO–d6) δ 0,40–0,44 (2H, m), 0,63–0,68 (2H, m), 1,23–1,24 (3H, d), 1,60–1,61 (4H, d), 1,74–1,75 (4H, d), 2,67–2,69 (1H, m), 3,17–3,25 (1H, m), 3,37–3,40 (1H, t) 3,56–3,59 (1H, t), 3,62–3,65 (1H, dd), 3,74–3,77 (1H, d), 3,94–3,99 (1H, dd), 4,22–4,24 (1H, d), 4,54 (1H, s), 6,43-6,44 (1H, d), 6,69 (1H, s), 7,49–7,51 (2H, d), 8,18–2,20 (2H, d), 8,53 (1H, s) Example 63i: 1H NMR (400MHz, DMSO-d6) δ 0.40-0.44 (2H, m), 0.63-0.68 (2H, m), 1.23-1.24 (3H, d ), 1.60–1.61 (4H, d), 1.74–1.75 (4H, d), 2.67–2.69 (1H, m), 3.17–3.25 (1H , m), 3.37-3.40 (1H, t) 3.56-3.59 (1H, t), 3.62-3.65 (1H, dd), 3.74-3.77 ( 1H, d), 3.94–3.99 (1H, dd), 4.22-4.24 (1H, d), 4.54 (1H, s), 6.43-6.44 (1H, d), 6.69 (1H, s), 7.49–7.51 (2H, d), 8.18-2.20 (2H, d), 8.53 (1H, s)

Ejemplo 63j: RMN 1H (400MHz, DMSO–d6) δ 0,41–0,45 (2H, m), 0,63–0,68 (2H, m), 1,15–1,19 (3H, t), 1,24–1,26 (3H, d), 2,56–2,60 (1H, m), 3,25–3,26 (1H, m), 3,33–3,42 (2H, m), 3,47–3,53 (1H, td), 3,64–3,67 (1H, dd), 3,75–3,78 (1H, d), 3,96–4,00 (1H, dd), 4,35–4,27 (1H, d), 4,57 (1H, s), 6,43-6,44 (1H, d), 7,13 (1H, s), 7,52–7,54 (2H, d), 8,40– 8,42 (2H, d), 8,57 (1H, s) 8,91–8,93 (1H, t) Example 63j: 1H NMR (400MHz, DMSO-d6) δ 0.41-0.45 (2H, m), 0.63-0.68 (2H, m), 1.15-1.19 (3H, t ), 1.24–1.26 (3H, d), 2.56–2.60 (1H, m), 3.25–3.26 (1H, m), 3.33–3.42 (2H , m), 3.47-3.53 (1H, td), 3.64-3.67 (1H, dd), 3.75-3.78 (1H, d), 3.96-4.00 (1H, dd), 4.35-4.27 (1H, d), 4.57 (1H, s), 6.43-6.44 (1H, d), 7.13 (1H, s), 7.52–7.54 (2H, d), 8.40– 8.42 (2H, d), 8.57 (1H, s) 8.91–8.93 (1H, t)

Ejemplo 63k: RMN 1H (400MHz, DMSO–d6) δ 0,41–0,44 (2H, m), 0,63–0,68 (2H, m), 1,22–1,25 (3H, m), 2,01 (2H, s), 2,24 (2H, s), 2,55–2,58 (1H, m), 2,99–3,01 (3H, d), 3,27 (3H, s), 3,35–3,39 (3H, m), 3,46–3,49 (1H, dd), 3,52–3,56 (1H, td), 3,62–3,66 (1H, dd), 3,74–3,77 (1H, d), 3,96–3,98 (1H, d), 4,21–4,24 (1H, d), 4,55 (1H, s), 6,43-6,44 (1H, d), 6,68–6,70 (1H, d), 7,50–7,52 (2H, d), 8,20–8,22 (2H, d), 8,54 (1H, s) Example 63k: 1H NMR (400MHz, DMSO-d6) δ 0.41–0.44 (2H, m), 0.63–0.68 (2H, m), 1.22–1.25 (3H, m ), 2.01 (2H, s), 2.24 (2H, s), 2.55-2.58 (1H, m), 2.99-3.01 (3H, d), 3.27 ( 3H, s), 3.35-3.39 (3H, m), 3.46-3.49 (1H, dd), 3.52-3.56 (1H, td), 3.62-3, 66 (1H, dd), 3.74-3.77 (1H, d), 3.96-3.98 (1H, d), 4.21-4.24 (1H, d), 4.55 ( 1H, s), 6.43-6.44 (1H, d), 6.68-6.70 (1H, d), 7.50-7.52 (2H, d), 8.20–8, 22 (2H, d), 8.54 (1H, s)

Ejemplo 63l: RMN 1H (400MHz, DMSO–d6) δ 0,41–0,44 (2H, m), 0,63–0,68 (2H, m), 1,23–1,25 (3H, d), 2,55–2,58 (1H, m), 3,02 (3H, s), 3,19 (2H, s), 3,24–3,25 (1H, m), 3,46–3,47 (1H, d), 3,49–3,54 (3H, m), 3,59–3,60 (1H, d), 3,61– 3,66 (2H, dd), 3,74–3,78 (1H, d), 3,95–3,98 (1H, dd), 4,21–4,22 (1H, d), 4,51 (1H, s), 6,44 (1H, s), 6,69–6,71 (1H, s), 7,50–7,52 (2H, d), 8,18–8,20 (2H, d), 8,55 (1H, s) Example 63l: 1H NMR (400MHz, DMSO-d6) δ 0.41-0.44 (2H, m), 0.63-0.68 (2H, m), 1.23-1.25 (3H, d ), 2.55–2.58 (1H, m), 3.02 (3H, s), 3.19 (2H, s), 3.24–3.25 (1H, m), 3.46– 3.47 (1H, d), 3.49-3.54 (3H, m), 3.59-3.60 (1H, d), 3.61-3.66 (2H, dd), 3, 74-3.78 (1H, d), 3.95-3.98 (1H, dd), 4.21-4.22 (1H, d), 4.51 (1H, s), 6.44 ( 1H, s), 6.69–6.71 (1H, s), 7.50–7.52 (2H, d), 8.18–8.20 (2H, d), 8.55 (1H, s)

Ejemplo 63m: RMN 1H (400MHz, DMSO–d6) δ 0,41–0,45 (2H, m), 0,63–0,68 (2H, m), 1,24–1,25 (3H, d), 1,74–1,78 (4H, m), 1,97–2,04 (3H, m), 2,55–2,61 (1H, m), 2,76–2,79 (2H, d), 3,21–3,26 (1H, m), 3,27 (1H, s), 3,47–3,53 (1H, td), 3,63–3,67 (1H, dd), 3,73–3,78 (2H, d), 3,80–3,84 (1H, m), 3,96–4,00 (1H, dd), 4,24–4,27 (1H, d), 4,58 (1H, s), 6,44–6,45 (1H, d), 7,12 (1H, s), 7,52–7,54 (2H, d), 8,38–8,40 (2H, d), 8,51–8,54 (1H, d), 8,57 (1H, s) Example 63m: 1H NMR (400MHz, DMSO – d6) δ 0.41–0.45 (2H, m), 0.63–0.68 (2H, m), 1.24–1.25 (3H, d ), 1.74-1.78 (4H, m), 1.97-2.04 (3H, m), 2.55-2.61 (1H, m), 2.76-2.79 (2H , d), 3.21-3.26 (1H, m), 3.27 (1H, s), 3.47-3.53 (1H, td), 3.63-3.67 (1H, dd ), 3.73–3.78 (2H, d), 3.80–3.84 (1H, m), 3.96-4.00 (1H, dd), 4.24–4.27 (1H , d), 4.58 (1H, s), 6.44-6.45 (1H, d), 7.12 (1H, s), 7.52–7.54 (2H, d), 8, 38–8.40 (2H, d), 8.51–8.54 (1H, d), 8.57 (1H, s)

Ejemplo 63n: RMN 1H (400MHz, DMSO–d6) δ 0,41–0,44 (2H,m), 0,63–0,68 (2H, m), 1,23–1,25 (3H, d), 2,56–2,59 (1H, m), 3,19–3,23 (1H, dd), 3,46–3,53 (1H, td), 3,62–3,66 (1H, dd), 3,75–3,78 (1H, d), 3,80–3,84 (1H, m), 3,96–3,99 (1H, dd), 4,23 (1H, s), 4,26–4–31 (1H, qd), 4,42–4,47 (1H, m), 4,53–4,58 (2H, m), 4,88–4,94 (1H, m), 5,72–5,73 (1H, d), 6,44–6,45 (1H, d), 7,04 (1H, s), 7,52–7,54 (2H, d), 8,20–8,23 (2H, d), 8,56 (1H, s) Example 63n: 1H NMR (400MHz, DMSO-d6) δ 0.41-0.44 (2H, m), 0.63-0.68 (2H, m), 1.23-1.25 (3H, d ), 2.56–2.59 (1H, m), 3.19–3.23 (1H, dd), 3.46–3.53 (1H, td), 3.62–3.66 (1H , dd), 3.75-3.78 (1H, d), 3.80-3.84 (1H, m), 3.96-3.99 (1H, dd), 4.23 (1H, s ), 4.26–4–31 (1H, qd), 4.42–4.47 (1H, m), 4.53–4.58 (2H, m), 4.88–4.94 (1H , m), 5.72-5.73 (1H, d), 6.44-6.45 (1H, d), 7.04 (1H, s), 7.52-7.54 (2H, d ), 8.20–8.23 (2H, d), 8.56 (1H, s)

Ejemplo 63o: RMN 1H (400MHz, DMSO–d6) δ 0,40–0,44 (2H, m), 0,63–0,68 (2H, m), 1,24–1,26 (3H, d), 2,55–2,59 (1H, m), 3,21–3,25 (1H, m), 3,47–3,53 (1H, td), 3,63–3,64 (1H, d), 3,66 (3H, s), 3,75–3,78 (1H, d), 3,96–4,00 (1H, dd), 4,24–4,28 (1H, d), 4,52–4,54 (2H, d), 4,58 (1H, s), 6,42–6,44 (1H, d), 6,65 (1H, s), 7,15 (1H, s), 7,50–7,51 (1H, t), 7,52–7,53 (2H, d), 8,38–8,40 (2H, d), 8,56 (1H, s) Example 63o: 1H NMR (400MHz, DMSO-d6) δ 0.40–0.44 (2H, m), 0.63–0.68 (2H, m), 1.24–1.26 (3H, d ), 2.55–2.59 (1H, m), 3.21–3.25 (1H, m), 3.47–3.53 (1H, td), 3.63–3.64 (1H , d), 3.66 (3H, s), 3.75–3.78 (1H, d), 3.96-4.00 (1H, dd), 4.24-4.28 (1H, d ), 4.52–4.54 (2H, d), 4.58 (1H, s), 6.42–6.44 (1H, d), 6.65 (1H, s), 7.15 ( 1H, s), 7.50–7.51 (1H, t), 7.52–7.53 (2H, d), 8.38–8.40 (2H, d), 8.56 (1H, s)

Ejemplo 63p: RMN 1H (400MHz, DMSO–d6) δ 0,41–0,45 (2H, m), 0,63–0,68 (2H, m), 1,25–1,27 (3H, d), 2,56–2,59 (1H, m), 2,91 (3H, s), 3,03 (3H, s), 3,20–3,24 (1H, m), 2,48–3,54 (1H, td), 3,64–3,68 (1H, dd), 3,76–3,79 (1H, d), 3,97–4,00 (1H, dd), 4,18–4,20 (2H, d), 4,26 (1H, d), 4,59 (1H, s), 6,46–6,47 (1H, d), 7,14 (1H, s), 7,54–7,56 (2H, d), 8,34–8,36 (2H, d), 8,59 (1H, s), 8,99–9,02 (1H, t) Example 63p: 1H NMR (400MHz, DMSO – d6) δ 0.41–0.45 (2H, m), 0.63–0.68 (2H, m), 1.25–1.27 (3H, d ), 2.56–2.59 (1H, m), 2.91 (3H, s), 3.03 (3H, s), 3.20–3.24 (1H, m), 2.48– 3.54 (1H, td), 3.64-3.68 (1H, dd), 3.76-4.79 (1H, d), 3.97-4.00 (1H, dd), 4, 18–4.20 (2H, d), 4.26 (1H, d), 4.59 (1H, s), 6.46–6.47 (1H, d), 7.14 (1H, s) , 7.54–7.56 (2H, d), 8.34–8.36 (2H, d), 8.59 (1H, s), 8.99–9.02 (1H, t)

Ejemplo 63q: RMN 1H (400MHz, DMSO–d6) δ 0,40–0,44 (2H, m), 0,49–0,53 (4H, m), 0,63–0,67 (2H, m), 1,22–1,24 (3H, d), 2,55–2,61 (2H, m), 2,87–2,88 (1H, d), 2,93 (2,95 (1H, m), 3,17–3,25 (1H, td) , 3,27 (1H, s), 3,47–3,54 (1H, td), 3,62–3,67 (1H, dd), 3,75–3,78 (1H, d), 3,94–3,98 (1H, dd), 4,21–4,24 (1H, d), 4,52 (1H, s), 6,42–6,43 (1H, d), 6,73 (1H, s), 7,49–7,51 (2H, d), 8,19–8,22 (2H, d), 8,53 (1H, s) Example 63q: 1H NMR (400MHz, DMSO – d6) δ 0.40-0.44 (2H, m), 0.49-0.53 (4H, m), 0.63-0.67 (2H, m ), 1.22–1.24 (3H, d), 2.55–2.61 (2H, m), 2.87–2.88 (1H, d), 2.93 (2.95 (1H , m), 3.17-3.25 (1H, td), 3.27 (1H, s), 3.47-3.54 (1H, td), 3.62-3.67 (1H, dd ), 3.75-3.78 (1H, d), 3.94-3.98 (1H, dd), 4.21-4.24 (1H, d), 4.52 (1H, s), 6.42–6.43 (1H, d), 6.73 (1H, s), 7.49–7.51 (2H, d), 8.19–8.22 (2H, d), 8, 53 (1H, s)

Ejemplo 63r: RMN 1H (400MHz, DMSO–d6) δ 0,14–0,18 (1H, m), 0,30–0,34 (1H, m), 0,40–0,43 (2H, m), 0,44–0,48 (1H, dq), 0,51–0,56 (1H, dq), 0,63–0,67 (2H, m), 1,06–1,10 (1H, m), 1,22–1,25 (3H, m), 2,54–2,59 (1H, m), 3,03– 3,06 (3H, d), 3,16–3,19 (1H, m), 3,20–3,25 (1H, m), 3,35–3,37 (1H, m), 3,46–3,53 (1H, td), 3,62–3,66 (1H, dd), 3,74– 3,77 (1H, d), 3,95–3,98 (1H, dd), 4,22–4,24 (1H, d), 4,55 (1H, s) 6,44–6,45 (1H, d), 6,70–6,71 (1H, d), 7,49–7,59 (2H, dd), 8,18–8,21 (2H, dd), 8,54–8,55 (1H, d) Example 63r: 1H NMR (400MHz, DMSO – d6) δ 0.14–0.18 (1H, m), 0.30–0.34 (1H, m), 0.40–0.43 (2H, m ), 0.44–0.48 (1H, dq), 0.51–0.56 (1H, dq), 0.63–0.67 (2H, m), 1.06–1.10 (1H , m), 1.22–1.25 (3H, m), 2.54–2.59 (1H, m), 3.03– 3.06 (3H, d), 3.16–3.19 (1H, m), 3.20-3.25 (1H, m), 3.35-3.37 (1H, m), 3.46-3.53 (1H, td), 3.62-3 , 66 (1H, dd), 3.74-3.77 (1H, d), 3.95-3.98 (1H, dd), 4.22-4.24 (1H, d), 4.55 (1H, s) 6.44–6.45 (1H, d), 6.70–6.71 (1H, d), 7.49–7.59 (2H, dd), 8.18–8, 21 (2H, dd), 8.54–8.55 (1H, d)

Ejemplo 63s: RMN 1H (400MHz, DMSO–d6) δ 0,41–0,45 (2H, m), 0,64–0,68 (2H, m), 1,24–1,25 (3H, d), 2,55–2,60 (1H, m), 3,17–3,25 (1H, m), 3,47–3,54 (1H, td), 3,63–3,67 (1H, dd), 3,75–3,78 (1H, d), 3,96–4,00 (1H, dd), 4,25–4,27 (1H, d), 4,57 (1H, s), 4,74–4,80 (4H, m), 5,04–5,13 (1H, m), 6,44–6,45 (1H, d), 7,11 (1H, s), 7,53–7,55 (2H, d), 8,46– 8,48 (2H, d), 8,58 (1H, s), 9,38–9,40 (1H, d) Example 63s: 1H NMR (400MHz, DMSO – d6) δ 0.41–0.45 (2H, m), 0.64–0.68 (2H, m), 1.24–1.25 (3H, d ), 2.55–2.60 (1H, m), 3.17–3.25 (1H, m), 3.47–3.54 (1H, td), 3.63–3.67 (1H , dd), 3.75–3.78 (1H, d), 3.96-4.00 (1H, dd), 4.25-4.27 (1H, d), 4.57 (1H, s ), 4.74–4.80 (4H, m), 5.04–5.13 (1H, m), 6.44–6.45 (1H, d), 7.11 (1H, s), 7.53–7.55 (2H, d), 8.46– 8.48 (2H, d), 8.58 (1H, s), 9.38–9.40 (1H, d)

Prueba (c): Ejemplo (63) 0,41 μM; Ejemplo (63a) 0,092 μM; Ejemplo (63b) 0,5 μM; Ejemplo (63c) 0,26 μM. Test (c): Example (63) 0.41 μM; Example (63a) 0.092 μM; Example (63b) 0.5 μM; Example (63c) 0.26 μM.

La preparación de ácido 2–[4–(ciclopropilcarbamoilamino)fenil]–6–[(3S)–3–metilmorfolin–4–il]pirimidin–4–carboxílico se describió anteriormente. The preparation of 2– [4– (cyclopropylcarbamoylamino) phenyl] –6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-4-carboxylic acid was described above.

Example 64:

1–[4–[4–(2–Ciclopentilsulfonilpropan–2–il)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]–3–ciclopropil– 5 urea 1– [4– [4– (2 – Cyclopentylsulfonylpropan – 2-yl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin – 2-yl] phenyl] –3 – cyclopropyl– 5 urea

Se añadió trietilamina (0,175 ml, 1,25 mmoles) a una mezcla de N–[4–[4–(2–ciclopentilsulfonilpropan–2–il)–6–[(3S)– 3–metilmorfolin–4–il]pirimidin–2–il]fenil]carbamato de fenilo (200 mg, 0,31 mmoles) y ciclopropilamina (1,25 mmoles) en NMP (2 ml) y se calentó a 75ºC durante 6 horas. La mezcla de reacción se purificó mediante HPLC preparativa Triethylamine (0.175 ml, 1.25 mmol) was added to a mixture of N– [4– [4– (2-cyclopentylsulfonylpropan-2-yl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin -2-yl] phenyl] phenyl carbamate (200 mg, 0.31 mmol) and cyclopropylamine (1.25 mmol) in NMP (2 ml) and heated at 75 ° C for 6 hours. The reaction mixture was purified by preparative HPLC

10 usando mezclas polares decrecientes de agua (que contiene 1% de NH3) y acetonitrilo como eluyentes, para dar el material deseado como un sólido (136 mg). 10 using decreasing polar mixtures of water (containing 1% NH3) and acetonitrile as eluents, to give the desired material as a solid (136 mg).

Espectro RMN: RMN 1H (400,132 MHz, DMSO–d6) δ 0,39–0,44 (2H, m), 0,63–0,67 (2H, m), 1,22 (3H, d), 1,40–1,48 (4H, m), 1,52–1,59 (4H, m), 1,70–1,80 (6H, m), 3,16–3,24 (1H, m), 3,46–3,54 (1H, m), 3,65 (1H, d), 3,77 (1H, d), 3,91–4,01 (2H, m), 4,23 (1H, d), 4,60 (1H, s), 6,44 (1H, d), 6,77 (1H, s), 7,51 (2H, d), 8,24 (2H, d), 8,55 (1H, s) NMR Spectrum: 1H NMR (400.132 MHz, DMSO – d6) δ 0.39–0.44 (2H, m), 0.63–0.67 (2H, m), 1.22 (3H, d), 1 , 40–1.48 (4H, m), 1.52–1.59 (4H, m), 1.70–1.80 (6H, m), 3.16–3.24 (1H, m) , 3.46-3.54 (1H, m), 3.65 (1H, d), 3.77 (1H, d), 3.91-4.04 (2H, m), 4.23 (1H , d), 4.60 (1H, s), 6.44 (1H, d), 6.77 (1H, s), 7.51 (2H, d), 8.24 (2H, d), 8 , 55 (1H, s)

15 Espectro LCMS: MH+ 528, tiempo de retención 2,43 min. 15 LCMS spectrum: MH + 528, retention time 2.43 min.

Los siguientes compuestos se obtuvieron de manera análoga a partir de N–[4–[4–(2–ciclopentilsulfonilpropan–2–il)– 6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]carbamato de fenilo o N–[4–[4–(ciclopentilsulfonilmetil)–6–[(3S)–3– metilmorfolin–4–il]pirimidin–2–il]fenil]carbamato de fenilo y la amina apropiada. The following compounds were obtained analogously from N– [4– [4– (2-cyclopentylsulfonylpropan-2-yl) - 6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] phenyl carbamate or N– [4– [4– (cyclopentylsulfonylmethyl) –6 - [(3S) –3– methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] phenyl carbamate and the appropriate amine.

64a 64th: N N N O S O O N H N H O 3–ciclobutil–1–[4–[4–(2– ciclopentilsulfonilpropan–2–il)–6–[(3S)– 3–metilmorfolin–4–il]pirimidin–2– il]fenil]urea 542 2,7 N N N O S O O N H N H O 3 – cyclobutyl – 1– [4– [4– (2– cyclopentylsulfonylpropan – 2-yl) –6 - [(3S) - 3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] urea 542 2.7

64b 64b: O 1–[4–[4–(2–ciclopentilsulfonilpropan–2– 516 2,42 OR 1– [4– [4– (2 – cyclopentyl sulfonylpropan – 2– 516 2.42

N N N S O O N H N H O N N N S O O N H N H O: il]pirimidin–2–il]fenil]–3–etil–urea il] pyrimidin – 2-yl] phenyl] –3-ethyl-urea

64c 64c: N N N O S O O N H N H O N 1–[4–[4–(2–ciclopentilsulfonilpropan–2– il)–6–[(3S)–3–metilmorfolin–4– il]pirimidin–2–il]fenil]–3–(2– dimetilaminoetil)urea 559 2,35 N N N O S O O N H N H O N 1– [4– [4– (2 – cyclopentylsulfonylpropan – 2– yl) –6 - [(3S) –3 – methylmorpholin-4– yl] pyrimidin – 2-yl] phenyl] –3– (2– dimethylaminoethyl) urea 559 2.35

64d 64d: N N N O S O O N H N H O OH 1–[4–[4–(2–ciclopentilsulfonilpropan–2– il)–6–[(3S)–3–metilmorfolin–4– il]pirimidin–2–il]fenil]–3–(2– hidroxietil)urea 532 2,04 N N N O S O O N H N H O OH 1– [4– [4– (2 – cyclopentylsulfonylpropan – 2– yl) –6 - [(3S) –3 – methylmorpholin-4– yl] pyrimidin – 2-yl] phenyl] –3– (2– hydroxyethyl) urea 532 2.04

64e 64e: O 1–[4–[4–(2–ciclopentilsulfonilpropan–2– 502 2,26 OR 1– [4– [4– (2 – cyclopentyl sulfonylpropan – 2– 502 2.26

N N N S O O N H N H O N N N S O O N H N H O: il]pirimidin–2–il]fenil]–3–metil–urea il] pyrimidin – 2-yl] phenyl] –3-methyl-urea

64f 64f: N N N O S O O N H N H O 3–ciclobutil–1–[4–[4– (ciclopentilsulfonilmetil)–6–[(3S)–3– metilmorfolin–4–il]pirimidin–2– il]fenil]urea 514 2,36 N N N O S O O N H N H O 3 – cyclobutyl – 1– [4– [4– (cyclopentylsulfonylmethyl) –6 - [(3S) –3– methylmorpholin-4-yl] pyrimidin – 2– yl] phenyl] urea 514 2.36

64g 64g: O 1–[4–[4–(ciclopentilsulfonilmetil)–6– 488 2,13 OR 1– [4– [4– (cyclopentyl sulfonylmethyl) –6– 488 2.13

N N N S O O N H N H O N N N S O O N H N H O: il]fenil]–3–etil–urea il] phenyl] –3-ethyl-urea

64h 64h: O 1–[4–[4–(ciclopentilsulfonilmetil)–6– 531 2,08 OR 1– [4– [4– (cyclopentyl sulfonylmethyl) –6– 531 2.08

Ejemplo 64a: RMN 1H (400,132 MHz, DMSO–d6) δ 1,22 (3H, d), 1,39–1,68 (10H, m), 1,69–1,80 (6H, m), 1,86 (2H, q), 2,17–2,25 (2H, m), 3,16–3,24 (1H, m), 3,46–3,55 (1H, m), 3,65 (1H, dd), 3,77 (1H, d), 3,95 (1H, quinteto), 4,14 (1H, q), 4,22 (1H, d), 4,60 (1H, s), 6,46 (1H, d), 6,78 (1H, s), 7,48 (2H, d), 8,23 (2H, d), 8,57 (1H, s) Example 64a: 1H NMR (400.132 MHz, DMSO-d6) δ 1.22 (3H, d), 1.39-1.68 (10H, m), 1.69-1.80 (6H, m), 1 , 86 (2H, q), 2.17-2.25 (2H, m), 3.16-3.24 (1H, m), 3.46-3.55 (1H, m), 3.65 (1H, dd), 3.77 (1H, d), 3.95 (1H, quintet), 4.14 (1H, q), 4.22 (1H, d), 4.60 (1H, s) , 6.46 (1H, d), 6.78 (1H, s), 7.48 (2H, d), 8.23 (2H, d), 8.57 (1H, s)

5 Ejemplo 64b: RMN 1H (400,132 MHz, DMSO–d6) δ 1,07 (3H, t), 1,22 (3H, d), 1,41–1,48 (4H, m), 1,51–1,57 (4H, m), 1,70–1,79 (6H, m), 3,12 (2H, q), 3,16–3,24 (1H, m), 3,50 (1H, dd), 3,65 (1H, d), 3,77 (1H, d), 3,91–4,00 (2H, m), 4,22 (1H, d), 4,60 (1H, s), 6,17 (1H, t), 6,77 (1H, s), 7,49 (2H, d), 8,22 (2H, d), 8,67 (1H, s) 5 Example 64b: 1H NMR (400.132 MHz, DMSO-d6) δ 1.07 (3H, t), 1.22 (3H, d), 1.41-1.48 (4H, m), 1.51– 1.57 (4H, m), 1.70-1.79 (6H, m), 3.12 (2H, q), 3.16-3.24 (1H, m), 3.50 (1H, dd), 3.65 (1H, d), 3.77 (1H, d), 3.91-4.00 (2H, m), 4.22 (1H, d), 4.60 (1H, s ), 6.17 (1H, t), 6.77 (1H, s), 7.49 (2H, d), 8.22 (2H, d), 8.67 (1H, s)

Ejemplo 64c: RMN 1H (400,132 MHz, DMSO–d6) δ 1,22 (3H, d), 1,41–1,48 (4H, m), 1,52–1,58 (4H, m), 1,69–1,79 (6H, m), 2,19 (6H, s), 2,33 (2H, t), 3,16–3,24 (3H, m), 3,50 (1H, td), 3,65 (1H, dd), 3,77 (1H, d), 3,90–4,01 (2H, m), Example 64c: 1H NMR (400.132 MHz, DMSO-d6) δ 1.22 (3H, d), 1.41-1.48 (4H, m), 1.52-1.58 (4H, m), 1 , 69–1.79 (6H, m), 2.19 (6H, s), 2.33 (2H, t), 3.16–3.24 (3H, m), 3.50 (1H, td ), 3.65 (1H, dd), 3.77 (1H, d), 3.90-4.01 (2H, m),

10 4,22 (1H, d), 4,59 (1H, s), 6,15 (1H, t), 6,78 (1H, s), 7,49 (2H, d), 8,23 (2H, d), 8,90 (1H, s) 10 4.22 (1H, d), 4.59 (1H, s), 6.15 (1H, t), 6.78 (1H, s), 7.49 (2H, d), 8.23 ( 2H, d), 8.90 (1H, s)

Ejemplo 64d: RMN 1H (400,132 MHz, DMSO–d6) δ 1,22 (3H, d), 1,41–1,47 (4H, m), 1,50–1,58 (4H, m), 1,70–1,79 (6H, m), 3,15–3,24 (3H, m), 3,44–3,54 (3H, m), 3,65 (1H, dd), 3,77 (1H, d), 3,91–4,00 (2H, m), 4,22 (1H, d), 4,60 (1H, s), 4,73 (1H, t), 6,26 (1H, t), 6,77 (1H, s), 7,49 (2H, d), 8,23 (2H, d), 8,82 (1H, s) Example 64d: 1H NMR (400.132 MHz, DMSO-d6) δ 1.22 (3H, d), 1.41-1.47 (4H, m), 1.50-1.58 (4H, m), 1 , 70–1.79 (6H, m), 3.15–3.24 (3H, m), 3.44–3.54 (3H, m), 3.65 (1H, dd), 3.77 (1H, d), 3.91-4.00 (2H, m), 4.22 (1H, d), 4.60 (1H, s), 4.73 (1H, t), 6.26 ( 1H, t), 6.77 (1H, s), 7.49 (2H, d), 8.23 (2H, d), 8.82 (1H, s)

Ejemplo 64e: RMN 1H (400,132 MHz, DMSO–d6) δ 1,22 (3H, d), 1,41–1,49 (4H, m), 1,51–1,58 (4H, m), 1,68–1,81 Example 64e: 1H NMR (400.132 MHz, DMSO-d6) δ 1.22 (3H, d), 1.41-1.49 (4H, m), 1.51-1.58 (4H, m), 1 , 68–1.81

15 (6H, m), 2,67 (3H, d), 3,16–3,24 (1H, m), 3,50 (1H, td), 3,65 (1H, dd), 3,77 (1H, d), 3,91–4,00 (2H, m), 4,22 (1H, d), 4,60 (1H, s), 6,07 (1H, t), 6,77 (1H, s), 7,50 (2H, d), 8,23 (2H, d), 8,75 (1H, s) 15 (6H, m), 2.67 (3H, d), 3.16-3.24 (1H, m), 3.50 (1H, td), 3.65 (1H, dd), 3.77 (1H, d), 3.91-4.00 (2H, m), 4.22 (1H, d), 4.60 (1H, s), 6.07 (1H, t), 6.77 ( 1H, s), 7.50 (2H, d), 8.23 (2H, d), 8.75 (1H, s)

Ejemplo 64f: RMN 1H (400,132 MHz, DMSO–d6) δ 1,24 (3H, d), 1,57–1,74 (6H, m), 1,82–1,90 (2H, m), 1,93–2,07 (4H, m), 2,17–2,25 (2H, m), 3,16–3,27 (1H, m), 3,50 (1H, td), 3,65 (1H, dd), 3,73–3,83 (1H, m), 3,99 (1H, dd), 4,10– 4,20 (2H, m), 4,45 (2H, s), 4,49 (1H, s), 6,47 (1H, d), 6,79 (1H, s), 7,47 (2H, d), 8,19 (2H, d), 8,56 (1H, s) Example 64f: 1H NMR (400.132 MHz, DMSO-d6) δ 1.24 (3H, d), 1.57-1.74 (6H, m), 1.82-1.90 (2H, m), 1 , 93-2.07 (4H, m), 2.17-2.25 (2H, m), 3.16-3.27 (1H, m), 3.50 (1H, td), 3.65 (1H, dd), 3.73-3.83 (1H, m), 3.99 (1H, dd), 4.10-4.20 (2H, m), 4.45 (2H, s), 4.49 (1H, s), 6.47 (1H, d), 6.79 (1H, s), 7.47 (2H, d), 8.19 (2H, d), 8.56 (1H , s)

Ejemplo 64g: RMN 1H (400,132 MHz, DMSO–d6) δ 1,07 (3H, t), 1,24 (3H, d), 1,60–1,74 (4H, m), 1,89–2,06 (4H, m), 3,09–3,16 (2H, m), 3,18–3,26 (1H, m), 3,46–3,54 (1H, m), 3,65 (1H, dd), 3,75–3,83 (2H, m), 3,99 (1H, dd), 4,17 (1H, d), 4,43 (2H, s), 4,49 (1H, s), 6,16 (1H, t), 6,79 (1H, s), 7,49 (2H, d), 8,19 (2H, d), 8,66 (1H, s) Example 64g: 1H NMR (400.132 MHz, DMSO-d6) δ 1.07 (3H, t), 1.24 (3H, d), 1.60-1.74 (4H, m), 1.89-2 , 06 (4H, m), 3.09-3.16 (2H, m), 3.18-3.26 (1H, m), 3.46-3.54 (1H, m), 3.65 (1H, dd), 3.75-3.83 (2H, m), 3.99 (1H, dd), 4.17 (1H, d), 4.43 (2H, s), 4.49 ( 1H, s), 6.16 (1H, t), 6.79 (1H, s), 7.49 (2H, d), 8.19 (2H, d), 8.66 (1H, s)

Ejemplo 64h: RMN 1H (400,132 MHz, DMSO–d6) δ 1,24 (3H, d), 1,60–1,74 (4H, m), 1,91–2,07 (4H, m), 2,19 (6H, s), 2,34 (2H, t), 3,16–3,22 (3H, m), 3,50 (2H, td), 3,65 (2H, dd), 3,74–3,83 (2H, m), 3,99 (2H, dd), 4,16 (1H, d), 4,44 (2H, s), 4,51 (1H, s), 6,17 (1H, t), 6,78 (1H, s), 7,49 (2H, d), 8,19 (2H, d), 8,89 (1H, s) Example 64h: 1H NMR (400.132 MHz, DMSO-d6) δ 1.24 (3H, d), 1.60-1.74 (4H, m), 1.91-2.07 (4H, m), 2 , 19 (6H, s), 2.34 (2H, t), 3.16-3.22 (3H, m), 3.50 (2H, td), 3.65 (2H, dd), 3, 74–3.83 (2H, m), 3.99 (2H, dd), 4.16 (1H, d), 4.44 (2H, s), 4.51 (1H, s), 6.17 (1H, t), 6.78 (1H, s), 7.49 (2H, d), 8.19 (2H, d), 8.89 (1H, s)

A continuación se describe la preparación de N–[4–[4–(2–ciclopentilsulfonilpropan–2–il)–6–[(3S)–3–metilmorfolin–4– il]pirimidin–2–il]fenil]carbamato de fenilo. The preparation of N– [4– [4– (2-cyclopentylsulfonylpropan – 2-yl) –6 - [(3S) –3-methylmorpholin-4– yl] pyrimidin-2-yl] phenyl] carbamate is described below. phenyl.

N–[4–[4–(2–Ciclopentilsulfonilpropan–2–il)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]carbamato de fenilo N– [4– [4– (2 – Cyclopentylsulfonylpropan – 2-yl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] phenyl carbamate

Se añadió cloroformiato de fenilo (0,635 ml, 5,06 mmoles) a 4–[4–(2–ciclopentilsulfonilpropan–2–il)–6–[(3S)–3– metilmorfolin–4–il]pirimidin–2–il]anilina (1,5 g, 3,37 mmoles) e hidrogenocarbonato de sodio (0,425 g, 5,06 mmoles) en dioxano (20 ml) a 5ºC en nitrógeno. La mezcla resultante se agitó a RT durante 2 horas. La mezcla de reacción se diluyó con acetato de etilo (200 ml), y se lavó con agua (125 ml). La capa orgánica se secó (MgSO4), se filtró y se evaporó para proporcionar el producto bruto el cual se trituró con una mezcla de éter dietílico e isohexano para dar el material deseado como un sólido blanco (1,30 g). Phenyl chloroformate (0.635 ml, 5.06 mmol) was added at 4– [4– (2-cyclopentylsulfonylpropan-2-yl) –6 - [(3S) –3– methylmorpholin-4-yl] pyrimidin-2-yl ] aniline (1.5 g, 3.37 mmol) and sodium hydrogen carbonate (0.425 g, 5.06 mmol) in dioxane (20 ml) at 5 ° C under nitrogen. The resulting mixture was stirred at RT for 2 hours. The reaction mixture was diluted with ethyl acetate (200 ml), and washed with water (125 ml). The organic layer was dried (MgSO4), filtered and evaporated to provide the crude product which was triturated with a mixture of diethyl ether and isohexane to give the desired material as a white solid (1.30 g).

Espectro RMN: RMN 1H (400,132 MHz, DMSO–d6) δ 1,23 (3H, d), 1,41–1,47 (2H, m), 1,50–1,57 (2H, m), 1,69–1,78 (4H, m), 1,79 (6H, d), 3,21 (1H, td), 3,51 (1H, td), 3,65 (1H, dd), 3,77 (1H, d), 3,92–4,01 (2H, m), 4,24 (1H, d), 4,62 (1H, s), 6,82 (1H, s), 7,23–7,31 (3H, m), 7,42–7,48 (2H, m), 7,64 (2H, d), 8,34 (2H, d), 10,45 (1H, s) NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.23 (3H, d), 1.41-1.47 (2H, m), 1.50–1.57 (2H, m), 1 , 69–1.78 (4H, m), 1.79 (6H, d), 3.21 (1H, td), 3.51 (1H, td), 3.65 (1H, dd), 3, 77 (1H, d), 3.92-4.01 (2H, m), 4.24 (1H, d), 4.62 (1H, s), 6.82 (1H, s), 7.23 –7.31 (3H, m), 7.42–7.48 (2H, m), 7.64 (2H, d), 8.34 (2H, d), 10.45 (1H, s)

Espectro LCMS: MH+ 565, tiempo de retención 3,0 min. LCMS spectrum: MH + 565, retention time 3.0 min.

4–[4–(2–Ciclopentilsulfonilpropan–2–il)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]anilina 4– [4– (2 – Cyclopentylsulfonylpropan – 2-yl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin – 2-yl] aniline

Se añadió cloruro de bis(trifenilfosfina)paladio(II) (200 mg, 0,28 mmoles) a 2–cloro–4–(2–ciclopentilsulfonilpropan–2– il)–6–[(3S)–3–metilmorfolin–4–il]pirimidina (1,66 g, 4,28 mmoles), 4–(4,4,5,5–tetrametil–1,3,2–dioxaborolan–2– il)anilina (1,406 g, 6,42 mmoles) y carbonato de sodio (10 ml, 20,00 mmoles) en una mezcla de etanol (5 ml), DMF (10 ml), agua (7 ml) y DME (25 ml) a RT. La mezcla resultante se desgasificó, y después se agitó a 95ºC durante 18 horas. La mezcla de reacción se dejó enfriar y se diluyó con acetato de etilo (200 ml), después se lavó con agua (2 x 150 ml), y salmuera (150 ml). La capa orgánica se secó (Na2SO4), se filtró y se evaporó para proporcionar el producto bruto. El producto bruto se purificó mediante cromatografía ultrarrápida en sílice, gradiente de elución 10 a 60% de acetato de etilo en isohexano, y el residuo obtenido se trituró con una mezcla de éter dietílico e isohexano para dar el material deseado como un sólido rosa pálido (1,52 g). Bis (triphenylphosphine) palladium (II) chloride (200 mg, 0.28 mmol) was added to 2-chloro-4- (2-cyclopentylsulfonylpropan-2-yl) -6 - [(3S) -3-methylmorpholin-4 -Yl] pyrimidine (1.66 g, 4.28 mmol), 4– (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (1,406 g, 6.42 mmol ) and sodium carbonate (10 ml, 20.00 mmol) in a mixture of ethanol (5 ml), DMF (10 ml), water (7 ml) and DME (25 ml) at RT. The resulting mixture was degassed, and then stirred at 95 ° C for 18 hours. The reaction mixture was allowed to cool and diluted with ethyl acetate (200 ml), then washed with water (2 x 150 ml), and brine (150 ml). The organic layer was dried (Na2SO4), filtered and evaporated to provide the crude product. The crude product was purified by flash chromatography on silica, gradient elution 10 to 60% ethyl acetate in isohexane, and the residue obtained was triturated with a mixture of diethyl ether and isohexane to give the desired material as a pale pink solid ( 1.52 g).

Espectro RMN: RMN 1H (400,132 MHz, DMSO–d6) δ 1,21 (3H, d), 1,41–1,50 (2H, m), 1,52–1,60 (2H, m), 1,69–1,80 (10H, m), 3,17 (1H, td), 3,49 (1H, td), 3,64 (1H, dd), 3,76 (1H, d), 3,90–3,99 (2H, m), 4,18 (1H, d), 4,56 (1H, s), 5,57 (2H, s), 6,61 (2H, d), 6,68 (1H, s), 8,06 (2H, d) NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.21 (3H, d), 1.41-1.50 (2H, m), 1.52–1.60 (2H, m), 1 , 69-1.80 (10H, m), 3.17 (1H, td), 3.49 (1H, td), 3.64 (1H, dd), 3.76 (1H, d), 3, 90–3.99 (2H, m), 4.18 (1H, d), 4.56 (1H, s), 5.57 (2H, s), 6.61 (2H, d), 6.68 (1H, s), 8.06 (2H, d)

Espectro LCMS: MH+ 445, tiempo de retención 2,42 min. LCMS spectrum: MH + 445, retention time 2.42 min.

2–Cloro–4–(2–ciclopentilsulfonilpropan–2–il)–6–[(3S)–3–metilmorfolin–4–il]pirimidina 2 – Chloro – 4– (2 – cyclopentylsulfonylpropan – 2-yl) –6 - [(3S) –3 – methylmorpholin-4-yl] pyrimidine

Se añadió terc–butóxido de sodio (5,56 mmoles) a una disolución de 2–cloro–4–(ciclopentilsulfonilmetil)–6–[(3S)–3– metilmorfolin–4–il]pirimidina (2 g, 5,56 mmoles) en DMF (10 ml) a –5ºC, seguido por la adición gota a gota de yodometano (0,365 ml) a –5ºC. Se añadieron terc–butóxido de sodio (5,56 mmoles) y yodometano (0,365 ml) adicionales, y la reacción se agitó a –5ºC toda la noche. La mezcla de reacción se diluyó con acetato de etilo (250 ml), y se lavó con agua (2 x 150 ml). La capa orgánica se secó (MgSO4), se filtró y se evaporó para proporcionar el producto bruto el cual se trituró con una mezcla de éter dietílico e isohexano para dar el material deseado como un sólido color crema (1,66 g). Sodium tert-butoxide (5.56 mmol) was added to a solution of 2-chloro-4- (cyclopentylsulfonylmethyl) -6 - [(3S) -3- methylmorpholin-4-yl] pyrimidine (2 g, 5.56 mmol) in DMF (10 ml) at –5 ° C, followed by the dropwise addition of iodomethane (0.365 ml) at –5 ° C. Additional sodium tert-butoxide (5.56 mmol) and iodomethane (0.365 ml) were added, and the reaction was stirred at -5 ° C overnight. The reaction mixture was diluted with ethyl acetate (250 ml), and washed with water (2 x 150 ml). The organic layer was dried (MgSO4), filtered and evaporated to provide the crude product which was triturated with a mixture of diethyl ether and isohexane to give the desired material as a cream-colored solid (1.66 g).

Espectro RMN: RMN 1H (400,132 MHz, DMSO–d6) δ 1,20 (4H, d), 1,46–1,61 (6H, m), 1,69–1,84 (12H, m), 1,70 (9H, s), 3,20 (3H, td), 3,45 (1H, td), 3,60 (1H, dd), 3,75 (1H, s), 3,85 (2H, q), 3,96 (1H, d), 4,06 (1H, d), 4,46 (1H, s), 6,90 (1H, s) NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.20 (4H, d), 1.46–1.61 (6H, m), 1.69-1.84 (12H, m), 1 , 70 (9H, s), 3.20 (3H, td), 3.45 (1H, td), 3.60 (1H, dd), 3.75 (1H, s), 3.85 (2H, q), 3.96 (1H, d), 4.06 (1H, d), 4.46 (1H, s), 6.90 (1H, s)

Espectro LCMS: MH+ 388, tiempo de retención 2,47 min. LCMS spectrum: MH + 388, retention time 2.47 min.

2–Cloro–4–(ciclopentilsulfonilmetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidina 2 – Chloro – 4– (cyclopentylsulfonylmethyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidine

Se añadió peróxido de hidrógeno (19,54 ml, 632 mmoles) a 2–cloro–4–(ciclopentilsulfanilmetil)–6–[(3S)–3– metilmorfolin–4–il]pirimidina (10,36 g, 31,60 mmoles), volframato de sodio dihidratado (0,208 g, 0,63 mmoles) (disuelto en una mínima cantidad de agua) y disolución de ácido sulfúrico 2M (0,177 ml) en dioxano (100 ml) a 55ºC al aire. La disolución resultante se agitó a 55ºC durante 2 horas. La mezcla de reacción se diluyó con acetato de etilo (100 ml), y se lavó con agua, y después con una disolución acuosa al 10% de metabisulfito de sodio. La capa orgánica se secó (MgSO4), se filtró y se evaporó para proporcionar el producto bruto. El producto bruto se purificó mediante cromatografía ultrarrápida en sílice, gradiente de elución 5 a 70% de acetato de etilo en isohexano, para dar el material deseado como una goma incolora (9,7 g). Hydrogen peroxide (19.54 ml, 632 mmol) was added to 2-chloro-4- (cyclopentylsulfanylmethyl) -6 - [(3S) -3- methylmorpholin-4-yl] pyrimidine (10.36 g, 31.60 mmol), sodium dihydrate volphramate (0.208 g, 0.63 mmol) (dissolved in a minimum amount of water) and 2M sulfuric acid solution (0.177 ml) in dioxane (100 ml) at 55 ° C in air. The resulting solution was stirred at 55 ° C for 2 hours. The reaction mixture was diluted with ethyl acetate (100 ml), and washed with water, and then with a 10% aqueous solution of sodium metabisulfite. The organic layer was dried (MgSO4), filtered and evaporated to provide the crude product. The crude product was purified by flash chromatography on silica, gradient elution 5 to 70% ethyl acetate in isohexane, to give the desired material as a colorless gum (9.7 g).

Espectro RMN: RMN 1H (400,132 MHz, DMSO–d6) δ 1,22 (3H, d), 1,64 (4H, m), 1,95 (4H, m), 3,24 (1H, m), 3,45 (1H, td), 3,60 (1H, dd), 3,71 (1H, m), 3,95 (2H, m), 4,35 (1H, s), 4,40 (2H, s), 6,91 (1H, s) NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.22 (3H, d), 1.64 (4H, m), 1.95 (4H, m), 3.24 (1H, m), 3.45 (1H, td), 3.60 (1H, dd), 3.71 (1H, m), 3.95 (2H, m), 4.35 (1H, s), 4.40 (2H , s), 6.91 (1H, s)

Espectro de masa: MH+360 Mass spectrum: MH + 360

2–Cloro–4–(ciclopentilsulfanilmetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidina 2 – Chloro – 4– (cyclopentylsulfanylmethyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidine

Se añadió DIPEA (9,62 ml, 55,57 mmoles) a ciclopentanotiol (5,93 ml, 55,57 mmoles), en DMF (80 ml) a RT en nitrógeno. La disolución resultante se agitó a RT durante 20 minutos. Se añadió 2–cloro–4–(yodometil)–6–[(3S)–3– metilmorfolin–4–il]pirimidina (13,1g, 37,05 mmoles) a la reacción y se agitó durante 2 horas a RT. La mezcla de reacción se diluyó con acetato de etilo (500 ml), y se lavó con agua (2 x 200 ml). La capa orgánica se secó (MgSO4), se filtró y se evaporó para proporcionar el producto bruto. El producto bruto se purificó mediante cromatografía ultrarrápida en sílice, gradiente de elución 0 a 30% de acetato de etilo en isohexano, para dar el material deseado como una goma incolora (11,13 g). DIPEA (9.62 ml, 55.57 mmol) was added to cyclopentanotiol (5.93 ml, 55.57 mmol), in DMF (80 ml) at RT in nitrogen. The resulting solution was stirred at RT for 20 minutes. 2-Chloro-4- (iodomethyl) -6 - [(3S) -3- methylmorpholin-4-yl] pyrimidine (13.1g, 37.05 mmol) was added to the reaction and stirred for 2 hours at RT. The reaction mixture was diluted with ethyl acetate (500 ml), and washed with water (2 x 200 ml). The organic layer was dried (MgSO4), filtered and evaporated to provide the crude product. The crude product was purified by flash chromatography on silica, gradient elution 0 to 30% ethyl acetate in isohexane, to give the desired material as a colorless gum (11.13 g).

Espectro RMN: RMN 1H (400,132 MHz, DMSO–d6) δ 1,20 (3H, d), 1,43 (2H, m), 1,53 (2H, m), 1,65 (2H, m), 1,94 (2H, m), 3,16 (2H, m), 3,44 (1H, td), 3,71 (1H, d), 3,95 (2H, m), 4,35 (1H, s), 6,79 (1H, s) Espectro de masa: MH+ 328 NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.20 (3H, d), 1.43 (2H, m), 1.53 (2H, m), 1.65 (2H, m), 1.94 (2H, m), 3.16 (2H, m), 3.44 (1H, td), 3.71 (1H, d), 3.95 (2H, m), 4.35 (1H, s) , 6.79 (1H, s) Mass spectrum: MH + 328

La preparación de 2–cloro–4–(yodometil)–6–[(3S)–3–metilmorfolin–4–il]pirimidina se describió anteriormente A continuación se describe la preparación de N–[4–[4–(ciclopentilsulfonilmetil)–6–[(3S)–3–metilmorfolin–4– il]pirimidin–2–il]fenil]carbamato de fenilo. The preparation of 2-chloro-4- (iodomethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine was described above. The preparation of N– [4– [4– (cyclopentylsulfonylmethyl) –6 - [(3S) –3 – methylmorpholin-4– is described below. il] pyrimidin-2-yl] phenyl] phenyl carbamate.

N–[4–[4–(Ciclopentilsulfonilmetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]carbamato de fenilo N– [4– [4– (Cyclopentylsulfonylmethyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] phenyl carbamate

Se añadió cloroformiato de fenilo (0,759 ml, 6,05 mmoles) a 4–[4–(ciclopentilsulfonilmetil)–6–[(3S)–3–metilmorfolin– 4–il]pirimidin–2–il]anilina (1,68 g, 4,03 mmoles) e hidrogenocarbonato de sodio (0,508 g, 6,05 mmoles) en dioxano (20 ml) a 5ºC en nitrógeno. La mezcla resultante se agitó a RT durante 2 horas. La mezcla de reacción se diluyó con acetato de etilo (200 ml), y se lavó con agua (125 ml). La capa orgánica se secó (MgSO4), se filtró y se evaporó para proporcionar el producto bruto el cual se trituró con una mezcla de éter dietílico e isohexano para dar el material deseado como un sólido blanco (2,10 g). Phenyl chloroformate (0.759 ml, 6.05 mmol) was added at 4– [4– (cyclopentylsulfonylmethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-2-yl] aniline (1.68 g, 4.03 mmol) and sodium hydrogen carbonate (0.508 g, 6.05 mmol) in dioxane (20 ml) at 5 ° C under nitrogen. The resulting mixture was stirred at RT for 2 hours. The reaction mixture was diluted with ethyl acetate (200 ml), and washed with water (125 ml). The organic layer was dried (MgSO4), filtered and evaporated to provide the crude product which was triturated with a mixture of diethyl ether and isohexane to give the desired material as a white solid (2.10 g).

Espectro RMN: RMN 1H (400,132 MHz, DMSO–d6) δ 1,25 (3H, d), 1,57–1,76 (4H, m), 1,93–2,08 (4H, m), 3,24 (1H, td), 3,47–3,54 (1H, m), 3,66 (1H, dd), 3,75–3,84 (2H, m), 3,99 (1H, dd), 4,20 (1H, d), 4,47 (2H, s), 4,52 (1H, s), 6,84 (1H, s), 7,24–7,31 (3H, m), 7,42–7,48 (2H, m), 7,64 (2H, d), 8,29 (2H, d), 10,47 (1H, s) NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.25 (3H, d), 1.57–1.76 (4H, m), 1.93–2.08 (4H, m), 3 , 24 (1H, td), 3.47-3.54 (1H, m), 3.66 (1H, dd), 3.75-3.84 (2H, m), 3.99 (1H, dd ), 4.20 (1H, d), 4.47 (2H, s), 4.52 (1H, s), 6.84 (1H, s), 7.24–7.31 (3H, m) , 7.42–7.48 (2H, m), 7.64 (2H, d), 8.29 (2H, d), 10.47 (1H, s)

Espectro LCMS: MH+ 537, tiempo de retención 2,75 min. LCMS spectrum: MH + 537, retention time 2.75 min.

4–[4–(Ciclopentilsulfonilmetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]anilina 4– [4– (Cyclopentylsulfonylmethyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] aniline

Se añadió cloruro de bis(trifenilfosfina)paladio(II) (118 mg, 0,17 mmoles) a 2–cloro–4–(ciclopentilsulfonilmetil)–6– [(3S)–3–metilmorfolin–4–il]pirimidina (1,67 g, 4,64 mmoles), 4–(4,4,5,5–tetrametil–1,3,2–dioxaborolan–2–il)anilina (1,525 g, 6,96 mmoles) y carbonato de sodio (10 ml, 20,00 mmoles) en una mezcla de etanol (6 ml), DMF (10 ml), agua (6 ml) y DME (20 ml) a RT. La mezcla resultante se desgasificó, y después se agitó a 95ºC durante 18 horas. La mezcla de reacción se diluyó con acetato de etilo (400 ml), y se lavó con agua (2 x 150 ml). La capa orgánica se secó (MgSO4), se filtró y se evaporó para proporcionar el producto bruto. El producto bruto se purificó mediante cromatografía ultrarrápida en sílice, gradiente de elución 10 a 60% de acetato de etilo en isohexano, para dar el material deseado como un sólido cristalino color crema (1,680 g). Bis (triphenylphosphine) palladium (II) chloride (118 mg, 0.17 mmol) was added to 2-chloro-4- (cyclopentylsulfonylmethyl) -6- [(3S) -3-methylmorpholin-4-yl] pyrimidine (1 , 67 g, 4.64 mmol), 4– (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (1,525 g, 6.96 mmol) and sodium carbonate ( 10 ml, 20.00 mmol) in a mixture of ethanol (6 ml), DMF (10 ml), water (6 ml) and DME (20 ml) at RT. The resulting mixture was degassed, and then stirred at 95 ° C for 18 hours. The reaction mixture was diluted with ethyl acetate (400 ml), and washed with water (2 x 150 ml). The organic layer was dried (MgSO4), filtered and evaporated to provide the crude product. The crude product was purified by flash chromatography on silica, gradient elution 10 to 60% ethyl acetate in isohexane, to give the desired material as a cream crystalline solid (1,680 g).

Espectro RMN: RMN 1H (400,132 MHz, DMSO–d6) δ 1,22 (3H, d), 1,58–1,73 (4H, m), 1,93–2,06 (4H, m), 3,19 (1H, td), 3,49 (1H, td), 3,64 (1H, dd), 3,74–3,82 (2H, m), 3,97 (1H, dd), 4,14 (1H, d), 4,39 (2H, s), 4,47 (1H, s), 5,57 (2H, s), 6,60 (2H, d), 6,67 (1H, s), 8,03 (2H, d) NMR Spectrum: 1H NMR (400.132 MHz, DMSO – d6) δ 1.22 (3H, d), 1.58–1.73 (4H, m), 1.93–2.06 (4H, m), 3 , 19 (1H, td), 3.49 (1H, td), 3.64 (1H, dd), 3.74-3.82 (2H, m), 3.97 (1H, dd), 4, 14 (1H, d), 4.39 (2H, s), 4.47 (1H, s), 5.57 (2H, s), 6.60 (2H, d), 6.67 (1H, s ), 8.03 (2H, d)

Espectro LCMS: MH+ 417, tiempo de retención 2,09 min. LCMS spectrum: MH + 417, retention time 2.09 min.

La preparación de 2–cloro–4–(ciclopentilsulfonilmetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidina se describió anteriormente. The preparation of 2-chloro-4- (cyclopentylsulfonylmethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine was described above.

Ejemplo 65: Example 65:

3 – Cyclopropyl – 1– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– [2– [2– (trifluoromethyl) phenyl] sulfonylpropan – 2-yl] pyrimidin– 2-yl ] phenyl] urea

O OR

NN

FF

F F OO F F OO

N S N S

N N

O OR

N N

N HH N HH

Se añadió trietilamina (0,197 ml, 1,40 mmoles) a una mezcla de N–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–[2–[2– (trifluorometil)fenil]sulfonilpropan–2–il]pirimidin–2–il]fenil]carbamato de fenilo (200 mg, 0,35 mmoles) y ciclopropilamina (1,40 mmoles) en NMP (2 ml) y se calentó a 75ºC durante 6 horas. La mezcla de reacción se Triethylamine (0.197 ml, 1.40 mmol) was added to a mixture of N– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– [2– [2– (trifluoromethyl) phenyl ] sulfonylpropan-2-yl] pyrimidin-2-yl] phenyl] phenyl carbamate (200 mg, 0.35 mmol) and cyclopropylamine (1.40 mmol) in NMP (2 ml) and heated at 75 ° C for 6 hours. The reaction mixture is

5 purificó mediante HPLC preparativa usando mezclas polares decrecientes de agua (que contiene 1% de NH3) y acetonitrilo como eluyentes, para dar el material deseado como un sólido (163 mg). 5 purified by preparative HPLC using decreasing polar mixtures of water (containing 1% NH3) and acetonitrile as eluents, to give the desired material as a solid (163 mg).

Espectro RMN: RMN 1H (400,132 MHz, DMSO–d6) δ 0,40–0,43 (2H, m), 0,63–0,66 (2H, m), 1,20 (3H, d), 1,84 (6H, d), 3,11–3,19 (1H, m), 3,49 (1H, dd), 3,64 (1H, dd), 3,76 (1H, d), 3,97 (1H, d), 4,13 (1H, d), 4,62 (1H, s), 6,41 (1H, d), 6,67 (1H, s), 7,32 (2H, d), 7,59 (2H, d), 7,78 (1H, d), 7,82–7,91 (2H, m), 7,97 (1H, d), 8,48 (1H, s) NMR Spectrum: 1H NMR (400.132 MHz, DMSO – d6) δ 0.40–0.43 (2H, m), 0.63–0.66 (2H, m), 1.20 (3H, d), 1 , 84 (6H, d), 3.11-3.19 (1H, m), 3.49 (1H, dd), 3.64 (1H, dd), 3.76 (1H, d), 3, 97 (1H, d), 4.13 (1H, d), 4.62 (1H, s), 6.41 (1H, d), 6.67 (1H, s), 7.32 (2H, d ), 7.59 (2H, d), 7.78 (1H, d), 7.82–7.91 (2H, m), 7.97 (1H, d), 8.48 (1H, s)

10 Espectro LCMS: MH+ 604, tiempo de retención 2,59 min. 10 LCMS spectrum: MH + 604, retention time 2.59 min.

Los siguientes compuestos se obtuvieron de manera análoga a partir de N–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–[2– [2–(trifluorometil)fenil]sulfonilpropan–2–il]pirimidin–2–il]fenil]carbamato de fenilo o N–[4–[4–[(3S)–3–metilmorfolin–4– il]–6–[[2–(trifluorometil)fenil]sulfonilmetil]pirimidin–2–il]fenil]carbamato de fenilo y la amina apropiada. The following compounds were obtained analogously from N– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– [2– [2– (trifluoromethyl) phenyl] sulfonylpropan – 2– il] pyrimidin-2-yl] phenyl] phenyl carbamate or N– [4– [4 - [(3S) –3-methylmorpholin-4– yl] –6 - [[2– (trifluoromethyl) phenyl] sulfonylmethyl] pyrimidin -2-yl] phenyl] phenyl carbamate and the appropriate amine.

65a 65th: O 3–ciclobutil–1–[4–[4–[(3S)–3– 618 2,83 OR 3 – cyclobutyl – 1– [4– [4 - [(3S) –3– 618 2.83

: metilmorfolin–4–il]–6–[2–[2– methylmorpholin – 4 – il] –6– [2– [2–

N N N S N H F F O O F N H O N N N S N H F F O O F N H O: (trifluorometil)fenil]sulfonilpropan–2– il]pirimidin–2–il]fenil]urea (trifluoromethyl) phenyl] sulfonylpropan-2-yl] pyrimidin-2-yl] phenyl] urea

65b 65b: O 3–etil–1–[4–[4–[(3S)–3–metilmorfolin–4– 592 2,60 OR 3 – ethyl – 1– [4– [4 - [(3S) –3 – methylmorpholin – 4– 592 2.60

: il]–6–[2–[2– il] –6– [2– [2–

65c 65c: O 3–(2–dimetilaminoetil)–1–[4–[4–[(3S)–3– 635 2,53 OR 3– (2 – dimethylaminoethyl) –1– [4– [4 - [(3S) –3– 635 2.53

N N N S N H F F O O F N H O N N N N S N H F F O O F N H O N: (trifluorometil)fenil]sulfonilpropan–2– il]pirimidin–2–il]fenil]urea (trifluoromethyl) phenyl] sulfonylpropan-2-yl] pyrimidin-2-yl] phenyl] urea

65d 65d: O 3–(2–hidroxietil)–1–[4–[4–[(3S)–3– 608 2,22 OR 3– (2 – hydroxyethyl) –1– [4– [4 - [(3S) –3– 608 2.22

N N N S N H F F O O F N H O OH N N N S N H F F O O F N H O OH: (trifluorometil)fenil]sulfonilpropan–2– il]pirimidin–2–il]fenil]urea (trifluoromethyl) phenyl] sulfonylpropan-2-yl] pyrimidin-2-yl] phenyl] urea

65e 65e: O 3–metil–1–[4–[4–[(3S)–3–metilmorfolin– 578 2,42 OR 3 – methyl – 1– [4– [4 - [(3S) –3 – methylmorpholin– 578 2.42

: 4–il]–6–[2–[2– 4 – il] –6– [2– [2–

65f 65f: N N N O S N H F F O O F N H O 3–ciclobutil–1–[4–[4–[(3S)–3– metilmorfolin–4–il]–6–[[2– (trifluorometil)fenil]sulfonilmetil]pirimidin– 2–il]fenil]urea 590 2,56 N N N O S N H F F O O F N H O 3 – cyclobutyl – 1– [4– [4 - [(3S) –3– methylmorpholin-4-yl] –6 - [[2– (trifluoromethyl) phenyl] sulfonylmethyl] pyrimidin– 2-yl] phenyl] urea 590 2.56

65g 65g: O 3–etil–1–[4–[4–[(3S)–3–metilmorfolin–4– 564 2,39 OR 3 – ethyl – 1– [4– [4 - [(3S) –3 – methylmorpholin – 4– 564 2.39

: il]–6–[[2–(trifluorometil)fenil]- il] –6 - [[2– (trifluoromethyl) phenyl] -

N N N S N H F F O O F N H O N N N S N H F F O O F N H O: sulfonilmetil]pirimidin–2–il]fenil]urea sulfonylmethyl] pyrimidin-2-yl] phenyl] urea

65h 65h: N N N O S N H F F O O F N H O N 3–(2–dimetilaminoetil)–1–[4–[4–[(3S)–3– metilmorfolin–4–il]–6–[[2– (trifluorometil)fenil]sulfonilmetil]pirimidin– 2–il]fenil]urea 607 1,32 N N N O S N H F F O O F N H O N 3– (2-dimethylaminoethyl) –1– [4– [4 - [(3S) –3– methylmorpholin-4-yl] –6 - [[2– (trifluoromethyl) phenyl] sulfonylmethyl] pyrimidin– 2-yl] phenyl ]urea 607 1.32

Ejemplo 65a: RMN 1H (400,132 MHz, DMSO–d6) δ 1,20 (3H, d), 1,57–1,68 (4H, m), 1,84 (6H, d), 2,18–2,25 (2H, m), 3,12–3,18 (1H, m), 3,45–3,53 (1H, m), 3,64 (1H, d), 3,76 (1H, d), 3,97 (1H, d), 4,09–4,18 (2H, m), 4,60 (1H, s), 6,43 (1H, d), 6,66 (1H, s), 7,29 (2H, d), 7,59 (2H, d), 7,78 (1H, d), 7,82–7,91 (2H, m), 7,97 (1H, d), 8,50 (1H, s) Example 65a: 1H NMR (400.132 MHz, DMSO-d6) δ 1.20 (3H, d), 1.57-1.68 (4H, m), 1.84 (6H, d), 2.18-2 , 25 (2H, m), 3.12-3.18 (1H, m), 3.45-3.53 (1H, m), 3.64 (1H, d), 3.76 (1H, d ), 3.97 (1H, d), 4.09-4.18 (2H, m), 4.60 (1H, s), 6.43 (1H, d), 6.66 (1H, s) , 7.29 (2H, d), 7.59 (2H, d), 7.78 (1H, d), 7.82-7.91 (2H, m), 7.97 (1H, d), 8.50 (1H, s)

5 Ejemplo 65b: RMN 1H (400,132 MHz, DMSO–d6) δ 1,06 (3H, t), 1,20 (3H, d), 1,82 (6H, d), 3,08–3,19 (2H, m), 3,49 (1H, dd), 3,64 (1H, dd), 3,77 (1H, d), 3,94–3,99 (1H, m), 4,12 (1H, d), 4,62 (1H, s), 6,14 (1H, t), 6,68 (1H, s), 7,30 (2H, d), 7,59 (2H, d), 7,77–7,80 (1H, m), 7,82–7,91 (2H, m), 7,97 (1H, d), 8,60 (1H, s) 5 Example 65b: 1H NMR (400.132 MHz, DMSO-d6) δ 1.06 (3H, t), 1.20 (3H, d), 1.82 (6H, d), 3.08-3.19 ( 2H, m), 3.49 (1H, dd), 3.64 (1H, dd), 3.77 (1H, d), 3.94-3.99 (1H, m), 4.12 (1H , d), 4.62 (1H, s), 6.14 (1H, t), 6.68 (1H, s), 7.30 (2H, d), 7.59 (2H, d), 7 , 77–7.80 (1H, m), 7.82–7.91 (2H, m), 7.97 (1H, d), 8.60 (1H, s)

Ejemplo 65c: RMN 1H (400,132 MHz, DMSO–d6) δ 1,20 (3H, d), 1,84 (6H, d), 2,20 (6H, s), 2,34 (2H, t), 3,09–3,21 (3H, m), 3,49 (1H, td), 3,64 (1H, dd), 3,76 (1H, d), 3,97 (1H, dd), 4,12 (1H, d), 4,61 (1H, s), 6,14 (1H, t), 6,67 (1H, s), Example 65c: 1H NMR (400.132 MHz, DMSO-d6) δ 1.20 (3H, d), 1.84 (6H, d), 2.20 (6H, s), 2.34 (2H, t), 3.09-3.21 (3H, m), 3.49 (1H, td), 3.64 (1H, dd), 3.76 (1H, d), 3.97 (1H, dd), 4 , 12 (1H, d), 4.61 (1H, s), 6.14 (1H, t), 6.67 (1H, s),

10 7,30 (2H, d), 7,59 (2H, d), 7,78 (2H, dd), 7,82–7,91 (2H, m), 7,97 (2H, d), 8,83 (1H, s) 10 7.30 (2H, d), 7.59 (2H, d), 7.78 (2H, dd), 7.82-7.91 (2H, m), 7.97 (2H, d), 8.83 (1H, s)

Ejemplo 65d: RMN 1H (400,132 MHz, DMSO–d6) δ 1,19 (3H, d), 1,85 (6H, d), 3,11–3,20 (3H, m), 3,43–3,53 (3H, m), 3,64 (1H, dd), 3,76 (1H, d), 3,97 (1H, dd), 4,13 (1H, d), 4,60 (1H, s), 4,72 (1H, t), 6,23 (1H, t), 6,67 (1H, s), 7,30 (2H, d), 7,59 (2H, d), 7,78 (1H, dd), 7,82–7,91 (2H, m), 7,95–7,99 (1H, m), 8,74 (1H, s) Example 65d: 1H NMR (400.132 MHz, DMSO-d6) δ 1.19 (3H, d), 1.85 (6H, d), 3.11-3.20 (3H, m), 3.43-3 , 53 (3H, m), 3.64 (1H, dd), 3.76 (1H, d), 3.97 (1H, dd), 4.13 (1H, d), 4.60 (1H, s), 4.72 (1H, t), 6.23 (1H, t), 6.67 (1H, s), 7.30 (2H, d), 7.59 (2H, d), 7, 78 (1H, dd), 7.82–7.91 (2H, m), 7.95–7.99 (1H, m), 8.74 (1H, s)

Ejemplo 65e: RMN 1H (400,132 MHz, DMSO–d6) δ 1,20 (3H, d), 1,84 (6H, d), 2,66 (3H, d), 3,15 (1H, td), 3,49 (1H, Example 65e: 1H NMR (400.132 MHz, DMSO-d6) δ 1.20 (3H, d), 1.84 (6H, d), 2.66 (3H, d), 3.15 (1H, td), 3.49 (1H,

15 td), 3,64 (1H, dd), 3,77 (1H, d), 3,97 (1H, dd), 4,12 (1H, d), 4,61 (1H, s), 6,02–6,07 (1H, m), 6,66 (1H, s), 7,31 (2H, d), 7,59 (2H, d), 7,76–7,80 (1H, m), 7,82–7,91 (2H, m), 7,95–7,99 (1H, m), 8,67 (1H, s) 15 td), 3.64 (1H, dd), 3.77 (1H, d), 3.97 (1H, dd), 4.12 (1H, d), 4.61 (1H, s), 6 , 02–6.07 (1H, m), 6.66 (1H, s), 7.31 (2H, d), 7.59 (2H, d), 7.76–7.80 (1H, m ), 7.82–7.91 (2H, m), 7.95–7.99 (1H, m), 8.67 (1H, s)

Ejemplo 65f: RMN 1H (400,132 MHz, DMSO–d6) δ 1,10 (3H, t), 1,20 (3H, d), 1,58–1,67 (2H, m), 1,81–1,92 (2H, m), 2,16–2,25 (2H, m), 3,12–3,22 (1H, m), 3,44–3,52 (1H, m), 3,63 (1H, d), 3,97 (1H, d), 4,06–4,17 (2H, m), 4,44 (1H, s), 4,77 (2H, s), 6,45 (1H, d), 6,71 (1H, s), 7,33 (2H, d), 7,71 (2H, d), 7,76–7,82 (1H, m), 7,87–7,93 (2H, m), 8,09 (1H, d), Example 65f: 1H NMR (400.132 MHz, DMSO-d6) δ 1.10 (3H, t), 1.20 (3H, d), 1.58-1.67 (2H, m), 1.81-1 , 92 (2H, m), 2.16-2.25 (2H, m), 3.12-3.22 (1H, m), 3.44-3.52 (1H, m), 3.63 (1H, d), 3.97 (1H, d), 4.06-4.17 (2H, m), 4.44 (1H, s), 4.77 (2H, s), 6.45 ( 1H, d), 6.71 (1H, s), 7.33 (2H, d), 7.71 (2H, d), 7.76–7.82 (1H, m), 7.87–7 , 93 (2H, m), 8.09 (1H, d),

20 8,52 (1H, s) 20 8.52 (1H, s)

Ejemplo 65g: RMN 1H (400,132 MHz, DMSO–d6) δ 1,07 (3H, t), 1,21 (3H, d), 3,08–3,22 (3H, m), 3,48 (1H, td), 3,64 (1H, dd), 3,77 (1H, d), 3,97 (1H, dd), 4,11 (1H, d), 4,44 (1H, s), 4,78 (2H, s), 6,15 (1H, t), 6,70 (1H, s), 7,35 (2H, d), 7,72 (2H, d), 7,79 (1H, t), 7,87–7,93 (2H, m), 8,08 (1H, d), 8,61 (1H, s) Example 65g: 1H NMR (400.132 MHz, DMSO-d6) δ 1.07 (3H, t), 1.21 (3H, d), 3.08-3.22 (3H, m), 3.48 (1H , td), 3.64 (1H, dd), 3.77 (1H, d), 3.97 (1H, dd), 4.11 (1H, d), 4.44 (1H, s), 4 , 78 (2H, s), 6.15 (1H, t), 6.70 (1H, s), 7.35 (2H, d), 7.72 (2H, d), 7.79 (1H, t), 7.87–7.93 (2H, m), 8.08 (1H, d), 8.61 (1H, s)

Ejemplo 65h: RMN 1H (400,132 MHz, DMSO–d6) δ 1,21 (3H, d), 2,19 (6H, s), 2,33 (2H, t), 3,13–3,22 (3H, m), 3,44– 3,53 (1H, m), 3,64 (1H, dd), 3,76 (1H, d), 3,97 (1H, dd), 4,10 (1H, d), 4,44 (1H, s), 4,76 (2H, s), 6,14 (1H, t), 6,70 (1H, s), 7,34 (2H, d), 7,71 (2H, d), 7,79 (1H, t), 7,87–7,92 (2H, m), 8,08 (1H, d), 8,84 (1H, s) Example 65h: 1H NMR (400.132 MHz, DMSO-d6) δ 1.21 (3H, d), 2.19 (6H, s), 2.33 (2H, t), 3.13-3.22 (3H , m), 3.44-3.53 (1H, m), 3.64 (1H, dd), 3.76 (1H, d), 3.97 (1H, dd), 4.10 (1H, d), 4.44 (1H, s), 4.76 (2H, s), 6.14 (1H, t), 6.70 (1H, s), 7.34 (2H, d), 7, 71 (2H, d), 7.79 (1H, t), 7.87-7.92 (2H, m), 8.08 (1H, d), 8.84 (1H, s)

A continuación se describe la preparación de N–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–[2–[2– (trifluorometil)fenil]sulfonilpropan–2–il]pirimidin–2–il]fenil]carbamato de fenilo. The preparation of N– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– [2– [2– (trifluoromethyl) phenyl] sulfonylpropan – 2-yl] pyrimidin- 2-yl] phenyl] phenyl carbamate.

N–[4–[4–[(3S)–3–Metilmorfolin–4–il]–6–[2–[2–(trifluorometil)fenil]sulfonilpropan–2–il]pirimidin–2–il]fenil]carbamato de fenilo N– [4– [4 - [(3S) –3 – Methylmorpholin-4-yl] –6– [2– [2– (trifluoromethyl) phenyl] sulfonylpropan – 2-yl] pyrimidin-2-yl] phenyl] carbamate phenyl

Se añadió cloroformiato de fenilo (0,542 ml, 4,32 mmoles) a 4–[4–[(3S)–3–metilmorfolin–4–il]–6–[2–[2– (trifluorometil)fenil]sulfonilpropan–2–il]pirimidin–2–il]anilina (1,5 g, 2,88 mmoles) e hidrogenocarbonato de sodio (0,363 g, 4,32 mmoles) en dioxano (20 ml) a 5ºC en nitrógeno. La mezcla resultante se agitó a RT durante 2 horas, después se diluyó con acetato de etilo (200 ml), y se lavó con agua (125 ml). La capa orgánica se secó (MgSO4), se filtró y se evaporó para proporcionar el producto bruto el cual se trituró con una mezcla de éter dietílico e isohexano para dar el material deseado como un sólido blanco (1,38 g). Phenyl chloroformate (0.542 ml, 4.32 mmol) was added at 4– [4 - [(3 S) –3-methylmorpholin-4-yl] –6– [2– [2– (trifluoromethyl) phenyl] sulfonylpropan – 2 -Yl] pyrimidin-2-yl] aniline (1.5 g, 2.88 mmol) and sodium hydrogen carbonate (0.363 g, 4.32 mmol) in dioxane (20 ml) at 5 ° C under nitrogen. The resulting mixture was stirred at RT for 2 hours, then diluted with ethyl acetate (200 ml), and washed with water (125 ml). The organic layer was dried (MgSO4), filtered and evaporated to provide the crude product which was triturated with a mixture of diethyl ether and isohexane to give the desired material as a white solid (1.38 g).

Espectro RMN: RMN 1H (400,132 MHz, DMSO–d6) δ 1,21 (3H, d), 1,85 (6H, d), 3,16 (1H, td), 3,45–3,54 (1H, m), 3,65 (1H, dd), 3,77 (1H, d), 3,97 (1H, dd), 4,15 (1H, d), 4,63 (1H, s), 6,71 (1H, s), 7,23–7,29 (3H, m), 7,42–7,47 (4H, m), 7,69 (2H, d), 7,78 (1H, d), 7,82–7,92 (2H, m), 7,98 (1H, d), 10,37 (1H, s) NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.21 (3H, d), 1.85 (6H, d), 3.16 (1H, td), 3.45-3.54 (1H , m), 3.65 (1H, dd), 3.77 (1H, d), 3.97 (1H, dd), 4.15 (1H, d), 4.63 (1H, s), 6 , 71 (1H, s), 7.23–7.29 (3H, m), 7.42–7.47 (4H, m), 7.69 (2H, d), 7.78 (1H, d ), 7.82–7.92 (2H, m), 7.98 (1H, d), 10.37 (1H, s)

Espectro LCMS: MH+ 641, tiempo de retención 3,08 min. LCMS spectrum: MH + 641, retention time 3.08 min.

4–[4–[(3S)–3–Metilmorfolin–4–il]–6–[2–[2–(trifluorometil)fenil]sulfonilpropan–2–il]pirimidin–2–il]anilina 4– [4 - [(3S) –3 – Methylmorpholin-4-yl] –6– [2– [2– (trifluoromethyl) phenyl] sulfonylpropan – 2-yl] pyrimidin-2-yl] aniline

O OR

NN

FF

F F OO F F OO

N S N S

N N

NH2 NH2

Se añadió cloruro de bis(trifenilfosfina)paladio(II) (200 mg, 0,28 mmoles) a 2–cloro–4–[(3S)–3–metilmorfolin–4–il]–6– [2–[2–(trifluorometil)fenil]sulfonilpropan–2–il]pirimidina (1,91 g, 4,12 mmoles), 4–(4,4,5,5–tetrametil–1,3,2– dioxaborolan–2–il)anilina (1,353 g, 6,18 mmoles) y carbonato de sodio (10 ml, 20,00 mmoles) en una mezcla de etanol (5 ml), DMF (10 ml), agua (7 ml) y DME (25 ml) a RT. La mezcla resultante se desgasificó, y después se agitó a 95ºC durante 18 horas. La mezcla de reacción se dejó enfriar y se diluyó con acetato de etilo (200 ml), y se lavó con agua (2 x 200 ml), y salmuera (100 ml). La capa orgánica se secó (Na2SO4), se filtró y se evaporó para proporcionar el producto bruto. El producto bruto se purificó mediante cromatografía ultrarrápida en sílice, gradiente de elución 10 a 60% de acetato de etilo en isohexano, y el material resultante se trituró con una mezcla de éter dietílico e isohexano para dar el material deseado como un sólido blanco (1,50 g). Bis (triphenylphosphine) palladium (II) chloride (200 mg, 0.28 mmol) was added to 2-chloro-4 - [(3S) -3-methylmorpholin-4-yl] –6– [2– [2– (trifluoromethyl) phenyl] sulfonylpropan-2-yl] pyrimidine (1.91 g, 4.12 mmol), 4– (4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl) aniline (1.353 g, 6.18 mmol) and sodium carbonate (10 ml, 20.00 mmol) in a mixture of ethanol (5 ml), DMF (10 ml), water (7 ml) and DME (25 ml) at RT. The resulting mixture was degassed, and then stirred at 95 ° C for 18 hours. The reaction mixture was allowed to cool and diluted with ethyl acetate (200 ml), and washed with water (2 x 200 ml), and brine (100 ml). The organic layer was dried (Na2SO4), filtered and evaporated to provide the crude product. The crude product was purified by flash chromatography on silica, gradient elution 10 to 60% ethyl acetate in isohexane, and the resulting material was triturated with a mixture of diethyl ether and isohexane to give the desired material as a white solid (1 , 50 g).

Espectro RMN: RMN 1H (400,132 MHz, DMSO–d6) δ 1,18 (3H, d), 1,82 (6H, d), 3,12 (1H, td), 3,47 (1H, td), 3,63 (1H, dd), 3,75 (1H, d), 3,95 (1H, dd), 4,08 (1H, d), 4,57 (1H, s), 5,47 (2H, s), 6,42 (2H, d), 6,56 (1H, s), 7,44 (2H, d), 7,78– 7,89 (3H, m), 7,92–7,96 (1H, m) NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.18 (3H, d), 1.82 (6H, d), 3.12 (1H, td), 3.47 (1H, td), 3.63 (1H, dd), 3.75 (1H, d), 3.95 (1H, dd), 4.08 (1H, d), 4.57 (1H, s), 5.47 (2H , s), 6.42 (2H, d), 6.56 (1H, s), 7.44 (2H, d), 7.78-7.89 (3H, m), 7.92–7, 96 (1H, m)

Espectro LCMS: MH+ 521, tiempo de retención 2,56 min. LCMS spectrum: MH + 521, retention time 2.56 min.

2–Cloro–4–[(3S)–3–metilmorfolin–4–il]–6–[2–[2–(trifluorometil)fenil]sulfonilpropan–2–il]pirimidina 2 – Chloro – 4 - [(3S) –3 – methylmorpholin-4-yl] –6– [2– [2– (trifluoromethyl) phenyl] sulfonylpropan – 2-yl] pyrimidine

NFNF

F F OO F F OO

N S N S

N Cl N Cl

O OR

Se añadió terc–butóxido de sodio (4,59 mmoles) a una disolución de 2–cloro–4–[(3S)–3–metilmorfolin–4–il]–6–[[2– (trifluorometil)fenil]sulfonilmetil]pirimidina (2 g, 4,59 mmoles) en DMF (10 ml) a –5ºC, seguido por la adición gota a gota de yodometano (0,030 ml) a –5ºC. Se añadieron terc–butóxido de sodio (4,59 mmoles) y yodometano (0,030 ml) adicionales, y la reacción se agitó a –5ºC durante toda la noche. Los productos orgánicos se eliminaron a vacío, y el residuo se repartió entre acetato de etilo (200 ml) y agua (100 ml). La capa orgánica se lavó con agua (100 ml), se secó (MgSO4), se filtró y se evaporó para proporcionar el producto bruto el cual se trituró con una mezcla de éter dietílico e isohexano para dar el material deseado como un sólido color crema (1,91 g). Sodium tert-butoxide (4.59 mmol) was added to a solution of 2-chloro-4 - [(3S) -3-methylmorpholin-4-yl] -6 - [[2- (trifluoromethyl) phenyl] sulfonylmethyl] pyrimidine (2 g, 4.59 mmol) in DMF (10 ml) at -5 ° C, followed by the dropwise addition of iodomethane (0.030 ml) at -5 ° C. Additional sodium tert-butoxide (4.59 mmol) and iodomethane (0.030 ml) were added, and the reaction was stirred at -5 ° C overnight. The organic products were removed in vacuo, and the residue was partitioned between ethyl acetate (200 ml) and water (100 ml). The organic layer was washed with water (100 ml), dried (MgSO4), filtered and evaporated to provide the crude product which was triturated with a mixture of diethyl ether and isohexane to give the desired material as a cream-colored solid. (1.91 g).

Espectro RMN: RMN 1H (400,132 MHz, DMSO–d6) δ 1,17 (3H, d), 3,13 (1H, td), 3,41 (1H, td), 3,57 (1H, dd), 3,71 (1H, d), 3,89–3,98 (2H, m), 4,46 (1H, s), 6,72 (1H, s), 7,87–8,02 (4H, m) NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.17 (3H, d), 3.13 (1H, td), 3.41 (1H, td), 3.57 (1H, dd), 3.71 (1H, d), 3.89-3.98 (2H, m), 4.46 (1H, s), 6.72 (1H, s), 7.87–8.02 (4H, m)

2–Cloro–4–[(3S)–3–metilmorfolin–4–il]–6–[[2–(trifluorometil)fenil]sulfonilmetil]pirimidina 2 – Chloro – 4 - [(3S) –3 – methylmorpholin-4-yl] –6 - [[2– (trifluoromethyl) phenyl] sulfonylmethyl] pyrimidine

O OR

NFNF

F F OO F F OO

N S N Cl N S N Cl

Se añadió 2–(trifluorometil)bencenosulfinato de sodio (10,24 g, 44 mmoles) a 2–cloro–4–(yodometil)–6–[(3S)–3– metilmorfolin–4–il]pirimidina (13 g, 36,77 mmoles), en acetonitrilo (500 ml) a RT en nitrógeno. La mezcla resultante se agitó a 80ºC durante 3 horas. Se añadió 2–(trifluorometil)bencenosulfinato de sodio adicional (10,2 g, 44 mmoles), y la reacción se calentó a 80ºC durante 1 hora. La mezcla de reacción se dejó enfriar y se concentró a vacío. El material se disolvió en acetato de etilo (500 ml), y se lavó con agua (200 ml). La capa orgánica se secó (MgSO4), se filtró y se evaporó para proporcionar el producto bruto. El producto bruto se purificó mediante cromatografía ultrarrápida en sílice, gradiente de elución 0 a 40% de acetato de etilo en isohexano, para dar el material deseado como un sólido color crema/naranja (9,48 g). Sodium 2– (trifluoromethyl) benzenesulphinate (10.24 g, 44 mmol) was added to 2-chloro-4– (iodomethyl) –6 - [(3 S) –3– methylmorpholin-4-yl] pyrimidine (13 g, 36.77 mmol), in acetonitrile (500 ml) at RT in nitrogen. The resulting mixture was stirred at 80 ° C for 3 hours. Additional 2 - (sodium trifluoromethyl) benzenesulphinate (10.2 g, 44 mmol) was added, and the reaction was heated at 80 ° C for 1 hour. The reaction mixture was allowed to cool and concentrated in vacuo. The material was dissolved in ethyl acetate (500 ml), and washed with water (200 ml). The organic layer was dried (MgSO4), filtered and evaporated to provide the crude product. The crude product was purified by flash chromatography on silica, gradient elution 0 to 40% ethyl acetate in isohexane, to give the desired material as a cream / orange solid (9.48 g).

Espectro RMN: RMN 1H (400,132 MHz, DMSO–d6) δ 1,18 (3H, d), 3,17 (1H, td), 3,43 (1H, td), 3,58 (1H, dd), 3,72 (1H, d), 3,93 (2H, m), 4,27 (1H, s), 4,68 (2H, s), 6,79 (1H, s), 7,94 (3H, m), 8,08 (1H, d) NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.18 (3H, d), 3.17 (1H, td), 3.43 (1H, td), 3.58 (1H, dd), 3.72 (1H, d), 3.93 (2H, m), 4.27 (1H, s), 4.68 (2H, s), 6.79 (1H, s), 7.94 (3H , m), 8.08 (1H, d)

Espectro LCMS: MH+ 436; tiempo de retención 2,35 min. LCMS spectrum: MH + 436; retention time 2.35 min.

2–(Trifluorometil)bencenosulfinato de sodio 2– (Sodium Trifluoromethyl) Benzenesulphinate

F Na+ F Na +

OOR

Se disolvió sulfito de sodio (3,92 ml, 81,88 mmoles) en agua y se agitó a RT 10 minutos. Se añadió bicarbonato de sodio (13,74 g, 163,52 mmoles), y la mezcla se agitó a 50ºC durante 1 hora. Se añadió gota a gota cloruro de 2– (trifluorometil)benceno–1–sulfonilo (12,62 ml, 81,76 mmoles) a la mezcla de reacción, que después se agitó a 50ºC durante 18 horas. La mezcla de reacción se evaporó hasta sequedad, y el residuo se suspendió en metanol (250 ml) y se agitó a RT durante 20 minutos. El sólido se eliminó por filtración, y el filtrado se evaporó para dar el material deseado (20,00 g). Sodium sulphite (3.92 ml, 81.88 mmol) was dissolved in water and stirred at RT 10 minutes. Sodium bicarbonate (13.74 g, 163.52 mmol) was added, and the mixture was stirred at 50 ° C for 1 hour. 2– (Trifluoromethyl) benzene-1-sulfonyl chloride (12.62 ml, 81.76 mmol) was added dropwise to the reaction mixture, which was then stirred at 50 ° C for 18 hours. The reaction mixture was evaporated to dryness, and the residue was suspended in methanol (250 ml) and stirred at RT for 20 minutes. The solid was removed by filtration, and the filtrate was evaporated to give the desired material (20.00 g).

Espectro RMN: RMN 1H (400,132 MHz, DMSO–d6) δ 7,40 (1H, d), 7,51 (1H, d), 7,64 (1H, d), 8,05 (1H, d) NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 7.40 (1H, d), 7.51 (1H, d), 7.64 (1H, d), 8.05 (1H, d)

A continuación se describe la preparación de N–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–[[2– (trifluorometil)fenil]sulfonilmetil]pirimidin–2–il]fenil]carbamato de fenilo. The preparation of N– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6 - [[2– (trifluoromethyl) phenyl] sulfonylmethyl] pyrimidin-2-yl] phenyl] is described below. phenyl carbamate.

30 N–[4–[4–[(3S)–3–Metilmorfolin–4–il]–6–[[2–(trifluorometil)fenil]sulfonilmetil]pirimidin–2–il]fenil]carbamato de fenilo 30 N– [4– [4 - [(3S) –3 – Methylmorpholin-4-yl] –6 - [[2– (trifluoromethyl) phenyl] sulfonylmethyl] pyrimidin-2-yl] phenyl] phenyl carbamate

Se añadió cloroformiato de fenilo (0,535 ml, 4,26 mmoles) a 4–[4–[(3S)–3–metilmorfolin–4–il]–6–[[2– (trifluorometil)fenil]sulfonilmetil]pirimidin–2–il]anilina (1,4 g, 2,84 mmoles) e hidrogenocarbonato de sodio (0,358 g, 4,26 mmoles) en dioxano (20 ml) a 5ºC en nitrógeno. La mezcla resultante se agitó a RT durante 2 horas, después la mezcla de reacción se diluyó con acetato de etilo (200 ml), y se lavó con agua (125 ml). La capa orgánica se secó (MgSO4), se filtró y se evaporó para proporcionar el producto bruto el cual se trituró con una mezcla de éter dietílico e isohexano para dar el material deseado como un sólido blanco (1,70 g). Phenyl chloroformate (0.535 ml, 4.26 mmol) was added at 4– [4 - [(3S) –3-methylmorpholin-4-yl] –6 - [[2– (trifluoromethyl) phenyl] sulfonylmethyl] pyrimidin – 2 -Yl] aniline (1.4 g, 2.84 mmol) and sodium hydrogen carbonate (0.358 g, 4.26 mmol) in dioxane (20 ml) at 5 ° C under nitrogen. The resulting mixture was stirred at RT for 2 hours, then the reaction mixture was diluted with ethyl acetate (200 ml), and washed with water (125 ml). The organic layer was dried (MgSO4), filtered and evaporated to provide the crude product which was triturated with a mixture of diethyl ether and isohexane to give the desired material as a white solid (1.70 g).

Espectro RMN: RMN 1H (400,132 MHz, DMSO–d6) δ 1,22 (3H, d), 3,19 (1H, td), 3,49 (1H, td), 3,64 (1H, dd), 3,77 (1H, d), 3,98 (1H, dd), 4,13 (1H, d), 4,47 (1H, s), 4,79 (2H, s), 6,75 (1H, s), 7,23–7,31 (3H, m), 7,42–7,51 (4H, m), 7,77–7,83 (2H, m), 7,87–7,92 (2H, m), 8,09 (1H, d), 10,39 (1H, s) NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.22 (3H, d), 3.19 (1H, td), 3.49 (1H, td), 3.64 (1H, dd), 3.77 (1H, d), 3.98 (1H, dd), 4.13 (1H, d), 4.47 (1H, s), 4.79 (2H, s), 6.75 (1H , s), 7.23–7.31 (3H, m), 7.42–7.51 (4H, m), 7.77–7.83 (2H, m), 7.87–7.92 (2H, m), 8.09 (1H, d), 10.39 (1H, s)

Espectro LCMS: MH+ 613, tiempo de retención 2,92 min. LCMS spectrum: MH + 613, retention time 2.92 min.

4–[4–[(3S)–3–Metilmorfolin–4–il]–6–[[2–(trifluorometil)fenil]sulfonilmetil]pirimidin–2–il]anilina 4– [4 - [(3S) –3 – Methylmorpholin-4-yl] –6 - [[2– (trifluoromethyl) phenyl] sulfonylmethyl] pyrimidin – 2-yl] aniline

O OR

NN

FF

F F OO F F OO

N S N S

N N

NH2 NH2

Se añadió cloruro de bis(trifenilfosfina)paladio(II) (300 mg, 0,43 mmoles) a 2–cloro–4–[(3S)–3–metilmorfolin–4–il]–6– [[2–(trifluorometil)fenil]sulfonilmetil]pirimidina (1,66 g, 3,81 mmoles), 4–(4,4,5,5–tetrametil–1,3,2–dioxaborolan–2– il)anilina (1,252 g, 5,71 mmoles) y carbonato de sodio (10 ml, 20,00 mmoles) en una mezcla de etanol (6 ml), DMF (10 ml), agua (6 ml) y DME (20 ml) a RT. La mezcla resultante se desgasificó, y después se agitó a 95ºC durante 18 horas. La mezcla de reacción se dejó enfriar, después se diluyó con acetato de etilo (400 ml), y se lavó con agua (2 x 200 ml). La capa orgánica se secó (MgSO4), se filtró y se evaporó para proporcionar el producto bruto. El producto bruto se purificó mediante cromatografía ultrarrápida en sílice, gradiente de elución 10 a 60% de acetato de etilo en isohexano, para dar el material deseado como un sólido cristalino color crema (1,40 g). Bis (triphenylphosphine) palladium (II) chloride (300 mg, 0.43 mmol) was added to 2-chloro-4 - [(3S) -3-methylmorpholin-4-yl] –6– [[2– (trifluoromethyl ) phenyl] sulfonylmethyl] pyrimidine (1.66 g, 3.81 mmol), 4– (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (1,252 g, 5, 71 mmol) and sodium carbonate (10 ml, 20.00 mmol) in a mixture of ethanol (6 ml), DMF (10 ml), water (6 ml) and DME (20 ml) at RT. The resulting mixture was degassed, and then stirred at 95 ° C for 18 hours. The reaction mixture was allowed to cool, then diluted with ethyl acetate (400 ml), and washed with water (2 x 200 ml). The organic layer was dried (MgSO4), filtered and evaporated to provide the crude product. The crude product was purified by flash chromatography on silica, gradient elution 10 to 60% ethyl acetate in isohexane, to give the desired material as a cream crystalline solid (1.40 g).

Espectro RMN: RMN 1H (400,132 MHz, DMSO–d6) δ 1,19 (3H, d), 3,14 (1H, td), 3,47 (1H, td), 3,62 (1H, dd), 3,75 (1H, d), 3,96 (1H, dd), 4,04–4,11 (1H, m), 4,41 (1H, s), 4,72 (2H, s), 5,51 (2H, s), 6,47 (2H, d), 6,59 (1H, s), 7,56 (2H, d), 7,76–7,81 (1H, m), 7,86–7,92 (2H, m), 8,07 (1H, d) NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.19 (3H, d), 3.14 (1H, td), 3.47 (1H, td), 3.62 (1H, dd), 3.75 (1H, d), 3.96 (1H, dd), 4.04-4.11 (1H, m), 4.41 (1H, s), 4.72 (2H, s), 5 , 51 (2H, s), 6.47 (2H, d), 6.59 (1H, s), 7.56 (2H, d), 7.76–7.81 (1H, m), 7, 86–7.92 (2H, m), 8.07 (1H, d)

Espectro LCMS: MH+ 493, tiempo de retención 2,35 min. LCMS spectrum: MH + 493, retention time 2.35 min.

La preparación de 2–cloro–4–[(3S)–3–metilmorfolin–4–il]–6–[[2–(trifluorometil)fenil]sulfonilmetil]pirimidina se describió anteriormente. The preparation of 2-chloro-4 - [(3S) -3-methylmorpholin-4-yl] -6 - [[2- (trifluoromethyl) phenyl] sulfonylmethyl] pyrimidine was described above.

Example 66:

3–Etil–1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(terc–butilsulfonilmetil)pirimidin–2–il]fenil]urea 3 – Ethyl – 1– [4– [4 - [(3S) –3 – methylmorpholin-4-yl] –6– (tert-butylsulfonylmethyl) pyrimidin – 2-yl] phenyl] urea

O OR

N N

N S N S

OO OO

N N

O OR

N N

N HH N HH

234 Se añadió hidrocloruro de etilamina (86,4 mg, 1,03 mmoles) a N–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(terc– butilsulfonilmetil)pirimidin–2–il]fenil]carbamato de fenilo (120 mg, 0,23 mmoles) y trietilamina (0,21 ml, 1,49 mmoles) en DMF (2 ml). La mezcla de reacción se dejó reposar a RT durante 65 horas. El producto bruto se purificó mediante HPLC preparativa usando mezclas polares decrecientes de agua (que contiene 1% de NH3) y acetonitrilo como 234 Ethylamine hydrochloride (86.4 mg, 1.03 mmol) was added to N– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (tert-butylsulfonylmethyl) pyrimidin – 2 -Yl] phenyl] phenyl carbamate (120 mg, 0.23 mmol) and triethylamine (0.21 ml, 1.49 mmol) in DMF (2 ml). The reaction mixture was allowed to stand at RT for 65 hours. The crude product was purified by preparative HPLC using decreasing polar mixtures of water (containing 1% NH3) and acetonitrile as

5 eluyentes, para dar el material deseado como un sólido incoloro (79,0 mg). 5 eluents, to give the desired material as a colorless solid (79.0 mg).

Espectro RMN: RMN 1H (399,9 MHz, DMSO–d6) δ 1,07 (3H, t), 1,25 (3H, d), 1,39 (9H, s), 3,10–3,25 (3H, m), 3,45– 3,54 (1H, m), 3,63–3,69 (1H, m), 3,79 (1H, d), 3,95–4,03 (1H, m), 4,18 (1H, d), 4,46 (3H, s), 6,18 (1H, t), 6,75 (1H, s), 7,50 (2H, m), 8,21 (2H, d), 8,68 (1H, s) NMR Spectrum: 1H NMR (399.9 MHz, DMSO – d6) δ 1.07 (3H, t), 1.25 (3H, d), 1.39 (9H, s), 3.10–3.25 (3H, m), 3.45-3.54 (1H, m), 3.63-3.69 (1H, m), 3.79 (1H, d), 3.95-4.03 (1H , m), 4.18 (1H, d), 4.46 (3H, s), 6.18 (1H, t), 6.75 (1H, s), 7.50 (2H, m), 8 , 21 (2H, d), 8.68 (1H, s)

Espectro LCMS: MH+ 476, tiempo de retención 2,04 min. LCMS spectrum: MH + 476, retention time 2.04 min.

10 Los siguientes compuestos se obtuvieron de manera análoga a partir de N–[4–[4–[(3S)–3–metilmorfolin–4–il]–6– (terc–butilsulfonilmetil)pirimidin–2–il]fenil]carbamato de fenilo o N–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(2–terc– butilsulfonilpropan–2–il)pirimidin–2–il]fenil]carbamato de fenilo y la amina apropiada. The following compounds were obtained analogously from N– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (tert-butylsulfonylmethyl) pyrimidin-2-yl] phenyl] carbamate of phenyl or N– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (2-tert-butylsulfonylpropan-2-yl) pyrimidin-2-yl] phenyl] phenyl carbamate and the appropriate amine.

66a 66th: O 3–ciclobutil–1–[4–[4–[(3S)–3– 502 2,25 OR 3 – cyclobutyl – 1– [4– [4 - [(3S) –3– 502 2.25

: metilmorfolin–4–il]–6–(terc– methylmorpholin – 4 – il] –6– (terc–

N N N S O O N H N H O N N N S O O N H N H O: butilsulfonilmetil)pirimidin–2–il]fenil]urea butylsulfonylmethyl) pyrimidin-2-yl] phenyl] urea

66b 66b: O 3–(2–dimetilaminoetil)–1–[4–[4–[(3S)– 519 1,97 OR 3– (2 – dimethylaminoethyl) –1– [4– [4 - [(3S) - 519 1.97

: 3–metilmorfolin–4–il]–6–(terc– 3 – methylmorpholin – 4 – il] –6– (terc–

N N N S O O N H N H O N N N N S O O N H N H O N: butilsulfonilmetil)pirimidin–2–il]fenil]urea butylsulfonylmethyl) pyrimidin-2-yl] phenyl] urea

66c 66c: N N N O S O O N H N H O 3–ciclopropil–1–[4–[4–[(3S)–3– metilmorfolin–4–il]–6–(2–terc– butilsulfonilpropan–2–il)pirimidin–2– il]fenil]urea 516 2,36 N N N O S O O N H N H O 3 – cyclopropyl – 1– [4– [4 - [(3S) –3– methylmorpholin-4-yl] –6– (2-tert-butylsulfonylpropan – 2-yl) pyrimidin – 2– yl] phenyl] urea 516 2.36

66d 66d: N N N O S O O N H N H O 3–ciclobutil–1–[4–[4–[(3S)–3– metilmorfolin–4–il]–6–(2–terc– butilsulfonilpropan–2–il)pirimidin–2– il]fenil]urea 530 2,64 N N N O S O O N H N H O 3 – cyclobutyl – 1– [4– [4 - [(3S) –3– methylmorpholin-4-yl] –6– (2-tert-butylsulfonylpropan – 2-yl) pyrimidin – 2– yl] phenyl] urea 530 2.64

66e 66e: O 3–etil–1–[4–[4–[(3S)–3–metilmorfolin– 504 2,34 OR 3 – ethyl – 1– [4– [4 - [(3S) –3 – methylmorpholin– 504 2.34

: 4–il]–6–(2–terc–butilsulfonilpropan–2– 4 – il] –6– (2 – tert-butylsulfonylpropan – 2–

N N N S O O N H N H O N N N S O O N H N H O: il)pirimidin–2–il]fenil]urea il) pyrimidin-2-yl] phenyl] urea

MH+ MH +: retención retention

(min.) (min.)

66f 66f: S O O N N N O N H N H O N 3–(2–dimetilaminoetil)–1–[4–[4–[(3S)– 3–metilmorfolin–4–il]–6–(2–terc– butilsulfonilpropan–2–il)pirimidin–2– il]fenil]urea 547 2,27 S O O N N N O N H N H O N 3– (2-dimethylaminoethyl) –1– [4– [4 - [(3S) - 3-methylmorpholin-4-yl] –6– (2-tert-butylsulfonylpropan – 2-yl) pyrimidin – 2– yl] phenyl ]urea 547 2.27

66g 66g: S O O N N N O N H N H O OH 3–(2–hidroxietil)–1–[4–[4–[(3S)–3– metilmorfolin–4–il]–6–(2–terc– butilsulfonilpropan–2–il)pirimidin–2– il]fenil]urea 520 1,98 S O O N N N O N H N H O OH 3– (2 – hydroxyethyl) –1– [4– [4 - [(3S) –3– methylmorpholin-4-yl] –6– (2-tert-butylsulfonylpropan – 2-yl) pyrimidin – 2– yl] phenyl ]urea 520 1.98

66h 66h: O 3–metil–1–[4–[4–[(3S)–3–metilmorfolin– 490 2,27 OR 3 – methyl – 1– [4– [4 - [(3S) –3 – methylmorpholin– 490 2.27

S O O S O O: N N N N H N H O il)pirimidin–2–il]fenil]urea N N N N H N H O il) pyrimidin-2-yl] phenyl] urea

Ejemplo 66a: RMN 1H (399,9 MHz, DMSO–d6) δ 1,24 (3H, d), 1,39 (9H, s), 1,54–1,69 (2H, m), 1,79–1,92 (2H, m), 2,15–2,27 (2H, m), 3,15–3,25 (1H, m), 3,51 (1H, t), 3,66 (1H, d), 3,78 (1H, d), 3,99 (1H, d), 4,10–4,22 (2H, m), 4,46 (3H, s), 6,46 (1H, d), 6,75 (1H, s), 7,48 (2H, d), 8,21 (2H, d), 8,1 (1H, s) Example 66a: 1H NMR (399.9 MHz, DMSO-d6) δ 1.24 (3H, d), 1.39 (9H, s), 1.54-1.69 (2H, m), 1.79 –1.92 (2H, m), 2.15-2.27 (2H, m), 3.15–3.25 (1H, m), 3.51 (1H, t), 3.66 (1H , d), 3.78 (1H, d), 3.99 (1H, d), 4.10-4.22 (2H, m), 4.46 (3H, s), 6.46 (1H, d), 6.75 (1H, s), 7.48 (2H, d), 8.21 (2H, d), 8.1 (1H, s)

5 Ejemplo 66b: RMN 1H (399,9 MHz, DMSO–d6) δ 1,24–1,25 (3H, m), 1,39 (9H, s), 2,19 (6H, s), 2,34 (2H, t), 3,19– 3,25 (1H, m), 3,45–3,56 (1H, m), 3,62–3,68 (1H, m), 3,79 (1H, d), 3,95–4,02 (1H, m), 4,08 (2H, q), 4,18 (1H, d), 4,46 (3H, s), 6,17 (1H, t), 6,75 (1H, s), 7,49 (2H, d), 8,21 (2H, d), 8,90 (1H, s) 5 Example 66b: 1H NMR (399.9 MHz, DMSO-d6) δ 1.24-1.25 (3H, m), 1.39 (9H, s), 2.19 (6H, s), 2, 34 (2H, t), 3.19– 3.25 (1H, m), 3.45–3.56 (1H, m), 3.62–3.68 (1H, m), 3.79 ( 1H, d), 3.95-4.02 (1H, m), 4.08 (2H, q), 4.18 (1H, d), 4.46 (3H, s), 6.17 (1H , t), 6.75 (1H, s), 7.49 (2H, d), 8.21 (2H, d), 8.90 (1H, s)

Ejemplo 66c: RMN 1H (399,9 MHz, DMSO–d6) δ 0,41–0,44 (2H, m), 0,63–0,68 (2H, m), 1,15 (9H, s), 1,21 (3H, d), 1,85 (3H, s), 1,88 (3H, s), 2,55–2,59 (1H, m), 3,18 (1H, dt), 3,51 (1H, dt), 3,66 (1H, dd), 3,78 (1H, d), 3,99 (1H, dd), Example 66c: 1H NMR (399.9 MHz, DMSO-d6) δ 0.41-0.44 (2H, m), 0.63-0.68 (2H, m), 1.15 (9H, s) , 1.21 (3H, d), 1.85 (3H, s), 1.88 (3H, s), 2.55-2.59 (1H, m), 3.18 (1H, dt), 3.51 (1H, dt), 3.66 (1H, dd), 3.78 (1H, d), 3.99 (1H, dd),

10 4,22 (1H, d), 4,51 (1H, br, s), 6,44 (1H, d), 6,88 (1H, s), 7,52 (2H, d), 8,27 (2H, d), 8,55 (1H, s) 10 4.22 (1H, d), 4.51 (1H, br, s), 6.44 (1H, d), 6.88 (1H, s), 7.52 (2H, d), 8, 27 (2H, d), 8.55 (1H, s)

Ejemplo 66d: RMN 1H (399,9 MHz, DMSO–d6) δ 1,15 (9H, s), 1,21 (3H, d), 1,58–1,68 (2H, m), 1,80–1,91 (8H, m), 2,15–2,25 (2H, m), 3,12–3,23 (1H, m), 3,45–3,55 (1H, m), 3,62–3,68 (1H, m), 3,78 (1H, d), 3,94–4,02 (1H, m), 4,08– 4,26 (2H, m), 4,51 (1H, br, s), 6,47 (1H, d), 6,88 (1H, s), 7,49 (2H, d), 8,26 (2H, d), 8,58 (1H, s) Example 66d: 1H NMR (399.9 MHz, DMSO-d6) δ 1.15 (9H, s), 1.21 (3H, d), 1.58-1.68 (2H, m), 1.80 –1.91 (8H, m), 2.15–2.25 (2H, m), 3.12–3.23 (1H, m), 3.45–3.55 (1H, m), 3 , 62–3.68 (1H, m), 3.78 (1H, d), 3.94–4.02 (1H, m), 4.08– 4.26 (2H, m), 4.51 (1H, br, s), 6.47 (1H, d), 6.88 (1H, s), 7.49 (2H, d), 8.26 (2H, d), 8.58 (1H, s)

Ejemplo 66e: RMN 1H (399,9 MHz, DMSO–d6) δ 1,07 (3H, t), 1,15 (9H, s), 1,21 (3H, d), 1,85 (3H, s), 1,88 (3H, s), Example 66e: 1H NMR (399.9 MHz, DMSO-d6) δ 1.07 (3H, t), 1.15 (9H, s), 1.21 (3H, d), 1.85 (3H, s ), 1.88 (3H, s),

15 3,10–3,24 (3H, m), 3,44–3,55 (1H, m), 3,62–3,68 (1H, m), 3,78 (1H, d), 3,94–4,01 (1H, m), 4,22 (1H, d), 4,51 (1H, br, s), 6,17 (1H, t), 6,88 (1H, s), 7,51 (2H, d), 8,26 (2H, d), 8,67 (1H, s) 15 3.10-3.24 (3H, m), 3.44-3.55 (1H, m), 3.62-3.68 (1H, m), 3.78 (1H, d), 3 , 94-4.01 (1H, m), 4.22 (1H, d), 4.51 (1H, br, s), 6.17 (1H, t), 6.88 (1H, s), 7.51 (2H, d), 8.26 (2H, d), 8.67 (1H, s)

Ejemplo 66f: RMN 1H (399,9 MHz, DMSO–d6) δ 1,15 (9H, s), 1,21 (3H, d), 1,85 (3H, s), 1,88 (3H, s), 2,19 (6H, s), 2,35 (2H, t), 3,13–3,23 (3H, m), 3,45–3,54 (1H, m), 3,62–3,68 (1H, m), 3,78 (1H, d), 3,94–4,01 (1H, m), 4,22 (1H, d), 4,52 (1H, br, s), 6,17 (1H, t), 6,88 (1H, s), 7,50 (2H, d), 8,26 (2H, d), 8,91 (1H, s) Example 66f: 1H NMR (399.9 MHz, DMSO-d6) δ 1.15 (9H, s), 1.21 (3H, d), 1.85 (3H, s), 1.88 (3H, s ), 2.19 (6H, s), 2.35 (2H, t), 3.13-3.23 (3H, m), 3.45-3.54 (1H, m), 3.62– 3.68 (1H, m), 3.78 (1H, d), 3.94-4.01 (1H, m), 4.22 (1H, d), 4.52 (1H, br, s) , 6.17 (1H, t), 6.88 (1H, s), 7.50 (2H, d), 8.26 (2H, d), 8.91 (1H, s)

20 Ejemplo 66g: RMN 1H (399,9 MHz, DMSO–d6) δ 1,15 (9H, s), 1,21 (3H, d), 1,85 (3H, s), 1,88 (3H, s), 3,12–3,22 (3H, m), 3,43–3,54 (3H, m), 3,62–3,68 (1H, m), 3,78 (1H, d), 3,95–4,01 (1H, m), 4,22 (1H, d), 4,51 (1H, br, s), 4,74 (1H, t), 6,27 (1H, t), 6,88 (1H, s), 7,50 (2H, d), 8,27 (2H, d), 8,82 (1H, s) Example 66g: 1H NMR (399.9 MHz, DMSO-d6) δ 1.15 (9H, s), 1.21 (3H, d), 1.85 (3H, s), 1.88 (3H, s), 3.12-3.22 (3H, m), 3.43-3.54 (3H, m), 3.62-3.68 (1H, m), 3.78 (1H, d) , 3.95-4.01 (1H, m), 4.22 (1H, d), 4.51 (1H, br, s), 4.74 (1H, t), 6.27 (1H, t ), 6.88 (1H, s), 7.50 (2H, d), 8.27 (2H, d), 8.82 (1H, s)

Ejemplo 66h: RMN 1H (399,9 MHz, DMSO–d6) δ 1,15 (9H, s), 1,21 (3H, d), 1,85 (3H, s), 1,88 (3H, s), 2,67 (3H, d), 3,14–3,23 (1H, m), 3,46–3,55 (1H, m), 3,63–3,69 (1H, m), 3,78 (1H, d), 3,96–4,02 (1H, m), 4,22 (1H, d), 4,52 (1H, br, Example 66h: 1H NMR (399.9 MHz, DMSO-d6) δ 1.15 (9H, s), 1.21 (3H, d), 1.85 (3H, s), 1.88 (3H, s ), 2.67 (3H, d), 3.14-3.23 (1H, m), 3.46-3.55 (1H, m), 3.63-3.69 (1H, m), 3.78 (1H, d), 3.96-4.02 (1H, m), 4.22 (1H, d), 4.52 (1H, br,

25 s), 6,06–6,12 (1H, m), 6,88 (1H, s), 7,52 (2H, d), 8,26 (2H, d), 8,77 (1H, s) 25 s), 6.06–6.12 (1H, m), 6.88 (1H, s), 7.52 (2H, d), 8.26 (2H, d), 8.77 (1H, s)

Prueba (c): Ejemplo (66c) 0,15 μM; Ejemplo (66d) 0,16 μM; Ejemplo (66e) 0,26 μM; Ejemplo (66f) 0,04 μM; Ejemplo (66g) 0,3 μM. Test (c): Example (66c) 0.15 μM; Example (66d) 0.16 μM; Example (66e) 0.26 μM; Example (66f) 0.04 μM; Example (66g) 0.3 μM.

A continuación se describe la preparación de N–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(2–terc–butilsulfonilpropan–2– il)pirimidin–2–il]fenil]carbamato de fenilo. The preparation of N– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (2-tert-butylsulfonylpropan – 2– yl) pyrimidin – 2-yl] phenyl] is described below. phenyl carbamate.

30 N–[4–[4–[(3S)–3–Metilmorfolin–4–il]–6–(2–terc–butilsulfonilpropan–2–il)pirimidin–2–il]fenil]carbamato de fenilo 30 N– [4– [4 - [(3S) –3-Methylmorpholin-4-yl] –6– (2-tert-butylsulfonylpropan-2-yl) pyrimidin-2-yl] phenyl] phenyl carbamate

Se añadió cloroformiato de fenilo (0,368 ml, 2,93 mmoles) a 4–[4–[(3S)–3–metilmorfolin–4–il]–6–(2–terc– butilsulfonilpropan–2–il)pirimidin–2–il]anilina (1,153 g, 2,67 mmoles) e hidrogenocarbonato de sodio (0,336 g, 4,00 mmoles) en dioxano (20 ml) a RT. La suspensión resultante se agitó a RT durante 2 horas. La mezcla de reacción se repartió entre acetato de etilo y agua. La disolución orgánica se secó (MgSO4), se filtró y se concentró a presión reducida. El residuo se cromatografió en sílice, eluyendo con 20%–70% de acetato de etilo en isohexano, para dar el material deseado como un sólido casi incoloro (1,42 g). Phenyl chloroformate (0.368 ml, 2.93 mmol) was added at 4– [4 - [(3S) -3-methylmorpholin-4-yl] -6– (2-tert-butylsulfonylpropan-2-yl) pyrimidin-2 -Yl] aniline (1,153 g, 2.67 mmol) and sodium hydrogen carbonate (0.336 g, 4.00 mmol) in dioxane (20 ml) at RT. The resulting suspension was stirred at RT for 2 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic solution was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was chromatographed on silica, eluting with 20% -70% ethyl acetate in isohexane, to give the desired material as an almost colorless solid (1.42 g).

Espectro RMN: RMN 1H (400,13 MHz, CDCl3) δ 1,25 (9H, s), 1,32 (3H, d), 1,95 (3H, s), 1,97 (3H, s), 3,31 (1H, dt), 3,61 (1H, dt), 3,76 (1H, dd), 3,83 (1H, d), 4,05 (1H, dd), 4,18 (1H, d), 4,47 (1H, br), 6,88 (1H, s), 7,10 (1H, br, s), 7,20–7,27 (3H, m), 7,41 (2H, t), 7,55 (2H, d), 8,43 (2H, d) NMR Spectrum: 1H NMR (400.13 MHz, CDCl3) δ 1.25 (9H, s), 1.32 (3H, d), 1.95 (3H, s), 1.97 (3H, s), 3.31 (1H, dt), 3.61 (1H, dt), 3.76 (1H, dd), 3.83 (1H, d), 4.05 (1H, dd), 4.18 (1H , d), 4.47 (1H, br), 6.88 (1H, s), 7.10 (1H, br, s), 7.20–7.27 (3H, m), 7.41 ( 2H, t), 7.55 (2H, d), 8.43 (2H, d)

Espectro LCMS: MH+ 553, tiempo de retención 3,05 min. LCMS spectrum: MH + 553, retention time 3.05 min.

4–[4–[(3S)–3–Metilmorfolin–4–il]–6–(2–terc–butilsulfonilpropan–2–il)pirimidin–2–il]anilina 4– [4 - [(3S) –3 – Methylmorpholin-4-yl] –6– (2-tert-butylsulfonylpropan – 2-yl) pyrimidin – 2-yl] aniline

Se añadió diclorobis(trifenilfosfina)–paladio(II) (0,103 g, 0,15 mmoles) a 2–cloro–4–[(3S)–3–metilmorfolin–4–il]–6–(2– terc–butilsulfonilpropan–2–il)pirimidina (1,10 g, 2,93 mmoles), 4–(4,4,5,5–tetrametil–1,3,2–dioxaborolan–2–il)anilina (0,833 g, 3,80 mmoles) y carbonato de sodio acuoso 2M (5,27 ml, 10,53 mmoles) en DMF (6 ml), DME (5 ml), etanol (5 ml) y agua (12,5 ml) a RT en nitrógeno. La reacción se purgó con nitrógeno durante 15 minutos, y la mezcla resultante se agitó a 80ºC durante 16 horas. La mezcla de reacción se diluyó con acetato de etilo y se lavó con agua. La disolución orgánica se secó (MgSO4), se filtró, y se concentró a presión reducida. El residuo se cromatografió en sílice, eluyendo con 25%–100% de acetato de etilo en isohexano, para dar el material deseado como un sólido amarillo (1,19 g). Dichlorobis (triphenylphosphine) - palladium (II) (0.103 g, 0.15 mmol) was added to 2-chloro-4 - [(3S) -3-methylmorpholin-4-yl] –6– (2– tert-butylsulfonylpropan– 2-yl) pyrimidine (1.10 g, 2.93 mmol), 4– (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (0.833 g, 3.80 mmol) and 2M aqueous sodium carbonate (5.27 ml, 10.53 mmol) in DMF (6 ml), DME (5 ml), ethanol (5 ml) and water (12.5 ml) at RT in nitrogen. The reaction was purged with nitrogen for 15 minutes, and the resulting mixture was stirred at 80 ° C for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The organic solution was dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was chromatographed on silica, eluting with 25% -100% ethyl acetate in isohexane, to give the desired material as a yellow solid (1.19 g).

Espectro RMN: RMN 1H (400 MHz, CDCl3) δ 1,24 (9H, s), 1,30 (3H, d), 1,93 (3H, s), 1,95 (3H, s), 3,28 (1H, dt), 3,60 (1H, dt), 3,75 (1H, dd), 3,82 (1H, d), 3,90 (2H, s), 4,03 (1H, dd), 4,16 (1H, d), 4,46 (1H, br), 6,72 (2H, d), 6,79 (1H, s), 8,26 (2H, d) NMR Spectrum: 1H NMR (400 MHz, CDCl3) δ 1.24 (9H, s), 1.30 (3H, d), 1.93 (3H, s), 1.95 (3H, s), 3, 28 (1H, dt), 3.60 (1H, dt), 3.75 (1H, dd), 3.82 (1H, d), 3.90 (2H, s), 4.03 (1H, dd ), 4.16 (1H, d), 4.46 (1H, br), 6.72 (2H, d), 6.79 (1H, s), 8.26 (2H, d)

Espectro LCMS: MH+ 433, tiempo de retención 2,42 min. LCMS spectrum: MH + 433, retention time 2.42 min.

2–Cloro–4–[(3S)–3–metilmorfolin–4–il]–6–(2–terc–butilsulfonilpropan–2–il)pirimidina 2 – Chloro – 4 - [(3S) –3 – methylmorpholin-4-yl] –6– (2-tert-butylsulfonylpropan – 2-yl) pyrimidine

O OR

N N

N S N S

OO OO

N Cl N Cl

Se añadió terc–butóxido de sodio (0,345 g, 3,59 mmoles) a 2–cloro–4–[(3S)–3–metilmorfolin–4–il]–6–(terc– butilsulfonilmetil)pirimidina (1,250 g, 3,59 mmoles) en DMF (30 ml) a 0ºC en nitrógeno. Se añadió yodometano (0,224 ml, 3,59 mmoles), y la disolución resultante se agitó a 0ºC durante 15 minutos. Se añadió terc–butóxido de sodio adicional (0,345 g, 3,59 mmoles) seguido por yodometano (0,224 ml, 3,59 mmoles), y la disolución resultante se agitó a 0ºC durante 1 hora. La reacción se diluyó con DCM (100 ml) y se lavó con agua (100 ml) y salmuera (100 ml). La capa orgánica se secó (MgSO4), se filtró, y el disolvente se evaporó para dar una goma que se cristalizó Sodium tert-butoxide (0.345 g, 3.59 mmol) was added to 2-chloro-4 - [(3S) -3-methylmorpholin-4-yl] -6- (tert-butylsulfonylmethyl) pyrimidine (1,250 g, 3 , 59 mmol) in DMF (30 ml) at 0 ° C in nitrogen. Iodomethane (0.224 ml, 3.59 mmol) was added, and the resulting solution was stirred at 0 ° C for 15 minutes. Additional sodium tert-butoxide (0.345 g, 3.59 mmol) was added followed by iodomethane (0.224 ml, 3.59 mmol), and the resulting solution was stirred at 0 ° C for 1 hour. The reaction was diluted with DCM (100 ml) and washed with water (100 ml) and brine (100 ml). The organic layer was dried (MgSO4), filtered, and the solvent evaporated to give a gum that crystallized.

lentamente. El producto bruto se cromatografió en sílice, eluyendo con 0–40% de acetato de etilo en DCM, para dar slowly. The crude product was chromatographed on silica, eluting with 0–40% ethyl acetate in DCM, to give

el material deseado como un sólido incoloro (1,14 g). Espectro RMN: RMN 1H (400 MHz, CDCl3) δ 1,28 (9H, s), 1,30 (3H, d), 1,84 (3H, s), 1,86 (3H, s), 3,27 (1H, dt), 3,54 (1H, dt), 3,69 (1H, dd), 3,79 (1H, d), 3,99–4,05 (2H, m), 4,30 (1H, br, s), 6,89 (1H, s). the desired material as a colorless solid (1.14 g). NMR Spectrum: 1H NMR (400 MHz, CDCl3) δ 1.28 (9H, s), 1.30 (3H, d), 1.84 (3H, s), 1.86 (3H, s), 3, 27 (1H, dt), 3.54 (1H, dt), 3.69 (1H, dd), 3.79 (1H, d), 3.99-4.05 (2H, m), 4.30 (1H, br, s), 6, 89 (1H, s).

Espectro LCMS: MH+ 376, 378, tiempo de retención 2,52 min. 2–Cloro–4–[(3S)–3–metilmorfolin–4–il]–6–(terc–butilsulfonilmetil)pirimidina LCMS spectrum: MH + 376, 378, retention time 2.52 min. 2 – Chloro – 4 - [(3S) –3 – methylmorpholin-4-yl] –6– (tert-butylsulfonylmethyl) pyrimidine

Una disolución de peróxido de hidrógeno (9,48 ml, 107,30 mmoles) (disolución acuosa al 35%) se añadió gota a gota a una disolución agitada de 2–cloro–4–[(3S)–3–metilmorfolin–4–il]–6–(terc–butilsulfanilmetil)pirimidina (9,82 g, 31,1 mmoles), volframato de sodio dihidratado (0,205 g, 0,62 mmoles) y ácido sulfúrico (0,6 ml, 1M, 0,6 mmoles) en dioxano (80 ml). La mezcla se calentó a 55ºC al aire durante 1 hora. Cuando la reacción se terminó, la disolución se diluyó con agua y se enfrió. Se añadió una disolución de metabisulfito de sodio (10% p/v) para destruir el peróxido restante. La disolución se extrajo con DCM, se secó (MgSO4) y se filtró para dar el material deseado como una goma casi incolora (9,34 g). A solution of hydrogen peroxide (9.48 ml, 107.30 mmol) (35% aqueous solution) was added dropwise to a stirred solution of 2-chloro-4 - [(3S) -3-methylmorpholin-4 –Il] –6– (tert-butylsulfanylmethyl) pyrimidine (9.82 g, 31.1 mmol), sodium volframate dihydrate (0.205 g, 0.62 mmol) and sulfuric acid (0.6 ml, 1M, 0, 6 mmol) in dioxane (80 ml). The mixture was heated at 55 ° C in air for 1 hour. When the reaction was terminated, the solution was diluted with water and cooled. A solution of sodium metabisulfite (10% w / v) was added to destroy the remaining peroxide. The solution was extracted with DCM, dried (MgSO4) and filtered to give the desired material as an almost colorless gum (9.34 g).

Espectro RMN: RMN 1H (399,9 MHz, CDCl3) δ 1,33 (3H, d), 1,44 (9H, s), 3,29 (1H, dt), 3,54 (1H, dt), 3,69 (1H, dd), 3,78 (1H, d), 3,97–4,13 (2H, m), 4,21 (2H, s), 4,30 (1H, br, s), 6,71 (1H, s). NMR Spectrum: 1H NMR (399.9 MHz, CDCl3) δ 1.33 (3H, d), 1.44 (9H, s), 3.29 (1H, dt), 3.54 (1H, dt), 3.69 (1H, dd), 3.78 (1H, d), 3.97-4.13 (2H, m), 4.21 (2H, s), 4.30 (1H, br, s) , 6.71 (1H, s).

Espectro LCMS: MH+ 348, 350, tiempo de retención 1,82 min. LCMS spectrum: MH + 348, 350, retention time 1.82 min.

2–Cloro–4–[(3S)–3–metilmorfolin–4–il]–6–(terc–butilsulfanilmetil)pirimidina 2 – Chloro – 4 - [(3S) –3 – methylmorpholin-4-yl] –6– (tert-butylsulfanylmethyl) pyrimidine

O OR

N N

N S N S

N Cl N Cl

Se añadió N–etildiisopropilamina (8,61 ml, 49,78 mmoles) a 2–metil–2–propanotiol (4,21 ml, 37,33 mmoles) en DMF (55 ml) a RT en nitrógeno. La disolución resultante se agitó a RT durante 20 minutos. Se añadió en una porción 2– cloro–4–(yodometil)–6–[(3S)–3–metilmorfolin–4–il]pirimidina (11,00 g, 31,11 mmoles) a la mezcla de reacción. La mezcla se agitó durante 4 horas a RT. La mezcla de reacción se colocó en un baño de agua a 60ºC durante 1,5 horas, y después se repartió entre acetato de etilo y agua. La capa orgánica se lavó con agua adicional y después se secó (MgSO4), se filtró y se evaporó para proporcionar el material deseado como una goma amarilla (10,02 g). N-ethyldiisopropylamine (8.61 ml, 49.78 mmol) was added to 2-methyl-2-propanothiol (4.21 ml, 37.33 mmol) in DMF (55 ml) at RT in nitrogen. The resulting solution was stirred at RT for 20 minutes. 2-Chloro-4- (iodomethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine (11.00 g, 31.11 mmol) was added to the reaction mixture. The mixture was stirred for 4 hours at RT. The reaction mixture was placed in a 60 ° C water bath for 1.5 hours, and then partitioned between ethyl acetate and water. The organic layer was washed with additional water and then dried (MgSO4), filtered and evaporated to provide the desired material as a yellow gum (10.02 g).

Espectro RMN: RMN 1H (399,9 MHz, CDCl3) δ 1,31 (3H, d), 1,34 (9H, s), 3,27 (1H, dt), 3,54 (1H, dt), 3,66–3,71 (3H, m), 3,78 (1H, d), 3,97–4,07 (2H, m), 4,31 (1H, br, s), 6,56 (1H, s) NMR Spectrum: 1H NMR (399.9 MHz, CDCl3) δ 1.31 (3H, d), 1.34 (9H, s), 3.27 (1H, dt), 3.54 (1H, dt), 3.66-3.71 (3H, m), 3.78 (1H, d), 3.97-4.07 (2H, m), 4.31 (1H, br, s), 6.56 ( 1H, s)

Espectro LCMS: MH+ 316, 318, tiempo de retención 2,61 min. LCMS spectrum: MH + 316, 318, retention time 2.61 min.

A continuación se describe la preparación de N–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(terc– butilsulfonilmetil)pirimidin–2–il]fenil]carbamato de fenilo. The preparation of N- [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (tert-butylsulfonylmethyl) pyrimidin-2-yl] phenyl] carbamate is described below.

N–[4–[4–[(3S)–3–Metilmorfolin–4–il]–6–(terc–butilsulfonilmetil)pirimidin–2–il]fenil]carbamato de fenilo N– [4– [4 - [(3S) –3 – Methylmorpholin-4-yl] –6– (tert-butylsulfonylmethyl) pyrimidin-2-yl] phenyl] phenyl carbamate

O OR

N N

N S OO N S OO

N N

O H Or h

Se añadió cloroformiato de fenilo (0,227 ml, 1,81 mmoles) a 4–[4–[(3S)–3–metilmorfolin–4–il]–6–(terc– butilsulfonilmetil)pirimidin–2–il]anilina (665 mg, 1,64 mmoles) e hidrogenocarbonato de sodio (207 mg, 2,47 mmoles) en dioxano (12 ml). La suspensión resultante se agitó a RT durante 1 hora. La mezcla se repartió entre acetato de Phenyl chloroformate (0.277 ml, 1.81 mmol) was added at 4– [4 - [(3S) -3-methylmorpholin-4-yl] -6– (tert-butylsulfonylmethyl) pyrimidin-2-yl] aniline (665 mg, 1.64 mmol) and sodium hydrogen carbonate (207 mg, 2.47 mmol) in dioxane (12 ml). The resulting suspension was stirred at RT for 1 hour. The mixture was partitioned between acetate

5 etilo y agua. La disolución orgánica se secó (MgSO4) y se concentró a presión reducida. El residuo se cromatografió en sílice, eluyendo con 25%–80% de acetato de etilo en isohexano, para dar el material deseado como una película seca amarilla (860 mg). 5 ethyl and water. The organic solution was dried (MgSO4) and concentrated under reduced pressure. The residue was chromatographed on silica, eluting with 25% -80% ethyl acetate in isohexane, to give the desired material as a yellow dry film (860 mg).

Espectro RMN: RMN 1H (400 MHz, CDCl3) δ 1,34 (3H, d), 1,44 (9H, s), 3,32 (1H, dt), 3,60 (1H, dt), 3,75 (1H, dd), 3,82 (1H, d), 4,04 (1H, dd), 4,20 (1H, d), 4,34 (2H, s), 4,46 (1H, br), 6,68 (1H, s), 7,10 (1H, s), 7,19–7,27 (3H, m), NMR Spectrum: 1H NMR (400 MHz, CDCl3) δ 1.34 (3H, d), 1.44 (9H, s), 3.32 (1H, dt), 3.60 (1H, dt), 3, 75 (1H, dd), 3.82 (1H, d), 4.04 (1H, dd), 4.20 (1H, d), 4.34 (2H, s), 4.46 (1H, br ), 6.68 (1H, s), 7.10 (1H, s), 7.19–7.27 (3H, m),

10 7,40 (2H, t), 7,53 (2H, d), 8,37 (2H, d) 10 7.40 (2H, t), 7.53 (2H, d), 8.37 (2H, d)

Espectro LCMS: MH+ 525, tiempo de retención 2,69 min. LCMS spectrum: MH + 525, retention time 2.69 min.

4–[4–[(3S)–3–Metilmorfolin–4–il]–6–(terc–butilsulfonilmetil)pirimidin–2–il]anilina 4– [4 - [(3S) –3 – Methylmorpholin-4-yl] –6– (tert-butylsulfonylmethyl) pyrimidin-2-yl] aniline

Se añadió diclorobis(trifenilfosfina)–paladio(II) (63 mg, 0,09 mmoles) a 2–cloro–4–[(3S)–3–metilmorfolin–4–il]–6– Dichlorobis (triphenylphosphine) -palladium (II) (63 mg, 0.09 mmol) was added to 2-chloro-4 - [(3S) -3-methylmorpholin-4-yl] -6–

15 (terc–butilsulfonilmetil)pirimidina (626 mg, 1,8 mmoles), 4–(4,4,5,5–tetrametil–1,3,2–dioxaborolan–2–il)anilina (513 mg, 2,34 mmoles) y carbonato de sodio acuoso 2M (3,24 ml, 6,48 mmoles) en DMF (3,75 ml), DME (5 ml), etanol (5 ml) y agua (12,5 ml) a RT en nitrógeno. La mezcla de reacción se purgó con nitrógeno durante 15 minutos, y la mezcla resultante se agitó a 80ºC durante 16 horas. La mezcla se repartió entre acetato de etilo y agua. La disolución orgánica se secó (MgSO4), se filtró, y se concentró a presión reducida. El residuo se cromatografió en 15 (tert-butylsulfonylmethyl) pyrimidine (626 mg, 1.8 mmol), 4– (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (513 mg, 2.34 mmoles) and 2M aqueous sodium carbonate (3.24 ml, 6.48 mmol) in DMF (3.75 ml), DME (5 ml), ethanol (5 ml) and water (12.5 ml) at RT in nitrogen. The reaction mixture was purged with nitrogen for 15 minutes, and the resulting mixture was stirred at 80 ° C for 16 hours. The mixture was partitioned between ethyl acetate and water. The organic solution was dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was chromatographed on

20 sílice, eluyendo con 25%–100% de acetato de etilo en isohexano, para dar el material deseado como un sólido amarillo (681 mg). 20 silica, eluting with 25% -100% ethyl acetate in isohexane, to give the desired material as a yellow solid (681 mg).

Espectro RMN: RMN 1H (400 MHz, CDCl3) δ 1,32 (3H, d), 1,43 (9H, s), 3,30 (1H, m), 3,60 (1H, m), 3,74 (1H, dd), 3,81 (1H, d), 3,89 (2H, s), 4,03 (1H, dd), 4,18 (1H, d), 4,31 (2H, d), 4,44 (1H, br), 6,61 (1H, s), 6,71 (2H, d), 8,21 (2H, d) NMR Spectrum: 1H NMR (400 MHz, CDCl3) δ 1.32 (3H, d), 1.43 (9H, s), 3.30 (1H, m), 3.60 (1H, m), 3, 74 (1H, dd), 3.81 (1H, d), 3.89 (2H, s), 4.03 (1H, dd), 4.18 (1H, d), 4.31 (2H, d ), 4.44 (1H, br), 6.61 (1H, s), 6.71 (2H, d), 8.21 (2H, d)

25 Espectro LCMS: MH+ 405, tiempo de retención 1,98 min. 25 LCMS spectrum: MH + 405, retention time 1.98 min.

La preparación de 2–cloro–4–[(3S)–3–metilmorfolin–4–il]–6–(terc–butilsulfonilmetil) pirimidina se describió anteriormente. The preparation of 2-chloro-4 - [(3S) -3-methylmorpholin-4-yl] -6- (tert-butylsulfonylmethyl) pyrimidine was described above.

Example 67:

1–[4–[4–[(3,5–Difluorofenil)sulfonilmetil]–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]–3–etil–urea 1– [4– [4 - [(3,5 – Difluorophenyl) sulfonylmethyl] –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin – 2-yl] phenyl] –3-ethyl-urea

O OR

N N

N F N F

OO OO

S N S N

O OR

N HH N HH

N N

F F

Se añadió N–[4–[4–[(3,5–difluorofenil)sulfonilmetil]–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]carbamato de fenilo (120 mg, 0,207 mmoles) a una mezcla de hidrocloruro de etilamina (86 mg, 1,03 mmoles) y trietilamina (0,2 ml, 1,49 mmoles) en DMF (1,5 ml) a RT. La mezcla de reacción se dejó reposar a RT durante 65 horas. El producto bruto se purificó mediante HPLC preparativa usando mezclas polares decrecientes de agua (que contiene 1% de N- [4– [4 - [(3,5-difluorophenyl) sulfonylmethyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] phenyl carbamate (120 mg was added , 0.207 mmol) to a mixture of ethylamine hydrochloride (86 mg, 1.03 mmol) and triethylamine (0.2 ml, 1.49 mmol) in DMF (1.5 ml) at RT. The reaction mixture was allowed to stand at RT for 65 hours. The crude product was purified by preparative HPLC using decreasing polar mixtures of water (containing 1% of

5 amoniaco) y acetonitrilo como eluyentes, para dar el material deseado como un sólido incoloro (19,0 mg). 5 ammonia) and acetonitrile as eluents, to give the desired material as a colorless solid (19.0 mg).

Espectro RMN: RMN 1H (399,9 MHz, DMSO–d6) δ 1,07 (3H, t), 1,22 (3H, d), 3,09–3,3 (3H, m), 3,44–3,3 (1H, m), 3,61–3,67 (1H, m), 3,78 (1H, d), 3,94–4,01 (1H, m), 4,09–4,18 (1H, m), 4,41 (1H, br, s), 4,87 (2H, s), 6,16 (1H, t), 6,71 (1H, s), 7,40 (2H, d), 7,58–7,64 (2H, m), 7,72–7,83 (3H, m), 8,65 (1H, s). NMR Spectrum: 1H NMR (399.9 MHz, DMSO-d6) δ 1.07 (3H, t), 1.22 (3H, d), 3.09-3.3 (3H, m), 3.44 –3.3 (1H, m), 3.61–3.67 (1H, m), 3.78 (1H, d), 3.94–4.01 (1H, m), 4.09–4 , 18 (1H, m), 4.41 (1H, br, s), 4.87 (2H, s), 6.16 (1H, t), 6.71 (1H, s), 7.40 ( 2H, d), 7.58-7.64 (2H, m), 7.72-7.83 (3H, m), 8.65 (1H, s).

Espectro LCMS: MH+ 532, tiempo de retención 2,29 min. LCMS spectrum: MH + 532, retention time 2.29 min.

10 Los siguientes compuestos se obtuvieron de manera análoga a partir de N–[4–[4–[(3,5–difluorofenil)sulfonilmetil]–6– [(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]carbamato de fenilo o N–[4–[4–[2–(3,5–difluorofenil)sulfonilpropan–2– il]–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]carbamato de fenilo y la amina apropiada. The following compounds were obtained analogously from N– [4– [4 - [(3,5-difluorophenyl) sulfonylmethyl] –6– [(3S) –3-methylmorpholin-4-yl] pyrimidin – 2– il] phenyl] phenyl carbamate or N– [4– [4– [2– (3,5-difluorophenyl) sulfonylpropan – 2– yl] –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin– 2-yl] phenyl] phenyl carbamate and the appropriate amine.

67a 67a: F N N N O S O O N H N H O F 3–ciclobutil–1–[4–[4–[(3,5– difluorofenil)sulfonilmetil]–6–[(3S)–3– metilmorfolin–4–il]pirimidin–2– il]fenil]urea 558 2,51 F N N N O S O O N H N H O F 3 – cyclobutyl – 1– [4– [4 - [(3,5– difluorophenyl) sulfonylmethyl] –6 - [(3S) –3– methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] urea 558 2.51

67b 67b: O 1–[4–[4–[(3,5–difluorofenil)sulfonilmetil]– 575 2,25 OR 1– [4– [4 - [(3,5 – difluorophenyl) sulfonylmethyl] - 575 2.25

F F: N N N S O O N H N H O F N 6–[(3S)–3–metilmorfolin–4–il]pirimidin– 2–il]fenil]–3–(2–dimetilaminoetil)urea N N N S O O N H N H O F N 6 - [(3S) –3 – methylmorpholin-4-yl] pyrimidin– 2-yl] phenyl] –3– (2-dimethylaminoethyl) urea

67c 67c: F N N N O S O O N H N H O F 3–ciclopropil–1–[4–[4–[2–(3,5– difluorofenil)sulfonilpropan–2–il]–6– [(3S)–3–metilmorfolin–4–il]pirimidin–2– il]fenil]urea 572 2,60 F N N N O S O O N H N H O F 3 – cyclopropyl – 1– [4– [4– [2– (3,5– difluorophenyl) sulfonylpropan – 2-yl] –6– [(3S) –3 – methylmorpholin-4-yl] pyrimidin – 2– il] phenyl] urea 572 2.60

67d 67d: F N N N O S O O N H N H O F 3–ciclobutil–1–[4–[4–[2–(3,5– difluorofenil)sulfonilpropan–2–il]–6– [(3S)–3–metilmorfolin–4–il]pirimidin–2– il]fenil]urea 586 2,81 F N N N O S O O N H N H O F 3 – cyclobutyl – 1– [4– [4– [2– (3,5– difluorophenyl) sulfonylpropan – 2 – yl] –6– [(3S) –3 – methylmorpholin-4-yl] pyrimidin – 2– il] phenyl] urea 586 2.81

67e 67e: F N N N O S O O N H N H O F 3–[4–[4–[2–(3,5–difluorofenil)sulfonilpropan–2–il]–6–[(3S)–3– metilmorfolin–4–il]pirimidin–2–il]fenil]–1– etil–urea 560 2,59 F N N N O S O O N H N H O F 3– [4– [4– [2– (3,5 – difluorophenyl) sulfonylpropan – 2-yl] –6 - [(3S) –3– methylmorpholin-4-yl] pyrimidin – 2-yl] phenyl] –1 - ethyl urea 560 2.59

67f 67f: O 1–[4–[4–[2–(3,5–difluorofenil) 603 2,57 OR 1– [4– [4– [2– (3,5 – difluorophenyl) 603 2.57

N N: sulfonilpropan–2–il]–6–[(3S)–3– metilmorfolin–4–il]pirimidin–2–il]fenil]–3– sulfonylpropan – 2 – il] –6 - [(3S) –3– methylmorpholin-4-yl] pyrimidin – 2-yl] phenyl] –3–

F F: N N S O O N H N H O F N (2–dimetilaminoetil)urea N N S O O N H N H O F N (2-dimethylaminoethyl) urea

67g 67g: O 1–[4–[4–[2–(3,5–difluorofenil) 576 2,23 OR 1– [4– [4– [2– (3,5 – difluorophenyl) 576 2.23

F F: N N S O O N H N H O F OH (2–hidroxietil)urea N N S O O N H N H O F OH (2-hydroxyethyl) urea

67h 67h: F N N N O S O O N H N H O F 1–[4–[4–[2–(3,5–difluorofenil)sulfonilpropan–2–il]–6–[(3S)–3– metilmorfolin–4–il]pirimidin–2–il]fenil]–3– metil–urea 546 2,44 F N N N O S O O N H N H O F 1– [4– [4– [2– (3,5 – difluorophenyl) sulfonylpropan – 2-yl] –6 - [(3S) –3– methylmorpholin-4-yl] pyrimidin – 2-yl] phenyl] –3 - methyl urea 546 2.44

Ejemplo 67a: RMN 1H (399,9 MHz, DMSO–d6) δ 1,22 (3H, d), 1,56–1,70 (2H, m), 1,80–1,94 (2H, m), 2,15–2,27 (2H, m), 3,14–3,24 (1H, m), 3,44–3,53 (1H, m), 3,61–3,67 (1H, m), 3,77 (1H, d), 3,95–4,02 (1H, m), 4,08–4,20 (2H, m), 4,41 (1H, br, s), 4,87 (2H, s), 6,46 (1H, d), 6,71 (1H, s), 7,38 (2H, d), 7,59–7,64 (2H, m), 7,72–7,83 (3H, m), 8,55 (1H, s). Example 67a: 1H NMR (399.9 MHz, DMSO-d6) δ 1.22 (3H, d), 1.56-1.70 (2H, m), 1.80-1.94 (2H, m) , 2.15-2.27 (2H, m), 3.14-3.24 (1H, m), 3.44-3.53 (1H, m), 3.61-3.67 (1H, m), 3.77 (1H, d), 3.95-4.02 (1H, m), 4.08-4.20 (2H, m), 4.41 (1H, br, s), 4 , 87 (2H, s), 6.46 (1H, d), 6.71 (1H, s), 7.38 (2H, d), 7.59-7.64 (2H, m), 7, 72–7.83 (3H, m), 8.55 (1H, s).

Ejemplo 67b: RMN 1H (399,9 MHz, DMSO–d6) δ 1,22 (3H, d), 2,19 (6H, s), 2,34 (2H, t), 3,14–3,23 (3H, m), 3,44– 3,54 (1H, m), 3,62–3,66 (1H, m), 3,77 (1H, d), 3,94–4,00 (1H, m), 4,06–4,14 (1H, m), 4,41 (1H, br, s), 4,87 (2H, s), 6,16 (1H, t), 6,71 (1H, s), 7,39 (2H, d), 7,58–7,64 (2H, m), 7,74–7,83 (3H, m), 8,88 (1H, s). Example 67b: 1H NMR (399.9 MHz, DMSO-d6) δ 1.22 (3H, d), 2.19 (6H, s), 2.34 (2H, t), 3.14–3.23 (3H, m), 3.44– 3.54 (1H, m), 3.62–3.66 (1H, m), 3.77 (1H, d), 3.94–4.00 (1H , m), 4.06-4.14 (1H, m), 4.41 (1H, br, s), 4.87 (2H, s), 6.16 (1H, t), 6.71 ( 1H, s), 7.39 (2H, d), 7.58-7.64 (2H, m), 7.74-7.83 (3H, m), 8.88 (1H, s).

Ejemplo 67c: RMN 1H (399,9 MHz, DMSO–d6) δ 0,39–0,45 (2H, m), 0,62–0,69 (2H, m), 1,23 (3H, d), 1,82 (6H, s), 2,54–2,60 (1H, m), 3,13–3,22 (1H, m), 3,46–3,54 (1H, m), 3,62–3,68 (1H, m), 3,78 (1H, d), 3,95–4,00 (1H, m), 4,18 (1H, d), 4,59 (1H, br, s), 6,43 (1H, s), 6,71 (1H, s), 7,16–7,23 (2H, d), 7,41 (2H, d), 7,60–7,67 (1H, m), 7,84 (2H, d), 8,53 (1H, s). Example 67c: 1H NMR (399.9 MHz, DMSO – d6) δ 0.39–0.45 (2H, m), 0.62–0.69 (2H, m), 1.23 (3H, d) , 1.82 (6H, s), 2.54-2.60 (1H, m), 3.13-3.22 (1H, m), 3.46-3.54 (1H, m), 3 , 62–3.68 (1H, m), 3.78 (1H, d), 3.95-4.00 (1H, m), 4.18 (1H, d), 4.59 (1H, br , s), 6.43 (1H, s), 6.71 (1H, s), 7.16–7.23 (2H, d), 7.41 (2H, d), 7.60–7, 67 (1H, m), 7.84 (2H, d), 8.53 (1H, s).

Ejemplo 67d: RMN 1H (399,9 MHz, DMSO–d6) δ 1,22 (3H, d), 1,56–1,69 (2H, m), 1,78–1,92 (8H, m), 2,17–2,26 (2H, m), 3,12–3,22 (1H, m), 3,46–3,53 (1H, m), 3,61–3,68 (1H, m), 3,78 (1H, d), 3,95–4,02 (1H, m), 4,10–4,22 (2H, m), 4,59 (1H, br, s), 6,46 (1H, d), 6,71 (1H, s), 7,15–7,23 (2H, m), 7,38 (2H, d), 7,60–7,68 (1H, m), 7,84 (2H, d), 8,55 (1H, s). Example 67d: 1H NMR (399.9 MHz, DMSO-d6) δ 1.22 (3H, d), 1.56-1.69 (2H, m), 1.78-1.92 (8H, m) , 2.17-2.26 (2H, m), 3.12-3.22 (1H, m), 3.46-3.53 (1H, m), 3.61-3.68 (1H, m), 3.78 (1H, d), 3.95-4.02 (1H, m), 4.10-4.22 (2H, m), 4.59 (1H, br, s), 6 , 46 (1H, d), 6.71 (1H, s), 7.15–7.23 (2H, m), 7.38 (2H, d), 7.60–7.68 (1H, m ), 7.84 (2H, d), 8.55 (1H, s).

Ejemplo 67e: RMN 1H (399,9 MHz, DMSO–d6) δ 1,08 (3H, t), 1,23 (3H, d), 1,83 (6H, s), 3,09–3,22 (3H, m), 3,50 (1H, t), 3,66 (1H, d), 3,78 (1H, d), 3,99 (1H, d), 4,19 (1H, d), 4,60 (1H, br, s), 6,16 (1H, s), 6,71 (1H, s), 7,21 (2H, s), 7,41 (2H, d), 7,59–7,69 (1H, m), 7,84 (2H, d), 8,65 (1H, s). Example 67e: 1H NMR (399.9 MHz, DMSO-d6) δ 1.08 (3H, t), 1.23 (3H, d), 1.83 (6H, s), 3.09-3.22 (3H, m), 3.50 (1H, t), 3.66 (1H, d), 3.78 (1H, d), 3.99 (1H, d), 4.19 (1H, d) , 4.60 (1H, br, s), 6.16 (1H, s), 6.71 (1H, s), 7.21 (2H, s), 7.41 (2H, d), 7, 59–7.69 (1H, m), 7.84 (2H, d), 8.65 (1H, s).

Ejemplo 67f: RMN 1H (400,13 MHz, DMSO–d6) δ 1,22 (3H, d), 1,80–1,83 (6H, m), 2,18 (6H, s), 2,34 (2H, t), 3,12– 3,23 (3H, m), 3,44–3,54 (1H, m), 3,63–3,67 (1H, m), 3,77 (1H, d), 3,94–4,01 (1H, m), 4,18 (1H, d), 4,59 (1H, br, s), 6,15 (1H, t), 6,70 (1H, s), 7,15–7,23 (2H, m), 7,39 (2H, d), 7,59–7,66 (1H, m), 7,84 (2H, d), 8,86 (1H, s). Example 67f: 1H NMR (400.13 MHz, DMSO-d6) δ 1.22 (3H, d), 1.80-1.83 (6H, m), 2.18 (6H, s), 2.34 (2H, t), 3.12-3.23 (3H, m), 3.44-3.54 (1H, m), 3.63-3.67 (1H, m), 3.77 (1H , d), 3.94-4.01 (1H, m), 4.18 (1H, d), 4.59 (1H, br, s), 6.15 (1H, t), 6.70 ( 1H, s), 7.15–7.23 (2H, m), 7.39 (2H, d), 7.59–7.66 (1H, m), 7.84 (2H, d), 8 , 86 (1H, s).

Ejemplo 67g: RMN 1H (400,13 MHz, DMSO–d6) δ 1,22 (3H, d), 1,80–1,83 (6H, m), 3,12–3,23 (3H, m), 3,40–3,53 (3H, m), 3,62–3,67 (1H, m), 3,77 (1H, d), 3,95–4,01 (1H, m), 4,18 (1H, d), 4,59 (1H, br, s), 4,73 (1H, t), 6,24 (1H, t), 6,70 (1H, s), 7,16–7,23 (2H, m), 7,39 (2H, d), 7,59–7,66 (1H, m), 7,84 (2H, d), 8,78 (1H, s). Example 67g: 1H NMR (400.13 MHz, DMSO-d6) δ 1.22 (3H, d), 1.80–1.83 (6H, m), 3.12–3.23 (3H, m) , 3.40–3.53 (3H, m), 3.62–3.67 (1H, m), 3.77 (1H, d), 3.95–4.01 (1H, m), 4 , 18 (1H, d), 4.59 (1H, br, s), 4.73 (1H, t), 6.24 (1H, t), 6.70 (1H, s), 7.16– 7.23 (2H, m), 7.39 (2H, d), 7.59-7.66 (1H, m), 7.84 (2H, d), 8.78 (1H, s).

Ejemplo 67h: RMN 1H (400,13 MHz, DMSO–d6) δ 1,22 (3H, d), 1,82 (6H, s), 2,66 (3H, d), 3,12–3,22 (1H, m), 3,44– 3,54 (1H, m), 3,60–3,68 (1H, m), 3,77 (1H, d), 3,93–4,00 (1H, m), 4,18 (1H, d), 4,58 (1H, br, s), 6,03–6,09 (1H, m), 6,70 (1H, s), 7,14–7,23 (2H, m), 7,40 (2H, d), 7,63 (1H, t), 7,83 (2H, d), 8,71 (1H, s). Example 67h: 1H NMR (400.13 MHz, DMSO-d6) δ 1.22 (3H, d), 1.82 (6H, s), 2.66 (3H, d), 3.12–3.22 (1H, m), 3.44– 3.54 (1H, m), 3.60–3.68 (1H, m), 3.77 (1H, d), 3.93–4.00 (1H , m), 4.18 (1H, d), 4.58 (1H, br, s), 6.03-6.09 (1H, m), 6.70 (1H, s), 7.14– 7.23 (2H, m), 7.40 (2H, d), 7.63 (1H, t), 7.83 (2H, d), 8.71 (1H, s).

A continuación se describe la preparación de N–[4–[4–[2–(3,5–difluorofenil)sulfonilpropan–2–il]–6–[(3S)–3– metilmorfolin–4–il]pirimidin–2–il]fenil]carbamato de fenilo. The preparation of N– [4– [4– [2– (3,5-difluorophenyl) sulfonylpropan-2-yl] –6 - [(3S) –3– methylmorpholin-4-yl] pyrimidin – 2 is described below. -Yl] phenyl] phenyl carbamate.

N–[4–[4–[2–(3,5–Difluorofenil)sulfonilpropan–2–il]–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]carbamato de fenilo N– [4– [4– [2– (3,5 – Difluorophenyl) sulfonylpropan – 2-yl] –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] carbamate phenyl

O OR

N N

N F OO N F OO

S N S N

O OR

O H Or h

N N

F F

Se añadió cloroformiato de fenilo (0,413 ml, 3,29 mmoles) a 4–[4–[2–(3,5–difluorofenil)sulfonilpropan–2–il]–6–[(3S)– 3–metilmorfolin–4–il]pirimidin–2–il]anilina (1,46 g, 2,99 mmoles) e hidrogenocarbonato de sodio (0,377 g, 4,48 mmoles) en dioxano (25 ml). La suspensión resultante se agitó a RT durante 1 hora. La mezcla se repartió entre acetato de etilo y agua. La disolución orgánica se secó (MgSO4), se filtró, y se concentró a presión reducida. El residuo se cromatografió en sílice, eluyendo con 25%–80% de acetato de etilo en isohexano, para dar una goma incolora. Este material se trituró con éter dietílico para dar el material deseado como un sólido cristalino incoloro (1,808 g). Phenyl chloroformate (0.413 ml, 3.29 mmol) was added at 4– [4– [2– (3,5-difluorophenyl) sulfonylpropan-2-yl] –6 - [(3S) - 3-methylmorpholin-4– il] pyrimidin-2-yl] aniline (1.46 g, 2.99 mmol) and sodium hydrogen carbonate (0.377 g, 4.48 mmol) in dioxane (25 ml). The resulting suspension was stirred at RT for 1 hour. The mixture was partitioned between ethyl acetate and water. The organic solution was dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was chromatographed on silica, eluting with 25% -80% ethyl acetate in isohexane, to give a colorless gum. This material was triturated with diethyl ether to give the desired material as a colorless crystalline solid (1.808 g).

Espectro RMN: RMN 1H (399,9 MHz, CDCl3) δ 1,36 (3H, d), 1,89 (6H, s), 3,34 (1H, dt), 3,63 (1H, dt), 3,79 (1H, dd), 3,86 (1H, d), 4,08 (1H, dd), 4,14 (1H, d), 4,48–4,58 (1H, m), 6,66 (1H, s), 6,88–6,95 (1H, m), 7,04 (1H, s), 7,08–7,13 (2H, m), 7,19–7,28 (3H, m), 7,38–7,44 (4H, m), 7,98 (2H, d). NMR Spectrum: 1H NMR (399.9 MHz, CDCl3) δ 1.36 (3H, d), 1.89 (6H, s), 3.34 (1H, dt), 3.63 (1H, dt), 3.79 (1H, dd), 3.86 (1H, d), 4.08 (1H, dd), 4.14 (1H, d), 4.48-4.58 (1H, m), 6 , 66 (1H, s), 6.88–6.95 (1H, m), 7.04 (1H, s), 7.08–7.13 (2H, m), 7.19–7.28 (3H, m), 7.38-7.44 (4H, m), 7.98 (2H, d).

Espectro LCMS: MH+ 609, tiempo de retención 3,26 min. LCMS spectrum: MH + 609, retention time 3.26 min.

4–[4–[2–(3,5–Difluorofenil)sulfonilpropan–2–il]–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]anilina 4– [4– [2– (3,5 – Difluorophenyl) sulfonylpropan – 2-yl] –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin – 2-yl] aniline

F F

Una corriente de nitrógeno se pasó a través de una mezcla de 2–cloro–4–[2–(3,5–difluorofenil)sulfonilpropan–2–il]– 6–[(3S)–3–metilmorfolin–4–il]pirimidina (1,4 g, 3,24 mmoles), 4–(4,4,5,5–tetrametil–1,3,2–dioxaborolan–2–il)anilina (0,923 g, 4,21 mmoles) y carbonato de sodio acuoso 2M (5,83 ml, 11,67 mmoles) en DMF (6 ml), DME (5 ml), etanol (5 ml) y agua (12,5 ml) a RT. La mezcla de reacción se trató con diclorobis(trifenilfosfina)paladio(II) (0,114 g, 0,16 mmoles) y se agitó a 80ºC durante 1 hora. La mezcla de reacción se diluyó con acetato de etilo y se lavó con agua. La disolución orgánica se secó (MgSO4) y se concentró a presión reducida. El residuo se cromatografió en sílice, eluyendo con 25%–60% de acetato de etilo en isohexano, para dar el material deseado como un sólido amarillo pálido (1,496 g). A stream of nitrogen was passed through a mixture of 2-chloro-4– [2– (3,5-difluorophenyl) sulfonylpropan-2-yl] - 6 - [(3S) –3-methylmorpholin-4-yl] pyrimidine (1.4 g, 3.24 mmol), 4– (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (0.923 g, 4.21 mmol) and carbonate of 2M aqueous sodium (5.83 ml, 11.67 mmol) in DMF (6 ml), DME (5 ml), ethanol (5 ml) and water (12.5 ml) at RT. The reaction mixture was treated with dichlorobis (triphenylphosphine) palladium (II) (0.114 g, 0.16 mmol) and stirred at 80 ° C for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with water. The organic solution was dried (MgSO4) and concentrated under reduced pressure. The residue was chromatographed on silica, eluting with 25% -60% ethyl acetate in isohexane, to give the desired material as a pale yellow solid (1.496 g).

Espectro RMN: RMN 1H (400 MHz, CDCl3) δ 1,34 (3H, d), 1,88 (6H, s), 3,32 (1H, dt), 3,63 (1H, dt), 3,77 (1H, dd), 3,82 (1H, s), 3,86 (2H, s), 4,05 (1H, dd), 4,12 (1H, d), 4,46–4,54 (1H, m), 6,57–6,62 (3H, m), 6,88–6,93 (1H, m), 7,08–7,12 (2H, m), 7,82 (2H, d). NMR Spectrum: 1H NMR (400 MHz, CDCl3) δ 1.34 (3H, d), 1.88 (6H, s), 3.32 (1H, dt), 3.63 (1H, dt), 3, 77 (1H, dd), 3.82 (1H, s), 3.86 (2H, s), 4.05 (1H, dd), 4.12 (1H, d), 4.46-4.54 (1H, m), 6.57-6.62 (3H, m), 6.88-6.93 (1H, m), 7.08-7.12 (2H, m), 7.82 (2H , d).

Espectro LCMS: MH+ 489, tiempo de retención 2,77 min. LCMS spectrum: MH + 489, retention time 2.77 min.

2–Cloro–4–[2–(3,5–difluorofenil)sulfonilpropan–2–il]–6–[(3S)–3–metilmorfolin–4–il]pirimidina 2 – Chloro – 4– [2– (3,5 – difluorophenyl) sulfonylpropan – 2 – yl] –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidine

F F

Se añadió terc–butóxido de sodio (0,336 g, 3,49 mmoles) a 2–cloro–4–[(3,5–difluorofenil)sulfonilmetil]–6–[(3S)–3– metilmorfolin–4–il]pirimidina (1,41 g, 3,49 mmoles) en DMF (30 ml) a 0ºC en nitrógeno. Se añadió yodometano (0,217 ml, 3,49 mmoles), y la disolución resultante se agitó a 0ºC durante 15 minutos. Se añadió terc–butóxido de sodio (0,336 g, 3,49 mmoles) seguido por yodometano (0,217 ml, 3,49 mmoles), y la disolución resultante se agitó a Sodium tert-butoxide (0.336 g, 3.49 mmol) was added to 2-chloro-4 - [(3,5-difluorophenyl) sulfonylmethyl] -6 - [(3S) -3- methylmorpholin-4-yl] pyrimidine (1.41 g, 3.49 mmol) in DMF (30 ml) at 0 ° C in nitrogen. Iodomethane (0.217 ml, 3.49 mmol) was added, and the resulting solution was stirred at 0 ° C for 15 minutes. Sodium tert-butoxide (0.336 g, 3.49 mmol) was added followed by iodomethane (0.217 ml, 3.49 mmol), and the resulting solution was stirred at

0ºC durante 1 hora. La reacción se vertió en agua (100 ml). El precipitado resultante se aisló por filtración y se secó 0 ° C for 1 hour. The reaction was poured into water (100 ml). The resulting precipitate was isolated by filtration and dried.

a vacío, para dar el producto deseado como un sólido incoloro (1,434 g). Espectro RMN: RMN 1H (399,9 MHz, CDCl3) δ 1,34 (3H, d), 1,77 (6H, s), 3,32 (1H, dt), 3,58 (1H, dt), 3,72 (1H, dd), 3,81 (1H, d), 3,97–4,05 (2H, m), 4,36 (1H, br, s), 6,69 (1H, s), 7,07–7,16 (3H, m). under vacuum, to give the desired product as a colorless solid (1,434 g). NMR Spectrum: 1H NMR (399.9 MHz, CDCl3) δ 1.34 (3H, d), 1.77 (6H, s), 3.32 (1H, dt), 3.58 (1H, dt), 3.72 (1H, dd), 3.81 (1H, d), 3.97-4.05 (2H, m), 4.36 (1H, br, s), 6.69 (1H, s), 7.07–7.16 ( 3H, m).

Espectro LCMS: MH+ 432, 434, tiempo de retención 2,78 min. 2–Cloro–4–[(3,5–difluorofenil)sulfonilmetil]–6–[(3S)–3–metilmorfolin–4–il]pirimidina LCMS spectrum: MH + 432, 434, retention time 2.78 min. 2 – Chloro – 4 - [(3,5 – difluorophenyl) sulfonylmethyl] –6 - [(3S) –3 – methylmorpholin-4-yl] pyrimidine

F F

Una disolución de volframato de sodio dihidratado (199 mg, 0,60 mmoles) en agua (2 ml) se añadió a una disolución agitada de 2–cloro–4–[(3,5–difluorofenil)sulfanilmetil]–6–[(3S)–3–metilmorfolin–4–il]pirimidina (11,23 g, 30,2 mmoles) y ácido sulfúrico 2M (0,302 ml, 0,60 mmoles) en dioxano (40 ml). Se añadió peróxido de hidrógeno (3,22 ml, 104,19 mmoles), y la mezcla se agitó a RT toda la noche. Se recogió un precipitado mediante filtración y se secó a vacío. El filtrado se repartió entre acetato de etilo y agua. La disolución orgánica se secó (MgSO4) y se concentró a presión reducida. El residuo se cromatografió en sílice, eluyendo con 5%–20% de acetato de etilo en DCM, y el producto obtenido se combinó con el material precipitado para dar el material deseado como un sólido casi incoloro (11,27 g). A solution of sodium volframate dihydrate (199 mg, 0.60 mmol) in water (2 ml) was added to a stirred solution of 2-chloro-4 - [(3,5-difluorophenyl) sulfanylmethyl] –6 - [( 3S) -3-methylmorpholin-4-yl] pyrimidine (11.23 g, 30.2 mmol) and 2M sulfuric acid (0.302 ml, 0.60 mmol) in dioxane (40 ml). Hydrogen peroxide (3.22 ml, 104.19 mmol) was added, and the mixture was stirred at RT overnight. A precipitate was collected by filtration and dried in vacuo. The filtrate was partitioned between ethyl acetate and water. The organic solution was dried (MgSO4) and concentrated under reduced pressure. The residue was chromatographed on silica, eluting with 5% -20% ethyl acetate in DCM, and the product obtained was combined with the precipitated material to give the desired material as an almost colorless solid (11.27 g).

Espectro RMN: RMN 1H (400 MHz, CDCl3) δ 1,34 (3H, s), 3,31 (1H, dt), 3,56 (1H, dt), 3,71 (1H, dd), 3,80 (1H, d), 3,98–4,10 (2H, m), 4,31 (2H, s), 6,55 (1H, s), 7,12 (1H, tt), 7,30–7,36 (2H, m). NMR Spectrum: 1H NMR (400 MHz, CDCl3) δ 1.34 (3H, s), 3.31 (1H, dt), 3.56 (1H, dt), 3.71 (1H, dd), 3, 80 (1H, d), 3.98-4.10 (2H, m), 4.31 (2H, s), 6.55 (1H, s), 7.12 (1H, tt), 7.30 –7.36 (2H, m).

Espectro LCMS: MH+ 404,406, tiempo de retención 2,32 min. LCMS spectrum: MH + 404.406, retention time 2.32 min.

2–Cloro–4–[(3,5–difluorofenil)sulfanilmetil]–6–[(3S)–3–metilmorfolin–4–il]pirimidina 2 – Chloro – 4 - [(3,5 – difluorophenyl) sulfanylmethyl] –6 - [(3S) –3 – methylmorpholin-4-yl] pyrimidine

F F

Se añadió DIPEA (8,07 ml, 46,67 mmoles) a 3,5–difluorobencenotiol (5,00 g, 34,22 mmoles), en DMF (55 ml) a RT en nitrógeno. La disolución resultante se agitó a RT durante 20 minutos. Se añadió en una porción 2–cloro–4– (yodometil)–6–[(3S)–3–metilmorfolin–4–il]pirimidina (11,00 g, 31,11 mmoles) a la mezcla de reacción. La mezcla se agitó durante 4 horas a RT. La mezcla de reacción se calentó en un baño de agua a 60ºC durante 1,5 horas antes de repartirla entre acetato de etilo y agua. La disolución orgánica se lavó con agua adicional, se secó (MgSO4), se filtró y se evaporó para proporcionar el material deseado como una goma (12,24 g). DIPEA (8.07 ml, 46.67 mmol) was added to 3,5-difluorobenzenethiol (5.00 g, 34.22 mmol), in DMF (55 ml) at RT in nitrogen. The resulting solution was stirred at RT for 20 minutes. 2-Chloro-4– (iodomethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine (11.00 g, 31.11 mmol) was added to the reaction mixture. The mixture was stirred for 4 hours at RT. The reaction mixture was heated in a 60 ° C water bath for 1.5 hours before being partitioned between ethyl acetate and water. The organic solution was washed with additional water, dried (MgSO4), filtered and evaporated to provide the desired material as a gum (12.24 g).

Espectro RMN: RMN 1H (399,9 MHz, CDCl3) δ 1,27 (3H, d), 3,24 (1H, dt), 3,52 (1H, dt), 3,66 (1H, dd), 3,76 (1H, d), 3,96–4,04 (4H, m), 4,21 (1H, br, s), 6,41 (1H, s), 6,59–6,66 (1H, m), 6,80–6,86 (2H, m). NMR Spectrum: 1H NMR (399.9 MHz, CDCl3) δ 1.27 (3H, d), 3.24 (1H, dt), 3.52 (1H, dt), 3.66 (1H, dd), 3.76 (1H, d), 3.96-4.04 (4H, m), 4.21 (1H, br, s), 6.41 (1H, s), 6.59-6.66 ( 1H, m), 6.80-6.86 (2H, m).

Espectro LCMS: MH+ 372,374, tiempo de retención 2,66 min. LCMS spectrum: MH + 372.374, retention time 2.66 min.

A continuación se describe la preparación de N–[4–[4–[(3,5–difluorofenil)sulfonilmetil]–6–[(3S)–3–metilmorfolin–4– il]pirimidin–2–il]fenil]carbamato de fenilo. The preparation of N– [4– [4 - [(3,5-difluorophenyl) sulfonylmethyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] carbamate is described below. of phenyl.

N–[4–[4–[(3,5–Difluorofenil)sulfonilmetil]–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]carbamato de fenilo N– [4– [4 - [(3,5 – Difluorophenyl) sulfonylmethyl] –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] phenyl carbamate

O OR

N N

N F OO N F OO

S S

N N

O OR

O H Or h

N N

F F

Se añadió cloroformiato de fenilo (0,208 ml, 1,66 mmoles) a 4–[4–[(3,5–difluorofenil)sulfonilmetil]–6–[(3S)–3– metilmorfolin–4–il]pirimidin–2–il]anilina (693 mg, 1,50 mmoles) e hidrogenocarbonato de sodio (190 mg, 2,26 mmoles) en dioxano (10 ml). La suspensión resultante se agitó a RT durante 1 hora. La mezcla se repartió entre Phenyl chloroformate (0.208 ml, 1.66 mmol) was added to 4– [4 - [(3,5-difluorophenyl) sulfonylmethyl] –6 - [(3S) –3– methylmorpholin-4-yl] pyrimidin – 2– il] aniline (693 mg, 1.50 mmol) and sodium hydrogen carbonate (190 mg, 2.26 mmol) in dioxane (10 ml). The resulting suspension was stirred at RT for 1 hour. The mixture was divided between

5 acetato de etilo y agua. La disolución orgánica se secó (MgSO4) y se concentró a presión reducida. El residuo se cromatografió en sílice, eluyendo con 25%–80% de acetato de etilo en isohexano, para dar el producto deseado como una película seca amarilla (827 mg). 5 ethyl acetate and water. The organic solution was dried (MgSO4) and concentrated under reduced pressure. The residue was chromatographed on silica, eluting with 25% -80% ethyl acetate in isohexane, to give the desired product as a yellow dry film (827 mg).

Espectro RMN: RMN 1H (399,9 MHz, CDCl3) δ 1,35 (3H, d), 3,33 (1H, dt), 3,61 (1H, dt), 3,76 (1H, dd), 3,83 (1H, d), 4,16 (1H, d), 4,38–4,48 (3H, m), 6,48 (1H, s), 6,98–7,08 (2H, m), 7,19–7,28 (4H, m), 7,32–7,47 (5H, m), 8,02 (2H, d). NMR Spectrum: 1H NMR (399.9 MHz, CDCl3) δ 1.35 (3H, d), 3.33 (1H, dt), 3.61 (1H, dt), 3.76 (1H, dd), 3.83 (1H, d), 4.16 (1H, d), 4.38-4.48 (3H, m), 6.48 (1H, s), 6.98–7.08 (2H, m), 7.19-7.28 (4H, m), 7.32-7.47 (5H, m), 8.02 (2H, d).

10 Espectro LCMS: MH+ 581, tiempo de retención 2,91 min. 10 LCMS spectrum: MH + 581, retention time 2.91 min.

4–[4–[(3,5–Difluorofenil)sulfonilmetil]–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]anilina 4– [4 - [(3,5 – Difluorophenyl) sulfonylmethyl] –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin – 2-yl] aniline

F F

Una corriente de nitrógeno se pasó a través de 2–cloro–4–[(3,5–difluorofenil)sulfonilmetil]–6–[(3S)–3–metilmorfolin– 4–il]pirimidina (0,727 g, 1,8 mmoles), 4–(4,4,5,5–tetrametil–1,3,2–dioxaborolan–2–il)anilina (0,513 g, 2,34 mmoles) y A stream of nitrogen was passed through 2-chloro-4 - [(3,5-difluorophenyl) sulfonylmethyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine (0.727 g, 1.8 mmol ), 4– (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (0.513 g, 2.34 mmol) and

15 carbonato de sodio acuoso 2M (3,24 ml, 6,48 mmoles) en DMF (3,75 ml), DME (5 ml), etanol (5 ml) y agua (12,5 ml) durante 15 minutos. La mezcla de reacción se trató con diclorobis(trifenilfosfina)paladio(II) (0,063 g, 0,09 mmoles), y la mezcla se agitó a 80ºC durante 16 horas. La mezcla se repartió entre acetato de etilo y agua. La disolución orgánica se secó (MgSO4) y se concentró a presión reducida. El residuo se cromatografió en sílice, eluyendo con 25%–60% de acetato de etilo en isohexano, para dar el producto deseado como un sólido amarillo (0,735 g). 15M 2M aqueous sodium carbonate (3.24 ml, 6.48 mmol) in DMF (3.75 ml), DME (5 ml), ethanol (5 ml) and water (12.5 ml) for 15 minutes. The reaction mixture was treated with dichlorobis (triphenylphosphine) palladium (II) (0.063 g, 0.09 mmol), and the mixture was stirred at 80 ° C for 16 hours. The mixture was partitioned between ethyl acetate and water. The organic solution was dried (MgSO4) and concentrated under reduced pressure. The residue was chromatographed on silica, eluting with 25% -60% ethyl acetate in isohexane, to give the desired product as a yellow solid (0.735 g).

20 Espectro RMN: RMN 1H (400 MHz, CDCl3) δ 1,33 (3H, t), 3,31 (1H, dt), 3,60 (1H, dt), 3,75 (1H, dd), 3,80–3,93 (3H, m), 4,01–4,08 (1H, dd), 4,15 (1H, d), 4,40 (3H, s), 6,40 (1H, s), 6,62 (2H, d), 7,01 (1H, tt), 7,32–7,38 (2H, m), 7,85 (2H, d). 20 NMR Spectrum: 1H NMR (400 MHz, CDCl3) δ 1.33 (3H, t), 3.31 (1H, dt), 3.60 (1H, dt), 3.75 (1H, dd), 3 , 80–3.93 (3H, m), 4.01-4.08 (1H, dd), 4.15 (1H, d), 4.40 (3H, s), 6.40 (1H, s ), 6.62 (2H, d), 7.01 (1H, tt), 7.32-7.38 (2H, m), 7.85 (2H, d).

Espectro LCMS: MH+ 461, tiempo de retención 2,46 min. LCMS spectrum: MH + 461, retention time 2.46 min.

La preparación de 2–cloro–4–[(3,5–difluorofenil)sulfonilmetil]–6–[(3S)–3–metilmorfolin–4–il]pirimidina se describió 25 anteriormente. The preparation of 2-chloro-4 - [(3,5-difluorophenyl) sulfonylmethyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine was described above.

Ejemplo 68: Example 68:

1– [4– [4– (2 – Cyclohexylsulfonylpropan – 2-yl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin – 2-yl] phenyl] –3 – cyclopropyl– urea

O OR

N N

N S N S

OO OO

O OR

N N

N HH N HH

N N

A una disolución de ciclopropilamina (53 mg, 0,93 mmoles) en DMF (2 ml) se añadió trietilamina (0,09 ml, 0,64 mmoles) seguido de N–[4–[4–(2–ciclohexilsulfonilpropan–2–il)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2– il]fenil]carbamato de fenilo (118 mg, 0,20 mmoles). La mezcla resultante se calentó hasta 50ºC y se agitó durante 2 horas. La mezcla de reacción se enfrió y se diluyó con DMF adicional (1 ml) antes de purificar la mezcla de reacción To a solution of cyclopropylamine (53 mg, 0.93 mmol) in DMF (2 ml) was added triethylamine (0.09 ml, 0.64 mmol) followed by N– [4– [4– (2-cyclohexylsulfonylpropan – 2 –Il) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] phenyl carbamate (118 mg, 0.20 mmol). The resulting mixture was heated to 50 ° C and stirred for 2 hours. The reaction mixture was cooled and diluted with additional DMF (1 ml) before purifying the reaction mixture.

Espectro RMN: RMN 1H (400,132 MHz, DMSO–d6) δ 0,40–0,44 (2H, m), 0,63–0,67 (2H, m), 1,00–1,19 (3H, m), 1,22 (3H, d), 1,24–1,37 (2H, m), 1,47–1,53 (1H, m), 1,64–1,82 (10H, m), 2,53–2,59 (1H, m), 3,20 (1H, td), 3,50 (1H, td), 3,65 (1H, dd), 3,71–3,78 (2H, m), 3,98 (1H, dd), 4,23 (1H, d), 4,56–4,62 (1H, m), 6,44 (1H, d), 6,75 (1H, s), 7,52 (2H, NMR Spectrum: 1H NMR (400.132 MHz, DMSO – d6) δ 0.40–0.44 (2H, m), 0.63–0.67 (2H, m), 1.00–1.19 (3H, m), 1.22 (3H, d), 1.24-1.37 (2H, m), 1.47-1.53 (1H, m), 1.64-1.82 (10H, m) , 2.53–2.59 (1H, m), 3.20 (1H, td), 3.50 (1H, td), 3.65 (1H, dd), 3.71–3.78 (2H , m), 3.98 (1H, dd), 4.23 (1H, d), 4.56-4.62 (1H, m), 6.44 (1H, d), 6.75 (1H, s), 7.52 (2H,

10 d), 8,25 (2H, d), 8,55 (1H, s). 10 d), 8.25 (2H, d), 8.55 (1H, s).

Espectro LCMS: MH+ 542, tiempo de retención 2,37 min. LCMS spectrum: MH + 542, retention time 2.37 min.

Los siguientes compuestos se obtuvieron de manera análoga a partir de N–[4–[4–(2–ciclohexilsulfonilpropan–2–il)– 6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]carbamato de fenilo o N–[4–[4–(ciclohexilsulfonilmetil)–6–[(3S)–3– metilmorfolin–4–il]pirimidin–2–il]fenil]carbamato de fenilo y la amina apropiada. The following compounds were obtained analogously from N– [4– [4– (2-cyclohexylsulfonylpropan-2-yl) - 6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] phenyl carbamate or N– [4– [4– (cyclohexylsulfonylmethyl) –6 - [(3S) –3– methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] phenyl carbamate and the appropriate amine.

15 Ejemplo 68a: RMN 1H (400,132 MHz, DMSO–d6) δ 1,02–1,18 (3H, m), 1,22 (3H, d), 1,25–1,35 (2H, m), 1,47–1,53 (1H, m), 1,57–1,91 (14H, m), 2,18–2,25 (2H, m), 3,20 (1H, td), 3,50 (1H, td), 3,65 (1H, dd), 3,70–3,78 (2H, m), 3,98 (1H, dd), 4,11–4,26 (2H, m), 4,55–4,61 (1H, m), 6,48 (1H, d), 6,75 (1H, s), 7,49 (2H, d), 8,24 (2H, d), 8,58 (1H, s). Example 68a: 1H NMR (400.132 MHz, DMSO-d6) δ 1.02-1.18 (3H, m), 1.22 (3H, d), 1.25-1.35 (2H, m), 1.47-1.53 (1H, m), 1.57-1.91 (14H, m), 2.18-2.25 (2H, m), 3.20 (1H, td), 3, 50 (1H, td), 3.65 (1H, dd), 3.70-3.78 (2H, m), 3.98 (1H, dd), 4.11-4.26 (2H, m) , 4.55-4.61 (1H, m), 6.48 (1H, d), 6.75 (1H, s), 7.49 (2H, d), 8.24 (2H, d), 8.58 (1H, s).

68a 68th: O 3–ciclobutil–1–[4–[4–(2– 556 2,59 OR 3 – cyclobutyl – 1– [4– [4– (2– 556 2.59

: ciclohexilsulfonilpropan–2–il)–6– cyclohexylsulfonylpropan – 2 – il) –6–

N N: [(3S)–3–metilmorfolin–4– [(3S) –3 – methylmorpholin – 4–

N N S N H N H OO O N N S N H N H OO O: il]pirimidin–2–il]fenil]urea il] pyrimidin – 2-yl] phenyl] urea

68b 68b: O 3–[4–[4–(2– 530 2,35 OR 3– [4– [4– (2– 530 2.35

N N S N H N H OO O N N S N H N H OO O: il]pirimidin–2–il]fenil]–1–etil–urea il] pyrimidin – 2-yl] phenyl] –1-ethyl-urea

68c 68c: N N N O S N H N H OO O N 1–[4–[4–(2– ciclohexilsulfonilpropan–2–il)–6– [(3S)–3–metilmorfolin–4– il]pirimidin–2–il]fenil]–3–(2– dimetilaminoetil)urea 573 2,26 N N N O S N H N H OO O N 1– [4– [4– (2– cyclohexylsulfonylpropan – 2-yl) –6– [(3S) –3 – methylmorpholin-4– yl] pyrimidin – 2-yl] phenyl] –3– (2– dimethylaminoethyl) urea 573 2.26

68d 68d: N N N O S N H N H OO O OH 1–[4–[4–(2– ciclohexilsulfonilpropan–2–il)–6– [(3S)–3–metilmorfolin–4– il]pirimidin–2–il]fenil]–3–(2– hidroxietil)urea 546 1,99 N N N O S N H N H OO O OH 1– [4– [4– (2– cyclohexylsulfonylpropan – 2-yl) –6– [(3S) –3 – methylmorpholin-4– yl] pyrimidin – 2-yl] phenyl] –3– (2– hydroxyethyl) urea 546 1.99

68e 68e: O 1–[4–[4–(2– 516 2,19 OR 1– [4– [4– (2– 516 2.19

N N S N H N H OO O N N S N H N H OO O: il]pirimidin–2–il]fenil]–3–metil–urea il] pyrimidin – 2-yl] phenyl] –3-methyl-urea

Tiempo de Time of

Ejemplo Example: Estructura NOMBRE LCMS MH+ retención Structure NAME LCMS MH + retention

(min.) (min.)

68f 68f: SO O N N N O N H N H O 3–ciclobutil–1–[4–[4– (ciclohexilsulfonilmetil)–6–[(3S)–3– metilmorfolin–4–il]pirimidin–2– il]fenil]urea 529 2,57 SO OR N N N O N H N H O 3 – cyclobutyl – 1– [4– [4– (cyclohexylsulfonylmethyl) –6 - [(3S) –3– methylmorpholin-4-yl] pyrimidin – 2-yl] phenyl] urea 529 2.57

68g 68g: O 3–[4–[4–(ciclohexilsulfonilmetil)–6– 503 2,32 OR 3– [4– [4– (cyclohexylsulfonylmethyl) –6– 503 2.32

: [(3S)–3–metilmorfolin–4– [(3S) –3 – methylmorpholin – 4–

SO O SO OR: N N N N H N H O il]pirimidin–2–il]fenil]–1–etil–urea N N N N H N H O il] pyrimidin – 2-yl] phenyl] –1-ethyl-urea

68h 68h: SO O N N N O N H N H O N 1–[4–[4–(ciclohexilsulfonilmetil)–6– [(3S)–3–metilmorfolin–4– il]pirimidin–2–il]fenil]–3–(2– dimetilaminoetil)urea 545 2,25 SO OR N N N O N H N H O N 1– [4– [4– (cyclohexylsulfonylmethyl) –6– [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] –3– (2– dimethylaminoethyl) urea 545 2.25

5 Ejemplo 68b: RMN 1H (400,132 MHz, DMSO–d6) δ 0,99–1,17 (6H, m), 1,22 (3H, d), 1,25–1,36 (2H, m), 1,47–1,53 (1H, m), 1,64–1,84 (10H, m), 3,10–3,16 (2H, m), 3,20 (1H, td), 3,50 (1H, td), 3,65 (1H, dd), 3,71–3,78 (2H, m), 3,98 (1H, dd), 4,23 (1H, d), 4,55–4,62 (1H, m), 6,17 (1H, t), 6,75 (1H, s), 7,51 (2H, d), 8,25 (2H, d), 8,68 (1H, s). 5 Example 68b: 1H NMR (400.132 MHz, DMSO-d6) δ 0.99-1.17 (6H, m), 1.22 (3H, d), 1.25-1.36 (2H, m), 1.47-1.53 (1H, m), 1.64-1.84 (10H, m), 3.10-3.16 (2H, m), 3.20 (1H, td), 3, 50 (1H, td), 3.65 (1H, dd), 3.71-3.78 (2H, m), 3.98 (1H, dd), 4.23 (1H, d), 4.55 –4.62 (1H, m), 6.17 (1H, t), 6.75 (1H, s), 7.51 (2H, d), 8.25 (2H, d), 8.68 ( 1H, s).

Ejemplo 68c: RMN 1H (400,132 MHz, DMSO–d6) δ 0,99–1,19 (3H, m), 1,22 (3H, d), 1,25–1,37 (2H, m), 1,48–1,53 (1H, m), 1,64–1,84 (10H, m), 2,18 (6H, s), 2,34 (2H, t), 3,17–3,24 (3H, m), 3,50 (1H, td), 3,65 (1H, dd), 3,70–3,78 Example 68c: 1H NMR (400.132 MHz, DMSO-d6) δ 0.99-1.19 (3H, m), 1.22 (3H, d), 1.25-1.37 (2H, m), 1 , 48–1.53 (1H, m), 1.64–1.84 (10H, m), 2.18 (6H, s), 2.34 (2H, t), 3.17–3.24 (3H, m), 3.50 (1H, td), 3.65 (1H, dd), 3.70-3.78

10 (2H, m), 3,98 (1H, dd), 4,23 (1H, d), 4,56–4,62 (1H, m), 6,17 (1H, t), 6,75 (1H, s), 7,50 (2H, d), 8,25 (2H, d), 8,91 (1H, s). 10 (2H, m), 3.98 (1H, dd), 4.23 (1H, d), 4.56-4.62 (1H, m), 6.17 (1H, t), 6.75 (1H, s), 7.50 (2H, d), 8.25 (2H, d), 8.91 (1H, s).

Ejemplo 68d: RMN 1H (400,132 MHz, DMSO–d6) δ 0,99–1,18 (3H, m), 1,22 (3H, d), 1,25–1,37 (2H, m), 1,47–1,53 (1H, m), 1,63–1,84 (10H, m), 3,16–3,24 (3H, m), 3,44–3,53 (3H, m), 3,65 (1H, dd), 3,70–3,78 (2H, m), 3,98 (1H, dd), 4,23 (1H, d), 4,56–4,63 (1H, m), 4,73 (1H, t), 6,26 (1H, t), 6,75 (1H, s), 7,50 (2H, d), 8,25 (2H, d), 8,82 (1H, s). Example 68d: 1H NMR (400.132 MHz, DMSO-d6) δ 0.99-1.18 (3H, m), 1.22 (3H, d), 1.25-1.37 (2H, m), 1 , 47–1.53 (1H, m), 1.63–1.84 (10H, m), 3.16–3.24 (3H, m), 3.44–3.53 (3H, m) , 3.65 (1H, dd), 3.70-3.78 (2H, m), 3.98 (1H, dd), 4.23 (1H, d), 4.56-4.63 (1H , m), 4.73 (1H, t), 6.26 (1H, t), 6.75 (1H, s), 7.50 (2H, d), 8.25 (2H, d), 8 , 82 (1H, s).

15 Ejemplo 68e: RMN 1H (400,132 MHz, DMSO–d6) δ 1,00–1,18 (3H, m), 1,22 (3H, d), 1,25–1,36 (2H, m), 1,47–1,52 (1H, m), 1,64–1,84 (10H, m), 2,66 (3H, d), 3,20 (1H, td), 3,50 (1H, td), 3,65 (1H, dd), 3,71–3,78 (2H, m), 3,98 (1H, dd), 4,23 (1H, d), 4,56–4,61 (1H, m), 6,08 (1H, q), 6,75 (1H, s), 7,52 (2H, d), 8,25 (2H, d), 8,76 (1H, s). Example 68e: 1H NMR (400.132 MHz, DMSO-d6) δ 1.00-1.18 (3H, m), 1.22 (3H, d), 1.25-1.36 (2H, m), 1.47-1.52 (1H, m), 1.64-1.84 (10H, m), 2.66 (3H, d), 3.20 (1H, td), 3.50 (1H, td), 3.65 (1H, dd), 3.71-3.78 (2H, m), 3.98 (1H, dd), 4.23 (1H, d), 4.56-4.61 (1H, m), 6.08 (1H, q), 6.75 (1H, s), 7.52 (2H, d), 8.25 (2H, d), 8.76 (1H, s) .

Ejemplo 68f: RMN 1H (400,132 MHz, DMSO–d6) δ 1,18–1,31 (6H, m), 1,41–1,49 (2H, m), 1,57–1,69 (3H, m), 1,82– 1,92 (4H, m), 2,18–2,28 (4H, m), 3,22 (1H, td), 3,34 (1H, tt), 3,50 (1H, td), 3,65 (1H, dd), 3,78 (1H, d), 3,99 (1H, dd), Example 68f: 1H NMR (400.132 MHz, DMSO-d6) δ 1.18-1.31 (6H, m), 1.41-1.49 (2H, m), 1.57-1.69 (3H, m), 1.82– 1.92 (4H, m), 2.18–2.28 (4H, m), 3.22 (1H, td), 3.34 (1H, tt), 3.50 (1H, td), 3.65 (1H, dd), 3.78 (1H, d), 3.99 (1H, dd),

20 4,09–4,22 (2H, m), 4,40–4,51 (3H, m), 6,48 (1H, d), 6,77 (1H, s), 7,48 (2H, d), 8,19 (2H, d), 8,58 (1H, s). 20 4.09-4.22 (2H, m), 4.40-4.51 (3H, m), 6.48 (1H, d), 6.77 (1H, s), 7.48 (2H , d), 8.19 (2H, d), 8.58 (1H, s).

Ejemplo 68g: RMN 1H (400,132 MHz, DMSO–d6) δ 1,07 (3H, t), 1,15–1,33 (6H, m), 1,39–1,50 (2H, m), 1,65–1,71 (1H, m), 1,86–1,92 (2H, m), 2,21–2,28 (2H, m), 3,09–3,16 (2H, m), 3,22 (1H, td), 3,34 (1H, tt), 3,50 (1H, td), 3,65 (1H, dd), 3,78 (1H, d), 3,99 (1H, dd), 4,13–4,21 (1H, m), 4,40–4,51 (3H, m), 6,18 (1H, t), 6,77 (1H, s), 7,50 (2H, d), 8,20 (2H, d), 8,68 (1H, s). Example 68g: 1H NMR (400.132 MHz, DMSO-d6) δ 1.07 (3H, t), 1.15-1.33 (6H, m), 1.39-1.50 (2H, m), 1 , 65–1.71 (1H, m), 1.86–1.92 (2H, m), 2.21–2.28 (2H, m), 3.09–3.16 (2H, m) , 3.22 (1H, td), 3.34 (1H, tt), 3.50 (1H, td), 3.65 (1H, dd), 3.78 (1H, d), 3.99 ( 1H, dd), 4.13-4.21 (1H, m), 4.40-4.51 (3H, m), 6.18 (1H, t), 6.77 (1H, s), 7 , 50 (2H, d), 8.20 (2H, d), 8.68 (1H, s).

25 Ejemplo 68h: RMN 1H (400,132 MHz, DMSO–d6) δ 1,16–1,33 (6H, m), 1,39–1,50 (2H, m), 1,65–1,71 (1H, m), 1,86– 1,92 (2H, m), 2,18 (6H, s), 2,21–2,27 (2H, m), 2,34 (2H, t), 3,17–3,26 (3H, m), 3,34 (1H, tt), 3,50 (1H, td), 3,65 (1H, dd), 3,78 (1H, d), 3,99 (1H, dd), 4,14–4,21 (1H, m), 4,40–4,51 (3H, m), 6,18 (1H, t), 6,77 (1H, s), 7,49 (2H, d), 8,20 (2H, d), 8,90 (1H, s). Example 68h: 1H NMR (400.132 MHz, DMSO-d6) δ 1.16-1.33 (6H, m), 1.39-1.50 (2H, m), 1.65-1.71 (1H , m), 1.86– 1.92 (2H, m), 2.18 (6H, s), 2.21-2.27 (2H, m), 2.34 (2H, t), 3, 17–3.26 (3H, m), 3.34 (1H, tt), 3.50 (1H, td), 3.65 (1H, dd), 3.78 (1H, d), 3.99 (1H, dd), 4.14-4.21 (1H, m), 4.40-4.51 (3H, m), 6.18 (1H, t), 6.77 (1H, s), 7.49 (2H, d), 8.20 (2H, d), 8.90 (1H, s).

A continuación se describe la preparación de N–[4–[4–(2–ciclohexilsulfonilpropan–2–il)–6–[(3S)–3–metilmorfolin–4– 30 il]pirimidin–2–il]fenil]carbamato de fenilo. The preparation of N– [4– [4– (2-cyclohexylsulfonylpropan – 2-yl) –6 - [(3S) –3-methylmorpholin-4–30 yl] pyrimidin-2-yl] phenyl] carbamate is described below. of phenyl.

30 N–[4–[4–(2–Ciclohexilsulfonilpropan–2–il)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]carbamato de fenilo 30 N– [4– [4– (2 – Cyclohexylsulfonylpropan – 2-yl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] phenyl carbamate

A una disolución de 4–[4–(2–ciclohexilsulfonilpropan–2–il)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]anilina (1,1 g, 2,40 mmoles) en 1,4–dioxano (12 ml) se añadió bicarbonato de sodio (0,302 g, 3,60 mmoles). Después se añadió gota a gota cloroformiato de fenilo (0,316 ml, 2,52 mmoles), y la mezcla resultante se agitó a RT durante 3 horas. La mezcla resultante se evaporó hasta sequedad, y el residuo se repartió entre agua (10 ml) y DCM (10 ml). La capa orgánica se separó y se evaporó hasta sequedad. El residuo se trituró con éter dietílico para dar el material deseado como un sólido (1,328 g). To a solution of 4– [4– (2-cyclohexylsulfonylpropan-2-yl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] aniline (1.1 g, 2.40 mmol) in 1,4-dioxane (12 ml) sodium bicarbonate (0.302 g, 3.60 mmol) was added. Then phenyl chloroformate (0.316 ml, 2.52 mmol) was added dropwise, and the resulting mixture was stirred at RT for 3 hours. The resulting mixture was evaporated to dryness, and the residue was partitioned between water (10 ml) and DCM (10 ml). The organic layer was separated and evaporated to dryness. The residue was triturated with diethyl ether to give the desired material as a solid (1.328 g).

Espectro RMN: RMN 1H (400,132 MHz, DMSO–d6) δ 0,99–1,18 (3H, m), 1,20–1,37 (5H, m), 1,46–1,52 (1H, m), 1,63–1,83 (10H, m), 3,21 (1H, td), 3,51 (1H, td), 3,65 (1H, dd), 3,69–3,79 (3H, m), 3,98 (1H, dd), 4,21–4,28 (1H, m), 4,56–4,64 (1H, m), 7,24–7,30 (3H, m), 7,45 (2H, t), 7,65 (2H, d), 8,36 (2H, d), 10,43 (1H, s). NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 0.99-1.18 (3H, m), 1.20-1.37 (5H, m), 1.46-1.52 (1H, m), 1.63-1.83 (10H, m), 3.21 (1H, td), 3.51 (1H, td), 3.65 (1H, dd), 3.69-3.79 (3H, m), 3.98 (1H, dd), 4.21-4.28 (1H, m), 4.56-4.64 (1H, m), 7.24-7.30 (3H , m), 7.45 (2H, t), 7.65 (2H, d), 8.36 (2H, d), 10.43 (1H, s).

Espectro LCMS: MH+ 579, tiempo de retención 3,11 min. LCMS spectrum: MH + 579, retention time 3.11 min.

4–[4–(2–Ciclohexilsulfonilpropan–2–il)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]anilina 4– [4– (2 – Cyclohexylsulfonylpropan – 2-yl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin – 2-yl] aniline

Una mezcla de 2–cloro–4–(2–ciclohexilsulfonilpropan–2–il)–6–[(3S)–3–metilmorfolin–4–il]pirimidina (1,18 g, 2,94 mmoles), disolución acuosa 2M de carbonato de sodio (5,5 ml, 11,00 mmoles) y 4–(4,4,5,5–tetrametil–1,3,2– dioxaborolan–2–il)anilina (0,907 g, 4,14 mmoles) en una mezcla de DMF (5 ml), agua (12,50 ml), etanol (5,00 ml) y DME (5,00 ml) se purgó con nitrógeno durante 10 minutos antes de tratarla con cloruro de bis(trifenilfosfina)paladio(II) (0,111 g, 0,16 mmoles). La mezcla agitada se calentó hasta 80ºC y se agitó en nitrógeno durante 2,5 horas. La mezcla de reacción se enfrió y se trató con acetato de etilo (50 ml) y agua (50 ml). La capa orgánica se separó y la acuosa se extrajo nuevamente con acetato de etilo (2 x 30 ml). Los productos orgánicos combinados se lavaron con salmuera, se secaron (MgSO4) y se evaporaron para proporcionar el producto bruto, el cual se purificó mediante cromatografía ultrarrápida en sílice, gradiente de elución 25 a 75% de acetato de etilo en isohexano, para dar el material deseado (1,130 g). A mixture of 2-chloro-4– (2-cyclohexylsulfonylpropan-2-yl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidine (1.18 g, 2.94 mmol), 2M aqueous solution of sodium carbonate (5.5 ml, 11.00 mmol) and 4– (4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl) aniline (0.907 g, 4.14 mmol ) in a mixture of DMF (5 ml), water (12.50 ml), ethanol (5.00 ml) and DME (5.00 ml) was purged with nitrogen for 10 minutes before being treated with bis (triphenylphosphine chloride) ) palladium (II) (0.111 g, 0.16 mmol). The stirred mixture was heated to 80 ° C and stirred under nitrogen for 2.5 hours. The reaction mixture was cooled and treated with ethyl acetate (50 ml) and water (50 ml). The organic layer was separated and the aqueous one was extracted again with ethyl acetate (2 x 30 ml). The combined organic products were washed with brine, dried (MgSO4) and evaporated to provide the crude product, which was purified by flash chromatography on silica, gradient elution 25 to 75% ethyl acetate in isohexane, to give the desired material (1,130 g).

Espectro RMN: RMN 1H (400,132 MHz, DMSO–d6) δ 0,99–1,23 (6H, m), 1,25–1,36 (2H, m), 1,47–1,53 (1H, m), 1,65–1,83 (10H, m), 3,18 (1H, td), 3,49 (1H, td), 3,64 (1H, dd), 3,73–3,81 (2H, m), 3,97 (1H, dd), 4,19 (1H, d), 4,52– 4,58 (1H, m), 5,54–5,57 (2H, m), 6,62 (2H, d), 6,64 (1H, s), 8,08 (2H, d). NMR Spectrum: 1H NMR (400.132 MHz, DMSO – d6) δ 0.99-1.23 (6H, m), 1.25-1.36 (2H, m), 1.47-1.53 (1H, m), 1.65-1.83 (10H, m), 3.18 (1H, td), 3.49 (1H, td), 3.64 (1H, dd), 3.73-3.81 (2H, m), 3.97 (1H, dd), 4.19 (1H, d), 4.52-5.58 (1H, m), 5.54-5.57 (2H, m), 6.62 (2H, d), 6.64 (1H, s), 8.08 (2H, d).

Espectro LCMS: MH+ 459, tiempo de retención 2,56 min. LCMS spectrum: MH + 459, retention time 2.56 min.

2 – Chloro – 4– (2 – cyclohexylsulfonylpropan – 2 – yl) –6 - [(3S) –3 – methylmorpholin-4-yl] pyrimidine

Una disolución enfriada (baño de hielo/agua) de 2–cloro–4–(ciclohexilsulfonilmetil)–6–[(3S)–3–metilmorfolin–4– il]pirimidina (1,26 g, 3,37 mmoles) en DMF (16 ml) se trató con terc–butóxido de sodio (0,324 g, 3,37 mmoles). La mezcla se agitó a 0ºC durante 5 minutos. Después se añadió yodometano (0,210 ml, 3,37 mmoles), y la mezcla se A cooled solution (ice / water bath) of 2-chloro-4– (cyclohexylsulfonylmethyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidine (1.26 g, 3.37 mmol) in DMF (16 ml) was treated with sodium tert-butoxide (0.324 g, 3.37 mmol). The mixture was stirred at 0 ° C for 5 minutes. Iodomethane (0.210 ml, 3.37 mmol) was then added, and the mixture was

agitó a 0ºC durante unos 10 minutos adicionales. Después se añadió terc–butóxido de sodio adicional (0,324 g, 3,37 mmoles), y la agitación se continuó durante unos 5 minutos adicionales antes de la adición de más yodometano (0,210 ml, 3,37 mmoles). La mezcla resultante se agitó a 0ºC durante unos 15 minutos adicionales. Después el baño de enfriamiento se retiró, y la reacción se dejó calentar, con agitación hasta RT. Se añadió agua (75 ml) a la mezcla de reacción, y el precipitado resultante se recogió mediante filtración por succión, se lavó con más agua (40 ml) y se secó para proporcionar el material deseado (1,180 g). stirred at 0 ° C for an additional 10 minutes. Then additional sodium tert-butoxide (0.324 g, 3.37 mmol) was added, and stirring was continued for an additional 5 minutes before the addition of more iodomethane (0.210 ml, 3.37 mmol). The resulting mixture was stirred at 0 ° C for an additional 15 minutes. Then the cooling bath was removed, and the reaction was allowed to warm, with stirring to RT. Water (75 ml) was added to the reaction mixture, and the resulting precipitate was collected by suction filtration, washed with more water (40 ml) and dried to provide the desired material (1,180 g).

Espectro RMN: RMN 1H (400,132 MHz, DMSO–d6) δ 1,04–1,15 (1H, m), 1,19–1,37 (7H, m), 1,54–1,60 (1H, m), 1,69 (6H, s), 1,70–1,80 (4H, m), 3,17–3,25 (1H, m), 3,45 (1H, td), 3,52–3,62 (2H, m), 3,72 (1H, d), 3,94 (1H, dd), 4,07 (1H, d), 4,39–4,48 (1H, m), 6,89 (1H, s). NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.04-1.15 (1H, m), 1.19-1.37 (7H, m), 1.54-1.60 (1H, m), 1.69 (6H, s), 1.70-1.80 (4H, m), 3.17–3.25 (1H, m), 3.45 (1H, td), 3.52 –3.62 (2H, m), 3.72 (1H, d), 3.94 (1H, dd), 4.07 (1H, d), 4.39-4.48 (1H, m), 6.89 (1H, s).

Espectro LCMS: MH+ 402, tiempo de retención 2,72 min. LCMS spectrum: MH + 402, retention time 2.72 min.

2–Cloro–4–(ciclohexilsulfonilmetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidina 2 – Chloro – 4– (cyclohexylsulfonylmethyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidine

A una disolución enfriada (baño de hielo/agua) de 2,4–dicloro–6–(ciclohexilsulfonilmetil)pirimidina (1,65 g, 5,34 mmoles) en DCM (25 ml) se añadió trietilamina (0,820 ml, 5,88 mmoles). La disolución resultante se trató, gota a gota durante 8 minutos, con una disolución de (3S)–3–metilmorfolina (609 mg, 6,02 mmoles) en DCM (5 ml). La mezcla se agitó a 6ºC durante 30 minutos. El baño de enfriamiento se retiró después, y la mezcla de reacción se dejó agitar toda la noche. Después se añadió agua (25 ml), y la mezcla de reacción se agitó durante 5 minutos. Después la capa orgánica se separó, se secó (MgSO4) y se evaporó para dar un aceite marrón bruto, el cual se purificó mediante cromatografía ultrarrápida en sílice, gradiente de elución 25 a 75% de acetato de etilo en isohexano, para dar el material deseado (1,440 g). To a cooled solution (ice / water bath) of 2,4-dichloro-6– (cyclohexylsulfonylmethyl) pyrimidine (1.65 g, 5.34 mmol) in DCM (25 ml) was added triethylamine (0.820 ml, 5, 88 mmol). The resulting solution was treated, dropwise over 8 minutes, with a solution of (3S) -3-methylmorpholine (609 mg, 6.02 mmol) in DCM (5 ml). The mixture was stirred at 6 ° C for 30 minutes. The cooling bath was then removed, and the reaction mixture was allowed to stir overnight. Water (25 ml) was then added, and the reaction mixture was stirred for 5 minutes. The organic layer was then separated, dried (MgSO4) and evaporated to give a crude brown oil, which was purified by flash chromatography on silica, gradient elution 25 to 75% ethyl acetate in isohexane, to give the material. desired (1,440 g).

Espectro RMN: RMN 1H (400,132 MHz, DMSO–d6) δ 1,15–1,45 (8H, m), 1,63–1,68 (1H, m), 1,81–1,87 (2H, m), 2,11–2,17 (2H, m), 3,15–3,25 (2H, m), 3,45 (1H, td), 3,60 (1H, dd), 3,73 (1H, d), 3,92–4,01 (2H, m), 4,30 (1H, br s), 4,39 (2H, s), 6,90 (1H, s). NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.15-1.45 (8H, m), 1.63-1.68 (1H, m), 1.81-1.87 (2H, m), 2.11-2.17 (2H, m), 3.15-3.25 (2H, m), 3.45 (1H, td), 3.60 (1H, dd), 3.73 (1H, d), 3.92-4.01 (2H, m), 4.30 (1H, br s), 4.39 (2H, s), 6.90 (1H, s).

Espectro LCMS: MH+ 374, tiempo de retención 2,24 min. LCMS spectrum: MH + 374, retention time 2.24 min.

2,4–Dicloro–6–(ciclohexilsulfonilmetil)pirimidina 2,4 – Dichloro – 6– (cyclohexylsulfonylmethyl) pyrimidine

Cl Cl

A una disolución agitada de 2,4–dicloro–6–(ciclohexilsulfanilmetil)pirimidina (1,53 g, 5,52 mmoles) en DCM (28 ml) se añadió, en porciones, ácido 3–cloroperoxibenzoico (3,09 g, 13,80 mmoles) durante un período de 20 minutos en nitrógeno, para controlar la temperatura por debajo de 28ºC. La suspensión resultante se agitó a RT durante 3 horas, después se añadió disolución saturada acuosa de hidrogenocarbonato de sodio (40 ml), y la mezcla de reacción se agitó durante 5 minutos. Después la capa orgánica se separó, se secó (MgSO4) y se evaporó hasta sequedad. El sólido resultante se volvió a disolver en DCM (40 ml) y se añadió una saturada acuosa disolución de hidrogenocarbonato de sodio (40 ml). La mezcla se agitó durante 15 minutos antes de separar la capa orgánica, secar (sobre MgSO4) y evaporar para proporcionar el material deseado (1,650 g). To a stirred solution of 2,4-dichloro-6– (cyclohexylsulfanylmethyl) pyrimidine (1.53 g, 5.52 mmol) in DCM (28 ml) was added, portionwise, 3-chloroperoxybenzoic acid (3.09 g, 13.80 mmol) over a period of 20 minutes under nitrogen, to control the temperature below 28 ° C. The resulting suspension was stirred at RT for 3 hours, then saturated aqueous sodium hydrogen carbonate solution (40 ml) was added, and the reaction mixture was stirred for 5 minutes. Then the organic layer was separated, dried (MgSO4) and evaporated to dryness. The resulting solid was redissolved in DCM (40 ml) and a saturated aqueous sodium hydrogen carbonate solution (40 ml) was added. The mixture was stirred for 15 minutes before separating the organic layer, drying (over MgSO4) and evaporating to provide the desired material (1,650 g).

Espectro RMN: RMN 1H (400,132 MHz, DMSO–d6) δ 1,12–1,46 (5H, m), 1,61–1,69 (1H, m), 1,80–1,88 (2H, m), 2,10–2,17 (2H, m), 3,22 (1H, tt), 4,73 (2H, s), 7,85 (1H, s). NMR Spectrum: 1H NMR (400.132 MHz, DMSO – d6) δ 1.12–1.46 (5H, m), 1.61–1.69 (1H, m), 1.80–1.88 (2H, m), 2.10-2.17 (2H, m), 3.22 (1H, tt), 4.73 (2H, s), 7.85 (1H, s).

Espectro LCMS: M–H– 307, tiempo de retención 2,26 min. LCMS spectrum: M – H– 307, retention time 2.26 min.

2,4–Dicloro–6–(ciclohexilsulfanilmetil)pirimidina 2,4 – Dichloro – 6– (cyclohexylsulfanylmethyl) pyrimidine

Cl Cl

Una suspensión de 6–(ciclohexilsulfanilmetil)–1H–pirimidin–2,4–diona (3,6 g, 14,98 mmoles) en oxicloruro de fósforo (15 ml, 160,93 mmoles) se calentó hasta 100ºC, durante un período de 15 minutos. La disolución naranja oscura resultante se agitó a 100ºC durante 7 horas. Después la mezcla de reacción se enfrió antes de evaporarla para obtener un aceite marrón viscoso el cual se repartió entre DCM (20 ml) y agua con hielo (20 ml). Después se añadió cuidadosamente y en porciones hidrogenocarbonato de sodio sólido, durante 30 minutos para controlar la efervescencia. Se añadieron alícuotas adicionales de agua (30 ml) y DCM durante la adición. Una vez que la efervescencia hubo cesado y el pH se hubo ajustado a 8, la mezcla se transfirió a un embudo de separación, y la capa orgánica se separó. La capa acuosa se extrajo nuevamente con DCM (2 x 50 ml), y las capas orgánicas combinadas se lavaron con salmuera (100 ml), se secaron (MgSO4) y se evaporaron para proporcionar el producto bruto, el cual se purificó mediante cromatografía ultrarrápida en sílice, gradiente de elución 10 a 40% de acetato de etilo en isohexano, para dar el material deseado (1,60 g). A suspension of 6– (cyclohexylsulfanylmethyl) -1 H -pyrimidin-2,4-dione (3.6 g, 14.98 mmol) in phosphorus oxychloride (15 ml, 160.93 mmol) was heated to 100 ° C for a period 15 minutes The resulting dark orange solution was stirred at 100 ° C for 7 hours. The reaction mixture was then cooled before evaporating to obtain a viscous brown oil which was partitioned between DCM (20 ml) and ice water (20 ml). Then solid sodium hydrogen carbonate was added carefully and portionwise for 30 minutes to control the effervescence. Additional aliquots of water (30 ml) and DCM were added during the addition. Once the effervescence had ceased and the pH had been adjusted to 8, the mixture was transferred to a separatory funnel, and the organic layer was separated. The aqueous layer was extracted again with DCM (2 x 50 ml), and the combined organic layers were washed with brine (100 ml), dried (MgSO4) and evaporated to give the crude product, which was purified by flash chromatography. on silica, gradient elution 10 to 40% ethyl acetate in isohexane, to give the desired material (1.60 g).

Espectro RMN: RMN 1H (400,132 MHz, DMSO–d6) δ 1,18–1,31 (5H, m), 1,51–1,58 (1H, m), 1,63–1,71 (2H, m), 1,86–1,93 (2H, m), 2,70–2,77 (1H, m), 3,85 (2H, s), 7,81 (1H, s). NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.18-1.31 (5H, m), 1.51-1.58 (1H, m), 1.63-1.71 (2H, m), 1.86-1.93 (2H, m), 2.70-2.77 (1H, m), 3.85 (2H, s), 7.81 (1H, s).

Espectro LCMS: M–H– 275, tiempo de retención 3,04 min. LCMS spectrum: M – H– 275, retention time 3.04 min.

6–(Ciclohexilsulfanilmetil)–1H–pirimidin–2,4–diona 6– (Cyclohexylsulfanylmethyl) –1H – pyrimidin – 2,4 – dione

O OR

Una disolución de ciclohexanotiol (10 ml, 81,74 mmoles) en DMF (150 ml) se trató con 1,8–diazabiciclo[5,4,0]undec– 7–eno (14 ml, 93,80 mmoles). La disolución resultante se agitó a RT durante 20 minutos. Después se añadió, en porciones, durante un período de 30 minutos 6–(clorometil)pirimidin–2,4(1H,3H)–diona (10 g, 62,28 mmoles) en nitrógeno, para mantener la temperatura interna por debajo de 35ºC. La disolución resultante se agitó a RT toda la noche. Después la mezcla de reacción se evaporó hasta sequedad, y el residuo se repartió entre DCM (100 ml) y agua (150 ml). Al mezclar se formó un precipitado, éste se eliminó mediante filtración por succión, y se secó a vacío, a 55ºC durante 2 horas para proporcionar el material deseado (6,45 g). Se obtuvo material deseado adicional (3,62 g) ajustando el filtrado a pH 2 mediante adición gota a gota de ácido clorhídrico 2M y eliminando el precipitado, lavando el precipitado con agua (100 ml) y secándolo en un horno de vacío. A solution of cyclohexanediol (10 ml, 81.74 mmol) in DMF (150 ml) was treated with 1.8-diazabicyclo [5.4.0] undec-7-ene (14 ml, 93.80 mmol). The resulting solution was stirred at RT for 20 minutes. Then 6- (chloromethyl) pyrimidin-2,4 (1H, 3H) -dione (10 g, 62.28 mmol) nitrogen was added portionwise over nitrogen to keep the internal temperature below 35 ° C The resulting solution was stirred at RT overnight. The reaction mixture was then evaporated to dryness, and the residue was partitioned between DCM (100 ml) and water (150 ml). Upon mixing a precipitate formed, it was removed by suction filtration, and dried under vacuum, at 55 ° C for 2 hours to provide the desired material (6.45 g). Additional desired material (3.62 g) was obtained by adjusting the filtrate to pH 2 by dropwise addition of 2M hydrochloric acid and removing the precipitate, washing the precipitate with water (100 ml) and drying it in a vacuum oven.

Espectro RMN: RMN 1H (400,132 MHz, DMSO–d6) δ 1,16–1,34 (5H, m), 1,51–1,58 (1H, m), 1,63–1,72 (2H, m), 1,87–1,96 (2H, m), 2,65–2,72 (1H, m), 3,41 (2H, s), 5,49 (1H, s), 10,75–10,96 (2H, m). NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.16–1.34 (5H, m), 1.51–1.58 (1H, m), 1.63–1.72 (2H, m), 1.87-1.96 (2H, m), 2.65-2.72 (1H, m), 3.41 (2H, s), 5.49 (1H, s), 10.75 –10.96 (2H, m).

Espectro LCMS: MH+ 241, tiempo de retención 0,99 min. LCMS spectrum: MH + 241, retention time 0.99 min.

A continuación se describe la preparación de N–[4–[4–(ciclohexilsulfonilmetil)–6–[(3S)–3–metilmorfolin–4– il]pirimidin–2–il]fenil]carbamato de fenilo. The preparation of N- [4– [4– (cyclohexylsulfonylmethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] carbamate is described below.

N–[4–[4–(Ciclohexilsulfonilmetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]carbamato de fenilo N– [4– [4– (Cyclohexylsulfonylmethyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] phenyl carbamate

Se añadió bicarbonato de sodio (113 mg, 1,35 mmoles) a una disolución de 4–[4–(ciclohexilsulfonilmetil)–6–[(3S)–3– metilmorfolin–4–il]pirimidin–2–il]anilina (370 mg, 0,86 mmoles) en 1,4–dioxano (5 ml). Se añadió gota a gota cloroformiato de fenilo (0,124 ml, 0,99 mmoles), y la mezcla resultante se agitó a RT durante 5 horas. La mezcla resultante se evaporó hasta sequedad, y el residuo se repartió entre DCM (5 ml) y agua (5 ml). La capa orgánica se Sodium bicarbonate (113 mg, 1.35 mmol) was added to a solution of 4– [4– (cyclohexylsulfonylmethyl) –6 - [(3S) –3– methylmorpholin-4-yl] pyrimidin-2-yl] aniline ( 370 mg, 0.86 mmol) in 1,4-dioxane (5 ml). Phenyl chloroformate (0.124 ml, 0.99 mmol) was added dropwise, and the resulting mixture was stirred at RT for 5 hours. The resulting mixture was evaporated to dryness, and the residue was partitioned between DCM (5 ml) and water (5 ml). The organic layer is

separó y se evaporó hasta sequedad. El residuo bruto se trituró con éter dietílico para dar el material deseado (429 mg). separated and evaporated to dryness. The crude residue was triturated with diethyl ether to give the desired material (429 mg).

Espectro RMN: RMN 1H (400,132 MHz, DMSO–d6) δ 1,16–1,33 (6H, m), 1,40–1,50 (2H, m), 1,64–1,70 (1H, m), 1,85–1,92 (2H, m), 2,21–2,28 (2H, m), 3,19–3,36 (2H, m), 3,50 (1H, td), 3,65 (1H, dd), 3,78 (1H, d), 3,99 (1H, dd), 4,16–4,23 (1H, m), 4,43–4,52 (3H, m), 6,81 (1H, s), 7,24–7,30 (3H, m), 7,43–7,47 (2H, m), 7,63 (2H, d), 8,30 (2H, d), 10,44 (1H, s). NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.16-1.33 (6H, m), 1.40-1.50 (2H, m), 1.64-1.70 (1H, m), 1.85–1.92 (2H, m), 2.21–2.28 (2H, m), 3.19–3.36 (2H, m), 3.50 (1H, td) , 3.65 (1H, dd), 3.78 (1H, d), 3.99 (1H, dd), 4.16-4.23 (1H, m), 4.43-4.52 (3H , m), 6.81 (1H, s), 7.24-7.30 (3H, m), 7.43-7.47 (2H, m), 7.63 (2H, d), 8, 30 (2H, d), 10.44 (1H, s).

Espectro LCMS: MH+ 551, tiempo de retención 2,88 min. LCMS spectrum: MH + 551, retention time 2.88 min.

4–[4–(Ciclohexilsulfonilmetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]anilina 4– [4– (Cyclohexylsulfonylmethyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] aniline

Una mezcla de 2–cloro–4–(ciclohexilsulfonilmetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidina (437 mg, 1,17 mmoles), 4– (4,4,5,5–tetrametil–1,3,2–dioxaborolan–2–il)anilina (381 mg, 1,74 mmoles) y disolución acuosa 2M de carbonato de sodio (0,60 ml, 1,20 mmoles) en una mezcla de DMF (2 ml), etanol (2 ml), agua (5 ml) y DME (2 ml) se purgó con nitrógeno durante 5 minutos antes de la adición de cloruro de bis(trifenilfosfina)paladio(II) (41,0 mg, 0,06 mmoles). La mezcla de reacción se calentó hasta 80ºC, en nitrógeno, y se agitó durante 3,5 horas. La mezcla de reacción se enfrió y se repartió entre acetato de etilo (25 ml) y agua (30 ml). La capa orgánica se separó, y la acuosa se volvió a extraer con acetato de etilo (2 x 25 ml). Los extractos orgánicos combinados se lavaron con salmuera saturada (50 ml), se secaron (MgSO4), se filtraron y se evaporaron para proporcionar el producto bruto, el cual se purificó mediante cromatografía ultrarrápida en sílice, gradiente de elución 25 a 75% de acetato de etilo en isohexano, para dar el material deseado (402 mg). A mixture of 2-chloro-4– (cyclohexylsulfonylmethyl) –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidine (437 mg, 1.17 mmol), 4– (4,4,5,5– tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (381 mg, 1.74 mmol) and 2M aqueous solution of sodium carbonate (0.60 ml, 1.20 mmol) in a mixture of DMF (2 ml), ethanol (2 ml), water (5 ml) and DME (2 ml) was purged with nitrogen for 5 minutes before the addition of bis (triphenylphosphine) palladium (II) chloride (41.0 mg, 0, 06 mmol). The reaction mixture was heated to 80 ° C, under nitrogen, and stirred for 3.5 hours. The reaction mixture was cooled and partitioned between ethyl acetate (25 ml) and water (30 ml). The organic layer was separated, and the aqueous one was reextracted with ethyl acetate (2 x 25 ml). The combined organic extracts were washed with saturated brine (50 ml), dried (MgSO4), filtered and evaporated to provide the crude product, which was purified by flash chromatography on silica, gradient elution 25 to 75% acetate of ethyl in isohexane, to give the desired material (402 mg).

Espectro RMN: RMN 1H (400,132 MHz, DMSO–d6) δ 1,16–1,32 (6H, m), 1,38–1,50 (2H, m), 1,64–1,70 (1H, m), 1,85–1,92 (2H, m), 2,20–2,27 (2H, m), 3,19 (1H, td), 3,31–3,40 (1H, m), 3,48 (1H, td), 3,64 (1H, dd), 3,77 (1H, d), 3,97 (1H, dd), 4,10–4,18 (1H, m), 4,38 (2H, s), 4,40–4,48 (1H, m), 5,57 (2H, s), 6,61 (2H, d), 6,66 (1H, s), 8,04 (2H, d). NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.16-1.32 (6H, m), 1.38-1.50 (2H, m), 1.64-1.70 (1H, m), 1.85–1.92 (2H, m), 2.20–2.27 (2H, m), 3.19 (1H, td), 3.31–3.40 (1H, m) , 3.48 (1H, td), 3.64 (1H, dd), 3.77 (1H, d), 3.97 (1H, dd), 4.10-4.18 (1H, m), 4.38 (2H, s), 4.40-4.48 (1H, m), 5.57 (2H, s), 6.61 (2H, d), 6.66 (1H, s), 8 , 04 (2H, d).

Espectro LCMS: MH+ 431, tiempo de retención 2,33 min. LCMS spectrum: MH + 431, retention time 2.33 min.

La preparación de 2–cloro–4–(ciclohexilsulfonilmetil)–6–[(3S)–3–metilmorfolin–4–il]pirimidina se describió anteriormente. The preparation of 2-chloro-4- (cyclohexylsulfonylmethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine was described above.

Example 69:

3–Ciclopropil–1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–[2–[(4–metil–1,3–tiazol–2–il)sulfonil]propan–2– il]pirimidin–2–il]fenil]urea 3 – Cyclopropyl – 1– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– [2 - [(4-methyl – 1,3-thiazol-2-yl) sulfonyl] propan –2– il] pyrimidin – 2 – il] phenyl] urea

O OR

Se añadió a ciclopropilamina (53 mg, 0,93 mmoles) una disolución de N–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–[2–[(4– metil–1,3–tiazol–2–il)sulfonil]propan–2–il]pirimidin–2–il]fenil]carbamato de fenilo (54 mg, 0,09 mmoles) en DMA (2 ml) y trietilamina (0,045 ml, 0,32 mmoles). La mezcla resultante se calentó hasta 50ºC durante 16 horas. La mezcla de reacción se enfrió y se vertió en agua (30 ml). El precipitado resultante se recogió mediante filtración por succión y se secó por succión para proporcionar el producto bruto, el cual se purificó mediante cromatografía ultrarrápida en sílice, gradiente de elución 25 a 75% de acetato de etilo en isohexano. Las fracciones que contenían el producto se evaporaron hasta sequedad, se trituraron con isohexano/éter dietílico y se secaron a vacío, a 50ºC, durante 1 hora para proporcionar el material deseado como un sólido blanco (38 mg). A solution of N– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– [2 - [(4– methyl – 1) was added to cyclopropylamine (53 mg, 0.93 mmol) , 3-thiazol-2-yl) sulfonyl] propan-2-yl] pyrimidin-2-yl] phenyl] phenyl carbamate (54 mg, 0.09 mmol) in DMA (2 ml) and triethylamine (0.045 ml, 0 , 32 mmol). The resulting mixture was heated to 50 ° C for 16 hours. The reaction mixture was cooled and poured into water (30 ml). The resulting precipitate was collected by suction filtration and dried by suction to provide the crude product, which was purified by flash chromatography on silica, gradient elution 25 to 75% ethyl acetate in isohexane. The fractions containing the product were evaporated to dryness, triturated with isohexane / diethyl ether and dried in vacuo, at 50 ° C, for 1 hour to provide the desired material as a white solid (38 mg).

Espectro RMN: RMN 1H (400,132 MHz, DMSO–d6) δ 0,40–0,44 (2H, m), 0,63–0,67 (2H, m), 1,21 (3H, d), 1,92 (6H, s), 2,42 (3H, s), 2,53–2,59 (1H, m), 3,16 (1H, td), 3,49 (1H, td), 3,64 (1H, dd), 3,77 (1H, d), 3,97 (1H, dd), 4,13–4,20 (1H, m), 4,52–4,58 (1H, m), 6,40–6,42 (1H, m), 6,69 (1H, s), 7,42 (2H, d), 7,68 (1H, d), 7,87 (2H, d), 8,51 (1H, s) NMR Spectrum: 1H NMR (400.132 MHz, DMSO – d6) δ 0.40–0.44 (2H, m), 0.63–0.67 (2H, m), 1.21 (3H, d), 1 , 92 (6H, s), 2.42 (3H, s), 2.53-2.59 (1H, m), 3.16 (1H, td), 3.49 (1H, td), 3, 64 (1H, dd), 3.77 (1H, d), 3.97 (1H, dd), 4.13-4.20 (1H, m), 4.52-4.58 (1H, m) , 6.40–6.42 (1H, m), 6.69 (1H, s), 7.42 (2H, d), 7.68 (1H, d), 7.87 (2H, d), 8.51 (1H, s)

Espectro LCMS: MH+ 557, tiempo de retención 2,33 min. LCMS spectrum: MH + 557, retention time 2.33 min.

Los siguientes compuestos se obtuvieron de manera análoga a partir de N–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–[2– [(4–metil–1,3–tiazol–2–il)sulfonil]propan–2–il]pirimidin–2–il]fenil]carbamato de fenilo o N–[4–[4–[(3S)–3– metilmorfolin–4–il]–6–[(4–metil–1,3–tiazol–2–il)sulfonilmetil]pirimidin–2–il]fenil]carbamato de fenilo y la amina apropiada. The following compounds were obtained analogously from N– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– [2– [(4-methyl – 1,3-thiazole– 2-yl) sulfonyl] propan – 2-yl] pyrimidin-2-yl] phenyl] phenyl carbamate or N– [4– [4 - [(3S) –3– methylmorpholin-4-yl] –6 - [( 4-methyl-1,3-thiazol-2-yl) sulfonylmethyl] pyrimidin-2-yl] phenyl] carbamate and the appropriate amine.

69a 69th: O 3–ciclobutil–1–[4–[4–[(3S)–3– 571 2,53 OR 3 – cyclobutyl – 1– [4– [4 - [(3S) –3– 571 2.53

: metilmorfolin–4–il]–6–[2–[(4–metil– methylmorpholin – 4 – il] –6– [2 - [(4 – methyl–

N N N S N H N H O NS O O N N N S N H N H O NS O O: 1,3–tiazol–2–il)sulfonil]propan–2– il]pirimidin–2–il]fenil]urea 1,3-thiazol-2-yl) sulfonyl] propan-2-yl] pyrimidin-2-yl] phenyl] urea

69b 69b: O 3–etil–1–[4–[4–[(3S)–3– 545 2,3 OR 3 – ethyl – 1– [4– [4 - [(3S) –3– 545 2.3

69c 69c: N N N O S N H N H O NS O O N 3–(2–dimetilaminoetil)–1–[4–[4– [(3S)–3–metilmorfolin–4–il]–6–[2– [(4–metil–1,3–tiazol–2– il)sulfonil]propan–2–il]pirimidin–2– il]fenil]urea 588 2,44 N N N O S N H N H O NS O O N 3– (2-dimethylaminoethyl) –1– [4– [4– [(3S) –3-methylmorpholin-4-yl] –6– [2– [(4-methyl – 1,3-thiazole – 2– il ) sulfonyl] propan – 2-yl] pyrimidin – 2-yl] phenyl] urea 588 2.44

69d 69d: O 3–(2–hidroxietil)–1–[4–[4–[(3S)–3– 561 1,99 OR 3– (2 – hydroxyethyl) –1– [4– [4 - [(3S) –3– 561 1.99

N N N S N H N H O NS O O OH N N N S N H N H O NS O O OH: 1,3–tiazol–2–il)sulfonil]propan–2– il]pirimidin–2–il]fenil]urea 1,3-thiazol-2-yl) sulfonyl] propan-2-yl] pyrimidin-2-yl] phenyl] urea

69e 69e: O 3–metil–1–[4–[4–[(3S)–3– 531 2,15 OR 3 – methyl – 1– [4– [4 - [(3S) –3– 531 2.15

69f 69f: N N N O S N H N H O NS O O 3–ciclobutil–1–[4–[4–[(3S)–3– metilmorfolin–4–il]–6–[(4–metil–1,3– tiazol–2–il)sulfonilmetil]pirimidin–2– il]fenil]urea 543 2,28 N N N O S N H N H O NS O O 3 – cyclobutyl – 1– [4– [4 - [(3S) –3– methylmorpholin-4-yl] –6 - [(4 – methyl – 1,3– thiazol – 2-yl) sulfonylmethyl] pyrimidin – 2– il] phenyl] urea 543 2.28

69g 69g: N N N O S N H N H O NS O O 3–etil–1–[4–[4–[(3S)–3– metilmorfolin–4–il]–6–[(4–metil–1,3– tiazol–2–il)sulfonilmetil]pirimidin–2– il]fenil]urea 517 2,04 N N N O S N H N H O NS O O 3 – ethyl – 1– [4– [4 - [(3S) –3– methylmorpholin-4-yl] –6 - [(4 – methyl – 1,3– thiazol – 2-yl) sulfonylmethyl] pyrimidin – 2– il] phenyl] urea 517 2.04

69h 69h: N N N O S N H N H O NS O O N 3–(2–dimetilaminoetil)–1–[4–[4– [(3S)–3–metilmorfolin–4–il]–6–[(4– metil–1,3–tiazol–2– il)sulfonilmetil]pirimidin–2– il]fenil]urea 560 2,14 N N N O S N H N H O NS O O N 3– (2-dimethylaminoethyl) –1– [4– [4– [(3S) –3-methylmorpholin-4-yl] –6 - [(4– methyl – 1,3-thiazol-2-yl) sulfonylmethyl] pyrimidin – 2– il] phenyl] urea 560 2.14

Ejemplo 69a: RMN 1H (400,132 MHz, DMSO–d6) δ 1,21 (3H, d), 1,57–1,68 (2H, m), 1,80–1,92 (2H, m), 1,92 (6H, s), 2,18–2,25 (2H, m), 2,41–2,42 (3H, m), 3,16 (1H, td), 3,49 (1H, td), 3,64 (1H, dd), 3,76 (1H, d), 3,97 (1H, dd), 4,11– 4,19 (2H, m), 4,51–4,58 (1H, m), 6,44 (1H, d), 6,69 (1H, s), 7,39 (2H, d), 7,68 (1H, d), 7,87 (2H, d), 8,53 (1H, s). Example 69a: 1H NMR (400.132 MHz, DMSO-d6) δ 1.21 (3H, d), 1.57-1.68 (2H, m), 1.80-1.92 (2H, m), 1 , 92 (6H, s), 2.18-2.25 (2H, m), 2.41-2.42 (3H, m), 3.16 (1H, td), 3.49 (1H, td ), 3.64 (1H, dd), 3.76 (1H, d), 3.97 (1H, dd), 4.11-4.19 (2H, m), 4.51-4.58 ( 1H, m), 6.44 (1H, d), 6.69 (1H, s), 7.39 (2H, d), 7.68 (1H, d), 7.87 (2H, d), 8.53 (1H, s).

5 Ejemplo 69b: RMN 1H (400,132 MHz, DMSO–d6) δ 1,07 (3H, t), 1,21 (3H, d), 1,92 (6H, s), 2,41–2,42 (3H, m), 3,09– 3,20 (3H, m), 3,49 (1H, td), 3,64 (1H, dd), 3,77 (1H, d), 3,97 (1H, dd), 4,14–4,19 (1H, m), 4,52–4,58 (1H, m), 6,14 (1H, t), 6,69 (1H, s), 7,41 (2H, d), 7,68 (1H, d), 7,87 (2H, d), 8,63 (1H, s). 5 Example 69b: 1H NMR (400.132 MHz, DMSO-d6) δ 1.07 (3H, t), 1.21 (3H, d), 1.92 (6H, s), 2.41-2.42 ( 3H, m), 3.09-3.20 (3H, m), 3.49 (1H, td), 3.64 (1H, dd), 3.77 (1H, d), 3.97 (1H , dd), 4.14-4.19 (1H, m), 4.52-4.58 (1H, m), 6.14 (1H, t), 6.69 (1H, s), 7, 41 (2H, d), 7.68 (1H, d), 7.87 (2H, d), 8.63 (1H, s).

Ejemplo 69c: RMN 1H (400,132 MHz, DMSO–d6) δ 1,21 (3H, d), 1,92 (6H, s), 2,20 (6H, s), 2,33–2,40 (2H, m), 2,42 (3H, s), 3,12–3,22 (3H, m), 3,49 (1H, td), 3,64 (1H, dd), 3,76 (1H, d), 3,97 (1H, dd), 4,16 (1H, d), 4,51–4,57 (1H, m), Example 69c: 1H NMR (400.132 MHz, DMSO-d6) δ 1.21 (3H, d), 1.92 (6H, s), 2.20 (6H, s), 2.33-2.40 (2H , m), 2.42 (3H, s), 3.12-3.22 (3H, m), 3.49 (1H, td), 3.64 (1H, dd), 3.76 (1H, d), 3.97 (1H, dd), 4.16 (1H, d), 4.51-4.57 (1H, m),

10 6,15 (1H, t), 6,69 (1H, s), 7,40 (2H, d), 7,68 (1H, s), 7,87 (2H, d), 8,87 (1H, s). 10 6.15 (1H, t), 6.69 (1H, s), 7.40 (2H, d), 7.68 (1H, s), 7.87 (2H, d), 8.87 ( 1H, s).

Ejemplo 69d: RMN 1H (400,132 MHz, DMSO–d6) δ 1,21 (3H, d), 1,92 (6H, s), 2,41 (3H, s), 3,13–3,21 (3H, m), 3,44– 3,52 (3H, m), 3,64 (1H, dd), 3,77 (1H, d), 3,97 (1H, dd), 4,13–4,19 (1H, m), 4,52–4,57 (1H, m), 4,72 (1H, t), 6,24 (1H, t), 6,69 (1H, s), 7,40 (2H, d), 7,68 (1H, s), 7,87 (2H, d), 8,78 (1H, s). Example 69d: 1H NMR (400.132 MHz, DMSO-d6) δ 1.21 (3H, d), 1.92 (6H, s), 2.41 (3H, s), 3.13-3.21 (3H , m), 3.44– 3.52 (3H, m), 3.64 (1H, dd), 3.77 (1H, d), 3.97 (1H, dd), 4.13-4, 19 (1H, m), 4.52-4.57 (1H, m), 4.72 (1H, t), 6.24 (1H, t), 6.69 (1H, s), 7.40 (2H, d), 7.68 (1H, s), 7.87 (2H, d), 8.78 (1H, s).

Ejemplo 69e: RMN 1H (400,132 MHz, DMSO–d6) δ 1,21 (3H, d), 1,92 (6H, s), 2,41–2,42 (3H, m), 2,66 (3H, d), 3,12– Example 69e: 1H NMR (400.132 MHz, DMSO-d6) δ 1.21 (3H, d), 1.92 (6H, s), 2.41-2.42 (3H, m), 2.66 (3H , d), 3.12–

15 3,20 (1H, m), 3,49 (1H, td), 3,64 (1H, dd), 3,76 (1H, d), 3,97 (1H, dd), 4,13–4,19 (1H, m), 4,51–4,57 (1H, m), 6,05 (1H, q), 6,69 (1H, s), 7,42 (2H, d), 7,68 (1H, d), 7,87 (2H, d), 8,72 (1H, s). 15 3.20 (1H, m), 3.49 (1H, td), 3.64 (1H, dd), 3.76 (1H, d), 3.97 (1H, dd), 4.13– 4.19 (1H, m), 4.51-4.57 (1H, m), 6.05 (1H, q), 6.69 (1H, s), 7.42 (2H, d), 7 , 68 (1H, d), 7.87 (2H, d), 8.72 (1H, s).

Ejemplo 69f: Ningún Espectro RMN Example 69f: No NMR Spectrum

Ejemplo 69g: Ningún Espectro RMN Example 69g: No NMR Spectrum

Ejemplo 69h: Ningún Espectro RMN Example 69h: No NMR Spectrum

20 A continuación se describe la preparación de N–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–[2–[(4–metil–1,3–tiazol–2– il)sulfonil]propan–2–il]pirimidin–2–il]fenil]carbamato de fenilo. 20 The preparation of N– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– [2 - [(4-methyl – 1,3-thiazole – 2– il) is described below ) phenyl sulfonyl] propan-2-yl] pyrimidin-2-yl] phenyl] carbamate.

N– [4– [4 - [(3S) –3 – Methylmorpholin-4-yl] –6– [2 - [(4-methyl-1,3-thiazol-2-yl) sulfonyl] propan – 2 – il ] pyrimidin-2-yl] phenyl] phenyl carbamate

O OR

N N

N SS N H.H

OO OO

O N O n

N N

O H Or h

N N

A una disolución de 4–[4–[(3S)–3–metilmorfolin–4–il]–6–[2–[(4–metil–1,3–tiazol–2–il)sulfonil]propan–2–il]pirimidin–2– il]anilina (340 mg, 0,72 mmoles) en 1,4–dioxano (4 ml) se añadió bicarbonato de sodio (90 mg, 1,08 mmoles). Después se añadió gota a gota cloroformiato de fenilo (0,104 ml, 0,83 mmoles), y la mezcla resultante se agitó a RT durante 6 horas. Después la mezcla de reacción se evaporó, y el residuo se repartió entre DCM (5 ml) y agua (5 ml). La capa orgánica se separó y la acuosa se extrajo de nuevo con más DCM (5 ml). Las capas orgánicas combinadas At a solution of 4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– [2 - [(4-methyl-1,3-thiazol-2-yl) sulfonyl] propan – 2– il] pyrimidin-2-yl] aniline (340 mg, 0.72 mmol) in 1,4-dioxane (4 mL) sodium bicarbonate (90 mg, 1.08 mmol) was added. Then phenyl chloroformate (0.104 ml, 0.83 mmol) was added dropwise, and the resulting mixture was stirred at RT for 6 hours. Then the reaction mixture was evaporated, and the residue was partitioned between DCM (5 ml) and water (5 ml). The organic layer was separated and the aqueous one was extracted again with more DCM (5 ml). The combined organic layers

se combinaron y se evaporaron hasta sequedad para proporcionar una goma ámbar, la cual se absorbió en éter dietílico (5 ml) y se trituró con tratamiento con ultrasonidos. El sólido resultante se recogió mediante filtración por succión y se secó para proporcionar el material deseado (334 mg). they were combined and evaporated to dryness to provide an amber gum, which was absorbed in diethyl ether (5 ml) and triturated with ultrasound treatment. The resulting solid was collected by suction filtration and dried to provide the desired material (334 mg).

Espectro RMN: RMN 1H (400,132 MHz, DMSO–d6) δ 1,22 (3H, d), 1,93 (6H, s), 2,41 (3H, s), 3,17 (1H, td), 3,49 (1H, td), 3,64 (1H, dd), 3,77 (1H, d), 3,98 (1H, dd), 4,15–4,22 (1H, m), 4,53–4,59 (1H, m), 6,73 (1H, s), 7,24–7,30 (3H, m), 7,45 (2H, t), 7,55 (2H, d), 7,68 (1H, m), 7,97 (2H, d), 10,39 (1H, s). NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.22 (3H, d), 1.93 (6H, s), 2.41 (3H, s), 3.17 (1H, td), 3.49 (1H, td), 3.64 (1H, dd), 3.77 (1H, d), 3.98 (1H, dd), 4.15-4.22 (1H, m), 4 , 53–4.59 (1H, m), 6.73 (1H, s), 7.24–7.30 (3H, m), 7.45 (2H, t), 7.55 (2H, d ), 7.68 (1H, m), 7.97 (2H, d), 10.39 (1H, s).

Espectro LCMS: MH+ 594, tiempo de retención 2,91 min. LCMS spectrum: MH + 594, retention time 2.91 min.

4–[4–[(3S)–3–Metilmorfolin–4–il]–6–[2–[(4–metil–1,3–tiazol–2–il)sulfonil]propan–2–il]pirimidin–2–il]anilina 4– [4 - [(3S) –3 – Methylmorpholin-4-yl] –6– [2 - [(4-methyl-1,3-thiazol-2-yl) sulfonyl] propan – 2-yl] pyrimidin– 2-yl] aniline

Una mezcla de 2–cloro–4–[(3S)–3–metilmorfolin–4–il]–6–[2–[(4–metil–1,3–tiazol–2–il)sulfonil]propan–2–il]pirimidina (480 mg, 1,15 mmoles), 4–(4,4,5,5–tetrametil–1,3,2–dioxaborolan–2–il)anilina (378 mg, 1,73 mmoles) y disolución acuosa 2M de carbonato de sodio (2,8 ml, 5,60 mmoles) en una mezcla de DMF (2 ml), 1,2–dimetoxietano (2 ml), etanol (2 ml) y agua (5 ml) se purgó con nitrógeno durante 10 minutos antes de la adición de cloruro de bis(trifenilfosfina)paladio(II) (54 mg, 0,08 mmoles). La mezcla de reacción se calentó hasta 85ºC y se agitó a esa temperatura, en nitrógeno, durante 3 horas. Después la mezcla de reacción se enfrió y se repartió entre acetato de etilo (50 ml) y agua (30 ml). La capa orgánica se separó y la capa acuosa se extrajo nuevamente con acetato de etilo (25 ml). Las capas orgánicas combinadas se lavaron con salmuera (50 ml), se secaron (MgSO4), se filtraron y se evaporaron para proporcionar el producto bruto, el cual se purificó mediante cromatografía ultrarrápida en sílice, gradiente de elución 25 a 75% de acetato de etilo en isohexano, para dar el material deseado (367 mg). A mixture of 2-chloro-4 - [(3S) –3-methylmorpholin-4-yl] –6– [2 - [(4-methyl-1,3-thiazol-2-yl) sulfonyl] propan – 2– il] pyrimidine (480 mg, 1.15 mmol), 4– (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (378 mg, 1.73 mmol) and solution 2M aqueous sodium carbonate (2.8 ml, 5.60 mmol) in a mixture of DMF (2 ml), 1,2-dimethoxyethane (2 ml), ethanol (2 ml) and water (5 ml) was purged with nitrogen for 10 minutes before the addition of bis (triphenylphosphine) palladium (II) chloride (54 mg, 0.08 mmol). The reaction mixture was heated to 85 ° C and stirred at that temperature, under nitrogen, for 3 hours. The reaction mixture was then cooled and partitioned between ethyl acetate (50 ml) and water (30 ml). The organic layer was separated and the aqueous layer was extracted again with ethyl acetate (25 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4), filtered and evaporated to provide the crude product, which was purified by flash chromatography on silica, gradient elution 25 to 75% acetate acetate. ethyl in isohexane, to give the desired material (367 mg).

Espectro RMN: RMN 1H (400,132 MHz, DMSO–d6) δ 1,19 (3H, d), 1,90 (6H, s), 2,43 (3H, s), 3,13 (1H, td), 3,48 (1H, td), 3,63 (1H, dd), 3,75 (1H, d), 3,96 (1H, dd), 4,09–4,15 (1H, m), 4,47–4,54 (1H, m), 5,50 (2H, s), 6,52 (1H, d), 6,58 (2H, s), 7,68–7,72 (3H, m). NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.19 (3H, d), 1.90 (6H, s), 2.43 (3H, s), 3.13 (1H, td), 3.48 (1H, td), 3.63 (1H, dd), 3.75 (1H, d), 3.96 (1H, dd), 4.09-4.15 (1H, m), 4 , 47–4.54 (1H, m), 5.50 (2H, s), 6.52 (1H, d), 6.58 (2H, s), 7.68–7.72 (3H, m ).

Espectro LCMS: MH+ 474, tiempo de retención 2,31 min. LCMS spectrum: MH + 474, retention time 2.31 min.

2–Cloro–4–[(3S)–3–metilmorfolin–4–il]–6–[2–[(4–metil–1,3–tiazol–2–il)sulfonil]propan–2–il]pirimidina 2 – Chloro – 4 - [(3S) –3 – methylmorpholin-4-yl] –6– [2 - [(4-methyl-1,3-thiazol-2-yl) sulfonyl] propan – 2-yl] pyrimidine

O OR

N N

N SS N H.H

OO OO

N Cl N N Cl N

A una disolución enfriada (baño de hielo/agua) de 2–cloro–4–[(3S)–3–metilmorfolin–4–il]–6–[(4–metil–1,3–tiazol–2– il)sulfonilmetil]pirimidina (612 mg, 1,57 mmoles) en DMF (8 ml) se añadió terc–butóxido de sodio (157 mg, 1,63 mmoles). La mezcla se agitó durante 5 minutos en nitrógeno, antes de la adición de yodometano (0,100 ml, 1,61 mmoles). La mezcla de reacción se dejó agitar, en el baño de enfriamiento, durante unos 10 minutos adicionales antes de la adición de más terc–butóxido de sodio (157 mg, 1,63 mmoles). Después de unos 5 minutos adicionales de agitación se añadió más yodometano (0,100 ml, 1,61 mmoles), y la mezcla de reacción se agitó, en nitrógeno, en el baño de enfriamiento durante 20 minutos. Después se retiró el baño de enfriamiento y la agitación se continuó durante unas 2 horas adicionales. Después se añadió agua (25 ml), y el precipitado resultante se recogó por filtración, se lavó con agua (50 ml) y se secó a vacío, a 50ºC, durante 2 horas para proporcionar el material deseado (487 mg). To a cooled solution (ice / water bath) of 2-chloro-4 - [(3S) -3-methylmorpholin-4-yl] -6 - [(4-methyl-1,3-thiazole-2-yl) sulfonylmethyl] pyrimidine (612 mg, 1.57 mmol) in DMF (8 ml) sodium tert-butoxide (157 mg, 1.63 mmol) was added. The mixture was stirred for 5 minutes under nitrogen, before the addition of iodomethane (0.100 ml, 1.61 mmol). The reaction mixture was allowed to stir, in the cooling bath, for an additional 10 minutes before the addition of more sodium tert-butoxide (157 mg, 1.63 mmol). After an additional 5 minutes of stirring, more iodomethane (0.100 ml, 1.61 mmol) was added, and the reaction mixture was stirred, under nitrogen, in the cooling bath for 20 minutes. Then the cooling bath was removed and stirring was continued for an additional 2 hours. Water (25 ml) was then added, and the resulting precipitate was collected by filtration, washed with water (50 ml) and dried under vacuum, at 50 ° C, for 2 hours to provide the desired material (487 mg).

Espectro RMN: RMN 1H (400,132 MHz, DMSO–d6) δ 1,19 (3H, d), 1,79 (6H, d), 2,46 (3H, s), 3,15 (1H, td), 3,43 (1H, td), 3,58 (1H, dd), 3,72 (1H, d), 3,93 (1H, dd), 3,96–4,03 (1H, m), 4,35–4,44 (1H, m), 6,78 (1H, s), 7,89 (1H, s). NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.19 (3H, d), 1.79 (6H, d), 2.46 (3H, s), 3.15 (1H, td), 3.43 (1H, td), 3.58 (1H, dd), 3.72 (1H, d), 3.93 (1H, dd), 3.96-4.03 (1H, m), 4 , 35-4.44 (1H, m), 6.78 (1H, s), 7.89 (1H, s).

Espectro LCMS: MH+ 417, tiempo de retención 2,28 min. LCMS spectrum: MH + 417, retention time 2.28 min.

2 – Chloro – 4 - [(3S) –3 – methylmorpholin-4-yl] –6 - [(4-methyl-1,3-thiazol-2-yl) sulfonylmethyl] pyrimidine

N N

N SS OO N SS OO

N Cl N N Cl N

A una disolución enfriada (baño de hielo/agua) de 2,4–dicloro–6–[(4–metil–1,3–tiazol–2–il)sulfonilmetil]pirimidina (901 mg, 2,78 mmoles) en DCM (12 ml) se añadió trietilamina (0,45 ml, 3,23 mmoles). La disolución resultante se trató gota a gota durante 3 minutos, con una disolución de (3S)–3–metilmorfolina (319 mg, 3,15 mmoles) en DCM (2,5 ml). La mezcla de reacción se agitó en nitrógeno durante 24 horas, dejándose calentar la reacción hasta RT. Se añadió agua (20 ml) a la mezcla de reacción y se agitó durante 15 minutos. Después la capa orgánica se separó, se secó (MgSO4) y se evaporó para dar el producto bruto, el cual se purificó mediante cromatografía ultrarrápida en sílice, gradiente de elución 25 a 75% de acetato de etilo en isohexano, para dar el material deseado (615 mg). To a cooled solution (ice / water bath) of 2,4-dichloro-6 - [(4-methyl-1,3-thiazol-2-yl) sulfonylmethyl] pyrimidine (901 mg, 2.78 mmol) in DCM (12 ml) triethylamine (0.45 ml, 3.23 mmol) was added. The resulting solution was treated dropwise for 3 minutes, with a solution of (3S) -3-methylmorpholine (319 mg, 3.15 mmol) in DCM (2.5 ml). The reaction mixture was stirred under nitrogen for 24 hours, allowing the reaction to warm to RT. Water (20 ml) was added to the reaction mixture and stirred for 15 minutes. The organic layer was then separated, dried (MgSO4) and evaporated to give the crude product, which was purified by flash chromatography on silica, gradient elution 25 to 75% ethyl acetate in isohexane, to give the desired material. (615 mg).

Espectro RMN : RMN 1H (400,132 MHz, DMSO–d6) δ 1,18 (3H, d), 2,49 (3H, s), 3,18 (1H, td), 3,43 (1H, td), 3,58 (1H, dd), 3,72 (1H, d), 3,86–3,96 (2H, m), 4,16–4,28 (1H, m), 4,82 (2H, s), 6,80 (1H, s), 7,89 (1H, d). NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.18 (3H, d), 2.49 (3H, s), 3.18 (1H, td), 3.43 (1H, td), 3.58 (1H, dd), 3.72 (1H, d), 3.86-3.96 (2H, m), 4.16-4.28 (1H, m), 4.82 (2H, s), 6.80 (1H, s), 7.89 (1H, d).

Espectro LCMS: MH+ 389, tiempo de retención 1,89 min. LCMS spectrum: MH + 389, retention time 1.89 min.

2,4–Dicloro–6–[(4–metil–1,3–tiazol–2–il)sulfonilmetil]pirimidina 2,4-Dichloro-6 - [(4-methyl-1,3-thiazol-2-yl) sulfonylmethyl] pyrimidine

Cl Cl

O OR

A una disolución enfriada (baño de hielo/agua) de 2,4–dicloro–6–[(4–metil–1,3–tiazol–2–il)sulfanilmetil]pirimidina (867 mg, 2,97 mmoles) en DCM (15 ml) se añadió en porciones, durante 10 minutos, ácido 3–cloroperoxibenzoico (1,42 g, 6,34 mmoles). La suspensión resultante se agitó en el baño de enfriamiento durante 15 minutos. El baño de enfriamiento se retiró después, y la mezcla de reacción se dejó calentar hasta RT y se agitó durante 22 horas. La reacción no se terminó, y se añadió ácido 3–cloroperoxibenzoico adicional (162 mg, 0,72 mmoles), y la mezcla se agitó durante una hora adicional. Se añadió disolución acuosa saturada de bicarbonato de sodio (20 ml) a la mezcla de reacción y se agitó durante 30 minutos. La capa orgánica se separó, se secó (MgSO4), se filtró y se evaporó para proporcionar el material deseado (912 mg). To a cooled solution (ice / water bath) of 2,4-dichloro-6 - [(4-methyl-1,3-thiazol-2-yl) sulfanylmethyl] pyrimidine (867 mg, 2.97 mmol) in DCM (15 ml) was added portionwise, for 10 minutes, 3-chloroperoxybenzoic acid (1.42 g, 6.34 mmol). The resulting suspension was stirred in the cooling bath for 15 minutes. The cooling bath was then removed, and the reaction mixture was allowed to warm to RT and stirred for 22 hours. The reaction was not terminated, and additional 3-chloroperoxybenzoic acid (162 mg, 0.72 mmol) was added, and the mixture was stirred for an additional hour. Saturated aqueous sodium bicarbonate solution (20 ml) was added to the reaction mixture and stirred for 30 minutes. The organic layer was separated, dried (MgSO4), filtered and evaporated to provide the desired material (912 mg).

Espectro RMN: RMN 1H (400,132 MHz, DMSO–d6) δ 2,48 (3H, d), 5,19 (2H, s), 7,84 (1H, s), 7,94–7,95 (1H, m). NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 2.48 (3H, d), 5.19 (2H, s), 7.84 (1H, s), 7.94–7.95 (1H , m).

Espectro LCMS: M–H– 322, tiempo de retención 1,47 min. LCMS spectrum: M – H– 322, retention time 1.47 min.

2,4–Dicloro–6–[(4–metil–1,3–tiazol–2–il)sulfanilmetil]pirimidina 2,4-Dichloro-6 - [(4-methyl-1,3-thiazol-2-yl) sulfanylmethyl] pyrimidine

Cl Cl

Una suspensión de 6–[(4–metil–1,3–tiazol–2–il)sulfanilmetil]–1H–pirimidin–2,4–diona (1,4 g, 5,48 mmoles) en oxicloruro de fósforo (6 ml, 64,37 mmoles) se calentó hasta 100ºC y se agitó durante 6 horas. La mezcla de reacción se enfrió antes de evaporarse, y el residuo se repartió entre DCM (30 ml) y agua con hielo (30 ml). Después se añadió cuidadosamente y en porciones durante 30 minutos hidrogenocarbonato de sodio, controlando la efervescencia. Una vez que la efervescencia hubo cesado y el pH se hubo ajustado a 8, la mezcla se trató con más DCM (30 ml) y agua (20 ml), se transfirió a un embudo de separación, y la capa orgánica se separó. La capa acuosa se extrajo nuevamente con DCM adicional (2 x 25 ml), y los extractos orgánicos combinados se lavaron con salmuera, se secaron (MgSO4) y se evaporaron hasta sequedad para proporcionar el producto bruto, el cual se purificó mediante cromatografía ultrarrápida en sílice, gradiente de elución 10 a 20% de acetato de etilo en isohexano, para dar el material deseado (0,90 g). A suspension of 6 - [(4-methyl-1,3-thiazol-2-yl) sulfanylmethyl] -1 H -pyrimidin-2,4-dione (1.4 g, 5.48 mmol) in phosphorus oxychloride (6 ml, 64.37 mmol) was heated to 100 ° C and stirred for 6 hours. The reaction mixture was cooled before evaporating, and the residue was partitioned between DCM (30 ml) and ice water (30 ml). Then sodium hydrogen carbonate was added carefully and portionwise for 30 minutes, controlling the effervescence. Once the effervescence had ceased and the pH had been adjusted to 8, the mixture was treated with more DCM (30 ml) and water (20 ml), transferred to a separatory funnel, and the organic layer was separated. The aqueous layer was extracted again with additional DCM (2 x 25 ml), and the combined organic extracts were washed with brine, dried (MgSO4) and evaporated to dryness to provide the crude product, which was purified by flash chromatography on silica, elution gradient 10 to 20% ethyl acetate in isohexane, to give the desired material (0.90 g).

Espectro RMN: RMN 1H (400,132 MHz, DMSO–d6) δ 2,31 (3H, d), 4,55 (2H, s), 7,23–7,24 (1H, m), 7,83 (1H, s). NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 2.31 (3H, d), 4.55 (2H, s), 7.23–7.24 (1H, m), 7.83 (1H , s).

Espectro LCMS: MH+ 292, tiempo de retención 2,33 min. 6–[(4–Metil–1,3–tiazol–2–il)sulfanilmetil]–1H–pirimidin–2,4–diona LCMS spectrum: MH + 292, retention time 2.33 min. 6 - [(4-Methyl-1,3-thiazol-2-yl) sulfanylmethyl] -1H-pyrimidin-2,4-dione

A una disolución de 4–metiltiazol–2–tiol (1,01 g, 7,70 mmoles) en DMF (15 ml) se añadió 1,8– To a solution of 4-methylthiazole-2-thiol (1.01 g, 7.70 mmol) in DMF (15 ml) was added 1.8–

5 diazabiciclo[5,4,0]undec–7–eno (1,4 ml, 9,38 mmoles). La disolución resultante se agitó a RT durante 30 minutos. Después se añadió en porciones, durante un período de 10 minutos, 6–(clorometil)pirimidin–2,4(1H,3H)–diona (1 g, 6,23 mmoles) en nitrógeno. La disolución resultante se agitó a RT durante 19 horas. Después la mezcla de reacción se evaporó hasta sequedad, y el residuo se repartió entre DCM (20 ml) y agua (20 ml). Un precipitado sólido, el cual se recogió por filtración por succión, se lavó con agua (20 ml) y se secó, a vacío, a 60ºC, durante 2 horas para 5 diazabicyclo [5.4,0] undec-7-ene (1.4 ml, 9.38 mmol). The resulting solution was stirred at RT for 30 minutes. Then 6– (chloromethyl) pyrimidin-2,4 (1 H, 3 H) -dione (1 g, 6.23 mmol) in nitrogen was added portionwise over a period of 10 minutes. The resulting solution was stirred at RT for 19 hours. The reaction mixture was then evaporated to dryness, and the residue was partitioned between DCM (20 ml) and water (20 ml). A solid precipitate, which was collected by suction filtration, washed with water (20 ml) and dried, under vacuum, at 60 ° C, for 2 hours to

10 proporcionar el material deseado (1,07 g, 67 %). Se obtuvo material deseado adicional (0,330 g) ajustando el filtrado a pH 2 con ácido clorhídrico 2M, filtrando el precipitado, lavándolo con agua (20 ml) y secándolo en un horno de vacío. 10 provide the desired material (1.07 g, 67%). Additional desired material (0.330 g) was obtained by adjusting the filtrate to pH 2 with 2M hydrochloric acid, filtering the precipitate, washing it with water (20 ml) and drying it in a vacuum oven.

Espectro RMN: RMN 1H (400,132 MHz, DMSO–d6) δ 2,34 (3H, d), 4,08 (2H, s), 5,43 (1H, s), 7,27 (1H, m), 11,01 (2H, s). NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 2.34 (3H, d), 4.08 (2H, s), 5.43 (1H, s), 7.27 (1H, m), 11.01 (2H, s).

15 Espectro LCMS: MH+ 256, tiempo de retención 0,53 min. 15 LCMS spectrum: MH + 256, retention time 0.53 min.

A continuación se describe la preparación de N–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–[(4–metil–1,3–tiazol–2– il)sulfonilmetil]pirimidin–2–il]fenil]carbamato de fenilo. The preparation of N– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6 - [(4-methyl-1,3-thiazol-2-yl) sulfonylmethyl] pyrimidine is described below. -2-yl] phenyl] phenyl carbamate.

N– [4– [4 - [(3S) –3 – Methylmorpholin-4-yl] –6 - [(4-methyl-1,3-thiazol-2-yl) sulfonylmethyl] pyrimidin-2-yl] phenyl] phenyl carbamate

O OR

N N

N SS N H.H

OO OO

N N

O N O n

N N

O H Or h

20 Se añadió cloroformiato de fenilo (0,190 ml, 1,51 mmoles) a 4–[4–[(3S)–3–metilmorfolin–4–il]–6–[(4–metil–1,3– tiazol–2–il)sulfonilmetil]pirimidin–2–il]anilina (450 mg, 1,01 mmoles), e hidrogenocarbonato de sodio (127 mg, 1,51 mmoles) en dioxano (10 ml) a 5ºC en nitrógeno. La mezcla resultante se agitó a RT durante 2 horas. La mezcla de reacción se diluyó con acetato de etilo (200 ml), y se lavó con agua (125 ml). La capa orgánica se secó (MgSO4), se 20 Phenyl chloroformate (0.190 ml, 1.51 mmol) was added at 4– [4 - [(3S) -3-methylmorpholin-4-yl] –6 - [(4-methyl-1,3-thiazole-2 -Yl) sulfonylmethyl] pyrimidin-2-yl] aniline (450 mg, 1.01 mmol), and sodium hydrogen carbonate (127 mg, 1.51 mmol) in dioxane (10 ml) at 5 ° C under nitrogen. The resulting mixture was stirred at RT for 2 hours. The reaction mixture was diluted with ethyl acetate (200 ml), and washed with water (125 ml). The organic layer was dried (MgSO4), dried

25 filtró y se evaporó para proporcionar el producto bruto el cual se trituró con una mezcla de éter dietílico e isohexano para proporcionar el material deseado (360 mg). 25 filtered and evaporated to provide the crude product which was triturated with a mixture of diethyl ether and isohexane to provide the desired material (360 mg).

Espectro RMN: RMN 1H (400,132 MHz, DMSO–d6) δ 1,22 (3H, d), 2,53 (3H, s) [oscurecido por DMSO], 3,20 (1H, td), 3,49 (1H, td), 3,64 (1H, dd), 3,77 (1H, d), 3,98 (1H, dd), 4,15 (1H, d), 4,45 (1H, s), 4,93 (2H, s), 6,77 (1H, s), 7,22– 7,32 (3H, m), 7,43–7,47 (2H, m), 7,56 (2H, d), 7,84 (1H, s), 7,97 (2H, d), 10,43 (1H, s). NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.22 (3H, d), 2.53 (3H, s) [obscured by DMSO], 3.20 (1H, td), 3.49 ( 1H, td), 3.64 (1H, dd), 3.77 (1H, d), 3.98 (1H, dd), 4.15 (1H, d), 4.45 (1H, s), 4.93 (2H, s), 6.77 (1H, s), 7.22– 7.32 (3H, m), 7.43–7.47 (2H, m), 7.56 (2H, d), 7.84 (1H, s), 7.97 (2H, d), 10.43 (1H, s).

30 Espectro LCMS: MH+ 566, tiempo de retención 2,66 min. 30 LCMS spectrum: MH + 566, retention time 2.66 min.

4–[4–[(3S)–3–Metilmorfolin–4–il]–6–[(4–metil–1,3–tiazol–2–il)sulfonilmetil]pirimidin–2–il]anilina 4– [4 - [(3S) –3 – Methylmorpholin-4-yl] –6 - [(4-methyl-1,3-thiazol-2-yl) sulfonylmethyl] pyrimidin-2-yl] aniline

Se añadió cloruro de bis(trifenilfosfina)paladio(II) (54,4 mg, 0,08 mmoles) a 2–cloro–4–[(3S)–3–metilmorfolin–4–il]– 6–[(4–metil–1,3–tiazol–2–il)sulfonilmetil]pirimidina (600 mg, 1,55 mmoles), 4–(4,4,5,5–tetrametil–1,3,2–dioxaborolan– 2–il)anilina (510 mg, 2,33 mmoles) y carbonato de sodio (5 ml, 10,00 mmoles) en una mezcla de DMF (6 ml), DME (12 ml), etanol (3 ml) y agua (3,5 ml) a RT en nitrógeno. La mezcla de reacción se vació y se volvió a llenar con nitrógeno varias veces, y la mezcla resultante se agitó a 95ºC durante 18 horas. La mezcla de reacción se diluyó con acetato de etilo (250 ml), y se lavó con agua (2 x 150 ml). La capa orgánica se secó (Na2SO4), se filtró y se evaporó para proporcionar el producto bruto, el cual se purificó mediante cromatografía ultrarrápida en sílice, gradiente de elución 10 a 70% de acetato de etilo en isohexano, para dar el material deseado (450 mg). Bis (triphenylphosphine) palladium (II) chloride (54.4 mg, 0.08 mmol) was added to 2-chloro-4 - [(3S) -3-methylmorpholin-4-yl] - 6 - [(4– methyl-1,3-thiazol-2-yl) sulfonylmethyl] pyrimidine (600 mg, 1.55 mmol), 4– (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (510 mg, 2.33 mmol) and sodium carbonate (5 ml, 10.00 mmol) in a mixture of DMF (6 ml), DME (12 ml), ethanol (3 ml) and water (3.5 ml) to RT in nitrogen. The reaction mixture was emptied and refilled with nitrogen several times, and the resulting mixture was stirred at 95 ° C for 18 hours. The reaction mixture was diluted with ethyl acetate (250 ml), and washed with water (2 x 150 ml). The organic layer was dried (Na2SO4), filtered and evaporated to provide the crude product, which was purified by flash chromatography on silica, gradient elution 10 to 70% ethyl acetate in isohexane, to give the desired material ( 450 mg)

Espectro RMN: RMN 1H (400,132 MHz, DMSO–d6) δ 1,19 (3H, d), 2,53 (3H, s), 3,15 (1H, td), 3,47 (1H, td), 3,62 (1H, dd), 3,75 (1H, d), 3,96 (1H, dd), 4,09 (1H, d), 4,40 (1H, s), 4,83 (2H, s), 5,54 (2H, s), 6,52 (2H, d), 6,60 (1H, s), 7,70 (2H, d), 7,81 (1H, s). NMR Spectrum: 1H NMR (400.132 MHz, DMSO-d6) δ 1.19 (3H, d), 2.53 (3H, s), 3.15 (1H, td), 3.47 (1H, td), 3.62 (1H, dd), 3.75 (1H, d), 3.96 (1H, dd), 4.09 (1H, d), 4.40 (1H, s), 4.83 (2H , s), 5.54 (2H, s), 6.52 (2H, d), 6.60 (1H, s), 7.70 (2H, d), 7.81 (1H, s).

Espectro LCMS: MH+ 446, tiempo de retención 2,0 min. LCMS spectrum: MH + 446, retention time 2.0 min.

La preparación de 2–cloro–4–[(3S)–3–metilmorfolin–4–il]–6–[(4–metil–1,3–tiazol–2–il)sulfonilmetil]pirimidina se describió anteriormente. The preparation of 2-chloro-4 - [(3S) -3-methylmorpholin-4-yl] -6 - [(4-methyl-1,3-thiazol-2-yl) sulfonylmethyl] pyrimidine was described above.

Ejemplo 70: Example 70:

3–Etil–1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(2–piridin–2–ilsulfonilpropan–2–il)pirimidin–2–il]fenil]urea 3 – Ethyl – 1– [4– [4 - [(3S) –3 – methylmorpholin-4-yl] –6– (2-pyridin-2-ylsulfonylpropan – 2-yl) pyrimidin – 2-yl] phenyl] urea

Una disolución de etilamina 2M en metanol (0,471 ml, 0,94 mmoles) a se añadió en una porción N–[4–[4–[(3S)–3– metilmorfolin–4–il]–6–(2–piridin–2–ilsulfonilpropan–2–il)pirimidin–2–il]fenil]carbamato de fenilo (120 mg, 0,21 mmoles) en DMF (2 ml) a RT en nitrógeno. La disolución resultante se agitó a RT durante 60 minutos. La mezcla de reacción se evaporó hasta sequedad, y el producto bruto se purificó mediante cromatografía ultrarrápida en sílice, gradiente de elución 0 a 7% de metanol en DCM, para dar el material deseado como una espuma blanca (103 mg). A solution of 2M ethylamine in methanol (0.471 ml, 0.94 mmol) a was added in one portion N– [4– [4 - [(3S) –3– methylmorpholin-4-yl] –6– (2-pyridin -2-ylsulfonylpropan-2-yl) pyrimidin-2-yl] phenyl] phenyl carbamate (120 mg, 0.21 mmol) in DMF (2 ml) at RT in nitrogen. The resulting solution was stirred at RT for 60 minutes. The reaction mixture was evaporated to dryness, and the crude product was purified by flash chromatography on silica, gradient elution 0 to 7% methanol in DCM, to give the desired material as a white foam (103 mg).

Espectro RMN: RMN 1H (399,902 MHz, DMSO–d6) δ 1,07 (t, 3H), 1,21 (d, 3H), 1,88 (s, 6H), 3,09–3,21 (m, 3H), 3,45–3,53 (m, 1H), 3,61–3,66 (m, 1H), 3,77 (d, 1H), 3,95–4,00 (m, 1H), 4,15 (d, 1H), 4,53 (s, 1H), 6,15 (t, 1H), 6,66 (s, 1H), 7,35 (d, 2H), 7,61–7,66 (m, 2H), 7,71 (d, 2H), 7,88–7,93 (m, 1H), 8,61 (s, 1H), 8,74–8,76 (m, 1H) NMR Spectrum: 1H NMR (399,902 MHz, DMSO-d6) δ 1.07 (t, 3H), 1.21 (d, 3H), 1.88 (s, 6H), 3.09–3.21 (m , 3H), 3.45-3.53 (m, 1H), 3.61-3.66 (m, 1H), 3.77 (d, 1H), 3.95-4.00 (m, 1H ), 4.15 (d, 1H), 4.53 (s, 1H), 6.15 (t, 1H), 6.66 (s, 1H), 7.35 (d, 2H), 7.61 –7.66 (m, 2H), 7.71 (d, 2H), 7.88–7.93 (m, 1H), 8.61 (s, 1H), 8.74–8.76 (m , 1 HOUR)

Espectro LCMS: MH+ 525,56, tiempo de retención 2,14 min. LCMS spectrum: MH + 525.56, retention time 2.14 min.

A continuación se describe la preparación de N–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(2–piridin–2–ilsulfonilpropan– 2–il)pirimidin–2–il]fenil]carbamato de fenilo. The preparation of N– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (2-pyridin-2-ylsulfonylpropan– 2-yl) pyrimidin-2-yl] is described below phenyl] phenyl carbamate.

N–[4–[4–[(3S)–3–Metilmorfolin–4–il]–6–(2–piridin–2–ilsulfonilpropan–2–il)pirimidin–2–il]fenil]carbamato de fenilo N– [4– [4 - [(3S) –3 – Methylmorpholin-4-yl] –6– (2-pyridin-2-ylsulfonylpropan-2-yl) pyrimidin-2-yl] phenyl] phenyl carbamate

O OR

N N

N S N S

OO OO

N N

O N O n

N N

O H Or h

Se añadió cloroformiato de fenilo (0,432 ml, 3,44 mmoles) a 4–[4–[(3S)–3–metilmorfolin–4–il]–6–(2–piridin–2– ilsulfonilpropan–2–il)pirimidin–2–il]anilina (1,3 g, 2,87 mmoles) e hidrogenocarbonato de sodio (0,482 g, 5,73 mmoles) en dioxano (20 ml) a RT. La suspensión resultante se agitó a RT durante 1 hora y después la mezcla de reacción se repartió entre acetato de etilo y agua. La disolución orgánica se secó (MgSO4) y se concentró a presión reducida. El residuo se cromatografió en sílice, eluyendo con 0%–20% de acetato de etilo en DCM, para dar el material deseado como una película seca amarilla (1,62 g). Phenyl chloroformate (0.432 ml, 3.44 mmol) was added at 4– [4 - [(3S) -3-methylmorpholin-4-yl] -6– (2-pyridin-2-ylsulfonylpropan-2-yl) pyrimidin -2-yl] aniline (1.3 g, 2.87 mmol) and sodium hydrogen carbonate (0.482 g, 5.73 mmol) in dioxane (20 ml) at RT. The resulting suspension was stirred at RT for 1 hour and then the reaction mixture was partitioned between ethyl acetate and water. The organic solution was dried (MgSO4) and concentrated under reduced pressure. The residue was chromatographed on silica, eluting with 0% -20% ethyl acetate in DCM, to give the desired material as a yellow dry film (1.62 g).

Espectro RMN: RMN 1H (399,902 MHz, CDCl3) δ 1,27 (d, 3H), 1,90 (s, 6H), 3,25 (m, 1H), 3,55 (m, 1H), 3,70 (m, 1H), 4,03 (m, 2H), 4,39–4,46 (m, 1H), 6,60 (s, 1H), 6,93 (s, 1H), 7,12–7,22 (m, 12H), 7,32 (m, 5H), 7,57 (m, 2H), 7,82 (d, 2H). NMR Spectrum: 1H NMR (399.902 MHz, CDCl3) δ 1.27 (d, 3H), 1.90 (s, 6H), 3.25 (m, 1H), 3.55 (m, 1H), 3, 70 (m, 1H), 4.03 (m, 2H), 4.39-4.46 (m, 1H), 6.60 (s, 1H), 6.93 (s, 1H), 7.12 –7.22 (m, 12H), 7.32 (m, 5H), 7.57 (m, 2H), 7.82 (d, 2H).

Espectro LCMS: MH+ 574,52, tiempo de retención 2,85 min. (Monitor Ácido). LCMS spectrum: MH + 574.52, retention time 2.85 min. (Acid Monitor).

4–[4–[(3S)–3–Metilmorfolin–4–il]–6–(2–piridin–2–ilsulfonilpropan–2–il)pirimidin–2–il]anilina 4– [4 - [(3S) –3 – Methylmorpholin-4-yl] –6– (2-pyridin-2-ylsulfonylpropan-2-yl) pyrimidin-2-yl] aniline

Se suspendieron tetrametil–1,3,2–dioxaborolan–2–il)anilina (0,773 g, 3,53 mmoles) y 2–cloro–4–[(3S)–3– metilmorfolin–4–il]–6–(2–piridin–2–ilsulfonilpropan–2–il)pirimidina (1,4 g, 3,53 mmoles) en una mezcla de DME (10 ml), etanol (10,00 ml), DMF (10,00 ml) y agua (10 ml) a RT en nitrógeno. La mezcla se purgó con nitrógeno, y se añadió cloruro de bis(trifenilfosfina)paladio(II) (0,124 g, 0,18 mmoles). La suspensión resultante se agitó a 80ºC durante 90 minutos en una atmósfera de nitrógeno. La mezcla de reacción se concentró y se diluyó con acetato de etilo (150 ml), y se lavó con agua (2 x 150 ml) y salmuera saturada (100 ml). La capa orgánica se secó (MgSO4), se filtró y se evaporó para proporcionar el producto bruto. El producto bruto se purificó mediante cromatografía ultrarrápida en sílice, gradiente de elución 0 a 40% de acetato de etilo en DCM, para dar el material deseado como una espuma amarilla (1,210 g). Tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (0.773 g, 3.53 mmol) and 2-chloro-4 - [(3S) -3- methylmorpholin-4-yl] -6- ( 2-pyridin-2-ylsulfonylpropan-2-yl) pyrimidine (1.4 g, 3.53 mmol) in a mixture of DME (10 ml), ethanol (10.00 ml), DMF (10.00 ml) and water (10 ml) at RT in nitrogen. The mixture was purged with nitrogen, and bis (triphenylphosphine) palladium (II) chloride (0.124 g, 0.18 mmol) was added. The resulting suspension was stirred at 80 ° C for 90 minutes under a nitrogen atmosphere. The reaction mixture was concentrated and diluted with ethyl acetate (150 ml), and washed with water (2 x 150 ml) and saturated brine (100 ml). The organic layer was dried (MgSO4), filtered and evaporated to provide the crude product. The crude product was purified by flash chromatography on silica, gradient elution 0 to 40% ethyl acetate in DCM, to give the desired material as a yellow foam (1,210 g).

Espectro RMN: RMN 1H (399,902 MHz, CDCl3) δ 1,25 (d, 3H), 1,89 (s, 6H), 3,22 (m, 1H), 3,54 (m, 1H), 3,66–3,80 (m, 4H), 3,97 (m, 1H), 4,05 (m, 1H), 4,42 (s, 1H), 6,46–6,53 (m, 3H), 7,28 (m, 1H), 7,55 (m, 2H), 7,64 (d, 2H), 8,61 (d, 1H). NMR Spectrum: 1H NMR (399,902 MHz, CDCl3) δ 1.25 (d, 3H), 1.89 (s, 6H), 3.22 (m, 1H), 3.54 (m, 1H), 3, 66–3.80 (m, 4H), 3.97 (m, 1H), 4.05 (m, 1H), 4.42 (s, 1H), 6.46–6.53 (m, 3H) , 7.28 (m, 1H), 7.55 (m, 2H), 7.64 (d, 2H), 8.61 (d, 1H).

Espectro LCMS: MH+ 454,58, tiempo de retención 1,88 min. LCMS spectrum: MH + 454.58, retention time 1.88 min.

2–Cloro–4–[(3S)–3–metilmorfolin–4–il]–6–(2–piridin–2–ilsulfonilpropan–2–il)pirimidina 2 – Chloro – 4 - [(3S) –3 – methylmorpholin-4-yl] –6– (2-pyridin-2-ylsulfonylpropan – 2-yl) pyrimidine

Se añadió yodometano (1,266 ml, 20,33 mmoles) a una disolución de 2–cloro–4–[(3S)–3–metilmorfolin–4–il]–6– (piridin–2–ilsulfonilmetil)pirimidina (2,5 g, 6,78 mmoles) y terc–butóxido de sodio (1,954 g, 20,33 mmoles) en DMF (50 ml) a 0ºC en nitrógeno. La disolución se dejó calentar lentamente hasta RT y se agitó a RT durante 1 hora. Se añadieron agua y acetato de etilo, y la disolución se agitó y se separó. Las capas de acetato de etilo combinadas se secaron (MgSO4) y se filtraron. El filtrado se evaporó, y el producto bruto se purificó mediante cromatografía ultrarrápida en sílice, gradiente de elución 0 a 60% de acetato de etilo en DCM, para dar el material deseado como un aceite amarillo que solidificó al reposar (1,77 g). Iodomethane (1,266 ml, 20.33 mmol) was added to a solution of 2-chloro-4 - [(3S) -3-methylmorpholin-4-yl] -6- (pyridin-2-ylsulfonylmethyl) pyrimidine (2.5 g, 6.78 mmol) and sodium tert-butoxide (1.954 g, 20.33 mmol) in DMF (50 ml) at 0 ° C under nitrogen. The solution was allowed to warm slowly to RT and stirred at RT for 1 hour. Water and ethyl acetate were added, and the solution was stirred and separated. The combined ethyl acetate layers were dried (MgSO4) and filtered. The filtrate was evaporated, and the crude product was purified by flash chromatography on silica, gradient elution 0 to 60% ethyl acetate in DCM, to give the desired material as a yellow oil that solidified on standing (1.77 g) .

Espectro RMN: RMN 1H (399,902 MHz, CDCl3) δ 1,26 (d, 3H), 1,77 (s, 6H), 3,22 (m, 1H), 3,49 (m, 1H), 3,64 (m, 1H), 3,74 (d, 1H), 3,89–3,98 (m, 2H), 4,27 (s, 1H), 6,67 (s, 1H), 7,46 (m, 1H), 7,73 (m, 1H), 7,80 (d, 1H), 7,82 (m, 1H). NMR Spectrum: 1H NMR (399,902 MHz, CDCl3) δ 1.26 (d, 3H), 1.77 (s, 6H), 3.22 (m, 1H), 3.49 (m, 1H), 3, 64 (m, 1H), 3.74 (d, 1H), 3.89-3.98 (m, 2H), 4.27 (s, 1H), 6.67 (s, 1H), 7.46 (m, 1H), 7.73 (m, 1H), 7.80 (d, 1H), 7.82 (m, 1H).

Espectro LCMS: MH+ 397,38, tiempo de retención 2,04 min. LCMS spectrum: MH + 397.38, retention time 2.04 min.

2–Cloro–4–[(3S)–3–metilmorfolin–4–il]–6–(piridin–2–ilsulfonilmetil)pirimidina 2 – Chloro – 4 - [(3S) –3 – methylmorpholin-4-yl] –6– (pyridin-2-ylsulfonylmethyl) pyrimidine

Una disolución acuosa al 35% de peróxido de hidrógeno (8,26 ml, 93,53 mmoles) se añadió gota a gota a una disolución agitada de 2–cloro–4–[(3S)–3–metilmorfolin–4–il]–6–(piridin–2–ilsulfanilmetil)pirimidina (10,5 g, 31,17 mmoles), volframato de sodio dihidratado (0,206 g, 0,62 mmoles) y ácido sulfúrico 2N (0,6 ml) en dioxano (300 ml) y después la disolución se calentó hasta 55ºC. La disolución se agitó a 55ºC durante 4 horas. Se añadió peróxido de hidrógeno adicional (8,26 ml), y la mezcla se agitó a 50ºC durante 18 horas. Se añadió ácido 3–cloroperoxibenzoico (5,38 g, 31,17 mmoles), y la mezcla se agitó a RT durante 2 horas. La disolución se diluyó con agua (500 ml) y se enfrió hasta 20ºC. Se añadió una disolución al 10% de metabisulfito de sodio para destruir cualquier peróxido restante, y la disolución se extrajo con acetato de etilo. La capa orgánica se secó (MgSO4) y se filtró. El producto bruto se purificó mediante cromatografía ultrarrápida en sílice, gradiente de elución 0 a 50% de acetato de etilo en DCM, para dar el material deseado como una goma amarilla (10,5 g). A 35% aqueous solution of hydrogen peroxide (8.26 ml, 93.53 mmol) was added dropwise to a stirred solution of 2-chloro-4 - [(3S) -3-methylmorpholin-4-yl] –6– (pyridin-2-ylsulfanylmethyl) pyrimidine (10.5 g, 31.17 mmol), sodium volphrama dihydrate (0.206 g, 0.62 mmol) and 2N sulfuric acid (0.6 ml) in dioxane (300 ml) and then the solution was heated to 55 ° C. The solution was stirred at 55 ° C for 4 hours. Additional hydrogen peroxide (8.26 ml) was added, and the mixture was stirred at 50 ° C for 18 hours. 3-Chloroperoxybenzoic acid (5.38 g, 31.17 mmol) was added, and the mixture was stirred at RT for 2 hours. The solution was diluted with water (500 ml) and cooled to 20 ° C. A 10% solution of sodium metabisulfite was added to destroy any remaining peroxide, and the solution was extracted with ethyl acetate. The organic layer was dried (MgSO4) and filtered. The crude product was purified by flash chromatography on silica, gradient elution 0 to 50% ethyl acetate in DCM, to give the desired material as a yellow gum (10.5 g).

Espectro RMN: RMN 1H (399,902 MHz, CDCl3) δ 1,24 (d, 3H), 3,20 (m, 1H), 3,46 (m, 1H), 3,61 (d, 1H), 3,71 (d, 1H), 3,90–3,98 (m, 2H), 4,21 (s, 1H), 4,51 (s, 2H), 6,50 (s, 1H), 7,51–7,53 (m, 1H), 7,86–7,95 (m, 2H), 8,72–8,74 (m, 1H) NMR Spectrum: 1H NMR (399,902 MHz, CDCl3) δ 1.24 (d, 3H), 3.20 (m, 1H), 3.46 (m, 1H), 3.61 (d, 1H), 3, 71 (d, 1H), 3.90-3.98 (m, 2H), 4.21 (s, 1H), 4.51 (s, 2H), 6.50 (s, 1H), 7.51 –7.53 (m, 1H), 7.86–7.95 (m, 2H), 8.72–8.74 (m, 1H)

Espectro LCMS: MH+ 369,37, tiempo de retención 1,73 min. LCMS spectrum: MH + 369.37, retention time 1.73 min.

2–Cloro–4–[(3S)–3–metilmorfolin–4–il]–6–(piridin–2–ilsulfanilmetil)pirimidina 2 – Chloro – 4 - [(3S) –3 – methylmorpholin-4-yl] –6– (pyridin-2-ylsulfanylmethyl) pyrimidine

Se añadió DIPEA (8,77 ml, 50,71 mmoles) a 2–mercaptopiridina (3,80 g, 34,22 mmoles), en DMF (300 ml) a RT en una atmósfera de nitrógeno. La disolución resultante se agitó a RT durante 15 minutos. Se añadió en porciones durante 5 minutos 2–cloro–4–(yodometil)–6–[(3S)–3–metilmorfolin–4–il]pirimidina (11 g, 31,11 mmoles), y la mezcla se agitó a RT durante 3 horas. La mezcla de reacción se evaporó hasta sequedad y se volvió a disolver en DCM (200 ml) y se lavó secuencialmente con disolución saturada de hidrogenocarbonato de sodio (100 ml) y salmuera saturada (50 ml). La capa orgánica se secó (MgSO4), se filtró y se evaporó para proporcionar el producto bruto. El producto bruto se purificó mediante cromatografía ultrarrápida en sílice, gradiente de elución 0 a 20% de acetato de etilo en DCM, para dar el material deseado como un aceite de color bonceado (10,50 g). La RMN muestra la presencia de 0,6 eq. de ácido m–clorobenzoico. Este material se usó en el paso subsiguiente sin purificación adicional. DIPEA (8.77 ml, 50.71 mmol) was added to 2-mercaptopyridine (3.80 g, 34.22 mmol), in DMF (300 ml) at RT under a nitrogen atmosphere. The resulting solution was stirred at RT for 15 minutes. 2-Chloro-4- (iodomethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine (11 g, 31.11 mmol) was added portionwise, and the mixture was stirred at RT during 3 hours. The reaction mixture was evaporated to dryness and re-dissolved in DCM (200 ml) and washed sequentially with saturated sodium hydrogen carbonate solution (100 ml) and saturated brine (50 ml). The organic layer was dried (MgSO4), filtered and evaporated to provide the crude product. The crude product was purified by flash chromatography on silica, gradient elution 0 to 20% ethyl acetate in DCM, to give the desired material as a boncerated oil (10.50 g). NMR shows the presence of 0.6 eq. of m-chlorobenzoic acid. This material was used in the subsequent step without further purification.

Espectro RMN: RMN 1H (399,902 MHz, CDCl3) δ 1,23 (d, 3H), 3,17–3,25 (m, 1H), 3,46–3,54 (m, 1H), 3,62–3,67 (m, 1H), 3,74 (d, 1H), 3,93–4,01 (m, 2H), 4,20 (s, 1H), 4,29–4,38 (m, 2H), 6,60 (s, 1H), 6,99–7,02 (m, 1H), 7,20 (d, 1H), 7,47–7,51 (m, 1H), 8,40–8,42 (m, 1H). NMR Spectrum: 1H NMR (399,902 MHz, CDCl3) δ 1.23 (d, 3H), 3.17-3.25 (m, 1H), 3.46-3.54 (m, 1H), 3.62 –3.67 (m, 1H), 3.74 (d, 1H), 3.93-4.01 (m, 2H), 4.20 (s, 1H), 4.29-4.38 (m , 2H), 6.60 (s, 1H), 6.99–7.02 (m, 1H), 7.20 (d, 1H), 7.47–7.51 (m, 1H), 8, 40–8.42 (m, 1 H).

Espectro LCMS: MH+ 337,48, tiempo de retención 2,19 min. LCMS spectrum: MH + 337.48, retention time 2.19 min.

Ejemplo 71: Example 71:

3–Etil–1–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(piridin–2–ilsulfonilmetil)pirimidin–2–il]fenil]urea 3 – Ethyl – 1– [4– [4 - [(3S) –3 – methylmorpholin-4-yl] –6– (pyridin-2-ylsulfonylmethyl) pyrimidin – 2-yl] phenyl] urea

Una disolución 2M de etilamina en metanol (0,495 ml, 0,99 mmoles) se añadió en una porción a una disolución de N–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(piridin–2–ilsulfonilmetil)pirimidin–2–il]fenil]carbamato de fenilo (120 mg, 0,22 mmoles) en DMF (2 ml) a RT en nitrógeno. La disolución resultante se agitó a RT durante 60 minutos. La mezcla de reacción se evaporó hasta sequedad, y el producto bruto se purificó mediante cromatografía ultrarrápida en sílice, gradiente de elución 0 a 7% de metanol en DCM, para dar el material deseado como una espuma blanca (83 mg). A 2M solution of ethylamine in methanol (0.495 ml, 0.99 mmol) was added in one portion to a solution of N– [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– ( Pyridin-2-ylsulfonylmethyl) pyrimidin-2-yl] phenyl] phenyl carbamate (120 mg, 0.22 mmol) in DMF (2 ml) at RT in nitrogen. The resulting solution was stirred at RT for 60 minutes. The reaction mixture was evaporated to dryness, and the crude product was purified by flash chromatography on silica, gradient elution 0 to 7% methanol in DCM, to give the desired material as a white foam (83 mg).

Espectro RMN: RMN 1H (399,902 MHz, DMSO–d6) δ 1,07 (t, 3H), 1,20 (d, 3H), 3,09–3,22 (m, 3H), 3,44–3,52 (m, 1H), 3,61–3,65 (m, 1H), 3,76 (d, 1H), 3,95–4,00 (m, 1H), 4,12 (d, 1H), 4,40 (s, 1H), 4,85 (q, 2H), 6,14 (t, 1H), 6,69 (s, 1H), 7,35 (d, 2H), 7,66 (d, 2H), 7,79–7,82 (m, 1H), 7,90 (d, 1H), 8,08–8,13 (m, 1H), 8,62 (s, 1H), 8,93 (d, 1H). NMR Spectrum: 1H NMR (399,902 MHz, DMSO – d6) δ 1.07 (t, 3H), 1.20 (d, 3H), 3.09–3.22 (m, 3H), 3.44–3 , 52 (m, 1H), 3.61-3.65 (m, 1H), 3.76 (d, 1H), 3.95-4.00 (m, 1H), 4.12 (d, 1H ), 4.40 (s, 1H), 4.85 (q, 2H), 6.14 (t, 1H), 6.69 (s, 1H), 7.35 (d, 2H), 7.66 (d, 2H), 7.79–7.82 (m, 1H), 7.90 (d, 1H), 8.08–8.13 (m, 1H), 8.62 (s, 1H), 8.93 (d, 1 H).

Espectro LCMS: MH+ 497,49, tiempo de retención 1,66 min. LCMS spectrum: MH + 497.49, retention time 1.66 min.

A continuación se describe la preparación de N–[4–[4–[(3S)–3–metilmorfolin–4–il]–6–(piridin–2– ilsulfonilmetil)pirimidin–2–il]fenil]carbamato de fenilo. The preparation of N- [4– [4 - [(3S) –3-methylmorpholin-4-yl] –6– (pyridin-2-ylsulfonylmethyl) pyrimidin-2-yl] phenyl] carbamate phenyl is described below.

N–[4–[4–[(3S)–3–Metilmorfolin–4–il]–6–(piridin–2–ilsulfonilmetil)pirimidin–2–il]fenil]carbamato de fenilo N– [4– [4 - [(3S) –3 – Methylmorpholin-4-yl] –6– (pyridin-2-ylsulfonylmethyl) pyrimidin-2-yl] phenyl] phenyl carbamate

Se añadió cloroformiato de fenilo (0,390 ml, 3,10 mmoles) a 4–[4–[(3S)–3–metilmorfolin–4–il]–6–(piridin–2– ilsulfonilmetil)pirimidin–2–il]anilina (1,1 g, 2,59 mmoles) e hidrogenocarbonato de sodio (0,434 g, 5,17 mmoles) en dioxano (25 ml) a RT. La suspensión resultante se agitó a RT durante 1 hora. La mezcla se repartió entre acetato de etilo y agua. La disolución orgánica se separó, se secó (MgSO4) y se concentró a presión reducida. El residuo se purificó mediante cromatografía ultrarrápida en sílice usando un gradiente de elución de 0%–20% de acetato de etilo en DCM, para dar el material deseado como una espuma amarilla (1,130 g). Phenyl chloroformate (0.390 ml, 3.10 mmol) was added at 4– [4 - [(3S) -3-methylmorpholin-4-yl] -6– (pyridin-2-ylsulfonylmethyl) pyrimidin-2-yl] aniline (1.1 g, 2.59 mmol) and sodium hydrogen carbonate (0.434 g, 5.17 mmol) in dioxane (25 ml) at RT. The resulting suspension was stirred at RT for 1 hour. The mixture was partitioned between ethyl acetate and water. The organic solution was separated, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica using an elution gradient of 0% -20% ethyl acetate in DCM, to give the desired material as a yellow foam (1,130 g).

Espectro RMN: RMN 1H (399,902 MHz, CDCl3) δ 1,25 (d, 3H), 3,23 (m, 1H), 3,52 (m, 1H), 3,65–3,68 (m, 1H), 3,75 (d, 1H), 3,95–3,99 (m, 1H), 4,05–4,11 (m, 2H), 4,31–4,38 (m, 1H), 4,63 (q, 2H), 6,39 (s, 1H), 6,95 (s, 1H), 7,13 (m, 2H), 7,17–7,21 (m, 1H), 7,34 (m, 4H), 7,48 (m, 1H), 7,75–7,85 (m, 4H), 8,77–8,79 (m, 1H). NMR Spectrum: 1H NMR (399,902 MHz, CDCl3) δ 1.25 (d, 3H), 3.23 (m, 1H), 3.52 (m, 1H), 3.65-3.68 (m, 1H ), 3.75 (d, 1H), 3.95–3.99 (m, 1H), 4.05–4.11 (m, 2H), 4.31–4.38 (m, 1H), 4.63 (q, 2H), 6.39 (s, 1H), 6.95 (s, 1H), 7.13 (m, 2H), 7.17–7.21 (m, 1H), 7 , 34 (m, 4H), 7.48 (m, 1H), 7.75-7.85 (m, 4H), 8.77-8.79 (m, 1H).

Espectro LCMS: MH+ 546,49, tiempo de retención 2,54 min. LCMS spectrum: MH + 546.49, retention time 2.54 min.

4–[4–[(3S)–3–Metilmorfolin–4–il]–6–(piridin–2–ilsulfonilmetil)pirimidin–2–il]anilina 4– [4 - [(3S) –3 – Methylmorpholin-4-yl] –6– (pyridin-2-ylsulfonylmethyl) pyrimidin-2-yl] aniline

Se añadió carbonato de sodio (7,32 ml, 14,64 mmoles) a 4–(4,4,5,5–tetrametil–1,3,2–dioxaborolan–2–il)anilina (0,891 g, 4,07 mmoles) y 2–cloro–4–[(3S)–3–metilmorfolin–4–il]–6–(piridin–2–ilsulfonilmetil)pirimidina (1,5 g, 4,07 mmoles) en una mezcla de DME (10 ml), etanol (10,00 ml), DMF (10,00 ml) y agua (10 ml) a RT en nitrógeno. La mezcla se purgó con nitrógeno tres veces, se añadió cloruro de bis(trifenilfosfina)paladio(II) (0,143 g, 0,20 mmoles), y la mezcla se purgó nuevamente con nitrógeno. La suspensión resultante se agitó a 80ºC durante 90 minutos. La mezcla de reacción se evaporó hasta sequedad y se suspendió en acetato de etilo (150 ml), y se lavó con agua (2 x 150 ml) y salmuera saturada (100 ml). La capa orgánica se secó (MgSO4), se filtró y se evaporó para proporcionar el producto bruto. El producto bruto se purificó mediante cromatografía ultrarrápida en sílice, gradiente de elución 0 a 40% de acetato de etilo en DCM, para dar el material deseado como una espuma amarilla (1,21 g). Sodium carbonate (7.32 ml, 14.64 mmol) was added to 4– (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (0.891 g, 4.07 mmol) and 2-chloro-4 - [(3S) -3-methylmorpholin-4-yl] -6- (pyridin-2-ylsulfonylmethyl) pyrimidine (1.5 g, 4.07 mmol) in a mixture of DME ( 10 ml), ethanol (10.00 ml), DMF (10.00 ml) and water (10 ml) at RT in nitrogen. The mixture was purged with nitrogen three times, bis (triphenylphosphine) palladium (II) chloride (0.143 g, 0.20 mmol) was added, and the mixture was purged again with nitrogen. The resulting suspension was stirred at 80 ° C for 90 minutes. The reaction mixture was evaporated to dryness and suspended in ethyl acetate (150 ml), and washed with water (2 x 150 ml) and saturated brine (100 ml). The organic layer was dried (MgSO4), filtered and evaporated to provide the crude product. The crude product was purified by flash chromatography on silica, gradient elution 0 to 40% ethyl acetate in DCM, to give the desired material as a yellow foam (1.21 g).

Espectro RMN: RMN 1H (399,902 MHz, CDCl3) δ 1,23 (d, 3H), 3,16–3,24 (m, 1H), 3,47–3,55 (m, 1H), 3,63–3,68 (m, 1H), 3,71–3,80 (m, 3H), 3,92–3,98 (m, 1H), 4,02–4,09 (m, 1H), 4,30–4,37 (m, 1H), 4,59 (q, 2H), 6,32 (s, 1H), 6,48– 6,53 (m, 2H), 7,44–7,49 (m, 1H), 7,67 (d, 2H), 7,73–7,83 (m, 2H), 8,77–8,79 (m, 1H). NMR Spectrum: 1H NMR (399.902 MHz, CDCl3) δ 1.23 (d, 3H), 3.16-3.24 (m, 1H), 3.47-3.55 (m, 1H), 3.63 –3.68 (m, 1H), 3.71–3.80 (m, 3H), 3.92–3.98 (m, 1H), 4.02–4.09 (m, 1H), 4 , 30–4.37 (m, 1H), 4.59 (q, 2H), 6.32 (s, 1H), 6.48– 6.53 (m, 2H), 7.44–7.49 (m, 1H), 7.67 (d, 2H), 7.73-7.83 (m, 2H), 8.77-8.79 (m, 1H).

Espectro LCMS: MH+ 426,48, tiempo de retención 1,24 min. (Monitor Ácido). LCMS spectrum: MH + 426.48, retention time 1.24 min. (Acid Monitor).

La preparación de 2–cloro–4–[(3S)–3–metilmorfolin–4–il]–6–(piridin–2–ilsulfonilmetil)pirimidina se describió anteriormente. The preparation of 2-chloro-4 - [(3S) -3-methylmorpholin-4-yl] -6- (pyridin-2-ylsulfonylmethyl) pyrimidine was described above.

Ejemplo 72: Example 72:

1– [4– [4– [2– (4 – Chlorophenyl) sulfonylpropan – 2-yl] –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin – 2-yl] phenyl] –3– cyclopropyl -urea

O OR

N N

N S OO N S OO

O OR

N N

N HH N HH

NCl NCl

Se añadió ciclopropilamina (0,139 ml, 1,98 mmoles) a N–[4–[4–[2–(4–clorofenil)sulfonilpropan–2–il]–6–[(3S)–3– metilmorfolin–4–il]pirimidin–2–il]fenil]carbamato de fenilo (150 mg, 0,25 mmoles) en DMF (2 ml). La disolución resultante se agitó a 60ºC durante 5 horas. La mezcla se evaporó hasta sequedad, y el residuo se repartió entre Cyclopropylamine (0.139 ml, 1.98 mmol) was added to N– [4– [4– [2– (4-chlorophenyl) sulfonylpropan-2-yl] –6 - [(3S) –3– methylmorpholin-4-yl ] Pyrimidin-2-yl] phenyl] phenyl carbamate (150 mg, 0.25 mmol) in DMF (2 ml). The resulting solution was stirred at 60 ° C for 5 hours. The mixture was evaporated to dryness, and the residue was partitioned between

5 acetato de etilo (30 ml) y agua (30 ml). La capa orgánica se lavó con agua (2 x 30 ml) y salmuera saturada (30 ml), se secó (MgSO4), se filtró y se evaporó hasta sequedad. El residuo se purificó mediante cromatografía ultrarrápida en sílice, gradiente de elución 30 a 60% de acetato de etilo en isohexano. Las fracciones puras se evaporaron hasta sequedad, y el residuo se trituró con éter dietílico para dar el material deseado como un sólido blanco (92 mg). 5 ethyl acetate (30 ml) and water (30 ml). The organic layer was washed with water (2 x 30 ml) and saturated brine (30 ml), dried (MgSO4), filtered and evaporated to dryness. The residue was purified by flash chromatography on silica, gradient elution 30 to 60% ethyl acetate in isohexane. The pure fractions were evaporated to dryness, and the residue was triturated with diethyl ether to give the desired material as a white solid (92 mg).

Espectro RMN: RMN 1H (399,902 MHz, CDCl3) δ 0,70 (2H, s), 0,88 (2H, s), 1,34 (3H, d), 1,86 (6H, s), 2,63 (1H, t), NMR Spectrum: 1H NMR (399,902 MHz, CDCl3) δ 0.70 (2H, s), 0.88 (2H, s), 1.34 (3H, d), 1.86 (6H, s), 2, 63 (1H, t),

10 3,33 (1H, td), 3,63 (1H, td), 3,78 (2H, dd), 3,85 (2H, d), 4,06 (1H, dd), 4,14 (1H, d), 4,49 (1H, d), 4,88 (1H, s), 6,63 (1H, s), 6,93 (1H, s), 7,30 (4H, d), 7,39 (2H, d), 7,47 (2H, d), 7,87 (2H, d). 10 3.33 (1H, td), 3.63 (1H, td), 3.78 (2H, dd), 3.85 (2H, d), 4.06 (1H, dd), 4.14 ( 1H, d), 4.49 (1H, d), 4.88 (1H, s), 6.63 (1H, s), 6.93 (1H, s), 7.30 (4H, d), 7.39 (2H, d), 7.47 (2H, d), 7.87 (2H, d).

Espectro LCMS: MH+ 570, 572, tiempo de retención 2,63 min. LCMS spectrum: MH + 570, 572, retention time 2.63 min.

Los siguientes compuestos se obtuvieron de manera análoga a partir de N–[4–[4–[2–(4–clorofenil)sulfonilpropan–2– il]–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]carbamato de fenilo o N–[4–[4–[(4–clorofenil)sulfonilmetil]–6– The following compounds were obtained analogously from N– [4– [4– [2– (4-chlorophenyl) sulfonylpropan – 2– yl] –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin –2 – yl] phenyl] phenyl carbamate or N– [4– [4 - [(4-chlorophenyl) sulfonylmethyl] –6–

15 [(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]carbamato de fenilo y la amina apropiada. 15 [(3S) -3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] phenyl carbamate and the appropriate amine.

72a 72nd: Cl O 1–[4–[4–[2–(4–clorofenil)sulfonilpropan– 2–il]–6–[(3S)–3–metilmorfolin–4– 584, 586 2,86 Cl OR 1– [4– [4– [2– (4-chlorophenyl) sulfonylpropan– 2-yl] –6 - [(3S) –3 – methylmorpholin – 4– 584, 586 2.86

SO O SO OR: N N N N H N H O il]pirimidin–2–il]fenil]–3–ciclobutil–urea N N N N H N H O il] pyrimidin – 2-yl] phenyl] –3 – cyclobutyl-urea

72b 72b: Cl O 1–[4–[4–[2–(4–clorofenil)sulfonilpropan– 2–il]–6–[(3S)–3–metilmorfolin–4– 544, 546 2,46 Cl OR 1– [4– [4– [2– (4-chlorophenyl) sulfonylpropan– 2-yl] –6 - [(3S) –3 – methylmorpholin – 4– 544, 546 2.46

SO O SO OR: N N N N H N H O il]pirimidin–2–il]fenil]–3–metil–urea N N N N H N H O il] pyrimidin – 2-yl] phenyl] –3-methyl-urea

72c 72c: Cl O 1–[4–[4–[2–(4–clorofenil)sulfonilpropan– 2–il]–6–[(3S)–3–metilmorfolin–4– 558, 560 2,63 Cl OR 1– [4– [4– [2– (4-chlorophenyl) sulfonylpropan– 2-yl] –6 - [(3S) –3 – methylmorpholin – 4– 558, 560 2.63

SO O SO OR: N N N N H N H O il]pirimidin–2–il]fenil]–3–etil–urea N N N N H N H O il] pyrimidin – 2-yl] phenyl] –3-ethyl-urea

72d 72d: S Cl O O N N N O N H N H O N 1–[4–[4–[2–(4–clorofenil)sulfonilpropan– 2–il]–6–[(3S)–3–metilmorfolin–4– il]pirimidin–2–il]fenil]–3–(2– dimetilaminoetil)urea 601, 603 2,51 S Cl O O N N N O N H N H O N 1– [4– [4– [2– (4-chlorophenyl) sulfonylpropan– 2-yl] –6 - [(3S) –3-methylmorpholin-4– yl] pyrimidin – 2-yl] phenyl] –3– ( 2– dimethylaminoethyl) urea 601, 603 2.51

72e 72e: S Cl O O N N N O N H N H O (S)–1–(4–(4–((4–clorofenilsulfonil)metil)–6–(3–metilmorfolino)pirimidin–2– il)fenil)–3–ciclobutilurea 556, 558 2,56 S Cl O O N N N O N H N H O (S) –1– (4– (4 - ((4-chlorophenylsulfonyl) methyl) –6– (3-methylmorpholino) pyrimidin – 2– yl) phenyl) –3 – cyclobutylurea 556, 558 2.56

72f 72f: S Cl O O N N N O N H N H O 1–[4–[4–[(4–clorofenil)sulfonilmetil]–6– [(3S)–3–metilmorfolin–4–il]pirimidin–2– il]fenil]–3–etil–urea 530, 532 2,38 S Cl O O N N N O N H N H O 1– [4– [4 - [(4-chlorophenyl) sulfonylmethyl] –6– [(3S) -3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] –3-ethyl-urea 530, 532 2.38

Ejemplo 72a: RMN 1H (399,902 MHz, CDCl3) δ 1,34 (3H, d), 1,72 (2H, m), 1,86 (2H, m), 1,86 (6H, s), 2,39 (2H, m), 3,32 (1H, ddd), 3,63 (1H, ddd), 3,77 (1H, dd), 3,85 (1H, d), 4,06 (1H, dd), 4,14 (1H, d), 4,31 (1H, dtt), 4,49 (1H, br.d), 4,86 (1H, d), 6,29 (1H, s), 6,63 (1H, s), 7,27 (2H, d), 7,29 (2H, d), 7,47 (2H, d), 7,86 (2H, d). Example 72a: 1H NMR (399.902 MHz, CDCl3) δ 1.34 (3H, d), 1.72 (2H, m), 1.86 (2H, m), 1.86 (6H, s), 2, 39 (2H, m), 3.32 (1H, ddd), 3.63 (1H, ddd), 3.77 (1H, dd), 3.85 (1H, d), 4.06 (1H, dd ), 4.14 (1H, d), 4.31 (1H, dtt), 4.49 (1H, br.d), 4.86 (1H, d), 6.29 (1H, s), 6 , 63 (1H, s), 7.27 (2H, d), 7.29 (2H, d), 7.47 (2H, d), 7.86 (2H, d).

Ejemplo 72b: RMN 1H (399,902 MHz, CDCl3) δ 1,34 (3H, d), 1,86 (6H, s), 2,86 (3H, d), 3,32 (1H, ddd), 3,62 (1H, ddd), 3,77 (1H, dd), 3,84 (1H, d), 4,06 (1H, dd), 4,13 (1H, d), 4,48 (1H, br.d), 4,81 (1H, q), 6,52 (1H, s), 6,62 (1H, s), 7,28 (2H, d), 7,29 (2H, d), 7,47 (2H, d), 7,87 (2H, d). Example 72b: 1H NMR (399.902 MHz, CDCl3) δ 1.34 (3H, d), 1.86 (6H, s), 2.86 (3H, d), 3.32 (1H, ddd), 3, 62 (1H, ddd), 3.77 (1H, dd), 3.84 (1H, d), 4.06 (1H, dd), 4.13 (1H, d), 4.48 (1H, br .d), 4.81 (1H, q), 6.52 (1H, s), 6.62 (1H, s), 7.28 (2H, d), 7.29 (2H, d), 7 , 47 (2H, d), 7.87 (2H, d).

Ejemplo 72c: RMN 1H (399,902 MHz, CDCl3) δ 1,17 (3H, t), 1,34 (3H, d), 1,86 (6H, s), 3,32 (2H, dq), 3,32 (1H, ddd), 3,62 (1H, ddd), 3,77 (1H, dd), 3,84 (1H, d), 4,06 (1H, dd), 4,13 (1H, d), 4,49 (1H, br.d), 4,78 (1H, t), 6,46 (1H, s), 6,62 (1H, s), 7,28 (2H, d), 7,29 (2H, d), 7,47 (2H, d), 7,86 (2H, d). Example 72c: 1H NMR (399.902 MHz, CDCl3) δ 1.17 (3H, t), 1.34 (3H, d), 1.86 (6H, s), 3.32 (2H, dq), 3, 32 (1H, ddd), 3.62 (1H, ddd), 3.77 (1H, dd), 3.84 (1H, d), 4.06 (1H, dd), 4.13 (1H, d ), 4.49 (1H, br.d), 4.78 (1H, t), 6.46 (1H, s), 6.62 (1H, s), 7.28 (2H, d), 7 , 29 (2H, d), 7.47 (2H, d), 7.86 (2H, d).

Ejemplo 72d: RMN 1H (399,90 MHz, CDCl3) δ 1,34 (3H, d), 1,85 (6H, s), 2,32 (6H, s), 2,53 (2H, t), 3,31 (1H, ddd), 3,33 (2H, dt), 3,62 (1H, ddd), 3,77 (1H, dd), 3,84 (1H, d), 4,06 (1H, dd), 4,14 (1H, d), 4,49 (1H, br.d), 5,29 (1H, br.s), 6,61 (1H, s), 7,29 (2H, d), 7,33 (2H, d), 7,47 (2H, d), 7,83 (2H, d), 8,41 (1H, v.br.s). Example 72d: 1H NMR (399.90 MHz, CDCl3) δ 1.34 (3H, d), 1.85 (6H, s), 2.32 (6H, s), 2.53 (2H, t), 3.31 (1H, ddd), 3.33 (2H, dt), 3.62 (1H, ddd), 3.77 (1H, dd), 3.84 (1H, d), 4.06 (1H , dd), 4.14 (1H, d), 4.49 (1H, br.d), 5.29 (1H, br.s), 6.61 (1H, s), 7.29 (2H, d), 7.33 (2H, d), 7.47 (2H, d), 7.83 (2H, d), 8.41 (1H, v.br.s).

Ejemplo 72e: RMN 1H (399,902 MHz, CDCl3) δ 1,33 (3H, d), 1,71 (2H, m), 1,84 (2H, m), 2,37 (2H, m), 3,30 (1H, ddd), 3,59 (1H, ddd), 3,74 (1H, dd), 3,82 (1H, d), 4,04 (1H, dd), 4,14 (1H, d), 4,30 (2H, dtt), 4,38 (2H, s), 4,39 (1H, d), 4,97 (1H, d), 6,44 (1H, s), 6,49 (1H, s), 7,31 (2H, d), 7,43 (2H, d), 7,70 (2H, d), 7,87 (2H, d). Example 72e: 1H NMR (399.902 MHz, CDCl3) δ 1.33 (3H, d), 1.71 (2H, m), 1.84 (2H, m), 2.37 (2H, m), 3, 30 (1H, ddd), 3.59 (1H, ddd), 3.74 (1H, dd), 3.82 (1H, d), 4.04 (1H, dd), 4.14 (1H, d ), 4.30 (2H, dtt), 4.38 (2H, s), 4.39 (1H, d), 4.97 (1H, d), 6.44 (1H, s), 6.49 (1H, s), 7.31 (2H, d), 7.43 (2H, d), 7.70 (2H, d), 7.87 (2H, d).

Ejemplo 72f: RMN 1H (399,902 MHz, CDCl3) δ 1,17 (3H, t), 1,33 (3H, d), 3,30 (1H, ddd), 3,32 (2H, dq), 3,60 (1H, ddd), 3,74 (1H, dd), 3,83 (1H, d), 4,05 (1H, dd), 4,15 (1H, d), 4,38 (2H, s), 4,42 (1H, br.d), 4,77 (1H, t), 6,44 (1H, s), 6,47 (1H, s), 7,31 (2H, d), 7,43 (2H, d), 7,70 (2H, d), 7,88 (2H, d). Example 72f: 1H NMR (399.902 MHz, CDCl3) δ 1.17 (3H, t), 1.33 (3H, d), 3.30 (1H, ddd), 3.32 (2H, dq), 3, 60 (1H, ddd), 3.74 (1H, dd), 3.83 (1H, d), 4.05 (1H, dd), 4.15 (1H, d), 4.38 (2H, s ), 4.42 (1H, br.d), 4.77 (1H, t), 6.44 (1H, s), 6.47 (1H, s), 7.31 (2H, d), 7 , 43 (2H, d), 7.70 (2H, d), 7.88 (2H, d).

A continuación se describe la preparación de N–[4–[4–[2–(4–clorofenil)sulfonilpropan–2–il]–6–[(3S)–3–metilmorfolin– 4–il]pirimidin–2–il]fenil]carbamato de fenilo. The preparation of N– [4– [4– [2– (4-chlorophenyl) sulfonylpropan-2-yl] –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl is described below. ] phenyl] phenyl carbamate.

N–[4–[4–[2–(4–clorofenil)sulfonilpropan–2–il]–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]fenil]carbamato de fenilo N– [4– [4– [2– (4-chlorophenyl) sulfonylpropan – 2-yl] –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin-2-yl] phenyl] phenyl carbamate

H H

Se añadió gota a gota cloroformiato de fenilo (0,256 ml, 2,04 mmoles) a 4–[4–[2–(4–clorofenil)sulfonilpropan–2–il]– 6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]anilina (850 mg, 1,85 mmoles) e hidrogenocarbonato de sodio (233 mg, 2,78 mmoles) en dioxano (20 ml) a RT. La suspensión resultante se agitó a RT durante 2 horas. La mezcla de reacción se diluyó con acetato de etilo (100 ml) y se lavó con agua (2 x 100 ml) y salmuera saturada (50 ml). La capa orgánica se secó (MgSO4), se filtró y se evaporó. El producto bruto se purificó mediante cromatografía ultrarrápida en sílice, gradiente de elución 30 a 50% de acetato de etilo en isohexano. Las fracciones puras se evaporaron hasta sequedad para proporcionar el material deseado como un sólido blanco (955 mg). Phenyl chloroformate (0.256 ml, 2.04 mmol) was added dropwise to 4– [4– [2– (4-chlorophenyl) sulfonylpropan-2-yl] - 6 - [(3S) –3-methylmorpholin-4 -Yl] pyrimidin-2-yl] aniline (850 mg, 1.85 mmol) and sodium hydrogen carbonate (233 mg, 2.78 mmol) in dioxane (20 ml) at RT. The resulting suspension was stirred at RT for 2 hours. The reaction mixture was diluted with ethyl acetate (100 ml) and washed with water (2 x 100 ml) and saturated brine (50 ml). The organic layer was dried (MgSO4), filtered and evaporated. The crude product was purified by flash chromatography on silica, gradient elution 30 to 50% ethyl acetate in isohexane. The pure fractions were evaporated to dryness to provide the desired material as a white solid (955 mg).

Espectro RMN: RMN 1H (399,902 MHz, CDCl3) δ 1,34 (3H, d), 3,32 (1H, ddd), 3,61 (1H, ddd), 3,75 (1H, dd), 3,84 (1H, d), 4,05 (1H, dd), 4,16 (1H, br.d), 4,38 (2H, s), 4,43 (1H, br.d), 6,46 (1H, s), 7,03 (1H, s), 7,21 (2H, d), 7,25 (1H, dd), 7,40 (2H, d), 7,43 (2H, dd), 7,45 (2H, d), 7,70 (2H, d), 7,92 (2H, d) NMR Spectrum: 1H NMR (399,902 MHz, CDCl3) δ 1.34 (3H, d), 3.32 (1H, ddd), 3.61 (1H, ddd), 3.75 (1H, dd), 3, 84 (1H, d), 4.05 (1H, dd), 4.16 (1H, br.d), 4.38 (2H, s), 4.43 (1H, br.d), 6.46 (1H, s), 7.03 (1H, s), 7.21 (2H, d), 7.25 (1H, dd), 7.40 (2H, d), 7.43 (2H, dd) , 7.45 (2H, d), 7.70 (2H, d), 7.92 (2H, d)

Espectro LCMS: MH+ 579, 581, tiempo de retención 2,94 min. LCMS spectrum: MH + 579, 581, retention time 2.94 min.

4–[4–[2–(4–Clorofenil)sulfonilpropan–2–il]–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]anilina 4– [4– [2– (4 – Chlorophenyl) sulfonylpropan – 2-yl] –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin – 2-yl] aniline

Se añadió carbonato de sodio (2M en agua, 6,69 ml, 13,38 mmoles) a 4–(4,4,5,5–tetrametil–1,3,2–dioxaborolan–2– il)anilina (0,815 g, 3,72 mmoles) y 2–cloro–4–[2–(4–clorofenil)sulfonilpropan–2–il]–6–[(3S)–3–metilmorfolin–4– il]pirimidina (1,60 g, 3,72 mmoles) en una mezcla de DME (10 ml), etanol (10,00 ml), DMF (10,00 ml) y agua (20 ml) a RT en nitrógeno. La mezcla se desgasificó y se purgó con nitrógeno tres veces. Se añadió cloruro de bis(trifenilfosfina)paladio(II) (0,130 g, 0,19 mmoles), y la mezcla se desgasificó y se purgó con nitrógeno unas tres veces adicionales. La suspensión resultante se agitó en nitrógeno a 80ºC durante 90 minutos. La mezcla de reacción se concentró y se diluyó con acetato de etilo (150 ml) y se lavó con agua (2 x 150 ml) y salmuera saturada (100 ml). La capa orgánica se secó (MgSO4), se filtró y se evaporó. El producto bruto se purificó mediante cromatografía ultrarrápida en sílice, gradiente de elución 30 a 45% de acetato de etilo en isohexano, para dar el material deseado como un sólido blanco (1,502 g). Sodium carbonate (2M in water, 6.69 ml, 13.38 mmol) was added to 4– (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (0.815 g , 3.72 mmol) and 2-chloro-4– [2– (4-chlorophenyl) sulfonylpropan-2-yl] –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidine (1.60 g, 3.72 mmol) in a mixture of DME (10 ml), ethanol (10.00 ml), DMF (10.00 ml) and water (20 ml) at RT in nitrogen. The mixture was degassed and purged with nitrogen three times. Bis (triphenylphosphine) palladium (II) chloride (0.130 g, 0.19 mmol) was added, and the mixture was degassed and purged with nitrogen an additional three times. The resulting suspension was stirred under nitrogen at 80 ° C for 90 minutes. The reaction mixture was concentrated and diluted with ethyl acetate (150 ml) and washed with water (2 x 150 ml) and saturated brine (100 ml). The organic layer was dried (MgSO4), filtered and evaporated. The crude product was purified by flash chromatography on silica, gradient elution 30 to 45% ethyl acetate in isohexane, to give the desired material as a white solid (1.502 g).

Espectro RMN: RMN 1H (399,902 MHz, CDCl3) δ 1,33 (3H, d), 1,84 (6H, s), 3,31 (1H, ddd), 3,62 (1H, ddd), 3,77 (1H, dd), 3,84 (1H, d), 3,86 (2H, s), 4,05 (1H, dd), 4,13 (1H, br.d), 4,48 (1H, br.d), 6,57 (1H, s), 6,60 (2H, d), 7,30 (2H, d), 7,47 (2H, d), 7,72 (2H, d). NMR Spectrum: 1H NMR (399,902 MHz, CDCl3) δ 1.33 (3H, d), 1.84 (6H, s), 3.31 (1H, ddd), 3.62 (1H, ddd), 3, 77 (1H, dd), 3.84 (1H, d), 3.86 (2H, s), 4.05 (1H, dd), 4.13 (1H, br.d), 4.48 (1H , br.d), 6.57 (1H, s), 6.60 (2H, d), 7.30 (2H, d), 7.47 (2H, d), 7.72 (2H, d) .

Espectro LCMS: MH+ 487, 489, tiempo de retención 2,64 min. LCMS spectrum: MH + 487, 489, retention time 2.64 min.

2 – Chloro – 4– [2– (4 – chlorophenyl) sulfonylpropan – 2-yl] –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidine

Se añadió gota a gota yoduro de metilo (0,310 ml, 4,97 mmoles) a 2–cloro–4–[(4–clorofenil)sulfonilmetil]–6–[(3S)–3– metilmorfolin–4–il]pirimidina (2,00 g, 4,97 mmoles) y terc–butóxido de sodio (0,478 g, 4,97 mmoles) en DMF (50 ml) a 0ºC durante un período de 5 minutos en nitrógeno. La disolución resultante se agitó a 0ºC durante 15 minutos. Se añadió terc–butóxido de sodio (0,478 g, 4,97 mmoles) a 0ºC, seguido por yoduro de metilo (0,310 ml, 4,97 mmoles), y la mezcla se agitó durante una hora adicional a 0ºC. La mezcla se vertió en agua se agitó rápidamente (700 ml); el precipitado resultante se recogió por filtración, se lavó con agua y se secó a vacío para dar el material deseado como un sólido blanco (1,79 g) Methyl iodide (0.310 ml, 4.97 mmol) was added dropwise to 2-chloro-4 - [(4-chlorophenyl) sulfonylmethyl] -6 - [(3S) -3- methylmorpholin-4-yl] pyrimidine ( 2.00 g, 4.97 mmol) and sodium tert-butoxide (0.478 g, 4.97 mmol) in DMF (50 ml) at 0 ° C for a period of 5 minutes under nitrogen. The resulting solution was stirred at 0 ° C for 15 minutes. Sodium tert-butoxide (0.478 g, 4.97 mmol) was added at 0 ° C, followed by methyl iodide (0.310 ml, 4.97 mmol), and the mixture was stirred for an additional hour at 0 ° C. The mixture was poured into water, stirred rapidly (700 ml); The resulting precipitate was collected by filtration, washed with water and dried in vacuo to give the desired material as a white solid (1.79 g).

Espectro RMN: RMN 1H (399,902 MHz, CDCl3) δ 1,34 (3H, d), 1,74 (6H, s), 3,30 (1H, ddd), 3,57 (1H, ddd), 3,72 (dd, 1H), 3,81 (1H, d), 4,02 (2H, m), 4,33 (1H, br.s), 6,71 (1H, s), 7,45 (2H, d), 7,50 (2H, d). NMR Spectrum: 1H NMR (399.902 MHz, CDCl3) δ 1.34 (3H, d), 1.74 (6H, s), 3.30 (1H, ddd), 3.57 (1H, ddd), 3, 72 (dd, 1H), 3.81 (1H, d), 4.02 (2H, m), 4.33 (1H, br.s), 6.71 (1H, s), 7.45 (2H , d), 7.50 (2H, d).

Espectro LCMS: MH+ 430, 432, tiempo de retención 2,68 min. LCMS spectrum: MH + 430, 432, retention time 2.68 min.

2–Cloro–4–[(4–clorofenil)sulfonilmetil]–6–[(3S)–3–metilmorfolin–4–il]pirimidina 2 – Chloro – 4 - [(4 – chlorophenyl) sulfonylmethyl] –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidine

Se añadió en una porción sal sódica del ácido 4–clorobencenosulfínico (5,39 g, 27,15 mmoles) a 2–cloro–4– (yodometil)–6–[(3S)–3–metilmorfolin–4–il]pirimidina (8,00 g, 22,63 mmoles) en acetonitrilo (400 ml) a RT. La suspensión resultante se agitó a 85ºC a reflujo durante 5 horas. La mezcla de reacción se concentró y se diluyó con DCM (400 ml) y se lavó con agua (400 ml). La capa orgánica se secó (MgSO4), se filtró y se evaporó. El producto bruto se purificó mediante cromatografía ultrarrápida en sílice, gradiente de elución 25 a 40% de acetato de etilo en isohexano, para dar el material deseado como un sólido blanco (6,90 g). Sodium salt of 4-chlorobenzenesulfinic acid (5.39 g, 27.15 mmol) was added to 2-chloro-4– (iodomethyl) –6 - [(3 S) –3-methylmorpholin-4-yl] pyrimidine (8.00 g, 22.63 mmol) in acetonitrile (400 ml) at RT. The resulting suspension was stirred at 85 ° C at reflux for 5 hours. The reaction mixture was concentrated and diluted with DCM (400 ml) and washed with water (400 ml). The organic layer was dried (MgSO4), filtered and evaporated. The crude product was purified by flash chromatography on silica, gradient elution 25 to 40% ethyl acetate in isohexane, to give the desired material as a white solid (6.90 g).

Espectro RMN: RMN 1H (399,902 MHz, CDCl3) δ 1,33 (3H, d), 3,30 (1H, ddd), 3,55 (1H, ddd), 3,70 (1H, dd), 3,80 (1H, d), 4,02 (2H, m), 4,28 (1H, br.s), 4,29 (2H, s), 6,55 (1H, s), 7,51 (2H, d), 7,70 (2H, d). NMR Spectrum: 1H NMR (399.902 MHz, CDCl3) δ 1.33 (3H, d), 3.30 (1H, ddd), 3.55 (1H, ddd), 3.70 (1H, dd), 3, 80 (1H, d), 4.02 (2H, m), 4.28 (1H, br.s), 4.29 (2H, s), 6.55 (1H, s), 7.51 (2H , d), 7.70 (2H, d).

Espectro LCMS: MH+ 402, 404, tiempo de retención 2,26 min. LCMS spectrum: MH + 402, 404, retention time 2.26 min.

A continuación se describe la preparación de N–[4–[4–[(4–clorofenil)sulfonilmetil]–6–[(3S)–3–metilmorfolin–4– il]pirimidin–2–il]fenil]carbamato de fenilo. The preparation of N– [4– [4 - [(4-chlorophenyl) sulfonylmethyl] –6 - [(3S) –3-methylmorpholin-4– yl] pyrimidin-2-yl] phenyl] phenyl carbamate is described below. .

N– [4– [4 - [(4 – Chlorophenyl) sulfonylmethyl] –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin – 2-yl] phenyl] phenyl carbamate

H H

Se añadió gota a gota cloroformiato de fenilo (0,256 ml, 2,04 mmoles) a 4–[4–[(4–clorofenil)sulfonilmetil]–6–[(3S)–3– metilmorfolin–4–il]pirimidin–2–il]anilina (850 mg, 1,85 mmoles) e hidrogenocarbonato de sodio (233 mg, 2,78 mmoles) en dioxano (20 ml) a RT. La suspensión resultante se agitó a RT durante 2 horas. La mezcla de reacción se diluyó con acetato de etilo (100 ml), se lavó con agua (2 x 100 ml) y salmuera saturada (50 ml). La capa orgánica se secó (MgSO4), se filtró y se evaporó. El producto bruto se purificó mediante cromatografía ultrarrápida en sílice, gradiente de elución 30 a 50% de acetato de etilo en isohexano, para dar el material deseado como un sólido blanco (955 mg). Phenyl chloroformate (0.256 ml, 2.04 mmol) was added dropwise to 4– [4 - [(4-chlorophenyl) sulfonylmethyl] –6 - [(3S) –3– methylmorpholin-4-yl] pyrimidin – 2 -Il] aniline (850 mg, 1.85 mmol) and sodium hydrogen carbonate (233 mg, 2.78 mmol) in dioxane (20 ml) at RT. The resulting suspension was stirred at RT for 2 hours. The reaction mixture was diluted with ethyl acetate (100 ml), washed with water (2 x 100 ml) and saturated brine (50 ml). The organic layer was dried (MgSO4), filtered and evaporated. The crude product was purified by flash chromatography on silica, gradient elution 30 to 50% ethyl acetate in isohexane, to give the desired material as a white solid (955 mg).

Espectro RMN: RMN 1H (399,902 MHz, CDCl3) δ 1,34 (3H, d), 3,32 (1H, ddd), 3,61 (1H, ddd), 3,75 (1H, dd), 3,84 (1H, d), 4,05 (1H, dd), 4,16 (1H, br.d), 4,38 (2H, s), 4,43 (1H, br.d), 6,46 (1H, s), 7,03 (1H, s), 7,21 (2H, d), 7,25 (1H, dd), 7,40 (2H, d), 7,43 (2H, dd), 7,45 (2H, d), 7,70 (2H, d), 7,92 (2H, d). NMR Spectrum: 1H NMR (399,902 MHz, CDCl3) δ 1.34 (3H, d), 3.32 (1H, ddd), 3.61 (1H, ddd), 3.75 (1H, dd), 3, 84 (1H, d), 4.05 (1H, dd), 4.16 (1H, br.d), 4.38 (2H, s), 4.43 (1H, br.d), 6.46 (1H, s), 7.03 (1H, s), 7.21 (2H, d), 7.25 (1H, dd), 7.40 (2H, d), 7.43 (2H, dd) , 7.45 (2H, d), 7.70 (2H, d), 7.92 (2H, d).

4–[4–[(4–Clorofenil)sulfonilmetil]–6–[(3S)–3–metilmorfolin–4–il]pirimidin–2–il]anilina 4– [4 - [(4 – Chlorophenyl) sulfonylmethyl] –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidin – 2-yl] aniline

Se añadió carbonato de sodio (2M en agua, 4,47 ml, 8,95 mmoles) a 4–(4,4,5,5–tetrametil–1,3,2–dioxaborolan–2– il)anilina (0,572 g, 2,61 mmoles) y 2–cloro–4–[(4–clorofenil)sulfonilmetil]–6–[(3S)–3–metilmorfolin–4–il]pirimidina (1,00 g, 2,49 mmoles) en una mezcla de DME (6,00 ml), DMF (6,00 ml), etanol (6,00 ml) y agua (14,00 ml) a RT. La mezcla se desgasificó y se purgó con nitrógeno tres veces. Se añadió cloruro de bis(trifenilfosfina)paladio(II) (0,087 g, 0,120 mmoles), y la mezcla se desgasificó y se purgó con nitrógeno unas tres veces adicionales. La suspensión resultante se agitó en nitrógeno a 80ºC durante 90 minutos. La mezcla de reacción se concentró y se diluyó con acetato de etilo (100 ml) y se lavó con agua (2 x 100 ml). La capa orgánica se secó sobre (MgSO4), se filtró y se evaporó. El producto bruto se purificó mediante cromatografía ultrarrápida en sílice, gradiente de elución 30 a 60% de acetato de etilo en isohexano, para dar el material deseado como un sólido blanco (0,980 g). Sodium carbonate (2M in water, 4.47 ml, 8.95 mmol) was added to 4– (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (0.572 g , 2.61 mmol) and 2-chloro-4 - [(4-chlorophenyl) sulfonylmethyl] –6 - [(3S) –3-methylmorpholin-4-yl] pyrimidine (1.00 g, 2.49 mmol) in a mixture of DME (6.00 ml), DMF (6.00 ml), ethanol (6.00 ml) and water (14.00 ml) at RT. The mixture was degassed and purged with nitrogen three times. Bis (triphenylphosphine) palladium (II) chloride (0.087 g, 0.115 mmol) was added, and the mixture was degassed and purged with nitrogen an additional three times. The resulting suspension was stirred under nitrogen at 80 ° C for 90 minutes. The reaction mixture was concentrated and diluted with ethyl acetate (100 ml) and washed with water (2 x 100 ml). The organic layer was dried over (MgSO4), filtered and evaporated. The crude product was purified by flash chromatography on silica, gradient elution 30 to 60% ethyl acetate in isohexane, to give the desired material as a white solid (0.980 g).

5 Espectro RMN: RMN 1H (399,902 MHz, CDCl3) δ 1,33 (3H, d), 3,30 (1H, ddd), 3,60 (1H, ddd), 3,74 (1H, dd), 3,82 (1H, d), 3,87 (2H, s), 4,04 (1H, dd), 4,15 (1H, m), 4,36 (2H, s), 4,42 (1H, br.s), 6,39 (1H, s), 6,62 (2H, d), 7,44 (2H, d), 7,69 (2H, d), 7,73 (2H, d). 5 NMR Spectrum: 1H NMR (399.902 MHz, CDCl3) δ 1.33 (3H, d), 3.30 (1H, ddd), 3.60 (1H, ddd), 3.74 (1H, dd), 3 , 82 (1H, d), 3.87 (2H, s), 4.04 (1H, dd), 4.15 (1H, m), 4.36 (2H, s), 4.42 (1H, br.s), 6.39 (1H, s), 6.62 (2H, d), 7.44 (2H, d), 7.69 (2H, d), 7.73 (2H, d).

Espectro LCMS: MH+ 459, 461, tiempo de retención 2,34 min. LCMS spectrum: MH + 459, 461, retention time 2.34 min.

La preparación de 2–cloro–4–[(4–clorofenil)sulfonilmetil]–6–[(3S)–3–metilmorfolin–4–il]pirimidina se describió 10 anteriormente. The preparation of 2-chloro-4 - [(4-chlorophenyl) sulfonylmethyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine was described above.

Claims

1. A compound of formula (I)

formula (I)

or a pharmaceutically acceptable salt thereof; in which

m is 0, 1, 2, 3 or 4;

1Y and Y2 are independently N or CR8 with the proviso that one of 1Y and Y2 is N and the other is CR8;

X is a linker group selected from –CR4 = CR5–, –CR4 = CR5CR6R7–, –CR6R7CR5 = CR4–, –C∃C–, –C∃CCR6R7–, –CR6R7C∃C–, –NR4CR6R7–, –OCR6R7– , –SCR6R7–, –S (O) CR6R7–, –S (O) 2CR6R7–, –C (O) NR4CR6R7–, - NR4C (O) CR6R7–, –NR4C (O) NR5CR6R7–, –NR4S (O) 2CR6R7–, –S (O) 2NR4CR6R7–, –C (O) NR4–, –NR4C (O) -, - NR4C (O) NR5–, –S (O) 2NR4– and –NR4S (O) 2–;

R 1 is a group selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, C 1-6 carbocyclyl alkyl, heterocyclyl and C 1-6 heterocyclyl alkyl, said group being optionally substituted with one or more substituent groups selected from halo, cyano, nitro, R9, –OR9, –SR9, –SOR9, –SO2R9, –COR9, –CO2R9, - CONR9R10, –NR9R10, –NR9COR10, –NR9CO2R10, –NR9CONR10R15, –NR9CO15 and -NR9SO2R10;

R2 is a group selected from C1-6 alkyl, carbocyclyl and heterocyclyl, said group being substituted with-NR17CONR18R19 and optionally substituted with one or more substituent groups independently selected from halo, cyano, nitro, -R11, -OR11, -SR11, –SOR11, –SO2R11, –COR11, –CO2R11, –CONR11R12, –NR11R12, - NR11COR12, and –NR11COCONR12R16;

each R3, when present, is independently selected from halo, cyano, nitro, –R13, –OR13, –SR13, - SOR13, –SO2R13, –COR13, –CO2R13, –CONR13R14, –NR13R14, –NR13COR14, –NR13CO2R14 and –NR13SO2R14;

R4 and R5 are independently hydrogen or C1-6 alkyl;

or R1 and R4, together with the atom or atoms to which they are attached, form a 4- to 10-membered carbocyclic or heterocyclic ring in which 1, 2 or 3 annular carbon atoms are optionally replaced by N, O or S, and said ring being optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, C1-6 halo-alkyl, C1- halo-alkoxy 6, hydroxy-C 1-6 alkyl, hydroxy-C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkoxy, amino, C 1-6 alkyl, amino, bis (C1-6 alkyl) amino, C1-6 amino-alkyl, (C1-6 alkyl) -amino-C1-6 alkyl, bis (C1-6 alkyl) -amino-C1-6 alkyl, cyano-alkyl C 1-6, C 1-6 alkyl sulfonyl, C 1-6 alkyl sulfonylamino, C 1-6 alkyl sulfonyl- (C 1-6 alkyl) -amino, sulfamoyl, C 1-6 alkyl sulfamoyl, bis (C 1-6 alkyl) - sulfamoyl, C1-6 alkanoyl-amino, C1-6 alkanoyl- (C1-6 alkyl) -amino, carbamoyl, C1-6 alkylcarbamoyl and bis (C1-6 alkyl) -carbamoyl;

R6 and R7 are independently selected from hydrogen, halo, cyano, nitro and C1-6 alkyl;

R8 is selected from hydrogen, halo, cyano and C1-6 alkyl;

R9 and R10 are independently hydrogen or a group selected from C1-6 alkyl, carbocyclyl, C1-6 carbocyclyl alkyl, heterocyclyl and C1-6 heterocyclyl alkyl, said group being optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, halo C1-6 alkyl, halo C1-6 alkoxy, hydroxy C1-6 alkyl, hydroxy C1- alkoxy 6, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkoxy, amino, C 1-6 alkyl, bis (C 1-6 alkyl) -amino, C 1-6 amino-alkyl , (C 1-6 alkyl) -Camino-C 1-6 alkyl, bis (C 1-6 alkyl) -amino-C 1-6 alkyl, cyano-C 1-6 alkyl, C 1-6 alkyl sulfonyl, C 1-6 alkyl 6-sulfonylamino, C1-6 alkyl sulfonyl- (C1-6 alkyl) -amino, sulfamoyl, C1-6 alkyl sulfamoyl, bis (C1-6 alkyl) -sulfamoyl, C1-6 alkanoyl-amino, C1-6 alkanoyl- ( C1-6 alkyl) -amino, carbamoyl, C1-6 alkylcarbamoyl and bis (C1-6 alkyl) -carbamoyl;

R11

, R12, R17 and R18 are independently hydrogen or a group selected from C1-6 alkyl, carbocyclyl, C1-6 carbocyclyl alkyl, heterocyclyl and C1-6 heterocyclyl alkyl, said group being optionally substituted with one or more groups substituents selected from halo, cyano, nitro, hydroxy, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxy-alkyl, hydroxy-alkoxy C1-6, C1-6 alkoxy-C1-6 alkyl, C1-6 alkoxy C1-6 alkoxy, amino, C1-6-alkyl, bis (C1-6 alkyl) -amino, amino-C1- alkyl 6, (C1-6 alkyl) -amino-C16 alkyl, bis (C1-6 alkyl) -amino-C1-6 alkyl, cyano-C1-6 alkyl, C1-6 alkyl sulfonyl, C1-6 alkanoyl -amino, C1-6 alkanoyl (C1-6 alkyl) -amino, carbamoyl, C1-6 alkylcarbamoyl and bis (C1-6 alkyl) -carbamoyl;

R13, R14, R15, R16

and R19 are independently hydrogen or a group selected from C1-6 alkyl, carbocyclyl, carbocyclyl-C1-6 alkyl, heterocyclyl and heterocyclyl-C1-6 alkyl, said group being optionally substituted with one or more substituent groups selected from halo , cyano, nitro, hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 hydroxy-alkyl, C1-6 hydroxy-alkoxy , C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkoxy, amino, C 1-6 alkyl, bis (C 1-6 alkyl) -amino, C 1-6 amino-alkyl, (alkyl C1-6) -amino-C16 alkyl, bis (C1-6 alkyl) -amino-C1-6 alkyl, cyano-C1-6 alkyl, C1-6 alkyl sulfonyl, C1-6 alkyl sulfonylamino, alkyl C1-6sulfonyl- (C1-6 alkyl) -amino, sulfamoyl, C1-6 alkyl-sulfamoyl, bis (C1-6 alkyl) -sulfamoyl, C1-6-amino alkanoyl, C1-6 alkanoyl- (C1-6 alkyl) -amino, carbamoyl, C1-6 alkylcarbamoyl and bis (C1-6 alkyl) -carbamoyl;

or R18 and R19, together with the nitrogen atom to which they are attached, form a 3 to 10 membered heterocyclic ring in which 1 or 2 annular carbon atoms are optionally replaced by N, O or S, and said ring being optionally substituted with one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, C1-6 halo-alkyl, C1-6 halo-alkoxy, hydroxy-alkyl C1-6, hydroxy-C1-6 alkoxy, C1-6 alkoxy-C1-6 alkyl, C1-6 alkoxy-C1-6 alkoxy, amino, C1-6-alkyl, bis (C1-6 alkyl ) -amino, C1-6 amino-alkyl, (C1-6 alkyl) -amino-C1-6 alkyl, bis (C1-6 alkyl) -amino-C1-6 alkyl, cyano-C1-6 alkyl , C1-6-sulfonyl alkyl, C1-6-sulfonylamino alkyl, C1-6-sulfonyl- (C1-6 alkyl) -amino, sulfamoyl, C1-6-sulfamoyl alkyl, bis (C1-6 alkyl) sulfamoyl, alkanoyl C1-6-amino, C1-6 alkanoyl- (C1-6 alkyl) -amino, carbamoyl, C1-6-carbamoyl alkyl and bis (C16 alkyl) carbamoyl.

2. A compound, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein the compound of formula (I) is a compound of formula (Ia) or (Ib)

OR

R3

N N

1Y

Y2 1Y

Y2

X

N

X

N

(Ia) (Ib)

or a pharmaceutically acceptable salt thereof,

in which R3 is methyl, and

R1, R2, X, Y1 and Y2 are as defined for the compound of formula (I) as claimed in claim 1.

3. 3.: Un compuesto, o una sal farmacéuticamente aceptable del mismo, de acuerdo con la reivindicación 1 ó 2, en el que Y1 es CH e Y2 es N. A compound, or a pharmaceutically acceptable salt thereof, according to claim 1 or 2, wherein Y1 is CH and Y2 is N.

4. Four.: Un compuesto, o una sal farmacéuticamente aceptable del mismo, de acuerdo con una cualquiera de las reivindicaciones 1 a 3, en el que X es un grupo enlazador seleccionado de -NR4CH2-, -OCH2-, -OCH(CH3)-, OC(CH3)2-, -SCH2-, -SCH(CH3)-, -SC(CH3)2-, -S(O)CH2-, -S(O)CH(CH3)-, -S(O)C(CH3)2-, -S(O)2CH2-, S(O)2CH(CH3)-, -S(O)2C(CH3)2-, -C(O)NR4- y -NR4C(O)-. A compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 3, wherein X is a linker group selected from -NR4CH2-, -OCH2-, -OCH (CH3) -, OC ( CH3) 2-, -SCH2-, -SCH (CH3) -, -SC (CH3) 2-, -S (O) CH2-, -S (O) CH (CH3) -, -S (O) C ( CH3) 2-, -S (O) 2CH2-, S (O) 2CH (CH3) -, -S (O) 2C (CH3) 2-, -C (O) NR4- and -NR4C (O) -.

5. 5.: Un compuesto, o una sal farmacéuticamente aceptable del mismo, de acuerdo con la reivindicación 4, en el que X es -S(O)2C(CH3)2-. A compound, or a pharmaceutically acceptable salt thereof, according to claim 4, wherein X is -S (O) 2C (CH3) 2-.

6. 6.: Un compuesto, o una sal farmacéuticamente aceptable del mismo, de acuerdo con una cualquiera de las reivindicaciones 1 a 5, en el que R1 es un grupo seleccionado de metilo, etilo, isopropilo, terc–butilo, ciclopropilo, ciclopentilo, ciclohexilo, –CH2CH2OH, –CH2CH2OMe, –CH2CH2NMe2, –CH2CH2NC(O)CH3, –CH2CONH2, fenilo, 3,5– difluorofenilo, 4–fluorofenilo, 2–clorofenilo, 4–clorofenilo, 2–trifluorometilfenilo, 2–metoxifenilo, 2–metilfenilo, 4– acetamidofenilo, 4–aminofenilo, piridin–4–ilo, piridin–2–ilo, oxetan–3–ilo, 2–oxopirolidin–3–ilo, 1–metilimidazol–5– ilmetilo, 1–metilpirrolidin–3–ilo, tiazol–2–ilo, 4–metiltiazol–2–ilo, y 3–metil–1,3,4–tiadiazol–2–ilo. A compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 5, wherein R1 is a group selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, -CH2CH2OH , –CH2CH2OMe, –CH2CH2NMe2, –CH2CH2NC (O) CH3, –CH2CONH2, phenyl, 3,5– difluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 4-chlorophenyl, 2-trifluoromethylphenyl, 2-methoxyphenyl, 2-methylphenyl - acetamidophenyl, 4-aminophenyl, pyridin-4-yl, pyridin-2-yl, oxetan-3-yl, 2-oxopyrolidin-3-yl, 1-methylimidazole-5-ylmethyl, 1-methylpyrrolidin-3-yl, thiazole -2-yl, 4-methylthiazole-2-yl, and 3-methyl-1,3,4-thiadiazole-2-yl.

7. A compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 6, wherein R2 is

A1

R17 R18

wherein A1 and A2 are selected from CH or N, with the proviso that at least one of A1 or A2 is CH.

8. 8.: Un compuesto, o una sal farmacéuticamente aceptable del mismo, de acuerdo con la reivindicación 7, en el que R17 es hidrógeno. A compound, or a pharmaceutically acceptable salt thereof, according to claim 7, wherein R17 is hydrogen.

9. 9.: Un compuesto, o una sal farmacéuticamente aceptable del mismo, de acuerdo con la reivindicación 7 u 8, en el que R18 es hidrógeno. A compound, or a pharmaceutically acceptable salt thereof, according to claim 7 or 8, wherein R18 is hydrogen.

10. 10.: Un compuesto, o una sal farmacéuticamente aceptable del mismo, de acuerdo con una cualquiera de las reivindicaciones 1 a 8, en el que R19 es hidrógeno o un grupo seleccionado de metilo, etilo, propilo, i–propilo, butilo, i–butilo, t–butilo, pentilo, ciclopropilo, ciclobutilo, ciclopentilo, ciclohexilo,–CH2(ciclopropilo), –CH2CH2NMe2, – CH(CH3)CH2OH, –C(CH3)2CH2OH, –CH2CH2OH, –CH2CH2CH2OH, 4–metilfenilo, 4–clorofenilo, 4–trifluorometilfenilo, 4–fluorofenilo, 4–metoxifenilo, 3,4–difluorofenilo, tien–2–ilo, –CH2(imidazol–2–ilo), –CH2(imidazol–3–ilo), isoxazol–3– ilo, 6–oxo–1H–piridin–2–ilo, 5–metilisoxazol–3–ilo, 1–metilpirazol–4–ilo, –CH2(1–metilpirazol–4–ilo), 6–metoxipiridin– 3–ilo, 5–fluoropiridin–2–ilo, piridinil–2–ilo, pirimidin–2–ilo, y 1H–pirazol–3–ilo. A compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 8, wherein R19 is hydrogen or a group selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2 (cyclopropyl), -CH2CH2NMe2, - CH (CH3) CH2OH, -C (CH3) 2CH2OH, -CH2CH2OH, -CH2CH2CH2OH, 4-methylphenyl, 4-chlorophenyl , 4-trifluoromethylphenyl, 4-fluorophenyl, 4-methoxyphenyl, 3,4-difluorophenyl, thien-2-yl, -CH2 (imidazol-2-yl), -CH2 (imidazol-3-yl), isoxazol-3-yl , 6-oxo-1H-pyridin-2-yl, 5-methylisoxazol-3-yl, 1-methylpyrazole-4-yl, -CH2 (1-methylpyrazole-4-yl), 6-methoxypyridin-3-yl, 5 -Fluoropyridin-2-yl, pyridinyl-2-yl, pyrimidin-2-yl, and 1H-pyrazole-3-yl.

11. eleven.: Un compuesto, o una sal farmacéuticamente aceptable del mismo, de acuerdo con la reivindicación 1, seleccionado de uno cualquiera de 1-Etil-3-[4-[4-[(3S)-3-metilmorfolin-4-il]-6-(metilsulfonilmetil)pirimidina-2-il]fenil]urea, 1-(4-metoxifenil)-3-[4-[4-[(3S)-3-metilmorfolin-4-il]-6-(metilsulfonilmetil)pirimidina-2-il]fenil]urea, 1-[4-[4-[(3S)-3-metilmorfolin-4-il]-6-(metilsulfonilmetil)pirimidina-2-il]fenil]-3-fenil-urea, 3-[4-[4-[(3S)-3-metilmorfolin-4-il]-6-(metilsulfonilmetil)pirimidina-2-il]fenil]-1-propan-2-il-urea, 3-(4-fluorofenil)-1-[4-[4-[(3S)-3-metilmorfolin-4-il]-6-(metilsulfonilmetil)pirimidina-2-il]fenil]urea, 1-[2-fluoro-4-[4-[(3S)-3-metilmorfolin-4-il]-6-(metilsulfonilmetil)pirimidina-2-il]fenil]-3-(4-fluorofenil)urea, 1-[2-fluoro-4-[4-[(3S)-3-metilmorfolin-4-il]-6-(metilsulfonilmetil)pirimidina-2-il]fenil]-3-fenil-urea, 3-(4-fluorofenil)-1-[2-metoxi-4-[4-[(3S)-3-metilmorfolin-4-il]-6-(metilsulfonilmetil)pirimidina-2-il]fenil]urea, 3-[2-metoxi-4-[4-[(3S)-3-metilmorfolin-4-il]-6-(metilsulfonilmetil)pirimidina-2-il]fenil]-1-(4-metoxifenil)urea, 3-(4-fluorofenil)-1-[5-[4-[(3S)-3-metilmorfolin-4-il]-6-(metilsulfonilmetil)pirimidina-2-il]piridina-2-il]urea, 1-etil-3-[5-[4-[(3S)-3-metilmorfolin-4-il]-6-(metilsulfonilmetil)pirimidina-2-il]piridina-2-il]urea, N-[4-[4-[(3S)-3-metilmorfolin-4-il]-6-(metilsulfonilmetil)pirimidina-2-il]fenil]azetidina-1-carboxamida, 1-(2-metoxietil)-1-metil-3-[4-[4-[(3S)-3-metilmorfolin-4-il]-6-(metilsulfonilmetil)pirimidina-2-il]fenil]urea, 1,1-dimetil-3-[4-[4-[(3S)-3-metilmorfolin-4-il]-6-(metilsulfonilmetil)pirimidina-2-il]fenil]urea, 3-[2-metoxi-4-[4-[(3S)-3-metilmorfolin-4-il]-6-(metilsulfonilmetil)pirimidina-2-il]fenil]-1,1-dimetil-urea, 1-metil-3-[4-[4-[(3S)-3-metilmorfolin-4-il]-6-(metilsulfonilmetil)pirimidina-2-il]fenil]urea, 3-[2-fluoro-4-[4-[(3S)-3-metilmorfolin-4-il]-6-(metilsulfonilmetil)pirimidina-2-il]fenil]-1-metil-urea, 3-[2-fluoro-4-[4-[(3S)-3-metilmorfolin-4-il]-6-(metilsulfonilmetil)pirimidina-2-il]fenil]-1,1-dimetil-urea, A compound, or a pharmaceutically acceptable salt thereof, according to claim 1, selected from any one of 1-Ethyl-3- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6 - (Methylsulfonylmethyl) pyrimidine-2-yl] phenyl] urea, 1- (4-methoxyphenyl) -3- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine -2-yl] phenyl] urea, 1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] phenyl] -3-phenyl-urea , 3- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] phenyl] -1-propan-2-yl-urea, 3- ( 4-fluorophenyl) -1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] phenyl] urea, 1- [2-fluoro-4 - [4 - [(3S) -3-Methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] phenyl] -3- (4-fluorophenyl) urea, 1- [2-fluoro-4- [4 - [(3S) -3-Methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] phenyl] -3-phenyl-urea, 3- (4-fluorophenyl) -1- [2- methoxy-4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] phenyl] urea, 3- [2-methoxy-4- [4 - [( 3S) -3-methylmorpholin -4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] phenyl] -1- (4-methoxyphenyl) urea, 3- (4-fluorophenyl) -1- [5- [4 - [(3S) - 3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] pyridine-2-yl] urea, 1-ethyl-3- [5- [4 - [(3S) -3-methylmorpholin-4 -yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] pyridine-2-yl] urea, N- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] phenyl] azetidine-1-carboxamide, 1- (2-methoxyethyl) -1-methyl-3- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (Methylsulfonylmethyl) pyrimidine-2-yl] phenyl] urea, 1,1-dimethyl-3- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2- il] phenyl] urea, 3- [2-methoxy-4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] phenyl] -1,1- dimethyl-urea, 1-methyl-3- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] phenyl] urea, 3- [2- fluoro-4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] phenyl] -1-methyl-urea, 3- [2-fluoro-4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] phenyl] -1, 1-dimethyl urea,

1- [2-Methyl-4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] phenyl] -3-phenyl-urea, 1-ethyl- 3- [2-Methoxy-4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] phenyl] urea, 1- [2-Chloro-4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] phenyl] -3-phenyl-urea, 1- [3- [4 - [(3S) - 3-Methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] phenyl] -3-phenyl-urea, 1-Methyl-1- [4- [4 - [(3S) -3-methylmorfolin- 4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] phenyl] -3-phenyl-urea, 1-Ethyl-3- [2-fluoro-4- [4 - [(3S) -3-methylmorpholin- 4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] phenyl] urea, N- [2-Fluoro-4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl ) pyrimidine-2-yl] phenyl] azetidine-1-carboxamide, 3- [2-fluoro-4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2- il] phenyl] -1-propan-2-yl-urea, 3- [2-methoxy-4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2- il] phenyl] -1-methyl-urea, 1- (2-methoxyethyl) -3- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsul fonylmethyl) pyrimidine-2-yl] phenyl] urea, 1- (2-methoxyethyl) -3- [2-methoxy-4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl ) pyrimidine-2-yl] phenyl] urea, 3- [2-Fluoro-4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] phenyl] -1- (2-methoxyethyl) -1-methyl-urea, 3- [2-fluoro-4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2- il] phenyl] -1- (2-methoxyethyl) urea, 1-Ethyl-3- [4- [4- (hydroxymethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl ] phenyl] urea, 1- [4- [4- (Hydroxymethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3-phenyl-urea, 1- ( 4-methylphenyl) -3- [4- [4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine-2-yl] phenyl] urea, 3- (4-chlorophenyl) -1- [4- [4 - (Methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine-2-yl] phenyl] urea, 1- [4- [4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine-2-yl] phenyl ] -3- [4- (trifluoromethyl) phenyl] urea, 1- (3,5-dimethylphenyl) -3- [4- [4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine-2-yl] phenyl] urea, 3- [2- (difluoromethoxy) phenyl] -1- [4- [4- (methylsulfonylmethyl) -6-morphol in-4-yl-pyrimidine-2-yl] phenyl] urea, 3- (4-fluorophenyl) -1- [4- [4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine-2-yl] phenyl] urea, 3- (3-chloro-4-fluoro-phenyl) -1- [4- [4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine-2-yl] phenyl] urea, 1- [4- [4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine-2-yl] phenyl] -3-phenyl-urea, 1- (4-methoxyphenyl) -3- [4- [4- ( Methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine-2-yl] phenyl] urea, 3- [4- [4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine-2-yl] phenyl] - 1-pentyl-urea, 3- (3,4-difluorophenyl) -1- [4- [4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine-2-yl] phenyl] urea, 3-cyclohexyl- 1- [4- [4- (Methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine-2-yl] phenyl] urea, 1-ethyl-3- [4- [4- (methylsulfonylmethyl) -6-morpholin- 4-yl-pyrimidine-2-yl] phenyl] urea, 3- [4- [4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine-2-yl] phenyl] -1-propyl-urea, 1 - (3-ethylphenyl) -3- [4- [4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine-2-yl] phenyl] urea, 3- (2-furylmethyl) -1- [4- [4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine-2-yl] phenyl] urea, 1- [4- [4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine-2-yl] phenyl] -3- (2-thiophene-2-ylethyl) urea, 1- [4- [ 4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine-2-yl] phenyl] -3-thiophene-2-yl-urea, 3-Cyclopropyl-1- [4- [4- (methylsulfonylmethyl) -6 -morpholin-4-yl-pyrimidine-2-yl] phenyl] urea, 1- [4- [4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine-2-yl] phenyl] -3-tert- Butyl-urea, N- [2 - [[4- [4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine-2-yl] phenyl] carbamoylamino] ethyl] acetamide, 1- (2-dimethylaminoethyl) - 1-methyl-3- [4- [4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine-2-yl] phenyl] urea, 3- (1H-imidazol-2-ylmethyl) -1- [4 - [4- (Methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine-2-yl] phenyl] urea, 1-cyclopropyl-1-methyl-3- [4- [4- (methylsulfonylmethyl) -6-morpholin- 4-yl-pyrimidine-2-yl] phenyl] urea, 1- [4- [4 - [(3S) -3-Methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] phenyl] - 3- (2-methylpropyl) urea, 1- [3- [4 - [(3S) -3-Methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] phenyl] -3-propan-2 -yl-urea, 3-Ethyl-1- [3- [4 - [(3S) -3-methylmorf olin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] phenyl] urea, 1- [2-Chloro-4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] phenyl] -3-ethyl-urea, 3-Methyl-1- [2-methyl-4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] phenyl] urea, 3- [4- [4- (Hydroxymethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -1 , 1-dimethyl-urea, N- [2 - [[6 - [(3S) -3-methylmorpholin-4-yl] -2- [4- (phenylcarbamoylamino) phenyl] pyrimidine-4-yl] methylsulfonyl] ethyl] acetamide, 1- [4- [4- (Benzenesulfonylmethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3-phenyl-urea, 3- [4- [ 4- (Cyanomethylsulfonylmethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -1,1-dimethyl-urea, 1,1-Dimethyl-3- [4- [ 4 - [(3S) -3-methylmorpholin-4-yl] -6- (propan-2-ylsulfonylmethyl) pyrimidine-2-yl] phenyl] urea, 3- [4- [4- (Benzenesulfonylmethyl) -6- [ (3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -1,1-dimethyl-urea, N- [2 - [[2- [4- (Dimethylcarbamoylamino) phenyl] -6- [ (3S) -3-Methylmorpholin-4-yl] pyrimidine-4-yl] methylsulfonyl] ethyl] acetamide, 2 - [[ 2- [4- (Dimethylcarbamoylamino) phenyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-4-yl] methylsulfonyl] acetamide, 1- [4- [4- (Hydroxymethyl) -6- [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3-methyl-urea, 1- [4- [4- (Cyclohexylsulfonylmethyl) -6 - [(3S) -3-methylmorpholin -4-yl] pyrimidine-2-yl] phenyl] -3-methyl-urea, 1- [4- [4- (benzenesulfonylmethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2 -yl] phenyl] -3-methyl-urea, 1- [4- [4 - [(4-fluorophenyl) sulfonylmethyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3-methyl-urea, N- [4 - [[2- [4- (methylcarbamoylamino) phenyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-4-yl] methylsulfonyl] phenyl] acetamide, 3-methyl-1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (propan-2-ylsulfonylmethyl) pyrimidine-2-yl] phenyl] urea, 1 - [4- [4- (2-Hydroxyethylsulfonylmethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3-methyl-urea, 3-methyl-1- [ 4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (pyridine-4-ylsulfonylmethyl) pyrimidine-2-yl] phenyl] urea, 1- [4- [4- (Cyclohexylsulfanylmethyl) - 6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] feni l] -3-methyl-urea, 3-methyl-1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (phenylsulfanylmethyl) pyrimidine-2-yl] phenyl] urea, 1- [4- [4 - [(4-fluorophenyl) sulfanylmethyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3-methyl-urea, N- [ 4 - [[2- [4- (methylcarbamoylamino) phenyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-4-yl] methylsulfanyl] phenyl] acetamide, 3-methyl-1- [4 - [4 - [(3S) -3-Methylmorpholin-4-yl] -6- (propan-2-ylsulfanylmethyl) pyrimidine-2-yl] phenyl] urea, 1- [4- [4- (2-hydroxyethylsulfanylmethyl)] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3-methyl-urea, 3-methyl-1- [4- [4 - [(3S) -3- methylmorpholin-4-yl] -6- (Pyridine-4-ylsulfanylmethyl) pyrimidine-2-yl] phenyl] urea, 3- [4- [4- (Benzenesulfonylmethyl) -6-morpholin-4-yl-pyrimidine-2- il] phenyl] -1-methyl-urea, 3- [4- [4- (benzenesulfonylmethyl) -6-morpholin-4-yl-pyrimidine-2-yl] phenyl] -1-ethyl-urea, 1- [4 - [4- (benzenesulfonylmethyl) -6-morpholin-4-yl-pyrimidine-2-yl] phenyl] -3-cyclopropyl-urea, 3- [4- [4- (benzenesulfonylmethyl) -6-morpholin-4-yl -pyrimidine-2-yl] phenyl] -1- (2-dimethylaminoethyl) urea, 3- [4- [4- (benzenesulfonylmethyl) -6-morpholin-4-yl-pyrimidine-2-yl] phenyl] -1- (1-methyl-4-piperidyl) urea, 3- [4- [4- [4- (benzenesulfonylmethyl) -6-morpholin] 4-yl-pyrimidine-2-yl] phenyl] -1- (2-methoxyethyl) urea, 3- [4- [4- (benzenesulfonylmethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine -2-yl] phenyl] -1-ethyl-urea, 1- [4- [4- (benzenesulfonylmethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] - 3-cyclopropyl-urea, 1- [4- [4- (benzenesulfonylmethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3- (2-dimethylaminoethyl) urea , 1- [4- [4- (benzenesulfonylmethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3- (1-methyl-4-piperidyl) urea, 1- [4- [4- (benzenesulfonylmethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3- (2-methoxyethyl) urea, 3-methyl-1 - [4- [4-morpholin-4-yl-6- (propan-2-ylsulfonylmethyl) pyrimidine-2-yl] phenyl] urea, 1-ethyl-3- [4- [4-morpholin-4-yl- 6- (propan-2-ylsulfonylmethyl) pyrimidine-2-yl] phenyl] urea, 3-cyclopropyl-1- [4- [4-morpholin-4-yl-6- (propan-2-ylsulfonylmethyl) pyrimidine-2- il] phenyl] urea, 3- (2-dimethylaminoethyl) -1- [4 - [4-morpholin-4-yl-6- (propan-2-ylsulfonylmethyl) pyrimidine-2-yl] phenyl] urea, 3- (1-methyl-4-piperidyl) -1- [4- [4-morpholin -4-yl-6- (propan-2-ylsulfonylmethyl) pyrimidine-2-yl] phenyl] urea, 3- (2-methoxyethyl) -1- [4- [4-morpholin-4-yl-6- (propan -2-ylsulfonylmethyl) pyrimidine-2-yl] phenyl] urea, 1-ethyl-3- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (propan-2-ylsulfonylmethyl) pyrimidine-2-yl] phenyl] urea, 3-cyclopropyl-1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (propan-2-ylsulfonylmethyl) pyrimidine-2-yl ] phenyl] urea, 3- (2-dimethylaminoethyl) -1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (propan-2-ylsulfonylmethyl) pyrimidine-2-yl] phenyl] urea, 1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (propan-2-ylsulfonylmethyl) pyrimidine-2-yl] phenyl] -3- (1-methyl -4-piperidyl) urea, 3- (2-methoxyethyl) -1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (propan-2-ylsulfonylmethyl) pyrimidine-2- il] phenyl] urea, 3-Methyl-1- [4- [4- (2-methylsulfonylpropan-2-yl) -6-morpholin-4-yl-pyrimidine-2-yl] phenyl] urea, 1-ethyl- 3- [4- [4- (2-Methylsulfonylpropan-2-yl) -6-morpholin-4-yl-pyrimidine-2-yl] phenyl] urea, 3-cycle propyl-1- [4- [4- (2-methylsulfonylpropan-2-yl) -6-morpholin-4-yl-pyrimidine-2-yl] phenyl] urea, 3- (2-dimethylaminoethyl) -1- [4 - [4- (2-Methylsulfonylpropan-2-yl) -6-morpholin-4-yl-pyrimidine-2-yl] phenyl] urea, 3- (1-methyl-4-piperidyl) -1- [4- [ -4- (2-Methylsulfonylpropan-2-yl) -6-morpholin-4-yl-pyrimidine 2-yl] phenyl] urea, 3- (2-methoxyethyl) -1- [4- [4- (2-methylsulfonylpropan -2-yl) -6-morpholin-4-yl-pyrimidine-2-yl] phenyl] urea, 3-methyl-1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] - 6- (2-Methylsulfonylpropan-2-yl) pyrimidine-2-yl] phenyl] urea, 1-ethyl-3- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- ( 2-Methylsulfonylpropan-2-yl) pyrimidine-2-yl] phenyl] urea, 3-cyclopropyl-1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (2-methylsulfonylpropan -2-yl) pyrimidine-2-yl] phenyl] urea, 3- (2-dimethylaminoethyl) -1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (2- Methylsulfonylpropan-2-yl) pyrimidine-2-yl] phenyl] urea, 1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (2-methylsulfonylpropan-2-yl) pyrimidine -2-yl] phenyl] -3- (1-methyl-4-piperidyl) urea, 3- (2-methoxyethyl) -1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (2- Methylsulfonylpropan-2-1) pyrimidine-2-yl] phenyl] urea, 1- [4- [4 - [(3S) -3-Methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] phenyl ] -3- (1,2-oxazol-3-yl) urea, 1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] phenyl] -3-pyrimidine-2-yl-urea, 1- (2,6-dimethylphenyl) -3- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] phenyl] urea, 1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] phenyl] -3- (6 -oxo-1H-pyridine-2-yl) urea, 3- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] phenyl] -1 - (5-methyl-1,2-oxazol-3-yl) urea, 3- [4- [4 - [(3 S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2- il] phenyl] - 1- (5-methyl-1,2-oxazol-4-yl) urea, 1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl ) pyrimidine-2-yl] phenyl] -3- (1-methylpyrazol-4-yl) urea, 1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] phenyl] -3- (2-oxo-1H-pyridine-4-yl) urea, 3- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) piri midina-2-yl] phenyl] -1- (1,3,5-trimethylpyrazol-4-yl) urea, 1- (3,5-dimethyl-1 H -pyrazol-4-yl) -3- [4- [ 4 - [(3 S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] phenyl] urea, 3-Methyl-l- [1- [4 - [(3S) -3 -methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] -4-piperidyl] urea, 1-ethyl-3- [1- (4 - [(3S) -3-methylmorpholin-4-yl ] -6- (methylsulfonylmethyl) pyrimidine-2-yl] -4-piperidyl] urea,

1- [4- [4 - [(3S) -3-Methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] phenyl] -3- (2-pyridine-2-ylethyl) urea, 1- [4- [4 - [(3S) -3-Methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] phenyl] -3- (pyridine-3-ylmethyl) urea, 3- [2- (1H-imidazol-4-yl) ethyl] -1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] phenyl] urea, 3- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] phenyl] -1 - [(5-methylpyrazin-2-yl) methyl] urea, 1- [4- [4 - [(3S) -3-Methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] phenyl] -3- (pyridine-2-ylmethyl) urea, 1- [4- [4 - [(3S) -3-Methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] phenyl] -3- (pyridine-4-ylmethyl) urea, 3 - [(4-methoxyphenyl) methyl] -1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] phenyl] urea, 1- [4- [4 - [(3S) -3-Methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] phenyl] -3 - [(1-methylpyrazol-4-yl) methyl] area, 3- [4- [4 - [(3S) -3-Methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] phenyl] -1 - [(5-methyl-1,2-oxazol- 3-yl) methyl] urea, 3 - [(3-dimethylaminophenyl) methyl] -1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] phenyl] urea, 1- [4- [4 - [(3S) -3-Methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] phenyl] -3- (1,3-thiazol-5-ylmethyl) urea , 3-methyl-1- [1- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] pyrazol-3-yl] urea, 1-ethyl-3- [1- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] pyrazol-3-yl] urea, 3-cyclopropyl-1- [1- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] pyrazol-3-yl] urea, 3-methyl-1- [1- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (2-methylsulfonylpropan-2-yl) pyrimidine-2-yl] -4-piperidyl] urea, 1-ethyl-3- [1- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (2-methylsulfonylpropan-2-yl) pyrimidine-2-yl] -4-piperidyl] urea, 3-cyclopropyl-1- [1- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (2-methylsulfonylpropan-2-yl) pyrimidine-2-yl] -4-piperidyl] urea, 1- [1- [4 - [(3S) -3-Methylmorpholin-4-yl] -6- (2-methylsulfonylpropan-2-yl) pyrimidine-2-yl] -4-piperidyl] -3 - [(1 -methylpyrazol-4-yl) methyl]

urea, 3-cyclopropyl-1- [5- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] pyridine-2-yl] urea, 1- [4- [4 - [(3S) -3-Methylmorpholin-4-yl] -6- (2-methylsulfonylpropan-2-yl) pyrimidine-2-yl] phenyl] -3- (1,2-oxazol -3-yl) urea, 3- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (2-methylsulfonylpropan-2-yl) pyrimidine-2-yl] phenyl] -1- (5-methyl-1 , 2-oxazol-3-yl) urea, 1- [4- [4 - [(3S) -3-Methylmorpholin-4-yl] -6- (2-methylsulfonylpropan-2-yl) pyrimidine-2-yl] phenyl] -3-pyrimidine-2-yl- urea, 1- [4- [4 - [(3S) -3-Methylmorpholin-4-yl] -6- (2-methylsulfonylpropan-2-yl) pyrimidine-2-yl] phenyl] -3- (1 H -pyrazol-3 -il) urea, 1- [4- [4 - [(3S) -3-Methylmorpholin-4-yl] -6- (2-methylsulfonylpropan-2-yl) pyrimidine-2-yl] phenyl] -3-phenyl-urea, 3- (6-methoxypyridine-3-yl) -1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (2-methylsulfonylpropan-2-yl) pyrimidine-2-yl ] phenyl] urea, 3- (5-fluoropyridine-2-yl) -1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (2-methylsulfonylpropan-2-yl) pyrimidine-2-yl ] phenyl] urea, 1- [5- [4 - [(3S) -3-Methylmorpholin-4-yl] -6- (2-methylsulfonylpropan-2-yl) pyrimidine-2-yl] pyrimidine-2-yl] -3 - [( 1-methylpyrazol-4-yl) methyl]

urea, 3-cyclopropyl-1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] phenyl] urea, 1- [2,6-Difluoro-4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (2-methylsulfonylpropan-2-yl) pyrimidine-2-yl] phenyl] -3- methyl urea, 3- [2,6-Difluoro-4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (2-methylsulfonylpropan-2-yl) pyrimidine-2-yl] phenyl] -1- ethyl urea, 3-cyclopropyl-1- [2,6-difluoro-4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (2-methylsulfonylpropan-2-yl) pyrimidine-2-yl] phenyl ]urea, 1- (2,6-Difluoro-4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (2-methylsulfonylpropan-2-yl) pyrimidine-2-yl] phenyl] -3- [(1-methylpyrazol-4

il) methyl] urea, 1-ethyl-3- [5- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (2-methylsulfonylpropan-2-yl) pyrimidine-2-yl] pyrimidine-2-yl] urea , 3-cyclopropyl-1- [5- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (2-methylsulfonylpropan-2-yl) pyrimidine-2-yl] pyrimidine-2-yl] urea , 3-methyl-1- [5- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (2-methylsulfonylpropan-2-yl) pyrimidine-2-yl] pyridine-2-yl] urea ,

1-ethyl-3- [5- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (2-methylsulfonylpropan-2-yl) pyrimidine-2-yl] pyridine-2-yl] urea , 3-cyclopropyl-1- [5- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (2-methylsulfonylpropan-2-yl) pyrimidine-2-yl] pyridine-2-yl] urea, 3- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (2-methylsulfonylpropan-2-yl) pyrimidine-2-yl] phenyl] -1-propyl-urea, 1- [4- [4 - [(3S) -3-Methylmorpholin-4-yl] -6- (2-methylsulfonylpropan-2-yl) pyrimidine-2-yl] phenyl] -3-propan-2-yl- urea, 3-cyclobutyl-1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (2-methylsulfonylpropan-2-yl) pyrimidine-2-yl] phenyl] urea, 3 - (1-hydroxy-2-methyl-propan-2-yl) -1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (2-methylsulfonylpropan-2-yl) pyrimidine-2-yl] phenyl] urea, 1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (2-methylsulfonylpropan-2-yl) pyrimidine-2-yl] phenyl ] -3- (pyridine-3-ylmethyl) urea, 3 - [(2R) -1-hydroxypropan-2-yl] -1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (2-Methylsulfonylpropan-2-yl) pyrimidine-2-yl] phenyl] urea, 3- (cyclopropylmethyl) -1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] - 6- (2-Methylsulfonylpropan-2-yl ) pyrimidine-2-yl] phenyl] urea, 1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (2-methylsulfonylpropan-2-yl) pyrimidine-2-yl] phenyl] -3- (pyridine-4-ylmethyl) urea, 3- (3-hydroxypropyl1) -1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (2-methyl sulfonylpropan -2-yl) pyrimidine-2-yl] phenyl] urea, 1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (2-methylsulfonylpropan-2-yl) pyrimidine- 2-yl] phenyl] -3- (2-methylpropyl) urea, 3- (1H-imidazol-2-ylmethyl) -1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] - 6- (2-Methylsulfonylpropan-2-yl) pyrimidine-2-yl] phenyl] urea, 1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (2-methylsulfonylpropan- 2-yl) pyrimidine-2-yl] phenyl] -3 - [(1-methylpyrazol-4-yl) methyl] urea, 3- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (2-Methylsulfonylpropan-2-yl) pyrimidine-2-yl] phenyl] -1 - [(5-methyl-1,2-oxazol-3-yl) methyl] urea, 1- [4- [4 - [(35) -3-Methylmorpholin-4-yl] -6- (2-methylsulfonylpropan-2-yl) pyrimidine-2-yl] phenyl] -3- (1-pyridine-3-ylethyl) urea, 1- [4- [4 - [(3S) -3-Methylmorpholin-4-yl] -6- (2-methylsulfonylpropan-2-yl) pyrimidine-2-yl] phenyl] -3- (1 H -pyrazol-3-ylmethyl ) urea, 1- [4- [4 - [(3S) -3-m ethylmorpholin-4-yl] -6- (2-methylsulfonylpropan-2-yl) pyrimidine-2-yl] phenyl] -3 - [(1-methylpyrazol-3-yl) methyl] urea, 1,1-dimethyl-3 - [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (2-methylsulfonylpropan-2-yl) pyrimidine-2-yl] phenyl] urea, N- [4- [4- [(3S) -3-Methylmorpholin-4-yl] -6- (2-methylsulfonylpropan-2-yl) pyrimidine-2-yl] phenyl] morpholine-4-carboxamide, 4-hydroxy-N- [4- [4 - [(3S) -3-Methylmorpholin-4-yl] -6- (2-methylsulfonylpropan-2-yl) pyrimidine-2-yl] phenyl] piperidine-1-carboxamide, 3-hydroxy-N- [4- [ 4 - [(3S) -3-Methylmorpholin-4-yl] -6- (2-methylsulfonylpropan-2-yl) pyrimidine-2-yl] phenyl] piperidine-1-carboxamide, N- [4- (4- [ (3S) -3-Methylmorpholin-4-yl] -6- (2-methylsulfonylpropan-2-yl) pyrimidine-2-yl] phenyl] azetidine-1-carboxamide, 3-hydroxy-N- [4- [4- [(3S) -3-Methylmorpholin-4-yl] -6- (2-methylsulfonylpropan-2-yl) pyrimidine-2-yl] phenyl] azetidine-1-carboxamide, 1-cyclopropyl-1-methyl-3- [ 4- [4 - [(3S) -3-Methylmorpholin-4-yl] -6- (2-methylsulfonylpropan-2-yl) pyrimidine-2-yl] phenyl] urea, 3-methyl-1- [5- [ 4 - [(3S) -3-methylmorpholin-4-yl] -6- (2-methylsulfonylpropan-2-yl ) pyrimidine-2-yl] pyrimidine-2-yl] urea, 1- [5- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (2-methylsulfonylpropan-2-yl) pyrimidine- 2-yl] pyridine-2-yl] -3 - [(1-methylpyrazol-4

il) methyl] urea, 3- (2-hydroxyethyl) -1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (2-methylsulfonylpropan-2-yl) pyrimidine-2 -yl] phenyl] urea, 1- [1- [4 - [(3S) -3-Methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] pyrazol-3-yl] -3-phenyl -urea, 3- (4-methoxyphenyl) -1- [1- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] pyrazol-3-yl] urea, 3- (4-fluorophenyl) -1- [1- [4 - [(35) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] pyrazol-3-yl] urea , N- [Methyl-2 - [[2- [4- (methylcarbamoylamino) phenyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-4-yl] methylsulfonyl] acetamide, 2 - [[ 2- [4- (methylcarbamoylamino) phenyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-4-yl] methylsulfonyl] acetamide, N- [2 - [[2- [4- (methylcarbamoylamino) ) phenyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-4-yl] methylsulfonyl] ethyl] acetamide, N-Methyl-2 - [[2- [4- (methylcarbamoylamino) phenyl] - 6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-4-yl] methylsulfanyl] acetamide, 2 - [[2- [4- (methylcarbamoylamino) phenyl] -6 - [(3S) -3-methylmorpholin -4-yl] pyrimidine-4-yl] methylsulfanyl] acetamide, N- [2 - [[2- [4- (methylcarbamoylamino) phenyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-4-yl] methylsulfanyl] ethyl] acetamide, 1- [4 - [4 - [(3S) -3-Methylmorpholin-4-yl] -6- (morpholin-4-ylmethyl) pyrimidine-2-yl] phenyl] -3-phenyl-urea, 1- [4- [4- [(3S) -3-Methylmorpholin-4-yl] -6- (phenoxymethyl) pyrimidine-2-yl] phenyl] -3-phenyl-urea, 1- [4- [4 - [(3S) -3-Methylmorpholin -4-yl] -6 - [(2-oxopyrrolidine-3-yl) sulfonylmethyl] pyrimidine-2-yl] phenyl] -3-phenyl-urea, 1- [4- [4 - [(3S) -3- Methylmorpholin-4-yl] -6 - [(2-oxopyrrolidine-3-yl) sulfanylmethyl] pyrimidine-2-yl] phenyl] -3-phenyl-urea, 1- [4- [4- (Anilinomethyl) -6- [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3-phenyl-urea, 1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] - 6 - [(4-methylpiperazin-1-yl) methyl] pyrimidine-2-yl] phenyl] -3-phenyl-urea, 1- (4- [4 - [(cyclopropylamino) methyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3-phenyl-urea, 1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6 - [[ (1-methyl-4-piperidyl) amino] methyl] pyrimidine-2-yl] phenyl] -3-phenyl-urea, 1- [4- [4 - [(cyclopropyl-methyl-amino) methyl] -6- [ (3S) -3-methylmorph lin-4-yl] pyrimidine-2-yl] phenyl] -3-phenyl-urea, 1- [4- [4 - [(3S) -3-Methylmorpholin-4-yl] -6 - [(1-methyl -4-piperidyl) oxymethyl] pyrimidine-2-yl] phenyl] -3-phenyl-urea, 1- [4- [4- (Methoxymethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine -2-yl] phenyl] -3-phenyl-urea, 3-Methyl-1- [4- [4 - [(1-methylimidazol-2-yl) sulfonylmethyl] -6 - [(3S) -3-methylmorpholin- 4-yl] pyrimidine-2-yl] phenyl] urea, 1- [4- [4 - [(2-chlorophenyl) sulfonylmethyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2- il] phenyl] -3-methyl-urea, 1- [4- (4 - [(2-methoxyphenyl) sulfonylmethyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl ] -3-methyl-urea, 1- [4- [4- (1H-imidazol-2-ylsulfonylmethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] - 3-methyl-urea, 1- [4- [4 - [(4-aminophenyl) sulfonylmethyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3-methyl -urea, 3-methyl-1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6 - [(2-methylphenyl) sulfonylmethyl] pyrimidine-2-yl] phenyl] urea, 3 -methyl-1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (pyridine-2-ylsulfonylmethyl) pyrimidine-2-yl] phenyl] urea, 3-methyl-1- [4- [4 - [(3S) -3-m ethylmorpholin-4-yl] -6- (1,3-thiazol-2-ylsulfonylmethyl) pyrimidine-2-yl] phenyl] urea, 3-methyl-1- [4- [4 - [(3S) -3-methylmorpholin -4-yl] -6 - [(4-methyl-1,3-thiazol-2-yl) sulfonylmethyl] pyrimidine-2-yl] phenyl] urea, 3-Methyl-1- [4- [4 - [( 1-methylimidazol-2-yl) sulfanylmethyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] urea, 1- [4- [4 - [(2-chlorophenyl) sulfanylmethyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3-methyl-urea, 1- [4- [4 - [(2-methoxyphenyl) sulfanylmethyl] - 6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3-methyl-urea, 1- [4- [4- (1H-imidazol-2-ylsulfanylmethyl) -6- [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3-methyl-urea, 1- [4- [4 - [(4-aminophenyl) sulfanylmethyl] -6 - [(3S ) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3-methyl-urea, 3-methyl-1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6 - [(2-methylphenyl) sulfanylmethyl] pyrimidine-2-yl] phenyl] urea, 3-methyl-1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- ( pyridine-2-ylsulfanylmethyl) pyrimidine-2-yl] phenyl] urea, 3-methyl-1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (1,3-thiazole -2-ilsulfanilme til) pyrimidine-2-yl] phenyl] urea, 3-methyl-1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6 - [(4-methyl-1,3- thiazol-2-yl) sulfanylmethyl] pyrimidine-2-yl] phenyl] urea, [4- [4- (Methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine-2-yl] phenyl] urea, 1- [4 - [4- (Methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine-2-yl] phenyl] -3- (1,2-oxazol-3-yl) urea, 1- (5-methyl-1,2 -oxazol-3-yl) -3- [4- [4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine-2-yl] phenyl] urea, 1- (1-methylpyrazol-3-yl) - 3- [4- [4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine-2-yl] phenyl] urea, 3- (1-Hydroxypropan-2-yl) -1- [4- [4- [(3S) -3-Methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] phenyl] urea, 3- (3-dimethylaminopropyl) -1- [4- [4 - [(3S) - 3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] phenyl] urea, 3- (3-methoxypropyl) -1- [4- [4 - [(3S) -3-methylmorpholin-4 -yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] phenyl] urea, N- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2- il] phenyl] pyrrolidinae-1-carboxamide, N- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl ) pyrimidine-2-yl] phenyl] morpholine-4-carboxamide, 4-hydroxy-N- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2- il] phenyl] piperidine-1-carboxamide, 1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] phenyl] -3-tert- butyl-urea, 3- (2-dimethylaminoethyl) -1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] phenyl] urea, 3 - (2-hydroxyethyl) -1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] phenyl] urea, 3-hydroxy-N- [4- [4 - [(3S) -3-Methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] phenyl] piperidine-1-carboxamide, 1- (2-dimethylaminoethyl) -1-methyl -3- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] phenyl] urea, 1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] phenyl] -3- (2-morpholin-4-ylethyl) urea, 3- (1H-imidazol-2-ylmethyl) -1 - [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] phenyl] urea, 1-cyclopropyl-1-methyl-3- [4- [ 4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsu lfonylmethyl) pyrimidine-2-yl] phenyl] urea, (3S) -3-methyl-N- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2 -yl] phenyl] morpholine-4-carboxamide, 3-Cyclopropyl-1- [4- [4 - [(3S) -3-methylmorfoline-4-carbonyl] -6 - [(3S) -3-methylmorpholin-4- il] pyrimidine-2-yl] phenyl] urea, N-cyclopropyl-2- [4- (cyclopropylcarbamoylamino) phenyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-4-carboxamide, 3- cyclopropyl-1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (4-methylpiperazine-1-carbonyl) pyrimidine-2-yl] phenyl] urea, 3-Cyclopropyl-1 - [4- [4- (2-hydroxypropan-2-yl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] urea, 1- [4- [4- (2-Hydroxypropan-2-yl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3 - [(1-methylpyrazol-4-yl) methyl] urea, 1- [4- [4- (Hydroxymethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3- (1,2-oxazol-3-yl) urea , N- [2 - [[6 - [(3S) -3-methylmorpholin-4-yl] -2- [4- (1,2-oxazol-3-ylcarbamoylamino) phenyl] pyrimidine-4-yl] methylsulfonyl] ethyl] acetamide, 1- [4- [4- (2-hydroxyethylsulfonylmethyl) -6 - [(3S) -3-methylmorpholin-4-i l] pyrimidine-2-yl] phenyl] -3- (1,2-oxazol-3-yl) urea, 1- [4- [4- (2-Hydroxypropan-2-yl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3- (1,2-oxazol-3-yl) urea, 3-Cyclopropyl-1- [4- [4- (hydroxymethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] urea, 3-Cyclopropyl-1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] - 6- (pyridine-4-ylsulfonylmethyl) pyrimidine-2-yl] phenyl] urea, 2 - [[2- [4- (cyclopropylcarbamoylamino) phenyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine -4-yl] methylsulfonyl] -N-methyl-acetamide, 3-cyclopropyl-1- [4- [4 - [(4-fluorophenyl) sulfonylmethyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] urea, N- [4 - [[2- [4- (cyclopropylcarbamoylamino) phenyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-4-yl] methylsulfonyl ] phenyl] acetamide, 3-cyclopropyl-1- [4- [4- (2-hydroxyethylsulfonylmethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] urea, 3- cyclopropyl-1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (1,3-thiazol-2-ylsulfonylmethyl) pyrimidine-2-yl] phenyl] urea, 3-cyclopropyl -1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6 - [[2- (trifluorome til) phenyl] sulfonylmethyl) pyrimidine-2-yl] phenyl] urea, 3-cyclopropyl-1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6 - [(5-methyl- 1,3,4-thiadiazol-2-yl) sulfonylmethyl] pyrimidine-2-yl] phenyl] urea, 2 - [[2- [4- (cyclopropylcarbamoylamino) phenyl] -6 - [(3S) -3-methylmorpholin- 4-yl] pyrimidine-4-yl] methylsulfonyl] acetamide, 3-cyclopropyl-1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6 - [(4-methyl-1, 3-thiazol-2-yl) sulfonylmethyl] pyrimidine-2-yl] phenyl] urea, N- [2 - [[2- [4- (cyclopropylcarbamoylamino) phenyl] -6 - [(3S) -3-methylmorpholin-4 -yl] pyrimidine-4-yl] methylsulfonyl] ethyl] acetamide, 1- [4- [4- (1-adamantylsulfonylmethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3-cyclopropyl-urea, 3-Cyclopropyl-1- [4- [4- (3-hydroxypropylsulfonylmethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] urea, 3-Cyclopropyl-1- [4- [4- (3-hydroxypropylsulfanylmethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] urea, 1- (2- Hydroxyethyl) -1-methyl-3- [4- [4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine-2-yl] phenyl] urea, N- [4- [4- (methylsulfonylmethyl) -6 -morpholin-4-i l-pyrimidin-2-yl] fenii] piperidine-1-carboxamide, 1- (2-methylpropyl) -3- [4- [4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine-2-yl] phenyl] urea, 1- (3-methoxypropyl) -3- [4- [4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine-2-yl] phenyl] urea, 1- (4-dimethylaminobutyl) - 3- [4- [4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine-2-yl] phenyl] urea, 1- [4- [4- (methylsulfonylmethyl) -6-morpholin-4-yl- pyrimidine-2-yl] phenyl] -3- [2- (2-oxoimidazolidine-1-yl) ethyl] urea, N- [4- [4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine-2 -yl] phenyl] pyrrolidinae-1-carboxamide, N- [4- [4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine-2-yl] phenyl] morpholine-4-carboxamide, 4-hydroxy-N - [4- [4- (Methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine-2-yl] phenyl] piperidine-1-carboxamide, 1- (1-methoxypropan-2-yl) -3- [4- [4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine-2-yl] phenyl] urea, 1- (2-dimethylaminoethyl) -3- [4- [4- [methylsulfonylmethyl) -6-morpholin-4 -yl-pyrimidine-2-yl] phenyl] urea, 3- (2-hydroxyethyl) -1- [4- [4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine-2-yl] phenyl] urea, 1-ethyl-1-methyl-3- [4- [4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine-2-yl] phenyl] urea, 3-hydroxy-N- [4 - [4- (Methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine-2-yl] phenyl] piperidine-1-carboxamide, 3-methylsulfonyl-N- [4- [4- (methylsulfonylmethyl) -6-morpholin- 4-yl-pyrimidine-2-yl] phenyl] pyrrolidinae-1-carboxamide, 1- [4- [4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine-2-yl] phenyl] -3- ( 2-morpholin-4-ylethyl) urea, 1- (2,2-dimethylpropyl) -3- [4- [4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine-2-yl] phenyl] urea, 3- (3-hydroxypropyl) -1- [4- [4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine-2-yl] phenyl] urea, 1-benzyl-1-methyl-3- [4 - [4- (Methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine-2-yl] phenyl] urea, 1- (2-ethoxyethyl) -3- [4- [4- (methylsulfonylmethyl) -6-morpholin- 4-yl-pyrimidine-2-yl] phenyl] urea, 1- (1-hydroxypropan-2-yl) -3- [4- [4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine-2- il] phenyl] urea, 1- [4- [4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine-2-yl] phenyl] -3- (oxan-4-yl) urea, N- [4 - [4- (methylsulfonylmethyl) -6-morphol in-4-yl-pyrimidine-2-yl] phenyl] -3-oxo-piperazine-1-carboxamide, 1- [2- (4-methylpiperazin-1-yl) ethyl] -3- [4- [4- (Methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine-2-yl] phenyl] urea, 1-methyl-1- (2-methylsulfonylethyl) -3- [4- [4- (methylsulfonylmethyl) -6-morpholin- 4-yl-pyrimidine-2-yl] phenyl] urea, N'-methyl-N- [4- [4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine-2-yl] phenyl] piperidine-1 , 4-dicarboxamide, N, N-dimethyl-2 - [[4- [4- (methylsulfonylmethyl) -6-morpholin-4-yl-pyrimidine-2-yl] phenyl] carbamoylamino] acetamide, 4-methyl-N- [4- [4 - [(3S) -3-Methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] phenyl] -3-oxo-piperazine-1-carboxamide, 4-dimethylamino-N- [4- [4 - [(3S) -3-Methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] phenyl] piperidine-1-carboxamide, 3-Methyl-1- [5- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] -1,3-thiazol-2-yl] urea, 1- [5- [4 - [(3S ) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] -1,3-thiazol-2-yl] -3-propan-2-yl-urea, 1-ethyl-3- [5- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsul fonylmethyl) pyrimidine-2-yl] -1,3-thiazol-2-yl] urea, 1- [5- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine- 2-yl] -1,3-thiazol-2-yl] -3-phenyl-urea, 3- (4-fluorophenyl) -1- [5- [4 - [(3S) -3-methylmorpholin-4-yl ] -6- (methylsulfonylmethyl) pyrimidine-2-yl] -1,3-thiazol-2-yl] urea, 1-cyclopropyl-1-methyl-3- [5- [4 - [(3S) -3-methylmorpholin -4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] -1,3-thiazol-2-yl] urea, 3- (4-methoxyphenyl) -1- [5- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] -1,3-thiazol-2-yl] urea, 3- (2-dimethylaminoethyl) -1- [5- [4- [(3S) -3-Methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] -1,3-thiazol-2-yl] urea, 1- [5- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] -1,3-thiazol-2-yl] -3- (1-methylpyrazol-4-yl) urea, 3-cyclopropyl- 1- [5- [4 - [(3S) -3-Methylmorpholin-4-yl] -6- (methylsulfonylmethyl) pyrimidine-2-yl] -1,3-thiazol-2-yl] urea, 3-Methyl- 1- [5- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (2-methylsulfonylpropan-2-yl) pyrimidine-2-yl] -1,3-thiazol-2-yl] urea, 3-cyclopropyl-1- [5- [4 - [(3S) -3- methylmorpholin-4-yl] -6- (2-methylsulfonylpropan-2-yl) pyrimidine-2-yl] -1,3-thiazol-2-yl] urea, 1- [5- [4 - [(3S) - 3-methylmorpholin-4-yl] -6- (2-methylsulfonylpropan-2-yl) pyrimidine-2-yl] -1,3-thiazol-2-yl] -3- (1-methylpyrazol-4-yl) urea , 1- [5- [4 - [(3S) -3-Methylmorpholin-4-yl] -6- (2-methylsulfonylpropan-2-yl) pyrimidine-2-yl] -1,3-thiazol-2-yl ] -3 - [(1-methylpyrazol-4-yl)

methyl] urea, 1-ethyl-3- [5- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (2-methylsulfonylpropan-2-yl) pyrimidine-2-yl] -1, 3-thiazol-2-yl] urea, 3-Cyclobutyl-1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (pyridine-4-ylsulfonylmethyl) pyrimidine-2-yl ] phenyl] urea, 3-ethyl-1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (pyridine-4-ylsulfonylmethyl) pyrimidine-2-yl] phenyl] urea, 3- (2-dimethylaminoethyl) -1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (pyridine-4-ylsulfonylmethyl) pyrimidine-2-yl] phenyl] urea, 3 -Cyclopropyl-1- [4- [4 - [(cyclopropylamino) methyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] urea, 3-Cyclopropyl-1- [ 4- [4 - [(2-hydroxyethyl-methyl-amino) methyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] urea, 3-Cyclopropyl-1- [ 4- [4 - [(3S) -3-methylmorpholin-4-yl] -6 - [(4-methylpiperazin-1-yl) methyl] pyrimidine-2-yl] phenyl] urea, 3-Cyclopropyl-1- [ 4- [4 - [(2-Methoxyethylamino) methyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] urea, 3-Cyclopropyl-1- [4- [4 - (dimethylaminomethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] urea, 3-Cyclopropyl-1- [ 4- [4 - [(3-dimethylaminopropylamino) methyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] urea, 3-Cyclopropyl-1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (morpholin-4-ylmethyl) pyrimidine-2-yl] phenyl] urea, 3-Cyclopropyl-1- [4- [4 - [(2- dimethylaminoethylamino) methyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] urea, 3-Cyclopropyl-1- [4- [4 - [(4-methyl-1, 4-diazepan-1-yl) methyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] urea, 3-Cyclopropyl-1- [4- [4 - [[ (1-hydroxy-2-methyl-propan-2-yl) amino] methyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] urea, 3-Cyclopropyl-1 - [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6 - [(3-oxopiperazin-1-yl) methyl] pyrimidine-2-yl] phenyl] urea, 3-Cyclopropyl-1 - [4- [4 - [(3-hydroxyazetidine-1-yl) methyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] urea, 3-Cyclopropyl-1 - [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6 - [[(3S) -3-methylmorpholin-4-yl] methyl] pyrimidine-2-yl] phenyl] urea, 3 -Cyclopropyl-1- [4- [4 - [(1,1-dioxo-1,4-thiazinan-4-yl) methyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2 -yl] phenyl] urea, 1- [4- [4- (Hydroxymethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3 - [(1-methylpyrazol-4-yl) methyl] urea, 1- [4- [4 - [(3S) -3-Methylmorpholin-4-yl] -6 - [(4-methylpiperazin-1-yl) methyl] pyrimidine-2-yl] phenyl] -3 - [(1 -methylpyrazol-4-yl) methyl] urea, 1- [4- [4 - [(cyclopropylamino) methyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] - 3 - [(1-methylpyrazol-4-yl) methyl] urea, 1- [4- [4 - [(cyclopropyl-methyl-amino) methyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3 - [(1-methylpyrazol-4-yl) methyl] urea, N- [2 - [[6 - [(3S) -3-methylmorpholin-4-yl] -2- [4 - [(1-methylpyrazol-4-yl) methylcarbamoylamino] phenyl] pyrimidine-4-yl] methylsulfonyl] ethyl]

acetamide,

2 - [[6 - [(3S) -3-methylmorpholin-4-yl] -2- [4 - [(1-methylpyrazol-4-yl) methylcarbamoylamino] phenyl] pyrimidine-4-yl] methylsulfonyl] acetamide, 1 - [4- [4- (2-hydroxyethylsulfonylmethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3 - [(1-methylpyrazol-4-yl) methyl ] urea, 1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (pyridine-4-ylsulfonylmethyl) pyrimidine-2-yl] phenyl] -3 - [(1-methylpyrazole -4-yl) methyl] urea, N- [2 - [[6 - [(3S) -3-Methylmorpholin-4-yl] -2- [4 - [(1-methylpyrazol-4-yl) methylcarbamoylamino] phenyl ] pyrimidine-4-yl] methylsulfanyl] ethyl]

acetamide,

2 - [[6 - [(3S) -3-methylmorpholin-4-yl] -2- [4 - [(1-methylpyrazol-4-yl) methylcarbamoylamino] phenyl] pyrimidine-4-yl] methylsulfanyl] acetamide, 1 - [4- (4- (2-hydroxyethylsulfanylmethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3 - [(1-methylpyrazol-4-yl) methyl ]urea,

1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (pyridine-4-ylsulfanylmethyl) pyrimidine-2-yl] phenyl] -3 - [(1-methylpyrazole-4- il) methyl] urea, 3-Cyclopropyl-1- [4- [4- (methoxymethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] urea, 3-Cyclopropyl -1- [4- [4- (cyclopropylsulfonylmethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] urea, 3-Cyclopropyl-1- [4- [4- (2-Cyclopropylsulfonylpropan-2-yl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] urea, 1- [4- [4- (2-Cyclopropylsulfonylpropan-2- il) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3-methyl-urea, 1- [4- [4- (2-cyclopropylsulfonylpropan-2-yl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3- (1-hydroxy-2-methyl

propan-2-yl) urea, 1- [4- [4- (2-cyclopropylsulfonylpropan-2-yl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] - 3- (2-dimethylaminoethyl) urea, 1- [4- [4- (2-cyclopropylsulfonylpropan-2-yl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3- (1-methylpyrazol-4-yl) urea, 1- [4- [4- (cyclopropylsulfonylmethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] - 3-methyl-urea, 1- [4- [4- (cyclopropylsulfonylmethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3- (1-hydroxy-2 -methyl-propan-2-yl) urea, 1- [4- [4- (cyclopropylsulfonylmethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3- ( 2-dimethylaminoethyl) urea, 1- [4- [4- (cyclopropylsulfonylmethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3- (1-methylpyrazole-4 -yl) urea, 3-cyclobutyl-1- [4- [4- (2-cyclopropylsulfonylpropan-2-yl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] urea, 1- [4- [4- (2-cyclopropylsulfonylpropan-2-yl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3- (2-hydroxyethyl ) urea, 1- [4- [4- (cyclopropylsulfonylmethyl) -6 - [(3S) -3-m ethylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3-ethyl-urea, 1- [4- [4- (2-cyclopropylsulfonylpropan-2-yl) -6 - [(3S) -3-methylmorpholin- 4-yl] pyrimidine-2-yl] phenyl] -3-ethyl-urea, 3-cyclobutyl-1- [4- [4- (cyclopropylsulfonylmethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] urea, 3-Methyl-1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (2-pyridine-4-ylsulfonylpropan-2-yl ) pyrimidine-2-yl] phenyl] urea, 3-ethyl-1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (2-pyridine-4-ylsulfonylpropan-2- il) pyrimidine-2-yl] phenyl] urea, 3-cyclopropyl-1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (2-pyridine-4-ylsulfonylpropan-2 -yl) pyrimidine-2-yl] phenyl] urea, 3-cyclobutyl-1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (2-pyridine-4-ylsulfonylpropan- 2-yl) pyrimidine-2-yl] phenyl] urea, 3- (2-hydroxyethyl) -1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (2-pyridine -4-ylsulfonylpropan-2-yl) pyrimidine-2-yl] phenyl] urea, 3- (2-dimethylaminoethyl) -1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6 - (2-Pyridine-4-ylsulfonylpropan-2-yl) pyrimidine-2-yl] phenyl] urea, 3-Ethyl-1- [4- [4- (2-hydroxyethylsulfonylm ethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] urea, 3-cyclobutyl-1- [4- [4- (2-hydroxyethylsulfonylmethyl) -6 - [( 3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] urea, 3- (2-dimethylaminoethyl) -1- [4- [4- (2-hydroxyethylsulfonylmethyl) -6 - [(3S) - 3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] urea, 3-Cyclobutyl-1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (propan-2 -ilsulfonylmethyl) pyrimidine-2-yl] phenyl] urea, 3- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (propan-2-ylsulfonylmethyl) pyrimidine-2-yl] phenyl] -1-propyl-urea, 1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (propan-2-ylsulfonylmethyl) pyrimidine-2-yl] phenyl] -3 - (2-methylpropyl) urea, 3- (3-hydroxypropyl) -1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (propan-2-ylsulfonylmethyl) pyrimidine-2 -yl] phenyl] urea, 1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (propan-2-ylsulfonylmethyl) pyrimidine-2-yl] phenyl] -3- [ 4- (trifluoromethyl) phenyl] urea, 1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6-propan-2-ylsulfonylmethyl) pyrimidine-2-yl] phenyl] -3- pyridine-2-yl-urea, 1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (propan-2-ylsulfon ilmethyl) pyrimidine-2-yl] phenyl] -3-propan-2-yl-urea, 3- (1-hydroxy-2-methyl-propan-2-yl) -1- [4- [4 - [(3S ) -3-methylmorpholin-4-yl] -6- (propan-2-ylsulfonylmethyl) pyrimidine-2-yl] phenyl] urea, 1- [4- [4 - [(3S) -3-methylmorpholin-4-yl ] -6- (propan-2-ylsulfonylmethyl) pyrimidine-2-yl] phenyl] -3- (1-methylpyrazol-4-yl) urea, 3-methyl-1- [4- [4 - [(3S) - 3-methylmorpholin-4-yl] -6- (2-propan-2-ylsulfonylpropan-2-yl) pyrimidine-2-yl] phenyl] urea, 1-ethyl-3- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (2-propan-2-ylsulfonylpropan-2-yl) pyrimidine-2-yl] phenyl] urea, 1- [4- [4 - [(3S) -3- methylmorpholin-4-yl] -6- (2-propan-2-ylsulfonylpropan-2-yl) pyrimidine-2-yl] phenyl] -3-propan-2-yl-urea, 3-cyclopropyl-1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (2-propan-2-ylsulfonylpropan-2-yl) pyrimidine-2-yl] phenyl] urea, 3-cyclobutyl-1- [4 - [4 - [(3S) -3-methylmorpholin-4-yl] -6- (2-propan-2-ylsulfonylpropan-2-yl) pyrimidine-2-yl] phenyl] urea, 3- (2-hydroxyethyl) -1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (2-propan-2-ylsulfonylpropan-2-yl) pyrimidine-2-yl] phenyl] urea, 3- (1-hydroxy-2-methyl-propan-2-yl ) -1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (2-propan-2-ylsulfonylpropan-2-yl) pyrimidine-2

il] phenyl] urea, 3- (2-dimethylaminoethyl) -1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (2-propan-2-ylsulfonylpropan-2-yl ) pyrimidine-2-yl] phenyl] urea, 3- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (2-propan-2-ylsulfonylpropan-2-yl) pyrimidine- 2-yl] phenyl] -1-propyl-urea, 1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (2-propan-2-ylsulfonylpropan-2-yl) pyrimidine-2-yl] phenyl] -3- (2-methylpropyl) urea, 3- (3-hydroxypropyl) -1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (2-propan-2-ylsulfonylpropan-2-yl) pyrimidine-2-yl] phenyl] urea, 1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (2- propan-2-ylsulfonylpropan-2-yl) pyrimidine-2-yl] phenyl] -3- [4- (trifluoromethyl) phenyl] urea, 1- [4- [4 - [(3S) -3-methylmorpholin-4- il] -6- (2-propan-2-ylsulfonylpropan-2-yl) pyrimidine-2-yl) phenyl] -3-pyridine-2-yl-urea, 1- [4- [4 - [(3S) - 3-methylmorpholin-4-yl] -6- (2-propan-2-ylsulfonylpropan-2-yl) pyrimidine-2-yl] phenyl] -3- (1-methylpyrazol-4-yl) urea, 3-Cyclobutyl- 1- [4- [4 - [(4-fluorophenyl) sulfonylmethyl] -6 - ((3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] urea, 1-ethyl-3- [4 - [4 - [(4-fluorophenyl) sulfo nylmethyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] urea, 1- [4- [4 - [(4-fluorophenyl) sulfonylmethyl] -6 - [(3S ) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3-propan-2-yl-urea, 1- [4- [4 - [(4-fluorophenyl) sulfonylmethyl] -6 - [( 3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3- (2-hydroxyethyl) urea, 1- [4- [4 - [(4-fluorophenyl) sulfonylmethyl] -6 - [( 3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3- (1-hydroxy-2-methyl-propan-2-yl) urea, 3- (2-dimethylaminoethyl) -1- [ 4- [4 - [(4-fluorophenyl) sulfonylmethyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] urea, 3- [4- [4 - [(4 -fluorophenyl) sulfonylmethyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -1-propyl-urea, 1- [4- [4 - [(4-fluorophenyl) sulfonylmethyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3- (2-methylpropyl) urea, 1- [4- [4 - [(4-nuorophenyl) sulfonylmethyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3- (3-hydroxypropyl) urea, 1- [4- [4 - [(4-fluorophenyl) sulfonylmethyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3- [4- (trifluoromethyl) phenyl] urea, 1- [4- [4 - [(4-fluorophenyl) sulfonylmethyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3-pyridine-2-yl-urea , 1- [4- [4- [2- (4-fluorophenyl) sulfonylpropan-2-yl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3- methyl urea, 1-ethyl-3- [4- [4- [2- (4-fluorophenyl) sulfonylpropan-2-yl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2- il] phenyl] urea, 1- [4- [4- [2- (4-fluorophenyl) sulfonylpropan-2-yl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3-propan-2-yl-urea, 3-cyclobutyl-1- [4- [4- [2- (4-fluorophenyl) sulfonylpropan-2-yl] -6 - [(3S) -3-methylmorpholin -4-yl] pyrimidine-2-yl] phenyl] urea, 3- (2-dimethylaminoethyl) -1- [4- [4- [2- (4-fluorophenyl) sulfonylpropan-2-yl] -6 - [( 3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] urea, 1- [4- [4- [2- (4-fluorophenyl) sulfonylpropan-2-yl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3- (2-hydroxyethyl) urea, 3-cyclopropyl-1- [4- [4- [2- (4-fluorophenyl) sulfonylpropan-2 -il] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] urea, 3-Cyclopropyl-1- [4- [4- (2-ethylsulfonylpropan-2-yl) -6 - [(3S) -3- methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] urea, 1- [4- [4- (2-ethylsulfonylpropan-2-yl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine -2-yl] phenyl] -3-methyl-urea, 1-ethyl-3- [4- [4- (2-ethylsulfonylpropan-2-yl) -6 - [(3S) -3-methylmorpholin-4-yl ] pyrimidine-2-yl] phenyl] urea, 3- (2-dimethylaminoethyl) -1- [4- [4- (2-ethylsulfonylpropan-2-yl) -6 - [(3S) -3-methylmorpholin-4- il] pyrimidine-2-yl] phenyl] urea, 1- [4- [4- (2-ethylsulfonylpropan-2-yl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl ] phenyl] -3- (2-hydroxyethyl) urea, 3-cyclobutyl-1- [4- [4- (2-ethylsulfonylpropan-2-yl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] urea, 3-cyclobutyl-1- [4- [4- (ethylsulfonylmethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] urea , 1-ethyl-3- [4- [4- (ethylsulfonylmethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] urea, 3- (2-dimethylaminoethyl) - 1- [4- [4- (ethylsulfonylmethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] urea, 3-Cyclopropyl-1- [4- [4- [ (3S) -3-Methylmorpholin-4-yl] -6- (morpholine-4-carbonyl) pyrimidine-2-yl] phenyl] urea, 3-cyclopropyl-1- [4 - [4- (1,4-diazepane-1-carbonyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] urea, 3-cyclopropyl-1- [4- [4- (1,1-dioxo1,4-thiazinane-4-carbonyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] urea, 3-cyclopropyl-1- [4- [4 - [(2R, 6S) -2,6-dimethylmorfoline-4-carbonyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] urea, 2 - [4- (cyclopropylcarbamoylamino) phenyl] -N, N-dimethyl-6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-4-carboxamide, 2- [4- (cyclopropylcarbamoylamino) phenyl] -N- (2-hydroxyethyl) -N-methyl-6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-4-carboxamide, 2- [4- (cyclopropylcarbamoylamino) phenyl] -N- (2-methoxyethyl) - 6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-4-carboxamide, 2- [4- (cyclopropylcarbamoylamino) phenyl] -N-methyl-6 - [(3S) -3-methylmorpholin-4-yl ] -N- (1-methylpyrrolidine-3-yl) pyrimidine

4-carboxamide, 3-cyclopropyl-1- [4- [4- (4-hydroxypiperidine-1-carbonyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] urea , 1- [4- [4- (azepane-1-carbonyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3-cyclopropyl-urea, 2- [ 4- (cyclopropylcarbamoylamino) phenyl] -N-ethyl-6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-4-carboxamide, 2- [4- (cyclopropylcarbamoylamino) phenyl] -N- (2-dimethylaminoethyl ) -N-methyl-6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine

4-carboxamide, 2- [4- (cyclopropylcarbamoylamino) phenyl] -N- (2-methoxyethyl) -N-methyl-6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-4-carboxamide, 2- [4 '- (cyclopropylcarbamoylamino) phenyl] -6 - [(3S) -3-methylmorpholin-4-yl] -N- (1-methyl-4-piperidyl) pyrimidine-4-carboxamide, 3-cyclopropyl-1- [ 4- [4- (3-Hydroxyazetidine-1-carbonyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] urea, 2- [4- (cyclopropylcarbamoylamino) phenyl] -N - [(3-methylimidazol-4-yl) methyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine

4-carboxamide, 2- [4- (cyclopropylcarbamoylamino) phenyl] -N- (dimethylcarbamoylmethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-4-carboxamide, N-cyclopropyl-2- [4 - (cyclopropylcarbamoylamino) phenyl] -N-methyl-6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-4-carboxamide, 2- [4- (cyclopropylcarbamoylamino) phenyl] -N- (cyclopropylmethyl) -N -methyl-6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine

4-carboxamide, 2- [4- (cyclopropylcarbamoylamino) phenyl] -6 - [(3S) -3-methylmorpholin-4-yl] -N- (oxetan-3-yl) pyrimidine-4-carboxamide, 1- [4 - [4- (2-Cyclopentylsulfonylpropan-2-yl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3-cyclopropyl-urea, 3-cyclobutyl-1- [4- [4- (2-Cyclopentylsulfonylpropan-2-yl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] urea, 1- [4- [4- ( 2-cyclopentylsulfonylpropan-2-yl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3-ethyl-urea, 1- [4- [4- (2- cyclopentylsulfonylpropan-2-yl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3- (2-dimethylaminoethyl) urea, 1- [4- [4- (2 -cyclopentylsulfonylpropan-2-yl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3- (2-hydroxyethyl) urea, 1- [4- [4- ( 2-cyclopentylsulfonylpropan-2-yl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3-methyl-urea, 3-cyclobutyl-1- [4- [4 - (cyclopentylsulfonylmethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] urea, 1- [4- [4- (cyclopentylsulfonylmethyl) -6 - [(3S) -3 -methylmorpholin-4-yl] pyrimidine-2-yl] feni l] -3-ethyl-urea, 1- [4- [4- (cyclopentylsulfonylmethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3- (2- dimethylaminoethyl) urea, 3-Cyclopropyl-1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- [2- [2- (trifluoromethyl) phenyl] sulfonylpropan-2-yl] pyrimidine -2-yl] phenyl] urea, 3-cyclobutyl-1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- [2- [2- (trifluoromethyl) phenyl] sulfonylpropan- 2-yl] pyrimidine-2-yl] phenyl] urea, 3-ethyl-1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- [2- [2- (2- trifluoromethyl) ) phenyl] sulfonylpropan-2-yl] pyrimidine-2-yl] phenyl] urea, 3- (2-dimethylaminoethyl) -1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6 - [2- [2- (trifluoromethyl) phenyl] sulfonylpropan-2-yl] pyrimidine

2-yl] phenyl] urea, 3- (2-hydroxyethyl) -1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- [2- [2- (trifluoromethyl) phenyl ] sulfonylpropan-2-yl] pyrimidine-2-yl] phenyl] urea, 3-methyl1-1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- [2- [2 - (trifluoromethyl) phenyl] sulfonylpropan-2-yl] pyrimidine-2-yl] phenyl] urea, 3-cyclobutyl-1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- [[2- (trifluoromethyl) phenyl] sulfonylmethyl] pyrimidine-2-yl] phenyl] urea, 3-ethyl-1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- [ [2- (trifluoromethyl) phenyl] sulfonylmethyl] pyrimidine-2-yl] phenyl] urea, 3- (2-dimethylaminoethyl) -1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] - 6 - [[2- (trifluoromethyl) phenyl] sulfonylmethyl] pyrimidine-2-yl] phenyl] urea, 3-Ethyl-1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6 - (tert-butylsulfonylmethyl) pyrimidine-2-yl] phenyl] urea, 3-cyclobutyl-1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (tert-butylsulfonylmethyl) pyrimidine -2-yl] phenyl] urea, 3- (2-dimethylaminoethyl) -1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (tert-butylsulfonylmethyl) pyrimidine-2- il] phenyl] urea, 3-cyclopropyl-1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (2-tert-butylsulfonylpropan-2-yl) pyrimidine-2-yl] phenyl] urea, 3-cyclobutyl-1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- ( 2-tert-butylsulfonylpropan-2-yl) pyrimidine-2-yl] phenyl] urea, 3-ethyl-1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (2 -tert-butylsulfonylpropan-2-yl) pyrimidine-2-yl] phenyl] urea, 3- (2-dimethylaminoethyl) -1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6 - (2-tert-butylsulfonylpropan-2-yl) pyrimidine-2-yl] phenyl] urea, 3- (2-hydroxyethyl) -1- [4- [4 - [(3S) -3-methylmorpholin-4-yl ] -6- (2-tert-butylsulfonylpropan-2-yl) pyrimidine-2-yl] phenyl] urea, 3-methyl-1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (2-tert-butylsulfonylpropan-2-yl) pyrimidine-2-yl] phenyl] urea, 1- [4- [4 - [(3,5-Difluorophenyl) sulfonylmethyl] -6 - [(3S) - 3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3-ethyl-urea, 3-cyclobutyl-1- [4- [4 - [(3,5-difluorophenyl) sulfonylmethyl] -6 - [( 3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] urea, 1- [4- [4 - [(3,5-difluorophenyl) sulfonylmethyl] -6 - [(3S) -3-methylmorpholin -4-yl] pyrimidine-2-yl] phenyl] -3- (2-dimethylaminoethyl) urea, 3-cyclopropyl-1- [4- (4- [2- (3,5-d ifluorophenyl) sulfonylpropan-2-yl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] urea, 3-cyclobutyl-1- [4- [4- [2- ( 3,5-difluorophenyl) sulfonylpropan-2-yl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] urea, 3- [4- [4- [2- ( 3,5-difluorophenyl) sulfonylpropan-2-yl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -1-ethyl-urea, 1- [4- [4 - [2- (3,5-Difluorophenyl) sulfonylpropan-2-yl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3- (2-dimethylaminoethyl)

urea, 1- [4- [4- [2- (3,5-difluorophenyl) sulfonylpropan-2-yl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3- (2-hydroxyethyl) urea, 1- [4- [4- [2- (3,5-difluorophenyl) sulfonylpropan-2-yl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3-methyl-urea, 1- [4- [4- (2-Cidohexylsulfonylpropan-2-yl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine- 2-yl] phenyl] -3-cyclopropyl-urea, 3-cyclobutyl-1- [4- [4- (2-cyclohexylsulfonylpropan-2-yl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] urea, 3- [4- [4- (2-cyclohexylsulfonylpropan-2-yl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl ] -1-ethyl-urea, 1- [4- [4- (2-cyclohexylsulfonylpropan-2-yl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] - 3- (2-dimethylaminoethyl) urea, 1- [4- [4- (2-cyclohexylsulfonylpropan-2-yl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3- (2-hydroxyethyl) urea, 1- [4- [4- (2-cidohexylsulfonylpropan-2-yl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl ] -3-methyl-urea, 3-cyclobutyl-1- [4- [4- (cyclohexylsulfonylmethyl) -6 - [(3S) -3-methylmorpholin-4- il] pyrimidine-2-yl] phenyl] urea, 3- [4- [4- (cyclohexylsulfonylmethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -1- ethyl-urea, 1- [4- [4- (cyclohexylsulfonylmethyl) -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3- (2-dimethylaminoethyl) urea, 3 -Cyclopropyl-1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- [2 - [(4-methyl-1,3-thiazol-2-yl) sulfonyl] propan- 2-yl] pyrimidine-2-yl] phenyl] urea, 3-cyclobutyl-1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- [2 - [(4-methyl -1,3-thiazol-2-yl) sulfonyl] propan-2-yl] pyrimidine-2-yl] phenyl] urea, 3-ethyl-1- [4- [4 - [(3S) -3-methylmorpholin- 4-yl] -6- [2 - [(4-methyl-1,3-thiazol-2-yl) sulfonyl] propan-2-yl] pyrimidine-2-yl] phenyl] urea, 3- (2-dimethylaminoethyl) ) -1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- [2 - [(4-methyl-1,3-thiazol-2-yl) sulfonyl] propan-2 -il] pyrimidine-2

il] phenyl] urea,

3- (2-hydroxyethyl) -1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- [2 - [(4-methyl-1,3-thiazol-2-yl ) sulfonyl] propan-2-yl] pyrimidine-2-yl] phenyl] urea, 3-methyl-1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- [2 - [( 4-methyl-1,3-thiazol-2-yl) sulfonyl] propan-2-yl] pyrimidine-2-yl] phenyl] urea, 3-cyclobutyl-1- (4- [4 - [(3S) -3 -methylmorpholin-4-yl] -6 - [(4-methyl-1,3-thiazol-2-yl) sulfonylmethyl] pyrimidine-2-yl] phenyl] urea, 3-ethyl-1- [4- [4- [(3S) -3-methylmorpholin-4-yl] -6 - [(4-methyl-1,3-thiazol-2-yl) sulfonylmethyl] pyrimidine-2-yl] phenyl] urea, 3- (2-dimethylaminoethyl) ) -1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6 - [(4-methyl-1,3-thiazol-2-yl) sulfonylmethyl] pyrimidine-2-yl] phenyl] urea, 3-Ethyl-1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (2-pyridine-2-ylsulfonylpropan-2-yl) pyrimidine-2-yl ] phenyl] urea, 3-Ethyl-1- [4- [4 - [(3S) -3-methylmorpholin-4-yl] -6- (pyridine-2-ylsulfonylmethyl) pyrimidine-2-yl] phenyl] urea, 1- [4- [4- [2- (4-Chlorophenyl) sulfonylpropan-2-yl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3-cyclopropyl -urea, 1- [4- [4- [2- (4-chlorophenyl) sulfonylpropan-2-yl] -6 - [(3S) - 3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3-cyclobutyl-urea, 1- [4- [4- [2- (4-chlorophenyl) sulfonylpropan-2-yl] -6 - [( 3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3-methyl-urea, 1- [4- (4- [2- (4-chlorophenyl) sulfonylpropan-2-yl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3-ethyl-urea, 1- [4- (4- [2- (4-chlorophenyl) sulfonylpropan-2-yl ] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3- (2-dimethylaminoethyl) urea, (S) -1- (4- (4 - ((4 -chlorophenylsulfonyl) methyl) -6- (3-methylmorpholino) pyrimidine-2-yl) phenyl) -3-cyclobutylurea, and 1- [4- [4 - [(4-chlorophenyl) sulfonylmethyl] -6 - [(3S) -3-methylmorpholin-4-yl] pyrimidine-2-yl] phenyl] -3-ethyl-urea, or a pharmaceutically acceptable salt thereof.

12. 12.: Un compuesto de fórmula (I) o una sal farmacéuticamente aceptable del mismo de acuerdo con una cualquiera de las reivindicaciones 1 a 11, para uso como un medicamento en el tratamiento de una enfermedad proliferativa. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, for use as a medicament in the treatment of a proliferative disease.

13. 13.: El uso de un compuesto de fórmula (I) o una sal farmacéuticamente aceptable del mismo como se define en una cualquiera de las reivindicaciones 1 a 11, en la fabricación de un medicamento para uso en el tratamiento de una enfermedad proliferativa. The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 11, in the manufacture of a medicament for use in the treatment of a proliferative disease.

14. 14.: Una composición farmacéutica que comprende un compuesto de fórmula (I) como se define en una cualquiera de las reivindicaciones 1 a 11, o una sal farmacéuticamente aceptable del mismo, en asociación con un diluente o vehículo farmacéuticamente aceptable. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier.

15. fifteen.: Un compuesto de fórmula (I) como se define en una cualquiera de las reivindicaciones 1 a 11, o una sal farmacéuticamente aceptable del mismo, para uso como un medicamento. A compound of formula (I) as defined in any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, for use as a medicament.