TW200817384A - Compounds-943 - Google Patents

Abstract

A compound of formula (I) or a pharamaceutically acceptable salt thereof, processes for their preparation, pharmaceutical compositions containing them and their use in therapy, for example in the treatment of proliferative disease such as cancer and particularly in disease mediated by an mTOR kinase and/or one or more PI3K enzyme.

Description

200817384 IX. Description of the Invention: [Technical Field] The present invention relates to a morpholinyl pyrimidine derivative, a process for the preparation thereof, a pharmaceutical composition containing the same, and a therapeutic thereof, for example, in the treatment of a proliferative disease such as cancer And, in particular, for use in diseases mediated by mTOR kinase and/or one or more PI3K enzymes. [Prior Art] It is now very clear that the imbalance between oncogenes and tumor-suppressor genes (which contribute to the formation of malignant tumors, for example, by increased cell proliferation or increased cell survival rate) is also known by the ΡΒΚ/mTOR ethnic group. The signaling pathway of the media has a central role in many cellular processes, including hyperplasia and survival, and the dysregulation of these pathways is a causative factor in a wide range of human cancers and other diseases. The mammal of rapamycin (sirolimus) is labeled as the enzyme mTOR. This enzyme belongs to the phospholipid inositol (PI) kinase-associated kinase (PIKK) population of protein kinases, which also includes ATM, ATR, I, DNA-PK and hSMG-1. mTOR, like other members of the PIKK group, does not have measurable lipid kinase activity, but instead functions as a serine/threonine kinase. Many of the messages are based on the use of rapamycin, which first binds to the 12 kDa immunoglobulin FK506-binding protein (FKBP 12), and this complex inhibits mTOR release. Message (Tee and Blenis, Symposium on Cellular and Developmental Biology, 2005, 16, 29-37) The 〇mTOR protein line contains a catalytic kinase functional site, a FKBP12-rapamycin binding (FRB) functional site, close to C- End and up to 20 longitudinal rows 123642 200817384 Repeated HEAT body at the N-terminus to infer the functional site, as well as FRAP-ATM_TRRAP (FAT) and FAT C-terminal functional sites (Huang and Houghton, pharmacological current insights) , 2003, 3, 371-377). mTOR kinase is a key regulator of cell growth and has been shown to regulate a wide range of cellular functions, including translation, transcription, mRNA conversion, protein stability, actin cytoskeletal structure Recombination and autologous consumption (Jacinto and Hall, Natural Review of Molecular and Cellular Biology, 2005, 4, 117-126). The mTOR kinase system will be derived from growth factors (such as insulin or insulin-like growth factors) and nutrients (such as amine groups). The message of acid and glucose is integrated to regulate cell growth. The mTOR kinase is activated by the growth factor via the PI3K_Akt pathway. mTOR kinase is the most abundant in mammalian cells. A well-characterized function is to regulate translation through two pathways, ie activation of ribosome S6K1, to improve translation of mRNA with 5'-terminal pyrimidine (TOP), and 4E-BP1 Inhibition to allow CAP-dependent mRNA translation. In general, researchers have used inhibition of rapamycin and related rapamycin analogues based on their specificity for mTOR as an intracellular marker, Discover the physiology and pathology roles of mTOR. However, recent data indicate that rapamycin has a mutable signaling effect on mTOR and indicates that direct inhibition of mTOR kinase functional sites is comparable to that achieved by rapamycin. Broad anticancer activity (Edinger et al., Cancer Research, 2003, 63, 8451-8460). Thus, potent and selective inhibitors of mTOR kinase activity can be used to allow for a more complete understanding of mTOR kinase function and to provide useful therapeutic agents.

There are considerable reports that the pathway upstream of mTOR, such as the PI3K 123642 200817384 pathway, is 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, components of the PI3K pathway are mutated in different human tumors, including activating mutations in growth factor receptors, and amplification and/or overexpression of PI3K and Akt. In addition, there is evidence that endothelial cell proliferation can also be based on mTOR signaling. Endothelial cell proliferation is stimulated by the activation of vascular endothelial growth factor (VEGF) signaling pathway by PI3K-Akt-mTOR (Dancey, Expert Insights on Research Drugs, 2005, 14, 313-328). Furthermore, the mTOR kinase signaling message is influenced by factor-1 a (HIF-1 α) caused by hypoxia, and partially controls VEGF synthesis (Hudson et al., Molecular and Cell Biology, 2002). , 22, 7004_7014). Therefore, tumor angiogenesis can be determined in two ways, depending on the message from mTOR kinase, through tumor and stromal cells, synthesis by VEGF hypoxia, and VEGF stimulation through endothelial proliferation and survival, after ΡΒΚ-Akt- mTOR sends a message. These findings indicate that pharmacological inhibitors of mTOR kinase should have therapeutic value to treat various forms of cancer, including solid tumors such as carcinomas and sarcomas, and leukemias and lymphoid malignancies. In particular, inhibitors of mTOR kinase should have therapeutic value for the treatment of, for example, breast, colorectal, lung (including small cell lung cancer, non-small cell lung cancer, and bronchial pulmonary cell carcinoma) and cancer of the prostate, with bile ducts, bones, Bladder, head and neck, kidney, liver, gastrointestinal tissue, esophagus, ovary, pancreas, skin, testicular, thyroid, uterus, cervix and vaginal cancer, and leukemia (including all and 123642 200817384 CML), multiple Sexual myeloma and lymphoma. In addition to tumorigenesis, it has been shown that the mTOR kinase system plays a role in an array of defective tumor syndromes. Recent studies have confirmed that tumor suppressor gene proteins, such as TSC1, TSC2, PTEN, and LKB1, closely control mTOR kinase signaling. Loss of these tumor suppressor proteins results in a range of defective tumor symptoms due to elevated mTOR kinase signaling (Tee and Blenis, Cell and Development Biology Symposium, 2005, 16, 29-37) . Regulatory dysfunction of mTOR kinase has established molecularly linked clusters including Peutz-Jeghers syndrome (PJS), Cowden disease, Bannayan-Riley-Ruvalcaba syndrome (BRRS), Proteus syndrome, Lhermitte-Duclos disease and crude Long induration (TSC) (Inoki et al, Nature Genetics, 2005, 37, 19-24). Patients with these syndromes develop characteristic benign tumor tumors in multiple organs. Recent studies have revealed the role of mTOR kinase in other diseases (Easton & Houghton, Professional Insights on Therapeutic Subjects, 2004, 8, 551_564). Rapamycin has been shown to be an effective immunosuppressive agent by inhibiting the proliferation of T cells, B cell antigens, and antibody production (Sehgal, Transplantation Journal, 2003, 35, 7S-14S), and Thus mTOR kinase inhibitors can also be useful immunosuppressive agents. Inhibition of the kinase activity of mTOR can also be used to prevent restenosis, which means controlling the undesired proliferation of normal cells in the distribution of blood vessels, which is in response to the introduction of vascular stents in the treatment of gold tube distribution diseases (Morice et al., New England). Lan Medicine Journal, 2002, 346, 1773-1780). Furthermore, 'rapamycin analogues, everolimus, can reduce the severity and incidence of cardiac allograft vascular disease (Eisen et al., New England Medical 123642 200817384) 2003, 349, 847-858). The improved mT〇R kinase activity is associated with cardiac hypertrophy, which is of clinical importance as a result of the risk of heart failure and the increase in cell size of cardiomyocytes (Tee & Blenis, Cell and Developmental Biology Symposium, Fine, % Melon 37) Therefore, it is expected that mT〇R kinase inhibitors are valuable in the prevention and treatment of a wide variety of diseases other than cancer. It is also generally known that many of these morpholinyl pyrimidine derivatives have an inhibitory activity against the phospholipid inositol (PI) 3-kinase group of the pro-mother. C Phospholipid creatinine (PI) 3_kinase (PI3K) is a lipid kinase that is present everywhere, which acts as a downstream of cell surface receptors and as a signal transducer in the pathogenesis of intracellular membranes and proteins. All PI3K are bispecific enzymes with lipid kinase activity which phosphorylate phosphoinositide at the 3-hydroxyl position and less fully characterized protein kinase activity. Lipid product of PI3K·catalytic reaction, including phospholipid inositol 3,4,5-triphosphate [ΡΙ(3,4,5)ρ", phospholipid inositol 3,4-bisphosphate [PI(3, 4) P2] and phospholipid inositol 3_monopot acid salt [PI(3)P], which constitutes a second messenger in a variety of message transduction pathways, including gastric I' cell proliferation, adhesion, survival, cytoskeleton The necessary route for rearrangement and cystic passage. The PI(3)P is present in all cells in the composition and its content does not change significantly after the stimulant stimulation. Conversely, PI(3,4)P2 and ρι(3,4 5)p3 are not nominally present in most cells, but they accumulate rapidly when stimulated by a stimulant. PI3K-producing the downstream action of the second messenger of 3-phosphoinositide, which is mediated by the molecule of the rod, which contains < phytic acid inositol binding functional moiety, rugby pleckstrin homologue (PH The functional site, and the recently confirmed FYVE and phox functional sites of 123642 -10- 200817384. For well-characterized proteins of PI3K, PDK1 and protein kinase B (PKB) are included. In addition, tyrosine kinases, such as Btk and Itk, are dependent on PI3K activity. The PI3K population of lipid kinases can be classified into three groups based on their physiological specificity (Vanhaesebroeck et al., Trends in Biol. Sci., 1997, 22, 267). Class III PI3K enzymes alone phosphorylate PI. In contrast, the class II PI3K enzyme phosphorylates both PI and PI 4-phosphate [PI(4)P]. Type I Π3Κ Enzymes phosphorylate PI, PI(4)P and PI 4,5-bisphosphate [PI(4,5)P2], but only PI(4,5)P2 is physiological. The upper cells are stressed. Phosphorylation of PI(4,5)P2 produces a lipid second messenger PI(3,4,5)P3. The more distantly related members of the lipid kinase supergroup are the class IV kinases, such as mTOR (discussed above), and the DN A-dependent kinase, which causes the protein to undergo endogenous serine/threonine residues. Basic. The most studied and understood PI3K lipid kinase is the class I PI3K enzyme. Class I PI3K is a heterodimer comprising a pllO catalytic subunit and a regulatory subunit. This ethnic group is further divided into species la and species lb enzymes based on regulatory partners and regulatory mechanisms. The species la enzyme contains three different catalytic subunits (ρΙΙΟα, pll0/3, and ρΙΙΟδ), which are dimerized with five different regulatory subunits (ρ85 α, ρ55 α, ρ50 α, ρ85 /5, and ρ55, all of which are catalytically The unit is capable of interacting with all regulatory subunits to form a variety of heterodimers. The species la ΡΙ3Κ is typically used to regulate the subunit SH2 functional site with activating receptors or zygote or protein such as IRS-1. The interaction of tyrosine residues is activated in response to growth factor stimulation of the receptor tyrosine kinase. Both pll〇a and pllO million are structurally represented by all of the cell types by 123642 -11 - 200817384 However, the pl1〇d expression is more restricted to the white blood cell population and some epithelial cells. In contrast, the single species Ib enzyme system contains a pi 1〇 γ catalytic subunit that interacts with the pl〇1 regulatory subunit. Furthermore, 'the species Ib enzyme is activated in response to the G_protein coupled receptor system (GPCR), and its performance is shown to be restricted by white blood cells and cardiomyocytes. Evidence-based display type la PI3K enzymes in a variety of human cancers pole 'either directly or indirectly contribute to tumorigenesis (Vivanco and

Sawyers, Nature Reviews Cancel, 2002, 2, 489_501). For example, ρΙΙΟα

The unit is amplified in tumors such as the ovaries (Shayesteh et al, Nature Genetics, 1999, 21, 99-102) and the cervix (Ma et al, oncogene, 2000, 19, 2739-2744). More recently, activating mutants within the catalytic position of the pii〇α catalytic subunit have been associated with a variety of other tumors, such as the colorectal region and breast and lung tumors (Samuels et al, Science, 2004, 304, 554). Tumor-associated mutations in the ρ85 alpha regulatory subunit have also been identified in cancer, such as ovarian and colon cancer (Philp et al, Cancer Research, 2001, 61, 7426-7429). In addition to its direct effect, it is generally believed that the activation of the species la PI3K contributes to the tumorigenesis event, which occurs upstream of the signaling pathway, for example by receptor tyrosine kinase, GPCR system or ligand integrin dependence. Sex or ligand independent activation (Vara et al, Review of Cancer Therapy, 2004, 30, 193-204). Examples of such upstream signaling pathways include overexpression of the receptor tyrosine kinase erbB2 in a variety of tumors that result in activation of the PI3K vector pathway (Harari et al, Oncogene, 2000, 19, 6102-6114), Overexpression with ras oncogenes (Kauffmann-Zeh et al, Nature 1997, 385, 544-548). In addition, the category la PI3K 123642 •12- 200817384 can indirectly contribute to the development of tumors caused by various downstream signaling events. For example, it will catalyze the loss of PI(3,4,5)P3 conversion to Π(4,5)Ρ22ΡΤΕΝ, the loss of tumor suppressor gene phosphatase, and the production of n (3,4, via a wide range of PI3K vectors). 5) P3 dysregulated tumors are associated (Simpson and Parsons, Exp. Cell Res., 2001, 264, 29-41). Furthermore, the enhancement of the role of other PI3K media signaling events can contribute to a variety of cancers, for example, through the activation of Akt (Nicholson and Anderson, Cell Signaling, 2002, 14, 381-395). In addition to its role in the message of proliferation and survival in vector tumor cells, there is evidence that the species la PI3K enzyme promotes tumorigenesis in tumor-associated stromal cells. For example, it is known that PI3K signaling plays an important role in mediator endothelial cells in response to angiogenic factors such as VEGF angiogenesis events (Abid et al., Arterioscler. Thromb. Vase. Biol., 2004, 24, 294- 300). Since species I Π 3 Κ enzymes also involve motility and migration (Sawyer, Expert Opinion Investig. Drugs, 2004, 13, 1-19), PI3K enzyme inhibitors should provide therapeutic benefit by inhibiting tumor cell invasion and metastasis. In addition, the class I PI3K enzyme plays an important role in the regulation of immune cells that contribute to the pre-neoplastic action of inflammatory cells (Coussens and Werb, Nature, 2002, 420, 860-867). These findings indicate that the pharmacological inhibitors of the class I PI3K enzymes have therapeutic value in the treatment of various diseases, including various forms of cancer diseases, including solid tumors such as carcinomas and sarcomas, and leukemias and lymphoid malignancies. In particular, inhibitors of the class I PI3K enzymes should have therapeutic value for the treatment of, for example, the breast, colorectal, lung (including small cell lung cancer, non-small cells 123642 -13 - 200817384 lung cancer and bronchial pulmonary cell carcinoma) and prostate Cancer, cancer with bile ducts, bones, bladder, head and neck, kidneys, liver, gastrointestinal tissue, esophagus, ovaries, pancreas, skin, testicles, verrucous glands, uterus, cervix and vulva, and leukemia Including ALL and CML), multiple myeloma and lymphoma. PI3Kr, the species lb PI3K, was activated by GPCR, which was finally confirmed in mice lacking the enzyme. Therefore, neutrophils and macrophages derived from PI3K r-deficient animals fail to produce PI(3,4,5)P3 in response to various chemokines (such as IL-8, C5a, fMLP and MHMa). The stimuli, however, the signalling of the species la PI3K by the protein tyrosine kinase coupling receptor remains 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). Furthermore, the phosphorylation of PI(3,4,5)P3 by PKB was not initiated by such GPCR ligands in cells without ΡΙ3Κτ. As a result, it was confirmed that at least in resting hematopoietic cells, ΡΙ3Κγ is a separate Κ3Κ isomeric recombinant which is activated in vivo by GPCR. When the neutrophil-derived neutrophils and peritoneal macrophage cell lines derived from wild-type and ΡΙ3Κ mice were tested in vitro, they showed reduced but not completely eliminated performance in the chemotaxis and adhesion assays. However, this translates into a sharp decrease in neutrophil infiltration of IL-8-driven neutrophils into tissues (Hirsch et al., Science, 2000, 287 (5455), 1049-1053). Recent data indicate that the PI3K7 system is involved in the path-finding process, rather than the mechanical force generation of motility, since random migration does not diminish in cells lacking PI3KT (Hannigan et al., Proc. Nat. Acad, of Science of USA·, 2002, 99(6), 3603_8). Linking pi3Kr to the pathology of respiratory diseases is accompanied by a demonstration that pdkt 123642 -14- 200817384 has a central role in the regulation of lung infiltration and activation by endotoxin in neutrophils that causes acute lung injury ( Yum et al, J. Immunology, 2001, 167 (11), 6601-8). Although the Π3 被 is highly expressed in white blood cells, the loss does not seem to interfere with the fact of hematopoiesis, and the fact that the ΡΙ3ΡΙ7 mouse family can survive and fertile, further means that this Ι>Ι3Κ isomeric recombinant acts as Potential drug targets. The work of removing mice has also established that Κ3Κτ is an essential amplifier for mast cell activation (Laffargue et al., Immunity, 2002, 16(3), 441-451). Therefore, in addition to tumorigenesis, there is evidence that the species I PI3K enzyme plays a role in other diseases (Wymann et al., Trends in Pharmacology, 2003, 24, 366-376). Both the la PI3K enzyme and the single species lb enzyme have important roles in the cells of the immune system (Koyasu, Nature Immunology, 2003, 4, 313-319), and therefore are related to the treatment of inflammatory and allergic indications. Subject. Recent reports have shown that mice lacking PI3Kr and PI3K5 are viable but have attenuated inflammatory and allergic responses (Ali et al, Nature, 2004, 431 (7011), 1007-11). Inhibition of PI3K can also be used to treat cardiovascular disease via anti-inflammatory effects or directly by affecting cardiomyocytes (Prasad et al., Trends in Cardiovascular Medicine, 2003, 13, 206-212). Therefore, inhibitors of the species I PI3K enzyme are expected to be valuable in the prevention and treatment of a wide variety of diseases other than cancer. Several compounds that inhibit PI3K and phospholipid creatinine (PI) kinase-associated kinase (PBKK) have been identified, including wortmannin and the ecdysone derivative LY294002. These compounds are rationally specific inhibitors of PI3K and PI3KK over other kinases, but they lack efficacy and show little selectivity in the PI3K population 123642 -15-200817384. Accordingly, it is generally desirable to provide further effective mTOR & / or PI3K inhibitors for the treatment of cancer, inflammatory or obstructive airway diseases, immunity or cardiovascular disease. The morpholinyl pyrimidine derivative and the ΡΙ3 Κ inhibitor are known in the art. International Patent Application No. WO 2004/048365 discloses a compound having ΡΙ3Κ enzyme inhibitory activity and which can be used for treating cancer. These compounds are arylamino- and heteroarylamino-substituted pyrimidines which differ from the compounds of the invention with regard to their arylamino- and heteroarylamino substituents. These substituents are not equivalent to the -XR1 substituent of the present invention. Inhibitors of pi3K activity useful in the treatment of cancer are also disclosed in European Patent Application Serial No. 277 738, which is incorporated herein by reference to the entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire- A 3,2-d]pyrimidine derivative, a tricyclic heteroaryl compound substituted with a 4 morpholino group, but not a monocyclic pyrimidine derivative. Many compounds, such as 4_fosfosin, ketones (phenylsulfonylmethylidene-4_yl% bite with 4-in [(benzoic)methyl]_2_咐. Keifu: has been registered in the Chemical Abstracts f library, but has not pointed out the availability, and did not indicate that these compounds have mTOR and / or ΡΙ3 κ inhibitory activity or useful therapeutic properties. ° He see 杲 1? Fulin 17 唆 唆 derivative has the therapeutic properties that can be used. Under the constraints of the theory, the therapeutic value of He Bio is derived from its resistance to mT0R - filial and / or - or more fine K enzyme (# Inhibitory activity of the species Ia enzyme and/or species Ib 123642 • 16 · 200817384 enzymes. Since the signaling pathways mediated by the PI3K/mT〇R population have a central role in many cellular processes including proliferation and survival, And because the dysregulation of these pathways is a causative factor in a wide range of human cancers and other diseases: it is expected that these derivatives will be therapeutically useful. In particular, it is expected that the derivatives will have anti-proliferation and/or Cell withering properties, this ~ Mingba can be used to treat hyperplasia Disease, such as cancer. The compounds of the invention may also be used to inhibit uncontrolled cell proliferation due to various non-malignant

Sexual diseases occur, such as inflammatory diseases, obstruction of airway diseases, immune diseases or cardiovascular diseases. In general, the compounds of the present invention have an effective inhibitory activity against kinases that are resistant to 1117 〇, but this compound may also have potent inhibitory activity against one or more PI3K enzymes (e.g., species la enzyme and/or species Ib enzyme). [Summary of the Invention]

According to one aspect of the invention, there is provided a compound of formula (I)

(R3)m

R1

R2 Formula (I) or a pharmaceutically acceptable salt thereof; wherein 〇, 1, 2, 3 or 4; 1γ and Y2 are independently N or CR8, provided that one of the oximes is N and the other is CR8 ; X is a linking group selected from -CR4=Cr5-, _cr4=cr5cr6r7, _cr6r7cr5 = 123642 -17- 200817384 CR4- ' -C = C-, -C = CCR6R7-, _cr6r7CeC-, -NR4CR6R7-, -OCR6R7 -, -SCR6R7·, -S(0)CR6R7-, -s(o)2cr6r7-, -C(0)NR4CR6R7_, -NR4C(0)CR6R7-, -NR4C(0)NR5CR6R7-, -NR4S(0) 2CR6R7-, -S(0)2NR4CR6R7-, -C(0)NR4-, -NR4C(0)-, -NR4 C(0)NR5 -, -S(0)2 NR4 - and -NR4 s(〇) 2 _ ; R 1 is a group selected from the group consisting of hydrazine, Ch alkyl group, C 2_6 alkenyl group, c 2_6 alkynyl group, carbocyclic group, carbocyclylalkyl group, heterocyclic group and heterocyclic group c1-6 alkyl group, which is a group system

Substituted by one or more substituents selected from halo, cyano, nitro, R9, -OR9, -SR9, -SOR9, -S02R9, -COR9, -C02R9, -CONR9R10, -NR9R10, 9C〇R10, 9c〇2Rl0, -nr9conr10r15, -nr9coconr10r15 and _Dish 98〇21110; R2 is a group selected from C! 4 alkyl, carbocyclic group and heterocyclic group, this group is -NR1 7 CONR18 R1 9 substituted, and optionally substituted by one or more substituents, the substituents being independently selected from halo, cyano, nitro, -Ri丨, _〇Rl丨, -SRli, -SOR11, -S02Rn, -COR11, -C02Ru, -CONRnRi2, _NRiiRi2, -NR11 COR1 2 and -NR11 COCONR12 R1 6 ; each R, when present, is independently selected from the group consisting of _ group, cyano group, nitro group, _r1S, -〇] SOR, - S02R13, -COR13, -CC^R", _C0NR13R 13 1 4 , n____ , -SR1 3R14, -NR13R14 . .NR13c〇r14 ^ .NR13C〇2Rl4^.NRl3s〇2Rl4 . R4 and Rs are independently hydrogen or q_6 alkane a group of filaments and R4 and those attached thereto - or a plurality of pro-H forms a 4 to 10-membered carbon ring or heterocyclic ring 'where ls 2 or 3 ring carbon atoms are optionally taken, or S replacement 'and the ring is treated as appropriate — Substituted by a plurality of substituents selected from the group consisting of a south group, a cyano group, a decyl group, a thiol group, a aryl group, a decyl group, 123642 -18 - 200817384 <^_6 alkoxy group, a halogenated Ci-6 alkyl group, a halogen Alkyloxy group, hydroxy Ci-6 alkyl group, transyl group C-6 alkoxy group, Cl-6 alkoxy group C 6 alkyl group, Cl -6 alkoxy group C 6 alkoxy group, amine group , Cu alkylamino group, bis((V6 alkyl)amino group, amine 〇v6 alkyl group, (Cu alkyl)amino group q-6 alkyl group, bis-6 alkyl)amino group Ci-6 alkyl group, Aromatic group of Ci-6, a hydrocarbyl group of Ci-6, a base of Ci-6, a base of Ci-6, an amine group, a Ci-6 alkylsulfonyl-6 alkylamine group, an amine sulfonyl group , Ci-6 alkylamine sulfonyl, bis(Ch alkyl)amine sulfonyl, Cu alkyl amide, (6-6 alkyl sulfonyl (Ch alkyl) amine, amine methyl sulfhydryl, <^ -6 alkylamine methyl hydrazino and bis(Cu alkyl) amine carbaryl; R6 and R7 are independently selected from the group consisting of hydrogen, halo, cyano, nitro and CV6 alkyl; R8 is selected from hydrogen and halo. , cyano and (^_6 alkyl; R9 and R1G are independently hydrogen or selected from the group consisting of Cu alkyl, carbocyclyl, carbocyclyl Ci 6 alkyl, heterocyclic and heterocyclic q _6 alkyl Group, this group The case is substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, cv6 alkyl, (6-alkoxy, i-based 〇ν6 alkyl, dentyl), oxygenated Base, hydroxy (^_6 alkyl, hydroxy q. 6 alkoxy, c 6 alkoxy Cl 6 alkyl, cw alkoxy Cl. 6 alkoxy, amine, q-6 alkylamino, double (Ci 6 alkyl)amino, aminoCh alkyl, (Cl-6 alkyl)amino Cu alkyl, bis(Ci6 alkyl)amino ci-6 alkyl, cyano cv6 alkyl, cv6 alkylsulfonyl , Ci 6 calcined kebab ^ & ylamino group, (^6 alkylsulfonyl (Cu alkyl) amine group, amine continuation base, C1·6 alkylamine sulfonyl group, bis(Cl_6 alkyl) Aminesulfonyl, Ci6 alkanoylamino, alkylalkyl (Ci^alkyl)amine, aminecarboxamidine, Ci.6 alkylaminecarbamyl and bis(C1-6alkyl)amine fluorenyl ; 圮^圮夂^ and 圮" are independently hydrogen' or selected from: ^alkyl-carbocyclyl, 123642 •19- 200817384 carbocyclic Cn alkyl, heterocyclic and heterocyclic Ci 6 alkane a group of a group, which is optionally substituted by one or more substituents selected from the group consisting of a yl group, a cyano group, a nitro group, a hydroxyl group, (V6) Base, (^_6 alkoxy group, dentate core ^ alkyl group, halogen group Ch calcined base, trans group C -6 · alkyl group, via group (^·6 alkoxy group, (^_6 alkoxy group Ci-) 6 alkyl, Ch alkoxy Ci-6 alkoxy, amine, Ch alkylamino, bis(Cu alkyl)amine, amine Cu alkyl, (Cu alkyl) amine Ci-6 alkyl , double (Ci_6 yard base) 3⁄4 base C1>>6 alkyl group, cyano c1-6 alkyl group, Ci-6 alkyl group, Ci_6 alkanoyl group, Cu alkyl group (Cl-6 alkyl group) An amine group, an amine methyl sulfhydryl group, a Cu alkyl amine carbhydryl group and a bis (c 1-6 alkyl) amine carbaryl group; R, R, R, R 6 and R 19 are independently hydrogen or selected from q. a group of a 6 alkyl group, a carbocyclic group, a carbocyclic group -6 alkyl group, a heterocyclic group and a heterocyclic group Ci6 alkyl group, the group being optionally substituted by one or more substituents selected from the group consisting of Halo, cyano, nitro, hydroxy, (V6 alkyl, Cl-6 alkoxy, *Ci 6 alkyl, halo Ci-6 alkoxy, hydroxy c1-6 alkyl, hydroxy Cil alkoxy, Ci -6 alkoxy Q-6 alkyl, Ci-6 alkoxy (^_6 alkoxy, amine, Ci-6 alkylamino, bis(Cw alkyl) amine, amino C1-6 alkyl, ( Cu alkyl)amino-based Cl_6 alkyl, double (Cl·6 alkyl)Amino C!·6 alkyl, cyano-Ch alkyl, Ci-6 alkyl acid group, Q -6 alkyl group, q -6 alkyl fluorenyl group (c) _ 6 alkyl) amine group, amine sulfonic acid group, Cu alkyl amine sulfonyl group, bis (Cl-6 alkyl) amine sulfonyl group, Ci 6 ruthenium amide group, C -6 alkyl hydrazine a (Cu alkyl)amino group, an amine methyl sulfhydryl group, a (meth)ylfee-based and a bis(Cle6 alkyl) amine group; or R18 and R19 together with the nitrogen atom to which they are attached form 3 - to 10_membered heterocyclic ring wherein 1 or 2 ring carbon atoms are optionally replaced by N, hydrazine or S, and the ring system is optionally substituted by one or more substituents selected from halo, cyanide 123642 -20 - 200817384 base, nitro, hydroxy, Ch alkyl, Cl_6 alkoxy, _alkyl, halo Cn alkoxy, via (^6 alkyl, via (^-6 alkoxy) , Ch alkoxy q-6 alkyl, Ci-6 alkoxy Ci-6 alkoxy, amine, Ci-6 alkylamine, bis(Cl-6 alkyl)amine, amine C _6 alkyl (Ci-6 alkyl)amino-Ci-6 alkyl, bis(Ci-6 alkyl)aminoalkyl, cyanoq.6 alkyl, (^-6 alkylsulfonyl, Q-6 alkyl) Sulfonyl Amine, q · 6 alkyl thiol (C! - 6 alkyl) amine group, amine sulfonyl group, Cu alkyl amine sulfonyl group, bis (Cl-6 alkyl) amine sulfonyl group, Cl_6 Amine amino group, Ci-6 alkyl fluorenyl (Ch alkyl) amine group, amine methyl sulfhydryl group, Cu alkyl amine methyl sulfhydryl group and bis (Cu alkyl) amine methyl sulfonyl group; for use as a medicament for treating proliferative diseases use. According to another aspect of the invention, there is provided a compound of formula (I)

Or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3 or 4; Y and Y2 are independently N or CR8, provided that one of 1 γ and Y2 is N and the other is CR8; X is a linking group selected from -CR4=CR5-, -Cr4=cr5cr6r7_, -CR6R7CR5=CR4_, -C three C-, -CeCCR6R7_, -CR6R7CeC_, -NR4 CR6 R7 _, _〇CR6 r7 _, _scr6 r7 _ , _s(〇)cr6 R7 ·, side 2 cr6 r7, -c(0)nr4cr6r7-, -NR4c(〇)CR6R7-, _nr4c(o)nr5Cr6r7_, 123642 -21 - 200817384 -NR4S(0)2CR6R7>> -S(〇)2NR4CR6R7- > -C(0)NR4- ^ -NR4C(0>> -NR4 C(0)NR5 -, -S(0)2 NR4 - and -NR4 Chat 2 _ ; R1 is a group selected from the group consisting of Q -6 alkyl, C 2 -6 alkenyl, 〇 2 · 6 alkynyl, carbocyclyl 'carbocyclyl Q-6 alkyl, heterocyclic, and heterocyclic Ci-6 alkyl, this group Substituting one or more substituents, the substituents being selected from the group consisting of _ group, cyano group, nitro group, R9, -OR9, -SR9, -SOR9, -S02R9, -COR9, -C02R9, -CONR9R1(), -NR9R10 ^ NR9 COR10 ^ -NR9C02R10 ^ -NR9 CONR10 R15 , NR9 COCONR1 0 R15 and NR9 S02 R1 〇; ^ or X-R1 is -CR6R7〇H; R2 is selected from C 6-1·6 alkyl, carbocyclic group and Heterocycle a group substituted by -NR CONR1 8 R1 9 and optionally substituted with one or more substituents independently selected from halo, cyano, nitro, -R1 1, -QRl 1 1, -SOR11, -S02Ru, _CORu, -C02Rn, -CONRHrU, _nriir12, NR11 COR1 2 and _NRi i COCONR12 R16 ; each R3 ', when present, is independently selected from halo, cyano, nitro, _Rl 3, _〇Rl 3, 〆-SRl3, -SOR", _S〇2R13, _C0R13, _c〇2Rl3, c〇nr13r14 K-NRl3R14, _NR13COR14, _NR13C02R14 and ”"s〇2Ri4; R4 and R5 are independently hydrogen or Or a combination of one or more atoms to form a 4- to 10-membered carbon ring or heterocyclic ring, wherein 丨, 2 or 3 ring carbon atoms are Substituting N, 0 or S, and the ring is optionally substituted by one or more substituents selected from the group consisting of i, cyano, nitro, hydroxy, keto, 6 alkyl, 1-6 Alkoxy group, _ group Ch alkyl group, tooth base. , alkoxy group, carbyl hydroxy group Cw alkoxy group, q-6 alkoxy Cyalkyl group, Ci6 alkoxy group 123642 -22- 200817384 alkoxy group, amine group, Ci 6 alkylamino group, double (Ci 6 alkyl)amino, amine Ci 6 alkyl, (Cu alkyl) amine C 6 alkyl, bis (Ci 6 alkyl) amine Ci-6 alkyl, aryl alkyl, Ci 6 alkyl sulfonyl , Ci6 alkylsulfonylamino, Ci6 alkylsulfonyl (Cl. 6 alkyl) amine, aminesulfonyl, q-6 alkylamine sulfonyl, bis(Ci-6 alkyl)amine Sulfonyl, Ci 6 alkanoylamino, 6 alkylalkyl (CH alkyl) amine, amine methyl sulfonyl, C16 alkyl amine carbaryl and bis(Ci6 alkyl) urethane; R6 and R7 Independently selected from the group consisting of hydrogen, halo, cyano, nitro & Ci-6 alkyl; R8 is selected from the group consisting of hydrogen, halo, cyano and C 6 alkyl; R 9 and R 1 () are independently hydrogen or are selected from Cl a group of a 6 alkyl group, a carbocyclic group, a carbocyclic group Ci 6 alkyl group, a heterocyclic group and a heterocyclic group C1-6 alkyl group, which group is optionally substituted by one or more substituents, and the substituent is selected From _ group, cyano group, nitro group, hydroxyl group, cv6 alkyl group, (^.6 alkoxy group, halo group (^_6 alkyl group, _ group (^_6 alkoxy group) ^·6 alkyl, hydroxy cle6 alkoxy, Ci-6 alkoxy (^_6 alkyl, ci·6 alkoxy Cn alkoxy, amine, Ch acryl, bis(c1-6 alkyl) Amino, amino Cu alkyl, (c1-6 alkyl) amino Cu alkyl, bis (Cl 6 alkyl) amine (^-6 alkyl, cyano c1-6 alkyl, Cl-6 alkyl sulfonate) Sulfhydryl, Ci6, mercaptoalkyl, alkylsulfonyl (Cl-6 alkyl) amine, amine sulfonyl, alkylamine sulfonyl, bis(C16 alkyl)amine sulfonyl, C1_6 alkane Amidino, Cu alkyl fluorenyl 6-6 alkyl) amine, amine carbaryl, cl6 alkylamine carbhydryl and bis(Cw alkyl)amine carbaryl; RU, R12, R17 and R18 are independent Is hydrogen, or a group selected from the group consisting of a C 6 alkyl group, a carbocyclic group, a carbocyclic group Ci 6 alkyl group, a heterocyclic group and a heterocyclic group Ci 6 alkyl group, which group is optionally substituted by one or more substituents, The substituent is selected from the group consisting of: I group, cyano group, 123642 -23 - 200817384 nitro group, thiol group, Ch alkyl group, Ch alkoxy group, _ group Cn alkyl group, halogen group Ci-6 alkoxy group, hydroxyalkyl group, Hydroxy Ci-6 alkoxy, Ci-6 alkoxy Ci-6 alkyl, Ch alkoxy Ci-6 alkoxy, amine, CV6 alkylamino, bis(CV6 alkyl Amino, aminoCh alkyl, (Cu alkyl)amino Cu alkyl, bis(cie6 alkyl)amino Ci-6 alkyl, cyano Ci-6 alkyl, Ci-6 alkylsulfonyl , alkynylamino, q-6 alkanoyl (Ch alkyl) amine, amine methyl sulfhydryl, (V6 alkyl amine carbaryl and bis (Ch alkyl) amine fluorenyl; 圮 3, 圮 4 , 圮5, 圮6 and 圮9 are independently hydrogen, or are selected from (::1_6 alkyl, carbocyclyl, oxime-based C! -6 alkyl, hetero-yl and heterocyclic -6) a group which is optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, Cyalkyl, Cl-6 alkoxy! a cyanoalkyl group, a halogen group (^-6 alkoxy group, a hydroxy cle6 alkyl group, a hydroxy q-6 alkoxy group, a Ci-6 alkoxy group q-6 alkyl group, a c^6 alkoxy group 6 alkoxy group, Amino, 〇16 alkylamino, bis(Ch alkyl)amino, amino C1-6 alkyl, (Ci6 alkyl)amino·Ci6 alkyl, bis(Ch alkyl)amino Cyalkyl, cyano Ci6 alkyl, Ci 6 alkylsulfonyl, Cu alkylsulfonylamino, Ci 6 alkylsulfonyl (Ci 6 alkyl) amine, amine sulfonyl, Cu alkylamine sulfonyl, Bis(CH alkyl)amine sulfonyl, q-6 alkanoylamino, Ci.6 alkylalkyl (Ci6 alkyl) amine, amine sulfhydryl, alkylamine methyl thiol and bis (CH alkyl) Aminyl group; or R and R together with the nitrogen atom to which they are attached form a 3 to 1 〇 _ % %, wherein 1 or 2 裱 carbon atoms are replaced by N, 0 or S as appropriate, and ί clothing is optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, thiol, Cl-6 alkyl 'Cb6 alkoxy, i-based (: 6 alkyl, Halogen Ch, alkoxy group, base group, base group, 1_6 alkoxy group, Ci-6, 123642, 24-200817384, milk-based Ci_6 alkyl group, Ci_6 alkoxy group Ci- 6 alkoxy, amine, Ci-6 amine group, bis-A-6 alkyl) amine, amine q-6 alkyl, -6 alkyl) amine C!-6 alkyl, double (C^ Alkyl)amino q-6 alkyl, cyano (^_6 alkyl, alkylsulfonyl, -6 alkyl, aryl, Ci-6, alkyl (Ci-6) Amino group, amine fluorenyl group, -6 alkyl amide group acid group, bis% -6 alkyl group, amine sulfonic acid group, q-6 alkyl alkanoyl group, alkyl fluorenyl group (Cu alkyl) amine group, amine Mercapto, (6-6 alkylamine methyl sulfhydryl and bis((V6 alkyl))aminocarbyl; for use as a medicament for the treatment of proliferative diseases. According to another aspect of the invention, a formula (I) is provided Compound

Formula (I) or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3 or 4; W and Y2 are independently N or CR8, provided that one of Y and Y2 is N, and One is CR8; X is a linking group selected from -CR4=CR5-, -CR4=CR5CR6R7-, -CR6R7CR5=CR4-, -C tri-C-, -CeCCR6R7-, -CR6R7CeC-, -NR4CR6R7-, -〇CR6R7 -, -SCR6R7-, -S(0)CR6R7-, -S(0)2CR6R7-, -C(0)NR4CR6R7_, -NR4C(0)NR5CR6R7_, -S(0)2NR4CR6R7_, -C(O)·4 , -NR4 C(O)-, -NR4 C(0)NR5 -, -S(0)2, and _NR4 s(0)2; R1 is selected from Q.6 alkyl, (: 2-6 a group of an alkenyl group, an A4 alkynyl group, a carbocyclic group, a carbocyclic group 123642-25-200817384 q-6 alkyl group, a heterocyclic group and a heterocyclic group Ci_6 alkyl group, which group is optionally one or more Substituted by a substituent, the substituent is selected from the group consisting of halo, cyano, nitro, R9, -OR9, -SR9, _S0R9, _s〇2R9, _c〇r9, _c〇2R9, _c〇nr9r1〇, NR R -NR9 COR10 ' -NR9C02R10 '-NR9 CONR10 R15 --NR9 COCONR1 0 R15 A -NR9 S02 R1 0 ; or X-R1 is -CR6 R7 〇H ; R2 is a group selected from the group consisting of q alkyl, carbocyclic and heterocyclic. This group was replaced by "-NR1 YONR1 8RJ 9 Substituted by one or more substituents, the substituents are independently selected from halo, cyano, nitro, -R1 1, -〇Rl 1, _SRl 1, SOR11, -S02Rn, -COR11, -C02Ru, -CONRnR12 , -NRnR12, NR11 COR1 2 and -NRi i COCONR12 Ri 6 ; each R3 ', when present, is independently selected from the group consisting of halo, cyano, nitro, -Rl 3, -〇Rl 3, -SR13, -SOR13, -S〇2R"...C〇R13, -C〇2R13, _C〇NR13R14, -NR13R14 ^ -NRl3C〇R14 λ .NRl3C〇2Rl4A.NR13S〇2R14 ; R4 and R5 are independently hydrogen or q_6 alkyl; R1 and R4 together with one or more of the atoms to which they are attached form a winter to 1 碳 carbon cyclic or heterocyclic ring wherein 丨, 2 or 3 ring carbon atoms are optionally replaced by N ' Ο or S' And the ring is optionally substituted by one or more substituents selected from the group consisting of a yl group, a cyano group, a nitro group, a hydroxyl group, a ketone group, a Ci6 alkyl group, a q-6 alkoxy group, a dentate group (^-6). Alkyl, dentate Ci 6 alkoxy, hydroxy Ci 6 alkyl, hydroxy Q-6 alkoxy, C 6 alkoxy Ci 6 alkyl, Ci 6 alkoxy Ci 6 alkoxy, amine, Cu Alkylamine, bis(Ci6 alkyl)amine, amine-based Ci6, (Cu burned) An alkyl c1-6 alkyl group, a bis(Ci-6 alkyl)amino group C 6 alkyl group, a cyano A·6 alkyl group, a c 6 alkylsulfonyl group, a Ci 6 alkylsulfonylamino group, Ci-6 123642 -26- 200817384 Alkylsulfonyl (Ci_6 alkyl)amine, amidoxime, q-6 alkylsulfonyl, bis(Ch alkyl)aminesulfonyl, Cu alkane An amine group, a Cu alkyl fluorenyl (Ch alkyl) amine group, an amine sulfhydryl group, an alkyl amine carbhydryl group and a bis (Ch alkyl) amine carbaryl group; R6 and R7 are independently selected from hydrogen, a halogen group, a cyano group, a nitro group and a C! _6 alkyl group; R8 is selected from the group consisting of hydrogen, a halogen group, a cyano group and a Cu alkyl group; the R9 and R1G systems are independently hydrogen or are selected from the group consisting of a C1-6 alkyl group, a carbocyclic group, and a carbon ring* a group of a Cl-6 alkyl group, a heterocyclic group and a heterocyclic group Ci_6 alkyl group, which group is optionally substituted by one or more substituents selected from the group consisting of a benzyl group, a cyano group, a nitro group, and a thio group. , (^1_6 alkyl, (!; 1_6 alkoxy, halo (111-6 alkyl, 1 ^ (^1-6 alkoxy, hydroxy (^_6 alkyl, hydroxy C1-6 alkoxy) , (^-6 alkoxy Ci_6 alkyl, q-6 alkoxy cv6 alkoxy, amine, Cl-6 alkylamino, bis((:1_6 alkyl)amino, amino Cu alkyl, (C L_6 alkyl)amino-based Cl_6 alkyl, bis(Ci-6 alkyl)amine C!·6 alkyl, cyano Ci-6 alkyl, Ci6 alkylsulfonyl, Ci6 alkylthiol , cle6 alkylsulfonyl (Cl_6 alkyl) amine, amine sulfonyl, Cu alkylsulfonyl, bis(Ci 6 alkyl)amine sulfonyl, Ci 6 alkanoyl, Cu alkane a (c1-0 alkyl)amino group, an amine carbenyl group, a Ci6 alkylamine carbenyl group, and a bis(Ch alkyl)amine fluorenyl group;

Rn, R12, R17 and R18 are independently hydrogen or a group selected from the group consisting of a q-6 alkyl group, a carbocyclic group, a fluorenyl group, a heterocyclic group and a heterocyclic group q alkyl group. Depending on the case, it may be substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, thiol, (V6 alkyl, Ci 6 alkoxy, ketone, haloalkoxy) , hydroxyCl 4 alkyl, hydroxyalkoxy, Ci6 alkoxy Cyalkyl, Ch alkoxy Ci-6 alkoxy, amine, Ch alkylamino, bis 123642 -27- 200817384 (Cu alkyl) amine, Amino cw alkyl, (Cl6 alkyl)amino Cu alkyl, bis(q-6 alkyl)amino C!-6 alkyl, cyano Ci 6 alkyl, Ci-6 alkylsulfonyl, Cu alkanoguanidino, Cu alkylalkyl (Cl6 alkyl) amine, amine sulfhydryl, Cu alkylamine methyl thiol and bis(Ci_6 alkyl) amine methyl sulfhydryl; R13, ruler 14, !^5 , 6 and R19 are independently hydrogen or a group selected from the group consisting of a Cp6 alkyl group, a carbocyclic group, a carbocyclic alkyl group, a heterocyclic group and a heterocyclic group Ci-6 alkyl group, which is optionally the case Substituted by one or more substituents selected from halo, cyano, nitro, hydroxy, Cyalkyl, Cl-6 alkoxy ,||Cl-6 alkyl, haloQ-6 alkoxy, hydroxy (^_6 alkyl, hydroxyCl_6 alkoxy, alkoxyalkyl, Q·6 alkoxy fluorene: ^6 alkoxy Amino group, amine group, (^_6 alkylamino group, bis(CV6 alkyl)amino group, amino Cu alkyl group, (c1-6 alkyl) amine group (ν6 alkyl group, bis(Ch alkyl) amine group <;^-6 alkyl, cyano Ci6 alkyl, Cl-6 alkylsulfonyl, Cu alkylsulfonylamino, q-6 alkylsulfonyl ((V6 alkyl) amine, amine sulfonyl) , Cu alkylamine sulfonyl, bis(Ci 6 alkyl)amine sulfonyl, cl 6 alkyl amide, Cu alkyl sulfonyl (Cw alkyl) amine, amine sulfhydryl, Cu alkyl amine Mercapto and bis(Ch alkyl)amine fluorenyl; or R18 together with R19 and the nitrogen atom to which they are attached form a 3 to 10 membered heterocyclic ring, wherein 1 or 2 ring carbon atoms are optionally taken by n , hydrazine or S substitution, and the ring is optionally substituted by one or more substituents selected from the group consisting of glutenyl, cyano, nitro, hydroxy, alkyl, Cl-6 alkoxy, haloCl-6 , haloalkoxy, hydroxy Ci-6 alkyl, hydroxy<^6 alkoxy, Ci-6 alkoxy C^6 alkyl, Ci-6 alkoxy c1-6 alkoxy, amine Base, Ci-6 alkylamino group, bis(cv6 alkyl)amino group, amine Cu alkyl group, (Cl-6 alkyl) amino group Cu alkyl group, bis(Ci-6 alkyl)amino group Ci-6 Alkyl group, cyano Cn alkyl group, Ci-6 base code 醯123642 -28- 200817384 base [I -6 alkyl group decylamino group, Q -6 alkyl decanoic acid group _ 6 gal group) amine group , amine 〜 yl, cw alkylamine hydrazino, bis(c16 alkyl)amine sulfonyl, q -6 alkyl amide, Cl-0 alkyl (Ch alkyl) amine, amine methyl sulfhydryl , Cl_6 alkylamine methyl sulfhydryl and bis (Cl 6 alkyl) amine methyl thiol; for use as a medicament for the treatment of proliferative diseases. According to another aspect of the present invention, there is provided a use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a proliferative disorder, c [%/,

m is 0, 1, 2, 3 or 4; ΐγ and Y2 are independently N or CR8, provided that one of Ιγ and Y2 is N and the other is CR8; X is a linking group selected from -CR4=CR5 -, cr4=cr5cr6r7 _, -CR6R7CR5=CR4_, -CEC-, -CeCCR6R7-, _CR6R7C, three c·, -NR4CR6R7- > -OCR6R7-, -SCR6R7- > -S(0)CR6R7- ^ -S( 0) 2CR6R7- > -C(0)NR4CR6R7·, 4〇;〇)〇161^-, -NR4S(0)2CR6R7-, -S(0)2NR4CR6R7-, -C(0)NR4-, -NR4c (0y, -NR4 C(0)NR5 -, _S(〇)2 NR4 _ and view 4 s(〇)2 _ ;

R1 is a group selected from the group consisting of hydrogen, Cl-6 alkyl, c2-6 alkenyl, c2-6 fast group, carbocyclic group, carbon% group (^-6 alkyl group, heterocyclic group and heterocyclic group Ci 6 alkyl group). The group is 123642 -29-200817384. The substituent is substituted by a plurality of substituents selected from the group consisting of _ group, an aryl group, a terracotta R, a spectroscopy 9, a -S0R9, a -S02R9, a -COR9, a -C02R9, , Qing, 服9c〇Rl0, gift..., -NR9CONR1〇R15 λ -NR^COCONR^RI^nrPs^^o; R is a group selected from the group consisting of an alkyl group, a carbocyclic group and a heterocyclic group. Substituted by -NR^CONR^r^^ α, ad, and as the condition is replaced by one or more substituents,

The substituents are independently selected from the group consisting of _ group, cyano group, nitro group, R11, -OR11, _SR11, SOR > -S02R11 . .C〇Rl 1 N .c〇2Ri 1 N .C〇NRl 1 R1 2 Λ .NR1 1 R1 2 Λ -NR11 COR1 2 and 11 c〇c〇NRl 2 Rl 6 ; each R ^ exists in the day, independently selected from halo, cyano, nitro, _Rl 3, _〇Rl 3, -SR13 ^ -SOR13 > -S02R13 ^ -COR13 > -C02R13 ^ -CONR13R14 ^ -NRHRM, ·NRUCOrM, 视"c〇2Rl4A 138〇^14; R4 and R5 are independently hydrogen or c 1-6 alkyl; Or R1 and R4 together with one or more of the atoms to which they are attached form a 4 to 1 ring-shaped ring or a heterocyclic ring, wherein 2, 3 or 3 ring carbon atoms are optionally N, Ο Or S is substituted, and the ring is optionally substituted by one or more substituents selected from the group consisting of i, cyano, nitro, hydroxy, keto, Ci 6 alkyl, Ci-6 alkoxy, halo Cb6 Alkyl, _yl Cle6 alkoxy, hydroxy (^-6 alkyl, hydroxy c^6 alkoxy, q-6 alkoxy Ci-6 alkyl, 〇ν6 alkoxy cv6 alkoxy, amine, Ci- 6 alkylamino, bis(Cu alkyl)amine, amine Cu alkyl, (Ch alkyl)aminoCh alkyl, bis(Ch alkyl) Ci_6 alkyl, cyano Ci-6 alkyl, Ci-6 alkylsulfonyl, Cil alkylsulfonylamino, Ci-6 alkylsulfonyl (C!-6 alkyl) amine, amine sulfonate Sulfhydryl, Cu alkylamine sulfonyl, bis(Cw alkyl)amine sulfonyl, Cu alkanoyl, Cu alkanoyl (Ch alkane 123642 -30- 200817384) amine, amine methyl sulfhydryl, Ci 6 alkylamine sulfhydryl and bis 6 alkyl)amine oxime, R6 and R7 are independently selected from the group consisting of hydrogen, _ group, cyano group, nitro group and alkyl group; R8 is selected from hydrogen, halogen group and cyanide And q _6 alkyl; 妒 and 圮 0 are independently hydrogen, or a group selected from the group consisting of an alkyl group, a carbocyclic group, a carbocyclic group Cl_6, a heterocyclic group and a heterocyclic group C 6 alkyl group. Substituted by one or more substituents selected from halo, cyano, nitro, thiol, Cw alkyl, cl-6 alkoxy, haloCi6 alkyl, _*Ci 6 Alkoxy, alkylalkyl, hydroxyCh alkoxy, <^_6 alkoxy (^6 alkyl, C!6 alkoxy Cl-6 alkoxy, amine, Cl-6 alkylamine, bis ( (:1_6 alkyl)amino group, amino Cu alkyl group, ((V6 alkyl)amino group Cu alkyl group, bis(Cl_6 alkyl)amino group Cl-6 alkyl group, gas Base Cl-6 alkyl, Cl-6 alkyl acid group, Cl alkyl sulfonate amine group, Ci_6 alkylsulfonyl (Cu alkyl) amine group, amine sulfonyl group, Cu alkyl amine sulfonium sulfonate Base, bis(Cl_6 alkyl)amine sulfonyl group, Ci 6 alkanoguanamine group, Cu alkyl fluorenyl (Cl 6 alkyl) amine group, amine carbaryl group, alkyl amine carbaryl group and bis (Ch alkyl group) Aminomethyl sulfhydryl;

Rn, R12, R17 and R18 are independently hydrogen or a group selected from the group consisting of a Cu alkyl group, a carbocyclic group, a carbocyclic group q-6 alkyl group, a heterocyclic group and a heterocyclic group C1-6 alkyl group. The group is optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, C^6 alkyl, (^-6 alkoxy, haloCi-6 alkyl, halo) Ci-2-alkoxy, hydroxy (^_6 alkyl, hydroxy Ci-6 alkoxy, Cil alkoxy C1·6 alkyl, Ci·6 oxy cle6 alkoxy, amine, Ci-6 Acrylamine, bis(Ch alkyl)amine, amine Cu alkyl, (Cm alkyl)aminoCh alkyl, bis(Ci-6 alkyl)amine Cle6 alkyl, cyanoC alkyl, cumane Sulfonium sulfonate 123642 -31 - 200817384 base, Ch-burning amine group, Cu alkylalkyl (Ci 6 alkyl) amine group, amine methyl sulfhydryl group, (V6 alkyl amine sulfhydryl group and bis (Cl 6 alkyl) amine Sulfhydryl; R13, R14, R15, R16 and R19 are independently hydrogen or selected from the group consisting of 6 alkyl, carbocyclyl, carbocyclyl, -6 alkyl, heterocyclic and heterocyclic Ci 6 a group of an alkyl group which is optionally substituted by one or more substituents selected from the group consisting of a cyano group, a cyano group, a nitro group, a hydroxy group, and a (^-6 alkane group). , (^_6 alkoxy, halo (^_6 alkyl, haloalkoxy, hydroxy c^6 alkyl, hydroxy C1-6 alkoxy, Ci 6 alkoxy Q-6 alkyl, q — 6 alkoxyalkoxy, amino, alkylamino, bis(Ci-6 alkyl)amine, amine C!-6 alkyl, (c1-6 alkyl)amino Ci-6 alkyl, bis (Ch alkyl Amino-Ci-6 alkyl, cyano c1-6 alkyl, Ci-6 alkylsulfonyl, Cu alkylsulfonylamino, Cu alkylsulfonyl (Cu alkyl) amine, amine Sulfonyl, Cu alkylamine sulfonyl, bis(c1-6 alkyl)amine sulfonyl, Cu alkanoyl, Cu alkylalkyl (Cu alkyl) amine, amine methyl sulfonyl, cumane a carbamide group and a bis(CV6 alkyl) amidino group; or R18 together with R19 and the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic ring, wherein 1 or 2 ring carbon atoms are The condition is replaced by n, hydrazine or S, and the ring is optionally substituted with one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, Ci.6 alkyl, C.sub.6 alkoxy, Tooth group (^_6 alkyl, halo (^-6 alkoxy, hydroxy C!-6 alkyl, hydroxy Ci-6 alkoxy, Ci-6 alkoxy (^-6 alkyl, Cle6 alkoxy) Ci- 6 alkoxy group, amine group, Ci_6 alkylamino group, bis(C-6-6alkyl)amino group, amine group C]-6 alkyl group, (C!6 alkyl group) amine group Ci-6 alkyl group, double (Ci-6 alkyl)amino-based Cl-6 alkyl, cyano-Ci-6 alkyl, Ch-alkylsulfonyl, CV6 alkylsulfonylamino, Cu alkylsulfonyl (Cu alkyl) amine Aminesulfonyl, (V6 alkylamine sulfonyl, bis(c1-6 alkyl)amine sulfonyl, Cl_6 123642 -32- 200817384 alkanoyl, Cu alkyl sulfonyl (Ch alkyl) amine Amine oxime, Cu alkylamine methyl sulfhydryl and bis (CV6 alkyl) amine carbaryl. According to another aspect of the present invention, there is provided a use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a proliferative disorder,

Wherein m is 0, 1, 2, 3 or 4; W and Y2 are independently N or CR8, provided that one of 1Y and Y2 is N and the other is CR8; X is a linking group selected from - CR4=CR5-, -CR4=CR5CR6R7-, , -CeC-, -CeCCW-, three C-, -NR4CR6R7-, -OCR6R7_ ' -SCR6R7-, -S(0)CR6R7·, -S(0)2CR6R7- , -c(o)nr4cr6r7-, -nr4c(o)cr6r7-, -nr4c(o)nr5cr6r7-, -NR4S(0)2CR6R7-, -S(0)2NR4CR6R7-, -C(0)NR4-,- NR4C(0)-, -NR4 C(0)NR5 ·, -S(0)2 NR4 - and -NR4 S(0)2 -; R1 is selected from an alkyl group, a C2_6 alkenyl group, a C2-6 alkynyl group, a carbocyclic group, a carbocyclic group Cu alkyl group, a heterocyclic group and a heterocyclic group (^-6 alkyl group), the group being optionally substituted by one or more substituents selected from a halogen group and a cyanogen group Base, nitro, -R9, -OR9, -SR9, -SOR9, -S02R9, -COR9, -C02R9, -CONR9R10, -NR9 R1 0, -NR9 COR10, -NR9C02R10, -NR9 CONR1 0 R15, 123642 -33 - 200817384 -NR9 COCONRi 〇Ri 5 and 〇s〇2 r1 ” or X-R1 is -CR6 R7 〇H ; R is a group selected from the group consisting of C 66 alkyl, carbocyclic group and fluorenyl group. The group is replaced by -NR17C0NR18R19, depending on one or more conditions Substituted by a substituent, the substituent is independently selected from the group consisting of i, cyano, nitro...R11, n, n, -SOR, -S02 R11, -COR11, :C〇2 Ri 1, c〇NRl i Rl 2 NRl i r1 2 -NR11 COR1 2 and, NR" COCONR12 ri 6 ·

Each R3, when present, is independently selected from the group consisting of halo, cyano, nitro, _rU, _〇Rn, -SR13, -SOR13, -S〇2R", _c〇R", -C〇2Ri3, c〇 Nr13r14 -NR13R14 > -NR13COR14 - -NR13C02R14^-NR13S02R14 ; R4 and R5 are independently hydrogen or C 6 alkyl; or R1 and R4 together with one or more of the atoms to which they are attached form 4_ to 1〇 a carbon cyclic or heterocyclic ring wherein 1, 2 or 3 ring carbon atoms are optionally substituted by N, hydrazine or S, and the ring is optionally substituted by one or more substituents selected from the group consisting of Halo, cyano, nitro, hydroxy, keto, q _6 alkyl, Ci-6 alkoxy, yl ch-alkyl, ii alkoxy, via Cn alkyl, hydroxy (V6 alkoxy, CV6 Alkoxy CV6 alkyl, CV6 alkoxy Ch alkoxy, amine, q.6 alkylamino, bis(Cu alkyl)amine, amine Cu alkyl, (Ci-6 alkyl) amine Ci-6 alkyl, bis(Cu alkyl)aminoCh alkyl, cyano Ci-6 alkyl, Ci-6 alkylsulfonyl, Ci-6 alkylsulfonylamino, alkylsulfonyl ( Ch alkyl)amino, amidoxime, Ci-6 alkylamine sulfonyl, bis(Ch alkyl)amine sulfonyl C _6 alkyl amidino group, Ci-6 alkyl fluorenyl (Ch alkyl) amine group, amine sulfhydryl group, Ci-6 alkylamine methyl sulfhydryl group and bis (Ci-6 alkyl) amine fluorenyl group; 123642 -34- 200817384 r6 and r7 are independently selected from the group consisting of hydrogen, halo, cyano, nitro and Cu alkyl; R8 is selected from hydrogen, halo, cyano and Cl-6 alkyl; R9 and R1G are independently hydrogen Or a group selected from the group consisting of a Ci6 alkyl group, a carbocyclic group, a carbocyclic alkyl group, a heterocyclic group and a heterocyclic alkyl group, the group being optionally substituted by one or more substituents selected from the group consisting of _ group, cyano group, nitro group, thiol group, (^_6 alkyl group, Cl_6 alkoxy group, functional group Ch alkyl group, halo group C 6 alkoxy group, hydroxyalkyl group, hydroxy Ci-6 alkoxy group, q- 6 alkoxy Cij alkyl, alkoxy Ci-6 alkoxy, amine, Ch alkylamino, bis(Ch alkyl)amine, amine CV6 alkyl, (Ci.6 alkyl)amine (V6 alkyl, bis(Ch alkyl)amino-Ci-6 alkyl, cyano-Cu alkyl, alkylsulfonyl, Cu alkylsulfonylamino, Cu alkylsulfonyl (Ci-6) Alkyl)amino, aminsulfonyl, Cu alkylamine sulfonyl, bis((-6-)alkylsulfonyl, Cu alkanoyl, alkanoyl (C I-6 alkyl)amino group, amine carbaryl group, Cu alkylamine fluorenyl group and bis(Ch alkyl)aminocarbamyl group; 1111, 1112, 1117 and 1118 are independently hydrogen or selected from 0: a group of a 1_6 alkyl group, a carbocyclic group, a carbocyclic group Ci-6 alkyl group, a heterocyclic group, and a heterocyclic group Ci-6 alkyl group, which group is optionally substituted by one or more substituents, and a substituent Selected from the group consisting of ii, cyano, nitro, hydroxy, (V6 alkyl, Ci-6 alkoxy, i-alkyl, haloCl-6 alkoxy, light-based Ci-6 alkyl, trans-Cl -6 alkoxy, Cl-6 alkoxy Cyalkyl, (V6 alkoxy Ci-6 alkoxy, amine, c -6 alkylamine, bis(Cu alkyl)amine, amine Ch Alkyl, ((V6 alkyl)amino Cualkyl, bis(Ci-6 alkyl)amino Ci-6 alkyl, cyano Ci-6 alkyl, C^6 alkylsulfonyl, Cu decylamine Base, Cu alkyl fluorenyl ((^_6 alkyl)amino group, amine fluorenyl group, q _ 6 alkylamine carbhydryl group and bis (Ch alkyl) amine fluorenyl group; 123642 - 35 - 200817384 R ' R , R1 5, R1 6 and R1 9 are independently hydrogen or a group selected from the group consisting of a q 6 alkyl group, a carbocyclic group, a carbocyclic group Ci 6 alkyl group, a heterocyclic group and a heterocyclic group C 6 alkyl group. system The case is substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, q-6 alkyl, alkoxy, i-based (^-6 alkyl, halo-Ci-6 alkoxy) Base, hydroxy c^6 alkyl, hydroxyalkoxy, alkoxy C^6 alkyl, q-6 alkoxy Cle6 alkoxy, amine, (^-6 alkylamino, bis(Ci-6) Amino group, amino group Ci-6 alkyl group, (Cu alkyl) amino group Cu alkyl group, bis(Cl-6 alkyl)amino group C! -6 alkyl group, gas-based Ci-6 group, Ci- 6 alkyl base, Ci-6 alkyl 26Si & amine group, C! · 6 alkyl base acid (C! _ 6 alkyl) amine, amine sulfonyl, q-6 alkyl sulfonate Mercapto, bis(Cu alkyl)amine sulfonyl, Ci_6 alkyl amide, Ci-6 alkyl fluorenyl (Cu alkyl) amine, amine methyl sulfhydryl, alkyl amine carbhydryl and bis (Cu alkane Or an indenyl group; or R18 together with R19 and the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic ring wherein one or two ring carbon atoms are optionally replaced by N, hydrazine or S, and The ring is optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, thiol, C!-6 alkyl, CBu 6 alkoxy, halo Ci _ 6 alkyl, halo C^-6 alkoxy, hydroxy Cil alkyl, hydroxy q-6 alkoxy, (^_6 alkoxy C!-6 alkyl, Ci -6 alkoxy Ci-6 burning oxygen Base, amine group, acrylamine group, bis(Ci-6 alkyl)amino group, amine Ci-6 alkyl '(Ci_6 alkyl)amino group Ci_6 alkyl group, bis(Ci-6 alkyl) amine group Ci_6 Alkyl, cyano (^_6 alkyl, alkylsulfonyl, (V6 alkylsulfonylamino), cv6 alkylsulfonyl (Cu alkyl) amine, amine sulfonyl, Ci-6 alkane Amidoxime, bis(C!-6 alkyl)amine sulfonyl, Ci-6 alkanoylamino, Ci-6 alkanoyl (Ch alkyl) amine, amine carbaryl, Cu alkylamine Formamyl and bis(Ch alkyl)amine mercapto. 123642 -36 - 200817384 according to another aspect of the invention, there is provided a use of a compound of formula 1 or a pharmaceutically acceptable salt for the manufacture of a medicament for the treatment of a proliferative disorder;

Wherein m is 0, 1, 2, 3 or 4; 1Y and Y2 are independently N or CR8, provided that one of 1 γ and γ2 is N and the other is CR8; X is a linking group selected from _cr4 =cr5- , -〇ι4:=αι5αι6ιι7_ , -CR6R7CR5 =GR4 -, ξ ο, -G Ξ GCR6R7-, R7C three C-, -NR4CR6R7·, -OCR6R7 ... SCR6R7~s(〇)cr6r7, _s(〇) 2Cr6r7, -C(0)NR4Cr6r7-, -NR4c(〇)nr5cr6r7-, _s(〇)2Nr4cr6r7, •C(O) clothes 4 _, 视4 C(〇卜胤4 c(〇辉5 s(〇 2) 4 _ and __ R1 is selected from (V6 alkyl, C: 2·6 alkenyl, c: 2·6 alkynyl, carbocyclyl, carbocyclyl C! -6 alkyl, heterocyclic and a group of a heterocyclic group C!-6 alkyl group, which group is optionally substituted by one or more substituents selected from the group consisting of halo, cyano, fluorenyl, -R9, -OR9, -SR9, - SOR9, -S02R9, -COR9, -C02R9, ·(:〇¥〇, -NR9R10 ^ -NR9 COR10 ^ -NR9C02R10 . -NR9 CONR10 R15 ^ -Nr^COCONR^E^l-NI^SC^R10; R2 is a group selected from the group consisting of C!-6 alkyl, carbocyclyl and heterocyclyl, which group is substituted by -NR1 7 CONR18 R1 9 and optionally substituted by one or more substituents, 123642 • 37- 200817384 The substituents are independently selected from _ group, cyano group, nitro group, water n, _〇Rll, -sr11, SOR S02 R i . -COR11 - -C02 R11 &gt; -CONR11R1 2 &gt; -NR11 R12 &gt; -NR11 COR1 2 and ·]s^Ri 1 cqcqnR1 2 R1 6 ; each R3, when present, is independently selected from the group consisting of _ group, cyano group, nitro group, _r13, _〇r1S, -SR, -SOR 3, _s〇2R13, -COR13, -C02R13, -CONR13R14, -nr13r14, -nr&quot;cor14 ... R&quot;c〇2Rl4&amp; nr13s〇2R14 · R4 and R5 are independently hydrogen or Ci 6 alkyl; or R1 and R4 are linked to them. One or more atoms are taken together to form a 1 碳 carbon cyclic or heterocyclic ring, wherein 丨, 2 or 3 ring carbon atoms are optionally replaced by N, Ο or S' and the ring is optionally treated by one or Substituted by a plurality of substituents, the substituent is selected from the group consisting of a benzyl group, a cyano group, a nitro group, a hydroxyl group, a ketone group, a Ci_6 alkyl group, a Ch calcinyl group, a yl group (^6 alkyl group, a halogen group (^_6 alkoxy group, Light base (^_6 alkyl, hydroxy Cm alkoxy, CV6 alkoxy Ci-6 alkyl, Ci-6 alkoxy (ν6 alkoxy, amine, Cu alkylamino, bis((ν6 alkyl)), Amino Cu alkyl, (Cu alkyl) amino Cu alkyl, bis (Cu alkyl) amine Ci. 6 alkane a cyano group, a cyano C^·6 alkyl group, a Ci-6 alkylsulfonyl group, a Ci-6 alkylsulfonylamino group, a (^_6 alkyl group (C! -6 alkyl) amine group, Aminesulfonyl, -6 alkyl sulfonyl, bis(Ci-6 alkyl) sulfonyl, Cu succinyl, Cu succinyl (Ch alkyl) amine, amine methyl sulfhydryl, Ch alkylamine mercapto and bis(CV6 alkyl)amine mercapto; R6 and R7 are independently selected from the group consisting of hydrogen, halo, cyano, nitro and CV6 alkyl; R8 is selected from hydrogen, halo, Cyano and 4-6 alkyl; R9 and R1 G are independently hydrogen, or are selected from the group consisting of q-6 alkyl, carbocyclyl, carbocyclyl q_6 alkyl, heterocyclyl and heterocyclyl. The group, which is optionally substituted by one or more substituents, is selected from the group consisting of halo, cyano, nitro, hydroxy, cv6 alkyl, 〇^_6 alkoxy, i group, as the case may be, 123642 - 38 - 200817384 Cu alkyl, _yl (^-6 alkoxy, hydroxyalkyl, hydroxy Ci-6 alkoxy, α_6 alkoxy q-6 alkyl' (^_6 alkoxy <^·6 alkoxy, amine Base, (^_6 alkylamino group, bis((V6 alkyl)amino group, amino group cv6 alkyl group, (Ch alkyl)amino group Cu alkyl group, bis(Ch alkyl)amino group Ci-6 alkyl group Quanji Ci-6 alkyl, Ci-6 alkyl acid group, Cl-6 alkylsulfonylamino group, Ciw alkylsulfonyl (Ch alkyl) amine group, amine sulfonyl group, Cu alkyl group Aminesulfonyl, bis(c1-6 alkyl)amine sulfonyl, CV6 alkanoylamine, Cu alkylalkyl (Cu alkyl) amine, amine methyl sulfonyl, Cu alkyl amine methyl thiol and double (Cu alkyl) amine sulfhydryl;

Rn, R12, R17 and R18 are independently hydrogen or a group selected from the group consisting of a Cb6 alkyl group, a carbocyclic group, a carbocyclic group &lt;^6 alkyl group, a heterocyclic group and a heterocyclic group Ci 6 alkyl group. The group is optionally substituted by one or more substituents selected from the group consisting of dentate, cyano, nitro, hydroxy, q.6 alkyl, Cl-6 alkoxy, _*Ci 6 alkyl, halo q- 6 alkoxy, hydroxy c 6 alkyl, hydroxy C 14 alkoxy, C 16 alkoxy CV 6 alkyl, c 6 alkoxy Cy alkoxy, amine, Ci 6 alkylamino, bis (Cu alkane Amino group, amino group cw alkyl group, (Ci6 alkyl)amino group Ci-6 alkyl group, bis(Ci-6 alkyl)amino group C!·6 alkyl group, cyano Ci 6 alkyl group, (^ ^alkylsulfonyl, Cu alkanoyl, q.6 alkylalkyl (Ci6 alkyl) amine, amine methyl sulfonyl, Cu alkyl amine methyl thiol and bis (ci 6 alkyl) amine formazan It13': R14': R15': R16 and R19 are independently hydrogen' or are selected from the group consisting of a chromo group, a carbocyclic group, a carbocyclic group, a ^6 alkyl group, a heterocyclic group and a heterocyclic group Ci6 alkyl group. a group, which is optionally substituted with - or a plurality of substituents selected from the group consisting of a picture group, a cyano group, a nitro group, a hexyl group, a CH alkoxy group, !i Cl.6 alkyl, 123642 -39- 200817384 Halo Ci-6 alkoxy, hydroxy c!-6 alkyl, hydroxy (^_6 alkoxy, (^_6 alkoxy Ci-6 alkyl, Ci-) 6 alkoxy (^_6 alkoxy, amine, Ci-6 alkylamino, bis(Cl-6)alkyl, amine q-6 alkyl, (Ci-6 alkyl) amine Ci - 6 alkyl, bis(Cl-6 alkyl)amino-6 alkyl, nitrogen A _6, -6 alkyl, (V6 alkylsulfonylamino, Cu alkylsulfonyl) (Ci-6 alkyl)amino, sulfonyl, Ci-6 alkylamine sulfonyl, bis(Ch alkyl)amine sulfonyl, Cn alkanoyl, Ci-6 alkyl fluorenyl (( ^_6 alkyl)amino, amidyl, alkylamine, and bis(cv6 alkyl)aminecarbamyl; or R18, together with R19 and the nitrogen atom to which they are attached, form 3- to 10- a heterocyclic ring in which one or two ring carbon atoms are optionally replaced by N, hydrazine or S, and the ring is optionally substituted by one or more substituents selected from the group consisting of halo, cyano and nitro , hydroxy, Ch alkyl, Ch alkoxy, _ group &lt; ^ -6 alkyl, halo &lt; ^ 6 alkoxy, hydroxy (^ 6 alkyl, hydroxy (^-6 alkoxy, alkoxy) Ci-6 alkyl q _6 alkoxy Ci-6 alkoxy, amine, Ci-6 alkylamino, bis(Cu alkyl)amine, amine Cu alkyl, (Cu alkyl)amino cv6 alkyl, double ( C^alkyl)amino cv6 alkyl, cyano Ci-6 alkyl, Cu alkylsulfonyl, Cu alkylsulfonylamino, Cu alkylsulfonyl (Cu alkyl) amine, amine sulfonium Base, Ci-6 alkylamine sulfonyl, bis(Cu alkyl)amine sulfonyl, Cu alkanoyl, Cu alkyl hydrazide (Ch alkyl) amine, amine carbaryl, Ci-6 alkylamine Formyl and bis(Cu alkyl)amine fluorenyl. According to a further aspect of the invention there is also provided a compound of formula (I) 123642 - 40 - 200817384

Formula (I) or a pharmaceutically acceptable salt thereof; wherein m is 0, 1, 2, 3 or 4; W and Y2 are independently N or CR8, provided that one of 1Y and Y2 is N, and the other Is CR8; X is a linking group selected from -CR4=CR5-, -CR4=CR5CR6R7-, -CR6R7CR5=CR4-, -C tri-C-, -C tri CCR6R7-, -CR6R7CeC-, -NR4CR6R7- &gt; - OCR6R7- - -SCR6R7- ^ -S(0)CR6R7- &gt; -S(0)2CR6R7- ' _C(0)NR4CR6R7-, -nr4c(o)cr6r7-, -nr4c(o)nr5cr6r7-, -NR4S( 0) 2CR6R7-, -S(0)2 Service 4CR6R7-, -C(0)NR4-, -NR4C(0)-, -NR4 C(0)NR5 -, -(〇)2 NR4 - and -NR4 S (0)2 -;

R1 is a group selected from the group consisting of a mouse, a Ci-6 carbonyl group, a C2-6 fine group, a C2-6 fast group, a carbon bad group, a stone cyclyl-6 alkyl group, a heterocyclic group, and a heterocyclic group q _6 alkyl group. This group is optionally substituted by one or more substituents selected from the group consisting of cyano, cyano, nitro, -R9, -OR9, -SR9, -SOR9, -02R9, -COR9, -C02R9, -CONR9R10 -NR9R10, -NR9 COR10, -NR9C02R10, -NR9CONR10R15, -NR9COCONR10R15 and NR9S02R10; R2 is a group selected from the group consisting of an alkyl group, a carbocyclic group and a heterocyclic group, and this group is replaced by ?nrhconr1 sr1 9 and The case is substituted by one or more substituents independently selected from halo, cyano, nitro, -R11, -OR11, -SR11, 123642 -41 - 200817384 _SORn, -S02Ru, -COR11, -C02Rn, - CONRnR12, -NRnR12, -NR11 COR1 2 and -NR11 COCONR1 2 R1 6 ; each R3, when present, is independently selected from halo, cyano, nitro, -Rl 3, -ORl 3, -R13, -SOR13 , -S02R13, -COR13, -C02R13, -CONR13R14, -NR13R14, -NRi3c〇Ri4, - (a) kiss rule "and view (a) ruler"; R4 and R5 are independently hydrogen or (: 6 alkyl; or Rl and R4 and their offices One or more atoms together form a 4- to 10-membered carbon ring or heterocyclic ring wherein 1, 2 or 3 ring carbon atoms are optionally replaced by N, Ο or S, and the ring is viewed The case is substituted by one or more substituents selected from the group consisting of a yl group, a cyano group, a nitro group, a hydroxy group, a ketone group, a (^-6 alkyl group, a Ci-6 alkoxy group, a group of a base group, a functional group ^^ alkoxy, via Ci_6 alkyl, hydroxy Ci-6 alkoxy, Cl-6 alkoxy Cl-6 alkyl, Cl-6 alkoxy Ci6 alkoxy, amine, CV6 alkylamino, bis (Ch alkyl Amino group, amine group Cl_6 alkyl group, ((V6 alkyl)amino group Cl_6 alkyl group, bis(Cl_6 alkyl)amino group Ci-6 alkyl group, cyano Q-6 alkyl group, Ci -6 alkyl group Base, Ci -6 burning base sulfhydryl group, q _6 alkyl group (CV 6 alkyl) amine group, amine sulfonyl group, C! -6 alkyl group, bis (Cw alkyl) Aminesulfonyl, Cu alkanoyl, Cu alkyl sulfonyl (Ch alkyl) amine, amine sulfhydryl, alkyl amine fluorenyl and bis (&lt;^6 alkyl) amine carbenyl; R6 Independently selected from the group consisting of hydrogen, halo, cyano, nitro and 〇1_6 alkyl; R8 is selected from the group consisting of hydrogen, halo, cyano and Ci-6 alkyl; Is independent of the R system, or a group selected from the group consisting of a q-6 alkyl group, a carbocyclic group, a carbocyclic group, a q6 alkyl group, a hetero chelating group, and a heterofluorenyl Ci-6 group. Substituted by one or more substituents, the substituent is selected from the group consisting of cyano, cyano, nitro, hydroxy, 123642-42-200817384 hydroxy, Ci-6 alkyl, Ch alkoxy, halo (ν6 alkyl, Halo CV6 alkoxy group, hydroxy group (V6 alkyl group, trans group (^-6 alkoxy group, ¢^-6 alkoxy group Ch alkyl group, (V6 alkoxy group (V6 alkoxy group, amine group, &lt; ^_6 alkylamino, bis((^_6 alkyl)amino, amino Cualkyl, (Cu alkyl)aminoCh alkyl 'bis(Cu alkyl) te-based Ci-6 alkyl, oxy Ci-6 alkyl, Ci-6 alkyl acid group, Ci-6 alkylsulfonylamino group, Α6 alkylsulfonyl (Ci-6 alkyl) amine group, amine sulfonyl group, Cu alkyl group Aminesulfonyl, bis(Ch alkyl)amine sulfonyl, Cl-6 alkanoyl, (V6 alkyl fluorenyl (〇ν6 alkyl) amine, amine methyl sulfonyl, Cl-6 alkylamine fluorenyl And bis(Cle6 alkyl)amine carbenyl; the ruthenium 11,1112,1117 and 1118 are independently hydrogen or are selected from (:1_6 alkyl, carbocyclyl, carbocyclyl Ci-6 alkyl, hetero And a heterocyclic Cil alkyl group, the group being optionally substituted by one or more substituents selected from the group consisting of a yl group, a cyano group, a nitro group, a hydroxyl group, a (^-6 alkyl group, an alkoxy group) Base, _ group (^_6 alkyl, halo Ci-6 alkoxy, hydroxy C^6 alkyl, hydroxy Cil alkoxy, Ci-6 alkoxy Ci. 6 alkyl, Ci_6 alkoxy Ci- 6 alkoxy group, amine group, Ci-6 alkylamino group, bis(Ch alkyl)amino group, aminoCh alkyl group, (Cl-6 alkyl)amino group C 6 alkyl group, bis(Ci_6 alkyl)amino group Cn An alkyl group, a cyano group c1-6 alkyl group, a (^-6 alkyl group, a Cu alkyl amidino group, a Ci-6 alkyl alkano group (c1-6 alkyl) amine group, an amine methyl group, a Cu alkylamine Mercapto and bis(Ch alkyl)amine carbenyl; R 3, R14, R15, R16 and R19 are independently hydrogen or selected from. a 6-alkyl group, a carbocyclic group, and a carbocyclic group. a group of a -6 alkyl group, a heterocyclic group and a heterocyclic group Ci6 alkyl group, the group being optionally substituted by one or more substituents selected from the group consisting of a halogen group, a cyano group, a nitro group, a hydroxyl group, and a Cy group. Alkyl, cl-6 alkoxy, _yl 1-6 alkyl, haloq-6 alkoxy, hydroxy C!-6 alkyl, hydroxy Ci 6 alkoxy, €16 alkane 123642 -43 - 200817384 Oxygen Chyryl, alkoxy Ci 6 alkoxy, amine, Ci 6 alkylamino, bis(Cu-based) amine, amine cle6 alkyl, (Cl-6 alkyl) amine Cu alkyl , bis(Cu alkyl)amino Cu alkyl, cyano Ci6 alkyl, Ci6 alkylsulfonyl, Cu alkylsulfonylamino, c16 alkylsulfonyl (Ci6 alkyl) amine, amine Sulfonyl, Cu alkylamine sulfonyl, bis(Ci 6 alkyl)amine sulfonyl, cl 6 alkanoic acid amine, c oxalic acid (cw alkyl) amine group, amine methyl sulfonyl group, Cl 6 olefin a carbamide group and a bis(Q -6 alkyl) amidino group;

Or R18 together with R19 and the nitrogen atom to which they are attached form a 3 to 10-membered heterocyclic ring, wherein 1 or 2 ring carbon atoms are optionally replaced by n, hydrazine or S, and the ring is optionally Substituted by a plurality of substituents selected from the group consisting of a yl group, a cyano group, a nitro group, a hydroxyl group, an alkyl group, a Cl_6 alkoxy group, a functional group C1-6 alkyl group, a halogen group (^_6 alkoxy group, a hydroxyl group (^) _6 alkyl, hydroxy Cl-6 alkoxy, CV6 alkoxy (^1-6 alkyl, 1-6 alkoxy (!11-6 alkoxy, amine, (^1-6 alanine) Base, bis(Cl-6 alkyl)amino group, amine group Ci 6 alkyl group, (C! -6 alkyl group) amine group C!-6 alkyl group, bis(CV6 alkyl)amino group cv6 alkyl group, Cyano Cl 6 alkyl, Cl-6 alkylsulfonyl, Cu alkylsulfonylamino, Cu alkylsulfonyl (Cu alkyl) amine, amine sulfonyl, Cu alkylamine sulfonium Base, bis(Cl_6 alkyl)amine sulfonyl group, Cu burnt amine group, Cl-6 acid group (Cl-6 alkyl) amine group, urethane group, Ci-6 alkyl amide group and double (Cu alkyl)amine oxime. According to a further aspect of the invention, a compound R1 of formula (I) is also provided

Or (IV) 123642-44-200817384 or a pharmaceutically acceptable salt thereof; wherein m is 0, 1, 2, 3 or 4; ^ is independently N or CR8 from Y2, provided that one of 1Y and Y2 is N, and the other is CR8; X is a linking group selected from -CR4=CR5-, -CR4=CR5CR6; R7_, -CR6R7CR5=CR4-, -CeC-, -CeCCR6R7-, -CR6R7CeC-, -nr4cr6r7-, -〇CR6R7-, -scr6r7-, -S(0)CR6R7-, -S(0)2CR6R7-, -C(0)NR4CR6R7- &gt; -NR4C(0)CR6R7- &gt; -NR4C(0)NR5CR6R7- i -NR4S(0)2CR6R7-, -S(0)2NR4CR6R7-, -C(0)NR4-, 4C, -NR4 C(0)NR5 -, -(〇)2 NR4 - and -NR4 S (0) 2 -; R1 is selected from the group consisting of G-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, carbocyclyl, carbocyclyl Q-6 alkyl, heterocyclyl and heterocyclic q- a 6-alkyl group, which is optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, -R9, -OR9, -SR9, -SOR9, -〇2R9 , -COR9, -C02R9, -CONR9R1(), -NR9R10, -NR9COR10, -nr9co2r10, -NR9CONR10R15 ' -NR9 COCONR1 0 R15 and NR9 S02 R1 〇; or X-R1 is -CR6R7OH; R2 is selected from q -6 a group of an alkyl group, a carbocyclic group, and a heterocyclic group, this group Substituted by -NR17CONR18R19, and optionally substituted by one or more substituents, the substituents are independently selected from halo, cyano, nitro, -R11, -OR11, -SR11, -SOR11, -S02Rn "COR11,- C02Rn, -CONRnR12, -NRnR12, -NR11 COR1 2 and -NR11 COCONR12 R1 6 ; each R3, when present, is independently selected from halo, cyano, nitro, -R13, -OR13, -R13, -SOR13 , -S〇2Rl3, -C〇R13, -C〇2R13, -C〇NR13R14, 123642 -45- 200817384 depending on 13r14, -NR13COR14, _nr13co2r14 and -nr13so2r14; R4 and R5 are independently hydrogen or Ci_6 alkyl; R1 and R4 together with one or more of the atoms to which they are attached form a 4- to 1-membered carbon ring or a heterocyclic ring wherein 1, 2 or 3 ring carbon atoms are optionally N, hydrazine or s is substituted, and the ring is optionally substituted with one or more substituents selected from the group consisting of a yl group, a cyano group, a nitro group, a hydroxyl group, a ketone group, a C16 alkyl group, a Cl. 6 alkoxy group, Alkyl, halo-Ci6 alkoxy, hydroxy (^^alkyl, trans-Ch alkoxy, Cl-6 alkoxy Ci6 alkyl, Ci6 alkoxy Ci6 alkoxy, amine, Cu alkylamino, double (Ch alkyl)amino, amine (V6 alkyl, 4 alkyl) amine C1-6 alkyl, bis(Ci-6 alkyl)amino q-6 alkyl, cyano C1-6 alkyl , c16 alkylsulfonyl, Ci6 alkylsulfonylamino, Ci6 alkylsulfonyl (Ci-6 alkyl) amine, amine sulfonyl, (^-6 alkyl sulfonyl, double ( Cu alkyl)amine sulfonyl group, Cl_6 alkanoguanidino group, Cl6 alkyl fluorenyl group ((::1_6 alkyl)amino group, amine carbaryl group, Cu alkylamine carbhydryl group and bis(Ci alkyl) amine R6 and R7 are independently selected from the group consisting of hydrogen, halo, cyano, nitro and Ci-6 alkyl; R8 is selected from the group consisting of hydrogen, halo, cyano and &lt;^_6 alkyl; R9 and R1G Independently hydrogen, or a group selected from the group consisting of a C1-6 alkyl group, a carbocyclic group, a carbocyclic group C16 alkyl group, a heterocyclic group, and a heterocyclic group Ci-6, which is optionally one or more Substituted by a substituent selected from the group consisting of i, cyano, nitro, hydroxy, &lt;^-6 alkyl, (^-6 alkoxy, i-based cv6 alkyl, haloCh-alkane Base, hydroxy Ci-6 alkyl, hydroxy Cil alkoxy, (^-6 alkoxy Ci-6 alkyl, C] [_6 alkoxy Ch alkoxy, amine, Ch acryl, bis ( (^_6 alkyl)amino group, amino Cu alkyl group, (Ci-6 alkyl) amino group Cu alkyl group, bis((V6 123642 -46 - 200817384 alkyl) alkyl hydrazine 1-6 alkyl group, hydrazine Base (2; 1_6 alkyl, (111-6 alkyl), (^1/-6 alkylsulfonylamino, alkylsulfonyl (Cl-6 alkyl) amine, amine thiol, Cu alkylamine sulfonyl group, bis(Cl_6 alkyl)amine sulfonyl group, Ci 6 succinic acid amine group, Q -6 oleoyl group (q -6 alkyl group) amine group, urethane group, q -6 fluorenyl group Aminomethyl hydrazino and bis(CV6 alkyl)amine carbenyl; R11, R12, R17 and R18 are independently hydrogen or selected from C, 6 alkyl, carbocyclyl, carbocyclyl C! -6 alkyl, a group of a heterocyclic group and a heterocyclic group q -6 alkyl group, which group is optionally substituted by one or more substituents selected from the group consisting of a yl group, a cyano group, a nitro group, a hydroxyl group, and a C 6 alkane group. Base, q.6 alkoxy, functional group (^_6 alkyl, halo (^_6 alkoxy, hydroxy (^_6 alkyl, hydroxy (^.6 alkoxy, (^_6 alkoxy CV6 alkane) Base, c^6 alkoxy Ch alkoxy, amino, alkylamino, bis(Cu alkyl)amine, amine Cu alkyl, (Cl-6 alkyl)amino c16 alkyl, bis(Cm alkyl)amino C 6 alkane , cyano Cl-6 alkyl, Cl-6 alkylsulfonyl, Cu alkanoyl, Cu alkyl sulfonate (Cl 6 alkyl) amine, amine methyl sulfhydryl, Cu alkyl carbamide Bis(Ch alkyl)aminecarbamyl; R13, R14, R15, R16 and R19 are independently hydrogen or are selected from Ci-6 alkyl, carbocyclyl, carbocyclyl. a group of a 6-alkyl group, a heterocyclic group and a heterocyclic group Ci 6 alkyl group, which group is optionally substituted by one or more substituents selected from a halogen group, a cyano group, a nitro group, a hydroxyl group, Ci_6 alkyl, Cl_6 alkoxy, haloCi 6 alkyl, haloalkoxy, hydroxy (^-6 alkyl, hydroxy Ci 6 alkoxy, 〇16 alkoxy C^6 alkyl, Ci-6 Alkoxy (^_6 alkoxy, amine, Ci-6 alkylamino, bis(Ch alkyl)amine, amine Ci-6 alkyl, (Ci6 alkyl)amine Ci6 alkyl, double (C^ Alkyl)amino C^6 alkyl, cyano Ci6 alkyl, Ci6 alkylsulfonyl, (V6 alkylsulfonylamino, Cu alkylsulfonyl ((6-6))), 123642 -47- 200817384 Aminosulfonyl, CV6 alkylamine sulfonyl, bis(Cu alkyl)amine sulfonyl, cv6 alkyl amide, Cu alkyl sulfonyl (Ch alkyl) amine, amine formazan a C.-6 alkylamine carbenyl group and a bis(Ci_6 alkyl)amine carbenyl group; or R18 together with R19 and the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic ring, wherein 1 or The two ring carbon atoms are optionally replaced by N, hydrazine or S, and the ring system is optionally substituted by one or more substituents, The group is selected from the group consisting of a halogen group, a cyano group, a nitro group, a hydroxyl group, a CV6 alkyl group, a Ci-6 alkoxy group, a halogen group (^-6 alkyl group, a halogen alkoxy group, a hydroxyl group Ci-6 alkyl group, a hydroxyl group (^_6 alkane). Oxyl, alkoxyalkyl, (^-6 alkoxy (^-6 alkoxy, amine, (6-6 alkylamino), bis(CV6 alkyl) amine, aminoCh alkyl, (Cu Alkyl)aminoalkylalkyl, bis(Cy alkyl)aminoalkyl, cyano Ci-6 alkyl, 4-6 alkylsulfonyl, Cu alkylsulfonylamino, Ci 6 alkylsulfonyl ( Ci 6 alkyl)amine, amine sulfonate, C!-6 alkylamine sulfonyl, bis(Cl-6 alkyl)amine sulfonyl, Cu aryl, (ν6 alkyl sulfonyl (Cw alkyl) Amino, amine, mercapto, Cu alkyl fe: mercapto and bis(c1-6 alkyl)amine mercapto. According to a further aspect of the invention, a compound of formula (1) is also provided

R2 Formula (I) or a pharmaceutically acceptable salt thereof; wherein m is 〇, 1, 2, 3 or 4; ¥ and ¥2 are independent aN4CR8, provided that one of seven and 丫2 is N, and another 123642 •48- 200817384 One is CR8; X is a linking group selected from -CRkCR5-, -cr4=cr5cr6r7-, -0:116117〇15=〇^4-, -CEC-, _C three CCW·, -GI^R ^CeC-, -NR4CR6R7-, -ocr6r7-, -SCR6R7-, -S(0)CR6R7-, -S(0)2CR6R7-, -C(0)NR4CR6R7-, -NR4C(0)NR5CR6R7-, -S (0)2NR4CR6R7 ... -C(0)NR4 -, -NR4 C(O)-, -NR4 C(0)NR5 -, -S(0)2 NR4 - and -NR4 S(0)2 -;

R1 is a group selected from the group consisting of C!-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, carbocyclyl, carbocyclyl C^6 alkyl, heterocyclic and heterocyclic q-6 alkyl The group is optionally substituted by one or more substituents selected from the group consisting of _ group, cyano group, nitro group, -R9, -OR9, -SR9, -SOR9, -〇2r9, -COR9, - C02R9, -CONR9R10, -NR9R10 &gt; -NR9 COR10 . -NR9C02R10 ^ -NR9 CONR10 R15 &gt; -NR9 COCONR1 0 R15 and NR9 S02 R1 〇; or X-R1 is -CR6R7〇H; R2 is selected from C^6 a group of an alkyl group, a carbocyclic group, and a heterocyclic group, which is substituted by -NR CONR1 8Ri 9 and optionally substituted with one or more substituents independently selected from halo, cyano, and nitrate Base, _Rl丨, _〇Rl丨, _SRl i, -SOR11, -S〇2 R&quot;, -corI 1, _c〇2 Rl i, c〇NRl i Rl 2 NRl i Rl 2 -NR11 COR1 2 ^ eNRi l COCONR12 R1 6 ; each =, when present, is independently selected from halo, cyano, nitro, _Rl 3, -〇r1 3, SOR, _S〇2R13, c〇r13, c〇2R13, -C〇NR13R14 , R tear 13 (: 01114, -NR13C02R14 and -NRi3S 〇 2Ri4; R4 and, independently hydrogen or c 1-6 alkyl; Connecting one or more atoms together to form a 4- to 10-membered carbon ring or a heterocyclic ring &amp; g ^ ^ ′′ where I 2 or 3 ring carbon atoms are optionally 123642 -49- 200817384 N, 0 or S is substituted, and the ring is optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, keto, alkyl, alkoxy, haloCl-0 , halo-Ci-6 alkoxy, hydroxy Ci 6 alkyl, hydroxy CV6 alkoxy, Ci 6 alkoxy Ci 6 alkyl, Ci 6 alkoxy 6 alkoxy, amine, C 6 alkylamine Base, bis(Cl_6 alkyl)amino group, amine group Ci6 alkyl group, (c!-6 alkyl)amino group c1-6 alkyl group, bis(Ci_6 alkyl)amino group Cu alkyl group, cyano group C! Anthracenyl, Q · 6 垸 醯 醯, q _6 alkyl hydrazino, q alkyl sulfonyl (Ch alkyl) amine, amine sulfonyl, Cl 6 alkyl sulfonyl, double (Ci_6 alkyl)amine sulfonyl, Cl6 alkanoyl, Ci6 alkanoyl (Ci6 alkyl) amine, amine sulfhydryl, Cu alkylamine fluorenyl and bis(Cu alkyl)amine formazan R6 and R7 are independently selected from the group consisting of hydrogen, halo, cyano, nitro &amp; Cl6 alkyl; R8 is selected from hydrogen, i-based, cyanide &amp;Cl_6 alkyl; R9 and R1G are independently hydrogen, or a group selected from the group consisting of Ci-6 alkyl, carbocyclic, carbocyclic Cu, hetero- and heterocyclyl Cl-6. This group is optionally substituted by one or more substituents selected from the group consisting of benzyl, cyano, nitro, hydroxy, Ci-6 alkyl, Ch alkoxy, haloCh alkyl, halo (^- 6 alkoxy, hydroxy Ci-6 alkyl, hydroxyalkoxy, (^-6 alkoxy Ci-6 alkyl, C1-6 alkoxy (ν6 alkoxy, amine, Ch alkylamino, bis (Ch) Alkyl)amino, aminoCh alkyl, (Cu alkyl)amino Cu alkyl, bis(Cu alkyl)amine based Ci_6 alkyl, cyano Cl-6 alkyl, Ci_6 alkyl base, Cl-6 alkylsulfonylamino, Ci_6 alkylsulfonyl (Ci-6 alkyl) amine, aminesulfonyl, Ci-6 alkylamine sulfonyl, bis(Cu alkyl)amine sulfonyl , Ci-6 alkanoylamino, (V6 alkyl fluorenyl ((^-6 alkyl)) amine, amine sulfhydryl, Cu alkylamine 123642 -50- 200817384 formazanyl and bis(Ch alkyl)amine A Sulfhydryl; R11, R12, R17 and R18 are independently hydrogen or selected from the group consisting of 6 alkyl, carbocyclyl, carbocyclyl &lt;^_6 alkyl, heterocycle And a group of a heterocyclic group Ci_6 alkyl group, which group is optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, C^6 alkyl, Cm alkoxy Base, dentate group (^_6 alkyl, halo ci-6 alkoxy, hydroxy CV6 alkyl, hydroxy Ci6 alkoxy, Ci-6 alkoxy Ch alkyl, CV6 alkoxyCh alkoxy, amine, Cl-6 alkylamino 'bis(Ch alkyl)amino, amino Cu alkyl, (Cl-6 alkyl) amine Ci-6 alkyl, bis(c^alkyl)amino c!-6 alkyl , cyano Ci 6 alkyl, Ci 6 alkylsulfonyl, Cu alkyl amide, Cu alkyl sulfonyl (Cl-6 alkyl) amine, amine methyl sulfhydryl, Cl alkyl amine fluorenyl and double (Ch alkyl)amine mercapto; R13, R14, R15, R16 and R19 are independently hydrogen or selected from Ci-6 alkyl, carbocyclyl, carbocyclic -6 alkyl, heterocyclyl and a group of a heterocyclic group C 6 alkyl group, which group is optionally substituted by one or more substituents selected from a halogen group, a cyano group, a nitro group, a hydroxyl group, a c 6 alkyl group, a C 6 alkoxy group. , 基 乂 乂 alkyl, _ yl 4 -6 alkoxy, hydroxyalkyl, hydroxy CL 6 alkoxy, c 1-6 alkoxy Ci-6 alkyl, Ci-6 alkoxy (^-6 alkoxy group, amine group, (^-6 alkylamino group, bis(Ch alkyl)amino group, amine cv6 alkyl group, (cv6 alkyl)amino group C1-6 alkyl group, and (C! -6 alkyl) amine alkyl, cyano Ci-6 alkyl, C1-6 alkyl acid group, ci · 6 alkyl sulfhydryl amine, Cu alkyl thiol (Ci alkyl) amine Alkylsulfonyl, q-6 alkylamine sulfonyl, bis(q.6 alkyl)amine sulfonyl, c1-6 decylamine, Cl-6 aryl (Cl -6 alkyl) An amine group, an amine aryl group, a decylaminomethyl group and a bis(Ch alkyl) aminyl group; or R18 together with R19 and the nitrogen atom to which they are attached form a 3- to ίο- 51 - 200817384

a ring wherein one or two ring carbon atoms are optionally replaced by n, hydrazine or S, and the ring is optionally substituted by one or more substituents selected from the group consisting of a dentate group, a cyano group, a fluorenyl group, and a Base, Cy alkyl, alkoxy, haloalkyl, alkoxy, hydroxy Ci 6 alkyl, hydroxy Ci 6 alkoxy, Ci 6 alkoxy Cyalkyl, α 6 alkoxy Cl-6 alkoxy Base, amine group, Ci_$ amine group, bis(Ch alkyl)amino group, amino group C 6 alkyl group, (Ci 6 alkyl)amino group Ci 6 alkyl group, bis(Ch alkyl)amino group (^ 6 alkyl group) , cyano c1-6 alkyl, Ci-6 alkylsulfonyl, C!6 alkylsulfonylamino, Ci6 alkylsulfonyl (Ci6 alkyl) amine, amine sulfonyl, Cm alkane Acesulfame group, bis(Ci 6 alkyl)amine sulfonyl group, Ci 6 alkanoylamino group, Cu alkyl fluorenyl ((6-6 alkyl) amine group, amine methyl sulfonyl group, alkyl group Mercapto and bis(Cualkyl)aminecarbamyl. Certain compounds of formula (I) can exist in stereoisomeric forms. It is to be understood that the present invention encompasses all geometric and optical isoforms of the compounds of formula (I). And mixtures thereof, including racemates, tautomers and mixtures thereof One aspect of the invention. Solvates and mixtures thereof also form aspects of the invention. For example, suitable solvates of the compounds of formula (I) are, for example, hydrates such as hemihydrate, monohydrate, dihydrate. Or a trihydrate, or a substituted amount thereof. The present invention relates to a compound of the formula (1) as defined herein, and a salt thereof. The salt used in the pharmaceutical composition is a pharmaceutically acceptable salt, but other salts It can be used in the manufacture of the compound of the formula (I) and a pharmaceutically acceptable salt thereof. For example: The pharmaceutically acceptable salt of the present invention may include the acid of the formula (I) which is deficient in human from 4 Δ + a salt which is sufficiently basic to include such a salt. Such acid addition salts include, but are not limited to, fumarate, methylate, hydrochloride, 123642 • 52- 200817384 hydrogen oxalate, a citrate and a maleate, and a salt formed with phosphoric acid and sulfuric acid. Further, in the case where the compound of the formula (1) is sufficiently acidic, the salt is a salt, and examples include, but are not limited to, metal oxime, Such as sodium or unloading, soil testing metal salts such as calcium or magnesium, or organic Salts, such as triethylamine, ethanolamine, di ^ alcohol amines, triethanolamine, morpholine fu #, N. Hexachloro-methyl-piperidine-e, of N_ ethyl piperidine, dibenzylamine or amino acids, such as lysine.

The compounds of formula (I) may also be provided as esters, and especially in vivo. An in vivo hydrolyzable vinegar comprising a compound of the formula (1), which is, for example, a pharmaceutically acceptable ester which is cleaved in the human or animal body to produce a parent acid or an alcohol. Such an ester can be confirmed by, for example, administering a test compound to a test animal in an intravenous manner, followed by examining the body fluid of the test animal. Suitable pharmaceutically acceptable esters for the carboxy group, including alkoxymethyl hydrazines, such as methoxymethyl, Cl-6 alkyl alkoxymethyl group, T T dimethyl ethoxylated oxy group Methyl, decyl ester, c38 cycloalkoxycarbonyl (oxy C. 6 alkyl ester, such as 1-cyclohexylcarbonyloxyethyl, u-dioxosin-2-one methyl a vinegar such as 5-methyl-1)3-dioxolanesyl-side methyl group, and a Cl-6-oxygenated oxyethyl ester such as methoxymethoxy-methoxyethyl; It can be formed at any of the carboxyl groups in the compounds of the invention. Appropriately pharmaceutically acceptable for hydroxy groups, including inorganic s, such as phosphates (including aminophosphate cyclic esters) and π-methoxyalkyl ethers, and due to ester decomposition A related compound caused by in vivo hydrolysis of the parent hydroxyl group. Examples of the α-nonoxyalkyl ethers include ethoxycarbonylmethoxy and 2,2-dimethylpropoxymethoxy. For hydroxyl groups, 123642 - 53 - 200817384 in vivo hydrolyzable oxime groups can be formed, the choice of which includes Ch. a sulfhydryl group, such as a formic acid group, an ethyl ketone group, a benzoyl group, a phenylethyl group, a substituted benzyl group and a phenethyl group; a (tetra) group (to obtain a (four) carbonic acid §), The thiol group and the hydrazone or hexahydro hydrazine ruthenyl group are bonded to the 3 or 4 position of the benzamidine ring from a ring nitrogen atom via a methylene linking group. Other in vivo hydrolysable esters of interest include, for example, RAqopc!.6 alkyl-co-, wherein RA is, for example, benzyloxyalkyl or phenyl. Among such esters, suitable substituents on the phenyl group include, for example, 4-ethoxylated groups;: _Cl.4 oxime-based carbazino group and N-(di-amino-ethyl) N q _4 decylamine Mercapto group (to obtain amino phthalic acid esters); bis 4-alkylamino group and (iv) acetyl group. Examples of the ring substituents on the phenylethyl and benzylidene groups, including the amine fluorenyl group, the Cw alkylaminomethyl group, and the dioxane

Hexahydropyridinyl-C1_4 alkyl, hexahydropyrryl-c14 alkyl and morpholinyl-Cl-4 alkyl. The compound of formula (1) can also be administered in the form of a prodrug which is decomposed in the human or animal body to obtain a compound of formula (I). Various prodrug forms are known in the art. For examples of such prodrug derivatives, see: a) Design of prodrugs, edited by Η·Bundgaard (Elsevier, 1985), and Enzymology, Vol. 42, pp. 309-396, by K_ Edited by Widder et al. (University Press, 1985); b) Textbook on Drug Design and Development, edited by Krogsgaard-Larsen and Η. Bundgaard, Chapter 5, Design and Application of Prodrugs, by Bundgaard , pp. 113-191 (1991); 123642 -54- 200817384 C) Η· Bundgaard, Development of Drug Delivery Review, 8, 丨 (1992); d) H. Bimdgaard et al., Journal of Medical Sciences, 77, 285 (1988); and e) Ν· Kakeya et al., Chem Pharm Bull, 32, 692 (1984). In this patent specification, the term "Cpq alkyl," includes both straight-chain and branched-chain alkyl groups. . However, references to individual alkyl groups, such as propyl, are exclusively referred to as straight-chain variants (ie, n-propyl and isopropyl), while references to individual branched alkyl groups are, for example, " The third _butyl group refers only to the branched chain variant. The prefix Cp q (where 1) and (1 is an integer) in cp_q alkyl and other terms indicate the range of carbon atoms present in the group, for example, alkyl includes q alkyl (fluorenyl), C2 Alkyl (ethyl), A alkyl (propyl, hydrazine such as n-propyl and isopropyl) and C4 alkyl (n-butyl, second-butyl, isobutyl and second butyl) .

The term Cp-q alkoxy includes alkyl.

The term Cp - q burns thiol, including _c(〇). The term i-based includes fluoro, chloro, bromo and iodo. The f' carbocyclyl group π is a saturated, unsaturated or partially saturated monocyclic, bicyclic tricyclic ring system containing from 3 to 14 ring atoms, wherein the ring CH2 group can be replaced by a 〇=〇 group . "Carbocyclyl" includes "aryl", "Cp q cycloalkyl, and % cycloalkenyl". The pq π aryl π is an aromatic monocyclic, bicyclic or tricyclic carbocyclic ring system. "Cp_q cycloalkenyl" is an unsaturated or partially saturated monocyclic, bicyclic or cyclic anthracycline ring system containing at least one C=c bond, and wherein the ring group can be C= 0 group substitution. nCp_qi^alkyl" is a saturated monocyclic, bicyclic or tricyclic carbocyclic ring system 123642-55-200817384, and the %CH2 group can be replaced by a hydrazine group. , unsaturated or partially saturated monocyclic, bicyclic or di: Γ:, 14 ring atoms, where ', k is from nitrogen, sulfur or oxygen, the ring γ or sulfur atom can be oxidized, and the sound in the basin CH; ^ linking 'and wherein the ring gas, heterocyclic group" includes, heteroaryl ... can be replaced by a c=° group. Miscellaneous I. Miscellaneous, and ', ring heteropoly. II: Aryl&quot; is an aromatic monocyclic, bicyclic or tricyclic heterocyclic group, especially having 5 to 10 rings Atom, in the middle of the stone, the 2, 3 or 4% atomic system is selected from nitrogen, | or milk, and its nitrogen or sulfur can be oxidized. &quot;Huanxian County, for the residue and or a ligament, bi- or tricyclic hetero-based ring system, in particular having 5 to 1 ring atoms, wherein &quot;3 ^ ring atoms are selected from nitrogen, sulfur or oxygen - the ring may be a carbon or nitrogen linkage And "the nucleus nitrogen or sulfur atom can be oxidized, and the ring is called a group

Group replacement. I ''cycloheteroalkyl" is a saturated monocyclic, bicyclic or tricyclic ring, especially having 5 to 1 ring atoms, wherein ... - _ self-emulsion, sulfur or oxygen, the ring may be carbon or Nitrogen bonding, and wherein a ring nitrogen or sulfur atom can be emulsified' and wherein the ring CH2 group can be replaced by a c= hydrazine group. The present specification can utilize compound terminology to describe a group containing more than one official soil unless It is also stated that 'otherwise such terms are to be interpreted as being as defined in the art. For example, a carbocyclic group C&quot; a group includes a cvq wire substituted with a carbocyclic group, and the heterocyclic group includes a heterocyclic ring. The C&quot;C.&quot;(C&quot;alkyl) amine group of Kigo includes an amine group which is substituted by two Cp-q alkyl groups which are different in the same bite. A 123642-56-200817384 Halo Cp_q alkyl group is Cpi An alkyl group which is substituted by 1 or more dentate substituents 'and especially 1, 2 or 3 halo substituents. Similarly, other generic terms containing halo groups, such as halo Cp-q alkoxylates a group which may contain 1 or more halo substituents, and particularly hydrazine, 2 or 3 i-substituent substituents. Hydroxy Cp_q alkyl group is Cp_q a group which is substituted by 1 or more hydroxy groups, and particularly by 1, 2 or 3 hydroxy substituents. Similarly, other generic terms containing hydroxy groups, such as hydroxy Cp_q alkoxy, may contain 1 or More, and in particular 1, 2 or 3 hydroxy substituents.

Cp - q alkoxy Cp _ q alkyl is Cp _ q alkyl, which is substituted by 1 or more Cp _ q alkoxy substituents, and in particular 1, 2 or 3 Cp_q alkoxy substituents Replace. Likewise, other generic terms containing Cp-q alkoxy, such as Cpq alkoxy Cp-q alkoxy, may contain 1 or more Cp_q alkoxy substituents, and in particular 1, 2 or 3 Cp_q alkoxy substituent. Where the substituent is selected from the group consisting of η1 or 21', 1, 1, 2 or 3,, or, '1, 2, 3 or 4' groups or substituents, it should be understood that this definition includes All substituents are selected from one of the specified groups, meaning that all substituents are the same ' or the substituents are selected from two or more of the specified groups, meaning that the substituents are not identical. The compounds of the invention have been computerized The software (ACD/named version 8 〇) is named. ''Proliferative diseases'' include malignant diseases such as cancer, and non-malignant diseases such as inflammatory diseases, obstructive airways diseases, immune diseases or cardiovascular diseases. Suitable meanings of a group or any part or substituent of such a group include: 123642 -57- 200817384 About c1M alkyl: About (: 6 alkyl: About C3-6 cycloalkyl: About CS-0 ring Alkyl (^_4 alkyl f about aryl) · About aryl Ci-4 alkyl: About carbocyclic: About i group: About C1M alkoxy: f About Ci-6 alkoxy: About Cl-6 Alkyl fluorenyl: About heteroaryl: 123642 Methyl, ethyl, propyl, butyl '2-methyl propyl And third - butyl;

Ci-4 alkyl, pentyl, 2,2-dimethylpropyl, 3-methylbutyl and hexyl; cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; cyclopropylmethyl, ring Propylethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl; phenyl and decyl; benzyl, phenethyl, decylmethyl and decylethyl; aryl, cyclohexenyl And (: 3_6 cycloalkyl; fluoro, chloro, bromo and iodo; methoxy, ethoxy, propoxy and isopropoxy; C1M alkoxy, pentyloxy, 1-ethyl Propyloxy and hexyloxy; ethyl hydrazino, propyl fluorenyl and 2-mercaptopropyl fluorenyl; leaf tσ base, taste. sitting group, P quinidine, 舜 4 wood base, 0 dense σ base, Ρ吩基, !fT 比洛基, 峨σ siting base, dish ϋ sitting base, P plug σ siting base, trisalyl group, ρ 峻 基 base, different 17 σ siting base, -58- 200817384 吱 基 嗒, 嗒Ploughing base, pyridinyl group, p-p-based, strepto-furanyl, dibenzofuranyl, and benzopyrhenyl; on heteroaryl Ci, 峨σ, methyl, pyrrolyl Base, m-methyl, misoethyl, ρ-saltylmethyl, pyrazolylethyl, furan F-based, furylethyl, pyrenylmethyl, porphinylethyl, pyridylmethyl, pyridylethyl, pyridylmethyl, pyridinylethyl, pyrimidinylmethyl, pyrimidinyl Base, pyrimidinylpropyl, pyrimidinylbutyl, imidazolylpropyl, imidazolylbutyl, quinolylpropyl, 1,3,4-tripropenylpropyl and p-indenylthio; Base: heteroaryl, tetrahydropyrrolyl, isoquinolyl, p-quinone, benzothiazolyl, benzop-oxazolyl, hexahydropyridyl, hexahydropyridinyl, nitrotetradecyl , wheylinyl, tetrahydroisoindole quinone, tetrahydronyl quinalyl, indanyl, dihydro-2-indole, piperidyl and tetrahydrofuranyl. It should be noted that there is no limitation. The specific examples used in the description of the terms used herein and the specific meanings of 123642 -59-200817384 m, X, 1Y and Υ2, R1, R2 and R3 are as follows. Such a meaning may be combined with any aspect of the invention or In part, any definition, claim or specific embodiment as defined herein is used. m In one aspect of the invention, m is 0, 1, 2 or 3. On the other hand, m is 0, 1 or 2. In a further aspect, m is 0 or 1. On the other hand, m is 0, so R3 is absent. On the other hand, m is 1, and R3 Is a methyl group. 1γ and γ2 In one aspect of the invention, 1Υ is Ν and Υ2 is CR8. On the other hand, iy is Ν and Υ2 is CH. On the other hand, 1Y is CR8, and Y2 is In a further aspect, 1Y is CH or CF, and Y2 is N. In yet another aspect, 1Y is CH and Y2 is N.

X In one aspect of the invention, X is a linking group selected from the group consisting of -nr4cr6r7-, -OCR6R7-, -SCR6R7-, -s(o)cr6r7-, -s(o)2cr6r7-, -c(o)nr4cr6r7- -nr4c(o)nr5cr6r7-, -S(0)2NR4CR6R7-, -NR4C(0)-, -C(0)NR4-, -S(0)2NR4- and -NR4S(0)2-. In another aspect, X is a linking group selected from the group consisting of -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S(0)CR6R7-, -S(0)2CR6R7-, -C(0)NR4CR6R7-, -NR4 C(0)NR5 CR6 R7, -S(0)2 NR4 CR6 R7, -C(0)NR4 - and -NR4 c(0)-. In a further aspect, X is a linking group selected from the group consisting of -NR4CR6R7-, -OCR6R7-, 123642-60-200817384-scr6r7-, -s(o)cr6r7-, -s(o)2cr6r7-, -C(0)NR4 -and-nr4c(o)-. In a further aspect, X is a linking group selected from the group consisting of -NR4CR6R7-, -OCR6R7-, -scr6r7-, -s(o)cr6r7., and -S(0)2CR6R7-. In yet another aspect, X is a linking group selected from the group consisting of -8161117-, -8(0)016117-, and -s(o)2cr6r7-.

In another aspect, X is a linking group selected from the group consisting of -NR4CH2-, -OCH2-, -OCH(CH3)-, -OC(CH3)2-, -SCH2., -SCH(CH3)-, -SC(CH3) ) 2-, -S(0)CH2-, -S(0)CH(CH3)-, -S(0)C(CH3)2-, -S(0)2CH2-, -S(0)2CH( CH3)-, -S(0)2C(CH3)2-, -C(0)NR4- and -NR4C(0)-. In another aspect, X is a linking group selected from the group consisting of -NR4CH2-, -OCH2-, -SCH2-, -S(0)CH2-, -S(0)CH2-, -S(0)2CH2-, -C (0) NR4- and -NR4C(0)- 〇 On the other hand, X is a linking group selected from -NR4CH2-, -OCH2-, -OCH(CH3)-, -OC(CH3)2-, -SCH2 -, -SCH(CH3)-, -SC(CH3)2-, -S(0)CH2v, -S(0)CH(CH3)-, -S(0)C(CH3)2-, -s( o) 2ch2-, -s(o)2ch(ch3)- and -s(o)2 C(CH3)2 - 〇 On the other hand, X is a linking group selected from _NR4CH2-, -OCH2-, -sch2-, -s(o)ch2-, -s(o)ch2- and -S(0)2CH2-. In a further aspect, X is a linking group selected from the group consisting of -NHCH2-, -N(CH3)CH2-, -OCH2-, -OCH(CH3)-, -OC(CH3)2-, _SCH2-, -SCH(CH3) -, -sc(ch3)2-, -s(o)ch2-, -S(0)CH(CH3)-, -S(0)C(CH3)2-, -S(0)2CH2-, - S(0)2CH(CH3)-, -S(0)2C(CH3)2-, -C(0)NH-, -C(0)N(CH3)-, -NHC(O), and -N( CH3) C(0)·. In a further aspect, x is a linking group selected from the group consisting of -nhch2---N(CH3)CH2-, 123642-61 - 200817384 -OCH2-, -SCH2-, -S(0)CH2-, -S(0)2CH2 -, -C(0)NH-, -C(0)N(CH3)-, -NHC(O)-, and -N(CH3)C(0)-. In still another aspect, X is a linking group selected from the group consisting of -NHCH-, -N(CH3)(113⁄4 -, -OCH2-, -OCH(CH3)., -OC(CH3)2-, -sch2-, -SCH(CH3)-, -SC(CH3)2-, -S(0)CH2-, 4(0)01(013)-, -s(o)c(ch3)2-, -S(0) 2CH2-, -S(0)2CH(CH3)-, and -S(0)2C(CH3)2-. In yet another aspect, X is a linking group selected from the group consisting of -NHCH2 -, -N(CH3)CH2 - -och2-, -sch2-, and -s(o)2ch2-. On the other hand, X is -SCH2- or -S(0)2CH2-. On the other hand, X is -SCH2-, -SCH( CH3)- or -SC(CH3)2-. On the other hand, X is -s(o)ch2 -, -s(o)ch(ch3)- or -s(o)c(ch3)2 -. In another aspect, X is -S(0)2CH2-, -S(0)2CH(CH3)- or -S(0)2C(CH3)2-. On the other hand, X is -S(0) 2CH2-. In another aspect, X is -S(0)2C(CH3)2-. R1 In one aspect of the invention, R1 is selected from the group consisting of C4 alkyl, c3_1()cycloalkyl, aryl, a group of a C3-10 cycloalkylalkyl group, an arylCi-4 alkyl group, a cycloheteroalkyl group, a heteroaryl group, a cycloheteroalkyl group (^-4 alkyl group, a heteroaryl Ci-4 alkyl group) The group is optionally substituted by one or more substituents selected from the group consisting of i, cyano, nitro, R9, -OR9, -COR9, -CONR9 R10, -NR9R10 and -NR9COR10. In another aspect, R1 is selected from the group consisting of adamantyl, decyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, Phenyl, benzyl, phenethyl, tetrahydroP, phenyl, P, phenyl, sulphate, P, sulphate, sulphate, 123642-62-200817384 pyrenyl, pyridyl, pyrimidinyl , pyridinyl, tetrahydropyrrolylmethyl, tetrahydropyrrolylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, pyrazolylmethyl, pyrazolylethyl , furylmethyl, furylethyl, pyrenylmethyl, thienylethyl, pyridylmethyl, pyridylethyl, pyrimidinylmethyl, pyrimidinylethyl, pyridylmethyl and pyrene a group of a thio group, which is optionally substituted with 2 or 3 substituents selected from the group consisting of halo, cyano, nitro, R9, _R9, _C〇R9, _C〇NR9 R1 0, -NR9R10 and -NR9COR10 In a further aspect 'R1 is selected from the group consisting of methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentylcyclohexyl, benzene Base, benzyl, a group of ethyl, pyridyl, pyrazolylethyl, furylmethyl, thienylmethyl, decylmethyl, pyridazolylmethyl and pyridylethyl, as appropriate Substituted by 1 or 2 substituents selected from the group consisting of amino, yl, cyano, methyl, decyloxy, trifluoromethyl, trifluoromethoxy, -NHCOCH3, -CONH2 and -CONHCH3 In another aspect, R1 is selected from the group consisting of methyl, ethyl, isopropyl, cyclopropyl, cyclohexyl, -CH2CH2OH, -CH2CH2NC(0)CH3, phenyl, 4-fluorophenyl, 2-chlorophenyl, 2-trifluoromethylphenyl, 2-methoxyphenyl, 2-methylphenyl, 4-ethylamidophenyl, 4-aminophenyl, pyridyl yl, pyridin-2-yl, 2 a group of ketotetrahydropyrrol-3-yl, pyrazol-2-yl, 4-methylthiazol-2-yl and 3-methyl-1,3,4-dioxa-2-yl. In another aspect, R1 is selected from the group consisting of methyl, isopropyl, cyclopropyl, cyclohexyl, -CH2CH2OH, -CH2CH2NC(0)CH3, -CH2CONH2, phenyl, 4-fluorophenyl, 2-chlorobenzene Base, 2-trifluoromethylphenyl, 2-methoxyphenyl, 2-mercapto 123642-63 - 200817384 phenyl, 4-ethylguanidinophenyl, 4-aminophenyl, pyridinyl, Tons of 2-_2, 2-ketotetrahydropyrrole, thiazol-2-yl, 4-methylcarbazole, and 3-methyl-1,3,4-pyrazol-2-yl The group. In another aspect, R1 is methyl or cyclopropyl. In another aspect, R1 is methyl. X-R1 In a particular embodiment, X-R1 is -C(CH3)2〇h or -CH2〇H. In a particular embodiment, X-R1 is -CH2OH. R2 In one aspect of the invention, R2 is selected from carbocyclyl or heterocyclyl, the group being substituted by -NR17CONR18R19 and optionally substituted by one or more substituents independently selected from halo, cyanide Base, nitro, -R11, _〇Ri 1, &lt;QRl i, -CONRnR12, -NRnR12 and -NRnCOR12 In one aspect of the invention, R2 is selected from a carbocyclic or heterocyclic group, which is a group Substituted by -NHCONR18R19, and optionally substituted with one or more substituents, the substituents are independently selected from halo, cyano, schishyl, -R11, 1, 1, -CONR11R12, -NR11 R1 2 and -NR11 COR12. In one aspect of the invention, R2 is selected from carbocyclyl or heterocyclyl, the group being substituted by -NHCONHR19 and optionally substituted by one or more substituents independently selected from halo, cyano , nitro, -R11, -ORi 1, &lt;(3R11, -CONR11R12, -NR11R1 2 and -NR11 COR12. In one aspect of the invention, the R2 is selected from a 5 or 6 membered carbocyclic or heterocyclic group, This group is substituted by -NR17CONR18R19 and optionally substituted by one or more substituents independently selected from halo, cyano, nitro, -Ri 1, _0Ri 1, 123642 -64 - 200817384 -COR11, -CONRnR12, -NRURU and NR11(:〇Rl2. In one aspect of the invention, the R2 is selected from a 5- or 6-membered carbocyclic or heterocyclic ring, which is substituted by -NHCONR^Ri9 and optionally One or more of the substituents 'substituents' are independently selected from the group consisting of halo, cyano, nitro, _Rl ii, -COR11, -CONRnR12, -NR11!^ and _NRllc〇Rl2. In one aspect of the invention, R2 Is selected from a 5- or 6-membered carbocyclic or heterocyclic group, which is substituted by -NHCONHRi9, and optionally substituted by one or more substituents, the substituents being independently selected from halo, cyano, a group, Rl i, _〇r1 i, _CORn, _CONRnR12, -NRHR12 and iic〇r12. In one aspect of the invention, R2 is selected from a 6-membered aryl group and a 5 or 6-membered heteroaryl group, which group Is substituted by -NR17CONR18Ri9, and optionally substituted by one or more substituents independently selected from halo, cyano, phenyl, _Rl, -ORU'-COR^-CONRURn'-NRHRl^ncoRiz. In one aspect of the invention, R2 is selected from the group consisting of 6 membered aryl and 5 or 6 membered heteroaryl, which group is substituted by -NHCONR18R19 and optionally substituted with one or more substituents independently selected from halo Base, cyano, nitro, -RU, -OR11, -COR11, -CONR11R12, -NR11 R! 2 and _NRi! c〇Ri 2. In one aspect of the invention, R2 is selected from a 6-membered aryl group and a 5 or 6 membered heteroaryl group which is substituted by -NHCONHR19 and optionally substituted with one or more substituents independently selected from halo, cyano, nitro, -R11, -OR11, - COR11, -CONR11R12, -NR11R12&amp;-NR11COR12. In another aspect, R2 is selected from the group consisting of phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiol, thiophene, fluorenyl, thiol, Thalatin and P thiophene group, this group is substituted by -nr17conr18r19, and optionally substituted by one or more substituents 123642-65-200817384, the substituents are independently selected from halo, cyano, nitro, _R1 1, -〇 Rl i, -COR11, -CONR11 R12, -NRi 1 r1 2 and _NRi 1 c〇Ri 2. In another aspect, R2 is selected from the group consisting of phenyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, pyrenyl, pyridyl, pyrimidinyl, hydrazine, and pyrazolyl, the group being -NHCONR18Ri Substituted 9 and optionally substituted by one or more substituents independently selected from halo, cyano, nitro, -Ri i, -〇Rl i, -COR11, -CONR11 R1 2, _NR1 1 Ri 2 And -NR1 1 c〇Rl 2. In another aspect, R2 is selected from the group consisting of phenyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, pyrenyl, pyridyl, pyrimidinyl, hydrazine, and thiazolyl, and the group is -NHCONHR1 9 Substituting 'and optionally substituted by one or more substituents, the substituents are independently selected from halo, cyano, nitro, -R1 1, -〇Rl丨, _c〇Rl i, -CONR11R1 2, -NRi i Ri 2 and - Fox 11 c〇Ri 2. On the other hand, 'r2 is selected from the group consisting of phenyl, oxime, miso, p. thiol, furyl, pyrenyl, pyridyl, pyrimidinyl, hydrazine and thiazolyl. This group is -NR17CONR18Ri9 substituted, and optionally substituted by one or more substituents independently selected from fluoro, methyl, decyloxy, decyl, cyanomethyl, -CONH2, -CONHCH3, and -CON(CH3) )2. In another aspect, R2 is selected from the group consisting of phenyl, pyrrolyl, imidazolyl, glucosinyl, furyl, pyrenyl, pyridyl, pyrimidinyl, hydrazine, and carbazolyl, and the group is -NHCONR18R19 Substituted, and optionally substituted by one or more substituents, the substituents are independently selected from the group consisting of fluoro, methyl, methoxy, hydroxyindenyl, cyanoindolyl, -CONH2, -CONHCH3, and -CON(CH3)2 . In another aspect, R2 is selected from the group consisting of phenyl, pyrrolyl, imidazolyl, pyrazolyl, indolyl, thienyl, pyridyl, pyrimidinyl, hydrazine, and pyrazolyl, and this 123642-66-200817384 The group is substituted by -NHCONHR19 and, as the case may be, substituted by one or more substituents independently selected from the group consisting of fluoro, methyl, decyloxy, hydroxymethyl, cyanomethyl, -CONH2, -CONHCH3 and - CON(CH3)2. In another aspect, R2 is phenyl or pyridyl, substituted by -1170^11181119, and optionally substituted with one or more substituents independently selected from fluoro, methyl, methoxy, hydroxy Base, cyanomethyl, -conh2, -conhch3 and -con(ch3)2. In another aspect, R2 is phenyl or pyridyl, substituted by -NHCONR18R19, and optionally substituted with one or more substituents independently selected from fluoro, methyl, methoxy, hydroxymethyl, cyano Methyl, -conh2, -CONHCH3 and -CON(CH3)2 In another aspect, R2 is phenyl or pyridyl, substituted by -NHCONHR19, and optionally substituted by one or more substituents, substituents Independently selected from the group consisting of fluoro, methyl, methoxy, hydroxymethyl, cyanomethyl, -conh2, -CONHCH3, and -CON(CH3)2. In another aspect, R2 is phenyl or pyridyl, optionally substituted by -NR17CONR18R19. In another aspect, R2 is phenyl or pyridyl, optionally substituted by NHCONR1 SR1 9 . In another aspect, R2 is phenyl or pyridyl, optionally substituted by NHCONHR1 9 . On the other hand, R2 is 123642 -67- 200817384

Wherein A1 and A2 are selected from CH or N, provided that at least one of Αι or a2 is CH 于 on the other hand, R 2 is

Wherein A1 and A2 are selected from CH or N, provided that at least one of Αι or a2 is CH. On the other hand, R2 is

VV Η Η where Α1 and Α2 are selected from ch or Ν, provided that at least one of Αι or a2 is CH. V R4 In one aspect of the invention, R 4 is hydrogen or methyl. In another aspect, R4 is hydrogen. R4 and R1 are another aspect of the invention, when it is again a _nr4c(〇)cr6r7_ '-NR4C(〇)NR5CR6R7. ^ .NR4S(〇)2Cr6r7. ^ _^4〇(〇)_ ^ NR C( 0) NR - or 4 s(〇)2 _, R1 and r4 together with one or more of the atoms to which they are attached form a 4- to 10-membered heterocyclic ring, wherein 丨, 2 or 3 ring carbon atoms 123642 -68· 200817384 is optionally substituted by N, hydrazine or S, and the ring is optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, thio, keto, Ci_6 alkyl, Ci-6 alkoxy, fluorenyl Ci-6 alkyl, halo Ci-6 oxime, hydroxy (V6 alkyl, hydroxy Ci-6 alkoxy, (v6 alkoxy (^) _6 alkyl, Cn alkoxy C!-6 alkoxy, amine, CV6 alkylamino, bis(Cu alkyl)amine, aminoCh alkyl, (Cu alkyl)aminoCh alkyl, Bis(Cu alkyl)amino Q-6 alkyl, cyano Ci-6 alkyl, Ci-6 alkylsulfonyl, Cu alkylsulfonylamino, cv6 alkylsulfonyl (cv6 alkyl) An amine group, an amine sulfonyl group, a (ν6 alkylamine sulfonyl group, a bis(Ch alkyl)amine sulfonyl group, an alkanoylamino group, an alkyl fluorenyl (Cu alkyl) amine group, an amine methyl sulfhydryl group, C Ualkylamine fluorenyl and bis(Ch alkyl)aminecarbamyl. In another aspect of the invention, when X is -NR4CR6R7-, -nr4c(o)cr6r7_, -nr4c(o)nr5cr6r7_, -NR4S (0) When 2CR6R7_, -NR4C(0)-, -NR4C(0)NR5- or -NR4S(0)2 -, R1 and R4 together with one or more of the atoms to which they are attached form 4-, 5- a 6- or 7-membered heterocyclic ring wherein i ring carbon atoms are optionally substituted by N or hydrazine, and the ring is optionally substituted by one or more substituents selected from the group consisting of i groups, cyano groups, Nitro, hydroxy, keto, Ch alkyl, Ci_6 alkoxy, yl c6, yl (^-6 alkoxy, hydroxy Ci-6 alkyl, hydroxy Ci-6 alkoxy, alkoxy ( ^_6 alkyl, alkoxy Ci-6 alkoxy, amine, Ch an amine group, bis(Cu alkyl) amine group, amine Cu alkyl group, (Cu alkyl) amino group Ch alkyl group, double (Ci-6 alkyl)aminoCh alkyl, cyano (^-6 alkyl, Ci-6 alkylsulfonyl, C16 alkyl sulfhydryl, alkyl oxyalkyl (Ci-6) Amino group, amine fluorenyl group, Cu alkylamine sulfonyl group, bis(c1-6 alkyl)amine sulfonyl group, Cu sputum 123642-69- 200817384 Amino group, CV6 alkyl fluorenyl group (Ci-6 alkyl An amine group, an amine methyl sulfhydryl group, a Cu alkyl amine carbhydryl group, and a bis (Ci -6 alkyl) amine carbaryl group. In another aspect of the invention, when X is -NR4CR6R7-, 4c(o) When cr6r7_, -nr4c(o)nr5cr6r7_, -nr4s(o)2cr6r7-, -NR4C(0)-, -NR4C(0)NR5 - or -NR4S(0)2 -, R1 and R4 are connected to them One or more atoms together form a 5- or 6-membered heterocyclic ring wherein one ring carbon atom is optionally replaced by N or hydrazine, and the ring is optionally substituted with one or more substituents selected from the group consisting of _ group, cyano group, nitro group, hydroxy group, keto group, (V6 alkyl group, alkoxy group, halo group (^_6 alkyl group, haloCh alkoxy group, thiol group, base group Ci-6) Oxy, cv6 alkoxy-Ch-alkyl, cv6 alkoxy Ci-6 alkoxy, amine, alkylamino, bis((^-6 alkyl)amine, amine Cualkyl, (Ch alkyl Amino cv6 alkyl, bis(cle6 alkyl)amino-based Cl-6 alkyl, gas-based Ci_6 alkyl, Cl-6 alkyl base, Cl-6 alkyl base, Ci-6 Alkyl group (Ci-6 alkyl) amine group, amine sulfonyl group, Cu alkyl amide group, bis(Ci-6 alkyl) amine fluorenyl group 'q-6 sulphonylamine group, Ci 4 alkane (Α-ό alkyl) amino, carbamoyl acyl, q-6 acyl and alkyl amine bis (Cu alkyl) amine Yue acyl. In another aspect of the invention, when again _nr4cr6r7-, -NR4 C(0)CR6 R7 -, -NR4 C(0)NR5 CR6 R7 -, -NR4 s(〇)2 CR6 R7 -, -NR4C( When 0)-, -NR4C(0)NR5 - or -NR4S(0)2-, R1 and R4 together with one or more of the atoms to which they are attached form a 6- or 7-membered heterocyclic ring, wherein 1 ring The carbon atom is optionally substituted by N or hydrazine, and the ring is optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, thiol, keto, (V6), (^6 alkoxy, haloCi-6 alkyl, _ylfluorenyl 16 alkoxy, 123642 -70-200817384 hydroxyalkyl, hydroxyCh alkoxy, C!-6 alkoxy C -6 alkyl , Ch alkoxy (^_6 alkoxy, amine, alkylamino, bis(C!-6 alkyl)amine, aminoalkyl, (Ch alkyl)amine (^-6 alkyl, Bis(Ch alkyl)amino hydrazine 1_6 alkyl, cyano hydrazine 1_6 alkyl, (!! 1_6 danic acid, 匚1-6 alkyl sulphate, CV6 alkyl sulfonyl ( Cl_6 alkyl)amino, aminsulfonyl, Cl 6 alkyl sulfonyl, bis(Ci-6 alkyl)amine sulfonyl, Ci-6 alkanoyl, (^_6 sulphur-based (Cu Alkyl)amine, amine Indenyl, Ci-6 alkylamine, mercapto and bis(CV6 alkyl)amine indenyl. R5 In one aspect of the invention, R5 is hydrogen or methyl. In another aspect, R5 is hydrogen. In one aspect, R5 is methyl. R6 In one aspect of the invention, R6 is hydrogen or fluorenyl. In another aspect, R6 is hydrogen. In another aspect, R6 is methyl. R7 is in the aspect of the invention, V is hydrogen or methyl. In another aspect, R7 is hydrogen. In another aspect, R7 is methyl. R8 In the aspect of the invention, R8 is hydrogen or i. In another aspect, hydrazine is hydrogen or In the aspect of the invention, R9 is hydrogen, or a C1-4 alkyl group, optionally substituted by U2 or 3 substituents. The substituent is selected from the group consisting of Halo, cyano, nitro, thiol, q. 4 alkoxy, amine, c^4 alkylamino and bis(Cl-4 alkyl)amine. On the other hand, R9 is hydrogen or Cly The base is optionally substituted with 2 or 3 halo substituents. In a further aspect, R9 is hydrogen, methyl or trifluoromethyl.

Rio

k In one aspect of the invention, R10 is hydrogen. R&quot; In one aspect of the invention, Rii is hydrogen, or a group selected from the group consisting of Ci4 alkyl, aryl and bad heteroalkyl, the group being optionally deuterated, 2 or 3 selected from halo, hydroxy And a group substituted with a cyano group. In another aspect, R11 is hydrogen, and the methyl group is optionally substituted with a hydroxy or cyano group, a phenyl group or a tetrahydroindenyl group. In another aspect, R11 is hydrogen or methyl. R12 In one aspect of the invention, R!2 is hydrogen or methyl. R17 In one aspect of the invention, the Ri7 disk and ^^^ are 虱, or a group selected from the group consisting of an alkyl group, an aryl group, and a cycloalkyl group, and the base phase diagram is optionally 1, 2 or 3 Substituted by a group selected from a halogen group, a hydroxyl group and a cyano group. On the other hand, R17 is a &lt; 奇,田甘马2 methyl group which is optionally substituted with a hydroxyl group or a cyano group, a phenyl group or a tetrahydroindolyl group. 123642 -72- 200817384 In another aspect, R17 is hydrogen or methyl. In another aspect, R17 is hydrogen. R18 In one aspect of the invention, R18 is hydrogen or methyl. In one aspect of the invention, R18 is hydrogen. R19 In one aspect of the invention, R19 is hydrogen or is selected from the group consisting of alkyl, 03-6 cycloalkyl, aryl, heteroaryl, aryl (^-6 alkyl and heteroaryl (^-6 alkyl) groups, This group is optionally substituted by one or more substituents selected from halo, cyano, nitro, hydroxy, C.sub.6 alkyl, Ch alkoxy, _-Ci-6 alkyl, halo c ^-6 alkoxy, hydroxy cv6 alkyl, hydroxy (^_6 alkoxy, CV6 alkoxyCh alkyl, cv6 alkoxy (v6 alkoxy, amine, Ch alkylamino, bis ((V6) Alkyl)amino, aminyl cv6 alkyl, (cv6 alkyl)amino 〇ν6 alkyl, bis(cv6 alkyl)aminoChalkyl, cyanoCl-6 alkyl, Ch alkylsulfonyl, alkane Alkylsulfonylamino, fluorene: 6 alkylsulfonyl ((v6 alkyl) amine, amine sulfonyl, alkyl amine sulfonyl, bis (Ch alkyl) amine sulfonyl, C! - 6 succinic acid amine, Ci - 6 sulphonyl (C! -6 alkyl) amine amide amide group, Cu alkyl amine carbhydryl group and bis (Cu alkyl) amine mercapto group. In one aspect of the invention, R19 is hydrogen or is selected from the group consisting of C 6 alkyl, (: 3-6 cycloalkyl, phenyl, decyl, pyrrolyl, imidazolyl, iso Azolyl, pyrazolyl, fluorenyl, disc phenyl, molybdenum, thiol, phenyl, hydrazide, quinolyl, benzimidazolyl, benzo Furanyl, dibenzofuranyl, benzo far phenyl, phenyl Cl-6 alkyl, cumyl Cl-6, P to P, Cl -6 alkyl, imidazolyl cle6 alkyl, isoxazole Ci-2-alkyl, pyrazolyl Ci_6 alkane 123642-73 · 200817384 base, furyl Ci-6 alkyl, thienyl (^-6 alkyl, pyridylalkyl, benzylidene (V6 alkyl, sorghum) a base c1-6 alkyl group, a nitrogen (9) fluorenyl Ci-6 alkyl group, a fluorenyl Ci-6 alkyl group, a porphyrinyl Ci-6 alkyl group, a benzimidazolyl Ci-6 alkyl group, a benzofuranyl group ( a group of an alkyl group, a dibenzofuranyl group, a group of a benzopyranyl C!-6 group, which is optionally substituted by one or more substituents, and the substituent is selected from the group consisting of S group, cyano group, nitro group, hydroxyl group, Ci -6 alkyl group, (^_6 alkoxy group, i group cv6 alkyl group, i group Q-6 alkoxy group, hydroxy cv6 alkyl group, hydroxy Ci-6 alkoxy group , CV6 alkoxy CV6 alkyl, Ci-6 alkoxy CV6 alkoxy, amine, C!-6 alkylamino, bis(Ch alkyl)amine, amine Ci j alkyl, ((V6 alkyl)amino Cu alkyl, bis(Cu alkyl)amino Cu alkyl, cyano C!-6 alkyl, C!-6 alkyl, SI, Cj _ 6 Alkylamino, Cj -6 alkylsulfonyl (Ci-6 alkyl)amine, amidoxime, Ci-6 alkylamine sulfonyl, bis(Q-6 alkyl)amine sulfonate Anthracenyl, Ci_6 alkanoylamino, Cu alkylalkyl (Ch alkyl) amine, amine methyl sulfonyl, Cu alkyl amine fluorenyl and bis (Ci-6 alkyl) amine carbaryl. In one aspect of the invention, R1 9 is hydrogen or is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, cyclopropyl, Cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, imidazolylhydrazino, isosaki sigma, leaf 1: sulfhydryl, p-butenylmethyl, leaf I: bite and sigma a group which is optionally substituted by one or more substituents selected from the group consisting of halo, cyano, schishyl, thiol, Cl-6 alkyl, Ch alkoxy, halo G-6 Alkyl, alkoxy, hydroxyalkyl, hydroxy (^_6 alkoxy, cv6 alkoxy (ν6 alkyl, Ch alkoxy Cb6 alkoxy, amine, Ch alkylamino, bis (Ci-6) Alkyl)amino, aminyl c^6 alkyl, (Cu alkyl)amino group 123642-74- 200817384 ◦ ^ 烧 〜 双 双 双 双 双 ^ 丨 丨 丨 〜 〜 〜 〜 〜 〜 〜 〜 〜 Alkyl sulfonyl group, (^_6 alkylsulfonylamino group, Ci-6 alkylsulfonyl group ((^-6 alkyl)amino group, amine sulfonyl group, &lt;^ -6 alkylamine sulfonyl, bis((^_6 alkyl)amine acid group, Ci-6 sulphonylamine, Ci-6 succinic acid group (Ci-6 alkyl) amine group, amine A a group, (^_6 alkylamine carbhydryl group and bis((6-6 alkyl))aminomethane group. In one aspect of the invention, R19 is hydrogen or is selected from the group consisting of methyl, ethyl, propyl, iso- Propyl, butyl, iso-butyl, tert-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2 (cyclopropyl), -CH2CH2NMe2, -CH (CH3 CH2OH, -C(CH3)2CH2OH, -CH2CH2OH, -CH2CH2CH2OH, 4-mercaptophenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, 4-fluorophenyl, 4-methoxyphenyl , 3,4-difluorophenyl, far phen-2-yl, -CH2 (mouth azole-2-yl), -CH2 (isox-3-yl), isoxazolyl-3-yl, 6 -keto-1H-pyridin-2-yl, 5-methyliso g-sial-3-yl, 1-methyl-proparg-4-yl, -CH2(1-methylpyridin-4-yl), a group of 6-methoxy p is more than a -3-yl group, a 5-oxyindole quinol-2-yl group, a p-sigma-denyl-2-yl group, and a 1 Η·ρ-salt-3-yl group. In another aspect, R19 is selected from the group consisting of methyl, ethyl, propyl, and ring.

A group of propyl, cyclobutyl, -CH2CH2OH, -CH2CH2NMe2, -C(Me)2CH2OH and 1Η-ρ than indol-3-yl. R18 and R19 In one aspect of the invention, R18 and R1 9 together with the nitrogen atom to which they are attached form a 6-membered heterocyclic ring wherein one ring carbon atom is optionally replaced by n or hydrazine, and the ring is viewed The case is substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, (^-6 alkyl, alkoxy, halo-Ci-6 alkyl, i-based &lt;^_6-alkane Oxyl, hydroxyCh alkyl, hydroxy (^^ alkoxy, 123642 -75 - 200817384

Ch alkoxy&lt;^6 alkyl, Cl-6 alkoxy Cl-6 alkoxy, amine, Ci 6 acrylamine, bis(Cw alkyl)amine, amine Cl-6 alkyl, (Cl-6 alkyl) Amino C 6 alkyl, bis(Cl-6 alkyl)amine Ci 6 alkyl, cyano Ci 6 alkyl, Ci 6 alkyl group, C1_6 alkylsulfonylamino, c16 alkane Alkylsulfonyl (c16 alkyl)amino group, aminsulfonyl group, a C4 alkylamine sulfonyl group, a bis(CH alkyl)amine group, a Cu alkanoamine group, a Cl 6 alkyl alkane group (Cl-6) Alkyl)amino, amine oxime, Cu alkylamine sulfhydryl and bis(Cl-6 alkyl)amine mercapto. In one aspect of the invention, Ri8 and Ri9 together with the nitrogen atom to which they are attached form a carbaryl ring. In one aspect of the invention, there is provided a subset of a compound of formula (I) or a pharmaceutically acceptable salt thereof; m is 0, 1 or 2; Y and Y are independently N or CR8, provided that 1 Y and Y2 are One is n and the other is CR8; X is a linking group selected from -NR4CR6R7-, -〇CR6R7·, -SCR6R7_, S(0)CR6 R7 -, -s(0)2 CR6 R7 -, -C( 0) NR4 CR6 R7 -, -NR4 C(0)NR5 CR6 R7 -, -S(0)2NR4CR6R7·, -NR4C(0)-, -S(0)2NR4- and -NR4S(0)2-; R1 a group selected from the group consisting of a Q-6 alkyl group, a cyclyl-carbocyclyl c1-6 alkyl group, a heterocyclic group, and a heterocyclic group Q alkyl group, which group is optionally substituted by one or more substituents a substituent selected from the group consisting of i, cyano, nitro, R9, -OR9, _C〇R9, -CONR9R1(), -NR9R1()&amp;-NR9COR1G; or X-R1 is -C(CH3)2 OH or -CH2OH; R2 is selected from the group consisting of aryl and heteroaryl, which is substituted by -nr1^ONR1 Sr1 9 and optionally substituted by one or more substituents independently selected from the group 123642 -76- 200817384, cyano, nitro, -R&quot;, 〇RU, _c〇Rll, _c〇nr11r12, -11R12 and -NR11 COR12; each R3, when present, is methyl; R4 and R5 are independently hydrogen Cl_6 alkyl; or when X is -NR4CR6R7_, _ withdraws 4 (^^ or -NR4S(0)2, R1 and R4 are connected to them or a plurality of atoms together form 4_,5-,6- Or a 7-membered heterocyclic ring wherein the ring carbon atom is optionally substituted by N or hydrazine, and the ring is optionally substituted by one or more substituents selected from the group consisting of halo, cyano and fluorenyl groups. , mercapto, _ group, CV6 alkyl, 〇ν6 alkoxy, haloq-6 alkyl, halosulfonium alkoxy, hydroxy Ci6 alkyl, hydroxy Ci_6 alkoxy, C!-6 alkane Oxyl c 6 alkyl, (^-6 alkoxy Ciw alkoxy, amine, Cb6 alkylamino, bis(Ci-6 alkyl) amine, amine Ci6 alkyl, alkyl) amine C^6 alkyl, bis(Cl_6 alkyl)amino-Ci 6 alkyl, cyano Ci 6 alkyl, Q-6 alkylsulfonyl, Ci-6 alkylsulfonylamino, q-6 alkylsulfonyl (Cw alkyl)amino, amidoxime, Ci6 alkylamine sulfonyl, bis(Ch^alkyl)amine sulfonyl, Cu alkanoyl, alkino (Ci-6 alkyl)amine, Aminomethyl hydrazino, q4 alkylamine fluorenyl and bis(Cl-6 alkyl)amine carbaryl; r6 and R7 are independently selected from the group consisting of hydrogen, halo, cyano and nitro Cu alkyl; R8 is selected from the group consisting of hydrogen, halo, cyano and (^-6 alkyl; R9 and Rie are independently hydrogen, or a group selected from Ci-6 alkyl, carbocyclic and heterocyclic groups' The group is optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, q-6 alkyl, alkoxy, haloCl-6, ki-Ci-6 Alkoxy group, via group Ci-6 alkyl group, via group Ch alkoxy group, Ci-6 alkoxy group C 6 alkyl group, Cl 6 alkoxy group Ci-6 alkoxy group, amine group, 123642 -77- 200817384

a Cu alkylamino group and a bis(Ch alkyl)amino group; R, R, R and R18 are independently hydrogen ' or a group selected from the group consisting of a q 6 alkyl group, a carbocyclic group and a heterocyclic group, the group The case is substituted by one or more substituents selected from the group consisting of i, cyano, nitro, hydroxy, alkyl, (^-6 alkoxy, i-based C^6 alkyl, !|yl (^6 alkane) Oxyl, hydroxy Cw alkyl, hydroxy Cm alkoxy, C -6 alkoxy C!·6 alkyl, CV6 alkoxy (^6 alkoxy, amine, C!-6 alkylamino and bis ( Ch alkyl)amino; and R19 is hydrogen or a group selected from the group consisting of Cu alkyl, C3-6 cycloalkyl, aryl, heteroaryl, aryl Q-6 alkyl and heteroaryl Cl-6 alkyl, The group is optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, C!-6 alkoxy, halo Ci-6 alkyl , 13⁄4-based Ch alkoxy, hydroxy Q-6 alkyl, hydroxy c1-6 alkoxy, c1-6 alkoxy Ci 6 alkyl, Ci·6 alkoxy Ci·6 alkoxy, amine group, Alkylamino group, bis((6-alkyl)amino group, amino-based Cu alkyl group, (Ci_6 alkyl)amino-based Cu alkyl group, bis(Cl_6 alkyl)amino-based Cyalkyl group, cyano group c1-6 Base, Cl_6 alkylsulfonyl, €16 alkylsulfonylamino, Cu alkylsulfonyl (Ci-6 alkyl) amine, amine sulfonyl, Cl. 6 alkyl sulfonyl, double (Ci_6 alkyl)amine sulfonyl, Ci-6 amide amino group, Q-6 decyl (c1-6 alkyl) amine group, amine methyl sulfhydryl group, Cl 6 alkylamine carbhydryl group and bis (Ci-6) Alkylaminocarbazide; or R18 together with R19 and the nitrogen atom to which they are attached form a heterocyclic ring, wherein one ring carbon atom is optionally replaced by N or hydrazine, and the ring is optionally Substituted by a plurality of substituents, the substituent is selected from the group consisting of a benzyl group, a cyano group, a nitro group, a hydroxyl group, a Ci-6 alkyl group, a cw alkoxy group, a halo-Ch-alkyl group, a hydryl-Cy alkoxy group, a trans-Ch-alkyl group. Base, hydroxy C16 alkoxy, Ci6 alkoxy c1-6 alkyl, Ci6 123642 -78- 200817384 alkoxy c!_6 alkoxy 'amine, Cu alkylamino, bis(Ch alkyl) amine , Amino-based Cu-based, (Ch-alkyl)-amino-based Cu-based, bis(Cu-based) amine-based Ci-6 alkyl, cyano C _6 alkyl, Ci-6 alkyl-based succinyl' Cn Anthranyl acid group, C!-6 alkyl group acid group (Cl-6 alkyl) amine group, amine acid group, Cl -6 alkyl sulfonate Mercapto, bis(Ch alkyl)amine sulfonyl, Cu alkanoamine, Cl_6 decyl (q-6 alkyl) amine, amine methyl sulfhydryl, q-6 alkyl carbamide, and bis (Cl-6 alkyl) amineyl. In another aspect of the invention, there is provided a subset of a compound of formula (I) or a pharmaceutically acceptable salt thereof; m is 0, 1 or 2; W is independent of Y2 Is N or CR8, provided that one of 1Y and Y2 is N and the other is CR8; X is a linking group selected from -NR4CH2-, -OCH2-, -〇CH(CH3)-, -OC(CH3) 2-, -SCH2-, -SCH(CH3)-, -SC(CH3)2_, -S(0)CH2_, -s(o)ch(ch3)-, -s(o)c(ch3)2- , -s(o)2ch2-, -s(0)2ch(ch3)-, _S(0)2 C(CH3)2 -, -C(0)NR4 - and -NR4 C(0)_ ; R1 is Selected from the group of King Kong, methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, phenethyl, tetrahydro P Base, batch σ each base, feeding base, P thiol group, fluorenyl group, P thiophene group, phyllopinyl group, mouth. Stationary, 卩 Ρ Ρ 基, tetrahydropyrrolidylmethyl, tetrahydroanthracene σ yl ethyl, external b fluorenyl thiol, external 1: rosylethyl, imidyl methyl, taste saliva Ethyl ethyl, 比 坐 基 methyl, p 嗤 乙基 ethyl, thiol thiol, butyl ethyl, far phenyl methyl, ρ exemplyl ethyl, outer 1: bite Base, ρ is decylethyl. a group of a dimethyl group, a fluorenyl succinyl group, an external b ρ well group methyl group, and an external phenyl phenyl group, 123642 -79- 200817384 This group is optionally 2 or 3 substituents. Substituted, the substituent is selected from the group consisting of halo, cyano, nitro, r9, _or9, _c〇r9, _c〇nr9r10, -9r1〇 and -NR9 COR1 〇; or X_Rl is -C(CH3)2 〇H or -Ch2 〇H,·R is selected from 5 or 6 membered aryl and heteroaryl groups, this group is substituted by -nhconw Sr19, and optionally substituted by one or more substituents independently selected from halo, cyanide , nitro, -Rii, _〇Rii, _c〇Rli, _c〇NRllRl2, _NRllRl2 and -NR11 COR12; , each R3 ', when present, is methyl; R4 is hydrogen or C! _ 6 alkyl; Or when X is _NR4CH2_ or -NR4c(0)-, R1 and R4 together with one or more of the atoms to which they are attached form a 5- or 6-membered heterocyclic ring, wherein one ring carbon atom is optionally the case Substituted by N or hydrazine, and the ring is optionally substituted by one or more substituents. 'Substituents are selected from halo, cyano, nitro, thiol, q -6 alkyl, q alkoxy, dentate hydrazine ^6 alkyl, _ group (^_6 alkoxy, hydroxy (^_6 alkyl, hydroxy q 6 alkoxy, alkoxyCh alkyl, Ci-6 alkoxy&lt;^6 alkane (.oxy, amine, Cu alkylamino, bis(Ch alkyl)amino, amine Ci-6 alkyl , (.1-6 alkyl)amino 〇1-6 alkyl, bis((^1_6 alkyl)amine (111-6 alkyl, cyano Ci-6 alkyl, Ci-6 alkylsulfonate) Base, Ci-6 alkylsulfonylamino group, Ci_6 alkylsulfonyl (Ch alkyl) amine group, amine sulfonyl group, Cu alkyl amine sulfonyl group, bis(Ci-6 alkyl) amine Acid group, Cu succinic acid amine group, Cu sulphonyl group ((^-6 alkyl group) amine group, amine carbaryl group, Cu alkylamine carbhydryl group and bis(Ci_6 alkyl) amine carbaryl group; R8 system selection From hydrogen, halo, cyano and C!-6 alkyl; 123642 - 80 - 200817384 R9 and R1G are independently hydrogen or a group selected from the group consisting of a C6 alkyl group, a carbocyclic group and a heterocyclic group. The group is optionally substituted by one or more substituents selected from the group consisting of i group, cyano group, nitro group, hydroxyl group, Cl-6 alkyl group, Ci-6 alkoxy group, halogen group q·6 alkyl group, i group Cl_6 alkoxy, hydroxyCl4 alkyl, hydroxy Ci 6 alkoxy, alkoxy Cl-6 alkyl, Ci6 alkoxy Cl-6 alkoxy, amine, (V6 alkylamino and bis (Cl- 6 alkyl)amino group ;

Rn, R12 and R18 are independently hydrogen or a group selected from the group consisting of a C1-6 alkyl group, a carbocyclic group and a heterocyclic group, the group being optionally substituted by one or more substituents selected from the group consisting of i groups, Cyano, nitro, hydroxy, (^_6 alkyl, alkoxy, halo CV6 alkyl, _*Cl_6 alkoxy, hydroxy (^6 alkyl, hydroxy (^.6 alkoxy, cv6 alkoxy) a C1-alkyl group, a Ch alkoxy cv6 alkoxy group, an amine group, a Cb6 alkylamino group, and a bis(Cl-6 alkyl)amino group; and R19 is hydrogen or is selected from an alkyl group, a c3-6 cycloalkyl group a group of an aryl group, a heteroaryl group, an arylalkyl group, and a heteroaryl Cualkyl group, which group is optionally substituted by one or more substituents selected from the group consisting of a benzyl group, a cyano group, and a thiol group. , mercapto, Cb6 alkyl, Ch alkoxy, halo-Ch-alkyl, iiSCu alkoxy, via-based Cl-6 alkyl, via-Cl_6 calcined, Cl-6 alkoxy Cl-6 , Ci-6 alkoxy Ci_6 alkoxy, amine, Cu alkylamino, bis(Cw alkyl)amine, amine (V6 alkyl, (Cu alkyl) amine Cu alkyl, bis ( CV6 alkyl)amino 〇ν6 alkyl, cyano Ci-6 alkyl, Ci-6 alkylsulfonyl, C -6 alkylsulfonylamino, cv6 Alkylsulfonyl (Ci-6 alkyl)amine, amidoxime, Cl-6 alkylamine sulfonyl, bis(Ci-6 alkyl)amine sulfonyl, alkanoyl, Ci-6 Alkenyl (Ch alkyl) amine, amine sulfhydryl, Cu alkyl amine methyl thiol and bis (Ch alkyl) amine methyl sulfhydryl; 123642 - 81 - 200817384 or R and R19 and their attached The nitrogen atom together form a 6-membered heterocyclic ring, wherein one ring post atomic system is optionally replaced by N or hydrazine, and the ring system is optionally substituted by one or more substituents selected from a halogen group, a cyano group, Nitro, hydroxy, ci-6 alkyl, Q-6 alkoxy, halo (^-6 alkyl, haloalkoxy, alkyl, benzyl (^-6 alkoxy, Ch alkoxy (^_6) An alkyl group, a Cb6 alkoxy Cu alkoxy group, an amine group, a Cu alkylamino group, a bis(Cl_6 alkyl)amino group, an amine group, an alkyl group, a (C) group, an amine group, and a bis (Cu) group. Alkyl Cl_6 alkyl, cyano (^-6 alkyl, Ci-6 alkylsulfonyl, Ci-6 alkylsulfonylamino, Ci-6 alkylsulfonyl (Cu) Amine, amine acid group, C16 alkylamine sulfonyl group, bis(Ch alkyl)amine sulfonyl group, Ch alkanoguanidino group, Ci -6 octyl group (q _6) Amino group, urethane group, Ci-6 alkylaminocarbamyl group and bis(C!6 alkyl)amine mercapto group. Another specificity of the compound of formula (I) or a pharmaceutically acceptable salt thereof In the species; m is 0 or 1; 4 is (:11, and Y2 is N; X is a linking group selected from -S(0)2 CH2 -, -S(0)2 CH(CH3)-, and -s (0) 2 C(CH3 ) 2 -; R 1 is selected from the group consisting of methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentylcyclohexyl, phenyl, a group based on thiol, phenethyl, P, CT, pyrazolylethyl, furylmethyl, thienylmethyl, thiazolyl fluorenyl, pyrimidine succinylmethyl and oximeyl ethyl, This group is optionally substituted by 1 or 2 substituents selected from the group consisting of amino, yl, cyano, methyl, methoxy, trifluoromethyl, trifluoromethoxy, -nhcoch3, - CONH2 and -conhch3; 123642 -82- 200817384 or -XR1 is -C(CH3)2 OH or -CH2 OH; R2 is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, phenyl , pyridyl, pyrimidinyl, hydrazine, and pyrazolyl, this group is replaced by -NHCONHR19, and optionally one or more Substituted, the substituents are independently selected from halo, cyano, nitro, -Ri 1, -R1, _c〇Rl 1, -CONR11R1 2, -NR11R12 and _11 c〇r1 2 ; R3, when When present, it is a methyl group; R, R12 and R18 are independently hydrogen or a group selected from the group consisting of a 6 alkyl group, a carbocyclic group and a heterocyclic group, and this group is optionally substituted by one or more substituents. The substituent is selected from the group consisting of a halogen group, a cyano group, a nitro group, a hydroxyl group, a q_6 alkyl group, a q·6 alkoxy group, a halogen group C!·6 alkyl group, a _ group Ch alkoxy group, a thiol group, and a base group. Alkoxy group, Ch alkoxy Cl-6 alkyl group, Cm alkoxy cv6 alkoxy group, amine group, Ch alkylamino group and bis(Ch alkyl)amino group; and R19 is hydrogen or selected from ( a group of ^_6 alkyl, C3_6 cycloalkyl, aryl, heteroaryl, aryl C!·6 alkyl and heteroaryl Q-6 alkyl, this group being optionally substituted by one or more Substituted, the substituent is selected from the group consisting of halo, cyano, nitro, hydroxy, alkyl, Ci-6 alkoxy, functional Ci-6 alkyl, haloC-6 alkoxy, hydroxy Q-6 alkyl, Hydroxy (^-6 alkoxy, (^_6 alkoxy Cb6 alkyl, Cl-6 alkoxy (^_6 alkoxy, amine, Ch alkylamino, (Cle6 alkyl) amine, amino Cu alkyl, (Cu alkyl) amino Cu alkyl, bis (Cu alkyl) aminoalkyl, cyano (^ 6 alkyl, Ci-6 alkyl sulfonate) Sulfhydryl, (^-6 alkylsulfonylamino, Cu alkylsulfonyl (Ci-6 alkyl) amine, amine sulfonyl, C!-6 alkylamine sulfonyl, double _6 Alkyl sulfonyl, q-6 alkanoyl, C 6 alkyl alkyl (( 6 6 alkyl) amine, amine methyl sulfhydryl, Ci 6 alkylamine carbaryl 123642 - 83 - 200817384 and Bis(q-6 alkyl)amine fluorenyl. In a further specific class of the compound of formula (I) or a pharmaceutically acceptable salt thereof; m is 1; X is a linking group selected from the group consisting of -S(0)2 CH2 _, -S(0)2 CH(CH3)- And -S(0)2 C(CH3)2 4 is CH, and Y2 is N. R1 is selected from the group consisting of methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl 'phenyl, fluorenyl, phenethyl, pyridyl, a group of pyrazolylethyl, furylmethyl, thienyl fluorenyl, thiazolylmethyl, pyrimidazolylmethyl and pyrhaylethyl, which groups are optionally substituted by 1 or 2 substituents Substituted, the substituent is selected from the group consisting of an amine group, a halogen group, a cyano group, a methyl group, a methoxy group, a trifluoromethyl group, a trifluoromethoxy group, -NHCOCH3, -CONH2, and -conhch3; Substituted by -NHCONHR19 and optionally substituted by one or more substituents independently selected from the group consisting of fluoro, methyl, methoxy, hydroxymethyl, cyanomethyl, -C〇NH2, -CONHCH3 and -con(ch3)2; R3 is methyl; and R is 虱' or selected from methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrenyl, imidazolylhydrazino, isoxazolyl, pyrazolyl, pyridyl fluorenyl, pyridyl and pyrimidinyl groups Group, this group is replaced by one or more depending on the situation Substituted, the substituent is selected from the group consisting of a cyano group, a cyano group, a nitro group, a hydroxyl group, a Cl-6 alkyl group, a Ci-6 alkoxy group, a yl group of a fluorenyl group, a hydroxy group, a hydroxy group, and a hydroxy group. Alkoxy, Ci_6 alkoxy 6 alkyl, 123642 -84 - 200817384 alkoxy Ci-6 alkoxy, amine, Ci-6 alkylamino, bis((^-6 alkyl)amine, amine Cu alkyl, (CV6 alkyl)amino Cu alkyl, bis(CV6 alkyl)amine Ci-6 alkyl, cyano Ci-6 alkyl, Ci-6 alkylsulfonyl 'alkylsulfonylamine Base, (^_6 alkylsulfonyl (Cu alkyl) amine group, amine sulfonyl group, (ν6 alkylamine sulfonyl group, bis(Ch alkyl) amine sulfonyl group, (ν6 alkanoamine group, (ν6 alkanoyl group (&lt;^_6 alkyl)amino group, amine sulfhydryl group, Cu alkylamine methyl hydrazino group and bis(Ch alkyl) amine carbaryl group. In the compound of formula (I) or its pharmacy Further specific species of acceptable salts; m is 1; X is a linking group selected from the group consisting of -S(0)2 CH2 -, -S(0)2 CH(CH3)-, and -s(0)2 C(CH3 2 W is CH and Y2 is N; R1 is selected from the group consisting of methyl, ethyl, isopropyl, cyclopropyl, cyclohexyl, -CH2CH2OH, -CH2CH2NC(0)CH3, -CH2CONH2, phenyl, 4- fluorine Base, 2-chlorophenyl, 2-trimethylphenyl, 2-methoxyphenyl, methylphenyl, 4-ethylaminophenyl, 4-aminophenyl, pyridin-4-yl , pyridin-2-yl, 2-ketotetrahydropyrrol-3-yl, pyrazol-2-yl, 4-methylthiazol-2-yl and 3-methyl-1,3,4-pyrimidine a group based on -2-yl; R2 is

Wherein A1 and A2 are selected from Ch or N, provided that at least one of A1 or A2 is CH; 123642-85 - 200817384 R17 is hydrogen; R18 is hydrogen; R19 is hydrogen, or is selected from methyl, ethyl, and C. Base, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2 (cyclopropyl), -CH2CH2NMe2 -CH(CH3)CH2OH, -C(CH3)2CH2OH, -CH2CH2OH, -CH2CH2CH2OH, 4-mercaptophenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, 4-fluorophenyl, 4- Phenoxyphenyl, 3,4-difluorophenyl, pyrimen-2-yl, -CH2 (imidazol-2-yl), -CH2 (imidazol-3-yl), isoxazolyl-3-yl, 6-酉同基咬-2-yl, 5-methyliso-supplementary σ--3-yl, 1-methyl? Than the -4- group, -CH2 (1-methyl ρ than 嗤-4-yl), 6- methoxyl than the -3- group, 5-carbon group? a group of -3 -, - 2 - and 1 -H -^ 0 -3 - groups; and R3 is a methyl group. In a further specific class of the compound of formula (I) or a pharmaceutically acceptable salt thereof; m is 1; X is a linking group selected from the group consisting of -S(0)2ch2-, -s(o)2ch(ch3)- And -s(o)2 C(CH3 )2 -; 々为匸!! And Y2 is N; R1 is selected from the group consisting of fluorenyl, isopropyl 'cyclopropyl, cyclohexyl, -CH2CH2OH, ?ch2ch2nc(o)ch3, -CH2CONH2, phenyl, 4-fluorophenyl, 2-chlorobenzene Base, 2-trifluorodecylphenyl, 2-methoxyphenyl, 2-methylphenyl, 4-ethylaminophenyl, 4-aminophenyl, π-bit-4-yl, hydrazine Benzoate, 2-W-based tetrahydro-hydropurple-3-yl, oxazol-2yl, 4-methylpyrazol-2-yl and 3-methyl-1,3,4·^ thiadiazole- 2-base 123642 -86 - 200817384 group; R2 is

Wherein A1 and A2 are selected from CH or N, provided that at least one of eight or eight is CH; R17 is hydrogen; R18 is hydrogen; R19 is hydrogen, or is selected from the group consisting of methyl, ethyl, propyl, and iso _propyl, butyl, isobutyl, tert-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH〆cyclopropyl), _CH2CH2NMe2, -CH (CH3 CH2OH, -C(CH3)2CH2OH, -CH2CH2OH, -CH2CH2CH2〇H, 4-methylphenyl, 4-chlorophenyl, trifluoromethylphenyl, 4-fluorophenyl, 4-methoxyphenyl , 3,4-difluorophenyl, thiophen-2-yl, -CH2 (isoxyl-2-yl), -CH2 (isoxazole-3-yl), isoxazolyl, 6-keto- 1H-pyridin-2-yl, 5-methylisooxazol-3-yl, 1-methylpyrazol-4-yl, _CH2(1-methylpyrazol-4-yl), 6-methoxy a group of pyridin-3-yl, 5-fluoropyridin-2-yl, pyrimidin-2-yl and 1H-pyrazolyl; and R3 is a fluorenyl group. In a further specific class of a compound of formula (I) or a pharmaceutically acceptable salt thereof; m is 1; 123642 -87- 200817384 X is a linking group selected from the group consisting of -S(0)2 CH2 -, -S(0)2 CH(CH3)- and _S(0)2 C(CH3)2 1Y is CH, and Y2 is N; R1 is methyl or cyclopropyl; R2 is

Wherein A1 and A2 are selected from CH or N, provided 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-pyrazol-3-yl; and R3 is methyl.

In one aspect of the invention, there is provided a subset of compounds of formula (I), wherein the compound of formula (I) is a compound of formula (la) or (lb)

(la) (lb) or a pharmaceutically acceptable salt thereof; W and Y2 are independently N or CR8, provided that one of 1Y and Y2 is N, and the other 123642-88-200817384 is CR8; X is a linking group , selected from -KR4CR6R7_, _〇CR6R7_, _SCR6R7_, -S(0)CR6R7- . -S(0)2CR6R7- . -C(0)NR4CR6R7. . -NR4C(0)NR5 CR6R7_, -S(0)2NR4CR6R7_ , _nr4C(〇)_, _s(〇)2Nr4 and -NR4S(0)2-; R1 is selected from C--6 alkyl, carbocyclyl, carbocyclic*Ci_6 alkyl, heterocyclic and heterorubic a group of a Ci alkyl group, which is optionally substituted by one or more substituents. 'Substituents are selected from the group consisting of _ group, cyano group, nitro group, R9, -〇R9, _c〇R9, (-CONR9 R1 G , -NR9Ri ο and -Nr9 c〇Ri 0 ; or X-R1 is -C(CH3)2 OH or -CH2 OH; R2 is selected from aryl and heteroaryl groups, this group is -NRi 7c〇nri Substituting sRi 9 and optionally substituted by one or more substituents independently selected from halo, cyano, nitro, _Ri1, 〇R1, _C〇Rl 1, _C()NRl i Rl 2 NR1 丨Rl 2 and -NR11 COR1 2 ; R3 is methyl; /R4 and R5 are independently hydrogen or Ci6 alkyl; or old X is -NR4CR6R7-, -NR4C(0)NR5CR6R7-, -NR4C(0)- or

When -NR4S(0)2_, Ri and R4 together with one or more of the atoms to which they are attached form a 4-, 5-, 6- or 7-membered heterocyclic ring, wherein i ring carbon atoms are optionally ^^ or 〇 substitution, and the ring is optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, keto, Ci-6 alkyl, CH alkoxy, halo Cm alkyl, dentyl-6-6 alkoxy, hydroxy Gy alkyl, hydroxy Ci6 alkoxy, alkoxy C10 alkyl, Ci-6 alkoxy C1_6 alkoxy, amine, Ch alkylamino, double (Ci_6 alkyl)amino, aminoCh alkyl, (CH 123642 -89-200817384 alkyl)amino Cu alkyl, bis(Ch alkyl)amino C 6 alkyl, cyano Cl 6 alkyl, Ci- 6 alkylsulfonyl, Cn alkyl acid amine, q_6 alkyl sulfonium δ &amp; base (Ci · 6 alkyl) amine, amine thiol, Ci · 6 alkyl amine base, double (Ci _ 6 alkyl) amine sulfhydryl, G -6 ruthenium amide, C! -6 ruthenium (q -6 6-base) amine group, amine methyl sulfonyl group, Ci-6 alkylamine methyl sulfhydryl group and Bis(Cle6 alkyl)amine mercapto; R6 and R7 are independently selected from the group consisting of hydrogen, halo, cyano, nitro and q _6 alkyl; R8 is selected Hydrogen, halo, cyano and -6 alkyl; R9 and R10 are independently hydrogen or a group selected from C -6 alkyl, carbocyclyl and heterocyclyl, which groups are optionally Substituted by one or more substituents selected from halo, cyano, nitro, hydroxy, (^-6 alkyl, (^-6 alkoxy, haloalkyl, halo Ci-6 alkoxy, Hydroxy Ci-6 alkyl, hydroxy Cu alkoxy, Ch alkoxy Ci-6, C; [_6 alkoxy (^-6 alkoxy, amine, Ch alkylamino and bis (Ch alkane) Amino group; R1 Sr1 2, 尺 17 and R 18 are independently hydrogen or a group selected from the group consisting of a Ci-6 alkyl group, a carbocyclic group and a heterocyclic group, and the group is optionally substituted by one or more substituents. a substituent selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, Ci-6 alkoxy, halo-Ch-alkyl, dentate alkoxy, via-based Cn-based, trans-base c ^6 alkoxy, (^_6 alkoxy q-6 alkyl, cv6 alkoxy cv6 alkoxy, amine, CV6 alkylamino and bis(Cu alkyl)amine; and R19 is hydrogen, or a group selected from the group consisting of (^_6 alkyl, C3_6 cycloalkyl, aryl, heteroaryl, aryl Ci-6 alkyl, and heteroaryl Cl-6 alkyl, The group is optionally substituted by one or more substituents selected from the group consisting of ii, cyano, nitro, hydroxy, ci-6 alkyl, Ci-6 alkoxy, and functional (^-6 alkyl, alkane) Oxyl, hydroxy Ci-0 alkyl, hydroxy CCl 6 alkoxy, (^_6 alkoxy Cb6 alkyl, 123642 -90- 200817384 C!_6 alkoxy Ci-6 alkoxy, amine, c1-6 alkylamine Base, bis(Ci6 alkyl)amino group, amine Cu alkyl group, (Cu alkyl) amino group Cl-6 alkyl group, bis((:1_6 alkyl)amino group (V6 alkyl group, cyanoalkyl group, Cl_6 alkane) Sulfosyl group, Ci 6 alkylsulfonate amino group, Cu alkylsulfonyl (Ch alkyl) amine group, amine sulfonyl group, Cu alkyl amine sulfonyl group, bis (Ch alkyl) amine sulfonate Sulfhydryl, Cl_6 alkanoylamino, (^_6 alkylalkyl (Cu alkyl) amine, amine methyl sulfhydryl, cl 6 alkylamine carbhydryl and bis (Ch alkyl) amine fluorenyl; or R 18 and R19 and the nitrogen atom to which they are attached form a heterocyclic ring, wherein (one ring carbon atom is optionally substituted by N or hydrazine, and the ring is optionally substituted by one or more substituents, and the substituent is selected From _ group, cyano group, nitro group, hydroxyl group, C^-6 alkyl group, Ch alkoxy group, _ group C!-6 Alkyl, _ylCh alkoxy, hydroxy Ci.6 alkyl, hydroxyCh alkoxy, Ci-6 alkoxyalkyl, (^-6 alkoxy C!-6 alkoxy, amine, Ci-6 alkylamino group, bis(qalkyl)amino group, amine C!-6 alkyl group, (Ch alkyl) amine group C! -6 alkyl group, bis(Cu alkyl) amine group Ci-6 burn Base, gas-based Ci-6 burning base, Ci -6 burning base, Ci-6 burning base amine, C!-6 burning base ( (C _ 6 alkyl) amine group, Amino acid group, C!-6, alkylamine hydrazino, bis(indolyl)alkylamine, (^_6 alkanoamine, (^_6 alkyl sulfonyl) Alkyl, amidino, Ci-6 alkylamine, mercapto and bis((1-6)alkylcarbamyl. In another aspect of the invention, a subset of a compound of formula (I) is provided, wherein the compound of formula (I) is a compound of formula (la) or (lb) 123642 -91 - 200817384

Or a pharmaceutically acceptable salt thereof; W and Y2 are independently N or CR8, provided that one of 1Y and Y2 is N and the other is CR8;

X is a linking 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(0)2CH(CH3)-, - S(0)2 C(CH3)2 -, -C(0)NR4 - and -NR4 C(O)-; R1 is selected from the group consisting of adamantyl, decyl, ethyl, propyl, butyl, isobutyl Base, tri-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, phenethyl, tetrahydroanthracene, 17 bases, 1:7 m, sigma, 吱Cyclol, p-sepeno, yttrium sigma, 0 sigma, 卩p p, tetrahydroquinone, 17 methyl, tetrahydroanthracene, 17 ethyl, pyrrolylmethyl, pyrrole Ethyl ethyl, imidazolylmethyl, imidazolylethyl, pyrazolylmethyl, pyrazolylethyl, furylmethyl, furylethyl, pyrenyl fluorenyl, fenyl phenyl, ? a group of a specific methyl group, a 1,11-ethyl group, a methyl group, a pyrimidinyl group, a pyridylmethyl group, and a pyridyl group. This group is 1,2 as the case may be. Or substituted with 3 substituents selected from halo, cyano, nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R10 and -NR9 COR10; or X-R1 is -C(CH3)2 OH Or -CH2 OH ; 123642 -92- 200817384 R is a 5- or 6-membered aryl and heteroaryl group, this group is substituted by 8r1 9 'and optionally substituted with - or multiple substituents, #代基独立Selected from halo, cyano, nitro, -Rll, _〇Rl 1, _c〇Rl i, _c〇NRl lRl2, _胤! iRi2 and -NR11 COR12; R3 is methyl; R4 is hydrogen or CV6 alkyl Or when X is -NR4CH2_ or -NR4C(〇)-, Ri and R4 together with one or more of the atoms to which they are attached form a 5- or 6-membered heterocyclic ring, wherein the ring carbon atoms are The condition is replaced by N or hydrazine, and the ring is optionally substituted with one or more substituents selected from the group consisting of halo, cyano, nitro, thio, Ci-6 alkyl, Cl-6 alkoxy , haloalkyl, _yl (^_6 alkoxy, hydroxy Ci 6 alkyl, hydroxy Ci-6 alkoxy, Alkoxy c1-6 alkyl, Ci-6 alkoxy. decyloxy, amine, Cu alkylamino, bis(Cu alkyl)amine, amine (316 alkyl, (Cu alkyl) Amino group (V6 alkyl group, bis(Cl_6 alkyl)amino group Ci_6 alkyl group, cyanoCi6 alkyl group, G ·6 alkyl group, C! -6 alkyl group, q _6 alkane Alkylsulfonyl (Ci_6 alkyl)amine, sulfonyl, Cu alkylamine sulfonyl, bis(Cu alkyl)amine sulfonyl, Cu alkanoyl, Cu alkyl thiol (Ci-6) An alkyl)amino group, an amine carbaryl group, a Ci-6 alkylamine carbhydryl group, and a bis(c1-6 alkyl)amine carbaryl group; R8 is selected from the group consisting of hydrogen, a halogen group, a cyano group, and a CV6 alkyl group; R9 and R1G are independently hydrogen or a group selected from the group consisting of a V6 alkyl group, a carbocyclic group and a heterocyclic group, and the group is optionally substituted by one or more substituents selected from a halogen group and a cyanogen group. Base, nitro, hydroxy, alkyl, (^_6 alkoxy, haloCi-6 alkyl, haloCi-6 alkoxy, hydroxy Ci-6 alkyl, hydroxy Ci-6 alkoxy 123642-93 - 200817384, Ci-6 alkoxy Ci -6 alkyl, Ci-6 alkoxy Ci-6 alkoxy, amine, &lt;^_6 alkylamino and bis(Ci_6 alkyl)amine R11, !^ 2 and R18 are independently hydrogen or a group selected from the group consisting of (^-6 alkyl, carbocyclyl and heterocyclic groups, which are optionally substituted by one or more substituents, substituents; Selected from fluorenyl, cyano, decyl, thiol, Ch alkyl, Cu alkoxy, halo (V6 alkyl, _yl (^-6 alkoxy, hydroxy (^_6 alkyl, hydroxy Ch alkoxy) Alkyl, Ci-6 alkoxy (^-6 alkyl, Ci-6 alkoxy Ci-6 alkoxy, amine, Cb6 alkylamino and bis(Ci-6 alkyl)amine; and R19 is hydrogen, or a group selected from the group consisting of Ci-6 alkyl, C3_6 cycloalkyl, aryl, heteroaryl, aryl q.6 alkyl and heteroaryl Ci-6 alkyl, this group being optionally substituted by one or more Substituted, the substituent is selected from the group consisting of i, cyano, nitro, hydroxy, Ci-6 alkyl, alkoxy, ! I-based Ch alkyl, halo (V6 alkoxy, hydroxy Ci-6 alkyl, hydroxy Ci-6 alkoxy, Ci-6 alkoxy Ci-6 alkyl, 匸1-6 alkoxy (^ 1-6 alkoxy group, amine group, (^_6 amine group, bis(〇1-6 alkyl) amine group, amine Cu alkyl group, (Cu alkyl) amine group Cu alkyl group, bis(Ci_6 alkane) Amino CV6 alkyl, cyano Ci-6 alkyl, Ch alkylsulfonyl, Ci-6 alkylsulfonylamino, alkylsulfonyl (Ch alkyl) amine, amine sulfonyl, Q· 6 alkylamine sulfonyl, bis(Ch alkyl)amine sulfonyl, q-6 alkanoylamino, alkylalkyl (Ch alkyl) amine, amine methyl sulfonyl, Cl 6 alkylamine fluorenyl And a bis(Cu alkyl)amine carbenyl group; or R18 together with R19 and the nitrogen atom to which they are attached form a 6-membered heterocyclic ring, wherein one ring carbon atom is optionally replaced by N or hydrazine, and the ring Depending on the case, it may be substituted by one or more substituents selected from the group consisting of !|, cyano, nitro, hydroxy, (V6 alkyl, Ch alkoxy, dentyl, yl (^6) Alkoxy, 123642 -94- 200817384 Hydroxy Ci-6 alkyl, hydroxy Ci-6 alkoxy, C -6 alkoxy Ch alkyl, alkoxy alkoxy, amine , Ci-6 alkylamino, bis(Ch alkyl)amine, amino CV6 alkyl, (Cu alkyl)aminoCh alkyl, bis(Cu alkyl)amino q-6 alkyl, cyano Ci-6 alkyl, (^_6 alkylsulfonyl, Ci-6 alkylsulfonylamino, Cu alkylsulfonyl (Ci-6 alkyl) amine, amine sulfonyl, Cu alkyl Aminesulfonyl, bis((^_6 alkyl)aminesulfonyl, Ci-6 alkanoylamino, Cu alkylalkyl (Ci-6 alkyl) amine, amine methyl sulfonyl, Ci-6 alkyl Aminomethyl thiol and bis (Cu alkyl) amine carbaryl.

In another specific class of compounds of formula (I), the compound of formula (I) is a compound of formula (la) or (lb) R3, N^^R3

(la) (lb) or a pharmaceutically acceptable salt thereof;

W is CH and Y2 is N; X is a linking group selected from -S(0)2 CH2 ·, -S(0)2 CH(CH3)-, and -s(0)2 C(CH3)2 R is Selected from decyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, decyl, phenethyl, pyridyl, pyrazole a group of a benzyl group, a fluorenylmethyl group, a psecenylmethyl group, a far sialylmethyl group, a dioxazolylmethyl group, and a pyridylethyl group, which is optionally taken or 2 Substituted by a substituent, the substituent is selected from the group consisting of an amine group, a functional group, a cyano group, a methyl group, a methoxy group, a trifluoromethyl group, a trifluoromethoxy group, a _c 〇 2 and a 123642-95 - 200817384 -conhch3; or -XR1 is -C(CH3)2 OH or -ch2 OH; R2 is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, pyrenyl, pyridyl, pyrimidinyl, hydrazine, and pyrimidine Zizolyl, this group is substituted by -NHCONHR1 9 and optionally substituted by one or more substituents independently from the halo, the gas group, the stone Schottky, 1, -R1, _C〇r1, -CONR11 R1 2, -NR11 R1 2 and 1 COR1 2 ; R3 is methyl; R11,! ^2 and R18 are independently hydrogen or a group selected from a Cu alkyl group, a carbocyclic group and a heterocyclic group. This group is optionally substituted by one or more substituents selected from the group consisting of i groups and cyanogens. Base, nitro, hydroxy, q _6 alkyl, (^_6 alkoxy, halo Q-6 alkyl, halo Ciw alkoxy, hydroxy (^_6 alkyl, hydroxy Cn alkoxy, Ci-6) Alkoxy Ci-6 alkyl, CV6 alkoxy (^-6 alkoxy, amine, Cb6 alkylamino and bis(Ch alkyl)amine; and R is hydrogen' or selected from Ci_6 alkyl, C3 a group of -6 cycloalkyl, aryl, heteroaryl, aryl C^6 alkyl and heteroaryl Ci-6 alkyl groups, the group being optionally substituted by one or more substituents, substituents Selected from a group, a cyano group, a nitro group, a hydroxyl group, a Ci-6 alkyl group, a Ch alkoxy group, an alkyl group, a ii group Cu alkoxy group, a hydroxyl group Ci-6 alkyl group, a hydroxyl group (^_6 alkoxy group, Alkoxy (^_6 alkyl, C!-6 alkoxyCh alkoxy, amine, Ci-6 alkylamino, bis(cv6 alkyl) amine, amino Cu alkyl, (C -6 alkyl) An amino Cu alkyl group, a bis(Cu alkyl)amino group Ci-6 alkyl group, a cyano Ci-6 alkyl group, a (ν6 alkylsulfonyl group, a CV6 alkyl group, an amine group, C; 1 - 6 yard base (Cl - 6 alkyl) amine, amine base, Cu alkyl amine sulfonyl, bis (q-6 alkyl) amine sulfonyl, Cu decyl amide Base, 123642 -96- 200817384

Cu alkyl fluorenyl (Ci-6 alkyl) amine group, amine carbaryl group, alkyl amine carbaryl group and bis (Cu alkyl) amine carbaryl group. In a further particular class of compounds of formula (I), the compound of formula (I) is a compound of formula (la) or (lb)

R

R2 or a pharmaceutically acceptable salt thereof; X is a linking group selected from the group consisting of -s(o)2ch2-, -s(o)2ch(ch3)_ and -s(o)2 C(CH3)2 iY Is CH, and Y2 is N; R1 is selected from the group consisting of decyl, ethyl, propyl, butyl, isobutyl, tert-butyl,

Cyclopropyl, cyclopentylcyclohexyl, phenyl, benzyl, phenethyl, pyridyl, pyrazolylethyl, furylmethyl, thienylmethyl, pyrazolylmethyl, pyrimidazolyl a group having a pyridylethyl group, which is optionally substituted by 1 or 2 substituents selected from the group consisting of an amine group, a halogen group, a cyano group, a methyl group, a methoxy group, and a trifluoromethyl group. , trifluoromethoxy, -NHCOCH3, -CONH2 and -conhch3; R2 is phenyl or pyridyl, substituted by NHCONHR19, and optionally substituted by one or more substituents, independently selected from fluoro, A , methoxy, hydroxymethyl, cyanoguanidino, -conh2, -CONHCH3 and -CON(CH3)2; R3 is methyl; and R19 is hydrogen or is selected from methyl, ethyl, propyl, Isopropyl, butyl, iso-123642 -97- 200817384

Butyl, tert-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, imidazolylhydrazyl, isoxazolyl, pyrazolyl, pyrazolyl a group of a methyl group, a pyridyl group and a pyrimidinyl group, which group is optionally substituted by one or more substituents selected from the group consisting of a yl group, a cyano group, a nitro group, a hydroxyl group, (^-6 alkyl group, cv6). Alkoxy, halo (ν6 alkyl, haloalkoxy, hydroxy Ci-6 alkyl, hydroxyCh alkoxy, Ci-6 alkoxy Ci-6 alkyl, Cy alkoxy Cu alkoxy, amine Base, C!_6 alkylamino group, bis(Cu alkyl)amine group, amine Cu alkyl group, (cv6 alkyl)amino group Cu alkyl group, bis(Cu alkyl)amino group q-6 alkyl group, cyanide Ci-2-alkyl, alkylsulfonyl, Ci-6 alkylsulfonylamino, Cu alkylsulfonyl (Ci-6 alkyl) amine, amine sulfonyl, Ch alkyl sulfonate Mercapto, bis(Ch alkyl)amine sulfonyl 'Cu alkyl amide amine, alkyl fluorenyl (Cu alkyl) amine group, amine sulfhydryl group, Cu alkyl amine carbhydryl group and bis (Cl-6 sinter A further specific species of the compound of formula (I), wherein the compound of formula (I) is a compound of formula (la) or (lb)

Or a pharmaceutically acceptable salt thereof; m is 1; X is a linking group selected from the group consisting of -s(0)2 CH2 -, -S(0)2 CH(CH3)-, and -s(0)2 C(CH3 ) 2 1Y is CH and Y2 is N. 123642 -98- 200817384 R1 is selected from the group consisting of methyl, ethyl, isopropyl, cyclopropyl, cyclohexyl, _CH2CH2OH, -CH2CH2NC(0)CH3, -CH2CONH2, phenyl, 4-fluorophenyl, 2-chloro Phenyl, 2-trifluoromethylphenyl, 2-methoxyphenyl, 2-methylphenyl, 4-ethylamidophenyl, 4-aminophenyl, p-bit-4-yl, T. deg-2-yl, 2-mercaptotetrazine p pir-3-yl, pyrazol-2-yl, 4-methylpyrazol-2-yl and 3-mercapto-1,3,4 a group of pyrimidin-2-yl; R2 is

Wherein A1 and A2 are selected from CH or N, provided that at least one of A1 or A2 is CH; R17 is hydrogen; R18 is hydrogen; and R19 is hydrogen, or is selected from methyl, ethyl, propyl, iso- Propyl, butyl, iso-butyl, tert-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, pyrimen-2-yl, -CH2 (imidazol-2-yl), -CH2 (imidazol-3-yl), isoxazolyl-3-yl, 6-keto -1H-pyridin-2-yl, 5-methylisoxazol-3-yl, 1-methylpyrazol-4-yl, -CH2(1-methylpyrazol-4-yl), 6-A a group of oxypyridin-3-yl, 5-fluoropyridin-2-yl'pyrimidin-2-yl and 1H-pyrazole-3-123642-99-200817384; and R3 is methyl. In a further particular class of compounds of formula (I), the compound of formula (I) is a compound of formula (la) or (lb)

R2

Or a pharmaceutically acceptable salt thereof; m is 1; X is a linking group selected from the group consisting of -S(0)2 CH2 -, -S(0)2 CH(CH3)-, and -S(0)2 C(CH3 ) 2 ·; 1Y is CH, and Y2 is N;

R1 is selected from the group consisting of methyl, isopropyl, cyclopropyl, cyclohexyl, -CH2CH2OH, -CH2CH2NC(0)CH3, -CH2CONH2, phenyl, 4-fluorophenyl, 2-chlorophenyl, 2-trifluoro Nonylphenyl, 2-methoxyphenyl, 2-mercaptophenyl, 4-ethylamidophenyl, 4-aminophenyl, butyl-4-yl, p-sigma-2-yl , 2-mercaptotetrazine p, pilo-3-yl, pyrazol-2-yl, 4-methylpyrazol-2-yl and 3-methyl-1,3,4-pyrazol-2- Base group; R2 is

Wherein Α1 and Α2 are selected from CH or hydrazine, provided that at least one of 123642-100-200817384 of Α1 or Α2 is CH; R17 is hydrogen; R18 is hydrogen; and R19 is hydrogen or is selected from methyl or ethyl. , propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2 (cyclopropyl), - CH2CH2NMe2, -CH(CH3)CH2OH, -C(CH3)2CH2OH, -CH2CH2OH, -CH2CH2CH2〇H, 4-methylphenyl, 4-chlorophenyl, winter trifluoromethylphenyl, 4-fluorophenyl , 4-methoxyphenyl, 3,4-difluorophenyl, pyrimido-2-yl, -CH2 (meta-salt-2-yl), _CH2 (miso-3-yl), iso-p- Benzyl-3-yl, 6-keto-1H-pyridyl 1 , 5-mercaptopurine _3_yl, 1-mercapto p-salt-4-yl, -CH 2 fluorenylmethylhydrazine. a group based on an ice group), a 6-methoxypyridin-3-yl group, a 5-fluoropyridin-2-yl group, a pyrimidine-2-yl group, and a 1H_p ratio of a saliva-3 group; and R3 is a methyl group. In a further particular class of compounds of formula (I), the compound of formula (I) is a compound of formula (^) or (lb)

Or a pharmaceutically acceptable salt thereof; m is 1; 123642 - 101 200817384 X is a linking group selected from the group consisting of -s(0)2 ch2 -, -S(0)2 CH(CH3)-, and -S(0) 2 C(CH3 )2 W is CH and Y2 is N. R1 is a fluorenyl group or a cyclopropyl group; R2 is

Wherein A1 and A2 are selected from CH or N, provided that at least one of A1 or A2 is CH; R17 is hydrogen; R18 is hydrogen; and R9 is hydrogen' or is selected from the group consisting of methyl, ethyl, propyl and cyclopropane. a group of a group, a cyclobutyl group, a -CH2CH2〇H, -CH2CH2NMe2, -C(Me)2CH2OH, and a 1Η-ρ specific 嗤-3 group; and R3 is a methyl group. Another aspect of the invention provides a compound or combination of compounds selected from any one of the Examples, or a pharmaceutically acceptable salt thereof. The invention also provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof. A compound of formula (I), wherein X = -S(0)2CR6R7-, can be obtained by reacting a compound of formula (I) wherein χ = SCr6 R7 _, for example, using Oxone 8, at room temperature in a mixed solvent system of water and ethanol Made by oxidation. 123642 -102- 200817384

A compound of formula (I), wherein R1 X = R1 〇CR6R7-, by a compound of formula (1) wherein R1X = HOCR6R7-, and a compound of formula (II) wherein L1 is a leaving group (eg, i-based, toluenesulfonyl, Methanesulfonyl, etc., prepared as appropriate under appropriate conditions, such as triethylamine' in the presence of a solvent such as tetrahydrofuran or N,N-dimethylformamide.

a compound of the formula (I), wherein ί^χ^ι^ι^Να^κ7-, by a compound of the formula (I) wherein Rix = HR4NCR6R7-, and a compound of the formula (II), wherein L1 is a leaving group (such as i Base, toluenesulfonyl, methanesulfonyl, etc., depending on the case, such as triethylamine' and solvent, such as tetrahydrofuran or N,N-dimercaptocaramine in the presence of; or It is prepared by reacting a compound of the formula (7) wherein Rix = HR4NCR6R7- with a compound of the formula (ΠΙ) in the presence of a suitable reducing agent such as NaCNBH3. R1 - L1 [〇&gt;\ [〇&gt;3)m

A compound of formula (I) wherein X1==S(0)2CR6R7-, -SCR6R7-, -OCR6R7-, -R4NCR6R7-, -S(0)CR6R7-, via a compound of formula (IV) wherein L1 is detached a base (such as iS-based, toluene-based sulfhydryl, ortho-xanthine, etc.), and a compound of formula (V) 123642-103 - 200817384, optionally with a suitable base, such as triethylamine, with a solvent such as tetrahydroxanthene or It is prepared by reacting in the presence of N,N-dimethylformamide.

A compound of formula (I), wherein X = -SCR6R7-, can be prepared as a compound of formula (IV) wherein L1 is a leaving group (e.g., halo, toluenesulfonyl, methanesulfonyl, etc.), and sulfur The urea is reacted in a suitable solvent such as ethanol to produce a compound of formula (VI) which is subsequently combined with a compound of formula (π) in a suitable base such as sodium hydroxide and a solvent such as N,N-didecyl. The reaction is carried out in the presence of formamide.

A compound of formula (I), wherein X = -R4NC(0)-, can be reacted by a compound of formula (VII) with a compound of the formula ,^Ι14, followed by appropriate activation of the carboxylic acid by methods known in the literature, such as A coupling agent, such as H ATU, or converted to barium chloride.

A compound of formula (I), wherein X = -S(0)2CR6R7-, can be reacted continuously with a compound of formula (VIII) by a compound of formula (1) wherein X = -S(0)2 CIV, followed by a formula ( IX) a compound wherein L1 is a leaving group (such as !i group, toluenesulfonyl group, 123642-104-200817384 methanesulfonyl group, etc.), in the presence of a suitable base, such as sodium hydride or potassium third alcohol, in a suitable solvent , for example, tetrahydrofuran or n, n-dimethylformamidine can be reacted.

CM A compound of the formula (I), wherein Wx^^hocr^r7-, can be prepared by reacting a compound of the formula (XI) with a suitable organometallic reagent of the formula (XI) and, for example, a Grignard reagent, in a suitable solvent. In the case of "different from R7, it is possible to use a technique known in the literature, such as conversion of a compound of formula (X) to Weinreb decylamine, and reaction with an organometallic reagent of formula (XI), and then in a subsequent step, Reaction with an organometallic reagent of formula (XII).

R6—Μ (XI)

R~M (XII) The compound of the formula (I) can be prepared from a compound of the formula (L) wherein the L2 is a leaving group (e.g., halo, toluenesulfonyl, methanesulfonyl, -SMe, _S(0)2Me, etc.) Using a suitable organometallic reagent (such as dihydroxyborane R2B (〇H) 2 or dihydroxyborane R 2 B (〇R) 2 , etc.) in the presence of a suitable metal catalyst (such as palladium or copper) in a suitable solvent In the middle, such as 丨, 4_ dioxane. Alternatively, in the case where R2 is bonded to the pyrimidine ring via a nitrogen, oxygen or sulfur atom, the compound of formula (1) can be prepared from a compound of formula (XIII) wherein L2 is a leaving group (e.g., halo, toluenesulfonyl, methanesulfonyl) , -SMe, -S(0)2Me, etc.), in the presence of the desired amine, alcohol or &lt;alcohol' in the presence of a suitable test, such as a carbonic acid clock, in a suitable solvent 譬123642 -105 - 200817384 such as N, Reaction in t-dimercaptocaramine. [片 [v)m, L2

(I) (XIII) It should be understood that a compound of formula (xm) can be converted to another compound, by oxidation or alkylation, either by the techniques listed above or known in the literature. Action, reductive amination, and the like. a compound of the formula (XIII), wherein xk -S(0)2CR6R7_, _scr6r7_, _OCH6R7_, _r4ncr6r7_, _s(〇)cr6r7_, may be a compound of the formula (χιν), wherein L1 is a leaving group (eg, fluorenyl, toluenesulfonyl, Methanesulfonyl, etc., and the compound of the formula (V), if appropriate, are prepared by reacting with a solvent such as tetrahydrofuran or hydrazine or hydrazine-dimethylformamide as appropriate.

〔V

A compound of the formula (XIII), wherein X = _SCR6R7-, can be prepared in the following manner, a compound of the formula (XIV) wherein L1 is a leaving group (such as a functional group, a toluenesulfonyl group, a methanesulfonyl group, etc.), and a thiourea Reacting in a suitable solvent such as ethanol to produce a compound of formula (XV) which is then subsequently combined with a compound of formula (II) in a suitable base, such as sodium hydroxide, with a solvent such as N,N-dimethyl The reaction is carried out in the presence of decylamine.

R°i(R3)m rl.li Ο

...,

-► h2n 123642 •106- (XIII) 200817384 Compound of the formula (Χπι), where χ = _R4NC(0)_, can be reacted by a compound of the formula (χνι) with an amine, followed by appropriate activation of the carboxylic acid, by literature Known methods, such as the use of a coupling agent, such as HATU, or converted into

A compound of the formula (ΧΙΠ), wherein X = _s(〇)2cr6R7-, can be reacted continuously with a compound of formula (VIII) by a compound of formula (χιπ) wherein X = -SCOTCH2-, followed by a compound of formula (IX) Where Li is a cleavage group (eg, benzyl, fluorene, hydrazine, hydrazine, etc.), in the presence of a suitable test, such as sodium hydride or potassium butoxide, in a suitable solvent such as tetrahydrofuran Or made by reacting with N,N-dimethyl decylamine.

A compound of formula (XIII), wherein Ri X = h〇CR6R7-, can be prepared by reacting a compound of formula (XVII) with a suitable organometallic reagent of formula (XI) and formula (XII), such as a Grignard reagent, in a suitable solvent. to make. In the case where R6 and R7 are different, a technique known in the literature, such as conversion of a compound of formula (XVII) to Weinreb decylamine, and reaction with an organometallic reagent of formula (XI), and then in a subsequent step, may be used. Reaction with an organometallic reagent of formula (XII). 123642 -107- 200817384

The compound of formula (IV) can be prepared from a compound of formula (XIV) wherein l2 is a leaving group (e.g., halo, toluenesulfonyl, decanesulfonyl...SMe, -S(〇)2Me, etc.), and L1 is detached Base (such as _ group, acesulfonyl sulfonyl group, methane sulfonyl group, etc.), using an appropriate organometallic reagent (such as dihydroxyborane r2b (〇h) 2 or dihydroxy sulfonate S for 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, in the case where R2 is attached to the pyrimidine ring via a nitrogen, oxygen or sulfur atom, the compound of formula (IV) can be prepared from a compound of formula (XIV) wherein l2 is a leaving group (eg, halo, toluenesulfonyl, ketone) Anthocyanin, -SMe, -S(0)2Me, etc.) in the form of a desired amine, alcohol or thiol in the presence of a suitable base, such as potassium carbonate, in a suitable solvent such as N, N-di Reaction in methylformamide.

In the case of a pyrimidine ring, wherein L2 is a compound of the formula (X), a compound of the formula (XVII) wherein L2 is a leaving group (such as a halogen group, a toluenesulfonyl group, a methanesulfonyl group, a -SMe, _S(〇)2Me, etc.), and R is hydrogen or alkyl, using an appropriate organometallic reagent (such as dihydroxyl-r2b(oh)2 or di-l-based t-boiler r2b(〇r)2#), (iv) when metal touch In the presence of a medium such as palladium or copper, a compound of the formula (x) which is attached to the pyrimidine ring via a nitrogen, oxygen or sulfur atom in a suitable solvent, such as palladium or copper, can be prepared from the formula ( XVII) Compound 123642 200817384 (such as halo, toluene, acetamyl, _SMe, _S(G)2Me, etc.) in the presence of the desired amine, alcohol or thiol, in the presence of a suitable base, for example Carbon, potassium 'reacts in a suitable solvent such as N,N-dimercaptocarbamide.

L2 (XVII)

〔V

0 (X)

The compound of the formula (XVIII) can be prepared from the compound of the formula (XIX), and the L2 of the compound (XIX) is a leaving group (such as a halogen group, a toluenesulfonyl group, a methanesulfonyl group, a _SMe, a _s (an oxime, etc. using an appropriate organometallic reagent ( For example, dihydroxyborane r2b (〇h^ or dihydroxy side vinegar R2B(OR)2, etc.) in the presence of a suitable metal catalyst (such as copper or copper) in a suitable solvent, such as dioxane. In the case where R2 is bonded to the pyrimidine ring via a nitrogen, oxygen or sulfur atom, a compound of the formula (χνπι) can be prepared from a compound of the formula (XIX) wherein L2 is a leaving group (such as a halogen group, a sulfonyl group, a decane group). Sulfonyl, _SMe, -S(〇) 2Me, etc., in a way that is needed

The amine, alcohol or thiol is reacted in the presence of a suitable base, such as potassium carbonate, in a suitable solvent such as N,N-dimethylformamide.

The compound of the formula (XX) can be produced from a compound of the formula (XXI) wherein L2 is a leaving group (e.g., halo, acesulfonyl, methanesulfonyl, -SMe, -S(0)2Me, etc.), using an appropriate organic a metal reagent (such as dihydroxyborane r2b(〇h)2 or dihydroxyborane R2B(OR)2, etc.) in the presence of a suitable metal catalyst (such as palladium or copper) in a suitable solvent, such as hydrazine, 4_ Dioxane. Alternatively, in the case where R2 is attached to the pyrimidine ring via nitrogen, 123642 200817384 oxygen or a &lt; atom, the compound of formula (XXI) can be prepared from a compound of formula (XXI) wherein l2 is a leaving group (eg, halo, toluene) , methane ~ base, _SMe, -S (〇) 2Me, etc." is in the form of a suitable test with the desired amine, sage or sulphate, such as potassium carbonate, in a suitable solvent such as hydrazine, = _ Reaction in carbamide.

L2/, n^\l2 (XXI) 〇m C 3~(r3)-

l2An 八 r2 (XX)

弋 () a substance, wherein l1 is a detachment group (such as a dentate group, a toluenesulfonyl group, a methane κ I group, etc.), which can be obtained by a compound of the formula (brother) and a compound of the formula, depending on the presence of a suitable base. For example, triethylamine is prepared by reacting in a suitable solvent such as dimethylformamide.

(XXII)

The 式 (疋) compound can be converted into another formula (χχιι), by techniques such as those listed above or known in the literature, such as oxidation, alkylation, Reductive amination and the like. a compound of the formula (IV), wherein Li is a leaving group (such as a benzyl group, a toluenesulfonyl group, ..., an I group, etc.), which may be present via a compound of the formula (χχιν) and a compound of the formula (XX), optionally in the presence of a suitable base It is prepared by reacting, for example, triethylamine in a suitable solvent, a gentleman's monomethylcarbamide. 123642 -110- 200817384

a compound of the formula (X), wherein L1 is a leaving group (such as _ group, toluyl fluorenyl group, methyl hydrazide~ fluorenyl hydrazide) and R is hydrogen or a Ch alkyl group, which is a compound of the formula (χ^ν) The compound of XXIII), if appropriate, is reacted in the presence of a suitable base, such as triethylamine, in a suitable solvent such as hydrazine, hydrazine-dimethylformamide.

A compound of the formula (XVIII) wherein L1 is a leaving group (e.g., a halo group, a toluene xanthyl group, a methanesulfonyl group, etc.) may be suitably present in the presence of a compound of the formula (XXVI) and a compound of the formula (χχπι), for example, Triethylamine is prepared by reacting in a suitable solvent such as hydrazine or hydrazine-dimethylformamide.

(XXVI) (XVIII) A compound of the formula (XX) wherein L1 is a leaving group (e.g., benzyl, toluenesulfonyl, methanesulfonyl, etc.), and L2 is a leaving group (e.g., halo, toluenesulfonyl, methane) Sulfhydryl, -SMe, -S(0)2Me, etc., can be converted to the compound of formula (XXIII) by the formula (χχνπ), as appropriate in the presence of a suitable test, such as triethylamine, in a suitable solvent such as N It is prepared by reacting with N-dimethylformamide. 123642 -111 - 200817384

(XX Chuan)

(XXVII)

(XX) a compound of the formula _), wherein the ruthenium is detached from the base (such as a commercial base, a toluene, a toluene base, etc.), and the L2 is a detachment group (such as a lyophilized base, a toluene-based base, and a refractory base) , -SMe, _s(0)2Me, etc., via a compound of formula (xx) and a compound of formula (XXIII), optionally in the presence of a suitable base such as triethylamine, in a suitable solvent such as N,N-dimethyl Made by the reaction of formamide. R〇, ^ 〔&gt; Ο

HR, X into human L2 R, x eight N eight L2 (XXIII) (10) Chuanxiong, L (XXVIII) (Xili) It should be understood that the compound of formula (XIII) can be converted into another compound of formula (ΧΙΙΙ) By techniques such as those listed above or known in the literature, such as oxidation, alkylation, reductive amination, and the like.

a compound of the formula (XIV) wherein L1 is a leaving group (such as a sulfhydryl group, a pyrolyl sulfonium group, a methanesulfonyl group, etc.), and L2 is a leaving group (such as a halogen group, a toluenesulfonyl group, a methanesulfonyl group, a -SMe, -S(0)2Me, etc., via a compound of formula (XXIX) and a compound of formula (XXIII), optionally in the presence of a suitable assay, such as triethylamine, in a suitable solvent such as N,N-dimethylformamide Made by reaction.

a compound of the formula (XVII), wherein L1 is a leaving group (e.g., a halo group, a toluenesulfonyl group, a methanesulfonyl group, etc.), and L2 is a leaving group (e.g., i group, toluenesulfonyl 123642-112-200817384, a Sulfhydryl, -SMe, -S(0)2Me, etc., and R is hydrogen or Ch alkyl, via a compound of formula (XXX) and a compound of formula (XXIII), optionally in the presence of a suitable base, such as triethyl The amine is prepared by reacting in a suitable solvent such as N,N-dimercaptocarbamide.

A compound of the formula (XIX), wherein L1 is a leaving group (such as _ group, toluene acid group, orthocalcic acid hydrazide), and L2 is a leaving group (such as _ group, toluene xanthine group, orthocalcium group) , -SMe, -S(O)2 Me, etc.), via a compound of formula p〇QQ) and a compound of formula (XXIII), optionally in the presence of a suitable assay, such as triethylamine, in a suitable solvent such as N, N- It is prepared by reacting in dimethylformamide. Π

a compound, such as a tribasic compound and a compound of formula (XXIII), optionally in the presence of a suitable base,

A compound of formula (I), wherein R1X = H2NCH2_, can be prepared by reduction from 123642 - 113 - 200817384 of the compound of formula (XVIII), for example hydrogen, with a suitable catalyst such as palladium on carbon in a suitable solvent such as ethanol. effect. Γ\ Λ 〔〇χ h(R3)m

Nc^'nT’, r2 (XVIII)

I2Ν^ν~ (I) A compound of formula (I), wherein Ri X = H2Nc(〇)_, can be prepared from a compound of formula (xvm) by hydrolysis, for example, with sodium hydroxide in a suitable solvent such as a mixture of water and ethanol. effect. NC,, n^r2 (XVIII)

A compound of formula 1 wherein Rlx = H2NCR6R7_ can be prepared from a compound of formula (XVIII) by reaction with an organometallic oxime (XI) and (oxime). R6^ Ox R6 — Μ (XI) nct, fsr, r2 (XVIII)

Compounds of formula (XIII) wherein r1x = H2nCH2_ may be prepared by reduction from a compound of formula (XIX), such as hydrogen, with a suitable catalyst such as palladium on carbon, as appropriate. The hydrogenation of a solvent such as ethanol. —Y又^ c人N人L N(T 'n&quot;^l2 (XIX)

H2N&gt;^\ 八二 2 (ΧΙΠ) 弋(XIII) compound, wherein Rl x = H2NC (〇>, can be prepared from a compound of the formula by using, for example, sodium hydroxide in a suitable solvent such as a mixture of water and ethanol 123642-114 - Hydrolysis in 200817384 [V NΪΧ NCH2 (XIX)

A compound of the formula (XIII), wherein RiX == H ΝΓ 6 7 叮, _丄t A MLR R -, can be passed via an organic metal reagent (XI). Reaction with (ΧΠ) to prepare a compound of formula I (χιχ). , 'R O 〔〇&gt;(R\ R~M (XI)

(ΧΠ)

(X,X) (X.„) It should be understood that the 'R2 group can be first a carbon ring or a heterogeneous amine at any stage T (as the case may be protected nitrogen, such protection groups include but are not limited to nitrate Introduction of a base, a third-butoxyaminocarbamate, etc., which can be converted into a vein after the synthesis (after appropriate removal of protection), by either isocyanuric acid (or In other cases, it is a direct reaction of an activated group such as phenoxy urethane or the like, or by activation of an amine (for example, the use of a gas or a formation of a phenoxyamino group). And subsequent reactions with amines, or other methods known to form urea in the literature. It is clear that certain different ring substituents in the compounds of the invention may be introduced by standard aromatic substitution reactions, or Conventional functional group upgrading processes are produced either before or immediately following the methods mentioned above, and thus two packs: in terms of the method of the invention. For example, a compound of formula (7) can be substituted by a = aromatic substitution reaction. 'Or by the use of functional group modification method, is converted into, compound ° such reaction and modification' For example, the substituent is replaced by the introduction of the substituent 'reaction of the substituent, the substituent is burned 123642-115-200817384, and the oxidation of the substituent. The reagents and reaction components for this procedure are chemical. It is well known in the art that specific examples of aromatic substitution reactions include the introduction of a nitro group, the use of concentrated nitric acid, the introduction of a sulfhydryl group, the use of, for example, hydrazine and Lewis acid (such as aluminum trichloride) under Friedel Crafts conditions; The introduction of alkyl groups, the use of alkyl-based and Lewis acid (such as aluminum tri-aluminum), under Friedel Crafts conditions; and the introduction of dentate groups. Specific examples of upgrading, including the reduction of the base to the amine group, borrow Catalytic hydrogenation by, for example, nickel catalyst, or iron treatment in the presence of hydrochloric acid, and heating; oxidation of the alkylthio group to a sulfhydryl or a ruthenium group. It should also be understood that in this context In some of the reactions mentioned, it is necessary/need to protect any sensitive groups in the compound, where it is necessary or necessary to protect, as well as suitable methods for protection, as is known to those skilled in the art. The protecting group can be used according to standard practice (for instructions, see TW Green, Protective Groups for Organic Synthesis, J0hn Wiley &amp; s(10), VIII. Therefore, if the reactant contains a group such as an amine group, a carboxyl group or a hydroxyl group, It may be desirable to protect the group in some of the reactions mentioned herein. Suitable protecting groups for an amine or alkylamine group are, for example, a fluorenyl group, such as an alkyl group, such as an ethyl group, an aerobic group, such as a An oxo group, an ethoxylated group or a tert-butoxycarbonyl group, an arylmethoxycarbonyl group, such as a benzyloxycarbonyl group, an indenyl group, for example, a benzyl group. The removal conditions for the above protecting group must be followed. Changing with the choice of protecting group. Thus, for example, a saccharyl group, a sulfhydryl group or an alkoxycarbonyl group, or an aryl fluorenyl group can be removed, for example, by hydrolysis with a suitable base, such as an alkali metal hydroxide. For example, lithium hydroxide or sodium. Alternatively, an indenyl group, such as a tert-butoxycarbonyl group, can be removed, for example, by treatment with an appropriate 123642-116-200817384 acid, such as hydrochloric acid, sulfuric acid or phosphoric acid or trifluoroacetic acid, and an arylmethoxycarbonyl group, such as benzyl. The oxycarbonyl group can be removed, for example, by hydrogenation on a catalyst such as carbon loading or by treatment with Lewis acid, such as ginseng (trifluoroacetate). A suitable alternative protecting group for the primary amine group is, for example, a decanoic acid group which can be removed via treatment with an alkylamine such as dimethylaminopropylamine or by cultivating. Suitable protecting groups for the search are, for example, anthracenyl groups such as an alkane group, such as an ethyl fluorenyl group, an aryl fluorenyl group, such as a benzylidene group, or an arylmethyl group, such as a butyl group, with respect to the removal of the above protecting group. The protection conditions will have to change with the choice of protection f. Thus, for example, an anthracenyl group, such as an alkane group, or an aryl group can be removed, for example, via hydrolysis with a suitable base, such as an alkali-oxide, such as lithium or sodium hydroxide. Alternatively, an arylmethyl group, a hydrazine group, such as a hunter, is removed by hydrogenation on a catalyst, such as carbon 戟I bar. It is appropriate for the carboxyl group to be in the form of a acetal group, for example, a acetate group, such as methyl sulphate, which may, for example, be oxidized by a hydrolysis of a base, or for example, a third _ Ding Mei, "decomposed and removed, such as hydrogen, such as organic acids, such as: vinegar V:: such as: acid treatment is removed, hydrogenation on the catalyst 3 歹 | the following, which can for example borrow Removed by the action of two functions, such as carbon loading. Μ» soil can be removed by any of the well-known techniques in the synthesis. "Under the use of chemistry, many of the definitions herein are the invention. Further features, and these are provided for biological testing. 123642 - 117 - 200817384 The following assays can be used to measure the compounds of the invention as mTOR kinase inhibitors, as PI3 kinase inhibitors, as a living organism for the activation of signaling pathways by PI3 kinase An external inhibitor, and a role as an in vitro inhibitor of MDA-MB-468 human breast cancer cell proliferation. (8) In vitro mTOR kinase assay This assay uses AlphaScreen technology (Gray et al., Analytical Biochemistry, 2003, 313: 234-245) to determine the ability of a test compound to inhibit phosphorylation by recombinant mTOR. The C-terminal truncation of the mTOR covering the amino acid residues 1362 to 2549 of mTOR (EMBL acceptor number L34075) is stably expressed in HEK293 cells as a FLAG-tagged fusion, as by Vilella-Bach et al., Chemical Journal, 1999, 274, 4266_4272. The HEK293 FLAG-tagged mTOR (1362-2549) stable cell line was routinely maintained at 37 ° C with 5% C02 in serum containing 10% heat-inactivated bovine fetal serum (FCS; Sigma, Poole, Dorset, UK, catalog number F0392), 1% L-brutamine (Gibco, Cat. No. 25030-024) and 2 mg/ml base factor (G418 sulfate; Invitrogen, UK catalog number 10131-027) Dulbecco's denaturation Eagle growth medium (DMEM; Invitrogen, Paisley, UK catalog number 41966-029) reached 70-90% confluence. Following expression in the mammalian HEK293 cell line, the expressed protein is labeled using the FLAG epitope and purified using standard purification techniques. The test compound was prepared as a 10 mM stock solution in DMSO and diluted in water as needed to give a range of final assay concentrations. Aliquots of each compound dilution (2 microliters) were placed in a Greinei* 384-well low volume (LV) white 123642-118-200817384 color polystyrene plate (Greiner Bio-one) well. Recombinant purified mTOR enzyme, 1 //M biotinylated peptide receptor (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 UK), ATP (20 /iM) and buffer solution [containing Tris-HCl ρΗ7·4, buffer (50 mM) A mixture of 30 μl of EGTA (0.11 mM), bovine serum albumin (0.5 mg/ml), DTT (1.25 mM) and manganese chloride (10 mM) was stirred at room temperature for 90 minutes. A control well that produces the highest message corresponding to the highest enzyme activity, produced by replacing the test compound with 5% DMSO. A control well that produces the lowest message corresponding to complete inhibition of the enzyme is by adding EDTA (83 mM) In place of the test compound, the test solutions were incubated at room temperature for 2 hours by buffering with EDTA (50 mM), bovine serum albumin (BSA; 0.5 mg/ml) and Tris-HCl ρΗ7·4. 10 μl of a mixture (50 mM) containing p70 S6 kinase (T389) 1A5 monoclonal antibody (cell signaling technology, catalog number 9206B), and adding AlphaScreen streptavidin donor and protein A acceptor beads Granules (200 ng; Perkin Elmer, catalog number 6760002B V and 6760137R, respectively), stop each reaction, and leave the test plate at room temperature for about 20 hours in the dark. Will be due to the thunder at 680 nm The signal generated by the excitation of the light was read using a Packard Envision instrument. The biotinylated peptide system was formed on the spot due to the structure of the mTOR mediator. AlphaScreen streptavidin donor Granule-associated phosphonylated biotinylated peptides form a complex with p70 S6 kinase (T389) 1A5 monoclonal antibody associated with AlphaScreen protein A receptor beads. At 680 nm When the laser light is excited, the donor bead: acceptor beads 123642 -119- 200817384 granule complex produces a signal that can be measured. Therefore, the presence of mT〇R kinase activity causes a detection signal. The presence of the mTOR kinase inhibitor The signal intensity is reduced. The mTOR enzyme inhibition of the compound to be tested is expressed as the ic5 Q value. (b) The active PI3K enzyme assay uses AlphaScreen technology (Gray et al., Analytical Biochemistry, 2003). , 313: 234-245) to determine the ability of a test compound to inhibit the phosphorylation of a recombinant type I PI3K enzyme by the lipid ρι (4,5) Ρ2. The human PI3K catalyzes and modulates the subunit-encoded DNA. Fragments, using standard molecular biology and PCR asexual propagation techniques, are isolated from the CDNA gene bank. Selected DNA fragments are used to generate baculovirus expression vectors. Specifically, each 卩110〇:,?110 ?110 (5 Type 1 &amp; human ? 131 ^ 卩 110 isomeric recombinant (for ρ ΙΙΟ α, p ll 0/5 and p ll0 (5 EMBL acceptance number is HSU79143, S67334, Y10055, respectively) full-length DNA, by the second generation asexual reproduction to pDESTIO vector ( Invitrogen Ltd., Fountain Drive, Paisley, UK). This vector is a channel adaptation variant of Fastbacl containing the 6-His epitope tag. Corresponding to the truncated form of the type lb human PI3K pll〇T isomeric recombinant (EMBL accepting number X8336A) of amino acid residues 144-1102, and the full-length human ρ85 α regulatory subunit (EMBL accepting number HSP13KIN), also The second generation is asexually propagated into the pFastBacl vector containing the 6-His epitope tag. The type la pi 10 construct is co-expressed with the p85 alpha regulatory subunit. After expression in a baculovirus system using standard baculovirus expression techniques, the expressed protein was purified using His epitope tagged ' using standard purification techniques. 123642 -120- 200817384 DNA corresponding to the amino acid 263 to 380 of the human general receptor for the functional site of phosphoinositide (Grpl) PH, using standard molecular biology and PCR vegetative propagation techniques, isolated from the cDNA gene Library. The resulting DNA fragment was sub-proliferatively propagated into the pGEX 4T1 E. coli expression vector (Amersham Pharmacia Biotech, Rainham, Essex, UK) containing the GST epitope tag, as by Gray et al., Analytical Biochemistry, 2003, 313: 234-245). The GST-tagged Gipl PH functional site was expressed and purified using standard techniques. The test compound was prepared as a 10 mM stock solution in DMSO and diluted to water as needed to give a range of final assay concentrations. A aliquot of each compound dilution (2 microliters) was placed in a well of Greiner 384-well low volume (LV) white polystyrene board (Greiner Bio-one, Brunei Way, Stonehouse, Gloucestershire, UK catalog number 784075). . Each selected recombinant purified Π3Κ enzyme (15 ng), DiC8»PI(4,5)P2 substrate (40 //M; Cell Information Company, Kinnear Road, Columbus, USA, catalog number 901), gland taste Triphosphate (ATP; 4 //Μ) and buffer solution [containing Tris-HCl ρΗ7·6 buffer (40 mM, 10 μl), 3-[(3-cholestyrylpropyl) dimethylammonium A mixture of the base]_1-propanesulfonate (CHAPS; 0.04%), dithiothreitol (DTT; 2 mM) and magnesium chloride (10 mM) was stirred at room temperature for 20 minutes. A control well that produces the lowest message corresponding to the highest enzyme activity is produced by replacing the test compound with 5% DMSO. A control well that produces the highest message corresponding to the complete inhibition of the enzyme is replaced by the addition of wortmannin (6 // Μ; Calbiochem / Merck Biotech, Padge Road, Beeston, Nottingham, UK catalog number 681675) Produced by the test compound. These test solutions were also stirred at room temperature for 20 minutes. 123642 -121 - 200817384 Each reaction was stopped by the addition of 10 μl of a mixture of EDTA (100 mM), bovine serum albumin (BSA, 0.045%) and Tris-HCl ρΗ7·6 buffer (40 mM). Add biotinylated-DiC8-PI(3,4,5)P3 (50 nM; Cell Signaling, catalog number 107), recombinant purified GST-Grpl ΡΗ protein (2.5 ηΜ) and AlphaScreen anti-GST donor and acceptor Beads (100 ng; Packard Biotech Co., Ltd., Station Road, Pangboume, Berkshire, UK, catalog number 6760603 M), and leave the assay plate in the dark for about 5 to 20 hours at room temperature. The resulting signal, which was generated by excitation of the laser light at 680 nm, was read using a Packard AlphaQuest instrument. PI(3,4,5)P3 is formed in the field due to the phosphorylation of PI3K by PI(4,5)P2. The GST-Grpl PH functional site protein associated with AlphaScreen anti-GST donor beads forms a complex with biotinylated PI(3,4,5)P3 associated with Alphascreen Streptavidn acceptor beads. The PI(3,4,5)P3 line produced by the enzyme competes with the biotinylated PI(3,4,5)P3 to bind to the PH functional site protein. When excited by laser light at 680 nm, the donor bead: acceptor bead complex produces a signal that can be measured. Therefore, PI3K enzyme activity to form PI (3,4,5) P3 and subsequent competition with biotinylated PI (3,4,5) P3 will result in a reduced signal. The signal intensity was restored in the presence of a PI3K enzyme inhibitor. The P13K enzyme inhibitory system for the compound to be tested is expressed by the IC5G value. (c) Active façade thiol-Ser473 Akt assay This assay measures the ability of a test compound to inhibit the phosphorylation of serine 473 in Akt using Acumen Explorer technology (Acumen Bioscience) A plate reader that can be used to quickly quantify the characteristics of images produced by laser scanning 123642-122-200817384. The MDA-MB-468 human breast cancer cell line (LGC Promochem, Teddington, Middlesex, UK, Cat. No. HTB-132) was routinely accompanied by 5% C02 at 37 ° C with 10% heat inactivation. FCS reached 70-90% confluence with DMEM in 1% L-bromoamide. For this assay, cells were detached from the culture flask using ''Accutase' (Innovative Cell Technology, Inc., San Diego, CA, USA; catalog number AT104) using standard tissue culture methods and resuspended in the medium to obtain each 1.7xl05 cells in milliliters. Inoculate a aliquot (90 μl) into each of the 60 internal wells of a black Packard 96 well plate (PerkinElmer, Boston, MA, USA; catalog number 6005182) to obtain a density of ~15000 cells per well. The aliquot of the medium (90 μl) was placed in an external well to prevent edge effects. The cells were incubated overnight at 37 ° C with 5% CO 2 to allow them to adhere. On day 2, the cells were The test compound was treated and incubated at 5% CO 2 for 2 hours at 37° C. The test compound was prepared as a 10 mM stock solution in DMSO and serially diluted with growth medium as needed to obtain a range. The concentration is 10 times the final test concentration required. The aliquot of each compound dilution (10 microliters) is placed in the well (in triplicate) to obtain the final desired concentration. The plates, each containing a well having a final concentration of 1 〇〇//M LY294002 (Calbiochem, Beeston, UK, catalog number 440202). As the highest response control, the well system contained 1% DMSO in place of the test compound. The contents of the plate were fixed by treatment with 1.6% aqueous formic acid (Sigma, Poole, Dorset, UK, Cat. No. F1635) for 1 hour at room temperature. 123642 -123- 200817384 All subsequent aspiration and washing steps were performed using Tecan 96 The well plate scrubber (sucking speed 10 mm/sec) was carried out. The fixing solution was removed and the contents of the plate were washed with phosphate buffered saline (PBS; 50 μl; Gibco, Cat. No. 10010015). The contents were treated at room temperature with one aliquot (50 μl) of cell osmosis buffer containing PBS and 0.5% Tween 20 mixture. Remove ''osmosis'' buffer, and The specific binding site was blocked by a one-part (50 μl) blocking buffer containing 5% dry skimmed milk [&quot;Marvel" (registered) for 1 hour at room temperature. Trademark); Pre The mier beverage, Stafford, GB] is in a mixture of PBS and 0.05% Tween-20. Remove ''block n buffer' and place the rabbit anti-phosphonium-Akt (Ser473) antibody solution diluted 1:500 in the "blocked" buffer at room temperature (50 per well) Microliters; cells send messages, Hitchin, Herts, UK, catalog number 9277) for 1 hour. The cells were washed three times in a mixture of PBS and 0.05% Tween-20. Next, the cells were at room temperature with goat anti-rabbit IgG labeled with Alexafluor 488 diluted 1:500 in ''blocking π buffer' (50 μL per well; Molecular Probes Invitrogen GmbH, Paisley, UK, Catalog No. A11008) was incubated for 1 hour. The cells were washed 3 times with a mixture of PBS and 0.05% Tween-20. One serving of PBS (50 microliters) was added to each well and the plate was sealed with a black plate stopper and the fluorescent signal was detected and analyzed. The fluorescence dose obtained from each compound was analyzed in response to the data, and the degree of inhibition of the serine 473 in Akt was expressed as an IC50 value. (d) In vitro MDA-MB-468 human breast cancer proliferation assay This assay measures the ability of a test compound to inhibit cell proliferation using a Cellomics array scan technique. MDA-MB-468 Human Breast Cancer Fine 123642 -124- 200817384 The cell line (LGC Promochem, Cat. No. HTB-132) was maintained in a routine manner as described in Biological Test (b) herein. For this proliferation assay, cells were detached from the culture flask using Accutase and inoculated into the inner 60 wells of a black Packard 96 well plate at a density of 8000 cells per well in 100 microliters of complete growth medium. The external well contains 100 microliters of sterile PBS. The cells were incubated overnight at 37 ° C with 5% CO 2 to allow them to adhere. On day 2, cells were treated with the test compound and incubated at 37 ° C for 48 hours with 5% CO 2 . The test compound was prepared as a 10 mM stock solution in DMSO and serially diluted with growth medium as needed to obtain a range of test concentrations. A aliquot of each compound dilution (50 μL) was placed in the well, and the cells were cultured at 37 ° C for 2 days at 5% CO 2 . Each plate contained a control well that did not have a test compound. On day 4, BrdU labeling reagent (Sigma, Cat. No. B9285) at the final dilution of 1:1000 was added 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 a 1 liter microliter mixture of ethanol and glacial acetic acid (90% ethanol, 5% glacial acetic acid, and 5% water) at room temperature for 30 minutes. The cells in each well were washed twice with PBS (100 microliters). An aqueous solution of hydrochloric acid (2M, 100 microliters) was added to each well. After 20 minutes at room temperature, the cells were washed twice with PBS. Hydrogen peroxide (3%, 50 microliters; Sigma, catalog number H1009) was added to each well. After 10 minutes at room temperature, the well was washed again with PBS.

BrdU was infused with a mouse anti-BrdU antibody (50 μl; 123642 -125 - 200817384) diluted 1 · 40 in PBS containing 1% BSA and 0.05% Tween-20 at room temperature

Caltag, Burlingame, CA, US; catalog number MD5200) was cultured for 1 hour and was detected. The unbound anti-system was removed with two washes of PBS. For imaging of BrdU incorporated, cells were treated with PBS (50 μl) and 0.05% Tween_20 buffer containing 1:1000 dilution of Alexa Fluor 488-labeled goat anti-mouse IgG for 1 hour at room temperature. . For nuclear visualization, a 1:1000 dilution of Hoechst dye (Molecular Probes, catalog number H3570) was added. The plates were washed sequentially with PBS. Next, PBS (100 microliters) was added to each well and scanned using a Cellomics array to analyze the plates to assess the total number of cells and the number of BrdU positive cells. The fluorescence dose response data obtained for each compound was analyzed, and the degree of inhibition of MDA-MB-468 cell growth was expressed as IC5 〇 value. While the pharmacological properties of the compounds of formula (I) are expected to vary with structural changes, in general, the activity possessed by the compounds of formula (I) may be one or more of the above tests (8) to (d) In the following concentrations or doses: - Test (8) · · - IC5G for mTOR kinase, below 10 //M, especially 0.001-0.5 //M, for many compounds; for Example 34b, IC50 In two cases, the values are 0.155 and 0.093 //M. Test (b): - IC5 〇 for pllOr _ type lb human PI3K, below 10 //M, especially 0.001-0.5 //M, for many compounds; and IC5〇 for ρΙΙΟα type la human PI3K, at low At 10 //M, especially 0.001-0.5, for many compounds; for Example 34b, IC5G is measured in two cases, with values of 123642 -126-200817384 being 91.2 and 57.8 //Μ. Test (c): • IC5 〇 for azine 473 in Akt, below 1 ,, especially 0.1-20 // Μ, for many compounds; for Example 34b, ICw is measured in two cases, The values are 1.361 and 0.654. Test (d): - IC5 〇 below 20 //M;

The compounds of the invention are advantageous because of their pharmacological activity. Specifically, the compound of the present invention modulates (particularly inhibits) mT〇R kinase and/or phosphoinositide-3-kinase-3-kinase (PI3K) enzyme, such as the species ia ρΙ3κ enzyme (eg, ΡΙ3Κα, ΡΙ3Κ/3 and ΡΙ3Κ 5) with the species lb ΡΙ3Κ enzyme (ΡΙ3Κ r). More specifically, the compounds of the invention modulate (particularly inhibit) mT〇R kinase. More specifically, the compound of the present invention modulates (particularly inhibits) one or more PI3K enzymes. The inhibitory properties of the compounds of formula (I) can be confirmed using the test procedures set forth herein and in the experimental paragraphs. Thus, the compound of formula 1 can be used in the treatment (or treatment or prevention) of symptoms/diseases in humans and non-human animals by mTOR kinase and/or one or more I3K enzymes, and in particular by order (10) Mediated by kinases. The invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable salt of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein, accompanied by a pharmaceutically acceptable diluent or carrier. The composition of the present invention may be in a form suitable for oral use (for example, as a tablet, a tablet hard or soft capsule, an aqueous or oily suspension, an emulsion, a dispersible powder or granule, a syrup or an elixir), a paste, Ointment, gel or aqueous or oily solution or topical use (for example, as a milk suspension), by inhalation administration 123642 -127-200817384 or (4) gas transfer), by means of static: Γ: lower, medicine (for example, as sterile water) Or oily solution, Jiji intraperitoneal or intramuscular administration, or as a suppository for rectal administration). The compositions of the present invention may be prepared by conventional procedures known in the art. Thus, 7 or 2, the composition s used has, for example, a plurality of colors, sweetening, latitude and/or preservatives. f The combination with one or more excipients to produce the active ingredient in a single dosage form will vary depending on the host to be treated and the particular route of administration. For example: a formula intended for oral administration to humans will usually contain a gram of a lingual agent (more suitably u 250 mg, eg 1 JL 100 mg), blended with an appropriate and suitable amount of excipients. Approximately 5 of the composition was changed to: a violent weight percentage. ^ The dosage size for the therapeutic or prophylactic purpose of the compound of formula I, when narrowed depending on the nature and severity of the disease state, the age and sex of the animal or patient and the route of administration of the drug&apos; vary according to conventional medical principles. In the case of the use of a compound of formula (I) for therapeutic or prophylactic purposes, it is administered in a conventional manner such that, for example, a daily dose in the range of i mg/kg to 100 mg/kg = weight is accepted, I need to be separated Dosage is given. In general, the lower dose is administered when the parenteral route is employed. Thus, for example, for intravenous administration, dosages in the range of, for example, i mg/kg to 25 mg/kg body weight are generally used. Similarly, for administration by inhalation: r is a dose in the range of, for example, i mg/kg to 25 mg/kg body weight. Typically, the unit dosage form will contain from about 10 mg to about 0.05 g of the invented 123642.128-200817384 compound. As stated herein, mTOR kinase and PI3K enzyme are known to have roles in tumorigenesis and many other diseases. We have found that the compound of formula (1) has potent antitumor activity and is generally believed to be obtained by inhibiting mT〇R kinase and/or one or more Π3Κ enzymes. Thus, the compounds of the invention are valuable as anti-tumor agents. In particular, the compounds of the invention are valuable as anti-proliferative, cellular dying and/or anti-invasive agents for inhibiting and/or treating solid and/or liquid tumor diseases. It is expected that the compounds of the present invention can be used for the prevention or treatment of tumors which are sensitive to inhibition of mT〇R and/or one or more PI3K enzymes (e.g., species Ia PI3K enzyme and species Ib auxin). Furthermore, it is expected that the compounds of the present invention can be used for the prevention or treatment of tumors which are mediated alone or in part by mT〇R and/or one or more ρΐ3κ enzymes (e.g., species IaPI3K enzyme and species! bPI3K enzyme). Thus, such compounds can be used to produce mTOR enzyme inhibition in warm-blooded animals in need of such treatment. Certain compounds can be used to produce PI3K enzyme inhibition in warm-blooded animals in need of such treatment. As stated herein, inhibitors of mT〇R kinase and/or one or more PI3K enzymes should have a therapeutic value of I for the treatment of proliferative diseases such as cancer, and in particular solid tumors such as carcinomas and sarcomas, and leukemias and lymphoids. Malignant: disease, and especially treatment of breast, colorectal, lung (including small cell lung cancer, non-small cell lung cancer and bronchial lung cancer) and cancer of the prostate, with leftovers, and - 苫 ° 月, bladder , head and neck, kidney, liver, gastrointestinal group:: esophagus, nest, pancreas, skin, testicular, thyroid, uterus, child and female genital cancer, and leukemia [including acute lymphoblastic leukemia (ALL) 123642 -129- 200817384 The use of anti-proliferative effects. According to this aspect of the invention, there is provided the use of a compound of formula (1), or a pharmaceutically acceptable salt thereof, as defined herein, for the manufacture of a medicament for use in the production of an anti-proliferation in a warm-blooded animal such as a human. effect. Person::: The advancement of the month-step provides the use of the formula (I) of the formula (I) as defined herein, and the use of salt in the blood-stained animal, such as humans, to produce cell dying. According to a further feature of this aspect of the invention, there is provided a use of a compound of formula 1 as defined herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament, in combination with chronic myelogenous leukemia (CMI^ further conjugate according to the invention) Or a pharmaceutically acceptable salt thereof for use as a medicament. A further aspect according to the invention, or a pharmaceutically acceptable salt thereof, for producing an anti-proliferative effect. Further coma according to the invention or a pharmaceutically acceptable salt thereof To produce a cell dying effect. According to a further feature of the present invention or a pharmaceutically acceptable salt thereof for inhibiting and/or treating a proliferative disease, a further aspect according to the present invention or a pharmaceutically acceptable salt thereof, multiple bone Zhao tumors and lymphomas. The formula (I) as defined herein is provided to provide a formula (I) as defined herein in a warm-blooded animal such as a human. An animal, such as a human, provides a formula (I) as defined herein to provide a formula (I) as defined herein in a warm-blooded animal, such as a human, for use in a warm-blooded animal such as a human, such as cancer. The use of an invasive agent provides a formula (I) as defined herein in a warm-blooded animal such as a human, in 123642-130-200817384. The drug is used to produce a cellular nulling effect in a warm-blooded animal such as a human. A further step is to provide a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein, for use in the manufacture of a medicament, in a warm-blooded animal such as a human, ^. It is used as an anti-invasive agent for inhibiting and/or treating proliferative diseases such as cancer. According to the aspect of the present invention, the characteristics of push and V are provided in a warm-blooded animal such as human φ吝 which is in need of treatment. A method for anti-proliferative effect, which comprises administering to the animal an effective amount of a compound of the formula (I), or a pharmaceutically acceptable salt, as defined in the present invention. Step feature A method for inhibiting and/or treating an anti-invasive effect of a solid tumor disease in a warm-to-treat animal, such as a human, in need of treatment, comprising administering to the animal an effective amount of a compound of formula 1 as defined herein Or a pharmaceutically acceptable salt thereof. According to a further aspect of the present invention and the π^ aspect, a compound of the formula (1) as defined herein or a succinctly acceptable dish thereof; The agent is used in a warm-blooded animal such as a human to prevent or treat a proliferative disease, such as cancer. According to this aspect of the invention, further ^ ^ ^ ^ π 乂 妓, provides a warm-blooded animal such as a human in need of treatment , ^ # ^ 顶|方方的方法或治疗性的治疗的方法的方法的方法的方法。 # 方 方 方 方 方 方 方 方 方 方 方 方 方 方 方 方 方 方 方 方 方 方 方 方 方 方 方 方 方 方 方 方 方 方 方 方 方 方According to a further aspect of the invention, the human L bucket, the * mouth m L are known to be a compound of the formula (I) as defined herein or a succinctly acceptable 趟, Ρ β / 七々夕 from η 风乂Prevention or treatment of mTO Inhibition of R kinase and/or one or more PI3K enzymes (sounds, words such as la enzymes and/or species lb 123642 -131 200817384 PBK enzymes) is a sensitive tumor involving the proliferation and survival of tumor cells. Information transduction steps for intrusion and migrating capabilities. According to a further feature of this aspect of the invention, there is provided a use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein, for the manufacture of a medicament for the prophylaxis or treatment of mT0R kinase and/or The inhibition of a variety of Κ3Κ enzymes (such as the species la enzyme and/or the species Ib ΡΙ3Κ enzyme) is a sensitive tumor involving a signal transduction step that leads to the proliferation, survival, invasion and migration of tumor cells. According to a further feature of this aspect of the invention, there is provided a method of preventing or treating a tumor which is sensitive to inhibition of mTOR kinase and/or one or more pi3K enzymes, such as an enzyme and/or species Ib PI3K enzyme, A signal transduction step involving the ability to cause proliferation, survival, invasion and migration of tumor cells, the method comprising administering to the animal an effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof . According to a further aspect of the invention there is provided a pharmaceutically acceptable salt of formula 1 as defined herein, or a pharmaceutically acceptable salt thereof, for use in providing mT〇R kinase inhibition and/or PI3K enzyme inhibition (eg, species Ia pi3K enzyme) Or species than Π3Κ enzyme inhibition). According to a further feature of this aspect of the invention, there is provided a use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein, for the manufacture of a medicament for providing cucurbit 011 kinase inhibition and/or Immortal enzyme inhibition (such as the species la PI3K enzyme or species Ib PI3K enzyme inhibition). According to a further aspect of the present invention, there is also provided a method for providing (5) dish kinase inhibition 1 / or H3K enzyme inhibition (such as species Ia ρΐ3Κ enzyme or 123642 -132-200817384 species IbPI3K enzyme inhibition). A * A τ &quot;, 匕 才 又 又 有效 有效 有效 有效 有效 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 Substance 1:=Mingzhijin: The step characteristic is to provide the formula as defined in this article! Compounding:: two can be used for the treatment of cancer, inflammatory diseases, obstructive rolling disease, immune disease or cardiovascular disease. According to a further surname of the present invention, a combination of formula I as defined herein is provided.

Or a pharmaceutically acceptable salt thereof for use in the treatment of solid tumors such as carcinomas and sarcomas, and leukemias and lymphoid malignancies. According to the advanced step characteristics of the jurisdiction, a compound of the formula ι as defined herein, or a salt that can be used for the treatment of breast, colorectal, lung (including small cell lung cancer, non-small cell lung cancer) is provided. And tracheal tuberculosis) and cancers such as the gland. According to the present invention, a pharmaceutically acceptable salt of the formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of the bile duct, bone, bladder, head and neck, kidney, liver , gastrointestinal tissue, esophagus, India, pancreas, skin, sputum, verrucous, uterus, cervix and female genital cancer, and leukemia (including ALL and CML), multiple osteosarcoma and lymphoma. According to a further feature of the invention there is provided a use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein, for the manufacture of a medicament for the treatment of cancer, inflammatory diseases, obstructive airway diseases, immunity Disease or cardiovascular disease. According to a further feature of the invention there is provided a use of a compound of formula 1 as defined herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of solid tumors, such as carcinomas and sarcomas, and leukemias and lymphoids 123642 -133 - 200817384 A malignant condition. According to the present invention, the wind system provides a compound of the formula (1) as defined herein or a music-study a stagnation, .ffl., Λ &amp; For the purpose, the medicament is used for treating breast, swell, and. Intestinal ", lung (including small cell lung cancer, # small cell lung cancer and bronchial tuberculosis) and pruritus of the prostate. Further features of the 'providing a compound of formula 1 as defined herein or its musically acceptable #的接的盐的制药的用途的用,的药剂

It is used for the treatment of bile ducts, bones, bladder and shellfish, head and neck, kidney, liver, gastrointestinal tissue, esophagus, nest, sputum, skin, bi pills, thyroid, uterus, cervix and female genitals. Cancer, and leukemia (including sputum and CML), multiple myeloma and lymphoma. According to a further feature of the present invention, the genus is provided in a warm-blooded animal, such as a human, in need of treatment, for treating pain, all, producing, sputum, cancer, fire disease, obstructive airway disease, immune disease or cardiovascular disease. A method of aging, soil-, B戾/C of the disease comprising administering an effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof. According to a further feature of the present invention, there is provided a method for treating solid tumors, such as cancer and sarcoma, and leukemia and lymphoid malignant diseases, in a warm-blooded animal such as a human in need of treatment, comprising administering an effective amount A compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof. According to a further feature of the present invention, there is provided a method for treating breast, colorectal, lung (including small cell lung cancer, non-small cell lung cancer, and tracheal lung cancer) and cancer of the prostate in a warm-blooded animal such as a human in need of treatment. A method comprising administering an effective amount of a compound of formula (1), as defined herein, or a pharmaceutically acceptable salt thereof. 123642 -134- 200817384 A one-step feature is to provide a blood-feeding animal according to the present invention at a temperature requiring treatment, such as human _ Φ W _ _ _ , dry treatment bile duct, bone, bladder, head and neck, kidney, liver, Stomach gland 纟 her ^ month%, and weaving, eating this, ovary, pancreas, skin, testicles, thyroid, uterus, early &lt;τ&lt;5 thousand 颏 颏 and female yin cancer, and leukemia (including all /, CML) A method of idiopathic myeloma and lymphoma comprising administering a compound of formula 1 as hereinbefore defined, or a pharmaceutically acceptable salt thereof. As described herein, the in vivo effect of the compound of formula (1) can be administered in formula (I).

After the compound is applied by one or more of the metabolic products formed in the human or animal body. The invention further relates to a combination therapy wherein a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or formulation comprising a compound of formula (I), is used in combination with another treatment for the treatment of oncological diseases, Simultaneously or sequentially or in combination preparation. Specifically, the treatments defined herein may be administered alone or in addition to the compounds of the invention, may involve conventional surgery or radiation therapy or chemotherapy. Thus, the compounds of the invention may also be combined with existing therapeutic agents to treat cancer. Suitable agents for use in combination include: - (1) anti-proliferative/anti-tumor drugs and combinations thereof, such as those used in medical oncology, such as alkylating agents (eg, cisplatin, carbonamine) Platinum, cyclophosphamide, nitrogen-based, present alanine, chlorambucil, busulphan, and nitrosourea; antimetabolites (eg, antifolates, such as fluorine) Pyrimidines, such as 5-fluorouracil, with tegafor, raltitrexed, amine formazan, arabinose, hydroxyurea, and sinensis 123642 • 135 - 200817384 gemcitabine Anti-tumor antibiotics (eg, anthracyclines such as adriamycin, bleomycin, erythromycin, daunorubicin, erythromycin, edemamycin, mitomycin) -C, dycomycin and mithramycin; anti-mitotic agents (such as periwinkle plant tests, such as Changchun new test, periwinkle test, vinca, vinorelbine and yew material) , for example, paclitaxel and tax〇tere; and topological differences Enzyme inhibitors (eg epipodophyllotoxins such as etop〇side and teniposide, amsacrine, top〇tecan and hi-tree) (ii) cytostatics such as anti-estrogens (eg, tamoxifen, toremifene, raloxifene, droloxifene, and iodoxyfene) )), estrogen receptor down-regulator (such as Folvestrant), anti-androgen (such as bicalutamide, flutamide, ruthenium) (nilutamide) and cyproterone acetate), LHRH antagonists or LHRH motivators (eg goserelin, leuprorelin and buserelin), pregnancy Hormones (such as megestrol acetate), aromatase inhibitors (such as anastrozole, letrozole, vorazole, and exemestane) And inhibitors of 5 α-reductase, such as finasteride; (iii) anti-invasive agents For example, a c-Src kinase family inhibitor, such as 4-(6-carbyl-2,3-indenylenedioxyanilino)-7-[2-(4-methylhexahydropyrazine-1-yl) Ethoxy]-5-tetrahydropiperidinyloxyquinazoline (AZD0530; International Patent Application WO 01/94341) and N-(2-chloro-6-methylphenyl)-2-{ 6-[4-(2-hydroxyethyl)hexahydropyrazine 123642 -136- 200817384 -1-yl]-2-methylglycine-4-ylaminopyrazole carboxamide (Daratinib) (dasatimb) 'BMS-354825; J. Med·Chem., 2004, 47, 6658-6661), and metalloproteinase inhibitors, such as marimastat and urokinase plasminogen activator (iv) inhibitors of receptor function; (iv) inhibitors of growth factor function: for example, such inhibitors include growth factor antibodies and growth factor receptor antibodies (eg, anti-erbB2 antibody, trastuzumab [HerceptinTM] And anti-antibodies (Cetuximab [C225]); such inhibitors also include, for example, tyrosine kinase inhibitors, such as inhibitors of the epidermal growth factor population (eg, EGFR group tyrosine kinase inhibitors) , such as N-(3_gas-based fluorophenyl) _7_methoxy_6_(3_morpholinylpropoxy)&gt; quinazolin-4-amine (gefltinib, zm839), team (3_ethynylphenyl)-6, 7-Bis(2-methoxyethoxy)oxazoline eramide (erlotinib, OSI-774) and 6-acrylamido-based _N_(3-chloro-l-fluorophenyl) )_7_(3_morpholinopropoxy)quinazolinamine (α 1〇33), and erbB2 tyrosine kinase inhibitors, such as lapatinib, hepatocyte growth factor population Inhibitors, inhibitors of growth factor populations derived from platelets, such as imatinib, inhibitors of serine/threonine kinase (eg, Ras/Raf signaling inhibitors such as farnesyltransferase inhibition) Agents, such as sorafenib (BAY 43-9006), and inhibitors of cells that send meK and/or _ kinases; (v) anti-angiogenic agents, such as vascular endothelial growth factor The role [eg, anti-vascular endothelial growth factor antibody bevacizumab (AvastinTM), and VEGF receptor tyrosine kinase inhibitors, such as 4-(4-Molyl-2- Dimethylanilide) methoxy^μmethylhexahydropyridyl = ice 123642 -137- 200817384 quinoneoxy)quinazoline (ZD6474; Example 2 in WO 01/32651), 4-(4-fluoro Benzyl-2-methylindole-5-yloxy) methoxy-7-(3-tetrahydropyrrol-1-ylpropoxy)quinazoline (AZD2171; examples in WO 00/47212 240), vatalanib (PTK787; WO 98/35985) and SU11248 (sunitinib; WO 01/60814), and compounds that act by other mechanisms (eg Reno) Linomide, an inhibitor of integrin αν /33 function and angiogenin); (vi) vascular injury agents, such as the windmill bacteriocin A4, and international patent application WO 99/02166, WO 00 /40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213; (vii) anti-significant therapeutic agents, for example for those listed above, such as ISIS 2503 , an anti-ras anti-significant; (viii) gene therapy pathways, including pathways to replace the amnestic gene, such as p53 or BRCA1 or BRCA2, GDEPT (gene-guided enzyme prodrug therapy) Pathways, such as the use of cytosine deaminase, thymidine kinase or bacterial tribasase reductase, and ways to increase patient tolerance to chemotherapy or radiation therapy, such as multidrug resistance gene therapy; and (ix) immunotherapy Routes, including in vitro and in vivo pathways that increase the immunogenicity of the patient's tumor cells, such as by the transfer of cytokines, such as interleukin-2, interleukocytokinin 4 or granulocyte-macrophage colonies Stimulating factors, pathways that reduce T-cell energy, pathways transfected with immune cells (such as cytokine-transfected dendritic cells), cytokine-transfected tumor cell lines, and anti-heredital use The route of the type antibody. [Embodiment] 123642 - 138 - 200817384 The present invention will now be further explained with reference to the following illustrative examples. Unless otherwise stated, the starting materials are commercially available. All solvents and commercially available reagents are laboratory grade and are used as soon as they are received. In these examples, the 1 H NMR spectra were recorded on a Brnker DPX 300 (300 MHz), a Brnker DRX 400 (400 MHz) instrument, or a Bruker DRX 500 (500 MHz) instrument. The central absorption peak of chloroform-d ((?η7·27 ppm), dimethyl sulfoxide-d〆δπ2·50 ppm) or acetone (dH2.05 ppm) was used as an internal reference. The following abbreviations have been used: s, singlet; d, doublet; t, triplet; q, quadruple; m, multiplet; br, broad. Column chromatography was performed using Shiqi gum (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 in the preparative HPLC using a mixture of acetonitrile and water [containing 0.1% trifluoroacetic acid (TFA)). As a dissolving agent, at a flow rate of 10 ml/min. The following method is used for liquid chromatography (LC) / mass spectrometry (MS) analysis · · HPLC: Agilent 1100 or Waters Alliance HT (2790 &amp; 2795) mass spectrometer · Waters ZQ ESCi HPLC column The standard HPLC column is Phemonenex Gemini C18 5 micron, 50 x 2 mm. The mobile phase used in the acidic HPLC method is: mobile phase A: water mobile phase B: acetonitrile mobile phase C: 1% formic acid in 50: 50 water:

MeCN (v/v) 123642 • 139- 200817384 The method was then quickly balanced, using a flow rate of 5 ml for 0.45 minutes. Four general HPLC methods are available: 5 minutes to monitor the acid method time/minute mobile phase A: mobile phase B: mobile phase C: curve flow rate / ml / min 0.00 95 0 5 1 1.1 4 0 95 5 6 1.1 4.5 0 95 5 6 1.1 Early Acidic Method for Early Dissolved Compounds Time/Min Mobile Phase A: Mobile Phase B: Mobile Phase C: Curved Flow Rate / mL/min 0.00 95 0 5 1 1.1 4 57.5 37.5 5 6 1.1 4.5 57.5 37.5 5 6 1.1 Intermediate phase-dissolved compounds Intermediate period time/minute Mobile phase A: Mobile phase B: Mobile phase C: Curved flow rate / ml/min 0.00 95 0 5 1 1.1 0.01 67.5 27.5 5 6 1.1 4.5 27.5 67.5 5 6 1.1 Late Acidic Method for Late Dissolved Compounds Time/Min Mobile Phase A: Mobile Phase B: Mobile Phase C: Curved Flow Rate / mL/min 0.00 95 0 5 1 1.1 0.01 27.5 67.5 5 6 1.1 123642 -140- 200817384

On the need, four kinds of comparison

In some cases, the compound of the quasi-acid method is ionized or chromatographically separated. An exemplary HPLC method can be employed. The mobile phase used was: mobile phase A: mobile phase B: mobile phase D: each method followed by a rapid equilibrium 〇 45 minutes. May be unsuitable. In this case water acetonitrile 0.1% 880 ammonia in acetonitrile, using a flow rate of 5 ml,

123642 -141 - 200817384 Time/minute Mobile phase A : 1~τ mesh mobile phase B : 0.00 95 0 0.01 67.5 27.5 4.5 --~—— '27.5 67.5 Mobile phase C : Late alkaline method of compound

Time / minute 0.000.01 4.5 Mobile phase A : 95 - TL5 5 Mobile phase B : Mobile phase C : Curve rate rising clock Flowing millimeters 67.5 95 6 6

.1.1 lx ~ 1A u ~~~--- The following methods are used for liquid chromatography (LC) / mass spectrometry (MS) analysis: - Instrument: Agilent 1100; Column: Waters,, Symmetry, X 3〇 Mm; mass spectrometry, using chemical ionization (APCI); flow rate: 〇·7 ml/min; absorption wavelength: 254 nm; solvent A: water + 0.1% TFA; solvent B: acetonitrile + 0.1% TFA; solvent gradient Liquid: 15-95% solvent B over 2.7 minutes followed by 95% solvent B over 0.3 minutes. The following method was used for LC analysis: - Method A: - Instrument: Agilent 1100; Column: Kromasil C18 reverse phase, 100 x 3 mm '5 micron particle size; Solvent A: 0.1% TFA / water, solvent B: 〇 〇 8% TFA / acetonitrile · 'flow rate: 1 ml / min; solvent gradient · · 1 〇 1 〇〇 % solvent B, after 20 minutes, followed by 100% solvent B, after 1 minute; absorption wavelength : 220, 254 and 280 nm. In general, the retention time of the product is noted. 123642 -142- 200817384 Method B: - Instrument: Agilent 1100; Column: Waters,, Xterra', C8 reverse phase silicone, 100 x 3 mm, 5 micron particle size; Solvent A: 0.015 M ammonia in water, solvent B : acetonitrile; flow rate: 1 ml/min, solvent gradient: 10-100% solvent B over 20 minutes followed by 100% solvent B over 1 minute; absorption wavelengths · 220, 254 and 280 nm. In general, the retention time of the product is noted. The following abbreviations are used herein or in the following illustrative examples: - HPLC High Performance Liquid Chromatography

HBTU hexafluorophosphate 0-(benzotriazole small group)-N,N,N',N'-tetramethylguanidine; HATU hexafluorophosphate 0 (7-nitrobenzotriazole small group)-N,N , N', N'-tetramethylguanidine; HOBT 1-hydroxybenzotriazole; HOAT 1-hydroxy-7-azabenzotriazole; NMP N-mercaptotetrahydropyrrole-2·one; DMSO Amidoxime; DMF N,N-dimethyldecylamine; DMA N,N-dimethylacetamide; THF tetrazolium; DME 1,2-dimethoxyethane; DCCI dicyclohexylcarbylation Diimine;

MeOH methanol;

MeCN acetonitrile; DCM di-methane; DIPEA N,N-diisopropylethylamine; DBU 1,8-diazabicyclo[5.4.0]undec-7-ene; 123642 -143 - 200817384 RT room temperature ( Approximately 17 to 25 ° C); tR residence time; m / z mass / charge ratio. Chemical names are generated by software using Lexichem ToolKit (version 1.40) from OpenEye Scientific Software (www.eyesopen.com) to produce iupAC suitable names. Example 1:

1·Ethyl-3-[4_[4_[(3S)-3_methylmorpholine_4_yl]-6_(nonylsulfonylmethylidene-2-yl)phenyl]urea

4-[4-[(3S)-3-Methylphenoflavin-4-yl]-6-(曱石黄毛methyl) σ定定_2-yl] aniline (100 mg, 0.28 m Mohr) was dissolved in dioxane (4 ml). Ethyl isocyanate (0.109 ml, 1.38 mmol) was added and the reaction was heated at 7 (rc) for 4 h. The reaction was completed and evaporated to dryness. 10-50% ethyl acetate in the alkane is dissolved, and 3-ethyl-l-[4-[4-[(3S)-3-methyl-wufolin-4-yl]-6-(曱石)醯 。 。 定 定 基 基 基 基 基 基 基 基 基 基 基 113 113 113 113 113 113 113 113 113 113 113 113 113 113 113 113 113 113 113 113 113 113 113 113 113 113 113 113 113 113 113 113 113 113 113 113 113 113 113 113 d, 3H), 3.11 (q, 2H), 3·20 (s, 3H), 3.29 (m, 2H), 3.5 (m5 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) LCMS spectrum: MH+ 434, retention time l37 minutes, method 5 minutes acid 123642 -144- 200817384 The compounds shown in the table are similar to 3-ethyl-l-[4-[4-[ The form of (3S)-3_methylphenothonine-based]-6-(methylsulfonylmethylididin-2-yl)phenyl]urea is prepared by reacting a suitable isocyanate with an appropriate aniline. Instance structure name LCMS MH+ retention time ( Minutes) Note la [丄0 person NH ΗΦ OMe 1-(4-methoxyphenyl) -3-[4-[4-[(3S)-3-indolyl porphyrin _4_yl]-6- (Methanesulfonylmethyl)pyrimidin-2-yl]phenyl]urea 512 2.19 Ethyl acetate slurry, then chromatographic purification lb 0, 0 Ηό l-[4-[4-[(3S)-3- Methylmorpho-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl]phenyl]-3-phenyl-urea 482 2.26 Chromatography, elution with 0-8% MeOH/DCM Lc [λ dVi 〇3-[4-[4-[(3S&gt;3-Mercaptophyrin-4-yl]-6-(methylsulfonylmethyl) pyridin-2-yl]phenyl ]-1-propan-2·yl-month urine 448 1.90 chromatography, eluted with 0-8% MeOH/DCM le λ 父 乂 ^ ^ ^ Η F F F F F 3-(4-fluorophenyl)-1 -[4-[4-[(3S)-3-methylphenoflavin-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl]phenyl]mai 500 2.05 Ester development 123642 -145- 200817384 Example structure name LCMS MH+ retention time (minutes) Note If F 1-[2-Fluoro-4-[4-[(3S)-3-methylphenoline p--4-yl ]-6-(Methanesulfonylmethyl) &gt; succinyl-2-yl]phenyl]-3-(4-p-phenyl)urea 518 2.38 Purification by reverse phase chromatography ig 0 V human FH0 1- [2-Fluoro-4-[4-[(3S)-3-A吗福普林-4-yl]-6_(methylsulfonylmethyl)pyrimidin-2-yl]phenyl]-3-phenyl-urea 500 2.36 Purification by reverse phase chromatography lh α λ human NH 〇ΜθΗφ F 3-(4-fluorophenyl)-1-[2-methoxy-4-[4-[(3S)_3-methyl? S Sulin-4-;^]-6_ (Methanesulfonate) Methyl)pyrimidin-2-yl]phenyl]urea 529 2.22 Crystallization from NMP/water 'and then liquefied with EtOAc. li α χ human NH Η Η φ ΟΜβ 3-[2·曱 oxy-4-[4-[(3S -3-methylmoffin-4-yl]-6-(methylsulfonyl fluorenyl)pyrimidin-2-yl]phenyl]-1-(4-methoxyphenyl)urea 542 2.06 from NMP /Water Crystallization' then developed with EtOAc 123642 146-200817384 Lean structure name LCMS ΜΗ+ retention time (minutes) Note ^ Ij 3-(4-fluorophenyl)-1-[5-[4-[(3S) Methylwfolin-4-yl]_6-(anthracenesulfonyl)pyrimidin-2-yl]. Specific butyl-2-yl urea 501 2.26 from dimethyl hydrazine / water crystallized lk [λ Η H 1_ethyl each [5-[4-[(3S)-3-methyl 福福普林-4- ]]-6-(methyl sulfonylmethyl) π π·2-yl] pyridin-2-yl]urea 435 1.51 by reverse phase layer jin purification Example la : 1H NMR (399.9 MHz, DMSO-d6) ( 5 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 lb: 1 H NMR (399.9 MHz, DMSO-d6) ά 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 lc ·· 1H NMR (399.9 MHz, DMSO-d6) δ 1.10 (d, 6H), 1.24 (d, 3H), 3.29 (s5 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 (s5 1H) Example Id : 1 H NMR (399.9 MHz, DMSO_d6) 5 1.25-1.27 (m, 3H), 3.22 (s, 123642 -147 - 200817384 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: 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) Example If: iH NMR (399.9 MHz, DMSO-d6) 5 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 lg : 1H NMR (399.9 MHz, DMSO-d6) 5 1.25-L27 (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 lh : 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 (m5 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) 123642 - 148- 200817384 Example li : NMR (399.9 MHz, DMSO-d6) δ 1 27 (d5 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 (m5 1H),9·70 (s,1H), 10.52 (s,1H) Example lj : 1H NMR (399.9 MHz , DMSO-d6) (5 U2 (t, 3H), 1.25-1.26 (m5 3H), 3.20 (s, 3H) 5 3.22-3.24 (m, 2H), 3.26 (m, 1H), 3.47-3.54 (m ,1H)5 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) Test (8): Example (1) 0.0062 //M ; Example (la) 0.062 //M; instance (lb) 0.013 //M; instance (lc) 0.078 //M; instance (Id) 0.042 //M; instance (le) 0.32 //M ; instance (If) 0.36 /iM; instance (lg) 0.96; example (lh) 1.2 //M; instance (li) 0·55 //M; example (lj) 0.043 //M. present amine 4-[4-[(3S)- 3-methylfosfos-4-yl]-6-(methyl-branched methyl)-u-sigma _2_yl]phenylamine and 2-fluoro-4-[4-[(3S)-3-methylphenoflavin-4-yl]-6-(methionylmethyl)-l-pyridin-2-yl]aniline The preparation is described below.

4-[4-[(3S)_3_methylphenofyl _4_yl]_6-(methyl hydrazinomethyl), fluorenyl] aniline makes N-[4-[4-[(3S)- 3-methylmorpholine _4_yl]methanesulfonylmethyl) saponin-2_yl]phenyl]carbamic acid tert-butyl ester (1·09 g, 2·35 mmol) dissolved In methanol (5 ml), 4 Torr of hydrogen peroxide (5 ml) in dioxane was added. The solution was stirred at rt overnight. Water (5 ml) was added followed by sodium bicarbonate solution until a neutral pH was reached (~2 mL). The liquid phase was separated and the organic phase was washed with water (10 mL). The organic layer was dried (MgSO.sub.4), evaporated and evaporated. NMR spectrum: 1H NMR (399.9 MHz, DMSO-d6) 5 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) LCMS spectrum: MH+ 363, retention time 1.02 min, method 5 min. acid N-[4-[4-[(3S)-3-methylmorphofolin-4-yl]_6-(methylsulfonylmethyl) Xiaobiting-2_based j phenyl] carbamic acid tert-butyl ester

2-Phenyl-4-[(3S)-3-methylphenoflavin-4-yl]-6·(methionine methyl)Brigade sigma C (L0 g, 3.27 mmol) Dissolved in a solution (7 ml) of 18% DMF in a mixture of 7:3:2 DME··water:ethanol. Then, [4_[(2-methylpropan-2-yl)oxycarbonylamino]phenyl]dihydroxyborane (U65 g, 4.91 mmol), 2 碳 sodium carbonate solution (4 ml) and Chlorobis(triphenylphosphine) was added to the solution (115 mg, 〇ΐ6 mmol) and refluxed for 5 hours in a nitrogen atmosphere at 9 (rc). The reaction was allowed to cool to room temperature then to ethyl acetate. The organic solvent was dehydrated and dried with magnesium sulfate, filtered, and concentrated to dry wine. The crude oil was dissolved in dichloromethane and filtered to remove insoluble materials. 123642 -150- 200817384 The beige solid was precipitated from the filtrate, and the filtrate was filtered again. The solid was analyzed, and the hydrazine dihydroxyborane was found, and the filtrate contained the product and several impurities. The filtrate and the solution were purified by chromatography on the stone. Ethyl acetate was dissolved in isopropyl alcohol. The ethyl acetate was dissolved to give the desired compound as orange oil (53 mg). LCMS spectrum: MH+ 463, retention time 2. 23 minutes, method 5 minutes acid 2_Gasyl-4-[(3S)-3_methylmorpholine_4_yl μ6_(methylsulfonylmethyl), pyridine

〇. Dissolve 2,4-dichloro-6-(methylsulfonylmethyl)p-pyridine (3 g, 〇13 mol) in two gas-burning' and stir at -5 °C ( Under nitrogen). Triethylamine (17.4 mL, 0.13 mol) was added to give a clear brown solution. (38)_3_Methylphenoline was dissolved in dichloromethane and added dropwise to keep the reaction below -5 〇c. Then, the cooling bath was removed and the mixture was stirred for 1 hour. The reaction mixture was heated under reflux for 2 hours, then the reaction mixture was washed with water, dried and evaporated. The crude material was purified by preparative HPLC to give the desired material (19.3 g). NMR spectrum·· 1H NMR (400.13 MHz, DMSO-d6) δ 1.21-1.23 (m, 3H), 3.11 (s, 3Η), 3·19-3_26 (m, 1Η), 3.42-3.49 (m, 1Η) , 3.58-3.62 (1Η, 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 spectra :MH+ 306, residence time L42 minutes, method 5 minutes acid 2,4-digas «methanesulfonylmethyl)pyrimidine

Add 6-(methylsulfonylmethyl)·1Η-pyrimidine-2,4-dione (132 g, 0.65 mol) to 123642 -151 - 200817384 to gasified phosphonium (1.2 L) and The mixture was heated to reflux for 16 hours and then cooled to room temperature. The excess gasified phosphonium was removed in vacuo and the residue was azeotroped with Km (2 X 500 liters) and dissolved in dichloromethane. Next, the mixture was slowly poured onto ice (4 L) and stirred for 2 min, then extracted with dichloromethane (3 X 1 L) (filtered out of insoluble black material and discarded) and ethyl acetate ( 2 X 1 liter) extraction. The extracts were combined, dried and evaporated to dryness crystals crystals This material was used without further purification. NMR spectrum: 1H NMR (400·13 MHz, DMS〇_d6) occupies 3 13 (s, 3H), 4 79 (s, 2 Η), 7_87 (s, 1 Η) LCMS spectrum: MH+ 239, retention time 丨·^ Minutes, method 5 minutes acid 6-(methylsulfonylmethyl)-m-pyrimidine_2,4-dione fluorene 6-(gasmethyl)-purine-pyrimidine-2,4-dione ( 175 g, 1 〇 9 mol) was dissolved in DMF (2 liters) and added with methane sulfinate sodium salt (ΐ33·5 g, I&quot; Moore). The reaction was heated to (10) for 2 hours, then allowed to cool, and the suspension was filtered and taken to give &lt;RTI ID=0.0&gt;&gt; The water-washed crude material is 'subtracted', and the buddha is picked up. The picker is developed with A. The solid is filtered, and then developed with isohexane, leaving the desired human 舲*廿々的的化化物,为黄固体(250 g). This material was used without further purification. 6-(Chloromethyl ΗΗ·. 密 is a commercially available substance. 2-Fluoro.4·[4·〗 〖called 3_methyl 福福心·基卜6•(四)醯基甲细咬_2_基】aniline 123642 -152- 200817384

Dissolving 2-chloro-4-[(3S)-3-methylmorpholine-4-yl]_6_(methylsulfonylmethyl)pyrimidine (860 g) in 7 · 3 : 2 DME: water : 18% DMF in ethanol (21 ml total solvent volume). Then, yttrium dimethylbutyrate-based boronic fluoroanilide (1 〇〇 5 g), 2 M sodium carbonate (4 liters), and dichlorobis (triphenylphosphine) (99 mg) were added to the f solution. And under reflux, at 9 〇. Heat in a nitrogen atmosphere for 5 hours. The reaction was partitioned between DCM (50 mL) and water (5 mL). The organic extract was dried over magnesium sulfate, filtered and concentrated in vacuo. The brown oil was dissolved in dichloromethane and filtered to remove fine material and loaded onto the corresponding material for purification &lt;&quot;&gt;&gt; The purified product was obtained as a pale yellow oil. LCMS spectrum: MH+ 381, retention time l32 min, method 5 min acid 5-[4-[(3S)-3-methylmorpholine winter base] winter (methanesulfonylmethyl) hydrazide: yl (10) pyridine 2-amine

Dissolve 2_chloro-based [(3S)-3-methylphenofyrene-based]-6-(methionylmethyl) spray (363 mg, ι·19 mmol) in 18% DMF is in a solution of 7:3:2 DME • Water: a mixture of ethanol (7 ml). 5-(4,4,5,5-tetramethyldioxanthene-2-yl)pyridin-2-amine (496 mg, 2.25 mmol), 2M sodium carbonate solution (2 ml) And dichlorobis(triphenylphosphine)palladium (42 mg) was added to the solution 123642-153 - 200817384' and it was heated under reflux at 90 ° C for 90 minutes under nitrogen atmosphere. The organic product was dehydrated and dried over magnesium sulfate, filtered, and concentrated in vacuo to give the desired product as a yellow oil (41 mg). , used without further purification. LCMS spectrum: MH+ 364, retention time 〇·89 min, method 5-min acid 2-methoxy-4-[4-[(3S)-3-methylmorpholine_4 _ base]-6-(methylsulfonyl fluorenyl) pyridin-2-yl] aniline

Dissolve 2_Chloro-4-[(3S)-3-indolyl porphyrin-4_yl]·6-(methylsulfonyl fluorenyl), a bite (700 mg, 2.29 mmol) 18% DMF is in a solution of 7:3:2 DME ··water: a mixture of ethanol (7 ml). Then, (4) an amine group of methoxy-phenyl) dihydroxyboron (574 mg, 3.43 mmol), 2 Μ sodium carbonate solution ν (4 liters) and a mouse double (two lin) (81 House gram) was added to the solution and refluxed at 90 C for 1 hour. The reaction was allowed to cool to room temperature then partitioned between ethyl acetate (5 mL) and water (50 mL). The residue was dissolved in methylene chloride and filtered to remove insoluble material. The filtrate was purified using the relevant materials. NMR spectrum: iHNMR (399.9 MHz, DMSO-d6) δ 1.24 (d, 3H), 3.17-3.21 (m, 1 Η), 3_23 (s, 3 Η), 3.47-3.54 (m, 1 Η), 3.64-3.67 (m ,1Η),3·78 (d,1Η), 3·83 (s,3H),3.97-4.01 (m,1H),4.16 (d,1H),4.46 (s,3H),5·23 (s , 2H), 123642 -154- 200817384 6.68-6.70 (m,1Η),6·69 (s,1Η),7·77 (m,iH),7.97 (s,1H) LCMS spectrum: MH+ 393, residence time U7 min, 5 min acid method Example 2: Phenyl] nitrotetradecane small carboxamide N_[4-[M(3S)_3_methylmorpholine ice-based]_6_(methylsulfonylmethyl)pyrimidine _2•基]

The phosgene 2 〇〇 / 〇 solution in toluene (〇·245 liters, 〇·5 〇 millimolar) was diluted with methyl chloride (0.5 ml). Dissolve 4-[4-[(3S)-3-methylmorpholine]yl (methanesulfonylmethyl)-cyano-2-yl]aniline (150 mg, 〇·41 mmol) In dichloromethane (2 liters) and pyridine (〇·5 ml). It was added dropwise to the phosgene solution over 2 minutes. The reaction was stirred at room temperature for 1 hour. Then, a nitrogen tetramine (0.034 ml, 〇. 50 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction was partitioned between water and ethyl acetate (25 mL each). The organic layer was dried over magnesium sulfate and evaporated to dryness. 1 〇 70% ethyl acetate was dissolved to give the desired material as a yellow foam (5 mg, 25%). NMR spectrum····················· 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 (t5 5H), 4.17 (s5 1H)? 4.49 (s3 3H), 6.79 (s5 1H)5 7.62-7.64 (m5 2H), 8.20-8.23 (m, 2H)5 8.57 (s, 1H) LCMS spectrum: MH+ 446, Retention time L37 minutes, method 5 minutes acid The following compounds are similar to N-[4-[4-[(3S)-3-methylphenoflavin-4-yl]-6-(曱123642 -155- 200817384 sulfonate The method of decylmethyl)pyrimidin-2-yl]phenyl]azatetraindole-1-carboxamide is prepared from 4-[4-[(3S)-3-methylmorphin-4-yl ]-6·(甲石黄驴基 methyl)σ密11定-2-yl]aniline with the appropriate amine. Example structure name LCMS ΜΗ+ retention time (minutes) Note 2a Cx Η 1 1-(2-methoxy Base ethyl)-1- Benzyl-3-[4-[4-[(3S)-3-methylindol^lin-4-yl]-6-(methyl succinylmethyl&gt; lymid-2-yl]phenyl] Urea 478 1.46 N/a 2b 0..., 1,1-dimethyl-3-[4-[4-[(3S)-3-methylindol^lin-4-yl]-6- (Methanesulfonyl fluorenyl)pyrimidin-2-yl]phenyl]urea 434 1.28 Purification by reverse phase chromatography 2c 0, 3-[2-methoxy-4_ [4-[(3S)-3-) Kefufu p--4-yl] -6-(methylsulfonyl fluorenyl) guate-2-yl]phenyl]-u-diinyl group 464 1.54 Purified by reverse phase chromatography 2d 0 UN儿f Η H 1-methyl·3-[4-[4 -[(3S)-3-indenyl sulphate -4-.^]·6_(methylsulfonyl fluorenyl)pyrimidine -2-yl] phenyl]urea 420 1.19 Purified by reverse phase chromatography 123642 -156- 200817384 Example structure name LCMS MH+ residence time (minutes) 2e 0, %eXV human / JHH Η2-fluorenyl ice [4-[( 3S)-3-methylphenoflavin-4-yl]_ 6-(methionyl fluorenyl)pyrimidin-2-yl]phenyl&gt;1-methyl- earning 438 1.44 by reverse phase chromatography Purification 2f [. 〕 〇,, st^X 八3-[2-Fluoro-4-[4-[(3S)-3-methylphenoline p--4-yl]-6-(nonylsulfonylmethyl) Pyrimidine-2-yl]phenyl H,i-dimethyl-urea 452 1.55 Purification by reverse phase chromatography Example 2a: 1H NMR (399.9 MHz, DMSO-d6) 5 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 2b: 1H NMR (399.9 MHz, DMSO-d6) 5 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 2e: 1H NMR (399.9 MHz, DMSO-d6) (5 1.25-1.27 (m, 3H), 2.97 (s, 6H), 3.18 (m, 1H), 3.23 (s, 3H), 3.48-3.55 (m, 1H), 3.65-3.69 (m , 1H), 3.79 (d, 1H), 3.93 (s, 3H), 3.98-4.02 (m , 1H), 4.20 (d, 1H), 4.47 (s, 1H), 4.51 (s, 2H), 6.82 (s, 1H), 7.52 (s, 1H), 7.91-7.94 (m, 2H), 8.00 ( s, 1H) Example 2d: 1H NMR (399.9 MHz, DMSO-d6) 6 1.25 (d, 3H), 2.66-2.67 (d, 123642 -157 - 200817384 3H), 3·21 (s, 3H), 3.23 ( d,1H), 3.47-3.54 (m,1H), 3.64-3.68 (m,1Η),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 2e: 1H NMR (399.9 MHz, DMSO-d6) 5 1·24·1·26 (m, 3H), 2.69 (d, 3H), 3.23-3.24 (m, 1H), 3.26-3.27 (m , 1H), 3.20 (s5 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 (q5 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 2f: 1H NMR (399.9 MHz, DMSO-d6) 5 1.25-1.27 (m, 3H), 2.96 (s, 6H), 3.20 (s, 3H), 3.48-3.55 (m, 1H), 3.64-3.68 (m5 1H), 3.79 (d, 1H), 3.9 8-4.02 (m,1H),4·21 (t,1H),4.40 (m,1H),4.51 (s,2H),6·85 (s,1H), 7.68 (t,1H),8.02- 8.11 (m5 2H), 8.15 (s, 1H) Test (8): Example (7) 0.31 //M; Example (2a) 2·3 //M; Example (2b) 0.29 //M ; Example (2c) 1.2 //M Example (2d) 0.0068 //M; Example (2e) 0.038 /M; Example (2f) 1.7 μΜ. Example 3: 1_[2·methyl-4-[4-[(3S)-3-methyl?福淋_4-基】-6-(methyl-mercaptomethyl)pyrimidin-2-yl]phenyl]-3-phenyl-urea

2-Methyl-4-[4-[(3S)-3-methylphenoflavin-4-yl]-6-(methioninyl)-glycolyl-2-yl]aniline (13 mg , 〇·34 mmol) dissolved in L4-dioxane (4 ml). Phenyl isocyanate (〇_〇 38 ml, 〇·34 mmol) was added, and the reaction 123642-158·200817384 was heated at 75 C for 3 leaflets. The reaction mixture was evaporated to dryness crystals crystals crystals crystals NMR spectrum: 1 η nmr (400·13 MHz, DMS〇_d6) $ i 25 (s, 3H), 2 % &amp; 3H), 3.21 (s, 3H), 3.23-326 (m, 1H), 3.48 -3.55 (m,1H),3.64-3.68 (m,1H), 3J9 (d,1H),4·〇〇(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) LCMS spectrum: MH+ 496, retention time 2.08 min, method 5 minutes acidification of the whole system in a similar manner from the appropriate aniline and isocyanate. Example structure name LCMS MH+ retention time (minutes) Note 3a [λ Uhn 儿 r 1-ethyl each [2-methoxy-4-[4-[(3S)-3-methyl 福福普林-4- ]--6-(methyl fluorenylmethyl)pyrimidin-2-yl]phenyl]urea 464 1.54 by reverse phase chromatography followed by normal phase chromatography to purify 3b [λ 〇p rS H2-chloro-4- [4-[(3S)-3-Methylmorpholine-4-yl]-6-(nonylsulfonylmethyl)glycin-2-yl]phenyl]-3-phenyl-month urine 515 2.51 was purified on silica gel, and dissolved in 0-4 〇/〇 methanol in DCM. 3c Cx HH4-[(3S)-3-methylorfosin-4-yl]-6-(methioninyl fluorenyl) Pyrimidin-2-yl]phenyl]-3-phenyl-urea 481 2.30 Purified by recrystallization from DMF/water (twice), followed by acetonitrile. 123642 - 159 - 200817384 Example structure name LCMS MH+ retention time (minutes) Note 3d cx : s ^ aAJ 〇 1 H 1-methyl _l-[4-[4_ [(3S)-3-methylorfosyl phenyl-4-yl]-6- (valium fluorenylmethyl) Pyrimidine-2-yl]phenyl&gt;3-phenyl-urea 496 2.18 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 (m5 1H) Example 3b: 1H NMR (400.13 MHz, DMSO-d6) 5 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 (m5 1H), 4.20 (d5 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) Example 3c: 1H NMR (400.13 MHz, DMSO-d6) 5 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 (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) Example 3d: iH 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 (s5 1H), 6.96 (t,1H),7·24 (t,2H),7 · 44 123642 -160- 200817384 (m, 4H), 8.33 (s, 1H), 8.35 (s, 2H) Test (&amp;): Example (3) 1.5 / ^; Example (3 &amp;) 0.1 / ^; (313)0.44/^/[; Example (3c) 3.3 //M; Example (3 sentences 2.9 //Μ· 2 methyl 4 [4 [(3S)-3-methyl phloate _4_ base] The preparation of 6_(methyl sulphate thiol) 0 dimethyl-2-yl] aniline is described below. 2-methyl-4-[4-[(3S)-3-methylmorpholine-methanol] each (methanesulfonylmethyl)pyrimidine-2-yl]aniline

4-&gt; odoryl-2-methylaniline (1 gram, 5.37 mmol), potassium acetate (159 g, 16.1 mmol) and 4,4,5,5-tetradecyl-2 -(4,4,5,5-tetradecyl-oxoborthene-2-yl)-1,3,2-oxooxacillin (1.64 g, 6.45 mmol) dissolved in ι, 4_ In dioxane (20 ml), the solution was degassed for 5 minutes. Dioxobis(triphenylphosphine)palladium (264 mg, 0.32 mmol) was added and the reaction was stirred at 9 (rc) for 4 h. 2-chloro-4-[(3S)-3-methyl Morpholine-4-yl]«methanesulfonyl fluorenylpyrimidine (1·65 g, 5.37 mmol), ethanol (1.5 ml), 2M aqueous sodium carbonate solution (3 ml), and dichlorobis(triphenyl) Phosphine) palladium (264 mg). The reaction was kept at 9 Torr: for 18 hours and then allowed to cool to room temperature. Water (15 ml) and ethyl acetate (15 ml) were added and the mixture was filtered to remove insoluble impurities. The liquid phase was separated and the aqueous layer was extracted with diethyl ether (15 mL). The combined organic material was dried (MgS 4) and concentrated in vacuo. The residue was chromatographed on silica gel eluting EtOAc (EtOAc) 123642 • 161 - 200817384 NMR spectrum: 4 NMR (400·13 MHz, DMSO-d6) 5 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) LCMS Spectrum: MH+ 377, residence time 1.21 minutes, method 5-minute acid 2-carbyl-4-[4-[(3S)-3-indolyl oxafolin-4-yl]-6-(methylsulfonylmethyl) The preparation of the guanidin-2-yl]amine is described below. 2-Alkyl-4_[4-[(3S)-3_indolyl phenanthren-4-yl]_6-(A succinylmethyl) shouting -2 yl aniline

4-Bromo-2-aniline (1.00 g, 4.84 mmol), acetic acid unloaded (1.58 g, 14.5 mmol) and bis(pinyl) diboron (ι·64 g, 5.81 mmol) The ear was dissolved in 1,4-dioxane (20 ml). The solution was degassed under nitrogen for 5 minutes. [U'-bis(diphenylphosphino)dicyclopentadienyl iron] (213 mg, 0.29 mmol) was added. The reaction was stirred at 90 ° C for 4 hours. Add ethanol (1.5 ml), 2-chloro-4-[(3S)-3-methylmorphinyl]-6-(methionine methyl η 定 (Im 49 g, 4.84 Mo Ear), 2 Μ sodium carbonate solution (5.4 ml) and [1, Γ-bis(diphenylphosphino) dicyclopentazen iron] (213 mg), and heating was continued for 18 hours. The reaction was evaporated to dryness. The residue was partitioned between water (15 mL) and ethyl acetate. The transition mixture was removed to remove the insoluble material, the liquid phase was separated, and the aqueous layer was washed with ethyl acetate (15 ml). The combined organics were dried over magnesium sulfate and evaporated to a yellow oil. The crude product was purified by chromatography on EtOAc EtOAc EtOAc EtOAc (EtOAc) NMR spectrum: lH NMR (400.13 MHz, DMSO-d6) 5 1·22·1·24 (m, 3H), 3·18 (s, 3 Η), 3.19-3.21 (m, 1 Η), 3.45-3.52 (m ,1Η), 3.62-3.65 (m,1Η),3·77 (d,1H),3.96-4.00 (m,ih),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) LCMS spectrum: MH+ 397, retention time 1.64 minutes, method 5 min acid H4_[ The preparation of (3S)-3-methylmorpholine-4-yl]-6-(nonylsulfonylmethyl)u-mididine-2-yl]aniline is described below. 3-[4-[(3S)methyl-m-fosfosin_4·kib 6-(methylsulfonylmethyl), pyridine: phenyl) aniline

Dissolve 2-chloro-4-[(3S)-3-methylnorfos-4-yl]-6-(methylsulfonylmethyl) oxime (1.50 g, 4.91 mmol) In 7:3:2 dimethoxyethane: water: 18% DMF (15 ml) in ethanol. (3-Aminophenyl)dihydroxyborane (101 g, 7.36 mmol), 2 Μ sodium carbonate (5 ml) and dichlorobis(triphenylphosphine) (173 mg, 0·25 mmol) ) added to the solution. The reaction was refluxed for 9 hours under argon and nitrogen atmosphere, then the reaction was cooled and partitioned between ethyl succinate (5 mL) and water (50 mL). The dried magnesium sulfate was dried, filtered, and evaporated to dryness. The brown oil formed was dissolved in DCM and filtered to remove insoluble material, and then the filtrate was chromatographed on silica gel to 0-4 in DCM. % methanol was dissolved to give the desired product as a yellow oil (1.61 g). </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> NMR spectroscopy: 4 NMR (400.13 MHz, DMSO-d6) 5 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) LCMS spectrum: MH+ 364, retention time 〇·93 minutes, method 5 minutes acid Ν-methyl-4-[4-[(3S) 曱 吗 吗 福 _ _ 4 4 各 各 各The preparation of (methylglycosylmethyl) hydrazin-2-yl] aniline is described below. N-Methyl-4-[4-[(3S)-3- Four groups do morpholine ice-yl] _6_ (methanesulfonamide acyl methyl), piperidin-tight -2_-yl] aniline

2_Chloro-4-[(3S)-3-methylmorpholine 4·yl] each (sulfonylmethyl) stilbene (1.01 g, 3.30 mmol) was dissolved in 7:3: 2 Dimethoxyethane: 18% DMF (7 ml) in water·ethanol. N-methylidene (4,4,5,5-tetramethyl), 3,2-dioxooxazol-2-yl)aniline (ι·00 g, 4·29 mmol), 2M Sodium carbonate solution (4 ml) and dichlorobis(triphenylphosphine)palladium (116 mg, 〇16 mmol) were added to the solution. The reaction was refluxed for 3 hours at 90 C under a nitrogen atmosphere. then mixture was evaporated and partitioned between ethyl acetate (3 mL) and water (3 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 the insoluble material. The filtrate was then chromatographed on silica gel and eluted with 0-4% methanol in DCM to give the desired product as a yellow foam. (U2 grams, 9〇%). 123642 -164- 200817384 NMR spectrum: 1H NMR (400.13 MHz, DMSOd6) 6 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) LCMS spectrum: MH+ 377, retention time 1.33 minutes, method 5 min acid Example 4: 1-Ethyl-3-[2-fluoro-[4-[4-[(3S)-3-indolyl]-indolyl-4-yl]-6-(methylphenylsulfonyl)pyrimidine -2-yl]phenyl]urea

The bis(trichloromethyl)S carbonate (44 mg, 〇·ΐ 6 mmol) was dissolved in DCM (0.25 mL) to give a colorless solution. 2·Fluoro-4-[4-[(3S)-3-methylphenoflavin-4-yl]-6-(methioninylmethyl)u-mididine-2-yl]aniline (140 mg , 0.39 mmol; dissolved in DCM (2.0 mL) and pyridine (〇 2 mL). The resulting solution was added dropwise to a solution of bis(trichloromethylene carbonate) at 〇 ° C, and the mixture was allowed to warm to room temperature, then stirred for 1 Torr. Ethylamine (2M in THF, 0.5) </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The residue was purified by EtOAc EtOAc (EtOAc: EtOAc: EtOAc: , 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 123642 -165- 200817384 (m,3H),6·68 (t,1H) , 6.81 (s, 1H), 8.01-8.08 (m, 2H), 8.29 (t, 1 Η), 8. 47 (d, 1H) Mass Spectrum: The following compounds were prepared in a similar manner using the appropriate aniline and amines. Example structure name LCMS MH+ retention time (minutes) 4a λλΝ-[ 2-fluoro-4-[4-[(3S)-3-methyl-fusino]--4-yl]-6-(methanesulfonylmethyl) ♦ dimethyl-2-yl]phenyl] Nitrogen tetradec-1-carboxamide 463 1.61 4b Cl Η [ 3-[2-Fluoro-4-[4-[(3S) -3 -methylmorpho-p-lin-4-yl]-6-( Methanesulfonylmethyl) acetophenone-2-yl]phenyl]-1-propan-2-yl-urea 465 1.83 4c [°Λ J Η Η 3-[2-methoxy-4-[4- [(3S)-3-Methylmorpholine-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl]phenyl]-1-methyl-urea 450 1.36 4d^ 0 ^ Human ~., Η Η 1-(2-decyloxyethyl)-3 _[4-[4-[(3S)-3-indolyl carbaryl-4-yl]-6-(sulfonamide) Methyl)pyrimidin-2-yl]phenyl]urea 464 1.32 4e* 0 Υλ 〜,1·(2-methoxyethyl)-3 -[2-methoxy-4-[4-[ (3S)-3-Methylmorpholine-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl]phenyl]urea 440 1.47 123642 -166- 200817384 Example structure name LCMS MH+ (minutes) 4f* A JL 〆〇, ^—[N],&quot; ~. , 3-[2-Mercapto-4-[4-[(3S)-3-indolyl]-indol-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl]phenyl ]-1-(2-decyloxyethyl)-1-methyl-urea 495 1/74 4g* 0 Υλ 〜. , H2-fluoro-based winter [4-[(3S)-3- 3-indolyl-4-indolyl]-6-(nonylsulfonylmethyl)pyrimidin-2-yl]phenyl]-1-( 2-Methoxyethyl)urea 482 1.87 was chromatographed on Shiqi gum and dissolved in 0-5% methanol in DCM. Example 4a: !Η NMR (400.13 MHz, DMSO-d6) 5 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 (t5 5H), 4.19 (d,1H), 4.50 (s,3H), 6.84 (s,1H) , 7.83-7.87 (m,1H), 8.04 (d,1H), 8.08-8.10 (m,1H), 8.18 (s,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) Example 4c: Old 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, 1H), 6.85 (d5 1H), 7.90 (s, 1H), 8.11 (s, 1H), 8.22-8.24 (m, 1H) 123642 -167- 200817384 Example 4d: NMR (400.13 MHz, DMSO-d6) ά 1·24 (d, 3H), 3.19-3.24 (m, 2Η), 3·21 (s5 3Η), 3·27 (s, 3Η), 3·40 (t, 2Η) , 3.47-3.53 (m,1Η), 3.63-3.67 (m,1H), 3.78 (d5 1H), 3.97-4.01 (m,1H), 4.17 (s,1H),4·49 (s, 3H), 6.27 (t,1H), 6.77 (s5 1H), 7.47-7.51 (m, 2H), 8.19-8.23 (m, 2H), 8.78 (s, 1H) Example 4e: 1H NMR (399.9 MHz, DMSO-d6) 5 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 (ls? H) Example 4f: 1H NMR (400.13 MHz, DMSO-d6) 5 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 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) Test (a): Example (4) 〇·〇31 /iM; Example (4a) 1 //M; Example ( 4b) 0.14 //M; instance (4c) 0·8 //M; instance (4d) 0_17; instance (4e) 0.6 //M; instance (4f) 〇·68 //M; instance (4g) 0.83 / /M· Example 5: 1-ethyl_3_[4-[4-(hydroxymethyl)-6-[(3S)-3-methylmorpholine-4-yl]pyrimidin-2-yl]benzene Urea]123642 -168· 200817384

1-[4_[4-[(Dimethyl-t-butyl-butyl)-yloxy)][(38)_3_indolyl-norfos-4-yl]pyrimidinyl Phenyl]_3_ethyl-urea (1 〇 4 mg) was dissolved in THF (10 liters) and TBAF (10 M solution, 〇 22 mL) was added. The reaction was stirred at room temperature for 1 hour and then passed down the SCX-2 column. The column was washed with methanol and the desired material was dissolved in claw ammonia in methanol. The residue was concentrated in vacuo to give the desired compound (j. NMR spectrum: 1 η NMR (399.9 MHz, DMSO-d6) 6 1·07 (3H, t), 1.23 (3H, d), 3.11-3.16 (2Η, m), 3.19-3.23 (1Η, m), 3 ·49 (1Η,d),3.62-3.66 (1Η,m), 3.77 (1H5 d)? 3.95-3.99 (1H? m)? 4.16 (1H?d)? 4.45 (2H?d)5 4.48 (1H? s)5 5·38 (1H, s), 6.14 (1H, t) 5 6_66 (1H, s), 7.46 (2H, d) 5 8·19 (2H, d), 8·62 (1H, s) Mass spectrometry; M+H+372. Test (a): 0.063 //M. l-[4_[4-[(Dimethyl-tert-butyl-decyl)oxymethyl]-6_[(38 The preparation of _3_methylmorpholine fluoro] oxalyl-2-yl]phenyl]-3-ethyl-urea is described below. Η4·[4-[(Dimethyl-tert-butyl-monmanyl)oxymethyl]-6_[(3S)_3_methylmorpholine-4-yl]pyrimidin-2-yl] Phenyl]-3_ethyl-urea

123642 -169- 200817384 4-[4-[(Dimethyl-t-butyl-oxalinyl)oxymethyl][[3S)methyl-methylfosfosin-4-yl] Benzyl]aniline (250 mg) was dissolved in 1, dioxin (4 ml), and ethyl isocyanate (〇·144 ml) was added. The reaction was heated to 120 ° C in a microwave reaction for 1 hour. The reaction was concentrated in vacuo and the residue was crystallised eluted eluted eluted eluted The desired compound (106 mg) was obtained as white solid. Mass spectrometry; M+H+486. 4_[4-[(Dimethyl-tert-butyl-muteyl)oxymethyl]_6 [(3S)methyl-m-propofolin-4-yl]pyrimidine -2-yl] aniline

[2-(4-Aminophenyl)-6-[(3S)-3-methylphenoflavin-4-yl]-hydrocarbyl]methanol (1.54 g) was dissolved in DCM (60 mL) The third butyl dimethyl decane (928 mg) was gasified and imidazole was added. The mixture was stirred at room temperature for 5 hours, then 'filtered' and concentrated in vacuo. The residue was chromatographed on EtOAc (EtOAc) elute NMR spectrum··咜NMR (399.9 MHz, DMSO-d6) 5 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), 4.60 (2H,s),5·48 (2H,d), 6.50 (1H,s),6.57-6.59 (2H,m), 8.02-8.04 (2H,m) Mass Spectrometry ;M+H+415. 123642 -170- 200817384

[2-(4-Aminophenyl)_6-[(3S)-3-methylmorpholine yl]pyrimidin-4-yl] decyl alcohol makes N-[4-[4-(hydroxymethyl) -6-[(3S)-3-methylmorpholine piperidinyl sulfhydryl] phenyl] carbamic acid tert-butyl ester (1.20 g) in 4M hydrogen chloride (5 ml) dissolved in dioxane Within with dioxane (5 ml). The reaction was spoiled for 18 hours then DCM (10 mL) was added to help dissolve material. The reaction was re-mixed at 4 ° C for 18 hours and then evaporated to dryness. The solid was suspended in dcm (20 mL) and a mixture of saturated aqueous sodium bicarbonate (6 mL) and water (4 mL). The organic material was separated, dried (MgSO4) elute NMR spectrum: 1H NMR (399.9 MHz, DMSO-d6) 6 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 5·32 (1H,t),5· 47 (2H, s), 6.57-6.59 (3H, m)5 8.02-8.04 (2H, m) MS; M+H+301. N-[4-[4-(hydroxymethyl)-6_[(3S )-3-methylmorpholine-4-yl]pyrimidin-2-yl]phenyl]aminocarboxylic acid tert-butyl ester

[2-Chloro-6-[(3S)-3-methylnorfosolin-4-yl hydrazide] sterol (2·44 g), (4-Boc-aminophenyl) Hydroxyborane (4.76 g), 2M solution of sodium chlorate 123642 -171 - 200817384 (10 ml) and solvent mixture (18% DMF in 7:3: 2 DME: water: ethanol) (35 ml) The mixture was degassed. Dichlorobis(triphenylphosphine) was added (3 oz) 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 (2 mL), washed with brine (100 ml), and dried (MgS? The crude material was chromatographed on silica gel eluting with EtOAc (EtOAc) Mass spectrometry; Μ+Η+401.

[2_气基_6-[(3S)-3-indolyl porphyrin-4-4-yl]pyrimidin-4-yl]methanol

2-Chloro-6-[(3S)-3-methylphenothonine-based] Methyl 4-methyl-propionate (3.15 g) was dissolved in anhydrous THF (20 mL) under nitrogen Cool to 〇 °c. A lithium borohydride solution (2.0 mM in THF, 6.09 ml) was added dropwise. The solution was allowed to warm to room temperature and stirred for 1 hour. The reaction was quenched with water (2 () mL) then evaporated to dryness. The residue was dissolved in ethyl acetate (15 mL) and water (150 mL) The organic material was concentrated in vacuo to give the desired compound (m. NMR spectrum: iH NMR (399.9 MHz, DMSO-d6) δ 1.20-1.21 (3 Η, 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) mass spectrometry; M+H+244. 2-Chloro-6-[(3S)-3-methylorfos-4-yl], bite_4_sodium sulphate 123642-172- 200817384

Methyl 2,6-dichloropyrimidine-4.carboxylate (5.00 g) was dissolved in DCM (120 mL). (3S)-3-Methylmorpholine (2.49 g) was dissolved in triethylamine (3.70 mL) and DCM (10 mL) was added dropwise to the solution over 1 min. The reaction was allowed to stand at room temperature for 1 hour, then the mixture was concentrated in vacuo and evaporated in EtOAc. The organic material was washed with water (150 ml) and dehydrated (MgS04). The crude material was chromatographed eluted eluted elut elut elut elut elut elut elut elut NMR spectrum: 1H NMR (399.9 MHz, DMSO-d6) 5 1.22-1.24 (3 Η, 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) MS; +H+272. Example 6: l-[4-[4-(Methyl)-6-[(3S)-3_methylphenofin-4_yl], _2_yl]phenyl Phenyl-urea

1-(4-Molyphenyl)-3-phenyl-urea (960 mg), acetic acid unloaded (969 mg), bis(pinyl)diboron (1.01 g) dissolved in 1,4-dioxane Lu Yu (5 〇 ml). The solution was degassed for 5 minutes, then 1,1'-bis(diphenylphosphino)dicyclopentadienyldichloro-I-bar (II) gas-fired adduct (162 gram) was added and the reaction was carried out. Heat to (10) 123642 -173 - 200817384 °C 'over 3 hours. Add another l,r-bis(diphenylphosphino)dicyclopentadienyl iron dichloropalladium(II) digas methane adduct (162 mg) and stir the reaction at 80 ° C for a further 3 hour. [2-Alkyl-6-[(3S)-3-methylmorpholine yl) pyrimidine was added. Ding-4-yl]methanol (803 mg), ethanol (3.75 ml), 2M sodium carbonate solution (6.9 ml) and 1, Γ«•bis(diphenylphosphino)dicyclopentadienyl iron dichloropalladium ( II) Dichloromethane adduct (162 mg) and heating for 16 hours. Add more ethanol (5 ml) and U'-bis(diphenylphosphino)dicyclopentadienyl iron dichloropalladium (II) dichloromethane adduct (162 mg) and stir the reaction for 5 more After an hour, it was then allowed to cool and neutralized with 2 Torr hydrochloric acid. The reaction mixture was passed through three SCX-2 columns, each time the sample was loaded and washed with methanol, followed by removal of the desired material with 7 氨 ammonia in methanol. The solution was concentrated in vacuo and EtOAc EtOAc m. NMR spectrum: 4 NMR (DMSO-d6) 5 1_24 (3Η,d), 3,20-3.24 (1Η,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), 7.46-748 (2H, m), 7.52-7.56 (2H, m), 8.25 -8.27 (2H,m),8·68 (1H,s),8·87 (1H,s) MS; M+H+419. Test (a): 0.56 //M.

[2-Chloro-6-[(3S)-3-methylmorpholine]pyrimidinyl]methanol was prepared as described above. Example 7: 3-[4-[4-(Methylsulfonylmethyl)-6-morpholine-4-yl-pyrimidin-2-yl]phenyl H-propene: 123642 -174- 200817384

4-[4-(Indolyl sulfonyl hydrazino), fluoxetine, phenyl-pyrimidinyl] aniline (7) mg '〇·2 mmol) with isopropyl isocyanate (0.1 ml, 1 mmol) The residue was heated in EtOAc (2 mL) EtOAc (EtOAc). The solid was then dried under vacuum <RTI ID=0.0></RTI> </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; , Gu Gu ~ 占 i" Feng, 3 2 &amp; 3H), 3.7 (m, 8H), 3.76 (m, 1H), 4.48 (s, 2H), 6.G5 (d, 1H), 6.8 (s ,1H), 7.48 (d,2H),8·2 (d,2H), 8.54 (s,1H) The following compounds were prepared in a similar manner using the appropriate isocyanate from methyl pyridine 2-amino aniline oxime Appreciation structure name J makeup 0 LCMS MH+ retention time (minutes) 7a 0 — Η Η ^(4·methylphenyl)-3-[4_ [4-(methionylmethyl) -6-?福琳_4_基_口密基基]phenyl]urea 482.03 2.15 7b 0 Η Η 3-(4-Phenylphenyl)-1_[4-[4-(methylsulfonylmethyl)-6-formin. Lin-4-yl-spray-based]phenyl]urea 501.95 2.26 123642 -175- 200817384 Example structure name LCMS MH+ retention time (minutes) 7c 0 and XT Η Η 1-[4·[4-(methylsulfonylmethyl)-6-, phenanthrene. lin-4-yl-pyrimidine -2-yl]phenyl]-3-[4-(trifluoromethyl)phenyl]urea 536.00 2.39 7d 0 Η Η 1-(3,5-dimethylphenyl)-3-[4-[ 4-(Methanesulfonylmethyl)-6-Rhofolin-4-4-yl-U dense TJ-but-2-yl]phenyl]urea 496.05 2.29 7e 0 Η 〇 〇yF F 3-[2-(two Fluoromethoxy)phenyl]-1-4-[4-(indolylxanthylmethyl)-6-morphin p-lin-4-yl--bromo-2-yl]phenyl]urea 533.97 2.25 7f 0 Η Η 3-(4-fluorophenyl)-H4-[4-(methylsulfonylmethyl)-6-norfosin-4-ylindole-2-yl]phenyl]urea 485.97 2.07 7g minus 〇 1 person Η Η 3-(3-carbyl-4-phenylphenyl) small [4-[4-(methanesulfonylmethyl)-6-?? 4 wood-4_ base-TJ dense sigma -2-yl]phenyl]urea 519.96 2.29 7h^ 0 'stA〇L Human X) Η Η 1-[4-[4-(methylsulfonylmethyl)-6-norfosin-4-yl _. Σσ定-2-yl]phenyl]-3-phenyl-urea 468.56 3.00 7i* 0 ,〇sAxvcr Η Η 1-(4-methoxyphenyl)-3-[4-[4-( Styrene methyl) -6-?Fu^ Lin-4-yl-. Michidine-2-yl]phenyl]urea 498.60 2.93 123642 -176- 200817384 Example structure name LCMS MH+ retention time (minutes) 7Γ 0 Ά人/ Η Η 3-[4-[4-(sulfonylmethyl) )-6-?福^林-4-基_.唆-2-yl]phenyl]-1-indenyl-pulse 462.64 3.02 7k^ [:] yAx, j〇c: Η Η 3-(3,4-di-phenyl)-1_ [4-[ 4-(nonylsulfonylmethyl)-6-ifu^lin-4-yl-pyrimidin-2-yl]phenyl]urea 504.59 Ή* C] ^Α〇Η Η 3-3⁄4 hexyl-1-[ 4-[4-(methylmercaptomethyl)-6-?-fusin-lin-4-phenyl-indole-2-yl]phenyl]urea 474.63 3.02 7m^ 0 0 认儿Ν, Η Η 1- Ethyl-3_[4·[4-(methylsulfonylmethyl)-6-morpho-p--4-yl-.密0定-2-yl] phenyl]urea 420.60 2.49 Ίη* 0 yAw Η Η 3-[4-[4-(indolylmethyl)-6-morpho-4-yl-pyrimidine-2- ]]phenyl]-1-propyl-month urine 434.61 2.66 7〇^ 0 °ϊ:ΑαΝιΝ^6 Η Η 1-(3-ethylphenyl)-3-[4_ [4-(Continuous S&amp; Methyl) -6-? Lin-4-yl^-3⁄4 pyridine-2-yl]phenyl]urea 496.62 3.29 7ρ* 0 : saW. Η Η 3-(2-Ethylmethyl)-1-[4-[4-(methylsulfonylmethyl)-6-morphine p-lin-4-yl-pyrimidin-2-yl]phenyl ]urea 472.58 2.76 7q* 0 Η Η 1-[4-[4-(methyl sulphatemethyl)-6-moff-4-yl_.唆-2-yl]phenyl]-3-(2-desophen-2-ylethyl)urea 502.58 2.96 123642 -177- 200817384 Example structure name LCMS ΜΗ+ retention time (minutes) 7r* 〔:〕 Η Η 1-[4-[4-(Indolylsulfonylmethyl)_6_Nalufolinyl-pyrimidin-2-yl]phenyl]-3-sulfon-2-yl-urea 474.54 2.92 Compound Further purification by preparative hplc. Example 7a: 1H NMR (400.13 MHz, DMSO-d6) (5 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 7b: 1H NMR (400.13 MHz, DMSOd6) 5 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 7c: 1H NMR (400.13 MHz, DMSO-d6) ) 5 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 (s5 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) Example 7e: W NMR (400.13 MHz, DMSO-d6) 5 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 7f: 1 H NMR (400.13 MHz, DMSO-d6) 5 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 (s5 1H) 123642 -178- 200817384 Example 7g : 1H NMR (400.13 MHz, DMSO-d6) 5 3·21 (s, 3H), 3.72 (s, 8H), 4.49 (s, 2H), 6.84 (s, 1H), 7·34 (m, 2H), 7.56 (m, 2Η), 7·8 (m, 1H), 8·28 (m, 2H), 8.95 (s, 1H), 9·05 (s, 1H) Example 7i: 1H NMR (400.13 MHz, DMSOd6) 5 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 7j : iH NMR (400.13 MHz, DMSO-d6) 5 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), Γ: 6.2 (t, 1H), 6.81 (s, 1H), 7.49 (d, 2H), 8.20 (d, 2H), 8.66 (s, 1H) 7m: 1H NMR (400.13 MHz, DMSO-d6) 5 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 7n: iH NMR (400.13 MHz, DMSO-d6) 5 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 (d5 2H), 8.20 (d, 2H), 8.69 (s, 1H) Example 7o: 1 H NMR (400.13 MHz, DMSO-d6) δ 1.19 (t, 3H), 2.55 (q, 2H),

V 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 7p: 4 NMR (400.13 MHz, DMSO-d6) ά 3.20 (s5 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 7q: 4 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) 123642 -179- 200817384 Test (8): Example (7) 0.17 //Μ; Example (7a) 0· 28 //Μ; instance (7b) 0.42 /Μ; instance (7c) 1·7 /iM; instance (7d) 2·6 //Μ; instance (7e) 2.6 //Μ; instance (7f) 〇·〇 29 //Μ; instance (7g) 1·3 //Μ; instance (7h) 0.24 /Μ; instance (7i) 0.032 // M; instance (7j) 1.9 //M; instance (7k) 0.72 //M ;Example (71) 7 //M; instance (7m) 〇·〇81 //Μ; instance (7n) 0.2 //Μ; instance (7〇) 1·7 //Μ; instance (7p) 3.8 //Μ; instance (7q) 1·7 //Μ; Example (7r) 0.19 //Μ·4-[4-(Methanesulfonylmethyl)-6-moffinyl-methylene-glycidin-2-yl]aniline preparation In the following: 4-[4-(methyl hydrazinomethyl) _6• 福福 p 林-4-yl-, biti-2-yl] aniline

2-indolethio-4-(methyl sulfonylmethyl)&gt;6-moffolin _4_yl-n-m-m (n oo gram '3.3 millimolar), 4-aminophenyldihydroxy Borane (9〇4 mg, 6.60 mmol), 4 phen-2-carboxylic acid copper (1) (1.64 g, 8.58 mmol), Pd(PPh3)4 (153 mg '0.04 equivalent, 〇·ΐ3 Add to the microwave vessel and add 4 dioxane (20 ml). The system was degassed with n2, sealed, and heated in a microwave reaction for 1 hour at 130 ° C. The title compound was obtained as an off-white solid (988 mg). LCMS spectrum: MH+ 349.41, retention time ι·43, method. : Monitoring acid NMR spectrum·· 1 η NMR (300.132 MHz, DMSO) accounted for 3.20 (3Η, s), 3.61-3.83 (8Η, m), 4·43 (2Η, s), 5.57 (1Η, s)5 6.60 (2Η,d),6·70 (1Η,s),8.04 (2Η,d) 2-Methylthio-4-(nonylsulfonylmethylmorpholine_4_yl-pyrimidine 123642 -180- 200817384

It was heated in the chlorinated scale (0 ml) for about i hours. Evaporation and emulsification is light, and the residue is extracted with sodium hydroxide solution, and extracted in the acid acetamate, and then the resulting mixture is dehydrated and dried by sulfuric acid, and the crude is obtained by considering the sub-reading to the dry wine. Chlorine based product. Then, dissolve it

In DCM, morpholine (319 mmol, 28 mL) was added and the reaction was stirred at room temperature Q. The filtrate was concentrated to provide more solids and the combined yield was η·? g. NMR spectrum: 1H NMR (300.132 MHz, DMS 〇) occupies 2 45 (s, 3 Η), 3 classes % (m, 8H), 4.37 (s, 2H), 6.66 (s, 1H) ppm. LCMS spectrum: MH+ 304.50 , residence time 149 minutes, method: monitoring alkaline 2-methylthio-6- (anthracene methyl) shouting ice alcohol, five \ make 6-(gasmethyl)-2-methylthio- Phenidyl alcohol (19.07 g, 1 mmol) was suspended in acetonitrile (400 mL). To this stirred suspension was added sodium methanesulfinate (12.255 g, 120 mmol) and DMF (1 mL). The reaction was then heated to 1 (9) C&apos; to obtain a dark suspension and monitored by lcms. Upon completion, the solvent was removed and the product formed was taken in EtOAc:EtOAc (EtOAc) The precipitate formed was collected from EtOAc EtOAc (EtOAc) (EtOAc). NMR spectrum: iH NMR (300.132 MHz, DMSO) 5 2.50 (s, 3H), 3_12 (s5 3H), 4.39 (s, 2H), 6.25 (s, 1H), 13·09 (s, 1H) ppm·LCMS Spectrum: MH+ 235.2, retention time 〇·5 minutes, method: 5 minutes early detection of 6-(gasmethyl)·2-methylthio-pyrimidine-4-alcohol

S-Methyl-2-thioisourea sulfate (20 g, 71.85 mmol), 4-chloroacetic acid ethyl acetate (10.755 ml, 79.04 mmol) and sodium carbonate (13.925 g, 107.78) Monomolar) was dissolved in water (1 mL) and stirred at room temperature overnight. The reactants were monitored by TLC, and once completed, the reaction precipitate was collected, and the supernatant was neutralized with 6 Torr of hydrochloric acid to give a more reaction precipitate which was also collected. The accumulated precipitate was then washed with water (x3) and a gray solid was obtained. Let it be at 60 in a vacuum. (: Drying for 48 hours to give the desired compound as a pale yellow/white solid, 43.2 g. NMR spectrum: 4 NMR (300.132 MHz, CDC13) δ 2.59 (s, 3H), 4.35 (s 2 Η), 6.41 ( s,1Η), 12.70 (s,1Η) ppm. Mass spectrometry: M+190. 4-[4-(methyl sulphatemethyl)-6-moffin-4-yl dimethyl-2-yl] aniline It can be prepared from 2,4-dioxa-6-(nonylsulfonylmethyl)pyrimidine as described below. 4-[4-(Methanesulfonylmethyl)-6-morpholine-4-yl - shouting pyridine-2·yl] aniline 123642 -182- 200817384

2-Chloro-4-(methylsulfonylmethyl)-6-ifosin-4-yl-pyrimidine (5 g, 17.1 mmol) was dissolved in DMF: DME: water: ethanol (16.5 ml· · 41 ml: 18 ml: 12 ml) in a mixture. Add 4-(4,4,5,5-tetramethyl-anthracene, 3,2·dioxobicin-2-yl) strepamine (5.62 g '25.6 Amol), sodium carbonate 2 Μ aqueous solution ( 25 ml) and dichlorobis(triphenylphosphine) (600 mg), and the mixture was refluxed for 5 hours under a nitrogen atmosphere. The mixture was allowed to cool, diluted with water and extracted in dcm. The organic layer was dried over Na2SO4, filtered and evaporated. The crude material was dissolved in a minimum amount of hot DCM, then hexanes were added and the precipitate was filtered to give the desired material (1.6 g). LCMS spectroscopy: ΜΗ + 349, retention time 1.48 min. Method: NMR NMR spectroscopy iH NMR (4 〇〇 _ 13 MHz, DMSO-d6) 5 3.20 (3 Η, s), 3.67-3.72 (8H, m), 4.43 (2H,s)5 5.55-5.56 (2H,m)5 6.59 (2H,d),6·70 (1H,s),8.03 (2H,d) 2-carbyl-4_(methylsulfonylmethyl) Winter porphyrin winter base-pyrimidine

A suspension of 2,4-digas·6-(methylsulfonylmethyl) sulfinium (10.56 g) in DCM (230 mL) was stirred magnetically (under nitrogen) and cooled to -5 °C. Triethylamine (6·78 house liter) was added, followed by dropwise addition of a solution of morphine (3.85 ml) in DCM (30 liters) to keep the reaction temperature below -5 °C. The reaction was allowed to stand under the chamber for 1 hour and then the organic mixture was washed with water (300 mL). The organic phase of 123642 -183 - 200817384 was dehydrated and dried (MgSCXO, filtered, and evaporated to a brown solid, which was chromatographed on silica gel eluting with 50% ethyl acetate in DCM to give the desired material (6.81 g). 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) mass spectrum: MH+ 292. Example 8: 3_cyclopropyl_l-[4_[4-(methyl hydrazinomethyl)·6-fofolin_4_yl-ton bite_ 2_基】Benzyl]urea 0 Η Η Ν-[4-[4-(methylsulfonylmethyl) each phenoline winter base "Mididine-2-yl]phenyl] carbamic acid benzene Ester (94 mg, 0.2 mmol), cyclopropylamine (〇〇69 mL, i 耄mole) and triethylamine (0.090 mL, 〇 _65 mmol) in nm (1_2 mL) /Cellate, heated at 50-70 C for 2 hours. Then, the mixture was directly purified using preparative HPLC (monitoring basic method) to give the desired material. LCMS spectrum: MH+ 432, retention time 2.42 minutes Method Basics The following compounds are dissolved in a similar manner using either hydrazine or DMF. , from the desired phenyl carbamate and the appropriate amine. 123642 -184- 200817384 Example structure name LCMS MH+ retention time (minutes) Note 8a 〔:〕 Η H 1-[4-[4-(methylsulfonyl) Methyl)-6-morphine-3-indolyl-n-butyl-2-yl]phenyl]-3-second-butyl- earning 448 2.82 8b 0 〇v Η H N-[2_[[4 -[4-(Methanesulfonylmethyl)-6-morphine-4-yl-Salt-2-yl]phenyl]aminodecylamino]ethyl]acetamide 478 2.24 8c 0 〇, Λ~Ν, 1-(2-dimethylaminoethyl)-1-methyl_3-[4-[4-(methylsulfonylmethyl)-6-? _基密σ定-2-yl]phenyl]urea 478 2.6 8d 0 ,SPJ0^ 0 4 people!φ 3-(1Η-imidazol-2-ylindenyl)-1-[4-[4-(甲石石酿基基)-6-, or 4-amino]phenyl]urea 472 2.11 8e 〔:〕 Η 1 1-3⁄4 propyl-1-methyl-3- [4-[4·(Methanesulfonylmethyl)-6-?-fusin-4-indolyl]. dimethyl-2-yl]phenyl]urea 446 2.45 123642 -185 - 200817384 Example structure name LCMS MH+ Residence time (minutes) Note 8f. U-R Η Η 1 l-[4-[4-[(3S)-3-Mercaptophyrin-4-yl]-6-(A S& Methyl Group&gt; -yl]phenyl]-3-(2-methylpropyl)urea 462 2.84 8g Cx l-[3-[4-[(3S)-3-indolyl-norfos-4-yl]-6- (M-acid acid methyl)pyrimidin-2-yl]phenyl]-3-propan-2-yl-urea 448 1.71 Purified by decyl alcohol for 8 h [乂3-ethyl-1-[3-[4_ [(3S)-3-Methylmorpholine-4-yl]-6- (methanesulfonylmethylidene 17-but-2-yl)phenyl]urea 434 1.71 purified from methanol by recrystallization 8i [ λ 〇〇itS Η Η 1-[2-Chloro-4-[4_[(3S)-3-methyl] § p-lin_4-yl^]-6_(methylsulfonylmethyl)pyrimidine- 2-yl]phenyl]-3-ethyl-urea 468 1.78 8j 〔°Λ 〇〇itS Η Η 3-methyl-l-[2-methyl-4-[4-[(3S)-3- Methylwfolin-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl]phenyl]urea 434 1.28 Example 8g: iHNMR (400·13 MHz, DMSO-d6) 5 1.11 ( d,6H),1·26 (d,3H), 123642 -186 - 200817384 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 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 Γ (t, 1H), 8.55 (s, 1H) Example 8i: 1H NMR (400.13 MHz, DMSO-d6) 5 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 (d5 1H), 4·46 (s, 1H), 4.50 (s, 2H), 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) 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), 3.22-3.2 6 (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) Test (a): Example (8) 0.031 //M ; instance (8a) 0.47 //M ; instance (8b) 0.42 // M ; instance (8c) 2.2 //M ; instance (8d) 0.57 //M ; instance (8e) 0·28 // M; example (8f) 0.3 //M; instance (8g) 0.96 /zM; instance (8h) 0.92 //M; instance (8i) 1.4 //M; instance (8j) 0·16 //M. N- The preparation of [4-[4-(methylsulfonylmethyl))isofur-4-yl-pyridin-2-yl]phenyl]carbamic acid phenyl ester is described below. 123642 •187- 200817384 N-[4-[4-(Methylsulfonylmethyl)_6_morpholine_4_yl-pyridin-2-yl]phenyl]amino phenyl methacrylate

Phenyl phthalate (1.33 ml, 10.6 mmol) was added to sodium bicarbonate (1.34 g, 15.9 mmol) and 4_[4_(methylsulfonylmethyl) under 〇5艽Morpholine-4-yl-n-pyridin-2-yl]aniline (3.7 g, 1 〇 6 mmol) in a mixture of dioxane (15 liters). The reaction was stirred at room temperature for 3 h, evaporated and then taken in DCM. The organic mixture was washed with water, dried <RTI ID=0.0>(~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ LCMS spectrum MH+ 470, retention time 2.18, Method: NMR spectroscopy 1H NMR (400.13 MHz, DMSO_d6) (5 3·22 (3H, s), 3·58 (4H, s), 3.73 (4H, s), 4·50 (2H, s), 6·88 (1H, s), 7·24·7·30 (3H, m), 7·43-7·47 (2H, m), 7·63 (2H, d), 8·30 (2H, d), 10.45 (1H, S). The following phenyl carbamates were prepared in a similar manner from the appropriate aniline. Structural name LCMS MH+ retention time (minutes) NMR lU NMR (400.13 MHz) , DMSO-d6) [λ N-[4-[4-[(3S)-3-indolyl oxifen-4-yl] each (methanesulfonylmethyl) oxa-2-yl]phenyl Phenyl phenyl ester 483 2.37 123642 -188- 200817384

ί % structure

The above-mentioned desired name is LCMS MH+. The time between hours of N-[3-[4-[(3S)-3-indolyl-4-indolyl]-6-(methylsulfonylmethyl)pyrimidine Benzyl-2-phenyl]phenylcarbamate N-[2-Chloro-4-[4-[(3S)-3-methylindolin-4-yl]-6-(methylsulfonate) Phenylmethyl)pyrimidin-2-yl]phenyl]carbamic acid phenyl ester N-[2-methyl-4-[4-[(3S)-3-methylphenoflavin-4-yl]- Phenyl 6-(nonylsulfonylmethyl)pyrimidin-2-yl]phenyl]carbamic acid 482 517 496 2.36 2.40 NMR 1H NMR (400.13 MHz, DMSO-d6) δ 1.26 (d5 3Η)5 3.23 (s , 3Η), 3.21-3.29 (m, 1H), 3.49-3.54 (m, 1H), 3.58 (s, 1H), 3.64-3.68 (m, 1H), 3.79 (d, 1H), 3.98-4.06 (m , 1H), 4.19 (d, 1H), 4.53 (s, 2H), 6.87 (s5 1H), 7.23-7.31 (m, 2H), 7.42 (d, 1H), 7·44_7·47 (m, 2H) , 7.61-7.66 (m,1H), 7.71 (d,1H),8.02-8.05 (m, 1H), 8.50 (t,1H), 10.36 (s,1H)_ 5 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 (m5 2H)5 7.42-7.45 (m,2H), 7.84 (d,1H), 8.29-8.31 (m, 1H), 8.39 (d,1H), 9_83 (s, 1H) 1.61 Preparation of aniline is described in the previous paragraph 123642 -189- 200817384 Example 9: l-[4-[4-[(3S)-3-methylmorpholine_4_yl]_6_(C _2_ sulfamoylmethyl)pyrimidine-2-yl]phenyl]_3_phenyl-urea

L-[4-[4-[(3S)-3-Mercaptophyrin-4-4-yl]-6-(propan-2-ylthiomethyl) is thiophene-2-yl]phenyl] -3-Phenyl-urea (78 mg) was dissolved in 1,4-dioxane (6 mL) and water (1 mL). The solution was allowed to cool to 〇 ° C and 3- methoxyperoxybenzoic acid (75%) (34 mg) was added followed by sodium permanganate (4 mM). The reaction was stirred at room temperature for 2 hours. The reaction was loaded onto an SCx_2 column, the column was washed with methanol, and the desired material was dissolved in 7N ammonia in methanol. The fractions were concentrated in vacuo to give the desired crystals crystals crystals. NMR spectrum: 1 H NMR (399.9 MHz, DMSO-d6) 5 1·25 (3H, d), 1.31-1.38 (6 Η, m), 3.18-3.24 (1 Η, m), 3.48-3.58 (2 Η, m) , 3.64-3.68 (1Η, 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) mass spectrum; M+H+510. Test (8): 0.59 //M. l-[4-[4-[(3S) -3-methylmorpholine-4-yl]-6-(propan-2-ylthiomethyl)pyrimidin-2-yl]phenyl]-3_phenyl-urea 123642 -190- 200817384

Isopropyl mercaptan (0.075 ml) was dissolved in acetonitrile (5 ml) and nitrogen bicyclo[5_4.0] eleven-7-dish (0.12^:l). The reaction was stirred at room temperature for 1 min, then l-[4-[4-[(3S)_3-methylmorpholine-4-yl]-6- (-) in acetonitrile (5 mL) Sulfomethyloxymethyl) cyano-2-yl]phenyl] phenyl]urea (228 mg). The reaction was stirred for 30 minutes and then concentrated in vacuo. The residue was chromatographed on EtOAc (EtOAc) elute Mass spectrometry; M+H+478. l_[4-[4-[(3S)_3-methylhoffene _4_yl]-6-(methyl hydrazinyloxymethyl), _2 base] Phenyl]-3-phenyl-urea

1-[4-[4-(Rosin to methyl)_6_[(3S)-3-methylphenoline p-linyl-4-yl]u 唆2·yl]phenyl]-3-phenyl - Urea (388 mg) was dissolved in DCM (15 mL) and triethylamine ( 194 mL). Add chlorinated sulfonium sulfonate (〇1〇8 ml), and the reaction was stirred at TC for 90 min. The reaction mixture was concentrated in vacuo and taken between DCM (20 mL) and water (1 mL) The organic phase was washed with brine (10 ml), dried (MgSO.sub.4), and concentrated in vacuo to give the desired compound (273 mg) as solid. 1-[4-[4 -(Methyl)-6-[(3S)-3-methylphenothonine)] phenyl 123642 -191 - 200817384 The preparation of 3-phenyl J urine is described above. Example 10: Kifufosin-4_yl]pyrimidin-2-yl]phenyl]«[Mountain 3-[4-[4-(methyl)-6-丨dimethyl-[N]vf

3-(4-Bromophenylhydrazinium) dimethyl ketone (825 mg), acetic acid unloaded (tetra) imaginary and bis(pinyl)diboron (10) g) dissolved in dioxane (45 ml) in. The solution was degassed for 5 minutes 'then' then added u, bis(diphenylphosphino)dicyclopentadienyldichloro-(π)dichloromethane adduct (167 mg) and the reaction was heated to 85 ° C, after 3 hours. Add [2_Chloryl sulphate methyl phloem]. Bite-4-yl]methanol (828 mg), ethanol (3.75 ml), 2M sodium carbonate solution (8.53 ml) and 1,1'-bis(diphenylphosphino)dicyclopentadienyl iron Chloro palladium (9) a gas-gas calcined adduct (167 house grams), and continued to heat for 6 hours. The reaction was cooled and evaporated to dryness eluting EtOAcqqqqqqq The organic material was dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was chromatographed on EtOAc (EtOAc) elute NMR spectrum: 4 NMR (DMSO-d6) 5 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)5 3.96-4.00 (1H5 m)? 4.18 (1H5 d)5 4.45-4.50 (3H? m)5 5.38 (1H? t)? 6.66 (13⁄4 s), 7.55-7.59 (2H, m), 8.18-8.22 (2H, m), 8·45 (1H, s) 123642 -192- 200817384 Mass Spectrometry; M+H+372· Test (a): 19 The preparation of 3-(4-bromophenyl)-1,1-dimethyl-urea is described below. 3-(4-bromophenyldimethyl-monthly urine

4-Bromophenyl isocyanate (1 gram) was dissolved in THF (30 mL). Dimethylamine (2.0 M in THF, 2.78 mL) was added to the solution and the mixture was stirred at room temperature for 2 hr. The reaction was filtered, EtOAc (EtOAc m. NMR spectroscopy · 4 NMR (DMSO-d6) 5 2.90 (6H, s), 7.37-7.40 (2H, m), 7.45-7.47 (2H, m), 8.37 (1H, s) mass spectrum; M+H+244. Example 11: N-[2_[[6-[(3S)-3-indolyl porphyrin _4_ kib 2 (aniline carbylamino) phenyl] (; pyrimidine winter base) Acetylamine

Making N-[2-[[6-[(3S)-3-methylmorpholinyl][Winter (aniline carbylamino)phenyl]pyrimidinyl]methylthio]ethyl] acetamidine Amine (1 mg) dissolved in hydrazine, 4 dioxin

123642 • 193 - 200817384 g). The reaction was stirred at room temperature for 2 hours. Additional 3 - chloroperbenzoic acid (4 oz) and sodium permanganate (4 mg) were added and the reaction was stirred for an additional hour. The reaction was loaded onto an SCX-2 column, washed with methanol, and the desired material was removed with 7N ammonia in methanol. The substance to be isolated is white solid (102 mg). NMR^If : ^NMRCDMSO^) 5 1.25 (3H5 d)5 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), f 3.79 (1H? d)5 3.98-4.01 (1H? m)5 4.18 (1H? d)? 4.49 (1H5 s)5 4.53 (2H5 s)? 6.80 (1H' s)' 6'99 (1H,t),7.31 (2H,d),7.46-7.49 (2H,m)5 7.57 (2H,d), 8.16 (1H,t) , 8.27 (2H, d), 8.70 (1H, s), 8.92 (1H, s) mass spectrometry; M+H+553. Test (a): 0.14 //M. N-[2-[[6- The preparation of [(3S)-3-methylmorpholine bucket base] (aniline-mercaptoamino)phenyl]-pyridin-4-yl]methylthio]ethyl]acetamide is described below. . N_[2_[[6_[(3S)_3-methylmorpholine-4-yl]_2_[4-(anilinecarbamimidino)phenyl]pyrimidine]methylthio]ethyl]ethyl hydrazine amine

N-Ethyl cysteamine (86 ml in acetonitrile) was dissolved in acetonitrile. Then, DBU ((20 ml) was added to the solution and it was stirred at room temperature for 15 minutes. Each methyl methionine in the acetonitrile (5 ml)]-heart (methanesulfonyloxy) Methyl)pyrimidin-2-yl]phenyl]_3_phenyl-urea (228 mg) was added to the reaction and stirred for 3 minutes. The reaction was concentrated in vacuo to give the crude material 123642-194-200817384 The residue was purified on EtOAc (EtOAc m.) The preparation of 3S)-3-methylmorpholine +yl]methyl(methylsulfonyloxyindenyl) cyano-2-yl]phenyl] phenyl-urea is described above. Example 12: 1 -[4-[4-(Benzene decylmethyl)_H(3S) each methylfofolin phenyl]pyrimidine:yl]phenyl]-3-phenyl-urea

L-[4-[4-[(3S)-3·Methylmorpholine-4-yl]-6-(phenylthiomethyl))-2-yl]phenyl]_3_benzene The base-urea (62 mg) was dissolved in 1, dioxin (6 ml) and water (1 ml). The solution was cooled to 0 ° C and 3-chloroperbenzoic acid (75%) (26 g) was added followed by sodium sulphate (30 mg). The reaction was stirred at room temperature for 2 hours, then additional 3- gas benzoic acid (4 mg) and sodium permanganate (4 mg). The reaction was stirred for an additional hour. Then, the reaction was loaded onto a column of SCX-2, washed with methanol, and the desired material was removed with 7N ammonia in methanol. The substance is isolated as a pale yellow solid (64 mg). NMR spectrum: 4 NMR (DMSO-d6) 5 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) 5 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 (lH, s). 123642 -195- 200817384 Mass spectrometry; M+H+544. Test (8): 0.23 //Μ. H4- The preparation of [4-[(3S)-3-methylphenoxy t4.yl)phenylphenylmethylpyrimidin-2-yl]phenyl K3-phenyl-urea is described below. 1 [4 [4 [(3S) 3 methylmafulin 4 base] winter (phenylthiomethyl(tetra) 7 |yl]phenyl]-3-phenyl-urea

The thiophenol (0.029 ml) was dissolved in acetonitrile (3 mL). Then, (0.043 ml) was added to the solution, which was stirred at room temperature for 15 minutes. 1-[4-[4_[(3S)_3_Methylfosfolinine] each (nonylsulfonyloxyindenyl) ridin-2-yl] phenyl]-3-phenyl^ (8 mg) was added to the reaction and stirred for 3 minutes. The reaction was concentrated in vacuo and EtOAc EtOAc m. : 3-[4-[4-(Cyanomethylsulfonylmethyl"-[(Kunylmethylmorpholine), bite_2_yl]phenyl]-1,1-dimethyl- Urea

3·[4_[4-(Cyanomethylthiomethyl)-6-[(3S)-3·methylmorpholine] is fed to -2-yl]phenyl]-l,l- Dimercapto-urea (162 mg) was dissolved in 1,4-dioxane (6 ml) 123642 - 196 - 200817384 with water (1 ml). The solution was cooled to 〇 ° C and 3-chloroperbenzoic acid (75%) (79 g) was added followed by sodium permanganate (10 mg). The reaction was stirred at room temperature for 2 hours. Additional 3- gas benzoic acid (4 mg) and sodium permanganate (45 mg) were added and the reaction was stirred for 1 hour. The reaction was loaded onto a SCX-2 column, washed with methanol, and the desired material was removed with a pad of ammonia in methanol. The substance to be isolated is a white solid (I? mg). NMR spectrum · 1H NMR (DMSad6) δ 1·25 (3Η,d)5 2.96 (6Η,s),3·18 (1Η, d)5 3.47-3.54 (1H? m)5 3.64-3.67 (1H, m ) 5 3.79 (1H5 d)5 3.98-4.01 (1H, m)? 4·17 (1H, s), 4·46 (1H, d), 4·74 (2H, s) 5 5.10 (2H, d) ,6·82 (1H,s), 7·59-7·61 (2H,m),8.21-8.23 (2H,m),8·49 (1H,s) mass spectrometry; M+H+459. Test (8) :2.1 3-[4-[4-(Cyanomethylthiomethyl)&gt;6_[(3S)_3_methylmorpholine]pyrimidinyl]phenyl]·1,1-dimethyl - Preparation of urea is described below. 3_[4·[4_(Cyanomethylthiomethyl)_6_[(3S)-3·methylmorpholine_4_yl]pyrimidin-2-yl]phenyl H4-dimethyl-urea

3-[4-[4-(石厌iminoiminothiomethyl)_6_[(3S)-3·methyl-ofoline-4-yl]-carboxylidene]phenyl]-1, 1-Dimethyl-urea (〇·38 mmol) was dissolved in DMF (2 mL). This was treated with bromoacetonitrile (0.030 mL) then EtOAc (EtOAc) (EtOAc) The reaction mixture was concentrated in vacuo, and the residue was applied to a column of SCX-2, eluted with the desired alcohol in the form of 123642-197-200817384, and the desired substance was removed with 7N ammonia in methanol' and used. There is no need for further chromatography. Mass spectrometry; M+H+427. 3 --(carbamoylimidothiomethyl) winter [(3 private methyl flufen _4· pyridine azide-2-yl) phenyl] _1,1 _Dimethyl-urea

To make 3 Yang (via methyl &gt; 6 _3_ 曱 吗 福 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ With triethylamine (〇〇79 ml), and the solution was cooled to (TC. Add chloromethyl sulfonate (_ml) and the mixture was stirred at room temperature for 15 min. Solvent and replace with ethanol (5 mL) followed by thiourea (32 mg then, then allowed to cool, and used without further purification to heat the reaction to 70 ° C for 30 minutes

Concentrate in a vacuum to obtain the desired substance. Mass spectrometry; M+H+430. Example 14: U-dimethyl·3·[4·[4·_·3·曱基富福" base] butterfly_2 base-branched methyl) mouth bite-2 -yl]phenyl]

The u-dimethyl group [Jiang ^ 123642 -198- 200817384 methyl)pyrimidinyl]phenyl]urea (163 mg) was dissolved in M-dioxane (6 ml) and water (1 ml). The solution was cooled to 〇t: and 3_chloroperbenzoic acid (75%) (79 mg) was added followed by sodium permanganate (92 mg). The reaction was stirred at room temperature for 2 hours, then additional chloroperbenzoic acid (2 oz) and sodium permanganate (25 mg) were added. The reaction was stirred for 1 hour, then loaded onto a SCX-2 column, washed with methanol, and the desired material was removed with a pad of ammonia in methanol. The desired substance (90 mg) was isolated as a white solid. NMR spectrum: 1H NMR (DMSO_d6) 25 (3H, d), i % heart 37 (6h, called 2.95 (6H? s) 5 3.21-3.26 (2H5 m)? 3.47-3.54 (2H5 m)5 3.64-3.67 ( 1H5 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)5 8.17-8.20 (2H,m),8·48 (1H,s) mass spectrum;M+H+462. Test (4):0.42 //M. l,l-dimethyl The preparation of each (propylidinothiomethyl)&lt;melidin-2-yl]phenyl]urea is described below. 1,1-Dimercapto-H4-[4-[ (3S)_3-methylmorpholine skyl b 6_(propyl: thiomethylmethyl)pyrimidin-2-yl]phenyl]urea

3-[4-[4-(Hydroxymethyl)-6-[(3S)-3-methylmorpholine + carbamicinyl]phenyl]], 1-dimethyl-urea (140 mg ) Dissolve in DCM (5 mL) and triethylamine (〇·〇 79 mL) and cool the solution to 0 °C. Add the sucrose sulphate (44 ml), and stir the reaction at room temperature for 15 minutes, then dilute in the vacuum 123642 -199-200817384 to obtain methane sulfonate, which is used. No further purification is required. Isopropyl mercaptan (0.062 ml) was dissolved in acetonitrile (5 mL). Next, DBU (〇〇99 ml) was added to the solution, and it was stirred at room temperature for 5 minutes. The crude methanesulfonate from the above was suspended in acetonitrile (5 ml) and added to the mercaptan solution. The reaction was left to stir at room temperature for 1 hour, then additional DBU (0.099 liters) was added and the mixture was stirred at room temperature for 3 min. The reaction mixture was concentrated in vacuo to give the desired material which was used without further purification. Mass spectrometry; M+H+430. Example 15: 3-[4-[4-(phenylsulfonylmethyl) winter [(3S) methyl methorphanyl winter) pyrimidine: phenyl] H, l -Dimethyl-urea

1,1-Dimercapto-3-[4_[4-[(3S)-3-methylmorpholine yl]_6_(phenylthiomethyl) &quot;melidin-2-yl]benzene The base urea (1% mg) was dissolved in 1,4- dioxin (ml) and water (1 ml). Allow the solution to cool to hydrazine. For example, 3-chloroperbenzoic acid (75%) (89 mg) was added followed by sodium catechol (96 mg). The reaction was stirred at room temperature for 16 hours and then additional 3 - chloroperbenzoic acid (2 mg) and sodium sulphate (25 mg) were added. The reaction was stirred for 1 hour, then loaded onto a scx.sub.2 column, washed with methanol, and the desired material was removed with 7N ammonia in methanol. The substance to be isolated is a white solid (9 mg). NMR spectrum: iHNMR (DMSO-d6) 5 1·20 (3H, d), 2.95 (6H, s), 3.13-3.20 123642 -200 - 200817384 (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 (2H,t),7.72-7.75 (1H,m),7·79-7·84 (4H,m), 8·43 (1H, s) mass spectrometry; M+H+496. Test (8): 1 //M. 1,1-dimethyl-3-[4-[4-[(3S)-3-indenyl] The preparation of the fullinyl-4-yl]-6-(phenylthiomethyl) hydrazin-2-yl]phenyl]urea is described below. 1,1-Dimethyl-3-[4_[4-[(3S)_3_methylmorpholine-4-yl]_6-(phenylthiomethyl)pyrimidin-2-yl]phenyl] Urea

The thiophenol (0.062 ml) was dissolved in acetonitrile (5 mL). Next, DBU (0.141 ml) was added to the solution, which was stirred at room temperature for 5 minutes. 1,1-Dimethyl-3-[4_[4_[(3S) each methylnorfosine bucket base]_6_(methylsulfonyloxyfluorenyl)&quot;MP2-yl]phenyl Urea (154 mg) was suspended in acetonitrile (5 mL) and added to the mercaptan. The reaction was allowed to stand at room temperature for 1 hour and then concentrated in vacuo to give the desired material which was used without further purification. Mass spectrometry; M+H+464. 1,1_Dimethyl_3_[4_[4-[(3S) each methylmorpholine·4_yl] winter (methylsulfonyloxymethyl)pyrimidine- 2-yl]phenyl]urea

123642 -201 - 200817384 3-(4-[4-(Methyl)&gt;6 side _3_methyl? '林冰基♦ 定定]Phenyl]-1,1: dimethyl-urea (384 mg Dissolve in (12 ml) and triethylamine (0.216 ml) and allow the solution to cool to 〇. A 7 ί 王 u U added methyl chloride sulfonate (0.121 ml)' and the reaction at room temperature Dissipate for 15 minutes, then concentrate in vacuo to give the desired material. Mass spectrum; M+H+450. Example 16: N-[2-[[2 (dimethylamine)]基卜6•叫3methyl 福福琳•4-基】 shouting pyridine-4_yl]methanesulfonyl]ethyl]acetamide

Making N-[2-[[2-[4-(dimethylaminecarbamimidino)phenyl]][(3S)_3_methylmorpholine]pyrimidinyl]methylthio] Ethyl]acetamide (158 mg) was dissolved in dioxin (6 ml) and water (1 ml). The solution was cooled to the hydrazine and added (3-chloroperbenzoic acid (75%) (116 mg) was added, then the mixture was stirred for 1 hour at room temperature for sodium permanganate (134 g) and then Charge to the scx-2 column, wash with methanol, and remove the desired material with the claw ammonia in methanol. Separate the desired material (84 mg) as a white solid. NMR Spectrum: ! η nmR _sad6) 25 (3H,d),i 83 (3H,s),2 % (6H, s), 3.20-3.25 (1H,m), 3.47-3.50 (1H,m),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) 5 8.16-8.19 (1H, m), 8·19-8·22 (2H, m), 8.49 (1H5 s) 123642 -202- 200817384 Mass Spectrometry; M+H+505. Test (8): 4 //Μ·乂[2-[[2-[4-(dimethylaminecarbamoylamino)phenyl]_6_[(3s) The preparation of _3·methylwufolin-4-yl]methylpyridin-4-yl]methylthio]ethyl]acetamide is described in the lower jaw-[2·[[2-[4-(dimethyl) Aminoguanidinoamino)phenyl1-6-[(38)methylphenofuran-4-yl] 唆4_yl 1 methylthio]ethyl]acetamide

Ν-Ethyl cysteamine (0.064 ml) was dissolved in acetonitrile (5 mL). DBU (0.141 liters) was then added to the solution and allowed to stir at room temperature for $5. 1,1-Methyl-3-[4-[4-[(3S)-3-indolyl porphyrin ice-based]-6-(methylsulfonyloxymethyl)pyrimidin-2-yl Phenyl]urea (154 mg) was suspended in acetonitrile (5 mL) and added to the mercaptan. The reaction was allowed to stand at room temperature for a few hours while stirring, and then concentrated in vacuo to give the desired material. Mass spectrometry; M+H+473. Example 17: 2-[[2-[4-(monomethylaminocarbamimidyl)phenyl]_6_[(3S)_3_methylmorpholine ice-based]pyrimidine -4·yl]methanesulfonyl]acetamide

2-[[2·[4-(monomethylaminocarbamimidyl)phenyl] each [(3s) each methyl kefa 123642 -203 - 200817384 porphyrin]pyrimidin-4-yl]A Thio[e]acetamide (158 mg) was dissolved in M-dioxane (6 mL) and water (1 mL). The solution was allowed to cool to dryness and chloroperbenzoic acid (75%) (123 mg) was added followed by sodium permanganate (143 mg). The reaction was stirred at room temperature for 1 hour, then loaded onto a scx.sub.2 column, washed with methanol, and the desired material was removed with 7N ammonia in methanol. The desired substance (55 mg) was obtained as a white solid. NMR spectrum: 1H NMR (DMSO-d6) 5 1.25 (3H, d)5 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 (2H5 s), 4.47 (1H,s),4·67 (2H,s),6 · 77 (1H, s), 7.53 (1H, s), 7·58·7·61 (2H, m), 7·79 (1H, s), 8.17-8.21 (2H, m), 8.49 (1H, s) mass spectrometry; M+H+477. Test (8): 1.1 //M. 2-[[2-[4-(monomethylaminocarbamimidyl)phenyl]_6-[(3S)-3- The preparation of methylwfolin-4_yl h-butyl-4-yl]methylthio]etheneamine is described below. 2_[丨2_丨4_(didecylaminodecylamino)phenyl winter [(3S) fluorenylmorpholinoyl]pyrimidin-4-yl]methylthio]acetamide

Benzyl-3_[4-[4-[(3S)-3-methylphenoflavin-4-yl]-6-(methylsulfonyloxyindolyl)&lt;melidin-2-yl] Phenyl]urea (154 mg) was dissolved in ethanol (5 ml) and thiourea (29 mg) was added. Then, the reaction was heated to 70 ° C for 30 minutes and then concentrated in vacuo. Dissolved in DMF (2 mL) and treated with 2-bromoethylamine (52 mg) then EtOAc (EtOAc EtOAc (EtOAc) Stir for 30 minutes at ambient temperature. Concentrate the reaction mixture in vacuo 'and then' onto the SCX-2 column, wash with methanol, and remove the desired material with 7N ammonia in methanol. Use the desired material without further purification Mass spectrometry; M+H+445. Example 18: 1-[4-[4-(sulfenyl)-6-[(3S)-3-methylmorpholine-4-yl]pyrimidin-2-yl Phenyl]methyl-urea

Dissolve 1-(4-bromophenyl)-indenyl-urea (2.5 g), potassium acetate (3.12 g) and bis(pinyl) diboron (3.33 g) in ι,4 - in dioxane (120 ml). The solution was degassed for 5 minutes, then a mixture of bis(diphenylphosphino)dicyclopentadienyldichloro Ib (II) dichloromethane adduct (535 mg) was added and the reaction was heated to 9〇. Hey, it took 3 hours. Additional u'-bis(diphenylphosphino)dicyclopentadienyl iron dichloride (II) dichloromethane adduct (25 mg) was added and heating was continued for an additional hour. Add [2-Chloro-6-[(3S)_3-methylmorpho-4-yl], pyridine-4-yl]methanol (2.66 mg), ethanol (9.5 ml), 2M sodium carbonate solution (27.3 ML) and 1, bis-bis(diphenylphosphino)dicyclopentadienyl iron dichloropalladium (9) dichloromethane adduct (535 mg)' and heating was continued for 16 hours. The reaction was allowed to cool and evaporated to dryness. EtOAc m. The organic material was dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was chromatographed eluted EtOAc EtOAc EtOAc EtOAc NMR spectrum: 4 NMR (DMSO-d6) 5 1·23 (3H,d), 2·66 (3H,d)5 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) mass spectrometry; M+H+358. Test (a): 0.12 //M. Preparation of 1-(4-bromophenyl)-3-methyl-urea is described below . 1-(4-bromophenyl)-3-methyl-urea

4-Bromophenyl isocyanate (2.50 g) was dissolved in THF (75 mL). The indoleamine (2.0 Torr in THF) was added to the solution and stirred at room temperature for 1 hour. The reaction was filtered and vacuumed to dryness. The crude material was chromatographed on EtOAc (EtOAc) elute NMR spectrum: 1H NMR (DMSO-d6) 5 2.64 (3Η,d),6·03 (1Η,d),7·37 (4Η, s), 8.61 (1H, s) mass spectrum; M+H+229. Example 19: l-[4-[4-(cyclohexyl-decylmethyl)-6_[(3s)-3_indolyl whiffin ice base] mouth bite_2_yl]phenyl]-3_A Base-pulse 123642 -206 - 200817384

H4-[wood (cyclohexylthioguanidino)_6_[(3S) each methyl morpholine bucket base]. The phenyl]I-methylurea (〇·35 mmol) was dissolved in 154-dioxane (5 ml) and water (1 ml). To the solution was added 3-chloroperbenzoic acid (75%) (121 mg), followed immediately by sodium permanganate (14 mg), and the reaction was stirred at room temperature for 1 hour. Additional 3-chloroperbenzoic acid (75%) (121 mg) and sodium permanganate (140 mg) were added and the reaction was stirred at room temperature for a few hours. Additional 3-chloroperbenzoic acid (75%) (121 mg) and sodium permanganate (14 mg) were added and the reaction was stirred at room temperature for an additional 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 preparative HPLC (basic) to give the desired material (74 mg) as white solid. Surface spectrum A NMR _Sad6) (7H, m), 142 (1H, do (^48 d), 1.68 (1H, d), 1.89 (2H, d), 2.25 (3H, d)5 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)5 6.08 (1H, t), 6.77 (1H, s), 7.50-7.52 (2H,m)5 8.19-8.21 (2H,m) mass spectrometry; M+H+488. Prepared in a similar manner from the appropriate sulfide. 123642 -207. 200817384 Example 19a Structure name 1·[4-[4-(phenylsulfonylmethyl)_6_[(3S)-3-methylmorpholine bucket base] Pyrimidin-2-yl]phenyl]-3-methyl-urea LCMS MH+ 482 19b [Into 1-[4-[4-[(4-fluorophenyl)sulfonylmethyl]-6-[(3S )-3-methylmorpholine-4-yl]pyrimidin-2-yl]phenyl] •3-methyl-June 500 19c 〇,

Further N-[4-[[2-[4-(methylamine-carbamoylamino)phenyl]-6-[(3S)-3-methylphenoline p--4-yl] 4-yl]methanesulfonyl]phenyl]acetamide 539 19d 〔

3-methylsuccinyl [4-[4-[(3S)-3-methylindolin-4-yl]-6-(propan-2-ylglyphthyridylmethyl)pyrimidin-2-yl]phenyl ]urea 448 19e

[N]~°CsUiX 1-[4-[4-(2-Ethyl-xanthionylmethyl)-6-[(3S)-3-methylphenoxyp-lin-4-yl]- 2-yl]phenyl]-3-indenyl-urea 450 19f 〇[A!ΪΑα(fork 3-methyl small [4-[4-[(3S)-3_methyl? ]-6-(ρ 比σ定-4-ylsulfonylhydrazino)pyrimidin-2-yl]phenyl]urea 483 Example 19a: 4 NMR (DMSO-d6) δ 1·18 (3Η,d)5 2·66 (3Η,q),3.11-3.19 (1H,m),3.43-3.50 (1H,m), 3.60-3.63 (1H,m)5 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 19b: 4 NMR ( DMSO-d6) δ 1_20 (3H,d)5 2.66 (3H5 d),3.14-3.21 123642 -208 - 200817384 (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)5 7.43-7.48 (2H,m),7.77-7.80 (2H,m),7.85-7.89 (2H, m),8.71 ( 1H, s) Example 19c: iH NMR (DMSO-d6) δ 1·18 (3H, d), 2.13 (3H, s) 5 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 (2H, d), 7.82 (2H, d), 8.68 (1H, s), 10.37 (1H, s) Example 19d: iH NMR (DMSO-d6) 5 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 (2H5 m)? 8.17-8.19 (2H, m)? 8.73 (1H, s) Example 19e: NMR (DMSO-d6) 5 1.24 (3H,d),2·66 (2H,s)5 2· 68 (2H, q), 3.21-3.26 (1H, m), 3.51 (3H, t), 3.63-3.67 (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) Example 19f: iH NMR (DMSO-d6) 5 1.20-1.25 (3H,m),2·6 6 (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) Test (a): Example (19) 0.25 //M; instance (19a) 0.0047 //M; instance (19b) 0.033 //M; instance (19c) 0.022 //M; instance (19d) 0.066 //M; instance (19e) 0.011 /iM ; instance ( 19f) 0.027 /iM. 123642 -209- 200817384 1-[4-[4-(cyclohexylthiomethyl&gt;6 side _3_methylpheno 4 ·4·yl]] rididine ·2·yl] The preparation of phenyl]-3-methyl-urea is described below. Η4-[4-(cyclohexylthiomethyl)_6[called 3_methyl 福福] 林冰基(四)咬_2·基】 phenyl]-3-methyl-urea

Cyclohexanethiol (0.61 mmol) was dissolved in acetonitrile (4 mL). Then DBU (0.050 liters) was added and the solution was stirred at room temperature for 5 minutes. 3_Methyl-H4-[4-[(3S)-3·methylmorpholine yl]_6_(oxasulfonyloxymethyl sulphon-2-yl)phenyl]urea (151 mg) This was dissolved in acetonitrile (2 mL), EtOAc (EtOAc)EtOAc. The following sulfides were prepared in a similar manner from 3-mercapto[4-[4_[(3S)_3-methylmorpholine-4-yl]-6-(methylsulfonyloxymethyl) ethidine -2_yl]phenyl and the appropriate thiol. Structural name Cx 〇rs々aNV Η Η 3-methyl_l-[4-[4-[(3S)-3-methylmorpholine ice-based] -6-(phenylthiomethyl)pyrimidin-2-yl]phenyl]urea&quot; 1 FjasJ^Nv Η Η 1-[4-[4-[(4-fluorophenyl)thiomethyl] i|X3S&gt;3-Methylphenoline-4-yl]ϋ密唆-2-yl]phenyl]_3_methyl-moon urine 123642 -210- 200817384 Structure name 0„ vrAxv Η Η Η Ν-[ 4-[[2-[4-(methylaminocarbamimidyl)phenyl]][(3S)-3-methylinfos-4-yl]-pyridinyl]methylthio]benzene Acetylamine [λ 丫Αχν Η 甲基 methyl-l-[4-[4-[(3S)-3-methyl holphaline·4_ ]_ 6-(propan-2-ylthiomethyl)pyrimidin-2-yl]phenyl]urea 0 〇 1-[4-[4-(2-hydroxyethylthiomethyl)-6- [(3S)-3-methylphenoflavin-4-yl]η唆唆-2-yl]phenyl]_3_methyl-urea 0;, Η Η 3-methyl-l-[4-[4 -[(3S)-3-methylphenoflavin-4_yl]_6-(pyridin-4-ylthiomethyl)pyrimidin-2-yl-1-yl]urea 3-methyl-l-[4- [4-[(3S)_3-Methylmorpholine)] The preparation of each (methanesulfonyloxymethyl)&gt;mididin-2-yl]phenyl]urea is described below. -H4_[4-[(3S)_3·methylmorpholine-4 base] winter (methanesulfonyloxymethyl)pyrimidin-2-yl]phenyl]urea

Partially dissolve H4-[4-(methyl)-6-[(3S&gt;3-methylmorpholine)-phenyl-pyridyl]phenyl]-3-methyl-urea (1.24 g) In DCM (3 mL) and triethylamine (1)· 724 mL), the solution was cooled to crc. Methane chloride sulfonium chloride (〇4〇5 ml) was added, and the reaction was stirred at room temperature for 15 minutes and then concentrated in vacuo to give the desired material. Mass spectrometry; M+H+436. 123642-211 . 200817384 Example 20: 3-[4-[4-(phenylsulfonylmethyl)-6·morphine-porphyrin-pyrimyl-2-yl]phenyl] Methyl

Dissolve (4_{4-morpholine_4_yl[(phenylsulfonyl)indolyl]pyrimidin-2-yl}phenyl)carbamic acid phenyl ester (250 mg, 〇·45 mmol) In DMF (5 ml). Add (and add triethylamine (0.188 ml, 1.35 mmol) followed by methylamine (2 Μ in THF < 1.1 mL) and heat the solution at 50 ° C for one hour. The oil was concentrated in vacuo, and the obtained oil was purified by chromatography eluting eluting eluting eluting eluting eluting eluting NMR (400.13 MHz, DMSO-d6) 5 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) i LCMS spectrum: MH+ 468, retention time 1.76 Minutes, method 5 minutes The compound shown in the base table is similar to hydrazine, _(4·{4_?Fofosine)[[phenylsulfonyl)methyl]pyrimidin-2-yl}phenyl)urea By way of reaction, the appropriate amine is reacted with the appropriate urethane and purified by chromatography on either tannin or by preparative HPLC. 123642 • 212- 200817384 Example Structure Name LCMS MH+ Residence Time (minutes ) 20a 0 0 0 σ 乂人' Η Η 3-[4-[ 4-(Benzenesulfonyl)-6-Rhofolin-4-:^ _ 笛 σ定-2-yl]phenyl]-1 -ethyl-urea 482 1.98 20b 0 0 0 jTS 〇rs' N, human Η Η 1-[4-[4-(phenylphosphinylmethyl)-6-?-fusin^lin-4-yl-.-mididin-2-yl]phenyl]-3-cyclopropane Base-urea 494 1.92 20c 0 o^W, Η Η 3-[4-[4-(phenylsulfonylmethyl)-6-formin. Lin-4-yl-σ-mididin-2-yl]benzene ]]-1-(2-dimethylaminoethyl) urinary 525 1.98 20d 0 Η Η 3-[4-[4-(phenylsulfonylmethyl)-6-ifu^lin-4-yl -3⁄4 pyridine-2-yl]phenyl]-1-(1-methyl-4-six-speaking sigma) monthly urine 551 1.93 20e Ο σ^Νχ/ Η Η 3-[4-[4-(benzene Sulfomethyl)-6-?? 1(2林-4_基-3⁄4 σ定-2-yl]phenyl]-1-(2-methoxyethyl)urea 512 1.77 20f σΊν Η Η 3-[4-[4-(Benzenesulfonylmethyl)-6-[(3S)-3-methylphenofyl-4_yl]σ密ϋ定-2-yl]phenyl]-1- Ethyl·monthly 496 2.06 2〇g α as〇AD.N^ Η Η 1-[4-[4-(phenylsulfonylmethyl)_6-[(3S&gt;3-methylorfo 4 -4 -base].唆-2-yl] phenyl]-3-3⁄4 propyl _ month urine 508 2.08 20h CX αν々α//, Η Η 1-[4-[4-(phenylsulfonyl fluorenyl)-6- [(3S)-3-Methylnorfos-4-yl]Nandidin-2-yl]phenyl]-3-(2-dimethylaminoethyl)urea 539 1.94 123642 -213 - 200817384 Examples Structure name LCMS ΜΗ+ Residence time (minutes) 20i 0, c^Aa Person; a Η H 1-[4-[4·(Benzene benzyl)-6-[(3S)-3-methyl? Fulin-4-based]. Cyclodecyl-2-yl]phenyl]-3-(1-methyl-4-hexahydropyridyl)urea 565 1.94 2〇j Cx Η H 1_[4-[4-(phenylsulfonylmethyl) )-6-[(3S)-3-methylphenoline p--4-yl]-indolyl-2-yl]phenyl]-3-(2-methoxyethyl) vein 526 1.98 20k 0 Η H 3 ·Methyl-1-[4·[4-?? 4-4-yl-6-(propan-2-ylglycolylmethyl) guanidine-2-yl]phenyl]urea 434 1.47 201 〔:〕 Η H 1-ethyl-3-[4-[4-?-fusin-4-yl-6-(propan-2-ylsulfonylmethyl) ♦ 11-yl-2-yl ]Phenyl]urea 448 1.61 20m 0 for human Η Η 3-3⁄4 propyl- l-[4-[4-morpholine-4-yl-6-(propan-2-ylsulfonylmethyl)pyrimidine -2-yl]phenyl]urea 460 1.63 20n [:] , Αχ / / Η Η 3-(2-dimethylaminoethyl) -1_[4-[4-??|1 Lin-4-yl -6-(propan-2-ylmethylmethyl)XJ sigma-2-yl]phenyl]urea 491 1.59 20o 0 乂人xr Η Η 3-(1-methyl-4-six rats °定基)-1-[4-[4-?福17林-4·yl-6-(propan-2-yl-bromomethyl)11-succinyl-2-yl]phenyl]urea 517 1.61 123642 -214- 200817384 Example structure name LCMS MH+ retention time (minutes) 20p 0 Η Η 3-(2-methoxyethyl -1_ [4-[4-moffin-4-yl-6-(propan-2-ylsulfonylmethyl)pyrimidin-2-yl]phenyl]urea 478 1.53 20q 0, Η Η 1-B 3-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(propan-2-ylsulfonylmethyl)pyrimidin-2-yl]phenyl ]urea 462 1.75 20r 0. Η Η 3-cyclopropyl-l-[4-[4-[(3S) -3-indolyl-fufen-4-yl]-6-(propan-2-yl) Xanthoylmethyl) succinyl-2-yl]phenyl]urea 474 1.77 20s α Η Η 3-(2-dimethylaminoethyl) _l-[4-[4-[(3S)- 3-methyl phloem. Lin-4-yl]-6-(propan-2-ylsulfonylhydrazino)pyrimidin-2-yl]phenyl]urea 505 1.76 20t [乂Η Η l-[4-[4_[(3S)- 3-methylfosfosyl-4-xy-4-yl]-6-(propan-2-ylsulfonylmethyl)pyrimidin-2-yl]phenyl]-3-(1-indolyl-4-hexahydro) Pyridyl) urinary 531 1.77 20u θ',, for human / Η Η 3-(2-methoxyethyl)-1-[4-[4-[(3S)-3-methylorfolin p 4-yl]-6-(propan-2-ylglycosylmethyl)pyrimidin-2-yl]phenyl]urea 492 1.67 Example 20a: iH NMR (400.13 MHz, DMSO-d6) 5 1·00 (t, 3H), 3.05 (m, 2H), 3.56 (s, 4H), 3·63 (m5 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) 123642 -215 - 200817384 Example 20b: iH NMR (400.13 MHz, DMSO-d6) (5 0·42 (m, 2H), 0·65 (m, 2H), 2.55 (m, 1H), 3.64 (m, 4H), 3·71 (m, 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 20c: 1H NMR (400.13 MHz, DMSO-d6) 6 2.20 (s, 6H), 2.38 (t, 2H), 3.20 (m, 2H), 3.63 (s , 4H), 3.70 (s, 4H), 4.69 (s5 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 20d: iH NMR (400.13 MHz, DMSO-d6) 5 1.49 (m, 2H), 1.86 (m, f &gt; 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 (m, 3H), 8.76 (s, 1H) Example 20e: iH NMR (400.13 MHz, DMSO-d6 5 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 20f: 1H NMR ( 400.13 MHz, DMSO-d6) 5 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) Example 20g: iH NMR (400.13 MHz, DMSO-d6) 5 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 (s5 1H) Example 20h: iH NMR (400.13 MHz, DMSO-d6) 5 1·19 (d, 3H), 2.23 (s, 123642 -216 - 200817384 6H), 2.40 (t, 2H), 3.21 (m, 3H) , 3.47 (m, 1Η), 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 20i: 4 NMR (400.13 MHz, DMSO-d6) d U9 (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, ih), 4.08 (d, 1H), 4.35 (s, 1H), 4.6 9 (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 20j: iHNMR (400.13 MHz, DMSO-d6) δ 1.20 (d,3H)5 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 20k: NMR (400_13 MHz, DMSO-d6) 5 l_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 201: 4 NMR (400.13 MHz, DMSO-d6) 5 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 (s5 1H), 7.51 (d, 2H), 8.18 (d, 2H), 8.68 (s, 1H) Example 20m: iH 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 (s5 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 20n: iH NMR (400.13 MHz, DMSO-d6) ά 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), 123642 -217- 200817384 6.56 (t, 1H), 6.83 (s, 1H), 7.55 (d, 2H), 8. 21 (d, 2H), 9.10 (s, 1H) Example 20o · · iH NMR (400.13 MHz, DMSO-d6) (5 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 20p: iH NMR (400.13 MHz, DMSO-d6) 5 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 20q: iH NMR (400.13 MHz, DMSO-d6) 6 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) 5 6.77 (s, 1H), 7.50 (d, 2H), 8.18 (d, 2H), 8.65 (s, 1H) Example 20r: iH NMR (400.13 MHz , DMSO-d6) 5 0.42 (m, 2H), 0.65 (m, 2H), 1.25 (d, 3H), 1.37 (d5 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 20s: iH NMR (400.13 MHz, DMSO-d6) 5 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 (d5 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 20t: iH NMR (400.13 MHz, DMSO-d6) 5 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, 123642 -218- 200817384 1H), 7.48 (d, 2H), 8.18 (d, 2H) , 8·56 (s, 1H) Example 20u: iH NMR (400.13 MHz, DMSO-d6) 5 1_24 (d, 4H), 1.36 (m, 6H), 3.18 (d, 3H), 3.24 (m5 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) Test (8): Examples (20) 0.043 //M; instance (20a) 0.15 /zM; instance (20b) 0.17 //M; instance (20c) 1 ; instance (20d) 1.6 //M; instance (20e) 2.1 //M; instance (20f) 0.035 //M; instance (20g) 0.039 //M; instance (20h) 0_44 //M; instance (20i) 0·7 //M; instance (20j) 0.75 //M; instance (20k) 0.036 //M; instance (201) 0.074 //M; instance (20m) 0.081 //M; instance (20η) 0·86 //M; instance (20o) 1.3 //M; instance (20p) 0.91 /^ M; example (20 q) 0.039 //M; instance (20r) 0.094 // M; instance (20s) 0.62 //M; instance (20t) 0.6 //M; example (20u) 0.27 //M. urethane, ( 4-{4-Morfosolin-4-yl-6-[(phenylsulfonyl)methyl]-piperidin-2-yl}phenyl)carbamic acid phenyl ester, ... {4-7 3S)_3_A Phenylmorpholine yl]-6-[(phenylsulfonyl)methyl]pyrimidin-2-yl}phenyl)aminophenyl decanoate, (4-{4-[(isopropylsulfonyl) )methyl]isoflurane borneylpyrimidin-2-ylphenyl)aminobenzoic acid benzoquinone, (4-{4-[(isopropylsulfonyl)indolyl]-6_[(38) The preparation of -3-3-mercapto-oprofenyl P, a phenyl phenyl phthalate, is described below. (4-{4-Mofolin ice-based-6-[(phenylsulfonyl)methyl]pyrimidin-2-yl]phenyl)amino phenylate

(4-{4-Morfosin-4-yl-[(phenylsulfonyl)methyl]-nosine-2-ylphenyl)amine 123642 •219- 200817384 (1 g, 2.44 mmol) Soluble in dioxane (1 ml). Sodium bicarbonate (307 mg, 3.65 mmol) was added followed by phenyl chloroformate (3. The solvent was removed in vacuo and the formed oil was partitioned between 1 mL DCM and 1 mL water. The organic phase was dried over magnesium sulfate, filtered, and condensed in the air. The obtained milky yellow solid was chromatographed on silica gel eluting with 0-50% ethyl acetate to give the desired material as a white solid (7 mg). NMR spectrum·· ! H NMR (400J3 MHz, DMS0-d6) 5 3·64 (s, 4H), 3 7〇 (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) LCMS Spectrum: MH+ 531 , retention time 2.61 minutes, method 5 minutes alkali (4_{4_? 淋 -4--4-yl-6-[(phenylphenylidene) methyl), bite _2 丨 phenyl) amine

4-{2- gas-based [(phenylsulfonyl)methyl]p-melidine ice-based] phenanthroline (3.3 g, 9.33 mmol) dissolved in 18% DMF at 7: 3: 2 In a solution (36 ml) of a mixture of dimethoxyethane·water:ethanol. Then, add [4-(4,4,5,5_four A

Base-1,3,2-oxo-oxan-2-yl)phenyl]amine (3.07 g, 13.99 mmol), 2M solution of sodium thioate (12 ml) and dichlorobis(triphenylphosphine) The catalyst (328 mg, 〇47 耄mol) was passed and the reaction was refluxed at 90 ° C for 2 hours under nitrogen atmosphere. The reaction was allowed to cool to room temperature and then partitioned between ethyl acetate (2 mL) and water (2 mL). The organic material was dried over magnesium sulfate, filtered, EtOAc EtOAc (EtOAc) The crude oil was dissolved in dcm and filtered to remove insoluble materials. The beige solid precipitated from the filtrate and the filtrate was filtered again. The solid was analyzed and the desired material (2.2 g) was found. NMR spectrum: 1 H NMR (400.13 MHz, DMSO-d6) 6 3.60 (m, 4 Η), 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) LCMS spectrum: MH+ 411, retention time uo min, method 5 min. base 4-{2- gas-based 6-[(phenylsulfonyl)methyl]pyrimidinyl)}fosfoline

2,4-di-gas-6-[(phenylxanthyl)methyl]indole (6 g, 19.8 mmol) was dissolved in DCM (50 mL) and stirred at _5 ° C Under nitrogen). Triethylamine (3.06 ml, 21.8 mmol) was added to give a clear brown solution. The flavonoid (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 (5 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was chromatographed on EtOAc EtOAc (EtOAc) NMR spectrum: 1 η NMR (400.13 MHz, DMSO-d6) 5 3.53 (s, 4H) 3 65 4H), 4·61 (s, 2H), 6·71 (s, 1H), 7_64 (t, 2H) , 7.77 (m, 3H) LCMS spectrum: mh + 354, residence time L50 minutes, method knife test 2,4-digas j [(phenylsulfonyl) methyl] mouth aglyll 123642 -221 - 200817384

苯 Add phenylsulfonyl)methyl h-pyridine-2,4 (1Η,3Η)·dione (13·3 g, 49 mmol) to phosphonium chloride (1 mL) and The mixture was heated to reflux for 16 hours. The reaction was then allowed to cool to room temperature and excess phosphine chloride was removed in vacuo. The residue was azeotroped with toluene (2 X 1 mL) and dissolved in DCM. The mixture was then poured onto ice (1 L) and allowed to stand for 20 min then extracted with DCM (3 X 500 mL). The combined extracts were dried with EtOAc (EtOAc)EtOAc. This material was used without further purification. NMR spectra: 1H nmr (4〇〇13 MHz, DMSad6) 49.7 (s, 2Η), 7 milk 2Η), 7.72 (s, 1Η), 7.79 (m, 3Η) LCMS spectrum: M-Η 301, retention Time 2.08 minutes, method 5 minutes alkaline hydrazine (phenylsulfonyl) fluorenyl] pyridine _2, 4 (ιη, 3 Η)-dione

6-(Alkylmethyl)-purine-pyrimidine-2,4-dione (8 g, 50 mmol) was dissolved in DMF (200 mL) and sodium benzenesulfinate (9.8 g, 60 millimoles). The reaction was heated to 125 &lt;0&gt;C for 2 h then allowed to cool and the suspension was taken and concentrated in vacuo to give a yellow solid. The crude material was washed with water (1 EtOAc), filtered, and then EtOAc (EtOAc) This material is used without further purification. NMR spectrum: 1 η NMR (400.13 MHz, DMSO-d6) 5 4.46 (s, 2H), 7.69 (t, 123642 -222 - 200817384 2H), 7·81 (m, 1H), 7.87 (m, 3H), 1() 85 &amp; ih),uu 6-(gas-based mercapto ketone is commercially available just (10)w kefu ♦• 6_((material ^ phenyl) phenyl carbamate 丞W bite_2_ base }

(4-{4-[(3S)-3-Methylphenoline·4夷1 beautiful, shot with /4 base] ah (this stone yellow base) methyl] bite-2-base }本基)amine (2 grams, 4.71 millimolar, spray

Soldiers}/taken in dioxane (20 ml). Sodium bicarbonate (594 mg, 7.07 mmol, 古 旲) was added, followed by phenyl chloroformate (0.593 &quot;m&quot;&apos; and the reaction was stirred at room temperature for 2 hours. The solvent was removed in vacuo and the formed oil was partitioned between 20 mL and 2 mL water. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The obtained milky yellow solid was chromatographed on the surface of the residue, and the obtained material was obtained as a white solid (U g). Leg light ϋ: 1Η NMR (槪13 MHz, D Na (4)〗 2G (d, 3H), 3 17 (m, )' 48 (m, 1H), 3·63 (m5 1H), 3·76 (d, 1H), 3.97 (m, 1H), 4.11 (d, 1H), 4.37 (s, 1H)? 4.72 (s, 2H)? 6.65 (s5 1H), 7.27 (m? 3H)? 7.45 (t, 2H) 7.51 (d? 2H), 7.62 (t, 2H), 7.74 (t, 1H), 7.82 (d5 2H), 7.90 (d, 2H), 10.38 (s, 1H) lcms spectrum · · MH+ 545, Retention time 2.7 minutes, method 5 minutes base (H4_[(3S)4 methyl porphyrin 4 Η Η [(phenylsulfonyl) methyl] mouth bite _2 _ yl) amine 123642 - 223 - 200817384

(4-{4-[(3S)-3-Methylnorfos-4-yl]-6-[(phenylphosphonium)methyl]] succinyl-2-yl}phenyl)amino Tri-butyl formate (3.1 g, 5.91 mmol) was dissolved in DCM (20 mL) and trifluoroacetic acid (1 mL). The reaction mixture was stirred at rt EtOAc (EtOAc) The organic phase was collected, dried (MgSO4) elut NMR spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1.22 (d, 3 Η), 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) LCMS spectrum: MH+ 425, retention time 2.03 min, method 5 min base (4-{4_[(3S)-3-methylmorpholine _ 4_yl] winter [(phenylsulfonyl)methyl]-piperidin-2-yl}phenyl) carbamic acid tert-butyl ester

(3S)-4-{2-Chloro-6-[(phenylsulfonyl)methyl]σ-melidine ice-based 3-methylmorpholine (3.2 g, 8.70 mmol) was dissolved in 18 〇/〇 DMF is in a solution (36 ml) of a mixture of 7:3:2 dimethoxyethane:water:ethanol. Then, [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)phenyl]aminocarboxylic acid was added to the third - 123642 -224- 200817384 Ester (4·16 g, 13.05 mmol), 2M sodium carbonate solution (8 ml) and dioxane (triphenylphosphine) catalyst (306 mg, 0.43 mmol) and the reaction was at 9 〇. It was refluxed for 2 hours under a nitrogen atmosphere at °C. The reaction was cooled to rt then partitioned between ethyl acetate (20 mL) and water (20 mL). The organic material was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude solid was chromatographed on EtOAc EtOAc (EtOAc) NMR spectrum: 1H NMR (400_13 MHz, DMSO-d6) 5 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 (m5 1H), 7.82 (m, 4H), 9.49 (s, 1H) LCMS spectrum: MH+ 525, retention time 2 to 80 minutes, method 5 minutes alkali (3S) -4-{2- gas-based-6-[(phenylphenanthryl)methyl] shouted to bite ice base}-3-methyl phloem

σ 2,4-Dichloro·6-[(phenylxanthyl)methyl]σ-mididine (2.8 g, 9.24 mmol) dissolved in DCM (20 mL) at -5 °C Stir (under nitrogen). Triethylamine (1·42 liter, 10.17 mmol) was added to obtain a clear brown solution. (3 phantom methyl morpholine (935 mg, 9.24 mmol) was dissolved in DCM and added dropwise, keeping the reactant below _5. (:. Then the cooling bath was removed and the reaction was mixed The mixture was stirred at room temperature for 1 hour. Then, the reaction mixture was washed with water (5 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was chromatographed on silica gel in DCM After 〇5〇% ethyl acetate was dissolved, and 123642 • 225 - 200817384 gave the desired substance as a white solid (2.6 g). NMR spectrum · · iHNMR (4 〇〇 13 MHz DMS 〇d6) accounted for 1 i5 (d3H), 3i5 (4) 1H)3 3.42 (m? 1H)? 3.56 (m, 1H), 3.72 (d? 1H), 3.92 (m? 2H)? 4.15 (s? 1H), 4.62 (s? 2HX 6.66 (s? 1H) 7.74 (t5 1H)? 7.76 (t? 1H), 7.78 (d? 1H)5 7.80 (m? 2H) LCMS spectrum: MH+ 368, retention time 195 minutes, method $ minute base (4-{4-[ (isopropylsulfonyl)methyl]_6_morpholine 4ylpyrimidin-2-yl}phenyl) phenyl carbamate

Dissolve (4-{4-[(isopropylsulfonyl)methyl]-formolfosinylpyrimidin-2-ylphenyl)amine (1.5 g, 3.98 mmol) in dioxane (1 〇 ml). Sodium hydrogencarbonate (503 mg, 5.98 mmol) was added followed by phenyl chloroformate (5 </ RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; The solvent was removed in the air and the formed oil was partitioned between 1 mL of DCM and 1 mL of water. The organic phase was dried over magnesium sulfate, filtered, and taken in vacuo. The obtained milky yellow solid was chromatographed on Shiqi gum to 0-50 〇/ in DCM. The ethyl acetate was dissolved to give the desired material as a white solid (1.5 g). NMR light: 1H NMR (400.13 MHz, DMSO-d6) 5 1.30 (d, 6H), 3.45 (m 1H), 3·65 (s, 8H), 4.40 (s, 2H), 6.78 (s, 1H) , 7.2G (m, 3H), 7·38 (t, 2H) 7.56 (d, 2H), 8·22 (d, 2H), 10.37 (s5 iH) 'LCMS spectrum · · MH+ 497, residence time 2· 54 minutes, method 5 minutes, base 123642 -226- 200817384 (4-{4-((isopropyl benzyl) methyl + 福福, 林

• 4_基基咬-2_基}phenyl)amine nh2 (4-{4_[(isopropylsulfonyl)methyl]_6_morpholine) The carboxylic acid second-butyric acid (2.7 g, 5.67 mmol) was dissolved in DCM (2 mL) and then difluoroacetic acid (10 mL). The reaction mixture was stirred at room temperature for 2 hr then diluted with EtOAc (EtOAc) The organic phase was collected, dried over magnesium sulfate, filtered, and evaporated, NMR spectrum: 1 H NMR (400.13 MHz, DMSO-d6) 5 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)

LCMS spectrum: MH+ 377, retention time] ^! minutes, method 5 minutes base (4-{4-[(isopropyl decyl) fluorenyl 1-6_ whal-4-pyrimidine-2_ Base phenyl) carbamic acid tert-butyl ester

4-{2-Chloro-6-[(isopropylsulfonyl)methyl]. Michidine _4-yl} whollen (15 g, 4.69 mmol) dissolved in 18% DMF in 7:3:2 dimethoxyethane: water: a mixture of ethanol (36 ml )Inside. Then, {4_[(t-butoxycarbonyl)amino]phenyl}dihydroxyborane (1.67 g, 7.04 mmol), 2Μ 123642 -227 - 200817384 sodium carbonate solution (12 ml) and dichlorobis (Triphenylphosphine) catalyst (165 mg, 〇 23 mmol), and the reaction was refluxed at 90 ° C for 2 hours under nitrogen atmosphere. The reaction was allowed to cool to room temperature and then partitioned between ethyl acetate (2 mL) and water (2 mL). The organic material was dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude oil was dissolved in DCM and filtered to remove insoluble material. The brown solid precipitated from the filtrate and the filtrate was filtered again. The solid was analyzed and the desired material (19 g) was found. NMR spectroscopy························ ), 6.83 (s, 1H), 7·57 (d, 2H), 8.22 (d, 2H), 9·56 (s, 1H) LCMS spectrum: MH+ 477, retention time 2.50 minutes, method 5 minutes alkali 4· {2- gas-based-6-[(phenylsulfonyl)methyl]pyrimidinyl aryl porphyrin

2,4_one gas [(isopropylsulfonyl)methyl; h-pyridine (2.65 g, 9.85 mmol) was dissolved in DCM (50 mL) and stirred at -5 Under nitrogen). Triethylamine (1.5 ml, 10.84 mmol) was added to obtain a clear brown solution. The morphine (0·86 ml, 9.85 mmol) was dissolved in DCM and added dropwise, keeping the reaction below. The cooling bath was then removed and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then washed with water (5 mL), dried over Celite, filtered and concentrated in vacuo. The crude material was chromatographed on silica gel eluting with 5% ethyl acetate in DCM to give the desired material (2.5 g). 123642 -228- 200817384 NMR spectrum: 1H NMR (400.13 MHz, DMSO-d6) δ 1·30 (d, 6H), 3·42 (m, 1H), 3.62 (s, 4H), 3·68 (m5 4H ), 4.42 (s, 2H), 6.95 (s, 1H) LCMS spectrum: MH+ 320, retention time 1.51 minutes, method 5 minutes alkali two gas-6-[(isopropyl aryl) thiol] bite

2,4-dioxa-6-[(isopropylthio)methyl]-glycine (6.2 g, 26.16 mmol) was dissolved in DCM (100 mL) and 3,5- Dichlorobenzene carboic acid (13.5 grams, 78.4 house moles), after 1 minute. The reaction was stirred at room temperature for 4 hours. Then, the reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate (5 mL) and dried over magnesium sulfate, filtered, and concentrated in vacuo to give a yellow solid. Purification by normal phase chromatography, eluting with EtOAc &lt;RTI ID=0.0&gt;&gt; NMR spectrum: iHNMR (400.13 MHz, DMSO-d6) 5 1.25 (d, 6 Η), 3.43 (m, lH), 4.77 (s5 2H)5 7.87 (S) 1H) LCMS spectrum: M_H267, retention time L64 min, method 5 minutes alkaline digas-6-[(isopropylthio)methyl], bite

Add 6-[(isopropylthio)methyl]pyrimidine_2,4(1H,3H)-dione (8 g, 4 〇 mmol) to gasified phosphonium (100 ml) and The mixture was heated to reflux for 16 hours. The reaction was then allowed to cool to room temperature and excess palladium chloride was removed in vacuo. The residue was azeotroped with toluene (2 χ 1 mL) and was taken up in DCM. Then, the mixture was poured slowly to 0 liters of ice, and stirred at 123642 - 229 - 200817384 for 20 minutes, and then extracted with DCM (3 χ 5 mL). The combined extracts were dried with EtOAc (EtOAc m. This material was used without further purification. NMR spectrum·· 1H NMR (400·13 MHz, DMSad6) 3 } 21 (d, 6H), 2 % (4) 1H), 3.85 (s, 2H), 7.82 (s, 1H) LCMS spectrum··Retention time 2· 51 minutes, method 5 minutes, basic hydrazine (isopropylthio)methyl] hydrazide 2,4 (111,311)-dione

6-(Chloromethyl)-purine-pyrimidine-2,4-dione (8 g, 50 mmol) was dissolved in acetonitrile (200 mL), and l58-diazabicyclo[5·4 was added. 〇] decantene, 87.19 mmol, and the reaction was stirred at room temperature for 15 min. Isopropyl mercaptan (8-1 ml, 87.19 mmol) was then added and the reaction was stirred at room temperature for additional 2 hours. The solvent was removed in vacuo and the brown oil formed was dissolved in DCM and washed with water. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The oil formed was chromatographed on silica gel eluting with 0-10% methanol in DCM to give the desired material as white solid (8 g). NMR spectrum: 1 H NMR (400.13 MHz, DMSO-d6) 51·21 (d, 6 Η), 2.90 (m, 1H), 3.42 (s, 2H), 5.49 (s, 1H), 10.82 (s, 1H) , 10.94 (s, 1H) LCMS spectrum: M-H199, retention time 〇 · 63 minutes, method 5 minutes alkaline 6-(chloromethyl)-1Η-biting-2,4-di g are commercially available Available substances. (M4_[(isopropylsulfonyl)methyl l-6_[(3S) each methylmorpholine + base], biting _2_yl}phenyl) phenyl carbamate 123642 - 230- 200817384

(4-{4-[(isopropylsulfonyl)methyl] each [(3S&gt;3-methylmorpholine)-based butyl-2-yl}benzyl)amine (1.5 g, 3.84 mmoles dissolved in dioxane (1 mL). Add sodium bicarbonate (485 mg, 5.76 mmol) followed by stearyl chloroformate (0.484 liters, 3.84 house moles) and The reaction was stirred at room temperature for 2 hours. The solvent was removed in vacuo and the formed oil was partitioned between 1 mL of DCM and 10 liters of water. The organic phase was dried over magnesium sulfate. , </ RTI> </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> </ RTI> </ RTI> <RTIgt; Spectra: WNMR (400.13 MHz, DMSO-d6) 5 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 (s5 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) LCMS spectrum: MH+511, retention time 2.67 minutes, method 5 min (4- {4 - [(isopropyl-acyl sulfo) methyl] _6 - [(3S) -3- methylmorpholine-4-yl] phenyl} pyrimidin-2-yl) amine

(4-{4-[(isopropylsulfonyl)methyl]_6_[(3s)-3-methylmorpholine-4-yl]-mellyl-2-yl}phenyl)amino Formic acid tert-butyl ester (3.2 g, 6.52 mmol) was dissolved in 123642-231 - 200817384 DCM (20 mL) and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at room temperature for 2 hr then diluted with EtOAc EtOAc. The organic phase was collected, dried over magnesium sulfate, filtered, and concentrated in vacuo to give the desired material as a creamy solid (2.4 g). NMR spectrum: 1H NMR (400.13 MHz, DMSO-d6 U U2 (d, 3H), L35 (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) LCMS spectrum: MH+ 391, retention time ι·84 min, method 5 min base (4_{4_[(isopropylsulfonyl)methyl) 】 each [(3S)_3_methylmorpholine _4 base] 喊 _2 _ _ _ _2 】 旨 旨 旨 旨 旨

Dissolve (3S)-4_{2-Chloro-6·[(isopropyl sulphate) thiol]-Bist-4-Kip 3 曱 吗 吗 4 (2.0 g ' 5.99 mmol) dissolved in 18 % DMF is in a solution (16 ml) of a mixture of 7 ······· 2 dimethoxyethane:water··ethanol. Then, {4-[(T-butoxycarbonyl)amino]phenyl}dihydroxyborane (213 g, 8 99 mmol), 2 M sodium carbonate solution (8 ml) and dichlorobis (three) were added. Phenylphosphine) palladium catalyst (211 mg '0.30 mmol) and the reaction was refluxed for 9 hours under 9 Torr. The reaction was allowed to cool to room temperature then partitioned between ethyl acetate (2 mL) and water (20 mL). The organic material was dried over magnesium sulfate, filtered, and concentrated in vacuo. The obtained milky yellow solid was chromatographed on EtOAc EtOAc: EtOAc (EtOAc: EtOAc) NMR spectrum: 1H NMR (400.13 MHz, DMSO-d6) 5 1.36 (m, 6 Η), 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) LCMS spectrum: MH+ 491, retention time 2_67 minutes, method 5 minutes base (3S)-4-{2-carbyl-6-[(isopropyl decyl)methyl] shout bite winter Ketamine

2,4-Gas-6-[(isopropyl sulphate)methyl] succinic (2.65 g, 9.85 mmol) was dissolved in DCM (50 mL) and stirred at _ 5 ° C ( Under nitrogen). Triethylamine (1.5 ml, 10.84 mmol) was added to obtain a clear brown solution. 3S_3_Methylverine (997 mg, 9.85 mmol) was dissolved in DCM and added dropwise, keeping the reaction below _5t:. The cooling bath was then removed and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with water (50 ml), dried over magnesium sulfate, filtered and evaporated. The crude material was chromatographed on silica gel eluting with EtOAc (EtOAc) NMR spectrum: 1 H NMR (400.13 MHz, DMSO-d6) δ 1.22 (d, 3H), 1.31 (d, 6H), 3.22 (m, 1H), 3.43 (m5 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) LCMS spectrum: MH+ 332, retention time uo minutes, method 5 minutes alkali 123642 -233 · 200817384 Example 21: 3-Methyl_l_[4_[4-(2-Methanesulfonylpropan-2-ylindole-morpholine-fedyl)-yl-pyridyl-2-yl]phenyl]

((4-{4-|&gt;Methyl-!-(methylsulfonyl)ethyl]norfosin borneylpyrimidin-2-yl} / phenyl) phenyl carbamate (丨16 mg, 〇 • 22 mmol) dissolved in DMF (3 mL). Diethylamine (0.098 ml, 0.7 mmol) was added followed by methylamine (2M in THF &lt;RTIgt; The mixture was stirred at 5 ° C for 1 hour to give the desired material &lt;&gt;&gt; NMR spectrum: 1H NMR (400.13 MHz, DMSO-d6) 5 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) (LCMS spectrum: MH+ 434, retention time 1.64 min, method 5 min. In a similar manner, either (4-{4-|&gt;methyl-1-(methylsulfonyl)ethyl]-6-morpholine-4-ylpyrimidin-2-yl}phenyl)amine Phenyl benzoate or (4-{4-[1-methyl succinyl)ethyl]_6_[(3S)_3_f keifoff # -4-yl] benzoate-2-yl}phenyl Phenyl carboxylate with the appropriate amine. 123642 -234- 200817384 Example structure name LCMS ΜΗ+ retention time (minutes) 21a 〔:〕 Η H 1-ethyl-3-[4-[4-(2-methane) Mercaptopropan-2-yl)-6-?-fu-p-lin-4-yl-. dimethyl-2-yl]phenyl]urea 448 1.78 21b 0 Η H 3-cyclopropyl-l-[4-[ 4-(2-Methanesulfonylpropan-2-yl)-6-hoofan p-lin-4-yl-- succinyl-2-yl]phenyl]urea 460 1.91 21c 0 person, Η H 3- (2-dimethylaminoethyl) 1-[4_[4-(2-methanesulfonylpropan-2-yl)-6-morphine p- 4- 4-benzylidene-2-yl]benzene base] 491 1.71 21d 0 Parent A〇L human jCT Η H 3-(1-methyl-4-hexamethylpyridinyl)-1-[4-[4-(2-methanesulfanylpropan-2-yl) )-6-ofoline-4-yl-yt-2-yl]phenyl]urea 517 1.75 21e 0 y々a human / Η H 3-(2-methoxyethyl)-1_ [4- [4-(2-oxasulfonylpropan-2-yl)-6-isofyl]--4-yl-pyrimidin-2-yl]phenyl]urea 478 1.72 21f 0, ^A〇lnv Η H 3 -Methyl-l-[4-[4-[(3S)-3-methylnorfos _4_yl]-6-(2-methyl sylvestreyl-2-yl) Τ3 dense sigma- 2-yl]phenyl]urea 448 1.76 21g a Η H 1-ethyl-3-[4-[4-[(3S)-3-methylnorfos-4-yl] _6-(2-A石 酿 丙 -2- -2- -2- -2- -2- 462 462 462 σ 基 基 基 基 462 462 462 462 462 462 462 462 Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ LC LC LC LC LC LC Γ Γ Γ Γ Γ Γ Γ Γ Propyl-l-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(2-methylglycosylpropan-2-yl)pyrimidin-2-yl]benzene Urea] 474 1.93 21i 卜0&quot;, human, Η Η 3-(2-dimethylaminoethyl)-H4-[4-[(3S)-3-methylmorpholine-4-yl]- 6-(2-Methanesulfonylpropan-2-yl succinyl-2-yl]phenyl]urea 505 1.83 21j α Η Η l-[4-[4-[(3S)-3-methyl? blessing Lin -4_ yl] -6- (2-stone yellow &amp; &amp;-2-yl). Σσ定-2_ yl]phenyl]-3-(1-methyl-4-hexahydropyridyl) urinary 531 1.86 21k θ' human / Η Η 3-(2•methoxyethyl)-1 -[4-[4-[(3S)-3-indolyl phenanthren-4-yl]-6-(2-methyl feldspar fcylpropan-2-yl)13 sigma-2-yl] Phenyl]urea 492 1.84 Example 21a: W NMR (400.13 MHz, DMSO-d6) 6 1.07 (t,3H),1·77 (s, 6H), 3.04 (s, 3H), 3.13 (m, 2H), 3·73 (s5 8H), 6.15 (t, 1H), 6.79 (s, 1H), 7.50 (d, 2H), 8.24 (d, 2H), 8.66 (s, 1H) Example 21b : 1 H NMR (400.13 MHz, DMSO-d6) (5 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 21c: NMR (400.13 MHz, DMSO-d6) 5 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 123642 -236 - 200817384 (s, 1H), 7.49 (d, 2H), 8.24 (d, 2H), 8.90 (s, 1H) Example 21d: iH NMR (400.13 MHz, DMSO-d6) 5 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 21e: iH NMR (400.13 MHz, DMSO-d6) ά 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 21f: iH NMR (400.13 MHz, DMSO-d6) 5 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 21g: NMR (400.13 MHz, DMSO-d6) d 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 21h: NMR (400.13 MHz, DMSO-d6) 6 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 (d5 2H), 8.54 (s, 1H) Example 21i: iH NMR (400.13 MHz, DMSO-d6) (5 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) 123642 - 237 - 200817384 Example 21j: 4 NMR (400.13 MHz, DMSO- D6) 5 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 21k: β NMR (400.13 MHz, DMSO-d6) 5 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) Test (a): Example (21) 0.05 //M; Example (21a) 0·73 //M; Example (21b) 0.36 //M; instance (21c) 0.48 //M; instance (21d) 0·27 //M; instance (21e) 1 //M ; instance (21f) 0·017 //M; instance (21g) 0· 02 //M; instance (21h) 0.028 //M; instance (21i) 0.076 /zM; instance (21j) 0·51 //M; instance (21k) 0.31 //M. (4-{4-[l -Methyl-1-(methyl succinyl)ethyl]-6-fosfos-4-yl quinone _2-yl}phenyl)amino decanoate and (4-{4-[ The preparation of 1-methyl small (methanesulfonyl)ethyl]-6-K3S)_3_methylmorpholine phenyl]pyrimidin-2-yl}phenyl) carbamic acid phenyl ester is described below. (4_{4-[1-methyl_1-(methylsulfonyl)ethyl-6·norfosolin-4-ylpyrimidin-2-yl}phenyl) phenyl carbamate

(4-{4-[1-Methyl-1-(methionine)ethyl]-6-norfosine-4_yl η 密_2_&amp;丨 基 )) amine (1·5 Gram, 3.98 mmol is dissolved in dioxane (15 ml). Add 123642 -238 - 200817384 sodium bicarbonate (503 mA·g, 5.98 mmol) followed by phenyl chloroformate (〇5〇2 宅升' 3.98 house Moer) and the reaction was searched at room temperature Drop 2 hours. The solvent was removed in vacuo and the formed oil was partitioned between 2 mL of DCM and 2 mL of water. The organic phase was dried over magnesium sulfate, dried, and concentrated in vacuo. The obtained milky yellow solid was chromatographed on EtOAc (EtOAc) elute NMR spectrum: 1H NMR (400.13 MHz, DMSO-d6) 5 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)5 7.45 (t,2H), 7.51 (d, 2H), 7.62 (t5 2H), 7.74 (t, 1H), 7.82 (d5 2H), 7.90 (d, 2H), 10.38 (s, 1H) LCMS spectrum: MH+ 545, retention time 2·7 Minutes, method 5 minutes test (4_{4·[1·methyl·1-(methyl decyl)ethyl]_6_wufolin-4-yl, ind-2-yl}phenyl)amine

(4-{4-[1-Methyl-1-(methyl sulphate)ethyl]-6-norfosin-4-yl-p-but-2-yl}phenyl)aminocarbamic acid tert-butyl The ester (2.6 g, 5.46 mmol) was dissolved in DCM (20 mL). The reaction mixture was stirred at rt EtOAc (EtOAc) The organic phase was collected, dried over magnesium sulfate, filtered, and concentrated in vacuo to give the desired material as a creamy solid (2·1 g). NMR spectrum: 4 NMR (400.13 MHz, DMSO-d6) 5 L75 (s, 6 Η), 3·03 (s. 123642 - 239 - 200817384 3H), 3.71 (S, 8H), 5.56 (s, 2H), 6.61 (d, 2H), 6.69 (s, 1H), 8.07 (d, 2H) LCMS spectrum: MH+ 377, retention time i84 min, method 5 min test (4-{4-[l-methyl-1-(A) Sulfonic acid)ethyl]6-morpholine piperidin-2-yl}phenyl) butyl formate

^ (3S)-4-{2-carbyl-6-[l-methyl+(methylsulfonyl)ethyl]-endridinyl}}-methyl-methylfoline (1.75 g, 5.47 m) Mohr) was dissolved in a solution (18 ml) of 18% DMF in a mixture of 7:3:2 dimethoxyethane:water:ethanol. Then, [4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron-2-yl)phenyl]carbamic acid tert-butyl ester (2.62 g, 8.2 millimoles) '2M sodium carbonate solution (8 ml) and digas bis(triphenylphosphine) palladium catalyst (192 mg, 〇 · 27 mmol), and the reaction at 90 ° C and nitrogen atmosphere Reflux for 2 hours. The reaction was cooled to room temperature and then worked-up between ethyl acetate (20 ml) and water (20 ml). The material I was dehydrated and dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude solid was chromatographed on silica gel eluting EtOAc (EtOAc) NMR spectrum: iH NMR (400.13 MHz, DMSO-d6) 5 1.50 (s, 9 Η), 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) LCMS spectrum·· MH+ 477, retention time 2.66 minutes, method 5 minutes test 4-{2-carbylmethyl-1_ (Methanesulfonyl)ethyl]pyrimidinyl]Keflin 123642 -240- 200817384

The chloro-6-[(sulfonyl)methyl], pyridine-4-yl} oxalin (2.9 g, 9.94 mmol) was dissolved in DMF (20 mL) and the reaction was cooled to _5t. Sodium 2-butoxide (956 mg, 9.94 mmol) was added to the reaction followed by methyl iodide (6 mL, 9.94 mmol) and maintained at -5. Your majesty. Then, a second equivalent of sodium tributoxide (956 mg, 9.94 mmol) with iodine f methane (0.6 ml, 9.94 mmol) was added and the reaction was stirred for 1 hour. Then, at room temperature for 4 hours. DCM (2 mL) was added and the mixture was washed with &lt The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude solid was chromatographed on silica gel eluting with 0-50% ethyl acetate in dcm to give the desired material as white solid (1·7 g). NMR spectrum: i η calendar (4〇〇13 MHz, DMS〇d6) 5 i (10) &amp; 6H), 2 99 (s, 3H), 3·67 (s, 8Η) 5 6·91 (s, 1H) , LCMS spectrum: MH + 32 〇, retention time 167 minutes, method 5 minutes base (4-{4-[l_methyl small (methylsulfonyl) ethyl _H (3S) each methyl morpholine _4 Phenylpyrimidin-2-yl}p-phenyl) phenyl carbamate

(4-{4-[1-Methyl-succinyl)ethyl]_6-[(3S)-3-methylphenofin-4_yl]-carin-2-yl}phenyl) The amine (3.6 g, 8.77 mmol) was dissolved in dioxane (2〇123642 • 241 - 200817384 ml). Sodium bicarbonate (1_1 g, 13.15 mmol) was added followed by 1 ml of chloroform (1.1 liters &apos; The solvent was removed in vacuo and the formed oil was partitioned between 20 mL dcm and 20 mL water. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The obtained milky yellow solid was chromatographed on EtOAc (EtOAc) elute NMR spectrum: 1 η NMR (400.13 MHz, DMSO-d6) (5 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) 5 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) LCMS spectrum: MH+ 511, retention time 2.7 minutes, method 5 minutes base (4-{ 4-[1·Methyl small (methylsulfonyl)ethyl]_6_[(3S)_3_indolyl porphyrin ice base] bite-2-yl}phenyl)amine

(3S)_4_{2-Chloro-6-[l-methyl-small (methylsulfonyl)ethyl]-glycolylsyl}-3-indolyl porphyrin (2_2 g, 6.59 mmol) Dissolved in a solution of 18% DMF in a mixture of 7:3:2 dimethoxyethane:water:ethanol (18 mL). Then 'add [4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron-2-yl)phenyl]amine (2.17 g ' 9.89 mmol), 2M Sodium carbonate solution (8 ml) and dioxobis(triphenylphosphine), a bar catalyst (232 mg, 0.33 mmol), and the reaction was refluxed at 90 ° C for 2 hours under nitrogen atmosphere. The reaction was allowed to cool to rt then partitioned between ethyl acetate (20 EtOAc EtOAc &lt The organic material was dehydrated and dried under magnesium sulfate to &lt;RTI ID=0.0&gt; The crude solid was chromatographed on EtOAc (EtOAc) elute elute LCMS spectrum: MH+ 389, retention time 1 · 〇〇 min, method 5 minutes base (3S)-4-{2-carbyl-6-(1-methyl_1•(methyl)ethyl), Biting winter base

(3S) Winter {2-Chloro-6-[(oxasulfonyl)methyl]-glycine_4_yl}·3_methylmorpholine (2.1 g, 6.87 mmol) was dissolved in DMF (2 mM) and the reaction was cooled to -5 C. Tris-butanol (650 mg, 6.87 mmol) was added to the reaction followed by anthraquinone (0.4 mL, 6.87 mmol) maintaining the temperature at _5 c. Then a second equivalent of sodium tributoxide (650 mg, 6.87 mmol) and methyl iodide (0.4 mL, 6.87 mmol) were added and the reaction was stirred at ° C for 1 h. Then at room temperature for 4 hours. DCM (20 mL) was added and the reaction was washed with 2M aqueous hydrochloric acid (2 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude solid was chromatographed on silica gel eluting with 0-50% ethyl acetate in DCM to give the desired material (2.2 g NMR spectrum: 1H NMR (400.13 MHz, DMSO-d6) ό 1.21 (d, 3H ), 1.68 (s, 6Η), 2·74 (s, 3Η), 3·21 (m, 1Η), 3·45 (m, 1Η), 3·59 (m, 1Η), 3.73 (d, 1Η) ), 3.94 (m, 1H), 4.07 (d, 1H), 4.45 (s, 1H), 6.86 (s, 1H) 123642 -243 - 200817384 LCMS spectrum: MH+ 334, residence time 1.85 minutes, method 5 minutes Base Example 22: l-[4-[4_[(3S)-3曱-Mercaptophen-4-yl]_6-(methylsulfonylmethyl)-l-pyridin-2-yl]phenyl]_3_( 1,2_carbazole group) urea

Benzene N-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(methylsulfonylmethyl)-n-ytidine-2-yl]phenyl]aminocarboxylate The ester (170 mg, 〇 35 mmol) was dissolved in DMF (15 mL). Triethylamine (0.147 mL, 1.06 mmol) was added. Add 1,2-唠. 3-Amine (198 mg, 2.35 mmol) was added and the reaction was stirred at 6 ° C for 2 h. The reaction was evaporated to dryness crystals crystals crystals crystals NMR spectrum: NMR (400.13 MHz, DMSOd6) 5 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)5 8.75 (1H,d),9.07 (1H,s)5 9.62 (1H,s) LCMS spectrum: MH+ 473, retention time L63 min, method of monitoring acid The following compounds were prepared in a similar manner from N_[4-[4_[(3S&gt;_3-methylmorpholine)-(methylsulfonyl)-methyl Phenyl]phenyl]amino decanoic acid phenyl ester with the appropriate amine. 123642 -244- 200817384 Example structure name LCMS ΜΗ+ residence time (minutes) 22a 〔:x person again:) Η H l-[4-[4- [(3S)-3-methylnorfosin-4_yl] each (methanesulfonylmethyl) η 密 乙 乙-2-yl]phenyl]-3-pyrimidin-2-yl-urea 484 1.60 22b Cx 1-(2,6-Dimethylphenyl)-3-[4-[4-[(3S)-3-methylmorpholine-4-yl]_6-(methylsulfonylmethyl) Pyrimidine-2-yl]phenyl]urea 510 1.98 22c CX l-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(methylsulfonylmethyl) Pyrimidine-2-yl]phenyl]-3- (6-酉同基-1H-^ σ定_2_基) 月尿499 499 1.35 22d a °s^〇lnxn^ Η H 3-[4-[4-[(3S)-3-methyl?啉-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl]phenyl]-1-(5-methyl-1,2'-oxazol-3-yl)urea 487 1.72 22e Cx Η H ' 3-[4-[4-[(3S)-3-Methylmorpholine-4-yl]-6-(methylsulfonylmethyl succinyl-2-yl]phenyl] -1-(5·methyl-1,2-oxazol-4-yl)urea 487 1.46 22f Η H H4-[4-[(3S)-3-methylmorpholine-4-yl]-6 -(Methanesulfonylmethyl). Met. _2_yl]phenyl]-3-(1-methylpyrazol-4-yl)urea 486 1.27 22g Cx 'Cold a person Η H l- [4-[4-[(3S)-3-methylmorpholine-4-yl]-6·(methylsulfonylmethyl)))-2-yl]phenyl]_3_ (2-sun-based -lH-p ratio. Ding-4-yl) monthly urine 499 1.21 22h C:X Η H ' 3-[4-[4-[(3S)-3-methylorfosin-lin-4-yl]-6-(methionite Styromethyl)17-succinyl-2-yl]phenyl]-1-(1,3,5-trimethylpyrazol-4-yl)urea 514 1.29 123642 -245- 200817384 Example structure name LCMS MH+ Residence time (minutes) 22i a Η H ' 1-(3,5-Dimethyl-1H-pyrazol-4-yl)-3-[4-[4-[(3S)-3-methyl? Plin-4·yl]-6-(methyl sulfonylmethyl) hydrazin-2-yl] phenyl]urea 500 1.21 Example 22a: 1H NMR (400.13 MHz, DMSO-d6) 5 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 22b: 1H NMR (400.13 MHz, DMSO -d6) (5 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)5 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 Example 22c: 1H NMR (400.13 MHz, DMSO-d6) 5 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 (2H,d),8·28·8·30 (2H,m),9·28 (1H,s) 22d: iH NMR (400.13 MHz, DMSO-d6) 5 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)5 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) 123642 -246- 200817384 Examples 22e : 1 H NMR (400.13 MHz, DMSO-d6) 5 1.25 (3H, d), 2.37 (3H, s), 3·21 (3H, s), 3.22-3.26 (1H, m), 3.47-3.54 ( 1H,m),3.64-3.67 (1H,m), 3·78 (1H,d),3.97-4.01 (1H,m),4.18 (1H,s)5 4·49 (3 H, 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) Example 22f: iH 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)5 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 22g: iH NMR (400.13 MHz, DMSO-d6) 5 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) 5 11.04 (1H, s) Example 22h: 1 H NMR (400.13 MHz, DMSO-d6) 5 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) 22i : 1 H NMR (400.13 MHz, DMSO-d6) 6 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) 123642 -247- 200817384 Test (a): Example (22a) 0.06 //Μ; Example (22b) 1·6 //Μ; Example (22d) 0.0048 //Μ; Example (22e) 0·56 // Μ; example (22f) 0.091 //Μ; instance (22g) 0.0045 //Μ; instance (22h) 1·5 //Μ; instance (22i) 4.3 _· test (c): instance (22c) 0.21 // Μ·N-[4-[4-[(3S)-3-indolyl-norfos-4-yl]-6-(methylmercaptomethyl succinyl-2-yl]phenyl]amino The preparation of phenyl formate is described above. Example 23: 3·Methyl-l-[l-[4-[(3S)-3-methylnorfos _4_yl]-6_(Aminomethyl) mouth bit-2-yl] -4-hexanitrogen p

N-[l-[4-[(3S)-3-methylpheno #木-4-yl]-6-(methylsulfonylmethyl) pulverized · 2 yl]-4-hexahydropyridine Phenyl phenyl carbamate (220 mg, 〇 45 mmol) was dissolved in DMF (3 mL). Triethylamine (〇·188 ml, 135 mmol) was added, followed by 2-methylamine (1.2 mL, 2.25 mmol) in THF. The mixture was stirred at 5 ° C for 3 hours. The mixture was evaporated to dryness eluting with EtOAc EtOAc (EtOAc) NMR spectrum: iH nmR (4〇〇13 丽2, DMS〇^) δ i 17 yang1·20-1·27 (2H,m), 1.77 (2H,d)5 2_54 (3H,d),2 ·99 (2H,d)5 3·08 (1H,d), 3.12 (3H,s),3.37-3.40 (1H,m)5 3·43 (1H,d),3.57 (1H,d),3 ·71 (1H, φ 3.91 (1H5 d)5 3.94 (1H? d)5 4.23 (2H5 s)5 4.26 (13⁄4 d)5 4.42 (2H, d)5 5.57 (1H,q),5·83 (1H , d), 6.14 (1H, s) 123642 -248- 200817384 LCMS spectrum: MH+ 427, retention time 0.85 minutes, method 5 minutes acid The following compounds were prepared in a similar manner from N-[l-[4-[(3S -3-mercapto-oxafolin-4-yl] phenyl sulfonylmethylpyrimidin-2-yl H-hexahydropyridyl]carbamate and an appropriate amine. Example structure name LCMS MH + Residence time (minutes) Note 23a [.] 〇4 persons Η 1-ethyl; [1-[4-[(3S)-3-methylmorpholine-4-yl] each (methylsulfonyl) Methyl)pyrimidin-2-yl]-4-hexahydrop-pyridyl]urea 441 1.03 Purification by reverse phase chromatography Example 23a: 4 NMR (400.13 MHz, DMSO-d6) 5 0·98 (3H, t) , U3-1.18 (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) test ( a): Example (23) 5.6 //M; Example (23a) 3.7 //M. N-[l-[4-[(3S)_3-Methyl-Walfolin-4-yl]-6-(A The preparation of scutellarin methyl) _2_2_ yl]-4-hexahydrop to butyl amide is described below. N-[1_[4-[(3S)_3-indolyl porphyrin-4_yl] winter (methanesulfonylmethyl) _2_2_yl]_4_hexahydropyridyl] phenyl carbamate

L-[4-[(3S)-3-Methylnorfos-4-yl]·6-(methionylmethyl)-biting·2_yl] 123642 -249- 200817384 Hexahydropyridine Dipamine (500 mg, 1.35 mmol) was dissolved in dioxane (1 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 liquid was stirred at room temperature for 3 hours. Add phenyl chloroformate (〇·〇2ΐ ml, 〇·27 mmol) with sodium hydrogen sulphate (21 mg, 0.12 mmol). It was continuously allowed to stand at room temperature for J hours, and the reaction mixture was evaporated to dryness and partitioned between water (1 ml) and ethyl acetate (10 ml). The water was extracted with a second portion of acetic acid (1 Torr). The combined organic material was dried over magnesium sulfate and evaporated to give the desired material (yield: 701 mg). NMR spectrum: β NMR (400.13 MHz, DMSO-d6) 5 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) LCMS spectrum: MH+ 490, retention time ι·58 min, method for monitoring acid l_[4-[(3S)-3-methylmorpholine-4-yl] _6-(Methanesulfonylmethyl)cyclopyridine_2_yl]hexahydropi-biti-4-amine

Making N-[l-[4-[(3S)-3-methylmorpholine yl) each (nonylsulfonylmethyl)-piperidin-2-yl]-4-hexahydropyridyl]amine Tri-butyl formate (〇〇克, 2.77 mmol) was dissolved in methanol (10 mL). 4M hydrochloric acid (10 ml) in dioxane was added. The reaction was stirred at room temperature for 3 hours. Saturated sodium bicarbonate water 123642 -250 - 200817384 solution was added until pH 7 was reached and the organic solvent was removed in vacuo. Water (20 mL) was added and the product was crystallised from ethyl acetate The aqueous layer was extracted with a second portion of ethyl acetate (25 mL). The combined organic material was evaporated to give the desired material as a yellow foam (1.05 g). NMR spectrum: NMR (400.13 MHz, DMSO-d6) 5 1·17 (3H, d), 1.69-1.73 (2H, m)5 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)5 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) LCMS spectrum: MH+ 370, The residence time was 0.48 minutes, and the method was monitored for acid N-[l-[4_[(3S)-3-indolyl phenanthroline-4-yl]_6-(methylsulfonylmethyl)acridin-2-yl] ice Hexahydropyridyl] methic acid tert-butyl ester

Add 2-chloro hydrazine [(3S)_3-methylmorpholine-4-yl] each (nonylsulfonylmethyl) hydrazide (1·〇〇克, 3·27 mmol), potassium carbonate (498 mg, 3.60 mmol) and tert-butyl-(4-hexahydropyridyl)amine decanoate (721 mg, 3. 6 mmol). Acetonitrile (10 ml) was added, and the mixture was heated under reflux for 4 hr. The acetonitrile was decanted to leave a white solid which was partitioned between water (4 mL) and ethyl acetate (60 mL). The liquid phase was separated and the aqueous layer was extracted with a second portion of ethyl acetate (40 mL). The combined organic material was evaporated to dryness to give the desired material as a creamy solid (1·32 g). NMR spectrum: ιΗ Li (4〇〇13 MHz, DMS〇d6) occupies i 16 ι 18 (Twisted melon) 123642 -251 - 200817384 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) 5 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) LCMS spectrum: MH+ 470 'Retention time ι·39 min, method for monitoring acid 2-chloro- The preparation of 4-[(3S)-3-methylorfosin-4-yl]-6-(methioninylmethyl)indole is described above. Example 24: l-[4-[4-[(3S)_3_methylphenoflavin-4-yl]-6-(methylmercaptomethyl), pyridine_2_yl]phenyl]·3 ·(2·〃比 bit-2-ylethyl) gives &gt;

Benzyl N-[4-[4-[(3S)-3-methylphenoflavin-4-yl]-6-(methylglycosylmethylmethylene-2-yl]phenyl]carbamate (242 mg, 0.50 mmol) in DMF (1.5 mL). Add triethylamine (0.209 mL, 1.50 mmol). Add 2-pyridin-2-ylethylamine (306 mg, 2.50 mmol) The reaction was stirred at EtOAc (3 mL). EtOAc (EtOAc) D6) 5 1·24 (3H,d),2·94 (2H,t),3·21 (3H,s)5 3.22-3.26 (1H,m),3·48 (1H,d),3.50- 3.54 (2H,m), 3.63-3.67 (1H,m),3_78 (1H,d),3.97-4.00 (1H,m)5 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 123642 -252- 200817384 (1H5 s) LCMS spectrum MH+ 511 amine retention time L67 minutes, method 5 minutes for compounds In a similar manner, from the appropriate urethane (10) and appropriate Example 24a structure

Name LCMS MH+ ί

Fork 24b 24e 24f 123642

〇,·0 fS again

XNH

H4-[4-[(3S)-3-indolyl porphyrin + yl) each (methanesulfonylmethyl)pyrimidin-2-yl]phenyl]-3-dine-3-ylmethyl)urea 3-[2-(1Η-°米施-4-yl)ethyl H-[4_[4-[(3S)-3·methylwfolin_4_yl]-6-(甲石黄酉篮Methyl &gt; Michidine-2-yl]phenyl]urea 3-[4-[4-[(3S)-3-f-yl] oxalinyl]-6·(methylsulfonylmethyl) 3⁄4 σ定-2-yl]phenyl]-1-[(5-methyl峨ρ well-2-yl)methyl]urea H4-[4-[(3S)-3-methyllin-4-yl ]-6-(Methanesulfonylmethyl)pyrimidin-2-yl]phenyl]-3-indolyl-2-ylmethyl)urea residence time (minutes) 1.56 α

[Ν],

Fork l-[4-[4-[(3S)-3-indolyl-norfos-4-yl]-6_(methioninylmethyl)-pyridin-2-yl]phenyl]-3-(external Amidinoylmethyl)urea 3-[(4-methoxyphenyl)methyl]-l-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6 -(曱 醯 醯 甲基 methyl) 唆 唆-2-yl] stupid] urea 497 1. 55 526 2. 04 -253 - 200817384 Example structure name LCMS MH+ retention time (minutes) 24g 0, SN-N Η H H4-[4-[(3S) each methylmorpholine-4-yl]-6·(methylsulfonate) Methyl) σ σ 定 · 2- 2- 2- 2- 2- 2- 2- 2- 2- 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 50 24h Cx Η H 3-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(methylsulfonylmethyl) hydrazin-2-yl] Phenyl]-1-[(5-methyl-1,2-oxazol-3-yl)methyl]urea 501 1. 73 24i CX XA# Η H 3-[(3-Dimethylaminophenyl)methyl] small [4-[4_[(3S)-3-methylorfosin _4_yl]-6- (A stone yellow base methyl). Bite-2·yl]phenyl]urea 539 2. 15 24j Cx Η H l-[4-[4-[(3S)_3-methylmorpholine-4-yl](methanesulfonylmethyl)pyrimidin-2-yl]phenyl]-3- (1,3-pyrazol-5-ylmethyl)urea 503 1. 58 24k 0 W , 0 3-mercapto-l-[l-[4-[(3S)-3-methylinfosin-4-yl]-6_(methioninyl)pyrimidine- 2-yl]pyrazol-3-yl]urea 410 2. 18 241 CX / 1-ethyl-3-[l-[4-[(3S)-3-methylnorfos _4_yl]-6-(methylglycosylmethyl)pyrimidin-2-yl] Pyrazol-3-yl]urea 424 2. 29 24m Cx nlVvh 〇3-cyclopropyl-l-[l-[4-[(3S)-3-methylindol^lin-4-yl]-6-(methylsulfonylmethyl)pyrimidine- 2-yl]pyrazol-3-yl]urea 436 2. 30 123642 -254- 200817384 Example structure name LCMS MH+ retention time (minutes) 24η [λ private α human Η 甲基 3-methyl-l-[l-[4-[(3S)-3-methylmorpholine- 4-yl]-6-(2-methyl feldsparinylpropan-2-yl phenyl. dimethyl-2-yl]-4-hexanitrogen] hydrazinyl] urinary 455 63 24〇Η Η 1-Ethyl-3-[l-[4-[(3S)-3-methylmorpholine-4-yl]-6-(2-methyl-naphedrine-propan-2- Base) ♦ ° 定 -2 yl]-4-hexahydropyridyl]urea 469 1. 76 24ρ 0.  Ααν Η Η 3-Cyclopropyl-Hl-[4-[(3S)-3-methylmorpholine-4-yl]-6-(2-methylsulfonylpropan-2-yl)pyrimidine- 2-yl]-4-hexanitrogen is sigma-based] monthly urine 481 1. 80 24q α 矽αχ? Η Η l-[l_[4-[(3S)-3-methylphenoline p-lin-4-yl]-6-(2-methyl-branched propan-2-yl).密定-2-yl]-4-hexahydropyridyl]-3-[(l-methylpyran-4-yl)methyl]urea 535 1. 69 24r 0, Η Η 3-cyclopropyl_H5-[4_[(3S)-3-methylmorphin-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl] Pyridin-2-yl]urea 446 1. 56 24s 0.  °5ΛαΝιΝχ. 〇Η Η l-[4-[4-[(3S)-3-Methylmorpholine-4-yl]-6-(2-methanesulfonylpropan-2-yl)0 sigma-2 -yl]phenyl]-3-(1,2-oxazol-3-yl)urea 501 1. 64 24t α Η Η 3-[4-[4-[(3S)-3-Methylmorpholine-4-yl]-6-(2-methylsulfonylpropan-2-yl). Bite-2-yl]phenyl]-1-(5-fluorenyl-1,2-oxazol-3-yl)urea 515 2. 22 123642 -255 - 200817384 Example structure name LCMS MH+ retention time (minutes) 24u 0, Η H l-[4-[4-[(3S)-3-indolyl oxafolin-4-yl]-6-( 2-Methanesulfonylpropan-2-yl)°Bitter-2-yl]phenyl]-3-°Min-2-yl-month urine 512 2. 10 24v CX °s'^aNxN^H Η H l-[4-[4-[(3S)-3-methylmorpholine_4_yl]-6-(2-methylsulfonylpropan-2- -yl) ♦ σ-but-2-yl]phenyl]-3-(1Η-pyrazol-3-yl)urea 500 2. 05 24w Cx human j〇Η H l-[4_[4-[(3S)-3-methylmorpholine_4_yl]-6-(2-methylsulfonylpropan-2-yl) σ定-2-yl]benyl]-3-phenyl-pulse 510 2. 40 24x cx ’ said a person jg. Η H 3-(6•Methoxypyridin-3-yl)-l_[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(2-methanesulfonate Mercaptopropan-2-yl)Nandyl-2-yl]phenyl]urea 541 2. 14 24y a push OAX/ Η H 3-(5-gas-based p ratio σ-but-2-yl)_ l_[4-[4-[(3S)-3-methylmorpholine-4-yl]- 6-(2-Methanesulfonylpropan-2-yl) σ-succinyl-2-yl]phenyl]urea 529 2. 39 24z Cx Η H l-[5-[4-[(3S)-3-indolyl-fusin-p--4-yl]-6-(2-A-S-Sylyl-2-yl) 唆-2-yl]-mouth-2-yl]-3-[(l-methylpyrazol-4-yl)methyl]urea 530 1. 68 24aa a Η H 3-3⁄4 propyl-l-[4-[4-[(3S)-3·methylmorpholine-4-yl]-6-(methylsulfonylmethyl)pyrimidine-2 -yl]phenyl]urea 446 1. 38 123642 -256- 200817384 Example structure name LCMS ΜΗ+ residence time (minutes) 24ab [λ 〇〇rS jl Η Η 1-[2,6-difluoro-4-[4-[(3S)-3-methyl) Morpholine-4_yl]-6-(2-methylsulfonylpropan-2-yl)pyrimidin-2-yl]phenyl]-3-methyl-moon urine 484 2. 44 24ac θ' 0 〇itS ^ Η Η 3-[2,6-Difluoro-4-[4-[(3S)-3·methylnorfosin?-4-yl]-6-(2-A Rhein-based propionyl-2-yl) sulfonium-2-yl]phenyl]-1-ethyl-urea 498 2. 56 24ad 0 0 iTS 二Η Η 3-ί辰propyl-1-[2,6-disorder-[4-[(3S)-3-methylorfosin^lin•4-yl]-6-( 2-methanesulfonyl propyl-2*·yl) sulfhydryl]phenyl]urea 510 2. 58 24ae θ' ^ Η Η 1-[2,6-Difluoro-4-[4-[(3S)-3-indolyl]-indol-4-yl]-6-(2-methyllithic acid Prop-2-yl) σ 定 -2--2-yl]phenyl]-3-[(1-indolylpyrazol-4-yl)methyl]urea 564 2. 46 24af CX , for humans Η Η 1-ethyl-3-[5-[4-[(3S)-3-methylnorfos-4-yl]-6-(2-methyl stellite Prop-2-yl)u-densidine·2_yl]pyrimidine_2-yl]urea 464 1. 86 24ag 0, Η Η 3-cyclopropyl-H5-[4-[(3S)-3-methylindol 1 (1 Lin·4-yl]-6·(2-methylsulfonylpropyl-2) - 基基密唆-2-yl] mouth bite-2-yl]urea 476 1. 88 24ah α Η Η 3-Methyl-l-[5-[4-[(3S)-3-methylphenoflavin-4-yl]-6-(2-methyl-yellow-flavor-2- ) ^ 定 -2- -2-yl]pyridin-2-yl]urea 449 1. 77 123642 - 257 - 200817384 Example structure name LCMS MH+ retention time (minutes) 24ai Η Η 1-ethyl-3-[5-[4-[(3S)-3-methyl 福福^林_4-基] -6-(2-Ajungylpropan-2-yl)♦唆-2-yl]17 than ϋ定·2-基]脉463 92 24aj 0&quot; Η Η 3-cyclopropyl-l-[5-[4-[(3S)-3-methylinfos 12lin-4-yl]-6-(2_methylsulfonylpropan-2- -yl)pyrimidin-2-yl]pyridin-2-yl]urea 475 1. 95 24ak Cx Human / Η Η 3-[4-[4-[(3S)-3-Methylphenoxyp-4-yl]-6-(2-methyl-propionylpropan-2-yl)pyrimidine -2-yl]phenyl]-1-propyl-urea 476 1. 92 24al CX, ?5χίΛαΝχΛ Η Η l-[4-[4-[(3S)-3-Mercaptophyrin-4-yl]-6-(2-methylsulfonylpropan-2-yl)° Dense sigma-2-yl]phenyl]-3-propan-2-yl-moon urine 476 2. 08 24am Cx Η Η 3-Cyclobutyl-l-[4-[4-[(3S)-3-methylnorfos-4-yl]-6-(2-oxasulfonylpropan-2- Base pyrimidine-2-yl]phenyl]urea 488 2. 15 24an ο.  ?s^〇lninjCh Η Η 3-(1-Phenyl-2-methylpropan-2-yl)-l-[4-[4-[(3S)-3-methylphenoflavin-4-yl ]-6-(2-methyl sulfonylpropan-2-yl)^ dimethyl-2-yl] phenyl]urea 506 1. 88 24ao Cx Η Η l-[4-[4-[(3S)-3-Methylmorpholine-4-yl]-6-(2-methylsulfonylpropan-2-yl). Cyclosyl-2-yl]phenyl]-3-(pyridin-3-ylmethyl)urea 525 1. 83 24ap 〔:χ, :sAx χ Η Η 3-[(2R)-l-propan-2-yl]methylmorpholine-4_yl]-6-(2-methanesulfonylpropan-2- -yl)pyrimidin-2-yl]phenyl]urea 492 1. 71 123642 -258 - 200817384 EXAMPLES Structure Name LCMS MH+ retention time (minutes) 24aq CX Η H 3-(cyclopropylmethyl)-l-[4-[4-[(3S)-3-methyl phlophone.林-4_基]-6-(2-methyl feldsellylpropan-2-yl) oxime-2-yl]phenyl]urea 488 2. 14 24ar Cx ;sPAx again? Η H l-[4-[4-[(3S)-3-Methylmorpholine-4-yl]-6-(2-methylsulfonylpropan-2-yl)). Ding-2-yl]phenyl]-3-(^ than sigma-4-ylmethyl) monthly urine 525 1. 81 24as Ο&quot;, Η H 3-(3-hydroxypropyl)-l-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(2-methanesulfonate) Acid-propionyl-2-yl)pyrimidin-2-yl]phenyl]urea 492 1. 66 24at Cx human 丫Η H l_[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(2-methylsulfonylpropan-2-yl) ♦ bite- 2-yl]phenyl]-3-(2-methylpropyl)urea 490 2. 24 24au cx VnXtnh Η H 3-(1Η-imidazol-2-ylmethyl)-l-[4-[4-[(3S)-3-methylmorpholine-4-yl]_6-(2- Methylsulfonylpropan-2-yl) hydrazino-2-yl]benzyl]urea 514 1. 76 24av Η H l-[4-[4-[(3S)-3-Methylmorpholine_4_yl]-6-(2-methylsulfonylpropan-2-yl) ° dense σ- 2·yl]phenyl]-3-[(1-methylpyrazol-4-yl)methyl]urea 528 1. 93 24aw CX Η H 3-[4-[4-[(3S)-3-Methylmorpholine-4-yl]-6-(2-methylsulfonylpropan-2-yl)-- 2-yl]phenyl]sodium [(5-fluorenyl-1,2-carbazoleyl)methyl]urea 529 2. 01 123642 -259- 200817384 Example Structure Name LCMS ΜΗ+ Residence Time (minutes) 24ax cx Η Η l_[4-[4-[(3S)-3_Methylorfosyllin-4-yl]-6-( 2-曱-acid propyl-2-yl) σ ϋ -2- -2- -2-yl] phenyl]-3-(1-ρ σ σ-3-ylethyl)urea 539 1. 91 24ay θ' Η Η l-[4-[4-[(3S)-3·Methylorfosyl-p--4-yl]-6-(2·曱石黄-S-L-propyl-2-yl) Pyrimidin-2-yl]phenyl]each (1Η-pyrazol-3-ylmethyl)urea 514 1. 75 24az Cx 方Η Η l_[4-[4-[(3S)-3-Methylphenoxyp-4-yl]-6-(2-methyl-propenylpropan-2-yl), ϋ定-2-yl]phenyl]each [(1-mercaptopyrazole-3-yl)methyl]urea 528 1. 84 24ba Cx Η 1 1,1-Dimethyl-3-[4-[4-[(3S) -3-methylpheno-4-mu-4-yl]-6-(2-methanesulfonylpropyl -2-yl)pyrimidin-2-yl]phenyl]urea 462 1. 87 24bb Cx H N-[4-[4-[(3S)-3-Methylmorpholine-4-yl]-6-(2-methylsulfonylpropan-2-yl). Dimethyl-2-yl]phenyl]norfosin-4-carboxamide 504 84 24bc Cx H ^ OH 4-hydroxy-N-[4-[4-[(3S)-3-methylnorfos-4-yl]-6-(2-methyl-naphedrine-propan-2- Methyl) phenyl-2-yl]phenyl]hexahydropyridine_1_carboxamide 518 68 24bd 3-hydroxy-N-[4-[4-[(3S)-3-methylnorfos-4-yl]-6-(2-methyl-yellow-propyl-2-yl)♦ σ Ding-2-yl]phenyl]hexahydropyridine-1-carbophthalide 518 1. 75 123642 -260- 200817384 Example structure name LCMS MH+ residence time (minutes) 24be [λ N-[4-[4-[(3S)-3-methylnorfos-4-yl]-6-(2-醯 醯 丙 丙 -2- 基 基 基 & 密 密 密 密 密 474 474 474 474 474 474 474 474 474 474 91 24bf [λ Η U0H 3·hydroxy-N_[4-[4-[(3S)-3-methylinfosin-p--4-yl]-6·(2-methylglycolylpropan-2- ) tr 定 -2- -2--2-yl]phenyl] nitrotetrazole-1-propanol 490 1. 62 24bg α Η 1 1-cyclopropyl-1-methyl-3-[4-[4-[(3S)-3_methylphenoflavinyl]-6-(2-methylsulfonylpropyl -2-yl)pyrimidin-2-yl]phenyl]urea 488 2. 18 24bh α Η Η 3-mercapto small [5-[4-[(38)-3-methylorfosyl-p--4-yl]-6-(2-methylglycoside-propionyl-2-phenylidene σ Ding-2-yl]pyrimidin-2-yl]urea 450 1. 70 24bi Ί? Η Η H5_[4_[(3S)-3_f kefafil-4_yl]-6·(2-曱 醢 丙 propyl-2-yl) 咬 -2--2-yl]ρ 比-2-yl]-3-[(1-methylindole-4-yl)methyl]urea 529 1. 75 24bj 〔:χ; said α/, Η Η 3-(2-hydroxyethyl)-i-[4-[4-[(3S) -3-methylphenoflavin-4-yl]-6- (2-methylglycosylpropan-2-yl). Michidine-2-yl]phenyl]urea 478 1. 61 Example 24a ·· W NMR (400. 13 MHz, DMSO-d6) 5 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, 123642 • 261 · 200817384 d), 8. 46-8. 47 (1H, m), 8. 55 (1H,d), 8. 88 (1H, s) Example 24b: 1H NMR (400. 13 MHz, DMSO-d6) (5 1·24 (3H, d), 2.67 (2H, t), 3. 21 (3H, s), 3. 24 (1H, d), 3. 34-3. 39 (2H5 m), 3. 47-3. 53 (1H, m) 5 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 24c : 1 H NMR (400. 13 MHz, DMSO-d6) 5 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 24d ·· 1H NMR (400. 13 MHz, DMSO-d6) 5 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 24e: iH NMR (400-13 MHz, DMSO-d6) 5 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)5 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 24f: iH NMR (400. 13 MHz, DMSO-d6) (5 1·24 (3H, d), 3·21 (3H, s), 3·24 (1H, d), 3. 47-3. 53 (1H, m), 3. 63-3. 67 (1H, m) 5 3. 74 (3H, s) 5 3. 78 (1H,d),3·97-4·01 (1H,m),4·17 (1H,d),4. 25 (2H,d), 4. 48-4. 48 (2H,m), 123642 -262- 200817384 6·59 (1H,t)5 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 24g: iH NMR (400. 13 MHz, DMSO-d6) 5 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)5 4. 19 (1H, s) 5 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 24h ·· NMR (400. 13 MHz, DMSO-d6) (5 1·24 (3H, d), 2·38 (3H, fs), 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 24i: iH NMR (400. 13 MHz, DMSO-d6) 5 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 f (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 24j ·· iH NMR (400. 13 MHz, DMSO-d6) 5 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) 5 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)5 8. 21-8. 24 (2H, m), 8·87 (1H, s) 5 8. 97 (1H,d) Example 24k: iH 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), 123642 -263 - 200817384 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 241: 1 H NMR (400. 13 MHz, DMSO-d6) (5 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)5 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 24m ·· iH NMR (400. 13 MHz, DMSO-d6) 5 0·39-0·43 (2H, m), 0. 64-0. 69 (2H5 m)5 1. 25 (3H5 d), 2. 56-2. 60 (1H? m)5 3. 22 (3H5 s)5 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 24n: iH NMR (400. 13 MHz, DMSO-d6) 5 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 24o: iH 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) Example 24p : 1H NMR (400. 13 MHz, DMSO-d6) 5 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) 5 2. 37-2. 43 (1H? m)? 2. 75 (13⁄4 s) 5 2. 98 (3H5 s)? 2. 96-3. 01 (1H3 123642 -264- 200817384 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)5 4·44 (2H,d), 5·72 (1H,d),5·97 (1H,d),6. 14 (1H, s) Example 24q: iH NMR (400. 13 MHz, DMSO-d6) 5 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 24r: iH NMR (400. 13 MHz, DMSO-d6) 5 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 24s ·· iH NMR (400. 13 MHz, DMSO-d6) 5 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)5 3. 97-4. 01 (1H, m), 4. 25 (1H,d)5 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 (1H5 s) Example 24t : iH NMR (400. 13 MHz, DMSO-d6) 5 1. 24 (3H,d),1·78 (6H, d), 2. 38(3H,d), 3. 04 (3H, s), 3. 19-3. 25(lH,m)53. 47-3. 54 (lH,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 24u : 1 H NMR (400. 13 MHz, DMSO-d6) 5 1. 24 (3H,d), 1. 78 (6H, 123642 -265 - 200817384 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) 5 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 24v : 1 H NMR (400. 13 MHz, DMSO-d6) 5 1. 25 (3H,d)5 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 24w : 1 H NMR (400. 13 MHz, DMSO-d6) 5 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)5 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)5 8·71 (1H,s), 8. 91 (1H, s) Example 24x : 1 H NMR (400. 13 MHz, DMSO-d6) 5 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) Example 24y ·· 1 H NMR (400. 13 MHz, DMSO-d6) 5 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) 123642 - 266- 200817384 Example 24z : 1H NMR (400. 13 MHz, DMSO-d6) 5 1. 24 (3H,d), 1. 77 (6H, s), 3. 00 (3H, s) 5 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)5 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 24aa: iH 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) Example 24ab : 1H NMR (399. 9 MHz, DMSO-d6) 5 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 24ac : iH 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 (2H5 m), 3. 20-3. 27 (1H, m) 5 3. 47-3. 54 (1H, m) 5 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)5 6. 85 (1H, s), 7·95-8·01 (2H, m), 8. 05 (13⁄4 s) Example 24ad : NMR (399. 9 MHz, DMSO-d6) 5 0. 43-0. 47 (2H,m), 0. 63-0. 67 (2H, m), 1. 25 (3H,d), 1. 79 (63⁄4 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) 123642 -267- 200817384 Example 24ae: iH NMR (399. 9 MHz, DMSO-d6) 5 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 24af: 1H NMR (399. 9 MHz, DMSO-d6) 5 1_15 (3H, t), 1. 25 (3H,d), 1·78 (6H,d)5 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 24ag : iH 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)5 4. 63 (1H, s) 5 6. 84 (1H, s), 9. 13 (1H,d)5 9. 38 (2H, s), 10. 07 (1H, s) Example 24ah : 1 H NMR (399. 9 MHz, DMSO-d6) 5 1. 24 (3H,d)5 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)5 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 24ai: 1 H NMR (399. 9 MHz, DMSO-d6) 5 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) 123642 -268- 200817384 Example 24aj : iH 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) Example 24ak : iH NMR (399. 9 MHz, DMSO-d6) δ 0. 90 (3H, t), 1. 24 (33⁄4 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)5 7. 49-7. 52 (2H, m), 8. 23-8. 25 (2H, m), 8. 66 (1H, s) Example 24al : 1H NMR (399. 9 MHz, DMSO-d6) 5 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) Example 24am : 1H NMR (399. 9 MHz, DMSO-d6) 5 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 24an : iH 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, 123642 -269- 200817384 d),8·74 (1H,s) Example 24ao : iH NMR (399. 9 MHz, DMSO-d6) (5 1·24 (3H, d), 1.78 (6H, d), 3·04 (3H, s), 3. 19-3. 25 (1H, m), 3. 47-3. 54 (1H, m) 5 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 24ap ·· iH NMR (399. 9 MHz, DMSO_d6) 5 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) 5 3. 34-3. 42 (2H, m), 3. 47-3. 54 (1H, m), 3·65 (1H, d), 3. 70-3. 74 (1H, m), 3. 78 (1H5 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 24aq: iH NMR (399. 9 MHz, DMSO-d6) 5 0. 18-0. 22 (2H,m), 0. 42-0. 47 (2H,m)5 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 24ar : 1H NMR (400. 13 MHz, DMSO-d6) 5 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 24as : 1 H NMR (400. 13 MHz, DMSO-d6) 5 1·23 (3H, d), 1. 56-1. 62 (2H, m), 1. 76 (3H, s), L77 (3H, s), 3. 04 (3H, s), 3. 14-3. 19 (2H, m), 3. 20-3. 24 (1H? m)5 3. 44-3. 47 (2H5 m)5 3. 49-3. 52 (1H? m), 3. 62-3. 66 (1H? 123642 -270 - 200817384 m), 3·77 (1H, d), 3. 96-4. 00 (1H, m), 4·22 (1H, s), 4. 52 (1H, t), 4·59 (1H, s) 5 6. 22 (1H, t), 6. 74 (1H, s), 7. 48-7. 51 (2H,m),8·23 (2H,d),8·75 (1H,s) Example 24at ·· 1H NMR (400. 13 MHz, DMSO-d6) 6 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 24au : 1H NMR (400. 13 MHz, DMSO-d6) 5 1. 23 (3H,d), 1. 76 (3H, r ; , 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 24av ·· 1 H NMR (400. 13 MHz, DMSOd6) 6 1. 23 (3H,d),1·76 (3H, s), 1. 77 (3H, s) 5 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) 5 3·79 (3H, s), 3. 96-4. 00 (1H, m), 4·12 (2H, r d), 4·23 (1H, s), 4. 60 (1H, s), 6.44 (1H, t), 6. 74 (1H, s), 7·35 (1H, s), 7. 50 l (2H, d), 7. 60 (1H, s), 8·24 (2H, d), 8.74 (1H, s) Example 24aw: 1H NMR (400. 13 MHz, DMSO-d6) 5 1. 23 (3H,d),1·76 (3H, s),1·77 (3H,s)5 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)5 6. 71 (1H, s), 6. 74 (1H, s), 7. 52 (2H,d), 8. 25 (2H,d), 8. 96 (1H, s) Example 24ax : 1 H NMR (400. 13 MHz, DMSO-d6) 5 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) 5 3. 45-3. 52 123642 -271 - 200817384 (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) Example 24ay : 1 H NMR (400. 13 MHz, DMSO-d6) (5 1. 23 (3H,d), 1. 76 (3H, s), 1. 77 (3H, s), 3. 04 (3H, s) 5 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 24az : 1H NMR (400. 13 MHz, DMSO-d6) 5 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) Example 24ba : 1H NMR (400. 13 MHz, DMSO-d6) 5 1·23 (3H, d), 1. 77 (3H, s), 1. 77 (3H, s), 2. 95 (6H, s) 5 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 24bb ·· 1H NMR (400. 13 MHz, DMSO-d6) 5 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), 349-3. 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 (13⁄4 s), 6·75 (1H, s), 7_59 (2H, d), 8. 25 (2H,d), 8. 77 (1H, s) Example 24bc : 1H NMR (400. 13 MHz, DMSO-d6) 5 1. 23 (3H,d), 1. 29-1. 38 123642 -272- 200817384 (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 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) Example 24be : 1 H 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) Example 24bf : 1 H NMR (400. 13 MHz, DMSO-d6) 5 1. 23 (3H,d), 1. 76 (3H, s), 1. 77 (3H, s), 3. 04 (3H, s) 5 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 (23⁄4 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 24bg: 1 H 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) 5 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), 123642-273 - 200817384 7. 63- 7. 66 (2H,m),8·24 (2H,d),8. 43 (1H, s) Example 24bh : 1H NMR (400. 13 MHz, DMSO-d6) (5 1. 23 (3H,d), 1. 77 (3H, s), 1. 77 (3H, s), 2-80 (3H, d) 5 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) 5 6·84 (1H, s), 8. 98 (1H,d),9·37 (2H,s),10. 11 (1H, s) Example 24bi : 1H NMR (400. 13 MHz, DMSO-d6) 5 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 24bj : 1 H 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) Test (a): Example (24) 0. 34 //M; instance (24a) 0. 082 //M; instance (24b) 0. 038 //M; instance (24c) 0. 56 //M; instance (24d) 4. 4 //M; instance (24e) 0·81 //M; instance (24f) 4. 5 //M; instance (24g) 0_31 /zM; instance (24h) 4. 4 //M; instance (24i) 0·33 //M; instance (24j) 0. 22 //M; instance (24k) 0. 18 //M; instance (241) 0·84 //M; instance (24m) 0·65 //M; instance (24η) 3·2 _ ; instance (24o) 3. 4 # ; instance (24p) 0. 89 //M; instance (24q) 5·8 //M; instance (24r) 0. 34 //M ; Example (24s) 0. 0047 //M; instance (24t) 0_012 //M; instance (24u) 0. 12 //M ; instance (24v) 0. 055 //M; instance (24w) 0. 034 //M; instance (24x) 0. 1 //M; example (24y) 2. 2 //M; instance (24z) 0. 37 //M; instance (24aa) 0·11 //M; example 123642 -274- 200817384

(24ab) 0·042 //Μ; instance (24ac) 0.048 _ ; instance (24ad) 0.51 //Μ; instance (24ae) 0·24 //Μ; instance (24bh) 0·012 //Μ; instance ( 24bi) 0·43 /ζΜ; instance (24bj) 0_051 //JVL test (c) · instance (24af) 1·4 /ζΜ; instance (24ag) 0·32 //Μ; instance (24ah) 0·51 //Μ; instance (24ai) 0·26; instance (24aj) 0.45 //Μ; instance (24ak) 0·21 // Μ; instance (24al) 0·038 //Μ; instance (24am) 0·21 //Μ; instance (24an) 1·8 // Μ; instance (24ao) 0·24 _; instance (24ap) 0.077 //Μ; instance (24aq) 2 //Μ; instance (24ar) 0·049 / /Μ; instance (24as) 0.22 //Μ; instance (24at) 0.089 //Μ; instance (24au) 2·4 //Μ; instance (24av) 4·9 //Μ; instance (24aw) 3.4 // Μ; instance (24ax) 0·64 //Μ; instance (24ay) 7·9 //Μ; instance (24az) 5.6 //Μ; instance (24ba) 5.1 //Μ; instance (24bb) 7.8 //Μ Example (24bc) 0.69 /iM; Example (24bd) 3.2 /iM; Example (24be) 4.9 //M; Example (24bf) 6.7 //M ; Example (24bg) 2.4 μΜ. N-[4-[4- [(3S)-3-methylmorpholine-4-yl]-6-(nonylsulfonylmethyl)pyrimidin-2-yl]phenyl]amine Phenyl formate and (4-{4-[1-methyl-1-(methylsulfonyl)ethyl]-6-[(3S)-3-methylmorpholine-4-yl]pyrimidine- The preparation of 2-phenyl}phenyl) carbamic acid phenyl ester is described above. The following urethanes are similar to the above N-[l-[4-[(3S)-3-methylmorpholine-4-yl]-6-(nonylsulfonylmethyl)pyrimidin-2- The phenyl]-4-hexahydropyridyl]amino decanoate is prepared in the manner of the appropriate amine or amine. Structure name LCMS MH+ retention time (minutes) Note 123642 -275 - 200817384 Structure name LCMS MH+ "^ retention time (minutes) Note 0, side support P N_[l-[4-[(3S)-3-methyl? Phenyl-4-yl]-6-(nonylsulfonylmethyl)pyrimidin-2-yl]pyrazol-3-yl]carbamic acid phenyl ester 495 2.09 Purified by chromatography using 0-55 in isohexane % ethyl acetate a 〇p ^ a/0o N-|&gt;[4-[(3S)-3-methylnorfos-4-yl]-6-(2-methyl sulphate-propionyl-2 -Benzyl-2-yl]-4-hexahydropyridinyl] phenyl carbamate 518 2.34 a 0 0 N-[5-[4-[(3S)-3-methylmorpholine-4- Benzyl]-6-(2-methanesulfonylpropan-2-yl)p-dimethyl-2-phenyl&gt; dimethyl-2-yl]phenyl phenyl amide 2.21. Purification by chromatography using DCM 0-3% methanol °'sPAr&gt;/0&lt;) N-[5-[4-[(3S)-3-methylmorpholine-4-yl]-6-(2-methanesulfonyl-propyl Benzyl-2-pyrimidin-2-yl]indole-2-yl]phenyl carbamate 512 2.60 Purified by chromatography using 0-3% methanol a 〇〇fS in DCM ». X) ( S)-2,6-difluoro-4-(4-(3-methylmorpholine)&gt;6-(2-(2-sulfonyl)propan-2-yl)pyrimidin-2-yl)benzene Phenyl phenyl 547 2.67 (S)_2,6·Difluoro-4-(4-(3-methylnorfosyl)-6_(2-(methylphenyl)propan-2-yl)-indolyl-2-yl) Phenyl phenyl carbamate: ^ NMR (400.13 MHz, DMSO-d6) δ 1.25 (3H5 d) 5 1.79 (6Η, d)3 3.00 (3H? s)? 3.20-3.27 (1H5 m)5 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), 123642 -276- 200817384 8.08 (2H,d),9·96 (1H,s) l-[4-[(3S)-3·methylmorpholine_4_yl] each (methanesulfonyl fluorenyl) shhidine_2_ The preparation of the base batch of salino is described below. 1_[4-((3S)_3-methylmorpholine-4-yl] winter (methanesulfonylmethyl)-pyroline-2-yl (tetrazole-3) _amine

2-Chloro-4-[(3S)-3-indolyl phenanthroline-4-yl]_6·(methylsulfonylmethyl) hydrazide (1·〇〇克), 1H-pyrazole- 3-Amine (300 mg) and potassium carbonate (498 mg) were dissolved in nitrile (20 mL). The mixture was heated under reflux for 24 hours. The reaction was diluted with EtOAc (20 mL) andEtOAcEtOAc. The 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 chromatography on silica gel eluting with EtOAc EtOAc EtOAc NMR spectrum: NMR (400.13 MHz, DMSO-d6) 5 1·23 (3 Η, 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) LCMS spectrum: MH+ 490, retention time 1.58 minutes, method monitoring Acid l-[4-[(3S)-3-methylnorfos-4-yl]·6·(2-methylglycopropan-2-yl)Nandrolidine-2-yl]hexahydro Pyridin-4-amine is similar to 1-[4-[(3S)-3-indolyl phenanthroline-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl]hexahydropyridine 4-Amine two-step procedure from (3S)-4-{2-chloro-6-[l-methylsuccinyl)ethyl]pyrimidin-4-yl}·3- Base 123642 - 277 - 200817384 Novolaline and N-(4-hexahydropyridyl)carbamic acid tert-butyl ester. Structure name LCMS MH+ retention time (minutes) [X l-[4-[(3S)-3-methylphenoline p-4-yl]-6-(2-methylsulfonylpropan-2-yl) Indole-2-yl]hexahydrop-pyridin-4-amine 398 0.94 [°λ N-[l-[4-[(3S)-3-methylmorpholine-4-yl]-6-(2 - oxasulfonylpropan-2-yl)pyrimidin-2-yl]-4-hexahydropyridyl]amino decanoic acid tert-butyl ester 498 2.43 l-[4-[(3S)_3-methyl?福普-4-yl]-6-(2-methylphenylpropan-2-yl) shouting-2-yl] hexahydropyridine-4_amine: ^ NMR (400.13 MHz, DMSO-d6) 5 1 ·27 (3H,d), 1·75 (6H,s)5 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-[l-[4-[(3S)-3-曱】 】 】 】 】 】 】 】 】 】 】 】 】 -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 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) 5 4.56 (2H, d), 6.07 (1H, s) (3S)-4-{2- The preparation of chloro-6-[l-methyl-i-(methyl-decyl)ethyl]pyrimidine_4_ylbu-3.methylmorpholine is described above. 5-[4-[(3S )-3-mercapto-oxalinolyl]-6-(2-methylsulfonylpropan-2-yl)pyridin-2-yl]-mouth-2-amine with 5-[4_[(3S)- 3-Methylmorpholine-4-yl]-6-(2•oxasulfonylpropane 123642-278-200817384-2-yl)-l-pyridin-2-yl> is similar to pyridine-2-amine (4-{4-[l-Methyl-1-(methylsulfonyl)ethyl]-6-[(3S)-3-indolyl phenanthrene p--4-yl]. The method described in the form of '3S)-4-{2·gasyl-6-[l-mercapto-1·(A) .密u定-4-yl}·_3-methyl-of-off 11 forest. Structure name LCMS ΜΗ+ retention time (minutes) α 5-[4-[(3S)-3-methylphenoflavin-4-yl]-6-(2-methylsulfonylpropan-2-yl)pyrimidine -2-yl]glycin-2-amine 393 1.57 CX 5-[4-[(3S)-3-methylphenoflavin-4-yl]-6-(2-methylglycosylpropan-2-yl) ) ϋ -2- -2-yl] 峨唆-2-amine 392 1.16 5-[4_[(3S)-3-methylmorpholine-4-yl]-6-(2-methanesulfonyl propyl- 2·yl)pyrimidin-2-yl]pyrimidin-2-amine: 1 H 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) 5 4.22 ( 1H,d),4·57 (1H,s)5 6_74 (1H,s), 7.11 (2H? s)? 9.09 (2H? s) 5-[4_[(3S)_3_Methyl-Fluorine- 4_基]_6_(2_曱sulfonylpropan-2-yl)- phen-2-yl]pyridin-2-amine: 1H NMR (400.13 MHz, CDC13) 5 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), 8. 35-8.38 (1H, m), 9.08-9.09 (1H, m) 2,6-difluoro-4-[4-[(3S)_3_methylmorpholine + yl] each (2_methylsulfonate) The preparation of propylidene-2-yl)benzidine-2-ylaniline is described below. 2,6-difluoro-4-[4-{(3S)-3_indolyl porphyrin-4_yl] each (2-methanesulfonyl propylidene) pain 123642 -279- 200817384 pyridine] aniline

4-bromo-2,6-difluoro-aniline (400 mg, 1.92 mmol), acetic acid unloading (566 mg, 5.77 mmol) and 4,4,5,5-tetradecyl- 2-(4,4,5,5-tetramethyl-1,3,2-dioxanthene-2-yl)-1,3,2-oxo side 圜 (587 mg, 2.31 mmol) The ear is dissolved in 1,4_, dioxane (5 ml). The solution was degassed for 10 minutes, then u,-bis(diphenylphosphino)dicyclopentadienyl iron dichloropalladium (95 mg, 〇·ΐ 2 mmol) was added and the reaction was taken at 90 ° C. Stir for 3 hours. Add (3S)-4-{2-Chloro-6-[l-methylsuccinyl)ethyl]pyrimidin-4-yl}-3-methylmorpholine (450 mg, 1.35 m) Mohr), ethanol (1 ml), 2M sodium carbonate (1 ml) and 1,1,_bis(diphenylphosphino)-cyclopentadienyl iron dioxane (95 mg, 0.12 mmol), and Continue heating for 18 hours. The reaction was allowed to cool to rt then water (5 mL). Undissolved solids are removed by filtration. The liquid phase was separated and the aqueous phase was extracted with a second portion of ethyl acetate (30 mL). The combined organic material was dried over magnesium sulfate, filtered, and evaporated to dryness. The crude product was dissolved in DCM (25 mL), filtered to remove insoluble material, and the residue was purified by chromatography on silica gel eluting with _35% ethyl acetate in isohexane. The substance was an off-white solid (4 〇 2 mg). NMR spectrum: ιΗ Li (4〇〇13 MHz, DMS〇d6) occupies i 23 (3Η, do i is (6H,d),3·〇〇(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, 123642 -280- 200817384 d), 6.73 (1H, s), 7·83-7·85 (2H, m) LCMS spectrum: MH+ 427, retention time 2· Method for the monitoring of N-[5-[4-[(3S)-3-methylmorpholine-4-yl]-6-(methylsulfonylmethylidyl-2-yl)amine The preparation of benzoic acid Benzene is described below. N-[5-[4-[(3S)_3-methylwufolin-4-yl]_6·(methyl mercaptomethyl), bite _2 _基】竹匕 bit-2_ base] phenyl hydroxyacetate

5-[4-[(3S)-3-methylmorpholine yl]-6-(methylsulfonylmethyl) D-Bite_2-yl]

Pyridin-2-amine (770 mg, 2.12 mmol) is dissolved in dioxane (1 mL) and sodium bicarbonate (267 mg, 3.18 mmol) is added to obtain a thin yellow Slurry. Phenyl chloroformate (0.267 ml, 212 mmol) was added dropwise over a period of 1 min, the exotherm was controlled using a water bath, and the mixture was stirred at room temperature for one hour. Additional sodium bicarbonate (267 mg, 318 mmol) and phenyl benzoate (0·267 mL, 2.12 mmol) were added and the mixture was stirred at room temperature for 2 hr. Further, phenyl chloroformate (〇·267 ml, 212 mmol) was added, and the mixture was stirred at room temperature for 1 hour, followed by heating to a pit at 16:. The reaction was evaporated to dryness <RTI ID=0.0>: </RTI> <RTIgt; The white solid was filtered off, and mp EtOAc (EtOAc) The solid was allowed to dry at 40 C for 5 hours to give the product as a white solid (1). LCMS spectrum: brewing 484, residence time W minutes, method to monitor acid 5-[4-[(3S)_3·decyl porphyrin _4_yl] each (methanesulfonyl carbene bite 1 base wind 123642 -281 · 200817384 The preparation of pyridine-2-amine is described above. Example 25:

Hl-[4-[(3S)-3-methylmorpholine-4-yl] winter (methanesulfonylmethyl)pyrimidin-2-yl]-purine_3_yl]-3-phenyl - month urine O'

L-[4-[(3S)-3-Methylmorpholine-4-yl]-6-(methylsulfonylmethylidene-2-yl)pyrazol-3-amine (90 mg , 0.26 mmoles, dissolved in dioxane (4 ml). Add phenyl isocyanate (0.024 ml, 0.22 mmol) to the resulting solution. Heat the mixture at 80 °C. The solid was filtered and washed with diethyl ether (5 mL) to give the desired material as a white solid (66 mg). NMR spectrum: 4 NMR (400.13 MHz, DMSO-d6) of 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 (1H5 d) 4.14 (1H3 s)? 4.47 (13⁄4 m\ 4.51 (2H, d)? 6.60 (1H9 d), 6.81 (1H, s)? 7.01 (1H, t)? 7.29-7.33 (2H? m)? 7.47 ( 23⁄4 d)5 8.51 (1H5 d)5 9.18 (1H, s), 9.50 (1H, s)

123642 -282- 200817384 Example Structure Name LCMS MH+ Retention Time (minutes) 25a 3-(4-Phenoxyphenyl[4-[(3S)-3-indolyl]fosfolin-4-yl]-6-(A Sulfhydrylmethyl) mouth bite-2-yl p than spani-3-yl]urea 502 1.98 25b [&gt;&quot;F 3-(4·fluorophenyl)-1·[1-[4-[( 3S)-3-Methylformin-4-yl]-6-(methylsulfonylmethyl) gnat_2-yl>pyrazine-3-yl]urea 512 2.06 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 Example 25b: iH 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) 5 8.51 (1H, d), 9.17 (1H, s) 5 9.51 (1H, s) Test (a): Example (25) 1·9 //M; Example (25a) 4.4 /M; Example ( 25b) 4.4 /zM. Example 26: N-methyl_2_[[2-[4·(methylaminecarboxylamido)phenyl]-6_[(3S)methylmorpholine-4_ Aminopyrimidine _4_yl]methylsulfonyl] acetamamine 123642 -283 - 200817384

Making N-methyl_2-[[2-[4-(methylamine-mercaptoamino)phenyl]_6_[(3S)_3_methylphenofyl]-based thiophene]methylsulfide Acetylamine (0.35 mmol) was dissolved in M_dioxane HCl) and water (1 mL). m-CPBA (75%) (121 mg) was immediately added to the solution immediately after sodium permanganate (14 mg), and the reaction mixture was stirred at room temperature for 1 hour. An additional m-CPBA (75%) (121 mg) was then immediately added to the solution to sodium permanganate (140 mg) and stirred at room temperature for 1 hour. Another m_CPBA (75%) (121 mg) was added again, followed immediately by sodium chlorate (140 mg), and the reaction was stirred at room temperature for 1 hour. The reaction was loaded onto a Scx_3 (10 g) column which was washed with methanol and the product was eluted with TN ammonia in methanol. This material was further purified by preparative HPLC (1) to give the desired material (3 mg) as a white solid. I NMR spectrum: 1h NMR (400.13 MHz, DMSO-d6) (5 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) mass spectrum; M+H+477. The following compounds were prepared in a similar manner from the appropriate sulfides. 123642 -284- 200817384 Example Structure Name LCMS ΜΗ+ 26a nh2 Η Η 2-[[2-[4-(methylcarbamic acid amino)phenyl]-6-[(3S)-3-methylmorpholine-4-yl]u唆-4-yl]methanoxanthine] acetamidine 463 26b ^ ΝΗ , human / Η Η N-[2-[[2-[4-(methylaminecarbamidoamino)phenyl]·6 -[(38)-3-methylmorpholine-4-yl]pyrimidinyl]methylsulfonyl]ethyl]acetamide 491 Example 26a ·· 1 H NMR (400.13 MHz, DMSO-d6) 5 1·24 (3H,d),2·66 (3H, ί id), 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) -7.52 (3H,m),7·79 (1H,s),8·17-8·21 (2H, m),8·74 (1H,s) Example 26b ·· iH NMR (400.13 MHz, DMSO- D6) 5 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), V 8.14-8.21 (3H,m),8.74 (1H,s Test (a): Example (26) 0.029 //M; Example (26a) 0_037 //M; Example (26b) 0.041 μΜ. N-Methyl-2-[[2-[4-(methylamine A) The preparation of decylamino)phenyl]-6-[(3S)-3-methylmorpholine-4-yl]pyrimidinyl]methylthio]acetamide is described below. N-Mercapto-2-[[2-[4-(nonylaminodecylamino)phenyl]-6-[(3S)-3·indolylfosfolin-4-yl]pyrimidine-4 -yl 1 thiol]acetamide 123642 -285 - 200817384

N-decylsosyl-acetamide (〇·61 mmol) was dissolved in acetonitrile (4 mL). Then, DBU (0.050 ml) was added to the solution and stirred at room temperature for 5 minutes. Add 3-methyl-i-[4-[4-[(3S)-3-methylmorpholine yl]]methanesulfonyloxymethyl)pyrimidin-2-yl]phenyl]urea ( 151 mg) Bath in acetonitrile (2 mL) and DBU (0.054 mL), and the mixture was stirred at room temperature for 2 hours and then concentrated in vacuo and used immediately in the next step. The following sulfides were made in a similar manner. Structure name c°x NH2 N ο Η Η 2-[[2-[4-(indolylcarbamoylamino)phenyl]-6-[(3S)-3-indolylmorpholine-4- N-[2-[[2-[4-(methylamine-carbamoylamino))]]]]]]]] Phenyl]each [(3S)-3-methylmorpholine piperidinyl sulfonyl-4-yl]methylthio]ethyl]acetamide 3-mercapto-l-[4-[4-[( The preparation of 3S)-3·methylmorpholine-4-yl]-6-(nonylsulfonyloxymethyl)peridazin-2-yl]phenyl]urea is described above. Example 27: l-[4-[4_[(3S)-3-indolyl-Walfolin-4-yl]-6-(moff-4-ylmethyl)nonan-2-yl]phenyl ]-3-phenyl-urea

123642 -286- 200817384 H4-[4-(hydroxymethyl) winter [(38&gt;3_曱;TI horse-brown olyl]pyrimidin-2-yl]phenyl]-3-benzyl-urea (90 (mg) is dissolved in dcm (5 * also, &gt; (5 house liters) and triethylamine (0.045 ml)' and the solution is cooled to 〇 ° C. The force is added to the mouse methane sulfonate (0.026 ml), The reaction was stirred at room temperature for 1 hour. Open the field. Add the morpholine (〇 2 ml), and allow the reaction to stand at room temperature for 72 hours, then concentrate in vacuo and borrow HPLC (inspective) purification, the desired compound of the bar, as a white solid. (Dirty spectrum...H NMR (400.13 hemp, DMs〇d6) accounted for i 2ΐ (3η, do 3 17 (4H, t), 3.46 -3.52 (4H, m), 3.63 (4H, d), 3.65 (lH, s), 3.76 (1Η, 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). Mass spectrometry; M+H+489. Test (4): (U9 //M. l-[4-[4_(hydroxymethyl)-6-[(3S)-3-indenyl] Preparation of porphyrin-based ice-based sigma-based 2-phenyl-urea Example 28: H4-[4_[(3S)-3-methylnorfosolin-4-yl] each (phenoxymethyl) saponin-2-yl]phenyl]-3-phenyl- Moon urine

L-[4-[4-[(3S)-3-Methylmorpholine-4·yl]-6_(oxasulfonyloxymethylfusin-2-yl]phenyl]-3 -Phenyl-urea was dissolved in DCM (5 mL), phenol (yield: 41 s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, The mixture was allowed to stand for 18 hours, then concentrated in vacuo, and purified by EtOAc (EtOAc) (EtOAc). MHz, DMSO-d6) 5 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) mass spectrometry; M+H+496. Test (a): 4.7 //M. l-[4-[4_[(3S)-3-methylmorpholine)]- The preparation of methanesulfonyloxymethyl)-piperidin-2-yl]phenyl]-3-phenyl-urea is described above. Example 29: l-[4_[ 4-[(3S)_3-methylphenoflavin-4·yl]-6_[(2-ketotetrahydroτ»bilo-3_yl)-decylmethyl]pyrimidin-2-yl]benzene Base]_3_phenyl-urea

1-[4-[4-[(3S)-3-Methylphenoxy-4-yl]-6-[(2-ketotetrahydroexo(:indol-3-yl)thiocarbonyl) ° σ 定 -2 · · · 苯基 苯基 苯基 苯基 苯基 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 -CPBA (75%) (113 mg), then immediately add sodium permanganate (125 mg) to the solution and leave to stand at room temperature for 1 hour. Charge the reaction to SCX-2 (10 g) tube On the column, 123642 -288 - 200817384 was washed with decyl alcohol and dissolved in 7N ammonia in methanol. The material was further purified by preparative HPLC (basic) to give the desired material (18 mg). White solid. NMR spectrum: 4 NMR (400.13 MHz, DMSO-d6) 6 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) 5 8.24-8.27 (2H, m), 8.38 ( 1H, s), 8·72 (1H, s), 8.92 (1H, s) mass spectrum; M+H+551. Test (4): 0.56 //M. l-[4-[4-[(3S) 3-methyl-moffoff p-lin-4-yl]_6_[(2·ketotetrahydrofuranyl) sulphate methyl; h-mididin-2-yl]phenyl]-3-phenyl·urea The preparative system is described below. l-[4-[4-[(3S)-3·indolyl carbaryl-4-yl]-6-[(2-fluorenyltetrahydrop-biloyl)thio Methyl]pyrimidin-2-yl]phenyl]-3-phenyl-urea

H4-[4-(Carboaminoiminothiomethyl&gt;6·[(3^3_methylmorpholine)]Nymphin-2-yl]phenyl]-3-phenyl -urea (125 mg) is dissolved in DMF (3 ml). The solution is then 3-oxo-tetrahydro-p-pyrrol-2-one (48 mg) followed by water in water (1 liter) Na (42 k) treatment, heated to 4 〇. 〇, and left to stir for 24 hours. Dilute the reaction with a small amount of methanol, and fill it onto the scx_2 column (2 gram), wash it with methanol, and methanol The middle of the claw ammonia dissolves the desired product of 123642 -289-200817384, and the desired substance is used without further characterization. 1-[4-[4-(Carbominoimidothiomethyl)-6 -[(3S)-3-fluorenylmorpholine·φ_yl]pain-2-yl]phenyl]-3-phenyl-urea

曱 吗 吗 福 啉 冬 冬 ] ] ] 各 各 各 各 各 各 各 各 各 各 各 865 865 865 865 865 865 865 865 865 865 865 865 865 865 865 865 865 865 865 865 ), and add \ plus thiourea (146 mg). The reaction was then heated to 7 ° C for 3 Torr, then allowed to cool and concentrated in vacuo to give the desired material which was used without further characterization. L-[4-[4-[(3S)-3-Methylphenanthene p-Alkyl) each (nonylsulfonyloxymethyl). The preparation of melamine-2-yl]phenyl]-3-phenyl-urea is described above. Example 30: 1-[4-[4-(anilinomethyl)-6-[(3S)-3-methylmorphine-4-yl]pyrimidin-2-yl]benzene, yl]-3-benzene Base-pulse

μ[4-[4-[(38)_3-methylmorpholine-4-yl]-6-(methylsulfonyloxymethyl) hydrazide dissolved in DCM solution (5 ml) -2_yl]phenyl] each phenyl-pulse (1 〇 5 mg, 0.21 mmol) was added to aniline (〇〇97 mL, 丨〇6 mmol) and stirred at room temperature for 18 hr. The mixture was vacuumed to dryness and purified by preparative HPLC (basic) to give the desired material (41 mg) as white solids 123642-290-200817384. NMR spectrum: 4 NMR (400.13 MHz, DMSO-d6) 5 1.15 (3H, d), 3·12-3·18 (1H, m), 3.43-3.50 (1H, m), 3.59-3.63 (1H, m ) 5 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,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)· mass spectrum; M+H+495. The following compounds were also prepared in a similar manner. Example structure name LCMS MH+ 30a ΝαΑ〇ι,Χ) Η H l-[4-[4-[(3S)_3-methylmorpholine-4-yl]-6-[(4-methylhexahydroindole) --i-yl)methyl]pyrimidin-2-yl]phenyl]-3·phenyl-urea 502 30b [X Η H H4-[4-[(cyclopropylamino)methyl]_6-[(3S曱-3-曱 吗 福 琳 冬 冬 ] 口 口 口 口 基 基 基 基 基 基 l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l Methylmorphine _4·yl]_6-[[(1-methyl-4-hexahydroindenyl)amino]methyl]indol-2-yl]phenyl]-3-phenyl- Urea 516 30d [X Η H 1-[4-[4-[(cyclopropyl-methyl-amino)indolyl]-6-[(3S)-3-methylmorpholine-4-yl] Pyrimidine-2-yl]phenyl]-3-phenyl-urea 473 Example 30a: iH NMR (400.13 MHz, DMSO-d6) 51.22 (3H,d),2·22 (3H, s)3 2.44 (2H5 d ) 2.53 (2H? d)5 2.56 (2H5 s)5 2.60-2.61 (1H? m)5 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 123642 -291 - 200817384 (1H, d), 3.96-4.00 (1H, m), 4·15 (1H, d), 4·47-4·49 (1H, m)5 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 30b: iH NMR (400.13 MHz, DMSO-d6) 5 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 30d: iH NMR (400.13 MHz, DMSO-d6) 5 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) Test (a) ··Example (30) 0.9 //M ; 30a) 0.12 //M; instance (30b) 0.18 //M; instance (30c) 1·1 //M; instance (30d) 0.28 //M. l-[4-[4-[(3S)-3 The preparation of -methylmorpho-4-yl]-6-(methylglycosyloxyindolyl y-mididin-2-yl]phenyl]-3-phenyl-urea is described above. Example 31: l-[4_[4_[(3S)-3-Methylmorpholine_4_yl]-6-[([methyl_4_hexahydropyridyl)oxymethyl]pyrimidine·2 _ base] phenyl] phenyl-urea 123642 -292- 200817384

Α-[4-[4-[(3S)-3_methylmorpholine_4_yl]-6_) in a solution of DCM (5 ml) and triethylamine (0.045 ml) (Methanesulfonyloxymethyl pyridine 1 yl) phenyl]-3-phenyl-urea (1 〇 5 mg) was added to hydroxy small methyl hexahydropyridine (5 eq.). DBU (0.158 ml) was added. It was stirred at room temperature for 18 hours. f The mixture was evaporated to dryness and purified by preparative HPLC (basic) to give the desired material (64 mg) as white solid. 517. Test (4): 0.35 /iM. l-[4-[4-[(3S)-3-Methyl-Walfolin-4-yl]-6·(Methanesulfonyloxymethyl)-bite- The preparation of 2-yl]phenyl]-3-phenyl-I urine is described above. Example 32: 1-[4_[4-(methoxymethyl)-6-[(3S)-3_A Kefulin _4_ base], bite base benzene: phenyl] phenyl-urea

L-[4-[4-[(3S)-3-Methylmorpholine-4-yl; |-6_(methionineoxymethyl)). Benzidyl]phenyl]_3_phenyl-urea (90 mg) was dissolved in DCM (5 mL) and triethylamine (0.045 mL). Sodium methoxide (33% in methanol) (〇〇73 ml) was added to the mixture, and the mixture was stirred at room temperature for 18 hrs, then quenched with water, and liquid separation. The organic phase was detached with sulfuric acid. 123642 • 293 - 200817384 The water was dried and evaporated to give a gum, which was purified by preparative hplc (basic) to give the desired compound (32 mg) as a white solid. NMR spectrum: β NMR (400.13 MHz, DMSO-d6) 5 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)5 7.55 (2H,d),8·26 (2H,d),8·69 (1H,s), 8 · 88 (1H, s) mass spectrometry; M+H+434. Test (a): 0.0062 /M. H4-[4-[(3S)-3-methylmorpholine-4-yl]_6-(曱The preparation of the sulfonyloxyindenyl)carin-2-yl]phenyl]-3-phenyl-urea is described above. Example 33: 3-Methyl-1-[4·[4-[(1·methylimidazolium-2-yl)-decylmethyl]-6-[(3S)-3·indolyl porphyrin-4 _ base] phen-2-yl] phenyl] urea

3-methyl-indole-[4-[4-[(μmethylimidazot-2-yl)thiomethyl]_6-[(3S)-3-methylphenothonine]- 2-Phenyl]phenyl]urea (〇·23 mmol) was dissolved in 1,4-dioxane (4 mL) and water (1 mL). m-CPBA (75%) (80 mg) was then added to the solution immediately after sodium benzoate (92 mg). The reaction was stirred at room temperature for 18 hours, then loaded onto a SCx 2 (1 gram) column which was washed with methanol and dissolved in 7N ammonia in methanol. The reaction was taken up in vacuo to dryness crystals eluted eluted eluted eluted elution NMR spectrum: 4 NMR (400.13 MHz, DMSO-d6) 5 U7-1.22 (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) mass spectrum; M+H+486. The following structure name LCMS MH+ 33a. Slave Η 1-[4-[4-[(2-chlorophenyl)-inosinylmethyl]-6-[(3S)-3-methylphenoflavin-4-yl]pyrimidin-2-yl Phenyl]-3-methyl-urea 516 33b 0 1-[4_[4-[(2-methoxyphenyl)) fluorenyl]-6_[(38)·3-methylfowlene 4-yl]pyrimidin-2-yl]phenyl]-3-methyl-urea 512 33c ^ 0, αν Η Η Η4-[4-(1Η-imidazol-2-ylsulfonylmethyl)-6 -[(3S)-3-indolyl carbaryl winter base] pyrimidin-2-yl]phenyl]-3-indenyl-urea 472 33d Λ 0, Η Η H4_[4-[(4-aminobenzene) Sulfhydrylmethyl]-6-[(3S)-3-methylmorpholine-4-yl]pyrimidin-2-yl]phenyl]-3-methyl-monthly 497 33e. 3-Methyl small [4-[4-[(3S)-3-methylmorpholine-4-yl]-6-[(2-methylphenyl)sulfonylmethyl]pyrimidin-2- ]]Phenyl]urea 496 123642 -295 - 200817384 Example structure name LCMS ΜΗ + 33f 〇a . 々XV Η H 3_Methyl small [4-[4-[(3S)-3·methylwufolin-4-yl]-6-(V is more than -2-yl) Pyrimidine-2-yl]phenyl]urea 483 33g Η H 3-indolyl_l-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(1 , 3-thiazol-2-ylglycolylmethyl)♦ σ定-2-yl]phenyl]monthly urine 489 33h ^ a Η H 3-methyl-l-[4-[4-[(3S) 3-methyl-moffoff p-lin-4-yl]-6-[(4-methyl-l,3-p sulphonyl-2-yl)-methylmethyl]pyrimidin-2-yl]benzene ] 503 Example 33a: iH 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 (1H, s). Example 33b: iH NMR (400.13 MHz, DMSO-d6) ά 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 33c: iH NMR (400.13 MHz, DMSO-d6) 5 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) 5 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) 123642 -296 - 200817384 Example 33d : iH NMR (400.13 MHz, DMSO-d6) (5 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 (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) Example 33e: NMR (400.13 MHz, DMSO-d6) 5 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)5 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 33f: iH NMR (400.13 MHz, DMSO-d6) 5 1.20 (3H, d), 2.65-2.68 (3H, m), 3.16-3.21 (1H , m), 3.44 - 3.51 (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 33g: iH 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 (2H, m), 7.84 (2H, d), 8.27-8.29 (2H, m), 8.71 (1H, s)_ Example 33h: iH NMR ( 400.13 MHz, DMSO-d6) 5 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 123642 -297 - 200817384 (1H,s) Test (8): Example (33) 0.84 //M ; Example (33a) 0.06 //M; Example (33b) 0.066 //M; Example (33c) 0.0014 &quot;M; Example (33d) 0.00031 //M; Example (33e) 0.088 //M ; Example (33f) 0.27 //M; example (33g) 0.021 //M; example (33h) 0.048 μΜ. 3-methyl·1·[4-[4_[(1-mercaptoimidazole-2-yl)thio)] The preparation of -6_[(3S)-3_methylmorpholine sulfo]piperidinyl-1 phenyl]urea is described below. r 3-methyl-1_[4·[4-[(1-methylimidazolyl-2-yl)thiomethyl l_6-[(3S)-3-methylmorpholine-4-yl]pyrimidine 2-yl]phenyl]urea==V ίι 〆〇,

Further, 1-mercaptoimidazole-2·· thiol (0.23 mmol) was dissolved in acetonitrile (2 ml), DBU (0.035 ml) was added, and the mixture was stirred at room temperature for 5 min. Add 3-methyl-l-[4-[4-[(3S)-3-methylmorpholine_4_yl]_6_(methylsulfonyloxyindenyl)-indol-2-yl]benzene A solution of urea (1 mg) in acetonitrile (2 ml) and DBu (0.034 ml), and the mixture was stirred at room temperature for 18 hours, then concentrated in vacuo to give the desired material. This material is used without further purification. Structure __ Name Η Η 1-[4-[4-[(2-Chlorophenyl)thiomethyl]·6_[(3S)_3-methylmorpholine), pyridine]phenyl] _3_曱基-urea 123642 -298 - 200817384 Structure name Η Η 1-[4-[4-[(2-methoxyphenyl)thiomethyl]-6-[(3S)-3-fluorenyl] Folinolin-4-yl]pyrimidin-2-yl]phenyl]methyl-urea hydrazine, r=\ ^ , ΗΝγΝ Λν sa^a human Η [ 1-[4-[4-(1Η_imidazole- 2-ylthiomethyl)-6-[(3S)-3-indolyl porphyrin-4-4]pyrimidin-2-yl]phenyl]-3-methyl-urea Η 1-[4 -[4-[(4-Aminophenyl)thiomethyl]-6-[(3S)-3-indolylfosfolin-4-yl]pyrimidin-2-yl]phenyl]-3- Methyl-urea Η Η 3-methyl-l-[4-[4-[(3S)-3-methylmorphinyl]-6-[(2-methylphenyl)thiomethyl spicy咬_2-yl]phenyl]urea p Λ; Η Η α ^ F=\ V Νγδ (Αν s^N^aNiN. Η Η 3-methyl-l-[4-[4-[(3S)_3_ Methyl^(pyridin-2-ylthiomethyl)pyrimidinyl]] 笨月尿尿i-[4-[4_[(3S)-3_f (l,3-p-sept-2-ylthio) Base) bite 2 - base] stupid ^ NYS Λ Η Η Η 3-f^-l-[4-[4-[(3S)-3-f [(4-methyl-1,3-plug) Zin-2-yl)thiomethyl 1 密 = yl] phenyl] urea J in 疋Winter—^__ 3_Methyl small [4_[4-[(3S) Winter Methylfosfolin-4-yl]-6·(Methanesulfonyloxymethyl)) σ 1 1 base] benzene The preparation of urea is described in the previous section. Example 34: Continuation of mercapto methyl flucon-4H bit-2-yl] stupid base] Peng ^ 123642 -299 - 200817384

N-[4-[4-(methylsulfonylfluorenyl)·6_fosfosin, phenylpyridinyl]phenyl]amino decanoate (110 g) was dissolved in DMF (2 ml) ) and added triethylamine (0.098 ml). 2-Aminopyrimidine (108 mg) was added and the reaction was stirred at 4 ° C for 2 h. Purification of the crude mixture by preparative hplc (alkaline) 'but 'only [4-[4-(methyl sulphate methyl) each sulphate p liningyl-pyrimidin-2-yl]phenyl]urea from the mixture ( 8 mg). NMR spectrum·· 1H NMR (400.13 MHz, DMSO-d6) 5 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) mass spectrum; M+H+392. The following compounds were prepared in a similar procedure. Example structure name LCMS MH+ 34a 0 〇r Η H l-[4-[4-(曱石黄醯基methyl&gt;6_?福 4 -4-基咬-2_基]phenyl] -3_(1, 2-oxazol-3-yl)urea 458 34b C] recognizes A0 Η H 1-(5-methyl-1,2-4 sani-3-yl) each [4_[4-(methanesulfonyl) )6_ oxalin-4-yl, indol-2-yl]phenyl]urea 472 34c Η H 1-(1-methylpyrazol-3-yl)-3-[4_[4- (A Phthalocyanine methyl)-6-moffinyl-m-yl-2-yl]phenyl]urea 471 Example 34a: iH NMR (400.13 MHz, DMSO-d6) 5 3.21 (3H, s), 3.73 (8H, 123642 -300- 200817384 s), 4·50 (2H, s), 6.85-6.87 (2H, m), 7.56-7.59 (2H, m), 8·28-8·31 (2H, m) , 8·75 (1H, d), 9.07 (1H, s), 9·62 (1H, s) Example 34b: iH NMR (400.13 MHz, DMS 〇d6) 5 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 34c: 1 H NMR (400.13 MHz, DMSO-d6) 5 3.21 (3H, s), 3· 72 (3H, s), 3·74 (8H, s), 4·49 (2H, s), 6·25 (1H, d), 6·8 4 (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)· Test (a): Example (34) 0.21 //M; Example (34a) 0.042 //M; Example (34b) 0.12 //M; Example (34c) 0.72 //M. N-[4-[4-( The preparation of methanesulfonyl fluorenyl) oxafolin-4-yl-pyrimidin-2-yl]phenyl]amino decanoic acid is described above. Example 35: 3-(1-hydroxypropan-2) _基)_l-[4-[4_[(3S) each methylnorfosph-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl]phenyl]urea

N [4-[4-[(3S)-3-methylphenoflavin-4-yl]-6-(methioninylmethyl) mouth. Addition of a solution of phenyl]phenyl]carbamic acid phenyl ester (110 mg, 〇.23 mmol) to triethylamine (〇〇79 liters, 0.68 Torr) in DMF (2 mL) Alkyl propyl alcohol (U4 耄 Moel). The reaction was stirred for 2 hours and then purified by preparative HPLC (basic) to give the desired material (22 mg). 123642 -301 - 200817384 NMR spectrum: β 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) 5 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) mass spectrum; M+H+463. Wang f, made by hydrazine compounding. Example structure yi - «j /jy u Name LCMS ΜΗ + 35a [X Η H M3-dimethylaminopropyl)·ΐ-[4_[4-[(3S)-3·methylmorpholine ice-based] -6-(Methanesulfonylmethyl) oxaridin-2-yl] phenyl]urea 491 35b 0, 3_0 methoxypropyl)-l-[4-[4-[(3S) •3·A Kefufuulin-4-yl]-6-(methioninylmercapto)pyrimidin-2-yl]phenylf-urea 478 35c [°λ N-[4-[4-[(3S)-3- Methylmorpho-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl]phenyl]tetrahydrop-pyryl-1-carboxamide 460 35d [°λ N-[4 -[4-[(3S)-3-methylmorpholine + yl]-6-(methioninylmethyl) σσ定_2_yl]phenyl] phenofyl glacial acesulfame 476 35e Cx 〇OH 4_hydroxy-N-[4-[4-[(3S)-3-methylphenoflavin-4-yl]·6·(曱石黄毛methyl)pyrimidin-2-yl]benzene ]] hexahydropyridine-1-carboxyguanamine 490 123642 -302- 200817384 Example structure name LCMS MH+ 35f a Η H ' l-[4_[4-[(3S)-3-indolylfosfolin-4-yl ]-6-(Methanesulfonylmethyl)pyrimidin-2-yl]phenyl]-3-di-butyl-moon urine 462 35g [X 0 ·〇fS i Η H 3-(2-dimethyl Aminoethyl)-1-[4-[4_[(3S)-3-methylmorpholine-4-yl]-6- (methane) Methyl)pyrimidin-2-yl]phenyl]urea 477 35h a ;s°^aA/°H Η H 3-(2-hydroxyethyl)-l-[4-[4-[(3S)- 3-methylfosfosin-4-yl]-6-(methionine methyl&gt; melidin-2-yl]phenyl]urea 450 35i cx Ά/cr 3-hydroxy-N-[ 4-[4-[(3S)-3-indolyl keifene. lin-4-yl]-6_(methionine methyl) 密 咬 _2 _ _2 _2 ] ] ] σ σ σ σ -1- 竣 胺 amine 490 35j MW, Η | 1-(2-dimethylaminoethyl)-1-methyl-3_[4-[4-[(3S)-3-methylmorpholine 4-yl]-6-(methyl sulfonylmethyl) succinyl-2-yl]phenyl]urea 491 35k O' &gt;lAa human/° Η H l-[4-[4-[(3S )-3-methylfosfolin-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl]phenyl]-3-(2-morpholine-4-ylethyl) Urea 486 351 O' ?s〇A&gt;/? Η H 3-(1Η-imidazole-2_ylindenyl)-1-[4_[4-[(3S)-3-indolyl? -yl]-6_(sulfonylmethyl)pyrimidin-2-yl]phenyl]urea 460 35m a qp Human H | 1-cyclopropyl-1-methyl-3-[4-[4-[ (3S) -3-methylmorphine-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl]phenyl]urea 460 123642 - 303 - 200817384 Example structure name LCMS MH+ 35n CX (3S)-3_ methyl -N-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl]phenyl]morpholine- 4-Carboxylimine 490 Example 35a: iH NMR (400.13 MHz, DMSO-d6) 6 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) 5 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 35b: iH NMR (400.13 MHz, DMSO-d6) 5 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 35c: iH NMR (400.13 MHz, DMSO-d6) 5 1.25 (3H, d), 1.85-1.88 (4H, m), 3·21 (3H, s), 3.40 (5H, m) 5 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), v 7.63-7.66 (2H, m), 8.19-8.22 (2H, m), 8.31 (1H, s) Example 35d: iH NMR (400.13 MHz, DMSO-d6) (5 5 1.25 (3H, d), 3.21 (3H, s), 3.33-3.34 (1H, m), 3·46 (5H ,t)5 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 35e: NMR (400.13 MHz, DMSO-d6 ) 6 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, 123642 -304· 200817384 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 35f: 1 H 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) 5 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 35g : 1H NMR (400.13 MHz, DMSO -d6) 5 1.24 (3H,d), 2.18 (6H, / % s), 2·34 (2H,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 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) Example 35i: iH NMR (400.13 MHz, DMSO-d6) 5 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 35j: 4 NMR (400.13 MHz, DMSO-d6) 5 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, 123642 - 305 - 200817384 s) Example 35k : 1H NMR (400.13 MHz, DMSOd6) 6 1.24 (3H,d),2·39 (2H, d), 2.41 (4H,d)5 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 351: iH NMR (400.13 MHz, DMSO-d6) (5 1 · 25 (3H, d) 5 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 (23⁄4 s),7.51-7.53 (2H,m) , 8.22 (2H,d)5 8.93 (1H, s), 11.84 (1H5 s) Example 35m : iH NMR (400.13 MHz, DMSO-d6) 5 0·69-0·73 (2H, m), 0.88-0.93 (2H,m),1·25 PH,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 35n: 1 H NMR (400.13 MHz, DMSO-d6 ) 5 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). Test (4): Example (35) 0.064 //M; Example (35a) 6.4 //M; Example (35b) 0.42 //M; Example (35c) 3.4; Example (35d) 3·2 / /M ;Instance (35e) 2.5 //M ; Example (35f) 0.82 //M ; Example (35g) 0.66 /zM ; Example (35h) 0.024 _ ; Example (35i) 0.77 //M ; Example (35j) 3.6 //M; instance (35k) 1.2 //M; instance (351) 123642 -306 - 200817384 0.47 //Μ; instance (35m) 2 //Μ; instance (35n) u N-[4-[4-[ The preparation of (3S)-3-mercapto-oxalinyl] phenyl(methylsulfonylfluorenyl)pyrimidin-2-yl]phenyl]carbamic acid is described above. Example 36: 3_cyclopropyl_l_[4-[4-[(3S)-3-methylmorpholine ice carbonyl] each [(3S)methylmorpholine-4-yl]pyrimidine-2 -phenyl]urea

2·[4·(cyclopropylaminecarbamimidino)phenyl]_6^3S)_3_methylmorphine winter base; h-pyridine-4·carboxylic acid (95 mg) dissolved in DMF ( 3 ml) and add (3S)-3-methyl phofenin. DIPEA (0.125 ml) and HATU (137 mg) were added, and the mixture was stirred at room temperature for 3 hr then concentrated in vacuo and partitioned between DCM (25 ml) and water (25 ml) . The organic layer was dried with EtOAc (EtOAc m. NMR spectrum · 4 NMR (400.13 MHz, DMSO-d6) 5 0.40-0.44 (2H, m), 0.63-0.67 (2H5 m)5 1.24 (6H? m)5 2.52-2.61 (1H5 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) 5 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) 5 7·51 (2H, d), 8.20 (2H, t), 8·54 (1H, s) mass spectrum; M+H+480. The following samples were prepared in a similar manner. 123642 • 307 - 200817384 Example structure name LCMS MH+ 36a Cx /Ν·Λχ Fork Η Ν-ί哀propyl-2-[4-(cyclopropylaminecarboxamido)phenyl]-6-[( 3S&gt;3-methylphenoflavin-4·yl]pyrimidine-4-carboxamide 436 36b θ' Η Η 3-cyclopropyl_1-[4-[4_[(38)-3-methyl? Phenanthroline·4·yl]-6-(4-methylhexahydropyrazine-1-carbonyl)pyrimidin-2-yl]phenyl]urea 479 Example 36a: 4 NMR (400.13 MHz, DMSO_d6) (5 0.39- 0.44 (2H,m)5 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) 5 3·77 (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). Example 36b: iH NMR (400.13 MHz, DMSO-d6) 5 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), 8.18-8.20 (2H, m), 8·54 (1H, s) · Test (a): Example (36) 0.062 //M; Example (36a) 2 · 9 //M; Example (36b) 0.18 μΜ. 2-[4-(Cyclopropylaminodecylamino)phenyl]-6-[(3S)-3-methylmorpholine-4- The preparation of the pyrimidine-4-carboxylic acid is described below. 2-[4-(Cyclopropylaminecarboxylamido)phenyl]-6-[(3S)-3-methylmorpholine-4 -基] 123642 - 308 - 200817384 Pyrimidine-4_carboxylic acid

Θα, 2-[4-(cyclopropylaminecarbamimidino)phenyl][[3s&gt;3-methylmorphobordol]pyrimidine+carboxylic acid oxime ester (350 mg) was dissolved in Add sodium hydroxide (67 mg) in water (15 ml), and the mixture was stirred at room temperature for 1 hour. Add 2 additional sodium hydroxide with THF (3 mL). After a few hours, 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. Drying at ° C for 18 hours gave the desired material (350 mg) as a white solid. NMR spectrum: iH 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 (1H5 m\ 3.63-3.66 (1H, m)5 3.75 (1H5 d)5 3.95-3.99 (13⁄4 m)5 4·14-4·17 (1H,m)5 4·48 (1H,d),6·92 (1H,s), 7.28 (1H,s ), 7.56 (2H, d), 8·22 (2H, d), 9.41 (1H, s) mass spectrum; M+H+398. 2-[4-(cyclopropylaminecarbamimidyl)phenyl ]-6-[(3S)-3- Methylmorpholine-4-yl]pyrimidine-4-carboxylic acid methyl ester

6-[(3S)-3-Methylmorpholine-4-yl]-2-[4-(phenoxycarbonylamino)phenyl] 123642 - 309 - 200817384 The ester (547 mg) was dissolved in DMF (8 mL) and triethylamine (yield: 59 mL). The reaction was taken at 4 Torr. The mixture was stirred for 2 hours, and then the mixture was evacuated to dryness and subjected to liquid separation between DCm (5 liters of house liter) and water (50 ml). The organic layer was dried (MgSO4) to dryness eluted eluted elut elut elut elut elut elut elut elut elut elut NMR spectrum: iH NMR (400.13 MHz, DMSO_d6) 5 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 (23⁄4 m) 5 8.22-8.25 (2H? m) 5 8.56 (1H, s) mass spectrometry; M+H+412. 6_[(3S)_3-methylmorpholine ice-based]_2_[4_(phenoxycarbonylamino)phenyl]midine

2-(4-Amine base)_6-[(3S)-3_methylphenoline p--4-yl]N-carboxylic acid methyl ester (400 mg) was dissolved in dioxane (10 ml), and sodium hydrogencarbonate (154 mg) and phenyl chloroformate (0·154 ml) were added dropwise. The mixture was stirred at room temperature for 16 hours, then dioxane was removed under reduced pressure and residue was partitioned between water (50 ml) and ethyl acetate (50 ml). The organic layer was dried over MgSO4, filtered, and evaporated, 123642 -310- 200817384 NMR spectrum: iH NMR (400.13 MHz, DMSO-d6) 5 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) mass spectrum; M+H+449. 2-(4-Aminophenyl)-6-[(3S)-3-methylmorpholine-4-yl]pyrimidine_ 4·Methyl carboxylate

f 2_(4-Aminophenyl)_6-[(3S)-3-methylinfos-4-yl] shouting -4-decanoic acid (1.15 g) in methanol (15 ml) Sulfuric acid (〇·〇ι ml) was added and the reaction was heated at 80 ° C for 24 hours. A small amount of active molecular sieve 4A was added to the reaction and stirred for 2 hours. The reaction was filtered, dried with EtOAc EtOAc m. The organic layer was filtered, dried over EtOAc EtOAc EtOAc NMR spectrum: 4 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), 8.06-8.08 (2H, m) MS; M+H+329. 2-(4-aminophenyl)-6-[(3S)-3 _Methylmorpholine_4_yl]pyrimidine-4_carboxylic acid 123642 -311 - 200817384

2_Chloro·6-[(3S)_3·Methylorfosin-4-indolyl]0 succinate-4-carboxylic acid A (1 gram) dissolved in 7 : 3 : 2 DME : Water: Is% Dmf (1 〇 ml) in a mixture of ethanol. Then, (4-aminophenyl)dihydroxyborane ester (1.21 g) and 2M sodium carbonate (5 ml) were added, and the solution was degassed for 5 minutes. Dioxane bis(triphenylphosphine) catalyst (130 mg) was added and the reaction was refluxed for 9 hours under rc and nitrogen atmosphere. The reaction was cooled, concentrated in vacuo and residue was taken from ethyl acetate. A liquid separation treatment between S (100 ml) and water (100 ml), the water phase is passed, and the volume is reduced in a vacuum. The formed solution is acidified with concentrated hydrochloric acid, and vacuumed to dryness to obtain the desired Mass spectrometry; M+H+315. Preparation of 2-chloro-{6-[(3S)-3-methylmorpholine]pyrimidinecarboxylic acid methyl ester is described above. Example 37: 3- Cyclopropyl small [4-[4_(2-hydroxypropan-2-yl)_6-[(3S)-3-methylmorpholine_4_yl], pyridine-2-yl]phenyl]

孓[2_Chloro-6-[(3S)-3-methylmorpholine]pyrimidinyl]propan-2-ol (7 g) is dissolved in 7:3: 2DME: water: ethanol 18% of the mixture 1) (4 liters) and added 4-(3-cyclopropylureido)phenyldihydroxyborane (98 mg) 123642 -312- 200817384 with 2M sodium carbonate (1 ml) ). Dioxobis(triphenylphosphine)palladium catalyst (9) milligrams was added and the solution was heated in a microwave reactor at 1 °C for 5 hours. The mixture was acidified with concentrated hydrochloric acid and directly charged to a column of 8 〇 2 column column. The column was washed with methanol, and then the product was dissolved in ammonia in methanol to obtain the desired substance (55 mg). ), as a white solid. Dirty spectrum: NMR _.13 MHz, purchase 6) (4) Just (2H, post 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), s), 5.17 (1H, s), 6.41 (1H, d), 6.80 (1H, s), 7·48 (2H,d)5 8·23 (2H,d), 8.50 (1H,s) mass spectrum; M+H+412. Test (a): 0.051 //M· 2 [2-Chloro-6-[(3S)-3-methylphenofin_4_yl]. The preparation of styrene-based ice-based propylene glycol is described below. 2·[2-Alkyl-6-[(3S)-3-methylmorpholine t-based]pyrimidinyl]propan-2-ol

α 2-Hydroxy-6-[(3S)-3-methylmorpholine]-carbazide (3 (8) mg) was dissolved in dry THF and cooled to _78t. Methylmagnesium bromide (3.0 M in diethyl ether, 0.74 mL) was added dropwise over 2 min then the mixture was stirred at -78 C for 20 min then warmed to room temperature. The reaction was stirred for a further 20 min then quenched with water (2 mL). The reaction volume was reduced to dryness and partitioned between ethyl acetate (5 mL) and water (5 mL) for 123642 - 313 - 200817384, and the organic layer was dried over magnesium sulfate and vacuumed. The desired substance was dried as a white solid (291 mg). NMR spectrum: (400.13 MHz, DMSO-d6) 5 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)5 3.91-3.94 (2H,m),4.34 (1H,s),5·28 (1H,s),6·87 (1H , s)· mass spectrometry; M+H+272. Preparation of 2_chloro-6-[(3S)-3-methylmorpholine winter base&gt; pyridine 4-carboxylic acid oxime ester is described in the previous article . Example 38: 1-[4·[4-(2-Hydroxypropyl-2-yl)-6-[(3S)-3-methylmorpholine·4·yl]pyrimidin-2-yl]phenyl] ·Η([methylpyrazol-4-yl)methyl]urea

Dissolve 2-0 chloro-6-[(3S)-3-methylinfos _4_yl]pyrimidin-4-yl]propan-2-ol (70 mg) in 7:3: 2 DME: Water: 18% DMF (4 ml) in a mixture of ethanol. Add 3-[(1-methylpyrazole-4.yl)methyl]-1-[4_(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2 -yl)phenyl]urea (115 mg) with 2M sodium carbonate (1 mL). Dichlorobis(triphenylphosphine) catalyst (10 mg) was added and the solution was heated in a microwave reactor at 〇〇 ° C for 5 hours. The mixture was acidified with concentrated hydrochloric acid and directly loaded onto a SCX-2 column (1 gram), and the column was washed with methanol, then the product was dissolved in 7N ammonia in methanol to give the desired material (55 mg). It is a white solid. 123642 -314- 200817384 NMR spectrum: β NMR (400.13 MHz, DMSO-d6) 5 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) mass spectrometry; M+H+466. Test (a): 1.3 //M. 2- [2 The preparation of chloro-6-[(3S)-3-methylphenoflavin-4-yl]pyrimidin-4-yl]propan-2-ol is described above. 3-[〇methyl峨嗤-4-yl)methyl]-i-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl) The preparation of phenyl]urea is described below. H(l-methyl峨嗤_4_yl)methyl] small [4_(4,4,5,5·tetramethyl-1,3,2-dioxaboron:yl)phenyl]urea

(4-Aminophenyl) dihydroxyborane decyl ester (2 〇〇 mg) was dissolved in anhydrous THF (5 liters), and sodium bicarbonate (116 mg) was added, followed by dropwise addition of chloroform Iphenyl ester (0.115 ml). The mixture was stirred at room temperature for 1 hour. Add (1 methylpyridine.sup.-4) to methylamine (1 〇 2 mg) and allow the reaction to stand at room temperature for 2 hours and then heat to π hours. Concentrate this in a vacuum. The residue was taken between DCM (25 mL) and water (7 mL). The organic matter was dehydrated and dried with magnesium sulfate, filtered, and pumped to dryness. This material was chromatographed on silica gel eluting with ethyl acetate, and the desired material (232 mg) was obtained as white solid. NMR spectrum: 4 NMR (400.13 MHz, DMSO-d6) 5 1.28 (12H, s), 3.79 (3H, s), 4.11 (2H, d)5 6.39 (lH,t), 7.34 (lH, s), 7.39 -7.41 (2H, m), 7.52-7·54 (2H, m), 7.59 (1H, s), 8.56 (1H, s) mass spectrum; M+H+357. Example 39 ·· f \ H4- [4-(Hydroxymethyl)-6-[(3S)-3-methylmorpholine-4·yl]pyrimidin-2-yl 1phenyl]_3-(1,2-oxazol-3-yl) Urea

[2-Alkyl-6_[(3S)-3-methylphenoflavin-4-yl]η 密子冰基]Methanol (5〇〇mg)&gt; Valley in 7 · 3 · 2 DME : Water : A mixture of ethanol in DMF (1 mL). Then, 3-(1,2-oxazolidine H-[4-(4A5,5-tetramethyldioxaboron-2-yl)phenyl]urea (811 mg) and 2M aqueous sodium carbonate solution (4 ml) was added to the solution, and the resulting mixture was degassed for 5 minutes. Dichlorobis(triphenylphosphine)palladium catalyst (73 mg) was added, and the solution was refluxed for 9 hours under 9 (rc and nitrogen atmosphere). The reaction was allowed to cool, then neutralized with concentrated hydrochloric acid and directly loaded onto a SCX-2 column (50 g), the column was washed with methanol, and the product was dissolved in 7N ammonia in methanol. The residue was purified by EtOAc (EtOAc) eluted eluted eluted eluted eluted -3.24 (1Η,m), 3.47-3.53 (1H,m),3.63-3.67 (1H,m),3·77 (1H,d), 123642 -316- 200817384 3·96-4_00 (1H,m) ,4·16-4·19 (1H,m),4·47 (2H,d),4·50 (1H,s)5 5·40 (1H, t),6.69 (13⁄4 s),6·87 (1H,d),7.53-7.56 (2H,m)5 8.27-8.29 (2H,m), 8.75-8.75 (1H,m)5 9.03 (1H,d)5 9.60 (1H,s) Mass Spectrometry ;M+H+411. Test (a): 0.075 //M.

[2 gas-based-6-[(3S)-3-methylphenoline p--4-yl]]]] The preparation of methanol has been described above. Preparation of (1,2)-salt-3-yl H-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron) phenyl]urea This is described below. 3-(1,2-carbazole-3-yl)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin -yl)phenyl]urea

The (4-amine basic group) di-acetone vinegar (1 g) was dissolved in anhydrous τηρ (30 liters), sodium hydrogencarbonate (576 mg) was added, and then phenyl chloroformate was added dropwise. (0.575 ml). Then, the mixture was stirred at room temperature for 1 hour. Add 3-aminoisoxazole (〇.506 ml), and leave the reaction in 4 (rc) for 16 hours. Add more 3_aminoisoxazole (〇·5〇6 ml) and carbonated Sodium hydrogenate (576 mg), and the mixture was heated to 75 ° C for 8 h then concentrated in vacuo and partitioned between DCM (50 mL) and water (50 mL). The layers were dried over MgSO4, EtOAc (EtOAc m.).jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj (400.13 MHz, DMSO-d6) 5 1.29 (12H, s), 5.89 123642 -317- 200817384 (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) mass spectrum; M+H+330. Example 40 ·· N-[2-[[6-[(3S)-3_曱基基福啉-4--4-yl 2-[4-(l,2-oxazol-3-ylaminocarbamoylamino)phenyl]pyrimidin-4-yl]methyl hydrazino]ethyl] acetamidine

L_[4-[4-[(3S)-3-Methylmorpholine-4-yl]-6-(methylsulfonyloxymethyl)glycin-2-yl]phenyl]-3 -(l,2-oxazol-3-yl)urea (89 mg, ι·ι8 mmol) partially dissolved in B (4 liters) and added ν_(2-thioethyl) Indoleamine (〇〇34 ml, 0·32 house Moer). DBU (0.055 mL, 0.36 mmol) was added and the mixture was stirred at room temperature for 6 hr then evaporated to dryness. This material was dissolved in 1,4-dioxane (2 ml) and m_CPBA (75%) (158 mg) in a solution of hydrazine, 'diox (2 liters), and then added immediately. A solution of sodium permanganate (175 mg) in water (1 liter). The reaction was stirred at room temperature for 1 hour, then loaded onto a column of SCX-2 (10 g), and the column was washed with methanol. And the product was dissolved in 7N ammonia in methanol. The material was purified by preparative hplc (basic) to give the desired material as a solid (13 mg). NMR spectrum · 1 η NMR (399.9 MHz, DMSO-d6 ) 5 1·26 (3H,d), 1.84 (3H, s), 3.24 (1H,d),3·52 (2H,t)5 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), 123642 -318- 200817384 8.76-8.77 (1H, m), 9.09 (1H,d), 9.62 (1H, s) mass spectroscopy; M+H+ 544. The following compounds were obtained in a similar manner from μ[4_[4_Κ3Pop 3_methylmorpholine-4-yl] Methanesulfonyloxy曱 ) _2 • • • _2 _2 _2 _2 _2 _2 _2 _2 _2 脲 脲 脲 脲 脲 脲 脲 脲 脲 脲 脲 脲 脲 脲 脲 脲 脲 脲 脲 脲 脲 脲 脲 脲 脲 脲 脲 脲 脲 脲 脲 脲 脲 脲 脲 脲 脲 脲(2-Hydroxyethylsulfonylmethyl 503)-6-[(3S)-3-methylphenoflavin-4-.hepta]&gt;yl]pyrimidin-2-yl]phenyl]-3-( 1,2-噚Η oxazol-3-yl)urea Example 40a: 1 H NMR (399.9 MHz, DMSO-d6) 5 1.26 (3H,d),3·24 (1H,d), 3·53 (3H ,t),3·65-3·68 (1H,m)5 3·79 (1H,d),3.93 (2H,q)5 3.98-4.02 (1H, m),4·20 (1H,s) ,4·51 (3H,d),5·20 (1H,t), 6.80 (1H,s)5 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). Test (c): Example (40) 0.1 //M; Example (40a) 0.055 /M· l-[4 -[4-[(3S)-3-indolyl pheno-p--4-yl]-6-(methioninyloxymethyl) guanyl]phenyl]-3-(1,2_唠The preparation of oxazolidinyl urea is described below. L-[4-[4_[(3S)-3-indolyl phenanthrene-4-yl] (methacyloxymethyl), _2_yl]phenyl]-3-(1,2 -carbazole base)

1-[4-[4-(Hydroxymethyl)_6_[(3S)-3-methylmorpholine]. Σσ定_2_基]Phenyl]·3-(1,2-oxazol-3-yl)urea (300 mg) partially dissolved in DCm (1 mL) with: ethylamine (0.153 mL) And the solution was cooled to (rc. methanesulfonate 123642-319-200817384 醯 (0.086 ml) was added, and the reaction was stirred at room temperature for 45 min., *. Then, the reaction was taken in water ( 2 house liters) washing, and dehydration and drying with magnesium sulfate. The vacuum is dried to dryness, and the desired substance is a yellow solid. / mass spectrum; M+H+489. Example 41: 1-[4 [4-(2-hydroxypropan-2-yl)_6-[(3S)_3-methylmorpholine bucket base] pyrimidine bit_2_yl]phenyl]_3-(1,2-carbazole each Urea

Add 2-[2-carbyl-6-[(3S)-3-methylmorpholine)pyrimidin-4-yl]propan-2-ol (160 mg, 0.59 mmol) to 7:3: 2 DME: water: 18% in a mixture of ethanol DMF (6 ml) 3-(1,2, oxazolidine)-1-[4-(4,4,5 5•tetramethyl-1 , 3,2-dioxo side, indole-2-yl)phenyl]urea (242 mg) with dioxobis(triphenylphosphine) in a catalyst (21 mg). The reaction was heated to ι ° C in a microwave reactor over 30 minutes and cooled to room temperature. The reaction mixture was acidified with 2M hydrochloric acid, and crude material was applied to a column of SCX (10 g), and the desired material was dissolved in 7N ammonia in methanol. This material was further purified by preparative HpLC, using a mixture of water (containing 1% NH3) and MeCN as a solvent to give the desired material (52 mg) as a white solid. NMR spectrum: 1H NMR (399.9 MHz, DMSO_d6) 5 1·24 (3H, d), 1.47 (6H, s), 3.18-3.25 (1 Η, m), 3.47-3.54 (1 Η, m), 3.64-3.67 ( 1Η, m), 3.78 (1Η, 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), 123642 -320- 200817384 9·〇6 (1H ,s),9·61 (1H,s) Mass Spectrum: M+H+439.4 Test (c): 0.047 //Μ. 2-[2-Chloryl each [(3S)_3-methylmorpholine ice-based Pyrimidine phenyl] propan-2-ol with 3 (1,2 oxazol-3-yl)-1-[4-(4,4,5,5-tetramethyldioxaboron-2-yl The preparation of both phenyl]ureas is described above. Example 42:

3-cyclopropyl-1-[4-[4-(hydroxymethyl)_6_[(3S)_3-indolyl porphyrin-4-yl], pyridine-2-yl]phenyl]urea

[2-Chloro-6-[(3S)_3_methylphenoline _4_yl]-biting ice-based] methanol (3·3 gram) dissolved in 7 · 3 · 2 DME: water: ethanol Within 18% DMF (5 〇 ml) of the mixture. Then, 4-(3-cyclopropylureido)phenyldihydroxyborane (4 92 g) and 2M sodium carbonate (5 ml) were added, and the solution was degassed for 5 min. Next, dichlorobis(triphenylphosphine)palladium catalyst (476 mg) was added to the solution and refluxed for 9 hours under 9 (rc and nitrogen atmosphere. The reaction was cooled, evaporated, and the residue was taken to DCM ( 200 ml) and water (2 ml) for liquid separation treatment. The organic layer was dried over magnesium sulfate, evaporated, and purified by chromatography on silica gel, eluting with 5% methanol in dcm. The material (4 33 g) was obtained as a yellow solid. NMR spectrum·· 1 NMR (400.13 MHz, DMSO-d6) (5 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), 123642 -321 - 200817384 4.15-4,8 (1H5 m)? 4.45 (2H?d)? 4.49 (1H5 d)5 538 (1H? t) 5 6.41 (1H d) 6.66 (1H? s)5 7.46-7.50 (23⁄4 m)5 8.18^8.22 (2H5 m)5 8.49 (1H5 s). 'Massage; M+H+384. Test (a): 0.19 //M.

[2-Benzyl-6-[(3S)-3-methylmorpholine]pyrimidin-4-yl]methanol has been described above. &lt; μ Example 43: 3-cyclopropyl small [4_[4-[(38) each methylmorpholine-4-yl]_6_(pyridine-4-ylsulfonylmethyl)pyrimidin-2-yl]benzene Urea

3-cyclopropyl·ΐ_[4-[4-[(38)_3-methylmorpholine-4-yl]_6_(methylsulfonyloxymethyl)pyrimidin-2-yl]phenyl] Urea (1 mg, 〇 24 mmol) was partially dissolved in acetonitrile (4 mL) and pyridine ice thiol (〇·38 mmol) was added. The reaction was stirred at rt for 1 h then EtOAc (EtOAc &lt The reaction was evaporated to dryness and dissolved in EtOAc (2 mL). A solution of m_cpBA (75%) (94 mg) in dioxane (2 ml), followed immediately as a solution of sodium permanganate (1 〇4 克) in water (1 liter), added to The reaction was taken and mixed under fox for 1 hour. Add another m-CpBA (yes..) (94 mg) solution in 込4_ monooxan (1 ml), then immediately sodium sulphate (1 〇 4 mg) in water (〇·5 The solution in ML) was stirred at room temperature for a few hours. The reaction mixture was loaded onto a SCX-2 (1 gram) column, and the 7N ammonia-dissolved product in methanol was washed with a methanol washing tube 123642-322-200817384. This material was purified by preparative HPLC (basic) to give the desired material as a solid (10 mg). NMR spectrum: ιΗ庞& _ 13 test, facial 〇 _ heart w _ pick (gong m), 0.63-0.67 (2H5 m) 5 L2i (3H5 d) 5 2.58^2.61 (1H? m)5 3.15-3.25 ( 1H? m)5 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) mass spectrum; M+H+509. The following compounds were prepared in a similar manner using the appropriate thiol alcohol. Example Structure Name LCMS ΜΗ+ 43a, NH[λ. '乂Human Η Η 2-[[2-[4-(cyclopropylaminecarbamimidino)phenyl]-6-[(3S)-3·decylmorpholine·4-yl]pyrimidine- 4-yl]methanesulfonyl]-indole-methyl-acetamide 503 43b Η Η 3-cyclopropyl small [4-[4-[(4-fluorophenyl))]- 6-[(3S)-3-indolyl-fusin-p--4-yl]♦ σ-but-2-yl]phenyl]urea 526 43c αν Η Η N-[4-[〇[4-(cyclopropyl) Aminoguanidinoamino)phenyl]-6-[(3S)-3-indolyl phenanthrene p--4-yl]17-succinyl-4-yl] sulfonyl]phenyl] Indoleamine 565 43d 〇Η α Η Η 3-cyclopropyl-1-[4·[4-(2-hydroxyethylsulfonylmethyl)-6-[(3S)-3-methylmorpholine ·4·yl]pyrimidin-2-yl]phenyl]urea 476 123642 -323 - 200817384 Example structure name LCMS MH+ 43e ^ a Η H 3-cyclopropyl-; U[4-[4-[(3S)- 3-methylfosfolin-4-yl]-6-(l,3-p-sial-2-pyrylxanthylmethyl)η密咬_2-yl]phenyl]urea 515 43f hit w 3- Cyclopropyl-l-[4-[4-[(3S)-3-methylmorpholine-4-yl;|each [[2-(trifluoromethyl)phenyl]sulfonylmethyl]] Pyrimidine-2-yl]phenyl]monthly 576 43g Γ〇Ί Η H 3-cyclopropyl_l-[4-[4-[(3S)-3-methylmorpholine-4-yl] -6-[(5-A -l,3,4-p-dioxa-2-yl)-branched thiol&gt;-mididin-2-yl]phenyl]urea 530 43h a Η H 2-[[2-[4-(cyclo Propylamine, mercaptoamino)phenyl]-6-[(3S)-3-methylmorpholine-4-yl]pyrimidin-4-yl]methylsulfonyl]acetamide 489 43i v, a Η H 3_cyclopropyl-l-[4-[4-[(3S)_3-methylmorphin-4-yl]_6-[(4-methyl-1,3-pyrazole-2 _ base) sulfonyl fluorenyl] oxime-2-yl] phenyl] urinary 529 43j λνη Cx, Η H N-[2-[[2-[4-(cyclopropylamine decylamino) Phenyl]-6-[(3S)-3-methylnorfos-4-yl]pyrimidinyl] sulfonyl]ethyl]acetamidamine 517 43k a. 1-[4-[4 -(1 - 金金烧基基醯基基)-6-[(3S)-3-Methylphenoline p--4-yl]pyrimidin-2-yl]phenyl]-3-cyclopropyl- Moon urine 598 Example 43a: 4 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 (1H5 m)5 4.15-4.19 (1H5 m)5 4.29 (2H, s)? 4.48 (1H? s)5 4.67 (2H? 123642 -324- 200817384 s), 6.43-6.44 ( 1H,m),6·77 (1H,s)5 7.50 (2H,d),8·19 (2H,d),8·31 (1H,t), 8·54 (1H,s) Example 43b: iH NMR (400.13 MHz, DMSO-d6) 5 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 43c: iH NMR (400.13 MHz, DMSO-d6) 5 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) 5 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 (1H5 s) Example 43d: iH NMR (400.13 MHz, DMSO-d6) 5 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)5 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 43e: iH NMR (400.13 MHz, DMSO-d6) 5 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)5 7.84 (2H,d), 8.27-8.29 (2H,m)5 8·50 (1H,s) 123642 -325 - 200817384 Example 43f: NMR (400.13 MHz, DMSO-d6) 5 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 43g: iH NMR (400.13 MHz, DMSO-d6) 6 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), f ' 6.44 (1H, s), 6.80 (1H, s), 7·43 (2H, d), 7.79 ( 2H,d),8·53 (1H,s) Example 43i: NMR (400.13 MHz, DMSO-d6) (5 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)5 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 43j: iH NMR (400.13 MHz, DMSO-d6) 5 0.40-0.44 (2H,m), t 0.63-0.67 (2H,m), 1.24 (3H,t),1.83 (3H,s),2·52- 2·60 (1H,m), 3.19-3.25 1. (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) Example 43k: iH 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) 123642 -326- 200817384 Test (a): Example (43) 0.076 //Μ; Example (43a) 0.087 //Μ; Example (43b) 0·15; Example (43c) 0.013 ;Instance (43d) 0.011 //Μ; instance (43e) 0·13 // M; instance (43f) 0·11 instance (43h) 0.0071 //M; instance (43i) 0.058 //Μ ; instance (43j) 1·8

Test (c): Example (43g) 1·9 //M; Example (43k) 2·9 //M 3-Cyclopropyl small [4-[4-[(3S)-3-methylmorpholine The preparation of _4_yl] each (nonylsulfonyloxymethyl) thiophene-2-yl]phenyl]urea is described below. 3·cyclopropyl_l_(4_[4-[(3S)-3-methylmorpholine-4-yl]_6-(methylsulfonyloxymethyl)pyrimidin-2-yl]phenyl] Urea

3-Cyclopropyl-l-[4-[4-(hydroxymethyl)_6-[(38)methyl-m-fosfosin]-ytidine-2-yl]-phenyl]urea (ι·83) Partially dissolved in dcm (50 ml) and triethylamine (1 ml), and the solution was cooled to 〇 °C. Methane chloride sulfonium chloride (1)·56 ml) was added, and the reaction was stirred at room temperature for 45 minutes. The reaction was then washed with water (1 mL) and the organic material was dried over magnesium sulfate. The solution was evacuated to dryness to give the desired material as a yellow solid. Mass spectrometry; Μ+Η+462. Example 44: 3-cyclopropyl-Η4 --propyl propyl alcohol methyl) each (tetra) 3-methylphenofon-4-yl]pyrimidine_2-yl]phenyl Pulse 123642 -327- 200817384

Add sodium permanganate monohydrate (38 mg, 0.24 mmol) to m-CPBA (33. 2 mg) in monohydrogen guanidine (2 ml) and water (1 ml) at 2 °C. , 0.19 millimolar) with 3·cyclopropyl_1[4_[冬(3hydroxypropylthiomethyl)_6_[(3 bucket 3·methylfofolin)pyrimidin-2-yl]benzene Base urea (44 mg, 0.10 mmol). The resulting solution was stirred at 2 ° C for 45 minutes, and the mixture was loaded onto a SCX-3 (5 g) column, which was dissolved from the column. The product was purified using 7M ammonia in methanol. This material was further purified by preparative HPLC using a mixture of water (containing 1% NH3) and acetonitrile as a dissolving agent to give the desired material (19 mg). White solid. NMR spectroscopy · NMR (400.13 MHz, DMSO-d6) (5 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) mass spectrometry; M+H+490 test (8)·1.8 3-cyclopropyl small [4-[4-(3-hydroxypropylthiomethyl)_6-[(3S)-3-methylphenoflavin-4-yl]pyridin-2-yl]benzene The preparation of urea is described below. 3-Cyclopropyl-1-[4-[4-(3-hydroxypropylthiomethyl)-6-[(3S)-3-methylmorpholine -4-yl]pyrimidin-2-yl]phenyl]urea 123642 -328 - 200817384

3-Cyclopropyl-H4-[4-[(3S)-3-indolylfosfolinine]_6_(methyl hydrazino) hydrazin-2-yl]phenyl]urea 100 mg) was partially dissolved in acetonitrile (4 ml) and added to 3-thiopropan-1-ol (〇·38 mmol). The reaction was stirred at room temperature for 1 hour. DBU (0.065 μl) was added to the reaction, and the mixture was stirred at room temperature for 18 hours. The mixture was concentrated in vacuo and purified by preparative HPLC to afford the desired material. (milligrams), as a white solid. Mass spectrum; Μ+Η+458. 3-cyclopropyl-l-[4-[4-[(3S)-3_methyl-wf-phenin-4-yl]-6-( The preparation of sulfonyloxymethyl)glycidin-2-yl]phenyl]urea is described above. Example 45: H2-ethyl group) small methyl _3_[4_[4_(methylsulfonyl) Methyl) each morpholine _4_ ki pyridine 2 _ phenyl phenyl

Ν_[4ΚMethanesulfonylmethyl) phenanthroline _4•yl, pyridin-2-yl]phenyl]carbamic acid phenyl ester (94 mg, 2 mmol) and triethylamine (0 〇) A solution of 9 ml, 9.2 mmoles in hydrazine (1 ml) was added to 2-methylaminoethanol (1 mM millimolar). The mixture was heated at 70 °C for 2 hours and the reaction was purified by preparative HPLC to give the desired compound. 123642 -329- 200817384 LCMS spectrum: MH+ 450, retention time 2.07 minutes. The following compounds were prepared in a similar manner from either N-[4-[4-(methylsulfonylmethyl)-6-morpholine-4-yl-pyrimidin-2-yl]phenyl]aminocarboxylic acid Phenyl ester or N-[4-[4-[(3S)-3-methylmorpholine-4-yl](methanesulfonylmethyl)pyrimidin-2-yl]phenyl]carbamic acid benzene Ester and appropriate amine. Example structure name LCMS ΜΗ+ retention time (minutes) 45a 0 N-[4-[4-(methylsulfonylmethyl)-6- 福福吓"-4-yl-mouth butyl-2-yl]benzene ]]Hexahydropyridine-1-carboxamide 460 2.74 45b [:] Is human 丫Η H ^(2-methylpropyl)_3-[4-[4-(methioninylmethyl)-6-? Fu 4 -4_yl-pyridin-2-yl]phenyl]urea 448 2.76 45c [:] ^a/ 1-(3-decyloxypropyl)-3-[4_[4-(methylsulfonate)曱 ) ) _ 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. (曱 醯 醯 甲基 methyl)-6-foline _4_ base-. Michridin-2-yl]phenyl]urea 491 2.8 45e 1-[4-[4-(methylglycosylmethyl)-6-morpho-p--4-yl. Bite-2-yl]phenyl]_3-[2-(2-ketoimidazolinidinyl)ethyl]urea 504 2.27 45f 0 and N-[4_[4-(methylsulfonylmethyl) _6_么福^林-4-基密σ定-2-yl]phenyl]tetrahydropyrrolecarboxylamine 446 2.56 123642 - 330 - 200817384 Example structure name LCMS ΜΗ+ retention time (minutes) 45g 〔:〕 H Ν-[4-[4-(oxasulfonylmethyl)-6-ifufu lin]-4-yl succinyl-2-yl]phenyl]morpholine-4-carboxamide 462 2.4 45h 0 H , ν^&quot;〇Η 4-hydroxy-indole-[4-[4-(methylsulfonylfluorenyl)-6-norfosolin-4-yl-but-2-yl]phenyl]hexa Gas batch °-1-carboxycarboxamide 476 2.28 45i 0 '3 for > human / Η 1 1-(1-methoxypropan-2-yl)-3-[4·[4-(methylsulfonate) Methyl)-6-moffolin-4-ylmelidine-2-yl]phenyl]urea 464 2.51 45j 0 Η Η 1-(2-dimethylaminoethyl) -3-[4·[ 4-(Methanesulfonylmethyl)-6-?-fusin-4-lin-4-yl-3⁄4-pyridin-2-yl]phenyl]urea 463 2.52 45k 0 human r Η Η 3_(2_^ to ethyl)- 1-[4-[4_(曱石黄毛基基)-6-,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, -1-methyl-3-[4_[4-(methylsulfonylmethyl) -6-whufolin-4-kimid sigma-2-yl]phenyl]urea 434 2.54 45m 0 0 3-hydroxy-indole_[4-[4-(methylsulfanylmethyl)-6-?福ρ林-4-yl-Fetal-2-yl]phenyl]hexanitrogen is sigma-1-carboxycarboxamide 476 2.35 123642 -331 - 200817384 Example structure name LCMS MH+ residence time (minutes) 45η 0 〇人〇Ί〇3-Methanesulfonyl-N-[4-[4-(methylsulfonylmethyl)-6-? Lin-4-yl sigma-2-yl]phenyl]tetrahydropyrrole-1-carboxamide 524 2.34 45〇0 °s^aNxN/° Η H 1-[4-[4-(sulfonyl) Methyl)·6- 福福?林-4-基-^密定定-2-yl]phenyl]-3-(2-isofan 117 lin-4-ylethyl) urinary 505 2.14 45ρ 0 :'s^aNxNy Η H 1-(2,2-dimethylpropyl)-3-[4-[4-(methylsulfonylmethyl)-6-ifu^lin-4-yl-mil 12-di-2-yl]phenyl]urea 462 2.68 45q C] Η H 3-(3-hydroxypropyl) small [4-[4-(methylsulfonylmethyl)-6-morphine p- 4-base-.唆-2-yl]phenyl]urea 450 2.05 45r 0 gas again? Η 1 1-decyl-small methyl-3-[4-[4-(methyl sulphatemethyl)-6-rhofophthyl-4-yl-♦ keto-2-yl]phenyl]urea 496 2.74 45s 0 Η H 1-(2-ethoxyethyl)-3_ [4-[4-(methylsulfonylmethyl)-6-? Ding-2-yl]phenyl]urea 464 2.29 45t 0 Η H 1_(1•hydroxypropan-2-yl)-3-[4-[4-(methyl continuation i-methyl)-6-? P-lin-4-kimididine-2-yl]phenyl]urea 450 2.09 45u Ο human j〇Η H 1-[4-[4-(methionine Si-methyl)-6·fofin -4-yl-Moutyridin-2-yl]phenyl]-3-(oxoindole-4-yl) earned 476 2.21 123642 - 332 - 200817384 Example structure name LCMS MH+ residence time (minutes) 45v 0 H k ^NH N-[4_[4-(Methanesulfonylmethyl)-6-?林-4-基密唆-2-yl]phenyl]-3-keto-hexahydromorphin-1-propanol 475 2.00 45w 0 Η H 1-[2-(4-methylhexahydropyridinium Plowing _1_yl)ethyl]-3_[4-[4-(methyl sulphate methyl)·6_ 福福^林-4-yl-11 succinyl-2-yl]phenyl]urea 518 2.11 45x 0 η ! 1-Methyl-1-(2-methylsulfonylethyl)-3-[4-[4-(甲石黄酉基曱基)-6-?福"林-4-基-密0定-2-yl]phenyl]urea 512 2.14 45y 0 H Ογΐ 0 Ν'-Methyl-N-[4-[4-(methylsulfanylmethyl)-6-??? 4-yl 0-but-2-yl]phenyl]hexahydropyridine-1,4-dicarboxyguanamine 516 2.07 45z 0 Η H Ν,Ν·dimercapto-2-[[4-[4-(曱Sulfomethyl)-6-fosfosin-4-yl-carin-2-yl]phenyl]aminecarboxylamidyl]acetamide 477 2.11 45aa a °s〇x^ 〇^nAn- V° H ^N, 4-methyl-N-[4-[4-[(3S)-3-indolyl-norfos-4-yl]-6-(methylsulfonylmethyl)pyrimidine-2 -yl]phenyl]-3-keto-hexahydropyrazine small carboxamide 489 1.23 123642 - 333 - 200817384 Example structure name LCMS MH+ residence time (minutes) 45ab 0&quot;, X aN^ 1 4-dimethylamine --N-[4-[4_ [(3S)-3·methylmorpholine•4-yl]-6-(A Mercaptomethyl)pyrimidin-2-yl]phenyl]hexahydropyridine carboxamide 518 1.6 Test (a): Example (45) 0·66 //Μ; Example (45a) 0.63 //Μ; Example ( 45b) 0·12 //Μ; instance (45c) 0·082 //Μ; instance (45d) 0.56 &quot;Μ; instance (45e) 0.56 // Μ ; instance (45f) 1·6 //Μ ; instance (45g) 0·041 //Μ; instance (45h) 0·14 //Μ; instance (45i) 3 //Μ; instance (45j) 0·72 //Μ; instance (45k) 0.049 //Μ; Example (451) 1·1 //Μ; instance (45m) 0·17 _; instance (45η) 0·63 //Μ; instance (45ο) 0·9 //Μ; instance (45ρ) 0·92 / /Μ; instance (45q) 0.032 //Μ; instance (45r) 0.41 //Μ; instance (45s) 0·3 //Μ; instance (45t) 0·082 _ ; instance (45u) 0·42 /Μ Example (45ν) 1·2 //Μ; instance (45w) 0·74 //Μ; instance (45χ) 1.1 //Μ; instance (45y) 1·2 //Μ; instance (45ζ) 1 // Μ; Example (45aa) 0·83 //Μ; Example (45ab) 0.39 μΜ. Ν_[4-[4-(Methanesulfonylmethyl)-6-morpholine-4-yl-pyrimidine-2- Phenyl]phenyl]carbamic acid phenyl ester with N-[4-[4-[(3S)_3-indolylmorpholine-4-yl]-6-(indolyl sulfhydryl)pyrimidin-2- Phenyl]amine The preparation of phenyl carbamate is described above. Example 46: 3_Methyl small [5-[4-[(3S)_3-indolyl oxafosin-4-yl]-6-(methylsulfonylmethyl)-hydan-2-yl]-1 , 3-pyrazole·2·yl]urea 123642 -334· 200817384

......, methanesulfonylmethyl) guanidinyl]-1,3-oxazol-2-yl] carbamic acid ester (1 mg, 〇 2 mmol) ^ (1 house Moer) and triethylamine (0.085 liters, 〇 6 mM ^ ^ ^ according to the mixture in the heating under view for 2 hours. This material is purified by preparative HPLC, and the desired substance, As a white solid (27 mg). LCMS spectrum: MH+ 427, retention time Μ min

L The following examples are of the class structure ~' 46a α ϊ ^\yvv- 46b [:x ^\yV} 0 H 46c - H5-[4-[(3S)-3-methylmorpholine-4-yl -6-(Methanesulfonylmethyl)piperidin-2-yl]-l,3-p-conazole-2-yl]-3-propan-2-yl-urea 1-ethyl-3-indole [4-[(3S)-3-Methylphenoxyp--4-yl]-6-(methylsulfonylmethyl)-pyridyl-2-yl]-1,3-pyrazol-2-yl Urea l-[5-[4-[(3S)-3-methylnorfos-4-yl]-6-(methioninemethyl) guanidin-2-yl]-1,3 - pyrazol-2-yl]-3-phenyl-urea 48 ds t+ residence time (minutes) 5 1.84 1 1.48 ) 1.86 123642 - 335 - 200817384 Example structure name LCMS MH+ residence time (minutes) 46d 〔:X , 3 -(4-fluorophenyl)-l-[5-[4-[(3S)-3-indolyl phenanthroline-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl] -1,3-pyrimidin-2-yl]urea 507 1.88 46e 0 1-cyclopropyl-1-methyl-3-[5-[4-[(3S)-3-methylmorpholine-4_ Base]-6-(methylsulfonylmethyl)pyrimidin-2-yl]-1,3-pyrazol-2-yl]urea 467 1.69 46f [:x. — 3-(4-methoxyphenyl)-1-[5-[4-[(3S)-3-methylmorpholine•4-yl]-6-(methylsulfonylmethyl) σ σ定-2-yl]-1,3-P-conazole-2-yl]urea 519 1.82 46g C:X ^VyrN' 3-(2-dimethylaminoethyl)-1_ [5-[4- [(3S)-3-Methylformin-4-yl]-6-(methyl succinylmethyl)pyrimidin-2-yl]·1,3-pyrazol-2-yl]urea 484 1.39 46h 〔;〕&quot;,, is V? 〇H l-[5-[4-[(3S)-3-methylorfosin^lin-4-yl]_6-(methioninemethyl)pyrimidine -2-yl]-1,3-thiazol-2-yl]·3-(1-methylpyrazole-4-yl)urea 493 1.25 46i 3-cyclopropyl-l-[5-[4-[ (3S) -3-methylmorpholine-4-yl] -6-(A S&amp;&gt; Methyl dimethyl thiophene -2 yl)-l,3-p-spin 11 syl--2-yl] Urea 453 1.59 Test (a): Example (46) 〇·14 //Μ; Example (46a) 0·35 //Μ; Example (46b) 0.0061; Example (46c) 0·45 //Μ; Example (46d) 0.85; example (46e) 0.71 //Μ; 123642 -336 - 200817384 instance (46f) 1·2 //Μ; instance (46g) 0·73 //Μ; instance (46h) 〇·〇63 _ ;Example (46i) 0·097 Dance N_[5-[4-[(3S)-3-methylphenoflavin-4-yl]-6-(methioninylmethyl). ]-1, The preparation of 3-indolyl-2-yl]aminocarboxylic acid is described below. N_[5-[4-[(3S)-3-methyl- orion-4-yl]-6- (A 醯 醯 methyl group), bite_2_ base]-1,3-pyrazol-2-yl] phenyl carbamate

5-[4-[(3S)-3-Methyl-Walfolin-4-yl]-6-(methyl-mercaptomethyl-Bite 2-yl]-1,3-disso-2-amine A solution of (1 g '2.71 mmol), sodium bicarbonate (342 mg) and phenyl chloroformate (0.511 ml) in dioxanol was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue is subjected to liquid separation between DCM and water, and the organic layer is dried over sodium sulfate and evaporated to give a foam. The foam is purified from a mixture of hexane and diethyl ether to give the desired material. White solid (U g) LCMS spectrum ΜΗ + 490, retention time 2.17, method to monitor acid. 5_[4_丨(3S)-3_methylmorpholine·4_yl]_6-(methylsulfonyl) Acridine-2-yl]-1,3-pyrazol-2-amine

N-[5-[4-[(3S)-3-methylmorpholine yl]-6-(methylsulfonyl fluorenyl) oxaridin-2-yl]-1,3-pyrazole-2 -yl]-N-[(2-decylpropan-2-yl)oxycarbonyl]carbamic acid III - 123642 -337 - 200817384 Butyl ester (1.7 g, 2.9 mmol) with TFA (8 The solution was stirred at room temperature for 16 hours at rt. The solvent was removed under reduced pressure and the residue was made basic with aqueous ammonia. The organic material was dried over sodium sulfate, filtered, and evaporated to give the desired material as white solid (1 g). NMR spectrum: 4 NMR (400.13 MHz, DMSO_d6) (M.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) 5 4.40 (2H, s), 5.75 (1H, s), 6·64 (1H, s), 7.40 (2H , s), 7.73 (1H, s) LCMS spectroscopy; MH+ 370, retention time 1.38 min, method for monitoring base N-[5-[4-[(3S)-3-methyl-wfolin-4-yl]- 6-(曱曱醯methylmethyl)pyrimidin-2-yl H,3-norazol-2-yl]_Ν·[(2_methylpropan-2- ) Oxycarbonyl] -carbamic acid tert - butyl ester

第三-[(2-Methylpropan-2-yl)oxycarbonyl]-indole-(5-tributylstannyl-1,3-oxazol-2-yl)carbamic acid tert-butyl ester (3)克, 5.1 mmol, 2-chloro hydrazine [(3S)-3-methylmorpholine-4-yl]-(methylsulfonylmethyl)pyrimidine (1 g, 3.2 mmol) and A mixture of palladium ruthenium (triphenylphosphine) (50 mg) in toluene (10 ml) was heated at 1 °C and nitrogen for 2 h. The mixture was chromatographed on silica gel to give the desired material (1.7 g). NMR spectrum: iH NMR (400.13 MHz, DMSO-d6) δ 1.20 (3H, d), 1.53 123642 - 338 - 200817384 (9H, s), 3·18 (3H, s), 3.55 (1H, t) 5 3 ·62 (1H,d),3·75 (1H,d)5 3·98 (1H,d), 4.10 (1H,s),3.90 (1H,s),3·98 (2H,s),6 · 80 (1H, s), 8.18 (1H, s) LCMS spectrum; MH+ 570, retention time 2.89 minutes, method monitoring test Ν-[(2-mercaptopropan-2-yl)oxycarbonyl] Butyl-stannyl-13-, terazolyl-2-ylcarbamic acid tert-butyl ester

Add n-butyllithium (1·6 Μ in hexane, 30 ml, 〇·48 mM) to diisopropylamine (6.7 mL) in THF (480 mL). 〇·48 Moer). The mixture was stirred at 〇 ° C for 30 minutes and then cooled to -78 ° C. Addition of N-[(2-methylpropan-2-yl)oxycarbonyl]-N-(l,3-oxazol-2-yl)carbamic acid tert-butyl ester (12 g, 〇·〇5 Mohr), and the solution was stirred for 3 minutes. Tributyltin chloride (16.3 ml) was added and the solution was stirred for 30 minutes and then allowed to warm to room temperature. The reaction was quenched with saturated aqueous ammonium sulfate (2 mL) and ethyl acetate. The organic material was dried over sodium sulfate, concentrated in vacuo and purified eluting eluting eluting eluting eluting NMR spectrum: iH NMR (400.13 MHz, DMSO-d6) 5 1·49 (18 Η, s) 5 7.50 (1 Η, d), 7.55 (1 Η, d) N-[(2-mercaptopropen-2-yl) Oxycarbonyl]-N-(l,3-pyrazol-2-yl)carbamic acid tert-butyl ester 123642 -339 - 200817384

2-Aminothiazole (5 g, 〇·〇5 mol), (2-methylpropionyl)oxycarbonyl second-butyl ester (27.8 g, 〇15 mol) and DMAp ( 1 〇〇 mg) A solution of ΤΗρ (1003⁄4 liter) was stirred under reflux overnight. The mixture was allowed to cool and concentrated in vacuo. The residue was chromatographed on EtOAc (EtOAc) elute f NMR spectrum: iH NMR (400.13 MHz, DMSO-d6) δ 1·49 (18H, s), 7.50 (1 Η, d), 7·55 (1 Η, d) LCMS spectrum MH-299, retention time 2.6 min, Method for Monitoring Base Example 47: 3-Methyl Small [5_[4-[(3S)-3-Methylmorpholine_4_yl]_6_(2_Methanesulfonylpropan-2-yl)pyrimidine-2 -yl]_1,3_oxazol-2-yl]urea

N-[5-[4-[(3S)_3-indolylfosfolinine]-6-(2-methylsulfonylpropan-2-yl)]-mididin-2-yl]-1, 3-thiazol-2-yl]amino decanoate (2 mg, 〇·39 mmol), methylamine (1.5 mmol) and triethylamine (〇·ΐ 63 ml, U6 mmol) The solution in NMP (3 ml) was heated at 7 ° C for 2 hours. The mixture was chromatographed on silica gel and eluted with hydrazine _50/0 decyl alcohol in ethyl acetate to give the desired material. NMR spectrum: 4 NMR (400.13 MHz, DMSO-d6) 5 1.22 (3H,d)5 1.70 123642 -340 - 200817384 (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) LCMS spectrum; MH+ 455, retention time 丨 is minutes. The following compounds are &lt; Ο Example structure less Vi / J乂° Name LCMS MH+ retention time (minutes) 47a 3-cyclopropyl-i-[5-[4_[(3S) -3-methylorfosin p____yl] -6-(2-methyl sulphate Propionin-2·yl&gt;Mididine-2-yl]-1,3-pyrazol-2-yl]urea 481 1.94 47b 〔乂\H5-[4-[(3S)-3-Methylmorphin-4-yl]-6-(2-methylsulfonylpropan-2-yl)-n-yl-2-yl]-1 , 3-pyrazol-2-yl]-3-(1-methylpyrazole-4-yl)urea 521 1.62 47c H5-[4-[(3S)-3-Methylphenoxy 4 Wood-4- ]]-6-(2·methionylpropan-2-ylindole-2-yl]-1,3-thiazol-2-yl]-3-[(1-methyl-exo-ta--4 -yl)methyl]urea 535 1.81 47d a, N 1-ethyl_3-[5-[4-[(3S)-3-indolyl] oxalin-4-yl]-6-(2- Methyl sulfonyl propan-2-yl) dimethyl 17-but-2-yl]-l,3-p-indole-2-yl]urea 469 1.95 Example 47a: ^ NMR (400.13 MHz, DMSO-d6) 5 0 ·45 (2Η,q),0.68 (2Η, q),1·20 (3Η,d), 1.70 (6Η,s),3·05 (3Η,s),3·20 (1Η,dd),3 ·48 (1Η, dd), 3·62 (1H, d), 3.75 (1H, d), 3.98 (1H, dd), 4·18 (1H, d), 4.55 (1H, s), 6.68 123642 -341 - 200817384 (1H, s), 6.75 (1H, s), 8·05 (1H, s), 11·0 (1H, s)_ Example 47b : 1H NMR (400.13 MHz, DMSO-d6 5 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) Example 47c: iH 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)5 3·98 (1H,d),4·05 (1H, q),4·18 (2H,s), 4.51 (1H,s),6·68 (1H,s),6·78 (1H,s),7·35 (1H,s), 7.62 (1H, s),8·09 (1H,s),10·60 (1H,s)· Test (a): Example (47) 0.26 //M; Example (47a) 1·2 //M; Example (47b) 0.41 //M; example (47c) 1.4; example (47d) 0.97 //M. N-[5-[4-[(3S)-3-methylphenoflavin-4-yl]-6-(2 The preparation of phenylglycosylpropan-2-yl) benzoate-2-yl]-1,3-ρ-sial-2-yl]carbamic acid phenyl ester is described below. Ν-[5-[4_丨(3S)-3-曱基吗福琳_4_基]-6_(2_甲醯醯基丙-2-yl) 喊 -2--2-yl]-1, Benzyl 3-pyrazol-2-yl]carbonate

5-[4-[(3S)-3-Methylmorpholine-4-yl]_6-(2-methylsulfonylpropan-2-yl)-methane-2-yl]-1,3 - 嗤-2-amine (1.05 g, 2.6 mmol), phenyl chloroformate (618 mg, 3.93⁄4 mol) and sodium bicarbonate (311 mg, 3·9 mmol) in dioxane The mixture was stirred at room temperature for 2 hours, then diluted with ethyl acetate and washed with water (150 ml) and brine (1 mL). 200817384 'and concentrate in vacuum. Make the residue from

Substrate]-1,3-pyrazol-2-amine, the substance is dehydrated and dried with magnesium sulfate, and the ethyl bond is recrystallized with hexane.

[/&gt;-nh2 2-Chloryl glacial [(3S)-3-methylfosfolinine] each (2-methylsulfonyl propylidene) pyrimidine (1.2 g, 3.6 mmol), N_[(2-methylpropenyl)oxycarbonyl]_team (5-tributylstannyl-1,3-pyrazol-2-yl)carbamic acid tert-butyl ester (31 g, 5.2 mmol) And a mixture of hydrazine (triphenylphosphine) palladium (2 mg) in toluene (3 ml) was heated at 110 C under nitrogen atmosphere overnight. The mixture was diluted with ethyl acetate and washed with water. The organic material was dehydrated and dried over magnesium sulfate, dried, and evaporated. The residue was dissolved in DCM (50 mL) EtOAc. After stirring for 2 hours, the mixture was evaporated and water was added. The mixture was tested with an aqueous ammonia solution and extracted with ethyl acetate. The organic material was 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). NMR spectrum: iH NMR (400.13 MHz, DMSO-d6) 5 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). LCMS spectrum; MH+ 398, retention time 1.76 min, method for monitoring base 2-chloro-4-[(3S)-3-methyl? Fulin-4-yl]_6-(2•methylsulfonylpropan-2-yl)pyrimidine 123642-343 - 200817384 ϋ定 and N-[(2-methylpropan-2-yl)oxyl The preparation of -N-(5-tributyltin-yl-l,3-p-n-n-yl-2-yl)carbamic acid tert-butyl ester is described above. Example 48: 3-Cyclobutyl-l-[4-[4-[(3S)-3-methylnorfos _4_yl]-6-(p-precipitate_4_yl-decylmethyl) Pyrimidine-2-yl]phenyl]urea

Add cyclobutylamine (0.074 ml, 0.87 mmol) to N-[4-[4-[(3S)-3-methylphenoflavin-4-yl]-6-indole -4- Basestone yellow-branched methyl hydrazino-2·yl]phenyl] carbamic acid phenyl ester (0·095 g, 0.17 mmol) and triethylamine (0·073 ml, 〇·52 mmol) The solution in DMF (3 ml) was then warmed 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 material was purified eluting elut elut elut elut NMR spectrum: 4 NMR (400.13 MHz, DMSO-d6) 6 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). LCMS spectrum: MH+ 523, retention time h96 minute. The following compounds were prepared in a similar manner from N_[4_[4-[(3S)_3·methylmorpholine-4-yl]-6-7-pyridin-4-ylsulfonylmethyl)-pyridin-2- Benzyl]phenyl] phenyl carbamate 123642 -344 - 200817384 with the appropriate amine. Example structure name LCMS MH+ retention time (minutes) 48a Cx as^aNxNj Η Η 3-ethyl_l-[4-[4-[(3S)-3-methylphenoflavin-4-yl] -6- (口口口定-4_基石黄醢基基)0密π定-2-基]本基]urea 497 48b [λ C^A〇l person /, Η Η 3-(2-dimethylamino B -l-[4-[4-[(3S)-3-Methylmorpholine-4-yl]-6-(pyridin-4-ylcarnitylmethyl)pyrimidin-2-yl] Phenyl]urea 540 Example 48a ·· 4 NMR (400.13 MHz, DMSO-d6) 5 1.05-1.09 (3H, t), 1.20-1.22 (3H, d), 3.09-3.16 (2H, m), 3.16-3.22 (1H, td) 5 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 (1H, s), 8.90-8·91 (2H, d). Example 48b : NMR (400.13 MHz, DMSO-d6) 5 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)5 7·35-7·37 (2H,d),7·65_7·67 (2H,d),7.81-7.82 (2H,q)5 7·96 (1H , s), 8.89-8.91 (2H? d). Test (c): Example (48) 0.038 //M; Example (48a) 0.25 //M· N-[4-[4-[(3S)-3 The preparation of phenylmethylphenoflavin-4-yl]_6-indole-4-ylphosphinylmethyl)pyrimidin-2-yl]phenyl]carbamic acid phenyl ester is described below. 123642 -345 - 200817384 N-[4-[4-[(3S)_3·Methylmorpholine_4_yl]_6 decapyridyl_4_ylsulfonylmethyl)pyrimidine_2_yl]benzene Phenyl carboxylate

Phenyl chloroformate (0. 029 ml, 〇·23 mmol) was added to 4-[4-[(3S)-3-methyl-n-Foline ice-based]_6_(pyridine bite ice) at room temperature Basestone xanthine methyl) guanidine / benzyl] aniline (0. 097 g, 0. 23 mmol) and sodium bicarbonate (0. 029 g, 〇 · 34 mmol) in dioxane In solution. The resulting slurry was stirred at room temperature for 2 hours. Additional gas phenyl formate (2 X 〇 〇〇 5 mL) was added to drive the reaction to completion. Then, water was 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 (yield: 98 g). NMR spectrum: 4 NMR (400.13 MHz, DMSO-d6) 6 1.21-1.23 (3 Η, 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), I 3.96-4.00 (1H,dd)5 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). LCMS spectrum: MH+ M6, s. 4_[4_[(3S)-3-methylphenoline _4_yl]·6-〇 咬 -4- -4- 基 基 甲基 甲基 基 -2 -2 -2 -2 -2 -2 -2 -2

123642 •346· 200817384 Add trans-dichlorobis(triphenylphosphine) (II) (0.039 g, 〇·06 house Mo) to 2_gas base bucket [(3S) at room temperature under nitrogen -3-methylmorpholine-4-yl]-6 heptadine·4·stone huangqiji T-base) guanidine (0.411 g, 1.11 mmol), 4-(4,4,5,5-four Methyl-1,3,2·dioxaboron-2-yl)aniline (〇·366 g, 1.67 mmol) and sodium carbonate (0.233 ml, 5.56 mmol) at 7:3: 2 DME : Water: a mixture of 18% DMF (1 ml) of an ethanol mixture. The resulting solution was stirred at 9 ° C for 5 hours. The reaction was allowed to cool and was diluted with ethyl acetate and water. The reaction mixture was extracted with ethyl acetate, and the combined organic material was dried (MgSO.sub.4), filtered, and evaporated. The crude product was chromatographed eluted EtOAc (EtOAc) NMR spectrum:! h NMR (400.13 MHz, DMSO-d6) 5 U9-1.20 (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)5 6·60 (1H,s), 7.48-7.50 (2H,d), 7.80-7.81 (2H, q),8·89-8_90 (2H , q). LCMS spectrum: MH+ 426, residence time uo minutes. 2-Alkyl-4-[(3S)_3-methylmorphin-4-yl]-6-decapyridyl-4-yl-decylmethyl), pyridine

Hydrogen peroxide solution (1 799 ml, 58.19 mmol) was added dropwise to the 2-methyl-4-[(3S)-3-methylmorpholine ice-based solution at 55 ° C under air. (pyridyl thiomethylmethyl) guanidine (0.980 g, 2.91 mmol), sodium tungstate dihydrate (〇〇〇5 123642 - 347 - 200817384 ml '0.06 mmol) and 2N sulfuric acid (0.075 ml) ) in a stirred solution in dioxane (200 ml) over a period of 5 minutes. The resulting solution was stirred at 55 ° C for 3 hours. Water (200 mL) was added and the mixture was evaporated. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Other materials were obtained by extracting the aqueous layer with DCM. The extract was dehydrated and dried (MgSO.sub.4), filtered, evaporated and purified eluting eluting eluting NMR spectrum: iH NMR (400.13 MHz, DMSO-d6) δ 1.17-U9 (3H, d), 3.14-3.22 (1 Η, td), 3.40-3.47 (1Η, td), 3·56_3·60 (1Η, dd ), 3.71-3.74 (1Η,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). LCMS spectrum: MH+ 369, retention time 1.39 min. 2·Vetyl-4-[(3S)-3_methylnorfos-4-yl]-6_(&gt; than bit -4-ylthio fluorenyl) bite

4-Mercaptopyridine (0.752 g, 6.77 mmol) was added to 2-carbyl-4-(E-methyl)-6-[(b) in hexane (100 liters) at room temperature and air. 3S)-3-Methylmorpholine-4-yl]carotidine (1.596 g, 4.51 mmol). Then DBU (0.3 mL, 2.01 mmol) was added and the resulting solution was stirred at room temperature for 2 min. Remove the solvent and add DCM. The reaction mixture was washed successively with water, and the organic layer was dried (MgSO.sub.4), and then evaporated. The crude product was chromatographed on Shiqi gum and dissolved in 0-2% methanol in DCM. The impure soluble fraction was further chromatographed on Shixia 123642 - 348 - 200817384 gel, dissolved in 0-4.5% methanol in DCM, and combined with the original pure soluble fraction to obtain the desired substance, which was yellow tannin (〇98). 〇克). NMR spectrum: NMR (400.13 MHz, DMSO-d6) 5 1.14-L16 (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)5 4.01 (2H,s)5 4·14 (1H,bs),6·43 (1H,s),7.04-7.06 (2H, d), 8·29_8·30 (2H, d)· LCMS spectrum: MH+ 337, retention time 1.62 minutes. 2-Alkyl_4-(Mothylmethyl)-6_[(3S)-3_methylmorpholine-4-yl]cyclopyridine

Sodium hydride (1.006 ml, 24.61 mmol) was added to 2-Chloro-4-[(3S)-3-methylphenoflylene-based]-6- in DCM at room temperature. (Methamidosyloxymethyl)pyrimidine (1.584 g, 4.92 mmol). The resulting solution was refluxed at 4 cc for 18 hours. The reaction mixture was diluted with DCM and washed with water. The organic layer was dried (MgSO.sub.4), filtered, and evaporated to give the desired product (1 sg). NMR spectrum: 4 NMR (400.13 MHz, CDC13) 1.27-1.28 (3H, d), 3.20-3.27 (1H, td)5 3.46-3.53 (1H, td)5 3.62-3.65 (1H3 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). LCMS spectrum: MH+ 354, retention time le85 min . 2-Phenyl-4-[(3S)-3·methyl-wufolin-4_yl]-6-(Alkyloxymethyl) shout

123642 -349- 200817384 Add gasified methanesulfonate (0.488 ml, 6.31 mmol) to [2-chloro-6-[(3S)_3-methyl) in DCM at 0 °C Fulin-4-yl] guanidine _4_yl]methanol (1.025 g, 4.21 mmol) with triethylamine (0.880 mL, 6.31 mmol), over a period of 2 min. The resulting solution was gradually warmed to room temperature over a period of 2 hours. The reaction mixture was diluted with DCM (50 mL) and washed with water. The organic layer was dried (MgSO.sub.4), filtered and evaporated. LCMS spectrum: MH+ 322, retention time l60 min. [2·Chloro-6-[(3S)-3·methylphenoline p-infrared base] σ densely biting ice base] Preparation of methanol is described in the foregoing. Example 49: 3-cyclopropyl small [4-[4_[(cyclopropylamino)methyl]_6_[(3S)-3.methylmorpholine-methanol]pyrimidin-2-yl]phenyl]urea

3-Lactyl-i-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(methylsulfonyloxymethyl)pyrimidinyl]benzene The urea (107 mg, 〇 23 mmol) was dissolved in DCM (5 mL) and added to cyclopropylamine mM. Triethylamine (〇162 liters of '1·16 house Moule) was added to the solution and stirred at room temperature for 18 hours. The reaction was evaporated to dryness eluting EtOAcqqqqqqq NMR spectrum. iH NMR (400.13 MHz, DMSO-d6) 5 0.29-0.31 (2Η, m), 0.34-0.44 (43⁄4 mX 〇.62.〇.67 (2H5 m)? 1.2M.27 (3H? m) , 2.13-2.17 (1H5 123642 -350- 200817384 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)· MS; M+H+ 423. The following compounds were prepared in a similar manner from 3-cyclopropyl-l-[4-[4-[(3S)-3-indolyl phenanthroline-4-yl] (methanesulfonyloxy) Methyl)pyrimidin-2-yl]phenyl]urea with the appropriate amine. Example structure name LCMS MH+ 49a [.] Ά ΙΑ SB 3_cyclopropyl-1_[4-[4-[(2_hydroxyethyl-) Methyl-amino)methyl]-6-[(3S)-3-methylmorpho-4-yl]pyrimidin-2-yl]phenyl]urea 441 49b [乂, ν〇Α: ΚΚ^ Η Η 3-cyclopropyl-l_[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-[(4·methylhexahydropyrylene-1-yl) Methyl]pyrimidin-2-yl]phenyl]urea 466 49c ηνΑ&gt;, 1 χ SB 3·cyclopropyl-1 -[4-[4-[(2-methoxyethylamino)methyl]-6-[(3S)-3·methylphenoflavin-4-yl]pyrimidin-2-yl]phenyl] Urea 441 49d Cx &quot;Άα ΙΑ Β人!^ 3-Cyclopropyl small [4-[4-(dimethylaminomethyl) each [(3S)-3·methylmorpholine 4-yl pyridine · 2_yl]phenyl]urea 411 49e "Λ[°],' ηνΑ&gt; ί X κ a 3-cyclopropyl small [4-[4-[(3-dimethylaminopropylamino)methyl] -6-[(3S)-3-methylphenanthene p--4-yl] gnacheer-2·yl]phenyl]urea 468 123642 -351 · 200817384 Example structure name LCMS ΜΗ+ 49f Cx °AaNiN^ Η H 3 —cyclopropyl-l-[4-[4_[(3S)-3-methylmorpholine-4-yl]-6-(morpholine-4-ylmethyl)pyrimidine_2-yl ]phenyl]urea 453 49g γ[°λ Η H 3-cyclopropyl_1-[4_[4-[(2-dimethylaminoethylamino)methyl]-6-[(3S)-3 -methylphenoflavin-4-yl] ° dense sigma -2 yl] phenyl]urea 454 49h Cx Η H 3-cyclopropyl_1-[4-[4-[(4-methyl-mouse)七囡烧^ -1_yl)methyl]-6-[(38)-3-methylmorphine _4_yl]pyrimidin-2-yl]phenyl]urea 480 49i ohCX Η H 3-cyclopropyl Base-l_[4-[4-[[(l-hydroxy-2.methyl-propan-2-yl)amino]methyl]-6-[(3S)_3-indolyl oxime-4- Base Yl] phenyl] urea 455 49j. [X Η Η 3_cyclopropyl-l-[4-[4-[(3S)-3-methylphenoxyp-lin-4-yl]-6-[(3-mercaptohexahydropyrazine - 1_yl)methyl]pyrimidin-1yl]phenyl]urea 456 49k Cx H0^W Η ί 3-ί-propyl-1-[4-[4-[(3_经基,^ 氮四圜- 1-yl)methyl]-6-[(3S)-3-methylphenoflavin-4-yl]pyrimidin-2-yl]phenyl]urea 439 491 a Η Η 3-cyclopropyl-l- [4_[4-[(3S)-3-Methylphenoxyp-4-yl]-6-[[(3S)-3-methylphenofy-4-yl]indolyl]. Σσ定-2-yl]phenyl]urea 467 Example 49a: 4 NMR (400.13 MHz, DMSO-d6) 3 0·40-0·44 (2H, m), 0.62-0.67 (2H, m), 1.21. -1.27 (3H,m)5 2.30 (3H,s),2·53-2·58 (1H,m), 3.14-3.21 (1H5 m), 3.46-3.58 (7H,m),3.62-3.66 (1H ,m),3.76 (1H,d), 3·95-3·99 (1H,m)5 4.15-4.18 (1H,m),4·45 (1H,t),4.48 (1H,s),6 · 42 (1H, 123642 -352- 200817384 d), 6.73 (1H, s), 7.47-7.49 (2H, m), 8.19-8.21 (2H, m), 8.50 (1H, s). Example 49b: iH NMR (400.13 MHz, DMSO-d6) (5 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 49c: iH NMR (400.13 MHz, DMSO-d6) 5 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)5 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 49d ·· iH NMR (400.13 MHz, DMSO-d6) (5 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)5 3·75 (1H , d), 3.95-3.98 (1H5 m)5 4.14-4.18 (1H5 m)5 4.46-4.48 (1H? m)? 6.44 (1H? d)5 6.61 (1H, s), 7.47-7.50 (2H, m ), 8.19-8.22 (2H, m), 8.53 (1H, s). Example 49e: no-spectrum example 49f: iH NMR (400.13 MHz, DMSO-d6) 5 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 49g: iH NMR (400.13 MHz, DMSO-d6) 5 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 123642 - 353 - 200817384 (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)5 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 49h :1!! NMR (400.13 MHz, DMSO-d6) 5 0.40-0.44 (2H, m), 0·62·0·67 (2H, m), 1.24 (3H, d), L46 (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)5 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 49i: NMR (400.13 MHz, DMSO-d6) (5 0.40-0.44 (2H, m) 5 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 49j: iH NMR (400.13 MHz, DMSO-d6) 5 0.40-0.44 (2H, m), 0.62-0.67 (2H, m), 1.2 M.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)· Test (a): Example (49) 0.033 //M; Example (49a) 0·15 //M; Example (49b) 0.014 He 1; Example (49c) 0.04 //M; Example (49e ) 0.032 //M ; instance (49f) 0.2 //M ; instance (49g) 0.087 /iM ; instance (49h) 0.18 //M ; Example (49i) 0.016 //M ; 123642 -354- 200817384 Example (49k) 0·014 /Μ; Example (491) 1.6 //Μ·Test (c): Example (49d) 0.62 //Μ; Example (49j 〇·ΐ3 /Μ·cyclopropyl-l-[4-[4-[(3S)-3-methylmorpholine_4·yl]_6_(methylsulfonyloxymethyl)&gt; The preparation of 2-yl]phenyl]urea is described above. Example 50: 3·cyclopropyl-1_[4-[4-[(1,1-dione-I-sedhadyl)-yl]][(38)methylphenoflavin]- 4-yl], indole-2-yl]phenyl]

3-cyclopropyl-l-[4-[4-[(3S)-3-methylmorpholine yl) each (methanesulfonyloxymethyl)pyrimidin-2-yl]phenyl] Urea (1 〇 7 mg, 〇 23 mmol) was dissolved in DCM (5 mL) and added to thiomorpholine (U6 mmol). Triethylamine (〇·162 house liter, 1.16 Torr) was added to the solution and stirred at room temperature for 18 hours. The reaction was evaporated to dryness in a mixture with water (1 mL). Between the house and the sorghum (110 mg, mash, and stir at room temperature for 1 hour. On the column, remove it with 7 Ν ammonia in methanol, and prepare HPLC (basic) for purification.得月匕涸, and dissolved in 1,4-dioxane (4 ml). Add m-chloroperbenzoic acid (100 mg, 〇58 tg '0.69 mmol) to one hour Fill the crude solution to the SCX-2 tube

Mg). NMR spectrum: iH^ was removed and evaporated to dryness. The desired material was obtained as a white solid (11H NMR (400.13 MHz, DMSO-d6) ^ 0.40-0.44

(23⁄4 ml (1H5 s)5 3.02 (3H? 3.70 (2H, s), 3.77 123642 -355 - 200817384 (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). Mass spectrum; M+H+501. Test (a): 0.0016 //M. 3-3⁄4 propyl-l-[4-[4-[(3S)-3_methyl? The preparation of leucine-4_yl]-6-(methionineoxymethyl&gt; melidin-2-yl]phenyl]urea is described above. Example 51: 1-[4_[4-( Hydroxymethyl)_6-[(3S)_3_methylmorpholine-methanol]pyrimidin-2-yl]phenyl]-3-[(l-fluorenyl-4-yl)methyl]urea

Add [2-carbyl-6-[(3S)-3-indolyl pheno-p-line-4-yl]-n-butyl]methanol (1_〇〇g, 4.10 mmol) to DME : EtOH : 18% of water 7 : 2 : 3 (18 ml) in DMF; H (l-methylpyrazolyl) methyl]]_[4_(4,4,5,5_4 Base-1,3,2-oxo-indole-2-yl)phenyl]urea (2.193 g, 6.16 mmol) with sodium carbonate (8.21 mL, 16.41 mmol) and degas the solution 5 minutes. Dichlorobis(triphenylphosphine)palladium (ruthenium) (0·144 g, 〇·21 mmol) was added to the mixture. The resulting solution was stirred at 85 ° C for 18 hours. The reaction was cooled and neutralized with concentrated hydrochloric acid. The crude product was purified by ion exchange chromatography using a scx 2 (5 gram) column, followed by further purification by flash chromatography, and the solution was dissolved in DCM to 7% methanol to give the desired material. As a white solid (963 mg). NMR spectrum: iH nmr (4〇〇13 脏2, DMS〇d^ 占(班句123642 356- 200817384 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 LCMS spectrum·· MH+ 438, retention time 1.37 minutes [2- gas-based-6-[(3S)-3_曱基福4-(4-mercapto-4-yl)methanol (1·〇〇克, 4.10 mmol) and 3-[(1-methylpyrazole)-yl]methyl][4-(4, The preparation of 4,5,5-tetramethyl-1,3,2-dioxaboron-2-yl)phenyl]urea is described above. Example 52: 1_[4-[4_[(3S) _3-methylphenoflavin-4_yl]-6_[(4.methylhexahydro-p-heptyl-1-yl)methyl]pyrimidin-2-yl]phenyl]_3_[(1_methylpyridyl) Azole 4_yl)methyl]urea

Add 1-methylhexahydropyrene to morphine (0.067 ml, 〇·6 〇 millimol) to triethylamine (0.084 mL, 0.60 mmol) at room temperature under nitrogen with i-[4-[ 4-[(3S)-3-Methylmorphine·4·yl]-6-(methioninyloxyindenyl). A solution of phenyl]-3-[(l-methyl-indolyl-4-yl)methyl]urea (155 mg, 0.30 mmol) in DCM (5 mL). The resulting solution was stirred at room temperature for 18 hours. The reaction mixture was evaporated. The crude product was purified by preparative HPLC using EtOAc (EtOAc:EtOAc) NMR spectrum: iH NMR (400.13 MHz, DMSO-d6) 5 ΐ·21 (3H,d),2·17 123642 -357 - 200817384 (3H,s),2·35 (8H,s),3·14- 3·21 (1H,m)5 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)5 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) · LCMS spectrum: MH+ 520, retention time 1.49 minutes. The following compounds were prepared in a similar manner from ^^[4-1:(38)-3-methylmorpholine-4-yl]-6-(methylsulfonyloxymethylmidine)phenyl ••Methylpyrazol-4-yl)methyl] vein with the appropriate amine. Example structure name LCMS MH+ retention time (minutes) 52a [λ Η H Η4-[4·[(cyclopropylamino)methyl]-6-[(3S)-3-methylwfolin _4_yl] carcinoma σ定-2-yl]phenyl]-3-[(1-methylpyrazol-4-yl)methyl]urea 477 1.66 52b 0&quot;, Η H 1_[4-[4-[(cyclopropyl) -methyl-amino)methyl]_6-[(3S)-3-methylmorpholine-4-yl]pyrimidin-2-yl]phenyl]-3-[(l-methylpyrazole- 4-yl)methyl]urea 491 1.89 Example 52a: 4 NMR (400.13 MHz, DMSO-d6) 6 0.28-0.33 (2H, m), 0.37-0.39 (1H, m), 1.21-1.26 (3H, m) ,1_36 (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). 123642 - 358 - 200817384 Example 52b ·· 4 NMR (400.13 MHz, DMSO-d6) 6 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 (1H, s), 6.40 (1H, t), 6·52 (1H5 s), 7·35 (1H, s), 7.46-7.49 (2H, m), 7.59 (1H , s), 8.21 (2H, d), 8.64 (1H, s). Test (8): Example (52) 1_4 //M; Example (52a) 0.33 /zM; Example (52b) 0.57 //M. l -[4-[4_[(3S)-3-Methylnorfos-4-yl]-6-(methionine-oxymethylmethyl). The preparation of ?2-yl]phenyl]_3_[(1-methylpyrazolyl)methyl]urea is described below. 1-[4_[4_[(3S)_3-methylfolfin-4_kib 6-(methyl hydrazinyloxymethyl)pyrimidine_2_yl]phenyl]-3·[(1_甲甲Base _4_yl) sulfhydryl

Methanesulfonate (0·246 ml, 3.15 mmol) was added dropwise to triethylamine (0.440 ml, 3.15 mmol) and 1-[4-[4- at 〇 ° C under nitrogen. (hydroxymethyl)-6-[(3S)_3-methylmorpholine-4-yl]- phenanthrene-2-yl]phenyl]·3_[(ι-methylpyrazole-donyl)methyl] Urea (920 mg, 2.10 mmol) in a solution in DCM (3 mL) over a period of 10 minutes. The resulting solution was stirred at 2 ° C for 45 minutes. The reaction mixture was washed with water (10 mL). The organic layer was dried (MgSO.sub.4), filtered and evaporated to give the desired material. LCMS spectrum: MH+ 516, retention time 1 β 72 min. 123642 - 359- 200817384 [4-[4-(Hydroxymethyl)-6-[(3S)-3-methylmorpholine-4-yl]pyrimidinyl]phenyl]-3·[(1- The preparation of methylpyrazolyl)methyl]urea is described above. Example 53: N-[2-[[6-[(3S)-3_methylphenoflavin-4-yl]-2_[4-[(1-methylindoleinyl)methylamine) Amino]phenyl]pyrimidinyl]methylsulfonyl]ethyl]acetamide

The m-gas perbenzoic acid (156 mg, 〇·9 〇 millimolar) was dissolved in dioxane (2 ml) at room temperature under nitrogen and dissolved in water (丨 ml). N-[2_[[6-[(3S)) is added dropwise to the dioxanthine (6 ml) and water (2 ml) by sodium perchlorate monohydrate (192 mg, 1 · 20 mmol) -3-indolyl porphyrin ice-based]_2-[4_[(1-methylpyrazolyl)methylamine-methylamino)phenyl]pyrimidinyl]methylthio]ethyl]ethyl Indoleamine (162 mg, 〇 30 mmol). The resulting solution was stirred at room temperature for 1 hour. The crude product was purified by ion exchange chromatography using a SCX column. The desired product was dissolved from the column, using 7 氨 ammonia in methanol, and the pure dissolved fraction was evaporated to dryness. The crude product was purified by preparative HPLC using EtOAc (EtOAc:EtOAc) NMR spectrum: lH (4〇〇·13 MHz, DMSO_d6) 5 1.24 (3H,d),1·83 (3H?s)5 3.18 (1H?m)5 3.50-3.58 (6H5 m)? 3.66- 3.67 (1H5 m)? 3.76 (1H? s)3 3-80 (3H? s)5 3.97 (1H, s)5 4.13 (2H, d)5 4.51 (3H? m)? 6.40 (1H5 d)? 6.78 (1H5 s)5 7.35 (1H5 s)? 7.48-7.51 (2H, m)5 7.59 (1H5 s)5 8.15 (1H? s)? 8.21 123642 -360- 200817384 (2H,d),8.69 (1H,s · · lcms spectrum: MH + 571, residence time L42 minutes / example structure name 7 ° LCMS MH + retention time (minutes) 53a [. ] ljlH2. Present Ax汐Η H 2-[[6-[(3S)-3-methylmorpholine_4_yl]_2-[4-[(l-methylpyrazolyl)methylaminemethanyl) Amino]phenyl]pyrimidin-4-yl]methanesulfonyl]acetamide 543 1.40 53b Ο OH as Wy Η H 1-[4-[4-(2-ethylethyl fluorenylmethyl)-6- [(3S)-3-methylphenoflavin-4-yl]pyrimidin-2-yl]phenyl]_3-[(1-methylpyrazol-4-yl)methyl]urea 530 1.43 52c wide, [n], Η H l-[4-[4_[(3S)-3·methyl? 1 福普林-4-yl]_6-(p is 0-1,4-sulfonylmethyl)pyrimidine -2·yl]phenyl]-3-[(l-methylpyrazolyl)methyl]urea 563 1.63 Example 53a: iH NMR (400.13 MHz, DMSO-d6) (5 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) 5 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 53b : 1H NMR (400.13 MHz , DMSO-d6) (5 1.24 (3H,d),3·22 (13⁄4 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), 123642 .361 200817384 7·35 (1H, s), 7.49-7.51 (2H, m), 7·59 (1H, s), 8_22 (2H,d),8·68 (1H,s)· Example 53c: iH 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). Test (a): Example (53) 0.64 // M; Example (53a) 0.6 //M; Example (53c) 0.03 μΜ. Test (c): Example (53b) 3 //M_ N-[2-[[6-[(3S)-3-methyl] Fulin-4-yl]-2-[4-[(l-methylpyrazol-4-yl)methylaminecarboxyamino]phenyl]pyrimidin-4-yl]methylthio]ethyl The preparation of acetaminophen is described below. N-[2_[[6-[(3S)_3·]-yloxalin-4-yl-l-2_[4-[(l-methylpyrazole-4-yl)methylamine mercaptoamine Phenyl]pyrimidin-4-yl 1methylthio]ethyl]acetamide

N-Ethyl cysteamine (〇·〇 56 ml, 0.53 mmol) was added to DBU (0.091 mL, 〇.60 mmol) and H4-[ 4-[(3S)-3-methylmorpholine-4-yl]-6-(methylsulfonyloxymethyl)pyrimidine_2·yl]phenyl]-3_[(1_methylpyridyl) Imidazole-4-yl)methyl lion (155 mg, 0.30 mmol). The resulting solution was stirred at room temperature for 5 hours. The reaction mixture was evaporated to give the desired material which was used without further purification. 123642 -362- 200817384 LCMS spectrum: MH+ 539, retention time 1.66 min. The following sulfides were prepared in a similar manner from 1-[4-[4-[(3S)-3-indolyl oxafosin-4-yl]-6-(methioninyloxymethyl) oxime- 2-Based]phenyl]-3-[(l-fluorenylindole-4-yl)methyl] vein with the appropriate thiol. Structure name, 2 〇, , .乂 乂 Η Η 2-[[6-[(3S)-3-Methylphenoxylated]-2-[4-[(1-methylpyrazol-4-yl)methylamine A醯 胺 ] [ [ [ [ [ [ [ [ [ [ [ [ [ [ 1-[4-[4-(2-hydroxyethylthiomethyl) _6_[(3S)_3_Methylorfos-4-yl]Nursing _2_yl]phenyl]_3-[(i-methylpyrazol-4-yl)methyl]urea Η 卜 [ 4-[4-[(3S)-3-methylphenofylidene]-6-0 is 唆-4-ylthiomethyl).密定定_2_基]Phenyl]_3-[(1-methylpyrazol-4-yl)methyl]urea H4-[4-[(3S)-3-methylmorpholine-4- Preparation of -6-(methylsulfonyloxymethyl), succinyl-2-yl]phenyl]-3·[(1-methylpyrazol-4-yl)methyl]urea Described in the previous article. Example 54: 3·Cyclopropyl_1-[4-[4-(methoxymethyl)-6-[(3S)-3-methylmorpholine ice-based] shouting base] phenyl] urea

3-Cyclopropyl-H4-[4-[(3S)-3-methylmorpholine]-[6-(indolyloxymethyl)pyrimidin-2-yl]phenyl]urea Mg, 〇·16 mmol) and potassium carbonate (9〇123642-363 - 200817384 mg, 0.65 mmol) were suspended in methanol (3 mL) and sealed into a microwave tube. The reaction was heated to 1 Torr in a microwave reactor. 〇, after 丨〇 minute, and cooled to room temperature. The crude product was purified by ion exchange chromatography using a 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 EtOAc (EtOAc) (EtOAc) NMR spectrum: iH NMR (400.13 MHz, DMSO-d6) 5 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 (3H5 s)? 3.45-3.52 (1H? m)? 3.62-3.66 (1H? m)5 3.75 (1H5 d), 3.95-3.98 (1H5 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). LCMS spectrum: MH+ 398, retention time 1.86 min. Test (c): 0.11 _ 3-cyclopropyl-l-[4-[4-[(3S)-3-methylmorpholine-4-yl] winter (methylsulfonyloxymethyl)pyrimidine The preparation of _2-yl]phenyl]urea is described above. Example 55: 3_cyclopropyl small [4-[4_(cyclopropylsulfonylmethyl)-6_[(3S)-3-methylmorpholine_4_yl], bit: base] phenyl] Urea

[4-(3·Cyclopropylureido)phenyl]dipyridyl succinyl ester (8 〇 mg, 〇·26 mmol), sodium carbonate (1.055 ml, 2·11 mmol) ), dichlorobis (three 123642-364-200817384 phenylphosphine), (II) (14. 8 mg, 〇·〇 2 mmol) and 2-chloro-4-(cyclopropylsulfonylmethyl) ) 6-[(3S)-3·methylmorpholine yl]pyrimidine (70 mg, 0.21 mmol) suspended in DME · ethanol·water 7 · 2 : 3 mixture of 18% DMF (4 ml Inside, and sealed into the microwave tube. The reaction was heated to 1 ° C in a microwave reactor over 10 minutes and cooled to room temperature. 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 EtOAc (EtOAc: EtOAc) NMR spectrum: iH NMR (400.13 MHz, DMSO-d6) 5 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)5 3.50 (1H,d)5 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). LCMS spectrum: mh + 472, retention time ι·8〇 min. Test (4): 0.062 // Μ. The preparation of 2-chloro-based ice (cyclopropylsulfonylmethylmethylmorpholine _4•yl)pyrimidine is described below. 2·Alkylcyclopropylsulfonyl Methyl)_6_[(3S)_3_methylmorpholine_4 base Π

V ·, J 将 Cycloalkane sulfinate sodium salt (381 mg, 2.97 mmol) was added in portions to acetonitrile (20 ml A 123642-365 - 200817384 base)-6-[(3S)-3-methylorfos-4-yl] mouth π set (700 mg, L98 mmol). The resulting suspension was stirred at 90 ° C for 3 hours. The reaction mixture was taken to dryness <RTI ID=0.0> and </ RTI> then dissolved in DCM (50 mL). The organic layer was dried (MgSO.sub.4), filtered and evaporated to give crude. The crude product was purified by flash chromatography eluting EtOAc (EtOAc) NMR spectrum: iH NMR (400.13 MHz, DMSOd6) 5 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). LCMS spectrum: MH+ 332, retention time 1.68 min. The preparation of 2-air-based ice (E-methylmethyl)-6-[(3S)-3-indolyl carbendene-4-yl spicy bite is described above. Example 56: 3-Cyclopropyl small [4_[4-(2-cyclopropylsulfonylpropan-2-yl)-6-[(3S)-3-indolylmorpholine-4-yl]pyrimidine -2-yl]phenyl]urea

[4-(3-Cyclopropylureido)phenyl]dihydroxyborane quinone ester (199 mg, 〇·66 mmol), 2-carbyl-4-(2-cyclopropyl sulfonate) Mercaptopropan-2-yl)-6-[(3S)-3-methylmorpholine-4-yl]pyrimidine (190 mg, 〇·53 mmol), sodium carbonate (1.320 ml, 2·64) Mol) and dichlorobis(triphenylphosphine) suspend (II) (37j mg, 〇·〇5 mM 123642 -366- 200817384 ears) in DME ··Water: EtOH 7 : 3 : 2 solution 18% DMF (4 ml) inside and sealed into the microwave tube. The reaction was heated to 100 ° C in a microwave reactor over 20 minutes and cooled to room temperature. The crude product was purified by ion exchange chromatography using an SCX column. The desired product was dissolved from the column, 7M ammonia in methanol was used, and the pure dissolved fraction was evaporated to dryness. The crude product was further purified by preparative HPLC using EtOAc (EtOAc: EtOAc: EtOAc) NMR spectrum: iH NMR (400.13 MHz, DMSO-d6) 5 0·40-0_44 (2H, m), 0.62-0.67 (2H, m), 0.78-0.83 (1H, m), 0.81 (1H, d)5 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)5 6.77 (1H,s), 7.49-7.51 (2H,m),8·23·8·25 (2H,m),8·52 (1H,s)·LCMS Spectrum: MH+ 500, residence time 2.04 minutes. Test (4): 2.4 // Μ. The preparation of the 2-gas base (2-cyclopropylsulfonylpropyl propylidene) winter [(3S)_3_methylmorpholine ice-based] sneeze is described below. 2-Alkyl-4-(2-cyclopropylsulfonylpropan-2-yl) each [(3S)methylmorpholine ice-based] pyrimidine

Methyl iodide (0·033 ml, 0·53 mmol) was added to sodium tributoxide (50.7 mg, 〇·53) in DMF 123642 -367 - 200817384 (2 ml) at -10 °C. Millol) with 2-chloro-4(cyclopropylsulfonylhydrazino)-6-[(3S)-3-methylmorpholine]pyrimidine (175 mg, 〇·53 mmol) In the ear). The resulting thick suspension was stirred at room temperature for 15 minutes to facilitate agitation. Methyl iodide (0.033 ml, 0.53 mmol) and sodium tributoxide (50.7 mg, 0.53 mmol) were added to the reaction again and the resulting suspension was stirred at room temperature for 15 min. . The reaction mixture was diluted with DCM (20 mL) The organic layer was dried (MgSO.sub.4), filtered, and evaporated to give the desired material. LCMS spectrum: MH+ 360, retention time 2.13 min. 2. Air-based ice (cyclopropyl sulphate methyl)-6_[(3S)-3-methylphenoflavin-4-yl]. The preparation of the pyridine is described above. Example 57: 1-[4_[4·(2-cyclopropionylpropanyl-2-yl)-6-[(3S)-3-methylmorphin _4_yl], pyridine-2-yl Phenyl]-3·methyl-urea

Methylamine (0.699 ml, ΐ·4 mmol) was added to N-[4-[4-(2-cyclopropylsulfonylpropan-2-yl)_6_[(3S&gt) in DMF (2 mL)曱 吗 吗 吗 啉 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 耄 耄 耄 耄 耄 耄 耄 耄 耄 耄 耄 耄 耄 耄 耄 耄 耄 耄 耄 耄 耄 耄 耄 耄 耄 耄 耄 耄The resulting solution was mixed for 2 hours under 4 Torr. The crude product was purified by preparative HpLC using a decreasing polar mixture of water (containing i%nh3) and MeCN as the dissolving agent. The desired material was obtained as a white solid (74.0 mg). </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> NMR spectroscopy: iH NMR (400·13 MHz, DMSO-d6) 5 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)5 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). LCMS spectrum: MH+ 474, residence time 1.92 minutes. Test (c) · Example 57) 0·25 _ ; instance (57a) 0.064 //Μ; instance (57b) 0.089 //Μ; instance (57c) 0.36 //Μ; instance (57d) 0·84 //Μ; instance (57e) 0 ·38 //Μ; instance (57f) 0.72 //Μ; instance (57g) 0.095 //Μ; instance (57h) 0.066 //Μ; instance (57i) 0·27 //Μ; instance (57j) 0· 07 //Μ; example (57k) 0.34 //Μ; example (571) 0.088 μΜ. Example structure name LCMS MH+ retention time (minutes) 57a [λ 1-[4·[4-(2-3⁄4 propyl scutane) -2-yl)-6-[(3S)-3-methylinfos-4-yl]pyrimidin-2-yl]phenyl]-3-(1-carbo-2-methyl-propyl- 2-Base) Monthly Urine 532 2.03 The following compounds were prepared in a similar manner from either Ν-[4-[4-(2-cyclopropylsulfonylpropan-2-yl)-6-[(3S)- Phenyl 3-hydrazinofosolin-4-yl]-piperidin-2-yl]phenyl]carbamate or hydrazine-[4-[4·(cyclopropylsulfonylmethyl)-6-[ (3S)-3-Methylfosino]pyrimidinyl]phenyl]carbamic acid phenyl ester and the appropriate amine. 123642 -369- 200817384 Example structure name LCMS MH+ retention time (minutes) 57b Η H l_[4_[4-(2-cyclopropylsulfonyllanylpropan-2-yl)-6· [(3S&gt;3-A Kifufolin-4-yl]pyrimidin-2-yl]phenyl]-3-(2-dimethylaminoethyl)urea 531 2.00 57c [X ,Αα人Η H 1-[4-[4- (2-3⁄4propyl fluorescein-2-yl)-6-[(3S)-3-methylorfosin 17 lin-4_yl h-pyridin-2-yl]phenyl] -3-(1 -methyl-trim-4-yl)urea 540 1.93 57d [X Η H 1-[4-[4-(cyclopropylsulfonylmethyl)-6-[(3S)-3-methylorfo ρ林-4-yl]17-mididin-2-yl]phenyl]-3-methyl-urea 446 1.56 57e Η H 1-[4-[4-(cyclopropylsulfonylmethyl)-6 -[(3S)-3-methylphenoflavin-4-yl] 口密0定-2-yl]phenyl]-3-(1-yl-2-methyl-propan-2-yl) Urea 504 1.70 57f Cx Η H 1-[4-[4-(cyclopropylsulfonylmethyl)-6-[(3S)-3-methylmorphin-4-yl]pyrimidine-2 -yl]phenyl]-3-(2-didecylaminoethyl) monthly urine 503 1.66 57g Η H 1-[4-[4-(cyclopropylsulfonylmethyl)-6-[(3S -3- 曱 吗 福 福 林 -4- -4- -4- ke ke ke ke ke ke ke ke ke ke ke ke ke ke ke ke ke ke ke ke ke ke ke ke ke ke ke ke ke ke ke 384 Example structure name LCMS ΜΗ+ retention time (minutes) 57h Cx Η H 3-cyclobutyl_1-[4-[4·(2-cyclopropylsulfonylpropan-2-yl) each [(3S) -3_Methylorfosin-4-lin-4_yl]1-decyl-2-yl]phenyl]urea 514 2.28 57i [:X, Η H 1-[4-[4-(2-cyclopropylsulfonate) Mercaptopropan-2-yl)-6-[(3S)-3-methylmorpholine-4-yl]pyrimidin-2-yl]phenyl]-3-(2-hydroxyethyl)urea 504 1.72 57j Cx Η H 1·[4·[4-(cyclopropylsulfonylmethyl)-6-[(3S)-3-indolylmorpholine-4-yl]pyridin-2-yl]phenyl ]-3-ethyl-urea 460 1.71 57k Cx Η H 1-[4-[4-(2·cyclopropylsulfonylpropan-2-yl)-6-[(3S) -3-methyl? Fuline _4_yl]pyrimidin-2-yl]phenyl]-3-ethyl-pula 488 2.04 571 ΗH 3-cyclobutyl·1-[4-[4-(cyclopropylsulfonylmethyl) _6-[(3S)-3_Methylphenoline p--4-yl]Nastagidine _2·yl]phenyl]urea 486 1.96 Example 57a: iH NMR (400.13 MHz, DMSO_d6) 5 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 (1 H,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,d)5 8.72 (lH,s). 123642 -371 - 200817384 Example 57b : 1H NMR (400.13 MHz, DMSO-d6) 5 0·79-0·84 (2H, m), 0·95 (2H,d), 1.23 (33⁄4 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 57c: 1H NMR (400.13 MHz, DMSO-d6) (5 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)5 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)5 7_53·7·56 (2H,m),7·76 (1H,s),8·27 (2H,d),8.38 (1H,s ), 8.82 (1H, s) Example 57d: NMR (400.13 MHz, DMSO-d6) 5 0.97-1.01 (2H, m), 1.03-1.09 (2H, m), 1·23-1·25 (3H, m), 2.67 (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). Example 57e: iH NMR (400.13 MHz, DMSO-d6) 5 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), 8.72 (1H, s Example 57f ·· 1H NMR (400.13 MHz, DMSO-d6) 5 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), 123642 -372- 200817384 7.47-7.49 (2H,m), 8.20-8.23 (2H,m),8.88 (1H,s). Example 57g: iH NMR (400.13 MHz, DMSO -d6) 6 0.99-1.02 (2H,m), 1.04-1.10 (2H,m),1·25 (3H,d),2·85-2·89 (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)5 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)5 8·82 (1H, s). Example 57h: iH 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)5 7.46-7.49 (2H,m),8·24 (2H,d),8·55 (1H,s). Example 5Ή : 1 H NMR (400.13 MHz, DMSO-d6) 5 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 57j: iH NMR (400.13 MHz, DMSO-d6) δ 0·97-1·01 (2H, m), 1.03-U0 (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 57k: 1H NMR (400.13 MHz, DMSO-d6) 5 0·78-0·83 (2H,m), 0.95 (2H,d),1·07 (3H,t),1.23 (3H,d),1.81 (6 H,d),2·75 (1H,d),3_15 (2H,d), 123642 -373 - 200817384 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 571 : 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)·Ν-[4·[4-(2·cyclopropylsulfonylpropan-2-yl)_6-[(3S The preparation of -3-methylmorpholine·4·yl]pyrimidin-2-yl]phenyl]carbamic acid phenyl ester is described below. [4-[4-(2_Cyclopropylsulfonylpropanyl-2-yl)_6-[(3S)_3-indolylmorpholine-4-yl]pyrimidine:yl]phenyl]aminocarboxylic acid Phenyl ester

Phenyl chloroformate (0.2 ml, 1.71 mmol) was added dropwise to 4-[4-(2-cyclopropylsulfonylpropan-2-_2) in dioxane (15 ml) under nitrogen. Base)-6-[(3S)-3-methylmorpholine]pyrimidin-2-yl]phenylamine (712 mg, ΐ 7ι 耄 耳) with sodium bicarbonate (215 mg, 2.56 mmol) In the ear). The resulting suspension was stirred at room temperature for 2 hours. The reaction mixture was evaporated to dry EtOAc (EtOAc)EtOAc. The organic layer was dried (MgSO.sub.4), filtered and evaporated to give the desired material (983 mg). ' 123642 -374- 200817384 NMR spectrum: W NMR (400.13 MHz, DMSO-d6) (5 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)5 6·80 (1H,s)5 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)· LCMS spectrum: MH+ 537, retention time 2.87 min. 4-[4-(2- Cyclopropyl-propenylpropan-2-yl)-6-[(3S)-3-methylmorphin-4-yl], butyl-2-yl] aniline

Dioxobis(triphenylphosphine)-saturated (II) (96 mg, 0.14 mmol) was added to DME: water: ethanol in 7:3:2 (20 ml) in 18% of DMF (4-amino group) Phenyl) dihydroxyborane oxime ester (747 mg, 3.41 mmol), 2-chloro-4-(2-3⁄4propyl-propionylpropan-2-yl)-6-[(3S) -3-Methylorfosyl p--4-yl] was sprayed (982 mg, 2.73 mmol) and sodium carbonate (6.82 mL, 13.64 mmol). The resulting solution was spoiled 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 chromatography eluting with EtOAc EtOAc (EtOAc) NMR spectrum:! h NMR (400.13 MHz, DMSO-d6) δ 0.79-0.83 (2H, m), 0.94-0.96 (2 Η, s), 1.21 (3 Η, d), 1.79 (6 Η 5 d), 2·74 (1 Η, m) ,3·17 (1Η,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 123642 -375 - 200817384 (1H,m),4.54 (1H,d)5 5.51-5.53 (2H,m),6·59 (2H,t),6·67 (1H,s),8·07 (2H,d) LCMS spectrum: MH+ 417, retention time 2.22 minutes. The preparation of 2_glycol-4-(2-cyclopropylsulfonylpropan-2-yl)-6-[(3S)-3-methylmorphine ice-based h-pyridine is described above. N-[4-[4-(Cyclopropylsulfonylmethyl)-6-[(3S)_3_methylmorpholine]. The preparation of benzoate phenyl-2-phenyl] phenyl carbamate is described below. N-[4-[4_(cyclopropylsulfonylmethyl)-6-[(3S)-3-methylmorpholine)pyrimidin-2-yl]phenyl]phenyl carbamic acid phenyl ester

Phenyl chloroformate (0.315 ml, 2-50 mmol) was added dropwise to 4-[4-(cyclopropylsulfonylfluorenyl)-6-[(3S&gt;) in dioxane (20 mL). 3-methyl- or phenoline-based [injection of 2-yl] aniline (972 mg, 2.50 mmol) with sodium bicarbonate (315 g ' 3.75 mmol). The resulting suspension was After stirring for 2 hours at room temperature, the reaction mixture was evaporated to dryness and redissolved in ethyl acetate (100 liters) and washed with water (1 mL). The organic layer was dried (MgS 〇 4) , filtered, and evaporated to give the desired material (1·35 g). NMR spectrum: 1h NMR (400.13 MHz, DMSO-d6) δ 0.98-1.03 (2 Η, m), 1·〇6·1·1〇 (2Η,m),1·26 (3Η,d),2·86-2·93 (1Η,m), 3.48-3.52 (1Η,m),3.58 (1H,s)5 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)5 7.24-7.29 (3H,m),7.43-7.47 (2H,m),7·65 (2H,d),8.31 (2H,d),10.47 (1H,s)·123642 -376- 200817384 LCMS Spectrum: MH+ 509, retention time 2.2 9 minutes. 4-[4-(Cyclopropylcylmethyl)_6_[(3S)-3-methylphenofylinyl] spray bite j base aniline

Dichlorobis(triphenylphosphine)-saturated (II) (96 mg, 0.14 mmol) was added to DME: water in ethanol: 7:3: 2% in DMF (20 mL) Phenyl phenyl) dihydroxy borane 呐 酯 ester (747 mg, 3.41 mmol), 孓 孓 -4 -4 ((cyclopropyl sulfonylmethyl) _6_[(3S)_3_ fluorenyl porphyrin Base] pyrimidine (9) $ mg, 2.73 millimoles) and sodium carbonate (6. 82 ml, 13.64 mmol). 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 purified by flash chromatography eluting EtOAc (EtOAc) NMR spectrum · · iH nmr (4〇〇13 MHz, DMS〇〇占97 ι 〇2 yang, called, 1·〇3·1·1〇(2H,m),1·23 (3H,d), 2·81_2·87 (1H,m),3·15-3·22 (1H,m), 3·46-3.52 (1Η,m),3.62-3.66 (1Η,m),3.77 (1Η,d) , 3.96-3.99 (1Η,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)· LCMS spectrum: MH+ 389, retention time 182. 2 gas-based 4-(cyclopropylsulfonylmethyl)_6-mute _3•Methylmorpholine bucket base] The preparation of pyrimidine bite is described above. 123642 -377 - 200817384 Example 58: 3·Methyl small [4-[4-[(3S) fluorenyl porphyrin _ 4_基】_6〇 啶 冰 冰 冰 醯 醯 丙 丙 丙 丙 丙 唆 唆 · · · · ] 脲

Add methylamine (2M solution in THF) (0.55 mL, u〇 millimol) to N-[4-[4-[(3S)-3-methyl- Phenyl-4-yl]-6n-demethyl-sulfonylpropan-2-yl)pyrimidin-2-yl]phenyl]carbamic acid phenyl ester (125 mg, 0.22 mmol) and triethylamine (〇· 〇92 ml, 〇66 mM). The resulting solution was stirred at 50 ° C overnight. The crude product was purified by preparative EtOAc EtOAc (EtOAc) eluted eluted eluted NMR spectrum · ^ NMR (400.13 MHz, DMSO-d6) 5 1.22-1.23 (3H,d), 1.82-1.83 (6H,d),2.66-2.67 (3H,d)5 3.15-3.23 (1H,td), 3.47-3.53 (1H,td)5 3.63-3.53 (1H,dd),3·76-3.79 (1H,d),3.96-4.00 (13⁄4 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). LCMS spectrum: MH+ 511, retention time 2.03 min. The following compounds were prepared in a similar manner from N_[4-[4_[(3S)methyl-methylfosfolin-4-yl]-tung (2•pyridin-4-ylsulfonylpropan-2-yl)pyrimidine Phenyl]phenyl] carbamic acid phenyl ester with the appropriate amine. 123642 •378 - 200817384 Example structure name LCMS ΜΗ+ residence time (minutes) 58a Cx Η H 3-ethyl-l-[4-[4-[(3S)-3-methylphenofyl-4-yl] -6-(2-Pyridin-4-ylsulfonylpropan-2-yl)pyrimidin-2-yl]phenyl]urea 525 2.17 58b [X Η H 3-cyclopropyl_l-[4-[4 -[(3S)-3-methylmorpholine ice-based] phloem-4-based base-propionyl-2-yl)pyrimidin-2-yl]phenyl]urea 537 2.19 58c Cx Η H 3-ring Butyl small [4-[4-[(3S) _3·methylphenoline p-4-yl]-6-(2-pyridin-4-ylsulfonylpropan-2-yl) mouth bite-2 -yl]phenyl]urea 551 2.39 58d [X Η H 3- (2-hydroxyethyl) small [4-[4-[(3S)-3·methylmorpholine 4-yl]-6-( 2 Qiao than bite -4 keel xanthine propion-2-yl butyl-2-yl] phenyl] urea 541 1.90 58e O', O^A〇l human /, Η H 3-(2-dimethylamino Ethyl)-H4-[4-[(3S)-3-methylphenoline p--4-yl]pyrimidin-4-yl-phenylpropan-2-yl)pyrimidin-2-yl]phenyl ]urea 568 2.36 Example 58a ·· 4 NMR (400.13 MHz, DMSO-d6) (5 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)5 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 (2H, q). 123642 -379 - 200817384 Example 58b ···················· 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 (2H5 q) Example 58c: iH NMR (400.13 MHz, DMSO-d6) 5 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 58d: 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), 3·44-3·48 (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)·Example 58e : iH NMR ( 400.13 MHz, DMSO-d6) 5 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,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 (2H5 q), 8·85 (1H,s)· 123642 -380 - 200817384 N-[4- [4-[(3S)-3_Methylorfosin, Lin·4·yl]_6_(tetra)唆-4_yl </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> The preparation lines are described below. N-[4-[4-[(3S)-3-methylmorpholine_4_yl]_6_(2_pyridine·4• sulfamoylpropyl)pyrimidin-2-yl]phenyl]amine Phenyl phthalate

Add phenyl chloroformate (〇 177 ml, 141 mmol) to 4_[4_[(3S&gt;3-methylfofofolan) in dioxane (175 ml) at room temperature under air. ]-6_(2-p than bite-4-base g)lanylpropan-2-ylindole-2-yl]aniline (0·640 g,! 41 mmol) with sodium bicarbonate (0.178 g, 2.12) The resulting slurry was stirred at room temperature for 2 hours. Two additional portions of phenylformate (2 X 〇·〇〇 5 mL) were added and the reaction was stirred at room temperature. Water was added to the reaction mixture, and the solid was filtered and dried in vacuo to dryness to dryness to give the desired substance as a tan solid (yield: 758 g). NMR spectrum · ^ NMR (400.13 MHz, DMSO-d6) 5 1.23-1.24 (3Η,d), 1.83-1.84 (6H5 d)? 3.17-3.24 (1H? td)5 3.48-3.53 (1H? td)5 3.64-3.67 (1H5 dd)5 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) · LCMS spectrum · · MH+ 572, when staying 2.82 min. 4-[4-[(3S)-3_Methylorfosin_4_yl]-6-(2_^ ratio. -4-yl-stone yellow with propyl-2-yl) mouth bite-2 -yl]aniline 123642 -381 - 200817384

Add (π) (0.050 g, 0.07 mmol) to trans-dichlorobis(triphenylphosphine) to a mixture of DME:water:ethanol (7:3:2) at room temperature under nitrogen. 2% chloro-4-[(3S)-3-methylmorpholine-4-yl]-6·(2-pyridine·4·sulfonylpropyl) in 18% DMF (30 ml) -2-yl) pyridine (0.560 g, 1.41 mmol), 4_(4,4,5,5-tetramethyl-1,3,2-dioxaboroin-2-yl)aniline (0.464 Gram, 2·12 millimoles) and stone sodium acidate (3.53 house liter '7.05 house Moer). The resulting solution was stirred under 5 hours. The reaction was allowed to cool and was partitioned between ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate. EtOAc (EtOAc m. LCMS spectrum: MH+ 454, retention time 2.18 minutes. 2_Chloro-4-[(3S)-3-methylmorpholine ice-based] (2•pyridyl ice-based sulfonyl-propyl)

2.63 millimoles) and will be 123642 • 382· 200817384

Water and ethyl acetate were added and the solution was separated. The aqueous layer was extracted twice with ethyl acetate&apos; and the combined organic material was dried to dryness &lt;RTI ID=0.0&gt; The crude product was chromatographed on silica gel eluting with EtOAc (EtOAc:EtOAc) H NMR (400.13 MHz? CDC13) ^ 1.27-1.29 (3H5 d)5 NMR spectrum·· 1 η NMR ΜΟΟ/Π Μ% (I·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). LCMS spectrum: MH+ 397, retention time ι·73 min b 2-Chloro-4-[(3S)-3_methyl? The preparation of porphyrin-4-yl]-6-(pyridylsylsulfonylmethyl)pyrimidine is described above. Example 59: 3-ethyl-l-[4_[4-(2-hydroxyethyl sulfonate) Mercaptomethyl) each [(3S) each methylmorpholine_4_yl]pyrimidine_2_yl]phenyl]urea

N-[4-[4-(2-Hydroxyethylsulfonylmethyl)_6_[(3S) oxomethylfosfosin] phenyl hydrazin-2-yl]phenyl] carbamic acid phenyl ester (〇〇73 g, 〇14 mmol), ethylamine (0.70 mmol) and triethylamine (0.42 mmol) combined and heated at 5 rc and air overnight. Purified by preparative HPLC using a decreasing polar mixture of water (containing 1% NH3) and MeCN as a solvent to give the desired material as a white solid (0.047 g). NMR spectrum: iH NMR (400.13 MHz, DMSO_d6) (5 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), 8.20-8.23 (2H, d), 8.66 (1H, s) · LCMS spectrum: MH+ 464, retention time 1.62 min. The following compounds were prepared in a similar manner from N- [4-[4-(2-Ethyl) Phenylphenyl-6-[(3S)-3-methylphenoflavin-4-yl]pyrimidin-2-yl]phenyl]carbazate with the appropriate amine. Example structure name LCMS MH+ retention time (minutes) 59a OH [into ΗH 3-cyclobutyl-l-[4-[4-(2-hydroxyethylsulfonylmethyl)-6-[(3S)-3-methylmorpholine•4- ] 啶 -2- -2-yl]phenyl]urea 490 1.84 59b OH [into Η H 3-(2-dimethylaminoethyl) -l-[4_[4-(2-ethyl-ethyl fluorenylmethyl) -6-[(3S)-3-methylmorpholine-4-yl]pyrimidin-2-yl]phenyl]urea 507 1.61 Example 59a: WNMR (400.13 MHz, DMSO-d6) δ 1·24· 1·25 (3H,d),1.57- 1.69 (2Η, m)5 1.82-1.92 (2Η5 m)5 2.18-2.25 (2Η? m)? 3.18-3.27 (1Η5 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) 5 6.46-6.48 (1H, d), 6·76 (1H, s), 7·47-7·49 ( 2H, d), 8.20-8.22 (2H, 123642 -384 - 200817384 d), 8.56 (1H, s). Example 59b: 4 NMR (400.13 MHz, DMSO-d6) 5 1.35-1.37 (3H, d), 3.37 (6H, s), 2.56-2.59 (2H, t), 3.31-3.38 (5H, 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)· N-[4-[4-(2-hydroxy-B) The preparation of phenylsulfonylmethyl)-6-[(3S)-3.methylmorpholine-4-yl]pyrimidin-2-yl]phenyl]carbamic acid phenyl ester is described below. N-[4-[4-(2-Hydroxyethylsulfonylmethyl)_6-[(3S)-3-methylmorpholine-4-yl]-cyano-2-yl]phenyl]amine Phenyl benzoate

Add phenyl chloroantimonate (0.046 ml, 〇·36 mmol) to 2-[[2-(4-aminophenyl) in dioxane (20 mL) at room temperature under air. _6-[(3S)-3-Methylorfos-4-yl] Mouth 4-yl]methylsulfonyl]ethanol (0.143 g, 0.36 mmol) with sodium bicarbonate (0.046 g, 0.55) Within a millimeter). The resulting slurry was stirred at room temperature for 2 hours. Water was added and the mixture was extracted three times with DCM. The combined organic material was dried (MgSO.sub.4), filtered, and concentrated in vacuo to afford the desired material as a yellow solid (0.228 g). NMR spectrum: 1h NMR (400.13 MHz, DMSO-d6) 5 1.24-1.26 (3Η,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, 123642 -385 - 200817384 m), 7.43-7.47 (2H, t), 7.63-7.65 (3H,d),8·31-8.33 (2H,d), 10.44 (1H,s)· LCMS spectrum: MH+ 513, retention time 2.28 min. 2_[[2-(4_Aminophenyl)-6-[(3S)-3_methylnorfos-4-yl] shouting 4-yl]

Nh2

Add (π) (1)·013 g, 〇·〇 2 mmoles to trans-dichlorobis(triphenylphosphine) to DME at room temperature and under nitrogen: water:ethanol (7:3:2) 2-[Indolyl-6-[(3S)-3-methylmorpholine-4-yl], biting _4_yl] in the 18% DMF (10 ml) of the mixture Ethanol (〇·ΐ22 g, 0.36 mmol), 4-(4,4,5,5-tetramethyl·1,3,2-dioxaboroin-2-yl)aniline (〇· 119 g, 〇·54 mmol) and sodium carbonate (0.908 ml, 1_82 mmol). The resulting solution was at 8 Torr. Mix underarm for 2 hours. The reaction was allowed to cool and was partitioned between ethyl acetate and water. The reaction mixture was extracted with EtOAc EtOAc (EtOAc)EtOAc. LCMS spectrum: ΜΗ + 393, retention time L3 〇 min. Η[2·Gas-6-[(3S)_3-methylmorpholine_4_yl]pyrimidinyl]methanesulfonyl]ethanol

CI added a 30% aqueous solution of hydrogen peroxide (0.225 ml, 7.29 mmol) to 2-carbyl-4-[(3S)-3-methylmorpholine-based]_6_[2_( Oxygen 圜_2_yloxy)ethyl 123642 - 386- 200817384 瓜瓜基methyl&gt; pyridine (0.11 gram, 〇·36 mmol), sodium tungstate dihydrate (2·4) mM, 0.0073 耄mol) in water (〇·2 ml) and 2N sulphuric acid (〇〇11 ml) in 丨, 4·1 oxane (1.4 ml) and methanol (1·4 ml) The solution was stirred and warmed to 55 under air. Hey. The resulting solution was at 55. The mixture was stirred for 4 hours, then water (5 mL) was added and the mixture was cooled. A 10% aqueous solution of sodium metabisulfite was added, followed by extraction of the entire solution with DCM. The organic material was dehydrated and dried (MgSO.sub.4), filtered, and concentrated in vacuo to give the desired material as viscous oil (198 g). LCMS spectrum: MH+ 336, retention time U8 min. 2-gas group _4_[(3S)-3_methylmorpholine_4_yl]_6-[2-(oxoindolin-2-yloxy)ethyl thiomethyl] shout

DIPEA (0·2ΐι克, ι·63 mmol) was added dropwise to 2-chloro-4-(indolylmethyl)-6-[(3S)- in acetonitrile at room temperature under air. 3-methylmorpholine-4-yl] 'bite (0.231 g, 〇·65 mmol) and 2_(tetrahydro-2H-pyran-2-yloxy)ethanethiol (〇·133 g ' 〇 · 82 millimoles inside. The resulting solution was stirred at room temperature for 1 hour. The solvent was removed and the reaction mixture was diluted with DCM and washed with water. The organic layer was dried (MgSO.sub.4), filtered and evaporated to give crude. The crude product was purified by flash chromatography eluting with EtOAc EtOAc (EtOAc) NMR spectrum·· 4 NMR (400.13 MHz, CDC13) 5 1.24-1.26 (3Η,d), 1.40-1.55 (4H,m),1.60-1.67 (1H,m),1.69-1.77 (1H,m),2.68 -2.71 (23⁄4 t), 123642 -387- 200817384 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), 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)&lt 4.52-4.54 (1H, t), 6.44 (1H, s). LCMS Spectrum: m/z (ES+) (M+H)+= 386; HPLC tR=2.11 min, MH+ 386, retention time 2.11 min. The preparation of 2-chloro-based ice (iodomethyl)-6-[(3S)_3-methylmorpholine-4-yl]pyrimidine is described above. % 123642 388 -

Claims (1)

200817384 X. Patent application scope: 1. A compound of the formula (I) - (R3) m 1 γ ^ ^ γ 2 R \ χ丄 (1) or a pharmaceutically acceptable salt thereof; wherein ί : m is 0, 1, 2, 3 or 4; 1 and Y2 are independently N or CR8, provided that one of Y and Y2 is N and the other is CR8; X is a linking group selected from _cr4=cr5-, -cr4= Cr5cr6r7-, -cr6r7cr5 = CR4-, -CeC-, -CeCCR6R7-, -CR6R7CeC-, -NR4CR6R7-, -ocr6r7-, -SCR6R7·, -S(0)CR6R7·, -S(0)2CR6R7-, - c(o)nr4cr6r7-, -nr4c(o)cr6r7-, -nr4c(o)nr5cr6r7-, -NR4S(0)2CR6R7_, _S(0)2NR4CR6R7-, -C(0)NR4-, -NR4C(0) -, -NR4 C(0)NR5 -, -S(0)2 NR4 - and -NR4 S(0)2 -; R1 is selected from hydrogen, Cu alkyl, C2_6 alkenyl, C2_6 alkynyl, carbocyclic group a group of a carbocyclylalkyl group, a heterocyclic group and a heterocyclylalkyl group, the group being optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, R9, -OR9, -SR9, -SOR9, -S02R9, -COR9, -C02R9, -CONR9R10, -NR9R10, NR9 COR10 &gt; _NR9C02R10, _NR9CONR10R15, -NR9COCONR10R15 and -NR9S02R10; R2 is selected from a group of a carbocyclic group, a carbocyclic group, and a heterocyclic group, which is substituted by 123642 200817384 -NR17CONR18R19, and is substituted by a tenth ring, a brother site, . ^ ^ and is substituted by one or more substituents, The group is independently selected from the group consisting of i group, cyano group, nitro group, _R11, _0R11, _SR11, -SOR11, -S02 R11, -CQRH, _C〇2 Ru, &lt;〇Νκ1! Rl 2 view i Rl 2 -NR11 COR12 and - NR11 COCONR12 R1 6 ; each R 'when present' is independently selected from halo, cyano, nitro, _r1 3, -OR13, -SR&quot;, -S0Rn, _s〇2Rl3, _c〇Rl3, c〇2Rl3, -conrur14, -nr13R14, _·13α) κ14, 服13. 〇2 is 14 and -nr13so2r14; ί I R4 and R5 are independently hydrogen or Ch alkyl; or R is formed by R and R4 and one or more atoms attached thereto to form a carbon ring or a heterocyclic ring. Wherein 1, 2 or 3 ring carbon atoms are optionally replaced by N, hydrazine or S, and the ring is optionally substituted by one or more substituents selected from the group consisting of halo, cyano and nitrate Base, thiol, keto, q -6 alkyl, Q-6 alkoxy, halo (^-6 alkyl, diyl Ci-6 alkoxy, hydroxy Ci-6 alkyl, hydroxy Cm alkoxy , Ci-6 alkoxyCh alkyl, (^-6 alkoxy Cn alkoxy, fe, Cl-6 aminyl, bis(Cl alkyl)amine, amine C1-6 alkyl ((V6 alkyl)amino cv6 alkyl, bis(Cu alkyl)amino Cu alkyl, cyano Ci-6 alkyl, C -6 alkylsulfonyl, Ci-6 alkylsulfonate Amino group, Q-6 alkylsulfonyl ((V6 alkyl) amine group, amine sulfonyl group, Cu alkyl amine sulfonyl group, bis(Ci_6 alkyl) amine sulfonyl group, Ci-6 alkane oxime Amine, Cu alkyl sulfonyl (Ch alkyl) amine group, amine methyl sulfhydryl group, Cu alkyl amine carbhydryl group and bis (Ci-6 alkyl) amine fluorenyl group; R6 and R7 are independently selected from hydrogen Halo, cyano, nitro and Ci -6 alkyl; R8 is selected from the group consisting of hydrogen, halo, cyano and hydrazine; 123642 200817384 R9 and R1G are independently hydrogen or are selected from Ci6 alkyl, a group of a carbocyclic group, a carbocyclic group q-6 alkyl group, a heterocyclic group and a heterocyclic group Ci-6 alkyl group, the group being optionally substituted by one or more substituents selected from the group consisting of A groups , cyano, nitro, thio, alkyl, Cl-6 alkoxy, halo C 6 alkyl, halo Q-6 alkoxy, hydroxy C 6 alkyl, hydroxy C1-6 alkoxy, Ci 6 alkoxy G-6 alkyl, Cn alkoxy (^_6 alkoxy, amine, C^-6 aminino, bis(Ch alkyl)amine, amine Ci6 alkyl, (Ci- 6 alkyl)amino-based Ci6 alkyl, bis(CV6 alkyl)amino Cu alkyl, cyano Cu alkyl, Cu alkylsulfonyl, Ci-6 alkylsulfonylamino, Cu alkylsulfonate Sulfhydryl (Ci-6 alkyl) amine group, amine sulfonyl group, Cu alkyl amine sulfonyl group, bis(Cu alkyl) amine sulfonyl group, C! 6 alkyl amidino group, alkyl fluorenyl group (Ch Alkyl)amine, aminomethylindenyl, Cu alkylaminecarbamyl and bis(Ch alkyl)aminecarbamyl; Rn, R12, R17 and R18 are independently hydrogen or selected from Cl-6 a group of a carbocyclic group, a carbocyclic group, a carbocyclic group (^-6 alkyl group, a heterocyclic group, and a heterocyclic group C1-6 alkyl group, the group being optionally substituted by one or more substituents selected from the group consisting of Halo, cyano, nitro, hydroxy, (^_6 alkyl '(^-6 alkoxy, halo (^-6 alkyl, halo Cle6 alkoxy, hydroxyalkyl, hydroxy &lt;^_6 Alkoxy, (^_6 alkoxy Ci-6 alkyl, Ci-6 alkoxy Ci-6 alkoxy, amine, Cle6 alkylamino, bis(〇1_6 alkyl)amine, amine ( !11_6 alkyl, ((1!1-6 alkyl) amine group. 1-6 alkyl, bis(Cu alkyl)amino Cu alkyl, cyano Cu alkyl, Cu alkylsulfonyl, Q-6 alkanoyl, C!-6 alkanoyl (C!- a 6 alkyl)amino group, an amine methyl sulfhydryl group, a C -6 alkylamine carbhydryl group, and a bis (c!-6 alkyl) amine carbaryl group; R 13 , R 14 , R 15 , R 16 and R 19 are independently hydrazine, or a group selected from the group consisting of a CV6 alkyl group, a carbocyclic group, a carbocyclic group -6 alkyl group, a heterocyclic group, and a heterocyclic group q-6 alkyl group, 123642 200817384 This group is optionally substituted by one or more substituents Substituted, the substituent is selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, Ci-6 alkoxy, haloCi-6 alkyl, yl (^-6 alkoxy, hydroxyalkyl, hydroxy Ci-6 alkoxy, CV6 alkoxy Q-6 alkyl, q-6 alkoxy Cm alkoxy, amine, Cm alkylamino, bis(Ch alkyl)amine, aminoCh alkyl , (Ci-6 alkyl)amino Cu alkyl, bis(〇ν6 alkyl)aminoCh alkyl, cyano (V6 alkyl 'Cl-6), -6 calcinyl Amine group, Ci-6 alkyl group (C -6 alkyl) amine group, amine sulfonyl group, (^-6 alkyl sulfonyl sulfhydryl group, bis(q-6 alkyl) amine sulfonyl group, Ci_6 Alkylamine, (^-6 Alkyl fluorenyl (〇^-6 alkyl)amino group, amine methyl sulfhydryl group, C!-6 alkyl amine carbaryl group and bis(Cu alkyl) amine carbaryl group; or R18 and R19 are linked to them The nitrogen atoms together form a 3- to 10-membered heterocyclic ring wherein one or two ring carbon atoms are optionally replaced by N, hydrazine or S, and the ring is optionally substituted with one or more substituents, substituents Selected from halo, gas, nitro, thiol, C!-6 alkyl, Ci-6 alkoxy, _yl C! ·6 alkyl, halo Cle6 alkoxy, hydroxy (^_6 alkyl, Hydroxy (^_6 alkoxy, Α6 alkoxy 4-6 alkyl, Ci-6 alkoxy (^_6 alkoxy, amine, C^6 alkylamino, bis(Ci-6 alkyl)amine Base, amine group &lt;^-6 alkyl, ((^_6 alkyl)amino Q-alkyl, bis(Cu alkyl)amino cv6 alkyl, cyano (V6 alkyl, Cu alkylsulfonate) Base, Ci-6 alkylsulfonylamino group, fluorenyl-alkylsulfonyl (Ch alkyl) amine group, amine sulfonyl group, Cu alkyl amine sulfonyl group, bis(Cu alkyl) amine sulfonium sulfonate Base, Cu alkanoguanamine, Ci-6 alkino (q-6 alkyl) amine, amine methyl sulfonyl, Cl-6 alkylamine carbaryl and bis(CV6 alkyl) amine carbaryl. 2. If request item 1 The compound or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (La) or (lb) 123642 200817384 Or a pharmaceutically acceptable salt thereof, wherein 1^, 112, 113, 丫1 and ¥2 are as defined for the compound of formula (I) as claimed in claim 1. 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R3 is methyl. The compound of any one of claims 1 to 3, wherein Y1 is CR8 and Y2 is N, or a pharmaceutically acceptable salt thereof. 5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein γΐ is CH and Υ2 is Ν. 6. A compound according to any one of claims 1 to 5, wherein X is a linking group selected from the group consisting of -NR4CR6R7-, -OCR6R7-, -scr6r7-, -s(o)cr6r7-, or a pharmaceutically acceptable salt thereof. , -S(0)2CR6R7-, -C(0)NR4CR6R7-, -NR4 C(0)NR5 CR6 R7 -, -S(0)2 NR4 CR6 R7, -C(0)NR4 _ and -NR4 C( O)-. 7. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein X is a linking group selected from the group consisting of -nr4cr6r7_, -ocr6r7-scr6r7---S(0)CR6R7-, -S(0)2CR6R7-, -C(0)NR4- and -NR4C(0)-. 8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein X is a linking group selected from the group consisting of -NR4CH2, -OCH2, _OCH(CH3)_, -OC(CH3)2-, -SCH2- , -SCH(CH3)-, -SC(CH3)2-, -s(o)ch2-, -s(o)ch(ch3)-, -S(0)C(CH3)2 S(〇)2 CH2 -, -s(0)2 CH(CH3), -S(0)2 C(CH3)2 -, -C(0)NR4· and -NR4 C(O)- 0 123642 200817384 9. If requested A compound of 8 or a pharmaceutically acceptable salt thereof, wherein hydrazine is -S(0)2CH2-, -S(0)2CH(CH3)- or -S(0)2C(CH3)2-. The compound of any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of adamantyl, decyl, ethyl, propyl, butyl, isobutyl, and third -butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, phenethyl, tetrahydro-P-l- yl, rosin, ti ti, p σ syl, fluorenyl, pyrenyl , pyr π-decyl, pyrimidinyl, pyridinyl, tetrahydropyridyl fluorenyl, tetrahydrofuroylethyl, external methyl, ρ-l-ylethyl, misomethyl, imidazolyl Ethyl, pyrazolylmethyl, pyrazolylethyl, furylmethyl, furylethyl, decenoylmethyl, u-secenylethyl, indenyl methyl, thiol a group of a pyridylmethyl group, a pyrimidinylethyl group, a pyridylmethyl group, and a pyridylethyl group, the group being optionally substituted by 1, 2 or 3 substituents selected from a halogen group , cyano, nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R10 and 9CORi. 11. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Ri is selected from the group consisting of methyl, ethyl 'propyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclo Pentylcyclohexyl, phenyl, aryl, phenethyl, P-pyridyl, decylethyl, furylmethyl, pyrenylmethyl, oxazolylmethyl, ρ-oxadiazolylmethyl And a group of ρ ρ 井 基 基 ' this group is optionally substituted by 1 or 2 substituents selected from an amine group, a yl group, a cyano group, a decyl group, a decyloxy group, a trifluoromethyl group Base, trifluoromethoxy, -nhcoch3, -conh2 and -CONHCH3. 12. The compound of claim η, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of methyl, ethyl, isopropyl, cyclopropyl, cyclohexyl, -CH2CH2〇H, 123642 200817384 -CH2CH2NC (0 CH3, phenyl, 4-fluorophenyl, 2·chlorophenyl, 2-trifluoromethylphenyl, 2-methoxyphenyl, 2-methylphenyl, 4-ethylaminophenyl , 4_ silk phenyl, pyridinyl, pyridyl-2-yl, 2__tetrahydropyrrole_3_yl, thiazol-2-yl, 4-methylpyrimidin-2-yl and 3- A group of base u, 4_disc. 13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein Ri is selected from the group consisting of methyl, isodecyl, cyclopropyl, cyclohexyl, even CH2〇h, -CH2CH2NC(0)CH3, benzene Base, 4-fluorophenyl, 2-chlorophenyl, 2•trifluoromethylphenyl, 2-methoxyphenyl, 2-methylphenyl, 4-ethylaminophenyl, 4-amine^ Phenyl, pyridinyl, pyridyl, 2_-tetrahydropyrrole-3-yl, pyrazol-2-yl, 4-methylpyrazol-2-yl and 3-methylpyrazole-2 Base group. 14. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein r1 is methyl or cyclopropyl. 15. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein r1 is methyl 0. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R2 is selected From a 5- or 6-membered carbocyclic or heterocyclic group, this group is substituted by -NR17C〇NRuRl9, and optionally substituted with one or more substituents independently selected from halo, cyano, nitro, -R11, -〇Ri 1, eC〇Ri 1, C0NRUR12, _NRnR12 and -NR&quot;COR12. The compound of claim 16 or a pharmaceutically acceptable salt thereof, wherein the r2 is selected from the group consisting of a 6-membered aryl group and a 5 or 6-membered heteroaryl group, the group being substituted by -NR1 7C〇NRl 8R1 9 , Substituted by one or more substituents, the substituents are independently selected from halo, cyano, nitro, _R1 1, 〇 R1, _c〇Rl 1, _c〇NRl lRl2, lRi2 and -NRUC〇Rl2 o The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein the r2 is selected from the group consisting of phenyl"pyridyl, (tetra)yl"indolyl"phoranyl"sembendyl"pyridyl, Pyrimidinyl, morphinyl, pyrazolyl, this group is substituted by -nr17c〇Nr18r19, and optionally substituted by _ or a plurality of substituents, the substituents are independently selected from halo-cyano~ xiaoji^^ Seven "丨^以^卜-C0NRllR12, -NRUR12 and view uCOR12 〇 19. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein R2 is selected from the group consisting of phenyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, thienyl, pyridyl, pyrimidinyl, purine , pyrazolyl, this group is substituted by -NRi7C〇NRuRl9, and optionally substituted by one or more substituents, the substituents are independently selected from fluoro, methyl, decyloxy, hydroxyindenyl, cyanoguanidine A compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein R2 is a strepyl or pyridyl group, substituted by -NR17c〇NR18R19, or a pharmaceutically acceptable salt thereof, And optionally substituted by one or more substituents, the substituents are independently selected from the group consisting of fluoro, methyl, methoxy, methyl, cyanoguanidino, -CONH2, -CONHCH3, and -CON(CH3)2. 21_ The compound of claim 20, or a pharmaceutically acceptable salt thereof, i, R2 Ά ', ', ,, V Wherein A1 and A2 are selected from CH or N, provided that at least one of A1 or A2 is ΛCH 〇22. The compound of any one of claims 16 to 21, or a pharmaceutically acceptable salt thereof, wherein R1 7 is hydrogen. The compound of any one of claims 16 to 22, wherein R18 is hydrogen, or a pharmaceutically acceptable salt thereof. The compound of any one of the preceding claims, wherein R19 is hydrogen or is selected from the group consisting of Cm alkyl, C3_6 cycloalkyl 'aryl, heteroaryl, aryl Ci, or a pharmaceutically acceptable salt thereof a group of a 6 alkyl group and a heteroaryl Cl. 6 alkyl group, which group is optionally substituted by one or more substituents selected from a group consisting of a group, an aryl group, a nitro group, a hydroxyl group, and a &lt;^ _6 alkyl, (^-6 alkoxy, _yl (^.6 alkyl, (dentate Ci_6 alkoxy, hydroxy Q-6 alkyl, hydroxycy alkoxy, (: 6 alkoxy core) -6 alkyl, alkoxyalkoxy, amine, Ci-6 alkylamino, (Cl.6 alkyl) amine, amine Ci-6 alkyl, (Ci-6 alkyl) amine C1- 6 alkyl, bis(Ch alkyl)amino-Ci-6 alkyl, cyano q-6 alkyl, alkylsulfonyl, (6-6 alkylsulfonylamino, Cle6 alkylsulfonyl ( (^-6 alkyl) Amino, amidoxime, alkylamine sulfonyl, bis(Ch alkyl)amine sulfonyl, Cu alkanoyl, CV6 alkanoyl (Ch alkyl) amine And a hydrazinyl group, a Ci-6 alkylamine carbhydryl group, and a bis(CV6 alkyl)amino fluorenyl group. The compound of claim 24 or a pharmaceutically acceptable salt thereof Wherein R19 is hydrazine or is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, decyl, cyclopropyl, cyclobutyl, cyclopentyl a group of a cyclohexyl group, a phenyl group, a porphinyl group, an imidazolylmethyl group, an isoxazolyl group, a pyrazolyl group, a pyrazolylmethyl group, a p-indenyl group, and a thiol group, which is optionally the case Substituted by one or more substituents selected from halo, cyano, nitro, hydroxy, C!-6 alkyl, -6 alkoxy, halo (: 6 alkyl, functional q-6 alkane Oxyl, hydroxy CV6 alkyl, hydroxy CV6 alkoxy, Ci-6 alkoxy CV6 alkyl, Ci-6 alkoxy (^-6 alkoxy, amine, Cu alkylamino, bis (Cu alkyl) Amino group, 123642 200817384 Amino Cu alkyl group, (Cu alkyl) amine Cu alkyl group, bis (Cu alkyl) amine group (^-6 alkyl group, cyano Ci-6 alkyl group, alkyl sulfonyl group) , Ci-6 alkylsulfonylamino, C!-6 alkyl thiol (Cl hexyl) amine, amine aryl, Ci-6 alkyl sulfonyl, bis (Cy alkyl Aminesulfonyl, (^_6 alkyl amidino, alkyl alkoxy (q-6 alkyl) amine, amine methyl sulfonyl, Ci-6 alkylamine fluorenyl A compound of claim 25, wherein R9 is hydrogen or is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. Butyl, iso-butyl, tert-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, porphin-2-yl, -CH2 (oxazol-2-yl), -CH2 (imidazole-3-yl), isoxazolyl-3-yl, 6-keto-1Η ·ρ ratio bite 2_ group, 5-methylisoindole-3-yl, 1·methyl P is more than 嗤-4-yl, -CH 2 (1-methylpyrazole-4-yl), 6- a group of a methoxypyridine-3-yl group, a 5-fluoropyridin-2-yl group, a pyrimidin-2-yl group, and a 1H-pyrazol-3-yl group. 27. The compound of claim 26, wherein R1 is selected from the group consisting of methyl, ethyl, propyl, cyclopropyl, cyclobutyl, _Ch2CH2〇h, -CH2 CI^NMe2, or a pharmaceutically acceptable salt thereof. _C(Me)2 ο!? 〇H and 1Η-pyrazole _3_ group. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is selected from any one of the examples, or a pharmaceutically acceptable salt thereof. The compound of the formula (I) according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, is used as a medicament for treating a proliferative disease. The use of a compound of the formula 1 according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a neoplastic disease. The use of a compound of the formula (1) according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, for producing an anti-proliferative effect in a warm-blooded animal such as a human. 32. Use of a compound of formula (I) according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the production of an antiproliferative effect in a warm-blooded animal such as a human . 33. A method of producing an anti-proliferative effect in a warm-blooded animal, such as a human, in need of treatment, which comprises administering to the animal an effective amount of a compound of formula (I) according to any one of claims 1 to 28, or A pharmaceutically acceptable salt. 34. A method of treating cancer, an inflammatory disease, an airway disease, an immune disease, or a cardiovascular disease in a warm-blooded animal, such as a human, in need of treatment, comprising administering an effective amount of any one of claims -28 to 28 A compound of formula 1, or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising a compound of the formula (1) according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier. The compound of the formula (I) according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, is used as a medicament. 123642 200817384 VII. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbol of the symbol of the representative figure is simple: 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: Formula (I) 123642