TUBULIN POLYMERIZATION INHIBITORS FIELD OF INVENTION [0001] The present invention relates to novel polycyclic compounds. The compounds according to the invention are useful as tubulin polymerization inhibitors, in particular for use in the treatment of hematological disorders and/or proliferative disorders. BACKGROUND OF INVENTION [0002] The microtubular cytoskeleton controls many vital functions in eukaryotic cells ranging from cell division to cell movement and vesicular transport. The main structural component of microtubules is the protein αβ-tubulin heterodimer. Microtubule-targeting agents (MTAs) can interfere with functions of microtubule to disrupt the formation of the mitotic spindle, eventually leading to mitotic arrest at the metaphase/interphase transition. Based on their effects on microtubule dynamics, MTAs are generally classified into two categories : microtubule-stabilizing agents (MSAs) or microtubule-destabilizing agents (MDAs). MSA such as epothilone, ixabepilone, and paclitaxel promote microtubule assembly and are commonly used as Standard of Care (SOC) for the treatment of breast cancer, but also for the treatment of ovarian cancer, prostate cancer and lung cancer. On the contrary, MDAs such as colchicine and Vinca alkaloids trigger microtubules disassembly into tubulin dimers and small oligomers. The Vinca alkaloids vincristine and vinblastine were the first MTAs to be approved more than half a century ago and are still commonly used in hemopathies such as leukemia, in particular Acute Myeloid Leukemia (AML). Colchicine was the first compound identified as an MTA and is the most commonly used drug to treat gout. However, colchicine is not used in cancer therapy due to its high toxicity at dosage required in cancer indications. [0003] Clinical success of MTAs has been notably limited by their toxicity and the emergence of drug resistance. Drug resistance is acquired over the course of treatment and has become a significant clinical issue. The most common mechanism of multidrug
resistance (MDR) is conferred by ATP-binding cassette (ABC) such as the P-glycoprotein (Pgp) transporter, which can actively transport drug molecules out of cells. There is also evidence that expression of certain tubulin isotypes, such as class III β-tubulin, can desensitize cells to microtubule drugs. Taxanes and Vinca alkaloids are especially susceptible to efflux by Pgp and are thus less effective against cells overexpressing the tubulin β-III isotype. [0004] Among the different classes of MTAs, colchicine-site ligands were probably the most studied. The colchicine site is buried into the intermediate domain of β-tubulin, which is located near the intra-dimer interface between the α- and β-tubulin subunits. By contrast, taxane-site ligands bind to a pocket of β-tubulin located on the luminal side of microtubules and ligands targeting the Vinca site bind at the inter-dimer interface between two longitudinally aligned tubulin dimers. Preclinical studies strongly suggest that CBSis are effective in suppressing the overexpression of tubulin isotypes and overcome drug resistance mediated by members of ABC family. Number of Colchicine binding site inhibitors (CBSis) have been reported in the past decades such as plinabulin, ABT751, combretastatin, lexibulin, Veru-111 and PTC596; however, none of these compounds has yet reached the commercial phase for cancer treatment. [0005] Consequently, there is still a need for small molecules with strong anti-proliferative potency, broad anti-proliferative activity against different cancer cell lines and/or preventing antiproliferative drug resistance (e.g., drug-resistance mechanisms associated with overexpression of efflux transporter such as Pgp, abnormal expression of β3-tubulin or expression of mutant P53). [0006] The Applicant surprisingly found that the compounds of formula (I) are potent tubulin polymerization inhibitors. It was also found that the compounds according to the invention trigger mitotic arrest in G2/M phase, and subsequently apoptosis. Moreover, it was found that the compounds according to the invention have broad anti-proliferative activity against different cancer cell lines. Therefore, the compounds according to the invention are of significant interest for the treatment of hematological and/or proliferative disorders, in particular to overcome drug resistances.
SUMMARY [0007] This invention thus relates to a compound of formula (I)
or a pharmaceutically acceptable salt and/or solvate thereof, wherein R
1-R
5, B, V, W, Y and Z are each independently as defined herein. [0008] According to some embodiments, the compound is of formula (II)
or a pharmaceutically acceptable salt and/or solvate thereof, wherein R
1, R
2, R
3, B and Y are each independently as defined herein. [0009] According to some embodiments, B is selected from phenyl, thiazole, oxazole, oxadiazole, isoxazole, thiadiazole, pyrazole, pyridine and pyrimidine; wherein the phenyl, the thiazole, the oxazole, the oxadiazole, the isoxazole, the thiadiazole, the pyrazole, the pyridine or the pyrimidine is optionally substituted by at least one methyl. According to some embodiments, B is a five-membered heteroaryl or a six-membered heteroaryl.
[0010] According to some embodiments, the compound is of formula (III)
or a pharmaceutically acceptable salt and/or solvate thereof, wherein R
1, R
2, R
3 and Y are each independently as defined herein. [0011] According to some embodiments, Y is CR
9, wherein R
9 is selected from hydrogen, C
1-C
10 alkyl and halogen. According to some embodiments, R
1 is C
1-C
10 alkyl. According to some embodiments, R
2 is hydrogen. According to some embodiments, R
1 is C1-C10 alkyl and/or R
2 is hydrogen. According to some embodiments, R
3 is C1-C10 alkyl group, wherein the C
1-C
10 alkyl is optionally substituted by OR
7, wherein R
7 is C
1-C
10 alkyl. According to some embodiments, the compound is selected from the compounds of Table 1 herein, and pharmaceutically acceptable salts and/or solvates thereof. [0012] This invention also relates to a pharmaceutical composition comprising a compound according to the invention and at least one pharmaceutically acceptable carrier. According to some embodiments, the pharmaceutical composition comprises the compound according to the invention as sole active pharmaceutical ingredient. According to some embodiments, the pharmaceutical composition further comprises another active pharmaceutical ingredient. [0013] This invention also relates to a compound according to the invention or a pharmaceutical composition according to the invention for use as a medicament. This invention also relates to a compound according to the invention or a pharmaceutical composition according to the invention for use in the treatment of hematological disorders and/or proliferative disorders. In some embodiments, the hematological disorder is selected from lymphoma, leukemia (such as acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic lymphoid leukemia (CLL) or chronic myeloid
leukemia (CML)), multiple myeloma (MM), myelodysplastic syndrome (MDS) and myelodysplasia with myelofibrosis. In some embodiments, the proliferative disorder is cancer; such as head and neck cancer, melanoma, kidney carcinoma, stomach carcinoma, liver carcinoma, colorectal carcinoma, pancreas carcinoma, larynx carcinoma, lung carcinoma, neuronal carcinoma, glioblastoma multiforme, osteosarcoma, fibrosarcoma, ovarian sarcoma, liposarcoma, Ewing sarcoma, breast carcinoma, ovary carcinoma or prostate carcinoma. According to some embodiments, the compound or the pharmaceutical composition is to be administered with at least another active pharmaceutical ingredient. DEFINITIONS [0014] In the present invention, the following terms have the following meanings: Chemical definitions [0015] Where chemical substituents are combinations of chemical groups, the point of attachment of the substituent to the molecule is by the last chemical group recited on the right of the name of the substituent. For example, an arylalkyl substituent is linked to the rest of the molecule through the alkyl moiety and it may by represented as follows: “aryl-alkyl-”. Unless otherwise indicated, the compounds were named using ChemBioDraw® Ultra 13.0.2 (PerkinElmer). [0016] “Alkoxy” refers to an alkyl-O- group. [0017] “Alkyl” refers to a saturated linear or branched hydrocarbon chain, typically comprising from 1 to 16 carbon atoms, preferably from 1 to 12 carbon atoms, more preferably from 1 to 8 carbon atoms, furthermore preferably from 1 to 6 carbon atoms. Alkyl groups may be monovalent or polyvalent (i.e., “alkylene” groups, which are divalent alkyl groups, are encompassed in “alkyl” definition). The alkyl group may optionally be substituted by one or more substituent(s) (for example 1 to 4 substituent(s), or for example 1, 2, 3 or 4 substituent(s)) selected from oxo, halogen, hydroxyl, nitro, amino, cyano, alkylamino, dialkylamino, alkoxy, haloalkyl, acyl, carbamoyl,
alkylsulfoxide, sulfamoyl, alkylthio and carboxyl. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl, pentyl and its isomers (e.g., n-pentyl, iso-pentyl), and hexyl and its isomers (e.g., n-hexyl, iso-hexyl). Particular examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl and t-butyl (including methylene, ethylene, n-propylene, n-butylene and n-butylene). [0018] “Amine” refers to derivatives of ammonia (NH3), wherein one or more hydrogen atoms have been replaced by a substituent such as, for example, alkyl or aryl. “Amino” refers to the -NH
2 group. [0019] “Aryl” refers to a cyclic, polyunsaturated, aromatic hydrocarbyl group comprising at least one aromatic ring and comprising from 5 to 12 carbon atoms, preferably from 6 to 10 carbon atoms. Aryl groups may be monovalent or polyvalent (e.g., divalent). Aryl groups may have a single ring (e.g., phenyl) or multiple aromatic rings fused together (e.g., naphthyl) or linked covalently. The aromatic ring may optionally include one to two additional rings (either cycloalkyl, heterocycloalkyl or heteroaryl) fused thereto. This definition of “aryl” encompasses the partially hydrogenated derivatives of the carbocyclic systems enumerated herein, as long as at least one ring is aromatic. The aryl group may optionally be substituted by one or more substituent(s) (for example 1 to 4 substituent(s), or for example 1, 2, 3 or 4 substituent(s)) selected from oxo, halogen, hydroxyl, nitro, amino, cyano, alkyl (e.g., methyl), alkylamino, dialkylamino, alkoxy, haloalkyl, acyl, carbamoyl, alkylsulfoxide, sulfamoyl, alkylthio and carboxyl. Non-limiting examples of aryl groups include phenyl, biphenyl, biphenylenyl, 5- or 6-tetralinyl, naphthalen-1- or -2-yl, 4-, 5-, 6 or 7-indenyl, 1- 2-, 3-, 4- or 5-acenaphthylenyl, 3-, 4- or 5-acenaphthenyl, 1- or 2-pentalenyl, 4- or 5-indanyl, 5-, 6-, 7- or 8-tetrahydronaphthyl, 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl, and 1-, 2-, 3-, 4- or 5-pyrenyl. A particular example of aryl group is phenyl. [0020] “Azido” refers to -N3 group, i.e., the azide functional group. [0021] “Cyano” refers to the -CN group.
[0022] “Cycloalkyl” refers to a cyclic alkyl group, typically comprising from 3 to 15 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 8 carbon atoms, further more preferably from 3 to 6 carbon atoms. Cycloalkyl groups may be monovalent or polyvalent (e.g., divalent). This definition of “cycloalkyl” encompasses polycyclic cycloalkyls (e.g., bicycles) and bridged cycloalkyl structures, including cycles bound together through one atom (“spiro”) or through two atoms. The cycloalkyl group may optionally be substituted by one or more substituent(s) (for example 1 to 4 substituent(s), or for example 1, 2, 3 or 4 substituent(s)) selected from oxo, halogen, hydroxyl, nitro, amino, cyano, alkyl (e.g., methyl), alkylamino, dialkylamino, alkoxy, haloalkyl, acyl, carbamoyl, alkylsulfoxide, sulfamoyl, alkylthio and carboxyl. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopropyl, cyclohexyl, cycoheptyl, cyclooctanyl, cyclononanyl, cyclodecanyl, norbornyl, adamantyl, bicyclo[2.2.2]octanyl, bicyclo[4.4.0]decanyl, bicyclo[3.2.1]octanyl, bicyclo[3.3.1]nonanyl, bicyclo[2.1.1]hexane, 2,3-dihydro-1H- indenyl, 1,2,3,4-tetrahydronaphthalenyl, decahydronaphthalenyl, 1,2,3,4-tetrahydronaphthalenyl, and octahydropentalenyl. [0023] “Cx-Cy” or “(Cx-Cy)” preceding the name of a group means that the group comprises from x to y carbon atoms, in accordance to common terminology in the chemistry field. [0024] “Halogen” refers to a fluorine, chlorine, bromine or iodine atom. [0025] “Heteroaryl” refers to aromatic rings or aromatic ring systems comprising from 5 to 15 carbon atoms, preferably from 4 to 12 carbon atoms, more preferably from 3 to 10 carbon atoms, having one or two rings which are fused together or linked covalently, wherein at least one ring is aromatic, and wherein one or more carbon atoms in one or more of these rings is replaced by oxygen, nitrogen and/or sulfur atoms. Heteroaryl groups may be monovalent or polyvalent (e.g., divalent). The nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized (e.g., sulfur may be oxidized as SO or SO
2). This definition of “heteroaryl” encompasses the partially hydrogenated derivatives of the carbocyclic systems enumerated herein, as well as ring systems including one or more fused non-aromatic
cycloalkyl and/or heterocycloalkyl ring(s), as long as at least one ring is aromatic. In one embodiment, the heteroaryl is bound to another group or molecule through a carbon atom, the binding atom is not selected among the heteroatoms included therein. In one embodiment, the heteroaryl is bound to another group or molecule through one of the heteroatoms included therein (e.g., a nitrogen). When substituted by one or more other group(s), an heteroaryl may be substituted either through a carbon atom or through a heteroatom (e.g., nitrogen), unless otherwise specified. The heteroaryl group may optionally be substituted by one or more substituent(s) (for example 1 to 4 substituent(s), or for example 1, 2, 3 or 4 substituent(s)) selected from oxo, halogen, hydroxyl, nitro, amino, cyano, alkyl (e.g., methyl), alkylamino, dialkylamino, alkoxy, haloalkyl, acyl, carbamoyl, alkylsulfoxide, sulfamoyl, alkylthio and carboxyl. Non-limiting examples of heteroaryl groups include pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, tetrazinyl, imidazo[2,1-b][1,3]thiazolyl, thieno[3,2- b]furanyl, thieno[3,2-b]thiophenyl, thieno[2,3-d][l,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazolo[l,5-a]pyridinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, 1,3-benzoxazolyl, 1,2-benzisoxazolyl, 2,1-benzisoxazolyl, 1,3-benzothiazolyl, 1,2-benzoisothiazolyl, 2,1-benzoisothiazolyl, benzotriazolyl, 1,2,3-benzoxadiazolyl, 2,1,3-benzoxadiazolyl, 1,2,3-benzothiadiazolyl, 2,1,3-benzothiadiazolyl, thienopyridinyl, purinyl, imidazo[l,2- a]pyridinyl, 6-oxo-pyridazin-l(6H)-yl, 2-oxopyridin-l(2H)-yl, 6-oxo-pyridazin-l(6H)-yl, 2-oxopyridin-l(2H)-yl, 1,3-benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl and quinoxalinyl. Non-limiting examples of heteroaryl groups comprising at least one fused non-aromatic ring include 2,3-dihydrobenzofuranyl, benzo[d][1,3]dioxolyl, indolinyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, 3,4-dihydro-2H- benzo[b][1,4]oxazinyl, 1,2,3,4-tetrahydroquinoxaline, 3,4-dihydro-2H- benzo[b][1,4]thiazine and 2,3-dihydrobenzo[b][1,4]oxathiine. [0026] “Heterocycloalkyl” refers to non-aromatic, fully saturated or partially unsaturated cyclic groups (for example, 3- to 7-membered monocyclic, 7- to 11-membered bicyclic, or containing a total of 3 to 10 ring atoms) which have at least one
heteroatom in at least one carbon atom-containing ring. Heterocycloalkyl groups may in particular be 3- to 7-membered, preferably 5- or 6-membered. Heterocycloalkyl groups may in particular be monocyclic or bicyclic, preferably monocyclic. Each ring of the heterocycloalkyl group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. In one embodiment, the heterocycloalkyl is bound to another group or molecule through a carbon atom,
the binding atom is not selected among the heteroatoms included therein. In one embodiment, the heterocycloalkyl is bound to another group or molecule through one of the heteroatoms included therein. When substituted by one or more other group(s), an heterocycloalkyl may be substituted either through a carbon atom or through a heteroatom (e.g., nitrogen), unless otherwise specified. The rings of multi-ring heterocycloalkyl groups may be fused, bridged and/or joined through one or more spiro atoms. This definition encompasses polycyclic heterocycloalkyls (e.g., bicycles) and bridged heterocycloalkyl structures, including cycles bound together through one atom (“spiro”) or through two atoms. The heterocycloalkyl group may optionally be substituted by one or more substituent(s) (for example 1 to 4 substituent(s), or for example 1, 2, 3 or 4 substituent(s)) selected from oxo, halogen, hydroxyl, nitro, amino, cyano, alkyl (e.g., methyl), alkylamino, dialkylamino, alkoxy, haloalkyl, acyl, carbamoyl, alkylsulfoxide, sulfamoyl, alkylthio and carboxyl. Non-limiting examples of heterocycloalkyl groups include aziridinyl, oxiranyl, thiiranyl, piperidinyl, azetidinyl, 2-imidazolinyl, pyrazolidinyl imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, succinimidyl, 3H-indolyl, indolinyl, isoindolinyl tetrahydropyran, 2H-pyrrolyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 4H-quinolizinyl, 2-oxopiperazinyl, piperazinyl, homopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, tetrahydro-2H-pyranyl, 2H- pyranyl, 4H-pyranyl, 3,4-dihydro-2H-pyranyl, oxetanyl, thietanyl, 3-dioxolanyl, 1,4-dioxanyl, 2,5-dioximidazolidinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl (e.g., tetrahydroisoquinolin-1-yl, tetrahydroisoquinolin-2-yl, tetrahydroisoquinolin-3-yl or tetrahydroisoquinolin-4-yl), thiomorpholinyl (e.g., thiomorpholin-4-yl), thiomorpholin-4-ylsulfoxide, thiomorpholin-4-ylsulfone,
1,3-dioxolanyl, 1,4-oxathianyl, 1,4-dithianyl, 1,3,5-trioxanyl, 1H-pyrrolizinyl, tetrahydro-1,1-dioxothiophenyl, N-formylpiperazinyl, and morpholinyl (e.g., morpholin-4-yl). [0027] “Hydroxy” refers to the -OH group. [0028] “Prodrug” refers to a pharmacologically acceptable derivative of a therapeutic agent (e.g., a compound according to the invention) whose in vivo biotransformation product is the therapeutic agent (active drug). Prodrugs are typically characterized by increased bioavailability and are readily metabolized in vivo into the active compounds. Non-limiting examples of prodrugs include amide prodrugs and carboxylic acid ester prodrugs. [0029] “Solvate” refers to a molecular complex comprising a compound of the invention and contains stoichiometric or sub-stoichiometric amounts of one or more pharmaceutically acceptable solvent molecule such as, for example, ethanol. The term “hydrate” refers to when the solvent is water. General definitions [0030] “About” is used herein to mean approximately, roughly, around, or in the region of. The term “about” preceding a figure means plus or less 10 % of the value of the figure. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth by 10%. [0031] “Active pharmaceutical ingredient”, “active ingredient” or “therapeutic agent” refer to a compound for therapeutic use and relating to health. Especially, a therapeutic agent (e.g., a compound according to the present invention) may be indicated for treating a disease (e.g., a hematological disorder and/or proliferative disorder). An active ingredient may also be indicated for improving the therapeutic activity of another therapeutic agent.
[0032] “Administration", or a variant thereof (e.g., “administering”), means providing a therapeutic agent alone or as part of a pharmaceutically acceptable composition, to the patient in whom/which the condition, symptom, or disease is to be treated. [0033] “Comprise” or a variant thereof (e.g., “comprises”, “comprising”) is used herein according to common patent application drafting terminology. Hence, “comprise” preceded by an object and followed by a constituent means that the presence of a constituent in the object is required (typically as a component of a composition), but without excluding the presence of any further constituent(s) in the object. Moreover, any occurrence of “comprise” or a variant thereof in the specification also encompasses narrower expression “consists essentially of”, further narrower expression “consist of” and any variants thereof (e.g., “consists of”, “consisting of”). [0034] “Human” refers to a male or female human subject at any stage of development, including neonate, infant, juvenile, adolescent and adult. [0035] “Patient” refers to a subject who/which is awaiting the receipt of, or is receiving medical care or was/is/will be the object of a medical procedure, or is monitored for the development of the targeted disease or condition. [0036] “Pharmaceutically acceptable” means that the ingredients of a composition are compatible with each other and not deleterious to the subject to which/whom it is administered. [0037] “Pharmaceutically acceptable carrier” refers to an excipient that does not produce an adverse, allergic or other untoward reaction when administered to an animal, preferably a human. It includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. For human administration, preparations should meet sterility, pyrogenicity, general safety and purity standards as required by regulatory offices, such as, e.g., FDA Office or EMA. Examples of pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminium stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes,
such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances (for example sodium carboxymethylcellulose), polyethylene glycol, polyacrylates, waxes, polyethylene- polyoxypropylene- block polymers, polyethylene glycol and wool fat. [0038] “Pharmaceutical composition” refers to a composition comprising at least one therapeutic agent (e.g., a compound according to the present invention) and at least one pharmaceutically acceptable carrier. [0039] “Subject” refers to an animal, typically a warm-blooded animal, preferably a mammal, more preferably a primate, furthermore preferably a human. In one embodiment, the subject is a “patient” as defined herein. In one embodiment, the subject is affected, preferably is diagnosed, with a disease. In one embodiment, the subject is at risk of developing a disease. Examples of risks factor include, but are not limited to, genetic predisposition, or familial history of the disease. [0040] “Therapeutically effective amount” (in short “effective amount”) refers to the amount of a therapeutic agent (e.g., a compound according to the present invention) that is sufficient to achieve the desired therapeutic, prophylactic or preventative effect in the patient to which/whom it is administered, without causing significant negative or adverse side effects to said patient. A therapeutically effective amount may be administered prior to the onset of the disease for a prophylactic or preventive action. Alternatively, or additionally, the therapeutically effective amount may be administered after initiation of the disease for a therapeutic action. [0041] “Treating”, “treatment” or “alleviation” refers to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) the targeted pathologic condition or disorder (herein a “disease”) (e.g., a hematological disorder and/or proliferative disorder). Those in need of treatment include those already with the disease as well as those prone to have the disease or those in whom the condition or disease is to be prevented. A patient is successfully “treated” for a disease if, after receiving a therapeutic amount of a therapeutic agent (e.g., a compound according
to the present invention), the patient shows observable and/or measurable reduction in or absence of one or more of the following: reduction in the number of pathogens; reduction in the percent of total cells that are pathogenic; and/or relief to some extent, one or more of the symptoms associated with the specific disease; reduced morbidity and mortality, and improvement in quality of life issues. The above parameters for assessing successful treatment and improvement in the disease are readily measurable by routine procedures familiar to a physician. DETAILED DESCRIPTION
[0042] An object of the invention is a compound of formula (I)
or a pharmaceutically acceptable salt and/or solvate thereof, wherein R
1-R
5, B, X, Y, V and W are as defined herein. [0043] In formula (I) herein, R
1 is selected from hydrogen, C
1-C
10 alkyl, cyano, CF
3, hydroxy, C1-C10 alkoxy and halogen. According to some embodiments, R
1 is C1-C10 alkyl. According to some embodiments, R
1 is hydrogen. In some preferred embodiments, R
1 is selected from hydrogen, CH
3, CF
3, OCH
3 and Cl. [0044] In formula (I) herein, R
2 is selected from hydrogen, C1-C10 alkyl, cyano, CF3, hydroxy, C1-C10 alkoxy and halogen. According to some embodiments, R
2 is hydrogen. In some preferred embodiments, R
2 is selected from hydrogen and CH
3.
[0045] In formula (I) herein, R
3 is selected from hydrogen, C1-C10 alkyl, C
3-C
10 cycloalkyl and C
2-C
11 heterocycloalkyl, wherein the C1-C10 alkyl is optionally substituted by at least one group selected from azido, cyano, -C(O)OR
6, OR
7, halogen, C3-C10 cycloalkyl, C
2-C
11 heterocycloalkyl, aryl and heteroaryl, wherein the C3-C10 cycloalkyl, the C2-C11 heterocycloalkyl, the aryl or the heteroaryl is optionally substituted by at least one group selected from C
1-C
10 alkyl, C
1-C
10 alkyl substituted by at least one OR
7, hydroxy, C
1-C
10 alkoxy, -C(O)OR
6 and halogen, and wherein R
6 and R
7 are each independently selected from hydrogen and C1-C10 alkyl. [0046] Herein, and in particular in the above definition of R
3, recitations such as “R
3 is selected from (…), wherein the C3-C10 cycloalkyl, the C2-C11 heterocycloalkyl, the aryl or the heteroaryl is optionally substituted
means that when a cycloalkyl or an heterocycloalkyl is present in R
3, said cycloalkyl or heterocycloalkyl may be substituted as indicated, regardless of whether said cycloalkyl or an heterocycloalkyl is the “primary group” of R
3 (e.g., R
3 is a C3-C10 cycloalkyl) or a substituent of the “primary group” of R
3 (e.g., R
3 is C
1-C
10 alkyl, wherein the C
1-C
10 alkyl is substituted by at least one C
3-C
10 cycloalkyl). [0047] According to some embodiments, R
3 is C1-C10 alkyl group, wherein the C1-C10 alkyl is optionally substituted by hydroxyl or OR
7, wherein R
7 is C1-C10 alkyl. In some embodiments, R
3 is C
1-C
10 alkyl group, wherein the C
1-C
10 alkyl is optionally substituted by OR
7, wherein R
7 is C1-C10 alkyl. [0048] In formula (I) herein, R
4 is selected from hydrogen, hydroxy, C1-C10 alkyl and C
1-C
10 alkoxy. According to some embodiments, R
4 is hydrogen. In some preferred embodiments, R
4 is selected from hydrogen and CH3.
[0049] In formula (I) herein, R
5 is selected from hydrogen, hydroxy, C1-C10 alkyl and C
1-C
10 alkoxy. According to some embodiments, R
5 is hydrogen. In some preferred embodiments, R
5 is selected from hydrogen and CH3. [0050] In formula (I) herein, B is an aryl, a five-membered heteroaryl or a six-membered heteroaryl. According to some embodiments, B is an aryl. According to some embodiments, B is a five-membered heteroaryl. According to some embodiments, B is a six-membered heteroaryl. According to some preferred embodiments, B is a five-membered heteroaryl or a six-membered heteroaryl. According to some embodiments, B is selected from phenyl, thiazole, oxazole, oxadiazole, isoxazole, thiadiazole, pyrazole, pyridine and pyrimidine; wherein the phenyl, the thiazole, the oxazole, the oxadiazole, the isoxazole, the thiadiazole, the pyrazole, the pyridine or the pyrimidine is optionally substituted by at least one methyl. In some embodiments, B is phenyl. In some embodiments, B is selected from thiazole, oxazole, oxadiazole, isoxazole, thiadiazole, pyrazole, pyridine and pyrimidine. In some preferred embodiments, B is selected from phenyl, thiazole, methyl-thiazole, oxazole, thiadiazole, pyrazole, pyridine and pyrimidine. In some further preferred embodiments, B is thiazole. [0051] In formula (I) herein, X is nitrogen or CR
8, wherein R
8 is selected from hydrogen, C
1-C
10 alkyl, cyano, CF
3, C
1-C
10 alkoxy and halogen. According to some embodiments, X is CR
8. In some preferred embodiments, X is selected from N, CH and CF. In some embodiments, X is CH. [0052] In formula (I) herein, Y is nitrogen or CR
9, wherein R
9 is selected from hydrogen, C
1-C
10 alkyl, cyano, CF
3, C
1-C
10 alkoxy and halogen. According to some embodiments, Y is CR
9. In some embodiments, Y is CR
9, wherein R
9 is selected from hydrogen, C1-C10 alkyl and halogen. In some preferred embodiments, Y is selected from N, CH, C-CH3, C-OCH
3, C-CF
3, C-OCH(CH
3)
2, C-Cl and C-F. In some embodiments, Y is CH. [0053] In formula (I) herein, V is NR
10, CR
11R
12 or oxygen, wherein R
10, R
11 and R
12 are each independently selected from hydrogen and C1-C10 alkyl. According to some embodiments, V is NR
10. In some preferred embodiments, V is selected from NH, CH
2 and O. In some embodiments, V is NH.
[0054] In formula (I) herein, W is C=O or CR
13R
14, wherein R
13 and R
14 each independently selected from hydrogen and C
1-C
10 alkyl. According to some embodiments, W is CR
13R
14. According to some embodiments, W is CHR
14. In some preferred embodiments, W is selected from C=O, CH2 and CH-CH3. In some embodiments, W is CH
2. [0055] According to some embodiments, Y is CR
9, wherein R
9 is selected from hydrogen, C1-C10 alkyl and halogen; R
1 is C1-C10 alkyl; R
2 is hydrogen; and R
3 is C1-C10 alkyl group, wherein the C
1-C
10 alkyl is optionally substituted by hydroxyl or OR
7, wherein R
7 is C
1-C
10 alkyl. In some embodiments, R
3 is C
1-C
10 alkyl group, wherein the C1-C10 alkyl is optionally substituted by OR
7, wherein R
7 is C1-C10 alkyl. [0056] In some embodiments, the compound of formula (I) is a compound of formula (II)
or a pharmaceutically acceptable salt and/or solvate thereof, wherein R
1, R
2, R
3, B and Y are each independently as defined under formula (I) herein. [0057] In some embodiments, the compound of formula (I) is a compound of formula (III)
or a pharmaceutically acceptable salt and/or solvate thereof, wherein R
1, R
2, R
3 and Y are each independently as defined under formula (I) herein.
[0058] According to one embodiment, the compound of formula (I) is selected from the compounds of Table 1 below, and pharmaceutically acceptable salts and/or solvates thereof. Table 1 Ex # Structure Name (IUPAC) 1-(4-(4-((1-(2- methoxyethyl)-1H- pyrazol-4- 001 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((1-methyl- 1H-pyrazol-4- yl)amino)pyrimidin- 002 2- yl)phenyl)imidazolidi n-2-one 1-(4-(2-((1-(2- methoxyethyl)-1H- pyrazol-4- 003 yl)amino)pyrimidin- 4- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((1-(3,5- dimethylbenzyl)-1H- pyrazol-4- 004 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-(2-((1-(3,5- dimethylbenzyl)-1H- pyrazol-4- 005 yl)amino)pyrimidin- 4- yl)phenyl)imidazolidi n-2-one
Ex # Structure Name (IUPAC) 1-(4-(6-((1-(2- propoxyethyl)-1H- pyrazol-4- 006 yl)amino)pyridin-2- yl)phenyl)imidazolidi n-2-one 1-(4-{2-[1-(2-Ethoxy- ethyl)-1H-pyrazol-4- 007 ylamino]-oxazol-5- yl}-phenyl)- imidazolidin-2-one 1-(4-{2-[1-(2-Ethoxy- ethyl)-1H-pyrazol-4- 008 ylamino]-thiazol-4- yl}-phenyl)- imidazolidin-2-one 1-(4-(5-((1-(2- ethoxyethyl)-1H- pyrazol-4-yl)amino)- 009 1,2,4-thiadiazol-3- yl)phenyl)imidazolidi n-2-one 3-(4-{2-[1-(2- Methoxy-ethyl)-3- 010 methyl-1H-pyrazol-4- ylamino]-thiazol-4- yl}-phenyl)- oxazolidin-2-one 1-(4-{5-[1-(2-Ethoxy- ethyl)-1H-pyrazol-4- 011 ylamino]-2H-pyrazol- 3-yl}-phenyl)- imidazolidin-2-one
Ex # Structure Name (IUPAC) 1-(4-{2-[1-(2- Methoxy-ethyl)-3- methyl-1H-pyrazol-4- 012 ylamino]-thiazol-4- yl}-phenyl)- pyrrolidin-2-one 1-(3-Fluoro-4-{2-[1- (3-methoxy-propyl)- 3-methyl-1H-pyrazol- 013 4-ylamino]-thiazol-4- yl}-phenyl)- imidazolidin-2-one 1-(4-(4-((1-(3- methoxypropyl)-3- (trifluoromethyl)-1H- pyrazol-4- 014 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one O 1-(4-{2-[1-(2-Ethoxy- ethyl)-3-methyl-1H- 015 O N N pyrazol-4-ylamino]- N oxazol-5-yl}-phenyl)- H
N N O N H imidazolidin-2-one 1-(4-(2-((1-(2- ethoxyethyl)-1H- pyrazol-4- 016 yl)amino)pyrimidin- 4- yl)phenyl)imidazolidi n-2-one 3-(4-(2-((1-(2- ethoxyethyl)-3- 017 methyl-1H-pyrazol-4- yl)amino)oxazol-5- yl)phenyl)oxazolidin- 2-one
Ex # Structure Name (IUPAC) 1-(4-(4-((1-(2- ethoxyethyl)-1H- pyrazol-4- 018 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-(2-((1-methyl- 1H-pyrazol-4- yl)amino)pyrimidin- 019 4- yl)phenyl)imidazolidi n-2-one O 1-(4-{2-[1-(2- Methoxy-ethyl)-1H- 020 O N N N pyrazol-4-ylamino]- H
N N oxa O N zol-5-yl}-phenyl)- H imidazolidin-2-one 1-(4-(2-((1-(2- ethoxyethyl)-1H- pyrazol-4- 021 yl)amino)oxazol-5- yl)-3- fluorophenyl)imidazo lidin-2-one 1-(4-(2-((1-(2- ethoxyethyl)-1H- pyrazol-4- 022 yl)amino)oxazol-5- yl)-2- fluorophenyl)imidazo lidin-2-one 1-(5-{2-[1-(2-Ethoxy- ethyl)-1H-pyrazol-4- 023 ylamino]-thiazol-4- yl}-pyridin-2-yl)- imidazolidin-2-one
Ex # Structure Name (IUPAC) 1-(4-(4-((1-ethyl-3- methyl-1H-pyrazol-4- yl)amino)pyrimidin- 024 2- yl)phenyl)imidazolidi n-2-one 1-(5-{2-[1-(2-Ethoxy- ethyl)-1H-pyrazol-4- 025 ylamino]-oxazol-5- yl}-pyridin-2-yl)- imidazolidin-2-one 1-(6-{2-[1-(2-Ethoxy- ethyl)-1H-pyrazol-4- 026 ylamino]-oxazol-5- yl}-pyridin-3-yl)- imidazolidin-2-one 1-(4-{2-[1-(2-Ethoxy- ethyl)-1H-pyrazol-4- ylamino]-thiazol-4- 027 yl}-3-methoxy- phenyl)-imidazolidin- 2-one 1-(4-(4-((1,3,5- trimethyl-1H- pyrazol-4- 028 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((1,3- dimethyl-1H-pyrazol- 4- 029 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one
Ex # Structure Name (IUPAC) 1-(4-(4-((1-ethyl-1H- pyrazol-4- yl)amino)pyrimidin- 030 2- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((1-isopropyl- 1H-pyrazol-4- 031 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-(2-((1,3- dimethyl-1H-pyrazol- 032 4-yl)amino)oxazol-5- yl)phenyl)imidazolidi n-2-one 3-(4-{2-[1-(2-Ethoxy- ethyl)-1H-pyrazol-4- 033 ylamino]-thiazol-4- yl}-phenyl)- oxazolidin-2-one 1-(4-{2-[1-(2-Ethoxy- ethyl)-1H-pyrazol-4- ylamino]-thiazol-4- 034 yl}-phenyl)-4-(R)- methyl-imidazolidin- 2-one 1-(4-(2-((1-(2- methoxyethyl)-1H- pyrazol-4- 035 yl)amino)thiazol-4- yl)phenyl)imidazolidi n-2-one 1-(5-{2-[1-(2-Ethoxy- ethyl)-3-methyl-1H- pyrazol-4-ylamino]- 036 oxazol-5-yl}-pyridin- 2-yl)-imidazolidin-2- one
Ex # Structure Name (IUPAC) 1-(5-{2-[1-(2-Ethoxy- ethyl)-5-methyl-1H- pyrazol-4-ylamino]- 037 oxazol-5-yl}-pyridin- 2-yl)-imidazolidin-2- one 1-(4-{2-[1-(2-Ethoxy- ethyl)-5-methyl-1H- 038 pyrazol-4-ylamino]- thiazol-4-yl}-phenyl)- imidazolidin-2-one 1-(4-(4-((1-(tert- butyl)-1H-pyrazol-4- yl)amino)pyrimidin- 039 2- yl)phenyl)imidazolidi n-2-one 1-(4-{2-[1-(2-Ethoxy- ethyl)-1H-pyrazol-4- 040 ylamino]-thiazol-4- yl}-phenyl)- pyrrolidine-2,5-dione 1-(4-(4-((1-methyl- 1H-pyrazol-4- yl)amino)pyrimidin- 041 2- yl)phenyl)pyrrolidin- 2-one 1-(4-(2-((1-isopropyl- 1H-pyrazol-4- 042 yl)amino)pyrimidin- 4- yl)phenyl)imidazolidi n-2-one
Ex # Structure Name (IUPAC) 1-(4-(2-((1-ethyl-3- methyl-1H-pyrazol-4- yl)amino)pyrimidin- 043 4- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((1-butyl-1H- pyrazol-4- yl)amino)pyrimidin- 044 2- yl)phenyl)imidazolidi n-2-one 1-(4-(2-((1-(tert- butyl)-1H-pyrazol-4- yl)amino)pyrimidin- 045 4- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((1-butyl-3,5- dimethyl-1H-pyrazol- 4- 046 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((1- neopentyl-1H- pyrazol-4- 047 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((1-(sec- butyl)-1H-pyrazol-4- yl)amino)pyrimidin- 048 2- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((1-(pentan-3- yl)-1H-pyrazol-4- yl)amino)pyrimidin- 049 2- yl)phenyl)imidazolidi n-2-one
Ex # Structure Name (IUPAC) 1-(4-(4-((1- cyclopentyl-1H- pyrazol-4- 050 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-(2-((1-butyl-1H- pyrazol-4- yl)amino)pyrimidin- 051 4- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((1-benzyl- 1H-pyrazol-4- yl)amino)pyrimidin- 052 2- yl)phenyl)imidazolidi n-2-one 1-(4-{2-[1-(2-Ethoxy- ethyl)-1H-pyrazol-4- ylamino]-thiazol-4- 053 yl}-phenyl)-5-(R)- methyl-imidazolidin- 2-one 1-(4-(4-((1-hexyl-1H- pyrazol-4- yl)amino)pyrimidin- 054 2- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((1-(3,5- dimethoxybenzyl)- 1H-pyrazol-4- 055 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one
Ex # Structure Name (IUPAC) 1-(4-(2-((1-hexyl-1H- pyrazol-4- yl)amino)pyrimidin- 056 4- yl)phenyl)imidazolidi n-2-one 1-(4-(2-((1-(3,5- dimethoxybenzyl)- 1H-pyrazol-4- 057 yl)amino)pyrimidin- 4- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((1-(3- methoxybenzyl)-1H- pyrazol-4- 058 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-(2-((1-(3- methoxybenzyl)-1H- pyrazol-4- 059 yl)amino)pyrimidin- 4- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((1-heptyl- 1H-pyrazol-4- yl)amino)pyrimidin- 060 2- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((1-(4- methoxy-3,5- dimethylbenzyl)-1H- 061 pyrazol-4- yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one
Ex # Structure Name (IUPAC) 1-(4-(2-((1-(4- methoxy-3,5- dimethylbenzyl)-1H- pyrazol-4- 062 yl)amino)pyrimidin- 4- yl)phenyl)imidazolidi n-2-one 3-(4-{2-[1-(2-Ethoxy- ethyl)-3-methyl-1H- 063 pyrazol-4-ylamino]- thiazol-4-yl}-phenyl)- oxazolidin-2-one 1-(4-(4-((1-(4,4,4- trifluorobutyl)-1H- pyrazol-4- 064 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(3-methoxy-4-(2- ((1-(2-methoxyethyl)- 1H-pyrazol-4- 065 yl)amino)thiazol-4- yl)phenyl)imidazolidi n-2-one 1-(4-{2-[1-(2-Ethoxy- ethyl)-1H-pyrazol-4- ylamino]-thiazol-4- 066 yl}-3-methyl- phenyl)-imidazolidin- 2-one
Ex # Structure Name (IUPAC) 1-(4-(2-((1-(2- methoxyethyl)-1H- pyrazol-4- 067 yl)amino)thiazol-4- yl)-3- methylphenyl)imidaz olidin-2-one 1-(4-{2-[1-(2-Ethoxy- ethyl)-1H-pyrazol-4- ylamino]-thiazol-4- 068 yl}-3-methoxy- phenyl)-(R)-4- methyl-imidazolidin- 2-one 1-(4-{2-[1-(2-Ethoxy- ethyl)-1H-pyrazol-4- 069 ylamino]-thiazol-4- yl}-3-fluoro-phenyl)- imidazolidin-2-one 1-(3-Methoxy-4-{2- [1-(3-methoxy- propyl)-1H-pyrazol- 070 4-ylamino]-thiazol-4- yl}-phenyl)- imidazolidin-2-one 1-(4-{2-[1-(2- Methoxy-ethyl)-1H- pyrazol-4-ylamino]- 071 thiazol-4-yl}-3- fluoro-phenyl)- imidazolidin-2-one 3-(4-{2-[1-(2-Ethoxy- ethyl)-1H-pyrazol-4- ylamino]-thiazol-4- 072 yl}-3-methyl- phenyl)-oxazolidin-2- one
Ex # Structure Name (IUPAC) 1-(4-(4-((1-(3- fluorobenzyl)-1H- pyrazol-4- 073 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-{2-[1-(2-Ethoxy- ethyl)-1H-pyrazol-4- ylamino]-thiazol-4- 074 yl}-3-isopropoxy- phenyl)-imidazolidin- 2-one 3-(4-{2-[1-(2-Ethoxy- ethyl)-1H-pyrazol-4- ylamino]-thiazol-4- 075 yl}-3-methoxy- phenyl)-oxazolidin-2- one 3-(4-{2-[1-(2-Ethoxy- ethyl)-1H-pyrazol-4- 076 ylamino]-thiazol-4- yl}-3-fluoro-phenyl)- oxazolidin-2-one 1-(4-{2-[1-(2-Ethoxy- ethyl)-5-methyl-1H- pyrazol-4-ylamino]- 077 thiazol-4-yl}-3- methoxy-phenyl)- imidazolidin-2-one 1-(4-{2-[1-(2-Ethoxy- ethyl)-3-methyl-1H- pyrazol-4-ylamino]- 078 thiazol-4-yl}-3- methoxy-phenyl)- imidazolidin-2-one
Ex # Structure Name (IUPAC) 1-(4-(4-((1- (difluoromethyl)-1H- pyrazol-4- 079 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((1-methyl-3- (trifluoromethyl)-1H- pyrazol-4- 080 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-{2-[1-(2-Ethoxy- ethyl)-3-methoxy- 081 1H-pyrazol-4- ylamino]-thiazol-4- yl}-phenyl)- imidazolidin-2-one 1-(4-{2-[1-(2-Ethoxy- ethyl)-3-methoxy- 1H-pyrazol-4- 082 ylamino]-thiazol-4- yl}-3-methoxy- phenyl)-imidazolidin- 2-one 1-(4-{2-[1-(2-Ethoxy- ethyl)-3-methyl-1H- 083 pyrazol-4-ylamino]- thiazol-4-yl}-phenyl)- imidazolidin-2-one
Ex # Structure Name (IUPAC) 1-(3-Fluoro-4-{2-[1- (3-methoxy-propyl)- 1H-pyrazol-4- 084 ylamino]-thiazol-4- yl}-phenyl)- imidazolidin-2-one 1-(3'-((1-isopropyl- 1H-pyrazol-4- 085 yl)amino)-[1,1'- biphenyl]-4- yl)imidazolidin-2-one 1-(4-{2-[3-Chloro-1- (2-ethoxy-ethyl)-1H- 086 pyrazol-4-ylamino]- thiazol-4-yl}-phenyl)- imidazolidin-2-one 1-(4-{2-[1-(2-Ethoxy- ethyl)-1H-pyrazol-4- 087 ylamino]-5-methyl- thiazol-4-yl}-phenyl)- imidazolidin-2-one 1-(4-{2-[1-(2-Ethoxy- ethyl)-3-methyl-1H- pyrazol-4-ylamino]- 088 thiazol-4-yl}-3- fluoro-phenyl)- imidazolidin-2-one 1-(4-{2-[1-(2-Ethoxy- ethyl)-5-methyl-1H- 089 pyrazol-4-ylamino]- thiazol-4-yl}-3- fluoro-phenyl)- imidazolidin-2-one
Ex # Structure Name (IUPAC) 1-(3-Chloro-4-{2-[1- (3-methoxy-propyl)- 1H-pyrazol-4- 090 ylamino]-thiazol-4- yl}-phenyl)- pyrrolidin-2-one 1-(4-(4-((1-(2,2,2- trifluoroethyl)-1H- pyrazol-4- 091 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(3-Chloro-4-{2-[1- (2-ethoxy-ethyl)-3- methyl-1H-pyrazol-4- 092 ylamino]-thiazol-4- yl}-phenyl)- pyrrolidin-2-one 1-(4-(4-((1-(2,2- difluoroethyl)-1H- pyrazol-4- 093 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-{2-[1-(2-Ethoxy- ethyl)-1H-pyrazol-4- 094 ylamino]-thiazol-4- yl}-3-methoxy- phenyl)-pyrrolidin-2- one 1-(4-(2-((1-(2,2- difluoroethyl)-1H- pyrazol-4- 095 yl)amino)pyrimidin- 4- yl)phenyl)imidazolidi n-2-one
Ex # Structure Name (IUPAC) 1-(4-(2-((1-(2,2,2- trifluoroethyl)-1H- pyrazol-4- 096 yl)amino)pyrimidin- 4- yl)phenyl)imidazolidi n-2-one 1-(4-{2-[1-(2- [1,2,4]Triazol-1-yl- ethyl)-1H-pyrazol-4- 097 ylamino]-thiazol-4- yl}-phenyl)- imidazolidin-2-one 1-(4-(4-((1-propyl- 1H-pyrazol-4- yl)amino)pyrimidin- 098 2- yl)phenyl)imidazolidi n-2-one 1-(4-(2-((1-(2,2,3,3,3- pentafluoropropyl)- 1H-pyrazol-4- 099 yl)amino)pyrimidin- 4- yl)phenyl)imidazolidi n-2-one 1-(4-(2-((1-propyl- 1H-pyrazol-4- yl)amino)pyrimidin- 100 4- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((1-(2,2,3,3,3- pentafluoropropyl)- 1H-pyrazol-4- 101 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one
Ex # Structure Name (IUPAC) 1-(4-(4-((1- cyclopropyl-1H- pyrazol-4- 102 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((1- cyclobutyl-1H- pyrazol-4- 103 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((1-(oxetan-3- yl)-1H-pyrazol-4- 104 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-(2-((1-(1- hydroxy-2- methylpropan-2-yl)- 1H-pyrazol-4- 105 yl)amino)pyrimidin- 4- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((1-(1- hydroxypropan-2-yl)- 1H-pyrazol-4- 106 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-{2-[1-(3- Methoxy-propyl)-3- methyl-1H-pyrazol-4- 107 ylamino]-thiazol-4- yl}-phenyl)- imidazolidin-2-one
Ex # Structure Name (IUPAC) 1-(4-{2-[1-(2- Methoxy-ethyl)-3- methyl-1H-pyrazol-4- 108 ylamino]-thiazol-4- yl}-phenyl)- imidazolidin-2-one 2-methyl-2-(4-((2-(4- (2-oxoimidazolidin- 1- 109 yl)phenyl)pyrimidin- 4-yl)amino)-1H- pyrazol-1- yl)propanenitrile 1-(4-{5-[1-(2-Ethoxy- ethyl)-1H-pyrazol-4- ylamino]-2H-pyrazol- 110 3-yl}-3-methoxy- phenyl)-imidazolidin- 2-one 1-(4-(4-((1-(1- methoxypropan-2- yl)-1H-pyrazol-4- 111 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-(2-((1-(1- methoxy-2- methylpropan-2-yl)- 112 1H-pyrazol-4- yl)amino)pyrimidin- 4- yl)phenyl)imidazolidi n-2-one 1-(4-(2-((1-(1- methoxypropan-2- yl)-1H-pyrazol-4- 113 yl)amino)pyrimidin- 4- yl)phenyl)imidazolidi n-2-one
Ex # Structure Name (IUPAC) 2-methyl-2-(4-((4-(4- (2-oxoimidazolidin- 1- 114 yl)phenyl)pyrimidin- 2-yl)amino)-1H- pyrazol-1- yl)propanenitrile 2-(4-((2-(4-(2- oxoimidazolidin-1- yl)phenyl)pyrimidin- 115 4-yl)amino)-1H- pyrazol-1- yl)propanenitrile 1-(4-(2-((1- cyclopropyl-1H- pyrazol-4- 116 yl)amino)pyrimidin- 4- yl)phenyl)imidazolidi n-2-one 1-(4-{5-[1-(2-Ethoxy- ethyl)-1H-pyrazol-4- 117 ylamino]-2H-pyrazol- 3-yl}-3-fluoro- phenyl)-imidazolidin- 2-one 1-(4-{2-[1-(2-Azido- ethyl)-1H-pyrazol-4- 118 ylamino]-thiazol-4- yl}-phenyl)- imidazolidin-2-one 1-(3-Methoxy-4-{2- [1-(3-methoxy- 119 propyl)-3-methyl-1H- pyrazol-4-ylamino]- thiazol-4-yl}-phenyl)- imidazolidin-2-one
Ex # Structure Name (IUPAC) 1-(4-(4-((1-isopropyl- 3-methyl-1H-pyrazol- 4- 120 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((1-(1- methoxybutan-2-yl)- 1H-pyrazol-4- 121 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-(2-((1-(1- methoxybutan-2-yl)- 1H-pyrazol-4- 122 yl)amino)pyrimidin- 4- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((1-(1- ethoxypropan-2-yl)- 1H-pyrazol-4- 123 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-(2-((1-(1- ethoxybutan-2-yl)- 1H-pyrazol-4- 124 yl)amino)pyrimidin- 4- yl)phenyl)imidazolidi n-2-one 1-(4-(2-((1-(1- ethoxypropan-2-yl)- 1H-pyrazol-4- 125 yl)amino)pyrimidin- 4- yl)phenyl)imidazolidi n-2-one
Ex # Structure Name (IUPAC) 1-(4-{2-[1-(2- Methoxy-ethyl)-3- methyl-1H-pyrazol-4- 126 ylamino]-thiazol-4- yl}-phenyl)-4-(R)- methyl-imidazolidin- 2-one 1-(3-Fluoro-4-{2-[1- (2-methoxy-ethyl)-3- methyl-1H-pyrazol-4- 127 ylamino]-thiazol-4- yl}-phenyl)- imidazolidin-2-one 1-(4-(4-((1-(1- methoxy-3- methylbutan-2-yl)- 128 1H-pyrazol-4- yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((1-(2,2- difluorocyclopropyl)- 1H-pyrazol-4- 129 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-(2-((1-(1- methoxy-3- methylbutan-2-yl)- 1H-pyrazol-4- 130 yl)amino)pyrimidin- 4- yl)phenyl)imidazolidi n-2-one 1-(4-(2-((1-(2,2- difluorocyclopropyl)- 1H-pyrazol-4- 131 yl)amino)pyrimidin- 4- yl)phenyl)imidazolidi n-2-one
Ex # Structure Name (IUPAC) 1-(4-(4-((1-(2- methoxy-2- methylpropyl)-1H- pyrazol-4- 132 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one (R)-1-(4-(4-((1- isopropyl-1H- pyrazol-4- 133 yl)amino)pyrimidin- 2-yl)phenyl)-4- methylimidazolidin- 2-one 1-(4-(2-((1-(2- methoxy-2- methylpropyl)-1H- pyrazol-4- 134 yl)amino)pyrimidin- 4- yl)phenyl)imidazolidi n-2-one 1-(4-(2-((1-(1- ethoxy-3- methylbutan-2-yl)- 1H-pyrazol-4- 135 yl)amino)pyrimidin- 4- yl)phenyl)imidazolidi n-2-one (R)-1-(4-(4-((1-(2- methoxypropyl)-1H- pyrazol-4- 136 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((1-isopropyl- 1H-pyrazol-4- yl)amino)pyrimidin- 137 2-yl)phenyl)-4,4- dimethylimidazolidin -2-one
Ex # Structure Name (IUPAC) (S)-1-(4-(4-((1-(2- methoxypropyl)-1H- pyrazol-4- 138 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((1-isopropyl- 3-(trifluoromethyl)- 1H-pyrazol-4- 139 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one N N 1-(4-(4-((1,5- N dimethyl-1H-pyrazol- N N 4- 140 H yl)amino)pyrimidin- N 2- HN yl)phenyl)imidazolidi O n-2-one 1-(4-(2-((1-isopropyl- 3-(trifluoromethyl)- 1H-pyrazol-4- 141 yl)amino)pyrimidin- 4- yl)phenyl)imidazolidi n-2-one 1-(4-(2-((1,5- dimethyl-1H-pyrazol- 4- 142 yl)amino)pyrimidin- 4- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((1-(3- methoxypropyl)-1H- pyrazol-4- 143 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one
Ex # Structure Name (IUPAC) 1-(4-{2-[1-(3- Methoxy-propyl)-3- methyl-1H-pyrazol-4- 144 ylamino]-thiazol-4- yl}-3-methyl- phenyl)-imidazolidin- 2-one 1-(4-(4-((1-(2- methoxyethyl)-3- (trifluoromethyl)-1H- pyrazol-4- 145 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 3-(4-{2-[1-(3- Methoxy-propyl)-1H- 146 pyrazol-4-ylamino]- thiazol-4-yl}-phenyl)- oxazolidin-2-one 3-(3-Fluoro-4-{2-[1- (3-methoxy-propyl)- 147 1H-pyrazol-4- ylamino]-thiazol-4- yl}-phenyl)- oxazolidin-2-one 3-(3-Fluoro-4-{2-[1- (2-methoxy-ethyl)- 148 1H-pyrazol-4- ylamino]-thiazol-4- yl}-phenyl)- oxazolidin-2-one 1-(4-{2-[1-(3- Methoxy-propyl)-1H- 149 pyrazol-4-ylamino]- thiazol-4-yl}-phenyl)- imidazolidin-2-one 3-(4-{2-[1-(2- Methoxy-ethyl)-1H- 150 pyrazol-4-ylamino]- thiazol-4-yl}-phenyl)- oxazolidin-2-one
Ex # Structure Name (IUPAC) 1-(4-{2-[1-(2-Ethoxy- ethyl)-1H-pyrazol-4- 151 ylamino]-thiazol-4- yl}-phenyl)- pyrrolidin-2-one 1-(4-(4-((1- (cyclopropylmethyl)- 1H-pyrazol-4- 152 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((1-((3- (methoxymethyl)oxet an-3-yl)methyl)-1H- pyrazol-4- 153 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((1-(1,4- dimethoxybutan-2- yl)-1H-pyrazol-4- 154 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((1-(3- methoxycyclobutyl)- 1H-pyrazol-4- 155 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((3-methoxy- 1-methyl-1H-pyrazol- 4- 156 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one
Ex # Structure Name (IUPAC) 3-(4-{2-[1-(2-Ethoxy- ethyl)-3-methyl-1H- pyrazol-4-ylamino]- 157 thiazol-4-yl}-3- fluoro-phenyl)- oxazolidin-2-one 3-(4-{2-[1-(2-Ethoxy- ethyl)-3-methyl-1H- 158 pyrazol-4-ylamino]- thiazol-4-yl}-phenyl)- oxazolidin-2-one 1-(4-{2-[1-(2-Ethoxy- ethyl)-1H-pyrazol-4- 159 ylamino]-thiazol-4- yl}-3-fluoro-phenyl)- pyrrolidin-2-one 1-(4-{2-[1-(2-Ethoxy- ethyl)-3-methyl-1H- 160 pyrazol-4-ylamino]- thiazol-4-yl}-phenyl)- pyrrolidin-2-one 1-(4-{2-[1-(2-Ethoxy- ethyl)-3-methyl-1H- 161 pyrazol-4-ylamino]- thiazol-4-yl}-3- fluoro-phenyl)- pyrrolidin-2-one 1-(4-{2-[1-(3- Methoxy-propyl)-3- 162 methyl-1H-pyrazol-4- ylamino]-thiazol-4- yl}-phenyl)- pyrrolidin-2-one 3-(3-Fluoro-4-{2-[1- (2-methoxy-ethyl)-3- 163 methyl-1H-pyrazol-4- ylamino]-thiazol-4- yl}-phenyl)- oxazolidin-2-one 1-(3-Fluoro-4-{2-[1- (2-methoxy-ethyl)-3- methyl-1H-pyrazol-4- 164 ylamino]-thiazol-4- yl}-phenyl)- pyrrolidin-2-one
Ex # Structure Name (IUPAC) 3-(3-Fluoro-4-{2-[1- (2-methoxy-ethyl)-3- methyl-1H-pyrazol-4- 165 ylamino]-thiazol-4- yl}-phenyl)- oxazolidin-2-one 1-(3-Fluoro-4-{2-[1- (3-methoxy-propyl)- 3-methyl-1H-pyrazol- 166 4-ylamino]-thiazol-4- yl}-phenyl)- pyrrolidin-2-one 3-(4-{2-[1-(2-Ethoxy- ethyl)-1H-pyrazol-4- ylamino]-thiazol-4- 167 yl}-phenyl)-(R)-5- methyl-oxazolidin-2- one 1-(4-{2-[1-(2- Methoxy-ethyl)-1H- 168 pyrazol-4-ylamino]- thiazol-4-yl}-phenyl)- pyrrolidin-2-one 1-(4-{2-[1-(3- Methoxy-propyl)-1H- 169 pyrazol-4-ylamino]- thiazol-4-yl}-phenyl)- pyrrolidin-2-one 1-(3-Fluoro-4-{2-[1- (3-methoxy-propyl)- 1H-pyrazol-4- 170 ylamino]-thiazol-4- yl}-phenyl)- pyrrolidin-2-one 1-(3-Fluoro-4-{2-[1- (2-methoxy-ethyl)- 1H-pyrazol-4- 171 ylamino]-thiazol-4- yl}-phenyl)- pyrrolidin-2-one
Ex # Structure Name (IUPAC) 1-(4-{2-[1-(2-Ethoxy- ethyl)-1H-pyrazol-4- ylamino]-thiazol-4- 172 yl}-3-trifluoromethyl- phenyl)-imidazolidin- 2-one 1-(4-{5-[1-(2-Ethoxy- ethyl)-1H-pyrazol-4- ylamino]-2H-pyrazol- 173 3-yl}-3-fluoro- phenyl)-pyrrolidin-2- one 1-(4-{2-[1-(3-Ethoxy- propyl)-1H-pyrazol- 174 4-ylamino]-thiazol-4- yl}-phenyl)- imidazolidin-2-one 1-(4-{2-[1-(2-Ethoxy- ethyl)-1H-pyrazol-4- 175 ylamino]-thiazol-4- yl}-phenyl)-4-(R)- hydroxy-pyrrolidin-2- one 1-(3-Chloro-4-{2-[1- (2-ethoxy-ethyl)-1H- 176 pyrazol-4-ylamino]- thiazol-4-yl}-phenyl)- imidazolidin-2-one 1-(3-Chloro-4-{2-[1- (3-methoxy-propyl)- 1H-pyrazol-4- 177 ylamino]-thiazol-4- yl}-phenyl)- imidazolidin-2-one 1-(3-Chloro-4-{2-[1- (2-ethoxy-ethyl)-3- methyl-1H-pyrazol-4- 178 ylamino]-thiazol-4- yl}-phenyl)- imidazolidin-2-one
Ex # Structure Name (IUPAC) 1-(4-{2-[1-(2- [1,2,3]Triazol-2-yl- ethyl)-1H-pyrazol-4- 179 ylamino]-thiazol-4- yl}-phenyl)- imidazolidin-2-one 1-(4-{2-[1-(2- [1,2,3]Triazol-1-yl- ethyl)-1H-pyrazol-4- 180 ylamino]-thiazol-4- yl}-phenyl)- imidazolidin-2-one 1-(3-Chloro-4-{2-[1- (2-ethoxy-ethyl)-1H- 181 pyrazol-4-ylamino]- thiazol-4-yl}-phenyl)- pyrrolidin-2-one 3-(4-{4-[4-(2-Oxo- imidazolidin-1-yl)- 182 phenyl]-thiazol-2- ylamino}-pyrazol-1- yl)-propionic acid ethyl ester 2-[2-(4-{4-[4-(2-Oxo- imidazolidin-1-yl)- phenyl]-thiazol-2- ylamino}-pyrazol-1- 183 yl)-ethyl]-2H- [1,2,3]triazole-4- carboxylic acid methyl ester 1-(4-{2-[1-(2- Imidazol-1-yl-ethyl)- 1H-pyrazol-4- 184 ylamino]-thiazol-4- yl}-phenyl)- imidazolidin-2-one 1-(3-Chloro-4-{2-[1- (3-methoxy-propyl)- 3-methyl-1H-pyrazol- 185 4-ylamino]-thiazol-4- yl}-phenyl)- pyrrolidin-2-one
Ex # Structure Name (IUPAC) 1-(3-Chloro-4-{2-[1- (3-methoxy-propyl)- 3-methyl-1H-pyrazol- 186 4-ylamino]-thiazol-4- yl}-phenyl)- imidazolidin-2-one [0059] All references to compounds of formula (I) include references to salts, solvates, multi-component complexes and/or liquid crystals thereof. All references to compounds of formula (I) include references to polymorphs and/or crystal habits thereof. All references to compounds of formula (I) include references to pharmaceutically acceptable prodrugs thereof. All references to compounds of formula (I) include references to isotopically labelled compounds of formula (I), including deuterated compounds of formula (I). The compounds of formula (I) and subformulae thereof may contain at least one asymmetric center and thus may exist as different stereoisomeric forms. Accordingly, all references to compounds of formula (I) include references to all possible stereoisomers and includes not only the racemic compounds but the individual enantiomers and their non racemic mixtures as well. When a compound is desired as a single enantiomer, such single enantiomer may be obtained by stereospecific synthesis, by resolution of the final product or any convenient intermediate, or by chiral chromatographic methods as each are known in the art. Resolution of the final product, an intermediate, or a starting material may be carried out by any suitable method known in the art. [0060] The compounds of the invention may be in the form of pharmaceutically acceptable solvates. Pharmaceutically acceptable solvates of the compounds of formula (I) include hydrates thereof. [0061] The compounds of the invention may be in the form of pharmaceutically acceptable salts. Pharmaceutically acceptable salts of the compounds of formula (I) include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide,
hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinafoate salts. Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, 2- (diethylamino)ethanol, diolamine, ethanolamine, glycine, 4-(2-hydroxyethyl)- morpholine, lysine, magnesium, meglumine, morpholine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts. When the compounds of formula (I) contain an acidic group as well as a basic group, the compounds of the invention may also form internal salts, and such compounds are within the scope of the invention. When the compounds of the invention contain a hydrogen donating heteroatom (e.g., NH), the invention also covers salts and/or isomers formed by transfer of said hydrogen atom to a basic group or atom within the molecule Pharmaceutically acceptable salts of compounds of formula (I) may be prepared by one or more of these methods: (i) by reacting the compound of formula (I) with the desired acid; (ii) by reacting the compound of formula (I) with the desired base; (iii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of formula (I) or by ring-opening a suitable cyclic precursor, e.g., a lactone or lactam, using the desired acid; and/or (iv) by converting one salt of the compound of formula (I) to another by reaction with an appropriate acid or by means of a suitable ion exchange column. All these reactions are typically carried out in solution. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the salt may vary from completely ionized to almost non-ionized. Pharmaceutical composition [0062] Another object of the present invention is a composition comprising a compound according to the invention as described herein. According to some embodiments, the composition further comprises at least one pharmaceutically acceptable carrier, so that the composition is a “pharmaceutical composition” as defined herein.
[0063] According to some embodiments, the pharmaceutical composition comprises the compound according to the invention as sole active pharmaceutical ingredient. According to other embodiments, the pharmaceutical composition further comprises at least another active pharmaceutical ingredient (i.e., an active pharmaceutical ingredient that is not a compound according to the invention). In some embodiments, the at least another active pharmaceutical ingredient is suitable for treating a hematological disorder and/or a proliferative disorder. [0064] Another object of the present invention is a medicament comprising a compound according to the invention as described herein. Kit [0065] Another object of the present invention is a kit of parts (in short “kit”) comprising a compound or composition according to the invention as described herein. According to some embodiments, the kit comprises a manufacture such as, for example, a package or a container. According to some embodiments, the kit comprises instructions for use. The kit may be promoted, distributed, or sold as a unit for performing the medical uses of the present invention. [0066] According to some embodiments, the kit comprises: a pharmaceutical composition comprising the compound according to the invention, and another separate pharmaceutical composition comprising at least another active pharmaceutical ingredient. In some embodiments, the at least another active pharmaceutical ingredient is suitable for treating a hematological disorder and/or a proliferative disorder. Medical uses [0067] Another object of the present invention is a compound or a composition (in particular, a pharmaceutical composition) according to the invention, as described herein, for use as a medicament. [0068] Another object of the present invention is a compound or a composition according to the invention, as described herein, for use in the treatment of a hematological disorder and/or a proliferative disorder.
[0069] Another object of the present invention is a method for treating a hematological disorder and/or a proliferative disorder in a subject in need thereof. Another object of the present invention is the use of a compound or a composition according to the invention, as described herein, in the manufacture of a medicament for the treatment of a hematological disorder and/or a proliferative disorder. Another object of the present invention is the use of a compound or a composition according to the invention, as described herein, for treating a hematological disorder and/or a proliferative disorder. [0070] According to one embodiment, the method or the use comprises a step of administering to a subject a therapeutically effective amount of a compound, a composition or a medicament according to the invention, as described herein. [0071] According to some embodiments, the hematological disorder to be treated by the method or the use of the invention is lymphoma, leukemia, multiple myeloma (MM), myelodysplastic syndrome (MDS) or myelodysplasia with myelofibrosis. In some embodiments, the leukemia is acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic lymphoid leukemia (CLL) or chronic myeloid leukemia (CML). According to some embodiments, the proliferative disorder to be treated by the method or the use of the invention is cancer. In some embodiments, the cancer is a solid cancer. In some embodiments, the cancer is head and neck cancer, melanoma, kidney carcinoma, stomach carcinoma, liver carcinoma, colorectal carcinoma, pancreas carcinoma, larynx carcinoma, lung carcinoma, neuronal carcinoma, glioblastoma multiforme, osteosarcoma, fibrosarcoma, ovarian sarcoma, liposarcoma, Ewing sarcoma, breast carcinoma, ovary carcinoma or prostate carcinoma. [0072] According to one embodiment, the compound or the composition or the medicament according to the invention, as described herein, is to be administered to a subject, and may be formulated using methods well-known in the art. Non-limiting examples of forms adapted for administration include solutions (such as, for example, sterile aqueous solutions), gels, dispersions, emulsions, suspensions and solid forms suitable for using to prepare solutions or suspensions upon the addition of a liquid prior to use (such as, for example, powder or liposomal forms). The compound or the composition or the medicament according to the invention, as described herein, may be
administered using administration route well-known in the art such as, for example, parenterally, orally, by inhalation, spray, rectally, nasally, or via an implanted reservoir. [0073] It will be however understood that the total daily usage of the compound, the composition or the medicament will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disease being treated and the severity of the disease; activity of the compound employed; the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific therapeutic agent employed; the duration of the treatment; drugs used in combination or coincidental with the specific therapeutic agent employed; and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. The total dose required for each treatment may be administered by multiple doses or in a single dose. [0074] In one embodiment, the dosage of the compound is about 0.01 to 500 mg per kg patient body weight per day, which can be administered in single or multiple doses. Preferably, the dosage level will be about 0.1 to about 250 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day. A suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be about 0.05 to 0.5, about 0.5 to 5 or about 5 to 50 mg/kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing from about 1.0 to 1000 milligrams of the active ingredient, particularly about 1.0, about 5.0, about 10.0, about 15.0, about 20.0, about 25.0, about 50.0, about 75.0, about 100.0, about 150.0, about 200.0, about 250.0, about 300.0, about 400.0, about 500.0, about 600.0, about 750.0, about 800.0, about 900.0, and about 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend
upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy. [0075] According to some embodiments, the compound or the composition or the medicament according to the invention, as described herein, is to be administered as sole active pharmaceutical ingredient. According to other embodiments, the compound or the composition or the medicament according to the invention, as described herein, is to be administered with at least another active pharmaceutical ingredient. According to other embodiments, the compound or the composition or the medicament according to the invention, as described herein, is to be administered before at least another active pharmaceutical ingredient, concomitantly with at least another active pharmaceutical ingredient, and/or after at least another active pharmaceutical ingredient. In some embodiments, the composition or the medicament according to the invention, as described herein, is a combined preparation for sequential, simultaneous or separate use in the treatment of hematological disorders and/or proliferative disorders. In some embodiments, the at least another active pharmaceutical ingredient is suitable for treating a hematological disorder and/or a proliferative disorder.
[0076] The compound according to the invention as described herein may be manufactured by means of synthetic methods well-known in the art. [0077] Another object of the present invention is a process for manufacturing a compound of the invention. Compounds of the invention can be prepared by several methods including the methods outlined in Schemes 1-7 hereinbelow, wherein the substituents are as defined under formula (I) herein and A represents the following moiety:
, except where otherwise indicated.
[0078] Accordingly, the synthesis of the aminooxazole derivatives of formula I-a can be performed by firstly reacting aromatic aldehydes V with p-toluenesulfonylmethyl isocyanide (TosMIC) to prepare the corresponding oxazole derivatives II using the method of Van Leusen et al. (Tetrahedron Lett., 1972, 23, 2369) (Scheme 1). The non- commercial aldehydes can be prepared using literature methods to introduce the aldehyde group either from the corresponding brominated aromatic compound using an organometallic reagent and DMF or from the oxidation of corresponding toluene according to the method of Frey et al. (Tetrahedron Lett., 2001, 39, 6815) or from the reaction employing the dibromination of bromo-picolines followed by hydrolysis using an aqueous solution of calcium carbonate used in the method of Bombrun et al. (Tetrahedron Lett., 2005, 36, 6033). The compounds of structure II can then be further functionalised by deprotonation of the oxazole moiety by a suitable organic base and subsequent electrophilic chlorination to afford the 2-chlorooxazole coumpounds III. A direct nucleophilic displacement reaction by aminopyrazole compounds IV, in the presence of a suitable solvent such as an alcohol (e.g., ethanol) and with heating at elevated temperature, can be used to afford the final target aminooxazole compounds of formula I-a.
Scheme 1 [0079] The aminothiazole derivatives of formula I-b can be prepared using the Hantzsch reaction of the 2-bromoketone VII and thiourea derivatives VI under basic conditions in the presence of a suitable solvent such as an alcohol (e.g., ethanol) and with heating at elevated temperature (Scheme 2).
Scheme 2 [0080] Compounds of formula I-c may alternatively be prepared through copper- or palladium-catalyzed coupling reactions according to Scheme 3 below, by reacting compound IX and optionally substituted heterocycles A, where Q is I, Br or Cl. A person of ordinary skill in the art will recognize that compounds IX may be prepared according to the protocols outlined in Schemes 1 and 2 above.
Scheme 3 [0081] Alternatively, compounds of formula I-d may also be prepared in two steps by the nucleophilic aromatic substitution of substituted pyrazole compounds IV with di-halogeno heteroaryl compounds (Q-B-Q) to give intermediates XI (Scheme 4). The non-commercial amino pyrazoles IV can be prepared by N-alkylation of the corresponding 4-nitropyrazole compound then reduction of the nitro group (for examples see WO 2015/089337 or WO 2012/061337). The intermediate compounds XI can be further functionalized by a Suzuki coupling with the boronic acid pinacol ester intermediates XII (V = NH, O or N-Tr) to afford compounds of formula I-d.
Scheme 4 [0082] The analogues of intermediate XII where V = NH can be prepared according to the method described for example 225 in EP 2857400 (2015) in two steps from the corresponding p-amino boronic acid ester XIII by reaction with 2-chloroethylisocyanate then cyclisation in the presence of base (Scheme 5). Further analogues of intermediate XII (V = O or N-Tr) can be prepared from the corresponding brominated aromatic boronic acid ester XIV by a palladium-catalyzed Suzuki coupling reaction with the corresponding cyclic compounds XV (Scheme 5). In the case of the N-trityl compounds XVI, an additional step of deprotection is required by treatment with TFA to afford the compounds of formula I-e (V = NH) (Scheme 6).
Scheme 6 [0083] Further analogues can be prepared by a modified order of the above steps. For these compounds, the di-halogeno heteroaryl compounds (Q-B-Q) can be reacted with the boronic acid ester compounds XII (V = N-Tr) under classical Suzuki coupling conditions to afford the intermediates XVII (Scheme 7). Coupling of these intermediates XVII with 4-aminopyrazoles IV gives the N-trityl protected compounds of formula I-f (V = N-Tr) which can be deprotected with TFA as in Scheme 6 hereinabove.
Scheme 7 EXAMPLES [0084] The present invention is further illustrated by the following examples. Example 1: Synthesis of the compounds Example 1-1: General synthetic procedures [0085] Compounds of the invention were prepared by several methods including the synthetic methods disclosed hereinabove in the Detailed Description, in particular as shown in Schemes 1-7 herein. However, the synthetic methods described hereinabove are merely exemplary, and the compounds of the invention may be synthesized by alternate routes as appreciated by a person of ordinary skill in the art. Example 1-2: Examples of compound synthesis [0086] The invention will be more fully understood by reference to the following preparative examples, but they should not be construed as limiting the scope of the invention. Materials and methods [0087] General: All chemicals used were commercial reagent grade products. Solvents were of anhydrous commercial grade and were used without further purification. The progress of the reactions was monitored by thin layer chromatography using precoated silica gel 60F 254, Merck TLC plates, which were visualized under UV light. Multiplicities in
1H NMR spectra are indicated as singlet (s), broad singlet (br s), doublet (d), triplet (t), quadruplet (q), doublet of doublets (dd) and multiplet (m) and the NMR
spectra were performed either on a Bruker Avance 300, 360 or 400 MHz spectrometer. Mass spectra were performed by Electrospray Ionisation Mass Spectrometry (ESI MS) in positive mode or by Atmospheric Pressure Chemical Ionization Mass Spectrometry (APCI MS) in positive mode. [0088] LCMS methods: Method A: This method was run on a high-performance liquid chromatography (HPLC) Waters AutoPurification instrument coupled to an SQD mass spectrometer. The gradient used was: starting at t = 0.0 min with 5% of MeCN + 0.1% formic acid in water + 0.1% formic acid with a linear gradient to t = 5.0 min reaching 100% MeCN + 0.1% formic acid ; then staying at this state from t = 5.0 min until t = 10.0 min. The column used was a Nucleoshell 5µm RP18plus 4.6 x 150mm. The detection instrument used was a single quadrupole mass spectrometer (SQD) using ESI positive mode. Method B: This method was run on HPLC 2695 Alliance, Waters coupled to a ZMD mass spectrometer instrument. The gradient used was : starting at t = 0.0 min with 0% of MeCN + 0.04 % formic acid in water; then a linear gradient to t = 3.1 min reaching 100% of MeCN + 0.04 % formic acid; then staying at this state to t = 3.8 min and decreasing to 0% of MeCN + 0.04 % formic acid in water at t = 4.8 min. The column used was a Sunfire 2.1 x 50 mm dp: 3.5 µm. Abbreviations aqu aqueous solution BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl n-Buli n-Butyl lithium t-BuOH tert-Butyl alcohol CaCO3 Calcium carbonate CCl4 Carbon tetrachloride C
2Cl
6 Hexachloroethane CDCl3 Deuterochloroform Cs2CO3 Cesium carbonate CuI Copper (I) Iodide DCC Dicyclohexylcarbodiimide DCM Dichloromethane
DIPEA Diisopropylethylamine DIAD Diisopropyl azodicarboxylate DMA Dimethylacetamide DMAP 4-Dimethylaminopyridine DMF Dimethylformamide DMSO-d6 Hexadeuterodimethyl sulfoxide EDCI 1-Ethyl-3-(3-dimethyl aminopropyl)carbodiimide EtOAc Ethyl acetate EtOH Ethanol Et2O Diethyl ether Et3N Triethylamine h Hour(s) HOBt Hydroxybenzotriazole iPrOH 2-Propanol K
2CO
3 Potassium carbonate KHCO3 Potassium hydrogen carbonate KOtBu Potassium tert-butoxide LiHMDS Lithium bis(trimethylsilyl)amide MeCN Acetonitrile MeOH Methanol MgSO4 Magnesium sulfate mins Minutes NaCl Sodium chloride Na2CO3 Sodium carbonate NaH Sodium hydride NaHCO3 Sodium hydrogen carbonate NaNO2 Sodium nitrite NaOEt Sodium ethoxide NaOH Sodium hydroxide NBS N-bromo-succinimide NH4Cl Ammonium chloride NH
4SCN Ammonium thiocyanate
NMP N-Methyl-pyrrolidin-2-one NaOtBu Sodium tert-butoxide NMR Nuclear magnetic resonance Pd/C Palladium on carbon Pd
2(dba)
3 Tris(dibenzylideneacetone)dipalladium(0) Pd(OAc)2 Palladium (II) acetate Pd(PPh3)4 Tetrakis(triphenylphosphine)palladium(0) PE Petroleum ether (PhCO)
2O
2 Benzoyl peroxide RT Room temperature sat. aqu saturated aqueous SnCl
2.2H
2O Tin (II) chloride dihydrate SiO2 Silica gel TFA Trifluoroacetic acid THF Tetrahydrofuran TosMIC p-Toluenesulfonylmethyl isocyanide tR Retention time XantPhos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene Synthesis of Compound 001
Scheme 8
[0089] Preparation of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)imidazolidin-2-one (1b). Intermediate 1b was prepared in 2 steps using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline 1a and 2-chloroethyl isocyanate and Et3N then KOtBu according to the method described for example 225 in EP2857400 (2015). The crude product was purified by column chromatography (Puriflash) on SiO
2 eluting with 2-5% EtOH in DCM to afford 1b as a white solid (2.43g, 59%).
1H NMR (400 MHz, DMSO-d6) δ 7.68 – 7.44 (m, 4H), 7.06 (s, 1H), 3.97 – 3.75 (m, 2H), 3.41 (dd, J = 9.2, 6.8 Hz, 2H), 1.28 (s, 12H). [0090] Preparation of 1-(2-methoxyethyl)-4-nitro-1H-pyrazole (1d). In a similar fashion to the method described in WO 2015/089337 (p125-6), a mixture of 4-nitro-1H- pyrazole 1c (2.00g, 17.6mmol) and 1-bromo-2-methoxyethane (1.66ml, 17.6mmol) and K
2CO
3 (5.47g, 39.6mmol) in MeCN (50ml) was heated to 80°C for 18h. The cooled mixture was treated with water and extracted with DCM. The combined organics were dried over MgSO4, filtered and evaporated then purified by column chromatography on SiO
2 (Puriflash) eluting with 0-5% EtOH in DCM to afford 1d as a clear oil (2.77g,92%).
1H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.26 (s, 1H), 4.34 (t, J = 5.2 Hz, 2H), 3.79 – 3.64 (m, 2H), 3.23 (s, 3H). [0091] Preparation of 1-(2-methoxyethyl)-1H-pyrazol-4-amine (1e). A solution of intermediate 1d (2.75g, mmol) in EtOH (50ml) was treated with 10% Pd/C and stirred under an atmosphere of H2 at ambient temperature and pressure for 18h. The mixture was filtered and evaporated to afford crude 1e as a red oil.
1H NMR (400 MHz, Chloroform- d) δ 7.16 (d, J = 1.0 Hz, 1H), 7.09 (d, J = 0.9 Hz, 1H), 4.16 (t, J = 5.3 Hz, 2H), 3.69 (t, J = 5.3 Hz, 2H), 3.33 (s, 3H). [0092] Preparation of 2-chloro-N-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyrimidin-4- amine (1g). A stirred solution of 2,4-dichloropyrimidine 1f (500mg, 3.36mmol), 1e (474mg, 3.36mmol) and Et3N (515µL, 3.70mmol) in iPrOH (20ml) was heated to reflux under argon for 18h. The cooled mixture was treated with water then extracted with DCM. The combined organics were dried over MgSO
4, filtered and evaporated then purified by column chromatography on SiO
2 (Puriflash) eluting with 0-2% EtOH in DCM to afford 1g as a brown oil which solidified on standing (464mg, 54%).
1H NMR (400 MHz,
DMSO-d6) δ 10.01 (s, 1H), 8.05 (d, J = 5.9 Hz, 1H), 7.93 (s, 1H), 7.53 (s, 1H), 6.61 (d, J = 5.9 Hz, 1H), 4.24 (t, J = 5.3 Hz, 2H), 3.67 (t, J = 5.3 Hz, 2H), 3.23 (s, 3H). [0093] Preparation of 1-(4-(4-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin- 2-yl)phenyl)imidazolidin-2-one (001). A sealed tube was charged with 1g (100mg, 0.394mmol), 1b (136mg, 0.473mmol), Pd(PPh
3)
4 (23mg, 0.0197mmol), K
2CO
3 (163mg, 1.18mmol), dioxane (5ml) and water (1ml) and degassed with a stream of argon for 5 mins. The tube was sealed and heated with stirring to 100°C for 18h then cooled and treated with water and extracted with a mixture of DCM and EtOH. The combined organics were dried over MgSO
4, filtered and evaporated then purified by column chromatography on SiO2 (Puriflash) eluting with 5-15% EtOH in DCM to afford compound 001 as a white solid (46 mg, 31%) after trituration from DCM with pentane.
1H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 1H), 8.32 – 8.27 (m, 2H), 8.25 (d, J = 5.8 Hz, 1H), 8.10 (s, 1H), 7.72 – 7.67 (m, 2H), 7.59 (s, 1H), 7.08 (s, 1H), 6.52 (d, J = 5.9 Hz, 1H), 4.30 (t, J = 5.2 Hz, 2H), 3.95 – 3.88 (m, 2H), 3.71 (t, J = 5.2 Hz, 2H), 3.49 – 3.38 (m, 2H), 3.28 (s, 3H). Synthesis of Compound 002
Scheme 9 [0094] Preparation of 2-Chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (2b). Intermediate 2b was prepared as for intermediate 1g above from 2,4-dichloropyrimidine 1f and 1-methyl-1H-pyrazol-4-amine 2a to afford 2b as a beige solid (1.70g, 79%) after purification by column chromatography on SiO2 (Puriflash) eluting with 5% EtOH in DCM.
1H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 8.05 (d, J = 5.9 Hz, 1H), 7.90 (s, 1H), 7.49 (s, 1H), 6.61 (d, J = 6.0 Hz, 1H), 3.83 (s, 3H). [0095] Preparation of 1-(4-(4-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-2- yl)phenyl)imidazolidin-2-one (002). Compound 002 was then prepared from 2b and 1b as described for compound 001 above to afford compound 002 as a beige solid (60 mg,
45%).
1H NMR (400 MHz, DMSO-d6) δ 9.49 (s, 1H), 8.31 (d, J = 8.9 Hz, 2H), 8.25 (d, J = 5.8 Hz, 1H), 8.03 (s, 1H), 7.71 (d, J = 8.9 Hz, 2H), 7.59 (s, 1H), 7.09 (s, 1H), 6.53 (d, J = 5.8 Hz, 1H), 3.97 – 3.90 (m, 2H), 3.89 (s, 3H), 3.45 (t, J = 7.9 Hz, 2H), 3.33 (s, 3H). Synthesis of Compound 003
[0096] Preparation of 1-tritylimidazolidin-2-one (3b). A solution of imidazolidin-2-one 3a (20.0g, 230mmol), triphenylmethyl chloride (65.0g, 230mmol) and Et3N (65ml, 460mmol) in anhydrous DCM (200ml) was stirred at RT for 42h. The mixture was diluted with water, extracted with DCM and the combined organics washed twice with brine, dried over MgSO
4, filtered and evaporated to afford 3b as a white solid (60.8g, 80%).
1H NMR (300 MHz, DMSO-d6) δ 7.47 – 7.32 (m, 6H), 7.33 – 7.22 (m, 6H), 7.22 – 7.12 (m, 3H), 6.40 (s, 1H), 3.32 – 3.09 (m, 4H). [0097] Preparation of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3- tritylimidazolidin-2-one (3d). A sealed tube was charged with intermediate 3b (3.19, 9.71mmol), 2-(4-bromophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 3c (2.50g, 8.83mmol), Pd
2(dba)
3 (647mg, 0.706mmol), XantPhos (1.02g, 1.77mmol), Cs
2CO
3 (6.33g, 19.4mmol) and dioxane (30ml) and degassed with a stream of argon for 5 mins. The tube was sealed and heated with stirring to 100°C for 18h then the cooled mixture was diluted with water and extracted with EtOAc. The combined organics were dried over MgSO
4, filtered and evaporated then purified by column chromatography on SiO
2 (Puriflash) eluting with 0-20% EtOAc in cyclohexane to afford 3d as a yellow foam (4.00g, 85%).
1H NMR (400 MHz, DMSO-d6) δ 7.61 – 7.53 (m, 2H), 7.50 – 7.36 (m, 8H), 7.34 – 7.27 (m, 6H), 7.24 – 7.19 (m, 3H), 3.88 – 3.77 (m, 2H), 3.44 (t, J = 7.5 Hz, 2H), 1.37 – 1.19 (m, 12H).
[0098] Preparation of 1-(4-(2-chloropyrimidin-4-yl)phenyl)-3-tritylimidazolidin-2- one (3e). A sealed tube was charged with 3d (3.82g, 7.20mmol), 2,4-dichlropyrimidine 1f (2.15g, 14.4mmol), Pd(PPh3)4 (166mg, 0.144mmol), 0.4M aqu. Na2CO3 (43ml, 17.3mmol) and MeCN (53ml) and degassed with a stream of argon for 5 mins. The tube was sealed and heated with stirring to 100°C for 18h then the cooled mixture was diluted with water and extracted with EtOAc. The combined organics were dried over MgSO4, filtered and evaporated and the residue purified by column chromatography on SiO2 (Puriflash) eluting with 0-30% EtOAc in cyclohexane to afford 3e as a yellow foam (3.08g, 83%).
1H NMR (300 MHz, DMSO-d
6) δ 8.72 (d, J = 5.4 Hz, 1H), 8.13 (d, J = 8.9 Hz, 2H), 8.05 (d, J = 5.4 Hz, 1H), 7.64 (d, J = 9.0 Hz, 2H), 7.44 – 7.39 (m, 6H), 7.36 – 7.29 (m, 6H), 7.26 – 7.19 (m, 3H), 3.90 (t, J = 7.5 Hz, 2H), 3.48 (t, J = 7.5 Hz, 2H). [0099] Preparation of 1-(4-(2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin- 4-yl)phenyl)imidazolidin-2-one (003). A sealed tube was charged with 3e (200mg, 0.387mmol), 1e (55mg, 0.387mmol), Pd2(dba)3 (30mg, 0.031mmol), XantPhos (47mg,0.077 mmol), Cs
2CO
3 (287mg, 0.851mmol) and dioxane (5ml) and degassed with a stream of argon for 5 mins. The tube was sealed and heated with stirring to 100°C for 18h. The cooled mixture was treated with water and extracted with DCM. The combined organics were dried over MgSO
4, filtered and evaporated then purified by column chromatography on SiO
2 (Puriflash) eluting with 0-5% EtOH in DCM to afford crude 3f as a black gum. This gum was treated with 1.25M HCl in EtOH (10ml) was stirred at 50°C for 2h. The mixture was taken to pH8 with sat. aqu. NaHCO3. then extracted with DCM and the combined organics dried over MgSO
4, filtered and evaporated. The residue was purified by column chromatography on SiO2 (Puriflash) eluting with 0-15% EtOH in DCM to afford compound 003 as a yellow solid (13mg, 9%).
1H NMR (400 MHz, DMSO-d
6) δ 9.41 (s, 1H), 8.42 (d, J = 5.2 Hz, 1H), 8.16 – 8.08 (m, 2H), 7.99 (s, 1H), 7.75 – 7.71 (m, 2H), 7.57 (s, 1H), 7.23 (d, J = 5.3 Hz, 1H), 7.12 (s, 1H), 4.25 (t, J = 5.3 Hz, 2H), 3.96 – 3.89 (m, 2H), 3.68 (t, J = 5.3 Hz, 2H), 3.47 – 3.42 (m, 2H), 3.26 (s, 3H).
Synthesis of Compound 004
Scheme 11 [0100] Preparation of 1-(3,5-dimethylbenzyl)-1H-pyrazol-4-amine (4b). Intermediate 4b was prepared in 2 steps from 4-nitro-1H-pyrazole 1c and 3,5-dimethylbenzyl bromide via 1-(3,5-dimethylbenzyl)-4-nitro-1H-pyrazole 4a and hydrogenation with palladium catalyst as described for intermediate 1e above to afford 4b as a purple oil (641mg, 78%).
1H NMR (400 MHz, DMSO-d6) δ 7.03 (s, 1H), 6.92 (s, 1H), 6.89 (s, 1H), 6.78 (s, 2H), 5.02 (s, 2H), 3.82 (s, 2H), 2.22 (s, 6H). [0101] Preparation of 2-chloro-N-(1-(3,5-dimethylbenzyl)-1H-pyrazol-4-yl)pyrimidin- 4-amine (4c) and 4-chloro-N-(1-(3,5-dimethylbenzyl)-1H-pyrazol-4-yl)pyrimidin-2- amine (4d). A mixture of regioisomers 4c and 4d was prepared as for intermediate 1g above from 2,4-dichloropyrimidine 1f and 1-(3,5-dimethylbenzyl)-1H-pyrazol-4-amine 4b. Purification by column chromatography on SiO2 (Puriflash) eluting with 2-5% EtOH in DCM gave 4d as a beige solid (104mg, 10%; eluted first) then 4c as a white solid (749mg, 75%; eluted last). 4c :
1H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 8.05 (d, J = 5.9 Hz, 1H), 7.96 (s, 1H), 7.55 (s, 1H), 6.92 (s, 1H), 6.86 (s, 2H), 6.61 (d, J = 5.9 Hz, 1H), 5.23 (s, 2H), 2.24 (s, 6H). 4d :
1H NMR (400 MHz, DMSO-d6) δ 9.82 (s, 1H), 8.36 (d, J = 5.1 Hz, 1H), 7.91 (s, 1H), 7.54 (s, 1H), 6.91 (s, 1H), 6.85 (s, 2H), 6.81 (d, J = 5.2 Hz, 1H), 5.20 (s, 2H), 2.23 (s, 6H).
[0102] Preparation of 1-(4-(4-((1-(3,5-dimethylbenzyl)-1H-pyrazol-4- yl)amino)pyrimidin-2-yl)phenyl) imidazolidin-2-one (004). Compound 004 was prepared from 4c and 1b as for compound 001 above to afford 004 as a white solid (60mg, 38%). 1H NMR (400 MHz, DMSO-d6) δ 9.53 (s, 1H), 8.24 (d, J = 5.8 Hz, 1H), 8.23 – 8.19 (m,
[0104] Preparation of 1-(2-ethoxyethyl)-4-nitro-1H-pyrazole (6a). A mixture of 4-nitropyrazole 1c (2.00g, 17.7mmol), 1-bromo-2-ethoxyethane (1.99ml, 17.7mmol) and K2CO3 (5.50g, 39.8mmol) in MeCN (50ml) was stirred at 80°C for 3h. Water was added and mixture extracted with EtOAc, then the combined organics were dried over MgSO4, filtered and evaporated. The residue was purified by column chromatography on SiO
2 (Puriflash) using 0 to 5% EtOH in DCM to give intermediate 6a as a clear mobile oil (2.90g, 88%).
1H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.26 (s, 1H), 4.33 (t, J = 5.3 Hz, 2H), 3.76 (t, J = 5.3 Hz, 2H), 3.42 (q, J = 7.0 Hz, 2H), 1.04 (t, J = 7.0 Hz, 3H). [0105] Preparation of 1-(2-ethoxyethyl)-1H-pyrazol-4-amine (6b). To a solution of intermediate 6a (2.89g, 15.6mmol) in ethanol (35ml) was added 10% Pd/C (289mg, 10% wt.). The reaction mixture was stirred at room temperature and pressure for 2h then the mixture was filtered and the filtrate concentrated to give intermediate 6b as a red mobile oil (2.43g, quant.).
1H NMR (400 MHz, DMSO-d6) δ 7.02 (s, 1H), 6.89 (s, 1H), 4.04 (t, J = 5.6 Hz, 2H), 3.77 (s, 2H), 3.62 (t, J = 5.6 Hz, 2H), 3.39 (q, J = 7.0 Hz, 2H), 1.07 (t, J = 7.0 Hz, 3H). [0106] Preparation of 1-(4-(6-bromopyridin-2-yl)phenyl)-3-tritylimidazolidin-2- one (6d). Prepared as for intermediate 3e above from 3d and 2,6-dibromopyridine 6c using Pd(PPh
3)
4 and Cs
2CO
3 in dioxane / water to afford 6d as a beige solid (680mg, 57%).
1H NMR (400 MHz, DMSO-d
6) δ 8.02 – 7.92 (m, 2H), 7.78 (t, J = 7.8 Hz, 1H), 7.64 – 7.49 (m, 4H), 7.46 – 7.39 (m, 6H), 7.33 (t, J = 7.7 Hz, 6H), 7.26 – 7.19 (m, 3H), 3.89 (dd, J = 8.6, 6.5 Hz, 2H), 3.47 (dd, J = 8.5, 6.6 Hz, 2H). [0107] Preparation of 1-(4-(6-((1-(2-ethoxyethyl)-1H-pyrazol-4-yl)amino)pyridin-2- yl)phenyl)imidazolidin-2-one (006). Compound 006 was then prepared as for 3f above from 6b and 6d using Pd2(dba)3, XantPhos, NaOtBu in dioxane to afford crude 6e. Treatment of crude 6e with a 1.25N solution of HCl in EtOH at 50°C for 2h as described for the preparation of compound 003 above afforded 006 as a beige powder (35mg, 17%).
1H NMR (300 MHz, DMSO-d6) δ 8.86 (s, 1H), 8.09 – 7.95 (m, 3H), 7.73 – 7.63 (m, 2H), 7.59 – 7.47 (m, 2H), 7.15 (d, J = 7.4 Hz, 1H), 7.04 (s, 1H), 6.58 (d, J = 8.2 Hz, 1H), 4.25 (t, J = 5.3 Hz, 2H), 3.91 (dd, J = 9.4, 6.6 Hz, 2H), 3.73, (t, J = 5.3 Hz, 2H), 3.45 (q, J = 7.0 Hz, 4H), 1.08 (t, J = 7.0 Hz, 3H).
Synthesis of Compound 007
Scheme 14 [0108] Preparation of 5-(4-iodophenyl)oxazole (7b). To a solution of 4-iodobenzaldehyde 7a (15.0g, 64.7mmol) in MeOH (150ml) were added K2CO3 (26.8g, 194mmol) and TosMIC (15.2g, 77.6mmol). The reaction mixture was stirred at room temperature for 16 hours. The mixture was evaporated to dryness, diluted with water and extracted with EtOAc twice. The combined organics were washed with water then with a saturated solution of NaCl, dried over MgSO
4, filtered and evaporated. The final product was purified by silica gel chromatography using 30 % EtOAc/cyclohexane as eluent to give intermediate 7b as a yellow solid (10.7g, 61%).
1H NMR (500 MHz, DMSO-d6) δ 8.47 (s, 1H), 7.86 (d, J = 8.4 Hz, 2H), 7.76 (s, 1H), 7.54 (d, J = 8.4 Hz, 2H). [0109] Preparation of 5-(4-iodophenyl)-2-chlorooxazole (7c). To a stirred solution of intermediate 7b (5.40g, 19.9mmol) in dry THF (55ml) was added a 1M solution of LiHMDS in THF (21.9ml, 21.9mmol) dropwise at -78°C. The reaction mixture was stirred at -78°C for 30mins then C
2Cl
6 (1.09g, 4.62mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with water and extracted with EtOAc twice. The combined organics were washed with water, then with a saturated aqueous solution of NaCl, dried over MgSO
4, filtered and evaporated. The final product was purified by silica gel chromatography using 0 to 20 % EtOAc/cyclohexane as eluent to give intermediate 7c (4.80g, 79%).
1H NMR (500 MHz, DMSO-d6) δ 7.87 (d, J = 8.6 Hz, 2H), 7.86 (s, 1H), 7.50 (d, J = 8.5 Hz, 2H).
[0110] Preparation of N-(1-(2-ethoxyethyl)-1H-pyrazol-4-yl)-5-(4-iodophenyl)oxazol- 2-amine (7d). To a solution of intermediate 7c (512mg, 1.68mmol) in dry iPrOH (6 ml) were added intermediate 6b (260mg, 1.68mmol) and a 1M aqueous solution of HCl (400 µl, 0.400mmol) and the mixture stirred at 80°C for 5h. The cooled mixture was evaporated to dryness, diluted with water and extracted with EtOAc twice. The combined organics were dried over MgSO4, filtered and evaporated. The final product was purified by silica gel chromatography using EtOAc/MeOH as eluent to give intermediate 7d (78mg, 11%).
1H NMR (500 MHz, DMSO-d6) δ 9.98 (s, 1H), 7.83 (s, 1H), 7.77 (d, J = 8.5 Hz, 2H), 7.46 (d, J = 13.2 Hz, 2H), 7.35 (d, J = 8.5 Hz, 2H), 4.22 (t, J = 5.5 Hz, 2H), 3.71 (t, J = 5.5 Hz, 2H), 3.43 (q, J = 7.0 Hz, 2H), 1.08 (t, J = 7.0 Hz, 3H). [0111] Preparation of 1-(4-(2-((1-(2-ethoxyethyl)-1H-pyrazol-4-yl)amino)oxazol-5- yl)phenyl)imidazolidin-2-one (007). In a sealed tube, to a solution of 7d (78mg, 0.184mmol) in dry dioxane (2.3mL) were added successively 2-imidazolidinone 3a (159mg, 1.84mmol), cesium carbonate (132mg, 0.405mmol) and XantPhos (21mg, 0.037mmol). The reaction mixture was degassed with nitrogen for 20 minutes before the addition of Pd2(dba)3 (14mg, 0.015mmol). The reaction mixture was stirred at 110°C for 16 hours, then the cooled mixture was diluted with water and extracted with EtOAc. The combined organics were washed with a saturated solution of NaHCO
3 then brine, dried over MgSO
4, filtered and evaporated. The final product was purified by silica gel chromatography using 0 to 10 % MeOH/EtOAc as eluent to give compound 007 as beige powder (9mg, 13%).
1H NMR (500 MHz, DMSO-d6) δ 9.86 (s, 1H), 7.83 (s, 1H), 7.62 (d, J = 8.7 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H), 7.43 (s, 1H), 7.25 (s, 1H), 7.00 (s, 1H), 4.22 (t, J = 5.5 Hz, 2H), 3.90 – 3.85 (m, 2H), 3.71 (t, J = 5.5 Hz, 2H), 3.46 – 3.35 (m, 4H), 1.09 (t, J = 7.0 Hz, 3H).
Synthesis of Compound 008
Scheme 15 [0112] Preparation of 1-(1-(2-ethoxyethyl)-1H-pyrazol-4-yl)thiourea (8a). To a solution of ammonium thiocyanate (497mg, 6.53mmol) in acetone (8ml) was added dropwise at room temperature benzoyl chloride (690µl, 5.94mmol). The reaction mixture was stirred for 20mins at 70°C then a solution of intermediate 6b (922mg, 5.94mmol) in acetone (9ml) was added and the reaction mixture was stirred at 70°C for a further 20mins. The mixture was evaporated, water was added and the mixture extracted with EtOAc. The combined organics were washed with brine then dried over MgSO
4, filtered and evaporated. The residue was dissolved in MeOH (17ml), treated with potassium carbonate (1.60g, 11.9mmol) and stirred at room temperature for 18h. Methanol was removed under reduced pressure and the residue was treated with water and extracted with EtOAc. The combined organics were dried over MgSO
4, filtered and evaporated to give intermediate 8a (151mg, 12%).
1H NMR (500 MHz, DMSO-d6) δ 9.32 (s, 1H), 7.86 (s, 2H), 7.41 (s, 1H), 7.24 (s, 1H), 4.18 (t, J = 5.5 Hz, 2H), 3.70 (t, J = 5.5 Hz, 2H), 3.42 (q, J = 7.0 Hz, 2H), 1.08 (t, J = 7.0 Hz, 3H). [0113] Preparation of 4-(4-bromophenyl)-N-(1-(2-ethoxyethyl)-1H-pyrazol-4- yl)thiazol-2-amine (8b). To a solution of 2,4'-dibromoacetophenone 8c (196mg, 0.705mmol) in EtOH (30ml) were added intermediate 8a (151mg, 0.75mmol) and potassium hydrogen carbonate (212mg, 2.11mmol). The reaction mixture was stirred at
80°C for 16 h, then the cooled mixture was evaporated, diluted with water and extracted with EtOAc. The combined organics were washed with brine then dried over MgSO
4, filtered and evaporated. The residue was purified by silica gel chromatography using EtOAc as eluent to give intermediate 8b as a beige powder (116mg, 42%).
1H NMR (500 MHz, DMSO-d
6) δ 9.94 (s, 1H), 8.01 (s, 1H), 7.91 – 7.83 (m, 2H), 7.63 – 7.58 (m, 2H), 7.51 (s, 1H), 7.30 (s, 1H), 4.26 (t, J = 5.4 Hz, 2H), 3.73 (t, J = 5.4 Hz, 2H), 3.45 (q, J = 7.0 Hz, 2H), 1.10 (t, J = 7.0 Hz, 3H). [0114] Preparation of 1-(4-(2-((1-(2-ethoxyethyl)-1H-pyrazol-4-yl)amino)thiazol-4- yl)phenyl)imidazolidin-2-one (008). In a sealed tube, to a solution of 8b (116mg, 0.295mmol) in dry dioxane (4 mL) were added successively 2-imidazolidinone 3a (254mg, 2.95mmol), cesium carbonate (211mg, 0.649mmol), XantPhos (34mg, 0.059mmol). The reaction mixture was degassed with nitrogen for 20 minutes before the addition of Pd2(dba)3 (22mg, 0.024mmol). The reaction mixture was stirred at 110°C for 16 h, then the cooled mixture was diluted with water and extracted with EtOAc. The combined organics were washed with a saturated solution of NaHCO
3, then brine and dried over MgSO4, filtered and evaporated. The final product was purified by silica gel chromatography using 0 to 20% MeOH in EtOAc as eluent to give intermediate compound 008 (38 mg, 32%).
1H NMR (500 MHz, DMSO-d6 δ 9.88 (s, 1H), 8.04 (s, 1H), 7.85 (d, J = 8.9 Hz, 2H), 7.60 (d, J = 8.9 Hz, 2H), 7.48 (s, 1H), 7.07 (s, 1H), 6.97 (s, 1H), 4.26 (t, J = 5.4 Hz, 2H), 3.94 – 3.86 (m, 2H), 3.73 (t, J = 5.4 Hz, 2H), 3.44 (p, J = 8.0, 7.5 Hz, 4H), 1.10 (t, J = 7.0 Hz, 3H).
Synthesis of Compound 009
Scheme 16 [0115] Preparation of 1-(2-ethoxyethyl)-4-isothiocyanato-1H-pyrazole (9a). A solution of intermediate 6b (800mg, 5.1 mmol) and thiocarbonyldiimidazole 9b (1.01g, 5.6 mmol) in dry DMF (15ml) was stirred at room temperature for 16 hours. The solvent was evaporated and the residue purified by silica gel chromatography using 50 % EtOAc in cyclohexane to give intermediate 9a (520mg, 51%).
1H NMR (500 MHz, Chloroform-d) δ 7.54 (s, 2H), 4.28 (t, J = 5.7 Hz, 2H), 3.80 (t, J = 5.6 Hz, 2H), 3.49 (q, J = 7.0 Hz, 2H), 1.17 (t, J = 7.0 Hz, 3H). [0116] Preparation of 3-(4-bromophenyl)-N-(1-(2-ethoxyethyl)-1H-pyrazol-4-yl)-1,2,4- thiadiazol-5-amine (9d). A solution of intermediate 9a (520mg, 2.64mmol), 4- bromobenzamidine hydrochloride 9c (1.24g, 5.27mmol) and dry Et
3N (767µl, 5.27mmol) in dry DMF (15 ml) was stirred at room temperature for 16 hours. DIAD (572µl, 2.90mmol) was added and the mixture was stirred at RT for a further 16 hours. Water was added and the crude product was extracted with EtOAc. The combined organics were washed with a saturated aqueous solution of NaHCO
3, then with water and then with brine and dried over MgSO4, filtered and evaporated. The residue was purified by silica gel chromatography using 30 to 50 % EtOAc/cyclohexane as eluent to give intermediate 9d (500mg, 48%).
1H NMR (500 MHz, Chloroform-d) δ 8.06 (d, J = 8.5 Hz, 2H), 7.80 (s, 2H), 7.59 (d, J = 8.5 Hz, 2H), 4.36 (t, J = 5.7 Hz, 2H), 3.86 (t, J = 5.7 Hz, 2H), 3.52 (q, J = 7.0 Hz, 2H), 1.19 (t, J = 7.0 Hz, 3H).
[0117] Preparation of 1-(4-(5-((1-(2-ethoxyethyl)-1H-pyrazol-4-yl)amino)-1,2,4- thiadiazol-3-yl)phenyl)-3-tritylimidazolidin-2-one (9e). In a sealed tube, to a solution of intermediate 9d (500mg, 1.27mmol) in dry dioxane (10mL) were added successively intermediate 3b (500mg, 1.52mmol), cesium carbonate (828mg, 2.54mmol) and XantPhos (69mg, 0.12mmol). The reaction mixture was degassed with nitrogen for 20 minutes before the addition of Pd2(dba)3 (5 mg, 0.06mmol). The tube was sealed and the mixture was stirred at 110°C for 16 hours. The cooled mixture was diluted with water and extracted with EtOAc twice. The combined organics were washed with water then with a saturated solution of NaCl and dried over MgSO
4, filtered and evaporated. The residue was purified by silica gel chromatography using 60 to 90 % EtOAc/cyclohexane as eluent to give intermediate 9e (440 mg, 53%).
1H NMR (500 MHz, Chloroform-d) δ 8.09 (d, J = 8.8 Hz, 2H), 7.78 (s, 2H), 7.57 (d, J = 8.8 Hz, 2H), 7.52 – 7.44 (m, 8H), 7.35 – 7.28 (m, 4H), 7.26 – 7.20 (m, 8H), 3.84 (d, J = 6.4 Hz, 2H), 3.54 (d, J = 7.2 Hz, 2H), 3.52 – 3.49 (m, 4H), 3.41 – 3.35 (m, 2H), 1.18 (t, J = 7.0 Hz, 3H). [0118] Preparation of 1-(4-(5-((1-(2-ethoxyethyl)-1H-pyrazol-4-yl)amino)-1,2,4- thiadiazol-3-yl)phenyl)imidazolidin-2-one (009). To a solution of intermediate 9e (440mg, 0.69mmol) in DCM (20 ml) was added dropwise TFA (5.0ml). The reaction mixture was stirred at RT for 16 hours. The solvent was evaporated, a saturated solution of NaHCO
3 was added and the crude product was extracted with DCM. The combined organics were washed with water then with brine, then dried over MgSO4, filtered and evaporated. The reaction mixture was triturated with DCM and filtered. The resulting solid was purified by silica gel chromatography using 5 % MeOH/DCM as eluent to give compound 009 (110mg, 40%).
1H NMR (500 MHz, Chloroform-d) δ 8.17 (d, J = 8.7 Hz, 2H), 7.80 (s, 2H), 7.67 (d, J = 8.7 Hz, 2H), 4.36 (t, J = 5.6 Hz, 2H), 4.05 – 4.00 (m, 2H), 3.86 (t, J = 5.7 Hz, 2H), 3.67 – 3.62 (m, 2H), 3.51 (q, J = 7.0 Hz, 2H), 1.19 (t, J = 7.0 Hz, 3H).
Synthesis of Compound 010
Scheme 17 [0119] Preparation of 1-(2-methoxyethyl)-3-methyl-4-nitro-1H-pyrazole (10b). A solution of 4-nitro-3-methyl-1H-pyrazole 10a (6.00g, 47.2mmol), 1-bromo-2- methoxyethane (6.66ml, 70.8mmol) and potassium carbonate (13.0g, 94.4mmol) in dry butan-2-one (180ml) was stirred at 80°C for 16h. The solvent was evaporated then water was added and the crude product was extracted with EtOAc. The combined organics were washed with water then with brine and dried over MgSO
4, filtered and evaporated. The residue was purified by silica gel chromatography using 0 to 70 % EtOAc/cyclohexane to give intermediate 10b as a colorless oil (8.30g, 95%).
1H NMR (400 MHz, DMSO-d6) δ 8.76 (s, 1H), 4.27 (t, J = 5.2 Hz, 2H), 3.73 – 3.66 (m, 2H), 3.24 (s, 3H), 2.43 (s, 3H). [0120] Preparation of 1-(2-methoxyethyl)-3-methyl-1H-pyrazol-4-amine (10c). To a solution of intermediate 10b (8.30g, 44.8mmol) in EtOH (200ml), was added 10% palladium on carbon (830mg). Hydrazine monohydrate (5.40ml, 111mmol) was added dropwise at 0°C. The reaction mixture was stirred at room temperature for 2 hours and at 60°C for 16 hours. The hot mixture was then filtered over Celite
® and washed with ethanol. The filtrate was concentrated to give intermediate 10c as a red oil (7.10g) which was used directly in the next step.
1H NMR (400 MHz, DMSO-d
6) δ 6.95 (s, 1H), 3.98 (t, J = 5.5 Hz, 2H), 3.56 (td, J = 5.5, 1.8 Hz, 2H), 3.51 (s, 2H), 3.22 (s, 3H), 1.99 (s, 3H). [0121] Preparation of 4-iodo-N-((1-(2-methoxyethyl)-3-methyl-1H-pyrazol-4- yl)carbamothioyl)benzamide (10e). A solution of ammonium thiocyanate (3.83g,
50.3mmol) and 4-iodobenzoyl chloride 10d (12.8g, 48.0mmol) in acetone (50ml) was stirred at 70°C for 30mins then treated with a solution of intermediate 10c (7.10g, 45.8mmol) in acetone (40ml). After stirring for 1h at 70°C, the mixture was evaporated then water was added and the solid was filtered, washed with water and cyclohexane. The solid was solubilized in a small amount of DCM and MTBE was added until a solid formed. The solid was filtered, then dried under vacuum to give intermediate 10e as a white powder (2.60g, 13%).
1H NMR (400 MHz, DMSO-d6) δ 12.57 (s, 1H), 11.67 (s, 1H), 8.43 (s, 1H), 7.93 (d, J = 8.5 Hz, 2H), 7.75 (d, J = 8.5 Hz, 2H), 4.19 (t, J = 5.3 Hz, 2H), 3.66 (t, J = 5.3 Hz, 2H), 3.24 (s, 3H), 2.18 (s, 3H). [0122] Preparation of 1-(1-(2-methoxyethyl)-3-methyl-1H-pyrazol-4-yl)thiourea (10f). A solution of intermediate 10e (2.60g, 5.85mmol) with potassium carbonate (1.62g, 11.7mmol) in MeOH (15ml) was stirred at room temperature for 3 hours. Methanol was removed under reduced pressure and the residue was treated with water and extracted with EtOAc. The combined organics were washed with brine, then dried over MgSO4, filtered and evaporated and the residue triturated with ether to give intermediate 10f as a white powder (1.10g, 87%).
1H NMR (500 MHz, DMSO-d6) δ 8.89 (s, 1H), 7.68 – 7.56 (m, 2H), 6.59 (s, 1H), 4.11 (t, J = 5.5 Hz, 2H), 3.64 (t, J = 5.5 Hz, 2H), 3.23 (s, 3H), 2.02 (s, 3H). [0123] Preparation N-(1-(2-methoxyethyl)-3-methyl-1H-pyrazol-4-yl)-4-(4- nitrophenyl)thiazol-2-amine (10h). To a solution of 2-bromo-4’-nitroacetophenone 10g (512mg, 2.10mmol) in EtOH (10ml) were added intermediate 10f (450mg, 2.10mmol) and potassium hydrogen carbonate (631mg, 6.30mmol). The reaction mixture was stirred at 80°C for 4 hours. The cooled mixture was evaporated to dryness, diluted with water and extracted with EtOAc. The combined organics were dried over MgSO4, filtered and evaporated to give intermediate 10h as a brown solid (723mg, 96%).
1H NMR (400 MHz, DMSO-d6) δ 9.49 (s, 1H), 8.27 (d, J = 9.0 Hz, 2H), 8.14 (d, J = 9.0 Hz, 2H), 8.07 (s, 1H), 7.58 (s, 1H), 4.20 (t, J = 5.4 Hz, 2H), 3.68 (t, J = 5.4 Hz, 2H), 3.27 (s, 3H), 2.15 (s, 3H). [0124] Preparation of 4-(4-aminophenyl)-N-(1-(2-methoxyethyl)-3-methyl-1H-pyrazol- 4-yl)thiazol-2-amine (10i). To a solution of intermediate 10h (723 mg, 2.01 mmol) in EtOH/DCM (18/9 ml), was added SnCl2.2H2O (2.60g, 11.5mmol) and the reaction
mixture was stirred at room temperature for 16 hours. Water was added and the mixture taken to a basic pH by addition of a 2.5M aqueous solution of NaOH. The crude product was extracted with DCM and the combined organics were washed with water and with brine then dried over MgSO4, filtered and evaporated to give intermediate 10i as a red powder (612mg, 92%).
1H NMR (400 MHz, DMSO-d
6) δ 9.19 (s, 1H), 8.03 (s, 1H), 7.55 (d, J = 8.5 Hz, 2H), 6.73 (s, 1H), 6.57 (d, J = 8.6 Hz, 2H), 5.18 (s, 2H), 4.18 (t, J = 5.3 Hz, 2H), 3.67 (t, J = 5.3 Hz, 2H), 3.27 (s, 3H), 2.13 (s, 3H). [0125] Preparation of 3-(4-(2-((1-(2-methoxyethyl)-3-methyl-1H-pyrazol-4- yl)amino)thiazol-4-yl)phenyl)oxazolidin-2-one (010). To a solution of intermediate 10i (300mg, 0.911mmol) in dry DCM (4.5ml) was added at RT triethylamine (380µl, 2.73mmol). 2-Chloroethyl chloroformate 10j (850µl, 0.819mmol) was then added dropwise at 0°C and the reaction mixture stirred at room temperature for 4 hours. Water was added and the crude product was extracted with DCM. The combined organics were dried over MgSO4, filtered and evaporated. The resulting product was then dissolved in dry THF (4.5 ml) and KOtBu (307 mg, 2.73 mmol) was added portion wise and the reaction mixture stirred at room temperature for 1.5 h. Water was added and the crude product was extracted with EtOAc. The combined organics were washed with water, with brine then dried over MgSO
4, filtered and evaporated. The residue was purified by silica gel chromatography using 0/60/40 to 10/90/0 % MeOH/EtOAc/cyclohexane to give compound 010 as a beige powder (80mg, 22%).
1H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 8.05 (s, 1H), 7.90 (d, J = 8.8 Hz, 2H), 7.61 (d, J = 8.8 Hz, 2H), 7.12 (s, 1H), 4.50 – 4.41 (m, 2H), 4.19 (t, J = 5.3 Hz, 2H), 4.14 – 4.05 (m, 2H), 3.67 (t, J = 5.3 Hz, 2H), 3.26 (s, 3H), 2.14 (s, 3H).
Synthesis of Compound 011
Scheme 18 [0126] Preparation of 1-(4-bromophenyl)-3-((1-(2-ethoxyethyl)-1H-pyrazol-4- yl)amino)-3-(methylthio)prop-2-en-1-one (11a). To a solution of intermediate 6b (580mg, 3.74mmol) in dry DCM (30ml) were added dropwise successively at 0°C DIPEA (2.0ml, 11.2mmol) and thiophosgene (280µl, 3.74mmol). The reaction mixture was stirred at room temperature for 30mins then water was added and the crude product was extracted with DCM. The combined organics were washed with water then dried over MgSO4, filtered and evaporated. The residue was then dissolved in dry DMF (17ml) and added to a solution which had been previously prepared by the treatment of a solution of 4’-bromoacetophenone 11b (744mg, 3.74mmol) in dry DMF (10ml) with NaH (60% in oil) (179mg, 4.48mmol) at 0°C. The reaction mixture was stirred at RT for 45 mins then iodomethane (230µl, 3.74mmol) was added dropwise at 0°C and the reaction mixture was stirred at RT for 45 mins. Water was added and the crude product was extracted with EtOAc. The combined organics were washed with sat. aqu. NaHCO3 solution and with brine then dried over MgSO4, filtered and evaporated. The product was purified by silica gel chromatography using 0 to 50 % EtOAc/cyclohexane as eluent to give intermediate 11a as a brown oil (374mg, 25%).
1H NMR (500 MHz, DMSO-d
6) δ 13.15 (s, 1H), 7.90 (d, J = 8.8 Hz, 3H), 7.67 (d, J = 8.5 Hz, 2H), 7.54 (s, 1H), 5.94 (s, 1H), 4.24 (t, J = 5.4
Hz, 2H), 3.73 (t, J = 5.4 Hz, 2H), 3.42 (q, J = 7.0 Hz, 2H), 2.53 (s, 3H), 1.08 (t, J = 7.0 Hz, 3H). [0127] Preparation of 5-(4-bromophenyl)-N-(1-(2-ethoxyethyl)-1H-pyrazol-4-yl)-1H- pyrazol-3-amine (11c). To a solution of intermediate 11a (374mg, 0.910mmol) in isopropanol (9.5ml) was added hydrazine monohydrate (50µl, 1.03mmol) and the mixture stirred at 83°C for 4 hours. The solvent was evaporated and the product was purified by silica gel chromatography using 0 to 100 % EtOAc/cyclohexane as eluent to give intermediate 11c as a beige powder (291mg, 85%).
1H NMR (500 MHz, DMSO-d
6) δ 12.18 (s, 1H), 7.95 (s, 1H), 7.70 – 7.66 (m, 3H), 7.62 (d, J = 8.6 Hz, 2H), 7.32 (s, 1H), 6.08 (s, 1H), 4.17 (t, J = 5.5 Hz, 2H), 3.70 (t, J = 5.5 Hz, 2H), 3.43 (q, J = 7.0 Hz, 2H), 1.09 (t, J = 7.0 Hz, 3H). [0128] Preparation of 1-(4-(3-((1-(2-ethoxyethyl)-1H-pyrazol-4-yl)amino)-1H-pyrazol- 5-yl)phenyl)-3-tritylimidazolidin-2-one (11d). In a sealed tube, to a solution of intermediate 11c (291mg, 0.773mmol) in dry NMP (7.5ml) were added successively intermediate 3b (762mg, 2.32mmol), cesium carbonate (630mg, 1.93mmol) and XantPhos (90mg, 0.155mmol). The reaction mixture was degassed with nitrogen for 20 minutes before the addition of Pd2(dba)3 (57mg, 0.062mmol) and the tube sealed and heated to 130°C for 16 hours. The cooled mixture was diluted with water and extracted with EtOAc. The combined organics were washed with water, dried over MgSO
4, filtered and evaporated. The residue was purified by preparative silica gel plate chromatography using 100 % EtOAc as eluent to give intermediate 11d as a beige powder (35 mg, 7%).
1H NMR (500 MHz, DMSO-d
6) δ 7.86 (s, 1H), 7.66 (s, 1H), 7.60 (d, J = 8.7 Hz, 2H), 7.48 (d, J = 8.6 Hz, 2H), 7.45 – 7.40 (m, 7H), 7.35 – 7.29 (m, 8H), 7.24 (d, J = 7.3 Hz, 3H), 4.16 (t, J = 5.5 Hz, 2H), 3.85 (t, J = 7.6 Hz, 2H), 3.69 (t, J = 5.5 Hz, 2H), 3.48 – 3.39 (m, 4H), 1.09 (t, J = 7.0 Hz, 3H). [0129] Preparation of 1-(4-(3-((1-(2-ethoxyethyl)-1H-pyrazol-4-yl)amino)-1H-pyrazol- 5-yl)phenyl)imidazolidin-2-one (011). To a solution of intermediate 11d (35mg, 0.056mmol) in DCM (2ml) was added dropwise TFA (100µl). The reaction mixture was stirred at room temperature for 4 hours. The mixture was made basic with a 2.5M aqueous solution of NaOH and the crude product was extracted with DCM. The combined
organics were washed with brine then dried over MgSO4, filtered and evaporated. The residue was purified by preparative silica gel plate chromatography using 10 % MeOH/DCM as eluent to give compound 011 as a white powder (3mg, 14%).
1H NMR (500 MHz, DMSO-d6) δ 12.08 (s, 1H), 7.85 (s, 1H), 7.71 – 7.59 (m, 5H), 7.31 (s, 1H), 7.00 (s, 1H), 5.97 (s, 1H), 4.16 (t, J = 5.5 Hz, 2H), 3.91 – 3.85 (m, 2H), 3.70 (t, J = 5.8 Hz, 2H), 3.45 – 3.41 (m, 4H), 1.09 (t, J = 7.0 Hz, 3H). Synthesis of Compound 012
Scheme 19 [0130] Preparation of 1-(4-(2-((1-(2-methoxyethyl)-3-methyl-1H-pyrazol-4- yl)amino)thiazol-4-yl)phenyl)pyrrolidin-2-one (012). To a solution of intermediate 10i (312mg, 0.947mmol) and HATU (360mg, 0.947mmol) in dry DMF (10 ml) at RT were added 4-chlorobutyric acid 12a (100µl, 0.947mmol) and triethylamine (263µl, 1.89mmol). The reaction mixture was stirred at room temperature for 4h then water was added and the crude product extracted with DCM. The combined organics were washed with a saturated solution of NaHCO3 twice, then with water and with brine then dried over MgSO4, filtered and evaporated. The resulting product was dissolved in dry THF (5 ml) and treated with KOtBu (319mg, 2.84mmol) portionwise and the reaction mixture was stirred at room temperature for 1.5h. Water was added and the crude product was extracted with EtOAc. The combined organics were washed with brine then dried over MgSO
4, filtered and evaporated. The residue was purified by silica gel chromatography using 0/60/40 to 10/90/0 % MeOH/EtOAc/cyclohexane to give compound 012 as an orange solid (214mg, 57%).
1H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 8.05 (s, 1H), 7.88 (d, J = 8.8 Hz, 2H), 7.70 (d, J = 8.8 Hz, 2H), 7.11 (s, 1H), 4.19 (t, J = 5.3 Hz, 2H), 3.87 (t, J = 7.0 Hz, 2H), 3.67 (t, J = 5.3 Hz, 2H), 3.26 (s, 3H), 2.14 (s, 3H), 2.09 (q, J = 7.4 Hz, 2H).
Synthesis of Compound 013
Scheme 20 [0131] Preparation of 1-(3-methoxypropyl)-3-methyl-4-nitro-1H-pyrazole (13a). A solution of 4-nitro-3-methyl-1H-pyrazole 10a (2.00g, 15.7mmol), 3-bromo-1- methoxypropane (2.60ml, 23.1mmol) and potassium carbonate (4.30g, 31.1mmol) in dry butan-2-one (60 ml) was stirred at 80°C for 16 hours. The cooled mixture was evaporated then water was added and the crude product was extracted with EtOAc. The combined organics were washed with brine, dried over MgSO
4, filtered and evaporated. The final product was purified by silica gel chromatography using 0 to 60 % EtOAc/cyclohexane to give a mixture of regioisomers 13a and 13b as a yellow oil (2.70g, 86% overall yield). 13a :
1H NMR (400 MHz, DMSO-d
6) δ 8.78 (s, 1H), 4.16 (m, 2H), 3.30 (m, 2H), 3.22 (s, 3H), 2.42 (s, 3H), 2.08 – 1.92 (m, 2H). [0132] Preparation of 1-(3-methoxypropyl)-3-methyl-1H-pyrazol-4-amine (13c). To a solution of a mixture of regioisomers 13a and 13b (2.70g, 13.6mmol) in EtOH (50 ml),
was added 10% Pd/C (1.0g) then hydrazine monohydrate (1.80ml, 36.6mmol) was added dropwise at 0°C. The reaction mixture was stirred at 0°C for 20 mins then at RT for 30 mins. The mixture was filtered over a Celite® pad and washed with ethanol. The filtrate was concentrated to give a crude mixture of regioisomers 13c and 13d as a colorless oil (2.40g) which used directly for the next step. 13c :
1H NMR (400 MHz, DMSO-d6) δ 6.92 (s, 1H), 3.86 (m, 2H), 3.52 (br s, 2H), 3.25 (m, 2H), 3.21 (s, 3H), 1.98 (s, 3H), 1.87 (m, 2H). [0133] Preparation of 4-iodo-N-((1-(3-methoxypropyl)-3-methyl-1H-pyrazol-4- yl)carbamothioyl) benzamide (13e). A solution of ammonium thiocyanate (1.18g, 15.8mmol) and 4-iodobenzoyl chloride 10d (3.97g, 14.9mmol) in acetone (18ml) was stirred at 70°C for 30mins. Then a solution of mixture of intermediates 13c and 13d (2.40g, 14.2mmol) in acetone (18 ml) was added and the mixture was stirred at 70°C for a further 30mins. The mixture was evaporated then water was added and the mixture extracted with EtOAc. The combined organics were washed with brine then dried over MgSO
4, filtered and evaporated. The final product was purified by silica gel chromatography using 0 to 50 % EtOAc in cyclohexane as eluent to give intermediate 13e as a white powder (1.90g, 29%).
1H NMR (400 MHz, DMSO-d6) δ 12.56 (s, 1H), 11.56 (s, 1H), 8.39 (s, 1H), 7.93 (m, 2H), 7.75 (m, 2H), 4.08 (t, J = 6.7 Hz, 2H), 3.28 (m, 2H), 3.24 (s, 3H), 2.18 (s, 3H), 2.02 – 1.92 (m, 2H). [0134] Preparation of 1-(1-(3-methoxypropyl)-3-methyl-1H-pyrazol-4-yl)thiourea (13f). A solution of intermediate 13e (1.90g, 4.15mmol) with potassium carbonate (1.15g, 8.29mmol) in MeOH (50ml) was stirred at room temperature for 18h. The solvent was evaporated and the solid treated with water and extracted with DCM. The combined organics were dried over MgSO4, filtered and evaporated then triturated with cyclohexane then ether to give intermediate 13f as a white powder (760mg, 80%).
1H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 1H), 7.66 (br s, 2H), 7.31 (br s, 1H), 6.65 (br s, 1H), 3.99 (t, J = 7.0 Hz, 2H), 3.29 (m, 2H), 3.23 (s, 3H), 2.02 (s, 3H), 1.99 – 1.91 (m, 2H). [0135] Preparation of 4-(4-bromo-2-fluorophenyl)-N-(1-(3-methoxypropyl)-3-methyl- 1H-pyrazol-4-yl)thiazol-2-amine (13h). To a solution of 2-bromo-1-(4-bromo-2- fluorophenyl)ethan-1-one 13g (259mg, 0.876mmol) in EtOH (20 ml) were added
intermediate 13f (200mg, 0.876mmol) and potassium hydrogen carbonate (263mg, 2.63mmol). The reaction mixture was stirred at 80°C for 18h then the cooled mixture was evaporated to dryness, diluted with water and extracted with EtOAc. The combined organics were washed with brine then dried over MgSO4, filtered and evaporated. The final product was purified by silica gel chromatography using 0 to 100 % EtOAc as eluent to give intermediate 13h as an oil (127mg, 34%).
1H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 8.03 (t, J = 8.5 Hz, 1H), 7.98 (s, 1H), 7.62 (dd, J = 11.2 Hz, 2.0 Hz, 1H), 7.50 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 7.14 (d, J = 2.6 Hz, 1H), 4.07 (t, J = 6.9 Hz, 2H), 3.29 (t, J = 6.0 Hz, 2H), 3.24 (s, 3H), 2.14 (s, 3H), 1.18 (t, J = 7.1 Hz, 2H). [0136] Preparation of 1-(3-fluoro-4-(2-((1-(3-methoxypropyl)-3-methyl-1H-pyrazol-4- yl)amino) thiazol-4-yl)phenyl)-3-tritylimidazolidin-2-one (13i). In a sealed tube, to a solution of intermediate 13h (127mg, 0.299mmol) in dry NMP (3.5ml) were added successively intermediate 3b (108mg, 0.328mmol), cesium carbonate (243mg, 0.748mmol) and XantPhos (35mg, 0.060mmol). The reaction mixture was degassed with nitrogen for 20 minutes before the addition of Pd
2(dba)
3 (22mg, 0.024mmol) then stirred at 130°C for 18h. The cooled mixture was diluted with water and extracted with EtOAc. The combined organics were washed with water then dried over MgSO4, filtered and evaporated. The final product was purified by silica gel chromatography using 0 to 100 % EtOAc in cyclohexane as eluent to give intermediate 13i as a white powder (88mg, 44%).
1H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 8.02 – 7.95 (m, 2H), 7.42 (d, J = 7.9 Hz, 6H), 7.34 (t, J = 7.4 Hz, 7H), 7.24 (t, J = 7.2 Hz, 4H), 6.95 (d, J = 2.2 Hz, 1H), 4.06 (t, J = 6.6 Hz, 2H), 3.87 (t, J = 7.4 Hz, 2H), 3.47 (t, J = 7.5 Hz, 2H), 3.29 (s, 2H), 3.23 (s, 3H), 2.13 (s, 3H), 2.00 – 1.93 (m, 2H). [0137] Preparation of 1-(3-fluoro-4-(2-((1-(3-methoxypropyl)-3-methyl-1H-pyrazol-4- yl)amino)thiazol-4-yl)phenyl)imidazolidin-2-one (013). To a solution of intermediate 13i (88mg, 0.131mmol) in DCM (2 ml) was added dropwise TFA (110µl, 1.44mmol) and the mixture was stirred at room temperature for 3h. The mixture was stirred with a saturated solution of NaHCO
3 for 1h then extracted with DCM and washed with brine. The combined organics were dried over MgSO
4, filtered and evaporated and the residue was purified by preparative silica gel plate chromatography using 5/95% MeOH/DCM to give
compound 013 as a beige powder (36mg, 64%).
1H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 8.04 – 7.97 (m, 2H), 7.64 (dd, J = 15.0, 2.1 Hz, 1H), 7.36 (dd, J = 8.8, 2.1 Hz, 1H), 7.15 (s, 1H), 6.95 (d, J = 2.4 Hz, 1H), 4.08 (t, J = 6.9 Hz, 2H), 3.93 – 3.86 (m, 2H), 3.47 – 3.40 (m, 2H), 3.29 (d, J = 6.2 Hz, 2H), 3.24 (s, 3H), 2.14 (s, 3H), 2.01 – 1.94 (m, 2H). Synthesis of Compound 014
[0138] Preparation of 1-(3-methoxypropyl)-4-nitro-3-(trifluoromethyl)-1H- pyrazole (14b). A solution of 4-nitro-3-(trifluoromethyl)-1H-pyrazole 14a (1.00g, 5.52mmol) in MeCN (20ml) was treated with K
2CO
3 (1.72g, 12.4mmol) and 1-bromo-3- methoxypropane (621µl, 5.52mmol) and heated to 80°C for 4h. Water was added and the mixture extracted with DCM. The combined organics were dried over MgSO4, filtered and evaporated to give 14b as an orange oil (1.32g, 94%). 1H NMR (400 MHz, DMSO- d6) δ 9.17 (s, 1H), 4.31 (t, J = 7.1 Hz, 2H), 3.34 (t, J = 6.0 Hz, 2H), 3.21 (s, 3H), 2.07 (p, J = 6.4 Hz, 2H). [0139] Preparation of 1-(3-methoxypropyl)-3-(trifluoromethyl)-1H-pyrazol-4- amine (14c). A solution of intermediate 14b (1.31g, 5.17mmol) in EtOH was treated with 10% palladium on carbon (130mg) and stirred under an atmosphere of hydrogen at room
temperature and pressure overnight. The mixture was filtered and evaporated to give 14c as a black crystalline solid (979mg, 85%)
1H NMR (400 MHz, DMSO-d
6) δ 7.21 (s, 1H), 4.21 (s, 2H), 4.04 (t, J = 7.0 Hz, 2H), 3.26 (t, J = 6.2 Hz, 2H), 3.22 (s, 3H), 1.94 (p, J = 6.6 Hz, 2H). [0140] Preparation of 2-(4-bromophenyl)pyrimidin-4-ol (14e). A mixture of 4-bromobenzimidamide hydrochloride 9c (5.00g, 21.2mmol) and K2CO3 (2.93g, 21.2mmol) in EtOH (100ml) was treated with ethyl propiolate 14d (2.16ml, 21.2mmol) and heated to reflux overnight. The mixture was cooled to RT and filtered and the filtrate concentrated to an orange slurry. To this mixture was added water (100ml) and 1M aqu HCl to pH2 and the solid removed by filtration. The solid was treated with THF and the solvent evaporated, then this procedure was repeated. The solid product was dried in the desiccator at 80°C to give 14e as a pale orange solid (4.63g, 87%).
1H NMR (400 MHz, DMSO-d6) δ 8.13 (d, J = 6.5 Hz, 1H), 8.11 – 8.02 (m, 2H), 7.81 – 7.65 (m, 2H), 6.41 (d, J = 6.5 Hz, 1H). [0141] Preparation of 2-(4-bromophenyl)-4-chloropyrimidine (14f). A mixture of intermediate 14e (4.60g, 18.3mmol) in POCl3 (50ml) was heated to reflux for 1h. The cooled mixture was evaporated and the residue treated with water and extracted with DCM. The combined organics were dried over MgSO
4, filtered and evaporated then purified by column chromatography on SiO
2 (Puriflash) eluting with 0-10% EtOAc in cyclohexane to give 14f as a yellow solid (3.06g, 62%).
1H NMR (400 MHz, DMSO-d6) δ 8.95 – 8.83 (m, 1H), 8.31 – 8.20 (m, 2H), 7.80 – 7.71 (m, 2H), 7.71 – 7.59 (m, 1H). [0142] Preparation of 2-(4-bromophenyl)-N-(1-(3-methoxypropyl)-3-(trifluoromethyl)- 1H-pyrazol-4-yl)pyrimidin-4-amine (14g). A mixture of intermediate 14f (300mg, 1.11mmol) and 14c (248mg, 1.11mmol) in iPrOH (10ml) and c. HCl (5 drops) was heated in a sealed tube under argon overnight. The cooled mixture was treated with sat aqu NaHCO3 solution and extracted with DCM. The combined organics were dried over MgSO4, filtered and evaporated then purified by column chromatography on SiO2 (Puriflash) eluting with 10-50% EtOAc in cyclohexane to give 14g as a pale yellow gum (332mg, 66%).
1H NMR (400 MHz, DMSO-d
6) δ 9.07 (s, 1H), 8.35 (d, J = 5.9 Hz, 1H),
8.31 (s, 1H), 8.25 – 8.15 (m, 2H), 7.73 – 7.56 (m, 2H), 6.70 (s, 1H), 4.28 (t, J = 7.0 Hz, 2H), 3.35 (t, J = 6.1 Hz, 2H), 3.23 (s, 3H), 2.08 (p, J = 6.6 Hz, 2H). [0143] Preparation of 1-(4-(4-((1-(3-methoxypropyl)-3-(trifluoromethyl)-1H-pyrazol-4- yl)amino)pyrimidin-2-yl)phenyl)-3-tritylimidazolidin-2-one (14h). Intermediate 14h was prepared as for intermediate 9e above from 14g with intermediate 3b, Pd
2(dba)
3, XantPhos and Cs2CO3 in dioxane (409mg, 83%).
1H NMR (400 MHz, DMSO-d6) δ 8.96 (s, 1H), 8.39 – 8.27 (m, 2H), 8.25 – 8.09 (m, 2H), 7.59 – 7.52 (m, 2H), 7.45 – 7.38 (m, 6H), 7.38 – 7.30 (m, 6H), 7.30 – 7.14 (m, 4H), 4.27 (t, J = 6.9 Hz, 2H), 3.87 (dd, J = 8.6, 6.5 Hz, 2H), 3.46 (dd, J = 8.5, 6.5 Hz, 2H), 3.33 (t, J = 6.1 Hz, 2H), 3.21 (s, 3H), 2.14 – 2.01 (m, 2H). [0144] Preparation of 1-(4-(4-((1-(3-methoxypropyl)-3-(trifluoromethyl)-1H-pyrazol-4- yl)amino)pyrimidin-2-yl)phenyl)imidazolidin-2-one (014). Compound 014 was prepared as for compound 013 above from 14h and TFA in DCM (158mg, 60%).
1H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.34 (s, 1H), 8.31 (d, J = 5.7 Hz, 1H), 8.23 (d, J = 8.7 Hz, 2H), 7.71 – 7.63 (m, 2H), 7.06 (s, 1H), 6.65 (s, 1H), 4.29 (t, J = 6.9 Hz, 2H), 3.90 (dd, J = 9.2, 6.7 Hz, 2H), 3.43 (t, J = 8.0 Hz, 2H), 3.35 (t, J = 6.1 Hz, 2H), 3.24 (s, 3H), 2.08 (p, J = 6.6 Hz, 2H). By repeating the methods described above using the appropriate starting materials and conditions, as well as the general knowledge in the art, the additional analogues compounds shown in Table 1 hereinabove and listed in Table 2 below were prepared and characterized. Example 1-3: Analytical data for synthetized compounds [0145] The analytical data for the final compounds are presented on the following Table 2. Table 2 Ex # Name (IUPAC) LC-MS or NMR 1-(4-(4-((1-(2-methoxyethyl)-1H-pyrazol- m/z 380.1 (M+H) 001 4-yl)amino)pyrimidin-2- tR = 1.11 mins yl)phenyl)imidazolidin-2-one Method B
Ex # Name (IUPAC) LC-MS or NMR 1-(4-(4-((1-methyl-1H-pyrazol-4- m/z 336.1 (M+H) 002 yl)amino)pyrimidin-2- t
R = 1.08 mins yl)phenyl)imidazolidin-2-one Method B 1-(4-(2-((1-(2-methoxyethyl)-1H-pyrazol- m/z 380.2 (M+H) 003 4-yl)amino)pyrimidin-4- tR = 1.30 mins yl)phenyl)imidazolidin-2-one Method B 1-(4-(4-((1-(3,5-dimethylbenzyl)-1H- m/z 440.2 (M+H) 004 pyrazol-4-yl)amino)pyrimidin-2- tR = 1.32 mins yl)phenyl)imidazolidin-2-one Method B 1-(4-(2-((1-(3,5-dimethylbenzyl)-1H- m/z 440.2 (M+H) 005 pyrazol-4-yl)amino)pyrimidin-4- tR = 1.56 mins yl)phenyl)imidazolidin-2-one Method B 1-(4-(6-((1-(2-propoxyethyl)-1H-pyrazol- m/z 393.2 (M+H) 006 4-yl)amino)pyridin-2- tR = 1.33 mins yl)phenyl)imidazolidin-2-one Method B 1-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol- m/z 383.1 (M+H) 007 4-ylamino]-oxazol-5-yl}-phenyl)- tR = 1.33 mins imidazolidin-2-one Method B 1-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol- m/z 399.2 (M+H) 008 4-ylamino]-thiazol-4-yl}-phenyl)- tR = 1.42 mins imidazolidin-2-one Method B 1-(4-(5-((1-(2-ethoxyethyl)-1H-pyrazol-4- m/z 434.2 (M+H) 009 yl)amino)-1,2,4-thiadiazol-3- t
R = 1.49 mins yl)phenyl)imidazolidin-2-one Method B 3-(4-{2-[1-(2-Methoxy-ethyl)-3-methyl- m/z 400.2 (M+H) 010 1H-pyrazol-4-ylamino]-thiazol-4-yl}- t
R = 1.40 mins phenyl)-oxazolidin-2-one Method B 1-(4-{5-[1-(2-Ethoxy-ethyl)-1H-pyrazol- m/z 382.3 (M+H) 011 4-ylamino]-2H-pyrazol-3-yl}-phenyl)- t
R = 1.26 mins imidazolidin-2-one Method B 1-(4-{2-[1-(2-Methoxy-ethyl)-3-methyl- m/z 398.2 (M+H) 012 1H-pyrazol-4-ylamino]-thiazol-4-yl}- t
R = 1.42 mins phenyl)-pyrrolidin-2-one Method B 1-(3-Fluoro-4-{2-[1-(3-methoxy-propyl)- m/z 431.3 (M+H) 013 3-methyl-1H-pyrazol-4-ylamino]-thiazol- t
R = 1.48 mins 4-yl}-phenyl)-imidazolidin-2-one Method B 1-(4-(4-((1-(3-methoxypropyl)-3- m/z 462.6 (M+H) (trifluoromethyl)-1H-pyrazol-4- 014 tR = 6.82 mins yl)amino)pyrimidin-2- Method A yl)phenyl)imidazolidin-2-one 1-(4-{2-[1-(2-Ethoxy-ethyl)-3-methyl-1H- m/z 397.4 (M+H) 015 pyrazol-4-ylamino]-oxazol-5-yl}-phenyl)- tR = 1.31 mins imidazolidin-2-one Method B
Ex # Name (IUPAC) LC-MS or NMR 1-(4-(2-((1-(2-ethoxyethyl)-1H-pyrazol-4- m/z 394.2 (M+H) 016 yl)amino)pyrimidin-4- t
R = 1.40 mins yl)phenyl)imidazolidin-2-one Method B 3-(4-(2-((1-(2-ethoxyethyl)-3-methyl-1H- m/z 398.2 (M+H) 017 pyrazol-4-yl)amino)oxazol-5- tR = 1.36 mins yl)phenyl)oxazolidin-2-one Method B 1-(4-(4-((1-(2-ethoxyethyl)-1H-pyrazol-4- m/z 394.2 (M+H) 018 yl)amino)pyrimidin-2- tR = 1.16 mins yl)phenyl)imidazolidin-2-one Method B 1-(4-(2-((1-methyl-1H-pyrazol-4- m/z 336.1 (M+H) 019 yl)amino)pyrimidin-4- tR = 1.28 mins yl)phenyl)imidazolidin-2-one Method B 1-(4-{2-[1-(2-Methoxy-ethyl)-1H-pyrazol- m/z 369.2 (M+H) 020 4-ylamino]-oxazol-5-yl}-phenyl)- tR = 1.27 mins imidazolidin-2-one Method B 1-(4-(2-((1-(2-ethoxyethyl)-1H-pyrazol-4- m/z 401.2 (M+H) 021 yl)amino)oxazol-5-yl)-3- tR = 1.39 mins fluorophenyl)imidazolidin-2-one Method B 1-(4-(2-((1-(2-ethoxyethyl)-1H-pyrazol-4- m/z 401.2 (M+H) 022 yl)amino)oxazol-5-yl)-2- tR = 1.34 mins fluorophenyl)imidazolidin-2-one Method B 1-(5-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol- m/z 400.3 (M+H) 023 4-ylamino]-thiazol-4-yl}-pyridin-2-yl)- t
R = 1.41 mins imidazolidin-2-one Method B 1-(4-(4-((1-ethyl-3-methyl-1H-pyrazol-4- m/z 364.2 (M+H) 024 yl)amino)pyrimidin-2- t
R = 1.14 mins yl)phenyl)imidazolidin-2-one Method B 1-(5-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol- m/z 384.3 (M+H) 025 4-ylamino]-oxazol-5-yl}-pyridin-2-yl)- t
R = 1.35 mins imidazolidin-2-one Method B 1-(6-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol- m/z 384.3 (M+H) 026 4-ylamino]-oxazol-5-yl}-pyridin-3-yl)- t
R = 1.30 mins imidazolidin-2-one Method B 1-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol- m/z 429.2 (M+H) 027 4-ylamino]-thiazol-4-yl}-3-methoxy- t
R = 1.36 mins phenyl)-imidazolidin-2-one Method B 1-(4-(4-((1,3,5-trimethyl-1H-pyrazol-4- m/z 364.2 (M+H) 028 yl)amino)pyrimidin-2- tR = 1.10 mins yl)phenyl)imidazolidin-2-one Method B 1-(4-(4-((1,3-dimethyl-1H-pyrazol-4- m/z 350.1 (M+H) 029 yl)amino)pyrimidin-2- tR = 1.09 mins yl)phenyl)imidazolidin-2-one Method B 1-(4-(4-((1-ethyl-1H-pyrazol-4- m/z 350.4 (M+H) 030 yl)amino)pyrimidin-2- tR = 1.13 mins yl)phenyl)imidazolidin-2-one Method B
Ex # Name (IUPAC) LC-MS or NMR 1-(4-(4-((1-isopropyl-1H-pyrazol-4- m/z 363.9 (M+H) 031 yl)amino)pyrimidin-2- t
R = 1.17 mins yl)phenyl)imidazolidin-2-one Method B 1-(4-(2-((1,3-dimethyl-1H-pyrazol-4- m/z 339.4 (M+H) 032 yl)amino)oxazol-5- tR = 1.24 mins yl)phenyl)imidazolidin-2-one Method B 3-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol- m/z 400.1 (M+H) 033 4-ylamino]-thiazol-4-yl}-phenyl)- tR = 1.46 mins oxazolidin-2-one Method B 1-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol- m/z 413.2 (M+H) 034 4-ylamino]-thiazol-4-yl}-phenyl)-4-(R)- tR = 1.46 mins methyl-imidazolidin-2-one Method B 1-(4-(2-((1-(2-methoxyethyl)-1H-pyrazol- m/z 385.2 (M+H) 035 4-yl)amino)thiazol-4- tR = 1.32 mins yl)phenyl)imidazolidin-2-one Method B 1-(5-{2-[1-(2-Ethoxy-ethyl)-3-methyl-1H- m/z 398.3 (M+H) 036 pyrazol-4-ylamino]-oxazol-5-yl}-pyridin- tR = 1.26 mins 2-yl)-imidazolidin-2-one Method B 1-(5-{2-[1-(2-Ethoxy-ethyl)-5-methyl-1H- m/z 398.3 (M+H) 037 pyrazol-4-ylamino]-oxazol-5-yl}-pyridin- tR = 1.25 mins 2-yl)-imidazolidin-2-one Method B 1-(4-{2-[1-(2-Ethoxy-ethyl)-5-methyl-1H- m/z 413.3 (M+H) 038 pyrazol-4-ylamino]-thiazol-4-yl}-phenyl)- t
R = 1.37 mins imidazolidin-2-one Method B 1-(4-(4-((1-(tert-butyl)-1H-pyrazol-4- m/z 378.1 (M+H) 039 yl)amino)pyrimidin-2- t
R = 1.21 mins yl)phenyl)imidazolidin-2-one Method B 1-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol- m/z 412.2 (M+H) 040 4-ylamino]-thiazol-4-yl}-phenyl)- t
R = 1.43 mins pyrrolidine-2,5-dione Method B 1-(4-(4-((1-methyl-1H-pyrazol-4- m/z 335.1 (M+H) 041 yl)amino)pyrimidin-2- t
R = 1.14 mins yl)phenyl)pyrrolidin-2-one Method B 1-(4-(2-((1-isopropyl-1H-pyrazol-4- m/z 364.4 (M+H) 042 yl)amino)pyrimidin-4- t
R = 1.38 mins yl)phenyl)imidazolidin-2-one Method B 1-(4-(2-((1-ethyl-3-methyl-1H-pyrazol-4- m/z 364.5 (M+H) 043 yl)amino)pyrimidin-4- tR = 1.32 mins yl)phenyl)imidazolidin-2-one Method B 1-(4-(4-((1-butyl-1H-pyrazol-4- m/z 378.2 (M+H) 044 yl)amino)pyrimidin-2- tR = 1.22 mins yl)phenyl)imidazolidin-2-one Method B 1-(4-(2-((1-(tert-butyl)-1H-pyrazol-4- m/z 378.2 (M+H) 045 yl)amino)pyrimidin-4- tR = 1.43 mins yl)phenyl)imidazolidin-2-one Method B
Ex # Name (IUPAC) LC-MS or NMR 1-(4-(4-((1-butyl-3,5-dimethyl-1H- m/z 406.2 (M+H) 046 pyrazol-4-yl)amino)pyrimidin-2- t
R = 1.23 mins yl)phenyl)imidazolidin-2-one Method B 1-(4-(4-((1-neopentyl-1H-pyrazol-4- m/z 392.2 (M+H) 047 yl)amino)pyrimidin-2- tR = 1.25 mins7 yl)phenyl)imidazolidin-2-one Method B 1-(4-(4-((1-(sec-butyl)-1H-pyrazol-4- m/z 378.2 (M+H) 048 yl)amino)pyrimidin-2- tR = 1.21 mins yl)phenyl)imidazolidin-2-one Method B 1-(4-(4-((1-(pentan-3-yl)-1H-pyrazol-4- m/z 392.2 (M+H) 049 yl)amino)pyrimidin-2- tR = 1.25 mins yl)phenyl)imidazolidin-2-one Method B 1-(4-(4-((1-cyclopentyl-1H-pyrazol-4- m/z 390.2 (M+H) 050 yl)amino)pyrimidin-2- tR = 1.25 mins yl)phenyl)imidazolidin-2-one Method B 1-(4-(2-((1-butyl-1H-pyrazol-4- m/z 378.1 (M+H) 051 yl)amino)pyrimidin-4- tR = 1.45 mins yl)phenyl)imidazolidin-2-one Method B 1-(4-(4-((1-benzyl-1H-pyrazol-4- m/z 412.2 (M+H) 052 yl)amino)pyrimidin-2- tR = 1.23 mins yl)phenyl)imidazolidin-2-one Method B 1-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol- m/z 413.3 (M+H) 053 4-ylamino]-thiazol-4-yl}-phenyl)-5-(R)- t
R = 1.46 mins methyl-imidazolidin-2-one Method B 1-(4-(4-((1-hexyl-1H-pyrazol-4- m/z 406.2 (M+H) 054 yl)amino)pyrimidin-2- t
R = 1.33 mins yl)phenyl)imidazolidin-2-one Method B 1-(4-(4-((1-(3,5-dimethoxybenzyl)-1H- m/z 472.2 (M+H) 055 pyrazol-4-yl)amino)pyrimidin-2- t
R = 1.26 mins yl)phenyl)imidazolidin-2-one Method B 1-(4-(2-((1-hexyl-1H-pyrazol-4- m/z 406.2 (M+H) 056 yl)amino)pyrimidin-4- t
R = 1.58 mins yl)phenyl)imidazolidin-2-one Method B 1-(4-(2-((1-(3,5-dimethoxybenzyl)-1H- m/z 472.3 (M+H) 057 pyrazol-4-yl)amino)pyrimidin-4- t
R = 1.47 mins yl)phenyl)imidazolidin-2-one Method B 1-(4-(4-((1-(3-methoxybenzyl)-1H- m/z 442.4 (M+H) 058 pyrazol-4-yl)amino)pyrimidin-2- tR = 1.25 mins yl)phenyl)imidazolidin-2-one Method B 1-(4-(2-((1-(3-methoxybenzyl)-1H- m/z 442.2 (M+H) 059 pyrazol-4-yl)amino)pyrimidin-4- tR = 1.46 mins yl)phenyl)imidazolidin-2-one Method B 1-(4-(4-((1-heptyl-1H-pyrazol-4- m/z 420.2 (M+H) 060 yl)amino)pyrimidin-2- tR = 1.38 mins yl)phenyl)imidazolidin-2-one Method B
Ex # Name (IUPAC) LC-MS or NMR 1-(4-(4-((1-(4-methoxy-3,5- dimethylbenzyl)-1H-pyrazol-4- m/z 470.3 (M+H) 061 t
R = 1.31 mins yl)amino)pyrimidin-2- yl)phenyl)imidazolidin-2-one Method B 1-(4-(2-((1-(4-methoxy-3,5- dimethylbenzyl)-1H-pyrazol-4- m/z 470.3 (M+H) 062 t = 1.55 mins yl)amino)pyrimidin-4- R yl)phenyl)imidazolidin-2-one Method B 3-(4-{2-[1-(2-Ethoxy-ethyl)-3-methyl-1H- m/z 414.2 (M+H) 063 pyrazol-4-ylamino]-thiazol-4-yl}-phenyl)- tR = 1.50 mins oxazolidin-2-one Method B 1-(4-(4-((1-(4,4,4-trifluorobutyl)-1H- m/z 432.2 (M+H) 064 pyrazol-4-yl)amino)pyrimidin-2- t
R = 1.24 mins yl)phenyl)imidazolidin-2-one Method B 1-(3-methoxy-4-(2-((1-(2-methoxyethyl)- m/z 415.1 (M+H) 065 1H-pyrazol-4-yl)amino)thiazol-4- t
R = 1.34 mins yl)phenyl)imidazolidin-2-one Method B 1-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol- m/z 413.3 (M+H) 066 4-ylamino]-thiazol-4-yl}-3-methyl- t
R = 1.37 mins phenyl)-imidazolidin-2-one Method B 1-(4-(2-((1-(2-methoxyethyl)-1H-pyrazol- m/z 399.1 (M+H) 067 4-yl)amino)thiazol-4-yl)-3- t
R = 1.33 mins methylphenyl)imidazolidin-2-one Method B 1-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol- m/z 443.2 (M+H) 068 4-ylamino]-thiazol-4-yl}-3-methoxy- tR = 1.44 mins phenyl)-(R)-4-methyl-imidazolidin-2-one Method B 1-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol- m/z 417.2 (M+H) 069 4-ylamino]-thiazol-4-yl}-3-fluoro- tR = 1.34 mins phenyl)-imidazolidin-2-one Method B 1-(3-Methoxy-4-{2-[1-(3-methoxy- m/z 429.2 (M+H) 070 propyl)-1H-pyrazol-4-ylamino]-thiazol-4- tR = 1.36 mins yl}-phenyl)-imidazolidin-2-one Method B 1-(4-{2-[1-(2-Methoxy-ethyl)-1H-pyrazol- m/z 403.1 (M+H) 071 4-ylamino]-thiazol-4-yl}-3-fluoro- tR = 1.39 mins phenyl)-imidazolidin-2-one Method B 3-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol- m/z 414.1 (M+H) 072 4-ylamino]-thiazol-4-yl}-3-methyl- tR = 1.47 mins phenyl)-oxazolidin-2-one Method B 1-(4-(4-((1-(3-fluorobenzyl)-1H-pyrazol- m/z 430.2 (M+H) 073 4-yl)amino)pyrimidin-2- tR = 1.25 mins yl)phenyl)imidazolidin-2-one Method B 1-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol- m/z 457.2 (M+H) 074 4-ylamino]-thiazol-4-yl}-3-isopropoxy- t
R = 1.50 mins phenyl)-imidazolidin-2-one Method B
Ex # Name (IUPAC) LC-MS or NMR 3-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol- m/z 490.2 (M+H) 075 4-ylamino]-thiazol-4-yl}-3-methoxy- t
R = 1.47 mins phenyl)-oxazolidin-2-one Method B 3-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol- m/z 418.2 (M+H) 076 4-ylamino]-thiazol-4-yl}-3-fluoro- tR = 1.52 mins phenyl)-oxazolidin-2-one Method B 1-(4-{2-[1-(2-Ethoxy-ethyl)-5-methyl-1H- m/z 443.2 (M+H) 077 pyrazol-4-ylamino]-thiazol-4-yl}-3- tR = 1.40 mins methoxy-phenyl)-imidazolidin-2-one Method B 1-(4-{2-[1-(2-Ethoxy-ethyl)-3-methyl-1H- m/z 443.2 (M+H) 078 pyrazol-4-ylamino]-thiazol-4-yl}-3- tR = 1.39 mins methoxy-phenyl)-imidazolidin-2-one Method B 1-(4-(4-((1-(difluoromethyl)-1H-pyrazol- m/z 372.2 (M+H) 079 4-yl)amino)pyrimidin-2- tR = 4.05 mins yl)phenyl)imidazolidin-2-one Method A 1-(4-(4-((1-methyl-3-(trifluoromethyl)- m/z 404.3 (M+H) 080 1H-pyrazol-4-yl)amino)pyrimidin-2- tR = 4.17 mins yl)phenyl)imidazolidin-2-one Method A 1-(4-{2-[1-(2-Ethoxy-ethyl)-3-methoxy- m/z 429.3 (M+H) 081 1H-pyrazol-4-ylamino]-thiazol-4-yl}- tR = 1.45 mins phenyl)-imidazolidin-2-one Method B 1-(4-{2-[1-(2-Ethoxy-ethyl)-3-methoxy- m/z 459.3 (M+H) 082 1H-pyrazol-4-ylamino]-thiazol-4-yl}-3- t
R = 1.43 mins methoxy-phenyl)-imidazolidin-2-one Method B 1-(4-{2-[1-(2-Ethoxy-ethyl)-3-methyl-1H- m/z 413.3 (M+H) 083 pyrazol-4-ylamino]-thiazol-4-yl}-phenyl)- t
R = 1.42 mins imidazolidin-2-one Method B 1-(3-Fluoro-4-{2-[1-(3-methoxy-propyl)- m/z 417.2 (M+H) 084 1H-pyrazol-4-ylamino]-thiazol-4-yl}- t
R = 1.46 mins phenyl)-imidazolidin-2-one Method B 1-(3'-((1-isopropyl-1H-pyrazol-4- m/z 362.4 (M+H) 085 yl)amino)-[1,1'-biphenyl]-4- t
R = 7.98 mins yl)imidazolidin-2-one Method A 1-(4-{2-[3-Chloro-1-(2-ethoxy-ethyl)-1H- m/z 433.2 (M+H) 086 pyrazol-4-ylamino]-thiazol-4-yl}-phenyl)- t
R = 1.48 mins imidazolidin-2-one Method B 1-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol- m/z 413.3 (M+H) 087 4-ylamino]-5-methyl-thiazol-4-yl}- tR = 1.39 mins phenyl)-imidazolidin-2-one Method B 1-(4-{2-[1-(2-Ethoxy-ethyl)-3-methyl-1H- m/z 431.3 (M+H) 088 pyrazol-4-ylamino]-thiazol-4-yl}-3-fluoro- tR = 1.48 mins phenyl)-imidazolidin-2-one Method B 1-(4-{2-[1-(2-Ethoxy-ethyl)-5-methyl-1H- m/z 431.3 (M+H) 089 pyrazol-4-ylamino]-thiazol-4-yl}-3-fluoro- tR = 1.48 mins phenyl)-imidazolidin-2-one Method B
Ex # Name (IUPAC) LC-MS or NMR 1-(3-Chloro-4-{2-[1-(3-methoxy-propyl)- m/z 432.1 (M+H) 090 1H-pyrazol-4-ylamino]-thiazol-4-yl}- t
R = 1.58 mins phenyl)-pyrrolidin-2-one Method B 1H NMR (400 MHz, DMSO- d6) δ 9.63 (s, 1H), 8.34 – 8.23 1-(4-(4-((1-(2,2,2-trifluoroethyl)-1H- (m, 4H), 7.73 – 7.67 (m, 3H), 091 pyrazol-4-yl)amino)pyrimidin-2- 7.09 (s, 1H), 6.56 (d, J = 5.8 yl)phenyl)imidazolidin-2-one Hz, 1H), 5.21 (q, J = 9.2 Hz, 2H), 3.98 – 3.87 (m, 2H), 3.52 – 3.40 (m, 2H). 1-(3-Chloro-4-{2-[1-(2-ethoxy-ethyl)-3- m/z 446.2 (M+H) 092 methyl-1H-pyrazol-4-ylamino]-thiazol-4- t
R = 1.60 mins yl}-phenyl)-pyrrolidin-2-one Method B 1H NMR (400 MHz, DMSO- d
6) δ 9.57 (s, 1H), 8.35 – 8.28 (m, 2H), 8.27 (d, J = 5.8 Hz, 1-(4-(4-((1-(2,2-difluoroethyl)-1H- 1H), 8.18 (s, 1H), 7.74 – 7.64 093 pyrazol-4-yl)amino)pyrimidin-2- (m, 3H), 7.08 (s, 1H), 6.54 (d, yl)phenyl)imidazolidin-2-one J = 5.9 Hz, 1H), 6.55 – 6.20 (m, 1H), 4.69 (td, J = 15.2, 3.8 Hz, 2H), 3.98 – 3.85 (m, 2H), 3.50 – 3.39 (m, 2H). 1-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol- m/z 428.2 (M+H) 094 4-ylamino]-thiazol-4-yl}-3-methoxy- tR = 1.52 mins phenyl)-pyrrolidin-2-one Method B 1H NMR (400 MHz, DMSO- d6) δ 9.49 (s, 1H), 8.44 (d, J = 5.2 Hz, 1H), 8.16 – 8.04 (m, 3H), 7.73 (d, J = 8.8 Hz, 2H), 1-(4-(2-((1-(2,2-difluoroethyl)-1H- 095 pyrazol-4-yl)amino)pyrimidin-4- 7.65 (s, 1H), 7.26 (d, J = 5.3 Hz, 1H), 7.13 (s, 1H), 6.28 (tt, yl)phenyl)imidazolidin-2-one J = 55.1, 3.8 Hz, 1H), 4.70 – 4.56 (m, 2H), 3.93 (dd, J = 9.2, 6.7 Hz, 2H), 3.44 (t, J = 8.0 Hz, 2H). 1H NMR (400 MHz, DMSO) δ 9.54 (s, 1H), 8.45 (d, J = 5.3 1-(4-(2-((1-(2,2,2-trifluoroethyl)-1H- Hz, 1H), 8.17 – 8.09 (m, 3H), 7.76 – 7.67 (m, 3H), 7.27 (d, 096 pyrazol-4-yl)amino)pyrimidin-4- yl)phenyl)imidazolidin-2-one J = 5.3 Hz, 1H), 7.13 (s, 1H), 5.14 (q, J = 9.3 Hz, 2H), 3.93 (dd, J = 9.2, 6.6 Hz, 2H), 3.44 (t, J = 8.0 Hz, 2H).
Ex # Name (IUPAC) LC-MS or NMR 1-(4-{2-[1-(2-[1,2,4]Triazol-1-yl-ethyl)- m/z 422.2 (M+H) 097 1H-pyrazol-4-ylamino]-thiazol-4-yl}- t
R = 1.30 mins phenyl)-imidazolidin-2-one Method B 1H NMR (400 MHz, DMSO- d6) δ 9.47 (s, 1H), 8.32 – 8.26 (m, 2H), 8.24 (d, J = 5.8 Hz, 1H), 8.03 (s, 1H), 7.69 (d, J = 1-(4-(4-((1-propyl-1H-pyrazol-4- 8.9 Hz, 2H), 7.61 (s, 1H), 098 yl)amino)pyrimidin-2- 7.08 (s, 1H), 6.52 (d, J = 5.9 yl)phenyl)imidazolidin-2-one Hz, 1H), 4.09 (t, J = 6.9 Hz, 2H), 3.92 (dd, J = 9.2, 6.7 Hz, 2H), 3.44 (t, J = 8.0 Hz, 2H), 1.81 (q, J = 7.2 Hz, 2H), 0.87 (t, J = 7.4 Hz, 3H). 1H NMR (400 MHz, DMSO- d
6) δ 9.55 (s, 1H), 8.45 (d, J = 5.2 Hz, 1H), 8.25 – 8.04 (m, 1-(4-(2-((1-(2,2,3,3,3-pentafluoropropyl)- 3H), 7.80 – 7.63 (m, 3H), 099 1H-pyrazol-4-yl)amino)pyrimidin-4- 7.28 (d, J = 5.3 Hz, 1H), 7.13 yl)phenyl)imidazolidin-2-one (s, 1H), 5.20 (t, J = 15.0 Hz, 2H), 3.93 (dd, J = 9.3, 6.7 Hz, 2H), 3.44 (t, J = 8.0 Hz, 2H). 1H NMR (400 MHz, DMSO- d
6) δ 9.40 (s, 1H), 8.42 (d, J = 5.2 Hz, 1H), 8.15 – 8.06 (m, 2H), 7.97 – 7.90 (m, 1H), 1-(4-(2-((1-propyl-1H-pyrazol-4- 7.76 – 7.68 (m, 2H), 7.57 (s, 100 yl)amino)pyrimidin-4- 1H), 7.23 (d, J = 5.3 Hz, 1H), yl)phenyl)imidazolidin-2-one 7.13 (s, 1H), 4.04 (t, J = 6.9 Hz, 2H), 3.98 – 3.88 (m, 2H), 3.50 – 3.40 (m, 2H), 1.78 (q, J = 7.2 Hz, 2H), 0.85 (t, J = 7.4 Hz, 3H). 1H NMR (400 MHz, DMSO- d6) δ 9.63 (s, 1H), 8.38 – 8.20 1-(4-(4-((1-(2,2,3,3,3-pentafluoropropyl)- (m, 4H), 7.77 – 7.64 (m, 3H), 101 1H-pyrazol-4-yl)amino)pyrimidin-2- 7.09 (s, 1H), 6.55 (d, J = 5.9 yl)phenyl)imidazolidin-2-one Hz, 1H), 5.27 (t, J = 15.0 Hz, 2H), 3.98 – 3.88 (m, 2H), 3.47 – 3.41 (m, 2H). 1-(4-(4-((1-cyclopropyl-1H-pyrazol-4- m/z 362.5 (M+H) 102 yl)amino)pyrimidin-2- tR = 6.46 mins yl)phenyl)imidazolidin-2-one Method A
Ex # Name (IUPAC) LC-MS or NMR 1-(4-(4-((1-cyclobutyl-1H-pyrazol-4- m/z 376.5 (M+H) 103 yl)amino)pyrimidin-2- t
R = 6.67 mins yl)phenyl)imidazolidin-2-one Method A 1-(4-(4-((1-(oxetan-3-yl)-1H-pyrazol-4- m/z 378.5 (M+H) 104 yl)amino)pyrimidin-2- tR = 6.40 mins yl)phenyl)imidazolidin-2-one Method A 1H NMR (300 MHz, DMSO- d6) δ 9.37 (s, 1H), 8.41 (d, J = 5.2 Hz, 1H), 8.20 – 7.99 (m, 1-(4-(2-((1-(1-hydroxy-2-methylpropan-2- 3H), 7.79 – 7.67 (m, 2H), 105 yl)-1H-pyrazol-4-yl)amino)pyrimidin-4- 7.61 (s, 1H), 7.22 (d, J = 5.3 yl)phenyl)imidazolidin-2-one Hz, 1H), 7.13 (s, 1H), 4.99 (s, 1H), 3.99 – 3.85 (m, 2H), 3.59 (s, 2H), 3.44 (dd, J = 9.2, 6.8 Hz, 2H), 1.48 (s, 6H). 1H NMR (500 MHz, DMSO- d6) δ 9.51 (s, 1H), 8.36 – 8.27 (m, 2H), 8.24 (d, J = 5.8 Hz, 1H), 8.11 (s, 1H), 7.69 (d, J = 1-(4-(4-((1-(1-hydroxypropan-2-yl)-1H- 8.9 Hz, 2H), 7.61 (s, 1H), 7.08 (s, 1H), 6.52 (d, J = 5.8 106 pyrazol-4-yl)amino)pyrimidin-2- yl)phenyl)imidazolidin-2-one Hz, 1H), 4.96 (t, J = 5.4 Hz, 1H), 4.43 – 4.34 (m, 1H), 3.92 (dd, J = 9.2, 6.7 Hz, 2H), 3.74 – 3.59 (m, 2H), 3.44 (dd, J = 8.9, 7.0 Hz, 2H), 1.42 (d, J = 6.8 Hz, 3H). 1-(4-{2-[1-(3-Methoxy-propyl)-3-methyl- m/z 413.2 (M+H) 107 1H-pyrazol-4-ylamino]-thiazol-4-yl}- tR = 1.39 mins phenyl)-imidazolidin-2-one Method B 1-(4-{2-[1-(2-Methoxy-ethyl)-3-methyl- m/z 399.2 (M+H) 108 1H-pyrazol-4-ylamino]-thiazol-4-yl}- tR = 1.37 mins phenyl)-imidazolidin-2-one Method B 2-methyl-2-(4-((2-(4-(2-oxoimidazolidin- m/z 389.6 (M+H) 109 1-yl)phenyl)pyrimidin-4-yl)amino)-1H- tR = 6.59 mins pyrazol-1-yl)propanenitrile Method A 1-(4-{5-[1-(2-Ethoxy-ethyl)-1H-pyrazol- m/z 412.2 (M+H) 110 4-ylamino]-2H-pyrazol-3-yl}-3-methoxy- t
R = 1.29 mins phenyl)-imidazolidin-2-one Method B 1-(4-(4-((1-(1-methoxypropan-2-yl)-1H- m/z 394.6 (M+H) 111 pyrazol-4-yl)amino)pyrimidin-2- t
R = 6.48 mins yl)phenyl)imidazolidin-2-one Method A 1-(4-(2-((1-(1-methoxy-2-methylpropan-
1H NMR (400 MHz, DMSO- 112 2-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4- d
6) δ 9.36 (s, 1H), 8.42 (d, J = yl)phenyl)imidazolidin-2-one 5.2 Hz, 1H), 8.16 – 8.09 (m,
Ex # Name (IUPAC) LC-MS or NMR 2H), 8.06 (s, 1H), 7.72 (d, J = 9.0 Hz, 2H), 7.62 (s, 1H), 7.22 (d, J = 5.2 Hz, 1H), 7.11 (s, 1H), 3.92 (t, J = 7.9 Hz, 2H), 3.55 (s, 2H), 3.50 – 3.37 (m, 2H), 3.21 (s, 3H), 1.51 (s, 6H). 1H NMR (400 MHz, DMSO- d
6) δ 9.38 (s, 1H), 8.42 (d, J = 5.3 Hz, 1H), 8.19 – 8.07 (m, 2H), 7.98 (s, 1H), 7.73 (d, J = 8.5 Hz, 2H), 7.59 (s, 1H), 1-(4-(2-((1-(1-methoxypropan-2-yl)-1H- 7.22 (dd, J = 5.3, 1.7 Hz, 1H), 113 pyrazol-4-yl)amino)pyrimidin-4- 7.11 (s, 1H), 4.52 (q, J = 6.5 yl)phenyl)imidazolidin-2-one Hz, 1H), 3.92 (t, J = 7.9 Hz, 2H), 3.69 – 3.59 (m, 1H), 3.55 (dd, J = 10.2, 4.9 Hz, 1H), 3.44 (t, J = 7.9 Hz, 2H), 3.23 (d, J = 1.7 Hz, 3H), 1.39 (d, J = 6.7 Hz, 3H). 2-methyl-2-(4-((4-(4-(2-oxoimidazolidin- m/z 389.6 (M+H) 114 1-yl)phenyl)pyrimidin-2-yl)amino)-1H- t
R = 7.43 mins pyrazol-1-yl)propanenitrile Method A 1H NMR (400 MHz, DMSO- d
6) δ 9.63 (s, 1H), 8.44 – 8.21 (m, 4H), 7.77 (s, 1H), 7.75 – 2-(4-((2-(4-(2-oxoimidazolidin-1- 7.59 (m, 2H), 7.07 (s, 1H), 115 yl)phenyl)pyrimidin-4-yl)amino)-1H- 6.57 (d, J = 5.9 Hz, 1H), 5.97 pyrazol-1-yl)propanenitrile (q, J = 7.1 Hz, 1H), 3.92 (t, J = 8.0 Hz, 2H), 3.44 (t, J = 7.9 Hz, 2H), 1.83 (d, J = 7.1 Hz, 3H). 1-(4-(2-((1-cyclopropyl-1H-pyrazol-4- m/z 362.5 (M+H) 116 yl)amino)pyrimidin-4- tR = 7.16 mins yl)phenyl)imidazolidin-2-one Method A 1-(4-{5-[1-(2-Ethoxy-ethyl)-1H-pyrazol- m/z 400.3 (M+H) 117 4-ylamino]-2H-pyrazol-3-yl}-3-fluoro- tR = 1.32 mins phenyl)-imidazolidin-2-one Method B 1-(4-{2-[1-(2-Azido-ethyl)-1H-pyrazol-4- m/z 431.3 (M+H) 118 ylamino]-thiazol-4-yl}-phenyl)- tR = 1.48 mins imidazolidin-2-one Method B 1-(3-Methoxy-4-{2-[1-(3-methoxy- m/z 443.4 (M+H) 119 propyl)-3-methyl-1H-pyrazol-4-ylamino]- t
R = 1.39 mins thiazol-4-yl}-phenyl)-imidazolidin-2-one Method B
Ex # Name (IUPAC) LC-MS or NMR 1-(4-(4-((1-isopropyl-3-methyl-1H- m/z 378.5 (M+H) 120 pyrazol-4-yl)amino)pyrimidin-2- t
R = 6.63 mins yl)phenyl)imidazolidin-2-one Method A 1-(4-(4-((1-(1-methoxybutan-2-yl)-1H- m/z 408.6 (M+H) 121 pyrazol-4-yl)amino)pyrimidin-2- tR = 6.59 mins yl)phenyl)imidazolidin-2-one Method A 1H NMR (400 MHz, DMSO- d6) δ 9.38 (s, 1H), 8.42 (d, J = 5.2 Hz, 1H), 8.18 – 8.07 (m, 2H), 7.97 (s, 1H), 7.78 – 7.69 (m, 2H), 7.60 (s, 1H), 7.22 (d, 1-(4-(2-((1-(1-methoxybutan-2-yl)-1H- J = 5.3 Hz, 1H), 7.11 (s, 1H), 4.27 (p, J = 7.1 Hz, 1H), 3.92 122 pyrazol-4-yl)amino)pyrimidin-4- yl)phenyl)imidazolidin-2-one (dd, J = 9.3, 6.7 Hz, 2H), 3.67 (dd, J = 10.1, 7.6 Hz, 1H), 3.58 (dd, J = 10.2, 4.5 Hz, 1H), 3.44 (dd, J = 9.1, 6.9 Hz, 2H), 3.22 (s, 3H), 1.77 (p, J = 7.3 Hz, 2H), 0.75 (t, J = 7.4 Hz, 3H). 1H NMR (400 MHz, DMSO- d6) δ 9.47 (s, 1H), 8.34 – 8.27 (m, 2H), 8.24 (d, J = 5.8 Hz, 1H), 8.09 (s, 1H), 7.69 (d, J = 8.9 Hz, 2H), 7.62 (s, 1H), 1-(4-(4-((1-(1-ethoxypropan-2-yl)-1H- 7.06 (s, 1H), 6.52 (d, J = 5.9 Hz, 1H), 4.55 (dq, J = 13.1, 123 pyrazol-4-yl)amino)pyrimidin-2- yl)phenyl)imidazolidin-2-one 6.7, 5.8 Hz, 1H), 3.92 (dd, J = 9.2, 6.7 Hz, 2H), 3.68 (dd, J = 10.2, 7.1 Hz, 1H), 3.62 (dd, J = 10.2, 4.9 Hz, 1H), 3.50 – 3.35 (m, 4H), 1.43 (d, J = 6.8 Hz, 3H), 1.06 (t, J = 7.0 Hz, 3H). 1H NMR (400 MHz, DMSO- d
6) δ 9.38 (s, 1H), 8.42 (d, J = 5.2 Hz, 1H), 8.11 (d, J = 8.6 Hz, 2H), 7.97 (s, 1H), 7.72 (d, 1-(4-(2-((1-(1-ethoxybutan-2-yl)-1H- J = 8.6 Hz, 2H), 7.60 (s, 1H), 124 pyrazol-4-yl)amino)pyrimidin-4- 7.22 (d, J = 5.2 Hz, 1H), 7.11 yl)phenyl)imidazolidin-2-one (s, 1H), 4.24 (d, J = 6.6 Hz, 1H), 3.92 (dd, J = 9.2, 6.7 Hz, 2H), 3.70 (dd, J = 10.3, 7.2 Hz, 1H), 3.62 (dd, J = 10.2, 4.8 Hz, 1H), 3.51 – 3.33 (m,
Ex # Name (IUPAC) LC-MS or NMR 4H), 1.78 (p, J = 7.3 Hz, 2H), 1.05 (t, J = 7.0 Hz, 3H), 0.74 (t, J = 7.3 Hz, 3H). 1H NMR (400 MHz, DMSO- d6) δ 9.38 (s, 1H), 8.42 (d, J = 5.2 Hz, 1H), 8.17 – 8.05 (m, 2H), 7.99 (s, 1H), 7.78 – 7.69 (m, 2H), 7.59 (s, 1H), 7.22 (d, 1-(4-(2-((1-(1-ethoxypropan-2-yl)-1H- J = 5.3 Hz, 1H), 7.11 (s, 1H), 125 pyrazol-4-yl)amino)pyrimidin-4- 4.50 (q, J = 6.5 Hz, 1H), 3.98 yl)phenyl)imidazolidin-2-one – 3.87 (m, 2H), 3.66 (dd, J = 10.2, 7.1 Hz, 1H), 3.59 (dd, J = 10.2, 5.0 Hz, 1H), 3.50 – 3.33 (m, 4H), 1.40 (d, J = 6.8 Hz, 3H), 1.06 (t, J = 7.0 Hz, 3H). 1-(4-{2-[1-(2-Methoxy-ethyl)-3-methyl- m/z 413.3 (M+H) 126 1H-pyrazol-4-ylamino]-thiazol-4-yl}- tR = 1.41 mins phenyl)-4-(R)-methyl-imidazolidin-2-one Method B 1-(3-Fluoro-4-{2-[1-(2-methoxy-ethyl)-3- m/z 417.2 (M+H) 127 methyl-1H-pyrazol-4-ylamino]-thiazol-4- tR = 1.42 mins yl}-phenyl)-imidazolidin-2-one Method B 1H NMR (400 MHz, DMSO- d6) δ 9.48 (s, 1H), 8.32 – 8.27 (m, 2H), 8.25 (d, J = 5.9 Hz, 1H), 8.07 (s, 1H), 7.74 – 7.66 (m, 2H), 7.61 (s, 1H), 7.07 (s, 1-(4-(4-((1-(1-methoxy-3-methylbutan-2- 1H), 6.51 (d, J = 5.9 Hz, 1H), 4.13 (td, J = 8.1, 3.5 Hz, 1H), 128 yl)-1H-pyrazol-4-yl)amino)pyrimidin-2- yl)phenyl)imidazolidin-2-one 3.99 – 3.88 (m, 2H), 3.83 (dd, J = 10.4, 8.0 Hz, 1H), 3.71 (dd, J = 10.3, 3.6 Hz, 1H), 3.48 – 3.39 (m, 2H), 3.24 (s, 3H), 2.13 (dq, J = 13.3, 7.0 Hz, 1H), 0.98 (d, J = 6.7 Hz, 3H), 0.71 (d, J = 6.7 Hz, 3H). 1-(4-(4-((1-(2,2-difluorocyclopropyl)-1H- m/z 398.6 (M+H) 129 pyrazol-4-yl)amino)pyrimidin-2- t
R = 6.63 mins yl)phenyl)imidazolidin-2-one Method A 1-(4-(2-((1-(1-methoxy-3-methylbutan-2- m/z 422.7 (M+H) 130 yl)-1H-pyrazol-4-yl)amino)pyrimidin-4- t
R = 7.46 mins yl)phenyl)imidazolidin-2-one Method A 1-(4-(2-((1-(2,2-difluorocyclopropyl)-1H-
1H NMR (400 MHz, DMSO- 131 pyrazol-4-yl)amino)pyrimidin-4- d
6) δ 9.50 (s, 1H), 8.45 (d, J = yl)phenyl)imidazolidin-2-one 5.2 Hz, 1H), 8.15 – 8.09 (m,
Ex # Name (IUPAC) LC-MS or NMR 2H), 8.08 (s, 1H), 7.76 – 7.71 (m, 2H), 7.67 (s, 1H), 7.26 (d, J = 5.3 Hz, 1H), 7.13 (s, 1H), 4.54 (q, J = 8.8 Hz, 1H), 3.97 – 3.88 (m, 2H), 3.44 (t, J = 8.0 Hz, 2H), 2.46 – 2.23 (m, 2H). 1H NMR (400 MHz, DMSO- d
6) δ 9.58 (s, 1H), 8.41 – 8.28 (m, 2H), 8.25 (d, J = 5.8 Hz, 1H), 8.13 (s, 1H), 7.76 – 7.62 1-(4-(4-((1-(2-methoxy-2-methylpropyl)- (m, 2H), 7.54 (s, 1H), 7.10 (s, 132 1H-pyrazol-4-yl)amino)pyrimidin-2- 1H), 6.52 (d, J = 5.9 Hz, 1H), yl)phenyl)imidazolidin-2-one 4.16 (s, 2H), 3.92 (dd, J = 9.3, 6.7 Hz, 2H), 3.43 (dd, J = 9.1, 6.9 Hz, 2H), 3.24 (s, 3H), 1.10 (s, 6H). (R)-1-(4-(4-((1-isopropyl-1H-pyrazol-4- m/z 378.6 (M+H) 133 yl)amino)pyrimidin-2-yl)phenyl)-4- tR = 6.70 mins methylimidazolidin-2-one Method A 1H NMR (400 MHz, DMSO- d6) δ 9.45 (s, 1H), 8.42 (d, J = 5.2 Hz, 1H), 8.12 (d, J = 8.6 Hz, 2H), 8.00 (s, 1H), 7.77 – 1-(4-(2-((1-(2-methoxy-2-methylpropyl)- 134 1H-pyrazol-4-yl)amino)pyrimidin-4- 7.65 (m, 2H), 7.53 (s, 1H), 7.24 (d, J = 5.3 Hz, 1H), 7.15 yl)phenyl)imidazolidin-2-one (s, 1H), 4.11 (s, 2H), 3.92 (d, J = 15.9 Hz, 2H), 3.50 – 3.38 (m, 2H), 3.21 (s, 3H), 1.09 (s, 6H). 1H NMR (400 MHz, DMSO- d
6) δ 9.42 (s, 1H), 8.42 (d, J = 5.2 Hz, 1H), 8.15 – 8.07 (m, 2H), 7.97 (s, 1H), 7.75 – 7.69 (m, 2H), 7.58 (s, 1H), 7.23 (d, J = 5.3 Hz, 1H), 7.15 (s, 1H), 1-(4-(2-((1-(1-ethoxy-3-methylbutan-2- 4.05 (s, 1H), 3.97 – 3.88 (m, 135 yl)-1H-pyrazol-4-yl)amino)pyrimidin-4- 2H), 3.82 (dd, J = 10.5, 7.7 yl)phenyl)imidazolidin-2-one Hz, 1H), 3.72 (dd, J = 10.4, 3.7 Hz, 1H), 3.49 – 3.40 (m, 3H), 3.40 – 3.35 (m, 1H), 2.10 (q, J = 7.1 Hz, 1H), 1.04 (t, J = 7.0 Hz, 3H), 0.96 (d, J = 6.7 Hz, 3H), 0.68 (d, J = 6.7 Hz, 3H).
Ex # Name (IUPAC) LC-MS or NMR 1H NMR (400 MHz, DMSO- d
6) δ 9.49 (s, 1H), 8.30 (d, J = 8.6 Hz, 2H), 8.25 (d, J = 5.8 Hz, 1H), 8.08 (s, 1H), 7.69 (d, J = 8.9 Hz, 2H), 7.59 (s, 1H), (R)-1-(4-(4-((1-(2-methoxypropyl)-1H- 7.06 (s, 1H), 6.52 (d, J = 5.9 136 pyrazol-4-yl)amino)pyrimidin-2- Hz, 1H), 4.17 (qd, J = 14.1, yl)phenyl)imidazolidin-2-one 5.3 Hz, 2H), 3.92 (dd, J = 9.3, 6.7 Hz, 2H), 3.78 – 3.63 (m, 1H), 3.44 (t, J = 8.0 Hz, 2H), 3.26 (d, J = 1.6 Hz, 3H), 1.08 (dd, J = 6.3, 1.5 Hz, 3H). 1-(4-(4-((1-isopropyl-1H-pyrazol-4- m/z 392.6 (M+H) 137 yl)amino)pyrimidin-2-yl)phenyl)-4,4- t
R = 6.80 mins dimethylimidazolidin-2-one Method A 1H NMR (400 MHz, DMSO- d
6) δ 9.49 (s, 1H), 8.30 (d, J = 8.9 Hz, 2H), 8.25 (d, J = 5.8 Hz, 1H), 8.08 (s, 1H), 7.69 (d, J = 8.7 Hz, 2H), 7.59 (s, 1H), (S)-1-(4-(4-((1-(2-methoxypropyl)-1H- 7.06 (s, 1H), 6.52 (d, J = 5.9 138 pyrazol-4-yl)amino)pyrimidin-2- Hz, 1H), 4.17 (qd, J = 14.1, yl)phenyl)imidazolidin-2-one 5.4 Hz, 2H), 3.92 (dd, J = 9.2, 6.8 Hz, 2H), 3.71 (td, J = 6.4, 4.7 Hz, 1H), 3.44 (t, J = 8.0 Hz, 2H), 1.08 (d, J = 6.2 Hz, 3H). 1-(4-(4-((1-isopropyl-3-(trifluoromethyl)- m/z 432.6 (M+H) 139 1H-pyrazol-4-yl)amino)pyrimidin-2- t
R = 6.96 mins yl)phenyl)imidazolidin-2-one Method A 1-(4-(4-((1,5-dimethyl-1H-pyrazol-4- m/z 350.5 (M+H) 140 yl)amino)pyrimidin-2- t
R = 6.38 mins yl)phenyl)imidazolidin-2-one Method A 1H NMR (400 MHz, DMSO- d
6) δ 8.64 (s, 1H), 8.39 (d, J = 5.3 Hz, 1H), 8.20 (s, 1H), 8.06 (d, J = 8.6 Hz, 2H), 7.69 1-(4-(2-((1-isopropyl-3-(trifluoromethyl)- 141 1H-pyrazol-4-yl)amino)pyrimidin-4- (d, J = 8.5 Hz, 2H), 7.29 (d, J = 5.3 Hz, 1H), 7.11 (s, 1H), yl)phenyl)imidazolidin-2-one 4.61 (p, J = 6.7 Hz, 1H), 3.91 (dd, J = 9.2, 6.7 Hz, 2H), 3.43 (t, J = 8.0 Hz, 2H), 1.47 (d, J = 6.7 Hz, 6H).
Ex # Name (IUPAC) LC-MS or NMR 1H NMR (400 MHz, DMSO- d
6) δ 8.62 (s, 1H), 8.33 (d, J = 5.2 Hz, 1H), 8.05 (d, J = 8.5 1-(4-(2-((1,5-dimethyl-1H-pyrazol-4- Hz, 2H), 7.69 (d, J = 8.6 Hz, 142 yl)amino)pyrimidin-4- 2H), 7.55 (s, 1H), 7.19 (d, J = yl)phenyl)imidazolidin-2-one 5.3 Hz, 1H), 7.10 (s, 1H), 3.91 (t, J = 7.9 Hz, 2H), 3.72 (s, 3H), 3.43 (t, J = 8.0 Hz, 2H), 2.19 (s, 3H). 1-(4-(4-((1-(3-methoxypropyl)-1H- m/z 394.6 (M+H) 143 pyrazol-4-yl)amino)pyrimidin-2- tR = 6.53 mins yl)phenyl)imidazolidin-2-one Method A 1-(4-{2-[1-(3-Methoxy-propyl)-3-methyl- m/z 427.2 (M+H) 144 1H-pyrazol-4-ylamino]-thiazol-4-yl}-3- tR = 1.38 mins methyl-phenyl)-imidazolidin-2-one Method B 1H NMR (400 MHz, DMSO- d6) δ 8.97 (s, 1H), 8.38 (s, 1H), 8.32 (d, J = 5.8 Hz, 1H), 1-(4-(4-((1-(2-methoxyethyl)-3- 8.25 (d, J = 8.8 Hz, 2H), 7.75 145 (trifluoromethyl)-1H-pyrazol-4- – 7.55 (m, 2H), 7.06 (s, 1H), yl)amino)pyrimidin-2- 6.68 (s, 1H), 4.42 (t, J = 5.1 yl)phenyl)imidazolidin-2-one Hz, 2H), 3.91 (dd, J = 9.2, 6.7 Hz, 2H), 3.76 (t, J = 5.1 Hz, 2H), 3.43 (t, J = 7.9 Hz, 2H), 3.31 (d, J = 1.0 Hz, 3H). 3-(4-{2-[1-(3-Methoxy-propyl)-1H- m/z 400.1 (M+H) 146 pyrazol-4-ylamino]-thiazol-4-yl}-phenyl)- t
R = 1.45 mins oxazolidin-2-one Method B 3-(3-Fluoro-4-{2-[1-(3-methoxy-propyl)- m/z 418.1 (M+H) 147 1H-pyrazol-4-ylamino]-thiazol-4-yl}- t
R = 1.51 mins phenyl)-oxazolidin-2-one Method B 3-(3-Fluoro-4-{2-[1-(2-methoxy-ethyl)- m/z 404.1 (M+H) 148 1H-pyrazol-4-ylamino]-thiazol-4-yl}- tR = 1.47 mins phenyl)-oxazolidin-2-one Method B 1-(4-{2-[1-(3-Methoxy-propyl)-1H- m/z 399.1 (M+H) 149 pyrazol-4-ylamino]-thiazol-4-yl}-phenyl)- tR = 1.36 mins imidazolidin-2-one Method B 3-(4-{2-[1-(2-Methoxy-ethyl)-1H-pyrazol- m/z 386.1 (M+H) 150 4-ylamino]-thiazol-4-yl}-phenyl)- tR = 1.41 mins oxazolidin-2-one Method B 1-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol- m/z 398.1 (M+H) 151 4-ylamino]-thiazol-4-yl}-phenyl)- tR = 1.47 mins pyrrolidin-2-one Method B
Ex # Name (IUPAC) LC-MS or NMR 1H NMR (400 MHz, DMSO- d
6) δ 9.50 (s, 1H), 8.30 (d, J = 8.5 Hz, 2H), 8.25 (d, J = 5.8 Hz, 1H), 8.17 (s, 1H), 7.69 (d, J = 8.5 Hz, 2H), 7.57 (s, 1H), 1-(4-(4-((1-(cyclopropylmethyl)-1H- 7.07 (s, 1H), 6.53 (d, J = 5.8 152 pyrazol-4-yl)amino)pyrimidin-2- Hz, 1H), 4.01 (d, J = 7.1 Hz, yl)phenyl)imidazolidin-2-one 2H), 3.92 (dd, J = 9.2, 6.8 Hz, 2H), 3.44 (t, J = 7.9 Hz, 2H), 1.26 (p, J = 5.4 Hz, 1H), 0.65 – 0.54 (m, 2H), 0.43 (d, J = 4.9 Hz, 2H). 1-(4-(4-((1-((3-(methoxymethyl)oxetan-3- yl)methyl)-1H-pyrazol-4- m/z 436.6 (M+H) 153 t
R = 6.44 mins yl)amino)pyrimidin-2- yl)phenyl)imidazolidin-2-one Method A 1H NMR (400 MHz, DMSO- d6) δ 9.49 (s, 1H), 8.40 – 8.27 (m, 2H), 8.25 (d, J = 5.8 Hz, 1H), 8.08 (s, 1H), 7.75 – 7.66 (m, 2H), 7.64 (s, 1H), 7.07 (s, 1H), 6.52 (d, J = 5.9 Hz, 1H), 1-(4-(4-((1-(1,4-dimethoxybutan-2-yl)- 4.52 (qd, J = 7.3, 4.4 Hz, 1H), 154 1H-pyrazol-4-yl)amino)pyrimidin-2- 3.97 – 3.89 (m, 2H), 3.71 (dd, yl)phenyl)imidazolidin-2-one J = 10.2, 7.7 Hz, 1H), 3.63 (dd, J = 10.2, 4.5 Hz, 1H), 3.49 – 3.40 (m, 2H), 3.24 (s, 4H), 3.19 (s, 3H), 3.17 – 3.06 (m, 1H), 2.02 (q, J = 6.7 Hz, 2H). 1-(4-(4-((1-(3-methoxycyclobutyl)-1H- m/z 406.6 (M+H) 155 pyrazol-4-yl)amino)pyrimidin-2- tR = 6.52 mins yl)phenyl)imidazolidin-2-one Method A 1-(4-(4-((3-methoxy-1-methyl-1H- m/z 366.5 (M+H) 156 pyrazol-4-yl)amino)pyrimidin-2- tR = 6.51 mins yl)phenyl)imidazolidin-2-one Method A 3-(4-{2-[1-(2-Ethoxy-ethyl)-3-methyl-1H- m/z 432.2 (M+H) 157 pyrazol-4-ylamino]-thiazol-4-yl}-3-fluoro- t
R = 1.53 mins phenyl)-oxazolidin-2-one Method B 3-(4-{2-[1-(2-Ethoxy-ethyl)-3-methyl-1H- m/z 414.1 (M+H) 158 pyrazol-4-ylamino]-thiazol-4-yl}-phenyl)- t
R = 1.46 mins oxazolidin-2-one Method B 1-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol- m/z 416.1 (M+H) 159 4-ylamino]-thiazol-4-yl}-3-fluoro- t
R = 1.55 mins phenyl)-pyrrolidin-2-one Method B
Ex # Name (IUPAC) LC-MS or NMR 1-(4-{2-[1-(2-Ethoxy-ethyl)-3-methyl-1H- m/z 412.2 (M+H) 160 pyrazol-4-ylamino]-thiazol-4-yl}-phenyl)- t
R = 1.49 mins pyrrolidin-2-one Method B 1-(4-{2-[1-(2-Ethoxy-ethyl)-3-methyl-1H- m/z 430.2 (M+H) 161 pyrazol-4-ylamino]-thiazol-4-yl}-3-fluoro- tR = 1.57 mins phenyl)-pyrrolidin-2-one Method B 1-(4-{2-[1-(3-Methoxy-propyl)-3-methyl- m/z 412.3 (M+H) 162 1H-pyrazol-4-ylamino]-thiazol-4-yl}- tR = 1.46 mins phenyl)-pyrrolidin-2-one Method B 3-(3-Fluoro-4-{2-[1-(2-methoxy-ethyl)-3- m/z 418.3 (M+H) 163 methyl-1H-pyrazol-4-ylamino]-thiazol-4- tR = 1.48 mins yl}-phenyl)-oxazolidin-2-one Method B 1-(3-Fluoro-4-{2-[1-(2-methoxy-ethyl)-3- m/z 416.3 (M+H) 164 methyl-1H-pyrazol-4-ylamino]-thiazol-4- tR = 1.50 mins yl}-phenyl)-pyrrolidin-2-one Method B 3-(3-Fluoro-4-{2-[1-(2-methoxy-ethyl)-3- m/z 432.3 (M+H) 165 methyl-1H-pyrazol-4-ylamino]-thiazol-4- tR = 1.51 mins yl}-phenyl)-oxazolidin-2-one Method B 1-(3-Fluoro-4-{2-[1-(3-methoxy-propyl)- m/z 430.4 (M+H) 166 3-methyl-1H-pyrazol-4-ylamino]-thiazol- tR = 1.54 mins 4-yl}-phenyl)-pyrrolidin-2-one Method B 3-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol- m/z 414.2 (M+H) 167 4-ylamino]-thiazol-4-yl}-phenyl)-(R)-5- t
R = 1.52 mins methyl-oxazolidin-2-one Method B 1-(4-{2-[1-(2-Methoxy-ethyl)-1H-pyrazol- m/z 384.2 (M+H) 168 4-ylamino]-thiazol-4-yl}-phenyl)- t
R = 1.45 mins pyrrolidin-2-one Method B 1-(4-{2-[1-(3-Methoxy-propyl)-1H- m/z 384.2 (M+H) 169 pyrazol-4-ylamino]-thiazol-4-yl}-phenyl)- t
R = 1.45 mins pyrrolidin-2-one Method B 1-(3-Fluoro-4-{2-[1-(3-methoxy-propyl)- m/z 398.3 (M+H) 170 1H-pyrazol-4-ylamino]-thiazol-4-yl}- t
R = 1.49 mins phenyl)-pyrrolidin-2-one Method B 1-(3-Fluoro-4-{2-[1-(2-methoxy-ethyl)- m/z 402.3 (M+H) 171 1H-pyrazol-4-ylamino]-thiazol-4-yl}- t
R = 1.55 mins phenyl)-pyrrolidin-2-one Method B 1-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol- m/z 467.4 (M+H) 4-ylamino]-thiazol-4-yl}-3- 172 t = 1.47 mins trifluoromethyl-phenyl)-imidazolidin-2- R Method B one 1-(4-{5-[1-(2-Ethoxy-ethyl)-1H-pyrazol- m/z 399.3 (M+H) 173 4-ylamino]-2H-pyrazol-3-yl}-3-fluoro- tR = 1.36 mins phenyl)-pyrrolidin-2-one Method B
Ex # Name (IUPAC) LC-MS or NMR 1-(4-{2-[1-(3-Ethoxy-propyl)-1H-pyrazol- m/z 413.3 (M+H) 174 4-ylamino]-thiazol-4-yl}-phenyl)- t
R = 1.42 mins imidazolidin-2-one Method B 1-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol- m/z 414.3 (M+H) 175 4-ylamino]-thiazol-4-yl}-phenyl)-4-(R)- tR = 1.34 mins hydroxy-pyrrolidin-2-one Method B 1-(3-Chloro-4-{2-[1-(2-ethoxy-ethyl)-1H- m/z 433.3 (M+H) 176 pyrazol-4-ylamino]-thiazol-4-yl}-phenyl)- tR = 1.48 mins imidazolidin-2-one Method B 1-(3-Chloro-4-{2-[1-(3-methoxy-propyl)- m/z 433.1 (M+H) 177 1H-pyrazol-4-ylamino]-thiazol-4-yl}- tR = 1.45 mins phenyl)-imidazolidin-2-one Method B 1-(3-Chloro-4-{2-[1-(2-ethoxy-ethyl)-3- m/z 447.2 (M+H) 178 methyl-1H-pyrazol-4-ylamino]-thiazol-4- tR = 1.43 mins yl}-phenyl)-imidazolidin-2-one Method B 1-(4-{2-[1-(2-[1,2,3]Triazol-2-yl-ethyl)- m/z 422.1 (M+H) 179 1H-pyrazol-4-ylamino]-thiazol-4-yl}- tR = 1.34 mins phenyl)-imidazolidin-2-one Method B 1-(4-{2-[1-(2-[1,2,3]Triazol-1-yl-ethyl)- m/z 422.1 (M+H) 180 1H-pyrazol-4-ylamino]-thiazol-4-yl}- tR = 1.29 mins phenyl)-imidazolidin-2-one Method B 1-(3-Chloro-4-{2-[1-(2-ethoxy-ethyl)-1H- m/z 432.1 (M+H) 181 pyrazol-4-ylamino]-thiazol-4-yl}-phenyl)- t
R = 1.57 mins pyrrolidin-2-one Method B 3-(4-{4-[4-(2-Oxo-imidazolidin-1-yl)- m/z 427.2 (M+H) 182 phenyl]-thiazol-2-ylamino}-pyrazol-1-yl)- t
R = 1.44 mins propionic acid ethyl ester Method B 2-[2-(4-{4-[4-(2-Oxo-imidazolidin-1-yl)- m/z 480.2 (M+H) 183 phenyl]-thiazol-2-ylamino}-pyrazol-1-yl)- t
R = 1.40 mins ethyl]-2H-[1,2,3]triazole-4-carboxylic acid Method B methyl ester 1-(4-{2-[1-(2-Imidazol-1-yl-ethyl)-1H- m/z 421.2 (M+H) 184 pyrazol-4-ylamino]-thiazol-4-yl}-phenyl)- tR = 1.14 mins imidazolidin-2-one Method B 1-(3-Chloro-4-{2-[1-(3-methoxy-propyl)- m/z 446.1 (M+H) 185 3-methyl-1H-pyrazol-4-ylamino]-thiazol- tR = 1.51 mins 4-yl}-phenyl)-pyrrolidin-2-one Method B 1-(3-Chloro-4-{2-[1-(3-methoxy-propyl)- m/z 447.1 (M+H) 186 3-methyl-1H-pyrazol-4-ylamino]-thiazol- tR = 1.43 mins 4-yl}-phenyl)-imidazolidin-2-one Method B
Example 2: Biological assays Example 2-1: In vitro tubulin polymerization assay Materials and methods [0146] The assay was performed using a fluorescence-based Tubulin Polymerization Assay Kit (Cytoskeleton cat. # BK011P) and following the manufacturer’s instructions. In brief, purified porcine brain tubulin was prepared at 2 mg/ml tubulin in 80 mM PIPES pH 6.9, 2.0 mM MgCl2, 0.5 mM EGTA, 1.0 mM GTP (guanosine triphosphate) and 15% glycerol and kept on ice. Tubulin was then incubated with a 10µM solution of each test compound or control compound in the presence of 1 mM GTP in PIPES-based polymerization buffer at 37°C. Polymerization was followed by fluorescence enhancement due to the incorporation of a fluorescent reporter into microtubules (MT) as polymerization occurs. The experiments were performed in duplicates and results are expressed as the percentage of inhibition of MT polymerization obtained at the end of the experiment relative to the control DMSO. Results [0147] The results of this assay are presented in Table 3 below. Table 3: Tubulin polymerization inhibition at the concentration of 10µM Ex. 001 002 006 029 030 031 046 004 005 080 % of tubulin polymerization 100 100 90 100 100 100 100 100 50 100 inhibition Table 3 (continued) Ex. 039 008 015 007 022 023 % of tubulin polymerization i
nhibition 100 100 100 90 100 80
Table 3 (continued) Ex. 027 033 066 069 081 083 086 087 % of tubulin polymerization 100 100 100 100 90 100 40 100 inhibition [0148] Therefore, it was observed that the class of compounds of formula (I) of the invention were able to inhibit Tubulin Polymerization. The listed compounds in Table 3 are well representing the class of compounds of formula (I). Example 2-2: Cell cycle analysis: G2/M arrest after 24h treatment with compounds Materials and methods [0149] HCT116 cells (human colon cancer cell line) were plated in 24-well plates at a cell density of 105 cells/mL/well in their culture medium. The next day, the culture medium was removed and replaced with a culture medium containing 100 nM of the tested compound. After 24 hours of treatment, the culture medium was removed, the cells were washed once with PBS 1X and trypsinized in a solution of 0.05% Trypsine-EDTA (lifetech cat. # 25300-054). The cells were then resuspended in culture medium and transferred to a 96 well plate. The plate was centrifuged, and the cell pellets were washed twice in cold PBS. The cell pellets were then resuspended in the propidium iodide staining solution containing 0.1% NP40, 0.1% sodium citrate, 50 μg/mL propidium iodide, and 0.2 mg/mL RNAse A. The cells were analyzed immediately for DNA content using an Accuri 6 cytometer. Results are expressed as a percentage of live cells that accumulate in the G2/M phase of the cell cycle. Results [0150] The results of this assay are presented in Table 4 below. Table 4: Results of the cell cycle analysis, expressed as a percentage of live cells that accumulate in the G2/M phase of the cell cycle % G2/M arrest @ 24h Example compound number G2/M arrest > 90%
001, 004, 005, 008, 013, 014, 015, 016, 018, 024, 0
27, 029, 033, 044, 046, 048, 054, 071, 077, 080,
084, 092, 094, 098, 102, 103, 107, 108, 111, 116, 118, 120, 123, 124, 125, 127, 129, 130, 132, 134, 135, 136, 139, 141, 143, 144, 145, 149, 151, 152, 155, 159, 178, 181, 185 and 186 002, 003, 006, 007, 017, 021, 025, 030, 031, 034, 035, 038, 042, 043, 045, 047, 049, 050, 051, 052, 60% < G2/M arrest ≤ 055, 064, 065, 066, 069, 070, 076, 079, 083, 088, 90% 090, 093, 097, 100, 113, 114, 117, 119, 121, 122, 128, 131, 138, 161, 166, 169, 174, 176, 177, 179 and 182 009, 010, 011, 012, 019, 020, 022, 023, 026, 028, 032, 036, 037, 039, 040, 041, 053, 056, 057, 058, 059, 060, 061, 062, 063, 067, 068, 072, 073, 074, 45% ≤ G2/M arrest ≤ 075, 078, 081, 082, 086, 087, 089, 091, 095, 096, 60% 099, 101, 104, 105, 106, 109, 110, 112, 115, 126, 133, 137, 140, 142, 146, 147, 148, 150, 153, 154, 156, 157, 158, 160, 162, 163, 164, 165, 167, 168, 170, 171, 172, 173, 175, 180, 183 and 184 [0151] Microtubules play a critical role in determining cell shape and polarity, facilitating cellular movement and intracellular transport, and segregating chromosomes during mitosis. In mitosis, interphase microtubules disappear and are replaced with a new network of microtubules that interact with the mitotic spindle to distribute chromatids equally between the two daughter cells. Disruption of microtubules arrests the cell division cycle at the G2/M checkpoint, preventing cell division and triggering apoptosis. [0152] Thus, it was observed that the class of compounds of formula (I) of the invention were able to cause G2/M mitotic arrest. The listed compounds in Table 4 are well representing the class of compounds of formula (I). Example 2-3: Cell-based proliferation screening of compounds Materials and Methods [0153] CellTiter-Blue cell-based survival/proliferation assay (Promega G8080) was performed on tumor cell lines. A total of 1.10
4 cells/well/50µl were seeded in a 96-well plate. The following day, treatment was initiated by addition of a drug solution of tested compound of 1/10 serial dilutions ranging from 0 to 10µM. Cells were grown for 48h at 37°C and then incubated with 10 µl/well of Promega CellTiter-Blue reagent for 4 h at 37°C. The amount of resorufin dye formed was quantified by its fluorescence emission
at 590 nm using a scanning multiwell spectrophotometer (OPTIMA, BMG labtech, France). A blank well without cells was used as a background control for the spectrophotometer. The positive control of the assay corresponds to the cell proliferation obtained in the absence of drug treatment (100% proliferation), i.e., in absence of tested compound. Each sample was done in duplicates, and the experiment was repeated at least twice. The results presented below are expressed as IC50 (i.e., concentration required to obtain 50% inhibition of the proliferation observed in absence of treatment), with “++++” corresponding to IC
50 ≤ 100 nM, “+++” to 100 < IC
50 ≤ 500 nM, “++” to 500 < IC
50 ≤ 1000 nM, and “+” o IC
50 > 1000 nM, N.D.: not determined. [0154] Cell lines tested were: HL60, MOLM14, NOMO1, THP1, HUT78, CCRF_CEM, KARPAS 299, REC1, NALM6, A549, H1299, HEP2, HGC27, HRT18, PANC_1, PLC PRF5, U118, U87_MG, Tov21G, 786-O, ACHN, PC3, LnCaP, DU145, MCF7, MDA- MB-468, SW872, SK-N-MC, A4573, U2OS, WEHI164, and MESSA. Results [0155] The results of this assay are presented in Table 5 and Table 6 below. Table 5. Anti-tumoral activity of the compounds of formula (I) on hematopoietic tumor cell lines (measured IC50) E
x. Leukemia H
L60 MOLM14 NOMO1 THP1 001 ++++ N.D. N.D. N.D. 008 ++++ ++++ ++++ ++++ 015 +++ ++ +++ +++ 0
16 ++++ ++++ ++++ ++++ 0
24 ++++ ++++ ++ ++++ 0
27 ++++ +++ ++++ ++++ 0
29 ++++ +++ +++ ++++ 0
31 ++++ ++++ +++ ++++ 0
33 ++++ ++++ ++++ ++++ 034 ++++ N.D. N.D. N.D. 048 ++++ N.D. N.D. N.D. 071 ++++ N.D. N.D. N.D. 076 ++++ N.D. N.D. ++++ 0
77 ++++ N.D. N.D. N.D. 0
80 ++++ N.D. N.D. ++++
083 ++++ N.D. ++ ++++ 0
84 ++++ N.D. N.D. N.D. 098 ++++ N.D. ++++ ++++ 102 ++++ N.D. N.D. N.D. 103 ++++ N.D. N.D. N.D. 107 ++++ ++++ ++++ ++++ 1
08 ++++ N.D. N.D. N.D. 1
11 +++ N.D. N.D. N.D. 0
13 +++ ++++ ++++ ++++ 1
18 +++ +++ +++ +++ 1
24 +++ +++ ++++ + 1
27 + ++++ ++++ ++++ 130 + ++++ ++++ ++++ 132 ++++ ++++ +++ + 135 +++ ++++ ++++ ++++ 139 ++++ ++++ N.D. N.D. 1
43 +++ ++++ N.D. N.D. 0
14 +++ ++++ N.D. N.D. 1
45 ++++ ++++ N.D. N.D. 1
49 ++++ ++++ ++++ ++++ 1
51 +++ ++++ N.D. N.D. 1
52 +++ ++++ N.D. N.D. 155 ++++ ++++ ++++ ++++ 159 ++++ N.D. N.D. N.D. 166 ++++ +++ +++ ++++ 169 ++++ ++++ +++ +++ 1
78 +++ ++++ ++++ ++++ 1
81 ++++ N.D. N.D. N.D. Table 5 (continued)
Ex. Lymphoma T Lymphoma B H
UT78 CCRF_CEM KARPAS 299 REC1 NALM6 001 ++++ ++++ ++++ ++++ ++++
008 ++++ ++++ ++++ ++++ ++++
015 +++ +++ +++ +++ ++
016 ++++ ++++ ++++ ++++ ++++ 024 ++++ ++++ ++++ ++++ ++++ 027 ++++ ++++ ++++ ++++ ++++ 029 ++++ ++++ ++++ ++++ ++++ 031 ++++ ++++ ++++ ++++ ++++
033 ++++ ++++ ++++ ++++ ++++
034 ++++ ++++ ++++ ++++ ++++
048 ++++ ++++ ++++ ++++ ++++
071 ++++ ++++ ++++ ++++ ++++ 0
76 +++ +++ +++ +++ +++ 077 ++++ ++++ ++++ ++++ ++++ 080 ++++ ++++ ++++ ++++ ++++ 083 ++++ ++++ ++++ ++++ ++++ 084 ++++ ++++ ++++ ++++ ++++ 0
98 ++++ ++++ ++++ ++++ ++++ 1
02 ++++ ++++ ++++ ++++ ++++ 1
03 ++++ ++++ ++++ ++++ ++++ 1
07 ++++ ++++ ++++ ++++ ++++ 1
08 ++++ ++++ ++++ ++++ ++++ 1
11 ++++ ++++ ++++ ++++ +++ 013 ++++ ++++ ++++ ++++ ++++ 118 ++++ +++ +++ ++++ +++ 124 ++++ ++++ ++++ ++++ ++++ 127 ++++ ++++ ++++ ++++ ++++ 1
30 ++++ ++++ ++++ ++++ ++++ 1
32 N.D. N.D. N.D. N.D. N.D. 1
35 ++++ ++++ ++++ ++++ ++++ 1
39 ++++ ++++ ++++ ++++ ++++ 1
43 ++++ ++++ ++++ ++++ ++++ 0
14 ++++ ++++ ++++ ++++ ++++ 145 ++++ ++++ ++++ ++++ ++++ 149 ++++ ++++ ++++ ++++ ++++ 151 ++++ ++++ ++++ ++++ ++++ 152 ++++ ++++ ++++ ++++ ++++ 1
55 ++++ ++++ ++++ ++++ ++++ 1
59 ++++ ++++ ++++ ++++ ++++ 1
66 ++++ ++++ ++++ ++++ ++++ 1
69 ++++ ++++ ++++ ++++ ++++ 1
78 ++++ ++++ ++++ ++++ ++++ 1
81 ++++ ++++ ++++ ++++ ++++ Table 6: Anti-tumoral activity of the compounds of formula (I) on solid tumor cell lines (measured IC50) E
x. Lung Lung Larynx Stomach Colon A
549 H1299 HEP2 HGC27 HRT18 001 ++++ ++++ ++++ ++++ ++++ 008 ++++ ++++ ++++ ++++ ++++ 015 +++ ++++ ++++ ++++ ++++ 0
16 ++++ ++++ ++++ ++++ ++++ 0
24 ++++ ++++ ++++ ++++ ++++ 0
27 ++++ ++++ ++++ ++++ ++++ 0
29 ++++ ++++ ++++ ++++ ++++
++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ +++ N.D. ++++ ++++ N.D. ++++ ++++ ++++ ++++ ++++ +++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ N.D. N.D. N.D. N.D. N.D. ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ Table 6 (continued)
Ex. Pancreas Liver Glioblastoma P
ANC_1 PLC PRF5 U118 U87_MG 001 ++++ ++++ ++++ ++++
008 ++++ ++++ ++++ ++++
015 +++ ++++ ++++ ++++
016 ++++ ++++ ++++ ++++ 0
24 ++++ ++++ ++++ ++++ 027 ++++ ++++ ++++ ++++ 029 ++++ ++++ ++++ ++++ 031 ++++ ++++ ++++ ++++ 033 ++++ ++++ ++++ ++++ 0
34 ++++ ++++ ++++ ++++ 0
48 ++++ ++++ ++++ ++++ 0
71 ++++ ++++ ++++ ++++ 0
76 ++++ ++++ +++ +++ 0
77 ++++ ++++ ++++ ++++ 0
80 ++++ ++++ ++++ ++++ 083 ++++ ++++ ++++ ++++ 084 ++++ ++++ ++++ ++++ 098 ++++ ++++ ++++ ++++ 102 ++++ ++++ ++++ ++++ 1
03 ++++ ++++ ++++ ++++ 1
07 ++++ ++++ ++++ ++++ 1
08 ++++ ++++ ++++ ++++ 1
11 ++++ ++++ ++++ ++++ 0
13 ++++ ++++ ++++ ++++ 1
18 +++ ++++ ++++ ++++ 124 ++++ ++++ ++++ ++++ 127 ++++ ++++ ++++ ++++ 130 ++++ ++++ ++++ ++++ 132 N.D. N.D. N.D. N.D. 1
35 ++++ ++++ ++++ ++++ 1
39 ++++ ++++ ++++ ++++ 1
43 ++++ ++++ ++++ ++++ 0
14 ++++ ++++ ++++ ++++ 1
45 ++++ ++++ ++++ ++++ 1
49 ++++ ++++ ++++ ++++ 151 ++++ ++++ ++++ ++++ 152 ++++ ++++ ++++ ++++ 155 ++++ ++++ ++++ ++++ 159 ++++ ++++ ++++ ++++ 1
66 ++++ ++++ ++++ ++++ 1
69 ++++ ++++ ++++ ++++ 1
78 ++++ ++++ ++++ ++++ 1
81 ++++ ++++ ++++ ++++ Table 6 (continued) Ex. Ovarian Kidney Prostate Breast
Tov21G 786-O ACHN PC3 LnCaP DU145 MCF7 MDA- M
B-468 ++++ + ++++ ++++ ++++ ++++ +++ ++++ + ++++ ++++ ++++ ++++ ++++ ++++ +++ N.D. +++ +++ +++ +++ +++ +++ ++ +++ ++++ ++++ ++++ +++ ++++ ++++ +++ + ++++ ++++ ++++ ++++ ++++ ++++ +++ + ++++ ++++ ++++ ++++ ++++ ++++ ++ + ++++ ++++ ++++ ++++ ++++ ++++ +++ +++ ++++ ++++ ++++ ++ ++++ ++++ +++ +++ ++++ ++++ ++++ +++ ++++ ++++ +++ ++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ +++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ +++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ +++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ + ++++ ++++ ++++ ++++ ++++ ++++ ++++ + ++++ ++++ ++++ ++++ +++ ++++ ++++ +++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ +++ ++++ ++++ ++++ N.D. ++++ ++++ ++++ N.D. ++++ ++++ ++++ ++++ ++++ ++++ N.D. N.D. ++ +++ +++ ++++ +++ +++ ++++ N.D. ++++ ++++ N.D. ++++ N.D. ++++ ++++ N.D. ++++ ++++ ++++ ++++ ++++ ++++ ++++ N.D. ++++ ++++ ++++ ++++ ++++ ++++ ++++ N.D. ++++ ++++ N.D. N.D. N.D. ++++ +++ N.D. ++++ ++++ ++++ ++++ ++++ ++++ ++++ N.D. ++++ ++++ ++++ ++++ N.D. N.D. ++++ N.D. ++++ ++++ ++++ ++++ N.D. N.D. ++++ N.D. ++++ ++++ ++++ ++++ N.D. N.D. ++++ N.D. ++++ ++++ ++++ ++++ N.D. N.D. N.D. N.D. ++++ ++++ ++++ ++++ ++++ ++++ ++ N.D. ++++ ++++ ++++ ++++ N.D. N.D. ++++ N.D. ++++ ++++ ++++ ++++ N.D. N.D. N.D. N.D. ++++ ++++ ++++ ++++ ++++ ++++ N.D. N.D. N.D. N.D. N.D. ++++ N.D. N.D. N.D. N.D. +++ +++ ++++ ++++ +++ +++ N.D. N.D. ++++ ++++ ++++ ++++ ++++ ++++ N.D. N.D. ++++ ++++ ++++ ++++ ++++ ++++
181 N.D. N.D. N.D. N.D. N.D. ++++ N.D. N.D. Table 6 (continued) arcoma
Sar Ovarian Lipos
coma E
wing Osteosarcoma Fibrosarcoma Sarcoma Ex. SW872
SK-N- M
C A4573 U2OS WEHI164 MESSA 001 ++++ ++++ ++++ ++++ N.D. ++++ 008 N.D. N.D. N.D. N.D. N.D. ++++ 015 ++++ ++++ ++++ +++ N.D. ++
016 N.D. N.D. ++++ ++++ N.D. ++++
024 N.D. N.D. ++++ ++++ N.D. ++++
027 ++++ ++++ ++++ ++++ ++++ +++ 029 N.D. N.D. ++++ ++++ N.D. ++++ 031 ++++ ++++ ++++ ++++ ++++ ++++ 033 ++++ ++++ ++++ ++++ ++++ ++++ 034 ++++ ++++ ++++ ++++ ++++ ++++ 048 N.D. N.D. ++++ ++++ N.D. ++++ 071 N.D. N.D. ++++ ++++ N.D. N.D. 076 ++++ ++++ +++ +++ ++++ ++++
077 N.D. N.D. ++++ ++++ N.D. ++++
080 ++++ ++++ ++++ ++++ N.D. ++++
083 ++++ ++++ ++++ ++++ ++++ ++++ 084 ++++ ++++ ++++ ++++ N.D. ++++ 098 N.D. N.D. ++++ ++++ N.D. ++++ 102 ++++ ++++ ++++ ++++ N.D. N.D. 103 ++++ ++++ ++++ ++++ N.D. N.D. 107 ++++ ++++ ++++ ++++ ++++ ++++ 108 ++++ ++++ ++++ ++++ N.D. N.D. 111 ++++ ++++ ++++ ++++ N.D. N.D.
013 ++++ ++++ ++++ ++++ ++++ ++++
118 ++++ ++++ ++++ ++++ ++++ N.D.
124 ++++ ++++ ++++ ++++ N.D. N.D. 127 ++++ ++++ ++++ ++++ N.D. N.D. 130 ++++ ++++ ++++ ++++ N.D. N.D. 132 N.D. N.D. N.D. N.D. N.D. N.D. 135 ++++ ++++ ++++ ++++ N.D. N.D. 139 ++++ ++++ ++++ ++++ N.D. N.D. 143 ++++ ++++ ++++ ++++ N.D. N.D. 014 ++++ ++++ ++++ ++++ ++++ ++++
145 ++++ ++++ ++++ ++++ N.D. N.D.
149 ++++ ++++ ++++ ++++ ++++ ++++
151 ++++ ++++ ++++ ++++ N.D. N.D. 152 ++++ ++++ ++++ ++++ N.D. N.D.
155 ++++ ++++ ++++ ++++ N.D. N.D. 1
59 ++++ ++++ ++++ ++++ ++++ N.D. 166 ++++ ++++ ++++ ++++ ++++ ++++ 169 ++++ ++++ ++++ ++++ N.D. ++++ 178 ++++ ++++ ++++ ++++ ++++ ++++ 181 ++++ ++++ ++++ ++++ ++++ ++++ [0156] The IC
50 given in Table 5 and Table 6 above are expressed as: ++++: IC
50 ≤ 100 nM, +++: 100 < IC
50 ≤ 500 nM, ++: 500 < IC
50 ≤ 1000 nM, +: IC
50 > 1000 nM, N.D.: Not Determined. [0157] Therefore, it was observed a very effective antiproliferative activity on the cell lines listed above by the class of compounds of formula (I) of the invention. The listed compounds in Table 5 and Table 6 are well representing the class of compounds of formula (I).
or a pharmaceutically acceptable salt and/or solvate thereof, wherein R1, R2, R3, B and Y are each independently as defined herein. [0009] According to some embodiments, B is selected from phenyl, thiazole, oxazole, oxadiazole, isoxazole, thiadiazole, pyrazole, pyridine and pyrimidine; wherein the phenyl, the thiazole, the oxazole, the oxadiazole, the isoxazole, the thiadiazole, the pyrazole, the pyridine or the pyrimidine is optionally substituted by at least one methyl. According to some embodiments, B is a five-membered heteroaryl or a six-membered heteroaryl.
[0010] According to some embodiments, the compound is of formula (III)
or a pharmaceutically acceptable salt and/or solvate thereof, wherein R1, R2, R3 and Y are each independently as defined herein. [0011] According to some embodiments, Y is CR9, wherein R9 is selected from hydrogen, C1-C10 alkyl and halogen. According to some embodiments, R1 is C1-C10 alkyl. According to some embodiments, R2 is hydrogen. According to some embodiments, R1 is C1-C10 alkyl and/or R2 is hydrogen. According to some embodiments, R3 is C1-C10 alkyl group, wherein the C1-C10 alkyl is optionally substituted by OR7, wherein R7 is C1-C10 alkyl. According to some embodiments, the compound is selected from the compounds of Table 1 herein, and pharmaceutically acceptable salts and/or solvates thereof. [0012] This invention also relates to a pharmaceutical composition comprising a compound according to the invention and at least one pharmaceutically acceptable carrier. According to some embodiments, the pharmaceutical composition comprises the compound according to the invention as sole active pharmaceutical ingredient. According to some embodiments, the pharmaceutical composition further comprises another active pharmaceutical ingredient. [0013] This invention also relates to a compound according to the invention or a pharmaceutical composition according to the invention for use as a medicament. This invention also relates to a compound according to the invention or a pharmaceutical composition according to the invention for use in the treatment of hematological disorders and/or proliferative disorders. In some embodiments, the hematological disorder is selected from lymphoma, leukemia (such as acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic lymphoid leukemia (CLL) or chronic myeloid
leukemia (CML)), multiple myeloma (MM), myelodysplastic syndrome (MDS) and myelodysplasia with myelofibrosis. In some embodiments, the proliferative disorder is cancer; such as head and neck cancer, melanoma, kidney carcinoma, stomach carcinoma, liver carcinoma, colorectal carcinoma, pancreas carcinoma, larynx carcinoma, lung carcinoma, neuronal carcinoma, glioblastoma multiforme, osteosarcoma, fibrosarcoma, ovarian sarcoma, liposarcoma, Ewing sarcoma, breast carcinoma, ovary carcinoma or prostate carcinoma. According to some embodiments, the compound or the pharmaceutical composition is to be administered with at least another active pharmaceutical ingredient. DEFINITIONS [0014] In the present invention, the following terms have the following meanings: Chemical definitions [0015] Where chemical substituents are combinations of chemical groups, the point of attachment of the substituent to the molecule is by the last chemical group recited on the right of the name of the substituent. For example, an arylalkyl substituent is linked to the rest of the molecule through the alkyl moiety and it may by represented as follows: “aryl-alkyl-”. Unless otherwise indicated, the compounds were named using ChemBioDraw® Ultra 13.0.2 (PerkinElmer). [0016] “Alkoxy” refers to an alkyl-O- group. [0017] “Alkyl” refers to a saturated linear or branched hydrocarbon chain, typically comprising from 1 to 16 carbon atoms, preferably from 1 to 12 carbon atoms, more preferably from 1 to 8 carbon atoms, furthermore preferably from 1 to 6 carbon atoms. Alkyl groups may be monovalent or polyvalent (i.e., “alkylene” groups, which are divalent alkyl groups, are encompassed in “alkyl” definition). The alkyl group may optionally be substituted by one or more substituent(s) (for example 1 to 4 substituent(s), or for example 1, 2, 3 or 4 substituent(s)) selected from oxo, halogen, hydroxyl, nitro, amino, cyano, alkylamino, dialkylamino, alkoxy, haloalkyl, acyl, carbamoyl,
alkylsulfoxide, sulfamoyl, alkylthio and carboxyl. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl, pentyl and its isomers (e.g., n-pentyl, iso-pentyl), and hexyl and its isomers (e.g., n-hexyl, iso-hexyl). Particular examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl and t-butyl (including methylene, ethylene, n-propylene, n-butylene and n-butylene). [0018] “Amine” refers to derivatives of ammonia (NH3), wherein one or more hydrogen atoms have been replaced by a substituent such as, for example, alkyl or aryl. “Amino” refers to the -NH2 group. [0019] “Aryl” refers to a cyclic, polyunsaturated, aromatic hydrocarbyl group comprising at least one aromatic ring and comprising from 5 to 12 carbon atoms, preferably from 6 to 10 carbon atoms. Aryl groups may be monovalent or polyvalent (e.g., divalent). Aryl groups may have a single ring (e.g., phenyl) or multiple aromatic rings fused together (e.g., naphthyl) or linked covalently. The aromatic ring may optionally include one to two additional rings (either cycloalkyl, heterocycloalkyl or heteroaryl) fused thereto. This definition of “aryl” encompasses the partially hydrogenated derivatives of the carbocyclic systems enumerated herein, as long as at least one ring is aromatic. The aryl group may optionally be substituted by one or more substituent(s) (for example 1 to 4 substituent(s), or for example 1, 2, 3 or 4 substituent(s)) selected from oxo, halogen, hydroxyl, nitro, amino, cyano, alkyl (e.g., methyl), alkylamino, dialkylamino, alkoxy, haloalkyl, acyl, carbamoyl, alkylsulfoxide, sulfamoyl, alkylthio and carboxyl. Non-limiting examples of aryl groups include phenyl, biphenyl, biphenylenyl, 5- or 6-tetralinyl, naphthalen-1- or -2-yl, 4-, 5-, 6 or 7-indenyl, 1- 2-, 3-, 4- or 5-acenaphthylenyl, 3-, 4- or 5-acenaphthenyl, 1- or 2-pentalenyl, 4- or 5-indanyl, 5-, 6-, 7- or 8-tetrahydronaphthyl, 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl, and 1-, 2-, 3-, 4- or 5-pyrenyl. A particular example of aryl group is phenyl. [0020] “Azido” refers to -N3 group, i.e., the azide functional group. [0021] “Cyano” refers to the -CN group.
[0022] “Cycloalkyl” refers to a cyclic alkyl group, typically comprising from 3 to 15 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 8 carbon atoms, further more preferably from 3 to 6 carbon atoms. Cycloalkyl groups may be monovalent or polyvalent (e.g., divalent). This definition of “cycloalkyl” encompasses polycyclic cycloalkyls (e.g., bicycles) and bridged cycloalkyl structures, including cycles bound together through one atom (“spiro”) or through two atoms. The cycloalkyl group may optionally be substituted by one or more substituent(s) (for example 1 to 4 substituent(s), or for example 1, 2, 3 or 4 substituent(s)) selected from oxo, halogen, hydroxyl, nitro, amino, cyano, alkyl (e.g., methyl), alkylamino, dialkylamino, alkoxy, haloalkyl, acyl, carbamoyl, alkylsulfoxide, sulfamoyl, alkylthio and carboxyl. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopropyl, cyclohexyl, cycoheptyl, cyclooctanyl, cyclononanyl, cyclodecanyl, norbornyl, adamantyl, bicyclo[2.2.2]octanyl, bicyclo[4.4.0]decanyl, bicyclo[3.2.1]octanyl, bicyclo[3.3.1]nonanyl, bicyclo[2.1.1]hexane, 2,3-dihydro-1H- indenyl, 1,2,3,4-tetrahydronaphthalenyl, decahydronaphthalenyl, 1,2,3,4-tetrahydronaphthalenyl, and octahydropentalenyl. [0023] “Cx-Cy” or “(Cx-Cy)” preceding the name of a group means that the group comprises from x to y carbon atoms, in accordance to common terminology in the chemistry field. [0024] “Halogen” refers to a fluorine, chlorine, bromine or iodine atom. [0025] “Heteroaryl” refers to aromatic rings or aromatic ring systems comprising from 5 to 15 carbon atoms, preferably from 4 to 12 carbon atoms, more preferably from 3 to 10 carbon atoms, having one or two rings which are fused together or linked covalently, wherein at least one ring is aromatic, and wherein one or more carbon atoms in one or more of these rings is replaced by oxygen, nitrogen and/or sulfur atoms. Heteroaryl groups may be monovalent or polyvalent (e.g., divalent). The nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized (e.g., sulfur may be oxidized as SO or SO2). This definition of “heteroaryl” encompasses the partially hydrogenated derivatives of the carbocyclic systems enumerated herein, as well as ring systems including one or more fused non-aromatic
cycloalkyl and/or heterocycloalkyl ring(s), as long as at least one ring is aromatic. In one embodiment, the heteroaryl is bound to another group or molecule through a carbon atom, the binding atom is not selected among the heteroatoms included therein. In one embodiment, the heteroaryl is bound to another group or molecule through one of the heteroatoms included therein (e.g., a nitrogen). When substituted by one or more other group(s), an heteroaryl may be substituted either through a carbon atom or through a heteroatom (e.g., nitrogen), unless otherwise specified. The heteroaryl group may optionally be substituted by one or more substituent(s) (for example 1 to 4 substituent(s), or for example 1, 2, 3 or 4 substituent(s)) selected from oxo, halogen, hydroxyl, nitro, amino, cyano, alkyl (e.g., methyl), alkylamino, dialkylamino, alkoxy, haloalkyl, acyl, carbamoyl, alkylsulfoxide, sulfamoyl, alkylthio and carboxyl. Non-limiting examples of heteroaryl groups include pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, tetrazinyl, imidazo[2,1-b][1,3]thiazolyl, thieno[3,2- b]furanyl, thieno[3,2-b]thiophenyl, thieno[2,3-d][l,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazolo[l,5-a]pyridinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, 1,3-benzoxazolyl, 1,2-benzisoxazolyl, 2,1-benzisoxazolyl, 1,3-benzothiazolyl, 1,2-benzoisothiazolyl, 2,1-benzoisothiazolyl, benzotriazolyl, 1,2,3-benzoxadiazolyl, 2,1,3-benzoxadiazolyl, 1,2,3-benzothiadiazolyl, 2,1,3-benzothiadiazolyl, thienopyridinyl, purinyl, imidazo[l,2- a]pyridinyl, 6-oxo-pyridazin-l(6H)-yl, 2-oxopyridin-l(2H)-yl, 6-oxo-pyridazin-l(6H)-yl, 2-oxopyridin-l(2H)-yl, 1,3-benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl and quinoxalinyl. Non-limiting examples of heteroaryl groups comprising at least one fused non-aromatic ring include 2,3-dihydrobenzofuranyl, benzo[d][1,3]dioxolyl, indolinyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, 3,4-dihydro-2H- benzo[b][1,4]oxazinyl, 1,2,3,4-tetrahydroquinoxaline, 3,4-dihydro-2H- benzo[b][1,4]thiazine and 2,3-dihydrobenzo[b][1,4]oxathiine. [0026] “Heterocycloalkyl” refers to non-aromatic, fully saturated or partially unsaturated cyclic groups (for example, 3- to 7-membered monocyclic, 7- to 11-membered bicyclic, or containing a total of 3 to 10 ring atoms) which have at least one
heteroatom in at least one carbon atom-containing ring. Heterocycloalkyl groups may in particular be 3- to 7-membered, preferably 5- or 6-membered. Heterocycloalkyl groups may in particular be monocyclic or bicyclic, preferably monocyclic. Each ring of the heterocycloalkyl group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. In one embodiment, the heterocycloalkyl is bound to another group or molecule through a carbon atom,
or a pharmaceutically acceptable salt and/or solvate thereof, wherein R1-R5, B, X, Y, V and W are as defined herein. [0043] In formula (I) herein, R1 is selected from hydrogen, C1-C10 alkyl, cyano, CF3, hydroxy, C1-C10 alkoxy and halogen. According to some embodiments, R1 is C1-C10 alkyl. According to some embodiments, R1 is hydrogen. In some preferred embodiments, R1 is selected from hydrogen, CH3, CF3, OCH3 and Cl. [0044] In formula (I) herein, R2 is selected from hydrogen, C1-C10 alkyl, cyano, CF3, hydroxy, C1-C10 alkoxy and halogen. According to some embodiments, R2 is hydrogen. In some preferred embodiments, R2 is selected from hydrogen and CH3.
[0045] In formula (I) herein, R3 is selected from hydrogen, C1-C10 alkyl, C3-C10 cycloalkyl and C2-C11 heterocycloalkyl, wherein the C1-C10 alkyl is optionally substituted by at least one group selected from azido, cyano, -C(O)OR6, OR7, halogen, C3-C10 cycloalkyl, C2-C11 heterocycloalkyl, aryl and heteroaryl, wherein the C3-C10 cycloalkyl, the C2-C11 heterocycloalkyl, the aryl or the heteroaryl is optionally substituted by at least one group selected from C1-C10 alkyl, C1-C10 alkyl substituted by at least one OR7, hydroxy, C1-C10 alkoxy, -C(O)OR6 and halogen, and wherein R6 and R7 are each independently selected from hydrogen and C1-C10 alkyl. [0046] Herein, and in particular in the above definition of R3, recitations such as “R3 is selected from (…), wherein the C3-C10 cycloalkyl, the C2-C11 heterocycloalkyl, the aryl or the heteroaryl is optionally substituted
means that when a cycloalkyl or an heterocycloalkyl is present in R3, said cycloalkyl or heterocycloalkyl may be substituted as indicated, regardless of whether said cycloalkyl or an heterocycloalkyl is the “primary group” of R3 (e.g., R3 is a C3-C10 cycloalkyl) or a substituent of the “primary group” of R3 (e.g., R3 is C1-C10 alkyl, wherein the C1-C10 alkyl is substituted by at least one C3-C10 cycloalkyl). [0047] According to some embodiments, R3 is C1-C10 alkyl group, wherein the C1-C10 alkyl is optionally substituted by hydroxyl or OR7, wherein R7 is C1-C10 alkyl. In some embodiments, R3 is C1-C10 alkyl group, wherein the C1-C10 alkyl is optionally substituted by OR7, wherein R7 is C1-C10 alkyl. [0048] In formula (I) herein, R4 is selected from hydrogen, hydroxy, C1-C10 alkyl and C1-C10 alkoxy. According to some embodiments, R4 is hydrogen. In some preferred embodiments, R4 is selected from hydrogen and CH3.
[0049] In formula (I) herein, R5 is selected from hydrogen, hydroxy, C1-C10 alkyl and C1-C10 alkoxy. According to some embodiments, R5 is hydrogen. In some preferred embodiments, R5 is selected from hydrogen and CH3. [0050] In formula (I) herein, B is an aryl, a five-membered heteroaryl or a six-membered heteroaryl. According to some embodiments, B is an aryl. According to some embodiments, B is a five-membered heteroaryl. According to some embodiments, B is a six-membered heteroaryl. According to some preferred embodiments, B is a five-membered heteroaryl or a six-membered heteroaryl. According to some embodiments, B is selected from phenyl, thiazole, oxazole, oxadiazole, isoxazole, thiadiazole, pyrazole, pyridine and pyrimidine; wherein the phenyl, the thiazole, the oxazole, the oxadiazole, the isoxazole, the thiadiazole, the pyrazole, the pyridine or the pyrimidine is optionally substituted by at least one methyl. In some embodiments, B is phenyl. In some embodiments, B is selected from thiazole, oxazole, oxadiazole, isoxazole, thiadiazole, pyrazole, pyridine and pyrimidine. In some preferred embodiments, B is selected from phenyl, thiazole, methyl-thiazole, oxazole, thiadiazole, pyrazole, pyridine and pyrimidine. In some further preferred embodiments, B is thiazole. [0051] In formula (I) herein, X is nitrogen or CR8, wherein R8 is selected from hydrogen, C1-C10 alkyl, cyano, CF3, C1-C10 alkoxy and halogen. According to some embodiments, X is CR8. In some preferred embodiments, X is selected from N, CH and CF. In some embodiments, X is CH. [0052] In formula (I) herein, Y is nitrogen or CR9, wherein R9 is selected from hydrogen, C1-C10 alkyl, cyano, CF3, C1-C10 alkoxy and halogen. According to some embodiments, Y is CR9. In some embodiments, Y is CR9, wherein R9 is selected from hydrogen, C1-C10 alkyl and halogen. In some preferred embodiments, Y is selected from N, CH, C-CH3, C-OCH3, C-CF3, C-OCH(CH3)2, C-Cl and C-F. In some embodiments, Y is CH. [0053] In formula (I) herein, V is NR10, CR11R12 or oxygen, wherein R10, R11 and R12 are each independently selected from hydrogen and C1-C10 alkyl. According to some embodiments, V is NR10. In some preferred embodiments, V is selected from NH, CH2 and O. In some embodiments, V is NH.
[0054] In formula (I) herein, W is C=O or CR13R14, wherein R13 and R14 each independently selected from hydrogen and C1-C10 alkyl. According to some embodiments, W is CR13R14. According to some embodiments, W is CHR14. In some preferred embodiments, W is selected from C=O, CH2 and CH-CH3. In some embodiments, W is CH2. [0055] According to some embodiments, Y is CR9, wherein R9 is selected from hydrogen, C1-C10 alkyl and halogen; R1 is C1-C10 alkyl; R2 is hydrogen; and R3 is C1-C10 alkyl group, wherein the C1-C10 alkyl is optionally substituted by hydroxyl or OR7, wherein R7 is C1-C10 alkyl. In some embodiments, R3 is C1-C10 alkyl group, wherein the C1-C10 alkyl is optionally substituted by OR7, wherein R7 is C1-C10 alkyl. [0056] In some embodiments, the compound of formula (I) is a compound of formula (II)
or a pharmaceutically acceptable salt and/or solvate thereof, wherein R1, R2, R3, B and Y are each independently as defined under formula (I) herein. [0057] In some embodiments, the compound of formula (I) is a compound of formula (III)
or a pharmaceutically acceptable salt and/or solvate thereof, wherein R1, R2, R3 and Y are each independently as defined under formula (I) herein.
[0058] According to one embodiment, the compound of formula (I) is selected from the compounds of Table 1 below, and pharmaceutically acceptable salts and/or solvates thereof. Table 1 Ex # Structure Name (IUPAC) 1-(4-(4-((1-(2- methoxyethyl)-1H- pyrazol-4- 001 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((1-methyl- 1H-pyrazol-4- yl)amino)pyrimidin- 002 2- yl)phenyl)imidazolidi n-2-one 1-(4-(2-((1-(2- methoxyethyl)-1H- pyrazol-4- 003 yl)amino)pyrimidin- 4- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((1-(3,5- dimethylbenzyl)-1H- pyrazol-4- 004 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-(2-((1-(3,5- dimethylbenzyl)-1H- pyrazol-4- 005 yl)amino)pyrimidin- 4- yl)phenyl)imidazolidi n-2-one
Ex # Structure Name (IUPAC) 1-(4-(6-((1-(2- propoxyethyl)-1H- pyrazol-4- 006 yl)amino)pyridin-2- yl)phenyl)imidazolidi n-2-one 1-(4-{2-[1-(2-Ethoxy- ethyl)-1H-pyrazol-4- 007 ylamino]-oxazol-5- yl}-phenyl)- imidazolidin-2-one 1-(4-{2-[1-(2-Ethoxy- ethyl)-1H-pyrazol-4- 008 ylamino]-thiazol-4- yl}-phenyl)- imidazolidin-2-one 1-(4-(5-((1-(2- ethoxyethyl)-1H- pyrazol-4-yl)amino)- 009 1,2,4-thiadiazol-3- yl)phenyl)imidazolidi n-2-one 3-(4-{2-[1-(2- Methoxy-ethyl)-3- 010 methyl-1H-pyrazol-4- ylamino]-thiazol-4- yl}-phenyl)- oxazolidin-2-one 1-(4-{5-[1-(2-Ethoxy- ethyl)-1H-pyrazol-4- 011 ylamino]-2H-pyrazol- 3-yl}-phenyl)- imidazolidin-2-one
Ex # Structure Name (IUPAC) 1-(4-{2-[1-(2- Methoxy-ethyl)-3- methyl-1H-pyrazol-4- 012 ylamino]-thiazol-4- yl}-phenyl)- pyrrolidin-2-one 1-(3-Fluoro-4-{2-[1- (3-methoxy-propyl)- 3-methyl-1H-pyrazol- 013 4-ylamino]-thiazol-4- yl}-phenyl)- imidazolidin-2-one 1-(4-(4-((1-(3- methoxypropyl)-3- (trifluoromethyl)-1H- pyrazol-4- 014 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one O 1-(4-{2-[1-(2-Ethoxy- ethyl)-3-methyl-1H- 015 O N N pyrazol-4-ylamino]- N oxazol-5-yl}-phenyl)- HN N O N H imidazolidin-2-one 1-(4-(2-((1-(2- ethoxyethyl)-1H- pyrazol-4- 016 yl)amino)pyrimidin- 4- yl)phenyl)imidazolidi n-2-one 3-(4-(2-((1-(2- ethoxyethyl)-3- 017 methyl-1H-pyrazol-4- yl)amino)oxazol-5- yl)phenyl)oxazolidin- 2-one
Ex # Structure Name (IUPAC) 1-(4-(4-((1-(2- ethoxyethyl)-1H- pyrazol-4- 018 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-(2-((1-methyl- 1H-pyrazol-4- yl)amino)pyrimidin- 019 4- yl)phenyl)imidazolidi n-2-one O 1-(4-{2-[1-(2- Methoxy-ethyl)-1H- 020 O N N N pyrazol-4-ylamino]- HN N oxa O N zol-5-yl}-phenyl)- H imidazolidin-2-one 1-(4-(2-((1-(2- ethoxyethyl)-1H- pyrazol-4- 021 yl)amino)oxazol-5- yl)-3- fluorophenyl)imidazo lidin-2-one 1-(4-(2-((1-(2- ethoxyethyl)-1H- pyrazol-4- 022 yl)amino)oxazol-5- yl)-2- fluorophenyl)imidazo lidin-2-one 1-(5-{2-[1-(2-Ethoxy- ethyl)-1H-pyrazol-4- 023 ylamino]-thiazol-4- yl}-pyridin-2-yl)- imidazolidin-2-one
Ex # Structure Name (IUPAC) 1-(4-(4-((1-ethyl-3- methyl-1H-pyrazol-4- yl)amino)pyrimidin- 024 2- yl)phenyl)imidazolidi n-2-one 1-(5-{2-[1-(2-Ethoxy- ethyl)-1H-pyrazol-4- 025 ylamino]-oxazol-5- yl}-pyridin-2-yl)- imidazolidin-2-one 1-(6-{2-[1-(2-Ethoxy- ethyl)-1H-pyrazol-4- 026 ylamino]-oxazol-5- yl}-pyridin-3-yl)- imidazolidin-2-one 1-(4-{2-[1-(2-Ethoxy- ethyl)-1H-pyrazol-4- ylamino]-thiazol-4- 027 yl}-3-methoxy- phenyl)-imidazolidin- 2-one 1-(4-(4-((1,3,5- trimethyl-1H- pyrazol-4- 028 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((1,3- dimethyl-1H-pyrazol- 4- 029 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one
Ex # Structure Name (IUPAC) 1-(4-(4-((1-ethyl-1H- pyrazol-4- yl)amino)pyrimidin- 030 2- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((1-isopropyl- 1H-pyrazol-4- 031 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-(2-((1,3- dimethyl-1H-pyrazol- 032 4-yl)amino)oxazol-5- yl)phenyl)imidazolidi n-2-one 3-(4-{2-[1-(2-Ethoxy- ethyl)-1H-pyrazol-4- 033 ylamino]-thiazol-4- yl}-phenyl)- oxazolidin-2-one 1-(4-{2-[1-(2-Ethoxy- ethyl)-1H-pyrazol-4- ylamino]-thiazol-4- 034 yl}-phenyl)-4-(R)- methyl-imidazolidin- 2-one 1-(4-(2-((1-(2- methoxyethyl)-1H- pyrazol-4- 035 yl)amino)thiazol-4- yl)phenyl)imidazolidi n-2-one 1-(5-{2-[1-(2-Ethoxy- ethyl)-3-methyl-1H- pyrazol-4-ylamino]- 036 oxazol-5-yl}-pyridin- 2-yl)-imidazolidin-2- one
Ex # Structure Name (IUPAC) 1-(5-{2-[1-(2-Ethoxy- ethyl)-5-methyl-1H- pyrazol-4-ylamino]- 037 oxazol-5-yl}-pyridin- 2-yl)-imidazolidin-2- one 1-(4-{2-[1-(2-Ethoxy- ethyl)-5-methyl-1H- 038 pyrazol-4-ylamino]- thiazol-4-yl}-phenyl)- imidazolidin-2-one 1-(4-(4-((1-(tert- butyl)-1H-pyrazol-4- yl)amino)pyrimidin- 039 2- yl)phenyl)imidazolidi n-2-one 1-(4-{2-[1-(2-Ethoxy- ethyl)-1H-pyrazol-4- 040 ylamino]-thiazol-4- yl}-phenyl)- pyrrolidine-2,5-dione 1-(4-(4-((1-methyl- 1H-pyrazol-4- yl)amino)pyrimidin- 041 2- yl)phenyl)pyrrolidin- 2-one 1-(4-(2-((1-isopropyl- 1H-pyrazol-4- 042 yl)amino)pyrimidin- 4- yl)phenyl)imidazolidi n-2-one
Ex # Structure Name (IUPAC) 1-(4-(2-((1-ethyl-3- methyl-1H-pyrazol-4- yl)amino)pyrimidin- 043 4- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((1-butyl-1H- pyrazol-4- yl)amino)pyrimidin- 044 2- yl)phenyl)imidazolidi n-2-one 1-(4-(2-((1-(tert- butyl)-1H-pyrazol-4- yl)amino)pyrimidin- 045 4- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((1-butyl-3,5- dimethyl-1H-pyrazol- 4- 046 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((1- neopentyl-1H- pyrazol-4- 047 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((1-(sec- butyl)-1H-pyrazol-4- yl)amino)pyrimidin- 048 2- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((1-(pentan-3- yl)-1H-pyrazol-4- yl)amino)pyrimidin- 049 2- yl)phenyl)imidazolidi n-2-one
Ex # Structure Name (IUPAC) 1-(4-(4-((1- cyclopentyl-1H- pyrazol-4- 050 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-(2-((1-butyl-1H- pyrazol-4- yl)amino)pyrimidin- 051 4- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((1-benzyl- 1H-pyrazol-4- yl)amino)pyrimidin- 052 2- yl)phenyl)imidazolidi n-2-one 1-(4-{2-[1-(2-Ethoxy- ethyl)-1H-pyrazol-4- ylamino]-thiazol-4- 053 yl}-phenyl)-5-(R)- methyl-imidazolidin- 2-one 1-(4-(4-((1-hexyl-1H- pyrazol-4- yl)amino)pyrimidin- 054 2- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((1-(3,5- dimethoxybenzyl)- 1H-pyrazol-4- 055 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one
Ex # Structure Name (IUPAC) 1-(4-(2-((1-hexyl-1H- pyrazol-4- yl)amino)pyrimidin- 056 4- yl)phenyl)imidazolidi n-2-one 1-(4-(2-((1-(3,5- dimethoxybenzyl)- 1H-pyrazol-4- 057 yl)amino)pyrimidin- 4- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((1-(3- methoxybenzyl)-1H- pyrazol-4- 058 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-(2-((1-(3- methoxybenzyl)-1H- pyrazol-4- 059 yl)amino)pyrimidin- 4- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((1-heptyl- 1H-pyrazol-4- yl)amino)pyrimidin- 060 2- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((1-(4- methoxy-3,5- dimethylbenzyl)-1H- 061 pyrazol-4- yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one
Ex # Structure Name (IUPAC) 1-(4-(2-((1-(4- methoxy-3,5- dimethylbenzyl)-1H- pyrazol-4- 062 yl)amino)pyrimidin- 4- yl)phenyl)imidazolidi n-2-one 3-(4-{2-[1-(2-Ethoxy- ethyl)-3-methyl-1H- 063 pyrazol-4-ylamino]- thiazol-4-yl}-phenyl)- oxazolidin-2-one 1-(4-(4-((1-(4,4,4- trifluorobutyl)-1H- pyrazol-4- 064 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(3-methoxy-4-(2- ((1-(2-methoxyethyl)- 1H-pyrazol-4- 065 yl)amino)thiazol-4- yl)phenyl)imidazolidi n-2-one 1-(4-{2-[1-(2-Ethoxy- ethyl)-1H-pyrazol-4- ylamino]-thiazol-4- 066 yl}-3-methyl- phenyl)-imidazolidin- 2-one
Ex # Structure Name (IUPAC) 1-(4-(2-((1-(2- methoxyethyl)-1H- pyrazol-4- 067 yl)amino)thiazol-4- yl)-3- methylphenyl)imidaz olidin-2-one 1-(4-{2-[1-(2-Ethoxy- ethyl)-1H-pyrazol-4- ylamino]-thiazol-4- 068 yl}-3-methoxy- phenyl)-(R)-4- methyl-imidazolidin- 2-one 1-(4-{2-[1-(2-Ethoxy- ethyl)-1H-pyrazol-4- 069 ylamino]-thiazol-4- yl}-3-fluoro-phenyl)- imidazolidin-2-one 1-(3-Methoxy-4-{2- [1-(3-methoxy- propyl)-1H-pyrazol- 070 4-ylamino]-thiazol-4- yl}-phenyl)- imidazolidin-2-one 1-(4-{2-[1-(2- Methoxy-ethyl)-1H- pyrazol-4-ylamino]- 071 thiazol-4-yl}-3- fluoro-phenyl)- imidazolidin-2-one 3-(4-{2-[1-(2-Ethoxy- ethyl)-1H-pyrazol-4- ylamino]-thiazol-4- 072 yl}-3-methyl- phenyl)-oxazolidin-2- one
Ex # Structure Name (IUPAC) 1-(4-(4-((1-(3- fluorobenzyl)-1H- pyrazol-4- 073 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-{2-[1-(2-Ethoxy- ethyl)-1H-pyrazol-4- ylamino]-thiazol-4- 074 yl}-3-isopropoxy- phenyl)-imidazolidin- 2-one 3-(4-{2-[1-(2-Ethoxy- ethyl)-1H-pyrazol-4- ylamino]-thiazol-4- 075 yl}-3-methoxy- phenyl)-oxazolidin-2- one 3-(4-{2-[1-(2-Ethoxy- ethyl)-1H-pyrazol-4- 076 ylamino]-thiazol-4- yl}-3-fluoro-phenyl)- oxazolidin-2-one 1-(4-{2-[1-(2-Ethoxy- ethyl)-5-methyl-1H- pyrazol-4-ylamino]- 077 thiazol-4-yl}-3- methoxy-phenyl)- imidazolidin-2-one 1-(4-{2-[1-(2-Ethoxy- ethyl)-3-methyl-1H- pyrazol-4-ylamino]- 078 thiazol-4-yl}-3- methoxy-phenyl)- imidazolidin-2-one
Ex # Structure Name (IUPAC) 1-(4-(4-((1- (difluoromethyl)-1H- pyrazol-4- 079 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((1-methyl-3- (trifluoromethyl)-1H- pyrazol-4- 080 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-{2-[1-(2-Ethoxy- ethyl)-3-methoxy- 081 1H-pyrazol-4- ylamino]-thiazol-4- yl}-phenyl)- imidazolidin-2-one 1-(4-{2-[1-(2-Ethoxy- ethyl)-3-methoxy- 1H-pyrazol-4- 082 ylamino]-thiazol-4- yl}-3-methoxy- phenyl)-imidazolidin- 2-one 1-(4-{2-[1-(2-Ethoxy- ethyl)-3-methyl-1H- 083 pyrazol-4-ylamino]- thiazol-4-yl}-phenyl)- imidazolidin-2-one
Ex # Structure Name (IUPAC) 1-(3-Fluoro-4-{2-[1- (3-methoxy-propyl)- 1H-pyrazol-4- 084 ylamino]-thiazol-4- yl}-phenyl)- imidazolidin-2-one 1-(3'-((1-isopropyl- 1H-pyrazol-4- 085 yl)amino)-[1,1'- biphenyl]-4- yl)imidazolidin-2-one 1-(4-{2-[3-Chloro-1- (2-ethoxy-ethyl)-1H- 086 pyrazol-4-ylamino]- thiazol-4-yl}-phenyl)- imidazolidin-2-one 1-(4-{2-[1-(2-Ethoxy- ethyl)-1H-pyrazol-4- 087 ylamino]-5-methyl- thiazol-4-yl}-phenyl)- imidazolidin-2-one 1-(4-{2-[1-(2-Ethoxy- ethyl)-3-methyl-1H- pyrazol-4-ylamino]- 088 thiazol-4-yl}-3- fluoro-phenyl)- imidazolidin-2-one 1-(4-{2-[1-(2-Ethoxy- ethyl)-5-methyl-1H- 089 pyrazol-4-ylamino]- thiazol-4-yl}-3- fluoro-phenyl)- imidazolidin-2-one
Ex # Structure Name (IUPAC) 1-(3-Chloro-4-{2-[1- (3-methoxy-propyl)- 1H-pyrazol-4- 090 ylamino]-thiazol-4- yl}-phenyl)- pyrrolidin-2-one 1-(4-(4-((1-(2,2,2- trifluoroethyl)-1H- pyrazol-4- 091 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(3-Chloro-4-{2-[1- (2-ethoxy-ethyl)-3- methyl-1H-pyrazol-4- 092 ylamino]-thiazol-4- yl}-phenyl)- pyrrolidin-2-one 1-(4-(4-((1-(2,2- difluoroethyl)-1H- pyrazol-4- 093 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-{2-[1-(2-Ethoxy- ethyl)-1H-pyrazol-4- 094 ylamino]-thiazol-4- yl}-3-methoxy- phenyl)-pyrrolidin-2- one 1-(4-(2-((1-(2,2- difluoroethyl)-1H- pyrazol-4- 095 yl)amino)pyrimidin- 4- yl)phenyl)imidazolidi n-2-one
Ex # Structure Name (IUPAC) 1-(4-(2-((1-(2,2,2- trifluoroethyl)-1H- pyrazol-4- 096 yl)amino)pyrimidin- 4- yl)phenyl)imidazolidi n-2-one 1-(4-{2-[1-(2- [1,2,4]Triazol-1-yl- ethyl)-1H-pyrazol-4- 097 ylamino]-thiazol-4- yl}-phenyl)- imidazolidin-2-one 1-(4-(4-((1-propyl- 1H-pyrazol-4- yl)amino)pyrimidin- 098 2- yl)phenyl)imidazolidi n-2-one 1-(4-(2-((1-(2,2,3,3,3- pentafluoropropyl)- 1H-pyrazol-4- 099 yl)amino)pyrimidin- 4- yl)phenyl)imidazolidi n-2-one 1-(4-(2-((1-propyl- 1H-pyrazol-4- yl)amino)pyrimidin- 100 4- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((1-(2,2,3,3,3- pentafluoropropyl)- 1H-pyrazol-4- 101 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one
Ex # Structure Name (IUPAC) 1-(4-(4-((1- cyclopropyl-1H- pyrazol-4- 102 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((1- cyclobutyl-1H- pyrazol-4- 103 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((1-(oxetan-3- yl)-1H-pyrazol-4- 104 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-(2-((1-(1- hydroxy-2- methylpropan-2-yl)- 1H-pyrazol-4- 105 yl)amino)pyrimidin- 4- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((1-(1- hydroxypropan-2-yl)- 1H-pyrazol-4- 106 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-{2-[1-(3- Methoxy-propyl)-3- methyl-1H-pyrazol-4- 107 ylamino]-thiazol-4- yl}-phenyl)- imidazolidin-2-one
Ex # Structure Name (IUPAC) 1-(4-{2-[1-(2- Methoxy-ethyl)-3- methyl-1H-pyrazol-4- 108 ylamino]-thiazol-4- yl}-phenyl)- imidazolidin-2-one 2-methyl-2-(4-((2-(4- (2-oxoimidazolidin- 1- 109 yl)phenyl)pyrimidin- 4-yl)amino)-1H- pyrazol-1- yl)propanenitrile 1-(4-{5-[1-(2-Ethoxy- ethyl)-1H-pyrazol-4- ylamino]-2H-pyrazol- 110 3-yl}-3-methoxy- phenyl)-imidazolidin- 2-one 1-(4-(4-((1-(1- methoxypropan-2- yl)-1H-pyrazol-4- 111 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-(2-((1-(1- methoxy-2- methylpropan-2-yl)- 112 1H-pyrazol-4- yl)amino)pyrimidin- 4- yl)phenyl)imidazolidi n-2-one 1-(4-(2-((1-(1- methoxypropan-2- yl)-1H-pyrazol-4- 113 yl)amino)pyrimidin- 4- yl)phenyl)imidazolidi n-2-one
Ex # Structure Name (IUPAC) 2-methyl-2-(4-((4-(4- (2-oxoimidazolidin- 1- 114 yl)phenyl)pyrimidin- 2-yl)amino)-1H- pyrazol-1- yl)propanenitrile 2-(4-((2-(4-(2- oxoimidazolidin-1- yl)phenyl)pyrimidin- 115 4-yl)amino)-1H- pyrazol-1- yl)propanenitrile 1-(4-(2-((1- cyclopropyl-1H- pyrazol-4- 116 yl)amino)pyrimidin- 4- yl)phenyl)imidazolidi n-2-one 1-(4-{5-[1-(2-Ethoxy- ethyl)-1H-pyrazol-4- 117 ylamino]-2H-pyrazol- 3-yl}-3-fluoro- phenyl)-imidazolidin- 2-one 1-(4-{2-[1-(2-Azido- ethyl)-1H-pyrazol-4- 118 ylamino]-thiazol-4- yl}-phenyl)- imidazolidin-2-one 1-(3-Methoxy-4-{2- [1-(3-methoxy- 119 propyl)-3-methyl-1H- pyrazol-4-ylamino]- thiazol-4-yl}-phenyl)- imidazolidin-2-one
Ex # Structure Name (IUPAC) 1-(4-(4-((1-isopropyl- 3-methyl-1H-pyrazol- 4- 120 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((1-(1- methoxybutan-2-yl)- 1H-pyrazol-4- 121 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-(2-((1-(1- methoxybutan-2-yl)- 1H-pyrazol-4- 122 yl)amino)pyrimidin- 4- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((1-(1- ethoxypropan-2-yl)- 1H-pyrazol-4- 123 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-(2-((1-(1- ethoxybutan-2-yl)- 1H-pyrazol-4- 124 yl)amino)pyrimidin- 4- yl)phenyl)imidazolidi n-2-one 1-(4-(2-((1-(1- ethoxypropan-2-yl)- 1H-pyrazol-4- 125 yl)amino)pyrimidin- 4- yl)phenyl)imidazolidi n-2-one
Ex # Structure Name (IUPAC) 1-(4-{2-[1-(2- Methoxy-ethyl)-3- methyl-1H-pyrazol-4- 126 ylamino]-thiazol-4- yl}-phenyl)-4-(R)- methyl-imidazolidin- 2-one 1-(3-Fluoro-4-{2-[1- (2-methoxy-ethyl)-3- methyl-1H-pyrazol-4- 127 ylamino]-thiazol-4- yl}-phenyl)- imidazolidin-2-one 1-(4-(4-((1-(1- methoxy-3- methylbutan-2-yl)- 128 1H-pyrazol-4- yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((1-(2,2- difluorocyclopropyl)- 1H-pyrazol-4- 129 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-(2-((1-(1- methoxy-3- methylbutan-2-yl)- 1H-pyrazol-4- 130 yl)amino)pyrimidin- 4- yl)phenyl)imidazolidi n-2-one 1-(4-(2-((1-(2,2- difluorocyclopropyl)- 1H-pyrazol-4- 131 yl)amino)pyrimidin- 4- yl)phenyl)imidazolidi n-2-one
Ex # Structure Name (IUPAC) 1-(4-(4-((1-(2- methoxy-2- methylpropyl)-1H- pyrazol-4- 132 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one (R)-1-(4-(4-((1- isopropyl-1H- pyrazol-4- 133 yl)amino)pyrimidin- 2-yl)phenyl)-4- methylimidazolidin- 2-one 1-(4-(2-((1-(2- methoxy-2- methylpropyl)-1H- pyrazol-4- 134 yl)amino)pyrimidin- 4- yl)phenyl)imidazolidi n-2-one 1-(4-(2-((1-(1- ethoxy-3- methylbutan-2-yl)- 1H-pyrazol-4- 135 yl)amino)pyrimidin- 4- yl)phenyl)imidazolidi n-2-one (R)-1-(4-(4-((1-(2- methoxypropyl)-1H- pyrazol-4- 136 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((1-isopropyl- 1H-pyrazol-4- yl)amino)pyrimidin- 137 2-yl)phenyl)-4,4- dimethylimidazolidin -2-one
Ex # Structure Name (IUPAC) (S)-1-(4-(4-((1-(2- methoxypropyl)-1H- pyrazol-4- 138 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((1-isopropyl- 3-(trifluoromethyl)- 1H-pyrazol-4- 139 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one N N 1-(4-(4-((1,5- N dimethyl-1H-pyrazol- N N 4- 140 H yl)amino)pyrimidin- N 2- HN yl)phenyl)imidazolidi O n-2-one 1-(4-(2-((1-isopropyl- 3-(trifluoromethyl)- 1H-pyrazol-4- 141 yl)amino)pyrimidin- 4- yl)phenyl)imidazolidi n-2-one 1-(4-(2-((1,5- dimethyl-1H-pyrazol- 4- 142 yl)amino)pyrimidin- 4- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((1-(3- methoxypropyl)-1H- pyrazol-4- 143 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one
Ex # Structure Name (IUPAC) 1-(4-{2-[1-(3- Methoxy-propyl)-3- methyl-1H-pyrazol-4- 144 ylamino]-thiazol-4- yl}-3-methyl- phenyl)-imidazolidin- 2-one 1-(4-(4-((1-(2- methoxyethyl)-3- (trifluoromethyl)-1H- pyrazol-4- 145 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 3-(4-{2-[1-(3- Methoxy-propyl)-1H- 146 pyrazol-4-ylamino]- thiazol-4-yl}-phenyl)- oxazolidin-2-one 3-(3-Fluoro-4-{2-[1- (3-methoxy-propyl)- 147 1H-pyrazol-4- ylamino]-thiazol-4- yl}-phenyl)- oxazolidin-2-one 3-(3-Fluoro-4-{2-[1- (2-methoxy-ethyl)- 148 1H-pyrazol-4- ylamino]-thiazol-4- yl}-phenyl)- oxazolidin-2-one 1-(4-{2-[1-(3- Methoxy-propyl)-1H- 149 pyrazol-4-ylamino]- thiazol-4-yl}-phenyl)- imidazolidin-2-one 3-(4-{2-[1-(2- Methoxy-ethyl)-1H- 150 pyrazol-4-ylamino]- thiazol-4-yl}-phenyl)- oxazolidin-2-one
Ex # Structure Name (IUPAC) 1-(4-{2-[1-(2-Ethoxy- ethyl)-1H-pyrazol-4- 151 ylamino]-thiazol-4- yl}-phenyl)- pyrrolidin-2-one 1-(4-(4-((1- (cyclopropylmethyl)- 1H-pyrazol-4- 152 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((1-((3- (methoxymethyl)oxet an-3-yl)methyl)-1H- pyrazol-4- 153 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((1-(1,4- dimethoxybutan-2- yl)-1H-pyrazol-4- 154 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((1-(3- methoxycyclobutyl)- 1H-pyrazol-4- 155 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one 1-(4-(4-((3-methoxy- 1-methyl-1H-pyrazol- 4- 156 yl)amino)pyrimidin- 2- yl)phenyl)imidazolidi n-2-one
Ex # Structure Name (IUPAC) 3-(4-{2-[1-(2-Ethoxy- ethyl)-3-methyl-1H- pyrazol-4-ylamino]- 157 thiazol-4-yl}-3- fluoro-phenyl)- oxazolidin-2-one 3-(4-{2-[1-(2-Ethoxy- ethyl)-3-methyl-1H- 158 pyrazol-4-ylamino]- thiazol-4-yl}-phenyl)- oxazolidin-2-one 1-(4-{2-[1-(2-Ethoxy- ethyl)-1H-pyrazol-4- 159 ylamino]-thiazol-4- yl}-3-fluoro-phenyl)- pyrrolidin-2-one 1-(4-{2-[1-(2-Ethoxy- ethyl)-3-methyl-1H- 160 pyrazol-4-ylamino]- thiazol-4-yl}-phenyl)- pyrrolidin-2-one 1-(4-{2-[1-(2-Ethoxy- ethyl)-3-methyl-1H- 161 pyrazol-4-ylamino]- thiazol-4-yl}-3- fluoro-phenyl)- pyrrolidin-2-one 1-(4-{2-[1-(3- Methoxy-propyl)-3- 162 methyl-1H-pyrazol-4- ylamino]-thiazol-4- yl}-phenyl)- pyrrolidin-2-one 3-(3-Fluoro-4-{2-[1- (2-methoxy-ethyl)-3- 163 methyl-1H-pyrazol-4- ylamino]-thiazol-4- yl}-phenyl)- oxazolidin-2-one 1-(3-Fluoro-4-{2-[1- (2-methoxy-ethyl)-3- methyl-1H-pyrazol-4- 164 ylamino]-thiazol-4- yl}-phenyl)- pyrrolidin-2-one
Ex # Structure Name (IUPAC) 3-(3-Fluoro-4-{2-[1- (2-methoxy-ethyl)-3- methyl-1H-pyrazol-4- 165 ylamino]-thiazol-4- yl}-phenyl)- oxazolidin-2-one 1-(3-Fluoro-4-{2-[1- (3-methoxy-propyl)- 3-methyl-1H-pyrazol- 166 4-ylamino]-thiazol-4- yl}-phenyl)- pyrrolidin-2-one 3-(4-{2-[1-(2-Ethoxy- ethyl)-1H-pyrazol-4- ylamino]-thiazol-4- 167 yl}-phenyl)-(R)-5- methyl-oxazolidin-2- one 1-(4-{2-[1-(2- Methoxy-ethyl)-1H- 168 pyrazol-4-ylamino]- thiazol-4-yl}-phenyl)- pyrrolidin-2-one 1-(4-{2-[1-(3- Methoxy-propyl)-1H- 169 pyrazol-4-ylamino]- thiazol-4-yl}-phenyl)- pyrrolidin-2-one 1-(3-Fluoro-4-{2-[1- (3-methoxy-propyl)- 1H-pyrazol-4- 170 ylamino]-thiazol-4- yl}-phenyl)- pyrrolidin-2-one 1-(3-Fluoro-4-{2-[1- (2-methoxy-ethyl)- 1H-pyrazol-4- 171 ylamino]-thiazol-4- yl}-phenyl)- pyrrolidin-2-one
Ex # Structure Name (IUPAC) 1-(4-{2-[1-(2-Ethoxy- ethyl)-1H-pyrazol-4- ylamino]-thiazol-4- 172 yl}-3-trifluoromethyl- phenyl)-imidazolidin- 2-one 1-(4-{5-[1-(2-Ethoxy- ethyl)-1H-pyrazol-4- ylamino]-2H-pyrazol- 173 3-yl}-3-fluoro- phenyl)-pyrrolidin-2- one 1-(4-{2-[1-(3-Ethoxy- propyl)-1H-pyrazol- 174 4-ylamino]-thiazol-4- yl}-phenyl)- imidazolidin-2-one 1-(4-{2-[1-(2-Ethoxy- ethyl)-1H-pyrazol-4- 175 ylamino]-thiazol-4- yl}-phenyl)-4-(R)- hydroxy-pyrrolidin-2- one 1-(3-Chloro-4-{2-[1- (2-ethoxy-ethyl)-1H- 176 pyrazol-4-ylamino]- thiazol-4-yl}-phenyl)- imidazolidin-2-one 1-(3-Chloro-4-{2-[1- (3-methoxy-propyl)- 1H-pyrazol-4- 177 ylamino]-thiazol-4- yl}-phenyl)- imidazolidin-2-one 1-(3-Chloro-4-{2-[1- (2-ethoxy-ethyl)-3- methyl-1H-pyrazol-4- 178 ylamino]-thiazol-4- yl}-phenyl)- imidazolidin-2-one
Ex # Structure Name (IUPAC) 1-(4-{2-[1-(2- [1,2,3]Triazol-2-yl- ethyl)-1H-pyrazol-4- 179 ylamino]-thiazol-4- yl}-phenyl)- imidazolidin-2-one 1-(4-{2-[1-(2- [1,2,3]Triazol-1-yl- ethyl)-1H-pyrazol-4- 180 ylamino]-thiazol-4- yl}-phenyl)- imidazolidin-2-one 1-(3-Chloro-4-{2-[1- (2-ethoxy-ethyl)-1H- 181 pyrazol-4-ylamino]- thiazol-4-yl}-phenyl)- pyrrolidin-2-one 3-(4-{4-[4-(2-Oxo- imidazolidin-1-yl)- 182 phenyl]-thiazol-2- ylamino}-pyrazol-1- yl)-propionic acid ethyl ester 2-[2-(4-{4-[4-(2-Oxo- imidazolidin-1-yl)- phenyl]-thiazol-2- ylamino}-pyrazol-1- 183 yl)-ethyl]-2H- [1,2,3]triazole-4- carboxylic acid methyl ester 1-(4-{2-[1-(2- Imidazol-1-yl-ethyl)- 1H-pyrazol-4- 184 ylamino]-thiazol-4- yl}-phenyl)- imidazolidin-2-one 1-(3-Chloro-4-{2-[1- (3-methoxy-propyl)- 3-methyl-1H-pyrazol- 185 4-ylamino]-thiazol-4- yl}-phenyl)- pyrrolidin-2-one
Ex # Structure Name (IUPAC) 1-(3-Chloro-4-{2-[1- (3-methoxy-propyl)- 3-methyl-1H-pyrazol- 186 4-ylamino]-thiazol-4- yl}-phenyl)- imidazolidin-2-one [0059] All references to compounds of formula (I) include references to salts, solvates, multi-component complexes and/or liquid crystals thereof. All references to compounds of formula (I) include references to polymorphs and/or crystal habits thereof. All references to compounds of formula (I) include references to pharmaceutically acceptable prodrugs thereof. All references to compounds of formula (I) include references to isotopically labelled compounds of formula (I), including deuterated compounds of formula (I). The compounds of formula (I) and subformulae thereof may contain at least one asymmetric center and thus may exist as different stereoisomeric forms. Accordingly, all references to compounds of formula (I) include references to all possible stereoisomers and includes not only the racemic compounds but the individual enantiomers and their non racemic mixtures as well. When a compound is desired as a single enantiomer, such single enantiomer may be obtained by stereospecific synthesis, by resolution of the final product or any convenient intermediate, or by chiral chromatographic methods as each are known in the art. Resolution of the final product, an intermediate, or a starting material may be carried out by any suitable method known in the art. [0060] The compounds of the invention may be in the form of pharmaceutically acceptable solvates. Pharmaceutically acceptable solvates of the compounds of formula (I) include hydrates thereof. [0061] The compounds of the invention may be in the form of pharmaceutically acceptable salts. Pharmaceutically acceptable salts of the compounds of formula (I) include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide,
hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinafoate salts. Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, 2- (diethylamino)ethanol, diolamine, ethanolamine, glycine, 4-(2-hydroxyethyl)- morpholine, lysine, magnesium, meglumine, morpholine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts. When the compounds of formula (I) contain an acidic group as well as a basic group, the compounds of the invention may also form internal salts, and such compounds are within the scope of the invention. When the compounds of the invention contain a hydrogen donating heteroatom (e.g., NH), the invention also covers salts and/or isomers formed by transfer of said hydrogen atom to a basic group or atom within the molecule Pharmaceutically acceptable salts of compounds of formula (I) may be prepared by one or more of these methods: (i) by reacting the compound of formula (I) with the desired acid; (ii) by reacting the compound of formula (I) with the desired base; (iii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of formula (I) or by ring-opening a suitable cyclic precursor, e.g., a lactone or lactam, using the desired acid; and/or (iv) by converting one salt of the compound of formula (I) to another by reaction with an appropriate acid or by means of a suitable ion exchange column. All these reactions are typically carried out in solution. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the salt may vary from completely ionized to almost non-ionized. Pharmaceutical composition [0062] Another object of the present invention is a composition comprising a compound according to the invention as described herein. According to some embodiments, the composition further comprises at least one pharmaceutically acceptable carrier, so that the composition is a “pharmaceutical composition” as defined herein.
[0063] According to some embodiments, the pharmaceutical composition comprises the compound according to the invention as sole active pharmaceutical ingredient. According to other embodiments, the pharmaceutical composition further comprises at least another active pharmaceutical ingredient (i.e., an active pharmaceutical ingredient that is not a compound according to the invention). In some embodiments, the at least another active pharmaceutical ingredient is suitable for treating a hematological disorder and/or a proliferative disorder. [0064] Another object of the present invention is a medicament comprising a compound according to the invention as described herein. Kit [0065] Another object of the present invention is a kit of parts (in short “kit”) comprising a compound or composition according to the invention as described herein. According to some embodiments, the kit comprises a manufacture such as, for example, a package or a container. According to some embodiments, the kit comprises instructions for use. The kit may be promoted, distributed, or sold as a unit for performing the medical uses of the present invention. [0066] According to some embodiments, the kit comprises: a pharmaceutical composition comprising the compound according to the invention, and another separate pharmaceutical composition comprising at least another active pharmaceutical ingredient. In some embodiments, the at least another active pharmaceutical ingredient is suitable for treating a hematological disorder and/or a proliferative disorder. Medical uses [0067] Another object of the present invention is a compound or a composition (in particular, a pharmaceutical composition) according to the invention, as described herein, for use as a medicament. [0068] Another object of the present invention is a compound or a composition according to the invention, as described herein, for use in the treatment of a hematological disorder and/or a proliferative disorder.
[0069] Another object of the present invention is a method for treating a hematological disorder and/or a proliferative disorder in a subject in need thereof. Another object of the present invention is the use of a compound or a composition according to the invention, as described herein, in the manufacture of a medicament for the treatment of a hematological disorder and/or a proliferative disorder. Another object of the present invention is the use of a compound or a composition according to the invention, as described herein, for treating a hematological disorder and/or a proliferative disorder. [0070] According to one embodiment, the method or the use comprises a step of administering to a subject a therapeutically effective amount of a compound, a composition or a medicament according to the invention, as described herein. [0071] According to some embodiments, the hematological disorder to be treated by the method or the use of the invention is lymphoma, leukemia, multiple myeloma (MM), myelodysplastic syndrome (MDS) or myelodysplasia with myelofibrosis. In some embodiments, the leukemia is acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic lymphoid leukemia (CLL) or chronic myeloid leukemia (CML). According to some embodiments, the proliferative disorder to be treated by the method or the use of the invention is cancer. In some embodiments, the cancer is a solid cancer. In some embodiments, the cancer is head and neck cancer, melanoma, kidney carcinoma, stomach carcinoma, liver carcinoma, colorectal carcinoma, pancreas carcinoma, larynx carcinoma, lung carcinoma, neuronal carcinoma, glioblastoma multiforme, osteosarcoma, fibrosarcoma, ovarian sarcoma, liposarcoma, Ewing sarcoma, breast carcinoma, ovary carcinoma or prostate carcinoma. [0072] According to one embodiment, the compound or the composition or the medicament according to the invention, as described herein, is to be administered to a subject, and may be formulated using methods well-known in the art. Non-limiting examples of forms adapted for administration include solutions (such as, for example, sterile aqueous solutions), gels, dispersions, emulsions, suspensions and solid forms suitable for using to prepare solutions or suspensions upon the addition of a liquid prior to use (such as, for example, powder or liposomal forms). The compound or the composition or the medicament according to the invention, as described herein, may be
administered using administration route well-known in the art such as, for example, parenterally, orally, by inhalation, spray, rectally, nasally, or via an implanted reservoir. [0073] It will be however understood that the total daily usage of the compound, the composition or the medicament will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disease being treated and the severity of the disease; activity of the compound employed; the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific therapeutic agent employed; the duration of the treatment; drugs used in combination or coincidental with the specific therapeutic agent employed; and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. The total dose required for each treatment may be administered by multiple doses or in a single dose. [0074] In one embodiment, the dosage of the compound is about 0.01 to 500 mg per kg patient body weight per day, which can be administered in single or multiple doses. Preferably, the dosage level will be about 0.1 to about 250 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day. A suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be about 0.05 to 0.5, about 0.5 to 5 or about 5 to 50 mg/kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing from about 1.0 to 1000 milligrams of the active ingredient, particularly about 1.0, about 5.0, about 10.0, about 15.0, about 20.0, about 25.0, about 50.0, about 75.0, about 100.0, about 150.0, about 200.0, about 250.0, about 300.0, about 400.0, about 500.0, about 600.0, about 750.0, about 800.0, about 900.0, and about 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend
upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy. [0075] According to some embodiments, the compound or the composition or the medicament according to the invention, as described herein, is to be administered as sole active pharmaceutical ingredient. According to other embodiments, the compound or the composition or the medicament according to the invention, as described herein, is to be administered with at least another active pharmaceutical ingredient. According to other embodiments, the compound or the composition or the medicament according to the invention, as described herein, is to be administered before at least another active pharmaceutical ingredient, concomitantly with at least another active pharmaceutical ingredient, and/or after at least another active pharmaceutical ingredient. In some embodiments, the composition or the medicament according to the invention, as described herein, is a combined preparation for sequential, simultaneous or separate use in the treatment of hematological disorders and/or proliferative disorders. In some embodiments, the at least another active pharmaceutical ingredient is suitable for treating a hematological disorder and/or a proliferative disorder.
Scheme 2 [0080] Compounds of formula I-c may alternatively be prepared through copper- or palladium-catalyzed coupling reactions according to Scheme 3 below, by reacting compound IX and optionally substituted heterocycles A, where Q is I, Br or Cl. A person of ordinary skill in the art will recognize that compounds IX may be prepared according to the protocols outlined in Schemes 1 and 2 above.
Scheme 8
[0089] Preparation of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)imidazolidin-2-one (1b). Intermediate 1b was prepared in 2 steps using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline 1a and 2-chloroethyl isocyanate and Et3N then KOtBu according to the method described for example 225 in EP2857400 (2015). The crude product was purified by column chromatography (Puriflash) on SiO2 eluting with 2-5% EtOH in DCM to afford 1b as a white solid (2.43g, 59%). 1H NMR (400 MHz, DMSO-d6) δ 7.68 – 7.44 (m, 4H), 7.06 (s, 1H), 3.97 – 3.75 (m, 2H), 3.41 (dd, J = 9.2, 6.8 Hz, 2H), 1.28 (s, 12H). [0090] Preparation of 1-(2-methoxyethyl)-4-nitro-1H-pyrazole (1d). In a similar fashion to the method described in WO 2015/089337 (p125-6), a mixture of 4-nitro-1H- pyrazole 1c (2.00g, 17.6mmol) and 1-bromo-2-methoxyethane (1.66ml, 17.6mmol) and K2CO3 (5.47g, 39.6mmol) in MeCN (50ml) was heated to 80°C for 18h. The cooled mixture was treated with water and extracted with DCM. The combined organics were dried over MgSO4, filtered and evaporated then purified by column chromatography on SiO2 (Puriflash) eluting with 0-5% EtOH in DCM to afford 1d as a clear oil (2.77g,92%).1H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.26 (s, 1H), 4.34 (t, J = 5.2 Hz, 2H), 3.79 – 3.64 (m, 2H), 3.23 (s, 3H). [0091] Preparation of 1-(2-methoxyethyl)-1H-pyrazol-4-amine (1e). A solution of intermediate 1d (2.75g, mmol) in EtOH (50ml) was treated with 10% Pd/C and stirred under an atmosphere of H2 at ambient temperature and pressure for 18h. The mixture was filtered and evaporated to afford crude 1e as a red oil. 1H NMR (400 MHz, Chloroform- d) δ 7.16 (d, J = 1.0 Hz, 1H), 7.09 (d, J = 0.9 Hz, 1H), 4.16 (t, J = 5.3 Hz, 2H), 3.69 (t, J = 5.3 Hz, 2H), 3.33 (s, 3H). [0092] Preparation of 2-chloro-N-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyrimidin-4- amine (1g). A stirred solution of 2,4-dichloropyrimidine 1f (500mg, 3.36mmol), 1e (474mg, 3.36mmol) and Et3N (515µL, 3.70mmol) in iPrOH (20ml) was heated to reflux under argon for 18h. The cooled mixture was treated with water then extracted with DCM. The combined organics were dried over MgSO4, filtered and evaporated then purified by column chromatography on SiO2 (Puriflash) eluting with 0-2% EtOH in DCM to afford 1g as a brown oil which solidified on standing (464mg, 54%). 1H NMR (400 MHz,
DMSO-d6) δ 10.01 (s, 1H), 8.05 (d, J = 5.9 Hz, 1H), 7.93 (s, 1H), 7.53 (s, 1H), 6.61 (d, J = 5.9 Hz, 1H), 4.24 (t, J = 5.3 Hz, 2H), 3.67 (t, J = 5.3 Hz, 2H), 3.23 (s, 3H). [0093] Preparation of 1-(4-(4-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin- 2-yl)phenyl)imidazolidin-2-one (001). A sealed tube was charged with 1g (100mg, 0.394mmol), 1b (136mg, 0.473mmol), Pd(PPh3)4 (23mg, 0.0197mmol), K2CO3 (163mg, 1.18mmol), dioxane (5ml) and water (1ml) and degassed with a stream of argon for 5 mins. The tube was sealed and heated with stirring to 100°C for 18h then cooled and treated with water and extracted with a mixture of DCM and EtOH. The combined organics were dried over MgSO4, filtered and evaporated then purified by column chromatography on SiO2 (Puriflash) eluting with 5-15% EtOH in DCM to afford compound 001 as a white solid (46 mg, 31%) after trituration from DCM with pentane. 1H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 1H), 8.32 – 8.27 (m, 2H), 8.25 (d, J = 5.8 Hz, 1H), 8.10 (s, 1H), 7.72 – 7.67 (m, 2H), 7.59 (s, 1H), 7.08 (s, 1H), 6.52 (d, J = 5.9 Hz, 1H), 4.30 (t, J = 5.2 Hz, 2H), 3.95 – 3.88 (m, 2H), 3.71 (t, J = 5.2 Hz, 2H), 3.49 – 3.38 (m, 2H), 3.28 (s, 3H). Synthesis of Compound 002
Scheme 9 [0094] Preparation of 2-Chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (2b). Intermediate 2b was prepared as for intermediate 1g above from 2,4-dichloropyrimidine 1f and 1-methyl-1H-pyrazol-4-amine 2a to afford 2b as a beige solid (1.70g, 79%) after purification by column chromatography on SiO2 (Puriflash) eluting with 5% EtOH in DCM. 1H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 8.05 (d, J = 5.9 Hz, 1H), 7.90 (s, 1H), 7.49 (s, 1H), 6.61 (d, J = 6.0 Hz, 1H), 3.83 (s, 3H). [0095] Preparation of 1-(4-(4-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-2- yl)phenyl)imidazolidin-2-one (002). Compound 002 was then prepared from 2b and 1b as described for compound 001 above to afford compound 002 as a beige solid (60 mg,
45%).1H NMR (400 MHz, DMSO-d6) δ 9.49 (s, 1H), 8.31 (d, J = 8.9 Hz, 2H), 8.25 (d, J = 5.8 Hz, 1H), 8.03 (s, 1H), 7.71 (d, J = 8.9 Hz, 2H), 7.59 (s, 1H), 7.09 (s, 1H), 6.53 (d, J = 5.8 Hz, 1H), 3.97 – 3.90 (m, 2H), 3.89 (s, 3H), 3.45 (t, J = 7.9 Hz, 2H), 3.33 (s, 3H). Synthesis of Compound 003
[0096] Preparation of 1-tritylimidazolidin-2-one (3b). A solution of imidazolidin-2-one 3a (20.0g, 230mmol), triphenylmethyl chloride (65.0g, 230mmol) and Et3N (65ml, 460mmol) in anhydrous DCM (200ml) was stirred at RT for 42h. The mixture was diluted with water, extracted with DCM and the combined organics washed twice with brine, dried over MgSO4, filtered and evaporated to afford 3b as a white solid (60.8g, 80%).1H NMR (300 MHz, DMSO-d6) δ 7.47 – 7.32 (m, 6H), 7.33 – 7.22 (m, 6H), 7.22 – 7.12 (m, 3H), 6.40 (s, 1H), 3.32 – 3.09 (m, 4H). [0097] Preparation of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3- tritylimidazolidin-2-one (3d). A sealed tube was charged with intermediate 3b (3.19, 9.71mmol), 2-(4-bromophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 3c (2.50g, 8.83mmol), Pd2(dba)3 (647mg, 0.706mmol), XantPhos (1.02g, 1.77mmol), Cs2CO3 (6.33g, 19.4mmol) and dioxane (30ml) and degassed with a stream of argon for 5 mins. The tube was sealed and heated with stirring to 100°C for 18h then the cooled mixture was diluted with water and extracted with EtOAc. The combined organics were dried over MgSO4, filtered and evaporated then purified by column chromatography on SiO2 (Puriflash) eluting with 0-20% EtOAc in cyclohexane to afford 3d as a yellow foam (4.00g, 85%).1H NMR (400 MHz, DMSO-d6) δ 7.61 – 7.53 (m, 2H), 7.50 – 7.36 (m, 8H), 7.34 – 7.27 (m, 6H), 7.24 – 7.19 (m, 3H), 3.88 – 3.77 (m, 2H), 3.44 (t, J = 7.5 Hz, 2H), 1.37 – 1.19 (m, 12H).
[0098] Preparation of 1-(4-(2-chloropyrimidin-4-yl)phenyl)-3-tritylimidazolidin-2- one (3e). A sealed tube was charged with 3d (3.82g, 7.20mmol), 2,4-dichlropyrimidine 1f (2.15g, 14.4mmol), Pd(PPh3)4 (166mg, 0.144mmol), 0.4M aqu. Na2CO3 (43ml, 17.3mmol) and MeCN (53ml) and degassed with a stream of argon for 5 mins. The tube was sealed and heated with stirring to 100°C for 18h then the cooled mixture was diluted with water and extracted with EtOAc. The combined organics were dried over MgSO4, filtered and evaporated and the residue purified by column chromatography on SiO2 (Puriflash) eluting with 0-30% EtOAc in cyclohexane to afford 3e as a yellow foam (3.08g, 83%). 1H NMR (300 MHz, DMSO-d6) δ 8.72 (d, J = 5.4 Hz, 1H), 8.13 (d, J = 8.9 Hz, 2H), 8.05 (d, J = 5.4 Hz, 1H), 7.64 (d, J = 9.0 Hz, 2H), 7.44 – 7.39 (m, 6H), 7.36 – 7.29 (m, 6H), 7.26 – 7.19 (m, 3H), 3.90 (t, J = 7.5 Hz, 2H), 3.48 (t, J = 7.5 Hz, 2H). [0099] Preparation of 1-(4-(2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin- 4-yl)phenyl)imidazolidin-2-one (003). A sealed tube was charged with 3e (200mg, 0.387mmol), 1e (55mg, 0.387mmol), Pd2(dba)3 (30mg, 0.031mmol), XantPhos (47mg,0.077 mmol), Cs2CO3 (287mg, 0.851mmol) and dioxane (5ml) and degassed with a stream of argon for 5 mins. The tube was sealed and heated with stirring to 100°C for 18h. The cooled mixture was treated with water and extracted with DCM. The combined organics were dried over MgSO4, filtered and evaporated then purified by column chromatography on SiO2 (Puriflash) eluting with 0-5% EtOH in DCM to afford crude 3f as a black gum. This gum was treated with 1.25M HCl in EtOH (10ml) was stirred at 50°C for 2h. The mixture was taken to pH8 with sat. aqu. NaHCO3. then extracted with DCM and the combined organics dried over MgSO4, filtered and evaporated. The residue was purified by column chromatography on SiO2 (Puriflash) eluting with 0-15% EtOH in DCM to afford compound 003 as a yellow solid (13mg, 9%). 1H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.42 (d, J = 5.2 Hz, 1H), 8.16 – 8.08 (m, 2H), 7.99 (s, 1H), 7.75 – 7.71 (m, 2H), 7.57 (s, 1H), 7.23 (d, J = 5.3 Hz, 1H), 7.12 (s, 1H), 4.25 (t, J = 5.3 Hz, 2H), 3.96 – 3.89 (m, 2H), 3.68 (t, J = 5.3 Hz, 2H), 3.47 – 3.42 (m, 2H), 3.26 (s, 3H).
Synthesis of Compound 004
Scheme 11 [0100] Preparation of 1-(3,5-dimethylbenzyl)-1H-pyrazol-4-amine (4b). Intermediate 4b was prepared in 2 steps from 4-nitro-1H-pyrazole 1c and 3,5-dimethylbenzyl bromide via 1-(3,5-dimethylbenzyl)-4-nitro-1H-pyrazole 4a and hydrogenation with palladium catalyst as described for intermediate 1e above to afford 4b as a purple oil (641mg, 78%). 1H NMR (400 MHz, DMSO-d6) δ 7.03 (s, 1H), 6.92 (s, 1H), 6.89 (s, 1H), 6.78 (s, 2H), 5.02 (s, 2H), 3.82 (s, 2H), 2.22 (s, 6H). [0101] Preparation of 2-chloro-N-(1-(3,5-dimethylbenzyl)-1H-pyrazol-4-yl)pyrimidin- 4-amine (4c) and 4-chloro-N-(1-(3,5-dimethylbenzyl)-1H-pyrazol-4-yl)pyrimidin-2- amine (4d). A mixture of regioisomers 4c and 4d was prepared as for intermediate 1g above from 2,4-dichloropyrimidine 1f and 1-(3,5-dimethylbenzyl)-1H-pyrazol-4-amine 4b. Purification by column chromatography on SiO2 (Puriflash) eluting with 2-5% EtOH in DCM gave 4d as a beige solid (104mg, 10%; eluted first) then 4c as a white solid (749mg, 75%; eluted last). 4c : 1H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 8.05 (d, J = 5.9 Hz, 1H), 7.96 (s, 1H), 7.55 (s, 1H), 6.92 (s, 1H), 6.86 (s, 2H), 6.61 (d, J = 5.9 Hz, 1H), 5.23 (s, 2H), 2.24 (s, 6H). 4d : 1H NMR (400 MHz, DMSO-d6) δ 9.82 (s, 1H), 8.36 (d, J = 5.1 Hz, 1H), 7.91 (s, 1H), 7.54 (s, 1H), 6.91 (s, 1H), 6.85 (s, 2H), 6.81 (d, J = 5.2 Hz, 1H), 5.20 (s, 2H), 2.23 (s, 6H).
[0102] Preparation of 1-(4-(4-((1-(3,5-dimethylbenzyl)-1H-pyrazol-4- yl)amino)pyrimidin-2-yl)phenyl) imidazolidin-2-one (004). Compound 004 was prepared from 4c and 1b as for compound 001 above to afford 004 as a white solid (60mg, 38%). 1H NMR (400 MHz, DMSO-d6) δ 9.53 (s, 1H), 8.24 (d, J = 5.8 Hz, 1H), 8.23 – 8.19 (m,
[0104] Preparation of 1-(2-ethoxyethyl)-4-nitro-1H-pyrazole (6a). A mixture of 4-nitropyrazole 1c (2.00g, 17.7mmol), 1-bromo-2-ethoxyethane (1.99ml, 17.7mmol) and K2CO3 (5.50g, 39.8mmol) in MeCN (50ml) was stirred at 80°C for 3h. Water was added and mixture extracted with EtOAc, then the combined organics were dried over MgSO4, filtered and evaporated. The residue was purified by column chromatography on SiO2 (Puriflash) using 0 to 5% EtOH in DCM to give intermediate 6a as a clear mobile oil (2.90g, 88%). 1H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.26 (s, 1H), 4.33 (t, J = 5.3 Hz, 2H), 3.76 (t, J = 5.3 Hz, 2H), 3.42 (q, J = 7.0 Hz, 2H), 1.04 (t, J = 7.0 Hz, 3H). [0105] Preparation of 1-(2-ethoxyethyl)-1H-pyrazol-4-amine (6b). To a solution of intermediate 6a (2.89g, 15.6mmol) in ethanol (35ml) was added 10% Pd/C (289mg, 10% wt.). The reaction mixture was stirred at room temperature and pressure for 2h then the mixture was filtered and the filtrate concentrated to give intermediate 6b as a red mobile oil (2.43g, quant.).1H NMR (400 MHz, DMSO-d6) δ 7.02 (s, 1H), 6.89 (s, 1H), 4.04 (t, J = 5.6 Hz, 2H), 3.77 (s, 2H), 3.62 (t, J = 5.6 Hz, 2H), 3.39 (q, J = 7.0 Hz, 2H), 1.07 (t, J = 7.0 Hz, 3H). [0106] Preparation of 1-(4-(6-bromopyridin-2-yl)phenyl)-3-tritylimidazolidin-2- one (6d). Prepared as for intermediate 3e above from 3d and 2,6-dibromopyridine 6c using Pd(PPh3)4 and Cs2CO3 in dioxane / water to afford 6d as a beige solid (680mg, 57%). 1H NMR (400 MHz, DMSO-d6) δ 8.02 – 7.92 (m, 2H), 7.78 (t, J = 7.8 Hz, 1H), 7.64 – 7.49 (m, 4H), 7.46 – 7.39 (m, 6H), 7.33 (t, J = 7.7 Hz, 6H), 7.26 – 7.19 (m, 3H), 3.89 (dd, J = 8.6, 6.5 Hz, 2H), 3.47 (dd, J = 8.5, 6.6 Hz, 2H). [0107] Preparation of 1-(4-(6-((1-(2-ethoxyethyl)-1H-pyrazol-4-yl)amino)pyridin-2- yl)phenyl)imidazolidin-2-one (006). Compound 006 was then prepared as for 3f above from 6b and 6d using Pd2(dba)3, XantPhos, NaOtBu in dioxane to afford crude 6e. Treatment of crude 6e with a 1.25N solution of HCl in EtOH at 50°C for 2h as described for the preparation of compound 003 above afforded 006 as a beige powder (35mg, 17%). 1H NMR (300 MHz, DMSO-d6) δ 8.86 (s, 1H), 8.09 – 7.95 (m, 3H), 7.73 – 7.63 (m, 2H), 7.59 – 7.47 (m, 2H), 7.15 (d, J = 7.4 Hz, 1H), 7.04 (s, 1H), 6.58 (d, J = 8.2 Hz, 1H), 4.25 (t, J = 5.3 Hz, 2H), 3.91 (dd, J = 9.4, 6.6 Hz, 2H), 3.73, (t, J = 5.3 Hz, 2H), 3.45 (q, J = 7.0 Hz, 4H), 1.08 (t, J = 7.0 Hz, 3H).
Synthesis of Compound 007
Scheme 14 [0108] Preparation of 5-(4-iodophenyl)oxazole (7b). To a solution of 4-iodobenzaldehyde 7a (15.0g, 64.7mmol) in MeOH (150ml) were added K2CO3 (26.8g, 194mmol) and TosMIC (15.2g, 77.6mmol). The reaction mixture was stirred at room temperature for 16 hours. The mixture was evaporated to dryness, diluted with water and extracted with EtOAc twice. The combined organics were washed with water then with a saturated solution of NaCl, dried over MgSO4, filtered and evaporated. The final product was purified by silica gel chromatography using 30 % EtOAc/cyclohexane as eluent to give intermediate 7b as a yellow solid (10.7g, 61%).1H NMR (500 MHz, DMSO-d6) δ 8.47 (s, 1H), 7.86 (d, J = 8.4 Hz, 2H), 7.76 (s, 1H), 7.54 (d, J = 8.4 Hz, 2H). [0109] Preparation of 5-(4-iodophenyl)-2-chlorooxazole (7c). To a stirred solution of intermediate 7b (5.40g, 19.9mmol) in dry THF (55ml) was added a 1M solution of LiHMDS in THF (21.9ml, 21.9mmol) dropwise at -78°C. The reaction mixture was stirred at -78°C for 30mins then C2Cl6 (1.09g, 4.62mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with water and extracted with EtOAc twice. The combined organics were washed with water, then with a saturated aqueous solution of NaCl, dried over MgSO4, filtered and evaporated. The final product was purified by silica gel chromatography using 0 to 20 % EtOAc/cyclohexane as eluent to give intermediate 7c (4.80g, 79%). 1H NMR (500 MHz, DMSO-d6) δ 7.87 (d, J = 8.6 Hz, 2H), 7.86 (s, 1H), 7.50 (d, J = 8.5 Hz, 2H).
[0110] Preparation of N-(1-(2-ethoxyethyl)-1H-pyrazol-4-yl)-5-(4-iodophenyl)oxazol- 2-amine (7d). To a solution of intermediate 7c (512mg, 1.68mmol) in dry iPrOH (6 ml) were added intermediate 6b (260mg, 1.68mmol) and a 1M aqueous solution of HCl (400 µl, 0.400mmol) and the mixture stirred at 80°C for 5h. The cooled mixture was evaporated to dryness, diluted with water and extracted with EtOAc twice. The combined organics were dried over MgSO4, filtered and evaporated. The final product was purified by silica gel chromatography using EtOAc/MeOH as eluent to give intermediate 7d (78mg, 11%). 1H NMR (500 MHz, DMSO-d6) δ 9.98 (s, 1H), 7.83 (s, 1H), 7.77 (d, J = 8.5 Hz, 2H), 7.46 (d, J = 13.2 Hz, 2H), 7.35 (d, J = 8.5 Hz, 2H), 4.22 (t, J = 5.5 Hz, 2H), 3.71 (t, J = 5.5 Hz, 2H), 3.43 (q, J = 7.0 Hz, 2H), 1.08 (t, J = 7.0 Hz, 3H). [0111] Preparation of 1-(4-(2-((1-(2-ethoxyethyl)-1H-pyrazol-4-yl)amino)oxazol-5- yl)phenyl)imidazolidin-2-one (007). In a sealed tube, to a solution of 7d (78mg, 0.184mmol) in dry dioxane (2.3mL) were added successively 2-imidazolidinone 3a (159mg, 1.84mmol), cesium carbonate (132mg, 0.405mmol) and XantPhos (21mg, 0.037mmol). The reaction mixture was degassed with nitrogen for 20 minutes before the addition of Pd2(dba)3 (14mg, 0.015mmol). The reaction mixture was stirred at 110°C for 16 hours, then the cooled mixture was diluted with water and extracted with EtOAc. The combined organics were washed with a saturated solution of NaHCO3 then brine, dried over MgSO4, filtered and evaporated. The final product was purified by silica gel chromatography using 0 to 10 % MeOH/EtOAc as eluent to give compound 007 as beige powder (9mg, 13%). 1H NMR (500 MHz, DMSO-d6) δ 9.86 (s, 1H), 7.83 (s, 1H), 7.62 (d, J = 8.7 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H), 7.43 (s, 1H), 7.25 (s, 1H), 7.00 (s, 1H), 4.22 (t, J = 5.5 Hz, 2H), 3.90 – 3.85 (m, 2H), 3.71 (t, J = 5.5 Hz, 2H), 3.46 – 3.35 (m, 4H), 1.09 (t, J = 7.0 Hz, 3H).
Synthesis of Compound 008
Scheme 15 [0112] Preparation of 1-(1-(2-ethoxyethyl)-1H-pyrazol-4-yl)thiourea (8a). To a solution of ammonium thiocyanate (497mg, 6.53mmol) in acetone (8ml) was added dropwise at room temperature benzoyl chloride (690µl, 5.94mmol). The reaction mixture was stirred for 20mins at 70°C then a solution of intermediate 6b (922mg, 5.94mmol) in acetone (9ml) was added and the reaction mixture was stirred at 70°C for a further 20mins. The mixture was evaporated, water was added and the mixture extracted with EtOAc. The combined organics were washed with brine then dried over MgSO4, filtered and evaporated. The residue was dissolved in MeOH (17ml), treated with potassium carbonate (1.60g, 11.9mmol) and stirred at room temperature for 18h. Methanol was removed under reduced pressure and the residue was treated with water and extracted with EtOAc. The combined organics were dried over MgSO4, filtered and evaporated to give intermediate 8a (151mg, 12%).1H NMR (500 MHz, DMSO-d6) δ 9.32 (s, 1H), 7.86 (s, 2H), 7.41 (s, 1H), 7.24 (s, 1H), 4.18 (t, J = 5.5 Hz, 2H), 3.70 (t, J = 5.5 Hz, 2H), 3.42 (q, J = 7.0 Hz, 2H), 1.08 (t, J = 7.0 Hz, 3H). [0113] Preparation of 4-(4-bromophenyl)-N-(1-(2-ethoxyethyl)-1H-pyrazol-4- yl)thiazol-2-amine (8b). To a solution of 2,4'-dibromoacetophenone 8c (196mg, 0.705mmol) in EtOH (30ml) were added intermediate 8a (151mg, 0.75mmol) and potassium hydrogen carbonate (212mg, 2.11mmol). The reaction mixture was stirred at
80°C for 16 h, then the cooled mixture was evaporated, diluted with water and extracted with EtOAc. The combined organics were washed with brine then dried over MgSO4, filtered and evaporated. The residue was purified by silica gel chromatography using EtOAc as eluent to give intermediate 8b as a beige powder (116mg, 42%).1H NMR (500 MHz, DMSO-d6) δ 9.94 (s, 1H), 8.01 (s, 1H), 7.91 – 7.83 (m, 2H), 7.63 – 7.58 (m, 2H), 7.51 (s, 1H), 7.30 (s, 1H), 4.26 (t, J = 5.4 Hz, 2H), 3.73 (t, J = 5.4 Hz, 2H), 3.45 (q, J = 7.0 Hz, 2H), 1.10 (t, J = 7.0 Hz, 3H). [0114] Preparation of 1-(4-(2-((1-(2-ethoxyethyl)-1H-pyrazol-4-yl)amino)thiazol-4- yl)phenyl)imidazolidin-2-one (008). In a sealed tube, to a solution of 8b (116mg, 0.295mmol) in dry dioxane (4 mL) were added successively 2-imidazolidinone 3a (254mg, 2.95mmol), cesium carbonate (211mg, 0.649mmol), XantPhos (34mg, 0.059mmol). The reaction mixture was degassed with nitrogen for 20 minutes before the addition of Pd2(dba)3 (22mg, 0.024mmol). The reaction mixture was stirred at 110°C for 16 h, then the cooled mixture was diluted with water and extracted with EtOAc. The combined organics were washed with a saturated solution of NaHCO3, then brine and dried over MgSO4, filtered and evaporated. The final product was purified by silica gel chromatography using 0 to 20% MeOH in EtOAc as eluent to give intermediate compound 008 (38 mg, 32%). 1H NMR (500 MHz, DMSO-d6 δ 9.88 (s, 1H), 8.04 (s, 1H), 7.85 (d, J = 8.9 Hz, 2H), 7.60 (d, J = 8.9 Hz, 2H), 7.48 (s, 1H), 7.07 (s, 1H), 6.97 (s, 1H), 4.26 (t, J = 5.4 Hz, 2H), 3.94 – 3.86 (m, 2H), 3.73 (t, J = 5.4 Hz, 2H), 3.44 (p, J = 8.0, 7.5 Hz, 4H), 1.10 (t, J = 7.0 Hz, 3H).
Scheme 16 [0115] Preparation of 1-(2-ethoxyethyl)-4-isothiocyanato-1H-pyrazole (9a). A solution of intermediate 6b (800mg, 5.1 mmol) and thiocarbonyldiimidazole 9b (1.01g, 5.6 mmol) in dry DMF (15ml) was stirred at room temperature for 16 hours. The solvent was evaporated and the residue purified by silica gel chromatography using 50 % EtOAc in cyclohexane to give intermediate 9a (520mg, 51%).1H NMR (500 MHz, Chloroform-d) δ 7.54 (s, 2H), 4.28 (t, J = 5.7 Hz, 2H), 3.80 (t, J = 5.6 Hz, 2H), 3.49 (q, J = 7.0 Hz, 2H), 1.17 (t, J = 7.0 Hz, 3H). [0116] Preparation of 3-(4-bromophenyl)-N-(1-(2-ethoxyethyl)-1H-pyrazol-4-yl)-1,2,4- thiadiazol-5-amine (9d). A solution of intermediate 9a (520mg, 2.64mmol), 4- bromobenzamidine hydrochloride 9c (1.24g, 5.27mmol) and dry Et3N (767µl, 5.27mmol) in dry DMF (15 ml) was stirred at room temperature for 16 hours. DIAD (572µl, 2.90mmol) was added and the mixture was stirred at RT for a further 16 hours. Water was added and the crude product was extracted with EtOAc. The combined organics were washed with a saturated aqueous solution of NaHCO3, then with water and then with brine and dried over MgSO4, filtered and evaporated. The residue was purified by silica gel chromatography using 30 to 50 % EtOAc/cyclohexane as eluent to give intermediate 9d (500mg, 48%). 1H NMR (500 MHz, Chloroform-d) δ 8.06 (d, J = 8.5 Hz, 2H), 7.80 (s, 2H), 7.59 (d, J = 8.5 Hz, 2H), 4.36 (t, J = 5.7 Hz, 2H), 3.86 (t, J = 5.7 Hz, 2H), 3.52 (q, J = 7.0 Hz, 2H), 1.19 (t, J = 7.0 Hz, 3H).
[0117] Preparation of 1-(4-(5-((1-(2-ethoxyethyl)-1H-pyrazol-4-yl)amino)-1,2,4- thiadiazol-3-yl)phenyl)-3-tritylimidazolidin-2-one (9e). In a sealed tube, to a solution of intermediate 9d (500mg, 1.27mmol) in dry dioxane (10mL) were added successively intermediate 3b (500mg, 1.52mmol), cesium carbonate (828mg, 2.54mmol) and XantPhos (69mg, 0.12mmol). The reaction mixture was degassed with nitrogen for 20 minutes before the addition of Pd2(dba)3 (5 mg, 0.06mmol). The tube was sealed and the mixture was stirred at 110°C for 16 hours. The cooled mixture was diluted with water and extracted with EtOAc twice. The combined organics were washed with water then with a saturated solution of NaCl and dried over MgSO4, filtered and evaporated. The residue was purified by silica gel chromatography using 60 to 90 % EtOAc/cyclohexane as eluent to give intermediate 9e (440 mg, 53%). 1H NMR (500 MHz, Chloroform-d) δ 8.09 (d, J = 8.8 Hz, 2H), 7.78 (s, 2H), 7.57 (d, J = 8.8 Hz, 2H), 7.52 – 7.44 (m, 8H), 7.35 – 7.28 (m, 4H), 7.26 – 7.20 (m, 8H), 3.84 (d, J = 6.4 Hz, 2H), 3.54 (d, J = 7.2 Hz, 2H), 3.52 – 3.49 (m, 4H), 3.41 – 3.35 (m, 2H), 1.18 (t, J = 7.0 Hz, 3H). [0118] Preparation of 1-(4-(5-((1-(2-ethoxyethyl)-1H-pyrazol-4-yl)amino)-1,2,4- thiadiazol-3-yl)phenyl)imidazolidin-2-one (009). To a solution of intermediate 9e (440mg, 0.69mmol) in DCM (20 ml) was added dropwise TFA (5.0ml). The reaction mixture was stirred at RT for 16 hours. The solvent was evaporated, a saturated solution of NaHCO3 was added and the crude product was extracted with DCM. The combined organics were washed with water then with brine, then dried over MgSO4, filtered and evaporated. The reaction mixture was triturated with DCM and filtered. The resulting solid was purified by silica gel chromatography using 5 % MeOH/DCM as eluent to give compound 009 (110mg, 40%). 1H NMR (500 MHz, Chloroform-d) δ 8.17 (d, J = 8.7 Hz, 2H), 7.80 (s, 2H), 7.67 (d, J = 8.7 Hz, 2H), 4.36 (t, J = 5.6 Hz, 2H), 4.05 – 4.00 (m, 2H), 3.86 (t, J = 5.7 Hz, 2H), 3.67 – 3.62 (m, 2H), 3.51 (q, J = 7.0 Hz, 2H), 1.19 (t, J = 7.0 Hz, 3H).
Synthesis of Compound 010
Scheme 17 [0119] Preparation of 1-(2-methoxyethyl)-3-methyl-4-nitro-1H-pyrazole (10b). A solution of 4-nitro-3-methyl-1H-pyrazole 10a (6.00g, 47.2mmol), 1-bromo-2- methoxyethane (6.66ml, 70.8mmol) and potassium carbonate (13.0g, 94.4mmol) in dry butan-2-one (180ml) was stirred at 80°C for 16h. The solvent was evaporated then water was added and the crude product was extracted with EtOAc. The combined organics were washed with water then with brine and dried over MgSO4, filtered and evaporated. The residue was purified by silica gel chromatography using 0 to 70 % EtOAc/cyclohexane to give intermediate 10b as a colorless oil (8.30g, 95%).1H NMR (400 MHz, DMSO-d6) δ 8.76 (s, 1H), 4.27 (t, J = 5.2 Hz, 2H), 3.73 – 3.66 (m, 2H), 3.24 (s, 3H), 2.43 (s, 3H). [0120] Preparation of 1-(2-methoxyethyl)-3-methyl-1H-pyrazol-4-amine (10c). To a solution of intermediate 10b (8.30g, 44.8mmol) in EtOH (200ml), was added 10% palladium on carbon (830mg). Hydrazine monohydrate (5.40ml, 111mmol) was added dropwise at 0°C. The reaction mixture was stirred at room temperature for 2 hours and at 60°C for 16 hours. The hot mixture was then filtered over Celite® and washed with ethanol. The filtrate was concentrated to give intermediate 10c as a red oil (7.10g) which was used directly in the next step.1H NMR (400 MHz, DMSO-d6) δ 6.95 (s, 1H), 3.98 (t, J = 5.5 Hz, 2H), 3.56 (td, J = 5.5, 1.8 Hz, 2H), 3.51 (s, 2H), 3.22 (s, 3H), 1.99 (s, 3H). [0121] Preparation of 4-iodo-N-((1-(2-methoxyethyl)-3-methyl-1H-pyrazol-4- yl)carbamothioyl)benzamide (10e). A solution of ammonium thiocyanate (3.83g,
50.3mmol) and 4-iodobenzoyl chloride 10d (12.8g, 48.0mmol) in acetone (50ml) was stirred at 70°C for 30mins then treated with a solution of intermediate 10c (7.10g, 45.8mmol) in acetone (40ml). After stirring for 1h at 70°C, the mixture was evaporated then water was added and the solid was filtered, washed with water and cyclohexane. The solid was solubilized in a small amount of DCM and MTBE was added until a solid formed. The solid was filtered, then dried under vacuum to give intermediate 10e as a white powder (2.60g, 13%). 1H NMR (400 MHz, DMSO-d6) δ 12.57 (s, 1H), 11.67 (s, 1H), 8.43 (s, 1H), 7.93 (d, J = 8.5 Hz, 2H), 7.75 (d, J = 8.5 Hz, 2H), 4.19 (t, J = 5.3 Hz, 2H), 3.66 (t, J = 5.3 Hz, 2H), 3.24 (s, 3H), 2.18 (s, 3H). [0122] Preparation of 1-(1-(2-methoxyethyl)-3-methyl-1H-pyrazol-4-yl)thiourea (10f). A solution of intermediate 10e (2.60g, 5.85mmol) with potassium carbonate (1.62g, 11.7mmol) in MeOH (15ml) was stirred at room temperature for 3 hours. Methanol was removed under reduced pressure and the residue was treated with water and extracted with EtOAc. The combined organics were washed with brine, then dried over MgSO4, filtered and evaporated and the residue triturated with ether to give intermediate 10f as a white powder (1.10g, 87%). 1H NMR (500 MHz, DMSO-d6) δ 8.89 (s, 1H), 7.68 – 7.56 (m, 2H), 6.59 (s, 1H), 4.11 (t, J = 5.5 Hz, 2H), 3.64 (t, J = 5.5 Hz, 2H), 3.23 (s, 3H), 2.02 (s, 3H). [0123] Preparation N-(1-(2-methoxyethyl)-3-methyl-1H-pyrazol-4-yl)-4-(4- nitrophenyl)thiazol-2-amine (10h). To a solution of 2-bromo-4’-nitroacetophenone 10g (512mg, 2.10mmol) in EtOH (10ml) were added intermediate 10f (450mg, 2.10mmol) and potassium hydrogen carbonate (631mg, 6.30mmol). The reaction mixture was stirred at 80°C for 4 hours. The cooled mixture was evaporated to dryness, diluted with water and extracted with EtOAc. The combined organics were dried over MgSO4, filtered and evaporated to give intermediate 10h as a brown solid (723mg, 96%).1H NMR (400 MHz, DMSO-d6) δ 9.49 (s, 1H), 8.27 (d, J = 9.0 Hz, 2H), 8.14 (d, J = 9.0 Hz, 2H), 8.07 (s, 1H), 7.58 (s, 1H), 4.20 (t, J = 5.4 Hz, 2H), 3.68 (t, J = 5.4 Hz, 2H), 3.27 (s, 3H), 2.15 (s, 3H). [0124] Preparation of 4-(4-aminophenyl)-N-(1-(2-methoxyethyl)-3-methyl-1H-pyrazol- 4-yl)thiazol-2-amine (10i). To a solution of intermediate 10h (723 mg, 2.01 mmol) in EtOH/DCM (18/9 ml), was added SnCl2.2H2O (2.60g, 11.5mmol) and the reaction
mixture was stirred at room temperature for 16 hours. Water was added and the mixture taken to a basic pH by addition of a 2.5M aqueous solution of NaOH. The crude product was extracted with DCM and the combined organics were washed with water and with brine then dried over MgSO4, filtered and evaporated to give intermediate 10i as a red powder (612mg, 92%).1H NMR (400 MHz, DMSO-d6) δ 9.19 (s, 1H), 8.03 (s, 1H), 7.55 (d, J = 8.5 Hz, 2H), 6.73 (s, 1H), 6.57 (d, J = 8.6 Hz, 2H), 5.18 (s, 2H), 4.18 (t, J = 5.3 Hz, 2H), 3.67 (t, J = 5.3 Hz, 2H), 3.27 (s, 3H), 2.13 (s, 3H). [0125] Preparation of 3-(4-(2-((1-(2-methoxyethyl)-3-methyl-1H-pyrazol-4- yl)amino)thiazol-4-yl)phenyl)oxazolidin-2-one (010). To a solution of intermediate 10i (300mg, 0.911mmol) in dry DCM (4.5ml) was added at RT triethylamine (380µl, 2.73mmol). 2-Chloroethyl chloroformate 10j (850µl, 0.819mmol) was then added dropwise at 0°C and the reaction mixture stirred at room temperature for 4 hours. Water was added and the crude product was extracted with DCM. The combined organics were dried over MgSO4, filtered and evaporated. The resulting product was then dissolved in dry THF (4.5 ml) and KOtBu (307 mg, 2.73 mmol) was added portion wise and the reaction mixture stirred at room temperature for 1.5 h. Water was added and the crude product was extracted with EtOAc. The combined organics were washed with water, with brine then dried over MgSO4, filtered and evaporated. The residue was purified by silica gel chromatography using 0/60/40 to 10/90/0 % MeOH/EtOAc/cyclohexane to give compound 010 as a beige powder (80mg, 22%). 1H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 8.05 (s, 1H), 7.90 (d, J = 8.8 Hz, 2H), 7.61 (d, J = 8.8 Hz, 2H), 7.12 (s, 1H), 4.50 – 4.41 (m, 2H), 4.19 (t, J = 5.3 Hz, 2H), 4.14 – 4.05 (m, 2H), 3.67 (t, J = 5.3 Hz, 2H), 3.26 (s, 3H), 2.14 (s, 3H).
Scheme 20 [0131] Preparation of 1-(3-methoxypropyl)-3-methyl-4-nitro-1H-pyrazole (13a). A solution of 4-nitro-3-methyl-1H-pyrazole 10a (2.00g, 15.7mmol), 3-bromo-1- methoxypropane (2.60ml, 23.1mmol) and potassium carbonate (4.30g, 31.1mmol) in dry butan-2-one (60 ml) was stirred at 80°C for 16 hours. The cooled mixture was evaporated then water was added and the crude product was extracted with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered and evaporated. The final product was purified by silica gel chromatography using 0 to 60 % EtOAc/cyclohexane to give a mixture of regioisomers 13a and 13b as a yellow oil (2.70g, 86% overall yield). 13a : 1H NMR (400 MHz, DMSO-d6) δ 8.78 (s, 1H), 4.16 (m, 2H), 3.30 (m, 2H), 3.22 (s, 3H), 2.42 (s, 3H), 2.08 – 1.92 (m, 2H). [0132] Preparation of 1-(3-methoxypropyl)-3-methyl-1H-pyrazol-4-amine (13c). To a solution of a mixture of regioisomers 13a and 13b (2.70g, 13.6mmol) in EtOH (50 ml),
was added 10% Pd/C (1.0g) then hydrazine monohydrate (1.80ml, 36.6mmol) was added dropwise at 0°C. The reaction mixture was stirred at 0°C for 20 mins then at RT for 30 mins. The mixture was filtered over a Celite® pad and washed with ethanol. The filtrate was concentrated to give a crude mixture of regioisomers 13c and 13d as a colorless oil (2.40g) which used directly for the next step. 13c : 1H NMR (400 MHz, DMSO-d6) δ 6.92 (s, 1H), 3.86 (m, 2H), 3.52 (br s, 2H), 3.25 (m, 2H), 3.21 (s, 3H), 1.98 (s, 3H), 1.87 (m, 2H). [0133] Preparation of 4-iodo-N-((1-(3-methoxypropyl)-3-methyl-1H-pyrazol-4- yl)carbamothioyl) benzamide (13e). A solution of ammonium thiocyanate (1.18g, 15.8mmol) and 4-iodobenzoyl chloride 10d (3.97g, 14.9mmol) in acetone (18ml) was stirred at 70°C for 30mins. Then a solution of mixture of intermediates 13c and 13d (2.40g, 14.2mmol) in acetone (18 ml) was added and the mixture was stirred at 70°C for a further 30mins. The mixture was evaporated then water was added and the mixture extracted with EtOAc. The combined organics were washed with brine then dried over MgSO4, filtered and evaporated. The final product was purified by silica gel chromatography using 0 to 50 % EtOAc in cyclohexane as eluent to give intermediate 13e as a white powder (1.90g, 29%). 1H NMR (400 MHz, DMSO-d6) δ 12.56 (s, 1H), 11.56 (s, 1H), 8.39 (s, 1H), 7.93 (m, 2H), 7.75 (m, 2H), 4.08 (t, J = 6.7 Hz, 2H), 3.28 (m, 2H), 3.24 (s, 3H), 2.18 (s, 3H), 2.02 – 1.92 (m, 2H). [0134] Preparation of 1-(1-(3-methoxypropyl)-3-methyl-1H-pyrazol-4-yl)thiourea (13f). A solution of intermediate 13e (1.90g, 4.15mmol) with potassium carbonate (1.15g, 8.29mmol) in MeOH (50ml) was stirred at room temperature for 18h. The solvent was evaporated and the solid treated with water and extracted with DCM. The combined organics were dried over MgSO4, filtered and evaporated then triturated with cyclohexane then ether to give intermediate 13f as a white powder (760mg, 80%).1H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 1H), 7.66 (br s, 2H), 7.31 (br s, 1H), 6.65 (br s, 1H), 3.99 (t, J = 7.0 Hz, 2H), 3.29 (m, 2H), 3.23 (s, 3H), 2.02 (s, 3H), 1.99 – 1.91 (m, 2H). [0135] Preparation of 4-(4-bromo-2-fluorophenyl)-N-(1-(3-methoxypropyl)-3-methyl- 1H-pyrazol-4-yl)thiazol-2-amine (13h). To a solution of 2-bromo-1-(4-bromo-2- fluorophenyl)ethan-1-one 13g (259mg, 0.876mmol) in EtOH (20 ml) were added
intermediate 13f (200mg, 0.876mmol) and potassium hydrogen carbonate (263mg, 2.63mmol). The reaction mixture was stirred at 80°C for 18h then the cooled mixture was evaporated to dryness, diluted with water and extracted with EtOAc. The combined organics were washed with brine then dried over MgSO4, filtered and evaporated. The final product was purified by silica gel chromatography using 0 to 100 % EtOAc as eluent to give intermediate 13h as an oil (127mg, 34%).1H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 8.03 (t, J = 8.5 Hz, 1H), 7.98 (s, 1H), 7.62 (dd, J = 11.2 Hz, 2.0 Hz, 1H), 7.50 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 7.14 (d, J = 2.6 Hz, 1H), 4.07 (t, J = 6.9 Hz, 2H), 3.29 (t, J = 6.0 Hz, 2H), 3.24 (s, 3H), 2.14 (s, 3H), 1.18 (t, J = 7.1 Hz, 2H). [0136] Preparation of 1-(3-fluoro-4-(2-((1-(3-methoxypropyl)-3-methyl-1H-pyrazol-4- yl)amino) thiazol-4-yl)phenyl)-3-tritylimidazolidin-2-one (13i). In a sealed tube, to a solution of intermediate 13h (127mg, 0.299mmol) in dry NMP (3.5ml) were added successively intermediate 3b (108mg, 0.328mmol), cesium carbonate (243mg, 0.748mmol) and XantPhos (35mg, 0.060mmol). The reaction mixture was degassed with nitrogen for 20 minutes before the addition of Pd2(dba)3 (22mg, 0.024mmol) then stirred at 130°C for 18h. The cooled mixture was diluted with water and extracted with EtOAc. The combined organics were washed with water then dried over MgSO4, filtered and evaporated. The final product was purified by silica gel chromatography using 0 to 100 % EtOAc in cyclohexane as eluent to give intermediate 13i as a white powder (88mg, 44%). 1H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 8.02 – 7.95 (m, 2H), 7.42 (d, J = 7.9 Hz, 6H), 7.34 (t, J = 7.4 Hz, 7H), 7.24 (t, J = 7.2 Hz, 4H), 6.95 (d, J = 2.2 Hz, 1H), 4.06 (t, J = 6.6 Hz, 2H), 3.87 (t, J = 7.4 Hz, 2H), 3.47 (t, J = 7.5 Hz, 2H), 3.29 (s, 2H), 3.23 (s, 3H), 2.13 (s, 3H), 2.00 – 1.93 (m, 2H). [0137] Preparation of 1-(3-fluoro-4-(2-((1-(3-methoxypropyl)-3-methyl-1H-pyrazol-4- yl)amino)thiazol-4-yl)phenyl)imidazolidin-2-one (013). To a solution of intermediate 13i (88mg, 0.131mmol) in DCM (2 ml) was added dropwise TFA (110µl, 1.44mmol) and the mixture was stirred at room temperature for 3h. The mixture was stirred with a saturated solution of NaHCO3 for 1h then extracted with DCM and washed with brine. The combined organics were dried over MgSO4, filtered and evaporated and the residue was purified by preparative silica gel plate chromatography using 5/95% MeOH/DCM to give
compound 013 as a beige powder (36mg, 64%). 1H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 8.04 – 7.97 (m, 2H), 7.64 (dd, J = 15.0, 2.1 Hz, 1H), 7.36 (dd, J = 8.8, 2.1 Hz, 1H), 7.15 (s, 1H), 6.95 (d, J = 2.4 Hz, 1H), 4.08 (t, J = 6.9 Hz, 2H), 3.93 – 3.86 (m, 2H), 3.47 – 3.40 (m, 2H), 3.29 (d, J = 6.2 Hz, 2H), 3.24 (s, 3H), 2.14 (s, 3H), 2.01 – 1.94 (m, 2H). Synthesis of Compound 014
[0138] Preparation of 1-(3-methoxypropyl)-4-nitro-3-(trifluoromethyl)-1H- pyrazole (14b). A solution of 4-nitro-3-(trifluoromethyl)-1H-pyrazole 14a (1.00g, 5.52mmol) in MeCN (20ml) was treated with K2CO3 (1.72g, 12.4mmol) and 1-bromo-3- methoxypropane (621µl, 5.52mmol) and heated to 80°C for 4h. Water was added and the mixture extracted with DCM. The combined organics were dried over MgSO4, filtered and evaporated to give 14b as an orange oil (1.32g, 94%). 1H NMR (400 MHz, DMSO- d6) δ 9.17 (s, 1H), 4.31 (t, J = 7.1 Hz, 2H), 3.34 (t, J = 6.0 Hz, 2H), 3.21 (s, 3H), 2.07 (p, J = 6.4 Hz, 2H). [0139] Preparation of 1-(3-methoxypropyl)-3-(trifluoromethyl)-1H-pyrazol-4- amine (14c). A solution of intermediate 14b (1.31g, 5.17mmol) in EtOH was treated with 10% palladium on carbon (130mg) and stirred under an atmosphere of hydrogen at room
temperature and pressure overnight. The mixture was filtered and evaporated to give 14c as a black crystalline solid (979mg, 85%) 1H NMR (400 MHz, DMSO-d6) δ 7.21 (s, 1H), 4.21 (s, 2H), 4.04 (t, J = 7.0 Hz, 2H), 3.26 (t, J = 6.2 Hz, 2H), 3.22 (s, 3H), 1.94 (p, J = 6.6 Hz, 2H). [0140] Preparation of 2-(4-bromophenyl)pyrimidin-4-ol (14e). A mixture of 4-bromobenzimidamide hydrochloride 9c (5.00g, 21.2mmol) and K2CO3 (2.93g, 21.2mmol) in EtOH (100ml) was treated with ethyl propiolate 14d (2.16ml, 21.2mmol) and heated to reflux overnight. The mixture was cooled to RT and filtered and the filtrate concentrated to an orange slurry. To this mixture was added water (100ml) and 1M aqu HCl to pH2 and the solid removed by filtration. The solid was treated with THF and the solvent evaporated, then this procedure was repeated. The solid product was dried in the desiccator at 80°C to give 14e as a pale orange solid (4.63g, 87%). 1H NMR (400 MHz, DMSO-d6) δ 8.13 (d, J = 6.5 Hz, 1H), 8.11 – 8.02 (m, 2H), 7.81 – 7.65 (m, 2H), 6.41 (d, J = 6.5 Hz, 1H). [0141] Preparation of 2-(4-bromophenyl)-4-chloropyrimidine (14f). A mixture of intermediate 14e (4.60g, 18.3mmol) in POCl3 (50ml) was heated to reflux for 1h. The cooled mixture was evaporated and the residue treated with water and extracted with DCM. The combined organics were dried over MgSO4, filtered and evaporated then purified by column chromatography on SiO2 (Puriflash) eluting with 0-10% EtOAc in cyclohexane to give 14f as a yellow solid (3.06g, 62%).1H NMR (400 MHz, DMSO-d6) δ 8.95 – 8.83 (m, 1H), 8.31 – 8.20 (m, 2H), 7.80 – 7.71 (m, 2H), 7.71 – 7.59 (m, 1H). [0142] Preparation of 2-(4-bromophenyl)-N-(1-(3-methoxypropyl)-3-(trifluoromethyl)- 1H-pyrazol-4-yl)pyrimidin-4-amine (14g). A mixture of intermediate 14f (300mg, 1.11mmol) and 14c (248mg, 1.11mmol) in iPrOH (10ml) and c. HCl (5 drops) was heated in a sealed tube under argon overnight. The cooled mixture was treated with sat aqu NaHCO3 solution and extracted with DCM. The combined organics were dried over MgSO4, filtered and evaporated then purified by column chromatography on SiO2 (Puriflash) eluting with 10-50% EtOAc in cyclohexane to give 14g as a pale yellow gum (332mg, 66%). 1H NMR (400 MHz, DMSO-d6) δ 9.07 (s, 1H), 8.35 (d, J = 5.9 Hz, 1H),
8.31 (s, 1H), 8.25 – 8.15 (m, 2H), 7.73 – 7.56 (m, 2H), 6.70 (s, 1H), 4.28 (t, J = 7.0 Hz, 2H), 3.35 (t, J = 6.1 Hz, 2H), 3.23 (s, 3H), 2.08 (p, J = 6.6 Hz, 2H). [0143] Preparation of 1-(4-(4-((1-(3-methoxypropyl)-3-(trifluoromethyl)-1H-pyrazol-4- yl)amino)pyrimidin-2-yl)phenyl)-3-tritylimidazolidin-2-one (14h). Intermediate 14h was prepared as for intermediate 9e above from 14g with intermediate 3b, Pd2(dba)3, XantPhos and Cs2CO3 in dioxane (409mg, 83%). 1H NMR (400 MHz, DMSO-d6) δ 8.96 (s, 1H), 8.39 – 8.27 (m, 2H), 8.25 – 8.09 (m, 2H), 7.59 – 7.52 (m, 2H), 7.45 – 7.38 (m, 6H), 7.38 – 7.30 (m, 6H), 7.30 – 7.14 (m, 4H), 4.27 (t, J = 6.9 Hz, 2H), 3.87 (dd, J = 8.6, 6.5 Hz, 2H), 3.46 (dd, J = 8.5, 6.5 Hz, 2H), 3.33 (t, J = 6.1 Hz, 2H), 3.21 (s, 3H), 2.14 – 2.01 (m, 2H). [0144] Preparation of 1-(4-(4-((1-(3-methoxypropyl)-3-(trifluoromethyl)-1H-pyrazol-4- yl)amino)pyrimidin-2-yl)phenyl)imidazolidin-2-one (014). Compound 014 was prepared as for compound 013 above from 14h and TFA in DCM (158mg, 60%). 1H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.34 (s, 1H), 8.31 (d, J = 5.7 Hz, 1H), 8.23 (d, J = 8.7 Hz, 2H), 7.71 – 7.63 (m, 2H), 7.06 (s, 1H), 6.65 (s, 1H), 4.29 (t, J = 6.9 Hz, 2H), 3.90 (dd, J = 9.2, 6.7 Hz, 2H), 3.43 (t, J = 8.0 Hz, 2H), 3.35 (t, J = 6.1 Hz, 2H), 3.24 (s, 3H), 2.08 (p, J = 6.6 Hz, 2H). By repeating the methods described above using the appropriate starting materials and conditions, as well as the general knowledge in the art, the additional analogues compounds shown in Table 1 hereinabove and listed in Table 2 below were prepared and characterized. Example 1-3: Analytical data for synthetized compounds [0145] The analytical data for the final compounds are presented on the following Table 2. Table 2 Ex # Name (IUPAC) LC-MS or NMR 1-(4-(4-((1-(2-methoxyethyl)-1H-pyrazol- m/z 380.1 (M+H) 001 4-yl)amino)pyrimidin-2- tR = 1.11 mins yl)phenyl)imidazolidin-2-one Method B
Ex # Name (IUPAC) LC-MS or NMR 1-(4-(4-((1-methyl-1H-pyrazol-4- m/z 336.1 (M+H) 002 yl)amino)pyrimidin-2- tR = 1.08 mins yl)phenyl)imidazolidin-2-one Method B 1-(4-(2-((1-(2-methoxyethyl)-1H-pyrazol- m/z 380.2 (M+H) 003 4-yl)amino)pyrimidin-4- tR = 1.30 mins yl)phenyl)imidazolidin-2-one Method B 1-(4-(4-((1-(3,5-dimethylbenzyl)-1H- m/z 440.2 (M+H) 004 pyrazol-4-yl)amino)pyrimidin-2- tR = 1.32 mins yl)phenyl)imidazolidin-2-one Method B 1-(4-(2-((1-(3,5-dimethylbenzyl)-1H- m/z 440.2 (M+H) 005 pyrazol-4-yl)amino)pyrimidin-4- tR = 1.56 mins yl)phenyl)imidazolidin-2-one Method B 1-(4-(6-((1-(2-propoxyethyl)-1H-pyrazol- m/z 393.2 (M+H) 006 4-yl)amino)pyridin-2- tR = 1.33 mins yl)phenyl)imidazolidin-2-one Method B 1-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol- m/z 383.1 (M+H) 007 4-ylamino]-oxazol-5-yl}-phenyl)- tR = 1.33 mins imidazolidin-2-one Method B 1-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol- m/z 399.2 (M+H) 008 4-ylamino]-thiazol-4-yl}-phenyl)- tR = 1.42 mins imidazolidin-2-one Method B 1-(4-(5-((1-(2-ethoxyethyl)-1H-pyrazol-4- m/z 434.2 (M+H) 009 yl)amino)-1,2,4-thiadiazol-3- tR = 1.49 mins yl)phenyl)imidazolidin-2-one Method B 3-(4-{2-[1-(2-Methoxy-ethyl)-3-methyl- m/z 400.2 (M+H) 010 1H-pyrazol-4-ylamino]-thiazol-4-yl}- tR = 1.40 mins phenyl)-oxazolidin-2-one Method B 1-(4-{5-[1-(2-Ethoxy-ethyl)-1H-pyrazol- m/z 382.3 (M+H) 011 4-ylamino]-2H-pyrazol-3-yl}-phenyl)- tR = 1.26 mins imidazolidin-2-one Method B 1-(4-{2-[1-(2-Methoxy-ethyl)-3-methyl- m/z 398.2 (M+H) 012 1H-pyrazol-4-ylamino]-thiazol-4-yl}- tR = 1.42 mins phenyl)-pyrrolidin-2-one Method B 1-(3-Fluoro-4-{2-[1-(3-methoxy-propyl)- m/z 431.3 (M+H) 013 3-methyl-1H-pyrazol-4-ylamino]-thiazol- tR = 1.48 mins 4-yl}-phenyl)-imidazolidin-2-one Method B 1-(4-(4-((1-(3-methoxypropyl)-3- m/z 462.6 (M+H) (trifluoromethyl)-1H-pyrazol-4- 014 tR = 6.82 mins yl)amino)pyrimidin-2- Method A yl)phenyl)imidazolidin-2-one 1-(4-{2-[1-(2-Ethoxy-ethyl)-3-methyl-1H- m/z 397.4 (M+H) 015 pyrazol-4-ylamino]-oxazol-5-yl}-phenyl)- tR = 1.31 mins imidazolidin-2-one Method B
Ex # Name (IUPAC) LC-MS or NMR 1-(4-(2-((1-(2-ethoxyethyl)-1H-pyrazol-4- m/z 394.2 (M+H) 016 yl)amino)pyrimidin-4- tR = 1.40 mins yl)phenyl)imidazolidin-2-one Method B 3-(4-(2-((1-(2-ethoxyethyl)-3-methyl-1H- m/z 398.2 (M+H) 017 pyrazol-4-yl)amino)oxazol-5- tR = 1.36 mins yl)phenyl)oxazolidin-2-one Method B 1-(4-(4-((1-(2-ethoxyethyl)-1H-pyrazol-4- m/z 394.2 (M+H) 018 yl)amino)pyrimidin-2- tR = 1.16 mins yl)phenyl)imidazolidin-2-one Method B 1-(4-(2-((1-methyl-1H-pyrazol-4- m/z 336.1 (M+H) 019 yl)amino)pyrimidin-4- tR = 1.28 mins yl)phenyl)imidazolidin-2-one Method B 1-(4-{2-[1-(2-Methoxy-ethyl)-1H-pyrazol- m/z 369.2 (M+H) 020 4-ylamino]-oxazol-5-yl}-phenyl)- tR = 1.27 mins imidazolidin-2-one Method B 1-(4-(2-((1-(2-ethoxyethyl)-1H-pyrazol-4- m/z 401.2 (M+H) 021 yl)amino)oxazol-5-yl)-3- tR = 1.39 mins fluorophenyl)imidazolidin-2-one Method B 1-(4-(2-((1-(2-ethoxyethyl)-1H-pyrazol-4- m/z 401.2 (M+H) 022 yl)amino)oxazol-5-yl)-2- tR = 1.34 mins fluorophenyl)imidazolidin-2-one Method B 1-(5-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol- m/z 400.3 (M+H) 023 4-ylamino]-thiazol-4-yl}-pyridin-2-yl)- tR = 1.41 mins imidazolidin-2-one Method B 1-(4-(4-((1-ethyl-3-methyl-1H-pyrazol-4- m/z 364.2 (M+H) 024 yl)amino)pyrimidin-2- tR = 1.14 mins yl)phenyl)imidazolidin-2-one Method B 1-(5-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol- m/z 384.3 (M+H) 025 4-ylamino]-oxazol-5-yl}-pyridin-2-yl)- tR = 1.35 mins imidazolidin-2-one Method B 1-(6-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol- m/z 384.3 (M+H) 026 4-ylamino]-oxazol-5-yl}-pyridin-3-yl)- tR = 1.30 mins imidazolidin-2-one Method B 1-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol- m/z 429.2 (M+H) 027 4-ylamino]-thiazol-4-yl}-3-methoxy- tR = 1.36 mins phenyl)-imidazolidin-2-one Method B 1-(4-(4-((1,3,5-trimethyl-1H-pyrazol-4- m/z 364.2 (M+H) 028 yl)amino)pyrimidin-2- tR = 1.10 mins yl)phenyl)imidazolidin-2-one Method B 1-(4-(4-((1,3-dimethyl-1H-pyrazol-4- m/z 350.1 (M+H) 029 yl)amino)pyrimidin-2- tR = 1.09 mins yl)phenyl)imidazolidin-2-one Method B 1-(4-(4-((1-ethyl-1H-pyrazol-4- m/z 350.4 (M+H) 030 yl)amino)pyrimidin-2- tR = 1.13 mins yl)phenyl)imidazolidin-2-one Method B
Ex # Name (IUPAC) LC-MS or NMR 1-(4-(4-((1-isopropyl-1H-pyrazol-4- m/z 363.9 (M+H) 031 yl)amino)pyrimidin-2- tR = 1.17 mins yl)phenyl)imidazolidin-2-one Method B 1-(4-(2-((1,3-dimethyl-1H-pyrazol-4- m/z 339.4 (M+H) 032 yl)amino)oxazol-5- tR = 1.24 mins yl)phenyl)imidazolidin-2-one Method B 3-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol- m/z 400.1 (M+H) 033 4-ylamino]-thiazol-4-yl}-phenyl)- tR = 1.46 mins oxazolidin-2-one Method B 1-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol- m/z 413.2 (M+H) 034 4-ylamino]-thiazol-4-yl}-phenyl)-4-(R)- tR = 1.46 mins methyl-imidazolidin-2-one Method B 1-(4-(2-((1-(2-methoxyethyl)-1H-pyrazol- m/z 385.2 (M+H) 035 4-yl)amino)thiazol-4- tR = 1.32 mins yl)phenyl)imidazolidin-2-one Method B 1-(5-{2-[1-(2-Ethoxy-ethyl)-3-methyl-1H- m/z 398.3 (M+H) 036 pyrazol-4-ylamino]-oxazol-5-yl}-pyridin- tR = 1.26 mins 2-yl)-imidazolidin-2-one Method B 1-(5-{2-[1-(2-Ethoxy-ethyl)-5-methyl-1H- m/z 398.3 (M+H) 037 pyrazol-4-ylamino]-oxazol-5-yl}-pyridin- tR = 1.25 mins 2-yl)-imidazolidin-2-one Method B 1-(4-{2-[1-(2-Ethoxy-ethyl)-5-methyl-1H- m/z 413.3 (M+H) 038 pyrazol-4-ylamino]-thiazol-4-yl}-phenyl)- tR = 1.37 mins imidazolidin-2-one Method B 1-(4-(4-((1-(tert-butyl)-1H-pyrazol-4- m/z 378.1 (M+H) 039 yl)amino)pyrimidin-2- tR = 1.21 mins yl)phenyl)imidazolidin-2-one Method B 1-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol- m/z 412.2 (M+H) 040 4-ylamino]-thiazol-4-yl}-phenyl)- tR = 1.43 mins pyrrolidine-2,5-dione Method B 1-(4-(4-((1-methyl-1H-pyrazol-4- m/z 335.1 (M+H) 041 yl)amino)pyrimidin-2- tR = 1.14 mins yl)phenyl)pyrrolidin-2-one Method B 1-(4-(2-((1-isopropyl-1H-pyrazol-4- m/z 364.4 (M+H) 042 yl)amino)pyrimidin-4- tR = 1.38 mins yl)phenyl)imidazolidin-2-one Method B 1-(4-(2-((1-ethyl-3-methyl-1H-pyrazol-4- m/z 364.5 (M+H) 043 yl)amino)pyrimidin-4- tR = 1.32 mins yl)phenyl)imidazolidin-2-one Method B 1-(4-(4-((1-butyl-1H-pyrazol-4- m/z 378.2 (M+H) 044 yl)amino)pyrimidin-2- tR = 1.22 mins yl)phenyl)imidazolidin-2-one Method B 1-(4-(2-((1-(tert-butyl)-1H-pyrazol-4- m/z 378.2 (M+H) 045 yl)amino)pyrimidin-4- tR = 1.43 mins yl)phenyl)imidazolidin-2-one Method B
Ex # Name (IUPAC) LC-MS or NMR 1-(4-(4-((1-butyl-3,5-dimethyl-1H- m/z 406.2 (M+H) 046 pyrazol-4-yl)amino)pyrimidin-2- tR = 1.23 mins yl)phenyl)imidazolidin-2-one Method B 1-(4-(4-((1-neopentyl-1H-pyrazol-4- m/z 392.2 (M+H) 047 yl)amino)pyrimidin-2- tR = 1.25 mins7 yl)phenyl)imidazolidin-2-one Method B 1-(4-(4-((1-(sec-butyl)-1H-pyrazol-4- m/z 378.2 (M+H) 048 yl)amino)pyrimidin-2- tR = 1.21 mins yl)phenyl)imidazolidin-2-one Method B 1-(4-(4-((1-(pentan-3-yl)-1H-pyrazol-4- m/z 392.2 (M+H) 049 yl)amino)pyrimidin-2- tR = 1.25 mins yl)phenyl)imidazolidin-2-one Method B 1-(4-(4-((1-cyclopentyl-1H-pyrazol-4- m/z 390.2 (M+H) 050 yl)amino)pyrimidin-2- tR = 1.25 mins yl)phenyl)imidazolidin-2-one Method B 1-(4-(2-((1-butyl-1H-pyrazol-4- m/z 378.1 (M+H) 051 yl)amino)pyrimidin-4- tR = 1.45 mins yl)phenyl)imidazolidin-2-one Method B 1-(4-(4-((1-benzyl-1H-pyrazol-4- m/z 412.2 (M+H) 052 yl)amino)pyrimidin-2- tR = 1.23 mins yl)phenyl)imidazolidin-2-one Method B 1-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol- m/z 413.3 (M+H) 053 4-ylamino]-thiazol-4-yl}-phenyl)-5-(R)- tR = 1.46 mins methyl-imidazolidin-2-one Method B 1-(4-(4-((1-hexyl-1H-pyrazol-4- m/z 406.2 (M+H) 054 yl)amino)pyrimidin-2- tR = 1.33 mins yl)phenyl)imidazolidin-2-one Method B 1-(4-(4-((1-(3,5-dimethoxybenzyl)-1H- m/z 472.2 (M+H) 055 pyrazol-4-yl)amino)pyrimidin-2- tR = 1.26 mins yl)phenyl)imidazolidin-2-one Method B 1-(4-(2-((1-hexyl-1H-pyrazol-4- m/z 406.2 (M+H) 056 yl)amino)pyrimidin-4- tR = 1.58 mins yl)phenyl)imidazolidin-2-one Method B 1-(4-(2-((1-(3,5-dimethoxybenzyl)-1H- m/z 472.3 (M+H) 057 pyrazol-4-yl)amino)pyrimidin-4- tR = 1.47 mins yl)phenyl)imidazolidin-2-one Method B 1-(4-(4-((1-(3-methoxybenzyl)-1H- m/z 442.4 (M+H) 058 pyrazol-4-yl)amino)pyrimidin-2- tR = 1.25 mins yl)phenyl)imidazolidin-2-one Method B 1-(4-(2-((1-(3-methoxybenzyl)-1H- m/z 442.2 (M+H) 059 pyrazol-4-yl)amino)pyrimidin-4- tR = 1.46 mins yl)phenyl)imidazolidin-2-one Method B 1-(4-(4-((1-heptyl-1H-pyrazol-4- m/z 420.2 (M+H) 060 yl)amino)pyrimidin-2- tR = 1.38 mins yl)phenyl)imidazolidin-2-one Method B
Ex # Name (IUPAC) LC-MS or NMR 1-(4-(4-((1-(4-methoxy-3,5- dimethylbenzyl)-1H-pyrazol-4- m/z 470.3 (M+H) 061 tR = 1.31 mins yl)amino)pyrimidin-2- yl)phenyl)imidazolidin-2-one Method B 1-(4-(2-((1-(4-methoxy-3,5- dimethylbenzyl)-1H-pyrazol-4- m/z 470.3 (M+H) 062 t = 1.55 mins yl)amino)pyrimidin-4- R yl)phenyl)imidazolidin-2-one Method B 3-(4-{2-[1-(2-Ethoxy-ethyl)-3-methyl-1H- m/z 414.2 (M+H) 063 pyrazol-4-ylamino]-thiazol-4-yl}-phenyl)- tR = 1.50 mins oxazolidin-2-one Method B 1-(4-(4-((1-(4,4,4-trifluorobutyl)-1H- m/z 432.2 (M+H) 064 pyrazol-4-yl)amino)pyrimidin-2- tR = 1.24 mins yl)phenyl)imidazolidin-2-one Method B 1-(3-methoxy-4-(2-((1-(2-methoxyethyl)- m/z 415.1 (M+H) 065 1H-pyrazol-4-yl)amino)thiazol-4- tR = 1.34 mins yl)phenyl)imidazolidin-2-one Method B 1-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol- m/z 413.3 (M+H) 066 4-ylamino]-thiazol-4-yl}-3-methyl- tR = 1.37 mins phenyl)-imidazolidin-2-one Method B 1-(4-(2-((1-(2-methoxyethyl)-1H-pyrazol- m/z 399.1 (M+H) 067 4-yl)amino)thiazol-4-yl)-3- tR = 1.33 mins methylphenyl)imidazolidin-2-one Method B 1-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol- m/z 443.2 (M+H) 068 4-ylamino]-thiazol-4-yl}-3-methoxy- tR = 1.44 mins phenyl)-(R)-4-methyl-imidazolidin-2-one Method B 1-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol- m/z 417.2 (M+H) 069 4-ylamino]-thiazol-4-yl}-3-fluoro- tR = 1.34 mins phenyl)-imidazolidin-2-one Method B 1-(3-Methoxy-4-{2-[1-(3-methoxy- m/z 429.2 (M+H) 070 propyl)-1H-pyrazol-4-ylamino]-thiazol-4- tR = 1.36 mins yl}-phenyl)-imidazolidin-2-one Method B 1-(4-{2-[1-(2-Methoxy-ethyl)-1H-pyrazol- m/z 403.1 (M+H) 071 4-ylamino]-thiazol-4-yl}-3-fluoro- tR = 1.39 mins phenyl)-imidazolidin-2-one Method B 3-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol- m/z 414.1 (M+H) 072 4-ylamino]-thiazol-4-yl}-3-methyl- tR = 1.47 mins phenyl)-oxazolidin-2-one Method B 1-(4-(4-((1-(3-fluorobenzyl)-1H-pyrazol- m/z 430.2 (M+H) 073 4-yl)amino)pyrimidin-2- tR = 1.25 mins yl)phenyl)imidazolidin-2-one Method B 1-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol- m/z 457.2 (M+H) 074 4-ylamino]-thiazol-4-yl}-3-isopropoxy- tR = 1.50 mins phenyl)-imidazolidin-2-one Method B
Ex # Name (IUPAC) LC-MS or NMR 3-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol- m/z 490.2 (M+H) 075 4-ylamino]-thiazol-4-yl}-3-methoxy- tR = 1.47 mins phenyl)-oxazolidin-2-one Method B 3-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol- m/z 418.2 (M+H) 076 4-ylamino]-thiazol-4-yl}-3-fluoro- tR = 1.52 mins phenyl)-oxazolidin-2-one Method B 1-(4-{2-[1-(2-Ethoxy-ethyl)-5-methyl-1H- m/z 443.2 (M+H) 077 pyrazol-4-ylamino]-thiazol-4-yl}-3- tR = 1.40 mins methoxy-phenyl)-imidazolidin-2-one Method B 1-(4-{2-[1-(2-Ethoxy-ethyl)-3-methyl-1H- m/z 443.2 (M+H) 078 pyrazol-4-ylamino]-thiazol-4-yl}-3- tR = 1.39 mins methoxy-phenyl)-imidazolidin-2-one Method B 1-(4-(4-((1-(difluoromethyl)-1H-pyrazol- m/z 372.2 (M+H) 079 4-yl)amino)pyrimidin-2- tR = 4.05 mins yl)phenyl)imidazolidin-2-one Method A 1-(4-(4-((1-methyl-3-(trifluoromethyl)- m/z 404.3 (M+H) 080 1H-pyrazol-4-yl)amino)pyrimidin-2- tR = 4.17 mins yl)phenyl)imidazolidin-2-one Method A 1-(4-{2-[1-(2-Ethoxy-ethyl)-3-methoxy- m/z 429.3 (M+H) 081 1H-pyrazol-4-ylamino]-thiazol-4-yl}- tR = 1.45 mins phenyl)-imidazolidin-2-one Method B 1-(4-{2-[1-(2-Ethoxy-ethyl)-3-methoxy- m/z 459.3 (M+H) 082 1H-pyrazol-4-ylamino]-thiazol-4-yl}-3- tR = 1.43 mins methoxy-phenyl)-imidazolidin-2-one Method B 1-(4-{2-[1-(2-Ethoxy-ethyl)-3-methyl-1H- m/z 413.3 (M+H) 083 pyrazol-4-ylamino]-thiazol-4-yl}-phenyl)- tR = 1.42 mins imidazolidin-2-one Method B 1-(3-Fluoro-4-{2-[1-(3-methoxy-propyl)- m/z 417.2 (M+H) 084 1H-pyrazol-4-ylamino]-thiazol-4-yl}- tR = 1.46 mins phenyl)-imidazolidin-2-one Method B 1-(3'-((1-isopropyl-1H-pyrazol-4- m/z 362.4 (M+H) 085 yl)amino)-[1,1'-biphenyl]-4- tR = 7.98 mins yl)imidazolidin-2-one Method A 1-(4-{2-[3-Chloro-1-(2-ethoxy-ethyl)-1H- m/z 433.2 (M+H) 086 pyrazol-4-ylamino]-thiazol-4-yl}-phenyl)- tR = 1.48 mins imidazolidin-2-one Method B 1-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol- m/z 413.3 (M+H) 087 4-ylamino]-5-methyl-thiazol-4-yl}- tR = 1.39 mins phenyl)-imidazolidin-2-one Method B 1-(4-{2-[1-(2-Ethoxy-ethyl)-3-methyl-1H- m/z 431.3 (M+H) 088 pyrazol-4-ylamino]-thiazol-4-yl}-3-fluoro- tR = 1.48 mins phenyl)-imidazolidin-2-one Method B 1-(4-{2-[1-(2-Ethoxy-ethyl)-5-methyl-1H- m/z 431.3 (M+H) 089 pyrazol-4-ylamino]-thiazol-4-yl}-3-fluoro- tR = 1.48 mins phenyl)-imidazolidin-2-one Method B
Ex # Name (IUPAC) LC-MS or NMR 1-(3-Chloro-4-{2-[1-(3-methoxy-propyl)- m/z 432.1 (M+H) 090 1H-pyrazol-4-ylamino]-thiazol-4-yl}- tR = 1.58 mins phenyl)-pyrrolidin-2-one Method B 1H NMR (400 MHz, DMSO- d6) δ 9.63 (s, 1H), 8.34 – 8.23 1-(4-(4-((1-(2,2,2-trifluoroethyl)-1H- (m, 4H), 7.73 – 7.67 (m, 3H), 091 pyrazol-4-yl)amino)pyrimidin-2- 7.09 (s, 1H), 6.56 (d, J = 5.8 yl)phenyl)imidazolidin-2-one Hz, 1H), 5.21 (q, J = 9.2 Hz, 2H), 3.98 – 3.87 (m, 2H), 3.52 – 3.40 (m, 2H). 1-(3-Chloro-4-{2-[1-(2-ethoxy-ethyl)-3- m/z 446.2 (M+H) 092 methyl-1H-pyrazol-4-ylamino]-thiazol-4- tR = 1.60 mins yl}-phenyl)-pyrrolidin-2-one Method B 1H NMR (400 MHz, DMSO- d6) δ 9.57 (s, 1H), 8.35 – 8.28 (m, 2H), 8.27 (d, J = 5.8 Hz, 1-(4-(4-((1-(2,2-difluoroethyl)-1H- 1H), 8.18 (s, 1H), 7.74 – 7.64 093 pyrazol-4-yl)amino)pyrimidin-2- (m, 3H), 7.08 (s, 1H), 6.54 (d, yl)phenyl)imidazolidin-2-one J = 5.9 Hz, 1H), 6.55 – 6.20 (m, 1H), 4.69 (td, J = 15.2, 3.8 Hz, 2H), 3.98 – 3.85 (m, 2H), 3.50 – 3.39 (m, 2H). 1-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol- m/z 428.2 (M+H) 094 4-ylamino]-thiazol-4-yl}-3-methoxy- tR = 1.52 mins phenyl)-pyrrolidin-2-one Method B 1H NMR (400 MHz, DMSO- d6) δ 9.49 (s, 1H), 8.44 (d, J = 5.2 Hz, 1H), 8.16 – 8.04 (m, 3H), 7.73 (d, J = 8.8 Hz, 2H), 1-(4-(2-((1-(2,2-difluoroethyl)-1H- 095 pyrazol-4-yl)amino)pyrimidin-4- 7.65 (s, 1H), 7.26 (d, J = 5.3 Hz, 1H), 7.13 (s, 1H), 6.28 (tt, yl)phenyl)imidazolidin-2-one J = 55.1, 3.8 Hz, 1H), 4.70 – 4.56 (m, 2H), 3.93 (dd, J = 9.2, 6.7 Hz, 2H), 3.44 (t, J = 8.0 Hz, 2H). 1H NMR (400 MHz, DMSO) δ 9.54 (s, 1H), 8.45 (d, J = 5.3 1-(4-(2-((1-(2,2,2-trifluoroethyl)-1H- Hz, 1H), 8.17 – 8.09 (m, 3H), 7.76 – 7.67 (m, 3H), 7.27 (d, 096 pyrazol-4-yl)amino)pyrimidin-4- yl)phenyl)imidazolidin-2-one J = 5.3 Hz, 1H), 7.13 (s, 1H), 5.14 (q, J = 9.3 Hz, 2H), 3.93 (dd, J = 9.2, 6.6 Hz, 2H), 3.44 (t, J = 8.0 Hz, 2H).
Ex # Name (IUPAC) LC-MS or NMR 1-(4-{2-[1-(2-[1,2,4]Triazol-1-yl-ethyl)- m/z 422.2 (M+H) 097 1H-pyrazol-4-ylamino]-thiazol-4-yl}- tR = 1.30 mins phenyl)-imidazolidin-2-one Method B 1H NMR (400 MHz, DMSO- d6) δ 9.47 (s, 1H), 8.32 – 8.26 (m, 2H), 8.24 (d, J = 5.8 Hz, 1H), 8.03 (s, 1H), 7.69 (d, J = 1-(4-(4-((1-propyl-1H-pyrazol-4- 8.9 Hz, 2H), 7.61 (s, 1H), 098 yl)amino)pyrimidin-2- 7.08 (s, 1H), 6.52 (d, J = 5.9 yl)phenyl)imidazolidin-2-one Hz, 1H), 4.09 (t, J = 6.9 Hz, 2H), 3.92 (dd, J = 9.2, 6.7 Hz, 2H), 3.44 (t, J = 8.0 Hz, 2H), 1.81 (q, J = 7.2 Hz, 2H), 0.87 (t, J = 7.4 Hz, 3H). 1H NMR (400 MHz, DMSO- d6) δ 9.55 (s, 1H), 8.45 (d, J = 5.2 Hz, 1H), 8.25 – 8.04 (m, 1-(4-(2-((1-(2,2,3,3,3-pentafluoropropyl)- 3H), 7.80 – 7.63 (m, 3H), 099 1H-pyrazol-4-yl)amino)pyrimidin-4- 7.28 (d, J = 5.3 Hz, 1H), 7.13 yl)phenyl)imidazolidin-2-one (s, 1H), 5.20 (t, J = 15.0 Hz, 2H), 3.93 (dd, J = 9.3, 6.7 Hz, 2H), 3.44 (t, J = 8.0 Hz, 2H). 1H NMR (400 MHz, DMSO- d6) δ 9.40 (s, 1H), 8.42 (d, J = 5.2 Hz, 1H), 8.15 – 8.06 (m, 2H), 7.97 – 7.90 (m, 1H), 1-(4-(2-((1-propyl-1H-pyrazol-4- 7.76 – 7.68 (m, 2H), 7.57 (s, 100 yl)amino)pyrimidin-4- 1H), 7.23 (d, J = 5.3 Hz, 1H), yl)phenyl)imidazolidin-2-one 7.13 (s, 1H), 4.04 (t, J = 6.9 Hz, 2H), 3.98 – 3.88 (m, 2H), 3.50 – 3.40 (m, 2H), 1.78 (q, J = 7.2 Hz, 2H), 0.85 (t, J = 7.4 Hz, 3H). 1H NMR (400 MHz, DMSO- d6) δ 9.63 (s, 1H), 8.38 – 8.20 1-(4-(4-((1-(2,2,3,3,3-pentafluoropropyl)- (m, 4H), 7.77 – 7.64 (m, 3H), 101 1H-pyrazol-4-yl)amino)pyrimidin-2- 7.09 (s, 1H), 6.55 (d, J = 5.9 yl)phenyl)imidazolidin-2-one Hz, 1H), 5.27 (t, J = 15.0 Hz, 2H), 3.98 – 3.88 (m, 2H), 3.47 – 3.41 (m, 2H). 1-(4-(4-((1-cyclopropyl-1H-pyrazol-4- m/z 362.5 (M+H) 102 yl)amino)pyrimidin-2- tR = 6.46 mins yl)phenyl)imidazolidin-2-one Method A
Ex # Name (IUPAC) LC-MS or NMR 1-(4-(4-((1-cyclobutyl-1H-pyrazol-4- m/z 376.5 (M+H) 103 yl)amino)pyrimidin-2- tR = 6.67 mins yl)phenyl)imidazolidin-2-one Method A 1-(4-(4-((1-(oxetan-3-yl)-1H-pyrazol-4- m/z 378.5 (M+H) 104 yl)amino)pyrimidin-2- tR = 6.40 mins yl)phenyl)imidazolidin-2-one Method A 1H NMR (300 MHz, DMSO- d6) δ 9.37 (s, 1H), 8.41 (d, J = 5.2 Hz, 1H), 8.20 – 7.99 (m, 1-(4-(2-((1-(1-hydroxy-2-methylpropan-2- 3H), 7.79 – 7.67 (m, 2H), 105 yl)-1H-pyrazol-4-yl)amino)pyrimidin-4- 7.61 (s, 1H), 7.22 (d, J = 5.3 yl)phenyl)imidazolidin-2-one Hz, 1H), 7.13 (s, 1H), 4.99 (s, 1H), 3.99 – 3.85 (m, 2H), 3.59 (s, 2H), 3.44 (dd, J = 9.2, 6.8 Hz, 2H), 1.48 (s, 6H). 1H NMR (500 MHz, DMSO- d6) δ 9.51 (s, 1H), 8.36 – 8.27 (m, 2H), 8.24 (d, J = 5.8 Hz, 1H), 8.11 (s, 1H), 7.69 (d, J = 1-(4-(4-((1-(1-hydroxypropan-2-yl)-1H- 8.9 Hz, 2H), 7.61 (s, 1H), 7.08 (s, 1H), 6.52 (d, J = 5.8 106 pyrazol-4-yl)amino)pyrimidin-2- yl)phenyl)imidazolidin-2-one Hz, 1H), 4.96 (t, J = 5.4 Hz, 1H), 4.43 – 4.34 (m, 1H), 3.92 (dd, J = 9.2, 6.7 Hz, 2H), 3.74 – 3.59 (m, 2H), 3.44 (dd, J = 8.9, 7.0 Hz, 2H), 1.42 (d, J = 6.8 Hz, 3H). 1-(4-{2-[1-(3-Methoxy-propyl)-3-methyl- m/z 413.2 (M+H) 107 1H-pyrazol-4-ylamino]-thiazol-4-yl}- tR = 1.39 mins phenyl)-imidazolidin-2-one Method B 1-(4-{2-[1-(2-Methoxy-ethyl)-3-methyl- m/z 399.2 (M+H) 108 1H-pyrazol-4-ylamino]-thiazol-4-yl}- tR = 1.37 mins phenyl)-imidazolidin-2-one Method B 2-methyl-2-(4-((2-(4-(2-oxoimidazolidin- m/z 389.6 (M+H) 109 1-yl)phenyl)pyrimidin-4-yl)amino)-1H- tR = 6.59 mins pyrazol-1-yl)propanenitrile Method A 1-(4-{5-[1-(2-Ethoxy-ethyl)-1H-pyrazol- m/z 412.2 (M+H) 110 4-ylamino]-2H-pyrazol-3-yl}-3-methoxy- tR = 1.29 mins phenyl)-imidazolidin-2-one Method B 1-(4-(4-((1-(1-methoxypropan-2-yl)-1H- m/z 394.6 (M+H) 111 pyrazol-4-yl)amino)pyrimidin-2- tR = 6.48 mins yl)phenyl)imidazolidin-2-one Method A 1-(4-(2-((1-(1-methoxy-2-methylpropan- 1H NMR (400 MHz, DMSO- 112 2-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4- d6) δ 9.36 (s, 1H), 8.42 (d, J = yl)phenyl)imidazolidin-2-one 5.2 Hz, 1H), 8.16 – 8.09 (m,
Ex # Name (IUPAC) LC-MS or NMR 2H), 8.06 (s, 1H), 7.72 (d, J = 9.0 Hz, 2H), 7.62 (s, 1H), 7.22 (d, J = 5.2 Hz, 1H), 7.11 (s, 1H), 3.92 (t, J = 7.9 Hz, 2H), 3.55 (s, 2H), 3.50 – 3.37 (m, 2H), 3.21 (s, 3H), 1.51 (s, 6H). 1H NMR (400 MHz, DMSO- d6) δ 9.38 (s, 1H), 8.42 (d, J = 5.3 Hz, 1H), 8.19 – 8.07 (m, 2H), 7.98 (s, 1H), 7.73 (d, J = 8.5 Hz, 2H), 7.59 (s, 1H), 1-(4-(2-((1-(1-methoxypropan-2-yl)-1H- 7.22 (dd, J = 5.3, 1.7 Hz, 1H), 113 pyrazol-4-yl)amino)pyrimidin-4- 7.11 (s, 1H), 4.52 (q, J = 6.5 yl)phenyl)imidazolidin-2-one Hz, 1H), 3.92 (t, J = 7.9 Hz, 2H), 3.69 – 3.59 (m, 1H), 3.55 (dd, J = 10.2, 4.9 Hz, 1H), 3.44 (t, J = 7.9 Hz, 2H), 3.23 (d, J = 1.7 Hz, 3H), 1.39 (d, J = 6.7 Hz, 3H). 2-methyl-2-(4-((4-(4-(2-oxoimidazolidin- m/z 389.6 (M+H) 114 1-yl)phenyl)pyrimidin-2-yl)amino)-1H- tR = 7.43 mins pyrazol-1-yl)propanenitrile Method A 1H NMR (400 MHz, DMSO- d6) δ 9.63 (s, 1H), 8.44 – 8.21 (m, 4H), 7.77 (s, 1H), 7.75 – 2-(4-((2-(4-(2-oxoimidazolidin-1- 7.59 (m, 2H), 7.07 (s, 1H), 115 yl)phenyl)pyrimidin-4-yl)amino)-1H- 6.57 (d, J = 5.9 Hz, 1H), 5.97 pyrazol-1-yl)propanenitrile (q, J = 7.1 Hz, 1H), 3.92 (t, J = 8.0 Hz, 2H), 3.44 (t, J = 7.9 Hz, 2H), 1.83 (d, J = 7.1 Hz, 3H). 1-(4-(2-((1-cyclopropyl-1H-pyrazol-4- m/z 362.5 (M+H) 116 yl)amino)pyrimidin-4- tR = 7.16 mins yl)phenyl)imidazolidin-2-one Method A 1-(4-{5-[1-(2-Ethoxy-ethyl)-1H-pyrazol- m/z 400.3 (M+H) 117 4-ylamino]-2H-pyrazol-3-yl}-3-fluoro- tR = 1.32 mins phenyl)-imidazolidin-2-one Method B 1-(4-{2-[1-(2-Azido-ethyl)-1H-pyrazol-4- m/z 431.3 (M+H) 118 ylamino]-thiazol-4-yl}-phenyl)- tR = 1.48 mins imidazolidin-2-one Method B 1-(3-Methoxy-4-{2-[1-(3-methoxy- m/z 443.4 (M+H) 119 propyl)-3-methyl-1H-pyrazol-4-ylamino]- tR = 1.39 mins thiazol-4-yl}-phenyl)-imidazolidin-2-one Method B
Ex # Name (IUPAC) LC-MS or NMR 1-(4-(4-((1-isopropyl-3-methyl-1H- m/z 378.5 (M+H) 120 pyrazol-4-yl)amino)pyrimidin-2- tR = 6.63 mins yl)phenyl)imidazolidin-2-one Method A 1-(4-(4-((1-(1-methoxybutan-2-yl)-1H- m/z 408.6 (M+H) 121 pyrazol-4-yl)amino)pyrimidin-2- tR = 6.59 mins yl)phenyl)imidazolidin-2-one Method A 1H NMR (400 MHz, DMSO- d6) δ 9.38 (s, 1H), 8.42 (d, J = 5.2 Hz, 1H), 8.18 – 8.07 (m, 2H), 7.97 (s, 1H), 7.78 – 7.69 (m, 2H), 7.60 (s, 1H), 7.22 (d, 1-(4-(2-((1-(1-methoxybutan-2-yl)-1H- J = 5.3 Hz, 1H), 7.11 (s, 1H), 4.27 (p, J = 7.1 Hz, 1H), 3.92 122 pyrazol-4-yl)amino)pyrimidin-4- yl)phenyl)imidazolidin-2-one (dd, J = 9.3, 6.7 Hz, 2H), 3.67 (dd, J = 10.1, 7.6 Hz, 1H), 3.58 (dd, J = 10.2, 4.5 Hz, 1H), 3.44 (dd, J = 9.1, 6.9 Hz, 2H), 3.22 (s, 3H), 1.77 (p, J = 7.3 Hz, 2H), 0.75 (t, J = 7.4 Hz, 3H). 1H NMR (400 MHz, DMSO- d6) δ 9.47 (s, 1H), 8.34 – 8.27 (m, 2H), 8.24 (d, J = 5.8 Hz, 1H), 8.09 (s, 1H), 7.69 (d, J = 8.9 Hz, 2H), 7.62 (s, 1H), 1-(4-(4-((1-(1-ethoxypropan-2-yl)-1H- 7.06 (s, 1H), 6.52 (d, J = 5.9 Hz, 1H), 4.55 (dq, J = 13.1, 123 pyrazol-4-yl)amino)pyrimidin-2- yl)phenyl)imidazolidin-2-one 6.7, 5.8 Hz, 1H), 3.92 (dd, J = 9.2, 6.7 Hz, 2H), 3.68 (dd, J = 10.2, 7.1 Hz, 1H), 3.62 (dd, J = 10.2, 4.9 Hz, 1H), 3.50 – 3.35 (m, 4H), 1.43 (d, J = 6.8 Hz, 3H), 1.06 (t, J = 7.0 Hz, 3H). 1H NMR (400 MHz, DMSO- d6) δ 9.38 (s, 1H), 8.42 (d, J = 5.2 Hz, 1H), 8.11 (d, J = 8.6 Hz, 2H), 7.97 (s, 1H), 7.72 (d, 1-(4-(2-((1-(1-ethoxybutan-2-yl)-1H- J = 8.6 Hz, 2H), 7.60 (s, 1H), 124 pyrazol-4-yl)amino)pyrimidin-4- 7.22 (d, J = 5.2 Hz, 1H), 7.11 yl)phenyl)imidazolidin-2-one (s, 1H), 4.24 (d, J = 6.6 Hz, 1H), 3.92 (dd, J = 9.2, 6.7 Hz, 2H), 3.70 (dd, J = 10.3, 7.2 Hz, 1H), 3.62 (dd, J = 10.2, 4.8 Hz, 1H), 3.51 – 3.33 (m,
Ex # Name (IUPAC) LC-MS or NMR 4H), 1.78 (p, J = 7.3 Hz, 2H), 1.05 (t, J = 7.0 Hz, 3H), 0.74 (t, J = 7.3 Hz, 3H). 1H NMR (400 MHz, DMSO- d6) δ 9.38 (s, 1H), 8.42 (d, J = 5.2 Hz, 1H), 8.17 – 8.05 (m, 2H), 7.99 (s, 1H), 7.78 – 7.69 (m, 2H), 7.59 (s, 1H), 7.22 (d, 1-(4-(2-((1-(1-ethoxypropan-2-yl)-1H- J = 5.3 Hz, 1H), 7.11 (s, 1H), 125 pyrazol-4-yl)amino)pyrimidin-4- 4.50 (q, J = 6.5 Hz, 1H), 3.98 yl)phenyl)imidazolidin-2-one – 3.87 (m, 2H), 3.66 (dd, J = 10.2, 7.1 Hz, 1H), 3.59 (dd, J = 10.2, 5.0 Hz, 1H), 3.50 – 3.33 (m, 4H), 1.40 (d, J = 6.8 Hz, 3H), 1.06 (t, J = 7.0 Hz, 3H). 1-(4-{2-[1-(2-Methoxy-ethyl)-3-methyl- m/z 413.3 (M+H) 126 1H-pyrazol-4-ylamino]-thiazol-4-yl}- tR = 1.41 mins phenyl)-4-(R)-methyl-imidazolidin-2-one Method B 1-(3-Fluoro-4-{2-[1-(2-methoxy-ethyl)-3- m/z 417.2 (M+H) 127 methyl-1H-pyrazol-4-ylamino]-thiazol-4- tR = 1.42 mins yl}-phenyl)-imidazolidin-2-one Method B 1H NMR (400 MHz, DMSO- d6) δ 9.48 (s, 1H), 8.32 – 8.27 (m, 2H), 8.25 (d, J = 5.9 Hz, 1H), 8.07 (s, 1H), 7.74 – 7.66 (m, 2H), 7.61 (s, 1H), 7.07 (s, 1-(4-(4-((1-(1-methoxy-3-methylbutan-2- 1H), 6.51 (d, J = 5.9 Hz, 1H), 4.13 (td, J = 8.1, 3.5 Hz, 1H), 128 yl)-1H-pyrazol-4-yl)amino)pyrimidin-2- yl)phenyl)imidazolidin-2-one 3.99 – 3.88 (m, 2H), 3.83 (dd, J = 10.4, 8.0 Hz, 1H), 3.71 (dd, J = 10.3, 3.6 Hz, 1H), 3.48 – 3.39 (m, 2H), 3.24 (s, 3H), 2.13 (dq, J = 13.3, 7.0 Hz, 1H), 0.98 (d, J = 6.7 Hz, 3H), 0.71 (d, J = 6.7 Hz, 3H). 1-(4-(4-((1-(2,2-difluorocyclopropyl)-1H- m/z 398.6 (M+H) 129 pyrazol-4-yl)amino)pyrimidin-2- tR = 6.63 mins yl)phenyl)imidazolidin-2-one Method A 1-(4-(2-((1-(1-methoxy-3-methylbutan-2- m/z 422.7 (M+H) 130 yl)-1H-pyrazol-4-yl)amino)pyrimidin-4- tR = 7.46 mins yl)phenyl)imidazolidin-2-one Method A 1-(4-(2-((1-(2,2-difluorocyclopropyl)-1H- 1H NMR (400 MHz, DMSO- 131 pyrazol-4-yl)amino)pyrimidin-4- d6) δ 9.50 (s, 1H), 8.45 (d, J = yl)phenyl)imidazolidin-2-one 5.2 Hz, 1H), 8.15 – 8.09 (m,
Ex # Name (IUPAC) LC-MS or NMR 2H), 8.08 (s, 1H), 7.76 – 7.71 (m, 2H), 7.67 (s, 1H), 7.26 (d, J = 5.3 Hz, 1H), 7.13 (s, 1H), 4.54 (q, J = 8.8 Hz, 1H), 3.97 – 3.88 (m, 2H), 3.44 (t, J = 8.0 Hz, 2H), 2.46 – 2.23 (m, 2H). 1H NMR (400 MHz, DMSO- d6) δ 9.58 (s, 1H), 8.41 – 8.28 (m, 2H), 8.25 (d, J = 5.8 Hz, 1H), 8.13 (s, 1H), 7.76 – 7.62 1-(4-(4-((1-(2-methoxy-2-methylpropyl)- (m, 2H), 7.54 (s, 1H), 7.10 (s, 132 1H-pyrazol-4-yl)amino)pyrimidin-2- 1H), 6.52 (d, J = 5.9 Hz, 1H), yl)phenyl)imidazolidin-2-one 4.16 (s, 2H), 3.92 (dd, J = 9.3, 6.7 Hz, 2H), 3.43 (dd, J = 9.1, 6.9 Hz, 2H), 3.24 (s, 3H), 1.10 (s, 6H). (R)-1-(4-(4-((1-isopropyl-1H-pyrazol-4- m/z 378.6 (M+H) 133 yl)amino)pyrimidin-2-yl)phenyl)-4- tR = 6.70 mins methylimidazolidin-2-one Method A 1H NMR (400 MHz, DMSO- d6) δ 9.45 (s, 1H), 8.42 (d, J = 5.2 Hz, 1H), 8.12 (d, J = 8.6 Hz, 2H), 8.00 (s, 1H), 7.77 – 1-(4-(2-((1-(2-methoxy-2-methylpropyl)- 134 1H-pyrazol-4-yl)amino)pyrimidin-4- 7.65 (m, 2H), 7.53 (s, 1H), 7.24 (d, J = 5.3 Hz, 1H), 7.15 yl)phenyl)imidazolidin-2-one (s, 1H), 4.11 (s, 2H), 3.92 (d, J = 15.9 Hz, 2H), 3.50 – 3.38 (m, 2H), 3.21 (s, 3H), 1.09 (s, 6H). 1H NMR (400 MHz, DMSO- d6) δ 9.42 (s, 1H), 8.42 (d, J = 5.2 Hz, 1H), 8.15 – 8.07 (m, 2H), 7.97 (s, 1H), 7.75 – 7.69 (m, 2H), 7.58 (s, 1H), 7.23 (d, J = 5.3 Hz, 1H), 7.15 (s, 1H), 1-(4-(2-((1-(1-ethoxy-3-methylbutan-2- 4.05 (s, 1H), 3.97 – 3.88 (m, 135 yl)-1H-pyrazol-4-yl)amino)pyrimidin-4- 2H), 3.82 (dd, J = 10.5, 7.7 yl)phenyl)imidazolidin-2-one Hz, 1H), 3.72 (dd, J = 10.4, 3.7 Hz, 1H), 3.49 – 3.40 (m, 3H), 3.40 – 3.35 (m, 1H), 2.10 (q, J = 7.1 Hz, 1H), 1.04 (t, J = 7.0 Hz, 3H), 0.96 (d, J = 6.7 Hz, 3H), 0.68 (d, J = 6.7 Hz, 3H).
Ex # Name (IUPAC) LC-MS or NMR 1H NMR (400 MHz, DMSO- d6) δ 9.49 (s, 1H), 8.30 (d, J = 8.6 Hz, 2H), 8.25 (d, J = 5.8 Hz, 1H), 8.08 (s, 1H), 7.69 (d, J = 8.9 Hz, 2H), 7.59 (s, 1H), (R)-1-(4-(4-((1-(2-methoxypropyl)-1H- 7.06 (s, 1H), 6.52 (d, J = 5.9 136 pyrazol-4-yl)amino)pyrimidin-2- Hz, 1H), 4.17 (qd, J = 14.1, yl)phenyl)imidazolidin-2-one 5.3 Hz, 2H), 3.92 (dd, J = 9.3, 6.7 Hz, 2H), 3.78 – 3.63 (m, 1H), 3.44 (t, J = 8.0 Hz, 2H), 3.26 (d, J = 1.6 Hz, 3H), 1.08 (dd, J = 6.3, 1.5 Hz, 3H). 1-(4-(4-((1-isopropyl-1H-pyrazol-4- m/z 392.6 (M+H) 137 yl)amino)pyrimidin-2-yl)phenyl)-4,4- tR = 6.80 mins dimethylimidazolidin-2-one Method A 1H NMR (400 MHz, DMSO- d6) δ 9.49 (s, 1H), 8.30 (d, J = 8.9 Hz, 2H), 8.25 (d, J = 5.8 Hz, 1H), 8.08 (s, 1H), 7.69 (d, J = 8.7 Hz, 2H), 7.59 (s, 1H), (S)-1-(4-(4-((1-(2-methoxypropyl)-1H- 7.06 (s, 1H), 6.52 (d, J = 5.9 138 pyrazol-4-yl)amino)pyrimidin-2- Hz, 1H), 4.17 (qd, J = 14.1, yl)phenyl)imidazolidin-2-one 5.4 Hz, 2H), 3.92 (dd, J = 9.2, 6.8 Hz, 2H), 3.71 (td, J = 6.4, 4.7 Hz, 1H), 3.44 (t, J = 8.0 Hz, 2H), 1.08 (d, J = 6.2 Hz, 3H). 1-(4-(4-((1-isopropyl-3-(trifluoromethyl)- m/z 432.6 (M+H) 139 1H-pyrazol-4-yl)amino)pyrimidin-2- tR = 6.96 mins yl)phenyl)imidazolidin-2-one Method A 1-(4-(4-((1,5-dimethyl-1H-pyrazol-4- m/z 350.5 (M+H) 140 yl)amino)pyrimidin-2- tR = 6.38 mins yl)phenyl)imidazolidin-2-one Method A 1H NMR (400 MHz, DMSO- d6) δ 8.64 (s, 1H), 8.39 (d, J = 5.3 Hz, 1H), 8.20 (s, 1H), 8.06 (d, J = 8.6 Hz, 2H), 7.69 1-(4-(2-((1-isopropyl-3-(trifluoromethyl)- 141 1H-pyrazol-4-yl)amino)pyrimidin-4- (d, J = 8.5 Hz, 2H), 7.29 (d, J = 5.3 Hz, 1H), 7.11 (s, 1H), yl)phenyl)imidazolidin-2-one 4.61 (p, J = 6.7 Hz, 1H), 3.91 (dd, J = 9.2, 6.7 Hz, 2H), 3.43 (t, J = 8.0 Hz, 2H), 1.47 (d, J = 6.7 Hz, 6H).
Ex # Name (IUPAC) LC-MS or NMR 1H NMR (400 MHz, DMSO- d6) δ 8.62 (s, 1H), 8.33 (d, J = 5.2 Hz, 1H), 8.05 (d, J = 8.5 1-(4-(2-((1,5-dimethyl-1H-pyrazol-4- Hz, 2H), 7.69 (d, J = 8.6 Hz, 142 yl)amino)pyrimidin-4- 2H), 7.55 (s, 1H), 7.19 (d, J = yl)phenyl)imidazolidin-2-one 5.3 Hz, 1H), 7.10 (s, 1H), 3.91 (t, J = 7.9 Hz, 2H), 3.72 (s, 3H), 3.43 (t, J = 8.0 Hz, 2H), 2.19 (s, 3H). 1-(4-(4-((1-(3-methoxypropyl)-1H- m/z 394.6 (M+H) 143 pyrazol-4-yl)amino)pyrimidin-2- tR = 6.53 mins yl)phenyl)imidazolidin-2-one Method A 1-(4-{2-[1-(3-Methoxy-propyl)-3-methyl- m/z 427.2 (M+H) 144 1H-pyrazol-4-ylamino]-thiazol-4-yl}-3- tR = 1.38 mins methyl-phenyl)-imidazolidin-2-one Method B 1H NMR (400 MHz, DMSO- d6) δ 8.97 (s, 1H), 8.38 (s, 1H), 8.32 (d, J = 5.8 Hz, 1H), 1-(4-(4-((1-(2-methoxyethyl)-3- 8.25 (d, J = 8.8 Hz, 2H), 7.75 145 (trifluoromethyl)-1H-pyrazol-4- – 7.55 (m, 2H), 7.06 (s, 1H), yl)amino)pyrimidin-2- 6.68 (s, 1H), 4.42 (t, J = 5.1 yl)phenyl)imidazolidin-2-one Hz, 2H), 3.91 (dd, J = 9.2, 6.7 Hz, 2H), 3.76 (t, J = 5.1 Hz, 2H), 3.43 (t, J = 7.9 Hz, 2H), 3.31 (d, J = 1.0 Hz, 3H). 3-(4-{2-[1-(3-Methoxy-propyl)-1H- m/z 400.1 (M+H) 146 pyrazol-4-ylamino]-thiazol-4-yl}-phenyl)- tR = 1.45 mins oxazolidin-2-one Method B 3-(3-Fluoro-4-{2-[1-(3-methoxy-propyl)- m/z 418.1 (M+H) 147 1H-pyrazol-4-ylamino]-thiazol-4-yl}- tR = 1.51 mins phenyl)-oxazolidin-2-one Method B 3-(3-Fluoro-4-{2-[1-(2-methoxy-ethyl)- m/z 404.1 (M+H) 148 1H-pyrazol-4-ylamino]-thiazol-4-yl}- tR = 1.47 mins phenyl)-oxazolidin-2-one Method B 1-(4-{2-[1-(3-Methoxy-propyl)-1H- m/z 399.1 (M+H) 149 pyrazol-4-ylamino]-thiazol-4-yl}-phenyl)- tR = 1.36 mins imidazolidin-2-one Method B 3-(4-{2-[1-(2-Methoxy-ethyl)-1H-pyrazol- m/z 386.1 (M+H) 150 4-ylamino]-thiazol-4-yl}-phenyl)- tR = 1.41 mins oxazolidin-2-one Method B 1-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol- m/z 398.1 (M+H) 151 4-ylamino]-thiazol-4-yl}-phenyl)- tR = 1.47 mins pyrrolidin-2-one Method B
Ex # Name (IUPAC) LC-MS or NMR 1H NMR (400 MHz, DMSO- d6) δ 9.50 (s, 1H), 8.30 (d, J = 8.5 Hz, 2H), 8.25 (d, J = 5.8 Hz, 1H), 8.17 (s, 1H), 7.69 (d, J = 8.5 Hz, 2H), 7.57 (s, 1H), 1-(4-(4-((1-(cyclopropylmethyl)-1H- 7.07 (s, 1H), 6.53 (d, J = 5.8 152 pyrazol-4-yl)amino)pyrimidin-2- Hz, 1H), 4.01 (d, J = 7.1 Hz, yl)phenyl)imidazolidin-2-one 2H), 3.92 (dd, J = 9.2, 6.8 Hz, 2H), 3.44 (t, J = 7.9 Hz, 2H), 1.26 (p, J = 5.4 Hz, 1H), 0.65 – 0.54 (m, 2H), 0.43 (d, J = 4.9 Hz, 2H). 1-(4-(4-((1-((3-(methoxymethyl)oxetan-3- yl)methyl)-1H-pyrazol-4- m/z 436.6 (M+H) 153 tR = 6.44 mins yl)amino)pyrimidin-2- yl)phenyl)imidazolidin-2-one Method A 1H NMR (400 MHz, DMSO- d6) δ 9.49 (s, 1H), 8.40 – 8.27 (m, 2H), 8.25 (d, J = 5.8 Hz, 1H), 8.08 (s, 1H), 7.75 – 7.66 (m, 2H), 7.64 (s, 1H), 7.07 (s, 1H), 6.52 (d, J = 5.9 Hz, 1H), 1-(4-(4-((1-(1,4-dimethoxybutan-2-yl)- 4.52 (qd, J = 7.3, 4.4 Hz, 1H), 154 1H-pyrazol-4-yl)amino)pyrimidin-2- 3.97 – 3.89 (m, 2H), 3.71 (dd, yl)phenyl)imidazolidin-2-one J = 10.2, 7.7 Hz, 1H), 3.63 (dd, J = 10.2, 4.5 Hz, 1H), 3.49 – 3.40 (m, 2H), 3.24 (s, 4H), 3.19 (s, 3H), 3.17 – 3.06 (m, 1H), 2.02 (q, J = 6.7 Hz, 2H). 1-(4-(4-((1-(3-methoxycyclobutyl)-1H- m/z 406.6 (M+H) 155 pyrazol-4-yl)amino)pyrimidin-2- tR = 6.52 mins yl)phenyl)imidazolidin-2-one Method A 1-(4-(4-((3-methoxy-1-methyl-1H- m/z 366.5 (M+H) 156 pyrazol-4-yl)amino)pyrimidin-2- tR = 6.51 mins yl)phenyl)imidazolidin-2-one Method A 3-(4-{2-[1-(2-Ethoxy-ethyl)-3-methyl-1H- m/z 432.2 (M+H) 157 pyrazol-4-ylamino]-thiazol-4-yl}-3-fluoro- tR = 1.53 mins phenyl)-oxazolidin-2-one Method B 3-(4-{2-[1-(2-Ethoxy-ethyl)-3-methyl-1H- m/z 414.1 (M+H) 158 pyrazol-4-ylamino]-thiazol-4-yl}-phenyl)- tR = 1.46 mins oxazolidin-2-one Method B 1-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol- m/z 416.1 (M+H) 159 4-ylamino]-thiazol-4-yl}-3-fluoro- tR = 1.55 mins phenyl)-pyrrolidin-2-one Method B
Ex # Name (IUPAC) LC-MS or NMR 1-(4-{2-[1-(2-Ethoxy-ethyl)-3-methyl-1H- m/z 412.2 (M+H) 160 pyrazol-4-ylamino]-thiazol-4-yl}-phenyl)- tR = 1.49 mins pyrrolidin-2-one Method B 1-(4-{2-[1-(2-Ethoxy-ethyl)-3-methyl-1H- m/z 430.2 (M+H) 161 pyrazol-4-ylamino]-thiazol-4-yl}-3-fluoro- tR = 1.57 mins phenyl)-pyrrolidin-2-one Method B 1-(4-{2-[1-(3-Methoxy-propyl)-3-methyl- m/z 412.3 (M+H) 162 1H-pyrazol-4-ylamino]-thiazol-4-yl}- tR = 1.46 mins phenyl)-pyrrolidin-2-one Method B 3-(3-Fluoro-4-{2-[1-(2-methoxy-ethyl)-3- m/z 418.3 (M+H) 163 methyl-1H-pyrazol-4-ylamino]-thiazol-4- tR = 1.48 mins yl}-phenyl)-oxazolidin-2-one Method B 1-(3-Fluoro-4-{2-[1-(2-methoxy-ethyl)-3- m/z 416.3 (M+H) 164 methyl-1H-pyrazol-4-ylamino]-thiazol-4- tR = 1.50 mins yl}-phenyl)-pyrrolidin-2-one Method B 3-(3-Fluoro-4-{2-[1-(2-methoxy-ethyl)-3- m/z 432.3 (M+H) 165 methyl-1H-pyrazol-4-ylamino]-thiazol-4- tR = 1.51 mins yl}-phenyl)-oxazolidin-2-one Method B 1-(3-Fluoro-4-{2-[1-(3-methoxy-propyl)- m/z 430.4 (M+H) 166 3-methyl-1H-pyrazol-4-ylamino]-thiazol- tR = 1.54 mins 4-yl}-phenyl)-pyrrolidin-2-one Method B 3-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol- m/z 414.2 (M+H) 167 4-ylamino]-thiazol-4-yl}-phenyl)-(R)-5- tR = 1.52 mins methyl-oxazolidin-2-one Method B 1-(4-{2-[1-(2-Methoxy-ethyl)-1H-pyrazol- m/z 384.2 (M+H) 168 4-ylamino]-thiazol-4-yl}-phenyl)- tR = 1.45 mins pyrrolidin-2-one Method B 1-(4-{2-[1-(3-Methoxy-propyl)-1H- m/z 384.2 (M+H) 169 pyrazol-4-ylamino]-thiazol-4-yl}-phenyl)- tR = 1.45 mins pyrrolidin-2-one Method B 1-(3-Fluoro-4-{2-[1-(3-methoxy-propyl)- m/z 398.3 (M+H) 170 1H-pyrazol-4-ylamino]-thiazol-4-yl}- tR = 1.49 mins phenyl)-pyrrolidin-2-one Method B 1-(3-Fluoro-4-{2-[1-(2-methoxy-ethyl)- m/z 402.3 (M+H) 171 1H-pyrazol-4-ylamino]-thiazol-4-yl}- tR = 1.55 mins phenyl)-pyrrolidin-2-one Method B 1-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol- m/z 467.4 (M+H) 4-ylamino]-thiazol-4-yl}-3- 172 t = 1.47 mins trifluoromethyl-phenyl)-imidazolidin-2- R Method B one 1-(4-{5-[1-(2-Ethoxy-ethyl)-1H-pyrazol- m/z 399.3 (M+H) 173 4-ylamino]-2H-pyrazol-3-yl}-3-fluoro- tR = 1.36 mins phenyl)-pyrrolidin-2-one Method B
Ex # Name (IUPAC) LC-MS or NMR 1-(4-{2-[1-(3-Ethoxy-propyl)-1H-pyrazol- m/z 413.3 (M+H) 174 4-ylamino]-thiazol-4-yl}-phenyl)- tR = 1.42 mins imidazolidin-2-one Method B 1-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol- m/z 414.3 (M+H) 175 4-ylamino]-thiazol-4-yl}-phenyl)-4-(R)- tR = 1.34 mins hydroxy-pyrrolidin-2-one Method B 1-(3-Chloro-4-{2-[1-(2-ethoxy-ethyl)-1H- m/z 433.3 (M+H) 176 pyrazol-4-ylamino]-thiazol-4-yl}-phenyl)- tR = 1.48 mins imidazolidin-2-one Method B 1-(3-Chloro-4-{2-[1-(3-methoxy-propyl)- m/z 433.1 (M+H) 177 1H-pyrazol-4-ylamino]-thiazol-4-yl}- tR = 1.45 mins phenyl)-imidazolidin-2-one Method B 1-(3-Chloro-4-{2-[1-(2-ethoxy-ethyl)-3- m/z 447.2 (M+H) 178 methyl-1H-pyrazol-4-ylamino]-thiazol-4- tR = 1.43 mins yl}-phenyl)-imidazolidin-2-one Method B 1-(4-{2-[1-(2-[1,2,3]Triazol-2-yl-ethyl)- m/z 422.1 (M+H) 179 1H-pyrazol-4-ylamino]-thiazol-4-yl}- tR = 1.34 mins phenyl)-imidazolidin-2-one Method B 1-(4-{2-[1-(2-[1,2,3]Triazol-1-yl-ethyl)- m/z 422.1 (M+H) 180 1H-pyrazol-4-ylamino]-thiazol-4-yl}- tR = 1.29 mins phenyl)-imidazolidin-2-one Method B 1-(3-Chloro-4-{2-[1-(2-ethoxy-ethyl)-1H- m/z 432.1 (M+H) 181 pyrazol-4-ylamino]-thiazol-4-yl}-phenyl)- tR = 1.57 mins pyrrolidin-2-one Method B 3-(4-{4-[4-(2-Oxo-imidazolidin-1-yl)- m/z 427.2 (M+H) 182 phenyl]-thiazol-2-ylamino}-pyrazol-1-yl)- tR = 1.44 mins propionic acid ethyl ester Method B 2-[2-(4-{4-[4-(2-Oxo-imidazolidin-1-yl)- m/z 480.2 (M+H) 183 phenyl]-thiazol-2-ylamino}-pyrazol-1-yl)- tR = 1.40 mins ethyl]-2H-[1,2,3]triazole-4-carboxylic acid Method B methyl ester 1-(4-{2-[1-(2-Imidazol-1-yl-ethyl)-1H- m/z 421.2 (M+H) 184 pyrazol-4-ylamino]-thiazol-4-yl}-phenyl)- tR = 1.14 mins imidazolidin-2-one Method B 1-(3-Chloro-4-{2-[1-(3-methoxy-propyl)- m/z 446.1 (M+H) 185 3-methyl-1H-pyrazol-4-ylamino]-thiazol- tR = 1.51 mins 4-yl}-phenyl)-pyrrolidin-2-one Method B 1-(3-Chloro-4-{2-[1-(3-methoxy-propyl)- m/z 447.1 (M+H) 186 3-methyl-1H-pyrazol-4-ylamino]-thiazol- tR = 1.43 mins 4-yl}-phenyl)-imidazolidin-2-one Method B
Example 2: Biological assays Example 2-1: In vitro tubulin polymerization assay Materials and methods [0146] The assay was performed using a fluorescence-based Tubulin Polymerization Assay Kit (Cytoskeleton cat. # BK011P) and following the manufacturer’s instructions. In brief, purified porcine brain tubulin was prepared at 2 mg/ml tubulin in 80 mM PIPES pH 6.9, 2.0 mM MgCl2, 0.5 mM EGTA, 1.0 mM GTP (guanosine triphosphate) and 15% glycerol and kept on ice. Tubulin was then incubated with a 10µM solution of each test compound or control compound in the presence of 1 mM GTP in PIPES-based polymerization buffer at 37°C. Polymerization was followed by fluorescence enhancement due to the incorporation of a fluorescent reporter into microtubules (MT) as polymerization occurs. The experiments were performed in duplicates and results are expressed as the percentage of inhibition of MT polymerization obtained at the end of the experiment relative to the control DMSO. Results [0147] The results of this assay are presented in Table 3 below. Table 3: Tubulin polymerization inhibition at the concentration of 10µM Ex. 001 002 006 029 030 031 046 004 005 080 % of tubulin polymerization 100 100 90 100 100 100 100 100 50 100 inhibition Table 3 (continued) Ex. 039 008 015 007 022 023 % of tubulin polymerization inhibition 100 100 100 90 100 80
Table 3 (continued) Ex. 027 033 066 069 081 083 086 087 % of tubulin polymerization 100 100 100 100 90 100 40 100 inhibition [0148] Therefore, it was observed that the class of compounds of formula (I) of the invention were able to inhibit Tubulin Polymerization. The listed compounds in Table 3 are well representing the class of compounds of formula (I). Example 2-2: Cell cycle analysis: G2/M arrest after 24h treatment with compounds Materials and methods [0149] HCT116 cells (human colon cancer cell line) were plated in 24-well plates at a cell density of 105 cells/mL/well in their culture medium. The next day, the culture medium was removed and replaced with a culture medium containing 100 nM of the tested compound. After 24 hours of treatment, the culture medium was removed, the cells were washed once with PBS 1X and trypsinized in a solution of 0.05% Trypsine-EDTA (lifetech cat. # 25300-054). The cells were then resuspended in culture medium and transferred to a 96 well plate. The plate was centrifuged, and the cell pellets were washed twice in cold PBS. The cell pellets were then resuspended in the propidium iodide staining solution containing 0.1% NP40, 0.1% sodium citrate, 50 μg/mL propidium iodide, and 0.2 mg/mL RNAse A. The cells were analyzed immediately for DNA content using an Accuri 6 cytometer. Results are expressed as a percentage of live cells that accumulate in the G2/M phase of the cell cycle. Results [0150] The results of this assay are presented in Table 4 below. Table 4: Results of the cell cycle analysis, expressed as a percentage of live cells that accumulate in the G2/M phase of the cell cycle % G2/M arrest @ 24h Example compound number G2/M arrest > 90% 001, 004, 005, 008, 013, 014, 015, 016, 018, 024, 027, 029, 033, 044, 046, 048, 054, 071, 077, 080,
084, 092, 094, 098, 102, 103, 107, 108, 111, 116, 118, 120, 123, 124, 125, 127, 129, 130, 132, 134, 135, 136, 139, 141, 143, 144, 145, 149, 151, 152, 155, 159, 178, 181, 185 and 186 002, 003, 006, 007, 017, 021, 025, 030, 031, 034, 035, 038, 042, 043, 045, 047, 049, 050, 051, 052, 60% < G2/M arrest ≤ 055, 064, 065, 066, 069, 070, 076, 079, 083, 088, 90% 090, 093, 097, 100, 113, 114, 117, 119, 121, 122, 128, 131, 138, 161, 166, 169, 174, 176, 177, 179 and 182 009, 010, 011, 012, 019, 020, 022, 023, 026, 028, 032, 036, 037, 039, 040, 041, 053, 056, 057, 058, 059, 060, 061, 062, 063, 067, 068, 072, 073, 074, 45% ≤ G2/M arrest ≤ 075, 078, 081, 082, 086, 087, 089, 091, 095, 096, 60% 099, 101, 104, 105, 106, 109, 110, 112, 115, 126, 133, 137, 140, 142, 146, 147, 148, 150, 153, 154, 156, 157, 158, 160, 162, 163, 164, 165, 167, 168, 170, 171, 172, 173, 175, 180, 183 and 184 [0151] Microtubules play a critical role in determining cell shape and polarity, facilitating cellular movement and intracellular transport, and segregating chromosomes during mitosis. In mitosis, interphase microtubules disappear and are replaced with a new network of microtubules that interact with the mitotic spindle to distribute chromatids equally between the two daughter cells. Disruption of microtubules arrests the cell division cycle at the G2/M checkpoint, preventing cell division and triggering apoptosis. [0152] Thus, it was observed that the class of compounds of formula (I) of the invention were able to cause G2/M mitotic arrest. The listed compounds in Table 4 are well representing the class of compounds of formula (I). Example 2-3: Cell-based proliferation screening of compounds Materials and Methods [0153] CellTiter-Blue cell-based survival/proliferation assay (Promega G8080) was performed on tumor cell lines. A total of 1.104 cells/well/50µl were seeded in a 96-well plate. The following day, treatment was initiated by addition of a drug solution of tested compound of 1/10 serial dilutions ranging from 0 to 10µM. Cells were grown for 48h at 37°C and then incubated with 10 µl/well of Promega CellTiter-Blue reagent for 4 h at 37°C. The amount of resorufin dye formed was quantified by its fluorescence emission
at 590 nm using a scanning multiwell spectrophotometer (OPTIMA, BMG labtech, France). A blank well without cells was used as a background control for the spectrophotometer. The positive control of the assay corresponds to the cell proliferation obtained in the absence of drug treatment (100% proliferation), i.e., in absence of tested compound. Each sample was done in duplicates, and the experiment was repeated at least twice. The results presented below are expressed as IC50 (i.e., concentration required to obtain 50% inhibition of the proliferation observed in absence of treatment), with “++++” corresponding to IC50 ≤ 100 nM, “+++” to 100 < IC50 ≤ 500 nM, “++” to 500 < IC50 ≤ 1000 nM, and “+” o IC50 > 1000 nM, N.D.: not determined. [0154] Cell lines tested were: HL60, MOLM14, NOMO1, THP1, HUT78, CCRF_CEM, KARPAS 299, REC1, NALM6, A549, H1299, HEP2, HGC27, HRT18, PANC_1, PLC PRF5, U118, U87_MG, Tov21G, 786-O, ACHN, PC3, LnCaP, DU145, MCF7, MDA- MB-468, SW872, SK-N-MC, A4573, U2OS, WEHI164, and MESSA. Results [0155] The results of this assay are presented in Table 5 and Table 6 below. Table 5. Anti-tumoral activity of the compounds of formula (I) on hematopoietic tumor cell lines (measured IC50) Ex. Leukemia HL60 MOLM14 NOMO1 THP1 001 ++++ N.D. N.D. N.D. 008 ++++ ++++ ++++ ++++ 015 +++ ++ +++ +++ 016 ++++ ++++ ++++ ++++ 024 ++++ ++++ ++ ++++ 027 ++++ +++ ++++ ++++ 029 ++++ +++ +++ ++++ 031 ++++ ++++ +++ ++++ 033 ++++ ++++ ++++ ++++ 034 ++++ N.D. N.D. N.D. 048 ++++ N.D. N.D. N.D. 071 ++++ N.D. N.D. N.D. 076 ++++ N.D. N.D. ++++ 077 ++++ N.D. N.D. N.D. 080 ++++ N.D. N.D. ++++
083 ++++ N.D. ++ ++++ 084 ++++ N.D. N.D. N.D. 098 ++++ N.D. ++++ ++++ 102 ++++ N.D. N.D. N.D. 103 ++++ N.D. N.D. N.D. 107 ++++ ++++ ++++ ++++ 108 ++++ N.D. N.D. N.D. 111 +++ N.D. N.D. N.D. 013 +++ ++++ ++++ ++++ 118 +++ +++ +++ +++ 124 +++ +++ ++++ + 127 + ++++ ++++ ++++ 130 + ++++ ++++ ++++ 132 ++++ ++++ +++ + 135 +++ ++++ ++++ ++++ 139 ++++ ++++ N.D. N.D. 143 +++ ++++ N.D. N.D. 014 +++ ++++ N.D. N.D. 145 ++++ ++++ N.D. N.D. 149 ++++ ++++ ++++ ++++ 151 +++ ++++ N.D. N.D. 152 +++ ++++ N.D. N.D. 155 ++++ ++++ ++++ ++++ 159 ++++ N.D. N.D. N.D. 166 ++++ +++ +++ ++++ 169 ++++ ++++ +++ +++ 178 +++ ++++ ++++ ++++ 181 ++++ N.D. N.D. N.D. Table 5 (continued) Ex. Lymphoma T Lymphoma B HUT78 CCRF_CEM KARPAS 299 REC1 NALM6 001 ++++ ++++ ++++ ++++ ++++ 008 ++++ ++++ ++++ ++++ ++++ 015 +++ +++ +++ +++ ++ 016 ++++ ++++ ++++ ++++ ++++ 024 ++++ ++++ ++++ ++++ ++++ 027 ++++ ++++ ++++ ++++ ++++ 029 ++++ ++++ ++++ ++++ ++++ 031 ++++ ++++ ++++ ++++ ++++ 033 ++++ ++++ ++++ ++++ ++++ 034 ++++ ++++ ++++ ++++ ++++ 048 ++++ ++++ ++++ ++++ ++++
071 ++++ ++++ ++++ ++++ ++++ 076 +++ +++ +++ +++ +++ 077 ++++ ++++ ++++ ++++ ++++ 080 ++++ ++++ ++++ ++++ ++++ 083 ++++ ++++ ++++ ++++ ++++ 084 ++++ ++++ ++++ ++++ ++++ 098 ++++ ++++ ++++ ++++ ++++ 102 ++++ ++++ ++++ ++++ ++++ 103 ++++ ++++ ++++ ++++ ++++ 107 ++++ ++++ ++++ ++++ ++++ 108 ++++ ++++ ++++ ++++ ++++ 111 ++++ ++++ ++++ ++++ +++ 013 ++++ ++++ ++++ ++++ ++++ 118 ++++ +++ +++ ++++ +++ 124 ++++ ++++ ++++ ++++ ++++ 127 ++++ ++++ ++++ ++++ ++++ 130 ++++ ++++ ++++ ++++ ++++ 132 N.D. N.D. N.D. N.D. N.D. 135 ++++ ++++ ++++ ++++ ++++ 139 ++++ ++++ ++++ ++++ ++++ 143 ++++ ++++ ++++ ++++ ++++ 014 ++++ ++++ ++++ ++++ ++++ 145 ++++ ++++ ++++ ++++ ++++ 149 ++++ ++++ ++++ ++++ ++++ 151 ++++ ++++ ++++ ++++ ++++ 152 ++++ ++++ ++++ ++++ ++++ 155 ++++ ++++ ++++ ++++ ++++ 159 ++++ ++++ ++++ ++++ ++++ 166 ++++ ++++ ++++ ++++ ++++ 169 ++++ ++++ ++++ ++++ ++++ 178 ++++ ++++ ++++ ++++ ++++ 181 ++++ ++++ ++++ ++++ ++++ Table 6: Anti-tumoral activity of the compounds of formula (I) on solid tumor cell lines (measured IC50) Ex. Lung Lung Larynx Stomach Colon A549 H1299 HEP2 HGC27 HRT18 001 ++++ ++++ ++++ ++++ ++++ 008 ++++ ++++ ++++ ++++ ++++ 015 +++ ++++ ++++ ++++ ++++ 016 ++++ ++++ ++++ ++++ ++++ 024 ++++ ++++ ++++ ++++ ++++ 027 ++++ ++++ ++++ ++++ ++++ 029 ++++ ++++ ++++ ++++ ++++
++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ +++ N.D. ++++ ++++ N.D. ++++ ++++ ++++ ++++ ++++ +++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ N.D. N.D. N.D. N.D. N.D. ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ Table 6 (continued) Ex. Pancreas Liver Glioblastoma PANC_1 PLC PRF5 U118 U87_MG 001 ++++ ++++ ++++ ++++ 008 ++++ ++++ ++++ ++++ 015 +++ ++++ ++++ ++++
016 ++++ ++++ ++++ ++++ 024 ++++ ++++ ++++ ++++ 027 ++++ ++++ ++++ ++++ 029 ++++ ++++ ++++ ++++ 031 ++++ ++++ ++++ ++++ 033 ++++ ++++ ++++ ++++ 034 ++++ ++++ ++++ ++++ 048 ++++ ++++ ++++ ++++ 071 ++++ ++++ ++++ ++++ 076 ++++ ++++ +++ +++ 077 ++++ ++++ ++++ ++++ 080 ++++ ++++ ++++ ++++ 083 ++++ ++++ ++++ ++++ 084 ++++ ++++ ++++ ++++ 098 ++++ ++++ ++++ ++++ 102 ++++ ++++ ++++ ++++ 103 ++++ ++++ ++++ ++++ 107 ++++ ++++ ++++ ++++ 108 ++++ ++++ ++++ ++++ 111 ++++ ++++ ++++ ++++ 013 ++++ ++++ ++++ ++++ 118 +++ ++++ ++++ ++++ 124 ++++ ++++ ++++ ++++ 127 ++++ ++++ ++++ ++++ 130 ++++ ++++ ++++ ++++ 132 N.D. N.D. N.D. N.D. 135 ++++ ++++ ++++ ++++ 139 ++++ ++++ ++++ ++++ 143 ++++ ++++ ++++ ++++ 014 ++++ ++++ ++++ ++++ 145 ++++ ++++ ++++ ++++ 149 ++++ ++++ ++++ ++++ 151 ++++ ++++ ++++ ++++ 152 ++++ ++++ ++++ ++++ 155 ++++ ++++ ++++ ++++ 159 ++++ ++++ ++++ ++++ 166 ++++ ++++ ++++ ++++ 169 ++++ ++++ ++++ ++++ 178 ++++ ++++ ++++ ++++ 181 ++++ ++++ ++++ ++++ Table 6 (continued) Ex. Ovarian Kidney Prostate Breast
Tov21G 786-O ACHN PC3 LnCaP DU145 MCF7 MDA- MB-468 ++++ + ++++ ++++ ++++ ++++ +++ ++++ + ++++ ++++ ++++ ++++ ++++ ++++ +++ N.D. +++ +++ +++ +++ +++ +++ ++ +++ ++++ ++++ ++++ +++ ++++ ++++ +++ + ++++ ++++ ++++ ++++ ++++ ++++ +++ + ++++ ++++ ++++ ++++ ++++ ++++ ++ + ++++ ++++ ++++ ++++ ++++ ++++ +++ +++ ++++ ++++ ++++ ++ ++++ ++++ +++ +++ ++++ ++++ ++++ +++ ++++ ++++ +++ ++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ +++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ +++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ +++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ + ++++ ++++ ++++ ++++ ++++ ++++ ++++ + ++++ ++++ ++++ ++++ +++ ++++ ++++ +++ ++++ ++++ ++++ ++++ ++++ ++++ ++++ +++ ++++ ++++ ++++ N.D. ++++ ++++ ++++ N.D. ++++ ++++ ++++ ++++ ++++ ++++ N.D. N.D. ++ +++ +++ ++++ +++ +++ ++++ N.D. ++++ ++++ N.D. ++++ N.D. ++++ ++++ N.D. ++++ ++++ ++++ ++++ ++++ ++++ ++++ N.D. ++++ ++++ ++++ ++++ ++++ ++++ ++++ N.D. ++++ ++++ N.D. N.D. N.D. ++++ +++ N.D. ++++ ++++ ++++ ++++ ++++ ++++ ++++ N.D. ++++ ++++ ++++ ++++ N.D. N.D. ++++ N.D. ++++ ++++ ++++ ++++ N.D. N.D. ++++ N.D. ++++ ++++ ++++ ++++ N.D. N.D. ++++ N.D. ++++ ++++ ++++ ++++ N.D. N.D. N.D. N.D. ++++ ++++ ++++ ++++ ++++ ++++ ++ N.D. ++++ ++++ ++++ ++++ N.D. N.D. ++++ N.D. ++++ ++++ ++++ ++++ N.D. N.D. N.D. N.D. ++++ ++++ ++++ ++++ ++++ ++++ N.D. N.D. N.D. N.D. N.D. ++++ N.D. N.D. N.D. N.D. +++ +++ ++++ ++++ +++ +++ N.D. N.D. ++++ ++++ ++++ ++++ ++++ ++++ N.D. N.D. ++++ ++++ ++++ ++++ ++++ ++++
181 N.D. N.D. N.D. N.D. N.D. ++++ N.D. N.D. Table 6 (continued) arcoma Sar Ovarian Lipos coma Ewing Osteosarcoma Fibrosarcoma Sarcoma Ex. SW872 SK-N- MC A4573 U2OS WEHI164 MESSA 001 ++++ ++++ ++++ ++++ N.D. ++++ 008 N.D. N.D. N.D. N.D. N.D. ++++ 015 ++++ ++++ ++++ +++ N.D. ++ 016 N.D. N.D. ++++ ++++ N.D. ++++ 024 N.D. N.D. ++++ ++++ N.D. ++++ 027 ++++ ++++ ++++ ++++ ++++ +++ 029 N.D. N.D. ++++ ++++ N.D. ++++ 031 ++++ ++++ ++++ ++++ ++++ ++++ 033 ++++ ++++ ++++ ++++ ++++ ++++ 034 ++++ ++++ ++++ ++++ ++++ ++++ 048 N.D. N.D. ++++ ++++ N.D. ++++ 071 N.D. N.D. ++++ ++++ N.D. N.D. 076 ++++ ++++ +++ +++ ++++ ++++ 077 N.D. N.D. ++++ ++++ N.D. ++++ 080 ++++ ++++ ++++ ++++ N.D. ++++ 083 ++++ ++++ ++++ ++++ ++++ ++++ 084 ++++ ++++ ++++ ++++ N.D. ++++ 098 N.D. N.D. ++++ ++++ N.D. ++++ 102 ++++ ++++ ++++ ++++ N.D. N.D. 103 ++++ ++++ ++++ ++++ N.D. N.D. 107 ++++ ++++ ++++ ++++ ++++ ++++ 108 ++++ ++++ ++++ ++++ N.D. N.D. 111 ++++ ++++ ++++ ++++ N.D. N.D. 013 ++++ ++++ ++++ ++++ ++++ ++++ 118 ++++ ++++ ++++ ++++ ++++ N.D. 124 ++++ ++++ ++++ ++++ N.D. N.D. 127 ++++ ++++ ++++ ++++ N.D. N.D. 130 ++++ ++++ ++++ ++++ N.D. N.D. 132 N.D. N.D. N.D. N.D. N.D. N.D. 135 ++++ ++++ ++++ ++++ N.D. N.D. 139 ++++ ++++ ++++ ++++ N.D. N.D. 143 ++++ ++++ ++++ ++++ N.D. N.D. 014 ++++ ++++ ++++ ++++ ++++ ++++ 145 ++++ ++++ ++++ ++++ N.D. N.D. 149 ++++ ++++ ++++ ++++ ++++ ++++ 151 ++++ ++++ ++++ ++++ N.D. N.D. 152 ++++ ++++ ++++ ++++ N.D. N.D.
155 ++++ ++++ ++++ ++++ N.D. N.D. 159 ++++ ++++ ++++ ++++ ++++ N.D. 166 ++++ ++++ ++++ ++++ ++++ ++++ 169 ++++ ++++ ++++ ++++ N.D. ++++ 178 ++++ ++++ ++++ ++++ ++++ ++++ 181 ++++ ++++ ++++ ++++ ++++ ++++ [0156] The IC50 given in Table 5 and Table 6 above are expressed as: ++++: IC50 ≤ 100 nM, +++: 100 < IC50 ≤ 500 nM, ++: 500 < IC50 ≤ 1000 nM, +: IC50 > 1000 nM, N.D.: Not Determined. [0157] Therefore, it was observed a very effective antiproliferative activity on the cell lines listed above by the class of compounds of formula (I) of the invention. The listed compounds in Table 5 and Table 6 are well representing the class of compounds of formula (I).
or a pharmaceutically acceptable salt and/or solvate thereof, wherein R1 and R2 are each independently selected from hydrogen, C1-C10 alkyl, cyano, CF3, hydroxy, C1-C10 alkoxy and halogen; R3 is selected from hydrogen, C1-C10 alkyl, C3-C10 cycloalkyl and C2-C11 heterocycloalkyl, wherein said C1-C10 alkyl is optionally substituted by at least one group selected from azido, cyano, -C(O)OR6, OR7, halogen, C3-C10 cycloalkyl, C2-C11 heterocycloalkyl, aryl and heteroaryl, wherein said C3-C10 cycloalkyl, said C2-C11 heterocycloalkyl, said aryl or said heteroaryl is optionally substituted by at least one group selected from C1-C10 alkyl, C1-C10 alkyl substituted by at least one OR7, hydroxy, C1-C10 alkoxy, -C(O)OR6 and halogen, and wherein R6 and R7 are each independently selected from hydrogen and C1-C10 alkyl; R4 and R5 are each independently selected from hydrogen, hydroxy, C1-C10 alkyl and C1-C10 alkoxy; B is an aryl, a five-membered heteroaryl or a six-membered heteroaryl;
X is nitrogen or CR8, wherein R8 is selected from hydrogen, C1-C10 alkyl, cyano, CF3, C1-C10 alkoxy and halogen. Y is nitrogen or CR9, wherein R9 is selected from hydrogen, C1-C10 alkyl, cyano, CF3, C1-C10 alkoxy and halogen; V is NR10, CR11R12 or oxygen, wherein R10, R11 and R12 are each independently selected from hydrogen and C1-C10 alkyl; and W is C=O or CR13R14, wherein R13 and R14 each independently selected from hydrogen and C1-C10 alkyl. 2. The compound according to claim 1, wherein said compound is of formula (II)
or a pharmaceutically acceptable salt and/or solvate thereof, wherein R1, R2, R3, B and Y are each independently as defined in claim 1. 3. The compound according to claim 1 or claim 2, wherein B is selected from phenyl, thiazole, oxazole, oxadiazole, isoxazole, thiadiazole, pyrazole, pyridine and pyrimidine; wherein said phenyl, said thiazole, said oxazole, said oxadiazole, said isoxazole, said thiadiazole, said pyrazole, said pyridine or said pyrimidine is optionally substituted by at least one methyl.
4. The compound according to any one of claims 1 to 3, wherein B is a five-membered heteroaryl or a six-membered heteroaryl. 5. The compound according to claim 1, wherein said compound is of formula (III)
or a pharmaceutically acceptable salt and/or solvate thereof, wherein R1, R2, R3 and Y are each independently as defined in claim 1. 6. The compound according to any one of claims 1 to 5, wherein Y is CR9, wherein R9 is selected from hydrogen, C1-C10 alkyl and halogen. 7. The compound according to any one of claims 1 to 6, wherein R1 is C1-C10 alkyl and/or R2 is hydrogen. 8. The compound according to any one of claims 1 to 7, wherein R3 is C1-C10 alkyl group, wherein said C1-C10 alkyl is optionally substituted by OR7, wherein R7 is C1-C10 alkyl. 9. The compound according to claim 1 selected from: 001 1-(4-(4-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-2- yl)phenyl)imidazolidin-2-one 002 1-(4-(4-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-2- yl)phenyl)imidazolidin-2-one 003 1-(4-(2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)phenyl)imidazolidin-2-one 004 1-(4-(4-((1-(3,5-dimethylbenzyl)-1H-pyrazol-4-yl)amino)pyrimidin- 2-yl)phenyl)imidazolidin-2-one 005 1-(4-(2-((1-(3,5-dimethylbenzyl)-1H-pyrazol-4-yl)amino)pyrimidin- 4-yl)phenyl)imidazolidin-2-one 006 1-(4-(6-((1-(2-propoxyethyl)-1H-pyrazol-4-yl)amino)pyridin-2- yl)phenyl)imidazolidin-2-one
1-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol-4-ylamino]-oxazol-5-yl}- phenyl)-imidazolidin-2-one 1-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol-4-ylamino]-thiazol-4-yl}- phenyl)-imidazolidin-2-one 1-(4-(5-((1-(2-ethoxyethyl)-1H-pyrazol-4-yl)amino)-1,2,4- thiadiazol-3-yl)phenyl)imidazolidin-2-one 3-(4-{2-[1-(2-Methoxy-ethyl)-3-methyl-1H-pyrazol-4-ylamino]- thiazol-4-yl}-phenyl)-oxazolidin-2-one 1-(4-{5-[1-(2-Ethoxy-ethyl)-1H-pyrazol-4-ylamino]-2H-pyrazol-3- yl}-phenyl)-imidazolidin-2-one 1-(4-{2-[1-(2-Methoxy-ethyl)-3-methyl-1H-pyrazol-4-ylamino]- thiazol-4-yl}-phenyl)-pyrrolidin-2-one 1-(3-Fluoro-4-{2-[1-(3-methoxy-propyl)-3-methyl-1H-pyrazol-4- ylamino]-thiazol-4-yl}-phenyl)-imidazolidin-2-one 1-(4-(4-((1-(3-methoxypropyl)-3-(trifluoromethyl)-1H-pyrazol-4- yl)amino)pyrimidin-2-yl)phenyl)imidazolidin-2-one 1-(4-{2-[1-(2-Ethoxy-ethyl)-3-methyl-1H-pyrazol-4-ylamino]- oxazol-5-yl}-phenyl)-imidazolidin-2-one 1-(4-(2-((1-(2-ethoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)phenyl)imidazolidin-2-one 3-(4-(2-((1-(2-ethoxyethyl)-3-methyl-1H-pyrazol-4- yl)amino)oxazol-5-yl)phenyl)oxazolidin-2-one 1-(4-(4-((1-(2-ethoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-2- yl)phenyl)imidazolidin-2-one 1-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)phenyl)imidazolidin-2-one 1-(4-{2-[1-(2-Methoxy-ethyl)-1H-pyrazol-4-ylamino]-oxazol-5-yl}- phenyl)-imidazolidin-2-one 1-(4-(2-((1-(2-ethoxyethyl)-1H-pyrazol-4-yl)amino)oxazol-5-yl)-3- fluorophenyl)imidazolidin-2-one 1-(4-(2-((1-(2-ethoxyethyl)-1H-pyrazol-4-yl)amino)oxazol-5-yl)-2- fluorophenyl)imidazolidin-2-one 1-(5-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol-4-ylamino]-thiazol-4-yl}- pyridin-2-yl)-imidazolidin-2-one 1-(4-(4-((1-ethyl-3-methyl-1H-pyrazol-4-yl)amino)pyrimidin-2- yl)phenyl)imidazolidin-2-one 1-(5-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol-4-ylamino]-oxazol-5-yl}- pyridin-2-yl)-imidazolidin-2-one 1-(6-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol-4-ylamino]-oxazol-5-yl}- pyridin-3-yl)-imidazolidin-2-one 1-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol-4-ylamino]-thiazol-4-yl}- 3-methoxy-phenyl)-imidazolidin-2-one 1-(4-(4-((1,3,5-trimethyl-1H-pyrazol-4-yl)amino)pyrimidin-2- yl)phenyl)imidazolidin-2-one 1-(4-(4-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-2- yl)phenyl)imidazolidin-2-one
1-(4-(4-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-2- yl)phenyl)imidazolidin-2-one 1-(4-(4-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-2- yl)phenyl)imidazolidin-2-one 1-(4-(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)oxazol-5- yl)phenyl)imidazolidin-2-one 3-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol-4-ylamino]-thiazol-4-yl}- phenyl)-oxazolidin-2-one 1-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol-4-ylamino]-thiazol-4-yl}- phenyl)-4-(R)-methyl-imidazolidin-2-one 1-(4-(2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)thiazol-4- yl)phenyl)imidazolidin-2-one 1-(5-{2-[1-(2-Ethoxy-ethyl)-3-methyl-1H-pyrazol-4-ylamino]- oxazol-5-yl}-pyridin-2-yl)-imidazolidin-2-one 1-(5-{2-[1-(2-Ethoxy-ethyl)-5-methyl-1H-pyrazol-4-ylamino]- oxazol-5-yl}-pyridin-2-yl)-imidazolidin-2-one 1-(4-{2-[1-(2-Ethoxy-ethyl)-5-methyl-1H-pyrazol-4-ylamino]- thiazol-4-yl}-phenyl)-imidazolidin-2-one 1-(4-(4-((1-(tert-butyl)-1H-pyrazol-4-yl)amino)pyrimidin-2- yl)phenyl)imidazolidin-2-one 1-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol-4-ylamino]-thiazol-4-yl}- phenyl)-pyrrolidine-2,5-dione 1-(4-(4-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-2- yl)phenyl)pyrrolidin-2-one 1-(4-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)phenyl)imidazolidin-2-one 1-(4-(2-((1-ethyl-3-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)phenyl)imidazolidin-2-one 1-(4-(4-((1-butyl-1H-pyrazol-4-yl)amino)pyrimidin-2- yl)phenyl)imidazolidin-2-one 1-(4-(2-((1-(tert-butyl)-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)phenyl)imidazolidin-2-one 1-(4-(4-((1-butyl-3,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-2- yl)phenyl)imidazolidin-2-one 1-(4-(4-((1-neopentyl-1H-pyrazol-4-yl)amino)pyrimidin-2- yl)phenyl)imidazolidin-2-one 1-(4-(4-((1-(sec-butyl)-1H-pyrazol-4-yl)amino)pyrimidin-2- yl)phenyl)imidazolidin-2-one 1-(4-(4-((1-(pentan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-2- yl)phenyl)imidazolidin-2-one 1-(4-(4-((1-cyclopentyl-1H-pyrazol-4-yl)amino)pyrimidin-2- yl)phenyl)imidazolidin-2-one 1-(4-(2-((1-butyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)phenyl)imidazolidin-2-one 1-(4-(4-((1-benzyl-1H-pyrazol-4-yl)amino)pyrimidin-2- yl)phenyl)imidazolidin-2-one
1-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol-4-ylamino]-thiazol-4-yl}- phenyl)-5-(R)-methyl-imidazolidin-2-one 1-(4-(4-((1-hexyl-1H-pyrazol-4-yl)amino)pyrimidin-2- yl)phenyl)imidazolidin-2-one 1-(4-(4-((1-(3,5-dimethoxybenzyl)-1H-pyrazol-4- yl)amino)pyrimidin-2-yl)phenyl)imidazolidin-2-one 1-(4-(2-((1-hexyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)phenyl)imidazolidin-2-one 1-(4-(2-((1-(3,5-dimethoxybenzyl)-1H-pyrazol-4- yl)amino)pyrimidin-4-yl)phenyl)imidazolidin-2-one 1-(4-(4-((1-(3-methoxybenzyl)-1H-pyrazol-4-yl)amino)pyrimidin-2- yl)phenyl)imidazolidin-2-one 1-(4-(2-((1-(3-methoxybenzyl)-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)phenyl)imidazolidin-2-one 1-(4-(4-((1-heptyl-1H-pyrazol-4-yl)amino)pyrimidin-2- yl)phenyl)imidazolidin-2-one 1-(4-(4-((1-(4-methoxy-3,5-dimethylbenzyl)-1H-pyrazol-4- yl)amino)pyrimidin-2-yl)phenyl)imidazolidin-2-one 1-(4-(2-((1-(4-methoxy-3,5-dimethylbenzyl)-1H-pyrazol-4- yl)amino)pyrimidin-4-yl)phenyl)imidazolidin-2-one 3-(4-{2-[1-(2-Ethoxy-ethyl)-3-methyl-1H-pyrazol-4-ylamino]- thiazol-4-yl}-phenyl)-oxazolidin-2-one 1-(4-(4-((1-(4,4,4-trifluorobutyl)-1H-pyrazol-4-yl)amino)pyrimidin- 2-yl)phenyl)imidazolidin-2-one 1-(3-methoxy-4-(2-((1-(2-methoxyethyl)-1H-pyrazol-4- yl)amino)thiazol-4-yl)phenyl)imidazolidin-2-one 1-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol-4-ylamino]-thiazol-4-yl}- 3-methyl-phenyl)-imidazolidin-2-one 1-(4-(2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)thiazol-4-yl)- 3-methylphenyl)imidazolidin-2-one 1-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol-4-ylamino]-thiazol-4-yl}- 3-methoxy-phenyl)-(R)-4-methyl-imidazolidin-2-one 1-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol-4-ylamino]-thiazol-4-yl}- 3-fluoro-phenyl)-imidazolidin-2-one 1-(3-Methoxy-4-{2-[1-(3-methoxy-propyl)-1H-pyrazol-4-ylamino]- thiazol-4-yl}-phenyl)-imidazolidin-2-one 1-(4-{2-[1-(2-Methoxy-ethyl)-1H-pyrazol-4-ylamino]-thiazol-4-yl}- 3-fluoro-phenyl)-imidazolidin-2-one 3-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol-4-ylamino]-thiazol-4-yl}- 3-methyl-phenyl)-oxazolidin-2-one 1-(4-(4-((1-(3-fluorobenzyl)-1H-pyrazol-4-yl)amino)pyrimidin-2- yl)phenyl)imidazolidin-2-one 1-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol-4-ylamino]-thiazol-4-yl}- 3-isopropoxy-phenyl)-imidazolidin-2-one 3-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol-4-ylamino]-thiazol-4-yl}- 3-methoxy-phenyl)-oxazolidin-2-one
3-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol-4-ylamino]-thiazol-4-yl}- 3-fluoro-phenyl)-oxazolidin-2-one 1-(4-{2-[1-(2-Ethoxy-ethyl)-5-methyl-1H-pyrazol-4-ylamino]- thiazol-4-yl}-3-methoxy-phenyl)-imidazolidin-2-one 1-(4-{2-[1-(2-Ethoxy-ethyl)-3-methyl-1H-pyrazol-4-ylamino]- thiazol-4-yl}-3-methoxy-phenyl)-imidazolidin-2-one 1-(4-(4-((1-(difluoromethyl)-1H-pyrazol-4-yl)amino)pyrimidin-2- yl)phenyl)imidazolidin-2-one 1-(4-(4-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-4- yl)amino)pyrimidin-2-yl)phenyl)imidazolidin-2-one 1-(4-{2-[1-(2-Ethoxy-ethyl)-3-methoxy-1H-pyrazol-4-ylamino]- thiazol-4-yl}-phenyl)-imidazolidin-2-one 1-(4-{2-[1-(2-Ethoxy-ethyl)-3-methoxy-1H-pyrazol-4-ylamino]- thiazol-4-yl}-3-methoxy-phenyl)-imidazolidin-2-one 1-(4-{2-[1-(2-Ethoxy-ethyl)-3-methyl-1H-pyrazol-4-ylamino]- thiazol-4-yl}-phenyl)-imidazolidin-2-one 1-(3-Fluoro-4-{2-[1-(3-methoxy-propyl)-1H-pyrazol-4-ylamino]- thiazol-4-yl}-phenyl)-imidazolidin-2-one 1-(3'-((1-isopropyl-1H-pyrazol-4-yl)amino)-[1,1'-biphenyl]-4- yl)imidazolidin-2-one 1-(4-{2-[3-Chloro-1-(2-ethoxy-ethyl)-1H-pyrazol-4-ylamino]- thiazol-4-yl}-phenyl)-imidazolidin-2-one 1-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol-4-ylamino]-5-methyl- thiazol-4-yl}-phenyl)-imidazolidin-2-one 1-(4-{2-[1-(2-Ethoxy-ethyl)-3-methyl-1H-pyrazol-4-ylamino]- thiazol-4-yl}-3-fluoro-phenyl)-imidazolidin-2-one 1-(4-{2-[1-(2-Ethoxy-ethyl)-5-methyl-1H-pyrazol-4-ylamino]- thiazol-4-yl}-3-fluoro-phenyl)-imidazolidin-2-one 1-(3-Chloro-4-{2-[1-(3-methoxy-propyl)-1H-pyrazol-4-ylamino]- thiazol-4-yl}-phenyl)-pyrrolidin-2-one 1-(4-(4-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)amino)pyrimidin- 2-yl)phenyl)imidazolidin-2-one 1-(3-Chloro-4-{2-[1-(2-ethoxy-ethyl)-3-methyl-1H-pyrazol-4- ylamino]-thiazol-4-yl}-phenyl)-pyrrolidin-2-one 1-(4-(4-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)amino)pyrimidin-2- yl)phenyl)imidazolidin-2-one 1-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol-4-ylamino]-thiazol-4-yl}- 3-methoxy-phenyl)-pyrrolidin-2-one 1-(4-(2-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)phenyl)imidazolidin-2-one 1-(4-(2-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)amino)pyrimidin- 4-yl)phenyl)imidazolidin-2-one 1-(4-{2-[1-(2-[1,2,4]Triazol-1-yl-ethyl)-1H-pyrazol-4-ylamino]- thiazol-4-yl}-phenyl)-imidazolidin-2-one 1-(4-(4-((1-propyl-1H-pyrazol-4-yl)amino)pyrimidin-2- yl)phenyl)imidazolidin-2-one
1-(4-(2-((1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4- yl)amino)pyrimidin-4-yl)phenyl)imidazolidin-2-one 1-(4-(2-((1-propyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)phenyl)imidazolidin-2-one 1-(4-(4-((1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4- yl)amino)pyrimidin-2-yl)phenyl)imidazolidin-2-one 1-(4-(4-((1-cyclopropyl-1H-pyrazol-4-yl)amino)pyrimidin-2- yl)phenyl)imidazolidin-2-one 1-(4-(4-((1-cyclobutyl-1H-pyrazol-4-yl)amino)pyrimidin-2- yl)phenyl)imidazolidin-2-one 1-(4-(4-((1-(oxetan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-2- yl)phenyl)imidazolidin-2-one 1-(4-(2-((1-(1-hydroxy-2-methylpropan-2-yl)-1H-pyrazol-4- yl)amino)pyrimidin-4-yl)phenyl)imidazolidin-2-one 1-(4-(4-((1-(1-hydroxypropan-2-yl)-1H-pyrazol-4- yl)amino)pyrimidin-2-yl)phenyl)imidazolidin-2-one 1-(4-{2-[1-(3-Methoxy-propyl)-3-methyl-1H-pyrazol-4-ylamino]- thiazol-4-yl}-phenyl)-imidazolidin-2-one 1-(4-{2-[1-(2-Methoxy-ethyl)-3-methyl-1H-pyrazol-4-ylamino]- thiazol-4-yl}-phenyl)-imidazolidin-2-one 2-methyl-2-(4-((2-(4-(2-oxoimidazolidin-1-yl)phenyl)pyrimidin-4- yl)amino)-1H-pyrazol-1-yl)propanenitrile 1-(4-{5-[1-(2-Ethoxy-ethyl)-1H-pyrazol-4-ylamino]-2H-pyrazol-3- yl}-3-methoxy-phenyl)-imidazolidin-2-one 1-(4-(4-((1-(1-methoxypropan-2-yl)-1H-pyrazol-4- yl)amino)pyrimidin-2-yl)phenyl)imidazolidin-2-one 1-(4-(2-((1-(1-methoxy-2-methylpropan-2-yl)-1H-pyrazol-4- yl)amino)pyrimidin-4-yl)phenyl)imidazolidin-2-one 1-(4-(2-((1-(1-methoxypropan-2-yl)-1H-pyrazol-4- yl)amino)pyrimidin-4-yl)phenyl)imidazolidin-2-one 2-methyl-2-(4-((4-(4-(2-oxoimidazolidin-1-yl)phenyl)pyrimidin-2- yl)amino)-1H-pyrazol-1-yl)propanenitrile 2-(4-((2-(4-(2-oxoimidazolidin-1-yl)phenyl)pyrimidin-4-yl)amino)- 1H-pyrazol-1-yl)propanenitrile 1-(4-(2-((1-cyclopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)phenyl)imidazolidin-2-one 1-(4-{5-[1-(2-Ethoxy-ethyl)-1H-pyrazol-4-ylamino]-2H-pyrazol-3- yl}-3-fluoro-phenyl)-imidazolidin-2-one 1-(4-{2-[1-(2-Azido-ethyl)-1H-pyrazol-4-ylamino]-thiazol-4-yl}- phenyl)-imidazolidin-2-one 1-(3-Methoxy-4-{2-[1-(3-methoxy-propyl)-3-methyl-1H-pyrazol-4- ylamino]-thiazol-4-yl}-phenyl)-imidazolidin-2-one 1-(4-(4-((1-isopropyl-3-methyl-1H-pyrazol-4-yl)amino)pyrimidin-2- yl)phenyl)imidazolidin-2-one 1-(4-(4-((1-(1-methoxybutan-2-yl)-1H-pyrazol-4- yl)amino)pyrimidin-2-yl)phenyl)imidazolidin-2-one
1-(4-(2-((1-(1-methoxybutan-2-yl)-1H-pyrazol-4- yl)amino)pyrimidin-4-yl)phenyl)imidazolidin-2-one 1-(4-(4-((1-(1-ethoxypropan-2-yl)-1H-pyrazol-4- yl)amino)pyrimidin-2-yl)phenyl)imidazolidin-2-one 1-(4-(2-((1-(1-ethoxybutan-2-yl)-1H-pyrazol-4-yl)amino)pyrimidin- 4-yl)phenyl)imidazolidin-2-one 1-(4-(2-((1-(1-ethoxypropan-2-yl)-1H-pyrazol-4- yl)amino)pyrimidin-4-yl)phenyl)imidazolidin-2-one 1-(4-{2-[1-(2-Methoxy-ethyl)-3-methyl-1H-pyrazol-4-ylamino]- thiazol-4-yl}-phenyl)-4-(R)-methyl-imidazolidin-2-one 1-(3-Fluoro-4-{2-[1-(2-methoxy-ethyl)-3-methyl-1H-pyrazol-4- ylamino]-thiazol-4-yl}-phenyl)-imidazolidin-2-one 1-(4-(4-((1-(1-methoxy-3-methylbutan-2-yl)-1H-pyrazol-4- yl)amino)pyrimidin-2-yl)phenyl)imidazolidin-2-one 1-(4-(4-((1-(2,2-difluorocyclopropyl)-1H-pyrazol-4- yl)amino)pyrimidin-2-yl)phenyl)imidazolidin-2-one 1-(4-(2-((1-(1-methoxy-3-methylbutan-2-yl)-1H-pyrazol-4- yl)amino)pyrimidin-4-yl)phenyl)imidazolidin-2-one 1-(4-(2-((1-(2,2-difluorocyclopropyl)-1H-pyrazol-4- yl)amino)pyrimidin-4-yl)phenyl)imidazolidin-2-one 1-(4-(4-((1-(2-methoxy-2-methylpropyl)-1H-pyrazol-4- yl)amino)pyrimidin-2-yl)phenyl)imidazolidin-2-one (R)-1-(4-(4-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-2- yl)phenyl)-4-methylimidazolidin-2-one 1-(4-(2-((1-(2-methoxy-2-methylpropyl)-1H-pyrazol-4- yl)amino)pyrimidin-4-yl)phenyl)imidazolidin-2-one 1-(4-(2-((1-(1-ethoxy-3-methylbutan-2-yl)-1H-pyrazol-4- yl)amino)pyrimidin-4-yl)phenyl)imidazolidin-2-one (R)-1-(4-(4-((1-(2-methoxypropyl)-1H-pyrazol-4- yl)amino)pyrimidin-2-yl)phenyl)imidazolidin-2-one 1-(4-(4-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-2- yl)phenyl)-4,4-dimethylimidazolidin-2-one (S)-1-(4-(4-((1-(2-methoxypropyl)-1H-pyrazol-4- yl)amino)pyrimidin-2-yl)phenyl)imidazolidin-2-one 1-(4-(4-((1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-4- yl)amino)pyrimidin-2-yl)phenyl)imidazolidin-2-one 1-(4-(4-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-2- yl)phenyl)imidazolidin-2-one 1-(4-(2-((1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-4- yl)amino)pyrimidin-4-yl)phenyl)imidazolidin-2-one 1-(4-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)phenyl)imidazolidin-2-one 1-(4-(4-((1-(3-methoxypropyl)-1H-pyrazol-4-yl)amino)pyrimidin-2- yl)phenyl)imidazolidin-2-one 1-(4-{2-[1-(3-Methoxy-propyl)-3-methyl-1H-pyrazol-4-ylamino]- thiazol-4-yl}-3-methyl-phenyl)-imidazolidin-2-one
1-(4-(4-((1-(2-methoxyethyl)-3-(trifluoromethyl)-1H-pyrazol-4- yl)amino)pyrimidin-2-yl)phenyl)imidazolidin-2-one 3-(4-{2-[1-(3-Methoxy-propyl)-1H-pyrazol-4-ylamino]-thiazol-4- yl}-phenyl)-oxazolidin-2-one 3-(3-Fluoro-4-{2-[1-(3-methoxy-propyl)-1H-pyrazol-4-ylamino]- thiazol-4-yl}-phenyl)-oxazolidin-2-one 3-(3-Fluoro-4-{2-[1-(2-methoxy-ethyl)-1H-pyrazol-4-ylamino]- thiazol-4-yl}-phenyl)-oxazolidin-2-one 1-(4-{2-[1-(3-Methoxy-propyl)-1H-pyrazol-4-ylamino]-thiazol-4- yl}-phenyl)-imidazolidin-2-one 3-(4-{2-[1-(2-Methoxy-ethyl)-1H-pyrazol-4-ylamino]-thiazol-4-yl}- phenyl)-oxazolidin-2-one 1-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol-4-ylamino]-thiazol-4-yl}- phenyl)-pyrrolidin-2-one 1-(4-(4-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)amino)pyrimidin- 2-yl)phenyl)imidazolidin-2-one 1-(4-(4-((1-((3-(methoxymethyl)oxetan-3-yl)methyl)-1H-pyrazol-4- yl)amino)pyrimidin-2-yl)phenyl)imidazolidin-2-one 1-(4-(4-((1-(1,4-dimethoxybutan-2-yl)-1H-pyrazol-4- yl)amino)pyrimidin-2-yl)phenyl)imidazolidin-2-one 1-(4-(4-((1-(3-methoxycyclobutyl)-1H-pyrazol-4- yl)amino)pyrimidin-2-yl)phenyl)imidazolidin-2-one 1-(4-(4-((3-methoxy-1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-2- yl)phenyl)imidazolidin-2-one 3-(4-{2-[1-(2-Ethoxy-ethyl)-3-methyl-1H-pyrazol-4-ylamino]- thiazol-4-yl}-3-fluoro-phenyl)-oxazolidin-2-one 3-(4-{2-[1-(2-Ethoxy-ethyl)-3-methyl-1H-pyrazol-4-ylamino]- thiazol-4-yl}-phenyl)-oxazolidin-2-one 1-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol-4-ylamino]-thiazol-4-yl}- 3-fluoro-phenyl)-pyrrolidin-2-one 1-(4-{2-[1-(2-Ethoxy-ethyl)-3-methyl-1H-pyrazol-4-ylamino]- thiazol-4-yl}-phenyl)-pyrrolidin-2-one 1-(4-{2-[1-(2-Ethoxy-ethyl)-3-methyl-1H-pyrazol-4-ylamino]- thiazol-4-yl}-3-fluoro-phenyl)-pyrrolidin-2-one 1-(4-{2-[1-(3-Methoxy-propyl)-3-methyl-1H-pyrazol-4-ylamino]- thiazol-4-yl}-phenyl)-pyrrolidin-2-one 3-(3-Fluoro-4-{2-[1-(2-methoxy-ethyl)-3-methyl-1H-pyrazol-4- ylamino]-thiazol-4-yl}-phenyl)-oxazolidin-2-one 1-(3-Fluoro-4-{2-[1-(2-methoxy-ethyl)-3-methyl-1H-pyrazol-4- ylamino]-thiazol-4-yl}-phenyl)-pyrrolidin-2-one 3-(3-Fluoro-4-{2-[1-(2-methoxy-ethyl)-3-methyl-1H-pyrazol-4- ylamino]-thiazol-4-yl}-phenyl)-oxazolidin-2-one 1-(3-Fluoro-4-{2-[1-(3-methoxy-propyl)-3-methyl-1H-pyrazol-4- ylamino]-thiazol-4-yl}-phenyl)-pyrrolidin-2-one 3-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol-4-ylamino]-thiazol-4-yl}- phenyl)-(R)-5-methyl-oxazolidin-2-one
168 1-(4-{2-[1-(2-Methoxy-ethyl)-1H-pyrazol-4-ylamino]-thiazol-4-yl}- phenyl)-pyrrolidin-2-one 169 1-(4-{2-[1-(3-Methoxy-propyl)-1H-pyrazol-4-ylamino]-thiazol-4- yl}-phenyl)-pyrrolidin-2-one 170 1-(3-Fluoro-4-{2-[1-(3-methoxy-propyl)-1H-pyrazol-4-ylamino]- thiazol-4-yl}-phenyl)-pyrrolidin-2-one 171 1-(3-Fluoro-4-{2-[1-(2-methoxy-ethyl)-1H-pyrazol-4-ylamino]- thiazol-4-yl}-phenyl)-pyrrolidin-2-one 172 1-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol-4-ylamino]-thiazol-4-yl}- 3-trifluoromethyl-phenyl)-imidazolidin-2-one 173 1-(4-{5-[1-(2-Ethoxy-ethyl)-1H-pyrazol-4-ylamino]-2H-pyrazol-3- yl}-3-fluoro-phenyl)-pyrrolidin-2-one 174 1-(4-{2-[1-(3-Ethoxy-propyl)-1H-pyrazol-4-ylamino]-thiazol-4-yl}- phenyl)-imidazolidin-2-one 175 1-(4-{2-[1-(2-Ethoxy-ethyl)-1H-pyrazol-4-ylamino]-thiazol-4-yl}- phenyl)-4-(R)-hydroxy-pyrrolidin-2-one 176 1-(3-Chloro-4-{2-[1-(2-ethoxy-ethyl)-1H-pyrazol-4-ylamino]- thiazol-4-yl}-phenyl)-imidazolidin-2-one 177 1-(3-Chloro-4-{2-[1-(3-methoxy-propyl)-1H-pyrazol-4-ylamino]- thiazol-4-yl}-phenyl)-imidazolidin-2-one 178 1-(3-Chloro-4-{2-[1-(2-ethoxy-ethyl)-3-methyl-1H-pyrazol-4- ylamino]-thiazol-4-yl}-phenyl)-imidazolidin-2-one 179 1-(4-{2-[1-(2-[1,2,3]Triazol-2-yl-ethyl)-1H-pyrazol-4-ylamino]- thiazol-4-yl}-phenyl)-imidazolidin-2-one 180 1-(4-{2-[1-(2-[1,2,3]Triazol-1-yl-ethyl)-1H-pyrazol-4-ylamino]- thiazol-4-yl}-phenyl)-imidazolidin-2-one 181 1-(3-Chloro-4-{2-[1-(2-ethoxy-ethyl)-1H-pyrazol-4-ylamino]- thiazol-4-yl}-phenyl)-pyrrolidin-2-one 182 3-(4-{4-[4-(2-Oxo-imidazolidin-1-yl)-phenyl]-thiazol-2-ylamino}- pyrazol-1-yl)-propionic acid ethyl ester 2-[2-(4-{4-[4-(2-Oxo-imidazolidin-1-yl)-phenyl]-thiazol-2- 183 ylamino}-pyrazol-1-yl)-ethyl]-2H-[1,2,3]triazole-4-carboxylic acid methyl ester 184 1-(4-{2-[1-(2-Imidazol-1-yl-ethyl)-1H-pyrazol-4-ylamino]-thiazol- 4-yl}-phenyl)-imidazolidin-2-one 185 1-(3-Chloro-4-{2-[1-(3-methoxy-propyl)-3-methyl-1H-pyrazol-4- ylamino]-thiazol-4-yl}-phenyl)-pyrrolidin-2-one 186 1-(3-Chloro-4-{2-[1-(3-methoxy-propyl)-3-methyl-1H-pyrazol-4- ylamino]-thiazol-4-yl}-phenyl)-imidazolidin-2-one and pharmaceutically acceptable salts and/or solvates thereof. 10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 and at least one pharmaceutically acceptable carrier.
11. The pharmaceutical composition according to claim 10, wherein said pharmaceutical composition comprises the compound according to any one of claims 1 to 9 as sole active pharmaceutical ingredient. 12. The pharmaceutical composition according to claim 10, wherein said pharmaceutical composition further comprises another active pharmaceutical ingredient. 13. A compound according to any one of claims 1 to 9 or a pharmaceutical composition according to any one of claims 10 to 12 for use as a medicament. 14. A compound according to any one of claims 1 to 9 or a pharmaceutical composition according to any one of claims 10 to 12 for use in the treatment of hematological disorders and/or proliferative disorders; preferably wherein: said hematological disorder is selected from lymphoma, leukemia (such as acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic lymphoid leukemia (CLL) or chronic myeloid leukemia (CML)), multiple myeloma (MM), myelodysplastic syndrome (MDS) and myelodysplasia with myelofibrosis; and/or said proliferative disorder is cancer; such as head and neck cancer, melanoma, kidney carcinoma, stomach carcinoma, liver carcinoma, colorectal carcinoma, pancreas carcinoma, larynx carcinoma, lung carcinoma, neuronal carcinoma, glioblastoma multiforme, osteosarcoma, fibrosarcoma, ovarian sarcoma, liposarcoma, Ewing sarcoma, breast carcinoma, ovary carcinoma or prostate carcinoma. 15. The compound or the pharmaceutical composition for use according to claim 14, wherein said compound or said composition is to be administered with at least another active pharmaceutical ingredient.