Improved methods of using heterocyclic inhibitors of ERK1 and ERK2

Abstract

The present application relates to improved methods of using heterocyclic inhibitors of ERK1 and ERK2. In particular, the present application provides improved compositions, methods, kits, and dosing regimens using heterocyclic compounds and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, or stereoisomers thereof. These compositions, methods, kits, and dosing regimens are useful for modulating ERK1 / 2. By administering to a subject in need thereof a therapeutically effective amount of one or more compounds of Formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, or a composition of these, wherein X, Y, Z, J, M, and R1 to R8 are defined herein, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, or a composition of these, these compounds and methods are effective in treating conditions associated with aberrant modulation of the RAS / RAF / MEK / ERK pathway or that can be treated by inhibition of Erk1 / 2. # imgabs0 #

Description

[0001] This application is a divisional application of a Chinese patent application with an application date of October 22, 2020, an application number of 202080091003.4, and an invention title of "Improved Methods, Kits, Compositions, and Dosing Regimens Using Heterocyclic Inhibitors of ERK1 and ERK2" (the corresponding PCT application has an application date of October 22, 2020, and an application number of PCT / US2020 / 056936).

[0002] Incorporation by reference

[0003] This application claims the priority of U.S. Provisional Patent Application No. 62 / 926,869, which is hereby incorporated by reference in its entirety. Technical Field

[0004] The present disclosure relates to improved compositions, methods, kits, and dosing regimens for treating conditions such as cancer that are associated with dysregulation of the RAS / RAF / MEK / ERK pathway or are treatable by inhibiting ERK1 / 2 using heterocyclic inhibitors of ERK1 and ERK2. Background Art

[0005] ERK1 and ERK2 (collectively referred to as "ERK1 / 2") are related protein serine / threonine kinases that are particularly involved in the Ras-Raf-MEK-ERK signal transduction pathway, which is sometimes designated as the mitogen-activated protein kinase (MAPK) pathway. This pathway is thought to play a major role in regulating many fundamental cellular processes including one or more of cell proliferation, survival, adhesion, cycle progression, migration, differentiation, metabolism, and transcription. Activation of the MAPK pathway has been reported in numerous tumor types including lung cancer, colon cancer, pancreatic cancer, kidney cancer, and ovarian cancer. Thus, substances that can reduce activation may be attractive for potential treatment.

[0006] ERK1 / 2 appears to be activated by MEK through phosphorylation of both threonine and tyrosine residues, i.e., phosphorylation at Tyr204 / 187 and Thr202 / 185. Once activated, ERK1 / 2 catalyzes the phosphorylation of serine / threonine residues of more than 100 substrates and activates both cytoplasmic and nuclear proteins associated with cell growth, proliferation, survival, angiogenesis, and differentiation, all of which are hallmarks of the cancer phenotype. Thus, it may be beneficial to target ERK1 and ERK2 to develop and use ERK1 / 2 inhibitors as a way to inhibit tumor growth.

[0007] In addition, combinations of ERK inhibitors with other kinases such as MAPK inhibitors may have utility. Recently, researchers reported that dual inhibition of MEK and ERK by small molecule inhibitors is synergistic and serves to overcome acquired resistance to MEK inhibitors. See Hatzivassiliou et al., ERK Inhibition Overcomes Acquired Resistance to MEK Inhibition, Mol. Cancer Ther. 2012, 11, 1143 - 1154.

[0008] Small molecule ERK inhibitors have been reported in the literature including U.S. Patent No. 6,743,941, U.S. Patent No. 8,546,404, and Ren et al., Discovery of Highly Potent, Selective and Efficacious Small Molecule Inhibitors of ERK1 / 2, J. Med. Chem., 2015, 58(4), 1976 - 1991. A few ERK inhibitors (such as BVD - 523 and GDC - 0994) are in early clinical development. However, no ERK inhibitor has been reported to progress to late - stage clinical trials. Thus, there remains a need to develop improved and effective ERK1 / 2 inhibitors for the treatment of cancer. SUMMARY OF THE INVENTION

[0009] This disclosure relates to compositions, methods of treatment, dosing regimens, and kits using the compounds of this disclosure.

[0010] In one embodiment, the disclosure provides a method of treating a condition characterized by dysregulation of the RAS / RAF / MEK / ERK pathway or a condition treatable by inhibiting Erk 1 / 2, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) at regularly or irregularly scheduled doses; or a composition for treating a condition characterized by dysregulation of the RAS / RAF / MEK / ERK pathway or a condition treatable by inhibiting ERK1 / 2; or the use of a composition for the manufacture of a medicament for treating a condition characterized by dysregulation of the RAS / RAF / MEK / ERK pathway or a condition treatable by inhibiting ERK1 / 2, wherein the composition comprises a therapeutically effective amount of a compound of formula (I):

[0011]

[0012] and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, or stereoisomers thereof, wherein: R 1 is C 6-12An aryl or 5- to 10-membered heteroaryl, which is unsubstituted or substituted with 1-3 substituents selected from the following: halogen, C 1-6 alkyl, CN, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, -C 1-6 alkyl-O-C 1-6 alkyl, -C 1-6 alkyl-NH-C 1-6 alkyl, -C 1-6 alkyl-N-(C 1-6 alkyl)2, -C 1-6 alkyl-NH-C 1-6 alkyl-OH, -C 1-6 alkyl-NH-C 1-6 alkyl-C 3-10 cycloalkyl, -C 1-6 alkyl-NH-C 1-6 alkyl-NH-C 1-6 alkyl, -C 1-6 alkyl-NH-C(O)-C 1-6 alkyl, -C 1-6 alkyl-O-C(O)-C 1-6 alkyl, -C 1-6 alkyl-NH-C 0-6 alkyl-(4- to 6-membered heterocyclic group) or -C 1-6 alkyl-NH-C 0-6 alkyl-(5- to 6-membered heteroaryl), wherein the C 1-6 alkyl, cycloalkyl, heterocyclic group and / or heteroaryl is unsubstituted or substituted with 1-3 substituents selected from the following: halogen, C 1-6 alkyl, NH2, hydroxy C 1-6 alkyl or amino C 1-6 alkyl;

[0013] J is a linker group selected from -C(R 2 )(R 8 )(CH2)-;

[0014] R 2 and R8 are each independently H, C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, -C 1-6 alkyl-O-C 1-6 alkyl, -C 1-6 alkyl-NH-C 1-6 alkyl, -C 1-6 alkyl-N-(C 1-6 alkyl)2, -C 1-6 alkyl-NH-C 1-6Alkyl-OH, -C 1-6 Alkyl-NH-C 1-6 Alkyl-C 3-10 Cycloalkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl-NH-C 1-6 Alkyl, -C 1-6 Alkyl-NH-C(O)-C 1-6 Alkyl, -C 1-6 Alkyl-O-C(O)-C 1-6 Alkyl, -C 1-6 Alkyl-NH-C 0-6 Alkyl-(4 to 6-membered heterocyclic group), -C(O)-NH2, -C(O)-NH-C 1-6 Alkyl, -C(O)-N(C 1-6 Alkyl)2 or -C 1-6 Alkyl-NH-C 0-6 Alkyl-(5 to 6-membered heteroaryl), wherein the C 1-6 Alkyl, heterocyclic group or heteroaryl is unsubstituted or substituted with 1 - 3 substituents selected from: halogen, C 1-6 Alkyl, cycloalkyl, NH2, hydroxy C 1-6 Alkyl or amino C 1-6 Alkyl;

[0015] Or, R 2 , R 8 And the C atoms having R 2 Attached to R 8 Both are attached together to form a 3 - 10-membered cycloalkyl or 4 - 10-membered heterocyclic ring, wherein the cycloalkyl or heterocyclic ring is unsubstituted or substituted with 1 - 3 substituents selected from: hydroxy, halogen or C 1-6 Alkyl;

[0016] n is 0 to 6;

[0017] R 3 Is H or C 1-6 Alkyl, wherein the C 1-6 Alkyl is unsubstituted or substituted with 1 - 5 halogens;

[0018] M is a bond or NH;

[0019] X and Y are each independently CH, C-R 7 Or N;

[0020] Z is CH or N,

[0021] R 5 Is H, halogen, C 1-6 Alkyl or O-C 1-6 Alkyl, wherein C1-6 The alkyl group is unsubstituted or substituted by 1 to 5 halogens;

[0022] R 6 is H or C 1-6 alkyl group, wherein the C 1-6 alkyl group is unsubstituted or substituted by 1 to 5 halogens;

[0023] R 7 is C 1-6 alkyl group, wherein the C 1-6 alkyl group is unsubstituted or substituted by 1 to 5 halogens; and

[0024] R 4 is C 1-6 alkyl group, C 3-10 cycloalkyl group, C 4-10 cycloalkenyl group, -C 1-6 alkyl-phenyl group, -C 1-6 alkyl-(5- to 6-membered heteroaryl) group, -C 1-6 alkyl-(4- to 6-membered heterocyclic) group, 4- to 10-membered heterocyclic group, phenyl group or 5- to 10-membered heteroaryl group, wherein the alkyl group, cycloalkyl group, cycloalkenyl group, phenyl group, heteroaryl group or heterocyclic group is unsubstituted or substituted by 1 to 3 substituents selected from the following: halogen, CN, -C(O)-NH2, -C(O)-NH-C 1-6 alkyl group, -C(O)-N-(C 1-6 alkyl)2, -O-C 1-6 alkyl-NH2, -O-C 1-6 alkyl-NH-(C 1-6 alkyl), -O-C 1-6 alkyl-N(C 1-6 alkyl)2, 4- to 6-membered heterocyclic group, -C(O)-(4- to 6-membered heterocyclic group), -O-phenyl group, -O-C 1-6 alkyl-(4- to 6-membered heterocyclic group), C 1-6 alkyl group, C 2-6 alkynyl group, hydroxyl group, C 1-6 alkoxy group or hydroxy C 1-6 alkyl group, and the heterocyclic group or heteroaryl group is unsubstituted or substituted by 1 to 3 substituents selected from the following: halogen, C 1-6 alkyl group, -C(O)-C 1-6 alkyl group or 4- to 6-membered heterocyclic group. In one embodiment, the therapeutically effective amount is about 80 mg to about 350 mg.

[0025] In certain embodiments, the therapeutically effective amount is about 120 mg to about 250 mg; is about 120 mg, about 180 mg or about 250 mg; or is about 250 mg.

[0026] In certain embodiments, the compound of formula (I) is administered to a subject in need thereof once a week on a regular schedule; or once a week on an irregular schedule.

[0027] In certain embodiments, R 1 is C6-C 12 aryl or a 5- or 6-membered heteroaryl, which is unsubstituted or substituted with 1-3 substituents selected from the following: halogen, C 1-6 alkyl, CN, hydroxy C 1-6 alkyl or amino C 1-6 alkyl, wherein the C 1-6 alkyl is unsubstituted or substituted with 1-3 substituents selected from halogen.

[0028] In certain embodiments, R in the compound of formula (I) 1 is C6-C12 aryl, pyridyl, thienyl or thiazolyl, which is unsubstituted or substituted with 1-3 substituents selected from the following: halogen, C 1-6 alkyl, CN, hydroxy C 1-6 alkyl or amino C 1-6 alkyl, wherein the C 1-6 alkyl is unsubstituted or substituted with 1-3 substituents selected from halogen. In certain embodiments, R 1 is phenyl.

[0029] In certain embodiments, n is 0 or 1.

[0030] In certain embodiments, R 2 is C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, -C 1-6 alkyl-NH-C 1-6 alkyl, -C 1-6 alkyl-NH-C 0-6 alkyl-(4- to 6-membered heterocyclic group), -C(O)-NH2, -C(O)-NH-C 1-6 alkyl, -C(O)-N(C 1-6 alkyl)2, -C 1-6 alkyl-NH-C 1-6 alkyl-OH or -C 1-6 alkyl-NH-C 0-6 alkyl-(5- to 6-membered heteroaryl), wherein the C 1-6 alkyl, heterocyclic group or heteroaryl is unsubstituted or substituted with 1-3 substituents selected from the following: halogen, C 1-6 alkyl, NH2, hydroxy C 1-6 alkyl or amino C 1-6 alkyl, and R 8 is H.

[0031] In certain embodiments, R 2 is CH3, CH2OH, CH2NH2, -CH2NH(CH3), -CH2NHCH2CH2OH, -CH2NH-(tetrahydro-2H-pyran), or -CH2NH-CH2-(1H-pyrrole), and R 8 is H.

[0032] In certain embodiments, R 3 is H or CH3.

[0033] In certain embodiments, M is a bond.

[0034] In certain embodiments, X and Y are each independently CH, C-R 7 or N.

[0035] In certain embodiments, Z is N.

[0036] In certain embodiments, R 5 is H, halogen, or C 1-6 alkyl.

[0037] In certain embodiments, R 6 is H.

[0038] In certain embodiments, R4 is

[0039]

[0040] In one embodiment, the present disclosure provides a method of treating a condition characterized by dysregulation of the RAS / RAF / MEK / ERK pathway or treatable by inhibition of Erk 1 / 2, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (II) in regularly or irregularly scheduled doses:

[0041]

[0042] or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, wherein:

[0043] R 1 is phenyl or a 5- to 10-membered heteroaryl, which is unsubstituted or substituted with 1-3 substituents selected from: halogen, C 1-6 alkyl, CN, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, -C 1-6 alkyl-O-C 1-6 alkyl, -C 1-6 alkyl-NH-C 1-6 alkyl, -C1-6 alkyl-N-(C 1-6 alkyl)2, -C 1-6 alkyl-NH-C 1-6 alkyl-OH, -C 1-6 alkyl-NH-C 1-6 alkyl-C 3-10 cycloalkyl, -C 1-6 alkyl-NH-C 1-6 alkyl-NH-C 1-6 alkyl, -C 1-6 alkyl-NH-C(O)-C 1-6 alkyl, -C 1-6 alkyl-O-C(O)-C 1-6 alkyl, -C 1-6 alkyl-NH-C 0-6 alkyl-(4- to 6-membered heterocyclic group) or -C 1-6 alkyl-NH-C 0-6 alkyl-(5- to 6-membered heteroaryl), wherein the C 1-6 alkyl, cycloalkyl, heterocyclic group and / or heteroaryl is unsubstituted or substituted with 1-3 substituents selected from: halogen, C 1-6 alkyl, NH2, hydroxy C 1-6 alkyl or amino C 1-6 alkyl;

[0044] n is 0 to 6;

[0045] R 2 is C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, -C 1-6 alkyl-O-C 1-6 alkyl, -C 1-6 alkyl-NH-C 1-6 alkyl, -C 1-6 alkyl-N-(C 1-6 alkyl)2, -C 1-6 alkyl-NH-C 1-6 alkyl-OH, -C 1-6 alkyl-NH-C 1-6 alkyl-C 3-10 cycloalkyl, -C 1-6 alkyl-NH-C 1-6 alkyl-NH-C 1-6 alkyl, -C 1-6 alkyl-NH-C(O)-C 1-6 alkyl, -C 1-6 alkyl-O-C(O)-C 1-6 alkyl, -C 1-6 alkyl-NH-C0-6 alkyl-(4- to 6-membered heterocyclic group), -C(O)-NH2, -C(O)-NH-C 1-6 alkyl, -C(O)-N(C 1-6 alkyl)2 or -C 1-6 alkyl-NH-C 0-6 alkyl-(5- to 6-membered heteroaryl), wherein the C 1-6 alkyl, cycloalkyl, heterocyclic group or heteroaryl is unsubstituted or substituted with 1-3 substituents selected from the following: halogen, C 1-6 alkyl, NH2, hydroxyC 1-6 alkyl or aminoC 1-6 alkyl; and R 8 is H or C 1-6 alkyl;

[0046] Alternatively, R 2 , R 8 and the C atom attaching R 2 to R 8 both are joined together to form a 3- to 10-membered cycloalkyl or 4- to 10-membered heterocyclic ring, wherein the cycloalkyl or heterocyclic ring is unsubstituted or substituted with 1-3 substituents selected from the following: hydroxy, halogen or C 1-6 alkyl; R 3 is H or C 1-6 alkyl, wherein the C 1-6 alkyl is unsubstituted or substituted with 1-5 halogens;

[0047] M is a bond or NH;

[0048] X and Y are each independently CH, C-R 7 or N;

[0049] Z is CH or N,

[0050] R 5 is H, halogen, C 1-6 alkyl or O-C 1-6 alkyl, wherein C 1-6 alkyl is unsubstituted or substituted with 1-5 halogens;

[0051] R 6 is H or C 1-6 alkyl, wherein the C 1-6 alkyl is unsubstituted or substituted with 1-5 halogens;

[0052] R 7 is C 1-6 alkyl, wherein the C 1-6 alkyl is unsubstituted or substituted with 1-5 halogens; and

[0053] R 4is C 1-6 alkyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, -C 1-6 alkyl-phenyl, -C 1-6 alkyl-(5- to 6-membered heteroaryl), -C 1-6 alkyl-(4- to 6-membered heterocyclic group), 4- to 10-membered heterocyclic group, phenyl or 5- to 10-membered heteroaryl, wherein the alkyl, cycloalkyl, cycloalkenyl, phenyl, heteroaryl or heterocyclic group is unsubstituted or substituted with 1-3 substituents selected from: halogen, CN, -C(O)-NH2, -C(O)-NH-C 1-6 alkyl, -C(O)-N-(C 1-6 alkyl)2, -O-C 1-6 alkyl-NH2, -O-C 1-6 alkyl-NH-(C 1-6 alkyl), -O-C 1-6 alkyl-N(C 1-6 alkyl)2, 4- to 6-membered heterocyclic group, -C(O)-(4- to 6-membered heterocyclic group), -O-phenyl, -O-C 1-6 alkyl-(4- to 6-membered heterocyclic group), C 1-6 alkyl, C 2-6 alkynyl, hydroxyl, C 1-6 alkoxy or hydroxy C 1-6 alkyl, and the heterocyclic group or heteroaryl is unsubstituted or substituted with 1-3 substituents selected from: halogen, C 1-6 alkyl, -C(O)-C 1-6 alkyl or 4- to 6-membered heterocyclic group.

[0054] In one embodiment, the present disclosure provides a method for treating a condition characterized by dysregulation of the RAS / RAF / MEK / ERK pathway or treatable by inhibiting Erk 1 / 2, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (III) at regularly or irregularly scheduled doses:

[0055]

[0056] or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof,

[0057] wherein:

[0058] R 1 is phenyl or 5- to 10-membered heteroaryl, wherein the phenyl or heteroaryl is unsubstituted or substituted with 1-3 substituents selected from: halogen, C 1-6 alkyl, CN, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, -C1-6 Alkyl-O-C 1-6 Alkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl, -C 1-6 Alkyl-N-(C 1-6 Alkyl)2, -C 1-6 Alkyl-NH-C 1-6 Alkyl-OH, -C 1-6 Alkyl-NH-C 1-6 Alkyl-C 3-10 Cycloalkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl-NH-C 1-6 Alkyl

[0059] , -C 1-6 Alkyl-NH-C(O)-C 1-6 Alkyl, -C 1-6 Alkyl-O-C(O)-C 1-6 Alkyl, -C 1-6 Alkyl-NH-C 0-6 Alkyl-(4- to 6-membered heterocyclic group), -C 1-6 Alkyl-NH-C 0-6 Alkyl-(5- to 6-membered heteroaryl), -C(O)-NH2, -C(O)-NH-C 1-6 Alkyl or -C(O)-N(C 1-6 Alkyl)2

[0060] , wherein the C 1-6 Alkyl, cycloalkyl, heterocyclic group and / or heteroaryl is unsubstituted or substituted by 1-3 substituents selected from: halogen, C 1-6 Alkyl, hydroxy C 1-6 Alkyl or amino C 1-6 Alkyl;

[0061] n is 0 to 6;

[0062] R 3 is H or C 1-6 Alkyl, wherein the C 1-6 Alkyl is unsubstituted or substituted by 1-5 halogens;

[0063] M is a bond or NH;

[0064] X and Y are each independently CH, C-R 7 or N;

[0065] Z is CH or N,

[0066] R 5 is H, halogen, C 1-6 Alkyl or O-C 1-6An alkyl group, wherein C 1-6 the alkyl group is unsubstituted or

[0067] substituted by 1 to 5 halogens;

[0068] R 6 is H or C 1-6 an alkyl group, wherein C 1-6 the alkyl group is unsubstituted or substituted by 1 to 5 halogens;

[0069] R 7 is C 1-6 an alkyl group, wherein C 1-6 the alkyl group is unsubstituted or substituted by 1 to 5 halogens; and

[0070] R 4 is C 1-6 an alkyl group, C 3-10 a cycloalkyl group, C 4-10 a cycloalkenyl group, -C 1-6 an alkyl-phenyl group, -C 1-6 an alkyl-(5- to 6-membered heteroaryl) group, -C 1-6 an alkyl-(4- to 6-membered heterocyclic) group, a 4- to 10-membered heterocyclic group, a phenyl group or a 5- to 10-membered heteroaryl group, wherein the alkyl, cycloalkyl, cycloalkenyl, phenyl, heteroaryl or heterocyclic group is unsubstituted or substituted by 1 to 3 substituents selected from:

[0071] halogen, CN, -C(O)-NH2, -C(O)-NH-C 1-6 an alkyl group, -C(O)-N-(C 1-6 alkyl)2,

[0072] -O-C 1-6 alkyl-NH2, -O-C 1-6 alkyl-NH-(C 1-6 alkyl), -O-C 1-6 alkyl-N-(C 1-6 alkyl)2, a 4- to 6-membered heterocyclic group, -C(O)-(a 4- to 6-membered heterocyclic group), -O-phenyl, -O-C 1-6 alkyl-(a 4- to 6-membered heterocyclic group), C 1-6 alkyl, C 2-6 alkynyl, hydroxy, C 1-6 alkoxy or hydroxy C 1-6 alkyl, and the heterocyclic or heteroaryl group is unsubstituted or substituted by 1 to 3 substituents selected from: halogen, C 1-6 alkyl, C-(O)-C 1-6 alkyl or a 4- to 6-membered heterocyclic group.

[0073] The present disclosure also discusses compounds selected from:

[0074] (S)-1-(2-(Benzo[d][1,3]dioxol-5-ylamino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;

[0075] 1-(2-(Benzofuran-5-ylamino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;

[0076] 1-(2-(Benzofuran-5-ylamino)-5-methylpyrimidin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-3-carboxamide;

[0077] N-(3-chloro-2-(hydroxymethyl)benzyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0078] (S)-N-(1-(3-chloro-4-fluorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0079] 1-(2-((2,3-dihydrobenzofuran-5-yl)amino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;

[0080] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0081] N-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0082] N-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-(((S)-tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0083] N-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-(((R)-tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0084] 1-(2-(Chroman-6-ylamino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;

[0085] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-((4-fluoro-3-morpholinophenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0086] (S)-N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(2-((4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0087] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0088] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((4-morpholinophenyl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0089] (S)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0090] (R)-N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0091] (S)-N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0092] (S)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0093] N-(2-hydroxy-1-(thiophen-2-yl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0094] (S)-N-(2-Amino-1-(3-chlorophenyl)ethyl)-1-(2-((3,3-difluorocyclobutyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0095] (S)-N-(2-Amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0096] (S)-N-(2-(((1H-Pyrrol-2-yl)methyl)amino)-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0097] (S)-N-(3-Chloro-2-(hydroxymethyl)benzyl)-1-(5-methyl-2-(tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0098] (S)-N-(1-(3-Chlorophenyl)-2-(methylamino)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0099] (S)-N-(1-(3-Chlorophenyl)-2-((2-hydroxyethyl)amino)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide; and

[0100] N-(3-Chloro-5-fluoro-2-(hydroxymethyl)benzyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide,

[0101] or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof. The present disclosure also describes pharmaceutically acceptable salts of the compound according to claim 1, selected from:

[0102] (S)-N-(2-Amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide benzenesulfonate;

[0103] (S)-N-(2-Amino-1-(3-chlorophenyl)ethyl)-1-(2-((3,3-difluorocyclobutyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide benzenesulfonate;

[0104] (S)-N-(2-Amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide mandelate; and

[0105] (S)-N-(2-Amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide benzenesulfonate.

[0106] The present disclosure also relates to compositions and kits comprising a compound of formula (I-III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof, or a composition comprising a compound of formula (I-III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof; and methods of use and dosing regimens for treating conditions characterized by dysregulation of the RAS / RAF / MEK / ERK pathway or treatable by inhibition of ERK 1 / 2. In certain embodiments, the methods of use and dosing regimens include administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I-III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof in regularly or irregularly scheduled doses.

[0107] In certain embodiments, the present disclosure provides a method of treatment or dosing regimen that includes administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I-III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof in regularly or irregularly scheduled doses, wherein the therapeutically effective amount is from about 80 mg to about 350 mg; from about 120 mg to about 250 mg; or about 120 mg, about 180 mg or about 250 mg. In some embodiments, the therapeutically effective amount of a compound of formula (I), formula (II) or formula (III) constitutes a formulation comprising at least one compound of formula (I), formula (II) or formula (III).

[0108] In certain embodiments, the method of treatment or dosing regimen includes administering a compound of formula (I), formula (II) or formula (III) or a formulation comprising a compound of formula (I), formula (II) or formula (III) to a subject in need thereof once about weekly on a regular or irregular schedule.

[0109] In certain embodiments, the present disclosure provides formulations comprising compounds of formula (I-III), such as where the compound is (S)-N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide mandelate or (S)-N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide benzenesulfonate. In certain embodiments, the present disclosure provides a kit comprising one or more dosage forms of a compound or formulation of the present disclosure for treating a condition characterized by dysregulation of the RAS / RAF / MEK / ERK pathway or treatable by inhibiting Erk 1 / 2, and optionally instructions for administering the dosage form to a subject, where the instructions include the treatment methods or dosing regimens mentioned above. BRIEF DESCRIPTION OF THE DRAWINGS

[0110] Figure 1A , Figure 1B , Figure 1C and Figure 1D are a set of graphs showing the change in tumor volume over time in athymic nude mice bearing xenografts treated with the compositions of the present disclosure according to the following dosing regimens: upper left graph, once daily (QD); upper right graph, twice daily (BID); lower left graph, every three days (Q3D); and lower right graph, once a week (QW).

[0111] Figure 2 is the study design of the clinical trial described in Example 39 below.

[0112] Figure 3 is a swimmer plot showing clinical disease control and objective response in subjects receiving a once-daily dose of the test article at the indicated amounts. "SD" is stable disease.

[0113] Figure 4 is a swimmer plot showing clinical disease control and objective response in subjects receiving a once-weekly dose of the test article at the indicated amounts. "SD" is stable disease.

[0114] Figure 5A , Figure 5B and Figure 5C show replicas of scans of two subjects dosed with the test article as indicated, which show tumor regression.

[0115] Figure 6A and Figure 6BShow the plasma concentration changes over time of the test article administered daily at 10 mg / kg, 20 mg / kg, 40 mg / kg, 60 mg / kg, and 80 mg / kg, measured on Day 1 and Day 15.

[0116] Figure 6C and Figure 6D Show the Cmax and AUC of the test article at 10 mg / kg, 20 mg / kg, 40 mg / kg, 60 mg / kg, and 80 mg / kg, administered on Day 1 and Day 15.

[0117] Figure 7A and Figure 7B Show the plasma concentration changes over time of the test article measured on Day 1 and Day 15, administered weekly at 80 mg / kg, 120 mg / kg, 180 mg / kg, 250 mg / kg, and 350 mg / kg.

[0118] Figure 7C and Figure 7D Show the Cmax and AUC of the test article at 80 mg / kg, 120 mg / kg, and 180 mg / kg, administered on Day 1 and Day 15. Detailed Description

[0119] The present disclosure provides a compound of formula (I):

[0120]

[0121] or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, wherein:

[0122] R 1 is phenyl or a 5- to 10-membered heteroaryl, which is unsubstituted or substituted with 1-3 substituents selected from: halogen, C 1-6 alkyl, CN, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, -C 1-6 alkyl - O - C 1-6 alkyl, -C 1-6 alkyl - NH - C 1-6 alkyl, -C 1-6 alkyl - N - (C 1-6 alkyl)2, -C 1-6 alkyl - NH - C 1-6 alkyl - OH, -C 1-6 alkyl - NH - C 1-6 alkyl - C 3-10 cycloalkyl, -C 1-6 alkyl - NH - C 1-6 alkyl - NH - C 1-6 alkyl, -C1-6 alkyl-NH-C(O)-C 1-6 alkyl, -C 1-6 alkyl-O-C(O)-C 1-6 alkyl, -C 1-6 alkyl-NH-C 0-6 alkyl-(4- to 6-membered heterocyclic group) or -C 1-6 alkyl-NH-C 0-6 alkyl-(5- to 6-membered heteroaryl), wherein the C 1-6 alkyl, cycloalkyl, heterocyclic group and / or heteroaryl are unsubstituted or substituted with 1-3 substituents selected from: halogen, C 1-6 alkyl, NH2, hydroxy C 1-6 alkyl or amino C 1-6 alkyl;

[0123] J is a linker group selected from -C(R 2 )(R 8 )(CH2) n -;

[0124] R 2 and R 8 are each independently H, C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, -C 1-6 alkyl-O-C 1-6 alkyl, -C 1-6 alkyl-NH-C 1-6 alkyl, -C 1-6 alkyl-N-(C 1-6 alkyl)2, -C 1-6 alkyl-NH-C 1-6 alkyl-OH, -C 1-6 alkyl-NH-C 1-6 alkyl-C 3-10 cycloalkyl, -C 1-6 alkyl-NH-C 1-6 alkyl-NH-C 1-6 alkyl, -C 1-6 alkyl-NH-C(O)-C 1-6 alkyl, -C 1-6 alkyl-O-C(O)-C 1-6 alkyl, -C 1-6 alkyl-NH-C 0-6 alkyl-(4- to 6-membered heterocyclic group), -C(O)-NH2, -C(O)-NH-C 1-6 alkyl, -C(O)-N-(C 1-6 alkyl)2 or -C 1-6 alkyl-NH-C 0-6Alkyl-(5- to 6-membered heteroaryl), wherein said C 1-6 alkyl, cycloalkyl, heterocyclic group or heteroaryl is unsubstituted or substituted with 1 - 3 substituents selected from the following: halogen, C 1-6 alkyl, NH2, hydroxy C 1-6 alkyl or amino C 1-6 alkyl;

[0125] or R 2 、R 8 and the C atom attaching R 2 to R 8 both are linked together to form a 3 - to 10-membered cycloalkyl or 4 - to 10-membered heterocyclic ring, wherein said cycloalkyl or heterocyclic ring is unsubstituted or substituted with 1 - 3 substituents selected from the following: hydroxy, halogen or C 1-6 alkyl;

[0126] n is 0 to 6;

[0127] R 3 is H or C 1-6 alkyl, wherein said C 1-6 alkyl is unsubstituted or substituted with 1 - 5 halogens;

[0128] M is a bond or NH;

[0129] X and Y are each independently CH, C - R 7 or N;

[0130] Z is CH or N,

[0131] R 5 is H, halogen, C 1-6 alkyl or OC 1-6 alkyl, wherein C 1-6 alkyl is unsubstituted or substituted with 1 - 5 halogens;

[0132] R 6 is H or C 1-6 alkyl, wherein said C 1-6 alkyl is unsubstituted or substituted with 1 - 5 halogens;

[0133] R 7 is C 1-6 alkyl, wherein said C 1-6 alkyl is unsubstituted or substituted with 1 - 5 halogens; and

[0134] R 4 is C 1-6 alkyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, -C 1-6 alkyl - phenyl, -C 1-6Alkyl-(5- to 6-membered heteroaryl), C 1-6 Alkyl-(4- to 6-membered heterocyclic group), 4- to 10-membered heterocyclic group, phenyl or 5- to 10-membered heteroaryl, wherein the alkyl, cycloalkyl, cycloalkenyl, phenyl, heteroaryl or heterocyclic group is unsubstituted or substituted with 1-3 substituents selected from the following: halogen, CN, -C(O)-NH2, -C(O)-NH-C 1-6 Alkyl, -C(O)-N-(C 1-6 Alkyl)2, -O-C 1-6 Alkyl-NH2, -O-C 1-6 Alkyl-NH-(C 1-6 Alkyl), -O-C 1-6 Alkyl-N(C 1-6 Alkyl)2, 4- to 6-membered heterocyclic group, -C(O)-(4- to 6-membered heterocyclic group), -O-phenyl, -O-C 1-6 Alkyl-(4- to 6-membered heterocyclic group), C 1-6 Alkyl, C 2-6 Alkynyl, hydroxyl, C 1-6 Alkoxy or hydroxy C 1-6 Alkyl, and the heterocyclic group or heteroaryl is unsubstituted or substituted with 1-3 substituents selected from the following: halogen, C 1-6 Alkyl, -C(O)-C 1-6 Alkyl or 4- to 6-membered heterocyclic group.

[0135] The present disclosure also provides a compound of formula (II):

[0136]

[0137] Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof, wherein:

[0138] R 1 Is phenyl or 5- to 10-membered heteroaryl, which is unsubstituted or substituted with 1-3 substituents selected from the following: halogen, C 1-6 Alkyl, CN, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, -C 1-6 Alkyl-O-C 1-6 Alkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl, -C 1-6 Alkyl-N-(C 1-6 Alkyl)2, -C 1-6 Alkyl-NH-C 1-6 Alkyl-OH, -C 1-6 Alkyl-NH-C 1-6 Alkyl-C 3-10 Cycloalkyl, -C 1-6alkyl-NH-C 1-6 alkyl-NH-C 1-6 alkyl, -C 1-6 alkyl-NH-C(O)-C 1-6 alkyl, -C 1-6 alkyl-O-C(O)-C 1-6 alkyl, -C 1-6 alkyl-NH-C 0-6 alkyl-(4- to 6-membered heterocyclic group) or -C 1-6 alkyl-NH-C 0-6 alkyl-(5- to 6-membered heteroaryl), wherein the C 1-6 alkyl, cycloalkyl, heterocyclic group and / or heteroaryl is unsubstituted or substituted by 1-3 substituents selected from the following: halogen, C 1-6 alkyl, NH2, hydroxy C 1-6 alkyl or amino C 1-6 alkyl;

[0139] n is 0 to 6;

[0140] R 2 is C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, -C 1-6 alkyl-O-C 1-6 alkyl, -C 1-6 alkyl-NH-C 1-6 alkyl, -C 1-6 alkyl-N-(C 1-6 alkyl)2, -C 1-6 alkyl-NH-C 1-6 alkyl-OH, -C 1-6 alkyl-NH-C 1-6 alkyl-C 3-10 cycloalkyl, -C 1-6 alkyl-NH-C 1-6 alkyl-NH-C 1-6 alkyl, -C 1-6 alkyl-NH-C(O)-C 1-6 alkyl, -C 1-6 alkyl-O-C(O)-C 1-6 alkyl, -C 1-6 alkyl-NH-C 0-6 alkyl-(4- to 6-membered heterocyclic group), -C(O)-NH2, -C(O)-NH-C 1-6 alkyl, -C(O)-N(C 1-6 alkyl)2 or -C 1-6 alkyl-NH-C 0-6 alkyl-(5- to 6-membered heteroaryl), wherein the C 1-6The alkyl, cycloalkyl, heterocyclic group or heteroaryl group is unsubstituted or substituted by 1 to 3 substituents selected from the following: halogen, C 1-6 alkyl, NH2, hydroxy C 1-6 alkyl or amino C 1-6 alkyl; and

[0141] R 8 is H or C 1-6 alkyl;

[0142] Alternatively, R 2 , R 8 and the C atom attaching R 2 to R 8 both are joined together to form a 3- to 10-membered cycloalkyl or 4- to 10-membered heterocyclic group ring, wherein the cycloalkyl or heterocyclic group is unsubstituted or substituted by 1 to 3 substituents selected from the following: hydroxy, halogen or C 1-6 alkyl;

[0143] R 3 is H or C 1-6 alkyl, wherein the C 1-6 alkyl is unsubstituted or substituted by 1 to 5 halogens;

[0144] M is a bond or NH;

[0145] X and Y are each independently CH, C-R 7 or N;

[0146] Z is CH or N,

[0147] R 5 is H, halogen, C 1-6 alkyl or O-C 1-6 alkyl, wherein the C 1-6 alkyl is unsubstituted or substituted by 1 to 5 halogens;

[0148] R 6 is H or C 1-6 alkyl, wherein the C 1-6 alkyl is unsubstituted or substituted by 1 to 5 halogens;

[0149] R 7 is C 1-6 alkyl, wherein the C 1-6 alkyl is unsubstituted or substituted by 1 to 5 halogens; and

[0150] R 4 is C 1-6 alkyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, -C 1-6 alkyl-phenyl, -C 1-6alkyl-(5- to 6-membered heteroaryl), -C 1-6 alkyl-(4- to 6-membered heterocyclic group), 4- to 10-membered heterocyclic group, phenyl or 5- to 10-membered heteroaryl, wherein the alkyl, cycloalkyl, cycloalkenyl, phenyl, heteroaryl or heterocyclic group is unsubstituted or substituted with 1-3 substituents selected from the following: halogen, CN, -C(O)-NH2, -C(O)-NH-C 1-6 alkyl, -C(O)-N-(C 1-6 alkyl)2, -O-C 1-6 alkyl-NH2, -O-C 1-6 alkyl-NH-(C 1-6 alkyl), -O-C 1-6 alkyl-N(C 1-6 alkyl)2, 4- to 6-membered heterocyclic group, -C(O)-(4- to 6-membered heterocyclic group), -O-phenyl, -O-C 1-6 alkyl-(4- to 6-membered heterocyclic group), C 1-6 alkyl, C 2-6 alkynyl, hydroxy, C 1-6 alkoxy or hydroxyC 1-6 alkyl, and the heterocyclic group or heteroaryl is unsubstituted or substituted with 1-3 substituents selected from the following: halogen, C 1-6 alkyl, -C(O)-C 1-6 alkyl or 4- to 6-membered heterocyclic group.

[0151] In one embodiment, a compound of formula (II) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein:

[0152] R 1 is phenyl, pyridyl, thienyl or thiazolyl, which is unsubstituted or substituted with 1-3 substituents selected from the following: halogen, C 1-6 alkyl, CN, hydroxyC 1-6 alkyl or aminoC 1-6 alkyl, wherein the C 1-6 alkyl is unsubstituted or substituted with 1-3 substituents selected from halogen;

[0153] n is 0 to 1;

[0154] R 2 is C 1-6 alkyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, -C 1-6 alkyl-O-C 1-6 alkyl, -C 1-6 alkyl-NH-C 1-6 alkyl, -C 1-6 alkyl-N-(C 1-6 alkyl)2, -C1-6 alkyl-NH-C 1-6 alkyl-OH, -C 1-6 alkyl-NH-C 1-6 alkyl-C 3-10 cycloalkyl, -C 1-6 alkyl-NH-C 1-6 alkyl-NH-C 1-6 alkyl, -C 1-6 alkyl-NH-C(O)-C 1-6 alkyl, -C 1-6 alkyl-O-C(O)-C 1-6 alkyl, -C 1-6 alkyl-NH-C 0-6 alkyl-(4- to 6-membered heterocyclic group), -C(O)-NH2, -C(O)-NH-C 1-6 alkyl, -C(O)-N(C 1-6 alkyl)2 or -C 1-6 alkyl-NH-C 0-6 alkyl-(5- to 6-membered heteroaryl), wherein the C 1-6 alkyl, cycloalkyl, heterocyclic group or heteroaryl is unsubstituted or substituted with 1-3 substituents selected from: halogen, C 1-6 alkyl, NH2, hydroxy C 1-6 alkyl or amino C 1-6 alkyl; and

[0155] R 8 is H or C 1-6 alkyl;

[0156] Or, R 2 , R 8 and the C atom attaching R 2 to R 8 both are linked together to form a 3- to 6-membered cycloalkyl or 4- to 6-membered heterocyclic group ring, wherein the cycloalkyl or heterocyclic group is unsubstituted or substituted with 1-3 substituents selected from: hydroxy, halogen or C 1-6 alkyl;

[0157] R 3 is H or C 1-6 alkyl, wherein the C 1-6 alkyl is unsubstituted or substituted with 1-3 halogens;

[0158] M is a bond or NH;

[0159] X and Y are each independently CH, C-R 7 or N;

[0160] Z is CH or N,

[0161] R5 is H, halogen, C 1-6 alkyl or O-C 1-6 alkyl, where C 1-6 alkyl is unsubstituted or substituted with 1-3 halogens;

[0162] R 6 is H or C 1-6 alkyl, where the C 1-6 alkyl is unsubstituted or substituted with 1-3 halogens;

[0163] R 7 is C 1-6 alkyl, where the C 1-6 alkyl is unsubstituted or substituted with 1-3 halogens; and

[0164] R 4 is C 1-6 alkyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, -C 1-6 alkyl-phenyl, -C 1-6 alkyl-(5- to 6-membered heteroaryl), -C 1-6 alkyl-(4- to 6-membered heterocyclic group), 4- or 10-membered heterocyclic group, phenyl or 5- to 10-membered heteroaryl, where the alkyl, cycloalkyl, cycloalkenyl, phenyl, heteroaryl or heterocyclic group is unsubstituted or substituted with 1-3 substituents selected from: halogen, CN, -C(O)-NH2, -C(O)-NH-C 1-6 alkyl, -C(O)-N-(C 1-6 alkyl)2, -O-C 1-6 alkyl-NH2, -O-C 1-6 alkyl-NH-(C 1-6 alkyl), -O-C 1-6 alkyl-N(C 1-6 alkyl)2, 4- to 6-membered heterocyclic group, -C(O)-(4- to 6-membered heterocyclic group), -O-phenyl, -O-C 1-6 alkyl-(4- to 6-membered heterocyclic group), C 1-6 alkyl, C 2-6 alkynyl, hydroxy, C 1-6 alkoxy or hydroxy C 1-6 alkyl, and the heterocyclic group or heteroaryl is unsubstituted or substituted with 1-3 substituents selected from: halogen, C 1-6 alkyl, -C(O)-C 1-6 alkyl or 4- to 6-membered heterocyclic group.

[0165] In one embodiment, R 1 is unsubstituted or substituted C 6-12An aryl or an unsubstituted or substituted 5- to 10-membered heteroaryl. In one embodiment, R 1 is phenyl or a 5- to 6-membered heteroaryl containing 1-2 ring heteroatoms selected from O, N or S, wherein the phenyl or heteroaryl is unsubstituted or substituted by 1-3 substituents selected from the following: halogen, C 1-6 alkyl, CN, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, -C 1-6 alkyl-O-C 1-6 alkyl, -C 1-6 alkyl-NH-C 1-6 alkyl, -C 1-6 alkyl-N-(C 1-6 alkyl)2, -C 1-6 alkyl-NH-C 1-6 alkyl-OH, -C 1-6 alkyl-NH-C 1-6 alkyl-C 3-10 cycloalkyl, -C 1-6 alkyl-NH-C 1-6 alkyl-NH-C 1-6 alkyl, -C 1-6 alkyl-NH-C(O)-C 1-6 alkyl, -C 1-6 alkyl-O-C(O)-C 1-6 alkyl, -C 1-6 alkyl-NH-C 0-6 alkyl-(4- to 6-membered heterocyclic group) or -C 1-6 alkyl-NH-C 0-6 alkyl-(5- to 6-membered heteroaryl), wherein the C 1-6 alkyl, cycloalkyl, heterocyclic group and / or heteroaryl is unsubstituted or substituted by 1-3 substituents selected from the following: halogen, C 1-6 alkyl, NH2, hydroxy C 1-6 alkyl or amino C 1-6 alkyl. In one embodiment, R 1 is phenyl, pyridyl, thienyl or thiazolyl, which is unsubstituted or substituted by 1-3 substituents selected from the following: halogen, C 1-6 alkyl, CN, hydroxy C 1-6 alkyl or amino C 1-6 alkyl, wherein the C 1-6 alkyl is unsubstituted or substituted by 1-3 substituents selected from halogen. In one embodiment, R 1 is phenyl, pyridyl, thienyl or thiazolyl, which is unsubstituted or substituted by 1-3 substituents selected from the following: F, Cl, C 1-3 alkyl, CN, hydroxy C 1-3Alkyl or amino C 1-3 alkyl, wherein the C 1-3 alkyl is unsubstituted or substituted with 1 - 3 substituents selected from F. In one embodiment, R 1 is phenyl, pyridyl, thienyl or thiazolyl, which is unsubstituted or substituted with 1 - 3 substituents selected from the following: F, Cl, CH3, -C(CH3)3, CF3, -CH2OH, -CH2CH2OH, CH2NH2, CN or -C(CH3)2OH. In one embodiment, R 1 is phenyl, which is unsubstituted or substituted with 1 - 3 substituents selected from the following: F, Cl, CH3, -C(CH3)3, CF3, -CH2OH, -CH2CH2OH, CH2NH2, CN or -C(CH3)2OH.

[0166] In one embodiment, n is from 0 to 6. In one embodiment, n is from 0 to 2. In one embodiment, n is from 0 to 1. In one embodiment, n is 0.

[0167] In one embodiment, R 2 is C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, -C 1-6 alkyl - O - C 1-6 alkyl, -C 1-6 alkyl - NH - C 1-6 alkyl, -C 1-6 alkyl - N-(C 1-6 alkyl)2, -C 1-6 alkyl - NH - C 1-6 alkyl - OH, -C 1-6 alkyl - NH - C 1-6 alkyl - C 3-10 cycloalkyl, -C 1-6 alkyl - NH - C 1-6 alkyl - NH - C 1-6 alkyl, -C 1-6 alkyl - NH - C(O) - C 1-6 alkyl, -C 1-6 alkyl - O - C(O) - C 1-6 alkyl, -C 1-6 alkyl - NH - C 0-6 alkyl-(4 - to 6 - membered heterocyclic group), -C(O)-NH2, -C(O)-NH - C 1-6 alkyl, -C(O)-N(C 1-6 alkyl)2 or -C 1-6 alkyl - NH - C 0-6 alkyl-(5 - to 6 - membered heteroaryl), wherein the C1-6 An alkyl, cycloalkyl, heterocyclic or heteroaryl group is unsubstituted or substituted with 1 - 3 substituents selected from the following: halogen, C 1-6 alkyl, NH2, hydroxy C 1-6 alkyl or amino C 1-6 alkyl; and R 8 is H or C 1-6 alkyl. In one embodiment, R 2 is C 1-3 alkyl, hydroxy C 1-3 alkyl, amino C 1-3 alkyl, -C 1-3 alkyl - O - C 1-3 alkyl, -C 1-3 alkyl - NH - C 1-3 alkyl, -C 1-3 alkyl - N - (C 1-3 alkyl)2, -C 1-3 alkyl - NH - C 1-3 alkyl - OH, -C 1-3 alkyl - NH - C 1-3 alkyl - C 3-6 cycloalkyl, -C 1-3 alkyl - NH - C 1-3 alkyl - NH - C 1-3 alkyl, -C 1-3 alkyl - NH - C(O) - C 1-3 alkyl, -C 1-3 alkyl - O - C(O) - C 1-3 alkyl, -C 1-3 alkyl - NH - C 0-3 alkyl - (4 - to 6 - membered heterocyclic group), -C(O) - NH2, -C(O) - NH - C 1-3 alkyl, -C(O) - N(C 1-3 alkyl)2 or -C 1-3 alkyl - NH - C 0-3 alkyl - (5 - to 6 - membered heteroaryl), wherein the C 1-3 alkyl, cycloalkyl, heterocyclic or heteroaryl group is unsubstituted or substituted with 1 - 3 substituents selected from the following: halogen, C 1-3 alkyl, NH2, hydroxy C 1-3 alkyl or amino C 1-3 alkyl; and R 8 is H or C 1-3 alkyl. In one embodiment, R 2 is C 1-3 alkyl, hydroxy C 1-3 alkyl, amino C 1-3 alkyl, -C 1-3 alkyl - NH - C 1-3alkyl, -C 1-3 alkyl-NH-C 1-3 alkyl-OH, -C 1-3 alkyl-NH-C 0-3 alkyl-(4- to 6-membered heterocyclic group) or -C 1-3 alkyl-NH-C 0-3 alkyl-(5- to 6-membered heteroaryl); and R 8 is H. In one embodiment, R 2 is CH3, -CH2OH, -CH2NH2, -CH2OCH3, -CH2N(CH3)2, -CH2NH(CH3), -CH2NHCH2CH2OH, -CH2NHC(O)CH3, -CH2OC(O)CH(NH2)CH2CH(CH3)2, -C(O)NH2, -CH2NH-(tetrahydro-2H-pyran) or -CH2NHCH2-(pyrrole); and R 8 is H. In one embodiment, R 2 is CH3, -CH2OH, -CH2NH2, -CH2NH(CH3), -CH2NHCH2CH2OH, -CH2NH-(tetrahydro-2H-pyran) or -CH2NHCH2-(pyrrole); and R 8 is H. In one embodiment, R 2 is -CH2OH or -CH2NH2; and R 8 is H.

[0168] In another embodiment, R 2 , R 8 and the C atom attaching R 2 to R 8 both are connected together to form a 3- to 6-membered cycloalkyl or 4- to 6-membered heterocyclic ring, wherein the cycloalkyl or heterocyclic ring is unsubstituted or substituted with 1-3 substituents selected from: hydroxyl, halogen or C 1-6 alkyl. In one embodiment, R 2 , R 8 and the C atom attaching R 2 to R 8 both are connected together to form a 3- to 6-membered cycloalkyl, which is unsubstituted or substituted with 1-3 substituents selected from hydroxyl. In one embodiment, R 2 , R 8 and the C atom attaching R 2 to R 8 both are connected together to form a cyclobutyl, which is unsubstituted or substituted with hydroxyl.

[0169] In one embodiment, R 3 is H or C 1-6An alkyl group, wherein the C 1-6 alkyl group is unsubstituted or substituted with 1 - 5 halogens. In one embodiment, R 3 is H or C 1-3 alkyl group, wherein the C 1-6 alkyl group is unsubstituted or substituted with 1 - 3 halogens. In one embodiment, R 3 is H or CH3.

[0170] In one embodiment, M is a bond or NH. In one embodiment, M is a bond.

[0171] In one embodiment, X and Y are each independently CH, C - R 7 or N. In one embodiment, X is CH, C - CH3 or N. In one embodiment, X is CH. In one embodiment, Y is CH, C - CH3 or N. In one embodiment, Y is N.

[0172] In one embodiment, R 7 is C 1-6 alkyl group, wherein the C 1-6 alkyl group is unsubstituted or substituted with 1 - 5 halogens. In one embodiment, R 7 is C 1-6 alkyl group. In one embodiment, R 7 is CH3.

[0173] In one embodiment, Z is CH or N. In one embodiment, Z is N.

[0174] In one embodiment, R 5 is H, a halogen, C 1-6 alkyl group or O - C 1-6 alkyl group, wherein the C 1-6 alkyl group is unsubstituted or substituted with 1 - 5 halogens. In one embodiment, R 5 is H, Cl, F, C 1-3 alkyl group or - O - C 1-3 alkyl group, wherein the C 1-3 alkyl group is unsubstituted or substituted with 1 - 3 halogens. In one embodiment, R 5 is H, Cl, F, CH3 or –OCH3.

[0175] In one embodiment, R 6 is H or C 1-6 alkyl group, wherein the C 1-6 alkyl group is unsubstituted or substituted with 1 - 5 halogens. In one embodiment, R 6 is H or CH3. In one embodiment, R 6 is H.

[0176] In one embodiment, R 4 is C 1-6 alkyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, -C 1-6 alkyl-phenyl, -C 1-6 alkyl-(5- to 6-membered heteroaryl), -C 1-6 alkyl-(4- to 6-membered heterocyclic group), 4- to 10-membered heterocyclic group, phenyl or 5- to 10-membered heteroaryl, wherein the alkyl, cycloalkyl, cycloalkenyl, phenyl, heteroaryl or heterocyclic group is unsubstituted or substituted with 1-3 substituents selected from: halogen, CN, -C(O)-NH2, -C(O)-NH-C 1-6 alkyl, -C(O)-N-(C 1-6 alkyl)2, -O-C 1-6 alkyl-NH2, -O-C 1-6 alkyl-NH-(C 1-6 alkyl), -O-C 1-6 alkyl-N(C 1-6 alkyl)2, 4- to 6-membered heterocyclic group, -C(O)-(4- to 6-membered heterocyclic group), -O-phenyl, -O-C 1-6 alkyl-(4- to 6-membered heterocyclic group), C 1-6 alkyl, C 2-6 alkynyl, hydroxy, C 1-6 alkoxy or hydroxyC 1-6 alkyl, and the heterocyclic group or heteroaryl is unsubstituted or substituted with 1-3 substituents selected from: halogen, C 1-6 alkyl, -C(O)-C 1-6 alkyl or 4- to 6-membered heterocyclic group.

[0177] In one embodiment, R 4 is

[0178]

[0179]

[0180] wherein each L is independently selected from halogen, CN, C 2-6 alkynyl, C 1-6 alkoxy, -C(O)NHC 1-6 alkyl, -C(O)NH(C 1-6 alkyl)2, -O-C 1-6 alkyl-NHC 1-6 alkyl or -O-C 1-6 alkyl-N(C 1-6 alkyl)2, and x is 0, 1, 2 or 3.

[0181] In one embodiment, R 4 is C 1-6 alkyl, which is unsubstituted or substituted with 1 - 3 substituents selected from the following: hydroxy or C 1-6 alkoxy. In one embodiment, R 4 is

[0182] In one embodiment, R 4 is C 3-10 cycloalkyl or C 4-10 cycloalkenyl, which is unsubstituted or substituted with 1 - 3 substituents selected from the following: hydroxy, halogen or hydroxy C 1-6 alkyl. In one embodiment, R 4 is C 3-6 cycloalkyl or C 4-6 cycloalkenyl, which is unsubstituted or substituted with 1 - 3 substituents selected from the following: hydroxy, F, Cl or hydroxy C 1-3 alkyl. In one embodiment, R 4 is

[0183]

[0184] In one embodiment, R 4 is a 4 - to 10 - membered monocyclic or bicyclic heterocyclic group containing 1 - 2 ring heteroatoms or hetero groups selected from O, N, S, S(=O), S(=O)2 or C(=O), which is unsubstituted or substituted with 1 - 2 substituents selected from C 1-6 alkyl. In one embodiment, R 4 is a 4 - to 6 - membered monocyclic heterocyclic group containing 1 - 2 ring heteroatoms or hetero groups selected from O, N or S(=O)2, which is unsubstituted or substituted with 1 - 2 substituents selected from C 1-3 alkyl. In one embodiment, R 4 is

[0185]

[0186] In one embodiment, R 4 is phenyl, which is unsubstituted or substituted with 1 - 3 substituents selected from the following: halogen, CN, C 2-6 alkynyl, -C(O)-NH2, -C(O)-NH - C 1-6 alkyl, -C(O)-N-(C 1-6 alkyl)2, -O - C 1-6 alkyl - NH2, -O - C 1-6 alkyl - NH-(C 1-6 alkyl), -O - C 1-6 alkyl - N(C 1-6(alkyl)2, 4- to 6-membered heterocyclic group, -C(O)-(4- to 6-membered heterocyclic group), -O-phenyl, -O-C 1-6 alkyl-(4- to 6-membered heterocyclic group), C 1-6 alkyl, hydroxy, C 1-6 alkoxy or hydroxy C 1-6 alkyl, and the heterocyclic group or heteroaryl is unsubstituted or substituted with 1-3 substituents selected from: halogen, C 1-6 alkyl, -C(O)-C 1-6 alkyl or 4- to 6-membered heterocyclic group. In one embodiment, R 4 is

[0187]

[0188] where each L is independently selected from halogen, CN, C 2-6 alkynyl, C 1-6 alkoxy, C(O)NHC 1-6 alkyl or C(O)NH(C 1-6 alkyl)2, and n is 0, 1, 2, or 3. In one embodiment, each L is independently selected from F, Cl, CN, C 1-3 alkoxy, -C(O)N(CH3)2, and x is 0, 1, 2, or 3.

[0189] In one embodiment, R 4 is a 5- to 10-membered monocyclic or bicyclic heteroaryl containing 1-2 ring heteroatoms or hetero groups selected from N, O, C(=O), or S, which is unsubstituted or substituted with 1-3 substituents selected from: halogen, C 1-6 alkyl or C 4-6 cycloalkenyl. In one embodiment, R 4 is a 5- or 6-membered monocyclic heteroaryl containing 1-2 ring heteroatoms selected from N or O, which is unsubstituted or substituted with 1-3 substituents selected from: halogen or CH3. In one embodiment, R 4 is

[0190]

[0191] In one embodiment, R 4 is -C 1-6 alkyl-(5- to 6-membered heteroaryl), which is unsubstituted or substituted with 1-3 substituents selected from: halogen or C 1-6 alkyl. In one embodiment, R 4 is

[0192]

[0193] In one embodiment, R 4is - C 1-6 alkyl - phenyl, which is unsubstituted or substituted with 1 - 3 substituents selected from: halogen or C 1-6 alkyl. In one embodiment, R 4 is - CH2 - phenyl, which is unsubstituted or substituted with CH3. In one embodiment, R 4 is

[0194]

[0195] In one embodiment, R 4 is - C 1-6 alkyl - (4 - to 6 - membered heterocyclic group), which is unsubstituted or substituted with 1 - 3 substituents selected from: halogen or C 1-6 alkyl. In one embodiment, R 4 is

[0196]

[0197] In one embodiment, R 4 is

[0198]

[0199] In one embodiment, R 4 is

[0200]

[0201] In one embodiment, R 4 is

[0202]

[0203] In one embodiment, there is provided a compound of formula (II) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein:

[0204] R 1 is phenyl, pyridyl, thienyl or thiazolyl, which is unsubstituted or substituted with 1 - 3 substituents selected from: halogen, C 1-6 alkyl, CN, hydroxy C 1-6 alkyl or amino C 1-6 alkyl, wherein the C 1-6 alkyl is unsubstituted or substituted with 1 - 3 substituents selected from halogen;

[0205] n is 0;

[0206] R 2 is C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6Alkyl, -C 1-6 Alkyl-NH-C 0-6 Alkyl-(4- to 6-membered heterocyclic group), -C(O)-NH2, -C 1-6 Alkyl-NH-C 1-6 Alkyl-OH, -C 1-6 Alkyl-NH-C 1-6 Alkyl-C 3-10 Cycloalkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl-NH-C 1-6 Alkyl, -C(O)-NH-C 1-6 Alkyl, -C(O)-N(C 1-6 Alkyl)2 or -C 1-6 Alkyl-NH-C 0-6 Alkyl-(5- to 6-membered heteroaryl), wherein the C 1-6 Alkyl, cycloalkyl, heterocyclic group or heteroaryl is unsubstituted or substituted with 1-3 substituents selected from: halogen, C 1-6 Alkyl, NH2, hydroxy C 1-6 Alkyl or amino C 1-6 Alkyl; and

[0207] R 8 is H;

[0208] R 3 is H;

[0209] M is a bond;

[0210] X is CH;

[0211] Y is CH or N;

[0212] Z is N;

[0213] R 5 is H, halogen or C 1-6 Alkyl;

[0214] R 6 is H; and

[0215] R 4 is

[0216]

[0217] which may be unsubstituted or substituted with 1-3 substituents selected from: halogen or C 1-6 Alkoxy.

[0218] In one embodiment, there is provided a compound of formula (II) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein:

[0219] R 1 is phenyl or thienyl, which is unsubstituted or substituted by 1 - 3 substituents selected from the following: halogen, C 1-6 alkyl, CN, hydroxy C 1-6 alkyl or amino C 1-6 alkyl, wherein the C 1-6 alkyl is unsubstituted or substituted by 1 - 3 substituents selected from halogen;

[0220] n is 0;

[0221] R 2 is C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, -C 1-6 alkyl - NH - C 0-6 alkyl - (4 - to 6 - membered heterocyclic group), -C(O)-NH2, -C 1-6 alkyl - NH - C 1-6 alkyl - OH, -C 1-6 alkyl - NH - C 1-6 alkyl - C 3-10 cycloalkyl, -C 1-6 alkyl - NH - C 1-6 alkyl - NH - C 1-6 alkyl, -C(O)-NH - C 1-6 alkyl, -C(O)-N(C 1-6 alkyl)2 or -C 1-6 alkyl - NH - C 0-6 alkyl - (5 - to 6 - membered heteroaryl), wherein the C 1-6 alkyl, cycloalkyl, heterocyclic group or heteroaryl is unsubstituted or substituted by 1 - 3 substituents selected from the following: halogen, C 1-6 alkyl, NH2, hydroxy C 1-6 alkyl or amino C 1-6 alkyl; and

[0222] R 8 is H;

[0223] R 3 is H;

[0224] M is a bond;

[0225] X is CH;

[0226] Y is CH or N;

[0227] Z is N;

[0228] R 5 is H, halogen or C 1-6 alkyl;

[0229] R 6 is H; and

[0230] R 4 is

[0231]

[0232] which may be unsubstituted or substituted with 1 - 3 substituents selected from: halogen or C 1-6 alkoxy.

[0233] In one embodiment, there is provided a compound of formula (II) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein:

[0234] R 1 is phenyl, which is unsubstituted or substituted with 1 - 3 substituents selected from: F or Cl;

[0235] n is 0;

[0236] R 2 is CH2OH, CH2NH2, -CH2NH(CH3), -CH2NHCH2CH2OH, -C(O)NH2, -CH2NH-(tetrahydro-2H-pyran) or -CH2NH-CH2-(1H-pyrrole); and

[0237] R 8 is H;

[0238] R 3 is H;

[0239] M is a bond;

[0240] X is CH;

[0241] Y is N;

[0242] Z is N;

[0243] R 5 is CH3;

[0244] R 6 is H; and

[0245]

[0246] The present disclosure also provides a compound of formula (III):

[0247]

[0248] or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof, wherein:

[0249] R 1is phenyl or a 5- to 10-membered heteroaryl, wherein the phenyl or heteroaryl is unsubstituted or substituted with 1-3 substituents selected from the following: halogen, C 1-6 alkyl, CN, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, -C 1-6 alkyl - O - C 1-6 alkyl, -C 1-6 alkyl - NH - C 1-6 alkyl, -C 1-6 alkyl - N-(C 1-6 alkyl)2, -C 1-6 alkyl - NH - C 1-6 alkyl - OH, -C 1-6 alkyl - NH - C 1-6 alkyl - C 3-10 cycloalkyl, -C 1-6 alkyl - NH - C 1-6 alkyl - NH - C 1-6 alkyl, -C 1-6 alkyl - NH - C(O)-C 1-6 alkyl, -C 1-6 alkyl - O - C(O)-C 1-6 alkyl, -C 1-6 alkyl - NH - C 0-6 alkyl-(4- to 6-membered heterocyclic group), -C 1-6 alkyl - NH - C 0-6 alkyl-(5- to 6-membered heteroaryl), -C(O)-NH2, -C(O)-NH - C 1-6 alkyl or -C(O)-N(C 1-6 alkyl)2, wherein the C 1-6 alkyl, cycloalkyl, heterocyclic group and / or heteroaryl is unsubstituted or substituted with 1-3 substituents selected from the following: halogen, C 1-6 alkyl, hydroxy C 1-6 alkyl or amino C 1-6 alkyl;

[0250] n is 0 to 6;

[0251] R 3 is H or C 1-6 alkyl, wherein the C 1-6 alkyl is unsubstituted or substituted with 1-5 halogens;

[0252] M is a bond or NH;

[0253] X and Y are each independently CH, C - R 7 or N;

[0254] Z is CH or N,

[0255] R 5 is H, a halogen, C 1-6 alkyl or O-C 1-6 alkyl, wherein the C 1-6 alkyl is unsubstituted or substituted with 1 - 5 halogens;

[0256] R 6 is H or C 1-6 alkyl, wherein the C 1-6 alkyl is unsubstituted or substituted with 1 - 5 halogens;

[0257] R 7 is C 1-6 alkyl, wherein the C 1-6 alkyl is unsubstituted or substituted with 1 - 5 halogens; and

[0258] R 4 is C 1-6 alkyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, -C 1-6 alkyl - phenyl, -C 1-6 alkyl-(5 - to 6 - membered heteroaryl), -C 1-6 alkyl-(4 - to 6 - membered heterocyclic group), 4 - to 10 - membered heterocyclic group, phenyl or 5 - to 10 - membered heteroaryl, wherein the alkyl, cycloalkyl, cycloalkenyl, phenyl, heteroaryl or heterocyclic group is unsubstituted or substituted with 1 - 3 substituents selected from the following: halogen, CN, -C(O)-NH2, -C(O)-NH-C 1-6 alkyl, -C(O)-N-(C 1-6 alkyl)2, -O-C 1-6 alkyl - NH2, -O-C 1-6 alkyl - NH-(C 1-6 alkyl), -O-C 1-6 alkyl - N-(C 1-6 alkyl)2, 4 - to 6 - membered heterocyclic group, -C(O)-(4 - to 6 - membered heterocyclic group), -O - phenyl, -O-C 1-6 alkyl-(4 - to 6 - membered heterocyclic group), C 1-6 alkyl, C 2-6 alkynyl, hydroxy, C 1-6 alkoxy or hydroxy C 1-6 alkyl, and the heterocyclic group or heteroaryl is unsubstituted or substituted with 1 - 3 substituents selected from the following: halogen, C 1-6 alkyl, C-(O)-C 1-6 alkyl or 4 - to 6 - membered heterocyclic group.

[0259] In one embodiment, there is provided a compound of formula (III) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein:

[0260] R 1 is phenyl, pyridyl, thienyl or thiazolyl, which is unsubstituted or substituted by 1 - 3 substituents selected from the following: halogen, C 1-6 alkyl, CN, hydroxy C 1-6 alkyl or amino C 1-6 alkyl, wherein the C 1-6 alkyl is unsubstituted or substituted by 1 - 3 substituents selected from halogen;

[0261] n is from 1 to 2;

[0262] R 3 is H or C 1-6 alkyl, wherein the C 1-6 alkyl is unsubstituted or substituted by 1 - 3 halogens;

[0263] M is a bond or NH;

[0264] X and Y are each independently CH, C - R 7 or N;

[0265] Z is CH or N,

[0266] R 5 is H, halogen, C 1-6 alkyl or O - C 1-6 alkyl, wherein C 1-6 alkyl is unsubstituted or substituted by 1 - 3 halogens;

[0267] R 6 is H or C 1-6 alkyl, wherein the C 1-6 alkyl is unsubstituted or substituted by 1 - 3 halogens;

[0268] R 7 is C 1-6 alkyl, wherein the C 1-6 alkyl is unsubstituted or substituted by 1 - 3 halogens; and

[0269] R 4 is C 1-6 alkyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, - C 1-6 alkyl - phenyl, - C 1-6 alkyl - (5 - to 6 - membered heteroaryl), - C 1-6 alkyl - (4 - to 6 - membered heterocyclic group), 4 - to 10 - membered heterocyclic group, phenyl or 5 - to 10 - membered heteroaryl, wherein the alkyl, cycloalkyl, cycloalkenyl, phenyl, heteroaryl or heterocyclic group is unsubstituted or substituted by 1 - 3 substituents selected from the following: halogen, CN, - C(O) - NH2, - C(O) - NH - C1-6 alkyl, -C(O)-N-(C 1-6 alkyl)2, -O-C 1-6 alkyl-NH2, -O-C 1-6 alkyl-NH-(C 1-6 alkyl), -O-C 1-6 alkyl-N(C 1-6 alkyl)2, 4- to 6-membered heterocyclic group, -C(O)-(4- to 6-membered heterocyclic group), -O-phenyl, -O-C 1-6 alkyl-(4- to 6-membered heterocyclic group), C 1-6 alkyl, C 2-6 alkynyl, hydroxyl, C 1-6 alkoxy or hydroxy C 1-6 alkyl, and the heterocyclic group or heteroaryl is unsubstituted or substituted with 1-3 substituents selected from: halogen, C 1-6 alkyl, -C(O)-C 1-6 alkyl or 4- to 6-membered heterocyclic group.

[0270] In one embodiment, R 1 is unsubstituted or substituted C 6-12 aryl or unsubstituted or substituted 5- to 10-membered heteroaryl. In one embodiment, R 1 is phenyl or a 5- to 6-membered heteroaryl containing 1-2 ring heteroatoms selected from O, N or S, wherein the phenyl or heteroaryl is unsubstituted or substituted with 1-3 substituents selected from: halogen, C 1-6 alkyl, CN, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, -C 1-6 alkyl-O-C 1-6 alkyl, -C 1-6 alkyl-NH-C 1-6 alkyl, -C 1-6 alkyl-N-(C 1-6 alkyl)2, -C 1-6 alkyl-NH-C 1-6 alkyl-OH, -C 1-6 alkyl-NH-C 1-6 alkyl-C 3-10 cycloalkyl, -C 1-6 alkyl-NH-C 1-6 alkyl-NH-C 1-6 alkyl, -C 1-6 alkyl-NH-C(O)-C 1-6 alkyl, -C 1-6 alkyl-O-C(O)-C 1-6 alkyl, -C 1-6 alkyl-NH-C 0-6Alkyl-(4- to 6-membered heterocyclic group), -C 1-6 Alkyl-NH-C 0-6 Alkyl-(5- to 6-membered heteroaryl), C(O)-NH2, -C(O)-NH-C 1-6 Alkyl or -C(O)-N(C 1-6 Alkyl)2, wherein the C 1-6 Alkyl, cycloalkyl, heterocyclic group and / or heteroaryl is unsubstituted or substituted with 1 - 3 substituents selected from the following: halogen, C 1-6 Alkyl, NH2, hydroxy C 1-6 Alkyl or amino C 1-6 Alkyl. In one embodiment, R 1 is phenyl, pyridyl, thienyl or thiazolyl, which is unsubstituted or substituted with 1 - 3 substituents selected from the following: halogen, C 1-6 Alkyl, CN, hydroxy C 1-6 Alkyl or amino C 1-6 Alkyl, wherein the C 1-6 Alkyl is unsubstituted or substituted with 1 - 3 substituents selected from halogen. In one embodiment, R 1 is phenyl, pyridyl, thienyl or thiazolyl, which is unsubstituted or substituted with 1 - 3 substituents selected from the following: F, Cl, C 1-3 Alkyl, CN, hydroxy C 1-3 Alkyl or amino C 1-3 Alkyl, wherein the C 1-3 Alkyl is unsubstituted or substituted with 1 - 3 substituents selected from F. In one embodiment, R 1 is phenyl, pyridyl, thienyl or thiazolyl, which is unsubstituted or substituted with 1 - 3 substituents selected from the following: F, Cl, CH3, -C(CH3)3, CF3, -CH2OH, -CH2CH2OH, CH2NH2, CN or -C(CH3)2OH. In one embodiment, R 1 is phenyl, which is unsubstituted or substituted with 1 - 3 substituents selected from the following: F, Cl, CH3, -C(CH3)3, CF3, -CH2OH, -CH2CH2OH, CH2NH2, CN or -C(CH3)2OH.

[0271] In one embodiment, n is from 0 to 6. In one embodiment, n is from 1 to 2. In one embodiment, n is 1.

[0272] In one embodiment, R 3 is H or C 1-6 Alkyl, wherein the C 1-6 Alkyl is unsubstituted or substituted with 1 - 5 halogens. In one embodiment, R 3 is H or C1-3 alkyl, wherein the C 1-6 alkyl is unsubstituted or substituted with 1-3 halogens. In one embodiment, R 3 is H or CH3.

[0273] In one embodiment, M is a bond or NH. In one embodiment, M is a bond.

[0274] In one embodiment, X and Y are each independently CH, C-R 7 or N. In one embodiment, X is CH, C-CH3 or N. In one embodiment, X is CH. In one embodiment, Y is CH, C-CH3 or N. In one embodiment, Y is N.

[0275] In one embodiment, R 7 is C 1-6 alkyl, wherein the C 1-6 alkyl is unsubstituted or substituted with 1-5 halogens. In one embodiment, R 7 is C 1-6 alkyl. In one embodiment, R 7 is CH3.

[0276] In one embodiment, Z is CH or N. In one embodiment, Z is N.

[0277] In one embodiment, R 5 is H, halogen, C 1-6 alkyl or O-C 1-6 alkyl, wherein the C 1-6 alkyl is unsubstituted or substituted with 1-5 halogens. In one embodiment, R 5 is H, Cl, F, C 1-3 alkyl or -O-C 1-3 alkyl, wherein the C 1-3 alkyl is unsubstituted or substituted with 1-3 halogens. In one embodiment, R 5 is H, Cl, F, CH3 or –OCH3.

[0278] In one embodiment, R 6 is H or C 1-6 alkyl, wherein the C 1-6 alkyl is unsubstituted or substituted with 1-5 halogens. In one embodiment, R 6 is H or CH3. In one embodiment, R 6 is H.

[0279] In one embodiment, R 4 is C 1-6 alkyl, C3-10 cycloalkyl, C 4-10 cycloalkenyl, -C 1-6 alkyl-phenyl, -C 1-6 alkyl-(5- to 6-membered heteroaryl), -C 1-6 alkyl-(4- to 6-membered heterocyclic group), 4- to 10-membered heterocyclic group, phenyl or 5- to 10-membered heteroaryl, wherein the alkyl, cycloalkyl, cycloalkenyl, phenyl, heteroaryl or heterocyclic group is unsubstituted or substituted with 1-3 substituents selected from: halogen, CN, -C(O)-NH2, -C(O)-NH-C 1-6 alkyl, -C(O)-N-(C 1-6 alkyl)2, -O-C 1-6 alkyl-NH2, -O-C 1-6 alkyl-NH-(C 1-6 alkyl), -O-C 1-6 alkyl-N(C 1-6 alkyl)2, 4- to 6-membered heterocyclic group, -C(O)-(4- to 6-membered heterocyclic group), -O-phenyl, -O-C 1-6 alkyl-(4- to 6-membered heterocyclic group), C 1-6 alkyl, C 2-6 alkynyl, hydroxy, C 1-6 alkoxy or hydroxyC 1-6 alkyl, and the heterocyclic group or heteroaryl is unsubstituted or substituted with 1-3 substituents selected from: halogen, C 1-6 alkyl, -C(O)-C 1-6 alkyl or 4- to 6-membered heterocyclic group.

[0280] In one embodiment, R 4 is

[0281]

[0282]

[0283]

[0284] where each L is independently selected from halogen, CN, C 2-6 alkynyl, C 1-6 alkoxy, -C(O)NHC 1-6 alkyl, -C(O)NH(C 1-6 alkyl)2, -O-C 1-6 alkyl-NHC 1-6 alkyl or -O-C 1-6 alkyl-N(C 1-6 alkyl)2, and x is 0, 1, 2 or 3.

[0285] In one embodiment, R4 is C 1-6 alkyl, which is unsubstituted or substituted by 1 - 3 substituents selected from the following: hydroxyl or C 1-6 alkoxy. In one embodiment, R 4 is

[0286] In one embodiment, R 4 is C 3-10 cycloalkyl or C 4-10 cycloalkenyl, which is unsubstituted or substituted by 1 - 3 substituents selected from the following: hydroxyl, halogen or hydroxy C 1-6 alkyl. In one embodiment, R 4 is C 3-6 cycloalkyl or C 4-6 cycloalkenyl, which is unsubstituted or substituted by 1 - 3 substituents selected from the following: hydroxyl, F, Cl or hydroxy C 1-3 alkyl. In one embodiment, R 4 is

[0287]

[0288] In one embodiment, R 4 is a 4 - to 10 - membered heterocyclic group containing 1 - 2 ring heteroatoms or hetero - groups selected from O, N, S, S(=O), S(=O)2 or C(=O), which is unsubstituted or substituted by 1 - 2 substituents selected from C 1-6 alkyl. In one embodiment, R 4 is a 4 - to 6 - membered monocyclic heterocyclic group containing 1 - 2 ring heteroatoms or hetero - groups selected from O, N or S(O)2, which is unsubstituted or substituted by 1 - 2 substituents selected from C 1-3 alkyl. In one embodiment, R 4 is

[0289]

[0290] In one embodiment, R 4 is phenyl, which is unsubstituted or substituted by 1 - 3 substituents selected from the following: halogen, C 2-6 alkynyl, CN, -C(O)-NH2, -C(O)-NH - C 1-6 alkyl, -C(O)-N-(C 1-6 alkyl)2, -O - C 1-6 alkyl - NH2, -O - C 1-6 alkyl - NH-(C 1-6 alkyl), -O - C 1-6 alkyl - N(C 1-6(alkyl)2, 4- to 6-membered heterocyclic group, -C(O)-(4- to 6-membered heterocyclic group), -O-phenyl, -O-C 1-6 alkyl-(4- to 6-membered heterocyclic group), C 1-6 alkyl, hydroxy, C 1-6 alkoxy or hydroxy C 1-6 alkyl, and the heterocyclic group or heteroaryl is unsubstituted or substituted with 1-3 substituents selected from: halogen, C 1-6 alkyl, -C(O)-C 1-6 alkyl or 4- to 6-membered heterocyclic group. In one embodiment, R 4 is

[0291]

[0292] where each L is independently selected from halogen, CN, C 2-6 alkynyl, C 1-6 alkoxy, C(O)NHC 1-6 alkyl or C(O)NH(C 1-6 alkyl)2, and n is 0, 1, 2 or 3. In one embodiment, each L is independently selected from F, Cl, CN, C 1-3 alkoxy, -C(O)N(CH3)2, and x is 0, 1, 2 or 3.

[0293] In one embodiment, R 4 is a 5- to 10-membered monocyclic or bicyclic heteroaryl containing 1-2 ring heteroatoms or hetero groups selected from O, N, S, S(=O), S(=O)2 or C(=O), which is unsubstituted or substituted with 1-3 substituents selected from: halogen, C 1-6 alkyl or C 4-6 cycloalkenyl. In one embodiment, R 4 is a 5- or 6-membered monocyclic heteroaryl containing 1-2 ring heteroatoms selected from N or O, which is unsubstituted or substituted with 1-3 substituents selected from: halogen or CH3.

[0294] In one embodiment, R 4 is

[0295]

[0296] In one embodiment, R 4 is -C 1-6 alkyl-(5- to 6-membered heteroaryl), which is unsubstituted or substituted with 1-3 substituents selected from: halogen or C 1-6 alkyl. In one embodiment, R 4 is

[0297]

[0298] In one embodiment, R 4 is -C 1-6 alkyl-phenyl, which is unsubstituted or substituted with 1 - 3 substituents selected from: halogen or C 1-6 alkyl. In one embodiment, R 4 is -CH2-phenyl, which is unsubstituted or substituted with CH3. In one embodiment, R 4 is

[0299]

[0300] In one embodiment, R 4 is -C 1-6 alkyl-(4 - to 6-membered heterocyclic group), which is unsubstituted or substituted with 1 - 3 substituents selected from: halogen or C 1-6 alkyl. In one embodiment, R 4 is

[0301]

[0302] In one embodiment, R 4 is

[0303]

[0304] In one embodiment, R 4 is

[0305]

[0306] In one embodiment, R 4 is

[0307]

[0308] In one embodiment, there is provided a compound of formula (III) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein:

[0309] R 1 is phenyl or thienyl, which is unsubstituted or substituted with 1 - 3 substituents selected from: halogen, C 1-6 alkyl, CN, hydroxy C 1-6 alkyl or amino C 1-6 alkyl, wherein the C 1-6 alkyl is unsubstituted or substituted with 1 - 3 substituents selected from halogen;

[0310] n is 1;

[0311] R 3 is H;

[0312] M is a bond;

[0313] X is CH;

[0314] Y is N;

[0315] Z is N,

[0316] R 5 is H, halogen or C 1-6 alkyl;

[0317] R 6 is H; and

[0318] R 4 is

[0319]

[0320] which may be unsubstituted or substituted with 1 - 3 substituents selected from: halogen or C 1-6 alkoxy.

[0321] In one embodiment, there is provided a compound of formula (III) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein:

[0322] R 1 is phenyl, which is unsubstituted or substituted with 1 - 3 substituents selected from: halogen, C 1-6 alkyl, CN, hydroxy C 1-6 alkyl or amino C 1-6 alkyl, wherein the C 1-6 alkyl is unsubstituted or substituted with 1 - 3 substituents selected from halogen;

[0323] n is 1;

[0324] R 3 is H;

[0325] M is a bond;

[0326] X is CH;

[0327] Y is N;

[0328] Z is N,

[0329] R 5 is CH3;

[0330] R 6 is H; and

[0331] R 4 is

[0332]

[0333] It may be unsubstituted or substituted by 1 - 3 substituents selected from the following: halogen or C 1-6 alkoxy.

[0334] In one embodiment, there is provided a compound of formula (III) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein:

[0335] R 1 is phenyl, which is unsubstituted or substituted by 1 - 3 substituents selected from the following: halogen, CH2OH or CH2NH2;

[0336] n is 1;

[0337] R 3 is H;

[0338] M is a bond;

[0339] X is CH;

[0340] Y is N;

[0341] Z is N,

[0342] R 5 is CH3;

[0343] R 6 is H; and

[0344] R 4 is

[0345]

[0346] It may be unsubstituted or substituted by 1 - 3 substituents selected from the following: halogen or C 1-6 alkoxy.

[0347] In one embodiment, a compound of formula (III) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein:

[0348] R 1 is phenyl, which is substituted by 1 - 3 substituents selected from F, Cl, CH2OH or CH2NH2, and at least one ortho - position is substituted;

[0349] n is 1;

[0350] R 3 is H;

[0351] M is a bond;

[0352] X is CH;

[0353] Y is N;

[0354] Z is N,

[0355] R 5 is CH3;

[0356] R 6 is H; and

[0357] R 4 is

[0358]

[0359] In one embodiment, there is provided a compound of formula (III) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein:

[0360] R 1 is phenyl, which is substituted with 1-3 substituents selected from F, Cl, CH2OH or CH2NH2, and at least one ortho position is substituted with CH2OH or CH2NH2;

[0361] n is 1;

[0362] R 3 is H;

[0363] M is a bond;

[0364] X is CH;

[0365] Y is N;

[0366] Z is N,

[0367] R 5 is CH3;

[0368] R 6 is H; and

[0369] R 4 is

[0370]

[0371] In one embodiment, the compounds of the present disclosure are compounds selected from the following:

[0372] (S)-1-(2-(Benzo[d][1,3]dioxol-5-ylamino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;

[0373] 1-(2-(Benzofuran-5-ylamino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;

[0374] 1-(2-(Benzofuran-5-ylamino)-5-methylpyrimidin-4-yl)-N-(1-(3-chlorophenyl

[0375] )-2-hydroxyethyl)-1H-pyrrole-3-carboxamide;

[0376] N-(3-chloro-2-(hydroxymethyl)benzyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0377] (S)-N-(1-(3-chloro-4-fluorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0378] 1-(2-((2,3-dihydrobenzofuran-5-yl)amino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;

[0379] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0380] N-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0381] N-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-(((S)-tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0382] N-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-(((R)-tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0383] 1-(2-(Chroman-6-ylamino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;

[0384] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-((4-fluoro-3-morpholinophenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0385] N-(2-Amino-1-(3-chlorophenyl)ethyl)-1-(2-((4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0386] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0387] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((4-morpholinophenyl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0388] (S)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0389] (R)-N-(2-Amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0390] (S)-N-(2-Amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0391] (S)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-fluoro-2-((tetrahydro-2H-pyran-4-

[0392] yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0393] N-(2-Hydroxy-1-(thiophen-2-yl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0394] (S)-N-(2-Amino-1-(3-chlorophenyl)ethyl)-1-(2-((3,3-difluorocyclobutyl)am

[0395] ino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0396] (S)-N-(2-Amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0397] (S)-N-(2-(((1H-Pyrrol-2-yl)methyl)amino)-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0398] (S)-N-(3-chloro-2-(hydroxymethyl)benzyl)-1-(5-methyl-2-(tetrahydrofuran-3-

[0399] yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0400] (S)-N-(1-(3-chlorophenyl)-2-(methylamino)ethyl)-1-(5-methyl-2-((tetrahydro

[0401] -2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0402] (S)-N-(1-(3-chlorophenyl)-2-((2-hydroxyethyl)amino)ethyl)-1-(5-methyl-2-((tetra

[0403] hydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide; and

[0404] N-(3-chloro-5-fluoro-2-(hydroxymethyl)benzyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide,

[0405] or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof.

[0406] In certain embodiments, the compound is (S)-N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide benzenesulfonate.

[0407] In certain embodiments, the compound is (S)-N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide mandelate.

[0408] Sometimes in the present text, the compound (S)-N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide mandelate is referred to as "(S)-N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide (S)-2-hydroxy-2-phenylacetate".

[0409] Sometimes in the present text, the compound (S)-N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide benzenesulfonic acid salt is referred to as "(S)-N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide besylate".

[0410] In one embodiment, the compound of formula (I) as defined in each of the previous embodiments is a substantially pure stereoisomer.

[0411] The compounds of formula (I-III) are limited to those that are chemically viable and stable. Thus, combinations of substituents or variables in the compounds described above are admissible only if such compounds result in stable or chemically viable compounds. A stable compound or a chemically viable compound is one in which the chemical structure does not substantially change when maintained at a temperature of 40 °C or lower for at least one week in the absence of moisture or other chemically reactive conditions.

[0412] Unless otherwise stated or inconsistent with the context, the compounds of formula (I-III) and each of their species, alone or in combination, are also provided as the corresponding salts, prodrugs, solvates, hydrates, racemic forms, enantiomers, diastereomers, metabolites, and mixtures thereof, where practicable.

[0413] Representative "pharmaceutically acceptable salts" include, but are not limited to, water-soluble salts and water-insoluble salts. In one embodiment, the salt is a salt of a base. The salt can be a salt of a base selected from, for example, alkali metal salts, such as sodium, lithium or potassium salts; and organic bases, such as ammonium, monomethylammonium, dimethylammonium and trimethylammonium, monoethylammonium, diethylammonium and triethylammonium, monopropylammonium, dipropylammonium and tripropylammonium, ethyldimethylammonium, benzyl dimethylammonium, cyclohexylammonium, benzylammonium, dibenzylammonium, piperidinium, morpholinium, pyrrolidinium, piperazinium, 1-methylpiperidinium, 4-ethylmorpholinium, 1-isopropylpyrrolidinium, 1,4-dimethylpiperazinium, 1-n-butylpiperidinium, 2-methylpiperidinium, 1-ethyl-2-methylpiperidinium, monoethanolammonium, diethanolammonium and triethanolammonium, ethyldiethanolammonium, n-butylmonoethanolammonium, tris(hydroxymethyl)methylammonium, phenylmonoethanolammonium base, and other bases. In another embodiment, the salt is a salt of an acid. The salt can be a salt of an acid selected from, for example, acetic acid, propionic acid, lactic acid, citric acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malonic acid, mandelic acid, malic acid, phthalic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, methanesulfonic acid, naphthalenesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, camphorsulfonic acid, and other acids. Optionally, the compositions of the present disclosure can contain both pharmaceutically acceptable salts and free base forms of the compounds of the present disclosure. In one embodiment, the pharmaceutically acceptable salts of the compounds of the present disclosure are benzenesulfonate and mandelate. In another embodiment, the pharmaceutically acceptable salts of the compounds of the present disclosure are (S)-N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide benzenesulfonate and (S)-N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide mandelate.

[0414] In one embodiment, the compounds of formula (I-III), compositions, uses, methods of treatment, dosing regimens, and kits comprising the compounds of (I-III) may include the besylate, mandelate, or free base form of the compounds. In one embodiment, the compounds of formula (I-III), compositions, uses, methods of treatment, dosing regimens, and kits comprising the compounds of (I-III) may include (S)-N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide besylate (Example 302), (S)-N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide mandelate (Example 349), or the free base form (Example 275).

[0415] Using various methods known to those skilled in the art, prodrugs of the compounds of formula (I-III), such as those of Example 302, 349, or 275, can be used to modulate pharmacokinetic properties. See, for example, Jarkko Rautio et al., Nature Reviews Drug Discovery, 7:255-270 (2008), which is hereby incorporated by reference. In cases where the drug contains an amine moiety, such as when R 2 is CH2NH2, various prodrug methods have been reviewed by A. L. Simplício, Molecules, 13:519-547 (2008), which is hereby incorporated by reference. More specifically, carbamic (alkoxycarbonyloxy)alkyl esters, carbamic (acyloxy)alkyl esters, and carbamic (oxodioxolanyl)alkyl esters have been reported by Zhong Li, Bioorg. Med. Chem. Lett., 7:2909-2912 (1997); J. Alexander, J. Med. Chem., 34:78-81 (1991); J. Alexander, J. Med. Chem., 31:318-322 (1988); and J. Alexander, J. Med. Chem., 39:480-486 (1996) as effective prodrug strategies for amines, all of which are hereby incorporated by reference into this text. In one embodiment, the prodrug is an amide of formula (I-III), such as those of Example 302, 349, or 275. In one embodiment, when R 2 is CH2NH2, the amide is C(O)(C 1-6 alkyl), where C 1-6The alkyl group may be optionally substituted. In another embodiment, the prodrug is an ester of formula (I-III), such as Example 302, 349 or 275. In one embodiment, when R 2 is CH2OH, its ester is C(O)(C 1-6 alkyl), wherein the C 1-6 alkyl group may be optionally substituted.

[0416] In another embodiment, the compounds of the present disclosure may be solvates. As used herein, a "solvate" does not significantly alter the physiological activity or toxicity of the compound and can thus serve as a pharmacological equivalent of the non-solvated compound of the present disclosure. The term "solvate" as used herein is a combination, physical association, and / or solvation of a compound of the present disclosure with solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, the solvate may be discrete, such as when one or more solvent molecules are incorporated into the lattice of a crystalline solid. Thus, "solvate" encompasses both solution-phase solvates and isolable solvates. A hydrate is a particular form of solvate that includes water in the form of water of crystallization in a defined ratio.

[0417] The compounds described herein may contain asymmetric centers and may thus exist in enantiomeric forms. When the compounds of the present disclosure have two or more asymmetric centers, they may exist in diastereomeric forms. When the bonds to a chiral center in the formulas of the present disclosure are depicted as straight lines, it is to be understood that both the (R) and (S) configurations are included, and thus both enantiomers and mixtures thereof are included. Unless specifically indicated as having a particular stereochemistry, the present disclosure includes all such possible stereoisomers. It is well known in the art how to prepare substantially pure stereoisomers, such as by resolution of a racemic form or by synthesis from optically active starting materials. In one embodiment, the compounds of formula (I-III), such as Example 302, 349 or 275, are substantially pure stereoisomers. "Substantially pure stereoisomer" means a stereoisomeric form that is at least 95% pure relative to other stereoisomers of the same structure otherwise.

[0418] The following definitions are used in connection with the compounds described herein. Generally, the number of carbon atoms present in a given group is designated as "C x-y”, where x and y are the lower and upper limits, respectively. As used in the definitions herein, the number of carbon atoms refers to the carbon backbone and carbon branches, but does not include carbon atoms of substituents such as alkoxy substitution, etc. Unless otherwise indicated, the naming of substituents not explicitly defined herein is determined by naming the terminal portion of the functional group and the adjacent functional group towards the point of attachment in sequence from left to right. As used herein, “optionally substituted” means that at least one hydrogen atom on a specified atom such as a carbon or nitrogen atom is optionally replaced by other substituents, provided that the normal valence of the specified atom is not exceeded and the substitution results in a stable compound. When more than one substituent is present on an atom or group, the selected substituents are independent of each other (i.e., the same or different).

[0419] “Alkyl” refers to a hydrocarbon chain that can be a straight-chain or branched-chain alkyl. In one embodiment, “C 1-7 alkyl” means an alkyl containing 1 to 7 (including the end values) carbon atoms. In another embodiment, “C 1-6 alkyl” means an alkyl containing 1 to 6 (including the end values) carbon atoms. In another embodiment, “C 1-4 alkyl” means an alkyl containing 1 to 4 (including the end values) carbon atoms. Examples of alkyl of the hydrocarbon chain include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, and heptyl, where all isomers of these examples are considered.

[0420] “Substituted alkyl” refers to an alkyl as defined above substituted by groups including, but not limited to: one or more F, one or two Cl, one or two OH, an amino group, a (C 1-6 alkyl)amino (i.e., C 1-6 alkyl-NH-), a (diC 1-6 alkyl)amino (i.e., (alkyl)2N-), one or two C 1-6 alkoxy, a -NH-C(O)-C 1-6 alkyl, a -C(O)-NH2 group, a -C(O)-NH-(C 1-6 alkyl) group, a -C(O)-N-(C 1-6 alkyl)2 group, or a cyano group, or any combination of these substituents. “Substituted” means that one or more hydrogen atoms of the alkyl are replaced by the substituents listed above.

[0421] "Hydroxyalkyl" means -(alkyl)OH, where the alkyl is optionally substituted and as defined above. The OH portion of the hydroxyalkyl can be bonded to any carbon atom, such as any internal or terminal carbon atom of a hydrocarbon alkyl chain. Examples of hydroxyalkyl include, but are not limited to, -CH2OH, -CH2CH2OH, -CH(OH)CH3, -CH2CH2CH2OH, -CH2CH(OH)CH3, -CH(OH)CH2CH3, -C(OH)(CH3)2, -(2-hydroxy)-cyclopentyl, (3-hydroxy)-cyclobutyl, etc.

[0422] "C 3-10 Cycloalkyl" means a saturated cyclic alkyl having 3 to 10 carbon atoms that can be a monocyclic, bicyclic, polycyclic or fused / bridged ring system. Exemplary cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. Typical bridged cycloalkyls include, but are not limited to, adamantyl, noradamantyl, bicyclo[1.1.0]butanyl, norbornyl (bicyclo[2.2.1]heptanyl), etc. C 3-10 Cycloalkyl can be unsubstituted or substituted with one or more of the groups including, but not limited to: hydroxy, halogen or C 1-6 alkyl.

[0423] "C 4-10 Cycloalkenyl" means an unsaturated or partially saturated non-aromatic cyclic alkyl having 4 to 10 carbon atoms that can be a monocyclic, bicyclic, polycyclic or fused / bridged ring system. Exemplary cycloalkenyls include, but are not limited to, cyclobutene, cyclopentene, cyclohexene, cyclohex-1,4-diene, etc.

[0424] "C 2-6 Alkenyl" means a straight-chain or branched-chain monovalent hydrocarbon group having two to six carbon atoms containing at least one double bond. Exemplary alkenyls include, but are not limited to, vinyl, propenyl, etc.

[0425] "C 2-6 Alkynyl" means a straight-chain or branched-chain monovalent hydrocarbon group having two to six carbon atoms containing at least one triple bond. Exemplary alkynyls include, but are not limited to, ethynyl, propynyl, etc.

[0426] "Alkoxy" means (alkyl)O, where the alkyl is optionally substituted and as defined above. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy and butoxy. The alkyl of the alkoxy can be unsubstituted or substituted as defined above.

[0427] "Aryl" refers to a monocyclic, bicyclic or polycyclic aromatic hydrocarbon group containing carbon atoms. In one embodiment, the aryl contains 6 - 12 carbon atoms. In one embodiment, the aryl is phenyl. In one embodiment, the aryl is an aromatic or partially aromatic bicyclic group. In another embodiment, the aryl is naphthyl (such as α - naphthyl or β - naphthyl), 1,2,3,4 - tetrahydronaphthyl or indanyl. The aryl may be unsubstituted or substituted with one or more of the groups including but not limited to the following: halogen, C 1-6 alkyl, C 2-6 alkynyl, CN, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, -C 1-6 alkyl - O - C 1-6 alkyl, -C 1-6 alkyl - NH - C 1-6 alkyl, C 1-6 alkyl - N-(C 1-6 alkyl)2, -C 1-6 alkyl - NH - C 1-6 alkyl - OH, -C 1-6 alkyl - NH - C 1-6 alkyl - C 3-10 cycloalkyl, -C 1-6 alkyl - NH - C 1-6 alkyl - NH - C 1-6 alkyl, -C 1-6 alkyl - NH - C(O)-C 1-6 alkyl, -C 1-6 alkyl - O - C(O)-C 1-6 alkyl, -C 1-6 alkyl - NH - C 0-6 alkyl-(4 - to 6 - membered heterocyclic group) or -C 1-6 alkyl - NH - C 0-6 alkyl-(5 - to 6 - membered heteroaryl), wherein the C 1-6 alkyl, cycloalkyl, heterocyclic group and / or heteroaryl is unsubstituted or substituted with 1 - 3 substituents selected from the following: halogen, C 1-6 alkyl, hydroxy C 1-6 alkyl or amino C 1-6 alkyl. In one embodiment, the aryl may be substituted with one or more of the groups including but not limited to the following: halogen, CN, -C(O)-NH2, -C(O)-NH - C 1-6 alkyl, -C(O)-N-(C 1-6 alkyl)2, -O - C 1-6 alkyl - NH2, -O - C 1-6 alkyl - NH-(C 1-6 alkyl), -O - C 1-6 alkyl - N(C1-6 alkyl)2, 4- to 6-membered heterocyclic group, -C(O)-(4- to 6-membered heterocyclic group), -O-phenyl, -O-C 1-6 alkyl-(4- to 6-membered heterocyclic group), C 1-6 alkyl, C 2-6 alkynyl, hydroxyl, C 1-6 alkoxy or hydroxyl C 1-6 alkyl, wherein the heterocyclic group or heteroaryl is unsubstituted or substituted with 1-3 substituents selected from the following: halogen, C 1-6 alkyl, C(O)-C 1-6 alkyl or 4- to 6-membered heterocyclic group.

[0428] "Substituted phenyl" means phenyl substituted with one or more of the groups including but not limited to the following: halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, hydroxyl C 1-6 alkyl, amino C 1-6 alkyl, -C 1-6 alkyl-O-C 1-6 alkyl, -C 1-6 alkyl-NH-C 1-6 alkyl, C 1-6 alkyl-N-(C 1-6 alkyl)2, -C 1-6 alkyl-NH-C 1-6 alkyl-OH, -C 1-6 alkyl-NH-C 1-6 alkyl-C 3-10 cycloalkyl, -C 1-6 alkyl-NH-C 1-6 alkyl-NH-C 1-6 alkyl, -C 1-6 alkyl-NH-C(O)-C 1-6 alkyl, -C 1-6 alkyl-O-C(O)-C 1-6 alkyl, -C 1-6 alkyl-NH-C 0-6 alkyl-(4- to 6-membered heterocyclic group) or -C 1-6 alkyl-NH-C 0-6 alkyl-(5- to 6-membered heteroaryl), wherein the C 1-6 alkyl, cycloalkyl, heterocyclic group and / or heteroaryl is unsubstituted or substituted with 1-3 substituents selected from the following: halogen, C 1-6 alkyl, hydroxyl C 1-6 alkyl or amino C 1-6 alkyl. In one embodiment, phenyl may be substituted with one or more of the groups including but not limited to the following: halogen, CN, C2-6 alkynyl, -C(O)-NH2, -C(O)-NH-C 1-6 alkyl, -C(O)-N-(C 1-6 alkyl)2, -O-C 1-6 alkyl-NH2, -O-C 1-6 alkyl-NH-(C 1-6 alkyl), -O-C 1-6 alkyl-N(C 1-6 alkyl)2, 4- to 6-membered heterocyclic group, -C(O)-(4- to 6-membered heterocyclic group), -O-phenyl, -O-C 1-6 alkyl-(4- to 6-membered heterocyclic group), C 1-6 alkyl, hydroxy, C 1-6 alkoxy or hydroxy C 1-6 alkyl, wherein the heterocyclic group or heteroaryl is unsubstituted or substituted with 1-3 substituents selected from: halogen, C 1-6 alkyl, C(O)-C 1-6 alkyl or 4- to 6-membered heterocyclic group.

[0429] "Halogen" means F, Cl, Br or I.

[0430] "Heteroaryl" refers to a monocyclic, bicyclic or polycyclic aromatic or partially aromatic ring system having one to three heteroatoms or hetero groups selected from O, N, S, S(=O), S(=O)2 or C(=O). "Partially aromatic" refers to a polycyclic fused ring group in which at least one but not all of the rings are aromatic, such as a benzodioxolene group. In one embodiment, the heteroaryl is a 5- to 10-membered ring system. In another embodiment, the heteroaryl is a 5- to 6-membered ring system. Exemplary heteroaryl ring groups include but are not limited to furyl, oxazolyl, isoxazolyl, isothiazolyl, imidazolyl, triazolyl, thienyl, thiazolyl, pyridyl, pyrimidinyl, thiazinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, imidazothiazolyl, oxadiazolyl, indolizidinyl, dihydroindolyl, indazolyl, chromanyl, oxodihydroindolyl, indolyl, oxoindolyl, quinolinyl, 3,4-dihydroisoquinolin-2(1H)-yl, quinoxalinyl, benzofuryl, benzoxazolyl, benzo[d]isoxazolyl, benzo[d]thiazolyl, benzo[d][1,3]dioxolyl, 1H-benzo[d][1,2,3]triazolyl, 2H-indazolyl, 1H-indazolyl, quinoxalin-2-yl, 1H-benzo[d]imidazolyl, pyrazolo[1,5-a]pyridyl, dihydrobenzo[b][1,4]dioxinyl, (5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl), 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl, 5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl), 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazinyl, hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, 5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazinyl, pyrazolo[1,5a]pyridyl, and the like.

[0431] "Substituted heteroaryl" refers to the heteroaryl as defined above substituted with one or more of the groups including but not limited to: halogen, C 1-6 alkyl, CN, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, -C 1-6 alkyl - O - C 1-6 alkyl, -C 1-6 alkyl - NH - C 1-6 alkyl, -C 1-6 alkyl - N - (C 1-6 alkyl)2, -C 1-6 alkyl - NH - C 1-6 alkyl - OH, -C 1-6 alkyl - NH - C 1-6 alkyl - C 3-10 cycloalkyl, -C 1-6 alkyl - NH - C 1-6alkyl-NH-C 1-6 alkyl, -C 1-6 alkyl-NH-C(O)-C 1-6 alkyl, -C 1-6 alkyl-O-C(O)-C 1-6 alkyl, -C 1-6 alkyl-NH-C 0-6 alkyl-(4- to 6-membered heterocyclic group) or -C 1-6 alkyl-NH-C 0-6 alkyl-(5- to 6-membered heteroaryl), wherein the C 1-6 alkyl, cycloalkyl, heterocyclic group and / or heteroaryl is unsubstituted or substituted with 1-3 substituents selected from the following: halogen, C 1-6 alkyl, hydroxy C 1-6 alkyl or amino C 1-6 alkyl. In one embodiment, the heteroaryl can be substituted with one or more of the groups including but not limited to the following: halogen, C 1-6 alkyl, NH2, hydroxy C 1-6 alkyl or amino C 1-6 alkyl. In one embodiment, the heteroaryl can be substituted with one or more of the groups including but not limited to the following: halogen, CN, -C(O)-NH2, -C(O)-NH-C 1-6 alkyl, -C(O)-N-(C 1-6 alkyl)2, -O-C 1-6 alkyl-NH2, -O-C 1-6 alkyl-NH-(C 1-6 alkyl), -O-C 1-6 alkyl-N(C 1-6 alkyl)2, 4- to 6-membered heterocyclic group, -C(O)-(4- to 6-membered heterocyclic group), -O-phenyl, -O-C 1-6 alkyl-(4- to 6-membered heterocyclic group), C 1-6 alkyl, hydroxy, C 1-6 alkoxy or hydroxy C 1-6 alkyl, wherein the heterocyclic group or heteroaryl is unsubstituted or substituted with 1-3 substituents selected from the following: halogen, C 1-6 alkyl, C(O)-C 1-6 alkyl or 4- to 6-membered heterocyclic group.

[0432] "Heterocycle" or "heterocyclic group" refers to a monocyclic, bicyclic or polycyclic saturated ring system having one to three heteroatoms or hetero groups selected from O, N, S, S(=O), S(=O)2 or C(=O). The monocyclic heterocycle can be a 4- to 10-membered ring, while the bicyclic heterocycle contains two fused or bridged 4- to 6-membered rings having 5 to 10 ring atoms. Exemplary heterocyclic groups include, but are not limited to, azetidinyl, azepanyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl (thiolanyl), piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydro-2H-pyranyl, morpholinyl, thiomorpholinyl, dioxanyl, 2,5-diazabicyclo[2.2.1]heptane, 2,5-diazabicyclo[2.2.2]octane, and the like.

[0433] "Substituted heterocycle" or "substituted heterocyclic group" refers to a heterocycle or heterocyclic group substituted with one or more groups including, but not limited to, the following: halogen, CN, -C(O)-NH2, -C(O)-NH-C 1-6 alkyl, -C(O)-N-(C 1-6 alkyl)2, -O-C 1-6 alkyl-NH2, -O-C 1-6 alkyl-NH-(C 1-6 alkyl), -O-C 1-6 alkyl-N-(C 1-6 alkyl)2, 4- to 6-membered heterocyclic group, -C(O)-heterocyclic group, -O-phenyl, -O-C 1-6 alkyl-(4- to 6-membered heterocyclic group), C 1-6 alkyl, hydroxy, C 1-6 alkoxy or hydroxyC 1-6 alkyl, wherein the heterocyclic group or heteroaryl is unsubstituted or substituted with 1-3 substituents selected from the following: halogen, C 1-6 alkyl, C-(O)-C 1-6 alkyl or 4- to 6-membered heterocyclic group. In one embodiment, the heterocyclic group can be substituted with one or more groups including, but not limited to, the following: halogen, C 1-6 alkyl, NH2, hydroxyC 1-6 alkyl or aminoC 1-6 alkyl. In one embodiment, the heterocyclic group can be substituted with one or more groups including, but not limited to, the following: hydroxy, halogen or C 1-6 alkyl.

[0434] The term "comprise / comprises / comprising" shall be interpreted in an inclusive sense rather than an exclusive sense. The terms "consist / consisting" and its variations shall be interpreted in an exclusive sense rather than an inclusive sense.

[0435] As used herein, unless otherwise specified, the term "about" means a variation of 10% from a given reference value.

[0436] The terms "patient" or "subject" are used interchangeably herein and mean a mammal, such as a human or veterinary patient or subject, such as a mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate such as a monkey, chimpanzee, baboon, or gorilla.

[0437] The term "treating / treatment" is intended to cover the administration of a compound or composition of the present disclosure to a subject for the purpose of achieving an improvement in one or more conditions of a disease or disorder, including palliative treatment. A "therapeutically effective amount" is the minimum amount of an active compound that achieves treatment. For example, when used to treat a condition, a therapeutically effective amount of a compound of the present disclosure is an amount that substantially halts, slows, or reverses the progression of the condition or any accompanying symptoms. For example, when used to treat cancer, a therapeutically effective amount of a compound of the present disclosure is an amount that can slow the progression of cancer, reduce the number of cancer cells in a fluid (such as blood, peripheral cells, or lymph fluid), reduce tumor size, inhibit metastasis, inhibit tumor growth, and / or improve one or more symptoms of the cancer. For cancer treatment, efficacy can be measured, for example, by assessing tumor size and number, time to disease progression, and / or determining the response rate. As used herein, "condition" can include a disease or disorder.

[0438] The present disclosure also provides compositions comprising a compound of formula (I)-(III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Example 302, 349, or 275. Such compositions may comprise a pharmaceutically acceptable carrier and optionally other pharmaceutically inert or inactive ingredients. In another embodiment, a compound of formula (I-III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Example 302, 349, or 275, is present in a single composition. In another embodiment, a compound of formula (I-III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Example 302, 349, or 275, is combined with one or more other therapeutic agents as described below. The compositions of the present disclosure that are used or intended for use in treating a subject may also be regarded as and referred to as "formulations" or "pharmaceutical compositions".

[0439] The compositions of the present disclosure comprise an amount of at least one or more compounds of formula (I-III) or pharmaceutically acceptable salts, prodrugs, solvates, hydrates or stereoisomers thereof such as Example 302, 349 or 275, said compositions being effective for treating conditions characterized by dysregulation of the RAS / RAF / MEK / ERK pathway or treatable by inhibition of Erk 1 / 2. The dosage of the compound of formula (I-III) or pharmaceutically acceptable salts, prodrugs, solvates, hydrates or stereoisomers thereof such as Example 302, 349 or 275 to achieve a therapeutic effect will depend on factors such as the age, weight and sex of the patient and the route of administration. It is also contemplated that the compound of formula (I-III) or pharmaceutically acceptable salts, prodrugs, solvates, hydrates or stereoisomers thereof such as Example 302, 349 or 275 may be administered in unit dosage forms, and those skilled in the art will adjust the unit dosage forms accordingly to reflect the relative activity levels desired. The decision regarding the specific dosage to be employed (and the number of times this dosage is administered per unit time) is made at the discretion of the ordinarily skilled physician, and the dosage may be titrated to vary for a particular situation to produce the desired therapeutic effect. In one embodiment, the therapeutically effective amount is from about 0.01 mg / kg body weight to 10 mg / kg body weight. In another embodiment, the therapeutically effective amount is equal to or less than about 5 g / kg, about 500 mg / kg, about 400 mg / kg, about 300 mg / kg, about 200 mg / kg, about 100 mg / kg, about 50 mg / kg, about 25 mg / kg, about 10 mg / kg, about 1 mg / kg, about 0.5 mg / kg, about 0.25 mg / kg, about 0.1 mg / kg, about 100 μg / kg, about 75 μg / kg, about 50 μg / kg, about 25 μg / kg, about 10 μg / kg or about 1 μg / kg. The therapeutically effective amount of the compound of formula (I-III) or pharmaceutically acceptable salts, prodrugs, solvates, hydrates or stereoisomers thereof such as Example 302, 349 or 275 can be determined by the attending physician and may depend on the condition being treated, the compound being administered, the route of administration, age, weight, severity of the patient's symptoms and the type of patient and response.

[0440] In one embodiment, a therapeutically effective amount of a compound of formula (I-III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof, such as Example 302, 349 or 275, may be from about 80 mg to about 350 mg. In one embodiment, a therapeutically effective amount of a compound of formula (I-III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof, such as Example 302, 349 or 275, may be from about 120 mg to about 250 mg. In one embodiment, a therapeutically effective amount of a compound of formula (I-III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof, such as Example 302, 349 or 275, may be about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg or about 350 mg. In one embodiment, a therapeutically effective amount of a compound of formula (I-III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof, such as Example 302, 349 or 275, may be about 80 mg, about 120 mg, about 180 mg, about 250 mg or about 350 mg. In one embodiment, a therapeutically effective amount of a compound of formula (I-III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof, such as Example 302, 349 or 275, may be about 120 mg, about 180 mg or about 250 mg. In one embodiment, a therapeutically effective amount of a compound of formula (I-III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof, such as Example 302, 349 or 275, may be about 250 mg.

[0441] As used herein, the therapeutically effective amount refers to the total amount administered over a given period of time; that is, if more than one compound of formula (I-III) or a pharmaceutically acceptable salt, prodrug or solvate thereof, such as Example 302, 349 or 275, is administered, then the therapeutically effective amount corresponds to the total amount administered over that given period of time.

[0442] In one embodiment, the therapeutically effective amount of one or more doses may be higher than the therapeutically effective amount of one or more subsequent doses. In another embodiment, the therapeutically effective amount of one or more doses may be lower than the therapeutically effective amount of one or more subsequent doses. In one embodiment, the therapeutically effective amount may comprise one or more 250 mg doses and one or more subsequent 180 mg doses, 120 mg doses, or combinations thereof. In one embodiment, the therapeutically effective amount may comprise one or more 180 mg doses and one or more subsequent 120 mg doses. In one embodiment, the therapeutically effective amount may comprise one or more 120 mg doses and one or more subsequent 180 mg doses, 250 mg doses, or combinations thereof. In one embodiment, the therapeutically effective amount may comprise one or more 180 mg doses and one or more subsequent 250 mg doses.

[0443] A pharmaceutical composition containing a compound of formula (I-III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Example 302, 349, or 275, can be formulated neat or together with one or more pharmaceutical carriers for administration. The amount of one or more pharmaceutical carriers is determined according to the solubility and chemical properties of the compound of formula (I-III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Example 302, 349, or 275, the chosen route of administration, and standard pharmacological practice. The one or more pharmaceutical carriers can be solid or liquid and can comprise both solid and liquid carriers. A variety of suitable liquid carriers are known and can be readily selected by those skilled in the art. Such carriers can include, for example, DMSO, saline, buffered saline, hydroxypropyl cyclodextrin, and mixtures thereof. Similarly, a variety of solid carriers and excipients are known to those skilled in the art. The compounds of formula (I-III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Example 302, 349, or 275, can be administered by any suitable route, taking into account the specific condition for which they are targeted. The compounds of formula (I-III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Example 302, 349, or 275, can be delivered, for example, orally, by injection, inhalation (including oral, intranasal, and intratracheal), ophthalmically, transdermally, intravascularly, subcutaneously, intramuscularly, sublingually, intracranially, epidurally, rectally, and vaginally, and in other ways.

[0444] Although the compounds of formula (I-III) or their pharmaceutically acceptable salts, prodrugs, solvates, hydrates or stereoisomers such as Example 302, 349 or 275 may be administered alone, they may also be administered in the presence of one or more physiologically compatible pharmaceutical carriers. The carriers may be in dry or liquid form and must be pharmaceutically acceptable. Liquid pharmaceutical compositions are usually sterile solutions or suspensions. When liquid carriers are used for parenteral administration, they are desirably sterile liquids. Liquid carriers are commonly used to prepare solutions, suspensions, emulsions, syrups and elixirs. In one embodiment, the compounds of formula (I-III) or their pharmaceutically acceptable salts, prodrugs, solvates, hydrates or stereoisomers such as Example 302, 349 or 275 are dissolved in a liquid carrier. In another embodiment, the compounds of formula (I-III) or their pharmaceutically acceptable salts, prodrugs, solvates, hydrates or stereoisomers such as Example 302, 349 or 275 are suspended in a liquid carrier. Those skilled in the art of formulation will be able to select a suitable liquid carrier depending on the route of administration.

[0445] Alternatively, the compounds of formula (I-III) or their pharmaceutically acceptable salts, prodrugs, solvates, hydrates or stereoisomers such as Example 302, 349 or 275 may be formulated in a solid carrier. In one embodiment, the composition may be compressed into a unit dosage form, i.e., a tablet or a caplet. In another embodiment, the composition may be added to a unit dosage form, i.e., a capsule. In another embodiment, the composition may be formulated for administration in powder form. The solid carrier may perform a variety of functions, i.e., it may perform the functions of two or more of the excipients described below. For example, the solid carrier may also act as a flavoring agent, lubricant, solubilizer, suspending agent, filler, glidant, compression aid, binder, disintegrant or encapsulating material.

[0446] The composition may also be subdivided to contain a suitable amount of the compounds of formula (I-III) or their pharmaceutically acceptable salts, prodrugs, solvates, hydrates or stereoisomers such as Example 302, 349 or 275. For example, a unit dose may be a packaged composition, such as a packaged powder, vial, ampoule, pre-filled syringe or sachet containing a liquid.

[0447] Examples of excipients that can be combined with one or more compounds of formula (I-III) or pharmaceutically acceptable salts, prodrugs, solvates, hydrates or stereoisomers thereof such as Example 302, 349 or 275 include, but are not limited to, adjuvants, antioxidants, binders, buffers, coating agents, colorants, compression aids, diluents, disintegrants, emulsifiers, emollients, encapsulating materials, fillers, flavoring agents, glidants, granulating agents, lubricants, metal chelating agents, osmotic regulators, pH adjusters, preservatives, solubilizers, adsorbents, stabilizers, sweeteners, surfactants, suspending agents, syrups, thickening agents or viscosity regulators. See, for example, excipients described in "Handbook of Pharmaceutical Excipients", 5th Edition, edited by Rowe, Sheskey and Owen, APhA Publications (Washington, DC), December 14, 2005, which is incorporated herein by reference.

[0448] In one embodiment, the compositions of the present disclosure can be used in the form of an inhalant. For this route of administration, the compositions can be prepared as fluid unit doses with a compound of formula (I-III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof such as Example 302, 349 or 275 and a vehicle for delivery by a nebulizing spray pump or by a dry powder for insufflation.

[0449] In another embodiment, the composition can be used in the form of an aerosol, i.e., an oral or nasal aerosol. For this route of administration, the composition is formulated with a gas or liquefied propellant such as dichlorodifluoromethane, carbon dioxide, nitrogen, propane, etc. for use in a pressurized aerosol container. Delivery in a metered dose in one or more actuations is also provided.

[0450] In another embodiment, the composition can be administered by a sustained delivery device. As used herein, "sustained delivery" refers to the delayed or otherwise controlled delivery of a compound of formula (I-III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof such as Example 302, 349 or 275. Those skilled in the art are aware of suitable sustained delivery formulations or devices. For use in such sustained delivery devices, the compounds of formula (I-III) can be formulated as described herein.

[0451] In one embodiment, the compositions of the present disclosure are in tablet form and contain at least one compound of formula (I-III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof such as Example 302, 349 or 275 and a pharmaceutically acceptable carrier.

[0452] In one embodiment, the composition of the present disclosure is a tablet dosage form comprising a compound of formula (I) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof such as Example 302, 349 or 275 and a pharmaceutically acceptable excipient. In one embodiment, the tablet comprises granules containing a compound of formula (I) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof such as Example 302, 349 or 275, hydroxypropyl cellulose, crospovidone and microcrystalline cellulose. In one embodiment, the granules are prepared by dry granulation. In one embodiment, the granules are milled, mixed with an extragranular excipient such as magnesium stearate, and compressed into tablets. In one embodiment, the tablets are coated with II White. In one embodiment, the composition is a tablet dosage form comprising the mandelate salt of a compound of formula (I) and a pharmaceutically acceptable excipient. In one embodiment, the composition is a tablet dosage form comprising the benzenesulfonate salt of a compound of formula (I) and a pharmaceutically acceptable excipient.

[0453] In one embodiment, the composition is a tablet dosage form comprising a compound of formula (II) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof such as Example 302, 349 or 275 and a pharmaceutically acceptable excipient. In one embodiment, the tablet comprises granules containing a compound of formula (II) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof such as Example 302, 349 or 275, hydroxypropyl cellulose, crospovidone and microcrystalline cellulose. In one embodiment, the granules are prepared by dry granulation. In one embodiment, the granules are milled, mixed with an extragranular excipient such as magnesium stearate, and compressed into tablets. In one embodiment, the tablets are coated with II White. In one embodiment, the composition is a tablet dosage form comprising the mandelate salt of a compound of formula (II) and a pharmaceutically acceptable excipient. In one embodiment, the composition is a tablet dosage form comprising the benzenesulfonate salt of a compound of formula (II) and a pharmaceutically acceptable excipient.

[0454] In one embodiment, the composition is a tablet dosage form comprising a compound of formula (III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof and a pharmaceutically acceptable excipient. In one embodiment, the tablet comprises granules containing a compound of formula (III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof, hydroxypropyl cellulose, crospovidone and microcrystalline cellulose. In one embodiment, the granules are prepared by dry granulation. In one embodiment, the granules are milled, mixed with an extragranular excipient such as magnesium stearate, and compressed into tablets. In one embodiment, the tablets are II White coating. In one embodiment, the composition is a tablet dosage form comprising the mandelate salt of the compound of formula (III) and a pharmaceutically acceptable excipient. In one embodiment, the composition is a tablet dosage form comprising the benzenesulfonate salt of the compound of formula (III) and a pharmaceutically acceptable excipient.

[0455] In one embodiment, the composition of the present disclosure comprises at least one compound selected from the following:

[0456] (S)-1-(2-(Benzo[d][1,3]dioxol-5-ylamino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;

[0457] 1-(2-(Benzofuran-5-ylamino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;

[0458] 1-(2-(Benzofuran-5-ylamino)-5-methylpyrimidin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-3-carboxamide;

[0459] N-(3-Chloro-2-(hydroxymethyl)benzyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0460] (S)-N-(1-(3-Chloro-4-fluorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0461] 1-(2-((2,3-Dihydrobenzofuran-5-yl)amino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;

[0462] N-(1-(3-Chlorophenyl)-2-hydroxyethyl)-1-(2-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0463] N-((S)-1-(3-Chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0464] N-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-(((S)-tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0465] N-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-(((R)-tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0466] 1-(2-(chroman-6-ylamino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;

[0467] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-((4-fluoro-3-morpholinophenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0468] N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(2-((4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0469] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0470] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((4-morpholinophenyl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0471] (S)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0472] (R)-N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0473] (S)-N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0474] (S)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0475] N-(2-hydroxy-1-(thiophen-2-yl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0476] (S)-N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(2-((3,3-difluorocyclobutyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0477] (S)-N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0478] (S)-N-(2-(((1H-pyrrol-2-yl)methyl)amino)-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0479] (S)-N-(3-chloro-2-(hydroxymethyl)benzyl)-1-(5-methyl-2-(tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0480] (S)-N-(1-(3-chlorophenyl)-2-(methylamino)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0481] (S)-N-(1-(3-chlorophenyl)-2-((2-hydroxyethyl)amino)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide; and

[0482] N-(3-chloro-5-fluoro-2-(hydroxymethyl)benzyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide,

[0483] or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof; and a pharmaceutically acceptable carrier. For example, the compositions of the present disclosure comprise (S)-N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide benzenesulfonate or (S)-N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide mandelate and a pharmaceutically acceptable carrier. In another embodiment, the compositions of the present disclosure comprise (S)-N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide benzenesulfonate or (S)-N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide mandelate and a pharmaceutically acceptable carrier, and further comprise a pharmaceutically acceptable ingredient and an additional therapeutic agent.

[0484] In one embodiment, the composition of the present disclosure is a tablet dosage form comprising (S)-N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. In one embodiment, the tablet comprises granules containing (S)-N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide or a pharmaceutically acceptable salt thereof, hydroxypropyl cellulose, crospovidone and microcrystalline cellulose. In one embodiment, the granules are prepared by dry granulation. In one embodiment, the granules are milled, mixed with an extragranular excipient such as magnesium stearate, and compressed into tablets. In one embodiment, the tablets are coated with II White.

[0485] In one embodiment, the composition is a tablet dosage form comprising (S)-N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide mandelate and a pharmaceutically acceptable excipient. In one embodiment, the tablet comprises granules containing (S)-N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide mandelate, hydroxypropyl cellulose, crospovidone, and microcrystalline cellulose. In one embodiment, the granules are prepared by dry granulation. In one embodiment, the granules are milled, mixed with an extragranular excipient such as magnesium stearate, and compressed into tablets. In one embodiment, the tablets are coated with II White.

[0486] In one embodiment, the composition is a tablet dosage form comprising (S)-N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide benzenesulfonate and a pharmaceutically acceptable excipient. In one embodiment, the tablet comprises granules containing (S)-N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide benzenesulfonate, hydroxypropyl cellulose, crospovidone, and microcrystalline cellulose. In one embodiment, the granules are prepared by dry granulation. In one embodiment, the granules are milled, mixed with an extragranular excipient such as magnesium stearate, and compressed into tablets. In one embodiment, the tablets are coated with II White.

[0487] In addition to the above-described components for use in the compositions of the present disclosure, the compositions and kits described herein may contain one or more additional drugs or therapeutic agents in addition to the compounds of formula (I-III) or pharmaceutically acceptable salts, prodrugs, solvates, hydrates or stereoisomers thereof such as Example 302, 349 or 275. In one embodiment, the compositions and kits described herein may contain one or more additional drugs or therapeutic agents for the treatment of cancer, including cancers characterized by tumors, including solid tumors and "liquid" or non-solid tumor cancers (e.g., lymphoma). In one embodiment, the additional drug is a chemotherapeutic agent. Examples of chemotherapeutic agents include those described in "Physician's Desk Reference", 64th Edition, Thomson Reuters, 2010, which is hereby incorporated by reference. The therapeutically effective amount of the additional drug or therapeutic agent is well known to those skilled in the art, and for example, determining the amount of other drugs to be delivered is entirely within the ordinary skill of the attending physician.

[0488] The compound of formula (I-III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof such as Example 302, 349 or 275, and / or one or more additional drugs or one or more therapeutic agents can be formulated into a single composition and administered in a single composition. However, the present disclosure is not so limited. In other embodiments, the compound of formula (I-III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof such as Example 302, 349 or 275 can be administered separately from other compounds of formula (I-III) or pharmaceutically acceptable salts, prodrugs, solvates, hydrates or stereoisomers thereof such as Example 302, 349 or 275, and / or from other therapeutic (including chemotherapeutic) agents as desired in one or more compositions.

[0489] The present disclosure also provides a kit or package that includes a compound of formula (I-III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof such as Example 302, 349 or 275 as described herein, or a composition of a compound of formula (I-III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof. The kit can be organized and / or can include instructions to indicate a single composition or a combination of compositions to be employed at each desired time.

[0490] In certain embodiments, the kit comprises a package or container having a compound of formula (I-III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof formulated for the desired route of delivery, such as Example 302, 349 or 275 or a composition thereof. In certain embodiments, the kit comprises instructions for administration and optionally an insert regarding any active agent. In other embodiments, the kit may further comprise instructions for monitoring the circulating levels of a compound of formula (I-III), such as Example 302, 349 or 275, and optionally materials for performing such assays, including, for example, reagents, well plates, containers, labels or tags, etc. Such kits are readily packaged in a manner suitable for treating the desired indication. For example, the kit may include instructions for the use of a spray pump or other delivery device. Other suitable components making up such kits will be apparent to those skilled in the art, taking into account the desired indication and route of delivery.

[0491] The compounds of formula (I-III) or pharmaceutically acceptable salts, prodrugs, solvates, hydrates or stereoisomers thereof described herein, such as Example 302, 349 or 275, or compositions thereof can be formulated and administered in a single dose or continuously or periodically discontinuously. For continuous administration, the dosing regimens, treatment methods, packages or kits of the present disclosure can include the compounds of formula (I-III) or pharmaceutically acceptable salts, prodrugs, solvates, hydrates or stereoisomers thereof, such as Example 302, 349 or 275, in the form of each dosage unit (e.g., solution, lotion, tablet, pill or other units described above or used in drug delivery), and optionally instructions for administering the dose daily, weekly, twice a week, bi-weekly, or monthly or for another predetermined duration or as prescribed. When the compounds of formula (I-III) or pharmaceutically acceptable salts, prodrugs, solvates, hydrates or stereoisomers thereof, such as Example 302, 349 or 275, are to be delivered periodically in a discontinuous manner according to the treatment methods or dosing regimens of the present invention, packages or kits comprising the compounds of formula (I-III) or pharmaceutically acceptable salts, prodrugs, solvates, hydrates or stereoisomers thereof, such as Example 302, 349 or 275, or compositions thereof can include a placebo for administration to the subject during the periods when the compounds of formula (I-III) or pharmaceutically acceptable salts, prodrugs, solvates, hydrates or stereoisomers thereof, such as Example 302, 349 or 275, or compositions thereof are not being delivered. When it is desired to vary the composition of the present invention, the concentration of the components of the composition of the present invention, or the relative ratios of the compounds of formula (I-III) or pharmaceutically acceptable salts, prodrugs, solvates, hydrates or stereoisomers thereof, such as Example 302, 349 or 275 and other agents that make up the composition of the present invention over time, the package or kit can contain a series of dosage units that provide the desired variability when administered according to the treatment methods or dosing regimens of the present disclosure.

[0492] Many packages or kits for dispensing medicaments for achieving periodic use, including periodic oral administration, are known in the art. In one embodiment, the package has an indication for each period. In another embodiment, the package is a labeled blister pack, dial dispenser pack, or bottle.

[0493] The packaging component of the kit can be designed for administering a medicament, such as in the form of an inhaler, syringe, pipette, eye dropper or other such device, and a compound of formula (I-III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof, such as Example 302, 349 or 275, or a composition thereof, can be administered or delivered from the component to an affected area (such as the lung) of the body of a subject, injected into the subject, or even applied to and mixed with other components of the kit before or simultaneously with administration to the subject, all in accordance with the treatment methods or dosing regimens of the present disclosure.

[0494] The compound of formula (I-III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof, such as Example 302, 349 or 275, or a composition thereof, which constitutes the kit of the present disclosure, can be provided in a dry or lyophilized form. When the compound or composition of the present disclosure is provided in a dry or lyophilized form, reconstitution is generally carried out by adding a suitable solvent such as water or saline. It is contemplated that the solvent can be provided in the kit of the present disclosure or in another package.

[0495] The kit of the present disclosure can include a component for containing a vial or other container in a tightly restricted manner for commercial sale, such as an injection or blow-molded plastic container in which the required vial or other container is held. Regardless of the number or type of packaging or container, and as discussed above, the kit can also include or be packaged with a separate instrument for assisting in the injection / administration or placement of a compound of formula (I-III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof, such as Example 302, 349 or 275, or a composition thereof, within the body of a subject. Such an instrument can be an inhaler, syringe, pipette, forceps, measuring spoon, eye dropper or any such suitable delivery component.

[0496] In one embodiment, the kit of the present disclosure can optionally contain instructions for administering a compound of formula (I-III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof, such as Example 302, 349 or 275, or a composition thereof, to a subject suffering from a condition characterized by dysregulation of the RAS / RAF / MEK / ERK pathway or treatable by inhibiting Erk 1 / 2. In another embodiment, the kit of the present disclosure can optionally contain instructions for administering a compound of formula (I-III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof, such as Example 302, 349 or 275, or a composition thereof, to a subject suffering from a condition characterized by dysregulation of the RAS / RAF / MEK / ERK pathway or treatable by inhibiting Erk 1 / 2.

[0497] In another embodiment, a kit is provided and the kit contains a compound of formula (I-III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof, such as Example 302, 349 or 275 or a combination thereof, in a second dosage unit form, and one or more of the above-described carriers or excipients in a third dosage unit form. The kit may optionally contain instructions for administering the medicament and the compound of formula (I-III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof, such as Example 302, 349 or 275 or a combination thereof, to a subject having a disease or condition characterized by dysregulation of the RAS / RAF / MEK / ERK pathway or a disease or condition treatable by inhibition of Erk 1 / 2.

[0498] The compounds described herein, such as Example 302, 349 or 275, can be used to modulate conditions associated with the RAS / RAF / MEK / ERK pathway or treatable by inhibiting Erk 1 / 2. In one embodiment, such conditions are associated with abnormal cell proliferation. The term "abnormal cell proliferation" refers to the uncontrolled growth of cells that naturally occur in the mammalian body. In one embodiment, the condition characterized by abnormal cell proliferation is cancer, including but not limited to prostate cancer, head cancer, cervical cancer, eye cancer, oral cancer, throat cancer, esophageal cancer, bronchial cancer, laryngeal cancer, pharyngeal cancer, thoracic cancer, bone cancer, lung cancer, colon cancer, rectal cancer, stomach cancer, bladder cancer, uterine cancer, cervical cancer, breast cancer, ovarian cancer, vaginal cancer, testicular cancer, skin cancer, thyroid cancer, blood cancer, lymph node cancer, kidney cancer, liver cancer, bowel cancer, pancreatic cancer, brain cancer, central nervous system cancer, adrenal cancer, skin cancer, salivary gland cancer, small intestine cancer, bile duct cancer, leukemia or lymphoma, non-small cell lung cancer (NSCLC) or colorectal cancer, endometrial cancer, oropharyngeal cancer or stomach cancer. In one embodiment, the condition characterized by abnormal cell proliferation is melanoma skin cancer or lung cancer, colon cancer, breast cancer or prostate cancer. In another embodiment, abnormal cell proliferation is associated with solid tumors or blood cancers.In one embodiment, the condition is characterized by the following: colorectal Ca BRAF 506; colorectal Ca BRAF Gly12Asp (GGT>GAT) V, WT KRAS; colorectal Ca KRAS G12 any; endometrial KRAS G12 any; pancreatic Ca KRAS G12 any, melanoma NRAS Q61 any; colorectal Ca BRAF V600E: NRAS TW, KRAS WT; colorectal Ca KRAS Gly12Asp (GGT>GAT); gastric cancer RAS / RAF wt; melanoma NF1; colorectal Ca NRAS G13 any; colorectal Ca BRAF V600E; gallbladder Ca NF1 loss; pancreatic BRAF FRY-BRAF; ovarian–LGSC KRAS G12 any; melanoma BRAF; prostate Ca BRAF K601E; oropharyngeal ACC BRAF D594N; melanoma NRAS Q61 any; colorectal Ca KRAS G13 any; prostate Ca BRAF; NSCLC BRAF G466V; salivary gland Ca HRAS; melanoma BRAF–nm004333 rearrangement; cutaneous SCC BRAF-SGCE translocation; thyroid cancer (MTC) HRAS Q61R; melanoma BRAF; thyroid Ca NRAS Q61; melanoma GNA11 Q209L; uveal melanoma GNA11 Q209L; prostate Ca MAP3K1; small intestine Ca BRAF K601E; melanoma BRAF N581F; prostate Ca BRAF K601E; thyroid Ca BRAF V600E; melanoma NRAS Q61 any; NSCLC BRAF fusion; ovarian Ca KRAS; NSCLC BRAF (K601E); ovarian Ca BRAF, PIK3CA; colorectal Ca NRAS G12 any, KRAS G12 any; melanoma NRAS Q61 any; bile duct KRAS G12 any; and / or ovarian Ca RAS / RAF wt.

[0499] As used herein, the term "modulate" or variations thereof refers to the ability of a compound of formula (I-III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof such as Example 302, 349 or 275 or a composition thereof to modulate one or more components of a biological pathway. In one embodiment, "modulate" refers to inhibiting ERK1 / 2 activity. In another embodiment, modulation includes inhibiting the RAS / RAF / MEK / ERK pathway.

[0500] The activities of the compounds of formula (I-III) or pharmaceutically acceptable salts, prodrugs, solvates, hydrates or stereoisomers thereof, such as Example 302, 349 or 275, were determined in a variety of in vitro and in vivo assays. For example, using homogeneous time-resolved fluorescence (HTRF) technology, it was demonstrated that the compounds of the present disclosure caused inhibition of ERK1 and ERK2 enzyme activities in biochemical assays; representative data are provided in Table 3. In addition, the compounds of the present disclosure were found to be active in cell-based mechanistic assays; that is, inhibition of the phosphorylation of RSK1 (S380) (a downstream protein target of ERK1 / 2) by the compounds of the present disclosure was demonstrated by an enzyme-linked immunosorbent assay (ELISA) method. Representative data are provided in Table 3. The functional utility of the compounds of formula (I-III) or pharmaceutically acceptable salts, prodrugs, solvates, hydrates or stereoisomers thereof, such as Example 302, 349 or 275, as demonstrated by their activities in an in vitro tumor cell proliferation assay in a panel of tumor cell lines having mutations in the RAS / BRAF / MEK / ERK pathway; representative data are likewise provided in Table 3. The compounds of formula (I-III) or pharmaceutically acceptable salts, prodrugs, solvates, hydrates or stereoisomers thereof exhibit ERK1 / 2 inhibitory activity and can thus be used to inhibit abnormal cell growth in which the RAS / RAF / MEK / ERK pathway is operative. Accordingly, the compounds of formula (I-III) or pharmaceutically acceptable salts, prodrugs, solvates, hydrates or stereoisomers thereof, such as Example 302, 349 or 275, are effective in treating conditions such as cancer associated with abnormal cell growth effects regulated by RAS / RAF / MEK / ERK dysregulation. Those skilled in the art will recognize that there is a well-established correlation between activity in an in vitro tumor cell proliferation assay and anti-tumor activity in a clinical setting. For example, the therapeutic utility of a variety of agents such as taxol (Silvestrini, Stem Cells, 1993, 11(6):528-535), taxotere (Bissery, Anti Cancer Drugs, 1995, 6(3):330) and topoisomerase inhibitors (Edelman, Cancer Chemother. Pharmacol., 1996, 37(5):385-39) has been demonstrated by using in vitro tumor proliferation assays.

[0501] In one embodiment, there is provided a method for modulating the RAS / RAF / MEK / ERK pathway or for inhibiting Erk1 / 2, and the method comprises administering a therapeutically effective amount of a compound of formula (I-III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof, such as Example 302, 349 or 275, or a composition thereof, to a subject in need thereof.

[0502] In another embodiment, there is provided a method for treating a disease or condition characterized by abnormal cell growth resulting from dysregulated RAS / RAF / MEK / ERK pathway, and the method comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I-III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof such as Example 302, 349 or 275 or a composition thereof.

[0503] In another embodiment, there is provided a method for treating a disease or condition treatable by inhibiting ERK1 / 2, and the method comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I-III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof such as Example 302, 349 or 275 or a composition thereof.

[0504] A therapeutically effective amount of a compound of formula (I-III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof such as Example 302, 349 or 275 or a composition thereof can be provided based on a regular schedule, i.e., daily, weekly, twice a week, every two weeks, monthly, twice a month or annually, or an irregular schedule varying within a 12- or 24-hour period, days, weeks, months, etc. In one embodiment, a regular schedule can mean consisting of substantially similar intervals. In one embodiment, an irregular schedule can mean consisting of different intervals. In one embodiment, the therapeutically effective amount to be administered can vary. In one embodiment, the therapeutically effective amount of one or more doses, e.g., the first dose, is higher than the therapeutically effective amount of one or more subsequent doses. In another embodiment, the therapeutically effective amount of one or more doses, e.g., the first dose, is lower than the therapeutically effective amount of one or more subsequent doses. Equal doses can be administered at various intervals, including but not limited to about every 2 hours, about every 6 hours, about every 8 hours, about every 12 hours, about every 24 hours, about every 36 hours, about every 48 hours, about every 72 hours, about weekly, about every two weeks, about every three weeks, about every month and about every two months. The number and frequency of doses corresponding to a complete course of treatment will generally be determined according to the judgment of a health care practitioner. The therapeutically effective amount as described herein refers to the total amount administered within a given period; that is, if more than one compound of formula (I-III) or a pharmaceutically acceptable salt, prodrug or solvate thereof such as Example 302, 349 or 275 is administered, then the therapeutically effective amount corresponds to the total amount administered within a given period.

[0505] In one embodiment, a compound of formula (I-III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof such as Example 302, 349 or 275 or a composition thereof may be administered to a subject in need thereof using a regular or irregular dosing schedule. A regular schedule may consist of substantially similar intervals and an irregular schedule may consist of intervals of varying lengths. In another embodiment, a compound of formula (I-III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof such as Example 302, 349 or 275 or a composition thereof may be administered to a subject at approximately weekly, approximately bi-weekly, approximately tri-weekly, approximately monthly and approximately every two months using a regular or irregular schedule. In one embodiment, a compound of formula (I-III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof such as Example 302, 349 or 275 or a composition thereof may be administered to a subject once a week using a regular or irregular schedule. In one embodiment, a compound of formula (I-III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof such as Example 302, 349 or 275 or a composition thereof may be administered to a subject once a week using a regular schedule. The number and frequency of doses corresponding to a full course of treatment may be determined according to the judgment of a health care practitioner.

[0506] In one embodiment, a compound of formula (I-III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof such as Example 302, 349 or 275 or a composition thereof may be administered to a subject in need thereof in an amount of approximately 80 mg once a week, approximately 120 mg once a week, approximately 180 mg once a week, approximately 250 mg once a week or approximately 350 mg once a week using a regular or irregular schedule. In one embodiment, a compound of formula (I-III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof such as Example 302, 349 or 275 or a composition thereof may be administered to a subject in need thereof in an amount of approximately 120 mg once a week, approximately 180 mg once a week or approximately 250 mg once a week using a regular or irregular schedule. In one embodiment, a compound of formula (I-III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof such as Example 302, 349 or 275 or a composition thereof may be administered to a subject in need thereof in an amount of approximately 250 mg once a week using a regular or irregular schedule. In one embodiment, a compound of formula (I-III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof such as Example 302, 349 or 275 or a composition thereof may be administered to a subject in need thereof in an amount of approximately 250 mg once a week using an irregular schedule.

[0507] A therapeutically effective amount of a compound of formula (I-III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof disclosed herein, such as Example 302, 349 or 275, or a composition thereof, and a dosing regimen can provide an improved safety profile, PK profile, improved rash profile (e.g., less rash) and / or longer target residence time and broad activity in KRAS and BRAF models including BRAF and MEK inhibitor-resistant PDX models (as shown, for example, in FIGS. 1 to 7).

[0508] In one embodiment, a compound of formula (I-III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof, such as Example 302, 349 or 275, or a composition thereof can be formulated to achieve desired pharmacokinetic (PK) parameters such as those shown in Example 39 and FIGS. 6 to 7, and the methods and dosing regimens disclosed herein can achieve said parameters. In one embodiment, a compound of formula (I-III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof or a composition thereof, such as Example 302, 349 or 275, can be formulated in an amount of 120 mg QW to achieve one or more of the following PK parameters after administration of the compound or composition: an AUC of about 880 h*ng / mL to about 6120 h*ng / mL, about 1100 to about 5100 h*ng / mL, about 2480 to about 3720 h*ng / mL, or about 3100 h*ng / mL tau ; a C of about 68 ng / mL to about 2330 ng / mL, about 85 to about 1940 ng / mL, about 584 to about 876 ng / mL, or about 730 ng / mL max ; a C of about 11 ng / mL to about 48 ng / mL, about 14 to about 40 ng / mL, about 20 to about 30 ng / mL, or about 25 ng / mL min .

[0509] In one embodiment, a compound of formula (I-III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof or a composition thereof, such as Example 302, 349 or 275, can be formulated in an amount of 180 mg QW to achieve one or more of the following PK parameters after administration of the compound or composition: an AUC of about 1190 h*ng / mL to about 7080 h*ng / mL, about 1490 to about 5900 h*ng / mL, about 2400 to about 3600 h*ng / mL, or about 3000 h*ng / mL tau ; a C of about 80 ng / mL to about 1520 ng / mL, about 100 to about 430 ng / mL, about 184 to about 276 ng / mL, or about 230 ng / mLmax ; C of about 0.8 ng / mL to about 23 ng / mL, about 1.1 to about 19 ng / mL, about 4.8 to about 7.2 ng / mL, or about 5.6 ng / mL min .

[0510] In one embodiment, a compound of formula (I-III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof such as Example 302, 349 or 275 or a composition thereof can be formulated in an amount of 250 mg QW to achieve one or more of the following PK parameters after administration of the compound or composition: an AUC of about 1840 h*ng / mL to about 18,120 h*ng / mL, about 2300 to about 15,100 h*ng / mL, about 4400 to about 6600 h*ng / mL, or about 5500 h*ng / mL tau ; C of about 128 ng / mL to about 960 ng / mL, about 160 to about 800 ng / mL, about 400 to about 600 ng / mL, or about 500 ng / mL max ; C of about 0.4 ng / mL to about 60 ng / mL, about 0.5 to about 50 ng / mL, about 6.9 to about 10.3 ng / mL, or about 8.6 ng / mL min .

[0511] The compounds of formula (I-III) or pharmaceutically acceptable salts, prodrugs, solvates, hydrates or stereoisomers thereof such as Example 302, 349 or 275 have been shown to inhibit tumor growth in vivo after administration of the compound in human tumor xenograft models such as the A375 human melanoma xenograft model with a B-RAF V600E mutation, the HT-29 human colon cancer xenograft model with a B-RAF V600E mutation, the HCT116 human colon cancer xenograft model with a KRAS mutation, the A549 human lung cancer xenograft model with a KRAS mutation and the BxPC3 human pancreatic cancer xenograft model. The compound has also been shown to inhibit the level of phosphorylated RSK in tumors in the A375 xenograft model after treatment with the compound; this indicates effective inhibition of the target protein ERK1 / 2 in vivo by the compounds of the present disclosure. Those skilled in the art will recognize that there is a defined correlation between activity in human tumor xenograft models and anti-tumor activity in the clinical setting.

[0512] Compounds of formula (I-III) or pharmaceutically acceptable salts, prodrugs, solvates, hydrates or stereoisomers thereof such as Example 302, 349 or 275 having particularly promising utility can be identified by using the assays described herein. For example, those found to exhibit an IC in the ERK1 / 2 biochemical assay of less than 100 nM 50values and IC values less than 500 nM in phosphorylation of RSK1 and cell proliferation assays 50 A compound of formula (I-III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof, such as Example 302, 349 or 275, having a value and resulting in 40% or greater tumor growth inhibition in one or more human tumor xenograft models will be identified as a particularly useful compound of the present disclosure.

[0513] Examples 36 to 39 below also indicate that a compound of formula (I-III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof, such as Example 302, 349 or 275, can provide clinical efficacy similar to or better than once-daily dosing when administered at longer intervals such as once a week, twice a week or once every two weeks. See Figure 1 and Table 4. These data show that administering the compound of Example 302 at longer intervals (i.e., once a week, twice a week or every two weeks) provides activity similar to once-daily dosing.

[0514] In the clinical trials outlined in Example 39, the efficacy of a compound of formula (I-III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof, such as Example 302, 349 or 275, was further observed when administered daily or once a week, twice a week or once every two weeks. After administering (S)-N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide mandelate (Example 349) to cancer patients at a dose of 10 mg to 80 mg once a day, the best response of stable disease was observed in 5 out of 17 evaluable patients. When the compound of Example 349 was administered once a week in a dose range of 80 mg to 350 mg, the best response of partial remission was observed in 4 patients, with one patient achieving complete regression of target lesions. The best response of stable disease was observed in 14 additional patients, with an overall response rate of 18 responses out of 30 evaluable patients. These data indicate that when administered at intervals longer than once a day (i.e., once a week, twice a week or once every two weeks), the compound of Example 349 can provide clinical efficacy similar to or better than once-daily dosing.

[0515] In one embodiment, a method of treating a condition characterized by dysregulation of the RAS / RAF / MEK / ERK pathway or a condition treatable by inhibiting ERK1 / 2 comprises administering to a subject in need thereof a composition comprising a therapeutically effective amount of at least one compound of formula (I-III) as defined in each of the previous embodiments or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof, such as Example 302, 349 or 275. In one embodiment, the present disclosure provides a composition comprising a therapeutically effective amount of at least one compound of formula (I-III) as defined in each of the previous embodiments or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof, such as Example 302, 349 or 275, for treating a condition characterized by dysregulation of the RAS / RAF / MEK / ERK pathway or a condition treatable by inhibiting ERK1 / 2; or the use of such a composition for the manufacture of a medicament for treating a condition characterized by dysregulation of the RAS / RAF / MEK / ERK pathway or a condition treatable by inhibiting ERK1 / 2. In another embodiment, conditions treatable by the methods or dosing regimens of the present invention are prostate cancer, head cancer, neck cancer, eye cancer, oral cancer, throat cancer, esophageal cancer, bronchial cancer, laryngeal cancer, pharyngeal cancer, thoracic cancer, bone cancer, lung cancer, colon cancer, rectal cancer, gastric cancer, bladder cancer, uterine cancer, cervical cancer, breast cancer, ovarian cancer, vaginal cancer, testicular cancer, skin cancer, thyroid cancer, blood cancer, lymph node cancer, kidney cancer, liver cancer, bowel cancer, pancreatic cancer, brain cancer, central nervous system cancer, adrenal cancer, skin cancer or leukemia or lymphoma.

[0516] In one embodiment, a method of treating a condition characterized by dysregulation of the RAS / RAF / MEK / ERK pathway or a condition treatable by inhibiting ERK1 / 2 comprises administering to a subject in need thereof a composition comprising a therapeutically effective amount of at least one compound selected from the following:

[0517] (S)-1-(2-(benzo[d][1,3]dioxol-5-ylamino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;

[0518] 1-(2-(benzofuran-5-ylamino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;

[0519] 1-(2-(benzofuran-5-ylamino)-5-methylpyrimidin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-3-carboxamide;

[0520] N-(3-chloro-2-(hydroxymethyl)benzyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0521] (S)-N-(1-(3-chloro-4-fluorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0522] 1-(2-((2,3-dihydrobenzofuran-5-yl)amino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;

[0523] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0524] N-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0525] N-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-(((S)-tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0526] N-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-(((R)-tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0527] 1-(2-(chroman-6-ylamino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;

[0528] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-((4-fluoropyridin-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0529] N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(2-((4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0530] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0531] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((4-morpholinophenyl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0532] (S)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0533] (R)-N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0534] (S)-N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0535] (S)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0536] N-(2-hydroxy-1-(thiophen-2-yl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0537] (S)-N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(2-((3,3-difluorocyclobutyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0538] (S)-N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0539] (S)-N-(2-(((1H-pyrrol-2-yl)methyl)amino)-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0540] (S)-N-(3-chloro-2-(hydroxymethyl)benzyl)-1-(5-methyl-2-(tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0541] (S)-N-(1-(3-chlorophenyl)-2-(methylamino)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0542] (S)-N-(1-(3-chlorophenyl)-2-((2-hydroxyethyl)amino)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide; and

[0543] N-(3-chloro-5-fluoro-2-(hydroxymethyl)benzyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide,

[0544] or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof, such as Example 302, 349 or 275. For example, a method of treating a condition characterized by dysregulation of the RAS / RAF / MEK / ERK pathway or treatable by inhibiting ERK1 / 2 comprises administering to a subject in need thereof a composition of the present disclosure, the composition comprising (S)-N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide benzenesulfonate or (S)-N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide mandelate and a pharmaceutically acceptable carrier.

[0545] In one embodiment, the compositions disclosed herein can be used to treat conditions characterized by dysregulation of the RAS / RAF / MEK / ERK pathway or treatable by inhibiting ERK1 / 2. In one embodiment, the present disclosure provides the use of such compositions for the manufacture of a medicament for treating conditions characterized by dysregulation of the RAS / RAF / MEK / ERK pathway or treatable by inhibiting ERK1 / 2.

[0546] Method for preparing a compound

[0547] Methods for preparing compounds of formula (I-III), such as Example 302, 349 or 275, are set forth in the Examples and are summarized in the following Schemes. Those skilled in the art will recognize that the Schemes can be adjusted to produce other compounds of formula (I-III) and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates or stereoisomers.

[0548] In the following reactions described for preparing the compounds herein, it may be necessary to protect reactive functional groups such as hydroxyl, amino, imino, thio or carboxyl groups that are required in the final product to avoid their unnecessary participation in the reactions. Conventional protecting groups can be used according to standard protocols, see, e.g., Green et al., Protective Groups in Organic Chemistry, John Wiley & Sons, 1991.

[0549] The following Schemes outline the synthesis of compounds of formula (I-III), such as Example 302, 349 or 275. Examples following these Schemes are illustrated as representatives prepared in each Scheme and should not be construed as limiting the scope of the disclosure.

[0550] The following abbreviations are used and have the indicated definitions: MHz is megahertz (frequency), m is multiplet, t is triplet, d is doublet, s is singlet, br is broad, CDCl3 is deuterochloroform, calcd is calculated, min is minute, h is hour, g is gram, mmol is millimole, mL is milliliter, N is normality (concentration), M is molarity (concentration), μM is micromolar, ee is enantiomeric excess, °C is degrees Celsius, HPLC is high performance liquid chromatography, LC-MS is liquid chromatography - mass spectrometry, mp is melting point, NMR is nuclear magnetic resonance, TLC is thin layer chromatography, THF is tetrahydrofuran, MeOH is methanol, DCM is dichloromethane, DMF is N,N-dimethylformamide, DMSO is dimethyl sulfoxide, EtOH is ethanol, EtOAc is ethyl acetate, MeOH is methanol, RT is room temperature, HCl is hydrogen chloride or hydrochloric acid, TFA is trifluoroacetic acid, EtMgBr is ethylmagnesium bromide, n-BuLi is n-butyllithium, NaHCO3 is sodium bicarbonate, Na2CO3 is sodium carbonate, Na2SO4 is sodium sulfate, NMP is N-methyl-2-pyrrolidone, EDC or EDC·HCl is N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, TEA is triethylamine, DIPEA is diisopropylethylamine, HOBt is N-hydroxy-benzotriazole or N-hydroxy-benzotriazole hydrate, and T3P is propylphosphonic anhydride.

[0551] The present invention provides, but is not limited to, the following embodiments:

[0552] 1. A treatment method, which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) at regular or irregularly scheduled doses,

[0553]

[0554] or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof, wherein:

[0555] R 1 is aryl or 5- to 10-membered heteroaryl, which is unsubstituted or substituted with 1-3 substituents selected from the following: halogen, C 6-12 alkyl, CN, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, -C 1-6 alkyl-O-C 1-6 alkyl, -C 1-6 alkyl-NH-C 1-6 alkyl, -C 1-6 alkyl-N-(C 1-6 alkyl)2, -C 1-6 alkyl-NH-C 1-6 alkyl-OH, -C 1-6 alkyl-NH-C 1-6 alkyl-C 1-6 cycloalkyl, -C 3-10 alkyl-NH-C 1-6 alkyl-NH-C 1-6 alkyl-NH-C 1-6 alkyl, -C 1-6 alkyl-NH-C(O)-C 1-6 alkyl, -C 1-6 alkyl-O-C(O)-C 1-6 alkyl, -C 1-6 alkyl-NH-C 0-6 alkyl-(4- to 6-membered heterocyclic group) or -C 1-6 alkyl-NH-C 0-6 alkyl-(5- to 6-membered heteroaryl), wherein the C 1-6 alkyl, cycloalkyl, heterocyclic group and / or heteroaryl is unsubstituted or substituted with 1-3 substituents selected from the following: halogen, C 1-6 alkyl, NH2, hydroxyC 1-6 alkyl or aminoC 1-6 alkyl;

[0556] J is a linker group selected from -C(R 2 )(R 8 )(CH2)-;

[0557] R 2And R8 are each independently H, C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, -C 1-6 alkyl - O - C 1-6 alkyl, -C 1-6 alkyl - NH - C 1-6 alkyl, -C 1-6 alkyl - N-(C 1-6 alkyl)2, -C 1-6 alkyl - NH - C 1-6 alkyl - OH, -C 1-6 alkyl - NH - C 1-6 alkyl - C 3-10 cycloalkyl, -C 1-6 alkyl - NH - C 1-6 alkyl - NH - C 1-6 alkyl, -C 1-6 alkyl - NH - C(O)-C 1-6 alkyl, -C 1-6 alkyl - O - C(O)-C 1-6 alkyl, -C 1-6 alkyl - NH - C 0-6 alkyl-(4 - to 6 - membered heterocyclic group), -C(O)-NH2, -C(O)-NH - C 1-6 alkyl, -C(O)-N(C 1-6 alkyl)2 or -C 1-6 alkyl - NH - C 0-6 alkyl-(5 - to 6 - membered heteroaryl), wherein the C 1-6 alkyl, heterocyclic group or heteroaryl is unsubstituted or substituted by 1 - 3 substituents selected from: halogen, C 1-6 alkyl, cycloalkyl, NH2, hydroxy C 1-6 alkyl or amino C 1-6 alkyl;

[0558] Or R 2 、R 8 And having R 2 Attached to the C atoms of both R 8 Together to form a 3 - to 10 - membered cycloalkyl or 4 - to 10 - membered heterocyclic group ring, wherein the cycloalkyl or heterocyclic group is unsubstituted or substituted by 1 - 3 substituents selected from: hydroxy, halogen or C 1-6 alkyl;

[0559] n is 0 to 6;

[0560] R 3 is H or C 1-6 alkyl, wherein the C 1-6 alkyl is unsubstituted or substituted by 1 - 5 halogens;

[0561] M is a bond or NH;

[0562] X and Y are each independently CH, C-R 7 or N;

[0563] Z is CH or N,

[0564] R 5 is H, halogen, C 1-6 alkyl or O-C 1-6 alkyl, where the C 1-6 alkyl is unsubstituted or substituted by 1-5 halogens;

[0565] R 6 is H or C 1-6 alkyl, where the C 1-6 alkyl is unsubstituted or substituted by 1-5 halogens;

[0566] R 7 is C 1-6 alkyl, where the C 1-6 alkyl is unsubstituted or substituted by 1-5 halogens; and

[0567] R 4 is C 1-6 alkyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, -C 1-6 alkyl-phenyl, -C 1-6 alkyl-(5- to 6-membered heteroaryl), -C 1-6 alkyl-(4- to 6-membered heterocyclic group), 4- to 10-membered heterocyclic group, phenyl or 5- to 10-membered heteroaryl, where the alkyl, cycloalkyl, cycloalkenyl, phenyl, heteroaryl or heterocyclic group is unsubstituted or substituted by 1-3 substituents selected from: halogen, CN, -C(O)-NH2, -C(O)-NH-C 1-6 alkyl, -C(O)-N-(C 1-6 alkyl)2, -O-C 1-6 alkyl-NH2, -O-C 1-6 alkyl-NH-(C 1-6 alkyl), -O-C 1-6 alkyl-N(C 1-6 alkyl)2, 4- to 6-membered heterocyclic group, -C(O)-(4- to 6-membered heterocyclic group), -O-phenyl, -O-C 1-6 alkyl-(4- to 6-membered heterocyclic group), C 1-6 alkyl, C 2-6 alkynyl, hydroxyl, C 1-6 alkoxy or hydroxy C 1-6alkyl, and the heterocyclic group or heteroaryl group is unsubstituted or substituted with 1 - 3 substituents selected from the following: halogen, C 1-6 alkyl, -C(O)-C 1-6 alkyl or a 4 - to 6 - membered heterocyclic group,

[0568] wherein the therapeutically effective amount is from about 80 mg to about 350 mg.

[0569] 2. The method according to embodiment 1, wherein the compound is a compound of formula (II),

[0570]

[0571] or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof, wherein:

[0572] R 2 is C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, -C 1-6 alkyl - O - C 1-6 alkyl, -C 1-6 alkyl - NH - C 1-6 alkyl, -C 1-6 alkyl - N-(C 1-6 alkyl)2, -C 1-6 alkyl - NH - C 1-6 alkyl - OH, -C 1-6 alkyl - NH - C 1-6 alkyl - C 3-10 cycloalkyl, -C 1-6 alkyl - NH - C 1-6 alkyl - NH - C 1-6 alkyl, -C 1-6 alkyl - NH - C(O)-C 1-6 alkyl, -C 1-6 alkyl - O - C(O)-C 1-6 alkyl, -C 1-6 alkyl - NH - C 0-6 alkyl-(4 - to 6 - membered heterocyclic group), -C(O)-NH2, -C(O)-NH - C 1-6 alkyl, -C(O)-N(C 1-6 alkyl)2 or -C 1-6 alkyl - NH - C 0-6 alkyl-(5 - to 6 - membered heteroaryl), wherein the C 1-6 alkyl, heterocyclic group or heteroaryl group is unsubstituted or substituted with 1 - 3 substituents selected from the following: halogen, C 1-6 alkyl, cycloalkyl, NH2, hydroxy C 1-6 alkyl or amino C1-6 an alkyl group; and

[0573] R 8 is H or C 1-6 alkyl group;

[0574] Alternatively, R 2 , R 8 and the C atoms attaching R 2 to R 8 both are connected together to form a 3- to 10-membered cycloalkyl or 4- to 10-membered heterocyclic ring, wherein the cycloalkyl or heterocyclic ring is unsubstituted or substituted with 1-3 substituents selected from: hydroxyl, halogen or C 1-6 alkyl group; and

[0575] R 1 , R 3 , R 4 , R 5 , R 6 , n, M, X, Y and Z are as defined above.

[0576] 3. The method according to embodiment 1, wherein the therapeutically effective amount is about 120 mg to about 250 mg.

[0577] 4. The method according to embodiment 1, wherein the therapeutically effective amount is about 120 mg, about 180 mg or about 250 mg.

[0578] 5. The method according to embodiment 1, wherein the therapeutically effective amount is about 250 mg.

[0579] 6. The method according to embodiment 1, wherein the compound is administered to the subject about once a week on a regular schedule.

[0580] 7. The method according to embodiment 1, wherein the compound is administered to the subject about once a week on an irregular schedule.

[0581] 8. The method according to embodiment 1, wherein the compound is administered to the subject about twice a week on a regular schedule.

[0582] 9. The method according to embodiment 1, wherein the compound is administered to the subject about twice a week on an irregular schedule.

[0583] 10. The method according to embodiment 1, wherein the compound is administered to the subject about once every two weeks on a regular schedule.

[0584] 11. The method according to embodiment 1, wherein the compound is administered to the subject about once every two weeks on an irregular schedule.

[0585] 12. The method according to Embodiment 1, wherein:

[0586] R 1 is C6-C 12 aryl or a 5- or 6-membered heteroaryl, which is unsubstituted or substituted by 1-3 substituents selected from the following: halogen, C 1-6 alkyl, CN, hydroxy C 1-6 alkyl or amino C 1-6 alkyl, wherein the C 1-6 alkyl is unsubstituted or substituted by 1-3 substituents selected from halogen.

[0587] 13. The method according to Embodiment 1, wherein:

[0588] R 1 is phenyl, pyridyl, thienyl or thiazolyl, which is unsubstituted or substituted by 1-3 substituents selected from the following: halogen, C 1-6 alkyl, CN, hydroxy C 1-6 alkyl or amino C 1-6 alkyl, wherein the C 1-6 alkyl is unsubstituted or substituted by 1-3 substituents selected from halogen.

[0589] 14. The method according to Embodiment 1, wherein:

[0590] n is 0 or 1.

[0591] 15. The method according to Embodiment 1, wherein:

[0592] R 2 is C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, -C 1-6 alkyl-NH-C 1-6 alkyl, -C 1-6 alkyl-NH-C 0-6 alkyl-(4- to 6-membered heterocyclic group), -C(O)-NH2, -C(O)-NH-C 1-6 alkyl, -C(O)-N(C 1-6 alkyl)2, -C 1-6 alkyl-NH-C 1-6 alkyl-OH or -C 1-6 alkyl-NH-C 0-6 alkyl-(5- to 6-membered heteroaryl), wherein the C 1-6 alkyl, heterocyclic group or heteroaryl is unsubstituted or substituted by 1-3 substituents selected from the following: halogen, C 1-6 alkyl, NH2, hydroxy C 1-6 alkyl or amino C 1-6alkyl, and

[0593] R 8 is H.

[0594] 16. The method according to embodiment 1, wherein:

[0595] R 2 is CH3, CH2OH, CH2NH2, -CH2NH(CH3), -CH2NHCH2CH2OH, -CH2NH-(tetrahydro-2H-pyran) or -CH2NH-CH2-(1H-pyrrole), and

[0596] R 8 is H.

[0597] 17. The method according to embodiment 1, wherein:

[0598] R 3 is H or CH3.

[0599] 18. The method according to embodiment 1, wherein:

[0600] M is a bond.

[0601] 19. The method according to embodiment 1, wherein:

[0602] X and Y are each independently CH, C-R 7 or N; and

[0603] R 7 is CH3.

[0604] 20. The method according to embodiment 1, wherein:

[0605] Z is N.

[0606] 21. The method according to embodiment 1, wherein:

[0607] R 5 is H, halogen or C 1-6 alkyl.

[0608] 22. The method according to embodiment 1, wherein:

[0609] R 6 is H.

[0610] 23. The method according to embodiment 1, wherein:

[0611] R 4 is

[0612]

[0613] It may be unsubstituted or substituted by 1 - 3 substituents selected from the following: halogen or C 1-6 alkoxy group.

[0614] 24. The method according to Embodiment 1, wherein:

[0615] R 1 is phenyl, pyridyl, thienyl or thiazolyl, which is unsubstituted or substituted by 1 - 3 substituents selected from the following: halogen, C 1-6 alkyl, CN, hydroxy C 1-6 alkyl or amino C 1-6 alkyl, wherein the C 1-6 alkyl is unsubstituted or substituted by 1 - 3 substituents selected from halogen;

[0616] n is 0 or 1;

[0617] R 2 is C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, -C 1-6 alkyl - O - C 1-6 alkyl, -C 1-6 alkyl - NH - C 1-6 alkyl, -C 1-6 alkyl - N - (C 1-6 alkyl)2, -C 1-6 alkyl - NH - C 1-6 alkyl - OH, -C 1-6 alkyl - NH - C 1-6 alkyl - C 3-10 cycloalkyl, -C 1-6 alkyl - NH - C 1-6 alkyl - NH - C 1-6 alkyl, -C 1-6 alkyl - NH - C(O) - C 1-6 alkyl, -C 1-6 alkyl - O - C(O) - C 1-6 alkyl, -C 1-6 alkyl - NH - C 0-6 alkyl - (tetrahydro - 2H - pyran), -C(O) - NH2, -C(O) - NH - C 1-6 alkyl, -C(O) - N(C 1-6 alkyl)2 or -C 1-6 alkyl - NH - C 0-6 alkyl - (1H - pyrrole), wherein the C 1-6 alkyl is unsubstituted or substituted by 1 - 3 substituents selected from the following: halogen, C 1-6 alkyl, NH2, hydroxy C 1-6 alkyl or amino C1-6 alkyl; and

[0618] R 8 is H or C 1-6 alkyl;

[0619] Alternatively, R 2 , R 8 and the C atoms attaching R 2 to R 8 both are linked together to form a cyclobutyl group which is unsubstituted or substituted by a hydroxyl group;

[0620] R 3 is H or C 1-6 alkyl;

[0621] M is a bond or NH;

[0622] X and Y are each independently CH, C-R 7 or N;

[0623] Z is CH or N,

[0624] R 5 is H, halogen, C 1-6 alkyl or OC 1-6 alkyl, wherein the C 1-6 alkyl is unsubstituted or substituted by 1 - 5 halogens;

[0625] R 6 is H;

[0626] R 7 is C 1-6 alkyl; and

[0627] R 4 is

[0628]

[0629]

[0630] wherein each L is independently selected from halogen, CN, C 2-6 alkynyl, C 1-6 alkoxy, -C(O)NHC 1-6 alkyl, -C(O)NH(C 1-6 alkyl)2, -O-C 1-6 alkyl-NHC 1-6 alkyl or -O-C 1-6 alkyl-N(C 1-6 alkyl)2, and x is 0, 1, 2 or 3.

[0631] 25. The method according to embodiment 1, wherein:

[0632] R 1 is phenyl, pyridyl, thienyl or thiazolyl, which is unsubstituted or substituted by 1-3 substituents selected from the following: halogen, C 1-6 alkyl, CN, hydroxy C 1-6 alkyl or amino C 1-6 alkyl, wherein the C 1-6 alkyl is unsubstituted or substituted by 1-3 substituents selected from halogen;

[0633] n is 0;

[0634] R 2 is C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, -C 1-6 alkyl-NH-C 0-6 alkyl-(4- to 6-membered heterocyclic group), -C 1-6 alkyl-NH-C 1-6 alkyl, -C 1-6 alkyl-NH-C 1-6 alkyl-OH, -C(O)-NH2, -C(O)-NH-C 1-6 alkyl, -C(O)-N(C 1-6 alkyl)2 or -C 1-6 alkyl-NH-C 0-6 alkyl-(5- to 6-membered heteroaryl), wherein the C 1-6 alkyl is unsubstituted or substituted by 1-3 substituents selected from the following: halogen, C 1-6 alkyl, NH2, hydroxy C 1-6 alkyl or amino C 1-6 alkyl;

[0635] R 8 is H;

[0636] R 3 is H;

[0637] M is a bond;

[0638] X is CH;

[0639] Y is N;

[0640] Z is N;

[0641] R 5 is H, halogen or C 1-6 alkyl;

[0642] R 6 is H; and

[0643] R 4 is

[0644]

[0645] It may be unsubstituted or substituted with 1-3 substituents selected from: halogen or C 1-6 alkoxy.

[0646] 26. The method according to embodiment 1, wherein:

[0647] R 1 is phenyl or thienyl, which is unsubstituted or substituted with 1-3 substituents selected from: halogen, C 1-6 alkyl, CN, hydroxy C 1-6 alkyl or amino C 1-6 alkyl, wherein the C 1-6 alkyl is unsubstituted or substituted with 1-3 substituents selected from halogen;

[0648] n is 0;

[0649] R 2 is C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, -C 1-6 alkyl-NH-C 0-6 alkyl-(4- to 6-membered heterocyclic group), -C 1-6 alkyl-NH-C 1-6 alkyl, -C 1-6 alkyl-NH-C 1-6 alkyl-OH, -C(O)-NH2, -C(O)-NH-C 1-6 alkyl, -C(O)-N(C 1-6 alkyl)2 or -C 1-6 alkyl-NH-C 0-6 alkyl-(5- to 6-membered heteroaryl), wherein the C 1-6 alkyl is unsubstituted or substituted with 1-3 substituents selected from: halogen, C 1-6 alkyl, NH2, hydroxy C 1-6 alkyl or amino C 1-6 alkyl;

[0650] R 8 is H;

[0651] R 3 is H;

[0652] M is a bond;

[0653] X is CH;

[0654] Y is N;

[0655] Z is N;

[0656] R 5 is CH3;

[0657] R 6 is H; and

[0658] R 4 is

[0659]

[0660] 27. The method according to embodiment 1, wherein:

[0661] R 1 is phenyl, which is unsubstituted or substituted with 1 - 3 substituents selected from: F or Cl;

[0662] n is 0;

[0663] R 2 is CH2OH, CH2NH2, -CH2NH(CH3), -CH2NHCH2CH2OH,

[0664] -CH2NH-(tetrahydro-2H-pyran) or -CH2NH-CH2-(1H-pyrrole);

[0665] R 8 is H;

[0666] R 3 is H;

[0667] M is a bond;

[0668] X is CH;

[0669] Y is N;

[0670] Z is N;

[0671] R 5 is CH3;

[0672] R 6 is H; and

[0673] R 4 is

[0674]

[0675] 28. The method according to embodiment 1, wherein: the compound is a substantially pure stereoisomer.

[0676] 29. The method according to embodiment 1, wherein the compound is a hydrochloride, p-toluenesulfonate, benzenesulfonate, mandelate or trifluoroacetate.

[0677] 30. The method according to Embodiment 1, wherein the compound is:

[0678] (S)-1-(1-(3-chlorophenyl)-2-hydroxyethyl)-3-(1-(2-((2-chlorophenyl)amino)pyrimidin-4-yl)-1H-pyrazol-4-yl)urea;

[0679] (S)-1-(1-(3-chlorophenyl)-2-hydroxyethyl)-3-(1-(2-((2-chlorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrazol-4-yl)urea;

[0680] (S)-1-(1-(3-chlorophenyl)-2-hydroxyethyl)-3-(1-(2-(cyclopropylamino)-5-methylpyrimidin-4-yl)-1H-pyrazol-4-yl)urea;

[0681] (R)-1-(1-(2-((2-chlorophenyl)amino)pyrimidin-4-yl)-1H-pyrazol-4-yl)-3-(2-hydroxy-1-phenylethyl)urea;

[0682] 1-(1-(2-((2-chlorophenyl)amino)pyrimidin-4-yl)-1H-pyrazol-4-yl)-3-(1-(3-chlorophenyl)ethyl)urea;

[0683] (S)-1-(1-(3-chlorophenyl)-2-hydroxyethyl)-3-(1-(2-(cyclopropylamino)pyrimidin-4-yl)-1H-pyrazol-4-yl)urea;

[0684] (S)-1-(1-(2-((2-chlorophenyl)amino)pyrimidin-4-yl)-1H-pyrazol-4-yl)-3-(2-hydroxy-1-phenylethyl)urea;

[0685] (R)-1-(1-(2-(2-chlorophenyl)amino)pyrimidin-4-yl)-1H-pyrazol-4-yl)-3-(1-(3-chlorophenyl)ethyl)urea;

[0686] (S)-1-(1-(3-chlorophenyl)-2-hydroxyethyl)-3-(1-(2-((2-chlorophenyl)amino)pyrimidin-4-yl)-5-methyl-1H-pyrazol-4-yl)urea;

[0687] (S)-1-(1-(3-chlorophenyl)-2-hydroxyethyl)-3-(1-(2-(phenylamino)pyrimidin-4-yl)-1H-pyrazol-4-yl)urea;

[0688] 1-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-3-(1-(2-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)pyrimidin-4-yl)-1H-pyrazol-4-yl)urea;

[0689] 1 - ((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-3-(1-(2-((trans-4-hydroxycyclohexyl)amino)pyrimidin-4-yl)-1H-pyrazol-4-yl)urea;

[0690] (S)-1-(1-(2-((4-(4-acetylpiperazin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)-1H-pyrazol-4-yl)-3-(1-(3-chlorophenyl)-2-hydroxyethyl)urea;

[0691] 1-(1-(3-chlorophenyl)-2-hydroxyethyl)-3-(1-(2-(cyclopropylamino)pyrimidin-4-yl)-1H-pyrazol-4-yl)urea;

[0692] (S)-3-(1-(2-(cyclopropylamino)pyrimidin-4-yl)-1H-pyrazol-4-yl)-1-(2-hydroxy-1-phenylethyl)-1-methylurea;

[0693] (S)-1-(1-(2-((2-chloro-4-fluorophenyl)amino)pyrimidin-4-yl)-1H-pyrazol-4-yl)-3-(1-(3-chlorophenyl)-2-hydroxyethyl)urea;

[0694] (S)-1-(1-(2-(benzo[d][1,3]dioxol-5-ylamino)pyrimidin-4-yl)-1H-pyrazol-4-yl)-3-(1-(3-chlorophenyl)-2-hydroxyethyl)urea;

[0695] (S)-1-(1-(3-chlorophenyl)-2-hydroxyethyl)-3-(1-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-1H-pyrazol-4-yl)urea;

[0696] (S)-1-(1-(3-chlorophenyl)-2-hydroxyethyl)-3-(1-(5-methyl-2-(pyridin-3-ylamino)pyrimidin-4-yl)-1H-pyrazol-4-yl)urea;

[0697] (S)-1-(1-(3-chlorophenyl)-2-hydroxyethyl)-3-(1-(2-(pyridin-3-ylamino)pyrimidin-4-yl)-1H-pyrazol-4-yl)urea;

[0698] (S)-1-(1-(2-((2-chloro-4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrazol-4-yl)-3-(1-(3-chlorophenyl)-2-hydroxyethyl)urea;

[0699] (S)-1-(1-(3-chloro-4-fluorophenyl)-2-hydroxyethyl)-3-(1-(2-((2-chloro-4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrazol-4-yl)urea;

[0700] (S)-1-(1-(3-chloro-4-fluorophenyl)-2-hydroxyethyl)-3-(1-(2-((2-chlorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrazol-4-yl)urea;

[0701] 1-(1-(3-chlorophenyl)-2-hydroxyethyl)-3-(1-(2-(cyclopropylamino)-5-methylpyrimidin-4-yl)-1H-pyrazol-4-yl)urea;

[0702] (S)-1-(2-((2-chloro-4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-3-carboxamide;

[0703] (S)-1-(1-(3-chlorophenyl)-2-hydroxyethyl)-3-(1-(2-(cyclopropylamino)-5-fluoropyrimidin-4-yl)-1H-pyrazol-4-yl)urea;

[0704] 1-(2-((2-chloro-4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-3-carboxamide;

[0705] 1-(2-((2-chloro-4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;

[0706] 1-(1-(3-chlorophenyl)-2-hydroxyethyl)-3-(1-(2-(phenylamino)pyridin-4-yl)-1H-pyrazol-4-yl)urea;

[0707] (S)-1-(1-(3-chlorophenyl)-2-hydroxyethyl)-3-(1-(2-(phenylamino)pyridin-4-yl)-1H-pyrazol-4-yl)urea;

[0708] (S)-1-(2-((2-chloro-4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrazole-4-carboxamide;

[0709] 1-(1-(2-((2-chloro-4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrazol-4-yl)-3-(1-(3-chlorophenyl)-2-hydroxyethyl)urea;

[0710] 1-(1-(2-(Benzo[d][1,3]dioxol-5-ylamino)-5-methylpyrimidin-4-yl)-1H-pyrazol-4-yl)-3-(1-(3-chlorophenyl)-2-hydroxyethyl)urea;

[0711] (S)-1-(1-(3-chlorophenyl)-2-hydroxyethyl)-3-(1-(2-((3-ethynylphenyl)amino)pyrimidin-4-yl)-1H-pyrazol-4-yl)urea;

[0712] (S)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-(cyclopropylamino)-5-methylpyrimidin-4-yl)-1H-pyrazole-4-carboxamide;

[0713] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-(cyclopropylamino)-5-methylpyrimidin-4-yl)-1H-pyrazole-4-carboxamide;

[0714] 1-(2-(Benzo[d][1,3]dioxol-5-ylamino)-5-methylpyrimidin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrazole-4-carboxamide;

[0715] 1-(2-(Benzo[d][1,3]dioxol-5-ylamino)-5-methylpyrimidin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-3-carboxamide;

[0716] 1-(1-(3-chlorophenyl)-2-hydroxyethyl)-3-(1-(2-((2-chlorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrazol-4-yl)urea;

[0717] (S)-1-(1-(2-(Benzo[d][1,3]dioxol-5-ylamino)-5-methylpyrimidin-4-yl)-1H-pyrazol-4-yl)-3-(1-(3-chlorophenyl)-2-hydroxyethyl)urea;

[0718] 1-(2-((2-chloro-4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrazole-4-carboxamide;

[0719] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-(phenylamino)pyridin-4-yl)-1H-pyrrole-3-carboxamide;

[0720] 1-(2-(Benzo[d][1,3]dioxol-5-ylamino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;

[0721] (S)-1-(2-(Benzo[d][1,3]dioxol-5-ylamino)-5-methylpyrimidin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-imidazole-4-carboxamide;

[0722] (R)-1-(1-(3-chlorophenyl)-2-hydroxyethyl)-3-(1-(2-(phenylamino)pyridin-4-yl)-1H-pyrazol-4-yl)urea;

[0723] (S)-1-(2-(Benzo[d][1,3]dioxol-5-ylamino)-5-methylpyrimidin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrazole-4-carboxamide;

[0724] (R)-1-(1-(2-(Benzo[d][1,3]dioxol-5-ylamino)-5-methylpyrimidin-4-yl)-1H-pyrazol-4-yl)-3-(1-(3-chlorophenyl)-2-hydroxyethyl)urea;

[0725] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-(phenylamino)pyrimidin-4-yl)-1H-pyrazole-4-carboxamide;

[0726] (S)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-(phenylamino)pyrimidin-4-yl)-1H-pyrazole-4-carboxamide;

[0727] N-(2-amino-1-phenylethyl)-1-(2-((2-chloro-4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrazole-4-carboxamide;

[0728] (S)-1-(1-(2-(Benzo[d][1,3]dioxol-5-ylamino)-5-methylpyrimidin-4-yl)-1H-pyrazol-4-yl)-3-(2-hydroxy-1-phenylethyl)urea;

[0729] (R)-1-(1-(2-((2-chloro-4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrazol-4-yl)-3-(1-(3-chlorophenyl)-2-hydroxyethyl)urea;

[0730] (S)-1-(2-((2-chloro-4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-3-carboxamide;

[0731] 1-(2-(Benzo[d][1,3]dioxol-5-ylamino)-5-methylpyrimidin-4-yl)-N-(1-(3,5-dichlorophenyl)-2-hydroxyethyl)-1H-pyrrole-3-carboxamide; (S)-1-(2-(Benzo[d][1,3]dioxol-5-ylamino)-5-methylpyrimidin-4-yl)-N-(1-hydroxy-3-phenylpropan-2-yl)-1H-pyrrole-3-carboxamide;

[0732] (S)-1-(2-(Benzo[d][1,3]dioxol-5-ylamino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide; (R)-1-(1-(3-chlorophenyl)-2-hydroxyethyl)-3-(1-(2-((2-chlorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrazol-4-yl)urea;

[0733] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0734] 1-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;

[0735] (S)-1-(2-(Benzo[d][1,3]dioxol-5-ylamino)-5-methylpyrimidin-4-yl)-N-(2-methoxy-1-phenylethyl)-1H-pyrrole-3-carboxamide; 1-(2-(Benzofuran-5-ylamino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;

[0736] 1-(2-(Benzo[d][1,3]dioxol-5-ylamino)-5-fluoropyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;

[0737] 1-(2-((2-chlorophenyl)amino)-5-fluoropyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide; 1-(2-(Benzofuran-5-ylamino)-5-methylpyrimidin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-3-carboxamide;

[0738] (S)-N-(1-(3-chloro-4-fluorophenyl)-2-hydroxyethyl)-1-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0739] 1-(2-(benzo[d][1,3]dioxol-5-ylamino)-5-methylpyrimidin-4-yl)-N-(1-(3-chloro-2-fluorophenyl)-2-hydroxyethyl)-1H-pyrrole-3-carboxamide;

[0740] N-(2-hydroxy-1-phenylethyl)-1-(2-(phenylamino)pyridin-4-yl)-1H-pyrrole-3-carboxamide;

[0741] (S)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-(phenylamino)pyridin-4-yl)-1H-imidazole-4-carboxamide;

[0742] N-(2-hydroxy-1-phenylethyl)-1-(5-methyl-2-((4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0743] N-(2-hydroxy-1-phenylethyl)-1-(5-methyl-2-(phenylamino)pyridin-4-yl)-1H-pyrrole-3-carboxamide;

[0744] N-(2-hydroxy-1-phenylethyl)-1-(2-(((S)-1-hydroxybutan-2-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0745] 1-(2-(benzo[d][1,3]dioxol-5-ylamino)pyridin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;

[0746] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-(phenylamino)pyridin-4-yl)-1H-imidazole-4-carboxamide;

[0747] 1-(2-((2-chloro-4-fluorophenyl)amino)-5-methylpyridin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;

[0748] 1-(2-(benzofuran-5-ylamino)-5-methylpyridin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;

[0749] 1-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyridin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;

[0750] N-(2-hydroxy-1-phenylethyl)-1-(5-methyl-2-(pyridin-3-ylamino)pyridin-4-yl)-1H-pyrrole-3-carboxamide;

[0751] 1-(2-((2-chloro-4-fluorophenyl)amino)pyridin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;

[0752] N-(2-hydroxy-1-phenylethyl)-1-(5-methyl-2-((4-(piperazin-1-yl)phenyl)amino)pyridin-4-yl)-1H-pyrrole-3-carboxamide;

[0753] 1-(2-((4-fluorophenyl)amino)pyridin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;

[0754] 1-(2-((2-chloro-4-fluorophenyl)amino)-5-methylpyridin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-imidazole-4-carboxamide;

[0755] 1-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyridin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-imidazole-4-carboxamide;

[0756] (S)-1-(2-(benzo[d][1,3]dioxol-5-ylamino)-5-methylpyrimidin-4-yl)-N-(1-(3-chloro-4-fluorophenyl)-2-hydroxyethyl)-1H-pyrrole-3-carboxamide;

[0757] 1-(2-(benzo[d][1,3]dioxol-5-ylamino)-5-methylpyridin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-imidazole-4-carboxamide;

[0758] N-(2-hydroxy-1-phenylethyl)-1-(5-methyl-2-(phenylamino)pyridin-4-yl)-1H-imidazole-4-carboxamide;

[0759] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyridin-4-yl)-1H-imidazole-4-carboxamide;

[0760] 1-(2-((2-chloro-4-fluorophenyl)amino)-5-methylpyridin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-3-carboxamide;

[0761] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyridin-4-yl)-1H-pyrrole-3-carboxamide;

[0762] 1-(2-((2,2-dimethylbenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;

[0763] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-((2,2-dimethylbenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0764] (R)-1-(2-((2-chloro-4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-N-(2-(dimethylamino)-1-phenylethyl)-1H-pyrrole-3-carboxamide;

[0765] N-(2-amino-1-phenylethyl)-1-(2-((4-fluorophenyl)amino)-5-methylpyridin-4-yl)-1H-pyrrole-3-carboxamide;

[0766] N-(1-amino-3-phenylpropan-2-yl)-1-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyridin-4-yl)-1H-imidazole-4-carboxamide;

[0767] N-(2-hydroxy-1-phenylethyl)-1-(2-(((S)-1-hydroxybutan-2-yl)amino)-5-methylpyridin-4-yl)-1H-pyrrole-3-carboxamide;

[0768] 1-(2-((6-chlorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyrimidin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-3-carboxamide;

[0769] 1-(2-(benzo[d][1,3]dioxol-5-ylamino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-(pyridin-3-yl)ethyl)-1H-pyrrole-3-carboxamide;

[0770] 1-(2-(Benzo[d]oxazol-5-ylamino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;

[0771] N-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-(((R)-1-hydroxybutan-2-yl)amino)pyridin-4-yl)-1H-imidazole-4-carboxamide;

[0772] 1-(5-chloro-2-(phenylamino)pyridin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-imidazole-4-carboxamide;

[0773] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-((4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-4-methyl-1H-pyrrole-3-carboxamide;

[0774] 1-(2-((4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-4-methyl-1H-pyrrole-3-carboxamide;

[0775] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-(((S)-1-hydroxybutan-2-yl)amino)pyridin-4-yl)-1H-pyrrole-3-carboxamide;

[0776] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-((4-fluorophenyl)amino)pyrimidin-4-yl)-4-methyl-1H-pyrrole-3-carboxamide;

[0777] 1-(2-((2-chloro-4-fluorophenyl)amino)pyridin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-3-carboxamide;

[0778] (S)-1-(2-((2-chloro-4-fluorophenyl)amino)pyridin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-3-carboxamide;

[0779] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-((4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0780] 1-(2-((4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;

[0781] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-(cyclopropylamino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0782] (S)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-(cyclopropylamino)pyridin-4-yl)-1H-imidazole-4-carboxamide;

[0783] N-(2-hydroxy-1-phenylethyl)-1-(5-methyl-2-((1-phenylethyl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0784] 1-(2-((4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-imidazole-4-carboxamide;

[0785] N-(1-amino-3-phenylpropan-2-yl)-1-(2-((4-fluorophenyl)amino)pyridin-4-yl)-1H-pyrrole-3-carboxamide;

[0786] N-(2-hydroxy-1-phenylethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0787] N-(2-hydroxy-1-phenylethyl)-1-(5-methyl-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0788] 1-(2-((2-chloro-4-fluorophenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;

[0789] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0790] 1-(5-chloro-2-(phenylamino)pyridin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-3-carboxamide;

[0791] (S)-N-(1-(3-chloro-4-fluorophenyl)-2-hydroxyethyl)-1-(2-((4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0792] (S)-N-(1-(3-chloro-4-fluorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0793] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-((1-methoxybutan-2-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0794] N-(2-hydroxy-1-phenylethyl)-1-(5-methyl-2-((tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0795] 1-(2-((2-chloro-4-fluorophenyl)amino)-5-methoxypyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;

[0796] 1-(2-(ethylamino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;

[0797] 1-(2-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;

[0798] 1-(2-(benzofuran-5-ylamino)-5-methylpyrimidin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-imidazole-4-carboxamide;

[0799] N-((S)-1-(3-chloro-4-fluorophenyl)-2-hydroxyethyl)-1-(2-(((S)-1-hydroxybutan-2-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0800] N-(1-amino-3-phenylpropan-2-yl)-1-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyridin-4-yl)-1H-1,2,3-triazole-4-carboxamide;

[0801] N-(2-acetamido-1-phenylethyl)-1-(2-((4-fluorophenyl)amino)-5-methylpyridin-4-yl)-1H-pyrrole-3-carboxamide;

[0802] N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0803] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-((2,3-dihydrobenzofuran-5-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0804] 1-(2-((2,3-dihydrobenzofuran-5-yl)amino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;

[0805] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0806] 1-(2-((1H-indazol-5-yl)amino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;

[0807] N-(2-hydroxy-1-phenylethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0808] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-((4-fluoro-2-methoxyphenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0809] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-((3-fluoro-2-methoxyphenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0810] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-(pyrrolidin-3-ylamino)pyridin-4-yl)-1H-pyrrole-3-carboxamide;

[0811] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-(((S)-1-hydroxybutan-2-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0812] 1-(2-((1,3-dihydroxypropan-2-yl)amino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;

[0813] N-(2-hydroxy-1-phenylethyl)-1-(2-((4-methoxy-3-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0814] N-(2-hydroxy-1-phenylethyl)-1-(5-methyl-2-(pyridin-2-ylamino)pyridin-4-yl)-1H-pyrrole-3-carboxamide;

[0815] 2-(1-(2-((2-chloro-4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamido)-2-phenylethyl 2-amin-4-methylpentanoate;

[0816] N-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0817] N-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0818] 1-(2-((4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-2-methyl-1H-imidazole-4-carboxamide;

[0819] 1-(2-((4-fluoro-3-methoxyphenyl)amino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;

[0820] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-((4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0821] N-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0822] N-((S)-1-(3-chloro-4-fluorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0823] N-(2-Acetamido-1-(3-chlorophenyl)ethyl)-1-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0824] N-(2-Amino-1-(3-chlorophenyl)ethyl)-1-(2-((4-fluorophenyl)amino)-5-methylpyridin-4-yl)-1H-pyrrole-3-carboxamide;

[0825] N-(1-(3-Chlorophenyl)-2-hydroxyethyl)-1-(2-((2,2-difluorobenzo[d][1,3]dioxol-4-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0826] N-((S)-1-(3-Chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-(((S)-tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0827] N-((S)-1-(3-Chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-(((R)-tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0828] N-(1-(3-Chlorophenyl)-2-hydroxyethyl)-1-(2-((2,3-dihydrobenzofuran-5-yl)amino)pyridin-4-yl)-1H-imidazole-4-carboxamide;

[0829] N-(2-Amino-1-(3-chloro-4-fluorophenyl)ethyl)-1-(2-((4-fluorophenyl)amino)-5-methylpyridin-4-yl)-1H-pyrrole-3-carboxamide;

[0830] N-(1-(3-Chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydrofuran-3-yl)amino)pyridin-4-yl)-1H-pyrrole-3-carboxamide;

[0831] 1-(2-((2-Chloro-4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-imidazole-4-carboxamide;

[0832] N-(1-(3-Chlorophenyl)-2-hydroxyethyl)-1-(2-(((R)-1-hydroxybutan-2-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0833] 1-(5-chloro-2-(((R)-1-hydroxybutan-2-yl)amino)pyridin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-imidazole-4-carboxamide;

[0834] N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(2-((2-chloro-4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0835] N-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-((tetrahydrofuran-3-yl)amino)pyridin-4-yl)-1H-imidazole-4-carboxamide;

[0836] N-(1-(3-chloro-4-fluorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-(pyridin-3-ylamino)pyridin-4-yl)-1H-pyrrole-3-carboxamide;

[0837] 1-(2-(benzo[d][1,3]dioxol-5-ylamino)-5-methylpyrimidin-4-yl)-N-(1-(4-fluorophenyl)-2-hydroxyethyl)-1H-pyrrole-3-carboxamide;

[0838] 1-(2-(chroman-6-ylamino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;

[0839] N-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-(pyrrolidin-3-ylamino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0840] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-((4-fluoro-3-morpholinophenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0841] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0842] N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(2-((4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0843] N-(2-hydroxy-1-phenylethyl)-1-(5-methyl-2-((4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0844] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-((4-fluoro-3-(4-methylpiperazin-1-carbonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0845] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-(phenylamino)pyridin-4-yl)-1H-imidazole-4-carboxamide;

[0846] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-((5-fluoro-2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0847] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((3-methyl-4-(piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0848] (S)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-4-methyl-1-(2-(phenylamino)pyridin-4-yl)-1H-pyrrole-3-carboxamide;

[0849] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-((3-(3-(dimethylamino)propoxy)-4-methoxyphenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0850] 1-(2-((2,3-dihydrobenzofuran-6-yl)amino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;

[0851] 1-(2-(chroman-7-ylamino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;

[0852] N-(2-hydroxy-1-(m-tolyl)ethyl)-1-(5-methyl-2-(((S)-tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0853] N-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-((tetrahydrofuran-3-yl)amino)pyridin-4-yl)-1H-pyrrole-3-carboxamide;

[0854] N-(2-Hydroxy-1-phenylethyl)-1-(2-((tetrahydrofuran-3-yl)amino)pyridin-4-yl)-1H-pyrrole-3-carboxamide;

[0855] N-((S)-1-(3-Chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-(((tetrahydrofuran-2-yl)methyl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0856] N-(2-Amino-1-phenylethyl)-1-(2-((4-fluorophenyl)amino)-5-methylpyridin-4-yl)-1H-imidazole-4-carboxamide;

[0857] N-((S)-1-(3-Chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-(((S)-tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0858] N-(1-(3-Chloro-4-fluorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((pyridin-3-ylmethyl)amino)pyridin-4-yl)-1H-pyrrole-3-carboxamide;

[0859] N-(1-(3-Chlorophenyl)-2-hydroxyethyl)-1-(2-((3-(dimethylcarbamoyl)-4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0860] N-(1-(3-Chlorophenyl)-2-hydroxyethyl)-1-(2-(cyclohexylamino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0861] N-(1-(3-Chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((4-(methylcarbamoyl)phenyl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0862] 1-(2-(sec-Butylamino)-5-methylpyrimidin-4-yl)-N-((S)-1-(3-chloro-4-fluorophenyl)-2-hydroxyethyl)-1H-pyrrole-3-carboxamide;

[0863] N-(1-(3-Chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((2-oxoindolin-5-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0864] N-(1-(3-Chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((1-methylpiperidin-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0865] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0866] N-(1-(3-chloro-4-fluorophenyl)-2-hydroxyethyl)-1-(2-((2-hydroxycyclohexyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0867] N-(1-(3-chloro-4-fluorophenyl)-2-hydroxyethyl)-1-(2-((1-(hydroxymethyl)cyclopropyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0868] N-(1-(4-fluorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-(((S)-tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0869] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((4-morpholinophenyl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0870] N-(2-amino-1-phenylethyl)-1-(2-((4-fluorophenyl)amino)pyridin-4-yl)-1H-pyrrole-3-carboxamide;

[0871] N-((S)-2-hydroxy-1-(6-methylpyridin-2-yl)ethyl)-1-(5-methyl-2-(((S)-tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0872] N-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((1-methylpyrrolidin-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0873] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide hydrochloride;

[0874] (S)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0875] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-N-methyl-1-(5-methyl-2-(((S)-tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0876] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-((4-fluoro-3-(piperazin-1-yl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0877] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-(piperidin-4-ylamino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0878] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((4-(piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0879] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-((3-fluoro-4-(piperidin-4-yl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0880] (R)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0881] N-((R)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-(((S)-1-hydroxybutan-2-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0882] N-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-(((S)-1-hydroxybutan-2-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0883] N-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-(((S)-1-hydroxybutan-2-yl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0884] N-(2-amino-1-phenylethyl)-1-(2-((4-fluorophenyl)amino)pyridin-4-yl)-1H-imidazole-4-carboxamide;

[0885] 1-(2-((4-Fluorophenyl)amino)-5-methylpyridin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-imidazole-4-carboxamide;

[0886] N-(1-(3-Chlorophenyl)-2-hydroxyethyl)-1-(2-((4-fluoro-3-morpholinophenyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0887] N-(2-Amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0888] (S)-N-(2-Amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0889] (R)-N-(2-Amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0890] N-(1-(3-Chlorophenyl)-2-hydroxyethyl)-1-(2-(cyclohexylamino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0891] N-(2-Amino-1-phenylethyl)-1-(2-((4-fluorophenyl)amino)-5-methylpyridin-4-yl)-1H-imidazole-4-carboxamide, enantiomer #1;

[0892] N-(2-Amino-1-phenylethyl)-1-(2-((4-fluorophenyl)amino)-5-methylpyridin-4-yl)-1H-imidazole-4-carboxamide, enantiomer #2;

[0893] (S)-N-(1-(3-Chlorophenyl)-2-hydroxyethyl)-1-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0894] N-(2-Amino-1-(4-fluorophenyl)ethyl)-1-(2-((4-fluorophenyl)amino)-5-methylpyridin-4-yl)-1H-imidazole-4-carboxamide;

[0895] N-(2-Amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((4-phenoxyphenyl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0896] N-(2-Amino-1-(3-chlorophenyl)ethyl)-1-(2-((2-chloro-4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0897] N-(2-Hydroxy-1-(thiophen-2-yl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0898] N-(2-Hydroxy-1-(thiophen-3-yl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0899] N-(2-Amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0900] N-(2-Amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0901] N-(2-Hydroxy-1-(3-(trifluoromethyl)phenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0902] N-(2-Hydroxy-1-(m-tolyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0903] 1-{5-Methyl-2-[1-(tetrahydro-pyran-4-yl)-ethylamino]-pyrimidin-4-yl}-1H-pyrrole-3-carboxylic acid [(S)-1-(3-chloro-phenyl)-2-hydroxy-ethyl]-amide;

[0904] (S)-N-(1-(3-Chlorophenyl)-2-hydroxyethyl)-1-(2-((4,4-difluorocyclohexyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0905] (S)-1-(2-((2-Chloro-4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-imidazole-4-carboxamide;

[0906] N-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-(((1r,4S)-4-hydroxycyclohexyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0907] N-((1s,3s)-1-(3-chlorophenyl)-3-hydroxycyclobutyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0908] N-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-((1,1-dioxotetrahydrothiophen-3-yl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0909] N-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-(chroman-4-ylamino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0910] (S)-N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(2-((4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0911] (R)-N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(2-((4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0912] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((4-phenoxyphenyl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0913] N-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((2-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0914] N-(1-(3-chlorophenyl)-2-hydroxypropyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide (isomer #2);

[0915] N-(1-(3-chlorophenyl)-2-hydroxypropyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide (isomer #2);

[0916] N-(2-Amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0917] N-((S)-2-Amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-(((S)-tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0918] N-(2-Amino-1-(3-chlorophenyl)ethyl)-1-(2-((4-fluoro-3-morpholinophenyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0919] N-(1-(5-Chlorothiophen-2-yl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0920] N-(1-(3-(tert-Butyl)phenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0921] (S)-N-(2-Amino-1-(3-chlorophenyl)ethyl)-1-(2-((3,3-difluorocyclobutyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0922] (S)-N-(1-(3-Chlorophenyl)-2-hydroxyethyl)-1-(2-((1,3-dihydroxypropan-2-yl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0923] N-(2-Hydroxy-1-(5-methylthiophen-2-yl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0924] N-((S)-2-Amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-(((R)-tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0925] N-((S)-1-(3-Chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-(((R)-tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0926] (S)-N-(2-Amino-1-(3-chlorophenyl)ethyl)-1-(2-(benzo[d][1,3]dioxol-5-ylamino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0927] N-(2-Amino-1-(thiophen-2-yl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0928] (S)-N-(2-Amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-(oxetan-3-ylamino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0929] N-(2-Amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(2-(benzo[d][1,3]dioxol-5-ylamino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0930] N-((S)-2-Amino-1-(3-chlorophenyl)ethyl)-1-(2-(chroman-4-ylamino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0931] (S)-N-(2-Amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((3-morpholinophenyl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0932] N-(2-Amino-1-(5-chlorothiophen-2-yl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0933] (S)-N-(2-Amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0934] (R)-N-(2-Amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0935] (S)-N-(1-(3-Chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0936] N-(2-Amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(2-((3,3-difluorocyclobutyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0937] (S)-N-(2-Amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0938] N-(2-Amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-(((S)-tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0939] (S)-N-(2-Amino-1-(3-chlorophenyl)ethyl)-1-(2-((4,4-difluorocyclohexyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0940] (S)-N-(2-Amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(2-((3,3-difluorocyclobutyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0941] (R)-N-(2-Amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(2-((3,3-difluorocyclobutyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0942] N-(2-Amino-1-(5-chlorothiophen-2-yl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide (enantiomer #1);

[0943] N-(2-Amino-1-(5-chlorothiophen-2-yl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide (enantiomer #2);

[0944] N-((S)-2-Amino-1-(3-chlorophenyl)ethyl)-1-(2-(cyclohex-3-en-1-ylamino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0945] (S)-N-(1-(3-chloro-5-fluorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0946] (S)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((1-methylpiperidin-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0947] (S)-N-(2-(((1H-pyrrol-2-yl)methyl)amino)-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0948] (S)-N-(1-(3-chlorophenyl)-2-((tetrahydro-2H-pyran-4-yl)amino)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0949] N-(2-amino-1-(3-chlorophenyl)-2-oxoethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0950] (S)-N-(1-(3-chlorophenyl)-2-(dimethylamino)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0951] (S)-N-(1-(3-chlorophenyl)-2-(methylamino)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0952] (S)-N-(1-(3-chlorophenyl)-2-((2-hydroxyethyl)amino)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0953] (S)-N-(1-(3-chlorophenyl)-2-(neopentylamino)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0954] 1-[5-methyl-2-(tetrahydro-pyran-4-ylamino)-pyrimidin-4-yl]-1H-imidazole-4-carboxylic acid [(S)-1-(3-chloro-phenyl)-2-(cyclopropylmethyl-amino)-ethyl]-amide;

[0955] N–(2-(3-chloro-2-(hydroxymethyl)phenyl)propan-2-yl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide; or

[0956] (S)-N-(2-(3-chloro-2-(hydroxymethyl)phenyl)propan-2-yl)-1-(5-methyl-2-((tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide,

[0957] or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof.

[0958] 31. The method according to embodiment 1, wherein the compound is:

[0959] (S)-1-(2-(benzo[d][1,3]dioxol-5-ylamino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;

[0960] 1-(2-(benzofuran-5-ylamino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;

[0961] 1-(2-(benzofuran-5-ylamino)-5-methylpyrimidin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-3-carboxamide;

[0962] (S)-N-(1-(3-chloro-4-fluorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0963] 1-(2-((2,3-dihydrobenzofuran-5-yl)amino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;

[0964] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0965] N-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0966] N-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-(((S)-tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0967] N-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-(((R)-tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0968] 1-(2-(chroman-6-ylamino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide;

[0969] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-((4-fluoro-3-morpholinophenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0970] (S)-N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(2-((4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0971] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0972] N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((4-morpholinophenyl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0973] (S)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0974] (R)-N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0975] (S)-N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0976] (S)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide;

[0977] N-(2-hydroxy-1-(thiophen-2-yl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0978] (S)-N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(2-((3,3-difluorocyclobutyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0979] (S)-N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0980] (S)-N-(2-(((1H-pyrrol-2-yl)methyl)amino)-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide;

[0981] (S)-N-(1-(3-chlorophenyl)-2-(methylamino)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide; or

[0982] (S)-N-(1-(3-chlorophenyl)-2-((2-hydroxyethyl)amino)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide,

[0983] or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof.

[0984] 32. The method according to embodiment 1, wherein the compound is a pharmaceutically acceptable salt selected from the following:

[0985] (S)-N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide hydrochloride;

[0986] (S)-N-(2-Amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide p-toluenesulfonate;

[0987] (S)-N-(2-Amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide benzenesulfonate;

[0988] (S)-N-(2-Amino-1-(3-chlorophenyl)ethyl)-1-(2-((3,3-difluorocyclobutyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide hydrochloride;

[0989] (S)-N-(2-Amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide benzenesulfonate;

[0990] (S)-N-(2-Amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide mandelate;

[0991] (S)-N-(2-Amino-1-(3-chlorophenyl)ethyl)-1-(2-((3,3-difluorocyclobutyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide p-toluenesulfonate;

[0992] (S)-N-(2-Amino-1-(3-chlorophenyl)ethyl)-1-(2-((3,3-difluorocyclobutyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide benzenesulfonate;

[0993] (S)-N-(2-Amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide hydrochloride; and

[0994] ((S)-N-(1-(3-chlorophenyl)-2-((2-(methylamino)ethyl)amino)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide 2,2,2-trifluoroacetate.

[0995] 33. The method according to embodiment 31, wherein the compound is a pharmaceutically acceptable salt selected from the following:

[0996] (S)-N-(2-Amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide benzenesulfonate;

[0997] (S)-N-(2-Amino-1-(3-chlorophenyl)ethyl)-1-(2-((3,3-difluorocyclobutyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide benzenesulfonate;

[0998] (S)-N-(2-Amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide mandelate; and

[0999] (S)-N-(2-Amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide benzenesulfonate.

[1000] 34. A method of treating a condition treatable by inhibiting ERK1 / 2, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I),

[1001]

[1002] or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof, wherein:

[1003] R 1 is C 6-12 aryl or a 5- to 10-membered heteroaryl, which is unsubstituted or substituted with 1-3 substituents selected from: halogen, C 1-6 alkyl, CN, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, -C 1-6 alkyl-O-C 1-6 alkyl, -C 1-6 alkyl-NH-C 1-6 alkyl, -C 1-6 alkyl-N-(C 1-6 alkyl)2, -C 1-6 alkyl-NH-C 1-6 alkyl-OH, -C 1-6 alkyl-NH-C 1-6 alkyl-C 3-10 cycloalkyl, -C 1-6 alkyl-NH-C 1-6alkyl-NH-C 1-6 alkyl, -C 1-6 alkyl-NH-C(O)-C 1-6 alkyl, -C 1-6 alkyl-O-C(O)-C 1-6 alkyl, -C 1-6 alkyl-NH-C 0-6 alkyl-(4- to 6-membered heterocyclic group) or -C 1-6 alkyl-NH-C 0-6 alkyl-(5- to 6-membered heteroaryl), wherein the C 1-6 alkyl, cycloalkyl, heterocyclic group and / or heteroaryl is unsubstituted or substituted by 1-3 substituents selected from the following: halogen, C 1-6 alkyl, NH2, hydroxy C 1-6 alkyl or amino C 1-6 alkyl;

[1004] J is a linker group selected from -C(R 2 )(R 8 )(CH2)-;

[1005] R 2 and R8 are each independently H, C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, -C 1-6 alkyl-O-C 1-6 alkyl, -C 1-6 alkyl-NH-C 1-6 alkyl, -C 1-6 alkyl-N-(C 1-6 alkyl)2, -C 1-6 alkyl-NH-C 1-6 alkyl-OH, -C 1-6 alkyl-NH-C 1-6 alkyl-C 3-10 cycloalkyl, -C 1-6 alkyl-NH-C 1-6 alkyl-NH-C 1-6 alkyl, -C 1-6 alkyl-NH-C(O)-C 1-6 alkyl, -C 1-6 alkyl-O-C(O)-C 1-6 alkyl, -C 1-6 alkyl-NH-C 0-6 alkyl-(4- to 6-membered heterocyclic group), -C(O)-NH2, -C(O)-NH-C 1-6 alkyl, -C(O)-N(C 1-6 alkyl)2 or -C 1-6 alkyl-NH-C0-6 alkyl-(5- to 6-membered heteroaryl), wherein said C 1-6 alkyl, heterocyclic group or heteroaryl is unsubstituted or substituted by 1 to 3 substituents selected from the following: halogen, C 1-6 alkyl, cycloalkyl, NH2, hydroxy C 1-6 alkyl or amino C 1-6 alkyl;

[1006] Alternatively, R 2 , R 8 and having R 2 and R 8 both C atoms attached together to form a 3- to 10-membered cycloalkyl or 4- to 10-membered heterocyclic ring, wherein said cycloalkyl or heterocyclic ring is unsubstituted or substituted by 1 to 3 substituents selected from the following: hydroxy, halogen or C 1-6 alkyl;

[1007] R 3 is H or C 1-6 alkyl, wherein said C 1-6 alkyl is unsubstituted or substituted by 1 to 5 halogens;

[1008] M is a bond or NH;

[1009] X and Y are each independently CH, C-R 7 or N;

[1010] Z is CH or N,

[1011] R 5 is H, halogen, C 1-6 alkyl or O-C 1-6 alkyl, wherein C 1-6 alkyl is unsubstituted or substituted by 1 to 5 halogens;

[1012] R 6 is H or C 1-6 alkyl, wherein said C 1-6 alkyl is unsubstituted or substituted by 1 to 5 halogens;

[1013] R 7 is C 1-6 alkyl, wherein said C 1-6 alkyl is unsubstituted or substituted by 1 to 5 halogens; and

[1014] R 4 is C 1-6 alkyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, -C 1-6 alkyl-phenyl, -C 1-6 alkyl-(5- to 6-membered heteroaryl), -C 1-6alkyl-(4- to 6-membered heterocyclic group), 4- to 10-membered heterocyclic group, phenyl or 5- to 10-membered heteroaryl, wherein the alkyl, cycloalkyl, cycloalkenyl, phenyl, heteroaryl or heterocyclic group is unsubstituted or substituted with 1-3 substituents selected from the following: halogen, CN, -C(O)-NH2, -C(O)-NH-C 1-6 alkyl, -C(O)-N-(C 1-6 alkyl)2, -O-C 1-6 alkyl-NH2, -O-C 1-6 alkyl-NH-(C 1-6 alkyl), -O-C 1-6 alkyl-N(C 1-6 alkyl)2, 4- to 6-membered heterocyclic group, -C(O)-(4- to 6-membered heterocyclic group), -O-phenyl, -O-C 1-6 alkyl-(4- to 6-membered heterocyclic group), C 1-6 alkyl, C 2-6 alkynyl, hydroxy, C 1-6 alkoxy or hydroxyC 1-6 alkyl, and the heterocyclic group or heteroaryl is unsubstituted or substituted with 1-3 substituents selected from the following: halogen, C 1-6 alkyl, -C(O)-C 1-6 alkyl or 4- to 6-membered heterocyclic group,

[1015] wherein the therapeutically effective amount is about 80 mg to about 350 mg.

[1016] 35. The method according to embodiment 34, wherein the compound is a compound of formula (II),

[1017]

[1018] or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof, wherein:

[1019] R 2 is C 1-6 alkyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, -C 1-6 alkyl-O-C 1-6 alkyl, -C 1-6 alkyl-NH-C 1-6 alkyl, -C 1-6 alkyl-N-(C 1-6 alkyl)2, -C 1-6 alkyl-NH-C 1-6 alkyl-OH, -C 1-6 alkyl-NH-C 1-6 alkyl-C 3-10 cycloalkyl, -C 1-6Alkyl-NH-C 1-6 Alkyl-NH-C 1-6 Alkyl, -C 1-6 Alkyl-NH-C(O)-C 1-6 Alkyl, -C 1-6 Alkyl-O-C(O)-C 1-6 Alkyl, -C 1-6 Alkyl-NH-C 0-6 Alkyl-(4- to 6-membered heterocyclic group), -C(O)-NH2, -C(O)-NH-C 1-6 Alkyl, -C(O)-N(C 1-6 alkyl)2 or -C 1-6 Alkyl-NH-C 0-6 Alkyl-(5- to 6-membered heteroaryl), wherein the C 1-6 alkyl, heterocyclic group or heteroaryl is unsubstituted or substituted with 1-3 substituents selected from: halogen, C 1-6 alkyl, cycloalkyl, NH2, hydroxy C 1-6 alkyl or amino C 1-6 alkyl; and

[1020] R 8 is H or C 1-6 alkyl;

[1021] Alternatively, R 2 , R 8 and the C atom attaching R 2 to R 8 both are joined together to form a 3- to 10-membered cycloalkyl or 4- to 10-membered heterocyclic ring, wherein the cycloalkyl or heterocyclic ring is unsubstituted or substituted with 1-3 substituents selected from: hydroxy, halogen or C 1-6 alkyl; and

[1022] R 1 , R 3 , R 4 , R 5 , R 6 , n, M, X, Y and Z are as defined above.

[1023] 36. The method according to embodiment 34, wherein the treatment is directed to a condition of prostate cancer, head cancer, neck cancer, eye cancer, oral cancer, throat cancer, esophageal cancer, bronchial cancer, laryngeal cancer, pharyngeal cancer, thoracic cancer, bone cancer, lung cancer, colon cancer, rectal cancer, gastric cancer, bladder cancer, uterine cancer, cervical cancer, breast cancer, ovarian cancer, vaginal cancer, testicular cancer, skin cancer, thyroid cancer, blood cancer, lymph node cancer, kidney cancer, liver cancer, intestinal cancer, pancreatic cancer, brain cancer, central nervous system cancer, adrenal cancer, skin cancer or leukemia or lymphoma.

[1024] 37. The method according to embodiment 34, wherein the compound is administered to the subject approximately twice a week on a regular schedule.

[1025] 38. The method according to embodiment 34, wherein the compound is administered to the subject approximately twice a week on an irregular schedule.

[1026] 39. The method according to embodiment 34, wherein the compound is administered to the subject approximately once every two weeks on a regular schedule.

[1027] 40. The method according to embodiment 34, wherein the compound is administered to the subject approximately once every two weeks on an irregular schedule.

[1028] 41. A method of treatment, the method of treatment comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I),

[1029]

[1030] or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof, wherein:

[1031] J is a linker group selected from -C(R 2 )(R 8 )(CH2)-;

[1032] R 1 is C 6-12 aryl or a 5- to 10-membered heteroaryl, which is unsubstituted or substituted with 1-3 substituents selected from the following: halogen, C 1-6 alkyl, CN, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, -C 1-6 alkyl-O-C 1-6 alkyl, -C 1-6 alkyl-NH-C 1-6 alkyl, -C 1-6 alkyl-N-(C 1-6 alkyl)2, -C 1-6 alkyl-NH-C 1-6 alkyl-OH, -C 1-6 alkyl-NH-C 1-6 alkyl-C 3-10 cycloalkyl, -C 1-6 alkyl-NH-C 1-6 alkyl-NH-C 1-6 alkyl, -C 1-6 alkyl-NH-C(O)-C 1-6 alkyl, -C 1-6 alkyl-O-C(O)-C 1-6 alkyl, -C1-6 alkyl-NH-C 0-6 alkyl-(4- to 6-membered heterocyclic group) or -C 1-6 alkyl-NH-C 0-6 alkyl-(5- to 6-membered heteroaryl), wherein the C 1-6 alkyl, cycloalkyl, heterocyclic group and / or heteroaryl is unsubstituted or substituted by 1 - 3 substituents selected from: halogen, C 1-6 alkyl, NH2, hydroxy C 1-6 alkyl or amino C 1-6 alkyl;

[1033] R 2 is C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, -C 1-6 alkyl-O-C 1-6 alkyl, -C 1-6 alkyl-NH-C 1-6 alkyl, -C 1-6 alkyl-N-(C 1-6 alkyl)2, -C 1-6 alkyl-NH-C 1-6 alkyl-OH, -C 1-6 alkyl-NH-C 1-6 alkyl-C 3-10 cycloalkyl, -C 1-6 alkyl-NH-C 1-6 alkyl-NH-C 1-6 alkyl, -C 1-6 alkyl-NH-C(O)-C 1-6 alkyl, -C 1-6 alkyl-O-C(O)-C 1-6 alkyl, -C 1-6 alkyl-NH-C 0-6 alkyl-(4- to 6-membered heterocyclic group), -C(O)-NH2, -C(O)-NH-C 1-6 alkyl, -C(O)-N(C 1-6 alkyl)2 or -C 1-6 alkyl-NH-C 0-6 alkyl-(5- to 6-membered heteroaryl), wherein the C 1-6 alkyl, heterocyclic group or heteroaryl is unsubstituted or substituted by 1 - 3 substituents selected from: halogen, C 1-6 alkyl, cycloalkyl, NH2, hydroxy C 1-6 alkyl or amino C 1-6 alkyl; and

[1034] R 8 is H or C 1-6 alkyl;

[1035] Or, R 2 , R 8 and the attached R 2 to R 8 The C atoms of both are joined together to form a 3- to 10-membered cycloalkyl or 4- to 10-membered heterocyclic ring, wherein the cycloalkyl or heterocyclic ring is unsubstituted or substituted with 1-3 substituents selected from: hydroxyl, halogen, or C 1-6 alkyl;

[1036] R 3 is H or C 1-6 alkyl, wherein the C 1-6 alkyl is unsubstituted or substituted with 1-5 halogens;

[1037] M is a bond or NH;

[1038] X and Y are each independently CH, C-R 7 or N;

[1039] Z is CH or N,

[1040] R 5 is H, halogen, C 1-6 alkyl, or O-C 1-6 alkyl, wherein the C 1-6 alkyl is unsubstituted or substituted with 1-5 halogens;

[1041] R 6 is H or C 1-6 alkyl, wherein the C 1-6 alkyl is unsubstituted or substituted with 1-5 halogens;

[1042] R 7 is C 1-6 alkyl, wherein the C 1-6 alkyl is unsubstituted or substituted with 1-5 halogens; and

[1043] R 4 is C 1-6 alkyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, -C 1-6 alkyl-phenyl, -C 1-6 alkyl-(5- to 6-membered heteroaryl), -C 1-6 alkyl-(4- to 6-membered heterocyclic), 4- to 10-membered heterocyclic, phenyl, or 5- to 10-membered heteroaryl, wherein the alkyl, cycloalkyl, cycloalkenyl, phenyl, heteroaryl, or heterocyclic is unsubstituted or substituted with 1-3 substituents selected from: halogen, CN, -C(O)-NH2, -C(O)-NH-C 1-6 alkyl, -C(O)-N-(C 1-6(alkyl)2, -O-C 1-6 alkyl-NH2, -O-C 1-6 alkyl-NH-(C 1-6 alkyl), -O-C 1-6 alkyl-N(C 1-6 alkyl)2, 4- to 6-membered heterocyclic group, -C(O)-(4- to 6-membered heterocyclic group), -O-phenyl, -O-C 1-6 alkyl-(4- to 6-membered heterocyclic group), C 1-6 alkyl, C 2-6 alkynyl, hydroxy, C 1-6 alkoxy or hydroxy C 1-6 alkyl, and the heterocyclic group or heteroaryl is unsubstituted or substituted with 1-3 substituents selected from: halogen, C 1-6 alkyl, -C(O)-C 1-6 alkyl or 4- to 6-membered heterocyclic group,

[1044] wherein the therapeutically effective amount is about 250 mg, and the compound is administered to the subject about once a week on a regular schedule.

[1045] 42. The method according to embodiment 41, wherein the compound is a compound of formula (II),

[1046]

[1047] or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof, wherein:

[1048] R 2 is C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, -C 1-6 alkyl-O-C 1-6 alkyl, -C 1-6 alkyl-NH-C 1-6 alkyl, -C 1-6 alkyl-N-(C 1-6 alkyl)2, -C 1-6 alkyl-NH-C 1-6 alkyl-OH, -C 1-6 alkyl-NH-C 1-6 alkyl-C 3-10 cycloalkyl, -C 1-6 alkyl-NH-C 1-6 alkyl-NH-C 1-6 alkyl, -C 1-6 alkyl-NH-C(O)-C 1-6 alkyl, -C 1-6 alkyl-O-C(O)-C 1-6Alkyl, -C 1-6 Alkyl-NH-C 0-6 Alkyl-(4- to 6-membered heterocyclic group), -C(O)-NH2, -C(O)-NH-C 1-6 Alkyl, -C(O)-N(C 1-6 Alkyl)2 or -C 1-6 Alkyl-NH-C 0-6 Alkyl-(5- to 6-membered heteroaryl), wherein the C 1-6 Alkyl, heterocyclic group or heteroaryl is unsubstituted or substituted with 1-3 substituents selected from: halogen, C 1-6 Alkyl, cycloalkyl, NH2, hydroxy C 1-6 Alkyl or amino C 1-6 Alkyl; and

[1049] R 8 is H or C 1-6 Alkyl;

[1050] Or, R 2 , R 8 and the C atom attaching R 2 to R 8 both are connected together to form a 3- to 10-membered cycloalkyl or 4- to 10-membered heterocyclic ring, wherein the cycloalkyl or heterocyclic ring is unsubstituted or substituted with 1-3 substituents selected from: hydroxy, halogen or C 1-6 Alkyl; and

[1051] R 1 , R 3 , R 4 , R 5 , R 6 , n, M, X, Y and Z are as defined above.

[1052] 43. The method according to embodiment 41, wherein the compound is administered to the subject approximately twice a week on a regular schedule.

[1053] 44. The method according to embodiment 41, wherein the compound is administered to the subject approximately twice a week on an irregular schedule.

[1054] 45. The method according to embodiment 41, wherein the compound is administered to the subject approximately once every two weeks on a regular schedule.

[1055] 46. The method according to 41, wherein the compound is administered to the subject approximately once every two weeks on an irregular schedule.

[1056] 47. A dosing regimen, the dosing regimen comprising administering to a subject in need thereof a therapeutically effective amount of the compound of Embodiment 1 at regular or irregularly scheduled doses, wherein the therapeutically effective amount is from about 80 mg to about 350 mg.

[1057] 48. The dosing regimen according to Embodiment 47, wherein the therapeutically effective amount is from about 120 mg to about 250 mg.

[1058] 49. The dosing regimen according to Embodiment 47, wherein the therapeutically effective amount is about 120 mg, about 180 mg or about 250 mg.

[1059] 50. The dosing regimen according to Embodiment 47, wherein the therapeutically effective amount is about 250 mg.

[1060] 51. The dosing regimen according to Embodiment 47, wherein the compound is administered to the subject at regular intervals of about once a week.

[1061] 52. The dosing regimen according to Embodiment 47, wherein the compound is administered to the subject at irregular intervals of about once a week.

[1062] 53. The dosing regimen according to Embodiment 47, wherein the compound is administered to the subject at regular intervals of about twice a week.

[1063] 54. The dosing regimen according to Embodiment 47, wherein the compound is administered to the subject at irregular intervals of about twice a week.

[1064] 55. The dosing regimen according to Embodiment 47, wherein the compound is administered to the subject at regular intervals of about once every two weeks.

[1065] 56. The dosing regimen according to Embodiment 48, wherein the compound is administered to the subject at irregular intervals of about once every two weeks.

[1066] 57. A kit, the kit comprising one or more dosage forms for treating one or more diseases or conditions and instructions for administering the dosage forms to a subject, wherein the instructions comprise the method of Embodiment 1.

[1067] 58. The treatment method according to Embodiments 1, 34 and 41 and the dosing regimen according to Embodiment 47, wherein after administering the compound, the method or dosing regimen achieves an AUC of about 880 h*ng / mL to about 6120 h*ng / mL tau , a C of about 68 ng / mL to about 2330 ng / mL max and / or a C of about 11 ng / mL to about 48 ng / mLmin 。

[1068] 59. The treatment method as described in Embodiments 1, 34, and 41 and the dosing regimen as described in Embodiment 47, wherein after administering the compound, the method or dosing regimen achieves an AUC of about 1190 h*ng / mL to about 7080 h*ng / mL tau , a C of about 80 ng / mL to about 1520 ng / m max and / or a C of about 0.8 ng / mL to about 23 ng / mL min 。

[1069] 60. The treatment method as described in Embodiments 1, 34, and 41 and the dosing regimen as described in Embodiment 47, wherein after administering the compound, the method or dosing regimen achieves an AUC of about 1840 h*ng / mL to about 18,120 h*ng / mL tau , a C of about 128 ng / mL to about 960 ng / mL max and / or a C of about 0.4 ng / mL to about 60 ng / mL min 。

[1070] 61. The treatment method as described in Embodiments 1, 34, and 41 and the dosing regimen as described in Embodiment 47, wherein the compound is a benzenesulfonate salt.

[1071] 62. The treatment method as described in Embodiments 1, 34, and 41 and the dosing regimen as described in Embodiment 47, wherein the compound is a mandelate salt.

[1072] 63. The treatment method as described in Embodiments 1, 34, and 41 and the dosing regimen as described in Embodiment 47, wherein the compound is a free base.

[1073] 64. The treatment method as described in Embodiments 1, 34, and 41 and the dosing regimen as described in Embodiment 47, wherein the compound is (S)-N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide mandelate.

[1074] 65. The treatment method as described in Embodiments 1, 34, and 41 and the dosing regimen as described in Embodiment 47, wherein the compound is (S)-N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide benzenesulfonate.

[1075] 66. The treatment method as described in Embodiments 1, 34 and 41 and the dosing regimen as described in Embodiment 47, wherein the compound is (S)-N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide.

[1076] 67. An oral pharmaceutical composition comprising

[1077] (S)-N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide mandelate,

[1078] (S)-N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide benzenesulfonate, or

[1079] (S)-N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide benzenesulfonate,

[1080] wherein after administration of the compound, the composition provides an AUC of about 880 h*ng / mL to about 6120 h*ng / mL tau , a Cmax of about 68 ng / mL to about 2330 ng / mL max and / or a Cmin of about 11 ng / mL to about 48 ng / mL. min .

[1081] 68. An oral pharmaceutical composition comprising

[1082] (S)-N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide mandelate,

[1083] (S)-N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide benzenesulfonate, or

[1084] (S)-N-(2-Amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide benzenesulfonate,

[1085] wherein after administration of the compound, the composition provides an AUC of from about 1190 h*ng / mL to about 7080 h*ng / mL tau 、a C of from about 80 ng / mL to about 1520 ng / m max and / or a C of from about 0.8 ng / mL to about 23 ng / mL min 。

[1086] 69. An oral pharmaceutical composition, the oral pharmaceutical composition comprising

[1087] (S)-N-(2-Amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide mandelate,

[1088] (S)-N-(2-Amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide benzenesulfonate, or

[1089] (S)-N-(2-Amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide benzenesulfonate,

[1090] wherein after administration of the compound, the composition provides an AUC of from about 1840 h*ng / mL to about 18,120 h*ng / mL tau 、a C of from about 128 ng / mL to about 960 ng / mL max and / or a C of from about 0.4 ng / mL to about 60 ng / mL min 。

[1091] 70. The composition according to embodiment 67, 68 or 69, wherein the compound is (S)-N-(2-Amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide mandelate.

[1092] 71. The composition according to embodiment 70, wherein the composition further comprises mannitol, hydroxypropyl cellulose, microcrystalline cellulose, crospovidone, magnesium stearate and II White。

[1093] Scheme

[1094] Scheme 1

[1095]

[1096] Scheme 1 depicts a synthetic method for preparing a compound of formula (I), wherein M is NH, Z = N, X = N, J = -CH(R 2 )- or -CH(R 2 )CH2-, R 2 = H, C 1-4 alkyl, CH2OH, CH2OC 1-6 alkyl or CH2N(C 1-6 alkyl)2, and Y = CH. In one embodiment, 4-nitropyrazole [A] is reacted with 2,4-dichloropyrimidine [B] to provide pyrazolyl-pyrimidine [C]. The reaction is carried out in the presence of a base such as potassium carbonate in a suitable solvent such as acetone or dioxane. The reaction can be carried out at a high temperature up to the reflux temperature of the solvent. Then the intermediate [C] is reacted with the amine R 4 -NH2 to provide the intermediate [D]. The coupling reaction can be carried out in the presence of a palladium catalyst such as Pd2(dba)3 [bis(dibenzylideneacetone)palladium(0)], BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl) and potassium carbonate in a suitable solvent such as dioxane. The reaction can be carried out at a high temperature, for example, in a sealed glass tube at 90 °C in dioxane. Then the reduction of the nitro moiety in [D] provides the amino-pyrazolyl intermediate [E]. The reduction process can be carried out by reacting with zinc powder and ammonium chloride in a solvent such as THF:methanol (2:1) at a temperature such as 0 °C to 25 °C. Then the amine intermediate [E] is reacted with the amine [F] to form the compound of the present disclosure, i.e., urea (I-A). The coupling reaction can be carried out using CDI (1,1'-carbonyldiimidazole) in a solvent such as THF. The reaction can be carried out at a high temperature, for example, under microwave irradiation in THF at 85 °C to 120 °C. The coupling reaction can also be carried out by using 4-nitrophenyl chloroformate, pyridine and DIPEA (diisopropylethylamine) instead of CDI.

[1097] Scheme 2

[1098]

[1099] Scheme 2 depicts another synthetic method for preparing a compound of formula (I), wherein in this example, M is NH, Z = N, X = N, J = -CH(R 2 )- or -CH(R 2 )CH2-, R2 = H, C 1-4 alkyl, CH2OH, CH2OC 1-6 alkyl or CH2N(C 1-6 alkyl)2, and Y = CH. In this method, the intermediate [C] is prepared as described in Scheme 1, followed by a reduction process to provide the amino-pyrazole [G]. The reduction process can be carried out by reacting with zinc powder and ammonium chloride in a solvent such as THF:methanol (2:1) at a temperature such as 0 °C to 25 °C. Then the amine intermediate [G] is reacted with the amine [F] to form the urea intermediate [H]. The reaction can be carried out by using 4-nitrophenyl chloroformate, pyridine and DIPEA (diisopropylethylamine) at a temperature such as 0 °C to 25 °C in a suitable solvent such as DCM (dichloromethane). Then the intermediate [H] is reacted with the amine R 4 -NH2 to provide the compound (I-A) of the present disclosure. The coupling reaction can be carried out in the presence of a palladium catalyst such as Pd2(dba)3, BINAP and potassium carbonate in a suitable solvent such as dioxane. The reaction can be carried out at a high temperature, for example, in a sealed glass tube at 90 °C in dioxane. An alternative method for the last step is to react the intermediate [H] with the amine R 4 -NH2 in a sealed glass tube, heated in ethanol or isopropanol, optionally in the presence of DIPEA.

[1100] Scheme 3

[1101]

[1102] Scheme 3 depicts a synthetic method for preparing a compound of formula (I), where in this example, M is a bond, Z = N, J = -CH(R 2 )- or -CH(R 2 )CH2-, R 2 = H, C 1-4 alkyl, CH2OH, CH2OC 1-6 alkyl or CH2N(C 1-6 alkyl)2, and Y = CR 7 . In this method, 2,4-dichloropyrimidine or 2-chloro-4-bromopyrimidine [B] is reacted with the heterocyclic ester [J] to form the intermediate [K]. The reaction can be carried out in the presence of a base such as potassium carbonate in a suitable solvent such as acetonitrile. The reaction can be carried out at a high temperature up to the reflux temperature of the solvent. Then the intermediate [K] is reacted with the amine R 4-NH2 reacts to provide intermediate [L]. This coupling reaction can be carried out in a suitable solvent such as dioxane in the presence of a palladium catalyst such as Pd2(dba)3, BINAP and potassium carbonate. The reaction can be carried out at a high temperature, for example, in a sealed glass tube at 90 °C to 100 °C in dioxane. An alternative method for forming intermediate [L] is to react intermediate [K] with amine R in ethanol or isopropanol under heating in a sealed glass tube, optionally in the presence of DIPEA 4 -NH2 reaction. For example, by treating the ester moiety in intermediate [L] with an aqueous solution of sodium hydroxide or an aqueous solution of lithium hydroxide in a solvent such as methanol or THF at a temperature such as 0 °C to 50 °C, the ester moiety in intermediate [L] is hydrolyzed to provide the corresponding carboxylic acid [M]. Then, intermediate [M] is coupled with amine [F] to form the compound of the present disclosure, i.e., amide (I-B). This amide coupling reaction can be carried out by using an amide coupling reagent EDC [1-ethyl-3-(3-dimethylaminopropyl)carbodiimide], optionally in the presence of HOBt (1-hydroxybenzotriazole) and triethylamine, in a suitable solvent such as NMP (N-methyl-2-pyrrolidone). The reaction can be carried out at a temperature such as 0 °C to 25 °C. Alternatively, this coupling reaction can be carried out by using N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium N-oxide hexafluorophosphate (HATU) and N,N-diisopropylethylamine (DIPEA) in N,N-dimethylformamide (DMF).

[1103] It is also contemplated to use any of several other amide coupling reagents known to those skilled in the art, such as T3P (propylphosphonic anhydride).

[1104] Scheme 3a

[1105]

[1106] Scheme 3a depicts a variation of Scheme 3, in which the amide coupling reaction with amine [F] is carried out first, followed by reaction with pyrimidine [B], and then reaction with amine R 4 -NH2 reaction to provide the compound of the present disclosure, i.e., amide (I-B).

[1107] Scheme 4

[1108]

[1109] Scheme 4 depicts a synthetic method for preparing a compound of formula (I), where M is a bond, R 2 =CH2NH2, Z = N, and X = CR 7. In this method, 2,4-dichloropyrimidine or 2-chloro-4-bromopyrimidine [B] is coupled with a heterocyclic ester [N] to form an intermediate [O] by a method similar to the method for preparing [K] described in Scheme 3. The reaction of compound [O] with an amine R 4 -NH2 is carried out by a method similar to the method for preparing [L] described in Scheme 3 to form an intermediate [P]. Hydrolysis of the ester moiety in [P] is achieved by a method similar to the method for preparing [M] described in Scheme 3 to form the corresponding carboxylic acid [Q]. Subsequently, the intermediate [Q] is coupled with an amine [R] to form an amide [S] by using an amide coupling method such as those described for preparing (I-B) in Scheme 3. As an alternative, the ester intermediate [P] can be directly converted to (S) by reaction with an amine [R] in a suitable solvent such as toluene in the presence of trimethylaluminum. The reaction is carried out at a temperature such as from 0 °C to 100 °C, optionally using microwave irradiation. Reduction of the nitrile moiety in [S] is carried out by hydrogenation using Raney nickel in a methanolic ammonia solution to provide the corresponding amine (I-C), which is the compound of the present disclosure. The reaction is carried out, for example, at about room temperature under 25 psi of hydrogen for 16 hours.

[1110] Scheme 5

[1111]

[1112] Scheme 5 depicts another method for synthesizing a compound of formula (I), in this example, where M is a bond, Z = N, J = -CH(R 2 )- or -CH(R 2 )CH2-, R 2 = H, C 1-4 alkyl, CH2OH, CH2OC 1-6 alkyl or CH2N(C 1-6 alkyl)2, Y = N, and X = C-R 7 . In this method, an aldehyde structural unit [T] is reacted with 2,4-dichloropyrimidine (or 2-chloro-4-bromopyrimidine) to prepare an aldehyde intermediate [U], and then the aldehyde intermediate [U] is converted to the corresponding carboxylic acid intermediate [V] by a method known in the art. Subsequently, the intermediate [V] is coupled with an amine [F] by an amide coupling method such as that described in Scheme 3 to form an amide intermediate [W]. The reaction of [W] with an amine R 4 -NH2 carried out by a method such as the method for forming [L] described in Scheme 3 provides the compound (I-D) of the present disclosure.

[1113] Scheme 6

[1114]

[1115] Scheme 6 depicts another method for synthesizing a compound of formula (I), wherein M is a bond, Z = N, J = -CH(R 2 )- or -CH(R 2 )CH2-, R 2 = H, C 1-4 alkyl, CH2OH, CH2OC 1-6 alkyl or CH2N(C 1-6 alkyl)2, and X = C-R 7 . In this method, the intermediate [X] is prepared by a method similar to the method for preparing the intermediate [P] in Scheme 4. Then, the ester intermediate [X] is reacted with the amine [F] in a suitable solvent such as toluene in the presence of trimethylaluminum. The reaction is carried out at a temperature such as 0 °C to 100 °C, optionally using microwave radiation, to provide the compound (I-E) of the present disclosure. This method has particular utility when R 4 is an optionally substituted alkyl.

[1116] Scheme 7

[1117]

[1118] Scheme 7 depicts a method for preparing a compound of formula (I), wherein in this embodiment, M is a bond, Z = CH, J = -CH(R 2 )- or -CH(R 2 )CH2-, R 2 = H, C 1-4 alkyl, CH2OH, CH2OC 1-6 alkyl or CH2N(C 1-6 alkyl)2, and X = C-R 7 . In this method, 2-amino-4-bromopyridine [Y] is reacted with the iodide compound R 4 -I in the presence of a palladium(0) catalyst to provide the pyridine intermediate [Z]. Then, the intermediate [Z] is reacted with the heterocyclic ester [AA] to provide the intermediate [AB]. This reaction is carried out in a sealed glass tube at a temperature such as 25 °C to 150 °C, in the presence of copper(I) iodide, L-proline, and potassium phosphate, in a solvent such as DMF. The ester moiety in the intermediate [AB] is hydrolyzed by a method such as the method for forming [M] described in Scheme 3, and then the carboxylic acid intermediate [AC] is reacted with [F] using an amide coupling method such as those described in Scheme 3 to provide the compound (I-F) of the present disclosure. Alternatively, the method described in Scheme 6 can be used to directly convert the ester intermediate [AB] into (I-F) by using trimethylaluminum in a suitable solvent such as toluene.

[1119] Scheme 8

[1120]

[1121] Scheme 8 depicts another method for preparing a compound of formula (I), where in this case, M is a bond, Z = CH, J = -CH(R 2 )- or -CH(R 2 )CH2-, R 2 = H, C 1-4 alkyl, CH2OH, CH2OC 1-6 alkyl or CH2N(C 1-6 alkyl)2, X = CH, and Y = CH. In this method, 2-chloro-pyridine [AD] is oxidized, nitrated, and then reacted with an amine R 4 -NH2 to provide a 4-nitro-pyridine N-oxide intermediate [AG]. The N-oxy and nitro moieties in [AG] are reduced, and the 4-amino group in the resulting [AH] is converted to a bromo moiety. Then, the 4-bromo-pyridine intermediate [AI] is reacted with a suitable heterocycle such as a pyrrole derivative [AJ] to provide the compound (I-G) of the present disclosure.

[1122] Scheme 9

[1123]

[1124] Scheme 9 depicts a method for preparing a compound of formula (I), where in this example, M is a bond, Z = CH, X = C-R 7 , J = -CH(R 2 )-, and R 2 = CH2NH2. In this method, aspects of the general methods depicted in Schemes 4 and 7 are utilized and combined to provide the compound (I-H) of the present disclosure.

[1125] Scheme 10

[1126]

[1127] Scheme 10 depicts a method for preparing a compound of formula (I), where in this instance, M is a bond, Z = CH, J = -CH(R 2 )- or -CH(R 2 )CH2-, R 2 = H, C 1-4 alkyl, CH2OH, CH2OC 1-6 alkyl or CH2N(C 1-6 alkyl)2, R 5 = Cl, X = C-R 7, and Y = N. In this method, 4-chloro-pyridine [AL] is converted to 3,4-dichloro-pyridine [AO] in three steps, and then the 3,4-dichloro-pyridine [AO] is converted to the compound (I-J) disclosed herein in subsequent steps using a method similar to the method described in the above scheme.

[1128] Scheme 11

[1129]

[1130] Scheme 11 depicts a method for preparing a compound of formula (I), where in this example, M is a bond, Z = CH, R 2 = CH2NH2, X = C-R 7 , and Y = N. In this method, 2,4-dichloro-pyridine or 2-chloro-4-bromo-pyridine [AT] is reacted with a heterocyclic ester [AQ] in the presence of a base such as potassium carbonate in a suitable solvent such as DMF. The reaction can be carried out at room temperature to a high temperature such as 100 °C or the reflux temperature of the solvent. Then the 2-chloro-pyridine intermediate [AU] is reacted with the amine R 4 -NH2 to provide an intermediate [AV]. This coupling reaction can be carried out in the presence of a palladium catalyst such as Pd2(dba)3, BINAP and potassium carbonate in a suitable solvent such as dioxane. The reaction can be carried out at a high temperature, for example, in a sealed glass tube at 90 °C in dioxane, or using microwave radiation at 100 °C. Then, for example, by treating the ester moiety of the intermediate [AV] with an aqueous solution of sodium hydroxide or lithium hydroxide in a solvent such as methanol or THF at a temperature such as 0 °C to 50 °C, the ester moiety of the intermediate [AV] is hydrolyzed to provide the corresponding carboxylic acid [AW]. Then, the carboxylic acid [AW] is coupled with the amine [R] using an amide coupling method such as those described for the preparation of (I-B) in Scheme 3 to form an amide [AX]. The reduction of the nitrile moiety in [AX] is carried out by hydrogenation using Raney nickel in a methanolic ammonia solution to provide the corresponding amine (I-K), which is the compound disclosed herein. The reaction is carried out, for example, at about room temperature under 15 psi to 25 psi of hydrogen for about 6 to 16 hours.

[1131] Scheme 12

[1132]

[1133] Scheme 12 depicts a method for preparing a compound of formula (I), wherein in this example, M is a bond, Z = CH, X = N, and Y = N. In this method, 2,4-dichloro-pyridine (or 2-chloro-4-bromo-pyridine) [AT] is reacted with sodium azide to provide 4-azido-pyridine [AY], and then the 4-azido-pyridine [AY] is condensed with methyl propiolate to produce a triazole intermediate [AZ]. The ester moiety in the intermediate [AZ] is hydrolyzed by a method such as the method described in Scheme 11 to produce the corresponding carboxylic acid, and then the carboxylic acid is reacted with an amine such as [F] by using an amide coupling method such as the one described in Scheme 10, or the carboxylic acid is reacted with an amine such as [R] by using an amide coupling method such as the one described in Scheme 11 and then reduced, to provide the compound (I-L) of the present disclosure.

[1134] Scheme 13

[1135]

[1136] Scheme 13 depicts a method for preparing a compound of formula (I), wherein in this example, M is a bond, Z = CH, R 5 = H, and X = CR 7 . In this method, 2-fluoro-4-iodo-pyridine [BA] is reacted with an amine R 4 -NH2 to provide an intermediate [BB]. The reaction is carried out in a suitable solvent such as DMF or NMP, and can be carried out at a high temperature, for example, at 90 °C to 100 °C, in a sealed glass tube. Then the intermediate [BB] is reacted with a heterocyclic ester [N] to provide an intermediate [BC]. The reaction is carried out in a sealed glass tube, in a temperature range of 25 °C to a high temperature such as 100 °C to 150 °C, in the presence of L-proline, copper(I) iodide, and a base such as potassium carbonate, in a suitable solvent such as DMF or NMP. The ester moiety in the intermediate [BC] is hydrolyzed by a method such as the method described in Scheme 11 to produce the corresponding carboxylic acid, and then the carboxylic acid is reacted with an amine such as [F] by using an amide coupling method such as the one described in Scheme 10, or the carboxylic acid is reacted with an amine such as [R] by using an amide coupling method such as the one described in Scheme 11 and then reduced, to provide the compound (I-M) of the present disclosure.

[1137] Methods for synthetic structural units used in the synthesis for preparing a compound of formula (I) are set forth in the following schemes. Those skilled in the art will recognize that the schemes can be adjusted to produce other compounds of formula (I) as well as pharmaceutically acceptable salts, prodrugs, solvates, hydrates, or stereoisomers of the compounds of formula (I).

[1138] Scheme 14

[1139]

[1140] Scheme 15

[1141]

[1142] Examples of methods for preparing compounds such as (I-N) and (I-O) that can serve as prodrugs of the compound of formula (I) are illustrated in Schemes 18 and 19 below. Those skilled in the art will recognize that these schemes can be adjusted to produce additional compounds that can serve as prodrugs of the compound of formula (I).

[1143] Scheme 18

[1144]

[1145] Scheme 19

[1146]

[1147] Scheme 20

[1148]

[1149] Scheme 20 depicts another method for preparing the compound of formula (I), where in this example, M is a bond, R 2 =CH2NH2, Z = N, and X = CR 7 . This method provides an alternative to the method described in Scheme 4. In this method, the amino alcohol (in this embodiment, a single enantiomer) [BD] is converted to the N-Boc protected analogue [BE] by standard methods, and then the hydroxy moiety is converted to the corresponding methanesulfonate, for example, by reaction with methanesulfonyl chloride and triethylamine in a solvent such as dichloromethane. The methanesulfonate compound [BF] is then reacted with sodium azide to form the corresponding azide derivative [BG]. The azidation reaction is carried out in a suitable solvent such as DMF or NMP and can be carried out at elevated temperature, for example, at about 50 °C. The N-Boc group is then removed by standard methods, for example, by treatment with a dioxane solution of 4M HCl. The resulting amino azide compound [BH] is then coupled with the intermediate [Q] to form the amide [BI] using an amide coupling method such as those described for the preparation of (I-B) in Scheme 3. The azide moiety is reduced, for example, by reaction with zinc powder and ammonium chloride in a solvent such as methanol to provide the compound (I-P) of the present disclosure in the form of a single enantiomer in this example. Alternatively, the azide moiety is reduced with triphenylphosphine in an aqueous THF solution.

[1150] Examples

[1151] Unless otherwise specified, all reactions were carried out under a dry nitrogen and / or argon atmosphere. Unless otherwise stated, all starting materials, solvents, and reagents were purchased from commercial sources (such as Avocado Research Chemicals, Apollo Scientific Limited, Bepharma Ltd., Combi-Blocks Inc., Sigma Aldrich Chemicals Pvt. Ltd., Ultra Labs, Toronto Research Chemicals Inc., Chemical House, RFCL Limited, Spectro Chem Pvt. Ltd., Leonid Chemicals, Loba Chemie, Changzhou Yangyuan, NeoSynth., Rankem, etc.) and used as received without further purification, or the reagents could be synthesized by procedures known in the art. Generally, the progress of each reaction was monitored by TLC analysis.

[1152] Biotage was typically used One and (Teledyne Isco) automated flash purification systems to purify the crude products using the eluent combinations mentioned in the respective procedures. Flash chromatography was performed using silica gel (60 - 100, 100 - 200, and 230 - 400 mesh) from ChemLabs, with nitrogen and / or compressed air to flow the pressurized eluent. Preparative thin layer chromatography (Prep TLC) was performed using silica gel (GF 1500 μM 20 × 20 cm and GF 2000 μM 20 × 20 cm pre-scored plates, from Analtech, Inc. Delaware, USA). Analytical thin layer chromatography (TLC) was performed using pre-coated silica gel plates (Merck 60F 254 ). Visual detection was carried out with ultraviolet light, p-methoxybenzaldehyde staining, ninhydrin staining, 2,4-dinitrophenylhydrazine staining, potassium permanganate staining, or iodine. Reactions at lower temperatures were carried out by using cold baths such as H2O / ice at 0 °C and acetone / dry ice at -78 °C. Reactions under microwave conditions were carried out in a CEM Discover SP 909155 microwave oven. Melting points were determined using a LabIndia MR-VIS visual melting point apparatus. 1H NMR spectra were recorded at 400 MHz on a Varian V400 spectrometer Bruker 400 using tetramethylsilane as an internal reference at ambient temperature (unless otherwise indicated). Chemical shift values were quoted in δ (parts per million). Using 1 UPLC-SQD (Waters) and Agilent 1290 coupled with 6150 SQD The UHPLC machine records the mass spectra of all intermediates and final compounds. Using Agilent 1290 The UHPLC and Alliance (Waters) systems record HPLC chromatograms. Using Agilent LCMS, Agilent The UHPLC-SQD with diode array detector (DAD) detects LC-MS instruments, using BEH C18 column and HD C18 column (50 mm × 2.1 mm × 1.7 μm) & (50 mm × 2.1 mm ×

[1153] 1.8 μm), mobile phase of 0.01% formic acid and acetonitrile or 0.01% trifluoroacetic acid and acetonitrile, flow rate of 0.3 mL / min, column temperature of 70 or 50 °C, and run time of 3 to 5 min, record LCMS chromatograms. Using PDA with SQD and DAD with 6150 SQD instrument and the following conditions to determine the purity of each in the final compounds:

[1154] Condition 1: Column: BEH C18 (Waters); Mobile phase: 0.01% acetic acid / acetonitrile &

[1155] 0.01% acetic acid / methanol; Gradient: (B / %T): 0 / 0, 1.2 / 100, 2.5 / 100, 2.8 / 0, 3.0 / 0; Flow rate: 0.3 mL / min; Temperature: 70 °C; Run time: 3.0 min.

[1156] Condition 2: Column: HD C18; Mobile phase: 0.01% acetic acid / acetonitrile & 0.01% acetic acid / methanol; Gradient: (B / %T): 0 / 0, 2.5 / 100, 4.5 / 100, 4.8 / 0, 5.0 / 0; Flow rate: 0.3 mL / min; Temperature: 50 °C; Run time: 5.0 min

[1157] For use in the preparation of certain compounds of the present disclosure, the following intermediates were produced as follows.

[1158] Preparation Example 1: 2-Amino-2-(3-chlorophenyl)acetonitrile

[1159]

[1160] At room temperature, a solution of 3-chlorobenzaldehyde (5 g, 35.0 mmol) in methanol (100 mL) was purged with ammonia gas for 2 h. The mixture was cooled to 0 °C and trimethylsilyl cyanide (5.293 g, 53.0 mmol) was added. The mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by gradient column chromatography using ethyl acetate in hexane as the eluent to afford 2-amino-2-(3-chlorophenyl)acetonitrile as a yellow solid (4.8 g, 81% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.57 (s, 1H), 7.47–7.40 (m, 3H), 5.06 (s, 1H), 2.92 (s, 2H).

[1161] Preparation Example 2: 2-Amino-3-phenylpropanenitrile

[1162]

[1163] To a stirred solution of 2-phenylacetaldehyde (10.0 g, 83.33 mmol) in MeOH (50 mL) was added NH3 in MeOH (80.0 mL) and Ti(OiPr)4 (30.7 g, 108.33 mmol), and the resulting solution was stirred at room temperature for 2 h. Then trimethylsilyl cyanide (TMSCN) (14.88 g, 149.9 mmol) was added to the reaction mixture, and then the reaction mixture was stirred at room temperature for 20 h. The reaction mixture was quenched with water and the resulting white precipitate was filtered. The filtrate was concentrated under reduced pressure, combined with ethyl acetate, and washed with brine (2 x 15 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure, and the residue was purified by Combiflash, eluting with MeOH in DCM, to afford 2-amino-3-phenylpropanenitrile (5.4 g, 45%). 1H NMR (400 MHz, DMSO-d6): δ 7.37-7.21 (m, 5H), 3.93 (t, J = 7.2 Hz, 1H), 3.33-3.23 (m, 2H), 2.36 (brs, 2H). LC-MS calculated exact mass: 146.08, found (m / z): 147.04 [M+H] + 。

[1164] Representative Example of Scheme 1:

[1165] Example 1: (S)-1-(1-(3-chlorophenyl)-2-hydroxyethyl)-3-(1-(2-(2-chlorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrazol-4-yl)urea (Compound #2)

[1166]

[1167] Step 1: 2-Chloro-5-methyl-4-(4-nitro-1H-pyrazol-1-yl)pyrimidine.

[1168]

[1169] Heat a reaction mixture of 4-nitro-1H-pyrazole (1.0 g, 8.8 mmol), 2,4-dichloro-5-methylpyrimidine (1.18 g, 7.96 mmol), potassium carbonate (3.6 g, 26.4 mmol) and acetone (30 mL) at 65 °C for 6 h. Evaporate the reaction mixture; suspend the residue in water and extract with ethyl acetate. Dry the organic layer over sodium sulfate, evaporate, and purify the residue by silica gel column chromatography using ethyl acetate in hexane as the eluent to give 2-chloro-5-methyl-4-(4-nitro-1H-pyrazol-1-yl)pyrimidine (0.73 g, 56%). 1H NMR (400 MHz, CDCl3): 9.32 (s, 1H), 8.62 (s, 1H), 8.31 (s, 1H), 2.69 (s, 3H). LC-MS calculated exact mass: 239.02, found (m / z): 240.1 [M+H] + 。

[1170] Step 2: N-(2-Chlorophenyl)-5-methyl-4-(4-nitro-1H-pyrazol-1-yl)pyrimidin-2-amine.

[1171]

[1172] The reaction mixture of 2-chloro-5-methyl-4-(4-nitro-1H-pyrazol-1-yl)pyrimidine (0.4 g, 1.67 mmol), 2-chloroaniline (0.19 mL, 1.84 mmol), potassium carbonate (0.34 g, 2.5 mmol) and dioxane (15 mL) in a glass tube was purged with nitrogen for 20 min. Tris(dibenzylideneacetone)dipalladium(0) (0.076 g, 0.083 mmol) and BINAP (0.103 g, 0.167 mmol) were added to the reaction mixture, and the reaction mixture was purged with nitrogen for an additional 15 min. Then the tube was sealed and heated at 90 °C for 4 h. The reaction mixture was filtered through diatomaceous earth, and the filtrate was evaporated; the residue was suspended in water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, evaporated, and the residue was purified by silica gel column chromatography using ethyl acetate in 20% hexane as the eluent to give N-(2-chlorophenyl)-5-methyl-4-(4-nitro-1H-pyrazol-1-yl)pyrimidin-2-amine (0.33 g, 60%). 1H NMR (400 MHz, DMSO-d6): 9.23 (s, 1H), 9.17 (s, 1H), 8.61 (s, 1H), 8.54 (s, 1H), 7.78 (d, J = 8 Hz, 1H), 7.51 (d, J = 8 Hz, 1H), 7.35 (t, J = 8 Hz, 1H), 7.18 (t, 1H, J = 8 Hz), 2.38 (s, 3H). LC-MS calculated exact mass: 330.06, found (m / z): 331.1 [M+H] + .

[1173] Step 3: 4-(4-Amino-1H-pyrazol-1-yl)-N-(2-chlorophenyl)-5-methylpyrimidin-2-amine.

[1174]

[1175] To a solution of N-(2-chlorophenyl)-5-methyl-4-(4-nitro-1H-pyrazol-1-yl)pyrimidin-2-amine (0.33 g, 1.0 mmol) in THF:methanol (2:1) (10 mL) cooled to 0 °C was added zinc powder (0.39 g, 6.0 mmol) and ammonium chloride (0.43 g, 8.0 mmol). The mixture was stirred at room temperature for 30 min. The reaction mixture was filtered through diatomaceous earth and the filtrate was evaporated; the residue was suspended in water and extracted with DCM. The organic layer was dried over sodium sulfate and evaporated to give 4-(4-amino-1H-pyrazol-1-yl)-N-(2-chlorophenyl)-5-methylpyrimidin-2-amine (0.24 g, 80%). The product was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6): 8.63 (s, 1H), 8.26 (s, 1H), 7.83 (t, J = 8 Hz, 1H), 7.72 (s, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.42 (s, 1H), 7.38 - 7.32 (m, 1H), 7.13 - 7.11 (m, 1H), 4.39 (s, 2H), 2.40 (s, 3H). LC-MS calculated exact mass: 300.09, found (m / z): 301.1 [M+H] + .

[1176] Step 4: (S)-1-(1-(3-chlorophenyl)-2-hydroxyethyl)-3-(1-(2-(2-chlorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrazol-4-yl)urea.

[1177]

[1178] In a CEM microwave, at 85 °C, a reaction mixture of 4-(4-amino-1H-pyrazol-1-yl)-N-(2-chlorophenyl)-5-methylpyrimidin-2-amine (0.15 g, 0.5 mmol), 1,1'-carbonyldiimidazole (0.32 g, 2.0 mmol) and THF (5 mL) in a CEM microwave vial was stirred for 20 min.

[1179] (S)-2-Amino-2-(3-chlorophenyl)ethanol (0.25 g, 1.5 mmol) was added to the reaction mixture and stirred in a CEM microwave at 120 °C for 20 min. The reaction mixture was evaporated; the residue was suspended in water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, evaporated, and the residue was purified by preparative thin layer chromatography using methanol in DCM as the eluent to yield (S)-1-(1-(3-chlorophenyl)-2-hydroxyethyl)-3-(1-(2-(2-chlorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrazol-4-yl)urea (0.02 g, 8%). 1H NMR (400 MHz, DMSO-d6): δ 8.79 (s, 1H), 8.63 (s, 1H), 8.46 (s, 1H), 8.31 (s, 1H), 7.79 (s, 1H), 7.78 (s, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.35 - 7.26 (m, 4H), 7.13 (t, J = 7.8 Hz, 1H), 6.79 (d, J = 8 Hz, 1H), 4.99 - 4.91 (m, 1H), 4.74 - 4.72 (m, 1H), 3.65 - 3.55 (m, 2H), 2.41 (s, 3H). LC-MS m / z calculated exact mass: 497.11, found (m / z): 498.3 [M+H] + ; HPLC purity 99.17%.

[1180] Representative Example of Scheme 2:

[1181] Example 2: (S)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-4-(5-methoxy-1H-indazol-3-yl)-1H-pyrrole-2-carboxamide (Compound #20)

[1182]

[1183] Step 1: 2-Chloro-4-(4-nitro-1H-pyrazol-1-yl)pyrimidine.

[1184]

[1185] At 65 °C, a reaction mixture of 4-nitro-1H-pyrazole (4.0 g, 35.3 mmol), 2,4-dichloropyrimidine (5.23 g, 35.3 mmol), potassium carbonate (14.6 g, 106 mmol) and acetone (200 mL) was heated for 4 h. The reaction mixture was evaporated; the residue was suspended in water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, evaporated, and the residue was purified by silica gel column chromatography using ethyl acetate in hexane as the eluent to give 2-chloro-4-(4-nitro-1H-pyrazol-1-yl)pyrimidine (1.7 g, 21%). 1H NMR (400 MHz, CDCl3): 9.30 (s, 1H), 8.78 (d, J = 5.6 Hz, 1H) 8.32 (s, 1H), 7.74 (d, J = 5.2 Hz, 1H).

[1186] Step 2: 1-(2-Chloropyrimidin-4-yl)-1H-pyrazol-4-amine.

[1187]

[1188] Zinc powder (0.7 g, 10.6 mmol) and ammonium chloride (0.75 g, 14.16 mmol) were added to a solution of 2-chloro-4-(4-nitro-1H-pyrazol-1-yl)pyrimidine (0.4 g, 1.77 mmol) in THF:methanol (2:1) (20 mL) cooled to 0 °C. The mixture was stirred at room temperature for 30 min. The reaction mixture was filtered through diatomaceous earth, and the filtrate was evaporated; the residue was suspended in water and extracted with DCM. The organic layer was dried over sodium sulfate and evaporated to give 1-(2-chloropyrimidin-4-yl)-1H-pyrazol-4-amine (0.33 g, 97%). The product was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6): 8.60 (d, J = 5.6 Hz, 1H), 7.76 (s, 1H), 7.71 (d, J = 8 Hz, 1H), 7.58 (s, 1H), 5.21 (br s, 2H). LC-MS calculated exact mass: 195.03, found (m / z): 196.1 [M+H] + 。

[1189] Step 3: (S)-1-(1-(3-Chlorophenyl)-2-hydroxyethyl)-3-(1-(2-chloropyrimidin-4-yl)-1H-pyrazol-4-yl)urea.

[1190]

[1191] A mixture of 1-(2-chloropyrimidin-4-yl)-1H-pyrazol-4-amine (0.1 g, 0.51 mmol), pyridine (0.041 mL, 0.51 mmol) in DCM (6 mL) was cooled to 0 °C, then 4-nitrophenyl chloroformate (0.102 g, 0.51 mmol) was added, and the mixture was stirred at room temperature for 1.5 h. The reaction mixture was cooled to 0 °C, and DIPEA (0.28 mL, 1.53 mmol) and (S)-2-amino-2-(3-chlorophenyl)ethanol (0.088 g, 0.51 mmol) were added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with DCM and washed with water and brine. The organic layer was dried over sodium sulfate, evaporated, and the residue was purified by silica gel column chromatography using ethyl acetate in 60% hexane as the eluent to afford (S)-1-(1-(3-chlorophenyl)-2-hydroxyethyl)-3-(1-(2-chloropyrimidin-4-yl)-1H-pyrazol-4-yl)urea (0.045 g, 23%). 1H NMR (400 MHz, DMSO-d6): 8.74 (s, 1H), 8.68 (d, J = 5.6 Hz, 1H), 8.45 (s, 1H), 7.92 (s, 1H), 7.80 (d, J = 5.6 Hz, 1H,), 7.36 - 7.32 (m, 2H), 7.28 (d, J = 7.6 Hz, 2H), 6.96 (d, J = 8 Hz, 1H), 5.00 - 4.98 (m, 1H), 4.76 - 4.72 (m, 1H), 3.65 - 3.58 (m, 2H). LC-MS calculated exact mass: 392.06, found (m / z): 393.1 [M+H] + .

[1192] Step 4: (S)-1-(1-(2-(2-chloro-4-fluorophenyl)amino)pyrimidin-4-yl)-1H-pyrazol-4-yl)-3-(1-(3-chlorophenyl)-2-hydroxyethyl)urea.

[1193]

[1194] The mixture of (S)-1-(1-(3-chlorophenyl)-2-hydroxyethyl)-3-(1-(2-chloropyrimidin-4-yl)-1H-pyrazol-4-yl)urea (0.02 g, 0.05 mmol), 2-chloro-4-fluoroaniline (0.009 g, 0.06 mmol), potassium carbonate (0.01 g, 0.075 mmol) and dioxane (2 mL) in a glass tube was purged with nitrogen for 20 min. Tris(dibenzylideneacetone)dipalladium(0) (0.002 g, 0.0025 mmol) and BINAP (0.003 g, 0.005 mmol) were added to the reaction mixture, and the reaction mixture was purged with nitrogen for an additional 15 min. The tube was sealed and heated at 90 °C for 4 h. The reaction mixture was filtered through diatomaceous earth, and the filtrate was evaporated; the residue was suspended in water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, evaporated, and the residue was purified by silica gel column chromatography using ethyl acetate in 60% hexane as the eluent to give (S)-1-(1-(2-((2-chloro-4-fluorophenyl)amino)pyrimidin-4-yl)-1H-pyrazol-4-yl)-3-(1-(3-chlorophenyl)-2-hydroxyethyl)urea (0.003 g, 12%). 1H NMR (400 MHz, CDCl3, plus a few drops of MeOD): 8.50 (s, 1H), 8.33 (d, J = 5.2 Hz, 1H), 8.27 - 8.25 (m, 1H), 7.51 (s, 1H), 7.28 - 7.19 (m, 1H), 7.23 - 7.12 (m, 3H), 7.12 - 7.10 (m, 1H) 7.04 - 6.99 (m, 1H), 6.23 (d, J = 6.8 Hz, 1H) 4.87 - 4.84 (m, 1H), 3.81 - 3.77 (m, 1H), 3.64 - 3.61 (m, 1H). LC-MS calculated exact mass: 501.09, found (m / z): 502.3 [M+H] + . HPLC purity 98.17%.

[1195] Example 3: (S)-1-(1-(2-(benzo[d][1,3]dioxol-5-ylamino)-5-methylpyrimidin-4-yl)-1H-pyrazol-4-yl)-3-(2-hydroxy-1-phenylethyl)urea (Compound #55)

[1196]

[1197] Step 1: 2-chloro-5-methyl-4-(4-nitro-1H-pyrazol-1-yl)pyrimidine

[1198]

[1199] To a stirred solution of 4-nitro-1H-pyrazole (4.0 g, 35.36 mmol) in acetone (100 mL) was added potassium carbonate (14.66 g, 106.1 mmol). The mixture was stirred at room temperature for 15 min, then 2,4-dichloro-5-methylpyrimidine (5.76 g, 35.36 mmol) was added, and the mixture was then stirred at 70 °C for 8 h. The reaction was quenched with water (100 mL), extracted with ethyl acetate (3 x 100 mL), and then washed with brine (30 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by gradient column chromatography, eluting with ethyl acetate in 8% hexane to afford 2-chloro-5-methyl-4-(4-nitro-1H-pyrazol-1-yl)pyrimidine as a colorless solid (4.2 g, 50% yield). 1H NMR (400 MHz CDCl3): δ 9.31 (s, 1H), 8.61 (s, 1H), 8.31 (s, 1H), 2.68 (s, 3H). LC-MS calculated exact mass: 239.02, found (m / z): 240.2 [M+H] + 。

[1200] Step 2: 1-(2-Chloro-5-methylpyrimidin-4-yl)-1H-pyrazol-4-amine

[1201] To a stirred solution of 2-chloro-5-methyl-4-(4-nitro-1H-pyrazol-1-yl)pyrimidine (4.2 g, 17.2 mmol) in THF:methanol (50:25 mL) was added ammonium chloride (6.85 g, 172.0 mmol) and zinc (5.28 g, 87.4 mmol), and the reaction mixture was then stirred at room temperature for 30 min. The reaction mixture was then filtered through diatomaceous earth using methanol (50 mL), and the filtrate was evaporated under reduced pressure. It was then combined with water (100 mL) and extracted successively with ethyl acetate (3 x 100 mL) and brine (50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to afford 1-(2-chloro-5-methylpyrimidin-4-yl)-1H-pyrazol-4-amine as an off-white solid (3.0 g, 82% yield). 1H NMR (400 MHz CDCl3): δ 8.36 (s, 1H), 8.11 (s, 1H), 7.49 (d, J = 8 Hz, 1H), 3.19 (s, 2H), 2.62 (s, 3H). LC-MS calculated exact mass: 209.04, found (m / z): 210.2 [M+H] + 。

[1202] Step 3: (S)-1-(1-(2-Chloro-5-methylpyrimidin-4-yl)-1H-pyrazol-4-yl)-3-(2-hydroxy-1-phenylethyl)urea

[1203]

[1204] At 0 °C, 4-nitrophenyl chloroformate (0.23 g, 0.11 mmol) was added to a stirred solution of 1-(2-chloro-5-methylpyrimidin-4-yl)-1H-pyrazol-4-amine (0.2 g, 0.95 mmol) in DCM (15 mL), and then the mixture was stirred at room temperature for 2 h. Then, DIPEA (0.5 mL, 2.86 mmol), (S)-2-amino-2-phenylethanol (0.13 g, 0.95 mmol) in DCM (3 mL), and pyridine (0.08 mL, 0.95 mmol) were added to the mixture, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched by the addition of water (25 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure, washed with diethyl ether, and then dried under high vacuum to give (S)-1-(1-(2-chloro-5-methylpyrimidin-4-yl)-1H-pyrazol-4-yl)-3-(2-hydroxy-1-phenylethyl)urea (0.1 g, 28%) as an off-white solid. 1H NMR (400 MHz DMSO-d6): δ 8.68 (s, 1H), 8.61 (s, 1H), 8.52 (s, 1H), 7.89 (s, 1H), 7.3 (d, J = 4.4 Hz, 4H), 7.24 - 7.19 (m, 1H), 6.83 (d, J = 7.6 Hz, 1H), 4.93 (t, J = 5.2 Hz, 1H), 4.75 - 4.71 (m, 1H), 3.65 - 3.55 (m, 2H), 2.48 (s, 3H). LC-MS calculated exact mass: 372.11, found (m / z): 373.1 [M+H] + 。

[1205] Step 4: (S)-1-(1-(2-(benzo[d][1,3]dioxol-5-ylamino)-5-methylpyrimidin-4-yl)-1H-pyrazol-4-yl)-3-(2-hydroxy-1-phenylethyl)urea

[1206]

[1207] To a stirred solution of (S)-1-(1-(2-chloro-5-methylpyrimidin-4-yl)-1H-pyrazol-4-yl)-3-(2-hydroxy-1-phenylethyl)urea (0.1 g, 0.26 mmol) in dioxane (5 mL) was added potassium carbonate (0.055 g, 0.40 mmol), 1,3-benzodioxol-5-amine (0.044 g, 0.32 mmol) and 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.016 g, 0.026 mmol). The mixture was then degassed with argon for 20 min, followed by the addition of tris(dibenzylideneacetone)dipalladium(0) (0.012 g, 0.013 mmol), and the mixture was stirred at 100 °C in a sealed glass tube for 4 h. The reaction mixture was filtered through a bed of diatomaceous earth and the filtrate was quenched with water (15 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by gradient column chromatography, eluting with methanol in 3.5% DCM to afford (S)-1-(1-(2-(1,3-benzodioxol-5-ylamino)-5-methylpyrimidin-4-yl)-1H-pyrazol-4-yl)-3-(2-hydroxy-1-phenylethyl)urea (4 mg, 4%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.44 (s, 1H), 8.81 (s, 1H), 8.56 (s, 1H), 8.34 (d, J = 12.4 Hz, 1H), 7.77 (s, 1H), 7.37 (d, J = 1.6 Hz, 1H), 7.31 - 7.29 (m, 4H), 7.23 - 7.19 (m, 1H) 7.12 - 7.09 (m, 1H), 6.9 (d, J = 7.6 Hz, 1H), 6.8 (d, J = 8 Hz, 1H), 5.97 (s, 2H), 4.95 (s, 1H), 4.74 - 4.69 (m, 1H), 3.63 - 3.55 (m, 2H), 2.45 (s, 3H). LC-MS calculated exact mass: 473.18, found (m / z): 474.5 [M+H] + ; HPLC purity 98.33%, chiral HPLC purity 99.01%, mp 208.3 °C.

[1208] Representative Example of General Scheme 3:

[1209] Example 4: (S)-1-(2-((2-chloro-4-fluorophenyl)amino)-5-methylpyrimidin-4-yl

[1210] )-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-3-carboxamide (Compound #29)

[1211]

[1212] Step 1: Methyl 1-(2-chloro-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxylate

[1213] To a solution of methyl 1H-pyrrole-3-carboxylate (3.0 g, 24 mmol) in acetonitrile (100 mL) was added 2,4-dichloro-5-methylpyrimidine (5.9 g, 36 mmol) and potassium carbonate (6.6 g, 48 mmol). The reaction mixture was stirred at reflux for 12 h. The reaction mixture was diluted with ethyl acetate (500 mL), followed by washing with water and brine. The ethyl acetate layer was dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by gradient column chromatography using ethyl acetate in hexane as the eluent to afford methyl 1-(2-chloro-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxylate (3.2 g, 53%) as an off-white solid. 1 HNMR (400 MHz, CDCl3): δ 8.51 (s, 1H), 8.0 (s, 1H), 7.41 (d, J = 2.4 Hz, 1H,), 6.79 (t, J = 1.2 Hz, 1H,), 3.85 (s, 3H), 2.51 (s, 3H). Exact mass calculated for LC-MS: 251.05, found (m / z): 252.2 [M+H] + 。

[1214] Step 2: Methyl 1-(2-((2-chloro-4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxylate

[1215]

[1216] To a solution of methyl 1-(2-chloro-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxylate (0.3 g, 0.1195 mmol) in dioxane (10 mL) was added 2-chloro-4-fluoroaniline (0.17 g, 0.1195 mmol) and potassium carbonate (0.24 g, 1.17 mmol). The resulting reaction mixture was purged with nitrogen for 15 min, followed by the addition of 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.074 g, 0.119 mmol) and palladium(dibenzylideneacetone)dipalladium(0) (0.054 g, 0.059 mmol). The reaction mixture was stirred at 100 °C for 12 h. The reaction mixture was diluted with ethyl acetate (200 mL) and filtered through a bed of diatomaceous earth. The bed was washed with ethyl acetate (2 × 50 mL). The filtrate was washed several times with cold water, followed by brine. The organic layer was dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by gradient column chromatography using ethyl acetate in hexane as the eluent to afford methyl 1-(2-((2-chloro-4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxylate (0.25 g, 58%) as an off-white solid. 1 HNMR (400 MHz, CDCl3): δ 8.40–8.36 (m, 2H), 7.95 (s, 1H), 7.51 (s, 1H), 7.40 - 7.34 (m, 1H), 7.19 - 7.16 (m, 1H), 7.07–6.99 (m, 1H), 6.77 - 6.76 (m, 1H), 3.86 (s, 3H), 2.40 (s, 3H). LC-MS calculated exact mass: 360.08, found (m / z): 361.3 [M + H] + 。

[1217] Step 3: 1-(2-((2-chloro-4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxylic acid

[1218]

[1219] To a solution of methyl 1-(2-((2-chloro-4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxylate (0.25 g, 0.833 mmol) in methanol (20.0 mL) was added 2N sodium hydroxide solution (10 mL). The reaction mixture was stirred at 50 °C for 2 h. Methanol was removed under reduced pressure, and the pH was adjusted to about pH 6.5 - 7 by addition of dilute hydrochloric acid. The aqueous layer was extracted with ethyl acetate (3 × 50 mL), and the combined organic layers were dried over sodium sulfate, filtered, and evaporated under reduced pressure to afford 1-(2-((2-chloro-4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxylic acid as an off-white solid (0.17 g, 71%). 1 HNMR (400 MHz, DMSO-d6): δ 12.14 (s, 1H), 9.06 (s, 1H), 8.39 (s, 1H), 7.86 (s, 1H), 7.67 - 7.64 (m, 1H), 7.50 - 7.48 (m, 1H), 7.36 (t, J = 2.8 Hz, 1H), 7.24 - 7.19 (m, 1H), 6.57 (t, J = 2.0 Hz, 2H), 2.27 (s, 3H). LC-MS calculated exact mass: 346.06, found (m / z): 347.3 [M + H] + .

[1220] Step 4: (S)-1-(2-((2-chloro-4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-3-carboxamide

[1221]

[1222] To a solution of 1-(2-(2-chloro-4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxylic acid (0.05 g, 0.144 mmol) in NMP (2.0 mL) was added (S)-2-amino-2-(3-chlorophenyl)ethanol (0.029 g, 0.173 mmol), EDC (0.055 g, 0.288 mmol) and HOBt (0.005 g, 0.043 mmol). At room temperature, triethylamine (0.04 g, 0.432 mmol) was added dropwise to the resulting reaction mixture. The reaction mixture was stirred at room temperature for 15 h. The reaction mixture was poured into cold water (10 mL), and then extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was dissolved in a small volume of DCM and then diluted with ether. The solvent was gently decanted. The formed solid was washed with ether and n-pentane to afford (S)-1-(2-((2-chloro-4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-3-carboxamide (0.022 g, 31%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.99 (s, 1H), 8.37 (s, 1H), 8.25 (d, J = 8.4 Hz, 1H), 7.95 (s, 1H), 7.69 - 7.65 (m, 1H), 7.49 - 7.41 (m, 1H), 7.37–7.18 (m, 6H), 6.75 (s, 1H), 5.04 - 4.99 (m, 1H), 4.92 (br s, 1H), 3.65 - 3.64 (m, 2H), 2.28 (s, 3H). LC-MS calculated exact mass: 499.10, found (m / z): 500.3 [M + H] + ; HPLC purity: 99.03%, chiral HPLC: 99.66%.

[1223] Example 5: (S)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-(cyclopropylamino)-5-methylpyrimidin-4-yl)-1H-pyrazole-4-carboxamide (Compound #39)

[1224]

[1225] Step 1: Methyl 1-(2-chloro-5-methylpyrimidin-4-yl)-1H-pyrazole-4-carboxylate

[1226]

[1227] To a stirred solution of methyl 1H-pyrazole-4-carboxylate (1.00 g, 6.134 mmol) in acetonitrile (20 mL) was added potassium carbonate (2.543 g, 18.40 mmol), and the mixture was stirred at room temperature for 5 min. To the mixture was added 2,4-dichloro-5-methylpyrimidine (0.773 g, 6.134 mmol), and the mixture was stirred at 80 °C overnight. The mixture was cooled and water (15 mL) was added, and the mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over sodium sulfate, then evaporated under reduced pressure, and the residue was purified by gradient column chromatography using ethyl acetate in hexane as the eluent to afford methyl 1-(2-chloro-5-methylpyrimidin-4-yl)-1H-pyrazole-4-carboxylate (0.65 g, 42%) as a colorless solid. 1H NMR (400 MHz, CDCl3): δ 9.08 (s, 1H), 8.54 (s, 1H), 8.15 (s, 1H), 3.89 (s, 3H), 2.67 (s, 3H).

[1228] Step 2: Methyl 1-(2-(cyclopropylamino)-5-methylpyrimidin-4-yl)-1H-pyrazole-4-carboxylate

[1229] To a solution of methyl 1-(2-chloro-5-methylpyrimidin-4-yl)-1H-pyrazole-4-carboxylate (0.3 g, 1.18 mmol) in isopropanol (7 mL) were added DIPEA (0.43 mL, 2.47 mmol) and cyclopropylamine (0.09 mL, 1.3 mmol). At 85 °C, in a sealed glass tube, the reaction mixture was stirred overnight. The reaction mixture was cooled and quenched with water (10 mL), and extracted with ethyl acetate (3 × 10 mL). The organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure, and the residue was purified by gradient column chromatography using ethyl acetate in hexane as the eluent to afford methyl 1-(2-(cyclopropylamino)-5-methylpyrimidin-4-yl)-1H-pyrazole-4-carboxylate (0.17 g, 52%) as a colorless solid. 1H NMR (400 MHz, CDCl3): δ 8.97 (s, 1H), 8.27 (s, 1H), 8.09 (s, 1H), 5.26 (s, 1H), 3.87 (s, 3H), 2.80 - 2.76 (m, 1H), 2.47 (s, 3H), 0.87 - 0.83 (m, 2H), 0.56 (t, J = 7.2 Hz, 2H). LC-MS calculated exact mass: 273.12, found (m / z): 274.6 [M + H] + 。

[1230] Step 3: 1-(2-(Cyclopropylamino)-5-methylpyrimidin-4-yl)-1H-pyrazole-4-carboxylic acid

[1231] To a stirred solution of methyl 1-(2-(cyclopropylamino)-5-methylpyrimidin-4-yl)-1H-pyrazole-4-carboxylate (0.2 g, 0.72 mmol) in THF (7 mL) and water (1 mL) was added lithium hydroxide monohydrate (0.306 g, 7.29 mmol). The reaction mixture was stirred at 50 °C for 4 h. The mixture was cooled and concentrated under reduced pressure, and neutralized by addition of 1N HCl (pH ~7). The solid formed was filtered to afford 1-(2-(cyclopropylamino)-5-methylpyrimidin-4-yl)-1H-pyrazole-4-carboxylic acid as a colorless solid (0.122 g, 65%). 1H NMR (400 MHz, DMSO-d6): δ 12.0 (br s, 1H), 8.82 (s, 1H), 8.31 (s, 1H), 8.09 (s, 1H), 7.48 (s, 1H), 2.74 - 2.71 (m, 1H), 2.30 (s, 3H), 0.69 - 0.65 (m, 2H), 0.48 - 0.44 (m, 2H). LC-MS calculated exact mass: 259.11, found (m / z): 260.2 [M+H] + 。

[1232] Step 4: (S)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-(cyclopropylamino)-5-methylpyrimidin-4-yl)-1H-pyrazole-4-carboxamide

[1233]

[1234] To a stirred solution of 1-(2-(cyclopropylamino)-5-methylpyrimidin-4-yl)-1H-pyrazole-4-carboxylic acid (0.035 g, 0.134 mmol) in NMP (0.8 mL) was added EDC (0.051 g, 0.26 mmol), HOBt (0.005 g, 0.04 mmol) and triethylamine (0.05 mL, 0.4 mmol), and the mixture was then stirred at room temperature for 10 min. To this mixture was added (S)-2-amino-2-(3-chlorophenyl)ethanol (0.027 g, 0.16 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography using methanol in DCM as the eluent to afford (S)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-(cyclopropylamino)-5-methylpyrimidin-4-yl)-1H-pyrazole-4-carboxamide (0.011 g, 20%) as a colorless solid. 1H NMR (400 MHz, DMSO-d6): δ 9.00 (s, 1H), 8.61 (d, J = 8 Hz, 1H), 8.32 (s, 1H), 8.22 (s, 1H), 7.44 (d, J = 11.2 Hz, 2H), 7.36 - 7.27 (m, 3H), 5.07 - 5.01 (m, 1H), 4.98 - 4.95 (m, 1H), 3.66 - 3.65 (m, 2H), 2.76 - 2.73 (m, 1H), 2.34 (s, 3H), 0.68 (d, J = 5.2 Hz, 2H), 0.48 (d, J = 2.4 Hz, 2H). LC-MS calculated exact mass: 412.14, found (m / z): 413.2 [M+H] + ; HPLC purity 99.32%, chiral HPLC purity 99.76%.

[1235] Representative Example of General Scheme 4:

[1236] Example 6: N-(2-Amino-1-(3-chlorophenyl)ethyl)-1-(2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide (Compound #136)

[1237]

[1238] Step 1: Methyl 1H-pyrrole-3-carboxylate

[1239]

[1240] To a solution of 1H-pyrrole-3-carboxylic acid (4.3 g, 38.7 mmol) in methanol (40 mL) cooled to 0 - 5 °C was added 6N HCl (9 mL). The mixture was stirred at room temperature for 5 min and then heated under reflux overnight. The reaction mixture was cooled and concentrated under reduced pressure, then cooled to 0 °C and adjusted to pH ca. 7 by addition of saturated sodium bicarbonate. The mixture was extracted with ethyl acetate and the organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure to afford methyl 1H-pyrrole-3-carboxylate as a brown solid (4 g, 83%). 1 HNMR (400 MHz, CDCl3): δ 8.56 (br s, 1H), 7.43 (s, 1H), 6.75 (s, 1H), 6.65 (s, 1H), 3.92 (s, 3H). Exact mass calculated for LC-MS: 125.05, found (m / z): 126.2 [M + H] + 。

[1241] Step 2: Methyl 1-(2-chloro-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxylate

[1242] To a solution of methyl 1H-pyrrole-3-carboxylate (1.4 g, 11.2 mmol) in acetonitrile (50 mL) was added potassium carbonate (3.09 g, 22.4 mmol). The mixture was stirred at room temperature for 15 min and then 2,4-dichloro-5-methylpyrimidine (2.738 g, 16.8 mmol) was added. The resulting mixture was heated under reflux overnight. The reaction mixture was cooled, then evaporated under reduced pressure, combined with water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by gradient column chromatography using ethyl acetate in hexane as the eluent to afford methyl 1-(2-chloro-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxylate as a white solid (1.2 g, 43%). 1 HNMR (400 MHz, CDCl3): δ 8.50 (s, 1H), 7.99 (s, 1H), 7.40 - 7.39 (m, 1H), 6.78 - 6.77 (m, 1H), 3.85 (s, 3H), 2.51 (s, 3H). Exact mass calculated for LC-MS: 251.05, found (m / z): 252.3 [M + H] + 。

[1243] Step 3: Methyl 1-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxylate

[1244]

[1245] To a solution of methyl 1-(2-chloro-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxylate (3.1 g, 12.31 mmol) in dioxane (20 mL) was added potassium carbonate (2.549 g, 18.47 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.766 g, 1.231 mmol), and 2,2-difluorobenzo[d][1,3]dioxol-5-amine (2.23 g, 12.92 mmol). The reaction mixture was degassed with argon for 15 min, and then tris(dibenzylideneacetone)-dipalladium(0) (0.563 g, 0.615 mmol) was added. The resulting mixture was stirred in a sealed glass tube at 100 °C for 9 h. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was dissolved in water, extracted with ethyl acetate, and the combined organic phases were washed with water and brine. The combined organic phases were dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by gradient column chromatography using ethyl acetate in hexane as the eluent to afford methyl 1-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxylate (2.3 g, 48%) as an off-white solid. 1 HNMR (400 MHz, CDCl3): δ 8.34 (s, 1H), 7.95 (s, 1H), 7.69 (d, J = 1.6 Hz, 1H), 7.34 (t, J = 2.8 Hz, 1H), 7.23 (s, merged with CDCl3 peak, 1H), 7.06–6.99 (m, 2H), 6.78–6.77 (m, 1H), 3.86 (s, 3H), 2.40 (s, 3H). Exact mass calculated for LC-MS: 388.10, found (m / z): 389.3 [M+H] + 。

[1246] Step 4: 1-(2-((2,2-Difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxylic acid

[1247]

[1248] To a solution of methyl 1-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxylate (1.0 g, 2.5 mmol) in THF (40 mL) and water (20 mL) was added lithium hydroxide monohydrate (0.648 g, 15.4 mmol). The resulting mixture was heated to reflux at 70 °C for 12 h. The reaction mixture was cooled, then concentrated under reduced pressure, and adjusted to pH ca. 6 by addition of 1N HCl. The solid was filtered and washed with n-pentane and diethyl ether to afford 1-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxylic acid as a white solid (0.85 g, 88%). 1 HNMR (400 MHz, DMSO-d6): δ 11.98 (br s, 1H), 9.58 (s, 1H), 8.38 (s, 1H), 7.94 - 7.82 (m, 2H), 7.36 (d, 2H J = 8 Hz), 7.0 (d, 1H J = 8.4 Hz), 6.69 (s, 1H), 2.38 (s, 3H). LC-MS calculated exact mass: 374.08, found (m / z): 375.1 [M+H] + 。

[1249] Step 5: N-((3-chlorophenyl)(cyano)methyl)-1-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide

[1250] To a solution of 1-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxylic acid (0.2 g, 0.53 mmol) in DCM (15 mL) and THF (3 mL) was added triethylamine (0.2 mL, 1.6 mmol), and the mixture was stirred for 5 min under a nitrogen atmosphere. Then, 2-amino-2-(3-chlorophenyl)acetonitrile (0.1 g, 0.64 mmol), EDC (0.2 g, 1.06 mmol), and HOBt (0.021 g, 0.16 mmol) were added to the mixture. The resulting mixture was stirred overnight at room temperature. The reaction mixture was quenched with water and extracted with DCM. The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by gradient column chromatography using ethyl acetate in hexane as the eluent to afford N-((3-chlorophenyl)(cyano)methyl)-1-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide (0.1 g, 36%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.35 (s, 1H), 7.95 (s, 1H), 7.6 (s, 1H), 7.56 (s, 1H), 7.4 (d, J = 6.8 Hz, 1H), 7.41 - 7.38 (m, 3H), 7.0 - 6.99 (m, 2H), 6.6 (s, 1H), 6.4 (d, J = 8.8 Hz, 2H), 6.34 (d, J = 8.8 Hz, 2H), 2.4 (s, 3H). LC-MS calculated exact mass: 522.10, found (m / z): 523.2 [M + H] + , HPLC purity 98.03%.

[1251] Step 6: N-(2-Amino-1-(3-chlorophenyl)ethyl)-1-(2-((2,2-difluorobenzo[I][1,3]dioxol-5-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide

[1252]

[1253] At 0 °C, a methanol solution of ammonia (20 mL) was added to a solution of N-(3-chlorophenyl)(cyano)methyl)-1-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide (0.1 g, 0.191 mmol) in methanol (10 mL), and then Raney nickel (0.05 g) was added. At room temperature, the resulting reaction mixture was stirred overnight under a hydrogen atmosphere using a balloon. The reaction mixture was filtered through diatomaceous earth, and the filtrate was evaporated under reduced pressure. The residue was purified by gradient column chromatography using methanol in DCM as the eluent to afford N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide (0.03 g, 30%) as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 8.34 (s, 1H), 7.95 (s, 1H), 7.69 (d, J = 1.6 Hz, 1H), 7.34 (t, J = 2.8 Hz, 1H), 7.23 (s, merged with CDCl3 peak, 1H), 7.06–6.99 (m, 2H), 6.78–6.77 (m, 1H), 3.86 (s, 3H), 2.40 (s, 3H). Exact mass calculated by LC-MS: 526.13, found (m / z): 527.5 [M+H] + .

[1254] Example 7: N-(2-Amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide (Compound #225)

[1255]

[1256] Step 1: Methyl 1-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxylate

[1257] To a solution of methyl 1H-imidazole-4-carboxylate (10.37 g, 74.0 mmol) in acetonitrile (200 mL) was added 2,4-dichloro-5-methylpyrimidine (10 g, 61.7 mmol) and potassium carbonate (25.5 g, 185.2 mmol). Then, the mixture was stirred at room temperature under an inert atmosphere for 16 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by gradient column chromatography using ethyl acetate in hexane as the eluent to afford methyl 1-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxylate (11 g, 75%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.88 (s, 1H), 8.38 (s, 2H), 3.80 (s, 3H), 2.41 (s, 3H). LC-MS exact mass calculated: 252.04, found (m / z): 253.2 [M+H] + 。

[1258] Step 2: Methyl 1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxylate

[1259]

[1260] To a solution of methyl 1-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxylate (5 g, 19.7 mmol) in isopropanol (30 mL) was added DIPEA (7.658 g, 59.0 mmol) and tetrahydro-2H-pyran-4-amine (2.402 g, 23.0 mmol). The resulting mixture was stirred in a sealed glass tube at 100 °C for 17 h. The reaction mixture was cooled to room temperature and allowed to crystallize. The crystals were filtered, washed with hexane, and dried in vacuo to afford methyl 1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxylate (5.2 g, 83%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.36 (s, 1H), 8.30 (s, 1H), 8.27 (s, 1H), 7.39 (d, J = 7.6 Hz, 1H), 3.90 - 3.83 (m, 3H), 3.78 (s, 3H), 3.37 (t, J = 11.6 Hz, 2H), 2.16 (s, 3H), 1.82 (d, J = 12 Hz, 2H), 1.54–1.45 (m, 2H), LC-MS exact mass calculated: 317.15, found (m / z): 318.2 [M+H] + 。

[1261] Alternatively, methyl 1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxylate can be prepared as follows:

[1262]

[1263] Charge a reactor with N,N-dimethylacetamide (DMAC) (4.6 L), 1-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxylate (1150 g, 4.55 mol), DIPEA (3.2 L), and tetrahydro-2H-pyran-4-amine hydrochloride (940 g, 6.83 mol) in sequence. Heat the resulting mixture at 100 °C and stir until the HPLC content of 1-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxylate in the reaction mixture ≤ 5%. Cool the mixture, charge water into the reactor, and stir the mixture at 15 - 18 °C. Then cool the mixture and stir at 3 - 10 °C. Collect the solid by filtration, wash the filter cake with water, and dry it to afford methyl 1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxylate.

[1264] Step 3: N-((3-chlorophenyl)(cyano)methyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide

[1265]

[1266] Add 2-amino-2-(3-chlorophenyl)acetonitrile (0.392 g, 2.3 mmol) and trimethylaluminum (2 M toluene solution; 1.96 mL, 2.5 equiv) to a solution of methyl 1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxylate (0.500 g, 1.57 mmol) in toluene (20 mL). Stir the resulting mixture in a CEM microwave at 100 °C for 1 h. Quench the reaction mixture with water and extract with ethyl acetate. Wash the organic layer with cold water, dry over sodium sulfate, filter, and evaporate under reduced pressure. Purify the residue by gradient column chromatography twice using methanol in DCM as the eluent to yield N-((3-chlorophenyl)(cyano)methyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide (0.29 g) as a yellow solid. LC-MS exact mass calculated: 451.15, found (m / z): 452.2 [M+H] + 。

[1267] Step 4: N-(2-Amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide

[1268]

[1269] At 0 °C, under an inert atmosphere, nickel(II) chloride hexahydrate (0.552 g, 2.3 mmol) was added to a solution of N-((3-chlorophenyl)(cyano)methyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide (0.700 g, 1.54 mmol) in methanol (15 mL), and the mixture was then stirred to obtain a clear solution. At 0 °C, sodium borohydride (0.175 g, 4.6 mmol) was slowly added to the reaction mixture, and the mixture was then stirred at 0 °C for 10 min. The reaction mixture was filtered through diatomaceous earth, and the filtrate was evaporated under reduced pressure. The residue was purified by gradient column chromatography using methanol in dichloromethane as the eluent to afford N-(2-Amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide (racemic mixture) (0.050 g, 7%) as an off-white solid, which was used directly for chiral HPLC separation. Data obtained for individual batches prepared in a similar manner: 1H NMR (400 MHz, DMSO-d6): δ 8.53 (d, J = 8 Hz 1H), 8.32 (s, 1H), 8.25 (s, 1H), 8.06 (s, 1H), 7....

Claims

1. A method of treatment, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) in regularly or irregularly scheduled doses, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof, wherein: R 1 is C 6-12 an aryl or a 5- to 10-membered heteroaryl, which is unsubstituted or substituted with 1-3 substituents selected from the following: halogen, C 1-6 alkyl, CN, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, -C 1-6 alkyl-O-C 1-6 alkyl, -C 1-6 alkyl-NH-C 1-6 alkyl, -C 1-6 alkyl-N-(C 1-6 alkyl)2, -C 1-6 alkyl-NH-C 1-6 alkyl-OH, -C 1-6 alkyl-NH-C 1-6 alkyl-C 3-10 cycloalkyl, -C 1-6 alkyl-NH-C 1-6 alkyl-NH-C 1-6 alkyl, -C 1-6 alkyl-NH-C(O)-C 1-6 alkyl, -C 1-6 alkyl-O-C(O)-C 1-6 alkyl, -C 1-6 alkyl-NH-C 0-6 alkyl-(4- to 6-membered heterocyclic group) or -C 1-6 alkyl-NH-C 0-6 alkyl-(5- to 6-membered heteroaryl), wherein the C 1-6 alkyl, cycloalkyl, heterocyclic group and / or heteroaryl is unsubstituted or substituted with 1-3 substituents selected from the following: halogen, C 1-6 alkyl, NH2, hydroxy C 1-6 alkyl or amino C 1-6 alkyl; J is a linker group selected from -C(R 2 )(R 8 )(CH2)-; R 2 and R8 are each independently H, C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, -C 1-6 alkyl - O - C 1-6 alkyl, -C 1-6 alkyl - NH - C 1-6 alkyl, -C 1-6 alkyl - N-(C 1-6 alkyl)2, -C 1-6 alkyl - NH - C 1-6 alkyl - OH, -C 1-6 alkyl - NH - C 1-6 alkyl - C 3-10 cycloalkyl, -C 1-6 alkyl - NH - C 1-6 alkyl - NH - C 1-6 alkyl, -C 1-6 alkyl - NH - C(O)-C 1-6 alkyl, -C 1-6 alkyl - O - C(O)-C 1-6 alkyl, -C 1-6 alkyl - NH - C 0-6 alkyl-(4 - to 6 - membered heterocyclic group), -C(O)-NH2, -C(O)-NH - C 1-6 alkyl, -C(O)-N(C 1-6 alkyl)2 or -C 1-6 alkyl - NH - C 0-6 alkyl-(5 - to 6 - membered heteroaryl), wherein the C 1-6 alkyl, heterocyclic group or heteroaryl is unsubstituted or substituted with 1 - 3 substituents selected from: halogen, C 1-6 alkyl, cycloalkyl, NH2, hydroxy C 1-6 alkyl or amino C 1-6 alkyl; or R 2 、R 8 and having R 2 with R 8 The C atoms of both are attached together to form a 3- to 10-membered cycloalkyl or 4- to 10-membered heterocyclic group ring, wherein the cycloalkyl or heterocyclic group is unsubstituted or substituted with 1-3 substituents selected from: hydroxyl, halogen or C 1-6 alkyl; n is from 0 to 6; R 3 is H or C 1-6 alkyl, wherein said C 1-6 alkyl is unsubstituted or substituted with 1-5 halogens; M is a bond or NH; X and Y are each independently CH, C-R 7 or N; Z is CH or N, R 5 is H, halogen, C 1-6 alkyl or O-C 1-6 alkyl, where C 1-6 alkyl is unsubstituted or substituted by 1-5 halogens; R 6 is H or C 1-6 alkyl, wherein said C 1-6 alkyl is unsubstituted or substituted with 1 - 5 halogens; R 7 is C 1-6 alkyl, wherein said C 1-6 alkyl is unsubstituted or substituted with 1-5 halogens; and R 4 is C 1-6 alkyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, -C 1-6 alkyl-phenyl, -C 1-6 alkyl-(5- to 6-membered heteroaryl), -C 1-6 alkyl-(4- to 6-membered heterocyclic group), 4- to 10-membered heterocyclic group, phenyl or 5- to 10-membered heteroaryl, wherein the alkyl, cycloalkyl, cycloalkenyl, phenyl, heteroaryl or heterocyclic group is unsubstituted or substituted by 1-3 substituents selected from the following: halogen, CN, -C(O)-NH2, -C(O)-NH-C 1-6 alkyl, -C(O)-N-(C 1-6 alkyl)2, -O-C 1-6 alkyl-NH2, -O-C 1-6 alkyl-NH-(C 1-6 alkyl), -O-C 1-6 alkyl-N(C 1-6 alkyl)2, 4- to 6-membered heterocyclic group, -C(O)-(4- to 6-membered heterocyclic group), -O-phenyl, -O-C 1-6 alkyl-(4- to 6-membered heterocyclic group), C 1-6 alkyl, C 2-6 alkynyl, hydroxyl, C 1-6 alkoxy or hydroxy C 1-6 alkyl, and the heterocyclic group or heteroaryl is unsubstituted or substituted by 1-3 substituents selected from the following: halogen, C 1-6 alkyl, -C(O)-C 1-6 alkyl or 4- to 6-membered heterocyclic group, wherein the therapeutically effective amount is from about 80 mg to about 350 mg.

2. The method according to claim 1, wherein the compound is a compound of formula (II), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof, wherein: R 2 is C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, -C 1-6 alkyl - O - C 1-6 alkyl, -C 1-6 alkyl - NH - C 1-6 alkyl, -C 1-6 alkyl - N-(C 1-6 alkyl)2, -C 1-6 alkyl - NH - C 1-6 alkyl - OH, -C 1-6 alkyl - NH - C 1-6 alkyl - C 3-10 cycloalkyl, -C 1-6 alkyl - NH - C 1-6 alkyl - NH - C 1-6 alkyl, -C 1-6 alkyl - NH - C(O)-C 1-6 alkyl, -C 1-6 alkyl - O - C(O)-C 1-6 alkyl, -C 1-6 alkyl - NH - C 0-6 alkyl-(4 - to 6 - membered heterocyclic group), -C(O)-NH2, -C(O)-NH - C 1-6 alkyl, -C(O)-N(C 1-6 alkyl)2 or -C 1-6 alkyl - NH - C 0-6 alkyl-(5 - to 6 - membered heteroaryl), wherein the C 1-6 alkyl, heterocyclic group or heteroaryl is unsubstituted or substituted by 1 - 3 substituents selected from: halogen, C 1-6 alkyl, cycloalkyl, NH2, hydroxy C 1-6 alkyl or amino C 1-6 alkyl; and R 8 is H or C 1-6 alkyl; Alternatively, R 2 , R 8 and the attached R 2 with R 8 The C atoms of both are linked together to form a 3- to 10-membered cycloalkyl or 4- to 10-membered heterocyclic ring, wherein the cycloalkyl or heterocyclic ring is unsubstituted or substituted with 1-3 substituents selected from: hydroxy, halogen or C 1-6 alkyl; and R 1 、R 3 、R 4 、R 5 、R 6 、n, M, X, Y, and Z are as defined above.

3. The method according to claim 1, wherein the therapeutically effective amount is from about 120 mg to about 250 mg.

4. A method of treating a condition treatable by inhibiting ERK1 / 2, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) in regularly or irregularly scheduled doses, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof, wherein: R 1 is C 6-12 an aryl or a 5- to 10-membered heteroaryl, which is unsubstituted or substituted with 1-3 substituents selected from the following: halogen, C 1-6 alkyl, CN, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, -C 1-6 alkyl - O - C 1-6 alkyl, -C 1-6 alkyl - NH - C 1-6 alkyl, -C 1-6 alkyl - N-(C 1-6 alkyl)2, -C 1-6 alkyl - NH - C 1-6 alkyl - OH, -C 1-6 alkyl - NH - C 1-6 alkyl - C 3-10 cycloalkyl, -C 1-6 alkyl - NH - C 1-6 alkyl - NH - C 1-6 alkyl, -C 1-6 alkyl - NH - C(O)-C 1-6 alkyl, -C 1-6 alkyl - O - C(O)-C 1-6 alkyl, -C 1-6 alkyl - NH - C 0-6 alkyl-(4- to 6-membered heterocyclic group) or -C 1-6 alkyl - NH - C 0-6 alkyl-(5- to 6-membered heteroaryl), wherein the C 1-6 alkyl, cycloalkyl, heterocyclic group and / or heteroaryl is unsubstituted or substituted with 1-3 substituents selected from the following: halogen, C 1-6 alkyl, NH2, hydroxy C 1-6 alkyl or amino C 1-6 alkyl; J is a linker group selected from -C(R 2 )(R 8 )(CH2)-; R 2 and R8 are each independently H, C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, -C 1-6 alkyl - O - C 1-6 alkyl, -C 1-6 alkyl - NH - C 1-6 alkyl, -C 1-6 alkyl - N-(C 1-6 alkyl)2, -C 1-6 alkyl - NH - C 1-6 alkyl - OH, -C 1-6 alkyl - NH - C 1-6 alkyl - C 3-10 cycloalkyl, -C 1-6 alkyl - NH - C 1-6 alkyl - NH - C 1-6 alkyl, -C 1-6 alkyl - NH - C(O)-C 1-6 alkyl, -C 1-6 alkyl - O - C(O)-C 1-6 alkyl, -C 1-6 alkyl - NH - C 0-6 alkyl-(4 - to 6 - membered heterocyclic group), -C(O)-NH2, -C(O)-NH - C 1-6 alkyl, -C(O)-N(C 1-6 alkyl)2 or -C 1-6 alkyl - NH - C 0-6 alkyl-(5 - to 6 - membered heteroaryl), wherein the C 1-6 alkyl, heterocyclic group or heteroaryl is unsubstituted or substituted by 1 - 3 substituents selected from: halogen, C 1-6 alkyl, cycloalkyl, NH2, hydroxy C 1-6 alkyl or amino C 1-6 alkyl; Alternatively, R 2 , R 8 and having R 2 and R 8 both have their C atoms attached together to form a 3- to 10-membered cycloalkyl or 4- to 10-membered heterocyclic ring, where the cycloalkyl or heterocyclic ring is unsubstituted or substituted with 1-3 substituents selected from: hydroxy, halogen, or C 1-6 alkyl; R 3 is H or C 1-6 alkyl, wherein said C 1-6 alkyl is unsubstituted or substituted with 1-5 halogens; M is a bond or NH; X and Y are each independently CH, C-R 7 or N; Z is CH or N, R 5 is H, halogen, C 1-6 alkyl or O-C 1-6 alkyl, wherein C 1-6 alkyl is unsubstituted or substituted by 1-5 halogens; R 6 is H or C 1-6 alkyl, wherein said C 1-6 alkyl is unsubstituted or substituted by 1 - 5 halogens; R 7 is C 1-6 alkyl, wherein said C 1-6 alkyl is unsubstituted or substituted with 1-5 halogens; and R 4 is C 1-6 alkyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, -C 1-6 alkyl-phenyl, -C 1-6 alkyl-(5- to 6-membered heteroaryl), -C 1-6 alkyl-(4- to 6-membered heterocyclic group), 4- to 10-membered heterocyclic group, phenyl or 5- to 10-membered heteroaryl, wherein the alkyl, cycloalkyl, cycloalkenyl, phenyl, heteroaryl or heterocyclic group is unsubstituted or substituted with 1-3 substituents selected from: halogen, CN, -C(O)-NH2, -C(O)-NH-C 1-6 alkyl, -C(O)-N-(C 1-6 alkyl)2, -O-C 1-6 alkyl-NH2, -O-C 1-6 alkyl-NH-(C 1-6 alkyl), -O-C 1-6 alkyl-N(C 1-6 alkyl)2, 4- to 6-membered heterocyclic group, -C(O)-(4- to 6-membered heterocyclic group), -O-phenyl, -O-C 1-6 alkyl-(4- to 6-membered heterocyclic group), C 1-6 alkyl, C 2-6 alkynyl, hydroxy, C 1-6 alkoxy or hydroxy C 1-6 alkyl, and the heterocyclic group or heteroaryl is unsubstituted or substituted with 1-3 substituents selected from: halogen, C 1-6 alkyl, -C(O)-C 1-6 alkyl or 4- to 6-membered heterocyclic group, wherein the therapeutically effective amount is from about 80 mg to about 350 mg.

5. A method of treatment, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or stereoisomer thereof, wherein: J is a linker group selected from -C(R 2 )(R 8 )(CH2)-; R 1 is C 6-12 an aryl or a 5- to 10-membered heteroaryl, which is unsubstituted or substituted with 1-3 substituents selected from the following: halogen, C 1-6 alkyl, CN, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, -C 1-6 alkyl-O-C 1-6 alkyl, -C 1-6 alkyl-NH-C 1-6 alkyl, -C 1-6 alkyl-N-(C 1-6 alkyl)2, -C 1-6 alkyl-NH-C 1-6 alkyl-OH, -C 1-6 alkyl-NH-C 1-6 alkyl-C 3-10 cycloalkyl, -C 1-6 alkyl-NH-C 1-6 alkyl-NH-C 1-6 alkyl, -C 1-6 alkyl-NH-C(O)-C 1-6 alkyl, -C 1-6 alkyl-O-C(O)-C 1-6 alkyl, -C 1-6 alkyl-NH-C 0-6 alkyl-(4- to 6-membered heterocyclic group) or -C 1-6 alkyl-NH-C 0-6 alkyl-(5- to 6-membered heteroaryl), wherein the C 1-6 alkyl, cycloalkyl, heterocyclic group and / or heteroaryl is unsubstituted or substituted with 1-3 substituents selected from the following: halogen, C 1-6 alkyl, NH2, hydroxy C 1-6 alkyl or amino C 1-6 alkyl; R 2 is C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, -C 1-6 alkyl - O - C 1-6 alkyl, -C 1-6 alkyl - NH - C 1-6 alkyl, -C 1-6 alkyl - N-(C 1-6 alkyl)2, -C 1-6 alkyl - NH - C 1-6 alkyl - OH, -C 1-6 alkyl - NH - C 1-6 alkyl - C 3-10 cycloalkyl, -C 1-6 alkyl - NH - C 1-6 alkyl - NH - C 1-6 alkyl, -C 1-6 alkyl - NH - C(O)-C 1-6 alkyl, -C 1-6 alkyl - O - C(O)-C 1-6 alkyl, -C 1-6 alkyl - NH - C 0-6 alkyl-(4 - to 6 - membered heterocyclic group), -C(O)-NH2, -C(O)-NH - C 1-6 alkyl, -C(O)-N(C 1-6 alkyl)2 or -C 1-6 alkyl - NH - C 0-6 alkyl-(5 - to 6 - membered heteroaryl), wherein the C 1-6 alkyl, heterocyclic group or heteroaryl is unsubstituted or substituted by 1 - 3 substituents selected from: halogen, C 1-6 alkyl, cycloalkyl, NH2, hydroxy C 1-6 alkyl or amino C 1-6 alkyl; and R 8 is H or C 1-6 alkyl; Alternatively, R 2 , R 8 and the attached R 2 with R 8 The C atoms of both are joined together to form a 3- to 10-membered cycloalkyl or 4- to 10-membered heterocyclic ring, wherein the cycloalkyl or heterocyclic ring is unsubstituted or substituted with 1-3 substituents selected from: hydroxyl, halogen or C 1-6 alkyl; R 3 is H or C 1-6 alkyl, wherein said C 1-6 alkyl is unsubstituted or substituted with 1-5 halogens; M is a bond or NH; X and Y are each independently CH, C-R 7 or N; Z is CH or N, R 5 is H, halogen, C 1-6 alkyl or O-C 1-6 alkyl, wherein C 1-6 alkyl is unsubstituted or substituted by 1-5 halogens; R 6 is H or C 1-6 alkyl, wherein said C 1-6 alkyl is unsubstituted or substituted with 1-5 halogens; R 7 is C 1-6 alkyl, wherein said C 1-6 alkyl is unsubstituted or substituted with 1-5 halogens; and R 4 is C 1-6 alkyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, -C 1-6 alkyl-phenyl, -C 1-6 alkyl-(5- to 6-membered heteroaryl), -C 1-6 alkyl-(4- to 6-membered heterocyclic group), 4- to 10-membered heterocyclic group, phenyl or 5- to 10-membered heteroaryl, wherein the alkyl, cycloalkyl, cycloalkenyl, phenyl, heteroaryl or heterocyclic group is unsubstituted or substituted by 1-3 substituents selected from the following: halogen, CN, -C(O)-NH2, -C(O)-NH-C 1-6 alkyl, -C(O)-N-(C 1-6 alkyl)2, -O-C 1-6 alkyl-NH2, -O-C 1-6 alkyl-NH-(C 1-6 alkyl), -O-C 1-6 alkyl-N(C 1-6 alkyl)2, 4- to 6-membered heterocyclic group, -C(O)-(4- to 6-membered heterocyclic group), -O-phenyl, -O-C 1-6 alkyl-(4- to 6-membered heterocyclic group), C 1-6 alkyl, C 2-6 alkynyl, hydroxy, C 1-6 alkoxy or hydroxy C 1-6 alkyl, and the heterocyclic group or heteroaryl is unsubstituted or substituted by 1-3 substituents selected from the following: halogen, C 1-6 alkyl, -C(O)-C 1-6 alkyl or 4- to 6-membered heterocyclic group, wherein the therapeutically effective amount is about 250 mg and the compound is administered to the subject once a week on a regular schedule.

6. A dosing regimen, the dosing regimen comprising administering to a subject in need thereof a therapeutically effective amount of the compound of claim 1 in regularly or irregularly scheduled doses, wherein the therapeutically effective amount is from about 80 mg to about 350 mg.

7. A kit, the kit comprising one or more dosage forms for treating one or more diseases or conditions and instructions for administering the dosage forms to a subject, wherein the instructions comprise the method of claim 1.

8. An oral pharmaceutical composition, the oral pharmaceutical composition comprising (S)-N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide mandelate, (S)-N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide benzenesulfonate, or (S)-N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide benzenesulfonate, wherein the composition provides an AUC of from about 880 h*ng / mL to about 6120 h*ng / mL after administration of the compound tau , a C of from about 68 ng / mL to about 2330 ng / mL max and / or a C of from about 11 ng / mL to about 48 ng / mL min .

9. An oral pharmaceutical composition, the oral pharmaceutical composition comprising (S)-N-(2-Amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide mandelate, (S)-N-(2-Amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide benzenesulfonate, or (S)-N-(2-Amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide benzenesulfonate, wherein the composition provides an AUC of from about 1190 h*ng / mL to about 7080 h*ng / mL after administration of the compound tau 、a Cmax of from about 80 ng / mL to about 1520 ng / mL max and / or a Cmin of from about 0.8 ng / mL to about 23 ng / mL min .

10. An oral pharmaceutical composition, the oral pharmaceutical composition comprising (S)-N-(2-Amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide mandelate, (S)-N-(2-Amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide benzenesulfonate, or (S)-N-(2-Amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide benzenesulfonate, wherein the composition provides an AUC of from about 1840 h*ng / mL to about 18,120 h*ng / mL after administration of the compound tau , a C of from about 128 ng / mL to about 960 ng / mL max and / or a C of from about 0.4 ng / mL to about 60 ng / mL min .

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