COMPOUNDS AND COMPOSITIONS AS PROTEIN KINASE INHIBITORS
First Claim
Patent Images
1. A compound of Formula I:
- in which X is selected from a bond and NH;
Y is selected from a bond and NH;
R1 is selected from cyclohexyl, pyridinyl, quinolinyl, isoquinolinyl and phenyl;
wherein said cyclohexyl, pyridinyl, quinolinyl, isoquinolinyl or phenyl of R1 can be optionally substituted with 1 to 3 radicals independently selected from halo, C1-4alkyl, C1-6alkoxy, halo-substituted-C1-6alkyl, halo-substituted-C1-6alkoxy, —
NR5aR5b, —
OX1NR5aR5b and heterocyclyl;
wherein X1 is independently selected from a bond and C1-4alkylene; and
R5a and R5b are independently selected from hydrogen, C1-6alkyl, C1-6alkoxy, halo-substituted-C1-6alkyl and halo-substituted-C1-6alkoxy;
is selected from halo, C1-6alkyl, C1-6alkoxy, halo-substituted-C1-6alkyl and halo-substituted-C1-6alkoxy;
R2 is selected from halo, C1-6alkyl, C1-6alkoxy, halo-substituted-C1-6alkyl and halo-substituted-C1-6alkoxy;
R3 is heteroaryl substituted with 1 to 3 radicals independently selected from halo, cyano, C1-6alkyl, C1-6alkoxy, halo-substituted-C1-6alkyl, halo-substituted-C1-6alkoxy, C6-10aryl-C0-4alkyl, heteroaryl, heterocyclyl, —
X1NR5R5X1NR5OR5, —
X1NR5X1OR5, —
X1NR5X1C(O)NR5R5, —
X1S(O)2NR5R5, —
X1S(O)2R5, —
X1NR5R5, —
X1NR5OR5, —
X1C(O)R5, —
X1OX2OR5, —
OX1R5, —
X1R5, —
X1C(O)OR5, —
X1OR5 and —
X10X1OR5;
wherein each X1 is independently selected from a bond and C1-4alkylene;
X2 is C1-4alkylene; and
each R5 is independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C3-12cycloalkyl, C6-10aryl-C0-4alkyl, heteroaryl-C0-4alkyl and heterocyclyl;
wherein said aryl, cycloalkyl, heteroaryl or heterocyclyl substituents of R4 can optionally be further substituted with 1 to 3 radicals independently selected from halo, hydroxy, cyano, C1-6alkyl, C1-6alkoxy, halo-substituted-C1-6alkyl, halo-substituted-C1-6alkoxy, -L-OR6, -L-C(O)OR6, -L-C(O)NR6R6 and -L-R6;
wherein L is selected from a bond and C1-4alkylene; and
R6 is selected from hydrogen, C1-6alkyl and heterocyclyl;
with the proviso that R4 is not pyridin-3-yl substituted by a trifluoromethyl radical; and
the pharmaceutically acceptable salts thereof.
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Abstract
The invention provides a novel class of compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to beat or prevent diseases or disorders associated with abnormal or deregulated kinase activity, particularly diseases or disorders that involve abnormal activation of c-kit, PDGFRα and PDGFRβ kinases. Formula (I).
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Citations
32 Claims
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1. A compound of Formula I:
-
in which X is selected from a bond and NH; Y is selected from a bond and NH; R1 is selected from cyclohexyl, pyridinyl, quinolinyl, isoquinolinyl and phenyl;
wherein said cyclohexyl, pyridinyl, quinolinyl, isoquinolinyl or phenyl of R1 can be optionally substituted with 1 to 3 radicals independently selected from halo, C1-4alkyl, C1-6alkoxy, halo-substituted-C1-6alkyl, halo-substituted-C1-6alkoxy, —
NR5aR5b, —
OX1NR5aR5b and heterocyclyl;
wherein X1 is independently selected from a bond and C1-4alkylene; and
R5a and R5b are independently selected from hydrogen, C1-6alkyl, C1-6alkoxy, halo-substituted-C1-6alkyl and halo-substituted-C1-6alkoxy;
is selected from halo, C1-6alkyl, C1-6alkoxy, halo-substituted-C1-6alkyl and halo-substituted-C1-6alkoxy;R2 is selected from halo, C1-6alkyl, C1-6alkoxy, halo-substituted-C1-6alkyl and halo-substituted-C1-6alkoxy; R3 is heteroaryl substituted with 1 to 3 radicals independently selected from halo, cyano, C1-6alkyl, C1-6alkoxy, halo-substituted-C1-6alkyl, halo-substituted-C1-6alkoxy, C6-10aryl-C0-4alkyl, heteroaryl, heterocyclyl, —
X1NR5R5X1NR5OR5, —
X1NR5X1OR5, —
X1NR5X1C(O)NR5R5, —
X1S(O)2NR5R5, —
X1S(O)2R5, —
X1NR5R5, —
X1NR5OR5, —
X1C(O)R5, —
X1OX2OR5, —
OX1R5, —
X1R5, —
X1C(O)OR5, —
X1OR5 and —
X10X1OR5;
wherein each X1 is independently selected from a bond and C1-4alkylene;
X2 is C1-4alkylene; and
each R5 is independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C3-12cycloalkyl, C6-10aryl-C0-4alkyl, heteroaryl-C0-4alkyl and heterocyclyl;wherein said aryl, cycloalkyl, heteroaryl or heterocyclyl substituents of R4 can optionally be further substituted with 1 to 3 radicals independently selected from halo, hydroxy, cyano, C1-6alkyl, C1-6alkoxy, halo-substituted-C1-6alkyl, halo-substituted-C1-6alkoxy, -L-OR6, -L-C(O)OR6, -L-C(O)NR6R6 and -L-R6;
wherein L is selected from a bond and C1-4alkylene; and
R6 is selected from hydrogen, C1-6alkyl and heterocyclyl;
with the proviso that R4 is not pyridin-3-yl substituted by a trifluoromethyl radical; and
the pharmaceutically acceptable salts thereof.- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32)
in which; X is selected from a bond and NH; Y is selected from a bond and NH;
wherein either X or Y, but not both, is a bond;R3 is selected from halo, methyl, methoxy, trifluoromethyl and trifluoromethoxy; R4 is heteroaryl substituted with 1 to 3 radicals independently selected from halo, cyano, C1-6alkyl, C1-6alkoxy, halo-substituted-C1-6alkyl, halo-substituted-C1-6alkoxy, C6-10aryl-C0-4alkyl, heteroaryl, heterocyclyl, —
X1NR5R5, —
X1NR5OR5, —
X1NR5X1OR5, —
X1NR5X1C(O)NR5R5, —
X1S(O)2NR5R5, —
X1S(O)2R5, —
X1NR5R5, —
X1NR5OR5, —
X1C(O)R5, —
X1OX2OR5, —
OX1R5, —
X1R5, —
X1C(O)OR5, —
X1OR5 and —
X1OX1OR5;
wherein each X1 is independently selected from a bond and C1-4alkylene;
X2 is C1-4alkylene; and
each R5 is independently selected from hydrogen, C1-6alkyl, C2-4alkenyl, C3-12cycloalkyl, C6-10aryl-C0-4alkyl, heteroaryl-C0-4alkyl and heterocyclyl;wherein said aryl, cycloalkyl, heteroaryl or heterocyclyl substituents of R4 can optionally be further substituted with 1 to 3 radicals independently selected from halo, hydroxy, cyano, C1-6alkyl, C1-6alkoxy, halo-substituted-C1-6alkyl, halo-substituted-C1-6alkoxy, -L-OR6, -L-C(O)OR6, -L-C(O)NR6R6 and -L-R6;
wherein L is selected from a bond and C1-4alkylene; and
R6 is selected from hydrogen, C1-6alkyl and heterocyclyl;R7 is hydrogen; R8 is selected from hydrogen, halo, methoxy, amino, difluoromethoxy, trifluoromethyl, pyrrolidinyl, morpholino, 2-methyl-morpholino, 2,6-dimethyl-morpholino, cyano, —
NR5aR5b and methyl;
or R7 and R8 together with the carbon atoms to, which R7 and R8 are attached form phenyl;
wherein R5a and R5b are independently selected from hydrogen, C1-6alkyl, C1-6alkoxy, halo-substituted-C1-4alkyl and halo-substituted-C1-6alkoxy;R9 is selected from hydrogen, morpholino, halo, C1-6alkyl, C1-6alkoxy, halo-substituted-C1-6alkyl, halo-substituted-C1-6alkoxy, —
NR5aR5b, OX1NR5aR5b and heterocyclyl;
wherein X1 is independently selected from a bond and C1-4alkylene; and
R5a and R5b are independently selected from hydrogen, C1-6alkyl, C1-6alkoxy, halo-substituted-C1-6alkyl and halo-substituted-C1-6alkoxy.
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3. The compound of claim 2 in which:
- R3 is methyl; and
R4 is pyrazolyl, pyridinyl, indolyl, indolin-2-yl, thienyl, thiazolyl, 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl, furanyl, benzo[b]furanyl, 1,3,4-thiadiazolyl, benzo[b]thiophenyl, pyrrolyl, 1H-indazolyl, imidazo[1,2-a]pyridin-3-yl, oxazolyl, benzo[d]thiazol-6-yl, 1H-benzo[d][1,2,3]triazol-5-yl, quinolinyl, 1H-indolyl, 3,4-dihydro-2H-pyrano[2,3-b]pyridinyl, 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl and 2,3-dihydrofuro[2,3-b]pyridinyl;wherein said heteroaryls of R4 are substituted with 1 to 3 radicals independently selected from halo, hydroxy, cyano, methyl, amino, phenyl, hydroxy-ethyl(methyl)amino, piperidinyl, trifluoromethyl, 2-methyl allyloxy, cyclopropyl-methyl (propyl)amino-methyl, trifluoromethoxy, 3,4-dihydroisoquinolin-2(1H)-yl, amino-carbonyl-methyl(ethyl)amino-methyl, pyridinyl-methyl(ethyl)-amino-methyl, isopropyl(ethyl)-amino-methyl, propyl(ethyl)-amino-methyl, morpholino, butyl(methyl)amino-methyl, isobutyl(methyl)amino-methyl, benzyl(ethyl)amino-methyl, pyridinyl, pyrrolidinyl, azepanyl, hydroxy-propyloxy, ethyl, methoxy, methyl-carbonyl, ethoxy, propyloxy, t-butyl, benzyl, propyl, isopropyloxy, isopropyl, diethylamino-sulfonyl, methyl-sulfonyl, isopropyl-sulfonyl, diethyl-amino-methyl, trifluoroethoxy, piperidinyl, isoquinolinyl, (hydroxy-ethyl)(methyl)amino, difluoro-ethoxy, cyclopropyl, cyclopropyl-methoxy and tetrahydrofuranyl-oxy; wherein said aryl, cycloalkyl, heteroaryl or heterocyclyl substituents of R4 can optionally be further substituted with 1 to 3 radicals independently selected from halo, methyl, pyrrolidinyl-methyl, trifluoromethyl, hydroxy-methyl, hydroxy and cyano.
- R3 is methyl; and
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4. The compound of claim 3 in which R9 is selected from hydrogen and dimethyl-amino-propyloxy.
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5. The compound of claim 4 selected from:
- N-(3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-4-methylphenyl)-5-chloro-1H-indole-2-carboxamide;
N-(3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-4-methylphenyl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxamide;
N-(3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-4-methylphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide;
N-(3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-4-methylphenyl)-5-(trifluoromethyl)-2-methyloxazole-4-carboxamide;
N-(3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-4-methylphenyl)-2-morpholinopyridine-4-carboxamide;
N-(3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-4-methylphenyl)-6-methoxypyridine-3-carboxamide;
N-(3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-4-methylphenyl)-6-methoxypyridine-3-carboxamide;
N-(3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-4-methylphenyl)-1,5-dimethyl-1H-pyrazole-3-carboxamide;
N-(3-(4-(5-methylpyridin-3-yl)pyrimidin-2-ylamino)-4-methylphenyl)-1,5-dimethyl-1H-pyrazole-3-carboxamide;
N-(3-(4-(5-methoxypyridin-3-yl)pyrimidin-2-ylamino)-4-methylphenyl)-1,5-dimethyl-1H-pyrazole-3-carboxamide;
2-(2,2-difluoroethoxy)-N-(3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-4-methylphenyl)pyridine-4-carboxamide;
6-(2,2,2-trifluoroethoxy)-N-(3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-4-methylphenyl)pyridine-3-carboxamide;
3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-N-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-6-yl)-4-methylbenzamide; and
N-(3-(4-(5-methoxypyridin-3-yl)pyrimidin-2-ylamino)-4-methylphenyl)-1,5-dimethyl-1H-pyrazole-3-carboxamide.
- N-(3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-4-methylphenyl)-5-chloro-1H-indole-2-carboxamide;
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6. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 in combination with a pharmaceutically acceptable excipient.
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7. The pharmaceutical composition of claim 6, wherein the pharmaceutically acceptable excipient is suitable for parenteral administration.
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8. The pharmaceutical composition of claim 6, wherein the pharmaceutically acceptable excipient is suitable for oral administration.
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9. A method for modulating kinase activity, comprising administering to a system or a subject in need thereof, a therapeutically effective amount of the compound of claim 1 or pharmaceutically acceptable salts or pharmaceutical compositions thereof, thereby modulating said kinase activity.
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10. The method of claim 9, wherein said kinase is selected from c-kit, Abl, Lyn, MAPK14 (p38delta), PDGFRα
- , PDGFRβ
, ARG, BCR-Abl, BRK, EphB, Fms, Fyn, KDR, LCK, PDGF-R, b-Raf, c-Raf, SAPK2, Src, Tie2 and TrkB, or a combination thereof.
- , PDGFRβ
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11. The method of claim 9, wherein said kinase is c-kit kinase receptor.
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12. The method of claim 11, wherein the compound of claim 1 directly contacts the c-kit, PDGFRα
- and/or PADGRβ
kinase receptors.
- and/or PADGRβ
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13. The method of claim 12, wherein the contacting occurs in vitro or in vivo.
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14. A method for treating a disease or condition wherein modulation of kinase activity can prevent, inhibit or ameliorate the pathology and/or symptomology of the disease or condition, comprising administering to a subject a therapeutically effective amount of the compound of claim 1 or pharmaceutically acceptable salts or pharmaceutical compositions thereof, and optionally a therapeutically effective amount of a second agent.
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15. The method of claim 14, wherein said kinase is selected from c-kit, PDGFRα
- and PADGRβ
kinase receptors.
- and PADGRβ
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16. The method of claim 14, wherein the second agent is a bronchodilator, an anti-inflammatory agent, a leukotriene antagonist, or an IgE blocker.
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17. The method of claim 14, wherein the compound of claim 1 is administered prior to, simultaneously with, or after the second agent.
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18. The method of claim 14, wherein said disease or condition is a neoplastic disorder, an allergy disorder, an inflammatory disorder, an autoimmune disorder, a Plasmodium related disease, a mast cell associated disease, a graft-versus-host disease, a metabolic syndrome, a CNS related disorder, a neurodegenerative disorder, a pain condition, a substance abuse disorder, a prion disease, a cancer, a heart disease, a fibrotic disease, idiopathic arterial hypertension (IPAH), or primary pulmonary hypertension (PPH).
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19. The method of claim 18, wherein the neoplastic disorder is mastocytosis, gastrointestinal stromal tumor, small cell lung cancer, non-small cell lung cancer, acute myelocytic leukemia, acute lymphocytic leukemia, myelodyplastic syndrome, chronic myelogenous leukemia, colorectal carcinoma, gastric carcinoma, testicular cancer, glioblastoma or astrocytoma.
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20. The method of claim 18, wherein the allergy disorder is asthma, allergic rhinitis, allergic sinusitis, anaphylactic syndrome, urticaria, angioedema, atopic dermatitis, allergic contact dermatitis, erythema nodosum, erythema multiforme, cutaneous necrotizing venulitis, insect bite skin inflammation, or blood sucking parasite infestation.
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21. The method of claim 18, wherein the inflammatory disorder is rheumatoid arthritis, conjunctivitis, rheumatoid spondylitis, osteoarthritis or gouty arthritis.
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22. The method of claim 18, wherein the autoimmune disorder is multiple sclerosis, psoriasis, intestine inflammatory disease, ulcerative colitis, Crohn'"'"'s disease, rheumatoid arthritis, polyarthritis, local or systemic scleroderma, systemic lupus erythematosus, discoid lupus erythematosis, cutaneous lupus, dermatomyositis, polymyositis, Sjogren'"'"'s syndrome, nodular panarteritis, autoimmune enteropathy or proliferative glomerulonephritis.
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23. The method of claim 18, wherein the graft-versus-host disease is organ transplantation graft rejection.
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24. The method of claim 18, wherein the organ transplantation is kidney transplantation, pancreas transplantation, liver transplantation, heart transplantation, lung transplantation, or bone marrow transplantation.
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25. The method of claim 18, wherein the metabolic syndrome is type I diabetes, type II diabetes, or obesity.
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26. The method of claim 18, wherein the CNS related disorder is depression, dysthymic disorder, cyclothyinic disorder, anorexia, bulimia, premenstrual syndrome, post-menopause syndrome, mental slowing, loss of concentration, pessimistic worry, agitation, self-deprecation and decreased libido, an anxiety disorder, a psychiatric disorder or schizophrenia.
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27. The method of claim 18, wherein the neurodegenerative disorder is Alzheimer'"'"'s disease, Parkinson'"'"'s disease, Huntington'"'"'s disease, the prion diseases, Motor Neuron Disease (MND), or Amyotrophic Lateral Sclerosis (ALS).
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28. The method of claim 18, wherein the pain condition is acute pain, postoperative pain, chronic pain, nociceptive pain, cancer pain, neuropathic pain or psychogenic pain syndrome.
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29. The method of claim 18, wherein the substance use disorder is drug addiction, drug abuse, drug habituation, drug dependence, withdrawal syndrome or overdose.
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30. The method of claim 18, wherein the cancer is melanoma, gastrointestinal stromal tumor (GIST), small cell lung cancer, or other solid tumors.
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31. The method of claim 18, wherein the fibrotic disease is hepatitis C (HCV), liver fibrosis, nonalcoholic steatohepatitis (NASH), cirrhosis in liver, pulmonary fibrosis, or bone marrow fibrosis.
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32. The method of claim 18, wherein the Plasmodium related disease is malaria.
Specification