COMPOUNDS AND COMPOSITIONS AS PROTEIN KINASE INHIBITORS

• US 20100048539A1
• Filed: 11/02/2007
• Published: 02/25/2010
• Est. Priority Date: 11/03/2006
• Status: Abandoned Application

• Current Assignee: IRM LLC, Novartis Ag
• Original Assignee: IRM LLC, Novartis Ag
• Inventors: Wrona, Wojciech, Brooks, Clinton, Loren, Jon, Molteni, Valentina, Liu, Xiaodong, Nabakka, Juliet, Li, Xiaolin, Chianelli, Donatella, Perez, Lawrence B., Manley, Paul William, Breitenstein, Werner, Revesz, Laszlo
• Application Number:
  US12/513,498
• Publication Number:
  US 20100048539A1
• Time in Patent Office: Days
• US Class Current: 514/217.60
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/06 Antigout agents, e.g. antihyperuricemic or uricosuric agents
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 25/30 : for treating abuse or dependence
• CPC Class Codes: A61P 27/02 : Ophthalmic agents
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 : Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 : Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 33/06 : Antimalarials
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings
• CPC Class Codes: C07D 409/14 : containing three or more hetero rings
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings

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).

Claims

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, C_1-4alkyl, C_1-6alkoxy, halo-substituted-C_1-6alkyl, halo-substituted-C_1-6alkoxy, —

NR_5aR₅b, —

OX₁NR_5aR_5b and heterocyclyl;

wherein X₁ is independently selected from a bond and C_1-4alkylene; and

R_5a and R_5b are independently selected from hydrogen, C_1-6alkyl, C_1-6alkoxy, halo-substituted-C_1-6alkyl and halo-substituted-C_1-6alkoxy;

is selected from halo, C_1-6alkyl, C_1-6alkoxy, halo-substituted-C_1-6alkyl and halo-substituted-C_1-6alkoxy;

R₂ is selected from halo, C_1-6alkyl, C_1-6alkoxy, halo-substituted-C_1-6alkyl and halo-substituted-C_1-6alkoxy;

R₃ is heteroaryl substituted with 1 to 3 radicals independently selected from halo, cyano, C_1-6alkyl, C_1-6alkoxy, halo-substituted-C_1-6alkyl, halo-substituted-C_1-6alkoxy, C_6-10aryl-C_0-4alkyl, 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 C_1-4alkylene;

X₂ is C_1-4alkylene; and

each R₅ is independently selected from hydrogen, C_1-6alkyl, C_2-6alkenyl, C_3-12cycloalkyl, C_6-10aryl-C_0-4alkyl, heteroaryl-C_0-4alkyl 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, C_1-6alkyl, C_1-6alkoxy, halo-substituted-C_1-6alkyl, halo-substituted-C_1-6alkoxy, -L-OR₆, -L-C(O)OR₆, -L-C(O)NR₆R₆ and -L-R₆;

wherein L is selected from a bond and C_1-4alkylene; and

R₆ is selected from hydrogen, C_1-6alkyl and heterocyclyl;

with the proviso that R₄ is not pyridin-3-yl substituted by a trifluoromethyl radical; and

the pharmaceutically acceptable salts thereof.

2. The compound of claim 1 of Formula Ia:

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, C_1-6alkyl, C_1-6alkoxy, halo-substituted-C_1-6alkyl, halo-substituted-C_1-6alkoxy, C_6-10aryl-C_0-4alkyl, 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 C_1-4alkylene;

X₂ is C_1-4alkylene; and

each R₅ is independently selected from hydrogen, C_1-6alkyl, C_2-4alkenyl, C_3-12cycloalkyl, C_6-10aryl-C_0-4alkyl, heteroaryl-C_0-4alkyl 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, C_1-6alkyl, C_1-6alkoxy, halo-substituted-C_1-6alkyl, halo-substituted-C_1-6alkoxy, -L-OR₆, -L-C(O)OR₆, -L-C(O)NR₆R₆ and -L-R₆;

wherein L is selected from a bond and C_1-4alkylene; and

R₆ is selected from hydrogen, C_1-6alkyl 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, —

NR_5aR_5b and methyl;

or R₇ and R₈ together with the carbon atoms to, which R₇ and R₈ are attached form phenyl;

wherein R_5a and R_5b are independently selected from hydrogen, C_1-6alkyl, C_1-6alkoxy, halo-substituted-C_1-4alkyl and halo-substituted-C_1-6alkoxy;

R₉ is selected from hydrogen, morpholino, halo, C_1-6alkyl, C_1-6alkoxy, halo-substituted-C_1-6alkyl, halo-substituted-C_1-6alkoxy, —

NR_5aR_5b, OX₁NR_5aR_5b and heterocyclyl;

wherein X₁ is independently selected from a bond and C_1-4alkylene; and

R_5a and R_5b are independently selected from hydrogen, C_1-6alkyl, C_1-6alkoxy, halo-substituted-C_1-6alkyl and halo-substituted-C_1-6alkoxy.

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.

4. The compound of claim 3 in which R₉ is selected from hydrogen and dimethyl-amino-propyloxy.

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.

6. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 in combination with a pharmaceutically acceptable excipient.

7. The pharmaceutical composition of claim 6, wherein the pharmaceutically acceptable excipient is suitable for parenteral administration.

8. The pharmaceutical composition of claim 6, wherein the pharmaceutically acceptable excipient is suitable for oral administration.

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.

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.

11. The method of claim 9, wherein said kinase is c-kit kinase receptor.

12. The method of claim 11, wherein the compound of claim 1 directly contacts the c-kit, PDGFRα

and/or PADGRβ

kinase receptors.

13. The method of claim 12, wherein the contacting occurs in vitro or in vivo.

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.

15. The method of claim 14, wherein said kinase is selected from c-kit, PDGFRα

and PADGRβ

kinase receptors.

16. The method of claim 14, wherein the second agent is a bronchodilator, an anti-inflammatory agent, a leukotriene antagonist, or an IgE blocker.

17. The method of claim 14, wherein the compound of claim 1 is administered prior to, simultaneously with, or after the second agent.

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).

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.

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.

21. The method of claim 18, wherein the inflammatory disorder is rheumatoid arthritis, conjunctivitis, rheumatoid spondylitis, osteoarthritis or gouty arthritis.

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.

23. The method of claim 18, wherein the graft-versus-host disease is organ transplantation graft rejection.

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.

25. The method of claim 18, wherein the metabolic syndrome is type I diabetes, type II diabetes, or obesity.

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.

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).

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.

29. The method of claim 18, wherein the substance use disorder is drug addiction, drug abuse, drug habituation, drug dependence, withdrawal syndrome or overdose.

30. The method of claim 18, wherein the cancer is melanoma, gastrointestinal stromal tumor (GIST), small cell lung cancer, or other solid tumors.

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.

32. The method of claim 18, wherein the Plasmodium related disease is malaria.