Compounds and methods for kinase modulation, and indications therefor

Abstract

Compounds active on protein kinases are described, as well as methods of using such compounds to treat diseases and conditions associated with aberrant activity of protein kinases.

What is claimed is: 
     
         1 . A method for treating a subject suffering from or at risk of a Raf mediated disease or condition, comprising administering to the subject an effective amount of a compound selected from the group consisting of:
 6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-N-pyridin-3-yl-benzamide,   N-(6-acetylamino-pyridin-3-yl)-6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzamide,   6-chloro-2-fluoro-N-(6-methoxy-pyridin-3-yl)-3-(propane-1-sulfonylamino)-benzamide,   N-(2-acetylamino-pyrimidin-5-yl)-6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzamide,   6-chloro-2-fluoro-N-(6-isopropylamino-pyridin-3-yl)-3-(propane-1-sulfonylamino)-benzamide,   pyrrolidine-1-carboxylic acid {5-[6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzo ylamino]-pyridin-2-yl}-amide,   6-chloro-N-(3,5-dimethyl-isoxazol-4-yl)-2-fluoro-3-(propane-1-sulfonylamino)-benzamide,   N-(6-acetylamino-pyridin-3-yl)-2,6-difluoro-3-(propane-1-sulfonylamino)-benzamide,   6-chloro-N-(6-cyclopentylamino-pyridin-3-yl)-2-fluoro-3-(propane-1-sulfonylamino)-benzamide,   6-chloro-N-[5-(4-chloro-phenyl)-2H-pyrazol-3-yl]-2-fluoro-3-(propane-1-sulfonylamino)-benzamide,   6-chloro-2-fluoro-N-[6-(5-methyl-thiazol-2-ylamino)-pyridin-3-yl]-3-(propane-1-sulfonylamino)-benzamide,   6-chloro-N-[5-(4-chloro-benzyl)-[1,3,4]thiadiazol-2-yl]-2-fluoro-3-(propane-1-sulfonylamino)-benzamide,   6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-N-quinolin-3-yl-benzamide,   [2-[6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoylamino]-4H-[1,3,4]thiadiazin-(5E)-ylidene]-acetic acid ethyl ester,   6-chloro-N-(6-cyclopropylamino-pyridin-3-yl)-2-fluoro-3-(propane-1-sulfonylamino)-benzamide,   6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-N-{6-[(thiophen-2-ylmethyl)-amino]-pyridin-3-yl}-benzamide,   N-(6-benzylamino-pyridin-3-yl)-6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzamide,   6-chloro-2-fluoro-N-imidazo[1,2-a]pyridin-3-yl-3-(propane-1-sulfonylamino)-benzamide, propane-1-sulfonic acid {2,4-difluoro-3-[(5-methyl-isoxazol-3-ylamino)-methyl]-phenyl}-amide,   N-{5-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzylamino]-pyridin-2-yl}-acetamide,   propane-1-sulfonic acid [2,4-difluoro-3-(quinolin-3-ylamino methyl)-phenyl]-amide,   propane-1-sulfonic acid {3-[(6-chloro-pyridin-3-ylamino)-methyl]-2,4-difluoro-phenyl}-amide,   propane-1-sulfonic acid {2,4-difluoro-3-[(6-methoxy-pyridin-3-ylamino)-methyl]-phenyl}-amide,   quinoline-3-carboxylic acid [2,6-difluoro-3-(propane-1-sulfonylamino)-phenyl]-amide,   propane-1-sulfonic acid {2,4-difluoro-3-[(quinolin-3-ylmethyl)-amino]-phenyl}-amide,   propane-1-sulfonic acid [2,4-difluoro-3-(quinolin-3-yloxymethyl)-phenyl]-amide,   2,6-difluoro-3-(propane-1-sulfonylamino)-N-quinolin-3-yl-benzamide,   6-acetylamino-N-[2,6-difluoro-3-(2-fluoro-benzenesulfonylamino)-phenyl]-nicotinamide,   6-acetylamino-N-[2,6-difluoro-3-(3-fluoro-benzenesulfonylamino)-phenyl]-nicotinamide,   6-acetylamino-N-[3-(2,6-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-nicotinamide,   6-acetylamino-N-[3-(2,4-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-nicotinamide,   6-acetylamino-N-[3-(2,5-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-nicotinamide,   6-acetylamino-N-[2,6-difluoro-3-(3-fluoro-4-methoxy-benzenesulfonylamino)-phenyl]-nicotinamide,   6-acetylamino-N-[2,6-difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-phenyl]-nicotinamide,   6-acetylamino-N-[3-(4-difluoromethoxy-benzenesulfonylamino)-2,6-difluoro-phenyl]-nicotinamide,   6-acetylamino-N-[3-(3-difluoromethoxy-benzenesulfonylamino)-2,6-difluoro-phenyl]-nicotinamide,   6-acetylamino-N-[2,6-difluoro-3-(4-isopropyl-benzenesulfonylamino)-phenyl]-nicotinamide,   6-acetylamino-N-[3-(4-tert-butyl-benzenesulfonylamino)-2,6-difluoro-phenyl]-nicotinamide,   6-acetylamino-N-[2,6-difluoro-3-(4-propyl-benzenesulfonylamino)-phenyl]-nicotinamide,   6-acetylamino-N-[2,6-difluoro-3-(pyridine-2-sulfonylamino)-phenyl]-nicotinamide,   6-acetylamino-N-[2,6-difluoro-3-(pyridine-3-sulfonylamino)-phenyl]-nicotinamide,   6-acetylamino-N-[2,6-difluoro-3-(dimethylaminosulfonylamino)-phenyl]-nicotinamide,   6-acetylamino-N-[2,6-difluoro-3-(piperidine-1-sulfonylamino)-phenyl]-nicotinamide,   6-acetylamino-N-[2,6-difluoro-3-(morpholine-4-sulfonylamino)-phenyl]-nicotinamide,   6-acetylamino-N-[2,6-difluoro-3-(tetrahydro-pyran-4-sulfonylamino)-phenyl]-nicotinamide,   6-acetylamino-N-(3-cyclopentanesulfonylamino-2,6-difluoro-phenyl)-nicotinamide,   6-acetylamino-N-[2,6-difluoro-3-(pyrrolidine-1-sulfonylamino)-phenyl]-nicotinamide,   6-acetylamino-N-[2,6-difluoro-3-(3,3,3-trifluoro-propane-1-sulfonylamino)-phenyl]-nicotinamide,   1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid [2,6-difluoro-3-(2-fluoro-benzenesulfonylamino)-phenyl]-amide,   1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid [2,6-difluoro-3-(3-fluoro-benzenesulfonylamino)-phenyl]-amide,   1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid [3-(2,6-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide,   1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid [3-(2,4-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide,   1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid [3-(2,5-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide,   1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid [2,6-difluoro-3-(3-fluoro-4-methoxy-benzenesulfonylamino)-phenyl]-amide,   1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid [2,6-difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-phenyl]-amide,   1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid [3-(4-difluoromethoxy-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide,   1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid [3-(3-difluoromethoxy-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide,   1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid [2,6-difluoro-3-(4-isopropyl-benzenesulfonylamino)-phenyl]-amide,   1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid [3-(4-tert-butyl-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide,   1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid [2,6-difluoro-3-(4-propyl-benzenesulfonylamino)-phenyl]-amide,   1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid [2,6-difluoro-3-(pyridine-2-sulfonylamino)-phenyl]-amide,   1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid [2,6-difluoro-3-(pyridine-3-sulfonylamino)-phenyl]-amide,   1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid [2,6-difluoro-3-(dimethylamino sulfonylamino)-phenyl]-amide,   1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid [2,6-difluoro-3-(piperidine-1-sulfonylamino)-phenyl]-amide,   1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid [2,6-difluoro-3-(morpholine-4-sulfonylamino)-phenyl]-amide,   1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid [2,6-difluoro-3-(tetrahydro-pyran-4-sulfonylamino)-phenyl]-amide,   1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (3-cyclopentanesulfonylamino-2,6-difluoro-phenyl)-amide,   1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid [2,6-difluoro-3-(pyrrolidine-1-sulfonylamino)-phenyl]-amide,   1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid [2,6-difluoro-3-(3,3,3-trifluoro-propane-1-sulfonylamino)-phenyl]-amide,   3H-imidazo[4,5-b]pyridine-6-carboxylic acid [2,6-difluoro-3-(2-fluoro-benzenesulfonylamino)-phenyl]-amide,   3H-imidazo[4,5-b]pyridine-6-carboxylic acid [2,6-difluoro-3-(3-fluoro-benzenesulfonylamino)-phenyl]-amide,   3H-imidazo[4,5-b]pyridine-6-carboxylic acid [3-(2,6-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide,   3H-imidazo[4,5-b]pyridine-6-carboxylic acid [3-(2,4-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide,   3H-imidazo[4,5-b]pyridine-6-carboxylic acid [3-(2,5-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide,   3H-imidazo[4,5-b]pyridine-6-carboxylic acid [2,6-difluoro-3-(3-fluoro-4-methoxy-benzenesulfonylamino)-phenyl]-amide,   3H-imidazo[4,5-b]pyridine-6-carboxylic acid [2,6-difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-phenyl]-amide,   3H-imidazo[4,5-b]pyridine-6-carboxylic acid [3-(4-difluoromethoxy-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide,   3H-imidazo[4,5-b]pyridine-6-carboxylic acid [3-(3-difluoromethoxy-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide,   3H-imidazo[4,5-b]pyridine-6-carboxylic acid [2,6-difluoro-3-(4-isopropyl-benzenesulfonylamino)-phenyl]-amide,   3H-imidazo[4,5-b]pyridine-6-carboxylic acid [3-(4-tert-butyl-benzenesulfonylamino)-2,6-difluoro-phenyl]-amide,   3H-imidazo[4,5-b]pyridine-6-carboxylic acid [2,6-difluoro-3-(4-propyl-benzenesulfonylamino)-phenyl]-amide,   3H-imidazo[4,5-b]pyridine-6-carboxylic acid [2,6-difluoro-3-(pyridine-2-sulfonylamino)-phenyl]-amide,   3H-imidazo[4,5-b]pyridine-6-carboxylic acid [2,6-difluoro-3-(pyridine-3-sulfonylamino)-phenyl]-amide,   3H-imidazo[4,5-b]pyridine-6-carboxylic acid [2,6-difluoro-3-(dimethylamino sulfonylamino)-phenyl]-amide,   3H-imidazo[4,5-b]pyridine-6-carboxylic acid [2,6-difluoro-3-(piperidine-1-sulfonylamino)-phenyl]-amide,   3H-imidazo[4,5-b]pyridine-6-carboxylic acid [2,6-difluoro-3-(morpholine-4-sulfonylamino)-phenyl]-amide,   3H-imidazo[4,5-b]pyridine-6-carboxylic acid [2,6-difluoro-3-(tetrahydro-pyran-4-sulfonylamino)-phenyl]-amide,   3H-imidazo[4,5-b]pyridine-6-carboxylic acid (3-cyclopentanesulfonylamino-2,6-difluoro-phenyl)-amide,   3H-imidazo[4,5-b]pyridine-6-carboxylic acid [2,6-difluoro-3-(pyrrolidine-1-sulfonylamino)-phenyl]-amide,   3H-imidazo[4,5-b]pyridine-6-carboxylic acid [2,6-difluoro-3-(3,3,3-trifluoro-propane-1-sulfonylamino)-phenyl]-amide,   N-{5-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzyloxy]-pyridin-2-yl}-acetamide,   propane-1-sulfonic acid [3-(2-amino-pyridin-3-yloxymethyl)-2,4-difluoro-phenyl]-amide,   propane-1-sulfonic acid [2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridin-5-yloxymethyl)-phenyl]-amide,   N-{5-[2,6-difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzyloxy]-pyridin-2-yl}-acetamide,   N-[3-(2-amino-pyridin-3-yloxymethyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide,   N-[2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridin-5-yloxymethyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide,   N-(6-acetylamino-pyridin-3-yl)-2,6-difluoro-3-(2-fluoro-benzenesulfonylamino)-benzamide,   N-(6-acetylamino-pyridin-3-yl)-2,6-difluoro-3-(3-fluoro-benzenesulfonylamino)-benzamide,   N-(6-acetylamino-pyridin-3-yl)-3-(2,6-difluoro-benzenesulfonylamino)-2,6-difluoro-benzamide, N-(6-acetylamino-pyridin-3-yl)-3-(2,4-difluoro-benzenesulfonylamino)-2,6-difluoro-benzamide, N-(6-acetylamino-pyridin-3-yl)-3-(2,5-difluoro-benzenesulfonylamino)-2,6-difluoro-benzamide, 6-acetylamino-N-[2,6-difluoro-3-(3-fluoro-4-methoxy-benzenesulfonylamino)-phenyl]-nicotinamide,   N-(6-acetylamino-pyridin-3-yl)-2,6-difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzamide,   N-(6-acetylamino-pyridin-3-yl)-3-(4-difluoromethoxy-benzenesulfonylamino)-2,6-difluoro-benzamide,   N-(6-acetylamino-pyridin-3-yl)-3-(3-difluoromethoxy-benzenesulfonylamino)-2,6-difluoro-benzamide,   N-(6-acetylamino-pyridin-3-yl)-2,6-difluoro-3-(4-isopropyl-benzenesulfonylamino)-benzamide, N-(6-acetylamino-pyridin-3-yl)-3-(4-tert-butyl-benzenesulfonylamino)-2,6-difluoro-benzamide, N-(6-acetylamino-pyridin-3-yl)-2,6-difluoro-3-(4-propyl-benzenesulfonylamino)-benzamide,   N-(6-acetylamino-pyridin-3-yl)-2,6-difluoro-3-(pyridine-2-sulfonylamino)-benzamide,   N-(6-acetylamino-pyridin-3-yl)-2,6-difluoro-3-(pyridine-3-sulfonylamino)-benzamide,   N-(6-acetylamino-pyridin-3-yl)-2,6-difluoro-3-(dimethylaminosulfonylamino)-benzamide,   N-(6-acetylamino-pyridin-3-yl)-2,6-difluoro-3-(piperidine-1-sulfonylamino)-benzamide,   N-(6-acetylamino-pyridin-3-yl)-2,6-difluoro-3-(morpholine-4-sulfonylamino)-benzamide,   N-(6-acetylamino-pyridin-3-yl)-2,6-difluoro-3-(tetrahydro-pyran-4-sulfonylamino)-benzamide,   N-(6-acetylamino-pyridin-3-yl)-3-cyclopentanesulfonylamino-2,6-difluoro-benzamide,   N-(6-acetylamino-pyridin-3-yl)-2,6-difluoro-3-(pyrrolidine-1-sulfonylamino)-benzamide,   N-(6-acetylamino-pyridin-3-yl)-2,6-difluoro-3-(3,3,3-trifluoro-propane-1-sulfonylamino)-benzamide,   6-acetylamino-N-[2,6-difluoro-3-(propane-1-sulfonylamino)-phenyl]-nicotinamide,   1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid [2,6-difluoro-3-(propane-1-sulfonylamino)-phenyl]-amide, and   3H-imidazo[4,5-b]pyridine-6-carboxylic acid[2,6-difluoro-3-(propane-1-sulfonylamino)-phenyl]-amide,   
       or a pharmaceutically acceptable salt of any of the above compounds. 
     
     
         2 . A method for treating a subject suffering from or at risk of a B-Raf V600E mediated disease or condition, comprising administering to the subject an effective amount of a compound selected from the group consisting of:
 6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-N-pyridin-3-yl-benzamide,   N-(6-acetylamino-pyridin-3-yl)-6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzamide,   N-(2-acetylamino-pyrimidin-5-yl)-6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzamide,   6-chloro-2-fluoro-N-(6-isopropylamino-pyridin-3-yl)-3-(propane-1-sulfonylamino)-benzamide,   N-(6-acetylamino-pyridin-3-yl)-2,6-difluoro-3-(propane-1-sulfonylamino)-benzamide,   6-chloro-2-fluoro-N-[6-(5-methyl-thiazol-2-ylamino)-pyridin-3-yl]-3-(propane-1-sulfonylamino)-benzamide,   6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-N-quinolin-3-yl-benzamide,   6-chloro-N-(6-cyclopropylamino-pyridin-3-yl)-2-fluoro-3-(propane-1-sulfonylamino)-benzamide,   6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-N-{6-[(thiophen-2-ylmethyl)-amino]-pyridin-3-yl}-benzamide,   N-(6-benzylamino-pyridin-3-yl)-6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzamide,   6-chloro-2-fluoro-N-imidazo[1,2-a]pyridin-3-yl-3-(propane-1-sulfonylamino)-benzamide,   N-{5-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzylamino]-pyridin-2-yl}-acetamide,   propane-1-sulfonic acid [2,4-difluoro-3-(quinolin-3-ylaminomethyl)-phenyl]-amide,   propane-1-sulfonic acid {2,4-difluoro-3-[(quinolin-3-ylmethyl)-amino]-phenyl}-amide,   propane-1-sulfonic acid [2,4-difluoro-3-(quinolin-3-yloxymethyl)-phenyl]-amide, and   2,6-difluoro-3-(propane-1-sulfonylamino)-N-quinolin-3-yl-benzamide,   
       or a pharmaceutically acceptable salt of any of the above compounds. 
     
     
         3 . The method according to  claim 1 , wherein the Raf mediated disease or condition is a neurological disease selected from the group consisting of multi-infarct dementia, head injury, spinal cord injury, Alzheimer's disease and Parkinson's disease. 
     
     
         4 . The method according to  claim 1 , wherein the Raf mediated disease or condition is a neoplastic disease selected from the group consisting of melanoma, glioma, sarcoma, colorectal cancer, lung cancer, breast cancer, pancreatic cancer, thyroid cancer, renal cancer, ovarian cancer, histiocytic lymphoma, neurofibromatosis, acute myeloid leukemia, myelodysplastic syndrome, leukemia, tumor angiogenesis, medullary thyroid cancer, carcinoid, small cell lung cancer and pheochromocytoma. 
     
     
         5 . The method according to  claim 1 , wherein the Raf mediated disease or condition is a pain of neuropathic or inflammatory origin selected from the group consisting of acute pain, chronic pain, cancer-related pain and migraine. 
     
     
         6 . The method according to  claim 1 , wherein the Raf mediated disease or condition is a cardiovascular disease selected from the group consisting of heart failure, ischemic stroke, cardiac hypertrophy, thrombosis, atherosclerosis and reperfusion injury. 
     
     
         7 . The method according to  claim 1 , wherein the Raf mediated disease or condition is an inflammatory disease selected from the group consisting of ipsoriasis, arthritis and autoimmune diseases and conditions, osteoarthritis, endometriosis, scarring, vascular restenosis, fibrotic disorders, rheumatoid arthritis and inflammatory bowel disease. 
     
     
         8 . The method according to  claim 1 , wherein the Raf mediated disease or condition is a renal or prostatic disease selected from the group consisting of diabetic nephropathy, polycystic kidney disease, nephrosclerosis, glomerulonephritis and prostate hyperplasia. 
     
     
         9 . The method according to  claim 1 , wherein the Raf mediated disease or condition is a pulmonary disease selected from the group consisting of chronic obstructive pulmonary disease and acute respiratory distress syndrome. 
     
     
         10 . The method according to  claim 1 , wherein the Raf mediated disease or condition is a genetic developmental disease selected from the group consisting of Noonan's syndrome, Costello syndrome, LEOPARD syndrome, cardio-faciocutaneous syndrome, and neural crest syndrome abnormalities causing cardiovascular, skeletal, intestinal, skin, hair and endocrine disease. 
     
     
         11 . The method according to  claim 2 , wherein the B-Raf V600E mediated disease or condition is malignant melanoma.