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.

1 . A method for treating a subject suffering from or at risk of an A-Raf-mediated, B-Raf-mediated and/or c-Raf-1-mediated disease or condition, said method comprising administering to the subject an effective amount of a compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, a tautomer or an isomer thereof, wherein: 
         R 1  is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —OH, —NH 2 , —CN, —NO 2 , —C(O)OH, —S(O) 2 NH 2 , —C(O)NH 2 , —C(S)NH 2 , —NHC(O)NH 2 , —NHC(S)NH 2 , —NHS(O) 2 NH 2 , —OR 4 , —SR 4 , —NR 5 R 4 , —C(O)R 4 , —C(S)R 4 , —C(O)OR 4 , —C(O)NR 5 R 4 , —C(S)NR 5 R 4 , —S(O) 2 NR 5 R 4 , —NR 5 C(O)R 4 , —NR 5 C(S)R 4 , —NR 5 S(O) 2 R 4 , —NR 5 C(O)NH 2 , —NR 5 C(O)NR 5 R 4 , —NR 5 C(S)NH 2 , —NR 5 C(S)NR 5 R 4 , —NR 5 S(O) 2 NH 2 , —NR 5 S(O) 2 NR 5 R 4 , —S(O)R 4 , and —S(O) 2 R 4 ; 
         R 2  is selected from the group consisting of halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —OH, —NH 2 , —CN, —NO 2 , —C(O)OH, —S(O) 2 NH 2 , —C(O)NH 2 , —C(S)NH 2 , —NHC(O)NH 2 , —NHC(S)NH 2 , —NHS(O) 2 NH 2 , —OR 4 , —SR 4 , —NR 5 R 4 , —C(O)R 4 , —C(S)R 4 , —C(O)OR 4 , —C(O)NR 5 R 4 , —C(S)NR 5 R 4 , —S(O) 2 NR 5 R 4 , —NR 5 C(O)R 4 , —NR 5 C(S)R 4 , —NR 5 S(O) 2 R 4 , —NR 5 C(O)NH 2 , —NR 5 C(O)NR 5 R 4 , —NR 5 C(S)NH 2 , —NR 5 C(S)NR 5 R 4 , —NR 5 S(O) 2 NH 2 , —NR 5 S(O) 2 NR 5 R 4 , —S(O)R 4 , and —S(O) 2 R 4 ; 
         R 3  is selected from the group consisting of hydrogen, fluoro and chloro; 
         R 4  is selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that when R 4  is optionally substituted lower alkenyl, no alkene carbon thereof is bound to N, S, O, S(O), S(O) 2 , C(O) or C(S) of —OR 4 , —SW, —NR 5 R 4 , —C(O)R 4 , —C(S)R 4 , —C(O)OR 4 , —C(O)NR 5 R 4 , —C(S)NR 5 R 4 , —S(O) 2 NR 5 R 4 , —NR 5 C(O)R 4 , —NR 5 C(S)R 4 , —NR 5 S(O) 2 R 4 , —NR 5 C(O)NH 2 , —NR 5 C(O)NR 5 R 4 , —NR 5 C(S)NH 2 , —NR 5 C(S)NR 5 R 4 , —NR 5 S(O) 2 NH 2 , —NR 5 S(O) 2 NR 5 R 4 , —S(O)R 4 , or —S(O) 2 R 4 , optionally substituted lower alkynyl, provided, however, that when R 4  is optionally substituted lower alkynyl, no alkyne carbon thereof is bound to N, S, O, S(O), S(O) 2 , C(O) or C(S) of —OR 4 , —SR 4 , —NR 5 R 4 , —C(O)R 4 , —C(S)R 4 , —C(O)OR 4 , —C(O)NR 5 R 4 , —C(S)NR 5 R 4 , —S(O) 2 NR 5 R 4 , —NR 5 C(O)R 4 , —NR 5 C(S)R 4 , —NR 5 S(O) 2 R 4 , —NR 5 C(O)NH 2 , —NR 5 C(O)NR 5 R 4 , —NR 5 C(S)NH 2 , —NR 5 C(S)NR 5 R 4 , —NR 5 S(O) 2 NH 2 , —NR 5 S(O) 2 NR 5 R 4 , —S(O)R 4 , or —S(O) 2 R 4 , optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and 
         R 5  is selected from the group consisting of hydrogen and optionally substituted lower alkyl, provided, however, the compound is not 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         2 . The method of  claim 1 , wherein the compound is approved for administration to a human. 
     
     
         3 . The method of  claim 2 , wherein the disease or condition is selected from the group consisting of multi-infarct dementia, head injury, spinal cord injury, Alzheimer's disease, Parkinson's disease, melanoma, glioma, sarcoma, cancer of the colon, lung, breast, pancreas, thyroid, ovary, liver, or kidney, medullary thyroid cancer, carcinoid, small cell lung cancer, pheochromocytoma, lymphoma, neurofibromatosis, myelodysplastic syndrome, leukemia, tumor angiogenesis, neuropathic pain, inflammatory pain, acute pain, chronic pain, cancer-related pain, migraine, heart failure, ischemic stroke, cardiac hypertrophy, thrombosis, atherosclerosis, reperfusion injury, psoriasis, arthritis, osteoarthritis, endometriosis, scarring, vascular restenosis, fibrotic disorders, rheumatoid arthritis, inflammatory bowel disease, immunodeficiency diseases, organ transplant rejection, graft versus host disease, diabetic nephropathy, polycystic kidney disease, nephrosclerosis, glomerulonephritis, prostate hyperplasia, obesity,  Helicobacter pylori  infection, Hepatitis infection, Influenza virus infection, fever, sepsis, chronic obstructive pulmonary disease, acute respiratory distress syndrome, Noonan's syndrome, Costello syndrome, LEOPARD syndrome, cardio-faciocutaneous syndrome, neural crest syndrome abnormalities causing cardiovascular, skeletal, intestinal, skin, hair and endocrine diseases, sarcopenia, muscular dystrophy, motor neuron diseases, inflammatory myopathies, diseases of the neuromuscular junction, myopathies due to endocrine abnormalities, diseases of peripheral nerve, myotonia congenita, paramyotonia congenita, central core disease, nemaline myopathy, myotubular myopathy, periodic paralysis and metabolic diseases of muscle. 
     
     
         4 . The method of  claim 3 , wherein:
 R 1  is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —OH, —NH 2 , —CN, —NO 2 , —C(O)OH, —S(O) 2 NH 2 , —C(O)NH 2 , —C(S)NH 2 , —NHC(O)NH 2 , —NHC(S)NH 2 , —NHS(O) 2 NH 2 , —OR 7 , —SR 7 , —NR 8 R 7 , —C(O)R 7 , —C(S)R 7 , —C(O)OR 7 , —C(O)NR 8 R 7 , —C(S)NR 8 R 7 , —S(O) 2 NR 8 R 7 , —NR 8 C(O)R 7 , —NR 8 C(S)R 7 , —NR 8 S(O) 2 R 7 , —NR 8 C(O)NH 2 , —NR 8 C(O)NR 8 R 7 , —NR 8 C(S)NH 2 , —NR 8 C(S)NR 8 R 7 , —NR 8 S(O) 2 NH 2 , —NR 8 S(O) 2 NR 8 R 7 , —S(O)R 7 , and —S(O) 2 R 7 , wherein lower alkyl, lower alkenyl or lower alkynyl are optionally substituted with one or more substituents selected from fluoro, —OH, —NH 2 , C(O)OH, —C(O)NH 2 , —OR 7 , —NR 8 R 7 , —C(O)OR 7 , —C(O)NR 8 R 7 , cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R 1  or as substituents of lower alkyl, lower alkenyl or lower alkynyl are optionally substituted with one or more substituents selected from the group consisting of —OH, —NH 2 , —CN, —NO 2 , —S(O) 2 NH 2 , —C(O)NH 2 , —OR 9 , —SR 9 , —NHR 9 , —NR 8 R 9 , —NR 8 C(O)R 9 , —NR 8 S(O) 2 R 9 , —S(O) 2 R 9 , —S(O) 2 NR 8 R 9 , —C(O)R 9 , —C(O)NR 8 R 9 , halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;   R 2  is selected from the group consisting of halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —OH, —NH 2 , —CN, —NO 2 , —C(O)OH, —S(O) 2 NH 2 , —C(O)NH 2 , —C(S)NH 2 , —NHC(O)NH 2 , —NHC(S)NH 2 , —NHS(O) 2 NH 2 , —OR 7 , —SR 7 , —NR 8 R 7 , —C(O)R 7 , —C(S)R 7 , —C(O)OR 7 , —C(O)NR 8 R 7 , —C(S)NR 8 R 7 , —S(O) 2 NR 8 R 7 , —NR 8 C(O)R 7 , —NR 8 C(S)R 7 , —NR 8 S(O) 2 R 7 , —NR 8 C(O)NH 2 , —NR 8 C(O)NR 8 R 7 , —NR 8 C(S)NH 2 , —NR 8 C(S)NR 8 R 7 , —NR 8 S(O) 2 NH 2 , —NR 8 S(O) 2 NR 8 R 7 , —S(O)R 7 , and —S(O) 2 R 7 , wherein lower alkyl is optionally substituted with one or more substituents selected from fluoro, —OR 7 , —NR 8 R 7 , cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R 2  or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of —OH, —NH 2 , —CN, —NO 2 , —S(O) 2 NH 2 , —C(O)NH 2 , —OR 9 , —SR 9 , —NHR 9 , —NR 8 R 9 , —NR 8 C(O)R 9 , —NR 8 S(O) 2 R 9 , —S(O) 2 R 9 , —S(O) 2 NR 8 R 9 , —C(O)R 9 , —C(O)NR 8 R 9 , halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;   R 7  is selected from the group consisting of lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R 7  or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of —OH, —NH 2 , —CN, —NO 2 , —S(O) 2 NH 2 , —C(O)NH 2 , —OR 9 , —SR 9 , —NHR 9 , —NR 8 R 9 , —NR 8 C(O)R 9 , —NR 8 S(O) 2 R 9 , —S(O) 2 R 9 , —S(O) 2 NR 8 R 9 , —C(O)R 9 , —C(O)NR 8 R 9 , halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;   R 8  at each occurrence is independently hydrogen or lower alkyl; and   R 9  at each occurrence is independently selected from the group consisting of lower alkyl, heterocycloalkyl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, and heterocycloalkyl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, —CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy and fluoro substituted lower alkoxy.   
     
     
         5 . The method of  claim 4 , wherein
 R 1  is selected from the group consisting of hydrogen, —CN, —OR 7 , —SR 7 , —NR 8 R 7 , —NR 8 C(O)R 7 , —NR 8 S(O) 2 R 7 , —C(O)NR 8 R 7 , —C(O)R 7 , —S(O) 2 NR 8 R 7 , —S(O)R 7 , —S(O) 2 R 7 , halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R 1  or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of —OH, —NH 2 , —CN, —NO 2 , —S(O) 2 NH 2 , —C(O)NH 2 , —OR 9 , —SR 9 , —NHR 9 , —NR 8 R 9 , —NR 8 C(O)R 9 , —NR 8 S(O) 2 R 9 , —S(O) 2 R 9 , —S(O) 2 NR 8 R 9 , —C(O)R 9 , —C(O)NR 8 R 9 , halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; and   R 2  is selected from the group consisting of —CN, —OR 7 , —SR 7 , —NR 8 R 7 , —NR 8 C(O)R 7 , —NR 8 S(O) 2 R 7 , —C(O)NR 8 R 7 , —C(O)R 7 , —S(O) 2 NR 8 R 7 , —S(O)R 7 , —S(O) 2 R 7 , halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R 2  or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of —OH, —NH 2 , —CN, —NO 2 , —S(O) 2 NH 2 , —C(O)NH 2 , —OR 9 , —SR 9 , —NHR 9 , —NR 8 R 9 , —NR 8 C(O)R 9 , —NR 8 S(O) 2 R 9 , —S(O) 2 R 9 , —S(O) 2 NR 8 R 9 , —C(O)R 9 , —C(O)NR 8 R 9 , halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino.   
     
     
         6 . The method of  claim 5 , wherein:
 R 1  is hydrogen, —CN, —NR 8 R 7 , —OR 7 , —S(O) 2 R 7 , fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, —NR 8 R 7 , —OR 7  and —S(O) 2 R 7 , and   R 2  is —CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, —NR 8 R 7 , —OR 7  or —S(O) 2 R 7 .   
     
     
         7 . The method of  claim 6 , wherein:
 R 1  is hydrogen, —CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkoxy substituted C 2-6 alkoxy, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, mono-alkylamino, di-alkylamino, and cycloalkylamino, and   R 2  is —CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, mono-alkylamino, di-alkylamino, or cycloalkylamino.   
     
     
         8 . The method of  claim 3 , wherein the compound is selected from the group consisting of:
 4-Butoxy-N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-benzenesulfonamide,   N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-pyrazol-1-yl-benzenesulfonamide,   N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-isopropoxy-benzenesulfonamide,   4-tert-Butyl-N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-benzenesulfonamide,   N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-propyl-benzenesulfonamide,   N-{2,4-Difluoro-3-[5-(2-methoxy-ethoxy)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-isopropyl-benzenesulfonamide,   N-{2,4-Difluoro-3-[5-(4-methyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-isopropyl-benzenesulfonamide,   4-Difluoromethoxy-N-{2,4-difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-benzenesulfonamide,   N-{2,4-Difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-propyl-benzenesulfonamide,   N-{2,4-Difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-isopropyl-benzenesulfonamide,   N-{2,4-Difluoro-3-[5-(5-methyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-propyl-benzenesulfonamide,   N-{2,4-Difluoro-3-[5-(5-methyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-trifluoromethyl-benzenesulfonamide,   N-{2,4-Difluoro-3-[5-(1-methyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-propyl-benzenesulfonamide,   N-{3-[5-(1,5-Dimethyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-4-propyl-benzenesulfonamide,   N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2, 3-1)]pyridine-3-carbonyl)-phenyl]-4-trifluoromethyl-benzene sulfonamide,   N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzene sulfonamide,   (E)-3-{3-[2,6-Difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-acrylic acid methyl ester,   3-{3-[2,6-Difluoro-3-(4-trifluoromethyl-benzene sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-prop ionic acid methyl ester,   3-{3-[2,6-Difluoro-3-(4-trifluoromethyl-benzene sulfonylamino)-benzoyl]-1H-pyrrolo[2, 3-1)]pyridin-5-yl}-propionic acid,   3-{3-[2,6-Difluoro-3-(4-trifluoromethyl-benzene sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-ethyl-propionamide; and   pharmaceutically acceptable salts, tautomers, and isomers thereof.   
     
     
         9 . A method for treating a subject suffering from or at risk of an A-Raf-mediated, B-Raf-mediated and/or c-Raf-1-mediated disease or condition, said method comprising administering to the subject an effective amount of a compound of Formula II: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, a tautomer or an isomer thereof, wherein: 
         R 1  is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —OH, —NH 2 , —CN, —NO 2 , —C(O)OH, —S(O) 2 NH 2 , —C(O)NH 2 , —C(S)NH 2 , —NHC(O)NH 2 , —NHC(S)NH 2 , —NHS(O) 2 NH 2 , —OR 7 , —SR 4 , —NR 5 R 4 , —C(O)R 4 , —C(S)R 4 , —C(O)OR 4 , —C(O)NR 5 R 4 , —C(S)NR 5 R 4 , —S(O) 2 NR 5 R 4 , —NR 5 C(O)R 4 , —NR 5 C(S)R 4 , —NR 5 S(O) 2 R 4 , —NR 5 C(O)NH 2 , —NR 5 C(O)NR 5 R 4 , —NR 5 C(S)NH 2 , —NR 5 C(S)NR 5 R 4 , —NR 5 S(O) 2 NH 2 , —NR 5 S(O) 2 NR 5 R 4 , —S(O)R 4 , and —S(O) 2 R 4 ; 
         R 2a  is selected from the group consisting of halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —OH, —NH 2 , —CN, —NO 2 , —C(O)OH, —S(O) 2 NH 2 , —C(O)NH 2 , —C(S)NH 2 , —NHC(O)NH 2 , —NHC(S)NH 2 , —NHS(O) 2 NH 2 , —OR 4 , —SR 4 , —NR 5 R 4 , —C(O)R 4 , —C(S)R 4 , —C(O)OR 4 , —C(O)NR 5 R 4 , —C(S)NR 5 R 4 , —S(O) 2 NR 5 R 4 , —NR 5 C(O)R 4 , —NR 5 C(S)R 4 , —NR 5 S(O) 2 R 4 , —NR 5 C(O)NH 2 , —NR 5 C(O)NR 5 R 4 , —NR 5 C(S)NH 2 , —NR 5 C(S)NR 5 R 4 , —NR 5 S(O) 2 NH 2 , —NR 5 S(O) 2 NR 5 R 4 , —S(O)R 4 , and —S(O) 2 R 4 ; 
         R 3  is selected from the group consisting of hydrogen, fluoro and chloro; 
         R 4  is selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that when R 4  is optionally substituted lower alkenyl, no alkene carbon thereof is bound to N, S, O, S(O), S(O) 2 , C(O) or C(S) of —OR 4 , —SR 4 , —NR 5 R 4 , —C(O)R 4 , —C(S)R 4 , —C(O)OR 4 , —C(O)NR 5 R 4 , —C(S)NR 5 R 4 , —S(O) 2 NR 5 R 4 , —NR 5 C(O)R 4 , —NR 5 C(S)R 4 , —NR 5 S(O) 2 R 4 , —NR 5 C(O)NH 2 , —NR 5 C(O)NR 5 R 4 , —NR 5 C(S)NH 2 , —NR 5 C(S)NR 5 R 4 , —NR 5 S(O) 2 NH 2 , —NR 5 S(O) 2 NR 5 R 4 , —S(O)R 4 , or —S(O) 2 R 4 , optionally substituted lower alkynyl, provided, however, that when R 4  is optionally substituted lower alkynyl, no alkyne carbon thereof is bound to N, S, O, S(O), S(O) 2 , C(O) or C(S) of —OR 4 , —SR 4 , —NR 5 R 4 , —C(O)R 4 , —C(S)R 4 , —C(O)OR 4 , —C(O)NR 5 R 4 , —C(S)NR 5 R 4 , —S(O) 2 NR 5 R 4 , —NR 5 C(O)R 4 , —NR 5 C(S)R 4 , —NR 5 S(O) 2 R 4 , —NR 5 C(O)NH 2 , —NR 5 C(O)NR 5 R 4 , —NR 5 C(S)NH 2 , —NR 5 C(S)NR 5 R 4 , —NR 5 S(O) 2 NH 2 , —NR 5 S(O) 2 NR 5 R 4 , —S(O)R 4 , or —S(O) 2 R 4 , optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and 
         R 5  is selected from the group consisting of hydrogen and optionally substituted lower alkyl, provided, however, the compound is not 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         10 . The method of  claim 9 , wherein the compound is approved for administration to a human. 
     
     
         11 . The method of  claim 10 , wherein the disease or condition is selected from the group consisting of multi-infarct dementia, head injury, spinal cord injury, Alzheimer's disease, Parkinson's disease, melanoma, glioma, sarcoma, cancer of the colon, lung, breast, pancreas, thyroid, ovary, liver, or kidney, medullary thyroid cancer, carcinoid, small cell lung cancer, pheochromocytoma, lymphoma, neurofibromatosis, myelodysplastic syndrome, leukemia, tumor angiogenesis, neuropathic pain, inflammatory pain, acute pain, chronic pain, cancer-related pain, migraine, heart failure, ischemic stroke, cardiac hypertrophy, thrombosis, atherosclerosis, reperfusion injury, psoriasis, arthritis, osteoarthritis, endometriosis, scarring, vascular restenosis, fibrotic disorders, rheumatoid arthritis, inflammatory bowel disease, immunodeficiency diseases, organ transplant rejection, graft versus host disease, diabetic nephropathy, polycystic kidney disease, nephrosclerosis, glomerulonephritis, prostate hyperplasia, obesity,  Helicobacter pylori  infection, Hepatitis infection, Influenza virus infection, fever, sepsis, chronic obstructive pulmonary disease, acute respiratory distress syndrome, Noonan's syndrome, Costello syndrome, LEOPARD syndrome, cardio-faciocutaneous syndrome, neural crest syndrome abnormalities causing cardiovascular, skeletal, intestinal, skin, hair and endocrine diseases, sarcopenia, muscular dystrophy, motor neuron diseases, inflammatory myopathies, diseases of the neuromuscular junction, myopathies due to endocrine abnormalities, diseases of peripheral nerve, myotonia congenita, paramyotonia congenita, central core disease, nemaline myopathy, myotubular myopathy, periodic paralysis and metabolic diseases of muscle. 
     
     
         12 . The method of  claim 11 , wherein:
 R 1  is selected from the group consisting of hydrogen, —CN, —OR 7 , —SR 7 , —NR 8 R 7 , —NR 8 C(O)R 7 , —NR 8 S(O) 2 R 7 , —C(O)NR 8 R 7 , —C(O)R 7 , —S(O) 2 NR 8 R 7 , —S(O)R 7 , —S(O) 2 R 7 , halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R 1  or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of —OH, —NH 2 , —CN, —NO 2 , —S(O) 2 NH 2 , —C(O)NH 2 , —OR 9 , —SR 9 , —NHR 9 , —NR 8 R 9 , —NR 8 C(O)R 9 , —NR 8 S(O) 2 R 9 , —S(O) 2 R 9 , —S(O) 2 NR 8 R 9 , —C(O)R 9 , —C(O)NR 8 R 9 , halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; and   R 2a  is selected from the group consisting of —CN, —OR 7 , —SR 7 , —NR 8 R 7 , —NR 8 C(O)R 7 , —NR 8 S(O) 2 R 7 , —C(O)NR 8 R 7 , —C(O)R 7 , —S(O) 2 NR 8 R 7 , —S(O)R 7 , —S(O) 2 R 7 , halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R 2a  or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of —OH, —NH 2 , —CN, —NO 2 , —S(O) 2 NH 2 , —C(O)NH 2 , —OR 9 , —SR 9 , —NHR 9 , —NR 8 R 9 , —NR 8 C(O)R 9 , —NR 8 S(O) 2 R 9 , —S(O) 2 R 9 , —S(O) 2 NR 8 R 9 , —C(O)R 9 , —C(O)NR 8 R 9 , halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino.   
     
     
         13 . The method of  claim 12 , wherein:
 R 1  is hydrogen, —CN, —NR 8 R 7 , —OR 7 , —S(O) 2 R 7 , fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, —NR 8 R 7 , —OR 7  and —S(O) 2 R 7 , and   R 2a  is —CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, —NR 8 R 7 , —OR 7  or —S(O) 2 R 7 .   
     
     
         14 . The method of  claim 13 , wherein:
 R 1  is hydrogen, —CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkoxy substituted C 2-6 alkoxy, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, mono-alkylamino, di-alkylamino, and cycloalkylamino, and   R 2a  is —CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, mono-alkylamino, di-alkylamino, or cycloalkylamino.   
     
     
         15 . The method of  claim 11 , wherein the compound is selected from the group consisting of:
 3-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenylsulfamoyl]-benzoic acid,   N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3-difluoromethoxy-benzenesulfonamide,   3-Difluoromethoxy-N-{2,4-difluoro-3-[5-(5-methyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-benzenesulfonamide; and   pharmaceutically acceptable salts, tautomers, and isomers thereof.   
     
     
         16 . A method for treating a subject suffering from or at risk of an A-Raf-mediated, B-Raf-mediated and/or c-Raf-1-mediated disease or condition, comprising administering to the subject an effective amount of a compound of Formula III: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, a tautomer or an isomer thereof, wherein: 
         R 1  is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —OH, —NH 2 , —CN, —NO 2 , —C(O)OH, —S(O) 2 NH 2 , —C(O)NH 2 , —C(S)NH 2 , —NHC(O)NH 2 , —NHC(S)NH 2 , —NHS(O) 2 NH 2 , —OR 4 , —SR 4 , —NR 5 R 4 , —C(O)R 4 , —C(S)R 4 , —C(O)OR 4 , —C(O)NR 5 R 4 , —C(S)NR 5 R 4 , —S(O) 2 NR 5 R 4 , —NR 5 C(O)R 4 , —NR 5 C(S)R 4 , —NR 5 S(O) 2 R 4 , —NR 5 C(O)NH 2 , —NR 5 C(O)NR 5 R 4 , —NR 5 C(S)NH 2 , —NR 5 C(S)NR 5 R 4 , —NR 5 S(O) 2 NH 2 , —NR 5 S(O) 2 NR 5 R 4 , —S(O)R 4 , and —S(O) 2 R 4 ; 
         R 3  is selected from the group consisting of hydrogen, fluoro and chloro; 
         R 4  is selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that when R 4  is optionally substituted lower alkenyl, no alkene carbon thereof is bound to N, S, O, S(O), S(O) 2 , C(O) or C(S) of —OR 4 , —SW, —NR 5 R 4 , —C(O)R 4 , —C(S)R 4 , —C(O)OR 4 , —C(O)NR 5 R 4 , —C(S)NR 5 R 4 , —S(O) 2 NR 5 R 4 , —NR 5 C(O)R 4 , —NR 5 C(S)R 4 , —NR 5 S(O) 2 R 4 , —NR 5 C(O)NH 2 , —NR 5 C(O)NR 5 R 4 , —NR 5 C(S)NH 2 , —NR 5 C(S)NR 5 R 4 , —NR 5 S(O) 2 NH 2 , —NR 5 S(O) 2 NR 5 R 4 , —S(O)R 4 , or —S(O) 2 R 4 , optionally substituted lower alkynyl, provided, however, that when R 4  is optionally substituted lower alkynyl, no alkyne carbon thereof is bound to N, S, O, S(O), S(O) 2 , C(O) or C(S) of —OR 4 , —SR 7 , —NR 5 R 4 , —C(O)R 4 , —C(S)R 4 , —C(O)OR 4 , —C(O)NR 5 R 4 , —C(S)NR 5 R 4 , —S(O) 2 NR 5 R 4 , —NR 5 C(O)R 4 , —NR 5 C(S)R 4 , —NR 5 S(O) 2 R 4 , —NR 5 C(O)NH 2 , —NR 5 C(O)NR 5 R 4 , —NR 5 C(S)NH 2 , —NR 5 C(S)NR 5 R 4 , —NR 5 S(O) 2 NH 2 , —NR 5 S(O) 2 NR 5 R 4 , —S(O)R 4 , or —S(O) 2 R 4 , optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; 
         R 5  is selected from the group consisting of hydrogen and optionally substituted lower alkyl; and 
         R 6  is optionally substituted heteroaryl, provided, however, the compound is not 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         17 . The method of  claim 16 , wherein the compound is approved for administration to a human. 
     
     
         18 . The method of  claim 17 , wherein the disease or condition is selected from the group consisting of multi-infarct dementia, head injury, spinal cord injury, Alzheimer's disease, Parkinson's disease, melanoma, glioma, sarcoma, cancer of the colon, lung, breast, pancreas, thyroid, ovary, liver, or kidney, medullary thyroid cancer, carcinoid, small cell lung cancer, pheochromocytoma, lymphoma, neurofibromatosis, myelodysplastic syndrome, leukemia, tumor angiogenesis, neuropathic pain, inflammatory pain, acute pain, chronic pain, cancer-related pain, migraine, heart failure, ischemic stroke, cardiac hypertrophy, thrombosis, atherosclerosis, reperfusion injury, psoriasis, arthritis, osteoarthritis, endometriosis, scarring, vascular restenosis, fibrotic disorders, rheumatoid arthritis, inflammatory bowel disease, immunodeficiency diseases, organ transplant rejection, graft versus host disease, diabetic nephropathy, polycystic kidney disease, nephrosclerosis, glomerulonephritis, prostate hyperplasia, obesity,  Helicobacter pylori  infection, Hepatitis infection, Influenza virus infection, fever, sepsis, chronic obstructive pulmonary disease, acute respiratory distress syndrome, Noonan's syndrome, Costello syndrome, LEOPARD syndrome, cardio-faciocutaneous syndrome, neural crest syndrome abnormalities causing cardiovascular, skeletal, intestinal, skin, hair and endocrine diseases, sarcopenia, muscular dystrophy, motor neuron diseases, inflammatory myopathies, diseases of the neuromuscular junction, myopathies due to endocrine abnormalities, diseases of peripheral nerve, myotonia congenita, paramyotonia congenita, central core disease, nemaline myopathy, myotubular myopathy, periodic paralysis and metabolic diseases of muscle. 
     
     
         19 . The method of  claim 18 , wherein
 R 1  is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —OH, —NH 2 , —CN, —NO 2 , —C(O)OH, —S(O) 2 NH 2 , —C(O)NH 2 , —C(S)NH 2 , —NHC(O)NH 2 , —NHC(S)NH 2 , —NHS(O) 2 NH 2 , —OR 7 , —SR 7 , —NR 8 R 7 , —C(O)R 7 , —C(S)R 7 , —C(O)OR 7 , —C(O)NR 8 R 7 , —C(S)NR 8 R 7 , —S(O) 2 NR 8 R 7 , —NR 8 C(O)R 7 , —NR 8 C(S)R 7 , —NR 8 S(O) 2 R 7 , —NR 8 C(O)NH 2 , —NR 8 C(O)NR 8 R 7 , —NR 8 C(S)NH 2 , —NR 8 C(S)NR 8 R 7 , —NR 8 S(O) 2 NH 2 , —NR 8 S(O) 2 NR 8 R 7 , —S(O)R 7 , and —S(O) 2 R 7 , wherein lower alkyl, lower alkenyl or lower alkynyl are optionally substituted with one or more substituents selected from fluoro, —OH, —NH 2 , C(O)OH, —C(O)NH 2 , —OR 7 , —NR 8 R 7 , —C(O)OR 7 , —C(O)NR 8 R 7 , cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R 1  or as substituents of lower alkyl, lower alkenyl or lower alkynyl are optionally substituted with one or more substituents selected from the group consisting of —OH, —NH 2 , —CN, —NO 2 , —S(O) 2 NH 2 , —C(O)NH 2 , —OR 9 , —SR 9 , —NHR 9 , —NR 8 R 9 , —NR 8 C(O)R 9 , —NR 8 S(O) 2 R 9 , —S(O) 2 R 9 , —S(O) 2 NR 8 R 9 , —C(O)R 9 , —C(O)NR 8 R 9 , halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;   R 6  is heteroaryl optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —OH, —NH 2 , —CN, —NO 2 , —C(O)OH, —S(O) 2 NH 2 , —C(O)NH 2 , —C(S)NH 2 , —NHC(O)NH 2 , —NHC(S)NH 2 , —NHS(O) 2 NH 2 , —OR 7 , —SR 7 , —NR 8 R 7 , —C(O)R 7 , —C(S)R 7 , —C(O)OR 7 , —C(O)NR 8 R 7 , —C(S)NR 8 R 7 , —S(O) 2 NR 8 R 7 , —NR 8 C(O)R 7 , —NR 8 C(S)R 7 , —NR 8 S(O) 2 R 7 , —NR 8 C(O)NH 2 , —NR 8 C(O)NR 8 R 7 , —NR 8 C(S)NH 2 , —NR 8 C(S)NR 8 R 7 , —NR 8 S(O) 2 NH 2 , —NR 8 S(O) 2 NR 8 R 7 , —S(O)R 7 , and —S(O) 2 R 7 , wherein lower alkyl is optionally substituted with one or more substituents selected from fluoro, —OR 7 , —NR 8 R 7 , cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as a substituent of R 6  or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of —OH, —NH 2 , —CN, —NO 2 , —S(O) 2 NH 2 , —C(O)NH 2 , —OR 9 , —SR 9 , —NHR 9 , —NR 8 R 9 , —NR 8 C(O)R 9 , —NR 8 S(O) 2 R 9 , —S(O) 2 R 9 , —S(O) 2 NR 8 R 9 , —C(O)R 9 , —C(O)NR 8 R 9 , halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;   R 7  is selected from the group consisting of lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R 7  or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of —OH, —NH 2 , —CN, —NO 2 , —S(O) 2 NH 2 , —C(O)NH 2 , —OR 9 , —SR 9 , —NHR 9 , —NR 8 R 9 , —NR 8 C(O)R 9 , —NR 8 S(O) 2 R 9 , —S(O) 2 R 9 , —S(O) 2 NR 8 R 9 , —C(O)R 9 , —C(O)NR 8 R 9 , halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;   R 8  at each occurrence is independently hydrogen or lower alkyl; and   R 9  at each occurrence is independently selected from the group consisting of lower alkyl, heterocycloalkyl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, and heterocycloalkyl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, —CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy and fluoro substituted lower alkoxy.   
     
     
         20 . The method of  claim 18 , wherein:
 R 1  is hydrogen, —CN, —NR 8 R 7 , —OR 7 , —S(O) 2 R 7 , fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, —NR 8 R 7 , —OR 7  and —S(O) 2 R 7 , and   R 6  is heteroaryl optionally substituted with one or more of —CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, —NR 8 R 7 , —OR 7  or —S(O) 2 R 7 .   
     
     
         21 . The method of  claim 20 , wherein:
 R 1  is hydrogen, —CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkoxy substituted C 2-6 alkoxy, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, mono-alkylamino, di-alkylamino, and cycloalkylamino, and   R 6  is heteroaryl optionally substituted with one or more of —CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, mono-alkylamino, di-alkylamino, or cycloalkylamino.   
     
     
         22 . The method of  claim 18 , wherein the compound is selected from the group consisting of:
 Benzo[b]thiophene-3-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide,   5-Methyl-2-trifluoromethyl-furan-3-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide,   5-Oxazol-5-yl-thiophene-2-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide,   2-Oxo-2H-chromene-6-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide,   5-Isoxazol-5-yl-thiophene-2-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide,   Benzothiazole-6-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide,   1-Methyl-3-trifluoromethyl-1H-pyrazole-4-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide,   Benzo[1,2,5]thiadiazoe-5-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide,   5-Methyl-benzo[b]thiophene-2-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide,   5-Methyl-thiophene-2-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide,   1-Methyl-1H-pyrazole-3-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide,   Pyridine-2-sulfonic acid [2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide; and   pharmaceutically acceptable salts, tautomers, and isomers thereof.   
     
     
         23 . A kit comprising a compound of Formula I according to  claim 1 , wherein the compound is approved for a medical indication selected from the group consisting of multi-infarct dementia, head injury, spinal cord injury, Alzheimer's disease, Parkinson's disease, melanoma, glioma, sarcoma, cancer of the colon, lung, breast, pancreas, thyroid, ovary, liver, or kidney, medullary thyroid cancer, carcinoid, small cell lung cancer, pheochromocytoma, lymphoma, neurofibromatosis, myelodysplastic syndrome, leukemia, tumor angiogenesis, neuropathic pain, inflammatory pain, acute pain, chronic pain, cancer-related pain, migraine, heart failure, ischemic stroke, cardiac hypertrophy, thrombosis, atherosclerosis, reperfusion injury, psoriasis, arthritis, osteoarthritis, endometriosis, scarring, vascular restenosis, fibrotic disorders, rheumatoid arthritis, inflammatory bowel disease, immunodeficiency diseases, organ transplant rejection, graft versus host disease, diabetic nephropathy, polycystic kidney disease, nephrosclerosis, glomerulonephritis, prostate hyperplasia, obesity,  Helicobacter pylori  infection, Hepatitis infection, Influenza virus infection, fever, sepsis, chronic obstructive pulmonary disease, acute respiratory distress syndrome, Noonan's syndrome, Costello syndrome, LEOPARD syndrome, cardio-faciocutaneous syndrome, neural crest syndrome abnormalities causing cardiovascular, skeletal, intestinal, skin, hair and endocrine diseases, sarcopenia, muscular dystrophy, motor neuron diseases, inflammatory myopathies, diseases of the neuromuscular junction, myopathies due to endocrine abnormalities, diseases of peripheral nerve, myotonia congenita, paramyotonia congenita, central core disease, nemaline myopathy, myotubular myopathy, periodic paralysis and metabolic diseases of muscle. 
     
     
         24 . The kit of  claim 23 , wherein the compound is selected from the group consisting of:
 4-Butoxy-N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-benzenesulfonamide,   N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-pyrazol-1-yl-benzenesulfonamide,   N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-isopropoxy-benzenesulfonamide,   4-tert-Butyl-N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-benzenesulfonamide,   N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-propyl-benzenesulfonamide,   N-{2,4-Difluoro-3-[5-(2-methoxy-ethoxy)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-isopropyl-benzenesulfonamide,   N-{2,4-Difluoro-3-[5-(4-methyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-isopropyl-benzenesulfonamide,   4-Difluoromethoxy-N-{2,4-difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-benzenesulfonamide,   N-{2,4-Difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-propyl-benzenesulfonamide,   N-{2,4-Difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-isopropyl-benzenesulfonamide,   N-{2,4-Difluoro-3-[5-(5-methyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-propyl-benzenesulfonamide,   N-{2,4-Difluoro-3-[5-(5-methyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-trifluoromethyl-benzenesulfonamide,   N-{2,4-Difluoro-3-[5-(1-methyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-propyl-benzenesulfonamide,   N-{3-[5-(1,5-Dimethyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-4-propyl-benzenesulfonamide,   N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-trifluoromethyl-benzene sulfonamide,   N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzene sulfonamide,   (E)-3-{3-[2,6-Difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-acrylic acid methyl ester,   3-{3-[2,6-Difluoro-3-(4-trifluoromethyl-benzene sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-prop ionic acid methyl ester,   3-{3-[2,6-Difluoro-3-(4-trifluoromethyl-benzene sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-propionic acid,   3-{3-[2,6-Difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-ethyl-propionamide; and   
       pharmaceutically acceptable salts, tautomers, and isomers thereof. 
     
     
         25 . A kit comprising a compound of Formula II according to  claim 9 , wherein the compound is approved for a medical indication selected from the group consisting of multi-infarct dementia, head injury, spinal cord injury, Alzheimer's disease, Parkinson's disease, melanoma, glioma, sarcoma, cancer of the colon, lung, breast, pancreas, thyroid, ovary, liver, or kidney, medullary thyroid cancer, carcinoid, small cell lung cancer, pheochromocytoma, lymphoma, neurofibromatosis, myelodysplastic syndrome, leukemia, tumor angiogenesis, neuropathic pain, inflammatory pain, acute pain, chronic pain, cancer-related pain, migraine, heart failure, ischemic stroke, cardiac hypertrophy, thrombosis, atherosclerosis, reperfusion injury, psoriasis, arthritis, osteoarthritis, endometriosis, scarring, vascular restenosis, fibrotic disorders, rheumatoid arthritis, inflammatory bowel disease, immunodeficiency diseases, organ transplant rejection, graft versus host disease, diabetic nephropathy, polycystic kidney disease, nephrosclerosis, glomerulonephritis, prostate hyperplasia, obesity,  Helicobacter pylori  infection, Hepatitis infection, Influenza virus infection, fever, sepsis, chronic obstructive pulmonary disease, acute respiratory distress syndrome, Noonan's syndrome, Costello syndrome, LEOPARD syndrome, cardio-faciocutaneous syndrome, neural crest syndrome abnormalities causing cardiovascular, skeletal, intestinal, skin, hair and endocrine diseases, sarcopenia, muscular dystrophy, motor neuron diseases, inflammatory myopathies, diseases of the neuromuscular junction, myopathies due to endocrine abnormalities, diseases of peripheral nerve, myotonia congenita, paramyotonia congenita, central core disease, nemaline myopathy, myotubular myopathy, periodic paralysis and metabolic diseases of muscle. 
     
     
         26 . The kit of  claim 25 , wherein the compound is selected from the group consisting of:
 3-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenylsulfamoyl]-benzoic acid,   N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3-difluoromethoxy-benzenesulfonamide,   3-Difluoromethoxy-N-{2,4-difluoro-3-[5-(5-methyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-benzenesulfonamide; and   
       pharmaceutically acceptable salts, tautomers, and isomers thereof. 
     
     
         27 . A kit comprising a compound of Formula III according to  claim 16 , wherein the compound is approved for a medical indication selected from the group consisting of multi-infarct dementia, head injury, spinal cord injury, Alzheimer's disease, Parkinson's disease, melanoma, glioma, sarcoma, cancer of the colon, lung, breast, pancreas, thyroid, ovary, liver, or kidney, medullary thyroid cancer, carcinoid, small cell lung cancer, pheochromocytoma, lymphoma, neurofibromatosis, myelodysplastic syndrome, leukemia, tumor angiogenesis, neuropathic pain, inflammatory pain, acute pain, chronic pain, cancer-related pain, migraine, heart failure, ischemic stroke, cardiac hypertrophy, thrombosis, atherosclerosis, reperfusion injury, psoriasis, arthritis, osteoarthritis, endometriosis, scarring, vascular restenosis, fibrotic disorders, rheumatoid arthritis, inflammatory bowel disease, immunodeficiency diseases, organ transplant rejection, graft versus host disease, diabetic nephropathy, polycystic kidney disease, nephrosclerosis, glomerulonephritis, prostate hyperplasia, obesity,  Helicobacter pylori  infection, Hepatitis infection, Influenza virus infection, fever, sepsis, chronic obstructive pulmonary disease, acute respiratory distress syndrome, Noonan's syndrome, Costello syndrome, LEOPARD syndrome, cardio-faciocutaneous syndrome, neural crest syndrome abnormalities causing cardiovascular, skeletal, intestinal, skin, hair and endocrine diseases, sarcopenia, muscular dystrophy, motor neuron diseases, inflammatory myopathies, diseases of the neuromuscular junction, myopathies due to endocrine abnormalities, diseases of peripheral nerve, myotonia congenita, paramyotonia congenita, central core disease, nemaline myopathy, myotubular myopathy, periodic paralysis and metabolic diseases of muscle. 
     
     
         28 . The kit of  claim 27 , wherein the compound is selected from the group consisting of:
 Benzo[b]thiophene-3-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide,   5-Methyl-2-trifluoromethyl-furan-3-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide,   5-Oxazol-5-yl-thiophene-2-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide,   2-Oxo-2H-chromene-6-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide,   5-Isoxazol-5-yl-thiophene-2-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide,   Benzothiazole-6-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide,   1-Methyl-3-trifluoromethyl-1H-pyrazole-4-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide,   Benzo[1,2,5]thiadiazoe-5-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide,   5-Methyl-benzo[b]thiophene-2-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide,   5-Methyl-thiophene-2-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide,   1-Methyl-1H-pyrazole-3-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide,   Pyridine-2-sulfonic acid [2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide; and   
       pharmaceutically acceptable salts, tautomers, and isomers thereof.