COMPOUNDS AND METHODS FOR KINASE MODULATION, AND INDICATIONS THEREFOR

• US 20080167338A1
• Filed: 12/19/2007
• Published: 07/10/2008
• Est. Priority Date: 12/21/2006
• Status: Active Grant

• Current Assignee: Plexxikon Inc (Daiichi Sankyo Company Limited)
• Original Assignee: Plexxikon Inc (Daiichi Sankyo Company Limited)
• Inventors: Zhu, Hongyao, Spevak, Wayne, Shi, Shenghua, Mamo, Shumeye, Ibrahim, Prabha N., Gillette, Samuel J., Cho, Hanna
• Granted Patent: US 7,863,289 B2
• Time in Patent Office: Days
• US Class Current: 514/300
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• 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 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/16 : Anti-Parkinson drugs
• 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 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 3/14 : for calcium homeostasis vitamin D A61P3/02; parathyroid hormones A61P5/18; calcitonin A61P5/22; osteoporosis A61P19/10; bone metastasis A61P35/04
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 31/14 : for RNA viruses
• CPC Class Codes: A61P 31/16 : for influenza or rhinoviruses
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 35/04 : specific for metastasis
• CPC Class Codes: A61P 37/02 : Immunomodulators
• 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 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• 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: C07D 471/04 : Ortho-condensed systems

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.

Claims

1. A compound having the chemical structure of Formula I,

2. The compound of claim 1, wherein:

R¹ is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —

OH, —

NH₂, —

CN, —

NO₂, —

C(O)OH, —

S(O)₂NH₂, —

C(O)NH₂, —

C(S)NH₂, —

NHC(O)NH₂, —

NHC(S)NH₂, —

NHS(O)₂NH₂, —

OR⁷, —

SR⁷, —

NR⁸R⁷, —

C(O)R⁷, —

C(S)R⁷, —

C(O)OR⁷, —

C(O)NR⁸R⁷, —

C(S)NR⁸R⁷, S(O)₂NR⁸R⁷, —

NR⁸C(O)R⁷, —

NR⁸C(S)R⁷, —

NR⁸S(O)₂R⁷, —

NR⁸C(O)NH₂, —

NR⁸C(O)NR⁸R⁷, —

NR⁸C(S)NH₂, —

NR⁸C(S)NR⁸R⁷, —

NR⁸S(O)₂NH₂, —

NR⁸S(O)₂NR⁸R⁷, S(O)R⁷, and —

S(O)₂R⁷, wherein lower alkyl, lower alkenyl or lower alkynyl are optionally substituted with one or more substituents selected from fluoro, —

OH, —

NH₂, C(O)OH, —

C(O)NH₂, —

OR⁷, —

NR⁸R⁷, —

C(O)OR⁷, —

C(O)NR⁸R⁷, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R¹ 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, —

NH₂, —

CN, —

NO₂, —

S(O)₂NH₂, —

C(O)NH₂, —

OR⁹, —

SR⁹, —

NR⁸R⁹, —

NR⁸C(O)R⁹, —

NR⁸S(O)₂R⁹, —

S(O)₂R⁹, —

S(O)₂NR⁸R⁹, —

C(O)R⁹, —

C(O)NR⁸R⁹, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;

R² is selected from the group consisting of halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —

OH, —

NH₂, —

CN, —

NO₂, —

C(O)OH, S(O)₂NH₂, —

C(O)NH₂, —

C(S)NH₂, —

NHC(O)NH₂, —

NHC(S)NH₂, —

NHS(O)₂NH₂, —

OR⁷, —

SR⁷, —

NR⁸R⁷, —

C(O)R⁷, —

C(S)R⁷, —

C(O)OR⁷, —

C(O)NR⁸R⁷, —

C(S)NR⁸R⁷, —

S(O)₂NR⁸R⁷, —

NR⁸C(O)R⁷, —

NR⁸C(S)R⁷, —

NR⁸S(O)₂R⁷, —

NR⁸C(O)NH₂, —

NR⁸C(O)NR⁸R⁷, —

NR⁸C(S)NH₂, —

NR⁸C(S)NR⁸R⁷, —

NR⁸S(O)₂NH₂, —

NR⁸S(O)₂NR⁸R⁷, —

S(O)R⁷, and —

S(O)₂R⁷, wherein lower alkyl is optionally substituted with one or more substituents selected from fluoro, —

OR⁷, —

NR⁸R⁷, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R² or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of —

OH, —

NH₂, —

CN, —

NO₂, —

S(O)₂NH₂, —

C(O)NH₂, —

OR⁹, —

SR⁹, —

NR⁸R⁹, —

NR⁸C(O)R⁹, —

NR⁸S(O)₂R⁹, —

S(O)₂R⁹, —

S(O)₂NR⁸R⁹, —

C(O)R⁹, —

C(O)NR⁸R⁹, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;

R⁷ 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 R⁷ or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of —

OH, —

NH₂, —

CN, —

NO₂, —

S(O)NH), —

C(O)NH₂, —

OR⁹, —

SR⁹, —

NR⁸R⁹, —

NR⁸C(O)R⁹, —

NR⁸S(O)₂R⁹, —

S(O)₂R⁹, —

S(O)₂NR⁸R⁹, —

C(O)R⁹, —

C(O)NR⁸R⁹, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;

R⁸ at each occurrence is independently hydrogen or lower alkyl; and

R⁹ 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.

3. The compound of claim 2, wherein:

R¹ is selected from the group consisting of hydrogen, —

CN, —

OR⁷, —

SR⁷, —

NR⁸R⁷, —

NR⁸C(O)R⁷, —

NR⁸S(O)₂R⁷—

C(O)NR⁸R⁷, —

C(O)R⁷, —

S(O)₂NR⁸R⁷, —

S(O)R⁷, —

S(O)₂R⁷, 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 R¹ or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of —

OH, —

NH₂, —

CN, —

NO₂, —

S(O)₂NH₂, —

C(O)NH₂, —

OR⁹, —

SR⁹, —

NR⁸R⁹, —

NR⁸C(O)R⁹, —

NR⁸S(O)₂R⁹, —

S(O)₂R⁹, —

S(O)₂NR⁸R⁹, —

C(O)R⁹, —

C(O)NR⁸R⁹, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; and

R² is selected from the group consisting of —

CN, —

OR⁷, —

SR⁷, —

NR⁸R⁷, —

NR⁸C(O)R⁷, —

NR⁸S(O)₂R⁷, —

(CO)NR⁸R⁷, —

C(O)R⁷, —

S(O)₂NR⁸R⁷, —

S(O)R⁷, —

S(O)₂R⁷, 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 R² or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of —

OH, —

NH₂, —

CN, —

NO₂, —

S(O)₂NH₂, —

C(O)NH₂, —

OR⁹, —

SR⁹, —

NR⁸R⁹, —

NR⁸C(O)R⁹, —

NR⁸S(O)₂R⁹, —

S(O)₂R⁹, —

S(O)₂NR⁸R⁹, —

C(O)R⁹, —

C(O)NR⁸R⁹, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino.

4. The compound of claim 3, wherein:

R¹ is hydrogen, —

CN, —

NR⁸R⁷, —

OR⁷, —

S(O)₂R⁷, 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, —

NR⁸R⁷, —

OR⁷ and —

S(O)₂R⁷, and

R² is —

CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, —

NR⁸R⁷, —

OR⁷ or —

S(O)₂R⁷.

5. The compound of claim 4, wherein:

R¹ is hydrogen, —

CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkoxy substituted C_2-6alkoxy, 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

R² is —

CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, mono-alkylamino, di-alkylamino, or cycloalkylamino.

6. The compound of claim 1, 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-1r-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-1-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]-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-benzenesulfonamide,

N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide,

(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-benzenesulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-propionic acid methyl ester,

3-{3-[2,6-Difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-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

all salts, prodrugs, tautomers, and isomers thereof.

19. A composition comprising a pharmaceutically acceptable carrier;

and a compound according to claim 1.

20. 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 claim 1.

21. The method of claim 20, wherein the compound or composition is approved for administration to a human.

22. The method of claim 21, 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.

23. A kit comprising a compound according to claim 1.

24. The kit of claim 23, wherein the compound or composition 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.

7. A compound having the chemical structure of Formula II,

8. The compound of claim 7, wherein:

R¹ is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —

OH, —

NH₂, —

CN, —

NO₂, —

C(O)OH, —

S(O)₂NH₂, —

C(O)NH₂, —

C(S)NH₂, —

NHC(O)NH₂, —

NHC(S)NH₂, —

NHS(O)₂NH₂, —

OR⁷, —

SR⁷, —

NR⁸R⁷, —

C(O)R⁷, —

C(S)R⁷, —

C(O)OR⁷, —

C(O)NR⁸R⁷, —

C(S)NR⁸R⁷, —

S(O)₂NR⁸R⁷, —

NR⁸C(O)R⁷, —

NR⁸C(S)R⁷, —

NR⁸S(O)₂R⁷, —

NR⁸C(O)NH₂, —

NR⁸C(O)NR⁸R⁷, —

NR⁸C(S)NH₂, —

NR⁸C(S)NR⁸R⁷, —

NR⁸S(O)₂NH₂, —

NR⁸S(O)₂NR⁸R⁷, —

S(O)R⁷, and —

S(O)₂R⁷, wherein lower alkyl, lower alkenyl or lower alkynyl are optionally substituted with one or more substituents selected from fluoro, —

OH, —

NH₂, C(O)OH, —

C(O)NH₂, —

OR⁷, —

NR⁸R⁷, —

C(O)OR⁷, —

C(O)NR⁸R⁷, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R¹ 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, —

NH₂, —

CN, —

NO₂, —

S(O)₂NH₂, —

C(O)NH₂, —

OR⁹, —

SR⁹, —

NR⁸R⁹, —

NR⁸C(O)R⁹, —

NR⁸S(O)—

R⁹, —

S(O)₂R⁹, —

S(O)₂NR⁸R⁹, —

C(O)R⁹, —

C(O)NR⁸R⁹, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;

R^2a is selected from the group consisting of halogen, lower alkyl, cycloalkyl, heterocycloalkyl aryl, heteroaryl, —

OH, —

NH₂, —

CN, —

NO₂, —

C(O)OH, —

S(O)₂NH₂, —

C(O)NH₂, —

C(S)NH, —

NHC(O)NH₂, —

NHC(S)NH₂, —

NHS(O)₂NH₂, —

OR⁷, —

SR⁷, —

NR⁸R⁷, —

C(O)R⁷, —

C(S)R⁷, —

C(O)OR⁷, —

C(O)NR⁸R⁷, —

C(S)NR⁸R⁷, —

S(O)₂NR⁸R⁷, —

NR⁸C(O)R⁷, NR⁸C(S)R⁷, —

NR⁷S(O)₂R⁷, —

NR⁸C(O)NH₂, —

NR⁸C(O)NR⁸R⁷, —

NR⁸C(S)NH₂, —

NR⁸C(S)NR⁸R⁷, —

NR⁸S(O)₂NH₂, —

NR⁸S(O)₂NR⁸R⁷, —

S(O)R⁷, and —

S(O)₂R⁷, wherein lower alkyl is optionally substituted with one or more substituents selected from fluoro, —

OR⁷, —

NR⁸R⁷, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R^2a or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of —

OH, —

NH₂, —

CN, —

NO₂, —

S(O)₂NH₂, —

C(O)NH₂, —

OR⁹, —

SR⁹, —

NR⁸R⁸, —

NR⁸C(O)R⁸, —

NR⁸S(O)₂R⁹, —

S(O)₂R⁹, —

S(O)₂NR⁸R⁹, —

C(O)R⁹, —

C(O)NR⁸R⁹, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;

R⁷ 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 R⁷ or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of —

OH, —

NH₂, —

CN, —

NO₂, —

S(O)₂NH₂, —

C(O)NH₂, —

OR⁹, —

SR⁹, —

NR⁸R⁹, —

NR⁸C(O)R⁹, —

NR⁸S(O)₂R⁹, —

S(O)₂R⁹, —

S(O)₂NR⁸R⁹, —

C(O)R⁹, —

C(O)NR⁸R⁹, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;

R⁸ at each occurrence is independently hydrogen or lower alkyl; and

R⁹ at each occurrence is independently selected from the group consisting of lower alkyl, heterocycloalkyl and heteroaryl, wherein lower alkyl is optionally substituted with one of 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.

9. The compound of claim 8, wherein:

R¹ is selected from the group consisting of hydrogen, —

CN, —

OR⁷, —

SR⁷, —

NR⁸R⁷, —

NR⁸C(O)R⁷, —

NR⁸S(O)₂R⁷, —

C(O)NR⁸R⁷, —

C(O)R⁷, —

S(O)₂NR⁸R⁷, —

S(O)R⁷, —

S(O)—

R⁷, 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 R¹ or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of —

OH, —

NH₂, —

CN, —

NO₂, —

S(O)₂NH₂, —

C(O)NH₂, —

OR⁹, —

SR⁹, —

NR⁸R⁹, —

NR⁸C(O)R⁹, —

NR⁸S(O)₂R⁹, —

S(O)₂R⁹, —

S(O)₂NR⁸R⁹, —

C(O)R⁹, —

C(O)NR⁸R⁹, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; and

R^2a is selected from the group consisting of —

CN, —

OR⁷, —

SR⁷, —

NR⁸R⁷, —

NR⁸C(O)R⁷, —

NR⁸S(O)₂R⁷, —

C(O)NR⁸R⁷, —

C(O)R⁷, —

S(O)₂NR⁸R⁷, —

S(O)R⁷, —

S(O)₂R⁷, 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, —

NH₂, —

CN, —

NO₂, —

S(O)₂ N₂, —

C(O)NH₂, —

OR⁹, —

SR⁹, —

NR⁸R⁹, —

NR⁸C(O)R⁹, —

NR⁸S(O)₂R⁹, —

S(O)₂R⁹, —

S(O)₂NR⁸R⁹, —

C(O)R⁹, —

C(O)NR⁸R⁹, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino.

10. The compound of claim 9, wherein:

R¹ is hydrogen, —

CN, —

NR⁸R⁷, —

OR⁷, —

S(O)₂R⁷, 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, —

NR⁸R⁷, —

OR⁷ and —

S(O)₂R⁷, and

R^2a is —

CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, —

NR⁸R⁷, —

OR⁷ or —

S(O)₂R⁷.

11. The compound of claim 10, wherein:

R¹ is hydrogen, —

CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkoxy substituted C_2-6alkoxy, 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.

12. The compound of claim 7, wherein the compound is selected from the group consisting of:

3-[3-(5-Chloro-1-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

all salts, prodrugs, tautomers, and isomers thereof.

25. A composition comprising a pharmaceutically acceptable carrier;

and a compound according to claim 7.

26. 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 claim 7.

27. The method of claim 26, wherein the compound or composition is approved for administration to a human.

28. The method of claim 27, 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.

29. A kit comprising a compound according to claim 7.

30. The kit of claim 29, wherein the compound or composition 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.

13. A compound having the chemical structure of Formula III,

14. The compound of claim 13, wherein:

R¹ is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —

OH, —

NH—

, —

CN, —

NO₂, —

C(O)OH, —

S(O)₂NH₂, —

C(O)NH₂, —

C(S)NH₂, —

NHC(O)NH₂, —

NHC(S)NH₂, —

NHS(O)₂NH₂, —

OR⁷, —

SR⁷, —

NR⁸R⁷, —

C(O)R⁷, —

C(S)R⁷, —

C(O)OR⁷, —

C(O)NR⁸R⁷, —

C(S)NR⁸R⁷, —

S(O)₂NR⁸R⁷, —

NR⁸C(O)R⁷, —

NR⁸C(S)R⁷, —

NR⁸S(O)₂R⁷, —

NR⁸C(O)NH₂, —

NR⁸C(O)NR⁸R⁷, —

NR⁸C(S)NH₂, —

NR⁸C(S)NR⁸R⁷, —

NR⁵S(O)₂NH₂, —

NR⁸S(O)₂NR⁸R⁷, —

S(O)R⁷, and —

S(O)₂R⁷, wherein lower alkyl, lower alkenyl or lower alkynyl are optionally substituted with one or more substituents selected from fluoro, —

OH, —

NH₂, C(O)OH, —

C(O)NH₂, —

OR⁷, —

NR⁸R⁷, —

C(O)OR⁷, —

C(O)NR⁸R⁷, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R¹ 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, —

NH₂, —

CN, —

NO₂, —

S(O)₂NH₂, —

C(O)NH₂, —

OR⁹, —

SR⁹, —

NR⁸R⁹, —

NR⁸C(O)R⁹, —

NR⁸S(O)₂R⁹, —

S(O)₂R⁹, —

S(O)₂NR⁸R⁹, —

C(O)R⁹, —

C(O)NR⁸R⁹, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;

R⁶ is heteroaryl optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —

OH, —

NH₂, —

CN, —

NO₂, —

C(O)OH, —

S(O)₂NH₂, —

C(O)NH₂, —

C(S)NH₂, —

NHC(O)NH₂, —

NHC(S)NH₂, —

NHS(O)₂NH₂, —

OR⁷, —

SR⁷, —

NR⁸R⁷, —

C(O)R⁷, —

C(S)R⁷, —

C(O)OR⁷, —

C(O)NR⁸R⁷, —

S(O)₂NR⁸R⁷, —

NR⁸C(O)R⁷, —

NR⁸C(S)R⁷, —

NR⁸S(O)₂R⁷, —

NR⁸C(O)NH₂, —

NR⁸C(O)NR⁸R⁷, —

NR⁸C(S)NH₂, —

NR⁸C(S)NR⁸R⁷, —

NR⁸S(O)₂NH₂, —

NR⁸S(O)₂NR⁸R⁷, —

S(O)R⁸, and —

S(O)₂R⁷, wherein lower alkyl is optionally substituted with one or more substituents selected from fluoro, —

OR⁷, —

NR⁸R⁷, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as a substituent of R⁶ or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of —

OH, —

NH₂, —

CN, —

NO₂, —

S(O)₂NH₂, —

C(O)NH₂, —

OR⁹, —

SR⁹, —

NR⁸R⁹, —

NR⁸C(O)R⁹, —

NR⁸S(O)₂R⁹, —

S(O)₂R⁹, —

S(O)₂NR⁸R⁹, —

C(O)R⁹, —

C(O)NR⁹R⁹, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;

R⁷ 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 R⁷ or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of —

OH, —

NH₂, —

CN, —

NO₂, —

S(O)₂N14, —

C(O)NH₂, —

OR⁹, —

SR⁹, —

NR⁸R⁹, —

NR⁸C(O)R⁹, —

NR⁸S(O)₂R⁹, —

S(O)₂R⁹, —

S(O)₂NR⁸R⁹, —

C(O)R⁹, —

C(O)NR⁸R⁹, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;

R⁸ at each occurrence is independently hydrogen or lower alkyl; and

R⁹ 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.

15. The compound of claim 14, wherein:

R¹ is selected from the group consisting of hydrogen, —

CN, —

OR⁷, —

SR⁷, —

NR⁸R⁷, —

NR⁸C(O)R⁷, —

NR⁸S(O)₂R⁷, —

C(O)NR⁸R⁷, —

C(O)R⁷, —

S(O)₂NR⁸R⁷, —

S(O)R⁷, —

S(O)₂R⁷, 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 R¹ or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of —

OH, —

NH₂, —

CN, —

NO₂, —

S(O)₂NH₂, —

C(O)NH₂, —

OR⁹, —

SR⁸, —

NR⁸R⁹, —

NR⁸C(O)R⁹, —

NR⁸S(O)₂R⁹, —

S(O)₂R⁹, —

S(O)₂NR⁸R⁹, —

C(O)R⁹, —

C(O)NR⁸R⁹, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; and

R⁶ is heteroaryl optionally substituted with one or more substituents selected from the group consisting of —

CN, —

OR⁷, —

SR⁷, —

NR⁸R⁷, —

NR⁸C(O)R⁷, —

NR⁸S(O)₂R⁷, —

C(O)NR⁸R⁷, —

C(O)⁷, —

S(O)₂NR⁸R⁷, —

S(O)R⁷, —

S(O)₂R⁷, 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 a substituent of R⁶ or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of —

OH, —

NH₂, —

CN, —

NO₂, —

S(O)₂NH₂, —

C(O)NH₂, —

OR⁹, —

SR⁹, —

NR⁸R⁹, —

NR⁸C(O)R⁹, —

NR⁸S(O)₂R⁹, —

S(O)₂R⁹, —

S(O)₂NR⁸R⁹, —

C(O)R⁹, —

C(O)NR⁸R⁹, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino.

16. The compound of claim 15, wherein:

R¹ is hydrogen, —

CN, —

NR⁸R⁷, —

OR⁷, —

S(O)₂R⁷, 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, —

NR⁸R⁷, —

OR⁷ and —

S(O)₂R⁷, and

R⁶ is heteroaryl optionally substituted with one or more of —

CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, —

NR⁸R⁷, —

OR⁷ or —

S(O)₂R⁷.

17. The compound of claim 16, wherein:

R¹ is hydrogen, —

CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkoxy substituted C_2-6alkoxy, 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

R⁶ 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.

18. The compound of claim 13, 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-1-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

all salts, prodrugs, tautomers, and isomers thereof.

31. A composition comprising:

a pharmaceutically acceptable carrier; and

a compound according to claim 13.

32. 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 claim 13.

33. The method of claim 32, wherein the compound or composition is approved for administration to a human.

34. The method of claim 33, 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 congenital central core disease, nemaline myopathy, myotubular myopathy, periodic paralysis and metabolic diseases of muscle.

35. A kit comprising a compound according to claim 13.

36. The kit of claim 35, wherein the compound or composition 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, medullar, 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.