COMPOUNDS AND METHODS FOR KINASE MODULATION, AND INDICATIONS THEREFOR
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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.
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Citations
92 Claims
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1-15. -15. (canceled)
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16. A compound having the structure of Formula IIIm:
- View Dependent Claims (25, 26, 31, 35, 38, 39, 40, 41, 42, 43, 44, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92)
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25. A composition comprising:
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a pharmaceutically acceptable carrier; and a compound according to claim 16.
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26. A kit comprising a compound according to claim 16.
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31. A compound useful as an intermediate in the preparation of compounds according to claim 16, said compound having the structure of Formula VIIIa:
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35. A method for treating a subject suffering from or at risk of a protein kinase mediated disease or condition, comprising:
administering to said subject an effective amount of a compound according to claim 16.
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38. The method according to claim 35 wherein said protein kinase is selected from the group consisting of B-Raf, any mutation of B-Raf, c-Raf-1, and any mutation of c-Raf-1.
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39. The method according to claim 38 wherein said disease or condition is selected from the group consisting of ischemic stroke, multi-infarct dementia, head injury, spinal cord injury, Alzheimer'"'"'s disease, Parkinson'"'"'s disease, acute myeloid leukemia, melanoma. gliomas, sarcomas, histiocytic lymphoma, neurofibromatosis, myelodysplastic syndrome, tumor angiogenesis, thyroid cancer, liver cancer, colorectal cancer, pancreatic cancer, breast cancer, ovarian cancer, small cell lung cancer, acute pain, chronic pain, migraine, heart failure, cardiac hypertrophy, thrombosis, atherosclerosis, reperfusion injury, polycystic kidney disease, rheumatoid arthritis, inflammatory bowel disease, psoriasis, osteoarthritis, endometriosis, scarring, vascular restenosis, fibrotic disorders, immunodeficiency diseases, organ transplant rejection, graft versus host disease, diabetic nephropathy, nephrosclerosis, glomerulonephritis, prostate hyperplasia, metabolic syndrome, obesity, Helicobacter pylori infection, Influenza virus infection, fever, sepsis, chronic obstructive pulmonary disease, acute respiratory distress syndrome, Noonan'"'"'s syndrome, Costello syndrome, leopard syndrome, cardio-faciocutaneous syndrome, and neural crest syndrome abnormalities causing cardiovascular, skeletal, intestinal, skin, hair or endocrine diseases.
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40. The method according to claim 38 wherein said disease or condition is selected from the group consisting of ischemic stroke, multi-infarct dementia, head injury, spinal cord injury, Alzheimer'"'"'s disease, Parkinson'"'"'s disease, acute myeloid leukemia, melanoma, gliomas, sarcomas, histiocytic lymphoma, neurofibromatosis, myelodysplastic syndrome, tumor angiogenesis, thyroid cancer, liver cancer, colorectal cancer, pancreatic cancer, breast cancer, ovarian cancer, small cell lung cancer, acute pain, chronic pain, migraine, and polycystic kidney disease.
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41. The method according to claim 38 wherein said disease or condition is selected from the group consisting of acute myeloid leukemia, melanoma, thyroid cancer, liver cancer, colorectal cancer, pancreatic cancer, breast cancer, ovarian cancer, and small cell lung cancer.
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42. The method according to claim 38 wherein said disease or condition is melanoma, thyroid cancer or colorectal cancer.
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43. The compound of claim 16,
wherein: R81 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, —
CN, —
S(O)2NH2, —
C(O)NH2, —
OR68, —
SR68, —
NR69R68, —
C(O)R68, —
C(S)R68, —
C(O)NR69R68, —
S(O)2NR69R68, —
NR69C(O)R68, —
NR69S(O)2R68, —
S(O)R68, and —
S(O)2R68.
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44. The compound of claim 43,
wherein: -
lower alkyl as R68, R69, R79, R80, or R81, C2-6 alkyl as R112, lower alkenyl as R68 or R81, or lower alkynyl as R68 or R81 are optionally substituted with 1, 2, or 3 substituents selected from the group consisting of fluoro, —
NO2, —
CN, —
NR1aR1a, —
OC(O)R1a, —
OC(S)R1a, —
C(O)R1a, —
C(S)R1a, —
C(O)OR1a, —
C(S)OR1a, —
C(O)NR1aR1a, —
C(S)NR1aR1a, —
S(O)2NR1aR1a, —
C(NH)NR1aR1a, —
NR13C(O)R1a, —
NR1aC(S)R1a, —
NR1aS(O)2R1a, —
NR1aC(O)NR1aR1a, —
NR1aC(S)NR1aR1a, —
NR1aS(O)2NR1aR1a, —
S(O)R1a, —
S(O)2R1a, cycloalkyl, heterocycloalkyl, aryl and heteroaryl;cycloalkyl, heterocycloalkyl, aryl or heteroayl, as R68, R81, R112, or a substituent of lower alkyl, lower alkenyl or lower alkynyl are optionally substituted with 1, 2, or 3 substituents selected from the group consisting of halogen, —
NO2, —
CN, —
SR1a, —
NR1aR1a, —
OC(O)R1a, —
OC(S)R1a, —
C(O)R1a, —
C(S)R1a, —
C(O)OR1a, —
C(S)OR1a, —
C(O)NR —
C(S)NR1aR1a, —
S(O)2NR1aR1a, —
C(NH)NR1aR1a, —
NR1aC(O)R1a, —
NR1aC(S)R1a, —
NR1aS(O)2R1a, —
NR1aC(O)NR1aR1a, —
NR1aC(S)NR1aR1a, —
NR1aS(O)2NR1aR1a, —
S(O)R1a, —
S(O)2R1a, —
R1b and lower alkyl, wherein lower alkyl is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of fluoro, —
OH, —
NH2, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and —
R1b;R1a is selected from the group consisting of hydrogen, —
R1b, and lower alkyl, provided, however, that hydrogen is not bound to any of C(S), C(O), S(O), or S(O)2 of —
OC(O)R1a, —
OC(S)R1a, —
C(O)R1a, —
C(S)R1a, —
NR1aC(O)R1a, —
NR1aC(S)R1a, —
NR1aS(O)2R1a, —
S(O)R1a, or —
S(O)2R1a, wherein lower alkyl is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of fluoro, —
OH, —
NH2, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and —
R1b, provided, however, that any substitution of the alkyl carbon bound to O, S, or N of —
OR1a, —
SR1a, —
NR1aR1a, —
C(O)OR1a, —
C(S)OR1a, —
C(O)NR1aR1a, —
C(S)NR1aR1a, —
S(O)2NR1aR1a, —
C(NH)NR1aR1a, —
NR1aC(O)R1a, —
NR1aC(S)R1a, —
NR1aS(O)2R1a, —
NR1aC(O)NR1aR1a, —
NR1aC(S)NR1aR1a, or —
NR1aS(O)2NR1aR1a, is fluoro or —
R1b; andR1b is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halogen, —
CN, —
OH, —
NH2, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino.
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50. The compound of claim 16,
wherein: -
R81 is selected from the group consisting of hydrogen;
halogen;
C1-6 alkyl optionally substituted with carboxylic acid;
C2-6 alkenyl optionally substituted with carboxylic acid;
C1-6 alkoxy optionally substituted with methoxy or diethylamine;
carboxylic acid;
carboxylic acid methyl ester;
carboxylic acid ethylamide;
4-methyl-piperidin-1-yl;
4-methyl-piperazin-1-yl;
morpholin-4-yl;
phenyl-amino;
phenyl optionally substituted with halogen, —
CN, optionally fluoro substituted C1-6 alkyl, dimethylamine, methoxy, carboxylic acid, carboxylic acid amide, carboxylic acid-dimethyl amide, morpholine-4-carbonyl, morpholine, morpholine-4-methyl, or 2-methoxy-ethoxy;
midinyl optionally substituted with methoxy, morpholine, or 4-methyl-piperazin-1-yl;
4-meth 1-1H-imidazol-2-yl; and
N-methyl-pyrazolyl;R83 is selected from the group consisting of hydrogen, fluoro and chloro; R112 is selected from the group consisting of C2-6 alkyl;
phenyl optionally substituted with —
CN, —
NO2, acetamide, halogen, optionally fluoro substituted C1-6alkyl, optionally fluoro substituted C1-6 alkoxy, or oxazolyl;
2,3-dihydro-benzo[1,4]dioxin-6-yl;
methyl substituted thiazole, methyl substituted imidazole, thiophene optionally substituted with methyl, oxazole, isoxazole, or pyridine;
furan substituted with methyl or carboxylic acid methyl ester;
benzothiazol-6-yl;
benzo[b]thiophen-2-yl;
piperidin-1-yl; and
dimethylamine.
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51. The compound of claim 50, wherein R112 is C2-6 alkyl.
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52. The compound of claim 50, wherein R112 is piperidin-1-yl or dimethylamine.
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53. The compound of claim 50, wherein R112 is selected from the group consisting of 2,3-dihydro-benzo[1,4]dioxin-6-yl;
- and phenyl optionally substituted with —
CN, acetamide, halogen, optionally fluoro substituted C1-6 alkyl, optionally fluoro substituted C1-6 alkoxy, or oxazolyl.
- and phenyl optionally substituted with —
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54. The compound of claim 50, wherein R112 is selected from the group consisting of methyl substituted thiazole;
- methyl substituted imidazole;
thiophene optionally substituted with methyl, oxazole, isoxazole, or pyridine;
furan substituted with methyl or carboxylic acid methyl ester;
benzothiazol-6-yl; and
benzo[b]thiophen-2-yl.
- methyl substituted imidazole;
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55. The compound of claim 16, wherein the compound is selected from the group consisting of:
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Propane-1-sulfonic acid [2,4-difluoro-3-(5-ethoxy-1H-pyrrolo[1,3-b]pyridine-3-carbonyl)-phenyl]-amide, Propane-1-sulfonic acid [3-(5-ethoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide, Propane-1-sulfonic acid [2-fluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide, Propane-1-sulfonic acid {3-[5-(2-diethylamino-ethoxy)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide, Butane-1-sulfonic acid [2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide, and pharmaceutically acceptable salts thereof.
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56. The compound of claim 16, wherein the compound is selected from the group consisting of:
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Propane-1-sulfonic acid [2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide, Propane-1-sulfonic acid [2,4-difluoro-3-(5-isopropenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide, Propane-1-sulfonic acid [2,4-difluoro-3-(5-isopropyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide, Propane-1-sulfonic acid [2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide, Propane-1-sulfonic acid [4-chloro-2-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide, Propane-1-sulfonic acid [2-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide, 3-3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl-acrylic acid, 3-3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl-propionic acid, Butane-1-sulfonic acid [3-(chloro-1H-pyrrolo[2 b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide, Propane-1-sulfonic acid [2,4-difluoro-3-(5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide, Propane-1-sulfonic acid [4-chloro-3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide, and pharmaceutically acceptable salts thereof.
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57. The compound of claim 16, wherein the compound is selected from the group consisting of:
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3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid methyl ester, 3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid, 3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethylamide, and pharmaceutically acceptable salts thereof.
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58. The compound of claim 16, wherein the compound is selected from the group consisting of:
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Propane-1-sulfonic acid [4-chloro-2-fluoro-3-(5-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide, Propane-1-sulfonic acid [2,4-difluoro-3-(5-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide, Propane-1-sulfonic acid {3-[5-(4-dimethylamino-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide, Propane-1-sulfonic acid {2,4-difluoro-3-[5-(4-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide, Propane-1-sulfonic acid {2,4-difluoro-3-[5-(3-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide, Propane-1-sulfonic acid {3-[5-(3-dimethylamino-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide, Propane-1-sulfonic acid [2-fluoro-3-(5-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide, Propane-1-sulfonic acid {2,4-difluoro-3-[5-(3-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide, Propane-1-sulfonic acid {2,4-difluoro-3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide, Propane-1-sulfonic acid {3-[5-(3-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide, 3-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-benzoic acid, 4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-benzamide, 4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N,N-dimethyl-benzamide, Propane-1-sulfonic acid (2,4-difluoro-3-{5-[4-(morpholine-4-carbonyl)-phenyl]-1H-pyrrolo[2,3-b]pyri dine-3-carbonyl}-phenyl)-amide, Propane-1-sulfonic acid {2,4-difluoro-3-[5-(3-morpholin-4-yl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide, Propane-1-sulfonic acid {2,4-difluoro-3-[5-(3-morpholin-4-ylmethyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide, Propane-1-sulfonic acid {3-[5-(4-cyano-3,5-dimethyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide, 3-{3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-benzamide, Propane-1-sulfonic acid (2,4-difluoro-3-{5-[4-(2-methoxy-ethoxy)-phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-phenyl)-amide, 4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}2,N,N-trimethyl-benzamide, and pharmaceutically acceptable salts thereof.
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59. The compound of claim 16, wherein the compound is selected from the group consisting of:
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Propane-2-sulfonic acid [2,4-difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide, Propane-1-sulfonic acid [2-fluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide, Propane-1-sulfonic acid [2,4-difluoro-3-(5-pyridin-4-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide, Propane-1-sulfonic acid {2,4-difluoro-3-[5-(6-methoxy-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide, Propane-1-sulfonic acid {2,4-difluoro-3-[5-(6-morpholin-4-yl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide, Propane-1-sulfonic acid (2,4-difluoro-3-{5-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-phenyl)-amide, Propane-1-sulfonic acid {2,4-difluoro-3-[5-(4-methyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide, Propane-1-sulfonic acid {2,4-difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide, and pharmaceutically acceptable salts thereof.
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60. The compound of claim 16, wherein the compound is selected from the group consisting of:
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Propane-1-sulfonic acid [2,4-difluoro-3-(5-phenylamino-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide, Propane-1-sulfonic acid {2,4-difluoro-3-[5-(4-methyl-piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide, Propane-1-sulfonic acid {2,4-difluoro-3-[5-(4-methyl-piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide, and pharmaceutically acceptable salts thereof.
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61. The compound of claim 16, wherein the compound is selected from the group consisting of:
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Dimethylamine-1-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide, Dimethylamine-1-sulfonic acid [3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide, Dimethylamine-1-sulfonic acid [3-(5-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide, Piperidine-1-sulfonic acid [2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide, Piperidine-1-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide, Dimethylamine-1-sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide, and pharmaceutically acceptable salts thereof.
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62. The compound of claim 16, wherein the compound is selected from the group consisting of:
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N-{3-[5-(4-Chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-4-trifluoromethyl-benzenesulfonamide, N-[3-(5-Ethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide, N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3-fluoro-4-methyl-benzenesulfonamide, N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-methyl-benzenesulfonamide, N-(2,4-Difluoro-3-{5-[4-(2-methoxy-ethoxy)-phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-phenyl)-4-trifluoromethyl-benzenesulfonamide, N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]benzenesulfonamide, N-[2,4-Difluoro-3-(5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-benzenesulfonamide, N-{2,4-difluoro-3-[5-(2-methoxy-ethoxy)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-trifluoromethyl-benzenesulfonamide, N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2-methyl-benzenesulfonamide, N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-5-fluoro-2-methyl-benzenesulfonamide, N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3-methyl-benzenesulfonamide, N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2-methyl-benzenesulfonamide, N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-methyl-benzenesulfonamide, N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-isopropyl-benzenesulfonamide, N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-benzenesulfonamide, N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-5-fluoro-2-methyl-benzenesulfonamide, N-[2,4-Difluoro-3-(5-pyridin-3-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-trifluoromethyl-benzenesulfonamide, N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]benzenesulfonamide, N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide, and pharmaceutically acceptable salts thereof.
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63. The compound of claim 16, wherein the compound is selected from the group consisting of:
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N-[2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl]-3-methoxy-benzenesulfonamide, N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-methoxy-benzenesulfonamide, 4-Butoxy-N-[2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-benzenesulfonamide, N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3,4-dimethoxy-benzenesulfonamide, N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-methoxy-benzenesulfonamide, N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3-methoxy-benzenesulfonamide, N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,4-dimethoxy-benzenesulfonamide, 2,3-Dihydro-benzo[1,4]dioxine-6-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide, N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,5-dimethoxy-benzenesulfonamide, N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2,4-dimethoxy-benzenesulfonamide, 2,3-Dihydro-benzo[1,4]dioxine-6-sulfonic acid [2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide, N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-difluoromethoxy-benzenesulfonamide, and pharmaceutically acceptable salts thereof.
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64. The compound of claim 16, wherein the compound is selected from the group consisting of:
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4-Chloro-N-[2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-benzenesulfonamide, 3,4-Dichloro-N-[2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-benzenesulfonamide, N-[2,4-Difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-fluoro-benzenesulfonamide, N-[2,4-Difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-fluoro-benzenesulfonamide, N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3-fluoro-benzenesulfonamide, N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-fluoro-benzenesulfonamide, N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3,5-difluoro-benzenesulfonamide, N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-fluoro-benzenesulfonamide, N-{2,4-Difluoro-3-[5-(2-methoxy-ethoxy)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-fluoro-benzenesulfonamide, N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2-fluoro-benzenesulfonamide, and pharmaceutically acceptable salts thereof.
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65. The compound of claim 16, wherein the compound is selected from the group consisting of:
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N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-cyano-benzenesulfonamide, N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-oxazol-5-yl-benzenesulfonamide, N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-oxazol-5-yl-benzenesulfonamide, N-{4-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenylsulfamoyl]-phenyl}-acetamide, N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-nitro-benzenesulfonamide, N-{4-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenylsulfamoyl]-phenyl}-acetamide, 2-Cyano-N-[2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-benzenesulfonamide, 3-Cyano-N-[2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-benzenesulfonamide, and pharmaceutically acceptable salts thereof.
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66. The compound of claim 16, wherein the compound is selected from the group consisting of:
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Thiophene-3-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide, Benzo[b]thiophene-2-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide, 5-Pyridin-2-yl-thiophene-2-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide, Thiophene-2-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide, 2,5-Dimethyl-thiophene-3-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 [2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide, 2,5-Dimethyl-thiophene-3-sulfonic acid [2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide, 2,4-Dimethyl-thiazole-5-sulfonic acid [2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide, Benzothiazole-6-sulfonic acid [2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide, 2,4-Dimethyl-thiazole-5-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 [2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide, 1,2-Dimethyl-1H-imidazole-4-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide, 5-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenylsulfamoyl]-furan-2-carboxylic acid methyl ester, 5-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenylsulfamoyl]-2-methyl-furan-3-carboxylic acid methyl ester, 2,5-Dimethyl-furan-3-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide, 5-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenylsulfamoyl]-furan-2-carboxylic acid methyl ester, 5-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenylsulfamoyl]-2-methyl-furan-3-carboxylic acid methyl ester, 2,5-Dimethyl-furan-3-sulfonic acid [2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide, and pharmaceutically acceptable salts thereof.
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67. The compound of claim 16 that is N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,4-difluoro-benzenesulfonamide and any pharmaceutically acceptable salts thereof.
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68. The compound of claim 16 that is N-[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-trifluoromethyl-benzenesulfonamide and any pharmaceutically acceptable salts thereof.
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69. The compound of claim 16 that is N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3-trifluoromethyl-benzenesulfonamide and any pharmaceutically acceptable salts thereof.
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70. The compound of claim 16 that is N-[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide and any pharmaceutically acceptable salts thereof.
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71. The compound of claim 16 that is N-{2,4-difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-3-fluoro-benzenesulfonamide and any pharmaceutically acceptable salts thereof.
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72. The compound of claim 16 that is N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2-cyano-benzenesulfonamide and any pharmaceutically acceptable salts thereof.
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73. The compound of claim 16 that is N-{2,4-difluoro-3-[5-(6-methoxy-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-3-fluoro-benzenesulfonamide and any pharmaceutically acceptable salts thereof.
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74. The compound of claim 16 that is N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide and any pharmaceutically acceptable salts thereof.
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75. The compound of claim 16 that is N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3-cyano-benzenesulfonamide and any pharmaceutically acceptable salts thereof.
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76. The compound of claim 16 that is N-{2,4-difluoro-3-[5-(2-methoxy-ethoxy)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-3-fluoro-benzenesulfonamide and any pharmaceutically acceptable salts thereof.
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77. The compound of claim 16 that is N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-isopropyl-benzenesulfonamide and any pharmaceutically acceptable salts thereof.
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78. The compound of claim 16 that is N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-ethyl-benzenesulfonamide and any pharmaceutically acceptable salts thereof.
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79. The compound of claim 16 that is N-[2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2,5-dimethoxy-benzenesulfonamide and any pharmaceutically acceptable salts thereof.
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80. The compound of claim 16 that is dimethylamine-1-sulfonic acid [3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide and any pharmaceutically acceptable salts thereof.
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81. The compound of claim 16 that is butane-1-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide and any pharmaceutically acceptable salts thereof.
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82. The compound of claim 16 that is N-[2,4-difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-ethanesulfonamide and any pharmaceutically acceptable salts thereof.
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83. The compound of claim 16 that is propane-1-sulfonic acid [2,4-difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide and any pharmaceutically acceptable salts thereof.
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84. The compound of claim 16 that is propane-1-sulfonic acid [2,4-difluoro-3-(5-morpholin-4-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide and any pharmaceutically acceptable salts thereof.
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85. The compound of claim 16 that is propane-1-sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide and any pharmaceutically acceptable salts thereof.
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86. The compound of claim 16 that is propane-1-sulfonic acid {2,4-difluoro-3-[5-(4-trifluoromethyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide and any pharmaceutically acceptable salts thereof.
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87. The compound of claim 16 that is propane-1-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide and any pharmaceutically acceptable salts thereof.
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88. The compound of claim 16 that is propane-1-sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl}-amide and any pharmaceutically acceptable salts thereof.
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89. The compound of claim 16 that is propane-1-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide and any pharmaceutically acceptable salts thereof.
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90. The compound of claim 16 that is propane-1-sulfonic acid [4-chloro-2-fluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide and any pharmaceutically acceptable salts thereof.
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91. The compound of claim 16 that is propane-1-sulfonic acid [2-fluoro-3-(5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide and any pharmaceutically acceptable salts thereof.
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92. The compound of claim 16 that is propane-1-sulfonic acid {2,4-difluoro-3-[5-(2-methoxy-ethoxy)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide and any pharmaceutically acceptable salts thereof.
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25. A composition comprising:
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17-24. -24. (canceled)
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27-30. -30. (canceled)
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32-34. -34. (canceled)
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36-37. -37. (canceled)
Specification
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Current AssigneePlexxikon Inc (Daiichi Sankyo Company Limited)
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Original AssigneePlexxikon Inc (Daiichi Sankyo Company Limited)
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InventorsBollag, Gideon, Tsai, James, Artis, Dean R., Spevak, Wayne, Zhang, Jiazhong, Hirth, Klaus-Peter, Shi, Shenghua, Zhang, Chao, Mamo, Shumeye, Ibrahim, Prabha N., Bremer, Ryan, Gillette, Samuel J., Cho, Hanna
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Granted Patent
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Time in Patent OfficeDays
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Field of Search
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US Class Current514/228.200
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CPC Class CodesA61K 31/437 the heterocyclic ring syste...A61K 31/496 Non-condensed piperazines c...A61K 31/5377 not condensed and containin...A61P 1/00 Drugs for disorders of the ...A61P 1/04 for ulcers, gastritis or re...A61P 1/16 for liver or gallbladder di...A61P 1/18 for pancreatic disorders, e...A61P 11/00 Drugs for disorders of the ...A61P 11/06 AntiasthmaticsA61P 13/08 of the prostateA61P 13/12 of the kidneysA61P 15/08 for gonadal disorders or fo...A61P 17/00 Drugs for dermatological di...A61P 17/02 for treating wounds, ulcers...A61P 17/06 AntipsoriaticsA61P 19/02 for joint disorders, e.g. a...A61P 19/10 for osteoporosisA61P 21/04 for myasthenia gravisA61P 25/00 Drugs for disorders of the ...A61P 25/06 Antimigraine agentsA61P 25/14 : for treating abnormal movem...A61P 25/16 : Anti-Parkinson drugsA61P 25/28 : for treating neurodegenerat...A61P 27/02 : Ophthalmic agentsA61P 27/16 : OtologicalsA61P 29/00 : Non-central analgesic, anti...A61P 3/04 : Anorexiants; Antiobesity ag...A61P 3/06 : AntihyperlipidemicsA61P 3/10 : for hyperglycaemia, e.g. an...A61P 3/14 : for calcium homeostasis vit...A61P 31/04 : Antibacterial agentsA61P 31/16 : for influenza or rhinovirusesA61P 35/00 : Antineoplastic agentsA61P 35/02 : specific for leukemiaA61P 37/00 : Drugs for immunological or ...A61P 37/02 : ImmunomodulatorsA61P 37/06 : Immunosuppressants, e.g. dr...A61P 37/08 : Antiallergic agents antiast...A61P 43/00 : Drugs for specific purposes...A61P 7/00 : Drugs for disorders of the ...A61P 7/02 : Antithrombotic agents; Anti...A61P 9/00 : Drugs for disorders of the ...A61P 9/04 : Inotropic agents, i.e. stim...A61P 9/10 : for treating ischaemic or a...C07C 37/62 : by introduction of halogen;...C07C 39/27 : all halogen atoms being bou...C07C 45/00 : Preparation of compounds ha...C07C 45/673 : by change of size of the ca...C07C 45/71 : being hydroxy groupsC07C 47/565 : all hydroxy groups bound to...C07C 47/575 : containing ether groups, g...C07D 209/08 : with only hydrogen atoms or...C07D 471/04 : Ortho-condensed systems