Back to results
US 8,470,818 B2Granted
Compounds and methods for kinase modulation, and indications therefor
AssigneePlexxikon Inc.
InventorsPrabha N. Ibrahim, Dean R. Artis, Ryan Bremer, Shumeye Mamo, Chao Zhang, Jiazhong Zhang, Jianming Tsai, Klaus-Peter Hirth, Gideon Bollag, Wayne Spevak, Hanna Cho, Samuel J. Gillette, Shenghua Shi
Life of this patent
Estimating the term…
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.
Claims56
A method for treating a subject suffering from a B-Raf or c-Raf-1 protein kinase mediated disease or condition, said method comprising administering to the subject a compound effective for the treatment of the B-Raf or c-Raf-1 protein kinase mediated disease or condition, said compound having the structure of Formula IIIm:
- or a pharmaceutically acceptable salt thereof,
- 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;
- pyridinyl optionally substituted with methoxy, morpholine, or 4-methyl-piperazin-1-yl;
- 4-methyl-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 C1-6 alkyl, 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
- wherein said disease or condition is selected from the group consisting of 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, lung cancer, polycystic kidney disease and cardio-faciocutaneous syndrome.
25 more elements
A method for inhibiting a B-Raf or c-Raf-1 protein kinase activity in a subject in need thereof, said method comprising:
- administering to the subject an effective amount of a compound of Formula IIIm:
- 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, —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, —OR68, —SR68, —NR69R68, —C(O)R68, —C(S)R68, —C(O)OR68, —C(O)NR69R68, —C(S)NR69R68, —S(O)2NR69R68, —NR69C(O)R68, —NR69C(S)R68, —NR69S(O)2R68, —NR69C(O)NH2, —NR69C(O)NR69R68, —NR69C(S)NH2, —NR69C(S)NR69R68, —NR69S(O)2NH2, —NR69S(O)2NR69R68, —S(O)R68, and —S(O)2R68;
- R83 is selected from the group consisting of hydrogen, fluoro and chloro;
- R112 is selected from the group consisting of optionally substituted C2-6 alkyl, optionally substituted aryl, optionally substituted heteroaryl, and —NR79R80;
- R68 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that when R68 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 —OR68, —SR68, —NR69R68, —C(O)R68, —C(S)R68, —C(O)OR68, —C(O)NR69R68, —C(S)NR69R68, —S(O)2NR69R68, —NR69C(O)R68, —NR69C(S)R68, —NR69S(O)2R68, —NR69C(O)NH2, —NR69C(O)NR69R68, —NR69C(S)NH2, —NR69C(S)NR69R68, —NR69S(O)2NH2, —NR69S(O)2NR69R68, —S(O)R68, or —S(O)2R68, optionally substituted lower alkynyl, provided, however, that when R68 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 −OR68, —SR68, —NR69R68, —C(O)R68, —C(S)R68, —C(O)OR68, —C(O)NR69R68, —C(S)NR69R68, —S(O)2NR69R68, —NR69C(O)R68, —NR69C(S)R68, —NR69S(O)2R68, —NR69C(O)NH2, —NR69C(O)NR69R68, —NR69C(S)NH2, —NR69C(S)NR69R68, —NR69S(O)2NH2, —NR69S(O)2NR69R68, —S(O)R68, or —S(O)2R68, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
- R69 is selected from the group consisting of hydrogen and optionally substituted lower alkyl;
- and
- R79 and R80 are independently hydrogen or optionally substituted lower alkyl, or R79 and R80 combine with the nitrogen to which they are attached to form optionally substituted 5-7 membered heterocycloalkyl or a pharmaceutically acceptable salt thereof.
6 more elements
Dependencies are inferred from the claim text.