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US 8,710,038 B2Granted
Pyrazole kinase modulators and methods of use
AssigneeExelixis, Inc.
InventorsTae-Gon Baik, Chris A. Buhr, Sunghoon Ma, John M. Nuss, Zerom Tesfai, Longcheng Wang, Bryan K. S. Yeung
Life of this patent
Estimating the term…
Abstract
The present invention provides compounds for modulating protein kinase enzymatic activity for modulating cellular activities such as proliferation, differentiation, programmed cell death, migration and chemoinvasion. Compounds of the invention inhibit, regulate and/or modulate kinases. Methods of using the compounds and pharmaceutical compositions thereof to treat kinase-dependent diseases and conditions are also an aspect of the invention.
Claims8
A compound or pharmaceutically acceptable salt thereof of either formula VIIc or VIId,
- R3a and R3b, together with the nitrogen to which they are attached, combine to form an optionally substituted piperazinyl;
- R6 is —H, halogen, haloalkyl, —CN, —NO2, —OR3, —N(R3)R3, —S(O)0-2R3, —N(R3)C(═O)C(═O)N(R3)R3, —CO2R3, —C(═O)N(R3)R3, —N(R3)SO2R3, —N(R3)C(O)R3, —NCO2R3, —C(═O)R3, optionally substituted alkoxy, optionally substituted heterocyclyl, or optionally substituted lower alkyl;
- and
- R3 is —H, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted lower arylalkyl;
- p is one to five;
- wherein when any of said “alkyl, aryl, or heterocyclyl” are substituted, one or more hydrogen atoms of said alkyl, aryl, and heterocyclyl are replaced by alkyl, trifluoromethyl, hydroxypropyl, nitromethyl, aminoethyl, aryl, 4-hydroxyphenyl, 2,3-difluorophenyl, arylalkyl, 1-phenyl-ethyl, para-methoxyphenylethyl, heterocyclylalkyl, 1-pyridin-3-yl-ethyl, N-ethylmorphonlino, heterocyclyl, 5-chloro-pyridin-3-yl, 1-methyl-piperidin-4-yl, alkoxy, methoxyethoxy, hydroxypropyloxy, methylenedioxy, amino, methylamino, diethylamino, trifluoroacetylamino, amidino, aryloxy, para-chlorophenoxy, meta-aminophenoxy, para-phenoxyphenoxy, arylalkyloxy, 3-chlorobenzyloxy, meta-phenoxybenzyloxy, carboxy, carboalkoxy, carboxamido, benzyloxycarbonylamino, cyano, acyl, halogen, hydroxy, nitro, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, thiol, oxo, carbamyl, acylamino, hydrazino, hydroxylamino, or sulfonamide.
3 more elements
A compound selected from Table 3 or pharmaceutically acceptable salt thereof,
- TABLE 3
- Entry
- Name
- Structure
- 2
- N-[4-chloro-3- (trifluoromethyl)phenyl]-N′-(4- {3-[5-(4-ethylpiperazin-1-yl)- 1H-benzimidazol-2-yl]-1H- pyrazol-5-yl}phenyl)urea
- 3
- N-(3-ethylphenyl)-N′-(4-{3-[5- (4-ethylpiperazin-1-yl)-1H- benzimidazol-2-yl]-1H-pyrazol- 5-yl}phenyl)urea
- 4
- N-(4-{3-[5-(4-ethylpiperazin-1- yl)-1H-benzimidazol-2-yl]-1H- pyrazol-5-yl}phenyl)-N′-[3- (trifluoromethyl)phenyl]urea
- 5
- N-(3-acetylphenyl)-N′-(4-{3-[5- (4-methylpiperazin-1-yl)-1H- benzimidazol-2-yl]-1H-pyrazol- 5-yl}phenyl)urea
- 6
- N-(3,4-dichlorophenyl)-N′-(4- {3-[5-(4-methylpiperazin-1-yl)- 1H-benzimidazol-2-yl]- 1H-pyrazol-5-yl}phenyl)urea
- 7
- N-(3-bromophenyl)-N′-(4-{3-[6- (4-methylpiperazin-1-yl)-1H- benzimidazol-2-yl]-1H-pyrazol- 5-yl}phenyl)urea
- 8
- N-[4-fluoro-3- (trifluoromethyl)phenyl]-N′-(4- {3-[5-(4-methylpiperazin-1-yl)- 1H-benzimidazol-2-yl]-1H- pyrazol-5-yl}phenyl)urea
- 9
- N-(4-{3-[5-(4-methylpiperazin- 1-yl)-1H-benzimidazol-2-yl]-1H- pyrazol-5-yl}phenyl)-N′-[4- (phenyloxy)phenyl]urea
- 10
- N-(3-chlorophenyl)-N′-(4-{3-[5- (4-methylpiperazin-1-yl)-1H- benzimidazol-2-yl]-1H-pyrazol- yl}phenyl)urea
- 11
- N-[3,5-bis(methyloxy)phenyl]- N′-(4-{3-[6-(4-methylpiperazin- 1-yl)-1H-benzimidazol-2-yl]-1H- pyrazol-5-yl}phenyl)urea
- 12
- N-(4-{3-[5-(4-methylpiperazin- 1-yl)-1H-benzimidazol-2-yl]-1H- pyrazol-5-yl}phenyl)-N′-{4- [(trifluoromethyl)oxy]phenyl} urea
- 13
- N-(4-{3-[6-(4-methylpiperazin- 1-yl)-1H-benzimidazol-2-yl]-1H- pyrazol-5-yl}phenyl)-N′-[4- (trifluoromethyl)phenyl]urea
- 14
- N-[4-chloro-3- (trifluoromethyl)phenyl]-N′-(4- {3-[5-(4-methylpiperazin-1- yl)-1H-benzimidazol-2-yl]-1H- pyrazol-5-yl}phenyl)urea
- 15
- N-(4-{3-[5-(4-methylpiperazin- 1-yl)-1H-benzimidazol-2-yl]-1H- pyrazol-5-yl}phenyl)-N′-[3- (trifluoromethyl)phenyl]urea
- 16
- N-[4-chloro-3- (trifluoromethyl)phenyl]-N′-(4- {3-[4-(4-methylpiperazin-1- yl)phenyl]-1H-pyrazol-5- yl}phenyl)urea
- 17
- N-(3,4-dimethylphenyl)-N′-(4- {5-[4-(4-methylpiperazin-1- yl)phenyl]-1H-pyrazol-3- yl}phenyl)urea
- 18
- N-(4-chlorophenyl)-N′-(4-{3- [5-(4-methylpiperazin-1-yl)-1H- benzimidazol-2-yl]-1H-pyrazol- 5-yl}phenyl)urea
- 19
- N-(3,5-difluorophenyl)-N′-(4- {3-[5-(4-methylpiperazin-1-yl)- 1H-benzimidazol-2-yl]-1H- pyrazol-5-yl}phenyl)urea
- 20
- N-[3-(methyloxy)phenyl]-N′-(4- {3-[5-(4-methylpiperazin-1-yl)- 1H-benzimidazol-2-yl]-1H- pyrazol-5-yl}phenyl)urea
- 21
- N-[4-chloro-3- (trifluoromethyl)phenyl]-N′-(4- {3-[4-(4-ethylpiperazin-1- yl)phenyl]-1H-pyrazol-5- yl}phenyl)urea
- 22
- N-(3-fluorophenyl)-N′-(4-{3-[5- (4-methylpiperazin-1-yl)-1H- benzimidazol-2-yl]-1H-pyrazol- 5-yl}phenyl)urea
- 23
- N-(4-fluorophenyl)-N′-(4-{3-[5- (4-methylpiperazin-1-yl)-1H- benzimidazol-2-yl]-1H-pyrazol- 5-yl}phenyl)urea
- 24
- N-(3-cyanophenyl)-N′-(4-{3-[6- (4-methylpiperazin-1-yl)-1H- benzimidazol-2-yl]-1H-pyrazol- 5-yl}phenyl)urea
- 25
- N-(3,4-difluorophenyl)-N′-(4-{3- [5-(4-methylpiperazin-1-yl)-1H- benzimidazol-2-yl]-1H-pyrazol- 5-yl}phenyl)urea
- 26
- N-[3,4-bis(methyloxy)phenyl]- N′-(4-{3-[5-(4-methylpiperazin- 1-yl)-1H-benzimidazol-2-yl]-1H- pyrazol-5-yl}phenyl)urea
- 27
- N-[5-chloro-2- (methyloxy)phenyl]-N′-(4-{5-[4- (4-methylpiperazin-1-yl)phenyl]- 1H-pyrazol-3-yl}phenyl)urea
- 28
- N-(4-{5-[4-(4-methylpiperazin- 1-yl)phenyl]-1H-pyrazol-3- yl}phenyl)-N′-[4- (phenyloxy)phenyl]urea
- 29
- N-(2,4-difluorophenyl)-N′-(4-{3- [6-(4-ethylpiperazin-1-yl)-1H- benzimidazol-2-yl]-1H-pyrazol- 5-yl}phenyl)urea
- 30
- N-{4-[3-(1H-benzimidazol-2- yl)-1H-pyrazol-5-yl]phenyl}-N′- [4-chloro-3- (trifluoromethyl)phenyl]urea
- 31
- N-{4-[3-(1H-benzimidazol-2- yl)-1H-pyrazol-5-yl]phenyl}-N′- [2-fluoro-5- (trifluoromethyl)phenyl]urea
- 32
- N-(2,4-difluorophenyl)-N′-(4-{3- [5-(4-methylpiperazin-1-yl)-1H- benzimidazol-2-yl]-1H-pyrazol- 5-yl}phenyl)urea
- 34
- N-[3,5- bis(trifluoromethyl)phenyl]-N′- (4-{3-[5-(4-methylpiperazin-1- yl)-1H-benzimidazol-2-yl]-1H- pyrazol-5-yl}phenyl)urea
- 35
- N-(2-fluorophenyl)-N′-(4-{3-[5- (4-methylpiperazin-1-yl)-1H- benzimidazol-2-yl]-1H-pyrazol- 5-yl}phenyl)urea
- 38
- N-(5-fluoro-2-methylphenyl)-N′- (4-{3-[6-(4-methylpiperazin-1- yl)-1H-benzimidazol-2-yl]-1H- pyrazol-5-yl}phenyl)urea
- 39
- N-(4-{3-[5-(4-methylpiperazin- 1-yl)-1H-benzimidazol-2-yl]-1H- pyrazol-5-yl}phenyl)-N′- phenylurea
- 40
- N-[4-chloro-3- (trifluoromethyl)phenyl]-N′-(4- {3-[3-(4-methylpiperazin-1- yl)phenyl]-1H-pyrazol-5- yl}phenyl)urea
- 41
- N-(2,4-difluorophenyl)-N′-(4-{3- [4-(4-methylpiperazin-1- yl)phenyl]-1H-pyrazol-5- yl}phenyl)urea
- 42
- N-(2,3-dihydro-1,4-benzodioxin- 6-yl)-N′-(4-{5-[4-(4- methylpiperazin-1-yl)phenyl]- 1H-pyrazol-3-yl}phenyl)urea
- 43
- N-[2,4-bis(methyloxy)phenyl]- N′-(4-{5-[4-(4-methylpiperazin- 1-yl)phenyl]-1H-pyrazol-3- yl}phenyl)urea
- 46
- N-(4-{3-[4-(4-methylpiperazin- 1-yl)phenyl]-1H-pyrazol-5- yl}phenyl)-N′-(2- phenylethyl)ethanediamide
- 50
- N-[4-chloro-3- (trifluoromethyl)phenyl]-N′-[4- (3-phenyl-1H-pyrazol-5- yl)phenyl]urea
- 52
- 1,1-dimethylethyl{4-[3-(1H- benzimidazol-2-yl)-1H-pyrazol- 5-yl]phenyl}carbamate
- 53
- N-(5-fluoro-2-methylphenyl)-N′-(4-{5-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrazol-3-yl}phenyl)urea
- 64
- N-(1,1-dimethylethyl)-N′-(4-{3- [5-(4-ethylpiperazin-1-yl)-1H- benzimidazol-2-yl]-1H-pyrazol- 5-yl}phenyl)urea
- 76
- N-phenyl-N′-[4-(3-phenyl-1H- pyrazol-5-yl)phenyl]urea
- 77
- 4-[3-(1H-benzimidazol-2-yl)- 1H-pyrazol-5-yl]aniline
93 more elements
Dependencies are inferred from the claim text.