Quinoxalines as B Baf Inhhibitors
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Abstract
The invention relates to chemical compounds of the formula (I) or pharmaceutically acceptable salts thereof, which possess B Raf inhibitory activity and are accordingly useful for their anti cancer activity and thus in methods of treatment of the human or animal body. The invention also relates to processes for the manufacture of said chemical compounds, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments of use in the production of an anti-cancer effect in a warm blooded animal such as man.
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Citations
25 Claims
- 1. A compound of formula (I):
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12. A compound of formula (I) wherein:
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Ring A is phenyl, 1-methylpyrazol-3-yl, 1-methylpyrazol-5-yl, 1-t-butylpyrazol-5-yl, benzimidazol-2-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, thien-2-yl, thien-3-yl, fur-2-yl, 2,3-dihydro-1,4-benzodioxin-5-yl, 2,3-dihydro-1-benzofuran-7-yl, pyrimidin-4-yl, pyrimidin-5-yl, 1-methylimidazol-2-yl, indol-4-yl, indol-7-yl, 1-methylpyrrol-2-yl or pyrazin-2-yl; R1 is a substituent on carbon and is selected from fluoro, chloro, iodo, nitro, hydroxy, amino, sulphamoyl, methyl, trifluoromethyl, cyanomethyl, 3,5-dimethylpyrazol-1-ylmethyl, ethyl, 1-methyl-1-cyanoethyl, propyl, isopropyl, t-butyl, (1-hydroxycyclopentyl)ethynyl, cyclopropylethynyl, 3-hydroxyprop-1-yn-1-yl, 3-(1-methylpiperazin-4-yl)prop-1-yn-1-yl, 3-(cyclopentyl)prop-1-yn-1-yl, 3,3-dimethylprop-1-yn-1-yl, benzyloxy, 2-pyrrolidin-1-ylethoxy, propoxy, isopropoxy, butoxy, isobutoxy, methylthio, difluoromethylthio, mesyl, dimethylamino, N-methyl-N-(2-methoxyethyl)amino, acetyl, N,N-dimethylsulphamoyl, acetylamino, t-butoxycarbonylamino, 2,2-dimethylpropionylamino, mesylamino, cyclopropyl, 1-cyanocyclopropyl, 1-cyanocyclobutyl, 1-cyano-tetrahydro-2H-pyran-4-yl, thien-2-yl, pyrrol-1-yl, 2,5-dimethylpyrrol-1-yl, pyrid-3-yl, 2-methylthiazol-4-yl, morpholino and piperidin-1-yl; n is selected from 0-2;
wherein the values of R1 may be the same or different;Z is —
C(O)NH—
, —
NHC(O)—
or —
CH2NH—
;R1 is selected from hydrogen or bromo; R3 is selected from fluoro, chloro, bromo, methyl or methoxy; X is —
NHC(O)—
, —
NH—
or —
NHCH2—
;R4, R5, R6, R7 and R8 are independently selected from hydrogen, chloro, methyl, 3-(piperidin-1-yl)propylamino, 2-hydroxyethylamino, 2-(dimethylamino)ethylamino, 2-(morpholino)ethylamino, methylamino, N-methyl-N-ethylamino, N-methyl-N-(2-methylaminoethyl)amino, morpholino, 3-aminopropylamino or N-methyl-N-(3-direthylaminopropyl)amino; or a pharmaceutically acceptable salt thereof;
with the proviso that said compound is not N-(5-{[3-(dimethylamino)benzoyl]amino}-2-methylphenyl)quinoxaline-6-carboxamide.
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13. A compound of formula (I) selected from:
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N-(5-{[3-(1-cyano-1-methylethyl)-5-(3-hydroxyprop-1-yn-1-yl)benzoyl]amino}-2-methylphenyl)quinoxaline-6-carboxamide; N-(5-{[3-(1-cyano-1-methylethyl)benzoyl]amino}-2-methylphenyl)quinoxaline-6-carboxamide; N-[5-({3-(1-cyano-1-methylethyl)-5-[3-(4-methylpiperazin-1-yl)prop-1-yn-1-yl]benzoyl}amino)-2-methylphenyl]quinoxaline-6-carboxamide; N-(5-{[3-(benzyloxy)-5-(1-cyano-1-methylethyl)benzoyl]amino}-2-methylphenyl) quinoxaline-6-carboxamide; N-{5-[(3-tert-butylbenzoyl)amino]-2-methylphenyl}quinoxaline-6-carboxamide; N-(5-{[3-(1-cyano-1-methylethyl)-5-propylbenzoyl]amino}-2-methylphenyl)quinoxaline-6-carboxamide; N-(5-{[3-(1-cyano-1-methylethyl)-5-(2-pyrrolidin-1-ylethoxy)benzoyl]amino}-2-methylphenyl)quinoxaline-6-carboxamide; N-(5-{[3-(1-cyano-1-methylethyl)-5-methylbenzoyl]amino}-2-methylphenyl)quinoxaline-6-carboxamide; N-{5-[(3,5-di-tert-butylbenzoyl)amino]-2-methylphenyl}quinoxaline-6-carboxamide; and N-(5-{[3-(1-cyanocyclobutyl)benzoyl]amino}-2-methylphenyl)quinoxaline-6-carboxamide; or a pharmaceutically acceptable salt thereof.
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Specification