Pyridopyrimidinone inhibitors of kinases

Patent metadata

Field	Value
Publication number	US-9718821-B2
Application number	US-201313773906-A
Country	US
Kind code	B2
Filing date	Feb 22, 2013
Priority date	Feb 23, 2012
Publication date	Aug 1, 2017
Grant date	Aug 1, 2017

Abstract

The present invention relates to compounds of formula (I) or pharmaceutical acceptable salts,

wherein R 1 , R 2 , R 3 , R 4 , and B are defined in the description. The present invention relates also to compositions containing said compounds which are useful for inhibiting kinases such as wee-1 and methods of treating diseases such as cancer.

First claim

We claim:

1. The compound, or a pharmaceutically acceptable salt or solvate thereof, which is
ethyl 2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5-oxo-6-(prop-2-en-1-yl)-5,6-dihydropyrido[4,3-d]pyrimidine-8-carboxylate;
ethyl 2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5-oxo-6-phenyl-5,6-dihydropyrido[4,3-d]pyrimidine-8-carboxylate;
6-benzyl-N-methyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidine-8-carboxamide;
ethyl 6-benzyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidine-8-carboxylate;
ethyl 6-(2-chlorophenyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidine-8-carboxylate;
ethyl 2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidine-8-carboxylate;
6-benzyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}1-8-phenylpyrido[4,3-d]pyrimidin-5(6H)-one;
6-(2-methylbenzyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-8-phenylpyrido[4,3-d]pyrimidin-5(6H)-one;
8-bromo-6-(2,6-difluorobenzyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrido[4,3-d]pyrimidin-5(6H)-one;
6-(3-methylbenzyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-8-phenylpyrido[4,3-d]pyrimidin-5(6H)-one;
6-[2-fluoro-6-(trifluoromethyl)benzyl]-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-8-phenylpyrido[4,3-d]pyrimidin-5(6H)-one;
6-(2-fluorobenzyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-8-phenylpyrido[4,3-d]pyrimidin-5(6H)-one;
2-{[2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5-oxo-8-phenylpyrido[4,3-d]pyrimidin-6(5H)-yl]methyl}benzonitrile;
6-(2-chlorobenzyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-8-phenylpyrido[4,3-d]pyrimidin-5(6H)-one;
6-(2,6-dichlorobenzyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-8-phenylpyrido[4,3-d]pyrimidin-5(6H)-one;
6-(4-tert-butylbenzyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-8-phenylpyrido[4,3-d]pyrimidin-5(6H)-one;
6[2-fluoro-5-(trifluoromethyl)benzyl]-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-8-phenylpyrido[4,3-d]pyrimidin-5(6H)-one;
ethyl [2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5-oxo-8-phenylpyrido[4,3-d]pyrimidin-6(5H)-yl]acetate;
6-(2,6-dichlorophenyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-8-[(phenylamino)methyl]pyrido[4,3-d]pyrimidin-5(6H)-one;
6-(2,6-dichlorophenyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-8-{[(2,2,2-trifluoroethyl)amino]methyl}pyrido[4,3-d]pyrimidin-5(6H)-one;
8(1,3-benzothiazol-2-yl)-6-(2,6-dichlorophenyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrido[4,3-d]pyrimidin-5(6H)-one;
8-(1H-benzimidazol-2-yl)-6-(2,6-dichlorophenyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrido[4,3-d]pyrimidin-5(6H)-one;
6-(2,6-dichlorophenyl)-8-ethenyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrido[4,3-d]pyrimidin-5(6H)-one;
6-(2,6-dichlorophenyl)-8-ethyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrido[4,3-d]pyrimidin-5(6H)-one;
6-(2,6-dichlorophenyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidine-8-carbaldehyde;
6-(2,6-dichlorophenyl)-8-methyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrido[4,3-d]pyrimidin-5(6H)-one;
6-(2,6-dichlorophenyl)-8-methyl-2-[(2′-methyl-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-isoquinolin]-7′-yl)amino]pyrido[4,3-d]pyrimidin-5(6H)-one;
6-(2,6-dichlorophenyl)-2-(2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-isoquinolin]-7′-ylamino)-8-methylpyrido[4,3-d]pyrimidin-5(6H)-one;
6-(2,6-dichlorophenyl)-2-{[2-(dimethylamino)-2,3-dihydro-1H-inden-5-yl]amino}-8-methylpyrido[4,3-d]pyrimidin-5(6H)-one;
6-(2,6-dichlorophenyl)-8-ethenyl-2-[(2′-methyl-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-isoquinolin]-7′-yl)amino]pyrido[4,3-d]pyrimidin-5(6H)-one;
6,8-dimethyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrido[4,3-d]pyrimidin-5(6H)-one;
6-(2,6-dichlorophenyl)-8-(1H-imidazol-2-yl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrido[4,3-d]pyrimidin-5(6H)-one;
6-(2,6-dichlorophenyl)-2-({4-[4-(dimethylamino)piperidin-1-yl]phenyl}amino)-8-methylpyrido[4,3-d]pyrimidin-5(6H)-one;
6-(2,6-dichlorophenyl)-8-(difluoromethyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrido[4,3-d]pyrimidin-5(6H)-one;
6-(2,6-dichlorophenyl)-8-(fluoromethyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrido[4,3-d]pyrimidin-5(6H)-one;
6-(2,6-dichlorophenyl)-8-(hydroxymethyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrido[4,3-d]pyrimidin-5(6H)-one;
8-bromo-6-(cyclopropylmethyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrido[4,3-d]pyrimidin-5(6H)-one;
8-(cyclohex-1-en-1-yl)-6-(cyclopropylmethyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrido[4,3-d]pyrimidin-5(6H)-one;
8-(cyclopent-1-en-1-yl)-6-(cyclopropylmethyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrido[4,3-d]pyrimidin-5(6H)-one;
8-bromo-6-ethyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrido[4,3-d]pyrimidin-5(6H)-one;
8-(cyclohex-1-en-1-yl)-6-ethyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrido[4,3-d]pyrimidin-5(6H)-one;
6-(2,6-dichlorophenyl)-2-{[2-(dimethylamino)-2,3-dihydro-1H-inden-5-yl]amino}-8-ethenylpyrido[4,3-d]pyrimidin-5(6H)-one;
6-(2,6-dichlorophenyl)-2-({4-[4-(dimethylamino)piperidin-1-yl]phenyl}amino)-8-ethenylpyrido[4,3-d]pyrimidin-5(6H)-one;
6-(2,6-dichlorophenyl)-2-(2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-isoquinolin]-7′-ylamino)-8-ethenylpyrido[4,3-d]pyrimidin-5(6H)-one;
6-(2,6-dichlorophenyl)-8-ethenyl-2-{[4-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl]amino}pyrido[4,3-d]pyrimidin-5(6H)-one;
6-(2,6-dichlorophenyl)-8-(hydroxymethyl)-2-[(2′-methyl-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-isoquinolin]-7′-yl)amino]pyrido[4,3-d]pyrimidin-5(6H)-one;
6-(2,6-dichlorophenyl)-2-{[2-(dimethylamino)-2,3-dihydro-1H-inden-5-yl]amino}-8-(hydroxymethyl)pyrido[4,3-d]pyrimidin-5(6H)-one;
6-(2,6-dichlorophenyl)-2-({4-[4-(dimethylamino)piperidin-1-yl]phenyl}amino)-8-(hydroxymethyl)pyrido[4,3-d]pyrimidin-5(6H)-one;
6-(2,6-dichlorophenyl)-2-[(4,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino]-8-ethenylpyrido[4,3-d]pyrimidin-5(6H)-one;
6-(2,6-dichlorophenyl)-2-(2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-isoquinolin]-7′-ylamino)-8-(hydroxymethy)pyrido[4,3-d]pyrimidin-5(6H)-one;
6-(2,6-dichlorophenyl)-2-[(4,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino]-8-(hydroxymethyl)pyrido[4,3-d]pyrimidin-5(6H)-one;
6-(2,6-dichlorophenyl)-8-ethenyl-2-(1,2,3,4-tetrahydroisoquinolin-6-ylamino)pyrido[4,3-d]pyrimidin-5(6H)-one;
6-(2-chloro-6-fluorophenyl)-2-({4-[4-(dimethylamino)piperidin-1-yl]phenyl}amino)-8-ethenylpyrido[4,3-d]pyrimidin-5(6H)-one;
6-(2-chloro-6-fluorophenyl)-8-ethenyl-2-{[4-(4-methylpiperidin-4-yl)phenyl]amino}pyrido[4,3-d]pyrimidin-5(6H)-one;
6-(2-chloro-6-fluorophenyl)-8-ethenyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrido[4,3-d]pyrimidin-5(6H)-one;
6-(2-chloro-6-fluorophenyl)-8-ethenyl-2-[(2′-methyl-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-isoquinolin]-7′-yl)amino]pyrido[4,3-d]pyrimidin-5(6H)-one;
6-(2-chloro-6-fluorophenyl)-2-{[2-(dimethylamino)-2,3-dihydro-1H-inden-5-yl]amino}-8-ethenylpyrido[4,3-d]pyrimidin-5(6H)-one;
6-(2-chloro-6-fluorophenyl)-8-methyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrido[4,3-d]pyrimidin-5(6H)-one;
6-(2-chloro-6-fluorophenyl)-8-methyl-2-[(2′-methyl-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-isoquinolin]-7′-yl)amino]pyrido[4,3-d]pyrimidin-5(6H)-one;
6-(2-chloro-6-fluorophenyl)-2-{[2-(dimethylamino)-2,3-dihydro-1H-inden-5-yl]amino}-8-methylpyrido[4,3-d]pyrimidin-5(6H)-one;
6-(2-chloro-6-fluorophenyl)-2-({4-[4-(dimethylamino)piperidin-1-yl]phenyl}amino)-8-methylpyrido[4,3-d]pyrimidin-5(6H)-one;
6-(2-chloro-6-fluorophenyl)-8-methyl-2{-[4-(1-methylpiperidin-4-yl)phenyl]amino}pyrido[4,3-d]pyrimidin-5(6H)-one;
6-(2-chloro-6-fluorophenyl)-8-methyl-2-(1,2,3,4-tetrahydroisoquinolin-6-ylamino)pyrido[4,3-d]pyrimidin-5(6H)-one;
6-(2-chloro-6-fluorophenyl)-2-[(4,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino]-8-methylpyrido[4,3-d]pyrimidin-5(6H)-one;
6-(2-chloro-6-fluorophenyl)-2-(2′,3′-dihydro-1′H-spiro[cyclopropane

Assignees

• Abbvie Inc

Inventors

• Woods Keith W
• Mastracchio Anthony
• Lai Chunqiu
• Gandhi Viraj B
• Penning Thomas D

Classifications

• A61P35/02

  specific for leukemia · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• C07D471/14 Primary

  Ortho-condensed systems · CPC title