US 6,602,863 B1Granted

Irreversible inhibitors of tyrosine kinases

AssigneeWarner-Lambert Company

InventorsAlexander James Bridges, William Alexander Denny, Ellen Myra Dobrusin, Annette Marian Doherty, David William Fry, Dennis Joseph McNamara, Howard Daniel Hollis Showalter, Jeffrey B. Smaill, Hairong Zhou

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Abstract

The present invention provides compounds that are irreversible inhibitors of tyrosine kinases. Also provided is a method of treating cancer, restenosis, atherosclerosis, endometriosis, and psoriasis and a pharmaceutical composition that comprises a compound that is an irreversible inhibitor of tyrosine kinases.

Claims23

Dependent claims

A compound having the Formula II

wherein Q is
X is —D—E—F and Y is —SR4, —OR4, —NHR3 or hydrogen, or X is —SR4, —OR4, —NHR3 or hydrogen, and Y is —D—E—F;
D is
or absent;
provided that when E is
D is not
R1 is hydrogen, halogen, or C1-C6 alkyl;
R2, R3, and R4 are independently hydrogen, C1-C6 alkyl, —(CH2)n—N-piperidinyl, —(CH2)n—N-piperazinyl, —(CH2)n—N1-piperazinyl[N4—(C1-C6)alkyl], —(CH2)n—N-pyrrolidyl, —(CH2)n-pyridinyl, —(CH2)n—N-imidazoyl, —(CH2)n-imidazoyl, —(CH2)n—N-morpholino, —(CH2)n—N-thiomorpholino, —(CH2)n—N-hexahydroazepine or substituted C1-C6 alkyl, wherein the substituents are selected from —OH, —NH2, or
A and B are independently hydrogen, C1-C6 alkyl, —(CH2)nOH, —(CH2)n—N-piperidinyl, —(CH2)n—N-piperazinyl, —(CH2)n—N1-piperazinyl[N4-(C1-C6)alkyl], —(CH2)n—N-pyrrolidyl, —(CH2)n—N-pyridyl, —(CH2)n-imidazoyl or —(CH2)n—N-imidazoyl;
E1, E2, and E3 are independently halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C3-C8 cycloalkoxy, nitro, C1-C6 perfluoroalkyl, hydroxy, C1-C6 acyloxy, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —NH(C3-C8 cycloalkyl), —N(C3-C8 cycloalkyl)2, hydroxymethyl, C1-C6 acyl, cyano, azido, C1-C6 thioalkyl, C1-C6 sulfinylalkyl, C1-C6 sulfonylalkyl, C3-C8 thiocycloalkyl, C3-C8 sulfinylcycloalkyl, C3-C8 sulfonylcycloalkyl, mercapto, C1-C6 alkoxycarbonyl, C3-C8 cycloalkoxycarbonyl, C2-C4 alkenyl, C4-C8 cycloalkenyl, or C2-C4 alkynyl;
and
R5 is hydrogen, halogen, C1-C6-perfluoroalkyl, 1,1-difluoro(C1-C6)alkyl, C1-C6 alkyl, —(CH2)n—N-piperidinyl, —(CH2)n-piperazinyl, —(CH2)n-piperazinyl[N4—(C1-C6)alkyl], —(CH2)n-N-pyrrolidyl, —(CH2)n-pyridinyl, —(CH2)n—N-imidazoyl, —(CH2)n—N-morpholino, —(CH2)n—N-thiomorpholino,
—CH═CH—(C1-C6)alkyl, —(CH2)n—N-hexahydroazepine, —(CH2)nNH2, —(CH2)nNH(C1-C6 alkyl), —(CH2)nN(C1-C6 alkyl)2, -1-oxo(C1-C6)alkyl, carboxy, (C1-C6)alkyloxycarbonyl, N—(C1-C6)alkylcarbamoyl, phenyl or substituted phenyl, wherein the substituted phenyl can have from one to three substituents independently selected from Z1, z2, Z3 or a monocyclic heteroaryl group, and each C1-C6 alkyl group can be substituted with —OH, —NH2 or —NAB, where A and B are as defined above, R6 is hydrogen or C1-C6 alkyl;
and
n is 1 to 4, p is 0 or 1, and the pharmaceutically acceptable salts, esters, and amides thereof.

12 more elements

The compounds:

N-[4-(3-Bromo-phenylamino)-pyrido[4,3-d]pyrimidin-7-yl]-acrylamide;
N-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-acrylamide;
N-[4-(3-Methyl-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-acrylamide;
N-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-N-methylacrylamide;
N-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-methacrylamide;
N-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-ethenylsulfonamide;
N-[4-(3-Bromo-phenylamino)-benzo[b]thieno[3,2-d]pyrimidin-8-yl]acrylamide;
N-[4-(3-Bromo-phenylamino)-benzo-[b]thieno[3,2-d]pyrimidin-6-yl]acrylamide;
N-[4-(3-Bromo-phenylamino)-benzo[b]thieno[3,2-d]pyrimidin-7-yl]acrylamide;
N-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]penta-2,4-dienamide;
N-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]E-but-2-enamide;
N-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]cinnamide;
N-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-E,3-chloroacrylamide;
N-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-propynamide;
4-[(3-Bromo-phenyl)amino]-6-(ethenesulfonyl)pyrido-[3,4-d]pyrimidine;
Methyl N-[4-[(3-bromophenyl)amino]-P-ethenyl-pyrido[3,4-d]pyrimidin-6-yl]phosphonamidate;
N-[1-(3-Bromo-phenylamino)-9H-2,4,9-triaza-fluoren-7-yl]-acrylamide;
N-[4-(3-Bromo-phenylamino)-9H-1,3,9-triaza-fluoren-6-yl]-acrylamide;
N-[4-(3-Chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-acrylamide;
N-[4-(3-Chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-N-methyl-acrylamide;
(3-Chloro-4-fluoro-phenyl)-(6-ethenesulfinyl-pyrido[3,4-d]pyrimidin-4-yl]-amine;
(3-Bromo-phenyl)-(6-ethenesulfinyl-pyrido[3,4-d]pyrimidin-4-yl)-amine;
N-[4-(3-Bromo-phenylamino)-pyrido[4,3-d]-pyrimidin-7-yl]-N-(3-morpholin-4-yl-propyl)-acrylamide;
N-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]-pyrimidin-6-yl]-N-(3-morpholin-4-yl-propyl)-acrylamide;
N-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-N-(2-(N,N-dimethylamino)ethyl)acrylamide;
N-[4-(3-Bromo-phenylamino)-7-(3-morpholin-4-yl-propoxy)-pyrido[3,2-d]pyrimidin-6-yl]-acryl amide;
But-2-enedioic acid[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide (3-dimethylamino-propyl)-amide;
But-2-enedioic acid[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide(3-imidazol-1-yl-propyl)-amide;
4,4-Difluoro-8-morpholin-4-yl-oct-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;
8-Dimethylamino-4,4-difluoro-oct-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;
7-Dimethylamino-4,4-difluoro-hept-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;
4,4-Difluoro-7-morpholin-4-yl-hept-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;
6-Dimethylamino-hex-2-ynoic acid[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;
6-Morpholin-4-yl-hex-2-ynoic acid[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;
7-Dimethylamino-hept-2-ynoic acid[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;
7-Morpholin-4-yl-hept-2-ynoic acid[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;
5-Dimethylamino-pent-2-ynoic acid[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;
5-Morpholin-4-yl-pent-2-ynoic acid[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;
5-Imidazol-1-yl-pent-2-ynoic acid[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;
5-(4-Methyl-piperazin-1-yl-pent-2-ynoic acid[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;
4-[4-(3-Chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-ylcarbamoyl]-but-3-enoic acid 2-(4-methyl-piperazin-1-yl)-ethyl ester;
4-[4-(3-Chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-ylcarbamoyl]-but-3-enoic acid 2-(imidazol-1-yl)-ethyl ester;
Pent-2-enedioic acid 1-{[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide} 5-[(3-morpholin-4-yl-propyl)-amide];
Pent-2-enedioic acid 1-{[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide} 5-[(3-diethylamino-propyl)-amide];
4-[4-(3-Chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-ylcarbamoyl]-but-3-enoic acid 2-morpholin-4-yl-ethyl ester;
Pent-2-enedioic acid 1-{[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide} 5-{[3-4-methyl-piperazin-1-yl)-propyl]-amide};
(3-Chloro-4-fluoro-phenyl)-{6-[2-(3-dimethylamino-propoxy)-ethenesulfonyl]-pyrido[3,4-d]pyrimidin-4-yl}amine;
(3-Chloro-4-fluoro-phenyl)-(6-{2-[4-(4-methyl-piperazin-1-yl)-butylamino]-ethenesulfonyl}-pyrido[3,4-d]pyrimidin-4-yl)-amine;
4,4-Difluoro-8-morpholin-4-yl-oct-2-enoic acid[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;
8-Dimethylamino-4,4-difluoro-oct-2-enoic acid[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;
7-Dimethylamino-4,4-difluoro-hept-2-enoic acid[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;
4,4-Difluoro-7-morpholin-4-yl-hept-2-enoic acid[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;
6-Dimethylamino-hex-2-ynoic acid[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;
6-Morpholin-4-yl-hex-2-ynoic acid[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;
7-Dimethylamino-hept-2-ynoic acid[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;
7-Morpholin-4-yl-hept-2-ynoic acid[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;
5-Dimethylamino-pent-2-ynoic acid[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;
5-Morpholin-4-yl-pent-2-ynoic acid[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;
5-Imidazol-1-yl-pent-2-ynoic acid[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;
5-(4-Methyl-piperazin-1-yl)-pent-2-ynoic acid[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;
4-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-ylcarbamoyl]-but-3-enoic acid 2-(4-methyl-piperazin-1-yl)-ethyl ester;
4-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-ylcarbamoyl]-but-3-enoic acid 2-imidazol-1-yl-ethyl ester;
Pent-2-enedioic acid 1-{[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide} 5-[(3-morpholin-4-yl-propyl)-amide];
Pent-2-enedioic acid 1-{[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide} 5-[(3-diethylamino-propyl)-amide];
4-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-ylcarbamoyl]-but-3-enoic acid 2-morpholin-4-yl-ethyl ester;
Pent-2-enedioic acid 1-{[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide} 5-{[3-(4-methyl-piperazin-1-yl)-propyl]-amide};
(3-Bromo-phenyl)-6-[2-(3-dimethylamino-propoxy)-ethenesulfonyl]-pyrido[3,4-d]pyrimidin-4-yl}-amine;
(3-Bromo-phenyl)-(6-{2-[4-(4-methyl-piperazin-1-yl)-butylamino]-ethenesulfonyl}-pyrido[3,4-d]pyrimidin-4-yl)-amine;
(3-Bromo-phenyl)-[6-(5-morpholin-4-yl-pent-1-ene-1-sulfonyl)-pyrido[3,4-d]pyrimidin-4-yl]-amine;
3-[4-(1-Phenyl-ethylamino)-pyrido[3,4-d]pyrimidin-6-ylcarbamoyl]-acrylic acid 2-morpholin-4-yl-ethyl ester;
But-2-enedioic acid(4-imidazol-1-yl-butyl)-amide[4-(1-phenyl-ethylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;
4-[4-(1-Phenyl-ethylamino)-pyrido[3,4-d]pyrimidin-6-ylcarbamoyl]-but-3-enoic acid 3-diethylamino-propyl ester;
Pent-2-enedioic acid 5-{[2-(4-methyl-piperazin-1-yl)-ethyl]-amide} 1-{[4-(1-phenyl-ethylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide};
4,4-Difluoro-7-morpholin-4-yl-hept-2-enoic acid[4-(1-phenyl-ethylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;
7-Dimethylamino-4,4-difluoro-hept-2-enoic acid[4-(1-phenyl-ethylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;
7-Imidazol-1-yl-hept-2-ynoic acid[4-(1-phenyl-ethylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;
(3-Chloro-4-fluoro-phenyl)-[6-(5-morpholin-4-yl-pent-1-ene-1-sulfonyl)-pyrido[3,4-d]pyrimidin-4-yl]-amine;
and
6-Dimethylamino-hex-2-ynoic acid[4-(1-phenyl-ethylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide.

76 more elements

Dependencies are inferred from the claim text.

Facts

Application: 09/671,559Filed 27 Sep 2000 · division
Priority: 12 Apr 1996
Granted: 5 Aug 2003
Term ends: Not estimatedThe source records don’t support an estimate.

Classification18 codes

C07D 231/12
Having two or three double bonds between ring members or between ring members and non-ring members: with only hydrogen atoms, hydrocarbon or…
A61P 9/10
Drugs for disorders of the cardiovascular system: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary…
A61P 15/00
Drugs for genital or sexual disorders
A61P 17/06
Drugs for dermatological disorders: antipsoriatics

Family

Application60/015,351Us provisional application · filed 12 Apr 1996
PCT/US97/05778Parent of this division · filed 8 Apr 1997
Application09/155,501Parent of this division
US 6,344,459 B1Related patent
US 6,602,863 B1This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound having the Formula II

wherein Q is
X is —D—E—F and Y is —SR4, —OR4, —NHR3 or hydrogen, or X is —SR4, —OR4, —NHR3 or hydrogen, and Y is —D—E—F;
D is
or absent;
provided that when E is
D is not
R1 is hydrogen, halogen, or C1-C6 alkyl;
R2, R3, and R4 are independently hydrogen, C1-C6 alkyl, —(CH2)n—N-piperidinyl, —(CH2)n—N-piperazinyl, —(CH2)n—N1-piperazinyl[N4—(C1-C6)alkyl], —(CH2)n—N-pyrrolidyl, —(CH2)n-pyridinyl, —(CH2)n—N-imidazoyl, —(CH2)n-imidazoyl, —(CH2)n—N-morpholino, —(CH2)n—N-thiomorpholino, —(CH2)n—N-hexahydroazepine or substituted C1-C6 alkyl, wherein the substituents are selected from —OH, —NH2, or
A and B are independently hydrogen, C1-C6 alkyl, —(CH2)nOH, —(CH2)n—N-piperidinyl, —(CH2)n—N-piperazinyl, —(CH2)n—N1-piperazinyl[N4-(C1-C6)alkyl], —(CH2)n—N-pyrrolidyl, —(CH2)n—N-pyridyl, —(CH2)n-imidazoyl or —(CH2)n—N-imidazoyl;
E1, E2, and E3 are independently halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C3-C8 cycloalkoxy, nitro, C1-C6 perfluoroalkyl, hydroxy, C1-C6 acyloxy, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —NH(C3-C8 cycloalkyl), —N(C3-C8 cycloalkyl)2, hydroxymethyl, C1-C6 acyl, cyano, azido, C1-C6 thioalkyl, C1-C6 sulfinylalkyl, C1-C6 sulfonylalkyl, C3-C8 thiocycloalkyl, C3-C8 sulfinylcycloalkyl, C3-C8 sulfonylcycloalkyl, mercapto, C1-C6 alkoxycarbonyl, C3-C8 cycloalkoxycarbonyl, C2-C4 alkenyl, C4-C8 cycloalkenyl, or C2-C4 alkynyl;
and
R5 is hydrogen, halogen, C1-C6-perfluoroalkyl, 1,1-difluoro(C1-C6)alkyl, C1-C6 alkyl, —(CH2)n—N-piperidinyl, —(CH2)n-piperazinyl, —(CH2)n-piperazinyl[N4—(C1-C6)alkyl], —(CH2)n-N-pyrrolidyl, —(CH2)n-pyridinyl, —(CH2)n—N-imidazoyl, —(CH2)n—N-morpholino, —(CH2)n—N-thiomorpholino,
—CH═CH—(C1-C6)alkyl, —(CH2)n—N-hexahydroazepine, —(CH2)nNH2, —(CH2)nNH(C1-C6 alkyl), —(CH2)nN(C1-C6 alkyl)2, -1-oxo(C1-C6)alkyl, carboxy, (C1-C6)alkyloxycarbonyl, N—(C1-C6)alkylcarbamoyl, phenyl or substituted phenyl, wherein the substituted phenyl can have from one to three substituents independently selected from Z1, z2, Z3 or a monocyclic heteroaryl group, and each C1-C6 alkyl group can be substituted with —OH, —NH2 or —NAB, where A and B are as defined above, R6 is hydrogen or C1-C6 alkyl;
and
n is 1 to 4, p is 0 or 1, and the pharmaceutically acceptable salts, esters, and amides thereof.

12 more elements

Facts

Application

09/671,559Filed 27 Sep 2000 · division

Priority

12 Apr 1996

Granted

5 Aug 2003

Term ends

Not estimatedThe source records don’t support an estimate.

Classification18 codes

C07D 231/12
Having two or three double bonds between ring members or between ring members and non-ring members: with only hydrogen atoms, hydrocarbon or…
A61P 9/10
Drugs for disorders of the cardiovascular system: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary…
A61P 15/00
Drugs for genital or sexual disorders
A61P 17/06
Drugs for dermatological disorders: antipsoriatics