US 7,265,131 B2Granted

Isoquinolinone derivatives and their use as therapeutic agents

AssigneeExelixis, Inc.

InventorsAlan T Johnson, Satoru Kaneko, Raju Mohan, Kozo Oda, Edwin J Schweiger

Life of this patent

Estimating the term…

Abstract

Compounds of formula (I): wherein n, R1, R2, R3 and R7 are disclosed herein, are useful in treating disease-states associated with nuclear receptor activity. Pharmaceutical compositions comprising and methods of using said compounds are also disclosed herein.

Claims27

Dependent claims

A compound of formula (I);

wherein:
n is 1 to 4;
each R1 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, cyano, nitro, —R6, —OR4—R6—N(R4)2, —R6—C(O)OR4, —R6—C(O)N(R4)2, —R6—N(R4)C(O)R4, —R6—N(R4)C(O)OR5, —R6—S(O)tR4 (where t is 0 to 2), and —R6S(O)pN(R4)2, (where p is 1 or 2);
R2 is aryl optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, cyano, nitro, halo, haloalkyl, haloalkenyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —R6—OR4, —R6—N(R4)2, —R6—C(O)OR4, —R6—C(O)N(R4)2, —R6—N(R4)C(O)R4, —R6—N(R4)C(O)OR5, —R6—N(S(O)tR4)2 (where t is 0 to 2), —R6—N(R4)(S(O)tR4) (where t is 0 to 2), —R6—S(O)tR4 (where t is 0 to 2), and —R6—S(O)pN(R4)2 (where p is 1 or 2);
or R2 is heteroaryl optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, cyano, nitro, halo, haloalkyl, haloalkenyl, optionally substituted aryl, optionally subtituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —R6—OR4, —R6—N(R4)2, —R6—C(O)OR4, —R6—C(O)N(R4)2, —R6—N(R4)C(O)R4, —R6—N(R4)C(O)OR5, —R6—N(S(O)tR4)2 (where t is 0 to 2), —R6—N(R4)(S(O)tR4) (where t is 0 to 2), —R6—S(O)tR4 (where t is 0 to 2), and —R6—S(O)pN(R4)2 (where p is 1 or 2);
R3 is cycloalkylalkyl optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, cyano, nitro, halo, haloalkyl, haloalkenyl, —R6—OR4, —R6—N(R4)2, —R6—C(O)OR4, —R6—C(O)N(R4)2, —R6—N(R4)C(O)R4, —R6—N(R4)C(O)OR5, —R6—N(S(O)tR4)2 (where t is 0 to 2), —R6—N(R4)(S(O)tR4) (where t is 0 to 2), —R6—S(O)tR4 (where t is 0 to 2), and —R6—S(O)pN(R4)2 (where p is 1 or 2);
or R3 is aralkyl wherein the aryl group of the aralkyl substituent is substituted with one or more substituents selected from the group consisting of the alkyl, alkenyl, aryl, aralkyl, cyano, nitro, halo, haloalkyl, haloalkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —R6—OR4, —R6—N(R4)2, —R6—C(O)OR4, —R6—C(O)N(R4)2, —R6—N(R4)C(O)R4, —R6—N(R4)C(O)OR5, —R6—N(S(O)tR4)2 (where t is 0 to 2), —R6—N(R4)(S(O)tR4) (where t is 0 to 2), —R6—S(O)tR4 (where t is 0 to 2), and —R6—S(O)pN(R4)2 (where p is 1 or 2 );
or R3 is heteroarylalkyl wherein the heteroaryl group of the heteroarylakyl substituent is optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, aryl, aralkyl, cyano, nitro, halo, haloalkyl, haloalkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —R6—OR4, —R6—N(R4)2, —R6—C(O)OR4, —R6—C(O)N(R4)2, —R6—N(R4)C(O)R4, —R6—N(R4)C(O)OR5, —R6—N(S(O)tR4)2 (where t is 0 to 2), —R6—N(R4)(S(O)tR4) (where t is 0 to 2), —R6—S(O)1R4 (where t is 0 to 2), and —R6—S(O)pN(R4)2 (where p is 1 or 2);
each R4 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted hetercyclyl and optionally substituted heteroaryl;
each R5 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, and aralkyl;
each R6 is a direct bond or a straight or branched alkylene chain;
and
R7 hydrogen or aralkyl;
as a single stereoisomer, a mixture of stereoisomers, or as a racemic mixture of stereoisomers;
or as a solvate or polymorph;
or as a pharmaceutically acceptable salt thereof;
with the following provisos:
(a) when R7 is hydrogen, n is 1, R1 is chloro, methyl, trifluoromethyl or methoxy, and R3 is methyl, R2 can not be unsubstituted furanyl or thiophenyl optionally substituted by methyl;
(b) when R7 is hydrogen, n is 1 or 2, each R1 is independently halo, trifluoromethyl, an alkyl group of 1 to 3 carbons or —R6—OR4 where R6 is a direct bond and R4 is an alkyl group of 1 to 3 carbons, and R3 is an alkyl group of 1 to 3 carbons, R2 can not be phenyl optionally substituted by halo, an alkyl group of 1 to 3 carbons or —R6—OR4 where R6 is a direct bond and R4 is an alkyl group of 1 to 4 carbons;
(c) when R7 is hydrogen, n is 1, R1 is halo, methyl or methoxy, and R3 is methyl, R2 can not be oxazole;
(d) R1 is other than —R6—C(O)OR4 where R6 is a direct bond and R4 is alkyl of 1 to 3 carbons.

18 more elements

A compound of formula (I):

wherein:
n is 1 to 4;
each R1 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, cyano, nitro, —R6—OR4, —R6—N(R4)2, —R6—C(O)OR4, —R6—C(O)N(R4)2, —R6—N(R4)C(O)R4, —R6—N(R4)C(O)OR5, —R6—S(O)tR4 where t is 0 to 2), and —R6—S(O)pN(R4)2 (where p is 1 or 2),
R2 is heteroaryl optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, cyano, nitro, halo, haloalkyl, haloalkenyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —R6—OR4, —R6—N(R4)2, —R6—C(O)OR4, —R6—C(O)N(R4)2, —R6—N(R4)C(O)R4, —R6—N(R4)C(O)OR5, —R6—N(S(O)tR4)2 (where t is 0 to 2), —R6—N(R4)(S(O)tR4) (where t is 0 to 2), —R6—S(O)tR4 (where t is 0 to 2), and —R6—S(O)pN(R4)2 (where p is 1 or 2);
R3 is cycloalkylalkyl optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, cyano, nitro, halo, haloalkyl, haloalkenyl, —R6—OR4, —R6—N(R4)2, —R6—C(O)OR4, —R6—C(O)N(R4)2, —R6—N(R4)C(O)R4, —R6—N(R4)C(O)OR5, —R6—N(S(O)tR4)2 (where p is 0 or 2), —R6—N(R4)(S(O)tR4)(where t is 0 to 2), —R6—S(O)tR4 (where t is 0 to 2), and —R6—S(O)pN(R4)2 (where p is 1 or 2);
or R3 is aralkyl wherein the aryl group of the aralkyl substituent is optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, aryl, aralkyl, cyano, nitro, halo, haloalkyl, haloalkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —R6—OR4, —R6—N(R4)2, —R6—C(O)OR4, —R6—C(O)N(R4)2, —R6—N(R4)C(O)R4, —R6—N(R4)C(O)OR5, —R6—N(S(O)tR4)2 (where t is 0 to 2), —R6—N(R4)(S(O)tR4) (where t is 0 to 2), —R6—S(O)tR4 (where t is 0 to 2), and —R6—S(O)pN(R4)2 (where p is 1 or 2);
or R3 is heteroarylalkyl wherein the heteroaryl group of the heteroarylakyl substituent is optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, aryl, aralkyl, cyano, nitro, halo, haloalkyl, haloalkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —R6—OR4, —R6—N(R4)2, —R6—C(O)OR4, —R6—C(O)N(R4)2, —R6—N(R4)C(O)R4, —R6—N(R4)C(O)OR5, —R6—N(S(O)tR4)2 (where t is 0 to 2), —R6—N(R4)(S(O)tR4) (where t is 0 to 2), and —R6—S(O)tR4 (where t is 0 to 2), and —R6—S(O)pN(R4)2 (where p is 1 or 2);
each R4 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl and optionally substituted heteroaryl;
each R5 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, and aralkyl;
each R6 is a direct bond or a straight or branched alkylene chain;
and
R7 is hydrogen or aralkyl.

9 more elements

A compound selected from the group consisting of the following:

2-biphenyl-4-ylmethyl-3-m-tolyl-2H-isoquinolin-1-one;
2-(2,4-dimethylbenzyl)-3-m-tolyl-2H-isoquinolin-1-one;
2-benzyl-3-m-tolyl-2H-isoquinolin-1-one;
2-(2,4-dimethylbenzyl)-3-(3,5-dimethylphenyl)-2H-isoquinolin-1-one;
2-(2,4-dimethylbenzyl)-3-phenyl-2H-isoquinolin-1-one;
5-chloro-2-(2,4-dimethylbenzyl)-3-m-tolyl-2H-isoquinolin-1-one;
5-chloro-2-(4-methylbenzyl)-3-m-tolyl-2H-isoquinolin-1-one;
5-chloro-2-(2,4-dimethylbenzyl)-3-phenyl-2H-isoquinolin-1-one;
5-chloro-2-(4-methylbenzyl)-3-phenyl-2H-isoquinolin-1-one;
8-chloro-2-(2,4-dimethylbenzyl)-3-phenyl-2H-isoquinolin-1-one;
8-chloro-2-(2,4-dimethylbenzyl)-3-m-tolyl-2H-isoquinolin-1-one;
2-benzyl-8-chloro-3-m-tolyl-2H-isoquinolin-1-one;
2-benzyl-8-chloro-3-phenyl-2H-isoquinolin-1-one;
2-benzyl-8-methyl-3-m-tolyl-2H-isoquinolin-1-one;
8-methyl-2-(4-methylbenzyl)-3-m-tolyl-2H-isoquinolin-1-one;
2-(2,4-dimethylbenzyl)-8-methyl-3-m-tolyl-2H-isoquinolin-1-one;
2-benzyl-8-methyl-3-phenyl-2H-isoquinolin-1-one;
8-methyl-2-(4-methylbenzyl)-3-phenyl-2H-isoquinolin-1-one;
2-(2,4-dimethylbenzyl)-8-methyl-3-phenyl-2H-isoquinolin-1-one;
2-(2,4-dimethylbenzyl)-7-methyl-3-phenyl-2H-isoquinolin-1-one;
2-(2,4-dimethylbenzyl)-7-methyl-3-m-tolyl-2H-isoquinolin-1-one;
7-methyl-2-(4-methylbenzyl)-3-phenyl-2H-isoquinolin-1-one;
7-methyl-2-(4-methylbenzyl)-3-m-tolyl-2H-isoquinolin-1-one;
and
7-chloro-2-(2,4-dimethylbenzyl)-3-m-tolyl-2H-isoquinolin-1-one;
2-benzyl-7-methyl-3-m-tolyl-2H-isoquinolin-1-one;
2-benzyl-7-methyl-3-phenyl-2H-isoquinolin-1-one;
2-benzyl-6-methyl-3-m-tolyl-2H-isoquinolin-1-one;
2-benzyl-6-methyl-3-phenyl-2H-isoquinolin-1-one;
2-(2,4-dimethylbenzyl)-6-methyl-3-phenyl-2H-isoquinolin-1-one;
6-methyl-2-(4-methylbenzyl)-3-m-tolyl-2H-isoquinolin-1-one;
6-methyl-2-(4-methylbenzyl)-3-phenyl-2H-isoquinolin-1-one;
7-chloro-2-(2,4-dimethylbenzyl)-3-phenyl-2H-isoquinolin-1-one;
2-(4-methylbenzyl)-3-phenyl-2H-isoquinolin-1-one;
2-benzyl-3-phenyl-2H-isoquinolin-1-one;
3-(4-benzylphenyl)-2-(2,4-dimethylbenzyl)-8-methyl-2H-isoquinolin-1-one;
8-chloro-2-(2,4-difluorobenzyl)-3-(4′-methanesulfonyl-biphenyl-3-yl)-2H-isoquinolin-1-one;
8-chloro-2-(2,4-difluorobenzyl)-3-(3′-ethanesulfonyl-5′-trifluoromethyl-biphenyl-3-yl)-2H-isoquinolin-1-one;
8-chloro-2-(2,4-difluorobenzyl)-3-[3-(6-ethoxypyridin-3-yl)-phenyl]-2H-isoquinolin-1-one;
5-{3-[8-chloro-2-(2,4-difluorobenzyl)-1-oxo-1,2-dihydroisoquinolin-3-yl]-phenyl}-2-ethoxy-nicotinonitrile;
3-(3′,5′-bis-trifluoromethylbiphenyl-3-yl)-8-chloro-2-(2,4-difluorobenzyl)-2H-isoquinolin-1-one;
and
8-chloro-3-(3′-chloro-4′-ethoxybiphenyl-3-yl)-2-(2,4-difluorobenzyl)-2H-isoquinolin-1-one.

40 more elements

A compound selected from the group consisting of the following:

2-benzyl-3-(4-hydroxy-3,5-dimethylphenyl)-2H-isoquinolin-1-one;
2-(2,4-dimethylbenzyl)-3-(4-hydroxy-3,5-dimethylphenyl)-2H-isoquinolin-1-one;
2-(2,4-dimethylbenzyl)-3-(4-methoxyphenyl)-2H-isoquinolin-1-one;
2-benzyl-3-(4-hydroxyphenyl)-2H-isoquinolin-1-one;
2-(2,4-dimethylbenzyl)-3-(4-hydroxyphenyl)-2H-isoquinolin-1-one;
2-(2,4-dimethylbenzyl)-3-(4-hydroxy-3-methoxyphenyl)-2H-isoquinolin-1-one;
2-(2,4-dimethylbenzyl)-3-[3-methyl-4-(tetrahydropyran-2-yloxy)phenyl]-2H-isoquinolin-1-one;
2-(2,4-dimethylbenzyl)-3-(4-hydroxy-3-methylphenyl)-2H-isoquinolin-1-one;
2-(4-methylbenzyl)-3-(4-phenoxyphenyl)-2H-isoquinolin-1-one;
2-(2,4-dimethylbenzyl)-3-(4-phenoxyphenyl)-2H-isoquinolin-1-one;
2-(2,4-dimethylbenzyl)-3-(4-methylsulfanylphenyl)-2H-isoquinolin-1-one;
2-(4-methyl-benzyl)-3-(4-methylsulfanylphenyl)-2H-isoquinolin-1-one;
2-(2,4-dimethylbenzyl)-3-(3-methyl-4-phenoxyphenyl)-2H-isoquinolin-1-one;
2-benzyl-3-(4-phenoxyphenyl)-2H-isoquinolin-1-one;
5-chloro-2-(2,4-dimethylbenzyl)-3-(4-phenoxyphenyl)-2H-isoquinolin-1-one;
5-chloro-2-(4-methylbenzyl)-3-(4-phenoxyphenyl)-2H-isoquinolin-1-one;
2-(2,4-dimethylbenzyl)-5-fluoro-3-(4-phenoxyphenyl)-2H-isoquinolin-1-one;
2-benzyl-5-fluoro-3-(4-phenoxyphenyl)-2H-isoquinolin-1-one;
8-chloro-2-(2,4-dimethylbenzyl)-3-(4-phenoxyphenyl)-2H-isoquinolin-1-one;
2-benzyl-8-chloro-3-(4-phenoxyphenyl)-2H-isoquinolin-1-one;
2-benzyl-8-methyl-3-(4-phenoxyphenyl)-2H-isoquinolin-1-one;
8-methyl-2-(4-methylbenzyl)-3-(4-phenoxyphenyl)-2H-isoquinolin-1-one;
2-(2,4-dimethylbenzyl)-8-methyl-3-(4-phenoxyphenyl)-2H-isoquinolin-1-one;
2-(2,4-dimethylbenzyl)-7-methyl-3-(4-phenoxyphenyl)-2H-isoquinolin-1-one;
7-methyl-2-(4-methylbenzyl)-3-(4-phenoxyphenyl)-2H-isoquinolin-1-one;
2-benzyl-7-methyl-3-(4-phenoxyphenyl)-2H-isoquinolin-1-one;
2-benzyl-6-methyl-3-(4-phenoxyphenyl)-2H-isoquinolin-1-one;
2-(2,4-dimethylbenzyl)-6-methyl-3-(4-phenoxyphenyl)-2H-isoquinolin-1-one;
6-methyl-2-(4-methylbenzyl)-3-(4-phenoxyphenyl)-2H-isoquinolin-1-one;
7-chloro-2-(2,4-dimethylbenzyl)-3-(4-phenoxyphenyl)-2H-isoquinolin-1-one;
2-benzyl-7-chloro-3-(4-phenoxyphenyl)-2H-isoquinolin-1-one;
2-benzyl-6-chloro-3-(4-phenoxyphenyl)-2H-isoquinolin-1-one;
6-chloro-2-(2,4-dimethylbenzyl)-3-(4-phenoxyphenyl)-2H-isoquinolin-1-one;
2-benzyl-6,8-dimethyl-3-(4-phenoxyphenyl)-2H-isoquinolin-1-one;
2-(2,4-dimethylbenzyl)-6,8-dimethyl-3-(4-phenoxyphenyl)-2H-isoquinolin-1-one;
2-benzyl-5-methyl-3-(4-phenoxyphenyl)-2H-isoquinolin-1-one;
2-benzyl-5,6,7,8-tetramethyl-3-(4-phenoxyphenyl)-2H-isoquinolin-1-one;
2-(2,4-dimethylbenzyl)-5-methyl-3-(4-phenoxyphenyl)-2H-isoquinolin-1-one;
2-benzyl-8-methoxy-3-(4-phenoxyphenyl)-2H-isoquinolin-1-one;
2-(2,4-dimethylbenzyl)-8-fluoro-3-(4-phenoxyphenyl)-2H-isoquinolin-1-one;
8-chloro-2-(2,4-dichloro-benzyl)-3-(4-phenoxyphenyl)-2H-isoquinolin-1-one;
2-benzyl-8-fluoro-3-(4-phenoxyphenyl)-2H-isoquinolin-1-one;
2-(2,4-dimethylbenzyl)-3-(4-phenoxyphenyl)-8-trifluoromethyl-2H-isoquinolin-1-one;
2-(2,4-dimethylbenzyl)-8-methoxy-3-(4-phenoxyphenyl)-2H-isoquinolin-1-one;
8-chloro-2-(2,4-difluorobenzyl)-3-(4-phenoxyphenyl)-2H-isoquinolin-1-one;
7,8-dichloro-2-(2,4-dimethylbenzyl)-3-(4-phenoxyphenyl)-2H-isoquinolin-1-one;
8-chloro-2-(2,4-difluorobenzyl)-5-methyl-3-(4-phenoxyphenyl)-2H-isoquinolin-1-one;
6,7-dichloro-2-(2,4-difluorobenzyl)-3-(4-phenoxyphenyl)-2H-isoquinolin-1-one;
8-chloro-2-(2-chloro-4-fluoro-benzyl)-3-(4-phenoxyphenyl)-2H-isoquinolin-1-one;
5,6-dichloro-2-(2,4-difluorobenzyl)-3-(4-phenoxyphenyl)-2H-isoquinolin-1-one;
2-{4-[8-chloro-2-(2,4-difluorobenzyl)-1-oxo-1,2-dihydro-isoquinolin-3-yl]-phenoxy}-nicotinonitrile;
8-chloro-2-(2,4-difluorobenzyl)-3-(4-hydroxyphenyl)-2H-isoquinolin-1-one;
8-chloro-2-(2,4-difluorobenzyl)-3-[4-(pyrazin-2-yloxy)phenyl]-2H-isoquinolin-1-one;
2-{4-[2-(2,4-difluorobenzyl)-7-fluoro-1-oxo-1,2-dihydro-isoquinolin-3-yl]-phenoxy}-nicotinonitrile;
2-(2,4-difluorobenzyl)-7-fluoro-3-[4-(pyrazin-2-yloxy)phenyl]-2H-isoquinolin-1-one;
2-(2,4-difluorobenzyl)-7-fluoro-3-(4-phenoxyphenyl)-2H-isoquinolin-1-one;
2-(2,4-difluorobenzyl)-5-fluoro-3-[4-(pyrazin-2-yloxy)phenyl]-2H-isoquinolin-1-one;
2-{4-[2-(2,4-difluorobenzyl)-5-fluoro-1-oxo-1,2-dihydro-isoquinolin-3-yl]-phenoxy}-nicotinonitrile;
and
2-(2,4-difluorobenzyl)-5-fluoro-3-(4-phenoxyphenyl)-2H-isoquinolin-1-one.

57 more elements

A compound of formula (I):

wherein:
n is 0 to 4;
each R1 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, cyano, nitro, —R6—OR4, —R6—N(R4)2, —R6—C(O)OR4,R6—C(O)N(R4)2, —R6—N(R4)C(O)R4, —R6—N(R4)C(O)OR5, —R6—S(O)tR4 (where t is 0 to 2), and —R6—S(O)pN(R4)2 (where p is 1 or 2);
R2 is aryl optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, cyano, nitro, halo, haloalkyl, haloalkenyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —R6—OR4, —R6—N(R4)2, —R6—C(O)OR4, —R6—C(O)N(R4)2, —R6—N(R4)C(O)R4, —R6—N(R4)C(O)OR5, —R6—N(S(O)tR4)2(where t is 0 to 2), —R6—N(R4)(S(O)tR4) (where t is 0 to 2), R6—S(O)tR4 (where t is 0 to 2), and —R6—S(O)pN(R4)2 (where p is 1 or 2);
R3 is alkyl or cycloalkylalkyl optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, cyano, nitro, halo, haloalkyl, haloalkenyl, —R6—OR4, —R6—N(R4)2, —R6—C(O)OR4, —R6—C(O)N(R4)2, —R6—N(R4)C(O)R4, —R6—N(R4)C(O)OR5, —R6—N(S(O)tR4)2 (where t is 0 to 2), —R6—N(R4)(S(O)tR4) (where t is 0 to 2), —R6—S(O)tR4 (where t is 0 to 2), and —R6—S(O)pN(R4)2 (where p is 1 or 2);
or R3 is heteroarylalkyl wherein the heteroaryl group of the heteroarylakyl substituent is optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, aryl, aralkyl, cyano, nitro, halo, haloalkyl, haloalkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —R6—OR4, —R6—N(R4)2, —R6—C(O)OR4, —R6—C(O)N(R4)2, —R6—N(R4)C(O)R4, —R6—N(R4)C(O)OR5, —R6—N(S(O)tR4)2 (where t is 0 to 2), —R6—N(R4)(S(O)tR4) (where t is 0 to 2), —R6—S(O)tR4 (where t is 0 to 2), and —R6—S(O)pN(R4)2 (where p is 1 or 2);
each R4 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl,optionally substituted heterocyclyl and optionally substituted heteroaryl;
each R5 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, and aralkyl;
each R6 is a direct bond or a straight or branched alkylene chain;
and
R7 is hydrogen or aralkyl.

8 more elements

A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula (I):

wherein:
n is 0 to 4;
each R1 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, cyano, nitro, —R —OR4, —R6—N(R4)2, —R6—C(O)OR4, —R6—C(O)N(R4)2, —R6—N(R4)C(O)R4, —R6—N(R4)C(O)OR5, —R6—S(O)tR4 (where t is 0 to 2), —R6—S(O)pN(R4)2 (where p is 1 or 2);
R2 is aryl optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, cyano, nitro, halo, haloalkyl, haloalkenyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —R—OR4, —R6—N(R4)2, —R6—C(O)OR4, —R6—C(O)N(R4)2, —R6—N(R4)C(O)R4, —R6—N(R4)C(O)OR5, —R6—N(S(O)tR4)2 (where t is 0 to 2), —R6—N(R4)(S(O)tR4) (where t is 0 to 2), —R6—S(O)tR4 (where t is 0 to 2), and —R6—S(O)pN(R4)2 (where p is 1 to 2);
or R2 is heteroaryl optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, cyano, nitro, halo, haloalkyl, haloalkenyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —R6—OR4, —R6—N(R4)2, —R6—C(O)OR4, —R6—C(O)N(R4)2, —R6—R6—N(R4)C(O)R4, —R6—N(R4)C(O)OR5, —R6—R6—N(S(O)tR4)2 (where t is 0 to 2), —R6—N(R4)(S(O)tR4) (where t is 0 to 2), —R6—S(O)tR4 (where t is 0 to 2), and —R6—S(O)pN(R4)2(where p is 1 or 2);
R3 is cycloalkylalkyl optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, cyano, nitro, halo, haloalkyl, haloalkenyl, —R6—OR4, —R6—N(R4)2, —R6—C(O)OR4, —R6—C(O)N(R4)2, —R6—N(R4)C(O)R4, —R6—N(R4)C(O)OR5, —R6—N(S(O)tR4)2(where t is 0 to 2), —R6—N(R4) (S(O)tR4) (where t is 0 to 2), —R6—S(O)tR4 (where t is 0 to 2), and —R6—S(O)pN(R4)2 (where p is 1 or 2);
or R3 is aralkyl wherein the aryl group of the aralkyl substituent is substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, aryl, aralkyl, cyano, nitro, halo, haloalkyl, haloalkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —R6—OR4, —R6—N(R4)2, —R6—C(O)OR4, —R6—C(O)N(R4)2, —R6—R6—N(R4)C(O)R4, —R6—N(R4)C(O)OR5, —R6—N(S(O)tR4)2 (where t is 0 to 2), —R —N(R4)(S(O)tR4) (where t is 0 to 2), —R6—S(O)tR4 (where t is 0 to 2), and —R6—S(O)pN(R4)2 (where p is 1 or 2);
or R3 is heteroarylalkyl wherein the heteroaryl group of the heteroarylakyl substituent is optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, aryl, aralkyl, cyano, nitro, halo, haloalkyl, haloalkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —R6—OR4, —R —N(R4)2, —R6—C(O)OR4, —R6—C(O)N(R4)2, —R6—N(R4)C(O)R4, —R6—N(R4)C(O)OR5—R6—N(S(O)tR4)2 (where t is 0 to 2), —R6—N(R4) (S(O)tR4) (where t is 0 to 2), —R6—S(O)tR4 (where t is 0 to 2), and —R6—S(O)pN(R4)2 (where p is 1 or 2);
each R4 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl and optionally substituted heteroaryl;
each R5 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, and aralkyl;
each R6 is a direct bond or a straight or branched alkylene chain;
and
R7 is hydrogen or aralkyl;
as a single stereoisomer, a mixture of stereoisomers, or as a racemic mixture of stereoisomers;
or as a solvate or polymorph;
or as a pharmaceutically acceptable salt thereof;
with the following provisos:
(a) when R7 is hydrogen, n is 1, R1 is chloro, methyl, trifluoromethyl or methoxy, and R3 is methyl, R2 can not be unsubstituted furanyl or thiophenyl optionally substituted by methyl;
(b) when R7 is hydrogen, n is 1 or 2, each R1 is independently halo, trifluoromethyl, an alkyl group of 1 to 3 carbons or —R6—OR4 where R6 is a direct bond and R4 is an alkyl group of 1 to 3 carbons, and R3 is an alkyl group of 1 to 3 carbons, R2 can not be phenyl optionally substituted by halo, an alkyl group of 1 to 3 carbons or —R6—OR4 where R6 is a direct bond and R4 is an alkyl group of 1 to 4 carbons;
(c) when R7 is hydrogen, n is 1, R1 is halo, methyl or methoxy, and R3 is methyl, R2 can not be oxazole;
(d) R1 is other than —R6—C(O)OR4 where R6 is a direct bond and R4 is alkyl of 1 to 3 carbons.

18 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/738,964Filed 17 Dec 2003 · us provisional application
Priority: 20 Dec 2002
Published: US 2004/0204447 A114 Oct 2004
Granted: 4 Sep 2007
Term ends: Not estimatedThe source records don’t support an estimate.

Classification8 codes

C07D 405/04
Containing two hetero rings: directly linked by a ring-member-to-ring-member bond
A61P 3/06
Drugs for disorders of the metabolism: antihyperlipidemics
A61P 9/00
Drugs for disorders of the cardiovascular system
A61P 9/10
Drugs for disorders of the cardiovascular system: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary…

Family

Application60/435,851Us provisional application · filed 20 Dec 2002
US 2004/0204447 A1Pre-grant publication · published 14 Oct 2004
US 7,265,131 B2This patent

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

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Abstract

A compound of formula (I);

wherein:
n is 1 to 4;
each R1 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, cyano, nitro, —R6, —OR4—R6—N(R4)2, —R6—C(O)OR4, —R6—C(O)N(R4)2, —R6—N(R4)C(O)R4, —R6—N(R4)C(O)OR5, —R6—S(O)tR4 (where t is 0 to 2), and —R6S(O)pN(R4)2, (where p is 1 or 2);
R2 is aryl optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, cyano, nitro, halo, haloalkyl, haloalkenyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —R6—OR4, —R6—N(R4)2, —R6—C(O)OR4, —R6—C(O)N(R4)2, —R6—N(R4)C(O)R4, —R6—N(R4)C(O)OR5, —R6—N(S(O)tR4)2 (where t is 0 to 2), —R6—N(R4)(S(O)tR4) (where t is 0 to 2), —R6—S(O)tR4 (where t is 0 to 2), and —R6—S(O)pN(R4)2 (where p is 1 or 2);
or R2 is heteroaryl optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, cyano, nitro, halo, haloalkyl, haloalkenyl, optionally substituted aryl, optionally subtituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —R6—OR4, —R6—N(R4)2, —R6—C(O)OR4, —R6—C(O)N(R4)2, —R6—N(R4)C(O)R4, —R6—N(R4)C(O)OR5, —R6—N(S(O)tR4)2 (where t is 0 to 2), —R6—N(R4)(S(O)tR4) (where t is 0 to 2), —R6—S(O)tR4 (where t is 0 to 2), and —R6—S(O)pN(R4)2 (where p is 1 or 2);
R3 is cycloalkylalkyl optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, cyano, nitro, halo, haloalkyl, haloalkenyl, —R6—OR4, —R6—N(R4)2, —R6—C(O)OR4, —R6—C(O)N(R4)2, —R6—N(R4)C(O)R4, —R6—N(R4)C(O)OR5, —R6—N(S(O)tR4)2 (where t is 0 to 2), —R6—N(R4)(S(O)tR4) (where t is 0 to 2), —R6—S(O)tR4 (where t is 0 to 2), and —R6—S(O)pN(R4)2 (where p is 1 or 2);
or R3 is aralkyl wherein the aryl group of the aralkyl substituent is substituted with one or more substituents selected from the group consisting of the alkyl, alkenyl, aryl, aralkyl, cyano, nitro, halo, haloalkyl, haloalkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —R6—OR4, —R6—N(R4)2, —R6—C(O)OR4, —R6—C(O)N(R4)2, —R6—N(R4)C(O)R4, —R6—N(R4)C(O)OR5, —R6—N(S(O)tR4)2 (where t is 0 to 2), —R6—N(R4)(S(O)tR4) (where t is 0 to 2), —R6—S(O)tR4 (where t is 0 to 2), and —R6—S(O)pN(R4)2 (where p is 1 or 2 );
or R3 is heteroarylalkyl wherein the heteroaryl group of the heteroarylakyl substituent is optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, aryl, aralkyl, cyano, nitro, halo, haloalkyl, haloalkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —R6—OR4, —R6—N(R4)2, —R6—C(O)OR4, —R6—C(O)N(R4)2, —R6—N(R4)C(O)R4, —R6—N(R4)C(O)OR5, —R6—N(S(O)tR4)2 (where t is 0 to 2), —R6—N(R4)(S(O)tR4) (where t is 0 to 2), —R6—S(O)1R4 (where t is 0 to 2), and —R6—S(O)pN(R4)2 (where p is 1 or 2);
each R4 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted hetercyclyl and optionally substituted heteroaryl;
each R5 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, and aralkyl;
each R6 is a direct bond or a straight or branched alkylene chain;
and
R7 hydrogen or aralkyl;
as a single stereoisomer, a mixture of stereoisomers, or as a racemic mixture of stereoisomers;
or as a solvate or polymorph;
or as a pharmaceutically acceptable salt thereof;
with the following provisos:
(a) when R7 is hydrogen, n is 1, R1 is chloro, methyl, trifluoromethyl or methoxy, and R3 is methyl, R2 can not be unsubstituted furanyl or thiophenyl optionally substituted by methyl;
(b) when R7 is hydrogen, n is 1 or 2, each R1 is independently halo, trifluoromethyl, an alkyl group of 1 to 3 carbons or —R6—OR4 where R6 is a direct bond and R4 is an alkyl group of 1 to 3 carbons, and R3 is an alkyl group of 1 to 3 carbons, R2 can not be phenyl optionally substituted by halo, an alkyl group of 1 to 3 carbons or —R6—OR4 where R6 is a direct bond and R4 is an alkyl group of 1 to 4 carbons;
(c) when R7 is hydrogen, n is 1, R1 is halo, methyl or methoxy, and R3 is methyl, R2 can not be oxazole;
(d) R1 is other than —R6—C(O)OR4 where R6 is a direct bond and R4 is alkyl of 1 to 3 carbons.

18 more elements

Facts

Application

10/738,964Filed 17 Dec 2003 · us provisional application

Priority

20 Dec 2002

Published

US 2004/0204447 A114 Oct 2004

Granted

4 Sep 2007

Term ends

Not estimatedThe source records don’t support an estimate.

Classification8 codes

C07D 405/04
Containing two hetero rings: directly linked by a ring-member-to-ring-member bond
A61P 3/06
Drugs for disorders of the metabolism: antihyperlipidemics
A61P 9/00
Drugs for disorders of the cardiovascular system
A61P 9/10
Drugs for disorders of the cardiovascular system: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary…