IP Library › Granted Patent US 7,265,131

Granted Patent B2

US 7,265,131 · App. 10/738,964 · Granted Sep 4, 2007

Isoquinolinone derivatives and their use as therapeutic agents

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Quick Facts

Patent No.: US 7,265,131
App. No.: 10/738,964
Granted: Sep 4, 2007
Kind: B2

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Abstract

Compounds of formula (I): wherein n, R 1 , R 2 , R 3 and R 7 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.

Claims (358)

1. A compound of formula (I);

wherein:

n is 1 to 4;

each R 1 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, cyano, nitro, —R 6 , —OR 4 —R 6 —N(R 4 ) 2 , —R 6 —C(O)OR 4 , —R 6 —C(O)N(R 4 ) 2 , —R 6 —N(R 4 )C(O)R 4 , —R 6 —N(R 4 )C(O)OR 5 , —R 6 —S(O) t R 4 (where t is 0 to 2), and —R 6 S(O) p N(R 4 ) 2 , (where p is 1 or 2);

R 2 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 6 —OR 4 , —R 6 —N(R 4 ) 2 , —R 6 —C(O)OR 4 , —R 6 —C(O)N(R 4 ) 2 , —R 6 —N(R 4 )C(O)R 4 , —R 6 —N(R 4 )C(O)OR 5 , —R 6 —N(S(O) t R 4 ) 2 (where t is 0 to 2), —R 6 —N(R 4 )(S(O) t R 4 ) (where t is 0 to 2), —R 6 —S(O) t R 4 (where t is 0 to 2), and —R 6 —S(O) p N(R 4 ) 2 (where p is 1 or 2);

or R 2 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, —R 6 —OR 4 , —R 6 —N(R 4 ) 2 , —R 6 —C(O)OR 4 , —R 6 —C(O)N(R 4 ) 2 , —R 6 —N(R 4 )C(O)R 4 , —R 6 —N(R 4 )C(O)OR 5 , —R 6 —N(S(O) t R 4 ) 2 (where t is 0 to 2), —R 6 —N(R 4 )(S(O) t R 4 ) (where t is 0 to 2), —R 6 —S(O) t R 4 (where t is 0 to 2), and —R 6 —S(O) p N(R 4 ) 2 (where p is 1 or 2);

R 3 is cycloalkylalkyl optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, cyano, nitro, halo, haloalkyl, haloalkenyl, —R 6 —OR 4 , —R 6 —N(R 4 ) 2 , —R 6 —C(O)OR 4 , —R 6 —C(O)N(R 4 ) 2 , —R 6 —N(R 4 )C(O)R 4 , —R 6 —N(R 4 )C(O)OR 5 , —R 6 —N(S(O) t R 4 ) 2 (where t is 0 to 2), —R 6 —N(R 4 )(S(O) t R 4 ) (where t is 0 to 2), —R 6 —S(O) t R 4 (where t is 0 to 2), and —R 6 —S(O) p N(R 4 ) 2 (where p is 1 or 2);

or R 3 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, —R 6 —OR 4 , —R 6 —N(R 4 ) 2 , —R 6 —C(O)OR 4 , —R 6 —C(O)N(R 4 ) 2 , —R 6 —N(R 4 )C(O)R 4 , —R 6 —N(R 4 )C(O)OR 5 , —R 6 —N(S(O) t R 4 ) 2 (where t is 0 to 2), —R 6 —N(R 4 )(S(O) t R 4 ) (where t is 0 to 2), —R 6 —S(O) t R 4 (where t is 0 to 2), and —R 6 —S(O) p N(R 4 ) 2 (where p is 1 or 2 );

or R 3 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, —R 6 —OR 4 , —R 6 —N(R 4 ) 2 , —R 6 —C(O)OR 4 , —R 6 —C(O)N(R 4 ) 2 , —R 6 —N(R 4 )C(O)R 4 , —R 6 —N(R 4 )C(O)OR 5 , —R 6 —N(S(O) t R 4 ) 2 (where t is 0 to 2), —R 6 —N(R 4 )(S(O) t R 4 ) (where t is 0 to 2), —R 6 —S(O) 1 R 4 (where t is 0 to 2), and —R 6 —S(O) p N(R 4 ) 2 (where p is 1 or 2);

each R 4 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 R 5 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, and aralkyl;

each R 6 is a direct bond or a straight or branched alkylene chain; and

R 7 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 R 7 is hydrogen, n is 1, R 1 is chloro, methyl, trifluoromethyl or methoxy, and R 3 is methyl, R 2 can not be unsubstituted furanyl or thiophenyl optionally substituted by methyl;

(b) when R 7 is hydrogen, n is 1 or 2, each R 1 is independently halo, trifluoromethyl, an alkyl group of 1 to 3 carbons or —R 6 —OR 4 where R 6 is a direct bond and R 4 is an alkyl group of 1 to 3 carbons, and R 3 is an alkyl group of 1 to 3 carbons, R 2 can not be phenyl optionally substituted by halo, an alkyl group of 1 to 3 carbons or —R 6 —OR 4 where R 6 is a direct bond and R 4 is an alkyl group of 1 to 4 carbons;

(d) R 1 is other than —R 6 —C(O)OR 4 where R 6 is a direct bond and R 4 is alkyl of 1 to 3 carbons.

2. A compound of formula (I):

wherein:

n is 1 to 4;

each R 1 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, cyano, nitro, —R 6 —OR 4 , —R 6 —N(R 4 ) 2 , —R 6 —C(O)OR 4 , —R 6 —C(O)N(R 4 ) 2 , —R 6 —N(R 4 )C(O)R 4 , —R 6 —N(R 4 )C(O)OR 5 , —R 6 —S(O) t R 4 where t is 0 to 2), and —R 6 —S(O) p N(R 4 ) 2 (where p is 1 or 2),

R 2 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, —R 6 —OR 4 , —R 6 —N(R 4 ) 2 , —R 6 —C(O)OR 4 , —R 6 —C(O)N(R 4 ) 2 , —R 6 —N(R 4 )C(O)R 4 , —R 6 —N(R 4 )C(O)OR 5 , —R 6 —N(S(O) t R 4 ) 2 (where t is 0 to 2), —R 6 —N(R 4 )(S(O) t R 4 ) (where t is 0 to 2), —R 6 —S(O) t R 4 (where t is 0 to 2), and —R 6 —S(O) p N(R 4 ) 2 (where p is 1 or 2);

R 3 is cycloalkylalkyl optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, cyano, nitro, halo, haloalkyl, haloalkenyl, —R 6 —OR 4 , —R 6 —N(R 4 ) 2 , —R 6 —C(O)OR 4 , —R 6 —C(O)N(R 4 ) 2 , —R 6 —N(R 4 )C(O)R 4 , —R 6 —N(R 4 )C(O)OR 5 , —R 6 —N(S(O) t R 4 ) 2 (where p is 0 or 2), —R 6 —N(R 4 )(S(O) t R 4 )(where t is 0 to 2), —R 6 —S(O) t R 4 (where t is 0 to 2), and —R 6 —S(O) p N(R 4 ) 2 (where p is 1 or 2);

or R 3 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, —R 6 —OR 4 , —R 6 —N(R 4 ) 2 , —R 6 —C(O)OR 4 , —R 6 —C(O)N(R 4 ) 2 , —R 6 —N(R 4 )C(O)R 4 , —R 6 —N(R 4 )C(O)OR 5 , —R 6 —N(S(O) t R 4 ) 2 (where t is 0 to 2), —R 6 —N(R 4 )(S(O) t R 4 ) (where t is 0 to 2), —R 6 —S(O) t R 4 (where t is 0 to 2), and —R 6 —S(O) p N(R 4 ) 2 (where p is 1 or 2);

or R 3 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, —R 6 —OR 4 , —R 6 —N(R 4 ) 2 , —R 6 —C(O)OR 4 , —R 6 —C(O)N(R 4 ) 2 , —R 6 —N(R 4 )C(O)R 4 , —R 6 —N(R 4 )C(O)OR 5 , —R 6 —N(S(O) t R 4 ) 2 (where t is 0 to 2), —R 6 —N(R 4 )(S(O) t R 4 ) (where t is 0 to 2), and —R 6 —S(O) t R 4 (where t is 0 to 2), and —R 6 —S(O) p N(R 4 ) 2 (where p is 1 or 2);

each R 5 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, and aralkyl;

each R 6 is a direct bond or a straight or branched alkylene chain; and

R 7 is hydrogen or aralkyl.

3. The compound of claim 2 wherein:

n is 1 to4;

each R 1 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, cyano, nitro, —R 6 OR 4 , —OR 6 —N(R 4 ) 2 , —R 6 —C(O)OR 4 , —R 6 —C(O)N(R 4 ) 2 , —R 6 —N(R 4 )C(O)R 4 , —R 6 —N(R 4 )C(O)OR 5 , —R 6 —S(O) t R 4 (where t is 0 to 2), and —R 6 —S(O) p N(R 4 ) 2 (where p is 1 or 2);

R 3 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, —R 6 —OR 4 , —R 6 —N(R 4 ) 2 , —R 6 —C(O)OR 4 , —R 6 —C(O)N(R 4 ) 2 , —R 6 —N(R 4 )C(O)R 4 , —R 6 —N(R 4 )C(O)OR 5 , —R 6 —N(S(O) t R 4 ) 2 (where t is 0 to 2), —R 6 —N(R 4 )(S(O) t R 4 ) (where t is 0 to 2), —R 6 —S(O) t R 4 (where t is 0 to 2), and —R 6 —S(O) p N(R 4 )2 (where p is 1 or 2);

each R 5 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, and aralkyl;

each R 6 is a direct bond or a straight or branched alkylene chain; and

R 7 is hydrogen or aralkyl.

4. The compound of claim 3 wherein:

n is 1 to 4;

each R 1 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, cyano, nitro, —R 6 —OR 4 , —R 6 —N(R 4 ) 2 , —R 6 —C(O)OR 4 , —R 6 —C(O)N(R 4 ) 2 , —R 6 —N(R 4 )C(O)R 4 , —R 6 —N(R 4 )C(O)OR 5 , —R 6 —S(O) t R 4 (where t is 0 to 2), and —R 6 —S(O) p N(R 4 ) 2 (where p is 1 or 2);

R 3 is benzyl optionally substituted with one or more substituents selected from the group consisting of alkyl, aryl, cyano, nitro, halo, haloalkyl, —R 6 —OR 4 , —R 6 —N(R 4 ) 2 , —R 6 —C(O)OR 4 , and —R 6 —C(O)N(R 4 ) 2 ;

R 5 is selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, and aralkyl;

each R 6 is a direct bond or a straight or branched alkylene chain; and

R 7 is hydrogen.

5. The compound of claim 4 wherein:

n is 1 to 4;

each R 1 is independently selected from the group consisting of alkyl, halo, haloalkyl, cyano, nitro, —R 6 —OR 4 , —R 6 —N(R 4 ) 2 , —R 6 —C(O)OR 4 , and —R 6 —C(O)N(R 4 ) 2 ;

R 2 is thiophenyl, benzothiophenyl, furanyl or benzofuranyl, each optionally substituted with one or more substituents selected from the group consisting of alkyl, cyano, nitro, halo, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —R 6 —OR 4 , —R 6 —N(R 4 ) 2 , —R 6 —C(O)OR 4 , and —R 6 —C(O)N(R 4 ) 2 ;

each R 6 is a direct bond or a straight or branched alkylene chain; and

R 7 is hydrogen.

6. The compound of claim 5 wherein:

n is 1 to 4;

each R 1 is independently selected from the group consisting of alkyl, halo, haloalkyl, cyano, nitro, —R 6 —OR 4 , —R 6 —N(R 4 ) 2 , —R 6 —C(O)OR 4 , and —R 6 —C(O)N(R 4 ) 2 ;

R 2 is thiophenyl, benzothiophenyl, furanyl or benzofuranyl, each of which are optionally substituted with one or more substituents independently selected from the group consisting of halo, —R 6 —OR 4 , optionally substituted phenyl and optionally substituted pyridinyl;

each R 4 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl, and aralkyl;

each R 6 is a direct bond or a straight or branched alkylene chain; and

R 7 is hydrogen.

7. The compound of claim 6 wherein:

n is 1 to 4;

each R 1 is independently selected from the group consisting of alkyl, halo, haloalkyl, cyano, nitro, —R 6 —OR 4 , —R 6 —N(R 4 ) 2 , —R 6 —C(O)OR 4 , and —R 6 —C(O)N(R 4 ) 2 ;

each R 4 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl, and aralkyl;

each R 6 is a direct bond or a straight or branched alkylene chain; and

R 7 is hydrogen.

8. The compound of claim 7 selected from the group consisting of the following:

2-benzyl-3-thiophen-2-yl-2H-isoquinolin-1-one;

2-benzyl-3-furan-3-yl-2H-isoquinolin-1-one;

2-(2,4-dimethylbenzyl)-3-thiophen-3-yl-2H-isoquinolin-1-one;

2-(2,4-dimethylbenzyl)-3-furan-2-yl-2H-isoquinolin-1-one;

2-benzyl-3-thiophen-3-yl-2H-isoquinolin-1-one;

2-(2,4-dimethylbenzyl)-3-thiophen-2-yl-2H-isoquinolin-1-one;

3-benzo[b]thiophen-2-yl-2-(4-methylbenzyl)-2H-isoquinolin-1-one;

3-benzofuran-2-yl-2-(4-methylbenzyl)-2H-isoquinolin-1-one;

3-benzofuran-2-yl-2-(2,4-dimethylbenzyl)-2H-isoquinolin-1-one;

3-benzo[b]thiophen-2-yl-2-(2,4-dimethylbenzyl)-2H-isoquinolin-1-one; and

3-(5-bromothiophen-2-yl)-8-chloro-2-(2,4-difluorobenzyl)-2H-isoquinolin-1-one.

9. The compound of claim 6 wherein:

n is 1 to 4;

each R 1 is independently selected from the group consisting of alkyl, halo, haloalkyl, cyano, nitro, —R 6 —OR 4 , —R 6 —N(R 4 ) 2 , —R 6 —C(O)OR 4 , and —R 6 —C(O)N(R 4 ) 2 ;

R 2 is thiophenyl or furanyl, each of which is substituted with phenyl or pyridinyl, where the phenyl and the pyridinyl are each optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, cyano, nitro, —R 6 —OR 4 , —R 6 —N(R 4 ) 2 , —R 6 —C(O)OR 4 , —R 6 —C(O)N(R 4 ) 2 , —R 6 —N(S(O) t R 4 ) 2 (where t is 0 to 2), —R 6 —N(R 4 )(S(O) t R 4 ) (where t is 0 to 2), —R 6 —S(O) t R 4 (where t is 0 to 2), and —R 6 —S(O) p N(R 4 ) 2 (where p is 1 to 2);

each R 4 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl, and aralkyl;

each R 6 is a direct bond or a straight or branched alkylene chain; and

R 7 is hydrogen.

10. The compound of claim 9 selected from the group consisting of the following:

8-chloro-2-(2,4-difluorobenzyl)-3-[5-(3,4-dimethoxyphenyl)thiophen-2-yl]-2H-isoquinolin-1-one;

3-[5-(3,5-bis-trifluoromethylphenyl)thiophen-2-yl]-8-chloro-2-(2,4-difluorobenzyl)-2H-isoquinolin-1-one;

8-chloro-2-(2,4-difluorobenzyl)-3-[5-(4-methanesulfonylphenyl)thiophen-2-yl]-2H-isoquinolin-1-one;

8-chloro-3-[5-(3-chloro-4-ethoxyphenyl)thiophen-2-yl]-2-(2,4-difluorobenzyl)-2H-isoquinolin-1-one;

8-chloro-3-[5-(3-chloro-4-ethoxyphenyl)furan-2-yl]-2-(2,4-difluorobenzyl)-2H-isoquinolin-1-one;

3-[5-(3,5-bis-trifluoromethylphenyl)furan-2-yl]-8-chloro-2-(2,4-difluorobenzyl)-2H-isoquinolin-1-one;

8-chloro-2-(2,4-difluorobenzyl)-3-[5-(4-methanesulfonylphenyl)furan-2-yl]-2H-isoquinolin-1-one;

8-chloro-3-[4-(3-chloro-4-ethoxyphenyl)thiophen-2-yl]-2-(2,4-difluorobenzyl)-2H-isoquinolin-1-one;

3-[4-(3,5-bis-trifluoromethylphenyl)thiophen-2-yl]-8-chloro-2-(2,4-difluorobenzyl)-2H-isoquinolin-1-one;

8-chloro-2-(2,4-difluorobenzyl)-3-[4-(4-methanesulfonylphenyl)thiophen-2-yl]-2H-isoquinolin-1-one;

3-[4-(4-amino-3-trifluoromethylphenyl)thiophen-2-yl]-8-chloro-2-(2,4-difluorobenzyl)-2H-isoquinolin-1-one;

3-[4-(4-amino-3-chloro-phenyl)thiophen-2-yl]-8-chloro-2-(2,4-difluorobenzyl)-2H-isoquinolin-1-one;

8-chloro-2-(2,4-difluorobenzyl)-3-[4-(4-ethoxy-3-trifluoromethylphenyl)thiophen-2-yl]-2H-isoquinolin-1-one;

8-chloro-2-(2,4-difluorobenzyl)-3-[5-(4-ethoxy-3-trifluoromethylphenyl)thiophen-2-yl]-2H-isoquinolin-1-one;

3-[5-(4-amino-3-trifluoromethylphenyl)thiophen-2-yl]-8-chloro-2-(2,4-difluorobenzyl)-2H-isoquinolin-1-one;

3-[5-(4-amino-3-chloro-phenyl)thiophen-2-yl]-8-chloro-2-(2,4-difluorobenzyl)-2H-isoquinolin-1-one;

8-chloro-3-[4-(3-chloro-4-diethylamino-phenyl)thiophen-2-yl]-2-(2,4-difluorobenzyl)-2H-isoquinolin-1-one;

8-chloro-3-[4-(3-chloro-4-ethylamino-phenyl)thiophen-2-yl]-2-(2,4-difluorobenzyl)-2H-isoquinolin-1-one;

8-chloro-3-[4-(3-chloro-4-ethoxyphenyl)furan-2-yl]-2-(2,4-difluorobenzyl)-2H-isoquinolin-1-one;

3-[4-(3,5-bis-trifluoromethylphenyl)furan-2-yl]-8-chloro-2-(2,4-difluorobenzyl)-2H-isoquinolin-1-one;

8-chloro-2-(2,4-difluorobenzyl)-3-[5-(4-ethylamino-3-trifluoromethylphenyl)thiophen-2-yl]-2H-isoquinolin-1-one;

8-chloro-3-[5-(3-trifluoromethyl-4-(bis-methanesulfonylamino)-phenyl)thiophen-2-yl]-2-(2,4-difluorobenzyl)-2H-isoquinolin-1-one;

8-chloro-2-(2,4-difluorobenzyl)-3-[4-(4-methanesulfonylphenyl)furan-2-yl]-2H-isoquinolin-1-one;

8-chloro-2-(2,4-difluorobenzyl)-3-[5-(3-ethanesulfonyl-5-trifluoromethylphenyl)thiophen-2-yl]-2H-isoquinolin-1-one;

8-chloro-2-(2,4-difluorobenzyl)-3-[4-(3-ethanesulfonyl-5-trifluoromethylphenyl)furan-2-yl]-2H-isoquinolin-1-one;

3-[4-(4-amino-3-trifluoromethylphenyl)furan-2-yl]-8-chloro-2-(2,4-difluorobenzyl)-2H-isoquinolin-1-one;

8-chloro-2-(2,4-difluorobenzyl)-3-[5-(3-ethylsulfanyl-5-trifluoromethylphenyl)furan-2-yl]-2H-isoquinolin-1-one;

8-chloro-2-(2,4-difluorobenzyl)-3-[5-(3-ethanesulfonyl-5-trifluoromethylphenyl)furan-2-yl]-2H-isoquinolin-1-one;

8-chloro-2-(2,4-difluorobenzyl)-3-[4-(4-ethylamino-3-trifluoromethylphenyl)furan-2-yl]-2H-isoquinolin-1-one;

8-chloro-2-(2,4-difluorobenzyl)-3-[5-(6-ethoxy-pyridin-3-yl)-thiophen-2-yl]-2H-isoquinolin-1-one; and

5-{5-[8-chloro-2-(2,4-difluorobenzyl)-1-oxo-1,2-dihydro-isoquinolin-3-yl]-thiophen-2-yl}-2-ethoxy-nicotinonitrile.

11. The compound of claim 1 wherein:

n is 1 to 4;

each R 1 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, cyano, nitro, —R 6 —OR 4 , —R 6 —N(R 4 ) 2 , —R 6 —C(O)OR 4 , —R 6 —C(O)N(R 4 ) 2 , —R 6 —N(R 4 )C(O)R 4 , —R 6 —N(R 4 )C(O)OR 5 , —R 6 —S(O) t R 4 (where t is 0 to 2), and —R 6 —S(O) p N(R 4 ) 2 (where p is 1 or 2);

R 3 cycloalkylalkyl optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, cyano, nitro, halo, haloalkyl, haloalkenyl, —R 6 —OR 4 , —R 6 —N(R 4 ) 2 , —R 6 —C(O)OR 4 , —R 6 —C(O)N(R 4 ) 2 , —R 6 —N(R 4 )C(O)R 4 , —R 6 —N(R 4 )C(O)OR 5 , —R 6 —N(S(O) t R 4 ) 2 (where t is 0 to 2), —R 6 —N(R 4 )(S(O) t R 4 ) (where t is 0 to 2), —R 6 —S(O) t R 4 (where t is 0 to 2), and —R 6 —S(O) p N(R 4 ) 2 (where p is 1 or 2);

or R 3 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, —R 6 —OR 4 , —R 6 —N(R 4 ) 2 , —R 6 —C(O)OR 4 , —R 6 —C(O)N(R 4 ) 2 , —R 6 —N(R 4 )C(O)R 4 , —R 6 —N(R 4 )C(O)OR 5 , —R 6 —N(S(O) t R 4 ) 2 (where t is 0 to 2), —R 6 —N(R 4 )(S(O) t R 4 ) (where t is 0 to 2), —R 6 —S(O) t R 4 (where t is 0 to 2), and —R 6 —S(O) p N(R 4 ) 2 (where p is 1 or 2);

or R 3 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, —R 6 —OR 4 , —R 6 —N(R 4 ) 2 , —R 6 —C(O)OR 4 , —R 6 —C(O)N(R 4 ) 2 , —R 6 —N(R 4 )C(O)R 4 , —R 6 —N(R 4 )C(O)OR 5 , —R 6 —N(S(O) t R 4 ) 2 (where t is 0 to 2), —R 6 —N(R 4 )(S(O) t R 4 ) (where t is 0 to 2), —R 6 —S(O) t R 4 (where t is 0 to 2), and —R 6 —S(O) p N(R 4 ) 2 (where p is 1 or 2);

each R 5 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, and aralkyl;

each R 6 is a direct bond or a straight or branched alkylene chain; and

R 7 is hydrogen or aralkyl.

12. The compound of claim 11 wherein:

n is 1 to 4;

each R 1 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, cyano, nitro, —R 6 —OR 4 , —R 6 —N(R 4 ) 2 , —R 6 —C(O)OR 4 , —R 6 —C(O)N(R 4 ) 2 , —R 6 —N(R 4 )C(O)R 4 , —R 6 —N(R 4 )C(O)OR 5 , —R 6 —S(O) t R 4 (where t is 0 to 2), and —R 6 —S(O) p N(R 4 ) 2 (where p is 1 or 2);

R 3 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, —R 6 —OR 4 , —R 6 —N(R 4 ) 2 , —R 6 —C(O)OR 4 , —R 6 —C(O)N(R 4 ) 2 , —R 6 —N(R 4 )C(O)R 4 , —R 6 —N(R 4 )C(O)OR 5 , —R 6 —N(S(O) t R 4 ) 2 (where t is 0 to 2), —R 6 —N(R 4 )(S(O) t R 4 ) (where t is 0 to 2), —R 6 —S(O) t R 4 (where t is 0 to 2), and —R 6 —S(O) p N(R 4 ) 2 (where p is 1 or 2);

each R 5 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, and aralkyl;

each R 6 is a direct bond or a straight or branched alkylene chain; and

R 7 is hydrogen or aralkyl.

13. The compound of claim 12 wherein:

n is 1 to 4;

each R 1 is independently selected from the group consisting of alkyl, halo, haloalkyl, cyano, nitro, —R 6 —OR 4 , —R 6 —N(R 4 ) 2 , —R 6 —C(O)OR 4 , and —R 6 —C(O)N(R 4 ) 2 ;

R 2 is phenyl optionally substituted with one or more substituents selected from the group consisting of alkyl, cyano, nitro, halo, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —R 6 —OR 4 , —R 6 —N(R 4 ) 2 , —R6—C(O)OR 4 , —R 6 —C(O)N(R 4 ) 2 , and —R 6 —N(R 4 )C(O)R 4 ;

R 3 is benzyl substituted with one or more substituents selected from the group consisting of alkyl, aryl, cyano, nitro, halo, haloalkyl, —R 6 —OR 4 , —R 6 —N(R 4 ) 2 , —R 6 —C(O)OR 4 , and —R 6 —C(O)N(R 4 ) 2 ;

each R 4 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, and aralkyl;

each R 6 is a direct bond or a straight or branched alkylene chain; and

R 7 is hydrogen.

14. The compound of claim 13 wherein:

n is 1;

R 1 is alkyl or halo;

R 2 is phenyl optionally substituted with one or more substituents selected from the group consisting of alkyl, optionally substituted aryl and optionally substituted aralkyl; and

R 3 is benzyl substituted with one or more substituents selected from the group consisting of alkyl, halo and aryl.

15. 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.

16. The compound of claim 12 wherein:

n is 0 to 4;

each R 1 is independently selected from the group consisting of alkyl, halo, haloalkyl, cyano, nitro, —R 6 OR 4 , —R 6 —N(R 4 ) 2 , —R 6 —C(O)OR 4 , and —R 6 —C(O)N(R 4 ) 2 ;

R 2 is phenyl optionally substituted with one or more substituents selected from the group consisting of alkyl, —R 6 —OR 4 , and —R 6 —S(O) t R 4 (where t is 0 to 2);

R 3 is benzyl substituted with one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, cyano, nitro, halo, haloalkyl, cycloalkyl, heterocyclyl, —R 6 —OR 4 , —R 6 —N(R 4 ) 2 , —R 6 —C(O)OR 4 , —R 6 —C(O)N(R 4 ) 2 , —R 6 —N(R 4 )C(O)R 4 , —R 6 —N(R 4 )C(O)OR 5 , —R 6 —S(O) t R 4 (where t is 0 to 2), and —R 6 —S(O) p N(R 4 ) 2 (where p is 1 or 2);

each R 5 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, and aralkyl;

each R 6 is a direct bond or a straight or branched alkylene chain; and

R 7 is hydrogen or aralkyl.

17. The compound of claim 16 wherein:

n is 0 to 4;

each R 1 is independently selected from the group consisting of alkyl, halo, haloalkyl, cyano, nitro, —R 6 —OR 4 , —R 6 —N(R 4 ) 2 , —R 6 —C(O)OR 4 , and —R 6 —C(O)N(R 4 ) 2 ;

R 2 is phenyl optionally substituted with one or more substituents selected from the group consisting of alkyl, —R 6 —OR 4 , and —R 6 —S(O) t R 4 (where t is 0 to 2);

R 3 is benzyl substituted with one or more substituents selected from the group consisting of alkyl, halo, and haloalkyl;

each R 4 is independently selected from the group consisting of hydrogen, alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl and optionally substituted heteroaryl;

each R 6 is a direct bond; and

R 7 is hydrogen or aralkyl.

18. 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.

19. The compound of claim 12 wherein:

n is 0 or 1;

R 1 is alkyl or halo;

R 2 is phenyl optionally substituted with one or more substituents selected from the group consisting of cyano, halo, haloalkyl, —R 6 —OR 4 , —R 6 —N(R 4 ) 2 , —R 6 —C(O)OR 4 , and —R 6 —N(R 4 )C(O)R 4 ;

R 3 is benzyl substituted with one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, cyano, nitro, halo, haloalkyl, cycloalkyl, heterocyclyl, —R 6 —OR 4 , —R 6 —N(R 4 ) 2 , —R 6 —C(O)OR 4 , —R 6 —C(O)N(R 4 ) 2 , —R 6 —N(R 4 )C(O)OR 4 , —R 6 —N(R 4 )C(O)OR 5 , —R 6 —S(O) t R 4 (where t is 0 to 2), and —R 6 —S(O) p N(R 4 ) 2 (where p is 1 or 2);

each R 4 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, and aralkyl;

each R 5 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, and aralkyl;

each R 6 is a direct bond or a straight or branched alkylene chain; and

R 7 is hydrogen or aralkyl.

20. The compound of claim 19 wherein:

n is 0 or 1;

R 1 is alkyl or halo;

R 3 is benzyl wherein the phenyl group is substituted with one or more alkyl substituents;

each R 4 is independently selected from the group consisting of hydrogen, alkyl, aryl, and aralkyl; and

each R 6 is a direct bond.

21. A compound selected from the group consisting of the following:

N-[4-(2-benzyl-1-oxo-1,2-dihydroisoquinolin-3-yl)phenyl]acetamide;

3-(4-aminophenyl)-2-(2,4-dimethylbenzyl)-2H-isoquinolin-1-one;

3-(3,5-bis-trifluoromethylphenyl)-2-(2,4-dimethylbenzyl)-2H-isoquinolin-1-one;

4-[2-(2,4-dimethylbenzyl)-1-oxo-1,2-dihydroisoquinolin-3-yl]benzoic acid methyl ester;

2-(2,4-dimethylbenzyl)-3-(4-methoxy-3-trifluoromethylphenyl)-2H-isoquinolin-1-one;

N-{4-[2-(2,4-dimethylbenzyl)-1-oxo-1,2-dihydroisoquinolin-3-yl]phenyl}-acetamide;

4-[2-(2,4-dimethylbenzyl)-1-oxo-1,2-dihydroisoquinolin-3-yl]benzonitrile;

2-(2,4-dimethylbenzyl)-3-(3-trifluoromethylphenyl)-2H-isoquinolin-1-one;

2-(4-methylbenzyl)-3-(3-trifluoromethylphenyl)-2H-isoquinolin-1-one;

2-benzyl-3-(3-trifluoromethylphenyl)-2H-isoquinolin-1-one;

3-(4-bromophenyl)-2-(2,4-dimethylbenzyl)-2H-isoquinolin-1-one; and

3-(4-bromophenyl)-2-(4-methylbenzyl)-2H-isoquinolin-1-one.

22. A compound of formula (I):

wherein:

n is 0 to 4;

each R 1 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, cyano, nitro, —R 6 —OR 4 , —R 6 —N(R 4 ) 2 , —R 6 —C(O)OR 4 ,R 6 —C(O)N(R 4 ) 2 , —R 6 —N(R 4 )C(O)R 4 , —R 6 —N(R 4 )C(O)OR 5 , —R 6 —S(O) t R 4 (where t is 0 to 2), and —R 6 —S(O) p N(R 4 ) 2 (where p is 1 or 2);

R 2 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 6 —OR 4 , —R 6 —N(R 4 ) 2 , —R 6 —C(O)OR 4 , —R 6 —C(O)N(R 4 ) 2 , —R 6 —N(R 4 )C(O)R 4 , —R 6 —N(R 4 )C(O)OR 5 , —R 6 —N(S(O) t R 4 ) 2 (where t is 0 to 2), —R 6 —N(R 4 )(S(O) t R 4 ) (where t is 0 to 2), R 6 —S(O) t R 4 (where t is 0 to 2), and —R 6 —S(O) p N(R 4 ) 2 (where p is 1 or 2);

R 3 is alkyl or cycloalkylalkyl optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, cyano, nitro, halo, haloalkyl, haloalkenyl, —R 6 —OR 4 , —R 6 —N(R 4 ) 2 , —R 6 —C(O)OR 4 , —R 6 —C(O)N(R 4 ) 2 , —R 6 —N(R 4 )C(O)R 4 , —R 6 —N(R 4 )C(O)OR 5 , —R 6 —N(S(O) t R 4 ) 2 (where t is 0 to 2), —R 6 —N(R 4 )(S(O) t R 4 ) (where t is 0 to 2), —R 6 —S(O) t R 4 (where t is 0 to 2), and —R 6 —S(O) p N(R 4 ) 2 (where p is 1 or 2);

or R 3 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, —R 6 —OR 4 , —R 6 —N(R 4 ) 2 , —R 6 —C(O)OR 4 , —R 6 —C(O)N(R 4 ) 2 , —R 6 —N(R 4 )C(O)R 4 , —R 6 —N(R 4 )C(O)OR 5 , —R 6 —N(S(O) t R 4 ) 2 (where t is 0 to 2), —R 6 —N(R 4 )(S(O) t R 4 ) (where t is 0 to 2), —R 6 —S(O) t R 4 (where t is 0 to 2), and —R 6 —S(O) p N(R 4 ) 2 (where p is 1 or 2);

each R 4 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 R 5 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, and aralkyl;

each R 6 is a direct bond or a straight or branched alkylene chain; and

R 7 is hydrogen or aralkyl.

23. The compound of claim 22 wherein:

n is 0 to 4;

each R 1 is independently selected from the group consisting of alkyl, halo, haloalkyl, cyano, nitro, —R 6 —OR 4 , —R 6 —N(R 4 ) 2 , —R 6 —C(O)OR 4 , and —R 6 —C(O)N(R 4 ) 2 ;

R 3 is cycloalkylalkyl optionally substituted with one or more substituents selected from the group consisting of alkyl, cyano, nitro, halo, haloalkyl, —R 6 —OR 4 , —R 6 —N(R 4 ) 2 , —R 6 —C(O)OR 4 , and —R 6 —C(O)N(R 4 ) 2 ;

each R 6 is a direct bond or a straight or branched alkylene chain; and

R 7 is hydrogen or aralkyl.

24. The compound of claim 23 selected from the group consisting of the following:

8-chloro-2-cyclohexylmethyl-3-(4-phenoxyphenyl)-2H-isoquinolin-1-one;

25. The compound of claim 22 wherein:

n is 0 to 4;

each R 1 is independently selected from the group consisting of alkyl, halo, haloalkyl, cyano, nitro, —R 6 —OR 4 , —R 6 —N(R 4 ) 2 , —R 6 —C(O)OR 4 , and —R 6 —C(O)N(R 4 ) 2 ;

or R 3 is heteroarylalkyl optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, —R 6 —OR 4 , —R 6 —N(R 4 ) 2 , —R 6 —C(O)OR 4 , and —R 6 —C(O)N(R 4 ) 2 ;

each R 6 is a direct bond or a straight or branched alkylene chain; and

R 7 is hydrogen or aralkyl.

26. The compound of claim 25 selected from the group consisting of:

8-chloro-3-(4-phenoxyphenyl)-2-pyridin-3-ylmethyl-2H-isoquinolin-1-one-trifluoroacetic acid salt;

8-chloro-2-(5-methyl-furan-2-ylmethyl)-3-(4-phenoxyphenyl)-2H-isoquinolin-1-one; and

8-chloro-3-(4-phenoxyphenyl)-2-thiophen-2-ylmethyl-2H-isoquinolin-1-one.

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

wherein:

n is 0 to 4;

each R 1 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, cyano, nitro, —R —OR 4 , —R 6 —N(R 4 ) 2 , —R 6 —C(O)OR 4 , —R 6 —C(O)N(R 4 ) 2 , —R 6 —N(R 4 )C(O)R 4 , —R 6 —N(R 4 )C(O)OR 5 , —R 6 —S(O) t R 4 (where t is 0 to 2), —R 6 —S(O) p N(R 4 ) 2 (where p is 1 or 2);

R 2 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—OR 4 , —R 6 —N(R 4 ) 2 , —R 6 —C(O)OR 4 , —R 6 —C(O)N(R 4 ) 2 , —R 6 —N(R 4 )C(O)R 4 , —R 6 —N(R 4 )C(O)OR 5 , —R 6 —N(S(O) t R 4 ) 2 (where t is 0 to 2), —R 6 —N(R 4 )(S(O) t R 4 ) (where t is 0 to 2), —R 6 —S(O) t R 4 (where t is 0 to 2), and —R 6 —S(O) p N(R 4 ) 2 (where p is 1 to 2);

or R 2 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, —R 6 —OR 4 , —R 6 —N(R 4 ) 2 , —R 6 —C(O)OR 4 , —R 6 —C(O)N(R 4 ) 2 , —R 6 —R 6 —N(R 4 )C(O)R 4 , —R 6 —N(R 4 )C(O)OR 5 , —R 6 —R 6 —N(S(O) t R 4 ) 2 (where t is 0 to 2), —R 6 —N(R 4 )(S(O) t R 4 ) (where t is 0 to 2), —R 6 —S(O) t R 4 (where t is 0 to 2), and —R 6 —S(O) p N(R 4 ) 2 (where p is 1 or 2);

R 3 is cycloalkylalkyl optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, cyano, nitro, halo, haloalkyl, haloalkenyl, —R 6 —OR 4 , —R 6 —N(R 4 ) 2 , —R 6 —C(O)OR 4 , —R 6 —C(O)N(R 4 ) 2 , —R 6 —N(R 4 )C(O)R 4 , —R 6 —N(R 4 )C(O)OR 5 , —R 6 —N(S(O) t R 4 ) 2 (where t is 0 to 2), —R 6 —N(R 4 ) (S(O) t R 4 ) (where t is 0 to 2), —R 6 —S(O) t R 4 (where t is 0 to 2), and —R 6 —S(O) p N(R 4 ) 2 (where p is 1 or 2);

or R 3 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, —R 6 —OR 4 , —R 6 —N(R 4 ) 2 , —R 6 —C(O)OR 4 , —R 6 —C(O)N(R 4 ) 2 , —R 6 —R 6 —N(R 4 )C(O)R 4 , —R 6 —N(R 4 )C(O)OR 5 , —R 6 —N(S(O) t R 4 ) 2 (where t is 0 to 2), —R —N(R 4 )(S(O) t R 4 ) (where t is 0 to 2), —R 6 —S(O) t R 4 (where t is 0 to 2), and —R 6 —S(O) p N(R 4 ) 2 (where p is 1 or 2);

or R 3 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, —R 6 —OR 4 , —R —N(R 4 ) 2 , —R 6 —C(O)OR 4 , —R 6 —C(O)N(R 4 ) 2 , —R 6 —N(R 4 )C(O)R 4 , —R 6 —N(R 4 )C(O)OR 5 —R 6 —N(S(O) t R 4 ) 2 (where t is 0 to 2), —R 6 —N(R 4 ) (S(O) t R 4 ) (where t is 0 to 2), —R 6 —S(O) t R 4 (where t is 0 to 2), and —R 6 —S(O) p N(R 4 ) 2 (where p is 1 or 2);

each R 5 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, and aralkyl;

each R 6 is a direct bond or a straight or branched alkylene chain; and

R 7 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 R 7 is hydrogen, n is 1, R 1 is chloro, methyl, trifluoromethyl or methoxy, and R 3 is methyl, R 2 can not be unsubstituted furanyl or thiophenyl optionally substituted by methyl;

(d) R 1 is other than —R 6 —C(O)OR 4 where R 6 is a direct bond and R 4 is alkyl of 1 to 3 carbons.

Assignments (7)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 15, 2011

From: EXELIXIS, INC.

To: EXELIXIS PATENT COMPANY LLC

Reel/Frame 026138/0390 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 20, 2007

From: X-CEPTOR THERAPEUTICS, INC.

To: EXELIXIS, INC.

Reel/Frame 019585/0598 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 11, 2005

From: YUKIO SUGIMURA, EXECUTIVE VP & REPRESENTATIVE SANKYO CO. LTD.