Substituted dihydroisoquinolinone compounds

Abstract

This invention relates to compounds of general formula (I) in which R 1 , R 2 , R 3 , R 4 , L, X and Z are as defined herein, and the pharmaceutically acceptable salts thereof, to pharmaceutical compositions comprising such compounds and salts, and to methods of using such compounds, salts and compositions for the treatment of abnormal cell growth, including cancer.

We claim: 
     
         1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         R 1  is selected from the group consisting of H, F, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, C(O)R 5 , C 3 -C 8  cycloalkyl, 3-12 membered heterocyclyl and 5-12 membered heteroaryl, where each said C 1 -C 4  alkyl or C 1 -C 4  alkoxy is optionally substituted by one or more R 6 , and each said C 3 -C 8  cycloalkyl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl is optionally substituted by one or more R 7 ; 
         R 2  is H, F or C 1 -C 4  alkyl; 
         L is a bond or a C 1 -C 4  alkylene; 
         R 3  is selected from the group consisting of C 1 -C 4  alkyl, C 1 -C 4  alkoxy, OH, CN, C(O)R 8 , COOR 9 , NR 10 R 11 , OR 12 , C 3 -C 8  cycloalkyl, 3-12 membered heterocyclyl and 5-12 membered heteroaryl, where each said C 1 -C 4  alkyl or C 1 -C 4  alkoxy is optionally substituted by one or more R 6 , and each said C 3 -C 8  cycloalkyl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl is optionally substituted by one or more R 7 ; 
         R 4  is H, halo or C 1 -C 4  alkyl, where each said C 1 -C 4  alkyl is optionally substituted by one or more R 6 ; 
         R 5  is C 1 -C 4  alkyl, where each said C 1 -C 4  alkyl is optionally substituted by one or more R 14 ; 
         each R 6  is independently OH, F, CN or C 1 -C 4  alkoxy; 
         each R 7  is independently C 1 -C 4  alkyl, OH, F, CN, C 1 -C 4  alkoxy, ═O, CHO, C(O)R 13 , SO 2 R 13  or 3-6 membered heterocyclyl; 
         R 8  is C 1 -C 4  alkyl, where each said C 1 -C 4  alkyl is optionally substituted by one or more R 14 ; 
         R 9  is H or C 1 -C 4  alkyl, where each said C 1 -C 4  alkyl is optionally substituted by one or more R 14 ; 
         R 10  and R 11  are independently H or C 1 -C 4  alkyl, where each said C 1 -C 4  alkyl is optionally substituted by one or more R 14 ; 
         R 12  is selected from the group consisting of C 3 -C 8  cycloalkyl, 3-12 membered heterocyclyl and 5-12 membered heteroaryl, where each said C 3 -C 8  cycloalkyl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl is optionally substituted by one or more R 7 ; 
         each R 13  is independently C 1 -C 4  alkyl, where each said C 1 -C 4  alkyl is optionally substituted by one or more R 15 ; 
         each R 14  and R 15  is independently OH, F, CN or C 1 -C 4  alkoxy; and 
         X and Z are independently C 1 -C 4  alkyl, C 1 -C 4  fluoroalkyl, C 1 -C 4  alkoxy or C 1 -C 4  fluoroalkoxy. 
       
     
     
         2 . The compound or salt of  claim 1 , wherein R 2  is H. 
     
     
         3 . The compound or salt of  claim 1 , wherein R 4  is Cl, F, Br or CH 3 . 
     
     
         4 . The compound or salt of  claim 1 , wherein X is CH 3 , OCH 3  or OCHF 2  and Z is CH 3 . 
     
     
         5 . The compound or salt of  claim 1 , wherein R 1  is C 1 -C 4  alkoxy optionally substituted by one or more R 6 . 
     
     
         6 . The compound or salt of  claim 5 , wherein said C 1 -C 4  alkoxy is OCH 3 . 
     
     
         7 . The compound or salt of  claim 1 , wherein R 1  is C 1 -C 4  alkyl optionally substituted by one or more R 6 . 
     
     
         8 . The compound or salt of  claim 1 , wherein L is a bond and R 3  is 3-12 membered heterocyclyl optionally substituted by one or more R 7 . 
     
     
         9 . The compound or salt of  claim 8 , wherein said 3-12 membered heterocyclyl is selected from the group consisting of oxetanyl, tetrahydrofuranyl and tetrahydropyranyl, each optionally substituted by one or more R 7 . 
     
     
         10 . A compound of Formula (I-A): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 1  is C 1 -C 4  alkoxy; 
         R 2  is H; 
         L is a bond; 
         R 3  is 3-12 membered heterocyclyl, optionally substituted by one or more R 7 ; 
         R 4  is H or Cl; 
         each R 7  is independently C 1 -C 4  alkyl, OH, F, CN, C 1 -C 4  alkoxy, ═O, CHO, C(O)R 13 , SO 2 R 13  or 3-6 membered heterocyclyl; 
         each R 13  is independently C 1 -C 4  alkyl, where each said C 1 -C 4  alkyl is optionally substituted by one or more R 15 ; 
         each R 15  is independently OH, F, CN or C 1 -C 4  alkoxy; and 
         X and Z are independently C 1 -C 4  alkyl, C 1 -C 4  fluoroalkyl, C 1 -C 4  alkoxy or C 1 -C 4  fluoroalkoxy. 
       
     
     
         11 . The compound or salt of  claim 10 , wherein R 3  is 3-12 membered heterocyclyl selected from the group consisting of oxetanyl, tetrahydrofuranyl and tetrahydropyranyl, each optionally substituted by one or more R 7 . 
     
     
         12 . A compound that is 5,8-dichloro-2-[(4-methoxy-6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)methyl]-7-[(R)-methoxy(oxetan-3-yl)methyl]-3,4-dihydroisoquinolin-(2H)-one. 
     
     
         13 . A compound of formula (III): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         R 1  and R 3  are taken together to form a 3-12 membered heterocyclyl optionally substituted by one or more R 7 ; 
         R 2  is H, F or C 1 -C 4  alkyl; 
         R 4  is H, halo or C 1 -C 4  alkyl, where each said C 1 -C 4  alkyl is optionally substituted by one or more R 6 ; 
         each R 6  is independently OH, F, CN or C 1 -C 4  alkoxy; 
         each R 7  is independently C 1 -C 4  alkyl, OH, F, CN, C 1 -C 4  alkoxy, ═O, CHO, C(O)R 13 , SO 2 R 13  or 3-6 membered heterocyclyl; 
         each R 13  is independently C 1 -C 4  alkyl, where each said C 1 -C 4  alkyl is optionally substituted by one or more R 15 ; 
         each R 15  is independently OH, F, CN or C 1 -C 4  alkoxy; and 
         X and Z are independently C 1 -C 4  alkyl, C 1 -C 4  fluoroalkyl, C 1 -C 4  alkoxy or C 1 -C 4  fluoroalkoxy. 
       
     
     
         14 . The compound or salt of  claim 13 , wherein R 1  and R 3  are taken together to form a 3-12 membered heterocyclyl selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl and homopiperidinyl, each optionally substituted by one or more R 7 . 
     
     
         15 . The compound or salt of  claim 14 , wherein R 7  is CHO, C(O)R 13  or SO 2 R 13  and each R 13  is independently C 1 -C 4  alkyl optionally substituted by one or more R 15 . 
     
     
         16 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. 
     
     
         17 . A pharmaceutical composition comprising the compound of  claim 12  and a pharmaceutically acceptable carrier or excipient. 
     
     
         18 . A pharmaceutical composition comprising a compound of  claim 13 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. 
     
     
         19 . A method for the treatment of abnormal cell growth in a subject, comprising administering to the subject a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         20 . A method for the treatment of abnormal cell growth in a subject, comprising administering to the subject a therapeutically effective amount of a compound of  claim 13 , or a pharmaceutically acceptable salt thereof.