Specific inhibitors for vascular endothelial growth factor receptors

Abstract

The present application describes isoindoles and derivatives thereof, or pharmaceutically acceptable salt forms thereof, which are useful inhibitors of VEGFR.

1 . A method of treating cancer, comprising: administering a therapeutically effective amount of a compound of formula I or a stereoisomer or pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         ring A is selected from phenyl, pyridyl, and pyrimidyl; 
         ring A is substituted with:
 (a) 0-1 groups selected from O—C 7-20  alkyl, O—C 7-20  alkenyl, and O—C 7-20  alkynyl; 
 
       
       (b) 0-3 R groups; and,
   (c) 0-1 groups selected from methylene-dioxyl (—OCH 2 O—) and ethylene-dioxyl (—OCH 2 CH 2 O—);   
 R is selected from halogen, NO 2 , NR a R b , —CN, C 1-2  haloalkyl, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  alkoxy, CHO, C(O)C 1-6  alkyl, CO 2 —C 1-6  alkyl, C(O)NR a R b , S(O) 2 NR a R b , S(O) p —C 1-6  alkyl, phenyl, benzyl, and C 3-6  cycloalkyl; 
 L is a linear chain selected from n-propylene, n-butylene, and n-pentylene, wherein
 (a) from 0-2 of the methylene units are replaced by C═O; 
 (b) from 0-3 methylene units of L are replaced with a heteroatom selected from O, N, and S(O) p , provided that at least one methylene is present and other than an N—O or O—O bond is formed within L or at either attachment point of L; and, 
 (c) from 0-1 double bonds are present between the chain atoms of L; 
 
 L is substituted with 0-2 groups selected from C 1-4  alkyl, phenyl, benzyl, C 3-6  cycloalkyl, and NR a R b ; 
 alternatively, when L is 4-5 atoms in length, then three of the chain atoms optionally combine with a 2 atom bridge to form a 5 membered ring, the ring consisting of carbon atoms and 0-2 heteroatoms selected from O, N, and S(O) p , wherein the ring has 0-2 ring double bonds and from 0-1 atom of the 2 atom bridge is replaced by as carbonyl group; 
 alternatively, a carbon atom in ring A that is adjacent to the carbon atom to which linker L is attached can be attached to linker L through a (CH 2 ) 1-2  bridge to form a 5-6 membered ring, wherein optionally 1 methylene of the bridge is replaced by a carbonyl group; 
 R a  and R b  are independently at each occurrence selected from H and C 1-6  alkyl; 
 alternatively, NR a R b , independently at each occurrence, forms a 5-6 membered cyclic amine consisting of the shown nitrogen atom and 4-5 methylenes; 
 ring B is selected from phenyl, pyridyl, pyrimidyl, and 
 
       
         
           
           
               
               
           
         
       
       wherein the phenyl, pyridyl, and pyrimidyl rings are substituted with 1-3 R 1  groups;
 R 1  is independently selected from CO 2 H, halogen, NO 2 , NR a R b , —CN, C 1-2  haloalkyl, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  alkoxy, CHO, C(O)C 1-6  alkyl, CO 2 —C 1-6  alkyl, C(O)NR a R b , S(O) 2 NR a R b , S(O) p —C 1-6  alkyl, C 3-6  cycloalkyl, phenyl substituted with 0-2 R 2  groups, benzyl substituted with 0-2 R 2  groups, S-phenyl substituted with 0-2 R 2  groups, O-phenyl substituted with 0-2 R 2  groups, and NR a -phenyl substituted with 0-2 R 2  groups; 
 alternatively, ring B is substituted with 0-1 groups selected from methylene-dioxyl (—OCH 2 O—) and ethylene-dioxyl (—OCH 2 CH 2 O—); 
 R 2  is independently selected from CO 2 H, halogen, NH 2 , C 1-2  haloalkyl, C 1-6  alkyl, C 1-6  alkoxy, C(O)C 1-6  alkyl, and CO 2 C 1-6  alkyl; and, 
 p is independently selected from 0, 1, and 2. 
 
     
     
         2 . A method of  claim 1 , wherein:
 ring A is selected from phenyl and pyridyl;   ring A is substituted with 0-3 R groups;   ring A is substituted with 0-1 methylene-dioxyl (—OCH 2 O—);   R is selected from halogen, NO 2 , NR a R b , —CN, CF 3 , C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, C 1-4  alkoxy, CHO, C(O)C 1-4  alkyl, CO 2 —C 1-4  alkyl, C(O)NR a R b , S(O) 2 NR a R b , and S(O) p —C 1-6  alkyl;   L is a linear chain selected from n-propylene and n-butylene, wherein
 (a) from 0-1 of the methylene units are replaced by C═O; and, 
 (b) from 0-2 methylene units of L are replaced with a heteroatom selected from O and N, provided that other than an N—O or O—O bond is formed within L or at either attachment point of L; 
   L is substituted with 0-2 groups selected from C 1-4  alkyl, phenyl, and benzyl;   alternatively, when L is 4 atoms in length, then three of the chain atoms optionally combine with a 2 atom bridge to form a 5 membered ring, the ring consisting of carbon atoms and 0-2 heteroatoms selected from O, N, and S(O) p , wherein the ring has 0-1 ring double bonds;   alternatively, a carbon atom in ring A that is adjacent to the carbon atom to which linker L is attached can be attached to linker L through a (CH 2 ) 1-2  bridge to form a 5-6 membered ring, wherein optionally 1 methylene of the bridge is replaced by a carbonyl group;   R a  and R b  are independently at each occurrence selected from H and C 1-6  alkyl;   ring B is   
       
         
           
           
               
               
           
         
         p is independently selected from 0, 1, and 2. 
       
     
     
         3 . The method of  claim 2 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         4 . The method of  claim 3 , wherein the cancer is selected from: breast, colorectal, lung, prostate, and ovarian. 
     
     
         5 . A method of  claim 1 , wherein:
 ring A is selected from phenyl and pyridyl;   ring A is substituted with 1 group selected from O—C 7-20  alkyl, O—C 7-20  alkenyl, and O—C 7-20  alkynyl;   ring A is substituted with 0-1 R groups;   R is selected from halogen, CF 3 , C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, C(O)C 1-4  alkyl, and CO 2 —C 1-4  alkyl;   L is a linear chain selected from n-propylene, n-butylene, and n-pentylene, wherein
 (a) from 0-2 of the methylene units are replaced by C═O; 
 (b) from 0-3 methylene units of L are replaced with a heteroatom selected from O, N, and S(O) p , provided that at least one methylene is present; and, 
 (c) from 0-1 double bonds are present between the chain atoms of L; 
   L is substituted with 0-2 groups selected from C 1-4  alkyl, C 3-6  cycloalkyl, and NR a R b ;   R a  and R b  are independently at each occurrence selected from H and C 1-6  alkyl;   alternatively, independently at each occurrence, NR a R b  forms a 5-6 membered cyclic amine consisting of the shown nitrogen atom and 4-5 methylenes;   ring B is selected from phenyl and pyridyl, wherein the phenyl and pyridyl rings are substituted with 1-2 R 1  groups;   R 1  is independently selected from CO 2 H, halogen, NR a R b , CF 3 , C 1-4  alkyl, C 1-6  alkoxy, C 3-6  cycloalkyl, S-phenyl substituted with 0-2 R 2  groups, 0-phenyl substituted with 0-2 R 2  groups, and NR a -phenyl substituted with 0-2 R 2  groups;   R 2  is independently selected from CO 2 H, halogen, CF 3 , C 1-4  alkyl, and C 1-4  alkoxy;   p is independently selected from 0, 1, and 2.   
     
     
         6 . The method of  claim 5 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         7 . The method of  claim 6 , wherein the cancer is selected from: breast, colorectal, lung, prostate, and ovarian. 
     
     
         8 . A compound of formula I or a stereoisomer or pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         ring A is selected from phenyl, pyridyl, and pyrimidyl; 
         ring A is substituted with 0-1 groups selected from O—C 7-20  alkyl, O—C 7-20  alkenyl, and O—C 7-20  alkynyl; 
         ring A is substituted with 0-3 groups selected from halogen, NO 2 , NR a R b , —CN, C 1-2  haloalkyl, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  alkoxy, CHO, C(O)C 1-6  alkyl, CO 2 —C 1-6  alkyl, C(O)NR a R b , S(O) 2 NR a R b , S(O) p —C 1-6  alkyl, phenyl, benzyl, and C 3-6  cycloalkyl; 
         ring A is substituted with 0-1 groups selected from methylene-dioxyl (—OCH 2 O—) and ethylene-dioxyl (—OCH 2 CH 2 O—); 
         L is a linear chain selected from n-propylene, n-butylene, and n-pentylene, wherein
 (a) from 0-2 of the methylene units are replaced by C═O; 
 (b) from 0-3 methylene units of L are replaced with a heteroatom selected from O, N, and S(O) p , provided that at least one methylene is present and other than an N—O or O—O bond is formed within L or at either attachment point of L; and, 
 (c) from 0-1 double bonds are present between the chain atoms of L; 
 
         L is substituted with 0-2 groups selected from C 1-4  alkyl, phenyl, benzyl, C 3-6  cycloalkyl, and NR a R b ; 
         alternatively, when L is 4-5 atoms in length, then three of the chain atoms optionally combine with a 2 atom bridge to form a 5 membered ring, the ring consisting of carbon atoms and 0-2 heteroatoms selected from O, N, and S(O) p , wherein the ring has 0-2 ring double bonds and from 0-1 atom of the 2 atom bridge is replaced by as carbonyl group; 
         alternatively, a carbon atom in ring A that is adjacent to the carbon atom to which linker L is attached can be attached to linker L through a (CH 2 ) 1-2  bridge to form a 5-6 membered ring, wherein optionally 1 methylene of the bridge is replaced by a carbonyl group; 
         R a  and R b  are independently at each occurrence selected from H and C 1-6  alkyl; 
         alternatively, independently at each occurrence, NR a R b  forms a 5-6 membered cyclic amine consisting of the shown nitrogen atom and 4-5 methylenes; 
         ring B is selected from phenyl, pyridyl, pyrimidyl, and 
       
       
         
           
           
               
               
           
         
       
       wherein the phenyl, pyridyl, and pyrimidyl rings are substituted with 1-3 R groups;
 R is independently selected from CO 2 H, halogen, NO 2 , NR a R b , —CN, C 1-2  haloalkyl, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  alkoxy, CHO, C(O)C 1-6  alkyl, CO 2 —C 1-6  alkyl, C(O)NR a R b , S(O) 2 NR a R b , S(O) p —C 1-6  alkyl, C 3-6  cycloalkyl, phenyl substituted with 0-2 R 1  groups, benzyl substituted with 0-2 R 1  groups, S-phenyl substituted with 0-2 R 1  groups, O-phenyl substituted with 0-2 R 1  groups, and NR a -phenyl substituted with 0-2 R 1  groups; 
 alternatively, ring B is substituted with 0-1 groups selected from methylene-dioxyl (—OCH 2 O—) and ethylene-dioxyl (—OCH 2 CH 2 O—); 
 R 1  is independently selected from CO 2 H, halogen, NH 2 , C 1-2  haloalkyl, C 1-6  alkyl, C 1-6  alkoxy, C(O)C 1-6  alkyl, and CO 2 C 1-6  alkyl; and, 
 p is independently selected from 0, 1, and 2; 
 provided that the compound of formula I is other than one of the following compounds: 
 
       
         
           
           
               
               
           
         
       
     
     
         9 . A compound of  claim 8 , wherein the compound is selected from Table 2 or a stereoisomer or pharmaceutically acceptable salt thereof. 
     
     
         10 . A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of  claim 8  or a pharmaceutically acceptable salt form thereof. 
     
     
         11 . A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of  claim 9  or a pharmaceutically acceptable salt form thereof.