Arylmethoxy isoindoline derivatives and compositions comprising and methods of using the same

Abstract

Provided are 4′-arylmethoxy isoindoline compounds, and pharmaceutically acceptable salts, solvates, clathrates, stereoisomers, and prodrugs thereof. Methods of use, and pharmaceutical compositions of these compounds are disclosed.

What is claimed is: 
     
         1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: 
         X is C═O or CH 2 ; 
         R 1  is —Y—R 3 ; 
         R 2  is H or (C 1 -C 6 )alkyl; 
         Y is: 6 to 10 membered aryl, heteroaryl or heterocycle, each of which may be optionally substituted with one or more halogen; or a bond; 
         R 3  is: —(CH 2 ) n -aryl, —O—(CH 2 ) n -aryl or —(CH 2 ) n —O-aryl, wherein the aryl is optionally substituted with one or more: (C 1 -C 6 )alkyl, itself optionally substituted with one or more halogen; (C 1 -C 6 )alkoxy, itself substituted with one or more halogen; oxo; amino; carboxyl; cyano; hydroxyl; halogen; deuterium; 6 to 10 membered aryl or heteroaryl, optionally substituted with one or more (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or halogen; —CONH 2 ; or —COO—(C 1 -C 6 )alkyl, wherein the alkyl may be optionally substituted with one or more halogen;
 —(CH 2 ) n -heterocycle, —O—(CH 2 ) n -heterocycle or —(CH 2 ) n —O-heterocycle, wherein the heterocycle is optionally substituted with one or more: (C 1 -C 6 )alkyl, itself optionally substituted with one or more halogen; (C 1 -C 6 )alkoxy, itself substituted with one or more halogen; oxo; amino; carboxyl; cyano; hydroxyl; halogen; deuterium; 6 to 10 membered aryl or heteroaryl, optionally substituted with one or more (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or halogen; —CONH 2 ; or —COO—(C 1 -C 6 )alkyl, wherein the alkyl may be optionally substituted with one or more halogen; or 
 —(CH 2 ) n -heteroaryl, —O—(CH 2 ) n -heteroaryl or —(CH 2 ) n —O-heteroaryl, wherein the heteroaryl is optionally substituted with one or more: (C 1 -C 6 )alkyl, itself optionally substituted with one or more halogen; (C 1 -C 6 )alkoxy, itself substituted with one or more halogen; oxo; amino; carboxyl; cyano; hydroxyl; halogen; deuterium; 6 to 10 membered aryl or heteroaryl, optionally substituted with one or more (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or halogen; —CONH 2 ; or —COO—(C 1 -C 6 )alkyl, wherein the alkyl may be optionally substituted with one or more halogen; and 
 
         n is 0, 1, 2 or 3. 
       
     
     
         2 . The compound of  claim 1 , wherein X is CH 2 . 
     
     
         3 . The compound of  claim 1 , wherein Y is phenyl, and R 3  is —(CH 2 ) n -heterocycle. 
     
     
         4 . The compound of  claim 1 , wherein Y is heteroaryl, and R 3  is —(CH 2 ) n -heterocycle. 
     
     
         5 . The compound of  claim 1 , wherein Y is a bond. 
     
     
         6 . The compound of  claim 1 , wherein Y is a bond, and R 3  is —(CH 2 ) n -heterocycle or —(CH 2 ) n -heteroaryl. 
     
     
         7 . The compound of  claim 1 , which is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. 
     
     
         8 . A compound of formula (II): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: 
         R 4  is unsubstituted 9 to 10 membered bicyclic ring is benzothiazole, quinoline, isoquinoline, naphthalene, 2,3-dihydro-1H-indene, benzo[d][1,2,3]triazole, imidazo[1,2-a]pyridine, benzofuran, 2,3-dihydrobenzofuran, benzothiophene, benzo[d]oxazole isoindoline or chroman; 
         with the proviso that if the bicyclic ring is benzofuran or benzothiophene, then the ring is not connected to the isoindole ring through the 2-position. 
       
     
     
         9 . The compound of  claim 8 , which is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. 
     
     
         10 . A compound of formula (III): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: 
         X is CH 2  or C═O; 
         R 5 , R 6  and R 7  are each independently hydrogen, halogen, nitro, carbamoyl, amino, —SO 2 R 8 , —CONR 9 R 10 , —(C 1 -C 6 )alkyl or —(C 1 -C 6 )alkoxy, said alkyl or alkoxy may be optionally substituted with one or more halogen, amino, hydroxyl, or NR 9 R 10 ; 
         R 8  is: (C 1 -C 6 )alkyl, optionally substituted with (C 1 -C 6 )alkyl or (C 6 -C 10 )aryl; amino, optionally substituted with (C 1 -C 6 )alkyl or (C 6 -C 10 )aryl; or 6 to 10 membered heterocycle, optionally substituted with (C 1 -C 6 )alkyl or (C 6 -C 10 )aryl; 
         R 9  and R 10  are each independently hydrogen, 6 to 10 membered aryl, —COO—(C 1 -C 6 )alkyl, —(C 0 -C 6 )alkyl-CHO, —(C 0 -C 6 )alkyl-COOH, —(C 0 -C 6 )alkyl-NR 9′ R 10′ , —(C 0 -C 6 )alkyl-(5 to 10 membered heterocycle), —(C 1 -C 6 )alkyl-OH, —(C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, or (C 3 -C 6 )cycloalkyl; or 
         R 9  and R 10  together may form an optionally substituted 5 to 6 membered ring containing one or more heteroatoms; and 
         R 9′  and R 10′  are each independently hydrogen or (C 1 -C 6 )alkyl; 
         with the proviso that all of R 5 -R 7  cannot be hydrogen; and 
         with the proviso that if one of R 5 -R 7  is hydrogen and the remaining two of R 5 -R 7  are both chloride, then the two chloride atoms cannot be on 3 and 4 position of the phenyl ring. 
       
     
     
         11 . The compound of  claim 10 , wherein one of R 5 -R 7  is hydrogen, and the remaining two of R 5 -R 7  are each independently halogen, (C 1 -C 6 )alkoxy or (C 1 -C 6 )alkyl. 
     
     
         12 . The compound of  claim 10 , wherein two of R 5 -R 7  are hydrogen and the remaining one of R 5 -R 7  is halogen, (C 1 -C 6 )alkoxy or (C 1 -C 6 )alkyl. 
     
     
         13 . The compound of  claim 10 , which is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. 
     
     
         14 . A compound of formula (IV): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: 
         X is Nor C; 
         Y is CH 2  or C═O; 
         R 11  and R 12  are each independently hydrogen, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-(C 3 -C 6 )cycloalkyl, —(C 1 -C 6 )alkoxy, —(C 6 -C 10 )aryl, —CO(C 1 -C 6 )alkyl, —CO(C 3 -C 6 )cycloalkyl, —CO(C 6 -C 10 )aryl, —COO(C 1 -C 6 )alkyl, halogen, hydroxyl, oxo, 3 to 10 membered heterocycle, 6 to 10 membered heteroaryl, —NHCO(C 1 -C 6 )alkyl, —(CH 2 ) n -phenyl, —SO 2 (C 1 -C 6 )alkyl, —SO 2 (C 3 -C 6 )cycloalkyl, —SO 2 (C 6 -C 10 )aryl or —NR 14 R 15 , wherein the alkyl, aryl or heteroaryl portion of each of the groups may be optionally substituted with one or more halogen, hydroxyl or —(C 1 -C 6 )alkoxy; 
         R 13  is hydrogen or —(C 1 -C 6 )alkyl; 
         R 14  and R 15  are each independently hydrogen or —(C 1 -C 6 )alkyl; and 
         n is 0, 1, 2 or 3. 
       
     
     
         15 . The compound of  claim 14 , wherein X is N. 
     
     
         16 . The compound of  claim 14 , wherein Y is CH 2 . 
     
     
         17 . The compound of  claim 14 , which is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. 
     
     
         18 . A compound, which is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       pharmaceutically acceptable salt, solvate, or stereoisomer thereof. 
     
     
         19 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. 
     
     
         20 . A pharmaceutical composition comprising a compound of  claim 8 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. 
     
     
         21 . A pharmaceutical composition comprising a compound of  claim 18 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. 
     
     
         22 . A pharmaceutical composition comprising a compound of  claim 14 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. 
     
     
         23 . A pharmaceutical composition comprising a compound of  claim 18 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.