Bromodomain Inhibitors

Abstract

The present invention provides for compounds of formula (I) wherein R 1 , R 2 , R 3 , R 4 , R 6 , X 1 , and X 2 have any of the values defined in the specification, and pharmaceutically acceptable salts thereof, that are useful as agents in the treatment of diseases and conditions, including inflammatory diseases, cancer, and AIDS. Also provided are pharmaceutical compositions comprising compounds of formula (I).

1 . A compound of formula (I) or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is hydrogen, CD 2 CD 3 , C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, a C 3 -C 6  cycloalkyl, a phenyl, or a 5-6 membered monocyclic heteroaryl; wherein the C 3 -C 6  cycloalkyl, the phenyl, and the 5-6 membered monocyclic heteroaryl are each optionally substituted with 1, 2, 3, or 4 independently selected R x  groups; 
         R 2  is G 2a , C 1 -C 6  haloalkyl, or C 1 -C 6  alkyl wherein the C 1 -C 6  alkyl is optionally substituted with one substituent selected from the group consisting of G 2b  and —OH;
 G 2a  is a phenyl or a C 3 -C 6  monocyclic cycloalkyl; wherein each G 2a  is optionally substituted with 1, 2, 3, or 4 independently selected R x  groups; 
 G 2b  is phenyl optionally substituted with 1, 2, 3, or 4 independently selected R x  groups; 
 
         R 3  is C 1 -C 6  haloalkyl, C 1 -C 6  alkyl, or a C 3 -C 6  monocyclic cycloalkyl wherein the C 3 -C 6  monocyclic cycloalkyl is optionally substituted with 1, 2, 3, or 4 independently selected R x  groups; or 
         R 2  and R 3 , together with the carbon atom to which they are attached, form a C 3 -C 6  monocyclic cycloalkyl, a C 4 -C 6  monocyclic cycloalkenyl, or a 4-6 membered monocyclic heterocycle; wherein the C 3 -C 6  monocyclic cycloalkyl, the C 4 -C 6  monocyclic cycloalkenyl, and the 4-6 membered monocyclic heterocycle are each optionally substituted with 1, 2, 3, or 4 independently selected R x  groups; 
         R 4  is phenyl, pyridinyl, a C 3 -C 6  monocyclic cycloalkyl, or a C 4 -C 6  monocyclic cycloalkenyl; wherein each R 4  is optionally substituted with 1, 2, 3, or 4 independently selected R y  groups; or 
         R 4  is formula (a) 
       
       
         
           
           
               
               
           
         
         
           R 4a  and R 4b  are each independently halogen, C 4 -C 6  alkyl, or C 1 -C 6  haloalkyl; 
           R 4c  and R 4d  are each independently hydrogen, halogen, —CN, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, —S(C 1 -C 6  alkyl), —S(O) 2 (C 1 -C 6  alkyl), or —(C 1 -C 6  alkylenyl)-OH; 
           Y is C(R 4e ) or N; wherein R 4e  is hydrogen, halogen, —CN, C 1 -C 6  alkyl, or C 1 -C 6  haloalkyl; 
         
         R x , at each occurrence, is independently halogen, C 1 -C 6  alkyl, or C 1 -C 6  haloalkyl; 
         R y , at each occurrence, is independently halogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, —O(C 1 -C 6  alkyl), —O(C 1 -C 6  haloalkyl), or —(C 1 -C 6  alkylenyl)-OH; 
         X 1  and X 2  are C(R 5 ); or 
         one of X 1  and X 2  is N and the other is C(R 5 ); 
         R 5 , at each occurrence, is independently hydrogen or halogen; and 
         R 6  is hydrogen, halogen, —CN, C 1 -C 6  haloalkyl, or C 1 -C 6  alkyl. 
       
     
     
         2 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof, wherein
 R 1  is CD 2 CD 3 , C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, or a C 3 -C 6  cycloalkyl; wherein the C 3 -C 6  cycloalkyl is optionally substituted with 1, 2, 3, or 4 independently selected R x  groups. 
 
     
     
         3 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof, wherein
 R 2  is phenyl, cyclopropyl, cyclopentyl, C 4 -C 6  haloalkyl, or C 1 -C 6  alkyl wherein the C 1 -C 6  alkyl is optionally substituted with one substituent selected from the group consisting of G 2b  and —OH; and wherein the phenyl, the cyclopropyl, and the cyclopentyl are each optionally substituted with 1, 2, 3, or 4 independently selected R x  groups; and 
 R 3  is C 1 -C 6  haloalkyl, C 1 -C 6  alkyl, or a cyclopropyl wherein the cyclopropyl is optionally substituted with 1, 2, 3, or 4 independently selected R x  groups. 
 
     
     
         4 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof, wherein
 R 2  and R 3 , together with the carbon atom to which they are attached, form a C 3 -C 6  monocyclic cycloalkyl, a C 4 -C 6  monocyclic cycloalkenyl, or a 4-6 membered monocyclic heterocycle; wherein the C 3 -C 6  monocyclic cycloalkyl, the C 4 -C 6  monocyclic cycloalkenyl, and the 4-6 membered monocyclic heterocycle are each optionally substituted with 1, 2, 3, or 4 independently selected R x  groups. 
 
     
     
         5 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof, wherein
 R 4  is phenyl, pyridinyl, a C 3 -C 6  monocyclic cycloalkyl, or a C 4 -C 6  monocyclic cycloalkenyl; wherein each R 4  is optionally substituted with 1, 2, 3, or 4 independently selected R y  groups. 
 
     
     
         6 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof, wherein
 R 4  is formula (a) 
 
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound of  claim 6  or a pharmaceutically acceptable salt thereof, wherein
 R 4a  is halogen, C 1 -C 6  alkyl, or C 1 -C 6  haloalkyl; 
 R 4b  is halogen or C 1 -C 6  alkyl; 
 R 4d  is hydrogen or halogen; and 
 Y is C(R 4e ) or N; wherein R 4e  is hydrogen. 
 
     
     
         8 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof, wherein
 X 1  is N or C(R 5 ); 
 X 2  is C(R 5 ); and 
 R 5  is hydrogen. 
 
     
     
         9 . The compound of  claim 8  or a pharmaceutically acceptable salt thereof, wherein
 R 2  and R 3 , together with the carbon atom to which they are attached, form a C 3 -C 6  monocyclic cycloalkyl, a C 4 -C 6  monocyclic cycloalkenyl, or a 4-6 membered monocyclic heterocycle; wherein the C 3 -C 6  monocyclic cycloalkyl, the C 4 -C 6  monocyclic cycloalkenyl, and the 4-6 membered monocyclic heterocycle are each optionally substituted with 1, 2, 3, or 4 independently selected R x  groups. 
 
     
     
         10 . The compound of  claim 9  or a pharmaceutically acceptable salt thereof, wherein
 R 4  is formula (a); wherein
 R 4a  is halogen, C 4 -C 6  alkyl, or C 1 -C 6  haloalkyl; 
 R 4b  is halogen or C 1 -C 6  alkyl; 
 R 4d  is hydrogen or halogen; and 
 Y is C(R 4e ) or N; wherein R 4e  is hydrogen; and 
 
 R 6  is hydrogen or halogen. 
 
     
     
         11 . The compound of  claim 8  or a pharmaceutically acceptable salt thereof, wherein
 R 2  is phenyl, cyclopropyl, cyclopentyl, C 1 -C 6  haloalkyl, or C 1 -C 6  alkyl wherein the C 1 -C 6  alkyl is optionally substituted with one substituent selected from the group consisting of G 2b  and —OH; and wherein the phenyl, the cyclopropyl, and the cyclopentyl are each optionally substituted with 1, 2, 3, or 4 independently selected R x  groups; and 
 R 3  is C 1 -C 6  haloalkyl, C 1 -C 6  alkyl, or a cyclopropyl wherein the cyclopropyl is optionally substituted with 1, 2, 3, or 4 independently selected R x  groups. 
 
     
     
         12 . The compound of  claim 11  or a pharmaceutically acceptable salt thereof, wherein
 R 4  is phenyl, pyridinyl, a C 3 -C 6  monocyclic cycloalkyl, or a C 4 -C 6  monocyclic cycloalkenyl; wherein each R 4  is optionally substituted with 1, 2, 3, or 4 independently selected R y  groups; and 
 R 6  is hydrogen. 
 
     
     
         13 . The compound of  claim 12  or a pharmaceutically acceptable salt thereof, wherein
 X 1  is C(R 5 ); 
 X 2  is C(R 5 ); 
 R 5  is hydrogen; and 
 R 1 , R 2 , and R 3  are C 1 -C 6  alkyl. 
 
     
     
         14 . The compound of  claim 11  or a pharmaceutically acceptable salt thereof, wherein
 R 4  is formula (a); and 
 R 6  is hydrogen or halogen. 
 
     
     
         15 . The compound of  claim 14  or a pharmaceutically acceptable salt thereof, wherein
 R 4a  is halogen, C 1 -C 6  alkyl, or C 1 -C 6  haloalkyl; 
 R 4b  is halogen or C 1 -C 6  alkyl; 
 R 4d  is hydrogen or halogen; and 
 Y is C(R 4e ) or N; wherein R 4e  is hydrogen. 
 
     
     
         16 . The compound of  claim 14  or a pharmaceutically acceptable salt thereof, wherein
 R 4a  is C 1 -C 3  alkyl; 
 R 4b  is C 1 -C 3  alkyl; 
 R 4c  is hydrogen or halogen; 
 R 4d  is hydrogen; and 
 Y is C(R 4e ) or N wherein R 4e  is hydrogen. 
 
     
     
         17 . The compound of  claim 16  or a pharmaceutically acceptable salt thereof, wherein
 R 2  is C 1 -C 6  haloalkyl or C 1 -C 6  alkyl wherein the C 1 -C 6  alkyl is optionally substituted with one —OH; and 
 R 3  is C 1 -C 6  haloalkyl or C 1 -C 6  alkyl. 
 
     
     
         18 . The compound of  claim 16  or a pharmaceutically acceptable salt thereof, wherein
 R 1 , R 2 , and R 3  are C 1 -C 6  alkyl; and 
 Y is C(R 4e ) wherein R 4e  is hydrogen. 
 
     
     
         19 . The compound of  claim 18  or a pharmaceutically acceptable salt thereof, wherein
 X 1  is C(R 5 ); 
 X 2  is C(R 5 ); and 
 R 5  is hydrogen. 
 
     
     
         20 - 37 . (canceled) 
     
     
         38 . A method for treating cancer in a subject comprising administering a therapeutically effective amount of a compound of formula (I) according to  claim 1  or a pharmaceutically acceptable salt thereof, to a subject in need thereof. 
     
     
         39 . A method of treating a chronic kidney disease or condition in a subject comprising administering a therapeutically effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein said chronic kidney disease or condition is selected from the group consisting of: diabetic nephropathy, hypertensive nephropathy, HIV-associated nephropathy, glomerulonephritis, lupus nephritis, IgA nephropathy, focal segmental glomerulosclerosis, membranous glomerulonephritis, minimal change disease, polycystic kidney disease and tubular interstitial nephritis. 
     
     
         40 . A process for preparing compounds of formula (A), wherein the process comprises bromination of compounds of formula (B) 
       
         
           
           
               
               
           
         
         wherein 
         PG 1  is a nitrogen protecting group; and 
         R 105  is C 4 -C 6  alkyl.