Compositions and methods for treating neoplasia, inflammatory disease and other disorders

Abstract

The invention features compositions and methods for treating or preventing a neoplasia. More specifically, the invention provides compositions and methods for disrupting the interaction of a BET family polypeptide comprising a bromodomain with chromatin (e.g., disrupting a bromodomain interaction with an acetyl-lysine modification present on a histone N-terminal tail).

What is claimed is: 
     
         1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
       
       wherein
 X is N or CR 5 ;
 R 5  is H, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted; 
 R B  is H, alkyl, hydroxylalkyl, aminoalkyl, alkoxyalkyl, haloalkyl, hydroxy, alkoxy, or —COO—R 3 , each of which is optionally substituted; 
 
 ring A is aryl or heteroaryl;
 each R A  is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted; or any two R A  together with the atoms to which each is attached, can form a fused aryl or heteroaryl group; 
 
 R is alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of which is optionally substituted; 
 R 1  is —(CH 2 ) n -L, in which n is 0-3 and L is —COO—R 3 , —CO—R 3 , —CO—N(R 3 R 4 ), —S(O) 2 —R 3 , —S(O) 2 —N(R 3 R 4 ), N(R 3 R 4 ), N(R 4 )C(O)R 3 , optionally substituted aryl, or optionally substituted heteroaryl; 
 R 2  is H, D (deuterium), halogen, or optionally substituted alkyl; 
 each R 3  is independently selected from the group consisting of:
 (i) H, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; 
 (ii) heterocycloalkyl or substituted heterocycloalkyl; 
 (iii) —C 1 -C 8  alkyl, —C 2 -C 8  alkenyl or —C 2 -C 8  alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; —C 3 -C 12  cycloalkyl, substituted —C 3 -C 12  cycloalkyl, —C 3 -C 12  cycloalkenyl, or substituted —C 3 -C 12  cycloalkenyl, each of which may be optionally substituted; and 
 (iv) NH 2 , N═CR 4 R 6 ; 
 each R 4  is independently H, alkyl, al cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted; 
 or R 3  and R 4  are taken together with the nitrogen atom to which they are attached to form a 4-10-membered ring; 
 R 6  is alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted; or R 4  and R 6  are taken together with the carbon atom to which they are attached to form a 4-10-membered ring; 
 
 m is 0, 1, 2, or 3; 
 provided that
 (a) if ring A is thienyl, X is N, R is phenyl or substituted phenyl, R 2  is H, R B  is methyl, and R 1  is —(CH 2 ) n -L, in which n is 1 and L is —CO—N(R 3 R 4 ), then R 3  and R 4  are not taken together with the nitrogen atom to which they are attached to form a morpholino ring; 
 (b) if ring A is thienyl, X is N, R is substituted phenyl, R 2  is H, R B  is methyl, and R 1  is —(CH 2 ) n -L, in which n is 1 and L is —CO—N(R 3 R 4 ), and one of R 3  and R 4  is H, then the other of R 3  and R 4  is not methyl, hydroxyethyl, alkoxy, phenyl, substituted phenyl, pyridyl or substituted pyridyl; and 
 (c) if ring A is thienyl, X is N, R is substituted phenyl, R 2  is H, R B  is methyl, and R 1  is —(CH 2 ) n -L, in which n is 1 and L is —COO—R 3 , then R 3  is not methyl or ethyl; 
 or a salt, solvate or hydrate thereof. 
 
 
     
     
         2 - 94 . (canceled) 
     
     
         95 . The compound of  claim 1 , wherein the compound is a compound of formula IV: 
       
         
           
           
               
               
           
         
         wherein 
         X is N or CR 5 ;
 R 5  is H, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted; 
 R B  is H, alkyl, hydroxylalkyl, aminoalkyl, alkoxyalkyl, haloalkyl, hydroxy, alkoxy, or —COO—R 3 , each of which is optionally substituted; 
 
         ring A is aryl or heteroaryl;
 each R A  is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted; or any two R A  together with the atoms to which each is attached, can form a fused aryl or heteroaryl group; 
 
         R 1  is —(CH 2 ) n -L, in which n is 0-2 and L is —COO—R 3 , —CO—R 3 , —CO—N(R 3 R 4 ), —S(O) 2 —R 3 , —S(O) 2 —N(R 3 R 4 ), N(R 3 R 4 ), N(R 4 )C(O)R 3 , optionally substituted aryl, or optionally substituted heteroaryl; 
         R 2  is H, D, halogen, or optionally substituted alkyl; 
         each R 3  is independently selected from the group consisting of:
 (i) H, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; 
 (ii) heterocycloalkyl or substituted heterocycloalkyl; 
 (iii) —C 1 -C 8  alkyl, —C 2 -C 8  alkenyl or —C 2 -C 8  alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; —C 3 -C 12  cycloalkyl, substituted —C 3 -C 12  cycloalkyl, —C 3 -C 12  cycloalkenyl, or substituted —C 3 -C 12  cycloalkenyl, each of which may be optionally substituted; and 
 (iv) NH 2 , N═CR 4 R 6 ; 
 each R 4  is independently H, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted; 
 or R 3  and R 4  are taken together with the nitrogen atom to which they are attached to form a 4-10-membered ring; 
 R 6  is alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted; or R 4  and R 6  are taken together with the carbon atom to which they are attached to form a 4-10-membered ring; 
 
         m is 0, 1, 2, or 3; 
         provided that
 (a) if ring A is thienyl, X is N, R 2  is H, R B  is methyl, and R 1  is —(CH 2 ) n -L, in which n is 0 and L is —CO—N(R 3 R 4 ), then R 3  and R 4  are not taken together with the nitrogen atom to which they are attached to form a morpholino ring; 
 (b) if ring A is thienyl, X is N, R 2  is H, R B  is methyl, and R 1  is —(CH 2 ) n -L, in which n is 0 and L is —CO—N(R 3 R 4 ), and one of R 3  and R 4  is H, then the other of R 3  and R 4  is not methyl, hydroxyethyl, alkoxy, phenyl, substituted phenyl, pyridyl or substituted pyridyl; and 
 (c) if ring A is thienyl, X is N, R 2  is H, R B  is methyl, and R 1  is —(CH 2 ) n -L, in which n is 0 and L is —COO—R 3 , then R 3  is not methyl or ethyl; or
 a salt, solvate or hydrate thereof. 
 
 
       
     
     
         96 . The compound of  claim 95 , wherein:
 L is —COO—R 3 , optionally substituted aryl, or optionally substituted heteroaryl; and   R 3  is —C 1 -C 8  alkyl, which contains 0, 1, 2, or 3 heteroatoms selected from O, S, or N, and which may be optionally substituted.   
     
     
         97 . The compound of  claim 95 , wherein the compound is a compound of Formula II: 
       
         
           
           
               
               
           
         
       
       wherein
 X is N or CR 5 ;
 R 5  is H, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted; 
 R B  is H, alkyl, hydroxylalkyl, aminoalkyl, alkoxyalkyl, haloalkyl, hydroxy, alkoxy, or —COO—R 3 , each of which is optionally substituted; 
 
 each R A  is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted; or any two R A  together with the atoms to which each is attached, can form a fused aryl or heteroaryl group; 
 R is alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted; 
 R′ 1  is —COO—R 3 , —CO—R 3 , optionally substituted aryl, or optionally substituted heteroaryl;
 each R 3  is independently selected from the group consisting of: 
 (i) H, aryl, substituted aryl, heteroaryl, substituted heteroaryl; 
 (ii) heterocycloalkyl or substituted heterocycloalkyl; 
 (iii) —C 1 -C 8  alkyl, —C 2 -C 8  alkenyl or —C 2 -C 8  alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; —C 3 -C 12  cycloalkyl, substituted —C 3 -C 12  cycloalkyl; —C 3 -C 12  cycloalkenyl, or substituted —C 3 -C 12  cycloalkenyl; each of which may be optionally substituted; 
 
 m is 0, 1, 2, or 3; 
 provided that if R′ 1  is —COO—R 3 , X is N, R is substituted phenyl, and R B  is methyl, then R 3  is not methyl or ethyl; 
 or a salt, solvate or hydrate thereof. 
 
     
     
         98 . The compound of  claim 97 , wherein:
 R′ 1  is —COO—R 3 , optionally substituted aryl, or optionally substituted heteroaryl; and   R 3  is —C 1 -C 8  alkyl, which contains 0, 1, 2, or 3 heteroatoms selected from O, S, or N, and which may be optionally substituted.   
     
     
         99 . The compound of  claim 98 , wherein R′ 1  is —COO—R 3 , and R 3  is methyl, ethyl, propyl, i-propyl, butyl, sec-butyl, or t-butyl. 
     
     
         100 . The compound of  claim 95 , wherein the compound is a compound of formula III: 
       
         
           
           
               
               
           
         
       
       wherein
 X is N or CR 5 ;
 R 5  is H, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted; 
 R B  is H, alkyl, hydroxylalkyl, aminoalkyl, alkoxyalkyl, haloalkyl, hydroxy, alkoxy, or —COO—R 3 , each of which is optionally substituted; 
 
 ring A is aryl or heteroaryl;
 each R A  is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted; or any two R A  together with the atoms to which each is attached, can form a fused aryl or heteroaryl group; 
 
 R is alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted; 
 each R 3  is independently selected from the group consisting of:
 (i) H, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; 
 (ii) heterocycloalkyl or substituted heterocycloalkyl; 
 (iii) —C 1 -C 8  alkyl, —C 2 -C 8  alkenyl or —C 2 -C 8  alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; —C 3 -C 12  cycloalkyl, substituted —C 3 -C 12  cycloalkyl, —C 3 -C 12  cycloalkenyl, or substituted —C 3 -C 12  cycloalkenyl, each of which may be optionally substituted; and 
 (iv) NH 2 , N═CR 4 R 6 ; 
 each R 4  is independently H, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted; 
 or R 3  and R 4  are taken together with the nitrogen atom to which they are attached to form a 4-10-membered ring; 
 R 6  is alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted; or R 4  and R 6  are taken together with the carbon atom to which they are attached to form a 4-10-membered ring; 
 
 m is 0, 1, 2, or 3; 
 provided that:
 (a) if ring A is thienyl, X is N, R is phenyl or substituted phenyl, R B  is methyl, then R 3  and R 4  are not taken together with the nitrogen atom to which they are attached to form a morpholino ring; and 
 (b) if ring A is thienyl, X is N, R is substituted phenyl, R 2  is H, R B  is methyl, and one of R 3  and R 4  is H, then the other of R 3  and R 4  is not methyl, hydroxyethyl, alkoxy, phenyl, substituted phenyl, pyridyl or substituted pyridyl; and 
 
 or a salt, solvate or hydrate thereof. 
 
     
     
         101 . The compound of  claim 100 , wherein R is aryl or heteroaryl, each of which is optionally substituted. 
     
     
         102 . The compound of  claim 101 , wherein R is phenyl or pyridyl, each of which is optionally substituted. 
     
     
         103 . The compound of  claim 102 , wherein R is p-Cl-phenyl, o-Cl-phenyl, m-Cl-phenyl, p-F-phenyl, o-F-phenyl, m-F-phenyl or pyridinyl. 
     
     
         104 . The compound of  claim 100 , wherein R 3  is H, NH 2 , or N═CR 4 R 6 . 
     
     
         105 . The compound of  claim 100 , wherein each R 4  is independently H, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, or an optionally substituted heteroaryl. 
     
     
         106 . The compound of  claim 100 , wherein R 6  is alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted. 
     
     
         107 . The compound of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         108 . A compound represented by any one of the following structures: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a salt, solvate or hydrate thereof. 
     
     
         109 . A method of treating a condition in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of  claim 1 , or a pharmaceutical acceptable salt thereof, wherein the condition is selected from the group consisting of prostate cancer, renal cell carcinoma, hepatoma, lung cancer, breast cancer, colon cancer, neuroblastoma, glial blastoma multiforme, squamous cell carcinoma involving a NUT rearrangement, NUT midline carcinoma and non-small cell lung cancer.