Heteroaryl compounds useful as inhibitors of sumo activating enzyme

Abstract

Disclosed are chemical entities which are compounds of formula (I):or pharmaceutically acceptable salts thereof; wherein Y, Ra, Ra′, Rb, Rc, X1, X2, X3, Rd, Z1, and Z2 have the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry. Chemical entities according to the disclosure can be useful as inhibitors of Sumo Activating Enzyme (SAE). Further provided are pharmaceutical compositions comprising a compound of the disclosure and methods of using the compositions in the treatment of proliferative, inflammatory, cardiovascular, and neurodegenerative diseases or disorders.

1 .- 44 . (canceled) 
     
     
         45 . A chemical entity which is a compound or pharmaceutically acceptable salt of formula (VIa): 
       
         
           
           
               
               
           
         
         wherein: 
         m is 1; 
         X 1  is C(H), C(F), or N; 
         X 4  is S, O, or N(R n4 ); 
         X 5  is O, C(O), or C(R x5 )(R x5 ′), wherein X 5  is not O if X 4  is N(R n4 ) or S; 
         R a  and R a′  are hydrogen; 
         R b  is hydrogen; 
         R k  is hydrogen; 
         R n4  is hydrogen or C 1-4  alkyl; 
         R x5  is hydrogen, fluoro, hydroxyl, or C 1-4  alkyl; 
         R x5 ′ is hydrogen, fluoro, or C 1-4  alkyl, wherein R x5 ′ is not fluoro if R x5  is hydroxyl; 
         Z 1  is hydrogen, halogen, cyano, or optionally substituted C 1-4  aliphatic; 
         X 6  is C(R x6 ); 
         X 6 ′ is C(R x6 ′); and 
         each of R x6 , R x6 ′, R j  and R m  is independently hydrogen or halogen; 
         wherein at least one of R x6 , R x6 ′, R j  and R m  is hydrogen. 
       
     
     
         46 . The chemical entity of  claim 45 , wherein:
 X 1  is C(H);   X 4  is S or O;   X 5  is C(R x5 )(R x5 ′); and   Z 1  is optionally substituted C 1-4  aliphatic.   
     
     
         47 . The chemical entity of  claim 46 , wherein:
 R x5  is hydrogen or fluoro; and   R x5 ′ is hydrogen or fluoro.   
     
     
         48 . The chemical entity of  claim 45 , wherein:
 Z 1  is methyl; and   X 4  is O.   
     
     
         49 . The chemical entity of  claim 45 , wherein:
 each of R x6  and R x6 ′ is hydrogen.   
     
     
         50 . The chemical entity of  claim 45 , wherein at least one of R j  and R m  is chlorine. 
     
     
         51 . The chemical entity of  claim 45 , wherein both R j  and R m  are hydrogen. 
     
     
         52 . The chemical entity of  claim 45 , wherein the chemical entity is chosen from: 
       
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts thereof. 
     
     
         53 . The chemical entity of  claim 52 , wherein the chemical entity is chosen from:
 I-256 [(1R,2S,4R)-4-{[5-({4-[(1S)-3,4-dihydro-1H-isochromen-1-yl]-5-methyl-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate;   and   [(1R,2S,4R)-4-{[5-({4-[(1R)-3,4-Dihydro-1H-isochromen-1-yl]-5-methyl-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate;   I-256 a [(1R,2S,4R)-4-{[5-({4-[(1S)-3,4-dihydro-1H-isochromen-1-yl]-5-methyl-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate;   I-256b [(1R,2S,4R)-4-{[5-({4-[(1R)-3,4-dihydro-1H-isochromen-1-yl]-5-methyl-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate;   I-257 [(1R,2S,4R)-4-{[5-({4-[(1S)-7-Chloro-3,4-dihydro-1H-isochromen-1-yl]-5-methyl-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate;   and   [(1R,2S,4R)-4-{[5-({4-[(1R)-7-Chloro-3,4-dihydro-1H-isochromen-1-yl]-5-methyl-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate;   I-257a [(1R,2S,4R)-4-{[5-({4-[(1S)-7-Chloro-3,4-dihydro-1H-isochromen-1-yl]-5-methyl-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate;   I-257b [(1R,2S,4R)-4-{[5-({4-[(1R)-7-Chloro-3,4-dihydro-1H-isochromen-1-yl]-5-methyl-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate;   and pharmaceutically acceptable salts thereof.   
     
     
         54 . The chemical entity of  claim 53 , wherein the chemical entity is chosen from crystalline Form 1 of [(1R,2S,4R)-4-{[5-({4-[(1R)-3,4-Dihydro-1H-isochromen-1-yl]-5-methyl-2-thienyl}carbonyl) pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate of formula I-256b, and crystalline Form 1 of [(1R,2S,4R)-4-{[5-({4-[(1R)-7-Chloro-3,4-dihydro-1H-isochromen-1-yl]-5-methyl-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methylsulfamate of formula I-257b. 
     
     
         55 . A pharmaceutical composition comprising the chemical entity of  claim 45  and a pharmaceutically acceptable carrier. 
     
     
         56 . The pharmaceutical composition of  claim 55 , wherein the pharmaceutical composition is formulated to be administered orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically, bucally, or as an oral or nasal spray. 
     
     
         57 . The pharmaceutical composition of  claim 55 , wherein the pharmaceutical composition is a solid dosage form. 
     
     
         58 . The pharmaceutical composition of  claim 57 , wherein the solid dosage form is for oral administration. 
     
     
         59 . The pharmaceutical composition of  claim 58 , wherein the solid dosage form is selected from capsules, dragees, tablets, pills, powders, and granules. 
     
     
         60 . The pharmaceutical composition of  claim 55 , wherein the chemical entity is 
       
         
           
           
               
               
           
         
       
     
     
         61 . The pharmaceutical composition of  claim 60 , wherein the chemical entity is [(1R,2S,4R)-4-{[5-({4-[(1R)-3,4-Dihydro-1H-isochromen-1-yl]-5-methyl-2-thienyl}carbonyl) pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate of formula I-256b, or a pharmaceutically acceptable salt thereof. 
     
     
         62 . The pharmaceutical composition of  claim 55 , wherein the chemical entity is 
       
         
           
           
               
               
           
         
       
     
     
         63 . The pharmaceutical composition of  claim 62 , wherein the chemical entity is [(1R,2S,4R)-4-{[5-({4-[(1R)-7-Chloro-3,4-dihydro-1H-isochromen-1-yl]-5-methyl-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl] methylsulfamate of formula I-257b, or a pharmaceutically acceptable salt thereof. 
     
     
         64 . A pharmaceutical composition comprising crystalline Form 1 of [(1R,2S,4R)-4-{[5-({4-[(1R)-3,4-Dihydro-1H-isochromen-1-yl]-5-methyl-2-thienyl}carbonyl) pyrimidin-4-yl]amino}-2-hydroxycyclopentyl]methyl sulfamate of formula I-256b, or crystalline Form 1 of [(1R,2S,4R)-4-{[5-({4-[(1R)-7-Chloro-3,4-dihydro-1H-isochromen-1-yl]-5-methyl-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl] methylsulfamate of formula I-257b, and a pharmaceutically acceptable carrier.