Inhibitors of e1 activating enzymes

Abstract

This invention relates to compounds that inhibit E1 activating enzymes, pharmaceutical compositions comprising the compounds, and methods of using the compounds. The compounds are useful for treating disorders, particularly cell proliferation disorders, including cancers, inflammatory and neurodegenerative disorders; and inflammation associated with infection and cachexia.

1 - 33 . (canceled) 
     
     
         34 . A method for treating cancer in a patient in need thereof, comprising administering to the patient a compound of formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 stereochemical configurations depicted at asterisked positions indicate relative stereochemistry; 
 Ring A is selected from the group consisting of: 
 
       
         
           
           
               
               
           
         
         wherein one ring nitrogen atom in Ring A optionally is oxidized; 
         X is —C(R f1 ) 2 , —N(R f2 )—, or —O—; 
         Y is —O—, —S—, or —C(R m )(R n )—; 
         R a  is selected from the group consisting of hydrogen,
 fluoro, —CN, —N 3 , —OR 5 , —N(R 4 ) 2 , —NR 4 CO 2 R 5 , —NR 4 C(O)R 5 , —C(O)N(R 4 ) 2 , —C(O)R 5 , —OC(O)N(R 4 ) 2 , —OC(O)R 5 , —OCO 2 R 6 , or a C 1-4  aliphatic or C 1-4  fluoroaliphatic optionally substituted with one or two substituents independently selected from the group consisting of —OR 5x , —N(R 4x )(R 4y ), —CO 2 R 5x , or —C(O)N(R 4x )(R 4y ); or R a  and R b  together form ═O; or R a  and R c  together form a bond; 
 
         R b  is selected from the group consisting of hydrogen, fluoro, C 1-4  aliphatic, and C 1-4  fluoroaliphatic; or R b  and R a  together form ═O; or R b , taken together with R d  and the intervening carbon atoms, forms a fused cyclopropane ring, which is optionally substituted with one or two substituents independently selected from fluoro or C 1-4  aliphatic; or R b , taken together with R e  and the intervening carbon atoms, forms a fused cyclopropane ring, which is optionally substituted with one or two substituents independently selected from fluoro or C 1-4  aliphatic; 
         R c  is selected from the group consisting of hydrogen,
 fluoro, —CN, —N 3 , —OR 5 , —N(R 4 ) 2 , —NR 4 CO 2 R 6 , —NR 4 C(O)R 5 , —C(O)N(R 4 ) 2 , —C(O)R 5 , —OC(O)N(R 4 ) 2 , —OC(O)R 5 , —OCO 2 R 6 , or a C 1-4  aliphatic or C 1-4  fluoroaliphatic optionally substituted with one or two substituents independently selected from the group consisting of —OR 5x , —N(R 4x )(R 4y ), —CO 2 R 5x , or —C(O)N(R 4x )(R 4y ); or R a  and R c  together form a bond; or R c  and R d  together form ═O; 
 
         R d  is selected from the group consisting of hydrogen, fluoro, C 1-4  aliphatic, and C 1-4  fluoroaliphatic; or R d  and R c  together form ═O; or R d , taken together with R b  and the intervening carbon atoms, forms a fused cyclopropane ring, which is optionally substituted with one or two substituents independently selected from fluoro or C 1-4  aliphatic; or R d , taken together with R e′  and the intervening carbon atoms, forms a fused cyclopropane ring, which is optionally substituted with one or two substituents independently selected from fluoro or C 1-4  aliphatic; 
         R e  is hydrogen, or C 1-4  aliphatic; or R e , taken together with one R f  and the intervening carbon atoms, forms a 3- to 6-membered spirocyclic ring, which is optionally substituted with one or two substituents independently selected from fluoro or C 1-4  aliphatic; or R e , taken together with R m  and the intervening carbon atoms, forms a fused cyclopropane ring, which is optionally substituted with one or two substituents independently selected from fluoro or C 1-4  aliphatic; or R e , taken together with R b  and the intervening carbon atoms, forms a fused cyclopropane ring, which is optionally substituted with ore or two substituents independently selected from fluoro or C 1-4  aliphatic; 
         R e′  is hydrogen or C 1-4  aliphatic; or R e′ , taken together with R m  and the intervening carbon atoms, forms a fused cyclopropane ring, which is optionally substituted with one or two substituents independently selected from fluoro or C 1-4  aliphatic; or R e′ , taken together with R d  and the intervening carbon atoms, forms a fused cyclopropane ring, which is optionally substituted with one or two substituents independently selected from fluoro or C 1-4  aliphatic; 
         each R f  is independently hydrogen, fluoro, C 1-4  aliphatic, or C 1-4  fluoroaliphatic, provided that if X is —O— or —NH—, then R f  is not fluoro; or two R f  taken together form ═O; or two R f , taken together with the carbon atom to which they are attached, form a 3- to 6-membered carbocyclic ring; or one R f , taken together with R e  and the intervening carbon atoms, forms a 3- to 6-membered spirocyclic ring, which is optionally substituted with one or two substituents independently selected from fluoro or C 1-4  aliphatic; or one R f , taken together with an adjacent R f1  and the intervening carbon atoms, forms a cyclpropyl ring, which is optionally substituted with one or two substituents independently selected from fluoro or C 1-4  aliphatic; or one R f  and one R f1  together form a double bond; 
         each R f1  is independently hydrogen or fluoro; or one R f1 , taken together with an adjacent R f  and the intervening carbon atoms forms a cyclopropyl ring, which is optionally substituted with one or two substituents independently selected from fluoro or C 1-4  aliphatic; or one R f1  and one R f  together form a double bond; 
         R f2  is hydrogen, C 1-4  aliphatic, or C 1-4  fluoroaliphatic; 
         R g  is hydrogen,
 halo, —NO 2 , —CN, —C(R 5 )═C(R 5 ) 2 , —C═C—R 5 , —OR 5 , —SR 6 , —S(O)R 6 , —SO 2 R 6 , —SO 2 N(R 4 ) 2 , —N(R 4 ) 2 , —NR 4 C(O)R 5 , —NR 4 C(O)N(R 4 ) 2 , —N(R 4 )C(═NR 4 )—N(R 4 ) 2 , —N(R 4 )C(═NR 4 )—R 6 , —NR 4 CO 2 R 6 , —N(R 4 )SO 2 R 6 , —N(R 4 )SO 2 N(R 4 ) 2 , —O—C(O)R 5 , —OCO 2 R 6 , —OC(O)N(R 4 ) 2 , —C(O)R 5 , —CO 2 R 5 , —C(O)N(R 4 ) 2 , —C(O)N(R 4 )—OR 5 , —C(O)N(R 4 )C(═NR 4 )—N(R 4 ) 2 , —N(R 4 )C(═NR 4 )—N(R 4 )—C(O)R 5 , —C(═NR 4 )—N(R 4 ) 2 , —C(═NR 4 )—OR 5 , —N(R 4 )—N(R 4 ) 2 , —N(R 4 )—OR 5 , —C(═NR 4 )—N(R 4 )—OR 5 , —C(R 6 )═N—OR 5 , or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl; 
 
         each R h  independently is hydrogen, halo, —CN-, —OR 5 , —N(R 4 ) 2 , —SR 6 , or an optionally substituted C 1-4  aliphatic group; 
         R j  is hydrogen, —OR 5 , —SR 6 , —N(R 4 ) 2 , or an optionally substituted aliphatic, aryl, or heteroaryl group; 
         R k  is hydrogen, halo, —OR 5 , —SR 6 , —N(R 4 ) 2 , or an optionally substituted C 1-4  aliphatic group; 
         R m  is hydrogen, fluoro, —N(R 4 ) 2 , or an optionally substituted C 1-4  aliphatic group; or R m  and R n  together form ═O or ═C(R 5 ) 2 ; or R m  and R e , taken together with the intervening carbon atoms, form a fused cyclopropane ring, which is optionally substituted with one or two substituents independently selected from fluoro or C 1-4  aliphatic; or R m  and R e′ , taken together with the intervening carbon atoms, form a fused cyclopropane ring, which is optionally substituted with one or two substituents independently selected from fluoro or C 1-4  aliphatic; 
         R n  is hydrogen, fluoro, or an optionally substituted C 1-4  aliphatic group; or R m  and R n  together form ═O or ═C(R 5 ) 2 ; 
         each R 4  independently is hydrogen or an optionally substituted aliphatic, aryl heteroaryl, or heterocyclyl group; or two R 4  on the same nitrogen atom, taken together with the nitrogen atom, form an optionally substituted 4- to 8-membered heterocyclyl ring having, in addition to the nitrogen atom, 0-2 ring heteroatoms independently selected from N, O, and S; 
         R 4x  is hydrogen, C 1-4  alkyl, C 1-4  fluoroalkyl, or C 6-10  ar(C 1-4 )alkyl, the aryl portion of which may be optionally substituted; 
         R 4y  is hydrogen, C 1-4  alkyl, C 1-4  fluoroalkyl, C 1-4  ar(C 1-4 )alkyl, the aryl portion of which may be optionally substituted, or an optionally substituted 5- or 6-membered aryl, heteroaryl, or heterocyclyl ring; or 
         R 4x  and R 4y , taken together with the nitrogen atom to which they are attached, form an optionally substituted 4- to 8-membered heterocyclyl ring having, in addition to the nitrogen atom, 0-2 ring heteroatoms independently selected from N, O, and S; and 
         each R 5  independently is hydrogen or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group; 
         each R 5x  independently is hydrogen, C 1-4  alkyl, C 1-4  fluoroalkyl, or an optionally substituted C 6-10  aryl or C 6-10  ar(C 1-4 )alkyl; 
         each R 6  independently is an optionally substituted aliphatic, aryl, or heteroaryl group; and 
         m is 0, 1, 2, or 3, provided that Y is —C(R m )(R n )— when m is 0. 
       
     
     
         35 . The method of claim  0 , wherein the cancer is lung cancer, colorectal cancer, ovarian cancer, or a hematological cancer. 
     
     
         36 . (canceled)