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 . A compound of formula (I-A): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
       
       Ring A is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein one ring nitrogen atom in Ring A optionally is oxidized; 
         X is —CH 2 —, —CHF—, —CF 2 —, —NH—, or —O—; 
         Y is —O—, —S—, or —C(R m )(R n )—; 
         each R h  independently is hydrogen, halo, —CN, —OH, —O—(C 1-4  aliphatic), —NH 2 , —NH—(C 1-4  aliphatic), —N(C 1-4  aliphatic) 2 , —SH, —S—(C 1-4  aliphatic), 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, and 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 ; 
         R 1  is hydrogen, chloro, bromo, fluoro, iodo, —NR 7 R 8 , —R 9 , —SH, —SCH 3 , —OH, —OCH 3 , or —O—R 11 ; 
         R 2  is hydrogen, chloro, bromo, fluoro, iodo, —N(R 6 ) 2 , —CN, —O—(C 1-4  aliphatic), —OH, —SR 6 , or an optionally substituted C 1-4  aliphatic group; 
         R 3a  is selected from the group consisting of hydrogen, fluoro, —CN, —N 3 , hydroxy, —OR 21 , —NH 2 , —NH(R 21 ), —N(H)CO 2 R 21 , —N(H)C(O)R 21 , —CON(H)R 21 , —C(O)R 5 , —OC(O)N(H)R 21 , —OC(O)R 21 , —OC(O)OR 21 ,) OC(O)OR 21 , —C 1-4  fluoroaliphatic, or a —C 1-4  aliphatic 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 ); 
         R 3b  is selected from the group consisting of hydrogen, fluoro, C 1-4  aliphatic, and C 1-4  fluoroaliphatic; 
         R 3c  is selected from the group consisting of hydrogen, fluoro, —CN, —N 3 , hydroxy, —OR 21 , —NH 2 , —NH(R 21 ), —N(H)CO 2 R 21 , —N(H)C(O)R 21 , —CON(H)R 21 , —OC(O)N(H)R 21 , —OC(O)R 21 , —OC(O)OR 21 , —C 1-4  fluoroaliphatic, or a —C 1-4  aliphatic 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 ); 
         R 3d  is selected from the group consisting of hydrogen, fluoro, C 1-4  aliphatic, and C 1-4  fluoroaliphatic; 
         each R 4  is independently hydrogen, fluoro, C 1-4  aliphatic, or C 1-4  fluoroaliphatic; or two R 4 , taken together with the carbon atom to which they are attached, form a 3- to 6-membered carbocyclic ring; or one R 4 , taken together with R 5  and the intervening carbon atoms, forms a 3- to 6-membered spirocyclic ring; or two R 4  together form ═O; 
         R 5  is hydrogen, or C 1-4  aliphatic; or R 5 , taken together with one R 4  and the intervening carbon atoms, forms a 3- to 6-membered spirocyclic ring; 
         R 5′  is hydrogen, or C 1-4  aliphatic; 
         each R 6  is independently hydrogen or C 1-4  aliphatic; 
         R 7  is an optionally substituted C 1-10  aliphatic, aryl, heteroaryl, or heterocyclyl group; 
         R 8  is hydrogen or C 1-4  aliphatic; 
         R 9  is —V—Z—R 12a , —V—Z—R 12b , —R 12c  or an optionally substituted aliphatic, aryl, heterocyclyl, or heteroaryl group, wherein the heteroaryl group is attached at a carbon atom; 
         R 10  is an unsubstituted C 2-10  aliphatic, a substituted C 1-10  aliphatic, or an optionally substituted aryl, heteroaryl, or heterocyclyl; 
         R 11  is an unsubstituted C 2-10  aliphatic, a substituted C 1-10  aliphatic, or an optionally substituted aryl, heteroaryl, or heterocyclyl; 
         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 6-10  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; 
         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; 
         V is —S(O) 2 —, —S(O)—, —C(O)O—, —C(O)—, —C(NR 13 )═N—, —C(═N(R 13 ))-N(R 13 )—, —C(OR 11 )═N—, —CON(R 13 )—, —N(R 13 )C(O)—, —N(R 13 )C(O)N(R 13 )—, —N(R 13 )S(O) 2 —, —N(R 13 )SO 2 —N(R 13 )—, —N(R 13 )CO 2 —, —SO 2 N(R 13 )—, —OC(O)—, —OC(O)O—, —OC(O)N(R 13 )—, —N(R 13 )—N(R 13 )—; 
         Z is an optionally substituted C 1-6  alkylene chain, wherein the alkylene chain is optionally interrupted by —C(R 13 )═C(R 13 )—, —C≡C—, —O—, —S—, —N(R 13 )—, —N(R 13 )CO—, —N(R 13 )CO 2 —, —C(O)N(R 13 )—, —C(O)—, —C(O)—C(O)—, —CO 2 —, —OC(O)—, —OC(O)O—, —N(R 13 )C(O)N(R 13 )—, —N(R 13 )N(R 13 )—, —OC(O)N(R 13 )—, —S(O)—, —S(O) 2 —, —N(R 13 )S(O) 2 —, —S(O) 2 N(R 13 )—; 
         R 12a  is an optionally substituted aryl, heteroaryl, heterocyclyl, or cycloaliphatic group; 
         R 12b  is halo, —NO 2 , —CN, —OR 14 , —SR 15 , —N(R 16 ) 2 , —N(R 16 )C(O)R 15 , —N(R 16 )C(O)N(R 16 ) 2 , —N(R 16 )CO 2 R 14 , —O—CO 2 —R 14 , —OC(O)N(R 16 ) 2 , —OC(O)R 14 , —N(R 16 )—N(R 16 ) 2 , —N(R 16 )—OR 15 , —N(R 16 )S(O) 2 R 15 , or —N(R 16 )SO 2 —N(R 16 ) 2 , —C(R 14 )═C(R 14 ) 2 , —C(O)R 14 , —S(O)R 15 , —SO 2 R 15 , —SO 2 —N(R 16 ) 2 , —C(R 14 )═N—OR 14 , —CO 2 R 14 , —C(O)—C(O)R 14 , —C(O)R 14 , —C(O)N(R 16 ) 2 , —C(═NR 16 )—N(R 16 ) 2 , or —C(═NR 16 )—OR 14 ; 
         R 12c  is —NO 2 , —CN, —S(O)R 15 , —SO 2 R 15 , —SO 2 —N(R 16 ) 2 , —C(R 14 )═N—OR 14 , —N(R 16 )C(O)R 15 , —N(R 16 )C(O)N(R 16 ) 2 , —O—CO 2 —R 14 —, —OC(O)N(R 16 ) 2 , —OC(O)R 14 , —CO 2 R 14 , —C(O)—C(O)R 14 , —C(O)R 14 , —C(O)N(R 16 ) 2 , —C(═NR 16 )—N(R 16 ) 2 , —C(═NR 16 )—OR 14 , —N(R 16 )—N(R 16 ) 2 , —N(R 16 )—OR 15 , —N(R 16 )S(O) 2 R 15 , or —N(R 16 )SO 2 —N(R 16 ) 2 ; 
         each R 13  is independently hydrogen, or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group; 
         each R 14  independently is hydrogen, or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group; 
         each R 15  independently is an optionally substituted aliphatic, or aryl group; 
         each R 16  independently is an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group; or two R 16  on the same nitrogen atom, taken together with the nitrogen atom, form an optionally substituted five to eight membered heterocylyl ring having, in addition to the nitrogen atom, zero to two additional ring heteroatoms selected from the group consisting of N, O, and S; 
         each R 21  independently is an optionally substituted C 1-10  aliphatic, aryl, heteroaryl, or heterocyclyl group; and 
         m is 1, 2, or 3; 
         provided that 
         if Ring A is A-i, X is —O—, Y is —O— or —CH 2 —, R 2  is hydrogen or chloro, R 3a  is hydroxyl or —OCOR 21 , R 3b  is hydrogen, R 3c  is hydroxyl or —OCOR 21 , R 3d  is hydrogen, R 4  and R 5  are each hydrogen, and m is 1; then R 1  is bromo, fluoro, —NR 7 R 8 , —R 9 , —SR 10 , or —OR 11 , R 7  is a substituted aliphatic, or an optionally substituted aryl, heteroaryl, aralkyl, heteroaralkyl, cycloaliphatic, heterocyclyl, (cycloaliphatic)alkyl, or (heterocyclyl)alkyl, and R 9  is other than unsubstituted imidazole. 
       
     
     
         2 . The compound of  claim 1 , characterized by one or more of the following features:
 (a) X is —O—;   (b) Y is —O— or —CH 2 —;   (c) R 3a  is —OH;   (d) R 3b  and R 3d  are each independently hydrogen or C 1-4  aliphatic;   (e) R 3c  is hydrogen, fluoro, or —OR 5 ;   (f) R 5  and R 5′  are each hydrogen;   (g) each R 4  is hydrogen;   (h) each R 2  is hydrogen;   (i) R h  is hydrogen;   (j) R j  is hydrogen; and   (k) R k  is hydrogen, halo, or C 1-4  aliphatic.   
     
     
         3 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         X is —CH 2 —, —NH—, or —O—; 
         Y is —O—, or —CH 2 —; 
         Q is ═N— or ═CH—; 
         R 1  is chloro, bromo, fluoro, iodo, —NR 7 R 8 , —S—R 10 , or —O—R 11 ; 
         R 2  is hydrogen, chloro, bromo, fluoro, iodo, —N(R 6 ) 2 , —CN, —O—(C 1-4  aliphatic), —OH, —SR 6 , or an optionally substituted C 1-4  aliphatic group; 
         R 3a  is selected from the group consisting of hydrogen, hydroxy, —NH 2 , —C 1-4  aliphatic, fluoro, —CN, —C 1-4  fluoroaliphatic, —OR 21 , —NH(R 21 ), —N(H)CO 2 R 21 , —N(H)C(O)R 21 , —CON(H)R 21 , —OC(O)N(H)R 21 , —OC(O)R 21 , and —OC(O)OR 21 ; 
         R 3b  is selected from the group consisting of hydrogen, fluoro, C 1-4  aliphatic, and C 1-4  fluoroaliphatic; 
         R 3c  is selected from the group consisting of hydrogen, hydroxy, —NH 2 , —C 1-4  aliphatic, fluoro, —CN, —C 1-4  fluoroaliphatic, —OR 21 , —NH(R 21 ), —N(H)CO 2 R 21 , —N(H)C(O)R 21 , —CON(H)R 21 , —OC(O)N(H)R 21 , —OC(O)R 21 , and —OC(O)OR 21 ; 
         R 3d  is selected from the group consisting of hydrogen, fluoro, C 1-4  aliphatic, and C 1-4  fluoroaliphatic; 
         each R 4  is independently hydrogen or C 1-4  aliphatic; or two R 4 , taken together with the carbon atom to which they are attached, form a 3- to 6-membered carbocyclic ring; or one R 4 , taken together with R 5  and the intervening carbon atoms, forms a 3- to 6-membered spirocyclic ring; 
         R 5  is hydrogen, or C 1-4  aliphatic; or R 5 , taken together with one R 4  and the intervening carbon atoms, forms a 3- to 6-membered spirocyclic ring; 
         each R 6  is independently hydrogen or C 1-4  aliphatic; 
         R 7  is an optionally substituted C 1-10  aliphatic, aryl, heteroaryl, or heterocyclyl group; 
         R 8  is hydrogen or C 1-4  aliphatic; 
         R 9  is —V—Z—R 1 , —V—Z—R 12b , —R 12c , or an option ally substituted aliphatic, aryl, heterocyclyl, or heteroaryl group, wherein the heteroaryl group is attached at a carbon atom; 
         is an optionally substituted C 2-10  aliphatic, aryl, heteroaryl, or heterocyclyl; 
         R 11  is an optionally substituted C 2-10  aliphatic, aryl, heteroaryl, or heterocyclyl; 
         V is —S(O) 2 —, —S(O)—, —C(O)O—, —C(O)—, —C(NR 13 )═N—, —C(═N(R 13 ))—N(R 13 )—, —C(OR 11 )═N—, —CON(R 13 )—, —N(R 13 )C(O)—, —N(R 13 )C(O)N(R 13 )—, —N(R 13 )S(O) 2 —, —N(R 13 )SO 2 —N(R 13 )—, —N(R 13 )CO 2 —, —SO 2 N(R 13 )—, —OC(O)—, —OC(O)O—, —OC(O)N(R 13 )—, —N(R 13 )—N(R 13 )—; 
         Z is an optionally substituted C 1-6  alkylene chain, wherein the alkylene chain is optionally interrupted by —C(R 13 )═C(R 13 )—, —C≡C—, —O—, —S—, —N(R 13 )—, —N(R 13 )CO—, —N(R 13 )CO 2 —, —C(O)N(R 13 )—, —C(O)—, —C(O)—C(O)—, —CO 2 —, —OC(O)—, —OC(O)O—, —N(R 13 )C(O)N(R 13 )—, —N(R 13 )N(R 13 )—, —OC(O)N(R 13 )—, —S(O)—, —S(O) 2 —, —N(R 13 )S(O) 2 —, —S(O) 2 N(R 13 )—; 
         R 12a  is an optionally substituted aryl, heteroaryl, heterocyclyl, or cycloaliphatic group; 
         R 12b  is halo, —NO 2 , —CN, —OR 14 , —SR 15 , —N(R 16 ) 2 , —N(R 16 )C(O)R 15 , —N(R 16 )C(O)N(R 16 ) 2 , —N(R 16 )CO 2 R 14 , —O—CO 2 —R 14 , —OC(O)N(R 16 ) 2 , —OC(O)R 14 , —N(R 16 )—N(R 16 ) 2 , —N(R 16 )S(O) 2 R 15 , or —N(R 16 )SO 2 —N(R 16 ) 2 , —C(R 14 )═C(R 14 ) 2 , —C≡C—R 14 , —S(O)R 15 , —SO 2 R 15 , —SO 2 —N(R 16 ) 2 , —C(R 14 )═N—OR 14 , —CO 2 R 14 , —C(O)—C(O)R 14 , —C(O)R 14 , —C(O)N(R 16 ) 2 , —C(═NR 16 )—N(R 16 ) 2 , —C(═NR 16 )—OR 14 ; 
         R 12c  is —NO 2 , —CN, —S(O)R 15 , —SO 2 R 15 , —SO 2 —N(R 16 ) 2 , —C(R 14 )═N—OR 14 , —N(R 16 )C(O)R 15 , —N(R 16 )C(O)N(R 16 ) 2 , —O—CO 2 R 14 —, —OC(O)N(R 16 ) 2 , —OC(O)R 14 , —CO 2 R 14 , —C(O)—C(O)R 14 , —C(O)R 14 , —C(O)N(R 16 ) 2 , —C(═NR 16 )—N(R 16 ) 2 , —C(═NR 16 )—OR 14 , —N(R 16 )—N(R 16 ) 2 , —N(R 16 )S(O) 2 R 15 , or —N(R 16 )SO 2 —N(R 16 ) 2 ; 
         each R 13  is independently hydrogen, or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group; 
         each R 14  independently is hydrogen, or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group; 
         each R 15  independently is an optionally substituted aliphatic, or aryl group; 
         each R 16  independently is an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group; or two R 16  on the same nitrogen atom, taken together with the nitrogen atom, form an optionally substituted five to eight membered heterocylyl ring having, in addition to the nitrogen atom, zero to two additional ring heteroatoms selected from the group consisting of N, O, and S; and 
         each R 21  independently is an optionally substituted C 1-10  aliphatic, aryl, heteroaryl, or heterocyclyl group; 
         provided that: 
         if X is —O—, Y is —O— or —CH 2 —, Q is ═N—, R 2  is hydrogen or chloro, R 3a  is hydroxyl or —OCOR 21 , R 3b  is hydrogen, R 3c  is hydroxyl or —OCOR 21 , R 3d  is hydrogen, and R 4  and R 5  are each hydrogen; then R 1  is bromo, fluoro, —NR 7 R 8 , —R 9 , —SR 10 , or —OR 11 , and R 7  is a substituted aliphatic, or an optionally substituted aryl, heteroaryl, aralkyl, heteroaralkyl, cycloaliphatic, heterocyclyl, (cycloaliphatic)alkyl, or (heterocyclyl)alkyl. 
       
     
     
         4 . The compound of  claim 3 , characterized by one or more of the features (a) through (f):
 (a) R 3a  is selected from the group consisting of hydrogen, hydroxy, methoxy, C 1-4  aliphatic, C 1-4  fluoroaliphatic, and fluoro;   (b) R 3b  is hydrogen;   (c) R 3c  is hydrogen or hydroxy;   (d) R 3d  is hydrogen;   (e) each R 4  is hydrogen; and   (f) R 5  is hydrogen.   
     
     
         5 . The compound of  claim 4 , having the formula (IIA) or (II-B): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         6 . The compound of  claim 4 , having the formula (IIIA) or (III-B): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         7 . The compound of  claim 4 , having the formula (IV-A) or (IV-B): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         8 . The compound of  claim 1 , characterized by formula (V): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         Ring B is an optionally substituted 5- or 6-membered aryl or heteroaryl ring having zero to three ring nitrogen atoms and optionally one additional ring heteroatom selected from oxygen and sulfur; 
         substitutable ring carbon atoms in Ring B are substituted with 0-2 substituents independently selected from the group consisting of C 1-6  aliphatic, C 1-6  fluoroaliphatic, halo, —R a17 , —R b17 , —Z 17 —R a17 , and —Z 17 —R b17 , or two adjacent substituents, taken together with the intervening ring atoms, form an optionally substituted fused 5- or 6-membered aromatic or non-aromatic ring having 0-3 ring heteroatoms selected from the group consisting of O, N, and S; 
         Z 17  is an optionally substituted C 1-6  alkylene chain, wherein the alkylene chain optionally is interrupted by —C(R 14 )═C(R 14 )—, —C≡C—, —O—, —S—, —S(O)—, —S(O) 2 —, —SO 2 N(R 15 )—, —N(R 15 )—, —N(R 15 )C(O)—, —NR 15 C(O)N(R 15 )—, —N(R 15 )CO 2 —, —N(R 15 )SO 2 —, —C(O)N(R 15 )—, —C(O)—, —CO 2 —, —OC(O)—, —OC(O)O—, or —OC(O)N(R 15 )—, and wherein Z 17  or a portion thereof optionally forms part of a 3-7 membered ring; 
         each R a17  independently is an optionally substituted aryl, heteroaryl, heterocyclyl, or cycloaliphatic ring; and 
         each R b17  independently is —NO 2 , —CN, —C(R 14 )═C(R 14 ) 2 , —C≡C—R 14 , —OR 14 , —SR 15 , —S(O)R 15 , —SO 2 R 15 , —SO 2 N(R 16 ) 2 , —N(R 16 ) 2 , —NR 16 C(O)R 14 , —NR 16 C(O)N(R 16 ) 2 , —NR 16 CO 2 R 14 , —O—CO 2 R 14 , —OC(O)N(R 16 ) 2 , —O—C(O)R 14 , —CO 2 R 14 , —C(O)R 14 , —C(O)N(R 16 ) 2 , —C(O)N(R 16 )C(═NR 16 )—N(R 16 ) 2 , —C(═NR 16 ) 2 , —C(═NR 16 )—OR 14 , —C(R 14 )═N—OR 14 , —N(R 16 )C(═NR 16 )—N(R 16 ) 2 , —N(R 16 )SO 2 R 13 , —N(R 16 ) SO 2 N(R 16 ) 2 . 
       
     
     
         9 . The compound of  claim 8 , wherein Ring B is a phenyl ring substituted with 0-2 substituents independently selected from the group consisting of halo, —OH, —O(C 1-3  alkyl), —CN, —N(R 4 ) 2 , —C(O)(C 1-3  alkyl), —CO 2 H, —CO 2 (C 1-3  alkyl), —C(O)NH 2 , —C(O)NH(C 1-3  alkyl), —C 1-3  aliphatic, —C 1-3  fluoroaliphatic, —O(C 1-3  fluoroaliphatic), optionally substituted aryl, and optionally substituted heteroaryl. 
     
     
         10 . The compound of  claim 1 , wherein R 1  is C 1-10  aliphatic, —Z—R 12a , —Z—R 12b , -L-Z—R 12a , -L-Z—R 12b , -L-R 12a  or -L-R 12d ;
 L is —C(R 13 )═C(R 13 )— or —C≡C—; and 
 R 12d  is —NO 2 , —CN, —S(O)R 15 , —SO 2 R 15 , —SO 2 —N(R 16 ) 2 , —CO 2 R 14 , —C(O)R 14 , or —C(O)N(R 16 ). 
 
     
     
         11 . The compound of  claim 1 , wherein R 1  is —V—R 12a , —V—Z—R 12b , or —Z—V—R 12a . 
     
     
         12 . The compound of  claim 10 , characterized by formula (VI): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         W 1  is —Z—, -L-, —V—, —V—Z—, or —Z—V—; 
         Ring C is an optionally substituted 5- or 6-membered aryl, cycloaliphatic, heteroaryl, or heterocyclyl ring having zero to three ring nitrogen atoms and optionally one additional ring heteroatom selected from oxygen and sulfur; 
         substitutable ring carbon atoms in Ring C are substituted with 0-2 substituents independently selected from the group consisting of C 1-6  aliphatic, C 1-6  fluoroaliphatic, halo, —R a12 , —R b12 , —Z 12 —R a12 , and —Z 12 —R b12 , or two adjacent substituents on Ring C, taken together with the intervening ring atoms form an optionally substituted fused 5- or 6-membered aromatic or non-aromatic ring having 0-3 ring heteroatoms selected from the group consisting of O, N, and S; 
         Z 12  is an optionally substituted C 1-6  alkylene chain, wherein the alkylene chain optionally is interrupted by —C(R 14 )═C(R 14 )—, —C≡C—, —O—, —S—, —S(O)—, —S(O) 2 —, —SO 2 N(R 15 )—, —N(R 15 )—, —N(R 15 )C(O)—, —NR 15 C(O)N(R 15 )—, —N(R 15 )CO 2 —, —N(R 15 )SO 2 —, —C(O)N(R 15 )—, —C(O)—, —CO 2 —, —OC(O)—, —OC(O)O—, or —OC(O)N(R 15 )—, and wherein Z 12  or a portion thereof optionally forms part of a 3-7 membered ring; 
         each R a12  independently is an optionally substituted aryl, heteroaryl, heterocyclyl, or cycloaliphatic ring; and 
         each R b12  independently is —NO 2 , —CN, —C(R 14 )═C(R 14 ) 2 , —C≡C—R 14 , —OR 14 , —SR 15 , —S(O)R 15 , —SO 2 R 15 , —SO 2 N(R 16 ) 2 , —N(R 16 ) 2 , —NR 16 C(O)R 14 , —NR 16 C(O)N(R 16 ) 2 , —NR 16 CO 2 R 14 , —O—CO 2 R 14 , —OC(O)N(R 16 ) 2 , —O—C(O)R 14 , —CO 2 R 14 , —C(O)R 14 , —C(O)N(R 16 ) 2 , —C(O)N(R 16 )C(═NR 16 )—N(R 16 ) 2 , —C(═NR 16 )—N(R 16 ) 2 , —C(═R 16 )—OR 14 , —C(R 14 )═N—OR 14 , —N(R 16 )C(═NR 16 )—N(R 16 ) 2 , —N(R 16 )SO 2 R 15 , —N(R 16 )SO 2 N(R 16 ) 2 . In some embodiments, each R b12  independently is —CN, —N(R 4 ) 2 , —NR 4 C(O)R 5 , —NR 4 —C(O)N(R 4 ) 2 , —NR 4 CO 2 R 6 , —C(O)N(R 4 ) 2 , —CO 2 R 5 , or —OR 5 . 
       
     
     
         13 . The compound of  claim 12 , wherein:
 Z is a C 1-6  alkylene chain optionally substituted with one or two R x  or R y ;   each R x  independently is selected from the group consisting of -halo, —OH, —O(C 1-4  alkyl), —O(C 1-4  haloalkyl), —CN, —N(R 4 ) 2 , —C(O)(C 1-4 alkyl), —CO 2 H, —CO 2 (C 1-4 alkyl), —C(O)NH 2 , —C(O)NH(C 1-4 alkyl), or optionally substituted aryl;   each R y  independently is a C 1-3  aliphatic optionally substituted with. R x  or an optionally substituted aryl or heteroaryl group; or two R y  on the same carbon atom, taken together with the carbon atom to which they are attached form a 3- to 6-membered cycloaliphatic ring; and   Ring C is an optionally substituted phenyl ring or an optionally substituted C 3-6  cycloaliphatic ring.   
     
     
         14 . The compound of  claim 1 , wherein R 1  is —NR 7 R 8 , and the compound is characterized by formula (VII): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         R 8  is hydrogen or C 1-4  aliphatic; and 
         Ring D is an optionally substituted mono- or bicyclic aryl, heteroaryl, heterocyclyl, or cycloaliphatic ring. 
       
     
     
         15 . The compound of  claim 14 , wherein:
 each substitutable saturated ring carbon atom in Ring D is unsubstituted or substituted with ═O, ═S, ═C(R 14 ) 2 , ═N—N(R 16 ) 2 , ═N—OR 14 , ═N—NHC(O)R 14 , ═N—NHCO 2 R 15 , ═N—NHSO 2 R 15 ; ═N—R 14 ; or —R d ;   each substitutable unsaturated carbon atom in Ring D is unsubstituted or substituted with —R d ;   each R d  independently is selected from the group consisting of C 1-6  aliphatic, C 1-6  fluoroaliphatic, halo, —R a7 C, —R b7 , —Z 7 —R a7 , and —Z 7 —R b7 ;
 Z 7  is an optionally substituted C 1-6  alkylene chain, wherein the alkylene chain optionally is interrupted by —C(R 14 )═C(R 14 )—, —C≡C—, —O—, —S—, —S(O)—, —S(O) 2 —, —SO 2 N(R 15 )—, —N(R 15 )—, —N(R 15 )C(O)—, —NR 15 C(O)N(R 15 )—, —N(R 15 )CO 2 —, —N(R 15 )SO 2 —, —C(O)N(R 15 )—, —C(O)—, —CO 2 —, —OC(O)—, —OC(O)O—, or —OC(O)N(R 15 )—, and wherein Z 7  or a portion thereof optionally forms part of a 3-7 membered ring; 
 each R a7  independently is an optionally substituted aryl, heteroaryl, heterocyclyl, or cycloaliphatic ring; and 
 each R b7  independently is —NO 2 , —CN, —C(R 14 )═C(R 14 ) 2 , —C≡C—R 14 , —OR 14 , —SR 15 , —S(O)R 15 , —SO 2 R 15 , —SO 2 N(R 16 ) 2 , —N(R 16 ) 2 , —NR 16 C(O)R 14 ; —NR 16 C(O)N(R 16 ) 2 ; —NR 16 CO 2 R 14 ; —O—CO 2 R 14 , —OC(O)N(R 16 ) 2 , —O—C(O)R 14 , —CO 2 R 14 , —C(O)R 14 , —C(O)N(R 16 ) 2 , —C(O)N(R 16 )C(═NR 16 )—N(R 16 ) 2 ; —C(═NR 16 )—N(R 16 ) 2 , —C(═NR 16 )—OR 14 ; —C(R 14 )═N—OR 14 , —N(R 16 )C(═NR 16 )—N(R 16 ) 2 , —N(R 16 )SO 2 R 15 , —N(R 16 )SO 2 N(R 16 ) 2 . 
   
     
     
         16 . The compound of  claim 15 , wherein Ring D is an optionally substituted phenyl, naphthyl, or indanyl ring. 
     
     
         17 . The compound of  claim 15 , wherein Ring D is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       where
 each R 8p  independently is selected from the group consisting of ═O, fluoro, —OR 5x , or a C 1-4  aliphatic or C 1-4  fluoroaliphatic optionally substituted with —OR 5x , —N(R 4x )(R 4y ), —CO 2 R 5x , or —C(O)N(R 4x )(R 4y ), provided that R 8 P is other than —OR 5x  when located at a position adjacent to a ring oxygen atom; 
 s is 0, 1, or 2; and 
 t is 0, 1, or 2. 
 
     
     
         18 . The compound of  claim 1 , wherein R 1  is —O—R 11 , —S—R 10 , or —NR 7 R 8 ; 
       R 7 , R 10 , and R 11  are each independently —Z a R 18 , —Z a R 19 , or —Z b R 20 ;
 Z a  is an optionally substituted C 1-6  alkylene chain, wherein the alkylene chain is optionally interrupted by —C(R 13 )═C(R 13 )—, —C≡C—, —O—, —S—, —N(R 13 )—, —N(R 13 )CO—, —N(R 13 )CO 2 —, —C(O)N(R 13 )—, —C(O)—, —C(O)—C(O)—, —CO 2 —, —OC(O)—, —OC(O)O—, —N(R 13 )C(O)N(R 13 )—, —N(R 13 )N(R 13 )—, —OC(O)N(R 13 )—, —S(O)—, —S(O) 2 —, —N(R 13 )S(O) 2 —, —S(O) 2 N(R 13 )—; 
 Z b  is an optionally substituted C 2-6  alkylene chain, wherein the alkylene chain is optionally interrupted by —C(R 13 )═C(R 13 )—, —C≡C—, —O—, —S—, —N(R 13 )—, —N(R 13 )CO—, —N(R 13 )CO 2 —, —C(O)N(R 13 )—, —C(O)—, —C(O)—C(O)—, —CO 2 —, —OC(O)—, —OC(O)O—, —N(R 13 )C(O)N(R 13 )—, —N(R 13 )N(R 13 )—, —OC(O)N(R 13 )—, —S(O)—, —S(O) 2 —, —N(R 13 )S(O) 2 —, —S(O) 2 N(R 13 )—; 
 R 18  is an optionally substituted aryl, heteroaryl, heterocyclyl, or cycloaliphatic group; 
 R 19  is —C(R 14 )═C(R 14 ) 2 , —C≡C—R 14 , —S(O)R 15 , —SO 2 R 15 , —SO 2 —N(R 16 ) 2 , —C(R 14 )═N—OR 14 , —CO 2 R 14 , —C(O)—C(O)R 14 , —C(O)R 14 , —C(O)N(R 16 ) 2 , —C(═NR 16 )—N(R 16 ) 2 , or —C(═NR 16 )—OR 14 ; 
 R 20  is halo, —NO 2 , —CN, —OR 14 , SR 15 —, —N(R 16 ) 2 , —N(R 16 )C(O)R 15 , —N(R 16 )C(O)N(R 16 ) 2 , —N(R 16 )CO 2 R 14 , —O—CO 2 —R 14 , —OC(O)N(R 16 ) 2 , —OC(O)R 14 , —N(R 16 )—N(R 16 ) 2 , —N(R 16 )S(O) 2 R 15 , or —N(R 16 )SO 2 —N(R 16 ) 2 ; and 
 R 8  is hydrogen. 
 
     
     
         19 . The compound of  claim 18 , wherein:
 Z a  is a C 1-4  alkylene chain optionally substituted with one or two groups selected from the group consisting of —F, —OH, C 1-3  aliphatic and optionally substituted aryl; and   Z b  is a C 2-4  alkylene chain optionally substituted with one or two groups selected from the group consisting of —F, —OH, C 1-3  aliphatic and optionally substituted aryl.   
     
     
         20 . The compound of  claim 19 , characterized by formula (VIII): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
         wherein: 
         W 2  is —O—, —S—, or —N(R 8 )—; 
         Ring E is a mono- or bicyclic aryl, heteroaryl, heterocyclyl, or cycloaliphatic group;
 each substitutable ring nitrogen atom in Ring E is unsubstituted or is substituted with —C(O)R 14 , —C(O)N(R 16 ) 2 , —CO 2 R 14 , —SO 2 R 15 , —SO 2 N(R 16 ) 2 , or an optionally substituted aliphatic; 
 substitutable ring carbon atom in Ring E are substituted with 0-4 substituents independently selected from the group consisting of C 1-6  aliphatic, C 1-6  fluoroaliphatic, halo, —R a18 , —R b18 , —Z 18 —R a18 , and —Z 18 —R b18 ;
 Z 18  is an optionally substituted C 1-6  alkylene chain, wherein the alkylene chain optionally is interrupted by —C(R 14 )═C(R 14 )—, —C≡C—, —O—, —S—, —S(O)—, —S(O) 2 —, —SO 2 N(R 15 )—, —N(R 15 )—, —N(R 15 )C(O)—, —NR 15 C(O)N(R 15 )—, —N(R 15 )CO 2 —, —N(R 15 )SO 2 —, —C(O)N(R 15 )—, —C(O)—, —CO 2 —, —OC(O)—, —OC(O)O—, or —OC(O)N(R 15 )—, and wherein Z 18  or a portion thereof optionally forms part of a 3-7 membered ring; 
 each R a18  independently is an optionally substituted aryl, heteroaryl, heterocyclyl, or cycloaliphatic ring; and 
 each R b18  independently is —NO 2 , —CN, —C(R 14 )═C(R 14 ) 2 , —C≡C—R 14 , —OR 14 , —SR 15 , —S(O)R 15 , —SO 2 R 15 , —SO 2 N(R 16 ) 2 , —N(R 16 ) 2 , —NR 16 C(O)R 14 , —NR 16 C(O)N(R 16 ) 2 , —NR 16 CO 2 R 14 , —O—CO 2 R 14 , —OC(O)N(R 16 ) 2 , —O—C(O)R 14 , —CO 2 R 14 , —C(O)R 14 , —C(O)N(R 16 ) 2 , —C(O)N(R 16 )C(═NR 16 )—N(R 16 ) 2 , —C(═NR 16 )—N(R 16 ) 2 . —C(═NR 16 )—OR 14 , —C(R 14 )═N—OR 14 , —N(R 16 )C(═NR 16 )—N(R 16 ) 2 , —N(R 16 )SO 2 R 15 , —N(R 16 )SO 2 N(R 16 ) 2 . 
 
 
       
     
     
         21 . The compound of  claim 20 , wherein Ring E is a an optionally substituted C 3-6  cycloaliphatic, phenyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyrrolinyl, imidazolinyl, pyrazolinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, morpholinyl, piperazinyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or tetrahydropyrimidinyl ring. 
     
     
         22 . The compound of  claim 21 , wherein Ring E is an optionally substituted phenyl, naphthyl, indanyl, furanyl, thienyl, pyrrolyl, pyrrolidinyl, isoxazolyl, pyrazolyl, piperidinyl, piperazinyl, pyrazinyl, morpholinyl, benzothiophenyl, or benzodioxolyl ring. 
     
     
         23 . A pharmaceutical composition, comprising a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         24 . A method of decreasing an E1 enzyme activity in a sample, comprising contacting a sample with one or more compounds according to  claim 1 . 
     
     
         25 . The method of  claim 24 , wherein the E1 enzyme is selected from the group consisting of NAE, UAE, and SAE. 
     
     
         26 . The method of  claim 25 , wherein the E1 enzyme is NAE. 
     
     
         27 . A method of treating or ameliorating a disorder in a subject, the method comprising administering to a subject in need of such treatment an effective amount of one or more compounds according to  claim 1 , wherein the disorder is selected from the group consisting of cancer, an inflammatory disorder, a neurodegenerative disorder, inflammation associated with infection, and cachexia. 
     
     
         28 . The method of  claim 27 , wherein the disorder is cancer. 
     
     
         29 . The method of  claim 28 , wherein the cancer is lung cancer, colorectal cancer, ovarian cancer, or a hematological cancer. 
     
     
         30 . The method of  claim 27 , wherein the disorder is an immune response or vascular cell proliferation disorder.