Inhibitors of e1 activting 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 . (canceled) 
     
     
         2 . A compound of formula (I-A): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         stereochemical configurations depicted at asterisked positions indicate relative stereochemistry; 
         Ring A is selected from the group: 
       
       
         
           
           
               
               
           
         
         wherein one ring nitrogen atom in Ring A optionally is oxidized; 
         X is —CH 2 —, —CHF—, —CF 2 —, —NH—, or —O—, 
         Y is —O— or —S—; 
         R a  is 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 , C 1-4  aliphatic optionally substituted with one or two substituents independently selected from the group —OR 5x , —N(R 4x )(R 4y ), —CO 2 R 5x , and —C(O)N(R 4x )(R 4y ); or C 1-4  fluoroaliphatic optionally substituted with one or two substituents independently selected from the group —OR 5x , —N(R 4x )(R 4y ), —CO 2 R 5x , and —C(O)N(R 4x )(R 4y ); or R a  and R c  together form a bond; 
         R b  is selected from the group hydrogen, fluoro, C 1-4  aliphatic, and C 1-4  fluoroaliphatic; 
         R c  is 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 , C 1-4  aliphatic optionally substituted with one or two substituents independently selected from the group —OR 5x , —N(R 4x )(R 4y ), —CO 2 R 5x , and —C(O)N(R 4x )(R 4y ); or C 1-4  fluoroaliphatic optionally substituted with one or two substituents independently selected from the group —OR 5x , —N(R 4x )(R 4y ), —CO 2 R 5x , and —C(O)N(R 4x )(R 4y ); or R a  and R c  together form a bond; 
         R d  is selected from the group hydrogen, fluoro, C 1-4  aliphatic, and C 1-4  fluoroaliphatic; 
         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; 
         R e′  is hydrogen 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; 
         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(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 6 , 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; 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 ; 
         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 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; 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 1, 2, or 3. 
       
     
     
         3 . The compound of  claim 2 , or a pharmaceutically acceptable salt thereof, wherein:
 R g  is hydrogen, C 1-6  aliphatic, C 1-6 -fluoroaliphatic, halo, —R 1g , —R 2g , -T 1 -R 1g , -T 1 -R 2g , —V 1 -T 1 -R 1g , or —V 1 -T 1 -R 2g ;
 T 1  is a C 1-6  alkylene chain substituted with 0-2 independently selected R 3a  or R 3b , wherein the alkylene chain optionally is interrupted by —C(R 5 )═C(R 5 )—, —C≡C—, —O—, —S—, —S(O)—, —S(O) 2 —, —SO 2 N(R 4 )—, —N(R 4 )—, —N(R 4 )C(O)—, —NR 4 C(O)N(R 4 )—, —N(R 4 )C(═NR 4 )—N(R 4 )—, —N(R 4 )—C(═NR 4 )—, —N(R 4 )CO 2 —, —N(R 4 )SO 2 —, —N(R 4 )SO 2 N(R 4 )—, —OC(O)—, —OC(O)N(R 4 )—, —C(O)—, —CO 2 —, —C(O)N(R 4 )—, —C(═NR 4 )—N(R 4 )—, —C(NR 4 )═N(R 4 )—, —C(═NR 4 )—O—, or —C(R 6 )═N—O—, and wherein T 1  or a portion thereof optionally forms part of a 3-7 membered ring; 
 V 1  is —C(R 5 )═C(R 5 )—, —C≡C—, —O—, —S—, —S(O)—, —S(O) 2 —, —SO 2 N(R 4 )—, —N(R 4 )—, —N(R 4 )C(O)—, —NR 4 C(O)N(R 4 )—, —N(R 4 )C(═NR 4 )—N(R 4 )—, —N(R 4 )C(═NR 4 )—, —N(R 4 )CO 2 —, —N(R 4 )SO 2 —, —N(R 4 )SO 2 N(R 4 )—, —OC(O)—, —OC(O)N(R 4 )—, —C(O)—, —CO 2 —, —C(O)N(R 4 )—, —C(O)N(R 4 )—O—, —C(O)N(R 4 )C(═NR 4 )—N(R 4 )—, —N(R 4 )C(═NR 4 )—N(R 4 )—C(O)—, —C(═NR 4 )—N(R 4 )—, —C(NR 4 )═N(R 4 )—, —C(═NR 4 )—O—, or —C(R 6 )═N—O—; 
 each R 1g  independently is an optionally substituted aryl, heteroaryl, heterocyclyl, or cycloaliphatic ring; 
 each R 2g  independently is —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 , or —C(R 6 )═N—OR 5 ; 
 each R 3a  independently is selected from the group —F, —OH, —O(C 1-4  alkyl), —CN, —N(R 4 ) 2 , —C(O)(C 1-4  alkyl), —CO 2 H, —CO 2 (C 1-4  alkyl), —C(O)NH 2 , and —C(O)NH(C 1-4  alkyl); 
 each R 3b  independently is a C 1-3  aliphatic optionally substituted with R 3a  or R 7 , or two substituents R 3b  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 
 each R 7  independently is an optionally substituted aryl or heteroaryl ring. 
   
     
     
         4 . The compound of  claim 2 , or a pharmaceutically acceptable salt thereof, characterized by one or more of the following features:
 (a) X is —O—;   (b) Y is —O—;   (c) R a  is —OH;   (d) R b  and R d  are each independently hydrogen, fluoro, or C 1-4  aliphatic;   (e) R c  is hydrogen, fluoro, or —OR 5 ;   (f) R e  and R e′  are each hydrogen;   (g) each R f  is hydrogen;   (h) each R h  is hydrogen;   (i) R j  is hydrogen or C 1-4  aliphatic;   (j) R k  is hydrogen, halo, or C 1-4  aliphatic;   (k) m is 1; and   (l) stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry.   
     
     
         5 . The compound of  claim 4 , characterized by formula (III): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein Q is ═N— or ═C(R k )—. 
       
     
     
         6 . The compound of  claim 5 , or a pharmaceutically acceptable salt thereof, wherein:
 R g  is —V 1 -T 1 -R 1g , —V 1 —R 1g , -T 1 -R 1g , or -T 1 -V 1 —R 1g ;   V 1  is —C(R 5 )═C(R 5 ), —C≡C—, —O—, —S—, or —N(R 4 )—;   T 1  is a C 1-4  alkylene chain optionally substituted with one or two groups independently selected from fluoro, C 1-4  aliphatic optionally substituted with one or two substituents independently selected from the group —OR 5x , —N(R 4x )(R 4y ), —CO 2 R 5x , and —C(O)N(R 4x )(R 4y ), and C 1-4  fluoroaliphatic optionally substituted with one or two substituents independently selected from the group —OR 5x , —N(R 4x )(R 4y ), —CO 2 R 5x , and —C(O)N(R 4x )(R 4y ); and   R 1g  is an optionally substituted mono- or bicyclic aryl, heteroaryl, heterocyclyl, or cycloaliphatic group.   
     
     
         7 . The compound of  claim 6 , characterized by formula (V): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         V 1  is —N(R 8 )—, —O—, or —S—; 
         R 8  is hydrogen or C 1-4  aliphatic; 
         T 1  is a C 1-4  alkylene chain optionally substituted with one or two groups independently selected from fluoro, C 1-4  aliphatic optionally substituted with one or two substituents independently selected from the group —OR 5x , —N(R 4x )(R 4y ), CO 2 R 5x , and —C(O)N(R 4x )(R 4y ), and C 1-4  fluoroaliphatic optionally substituted with one or two substituents independently selected from the group —OR 5x , —N(R 4x )(R 4y ), —CO 2 R 5x , and —C(O)N(R 4x )(R 4y ); and 
         Ring C is a 3- to 8-membered heterocyclyl or cycloaliphatic ring, or a 5- or 6-membered aryl or heteroaryl ring, any of which rings is substituted with 0-2 R o  and 0-2 R 8o :
 each R o  independently is 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 , —C(═NR 4 )—N(R 4 )—OR 5 , —C(R 6 )═N—OR 5 , or an optionally substituted aliphatic, or an optionally substituted aryl, heterocyclyl, or heteroaryl group; or two R o  on the same saturated ring carbon atom; taken together with the carbon atom, form an optionally substituted 3- to 8-membered spirocyclic cycloaliphatic or heterocyclyl ring; or two adjacent R o , taken together with the intervening ring atoms, form an optionally substituted fused 4- to 8-membered aromatic or non-aromatic ring having 0-3 ring heteroatoms selected from the group O, N, and S; 
 each R 8o  independently is C 1-4  aliphatic, C 1-4 . fluoroaliphatic, halo, —OR 5x , —N(R 4x )(R 4y ), C 1-4  aliphatic optionally substituted with —OR 5x , —N(R 4x )(R 4y ), —CO 2 R 5x , or —C(O)N(R 4x )(R 4y ), 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 ); 
 
         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; and 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. 
       
     
     
         8 . The compound of  claim 7 , or a pharmaceutically acceptable salt thereof, wherein:
 T 1  is a C 1-2  alkylene chain optionally substituted with one or two groups independently selected from fluoro, C 1-4  aliphatic optionally substituted with one or two substituents independently selected from the group —OR 5x , —N(R 4x )(R 4y ), CO 2 R 5x , and —C(O)N(R 4x )(R 4y ), and C 1-4  fluoroaliphatic optionally substituted with one or two substituents independently selected from the group —OR 5x , —N(R 4x )(R 4y ), —CO 2 R 5x , and —C(O)N(R 4x )(R 4y ); and   Ring C is a C 3-6  cycloaliphatic, phenyl, oxazolyl, or isoxazolyl ring, any of which is substituted with 0-2 R 8o  and optionally is fused to an optionally substituted benzene, dioxolane, or dioxane ring.   
     
     
         9 . The compound of  claim 5 , characterized by formula (VI): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         T 1  is a C 1-4  alkylene chain optionally substituted with one or two groups independently selected from fluoro, C 1-4  aliphatic optionally substituted with one or two substituents independently selected from the group —OR 5x , —N(R 4x )(R 4y ), —CO 2 R 5x , and —C(O)N(R 4x )(R 4y ), and C 1-4  fluoroaliphatic optionally substituted with one or two substituents independently selected from the group —OR 5x , —N(R 4x )(R 4y ), —CO 2 R 5x , and —C(O)N(R 4x )(R 4y ); and 
         Ring C is a 3- to 8-membered heterocyclyl or cycloaliphatic ring, or a 5- or 6-membered aryl or heteroaryl ring, any of which rings is substituted with 0-2 R o  and 0-2 R 8o );
 each R o  independently is 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 5 , —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 , —C(═NR 4 )—N(R 4 )—OR 5 , —C(R 6 )═N—OR 5 , or an optionally substituted aliphatic, or an optionally substituted aryl, heterocyclyl, or heteroaryl group; or two R o  on the same saturated ring carbon atom, taken together with the carbon atom, form an optionally substituted 3- to 8-membered spirocyclic cycloaliphatic or heterocyclyl ring; or two adjacent R o , taken together with the intervening ring atoms, form an optionally substituted fused 4- to 8-membered aromatic or non-aromatic ring having 0-3 ring heteroatoms selected from the group O, N, and S; 
 each R 8o  independently is C 1-4  aliphatic, C 1-4  fluoroaliphatic, halo, —OR 5x , —N(R 4x )(R 4y ), C 1-4  aliphatic optionally substituted with —OR 5x , —N(R 4x )(R 4y ), —CO 2 R 5x , or —C(O)N(R 4x )(R 4y ), 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 ); 
 
         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; and each R 5x  independently is hydrogen, C 14  alkyl, C 1-4  fluoroalkyl, or an optionally substituted C 6-10  aryl or C 6-10  ar(C 1-4 )alkyl. 
       
     
     
         10 . The compound of  claim 9 , or a pharmaceutically acceptable salt thereof, wherein:
 T 1  is a C 1-2  alkylene chain optionally substituted with one or two groups independently selected from fluoro, C 1-4  aliphatic optionally substituted with one or two substituents independently selected from the group —OR 5x , —N(R 4x )(R 4y ), —CO 2 R 5x , and —C(O)N(R 4x )(R 4y ), and C 1-4  fluoroaliphatic optionally substituted with one or two substituents independently selected from the group —OR 5x , —N(R 4x )(R 4y ), —CO 2 R 5x , and —C(O)N(R 4x )(R 4y ); and   Ring C is phenyl, which is substituted with 0-2 R 8o  and optionally is fused to an optionally substituted benzene, dioxolane, or dioxane ring.   
     
     
         11 . The compound of  claim 5 , characterized by formula (VII): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         V 2  is —N(R 8 )—, —O—, or —S—: 
         R 8  is hydrogen or C 1-4  aliphatic; and 
         Ring D is an optionally substituted mono-, bi-, or tricyclic rind system. 
       
     
     
         12 . The compound of  claim 11 , or a pharmaceutically acceptable salt thereof, wherein Ring D is selected from the group furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, phenyl, naphthyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolizinyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, benzthiazolyl, benzothienyl, benzofuranyl, purinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, quinuclidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indanyl, phenanthridinyl, tetrahydronaphthyl, indolinyl, benzodioxanyl, benzodioxolyl, chromanyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, bicycloheptanyl and bicyclooctanyl. 
     
     
         13 . The compound of  claim 12 , or a pharmaceutically acceptable salt thereof, wherein:
 each substitutable saturated ring carbon atom in Ring D is unsubstituted or substituted with ═O, ═S, ═C(R 5 ) 2 , ═N—N(R 4 ) 2 , ═N—OR 5 , ═N—NHC(O)R 5 , ═N—NHCO 2 R 6 , ═N—NHSO 2 R 6 , ═N—R 5  or —R p ;   each substitutable unsaturated ring carbon atom in Ring D is unsubstituted or substituted with —R p ;   each substitutable ring nitrogen atom in Ring D is unsubstituted or substituted with —R 9p ;   each R p  independently is 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 5 , —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 , —O(═NR 4 )—OR 5 , —C(═NR 4 )—N(R 4 )—OR 5 , —C(R 6 )═N—OR 5 , or an optionally substituted aliphatic, or an optionally substituted aryl, heterocyclyl, or heteroaryl group; or two R p  on the same saturated carbon atom, taken together with the carbon atom to which they are attached, form an optionally substituted 3- to 6-membered spirocyclic cycloaliphatic ring; and   each R 9p  independently is —C(O)R 5 , —C(O)N(R 4 ) 2 , —CO 2 R 6 , —SO 2 R 6 , —SO 2 N(R 4 ) 2 , or a C 1-4  aliphatic optionally substituted with R 3  or R 7 .   
     
     
         14 . The compound of  claim 12 , or a pharmaceutically acceptable salt thereof, wherein:
 each R p  independently is selected from the group halo, C 1-6  aliphatic, C 1-6  fluoroaliphatic, —R 1p , —R 2p , -T 2 -R 1p , and -T 2 -R 2p ; or two R p  on the same saturated carbon atom, taken together with the carbon atom to which they are attached, form an optionally substituted 3- to 6-membered spirocyclic cycloaliphatic ring;   T 2  is a C 1-6  alkylene chain optionally substituted with R 3a  or R 3b ;   each R 1p  independently is an optionally substituted aryl, heteroaryl, or heterocyclyl group; and   each R 2p  independently is —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 , —C(═NR 4 )—N(R 4 )—OR 5 , or —C(R 6 )═N—OR 5 .   
     
     
         15 . The compound of  claim 14 , or a pharmaceutically acceptable salt thereof, wherein Ring D is an optionally substituted indanyl, tetrahydronaphthyl, or chromanyl. 
     
     
         16 . The compound of  claim 15 , or a pharmaceutically acceptable salt thereof, wherein:
 V 1  is —N(R 8 )—;   Ring D is:   
       
         
           
           
               
               
           
         
         each R p  independently is halo, —OR 5x , —N(R 4x )(R 4y ), —CO 2 R 5x , —C(O)N(R 4 )(R 4y ), C 1-4  aliphatic optionally substituted with —OR 5x , —N(R 4x )(R 4y ), —CO 2 R 5x , or —C(O)N(R 4x )(R 4Y ), 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 ); 
         each R 8p  independently is fluoro, —OR 5x , —N(R 4x )(R 4y ), —CO 2 R 5x , C(O)N(R 4x )(R 4y ), C 1-4  aliphatic optionally substituted with —OR 5x , —N(R 4x )(R 4y ), —CO 2 R 5x , or —C(O)N(R 4x )(R 4y ) 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 8p  is other than —OR 5x  or —N(R 4x )(R 4y ) when located at a position adjacent to a ring oxygen atom, and further provided that when two R 8p  are attached to the same carbon atom, one must be fluoro, —CO 2 R 5x , —C(O)N(R 4x )(R 4y ), C 1-4  aliphatic optionally substituted with —OR 5x , —N(R 4x )(R 4Y ), —CO 2 R 5x , or —C(O)N(R 4x )(R 4y ), 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 ); or two R 8p  on the same carbon atom together form ═O or ═C(R 5x ) 2 ; or two R 8p  on the same carbon atom are taken together with the carbon atom to which they are attached to form a 3- to 6-membered spirocyclic ring; 
         s is 0, 1, 2, 3, or 4; 
         t is 0, 1, or 2. 
       
     
     
         17 . (canceled) 
     
     
         18 . (canceled) 
     
     
         19 . (canceled) 
     
     
         20 . (canceled) 
     
     
         21 . (canceled) 
     
     
         22 . (canceled) 
     
     
         23 . (canceled) 
     
     
         24 . A compound of formula (XI) or formula (XII): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         depicted stereochemical configurations indicate absolute stereochemistry; 
         Ring A is selected from the group: 
       
       
         
           
           
               
               
           
         
         wherein one ring nitrogen atom in Ring A optionally is oxidized; 
         R b  is hydrogen; 
         R d  is hydrogen; 
         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; 
         each R f  independently is hydrogen, fluoro, C 1-4  aliphatic, or C 1-4  fluoroaliphatic; 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; 
         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 , —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 6 , —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, —C(R 6 )═N—OR 5 , or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl; 
         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 aa  is hydrogen or a hydroxyl protecting group; and 
         R bb  is hydrogen or a hydroxyl protecting group; 
         R cc  is hydrogen or a hydroxyl protecting group; or 
         R aa  and R bb  together form a cyclic dial protecting group; or 
         R aa  and R cc  together form a cyclic dial protecting group. 
       
     
     
         25 . The compound of  claim 24 , or a pharmaceutically acceptable salt thereof, characterized by formula (XIa) or (XIIa) 
       
         
           
           
               
               
           
         
         wherein Ar is an optionally substituted aryl group. 
       
     
     
         26 . The compound of  claim 24 , or a pharmaceutically acceptable salt thereof, selected from the group: 
       
         
           
           
               
               
           
         
         wherein Ar is an optionally substituted aryl group. 
       
     
     
         27 . The compound of  claim 24 , or a pharmaceutically acceptable salt thereof, wherein the compound is: 
       
         
           
           
               
               
           
         
         wherein R aa  and R cc  are each independently a hydroxyl protecting group, or R aa  and R cc  together form a cyclic diol protecting group. 
       
     
     
         28 . The compound of  claim 24 , or a pharmaceutically acceptable salt thereof, selected from the group: 
       
         
           
           
               
               
           
         
         wherein R aa  and R bb  are each independently a hydroxyl protecting group. 
       
     
     
         29 . A pharmaceutical composition, comprising a compound of formula (I-A): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein; 
         stereochemical configurations depicted at asterisked positions indicate relative stereochemistry; 
         Ring A is selected from the group: 
       
       
         
           
           
               
               
           
         
         wherein one ring nitrogen atom in Ring A optionally is oxidized; 
         X is —CH 2 —, —CHF—, —CF 2 —, —NH—, or —O—; 
         Y is —O— or —S—; 
         R a  is 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 , C 1-4  aliphatic optionally substituted with one or two substituents independently selected from the group —OR 5x , —N(R 4x )(R 4y ), —CO 2 R 5x , and —C(O)N(R 4x )(R 4y ), or C 1-4  fluoroaliphatic optionally substituted with one or two substituents independently selected from the group —OR 5x , —N(R 4x )(R 4y ), —CO 2 R 5x , and —C(O)N(R 4x )(R 4y ); or R a  and R c  together form a bond; 
         R b  is selected from the group hydrogen, fluoro, C 1-4  aliphatic, and C 1-4  fluoroaliphatic; 
         R c  is 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 , C 1-4  aliphatic optionally substituted with one or two substituents independently selected from the group —OR 5x , —N(R 4x )(R 4y ), —CO 2 R 5x , and —C(O)N(R 4x )(R 4y ), or C 1-4  fluoroaliphatic optionally substituted with one or two substituents independently selected from the group —OR 5x , —N(R 4x )(R 4y ), —CO 2 R 5x ; and —C(O)N(R 4x )(R 4y ); or R a  and R c  together form a bond; 
         R d  is selected from the group hydrogen, fluoro, C 1-4  aliphatic, and C 1-4  fluoroaliphatic; 
         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; 
         R e′  is hydrogen 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; 
         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 , —C 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, —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; 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 ; 
         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 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; 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 1, 2, or 3; and 
         a pharmaceutically acceptable carrier. 
       
     
     
         30 . The pharmaceutical composition of  claim 29 , formulated for administration to a human patient. 
     
     
         31 . (canceled) 
     
     
         32 . (canceled) 
     
     
         33 . (canceled) 
     
     
         34 . A method for treating cancer in a patient in need thereof, comprising administering to the patient a compound of formula (I-A): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 stereochemical configurations depicted at asterisked positions indicate relative stereochemistry; 
 Ring A is selected from the group: 
 
       
         
           
           
               
               
           
         
         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 )—; 
         R a  is 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 , C 1-4  aliphatic optionally substituted with one or two substituents independently selected from the group —OR 5x , —N(R 4x )(R 4y ), —CO 2 R 5x , and —C(O)N(R 4x )(R 4y ); or C 1-4  fluoroaliphatic optionally substituted with one or two substituents independently selected from the group —OR 5x , —N(R 4x )(R 4y ), —CO 2 R 5x ; and —C(O)N(R 4x )(R 4y ); or R a  and R c  together form a bond; 
         R b  is selected from the group hydrogen, fluoro, C 1-4  aliphatic, and C 1-4  fluoroaliphatic; 
         R c  is 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 , C 1-4  aliphatic optionally substituted with one or two substituents independently selected from the group —OR 5x , —N(R 4x )(R 4y ), —CO 2 R 5x , and —C(O)N(R 4x )(R 4y ); or C 1-4  fluoroaliphatic optionally substituted with one or two substituents independently selected from the group —OR 5x , —N(R 4x )(R 4y ), —CO 2 R 5x , and —C(O)N(R 4x )(R 4y ); or R a  and R c  together form a bond; 
         R d  is selected from the group hydrogen, fluoro, C 1-4  aliphatic, and C 1-4  fluoroaliphatic; 
         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; 
         R e′  is hydrogen 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; 
         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 6 , —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 6 , —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; 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 ; 
         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 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; 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 1, 2, or 3. 
       
     
     
         35 . The method of  claim 34 , wherein the cancer is lung cancer, colorectal cancer, ovarian cancer, or a hematological cancer. 
     
     
         36 . (canceled) 
     
     
         37 . The method of  claim 34 , wherein the cancer is a solid tumor. 
     
     
         38 . The method of  claim 37 , wherein the solid tumor is pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, renal cancer, hepatocellular cancer, lung cancer, ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancer, brain tumors, bone cancer, or soft tissue sarcoma. 
     
     
         39 . The method of  claim 37 , wherein the solid tumor is colorectal cancer, ovarian cancer, lung cancer, breast cancer, gastric cancer, prostate cancer, or pancreatic cancer. 
     
     
         40 . The method of  claim 35 , wherein the cancer is a hematological cancer selected from acute myeloid leukemia and myelodysplastic syndromes. 
     
     
         41 . The compound of  claim 2 , wherein the compound is selected from: 
       
         
           
                 
                 
               
                     
                     
                 
                     
                   Chemical Name 
                 
                     
                     
                 
                     
                 
                 
                 
               
                   I-55 
                   ((2S,3S,5R)-5-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H- 
                 
                     
                   pyrrolo-[2,3-d]pyrimidin-7-yl}-3-hydroxytetrahydrofuran-2- 
                 
                     
                   yl)methyl sulfamate 
                 
                   I-57 
                   {(2S,3S,5R)-5-[6-(benzylamino)-9H-purin-9-yl]-3-hydroxytetra- 
                 
                     
                   hydrofuran-2-yl}methyl sulfamate 
                 
                   I-58 
                   N-[((2S,3S,5R)-5-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H- 
                 
                     
                   pyrrolo-[2,3-d]pyrimidin-7-yl}-3-hydroxytetrahydrofuran-2-yl)- 
                 
                     
                   methyl]sulfamide 
                 
                     
                 
             
                
                
                
               
               
                
               
            
             
                
                
                
                
                
                
                
                
                
               
            
           
         
       
       or a pharmaceutically acceptable salt thereof.