Compounds useful as antagonists of ccr2

Abstract

The present invention provides compounds of general formula I: or a pharmaceutically acceptable salt thereof, wherein X, n, Y, and R 1 are defined generally and in subsets herein. Compounds of the invention are inhibitors of CCR2 and accordingly are useful for the treatment of a variety of inflammatory, allergic, and autoimmune diseases, disorders, or conditions.

1 . A compound of formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         n is 1 or 2; 
         Y is —Y 1 —Y 2 —, or —Y 3 —Y 4 — wherein:
 Y 1  is —SO 2 N(R′)—, —C(O)N(R′)—; —C(O)N(R′)C(O)—, —N(R′)SO 2 —, or —N(R′)SO 2 N(R′)—, 
 Y 2  is absent or is an optionally substituted C 1-6  alkylene chain, wherein one or two methylene units of Y 2  are optionally and independently interrupted by —O—, —S—, —N(R′)—, —C(O)—, —OC(O)—, —C(O)O—, —S(O)—, —S(O) 2 —, —C(O)N(R′)—, —N(R′)C(O)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —OC(O)N(R′)—, —N(R′)S(O) 2 —, or —S(O) 2 N(R′)—, or wherein Y 2 , or a portion thereof, is an optionally substituted ring selected from 3-6-membered cycloaliphatic, 3-6-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-membered aryl, or 5-6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 Y 3  is —N(R′)C(O)—, —NR′C(O)N(R′)—, —N(R′)C(O)O—; and 
 Y 4  is an optionally substituted C 1-6  alkylene chain, wherein one or two methylene units of Y 4  are optionally and independently interrupted by —O—, —S—, —N(R′)—, —C(O)—, —OC(O)—, —C(O)O—, —S(O)—, —S(O) 2 —, —C(O)N(R′)—, —N(R′)C(O)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —OC(O)N(R′)—, —N(R′)S(O) 2 —, or —S(O) 2 N(R′)—, 
 each R′ is independently hydrogen or optionally substituted C 1-6 aliphatic; 
 
         R 1  is an optionally substituted group selected from 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
         ring A is substituted at one or more carbon atoms with m independent occurrences of R 2 ; 
         m is 0-6; 
         each occurrence of R 2  is independently halogen, ═O, ═S, —CN, —R 2b , —N(R 2a ) 2 , —OR 2a , —SR 2b , —S(O) 2 R 2b , —C(O)R 2a , —C(O)OR 2a , —C(O)N(R 2a ) 2 , —S(O) 2 N(R 2a ) 2 , —OC(O)N(R 2a ) 2 , —N(R′)C(O)R 2a , —N(R′)SO 2 R 2b , —N(R′)C(O)OR 2a , —N(R′)C(O)N(R 2a ) 2 , or —N(R′)SO 2 N(R 2a ) 2 , or two occurences of R 2a  or R 2b  are optionally taken together with their intervening atom(s) to form an optionally substituted spiro, fused, or bridged ring selected from 6-membered aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or two occurrences of R ea , taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring having 1-3 additional heteroatoms selected from nitrogen, oxygen, or sulfur;
 each occurrence of R 2a  is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 each occurrence of R 2b  is independently an optionally substituted group selected from C 1-6 aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 
         ring B is substituted with r independent occurrences of —R 3 ; 
         r is 0-6; 
         each occurrence of R 3  is independently —R 3a , -T 1 -R 3d , or —V 1 -T 1 -R 3d , wherein:
 each occurrence of —R 3a  is independently halogen, —CN, —NO 2 , —R 3e , —N(R 3b ) 2 , —OR 3b , —SR 3c , —S(O) 2 R 3c , —C(O)R 3b , —C(O)OR 3b , —C(O)N(R 3b ) 2 , —S(O) 2 N(R 3b ) 2 , —OC(O)N(R 3b ) 2 , —N(R′)C(O)R 3b , —N(R′)SO 2 R 3c , —N(R′)C(O)OR 3b , —N(R′)C(O)N(R 3b ) 2 , or —N(R′)SO 2 N(R 3b ) 2 , or two occurences of R 3b  or R 3c  are optionally taken together with their intervening atom(s) to form an optionally substituted spiro, fused, or bridged ring selected from 6-membered aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or two occurrences of R 3b , taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring having 1-3 additional heteroatoms selected from nitrogen, oxygen, or sulfur; 
 each occurrence of R 3b  is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 each occurrence of R 1a  is independently an optionally substituted group selected from C 1-6 aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 each occurrence of R 3d  is independently an optionally substituted group selected from 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 each occurrence of V 1  is independently —C(R′)═C(R′)—, —C≡C—, —N(R′)—, —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O) 2 N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—, —N(R′)SO 2 —, —N(R′)C(O)O—, —NR′C(O)N(R′)—, —N(R′)SO 2 N(R′)—, —OC(O)—, or —C(O)N(R′)—O—; 
 each occurrence of T 1  is independently C 1-6  alkylene chain optionally substituted with R 3a , wherein the alkylene chain optionally is interrupted by —C(R′)═C(R′)—, —C≡C—, —N(R′)—, —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O) 2 N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—, —N(R′)SO 2 —, —N(R′)C(O)O—, —NR′C(O)N(R′)—, —N(R′)SO 2 N(R′)—, —OC(O)—, or —C(O)N(R′)—O— or wherein T 1  or a portion thereof optionally forms part of an optionally substituted 3-7 membered cycloaliphatic or heterocyclyl ring; 
 
         X is —O—, —S—, —SO 2 —, or —N(W—R 4 )—; 
         W is absent or is a group selected from —W 1 -L 2 -W 2 —, wherein W 1  and W 2  are each independently absent or are an optionally substituted C 1-3 alkylene chain, and L 2  is absent or is a group selected from —N(R)—, —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(O)O—, —C(O)N(R)—, —S(O) 2 N(R)—, —OC(O)N(R)—, —N(R)C(O)—, —N(R)SO 2 —, —N(R)C(O)O—, —N(R)C(O)N(R)—, —N(R)SO 2 N(R)—, —OC(O)—, or —C(O)N(R)—O—, wherein R is hydrogen or C 1- C 4 alkyl, provided that if W 1  is absent then L 2  is selected from —C(O)—, —C(O)O—, —C(O)O—, —S(O)—, —S(O) 2 —, —C(O)N(R)—, or —S(O) 2 N(R)—
 R 4  is an optionally substituted monocyclic or bicyclic ring selected from 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 
 
         provided that the compound is other than:
 a) 4-Morpholinebutanamide, N-[3-cyano-1-(tetrahydro-2H-pyran-4-yl)-3-pyrrolidinyl]-α-(cyclohexylmethyl)-γ-oxo-; 
 b) 4-Morpholinebutanamide, N-[3-cyano-1-(tetrahydro-2H-thiopyran-4-yl)-3-pyrrolidinyl]-α-(cyclohexylmethyl)-γ-oxo-; 
 c) 4-Morpholinecarboxamide, N-[(1S)-2-[[3-cyano-1-(1-methyl-4-piperidinyl)-3-pyrrolidinyl]amino]-1-(cyclohexylmethyl)-2-oxoethyl]-; 
 d) 4-Morpholinebutanamide, N-[3-cyano-1-(tetrahydro-2H-pyran-4-yl)-3-pyrrolidinyl]-α-(cyclohexylmethyl)-γ-oxo; 
 e) Benzeneacetamide, N-[(3S)-1-[1-(2-cyanophenyl)-4-piperidinyl]-3-pyrrolidinyl]-3,4-difluoro-, monohydrochloride; 
 f) Benzeneacetamide, 3,4-difluoro-N-[(3R)-1-[1-(2-nitrophenyl)-4-piperidinyl]-3-pyrrolidinyl]-, hydrochloride; 
 g) Benzeneacetamide, 3,4-difluoro-α-(1-methylethyl)-N-[(3R)-1-[1-(2-nitrophenyl)-4-piperidinyl]-3-pyrrolidinyl], hydrochloride; 
 h) Benzeneacetamide, N-[(3R)-1-[1-(2-cyanophenyl)-4-piperidinyl]-3-pyrrolidinyl]-3,4-difluoro-α-(1-methylethyl)-, (αS)—; 
 i) Benzeneacetamide, N-[(3R)-1-[1-(2-cyanophenyl)-4-piperidinyl]-3-pyrrolidinyl]-3,4-difluoro-α-(1-methylethyl)-, (αR)—; 
 j) Benzeneacetamide, N-[1′-(2-cyanophenyl)[1,4′-bipiperidin]-3-yl]-3,4-difluoro-; 
 k) [1,4′-Bipiperidine]-3-carboxamide, N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methyl-1′-propyl-; 
 1) [1,4′-Bipiperidine]-3-carboxamide, N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methyl-1′-(phenylmethyl)-; 
 m) [1,4′-Bipiperidine]-3-carboxamide,1′-[[2,6-bis(4-chlorophenyl)-4-pyridinyl]carbonyl]-N-methyl-N-(1-methyl-4-piperidinyl)-, (3R)—; 
 n) Benzeneacetamide, N-[1′-(2-cyanophenyl)[1,4′-bipiperidin]-3-yl]-3,4-difluoro-, monohydrochloride; and 
 o) Benzeneacetamide, N-[1′-(2-cyanophenyl)[1,4′-bipiperidin]-3-yl]-3,4-difluoro-. 
 
       
     
     
         2 . The compound of  claim 1 , wherein n is 1 and the compound has the structure of formula I-A: 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 2 , wherein r is 0, 1, or 2. 
     
     
         4 . The compound of  claim 3 , wherein r is 1 and the compound has the structure of formula I-B: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound of  claim 3 , wherein r is 2 and the compound has the structure of 1-B-i: 
       
         
           
           
               
               
           
         
         wherein the two occurrences of R 3 , taken together, form an optionally substituted 3-6-membered Spiro carbocyclic or heterocyclic ring. 
       
     
     
         6 . The compound of  claim 4  or  5 , wherein R′ is an optionally substituted aryl group. 
     
     
         7 . The compound of  claim 5 , wherein R 1  is an optionally substituted phenyl group. 
     
     
         8 . The compound of  claim 4  or  5 , wherein R 1  is an optionally substituted 5-8-membered monocyclic or 7-10-membered bicyclic heterocyclyl or heteroaryl ring having 1-4 heteroatoms independently selected from N, O, or S. 
     
     
         9 . The compound of  claim 8 , wherein R 1  is an optionally substituted group selected from: 
       
         
           
           
               
               
           
         
       
     
     
         10 . The compound of  claim 8 , wherein R 1  is an optionally substituted group selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         11 . The compound of  claim 4  or  5 , wherein:
 R 1  is an optionally substituted aryl group or R 1  is an optionally substituted 5-8-membered monocyclic or 7-10-membered bicyclic heterocyclyl or heteroaryl ring having 1-4 heteroatoms independently selected from N, O, or S, and 
 R 1  is optionally substituted with 1-3 occurrences of R 1a , wherein each occurrence of R 1a  is independently halogen, ═O, ═S, —CN, —NO 2 , —R 1c , —N(R 1b ) 2 , —SR 1c , —S(O) 2 R 1c , —C(O)R 1b , —C(O)OR 1b , —C(O)N(R 1b ) 2 , —S(O) 2 N(R 1b ) 2 , —OC(O)N(R 1b ) 2 , —N(R′)C(O)R 1b , —N(R′)SO 2 R 1c , N(R′)C(O)OR 1b , —N(R′)C(O)N(R 1b ) 2 , or —N(R′)SO 2 N(R 1b ) 2 , or two occurences of R 1b  or R 1c  are optionally taken together with their intervening atom(s) to form an optionally substituted spiro, fused, or bridged ring selected from 6-membered aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or two occurrences of R 1b , taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring having 1-3 additional heteroatoms selected from nitrogen, oxygen, or sulfur, wherein
 each occurrence of R 1b  is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and 
 each occurrence of R 1c  is independently an optionally substituted group selected from C 1-6 aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
 
 
     
     
         12 . The compound of  claim 11 , wherein each occurrence of R 1a  is independently ═O, halogen, —R 1c , —N(R 1b ) 2 , —OR 1b , or —SR 1c . 
     
     
         13 . The compound of  claim 11 , wherein each occurrence of R 1a  is independently C 1-4 fluoroalkyl, —O (C 1-4 -fluoroalkyl), or —S(C 1-4 -fluoroalkyl). 
     
     
         14 . The compound of  claim 4  or  5 , wherein Y is —Y 1 —Y 2 —, and Y 1  is —SO 2 N(R′)—, —C(O)NR′—, or —N(R′)S(O) 2 —. 
     
     
         15 . The compound of  claim 4  or  5 , wherein Y is —Y 3 —Y 4 —, and Y 3  is —N(R′)C(O)—. 
     
     
         16 . The compound of  claim 4  or  5 , wherein Y is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         17 . The compound of  claim 4  or  5 , wherein X is O. 
     
     
         18 . The compound of  claim 4  or  5 , wherein X is —N(W—R 4 ). 
     
     
         19 . The compound of  claim 4  or  5 , wherein X is O, m is 1, and R 2  is an optionally substituted group selected from a monocyclic 3-8-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a bicyclic 7-10-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a monocyclic 5-6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
     
     
         20 . The compound of  claim 4  or  5 , wherein X is —N(W—R 4 ) and R 4  is an optionally substituted group selected from a monocyclic 3-8-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a bicyclic 7-10-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a monocyclic 5-6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
     
     
         21 . The compound of  claim 4  or  5 , wherein X is —N(W—R 4 ), W is absent and R 4  is optionally substituted phenyl. 
     
     
         22 . The compound of  claim 4  or  5 , wherein:
 X is —N(W—R 4 ) and R 4  is an optionally substituted group selected from a monocyclic 3-8-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a bicyclic 7-10-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a monocyclic 5-6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or X is —N(W—R 4 ), W is absent and R 4  is optionally substituted phenyl, wherein: 
 R 4  is optionally substituted with 1-3 occurrences of R 4a  and each occurrence of R 4a  is independently —R 4b , -T 1 -R 4e , or —V 1 -T 1 -R 4e , wherein each occurrence of —R 4b  is independently halogen, —CN, —NO 2 , —R 4d , —N(R 4c ) 2 , —OR 4c , —S(O) 2 R 4d , —C(O)R 4c , —C(O)OR 4c , —C(O)N(R 4c ) 2 , —S(O) 2 N(R 4c ) 2 , —OC(O)N(R 4c ) 2 , —N(R′)C(O)R 4c , —N(R′)SO 2 R 4d , —N(R′)C(O)OR 4c , —N(R′)C(O)N(R 4c ) 2 , or —N(R′)SO 2 N(R 4c ) 2 , or two occurences of —R 4b , —R 4e  or —R 4d  are optionally taken together with their intervening atom(s) to form an optionally substituted spiro, fused, or bridged ring selected from 6-membered aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur or two occurrences of R 4c , taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring having 1-3 additional heteroatoms selected from nitrogen, oxygen, or sulfur;
 each occurrence of R 4c  is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 each occurrence of R 4d  is independently an optionally substituted group selected from C 1-6 aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 each occurrence of R 4e  is independently an optionally substituted group selected from 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 each occurrence of V 1  is independently —C(R′)═C(R′)—, —C≡C—, —N(R′)—, —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O) 2 N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—, —N(R′)SO 2 —, —N(R′)C(O)O—, —NR′C(O)N(R′)—, —N(R′)SO 2 N(R′)—, —OC(O)—, or —C(O)N(R′)—O—; 
 each occurrence of T 1  is independently C 1-6  alkylene chain optionally substituted with R 3a , wherein the alkylene chain optionally is interrupted by —C(R′)═C(R′)—, —N(R′)—, —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O) 2 N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—, —N(R′)SO 2 —, —N(R′)C(O)O—, —NR′C(O)N(R′)—, —N(R′)SO 2 N(R′)—, —OC(O)—, or —C(O)N(R′)—O— or wherein T 1  or a portion thereof optionally forms part of an optionally substituted 3-7 membered cycloaliphatic or heterocyclyl ring; 
 
 
     
     
         23 . The compound of  claim 21 , wherein the phenyl group is substituted with 1 or 2 occurrences of R 4a , wherein each occurrence of R 4a  is independently halogen, —CN, —C(O)N(R 4c ) 2 , —O(e), —S(R 4d ), —N(R 4c ) 2 , —C(O)O-T 1 -R 4e , —R 4d , or wherein two occurrences of R 4b , taken together with their intervening atoms, form a 5-6-membered spiro or fused carbocyclic or heterocyclyl ring. 
     
     
         24 . The compound of  claim 4  or  5 , wherein R 3  is —OR 3b , —SR 3 , —V 1 -T 1 -R 3d , or T 1 -R 3d , wherein V 1  is O or S, and T 1  is —CH 2 — or —CH 2 —CH 2 —. 
     
     
         25 . The compound of  claim 24 , wherein R 3b , R 3c , and R 3d  are each independently an optionally substituted group selected from C 1-4 alkenyl, C 1-4 alkynyl, C 1-4 alkyl, 5-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
     
     
         26 . The compound of  claim 25 , wherein R 3b , R 3c , and R 3d  are each independently optionally substituted C 1-4 alkenyl, C 1-4 alkynyl, C 1-4 alkyl, or an optionally substituted group selected from: 
       
         
           
           
               
               
           
         
       
     
     
         27 . The compound of  claim 24 , wherein R 3b , R 3c , and R 3d  are each independently an optionally substituted ring selected from bicyclic 8-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur or 8-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
     
     
         28 . The compound of  claim 27 , wherein R 3b , R 3c , and R 3d  are each independently optionally substituted with 1-3 occurrences of R 3e , wherein R 3e  is R f , halogen, —N(R g ) 2 , —OR g , —SR f , —S(O) 2 R f , —COR E , —COOR g , —CON(R g ) 2 , —CON(R g ) 2 , —S(O) 2 N(R g ) 2 , —CC(O)N(R g ) 2 , —NR′C(O)R f , —NR′S(O) 2 R f , wherein R f  is an optionally substituted C 1-6  aliphatic group and R g  is hydrogen or an optionally substituted C 1-6  aliphatic group. 
     
     
         29 . The compound of  claim 28 , wherein R 3b , R 3c , and R 3d  are each independently optionally substituted with 1-3 occurrences of R 3e , wherein R 3e  is C 1-4 aliphatic, C 1-4 haloaliphatic, or halogen. 
     
     
         30 . The compound of  claim 5 , wherein r is 2 and two occurrences of R 3 , taken together, form an optionally substituted 3-6-membered spiro carbocyclic or heterocyclic ring selected from: 
       
         
           
           
               
               
           
         
       
     
     
         31 . The compound of  claim 4 , wherein the compound has the structure of formula I-C: 
       
         
           
           
               
               
           
         
       
     
     
         32 . The compound of  claim 31 , wherein X is O and the compound has the structure of formula I-D: 
       
         
           
           
               
               
           
         
         wherein: 
         a) R 1  is an optionally substituted 5-8-membered monocyclic or 7-10-membered bicyclic heterocyclyl or heteroaryl ring having 1-4 heteroatoms independently selected from N, O, or S, wherein R 1  is optionally substituted with 1-3 occurrences of R 1a , wherein each occurrence of R 1a  is independently halogen, ═O, ═S, —CN, —NO 2 , —N(R 1b ) 2 , —OR 1b , —SR 1c , —S(O) 2 R 1c , —C(O)R 1b , —C(O)OR 1b , —C(O)N(R 1b ) 2 , —S(O) 2 N(R 1b ) 2 , —OC(O)N(R 1b ) 2 , —N(R′)C(O)R 1b , —N(R′)SO 2 R 1e , —N(R′)C(O)OR 1b , —N(R′)C(O)N(R 1b ) 2 , or —N(R′)SO 2 N(R 1b ) 2 , or two occurences of R 1b  or R 1c  are optionally taken together with their intervening atom(s) to form an optionally substituted spiro, fused, or bridged ring selected from 6-membered aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur or two occurrences of R 1b , taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring having 1-3 additional heteroatoms selected from nitrogen, oxygen, or sulfur, wherein:
 each occurrence of R 1b  is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and 
 each occurrence of R 1c  is independently an optionally substituted group selected from C 1-6 aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 
         b) Y is —NH(CO)CH 2 —, —NHS(O) 2 CH 2 , —NHC(O)—, —NH(CO)CH 2 NH—, or —NHS(O) 2 —; 
         c) m is 0 or 1, and when m is 1 R 2  is an optionally substituted group selected from a monocyclic 3-7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a bicyclic 7-10-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a monocyclic 5-6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and 
         d) R 3  is —OR 3b , —SR 3c , —V 1 -T 1 -R 3d , or T 1 -R 3d , wherein V 1  is O or S, and T 1  is —CH 2 — or —CH 2 —CH 2 —, wherein R 3b , R 3c , and R 3d  are each independently an optionally substituted group selected from C 1-4 alkenyl, C 1-4 alkynyl, C 1-4 alkyl, 5-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
       
     
     
         33 . The compound of  claim 32 , wherein:
 a) R 1  is an optionally substituted group selected from:   
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         and each occurrence of R 1a  is independently ═O, halogen, —R 1c , —N(R 1b ) 2 , —OR 1b , or —SR 1c ; and 
         b) R 3b , R 3c , and R 3d  are each independently optionally substituted C 1-4 alkenyl, C 1-4 alkynyl, C 1-4 alkyl, or an optionally substituted group selected from: 
       
       
         
           
           
               
               
           
         
         wherein R 3b , R 3c , and R 3d  are each independently optionally substituted with 1-3 occurrences of Rae, wherein R 3e  is C 1-4 aliphatic, C 1-4 haloaliphatic, or halogen. 
       
     
     
         34 . The compound of  claim 31 , wherein X is N(W—R 4 ), and the compound has the structure of formula I-E: 
       
         
           
           
               
               
           
         
         wherein: 
         a) R 1  is an optionally substituted 5-8-membered monocyclic or 7-10-membered bicyclic heterocyclyl or heteroaryl ring having 1-4 heteroatoms independently selected from N, O, or S, wherein R 1  is optionally substituted with 1-3 occurrences of R 1a , wherein each occurrence of R 1a  is independently halogen, ═O, —CN, —NO 2 , —R 1c , —N(R 1b ) 2 , —OR 1b , —SR 1c , —S(O) 2 R 1c , —C(O)R 1b , —C(O)OR 1b , —C(O)N(R 1b ) 2 , —S(O) 2 N(R 1b ) 2 , —OC(O)N(R 1b ) 2 , —N(R′)C(O)R 1b , —N(R′)SO 2 R 1c , —N(R′)C(O)OR 1b , —N(R′)C(O)N(R 1b ) 2 , or —N(R′)SO 2 N(R 1b ) 2 , or two occurences of R 1b  or R 1c  are optionally taken together with their intervening atom(s) to form an optionally substituted spiro, fused, or bridged ring selected from 6-membered aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur or two occurrences of R 1b , taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring having 1-3 additional heteroatoms selected from nitrogen, oxygen, or sulfur, wherein:
 each occurrence of R 1b  is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and 
 each occurrence of R 1c  is independently an optionally substituted group selected from C 1-6 aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 
         b) Y is —NH(CO)CH 2 —, —NHS(O) 2 CH 2 , —NHC(O)—, —NH(CO)CH 2 NH—, or —NHS(O) 2 —; 
         c) m is 0; 
         d) R 3  is —OR 3b , —SR 3c , —V 1 -T 1 -R 3d , or T 1 -R 3d , wherein V 1  is O or S, and T 1  is —CH 2 — or —CH 2 —CH 2 —, wherein R 3b , R 3c , and R 3d  are each independently an optionally substituted group selected from C 1-4 -alkenyl, C 1-4 alkynyl, C 1-4 alkyl, 5-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
         e) W is absent, and 
         f) R 4  is an optionally substituted group selected from a monocyclic 3-7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a bicyclic 7-10-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a monocyclic 5-6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
       
     
     
         35 . The compound of  claim 31 , wherein X is N(W—R 4 ), and the compound has the structure of formula I-E: 
       
         
           
           
               
               
           
         
         wherein: 
         a) R 1  is an optionally substituted 5-8-membered monocyclic or 7-10-membered bicyclic heterocyclyl or heteroaryl ring having 1-4 heteroatoms independently selected from N, O, or S, wherein R 1  is optionally substituted with 1-3 occurrences of R 1a , wherein each occurrence of R 1a  is independently halogen, ═O, —CN, —NO 2 , —R 1c , —N(R 1b ) 2 , —OR 1b , —SR 1c , —S(O) 2 R 1c , —C(O)R 1b , —C(O)OR 1b , —C(O)N(R 1b ) 2 , —S(O) 2 N(R 1b ) 2 , —OC(O)N(R 1b ) 2 , —N(R′)C(O)R 1b , —N(R′)SO 2 R 1c , —N(R′)C(O)OR 1b , —N(R′)C(O)N(R 1b ) 2 , or —N(R′)SO 2 N(R 1b ) 2 , or two occurences of R 1b  or R 1c  are optionally taken together with their intervening atom(s) to form an optionally substituted spiro, fused, or bridged ring selected from 6-membered aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur or two occurrences of R 1b , taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring having 1-3 additional heteroatoms selected from nitrogen, oxygen, or sulfur, wherein:
 each occurrence of R 1b  is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and 
 each occurrence of R 1c  is independently an optionally substituted group selected from C 1- 6aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 
         b) Y is —NH(CO)CH 2 —, —NHS(O) 2 CH 2 , —NHC(O)—, —NH(CO)CH 2 NH—, or —NHS(O) 2 —; 
         c) m is 0; 
         d) R 3  is —OR 3b , —SR 3c , —V 1 -T 1 -R 3d , or T 1 -R 3d , wherein V 1  is O or S, and T 1  is —CH 2 — or —CH 2 —CH 2 —, wherein R 3b , R 3c , and R 3d  are each independently an optionally substituted group selected from C 1-4 alkenyl, C 1-4 alkynyl, C 1-4 alkyl, 5-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
         e) W is absent, and 
         f) R 4  is optionally substituted phenyl. 
       
     
     
         36 . The compound of  claim 34  or  35 , wherein R 4  is optionally substituted with 1-3 occurrences of R 4a  each occurrence of R 4a  is independently —R 4b , -T 1 -R 4e , or —V 1 -T 1 -R 4e , wherein:
 each occurrence of —R ab  is independently halogen, —CN, —NO 2 , —R 4d , —N(R 4c ) 2 , OR 4c , —SR 4d , —S(O) 2 R 4d , —C(O)R 4c , —C(O)OR 4c , —C(O)N(R 4c ) 2 , —S(O) 2 N(R 4c ) 2 , —OC(O)N(R 4c ) 2 , —N(R′)C(O)R 4c , —N(R′)SO 2 R 4d , —N(R′)C(O)OR 4c , —N(R′)C(O)N(R 4c ) 2 , or —N(R′)SO 2 N(R 4c ) 2 , or two occurences of —R 4b , —R 4c  or —R 4d  are optionally taken together with their intervening atom(s) to form an optionally substituted spiro, fused, or bridged ring selected from 6-membered aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or two occurrences of R 40 , taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring having 1-3 additional heteroatoms selected from nitrogen, oxygen, or sulfur; 
 each occurrence of R oo  is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 each occurrence of R 4d  is independently an optionally substituted group selected from C 1-6 aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 each occurrence of R 4e  is independently an optionally substituted group selected from 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 each occurrence of V 1  is independently —C(R′)═C(R′)—, —N(R′)—, —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O) 2 N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—, —N(R′)SO 2 —, —N(R′)C(O)O—, —NR′C(O)N(R′)—, —N(R′)SO 2 N(R′)—, —OC(O)—, or —C(O)N(R′)—O—; and 
 each occurrence of T 1  is independently C 1-6  alkylene chain optionally substituted with R 3a , wherein the alkylene chain optionally is interrupted by —C(R′)═C(R′)—, —C≡C—, —N(R′)—, —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O) 2 N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—, —N(R′)SO 2 —, —N(R′)C(O)O—, —NR′C(O)N(R′)—, —N(R′)SO 2 N(R′)—, —OC(O)—, or —C(O)N(R′)—O— or wherein T 1  or a portion thereof optionally forms part of an optionally substituted 3-7 membered cycloaliphatic or heterocyclyl ring. 
 
     
     
         37 . The compound of  claim 34  or  35 , wherein:
 a) R 1  is an optionally substituted group selected from: 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         and each occurrence of R 1a  is independently ═O, halogen, —R 1c , —N(R 1b ) 2 , —OR 1b , or —SR 1c ; and 
         b) R 3b , R 3c , and R 3d  are each independently optionally substituted C 1-4 alkenyl, C 1-4 alkynyl, C 1-4 alkyl, or an optionally substituted group selected from: 
       
       
         
           
           
               
               
           
         
         wherein R 3b , R 3c , and R 3d  are each independently optionally substituted with 1-3 occurrences of Rae, wherein R 3e  is C 1-4 aliphatic, C 1-4 haloaliphatic, or halogen. 
       
     
     
         38 . The compound of  claim 5 , having the structure of formula I-F: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein the two occurrences of R 3 , taken together, form an optionally substituted 3-6-membered spiro carbocyclic or heterocyclic ring. 
       
     
     
         39 . The compound of  claim 38 , wherein X is O and the compound has the structure of formula I-G: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         a) R 1  is an optionally substituted 5-8-membered monocyclic or 7-10-membered bicyclic heterocyclyl or heteroaryl ring having 1-4 heteroatoms independently selected from N, O, or S, wherein R 1  is optionally substituted with 1-3 occurrences of R 1a , wherein each occurrence of R 1a  is independently halogen, ═O, ═S, —CN, —NO 2 , —R 1c , —N(R 1b ) 2 , —OR 1b , —SR 1c , —S(O) 2 R 1c , —C(O)R 1b , —C(O)OR 1b , —C(O)N(R 1b ) 2 , —S(O) 2 N(R 1b ) 2 , —OC(O)N(R 1b ) 2 , —N(R′)C(O)R 1b , —N(R′)SO 2 R 1e , —N(R′)C(O)OR 1b , —N(R′)C(O)N(R 1b ) 2 , or —N(R′)SO 2 N(R 1b ) 2 , or two occurences of R 1b  or R 1c  are optionally taken together with their intervening atom(s) to form an optionally substituted spiro, fused, or bridged ring selected from 6-membered aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur or two occurrences of R 1b , taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring having 1-3 additional heteroatoms selected from nitrogen, oxygen, or sulfur, wherein:
 each occurrence of R 1b  is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and 
 each occurrence of R 1c  is independently an optionally substituted group selected from C 1-6 aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 
         b) Y is —NH(CO)CH 2 —, —NHS(O) 2 CH 2 , —NHC(O)—, —NH(CO)CH 2 NH—, or —NHS(O) 2 —; 
         c) m is 0 or 1, and when m is 1 R 2  is an optionally substituted group selected from a monocyclic 3-7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a bicyclic 7-10-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a monocyclic 5-6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and 
         d) wherein the two occurrences of R 3 , taken together, form an optionally substituted 3-6-membered spiro carbocyclic or heterocyclic ring. 
       
     
     
         40 . The compound of  claim 39 , wherein:
 a) R′ is an optionally substituted group selected from:   
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         each occurrence of R 1a  is independently ═O, halogen, —R 1c , N(R 1b ) 2 , —OR 1b , or —SR 1c ; and 
         b) the Spiro ring formed from the two occurrences of R 3  is an optionally substituted ring selected from: cd 
       
       
         
           
           
               
               
           
         
       
     
     
         41 . The compound of  claim 38 , wherein X is N(W—R 4 ), and the compound has the structure of 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         a) R 1  is an optionally substituted 5-8-membered monocyclic or 7-10-membered bicyclic heterocyclyl or heteroaryl ring having 1-4 heteroatoms independently selected from N, O, or S, wherein R 1  is optionally substituted with 1-3 occurrences of R 1a , wherein each occurrence of R 1a  is independently halogen, ═O, —CN, —NO 2 , —R 1c , N(R 1b ) 2 , —OR 1b , —SR 1c , —S(O) 2 R 1c , —C(O)R 1b , —C(O)R 1b , —C(O)N(R 1b ) 2 , —S(O) 2 N(R 1b ) 2 , —OC(O)N(R 1b ) 2 , —N(R′)C(O)R 1b , —N(R′)SO 2 R 1c , N(R′)C(O)OR 1b , —N(R′)C(O)N(R 11 )) 2 , or —N(R′)SO 2 N(R 1b ) 2 , or two occurences of R 1b  or R 1c  are optionally taken together with their intervening atom(s) to form an optionally substituted spiro, fused, or bridged ring selected from 6-membered aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur or two occurrences of R 1b , taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring having 1-3 additional heteroatoms selected from nitrogen, oxygen, or sulfur, wherein:
 each occurrence of R 1b  is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and
 each occurrence of R 1c  is independently an optionally substituted group selected from C 1-6 aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 
 
         b) Y is —NH(CO)CH 2 —, —NHS(O) 2 CH 2 , —NHC(O)—, —NH(CO)CH 2 NH—, or —NHS(O) 2 —; 
         c) m is 0; 
         d) wherein the two occurrences of R 3 , taken together, form an optionally substituted 3-6-membered spiro carbocyclic or heterocyclic ring; 
         e) W is absent, and 
         R 4  is an optionally substituted group selected from a monocyclic 3-7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a bicyclic 7-10-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a monocyclic 5-6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
       
     
     
         42 . The compound of  claim 38 , wherein X is N(W—R 4 ), and the compound has the structure of formula I-H: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         a) R 1  is an optionally substituted 5-8-membered monocyclic or 7-10-membered bicyclic heterocyclyl or heteroaryl ring having 1-4 heteroatoms independently selected from N, O, or S, wherein R 1  is optionally substituted with 1-3 occurrences of R 1a , wherein each occurrence of R 1a  is independently halogen, ═O, —CN, —NO 2 , —R 1c , —N(R 1b ) 2 , —OR 1b , —S(O) 2 R 1c , —C(O)R 1b , —C(O)OR 1b , —C(O)N(R 1b ) 2 , —S(O) 2 N(R 1b ) 2 , —OC(O)N(R 1b ) 2 , —N(R′)C(O)R 1b , —N(R)SO 2 R 1c , —N(R′)C(O)OR 1b , —N(R′)C(O)N(R 1b ) 2 , or —N(R′)SO 2 N(R 1b ) 2 , or two occurences of R 1b  or R 1c  are optionally taken together with their intervening atom(s) to form an optionally substituted spiro, fused, or bridged ring selected from 6-membered aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur or two occurrences of R 1b , taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring having 1-3 additional heteroatoms selected from nitrogen, oxygen, or sulfur, wherein:
 each occurrence of R 1b  is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and 
 each occurrence of R 1c  is independently an optionally substituted group selected from C 1-6 aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 
         b) Y is —NH(CO)CH 2 —, —NHS(O) 2 CH 2 , —NHC(O)—, —NH(CO)CH 2 NH—, or —NHS(O) 2 —; 
         c) m is 0; 
         d) the spiro ring formed from the two occurrences of R 3  is an optionally substituted ring selected from: 
       
       
         
           
           
               
               
           
         
         e) W is absent, and 
         f) R 4  is optionally substituted phenyl. 
       
     
     
         43 . The compound of  claim 41  or  42 , wherein R 4  is optionally substituted with 1-3 occurrences of R 4a  and each occurrence of R 4a  is independently —R 4b , -T 1 -R 4e , or —V I -T 1 -R 4e , wherein:
 each occurrence of —R 4b  is independently halogen, —CN, —NO 2 , —R 4d , —N(R 4c ) 2 , —OR 4c , —SR 4d , —S(O) 2 R 4d , —C(O)R 4c , —C(O)OR 4c , —C(O)N(R 4c ) 2 , —S(O) 2 N(R 4c ) 2 , —OC(O)N(R 4c ) 2 , —N(R′)C(O)R 4c , —N(R′)SO 2 R 4d , —N(R′)C(O)OR 4c , —N(R′)C(O)N(R 4c ) 2 , or —N(R′)SO 2 N(R 4c ) 2 , or two occurences of R 4b , R 4c  or R 4d  are optionally taken together with their intervening atom(s) to form an optionally substituted spiro, fused, or bridged ring selected from 6-membered aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or two occurrences of R 4c , taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring having 1-3 additional heteroatoms selected from nitrogen, oxygen, or sulfur; 
 each occurrence of R 4c  is independently hydrogen or an optionally substituted group selected from Cl —6 aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 each occurrence of R 4d  is independently an optionally substituted group selected from C 1-6 aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 each occurrence of R 4e  is independently an optionally substituted group selected from 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 each occurrence of V 1  is independently —C(R′)═C(R′)—, —C≡C—, —N(R′)—, —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O) 2 N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—, —N(R′)SO 2 —, —N(R′)C(O)O—, —NR′C(O)N(R′)—, —N(R′)SO 2 N(R′)—, —OC(O)—, or —C(O)N(R′)—O—; and 
 each occurrence of T 1  is independently C 1-6  alkylene chain optionally substituted with R 3a , wherein the alkylene chain optionally is interrupted by —C(R′)═C(R′)—, —C≡C—, —N(R′)—, —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O) 2 N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—, —N(R′)SO 2 —, —N(R′)C(O)O—, —NR′C(O)N(R′)—, —N(R′)SO 2 N(R′)—, —OC(O)—, or —C(O)N(R′)—O— or wherein T 1  or a portion thereof optionally forms part of an optionally substituted 3-7 membered cycloaliphatic or heterocyclyl ring. 
 
     
     
         44 . The compound of  claim 41  or  42 , wherein:
 a) R 1  is an optionally substituted group selected from: 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         and each occurrence of R 1a  is independently —O, halogen, —R 1c , —N(R 1b ) 2 , —OR 1b , or —SR 1c ; and 
         b) the spiro ring formed from the two occurrences of R 3  is an optionally substituted ring selected from: 
       
       
         
           
           
               
               
           
         
       
     
     
         45 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound of formula I 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         n is 1 or 2; 
         Y is —Y 1 —Y 2 —, or —Y 3 —Y 4 — wherein:
 Y 1  is —SO 2 N(R′)—, —C(O)N(R′)—; —C(O)N(R′)C(O)—, —N(R′)SO 2 —, or —N(R′)SO 2 N(R′)—, 
 Y 2  is absent or is an optionally substituted C 1-6  alkylene chain, wherein one or two methylene units of Y 2  are optionally and independently interrupted by —O—, —S—, —N(R′)—, —C(O)—, —OC(O)—, —C(O)O—, —S(O)—, —S(O) 2 —, —C(O)N(R′)—, —N(R′)C(O)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —OC(O)N(R′)—, —N(R′)S(O) 2 —, or —S(O) 2 N(R′)—, or wherein Y 2 , or a portion thereof, is an optionally substituted ring selected from 3-6-membered cycloaliphatic, 3-6-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-membered aryl, or 5-6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 Y 3  is —N(R′)C(O)—, —NR′C(O)N(R′)—, —N(R′)C(O)O—; and 
 Y 4  is an optionally substituted C 1-6  alkylene chain, wherein one or two methylene units of Y 4  are optionally and independently interrupted by —O—, —S—, —N(R′)—, —C(O)—, —OC(O)—, —C(O)O—, —S(O)—, —S(O) 2 —, —C(O)N(R′)—, —N(R′)C(O)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —OC(O)N(R′)—, —N(R′)S(O) 2 —, or —S(O) 2 N(R′)—, 
 each R′ is independently hydrogen or optionally substituted C 1-6 aliphatic; 
 
         R 1  is an optionally substituted group selected from 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
         ring A is substituted at one or more carbon atoms with m independent occurrences of R 2 ; 
         m is 0-6; 
         each occurrence of R 2  is independently halogen, ═O, ═S, —CN, —R 2b , —N(R 2a ) 2 , —OR 2b , —SR 2b , —S(O) 2 R 2b , —C(O)R 2a , —C(O)OR 2a , —C(O)N(R 2a ) 2 , —S(O) 2 N(R 2a ) 2 , —OC(O)N(R 2a ) 2 , —N(R′)C(O)R 2a , —N(R′)SO 2 R 2b , —N(R′)C(O)OR 2a , —N(R′)C(O)N(R 2a ) 2 , or —N(R′)SO 2 N(R 2a ) 2 , or two occurences of R 2a  or R 2b  are optionally taken together with their intervening atom(s) to form an optionally substituted spiro, fused, or bridged ring selected from 6-membered aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or two occurrences of R 2a , taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring having 1-3 additional heteroatoms selected from nitrogen, oxygen, or sulfur;
 each occurrence of R 2a  is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 each occurrence of R 2b  is independently an optionally substituted group selected from C 1-6 aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 
         ring B is substituted with r independent occurrences of —R 3 ; 
         r is 0-6; 
         each occurrence of R 3  is independently —R 3a , -T 1 -R 3d , or —V 1 -T 1 -R 3d , wherein:
 each occurrence of —R 3a  is independently halogen, —CN, —NO 2 , —R 3c , —N(R 3b ) 2 , —OR 3b , —SR 3c , —S(O) 2 R 3c , —C(O)R 3b , —C(O)OR 3b , —C(O)N(R 3b ) 2 , —S(O) 2 N(R 3b ) 2 , —OC(O)N(R 3b ) 2 , —N(R′)C(O)R 3b , —N(R′)SO 2 R 3c , —N(R′)C(O)OR 3b , —N(R′)C(O)N(R 3b ) 2 , or —N(R′)SO 2 N(R 3b ) 2 , or two occurences of R 3b  or R 3c  are optionally taken together with their intervening atom(s) to form an optionally substituted spiro, fused, or bridged ring selected from 6-membered aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or two occurrences of R 3b , taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring having 1-3 additional heteroatoms selected from nitrogen, oxygen, or sulfur; 
 each occurrence of R 3b  is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 each occurrence of R 3c  is independently an optionally substituted group selected from C 1-6 aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 each occurrence of R 3d  is independently an optionally substituted group selected from 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 each occurrence of V 1  is independently —C(R′)═C(R′)—, —C≡C—, —N(R′)—, —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O) 2 N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—, —N(R′)SO 2 —, —N(R′)C(O)O—, —NR′C(O)N(R′)—, —N(R′)SO 2 N(R′)—, —OC(O)—, or —C(O)N(R′)—O—; 
 each occurrence of T 1  is independently C 1-6  alkylene chain optionally substituted with R 3a , wherein the alkylene chain optionally is interrupted by —C(R′)═C(R′)—, —C≡—, —N(R′)—, —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O) 2 N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—, —N(R′)SO 2 —, —N(R′)C(O)O—, —NR′C(O)N(R′)—, —N(R′)SO 2 N(R′)—, —OC(O)—, or —C(O)N(R′)—O— or wherein T 1  or a portion thereof optionally forms part of an optionally substituted 3-7 membered cycloaliphatic or heterocyclyl ring; 
 
         X is —O—, —S—, —SO 2 —, or —N(W—R 4 )—; 
         W is absent or is a group selected from —W 1 -L 2 -W 2 —, wherein W 1  and W 2  are each independently absent or are an optionally substituted C 1-3 alkylene chain, and L 2  is absent or is a group selected from —N(R)—, —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(O)O—, —C(O)N(R)—, —S(O) 2 N(R)—, —OC(O)N(R)—, —N(R)C(O)—, —N(R)SO 2 —, —N(R)C(O)O—, —N(R)C(O)N(R)—, —N(R)SO 2 N(R)—, —OC(O)—, or —C(O)N(R)—O—, wherein R is hydrogen or C 1- C 4 alkyl, provided that if W 1  is absent then L 2  is selected from —C(O)—, —C(O)O—, —C(O)O—, —S(O)—, —S(O) 2 —, —C(O)N(R)—, or —S(O) 2 N(R)—
 R 4  is an optionally substituted monocyclic or bicyclic ring selected from 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 
 
         provided that the compound is other than:
 a) 4-Morpholinebutanamide, N-[3-cyano-1-(tetrahydro-2H-pyran-4-yl)-3-pyrrolidinyl]-α-(cyclohexylmethyl)-γ-oxo-; 
 b) 4-Morpholinebutanamide, N-[3-cyano-1-(tetrahydro-2H-thiopyran-4-yl)-3-pyrrolidinyl]-α-(cyclohexylmethyl)-γ-oxo-; 
 c) 4-Morpholinecarboxamide, N-[(1S)-2-[[3-cyano-1-(1-methyl-4-piperidinyl)-3-pyrrolidinyl]amino]-1-(cyclohexylmethyl)-2-oxoethyl]-; 
 d) 4-Morpholinebutanamide, N-[3-cyano-1-(tetrahydro-2H-pyran-4-yl)-3-pyrrolidinyl]-α-(cyclohexylmethyl)-γ-oxo; 
 e) Benzeneacetamide, N-[(3S)-1-[1-(2-cyanophenyl)-4-piperidinyl]-3-pyrrolidinyl]-3,4-difluoro-, monohydrochloride; 
 f) Benzeneacetamide, 3,4-difluoro-N-[(3R)-1-[1-(2-nitrophenyl)-4-piperidinyl]-3-pyrrolidinyl]-, hydrochloride; 
 g) Benzeneacetamide, 3,4-difluoro-α-(1-methylethyl)-N-[(3R)-1-[1-(2-nitrophenyl)-4-piperidinyl]-3-pyrrolidinyl]-, hydrochloride; 
 h) Benzeneacetamide, N-[(3R)-1-[1-(2-cyanophenyl)-4-piperidinyl]-3-pyrrolidinyl]-3,4-difluoro-α-(1-methylethyl)-, (αS)—; 
 i) Benzeneacetamide, N-[(3R)-1-[1-(2-cyanophenyl)-4-piperidinyl]-3-pyrrolidinyl]-3,4-difluoro-α-(1-methylethyl)-, (αR)—; 
 j) [1,4′-Bipiperidine]-3-carboxamide,1′-[[2,6-bis(4-chlorophenyl)-4-pyridinyl]carbonyl]-N-methyl-N-(1-methyl-4-piperidinyl)-, (3R)—; 
 k) Benzeneacetamide, N-[1′-(2-cyanophenyl)[1,4′-bipiperidin]-3-yl]-3,4-difluoro-, monohydrochloride; and 
 l) Benzeneacetamide, N-[1′(2-cyanophenyl)[1,4′-b ippiperidin]-3-yl]-3,4-difluoro-. 
 
       
     
     
         46 . A method for treating an inflammatory disorder comprising administering to a subject an effective amount of a compound of formula I 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         n is 1 or 2; 
         Y is —Y 1 —Y 2 —, or —Y 3 —Y 4 — wherein:
 Y 1  is —SO 2 N(R′)—, —C(O)N(R′)—; —C(O)N(R′)C(O)—, —N(R′)SO 2 —, or —N(R′)SO 2 N(R′)—, 
 Y 2  is absent or is an optionally substituted C 1-6  alkylene chain, wherein one or two methylene units of Y 2  are optionally and independently interrupted by —O—, —S—, —N(R′)—, —C(O)—, —OC(O)—, —C(O)O—, —S(O)—, —S(O) 2 —, —C(O)N(R′)—, —N(R′)C(O)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —OC(O)N(R′)—, —N(R′)S(O) 2 —, or —S(O) 2 N(R′)—, or wherein Y 2 , or a portion thereof, is an optionally substituted ring selected from 3-6-membered cycloaliphatic, 3-6-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-membered aryl, or 5-6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 Y 3  is —N(R′)C(O)—, —NR′C(O)N(R′)—, —N(R′)C(O)O—; and 
 Y 4  is an optionally substituted C 1-6  alkylene chain, wherein one or two methylene units of Y 4  are optionally and independently interrupted by —O—, —S—, —N(R′)—, —C(O)—, —OC(O)—, —C(O)O—, —S(O)—, —S(O) 2 —, —C(O)N(R′)—, —N(R′)C(O)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —OC(O)N(R′)—, —N(R′)S(O) 2 —, or —S(O) 2 N(R′)—, 
 each R′ is independently hydrogen or optionally substituted C 1-6 aliphatic; 
 
         R 1  is an optionally substituted group selected from 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
         ring A is substituted at one or more carbon atoms with m independent occurrences of R 2 ; 
         m is 0-6; 
         each occurrence of R 2  is independently halogen, ═O, ═S, —CN, —R 2b , —N(R 2a ) 2 , —OR 2a , —SR 2b , —S(O) 2 R 2b , C(O)R 2a , —C(O)OR 2a , —C(O)N(R 2a ) 2 , —S(O) 2 N(R 2a ) 2 , —OC(O)N(R 2a ) 2 , —N(R′)C(O)R 2a , —N(R′)SO 2 R 2b , —N(R′)C(O)OR 2a , —N(R′)C(O)N(R 2a ) 2 , or —N(R′)SO 2 N(R 2a ) 2 , or two occurences of R 2a  or R 2b  are optionally taken together with their intervening atom(s) to form an optionally substituted spiro, fused, or bridged ring selected from 6-membered aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or two occurrences of R 2a , taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring having 1-3 additional heteroatoms selected from nitrogen, oxygen, or sulfur;
 each occurrence of R 2a  is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 each occurrence of R 2b  is independently an optionally substituted group selected from C 1- 6aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 
         ring B is substituted with r independent occurrences of —R 3 ; 
         r is 0-6; 
         each occurrence of R 3  is independently —R 3a , -T 1 -R 3d , or —V 1 -T 1 -R 3d , wherein:
 each occurrence of —R 3a  is independently halogen, —CN, —NO 2 , —R 3c , —N(R 3b ) 2 , —OR 3b , —SR 3c , —S(O) 2 R 3c , —C(O)R 3b , —C(O)OR 3b , —C(O)N(R 3b ) 2 , —S(O) 2 N(R 3b ) 2 , —OC(O)N(R 3b ) 2 , —N(R′)C(O)R 3b , —N(R′)SO 2 R 3e , —N(R′)C(O)OR 3b , —N(R′)C(O)N(R 3b ) 2 , or —N(R′)SO 2 N(R 3b ) 2 , or two occurences of R 3b  or R 3c  are optionally taken together with their intervening atom(s) to form an optionally substituted spiro, fused, or bridged ring selected from 6-membered aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or two occurrences of R 3b , taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring having 1-3 additional heteroatoms selected from nitrogen, oxygen, or sulfur; 
 each occurrence of R 3b  is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 each occurrence of R 3c  is independently an optionally substituted group selected from C 1- 6aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 each occurrence of R 3d  is independently an optionally substituted group selected from 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 each occurrence of V 1  is independently —C(R′)═C(R′)—, —C≡C—, —N(R′)—, —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O) 2 N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—, —N(R′)SO 2 —, —N(R′)C(O)O—, —NR′C(O)N(R′)—, —N(R′)SO 2 N(R′)—, —OC(O)—, or —C(O)N(R′)—O—; 
 each occurrence of T 1  is independently C 1-6  alkylene chain optionally substituted with R 3a , wherein the alkylene chain optionally is interrupted by —C(R′)═C(R′)—, —C≡—, —N(R′)—, —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(O)O—, —C(O)N(R′)—, —S(O) 2 N(R′)—, —OC(O)N(R′)—, —N(R′)C(O)—, —N(R′)SO 2 —, —N(R′)C(O)O—, —NR′C(O)N(R′)—, —N(R′)SO 2 N(R′)—, —OC(O)—, or —C(O)N(R′)—O— or wherein T 1  or a portion thereof optionally forms part of an optionally substituted 3-7 membered cycloaliphatic or heterocyclyl ring; 
 
         X is —O—, —S—, —SO 2 —, or —N(W—R 4 )—; 
         W is absent or is a group selected from —W 1 -L 2 -W 2 —, wherein W 1  and W 2  are each independently absent or are an optionally substituted C 1-3 alkylene chain, and L 2  is absent or is a group selected from —N(R)—, —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(O)O—, —C(O)N(R)—, —S(O) 2 N(R)—, —OC(O)N(R)—, —N(R)C(O)—, —N(R)SO 2 —, —N(R)C(O)O—, —N(R)C(O)N(R)—, —N(R)SO 2 N(R)—, —OC(O)—, or —C(O)N(R)—O—, wherein R is hydrogen or C 1- C 4 alkyl, provided that if W 1  is absent then L 2  is selected from —C(O)—, —C(O)O—, —C(O)O—, —S(O)—, —S(O) 2 —, —C(O)N(R)—, or —S(O) 2 N(R)—
 R 4  is an optionally substituted monocyclic or bicyclic ring selected from 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 
 
         provided that the compound is other than:
 a) 4-Morpholinebutanamide, N-[3-cyano-1-(tetrahydro-2H-pyran-4-yl)-3-pyrrolidinyl]-α-(cyclohexylmethyl)-γ-oxo-; 
 b) 4-Morpholinebutanamide, N-[3-cyano-1-(tetrahydro-2H-thiopyran-4-yl)-3-pyrrolidinyl]-α-(cyclohexylmethyl)-γ-oxo-; 
 c) 4-Morpholinecarboxamide, N-[(1S)-2-[[3-cyano-1-(1-methyl-4-piperidinyl)-3-pyrrolidinyl]amino]-1-(cyclohexylmethyl)-2-oxoethyl]-; 
 d) 4-Morpholinebutanamide, N-[3-cyano-1-(tetrahydro-2H-pyran-4-yl)-3-pyrrolidinyl]-α-(cyclohexylmethyl)-γ-oxo; 
 e) Benzeneacetamide, N-[(3S)-1-[1-(2-cyanophenyl)-4-piperidinyl]-3-pyrrolidinyl]-3,4-difluoro-, monohydrochloride; 
 f) Benzeneacetamide, 3,4-difluoro-N-[(3R)-1-[1-(2-nitrophenyl)-4-piperidinyl]-3-pyrrolidinyl]-, hydrochloride; 
 g) Benzeneacetamide, 3,4-difluoro-α-(1-methylethyl)-N-[(3R)-1-[1-(2-nitrophenyl)-4-piperidinyl]-3-pyrrolidinyl]-, hydrochloride; 
 h) Benzeneacetamide, N-[(3R)-1-[1-(2-cyanophenyl)-4-piperidinyl]-3-pyrrolidinyl]-3,4-difluoro-α-(1-methylethyl)-, (αS)—; 
 i) Benzeneacetamide, N-[(3R)-1-[1-(2-cyanophenyl)-4-piperidinyl]-3-pyrrolidinyl]-3,4-difluoro-α-(1-methylethyl)-, (αR)—; 
 j) [1,4′-Bipiperidine]-3-carboxamide,1′-[[2,6-bis(4-chlorophenyl)-4-pyridinyl]carbonyl]-N-methyl-N-(1-methyl-4-piperidinyl)-, (3R)—; 
 k) Benzeneacetamide, N-[1′-(2-cyanophenyl)[1,4′-bipiperidin]-3-yl]-3,4-difluoro-, monohydrochloride; and 
 l) Benzeneacetamide, N-[1′-(2-cyanophenyl)[1,4′-bipiperidin]-3-yl]-3,4-difluoro-. 
 
       
     
     
         47 . The method of  claim 46 , wherein the disorder is rheumatoid arthritis, multiple sclerosis, scleroderma, atherosclerosis, neuropathic pain, and type II diabetes. 
     
     
         48 . The method of  claim 47 , wherein the disorder is rheumatoid arthritis or multiple sclerosis.