Substituted piperazinyl-pyrrolidine compounds useful as chemokine receptor antagonists

Abstract

The present invention relates to compounds useful as Chemokine Receptor antagonists. Compounds of general formula I are provided: or pharmaceutically acceptable salts thereof. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compounds and compositions for the inhibition of Chemokine Receptors and also for the treatment of various diseases, conditions, or disorders, including acute or chronic inflammatory disease, cancer or osteolytic bone disorders.

1 . A compound of formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 x and y are each independently 1 or 2, provided that x and y are not simultaneously 2; 
 R 1  is fluoro, —R 3 , —OR 4 , —SR 4 , —COOR 4 , —COR 4 , —CON(R 4 ) 2 , —N(R 4 ) 2 , —SO 2 N(R 4 ) 2 , —NR 4 SO 2 R 3 , —NR 4 COR 4 , NR 4 CON(R 4 ) 2 , —CON(R 4 ) 2 , —OCOR 4 , or —OSO 2 R 4 ; 
 R 3  is an optionally substituted group selected from C 1- C 6 aliphatic or a 3-7-membered saturated, partially unsaturated, or aromatic monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 each occurrence of R 4  is independently hydrogen or an optionally substituted group selected from C 1- C 6 aliphatic or a 3-7-membered saturated, partially unsaturated, or aromatic monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or two R 4  on the same nitrogen atom, taken together with the nitrogen atom, form an optionally substituted 3-6-membered saturated, partially saturated, or aromatic ring having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 ring A is substituted with q occurrences of R A , wherein q is 0-2 and each R A  is independently halogen, —SO 2 N(R C ) 2 , —OR C , —SR C , —SO 2 R C , —COR C , —CO 2 R C , —N(R C ) 2 , —CON(R C ) 2 , —N(R C )COR C , —N(R C )CO 2 R C , —N(R C )CON(R C ) 2 , or an optionally substituted group selected from C 1- C 6 aliphatic or a 3-7-membered saturated, partially unsaturated, or aromatic monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or two occurrences of R A , or R A  and R 1 , taken together with their intervening atom(s), form an optionally substituted spiro or fused 3-6-membered saturated or partially unsaturated ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each R C  is independently hydrogen or an optionally substituted group selected from C 1- C 6 aliphatic or a 3-7-membered saturated, partially unsaturated, or aromatic monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or two occurrences of R C , taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-6-membered saturated, partially unsaturated, or aromatic ring having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 ring B is substituted with r occurrences of —R B  or -L-R B , wherein r is 0-2, L is a straight or branched C 1-4  alkylene and each occurrence of R B  is independently fluoro, —OR D , —SR D , COR D , —CO 2 R D , —N(R D ) 2 , —CON(R D ) 2 , —N(R D )COR D , or an optionally substituted group selected from C 1- C 6 aliphatic or a 3-7-membered saturated, partially unsaturated, or aromatic monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or two occurrences of R B , taken together with their intervening atom(s), form an optionally substituted spiro, fused or bridged 3-6-membered saturated, partially unsaturated, or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein each R D  is independently hydrogen or an optionally substituted group selected from C 1- C 6 aliphatic or a 3-7-membered saturated, partially unsaturated, or aromatic monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or two occurrences of R D , taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-6-membered saturated, partially unsaturated, or aromatic ring having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 n is 1 or 2; 
 R 2  is -T-Cy 2  or -Cy 2 , 
 wherein T, when present, is a C 1 -C 3 alkylene chain, wherein the alkylene chain is substituted with 0 or 1 occurrence of R 5a , and 0, 1, or 2 independent occurrences of R 5b , and wherein one or more methylene units in the C 1 -C 3 alkylene chain, as valency and stability permit, is optionally replaced by one or more independent occurrences of —CR 5c ═CR 5c —, —CO—, —SO 2 —, —O—, —S—, or —NR 5c —; 
 R 5a  is halogen, —CN, —OR 5c , —N(R 5c ) 2 , —SR 5c , or an optionally substituted group selected from C 1- C 6 aliphatic, or a 3-7-membered saturated, partially unsaturated, or aromatic monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 R 5b  is an optionally substituted group selected from C 1- C 6 aliphatic, or a 3-7-membered saturated, partially unsaturated, or aromatic monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 R 5c  is hydrogen, or an optionally substituted group selected from C 1- C 4 aliphatic, or a 3-7-membered saturated, partially unsaturated, or aromatic monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or two occurrences of R 5c , taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-6-membered saturated, partially unsaturated, or aromatic ring having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 Cy 2  is an optionally substituted group selected from a 3-7-membered saturated, partially unsaturated, or aromatic monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10-membered partially unsaturated, or aromatic bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 wherein Cy 2  is substituted with m independent occurrences of —R 6a , -G-R 6a , or —V-G-R 6a , and k occurrences of ═O, ═S, ═NR 7a , ═NR 7b , —R 6b , -G-R 6b , or —V-G-R 6b , wherein: 
 m is 0-3; 
 k is 0-2; 
 V is —O—, —N(R 7a )—, —S—, —SO—, —SO 2 —, —SO 2 N(R 7a )—, —N(R 7a )SO 2 —, —CO—, —CON(R 7a )—, —N(R 7a )CO—, or —CO 2 —; 
 G is an optionally substituted straight or branched C 1- C 4 alkylene chain that is optionally replaced by —CR 7a ═CR 7a —, —O—, —N(R 7a )—, —S—, —SO—, —SO 2 —, —SO 2 N(R 7a )—, —N(R 7a )SO 2 —, —CO—, —CON(R 7a )—, —N(R 7a )CO—, or —CO 2 —, provided that the replacing moiety is not directly bonded to V, —R 6a , or —R 6b ; 
 each —R 6a  is independently optionally substituted C 1- C 6  aliphatic, halogen, —OR 7a , —CN, —NO 2 , —SR 7a , —SO 2 N(R 7a ) 2 , —NR 7a SO 2 R 7a , —SO 2 R 7a , —COR 7a , —CO 2 R 7a , —N(R 7a ) 2 , —CON(R 7a ) 2 , —N(R 7a )COR 7a , —N(R 7a )CO 2 R 7a , or —N(R 7a )CON(R 7a ) 2 ; 
 each —R 6b  is independently —OR 7b , —SO 2 N(R 7b )(R 7c ), NR 7c SO 2 R 7b , —SO 2 R 7b , —COR 7b , —CO 2 R 7b , —N(R 7b )(R 7c ), —CON(R 7b )(R 7c ), —N(R 7c )COR 7b , —N(R 7c )CO 2 R 7b , —N(R 7c )CON(R 7b )(R 7c ), or an optionally substituted group selected from a 3-7-membered saturated, partially unsaturated, or aromatic monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10-membered saturated, partially unsaturated, or aromatic bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two occurrences of R 6b , taken together with their intervening atom(s), form a spiro, fused, or bridged optionally substituted 5-7-membered saturated, partially unsaturated, or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 each R 7a  is hydrogen or an optionally substituted C 1- C 6 aliphatic group; 
 each R 7c  is an optionally substituted group selected from a 3-7-membered saturated, partially unsaturated, or aromatic monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10-membered saturated, partially unsaturated, or aromatic bicyclic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and 
 each R 7c  is hydrogen or an optionally substituted group selected from a C 1- C 6 aliphatic group, a 7-membered saturated, partially unsaturated, or aromatic monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10-membered saturated, partially unsaturated, or aromatic bicyclic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or 
 R 7b  and R 7c , taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-6-membered saturated, partially unsaturated, or aromatic ring having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 X is N or CR 8 , 
 wherein R 8  is halogen, —R 9 , —OR 9 , —N(R 9 ) 2 , —SR 9 , —OCOR 9 , —COOR 9 , —CN, —CON(R 9 ) 2 , —COR 9 , —SO 2 R 9 , —SOR 9 , —NR 9 SO 2 R 9 , or —SO 2 N(R 9 ) 2 , wherein each R 9  is independently hydrogen or an optionally substituted C 1- C 6 aliphatic group; or 
 when X is CR 8 , R 8  and R 2 , taken together with the carbon atom to which they are bound, form an optionally substituted 3-6-membered spiro ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 Cy 1  is an optionally substituted group selected from a 5-8-membered partially unsaturated or aromatic unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-14-membered partially unsaturated or aromatic bicyclic or tricyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein Cy 1  is substituted with p independent occurrences of —R 10a , -J-R 10a , or W-J-R 10a , and j occurrences of ═O, ═S, ═NR 11a , ═NR 11b , —R 10b , -J-R 10b , or —W-J-R 10b , wherein: 
 p is 0-3; 
 j is 0-2; 
 W is —O—, —N(R 11a )—, —S—, —SO—, —SO 2 —, —SO 2 N(R 11a )—, —N(R 11a )SO 2 —, —CO—, —CON(R 11a )—, —N(R 11a )CO—, or —CO 2 —; 
 J is an optionally substituted straight or branched C 1- C 4 alkylene chain that is optionally replaced by —CR 11a ═CR 11a —, —O—, —N(R 11a )—, —S—, —SO—, —SO 2 —, —SO 2 N(R 11a )—, —N(R 11a )SO 2 —, —CO—, —CON(R 11a )—, —N(R 11a )CO—, or —CO 2 —, provided that the replacing moiety is not directly bonded to W, —R 10a , or —R 10b ; 
 each —R 10a  is independently optionally substituted C 1- C 6  aliphatic, halogen, —OR 11a , —CN, —NO 2 , —SR 11a , —SO 2 N(R 11a ) 2 , —NR 11a SO 2 R 11a , —SO 2 R 11a , —COR 11a , —CO 2 R 11a , —N(R 11a ) 2 , —CON(R 11a ) 2 , —N(R 11a )COR 11a , —N(R 11a )CO 2 R 11a , or —N(R 11 )CON(R 11a ) 2 ; 
 each —R 10b  is independently —OR 11b , —SR 11b , —SO 2 N(R 11b )(R 11c ), SO 2 R 11b , —SO 2 R 11b , —COR 11b , —CO 2 R 11b , —N(R 11b )(R 11c ), —CON(R 11b )(R 11c ), —N(R 11c )COR 11b , —N(R 11c )CO 2 R 11b , —N(R 11c )CON(R 11b )(R 11c ), or an optionally substituted group selected from a 3-7-membered saturated, partially unsaturated, or aromatic monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10-membered saturated, partially unsaturated, or aromatic bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two occurrences of R 10b , taken together with their intervening atom(s), form a spiro, fused, or bridged optionally substituted 5-7-membered saturated, partially unsaturated, or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 each R 11a  is hydrogen or an optionally substituted C 1- C 6 aliphatic group; 
 each R 11b  is an optionally substituted group selected from a 3-7-membered saturated, partially unsaturated, or aromatic monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10-membered saturated, partially unsaturated, or aromatic bicyclic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and 
 each R 11c  is hydrogen or an optionally substituted group selected from a C 1- C 6 aliphatic group, a 3-7-membered saturated, partially unsaturated, or aromatic monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10-membered saturated, partially unsaturated, or aromatic bicyclic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or 
 R 11b  and R 11c , taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-6-membered saturated, partially unsaturated, or aromatic ring having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur, 
 provided that: 
 A) when ring A is 
 
       
         
           
           
               
               
           
         
       
       R 1  is OH, n is 1, q and r are 0, X is CH, and R 2  is unsubstituted phenyl, then Cy 1  is not unsubstituted phenyl or phenyl substituted with —Br, —I, —NO 2 , or —NH 2 ; and
 B) when ring A is 
 
       
         
           
           
               
               
           
         
       
       R 1  is OH, q and r are 0, X is N, and R 2  is (3-CF 3 )phenyl-, then Cy 1  is not 6-(3-methyl-1,2,4-thiadiazol-5-yl)-3-pyridazinyl. 
     
     
         2 . The compound of  claim 1  having a structure of formulae II, III, or IV: 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 2  having a structure of formulae II-A, III-A, or IV-A: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 2  having a structure of formulae III-B, or IV-B: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound of  claim 1 , wherein:
 a) R 1  is —OR 4 , halogen, —OCOR 4 , —NR 4 SO 2 R 3 , or —NR 4 COR 4 ; q is 0, 1, or 2, and —R A  is halogen, an optionally substituted linear or branched C 1 -C 6 alkyl, an optionally substituted C 3 -C 6 cycloalkyl ring, or two occurrences of R A , taken together with the carbon atom(s) to which they are bound form an optionally substituted fused or spiro C 3 -C 6 cycloalkyl ring; or R 1  and R A,  taken together with the carbon atom(s) to which they are bound form an optionally substituted fused or spiro C 3 -C 6 cycloalkyl ring;   b) r is 0, 1, or 2, and —R B  is halogen, or an optionally substituted group selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or a fused or bridged 5- or 6-membered saturated ring having 0 heteroatoms;   c) R 2  is -Cy 2 , or -T-Cy 2 , and   when X is N, then T, when present, is a C 1 -C 3 alkylene chain substituted with 0 or 1 occurrence of R 5a , and 0, 1, or 2 independent occurrences of R 5b , and wherein one or more methylene units in the C 1 -C 3 alkylene chain is optionally replaced by —CO— or —SO 2 , or   when X is CR 8 , T, when present, is a C 1 -C 3 alkylene chain substituted with 0 or 1 occurrence of R 5a , and 0, 1, or 2 independent occurrences of R 5b , and wherein one or more methylene units in the C 1 -C 3 alkylene chain, as valency and stability permit, is optionally replaced by —CR 5a ═CR 5c —, —CO—, —O—, —S—, or —NR 5a —, and R 8  is hydrogen, C 1 -C 3 alkyl, —OH, —O(C 1 -C 3 allyl), —NH 2 , —N(C 1 -C 3 alkyl) 2 , —SH, —S(C 1 -C 3 alkyl), —CO(C 1 -C 3 alkyl), —COOH, or —COO(C 1 -C 3 alkyl);   Cy 2  is an optionally substituted ring selected from phenyl, naphthyl, a 5-6-membered monocyclic heteroaryl ring having 1-3 heteroatoms selected from nitrogen, oxygen, or sulfur, or an 8-10-membered bicyclic heteroaryl ring having 1-3 heteroatoms selected from nitrogen, oxygen, or sulfur,   wherein Cy 2  is substituted with 0, 1, or 2 independent occurrences of —R 6a , -G-R 6a , or —V-G-R 6a , and 0 or 1 occurrence of ═O, ═S, ═NR 7a , —NR 7b , —R 6b , -G-R 6b , or —V-G-R 6b , wherein:   each —R 6a , -G-R 6a , or —V-G-R 6a , when present, is independently —CN, —NO 2 , —OR 7a , —(CH 2 ) 1-4 OR 7a , —SR 7a , —(CH 2 ) 1-4 SR 7a , halogen, —COOR 7a , —(CH 2 ) 1-4 COOR 7a , —COR 7a , —(CH 2 ) 1-4 COR 7a , —CON(R 7a ) 2 , —(CH 2 ) 1-4 CON(R 7a ) 2 , —N(R 7a ) 2 , —(CH 2 ) 1-4 N(R 7a ) 2 , —SO 2 N(R 7a ) 2 , —(CH 2 ) 1-4 SO 2 N(R 7a ) 2 , —NR 7a SO 2 R 7a , or —(CH 2 ) 1-4 NR 7a SO 2 R 7a , or an optionally substituted C 1 -C 6 aliphatic group; and   each —R 6b , -G-R 6b  or —V-G-R 6b  is —OR 7b , —(CH 2 ) 1-4 OR 7b , —SR 7b , —(CH 2 ) 1-4 SR 7b , —COOR 7b , —(CH 2 ) 1-4 COOR 7b , —COR 7b , —(CH 2 ) 1-4 COR 7b , —CON(R 7b )(R 7c ), —(CH 2 ) 1-4 CON(R 7b )(R 7c ), —N(R 7b )(R 7c ), —(CH 2 ) 1-4 N(R 7b )(R 7c ), —SO 2 N(R 7b )(R 7c ), —(CH 2 ) 1-4 SO 2 N(R 7b )(R 7c ), —NR 7c SO 2 R 7b , —(CH 2 ) 1-4 NR 7e SO 2 R 7b , or an optionally substituted group selected from a 3-7-membered saturated, partially saturated, or aromatic monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10-membered saturated, partially unsaturated, or aromatic bicyclic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and   d) Cy 1  is an optionally substituted ring selected from phenyl, naphthyl, a 5-6-membered monocyclic heteroaryl ring having 1-3 heteroatoms selected from nitrogen, oxygen, or sulfur, or an 8-10-membered bicyclic heteroaryl ring having 1-3 heteroatoms selected from nitrogen, oxygen, or sulfur,   wherein Cy 1  is substituted with 0, 1, 2, or 3 independent occurrences of —R 10a , -J-R 10a , or —W-J-R 10a , and 0 or 1 occurrence of ═O, ═S, ═NR 11a , ═NR 11b , —R 10b , J-R 10b , or —W-J-R 10b , wherein:   each —R 10a , -J-R 10a , or —W-J-R 10a , when present, is independently —CN, —NO 2 , —OR 11a , —(CH 2 ) 1-4 OR 11a , —SR 11a , —(CH 2 ) 1-4 SR 11a , halogen, —COOR 11a , —(CH 2 ) 1-4 COOR 11a , —COR 11a , —(CH 2 ) 1-4 COR 11a , —CON(R 11a ) 2 , —(CH 2 ) 1-4 CON(R 11a ) 2 , —N(R 11a ) 2 , —(CH 2 ) 1-4 N(R 11a ) 2 , —SO 2 N(R 11a ) 2 , —(CH 2 ) 1-4 SO 2 N(R 11a ) 2 , —NR 11a SO 2 R 11a , —(CH 2 ) 1-4 NR 11a SO 2 R 11a , —NR 11a CON(R 11a )CON(R 11a ) 2 , —(CH 2 ) 1-4 NR 11a CON(R 11a ) 2 , —NR 11a COOR 11a , —(CH 2 ) 1-4 NR 11a COOR 11a , or an optionally substituted C 1 -C 6 aliphatic group; and   each —R 10b , -J-R 10b , or —W-J-R 10b  is —OR 11b , —(CH 2 ) 1-4 OR 11b , —SR 11b , —(CH 2 ) 1-4 OR 11b , —SR 11b , —(CH 2 ) 1-4 SR 11b , —COOR 11b , —(CH 2 ) 1-4 COOR 11b , —COR 11b , —(CH 2 ) 1-4 COR 11b ), —CON(R 11b )(R 11c ), —(CH 2 ) 1-4 CON(R 11b )(R 11c ), —N(R 11b )(R 11c ), —(CH 2 ) 1-4 N(R 11b )(R 11c ), —SO 2 N(R 11b )(R 11c ), —(CH 2 ) 1-4 SO 2 N(R 11b )(R 11c ), —NR 11c SO 2 R 11b , —(CH 2 ) 1-4 NR 11c SO 2 R 11b , —NR 11c CON(R 11b )(R 11c ), —(CH 2 ) 1-4 NR 11c CON(R 11b )(R 11c ), —NR 11c COOR 11b , —(CH 2 ) 1-4 NR 11c COOR 11b , or an optionally substituted group selected from a 3-7-membered saturated, partially saturated, or aromatic monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10-membered saturated, partially unsaturated, or aromatic bicyclic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.   
     
     
         6 . The compound of  claim 1 , wherein:
 a) R 1  is —OR 4 , halogen, —OCOR 4 , —NR 4 SO 2 R 3 , or —NR 4 COR 4 ; q is 0, 1, or 2, and —R A  is halogen, an optionally substituted linear or branched C 1 -C 6 alkyl, an optionally substituted C 3 -C 6 cycloalkyl ring, or two occurrences of R A , taken together with the carbon atom(s) to which they are bound form an optionally substituted fused or spiro C 3 -C 6 cycloalkyl ring; or R 1  and R A  taken together with the carbon atom(s) to which they are bound form an optionally substituted fused or spiro C 3 -C 6 cycloalkyl ring;   b) r is 0, 1, or 2, and —R B  is halogen, or an optionally substituted group selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or a fused or bridged 5- or 6-membered saturated ring having 0 heteroatoms;   c) R 2  is -Cy 2 , or -T-Cy 2 , and   when X is N, then T, when present, is a C 1 -C 3 alkylene chain substituted with 0 or 1 occurrence of R 5a , and 0, 1, or 2 independent occurrences of R 5b , and wherein one or more methylene units in the C 1 -C 3 alkylene chain is optionally replaced by —CO— or —SO 2 , or   when X is CR 8 , then T, when present, is a C 1 -C 3 alkylene chain substituted with 0 or 1 occurrence of R 5a , and 0, 1, or 2 independent occurrences of R 5b , and wherein one or more methylene units in the C 1 -C 3 allylene chain, as valency and stability permit, is optionally replaced by —CR 5c ═CR 5c —, —CO—, —O—, —S—, or —NR 5c —, and R 8  is hydrogen, C 1 -C 3 alkyl, —OH, —O(C 1 -C 3 alkyl), —NH 2 , —N(C 1 -C 3 allyl) 2 , —SH, —S(C 1 -C 3 alkyl), —CO(C 1 -C 3 alkyl), —COOH, or —COO(C 1 -C 3 alkyl);   Cy 2  is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, pyrazolyl, pyrrolyl, thiazolyl, isothiazolyl, thienyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, isoxazolyl, oxazolyl, furanyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3-dihydroimidazol-2-onyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, [1,8]naphthyridinyl, naphthyl, 1,3-dihydro-benzoimidazol-2-on-1-yl, indolyl, benzo[c]isoxazolyl, benzofuranyl, benzothienyl, benzo[c]isothiazolyl, benzooxazol-2-yl, 5H-pyrrolo[3,2-d]pyrimidinyl, furo[3,2-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, indanyl, benzo[d]isothiazolyl, benzo[d]isoxazolyl, benzo[1,3]dioxolyl, benzothiazolyl, benzimidazolyl, and indazolyl; wherein Cy 2  is substituted with 0, 1, or 2 independent occurrences of —R 6a , -G-R 6a , or —V-G-R 6a , and 0 or 1 occurrence of ═O, ═S, ═NR 7a , ═NR 7b , —R 6b , -G-R 6b , or —V-G-R 6b , wherein:   each —R 6a , -G-R 6a , or —V-G-R 6a , when present, is independently —CN, —NO 2 , —OR 7a , —(CH 2 ) 1-4 OR 7a , —SR 7a , —(CH 2 ) 1-4 SR 7a , halogen, —COOR 7a , —(CH 2 ) 1-4 COOR 7a , —(CH 2 ) 1-4 COR 7a , —CON(R 7a ) 2 , —(CH 2 ) 1-4 CON(R 7a ) 2 , —N(R 7a ) 2 , —(CH 2 ) 1-4 N(R 7a ) 2 , —SO 2 N(R 7a ) 2 , —(CH 2 ) 1-4 SO 2 N(R 7a ) 2 , —NR 7a SO 2 R 7a , or —(CH 2 ) 1-4 NR 7a SO 2 R 7a , or an optionally substituted C 1 -C 6 aliphatic group; and   each —R 6b , -G-R 6b , or —V-G-R 6b  is —OR 7b , —(CH 2 ) 1-4 OR 7b , —SR 7b , —(CH 2 ) 1-4 SR 7b , —COOR 7b , —(CH 2 ) 1-4 COOR 7b , —COR 7b , —(CH 2 ) 1-4 COR 7b , —CON(R 7b )(R 7c ), —(CH 2 ) 1-4 CON(R 7b )(R 7c ), —N(R 7b )(R 7c ), —(CH 2 ) 1-4 N(R 7b )(R 7c ), —SO 2 N(R 7b )(R 7c ), —(CH 2 ) 1-4 SO 2 N(R 7b )(R 71 ), —NR 7c SO 2 R 7b , —(CH 2 ) 1-4 NR 7c SO 2 R 7b , or an optionally substituted group selected from a 3-7-membered saturated, partially saturated, or aromatic monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10-membered saturated, partially unsaturated, or aromatic bicyclic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;   d) Cy 1  is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, pyrazolyl, pyrrolyl, thiazolyl, isothiazolyl, thienyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, isoxazolyl, oxazolyl, furanyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3-dihydroimidazol-2-onyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, [1,8]naphthyridinyl, naphthyl, 1,3-dihydro-benzoimidazol-2-on-1-yl, indolyl, benzo[c]isoxazolyl, benzofuranyl, benzothienyl, benzo[c]isothiazolyl, benzooxazol-2-yl, 5H-pyrrolo[3,2-d]pyrimidinyl, furo[3,2-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, indanyl, benzo[d]isothiazolyl, benzo[d]isoxazolyl, benzo[1,3]dioxolyl, benzothiazolyl, benzimidazolyl, indazolyl, purinyl, pyrido[2,3-d]pyrimidine, or pyrido[3,4-d]pyrimidine; wherein Cy 1  is substituted with 0, 1, 2, or 3 independent occurrences of —R 10a , -J-R 10a , or —W-J-R 10a , and 0 or 1 occurrence of ═O, ═S, ═NR 11a , ═NR 11b , —R 10b , -J-R 10b , or —W-J-R 10b , wherein:   each —R 10a , -J-R 10a , or —W-J-R 10a , when present, is independently —CN, —NO 2 , —OR 11a , —(CH 2 ) 1-4 OR 11a , —SR 11a , —(CH 2 ) 1-4 SR 11a , halogen, —COOR 11a , —(CH 2 ) 1-4 COOR 11a , —COR 11a , —(CH 2 ) 1-4 COR 11a , —CON(R 11a ) 2 , —(CH 2 ) 1-4 CON(R 11a ) 2 , —N(R 11a ) 2 , —(CH 2 ) 1-4 N(R 11a ) 2 , —SO 2 N(R 11a ) 2 , —(CH 2 ) 1-4 SO 2 N(R 11a ) 2 , —NR 11a SO 2 R 11a , —(CH 2 ) 1-4 NR 11a SO 2 R 11a , —NR 11a CON(R 11a )CON(R 11a ) 2 , —(CH 2 ) 1-4 NR 11a CON(R 11a ) 2 , —NR 11a COOR 11a , —(CH 2 ) 1-4 NR 11a COOR 11a , or an optionally substituted C 1 -C 6 aliphatic group; and   each —R 10b , -J-R 10b , or —W-J-R 10b  is —OR 11b , —(CH 2 ) 1-4 OR 11b , —SR 11b , —(CH 2 ) 1-4 OR 11b , —SR 11b , —(CH 2 ) 1-4 SR 11b , —COOR 11b , —(CH 2 ) 1-4 COOR 11b , —COR 11b , —(CH 2 ) 1-4 COR 11b ), —CON(R 11b )(R 11c ), —(CH 2 ) 1-4 CON(R 11b )(R 11c ), —N(R 11b )(R 11c ), —(CH 2 ) 1-4 N(R 11b )(R 11c ), —SO 2 N(R 11b )(R 11c ), —(CH 2 ) 1-4 SO 2 N(R 11b )(R 11c ), —NR 11c SO 2 R 11b , —(CH 2 ) 1-4 NR 11c SO 2 R 11b , —NR 11c CON(R 11b )(R 11c ), —(CH 2 ) 1-4 NR 11c CON(R 11b )(R 11c ), —NR 11c COOR 11b , —(CH 2 ) 1-4 NR 11c COOR 11b , or an optionally substituted group selected from a 3-7-membered saturated, partially saturated, or aromatic monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10-membered saturated, partially unsaturated, or aromatic bicyclic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.   
     
     
         7 . The compound of  claim 6 , wherein:
 a) R 1  is —OH, —O(C 1 -C 6 alkyl), —OCO(C 1 -C 6 alkyl), —NHSO 2 (C 1 -C 6 alkyl), —NHCO(C 1 -C 6 alkyl), or —F;   b) q is 0 or 1 and —R A  is optionally substituted linear or branched C 1 -C 6 alkyl, or halogen;   c) r is 0, 1, or 2, and —R B  is C 1 -C 3 alkyl, or two occurrences of R B , taken together with their intervening atom(s), form an optionally substituted fused or bridged 5 or 6-membered saturated, partially unsaturated, or aromatic ring having 0 heteroatoms;   d) R 2  is -Cy 2 , or -T-Cy 2 , and   X is N and T, when present, is —CH 2 —, —CO—, —CH 2 CH═CH—, or —CH 2 CH 2 —, or X is CR 8 , and T, when present, is —NR 5c —, or —O—, and R 8  is hydrogen, C 1 -C 3 alkyl, —OH, or —O(C 1 -C 3 allyl); and   Cy 2  is:   
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein Cy 2  is substituted with: 
         0, 1, or 2 occurrences of —R 6a  and each —R 6a , when present, is independently —Cl, —Br, —F, —CN, —NO 2 , —OR 7a , —SR 7a , —N(R 7a ) 2 , —COOR 7a , —COR 7a , —SO 2 N(R 7a ) 2 , —NR 7a SO 2 R 7a , —CON(R 7a ) 2 , —NR 7a COR 7a , or optionally substituted C 1 -C 6 alkyl, wherein each R 7a  is independently hydrogen, or optionally substituted C 1 -C 6 alkyl; and 
         0 or 1 occurrence of —R 6b , wherein —R 6b , when present is —OR 7b , —N(R 7b )(R 7c ), —COOR 7b , —COR 7b , —SO 2 N(R 7b )(R 7c ), —NR 7c SO 2 R 7b , —CON(R 7b )(R 7c ), —NR 7c COR 7b , or an optionally substituted 3-6-membered saturated, partially unsaturated, or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each R 7b  is independently an optionally substituted 3-6-membered saturated, partially unsaturated, or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and each R 7c  is independently hydrogen or an optionally substituted group selected from C 1 -C 6 alkyl or an optionally substituted 3-6-membered saturated, partially unsaturated, or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
         e) Cy 1  is: 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein Cy 1  is substituted with: 
         0, 1, or 2 occurrences of —R 10a  and each —R 10a , when present, is independently —Cl, —Br, —F, —CN, —NO 2 , —OR 11a , —SR 11a , —N(R 11a ) 2 , —NR 11a COR 11a , —CON(R 11a ) 2 , —SO 2 N(R 11a ) 2 , —NR 11a SO 2 R 11a , COOR 11a , COR 11a , —NR 11a CON(R 11a ) 2 , —NR 11a COOR 11a , or optionally substituted C 1 -C 6 alkyl, wherein each R 11a  is independently hydrogen, or optionally substituted C 1 -C 6 alkyl; and 
         0 or 1 occurrence of —R 10b , J-R 10b , or W-J-R 10b , wherein W is —N(R 11b ) or —O—, J is a C 1 -C 2 alkyl chain, and —R 10b , when present is —OR 11b , —SR 11b , —N(R 11b )(R 11c ), —NR 11c COR 11b , CON(R 11b )(R 11c ), —SO 2 N(R 11c )(R 11b ), —NR 11c SO 2 R 11b , —COOR 11b , COR 11b , —NR 11c CON(R 11b )(R 11c ), —NR 11c COOR 11b , or an optionally substituted 3-6-membered saturated, partially unsaturated, or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each R 11b  is independently an optionally substituted 3-6-membered saturated, partially unsaturated, or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and each R 11c  is independently hydrogen or an optionally substituted group selected from C 1 -C 6 alkyl or an optionally substituted 3-6-membered saturated, partially unsaturated, or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
       
     
     
         8 . The compound of  claim 7 , wherein:
 a) R 1  is —OH, —O(C 1 -C 6 alkyl) or F;   b) q is 0 or 1 and —R A  is —CH 3 , —CH 2 CH 3 , or F;   c) r is 0, 1 or 2, and —R B  is C 1 -C 3 allyl;   d) X is N, R 2  is -T-Cy 2 , T is —CH 2 — or —CO—; and Cy 2  is:   
       
         
           
           
               
               
           
         
       
       wherein Cy 2  is substituted with 0, 1, or 2 occurrences of —R 6a  and each —R 6a , when present, is independently —Cl, —Br, —F, —CN, —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 CH 3 , —CF 3 , —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —C(CH 3 ) 3 , —COOH, —COOCH 3 , —COOCH 2 CH 3 ;
 e) Cy 1  is a group selected from i, ii-a, ii-b, xxiv-a, xxiv-b, xxv-a, xxvi-a, xLiv-a, xLv-a, xLvi-a, or xLvii-a 
 wherein Cy 1  is substituted with: 
 0, 1, or 2 occurrences of R 10a , and each —R 10a  is independently —Cl, —Br, —F, —NO 2 , —CN, —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 CH 3 , —CF 3 , —OCF 3 , —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —C(CH 3 ) 3 , —CH(CH 3 ) 2 , t-Bu, —NHCOCH 3 , —NHCONHCH 3 , —SCH 3 , —SCH 2 CH 3 , —SCH 2 CH 2 CH 3 , —NH 2 , —NHCH 3 , —SO 2 NH 2 , —COOH, —COOCH 3 , —COOCH 2 CH 3 , —NHCH 3 , —N(CH 3 ) 2 , —NH(CH 2 CH 3 ), —N(CH 2 CH 3 ) 2 , —OC(CH 3 ) 2 CO 2 H, —OCH 2 CO 2 H, —C(CH 3 ) 2 OH, —CONH 2 , —NHCONH 2 , —NHCON(CH 3 ) 2 , or —NHCOOCH 3 , and 
 0 or 1 occurrence of —R 10b , J—R 10b , or W-J-R 10b , and —R 10b , J-R 10b , or W-J-R 10b  is morpholinyl, tetrazolyl, 
 
       
         
           
           
               
               
           
         
       
       phenyl, benzyl, —NHCO(phenyl), —NHCO(benzyl), —NH(phenyl), —NHCH 2 (phenyl), —NH(benzyl), —S(phenyl), —S(benzyl), —O(phenyl), or —O(benzyl), wherein the phenyl and benzyl groups are optionally substituted. 
     
     
         9 . The compound of  claim 8 , wherein R 1  is —OH. 
     
     
         10 . The compound of  claim 8 , wherein q is 0. 
     
     
         11 . The compound of  claim 8 , wherein r is 0. 
     
     
         12 . The compound of  claim 8 , wherein Cy 2  is substituted with 1 or 2 occurrences of —R 6a , and each —R 6a  is independently —Cl, —F, —CF 3 , —CH 3 , or —Br. 
     
     
         13 . The compound of  claim 8 , wherein Cy 2  is substituted with 1 occurrence of —R 6a , and —R 6a  is —Cl. 
     
     
         14 . The compound of  claim 8 , wherein Cy 2  is: 
       
         
           
           
               
               
           
         
         and each R 6a  is independently —Cl, —Br, —CH 3 , —CF 3 , or —F. 
       
     
     
         15 . The compound of  claim 8 , wherein Cy 2  is phenyl substituted with 1 or 2 occurrences of —R 6a , and each —R 6a  is independently —Cl, —F, —CF 3 , —CH 3 , or —Br. 
     
     
         16 . The compound of  claim 8 , wherein Cy 2  is phenyl substituted with 1 occurrence of —R 6a , and —R 6a  is —Cl. 
     
     
         17 . The compound of  claim 8 , wherein Cy 1  is 2-pyridyl (ii-a), pyrimidin-2-yl (iii-a), pyrimidin-4-yl (iii-b), quinolinyl (xxiv-a), or 4-quinaozlinyl (xxvi-a) 2-quinazolinyl (xLv-a), pyrido[2,3-d]pyrimidinyl (xLvi-a) or pyrido[3,4-d]pyrimidinyl (xLvii-a). 
     
     
         18 . The compound of  claim 8 , wherein Cy 1  is 2-pyridyl (ii-a), pyrimidin-2-yl (iii-a), 4-quinazoline (xxvi-a) or 2-quinazolinyl (xLv-a). 
     
     
         19 . The compound of  claim 1 , wherein the compound has the structure of formula II-A: 
       
         
           
           
               
               
           
         
         wherein: 
         a) R 1  is —OR 4 , halogen, —OCOR 4 , —NR 4 SO 2 R 3 , or —NR 4 COR 4 ; q is 0, 1, or 2, and —R A  is halogen, an optionally substituted linear or branched C 1 -C 6 alkyl, or an optionally substituted C 3 -C 6 cycloalkyl ring; 
         b) r is 0, 1, or 2, and —R B  is halogen, or an optionally substituted group selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or a fused or bridged 5- or 6-membered saturated ring having 0 heteroatoms; 
         c) R 2  is -Cy 2 , or -T-Cy 2 , and 
         when X is N, then T, when present, is —CO—, —CH 2 —, —CH 2 CH═CH—, or —CH 2 CH 2 —, or 
         when X is CR 8 , then T, when present, is —O— or —NR 5c —, and R 8  is hydrogen, C 1 -C 3 alkyl, —OH, —O(C 1 -C 3 alkyl), —NH 2 , —N(C 1 -C 3 alkyl) 2 , —SH, —S(C 1 -C 3 allyl), —CO(C 1 -C 3 alkyl), —COOH, or —COO(C 1 -C 3 alkyl); 
         Cy 2  is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, pyrazolyl, pyrrolyl, thiazolyl, isothiazolyl, thienyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, isoxazolyl, oxazolyl, furanyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3-dihydroimidazol-2-onyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, [1,8]naphthyridinyl, naphthyl, 1,3-dihydro-benzoimidazol-2-on-1-yl, indolyl, benzo[c]isoxazolyl, benzofuranyl, benzothienyl, benzo[c]isothiazolyl, benzooxazol-2-yl, 5H-pyrrolo[3,2-d]pyrimidinyl, furo[3,2-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, indanyl, benzo[d]isothiazolyl, benzo[d]isoxazolyl, benzo[1,3]dioxolyl, benzothiazolyl, benzimidazolyl, or indazolyl; wherein Cy 2  is substituted with 0, 1, or 2 independent occurrences of —R 6a  or —V-G-R 6a , and 0 or 1 occurrence of ═O, ═S, ═NR 7a , ═NR 7b —R 6b , -G-R 6b , or —V-G-R 6b , wherein: 
         each —R 6a , -G-R 6a , or —V-G-R 6a , when present, is independently —CN, —NO 2 , —OR 7a , —(CH 2 ) 1-4 OR 7a , —SR 7a , —(CH 2 ) 1-4 SR 7a , halogen, —COOR 7a , —(CH 2 ) 1-4 COOR 7a , —(CH 2 ) 1-4 COR 7a , —CON(R 7a ) 2 , —(CH 2 ) 1-4 CONR 7a ) 2 , —N(R 7a ) 2 , —(CH 2 ) 1-4 N(R 7a ) 2 , —SO 2 N(R 7a ) 2 , —(CH 2 ) 1-4 SO 2 N(R 7a ) 2 , —NR 7a SO 2 R 7a , or —(CH 2 ) 1-4 NR 2a SO 2 R 7a , or an optionally substituted C 1 -C 6 aliphatic group; and 
         each —R 6b , -G-R 6b , or —V-G-R 6b  is —OR 7b , —(CH 2 ) 1-4 OR 7b , —SR 7b , —(CH 2 ) 1-4 SR 7b , —COOR 7b , —(CH 2 ) 1-4 COOR 7b , —COR 7b , —(CH 2 ) 1-4 COR 7b , —CON(R 7b )(R 7c ), —(CH 2 ) 1-4 CON(R 7b )(R 7c ), —N(R 7b )(R 7c ), —(CH 2 ) 1-4 N(R 7b )(R 7c ), —SO 2 N(R 7b )(R 7c ), —(CH 2 ) 1-4 SO 2 N(R 7b )(R 7c ), —NR 7c SO 2 R 7b , —(CH 2 ) 1-4 NR 7c SO 2 R 7b , or an optionally substituted group selected from a 3-7-membered saturated, partially saturated, or aromatic monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10-membered saturated, partially unsaturated, or aromatic bicyclic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
         d) Cy 1  is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, pyrazolyl, pyrrolyl, thiazolyl, isothiazolyl, thienyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, isoxazolyl, oxazolyl, furanyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3-dihydroimidazol-2-onyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, [1,8]naphthyridinyl, naphthyl, 1,3-dihydro-benzoimidazol-2-on-1-yl, indolyl, benzo[c]isoxazolyl, benzofuranyl, benzothienyl, benzo[c]isothiazolyl, benzooxazol-2-yl, 5H-pyrrolo[3,2-d]pyrimidinyl, furo[3,2-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, indanyl, benzo[d]isothiazolyl, benzo[d]isoxazolyl, benzo[1,3]dioxolyl, benzothiazolyl, benzimidazolyl, indazolyl, purinyl, pyrido[2,3-d]pyrimidine, or pyrido[3,4-d]pyrimidine; wherein Cy 2  is substituted with 0, 1, 2, or 3 independent occurrences of —R 10a , -J-R 10a , or —W-J-R 10a , and 0 or 1 occurrence of ═O, ═S, ═NR 11b , —R 10b , -J-R 10b , or —W-J-R 10b , wherein: 
         each —R 10a , -J-R 10a , or —W-J-R 10a , when present, is independently —CN, —NO 2 , —OR 11a , —(CH 2 ) 1-4 OR 11a , —SR 11a , —(CH 2 ) 1-4 SR 11a , halogen, —COOR 11a , —(CH 2 ) 1-4 COOR 11a , —COR 11a , —(CH 2 ) 1-4 COR 11a , —CON(R 11a ) 2 , —(CH 2 ) 1-4 CON(R 11a ) 2 , —N(R 11a ) 2 , —(CH 2 ) 1-4 N(R 11a ) 2 , —SO 2 N(R 11a ) 2 , —(CH 2 ) 1-4 SO 2 N(R 11a ) 2 , —NR 11a SO 2 R 11a , —(CH 2 ) 1-4 NR 11a SO 2 R 11a , —NR 11a CON(R 11a )CON(R 11a ) 2 , —(CH 2 ) 1-4 NR 11a CON(R 11a ) 2 , —NR 11a COOR 11a , —(CH 2 ) 1-4 NR 11a COOR 11a , or an optionally substituted C 1 -C 6 aliphatic group; and 
         each —R 10b , -J-R 10b , or —W-J-R 10b  is —OR 11b , —(CH 2 ) 1-4 OR 11b , —SR 11b , —(CH 2 ) 1-4 OR 11b , —SR 11b , —(CH 2 ) 1-4 SR 11b , —COOR 11b , —(CH 2 ) 1-4 COOR 11b , —COR 11b , —(CH 2 ) 1-4 COR 11b ), —CON(R 11b )(R 11c ), —(CH 2 ) 1-4 CON(R 11b )(R 11c ), —N(R 11b )(R 11c ), —(CH 2 ) 1-4 N(R 11b )(R 11c ), —SO 2 N(R 11b )(R 11c ), —(CH 2 ) 1-4 SO 2 N(R 11b )(R 11c ), —NR 11c SO 2 R 11b , —(CH 2 ) 1-4 NR 11c SO 2 R 11b , —NR 11c CON(R 11b )(R 11c ), —(CH 2 ) 1-4 NR 11c CON(R 11b )(R 11c ), —NR 11c COOR 11b , —(CH 2 ) 1-4 NR 11c COOR 11b , or an optionally substituted group selected from a 3-7-membered saturated, partially saturated, or aromatic monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10-membered saturated, partially unsaturated, or aromatic bicyclic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
       
     
     
         20 . The compound of  claim 19 , wherein the compound has the structure of formula II-A-i: 
       
         
           
           
               
               
           
         
       
     
     
         21 . The compound of  claim 19 , wherein:
 a) q is 0 or 1 and A has the structure:   
       
         
           
           
               
               
           
         
       
       and R 1  is —OH, —O(C 1 -C 6 alkyl), —OCO(C 1 -C 6 alkyl), —NHSO 2 (C 1 -C 6 alkyl), —NHCO(C 1 -C 6 alkyl), or F; and —R A  is optionally substituted linear or branched C 1 -C 6 alkyl, or halogen; and
 b) r is 0, 1, or 2, and —R B  is —R B  is C 1 -C 3 alkyl, or two occurrences of R B , taken together with their intervening atom(s), form an optionally substituted fused or bridged 5 or 6-membered saturated, partially unsaturated, or aromatic ring having 0 heteroatoms; 
 c) Cy 1  is: 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein Cy 2  is substituted with:
 0, 1, or 2 occurrences of —R 6a  and each —R 6a , when present, is independently —Cl, —Br, —F, —CN, —NO 2 , —OR 73 , —SR 7a , —N(R 7a ) 2 , —COOR 7a , —COR 7a , —SO 2 N(R 7a ) 2 , —NR 7a SO 2 R 7a , —CON(R 7a ) 2 , —NR 7a COR 7a , or optionally substituted C 1 -C 6 alkyl, wherein each R 7a  is independently hydrogen, or optionally substituted C 1 -C 6 alkyl; and 
 0 or 1 occurrence of —R 6b , wherein —R 6b , when present is —OR 7b , —N(R 7b )(R 7c ), —COOR 7b , —COR 7b , —SO 2 N(R 7b )(R 7c ), —NR 7c SO 2 R 7b , —CON(R 7b )(R 7c ), —NR 7c COR 7b , or an optionally substituted 3-6-membered saturated, partially unsaturated, or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each R 7b  is independently an optionally substituted 3-6-membered saturated, partially unsaturated, or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and each R 7c  is independently hydrogen or an optionally substituted group selected from C 1 -C 6 alkyl or an optionally substituted 3-6-membered saturated, partially unsaturated, or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 d) -Cy 1  is: 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein Cy 1  is substituted with: 
         0, 1, or 2 occurrences of —R 10a  and each —R 10a , when present, is independently —Cl, —Br, —F, —CN, —NO 2 , —OR 11a , —N(R 11a ) 2 , —NR 11a COR 11a , —CON(R 11a ) 2 , —SO 2 N(R 11a ) 2 , COOR 11a , COR 11a , —NR 11a CON(R 11a ) 2 , —NR 11a COOR 11a , or optionally substituted C 1 -C 6 alkyl, wherein each R 11a  is independently hydrogen, or optionally substituted C 1 -C 6 alkyl; and 
         0 or 1 occurrence of —R 10b , J-R 10b , W-J-R 10b , wherein W is —N(R 1lb ) or —O—, J is a C 1 -C 2 alkyl chain, and —R 10b , when present is —OR 11b , —SR 11b , —N(R 11b )(R 11c ), —NR 11c COR 11b , CON(R 11b )(R 11c ), —SO 2 N(R 11c )(R 11b ), —NR 11c SO 2 R 11b , —COOR 11b , COR 11b , —NR 11 CON(R 11b )(R 11c ), —NR 11c COOR 11b , or an optionally substituted 3-6-membered saturated, partially unsaturated, or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each R 11b  is independently an optionally substituted 3-6-membered saturated, partially unsaturated, or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and each R 11c  is independently hydrogen or an optionally substituted group selected from C 1 -C 6 alkyl or an optionally substituted 3-6-membered saturated, partially unsaturated, or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
       
     
     
         22 . The compound of  claim 19 , wherein:
 a) q is 0 or 1 and ring A has the structure:   
       
         
           
           
               
               
           
         
       
       wherein R 1  is —OR 4 , and —R A  is —CH 3 , CH 2 CH 3 , or F;
 b) r is 0, 1, or 2, and —R B  is methyl; 
 c) R 2  is -Cy 2 , or -T-Cy 2 , and 
 when X is N, then T, when present, is —CO—, or —CH 2 —, or 
 when X is CR 8 , then T, when present, is —O— or —NR 5c —, and R 8  is hydrogen, C 1 -C 3 alkyl, —OH, or —O(C 1 -C 3 alkyl); 
 Cy 2  is: 
 
       
         
           
           
               
               
           
         
         wherein Cy 2  is substituted with 0, 1, or 2 occurrences of —R 6a  and each —R 6a , when present, is independently —Cl, —Br, —F, —CN, —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 CH 3 , —CF 3 , —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —C(CH 3 ) 3 , —COOH, —COOCH 3 , —COOCH 2 CH 3 ; 
         e) Cy 1  is selected from i, ii-a, xxiv-a, xxiv-b, xxv-a, xxvi-a, xLiv-a, xLv-a, xLvi-a, or xLvii-a, 
         wherein Cy 1  is substituted with: 
         0, 1, or 2 occurrences of R 10a , and each —R 10a  is independently —Cl, —Br, —F, —NO 2 , —CN, —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 CH 3 , —CF 3 , —OCF 3 , —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —C(CH 3 ) 3 , —CH(CH 3 ) 2 , t-Bu, —NHCOCH 3 , —NHCONHCH 3 , —SCH 3 , —SCH 2 CH 3 , —SCH 2 CH 2 CH 3 , —NH 2 , —NHCH 3 , —SO 2 NH 2 , —COOH, —COOCH 3 , —COOCH 2 CH 3 , —NHCH 3 , —N(CH 3 ) 2 , —NH(CH 2 CH 3 ), —N(CH 2 CH 3 ) 2 , —OC(CH 3 ) 2 CO 2 H, —OCH 2 CO 2 H, —C(CH 3 ) 2 OH, —CONH 2 , —NHCONH 2 , —NHCON(CH 3 ) 2 , or —NHCOOCH 3 , and 
         0 or 1 occurrence of —R 10b , J-R 10b , or W-J-R 10b , and —R 10b , J-R 10b , or W-J-R 10b  is morpholinyl, tetrazolyl, 
       
       
         
           
           
               
               
           
         
       
       phenyl, benzyl, —NHCO(phenyl), —NHCO(benzyl), —NH(phenyl), —NHCH 2 (phenyl), —NH(benzyl), —S(phenyl), —S(benzyl), —O(phenyl), or —O(benzyl), wherein the phenyl and benzyl groups are optionally substituted. 
     
     
         23 . The compound of  claim 22 , wherein R 1  is —OH. 
     
     
         24 . The compound of  claim 22 , wherein q is 0. 
     
     
         25 . The compound of  claim 22 , wherein r is 0. 
     
     
         26 . The compound of  claim 22 , wherein Cy 2  is substituted with 1 or 2 occurrences of —R 6a , and each —R 6a  is independently —Cl, —F, —CF 3 , —CH 3 , or —Br. 
     
     
         27 . The compound of  claim 22 , wherein Cy 2  is substituted with 1 occurrence of —R 6a , and —R 6a  is —Cl. 
     
     
         28 . The compound of  claim 22 , wherein Cy 2  is: 
       
         
           
           
               
               
           
         
         and each R 6a  is independently —Cl, —Br, —CH 3 , —CF 3 , or —F. 
       
     
     
         29 . The compound of  claim 22 , wherein Cy 2  is phenyl substituted with 1 or 2 occurrences of —R 6a , and each —R 6a  is independently —Cl, —F, —CF 3 , —CH 3 , or —Br. 
     
     
         30 . The compound of  claim 22 , wherein Cy 2  is phenyl substituted with 1 occurrence of —R 6a , and —R 6a  is —Cl. 
     
     
         31 . The compound of  claim 22 , wherein Cy 1  is 2-pyridyl (ii-a), pyrimidin-2-yl (iii-a), pyrimidin-4-yl (iii-b), quinolinyl (xxiv-a), or 4-quinaozlinyl (xxvi-a) 2-quinazolinyl (xLv-a), pyrido[2,3-d]pyrimidinyl (xLvi-a) or pyrido[3,4-d]pyrimidinyl (xLvii-a). 
     
     
         32 . The compound of  claim 22 , wherein Cy 1  is 2-pyridyl pyrimidin-2-yl (iii-a), 4-quinazoline (xxvi-a) or 2-quinazolinyl (xLv-a). 
     
     
         33 . The compound of  claim 32 , wherein Cy 1  is substituted with 1, 2, or 3 occurrences of R 10a , and each R ma  is independently —Cl, —Br, —F, —CH 3 , —CF 3 , —COOCH 3 , —CONH 2 , —NHCONH 2 , —NHCOOCH 3 , —NHCONHCH 3 , —CONHCH 3 , —C(CH 3 ) 2 OH, —OCH 3 , —OCH 2 CH 3 , —CN, -tetrazole, —NO 2 , —N(CH 3 ) 2 , - or COOH. 
     
     
         34 . The compound of  claim 32 , wherein j is 0 or 1, and p is 0, 1, 2, or 3, and each —R 10a  is independently —COOCH 3 , —CONH 2 , —OCH 3 , —Cl, —Br, —F, or —CF 3 , and —R 10b  is optionally substituted phenyl. 
     
     
         35 . A pharmaceutical composition comprising a therapeutically effective amount of compound of  claim 1 , and a pharmaceutically acceptable carrier, adjuvant, or vehicle. 
     
     
         36 . The composition of  claim 35 , comprising an additional therapeutic agent. 
     
     
         37 .- 46 . (canceled)