IP Library › Granted Patent US 8,796,271

Granted Patent B2

US 8,796,271 · App. 13/207,696 · Granted Aug 5, 2014

Heteroaryls and uses thereof

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Patent No.: US 8,796,271
App. No.: 13/207,696
Granted: Aug 5, 2014
Kind: B2

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Abstract

This invention provides compounds of formula IA-a or IB-a and subsets thereof: wherein Z, HY, R 1 , R 2 , G 1 , W, n, and A and subsets thereof are as described in the specification. The compounds are inhibitors of PI3K and are thus useful for treating proliferative, inflammatory, or cardiovascular disorders.

Claims (215)

1. A compound of formula IA-a or IB-a:

or a pharmaceutically acceptable salt thereof, wherein:

Z is S or Se;

R 1 is CY, —C(O)N(R 3 ) 2 , —C(O)OR 3 , —C(O)(NH)OH, —C(═NH)NHOH, —C(O)NR 3 N(R 3 ) 2 , —C(═N—NH 2 )NH 2 , or —C(═N)N(R 3 ) 2 , wherein

CY is

wherein:

G 2 is —N═, ═N—, or —N(R 3′ )—, wherein:

each occurrence of R 3 and R 3′ is independently hydrogen or an optionally substituted C 1-6 aliphatic, wherein:

X 1 , X 2 , and X 3 , are each independently N, NR 3′ , O, S, or CR 4 , provided that only one of X 1 , X 2 , or X 3 may be O, S, or NR 3′ ;

each occurrence of R 4 is independently hydrogen, —CN, halogen, —Z 3 —R 6 , or an optionally substituted group selected from C 1-6 aliphatic and 3-10-membered cycloaliphatic, wherein:

Z 3 is selected from an optionally substituted C 1-3 alkylene chain, —O—, —N(R 4a )—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —CO 2 —, —C(O)NR 4a —, —N(R 4a )C(O)—, —N(R 4a )CO 2 —, —S(O) 2 NR 4a —, —N(R 4a )S(O) 2 —, —OC(O)N(R 4a )—, —N(R 4a )C(O)NR 4a —, —N(R 4a )S(O) 2 N(R 4a )—, and —OC(O)—;

R 4a is hydrogen or an optionally substituted C 1-4 aliphatic, and

R 6 is hydrogen or an optionally substituted group selected from C 1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10-membered aryl, and 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

or wherein two adjacent occurrences of R 3′ or R 4 , taken together with the atom to which they are bound, form an optionally substituted fused group selected from 5-6-membered aryl and 5-6-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

Ring A is a group selected from 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10-membered aryl, and 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each occurrence of R 2 is independently —R 12a , -T 2 -R 12d , or —V 2 -T 2 -R 12d , and:

each occurrence of R 12a is independently halogen, —CN, —NO 2 , —R 12c , —N(R 12b ) 2 , —OR 12b , —SR 12c , —S(O) 2 R 12c , —C(O)R 12b , —C(O)OR 12b , —C(O)N(R 12b ) 2 , —S(O) 2 N(R 12b ) 2 , —OC(O)N(R 12b ) 2 , —N(R 12e )C(O)R 12b , —N(R 12e )SO 2 R 12c , —N(R 12e )C(O)OR 12b , —N(R 12e )C(O)N(R 12b ) 2 , or —N(R 12e )SO 2 N(R 12b ) 2 , or two occurrences of R 12b , taken together with a nitrogen atom to which they are bound, form an optionally substituted 4-7-membered heterocyclyl ring having 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur;

each occurrence of R 12b is independently hydrogen or an optionally substituted group selected from C 1 -C 6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each occurrence of R 12c is independently an optionally substituted group selected from C 1 -C 6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10-membered aryl, and 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each occurrence of R 12d is independently hydrogen or an optionally substituted group selected from 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10-membered aryl, and 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each occurrence of R 12e is independently hydrogen or an optionally substituted C 1-6 aliphatic group;

each occurrence of V 2 is independently —N(R 12e )—, —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(O)O—, —C(O)N(R 12e )—, —S(O) 2 N(R 12e )—, —OC(O)N(R 12e )—, —N(R 12e )C(O)—, —N(R 12e )SO 2 —, —N(R 12e )C(O)O—, —N(R 12e )C(O)N(R 12e )—, —N(R 12e )SO 2 N(R 12e )—, —OC(O)—, or —C(O)N(R 12e )—O—;

T 2 is an optionally substituted C 1 -C 6 alkylene chain wherein the alkylene chain optionally is interrupted by —N(R 13 )—, —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(O)O—, —C(O)N(R 13 )—, —S(O) 2 N(R 13 )—, —OC(O)N(R 13 )—, —N(R 13 )C(O)—, —N(R 13 )SO 2 —, —N(R 13 )C(O)O—, —N(R 13 )C(O)N(R 13 )—, —N(R 13 )S(O) 2 N(R 13 )—, —OC(O)—, or —C(O)N(R 13 )—O— or wherein T 2 or a portion thereof optionally forms part of an optionally substituted 3-7 membered cycloaliphatic or heterocyclyl ring, wherein R 13 is hydrogen or an optionally substituted C 1-4 aliphatic group;

n is 0 to 4;

W is —C(R 7 ) 2 —, wherein:

each occurrence of R 7 is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, 6-10-membered aryl, 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, —N(R 7b ) 2 , —OR 7a , —SR 7a , halo, and —CN;

each occurrence of R 7a is independently hydrogen or optionally substituted C 1-6 aliphatic or optionally substituted C 3-6 cycloaliphatic;

each occurrence of R 7b is independently hydrogen, optionally substituted C 1-6 aliphatic, optionally substituted C 3-6 cycloaliphatic, —C(O)R 7a , —C(O)OR 7a , S(O)R 7a , or —S(O) 2 R 7a ; or

wherein any two occurrences of R 7 , R 7a , or R 7b , taken together with the atom to which they are bound, form an optionally substituted group selected from a 3-6-membered cycloaliphatic ring, 6-10-membered aryl, 3-6-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

or wherein any two occurrences of R 7a and R 2 , or R 7b and R 2 taken together with the nitrogen atom to which they are bound, form an optionally substituted group selected from 3-6-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

G 1 is —CR 8 , wherein R 8 is H, —CN, halogen, —Z 2 —R 9 , C 1-6 aliphatic, or 3-10-membered cycloaliphatic, wherein:

Z 2 is selected from an optionally substituted C 1-3 alkylene chain, —O—, —N(R 8a )—, —S—, —S(O)—, S(O) 2 —, —C(O)—, —CO 2 —, —C(O)NR 8a —, —N(R 8a )C(O)—, —N(R 8a )CO 2 —, —S(O) 2 NR 8a —, —N(R 8a )S(O) 2 —, —OC(O)N(R 8a )—, —N(R 8a )C(O)NR 8a —, —N(R 8a )S(O) 2 N(R 8a )—, and —OC(O)—;

R 8a is hydrogen or an optionally substituted C 1-4 aliphatic, and

R 9 is hydrogen or an optionally substituted group selected from C 1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10-membered aryl, and 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and

HY is an optionally substituted group selected from:

wherein each occurrence of X 4 , X 5 , X 6 , and X 7 is independently —CR 10 or N, provided no more than two occurrences of X 4 , X 5 , X 6 , and X 7 are N;

each occurrence of Q 1 and Q 2 is independently S, O or —NR S ;

each occurrence of Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , and Y 9 is independently —CR 10 or N, provided no more than two occurrences of Y 6 , Y 7 , Y 8 , and Y 9 are N;

or wherein two adjacent occurrences of X 4 and X 5 , X 6 and X 7 , Y 1 and Q 1 , Y 3 and Q 2 , or Y 4 and Y 5 taken together with the atom to which they are bound, form an optionally substituted fused group selected from 5-6-membered aryl, and 5-6-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

wherein R 10 is —R 10b , —V 1 —R 10c , -T 1 -R 10b , or —V 1 -T 1 -R 10b wherein:

V 1 is —NR 11 —, —NR 11 —C(O)—, —NR 11 —C(S)—, —NR 11 —C(NR 11 )—, —NR 11 C(O)OR 10a —, —NR 11 C(O)NR 11 —, —NR 11 C(O)SR 10a —, —NR 11 C(S)OR 10a —, —NR 11 C(S)NR 11 —, —NR 11 C(S)SR 10a —, —NR 11 C(NR 11 )OR 10a —, —NR 11 C(NR 11 )NR 11 —, —NR 11 S(O) 2 —, —NR 11 S(O) 2 NR 11 —, —C(O)—, —CO 2 —, —C(O)NR 11 —, —C(O)NR 11 O—, —SO 2 —, or —SO 2 NR 11 —;

each occurrence of R 10a is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10-membered aryl, and 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

T 1 is an optionally substituted C 1 -C 6 alkylene chain wherein the alkylene chain optionally is interrupted by —N(R 11 )—, —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(O)O—, —C(O)N(R 11 )—, —S(O) 2 N(R 11 )—, —OC(O)N(R 11 )—, —N(R 11 )C(O)—, —N(R 11 )SO 2 —, —N(R 11a )C(O)O—, —NR 10a C(O)N(R 10a )—, —N(R 10a )S(O) 2 N(R 10a )—, —OC(O)—, or —C(O)N(R 11 )—O— or wherein T 1 forms part of an optionally substituted 3-7 membered cycloaliphatic or heterocyclyl ring;

each occurrence of R 10b is independently hydrogen, halogen, —CN, —NO 2 , —N(R 11 ) 2 , —OR 10a , —SR 10a , —S(O) 2 R 10a , —C(O)R 10a , —C(O)OR 10a , —C(O)N(R 11 ) 2 , —S(O) 2 N(R 11 ) 2 , —OC(O)N(R 11 ) 2 , —N(R 11 )C(O)R 10a , —N(R 11 )SO 2 R 10a , —N(R 11 )C(O)OR 10a , —N(R 11 )C(O)N(R 11 ) 2 , or —N(R 11 )SO 2 N(R 11 ) 2 , or an optionally substituted group selected from C 1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10-membered aryl, and 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each occurrence of R 10c is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10-membered aryl, and 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or

R 10a and R 10c taken together with a nitrogen atom to which they are bound form an optionally substituted 4-7-membered heterocyclyl ring having 0-1 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each occurrence of R 11 is independently hydrogen, —C(O)R 11a —CO 2 R 11a , —C(O)N(R 11a ) 2 , —C(O)N(R 11a )—OR 11a , SO 2 R 11a , —SO 2 N(R 11a ) 2 , or an optionally substituted group selected from C 1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10-membered aryl, and 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

wherein each occurrence of R 11a is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10-membered aryl, and 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each occurrence of R 5 is independently hydrogen, —C(O)R 5a , —CO 2 R 5a , —C(O)N(R 5b ) 2 , —SO 2 R 5a , —SO 2 N(R 5b ) 2 , or an optionally substituted group selected from C 1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10-membered aryl, and 5-10-membered heteroaryl having 1-5 heteratoms independently selected from nitrogen, oxygen, and sulfur;

wherein each occurrence of R 5a is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10-membered aryl, and 5-10-membered heteroaryl having 1-5 heteratoms independently selected from nitrogen, oxygen, and sulfur;

wherein each occurrence of R 5b is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10-membered aryl, and 5-10-membered heteroaryl having 1-5 heteratoms independently selected from nitrogen, oxygen, and sulfur; or two occurrences of R 5b taken together with the nitrogen atom to which they are bound, form an optionally substituted group selected from 3-6-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

2. A compound of formula IA or IB:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is CY, —C(O)N(R 3 ) 2 , —C(O)OR 3 , —C(O)(NH)OH, —C(═NH)NHOH, —C(O)NR 3 N(R 3 ) 2 , —C(═N—NH 2 )NH 2 , or —C(═N)N(R 3 ) 2 , wherein:

CY is

wherein

G 2 is —N═, ═N—, or —N(R 3′ )—, wherein:

each occurrence of R 3 and R 3′ is independently hydrogen or an optionally substituted C 1-6 aliphatic, wherein:

X 1 , X 2 , and X 3 , are each independently N, NR 3′ , O, S, or CR 4 , provided that only one of X 1 , X 2 , or X 3 may be O, S, or NR 3′ ;

each occurrence of R 4 is independently hydrogen, —CN, halogen, —Z 3 —R 6 , or an optionally substituted group selected from C 1-6 aliphatic and 3-10-membered cycloaliphatic, wherein:

R 4a is hydrogen or an optionally substituted C 1-4 aliphatic, and

or wherein two adjacent occurrences of R 3′ or R 4 , taken together with the atom to which they are bound, form an optionally substituted fused group selected from 5-6-membered aryl, and 5-6-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each occurrence of R 2 is independently —R 12a , -T 2 -R 12d , or —V 2 -T 2 -R 12d , and:

each occurrence of R 12a is independently halogen, —CN, —NO 2 , —N(R 12b ) 2 , —OR 12b , —SR 12c , —S(O) 2 R 12c , —C(O)R 12b , —C(O)OR 12b , —C(O)N(R 12b ) 2 , —S(O) 2 N(R 12b ) 2 , —OC(O)N(R 12b ) 2 , —N(R 12e )C(O)R 12b , —N(R 12e )SO 2 R 12c , —N(R 12e )C(O)OR 12b , —N(R 12e )C(O)N(R 12b ) 2 , or —N(R 12a )SO 2 N(R 12b ) 2 , or two occurrences of R 12b , taken together with a nitrogen atom to which they are bound, form an optionally substituted 4-7-membered heterocyclyl ring having 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur;

each occurrence of R 12b is independently hydrogen or an optionally substituted group selected from C 1 -C 6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10-membered aryl, and 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each occurrence of R 12d is independently hydrogen or an optionally substituted group selected from 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each occurrence of R 12e is independently hydrogen or an optionally substituted C 1-6 aliphatic group;

n is 0 to 4;

W is —C(R 7 ) 2 —, wherein:

each occurrence of R 7a is independently hydrogen or optionally substituted C 1-6 aliphatic or optionally substituted C 3-6 cycloaliphatic;

each occurrence of R 7b is independently hydrogen, optionally substituted C 1-6 aliphatic, optionally substituted C 3-6 cycloaliphatic, —C(O)R 7a , —C(O)OR 7a , S(O)R 7a , or —S(O) 2 R 7a ; or

or wherein any two occurrences of R 7a and R 2 , or R 7b and R 2 , taken together with the nitrogen atom to which they are bound, form an optionally substituted group selected from 3-6-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

G 1 is —CR 8 , wherein R 8 is H, —CN, halogen, —Z 2 —R 9 , C 1-6 aliphatic, or 3-10-membered cycloaliphatic, wherein:

R 8a is hydrogen or an optionally substituted C 1-4 aliphatic, and

HY is an optionally substituted group selected from:

wherein each occurrence of X 4 , X 5 , X 6 , and X 7 is independently —CR 10 or N, provided no more than two occurrences of X 4 , X 5 , X 6 , and X 7 are N;

each occurrence of Q 1 and Q 2 is independently S, O or —NR 5 ;

each occurrence of Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , and Y 9 is independently —CR 10 or N, provided no more than two occurrences of Y 6 , Y 7 , Y 8 , and Y 9 are N;

or wherein two adjacent occurrences of X 4 and X 5 , X 6 and X 7 , Y 1 and Q 1 , Y 3 and Q 1 , or Y 1 and Y 5 taken together with the atom to which they are bound, form an optionally substituted fused group selected from 5-6-membered aryl, and 5-6-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

wherein R 10 is —R 10b , —V 1 —R 10c , -T 1 -R 10b , or —V 1 -T 1 -R 10b wherein:

each occurrence of R 11 is independently hydrogen, —C(O)R 11a , —CO 2 R 11a , —C(O)N(R 11a ) 2 , —C(O)N(R 11a )—OR 11a , SO 2 R 11a , —SO 2 N(R 11a ) 2 , or an optionally substituted group selected from C 1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10-membered aryl, and 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

3. The compound of claim 1 or 2 , wherein R 1 is CY, and CY is

4. The compound of claim 1 or 2 , wherein X 1 is N, G 2 is —N(R 3′ )—, and X 2 and X 3 are CH.

5. The compound of claim 1 or 2 , wherein X 1 and X 2 are N, G 2 is —N(R 3′ )—, and X 3 is CH.

6. The compound of claim 1 or 2 , wherein X 3 is N, G 2 is —N(R 3′ )—, and X 1 and X 2 are CH.

7. The compound of claim 1 or 2 , wherein X 1 is N, X 2 is CH, X 3 is —N(R 3′ )— and G 2 is ═N—.

8. The compound of claim 1 or 2 , wherein HY is selected from:

wherein each occurrence of X 5 , X 6 , and X 7 is independently —CR 10 or N, provided no more than two occurrences of X 5 , X 6 , and X 7 are N;

each occurrence of Q 1 and Q 2 is independently S, O or —NR 5 ;

each occurrence of Y 1 and Y 7 is independently —CR 10 or N;

or wherein two adjacent occurrences of X 6 and X 7 , or Y 1 and Q 1 , taken together with the atom to which they are bound, form an optionally substituted fused group selected from 5-6-membered aryl and 5-6-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

9. The compound of claim 1 or 2 , wherein HY is selected from:

wherein each HY group is optionally additionally substituted with one or more occurrences of R 10 , and in xviii represents a single bond or a double bond.

10. The compound of claim 1 or 2 , wherein HY is selected from:

wherein each HY group is optionally additionally substituted with one or more occurrences of R 10 , and in xviii represents a single bond or a double bond.

11. The compound of claim 1 or 2 , wherein G 1 is CH.

12. The compound of claim 1 or 2 , wherein one occurrence of R 7 is hydrogen and the other occurrence of R 7 is hydrogen, optionally substituted C 1-6 aliphatic, —N(R 7b ) 2 , —OR 7a , —SR 7a , halo, or —CN; and wherein each occurrence of R 7a is independently hydrogen or optionally substituted C 1-6 aliphatic; and each occurrence of R 7b is independently hydrogen, optionally substituted C 1-6 aliphatic, —C(O)R 7a , or —S(O) 2 R 7a ; or wherein two occurrences of R 7b , taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-6-membered heterocyclic ring.

13. The compound of claim 12 , wherein W is —C(H)(N(R 7b ) 2 )—, —CH 2 — or —C(H)(OR 7a )—, wherein each occurrence of R 7a is independently hydrogen or optionally substituted C 1-6 aliphatic; and each occurrence of R 7b is independently hydrogen or optionally substituted C 1-6 aliphatic.

14. The compound of claim 1 or 2 , wherein Ring A is 6-10-membered aryl or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and n is 0 to 3.

15. The compound of claim 14 , wherein ring A is a group selected from:

wherein ring A is optionally further substituted by n occurrences of R 2 , and wherein R 2a is hydrogen or an optionally substituted group selected from C 1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10-membered aryl, and 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

16. The compound of claim 14 , wherein ring A is a group selected from:

17. The compound of claim 14 , wherein:

ring A is a naphthyl group; each occurrence of R 2 is independently halogen, C 1-3 alkyl, —CN, C 1-3 haloalkyl, —OC 1-3 alkyl, —OC 1-3 haloalkyl, —NHC(O)C 1-3 alkyl, —NHC(O)NHC 1-3 alkyl, —NHS(O) 2 C 1-3 alkyl, or —C(O)H; and n is 0 to 3.

18. The compound of claim 14 , wherein:

ring A is a phenyl group; each occurrence of R 2 is independently halogen, C 1-3 alkyl, —CN, C 1-3 haloalkyl, —OC 1-3 alkyl, —OC 1-3 haloalkyl, —NHC(O)C 1-3 alkyl, —NHC(O)NHC 1-3 alkyl, —NHS(O) 2 C 1-3 alkyl, or —C(O)H; and n is 0 to 3.

19. The compound of claim 17 , wherein ring A is a naphthyl group, R 2 is halogen and n is 1 to 2.

20. The compound of claim 17 , wherein ring A is a naphthyl group and n is 0.

21. The compound of claim 18 , wherein Ring A is a phenyl group, R 2 is halogen and n is 1 to 2.

22. A compound having the following formula II:

or a pharmaceutically acceptable salt thereof, wherein:

X 4 , X 5 and X 6 are each independently —CR 10 or N, provided no more than two occurrences of X 4 , X 5 and X 6 are N;

wherein R 10 is —R 10b , —V 1 —R 10c , -T 1 -R 10b , or —V 1 -T 1 -R 10b wherein:

T 1 is an optionally substituted C 1 -C 6 alkylene chain wherein the alkylene chain optionally is interrupted by —N(R 11 )—, —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, C(O)O—, —C(O)N(R 11 )—, —S(O) 2 N(R 11 )—, —OC(O)N(R 11 )—, —N(R 11 )C(O)—, —N(R 11 )SO 2 —, —N(R 11a )C(O)O—, —NR 10a C(O)N(R 10a )—, —N(R 10a )S(O) 2 N(R 10a )—, —OC(O)—, or —C(O)N(R 11 )—O— or wherein T 1 forms part of an optionally substituted 3-7 membered cycloaliphatic or heterocyclyl ring;

each occurrence of R 10b is independently hydrogen, halogen, —CN, —NO 2 , —N(R 11 ) 2 , —OR 10a , —SR 10a , —S(O) 2 R 10a , —C(O)R 10a , —C(O)OR 10a , —C(O)N(R 11 ) 2 , —S(O) 2 N(R 11 ) 2 , —OC(O)N(R 11 ) 2 , —N(R 11 )C(O)R 10a , —N(R 11 )SO 2 R 10a , —N(R 11 )C(O)OR 10a , —N(R 11 )C(O)N(R 11 ) 2 , —N(R 11 )SO 2 N(R 11 ) 2 , or an optionally substituted group selected from C 1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10-membered aryl, and 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

R 10a and R 10c , taken together with a nitrogen atom to which they are bound, form an optionally substituted 4-7-membered heterocyclyl ring having 0-1 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur;

wherein each occurrence of R 11a is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

wherein each occurrence of R 5b is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteratoms independently selected from nitrogen, oxygen, and sulfur; or two occurrences of R 5b taken together with the nitrogen atom to which they are bound, form an optionally substituted group selected from 3-6-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

or two adjacent groups selected from R 10 , X 4 , X 5 , and X 6 , taken together, form an optionally substituted group selected from 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10-membered aryl, and 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

R 1 is CY, —C(O)N(R 3 ) 2 , —C(O)OR 3 , —C(O)(NH)OH, —C(═NH)NHOH, —C(O)NR 3 N(R 3 ) 2 , —C(═N—NH 2 )NH 2 , or —C(═N)N(R 3 ) 2 , wherein:

CY is

wherein:

G 2 is —N═, ═N—, or —N(R 3′ )—, wherein:

each occurrence of R 3 and R 3′ is independently hydrogen or an optionally substituted C 1-6 aliphatic, wherein:

X 1 , X 2 , and X 3 , are each independently N, NR 3′ , O, S, or CR 4 , provided that only one of X 1 , X 2 , or X 3 may be O, S, or NR 3′ ;

each occurrence of R 4 is independently hydrogen, —CN, halogen, —Z 3 —R 6 , or an optionally substituted group selected from C 1-6 aliphatic, or 3-10-membered cycloaliphatic, wherein:

Z 3 is selected from an optionally substituted C 1-3 alkylene chain, —O—, —N(R 4a )—, —S—, —S(O)—, —S(O) 2 , —C(O)—, —CO 2 —, —C(O)NR 4a —, —N(R 4a )C(O)—, —N(R 4a )CO 2 —, —S(O) 2 NR 4a —, —N(R 4a )S(O) 2 —, —OC(O)N(R 4a )—, —N(R 4a )C(O)NR 4a —, —N(R 4a )S(O) 2 N(R 4a )—, and —OC(O)—;

R 4a is hydrogen or an optionally substituted C 1-4 aliphatic, and

or wherein two adjacent occurrences of R 3′ or R 4 , taken together with the atom to which they are bound, form an optionally substituted fused group selected from 5-6-membered aryl, and 5-6-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each occurrence of R 2 is independently —R 12a , -T 2 -R 12d , or —V 2 -T 2 -R 12d , and:

each occurrence of R 12b is independently hydrogen or an optionally substituted group selected from C 1 -C 6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10-membered aryl, and 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each occurrence of R 12d is independently hydrogen or an optionally substituted from 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each occurrence of R 12e is independently hydrogen or an optionally substituted C 1-6 aliphatic group;

n is 0 to 4;

W is —C(R 7 ) 2 —, wherein:

each occurrence of R 7 is independently hydrogen, or an optionally substituted group selected from C 1-6 aliphatic, 6-10-membered aryl, 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, —N(R 7b ) 2 , —OR 7a , —SR 7a , halo, or —CN;

each occurrence of R 7a is independently hydrogen or optionally substituted C 1-6 aliphatic or optionally substituted C 3-6 cycloaliphatic;

each occurrence of R 7b is independently hydrogen, optionally substituted C 1-6 aliphatic, optionally substituted C 3-6 cycloaliphatic, —C(O)R 7a , —C(O)OR 7a , S(O)R 7a , or —S(O) 2 R 7a ; or

wherein any two occurrences of R 7 , R 7a , or R 7b taken together with the atom to which they are bound, form an optionally substituted group selected from a 3-6-membered cycloaliphatic ring, 6-10-membered aryl, 3-6-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

G 1 is —CR 8 , wherein R 8 is H, —CN, halogen, —Z 2 —R 9 , C 1-6 aliphatic, or 3-10-membered cycloaliphatic, wherein:

R 8a is hydrogen or an optionally substituted C 1-4 aliphatic, and

23. The compound of claim 22 , wherein one of X 4 , X 5 , or X 6 is N.

24. The compound of claim 22 , wherein all of X 4 , X 5 , and X 6 are CR 10 .

25. The compound of claim 22 , wherein each occurrence of R 10 is independently selected from —CN, —OR 10a , —N(R 11 ) 2 halogen, C 1-4 alkyl, —N(R 11 )COR 10a , or wherein two occurrences of R 10 , taken together with the atoms to which they are bound form an optionally substituted group selected from a fused 5- or 6-membered cycloaliphatic, 4-10-membered heterocyclyl, 6-10-membered aryl and 5-10-membered heteroaryl ring, wherein the heterocyclyl and heteroaryl rings have 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

26. The compound of claim 22 , wherein R 1 is CY, and CY is

27. The compound of claim 26 , wherein X 1 is N, G 2 is —N(R 3′ )—, and X 2 and X 3 are CH.

28. The compound of claim 26 , wherein X 1 and X 2 are N, G 2 is —N(R 3′ )—, and X 3 is CH.

29. The compound of claim 26 , wherein X 3 is N, G 2 is —N(R 3′ )—, and X 1 and X 2 are CH.

30. The compound of claim 26 , wherein X 1 is N, X 2 is CH, X 3 is —N(R 3′ )— and G 2 is ═N—.

31. The compound of claim 22 , wherein Ring A is an optionally substituted 6-10-membered aryl or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and n is 0 to 3.

32. The compound of claim 31 , wherein ring A is a group selected from:

33. The compound of claim 31 , wherein ring A is a group selected from:

34. The compound of claim 31 , wherein:

35. The compound of claim 31 , wherein Ring A is a phenyl group optionally substituted with 1-3 independent occurrences of halogen, C 1-3 alkyl, —CN, C 1-3 haloalkyl, —OC 1-3 alkyl, —OC 1-3 haloalkyl, —NHC(O)C 1-3 alkyl, —NHC(O)NHC 1-3 alkyl, NHS(O) 2 C 1-3 alkyl, or —C(O)H; and n is 0 to 3.

36. The compound of claim 34 , wherein ring A is a naphthyl group, R 2 is halogen and n is 1 to 2.

37. The compound of claim 34 , wherein ring A is a naphthyl group and n is 0.

38. The compound of claim 35 , wherein Ring A is a phenyl group, R 2 is halogen and n is 1 to 2.

39. The compound of claim 22 , wherein one occurrence of R 7 is hydrogen and the other occurrence of R 7 is hydrogen, optionally substituted C 1-4 aliphatic, —N(R 7b ) 2 , —OR 7a , —SR 7a , halo, or —CN; and

wherein each occurrence of R 7a is independently hydrogen or optionally substituted C 1-6 aliphatic;

each occurrence of R 7b is independently hydrogen, optionally substituted C 1-6 aliphatic, —C(O)R 7a , or —S(O) 2 R 7a ; or

any two occurrences of R 7a and R 2 , or R 7b and R 2 taken together with the nitrogen atom to which they are bound, form an optionally substituted group selected from 3-6-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

40. The compound of claim 39 , wherein W is —C(H)(N(R 7b ) 2 )—, —CH 2 — or —C(H)(OR 7a )—, wherein each occurrence of R 7a is independently hydrogen or optionally substituted C 1-6 aliphatic; and each occurrence of R 7b is independently hydrogen or optionally substituted C 1-6 aliphatic.

41. A composition comprising a compound of any one of claims 1 , 2 , or 22 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

42. A compound selected from the group consisting of: