Substituted hydroxamic acids and uses thereof
This invention provides compounds of formula (I): wherein R 1a , R 1b , R a , R 2a , R 2b , R 1 , and X have values as described in the specification, useful as inhibitors of HDAC6. The invention also provides pharmaceutical compositions comprising the compounds of the invention and methods of using the compositions in the treatment of proliferative, inflammatory, infectious, neurological or cardiovascular diseases or disorders.
1. A compound of formula (I):
or a pharmaceutically acceptable salt thereof;
wherein:
each occurrence of R 1 is independently hydrogen, chloro, fluoro, —O—C 1-4 alkyl, cyano, hydroxy, C 1-4 alkyl, or C 1-4 fluoroalkyl;
one of R 2a and R 2b is R 1 , and the other is —C(O)—NH—OH;
X is N—R b ;
R 1d is taken together with R 1b to form a double bond;
R 1c is hydrogen, fluoro, bromo, —CH 2 —OR 4aa , —CH 2 N(R 4aa ) 2 , or C 1-4 alkyl;
R b is hydrogen, C 1-6 alkyl, benzyl, or phenyl; or R b is taken together with R 1b to form a double bond;
when X is C(R 1c )(R 1d ), R 1b is taken together with R 1d to form a double bond; and when X is N—R b , R 1b is taken together with R b to form a double bond, or is taken together with R a to form a double bond, or is taken together with R 1a to form C═O;
R 1a is hydrogen, fluoro, C 1-4 alkyl, C 1-4 fluoroalkyl, or G 1 ; or when X is N—R b , R 1a can be taken together with R 1b to form C═O;
R a is hydrogen, C 1-4 alkyl, or G; or when X is N—R b , R 1b can be taken together with R a to form a double bond;
G is hydrogen, —R 3 , -L 1 -R 3 , or -L 2 -V 1 —R 3 ;
G 1 is —NH 2 , —R 3 , -L 1 -R 3 , —V 2 —R 3 , -L 1 -V 2 —R 3 , or —V 2 -L 1 -R 3 ;
V 1 is —O—, —N(R 4a )—, —S—, —N(R 4a )—C(O)—, —C(O)—N(R 4a )—, —SO 2 —N(R 4a )—, —N(R 4a )—SO 2 —, —C(O)—, —SO 2 —, or —N(R 4a )—C(O)—N(R 4a )—;
V 2 is —O—, —N(R 4a )—, —C(O)—N(R 4a )—, —N(R 4a )—C(O)—N(R 4a )—, or —N(R 4a )—C(O)—O—;
L 1 is an unsubstituted or substituted C 1-4 alkylene chain;
L 2 is an unsubstituted or substituted C 2-4 alkylene chain;
each occurrence of R 4aa is independently hydrogen or C 1-4 alkyl;
R 3 is unsubstituted or substituted C 1-6 aliphatic, unsubstituted or substituted 3-10-membered cycloaliphatic, unsubstituted or substituted 4-10-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, unsubstituted or substituted 6-10-membered aryl, or unsubstituted or substituted 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and
each occurrence of R 4a is independently hydrogen, unsubstituted or substituted C 1-4 aliphatic, unsubstituted or substituted 3-10-membered cycloaliphatic, unsubstituted or substituted 4-10-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, unsubstituted or substituted 6-10-membered aryl, or unsubstituted or substituted 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
2. The compound of claim 1 , wherein:
R 2a is C(O)—NH—OH;
R 2b is R 1 ;
R b is taken together with R 1b to form a double bond; and
R a is G.
3. The compound of claim 1 , wherein:
each occurrence of R 1 is independently hydrogen, chloro, fluoro, cyano, hydroxy, methoxy, ethoxy, trifluoromethyl, methyl, or ethyl.
4. The compound of claim 1 , wherein:
each substitutable carbon chain atom in R 3 is unsubstituted or substituted with 1-2 occurrences of —R 5dd ;
each substitutable saturated ring carbon atom in R 3 is unsubstituted or substituted with ═O, ═C(R 5 ) 2 , or —R 5aa ;
each substitutable unsaturated ring carbon atom in R 3 is unsubstituted or is substituted with —R 5a ;
each substitutable ring nitrogen atom in R 3 is unsubstituted or substituted with —R 9b ;
each R 5a is independently halogen, —NO 2 , —CN, —C(R 5 )═C(R 5 ) 2 , —C≡C—R 5 , —OR 5 , —SR 6 , —S(O)R 6 , —SO 2 R 6 , —SO 2 N(R 4 ) 2 , —N(R 4 ) 2 , —NR 4 C(O)R 5 , —NR 4 C(O)N(R 4 ) 2 , —NR 4 CO 2 R 6 , —OC(O)N(R 4 ) 2 , —C(O)R 6 , —C(O)N(R 4 ) 2 , —N(R 4 )SO 2 R 6 , —N(R 4 )SO 2 N(R 4 ) 2 , unsubstituted or substituted C 1-6 aliphatic, unsubstituted or substituted 3-10-membered cycloaliphatic, unsubstituted or substituted 4-10-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, unsubstituted or substituted 6-10-membered aryl, or unsubstituted or substituted 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two adjacent R 5a , taken together with the intervening ring atoms, form an unsubstituted or substituted fused 5-10 membered aromatic ring or an unsubstituted or substituted 4-10 membered non-aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each occurrence of R 5aa is independently chloro, fluoro, hydroxy, unsubstituted or substituted C 1-6 aliphatic, —O(C 1-6 alkyl), —C 1-6 fluoroalkyl, —O—C 1-6 fluoroalkyl, cyano, —N(R 4 ) 2 , —C(O)(C 1-6 alkyl), —CO 2 H, —C(O)NH 2 , —C(O)NH(C 1-6 alkyl), —C(O)N(C 1-6 alkyl) 2 , —NHC(O)C 1-6 alkyl, —NHC(O)OC 1-6 alkyl, —NHC(O)NHC 1-6 alkyl, or —NHS(O) 2 Cl — 6 alkyl;
each occurrence of R 5dd is independently fluoro, hydroxy, —O(C 1-6 alkyl), cyano, —N(R 4 ) 2 , —C(O)(C 1-6 alkyl), —CO 2 H, —C(O)NH 2 , —C(O)NH(C 1-6 alkyl), —C(O)N(C 1-6 alkyl) 2 , —NHC(O)C 1-6 alkyl, —NHC(O)OC 1-6 alkyl, —NHC(O)NHC 1-6 alkyl, or —NHS(O) 2 C 1-6 alkyl;
each R 4 is independently hydrogen, unsubstituted or substituted C 1-6 aliphatic, unsubstituted or substituted 3-10-membered cycloaliphatic, unsubstituted or substituted 4-10-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, unsubstituted or substituted 6-10-membered aryl, or unsubstituted or substituted 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R 4 on the same nitrogen atom, taken together with the nitrogen atom, form an unsubstituted or substituted 5- to 6-membered heteroaryl or an unsubstituted or substituted 4- to 8-membered heterocyclyl having, in addition to the nitrogen atom, 0-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur;
each R 5 is independently hydrogen, unsubstituted or substituted C 1-6 aliphatic, unsubstituted or substituted 3-10-membered cycloaliphatic, unsubstituted or substituted 4-10-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, unsubstituted or substituted 6-10-membered aryl, or unsubstituted or substituted 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each R 6 is independently unsubstituted or substituted C 1-6 aliphatic, unsubstituted or substituted 3-10-membered cycloaliphatic, unsubstituted or substituted 4-10-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, unsubstituted or substituted 6-10-membered aryl, or unsubstituted or substituted 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each R 9b is independently —C(O)R 6 , —C(O)N(R 4 ) 2 , —CO 2 R 6 , —SO 2 R 6 , —SO 2 N(R 4 ) 2 , unsubstituted C 3-10 cycloaliphatic, C 3-10 cycloaliphatic substituted with 1-2 independent occurrences of R 7 or R 8 , unsubstituted C 1-6 aliphatic, or C 1-6 aliphatic substituted with 1-2 independent occurrences of R 7 or R 8 ;
each R 7 is independently unsubstituted or substituted 4-10-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, unsubstituted or substituted 6-10-membered aryl, or unsubstituted or substituted 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and
each R 8 is independently chloro, fluoro, —OR 5 , —CN, —N(R 4 ) 2 , —C(O)(C 1-6 alkyl), —CO 2 H, —CO 2 (C 1-6 alkyl), —C(O)NH 2 , —C(O)NH(C 1-6 alkyl), or —C(O)N(C 1-6 alkyl) 2 .
5. The compound of claim 4 , wherein:
each substitutable saturated ring carbon atom in R 3 is unsubstituted or substituted with —R 5aa ;
the total number of R 5a and R 5aa substituents is p;
p is 1-4;
each R 5a is independently halogen, cyano, nitro, hydroxy, unsubstituted C 1-6 aliphatic, C 1-6 aliphatic substituted with 1-2 independent occurrences of R 7 or R 8 , unsubstituted —O—C 1-6 alkyl, —O—C 1-6 alkyl substituted with 1-2 independent occurrences of R 7 or R 8 , C 1-6 fluoroalkyl, —O—C 1-6 fluoroalkyl, —NHC(O)R 6 , —C(O)NH(R 4 ), —NHC(O)O—C 1-6 alkyl, —NHC(O)NHC 1-6 alkyl, —NHS(O) 2 C 1-6 alkyl, —NHC 1-6 alkyl, —N(C 1-6 alkyl) 2 , 3-10-membered cycloaliphatic substituted with 0-2 occurrences of —R 7a , 4-10-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0-2 occurrences of —R 7a , 6-10-membered aryl substituted with 0-2 occurrences of —R 7a , or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0-2 occurrences of —R 7a ; and
each occurrence of R 7a is independently chloro, fluoro, C 1-6 aliphatic, C 1-6 fluoroalkyl, —O—C 1-6 alkyl, —O—C 1-6 fluoroalkyl, cyano, hydroxy, —CO 2 H, —NHC(O)C 1-6 alkyl, —NH 2 , —NHC 1-6 alkyl, —N(C 1-6 alkyl) 2 , —C(O)NHC 1-6 alkyl, —C(O)N(C 1-6 alkyl) 2 , —NHC(O)NHC 1-6 alkyl, —NHC(O)N(C 1-6 alkyl) 2 , or —NHS(O) 2 C 1-6 alkyl.
6. The compound of claim 4 , represented by formula (IV-b-i-a):
wherein:
R 1a′ is hydrogen, fluoro, or C 1-4 alkyl.
7. The compound of claim 6 , wherein:
G is -L 1 -R 3 , or -L 2 -V 1 —R 3 ; and
V 1 is —O— or —N(R 4a )—.
8. The compound of claim 7 , wherein:
each occurrence of R 1 is independently hydrogen, chloro, fluoro, cyano, hydroxy, methoxy, ethoxy, trifluoromethyl, methyl, or ethyl.
9. The compound of claim 7 , wherein:
each substitutable saturated ring carbon atom in R 3 is unsubstituted or substituted with —R 5aa ;
the total number of R 5a and R 5aa substituents is p;
p is 1-4;
each R 5a is independently halogen, cyano, nitro, hydroxy, unsubstituted C 1-6 aliphatic, C 1-6 aliphatic substituted with 1-2 independent occurrences of R 7 or R 8 , unsubstituted —O—C 1-6 alkyl, —O—C 1-6 alkyl substituted with 1-2 independent occurrences of R 7 or R 8 , C 1-6 fluoroalkyl, —O—C 1-6 fluoroalkyl, —NHC(O)R 6 , —C(O)NH(R 4 ), —NHC(O)O—C 1-6 alkyl, —NHC(O)NHC 1-6 alkyl, —NHS(O) 2 C 1-6 alkyl, —NHC 1-6 alkyl, —N(C 1-6 alkyl) 2 , 3-10-membered cycloaliphatic substituted with 0-2 occurrences of —R 7a , 4-10-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0-2 occurrences of —R 7a , 6-10-membered aryl substituted with 0-2 occurrences of —R 7a , or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0-2 occurrences of —R 7a ; and
each occurrence of R 7a is independently chloro, fluoro, C 1-6 aliphatic, C 1-6 fluoroalkyl, —O—C 1-6 alkyl, —O—C 1-6 fluoroalkyl, cyano, hydroxy, —CO 2 H, —NHC(O)C 1-6 alkyl, —NH 2 , —NHC 1-6 alkyl, —N(C 1-6 alkyl) 2 , —C(O)NHC 1-6 alkyl, —C(O)N(C 1-6 alkyl) 2 , —NHC(O)NHC 1-6 alkyl, —NHC(O)N(C 1-6 alkyl) 2 , or —NHS(O) 2 C 1-6 alkyl.
10. The compound of claim 9 , wherein:
R 1a′ is hydrogen; and
R 1 is hydrogen.
11. The compound of claim 4 , represented by formula (IV-b-ii-a):
wherein:
R 1a′ is hydrogen, fluoro, or C 1-4 alkyl.
12. The compound of claim 11 , wherein:
G is -L 1 -R 3 , or -L 2 -V 1 —R 3 ; and
V 1 is —O— or —N(R 4a )—.
13. The compound of claim 12 , wherein:
each occurrence of R 1 is independently hydrogen, chloro, fluoro, cyano, hydroxy, methoxy, ethoxy, trifluoromethyl, methyl, or ethyl.
14. The compound of claim 12 , wherein:
each substitutable saturated ring carbon atom in R 3 is unsubstituted or substituted with —R 5aa ;
the total number of R 5a and R 5aa substituents is p;
p is 1-4;
each R 5a is independently halogen, cyano, nitro, hydroxy, unsubstituted C 1-6 aliphatic, C 1-6 aliphatic substituted with 1-2 independent occurrences of R 7 or R 8 , unsubstituted —O—C 1-6 alkyl, —O—C 1-6 alkyl substituted with 1-2 independent occurrences of R 7 or R 8 , C 1-6 fluoroalkyl, —O—C 1-6 fluoroalkyl, —NHC(O)R 6 , —C(O)NH(R 4 ), —NHC(O)O—C 1-6 alkyl, —NHC(O)NHC 1-6 alkyl, —NHS(O) 2 C 1-6 alkyl, —NHC 1-6 alkyl, —N(C 1-6 alkyl) 2 , 3-10-membered cycloaliphatic substituted with 0-2 occurrences of —R 7a , 4-10-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0-2 occurrences of —R 7a , 6-10-membered aryl substituted with 0-2 occurrences of —R 7a , or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0-2 occurrences of —R 7a ; and
each occurrence of R 7a is independently chloro, fluoro, C 1-6 aliphatic, C 1-6 fluoroalkyl, —O—C 1-6 alkyl, —O—C 1-6 fluoroalkyl, cyano, hydroxy, —CO 2 H, —NHC(O)C 1-6 alkyl, —NH 2 , —NHC 1-6 alkyl, —N(C 1-6 alkyl) 2 , —C(O)NHC 1-6 alkyl, —C(O)N(C 1-6 alkyl) 2 , —NHC(O)NHC 1-6 alkyl, —NHC(O)N(C 1-6 alkyl) 2 , or —NHS(O) 2 C 1-6 alkyl.
15. The compound of claim 14 , wherein:
R 1a′ is hydrogen; and
R 1 is hydrogen.
16. The compound of claim 4 , represented by formula (IV-b-i-b):
wherein:
R a′ is hydrogen, or C 1-4 alkyl.
17. The compound of claim 16 , wherein:
G is —R 3 , or -L 1 -R 3 .
18. The compound of claim 17 , wherein:
each occurrence of R 1 is independently hydrogen, chloro, fluoro, cyano, hydroxy, methoxy, ethoxy, trifluoromethyl, methyl, or ethyl.
19. The compound of claim 17 , wherein:
each substitutable saturated ring carbon atom in R 3 is unsubstituted or substituted with —R 5aa ;
the total number of R 5a and R 5aa substituents is p;
p is 1-4;
each R 5a is independently halogen, cyano, nitro, hydroxy, unsubstituted C 1-6 aliphatic, C 1-6 aliphatic substituted with 1-2 independent occurrences of R 7 or R 8 , unsubstituted —O—C 1-6 alkyl, —O—C 1-6 alkyl substituted with 1-2 independent occurrences of R 7 or R 8 , C 1-6 fluoroalkyl, —O—C 1-6 fluoroalkyl, —NHC(O)R 6 , —C(O)NH(R 4 ), —NHC(O)O—C 1-6 alkyl, —NHC(O)NHC 1-6 alkyl, —NHS(O) 2 C 1-6 alkyl, —NHC 1-6 alkyl, —N(C 1-6 alkyl) 2 , 3-10-membered cycloaliphatic substituted with 0-2 occurrences of —R 7a , 4-10-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0-2 occurrences of —R 7a , 6-10-membered aryl substituted with 0-2 occurrences of —R 7a , or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0-2 occurrences of —R 7a ; and
each occurrence of R 7a is independently chloro, fluoro, C 1-6 aliphatic, C 1-6 fluoroalkyl, —O—C 1-6 alkyl, —O—C 1-6 fluoroalkyl, cyano, hydroxy, —CO 2 H, —NHC(O)C 1-6 alkyl, —NH 2 , —NHC 1-6 alkyl, —N(C 1-6 alkyl) 2 , —C(O)NHC 1-6 alkyl, —C(O)N(C 1-6 alkyl) 2 , —NHC(O)NHC 1-6 alkyl, —NHC(O)N(C 1-6 alkyl) 2 , or —NHS(O) 2 C 1-6 alkyl.
20. The compound of claim 19 , wherein:
R a′ is hydrogen; and
R 1 is hydrogen.
21. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.