Histone deacetylase inhibitors
The compounds provided herein are phenyl analine amides and are useful for inhibiting histone deacteylase (“HDAC”) enzymes, such as HDAC1, HDAC2, and HDAC3.
1. A compound having a structure of formula (II):
wherein:
R 3 is H or F;
R p is Cl or F;
Cy is a saturated heterocyclyl having 4-8 ring atoms, where at least one hetero atom is NH or N(C 1-6 alkyl) to form a secondary amine or tertiary amine, respectively, and optionally one or two additional heteroatoms are independently selected from the group consisting of O, NH, and N(C 1-6 alkyl); wherein a ring atom of Cy is bonded to the exocyclic double bond;
V is C(R y ) 2 ;
each R y is independently selected from the group consisting of H, F, C 1-6 alkyl, and C 3-6 cycloalkyl;
R 1 is H, phenyl, or monocyclic or bicyclic heteroaryl, where the phenyl and heteroaryl are each optionally substituted with 1-3 Rq; and
R q is independently halogen, OH, C 1-6 alkyl, fluoro(C 1-6 alkyl), hydroxy(C 1-4 alkyl), C 1-6 alkoxy, or fluoro(C 1-6 alkoxy);
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein R 3 is H.
3. The compound of claim 1 , wherein R 3 is F.
4. The compound of claim 1 , wherein Cy is a saturated heterocyclyl having 4-6 ring atoms where at least one heteroatom is NH to form a secondary amine.
5. The compound of claim 1 , wherein Cy is azetindinyl, pyrrolidinyl, piperidinyl, or 8-azabicyclo [3.2.1]octanyl.
6. The compound of claim 1 , wherein Cy is azetindinyl, piperidinyl, or 8-azabicyclo [3.2.1]octanyl; and V—R 1 is CH 2 -pyridyl, CH 2 -indolyl, C 1-6 alkyl, CH 2 -cyclopropyl, or CH 2 -phenyl, wherein the pyridyl is optionally substituted with C 1-6 alkyl.
7. The compound of claim 1 , wherein Cy is azetindinyl, piperidinyl, or 8-azabicyclo [3.2.1]octanyl; and V—R 1 is C 1-6 alkyl, CH 2 -cyclopropyl, CH 2 -pyridyl, or CH 2 -phenyl, wherein the pyridyl is optionally substituted with methyl.
8. The compound of claim 7 , wherein Cy is azetindinyl, and V—R 1 is CH 2 -cyclopropyl, CH 2 -pyridyl, or CH 2 -phenyl, wherein the pyridyl is optionally substituted with methyl.
9. The compound of claim 7 , wherein Cy is piperidinyl, and V—R 1 is C 1-6 alkyl or CH 2 -cyclopropyl.
10. The compound of claim 7 , wherein Cy is 8-azabicyclo [3.2.1]octanyl and V—R 1 is C 1-6 alkyl.
11. A pharmaceutical composition comprising a compound of claim 1 , or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
12. A method of selectively inhibiting HDAC3 (in vitro or in vivo), the method comprising contacting a cell with an effective amount of a compound of claim 1 , or pharmaceutically acceptable salt thereof.
13. A method of selectively inhibiting HDAC1 or HDAC2 (in vitro or in vivo), the method comprising contacting a cell with an effective amount of a compound of claim 1 , or pharmaceutically acceptable salt thereof.
14. A method of inhibiting HDAC1, HDAC2, and HDAC3 (in vitro or in vivo), the method comprising contacting a cell with an effective amount of a compound of claim 1 , or pharmaceutically acceptable salt thereof.
15. A compound having the structure:
or a pharmaceutically acceptable salt thereof.
16. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
17. A compound selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
18. A compound selected from the group consisting of
or a pharmaceutically acceptable salt thereof.