Histone deacetylase inhibitors
View Patent ↗Provided herein are compounds and methods for inhibiting histone deacetylase (“HDAC”) enzymes (e.g., HDAC1, HDAC2, and HDAC3).
1. A compound having a structure of formula (I), or a pharmaceutically acceptable salt thereof
wherein
ring A is a 4-7 membered saturated heterocycle containing one nitrogen ring atom or a 7-9 membered saturated bicyclic heterocycle containing one nitrogen ring atom;
Z is O, NR 3 , S, SO, or SO 2 ;
R 1 is H, C 1-6 alkyl, C 1-6 hydroxyalkyl, C(O)C 1-6 alkyl, C 0-3 alkylene-C 3-10 cycloalkyl, or saturated C 0-3 alkylene-C 2-5 heterocycle having 1 or 2 heteroatoms selected from O, S, N, and N(C 1-4 alkyl);
R 2 is H, F, Cl, or CH 3 ;
R 3 is H, C 1-6 alkyl, C 1-6 haloalkyl, C 0-3 alkylene-C 3-7 cycloalkyl, C(O)C 1-6 -alkyl, or C(O)C 0-3 alkylene-C 3-7 cycloalkyl; and
R 4 is H or C 1-3 alkyl.
2. The compound of claim 1 , wherein ring A is a 4-7 membered saturated heterocycle containing one nitrogen ring atom or a 7-9 membered bicyclic saturated heterocycle containing one nitrogen ring atom; Z is O, NR 3 , S, or SO 2 ; R 1 is C 1-6 alkyl, C 1-6 hydroxyalkyl, or C 0-3 alkylene-C 3-7 cycloalkyl; R 2 is H, F, Cl, or CH 3 ; R 3 is H, C 1-6 -alkyl, C 1-6 haloalkyl, C 0-3 alkylene-C 3-7 cycloalkyl, C(O)C 1-6 -alkyl, or C(O)C 0-3 alkylene-C 3-7 cycloalkyl; and R 4 is H or C 1-3 alkyl.
3. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 1 is H, C 1-6 -alkyl, C 1-6 hydroxyalkyl, C 0-3 alkylene-C 3-10 cycloalkyl, or saturated C 0-3 alkylene-C 2-5 heterocycle having 1 or 2 heteroatoms selected from O, S, N, and N(C 1-4 alkyl).
4. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 1 is C 1-6 alkyl, C 1-6 hydroxyalkyl, or C 0-3 alkylene-C 3-10 cycloalkyl.
5. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 1 is methyl, isopropyl, sec-butyl, CH 2 C(CH 3 ) 3 , or
6. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 1 is cyclopropyl, cyclobutyl, cyclohexyl, adamantanyl, CH 2 cyclopropyl, (1-methylcyclopropyl)methyl, CH 2 cyclobutyl, CH 2 cyclohexyl, CH 2 -adamantanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or morpholinyl.
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof,
wherein
ring A is selected from the group consisting of:
Z is O, NR 3 , S, SO, or SO 2 ;
R 1 is selected from the group consisting of H, CH 3 , C(O)CH 3 ,
R 2 is H, F, Cl, or CH 3 ;
R 3 is H, C 1-6 -alkyl, C 1-6 haloalkyl, C 0-3 alkylene-C 3-7 cycloalkyl, C(O)C 1-6 -alkyl, or C(O)C 0-3 alkylene-C 3-7 cycloalkyl; and
R 4 is H or C 1-3 alkyl.
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof,
wherein ring A is selected from the group consisting of
Z is O, NR 3 , S, SO, or SO 2 ; R 1 is selected from the group consisting of H, CH 3 , C(O)CH 3 ,
and R 3 is H, C 1-6 -alkyl, C 1-6 haloalkyl, C 0-3 alkylene-C 3-7 cycloalkyl, C(O)C 1-6 alkyl, or C(O)C 0-3 alkylene-C 3-7 cycloalkyl.
9. The compound or pharmaceutically acceptable salt of claim 1 , wherein ring A is selected from the group consisting of
10. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 2 is H.
11. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 1 is selected from the group consisting of
12. The compound or pharmaceutically acceptable salt of claim 1 , wherein ring A is selected from the group consisting of
Z is O or NR 3 ; and R 1 is selected from the group consisting of
13. The compound of claim 1 , wherein the compound of formula (I) is a compound of formula (III), or a pharmaceutically acceptable salt thereof
wherein Z is O, NR 3 , S, SO, or SO 2 ; R 1 is selected from the group consisting of
R 2 is H, F, Cl, or CH 3 ; R 3 is H, C 1-6 -alkyl, C 1-6 haloalkyl, C 0-3 alkylene-C 3-7 cycloalkyl, C(O)C 1-6 -alkyl, or C(O)C 0-3 alkylene-C 3-7 cycloalkyl; and R 4 is H or C 1-3 alkyl.
14. The compound or pharmaceutically acceptable salt of claim 1 , wherein Z is O, NR 3 , S, or SO 2 ; and R 1 is selected from the group consisting of
15. The compound of claim 1 having a structure selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
16. The compound of claim 1 selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
17. A pharmaceutical composition comprising the compound of claim 1 , or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
18. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.