HDAC6 selective inhibitors, preparation method therefor, and application thereof
Compounds serving as histone deacetylase 6 (HDAC6) selective inhibitors, and applications thereof in the preparation of drugs for treating HDAC6-related diseases. Specifically disclosed are a compound as represented by formula (I) and a pharmaceutically acceptable salt thereof.
1. A compound represented by formula (I), a pharmaceutically acceptable salt or a isomer thereof,
is a single bond or a double bond;
n is 0 or 1;
each of T 1 , T 2 is independently selected from the group consisting of CH, CH 2 , —C(═O)— and N;
T 3 is C or N;
each of Z 1 , Z 2 , Z 3 is CH;
L 1 is selected from the group consisting of a single bond, —NH— and —C(═O)—NH—;
R 1 is selected from the group consisting of C 1-3 alkyl, phenyl or 6-membered heteroaryl, each of which is optionally substituted by 1, 2 or 3 R;
R 2 is —H, F, Cl, Br or I;
Ring A is 4 to 7-membered heterocycloalkyl;
R is F, Cl, Br or I;
the “hetero” in 6-membered heteroaryl or 4 to 7-membered heterocycloalkyl is independently —NH—, N or —O—;
in any of the cases above, the number of heteroatom or heteroatom group is independently 1, 2 or 3, respectively.
2. The compound, the pharmaceutically acceptable salt or the isomer thereof as defined in claim 1 , wherein R 1 is selected from the group consisting of methyl, ethyl, isopropyl, phenyl and pyridyl, each of which is optionally substituted by 1, 2 or 3 R; or, ring A is selected from the group consisting of oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 1,3-dioxolanyl, 1,4-dioxepinyl, 1,4-dioxanyl, 1,4-oxazacycloheptyl and morpholinyl; or, the structural unit
3. The compound, the pharmaceutically acceptable salt or the isomer thereof as defined in claim 2 , wherein R 1 is selected from the group consisting of CH 3 ,
each of which is optionally substituted by 1, 2 or 3 R; or, ring A is selected from the group consisting of
or, the structural unit
4. The compound, the pharmaceutically acceptable salt or the isomer thereof as defined in claim 3 , wherein R 1 is selected from the group consisting of CH 3 ,
5. The compound, the pharmaceutically acceptable salt or the isomer thereof as defined in claim 3 , wherein the structural unit
6. The compound, the pharmaceutically acceptable salt or the isomer thereof as defined in claim 1 , wherein the structural unit
or, the structural unit
is selected from the group consisting of —CH 2 —, —NH—, —C(═O)—NH—,
7. The compound, the pharmaceutically acceptable salt or the isomer thereof as defined in claim 6 , wherein the structural unit
8. The compound, the pharmaceutically acceptable salt or the isomer thereof as defined in claim 7 , wherein the structural unit
is selected from the group consisting of
9. The compound, the pharmaceutically acceptable salt or the isomer thereof as defined in claim 8 , wherein the structural unit
is selected from the group consisting of
10. The compound, the pharmaceutically acceptable salt or the isomer thereof as defined in claim 1 , wherein the structural unit
is selected from the group consisting of
11. The compound, the pharmaceutically acceptable salt or the isomer thereof as defined in claim 10 , wherein the structural unit
is selected from the group consisting of
12. The compound, the pharmaceutically acceptable salt or the isomer thereof as defined in claim 1 , wherein the structural unit
13. The compound, the pharmaceutically acceptable salt or the isomer thereof as defined in claim 1 , which is selected from the group consisting of
wherein, ring A, R, R 2 , L 1 and n is as defined in claim 1 ;
R 1 is as defined in claim 1 .
14. The compound, the pharmaceutically acceptable salt or the isomer thereof as defined in claim 13 , which is
wherein,
each of E 1 , E 2 is independently —O—, —CH 2 — or —CH 2 —CH 2 —;
R, R 2 , L 1 and n is as defined in claim 1 .
15. The compounds or the pharmaceutically acceptable salt or the isomer thereof as defined in claim 1 , which is selected from the group consisting of
16. The compound, the pharmaceutically acceptable salt or the isomer thereof as defined in claim 15 is selected from the group consisting of
17. A pharmaceutical composition comprising a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof as defined in claim 1 as an active ingredient, as well as a pharmaceutically acceptable carrier.