Histone deacetylase inhibitors for immunomodulation in tumor microenvironment
The present disclosure generally relates to compounds class I HDAC inhibitors, their production and applications. The compounds possess epigenetic immunomodulatory activities in the tumor microenvironment (TME) and thus inhibit growth of tumor cells.
1. A compound of formula (I):
wherein W and Y are each independently selected from CH and N;
R 1 is each independently selected from hydrogen, halogen, C 1 -C 3 alkyl and halogenated C 1 -C 3 alkyl, and can be mono-, di-, tri- or tetra-substitution;
C 1 and C 2 are C atoms linked by a double bond;
Ar is selected from the group consisting of the following:
wherein Ar is linked to C 2 via the solid line;
R 2 has the same meaning as described for R 1 ; and
R 3 is hydrogen or C 1 -C 3 alkyl;
or a pharmaceutically acceptable salt, hydrate, stereoisomer or solvate thereof.
2. The compound of claim 1 , which has the formula (Ia):
wherein W, Y, R 1 , C 1 , C 2 and Ar have the same meaning as described in formula (I); or a pharmaceutically acceptable salt, hydrate, stereoisomer or solvate thereof.
3. The compound of claim 1 or a pharmaceutically acceptable salt, hydrate, stereoisomer or solvate thereof, wherein Ar is selected from the six-membered rings, and R 2 and the atom of Ar linked to C 2 are at para-positions.
4. The compound of claim 1 or a pharmaceutically acceptable salt, hydrate, stereoisomer or solvate thereof, wherein W and Y are selected from the following combinations: (1) W is N and Y is CH, (2) W is CH and Y is N, and (3) W and Y are CH.
5. The compound of claim 1 or a pharmaceutically acceptable salt, hydrate, stereoisomer or solvate thereof, wherein W is N and Y is CH.
6. The compound of claim 1 or a pharmaceutically acceptable salt, hydrate, stereoisomer or solvate thereof, wherein R 1 is F or fluorinated C 1 -C 3 alkyl.
7. The compound of claim 1 or a pharmaceutically acceptable salt, hydrate, stereoisomer or solvate thereof, wherein R 2 is C 1 -C 3 alkyl or fluorinated C 1 -C 3 alkyl.
8. The compound of claim 1 or a pharmaceutically acceptable salt, hydrate, stereoisomer or solvate thereof wherein the compound is:
9. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt, hydrate, stereoisomer or solvate thereof and a pharmaceutical acceptable carrier.
10. A pharmaceutical composition or pharmaceutical combination, comprising the compound of claim 1 or a pharmaceutically acceptable salt, hydrate, stereoisomer or solvate thereof, and one or more second agents.
11. The pharmaceutical composition or pharmaceutical combination of claim 10 , wherein the second agent is an immune checkpoint inhibitor, an NSAID, a TKI or an anti-cancer agent or a combination thereof.