# US 12,213,971 B2 · Histone deacetylase inhibitors for immunomodulation in tumor microenvironment

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- Number: US 12,213,971 B2
- Document ID: US12213971B2
- Status: Granted
- Kind: B2
- Application number: 18/310,387
- Filed: 2023-05-01
- Published: 2023-08-24
- Granted: 2025-02-04
- Earliest claimed: 2020-04-30
- Assignees: Great Novel Therapeutics Biotech & Medicals Corporation
- Applicants: Great Novel Therapeutics Biotech & Medicals Corporation
- Inventors: Jia-Shiong Chen; Mu-Hsuan Yang; Yi-Hong Wu; Sz-Hao Chu; Cheng-Han Chou; Ye-Su Chao; Chia-Nan Chen
- Web page: https://patentgrep.com/patent/US12213971B2

## CPC

- A61K 31/444: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 31/44: Non condensed pyridines; Hydrogenated derivatives thereof
- A61K 31/4406: only substituted in position 3, e.g. zimeldine (nicotinic acid A61K31/455)
- A61P 35/00: Antineoplastic agents
- C07D 213/56: Amides
- C07D 213/81: Amides; Imides
- C07D 213/82: in position 3
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

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.

## Claims

### Claim 1

A method for epigenetic immunomodulation of tumor microenvironment (TME) and/or treatment of cancer in a subject in need thereof, the method comprising administrating an effective amount of a compound of formula (I) to the subject:
wherein W and Y are each independently selected from CH and N;
R1 is each independently selected from hydrogen, halogen, C1-C3 alkyl and halogenated C1-C3 alkyl, and can be mono-, di-, tri- or tetra-substitution;
C1 and C2 are C atoms linked by a double bond;
Ar is selected from the group consisting of the following:
wherein Ar is linked to C2 via the solid line;
R2 has the same meaning as described for R1; and
R3 is hydrogen or C1-C3 alkyl;
or a pharmaceutically acceptable salt, hydrate, stereoisomer or solvate thereof.

### Claim 2 (depends on 1)

The method of claim 1, wherein the compound has the formula (Ia):
wherein W, Y, R1, C1, C2 and Ar have the same meaning as described in formula (I), or a pharmaceutically acceptable salt, hydrate, stereoisomer or solvate thereof.

### Claim 3 (depends on 1)

The method of claim 1, wherein in Formula (I) Ar is selected from the six-membered rings, and R2 and the atom of Ar linked to C2 are at para-positions.

### Claim 4 (depends on 1)

The method of claim 1, wherein in Formula (I) 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.

### Claim 5 (depends on 1)

The method of claim 1, wherein in Formula (I) W is N and Y is CH.

### Claim 6 (depends on 1)

The method of claim 1, wherein in Formula (I) R1 is F or fluorinated C1-C3 alkyl.

### Claim 7 (depends on 1)

The method of claim 1, wherein in Formula (I) R2 is C1-C3 alkyl or fluorinated C1-C3 alkyl.

### Claim 8 (depends on 1)

The method of claim 1, wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt, hydrate, stereoisomer or solvate thereof.

### Claim 9 (depends on 1)

The method of claim 1, wherein one or more second agent can be further administered in combination with the compound of formula (I).

### Claim 10 (depends on 9)

The method of claim 9, wherein the one or more second agent is an immune checkpoint inhibitor, an NSAID, a TKI or an anti-cancer agent or a combination thereof.

### Claim 11 (depends on 1)

The method of claim 1, wherein the method is for inducing cell cycle arrest of tumor cells, for inducing apoptosis of tumor cells, for inducing histone H3 acetylation, for inducing immune memory, for activating CTL, for decreasing immunosuppressive cells.

### Claim 12

A method for treating or preventing the disease associated with class I HDAC in a subject in need thereof comprising administrating an effective amount of a compound of formula (I) to the subject:
wherein W and Y are each independently selected from CH and N;
R1 is each independently selected from hydrogen, halogen, C1-C3 alkyl and halogenated C1-C3 alkyl, and can be mono-, di-, tri- or tetra-substitution;
C1 and C2 are C atoms linked by a double bond;
Ar is selected from the group consisting of the following:
wherein Ar is linked to C2 via the solid line;
R2 has the same meaning as described for R1; and
R3 is hydrogen or C1-C3 alkyl;
or a pharmaceutically acceptable salt, hydrate, stereoisomer or solvate thereof.

### Claim 13 (depends on 12)

The method of claim 12, wherein the compound has the formula (Ia):
wherein W, Y, R1, C1, C2 and Ar have the same meaning as described in formula (I), or a pharmaceutically acceptable salt, hydrate, stereoisomer or solvate thereof.

### Claim 14 (depends on 12)

The method of claim 12, wherein in Formula (I) Ar is selected from the six-membered rings, and R2 and the atom of Ar linked to C2 are at para-positions.

### Claim 15 (depends on 12)

The method of claim 12, wherein in Formula (I) 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.

### Claim 16 (depends on 12)

The method of claim 12, wherein in Formula (I) W is N and Y is CH.

### Claim 17 (depends on 12)

The method of claim 12, wherein in Formula (I) R1 is F or fluorinated C1-C3 alkyl.

### Claim 18 (depends on 12)

The method of claim 12, wherein in Formula (I) R2 is C1-C3 alkyl or fluorinated C1-C3 alkyl.

### Claim 19 (depends on 12)

The method of claim 12, wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt, hydrate, stereoisomer or solvate thereof.

### Claim 20 (depends on 12)

The method of claim 12, wherein one or more second agent can be further administered in combination with the compound of formula (I).

### Claim 21 (depends on 20)

The method of claim 20, wherein the one or more second agent is an immune checkpoint inhibitor, an NSAID, a TKI or an anti-cancer agent or a combination thereof.