# US 11,897,865 B2 · ABHD12 inhibitors and methods of making and using same

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- Number: US 11,897,865 B2
- Document ID: US11897865B2
- Status: Granted
- Kind: B2
- Application number: 17/055,081
- Filed: 2019-05-14
- Published: 2021-07-22
- Granted: 2024-02-13
- Earliest claimed: 2018-05-15
- Assignees: The Scripps Research Institute
- Applicants: The Scripps Research Institute
- Inventors: Daisuke Ogasawara; Taka-Aki Ichu; Jonathan Hulce; Benjamin F. Cravatt
- Web page: https://patentgrep.com/patent/US11897865B2

## CPC

- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- C07D 401/14: containing three or more hetero rings
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- C07D 213/75: Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 451/04: with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
- C07D 471/04: Ortho-condensed systems
- C07D 471/08: Bridged systems
- C07D 487/04: Ortho-condensed systems
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Provided herein are compounds and compositions useful as modulators of ABHD12. Furthermore, the subject compounds and compositions are useful as immunotherapies in treating, for instance, cancer or infectious diseases.

## Claims

### Claim 1

A compound of Formula (I):
wherein:
each R1 is independently selected from halogen, —CN, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, C1-6haloalkyl, —C(O)R2, —OR3, and phenyl optionally substituted with 1, 2, or 3 substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, and C1-6haloalkoxy;
each R2 is independently C1-6alkyl;
each R3 is independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -C1-6alkyl-C3-6cycloalkyl, C2-9heterocycloalkyl, phenyl, and -C1-6alkyl-phenyl, wherein C3-6cycloalkyl, -C1-6alkyl-C3-6cycloalkyl, C2-9heterocycloalkyl, phenyl, and -C1-6alkyl-phenyl are optionally substituted with 1, 2, or 3 substituents independently selected from halogen, C1-6alkyl, C1-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, and —C(O)OR4;
each R4 is independently C1-6alkyl; and
n is 0, 1, 2, or 3;
or a solvate, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof.

### Claim 2

A compound of Formula (II):
wherein:
each R1 is independently selected from halogen, —CN, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, C1-6haloalkyl, —C(O)R2, —OR3, and phenyl optionally substituted with 1, 2, or 3 substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, and C1-6haloalkoxy;
each R2 is independently C1-6alkyl;
each R3 is independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -C1-6alkyl-C3-6cycloalkyl, C2-9heterocycloalkyl, phenyl, and -C1-6alkyl-phenyl, wherein C3-6cycloalkyl, -C1-6alkyl-C3-6cycloalkyl, C2-9heterocycloalkyl, phenyl, and -C1-6alkyl-phenyl are optionally substituted with 1, 2, or 3 substituents independently selected from halogen, C1-6alkyl, C1-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, and —C(O)OR4;
each R4 is independently C1-6alkyl;
R5 is selected from halogen, —CN, C1-6alkenyl, C1-6alkynyl, C1-6haloalkyl, —C(O)R2, —OR3, and phenyl optionally substituted with 1, 2, or 3 substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, and C1-6haloalkoxy; and
n is 0, 1, 2, or 3;
or a solvate, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 2)

The compound of claim 2, or a solvate, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R5 is selected from halogen, —CN, C1-6alkynyl, C1-6haloalkyl, —C(O)R2, —OR3, and phenyl optionally substituted with 1 or 2 substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, and C1-6haloalkoxy.

### Claim 4 (depends on 3)

The compound of claim 3, or a solvate, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R5 is selected from halogen, C1-6haloalkyl, —OR3, and phenyl substituted with 1 or 2 substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, and C1-6haloalkoxy.

### Claim 5 (depends on 1)

The compound of claim 1, or a solvate, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein each R1 is independently selected from halogen, —CN, C1-6alkyl, C1-6alkynyl, C1-6haloalkyl, —C(O)R2, —OR3, and phenyl optionally substituted with 1 or 2 substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, and C1-6haloalkoxy.

### Claim 6 (depends on 5)

The compound of claim 5, or a solvate, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein each R1 is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, —OR3, and phenyl substituted with 1 or 2 substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, and C1-6haloalkoxy.

### Claim 7 (depends on 1)

The compound of claim 1, or a solvate, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein each R3 is independently selected from C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -C1-6alkyl-C3-6cycloalkyl, C2-9heterocycloalkyl, phenyl, and -C1-6alkyl-phenyl, wherein C3-6cycloalkyl, -C1-6alkyl-C3-6cycloalkyl, C2-9heterocycloalkyl, phenyl, and -C1-6alkyl-phenyl are optionally substituted with 1 or 2 substituents independently selected from halogen, C1-6alkyl, C1-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, and C(O)OR4.

### Claim 8 (depends on 7)

The compound of claim 7, or a solvate, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein each R3 is independently selected from C1-6alkyl, C1-6haloalkyl, phenyl, and -C1-6alkyl-phenyl, wherein phenyl and -C1-6alkyl-phenyl are optionally substituted with 1 or 2 substituents independently selected from halogen, C1-6alkyl, C1-6alkynyl, C1-6haloalkyl, C1-6alkoxy, and C1-6haloalkoxy.

### Claim 9 (depends on 8)

The compound of claim 8, or a solvate, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R3 is C1-6haloalkyl, phenyl, or -C1-6alkyl-phenyl, wherein phenyl or -C1-6alkyl-phenyl are optionally substituted with 1 or 2 substituents independently selected from halogen, C1-6haloalkyl, and C1-6haloalkoxy.

### Claim 10 (depends on 1)

The compound of claim 1, or a solvate, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein n is 1, 2, or 3.

### Claim 11 (depends on 10)

The compound of claim 10, or a solvate, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein n is 1 or 2.

### Claim 12 (depends on 11)

The compound of claim 11, or a solvate, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein n is 1.

### Claim 13 (depends on 11)

The compound of claim 11, or a solvate, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein n is 2.

### Claim 14 (depends on 2)

The compound of claim 2, selected from:
or a solvate, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof.

### Claim 15 (depends on 1)

The compound of claim 1, selected from:
or a solvate, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof.

### Claim 16

A compound selected from:
or a solvate, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof.

### Claim 17 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1, or a solvate, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

### Claim 18 (depends on 1)

A method of inhibiting ABHD12 activity in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of claim 1, or a solvate, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof.

### Claim 19 (depends on 1)

A method of inhibiting ABHD12 activity in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of claim 1, or a solvate, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein administration of the compound stimulates the patient's immune system.

### Claim 20 (depends on 1)

A method of inhibiting ABHD12 activity in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of claim 1, or a solvate, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein administration of the compound initiates an immune response.