# US 12,110,279 B2 · Triazolones, tetrazolones, and imidazolones, or their salts, and pharmaceutical compositions comprising the same

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- Number: US 12,110,279 B2
- Document ID: US12110279B2
- Status: Granted
- Kind: B2
- Application number: 17/726,323
- Filed: 2022-04-21
- Published: 2022-12-01
- Granted: 2024-10-08
- Earliest claimed: 2021-04-22
- Assignees: Yuhan Corporation
- Applicants: Yuhan Corporation
- Inventors: Hee Jae Tak; Eun Kyung Kim; Hyok Jun Cho; Cheol Hee Lim
- Web page: https://patentgrep.com/patent/US12110279B2

## CPC

- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- C07D 257/04: Five-membered rings
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/14: containing three or more hetero rings
- C07D 403/10: linked by a carbon chain containing aromatic rings
- C07D 405/10: linked by a carbon chain containing aromatic rings
- C07D 405/14: containing three or more hetero rings
- C07D 409/04: directly linked by a ring-member-to-ring-member bond
- C07D 409/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 409/14: containing three or more hetero rings
- C07D 413/10: linked by a carbon chain containing aromatic rings
- C07D 471/04: Ortho-condensed systems
- C07D 401/10: linked by a carbon chain containing aromatic rings
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present technology provides triazolones, tetrazolones, and imidazolones, or pharmaceutically acceptable salts thereof, preparation processes thereof, pharmaceutical compositions comprising the same, and uses thereof. The triazolones, tetrazolones, and imidazolones or their pharmaceutically acceptable salts exhibit inhibitory activity on VAP-1 and therefore can be usefully applied, e.g., for the treatment and prophylaxis of nonalcoholic hepatosteatosis (NASH).

## Claims

### Claim 1

A compound of Formula 1:
or a pharmaceutically acceptable salt thereof;
wherein
(i) X is N, and Y is N or CR2′; or
(ii) X is CR3, and Y is N or CR2;
R1 is hydrogen or fluoro;
R2 is hydrogen, C1-3 alkyl, halogen, phenyl, or benzyl;
R2′ is C1-3 alkyl, halogen, phenyl, or benzyl;
R3 is hydrogen, C1-3 alkyl, or phenyl;
n is 0 or 1;
A is a C6-C10 aryl group or a 5- to 10-membered heteroaryl group, wherein said heteroaryl group has 1 to 5 heteroatom ring members independently selected from O, N, and S; and wherein said aryl group or said heteroaryl group is optionally substituted with one or two substituents independently selected from the group consisting of C1-3 alkyl, halogen, and —R; and
R is a substituted or unsubstituted cyclic ring, optionally containing 1 to 5 heteroatom ring members independently selected from O, N, and S, and the cyclic ring is aromatic or non-aromatic.

### Claim 2 (depends on 1)

The compound or a pharmaceutically acceptable salt thereof of claim 1, wherein A is a C6-C10 aryl group optionally substituted with one or two substituents independently selected from the group consisting of C1-3 alkyl, halogen, and —R.

### Claim 3 (depends on 1)

The compound or a pharmaceutically acceptable salt thereof of claim 1, wherein A is a 5- to 10-membered heteroaryl group having 1 to 5 heteroatom ring members independently selected from O, N or S, wherein the heteroaryl group is optionally substituted with one or two substituents independently selected from the group consisting of C1-3 alkyl, halogen, and —R.

### Claim 4 (depends on 1)

The compound or a pharmaceutically acceptable salt thereof of claim 1, wherein R is substituted or unsubstituted phenyl.

### Claim 5 (depends on 1)

The compound or a pharmaceutically acceptable salt thereof of claim 1, wherein R is substituted or unsubstituted 5- to 10-membered heteroaryl having 1 to 5 heteroatom ring members independently selected from O, N, and S.

### Claim 6 (depends on 1)

The compound or a pharmaceutically acceptable salt thereof of claim 1, wherein R is substituted or unsubstituted non-aromatic 3- to 12-membered heterocyclic ring having 1 to 5 heteroatom ring members independently selected from O, N, and S.

### Claim 7 (depends on 1)

The compound or a pharmaceutically acceptable salt thereof of claim 1, wherein R is a cyclic ring selected from the group consisting of phenyl, pyridinyl, pyrazolyl, pyridine-2-onyl, benzodioxolyl, benzoxadiazolyl, 3,4-dihydroquinolin-2-onyl, and triazolo[1,5-a]pyridinyl; and wherein said cyclic ring is optionally substituted with one to three substituents independently selected from the group consisting of C1-6 alkyl, mono-C1-6 alkylamino, di-C1-6 alkylamino, C1-6 alkylsulfonyl, piperazinyl, and morpholinyl.

### Claim 8 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula 15:
or a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 8)

The compound or a pharmaceutically acceptable salt thereof of claim 8, wherein A is a 5- to 10-membered heteroaryl group having 1 to 5 heteroatom ring members independently selected from O, N, or S, wherein the heteroaryl group is optionally substituted with one or two substituents independently selected from the group consisting of C1-3 alkyl, halogen, and —R.

### Claim 10 (depends on 8)

The compound or a pharmaceutically acceptable salt thereof of claim 8, wherein R2′ is C1-3 alkyl.

### Claim 11 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula 16:
or a pharmaceutically acceptable salt thereof.

### Claim 12 (depends on 11)

The compound or a pharmaceutically acceptable salt thereof of claim 11, wherein A is a C6-C10 aryl group optionally substituted with one or two substituents independently selected from the group consisting of C1-3 alkyl, halogen, and —R.

### Claim 13 (depends on 11)

The compound or a pharmaceutically acceptable salt thereof of claim 11, wherein A is a 5- to 10-membered heteroaryl group having 1 to 5 heteroatom ring members independently selected from O, N or S, wherein the heteroaryl group is optionally substituted with one or two substituents independently selected from the group consisting of C1-3 alkyl, halogen, and —R.

### Claim 14 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula 17:
or a pharmaceutically acceptable salt thereof.

### Claim 15 (depends on 14)

The compound or a pharmaceutically acceptable salt thereof of claim 14, wherein A is a 5- to 10-membered heteroaryl group having 1 to 5 heteroatom ring members independently selected from O, N, or S, wherein the heteroaryl group is optionally substituted with one or two substituents independently selected from the group consisting of C1-3 alkyl, halogen, and —R.

### Claim 16 (depends on 1)

The compound or a pharmaceutically acceptable salt thereof of claim 1, wherein R1 is hydrogen.

### Claim 17 (depends on 1)

The compound or a pharmaceutically acceptable salt thereof of claim 1, wherein R1 is fluoro.

### Claim 18 (depends on 1)

The compound or a pharmaceutically acceptable salt thereof of claim 1, wherein n is 0.

### Claim 19 (depends on 1)

The compound or a pharmaceutically acceptable salt thereof of claim 1, wherein n is 1.

### Claim 20

A compound or a pharmaceutically acceptable salt thereof wherein the compound is:

### Claim 21 (depends on 1)

A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

### Claim 22 (depends on 1)

A method of inhibiting vascular adhesion protein-1 (VAP-1) in a mammal, comprising administering to the mammal a therapeutically effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

### Claim 23 (depends on 1)

A method of treating nonalcoholic hepatosteatosis (NASH) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 24

A method of preparing a compound of Formula 1a:
or a pharmaceutically acceptable salt thereof, wherein:
(i) X is N, and Y is N or CR2′; or
(ii) X is CR3, and Y is N or CR2;
R1 is hydrogen or fluoro;
R2 is hydrogen, C1-3 alkyl, halogen, phenyl, or benzyl;
R2′ is C1-3 alkyl, halogen, phenyl, or benzyl;
R3 is hydrogen, C1-3 alkyl, or phenyl;
n is 0 or 1;
A′ is a C6-C10 aryl group or a 5- to 10-membered heteroaryl group, wherein said heteroaryl group has 1 to 5 heteroatom ring members independently selected from O, N, and S; and
R′ is selected from the group consisting of C1-3 alkyl, halogen, and —R;
R is a substituted or unsubstituted cyclic ring, optionally containing 1 to 5 heteroatom ring members independently selected from O, N, and S, and the cyclic ring is aromatic or non-aromatic;
the method comprising:
(a) reacting a compound of Formula 2:
wherein PG is an amine protecting group;
with a compound of Formula 3:
Z—R′ (Formula 3)
wherein Z is —B(OH)2, B(C1-3alkoxy)2, or
to obtain a compound of Formula 1aa:
and
(b) removing PG from the compound of Formula 1aa under reaction conditions to obtain the compound of Formula 1a or a pharmaceutically acceptable salt thereof.

### Claim 25 (depends on 24)

The method of claim 24, wherein X is N, Y is CR2′, and n is 1; and the compound of Formula 2 is obtained by:
(a) reacting a compound of Formula 4:
with a compound of Formula 5:
to obtain a compound of Formula 6:
and
(b) reacting the compound of Formula 6 with a compound of Formula 11:
or
with a compound of Formula 12:
wherein Q is halogen;
under reaction conditions to obtain the compound of Formula 2.

### Claim 26 (depends on 24)

The method of claim 24, wherein X and Y are both N; and the compound of Formula 2 is obtained by:
(a) reacting a compound of Formula 7:
with trimethylsilyl azide under cyclization conditions to obtain a compound of Formula 8:
and
(b) reacting the compound of Formula 8 with a compound of Formula 11:
or with a compound of Formula 12:
wherein Q is halogen;
under reaction conditions to obtain the compound of Formula 2.

### Claim 27 (depends on 24)

The method of claim 24, wherein X is CH, Y is CH, and n is 1; and the compound of Formula 2 is obtained by:
reacting a compound of Formula 9:
with a compound of Formula 11:
or with a compound of Formula 12:
wherein Q is halogen;
under reaction conditions to obtain the compound of Formula 2.