3,3-difluoroallylamines or salts thereof and pharmaceutical compositions comprising the same

Patent metadata

Field	Value
Publication number	US-11168073-B2
Application number	US-201916712660-A
Country	US
Kind code	B2
Filing date	Dec 12, 2019
Priority date	Dec 14, 2018
Publication date	Nov 9, 2021
Grant date	Nov 9, 2021

Abstract

The present technology provides 3,3-difluoroallylamines or pharmaceutically acceptable salts thereof, preparation processes thereof, pharmaceutical compositions comprising the same, and uses thereof. The 3,3-difluoroallylamines or their pharmaceutically acceptable salts exhibit potent inhibitory activity on VAP-1 and therefore can be usefully applied, e.g., for the treatment and prophylaxis of nonalcoholic hepatosteatosis (NASH).

First claim

The invention claimed is:

1. A compound of Formula X

or a stereoisomer thereof or a pharmaceutically acceptable salt thereof;
wherein
n is 0, 1, or 2; and
A is an aryl group or a heterocyclic group, wherein said heterocyclic group has 1 to 5 heteroatom ring members independently chosen from 0, N, and S, and said heterocyclic group is aromatic or non-aromatic; and wherein said aryl group or said heterocyclic group is optionally substituted with one or two substituents independently selected from the group consisting of C 1-3 alkyl, halogen, benzyloxy, —R, —CH═CH—R, and —C≡C—R; and
R is a substituted or unsubstituted cyclic ring, optionally containing 1 to 5 heteroatom ring members independently chosen from O, N, and S, and said cyclic ring is aromatic or non-aromatic.

2. The compound, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, of claim 1 , wherein A is aryl optionally substituted with one or two substituents independently selected from the group consisting of C 1-3 alkyl, halogen, benzyloxy, —R, —CH═CH—R, and —C≡C—R.

3. The compound, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, of claim 2 , wherein A is phenyl substituted with one or two substituents independently selected from the group consisting of C 1-3 alkyl, halogen, benzyloxy, —R, —CH═CH—R, and —C≡C—R.

4. The compound, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, of claim 1 , wherein A is a heterocyclic group having 1 to 5 heteroatom ring members chosen from O, N, and S; said heterocyclic group is aromatic or non-aromatic; and
said heterocyclic group is optionally substituted with one or two substituents independently selected from the group consisting of C 1-3 alkyl, halogen, benzyloxy, —R, —CH═CH—R, and —C≡C—R.

5. The compound, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, of claim 4 , wherein A is an aromatic heterocyclic-group having 1 to 5 heteroatom ring members chosen from O, N, and S; and said aromatic heterocyclic group is optionally substituted with one or two substituents independently selected from the group consisting of C 1-3 alkyl, halogen, benzyloxy, —R, —CH═CH—R, and —C≡C—R.

6. The compound, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, of claim 5 , wherein A is pyridinyl, pyrazinyl, or thiophenyl, wherein A is optionally substituted with one or two substituents independently selected from the group consisting of C 1-3 alkyl, halogen, benzyloxy, —R, —CH═CH—R, and —C≡C—R.

7. The compound, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, of claim 1 , wherein R is a cyclic ring optionally containing 1-5 heteroatom ring members independently chosen from O, N, and S, and said cyclic ring is optionally substituted with one to three substituents independently selected from the group consisting of halogen, C 1-6 alkyl, difluoromethyl, trifluoromethyl, (cycloalkyl)alkyl, benzyl, C 1-6 alkoxy, amino, mono- or di-C 1-6 alkylamino, C 1-6 alkoxy-C 1-6 alkylamino, C 1-6 alkylcarbonylamino, mono- or di-C 1-6 alkylaminocarbonyl, mono- or di-C 1-6 alkylaminosulfonyl, C 1-6 alkyl sulfonyl, cycloalkylsulfonyl, C 1-6 alkylcarbonyl, morpholinylcarbonyl, piperazinyl, acetylpiperazinyl, morpholinyl, pyrazolyl, C 1-6 alkylpyrazolyl, triazolyl, pyrrolidinonyl, and pyrrolidinyl.

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

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

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

11. The compound of claim 1 of Formula 12

or a stereoisomer thereof or a pharmaceutically acceptable salt thereof;
wherein
R 1 is hydrogen, halogen, or C 1-3 alkyl; and
R 2 is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group, wherein said heteroaryl group has 1 to 5 heteroatom ring members independently chosen from O, N, and S.

12. The compound of claim 1 of Formula 13

or a stereoisomer thereof or a pharmaceutically acceptable salt thereof;
wherein
R 1 is hydrogen, halogen, or C 1-3 alkyl; and
R 2 is a benzyloxy group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heterocyclic group, wherein said heterocyclic group has 1 to 5 heteroatom ring members independently chosen from O, N, and S, and said heterocyclic group is aromatic or non-aromatic.

13. The compound of claim 1 of Formula 14

or a stereoisomer thereof or a pharmaceutically acceptable salt thereof;
wherein
R 1 is hydrogen, halogen, or C 1-3 alkyl; and
R 2 is a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group, wherein said heterocyclic group has 1 to 5 heteroatom ring members independently chosen from O, N, and S, and said heterocyclic group is aromatic or non-aromatic.

14. The compound of claim 13 of Formula 14a

or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

15. The compound of claim 13 of Formula 14b

or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

16. The compound of claim 13 of Formula 14c

or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

17. The compound of claim 1 of Formula 15

or a stereoisomer thereof or a pharmaceutically acceptable salt thereof;
wherein
R 1 is hydrogen or C 1-3 alkyl; and
R 2 is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl, wherein said heteroaryl group has 1 to 5 heteroatom ring members independently chosen from O, N, and S group.

18. The compound of claim 1 of Formula 16

or a stereoisomer thereof or a pharmaceutically acceptable salt thereof;
wherein R 2 is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl group, wherein said heteroaryl group has 1 to 5 heteroatom ring members independently chosen from O, N, and S.

19. The compound of claim 1 of Formula 17

or a stereoisomer thereof or a pharmaceutically acceptable salt thereof;
wherein
R 1 is hydrogen, halogen, or C 1-3 alkyl; and
R 2 is a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group, whe

Assignees

• Yuhan Corp

Inventors

• Han Tae Dong
• Tak Hee Jae
• Kim Eun Kyung
• Lee Eui Chul
• Park Sol
• Cho Hyok Jun
• Lim Cheol Hee
• Kim So Young
• Choi Hyun Ho
• Jeong Da Na
• Yang Na Yeon
• Ha Na Ry

Classifications

• C07F7/1892

  by reactions not provided for in C07F7/1876 - C07F7/1888 · CPC title

• C07F7/1804

  Compounds having Si-O-C linkages (Si-O-acyl linkages C07F7/1896) · CPC title

• C07C271/16

  to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms · CPC title

• C07C269/06

  by reactions not involving the formation of carbamate groups · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title