Derivatives having 1,2,3,4-tetrahydronaphthalene moiety or pharmaceutically acceptable salt thereof and pharmaceutical compositions comprising the same

Patent metadata

Field	Value
Publication number	US-12338237-B2
Application number	US-202017755852-A
Country	US
Kind code	B2
Filing date	Nov 12, 2020
Priority date	Nov 15, 2019
Publication date	Jun 24, 2025
Grant date	Jun 24, 2025

Abstract

Provided are a compound having a 1,2,3,4-tetrahydronaphthalene moiety or pharmaceutically acceptable salt thereof, of Formula 1

a pharmaceutical composition comprising the same and a use thereof, where the compound having a 1,2,3,4-tetrahydronaphthalene moiety or pharmaceutically acceptable salt thereof has an inhibitory activity against glucosylceramide synthase (GCS), and therefore can be usefully applied for preventing or treating various diseases associated with GCS, such as Gaucher disease, Fabry disease, Tay-Sachs disease, Parkinson's disease, etc.

First claim

The invention claimed is:

1. A compound of Formula 1 or pharmaceutically acceptable salt thereof:

wherein,
L is —O—, —CO—, —CR 1 R 2 —, or —NR 3 —,
R 1 and R 2 are, independently of each other, hydrogen; halogen; C 1 ˜C 6 alkyl; C 1 ˜C 6 alkyl having a nitrogen, oxygen, or sulfur atom; C 3 ˜C 10 cycloalkyl; 3- to 12-membered heterocyclic; or C 1 ˜C 6 alkoxy,
R 3 is hydrogen; C 1 ˜C 6 alkyl; C 1 ˜C 6 alkyl having a nitrogen, oxygen, or sulfur atom; C 3 ˜C 10 cycloalkyl; 3- to 12-membered heterocyclic; or C 1 ˜C 6 alkoxy,
X is hydrogen; halogen; C 1 ˜C 6 alkyl; C 1 ˜C 6 alkyl substituted with 1 to 3 halogens; C 1 ˜C 6 alkyl having a nitrogen, oxygen, or sulfur atom; C 1 ˜C 6 alkoxy; or C 1 ˜C 6 alkoxy substituted with 1 to 3 halogens,
Y, Q and Z are, independently of each other, —CR 4 R 5 —,
R 4 and R 5 are, independently of each other, hydrogen; halogen; C 1 ˜C 6 alkyl; C 1 ˜C 6 alkyl having a nitrogen, oxygen, or sulfur atom; C 3 ˜C 10 cycloalkyl; 3- to 12-membered heterocyclic; or C 1 ˜C 6 alkoxy; or R 4 and R 5 form a C 3 ˜C 10 cycloalkyl together with the carbon atom of Y, Q or Z to which they are attached,
W is a bond, —CH 2 —, —O—, —NH—, —CH 2 CH 2 —, —CH═CH—, or —C≡C—,
A ring is 6- to 12-membered aryl; 5- to 12-membered heteroaryl; C 3 ˜C 10 cycloalkyl; or 3- to 12-membered heterocyclic, and
X 1 , X 2 , X 3 , and X 4 are, independently of each other, hydrogen; cyano; halogen; C 1 ˜C 6 alkyl; C 1 ˜C 6 alkyl substituted with 1 to 3 halogens; C 3 ˜C 10 cycloalkyl; 3- to 12-membered heterocyclic; C 1 ˜C 6 alkoxy; C 1 ˜C 6 alkoxy-C 1 ˜C 6 alkoxy; C 1 ˜C 6 alkoxy substituted with 1 to 3 halogens; C 1 ˜C 6 alkylthio; morpholinyl; amino; mono- or di-C 1 ˜C 6 alkylamino; C 1 ˜C 6 alkylcarbonyl; hydroxy; or nitro.

2. The compound or pharmaceutically acceptable salt thereof as claimed in claim 1 , wherein L is —O—.

3. The compound or pharmaceutically acceptable salt thereof as claimed in claim 1 , wherein X is hydrogen; halogen; or C 1 ˜C 6 alkoxy.

4. The compound or pharmaceutically acceptable salt thereof as claimed in claim 1 , wherein R 4 and R 5 are, independently each other, hydrogen or C 1 ˜C 6 alkyl; or R 4 and R 5 form a C 3 ˜C 10 cycloalkyl together with the carbon atom of Y, Q or Z to which they are attached.

5. The compound or pharmaceutically acceptable salt thereof as claimed in claim 1 , wherein Y is —CH 2 —.

6. The compound or pharmaceutically acceptable salt thereof as claimed in claim 1 , wherein Q is —CH 2 —.

7. The compound or pharmaceutically acceptable salt thereof as claimed in claim 1 , wherein Y is —CH 2 —; Q is —CH 2 —; and Z is —CR 4 R 5 —; and R 4 and R 5 are, independently of each other, hydrogen or C 1 ˜C 6 alkyl; or R 4 and R 5 form be C 3 ˜C 10 cycloalkyl together with the carbon atom of Z.

8. The compound or pharmaceutically acceptable salt thereof as claimed in claim 1 , wherein W is a bond.

9. The compound or pharmaceutically acceptable salt thereof as claimed in claim 1 , wherein the A ring is phenyl, benzodioxolyl, 2,3-dihydrobenzodioxinyl, 2,3-dihydrobenzofuranyl, pyridinyl, pyrrolo[2.3-b]pyridinyl, pyrimidinyl, or thiophenyl.

10. The compound or pharmaceutically acceptable salt thereof as claimed in claim 1 , wherein X 1 , X 2 , X 3 , and X 4 are, independently of each other, hydrogen; cyano; halogen; C 1 ˜C 6 alkyl; C 1 ˜C 6 alkyl substituted with 1 to 3 halogens; C 3 ˜C 10 cycloalkyl; C 1 ˜C 6 alkoxy; C 1 ˜C 6 alkoxy-C 1 ˜C 6 alkoxy; C 1 ˜C 6 alkoxy substituted with 1 to 3 halogens; morpholinyl; mono- or di-C 1 ˜C 6 alkylamino; or C 1 ˜C 6 alkylcarbonyl.

11. The compound or pharmaceutically acceptable salt thereof as claimed in claim 1 , wherein
L is —O—,
X is hydrogen; halogen; or C 1 ˜C 6 alkoxy,
R 4 and R 5 are, independently of each other, hydrogen or C 1 ˜C 6 alkyl; or R 4 and R 5 form a C 3 ˜C 10 cycloalkyl together with the carbon atom of Y, Q or Z to which they are attached,
W is a bond,
A ring is phenyl, benzodioxolyl, 2,3-dihydrobenzodioxinyl, 2,3-dihydrobenzofuranyl, pyridinyl, pyrrolo[2.3-b]pyridinyl, pyrimidinyl, or thiophenyl, and
X 1 , X 2 , X 3 , and X 4 are, independently of each other, hydrogen; cyano; halogen; C 1 ˜C 6 alkyl; C 1 ˜C 6 alkyl substituted with 1 to 3 halogens; C 3 ˜C 10 cycloalkyl; C 1 ˜C 6 alkoxy; C 1 ˜C 6 alkoxy-C 1 ˜C 6 alkoxy; C 1 ˜C 6 alkoxy substituted with 1 to 3 halogens; morpholinyl; mono- or di-C 1 ˜C 6 alkylamino; or C 1 ˜C 6 alkylcarbonyl.

12. The compound or pharmaceutically acceptable salt thereof as claimed in claim 11 , wherein Y is —CH 2 —.

13. The compound or pharmaceutically acceptable salt thereof as claimed in claim 11 , wherein Q is —CH 2 —.

14. The compound or pharmaceutically acceptable salt thereof as claimed in claim 11 , wherein Y is —CH 2 —; Q is —CH 2 —; and Z is —CR 4 R 5 —; and R 4 and R 5 are, independently of each other, hydrogen or C 1 ˜C 6 alkyl; or R 4 and R 5 form a C 3 ˜C 10 cycloalkyl together with the carbon atom of Z.

15. The compound or pharmaceutically acceptable salt thereof as claimed in claim 1 , which is selected from the group consisting of:
(S)-quinuclidin-3-yl (6-(4-fluorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate;
(S)-quinuclidin-3-yl (6-(4-chlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate;
(S)-quinuclidin-3-yl (6-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate;
(S)-quinuclidin-3-yl (6-(4-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate;
(S)-quinuclidin-3-yl (6-(3-fluorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate;
(S)-quinuclidin-3-yl (6-(3-chlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate;
(S)-quinuclidin-3-yl (6-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate;
(S)-quinuclidin-3-yl (6-(3-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate;
(S)-quinuclidin-3-yl (6-(2-fluorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate;
(S)-quinuclidin-3-yl (6-(2-chlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate;
(S)-quinuclidin-3-yl (6-(2-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate;
(S)-quinuclidin-3-yl (6-(2-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate;
(S)-quinuclidin-3-yl (6-(4-(difluoromethoxy)phenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate;
(S)-quinuclidin-3-yl (6-(p-tolyl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate;
(S)-quinuclidin-3-yl (6-(3,4-difluorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate;
(S)-quinuclidin-3-yl (6-(2,5-difluorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate;
(S)-quinuclidin-3-yl (6-(3,5-difluorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate;
(S)-quinuclidin-3-yl (6-(2,4-difluorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate;
(S)-quinuclidin-3-yl (6-(2,3-difluorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate;
(S)-quinuclidin-3-yl (6-(2,3,4-trifluorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate;
(S)-quinuclidin-3-yl (6-(2,4,5-trifluorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate;
(S)-quinuclidin-3-yl (6-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate;
(S)-quinuclidin-3-yl (6-(2,5-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate;
(S)-quinuclidin-3-yl (6-(3,5-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate;
(S)-quinuclidin-3-yl (6-(4-(2-methoxyethoxy)phenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate;
(S)-quinuc

Assignees

• Yuhan Corp
• Green Cross Corp

Inventors

• Kim Dong-Hoon
• Joo Jae-Eun
• Lee Eui-Chul
• Han Tae-Dong
• Shin Seung-Yub
• Kwon Sool-Ki
• Kong Young-Gyu
• Ma Sang-Ho
• Son Ick-Hwan

Classifications

• C07D471/08 Primary

  Bridged systems · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title