Derivatives having 2,3-dihydro-1H-indene or 2,3-dihydrobenzofuran moiety or pharmaceutically acceptable salt thereof and pharmaceutical compositions comprising the same

Patent metadata

Field	Value
Publication number	US-12522602-B2
Application number	US-202017755843-A
Country	US
Kind code	B2
Filing date	Nov 12, 2020
Priority date	Nov 15, 2019
Publication date	Jan 13, 2026
Grant date	Jan 13, 2026

Abstract

Provided are a compound having a 2,3-dihydro-1H-indene or 2,3-dihydrobenzofuran moiety or pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising the same and a use thereof, where the compound having a 2,3-dihydro-1H-indene or 2,3-dihydrobenzofuran 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 a pharmaceutically acceptable salt thereof:

wherein,
L is —O—, —CO—, —CR 1 R 2 —, or —NR 3 —,
Y and Z are, independently of each other, —CR 1 R 2 —; —NR 3 —; —O—; or —S—,
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; or R 1 and R 2 form C 3 -C 10 cycloalkyl together with the carbon atom to which they are attached,
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,
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 alkoxy-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 substituted with 1 to 3 halogens; C 1 -C 6 alkoxy-C 1 -C 6 alkoxy; morpholinyl-C 1 -C 6 alkoxy; mono- or di-C 1 -C 6 alkylamino-C 1 -C 6 alkoxy; C 3 -C 10 cycloalkyl-C 1 -C 6 alkoxy; C 1 -C 6 alkylthio; 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 Y and Z are, independently of each other, —O— or —CR 1 R 2 —.

4 . The compound or pharmaceutically acceptable salt thereof as claimed in claim 3 , wherein R 1 and R 2 are, independently of each other, hydrogen or C 1 -C 6 alkyl; or R 1 and R 2 form C 3 -C 10 cycloalkyl together with the carbon atom to which they are attached.

5 . The compound or pharmaceutically acceptable salt thereof as claimed in claim 1 , wherein Y is —O—; and Z is —CR 1 R 2 —.

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

7 . The compound or pharmaceutically acceptable salt thereof as claimed in claim 1 , wherein W is a bond or —CH═CH—.

8 . The compound or pharmaceutically acceptable salt thereof as claimed in claim 1 , wherein the A ring is 6- to 12-membered aryl.

9 . The compound or pharmaceutically acceptable salt thereof as claimed in claim 8 , wherein the A ring is phenyl, naphthalenyl, or biphenyl.

10 . The compound or pharmaceutically acceptable salt thereof as claimed in claim 1 , wherein the A ring is 5- to 12-membered heteroaryl.

11 . The compound or pharmaceutically acceptable salt thereof as claimed in claim 10 , wherein the A ring is benzodioxolyl, pyridinyl, thiophenyl, quinolinyl, isoquinolinyl, benzofuranyl, benzo[b]thiophenyl, quinoxalinyl, or furanyl.

12 . The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the A ring is 3- to 12-membered heterocyclic.

13 . The compound or pharmaceutically acceptable salt thereof as claimed in claim 12 , wherein the A ring is 2,3-dihydrobenzodioxinyl, 2,3-dihydrobenzofuranyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, chromanyl, or 3,4-dihydro-2H-benzo[b][1,4]dioxepinyl.

14 . 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 alkoxy-C 1 -C 6 alkyl; C 1 -C 6 alkyl substituted with 1 to 3 halogens; C 3 -C 10 cycloalkyl; morpholinyl; C 1 -C 6 alkoxy; C 1 -C 6 alkoxy substituted with 1 to 3 halogens; C 1 -C 6 alkoxy-C 1 -C 6 alkoxy; morpholinyl-C 1 -C 6 alkoxy; mono- or di-C 1 -C 6 alkylamino-C 1 -C 6 alkoxy; C 3 -C 10 cycloalkyl-C 1 -C 6 alkoxy; C 1 -C 6 alkylthio; mono- or di-C 1 -C 6 alkylamino; or C 1 -C 6 alkylcarbonyl.

15 . The compound or pharmaceutically acceptable salt thereof as claimed in claim 1 , wherein
L is —O—, Y and Z are, independently of each other, —O— or —CR 1 R 2 —, R 1 and R 2 are, independently of each other, hydrogen or C 1 -C 6 alkyl; or R 1 and R 2 form C 3 -C 10 cycloalkyl together with the carbon atom to which they are attached, X is hydrogen, halogen, or C 1 -C 6 alkoxy, W is a bond or —CH═CH—, A ring is 6- to 12-membered aryl, 5- to 12-membered heteroaryl, 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 alkoxy-C 1 -C 6 alkyl; C 1 -C 6 alkyl substituted with 1 to 3 halogens; C 3 -C 10 cycloalkyl; morpholinyl; C 1 -C 6 alkoxy; C 1 -C 6 alkoxy substituted with 1 to 3 halogens; C 1 -C 6 alkoxy-C 1 -C 6 alkoxy; morpholinyl-C 1 -C 6 alkoxy; mono- or di-C 1 -C 6 alkylamino-C 1 -C 6 alkoxy; C 3 -C 10 cycloalkyl-C 1 -C 6 alkoxy; C 1 -C 6 alkylthio; mono- or di-C 1 -C 6 alkylamino; or C 1 -C 6 alkylcarbonyl.

16 . The compound or pharmaceutically acceptable salt thereof as claimed in claim 15 , wherein Y is —O—; and Z is —CR 1 R 2 —.

17 . The compound or pharmaceutically acceptable salt thereof as claimed in claim 15 , wherein the A ring is phenyl, naphthalenyl, or biphenyl.

18 . The compound or pharmaceutically acceptable salt thereof as claimed in claim 15 , wherein the A ring is benzodioxolyl, pyridinyl, thiophenyl, quinolinyl, isoquinolinyl, benzofuranyl, benzo[b]thiophenyl, quinoxalinyl, or furanyl.

19 . The compound or pharmaceutically acceptable salt thereof as claimed in claim 15 , wherein the A ring is 2,3-dihydrobenzodioxinyl, 2,3-dihydrobenzofuranyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, chromanyl, or 3,4-dihydro-2H-benzo[b][1,4]dioxepinyl.

20 . The compound or pharmaceutically acceptable salt thereof as claimed in claim 1 , which is selected from the group consisting of:
(S)-quinuclidin-3-yl (5-(4-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)carbamate; (S)-quinuclidin-3-yl (5-(4-chlorophenyl)-2,3-dihydro-1H-inden-1-yl)carbamate; (S)-quinuclidin-3-yl (5-(4-(trifluoromethyl)phenyl)-2,3-dihydro-1H-inden-1-yl)carbamate; (S)-quinuclidin-3-yl (5-(4-(trifluoromethoxy)phenyl)-2,3-dihydro-1H-inden-1-yl)carbamate; (S)-quinuclidin-3-yl (5-(3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)carbamate; (S)-quinuclidin-3-yl (5-(3-chlorophenyl)-2,3-dihydro-1H-inden-1-yl)carbamate; (S)-quinuclidin-3-yl (5-(3-(trifluoromethyl)phenyl)-2,3-dihydro-1H-inden-1-yl)carbamate; (S)-quinuclidin-3-yl (5-(3-(trifluoromethoxy)phenyl)-2,3-dihydro-1H-inden-1-yl)carbamate; (S)-quinuclidin-3-yl (5-(2-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)carbamate; (S)-quinuclidin-3-yl (5-(2-chlorophenyl)-2,3-dihydro-1H-inden-1-yl)carbamate; (S)-quinuclidin-3-yl (5-(2-(trifluoromethyl)phenyl)-2,3-dihydro-1H-inden-1-yl)carbamate; (S)-quinuclidin-3-yl (5-(2-(trifluoromethoxy)phenyl)-2,3-dihydro-1H-inden-1-yl)carbamate; (S)-quinuclidin-3-yl (5-(p-tolyl)-2,3-dihydro-1H-inden-1-yl)carbamate; (S)-quinuclidin-3-yl (5-(4-(

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
• Kim Ji-Hye

Classifications

• A61P43/00

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

• A61P25/16

  Anti-Parkinson drugs · CPC title

• A61K31/439

  the ring forming part of a bridged ring system, e.g. quinuclidine (8-azabicyclo [3.2.1] octanes A61K31/46) · CPC title

• C07D471/08 Primary

  Bridged systems · CPC title

• C07D453/02 Primary

  containing not further condensed quinuclidine ring systems · CPC title