Novel compounds having inhibitory activity against glucosylceramide synthase or pharmaceutically acceptable salt thereof, processes for preparing the same, and pharmaceutical compositions comprising the same

Patent metadata

Field	Value
Publication number	US-2023002380-A1
Application number	US-202017755858-A
Country	US
Kind code	A1
Filing date	Nov 12, 2020
Priority date	Nov 15, 2019
Publication date	Jan 5, 2023
Grant date	—

Abstract

Provided are a compound having a chromane, isochromane, thiochromane, or tetrahydroquinoline moiety or pharmaceutically acceptable salt thereof, a process for the preparation thereof, a pharmaceutical composition comprising the same and a use thereof, wherein the compound having a chromane, isochromane, thiochromane, or tetrahydroquinoline 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

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

wherein,
L is —O—, —CO—, —CR 1 R 2 —, or —NR 3 —,
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 is —CR 4 R 5 —; —NR 3 —; —O—; or —S—,
P is —CR 4 R 5 —,
Q is —O— or —CR 4 R 5 —,
Z is —CR 6 —,
R 1 and R 2 are, independently 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,
R 4 and R 5 are, independently 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 C 3 ˜C 10 cycloalkyl together with the carbon atom of P or Q to which they are attached,
R 6 is hydrogen; C 1 ˜C 6 alkyl; or C 1 ˜C 6 alkyl having a nitrogen, oxygen, or sulfur atom,
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 each other, hydrogen; cyano; halogen; C 1 ˜C 6 alkyl; C 1 ˜C 6 alkyl substituted with 1 to 3 halogens; C 1 ˜C 6 alkyl substituted with cyano or C 1 ˜C 6 alkoxy; C 3 ˜C 10 cycloalkyl; C 1 ˜C 6 alkenyl; 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 alkoxy substituted with C 3 ˜C 10 cycloalkyl or benzyl; C 1 ˜C 6 alkylthio; amino; mono- or di-C 1 ˜C 6 alkylamino; morpholinyl; pyrrolidinyl-sulfonyl; benzyl; 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 3 is C 1 ˜C 6 alkyl.

5 . The compound or pharmaceutically acceptable salt thereof as claimed in claim 1 , wherein R 4 , R 5 , and R 6 are, independently each other, hydrogen or C 1 ˜C 6 alkyl.

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

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

8 . The compound or pharmaceutically acceptable salt thereof as claimed in claim 1 , wherein Y is —S—.

9 . The compound or pharmaceutically acceptable salt thereof as claimed in claim 1 , wherein Y is —NR 3 —.

10 . The compound or pharmaceutically acceptable salt thereof as claimed in claim 1 , wherein W is a bond, —CH 2 —, or —CH═CH—.

11 . The compound or pharmaceutically acceptable salt thereof as claimed in claim 1 , wherein the A ring is phenyl, biphenyl, thiophenyl, pyrazolyl, thiazolyl, naphthalenyl, benzothiadiazolyl, benzodioxolyl, 2,3-dihydrobenzodioxinyl, benzofuranyl, 2.3-dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, 3,4-dihydro-1,4-benzoxazinyl, 3-oxo-3,4-dihydro-1,4-benzoxazinyl, benzothiophenyl, indolyl, indazolyl, isoquinolinyl, quinolinyl, 3,4-dihydro-benzodioxepinyl, benzo[c][1,2-5]oxadiazolyl, pyridinyl, 6-oxo-1,6-dihydropyridinyl, chromanyl, dibenzofuranyl, or pyrimidinyl.

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

13 . 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, Y is —CR 4 R 5 —; —NR 3 —; —O—; or —S—, P is —CR 4 R 5 —, Q is —O— or —CR 4 R 5 —, Z is —CR 6 —, R 3 is C 1 ˜C 6 alkyl, R 4 , R 5 , and R 6 are, independently each other, hydrogen or C 1 ˜C 6 alkyl, W is a bond, —CH 2 —, -or —CH═CH—, A ring is phenyl, biphenyl, thiophenyl, pyrazolyl, thiazolyl, naphthalenyl, benzothiadiazolyl, benzodioxolyl, 2,3-dihydrobenzodioxinyl, benzofuranyl, 2.3-dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, 3,4-dihydro-1,4-benzoxazinyl, 3-oxo-3,4-dihydro-1,4-benzoxazinyl, benzothiophenyl, indolyl, indazolyl, isoquinolinyl, quinolinyl, 3,4-dihydro-benzodioxepinyl, benzo[c][1,2-5]oxadiazolyl, pyridinyl, 6-oxo-1,6-dihydropyridinyl, chromanyl, dibenzofuranyl, or pyrimidinyl, and X 1 , X 2 , X 3 , and X 4 is, independently each other, hydrogen; cyano; halogen; C 1 ˜C 6 alkyl; C 1 ˜C 6 alkyl substituted with 1 to 3 halogens; C 1 ˜C 6 alkyl substituted with cyano or C 1 ˜C 6 alkoxy; C 3 ˜C 10 cycloalkyl; C 1 ˜C 6 alkenyl; 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 alkoxy substituted with C 3 ˜C 10 cycloalkyl or benzyl; morpholinyl; mono- or di-C 1 ˜C 6 alkylamino; pyrrolidinyl-sulfonyl; benzyl; tetrahydropyranyl; C 1 ˜C 6 alkylthio; or isoxazolyl.

14 . The compound or pharmaceutically acceptable salt thereof as claimed in claim 1 , which is selected from the group consisting of:
(S)-quinuclidin-3-yl (7-(3-fluorophenyl)chroman-4-yl)carbamate; (S)-quinuclidin-3-yl (7-(3-chlorophenyl)chroman-4-yl)carbamate; (S)-quinuclidin-3-yl (7-(3-(trifluoromethyl)phenyl)chroman-4-yl)carbamate; (S)-quinuclidin-3-yl (7-(3-(trifluoromethoxy)phenyl)chroman-4-yl)carbamate; (S)-quinuclidin-3-yl (7-(2-(methoxymethoxy)phenyl)chroman-4-yl)carbamate; (S)-quinuclidin-3-yl (7-(3-(methoxymethoxy)phenyl)chroman-4-yl)carbamate; (S)-quinuclidin-3-yl (7-(2-(2-methoxyethoxy)phenyl)chroman-4-yl)carbamate; (S)-quinuclidin-3-yl (7-(3-(2-methoxyethoxy)phenyl)chroman-4-yl)carbamate; (S)-quinuclidin-3-yl (7-(2-fluorophenyl)chroman-4-yl)carbamate; (S)-quinuclidin-3-yl (7-(2-chlorophenyl)chroman-4-yl)carbamate; (S)-quinuclidin-3-yl (7-(2-(trifluoromethyl)phenyl)chroman-4-yl)carbamate; (S)-quinuclidin-3-yl (7-(2-(trifluoromethoxy)phenyl)chroman-4-yl)carbamate; (S)-quinuclidin-3-yl (7-(4-fluorophenyl)chroman-4-yl)carbamate; (S)-quinuclidin-3-yl (7-(4-chlorophenyl)chroman-4-yl)carbamate; (S)-quinuclidin-3-yl (7-(4-(trifluoromethyl)phenyl)chroman-4-yl)carbamate; (S)-quinuclidin-3-yl (7-(4-(trifluoromethoxy)phenyl)chroman-4-yl)carbamate; (S)-quinuclidin-3-yl (7-(2-methoxyphenyl)chroman-4-yl)carbamate; (S)-quinuclidin-3-yl (7-(3-methoxyphenyl)chroman-4-yl)carbamate; (S)-quinuclidin-3-yl (7-(4-methoxyphenyl)chroman-4-yl)carbamate; (S)-quinuclidin-3-yl (7-(2-ethoxyphenyl)chroman-4-yl)carbamate; (S)-quinuclidin-3-yl

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

Classifications

• C07D453/02 Primary

  containing not further condensed quinuclidine ring systems · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title

• C07D471/08 Primary

  Bridged systems · 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

• A61P43/00

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