Isoquinoline derivatives useful as inhibitors of diacylglyceride O-acyltransferase 2

Patent metadata

Field	Value
Publication number	US-9828369-B2
Application number	US-201515508562-A
Country	US
Kind code	B2
Filing date	Aug 31, 2015
Priority date	Sep 5, 2014
Publication date	Nov 28, 2017
Grant date	Nov 28, 2017

Abstract

The present invention relates to a compound represented by formula I: and pharmaceutically acceptable salts thereof. The compounds of formula I are inhibitors of diacylglyceride O-acyltransferase 2 (“DGAT2”) and may be useful in the treatment, prevention and suppression of diseases mediated by DGAT2. The compounds of the present invention may be useful in the treatment of hepatic steatosis, diabetes mellitus, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cardio-renal diseases such as chronic kidney diseases and heart failure and related diseases and conditions.

First claim

What is claimed is:

1. A compound having structural Formula I:

or a pharmaceutically acceptable salt thereof wherein:
—X═Y— is —N═CH—, —CH═CH—, or —CH═N—;
M is
(1) bond,
(2) (C 1-2 )alkylene unsubstituted or substituted by 1-2 (C 1-3 )alkyl, halo, or phenyl,
(3) —NH—,
(4) (C 3-6 )cycloalkyl unsubstituted or substituted by 1-2 halo,
(5) 4- to 6-membered heterocyclyl containing 1-2 N heteroatoms, wherein the heterocyclyl is unsubstituted or substituted by —C(O)O(C 1-4 )alkyl,
(6) —(C 3-6 )cycloalkyl-S(O) 2 —*, or
(7) —CH 2 —O—*, wherein CH 2 is unsubstituted or substituted by 1-2 methyl;

wherein * indicates the point of attachment to ring A;
ring A is
(1) 4- or 6-membered heterocyclyl containing 1-2 heteroatoms selected from the group consisting of N, O, and S,
(2) fused 7- to 10-membered heterocyclyl containing 1-4 heteroatoms selected from the group consisting of N, O, and S,
(3) aryl,
(4) fused phenyl,
(5) 5- or 6-membered heteroaryl containing 1-4 heteroatoms selected from the group consisting of N, O, and S, or
(6) fused 8- to 10-membered heteroaryl containing 1-4 heteroatoms selected from the group consisting of N, O, and S,
(7) fused 5- to 10-membered bicyclic carbocyclyl, or
(8) 7- to 11-membered spirocyclic carbocyclyl;

wherein each ring is unsubstituted or substituted by 1-2 R 2 groups;
R 1 is

(2) (C 1-3 )alkyl-O—(C 1-6 )alkyl-,
(3) (C 1-3 )alkyl-OC(O)—(C 1-6 )alkyl-, or

ring B is
(1) phenyl, or
(2) 4- or 6-membered heterocyclyl containing 1-2 N heteroatoms;

R 2 is
(1) halo,
(2) halo(C 1-6 )alkyl,
(3) (C 1-6 )alkyl,
(4) (C 1-3 )alkoxy,
(5) halo(C 1-3 )alkoxy,
(6) cyano,
(7) hydroxy,
(8) phenyl unsubstituted or substituted by CF 3 , hydroxy, or halo,
(9) oxo,
(10) (C 1-3 )alkyl-S(O) 2 —,
(11) —C(O)O(C 1-4 )alkyl,
(12) (C 3-6 )cycloalkyl,
(13) phenoxy,
(14) benzyl,
(15) 5- or 6-membered heteroaryl containing 1-4 heteroatoms selected from the group consisting of N, O, and S, wherein the heteroaryl is unsubstituted or substituted by 1-2 methyl,
(16) 4- to 6-membered heterocyclyl containing 1-2 heteroatoms selected from the group consisting of N, O, and S, wherein the heterocyclyl is unsubstituted or substituted by oxo,
(17) —CH 2 -heteroaryl, wherein heteroaryl is a 5- or 6-membered heteroaryl containing 1-4 heteroatoms selected from the group consisting of N, O, and S, and wherein the heteroaryl is unsubstituted or substituted by hydroxyl,

R 3 is
(1) halo,
(2) cyano,
(3) (C 1-6 )alkyl,
(4) —C(O)O(C 1-4 )alkyl,
(5) —OC(O)N(H)(C 1-4 )alkyl,
(6) (C 1-3 )alkoxy,
(7) halo(C 1-3 )alkoxy,
(8) hydroxy,
(9) —C(O)N(R 4 ) 2
(10) (C 1-6 )alkyl-COOH,
(11) (C 1-3 )alkyl-O—(C 1-3 )alkyl, or
(12) —C(O)-heterocyclyl, wherein heterocyclyl is a 4- to 6-membered monocyclic ring containing 1-2 heteroatoms selected from the group consisting of N, O, and S,

R 4 is
(1) hydrogen, or
(2) (C 1-3 )alkyl;

m is 0, 1, 2, or 3; and
n is 0, 1 or 2.

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

3. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein ring B is phenyl.

4. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein ring A is aryl or fused phenyl.

5. The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl.

6. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein —X═Y— is —N═CH—.

7. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein ring A is 5- or 6-membered heteroaryl containing 1-4 heteroatoms selected from the group consisting of N, O, and S, or fused 8- to 10-membered heteroaryl containing 1-4 heteroatoms selected from the group consisting of N, O, and S.

8. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein ring A is 1,2,4-oxadiazolyl, 1H-pyrazolyl, quinolinyl, isoquinolinyl, indolizinyl, isoxazolyl, furanyl, pyridinyl, oxazolyl, benzo[d]isoxazolyl, quinoxalinyl, 1,2-dihydrophthalazinyl, thiazolyl, 1,2,3-thiadiazolyl, imidazolyl, pyrazinyl, 4H-1,2,4-triazolyl, 1H-tetrazolyl, or pyrimidinyl.

9. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein —X═Y— is —N═CH—.

10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is (C 1-3 )alkyl-O—(C 1-6 )alkyl- or (C 1-3 )alkyl-OC(O)—(C 1-6 )alkyl-.

11. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl.

12. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein —X═Y— is —N═CH—.

13. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein M is a bond; —NH—; (C 1-2 )alkylene unsubstituted or substituted by 1-2 (C 1-3 )alkyl, halo, or phenyl; or (C 3-6 )cycloalkyl unsubstituted or substituted by 1-2 halo.

14. The compound of claim 1 , which is

1
2-(3-methyl-1,2,4-oxadiazol-5-yl)-N-((5-(3-(trifluoromethoxy)phenyl)isoquinolin-8-

yl)methyl)cyclopropanecarboxamide,

2
methyl 3-(8-((2-(4-(trifluoromethyl)phenyl)acetamido)methyl)isoquinolin-5-yl)benzoate,

3
methyl 3-(8-(((1R,2R)-2-phenylcyclopropanecarboxamido)methyl)isoquinolin-5-

yl)benzoate,

4
methyl 3-(8-((2-(3-methyl-1,2,4-oxadiazol-5-

yl)cyclopropanecarboxamido)methyl)isoquinolin-5-yl)benzoate,

5
methyl 3-(8-((1-(4-(trifluoromethyl)phenyl)piperidine-4-

carboxamido)methyl)isoquinolin-5-yl)benzoate;

6
methyl 3-(8-((2-(4-phenoxyphenyl)acetamido)methyl)isoquinolin-5-yl)benzoate,

7
methyl 3-(8-((3-(tert-butyl)-1-methyl-1H-pyrazole-5-carboxamido)methyl)isoquinolin-5-

yl)benzoate,

8
methyl 3-(8-((1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-

carboxamido)methyl)isoquinolin-5-yl)benzoate,

9
methyl 3-(8-((1-methyl-3-propyl-1H-pyrazole-5-carboxamido)methyl)isoquinolin-5-

yl)benzoate,

10
methyl 3-(8-((spiro[2.4]heptane-1-carboxamido)methyl)isoquinolin-5-yl)benzoate,

11
8-((isoquinoline-1-carboxamido)methyl)-5-(3-

Assignees

• Merck Sharp & Dohme
• Imbriglio Jason
• London Clare
• Lu Zhijian
• Tata James
• Xiong Yusheng
• You Ming
• Youm Hye Won
• Merck Sharpe & Dohme Corp

Inventors

• Imbriglio Jason
• London Clare
• Lu Zhijian
• Tata James
• Xiong Yusheng
• You Ming
• Youm Hyewon

Classifications

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D417/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D217/02

  with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines · CPC title

• C07D413/12

  linked by a chain containing hetero atoms as chain links · CPC title