Indole derivatives useful as inhibitors of diacylglyceride O-acyltransferase 2

Patent metadata

Field	Value
Publication number	US-10947222-B2
Application number	US-201716461880-A
Country	US
Kind code	B2
Filing date	Nov 13, 2017
Priority date	Nov 18, 2016
Publication date	Mar 16, 2021
Grant date	Mar 16, 2021

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, nonalcoholic steatohepatitis (NASH), cardiorenal 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:
R 1 is
(1) aryl unsubstituted or substituted by 1-3 R 5 , or
(2) 5- or 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein the heteroaryl is unsubstituted or substituted by 1-3 R 5 , or
(3) 8- to 10-membered fused heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein the heteroaryl is unsubstituted or substituted by 1-3 R 5 ;
R 2 is

R 3 is
(1) —(C 1-6 )alkyl-O—(C 1-3 )alkyl,
(2) 4- to 7-membered monocyclic or 6- to 10-membered bicyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O, and S, wherein the heterocyclyl is unsubstituted or substituted by 1-3 R 7 ,
(3) —(C 1-6 )alkyl-heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O, and S, and wherein the heterocyclyl is a 5- to 7-membered ring, or
(4) —(C 1-6 )alkyl-pyridinyl, wherein the pyridinyl is unsubstituted or substituted with (C 1-3 )alkyl or halo(C 1-3 )alkyl, and wherein the alkyl is unsubstituted or substituted with a hydroxy;
R 4 is
(1) hydrogen,
(2) (C 1-3 )alkyl, or
(3) CN;
each R 5 is
(1) halo,
(2) (C 1-3 )alkyl,
(3) halo(C 1-3 )alkyl,
(4) (C 3-6 )cycloalkyl,
(5) —C(O)NH 2 ,
(6) —C(O)O(C 1-3 )alkyl,
(7) (C 1-3 )alkoxy,
(8) halo(C 1-3 )alkoxy,
(9) hydroxy,
(10) phenyl,
(11) —NHC(O)CH 3 ,
(12) 5- or 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein the heteroaryl is unsubstituted or substituted by 1-2 (C 1-3 )alkyl, or hydroxy,
(13) CN,
(14) hydroxy(C 1-3 )alkyl, or
(15) (C 1-3 )alkyl-heterocyclyl, wherein the heterocyclyl contains 1 or 2 heteroatoms independently selected from N, O, or S, and wherein the heterocyclyl is a 5- to 7-membered ring;
each R 6 is
(1) hydrogen, or
(2) halo;
each R 7 is
(1) oxo, or
(2) (C 1-3 )alkyl;
X is CH or N;
Y is CH or N;
n is 1 or 2.

2. The compound of claim 1 , wherein R 3 is —(C 1-6 )alkyl-O—(C 1-3 )alkyl; a 5- to 7-membered heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O, and S, wherein the heterocyclyl is unsubstituted or substituted by 1-3 R 7 ; or —(C 1-6 )alkyl-heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O, and S, and wherein the heterocyclyl is a 5- to 7-membered ring, or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2 , wherein R 2 is

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 2 , wherein R 3 is

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 4 , wherein R 2 is

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 4 , wherein R 3 is

or a pharmaceutically acceptable salt thereof.

7. The compound of claim 6 , wherein R 2 is

or a pharmaceutically acceptable salt thereof.

8. The compound claim 1 , wherein R 2 is

or a pharmaceutically acceptable salt thereof.

9. A compound of claim 1 , selected from the group consisting of
(1) 3-(2-chlorophenyl)-1-(4-fluorophenyl)-N-(3-methyl-1,1-dioxidotetrahydrothiophen-3-yl)-1H-indole-6-carboxamide,
(2) 3-(2-Chlorophenyl)-N-(1,1-dioxidotetrahydrothiophen-3-yl)-1-(4-fluorophenyl)-1H-indole-6-carboxamide,
(3) 3-(2-chlorophenyl)-1-(4-fluorophenyl)-N-(1-methoxypropan-2-yl)-1H-indole-6-carboxamide,
(4) 3-(2-chlorophenyl)-1-(4-fluorophenyl)-N-(2-methyl-1-morpholinopropan-2-yl)-1H-indole-6-carboxamide,
(5) (S)-3-(2-chlorophenyl)-1-(4-fluorophenyl)-N-(2-hydroxy-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-1H-indole-6-carboxamide,
(6) (S)-3-(2-chlorophenyl)-1-(4-fluorophenyl)-N-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-1H-indole-6-carboxamide
(7) (R)-3-(2-chlorophenyl)-1-(4-fluorophenyl)-N-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-1H-indole-6-carboxamide,
(8) 3-(2-chlorophenyl)-1-(4-fluorophenyl)-2-methyl-N-(3-methyl-1,1-dioxidotetrahydrothiophen-3-yl)-1H-indole-6-carboxamide,
(9) 3-(2-chlorophenyl)-2-cyano-1-(4-fluorophenyl)-N-(3-methyl-1,1-dioxidotetrahydrothiophen-3-yl)-1H-indole-6-carboxamide,
(10) 3-(3-(difluoromethoxy)phenyl)-1-(5-fluoropyridin-2-yl)-N-(3-methyl-1,1-dioxidotetrahydrothiophen-3-yl)-1H-indole-6-carboxamide,
(11) 3-(3-cyclopropylphenyl)-N-(1,1-dioxidotetrahydrothiophen-3-yl)-1-(5-fluoropyridin-2-yl)-1H-indole-6-carboxamide,
(12) 3-(3-cyclopropylphenyl)-1-(5-fluoropyridin-2-yl)-N-(3-methyl-1,1-dioxidotetrahydrothiophen-3-yl)-1H-indole-6-carboxamide,
(13) 3-(3-(difluoromethoxy)phenyl)-N-(1,1-dioxidotetrahydrothiophen-3-yl)-1-(5-fluoropyridin-2-yl)-1H-indole-6-carboxamide,
(14) 3-(2-chlorophenyl)-1-(5-fluoropyridin-2-yl)-N-(3-methyl-1,1-dioxidotetrahydrothiophen-3-yl)-1H-indole-6-carboxamide,
(15) 3-(2-chlorophenyl)-1-(5-fluoropyrimidin-2-yl)-N-(3-methyl-1,1-dioxidotetrahydrothiophen-3-yl)-1H-indole-6-carboxamide,
(16) 3-(3-cyclopropylphenyl)-1-(5-fluoropyrimidin-2-yl)-N-(3-methyl-1,1-dioxidotetrahydrothiophen-3-yl)-1H-indole-6-carboxamide,
(17) 3-(3-cyclopropylphenyl)-N-(1,1-dioxidotetrahydrothiophen-3-yl)-1-(5-fluoropyrimidin-2-yl)-1H-indole-6-carboxamide,
(18) 3-(3-(difluoromethoxy)phenyl)-1-(5-fluoropyrimidin-2-yl)-N-(3-methyl-1,1-dioxidotetrahydrothiophen-3-yl)-1H-indole-6-carboxamide,
(19) 3-(3-(difluoromethoxy)phenyl)-N-(1,1-dioxidotetrahydrothiophen-3-yl)-1-(5-fluoropyrimidin-2-yl)-1H-indole-6-carboxamide,
(20) 3-(4,6-dimethylpyridin-2-yl)-N-(1,1-dioxidotetrahydrothiophen-3-yl)-1-(4-fluorophenyl)-1H-indole-6-carboxamide,
(21) 3-(4-chloropyridin-2-yl)-N-(1,1-dioxidotetrahydrothiophen-3-yl)-1-(4-fluorophenyl)-1H-indole-6-carboxamide,
(22) N-(1,1-dioxidotetrahydrothiophen-3-yl)-1-(4-fluorophenyl)-3-(pyridin-2-yl)-1H-indole-6-carboxamide,
(23) N-(1,1-dioxidotetrahydrothiophen-3-yl)-1-(4-fluorophenyl)-3-(4-methylpyridin-2-yl)-1H-indole-6-carboxamide,
(24) 1-(4-fluorophenyl)-N-(3-methyl-1,1-dioxidotetrahydrothiophen-3-yl)-3-(4-methylpyridin-2-yl)-1H-indole-6-carboxamide,
(25) 3-(5-(difluoromethoxy)pyridin-3-yl)-1-(4-fluorophenyl)-N-(3-methyl-1,1-dioxidotetrahydrothiophen-3-yl)-1H-indole-6-carboxamide,
(26) 3-(3-Cyclopropylphenyl)-N-(1,1-dioxidotetrahydrothiophen-3-yl)-1-(4-fluorophenyl)-1H-indole-6-carboxamide,
(27) 3-(3-(difluoromethoxy)phenyl)-N-(1,1-dioxidotetrahydrothiophen-3-yl)-1-(4-fluorophenyl)-1H-indole-6-carboxamide,
(28) 3-(3-(difluoromethoxy)phenyl)-1-(4-fluorophenyl)-2-methyl-N-(3-methyl-1,1-dioxidotetrahydrothiophen-3-yl)-1H-indole-6-carboxamide,
(29) N-(1,1-dioxidotetrahydrothiophen-3-yl)-1-(4-fluorophenyl)-3-(2-methoxyphenyl)

Assignees

• Merck Sharp & Dohme
• Shen Dong Ming
• Graham Thomas H
• Jiang Jinlong
• Ding Fa Xiang
• Tudge Clare

Inventors

• Shen Dong-Ming
• Graham Thomas H
• Jiang Jinlong
• Ding Fa-Xiang
• Tudge Clare

Classifications

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D409/14

  containing three or more hetero rings · CPC title

• C07D409/12 Primary

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

• C07D401/12

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

• C07D209/10

  with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring · CPC title