Indazole derivatives useful as inhibitors of diacylglyceride O-acyltransferase 2

Patent metadata

Field	Value
Publication number	US-11104690-B2
Application number	US-201716461902-A
Country	US
Kind code	B2
Filing date	Nov 13, 2017
Priority date	Nov 18, 2016
Publication date	Aug 31, 2021
Grant date	Aug 31, 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, 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-c′:

or a pharmaceutically acceptable salt thereof wherein:
R 1 is

R 2 is

R 3 is

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

or R 3 and R 4 combine along with the nitrogen atom to which they are attached to form a 4- to 7-membered mono- or 6- to 10-membered bicyclic heterocyclyl ring, containing 1 or 2 heteroatoms independently selected from N, O and S, wherein the heterocyclyl ring is unsubstituted or substituted by 1-3 R 6 ; and
R 6 is
(1) (C 1-3 )alkyl,
(2) halo(C 1-3 )alkyl-,
(3) oxo,
(4) (C 3-6 )cycloalkyl,
(5) —C(O)O—(C 1-4 )alkyl,
(6) NH 2 ,
(7) hydroxy,
(8) phenyl unsubstituted or substituted by halo,
(9) hydroxy(C 1-3 )alkyl-,
(10) cyano,
(11) halo, or
(12) —S(O) 2 —(C 1-3 )alkyl.

2. The compound of claim 1 wherein R 3 and R 4 combine along with the nitrogen atom to which they are attached to form

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein R 2 is

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , wherein R 3 is

or a pharmaceutically acceptable salt thereof.

5. 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-indazole-6-carboxamide,
(2) 3-(2-Chlorophenyl)-N-(1,1-dioxidotetrahydrothiophen-3-yl)-1-(4-fluorophenyl)-1H-indazole-6-carboxamide,
(3) 3-(2-chlorophenyl)-1-(4-fluorophenyl)-N-{1-[1-oxido-6-(trifluoromethyl)pyridin-3-yl]ethyl}-1H-indazole-6-carboxamide,
(4) 3-(2-chlorophenyl)-1-(4-fluorophenyl)-N-{1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}-1H-indazole-6-carboxamide,
(5) 3-(2-chlorophenyl)-1-(4-fluorophenyl)-N-{(1S)-2-hydroxy-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-1H-indazole-6-carboxamide,
(6) 3-(2-chlorophenyl)-1-(4-fluorophenyl)-N-(1-methyl-2-oxopyrrolidin-3-yl)-1H-indazole-6-carboxamide,
(7) tert-butyl 4-[1-({[3-(2-chlorophenyl)-1-(4-fluorophenyl)-1H-indazol-6-yl]carbonyl}amino)ethyl]-1H-imidazole-1-carboxylate,
(8) N-[(3R,4R)-4-amino-1,1-dioxidotetrahydrothiophen-3-yl]-3-(2-chlorophenyl)-1-(4-fluorophenyl)-1H-indazole-6-carboxamide,
(9) 3-(2-chlorophenyl)-1-(4-fluorophenyl)-N-[4-hydroxy-1,1-dioxidotetrahydrothiophen-3-yl]-1H-indazole-6-carboxamide,
(10) 3-(2-chlorophenyl)-1-(4-fluorophenyl)-N-[6-(trifluoromethyl)pyridin-3-yl]-1H-indazole-6-carboxamide,
(11) 3-(2-chlorophenyl)-1-(4-fluorophenyl)-N-{(1R)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-1H-indazole-6-carboxamide,
(12) 3-(2-chlorophenyl)-1-(4-fluorophenyl)-N-[(1S)-2-methoxy-1-methylethyl]-1H-indazole-6-carboxamide,
(13) 3-(2-chlorophenyl)-1-(4-fluorophenyl)-N-{(1S)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-1H-indazole-6-carboxamide,
(14) 3-(2-chlorophenyl)-1-(4-fluorophenyl)-N-[1-(1H-imidazol-4-yl)ethyl]-1H-indazole-6-carboxamide,
(15) N-tert-butyl-3-(2-chlorophenyl)-1-(4-fluorophenyl)-1H-indazole-6-carboxamide,
(16) 3-(2-chlorophenyl)-1-(4-fluorophenyl)-N-[1-methyl-1-(1-methyl-1H-pyrazol-4-yl)ethyl]-1H-indazole-6-carboxamide,
(17) 3-(2-chlorophenyl)-N-[1-(3,5-dimethyl-1H-pyrazol-4-yl)ethyl]-1-(4-fluorophenyl)-1H-indazole-6-carboxamide,
(18) 3-(2-chlorophenyl)-1-(4-fluorophenyl)-N-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-1H-indazole-6-carboxamide,
(19) tert-butyl N-{[3-(2-chlorophenyl)-1-(4-fluorophenyl)-1H-indazol-6-yl]carbonyl}-beta-alaninate,
(20) 3-(2-chlorophenyl)-1-(4-fluorophenyl)-N-(2-sulfamoylethyl)-1H-indazole-6-carboxamide,
(21) 3-(2-chlorophenyl)-1-(4-fluorophenyl)-N-oxetan-3-yl-1H-indazole-6-carboxamide,
(22) 3-(2-chlorophenyl)-1-(4-fluorophenyl)-N-(1-methyl-5-oxopyrrolidin-3-yl)-1H-indazole-6-carboxamide,
(23) 3-(2-chlorophenyl)-6-[(3,3-dioxido-3-thia-6-azabicyclo[3.2.1]oct-6-yl)carbonyl]-1-(4-fluorophenyl)-1H-indazole,
(24) 3-(2-chlorophenyl)-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1-(4-fluorophenyl)-1H-indazole-6-carboxamide,
(25) 3-(2-chlorophenyl)-N-[2-(dimethylsulfamoyl)ethyl]-1-(4-fluorophenyl)-1H-indazole-6-carboxamide,
(26) 3-(2-chlorophenyl)-N-[2-(ethylsulfonyl)ethyl]-1-(4-fluorophenyl)-1H-indazole-6-carboxamide,
(27) 3-(2-chlorophenyl)-1-(4-fluorophenyl)-N-methyl-N-[1-(5-phenyl-1H-pyrazol-3-yl)ethyl]-1H-indazole-6-carboxamide,
(28) 3-(2-chlorophenyl)-1-(4-fluorophenyl)-N-{1-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-1H-indazole-6-carboxamide,
(29) 3-(2-chlorophenyl)-N-[(1,1-dioxidotetrahydrothiophen-3-yl)methyl]-1-(4-fluorophenyl)-1H-indazole-6-carboxamide,
(30) 3-(2-chlorophenyl)-1-(4-fluorophenyl)-N-{(1R)-2-hydroxy-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-1H-indazole-6-carboxamide,
(31) 3-(2-chlorophenyl)-1-(4-fluorophenyl)-N-(pyridin-3-ylmethyl)-1H-indazole-6-carboxamide,
(32) 3-(2-chlorophenyl)-1-(4-fluorophenyl)-N-(pyridin-2-ylmethyl)-1H-indazole-6-carboxamide,
(33) 3-(2-chlorophenyl)-1-(4-fluorophenyl)-N-(pyridin-4-ylmethyl)-1H-indazole-6-carboxamide,
(34) 3-(2-chlorophenyl)-1-(4-fluorophenyl)-N-[(1S)-1-(2-methylpyrimidin-5-yl)ethyl]-1H-indazole-6-carboxamide,
(35) 3-(2-chlorophenyl)-1-(4-fluorophenyl)-N-(imidazo[1,2-a]pyrimidin-2-ylmethyl)-1H-indazole-6-carboxamide,
(36) 3-(2-chlorophenyl)-1-(4-fluorophenyl)-N-[1-(4-methyl-4H-1,2,4-triazol-3-yl)ethyl]-1H-indazole-6-carboxamide,
(37) 3-(2-chlorophenyl)-1-(4-fluorophenyl)-N-(isoxazol-4-ylmethyl)-1H-indazole-6-carboxamide,
(38) 3-(2-chlorophenyl)-1-(4-fluorophenyl)-N-(pyrimidin-5-ylmethyl)-1H-indazole-6-carboxamide,
(39) 3-(2-chlorophenyl)-1-(4-fluorophenyl)-N-[2-(4H-1,2,4-triazol-4-yl)ethyl]-1H-indazole-6-carboxamide,
(40) 3-(2-chlorophenyl)-1-(4-fluorophenyl)-N-(1,2,5-thiadiazol-3-ylmethyl)-1H-indazole-6-carboxamide,
(41) 3-(2-chlorophenyl)-1-(4-fluorophenyl)-N-[1-(5-methyl-1,2,4-oxadiazol-3-yl)ethyl]-1H-indazole-6-carboxamide,
(42) 3-(2-chlorophenyl)-1-(4-fluorophenyl)-N-(2-hydroxy-1,1-dimethylethyl)-1H-indazole-6-carboxamide,
(43) 3-(2-chlorophenyl)-1-(4-fluorophenyl)-N-[1-(hydroxymethyl)cyclopentyl]-1H-indazole-6-carboxamide,
(44) 3-(2-chlorophenyl)-1-(4-fluorophenyl)-N-[(1-hydroxycyclohexyl)methyl]-1H-indazole-6-carboxamide,
(45) 3-(2-chlorophenyl)-1-(4-fluorophenyl)-N-(2-methoxyethyl)-1H-indazole-6-carboxamide,
(46) 3-(2-chlorophenyl)-1-(4-fluorophenyl)-N-[2-hydroxy-1-(hydroxymethyl)-1-methylethyl]-1H-indazole-6-carboxamide,
(47) 3-(2-chlorophenyl)-1-(4-fluorophenyl)-N-[4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]-1H-indazole-6-carboxamide,
(48) 3-(2-chlorophenyl)-1-(4-fluorophenyl)-N-[(1R,2S)-2-hydroxy-1-(3-m

Assignees

• Merck Sharp & Dohme
• Shen Dong Ming
• Graham Thomas H
• Liu Wensheng
• Tudge Clare
• Verras Andreas
• Jiang Jinlong

Inventors

• Shen Dong-Ming
• Graham Thomas H
• Liu Wensheng
• Tudge Clare
• Verras Andreas
• Jiang Jinlong

Classifications

• C07D409/14

  containing three or more hetero rings · CPC title

• C07D417/12

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

• A61P43/00

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

• A61P3/06

  Antihyperlipidemics · CPC title

• A61K31/422

  not condensed and containing further heterocyclic rings · CPC title