Diacylglyceride O-acyltransferase 2 inhibitors

Patent metadata

Field	Value
Publication number	US-12448384-B2
Application number	US-202318465497-A
Country	US
Kind code	B2
Filing date	Sep 12, 2023
Priority date	May 18, 2020
Publication date	Oct 21, 2025
Grant date	Oct 21, 2025

Abstract

Invented are compounds of formula I

and the pharmaceutically acceptable salts, esters, and prodrugs thereof, which are DGAT2 inhibitors. Also provided are methods of making compounds of Formula I, pharmaceutical compositions comprising compounds of Formula I, and methods of using these compounds to treat hepatic steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, type-2 diabetes mellitus, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardiorenal diseases such as chronic kidney diseases and heart failure and related diseases and conditions, comprising administering a compound of Formula I to a patient in need thereof.

First claim

What is claimed is:

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof wherein:
W is selected from N or C(H);
X is N
Y and Z are independently selected from N or C(R 5 ); and
R 1 is
(1) phenyl unsubstituted or substituted with 1, 2, or 3 R 6 , or
(2) 5- or 6-membered heteroaryl containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, and S, wherein the heteroaryl is unsubstituted or substituted with 1, 2, or 3 R 6 , or
(3) 8- to 10-membered fused heteroaryl containing 1, 2, 3 heteroatoms independently selected from N, O, and S, wherein the heteroaryl is unsubstituted or substituted with 1, 2, or 3 R 6 ;

R 2 is
(1) phenyl optionally mono-substituted or disubstituted with halogen,
(2) 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O, and S, wherein the heteroaryl is optionally mono-substituted or disubstituted with halogen, C 1-6 haloalkyl, C 1-6 alkyl, C(O)C 1-6 alkyl, C(O)(OH), or OH,
(3) C 1-6 alkyl unsubstituted or optionally mono-substituted, disubstituted or trisubstituted with halogen, OH, CF 3 , —CN, or (C 3-6 )cycloalkyl,
(4) (C 3-6 )cycloalkyl unsubstituted or optionally mono-substituted, disubstituted or trisubstituted with C 1-6 alkyl, halogen, OH, CF 3 , or —CN,
(5) 4- to 6-membered heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S wherein the heterocyclyl is unsubstituted or substituted by 1, 2, or 3 R 7 ,
(6) —CH 2 -aryl optionally mono-substituted or disubstituted with halogen,
(7) —CH 2 -tetrahydropyran, or
(8) —C 1-6 alkylC(O)NH 2 ;

R 3 is
(1) 4- to 7-membered heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S,
(2) —(C 1-6 )alkyl-heterocyclyl, wherein the heterocyclyl is a 3- to 6-membered ring containing 1 or 2 heteroatoms independently selected from N, O and S,
(3) —(C 1-6 )alkyl,
(4) —(C 3-6 )cycloalkyl,
(5) —(C 3-6 )cycloalkyl-heterocyclyl wherein the heterocyclyl is a 3- to 6-membered ring containing 1 or 2 heteroatoms independently selected from N, O and S,
(6) —(C 1-6 )hydroxyalkyl,
(7) —(C 1-6 )cyanoalkyl,
(8) —(C 1-6 )alkyl-S(O) 2 —(C 1-3 )alkyl,
(9) —(C 1-6 )alkyl-(C 3-6 )cycloalkyl, or
(10) —C( 1-6 )alkyl-N(R 11 ) 2 ,

wherein each cycloalkyl or heterocyclyl is unsubstituted or substituted with 1, 2, 3 or 4 R 9 , and
wherein each alkyl is unsubstituted or substituted with 1, 2, or 3 R 10 ;
R 4 is
(1) hydrogen, or
(2) (C 1-3 )alkyl,

or R 3 and R 4 , together with the nitrogen atom to which they are attached, combine to form a mono- or bicyclic heterocyclyl ring containing 1 N and optionally containing 1 additional heteroatom independently selected from N, O and S, wherein the heterocyclyl ring is unsubstituted or substituted by 1, 2, or 3 R 11 ;
when present, each R 5 is selected from
(1) hydrogen,
(2) (C 1-3 )alkyl,
(3) cyano, or
(4) halogen,

when present, each R 6 is independently selected from
(1) cyano,
(2) halogen,
(3) (C 1-6 )alkyl or OC 1-6 alkyl wherein the alkyl moiety is optionally substituted with cyano,
(4) (C 3-6 )cycloalkyl, optionally substituted with halogen, C 1-6 alkyl, C 1-6 haloalkyl, cyano, OH or OC 1-6 alkyl,
(5) —C(O)NH 2 ,
(6) O(C 3-6 )cycloalkyl wherein the cycloalkyl is optionally substituted with halogen, C 1-6 alkyl, C 1-6 haloalkyl, cyano, OH, or OC 1-6 alkyl,
(7) hydroxy,
(8) —N(R 11 ) 2 ,
(9) (C 1-6 )haloalkyl-,
(10) OC 1-6 haloalkyl,
(11) —SO 2 (C 1-6 )alkyl, or
(12) —SONH(C 1-6 )alkyl;

when present, each R 7 is independently selected from
(1) (C 1-6 )alkyl,
(2) halo,
(3) (C 1-6 )alkoxy-,
(4) (C 1-6 )haloalkyl-,
(5) (C 3-6 )cycloalkyl,
(6) hydroxy, or
(7) C(O)C 1-6 alkyl;

when present, each R 9 is independently selected from
(1) (C 1-6 )alkyl,
(2) (C 1-3 )haloalkyl-,
(3) oxo,
(4) (C 3-6 )cycloalkyl,
(5) —N(R 11 ) 2
(6) hydroxy,
(7) C 1-6 alkyl(OH),
(8) cyano,
(9) halo, or
(10) morpholinyl;

when present, R 10 is
(1) (C 1-3 )alkyl,
(2) (C 1-3 ) hydroxy alkyl-,
(3) (C 1-3 )alkoxy-,
(4) hydroxy,
(5) halogen,
(6) (C 1-3 )haloalkyl-,
(7) N(R 11 ) 2 , or
(8) C(O)NH 2 ; and

when present, R 11 is independently
(1) hydrogen,
(2) (C 1-3 )alkyl, or
(3) C(O)C 1-6 alkyl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is:
(a) phenyl unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, N(C 1-3 alkyl) 2 , CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, OC 1-6 alkyl, OC 1-6 haloalkyl, OC 3-6 cycloalkyl, S(O) 2 C 1-6 alkyl, OC 1-6 alkyl-CN, C 1-6 alkyl-CN, or NHC(O)C 1-6 alkyl, and wherein the cycloalkyl is optionally substituted with C 1-6 alkyl, C 1-6 haloalkyl, CN, OH, or OC 1-6 alkyl; or
(b) 5- or 6-membered heteroaryl containing 1 or 2 N atoms, wherein the heteroaryl is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, OC 1-6 alkyl, OC 1-6 haloalkyl, O—C 3-6 cycloalkyl, OC 1-6 alkyl-CN, or CN, and when the cycloalkyl is cyclopropyl, the cyclopropyl is optionally substituted with halogen, C 1-6 alkyl, C 1-6 haloalkyl, CN, OH, or OC 1-6 alkyl.

3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 1 is:
(a) phenyl optionally substituted with one to three substituents independently selected from halogen, hydroxy, N(C 1-3 alkyl) 2 , CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, OC 1-6 alkyl, OC 1-6 haloalkyl, OC 3-6 cycloalkyl, S(O) 2 C 1-6 alkyl, OC 1-6 alkyl-CN, C 1-6 alkyl-CN, or NHC(O)C 1-6 alkyl, and wherein the cycloalkyl is optionally substituted with C 1-6 alkyl, C 1-6 haloalkyl, CN, OH, or OC 1-6 alkyl;
(b) 6 membered heteroaryl containing one nitrogen atom optionally substituted with one to three substituents independently selected from halogen C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, OC 1-6 alkyl, OC 1-6 haloalkyl, O—C 3-6 cycloalkyl, OC 1-6 alkyl-CN or CN, and when the cycloalkyl is cyclopropyl, the cyclopropyl is optionally substituted with halogen, C 1-6 alkyl, C 1-6 haloalkyl, CN, OH, or OC 1-6 alkyl; or
(c) 5 membered heteroaryl containing 2 N atoms optionally substituted with C 1-6 alkyl.

4. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl optionally substituted with one to three substituents independently selected from halogen, OH, CN, CH 3 , CHF 2 , CF 3 , OC 1-6 alkyl, OC 1-6 alkylF 2 , cyclopropyl, O-cyclopropyl, O-cyclobutyl, C(F) 2 CH 3 , S(O) 2 CH 3 , OCH 2 CN, NHC(O)CH 3 , and wherein the cyclopropyl is optionally substituted with CH 3 , CF 3 , CN, OH, or OCH 3 .

5. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 1 is a 6 membered heteroaryl containing one nitrogen atom optionally substituted with one to three substituents independently selected from halogen, CN, CH 3 , cyclopropyl, OCHF 2 , OCF 3 , OCH 2 CH 3 , OCH 2 CHF 2 , OCH 2 CF 3 , O-cyclobutyl, O-cyclopropyl, or wherein the O-cyclopropyl is optionally substituted with halogen, CH 3 , CF 3 , CN, OH, or OCH 3 .

6. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 1 is a 5 membered heteroaryl containing 2 N atoms optionally substituted with CH 3 .

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is:
(a) 5- or 6-membered heteroaryl containing zero or one oxygen atoms and/or zero, one or two nitrogen atoms optionally mono-substituted or disubstituted with halogen, C 1-6 haloalkyl, C 1-6 alkyl, C(O)C 1-6 alkyl, or OH,
(b) C 1-6 alkyl unsubstituted or option

Assignees

• Merck Sharp & Dohme Llc

Inventors

• Lim Yeon-Hee
• Bao Jianming
• Ding Fa-Xiang
• Hugelshofer Cedric Lorenz
• Mak Victor W
• Roane James Patrick
• Sanzone Jillian R
• Shockley Samantha E
• Yen Rose

Classifications

• C07D409/12

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

• C07D231/56

  Benzopyrazoles; Hydrogenated benzopyrazoles · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D409/14

  containing three or more hetero rings · CPC title

• C07D209/10

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