IP Library › Granted Patent US 10,568,876

Granted Patent B2

US 10,568,876 · App. 15/508,550 · Granted Feb 25, 2020

Tetrahydroisoquinoline derivatives useful as inhibitors of diacylglyceride O-acyltransferase 2

Inventors: Jason Imbriglio (Piscataway, NJ); Rui Liang (East Brunswick, NJ); Clare London (Chatham, NJ); Kenneth Marby (San Diego, CA); James Tata (Westfield, NJ); Ming You (Monroe, NJ); Yusheng Xiong (Plainsboro, NJ)

Assignee: Merck Sharp & Dohme Corp.

A61K31/47 A61K31/16 C07C13/04 C07D217/06

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Quick Facts

Patent No.: US 10,568,876
App. No.: 15/508,550
Granted: Feb 25, 2020
Kind: B2

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USPTO Patent Center↗ Full Patent PDF↗

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.

Claims (406)

1. A compound having structural Formula I:

or a pharmaceutically acceptable salt thereof wherein:

X is

(1) —CO—

(2) —CONH—*,

(3) —CH 2 —,

(4) —S(O) 2 —,

(5) —CH 2 CO—*, or

(6) bond,

wherein * indicates the position of attachment to R 1 ;

R 1 is

(1) (C 1-9 )alkyl unsubstituted or substituted by hydroxy,

(2) halo(C 1-8 )alkyl unsubstituted or substituted by hydroxyl

(3) —(C 1-6 )alkyl-O—(C 1-3 )alkyl,

(4) —(C 1-6 )alkyl-COOR 6 ,

(5) —(C 1-6 )alkyl-aryl,

(6) —N(R 6 )(R 7 ),

(7) phenyl optionally substituted with 1-3R 8 , or

(8)(C 3-6 )cycloalkyl optionally substituted with 1-3R 8 ,

R 2 is

R 3 is

hydrogen,

alternatively R 2 and R 3 along with the carbon atom to which they are attached form a (C 3-7 )cycloalkyl;

R 4 is

(1) (C 1-6 )alkyl,

(2) halo(C 1-6 )alkyl,

(3) (C 1-6 )alkoxy,

(4) halo(C 1-6 )alkoxy,

(5) cyano,

(6) —CO 2 (C 1-6 )alkyl,

(7) hydroxy(C 1-6 )alkyl,

(8) —(C 1-3 )alkyl-aryl,

(9) phenyl,

(10) —N(H)—CO—(C 1-3 )alkyl,

(11) —N(H)—S(O) 2 —(C 1-3 )alkyl, or

(12) —C(O)N(H)R 7 ;

each R 6 is

(1) hydrogen, or

(2) (C 1-3 )alkyl;

each R 7 is

(1) hydrogen,

(2) (C 1-6 )alkyl,

(3) (C 3-6 )cycloalkyl, optionally substituted with 1-3 R 8 , or

(4) (C 1-3 )alkyl-aryl, optionally substituted with 1-3 R 8 ,

wherein each R 8 is

(1) (C 1-6 )alkyl,

(2) CF 3 ,

(3) halo,

(4) oxo,

(5) (C 1-3 )alkoxy,

(7) (C 3-6 )cycloalkyl,

(8) COOR 6 , or

(9) CN; and

n is 1.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein X is —CONH—*, wherein * indicates the position of attachment to R 1 .

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R 3 is hydrogen.

4. The compound of claim 1 which is:

N-(tert-butyl)-8-(((trans)-2-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopropane-

carboxamide)methyl)-5-(3-(trifluoromethoxy)phenyl)-3,4-dihydroisoquinoline-2(1H)-

carboxamide,

N-(tert-butyl)-8-(((1R,2S)-2-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopropane-

carboxamido)methyl)-5-(3-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-

carboxamide,

methyl 3-(2-(tert-butylcarbamoyl)-8-((2-(3-methyl-1,2,4-oxadiazol-5-

yl)cyclopropanecarboxamido)methyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)benzoate,

N-(tert-butyl)-5-(3-methoxyphenyl)-8-(((1S,2S)-2-(3-methyl-1,2,4-oxadiazol-5-

yl)cyclopropanecarboxamido)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide,

N-(tert-butyl)-8-(((1R,2R)-2-(3-methyl-1,2,4-oxadiazol-5-

yl)cyclopropanecarboxamido)methyl)-5-(3-(trifluoromethoxy)phenyl)-3,4-

dihydroisoquinoline-2(1H)-carboxamide,

methyl 3-(2-(tert-butylcarbamoyl)-8-((2-(3-methyl-1,2,4-oxadiazol-5-

yl)cyclopropanecarboxamido)methyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)benzoate,

5-(3-methoxyphenyl)-8-(((1S,2S)-2-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopropane-

carboxamido)methyl)-N-propyl-3,4-dihydroisoquinoline-2(1H)-carboxamide,

8-(((1S,2S)-2-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopropanecarboxamido)methyl)-N-

propyl-5-(3-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide,

N-((2-(2-(tert-butylamino)-2-oxoethyl)-5-(3-(trifluoromethoxy)phenyl)-1,2,3,4-

tetrahydroisoquinolin-8-yl)methyl)-2-(3-methyl-1,2,4-oxadiazol-5-

yl)cyclopropanecarboxamide,

N-((2-(2-(diethylamino)-2-oxoethyl)-5-(3-(trifluoromethoxy)phenyl)-1,2,3,4-

tetrahydroisoquinolin-8-yl)methyl)-2-(3-methyl-1,2,4-oxadiazol-5-

yl)cyclopropanecarboxamide,

N-((2-(2-(cyclopropylamino)-2-oxoethyl)-5-(3-(trifluoromethoxy)phenyl)-1,2,3,4-

tetrahydroisoquinolin-8-yl)methyl)-2-(3-methyl-1,2,4-oxadiazol-5-

yl)cyclopropanecarboxamide,

N-((2-(2-amino-2-oxoethyl)-5-(3-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-

8-yl)methyl)-2-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopropanecarboxamide,

N-((2-(2-((2,4-dimethoxybenzyl)amino)-2-oxoethyl)-5-(3-(trifluoromethoxy)phenyl)-

1,2,3,4-tetrahydroisoquinolin-8-yl)methyl)-2-(3-methyl-1,2,4-oxadiazol-5-

yl)cyclopropanecarboxamide,

N-((2-(2-(((1R,2S)-2-(methoxymethyl)cyclopentyl)amino)-2-oxoethyl)-5-(3-

(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)methyl)-2-(3-methyl-1,2,4-

oxadiazol-5-yl)cyclopropanecarboxamide,

N-((2-(2-(cyclobutylamino)-2-oxoethyl)-5-(3-(trifluoromethoxy)phenyl)-1,2,3,4-

tetrahydroisoquinolin-8-yl)methyl)-2-(3-methyl-1,2,4-oxadiazol-5-

yl)cyclopropanecarboxamide,

2-(3-methyl-1,2,4-oxadiazol-5-yl)-N-((2-(2-oxo-2-(((R)-1-phenylethyl)amino)ethyl)-5-(3-

(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-8-

yl)methyl)cyclopropanecarboxamide,

115

(1S,2S)-N-((2-(2-hydroxy-2-methylpropanoyl)-5-(3-methoxyphenyl)-1,2,3,4-

tetrahydroisoquinolin-8-yl)methyl)-2-(3-methyl-1,2,4-oxadiazol-5-

yl)cyclopropanecarboxamide,

116

(1S,2S)-N-((2-(2-hydroxy-2-methylpropanoyl)-5-(3-(trifluoromethyl)phenyl)-1,2,3,4-

tetrahydroisoquinolin-8-yl)methyl)-2-(3-methyl-1,2,4-oxadiazol-5-

yl)cyclopropanecarboxamide,

120

(1S,2S)-N-((2-(2-hydroxy-2-methylpropanoyl)-5-(3-(trifluoromethyl)phenyl)-1,2,3,4-

tetrahydroisoquinolin-8-yl)methyl)-2-(3-methyl-1,2,4-oxadiazol-5-

yl)cyclopropanecarboxamide,

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 which is:

N-(tert-butyl)-8-(((1R,2R)-2-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopropane-1-

carboxamido)methyl)-5-(3-(trifluoromethoxy)phenyl)-3,4-dihydroisoquinoline-2(1H)-

carboxamide,

N-(tert-butyl)-8-(((1S,2S)-2-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopropane-1-

carboxamido)methyl)-5-(3-(trifluoromethoxy)phenyl)-3,4-dihydroisoquinoline-2(1H)-

carboxamide,N-(isoxazol-3-yl)-8-(((1R,2R)-2-(3-methyl-1,2,4-oxadiazol-5-

yl)cyclopropane-carboxamido)methyl)-5-(3-(trifluoromethoxy)phenyl)-3,4-

dihydroisoquinoline-2(1H)-carboxamide,

N-(tert-butyl)-8-(((1R,2S)-2-(pyridin-3-yl)cyclopropanecarboxamido)methyl)-5-(3-

(trifluoro-methoxy)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide,

methyl 3-(2-(tert-butylcarbamoyl)-8-(((1R,2S)-2-(3-methyl-1,2,4-oxadiazol-5-

yl)cyclopropanecarboxamido)methyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)benzoate,

methyl 3-(2-(tert-butylcarbamoyl)-8-(((1S,2R)-2-(3-methyl-1,2,4-oxadiazol-5-

yl)cyclopropanecarboxamido)methyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)benzoate,

methyl 3-(2-(tert-butylcarbamoyl)-8-(((1R,2R)-2-(3-methyl-1,2,4-oxadiazol-5-

yl)cyclopropanecarboxamido)methyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)benzoate,

methyl 3-(2-(tert-butylcarbamoyl)-8-(((1S,2S)-2-(3-methyl-1,2,4-oxadiazol-5-

yl)cyclopropanecarboxamido)methyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)benzoate,

N-(tert-butyl)-5-(3-methoxyphenyl)-8-(((1R,2R)-2-(3-methyl-1,2,4-oxadiazol-5-

yl)cyclopropanecarboxamido)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide,

N-(tert-butyl)-5-(3-methoxyphenyl)-8-(((1S,2R)-2-(3-methyl-1,2,4-oxadiazol-5-

yl)cyclopropanecarboxamido)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide,

N-(tert-butyl)-8-(((1S,2S)-2-(3-methyl-1,2,4-oxadiazol-5-