Aryl dihydropyridinones and piperidinone MGAT2 inhibitors

Patent metadata

Field	Value
Publication number	US-10369140-B2
Application number	US-201815867825-A
Country	US
Kind code	B2
Filing date	Jan 11, 2018
Priority date	Dec 2, 2011
Publication date	Aug 6, 2019
Grant date	Aug 6, 2019

Abstract

The present invention provides compounds of Formula (I):

or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein all of the variables are as defined herein. These compounds are monoacylglycerol acyltransferase type 2 (MGAT2) inhibitors which may be used as medicaments.

First claim

What is claimed is:

1. A compound of Formula (I):

or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:
designates a single or double bond;
x and y can be both a single bond; when x is a double bond, then y is a single bond and R 4 and R 16 are absent; when y is a double bond, then x is a single bond and R 5 and R 16 are absent;
R 1 is independently selected from the group consisting of: —CONH(C 4-18 alkyl), —CONHC 2-8 haloalkyl, —CONH(CH 2 ) 1-8 Ph, —CONHCH 2 COC 2-8 alkyl, —(CH 2 ) m —(C 3-10 carbocycle substituted with 0-2 R b and 0-2 R g ), —(CH 2 ) m -(5- to 6-membered heteroaryl comprising: carbon atoms and 1-4 heteroatoms selected from N, NR e , O and S; wherein said heteroaryl is substituted with 0-1 R b and 0-2 R g ), and a C 1-12 hydrocarbon chain substituted with 0-3 R a ; wherein said hydrocarbon chain may be straight or branched, saturated or unsaturated;
R 2 is independently selected from the group consisting of: C 1-4 alkyl, C 3-4 cycloalkyl, and C 1-4 haloalkyl;
R 3 is independently selected from the group consisting of: H, F, Cl, C 1-4 alkyl and CN;
R 4 and R 5 are independently selected from the group consisting of: H, F, Cl, and C 1-4 alkyl;
when x is a single bond, R 3 and R 4 may be combined with the carbon atom to which they are attached to form a 3- to 6-membered carbocycle;
R 6 is independently R c or —(CH 2 ) n —(X) t —(CH 2 ) m R c ;
X is independently selected from the group consisting of: O, S, NH, CONH, and NHCO;
when y is a single bond, R 5 and R 6 may be combined with the carbon atom to which they are attached to form a 3- to 6-membered carbocycle;
R 11 , R 12 , R 13 , R 14 and R 15 are independently selected from the group consisting of: H, halo, C 1-4 alkyl substituted with 0-2 R i , C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, —(CH 2 ) m —C 3-6 cycloalkyl, CN, NR f R j , OR j , SR j , NHCO 2 (C 1-4 alkyl), NHSO 2 (C 1-4 alkyl), and a 4- to 6-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NR e , O, and S;
alternatively, R 11 and R 12 , together with the carbon atoms to which they are attached, combine to form a 5- to 6-membered carbocyclic ring or a 5- to 6-membered heterocyclic ring comprising: carbon atoms and 1-3 heteroatoms selected from N, NR e , O, and S;
alternatively, R 12 and R 13 , together with the carbon atoms to which they are attached, combine to form a 5- to 6-membered carbocyclic ring or a 5- to 6-membered heterocyclic ring comprising: carbon atoms and 1-3 heteroatoms selected from N, NR e , O, and S;
R 16 is independently selected from the group consisting of: H and C 1-4 alkyl;
R a is, at each occurrence, independently selected from the group consisting of: halo, OH,

C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, N(C 1-4 alkyl) 2 , —(CH 2 ) n —(X) t —(CH 2 ) m R c , and —(CH 2 ) n —(CH 2 O) m —(CH 2 ) n R f ;
R b is, at each occurrence, independently selected from the group consisting of: halo, OH, C 1-10 alkyl, C 1-10 alkoxy, C 1-10 haloalkyl, C 1-10 haloalkoxy, C 1-10 alkylthio, C 1-10 haloalkylthio, N(C 1-4 alkyl) 2 , —CONH(CH 2 ) 4-20 H, —O(CH 2 ) s O(C 1-6 alkyl), R c , —(CH 2 ) n —(X) t —(CH 2 ) m R c , and —(CH 2 ) n —(CH 2 O) m —(CH 2 ) n R f ;
R c is, at each occurrence, independently selected from the group consisting of: C 3-6 cycloalkyl substituted with 0-2 R d , C 3-6 cycloalkenyl substituted with 0-2 R d , —(CH 2 ) m -(phenyl substituted with 0-3 R d ), and a 5- to 6-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NR e , O, and S; wherein said heterocycle is substituted with 0-2 R d ;
R d is, at each occurrence, independently selected from the group consisting of: halo, OH, CN, NO 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, tetrazolyl, OBn and phenyl substituted with 0-2 R h ;
R e is, at each occurrence, independently selected from the group consisting of: H, C 1-8 alkyl, C 1-8 haloalkyl, benzyl optionally substituted with C 1-4 alkoxy, CO(C 1-4 alkyl) and COBn;
R f is, at each occurrence, independently selected from the group consisting of: H and C 1-4 alkyl;
R g , R h and R i are, at each occurrence, independently selected from the group consisting of: halo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, and C 1-4 haloalkoxy;
R j is, at each occurrence, independently selected from the group consisting of: C 1-4 alkyl, C 3-4 cycloalkyl and phenyl;
n, at each occurrence, is independently 0 or 1;
m, at each occurrence, is independently 0, 1, 2, 3, or 4
s, at each occurrence, is independently 1, 2, or 3; and
t, at each occurrence, is independently 0 or 1.

2. A compound according to claim 1 , wherein:
R 1 is independently selected from the group consisting of: —CONHC 4-18 alkyl, —CONH(CH 2 ) 1-8 Ph, C 1-12 alkyl substituted with 0-2 R a , C 1-12 alkenyl substituted with 0-2 R a , C 1-12 alkynyl substituted with 0-2 R a , —(CH 2 ) m -(phenyl substituted with 0-1 R b and 0-2 R g ), —(CH 2 ) m —(C 3-6 cycloalkyl substituted with 0-1 R b ), and —(CH 2 ) m -(5- to 6-membered heteroaryl substituted with 0-1 R b and 0-2 R g ), wherein said heteroaryl is selected from: pyridyl, oxazolyl, thiazolyl and

3. A compound according to claim 2 , wherein:
R 11 and R 15 are independently selected from the group consisting of: H, C 1-4 alkyl and halo;
R 12 and R 14 are independently selected from the group consisting of: H, halo, C 1-4 alkyl and C 1-4 alkoxy; and
R 13 is independently selected from the group consisting of: H, halo, C 1-4 alkyl substituted with 0-1 R i , C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, —(CH 2 ) m —C 3-4 cycloalkyl, CN, NR f R j , SR j , NHCO 2 (C 1-4 alkyl), NHSO 2 (C 1-4 alkyl), and a 4- to 6-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NR e , O, and S.

4. A compound according to claim 3 , wherein the compound is of Formula (II):

or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

5. A compound according to claim 4 , wherein:
R 1 is independently selected from the group consisting of: C 1-6 alkyl, C 3-6 cycloalkyl, —CONHC 4-18 alkyl, —CONHC 2-8 haloalkyl, —CONH(CH 2 ) 1-8 Ph, —(CH 2 ) m -(phenyl substituted with 1 R b and 0-2 R g ), and a 5- to 6-membered heteroaryl substituted with 0-1 R b and 0-2 R g , wherein said heteroaryl is selected from: pyridyl, oxazolyl, thiazolyl and

R 2 is independently selected from the group consisting of: C 1-4 alkyl and C 1-4 haloalkyl;
R 3 is independently selected from the group consisting of: H and F;
R 4 is independently selected from the group consisting of: H and F;
R 6 is independently R c or —(CH 2 ) n —(X) t —(CH 2 ) m R c ;
R 11 and R 15 are independently selected from the group consisting of: H, C 1-4 alkyl and halo;
R 12 and R 14 are independently selected from the group consisting of: H, halo, C 1-4 alkyl and C 1-4 alkoxy;
R 13 is independently selected from the group consisting of: H, halo, C 1-4 alkyl substituted with 0-1 C 1-4 alkoxy, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, —(CH 2 ) m —C 3-4 cycloalkyl, CN, N(C 1-4 alkyl) 2 , NHCO 2 (C 1-4 alkyl), NHSO 2 (C 1-4 alkyl), pyrazolyl, and morpholinyl;
alternatively, R 12 and R 13 ,

Assignees

• Bristol Myers Squibb Co

Inventors

• Turdi Huji
• Hangeland Jon J
• Lawrence R Michael
• Ahmad Saleem
• Meng Wei
• Brigance Robert Paul
• Devasthale Pratik
• Zhao Guohua

Classifications

• A61P9/12

  Antihypertensives · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P5/50

  for increasing or potentiating the activity of insulin · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title