Dihydropyridinone MGAT2 inhibitors

Patent metadata

Field	Value
Publication number	US-9822074-B2
Application number	US-201715618182-A
Country	US
Kind code	B2
Filing date	Jun 9, 2017
Priority date	May 29, 2013
Publication date	Nov 21, 2017
Grant date	Nov 21, 2017

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, a pharmaceutically acceptable salt, a polymorph, or a solvate thereof, wherein:
ring A is independently a 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 6 and 0-2 R 7 ;
R 1 is independently selected from: —(CH 2 ) m —(C 3-6 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: C 1-4 alkyl, C 3-4 cycloalkyl, and C 1-4 haloalkyl;
R 3 is independently selected from: H, F, C 1-4 alkyl and CN;
R 4 is independently selected from: H, F, and C 1-4 alkyl;
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 5 is independently selected from: C 1-4 alkyl, C 1-4 haloalkyl, N(C 1-4 alkyl) 2 , —(CH 2 ) m —C 3-6 carbocycle and —(CH 2 ) m -(4- to 6-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR e , O, and S);
R 6 is, at each occurrence, independently selected from: halogen, C 1-6 alkyl substituted with 0-2 R h , C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, —(CH 2 ) m —C 3-6 carbocycle, —(CH 2 ) m —NR f R i , CN, OR i , SR i , and a 4- to 6-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR e , O, and S;
R 7 is, at each occurrence, independently selected from: halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, and C 1-4 haloalkoxy;
alternatively, R 6 and R 7 , 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; wherein said heterocycle is substituted with 0-2 R g ;
R a is, at each occurrence, independently selected from: halogen, OH, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, N(C 1-4 alkyl) 2 , COOH, and —(CH 2 ) n —R c ;
R b is, at each occurrence, independently selected from: halogen, 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(C 4-20 alkyl), —CONH(C 4-20 haloalkyl), —O(CH 2 ) s O(C 1-6 alkyl), —O(CH 2 ) s O(C 1-6 haloalkyl), R c , and —(CH 2 ) n —(O) t —(CH 2 ) m R c ;
R c is, at each occurrence, independently selected from: 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: halogen, OH, CN, NO 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, tetrazolyl, OBn and phenyl;
R e is, at each occurrence, independently selected from: H, C 1-8 haloalkyl, —(CH 2 ) n —C 3-6 carbocycle, CO(C 1-4 alkyl), COBn, and a C 1-12 hydrocarbon chain substituted with 0-1 C 1-4 haloalkyl; wherein said hydrocarbon chain may be straight or branched, saturated or unsaturated;
R f is, at each occurrence, independently selected from: H and C 1-4 alkyl;
R g and R h are, at each occurrence, independently selected from: halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, and C 1-4 haloalkoxy;
R i is, at each occurrence, independently selected from: C 1-4 alkyl, C 3-4 cycloalkyl and phenyl;
n, at each occurrence, is independently 0, 1 or 2;
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:
ring A is independently selected from pyridyl, thienyl, thiazolyl, and pyrazolyl;

wherein each ring moiety is substituted with 0-1 R 6 and 0-2 R 7 ; and alternatively, R 6 and R 7 , together with the carbon atoms to which they are attached, combine to form a 6-membered carbocyclic ring.

3. A compound according to claim 2 , wherein:
ring A is independently selected from:

R 1 is independently selected from: —(CH 2 ) m —(C 3-6 carbocycle substituted with 1 R b and 0-2 R g ), —(CH 2 ) m -(thiazolyl substituted with 1 R b and 0-1 R g ), —(CH 2 ) m -(pyrazolyl substituted with 1 R b and 0-1 R g ), and a C 1-12 hydrocarbon chain substituted with 0-1 R a ; wherein said hydrocarbon chain may be straight or branched, saturated or unsaturated;
R 2 is independently selected from: C 1-4 alkyl and C 1-4 haloalkyl;
R 3 is independently selected from: H and F;
R 4 is independently selected from: H and F;
R 6 is, at each occurrence, independently selected from: halogen, C 1-6 alkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, N(C 1-4 alkyl) 2 , and —(CH 2 ) m —C 3-6 cycloalkyl;
R 7 is, at each occurrence, independently selected from: halogen, C 1-4 alkyl and C 1-4 alkoxy;
R a is, at each occurrence, independently selected from: halogen, OH, C 1-4 alkoxy, C 1-4 haloalkyl, and C 1-4 haloalkoxy;
R b is, at each occurrence, independently selected from: halogen, OH, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 haloalkyl, C 1-10 haloalkoxy, and benzoxy;
R c is, at each occurrence, independently selected from: —(CH 2 ) n —C 3-6 carbocycle and a C 1-12 hydrocarbon chain substituted with 0-1 C 1-4 haloalkyl; wherein said hydrocarbon chain may be straight or branched, saturated or unsaturated; and
R g is, at each occurrence, independently selected from: halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, and C 1-4 haloalkoxy.

4. A compound according to claim 3 , wherein:
ring A is independently selected from:

and

and
R 1 is independently selected from: —(CH 2 ) m -(phenyl substituted with 1 R b and 0-2 R g ) and a C 1-12 hydrocarbon chain substituted with 0-1 R a ; wherein said hydrocarbon chain may be straight or branched, saturated or unsaturated;
R 2 is independently selected from: C 1-4 alkyl and C 1-4 haloalkyl;
R 3 is independently selected from: H and F;
R 4 is independently selected from: H and F;
R 6 is independently selected from: halogen, C 1-6 alkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, N(C 1-4 alkyl) 2 , and —(CH 2 ) 0-1 —C 3-6 cycloalkyl;
R 7 is independently selected from: halogen, C 1-4 alkyl and C 1-4 alkoxy;
R a is, at each occurrence, independently selected from: halo, OH, C 1-4 alkoxy, C 1-4 haloalkyl, and C 1-4 haloalkoxy;
R b is, at each occurrence, independently selected from: halo, OH, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 haloalkyl, C 1-10 haloalkoxy, and benzoxy; and
R g is, at each occurrence, independently selected from: halo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, and C 1-4 haloalkoxy.

5. A compound according to claim 1 , wherein the compound is of Formula (II):

Assignees

• Bristol Myers Squibb Co

Inventors

• Ahmad Saleem
• Negash Lidet A

Classifications

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · 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