Dihydropyridinone MGAT2 inhibitors

Patent metadata

Field	Value
Publication number	US-9365558-B2
Application number	US-201414288422-A
Country	US
Kind code	B2
Filing date	May 28, 2014
Priority date	May 29, 2013
Publication date	Jun 14, 2016
Grant date	Jun 14, 2016

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 thereof, wherein:
ring A is independently phenyl; wherein said phenyl 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 ), 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;
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 ;
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;
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 );
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 phenyl, 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:

R 1 is independently selected from: —(CH 2 ) m —(C 3-6 carbocycle 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, 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 e 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:

 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):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof; wherein:
ring A:

R 1 is independently selected from:

 C 3-6 cycloalkyl 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 2 is independently selected from: CF 3 and CH 3 ;
R 5 is independently selected from: C 1-4 alkyl, C 1-4 haloalkyl, N(C 1-4 alkyl) 2 , C 3-6 cycloalkyl and Ph;
R 6 is, at each occurrence, independently selected from: halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, N(C 1-4 alkyl) 2 , and —(CH 2 ) 0-1 —C 3-4 cycloalkyl;
R b is independently selected from: C 1-8 alkyl, —O(CH 2 ) 1-6 CF 3 , and —O(CH 2 ) 1-4 CF 2 CF 3 ;
R e is, at each occurrence, independently selected from: —(CH 2 ) n —C 3-6 cycloalkyl 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 g is independently halogen; and

Assignees

• Bristol Myers Squibb Co

Inventors

• Ahmad Saleem
• Negash Lidet A

Classifications

• A61P43/00

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

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title