Dihydropyridinone MGAT2 inhibitors

Patent metadata

Field	Value
Publication number	US-9856244-B2
Application number	US-201715617079-A
Country	US
Kind code	B2
Filing date	Jun 8, 2017
Priority date	Mar 7, 2014
Publication date	Jan 2, 2018
Grant date	Jan 2, 2018

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, a solvate or a hydrate thereof, wherein:
ring A is independently selected from:

R 1 is independently selected from: (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, 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

R 6 is 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, CO(C 1-4 alkyl), —(CH 2 ) m —C 3-6 cycloalkyl, —(CH 2 ) m —NR f R i , CN, OR i , and SR i
R 7 is independently selected from: halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, and C 1-4 haloalkoxy;
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 , and —(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 alkyl, C 1-8 haloalkyl, —(CH 2 ) n —C 3-6 carbocycle, CO(C 1-4 alkyl) and COBn;
R f is, at each occurrence, independently selected from: H and C 1-4 alkyl;
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;
R h is, at each occurrence, independently selected from: OH, 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 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 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 1-4 alkyl substituted with 0-1 N(C 1-4 alkyl) 2 , C 1-4 alkoxy, and 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: 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, and C 1-10 haloalkoxy;
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;
m, at each occurrence, is independently 0, 1, 2 or 3; and
s, at each occurrence, is independently 1, 2, or 3.

3. A compound of Formula (IIa) or (IIb):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, a solvate or a hydrate thereof, within the scope of any of the above aspects, wherein:
R 1 is independently selected from:

and (a C 1-12 hydrocarbon chain; 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 tetrazolyl;
R 6 is independently selected from: halogen, C 1-4 alkyl substituted with 0-1 N(C 1-4 alkyl) 2 , C 1-4 alkoxy, and C 3-6 cycloalkyl;
R b is independently selected from: —O(CH 2 ) 1-6 CF 3 , and —O(CH 2 ) 1-4 CF 2 CF 3 ;
R e is independently selected from: —(CH 2 ) 1-6 CF 3 , and —(CH 2 ) 0-1 (C 3-6 cycloalkyl); and
R g is independently selected from: halogen and C 1-4 alkoxy.

4. A compound according to claim 3 , wherein:
R 1 is

5. A compound according to claim 1 , wherein the compound is selected from:

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, a solvate or a hydrate thereof.

6. A compound according to claim 1 , wherein the compound is selected from:

Assignees

• Bristol Myers Squibb Co

Inventors

• Meng Wei
• Zhao Guohua

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P3/06

  Antihyperlipidemics · 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

• A61P43/00

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

• A61P9/12

  Antihypertensives · CPC title