Substituted pyridinones as MGAT2 inhibitors

Patent metadata

Field	Value
Publication number	US-9974778-B2
Application number	US-201515316853-A
Country	US
Kind code	B2
Filing date	Jun 10, 2015
Priority date	Jun 11, 2014
Publication date	May 22, 2018
Grant date	May 22, 2018

Abstract

The present invention provides compounds of Formula (I): or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, or a solvate 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:
ring A is independently a 5- to 10-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 0-3 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 ),
R 2 is independently selected from: H, halogen, C 3-4 cycloalkyl, phenyl substituted with 0-2 R h , and C 1-12 hydrocarbon chain substituted with 0-3 R a ; wherein said hydrocarbon chain may be straight or branched, saturated or unsaturated;
R 3 is independently selected from: CO 2 H, —(CH 2 ) n —X—(CH 2 ) m R 4 , —CONHSO 2 R i , —NHCOX 1 SO 2 R i , 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 ;
X is independently selected from: CONH and NHCO;
X 1 is independently C 1-4 hydrocarbon chain optionally substituted with C 1-4 alkyl or C 3-4 cycloalkyl;
R 4 is 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 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, —(CH 2 ) m —C 3-6 cycloalkyl, —(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 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 , and —(CH 2 )N—(X) t —R c ;
R b is, at each occurrence, independently selected from: halogen, OH, C 1-10 alkyl, C 2-8 alkenyl, 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), —(CH═CH)(C 3-6 cycloalkyl), 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 4-8 cycloalkenyl substituted with 0-2 R d , 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: ═O, 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 independently selected from: halogen, OH, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, and C 1-4 haloalkoxy;
R h is independently selected from: halogen, C 1-4 alkoxy, C 1-4 haloalkoxy, and C 1-12 hydrocarbon chain substituted with 0-3 R a ; wherein said hydrocarbon chain may be straight or branched, saturated or unsaturated;
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 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;
provided that:
when R 1 is phenyl, 4-halo-Ph, or 3,4-diCl-Ph, then R 3 is other than CO 2 H.

2. A compound according to claim 1 , or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:
R 1 is independently selected from: —(CH 2 ) m —(C 3-6 carbocycle substituted with 1 R b and 0-2 R g ).

3. A compound according to claim 2 , or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:
ring A is independently a heteroaryl substituted with 0-1 R 6 ; wherein said heteroaryl is selected from: furanyl, thienyl, 1-R e -pyrrolyl, thiazolyl, 1-R e -pyrazolyl, and benzothienyl;
R 1 is independently selected from: C 3-6 cycloalkyl substituted 0-1 R g , C 5-6 cycloalkenyl substituted 0-1 R g , phenyl substituted with 1 R b and 0-1 R g ;
R 2 is independently selected from: H, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 1-4 alkoxy, and phenyl substituted with 0-1 C 1-6 alkyl;
R 3 is independently selected from: tetrazolyl,

tetrazolone, —NHCO(tetrazolyl), —CONH(pyridyl), —CONH(C 3-6 cycloalkyl), —CONH(phenyl substituted with 0-1 R d ), —CONHSO 2 (C 1-4 alkyl), —CONHSO 2 (C 3-6 cycloalkyl), —CONHSO 2 (isoxazolyl substituted with 0-1 C 1-4 alkyl), and —CONHSO 2 N(C 1-4 alkyl) 2 ;
R 6 is independently selected from: C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, N(C 1-4 alkyl) 2 , and —(CH 2 ) 1-4 (C 3-6 cycloalkyl);
R 7 is independently selected from: halogen and C 1-4 alkyl;
R b is independently selected from: C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, C 1-8 haloalkyl, C 1-8 haloalkoxy, —CONH(CH 2 ) 6-20 H, C 3-6 cycloalkyl substituted with 0-2 C 1-4 alkyl, C 4-8 cycloalkenyl substituted with 0-2 C 1-4 alkyl, —(O) t —(CH 2 ) m (C 3-6 cycloalkyl), —(CH═CH)(C 3-6 cycloalkyl), Ph, Bn, phenoxy, benzoxy, pyrimidinyl, pyrazinyl and —O-pyrimidinyl;
R d 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 e is independently selected from: H, C 1-6 alkyl, C 1-8 haloalkyl, and —(CH 2 ) n —(C 3-6 cycloalkyl); and
R g is independently selected from: halogen, OH, C 1-4 alkyl and C 1-4 alkoxy.

4. A compound according to claim 3 , or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:
ring A is independently selected from:

R 1 is independently selected from: C 3-6 cycloalkyl, C 5-6 cycloalkenyl, 1-halo-C 3-6 cycloalkyl, 1-OH—C 3-6 cycloalkyl, 4-R b -Ph;
R 2 is independently selected from: H, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 1-4 alkoxy, and phenyl substituted with 0-1 C 1-6 alkyl;
R 3 is independently selected from: tetrazolyl,

tetrazolone, —NHCO(tetrazolyl), —CONH(C 3-6 cycloalkyl), —CONHPh, —CONH(4-C 1-4 alkoxy-Ph), —CONH(4-C 1-4 haloalkoxy-Ph), —CONH(pyrid-3-yl), —CONHSO 2 (C 1-4 alkyl), —CONHSO 2 (C 3-6 cycloalkyl), —CONHSO 2 (isoxazolyl substituted with 0-1 C 1-4 alkyl), and —CONHSO 2 N(C 1-4 alkyl) 2 ;
R 6 is independently selected from: C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, N(C 1-4 alkyl) 2 , and —(CH 2 ) 1-4 (C 3-6 cycloalkyl);
R 7 is independently selected from: halogen and C 1-4 alkyl; and
R b is independently selected from: C 2-6 alkyl, C 2-6 alkenyl, —(CH 2 ) 1-6 CF 3 , —O(CH 2 ) 1-6 CF 3 , —(O) 0-1 —(CH 2 ) 1-4 (C 3-6 cycloalkyl), —(CH═CH)(C 3-6 cycloalkyl), C 3-6 cycloalkyl substituted with 0-2 C 1-4 alkyl, C 5-6 cycloalkenyl substituted with 0-2 C 1-4 alkyl, and Bn.

5. A comp

Assignees

• Bristol Myers Squibb Co

Inventors

• Devasthale Pratik
• Moore Fang
• Mignone James
• Wang Wei

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title

• A61P27/06

  Antiglaucoma agents or miotics · CPC title

• C07D405/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61K31/4418 Primary

  having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine · CPC title