Tetrazolone-substituted dihydropyridinone MGAT2 inhibitors

Patent metadata

Field	Value
Publication number	US-9688656-B2
Application number	US-201515123773-A
Country	US
Kind code	B2
Filing date	Mar 5, 2015
Priority date	Mar 7, 2014
Publication date	Jun 27, 2017
Grant date	Jun 27, 2017

Abstract

The present invention provides compounds of Formula (I): a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, 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, a pharmaceutically acceptable salt, a polymorph, a solvate or a hydrate thereof, wherein:
ring A is independently phenyl or a 5- to 6-membered heteroaryl comprising carbon atoms and 1-4 heteroatoms selected from N, NR e , O and S; wherein said phenyl and heteroaryl are 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 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 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 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 e ;
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 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 1 is independently selected from: (C 3-6 carbocycle substituted with 0-2 R b and 0-2 R g ), and (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 b and 0-2 R g );
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 b is, at each occurrence, independently selected from: halogen, C 1-10 alkyl, C 1-10 alkoxy, C 1-10 haloalkyl, C 1-10 haloalkoxy, C 1-10 alkylthio, 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), and —(CH 2 ) n —(O) t —(CH 2 ) m R c ; and
R d is, at each occurrence, independently selected from: halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, tetrazolyl, OBn and phenyl.

3. A compound according to claim 1 , wherein:
ring A is independently selected from phenyl, pyrrolyl, thienyl, thiazolyl, pyrazolyl, pyridyl, and pyrimidinyl; 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.

4. A compound according to claim 1 , 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 5-membered heteroaryl comprising carbon atoms and 1-2 heteroatoms selected from N, NR e , O and S; wherein said heteroaryl is substituted with 0-1 R b and 0-2 R g );
R 2 is independently selected from: C 1-4 alkyl and C 1-4 haloalkyl;
R 6 is independently selected from: halogen, C 1-6 alkyl with 0-1 OH, C 1-4 alkoxy, C 1-4 haloalkoxy, CO(C 1-4 alkyl), 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;
alternatively, R 6 and R 7 , together with the carbon atoms to which they are attached, combine to form a 6-membered carbocyclic ring;
R b is, at each occurrence, independently selected from: halogen, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 haloalkyl, C 1-10 haloalkoxy, and phenoxy;
R e is, at each occurrence, independently selected from: C 1-6 alkyl, C 1-8 haloalkyl, and —(CH 2 ) n —C 3-6 carbocycle; 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.

5. A compound of Formula (IIa), (IIb), (IIc), (IId), or (IIe):

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:

R e is independently selected from: CF 3 and CH 3 ;
R 6 is independently selected from: halogen, C 1-4 alkyl substituted with 0-1 OH, C 1-4 alkoxy, C 1-4 haloalkoxy, CO(C 1-4 alkyl), and —(CH 2 ) 0-1 —C 3-4 cycloalkyl;
R b is independently selected from: —(CH 2 ) 1-6 CF 3 , —(CH 2 ) 1-4 CF 2 CF 3 , —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: C 1-4 alkyl, —(CH 2 ) 1-6 CF 3 , and —(CH 2 ) 0-1 —C 3-4 cycloalkyl; and
R g is independently halogen.

6. A compound according to claim 5 , wherein:
R 1 is

Assignees

• Bristol Myers Squibb Co

Inventors

• Ahmad Saleem

Classifications

• A61P9/12

  Antihypertensives · 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

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title