Aryl dihydropyridinones and piperidinone MGAT2 inhibitors

Patent metadata

Field	Value
Publication number	US-10695328-B2
Application number	US-201916445913-A
Country	US
Kind code	B2
Filing date	Jun 19, 2019
Priority date	Dec 2, 2011
Publication date	Jun 30, 2020
Grant date	Jun 30, 2020

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 (II):

or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:
R 1 is independently selected from the group consisting of: C 1-6 alkyl, C 3-6 cycloalkyl, —CONHC 4-18 alkyl, —CONHC 2-8 haloalkyl, —CONH(CH 2 ) 1-8 Ph, —(CH 2 ) m -(phenyl substituted with 1 R b and 0-2 R g ), and a 5- to 6-membered heteroaryl substituted with 0-1 R b and 0-2 R g , wherein said heteroaryl is selected from: pyridyl, oxazolyl, thiazolyl and

R 2 is independently selected from the group consisting of: C 1-4 alkyl and C 1-4 haloalkyl;
R 3 is independently selected from the group consisting of: H and F;
R 4 is independently selected from the group consisting of: H and F;
R 6 is independently R c or —(CH 2 ) n —(X) t —(CH 2 ) m R c ;
R 11 and R 15 are independently selected from the group consisting of: H, C 1-4 alkyl and halo;
R 12 and R 14 are independently selected from the group consisting of: H, halo, C 1-4 alkyl and C 1-4 alkoxy;
R 13 is independently selected from the group consisting of: H, halo, C 1-4 alkyl substituted with 0-1 C 1-4 alkoxy, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, —(CH 2 ) m —C 3-4 cycloalkyl, CN, N(C 1-4 alkyl) 2 , NHCO 2 (C 1-4 alkyl), NHSO 2 (C 1-4 alkyl), pyrazolyl, and morpholinyl;
alternatively, R 12 and R 13 , 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;
R b is, at each occurrence, independently selected from the group consisting of: halo, OH, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 haloalkyl, C 1-10 haloalkoxy, —O(CH 2 ) s O(C 1-6 alkyl), N(C 1-4 alkyl) 2 , —CONH(CH 2 ) 6-20 H, —(CH 2 ) m (C 3-6 cycloalkyl), —(CH 2 ) m (C 4-6 cycloalkenyl), —O(CH 2 ) m (C 3-6 cycloalkyl), 4-C 1-4 alkoxy-Ph, —O(CH 2 ) m Ph, morpholinyl, pyridyl, 2-C 1-4 alkoxy-pyridin-5-yl, pyrimidinyl, pyrazinyl, and —O-pyrimidinyl;
R c is, at each occurrence, independently selected from the group consisting of: 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 the group consisting of: halo, OH, CN, NO 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, tetrazolyl, OBn and phenyl substituted with 0-2 Rh;
R e is, at each occurrence, independently selected from the group consisting of: H, C 1-8 alkyl, C 1-8 haloalkyl, benzyl optionally substituted with C 1-4 alkoxy, CO(C 1-4 alkyl) and COBn;
R f is, at each occurrence, independently selected from the group consisting of: H and C 1-4 alkyl;
R g and R h are, at each occurrence, independently selected from the group consisting of: halo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, and C 1-4 haloalkoxy;
n, at each occurrence, is independently 0 or 1;
m, at each occurrence, is independently 0, 1, 2 or 3;
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 the group consisting of: C 1-6 alkyl, —CONHC 4-18 alkyl, —CONH(CH 2 ) 1-8 Ph, and

R 6 is independently R c , OR c , —CONHR c , or —NHCOR c ;
R 12 is independently selected from the group consisting of: H, halo, C 14 alkyl and C 14 alkoxy;
R 13 is independently selected from the group consisting of: H, halo, C 14 alkyl substituted with 0-1 C 1-4 alkoxy, C 14 alkoxy, C 1-4 haloalkyl, C 14 haloalkoxy, —(CH 2 ) m —C 3-4 cycloalkyl, CN, N(C 1-4 alkyl) 2 , NHCO 2 (C 14 alkyl), NHSO 2 (C 1-4 alkyl), pyrazolyl, and morpholinyl;
alternatively, R 12 and R 13 , 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 saturated heterocyclic ring comprising: carbon atoms and 1-2 oxygen atoms;
R 14 is independently selected from the group consisting of: H and C 14 alkoxy;
R b is, at each occurrence, independently selected from the group consisting of: halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-10 haloalkoxy, —O(CH 2 ) s O(C 1-6 alkyl), —CONH(CH 2 ) 6-20 H, —(CH 2 ) m (C 3-6 cycloalkyl), —(CH 2 ) m (C 4-6 cycloalkenyl), —O(CH 2 ) m (C 3-6 cycloalkyl), phenoxy, benzoxy, morpholinyl, 2-C 1-4 alkoxy-pyridin-5-yl, pyrimidin-5-yl, pyrazin-2-yl and —O-pyrimidinyl; and
R c is, at each occurrence, independently selected from the group consisting of: C 3-6 cycloalkyl substituted with 0-2 R d , —(CH 2 ) m -(phenyl substituted with 0-3 R d ), and a heteroaryl selected from: oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, and pyrazinyl; wherein said heteroaryl is substituted with 0-2 R d .

3. A compound according to claim 2 , wherein:
R 1 is

R 6 is independently selected from the group consisting of: OPh, —CONH(C 3-6 cycloalkyl), —CONHPh, —CONH-(2-halo-Ph), —CONH-(3-halo-Ph), —CONH-(4-halo-Ph), —CONH-(4-C 1-4 alkyl-Ph), —CONH(4-OH-Ph), —CONH-(3-C 1-4 alkoxy-Ph), —CONH-(4-C 1-4 alkoxy-Ph), —CONH-(4-C 1-4 haloalkyl-Ph), —CONH-(4-C 1-4 haloalkoxy-Ph), —CONH-(4-CN-Ph), —CONH-(4-tetrazolyl-Ph), —CONH-(3-halo-4-C 1-4 alkyl-Ph), —CONH-(3-halo-4-C 1-4 alkoxy-Ph), —CONH(CH 2 ) 2 Ph, —CONH(4-(4-C 1-4 alkoxy-Ph)-thiazol-2-yl), —CONH(1-C 1-4 alkyl-pyrazol-3-yl), —CONH(5-C 1-4 alkoxy-pyrid-2-yl), —CONH(6-C 1-4 alkoxy-pyrid-3-yl), —CONH(5-C 1-4 alkoxy-pyrazin-2-yl), —CONH(6-C 1-4 alkoxy-pyridazin-3-yl), —NHCO(CH 2 )SO 2 (C 1-4 alkyl), —NHCOPh, —NHCO(2-C 1-4 alkyl-Ph), —NHCO(3-C 1-4 alkyl-Ph), —NHCO(4-C 1-4 alkyl-Ph), —NHCO(2-halo-Ph), —NHCO(3-halo-Ph), —NHCO(2-C 1-4 haloalkyl-Ph), —NHCO(2-C 1-4 haloalkoxy-Ph), —NHCO(2-halo-4-halo-Ph), —NHCO(2-halo-5-halo-Ph), —NHCO(oxazolyl), —NHCO(isoxazolyl), —NHCO(3-C 1-4 alkyl-isoxazol-5-yl), —NHCO(4-C 1-4 alkyl-isoxazol-5-yl), —NHCO(3-C 1-4 alkoxy-isoxazol-5-yl), —NHCO(4-C 1-4 alkoxy-isoxazol-5-yl), —NHCO(3-halo-isoxazol-5-yl), —NHCO(3-OBn-isoxazol-5-yl), —NHCO(3-(2-halo-Ph)-isoxazol-5-yl), —NHCO(3-(3-halo-Ph)-isoxazol-5-yl), —NHCO(5-C 1-4 alkyl-1H-pyrazol-3-yl), imidazolyl, —NHCO(5-C 1-4 alkyl-1,3,4-oxadiazol-2-yl), —NHCO(1-C 1-4 alkyl-1,2,3-triazol-4-yl), —NHCO(6-C 1-4 alkoxy-pyrid-3-yl), —NHCO(pyrazinyl), —NHCO(6-halo-pyridazin-3-yl), 5-C 1-4 haloalkyl-1,3,4-oxadiazol-2-yl, 3-NO 2 -1H-1,2,4-triazol-1-yl, tetrazolyl and 5-C 1-4 alkyl-tetrazol-1-yl;
R b is independently selected from the group consisting of: halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-8 haloalkoxy, —CONH(CH 2 ) 6-20 H, C 3-6 cycloalkyl, C 4-6 cycloalkenyl, —O(CH 2 ) m (C 3-6 cycloalkyl), phenoxy, benzoxy, pyrimidinyl, pyrazinyl and —O-pyrimidinyl; and
R g is independently selected from the group consisting of: halo and C 1-4 alkyl.

4. A compound according to claim 3 , wherein:
R 2 is independently selected from the group consisting of: CF 3 and Me

Assignees

• Bristol Myers Squibb Co

Inventors

• Turdi Huji
• Hangeland Jon J
• Lawrence R Michael
• Ahmad Saleem
• Meng Wei
• Brigance Robert Paul
• Devasthale Pratik
• Zhao Guohua

Classifications

• C07D417/04

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

• C07D413/04

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

• C07D413/14

  containing three or more hetero rings · CPC title

• C07F9/4006

  Esters of acyclic acids which can have further substituents on alkyl · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title