Aryl dihydropyridinones and piperidinone MGAT2 inhibitors

Patent metadata

Field	Value
Publication number	US-10966967-B2
Application number	US-202016879810-A
Country	US
Kind code	B2
Filing date	May 21, 2020
Priority date	Dec 2, 2011
Publication date	Apr 6, 2021
Grant date	Apr 6, 2021

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 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 ;

X is independently selected from the group consisting of: O, S, NH, CONH, and NHCO;
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 R h ;
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 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 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 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 saturated heterocyclic ring comprising: carbon atoms and 1-2 oxygen atoms;
R 14 is independently selected from the group consisting of: H and C 1-4 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 1-6 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 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 1-6 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;
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 selected from the group consisting of: OPh, —CONH(cyclopropyl), —CONH(cyclobutyl), —CONH(cyclopentyl), —CONH(cyclohexyl), —CONHPh, —CONH(4-F-Ph), —CONH(2-Cl-Ph), —CONH(4-Cl-Ph), —CONH(4-Me-Ph), —CONH(4-OH-Ph), —CONH(3-OMe-Ph), —CONH(4-OMe-Ph), —CONH(4-CF 3 -Ph), —CONH(4-OCF 3 -Ph), —CONH(1-Me-pyrazol-3-yl), —CONH(4-(1H-tetrazol-2-yl)-Ph), —CONH(4-(2H-tetrazol-5-yl)-Ph), —CONH(3-F-4-Me-Ph), —CONH(3-F-4-OMe-Ph), —CONH(CH 2 ) 2 Ph, —CONH(5-OMe-pyrid-2-yl), —CONH(6-OMe-pyrid-3-yl), —CONH(5-OMe-pyrazin-2-yl), —CONH(6-OMe-pyridazin-3-yl), —NHCO(CH 2 )SO 2 Me, —NHCOPh, —NHCO(2-Me-Ph)

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

• A61P5/50

  for increasing or potentiating the activity of insulin · CPC title

• A61K31/4418

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

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• C07D211/90

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title