Aryl dihydropyridinones and piperidinone MGAT2 inhibitors

Patent metadata

Field	Value
Publication number	US-9901572-B2
Application number	US-201715488642-A
Country	US
Kind code	B2
Filing date	Apr 17, 2017
Priority date	Dec 2, 2011
Publication date	Feb 27, 2018
Grant date	Feb 27, 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 (II):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof, wherein:
R 1 is —(CH 2 ) m -(phenyl substituted with 1 R b and 0-2 R g );
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: —CONH(C 1-6 alkyl), R c , —(CH 2 ) n —(X) t —(CH 2 ) m R c , —NHCO(CH 2 )SO 2 (C 1-4 alkyl), —NHCONH(C 1-4 alkyl), and —OCONH(C 1-4 alkyl);
X is independently selected from: O, S, NH, CONH, and NHCO;
R 11 and R 15 are independently selected from: H, C 1-4 alkyl and halo;
R 12 and R 14 are independently selected from: H, halo, C 1-4 alkyl and C 1-4 alkoxy;
R 13 is independently selected from: 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;
R b is, at each occurrence, independently selected from: 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: 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: 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 g and R h are, at each occurrence, independently selected from: 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

R 6 is independently selected from: —CONH(C 1-6 alkyl), —NHCO(CH 2 )SO 2 (C 1-4 alkyl), R c , OR c , —CONHR c , and NHCOR c ;
R 12 is independently selected from: H, halo, C 1-4 alkyl and C 1-4 alkoxy;
R 13 is independently selected from: 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;
R 14 is independently selected from: H and C 1-4 alkoxy;
R b is, at each occurrence, independently selected from: 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: 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: R c , —CONHR c , and —NHCOR c .

4. A compound according to claim 3 , wherein:
R 6 is independently selected from: —CONH(C 1-4 alkyl), —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), —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: 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: halo and C 1-4 alkyl.

5. A compound according to claim 4 , wherein:
R 2 is independently selected from: CF 3 and Me;
R 3 is independently selected from: H and F;
R 4 is independently selected from: H and F;
R 6 is independently selected from: 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), —NHCO(3-Me-Ph), —NHCO(4-Me-Ph), —NHCO(2-Cl-Ph), —NHCO(3-Cl-Ph), —NHCO(2-C1-4-F-Ph), —NHCO(2-C1-5-F-Ph), —NHCO(isoxazol-5-yl), —NHCO(3-Me-isoxazol-5-yl), —NHCO(4-Me-isoxazol-5-yl), —NHCO(3-OMe-isoxazol-5-yl), —NHCO(3-Br-isoxazol-5-yl), —NHCO(3-(2-Cl-Ph)-isoxazol-5-yl), —NHCO(3-(3-F-Ph)-isoxazol-5-yl), —NHCO(3-OBn-isoxazol-5-yl), 1H-imidazol-1-yl, —NHCO(5-Me-1,3,4-oxadiazol-2-yl), —NHCO(1-Me-1,2,3-triazol-4-yl), —NHCO(6-OMe-pyrid-3-yl), —NHCO(6-Cl-pyridazin-3-yl), 5-CF 3 -1,3,4-oxadiazol-2-yl, 1H-tetrazol-1-yl, 1H-tetrazol-3-yl, and 2H-tetrazol-5-yl;
R 11 and R 15 are independently selected from the group consisting of: H, Me, F, and Cl;
R 12 is independently selected from the group consisting of: H, F, Cl, Me and OMe;
R 13 is independently selected from the group consisting of: H, F, Cl, Br, Me, OMe, OEt, CH 2 OMe, CF 3 , CH 2 CF 3 , OCHF 2 , OCF 3 , CN, N(Me) 2 , cyclopropyl and cyclopropylmethyl;
R 14 is H;
R b is, at each occurrence, independently selected from the group consisting of: n-pentyl, methoxy, n-butoxy, i-butoxy, i-pentoxy, —O(CH 2 ) 1

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

• A61P9/12

  Antihypertensives · CPC title

• A61P5/50

  for increasing or potentiating the activity of insulin · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · 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