IP Library › Granted Patent US 9,688,656

Granted Patent B2

US 9,688,656 · App. 15/123,773 · Granted Jun 27, 2017

Tetrazolone-substituted dihydropyridinone MGAT2 inhibitors

Inventor: Saleem Ahmad (Wall, NJ)

Assignee: Bristol-Myers Squibb Company

C07D401/04 A61K31/4439 A61K45/06 C07D401/14 C07D409/14 C07D417/14

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 9,688,656
App. No.: 15/123,773
Granted: Jun 27, 2017
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

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.

Claims (179)

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

7. A compound according to claim 1 , wherein the compound is selected from:

or an enantiomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, a solvate or a hydrate thereof.

8. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a compound of claim 1 .

9. A pharmaceutical composition comprising a compound according to claim 1 and further comprising a dipeptidyl peptidase-IV (DPP4) inhibitor.

10. A method for the treatment of diabetes, hyperglycemia, gestational diabetes, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, hypertension, obesity, dyslipidemia, comprising administering to a patient in need of such treatment a therapeutically effective amount of at least a compound according to claim 1 .

11. A compound selected from:

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, a solvate or a hydrate thereof.

12. A compound according to claim 11 , wherein the compound is a racemic mixture of a compound having the following formula:

and its enantiomer, or a tautomer, a pharmaceutically acceptable salt, a polymorph, a solvate or a hydrate thereof.

13. A compound according to claim 11 , wherein the compound has the following formula: