IP Library › Granted Patent US 9,896,431

Granted Patent B2

US 9,896,431 · App. 15/602,515 · Granted Feb 20, 2018

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

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Quick Facts

Patent No.: US 9,896,431
App. No.: 15/602,515
Granted: Feb 20, 2018
Kind: B2

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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 (73)

1. A method for the treatment of impaired glucose tolerance, insulin resistance, hyperinsulinemia, Metabolic Syndrome, and/or glaucoma, comprising administering to a patient in need of such treatment a therapeutically effective amount of at least 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 c ;

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. The method according to claim 1 , comprising administering to a patient in need of such treatment a therapeutically effective amount of at least a compound of Formula (I), 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, 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, 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. The method according to claim 1 , comprising administering to a patient in need of such treatment a therapeutically effective amount of at least a compound of Formula (I), 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. The method according to claim 1 , comprising administering to a patient in need of such treatment a therapeutically effective amount of at least a compound of Formula (I), 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 method for the treatment of impaired glucose tolerance, insulin resistance, hyperinsulinemia, Metabolic Syndrome, and/or glaucoma, comprising administering to a patient in need of such treatment a therapeutically effective amount of at least 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 2 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. The method according to claim 5 , comprising administering to a patient in need of such treatment a therapeutically effective amount of at least a compound of Formula (IIa), (IIb), (IIc), (IId), or (IIe), wherein:

R 1 is

7. The method according to claim 1 , comprising administering to a patient in need of such treatment a therapeutically effective amount of at least a compound selected from:

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

8. The method according to claim 1 , comprising administering to a patient in need of such treatment a therapeutically effective amount of at least a compound selected from:

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

9. The method according to claim 8 , comprising administering to a patient in need of such treatment a therapeutically effective amount of at least a compound having the following formula: