Tetrazolone-substituted dihydropyridinone MGAT2 inhibitors
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.
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 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 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 1 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, 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 ; 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 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 (IIb), (IId), or (IIe):
or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, a solvate or a hydrate thereof, 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. 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 compound according to claim 1 , wherein the compound is selected from:
or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, a solvate or a hydrate thereof.
9. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a compound of claim 1 .
10. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a compound of claim 5 .
11. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a compound of claim 6 .
12. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a compound of claim 7 .
13. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a compound of claim 8 .
14. A pharmaceutical composition comprising a compound according to claim 1 and further comprising a dipeptidyl peptidase-IV (DPP4) inhibitor.
15. A pharmaceutical composition comprising a compound according to claim 5 and further comprising a dipeptidyl peptidase-IV (DPP4) inhibitor.
16. A pharmaceutical composition comprising a compound according to claim 7 and further comprising a dipeptidyl peptidase-IV (DPP4) inhibitor.
17. A pharmaceutical composition comprising a compound according to claim 8 and further comprising a dipeptidyl peptidase-IV (DPP4) inhibitor.
18. A method for the treatment of diabetes, hyperglycemia, impaired glucose tolerance, gestational diabetes, insulin resistance, hyperinsulinemia, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, Metabolic Syndrome, obesity, dyslipidemia, and/or glaucoma comprising administering to a patient in need of such treatment a therapeutically effective amount of at least a compound according to claim 1 .
19. A method for the treatment of diabetes, hyperglycemia, impaired glucose tolerance, gestational diabetes, insulin resistance, hyperinsulinemia, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, Metabolic Syndrome, obesity, dyslipidemia, and/or glaucoma comprising administering to a patient in need of such treatment a therapeutically effective amount of at least a compound according to claim 5 .
20. A method for the treatment of diabetes, hyperglycemia, impaired glucose tolerance, gestational diabetes, insulin resistance, hyperinsulinemia, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, Metabolic Syndrome, obesity, dyslipidemia, and/or glaucoma comprising administering to a patient in need of such treatment a therapeutically effective amount of at least a compound according to claim 6 .
21. A method for the treatment of diabetes, hyperglycemia, impaired glucose tolerance, gestational diabetes, insulin resistance, hyperinsulinemia, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, Metabolic Syndrome, obesity, dyslipidemia, and/or glaucoma comprising administering to a patient in need of such treatment a therapeutically effective amount of at least a compound according to claim 7 .
22. A method for the treatment of diabetes, hyperglycemia, impaired glucose tolerance, gestational diabetes, insulin resistance, hyperinsulinemia, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, Metabolic Syndrome, obesity, dyslipidemia, and/or glaucoma comprising administering to a patient in need of such treatment a therapeutically effective amount of at least a compound according to claim 8 .