Antidiabetic bicyclic compounds

1. A compound of formula I, or a pharmaceutically acceptable salt thereof:

wherein A is selected from the group consisting of —CH 2 —, —CF 2 —, —O—, —N(R 6 )—, —S—, —S(O)—, —S(O) 2 —, —C(═O)—, and —CH(OH)—;

B is selected from the group consisting of —CH 2 —, —CH 2 CH 2 —, and —CH(CH 3 )—;

or alternatively -A-B- is selected from the group consisting of —N(R 6 )C(═O)— and —C(═O)N(R 6 )—, or -A-B- represents two atoms that are connected to form one side of a 5-membered heteroaromatic ring having 1-3 heteroatoms independently selected from O, N and S, where the 5-membered heteroaromatic ring is optionally substituted with 1-3 groups independently selected from halogen, CH 3 , CF 3 , —OCH 3 , and —OCF 3 ;

X is selected from ═C(R 4 )— and ═N—; and Y is selected from ═C(R 5 )— and ═N—; with the proviso that X and Y are not both ═N—;

Z is —CR 7 R 8 CO 2 R 9 ;

Heterocycle is a 5-6 membered saturated or partly saturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from O, N and S;

Heteroaryl is a 5-6 membered monocyclic heteroaromatic ring having 1-3 heteroatoms independently selected from O, N and S;

R 1 , R 2 , R 3 , R 4 , and R 5 are each independently selected from the group consisting of H, halogen, —CN, —NO 2 , —C 1 -C 6 alkyl, —OC 1 -C 6 alkyl, —SC 1 -C 6 alkyl, —S(O) 2 C 1 -C 6 alkyl, —N(R 6 )(R 6 ), —N(R 6 )C(═O)C 1 -C 6 alkyl, —N(R 6 )S(O) 2 C 1 -C 6 alkyl, —C(═O)H, —C(═O)OH, —C(═O)OC 1 -C 6 alkyl, —C(═O)C 1 -C 6 alkyl, —C(═O)N(R 6 )(R 6 ), PhenylCH═CHC(═O)—, PhenylC(═O)CH═CH—, —C(═O)Phenyl, —C(═O)Naphthyl, —C(═O)Heterocyle, Heterocycle, Heteroaryl, C 3 -C 7 Cycloalkyl, Phenyl and Naphthyl;

wherein —C 1 -C 6 alkyl and the alkyl groups of —OC 1 -C 6 alkyl, —SC 1 -C 6 alkyl, —S(O) 2 C 1 -C 6 alkyl, —N(R 6 )C(═O)C 1 -C 6 alkyl, —N(R 6 )S(O) 2 C 1 -C 6 alkyl, —C(═O)OC 1 -C 6 alkyl, and —C(═O)C 1 -C 6 alkyl are optionally substituted with 1-5 halogens and optionally substituted with 1-2 groups independently selected from —OH, —OC 1 -C 3 alkyl optionally substituted with 1-5 halogens, —S(O) 2 C 1 -C 3 alkyl, —C(═O)C 1 -C 3 alkyl, —OC(═O)C 1 -C 3 alkyl, —NHC(═O)CH 3 , —NHC(═O)OC 1 -C 6 alkyl, —NHS(O) 2 CH 3 , —N(R 6 )(R 6 ), Heterocycle, Heteroaryl, C 3 -C 7 Cycloalkyl, Phenyl, and Naphthyl;

wherein Phenyl of PhenylCH═CHC(═O)—, Phenyl of PhenylC(═O)CH═CH—, —C(═O)Phenyl, —C(═O)Naphthyl, —C(═O)Heterocyle, Heterocycle, Heteroaryl, C 3 -C 7 Cycloalkyl, Phenyl and Naphthyl either as R 1 , R 2 , R 3 , R 4 , and R 5 or as substituents on R 1 , R 2 , R 3 , R 4 , and R 5 are optionally substituted with 1-4 substituents independently selected from halogen, —CN, —NO 2 , —OH, —C 1 -C 3 alkyl, —C(═O)C 1 -C 3 alkyl, —S(O) 2 C 1 -C 3 alkyl, and —OC 1 -C 3 alkyl, wherein the —C 1 -C 3 alkyl, —OC 1 -C 3 alkyl, —S(O) 2 C 1 -C 3 alkyl, and —C(═O)C 1 -C 3 alkyl substituents are optionally substituted with 1-5 halogens;

wherein optionally the pair of substituents R 1 and R 2 together represent a 3- or 4-carbon bridging group selected from —CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 —, and —CH═CH—CH═CH—, forming a fused cyclopentyl, cyclohexyl, or phenyl ring at the R 1 and R 2 positions, wherein said bridging group is optionally substituted with 1-3 groups independently selected from halogen, —OH, —CN, —NO 2 , —C 1 -C 3 alkyl, —OC 1 -C 3 alkyl, —SC 1 -C 3 alkyl, —S(O) 2 C 1 -C 3 alkyl, —CF 3 , and —OCF 3 ;

Each R 6 is independently selected from the group consisting of H and —C 1 -C 6 alkyl;

R 7 is selected from the group consisting of H and —C 1 -C 3 alkyl;

R 8 is selected from the group consisting of H, —OH, —C 1 -C 3 alkyl optionally substituted with 1-3 halogens, and —OC 1 -C 3 alkyl optionally substituted with 1-3 halogens and optionally with one group —C(═O)OR 10 ; and

R 9 and R 10 are independently selected from the group consisting of H and —C 1 -C 6 alkyl, wherein —C 1 -C 6 alkyl is optionally substituted with 1-5 halogens.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , and R 5 are independently selected from (1) H; (2) halogen; (3) —NO 2 ; (4) —CN; (5) —C 1-6 alkyl, which is optionally substituted with 1-5 halogens and optionally substituted with 1-2 substituents independently selected from —OH, —C(═O)C 1 -C 3 alkyl, and —OC 1-3 alkyl which is optionally substituted with 1-3 halogens; (6) —OC 1-6 alkyl, which is optionally substituted with 1-5 halogens and optionally with one Phenyl; (7) —C(═O)C 1 -C 3 alkyl, which is optionally substituted with 1-5 halogens; (8) —N(R 6 )(R 6 ); (9) —C(═O)N(R 6 )(R 6 ); (10) —C(═O)OC 1 -C 3 alkyl; (11) —S(O) 2 C 1 -C 3 alkyl; (12) Phenyl; (13) PhenylCH═CHC(═O)—; and (14) PhenylC(═O)CH═CH—; wherein Phenyl in all uses is optionally substituted with 1-3 groups independently selected from halogen, CH 3 , CF 3 , —OCH 3 , and —OCF 3 ; and

Each R 6 is independently selected from the group consisting of H and —C 1 -C 3 alkyl;

wherein optionally R 1 and R 2 together represent the 4-carbon chain —CH═CH—CH═CH—, forming a fused phenyl ring at the R 1 and R 2 positions, wherein said fused phenyl ring is optionally substituted with 1-3 substituents independently selected from halogen, —OH, —CN, —NO 2 , —C 1 -C 3 alkyl, —OC 1 -C 3 alkyl, —SC 1 -C 3 alkyl, —S(O) 2 C 1 -C 3 alkyl, —CF 3 , and —OCF 3 .

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from H, halogen, C 1 -C 5 alkyl optionally substituted with 1-5F, —OC 1 -C 5 alkyl optionally substituted with 1-5F, —CH 2 OH, —CH(OH)CH 3 , —CH(OH)CF 3 , —C(═O)H, —C(═O)CH 3 , —CN, —NO 2 , Phenyl, —OCH 2 Phenyl, —C(═O)OC 1 -C 3 alkyl, —S(O) 2 CH 3 , —C(═O)N(R 6 )(R 6 ), —N(R 6 )(R 6 ), PhenylCH═CHC(═O)—, and PhenylC(═O)CH═CH—, wherein Phenyl in each instance is optionally substituted with 1-3 groups independently selected from halogen, CH 3 , CF 3 , —OCH 3 , and —OCF 3 ;

Each R 6 is independently selected from H and CH 3 ;

wherein optionally R 1 and R 2 together represent the 4-carbon chain —CH═CH—CH═CH—, forming a fused phenyl ring at the R 1 and R 2 positions, wherein said fused phenyl ring is optionally substituted with 1-2 substituents independently selected from halogen, —C 1 -C 3 alkyl, —OC 1 -C 3 alkyl, —CF 3 , and —OCF 3 .

4. The compound of claim 1 , wherein each R 6 is independently selected from H and CH 3 .

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 together represent the 4-carbon chain —CH═CH—CH═CH—, forming a fused phenyl ring at the R 1 and R 2 positions, wherein said fused phenyl ring is optionally substituted with 1-3 substituents independently selected from halogen, —OH, —CN, —NO 2 , —C 1 -C 3 alkyl, —OC 1 -C 3 alkyl, —SC 1 -C 3 alkyl, —S(O) 2 C 1 -C 3 alkyl, —CF 3 , and —OCF 3 .

6. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein said fused phenyl ring is optionally substituted with 1-2 substituents independently selected from halogen, —C 1 -C 3 alkyl, —OC 1 -C 3 alkyl, —CF 3 , and —OCF 3 .

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of —CH 2 —, —CF 2 —, —O—, —N(R 6 )—, —S—, —S(O)—, —S(O) 2 —, —C(═O)—, and —CH(OH)—; and

B is selected from the group consisting of —CH 2 —, —CH 2 CH 2 —, and —CH(CH 3 )—;

or alternatively -A-B- is selected from the group consisting of —N(R 6 )C(═O)—, —C(═O)N(R 6 )—,

Each R 6 is independently selected from H and CH 3 .

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of —CH 2 —, —O—, —S—, —S(O) 2 —, —C(═O)—, and —CH(OH)—; and

B is selected from the group consisting of —CH 2 —, —CH 2 CH 2 —, and —CH(CH 3 )—;

or alternatively -A-B- is selected from the group consisting of —N(R 6 )C(═O)—, —C(═O)N(R 6 )—,

Each R 6 is independently selected from H and CH 3 .

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is —CR 7 R 8 CO 2 H;

R 7 is H;

R 8 is selected from the group consisting of H, —OH, CH 3 , and —OCH 2 C(═O)OR 10 ; and R 10 is selected from the group consisting of H and —C 1 -C 4 alkyl.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of —CH 2 —, —O—, —S—, —S(O) 2 —, —C(═O)—, and —CH(OH)—; and

B is selected from the group consisting of —CH 2 —, —CH 2 CH 2 —, and —CH(CH 3 )—;

or alternatively -A-B- is selected from the group consisting of —N(R 6 )C(═O)—, —C(═O)N(R 6 )—,

wherein R 1 is selected from the group consisting of H, halogen, C 1 -C 5 alkyl optionally substituted with 1-5F, —OC 1 -C 5 alkyl optionally substituted with 1-5F, —CH 2 OH, —CH(OH)CH 3 , —CH(OH)CF 3 , —C(═O)H, —C(═O)CH 3 , —CN, —NO 2 , —C(═O)OCH 3 , —S(O) 2 CH 3 , —C(═O)N(R 6 )(R 6 ), —N(R 6 )(R 6 ), and —OCH 2 Phenyl in which Phenyl is optionally substituted with 1-3 groups independently selected from halogen, CH 3 , CF 3 , —OCH 3 , and —OCF 3 ;

R 2 is selected from the group consisting of H, halogen, C 1 -C 3 alkyl optionally substituted with 1-3F, —OC 1 -C 3 alkyl optionally substituted with 1-3F, and Phenyl optionally substituted with 1-3 groups independently selected from halogen, CH 3 , CF 3 , —OCH 3 , and —OCF 3 ;

R 3 is selected from the group consisting of H, halogen, CH 3 , CF 3 , —OCH 3 , and —OCF 3 ;

R 4 is selected from the group consisting of H, halogen, CH 3 , CF 3 , —OCH 3 , —OCF 3 , C(═O)H, —C(═O)CH 3 , —C(═O)OCH 3 , —C(═O)N(R 6 )(R 6 ), —CN, —NO 2 , PhenylCH═CHC(═O)—, and PhenylC(═O)CH═CH—, wherein Phenyl in each instance is optionally substituted with 1-3 groups independently selected from halogen, CH 3 , CF 3 , —OCH 3 , and —OCF 3 ;

R 5 is H;

Each R 6 is independently selected from H and CH 3 ;

wherein optionally R 1 and R 2 together represent the 4-carbon chain —CH═CH—CH═CH—, forming a fused phenyl ring at the R 1 and R 2 positions, wherein said fused phenyl ring is optionally substituted with 1-2 substituents independently selected from halogen, —C 1 -C 3 alkyl, —OC 1 -C 3 alkyl, —CF 3 , and —OCF 3 ;

Z is —CR 7 R 8 CO 2 H;

R 7 is H;

R 8 is selected from the group consisting of H, —OH, CH 3 , and —OCH 2 C(═O)OR 10 ; and R 10 is selected from the group consisting of H and —C 1 -C 4 alkyl.

11. The compound of claim 10 , which is selected from the group consisting of the compounds below, or a pharmaceutically acceptable salt thereof:

Ex.

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48A

12. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

13. A method of treating type 2 diabetes mellitus in a patient in need of treatment comprising the administration to the patient of a therapeutically effective amount of the compound of formula I, or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising

(1) the compound of claim 1 , or a pharmaceutically acceptable salt thereof;

(2) one or more compounds selected from the group consisting of:

(a) PPAR gamma agonists and partial agonists;

(b) biguanides;

(c) protein tyrosine phosphatase-1B (PTP-1B) inhibitors;

(d) dipeptidyl peptidase IV (DP-IV) inhibitors;

(e) insulin or an insulin mimetic;

(f) sulfonylureas;

(g) α-glucosidase inhibitors;

(h) agents which improve a patient's lipid profile, said agents being selected from the group consisting of (i) HMG-CoA reductase inhibitors, (ii) bile acid sequestrants, (iii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iv) PPARα agonists, (v) cholesterol absorption inhibitors, (vi) acyl CoA:cholesterol acyltransferase (ACAT) inhibitors, (vii) CETP inhibitors, and (viii) phenolic anti-oxidants;

(i) PPARα/ dual agonists,

(j) PPARδ agonists,

(k) antiobesity compounds,

(l) ileal bile acid transporter inhibitors;

(m) anti-inflammatory agents;

(n) glucagon receptor antagonists;

(o) GLP-1;

(p) GIP-1;

(q) GLP-1 analogs;

(r) Glucokinase activators;

(s) GPR 119 agonists;

(t) GPR120 agonists; and

(u) Hydroxysterol dehydrogenase-1 (HSD-1) inhibitors; and

(3) a pharmaceutically acceptable carrier.