Indole acetic acid derivatives and their use as pharmaceutical agents

1. A compound of Formula (Ia)

wherein

R 1 is H;

R 2 is H or C 1 alkyl;

R 3 is H or C 1 alkyl;

Y is O or NR 5 ;

R 5 is H;

n is 3;

Ar is a ring radical selected from phenyl and a 6-membered heteroaryl ring containing up to three N atoms, said Ar being optionally substituted at any available position by 1 to 5 independently selected R 6 groups, and optionally fused to a 5- or 6-membered saturated carbocyclic ring, a 5- or 6-membered unsaturated carbocyclic ring, or a 5- or 6-membered heterocyclic ring containing up to 3 additional heteroatoms selected from N, O, and S, wherein

said fused ring may be optionally substituted at any available position by 1-4 independently selected R 7 groups, with the proviso that when R 1 , R 2 and R 3 are H, n is 3, Y is NR 5 , wherein R 5 H and Ar is a 6-membered heteroaryl ring, the 6-membered heteroaryl ring contains two or three N atoms;

R 6 is selected from the group consisting of

OH,

SH,

halo,

CN,

NO 2 ,

C(═O)OH,

(═O)—OC 1 -C 6 alkyl,

C(═O)—OC 3 -C 6 cycloalkyl,

NR 8 R 9 ,

C(═O)NR 8 R 9 ,

C(═S)NR 8 R 9 ,

C 1 -C 6 alkyl optionally substituted with halo, OH, NR 8 R 9 , or C 1 -C 6 alkoxy,

C 1 -C 6 haloalkyl,

C 1 -C 6 alkoxy,

C 1 -C 6 thioalkyl,

C 2 -C 6 alkenyl,

C 1 -C 6 haloalkoxy,

C 3 -C 6 cycloalkyl,

C 3 -C 6 cycloalkoxy,

phenoxy optionally substituted on the phenyl ring with halo, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy, and

a mono or bicyclic ring radical selected from the group consisting of phenyl optionally fused to a 5- or 6-membered saturated or partially unsaturated carbocyclic ring, or a 5- or 6-membered saturated or partially unsaturated heterocyclic ring containing from 1-3 heteroatoms selected from N, O, and S, and a 5- or 6-membered heterocyclic ring radical containing up to 4 heteroatoms selected from N, O, or S, optionally fused to a 5- or 6-membered saturated or partially unsaturated carbocyclic ring, or a 5- or 6-membered saturated or partially unsaturated heterocyclic ring containing from 1-3 heteroatoms selected from N, O, and S, said mono or bicyclic ring radical being optionally substituted with up to 5 of the following groups

halo,

hydroxy,

oxo,

CN,

C 1 -C 6 alkyl optionally substituted with halo, OH, NR 8 R 9 , or C 1 -C 6 alkoxy,

C 1 -C 6 haloalkyl,

C 1 -C 6 alkoxy,

C 1 -C 6 thioalkyl

C 1 -C 6 haloalkoxy,

C 3 -C 6 cycloalkyl,

C 3 -C 6 cycloalkoxy,

C 1 -C 6 acyl,

C(═O)OH,

CH 2 C(═O)OH,

NR 8 R 9 ,

C(═O)NR 8 R 9 ,

C(═O)OC 1 -C 6 alkyl, and

C(═O)OC 3 -C 6 cycloalkyl;

R 7 is selected from the group consisting of

oxo,

hydroxy,

halo,

CN,

NR 8 R 9 ,

C 1 -C 6 alkyl optionally substituted with OH, NR 8 R 9 , or C 1 -C 6 alkoxy,

C 1 -C 6 haloalkyl,

C 1 -C 6 alkoxy,

C 1 -C 6 thioalkyl,

C 1 -C 6 haloalkoxy,

C 3 -C 6 cycloalkyl, and

C 3 -C 6 cycloalkoxy;

R 8 and R 9 are independently selected from the group consisting of

H,

C 1 -C 6 alkyl optionally substituted with C 3 -C 6 cycloalkyl,

C 1 -C 6 acyl,

benzyl optionally substituted with halo, C 1 -C 6 alkoxy, (C 1 -C 6 )alkyl, CN, NH 2 , N[(C 1 -C 3 )alkyl] 2 , NO 2 , or CF 3 ,

C 3 -C 6 cycloalkyl, and

phenyl optionally substituted with halo, C 1 -C 6 alkoxy, (C 1 -C 6 )alkyl, CN, N[(C 1 -C 3 )alkyl] 2 , NO 2 ,or CF 3 ,

or

R 8 and R 9 may be taken together with the nitrogen atom to which they are attached to form a 5- or 6-membered heterocyclic ring optionally interrupted by NR 5 or O;

or the pharmacologically acceptable esters and salts thereof.

2. The compound of claim 1 , wherein

R 1 is H;

Y is O;

n is 3 ;

Ar is phenyl,

said phenyl being optionally substituted at any available position by 1 to 5 independently selected R 6 groups, and optionally fused to a 5- or 6-membered saturated carbocyclic ring, a 5- or 6-membered unsaturated carbocyclic ring, or a 5- or 6-membered heterocyclic ring containing up to 3 additional heteroatoms selected from N, O, and S, wherein

said fused ring may be optionally substituted at any available position by 1-4 independently selected R 7 groups;

and

R 2 , R 3 , R 6 , R 7 , R 8 , and R 9 are as defined in claim 1 .

3. The compound of claim 2 , wherein

Ar is phenyl, said phenyl being optionally substituted at any available position by 1 to 5 independently selected R 6 groups, and fused to a 5- or 6-membered saturated carbocyclic ring, a 5- or 6-membered unsaturated carbocyclic ring, or a 5- or 6-membered heterocyclic ring containing up to 3 additional heteroatoms selected from N, O, and S, wherein

said fused ring may be optionally substituted at any available position by 1-4 independently selected R 7 groups.

4. The compound of claim 1 , wherein

R 1 is H;

Y is O;

n is 3 ;

Ar is phenyl,

said phenyl being optionally substituted at any available position by 1 to 5 independently selected R 6 groups, and one or more substituents is a 5- or 6-membered heterocyclic ring radical containing up to 4 heteroatoms selected from N, O, or S, optionally fused to a 5- or 6-membered saturated or partially unsaturated carbocyclic ring, or a 5- or 6-membered saturated or partially unsaturated heterocyclic ring containing from 1-3 heteroatoms selected from N, O, and S, said mono or bicyclic ring radical being optionally substituted with up to 5 of the following groups

halo,

hydroxy,

oxo,

CN,

C 1 -C 6 alkyl optionally substituted with halo, OH, NR 8 R 9 , or C 1 -C 6 alkoxy,

C 1 -C 6 haloalkyl,

C 1 -C 6 alkoxy,

C 1 -C 6 thioalkyl

C 1 -C 6 haloalkoxy,

C 3 -C 6 cycloalkyl,

C 3 -C 6 cycloalkoxy,

C 1 -C 6 acyl,

C(═O)OH,

CH 2 C(═O)OH,

NR 8 R 9 ,

C(═O)NR 8 R 9 ,

C(═O)OC 1 -C 6 alkyl, and

C(═O)OC 3 -C 6 cycloalkyl;

and

R 2 , R 3 , R 6 , R 7 , R 8 , and R 9 are as defined in claim 1 .

5. The compound of claim 1 , wherein

R 1 is H;

Y is O;

n is 3;

Ar is a 6-membered heteroaryl ring containing up to three N atoms, said heteroaryl being optionally substituted at any available position by 1 to 5 independently selected R 6 groups, and optionally fused to a 5- or 6-membered saturated carbocyclic ring, a 5- or 6-membered unsaturated carbocyclic ring, or a 5- or 6-membered heterocyclic ring containing up to 3 additional heteroatoms selected from N, O, and S, wherein

said fused ring may be optionally substituted at any available position by 1-4 independently selected R 7 groups;

and

R 2 , R 3 , R 6 , R 7 , R 8 , and R 9 are as defined in claim 1 .

6. The compound of claim 1 , wherein

R 1 is H;

Y is NR 5 ;

n is 3;

Ar is a 6-membered heteroaryl ring containing up to three N atoms, said heteroaryl being substituted at any available position by 1 to 5 independently selected R 6 groups when the 6-membered heteroaryl ring contains one N atom and optionally substituted at any available position by 1 to 5 independently selected R 6 groups when the 6-membered heteroaryl ring contains two or three N atoms, and optionally fused to a 5- or 6-membered saturated carbocyclic ring, a 5- or 6-membered unsaturated carbocyclic ring, or a 5- or 6-membered heterocyclic ring containing up to 3 additional heteroatoms selected from N, O, and S, wherein

said fused ring may be optionally substituted at any available position by 1-4 independently selected R 7 groups;

and

R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , and R 9 are as defined in claim 1 .

7. A compound selected from the group consisting of (5-{3-[4-(4,5,6,7-tetrahydro-benzooxazol-2-yl)-phenoxy]-propoxy}-indol-1-yl)-acetic acid;

(5-{3-[4-(4-ethyl-oxazol-2-yl)-2-propyl-phenoxy]-propoxy}-indol-1-yl)-acetic acid;

(5-{3-[2-propyl-4-(4,5,6,7-tetrahydro-benzooxazol-2-yl)-phenoxy]-propoxy}-indol-1-yl)-acetic acid;

(5-{3-[4-(4-tert-butyl-oxazol-2-yl)-2-propyl-phenoxy]-propoxy}-3-methylindolyl)-acetic acid;

2-(5-{3-[4-(4-ethyl(1,3-oxazol-2-yl))-2-propylphenoxy]propoxy}-3-methylindolyl)acetic acid;

2-{3-methyl-5-[3-(2-propyl-4-(4,5,6,7-tetrahydrobenzoxazol-2-yl)phenoxy)propoxy]indolyl}propanoic acid;

2-{5-[3-(2-methoxy-4-(4,5,6,7-tetrahydrobenzothiazol-2-yl)phenoxy)propoxy]indolyl}acetic acid;

(5-{3-[4-(4-ethyl-thiazol-2-yl)-2-propyl-phenoxy]-propoxy}-indol-1-yl)-acetic acid;

2-{5-[3-(2-propyl-4-(4,5,6,7-tetrahydrobenzothiazol-2-yl)phenoxy)propoxy]indolyl}acetic acid;

2-(5-{3-[4-(4-ethoxy-5-methyl(1,3-thiazol-2-yl))-2-propylphenoxy]propoxy}indolyl)acetic acid;

2-[5-(3-{4-[5-(N,N-dimethylcarbamoyl)-4-methyl(1,3-thiazol-2-yl)]-2-propylphenoxy}propoxy)indolyl]acetic acid;

2-{5-[3-(2-propyl-4-(1,3-thiazol-2-yl)phenoxy)propoxy]indolyl}acetic acid;

(5-{3-[4-(6,7-dihydro-5H-pyrano[2,3-d]thiazol-2-yl)-2-propyl-phenoxy]-propoxy}-indol-1-yl)-acetic acid;

2-(5-{3-[4-(4,5,6,7-tetrahydro-benzothiazol-2-yl)-phenoxy]-propoxy}-indol-1-yl)-propionic acid;

(2S)-2-(5-{3-[4-(4ethoxy-5-methyl-thiazol-2-yl)-2-propyl-phenoxy]-propoxy}-indol-1-yl)-propionic acid;

(2R)-2-(5-{3-[4-(4-ethoxy-5-methyl-thiazol-2-yl)-2-propyl-phenoxy]-propoxy}-indol-1-yl)-propionic acid;

2-{3-methyl-5-[3-(2-propyl-4-(4,5,6,7-tetrahydrobenzothiazol-2-yl)phenoxy)propoxy]indolyl}acetic acid;

(2S)-2-(3-methyl-5-{3-[2-propyl-4-(4,5,6,7-tetrahydro-benzothiazol-2-yl)-phenoxy]-propoxy}-indol-1-yl)-propionic acid; and

(3-ethyl-5-{3-[2-propyl-4-(4,5,6,7-tetrahydro-benzothiazol-2-yl)-phenoxy]-propoxy}-indol-1-yl)-acetic acid.

8. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt or ester, in combination with a pharmaceutically acceptable carrier.

9. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier and one or more pharmaceutical agents.

10. The pharmaceutical composition of claim 9 , wherein the pharmaceutical agent is PPAR ligands, insulin secretagogues, sulfonylurea drugs, α-glucosidase inhibitors, insulin sensitizers, hepatic glucose output lowering compounds, insulin and insulin derivatives, biguanides, protein tyrosine phosphatase-1B, dipeptidyl peptidase IV, 11beta-HSD inhibitors, anti-obesity drugs, HMG-CoA reductase inhibitors, nicotinic acid, lipid lowering drugs, ACAT inhibitors, bile acid sequestrants, bile acid reuptake inhibitors, microsomal triglyceride transport inhibitors, fibric acid derivatives, β-blockers, ACE inhibitors, calcium channel blockers, diuretics, renin inhibitors, AT-1 receptor antagonists, ET receptor antagonists, neutral endopeptidase inhibitors, vasopepsidase inhibitors, and nitrates.

11. A method of treating a disease or condition selected from the group consisting of diabetes (type 1 or type 2), maturity-onset diabetes of the young (MODY), latent autoimmune diabetes adult (LADA), impaired glucose tolerance (IGT), impaired fasting glucose (IFG), and gestational diabetes, comprising administering to a mammal an effective amount of a compound of claim 1 .

12. The method of claim 11 , further comprising administering a PPAR ligand, an insulin sensitizer, a sulfonylurea, an insulin secretagogue, a hepatic glucose output lowering compound, an α-glucosidase inhibitor, biguanides, protein tyrosine phosphatase-1B (PTP-1B) inhibitors, dipeptidyl peptidase IV, 11beta-HSD inhibitors, insulin or insulin derivatives in combination with said compound of claim 1 .

13. The method of claim 11 , further comprising administering an anti-obesity drug in combination with said compound of claim 1 .

14. The method of claim 13 , wherein the anti-obesity drug is selected from β-3 agonists, CB-1 antagonists, neuropeptide Y5 inhibitors, ciliary neurotrophic factor and derivatives, appetite suppressants, and lipase inhibitors.

15. A method of treating lipid disorders in diabetic patients, comprising administering to a mammal an effective amount of a compound of claim 1 in combination with HMG-CoA reductase inhibitors, nicotinic acid, fatty acid lowering compounds, lipid lowering drugs, ACAT inhibitors, bile acid sequestrants, bile acid reuptake inhibitors, microsomal triglyceride transport inhibitors, or fibric acid derivatives.

16. A method of treating hypertension in diabetic patients, comprising administering to a mammal an effective amount of a compound of claim 1 in combination with β-blockers, ACE inhibitors, calcium channel blockers, diuretics, renin inhibitors, AT-1 receptor antagonists, ET receptor antagonists, neutral endopeptidase (NEP) inhibitors, vasopepsidase inhibitors, and nitrates.

17. A medicament comprising a compound according to any of claims 1 - 6 or 7 .

18. A medicament comprising a compound according to any of claims 1 - 6 or 7 in combination with at least one pharmaceutically acceptable, pharmaceutically safe carrier or excipient/diluent/adjuvants.

19. A medicament consisting of a compound according to any of claims 1 - 6 or 7 in combination with PPAR ligands, insulin secretagogues, sulfonylurea drugs, α-glucosidase inhibitors, insulin sensitizers, hepatic glucose output lowering compounds, insulin and insulin derivatives, biguanides, protein tyrosine phosphatase-1B, dipeptidyl peptidase IV, 11beta-HSD inhibitors, anti-obesity drugs, HMG-CoA reductase inhibitors, nicotinic acid, lipid lowering drugs, ACAT inhibitors, bile acid sequestrants, bile acid reuptake inhibitors, microsomal triglyceride transport inhibitors, fibric acid derivatives, β-blockers, ACE inhibitors, calcium channel blockers, diuretics, renin inhibitors, AT-1 receptor antagonists, ET receptor antagonists, neutral endopeptidase inhibitors, vasopepsidase inhibitors, and nitrates.

20. A process for preparing a medicament according to claim 18 , comprising combining at least one compound according to any of claims 1 - 6 or 7 with at least one pharmaceutically acceptable, pharmaceutically safe carrier or excipient/diluent/adjuvants, mixing the combination and bringing the combination into a suitable administration form.