6-(aryl-amido or aryl-amidomethyl)-naphthalen-2-yloxy-acidic derivatives as inhibitors of plasminogen activator inhibitor type-1 (PAI-1)

• US 6,589,970 B2
• Filed: 06/13/2002
• Issued: 07/08/2003
• Est. Priority Date: 06/20/2001
• Status: Expired due to Fees

• Current Assignee: Wyeth (Pfizer Inc.)
• Original Assignee: Wyeth (Pfizer Inc.)
• Inventors: Commons, Thomas Joseph, Trybulski, Eugene John, Croce, Susan Christman, Woodworth, Richard Page, Elokdah, Hassan Mahmoud, Crandall, David LeRoy
• Primary Examiner(s): McKane, Joseph K.
• Assistant Examiner(s): SMALL, ANDREA D SOUZA
• Application Number:
  US10/170,558
• Publication Number:
  US 20030045560A1
• Time in Patent Office: 390 Days
• Field of Search: 549/467, 549/488, 548/252, 548/374.1, 548/492, 548/236, 548/248, 560/21, 560/22, 514/374, 514/378, 514/381, 514/382, 514/406, 514/419, 514/470, 541/471, 541/569
• US Class Current: 514/382
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07C 233/73 of a carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 235/48 having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 2601/08 the ring being saturated
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07D 209/42 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 231/14 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 307/68 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 307/84 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 307/85 attached in position 2
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links

Abstract

This invention provides novel compounds, pharmaceutical compositions and methods of treating thrombotic disorders in mammals, the compounds having the formula:

Wherein: Ar is phenyl, naphthyl, furanyl, benzofuranyl, indolyl, pyrazolyl, oxazolyl, fluorenyl, phenylcycloalkane where the cycloalkane can be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl and Ar can be optionally substituted by 1 to 3 groups selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxy, phenyl-(CH₂)_0-6—, phenyl-(CH₂)_0-6O—, C₃-C₆ cycloalkyl, —(CH₂)—C₃-C₆ cycloalkyl, halogen, C₁-C₃ perflouroalkyl and C₁-C₃ perfluoroalkoxy where phenyl can be substituted with from 1 to 3 groups selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, phenyl, halogen, trifluoromethyl or trifluoromethoxy; R₁ is hydrogen, C₁-C₆ alkyl or phenyl-(CH₂)_1-6— where phenyl can be substituted with C₁-C₆ alkyl, C₁-C₆ alkoxy, halo, trifluoromethyl or trifluoromethoxy; R₂ and R₃ are H, C₁-C₆ alkyl, phenyl-(CH₂)_0-3—, halo and C₁-C₃ perfluoroalkyl where phenyl can be substituted with C₁-C₆ alkyl, C₁-C₆ alkoxy, halo, trifluoromethyl or trifluoromethoxy; R₄ is —CHR₅CO₂H or —CH₂-tetrazole where R₅ is H or benzyl; and n=0 or 1; or a pharmaceutically acceptable salt or ester form thereof.

Claims

1. A compound of the formula:

Wherein;

Ar is phenyl, naphthyl, furanyl, benzofuranyl, indolyl, pyrazolyl, oxazolyl, fluorenyl, phenylcycloalkane where the cycloalkane can be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl and Ar can be optionally substituted by from 1 to 3 groups selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxy, phenyl-(CH₂)_0-6—

, phenyl-(CH₂)_0-6O—

, C₃-C₆ cycloalkyl,

—

(CH₂)—

C₃-C₆ cycloalkyl, halogen, C₁-C₃ perflouroalkyl and C₁-C₃ perfluoroalkoxy where phenyl can be substituted with from 1 to 3 groups selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, phenyl, halogen, trifluoromethyl or trifluoromethoxy;

R₁ is hydrogen, C₁-C₆ alkyl or phenyl-(CH₂)_1-6—

where phenyl can be substituted with C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, trifluoromethyl or trifluoromethoxy;

R₂ and R₃ are independently hydrogen, C₁-C₆ alkyl, phenyl-(CH₂)_0-3—

, halogen and C₁-C₃ perfluoroalkyl where phenyl can be substitute with C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, trifluoromethyl or trifluoromethoxy.

R₄ is —

CHR₅CO₂H or —

CH₂-tetrazole where R₅ is hydrogen or benzyl; and

n=0 or 1;

or a pharmaceutically acceptable salt or ester form thereof.

2. A compound of claim 1 of the formulae 1 or 2:

R₁ is hydrogen, C₁-C₆ alkyl or phenyl-(CH₂)_1-6—

where phenyl can be substituted with C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, trifluoromethyl or trifluoromethoxy;

R₂ and R₃ are independently hydrogen, C₁-C₆ alkyl, phenyl-(CH₂)_0-3—

, halogen and C₁-C₃ perfluoroalkyl where phenyl can be substitute with C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, trifluoromethyl or trifluoromethoxy;

R₄ is —

CHR₅CO₂H or —

CH₂-tetrazole;

R₅ is hydrogen or benzyl;

R₆ is selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxy, phenyl-(CH₂)_0-6—

, phenyl-(CH₂)_0-6O—

, C₃-C₆, cycloalkyl, halogen, C₁-C₃ perflouroalkyl and C₁-C₃ perfluoroalkoxy;

where the phenyl ring in these R₆ groups can be substituted with C₁-C₆ alkyl, C₁-C₆ alkoxy, phenyl-(CH₂)_0-3—

, halogen, trifluoromethyl or trifluoromethoxy;

or a pharmaceutically acceptable salt or ester form thereof.

3. A compound of claim 1 of the formula:

wherein;

Ar is a moiety selected from the group of;

 

R₁ is hydrogen, C₁-C₆ alkyl or phenyl-(CH₂)_1-6—

where phenyl can be substituted with C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, trifluoromethyl or trifluoromethoxy;

R₂ and R₃ are independently hydrogen, C₁-C₆ alkyl, phenyl-(CH₂)_0-3—

, halogen and C₁-C₃ perfluoroalkyl where phenyl can be substitute with C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, trifluoromethyl or trifluoromethoxy;

R₄ is —

CHR₅CO₂H or —

CH₂-tetrazole;

R₅ is hydrogen or benzyl;

R₇ is selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxy, phenyl-(CH₂)_0-6—

, phenyl-(CH₂)_0-6O—

, C₃-C₆ cycloalkyl, halogen, C₁-C₃ perflouroalkyl and C₁-C₃ perfluoroalkoxy;

where the phenyl ring in these R₇ groups can be substituted with C₁-C₆ alkyl, C₁-C₆ alkoxy, phenyl, halogen, trifluoromethyl or trifluoromethoxy;

R₈ and R₉ are each independently selected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, phenyl-(CH₂)_0-3—

, halogen, trifluoromethyl or trifluoromethoxy;

or a pharmaceutically acceptable salt or ester form thereof.

4. A compound of claim 1 of the formula:

wherein;

R₁ is hydrogen, C₁-C₆ alkyl or phenyl-(CH₂)_1-6—

where phenyl can be substituted with C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, trifluoromethyl or trifluoromethoxy;

R₂ and R₃ are independently hydrogen, C₁-C₆ alkyl, phenyl-(CH₂)_0-3—

, halogen and C₁-C₃ perfluoroalkyl where phenyl can be substituted with C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, trifluoromethyl or trifluoromethoxy;

R₄ is —

CHR₅CO₂H or —

CH₂-tetrazole;

R₅ is hydrogen or benzyl;

R₇ is selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxy, phenyl-(CH₂)_0-6—

, phenyl-(CH₂)_0-6O—

, C₃-C₆, cycloalkyl, halogen, C₁-C₃ perflouroalkyl and C₁-C₃ perfluoroalkoxy;

where the phenyl ring in these R₇ groups can be substituted with C₁-C₆ alkyl, C₁-C₆ alkoxy, phenyl-(CH₂)_0-3—

, halogen, trifluoromethyl or trifluoromethoxy;

R₈ and R₉ are each independently selected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, phenyl, halogen, trifluoromethyl or trifluoromethoxy;

or a pharmaceutically acceptable salt or ester form thereof.

5. A compound of claim 1 of the formula:

wherein;

R₁ is hydrogen, C₁-C₆ alkyl or phenyl-(CH₂)_1-6—

where phenyl can be substituted with C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, trifluoromethyl or trifluoromethoxy;

R₂ and R₃ are independently hydrogen, C₁-C₆ alkyl, phenyl-(CH₂)_0-3—

, halogen and C₁-C₃ perfluoroalkyl where phenyl can be substitute with C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, trifluoromethyl or trifluoromethoxy;

R₄ is —

CHR₅CO₂H or —

CH₂-tetrazole;

R₅ is hydrogen or benzyl;

R₁₀ is selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxy, C₃-C₆, cycloalkyl, halogen, C₁-C₃ perflouroalkyl and C₁-C₃ perfluoroalkoxy;

R₁₁ is selected from C₁-C₆ alkyl, phenyl-(CH₂)_0-6—

, C₃-C₆ cycloalkyl, or —

(CH₂)—

C₃-C₆ cycloalkyl;

where the phenyl ring in these R₇ groups can be substituted with C₁-C₆ alkyl, C₁-C₆ alkoxy, phenyl, halogen, trifluoromethyl or trifluoromethoxy;

Or a pharmaceutically acceptable salt or ester form thereof.

6. A compound of claim 1 of the formula:

wherein;

R₁ is hydrogen, C₁-C₆ alkyl or phenyl-(CH₂)_1-6—

where phenyl can be substituted with C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, trifluoromethyl or trifluoromethoxy;

R₂ and R₃ are independently hydrogen, C₁-C₆ alkyl, phenyl-(CH₂)_0-3—

, halogen and C₁-C₃ perfluoroalkyl where phenyl can be substitute with C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, trifluoromethyl or trifluoromethoxy;

R₄ is —

CHR₅CO₂H or —

CH₂-tetrazole;

R₅ is hydrogen or benzyl;

R₈ and R₉ are each independently selected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, phenyl, halogen, trifluoromethyl or trifluoromethoxy;

or a pharmaceutically acceptable salt or ester form thereof.

7. A compound of claim 1 which is selected from the group of:

(6-{[Benzofuran-2-carbonyl)-amino]-methyl}-naphthalen-2-yloxy)-acetic acid;

Benzofuran-2-carboxylic acid [6-(2H-tetrazol-5-ylmethoxy-naphthalen-2-ylmethyl]-amide;

2-Butyl-benzofuran-3-carboxylic acid [6-(2H-tetrazol-5-ylmethoxy)-naphthalen-2-yl]-amide;

{6-[(2-Butyl-benzofuran-3-carbonyl)-amino]-naphthalen-2-yloxy}-acetic acid;

or

2-Butyl-benzofuran-3-carboxylic acid [5-bromo-6-(2H-tetrazol-5-ylmethoxy)-naphthalen-2-yl]-amide;

or

a pharmaceutically acceptable salt or ester form thereof.

8. A compound of claim 1 which is selected from the group of:

{1-Bromo-6-[(2-butyl-benzofuran-3-carbonyl)-amino]-naphthalen-2-yloxy}-acetic acid;

2-{1-Bromo-6-[(2-butyl-benzofuran-3-carbonyl)-amino]-naphthalen-2-yloxy}-3-phenyl-propionic acid;

2-Butyl-benzofuran-3-carboxylic acid [6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-amide;

(6-{[(2-butyl-benzofuran-3-carbonyl)-amino]-methyl}-naphthalen-2-yloxy)-acetate;

[6-({[5-(4-Chloro-phenyl)-2-methyl-furan-3-carbonyl]-amino}-methyl)-naphthalen-2-yloxy]-acetic acid;

or

[6-({[5-(4-Chloro-phenyl)-2-trifluoromethyl-furan-3-carbonyl]-amino}-methyl)-naphthalen-2-yloxy]-acetic acid;

or

a pharmaceutically acceptable salt or ester form thereof.

9. A compound of claim 1 which is selected from the group of:

(6-{[(1-phenyl-5-propyl-1H-pyrazole-4-carbonyl)-amino]-methyl}-naphthalen-2-yloxy)-acetic acid;

[6-({[1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carbonyl]-amino}-methyl)-naphthalen-2-yloxy]-acetic acid;

[6-({[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl]-amino}-methyl)-naphthalen-2-yloxy]-acetic acid;

(1-Bromo-6-{[(1-phenyl-5-propyl-1H-pyrazole-4-carbonyl)-amino]-methyl}-naphthalen-2-yloxy)-acetic acid;

or

[1-Bromo-6-({[1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl]-amino}-methyl)-naphthalen-2-yloxy]-acetic acid.

10. A compound of claim 1 which is selected from the group of:

2-Butyl-benzofuran-3-carboxylic acid [5-bromo-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-amide;

2-(1-Bromo-6-{[(2-butyl-benzofuran-3-carbonyl)-amino]-methyl}-naphthalen-2-yloxy)-3-phenyl-propionic acid;

(1-bromo-6-{[(2-butyl-benzofuran-3-carbonyl)-amino]-methyl}-naphthalen-2-yloxy)-acetate;

2-Methyl-benzofuran-3-carboxylic acid [5-bromo-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-amide;

or

2-Ethyl-benzofuran-3-carboxylic acid [5-bromo-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-amide;

or

a pharmaceutically acceptable salt or ester form thereof.

11. A compound of claim 1 which is selected from the group of:

1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid [5-bromo-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-amide;

2-Butyl-benzofuran-3-carboxylic acid [6-(1H-tetrazol-5-ylmethoxy)-5-p-tolyl-naphthalen-2-ylmethyl]-amide;

2-Butyl-benzofuran-3-carboxylic acid [5-phenyl-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-amide;

2-Butyl-benzofuran-3-carboxylic [5-(4-methoxy phenyl)-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-amide;

or

2-Butyl-benzofuran-3-carboxylic acid [5-(4-chloro-phenyl)-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-amide;

or

a pharmaceutically acceptable salt or ester form thereof.

12. A compound of claim 1 which is selected from the group of:

2-Butyl-benzofuran-3-carboxylic acid [5-(4-tert-butyl-phenyl)-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-amide;

(6-{[(2-Butyl-benzofuran-3-carbonyl)-amino]-methyl}-1-phenyl-naphthanen-2-yloxy)-acetic acid;

2-[6-{[(2-Butyl-benzofuran-3-carbonyl)-amino]-methyl}-1-(4-chloro-phenyl)-naphthalen-2-yloxy]-3-phenyl-propionic acid;

2-[6-{[(2-Butyl-benzofuran-3-carbonyl)-amino]-methyl}-1-(4-methoxy-phenyl)-naphthalen-2-yloxy]-3-phenyl-propionate;

or

2-Butyl-benzofuran-3-carboxylic acid [5-bromo-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-methyl-amide;

or

a pharmaceutically acceptable salt or ester form thereof.

13. A compound of claim 1 which is selected from the group of:

2-Ethyl-benzofuran-3-carboxylic acid [5-bromo-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-methyl-amide;

1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid [5-bromo-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-methyl-amide;

1-Benzyl-1H-indole-3-carboxylic acid [5-bromo-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-methyl-amide;

2-Butyl-benzofuran-3-carboxylic acid methyl-[6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2ylmethyl]-methyl-amide;

or

2-Butyl-1-methyl-1H-indole-3-carboxylic acid [5-bromo-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-methyl-amide;

or

a pharmaceutically acceptable salt or ester form thereof.

14. A compound of claim 1 which is selected from the group of:

1-Methyl-1H-indole-3-carboxylic acid [5-bromo-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-methyl-amide;

5-(3,5-Dichloro-phenoxy)-furan-2-carboxylic acid [5-bromo-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-methyl-amide;

3-Butyl-benzofuran-2-carboxylic acid [5-bromo-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-methyl-amide;

2-Benzyl-3-(1-bromo-6-{[(3-butyl-benzofuran-2-carbonyl)-methyl-amino]-methyl}-naphthalen-2-yloxy)-propionic acid;

or

3-Methyl-benzofuran-2-carboxylic acid [5-bromo-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-methyl-amide;

or

a pharmaceutically acceptable salt or ester form thereof.

15. A compound of claim 1 which is selected from the group of:

2-benzyl-3-(1-bromo-6-{[methyl-(3-methyl-benzofuran-2-carbonyl)-amino]-methyl}-naphthalen-2-yloxy)-propionate;

3-Methyl-benzofuran-2-carboxylic acid [5-bromo-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-amide;

2-(1-Bromo-6-{[(3-methyl-benzofuran-2-carbonyl)-amino]-methyl}-naphthalen-2-yloxy)-3-phenyl-propionic acid;

3-Phenethyl-benzofuran-2-carboxylic acid [5-bromo-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-methyl-amide;

or

2-(1-Bromo-6-{[methyl-(3-phenethyl-benzofuran-2-carbonyl)-amino]-methyl}-naphthalen-2-yloxy)-3-phenyl-propionic acid;

or

a pharmaceutically acceptable salt or ester form thereof.

16. A compound of claim 1 which is selected from the group of:

(1-Bromo-6-{[methyl-(3-phenethyl-benzofuran-2-carbonyl)-amino]-methyl}-naphthalen-2-yloxy)-acetic acid;

2-Butyl-benzofuran-3-carboxylic acid benzyl-[5-bromo-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-amide;

2-Methyl-benzofuran-3-carboxylic acid benzyl-[5-bromo-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-amide;

2-Ethyl-benzofuran-3-carboxylic acid benzyl-[5-bromo-6-(1H-tetrazol-5ylmethoxy)-naphthalen-2-ylmethyl)-amide;

or

2-Butyl-benzofuran-3-carboxylic acid [5-bromo-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-butyl-amide;

or

a pharmaceutically acceptable salt or ester form thereof.

17. A compound of claim 1 which is selected from the group of:

2-Methyl-benzofuran-3-carboxylic acid [5-bromo-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-butyl-amide;

2-[1-Bromo-6-({[5-(3,5-dichloro-phenoxy)-furan-2-carbonyl]-amino}-methyl)-naphthalen-2-yloxy]-3-phenyl-propionic acid;

2-(1-Bromo-6-{[(1-phenyl-5-propyl-1H-pyrazole-4-carbonyl)-amino]-methyl}-naphthalen-2-yloxy)-3-phenyl-propionic acid;

2-{1-Bromo-6-[4-cyclohexyl-benzoylamino)-methyl]-naphthalen-2-yloxy}-3-phenyl-propionic acid;

or

2-{1-Bromo-6-[(3,5-di-tert-butyl-benzoylamino)-methyl]-naphthalen-2-yloxy}-3-phenyl-propionic acid;

or

a pharmaceutically acceptable salt or ester form thereof.

18. A compound of claim 1 which is selected from the group of:

2-{1-Bromo-6-[(3-phenoxy-benzoylamino)-methyl]-naphthalen-2-yloxy}-3-phenyl-propionic acid;

2-(1-Bromo-6-{[(2-ethyl-benzofuran-3-carbonyl)-amino]-methyl}-naphthalen-2-yloxy)-3-phenyl-propionic acid;

2-[1-Bromo-6-({[1-4-chloro-phenyl)-cyclopentanecarbonyl]-amino}-methyl)-naphthalen-2-yloxy]-3-phenyl-propionic acid;

or

2-Bromo-6-({[5-(3-trifluoromethyl-phenyl)-furan-2-carbonyl]-amino}-methyl)-naphthalen-2-yloxy]-3-phenyl-propionic acid;

or

a pharmaceutically acceptable salt or ester form thereof.

19. A compound of claim 1 which is selected from the group of:

2-(1-Bromo-6-{[(4-cyclohexyl-benzoyl)-methyl-amino]-methyl}-naphthalen-2-yloxy)-3-phenyl-propionic acid;

2-(1-Bromo-6-{[(2-butyl-benzofuran-3-carbonyl)-methyl-amino]-methyl}naphthalen-2-yloxy)-3-phenyl-propionic acid;

2-(1-Bromo-6-{[methyl-(4′

-propyl-biphenyl-4-carbonyl)-amino]-methyl}-naphthalen-2-yloxy)-3-phenyl-propionic acid;

2-[1-Bromo-6-({[5-(3,5-dichloro-phenoxy)-furan-2-carbonyl]-methyl-amino}-methyl)-naphthalen-2-yloxy]-3-phenyl-propionic acid;

or

2-(1-Bromo-6-{[(3,5-di-tert-butyl-benzoyl)-methyl-amino]-methyl}-naphthalen-2-yloxy)-3-phenyl-propionic acid;

or

a pharmaceutically acceptable salt or ester form thereof.

20. A compound of claim 1 which is selected from the group of:

2-(1-Bromo-6-{[methyl-(1-phenyl-5-propyl-1H-pyrazole-4-carbonyl)-amino]-methyl}-naphthalen-2-yloxy)-3-phenyl-propionic acid;

2-[6-({Benzyl-[5-(3,5-dichloro-phenoxy)-furan-2-carbonyl]-amino}-methyl)-1-bromo-naphthalen-2-yloxy]-3-phenyl-propionic acid;

2-(6-{[Benzyl-(2-butyl-benzofuran-3-carbonyl)-amino]-methyl}-1-bromo-naphthalen-2-yloxy)-3-phenyl-propionic acid;

2-(6-{[Benzyl-(3,5-di-tert-butyl-benzoyl)-amino]-methyl}-1-bromo-naphthalen-2-yloxy)-3-phenyl-propionic acid;

or

2-(6-{[Benzyl-(4′

-propyl-biphenyl-4-carbonyl)-amino]-methyl}-1-bromo-naphthalen-2-yloxy)-3-phenyl propionic acid;

or

a pharmaceutically acceptable salt or ester form thereof.

21. A compound of claim 1 which is selected from the group of:

2-(6-{[Benzyl-(4-cyclohexyl-benzoyl)-amino]-methyl}-1-bromo-naphthalen-2-yloxy-3-phenyl-propionic acid;

2-(6-{[Benzyl-(1-phenyl-5-propyl-1H-pyrozole-4-carbonyl)-amino]-methyl}-1-bromo-naphthalen-2-yloxy)-3-phenyl-propionic acid;

(6-{[5-(2-Chloro-phenyl)-2-trifluoromethyl-furan-3-carbonyl]-amino}naphthalen-2-yloxy)-acetic acid;

(6-{[5-(3-Trifluoromethyl-phenyl)-furan-2-carbonyl]-amino}-naphthalen-2-yloxy)-acetic acid;

or

(6-{[1-(4-Chloro-phenyl)-cyclopentanecarbonyl]-amino}-naphthalen-2-yloxy)-acetic acid;

or

a pharmaceutically acceptable salt or ester form thereof.

22. A compound of claim 1 which is selected from the group of:

[6-(2-Benzyloxy-benzoylamino)-naphthalen-2-yloxy]-acetic acid;

[6-(3,5-Di-tert-butyl-benzoylamino)-naphthalen-2yl oxy]-acetic acid;

{6-[(5-Biphenyl-4-yl-2-trifluoromethyl-furan-3-carbonyl)-amino]-naphthalen-2-yloxy}-acetic acid;

(6-{[1-(4-Chloro-phenyl)-cyclohexanecarbonyl]-amino}-naphathalen-2-yloxy)-acetic acid;

or

(6-{[1-(4-Chloro-phenyl)-cyclobutanecarbonyl]-amino}-naphthalen-2-yloxy)-acetic acid;

or

a pharmaceutically acceptable salt or ester form thereof.

23. A compound of claim 1 which is selected from the group of:

[6-({[5-(2-Chloro-phenyl)-2-trifluoromethyl-furan-3-carbonyl]-amino}-methyl)-naphthalen-2-yloxy]-acetic acid;

[6-({[2-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-furan-3-carbonyl]-amino}methyl)-naphthalen-2-yloxy]-acetic acid;

{6-[(2-Phenethyl-benzoylamino)-methyl]-naphthalen-2-yloxy}-acetic acid;

[6-({[1-(4-Chloro-phenyl)-cyclopentanecarbonyl]-amino}-methyl)-naphthalen-2-yloxy]-acetic acid;

[6-({[5-(3-Trifluoromethyl-phenyl)-furan-2-carbonyl]-amino}-methyl)-naphthalen-2-yloxy]-acetic acid;

{6-[(3,5-Di-tert-butyl-benzoylamino)-methyl]-naphthalen-2-yloxy}-acetic acid;

or

(6-{[(1-Phenyl-cyclopentanecarbonyl)-amino]-methyl}-naphthalen-2-yloxy)-acetic acid;

or

a pharmaceutically acceptable salt or ester form thereof.

24. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt or ester form thereof, a pharmaceutically acceptable carrier or excipient.

25. A method of treatment of noninsulin dependent diabetes mellitus in a mammal, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt or ester form thereof.

26. A method of treatment or prevention of a prothrombotic or thrombotic state or event in a mammal, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt or ester form thereof.

27. A method of claim 26 wherein the prothrombotic or thrombotic state or event is associated with coronary artery or cerebrovascular disease.

28. A method of claim 26 wherein the prothrombotic or thrombotic state or event is formation of atherosclerotic plaques, venous and arterial thrombosis, myocardial ischemia, atrial fibrillation, deep vein thrombosis, coagulation syndromes, pulmonary fibrosis, cerebral thrombosis, thromboembolic complications of surgery or peripheral arterial occlusion.

29. A method for the treatment of stroke associated with or resulting from atrial fibrillation in a mammal, comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of claim 1.

30. A method for the treatment of deep vein thrombosis in a mammal, comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of claim 1.

31. A method for the treatment of myocardial ischemia in a mammal, comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of claim 1.

32. A method for the treatment of cardiovascular disease caused by noninsulin dependent diabetes mellitus in a mammal, comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of claim 1.

33. A method for the treatment of the formation of atherosclerotic plaques in a mammal, comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of claim 1.

34. A method for the treatment of chronic obstructive pulmonary disease in a mammal, comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of claim 1.

35. A method for the treatment of renal fibrosis in a mammal, comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of claim 1.

36. A method for the treatment of polycystic ovary syndrome in a mammal, comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of claim 1.

37. A method for the treatment of Alzheimer'"'"'s disease in a mammal, comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of claim 1.

38. A method for the treatment of cancer in a mammal, comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of claim 1.