Novel pyrazole-based HMG CoA reductase inhibitors

• US 20060111422A1
• Filed: 11/18/2005
• Published: 05/25/2006
• Est. Priority Date: 11/23/2004
• Status: Active Grant

• Current Assignee: Warner-Lambert Company LLC (Pfizer Inc.)
• Original Assignee: Warner-Lambert Company LLC (Pfizer Inc.)
• Inventors: Bowles, Daniel Merritt, Pfefferkorn, Jeffrey A., Choi, Chulho, Hutchings, Richard H., Park, William K. C.
• Granted Patent: US 7,446,121 B2
• Time in Patent Office: Days
• US Class Current: 514/406
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• 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: C07D 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• 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 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/06 linked by a carbon chain containing only aliphatic carbon atoms

Abstract

Novel compounds and pharmaceutical compositions useful as hypocholesterolemic and hypolipidemic agents are described. More specifically, potent inhibitors of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (“HMG CoA reductase”) are described. Methods of using such compounds and compositions to treat subjects, including humans, suffering from hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, atherosclerosis, Alzheimer'"'"'s Disease, benign prostatic hypertrophy (BPH), diabetes and osteoporosis are also described.

Claims

1. A compound of the formula (I):

2. A compound of claim 1 having the following (3R, 5R) stereospecific formula (Ia):

3. A compound of claim 1 or 2, wherein R₁ is optionally substituted C₁-C₇ alkyl or C₃-C₈ cycloalkyl.

4. A compound of claim 3, wherein R₃ is optionally substituted aryl.

5. A compound of claim 4, wherein R₁ is isopropyl.

6. A compound of claim 4, wherein R₃ is p-fluorophenyl.

18. A pharmaceutical composition comprising a compound of any one of claims 1-17 and a pharmaceutically acceptable carrier, diluent, solvent or vehicle.

19. A method of treating a subject suffering from hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, atherosclerosis, Alzheimer'"'"'s Disease, benign prostatic hypertrophy(BPH), diabetes and osteoporosis comprising administering a therapeutically effective amount of a compound of any one of claims 1-17 to the subject in need thereof.

23. A combination comprising a compound of any one of claims 1-17 and a pharmaceutically active agent.

24. The combination of claim 23, wherein said pharmaceutically active agent is a CETP inhibitor, a PPAR-activator, an MTP/Apo B secretion inhibitor, a cholesterol absorption inhibitor, HDL-cholesterol raising agent, triglyceride lowering agent, a cholesterol synthesis inhibitor, a cholesterol modulating agent, a fibrate, niacin, an ion-exchange resin, an antioxidant, an ACAT inhibitor, bile acid sequestrant, an anti-hypertensive agent, or an acetylcholine esterase inhibitor.

25. A pharmaceutical composition comprising the combination of claim 23 or 24 and a pharmaceutically acceptable carrier, diluent, solvent or vehicle.

7. A compound of formula (II):

8. A compound of claim 7, wherein R_2a is:

9. A compound of claim 7 or 8 having the following (3R, 5R) stereospecific formula (IIa):

10. A compound of formula (III):

11. A compound of claim 10 having the following (3R, 5R) stereospecific formula (IIIa):

12. A compound of formula (IV):

13. A compound of claim 12 having the following stereospecific formula (IVa):

14. A compound of formula (V):

15. A compound selected from the group consisting of:

(3R,5R)-7-[5-benzylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(2-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(2-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid;

(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid;

(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-methoxy-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methoxy-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-methoxy-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid;

(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methoxy-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid;

(3R,5R)-7-[5-(benzyl-methyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-[5-[(3-fluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-[5-[(4-fluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid;

(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[N-methyl-(R)-α

-methyl-benzylcarbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-[(R)-α

-methyl-benzylcarbamoyl]-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-[(S)-α

-methyl-benzylcarbamoyl]-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-[5-(benzyl-methyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid;

(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-[(R)-α

-methyl-benzylcarbamoyl]-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid;

(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-[(S)-α

-methyl-benzylcarbamoyl]-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid;

(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-phenethylcarbamoyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-methylcarbamoyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-[5-ethylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-[5-dimethylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

7-(5-Benzylcarbamoyl-4-isopropyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl)-3R,5R-dihydroxy-heptanoic acid;

7-(5-Benzylcarbamoyl-4-isopropyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl)-3R,5R-dihydroxy-heptanoic acid;

3R,5R-Dihydroxy-7-[4-isopropyl-5-(3-methyl-benzylcarbamoyl)-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-heptanoic acid;

3R,5R-Dihydroxy-7-[4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-heptanoic acid;

3R,5R-Dihydroxy-7-[4-isopropyl-5-(3-methoxy-benzylcarbamoyl)-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-heptanoic acid;

3R,5R-Dihydroxy-7-[4-isopropyl-5-(4-methoxy-benzylcarbamoyl)-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-heptanoic acid;

7-[5-(Benzyl-methyl-carbamoyl)-4-isopropyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-3R,5R-dihydroxy-heptanoic acid;

7-{5-[(3-Fluoro-benzyl)-methyl-carbamoyl]-4-isopropyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl}-3R,5R-dihydroxy-heptanoic acid;

7-{5-[(4-Fluoro-benzyl)-methyl-carbamoyl]-4-isopropyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl}-3R,5R-dihydroxy-heptanoic acid;

3R,5R-Dihydroxy-7-[4-isopropyl-2-(4-fluoro-phenyl)-5-[(R)α

-methyl-benzylcarbamoyl]-2H-pyrazol-3-yl]-heptanoic acid;

3R,5R-Dihydroxy-7-[4-isopropyl-2-(4-fluoro-phenyl)-5-[(S)-α

-methyl-benzylcarbamoyl]-2H-pyrazol-3-yl]-heptanoic acid;

3R,5R-Dihydroxy-7-{4-isopropyl-5-[N-methyl-(R)-α

-methyl-benzylcarbamoyl]-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl}-heptanoic acid;

3R,5R-Dihydroxy-7-{4-isopropyl-5-[N-methyl-(R)-α

-methyl-benzylcarbamoyl]-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl}-heptanoic acid;

3R,5R-Dihydroxy-7-[4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-hept-6-enoic acid;

3R,5R-Dihydroxy-7-[4-isopropyl-5-(3-methoxy-benzylcarbamoyl)-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-hept-6-enoic acid;

3R,5R-Dihydroxy-7-[4-isopropyl-5-(4-methoxy-benzylcarbamoyl)-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-hept-6-enoic acid;

3R,5R-Dihydroxy-7-(4-isopropyl-5-methylcarbamoyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl)-heptanoic acid;

7-(5-Ethylcarbamoyl-4-isopropyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl)-3R,5R-dihydroxy-heptanoic acid;

7-(5-Dimethylcarbamoyl-4-isopropyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl)-3R,5R-dihydroxy-heptanoic acid;

7-[5-(Benzyl-methyl-carbamoyl)-4-isopropyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-3R,5R-dihydroxy-hept-6-enoic acid;

3R,5R-Dihydroxy-7-[4-isopropyl-2-(4-fluoro-phenyl)-5-[(R)-α

-methyl-benzylcarbamoyl]-2H-pyrazol-3-yl]-hept-6-enoic acid;

3R,5R-Dihydroxy-7-[4-isopropyl-2-(4-fluoro-phenyl)-5-[(S)-α

-methyl-benzylcarbamoyl]-2H-pyrazol-3-yl]-hept-6-enoic acid;

(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(4-methyl-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-phenylcarbamoyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-[5-(3-fluoro-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-[5-(4-fluoro-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(1-methyl-1-phenyl-ethylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methoxymethyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(4-methoxy-benzyl)-methyl-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(3-methyl-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(3-methoxy-benzyl)-methyl-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-[5-(benzyl-ethyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-[5-(benzyl-isopropyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(1-phenyl-ethyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-[5-(cyclohexylmethyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(1-p-tolyl-ethylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-methoxymethyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[1-(3-methoxy-phenyl)-ethylcarbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-(2-(4-fluoro-phenyl)-4-isopropyl-5-[1-(4-methoxy-phenyl)-ethylcarbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(3-trifluoromethyl-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(4-trifluoromethyl-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-propylcarbamoyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-[5-(4-dimethylcarbamoyl-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(pyridin-2-ylmethyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-[2-(4-fluoro-phenyl)-5-(2-hydroxy-1-phenyl-ethylcarbamoyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(morpholine-4-carbonyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-isopropylcarbamoyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-[5-(cyclohexylmethyl-methyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-[5-(cyclopentylmethyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-[2-(4-fluoro-phenyl)-5-isobutylcarbamoyl-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-methyl-butylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-[5-cyclopentylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(2-phenyl-pyrrolidine-1-carbonyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-[5-(cyclobutylmethyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-[5-[(2,3-difluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-[5-(cyclopropylmethyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-[5-[(2,4-difluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(4-trifluoromethoxy-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-[5-butylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(piperidine-1-carbonyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(3-trifluoromethoxy-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-[5-cyclohexylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-[5-(4-cyano-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-[5-(3-cyano-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-[5-(cyclopentylmethyl-methyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-(2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2-methyl-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-[5-((2-fluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-[5-[(3,4-difluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-[5-(3-ethoxymethyl-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3yl]-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-[5-(4-ethyl-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(5-trifluoromethyl-pyridin-2-ylmethyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(6-trifluoromethyl-pyridin-3-ylmethyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(6-trifluoromethyl-piperidin-3-ylmethyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-isopropyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-phenyl-piperidine-1-carbonyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-phenyl-piperidine-1-carbonyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(6-methyl-pyridin-3-ylmethyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-[5-ethylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-phenylcarbamoyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid;

(3R,5R)-7-[5-(cyclohexylmethyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid;

(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-propylcarbamoyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid;

(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-isopropylcarbamoyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid;

(3R,5R)-7-[2-(4-fluoro-phenyl)-5-isobutylcarbamoyl-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid;

(3R,5R)-7-[5-cyclopentylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid;

(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-methyl-butylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid;

(3R,5R)-7-[5-(cyclopropylmethyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid;

(3R,5R)-7-[5-butylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid;

(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(3-trifluoromethoxy-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-hept-6-enoic acid;

(3R,5R)-7-[5-cyclohexylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid;

(3R,5R)-7-[5-(4-cyano-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid;

(3R,5R)-7-[5-(3-cyano-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid;

(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-methylcarbamoyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid;

(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2-methyl-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-hept-6-enoic acid;

(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(6-methyl-pyridin-3-ylmethyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-hept-6-enoic acid;

7-[5-[(2,6-difluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

7-[5-[(4-fluoro-2-methoxy-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2,3,4-trifluoro-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid;

7-(5-[(3-fluoro-4-methoxy-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2,3,6-trifluoro-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid;

7-[5-[(2,3-difluoro-4-methyl-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

7-[5-[(2,3-difluoro-6-methoxy-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

7-[5-[(3-fluoro-4-methyl-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

7-[5-[(4-fluoro-3-methyl-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

7-[5-[(2,3-difluoro-4-methoxy-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

7-[5-[(2-fluoro-3-methyl-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2,3,5-trifluoro-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid;

7-[5-[(3-fluoro-2-methoxy-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

7-[5-[(2-fluoro-3-methoxy-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;

7-[5-[(3-fluoro-2-methyl-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; and

(3R, 5R)-7-[2-(4-Fluoro-phenyl)-4-isopropyl-5-(2-phenyl-piperidine-1-carbonyl)-2H-pyrazol-3yl]-3,5-dihydroxy-heptanoic acid;

or

a pharmaceutically acceptable salt, ester, amide or prodrug thereof, or a pharmaceutically acceptable salt of the prodrug.

16. A compound of claim 15, wherein said pharmaceutically acceptable salt is a sodium salt.

17. A compound selected from the group consisting of:

1-(4-Fluoro-phenyl)-5-[2-(4-hydroxy-6-oxo-tetrahydro-pyran-2-y)-ethyl]-4-isopropyl-1H-pyrazole-3-carboxylic acid (3-fluoro-benzyl)-methyl-amide;

1-(4-Fluoro-phenyl)-5-[2-(4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-4-isopropyl-1H-pyrazole-3-carboxylic acid benzyl-methyl-amide; and

1-(4-Fluoro-phenyl)-5-[2-(4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-4-isopropyl-1H-pyrazole-3-carboxylic acid 4-methyl-benzylamide;

or

a pharmaceutically acceptable salt, ester, amide or prodrug thereof, or a pharmaceutically acceptable salt of the prodrug.

20. A compound of formula (VI):

21. A compound of formula (VII):

22. A compound of claim 21, wherein X is Br anion.

26. A process comprising the steps of:

(a) reacting a hydroxyl compound VII;

under conditions sufficient to form a compound IX;

(b) reacting a compound IX under conditions sufficient to form a compound X;

(c) reacting a compound X under conditions sufficient to form a compound XI;

(d) reacting a compound XI under conditions sufficient to form a compound XII;

(e) reacting a compound XII under conditions sufficient to form a compound XIII;

wherein for steps (a)-(e);

R₁ is hydrogen, halogen, C₁-C₇alkyl, C₃-C₈cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;

where alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl of R₁ is optionally substituted;

R₃ is hydrogen, C_1-6 alkyl, C_3-8cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;

where alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl of R₃ is optionally substituted;

n is 0, 1 or 2;

R⁷ is hydrogen, C₁-C₁₂ alkyl, aryl or aralkyl;

where alkyl, aryl or aralkyl of R⁷ is optionally substituted;

LG-O—

together is a leaving group; and

Z is R′

″

or R″

″

CX′

═

CX″

Y where

R′

″

is alkenyl;

R″

″

, X′ and

X″

are each hydrogen, alkyl, alkenyl, aryl, heteroaryl, or alkenyl substituent; and

Y is either a direct bond or a linker group.

27. A process comprising the steps of:

(a) reacting a compound XIV;

under conditions sufficient to form a compound XV;

(b) reacting a compound XV under conditions sufficient to form a compound XVI;

(c) reacting a compound XVI under conditions sufficient to form a compound XVII;

wherein for steps (a)-(c);

R₁ is hydrogen, halogen, C₁-C₇ alkyl, C₃-C₈ cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;

where alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl of R₁ is optionally substituted;

R₃ is hydrogen, C_1-6 alkyl, C_3-8cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;

where alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl of R₃ is optionally substituted;

R_2a and R_2b are each independently hydrogen, C₁-C₁₀ alkyl, C₃-C₈ cycloalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl;

where alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl of R_2a and R_2b is optionally substituted;

or R_2a and R_2b taken together with the nitrogen to which they are attached form a 4-11 member ring optionally containing at least one additional heteroatom selected from O, N and S, said ring being optionally substituted with at least one of aryl, aralkyl, heteroaryl, heteroaralkyl, C₁-C₁₀ alkyl, C₃-C₈ cycloalkyl, halogen, R⁷O—

, R⁷OOC(CH₂)_n—

, R⁷R⁸NCO(CH₂)_n—

, R⁷O₂S(CH₂)_n—

, R⁸R⁷NSO₂—

or NC—

;

R⁷and R⁸ are each independently hydrogen, C₁-C₁₂ alkyl, aryl or aralkyl;

where alkyl, aryl or aralkyl of R⁷and R⁸ is optionally substituted;

n is 0, 1 or 2;

LG-O—

together is a leaving group; and

Z is R′

″

or R″

″

CX′

═

CX″

Y where

R′

″

is alkenyl;

R″

″

, X′ and

X″

are each hydrogen, alkyl, alkenyl, aryl, heteroaryl, or alkenyl substituent; and

Y is either a direct bond or a linker group.