NOVEL PYRAZOLE-BASED HMG CoA REDUCTASE INHIBITORS

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.

1 . A compound of the formula (I): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is hydrogen, halogen, C 1 -C 7 alkyl, C 3 -C 8 cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; 
 where alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl of R 1  is optionally substituted; 
 R 2  is R 2b R 2a NCO(CH 2 ) n — or R 2b -J-C(O)NR 2a (CH 2 ) n —; 
 J is a direct bond, O, or N; 
 R 2a  and R 2b  are each independently hydrogen, C 1 -C 10  alkyl, C 3 -C 8  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, C 1 -C 10  alkyl, C 1 -C 10  haloalkyl, C 3 -C 8  cycloalkyl, halogen, R 7 O—, R 7 OOC(CH 2 ) n —, R 7 R 8 NCO(CH 2 ) n —, R 7 O 2 S(CH 2 ) n —, R 8 R 7 NSO 2 — or NC—; 
 R 7  and R 8  are each independently hydrogen, C 1 -C 12  alkyl, aryl or aralkyl; where alkyl, aryl or aralkyl of R 7  and R 8  is optionally substituted; 
 n is 0, 1 or 2; 
 R 3  is hydrogen, C 1-6  alkyl, C 3-8 cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; where alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl of R 3  is optionally substituted; and 
 --- is a bond or is absent. 
 
   
   
       2 . A compound according to  claim 1  having the following (3R,5R) stereospecific formula (Ia): 
     
       
         
         
             
             
         
       
     
   
   
       3 . A compound according to  claim 1  having the structural formula (II): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein:
 R 2a  and R 2b  are each independently hydrogen, C 1 -C 10  alkyl, C 3 -C 8  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, C 1 -C 10  alkyl, C 3 -C 8  cycloalkyl, halogen, R 7 O—, R 7 OOC(CH 2 ) n —, R 7 R 8 NCO(CH 2 ) n —, R 7 O 2 S(CH 2 ) n —, R 8 R 7 NSO 2 — or NC—; 
 R 7  and R 8  are each independently hydrogen, C 1 -C 12  alkyl, aryl or aralkyl; where alkyl, aryl or aralkyl of R 7  and R 8  is optionally substituted; 
 n is 0, 1, or 2; and 
 --- is a bond or is absent. 
 
   
   
       4 . A compound according to  claim 3 , wherein R 2a  is: 
     
       
         
         
             
             
         
       
       Where R 4  and R 5  are each independently hydrogen or lower alkyl; 
       q is 0, 1 or 2; 
       each R 6  is independently hydrogen, halogen, alkyl, haloalkyl, alkoxy, or cyano; and 
       p is 0, 1, 2, 3, 4, or 5. 
     
   
   
       5 . A compound according to  claim 4  having the following (3R,5R) stereospecific formula (IIa): 
     
       
         
         
             
             
         
       
     
   
   
       6 . A compound according to  claim 1  having the structure of formula (III): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
   
   
       7 . A compound according to  claim 6  having the following (3R,5R) stereospecific formula (IIIa): 
     
       
         
         
             
             
         
       
     
   
   
       8 . A compound of formula (IV): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is hydrogen, halogen, C 1 -C 7 alkyl, C 3 -C 8 cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; 
 where alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl of R 1  is optionally substituted; 
 R 2  is R 2b R 2a N(CH 2 ) n — or R 2b -J-C(O)NR 2a (CH 2 ) n —; 
 J is a direct bond, O, or N; 
 R 2a  and R 2b  are each independently hydrogen, C 1 -C 10  alkyl, C 3 -C 8  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, C 1 -C 10  alkyl, C 3 -C 8  cycloalkyl, halogen, R 7 O—, R 7 OOC(CH 2 ) n —, R 7 R 8 NCO(CH 2 ) n —, R 7 O 2 S(CH 2 ) n —, R 8 R 7 NSO 2 — or NC—; 
 R 7  and R 8  are each independently hydrogen, C 1 -C 12  alkyl, aryl or aralkyl; where alkyl, aryl or aralkyl of R 7  and R 8  is optionally substituted; 
 n is 0, 1 or 2; 
 R 3  is hydrogen, C 1-6  alkyl, C 3-8 cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; where alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl of R 3  is optionally substituted; and 
 --- is a bond or is absent. 
 
   
   
       9 . A compound according to  claim 8  having the following stereospecific formula (IVa): 
     
       
         
         
             
             
         
       
     
   
   
       10 . A compound of formula (V): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is hydrogen, halogen, C 1 -C 7 alkyl, C 3 -C 8 cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; 
 where alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl of R 1  is optionally substituted; 
 R 2  is R 2b R 2a NCO(CH 2 ) n — or R 2b -J-C(O)NR 2a (CH 2 ) n —; 
 J is a direct bond, O, or N; 
 R 2a  and R 2b  are each independently hydrogen, C 1 -C 10  alkyl, C 3 -C 8  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, C 1 -C 10  alkyl, C 3 -C 8  cycloalkyl, halogen, R 7 O—, R 7 OOC(CH 2 ) n —, R 7 R 8 NCO(CH 2 ) n —, R 7 O 2 S(CH 2 ) n —, R 8 R 7 NSO 2 — or NC—; 
 R 7  and R 8  are each independently hydrogen, C 1 -C 12  alkyl, aryl or aralkyl; where alkyl, aryl or aralkyl of R 7  and R 8  is optionally substituted; 
 n is 0, 1 or 2; 
 R 3  is hydrogen, C 1-6  alkyl, C 3-8 cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; where alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl of R 3  is optionally substituted; and 
 --- is a bond or is absent. 
 
   
   
       11 . A compound according to  claim 1  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-(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-(4-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-3-yl]-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-2H-pyrazol-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-3-yl]-3,5-dihydroxy-heptanoic acid; or 
     a pharmaceutically acceptable salt thereof. 
   
   
       12 . A compound of  claim 11 , wherein said pharmaceutically acceptable salt is a sodium salt. 
   
   
       13 . A compound according to  claim 8  selected from the group consisting of: 
     1-(4-Fluoro-phenyl)-5-[2-(4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-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 thereof. 
   
   
       14 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, solvent or vehicle. 
   
   
       15 . 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 at least one compound of  claim 1 , or a pharmaceutically acceptable salt thereof. 
   
   
       16 . A combination comprising a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and a second pharmaceutically active agent. 
   
   
       17 . The combination of  claim 16 , wherein said second 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. 
   
   
       18 . The combination of  claim 16  further comprising a pharmaceutically acceptable carrier, diluent, solvent or vehicle. 
   
   
       19 . (canceled) 
   
   
       20 . (canceled)