IP Library › Granted Patent US 7,148,226

Granted Patent B2

US 7,148,226 · App. 10/718,337 · Granted Dec 12, 2006

Inhibitors of hepatitis C virus RNA-dependent RNA polymerase, and compositions and treatments using the same

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Patent No.: US 7,148,226
App. No.: 10/718,337
Granted: Dec 12, 2006
Kind: B2

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Abstract

The invention relates to compounds of the formula 1 and to pharmaceutically acceptable salts, solvates, prodrugs and metabolites thereof, wherein W, Z, R 1 and R 2 , are as defined herein. The invention also relates to methods of treating Hepatitis C virus in mammals by administering the compounds of formula 1, and to pharmaceutical compositions for treating such disorders, which contain the compounds of formula 1. The invention also relates to methods of preparing the compounds of formula 1.

Claims (179)

1. Compounds of formula (4),

wherein:

R 1 is cyclopentyl;

R 3 is —(CR 8 R 9 ) t (4–10 membered heterocyclic), wherein t is an integer from 0 to 5, and the heterocyclic moiety is optionally substituted by 1 to 5 R 4 groups;

each R 4 is independently chosen from halo, C 1 –C 10 alkyl, and R 6 —O—, and each C 1 –C 10 alkyl may be optionally substituted by at least one substituent chosen from halo, trifluoromethyl, trifluoromethoxy, C 1 –C 10 alkyl, and cyano; or

when two adjacent R 4 groups are both C 1 –C 10 alkyl, they, together with the atoms to which they are attached, form a 3- to 7-membered ring, wherein in said ring any carbon atom may be replaced by a heteroatom chosen from N, O, and S, provided that two adjacent carbons are not both replaced by heteroatoms;

R 8 is hydrogen or C 1 –C 10 alkyl;

R 8 and R 9 are hydrogen;

z is an integer from 1 to 5; and

y is an integer from 0 to 5.

2. Compounds according to claim 1 , wherein:

R 3 is —(CH 2 ) t ([1,2,4]triazolo[1,5-a]pyrimidinyl), optionally substituted by 1 to 3 R 4 groups;

t is an integer from 1–3; and

y is an integer from 1 to 3.

3. Compounds according to claim 2 , wherein:

R 3 is —(CH 2 )([1,2,4]triazolo[1,5-a]pyrimidinyl), substituted by 1 to 3 R 4 groups;

each R 4 is independently chosen from halo and C 1 –C 10 alkyl optionally substituted with cyano; or

two adjacent R 4 groups are both C 1 –C 10 alkyl and, together with the atoms to which they are attached, form a 3- to 7-membered ring, wherein a carbon atom is replaced by a heteroatom chosen from N, O, and S;

z is an integer from 2 to 3; and

y is 2.

4. Compounds according to claim 3 , wherein:

R 3 is —(CH 2 )([1,2,4]triazolo[1,5-a]pyrimidinyl), substituted by 2 R 4 groups; and

each R 4 is independently chosen from halo, —CH 3 , and —C(CH 3 ) 2 CN.

5. Compounds according to claim 3 , wherein two adjacent R 4 groups are both C 1 –C 10 alkyl and, together with the atoms to which they are attached, form a 3- to 7-membered ring, wherein a carbon atom is replaced by a heteroatom chosen from N, O, and S.

6. Compounds according to claim 5 , wherein:

R 3 is —(CH 2 )([1,2,4]triazolo[1,5-a]pyrimidinyl), substituted by at least one substituent chosen from halo and methyl; and

two adjacent R 4 groups, together with the atoms to which they are attached form a 5-membered ring, wherein in said ring one carbon atom is replaced by O.

7. Compounds of formula (4b),

wherein:

R 3 is —(CH 2 )([1,2,4]triazolo[1,5-a]pyrimidinyl), substituted by at least one substituent chosen from halo and methyl;

Q is chosen from N, O, and S;

R 4a , R 4b , and R 4c are independently chosen from hydrogen, halo, C 1 –C 10 alkyl, and R 5 —O—; and

R 6 is chosen from hydrogen and C 1 –C 10 alkyl.

8. Compounds of formula (5),

wherein:

R 4a , R 4b , and R 4c are independently chosen from halo and C 1 –C 10 alkyl;

R 4d , R 4e , and R 4f are independently chosen from halo, R 6 —O—, and C 1 –C 10 alkyl, wherein said C 1 –C 10 alkyl is optionally substituted with at least one substituent chosen from halo and cyano; and

R 5 is C 1 –C 10 alkyl or hydrogen.

9. Compounds of formula (6),

wherein R 4 is halo.

10. Compounds according to claim 9 , wherein R 4 is chosen from fluorine and chlorine.

11. Compounds of formula (7),

wherein R 4 is halo.

12. Compounds according to claim 11 , wherein R 4 is chosen from fluorine and chlorine.

13. Compounds of formula (8),

wherein R 4 is halo.

14. Compounds according to claim 13 , wherein R 4 is chosen from fluorine and chlorine.

15. Compounds according to claim 2 , wherein:

R 3 is —(CH 2 )([1,2,4]triazolo[1,5-a]pyrimidinyl), optionally substituted by 1 to 3 R 4 groups,

each R 4 is independently chosen from halo, C 1 –C 10 alkyl, and R 8 —O—, and each C 1 –C 10 alkyl may be optionally substituted by at least one substituent chosen from halo, trifluoromethyl, trifluoromethoxy, C 1 –C 10 alkyl, and cyano;

z is an integer from 1 to 3; and

y is 2.

16. Compounds according to claim 15 , wherein:

R 6 is hydrogen or methyl; and

z is an integer from 2–3.

17. Compounds of formula (9),

wherein:

R 4a is halo or C 1 –C 10 alkyl;

R 4b , R 4c , and R 4d are independently chosen from C 1 –C 10 alkyl and R 6 —O—; and

R 6 hydrogen or methyl.

18. Compounds according to claim 17 , wherein:

R 4a is halo;

R 4b and R 4c are each R 6 —O—; and

R 4d is C 1 –C 10 alkyl.

19. Compounds according to claim 18 , wherein:

R 4a is fluorine or chlorine;

R 4b is —OCH 3 ;

R 4c is —OH; and

R 4d is —CH 2 CH 3 .

20. Compounds according to claim 19 , wherein R 4a is chlorine.

21. A compound of formula (10),

22. A compound of formula (11),

23. A compound chosen from;

6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a-pyrimidin-2-ylmethyl)-6-[2-(3-fluoro-4-methoxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;

6-[2-(3-tert-Butyl-phenyl)-ethyl]-6-cyclopentyl-3-(5,7-dymethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one;

6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(3-ethyl-4-hydroxy-phenyl)-ethyl]4-hydroxy-5,6-dihydro-pyran-2-one;

6-[2-(3-tert-Butyl-4-hydroxy-phenyl)-ethyl]-6-cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo(1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one;

6-[2-(3-Chloro-4-isopropoxy-phenyl)-ethyl]-6-cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo(1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one;

6-Cyclopentyl-6-[2-(3,5-dichloro-4-ethoxy-phenyl)-ethyl]-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one;

6-cyclopentyl-3-[(5,7-dimethyl[1,2,4]triazolo[1,5a]-pyrimidin-2-yl)methyl]-6-[2-(3-isopropylphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione;

7-({6-[2-(5-Chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-2-oxo-5,6-dihydro-2H-pyran-3-yl}methyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;

2-(4-{2-[2-Cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-2-methyl-propionitrile;

1-(4-{2-[2-Cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-cyclopropanecarbonitrile;

6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-3-(imidazo[1,2-a]pyrimidin-2-ylmethyl)-5,6-dihydro-2H-pyran-2-one;

6N-[4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4,6-dioxotetrahydro-2H-pyran-2-yl}ethyl)-2-ethylphenyl]-N-methylmethanesulfonamide;

2-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(1-methyl-1H-indol-5-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile;

6-[2-(3-Chloro-4-hydroxy-phenyl)-ethyl]-6-cyclopentyl-3-(5,7-dimethyl-[1,2,4]trlazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one;

6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(3-ethyl-4-methoxy-phenyl)-ethhyl]-4-hydroxy-5,6-dihydro-pyran-2-one;

3-(5-Chloro-1-isopropyl-1-benzoimidazol-2-ylsulfanyl)-6-cyclopentyl-6-[2-(3-fluoro-4-isopropoxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;

5-{6-Cyclopentyl-6-[2-(3-fluoro-4-isopropoxy-phenyl)-ethyl]-hydroxy-2-oxo-5,6-dihydro-2H-pyran-3-ylsulfanyl}-4-methyl-4H-[1,2,4]triazole-3-carboxylic acid methyl ester;

3-(5-Chloro-1-methyl-1H-benzoimidazol-2-ylsulfanyl)-6-cyclopentyl-6-[2-[4-(3,5-dimethyl-isoxazol-4-yl)-phenyl]-ethyl}-4-hydroxy-5,6-dihydro-pyran-2-one;

6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-3-{[5-(2-furyl)-4-methyl-4H-1,2,4-triazol-3-yl]thio}-4-hydroxy-5,6-dihydro-2H-pyran-2-one;

6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-3-[(5-pyridin-4-yl-4H-1,2,4-triazol-3-yl)thio]-5,6-dihydro-2H-pyran-2-one;

6-[2-(3-chloro-4-methoxyphenyl)ethy)]-3-[(5-chloro-1-methyl-1H-benzimidazol-2-yl)thio]-6-cyclopentyl-4-hydroxy-5,6-dihydro-2H-pyran-2-one;

6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-3-[(5-chloro-1-methyl-1H-benzimidazol-2-yl)thio]-6-cyclopentyl-4-hydroxy-5,6-dihydro-2H-pyran-2-one;

6-[2-(3-chloro-4-isopropoxyphenyl)ethyl]-3-[(5-chloro-1-methyl-1H-benzimidazol-2-yl)thio]-6-cyclopentyl-4-hydroxy-5,6-dihydro-2H-pyran-2-one;

8-({6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-2-oxo-5,6-dihydro-2H-pyran-3-yl}thio)-1,7-dihydro-6H-purin-6-one;

6-[2-(5-chlor-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-3-{[5-(4-hydroxyphenyl)-4H-1,2,4-triazol-3-yl]thio}-5,6-dihydro-2H-pyran-2-one;

ethyl 2-({6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-2-oxo-5,6-dihydro-2H-pyran-3-yl}thio)[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylate;

6-cyclopentyl-3-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-[2-(3-fluoro-4-isopropoxyphenyl)ethyl]4-hydroxy-5,6-dihydro-2H-pyran-2-one;

6-Cyclopenty-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(3-ethyl-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;

6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(3-ethyl-phenyl)-elhyl]4-hydroxy-5,6-dihydro-pyran-2-one;

2-[4-(2-{5-[(4-chloro-1-methyl-1H-pyrazol-3-yl)methyl]-2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fIuorophenyl]-2-methylpropanenitrile;

2-{4-[2-(2-Cyclopentyl-4,6-dioxo-5-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-2-methyl-propionitrile;

2-(4-{2-[2-Cyclopentyl-5-( 6 -methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4,6-dioxo-tetrahydro-pyran-2-yl)]-ethyl}-2-fluoro-phenyl)- 2 -methyl-propionitrile;

(+)-2-(4-{2-[2-Cyclopentyl-5-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4,6-dioxo-tetrahydro-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-2-methyl-propionitrile;

(−)-2-(4-{2-[2-Cyclopentyl-5-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4,6-dioxo-tetrahydro-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-2-methyl-propionitrile;

2-(4-{2-[5-(6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-2-cyclophenyl-4,6-dioxo-tetrahydro-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-2-methyl-propionitrile;

2-(4-{2-[2-Cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4,6-dioxo-tetrahydro-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-2-ethyl-butyronitrile;

1-(4-{2-[2-Cyclopentyl-5-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4,6-dioxo-tetrahydro-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-cyclopropanecarbonitrile;

1-(4-{2-[5-(6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-cyclopropanecarbonitrile;

6-Cyclopentyl-6-[2-(3ethyl-4-hydroxy-phenyl)-ethyl]-4-hydroxy-3-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-5,6-dihydro-pyran-2-one;

3-(6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-cyclopentyl-6-[2-(3-ethyl-4-hydroxy-phenyl)-ethyl]4-hydroxy-5,6-dihydro-pyran-2-one;

6-cyclopentyl-3-[(5,7-diethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-[2-(4-hydroxy-3-propylphenyl)ethyl]-5,6-dihydro-2H-pyran-2-one;

6-cyclopentyl-3-[(5,7-diethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-[2-(3-ethyl-4-hydroxyphenyl)ethyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one;

N-{2-[4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5,-a]pyrimidin-2-yl)methyl]-hydroxy-6-oxo-3,6-dehydro-2H-pyran-2-yl}ethyl)-2-ethylphenoxy]ethyl}acetamide;

2-(4-{2-[2-Cyclopentyl-5-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}-ethyl)-2,6-difluoro-phenyl)-2-methyl-propionitrile;

2-(4-{2-[2-Cyclopentyl-4-hydroxy-5-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2,6-difluoro-phenyl)-2-methyl-propionitrile;

2-(2-Chloro-4-{2-[2-cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-2-methyl-propionitrile;

1-(2-Chloro-4-{2-[2-cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-cyclopropanecarbonitrile;

6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-4-hydroxy-2-mothoxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;

(+)-2-(2-chloro-4-{2-[2-cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2yl]-ethyl}-phenyl)-methyl-propionitrile;

(−)-2-(2-chloro-4-{2-[2-cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-2-methyl-propionitrile;

(+)-2-4-{-2-[2-Cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2-fluorophenyl)-2-methylpropionitrile;

(−)-2-(4-{2-[2-Cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-hydro-2H-pyran-2-yl]-ethyl}-2-fluorophenyl)-2-methylpropionitrile;

(+)-3-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-cyclopentyl-6-[2-(5-ethyl-4-hydroxy-2-methoxyphenyl)ethyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one;

(−)-3-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-cyclopentyl-6-[2-(5-ethyl-4-hydroxy-2-melhoxyphenyl)ethyl]-hydroxy-5,6-dihydro-2H-pyran-2-one;

6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4,]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-4-hydroxy-2-methoxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;

(−)-6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-4-hydroxy-2-methoxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;

6-[2-(3-Chloro-5-ethyl-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one;

6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-2-methoxy-phenyl)-ethyl]4-hydroxy-5,6-dihydro-pyran-2-one;

6-[2-(3-Chloro-5-ethyl-4-hydroxy-phenyl)-ethyl)-6-cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one;

6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-{2-[3-ethyl-4-(2-hydroxy-ethoxy)-phenyl]-ethyl}-4-hydroxy-5,6-dihydro-pyran-2-one;

6-Cyclopentyl-6-[2-(3-cyclopropyl-4-methoxy-phenyl)-ethyl]-3-(5,7-dimethyl-[1,2,4]triazolo(1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one;

6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-4-hydroxy-2,3-dihydro-benzofuran-7-yl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;

(+)-6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-4-hydroxy-2,3-dihydro-benzofuran-7-yl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;

(−)-6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-4-hydroxy-2,3-dihydro-benzofuran-7-yl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;

6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-pyridin-3-yl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one; and

pharmaceutically acceptable salts, solvates and prodrugs of the foregoing compounds.

24. A compound chosen from:

2-[4-(2-{5-[(4-chloro-1-methyl-1H-pyrazol-3-yl)methyl]-2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile;

2-(4-{2-[2-Cyclopentyl-5-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)4,6-dioxo-tetrahydro-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-2-methyl-propionitrile;

(+)-2-(4-{2-[2-Cyclopentyl-5-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)4,6-dioxo-tetrahydro-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-2-methyl-propionitrile;

(−)-2-(4-{2-[2-Cyclopentyl-5-(6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4,6-dioxo-tetrahydro-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-2-methyl-propionitrile;

2-(4-{2-[5-(6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-2-methyl-propionitrile;

3-(6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-cyclopentyl-6-[2-(3-ethyl-4-hydroxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;

N-{2-[4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-ethylphenoxy]ethyl}acetamide;

2-(4-{2-[2-Cyclopentyl-5-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}-ethyl)-2,6-difluoro-phenyl)-2-methyl-propionitrile;

(+)-2-(2-chloro-4-{2-[2-cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-2-methyl-propionitrile;

(−)-2-(2-chloro-4-{2-[2-cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-2-methyl-propionitrile;

(+)-2-(4-{2-[2-Cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2-fluorophenyl)-2-methylpropionitrile;

(−)-2-(4-{2-[2-Cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2-fluorophenyl-2-methylpropionitrile;

(+)-3-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-cyclopentyl-6-[2-(5-ethyl-4-hydroxy-2-methoxyphenyl)ethyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one;

(−)-3-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-cyclopentyl-6-[2-(5-ethyl-4-hydroxy-2-methoxyphenyl)ethyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one;

1-(2-Chloro-4-{2-[2-cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-cyclopropanecarbonitrile;

6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-4-hydroxy-2-methoxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;

(−)-6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-4-hydroxy-2-methoxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;

6-[2-(3-Chloro-5-ethyl-4-hydroxy-phenyl)-ethyl]-6-cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one;

6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-{2-[3-ethyl-4-(2-hydroxy-ethoxy)-phenyl]-ethyl}4-hydroxy-5,6-dihydro-pyran-2-one;

6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-4-hydroxy-2,3-dihydro-benzofuran-7-yl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;

(+)-6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-4-hydroxy-2,3-dihydro-benzofuran-7-yl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;

(−)-6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-4-hydroxy-2,3-dihydro-benzofuran-7-yl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;

6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-6-[2-(5-ethyl-pyridin-3-yl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one; and

pharmaceutically acceptable salts, solvates and prodrugs of the foregoing compounds.

25. A compound chosen from:

(+)-2-(4-{2-[2-Cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2-fluorophenyl-2-methylpropionitrile;