2-Alkynyl-and 2-alkenyl-pyrazolo-[4,3-e]-1,2,4-triazolo-[1,5-c]-pyrimidine adenosine A2a receptor antagonists

1. A compound having the structural formula

or a pharmaceutically acceptable salt thereof, wherein

R is

R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from the group consisting of H, alkyl and alkoxyalkyl;

R 6 is H, alkyl, hydroxyalkyl or —CH 2 F;

R 7 , R 8 and R 9 are independently selected from the group consisting of H, alkyl, alkoxy, alkylthio, alkoxyalkyl, halo and —CF 3 ;

Z is R 10 -aryl, R 10 -heteroaryl or

R 10 is 1 to 5 substituents independently selected from the group consisting of hydrogen, alkyl, alkenyl, hydroxy, alkoxy, hydroxyalkyl, hydroxy-alkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxy-alkoxy-alkyl-, (di-alkoxy)-alkyl, (hydroxy)-alkoxyalkyl, R 15 -cycloalkyl, R 15 -cycloalkylalkyl, cycloalkyl-oxy, cycloalkyl-O-alkoxy, alkyl-SO 2 —, alkyl-SO—, halo, —CN, cyanoalkyl, —CHF 2 , —CF 3 , —OCHF 2 , —OCF 3 , —C(O)R 13 , —O-alkylene-C(O)OR 13 , —C(O)O-alkyl, —N(R 11 )(R 12 ), N(R 11 )(R 12 )-alkyl, N(R 11 )(R 12 )-alkoxy, —C(O)N(R 13 )(R 16 ), R 11 -heteroaryl, R 15 -heterocycloalkyl, R 15 -heterocycloalkyl-alkyl, R 15 -heterocycloalkyl-alkoxy, R 15 -heterocycloalkyl-oxy, CF 3 -alkylene-O-alkyl, CF 3 -hydroxyalkyl, (CF 3 )(hydroxy)alkoxy, cyano-alkoxy, -alkylene-C(O)—O-alkyl, —SO 2 —N(alkyl) 2 , (cycloalkyl)hydroxyalkyl, (hydroxyalkyl)alkoxy, (dihydroxy)alkyl, (dihydroxy)alkoxy, —C(═NOR 17 )-alkyl and —C(═NOR 17 )—CF 3 ;

or two R 10 groups on adjacent carbon ring atoms together form —O—CH 2 —O—, —O—(CH 2 ) 2 —O—, —CH 2 —O—(CH 2 ) 2 —O—, —O—(CH 2 ) 2 —, —(CH 2 ) 3 —O—, —O—(CH 2 ) 3 —O—, —(CH 2 ) 3 —, wherein the ring formed by the two R 10 substituents and the ring carbon atoms to which they are attached is substituted by R 16 ;

or two R 10 groups on adjacent carbon ring atoms together form —N(R 11 )—C(O)—O—, —N(R 11 )—C(O)—S—, —(CH 2 ) 2 CH(OR 18 )—, —CH 2 CH(OR 18 )CH 2 —, —(CH 2 ) 3 CH(OR 18 )—, —(CH 2 ) 2 CH(OR 18 )CH 2 —, —(CH 2 ) 2 C(O)—, —CH 2 C(O)CH 2 —, —(CH 2 ) 3 C(O)—, —(CH 2 ) 2 C(O)CH 2 —, —O(CH 2 ) 2 CH(OR 18 )— or —OCH 2 CH(OR 18 )CH 2 —, wherein the ring formed by two R 10 substituents and the ring carbon atoms to which they are attached is optionally substituted on a carbon atom by hydroxyalkyl or alkoxyalkyl;

each R 11 is independently selected from the group consisting of H and alkyl;

each R 12 is independently selected from the group consisting of H, alkyl, hydroxyalkyl, alkoxyalkyl, —C(O)-alkyl, —C(O)O-alkyl, (alkoxy)hydroxyalkyl, alkoxyalkyl-C(O)—, —SO 2 alkyl, -alkylene-C(O)alkyl and -alkylene-C(O)O-alkyl;

R 13 is H, alkyl or —CF 3 ;

R 14 is H, alkyl, alkoxyalkyl, alkyl-C(O)— or alkoxy-C(O)—;

R 15 is 1 to 3 substituents independently selected from the group consisting of H, alkyl, —OH, alkoxy, alkoxyalkyl and hydroxyalkyl; or two R 15 substituents, taken together with the carbon to which they are both attached, form a —C(═O)— group;

R 16 is H, alkyl, alkoxyalkyl, OH or hydroxyalkyl;

R 17 is H or alkyl; and

R 18 is H or alkyl.

2. A compound of claim 1 wherein R is —C≡CR 6 .

3. A compound of claim 2 wherein R 6 is H or alkyl.

4. A compound of claim 1 wherein R 2 , R 3 , R 4 and R 5 are each H.

5. A compound of claim 1 wherein Z is R 10 -aryl or R 10 -heteroaryl.

6. A compound of claim 5 wherein Z is R 10 -phenyl.

7. A compound of claim 6 wherein R 10 is 1, 2 or 3 substituents independently selected from the group consisting of H, halo, —C(O)R 13 , alkyl, alkoxy, hydroxyalkyl, (cycloalkyl)hydroxyalkyl, hydroxyalkoxy, alkoxyalkoxy, alkoxyalkyl, and cyanoalkyl.

8. A compound of claim 7 comprising two R 10 substituents wherein one R 10 is halo and the other R 10 is halo, —C(O)R 13 , alkyl, alkoxy, hydroxyalkyl, (cycloalkyl)hydroxyalkyl, hydroxyalkoxy, alkoxyalkoxy, alkoxyalkyl or cyanoalkyl.

9. A compound of claim 8 comprising two R 10 substituents wherein one R 10 is o-fluoro and the other R 10 is halo, —C(O)R 13 , alkyl, alkoxy, hydroxyalkyl, (cycloalkyl)hydroxyalkyl, hydroxyalkoxy, alkoxyalkoxy, alkoxyalkyl or cyanoalkyl.

10. A compound of claim 5 wherein Z is R 10 -heteroaryl.

11. A compound of claim 10 wherein Z is R 10 -benzoxazolyl or R 10 -benzisoxazolyl and R 10 is 1 or 2 substituents independently selected from the group consisting of H, halo and alkyl.

12. A compound of claim 11 wherein one R 10 is fluoro and one R 10 is methyl.

13. A compound of claim 1 wherein R is —C≡CR 6 , R 2 , R 3 , R 4 and R 5 are each H, and Z is R 10 -aryl or R 10 -heteroaryl.

14. A compound of claim 13 wherein Z is R 10 -phenyl and R 10 is two substituents wherein one R 10 is halo and the other R 10 is halo, —C(O)R 13 , alkyl, alkoxy, hydroxyalkyl, (cycloalkyl)hydroxyalkyl, hydroxyalkoxy, alkoxyalkoxy, alkoxyalkyl or cyanoalkyl.

15. A compound of claim 13 wherein Z is R 10 -benzoxazolyl or R 10 -benzisoxazolyl and R 10 is 1 or 2 substituents independently selected from the group consisting of H, halo and alkyl.

16. A compound of claim 1 selected from the group consisting of

17. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 in a pharmaceutically acceptable carrier.

18. A pharmaceutical composition comprising a therapeutically effective amount of a combination of a compound of claim 1 , and 1 to 3 other agents useful in treating Parkinson's disease in a pharmaceutically acceptable carrier.

19. A method of treating Parkinson's disease or depression, comprising administering an effective amount of a compound of formula I to a mammal in need of such treatment.

20. A method of treating Parkinson's disease comprising administering to a mammal in need of such treatment an effective amount of a combination of a compound of claim 1 , and 1 to 3 other agents useful in treating Parkinson's disease.

21. The method of claim 20 wherein the other agents are selected from the group consisting of L-DOPA, dopaminergic agonists, MAO-B inhibitors, DOPA decarboxylase inhibitors and COMT inhibitors.