2-propynyl adenosine analogs having A2A agonist activity and compositions thereof

1. A compound having formula (I):

wherein

Z is CR 3 R 4 R 5 ;

each R 1 is independently hydrogen, halo, OR a , SR a , (C 1 -C 8 )alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C 3 -C 8 )cycloalkyl, heterocyclyl, heterocyclyl(C 1 -C 8 )alkylene, aryl, aryl(C 1 -C 8 )alkylene, heteroaryl, heteroaryl(C 1 -C 8 )alkylene, CO 2 R a , R a C(═O)O, R a C(═O), OCO 2 R a , R a R b NC(═O)O, R b OC(═O)N(R a ), R a R b N, R a R b NC(═O), R a C(═O)N(R b ), R a R b NC(═O)N(R b ), R a R b NC(═S)N(R b ), R a OC(═S), R a C(═S), SSR a , R a S(═O), R a S(═O) 2 , or N═NR a ;

each R 2 is independently hydrogen, halo, (C 1 -C 8 )alkyl, (C 3 -C 8 )cycloalkyl, heterocyclyl, heterocyclyl(C 1 -C 8 )alkylene, aryl, aryl(C 1 -C 8 )alkylene, heteroaryl, or heteroaryl(C 1 -C 8 )alkylene; or

R 1 and R 2 and the atom to which they are attached is C═O, C═S or C═NR c ;

R 4 and R 5 together with the atoms to which they are attached form a ring selected from

wherein any ring comprising R 4 and R 5 is substituted with from 1 to 4 R 6 groups, such that q is 1 to 4;

wherein each R 6 is independently halo, OR a , SR a , (C 1 -C 8 )alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C 1 -C 8 )cycloalkyl, (C 6 -C 12 )bicycloalkyl, heterocyclyl or heterocyclyl (C 1 -C 8 )alkylene, aryl, aryl (C 1 -C 8 )alkylene, heteroaryl, heteroaryl(C 1 -C 8 )alkylene, CO 2 R a , R a C(═O)O, R a C(═O), OCO 2 R a , R a R b NC(═O)O, R b OC(═O)N(R a ), R a R b N, R a R b NC(═O), R a C(═O)N(R b ), R a R b NC(═O)N(R b ), R a R b NC(═S)N(R b ), R a OC(═S), R a C(═S), SSR a , R a S(═O), or NNR a ;

or two R 6 groups and the atom to which they are attached is C═O, C═S or two R 6 groups together with the atom or atoms to which they are attached form a carbocyclic or heterocyclic ring;

R 3 is halo, OR a , SR a , cyano, nitro, trifluoromethyl, trifluoromethoxy, (C 3 -C 8 )cycloalkyl, heterocyclyl, heterocyclyl(C 1 -C 8 )alkylene, aryl, aryl(C 1 -C 8 )alkylene, heteroaryl, heteroaryl(C 1 -C 8 )alkylene, CO 2 R a , R a C(═O)O, R a C(═O), OCO 2 R a , R a R b NC(═O)O, R b OC(═O)N(R a ), R a R b N, R a R b NC(═O), R a C(═O)N(R b ), R a R b NC(═O)N(R b ), R a R b NC(═S)N(R b ), R a OC(═S), R a C(═S), SSR a , R a S(═O), R a S(═O) 2 , or NNR a ;

each R 7 is independently hydrogen, (C 1 -C 8 )alkyl, (C 3 -C 8 )cycloalkyl, aryl or aryl(C 1 -C 8 )alkylene, heteroaryl, heteroaryl(C 1 -C 8 )alkylene-;

X is CH 2 OR a , CO 2 R a , OC(O)R a , CH 2 OC(O)R a , C(O)NR a R b , CH 2 SR a , C(S)OR a , OC(S)R a , CH 2 OC(S)R a , C(S)NR a R b or CH 2 N(R a )(R b );

wherein any of the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, groups of R 1 , R 2 , R 3 , R 6 and R 7 is optionally substituted on carbon with one or more (e.g. 1, 2, 3, or 4) substituents selected from the group consisting of halo, OR a , SR a , (C 1 -C 8 )alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C 3 -C 8 )cycloalkyl, (C 6 -C 12 )bicycloalkyl, heterocyclyl or heterocyclyl(C 1 -C 8 )alkylene, aryl, aryloxy, aryl (C 1 -C 8 )alkylene, heteroaryl, heteroaryl(C 1 -C 8 )alkylene, CO 2 R a , R a C(═O)O, R a C(═O), OCO 2 R a , R a R b NC(═O)O, R b OC(═O)N(R a ), R a R b N, R a R b NC(═O), R a C(═O)N(R b ), R a R b NC(═O)N(R b ), R a R b NC(═S)N(R b ), R a OC(═S), R a C(═S), SSR a , R a S(═O) p , R a R b NS(O) p , and N═NR a ;

wherein any (C 1 -C 8 )alkyl, (C 3 -C 8 )cycloalkyl, (C 6 -C 12 )bicycloalkyl, (C 1 -C 8 )alkoxy, (C 1 -C 8 )alkanoyl, (C 1 -C 8 )alkylene, or heterocyclyl, is optionally partially unsaturated;

R a and R b are each independently hydrogen, (C 1 -C 8 )alkyl, or (C 1 -C 8 )alkyl substituted with 1-3 (C 1 -C 8 )alkoxy, (C 3 -C 8 )cycloalkyl, (C 1 -C 8 )alkylthio, aryl, aryl(C 1 -C 8 )alkylene, heteroaryl, or heteroaryl(C 1 -C 8 )alkylene; or R a and R b , together with the nitrogen to which they are attached, form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring; and

R c is hydrogen or (C 1 -C 6 )alkyl;

m is 0 to 8 and p is 0 to 2;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein R 1 is hydrogen, OH, CH 2 OH, OCH 3 , OC(O)CH 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 or NHC(O)CH 3 .

3. The compound of claim 1 , wherein R 1 is hydrogen, OH, OCH 3 , OC(O)CH 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 or NHC(O)CH 3 .

4. The compound of claim 1 , wherein R 1 is hydrogen, OH, OMe, or NH 2 .

5. The compound of claim 1 , wherein R 1 is hydrogen, OH, or NH 2 .

6. The compound of claim 1 , wherein R 1 is hydrogen or OH.

7. The compound of claim 1 , wherein R 2 is hydrogen, (C 1 -C 8 )alkyl, cyclopropyl, cyclohexyl or benzyl.

8. The compound of claim 1 , wherein R 2 is hydrogen, methyl, ethyl or propyl.

9. The compound of claim 1 , wherein R 2 is hydrogen or methyl.

10. The compound of claim 1 , wherein R 2 is hydrogen.

11. The compound of claim 1 , wherein R 1 , R 2 and the carbon atom to which they are attached is carbonyl (C═O).

12. The compound of claim 1 , wherein R 3 is OH, OCH 3 , OC(O)CH 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 or NHC(O)CH 3 .

13. The compound of claim 1 , wherein R 3 is OH, OCH 3 , or NH 2 .

14. The compound of claim 1 , wherein R 3 is OH, or NH 2 .

15. The compound of claim 1 , wherein R 3 is OH.

16. The compound of claim 1 , wherein R 6 is (C 1 -C 8 )alkyl, or substituted (C 1 -C 8 )alkyl, OR a , CO 2 R a , R a C(═O), R a C(═O)O, R a R b N, R a R b NC(═O), or aryl.

17. The compound of claim 1 , wherein R 6 is (C 1 -C 8 )alkyl, OR a , CO 2 R a , R a C(═O), R a C(═O)O, R a R b N, R a R b NC(═O), or aryl.

18. The compound of claim 1 , wherein R 6 is methyl, ethyl, butyl, OH, OR a , CO 2 R a , R a C(═O), OC(═O)CH 2 CH 3 , CONR a R b , NR a R b or phenyl.

19. The compound of claim 1 , wherein R 6 is OH, OCH 3 , methyl, ethyl, t-butyl, CO 2 R a , CONR a R b , OC(O)CH 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , NHCH 2 CH 3 , or N(CH 2 CH 3 ) 2 .

20. The compound of claim 1 , wherein R 6 is methyl, ethyl, t-butyl, phenyl, CO 2 R a , CONR a R b , or C(═O)R a .

21. The compound of claim 1 , wherein R 6 is methyl, ethyl, CO 2 R a CONR a R b , or OC(O)CH 3 .

22. The compound of claim 1 , wherein R 6 is (CH 2 ) 1-2 OR a , (CH 2 ) 1-2 C(═O)OR a , (CH 2 ) 1-2 OC(═O)R a , (CH 2 ) 1-2 C(═O)R a , (CH 2 ) 1-2 OCO 2 R a , (CH 2 ) 1-2 NHR a , (CH 2 ) 1-2 NR a R b , (CH 2 ) 1-2 OC(═O)NHR a , or (CH 2 ) 1-2 OC(═O)NR a R b .

23. The compound of claim 1 , wherein R 6 is CH 2 OH, CH 2 OC(O)CH 3 , CH 2 OCH 3 , CH 2 C(═O)OCH 3 , CH 2 C(═O)CH 3 , CH 2 C(═O)CH 3 , CH 2 OCO 2 CH 3 , CH 2 NH(CH 3 ), Or (CH 2 ) 1-2 N(CH 3 ) 2 .

24. The compound of claim 1 , wherein R 6 is CH 2 OH, CH 2 OC(O)CH 3 , C(═O)OCH 3 , C(═O)CH 3 , OCO 2 CH 3 , OCO 2 CH 3 , CH 2 NH(CH 3 ), or (CH 2 ) 1-2 N(CH 3 ) 2 .

25. The compound of claim 1 , wherein R a and R b are independently hydrogen, (C 1 -C 4 )alkyl, aryl or aryl(C 1 -C 8 )alkylene.

26. The compound of claim 1 , wherein R a and R b are independently hydrogen, methyl or ethyl, phenyl or benzyl.

27. The compound of claim 1 , wherein R a is (C 1 -C 8 )alkyl.

28. The compound of claim 1 , wherein R a is methyl, ethyl, propyl or butyl.

29. The compound of claim 1 , wherein R a is, methyl, ethyl, i-propyl, i-butyl or tert-butyl.

30. The compound of claim 1 , wherein R a and R b form a ring.

31. The compound of claim 1 , wherein R 7 is hydrogen, alkyl, aryl or aryl(C 1 -C 8 )alkylene.

32. The compound of claim 1 , wherein R 7 is hydrogen, methyl or ethyl, phenyl or benzyl.

33. The compound of claim 1 , wherein R 7 is H or methyl.

34. The compound of claim 1 , wherein N(R 7 ) 2 is amino, methylamino, dimethylamino, ethylamino, pentylamino, diphenylethylamino, diethylamino, or benzylamino.

35. The compound of claim 1 , wherein —N(R 7 ) 2 is amino, methylamino, dimethylamino, ethylamino, diethylamino, or benzylamino.

36. The compound of claim 1 , wherein N(R 7 ) 2 is amino or methylamino.

37. The compound of claim 1 , wherein X is CH 2 OR a , CO 2 R a , OC(O)R a , CH 2 OC(O)R a , or C(O)NR a R b .

38. The compound of claim 1 , wherein X is CH 2 OR 2 , or C(O)NR a R b .

39. The compound of claim 1 , wherein X is CH 2 OH or C(O)NHCH 2 CH 3 .

40. The compound of claim 1 , wherein m is 0, 1, or 2.

41. The compound of claim 1 , wherein m is 0, or 1.

42. The compound of claim 1 , wherein R 4 , R 5 and the atom to which they are connected are

43. A compound of claim 1 , having the formula:

44. A compound of claim 1 , having the formula:

45. A compound of claim 1 , having the formula:

46. A compound of claim 1 , having the formula:

47. A compound of claim 1 , having the formula:

48. A therapeutic composition comprising a compound of claim 1 , in combination with a pharmaceutically acceptable carrier.

49. The composition of claim 48 further comprising a Type IV phosphodiesterase inhibitor.

50. The composition of claim 49 wherein the inhibitor is rolipram.

51. The composition of claim 48 , wherein the carrier is a liquid carrier.

52. The composition of claim 48 , which is adapted for parenteral, aerosol or transdermal administration.