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

1. A compound having formula (I):

wherein

Z is NR 4 R 5 ;

each R 1 is independently hydrogen, halo, —OR a , —SR a , (C 1 -C 8 )alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, C 3-8 cycloalkyl, heterocycle, heterocycle(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, heterocycle, heterocycle(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 nitrogen atom to which they are attached form a saturated or partially or fully unsaturated, mono-, or bicyclic-ring having 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms that can include 0-4 heteroatoms in addition to the nitrogen atom selected from non-peroxide oxy (—O—), thio (—S—), sulfinyl (—SO—), sulfonyl (—S(O) 2 —) or amine (—NR a —) in the ring;

wherein any ring comprising R 4 and R 5 is substituted with from 1 to 14 R 6 groups;

wherein each R 6 is independently halo, —OR a , —SR a , cyano, nitro, trifluoromethyl, trifluoromethoxy, (C 1 -C 8 )cycloalkyl, (C 6 -C 12 )bicycloalkyl, heterocycle or heterocycle (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, or C═S;

or two R 6 groups together with the atom or atoms to which they are attached can form a carbocyclic or heterocyclic ring;

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 or C(S)NR a R b or —CH 2 N(R a )(R b );

wherein any of the alkyl, cycloalkyl, heterocycle, aryl, or heteroaryl, groups of R 1 , R 2 , R 6 or R 7 is substituted on carbon with 0-4 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, heterocycle or heterocycle(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 )cyclo alkyl, (C 6 -C 12 )bicycloalkyl, (C 1 -C 8 )alkoxy, (C 1 -C 8 )alkanoyl, (C 1 -C 8 )alkylene, or heterocycle, can be saturated or 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 1 to 8 and p is 0 to 2;

provided that Z is not an N-alkylpiperazine group;

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 2 , 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 3 , wherein R 1 is hydrogen, OH, —OCH 3 , or NH 2 .

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

6. The compound of claim 5 , 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 7 , wherein R 2 is hydrogen, methyl, ethyl or propyl.

9. The compound of claim 8 , wherein R 2 is hydrogen or methyl.

10. The compound of claim 9 , 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 the ring comprising R 4 , R 5 and the nitrogen atom to which they are connected is a piperidine, dihydro-pyridine, tetrahydro-pyridine, piperazine, tetrahydro-pyrazine, dihydro-pyrazine, dihydro-pyrimidine, tetrahydro-pyrimidine, hexahydro-pyrimidine, imidazole, dihydro-imidazole, imidazolidine, pyrazole, dihydro-pyrazole, or pyrazolidine ring.

13. The compound of claim 12 , wherein the ring comprising R 4 and R 5 and the nitrogen atom to which they are connected is piperidine or piperazine.

14. The compound of claim 1 , wherein R 6 is —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.

15. The compound of claim 14 , wherein R 6 is —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.

16. The compound of claim 15 , wherein R 6 is 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.

17. The compound of claim 15 , wherein R 6 is OH, —OCH 3 , —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 .

18. The compound of claim 15 , wherein R 6 is phenyl, —CO 2 R a —CONR a R b , or —C(═O)R a .

19. The compound of claim 15 , wherein R 6 is —CO 2 R a —CONR a R b , or —OC(═O)CH 3 .

20. 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 NR a R b , or —(CH 2 ) 1-2 OC(═O)NR a R b .

21. The compound of claim 20 , wherein R 6 is —CH 2 OH, —CH 2 C(═O)CH 3 , —CH 2 OCH 3 , —CH 2 C(═O)OCH 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 .

22. 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 , —CH 2 NH(CH 3 ), or —(CH 2 ) 1-2 N(CH 3 ) 2 .

23. The compound of claim 1 , wherein the number of R 6 groups substituted on the R 4 R 5 ring is from 1 to 4.

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

25. The compound of claim 24 , wherein R a and R b are hydrogen, methyl or ethyl, phenyl or benzyl.

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

27. The compound of claim 26 , wherein R a is methyl, ethyl, propyl or butyl.

28. The compound of claim 26 , wherein R a is methyl, ethyl, i-propyl, i-butyl or tert-butyl.

29. The compound of claim 1 , wherein R a and R b together with the nitrogen to which they are attached, form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring.

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

31. The compound of claim 30 , wherein R 7 is hydrogen, methyl or ethyl, phenyl or benzyl.

32. The compound of claim 31 , wherein R 7 is H, or methyl.

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

34. The compound of claim 33 , wherein —N(R 7 ) 2 is amino, methylamino, dimethylamino; ethylamino; diethylamino or benzylamino.

35. The compound of claim 34 , wherein N(R 7 ) 2 is amino, or methylamino.

36. 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 .

37. The compound of claim 36 , wherein X is —CH 2 OR a or —C(O)NR a R b .

38. The compound of claim 37 , wherein X is —CH 2 OH or —C(O)NHCH 2 CH 3 .

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

40. The compound of claim 39 , wherein m 1.

41. The compound of claim 1 , wherein the ring comprising R 4 , R 5 and the nitrogen atom to which they are connected is selected from the group consisting of:

wherein q is 1 to 8.

42. The compound of claim 1 , wherein the rings comprising R 4 , R 5 and the atom to which they are connected are selected from the group consisting of:

43. The compound of claim 1 , wherein the ring comprising R 4 and R 5 is 4-piperazine-1-carboxylic acid methyl ester, 4 piperazine-1-carboxylic acid tert-butyl ester, 4-piperazine-1-carboxylic acid ethyl ester, 1-piperidine-4-carboxylic acid, 1-piperidine-4-carboxylic acid methyl ester, 1-piperidine-4-carboxylic acid tert-butyl ester, 1-piperidine-4-carboxylic acid ethyl ester, 1-piperidine-3-carboxylic acid methyl ester, or 1-piperidine-3-carboxylic acid tert-butyl ester.

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

wherein R a is H or methyl, ethyl, propyl, isopropyl, isobutyl, or t-butyl.

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

wherein R a is methyl or t-butyl.

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

wherein R a is H or methyl.

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

wherein R a and R b are each independently H, methyl, or ethyl.

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

wherein R a and R b are independently H or methyl.

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

wherein R 6 is C(O)CH 3 .

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

wherein Cyc is (C3-C8)mono- or bicycloalkyl.

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

wherein Het is a heteroaryl group.

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

wherein R a is H or methyl, ethyl, isopropyl, isobutyl, or t-butyl.

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

wherein R a and R b are each independently H, methyl, ethyl, isopropyl, or isobutyl.

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

55. The composition of claim 54 further comprising a Type IV phosphodiesterase inhibitor.

56. The composition of claim 55 wherein the inhibitor is rolipram.

57. The composition of claim 56 , wherein the carrier is a liquid carrier.

58. The composition of claim 57 , which is adapted for parenteral, aerosol or transdermal administration.