Pyrazolo[3,4-b]pyridines and imidazo[1,5-b]pyridazines as PDE1 inhibitors

1. A compound of formula (I)

wherein

Y 1 =N—R 1 , Y 2 =C and Y 3 =C, or

Y 1 =C—R 1 , Y 2 =N and Y 3 =C;

Z 1 is selected from NH, CH 2 , O and S;

Z 2 is selected from NH, CH 2 , O and S;

with the proviso that at least one of Z 1 and Z 2 is CH 2 ;

R 1 is selected from the group consisting of hydrogen, linear or branched C 1-4 alkyl and saturated monocyclic C 3-4 cycloalkyl, wherein said linear or branched C 1-4 alkyl and saturated monocyclic C 3-4 cycloalkyl can be optionally substituted with one or more halogen;

R 2 is selected from the group consisting of linear or branched C 1-6 alkyl, saturated monocyclic C 3-6 cycloalkyl, oxetanyl, tetrahydrofuranyl and tetrahydropyranyl, all of which can optionally be substituted with one or more halogen;

R 3 is a 5- or 6-membered heteroaryl, which can optionally be substituted with one or more substituents selected from linear or branched C 1-4 alkyl, linear or branched C 1-4 alkoxy and halogen, wherein said linear or branched C 1-4 alkyl and linear or branched C 1-4 alkoxy can be optionally substituted with one or more halogen, or

R 3 is a 9-membered bicyclic heteroaryl, which can optionally be substituted with one or more substituents selected from linear or branched C 1-4 alkyl, linear or branched C 1-4 alkoxy and halogen, wherein said linear or branched C 1-4 alkyl and linear or branched C 1-4 alkoxy can be optionally substituted with one or more halogen;

R 4 is a 5- or 6-membered heteroaryl, which can optionally be substituted with one or more substituents selected from linear or branched C 1-4 alkyl, linear or branched C 1-4 alkoxy and halogen, wherein said linear or branched C 1-4 alkyl and linear or branched C 1-4 alkoxy can be optionally substituted with one or more halogen, or

R 4 is a phenyl, which can optionally be substituted with one or more substituents selected from linear or branched C 1-4 alkyl, linear or branched C 1-4 alkoxy and halogen, wherein said linear or branched C 1-4 alkyl and linear or branched C 1-4 alkoxy can be optionally substituted with one or more halogen, or

R 4 is a pyridinone, which can optionally be substituted with one or more substituents selected from linear or branched C 1-4 alkyl, linear or branched C 1-4 alkoxy and halogen, wherein said linear or branched C 1-4 alkyl and linear or branched C 1-4 alkoxy can be optionally substituted with one or more halogen; or

R 4 is a 9-membered bicyclic heteroaryl, which can optionally be substituted with one or more substituents selected from linear or branched C 1-4 alkyl, linear or branched C 1-4 alkoxy and halogen, wherein said linear or branched C 1-4 alkyl and linear or branched C 1-4 alkoxy can be optionally substituted with one or more halogen;

or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 of formula (Ia)

wherein Z 1 , Z 2 , R 1 , R 2 , R 3 and R 4 are as defined in claim 1 ;

or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 of formula (Ib)

wherein Z 1 , Z 2 , R 1 , R 2 , R 3 and R 4 are as defined in claim 1 ;

or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1 , wherein Z 1 is NH.

5. The compound according to claim 1 , wherein Z 2 is CH 2 .

6. The compound according to claim 1 , wherein Z 1 is NH and Z 2 is CH 2 .

7. The compound according to claim 1 , wherein R 1 is a linear or branched C 1-4 alkyl.

8. The compound according to claim 1 , wherein R 2 is linear or branched C 1-6 alkyl.

9. The compound according to claim 1 , wherein

R 3 is a 5-membered heteroaryl selected from pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiazolyl and thiophenyl, all of which can optionally be substituted with a methyl; or

R 3 is a 6-membered heteroaryl, which can optionally be substituted with a substituent selected from methyl, trifluoromethyl or a linear or branched C 1-4 alkoxy; wherein said 6-membered heteroaryl is selected from pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl; or

R 3 is a 9-membered bicyclic heteroaryl, which is optionally substituted with one or more methyl.

10. The compound according to claim 1 , wherein

R 4 is a 5-membered heteroaryl selected from pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiazolyl and thiophenyl wherein said 5-membered heteroaryl can be optionally substituted with a methyl; or

R 4 is a 6-membered heteroaryl, which can optionally be substituted with a linear or branched C 1-4 alkoxy; wherein said 6-membered heteroaryl is selected from pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl; or

R 4 is a phenyl, which can optionally be substituted with one or more methyl; or

R 4 is a pyridinone, which can optionally be substituted with one or more methyl; or

R 4 is a 9-membered bicyclic heteroaryl, which can optionally be substituted with one or more methyl.

11. The compound according to claim 1 , wherein the compound is selected from the group consisting of:

2) 6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(2-methyloxazol-4-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;

3) 6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(1H-pyrazol-3-ylmethyl)pyrazolo[3,4-b]pyridin-4-amine;

4) 6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;

5) 6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;

6) 6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-(5-methyl-1H-pyrazol-3-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;

7) 6-(2-ethoxy-3-pyridyl)-3-isopropyl-N-[(2-ethoxy-4-pyridyl)methyl]-1-methyl pyrazolo[3,4-b]pyridin-4-amine;

8) 2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(1-methylimidazol-4-yl)methyl]imidazo[1,5-b]pyridazin-4-amine;

9) 2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(2-methyloxazol-4-yl)methyl]imidazo[1,5-b]pyridazin-4-amine;

10) 2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-(1H-pyrazol-3-ylmethyl)imidazo[1,5-b]pyrazin-4-amine;

11) 2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]imidazo[1,5-b]pyridazin-4-amine;

12) 2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]imidazo[1,5-b]pyridazin-4-amine;

13) 2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(5-methyl-1H-pyrazol-3-yl)methyl]imidazo[1,5-b]pyridazin-4-amine;

14) 2-(2-ethoxy-3-pyridyl)-5-isopropyl-N-[(5-methoxy-3-pyridyl)methyl]-7-methyl-imidazo[1,5-b]pyridazin-4-amine;

15) 2-(2-ethoxy-3-pyridyl)-5-isopropyl-N-[(2-methoxy-4-pyridyl)methyl]-7-methyl-imidazo[1,5-b]pyridazin-4-amine;

16) 2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(2-methyloxazol-5-yl)methyl]imidazo[1,5-b]pyridazin-4-amine;

17) 2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(2-methylthiazol-5-yl)methyl]imidazo[1,5-b]pyridazin-4-amine;

18) 2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-(1H-pyrazol-4-ylmethyl)imidazo[1,5-b]pyridazin-4-amine;

19) 6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;

20) 6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(2-methyltetrazol-5-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;

21) 6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(1-methylpyrazol-3-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;

22) 2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(1-methylpyrazol-4-yl)methyl]imidazo[1,5-b]pyridazin-4-amine;

23) 2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(2-methyltetrazol-5-yl)methyl]imidazo[1,5-b]pyridazin-4-amine;

24) 2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(1-methylpyrazol-3-yl)methyl]imidazo[1,5-b]pyridazin-4-amine;

25) 6-(2-ethoxy-3-pyridyl)-3-isopropyl-N-[(5-methoxy-3-pyridyl)methyl]-1-methyl-pyrazolo[3,4-b]pyridin-4-amine;

26) 6-(2-ethoxypyridin-3-yl)-3-isopropyl-1-methyl-N-((2-methyl-2H-1,2,3-triazol-4-yl)methyl) 1H-pyrazolo[3,4-b]pyridin-4-amine;

27) 6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(2-methyloxazol-5-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;

28) 6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(2-methylthiazol-5-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;

29) 6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(1-methyltriazol-4-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;

30) 6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-(1H-pyrazol-4-ylmethyl)pyrazolo[3,4-b]pyridin-4-amine;

31) 6-(2-ethoxy-3-pyridyl)-3-isopropyl-1l-methyl-N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;

32) 6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;

33) 3-isopropyl-1-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]-6-(2-propoxy-3-pyridyl)pyrazolo[3,4-b]pyridin-4-amine;

34) 3-isopropyl-1-methyl-N-[(1-methylimidazol-4-yl)methyl]-6-(2-propoxy-3-pyridyl)pyrazolo[3,4-b]pyridin-4-amine;

35) 6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(4-methylpyrimidin-2-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;

36) 6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-(pyrimidin-2-ylmethyl)pyrazolo[3,4-b]pyridin-4-amine;

37) 6-(2-ethoxy-3-pyridyl)-3-isopropyl-N-[(6-methoxy-3-pyridyl)methyl]-1-methyl-pyrazolo[3,4-b]pyridin-4-amine;

38) 6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[[2-(trifluoromethyl)-pyridyl]methyl]pyrazolo[3,4-b]pyridin-4-amine;

39) 6-(2-ethoxy-3-pyridyl)-3-isopropyl-N-[(4-methoxy-2-pyridyl)methyl]-1-methyl-pyrazolo[3,4-b]pyridin-4-amine;

40) 6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-(2-pyridylmethyl)pyrazolo[3,4-b]pyridin-4-amine;

41) 6-(2-ethoxy-3-pyridyl)-3-isopropyl-N-[(6-methoxy-2-pyridyl)methyl]-1-methyl-pyrazolo[3,4-b]pyridin-4-amine;

42) 6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-N-[(6-methyl-2-pyridyl)methyl]pyrazolo[3,4-b]pyridin-4-amine;

43) 2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-(1,2,4-oxadiazol-3-ylmethyl)imidazo[1,5-b]pyridazin-4-amine;

44) 2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(2-methyltriazol-4-yl)methyl]imidazo[1,5-b]pyridazin-4-amine;

45) 2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]imidazo[1,5-b]pyridazin-4-amine;

46) 2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]imidazo[1,5-b]pyridazin-4-amine;

47) (−)-2-(2-ethoxy-3-pyridyl)-7-methyl-N-[(1-methylpyrazol-4-yl)methyl]-5-[1-methylpropyl]imidazo[1,5-b]pyridazin-4-amine;

48) (+)-2-(2-ethoxy-3-pyridyl)-7-methyl-N-[(1-methylpyrazol-4-yl)methyl]-5-[1-methylpropyl]imidazo[1,5-b]pyridazin-4-amine;

49) (−)-2-(2-ethoxy-3-pyridyl)-7-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]-5-[1-methylpropyl]imidazo[1,5-b]pyridazin-4-amine;

50) (+)-2-(2-ethoxy-3-pyridyl)-7-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]-5-[1-methylpropyl]imidazo[1,5-b]pyridazin-4-amine;

51) (+)-2-(2-ethoxy-3-pyridyl)-7-methyl-N-(1H-pyrazol-3-ylmethyl)-5-[1-methylpropyl]imidazo[1,5-b]pyridazin-4-amine;

52) (−)-2-(2-ethoxy-3-pyridyl)-7-methyl-N-(1H-pyrazol-3-ylmethyl)-5-[1-methylpropyl]imidazo[1,5-b]pyridazin-4-amine;

53) (+)-2-(2-ethoxy-3-pyridyl)-N-[(2-methoxy-4-pyridyl)methyl]-7-methyl-5-[1-methylpropyl]imidazo[1,5-b]pyridazin-4-amine;

54) (−)-2-(2-ethoxy-3-pyridyl)-N-[(2-methoxy-4-pyridyl)methyl]-7-methyl-5-[1-methylpropyl]imidazo[1,5-b]pyridazin-4-amine;

55) 3-isopropyl-6-(2-methoxy-3-pyridyl)-1-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;

56) 3-(3-isopropyl-1-methyl-4-(((1-methyl-1H-1,2,4-triazol-3-yl)methyl)amino)-1H-pyrazolo[3,4-b]pyridin-6-yl)-1-methylpyridin-2(1H)-one;

57) 3-isopropyl-6-(3-methoxypyrazin-2-yl)-1-methyl-N-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)-1H-pyrazolo[3,4-b]pyridin-4-amine;

58) 3-isopropyl-1-methyl-6-(2-methyl-3-thienyl)-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;

59) 3-isopropyl-1-methyl-N-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)-6-(4-methyloxazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine;

60) 3-isopropyl-1-methyl-6-(4-methylthiazol-2-yl)-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;

61) 3-isopropyl-1-methyl-N-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)-6-(4-methylthiazol-5-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine;

62) 3-isopropyl-1-methyl-6-(5-methylthiazol-2-yl)-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;

63) 3-isopropyl-1-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]phenyl-pyrazolo[3,4-b]pyridin-4-amine;

64) 3-isopropyl-6-(4-methoxypyrimidin-5-yl)-1-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;

65) 3-isopropyl-1-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]-6-(2-thienyl)pyrazolo[3,4-b]pyridin-4-amine;

66) 6-(3-ethoxypyridazin-4-yl)-3-isopropyl-1-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;

67) 3-isopropyl-1-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]-6-(3-propoxypyridazin-4-yl)pyrazolo[3,4-b]pyridin-4-amine;

68) 6-(3-ethoxy-4-pyridyl)-3-isopropyl-1-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[3,4-b]pyridin-4-amine;

69) 2-(3-ethoxypyridazin-4-yl)-5-isopropyl-7-methyl-N-[(1-methylpyrazol-4-yl)methyl]imidazo[1,5-b]pyridazin-4-amine;

70) 2-(3-ethoxy-4-pyridyl)-5-isopropyl-7-methyl-N-[(1-methylpyrazol-4-yl)methyl]imidazo[1,5-b]pyridazin-4-amine;

71) 5-isopropyl-7-methyl-N-[(1-methylpyrazol-4-yl)methyl]-2-(2-propoxy-3-pyridyl)imidazo[1,5-b]pyridazin-4-amine;

72) 5-isopropyl-7-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]-2-(2-propoxy-3-pyridyl)imidazo[1,5-b]pyridazin-4-amine;

73) 2-(2-ethoxy-3-pyridyl)-N-[(2-fluoro-3-pyridyl)methyl]-5-isopropyl-7-methyl-imidazo[1,5-b]pyridazin-4-amine;

74) 2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-(2-pyridylmethyl)imidazo[1,5-b]pyridazin-4-amine;

75) 2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-(pyrimidin-2-ylmethyl)imidazo[1,5-b]pyridazin-4-amine;

76) 2-(2-ethoxy-3-pyridyl)-N-[(5-fluoropyrimidin-2-yl)methyl]-5-isopropyl-7-methyl-imidazo[1,5-b]pyridazin-4-amine;

77) 2-(2-ethoxy-3-pyridyl)-5-isopropyl-N-[(2-methoxy-3-pyridyl)methyl]-7-methyl-imidazo[1,5-b]pyridazin-4-amine;

78) 2-(2-ethoxy-3-pyridyl)-N-(imidazo[1,5-a]pyridin-5-ylmethyl)-5-isopropyl-7-methyl-imidazo[1,5-b]pyridazin-4-amine;

79) 2-(2-ethoxy-3-pyridyl)-N-(imidazo[1,2-a]pyridin-5-ylmethyl)-5-isopropyl-7-methyl-imidazo[1,5-b]pyridazin-4-amine;

80) 2-(2-ethoxy-3-pyridyl)-5-isopropyl-7-methyl-N-[[2-(trifluoromethyl)-3-pyridyl]methyl]imidazo[1,5-b]pyridazin-4-amine;

81) 2-(1,3-benzoxazol-7-yl)-5-isopropyl-7-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]imidazo[1,5-b]pyridazin-4-amine;

and pharmaceutically acceptable salts thereof.

12. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents and/or excipients.

13. The compound according to claim 2 , wherein Z 1 is NH.

14. The compound according to claim 2 , wherein Z 2 is CH 2 .

15. The compound according to claim 2 , wherein R 1 is a linear or branched C 1-4 alkyl.

16. The compound according to claim 2 , wherein R 2 is a linear or branched C 1-4 alkyl.

17. The compound according to claim 3 , wherein Z 1 is NH.

18. The compound according to claim 3 , wherein Z 2 is CH 2 .

19. The compound according to claim 3 , wherein R 1 is a linear or branched C 1-4 alkyl.

20. The compound according to claim 3 , wherein R 2 is a linear or branched C 1-4 alkyl.

21. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 11 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents and/or excipients.