Compounds, their use and preparation

1. A compound of Formula (I):

wherein

nx is 2–4,

R 0 and R 1 are each independently H or CH 3 ;

R 2 is H, C 1 –C 4 -alkyl, 2-hydroxyethyl, 2-cyanoethyl or tetrahydropyran-2-yl, C 1 –C 4 -acyl or C 1 –C 4 -alkoxycarbonyl;

R 3 –R 5 are each independently H, halogen, methyl or methoxy, provided that at least one of R 3 –R 5 is hydrogen;

X, Y, and Z are each independently CH or N;

A 1 is O, CH or CH 2 ;

A 2 is O, CH or (CH 2 ) n2 , wherein n2 is an integer 0–2;

the bond between A 1 and A 2 is a single or double bond;

A 3 is (CH 2 ) n3 , wherein n3 an integer 0–10;

A 4 is (CMe 2 ) n4 , wherein n4 is an integer 0–1;

A 5 is N or O;

A 6 and A 7 are each independently H, C 1 –C 4 -alkyl, amino-C 2 –C 4 -alkyl, N,N-di-C 1 –C 4 -alkylamino-C 2 –C 4 -alkyl, C 3 –C 6 -cycloalkyl; or when A 5 is nitrogen, A 6 and A 7 together with A 5 form a saturated heterocyclic ring;

A 8 is (CH 2 ) n8 , wherein n8 is an integer 0–2;

A 9 is H or CH 2 ;

or pharmaceutically acceptable salts, hydrates, geometrical isomers, tautomers, optical isomers, and N-oxides thereof; and

provided that when A 5 is N, then A 5 is substituted by only two of A 6 , A 7 and A 8 ; when A 5 is O, then A 5 is substituted by only one of A 6 , A 7 and A 8 ; and when A 9 is H, then A 8 is not a single bond between A 5 and A 9 .

2. The compound according to claim 1 , wherein R 0 is methyl.

3. The compound according to any one of claims 1 to 2 , wherein the carbon atom, to which the said methyl group R 0 is attached, is in the (R)-configuration.

4. The compound according to claim 1 , wherein R 0 is hydrogen.

5. The compound according to claim 1 , wherein R 1 is hydrogen.

6. The compound according to claim 1 , wherein X and Y both are nitrogen.

7. The compound according to claim 1 , wherein R 2 is H or methyl.

8. The compound according to claim 1 , wherein all of R 3 –R 5 are H.

9. The compound according to claim 1 , wherein A 6 and A 7 are each independently H, methyl, isopropyl, 2-ethylamine or form together a pyrrolidine or piperazine ring.

10. The compound according to claim 1 , which has the Formula (Ia):

wherein:

R 0 –R 5 , X, Y, and Z are as defined in any one of claims 1 to 8 ,

m is an integer 0–10,

n is an integer 0 or 1,

R 6 is NR 7 R 8 or OR 9 , wherein

R 7 and R 8 are each independently H or straight or branched C 1 –C 4 -alkyl;

or R 7 and R 8 form together with the nitrogen atom to which they are attached a saturated heterocyclic ring; and

R 9 is amino-C 2 –C 4 -alkyl or N,N-di-C 1 –C 4 -alkylamino-C 2 –C 4 -alkyl.

11. The compound according to claim 10 , wherein R 7 and R 8 are selected from H, methyl, isopropyl, or form together with the nitrogen atom to which they are attached a pyrrolidine or piperazine ring.

12. The compound according to any one of claims 10 or 11 , wherein R 9 is 2-aminoethyl.

13. The compound according to claim 10 , which compound is:

N,N-Dimethyl-(2-(3-[2-(2-(R)-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yloxy)-ethoxy]-pyridin-2-yloxy)-ethyl)-amine;

N,N-Diisopropyl-(2-(3-[2-(2-(R)-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yloxy)-ethoxy]-pyridin-2-yloxy)-ethyl)-amine;

N,N-Dimethyl-2-[(3-{2-[(3-piperazin-1-ylpyrazin-2-yl)oxy]ethoxy}pyridin-2-yl)oxy]ethanamine;

2-[(2R)-2-Methylpiperazin-1-yl]-3-(2-{[2-(2-pyrrolidin-1-ylethoxy)pyridin-3-yl]oxy}ethoxy)pyrazine,;

N,N-Dimethyl-4-({3-[2-({3-[(2R)-2-methylpiperazin-1-yl]pyrazin-2-yl}oxy)ethoxy]pyridin-2-yl}oxy)butan-1-amine;

N,N-Methyl-N-[2-({3-[2-({3-[(2R)-2-methylpiperazin-1-yl]pyrazin-2-yl}oxy)ethoxy]pyridin-2-yl}oxy)ethyl]propan-2-amine;

N,N-Dimethyl-3-({3-2-({3-[(2R)-2-methylpiperazin-1-yl]pyrazin-2-yl}oxy)ethoxy-2-yl}oxy)propan-1-amine;

N,N,2-Trimethyl-1-({3-[2-({3-[(2R)-2-methylpiperazin-1-yl]pyrazin-2-yl}oxy)ethoxy]pyridin-2-yl}oxy)propan-2-amine;

[2-({3-[2-({3-[(2R)-2-Methylpiperazin-1-yl]pyrazin-2-yl}oxy)ethoxy]pyridin-2-yl}oxy)ethyl]amine;

N-Methyl-2-({3-[2-({3-[(2R)-2-methylpiperazin-1-yl]pyrazin-2-yl}oxy)ethoxy]pyridin-2-yl}oxy)ethanamine;

2-{2-[{2-[2-(Dimethylamino)ethoxy]pyridin-3-yl}oxy]ethoxy}-3-[(2R)-2,4-dimethylpiperazin-1-yl]pyrazine;

2-[2-(2-[2-(Dimethylamino)ethoxy]phenoxy)ethoxy]-3-[(2R)-2-methylpiperazin-1-yl]pyrazine;

{2-[2-({3-[2-({3-[(2R)-2-Methylpiperazin-1-yl]pyrazin-2-yl}oxy)ethoxy]pyridin-2-yl}oxy)ethoxy]ethyl}amine

[6-({3-[2-({3-[(2R)-2-Methylpiperazin-1-yl]-pyrazin-2-yl}oxy)ethoxy]pyridin-2-yl}oxy)hexyl]amine;

[5-({3-[2-({3-[(2R)-2-Methylpiperazin-1-yl]pyrazin-2-yl}oxy)ethoxy]pyridin-2-yl}oxy)pentyl]amine

5-({3-[2-({3-[(2R)-2,4-Dimethylpiperazin-1-yl]-pyrazin-2-yl}oxy)ethoxy]pyridin-2yl}oxy)-N,N-dimethylpentan-1-amine; or

2-[(2R)-2-Methylpiperazin-1-yl]-3-(2-{[2-(2-piperazin-1-ylethoxy)pyridin-3-yl]oxy}ethoxy)pyrazine.

14. The compound according to any claim 1 , which has the Formula (Ib):

wherein:

R 0 –R 5 , X, Y, and Z are as in any one of claims 1 to 8 ,

o is an integer 0–2;

p is an integer 0–2,

q is an integer 0–1;

R 10 is H or C 1 –C 4 -alkyl.

15. The compound according to claim 14 , which compound is:

2-[(2R)-2-Methylpiperazin-1-yl]-3-[2-({2-[(1-methylpiperidin-4-yl)oxy]pyridin-3-yl}oxy)ethoxy]pyrazine, trifluoroacetate;

2-[(2R)-2-Methylpiperazin-1-yl]-3-[2-({2-[2-(1-methylpyrrolidin-2-yl)ethoxy]pyridin-3-yl}oxy)ethoxy]pyrazine, trifluoroacetate;

2-[(2R)-2-Methylpiperazin-1-yl]-3-(2-{[2-(piperidin-3-ylmethoxy)pyridin-3-yl]-oxy}ethoxy)pyrazine, trifluoroacetate;

2-[(2R)-2-Methylpiperazin-1-yl]-3-{2-[(2-{[(2S)-1-methylpyrrolidin-2-yl]-methoxy}pyridin-3-yl)oxy]ethoxy}pyrazine, trifluoroacetate.

16. The compound according to claim 1 , which has the Fommia (Ic):

wherein:

R 0 –R 5 , X, Y, and Z are as defined above,

t is an integer 1–11,

the orientation around the double bond may be either cis or trauis;

R 11 and R 12 are each independently H or straight or branched C 1 –C 4 -alkyl; or R 11 and R 12 form together with the nitrogen atom to which they are attached a saturated heterocyclic ring.

17. The compound according to claim 16 , wherein R 11 and R 12 are both methyl.

18. The compound according to any one of claims 16 or 17 , which compound is:

2-{2-[{2-[(1Z)-3-(Dimethylamino)prop-1-enyl]pyridin-3-yl}oxy]ethoxy}-3-[(2R)-2-methylpiperazin-1-yl]-pyrazine; or

2-{2-[{2-[(1E)-3-(Dimethylamino)prop-1-enyl]pyridin-3-yl}oxy]ethoxy}-3-[(2-methylpiperazin-1-yl]-pyrazine.

19. The compound according to claim 1 , which has the Formula (Id):

wherein:

R 0 –R 5 , X, Y, and Z are as defined above,

W is O or CH 2 ;

r is 1–11;

R 13 and R 14 are each independently H or straight or branched C 1 –C 4 -alkyl; or R 13 and R 14 form together with the nitrogen atom to which they are attached a saturated heterocyclic ring.

20. The compound according to claim 19 , wherein W is O, X═N, and Y═N.

21. The compound according to claim 19 , wherein r=t, W═CH 2 , X═N, Y═N, R 13 ═R 11 and R 14 ═R 12 ; where t, R 11 and R 12 are as defined for formula (Ic) in claim 16 .

22. The compound according to claim 19 , wherein R 13 and R 14 are both methyl.

23. The compound according to claim 19 , which compound is:

2-{2-[(2-{[2-(Dimethylamino)ethoxy]methyl}pyridin-3-yl)oxy]ethoxy}-3-[(2R)-2-methylpiperazin-1-yl]-pyrazine; or

2-{2-[{2-[3-(Dimethylamino)propyl]pyridin-3-yl}oxy]ethoxy}-3-[(2R)-2-methylpiperazin-1-yl]-pyrazine.

24. A pharmaceutical composition comprising a compound according to claim 1 , as an active ingredient, together with a pharmaceutically acceptable carrier.

25. The compound of claim 1 , wherein nx is 2.

26. The compound of claim 1 , wherein n3 is 0–7.

27. The compound of claim 1 , wherein n3 is 0–5.

28. The compound of claim 10 , wherein Z is N.

29. The compound of claim 10 , wherein m is 0–7.

30. The compound of claim 10 , wherein m is 0–5.

31. The compound of claim 10 , wherein the sum of m+n is at least 1.

32. The compound of claim 14 , wherein o and p are not both 0.

33. The compound of claim 14 , wherein R 10 is H or methyl.

34. The compound of claim 16 , wherein t is an integer 1–8.

35. The compound of claim 16 , wherein t is an integer 1–6.

36. The compound of claim 16 , wherein t is 1.

37. The compound of claim 19 , wherein r is 1–8.

38. The compound of claim 19 , wherein r is 1–6.

39. The compound of claim 19 , wherein r is 1 and W is CH 2 .

40. The compound of claim 19 , wherein r is 2 and W is O.