4-aminopyrimidine derivatives as histamine H

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is selected from:

(1) C 1-8 alkyl;

(2) C 3-8 cycloalkyl-C 0-6 alkyl;

(3) aryl-C 1-6 alkyl; wherein in groups (1) to (3) any alkyl group may be optionally substituted with one or more halogen groups and the C 3-8 cycloalkyl group may be optionally substituted with one or more substituents selected from C 1-4 alkyl, halogen and aryl;

(4) a group of formula (i)

(5) a group of formula (ii)

R 2 and R 3 form, together with the N atom to which they are bound, a saturated heterocyclic group that can be 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic, or 8- to 12-membered fused bicyclic, wherein said heterocyclic group can contain up to two N atoms and does not contain any other heteroatoms, and can be optionally substituted with one or more substituents independently selected from C 1-4 alkyl and NR a R b , provided that the heterocyclic group either contains 2 N atoms and is not substituted with an NR a R b group, or contains 1 N atom and is substituted with one NR a R b group; or

R 2 is selected from H and C 1-4 alkyl, and R 3 is selected from azetidinyl, pyrrolidinyl, piperidinyl and azepanyl, each of which may be optionally substituted with one or more C 1-4 alkyl groups;

R a is selected from H and C 1-4 alkyl;

R b is selected from H and C 1-4 alkyl;

or R a and R b form, together with the N atom to which they are bound, an azetidinyl, pyrrolidinyl, piperidinyl or azepanyl group, that may be optionally substituted with one or more C 1-4 alkyl groups;

R 4 and R 5 are each independently selected from H and C 1-4 alkyl, and additionally one of the R 4 or R 5 groups may be selected from aryl or C 3-6 cycloalkyl-C 0-6 alkyl, and additionally two R 4 and R 5 groups on a same C atom may be bound together forming with said C atom a C 3-8 cycloalkyl group;

R 6 is a group selected from C 1-8 alkyl, C 3-8 cycloalkyl-C 0-6 alkyl and aryl-C 0-4 alkyl, wherein any of said alkyl groups may be optionally substituted with one or more halogen groups and said C 3-8 cycloalkyl group may be optionally substituted with one or more substituents independently selected from C 1-4 alkyl, halogen and aryl;

R 7 is a saturated monocyclic 4- to 7-membered heterocyclic ring containing one O atom and not containing any other additional heteroatoms, wherein said ring may be bound to the rest of the molecule through any available C atom, and wherein R 7 may be optionally substituted with one or more groups independently selected from C 1-4 alkyl and halogen;

n is 1, 2 or 3;

p is 0, 1 or 2; and

aryl is a phenyl group optionally substituted with one or more groups independently selected from C 1-4 alkyl, halogen, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, cyano and amino.

2. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is (1) C 4-6 alkyl; (2) C 3-8 cycloalkyl-C 0-1 alkyl; or (3) aryl-C 1-2 alkyl.

3. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is a C 3-8 cycloalkyl-C 0-6 alkyl, wherein the alkyl group may be optionally substituted with one or more halogen groups and the C 3-8 cycloalkyl group may be optionally substituted with one or more substituents independently selected from C 1-4 alkyl, halogen and aryl.

4. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from a C 3-8 cycloalkyl optionally substituted with one or more substituents independently selected from C 1-4 alkyl, halogen and aryl.

5. A compound according to claim 4 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from cyclobutyl, cyclopentyl and cyclohexyl.

6. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is C 3-8 cycloalkyl-C 1 alkyl.

7. A compound according to claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 1 is cyclopropylmethyl.

8. A compound according to claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 1 is cyclohexylmethyl.

9. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1-8 alkyl or C 3-6 cycloalkyl-C 0-6 alkyl, wherein the alkyl group may be optionally substituted with one or more halogen groups and the C 3-8 cycloalkyl group may be optionally substituted with one or more substituents independently selected from C 1-4 alkyl, halogen and aryl.

10. A compound according to claim 9 , or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1-8 alkyl or C 3-6 cycloalkyl-C 0-6 alkyl.

11. A compound according to claim 10 , or a pharmaceutically acceptable salt thereof, wherein R 1 is C 4-6 alkyl or C 3-8 cycloalkyl-C 0-1 alkyl.

12. A compound according to claim 11 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from isobutyl, 2,2-dimethylpropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl and cyclopropylmethyl.

13. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is a C 1-6 alkyl optionally substituted with one or more halogen groups.

14. A compound according to claim 13 , or a pharmaceutically acceptable salt thereof, wherein R 1 is C 4-6 alkyl.

15. A compound according to claim 14 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from isobutyl and 2,2-dimethylpropyl.

16. A compound according to claim 15 , or a pharmaceutically acceptable salt thereof, wherein R 1 is isobutyl.

17. A compound according to claim 15 , or a pharmaceutically acceptable salt thereof, wherein R 1 is 2,2-dimethylpropyl.

18. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 form, together with the N atom to which they are bound, a saturated heterocyclic group that can be 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic, or 8- to 12-membered fused bicyclic, wherein said heterocyclic group can contain up to two N atoms and does not contain any other heteroatoms, and can be optionally substituted with one or more substituents independently selected from C 1-4 alkyl and NR a R b , provided that the heterocyclic group either contains 2 N atoms and is not substituted with an NR a R b group, or contains 1 N atom and is substituted with one NR a R b group.

19. A compound according to claim 18 , or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from:

wherein R c is selected from H or C 1-4 alkyl.

20. A compound according to claim 19 , or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) or (b).

21. A compound according to claim 20 , or a pharmaceutically acceptable salt thereof, wherein R c is H.

22. A compound according to claim 19 , or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a).

23. A compound according to claim 22 , or a pharmaceutically acceptable salt thereof, wherein R c is H.

24. A compound according to claim 19 , or a pharmaceutically acceptable salt thereof, wherein R a and R b are each independently selected from H and C 1-4 alkyl.

25. A compound according to claim 24 , or a pharmaceutically acceptable salt thereof, wherein R a and R b are each independently selected from H and methyl.

26. A compound according to claim 25 , or a pharmaceutically acceptable salt thereof, wherein R a is H and R b is methyl.

27. A compound according to claim 19 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from C 4-6 alkyl or C 3-8 cycloalkyl-C 0-1 alkyl and R 2 and R 3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b).

28. A compound according to claim 27 , or a pharmaceutically acceptable salt thereof, wherein R 1 is C 4-6 alkyl, R a and R b are each independently selected from H and methyl, and R c is H.

29. A compound according to claim 27 , or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a).

30. A compound according to claim 29 , or a pharmaceutically acceptable salt thereof, wherein R c is H.

31. A compound according to claim 30 , or a pharmaceutically acceptable salt thereof, wherein R a and R b are each independently selected from H and methyl.

32. A compound according to claim 31 , or a pharmaceutically acceptable salt thereof, wherein R 1 is C 3-8 cycloalkyl-C 0-1 alkyl.

33. A compound according to claim 31 , or a pharmaceutically acceptable salt thereof, wherein R 1 is C 4-6 alkyl.

34. A compound according to claim 33 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from isobutyl or 2,2-dimethylpropyl.

35. A compound according to claim 1 , wherein the compound of formula (I) is selected from:

2-Isobutyl-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-4-amine;

2-Isobutyl-6-(3-(methylamino)azetidin-1-yl)pyrimidin-4-amine;

2-(2,2-dimethylpropyl)-6-(3-(methylamino)azetidin-1-yl)pyrimidin-4-amine;

2-(2,2-dimethylpropyl)-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-4-amine;

2-Cyclohexylmethyl-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-4-amine;

2-Cyclohexylmethyl-6-(3-(methylamino)azetidin-1-yl)pyrimidin-4-amine;

2-(Cyclopropylmethyl)-6-(3-(methylamino)azetidin-1-yl)pyrimidin-4-amine; and

2-Cyclopropylmethyl-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-4-amine;

and pharmaceutically acceptable salts thereof.

36. A pharmaceutical composition which comprises a compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

37. A process for the preparation of a compound of formula (I), according to claim 1 , comprising:

(a) reacting a compound of formula II

with ammonia, benzophenoneimine, benzylamine or benzhydrylamine, wherein R 1 , R 2 and R 3 have the same meaning as described in claim 1 ;

(b) reacting a compound of formula VII with a compound of formula IV

wherein R 1 , R 2 and R 3 have the same meaning described in claim 1 and X is H or tert-butoxycarbonyl, followed if necessary by the removal of any protecting group that may be present; or

(c) reacting a compound of formula VIIB with a compound of formula IV

wherein R 8 is halogen, triflate or tosylate, R 1 , R 2 and R 3 have the same meaning described in claim 1 , and X is H or tert-butoxycarbonyl, followed if necessary by the removal of any protecting group that may be present; or

(d) when in a compound of formula (I), R 1 is R 1 ′—CH 2 —CH 2 —, treating a compound of formula IX with a source of hydrogen in the presence of a palladium catalyst

wherein R 1 ′ is selected from:

C 1-6 alkyl, C 3-6 cycloalkyl-C 0-4 alkyl, and aryl-C 0-4 alkyl, wherein any alkyl group may be optionally substituted by one or more halogen groups and the C 3-8 cycloalkyl group may be optionally substituted by one or more substituents independently selected from C 1-4 alkyl, halogen and aryl; or

R 1 ′ is a group of formula (i)

wherein n is 2 and R 4 and R 5 are each H; or

R 1 ′ is a group of formula (ii)

wherein p is 2, R 4 and R 5 are each H, and R 2 and R 3 are as described in claim 1 .