Pyrazolo[1,5-a]pyrimidine derivatives

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof; wherein:

A represents a phenyl, thienyl or thiazolyl ring, which bears 0-3 substituents independently selected from halogen, CN, C 1-4 alkyl, CF 3 and C 1-4 alkoxy;

X represents a monocyclic ring system comprising 5-6 ring atoms, of which 1-3 are selected from N, O and S and the remainder are C, said ring system bearing 0-3 substituents independently selected from halogen, CN, R 1 -L, R 1 O-L, R 1 R 2 N-L and R 1 CONR 2 ;

L represents a bond or a linking group selected from CO, (CO) m (CH 2 ) n , (CO) m (CH 2 ) n O, (CO) m (CH 2 ) n NR 2 and (CO) m (CH 2 ) n S;

m is 0 or 1;

n is 0, 1, 2, 3 or 4;

R 1 is selected from:

H;

C 1-6 alkyl which is optionally substituted with up to 3 halogen atoms or with OH, CN, C 3-6 cycloalkyl, C 1-4 alkoxy, C 1-4 alkoxycarbonyl, amino, C 1-4 alkylamino or di(C 1-4 alkyl)amino; and

phenyl or C 3-6 cycloalkyl, either of which is optionally substituted with up to 3 halogen atoms or with OH, CN, CF 3 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxycarbonyl, amino, C 1-4 alkylamino or di(C 1-4 alkyl)amino;

R 2 represents H or C 1-4 alkyl;

or R 1 and R 2 attached to the same nitrogen atom may complete a heterocycle of up to 7 ring atoms which is optionally substituted with up to 3 halogen atoms or with OH, CN, CF 3 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxycarbonyl, amino, C 1-4 alkylamino or di(C 1-4 alkyl)amino;

R 3 represents H or C 1-4 alkyl which is optionally substituted with OH, CN, CF 3 , C 1-4 alkoxy, amino, C 1-4 alkylamino or di(C 1-4 alkyl)amino;

R 4 is selected from:

(i) H;

(ii) C 1-8 alkyl or C 2-8 alkenyl, either of which optionally bears up to 3 substituents independently selected from halogen, OH, CN, CF 3 , OR 6 , SR 7 , SO 2 R 7 , SO 2 N(R 6 ) 2 , COR 6 , CO 2 R 6 , CON(R 6 ) 2 , N(R 6 ) 2 , NR 6 COR 7 and NR 6 SO 2 R 7 ; and

(iii) C 3-10 cycloalkyl, C 3-10 cycloalkylC 1-4 alkyl, Het, HetC 1-4 alkyl, aryl or arylC 1-4 alkyl, any of which optionally bears up to 3 substituents independently selected from halogen, OH, oxo, CN, CF 3 , R 7 , OR 6 , SR 7 , SO 2 R 7 , SO 2 N(R 6 ) 2 , COR 6 , CO 2 R 6 , CON(R 6 ) 2 , N(R 6 ) 2 , NR 6 COR 7 and NR 6 SO 2 R 7 ; where “aryl” refers to phenyl or 5- or 6-membered heteroaryl, either of which phenyl or heteroaryl is optionally fused to a 5- or 6-membered carbocycle or heterocycle, and “Het” refers to a nonaromatic mono- or bicyclic heterocyclic system of up to 10 ring atoms;

or R 3 and R 4 together may complete a mono- or bicyclic heterocyclic system of up to 10 ring atoms which optionally bears up to 3 substituents independently selected from halogen, OH, oxo, CN, CF 3 , R 7 , OR 6 , SR 7 , SO 2 R 7 , SO 2 N(R 6 ) 2 , COR 6 , CO 2 R 6 , CON(R 6 ) 2 , N(R 6 ) 2 , NR 6 COR 7 and NR 6 SO 2 R 7 ;

R 6 represents H or C 1-6 alkyl which is optionally substituted with up to 3 halogen atoms or with OH, CN, CF 3 , C 1-4 alkoxy, amino, C 1-4 alkylamino or di(C 1-4 alkyl)amino, or R 6 represents phenyl, benzyl or 5- or 6-membered heteroaryl, any of which optionally bears up to 3 substituents independently selected from halogen, OH, CN, CF 3 , C 1-4 alkyl, C 1-4 alkoxy, amino, C 1-4 alkylamino and di(C 1-4 alkyl)amino;

or two R 6 groups attached to the same nitrogen atom may complete a heterocycle of up to 6 ring atoms which optionally bears up to 3 substituents independently selected from halogen, OH, oxo, CN, CF 3 , C 1-4 alkyl, C 1-4 alkoxy, amino, C 1-4 alkylamino and di(C 1-4 alkyl)amino; and

R 7 has the same definition as R 6 except that R 7 is not H.

2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein X represents 2-oxo-1,2-dihydropyridin-4-yl which bears a substituent R 1 R 2 N(CH 2 ) p on the 1-position, where p is 2 or 3.

3. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein X represents 3-pyridine which is unsubstituted or substituted in the 6-position.

4. A compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein the substituent is selected from NH 2 , dimethylamino, piperazin-1-yl, 4-methylpiperazin-1-yl, 2-(morpholin-1-yl)ethylamino, cyclopropylmethoxy, acetylamino, 3-(dimethylamino)propoxy, methoxy, 2-hydroxy-2-methylpropylamino, morpholin-1-yl and 2-methoxyethylamino.

5. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein X represents optionally-substituted 5-membered heteroaryl.

6. A compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein X represents 1-methyl-1H-pyrazol-5-yl, 1-methyl-1H-pyrazol-4-yl, 1-methyl-1H-imidazol-4-yl, 1-benzyl-1H-pyrazol-4-yl, 1H-pyrrol-2-yl, 1H-pyrazol-3-yl, 3-thienyl, 3-furyl, 2-furyl, 5-acetyl-2-thienyl or 1H-pyrazol-4-yl.

7. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is a compound of formula II:

or a pharmaceutically acceptable salt thereof; wherein:

Z 1 represents S;

Z 2 represents N or CR 9 ; and

R 8 and R 9 are independently selected from H, halogen, CN, C 1-4 -alkyl, CF 3 and C 1-4 alkoxy.

8. A compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein Z 2 is CR 9 and R 8 is H, methyl or Cl; or Z 2 is N and R 8 is H, methyl or Cl.

9. A compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein X represents 1-methylpyrazol-4-yl.

10. A compound according to claim 7 or a

pharmaceutically acceptable salt thereof, wherein R 3 is H and R 4 represents:

where n is 0 or 1 and R 5 represents H, C 1-6 alkyl, phenyl or pyridyl, said phenyl or pyridyl optionally bearing a substituent selected from halogen, CF 3 , C 1-4 -alkyl and C 1-4 -alkoxy;

or R 4 represents:

where m is 0 or 1, V represents H, OH or NH 2 and W represents CH 2 , CF 2 or SO 2 .

11. A compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein R 4 is of formula (i)

where n is 0 or 1 and R 5 represents H, isopropyl, phenyl, 2-pyridyl, 5-fluoro-2-pyridyl or 6-methyl-2-pyridyl;

or wherein R 4 is of formula (ii)

and m is 1, V is NH 2 and W is CF 2 .

12. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X represents 1-methylpyrazol-4-yl.

13. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 is H and R 4 represents:

where n is 0 or 1 and R 5 represents H, C 1-6 alkyl, phenyl or pyridyl, said phenyl or pyridyl optionally bearing a substituent selected from halogen, CF 3 , C 1-4 -alkyl and C 1-4 -alkoxy;

or R 4 represents:

where m is 0 or 1, V represents H, OH or NH 2 and W represents CH 2 , CF 2 or SO 2 .

14. A pharmaceutical composition comprising a compound of formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.