Pyrazolo-pyridine derivatives as antiherpes agents

1. A compound of formula (I):

wherein:

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

each R 1 is the same or different and is independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, Ay, Het, —OR 7 , —OAy, —OR 10 Ay, —OHet, —OR 10 Het, —C(O)R 9 , —C(O)Ay, —C(O)Het, —CO 2 R 9 , —C(O)NR 7 R 8 , —C(O)NR 7 Ay, —C(O)NHR 10 Ay, —C(O)NHR 10 Het, —C(S)NR 9 R 11 , —C(NH)NR 7 R 8 , —C(NH)NR 7 Ay, —S(O) n R 9 —S(O) n Ay, —S(O) n Het, —S(O) 2 NR 7 R 8 , S(O) 2 NR 7 Ay, —NR 7 R 8 , —NR 7 Ay, —NHHet, —NHR 10 Ay, —NHR 10 Het, —R 10 cycloalkyl, —R 10 Ay, —R 10 Het, —R 10 O—C(O)R 9 , —R 10 O—C(O)Ay, —R 10 O—C(O)Het, —R 10 O—S(O) n R 9 , —R 10 OR 9 , —R 10 C(O)R 9 , —R 10 CO 2 R 9 , —R 10 C(O)NR 9 R 11 , —R 10 C(O)NR 7 Ay, —ROC(O)NHR 10 Het, —R 10 C(S)NR 9 R 11 , —R 10 C(NH)NR 9 R 11 , —R 10 SO 2 R 9 , —R 10 SO 2 NR 9 R 11 , —R 10 SO 2 NHCOR 9 , —R 10 NR 7 R 8 , —R 10 NR 7 Ay, —R 10 NHC(NH)NR 9 R 11 , cyano, nitro and azido;

or two adjacent R 1 groups together with the carbon atoms to which they are bonded form a cycloalkyl or a 5- or 6-membered heterocyclic group containing 1 or 2 heteroatoms;

each R 7 and R 8 are the same or different and are independently selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, cycloalkenyl, —C(O)R 9 , —CO 2 R 9 , —C(O)NR 9 R 11 , —C(S)NR 9 R 11 , —C(NH)NR 9 R 11 , —SO 2 R 10 , —SO 2 NR 9 R 11 , —R 10 cycloalkyl, —R 10 OR 9 , —R 10 C(O)R 9 , —R 10 CO 2 R 9 , —R 10 C(O)NR 9 R 11 , —R 10 C(S)NR 9 R 11 , —R 10 C(NH)NR 9 R 11 , —R 10 SO 2 R 10 , —R 10 SO 2 NR 9 R 11 , —R 10 SO 2 NHCOR 9 , —R 10 NR 9 R 11 , —R 10 NHCOR 9 , —R 10 NHSO 2 R 9 and —R 10 NHC(NH)NR 9 R 11 ;

each R 9 and R 11 are the same or different and are independently selected from the group consisting of H, alkyl, cycloalkyl —R 10 cycloalkyl, —R 10 OH, —R 10 (OR 10 ) w wherein w is 1–10, and —R 10 NR 10 R 10 ;

each R 10 is the same or different and is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl;

Ay is aryl;

Het is a 5- or 6-membered heterocyclic or heteroaryl group;

Y is N;

R 2 is selected from the group consisting of halo, alkyl, alkenyl, cycloalkyl, cycloalkenyl, Ay, Het, —OR 7 , —OAy, —OHet, —OR 10 Het, —S(O) n R 9 , —S(O) n Ay, —S(O) n Het, —S(O) n NR 7 R 8 —NR 7 R 8 , —NHHet, —NHR 10 Ay, —NHR 10 Het, —R 10 NR 7 R 8 and —R 10 NR 7 Ay;

n is 0, 1 or 2;

R 3 and R 4 are the same or different and are each independently selected from the group consisting of H, halo, alkyl, alkenyl, cycloalkyl, Ay, Het, —OR 7 , —OAy, —(O)R 7 , C(O)Ay, —CO 2 R 7 , —CO 2 Ay, —SO 2 NHR 9 , —NR 7 R 8 , —NR 7 Ay, —NHet, —NHR 10 Het, —R 10 cycloalkyl, —R 10 OR 7 , —R 10 OAy, —R 10 NR 7 R 8 and —R 10 NR 7 Ay;

Ring A is a 5–10 membered heterocyclic or heteroaryl group;

q is 0, 12, 3, 4 or 5; and

each R 5 is the same or different and is independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, Ay, Het, —OR 7 , —OAy, —OR 10 Ay, —OHet, —OR 10 Het, , —C(O)R 11 , —C(O)Ay, —C(O)Het, —CO 2 R 9 , —C(O)NR 7 R 8 , —C(O)NR 7 Ay, —C(O)NHR 10 Het, —C(S)NR 9 R 11 —C(NH)NR 7 R 8 , —C(NH)NR 7 Ay, —S(O) n R 9 , —S(O) 2 NR 7 R 8 , —S(O) 2 NR 7 Ay, —NR 7 R 8 , —NR 7 Ay, —NHHet, —NHR 10 Ay, —NHR 10 Het, —R 10 cycloalkyl, —R 10 Het, —R 10 OR 9 , —R 10 C(O)R 9 , —R 10 CO 2 R 9 , —R 10 C(O)NR 9 R 11 , —R 10 C(O)NR 7 Ay, —R 10 C(O)NHR 10 Het, —R 10 C(S)NR 9 R 11 , —R 10 C(NH)NR 9 R 11 , —R 10 SO 2 R 9 , —R 10 SO 2 NR 9 R 11 , —R 10 SO 2 NHCOR 9 , —R 10 NR 7 R 8 , —R 10 NR 7 Ay, —R 10 NHC(NH)NR 9 R 11 , cyano, nitro and azido;

or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 wherein p is 0, 1 or 2.

3. The compound according to claim 1 wherein p is 1.

4. The compound according to claim 1 wherein each R 1 is the same or different and is independently selected from the group consisting of halo, alkyl, Ay, Het, —OR 7 , —OAy, —C(O)Het, —CO 2 R 9 , —C(O)NR 7 R 8 , —C(O)NR 7 Ay, —C(O)NHR 10 Het, —S(O) n R 9 , —NR 7 R 8 , —NR 7 Ay, —NHHet, —NHR 10 Ay, —NHR 10 Het, —R 10 OR 9 , cyano, nitro and azido.

5. The compound according to claim 1 wherein each R 1 is the same or different and is independently selected from the group consisting of halo, alkyl, Het, —OR 7 , —C(O)NR 7 R 8 , —S(O) n R 9 , —NR 7 R 8 , —NR 7 Ay and —NHHet.

6. The compound according to claim 1 wherein R 2 is selected from the group consisting of Ay, Het, —OR 7 , —OHet, —OR 10 Het, —S(O) n R 9 , —NR 7 R 8 , —NHHet, —NHR 10 Het and —R 10 NR 7 R 8 .

7. The compound according to claim 1 wherein R 2 is selected from the group consisting of —NR 7 R 8 and Het.

8. The compound according to claim 1 wherein R 3 and R 4 are the same or different and are each independently selected from the group consisting of H, halo, alkyl, Ay, —OR 7 , —CO 2 R 7 , —NR 7 R 8 , —R 10 OR 7 and —R 10 NR 7 R 8 .

9. The compound according to claim 1 wherein R 3 and R 4 are each H.

10. The compound according to claim 1 wherein Ring A is selected from the group consisting of furan, pyridine, pyrimidine, thiazol, pyrazine, pyrrole, imidazole, oxazole, benzimidazole, quinoline, isoquinoline and quinoxoline.

11. The compound according to claim 1 wherein Ring A is selected from the group consisting of furan, thiazole, pyridine and pyrimidine.

12. The compound according to claim 1 wherein q is selected from the group consisting of 0, 1 and 2.

13. The compound according to claim 1 wherein q is 1.

14. The compound according to claim 1 wherein each R 5 is the same or different and is independently selected from the group consisting of halo, alkyl, alkenyl, Ay, Het, —OR 7 , —OAy, —CO 2 R 9 , —C(O)NR 7 R 8 , —C(O)NR 7 Ay, —S(O) 2 NR 7 R 8 , —NR 7 R 8 , —NR 7 Ay, —NHR 10 Ay, cyano, nitro and azido.

15. The compound according to claim 1 , wherein each R 5 is the same or different and is independently selected from the group consisting of halo, alkyl, —OR 7 , —NR 7 R 8 , cyano, nitro and azido.

16. A compound selected from the group consisting of:

N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-pyridinyl)pyrazolo[1,5-a]pyridin-7-amine;

N-Cyclopentyl-3-[2-(methylamino)-4-pyrimidinyl]-2-(4-pyridinyl)pyrazolo[1,5-a]pyridin-7-amine;

N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(3-pyridinyl)pyrazolo[1,5-a]pyridin-7-amine;

N-Cyclopentyl-N-(4-{2-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-3-yl}-2-pyrimidinyl)amine;

N-(4-{7-Chloro-2-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-3-yl}-2-pyrimidinyl)-N-cyclopentylamine;

N-Cyclopentyl-2,3-bis[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine;

N-(2-Methoxyethyl)-2,3-bis{2-[(2-methoxyethyl)amino]pyrimidin-4-yl}pyrazolo[1,5-a]pyridin-7-amine;

N-Butyl-2,3-bis[2-(butylamino)pyrimidin-4-yl-]pyrazolo[1,5-a]pyridin-7-amine;

N-Cyclopropyl-2,3-bis[2-(cyclopropylamino)pyrimidin-4-yl]pyrazolo[1,5-a]pyridin-7-amine;

7-Morpholin-4-yl-2,3-bis(2-morpholin-4-yl-pyrimidin-4-yl)pyrazolo[1,5-a]pyridine;

N-Isobutyl-2,3-bis[2-(isobutylamino)pyrimidin-4-yl]pyrazolo[1,5-a]pyridin-7-amine;

N-Benzyl-2,3-bis[2-(benzylamino)pyrimidin-4-yl]pyrazolo[1,5-a]pyridin-7-amine;

N-Isopropyl-2,3-bis[2-(isopropylamino)pyrimidin-4-yl]pyrazolo[1,5-a]pyridin-7-amine;

2-(2-Fluoro-4-pyridinyl)-3-[2-(methylsulfanyl)-4-pyrimidinyl]pyrazolo[1,5-a]pyridine;

4-[2-(2-Fluoro-4-pyridinyl)pyrazolo[1,5-a]pyridin-3-yl]-N-isopropyl-2-pyrimidinamine;

N-Isopropyl-4-{2-[2-(isopropylamino)-4-pyridinyl]pyrazolo[1,5-a]pyridin-3-yl}-2-pyrimidinamine;

3-[2(Cyclopropylamino)-4-pyrimidinyl]-N-isopropyl-2-[2-(isopropylamino)-4-pyridinyl]pyrazolo[1,5-a]pyridin-7-amine;

N-Cyclopentyl-2-[2-(cyclopentylamino)-4-pyridinyl]-3-[2-(isopropylamino)-4-pyridinyl]pyrazolo[1,5-a]pyridin-7-amine;

3-[2-(Cyclopentylamino)-4-pyrimidinyl]-N-isopropyl-2-[2-(isopropylamino) pyridinyl]pyrazolo[1,5-a]pyridin-7-amine;

N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-[2-(isopropylamino)-4-pyridinyl]pyrazolo[1,5-a]pyridin-7-amine;

N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridin-7-amine;

N-Cyclopentyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridin-7-amine;

N-Cyclopropyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridin-7-amine;

N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(2-furyl)pyrazolo[1,5-a]pyridin-7-amine;

3-[2-(Cyclopentylamino)-4-pyrimidinyl]-N-cyclopropyl-2-(2-furyl)pyrazolo[1,5-a]pyridin-7-amine;

2-(5-Bromo-2-furyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine; and

or a pharmaceutically acceptable salt thereof.

17. A process for preparing the compound according to claim 1 wherein R 3 and R 4 are H; said process comprising reacting a compound of formula (IX);

with a compound of formula (X);

18. A process for preparing the compound according to claim 1 , wherein R 3 is selected from the group consisting of of H, alkyl, cycloalkyl, alkenyl, Ay, Het, —OR 7 , —OAy, —C(O)R 7 , C(O)Ay, —CO 2 R 7 , —CO 2 Ay, —SO 2 NHR 9 , —NR 7 R 8 (where R 7 and R 8 are not H), —NR 7 Ay (where R 7 is not H), —R 10 cycloalkyl, —R 10 OR 7 , —R 10 OAy, —R 10 NR 7 R 8 and —R 10 NR 7 Ay, and R 4 is H, said process comprising reacting a compound of formula (XVI):

with a compound of formula (X):

19. A process for preparing the compound according to claim 1 , said process comprising reacting a compound of formula (XX):

with a compound of formula (X):

followed by oxidative aromatization.

20. A process for preparing the compound according to claim 1 , said process comprising reacting a compound of formula (XXII):

wherein X 1 is chloro, bromo or iodo;

with a compound of formula (XXIV):

wherein M 2 is selected from the group consisting of —B(OH) 2 , —B(ORa) 2 , —B(Ra) 2 , —Sn(Ra) 3 , Zn-halide, ZnRa, and Mg-halide, where Ra is alkyl or cycloalkyl and halide is halo.

21. A process for preparing the compound according to claim 1 , said process comprising reacting a compound of formula (XXIX):

with a 1-aminopyridinium salt of formula (XXX):

wherein Z- is a counter ion.

22. A process for preparing the compound according to claim 1 , said process comprising reacting a compound of formula (XXXVI):

with a suitable ring forming reagent.

23. A pharmaceutical composition comprising a compound according to claim 1 .

24. A pharmaceutical composition according to claim 23 further comprising a pharmaceutically acceptable carrier or diluent.

25. A pharmaceutical composition according to claim 23 further comprising an antiviral agent selected from the group consisting of aciclovir and valaciclovir.

26. A method for the treatment of a herpes viral infection selected from herpes simplex virus 1 and herpes simplex virus 2 in an animal, said method comprising administering to the animal a therapeutically effective amount of a compound according to claim 1 .

27. A method for the treatment of a condition or disease associated with a herpes viral infection selected from herpes simplex virus 1 and herpes simplex virus 2 in an animal, comprising administering to the animal a therapeutically effective amount of a compound according to claim 1 .