Abstract

Herpesviruses are a significant source of human disease; amongst these herpes simplex virus 1 (HSV-1) and HSV-2 are very prevalent and cause recurrent infections. We recently identified a pyrazolo[1,5-a]pyridine scaffold that showed promising activity against HSV-1 and HSV-2 in Vero cell antiviral assays. Here, we describe the synthesis and anti-herpetic activity of several 3-pyrimidinyl-2-phenylpyrazolo[1,5-a]pyridines with differing 2-phenyl substitution patterns. Approaches to rapidly access a number of analogs with different 2-phenyl substitution patterns are outlined. Several of the compounds described have comparable activity to acyclovir against HSV-1 and HSV-2.

Graphical abstract

Keywords: Pyrazolopyridines; Herpesviruses; Anti-viral compounds

Article Outline

1. Introduction

2. Chemistry

3. Results and discussion

4. Conclusions

5. Experimental

5.1. General

5.2. General procedure I (Scheme 1)

5.2.1. Synthesis of 2-(6-chloro-2-pyridinyl)-1-phenylethanone derivatives (D)

5.2.2. Synthesis of 2-(6-chloro-2-pyridinyl)-1-phenylethanone oximes (E)

5.2.3. Formation of 7-chloro-2-(phenyl)pyrazolo[1,5-a]pyridines (F)

5.2.4. 1-[7-Chloro-2-phenylpyrazolo[1,5-a]pyridin-3-yl]ethanone (G)

5.2.5. 1-[7-Cyclopentylamino-2-phenylpyrazolo[1,5-a]pyridin-3-yl]ethanone (H)

5.2.6. 1-[7-Cyclopentylamino-2-phenylpyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one (I)

5.2.7. Synthesis of guanidines (J)

5.2.8. N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-phenylpyrazolo[1,5-a]pyridin-7-amine (A)

5.3. General procedure II (Scheme 2)

5.3.1. 7-Chloro-2-phenylpyrazolo[1,5-a]pyridine-3-carbaldehydes (K)

5.3.2. 1-[7-Chloro-2-phenylpyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol (L)

5.3.3. 1-[7-Chloro-2-phenylpyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one (M)

5.3.4. 4-[7-Chloro-2-phenylpyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2- pyridinamine (N)

5.3.5. N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-phenylpyrazolo[1,5-a]pyridin-7-amine (A)

5.4. N-Butyl-3-[2-(butylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo [1,5-a]pyridin-7-amine (6)

5.4.1. 1-[7-(Butylamino)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone (40)

5.4.2. (2E)-1-[7-(Butylamino)-2-(4-fluorophenyl)-pyrazolo-[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one (41)

5.4.3. N-Butyl-3-[2-(butylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-7-amine (6)

5.5. N-Butyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-7-amine (7)

5.6. N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(3-fluorophenyl)pyrazolo[1,5-a]pyridin-7-amine (8)

5.7. 2-(4-Chlorophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine (9)

5.8. 2-(3-Chlorophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine (10)

5.9. 2-(4-Bromophenyl)-N-butyl-3-[2-(butylamino)-4-pyrimidinyl]pyrazolo-[1,5-a]pyridin-7-amine (11)

5.9.1. 1-(4-Bromophenyl)-2-(6-chloro-2-pyridinyl)ethanone (42)

5.9.2. 1-(4-Bromophenyl)-2-(6-chloro-2-pyridinyl)-ethanone oxime (43)

5.9.3. 2-(4-Bromophenyl)-7-chloropyrazolo[1,5-a]pyridine (44)

5.9.4. 1-[2-(4-Bromophenyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]ethanone (45)

5.9.5. 1-[2-(4-Bromophenyl)-7-(butylamino)pyrazolo[1,5-a]pyridin-3-yl]ethanone (46)

5.9.6. (2E)-1-[2-(4-Bromophenyl)-7-(butylamino)-pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one (47)

5.9.7. 2-(4-Bromophenyl)-N-butyl-3-[2-(butylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine (11)

5.10. 2-(3-Bromophenyl)-N-cyclopentyl-3-[2-(cyclopentyl-amino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine (12)

5.10.1. 1-(3-Bromophenyl)-2-(6-chloro-2-pyridinyl)ethanone (48)

5.10.2. 1-(3-Bromophenyl)-2-(6-chloro-2-pyridinyl)ethanone oxime (49)

5.10.3. 2-(3-Bromophenyl)-7-chloropyrazolo[1,5-a]pyridine (50)

5.10.4. 1-[2-(3-Bromophenyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]ethanone (51)

5.10.5. 1-[2-(3-Bromophenyl)-7-(cyclopentylamino)-pyrazolo[1,5-a]pyridin-3-yl]ethanone (52)

5.10.6. (2E)-1-[2-(3-Bromophenyl)-7-(cyclopentylamino)-pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one (53)

5.10.7. 2-(3-Bromophenyl)-N-cyclopentyl-3-[2-(cyclopentyl-amino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine (12)

5.11. 2-(2-Bromophenyl)-N-cyclopentyl-3-[2-(cyclopentyl-amino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine (13)

5.11.1. 1-(2-Bromophenyl)-2-(6-chloro-2-pyridinyl)-ethanone (54)

5.11.2. 1-(2-Bromophenyl)-2-(6-chloro-2-pyridinyl)-ethanone oxime (55)

5.11.3. 2-(2-Bromophenyl)-7-chloropyrazolo[1,5-a]pyridine (56)

5.11.4. 1-[2-(2-Bromophenyl)-7-chloropyrazolo[1,5-a]-pyridin-3-yl]ethanone (57)

5.11.5. 1-[2-(2-Bromophenyl)-7-(cyclopentylamino)pyrazolo[1,5-a]pyridin-3-yl]ethanone (58)

5.11.6. (2E)-1-[2-(2-Bromophenyl)-7-(cyclopentylamino)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one (59)

5.11.7. 2-(2-Bromophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine (13)

5.12. N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-phenylpyrazolo[1, 5-a]pyridin-7-amine (14)

5.13. N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-7-amine (15)

5.13.1. 2-(6-Chloro-2-pyridinyl)-1-(3-methylphenyl)-ethanone (60)

5.13.2. 2-(6-Chloro-2-pyridinyl)-1-(3-methylphenyl)-ethanone oxime (61)

5.13.3. 7-Chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin (62)

5.13.4. 7-Chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde (63)

5.13.5. 1-[7-Chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol (64)

5.13.6. 1-[7-Chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one (65)

5.13.7. 4-[7-Chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl- 2-pyrimidinamine (66)

5.13.8. N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(3-methylphenyl)-pyrazolo[1,5-a]pyridin-7-amine (15)

5.14. N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-[3- (trifluoromethyl)phenyl]pyrazolo[1,5-a]pyridin-7-amine (16)

5.15. N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine (17)

5.15.1. 2-(6-Chloro-2-pyridinyl)-1-(4-methoxyphenyl)-ethanone (67)

5.15.2. 2-(6-Chloro-2-pyridinyl)-1-(4-methoxyphenyl)-ethanone oxime (68)

5.15.3. 7-Chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridine (69)

5.15.4. 1-[7-(Chloro)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone (70)

5.15.5. 1-[7-(Cyclopentylamino)-2-(4-methoxyphenyl)-pyrazolo[1,5-a]pyridin-3-yl]ethanone (71)

5.15.6. (2E)-1-[7-(Cyclopentylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one (72)

5.15.7. N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl) pyrazolo[1,5-a]pyridin-7-amine (17)

5.16. N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(3-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine (18)

5.16.1. 2-(6-Chloro-2-pyridinyl)-1-(3-methoxyphenyl)-ethanone (73)

5.16.2. 2-(6-Chloro-2-pyridinyl)-1-(3-methoxyphenyl)-ethanone oxime (74)

5.16.3. 7-Chloro-2-(3-methoxyphenyl)pyrazolo[1,5-a]pyridine (75)

5.16.4. 7-Chloro-2-(3-methoxyphenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde (76)

5.16.5. 1-[7-Chloro-2-(3-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol (77)

5.16.6. 1-[7-Chloro-2-(3-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one (78)

5.16.7. 4-[7-Chloro-2-(3-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (79)

5.16.8. N-Cyclopentyl-3-[2-(cyclopenylamino)-4-pyrimidinyl]-2-(3-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine (18)

5.17. 4-{7-(Cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenol (19)

5.18. 3-{7-(Cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenol (20)

5.19. 2-[4-(Allyloxy)phenyl]-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine (21)

5.20. 2-(4-Butoxyphenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-pyrazolo[1,5-a]pyridin-7-amine (22)

5.21. N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-isobutoxyphenyl)-pyrazolo[1,5-a]pyridin-7-amine (23)

5.22. N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-[4-(cyclopropyl- methoxy)phenyl]-pyrazolo[1,5-a]pyridin-7-amine (24)

5.23. N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-[3- (cyclopropylmethoxy)phenyl]pyrazolo[1,5-a]pyridin-7-amine (25)

5.24. 2-[4-(Cyclobutylmethoxy)phenyl]-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine (26)

5.25. Ethyl (4-{7-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]-pyrazolo[1,5-a]pyridin-2-yl}phenoxy)acetate (27)

5.26. N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4- phenoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine (28)

5.27. N-{4-[2-(4-Aminophenyl)-7-(butylamino)pyrazolo-[1,5-a]pyridin-3-yl]-2-pyrimidinyl}-N-butylamine (29)

5.28. 2-(3-Aminophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine (30)

5.29. N-(3-{7-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a ]pyridin-2-yl}phenyl)acetamide (31)

5.30. N-(3-{7-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenyl)methanesulfonamide (32)

5.31. N-Butyl-3-[2-(butylamino)-4-pyrimidinyl]-2-[4-(cyclohexylamino)phenyl]pyrazolo[1,5-a]pyridin-7-amine (33)

5.32. N-Butyl-3-[2-(butylamino)-4-pyrimidinyl]-2-[4-(dimethylamino)phenyl]pyrazolo[1,5-a]pyridin-7-amine (34)

5.33. 2-[1,1′-Biphenyl]-4-yl-N-butyl-3-[2-(butylamino)-4-pyrimidinyl]pyrazolo[1,5-a ]pyridin-7-amine (35)

5.34. 2-[1,1′-Biphenyl]-3-yl-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine (36)

5.35. 3-{7-(Cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}benzonitrile (37)

5.36. 3-{7-(Cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo-[1,5-a]pyridin-2-yl}benzoic acid (38)

5.37. 3-{7-(Cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl] pyrazolo[1,5-a]pyridin-2-yl }benzamide (39)

5.38. HSV anti-viral assay

5.38.1. Cell culture and HSV infection

5.38.2. HSV DNA hybridization

5.39. Cytotoxicity assay

References