Substituted pyrazolo[1,5-a]pyrimidines as PI4K inhibitors

1. A compound of formula (I):

a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

wherein:

R 1 is C(O)NR 1a R 1b , OC 1-4 alkyl, S(O)R 1c , S(O) 2 NR 1a R 1b , or S(O) 2 R 1c ;

R 1a is C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkyl-OC 1-3 alkyl, tetrahydrofuranyl, or tetrahydropyranyl;

R 1b is H or C 1-3 alkyl; or

R 1a and R 1b , together with the nitrogen heteroatom to which they are attached, form a 4- to 7-membered heterocyclic ring;

wherein the 4- to 7-membered heterocyclic ring contains ring carbon atoms and optionally 1 ring oxygen heteroatom, wherein the total number of ring atoms including the nitrogen heteroatom attached to R 1a and R 1b , the ring carbon atoms, and the ring oxygen heteroatom is from 4 to 7; and

a) wherein the 4- to 7-membered heterocyclic ring is optionally substituted by 1 or 2 substituents independently selected from the group consisting of halo, C 1-3 alkyl, C 1-3 hydroxyalkyl, OH, OC 1-3 alkyl, and ═O; or

b) wherein the 4- to 7-membered heterocyclic ring is ortho-fused or spiro-fused to an unsubstituted 4- to 6-membered cycloalkyl ring or an unsubstituted, saturated 4- to 6-membered heterocyclic ring;

R 1c is C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 alkyl-OC 1-3 alkyl, OH, or OC 1-3 alkyl;

R 2 is H, halo, C 1-3 alkyl, or OR 2a ;

R 2a is H, CH 3 , CH 2 CH 3 , or CH 2 CH 2 CH 3 ;

R 3 is H or halo;

(i) R 4a is H, halo, or C 1-3 alkyl;

R 4b is C 1-3 alkyl, C 1-2 hydroxyalkyl, or cyclopropyl; or

R 4a and R 4b , together with the carbon atom to which they are attached, form a saturated 3- to 6-membered ring;

wherein the 3- to 6-membered ring contains ring carbon atoms and optionally 1 ring oxygen heteroatom, wherein the total number of the ring carbon atoms and the ring oxygen heteroatom is from 3 to 6; and

wherein the 3- to 6-membered ring is optionally substituted by 1 substituent selected from the group consisting of C 1-3 alkyl and C 1-2 hydroxyalkyl; and

R 4c is CH 2 OH, CH(OH)CH 3 , CH 2 CH 2 OH, or OH; or

(ii) R 4a is H, halo, C 1-3 alkyl, or OH;

R 4b is H, halo, or C 1-3 alkyl; and

R 4c is unsubstituted oxetanyl, unsubstituted tetrahydrofuranyl, or unsubstituted tetrahydropyranyl; or

(iii) R 4a is H; and

R 4b and R 4c , together with the carbon atom to which they are attached, form an unsubstituted oxetanyl, unsubstituted tetrahydrofuranyl, or unsubstituted tetrahydropyranyl; and

R 5 is pyrazol-1-yl or imidazol-2-yl;

wherein the pyrazol-1-yl is optionally substituted at the 4-position by 1 CH 3 substituent and optionally substituted at the 5-position by 1 C 1-3 alkyl substituent; and

wherein the imidazol-2-yl is optionally substituted at the 1-position by 1 C 1-3 alkyl substituent and optionally substituted at the 5-position by 1 CH 3 substituent.

2. The compound according to claim 1 , a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 is C(O)NR 1a R 1b or S(O) 2 R 1c .

3. The compound according to claim 2 , a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 is C(O)NR 1a R 1b .

4. The compound according to claim 3 , a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 1a is C 1-3 hydroxyalkyl or tetrahydropyranyl.

5. The compound according to claim 4 , a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 1a is C 1-3 hydroxyalkyl.

6. The compound according to claim 3 , a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 1a is CH 2 CH 2 OH, CH 2 CH 2 CH 2 OH, or CH(CH 3 )CH 2 OH.

7. The compound according to claim 3 , a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 1b is C 1-3 alkyl.

8. The compound according to claim 7 , a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 1b is CH 3 or CH 2 CH 3 .

9. The compound according to claim 1 , a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 2 is Cl, C 1-3 alkyl, or OR 2a .

10. The compound according to claim 9 , a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 2 is C 1-3 alkyl.

11. The compound according to claim 1 , a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 3 is H.

12. The compound according to claim 1 , a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

R 2 is H, Cl, C 1-3 alkyl, or OR 2a ;

R 2a is H, CH 3 , CH 2 CH 3 , or CH 2 CH 2 CH 3 ; and

R 3 is H or F.

13. The compound according to claim 1 , a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 4a is CH 3 .

14. The compound according to claim 1 , a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 4b is C 1-3 alkyl.

15. The compound according to claim 1 , a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

R 4a is CH 3 ; and

R 4b is CH 3 .

16. The compound according to claim 1 , a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

(i) R 4a is H, F, or C 1-3 alkyl;

R 4b is C 1-3 alkyl, C 1-2 hydroxyalkyl, or cyclopropyl; or

R 4a and R 4b , together with the carbon atom to which they are attached, form an saturated 3- to 6-membered ring;

wherein the 3- to 6-membered ring contains ring carbon atoms and optionally 1 ring oxygen heteroatom, wherein a total number of the ring carbon atoms and the ring oxygen heteroatom is from 3 to 6; and; and

wherein the 3- to 6-membered ring is optionally substituted by 1 substituent selected from the group consisting of C 1-3 alkyl and C 1-2 hydroxyalkyl; and

R 4c is CH 2 OH, CH(OH)CH 3 , CH 2 CH 2 OH, or OH; or

(ii) R 4a is H, F, C 1-3 alkyl, or OH;

R 4b is H, F, or C 1-3 alkyl; and

R 4c is unsubstituted oxetanyl, unsubstituted tetrahydrofuranyl, or unsubstituted tetrahydropyranyl; or

(iii) R 4a is H; and

R 4b and R 4c , together with the carbon atom to which they are attached, form an unsubstituted oxetanyl, unsubstituted tetrahydrofuranyl, or unsubstituted tetrahydropyranyl.

17. The compound according to claim 1 , a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 5 is imidazol-2-yl, wherein the imidazol-2-yl is optionally substituted at the 1-position by 1 C 1-3 alkyl substituent and optionally substituted at the 5-position by 1 CH 3 substituent.

18. The compound according to claim 1 , a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 5 is 1-methyl-1H-imidazol-2-yl.

19. The compound according to claim 1 , wherein the compound is of the following formula:

a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

wherein:

R 1 is C(O)NR 1a R 1b , OC 1-4 alkyl, S(O)R 1c , S(O) 2 NR 1a R 1b , or S(O) 2 R 1c ;

R 1a is C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, or C 1-3 alkyl-OC 1-3 alkyl;

R 1b is H or C 1-3 alkyl; or

R 1a and R 1b , together with the nitrogen heteroatom to which they are attached, form a 4- to 7-membered heterocyclic ring;

wherein the 4- to 7-membered heterocyclic ring contains ring carbon atoms and optionally 1 ring oxygen heteroatom, wherein the total number of ring atoms including the nitrogen heteroatom attached to R 1a and R 1b , the ring carbon atoms, and the ring oxygen heteroatom is from 4 to 7; and

a) wherein the 4- to 7-membered heterocyclic ring is optionally substituted by 1 or 2 substituents independently selected from the group consisting of halo, C 1-3 alkyl, OH, OC 1-3 alkyl, and ═O; or

b) wherein the 4- to 7-membered heterocyclic ring is ortho-fused or spiro-fused to an unsubstituted 4- to 6-membered cycloalkyl ring or an unsubstituted, saturated 4- to 6-membered heterocyclic ring;

R 1c is C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 alkyl-OC 1-3 alkyl, OH, or OC 1-3 alkyl;

R 2 is H, Cl, C 1-3 alkyl, or OR 2a ;

R 2a is H, CH 3 , CH 2 CH 3 , or CH 2 CH 2 CH 3 ;

R 3 is H or F;

R 4a is H or CH 3 ;

R 4b is C 1-3 alkyl or C 1-2 hydroxyalkyl; and

R 5 is pyrazol-1-yl or imidazol-2-yl;

wherein the pyrazol-1-yl is optionally substituted at the 4-position by 1 CH 3 substituent and optionally substituted at the 5-position by 1 C 1-3 alkyl substituent; and

wherein the imidazol-2-yl is optionally substituted at the 1-position by 1 C 1-3 alkyl substituent and optionally substituted at the 5-position by 1 CH 3 substituent.

20. The compound according to claim 1 , wherein the compound is of formula (Ic):

a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

wherein:

R 1 is C(O)NR 1a R 1b or S(O) 2 R 1c ;

R 1a is C 1-3 hydroxyalkyl or tetrahydropyranyl;

R 1b is C 1-3 alkyl; or

R 1a and R 1b , together with the nitrogen heteroatom to which they are attached, form a 4- to 7-membered heterocyclic ring;

wherein the 4- to 7-membered heterocyclic ring contains ring carbon atoms and optionally 1 ring oxygen heteroatom, wherein the total number of ring atoms including the nitrogen heteroatom attached to R 1a and R 1b , the ring carbon atoms, and the ring oxygen heteroatom is from 4 to 7; and

a) wherein the 4- to 7-membered heterocyclic ring is optionally substituted by 1 or 2 substituents independently selected from the group consisting of halo, C 1-3 alkyl, C 1-3 hydroxyalkyl, OH, OC 1-3 alkyl, and ═O; or

b) wherein the 4- to 7-membered heterocyclic ring is ortho-fused or spiro-fused to an unsubstituted 4- to 6-membered cycloalkyl ring or an unsubstituted, saturated 4- to 6-membered heterocyclic ring;

R 1c is C 1-3 hydroxyalkyl;

R 2 is H, Cl, C 1-3 alkyl, or OCH 3 ;

R 3 is H or F;

R 4a is CH 3 ;

R 4b is C 1-3 alkyl; and

R 5 is imidazol-2-yl, wherein the imidazol-2-yl is optionally substituted at the 1-position by 1 C 1-3 alkyl substituent and optionally substituted at the 5-position by 1 CH 3 substituent.

21. The compound according to claim 20 , a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

R 1a is C 1-3 hydroxyalkyl or tetrahydropyranyl; and

R 1b is C 1-3 alkyl.

22. The compound according to claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

23. The compound according to claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

24. The compound according to claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

25. The compound according to claim 1 , or a stereoisomer thereof, wherein the stereoisomer of the compound is:

or a pharmaceutically acceptable salt thereof.

26. The compound according to claim 1 , or a stereoisomer thereof, wherein the stereoisomer of the compound is:

27. The compound according to claim 1 , wherein the compound is:

28. The compound according to claim 1 , or a stereoisomer thereof, wherein the compound, or a stereoisomer thereof, is selected from the group consisting of:

29. A pharmaceutical formulation comprising a pharmaceutically acceptable excipient and a compound according to claim 1 , a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

30. A pharmaceutical formulation comprising a pharmaceutically acceptable excipient and the stereoisomer according to claim 25 , or a pharmaceutically acceptable salt thereof.

31. A pharmaceutical formulation comprising a pharmaceutically acceptable excipient and the stereoisomer according to claim 26 .

32. A method for inhibiting phosphatidylinositol 4-kinase III beta activity in a patient, wherein the method comprises administering to the patient in need thereof a therapeutically effective amount of a compound according to claim 1 , a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

33. The method according to claim 32 , wherein the patient has a viral infection.

34. The method according to claim 32 , wherein the patient has a disorder caused by or exacerbated by a viral infection, and wherein the disorder caused by or exacerbated by a viral infection is selected from the group consisting of acute bronchitis, asthma, bronchiectasis, bronchiolitis, chronic obstructive pulmonary disease, congestive heart failure, cystic fibrosis, otitis media, pneumonia, a secondary bacterial infection, and sinusitis.

35. The method according to claim 34 , wherein the disorder cause by or exacerbated by a viral infection is asthma.

36. The method according to claim 34 , wherein the disorder caused by or exacerbated by a viral infection is chronic obstructive pulmonary disease.

37. A method for inhibiting phosphatidylinositol 4-kinase III beta activity in a patient, wherein the method comprises administering to the patient in need thereof a therapeutically effective amount of the stereoisomer according to claim 25 , or a pharmaceutically acceptable salt thereof.

38. The method according to claim 37 , wherein the patient has a viral infection.

39. The method according to claim 37 , wherein the patient has a disorder caused by or exacerbated by a viral infection, and wherein the disorder caused by or exacerbated by a viral infection is selected from the group consisting of acute bronchitis, asthma, bronchiectasis, bronchiolitis, chronic obstructive pulmonary disease, congestive heart failure, cystic fibrosis, otitis media, pneumonia, a secondary bacterial infection, and sinusitis.

40. The method according to claim 39 , wherein the disorder caused by or exacerbated by a viral infection is asthma.

41. The method according to claim 39 , wherein the disorder caused by or exacerbated by a viral infection is chronic obstructive pulmonary disease.

42. A method for inhibiting phosphatidylinositol 4-kinase III beta activity in a patient wherein the method comprises administering to the patient in need thereof a therapeutically effective amount of the stereoisomer according to claim 26 .

43. The method according to claim 42 , wherein the patient has a viral infection.

44. The method according to claim 42 , wherein the patient has a disorder caused by or exacerbated by a viral infection, and wherein the disorder caused by or exacerbated by a viral infection is selected from the group consisting of acute bronchitis, asthma, bronchiectasis, bronchiolitis, chronic obstructive pulmonary disease, congestive heart failure, cystic fibrosis, otitis media, pneumonia, a secondary bacterial infection, and sinusitis.

45. The method according to claim 44 , wherein the disorder caused by or exacerbated by a viral infection is asthma.

46. The method according to claim 44 , wherein the disorder caused by or exacerbated by a viral infection is chronic obstructive pulmonary disease.