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

Patent metadata

Field	Value
Publication number	US-11649238-B2
Application number	US-201916961704-A
Country	US
Kind code	B2
Filing date	Jan 15, 2019
Priority date	Jan 17, 2018
Publication date	May 16, 2023
Grant date	May 16, 2023

Abstract

The invention relates to compounds of formula (I) which are inhibitors of kinase activity, pharmaceutical formulations containing the compounds and their uses in treating and preventing viral infections and disorders caused or exacerbated by the viral infectionwherein R1, R2, R3, R4a, R4b, R4c, R5, W, X, Y and Z are defined herein.

First claim

What is claimed is:

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 t

Assignees

• Glaxosmithkline Ip Dev Ltd

Inventors

• Barton Nicholas Paul
• Bertrand Sophie Marie
• Down Kenneth David
• Gray Matthew

Classifications

• A61P31/16

  for influenza or rhinoviruses · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• Y02A50/30

  Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change · CPC title

• A61P31/12

  Antivirals · CPC title