IP Library › Granted Patent US 11,034,698
Granted Patent B2
US 11,034,698 · App. 16/715,933 · Granted Jun 15, 2021

Pyrazolo[ 1,5a]pyrimidine derivatives as IRAK4 modulators

Inventors: Marian C. Bryan (South San Francisco, CA); Steven Do (South San Francisco, CA); Joy Drobnick (South San Francisco, CA); Alberto Gobbi (South San Francisco, CA); Tamiko Katsumoto (Millbrae, CA); James Richard Kiefer, Jr. (South San Francisco, CA); Jun Liang (South San Francisco, CA); Naomi S. Rajapaksa (South San Francisco, CA); Yongsheng Chen (Shanghai, CN); Liqiang Fu (Shanghai, CN); Kwong Wah Lai (Shanghai, CN); Zhiguo Liu (Shanghai, CN); John Wai (Shanghai, CN); Fei Wang (Shanghai, CN)
Assignee: Genentech, Inc.
C07D487/04C07D519/00
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Quick Facts
Patent No.
US 11,034,698
App. No.
16/715,933
Granted
Jun 15, 2021
Kind
B2
Abstract

Compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, and methods of use as Interleukin-1 Receptor Associated Kinase (IRAK4) inhibitors are described herein.

Claims (84)

1. A compound of Formula I:

or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein:

A 1 is CH 2 or NH;

R 1 is hydrogen;

R 3 is hydrogen, halogen, —OH, or C 1-3 alkyl;

R 4 is hydrogen, halogen, —NR 8 R 9 , —C(O)NR 8 R 9 , or a 3-7 membered monocyclic saturated or partially saturated heterocyclic group optionally substituted with one or more substituents selected from oxo, —NR 8 R 9 , or R 13 ;

R 5 is selected from the group consisting of —NHCH 3 , —N(CH 3 ) 2 , —C(CH 3 ) 2 OH, —OCH 3 , —OCH(CH 3 ) 2 , —OC(CH 3 ) 3 , —OCH 2 CH 3 , —OCHF 2 , —OCH 2 CF 3 , —OCH 2 CHF 2 , —CH 2 OCHF 2 , —CN,

R 8 and R 9 are, independently at each occurrence, hydrogen, C 1-6 alkyl optionally substituted with R 13 , —C(O)R 13 , C 3-6 cycloalkyl group, or a 3-7 membered saturated or partially saturated heterocyclic group;

R 13 is, independently at each occurrence, C 1-6 alkyl, —NH 2 , or halogen;

R 14 is selected from the group consisting of

and

R 16 is hydrogen, or C 1-3 alkyl optionally substituted with —NH 2 or —OH.

2. The compound of claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen.

3. The compound of claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of —Cl, —OH, —CH 3 .

4. The compound of claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen.

5. The compound of claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 4 is —Cl.

6. The compound of claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 4 is —C(O)NR 8 R 9 , wherein R 8 is hydrogen and R 9 is cyclopropyl.

7. The compound of claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 4 is —NR 8 R 9 , wherein R 8 is hydrogen and R 9 is —C(O)R 13 , wherein R 13 is methyl.

8. The compound of claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of —Cl

9. The compound of claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 5 is selected from the group consisting of —NHCH 3 , —N(CH 3 ) 2 , —C(CH 3 ) 2 OH, —OCH 3 , —OCH(CH 3 ) 2 , —OC(CH 3 ) 3 , —OCH 2 CH 3 , —OCHF 2 , —OCH 2 CF 3 , —OCH 2 CHF 2 , —CN,

10. The compound of claim 9 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 5 is selected from the group consisting of —OCHF 2 , —OCH 2 CHF 2 ,

11. The compound of claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 14 is selected from the group consisting of

12. The compound of claim 11 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 14 is

13. The compound of claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 16 is hydrogen.

14. The compound of claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 16 is —CH 2 OH.

15. A pharmaceutical composition comprising a compound of claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, carrier or diluent.

16. A compound according to claim 1 which compound is selected from the group consisting of:

(R)-N-(2-(2-Fluoro-3-hydroxy-3-methylbutyl)-6-((1-methyl-1H-pyrazol-4-yl)methoxy)-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

(R)-N-(6-(2,2-Difluoroethoxy)-2-(2-fluoro-3-hydroxy-3-methylbutyl)-1-oxoisoindolin-5-yl)pyrazolo[1,5-a[pyrimidine-3-carboxamide;

N-(2-((R)-2-Fluoro-3-hydroxy-3-methylbutyl)-6-(((1S,3R)-3-hydroxycyclopentyl)oxy)-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(2-((R)-2-Fluoro-3-hydroxy-3-methylbutyl)-6-(((1R,3S)-3-hydroxycyclopentyl)oxy)-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

(R)-N-(2-(2-Fluoro-3-hydroxy-3-methylbutyl)-6-((1-methylpiperidin-4-yl)oxy)-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

(R)-N-(6-Cyclopropoxy-2-(2-fluoro-3-hydroxy-3-methylbutyl)-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

(R)-N-(2-(2-Fluoro-3-hydroxy-3-methylbutyl)-6-(oxetan-3-ylmethoxy)-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

(R)-N-(6-(Cyclopentyloxy)-2-(2-fluoro-3-hydroxy-3-methylbutyl)-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

(R)-N-(6-Ethoxy-2-(2-fluoro-3-hydroxy-3-methylbutyl)-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

(R)-N-(2-(2-Fluoro-3-hydroxy-3-methylbutyl)-6-methoxy-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

(R)-N-(2-(2-Fluoro-3-hydroxy-3-methylbutyl)-6-(oxetan-3-yloxy)-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

(R)-N-(6-(Difluoromethoxy)-2-(2-fluoro-3-hydroxy-3-methylbutyl)-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

(R)-N-(2-(2-Fluoro-3-hydroxy-3-methylbutyl)-6-((1-methyl-1H-pyrazol-4-yl)oxy)-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

(R)-N-(6-(tert-Butoxy)-2-(2-fluoro-3-hydroxy-3-methylbutyl)-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

(R)-N-(6-(4-(2,2-Difluoroethyl)piperidin-1-yl)-2-(2-fluoro-3-hydroxy-3-methylbutyl)-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(6-Cyclopropyl-2-isopropyl-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

(R)-N-(6-Cyano-2-(2-fluoro-3-hydroxy-3-methylbutyl)-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

(R)-N-(2-(2-Fluoro-3-hydroxy-3-methylbutyl)-6-(4-morpholinopiperidin-1-yl)-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(2-((R)-2-Fluoro-3-hydroxy-3-methylbutyl)-6-((R)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(2-((R)-2-Fluoro-3-hydroxy-3-methylbutyl)-6-((7R,8aS)-7-methoxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

(R)-5-Chloro-N-(2-(2-fluoro-3-hydroxy-3-methylbutyl)-6-morpholino-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

(R)-N-(6-(4-((5-Ethylisoxazol-4-yl)methyl)piperazin-1-yl)-2-(2-fluoro-3-hydroxy-3-methylbutyl)-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

(R)-N-(6-(4-((3-Ethylisoxazol-4-yl)methyl)piperazin-1-yl)-2-(2-fluoro-3-hydroxy-3-methylbutyl)-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

(R)-N-(2-(2-Fluoro-3-hydroxy-3-methylbutyl)-6-(4-(oxetan-3-yl)piperazin-1-yl)-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

(R)-N-(6-(4-(2-(1H-Imidazol-1-yl)ethyl)piperazin-1-yl)-2-(2-fluoro-3-hydroxy-3-methylbutyl)-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(2-((R)-2-Fluoro-3-hydroxy-3-methylbutyl)-6-((7R,8aR)-7-methoxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(2-((R)-2-Fluoro-3-hydroxy-3-methylbutyl)-6-((7S,8aR)-7-methoxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

(R)-N-(2-(2-Fluoro-3-hydroxy-3-methylbutyl)-6-(4-(2-methoxyethyl)piperazin-1-yl)-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

(R)-N-(2-(2-Fluoro-3-hydroxy-3-methylbutyl)-6-(4-isopropylpiperazin-1-yl)-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

(R)-N-(2-(2-Fluoro-3-hydroxy-3-methylbutyl)-6-(4-(oxetan-3-ylmethyl)piperazin-1-yl)-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

(R)-N-(2-(2-Fluoro-3-hydroxy-3-methylbutyl)-6-(4-(3-methyloxetan-3-yl)piperazin-1-yl)-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

(R)-6-Chloro-N-(2-(2-fluoro-3-hydroxy-3-methylbutyl)-6-(4-(oxetan-3-yl)piperazin-1-yl)-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

((R)-N-(2-(2-Fluoro-3-hydroxy-3-methylbutyl)-6-(4-(oxetan-3-yl)piperazin-1-yl)-1-oxoisoindolin-5-yl)-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide;

(R)-N-(6-(4-(Azetidin-1-yl)piperidin-1-yl)-2-(2-fluoro-3-hydroxy-3-methylbutyl)-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

(R)-N-(2-(2-Fluoro-3-hydroxy-3-methylbutyl)-6-(4-(oxetan-3-yl)piperidin-1-yl)-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

(S)-N-(2-(4-Hydroxy-4-methylpentan-2-yl)-6-(4-(oxetan-3-yl)piperazin-1-yl)-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

126 (R)-N-(2-(4-Hydroxy-4-methylpentan-2-yl)-6-(4-(oxetan-3-yl)piperazin-1-yl)-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

(R)-N-(6-(4-(tert-Butyl)piperazin-1-yl)-2-(2-fluoro-3-hydroxy-3-methylbutyl)-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(2-((R)-2-Fluoro-3-hydroxy-3-methylbutyl)-6-(4-((1r,3R)-3-fluorocyclobutyl)piperazin-1-yl)-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(2-((R)-2-Fluoro-3-hydroxy-3-methylbutyl)-6-((S)-3-methyl-4-(oxetan-3-yl)piperazin-1-yl)-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(2-((R)-2-Fluoro-3-hydroxy-3-methylbutyl)-6-((R)-3-methyl-4-(oxetan-3-yl)piperazin-1-yl)-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

(R)-5-Acetamido-N-(6-(dimethylamino)-2-(2-fluoro-3-hydroxy-3-methylbutyl)-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

(R)-N-(6-((1-(2,2-Difluoroethyl)piperidin-4-yl)oxy)-2-(2-fluoro-3-hydroxy-3-methylbutyl)-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

(R)-N-(6-(4-Cyclobutylpiperazin-1-yl)-2-(2-fluoro-3-hydroxy-3-methylbutyl)-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

(R)-N-(6-(4-(3,3-difluorocyclobutyl)piperazin-1-yl)-2-(2-fluoro-3-hydroxy-3-methylbutyl)-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

(R)-N-(2-(2-Fluoro-3-hydroxy-3-methylbutyl)-6-((1-(oxetan-3-yl)piperidin-4-yl)oxy)-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

(R)-N-(2-(2-Fluoro-3-hydroxy-3-methylbutyl)-6-(5-methylpyridin-2-yl)-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

(R)-N-(2-(2-Fluoro-3-hydroxy-3-methylbutyl)-6-(2-hydroxypropan-2-yl)-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(6-(Dimethylamino)-7-(hydroxymethyl)-2-isopropyl-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(2-((R)-2-fluoro-3-hydroxy-3-methylbutyl)-6-(6-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(6-(4-(azetidin-1-yl)-3,3-difluoropiperidin-1-yl)-2-((R)-2-fluoro-3-hydroxy-3-methylbutyl)-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

(R)-N-(6-(4-(3,3-difluoroazetidin-1-yl)piperidin-1-yl)-2-(2-fluoro-3-hydroxy-3-methylbutyl)-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

(R)-N-(6-((difluoromethoxy)methyl)-2-(2-fluoro-3-hydroxy-3-methylbutyl)-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(2-((R)-2-fluoro-3-hydroxy-3-methylbutyl)-6-(octahydro-2H-cyclopenta[c]pyridin-2-yl)-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(2-((R)-2-fluoro-3-hydroxy-3-methylbutyl)-6-(hexahydrofuro[3,4-c]pyridin-5(3H)-yl)-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(2-(2-fluoro-2-(oxetan-3-yl)ethyl)-6-morpholino-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide; and,

N-(2-isopropyl-5-morpholino-3-oxo-2,3-dihydro-1H-indazol-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide.

Priority Claims (1)
WO PCT/CN2017/089358 · Jun 21, 2017 · international
Continuity (2)
Continuation PCTEP2018066320 · Jun 19, 2018
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