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

Patent metadata

Field	Value
Publication number	US-11034698-B2
Application number	US-201916715933-A
Country	US
Kind code	B2
Filing date	Dec 16, 2019
Priority date	Jun 21, 2017
Publication date	Jun 15, 2021
Grant date	Jun 15, 2021

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.

First claim

What is claimed is:

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-h

Assignees

• Genentech Inc

Inventors

• Bryan Marian C
• Do Steven
• Drobnick Joy
• Gobbi Alberto
• Katsumoto Tamiko
• Kiefer Jr James Richard
• Liang Jun
• Rajapaksa Naomi S
• Chen Yongsheng
• Fu Liqiang
• Lai Kwong Wah
• Liu Zhiguo
• Wai John
• Wang Fei

Classifications

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61P11/06

  Antiasthmatics · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P35/00

  Antineoplastic agents · CPC title