IRAK4 modulators

Patent metadata

Field	Value
Publication number	US-10899772-B2
Application number	US-201916715997-A
Country	US
Kind code	B2
Filing date	Dec 16, 2019
Priority date	Jun 21, 2017
Publication date	Jan 26, 2021
Grant date	Jan 26, 2021

Abstract

Compounds of Formula 0, and stereoisomers and pharmaceutically acceptable salts thereof, as well as 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 0:

or a stereoisomer or pharmaceutically acceptable salt thereof,
R 1 is C 1-6 alkoxy, oxetanyl, —NR x R y , or a 6-membered heteroaryl that is optionally substituted with R z ;
R 2 is halogen, oxo, CN, OH, C 1-6 alkyl, —(C 0-3 alkyl)-C 3-6 cycloalkyl group, a —(C 0-3 alkyl)-3-11 membered heterocyclic group, —NR a R b , —NR e C(O)R f , —NR e S(O) 1-2 R f , —C(O)(C 1-3 alkyl), —C(O)NR c R d , —C(O)OR f , —S(O) 1-2 NR c R d , or —(C 0-3 alkyl)-OP(O)(OC 1-3 alkyl) 2 ,
wherein any alkyl, cycloalkyl group, or heterocyclic group is independently optionally substituted with halogen; oxo; CN; OR f ; C 1-3 haloalkoxy; —C(O)(C 1-3 alkyl); —S—C 1-3 alkyl; or C 1-3 alkyl optionally substituted with OH, halogen, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, or a 3-8 membered heterocyclic group,
ring A is a 5-membered heteroaryl, a 6-membered heteroaryl, a 6-membered saturated or partially saturated heterocyclic group, or a 9-membered bicyclic heteroaryl that comprises at least two heteroatoms selected form the group consisting of N, O, and S, wherein ring A is optionally substituted with R m ; provided ring A is not an optionally substituted 9-membered bicyclic heteroaryl of the following formula,

R a , R b , R c and R d are, independently at each occurrence, hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl group, —(C 0-3 alkyl)-phenyl, a 3-11 membered saturated heterocyclic group, a 5-6 membered monocyclic heteroaryl ring, —C(O)R f , —C(O)OR f , —C(O)NR g R h , or —S(O) 1-2 R f , or R c and R d are taken together to form a 5-8 membered heterocyclic group,
wherein any alkyl, cycloalkyl group, phenyl, heterocyclic group, or heteroaryl ring is independently optionally substituted with halogen, oxo, CN, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, —OR f , —NR g R h , or a 5-6 membered monocyclic heteroaryl ring;
R e is, independently at each occurrence, hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl group,
wherein any alkyl or cycloalkyl group is independently optionally substituted with halogen, oxo, CN, OH, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, or C 1-3 haloalkoxy;
R f is, independently at each occurrence, hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl group, or a 3-11 membered saturated heterocyclic group, wherein any alkyl, cycloalkyl group, or heterocyclic group is independently optionally substituted with halogen, oxo, CN, OH, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, —OR e , or —NR g R h ;
R g and R h are, independently at each occurrence, hydrogen, C 1-3 alkyl, or C 3-6 cycloalkyl group, wherein any alkyl or cycloalkyl group is independently optionally substituted with halogen, oxo, CN, OH, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, or C 1-3 haloalkoxy;
each R m is, independently at each occurrence, halogen; oxo; CN; —OR v ; —S(O) 1-2 R v ; OH; C 1-6 alkoxy; —NR n R p ; —C(O)(C 1-3 alkyl); —(C 0-3 alkyl)C(O)NR r R s ; —S(O) 1-2 NR n R p ; —OP(O)(OC 1-3 alkyl) 2 ; C 3-10 cycloalkyl group optionally substituted with OH or halogen; a 3-11 membered saturated or partially saturated heterocyclic group optionally substituted with oxo or C 1-3 alkyl; a 5-6 membered monocyclic heteroaryl ring optionally substituted with halogen, oxo, CN, OH, C 1-4 alkoxy, —NR n R p , or C 1-4 alkyl optionally substituted with halogen, or OH; or C 1-4 alkyl optionally substituted with halogen, oxo, CN, OH, —O—C 1-3 alkyl, —S—C 1-3 alkyl, —SO 2 —C 1-3 alkyl, —NR n R p , —C(O)NR n R p , phenyl, C 3-10 cycloalkyl, a 3-11 membered saturated or partially saturated heterocyclic group optionally substituted with oxo, C 1-3 alkyl, or a 5-6 membered monocyclic heteroaryl ring optionally substituted with oxo, halogen, or C 1-3 alkyl;
R n , R p , R r and R s are, independently at each occurrence, hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl group, —(C 0-3 alkyl)-phenyl, a 3-11 membered saturated heterocyclic group, a 5-6 membered monocyclic heteroaryl ring, —C(O)R v , —C(O)OR v , —C(O)NR t R u , or —S(O) 1-2 R v , or R r and R s are taken together to form a 5-8 membered heterocyclic group,
wherein any alkyl, cycloalkyl group, phenyl, heterocyclic group, or heteroaryl ring is independently optionally substituted with halogen, oxo, CN, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, —OR v , —NR t R u , or a 5-6 membered monocyclic heteroaryl ring;
R t and R u are, independently at each occurrence, hydrogen, C 1-3 alkyl, or C 3-6 cycloalkyl group,
wherein any alkyl or cycloalkyl group is independently optionally substituted with halogen, oxo, CN, OH, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, or C 1-3 haloalkoxy;
R v is, independently at each occurrence, hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl group, or a 3-11 membered saturated heterocyclic group, wherein any alkyl, cycloalkyl group, or heterocyclic group is independently optionally substituted with halogen, oxo, CN, OH, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, —OR w , or —NR t R u ; and
R w is, independently at each occurrence, hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl group,
wherein any alkyl or cycloalkyl group is independently optionally substituted with halogen, oxo, CN, OH, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, or C 1-3 haloalkoxy;
R x and R y are, independently at each occurrence, C 1-6 alkyl, or R x and R y are taken together to form a 6-membered heterocyclic group that is optionally substituted with R z ;
each R z is, independently at each occurrence, halogen; oxo; CN; —S(O) 1-2 R v ; OH; C 1-6 alkoxy; —NR n R p ; —C(O)(C 1-3 alkyl); —(C 0-3 alkyl)C(O)NR n R p ; —S(O) 1-2 NR n R p ; —OP(O)(OC 1-3 alkyl) 2 ; C 3-10 cycloalkyl group optionally substituted with OH or halogen; a 3-11 membered saturated or partially saturated heterocyclic group optionally substituted with oxo or C 1-3 alkyl; a 5-6 membered monocyclic heteroaryl ring optionally substituted with halogen, oxo, CN, OH, C 1-4 alkoxy, —NR n R p , or C 1-4 alkyl optionally substituted with halogen, or OH; or C 1-4 alkyl optionally substituted with halogen, oxo, CN, OH, —O—C 1-3 alkyl, —S—C 1-3 alkyl, —SO 2 —C 1-3 alkyl, —NR n R p , —C(O)NR n R p , phenyl, C 3-10 cycloalkyl, a 3-11 membered saturated or partially saturated heterocyclic group optionally substituted with oxo, C 1-3 alkyl, or a 5-6 membered monocyclic heteroaryl ring optionally substituted with oxo, halogen, or C 1-3 alkyl.

2. The compound of claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 1 is —NR x R y .

3. The compound of claim 2 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R x and R y are taken together to form a 6-membered heterocyclic group that is optionally substituted with R z .

4. The compound of claim 2 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R x and R y are taken together to form a morpholino group that is optionally substituted with R z .

5. The compound of claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 1 is a 6-membered heteroaryl that is optionally substituted with R z .

6. The compound or salt of claim 5 wherein R 1 is pyridyl that is optionally substituted with R z .

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

Assignees

• Genentech Inc

Inventors

• Bryan Marian C
• Do Steven
• Katsumoto Tamiko
• Liang Jun
• Rajapaksa Naomi S
• Kiefer Jr James Richard
• Fu Liqiang

Classifications

• A61P1/00

  Drugs for disorders of the alimentary tract or the digestive system · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• A61P17/00

  Drugs for dermatological disorders · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title