IRAK4 modulators
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.
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
8. The compound of claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 2 is
9. The compound of claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 2 is
10. The compound of claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein ring A is selected from the group consisting of
11. The compound of claim 10 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein ring A is selected from the group consisting of
12. The compound of claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R m is selected from the group consisting of chloro, oxo, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, CN, methoxy, OH, isopropoxy, 2,2,2-trifluoroethyl, 1-hydroxyethyl, 1-methoxyethyl, 2-hydroxyprop-2-yl, morpholino, 20methylmorpholino, and 1H-pyrrol-3-yloxy.
13. The compound of claim 1 , selected from the group consisting of
or a stereoisomer or pharmaceutically acceptable salt thereof.
14. A pharmaceutical composition comprising a compound of a claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, carrier or diluent.