PYRAZOLO[1,5a]PYRIMIDINE DERIVATIVES AS IRAK4 MODULATORS

Abstract

Compounds of Formula 0, Formula I, and Formula II and methods of use as Interleukin-1 Receptor Associated Kinase (IRAK4) inhibitors are described herein.

What is claimed is: 
     
         1 . A compound of Formula 0: 
       
         
           
           
               
               
           
         
         or a stereoisomer or pharmaceutically acceptable salt thereof, 
         wherein: 
         R 1  is hydrogen or halogen; 
         R 3  is hydrogen, halogen, CN, OH, C 1-3 alkyl, C 2-3 alkenyl, C 3-7 cycloalkyl group, C 1 -C 3 alkanoyl, —(C 0 -C 3 alkyl)C(O)NR 6 R 7 , —(C 2-3 alkenyl)C(O)NR 6 R 7 , —S(O) 1-2 NR 6 R 7 , —NR 8 R 9 , —O—C 1-3 alkyl, a 3-7 membered monocyclic saturated or partially saturated heterocyclic group, a 5-6 membered monocyclic heteroaryl ring, or a 5-6 membered monocyclic aryl ring, 
         wherein any alkyl, alkanoyl, or alkenyl is independently optionally substituted by halogen, oxo, CN, OH, C 1-3 alkoxy, or C 1-3 haloalkoxy, and 
         wherein any cycloalkyl group, heterocyclic group, heteroaryl ring, or aryl ring is independently optionally substituted by halogen, oxo, CN, OH, C 1-3 alkyl, or C 1-3 haloalkyl; 
         R 4  is hydrogen, halogen, C 1-3 alkyl, C 2-3 alkenyl, —(C 0 -C 3 alkyl)C(O)R 13  —(C 2-3 alkenyl)C(O)NR 10 R 11 , —S(O) 12 NR 10 R 11 , a 3-7 membered monocyclic saturated or partially saturated heterocyclic group, —C(O)NR 8 R 9 , or —NR 8 R 9 , 
         wherein any alkyl, alkenyl, or heterocyclic group is independently optionally substituted by halogen, oxo, CN, OH, C 1-3 alkoxy, C 1-3 haloalkoxy, or a 3-7 membered monocyclic saturated or partially saturated heterocyclic group that may be optionally substituted with oxo; 
         R 5  is hydrogen, —CN, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl group, —NR 8 R 9 , —C(O)NR 8 R 9 , —O(C 3-7 cycloalkyl group), —O(C 1-3 alkyl)-3-8 membered cycloalkyl group, —O(C 0-3 alkyl)-3-8 membered saturated or partially saturated heterocyclic group, —O(C 1-3 alkyl)-phenyl, a —O(C 1-3  alkyl)-5-6 membered heteroaryl ring, a 3-11 membered saturated or partially saturated heterocyclic group, or a 5-6 membered monocyclic heteroaryl ring, 
         wherein any alkyl or alkoxy is independently optionally substituted by halogen, oxo, CN, OH, C 1-3 alkoxy, C 1-3 haloalkoxy, or a 3-11 membered saturated or partially saturated heterocyclic group that may be optionally substituted with (i) —C(O)(C 1-3 alkyl) optionally substituted with halogen or (ii) with C 1-3 alkyl optionally substituted with halogen, and 
         wherein any cycloalkyl group, heterocyclic group, phenyl, or heteroaryl ring is optionally substituted by halogen; oxo; CN; OH; C 1-6 alkoxy; —NR 8 R 9 ; —C(O)(C 1-3 alkyl); —(C 0-3 alkyl)C(O)NR 10 R 11 ; —S(O) 12 NR 8 R 9 ; —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 by halogen, oxo, CN, OH, C 1-3 alkyl, or C 1-3 haloalkyl; or C 1-4 alkyl optionally substituted by halogen, oxo, CN, OH, —O—C 1-3  alkyl, —S—C 1-3 alkyl, —SO 2 —C 1-3 alkyl, —NR 8 R 9 , —C(O)NR 8 R 9 , phenyl, C 3-10 cycloalkyl, a 3-11 membered saturated or partially saturated heterocyclic group optionally substituted with oxo or C 1-3  alkyl, or a 5-6 membered monocyclic heteroaryl ring optionally substituted with oxo, halogen, or C 1-3 alkyl; 
         A is a 3-11 membered heterocyclic group optionally substituted by 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 8 R 9 , —NR 12 C(O)R 13 , —NR 12 S(O) 12 R 13 , —C(O)(C 1-3 alkyl), —C(O)NR 10 R 11 , —C(O)OR 13 , —S(O) 1-2 NR 10 R 11 , or —(C 0-3 alkyl)-OP(O)(OC 1-3 alkyl) 2 , 
         wherein any alkyl, cycloalkyl group, or heterocyclic group is independently optionally substituted by halogen; oxo; CN; OR 13 ; 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, and 
         wherein when A is a 5-membered nitrogen containing heterocyclic group, the nitrogen atom is substituted; 
         R 6  and R 7  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 by halogen, oxo, CN, OH, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, or C 1-3 haloalkoxy; 
         R 8 , R 9 , R 10  and R 11  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 13 , —C(O)OR 13 , —C(O)NR 6 R 7 , or —S(O) 1-2 R 13 , or R 10  and R 11  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 by halogen, oxo, CN, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, —OR 13 , —NR 6 R 7 , or a 5-6 membered monocyclic heteroaryl ring; 
         R 12  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 by halogen, oxo, CN, OH, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, or C 1-3 haloalkoxy; 
         R 13  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 by halogen, oxo, CN, OH, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, —OR 12 , or —NR 6 R 7 ; and 
         R 16  is hydrogen, halogen, CN, or C 1-3 alkyl optionally substituted with —NH 2 , halogen, or CN. 
       
     
     
         2 . The compound of  claim 1 , further defined as a compound of Formula I: 
       
         
           
           
               
               
           
         
         or a stereoisomer or pharmaceutically acceptable salt thereof, 
         wherein: 
         R 1  is hydrogen or halogen; 
         R 3  is hydrogen, halogen, CN, OH, C 1-3 alkyl, C 2-3 alkenyl, C 3-7 cycloalkyl group, C 1 -C 3 alkanoyl, —(C 0 -C 3 alkyl)C(O)NR 6 R 7 , —(C 2-3 alkenyl)C(O)NR 6 R 7 , —S(O) 1-2 NR 6 R 7 , —NR 8 R 9 , a 3-7 membered monocyclic saturated or partially saturated heterocyclic group, a 5-6 membered monocyclic heteroaryl ring, or a 5-6 membered monocyclic aryl ring, 
         wherein any alkyl, alkanoyl, or alkenyl is independently optionally substituted by halogen, oxo, CN, OH, C 1-3 alkoxy, or C 1-3 haloalkoxy, and 
         any cycloalkyl group or other ring is independently optionally substituted by halogen, oxo, CN, OH, C 1-3 alkyl, or C 1-3 haloalkyl; 
         R 4  is hydrogen, halogen, C 1-3 alkyl, C 2-3 alkenyl, —(C 0 -C 3 alkyl)C(O)R 13  —(C 2-3 alkenyl)C(O)NR 10 R 11 , —S(O) 12 NR 10 R 11 , or —NR 8 R 9 ; 
         wherein any alkyl or alkenyl is independently optionally substituted by halogen, oxo, CN, OH, C 1-3 alkoxy, or C 1-3 haloalkoxy; 
         R 5  is hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl group, —NR 8 R 9 , —O(C 3-7 cycloalkyl group), —O(C 1-3 alkyl)-3-8 membered cycloalkyl group, —O(C 1-3 alkyl)-3-8 membered saturated or partially saturated heterocyclic group, —O(C 1-3 alkyl)-phenyl, a —O(C 1-3 alkyl)-5-6 membered heteroaryl ring, a 3-11 membered saturated or partially saturated heterocyclic group, or a 5-6 membered monocyclic heteroaryl ring, 
         wherein any alkyl or alkoxy is independently optionally substituted by halogen, oxo, CN, OH, C 1-3 alkoxy, or C 1-3 haloalkoxy, and 
         any cycloalkyl group or other ring is optionally substituted by halogen, oxo, CN, OH, C 1-6 alkoxy, —C(O)(C 1-3 alkyl), —(C 0-3 alkyl)C(O)NR 10 R 11 , —S(O) 12 NR 8 R 9 , —OP(O)(OC 1-3 alkyl) 2 , a 5-6 membered monocyclic heteroaryl ring optionally substituted by halogen, oxo, CN, OH, C 1-3 alkyl, or C 1-3 haloalkyl, or C 1-3 alkyl optionally substituted by halogen, oxo, CN, OH, phenyl, a 3-8 membered saturated heterocyclic group, a 5-6 membered monocyclic heteroaryl ring, or —NR 8 R 9 ; 
         A is a 3-11 membered heterocyclic group optionally substituted by halogen, oxo, CN, OH, C 1-6 alkyl, —(C 0 -C 3 alkyl)-C 3-6 cycloalkyl group, a —(C 0 -C 3 alkyl)-3-11 membered heterocyclic group optionally substituted by halogen, oxo, CN, OH, C 1-3 alkyl, or C 1-3 haloalkyl, —NR 8 R 9 , —NR 12 C(O)R 13 , —NR 12 S(O) 12 R 13 , —C(O)(C 1-3 alkyl), —C(O)NR 10 R 11 , —C(O)OR 13 , —S(O) 12 NR 10 R 11 , or —OP(O)(OC 1-3 alkyl) 2 , 
         wherein any alkyl, cycloalkyl group, or heterocyclic group is independently optionally substituted by halogen, oxo, CN, OH, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, or a 3-8 membered heterocyclic group; 
         wherein when A is a 5-membered nitrogen containing heterocyclic group, the nitrogen atom is substituted; 
         R 6  and R 7  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 by halogen, oxo, CN, OH, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, or C 1-3 haloalkoxy; 
         R 8 , R 9 , R 10  and R 11  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, —C(O)R 13 , —C(O)OR 13 , —C(O)NR 6 R 7 , or —S(O) 1-2 R 13 , or R 10  and R 11  are taken together to form a 5-8 membered heterocyclic group optionally substituted by halogen, oxo, CN, OH, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, or C 1-3 haloalkoxy; 
         wherein any alkyl, cycloalkyl group, or other ring is independently optionally substituted by halogen, oxo, CN, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, —OR 13 , or —NR 6 R 7 ; 
         R 12  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 by halogen, oxo, CN, OH, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, or C 1-3 haloalkoxy; 
         R 13  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 other ring is independently optionally substituted by halogen, oxo, CN, OH, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, —OR 12 , or —NR 6 R 7 ; and 
         R 16  is H, —Cl, —CN, or —CH 3 . 
       
     
     
         3 . The compound of  claim 1 , further defined as a compound of Formula II: 
       
         
           
           
               
               
           
         
         or a stereoisomer or pharmaceutically acceptable salt thereof, 
         wherein: 
         R 1  is hydrogen or halogen; 
         R 3  is hydrogen, halogen, CN, OH, C 1-3 alkyl, C 2-3 alkenyl, C 3-7 cycloalkyl group, C 1 -C 3 alkanoyl, —(C 0 -C 3 alkyl)C(O)NR 6 R 7 , —(C 2-3 alkenyl)C(O)NR 6 R 7 , —S(O) 1-2 NR 6 R 7 , —NR 8 R 9 , a 3-7 membered monocyclic saturated or partially saturated heterocyclic group, a 5-6 membered monocyclic heteroaryl ring, or a 5-6 membered monocyclic aryl ring, 
         wherein any alkyl, alkanoyl, or alkenyl is independently optionally substituted by halogen, oxo, CN, OH, C 1-3 alkoxy, or C 1-3 haloalkoxy, and 
         any cycloalkyl group or other ring is independently optionally substituted by halogen, oxo, CN, OH, C 1-3 alkyl, or C 1-3 haloalkyl; 
         R 4  is hydrogen, halogen, C 1-3 alkyl, C 2-3 alkenyl, —(C 0 -C 3 alkyl)C(O)R 13  —(C 2-3 alkenyl)C(O)NR 10 R 11 , —S(O) 12 NR 10 R 11 , or —NR 8 R 9 ; 
         wherein any alkyl or alkenyl is independently optionally substituted by halogen, oxo, CN, OH, C 1-3 alkoxy, or C 1-3 haloalkoxy; 
         R 5  is hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl group, —NR 8 R 9 , —O(C 3-7 cycloalkyl group), a 3-11 membered saturated or partially saturated heterocyclic group, or a 5-6 membered monocyclic heteroaryl ring, 
         wherein any alkyl or alkoxy is independently optionally substituted by halogen, oxo, CN, OH, C 1-3 alkoxy, or C 1-3 haloalkoxy, and 
         any cycloalkyl group or other ring is optionally substituted by halogen, oxo, CN, OH, —(C 0 -C 3 alkyl)C(O)NR 10 R 11 , —OP(O)(OC 1-3 alkyl) 2 , or C 1-3 alkyl optionally substituted by halogen, oxo, CN, OH, or —NR 8 R 9 ; 
         A is a 3-11 membered heterocyclic group optionally substituted by halogen, oxo, CN, OH, C 1-6 alkyl, C 3-6 cycloalkyl group, —NR 8 R 9 , —NR 12 C(O)R 13 , —NR 12 S(O) 12 R 13 , —C(O)NR 10 R 11 , —C(O)OR 13 , or —S(O) 1-2 NR 10 R 11 , 
         wherein any alkyl or cycloalkyl group is independently optionally substituted by halogen, oxo, CN, OH, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, or C 1-3 haloalkoxy; 
         wherein when A is a 5-membered nitrogen containing heterocyclic group, the nitrogen atom is substituted; 
         R 6  and R 7  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 by halogen, oxo, CN, OH, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, or C 1-3 haloalkoxy; 
         R 8 , R 9 , R 10  and R 11  are, independently at each occurrence, hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl group, a 3-11 membered saturated heterocyclic group, —C(O)R 13 , —C(O)OR 13 , —C(O)NR 6 R 7 , or —S(O) 1-2 R 13 , 
         wherein any alkyl, cycloalkyl group or other ring is independently optionally substituted by halogen, oxo, CN, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, —OR 13 , or —NR 6 R 7 ; 
         R 12  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 by halogen, oxo, CN, OH, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, or C 1-3 haloalkoxy; 
         R 13  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 other ring is independently optionally substituted by halogen, oxo, CN, OH, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, —OR 12 , or —NR 6 R 7 ; and 
         R 16  is H, —Cl, —CN, or —CH 3 . 
       
     
     
         4 . The compound of  claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 1  and R 4  are each hydrogen, and R 3  is hydrogen, OH, halogen, CH 3 , CH 2 OH, CH 2 F, OCHF 2 , CHF 2 , CF 3 , cyclopropyl, azetidinyl, CN, —C(O)CH 3 , —C(O)NH 2 , —C(O)NHCH 3 , —NHCH 3 , —SO 2 —NH 2 , or —SO 2 —NHCH 3 . 
     
     
         5 . The compound of  claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 1  and R 4  are each hydrogen, and R 3  is hydrogen, OH, CH 3 , or CH 2 OH. 
     
     
         6 . The compound of  claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 1  and R 4  are each hydrogen, and R 3  is Br, Cl, F, OCHF 2 , CHF 2 , or CF 3 . 
     
     
         7 . The compound of  claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 1  and R 4  are each hydrogen, and R 3  is cyclopropyl, azetidinyl, CN, —C(O)CH 3 , —C(O)NH 2 , —C(O)NHCH 3 , —NHCH 3 , —SO 2 —NH 2 , or —SO 2 —NHCH 3 . 
     
     
         8 . The compound of  claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 1  and R 3  are each hydrogen, and R 4  is Cl, CHF 2 , 
       
         
           
           
               
               
           
         
       
       or a stereoisomer thereof. 
     
     
         9 . The compound of  claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 1 , R 3 , and R 4  are each hydrogen. 
     
     
         10 . The compound of  claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 5  is a 3-11 membered saturated or partially saturated heterocyclic group optionally substituted by halogen, oxo, CN, OH, —(C 0-3 alkyl)C(O)NR 10 R 11 , —OP(O)(OC 1-3 alkyl) 2 , or C 1-3 alkyl optionally substituted by halogen, oxo, CN, OH, or —NR 8 R 9 . 
     
     
         11 . The compound of  claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 5  is an N-linked 3-11 membered saturated heterocyclic group optionally substituted by halogen, oxo, CN, OH, —(C 0-3 alkyl)C(O)NR 10 R 11 , —OP(O)(OC 1-3 alkyl) 2 , or C 1-3 alkyl optionally substituted by halogen, oxo, CN, OH, or —NR 8 R 9 . 
     
     
         12 . The compound of  claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the ring heteroatoms of the 3-11 membered saturated or partially saturated heterocyclic group of R 5  are selected from nitrogen and oxygen. 
     
     
         13 . The compound of  claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 5  is piperidinyl, piperazinyl, or morpholinyl, wherein any R 5  is optionally substituted by halogen; oxo; CN; OH; C 1-6 alkoxy; —NR 8 R 9 ; —C(O)(C 1-3 alkyl); —(C 0-3 alkyl)C(O)NR 10 R 11 ; —S(O) 1-2 NR 8 R 9 ; —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 by halogen, oxo, CN, OH, C 1-3 alkyl, or C 1-3 haloalkyl; or C 1-4 alkyl optionally substituted by halogen, oxo, CN, OH, —O—C 1-3  alkyl, —S—C 1-3 alkyl, —SO 2 —C 1-3 alkyl, —NR 8 R 9 , —C(O)NR 8 R 9 , phenyl, C 3-10 cycloalkyl, a 3-11 membered saturated or partially saturated heterocyclic group optionally substituted with oxo or C 1-3  alkyl, or a 5-6 membered monocyclic heteroaryl ring optionally substituted with oxo, halogen, or C 1-3 alkyl. 
     
     
         14 . The compound of  claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 5  is N-linked piperidinyl, N-linked piperazinyl, or N-linked morpholinyl, wherein any R 5  is optionally substituted by halogen, oxo, CN, OH, or C 1-3 alkyl optionally substituted by halogen, oxo, CN, or OH. 
     
     
         15 . The compound of  claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 5  is —CH 2 CH 3 , —C(CH 3 ) 2 , Cl, CN, cyclopropyl, —C(O)NH 2 , —OCH 3 , —OCH 2 CF 3 , —OCH 2 CHF 2 , —CF 3 , —CHF 2 , —OCF 3 , —OCHF 2 , —NHCH 3 , —N(CH 3 ) 2 , 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a stereoisomer thereof. 
     
     
         16 . The compound of  claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 5  is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a stereoisomer thereof. 
     
     
         17 . The compound of  claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 5  is 
       
         
           
           
               
               
           
         
       
     
     
         18 . The compound of  claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein A is a 3-11 membered, non-aromatic heterocyclic group. 
     
     
         19 . The compound of  claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein A is a 3-11 membered heterocyclic group comprising at least one oxygen as a ring atom and is optionally substituted by halogen, oxo, CN, OH, C 1-6 alkyl, C 3-6 cycloalkyl group, —NR 8 R 9 , —NR 12 C(O)R 13 , —NR 12 S(O) 12 R 13 , —C(O)NR 10 R 11 , —C(O)OR 13 , or —S(O) 1-2 NR 10 R 11 , wherein any alkyl or cycloalkyl group is independently optionally substituted by halogen, oxo, CN, OH, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, or C 1-3 haloalkoxy. 
     
     
         20 . The compound of  claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the following portion of Formula 0, Formula I, or Formula II 
       
         
           
           
               
               
           
         
         is further defined as 0-A, I-A, or II-A: 
       
       
         
           
           
               
               
           
         
         wherein A is a 5 or 6 membered ring optionally containing an additional ring heteroatom and wherein A is optionally substituted by halogen, oxo, CN, OH, C 1-6 alkyl, C 3-6 cycloalkyl group, —NR 8 R 9 , NR 12 C(O)R 13 , —NR 12 S(O) 1-2 R 13 , —C(O)NR 10 R 11 , —C(O)OR 13 , or —S(O) 1-2 NR 10 R 11 ,
 wherein any alkyl or cycloalkyl group is independently optionally substituted by halogen, oxo, CN, OH, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, or C 1-3 haloalkoxy. 
 
       
     
     
         21 . The compound of  claim 20 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein 0-A, I-A, or II-A is further defined as 0-B, I—B, or II-B: 
       
         
           
           
               
               
           
         
         wherein R 14  and R 15  are each selected from halogen, oxo, CN, OH, C 1-6 alkyl, C 3-6  cycloalkyl group, —NR 8 R 9 , —NR 12 C(O)R 13 , —NR 12 S(O) 12 R 13 , —C(O)NR 10 R 11 , —C(O)OR 13 , and —S(O) 1-2 NR 10 R 11 , 
         wherein any alkyl or cycloalkyl group is independently optionally substituted by halogen, oxo, CN, OH, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, or C 1-3 haloalkoxy; 
         or R 14  and R 15  together form a C 3-6 cycloalkyl group or saturated or partially saturated 3-6 membered heterocyclic group, 
         wherein any cycloalkyl group or other ring is independently optionally substituted by halogen, oxo, CN, OH, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, or C 1-3 haloalkoxy. 
       
     
     
         22 . The compound of  claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein A does not contain oxygen as a ring atom and is optionally substituted by halogen, oxo, CN, OH, C 1-6 alkyl, C 3-6 cycloalkyl group, —NR 8 R 9 , —NR 12 C(O)R 13 , —NR 12 S(O) 1-2 R 13 , —C(O)NR 10 R 11 , —C(O)OR 13 , or —S(O) 1-2 NR 10 R 11 , wherein any alkyl or cycloalkyl group is independently optionally substituted by halogen, oxo, CN, OH, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3  alkoxy, or C 1-3 haloalkoxy. 
     
     
         23 . The compound of  claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the following portion of Formula 0, Formula I, or Formula II 
       
         
           
           
               
               
           
         
         is further defined as 0-C, I-C, or II-C: 
       
       
         
           
           
               
               
           
         
         wherein the nitrogen comprises a substituent as defined in  claim 1 . 
       
     
     
         24 . The compound of  claim 23 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the following portion of Formula 0, Formula I, or Formula II 
       
         
           
           
               
               
           
         
         is further defined as 0-C, I-C, or II-C: 
       
       
         
           
           
               
               
           
         
         wherein the nitrogen of A is substituted by C 1-6 alkyl or C 3-6 cycloalkyl group, 
         wherein any alkyl or cycloalkyl group is independently optionally substituted by halogen, oxo, CN, OH, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, or C 1-3 haloalkoxy. 
       
     
     
         25 . The compound of  claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the following portion of Formula 0, Formula I, or Formula II 
       
         
           
           
               
               
           
         
         is selected from 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a stereoisomer thereof. 
       
     
     
         26 . The compound of  claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the following portion of Formula 0, Formula I, or Formula II 
       
         
           
           
               
               
           
         
         is selected from 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         and stereoisomers thereof. 
       
     
     
         27 . The compound of  claim 1 , wherein the compound is not 
       
         
           
           
               
               
           
         
       
     
     
         28 . The compound of  claim 1 , selected from the group consisting of the compounds of Tables 1, 2 and 3, or a stereoisomer or pharmaceutically acceptable salt thereof. 
     
     
         29 . 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. 
     
     
         30 . A method of preventing, treating, or lessening the severity of a disease or condition responsive to the inhibition of IRAK4 in a patient, comprising administering to the patient a therapeutically effective amount of a compound of  claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof. 
     
     
         31 . A method for treating cancer in a patient, comprising administering to the patient a therapeutically effective amount of a compound of  claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof. 
     
     
         32 . A method for treating an inflammatory or autoimmune disease in a patient, comprising administering to the patient a therapeutically effective amount of a compound of  claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof. 
     
     
         33 . The method of  claim 32 , wherein the disease is selected from the group consisting of Crohn's disease, ulcerative colitis, Irritable Bowel Disorder (IBD), asthma, graft versus host disease, allograft rejection, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, cutaneous lupus, psoriasis, systemic onset juvenile idiopathic arthritis, multiple sclerosis, neuropathic pain, gout, and gouty arthritis. 
     
     
         34 . A method of inhibiting IRAK4 in a cell, ex vivo, comprising contacting the cell with an effective amount of a compound of  claim 1 , or a stereoisomer or salt thereof. 
     
     
         35 . A method of inhibiting IRAK4 in a patient in need of therapy, comprising administering to the patient a therapeutically effective amount of a compound of  claim 1 .