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

Abstract

A method for treating an inflammatory or autoimmune disease with 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 method for treating an inflammatory or autoimmune disease in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula 0, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein 
       
         
           
           
               
               
           
         
         or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: 
         R 1  is hydrogen or halogen; 
         R 3  is halogen, CN, 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, Br, Cl, F, OCHF 2 , CHF 2 , or 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 ; 
         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) 1-2 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) 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; 
         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) 1-2 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 method of  claim 1 , 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, juvenile idiopathic arthritis, multiple sclerosis, neuropathic pain, gout, and gouty arthritis.