Isoxazolines as therapeutic agents

Abstract

The present invention provides compound of Formula (I) biologically active metabolites, pro-drugs, isomers, stereoisomers, solvates, hydrates and pharmaceutically acceptable salts thereof wherein the variables are defined herein. The compounds of the invention are useful for treating immunological conditions.

1 - 24 . (canceled) 
     
     
         25 . A pharmaceutical composition comprising a compound, biologically active metabolite, pro-drug, isomer, stereoisomer, solvate, hydrate or pharmaceutically acceptable salt of Formula (I), 
       
         
           
           
               
               
           
         
         wherein:
 A is 
 
       
       
         
           
           
               
               
           
         
         X is phenyl, benzo[1,4]oxazin-3-onyl, benzoxazolyl, 2,3-dihydrobenzo[1,4]dioxinyl, 2,3-dihydrobenzo furanyl, pyrazinonyl, or pyridinyl, each of which is optionally substituted with one or more substituents independently selected from Br, Cl, F, CF 3 , OCF 3 , (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy;
 Y is 2-methyl pyrimidinyl; 
 Z is 1,4-dioxanyl or piperidinyl, each of which is optionally substituted by one or more substituents independently selected from Br, Cl, F, —CF 3 , —CH 3 , CN, —C(O)OH, —C(O)OCH 3 , —C(O)CH 3 , —C(O)C(H)(CH 3 ) 2 , —C(O)-cyclopropyl, —C(O)-cyclobutyl, —C(O)CH 2 CN, —C(O)CH 2 OH, —C(O)C(CH 3 ) 2 OH, —C(O)CH 2 OCH 3 , —C(O)N(H)CH 2 CH 3 , —C(O)CH 2 N(CH 3 ) 2 , —C(O)CH 2 CH 2 N(CH 3 ) 2 , —C(O)CH 2 N(H)C(O)CH 3 , —C(O)CH 2 N(H)C(O)N(H)CH 3 , —C(O)CH 2 S(O) 2 CH 3 , —C(O)NH 2 , —C(O)N(CH 3 ) 2 , —C(O)N(H)CH 3 , —C(O)N(H)CH 2 CH 3 , —C(O)N(H)CH(CH 3 ) 2 , —C(O)N(H)CH 2 CH 2 OH, —C(O)N(CH 3 )CH 2 CH 2 OH, —S(O) 2 CH 3 , —S(O) 2 C(H)(CH 3 ) 2 , —CH 2 CN, —CH 2 OCH 3 , —CH 2 OH, —CH 2 CH 2 OH, —C(H)(CH 3 ) 2 OH, —CH 2 NH 2 , —CH 2 N(CH 3 ) 2 , —CH 2 N(H)C(O)CH 3 , —CH 2 N(H)C(O)N(H)CH 3 , —CH 2 N(H)C(O)N(CH 3 ) 2 , —CH 2 N(H)S(O) 2 CH 3 , —CH 2 N(H)C(O)CH 2 OH, —CH 2 N(H)C(O)C(CH 3 ) 2 OH, —CH 2 N(H)C(O)C(H)(OH)CH 3 , —CH 2 N(H)C(O)CH 2 CN, or —CH 2 S(O) 2 CH 3 ; 
 
         and a pharmaceutically acceptable carrier or excipient. 
       
     
     
         26 . A kit comprising the composition of  claim 25 , packaging and instructions for use. 
     
     
         27 . A method of treating a disease or condition in a subject in need of treatment, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of  claim 25 , wherein the disease or condition is selected from the group consisting of: osteoarthritis, a traumatic joint injury, and a degenerative joint disease. 
     
     
         28 . (canceled) 
     
     
         29 . The method of  claim 27 , wherein the traumatic joint injury is anterior cruciate ligament tear or meniscal tear. 
     
     
         30 . A pharmaceutical composition comprising a compound, biologically active metabolite, pro-drug, isomer, stereoisomer, solvate, hydrate or pharmaceutically acceptable salt of N-(4-fluoro-3-methoxybenzyl)-6-((S)-5-((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide, and a pharmaceutically acceptable carrier or excipient. 
     
     
         31 . A kit comprising the pharmaceutical composition of  claim 30 , packaging and instructions for use. 
     
     
         32 . A method of treating a disease or condition in a subject in need of treatment, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of  claim 30 , wherein the disease or condition is selected from the group consisting of: osteoarthritis, a traumatic joint injury, and a degenerative joint disease. 
     
     
         33 . The method of  claim 32 , wherein the traumatic joint injury is anterior cruciate ligament tear or meniscal tear.