Therapeutic compounds and compositions, and methods of use thereof

Abstract

Compounds and salts thereof that are useful as JAK kinase inhibitors are described herein. Also provided are pharmaceutical compositions that include such a JAK inhibitor and a pharmaceutically acceptable carrier, adjuvant or vehicle, and methods of treating or lessening the severity of a disease or condition responsive to the inhibition of a Janus kinase activity in a patient.

What is claimed is: 
     
         1 . A compound of Formula (I) 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
 R 1  is hydrogen or CH 3 ; 
 R 2  is halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, or —OR a , wherein R 2  is optionally substituted by one or more groups independently selected from the group consisting of halogen, C 1 -C 3 alkyl, cyano, hydroxy and oxo; 
 R a  is C 1 -C 6 alkyl, -phenyl-COR b R c , -phenyl-(3-6-membered heterocyclyl), or 3-11-membered heterocyclyl, wherein R a  is optionally substituted by one or more groups independently selected from the group consisting of halogen, C 1 -C 3 alkyl, cyano, hydroxy and oxo; 
 R b  and R c  are each independently hydrogen or CH 3 ; 
 R 3  is hydrogen or NH 2 ; 
 R 4  is hydrogen or CH 3 ; and 
 R 5  is hydrogen or NH 2 . 
 
     
     
         2 . The compound of  claim 1  or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1  is hydrogen. 
     
     
         3 . The compound of  claim 1  or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1  is CH 3 . 
     
     
         4 . The compound of  claim 1  or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3  is hydrogen. 
     
     
         5 . The compound of  claim 1  or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 4  and R 5  are each hydrogen. 
     
     
         6 . The compound of  claim 1  or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 , R 3 , R 4  and R 5  are each hydrogen. 
     
     
         7 . The compound of  claim 1  or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R2 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, or —OR a , wherein R 2  is optionally substituted by one or more groups independently selected from the group consisting of halogen, C 1 -C 3 alkyl, cyano, hydroxy and oxo. 
     
     
         8 . The compound of  claim 1  or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 2  is selected from the group consisting of halogen, C 1 -C 6 haloalkyl and C 1 -C 6 haloalkoxy. 
     
     
         9 . The compound of  claim 1  or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 2  is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         10 . A method of preventing, treating or lessening the severity of a disease or condition responsive to the inhibition of a Janus kinase activity 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. 
     
     
         11 . The method of  claim 10 , wherein the disease or condition is cancer, stroke, diabetes, hepatomegaly, cardiovascular disease, multiple sclerosis, Alzheimer's disease, cystic fibrosis, viral disease, autoimmune diseases, atherosclerosis, restenosis, psoriasis, rheumatoid arthritis, inflammatory bowel disease, asthma, allergic disorders, inflammation, neurological disorders, a hormone-related disease, conditions associated with organ transplantation (e.g., transplant rejection), immunodeficiency disorders, destructive bone disorders, proliferative disorders, infectious diseases, conditions associated with cell death, thrombin-induced platelet aggregation, liver disease, pathologic immune conditions involving T cell activation, CNS disorders or a myeloproliferative disorder. 
     
     
         12 . A pharmaceutical composition comprising a compound of  claim 1  or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition comprises microparticles of the compound suitable for inhaled delivery. 
     
     
         13 . The pharmaceutical composition of  claim 12 , wherein the microparticles are prepared by spray-drying, freeze-drying or micronisation. 
     
     
         14 . A kit can comprising:
 (a) a first pharmaceutical composition comprising a compound of  claim 1  or a pharmaceutically acceptable salt thereof; and   (b) instructions for use.   
     
     
         15 . The kit of  claim 14 , further comprising a second pharmaceutical composition comprising an agent for treatment of an inflammatory disorder, or a chemotherapeutic agent.