Tetrazole-substituted pyrazolopyrimidine inhibitors of jak kinases and uses thereof

Abstract

wherein R1, R2, R3, R4, R5 and R6 are as defined herein, 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 stereoismer or pharmaceutically acceptable salt thereof, 
       wherein:
 R 1  is: hydroxyl-C 1 -C 6 alkyl; —(CR a1 R a2 ) m -het 1 ; —(CR a1 R a2 ) n NR b R c ; or —(CR a1 R a2 ) m —C 3-6  cycloalkyl wherein the C 3-6 cycloalkyl moiety is substituted once with R d ; 
 R 2  is: halo; halo C 1 -C 6 alkoxy; C 1 -C 6 alkylthio; —SF 2 ; or C 3 -C 6 cycloalkyl; 
 R 3  is: hydrogen; or C 1 -C 6 alkyl; 
 R 4  is: hydrogen; or C 1 -C 6 alkyl; 
 R 5  is: hydrogen; or C 1 -C 6 alkyl; 
 R 6  is: hydrogen; or C 1 -C 6 alkyl; 
 or R 2  and R 6  together with the atoms to which they are attached may form a six-membered ring containing two heteroatoms each independently selected from O, N and S; 
 m is from 0 to 2; 
 n is from 0 to 3; 
 each R a1  is independently: hydrogen; or C 1 -C 6 alkyl; 
 each R a2  is independently: hydrogen; halo; or C 1 -C 6 alkyl; 
 R b  is: hydrogen; or C 1 -C 6 alkyl; 
 R c  is: hydrogen; C 1 -C 6 alkyl; an amino protecting group; or azetidinyl which may be unsubstituted or substituted once with C 1 -C 6 alkyl; 
 het 1  is a heterocyclyl selected from: azetidinyl; pyrrolidinyl; piperazinyl; piperidinyl; morpholinyl; and oxetanyl; each of which may be unsubstituted or substituted once with R d  and once or twice with R g ; 
 R d  is: —(CR a1 R a2 ) p -het 2 ; —(CR a1 R a2 ) q —NR e R f ; or —(CR a1 R a2 ) p —C 3-6 cycloalkyl wherein the C 3-6 cycloalkyl moiety is substituted once with —NR e R f ; 
 p is from 0 to 2; 
 q is from 0 to 4; 
 R e  is: hydrogen; or C 1 -C 6 alkyl; 
 R f  is: hydrogen; C 1 -C 6 alkyl; or —CH 2 C 2 N(CH 3 ) 2 ; 
 each R g  is: C 1 -C 6 alkyl; or halo; and 
 Het 2  is a heterocycle selected from: tetrahydropyranyl; azetidinyl; and pyrrolidinyl; each of which may be unsubstituted or substituted once with C 1 -C 6 alkyl or —NR e R f . 
 
     
     
         2 . The compound of  claim 1  or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 1  is —(CHR a ) m -het 1 ; or —(CHR a ) n —NR b R c , wherein the het 1  may be unsubstituted or substituted once with R d . 
     
     
         3 . The compound of  claim 1  or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 2  is: chloro; difluoromethoxy; methylethio; or cyclopropyl. 
     
     
         4 . The compound of  claim 1  or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 3 , R 4 , R 5 , R 6  and R a  are hydrogen. 
     
     
         5 . The compound of  claim 1  or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 2  and R 6  together with the atoms to which they are attached form a six-membered ring containing two heteroatoms each independently selected from O, N and S. 
     
     
         6 . The compound of  claim 1  or a stereoisomer or pharmaceutically acceptable salt thereof, wherein het 1  is azetidinyl, which may be unsubstituted or substituted once with R d . 
     
     
         7 . The compound of  claim 1 , wherein R is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a stereoisomer or pharmaceutically acceptable salt thereof. 
     
     
         8 . The compound of  claim 1 , wherein the compound is of formula (II) 
       
         
           
           
               
               
           
         
       
       or a stereoisomer or pharmaceutically acceptable salt thereof. 
     
     
         9 . The compound of  claim 1 , wherein the compound is of formula (IV) 
       
         
           
           
               
               
           
         
       
       or a stereoisomer or pharmaceutically acceptable salt thereof, 
       wherein X is —O— or —S—, and R g  is hydrogen or C 1 -C 6 alkyl. 
     
     
         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 comprising:
 (a) a first pharmaceutical composition comprising a compound of  claim 1  or a stereoisomer or 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.