Pyrazolo and triazolo bicyclic compounds as jak kinase inhibitors

Abstract

The invention provides compounds of formula (I):or a pharmaceutically-acceptable salt thereof, wherein the variables are defined in the specification, that are inhibitors of JAK kinases, particularly JAK3. The invention also provides crystalline forms, pharmaceutical compositions comprising such compounds, methods of using such compounds to treat gastrointestinal and other inflammatory diseases, and processes and intermediates useful for preparing such compounds.

1 - 46 . (canceled) 
     
     
         47 . A method for inhibiting JAK3 in a mammal, the method comprising administering to the mammal a compound of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         48 . The method of  claim 47 , wherein the compound or the pharmaceutically acceptable salt is administered orally. 
     
     
         49 . The method of  claim 47 , wherein the mammal is a human. 
     
     
         50 . The method of  claim 47 , where the compound is administered as a crystalline freebase form. 
     
     
         51 . The method of  claim 50 , wherein crystalline freebase form is characterized by a powder X-ray diffraction pattern comprising diffraction peaks at 2θ values of 9.67±0.20, 11.61±0.20, 17.61±0.20, 18.88±0.20, and 23.33±0.20. 
     
     
         52 . The method of  claim 51 , wherein the powder X-ray diffraction pattern further comprises additional diffraction peaks at 2θ values of 4.82±0.20, 15.69±0.20, and 16.19±0.20. 
     
     
         53 . The method of  claim 52 , wherein the powder X-ray diffraction pattern further comprises two or more additional diffraction peaks at 2θ values selected from 11.92±0.20, 12.98±0.20, 13.23±0.20, 16.45±0.20, 16.67±0.20, 19.39±0.20, 19.96±0.20, 20.14±0.20, 22.14±0.20, 23.84±0.20, 24.06±0.20, 24.29±0.20, 25.31±0.20, 25.63±0.20, 27.06±0.20, 27.31±0.20, 30.10±0.20, and 30.53±0.20. 
     
     
         54 . The method of  claim 50 , wherein the crystalline freebase form is characterized by a powder X-ray diffraction pattern in which the peak positions are substantially in accordance with the peak positions of the pattern shown in  FIG. 9 . 
     
     
         55 . The method of  claim 50 , wherein the crystalline freebase form is characterized by a differential scanning calorimetry trace recorded at a heating rate of 10° C. per minute which shows a maximum in endothermic heat flow at a temperature between 198° C. and 204° C. 
     
     
         56 . The method of  claim 50 , wherein the crystalline freebase form is characterized by a differential scanning calorimetry trace recorded at a heating rate of 10° C. per minute which shows a maximum in endothermic heat flow with a peak at 201.3° C.±2° C. 
     
     
         57 . The method of  claim 50 , wherein the crystalline freebase form is characterized by a differential scanning calorimetry trace substantially in accordance with that shown in  FIG. 10 . 
     
     
         58 . A method for inhibiting JAK3 in a mammal, the method comprising administering to the mammal a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         59 . The method of  claim 58 , wherein the pharmaceutical composition is administered orally. 
     
     
         60 . The method of  claim 58 , wherein the mammal is a human. 
     
     
         61 . The method of  claim 58 , wherein the pharmaceutical composition is in unit dosage form. 
     
     
         62 . The method of  claim 61 , wherein the unit dosage form comprises about 1 mg to about 400 mg of the compound or the pharmaceutically acceptable salt thereof. 
     
     
         63 . The method of  claim 61 , wherein the unit dosage form comprises about 5 mg to about 300 mg of the compound or the pharmaceutically acceptable salt thereof. 
     
     
         64 . The method of any one of  claims 61  to  63 , wherein the unit dose form is a capsule, a tablet, or a pill. 
     
     
         65 . The method of  claim 58 , where the compound is administered as a crystalline freebase form. 
     
     
         66 . The method of  claim 65 , wherein the crystalline freebase form is characterized by a powder X-ray diffraction pattern comprising diffraction peaks at 20 values of 9.67±0.20, 11.61±0.20, 17.61±0.20, 18.88±0.20, and 23.33±0.20. 
     
     
         67 . The method of  claim 66 , wherein the powder X-ray diffraction pattern further comprises additional diffraction peaks at 2θ values of 4.82±0.20, 15.69±0.20, and 16.19±0.20. 
     
     
         68 . The method of  claim 67 , wherein the powder X-ray diffraction pattern further comprises two or more additional diffraction peaks at 2θ values selected from 11.92±0.20, 12.98±0.20, 13.23±0.20, 16.45±0.20, 16.67±0.20, 19.39±0.20, 19.96±0.20, 20.14±0.20, 22.14±0.20, 23.84±0.20, 24.06±0.20, 24.29±0.20, 25.31±0.20, 25.63±0.20, 27.06±0.20, 27.31±0.20, 30.10±0.20, and 30.53±0.20. 
     
     
         69 . The method of  claim 65 , wherein the crystalline freebase form is characterized by a powder X-ray diffraction pattern in which the peak positions are substantially in accordance with the peak positions of the pattern shown in  FIG. 9 . 
     
     
         70 . The method of  claim 65 , wherein the crystalline freebase form is characterized by a differential scanning calorimetry trace recorded at a heating rate of 10° C. per minute which shows a maximum in endothermic heat flow at a temperature between 198° C. and 204° C. 
     
     
         71 . The method of  claim 65 , wherein the crystalline freebase form is characterized by a differential scanning calorimetry trace recorded at a heating rate of 10° C. per minute which shows a maximum in endothermic heat flow with a peak at 201.3° C.±2° C. 
     
     
         72 . The method of  claim 65 , wherein the crystalline freebase form is characterized by a differential scanning calorimetry trace substantially in accordance with that shown in  FIG. 10 .