Heteroaryl compounds, solid forms, preparation methods and uses thereof

Abstract

Provided herein are compounds, crystalline free forms, crystalline salt forms, and pharmaceutical compositions of Compound 1. Also provided are methods of preparing and methods of using the same, e.g., for inhibiting a kinase and/or for treating various diseases or disorders, such as autoimmune diseases.

1 . A compound having the following formula, or a pharmaceutically acceptable salt thereof or a hydrate or a solvate of the same: 
       
         
           
           
               
               
           
         
         which is in a crystalline form. 
       
     
     
         2 . (canceled) 
     
     
         3 . The compound of  claim 1 , which is in a crystalline Form I, characterized by (1) an X-ray powder diffraction (XRPD) pattern having one or more (e.g., 2, 4, 6, 8, or 10) of the following peaks: 7.5°, 11.7°, 20.9°, 22.3°, 23.6°, 24.8°, 25.3°, 26.5°, 27.0° and 30.2° (2 theta, 0.2°); (2) an XRPD pattern substantially the same as shown in  FIG.  1   a   ; (3) a Differential Scanning Calorimetry (DSC) pattern substantially the same as shown in  FIG.  1   b   ; or any combination thereof (e.g., (1) and (3), or (2) and (3)). 
     
     
         4 . The compound of  claim 1 , which is in a crystalline Form II, characterized by (1) an X-ray powder diffraction (XRPD) pattern having one or more (e.g., 2, 4, 6, 8, or 10) of the following peaks: 7.10, 7.7°, 11.10, 12.3°, 20.4°, 21.7°, 22.7°, 24.7°, 26.9° and 27.5° (2 theta, 0.2°); (2) an XRPD pattern substantially the same as shown in  FIG.  2   a   ; (3) a Differential Scanning Calorimetry (DSC) pattern substantially the same as shown in  FIG.  2   b   ; or any combination thereof (e.g., (1) and (3), or (2) and (3)). 
     
     
         5 . The compound of  claim 1 , which is in a crystalline Form III, characterized by (1) an X-ray powder diffraction (XRPD) pattern having one or more (e.g., 2, 4, 6, 8, or 10) of the following peaks: 7.0°, 9.7°,  14 . 10 , 14.5°, 17.2°, 18.2°, 19.6°, 21.3°, 24.10, and 27.00 (2 theta, 0.2°); (2) an XRPD pattern substantially the same as shown in  FIG.  3   a   ; (3) a Differential Scanning Calorimetry (DSC) pattern substantially the same as shown in  FIG.  3   b   ; or any combination thereof (e.g., (1) and (3), or (2) and (3)). 
     
     
         6 . The compound of  claim 1 , which is in a crystalline Form IV, characterized by (1) an X-ray powder diffraction (XRPD) pattern having one or more (e.g., 2, 4, 6, 8, or 9) of the following peaks: 5.6°, 7.6°, 11.3°, 15.2°, 21.0°, 21.7°, 22.8°, 24.0° and 26.8° (2 theta, +0.2°); (2) an XRPD pattern substantially the same as shown in  FIG.  4   a   ; (3) a Differential Scanning Calorimetry (DSC) pattern substantially the same as shown in  FIG.  4   b   ; or any combination thereof (e.g., (1) and (3), or (2) and (3)). 
     
     
         7 . The compound of  claim 1 , which is in a crystalline Form V, characterized by (1) an X-ray powder diffraction (XRPD) pattern having one or more (e.g., 2, 4, 6, 8, or 10) of the following peaks: 4.8°, 8.7°, 9.7°, 12.6°, 14.7°, 17.6°, 20.8°, 24.6°, 25.5° and 27.6° (2 theta, 0.2°); (2) an XRPD pattern substantially the same as shown in  FIG.  5   a   ; (3) a Differential Scanning Calorimetry (DSC) pattern substantially the same as shown in  FIG.  5   b   ; or any combination thereof (e.g., (1) and (3), or (2) and (3)). 
     
     
         8 . (canceled) 
     
     
         9 . (canceled) 
     
     
         10 . The compound of  claim 1 , which is in a crystalline Form VIII, characterized by (1) an X-ray powder diffraction (XRPD) pattern having one or more (e.g., 2, 4, 6, 8, or 10) of the following peaks: 6.7°, 7.4°, 9.4°, 13.6°, 18.7°, 19.0°, 20.8°, 21.9°, 23.6° and 35.7° (2 theta, 0.2°); (2) an XRPD pattern substantially the same as shown in  FIG.  8   a   ; (3) a Differential Scanning Calorimetry (DSC) pattern substantially the same as shown in  FIG.  8   b   ; or any combination thereof (e.g., (1) and (3), or (2) and (3)). 
     
     
         11 . (canceled) 
     
     
         12 . The compound of  claim 1 , which is in a crystalline Form X, characterized by (1) an X-ray powder diffraction (XRPD) pattern having one or more (e.g., 2, 4, 6, 8, or 9) of the following peaks: 7.4°, 7.9°, 9.4°, 11.7°, 20.7°, 22.0°, 22.6°, 23.6° and 26.4° (2 theta, +0.2°); (2) an XRPD pattern substantially the same as shown in  FIG.  10   a   ; (3) a Differential Scanning Calorimetry (DSC) pattern substantially the same as shown in  FIG.  10   b   ; or any combination thereof (e.g., (1) and (3), or (2) and (3)). 
     
     
         13 .- 30 . (canceled) 
     
     
         31 . The compound of  claim 1 , which is substantially pure. 
     
     
         32 . A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt or hydrate or solvate of  claim 1 , and optionally a pharmaceutically acceptable excipient. 
     
     
         33 . A method of modulating the function of IL-12, IL-23 and/or interferon-alpha in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound or pharmaceutically acceptable salt or hydrate or solvate of  claim 1 . 
     
     
         34 . A method of treating or preventing a proliferative, metabolic, allergic, autoimmune and/or inflammatory disease or disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound or pharmaceutically acceptable salt or hydrate or solvate of  claim 1 . 
     
     
         35 .- 38 . (canceled) 
     
     
         39 . A method of producing Compound 1, comprising:
 Step 4: deprotecting Compound 1-4 to produce Compound 1   
       
         
           
           
               
               
           
         
       
     
     
         40 . The method of  claim 39 , comprising:
 Step 3: oxidizing Compound 1-3 to produce Compound 1-4   
       
         
           
           
               
               
           
         
       
     
     
         41 . The method of  claim 39 , comprising:
 Step 2: acylating Compound 1-2 with cyclopropanecarbonyl chloride to produce Compound 1-3;   
       
         
           
           
               
               
           
         
       
     
     
         42 . The method of  claim 39 , comprising:
 Step 1: reacting Compound 1-1 with (2,4-dimethoxyphenyl) methaneamine to produce Compound 1-2;   
       
         
           
           
               
               
           
         
       
     
     
         43 . The method of  claim 39 , wherein Step 4 comprises deprotecting Compound 1-4 with an acid, such as trifluoroacetic acid. 
     
     
         44 . The method of  claim 40 , wherein Step 3 comprises oxidizing Compound 1-3 with potassium peroxomonosulfate as an oxidizing agent. 
     
     
         45 . The method of  claim 41 , wherein Step 2 is carried out at a temperature of about 50-80° C., preferably about 60-70° C., and more preferably at about 65° C. 
     
     
         46 . The method of  claim 42 , wherein Step 1 is carried out in the presence of cesium fluoride in N-methylpyrrolidone.