PROCESSES FOR THE PREPARATION OF (3S,4R)-3-ETHYL-4-(3H-IMIDAZO[1,2-alpha]PYRROLO[2,3-e]-PYRAZIN-8-YL)-N-(2,2,2-TRIFLUOROETHYL)PYRROLIDINE-1-CARBOXAMIDE AND SOLID STATE FORMS THEREOF

Abstract

The present disclosure relates to processes for preparing (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, solid state forms thereof, and corresponding pharmaceutical compositions, methods of treatment (including treatment of rheumatoid arthritis), kits, methods of synthesis, and products-by-process.

1 . A solid state form of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, wherein the solid state form is selected from the group consisting of:
 a) a crystalline hydrate of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide;   b) a crystalline hemihydrate of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide;   c) a crystalline hydrate of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide having an X-ray powder diffraction pattern characterized by peaks at 13.4±0.2, 15.1±0.2, and 21.7±0.2 degrees two theta when measured at about 25° C. with monochromatic Kα1 radiation;   d) a crystalline hydrate of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide wherein the crystalline hydrate has at least one characteristic selected from the group consisting of:
 i) an X-ray powder diffraction pattern substantially as shown in  FIG. 3C : 
 ii) a thermogravimetric analysis profile substantially as shown in  FIG. 4E ; 
 iii) a differential scanning calorimetry profile substantially as shown in  FIG. 5C ; 
 iv) a moisture sorption isotherm profile substantially as shown in  FIG. 6B , 
 v) an orthorhombic lattice type that has a P2 1 2 1 2 1  space group, a unit cell a value of about 12.7 Å, a unit cell b value of about 13.1 Å, and a unit cell c value of about 22.6 Å; and 
 vi) any combination of i) to v); 
   e) a crystalline hydrate of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide having an X-ray powder diffraction pattern characterized by peaks at 3.1±0.2, 9.3±0.2, and 12.0±0.2 degrees two theta when measured at about 25° C. with monochromatic Kα1 radiation;   f) a crystalline hydrate of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, wherein the crystalline hydrate has at least one characteristic selected from the group consisting of:
 vii) an X-ray powder diffraction pattern substantially as shown in  FIG. 3B ; 
 viii) a thermogravimetric analysis profile substantially as shown in  FIG. 4D ; 
 ix) a differential scanning calorimetry profile substantially as shown in  FIG. 5B ; and 
 x) any combination of vii) to ix); 
   g) amorphous freebase (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide;   h) a crystalline anhydrate of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide;   i) a crystalline anhydrate of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide having an X-ray powder diffraction pattern characterized by peaks at 8.0±0.2, 9.7±0.2, 14.2±0.2, 14.5±0.2, and 20.3±0.2 degrees two theta when measured at about 25° C. with monochromatic Kα1 radiation; and   j) a crystalline anhydrate of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, wherein the crystalline anhydrate has at least one characteristic selected from the group consisting of:
 xi) an X-ray powder diffraction pattern substantially as shown in  FIG. 3J ; 
 xii) a thermogravimetric analysis profile substantially as shown in  FIG. 4I : 
 xiii) a differential scanning calorimetry profile substantially as shown in  FIG. 5E ; 
 xiv) a moisture sorption isotherm profile substantially as shown in  FIG. 6D ; 
 xv) an orthorhombic lattice type that has a P2 1 212 space group, a unit cell a value of about 43.8 k, a unit cell b value of about 8.6 k, and a unit cell c value of about 9.2 k; and 
 xvi) any combination of xi) to xv). 
   
     
     
         2 - 10 . (canceled) 
     
     
         11 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a solid state form of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, wherein the solid state form is a solid state form of  claim 1 . 
     
     
         12 . The pharmaceutical composition of  claim 11 , wherein greater than about 90% by weight of the (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide in the composition is selected from the group consisting of:
 a) a crystalline hydrate of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)-pyrrolidine-1-carboxamide having an X-ray powder diffraction pattern characterized by peaks at 13.4±0.2, 15.1±0.2, and 21.7±0.2 degrees two theta when measured at about 25° C. with monochromatic Kα1 radiation;   b) a crystalline hydrate of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)-pyrrolidine-1-carboxamide having an X-ray powder diffraction pattern characterized by peaks at 3.1±0.2, 9.3±0.2, and 12.0±0.2 degrees two theta when measured at about 25° C. with monochromatic Kα1 radiation;   c) amorphous freebase (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide; and   d) a crystalline anhydrate of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)-pyrrolidine-1-carboxamide having an X-ray powder diffraction pattern characterized by peaks at 8.0±0.2, 9.7±0.2, 14.2±0.2, 14.5±0.2, and 20.3±0.2 degrees two theta when measured at about 25° C. with monochromatic Kα1 radiation.   
     
     
         13 . A pharmaceutical composition comprising (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide tartrate, from about 10 w/w % to about 35 w/w % of an organic acid selected from the group consisting of tartaric acid, fumaric acid, citric acid, succinic acid, malic acid, and combinations thereof, and a pharmaceutically acceptable carrier, wherein:
 a) the tartrate is crystalline (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide tartrate tetrahydrate;   b) the tartrate has an X-ray powder diffraction pattern characterized by peaks at 3.9±0.2, 6.8±0.2, and 14.1±0.2 degrees two theta when measured at about 25° C. with monochromatic Kα1 radiation; or   c) the tartrate has at least one characteristic selected from the group consisting of
 i) an X-ray powder diffraction pattern substantially as shown in  FIG. 3D ; 
 ii) a thermogravimetric analysis profile substantially as shown in  FIG. 4F ; 
 iii) a differential scanning calorimetry profile substantially as shown in  FIG. 5D ; 
 iv) a moisture sorption isotherm profile substantially as shown in  FIG. 6C ; and 
 v) any combination of i) to iv). 
   
     
     
         14 - 17 . (canceled) 
     
     
         18 . A pharmaceutical composition comprising a therapeutically effective amount of the (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide of any on of  claim 1  for use in treating:
 a JAK-1 associated condition in a subject suffering from or susceptible to the condition; or 
 a condition selected from the group consisting of rheumatoid arthritis, juvenile idiopathic arthritis, Crohn's disease, ulcerative colitis, psoriasis, plaque psoriasis, nail psoriasis, psoriatic arthritis, ankylosing spondylitis, alopecia areata, hidradenitis suppurativa, atopic dermatitis, and systemic lupus erythematosus in a subject suffering from or susceptible to the condition. 
 
     
     
         19 . (canceled) 
     
     
         20 . The pharmaceutical composition of  claim 18 , wherein the therapeutically effective amount of the (3 S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide is selected from the group consisting of 7.5 mg once daily, 15 mg once daily, 30 mg once daily, and 45 mg once daily. 
     
     
         21 . The pharmaceutical composition of  claim 20  wherein the (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide is the Freebase Hydrate Form C. 
     
     
         22 . A method for the preparation of the crystalline hydrate having an X-ray powder diffraction pattern characterized by peaks at 13.4±0.2, 15.1±0.2, and 21.7±0.2 degrees two theta when measured at about 25° C. with monochromatic Kα1 radiation of  claim 1 , the method comprising:
 dissolving (3 S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide in a solvent or mixture of solvents; and 
 initiating crystallization to provide the crystalline hydrate. 
 
     
     
         23 - 26 . (canceled) 
     
     
         27 . A method for the preparation of the crystalline hydrate having an X-ray powder diffraction pattern characterized by peaks at 3.1±0.2, 9.3±0.2, and 12.0±0.2 degrees two theta when measured at about 25° C. with monochromatic Kα1 radiation of  claim 1 , the method comprising:
 dissolving (3 S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide in a solvent or mixture of solvents comprising an anti-solvent; and 
 maintaining the solvent or mixture of solvents at a temperature less than about 15° C. for an amount of time sufficient to initiate crystallization of the crystalline hydrate. 
 
     
     
         28 . (canceled) 
     
     
         29 . A method for the preparation of the amorphous freebase (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide of  claim 1 , the method comprising dehydrating a crystalline hydrate of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide having an X-ray powder diffraction pattern characterized by peaks at 3.1±0.2, 9.3±0.2, and 12.0±0.2 degrees two theta when measured at about 25° C. with monochromatic Kα1 radiation to provide the amorphous freebase (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide. 
     
     
         30 . A method for the preparation of the amorphous freebase (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide of  claim 1 , the method comprising:
 dissolving (3 S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide in a solvent or mixture of solvents; and   adjusting the pH of the solvent or mixture of solvents to a pH greater than about 8 to initiate precipitation of the amorphous freebase (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide.   
     
     
         31 . A method for the preparation of the crystalline anhydrate of  claim 1 , the method comprising:
 dissolving (3 S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide in a solvent or mixture of solvents, wherein the solvent or mixture of solvents comprises less than about 0.15 wt. % of water; and   initiating crystallization to provide the crystalline anhydrate.   
     
     
         32 - 33 . (canceled) 
     
     
         34 . A crystalline hydrate of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide prepared by the process of  claim 22 . 
     
     
         35 - 37 . (canceled) 
     
     
         38 . A process for preparing (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically acceptable salt thereof, the process comprising:
 a) reacting a compound of formula (I)   
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof with trimethylsulfoxonium chloride to form a compound of formula (II) 
       
       
         
           
           
               
               
           
         
         wherein PG is a protecting group; 
         b) contacting the compound of formula (II) with LiX and a sulfonic acid to form a compound of formula (III) 
       
       
         
           
           
               
               
           
         
         wherein X is Br or C1; 
         c) reacting the compound of formula (III) with a compound of formula (IV) 
       
       
         
           
           
               
               
           
         
         to produce a compound of formula (V) 
       
       
         
           
           
               
               
           
         
         wherein R 1  is selected from the group consisting of alkyl, aryl, and —OR 2 ; R 2  is alkyl; and Ts is tosyl; 
         d) contacting the compound of formula (V) with a perfluoro acid anhydride and an organic base to form a compound of formula (VI) 
       
       
         
           
           
               
               
           
         
         e) deprotecting the compound of formula (VI) and forming a pharmaceutically acceptable salt of the compound of formula (VII): 
       
       
         
           
           
               
               
           
         
         f) reacting the pharmaceutically acceptable salt of the compound of formula (VII) with 2,2,2-trifluoroethylamine to produce (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide. 
       
     
     
         39 . (canceled) 
     
     
         40 . The process of  claim 38 , wherein the pharmaceutically acceptable salt of the compound of formula (I) is the compound of formula (Ib): 
       
         
           
           
               
               
           
         
         wherein the compound of formula (Ib) is prepared by: 
         (i) reacting carboxybenzyl-glycine ethyl ester with ethyl acrylate to form a compound of formula (VIII): 
       
       
         
           
           
               
               
           
         
         (ii) protecting the compound of formula (VIII) to form a compound of formula (IX): 
       
       
         
           
           
               
               
           
         
         wherein R 3  is selected from the group consisting of CF 3 SO 2 —; CH 3 SO 2 —; and tosyl; 
         (iii) contacting the compound of formula (IX) with one of ethyl boronic acid, ethyl magnesium bromide, or ethyl zinc chloride in the presence of a catalyst to form a compound of formula (X): 
       
       
         
           
           
               
               
           
         
         (iv) hydrolyzing the compound of formula (X) to produce the compound of formula (XI): 
       
       
         
           
           
               
               
           
         
         (v) converting the compound of formula (XI) to the compound of formula (XII): 
       
       
         
           
           
               
               
           
         
         (vi) contacting the compound of formula (XII) with dicyclohexylamine to form the compound of formula (Ib); 
         wherein Cbz is carboxybenzyl. 
       
     
     
         41 . The process of  claim 38 , wherein the pharmaceutically acceptable salt of the compound of formula (I) is the compound of formula (Ia): 
       
         
           
           
               
               
           
         
         wherein the compound of formula (Ia) is prepared by: 
         (i) hydrogenating ethyl pent-2-ynoate with a Lindlar catalyst to form (Z)-ethyl pent-2-enoate; 
         (ii) reacting (Z)-ethyl pent-2-enoate with N-(methoxymethyl)-N-(trimethylsilyl methyl)benzylamine to form a compound of formula (XIII) 
       
       
         
           
           
               
               
           
         
         (iii) deprotecting the compound of formula (XIII) to form a compound of formula (XIV) 
       
       
         
           
           
               
               
           
         
         (iv) hydrolyzing the compound of formula (XIV) to form a compound of formula (XV) 
       
       
         
           
           
               
               
           
         
         (v) reacting the compound of formula (XV) with N-benzyloxycarbonyloxy succinimide to form a compound of formula (XVI) 
       
       
         
           
           
               
               
           
         
         (vi) contacting the compound of formula (XVI) with (R)-1-(naphthalene-1-yl)ethanamine to form the compound of formula (Ia); 
         wherein Cbz is carboxybenzyl; Bn is benzyl; and Et is ethyl. 
       
     
     
         42 . A process for preparing (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically acceptable salt thereof, the process comprising:
 a) converting a compound of formula (XIa):   
       
         
           
           
               
               
           
         
         to a compound of formula (I): 
       
       
         
           
           
               
               
           
         
         wherein PG is a protecting group; 
         b) reacting the compound of formula (I) with trimethylsulfoxonium chloride to form a compound of formula (II) 
       
       
         
           
           
               
               
           
         
         c) contacting the compound of formula (II) with an anhydrous source of HBr or HCl to form a compound of formula (III) 
       
       
         
           
           
               
               
           
         
         wherein X is Br or Cl; 
         d) reacting the compound of formula (III) with a compound of formula (IV) 
       
       
         
           
           
               
               
           
         
         to produce a compound of formula (V) 
       
       
         
           
           
               
               
           
         
         wherein R 1  is selected from the group consisting of alkyl, aryl, and —OR 2 ; R 2  is alkyl; and Ts is tosyl; 
         e) contacting the compound of formula (V) with a perfluoro acid anhydride and an organic base to form a compound of formula (VI) 
       
       
         
           
           
               
               
           
         
         f) deprotecting the compound of formula (VI) and forming a pharmaceutically acceptable salt of the compound of formula (VII): 
       
       
         
           
           
               
               
           
         
       
       and
 g) reacting the pharmaceutically acceptable salt of the compound of formula (VII) with 2,2,2-trifluoroethylamine to produce (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide. 
 
     
     
         43 - 45 . (canceled) 
     
     
         46 . The process of  claim 42 , wherein:
 step b) comprises reacting the compound of formula (I) with trimethylsulfoxonium chloride in the presence of carbonyldiimidazole and a strong base to form the compound of formula (II);   step c) is conducted in tetrahydrofuran, and comprises contacting the compound of formula (II) with an anhydrous source of HBr to form the compound of formula (III);   step d) comprises reacting the compound of formula (III) with the compound of formula (IV) in the presence of lithium tert-butoxide to produce the compound of formula (V);   step f) comprises contacting the compound of formula (VII) with an acid to form the pharmaceutically acceptable salt of the compound of formula (VII);   the protecting group is carboxybenzyl;   the anhydrous source of HBr or HCl comprises no more than 0.2% water (by volume); or   the pharmaceutically acceptable salt of the compound of formula (VII) is selected from the group consisting of:   
       
         
           
           
               
               
           
         
       
     
     
         47 - 48 . (canceled) 
     
     
         49 . The process of  claim 42 , further comprising preparing a crystalline hydrate of (3 S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, the process comprising:
 dissolving (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide in a solvent or mixture of solvents; and   initiating crystallization to provide the crystalline hydrate;   wherein the crystalline hydrate is a hemihydrate; and   wherein the crystalline hemihydrate has an X-ray powder diffraction pattern characterized by peaks at 13.4±0.2, 15.1±0.2, and 21.7±0.2 degrees two theta when measured at about 25° C. with monochromatic Kα1 radiation.   
     
     
         50 . (canceled) 
     
     
         51 . A crystalline hydrate of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide prepared by the process of  claim 49 . 
     
     
         52 . The process of  claim 42 , further comprising preparing a crystalline hydrate of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, the process comprising:
 dissolving (3 S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide in a solvent or mixture of solvents comprising an anti-solvent; and   maintaining the solvent or mixture of solvents at a temperature less than about 15° C. for an amount of time sufficient to initiate crystallization of the crystalline hydrate;   wherein the crystalline hydrate has an X-ray powder diffraction pattern characterized by peaks at 3.1±0.2, 9.3±0.2, and 12.0±0.2 degrees two theta when measured at about 25° C. with monochromatic Kα1 radiation.   
     
     
         53 . (canceled) 
     
     
         54 . The process of  claim 42 , further comprising preparing an amorphous freebase (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, the process comprising:
 a) preparing a crystalline hydrate of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide by dissolving (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide in a solvent or mixture of solvents comprising an anti-solvent; and maintaining the solvent or mixture of solvents at a temperature less than about 15° C. for an amount of time sufficient to initiate crystallization of the crystalline hydrate; wherein the crystalline hydrate has an X-ray powder diffraction pattern characterized by peaks at 3.1±0.2, 9.3±0.2, and 12.0±0.2 degrees two theta when measured at about 25° C. with monochromatic Kα1 radiation; and   b) dehydrating the crystalline hydrate to provide the amorphous freebase (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide.   
     
     
         55 . The process of  claim 42 , further comprising preparing an amorphous freebase (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, the process comprising:
 dissolving (3 S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide in a solvent or mixture of solvents; and   adjusting the pH of the solvent or mixture of solvents to a pH greater than about 8 to initiate precipitation of the amorphous freebase (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide.   
     
     
         56 . (canceled) 
     
     
         57 . The process of  claim 42 , further comprising preparing a crystalline anhydrate of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, the process comprising:
 dissolving (3 S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide in a solvent or mixture of solvents, wherein the solvent or mixture of solvents comprises less than about 0.15 wt. % of water; and   initiating crystallization to provide the crystalline anhydrate.   
     
     
         58 . (canceled) 
     
     
         59 . A process for preparing (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically acceptable salt thereof, the process comprising:
 a) reacting a compound of formula (Ib)   
       
         
           
           
               
               
           
         
         with trimethylsulfoxonium chloride in the presence of carbonyldiimidazole and a strong base to form a compound of formula (IIa) 
       
       
         
           
           
               
               
           
         
         wherein Cbz is carboxybenzyl; 
         b) contacting the compound of formula (IIa) with lithium bromide and a sulfonic acid to form a compound of formula (IIIa) 
       
       
         
           
           
               
               
           
         
         c) reacting the compound of formula (IIIa) with a compound of formula (IVa) 
       
       
         
           
           
               
               
           
         
         in the presence of lithium tert-butoxide to produce a compound of formula (Va) 
       
       
         
           
           
               
               
           
         
         wherein R 2  is methyl or ethyl; and Ts is tosyl; 
         d) contacting the compound of formula (Va) with a perfluoro acid anhydride and an organic base to form a compound of formula (VIa) 
       
       
         
           
           
               
               
           
         
         e) deprotecting the compound of formula (VIa) to form a compound of formula (VII) 
       
       
         
           
           
               
               
           
         
         f) contacting the compound of formula (VII) with hydrochloric acid to form a compound of formula (VIIa) 
       
       
         
           
           
               
               
           
         
         g) reacting the compound of formula (VIIa) with 2,2,2-trifluoroethylamine in the presence of carbonyldiimidazole to produce (3 S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide. 
       
     
     
         60 . The process of  claim 59 , wherein:
 the strong base of step a) is potassium tert-butoxide;   the sulfonic acid of step b) is selected from the group consisting of methanesulfonic acid and p-toulenesulfonic acid;   the perfluoro acid anhydride of step d) is trifluoroacetic anhydride;   the organic base of step d) is pyridine;   the compound of formula (VIa) is deprotected using hydrogen gas and Pd(OH 2 )/C; and   the reaction of step g) is conducted in the presence of dipotassium phosphate and potassium hydroxide.   
     
     
         61 . A crystalline hydrate of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide prepared by the process of  claim 59 . 
     
     
         62 - 68 . (canceled) 
     
     
         69 . A pharmaceutical composition comprising:
 a) about 7.5 mg of (3 S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (Compound 1) freebase, or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or a crystalline anhydrate of Compound 1 in an amount sufficient to deliver to the subject about 7.5 mg of Compound 1 freebase equivalent; or   b) about 15 mg of Compound 1 freebase, or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or a crystalline anhydrate of Compound 1 in an amount sufficient to deliver to the subject about 15 mg of Compound 1 freebase equivalent; or   c) about 30 mg of Compound 1 freebase, or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or a crystalline anhydrate of Compound 1 in an amount sufficient to deliver to the subject about 30 mg of Compound 1 freebase equivalent; or   d) about 45 mg of Compound 1 freebase, or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or a crystalline anhydrate of Compound 1 in an amount sufficient to deliver to the subject about 45 mg of Compound 1 freebase equivalent,   wherein the pharmaceutical composition is used for:
 i) treating an adult subject having moderate to severely active rheumatoid arthritis, 
 ii) treating an adult subject having moderate to severely active rheumatoid arthritis, wherein the adult subject has had an inadequate response or tolerance to one or more disease-modifying antirheumatic drugs (DMARDS); 
 iii) treating structural damage associated with rheumatoid arthritis in an adult subject, such that the structural damage in the adult subject is inhibited or lessened; 
 iv) treating moderate to severely active rheumatoid arthritis in an adult subject, wherein the subject has symptoms selected from the group consisting of at least 6 swollen joints, at least 6 tender joints, and combinations thereof prior to treating; or 
 v) reducing signs and symptoms of rheumatoid arthritis in an adult subject with moderately to severely active rheumatoid arthritis. 
   
     
     
         70 - 78 . (canceled) 
     
     
         79 . The pharmaceutical composition of  claim 69 , wherein the crystalline hydrate of Compound 1 is administered in an amount sufficient to deliver to the subject about 15 mg of Compound 1 freebase equivalent, and administration of the crystalline hydrate achieves:
 a) a mean peak plasma concentration (C max ) for Compound 1 of from about 25 to about 70 ng/mL;   b) a time to peak plasma concentration (Tmax) for Compound 1 of from about 1.0 to about 6.0 hours;   c) a mean area under the plasma concentration time curve from time 0 to infinity (AUC inf ) for Compound 1 of from about 220 to about 450 ng*hours/mL;   d) a harmonic mean terminal half-life (t 1/2 ) for Compound 1 of from about 10.0 to about 14.0 hours;   e) a mean peak steady-state plasma concentration (C max,ss ) for Compound 1 of from about 27 to about 55 ng/mL;   f) a time to peak plasma concentration at steady-state (T max,ss ) of from about 1.5 to about 6.0 hours;   g) a mean steady-state area under the plasma concentration time curve from time 0 to 24 hours (AUC 24,ss ) for Compound 1 of from about 240 to about 325 ng*hours/mL;   h) a harmonic mean steady-state terminal half-life (t 1/2,ss ) for Compound 1 of from about 9.4 to about 10.5 hours;   i) a mean minimum steady-state plasma concentration (C min,ss ) for Compound 1 of from about 2.8 to about 3.2 ng/mL;   or any combination thereof.   
     
     
         80 - 89 . (canceled) 
     
     
         90 . The pharmaceutical composition of  claim 69 , wherein the crystalline hydrate of Compound 1 is administered in an amount sufficient to deliver to the subject about 30 mg of Compound 1 freebase equivalent, and administration of the crystalline hydrate achieves:
 a) a mean C max  for Compound 1 of from about 55 to about 85 ng/mL;   b) a T max  for Compound 1 of from about 1.0 to about 8.0 hours;   c) a mean AUC inf  for Compound 1 of from about 483 to about 660 ng-hours/mL;   d) a harmonic mean terminal half-life (t 1/2 ) for Compound 1 of from about 9.0 to about 12.0 hours;   e) a mean C max,ss  for Compound 1 of from about 65 to about 86 ng/mL;   f) a mean AUC 24,ss  for Compound 1 of from about 485 to about 658 n2-hours/mL;   g) a T max,ss  of from about 1.5 to about 6.0 hours;   h) a harmonic mean t 1/2,ss  for Compound 1 of from about 10.0 to about 14.5 hours;   i) a mean C min,ss  for Compound 1 of from about 3.5 to about 5.3 n2/mL; or any combination thereof.   
     
     
         91 - 99 . (canceled) 
     
     
         100 . The pharmaceutical composition of  claim 69 , wherein the crystalline hydrate is Freebase Hydrate Form C. 
     
     
         101 . A pharmaceutical composition comprising a crystalline hydrate or a crystalline anhydrate of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (Compound 1) and a pharmaceutically acceptable carrier, wherein the composition comprises the crystalline hydrate or the crystalline anhydrate in an amount sufficient to deliver about 7.5 mg of Compound 1 freebase equivalent or about 15 mg of Compound 1 freebase equivalent or about 30 mg of Compound 1 freebase equivalent or about 45 mg of Compound 1 freebase equivalent. 
     
     
         102 . The pharmaceutical composition of  claim 101 , comprising about 7.5 mg, or about 15 mg, or about 30 mg, or about 45 mg of the crystalline hydrate or the crystalline anhydrate. 
     
     
         103 . The composition of  claim 101 , wherein the crystalline hydrate is Freebase Hydrate Form C. 
     
     
         104 . The composition of  claim 103 , wherein the composition comprises about 15 mg of Freebase Hydrate Form C, and administration of the composition to a subject provides:
 (a) a mean C max  for Compound 1 of from about 25 to about 70 ng/mL;   (b) a T max  for Compound 1 of from about 1.0 hours to about 6.0 hours;   (c) a harmonic mean t 1/2  for Compound 1 of from about 10.0 to about 14.0 hours;   (d) a mean AUC inf  for Compound 1 of from about 220 to about 450 ng-hours/mL;   (e) a mean C max,ss  for Compound 1 of from about 27 to about 55 ng/mL;   (f) a mean AUC 24,ss  for Compound 1 of from about 240 to about 325 ng-hours/mL;   (g) a T max,ss  for Compound 1 of from about 1.5 to about 6.0 hours;   (h) a mean C min,ss  for Compound 1 of from about 2.8 to about 3.2 ng/mL;   (i) a harmonic mean t 1/2,ss  for Compound 1 of from about 9.4 to about 10.5 hours;   or any combination thereof.   
     
     
         105 . The composition of  claim 103 , wherein the composition comprises about 30 mg of Freebase Hydrate Form C, and administration of the composition to a subject provides:
 (a) a mean C max  for Compound 1 of from about 55 to about 85 ng/mL;   (b) a T max  for Compound 1 of from about 1.0 hours to about 8.0 hours;   (c) a harmonic mean t 1/2  for Compound 1 of from about 9.0 to about 12.0 hours;   (d) a mean AUC inf  for Compound 1 of from about 483 to about 660 ng-hours/mL;   (e) a mean C max,ss  for Compound 1 of from about 65 to about 85 ng/mL;   (f) a mean AUC 24,ss  for Compound 1 of from about 485 to about 658 ng-hours/mL;   (g) a T max,ss  for Compound 1 of from about 1.5 to about 6.0 hours;   (h) a mean C min,ss  for Compound 1 of from about 3.5 to about 5.3 ng/mL;   (i) a harmonic mean t 1/2,ss  for Compound 1 of from about 10.0 to about 14.5 hours;   or any combination thereof.   
     
     
         106 . (canceled) 
     
     
         107 . The pharmaceutical composition of  claim 101 , wherein the crystalline hydrate, or the crystalline anhydrate is in a once daily extended release formulation. 
     
     
         108 . An extended release formulation for oral administration comprising (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (Compound 1) or a pharmaceutically acceptable salt thereof, a hydrophilic polymer, and a pH modifier, wherein the hydrophilic polymer, in contact with water, forms a gel layer that provides an environment suitable for Compound 1 and the pH modifier to dissolve. 
     
     
         109 - 113 . (canceled) 
     
     
         114 . A process for preparing a pharmaceutical composition, the process comprising:
 (a) combining (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (Compound 1) or a pharmaceutically acceptable salt thereof, or a solid state form of Compound 1, and at least a portion of one additional composition component to form a dry granulation mixture;   (b) contacting the dry granulation mixture with a granulation fluid to form a wet granulation mixture;   (c) drying the wet granulation mixture to form a granulated material;   (d) milling the granulated material to form a milled granulated material;   (e) combining the milled granulation material with any remaining composition components; and   (f) compressing the composition to form the pharmaceutical composition.   
     
     
         115 . A once-daily extended release formulation comprising about 15 mg of a crystalline hydrate of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide; a release control polymer; and about 20 w/w % of tartaric acid, wherein the release control polymer comprises hydroxypropylmethyl cellulose, and the hydrate is Freebase Hydrate Form C. 
     
     
         116 . A once-daily extended release formulation comprising about 30 mg of a crystalline hydrate of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide; a release control polymer; and about 20 w/w % of tartaric acid, wherein the release control polymer comprises hydroxypropylmethyl cellulose, and the hydrate is Freebase Hydrate Form C.