PROCESSES FOR THE PREPARATION 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 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.

We claim: 
     
         1 . 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. 
     
     
         2 . The crystalline hydrate of  claim 1 , wherein the hydrate is a hemihydrate. 
     
     
         3 . The crystalline hydrate of  claim 1  or  2  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. 
     
     
         4 . The crystalline hydrate of any one of  claims 1  to  3 , wherein the crystalline hydrate has at least one characteristic selected from the group consisting of
 a) an X-ray powder diffraction pattern substantially as shown in  FIG. 3C ; 
 b) a thermogravimetric analysis profile substantially as shown in  FIG. 4E ; 
 c) a differential scanning calorimetry profile substantially as shown in  FIG. 5C ; 
 d) a moisture sorption isotherm profile substantially as shown in  FIG. 6B ; 
 e) 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 
 f) any combination of a) to e). 
 
     
     
         5 . The crystalline hydrate of  claim 1  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. 
     
     
         6 . The crystalline hydrate of  claim 1  or  claim 5 , wherein the crystalline hydrate has at least one characteristic selected from the group consisting of:
 a) an X-ray powder diffraction pattern substantially as shown in  FIG. 3B ; 
 b) a thermogravimetric analysis profile substantially as shown in  FIG. 4D ; 
 c) a differential scanning calorimetry profile substantially as shown in  FIG. 5B ; and 
 d) any combination of a) to c). 
 
     
     
         7 . 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. 
     
     
         8 . 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. 
     
     
         9 . The crystalline anhydrate of  claim 8  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. 
     
     
         10 . The crystalline anhydrate of  claim 8  or  claim 9 , wherein the crystalline anhydrate has at least one characteristic selected from the group consisting of:
 a) an X-ray powder diffraction pattern substantially as shown in  FIG. 3J ; 
 b) a thermogravimetric analysis profile substantially as shown in  FIG. 4I ; 
 c) a differential scanning calorimetry profile substantially as shown in  FIG. 5E ; 
 d) a moisture sorption isotherm profile substantially as shown in  FIG. 6D ; 
 e) an orthorhombic lattice type that has a P2 1 2 1 2 space group, a unit cell a value of about 43.8 Å, a unit cell b value of about 8.6 Å, and a unit cell c value of about 9.2 Å; and 
 f) any combination of a) to e). 
 
     
     
         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 selected from the group consisting of:
 a) a crystalline hydrate of any of  claims 1  to  6 ;   b) 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 7 ; and   c) a crystalline anhydrate of any one of  claims 8  to  10 .   
     
     
         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. 
     
     
         14 . The pharmaceutical composition of  claim 13 , wherein 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. 
     
     
         15 . The pharmaceutical composition of  claim 13  or  claim 14 , wherein 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. 
     
     
         16 . The pharmaceutical composition of any one of  claims 13  to  15 , wherein the tartrate has at least one characteristic selected from the group consisting of:
 a) an X-ray powder diffraction pattern substantially as shown in  FIG. 3D ; 
 b) a thermogravimetric analysis profile substantially as shown in  FIG. 4F ; 
 c) a differential scanning calorimetry profile substantially as shown in  FIG. 5D ; 
 d) a moisture sorption isotherm profile substantially as shown in  FIG. 6C ; and 
 e) any combination of a) to d). 
 
     
     
         17 . The pharmaceutical composition of any one of  claims 13  to  16 , 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 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. 
     
     
         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 one of  claims 1  to  10  for use in treating a JAK-1 associated condition in a subject suffering from or susceptible to the condition. 
     
     
         19 . 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 one of  claims 1  to  10  for use in treating 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. 
     
     
         20 . The pharmaceutical composition of  claim 18  or  claim 19 , wherein the 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 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 of  claim 2  or  claim 3 , the method 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. 
 
     
     
         23 . The method of  claim 22 , wherein the initiating crystallization step comprises seeding the solvent or mixture of solvents with crystals of the crystalline hydrate of  claim 2  or  claim 3 . 
     
     
         24 . The method of  claim 22  or  claim 23 , wherein the initiating crystallization step comprises both mixing the solvent or mixture of solvents and seeding the solvent or mixture of solvents with crystals of the crystalline hydrate of  claim 2  or  claim 3 . 
     
     
         25 . The method of any one of  claims 22  to  24 , wherein the method comprises adding an anti-solvent to the solvent or mixture of solvents, and both seeding the solvent or mixture of solvents with crystals of the crystalline hydrate of  claim 2  or  claim 3  and mixing the solvent or mixture of solvents. 
     
     
         26 . The method of any one of  claims 22  to  25 , wherein the crystallization occurs in a wet mill. 
     
     
         27 . A method for the preparation of the crystalline hydrate of  claim 5 , the method 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 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 . The method of  claim 27 , wherein the process further comprises seeding the solvent or mixture of solvents with crystals of the crystalline hydrate of  claim 5 . 
     
     
         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 7 , the method comprising dehydrating the crystalline hydrate of  claim 5  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 7 , the method 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   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 8  or  claim 9 , the method 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, 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 . The method of  claim 31 , wherein the solvent or mixture of solvents has a water activity of about 2.4% or less. 
     
     
         33 . The method of  claim 31  or  claim 32 , wherein the initiating crystallization step comprises:
 a) mixing the solvent or mixture of solvents; 
 b) seeding the solvent or mixture of solvents with crystals of the crystalline anhydrate of  claim 8  or  claim 9 ; or 
 c) both a) and b). 
 
     
     
         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 any one of  claims 22  to  26 . 
     
     
         35 . 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 27  or  claim 28 . 
     
     
         36 . 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 prepared by the process of  claim 29  or  claim 30 . 
     
     
         37 . 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 prepared by the process of any one of  claims 31  to  33 . 
     
     
         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 Cl; 
         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 . The process of  claim 38 , wherein step e) comprises contacting the compound of formula (VII) with an acid to form the pharmaceutically acceptable salt of the compound of formula (VII). 
     
     
         40 . The process of  claim 38  or  claim 39 , 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  or  claim 39 , 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 . The process of  claim 42 , wherein step f) comprises contacting the compound of formula (VII) with an acid to form the pharmaceutically acceptable salt of the compound of formula (VII). 
     
     
         44 . The process of  claim 42  or  claim 43 , wherein the protecting group is carboxybenzyl. 
     
     
         45 . The process of any one of  claims 42  to  44 , wherein the anhydrous source of HBr or HCl comprises no more than 0.2% water (by volume). 
     
     
         46 . The process of any one of  claims 42  to  45 , 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); and 
 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). 
 
     
     
         47 . The process of  claim 46 , wherein the anhydrous source of HBr is HBr/HOAc. 
     
     
         48 . The process of any one of  claims 38  to  47 , wherein the pharmaceutically acceptable salt of the compound of formula (VII) is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         49 . The process of any one of  claims 38  to  48 , 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 (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. 
 
     
     
         50 . The process of  claim 49 , 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 
     
     
         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  or  50 . 
     
     
         52 . The process of any one of  claims 38  to  48 , 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 (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. 
 
     
     
         53 . 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 52 . 
     
     
         54 . The process of any one of  claims 38  to  48 , 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 dehydrating the crystalline hydrate produced in the process of  claim 52  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 any one of  claims 38  to  48 , 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 (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 
 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 . 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 prepared by the process of  claim 54  or  55 . 
     
     
         57 . The process of any one of  claims 38  to  48 , 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 (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, 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 . 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 prepared by the process of  claim 57 . 
     
     
         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 (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. 
       
     
     
         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  or  60 . 
     
     
         62 . A compound of formula (II): 
       
         
           
           
               
               
           
         
         wherein PG is a protecting group. 
       
     
     
         63 . A process for preparing a compound of formula (V) 
       
         
           
           
               
               
           
         
       
       the process comprising:
 a) converting a compound of formula (XIa): 
 
       
         
           
           
               
               
           
         
         to a compound of formula (I) 
       
       
         
           
           
               
               
           
         
         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) 
       
       
         
           
           
               
               
           
         
         d) reacting the compound of formula (III) with a compound of formula (IV) 
       
       
         
           
           
               
               
           
         
         to produce the compound of formula (V); 
         wherein:
 PG is a protecting group; 
 X is Br or Cl; 
 R 1  is selected from the group consisting of alkyl, aryl, and —OR 2 ; 
 R 2  is alkyl; and 
 Ts is tosyl. 
 
       
     
     
         64 . The process of  claim 63 , wherein 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). 
     
     
         65 . A process for preparing a crystalline compound of formula (V) 
       
         
           
           
               
               
           
         
       
       the process comprising:
 a) reacting a compound of formula (III) 
 
       
         
           
           
               
               
           
         
         with a compound of formula (IV): 
       
       
         
           
           
               
               
           
         
         to produce the compound of formula (V); 
         wherein:
 PG is a protecting group; 
 X is Br or Cl; 
 R 1  is —OR 2 ; 
 R 2  is methyl or ethyl; and 
 Ts is tosyl. 
 
       
     
     
         66 . A compound of formula (VII): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         67 . The compound of  claim 66 , wherein the pharmaceutically acceptable salt of the compound of formula (VII) is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         68 . A process for preparing a compound of formula (Ib) 
       
         
           
           
               
               
           
         
         wherein Cbz is carboxybenzyl, the process comprising: 
         (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). 
       
     
     
         69 . A pharmaceutical composition for use in treating an adult subject having moderate to severely active rheumatoid arthritis, wherein the pharmaceutical composition comprises:
 a) about 7.5 mg 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) 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.   
     
     
         70 . The pharmaceutical composition of  claim 69  wherein the adult subject has had an inadequate response or tolerance to one or more disease-modifying antirheumatic drugs (DMARDS). 
     
     
         71 . A pharmaceutical composition for use in treating structural damage associated with rheumatoid arthritis in an adult subject, wherein the pharmaceutical composition comprises:
 a) about 7.5 mg per day 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) freebase or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1 in an amount sufficient to deliver to the subject about 7.5 mg per day of Compound 1 freebase equivalent; or   b) about 15 mg per day of Compound 1 freebase or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1 in an amount sufficient to deliver to the subject about 15 mg per day of Compound 1 freebase equivalent; or   c) about 30 mg per day of Compound 1 freebase or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1 in an amount sufficient to deliver to the subject about 30 mg per day of Compound 1 freebase equivalent; or   d) about 45 mg per day of Compound 1 freebase or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1 in an amount sufficient to deliver to the subject about 45 mg per day of Compound 1 freebase equivalent;   such that the structural damage in the adult subject is inhibited or lessened.   
     
     
         72 . A pharmaceutical composition for use in treating moderate to severely active rheumatoid arthritis in an adult subject, wherein the pharmaceutical composition comprises:
 a) about 7.5 mg per day 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) freebase or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1 in an amount sufficient to deliver to the subject about 7.5 mg per day of Compound 1 freebase equivalent; or   b) about 15 mg per day of Compound 1 freebase or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1 in an amount sufficient to deliver to the subject about 15 mg per day of Compound 1 freebase equivalent; or   c) about 30 mg per day of Compound 1 freebase or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1 in an amount sufficient to deliver to the subject about 30 mg per day of Compound 1 freebase equivalent; or   d) about 45 mg per day of Compound 1 freebase or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1 in an amount sufficient to deliver to the subject about 45 mg per day of Compound 1 freebase equivalent; and   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.   
     
     
         73 . A pharmaceutical composition for use in reducing signs and symptoms of rheumatoid arthritis in an adult subject with moderately to severely active rheumatoid arthritis, wherein the pharmaceutical composition comprises:
 a) about 7.5 mg per day 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) freebase or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or 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 per day of Compound 1 freebase or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or 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 per day of Compound 1 freebase or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or 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 per day of Compound 1 freebase or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1 in an amount sufficient to deliver to the subject about 45 mg of Compound 1 freebase equivalent.   
     
     
         74 . The pharmaceutical composition of any one of  claims 69  to  73 , wherein the use comprising administering to the subject about 7.5 mg, or about 15 mg, or about 30 mg, or about 45 mg per day of a crystalline hydrate or a crystalline anhydrate of Compound 1. 
     
     
         75 . The pharmaceutical composition of any one of  claims 69  to  74 , wherein the crystalline anhydrate is Freebase Anhydrate Form D. 
     
     
         76 . The pharmaceutical composition of any one of  claims 69  to  74 , wherein the crystalline hydrate of Compound 1 is administered in an amount sufficient to deliver to the subject about 7.5 mg of Compound 1 freebase equivalent. 
     
     
         77 . The pharmaceutical composition of any one of  claims 69  to  74  wherein the crystalline hydrate of Compound 1 is administered in an amount sufficient to deliver to the subject about 45 mg of Compound 1 freebase equivalent. 
     
     
         78 . The pharmaceutical composition of any one of  claims 69  to  74  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. 
     
     
         79 . The pharmaceutical composition of  claim 78 , wherein administration of the crystalline hydrate achieves a mean peak plasma concentration (C max ) for Compound 1 of from about 25 to about 70 ng/mL. 
     
     
         80 . The pharmaceutical composition of  claim 78  or  claim 79 , wherein administration of the crystalline hydrate achieves a time to peak plasma concentration (T max ) for Compound 1 of from about 1.0 to about 6.0 hours. 
     
     
         81 . The pharmaceutical composition of any one of  claims 78  to  80 , wherein administration of the crystalline hydrate achieves 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. 
     
     
         82 . The pharmaceutical composition of any one of  claims 78  to  81 , wherein administration of the crystalline hydrate achieves a harmonic mean terminal half-life (t 1/2 ) for Compound 1 of from about 10.0 to about 14.0 hours. 
     
     
         83 . The pharmaceutical composition of any one of  claims 78  to  82 , wherein the difference in the C max  for Compound 1 when the crystalline hydrate is administered in the fed versus the fasted state is selected from the group consisting of about 30% or less, about 20% or less, and about 10% or less. 
     
     
         84 . The pharmaceutical composition of any one of  claims 78  to  83 , wherein administration of the crystalline hydrate achieves a mean peak steady-state plasma concentration (C max,ss ) for Compound 1 of from about 27 to about 55 ng/mL. 
     
     
         85 . The pharmaceutical composition of any one of  claims 78  to  84 , wherein administration of the crystalline hydrate achieves a time to peak plasma concentration at steady-state (T max,ss ) of from about 1.5 to about 6.0 hours. 
     
     
         86 . The pharmaceutical composition of any one of  claims 78  to  85 , wherein administration of the crystalline hydrate achieves 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. 
     
     
         87 . The pharmaceutical composition of any one of  claims 78  to  86 , wherein administration of the crystalline hydrate achieves 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. 
     
     
         88 . The pharmaceutical composition of any one of  claims 78  to  87 , wherein administration of the crystalline hydrate achieves a mean minimum steady-state plasma concentration (C min,ss ) for Compound 1 of from about 2.8 to about 3.2 ng/mL. 
     
     
         89 . The pharmaceutical composition of any one of  claims 69  to  74 , 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. 
     
     
         90 . The pharmaceutical composition of  claim 89 , wherein administration of the crystalline hydrate achieves a mean C max  for Compound 1 of from about 55 to about 85 ng/mL. 
     
     
         91 . The pharmaceutical composition of  claim 89  or  claim 90 , wherein administration of the crystalline hydrate achieves a T max  for Compound 1 of from about 1.0 to about 8.0 hours. 
     
     
         92 . The pharmaceutical composition of any one of  claims 89  to  91 , wherein administration of the crystalline hydrate achieves a mean AUC inf  for Compound 1 of from about 483 to about 660 ng-hours/mL. 
     
     
         93 . The pharmaceutical composition of any one of  claims 89  to  92 , wherein administration of the crystalline hydrate achieves a harmonic mean terminal half-life (t 1/2 ) for Compound 1 of from about 9.0 to about 12.0 hours. 
     
     
         94 . The pharmaceutical composition of any one of  claims 89  to  93 , wherein the difference in the C max  for Compound 1 when the crystalline hydrate is administered in the fed versus the fasted state is selected from the group consisting of about 40% or less, about 30% or less, about 20% or less, and about 10% or less. 
     
     
         95 . The pharmaceutical composition of any one of  claims 89   94 , wherein administration of the crystalline hydrate achieves a mean C max,ss  for Compound 1 of from about 65 to about 86 ng/mL. 
     
     
         96 . The pharmaceutical composition of any one of  claims 89  to  95 , wherein administration of the crystalline hydrate achieves a mean AUC 24,ss  for Compound 1 of from about 485 to about 658 ng-hours/mL. 
     
     
         97 . The pharmaceutical composition of any one of  claims 89  to  96 , wherein administration of the crystalline hydrate achieves a T max,ss  of from about 1.5 to about 6.0 hours. 
     
     
         98 . The pharmaceutical composition of any one of  claims 89  to  97 , wherein administration of the crystalline hydrate achieves a harmonic mean t 1/2,ss  for Compound 1 of from about 10.0 to about 14.5 hours. 
     
     
         99 . The pharmaceutical composition of any one of  claims 89  to  98 , wherein administration of the crystalline hydrate achieves a mean C min,ss  for Compound 1 of from about 3.5 to about 5.3 ng/mL. 
     
     
         100 . The pharmaceutical composition of any one of  claims 69  to  74  and  76  to  99 , 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 . A pharmaceutical composition comprising about 7.5 mg, or about 15 mg, or about 30 mg, or about 45 mg of 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. 
     
     
         103 . The composition of  claim 101  or  claim 102 , 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 24,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 . The composition of  claim 101  or  claim 102 , wherein the crystalline anhydrate is Freebase Anhydrate Form D. 
     
     
         107 . The pharmaceutical composition of any one of  claims 69  to  100  or the composition of any one of  claims 101  to  106 , wherein the freebase, 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 . The extended release formulation of  claim 108 , wherein the environment suitable for Compound 1 to dissolve has a pH equal to or less than 3.8 at 37° C. 
     
     
         110 . The extended release formulation of  claim 108  or  claim 109 , wherein the pH modifier is selected from the group consisting of tartaric acid, fumaric acid, citric acid, succinic acid, and malic acid, and combinations thereof. 
     
     
         111 . The extended release formulation of any one of  claims 108  to  110 , wherein the pH modifier is present in an amount from 10 to 35 w/w %. 
     
     
         112 . The extended release formulation of any of  claims 108  to  111 , wherein the hydrophilic polymer is a cellulose derivative with a viscosity between 1000 and 150000 mPa-s. 
     
     
         113 . The extended release formulation of  claim 112 , wherein the hydrophilic polymer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxyethyl cellulose, and mixtures thereof. 
     
     
         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.