Process for the preparation of (3s, 4r) -3-ethyl-4 - (3h - imidazori, 2-apyrrolor2, 3-e1pyrazin-8-yl) - n - (222 - trifluoroethyl) pyrrolidine-l-carboxamide and solid state forms thereof

Abstract

Provided are solid state forms of one or more (3S, 4R) - 3-ethyl-4 - (3H - imidazo [l, 2-a] pynolo [2, 3-e] pyrazin-8-yl) - N - (222 - trifluoroethyl) pyrrolidine-l-carboxamide that can be used in the manufacture of pharmaceutically acceptable solid dosage forms, and corresponding pharmaceutical compositions, methods of manufacture, therapeutic methods (such as treating RA), kits, synthetic methods, and product-by-process.SOLUTION: There is provided a crystal hydrate of (3S, 4R) - 3-ethyl-4 - (3H - imidazori, 2-a1pyrrolo [2, 3-e] pyrazin-8-yl) - N - (222 - trifluoroethyl) pyrrolidine-l-carboxamide represented by the following formula.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 242,797, filed October 16, 2015, which claims the benefit of U.S. Provisional Patent Application No. 62 / 267,672, filed December 15, 2015; which claims the benefit of U.S. Provisional Patent Application No. 62 / 301,537, filed February 29, 2016; and which claims the benefit of U.S. Provisional Patent Application No. 62 / 352,380, filed June 20, 2016, all of which are incorporated herein by reference in their entireties.

[0002] The present disclosure relates to (a) methods for making (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 (referred to as "Compound 1"); (b) intermediates used in the preparation of Compound 1 and methods for making the intermediates; (c) solid state forms of Compound 1; (d) pharmaceutical compositions comprising one or more solid state forms of Compound 1 and, optionally, one or more additional therapeutic agents; (e) methods for treating Janus kinase-associated conditions (such as rheumatoid arthritis) by administering one or more solid state forms of Compound 1 to a subject in need thereof; (f) kits comprising a first pharmaceutical composition comprising a solid state form of Compound 1 and, optionally, a second pharmaceutical composition comprising one or more additional therapeutic agents; (g) methods for making the solid state forms of Compound 1; and (h) solid state forms of Compound 1 made by such methods. [Background technology]

[0003] (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") was first disclosed in International Patent Application WO 2011 / 068881 A1, which is incorporated herein by reference in its entirety. The compound has activity as a Janus kinase ("JAK") inhibitor, particularly as a JAK-1 inhibitor. Clinical trials evaluating the compound's use in the treatment of rheumatoid arthritis are currently underway. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] International Publication No. 2011 / 068881 Summary of the Invention [Problem to be solved by the invention]

[0005] The isolation and commercial-scale production of solid forms of Compound 1 and corresponding pharmaceutical formulations that have acceptable solid-state properties (e.g., chemical stability, thermal stability, solubility, hygroscopicity, and / or particle size, etc.), the manufacturability of the compound (e.g., yield, impurity rejection during crystallization, filtration characteristics, drying characteristics, and grinding characteristics, etc.), and the feasibility of the formulation (e.g., stability with respect to pressure or compaction force during tableting, etc.) poses a number of problems, which are discussed in greater detail below. Accordingly, there is currently a need for one or more solid forms of Compound 1 that have an acceptable balance of these properties and that can be used to prepare pharmaceutically acceptable solid formulations.

[0006] Additionally, currently known methods for preparing Compound 1 involve the use of particularly hazardous reagents, such as trimethylsilyldiazomethane or diazomethane, and do not produce crystalline products. Therefore, there is also a need for methods for preparing Compound 1 and pharmaceutically acceptable salts thereof that avoid the use of particularly hazardous reagents and that produce crystalline products and crystalline intermediates.

[0007] Furthermore, sustained peak plasma concentrations can theoretically be achieved by sustained-release systems. However, when such systems are made of hydrophilic polymers such as HPMC, they rarely provide pH-dependent drug release for pH-dependently soluble drugs, and they usually cannot achieve zero-order release except for practically insoluble drugs. Unexpectedly, it has been discovered that when tartaric acid is used as a pH modifier in such systems, Compound 1 can be released at a constant rate regardless of the pH of the environment.

[0008] In an unexpected finding, it was discovered that as tablets containing a hydrophilic polymer base system eroded, Compound 1 reacted with HPMC to produce a thicker gel layer, which delayed the release of Compound 1 from the tablet. The resulting gel layer provided a favorable environment for Compound 1 to dissolve. [Means for solving the problem]

[0009] In one aspect, the present disclosure relates to a method for making Compound 1, or a pharmaceutically acceptable salt thereof, comprising: a) a compound of formula (I):

[0010] [ka] or a pharmaceutically acceptable salt thereof with trimethylsulfoxonium chloride to give a compound of formula (II):

[0011] [ka] (PG is a protecting group); b) contacting a compound of formula (II) with LiX and a sulfonic acid to produce a compound of formula (III):

[0012] [ka] (X is Br or Cl); c) reacting a compound of formula (III) with a compound of formula (IV):

[0013] [ka] to produce a compound of formula (V):

[0014] [ka] wherein R1 is selected from the group consisting of alkyl, aryl, and -OR2; R2 is alkyl; and Ts is tosyl; d) contacting the compound of formula (V) with a perfluoroanhydride and an organic base to produce a compound of formula (VI):

[0015] [ka] To form; e) deprotecting the compound of formula (VI) to give a compound of formula (VII):

[0016] [ka] forming a pharmaceutically acceptable salt of; f) reacting a pharmaceutically acceptable salt of a compound of formula (VII) with 2,2,2-trifluoroethylamine to produce compound 1. Includes.

[0017] In another aspect, the present disclosure relates to a method for preparing Compound 1, or a pharmaceutically acceptable salt thereof, comprising: a) a compound of formula (Ib):

[0018] [ka] is reacted with trimethylsulfoxonium chloride in the presence of carbonyldiimidazole and a strong base to give a compound of formula (IIa):

[0019] [ka] (Cbz is carboxybenzyl); b) reacting a compound of formula (IIa) with lithium bromide and a sulfonic acid to give a compound of formula (IIIa):

[0020] [ka] To form; c) reacting a compound of formula (IIIa) with a compound of formula (IVa) in the presence of lithium tert-butoxide:

[0021] [ka] to produce a compound of formula (Va):

[0022] [ka] (R2 is methyl or ethyl; Ts is tosyl); d) contacting the compound of formula (Va) with a perfluoroanhydride and an organic base to produce a compound of formula (VIa):

[0023] [ka] To form; e) deprotecting the compound of formula (VIa) to give a compound of formula (VII):

[0024] [ka] To form; f) contacting a compound of formula (VII) with hydrochloric acid to produce a compound of formula (VIIa):

[0025] [ka] To form; g) reacting a compound of formula (VIIa) with 2,2,2-trifluoroethylamine in the presence of carbonyldiimidazole to produce compound 1. Includes.

[0026] In another aspect, the present disclosure relates to a method for making Compound 1, the method comprising: a) a compound of formula (I):

[0027] [ka] or a pharmaceutically acceptable salt thereof with trimethylsulfoxonium chloride to give a compound of formula (II):

[0028] [ka] (PG is a protecting group); b) contacting a compound of formula (II) with LiX and a sulfonic acid to produce a compound of formula (III):

[0029] [ka] (X is Br or Cl); c) reacting a compound of formula (III) with a compound of formula (IV):

[0030] [ka] to produce a compound of formula (V):

[0031] [ka] wherein R1 is selected from the group consisting of alkyl, aryl, and -OR2; R2 is alkyl; and Ts is tosyl; d) contacting the compound of formula (V) with a perfluoroanhydride and an organic base to produce a compound of formula (VI):

[0032] [ka] To manufacture; e) deprotecting the compound of formula (VI) to give a compound of formula (VII):

[0033] [ka] and contacting the compound of formula (VII) with hydrochloric acid to form a compound of formula (VIIb):

[0034] [ka] To form; f) contacting a compound of formula (VIIb) with a base to form a compound of formula (VII); g) reacting a compound of formula (VII) with 2,2,2-trifluoroethylamine to produce compound 1; h) contacting Compound 1 with L-tartaric acid to produce the tartrate salt of Compound 1; and i) contacting the tartrate salt with sodium carbonate and sodium bicarbonate to produce Compound 1. Includes.

[0035] In another aspect, the present disclosure relates to a method for preparing Compound 1, or a pharmaceutically acceptable salt thereof, comprising: a) a compound of formula (XIa):

[0036] [ka] with a compound of formula (I):

[0037] [ka] (PG is a protecting group); b) reacting a compound of formula (I) with trimethylsulfoxonium chloride to give a compound of formula (II)

[0038] [ka] To form; c) contacting a compound of formula (II) with an anhydrous source of HBr or HCl to produce a compound of formula (III)

[0039] [ka] (X is Br or Cl); d) reacting a compound of formula (III) with a compound of formula (IV)

[0040] [ka] to form a compound of formula (V)

[0041] [ka] wherein R1 is selected from the group consisting of alkyl, aryl, and -OR2; R2 is alkyl; and Ts is tosyl; e) contacting a compound of formula (V) with a perfluoroanhydride and an organic base to produce a compound of formula (VI)

[0042] [ka] To form; f) deprotecting the compound of formula (VI) to give a compound of formula (VII):

[0043] [ka] forming a pharmaceutically acceptable salt of g) reacting the pharmaceutically acceptable salt of the compound of formula (VII) with 2,2,2-trifluoroethylamine to produce compound 1. Includes.

[0044] In another aspect, the present disclosure provides a compound of formula (II):

[0045] [ka] (PG is a protecting group).

[0046] In another aspect, the disclosure provides a compound of formula (II):

[0047] [ka] (PG is a protecting group), Compounds of formula (I):

[0048] [ka] or a pharmaceutically acceptable salt thereof with trimethylsulfoxonium chloride to form a compound of formula (II).

[0049] In another aspect, the present disclosure provides a compound of formula (III):

[0050] [ka] A method for producing Compounds of formula (II):

[0051] [ka] with LiX and a sulfonic acid to form a compound of formula (III) where PG is a protecting group; and X is Br or Cl.

[0052] In another aspect, the present disclosure provides a compound of formula (Va)

[0053] [ka] (R2 is methyl or ethyl; Ts is tosyl).

[0054] In another aspect, the present disclosure provides a compound of formula (V):

[0055] [ka] A method for producing a) a compound of formula (XIa):

[0056] [ka] with a compound of formula (I):

[0057] [ka] To convert into; b) reacting a compound of formula (I) with trimethylsulfoxonium chloride to give a compound of formula (II):

[0058] [ka] To form; c) contacting a compound of formula (II) with an anhydrous source of HBr or HCl to produce a compound of formula (III):

[0059] [ka] To form; d) reacting a compound of formula (III) with a compound of formula (IV):

[0060] [ka] to produce a compound of formula (V): [In the formula, PG is a protecting group; X is Br or Cl; R1 is selected from the group consisting of alkyl, aryl, and -OR2; R2 is alkyl; and Ts is tosyl.

[0061] In another aspect, the disclosure provides a crystalline compound of formula (V):

[0062] [ka] A method for producing a) a compound of formula (III):

[0063] [ka] with a compound of formula (IV):

[0064] [ka] to produce a compound of formula (V) [In the formula, PG is a protecting group; X is Br or Cl; R1 is -OR2; R2 is methyl or ethyl; Ts is tosyl.] The present invention relates to a method comprising:

[0065] In another aspect, the present disclosure provides a compound of formula (IVa):

[0066] [ka] (R2 is methyl or ethyl, and Ts is tosyl).

[0067] In another aspect, the present disclosure provides a compound of formula (IVa):

[0068] [ka] (R2 is methyl or ethyl, and Ts is tosyl), a) a compound of formula (XVII):

[0069] [ka] is reacted with trimethylsilylacetylene in the presence of a catalyst to give a compound of formula (XVIII):

[0070] [ka] (TMS is trimethylsilyl); b) contacting a compound of formula (XVIII) with p-toluenesulfonyl chloride in the presence of a base to give a compound of formula (XIX)

[0071] [ka] (Ts is tosyl); and c) reacting a compound of formula (XIX) with a carbamate in the presence of a catalyst and a ligand to form a compound of formula (IVa), wherein the carbamate is selected from the group consisting of methyl carbamate and ethyl carbamate. The present invention relates to a method comprising:

[0072] In another aspect, the present disclosure provides a compound of formula (VII):

[0073] [ka] or a pharmaceutically acceptable salt thereof.

[0074] In another aspect, the present disclosure provides a compound of formula (Ib):

[0075] [ka] (Cbz is carboxybenzyl), (i) reacting carboxybenzyl-glycine ethyl ester with ethyl acrylate to give a compound of formula (VIII):

[0076] [ka] To form; (ii) protecting the compound of formula (VIII) to give a compound of formula (IX):

[0077] [ka] (R3 is selected from the group consisting of CF3SO2-; CH3SO2-; and tosyl); (iii) contacting the compound of formula (IX) with one of ethylboronic acid, ethylmagnesium bromide, or ethylzinc chloride in the presence of a catalyst to produce a compound of formula (X):

[0078] [ka] To form; (iv) hydrolyzing the compound of formula (X) to give a compound of formula (XI):

[0079] [ka] To manufacture; (v) reacting a compound of formula (XI) with a compound of formula (XII):

[0080] [ka] To convert into; (vi) contacting a compound of formula (XII) with dicyclohexylamine to form a compound of formula (Ib). The present invention relates to a method comprising:

[0081] In another aspect, the present disclosure relates to the dicyclohexylamine salt of (3R,4S)-1-((benzyloxy)carbonyl)-4-ethylpyrrolidine-3-carboxylate.

[0082] In one aspect, the present disclosure relates to pharmaceutically acceptable solid state forms of Compound 1.

[0083] In another aspect, the present disclosure relates to an amorphous free base of Compound 1.

[0084] In another aspect, the present disclosure relates to crystalline Compound 1.

[0085] In another aspect, the present disclosure relates to a crystalline hydrate of Compound 1.

[0086] In another aspect, the present disclosure relates to a crystalline tartrate salt of Compound 1.

[0087] In another aspect, the present disclosure relates to the free base hydrate form C of Compound 1.

[0088] In another aspect, the present disclosure relates to the free base hydrate form B of Compound 1.

[0089] In another aspect, the present disclosure relates to a crystalline anhydrate of Compound 1.

[0090] In another aspect, the present disclosure relates to the free base anhydrate form D of Compound 1.

[0091] In another aspect, the present disclosure relates to a pharmaceutical composition comprising one or more solid state forms of Compound 1 and a pharmaceutically acceptable carrier.

[0092] In another aspect, the disclosure relates to a pharmaceutical composition comprising one or more solid forms of Compound 1, 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. In one embodiment, the solid form is a tartrate salt hydrate. In one embodiment, the solid form is free base hydrate Form C.

[0093] In another aspect, the present disclosure relates to pharmaceutical compositions comprising one or more solid state forms of Compound 1 and, optionally, one or more additional therapeutic agents.

[0094] In another aspect, the present disclosure relates to a method for treating a JAK-associated condition (such as rheumatoid arthritis) in a human subject suffering from or susceptible to such a condition, comprising administering to the subject a therapeutically effective amount of a solid form of Compound 1. In another aspect, the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a solid form of Compound 1 as described herein for use in treating a JAK-associated condition (such as rheumatoid arthritis) in a subject, particularly a human subject suffering from or susceptible to such a condition.

[0095] In another aspect, the disclosure relates to methods of treating rheumatoid arthritis, the term "rheumatoid arthritis" including juvenile rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, Sjogren's syndrome, and psoriatic arthritis.

[0096] In another aspect, the disclosure relates to methods of treating inflammatory bowel disease, the term "inflammatory bowel disease" including Crohn's disease, pediatric Crohn's disease and ulcerative colitis.

[0097] In another aspect, the disclosure relates to a method for 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 human subject suffering from or susceptible to such a condition, comprising administering to the subject a therapeutically effective amount of a solid form of Compound 1. In another aspect, the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a solid state form of Compound 1 as described herein 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, particularly a human subject suffering from or susceptible to the condition.

[0098] In another aspect, the disclosure relates to a method of treating a JAK-associated condition (such as rheumatoid arthritis) in a human subject suffering from or susceptible to such a condition, comprising administering to the subject a solid-state form of Compound 1 in combination with one or more additional therapeutic agents (e.g., a therapeutic agent for treating rheumatoid arthritis that is not a JAK inhibitor). In another aspect, the disclosure relates to a pharmaceutical composition comprising a solid-state form of Compound 1 as described herein in combination with one or more additional therapeutic agents (e.g., a therapeutic agent for treating rheumatoid arthritis that is not a JAK inhibitor) for use in treating a JAK-associated condition (such as rheumatoid arthritis) in a subject, particularly a human subject suffering from or susceptible to such a condition.

[0099] In another aspect, the present disclosure relates to a method for treating moderately to severely active rheumatoid arthritis, comprising administering a therapeutically effective amount of Compound 1, in one or more forms disclosed herein, to a subject suffering from or susceptible to the condition. In certain aspects, such methods can comprise administering to the subject 7.5 mg once daily, 15 mg once daily, 30 mg once daily, or 45 mg once daily of Compound 1, in one or more forms disclosed herein. In this or another specific aspect, the subject can be administered Compound 1 in the free base form C. In this or yet another specific aspect, the subject can have had an inadequate response to methotrexate. In this or yet another specific aspect, the subject can have an inadequate response to a biopharmaceutical approved for rheumatoid arthritis. In this or yet another specific aspect, the subject can have not previously received a biopharmaceutical approved for rheumatoid arthritis.

[0100] In another aspect, the disclosure provides a method for treating an adult subject with moderately to severely active rheumatoid arthritis, comprising administering to the subject: a) about 7.5 mg of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1 in an amount sufficient to deliver the equivalent of about 7.5 mg of Compound 1 free base to the subject; or b) about 15 mg of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1 in an amount sufficient to deliver the equivalent of about 15 mg of Compound 1 free base to the subject. or c) about 30 mg of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1 in an amount sufficient to deliver the equivalent of about 30 mg of Compound 1 free base to the subject; or d) about 45 mg of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1 in an amount sufficient to deliver the equivalent of about 45 mg of Compound 1 free base to the subject. In one embodiment, the disclosure provides a pharmaceutical composition for use in treating an adult subject with moderately to severely active rheumatoid arthritis, said use comprising administering to said subject said pharmaceutical composition, wherein said pharmaceutical composition comprises: a) about 7.5 mg of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1 in an amount sufficient to deliver the equivalent of about 7.5 mg of Compound 1 free base to the subject; or b) about 15 mg of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1 in an amount sufficient to deliver the equivalent of about 15 mg of Compound 1 free base to the subject. or c) about 30 mg of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1 in an amount sufficient to deliver the equivalent of about 30 mg of Compound 1 free base to a subject; or d) about 45 mg of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1 in an amount sufficient to deliver the equivalent of about 45 mg of Compound 1 free base to a subject.

[0101] In another embodiment, the disclosure provides a method for treating rheumatoid arthritis-associated structural damage in an adult subject, comprising administering to the subject: a) about 7.5 mg / day of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1 in an amount sufficient to deliver the equivalent of about 7.5 mg / day of Compound 1 free base to the subject; or b) about 15 mg / day of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1 in an amount sufficient to deliver the equivalent of about 15 mg / day of Compound 1 free base to the subject. or c) about 30 mg / day of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1 in an amount sufficient to deliver the equivalent of about 30 mg / day of Compound 1 free base to the subject; or d) about 45 mg / day of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1 in an amount sufficient to deliver the equivalent of about 45 mg / day of Compound 1 free base to the subject; wherein structural damage is inhibited or reduced in an adult subject.In one embodiment, the disclosure provides a pharmaceutical composition for use in treating rheumatoid arthritis-associated structural damage in an adult subject, the use comprising administering to the subject the pharmaceutical composition, wherein the pharmaceutical composition is: a) about 7.5 mg / day of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1 in an amount sufficient to deliver the equivalent of about 7.5 mg / day of Compound 1 free base to the subject; or b) about 15 mg / day of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1 in an amount sufficient to deliver the equivalent of about 15 mg / day of Compound 1 free base to the subject. or c) about 30 mg / day of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1 in an amount sufficient to deliver the equivalent of about 30 mg / day of Compound 1 free base to a subject; or d) about 45 mg / day of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1 in an amount sufficient to deliver the equivalent of about 45 mg / day of Compound 1 free base to a subject; wherein structural damage in an adult subject is inhibited or reduced.

[0102] In another aspect, the disclosure provides a method for treating moderately to severely active rheumatoid arthritis in an adult subject, the method comprising administering to the subject: a) about 7.5 mg / day of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1 in an amount sufficient to deliver the equivalent of about 7.5 mg / day of Compound 1 free base to the subject; or b) about 15 mg / day of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1 in an amount sufficient to deliver the equivalent of about 15 mg / day of Compound 1 free base to the subject; or c) about 30 mg / day of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1 in an amount sufficient to deliver the equivalent of about 15 mg / day of Compound 1 free base to the subject. or d) about 45 mg / day of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1 in an amount sufficient to deliver the equivalent of Compound 1 free base to the subject about 45 mg / day; wherein the subject has, prior to treatment, a symptom selected from the group consisting of at least 6 swollen joints, at least 6 tender joints, and combinations thereof.In one embodiment, the disclosure provides a pharmaceutical composition for use in treating moderately to severely active rheumatoid arthritis in an adult subject, said use comprising administering to said subject said pharmaceutical composition, wherein said pharmaceutical composition is selected from the group consisting of: a) about 7.5 mg / day of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1 in an amount sufficient to deliver the equivalent of about 7.5 mg / day of Compound 1 free base to said subject; or b) about 15 mg / day of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1 in an amount sufficient to deliver the equivalent of about 15 mg / day of Compound 1 free base to said subject. or a crystalline anhydrate of Compound 1 in an amount sufficient to deliver the equivalent of about 30 mg / day of Compound 1 free base to a subject; or c) about 30 mg / day of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1 in an amount sufficient to deliver the equivalent of about 30 mg / day of Compound 1 free base to a subject; or d) about 45 mg / day of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1 in an amount sufficient to deliver the equivalent of about 45 mg / day of Compound 1 free base to a subject; wherein the subject has, prior to treatment, a symptom selected from the group consisting of at least 6 swollen joints, at least 6 tender joints, and combinations thereof.

[0103] In another aspect, the disclosure provides a method for reducing the signs and symptoms of rheumatoid arthritis in an adult subject with moderately to severely active rheumatoid arthritis, the method comprising administering to the subject: a) about 7.5 mg / day of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1 in an amount sufficient to deliver the equivalent of about 7.5 mg of Compound 1 free base to the subject; or b) about 15 mg / day of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1 in an amount sufficient to deliver the equivalent of about 15 mg of Compound 1 free base to the subject. or c) about 30 mg / day of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1 in an amount sufficient to deliver the equivalent of about 30 mg of Compound 1 free base to the subject; or d) about 45 mg / day of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1 in an amount sufficient to deliver the equivalent of about 45 mg of Compound 1 free base to the subject.In one embodiment, the disclosure provides a pharmaceutical composition for use in reducing the signs and symptoms of rheumatoid arthritis in an adult subject with moderately to severely active rheumatoid arthritis, said use comprising administering to said subject said pharmaceutical composition, wherein said pharmaceutical composition is selected from the group consisting of: a) about 7.5 mg / day of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1 in an amount sufficient to deliver the equivalent of about 7.5 mg of Compound 1 free base to the subject; or b) about 15 mg / day of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1 in an amount sufficient to deliver the equivalent of about 15 mg of Compound 1 free base to the subject. or c) about 30 mg / day of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1 in an amount sufficient to deliver the equivalent of about 30 mg of Compound 1 free base to a subject; or d) about 45 mg / day of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1 in an amount sufficient to deliver the equivalent of about 45 mg of Compound 1 free base to a subject.

[0104] In another aspect, the disclosure relates to a kit comprising one or more pharmaceutical compositions comprising a solid form of Compound 1. The kit may also include additional pharmaceutical compositions comprising one or more additional therapeutic agents and / or instructions, e.g., instructions for using the kit.

[0105] In another aspect, the present disclosure relates to methods for preparing solid-state forms of Compound 1.

[0106] In another aspect, the disclosure relates to solid state forms of Compound 1 prepared according to such methods.

[0107] In another aspect, the present disclosure relates to a method for treating an adult subject with moderately to severely active rheumatoid arthritis, the method comprising administering to the subject about 7.5 mg, about 15 mg, about 30 mg, or about 45 mg of Compound 1 free base, or a crystalline hydrate of Compound 1 in an amount sufficient to deliver about 7.5 mg, about 15 mg, about 30 mg, or about 45 mg of Compound 1 free base equivalent to the subject. In this or another specific embodiment, the hydrate can be a hemihydrate. In this or another specific embodiment, the hemihydrate can be free base hydrate Form C. In this or yet another specific embodiment, the subject can have an inadequate response or tolerance to one or more disease-modifying antirheumatic drugs (DMARDS), such as methotrexate. In this or yet another specific embodiment, the subject can be DMARD-naive. In this or yet another specific embodiment, the subject can be further administered one or more DMARDs.

[0108] In another aspect, the present disclosure relates to a method for treating rheumatoid arthritis-associated structural damage in an adult subject, the method comprising administering to the subject about 7.5 mg, or about 15 mg, or about 30 mg, or about 45 mg per day of Compound 1 free base, or a crystalline hydrate of Compound 1 in an amount sufficient to deliver the equivalent of about 7.5 mg, or about 15 mg, or about 30 mg, or about 45 mg per day of Compound 1 free base to the subject, thereby inhibiting or reducing structural damage in the adult subject. In this or another specific embodiment, the hydrate can be a hemihydrate. In this or another embodiment, the hemihydrate can be free base hydrate Form C.

[0109] In another embodiment, the present disclosure relates to a method for treating moderately to severely active rheumatoid arthritis in an adult subject, the method comprising administering to the subject about 7.5 mg, about 15 mg, about 30 mg, or about 45 mg per day of Compound 1 free base, or a crystalline hydrate of Compound 1 in an amount sufficient to deliver the equivalent of about 7.5 mg, about 15 mg, about 30 mg, or about 45 mg per day of Compound 1 free base to the subject, wherein the subject has a symptom selected from the group consisting of at least six swollen joints, at least six tender joints, and a combination thereof prior to treatment. In this or another specific embodiment, the hydrate can be a hemihydrate. In this or another embodiment, the hemihydrate can be free base hydrate Form C.

[0110] In another embodiment, the disclosure relates to a method for reducing the signs and symptoms of rheumatoid arthritis in an adult subject with moderate to severely active rheumatoid arthritis, the method comprising administering to the subject about 7.5 mg / day of Compound 1 free base, or a crystalline hydrate of Compound 1 in an amount sufficient to deliver the equivalent of about 7.5 mg of Compound 1 free base to the subject. In this or another specific embodiment, the hydrate can be a hemihydrate. In this or another embodiment, the hemihydrate can be free base hydrate Form C.

[0111] In another embodiment, the disclosure relates to a method for reducing the signs and symptoms of rheumatoid arthritis in an adult subject with moderate to severely active rheumatoid arthritis, the method comprising administering to the subject about 15 mg / day of Compound 1 free base, or a crystalline hydrate of Compound 1 in an amount sufficient to deliver the equivalent of about 15 mg of Compound 1 free base to the subject. In this or another specific embodiment, the hydrate can be a hemihydrate. In this or another embodiment, the hemihydrate can be free base hydrate Form C.

[0112] In another embodiment, the disclosure relates to a method for reducing the signs and symptoms of rheumatoid arthritis in an adult subject with moderate to severe active rheumatoid arthritis, the method comprising administering to the subject about 30 mg / day of Compound 1 free base, or a crystalline hydrate of Compound 1 in an amount sufficient to deliver the equivalent of about 30 mg of Compound 1 free base to the subject. In this or another specific embodiment, the hydrate can be a hemihydrate. In this or another embodiment, the hemihydrate can be free base hydrate Form C.

[0113] In another embodiment, the disclosure relates to a method for reducing the signs and symptoms of rheumatoid arthritis in an adult subject with moderate to severe active rheumatoid arthritis, the method comprising administering to the subject about 45 mg / day of Compound 1 free base, or a crystalline hydrate of Compound 1 in an amount sufficient to deliver the equivalent of about 45 mg of Compound 1 free base to the subject. In this or another specific embodiment, the hydrate can be a hemihydrate. In this or another embodiment, the hemihydrate can be free base hydrate Form C.

[0114] In another embodiment, the disclosure relates to a pharmaceutical composition comprising a crystalline hydrate of Compound 1 and a pharmaceutically acceptable carrier, the composition comprising the crystalline hydrate in an amount sufficient to deliver the equivalent of about 7.5 mg of Compound 1 free base. In this or another specific embodiment, the hydrate can be a hemihydrate. In this or another embodiment, the hemihydrate can be free base hydrate Form C.

[0115] In another embodiment, the disclosure relates to a method for reducing the signs and symptoms of rheumatoid arthritis in an adult subject with moderate to severe active rheumatoid arthritis, wherein the composition comprises the crystalline hydrate in an amount sufficient to deliver the equivalent of about 15 mg of Compound 1 free base. In this or another particular embodiment, the hydrate can be a hemihydrate. In this or another embodiment, the hemihydrate can be free base hydrate Form C.

[0116] In another embodiment, the disclosure relates to a method for reducing the signs and symptoms of rheumatoid arthritis in an adult subject with moderate to severe active rheumatoid arthritis, wherein the composition comprises the crystalline hydrate in an amount sufficient to deliver the equivalent of about 30 mg of Compound 1 free base. In this or another specific embodiment, the hydrate can be a hemihydrate. In this or another embodiment, the hemihydrate can be free base hydrate Form C.

[0117] In another embodiment, the disclosure relates to a method for reducing the signs and symptoms of rheumatoid arthritis in an adult subject with moderate to severe active rheumatoid arthritis, wherein the composition comprises the crystalline hydrate in an amount sufficient to deliver the equivalent of about 45 mg of Compound 1 free base. In this or another specific embodiment, the hydrate can be a hemihydrate. In this or another embodiment, the hemihydrate can be free base hydrate Form C.

[0118] In another embodiment, the disclosure relates to a method of treating an adult subject with moderately to severely active rheumatoid arthritis, the method comprising administering to the subject about 7.5 mg, or about 15 mg, or about 30 mg, or about 45 mg of a crystalline hydrate of Compound 1. In this or another specific embodiment, the hydrate can be a hemihydrate. In this or another embodiment, the hemihydrate can be free base hydrate Form C.

[0119] In another aspect, the present disclosure relates to a method for treating rheumatoid arthritis-associated structural damage in an adult subject, the method 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 of Compound 1, thereby inhibiting or reducing structural damage in the adult subject. In this or another specific aspect, the hydrate can be a hemihydrate. In this or another aspect, the hemihydrate can be free base hydrate Form C.

[0120] In another embodiment, the present disclosure relates to a method for treating moderately to severely active rheumatoid arthritis in an adult subject, the method 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 of Compound 1, wherein the subject has, prior to treatment, a symptom selected from the group consisting of at least six swollen joints, at least six tender joints, and combinations thereof. In this or another specific embodiment, the hydrate can be a hemihydrate. In this or another embodiment, the hemihydrate can be free base hydrate Form C.

[0121] In another embodiment, the disclosure relates to a method for reducing the signs and symptoms of rheumatoid arthritis in an adult subject with moderate to severely active rheumatoid arthritis, the method 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 of Compound 1. In this or another specific embodiment, the hydrate can be a hemihydrate. In this or another embodiment, the hemihydrate can be free base hydrate Form C.

[0122] In another aspect, the disclosure relates to a sustained-release formulation for oral administration comprising Compound 1 or a pharmaceutically acceptable salt thereof, a hydrophilic polymer, and a pH adjusting agent, wherein the hydrophilic polymer forms a gel layer upon contact with water that provides a suitable environment for dissolving Compound 1 and the pH adjusting agent.

[0123] In another aspect, the disclosure relates to a method for preparing a pharmaceutical composition, the method comprising: (a) combining Compound 1 or a pharmaceutically acceptable salt thereof, or a solid form of Compound 1, and at least a portion of one other 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 granular material; (d) milling the granular material to form a milled granular material; (e) combining the milled granular material with the remaining composition components; and (f) compressing the composition to form the pharmaceutical composition. [Brief explanation of the drawings]

[0124] [Figure 1A] FIG. 1 is a schematic diagram showing one method for preparing amorphous free base. [Figure 1B] FIG. 1 is a schematic diagram of one method for preparing free base hydrate form C. [Figure 1C] FIG. 1 is a schematic diagram showing one method for producing tartrate salt hydrate. [Figure 2A] Powder X-ray diffraction pattern corresponding to amorphous free base (due to precipitation). [Figure 2B] Powder X-ray diffraction pattern corresponding to the amorphous free base (by dehydration). [Figure 3A] 1 is a powder X-ray diffraction pattern corresponding to the free base solvate form A (isopropyl acetate / water solvate). [Figure 3B] 1 is a powder X-ray diffraction pattern corresponding to the free base hydrate form B. [Figure 3C] 1 is a powder X-ray diffraction pattern corresponding to free base hydrate form C. [Figure 3D] Powder X-ray diffraction pattern corresponding to the tartrate salt hydrate [the experimental PXRD pattern is shown at the bottom of Figure 3D, and the calculated PXRD pattern is shown at the top of Figure 3D]. [Figure 3E] 1 is a powder X-ray diffraction pattern corresponding to the hydrochloride salt solvate form AA. [Figure 3F]1 is a powder X-ray diffraction pattern corresponding to the hydrochloride solvate form BB. [Figure 3G] 1 is a powder X-ray diffraction pattern corresponding to the hydrochloride solvate form CC. [Figure 3H] 1 is a powder X-ray diffraction pattern corresponding to L-maleate form AAA. [Figure 3I] 1 is a powder X-ray diffraction pattern corresponding to the L-maleate form of BBB. [Figure 3J] 1 is a powder X-ray diffraction pattern corresponding to the free base anhydrous Form D. [Figure 4A] 1 is a thermogravimetric analysis thermogram corresponding to the amorphous free base (due to precipitation). [Figure 4B] 1 is a thermogravimetric analysis thermogram corresponding to the amorphous free base (by dehydration). [Figure 4C] 1 is a thermogravimetric analysis thermogram corresponding to free base solvate form A. [Figure 4D] 1 is a thermogravimetric analysis thermogram corresponding to free base hydrate form B. [Figure 4E] 1 is a thermogravimetric analysis thermogram corresponding to free base hydrate form C. [Figure 4F] 1 is a thermogravimetric analysis thermogram corresponding to the tartrate salt hydrate. [Figure 4G] 1 is a thermogravimetric analysis thermogram corresponding to the hydrochloride solvate form AA. [Figure 4H] 1 is a thermogravimetric analysis thermogram corresponding to the L-maleate form of BBB. [Figure 4I] 1 is a thermogravimetric analysis thermogram corresponding to the free base anhydrous Form D. [Figure 5A] 1 is a differential scanning calorimetry thermogram corresponding to the amorphous free base (by dehydration). [Figure 5B] 1 is a differential scanning calorimetry thermogram corresponding to free base hydrate form B. [Figure 5C] 1 is a differential scanning calorimetry thermogram corresponding to free base hydrate form C. [Figure 5D] 1 is a differential scanning calorimetry thermogram corresponding to tartrate salt hydrate. [Figure 5E] 1 is a differential scanning calorimetry thermogram corresponding to the free base anhydrous Form D. [Figure 6A] Moisture sorption isotherm corresponding to the amorphous free base (by dehydration). [Figure 6B] This is the moisture sorption isotherm corresponding to the free base hydrate form C. [Figure 6C] This is the moisture sorption isotherm corresponding to the tartrate salt hydrate. [Figure 6D] This is the moisture sorption isotherm corresponding to the free base anhydrous form D. [Figure 7] 1 is a comparison of the dissolution profiles of extended release tablets from Example 26 (free base hydrate form C) and Example 27 (amorphous free base) at pH 6.8. [Figure 8] 1 is a comparison of the dissolution profiles of extended release tablets from Example 24 (ER1), Example 25 (ER2), and Example 26 (ER3) in a dual pH system and at pH 6.8. [Figure 9] 1 is a comparison of the dissolution profiles of extended release tablets from Example 32 (ER4) and Example 33 (ER4, no mannitol) at pH 1.2, pH 6.8, or dual pH systems. [Figure 10] 1 is a comparison of the dissolution profiles of extended release tablets from Example 34 (ER5) at pH 1.2, pH 6.8, and dual pH systems. [Figure 11] 1 is a comparison of the dissolution profiles of extended release tablets from Example 35 (ER6) at pH 1.2, pH 6.8, and dual pH systems. [Figure 12] 1 is a comparison of the dissolution profiles of extended release tablets from Example 28 (ER7) and Example 32 (ER4) in a dual pH system. [Figure 13] 1 is a comparison of the dissolution profiles of extended release tablets from Example 31 (ER8) and Example 32 (ER4) in a dual pH system. [Figure 14] 1 is a comparison of the dissolution profiles of extended release tablets from Example 24 (ER1), Example 26 (ER3), and Example 32 (ER4) in a dual pH system. [Figure 15A]1 is a comparison of the dissolution profiles at pH 1.2 and 6.8 for extended release tablets from Example 43 containing HPMC as the release-controlling polymer and tartaric acid as the pH modifier. [Figure 15B] 1 is a comparison of the dissolution profiles at pH 1.2 and 6.8 for extended release tablets from Example 43 containing HPMC as the release-controlling polymer and citric acid as the pH modifier. [Figure 15C] 1 is a comparison of the dissolution profiles at pH 1.2 and 6.8 for the extended release tablets from Example 43 containing HPMC as the release-controlling polymer and succinic acid as the pH modifier. [Figure 15D] 1 is a comparison of the dissolution profiles at pH 1.2 and 6.8 for extended release tablets from Example 43 containing HPMC as the release-controlling polymer and fumaric acid as the pH modifier. [Figure 15E] 1 is a comparison of dissolution profiles at pH 1.2 and 6.8 for extended release tablets from Example 43 containing Carbopol® as the release-controlling polymer and tartaric acid as the pH modifier. [Figure 15F] 1 is a comparison of dissolution profiles at pH 1.2 and 6.8 for extended release tablets from Example 43 containing Carbopol® as the release-controlling polymer and citric acid as the pH modifier. [Figure 15G] 1 is a comparison of dissolution profiles at pH 1.2 and 6.8 for extended release tablets from Example 43 containing Carbopol® as the release-controlling polymer and succinic acid as the pH modifier. [Figure 15H] 1 is a comparison of dissolution profiles at pH 1.2 and 6.8 for extended release tablets from Example 43 containing Carbopol® as the release-controlling polymer and fumaric acid as the pH modifier. [Figure 16A] FIG. 1 shows Compound 1 mean plasma concentration-time following administration of a 12 mg immediate-release capsule (Regimen A) or a 15 mg once-daily extended-release tablet (Regimen B) under fasting conditions using a linear scale. [Figure 16B]FIG. 1 shows Compound 1 mean plasma concentration-time following administration of a 12 mg immediate-release capsule (Regimen A) or a 15 mg once-daily extended-release tablet (Regimen B) under fasting conditions using a semi-logarithmic scale. [Figure 17A] FIG. 1 shows Compound 1 mean plasma concentration-time following administration of a 24 mg dose (2 x 12 mg) immediate-release capsule (Regimen C) or a 30 mg once-daily extended-release tablet (Regimen D) under fasting conditions using a linear scale. [Figure 17B] FIG. 1 shows Compound 1 mean plasma concentration-time following administration of a 24 mg dose (2 doses of 12 mg) of immediate-release capsule (Regimen C) or a 30 mg once-daily extended-release tablet (Regimen D) under fasting conditions using a semi-logarithmic scale. [Figure 18A] FIG. 1 shows Compound 1 mean plasma concentration versus time following administration of a 30 mg extended-release tablet once daily under fasting conditions (Dosage Regimen D) or a 30 mg extended-release tablet once daily after a high-fat meal (Dosage Regimen E) using a linear scale. [Figure 18B] FIG. 1 shows Compound 1 mean plasma concentration versus time following administration of a 30 mg once-daily extended-release tablet under fasting conditions (Regimen D) or a 30 mg once-daily extended-release tablet following a high-fat meal (Regimen E) using a semi-logarithmic scale. [Figure 19] FIG. 1 shows Compound 1 mean plasma concentration versus time following administration of 15 mg once-daily extended-release tablets (Regimen F) or 30 mg once-daily extended-release tablets (Regimen G) for 7 days under non-fasting conditions. [Figure 20] FIG. 1 shows Compound 1 mean plasma concentration-time following administration of 6 mg twice-daily immediate-release capsules (Dosage Regimen K) or 15 mg once-daily extended-release tablets (Dosage Regimen L) over a 7-day period under fasting conditions. [Figure 21] FIG. 1 shows Compound 1 pre-morning dose trough concentrations (Ctrough) following administration of 6 mg twice-daily immediate-release capsules or 15 mg once-daily extended-release tablets over 7 days under fasting conditions. [Figure 22] FIG. 1 shows Compound 1 mean plasma concentration-time following administration of 12 mg twice-daily immediate-release capsules (Dosage Regimen M) or 30 mg once-daily extended-release tablets (Dosage Regimen N) over a 7-day period under fasting conditions. [Figure 23] FIG. 1 shows Compound 1 pre-morning dose trough concentrations (Ctrough) following administration of 12 mg twice-daily immediate-release capsules or 30 mg once-daily extended-release tablets over 7 days under fasting conditions. [Figure 24A] FIG. 1 shows Compound 1 mean plasma concentration versus time following administration of various 30 mg once-daily extended-release tablets with various concentrations of tartaric acid under fasting conditions using a linear scale. [Figure 24B] FIG. 1 shows Compound 1 mean plasma concentration versus time following administration of various 30 mg once-daily extended-release tablets with various concentrations of tartaric acid under fasting conditions using a log-linear scale. [Figure 25A] FIG. 1 shows Compound 1 mean plasma concentration-time following administration of a 30 mg once-daily extended-release tablet (ER10) under fasting conditions or after a high-fat meal (non-fasting) using a linear scale. [Figure 25B] FIG. 1 shows Compound 1 mean plasma concentration-time following administration of a 30 mg once-daily extended-release tablet (ER10) under fasting conditions or after a high-fat meal (non-fasting) using a log-linear scale. [Figure 26A] FIG. 1 shows individual changes in Compound 1 Cmax following administration of a 30 mg once-daily extended-release tablet (ER10) under fasting conditions or after a high-fat meal (non-fasting). [Figure 26B] FIG. 1 shows the individual changes in Compound 1 AUCinf following administration of a 30 mg once-daily extended-release tablet (ER10) under fasting conditions or after a high-fat meal (non-fasting). [Figure 27A] FIG. 1 shows Compound 1 mean plasma concentration-time following administration of a 30 mg once-daily extended-release tablet (ER11) under fasting conditions or after a high-fat meal (non-fasting) using a linear scale. [Figure 27B] FIG. 1 shows Compound 1 mean plasma concentration-time following administration of a 30 mg once-daily extended-release tablet (ER11) under fasting conditions or after a high-fat meal (non-fasting) using a log-linear scale. [Figure 28A]FIG. 1 shows individual changes in Compound 1 Cmax following administration of a 30 mg once-daily extended-release tablet (ER11) under fasting conditions or after a high-fat meal (non-fasting). [Figure 28B] FIG. 1 shows the individual changes in Compound 1 AUCinf following administration of a 30 mg once-daily extended-release tablet (ER11) under fasting conditions or after a high-fat meal (non-fasting). [Figure 29A] FIG. 1 shows Compound 1 mean plasma concentration-time following administration of a 30 mg once-daily extended-release tablet (ER12) under fasting conditions or after a high-fat meal (non-fasting) using a linear scale. [Figure 29B] FIG. 1 shows Compound 1 mean plasma concentration-time following administration of a 30 mg once-daily extended-release tablet (ER12) under fasting conditions or after a high-fat meal (non-fasting) using a log-linear scale. [Figure 30A] FIG. 1 shows individual changes in Compound 1 Cmax following administration of a 30 mg once-daily extended-release tablet (ER12) under fasting conditions or after a high-fat meal (non-fasting). [Figure 30B] FIG. 1 shows the individual changes in Compound 1 AUCinf following administration of a 30 mg once-daily extended-release tablet (ER12) under fasting conditions or after a high-fat meal (non-fasting). [Figure 31] FIG. 1 shows a plot of the pH of the gel formed on the surface of tablets containing various amounts of tartaric acid. [Figure 32A] FIG. 1 shows Compound 1 mean plasma concentration-time profiles following a single oral administration of Compound 1 immediate-release capsules to healthy subjects using a linear scale. [Figure 32B] FIG. 1 shows Compound 1 mean plasma concentration-time profiles following a single oral administration of Compound 1 immediate-release capsules to healthy subjects using a log-linear scale. [Figure 33] FIG. 1 shows Compound 1 mean plasma concentration-time profiles following multiple twice-daily oral administration of Compound 1 immediate-release capsules to healthy subjects. [Figure 34A] FIG. 1 shows dose-normalized Compound 1 mean Cmax after a single dose in healthy subjects (Single Dose, Cmax). [Figure 34B]FIG. 1 shows dose-normalized Compound 1 mean Cmax after multiple dosing (Multiple Dose, Cmax) in healthy and rheumatoid arthritis subjects. [Figure 34C] FIG. 1 shows dose-normalized Compound 1 AUC after a single dose in healthy subjects (single dose, AUC∞). [Figure 34D] FIG. 1 shows dose-normalized Compound 1 AUC after multiple dosing (multiple doses, AUC0-12) in healthy and rheumatoid arthritis subjects. [Figure 35A] FIG. 1 shows the absence of effect of concomitant methotrexate administration on Compound 1 dose-normalized AUC. [Figure 35B] FIG. 1 shows the absence of effect of concomitant Compound 1 administration on methotrexate dose-normalized AUC. [Figure 36A] Figure 1 shows ACR20, ACR50, and ACR70 response rates at 12 weeks after administration of placebo or various doses of Compound 1 to subjects with active rheumatoid arthritis and an inadequate response or intolerance to prior anti-TNF biological agents (*P<0.05; **P<0.01; ***P<0.001 vs. placebo; modified intent-to-treat population (NRI)). [Figure 36B] FIG. 1 shows ACR20 response rates at 12 weeks in the same population separated by number of prior anti-TNF biologic agents. [Figure 37A] FIG. 1 shows ACR20 response over time following administration of placebo or various doses of Compound 1 to subjects with active rheumatoid arthritis and an inadequate response or intolerance to prior anti-TNF biologic agents (*P<0.05; **P<0.01; ***P<0.001 vs. placebo; modified intent-to-treat population (NRI)). [Figure 37B] FIG. 1 shows ACR50 response over time after administration of placebo or various doses of Compound 1 to subjects with active rheumatoid arthritis and an inadequate response or intolerance to prior anti-TNF biologic agents (*P<0.05; **P<0.01; ***P<0.001 vs. placebo; modified intent-to-treat population (NRI)). [Figure 37C]FIG. 1 shows ACR70 response over time after administration of placebo or various doses of Compound 1 to subjects with active rheumatoid arthritis and an inadequate response or intolerance to prior anti-TNF biologic agents (*P<0.05; **P<0.01; ***P<0.001 vs. placebo; modified intent-to-treat population (NRI)). [Figure 37D] Figure 1 shows the mean change in DAS28(CRP) from baseline over time following administration of placebo or various doses of Compound 1 to subjects with active rheumatoid arthritis and an inadequate response or intolerance to a prior anti-TNF biologic agent (*P<0.05; **P<0.01; ***P<0.001 vs. placebo; modified intent-to-treat population (NRI)). [Figure 37E] FIG. 1 shows subjects in the same population who achieved a DAS28(CRP) score ≦3.2 or <2.6 at 12 weeks. [Figure 37F] FIG. 1 shows subjects in the same population who achieve low disease activity (LDA) or clinical remission (CR) based on Clinical Disease Activity Index (CDAI) criteria at 12 weeks (LDA is CDAI≦10; CR is CDAI≦2.8). [Figure 38A] FIG. 1 shows mean hemoglobin levels over time for all subjects following administration of placebo or various doses of Compound 1 to subjects with active rheumatoid arthritis and an inadequate response or intolerance to a prior anti-TNF biologic agent (safety analysis population and observational data (missing values ​​not imputed)). [Figure 38B] FIG. 1 shows the mean hemoglobin change from baseline over time in subjects with high-sensitivity C-reactive protein (hsCRP) greater than the upper limit of normal (ULN) (normal range for hemoglobin: 11.5 to 15.5 g / dL for women, 13.2 to 17.0 g / dL for men; ULN for hsCRP = 5 mg / L). [Figure 39] FIG. 1 shows subject retention in the study described in Example 55. [Figure 40A] FIG. 1 shows subject retention in the study described in Example 56. [Figure 40B]FIG. 1 shows subject retention in the study described in Example 56. [Figure 41] Figure 1 shows ACR20, ACR50, and ACR70 responses at 12 weeks after administration of placebo or various doses of Compound 1 to subjects with active rheumatoid arthritis and an inadequate response to methotrexate (*P<0.05; **P<0.01; ***P<0.001 vs. placebo; modified intent-to-treat population and NRI for missing values). [Figure 42A] Figure 1 shows ACR20 (NRI analysis) response over time after administration of placebo or various doses of Compound 1 to subjects with active rheumatoid arthritis and an inadequate response to methotrexate (*P<0.05; **P<0.01; ***P<0.001 vs. placebo; modified intention-to-treat population). [Figure 42B] Figure 1 shows ACR50 (NRI analysis) response over time after administration of placebo or various doses of Compound 1 to subjects with active rheumatoid arthritis and an inadequate response to methotrexate (*P<0.05; **P<0.01; ***P<0.001 vs. placebo; modified intention-to-treat population). [Figure 42C] 1 shows ACR70 (NRI analysis) response over time after administration of placebo or various doses of Compound 1 to subjects with active rheumatoid arthritis and an inadequate response to methotrexate (*P<0.05; **P<0.01; ***P<0.001 vs. placebo; modified intention-to-treat population). [Figure 42D] Figure 1 shows the mean change from baseline in DAS28(CRP) (observed cases) over time after administration of placebo or various doses of Compound 1 to subjects with active rheumatoid arthritis and an inadequate response to methotrexate (*P<0.05; **P<0.01; ***P<0.001 vs. placebo; modified intention-to-treat population). [Figure 43A]43A shows subjects achieving a DAS28(CRP) score of ≦3.2 or <2.6) at 12 weeks after administration of placebo or various doses of Compound 1 to subjects with active rheumatoid arthritis and an inadequate response to methotrexate (*P<0.05; **P<0.01; ***P<0.001 vs. placebo; modified intent-to-treat population (NRI)). [For FIG. 43A, the bottom numbers indicate the percentage of subjects who achieved both cutoffs; the middle numbers indicate the percentage of subjects who achieved the less stringent but not the more stringent cutoff; and the top numbers indicate the percentage of patients who achieved either cutoff.] [Figure 43B] FIG. 43B shows subjects achieving a CDAI≦10 or ≦2.8) at 12 weeks after administration of placebo or various doses of Compound 1 to subjects with active rheumatoid arthritis and an inadequate response to methotrexate (*P<0.05; **P<0.01; ***P<0.001 vs. placebo; modified intent-to-treat population (NRI)). [For FIG. 43B, the bottom numbers indicate the percentage of subjects who achieved both cutoffs; the middle numbers indicate the percentage of subjects who achieved the less stringent but not the more stringent cutoff; and the top numbers indicate the percentage of patients who achieved either cutoff.] [Figure 44A] FIG. 1 shows the mean change in hemoglobin from baseline over time by treatment group in all subjects (safety analysis population and observational data (missing values ​​not imputed)) following administration of placebo or various doses of Compound 1 to subjects with active rheumatoid arthritis and an inadequate response to methotrexate. [Figure 44B] 1 shows the mean change in hemoglobin from baseline over time by treatment group in subjects with hsCRP≦5 mg / mL at baseline after administration of placebo or various doses of Compound 1 to subjects with active rheumatoid arthritis and an inadequate response to methotrexate (safety analysis population and observational data (missing values ​​not imputed)). [Figure 44C]1 shows the mean change in hemoglobin from baseline over time by treatment group in subjects with hsCRP > 5 mg / mL at baseline after administration of placebo or various doses of Compound 1 to subjects with active rheumatoid arthritis and an inadequate response to methotrexate (safety analysis population and observational data (missing values ​​not imputed)). DETAILED DESCRIPTION OF THE INVENTION

[0125] This description uses examples to disclose the invention and to enable one skilled in the art to practice the invention, including making and using the disclosed solid forms or compositions, and performing the disclosed methods or processes. The patentable scope of the invention is defined by the claims, and may include other examples that occur to those skilled in the art. Such other examples are intended to be encompassed by the claims if they have elements that are no different from the literal language of the claims or if they contain equivalent elements.

[0126] I.<Definition> The section headings used in this section and throughout the disclosure are not intended to limit the invention.

[0127] Where numerical ranges are recited, each intervening number within the range is expressly contemplated with the same degree of precision. For example, the range 6 to 9 specifically contemplates the numbers 7 and 8 in addition to 6 and 9, and the range 6.0 to 7.0 specifically contemplates the numbers 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0. Similarly, all recited ratios are intended to include all subratios within the broader ratio.

[0128] The singular forms "a," "an," and "the" include plural references unless the context clearly indicates otherwise.

[0129] The term "about" generally refers to a range of numbers that one of ordinary skill in the art would consider equivalent to the recited value (i.e., having the same function or result). In many instances, the term "about" may include numbers that are rounded to the nearest significant figure.

[0130] The term "alkyl" refers to a straight or branched chain hydrocarbon that is fully saturated. For purposes of illustration, and not to be construed as limiting the scope of this invention, examples of alkyl include methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, and isomers thereof.

[0131] The term "alkenyl" refers to a hydrocarbon moiety containing 2 to 8 carbons, such as a straight-chain or branched hydrocarbon containing one or more double bonds. Examples of alkenyl include ethenyl, propenyl, and butenyl.

[0132] The term "amorphous" when applied to a chemical compound refers to a state in which the material lacks long-range order at the molecular level and, depending on temperature, may exhibit the physical properties of a solid or a liquid. Typically, such materials do not give a distinctive X-ray diffraction pattern and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs, which is typically characterized by a second-order change of state (a "glass transition").

[0133] The term "anhydrous" when applied to a compound refers to the solid state in which the compound does not contain structural water within the crystal lattice.

[0134] The term "aryl" refers to a monocyclic, bicyclic, or tricyclic hydrocarbon group. Examples include phenyl, naphthyl, biphenyl, and 1,2,3,4-tetrahydronaphthyl.

[0135] Unless the context otherwise requires, the terms "comprise," "comprises," and "comprising" are used with the clear understanding that they are to be interpreted inclusively rather than exclusively, and that applicant intends that each of these terms be so interpreted in interpreting this patent, including the appended claims.

[0136] The term "crystalline" as applied to a chemical compound refers to a solid phase in which the material has a regular, ordered internal structure at the molecular level and gives a characteristic X-ray diffraction pattern with defined peaks. When heated sufficiently, such materials also exhibit the properties of a liquid, but the change from solid to liquid is characterized by a phase change that is typically first order (the "melting point").

[0137] The term "crystalline purity" refers to the crystalline purity of a compound with respect to a particular crystalline form of the compound as determined by the X-ray powder diffraction analysis methods described herein.

[0138] The term "crystallization" as used throughout this application can refer to crystallization and / or recrystallization, depending on the applicable circumstances associated with the preparation of the compound.

[0139] The term "pharmaceutically acceptable" (such as when referring to a "pharmaceutically acceptable salt" or a "pharmaceutically acceptable diluent") refers to a material that is compatible with administration to a human subject, e.g., the material does not cause undesirable physiological effects. Examples of pharmaceutically acceptable salts are described in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use," Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002). Examples of pharmaceutically acceptable excipients are described in "Handbook of Pharmaceutical Excipients," Rowe et al., Ed. (Pharmaceutical Press, 7th Ed., 2012).

[0140] The term "subject" refers to a human subject.

[0141] The terms "treat" and "treatment" refer to ameliorating, suppressing, eradicating, reducing the severity, reducing the frequency of occurrence, preventing, reducing the risk of, slowing the progression of damage caused by, or slowing the onset of, a condition, or improving the quality of life of a patient suffering from the condition.

[0142] The term "Xantphos" refers to 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.

[0143] The abbreviation "2-MeTHF" refers to 2-methyltetrahydrofuran.

[0144] The abbreviation "ACN" refers to acetonitrile.

[0145] The abbreviation "AcOH" refers to acetic acid.

[0146] As used herein, the term "AUC24,ss" refers to the steady-state area under the plasma concentration-time curve from time zero to 24 hours after administration of the reference drug. The term "AUC12,ss" refers to the steady-state area under the plasma concentration-time curve from time zero to 12 hours after administration of the reference drug.

[0147] As used herein, the term "AUC" refers to the area under the plasma concentration-time curve from time zero to infinity after a single dose, calculated using the trapezoidal rule: AUC = AUC + C / k, where C is the last measured concentration and k is the calculated terminal elimination rate constant.

[0148] As used herein, the term "AUCt" refers to the area under the plasma concentration-time curve from the time of administration of the reference drug to the time of the last measured concentration calculated using the trapezoidal rule. "AUC24" refers to the area under the plasma concentration-time curve from time zero to 24 hours after administration of the reference drug after a single dose.

[0149] The abbreviation "Bn" refers to benzyl.

[0150] As used herein, the term "C12" is the plasma concentration of the reference drug observed 12 hours after a single dose or a specified number of doses of the reference drug. The term "C12,ss" refers to C12 measured at steady state.

[0151] As used herein, the term "C24" is the plasma concentration of the reference drug observed 24 hours after a single dose or a specified number of doses of the reference drug. The term "C24,ss" refers to C24 measured at steady state.

[0152] The abbreviation "Cbz" refers to carboxybenzyl.

[0153] The abbreviation "CDI" refers to carbonyldiimidazole.

[0154] The abbreviation "CV%" refers to the coefficient of variation expressed as a percentage. CV% is calculated according to the following equation: CV%=(SD / x)*100, where x is the mean value and SD is the standard deviation.

[0155] As used herein, the term "C" refers to the plasma concentration of a reference drug at T, expressed herein as ng / mL, resulting from oral ingestion of a single dose or a specified number of doses of a formulation or pharmaceutical composition, such as the formulations and compositions of the present disclosure. Unless otherwise specified, C refers to the overall maximum observed concentration.

[0156] As used herein, the term "Cmax,ss" refers to the steady-state Cmax of the reference drug during the dosing interval.

[0157] As used herein, the term "Cmin,ss" refers to the minimum steady-state plasma concentration of the reference drug during the dosing interval.

[0158] As used herein, the term "Ctrough" refers to the trough plasma concentration of a reference drug measured at the end of a dosing interval at steady state.

[0159] The abbreviation "DBU" refers to 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0160] The abbreviation "DCHA" refers to dicyclohexylamine.

[0161] The abbreviation "DCM" refers to dichloromethane.

[0162] The abbreviation "DIPEA" refers to diisopropylethylamine.

[0163] The abbreviation "DMA" refers to dimethylacetamide, or N,N-dimethylacetamide.

[0164] The abbreviation "DMAP" refers to 4-dimethylaminopyridine.

[0165] The abbreviation "DSC" means differential scanning calorimetry.

[0166] As used herein, the term "entering the environment of use" refers to contact of the disclosed formulation with the gastric fluids of the subject to which it is administered, or with fluids that simulate gastric fluids.

[0167] The abbreviation "EtB(OH)2" refers to ethylboronic acid.

[0168] The abbreviation "EtOAc" refers to ethyl acetate.

[0169] The abbreviation "Fe(acac)3" refers to iron(III) acetylacetonate.

[0170] The abbreviation "HDPE" refers to high-density polyethylene.

[0171] The abbreviation "HOAc" refers to acetic acid.

[0172] The abbreviation "HPMC" refers to hydroxypropyl methylcellulose.

[0173] The abbreviation "IPAc" refers to isopropyl acetate.

[0174] The abbreviation "KOtBu" refers to potassium tert-butoxide.

[0175] The abbreviation "LiOtBu" refers to lithium tert-butoxide.

[0176] The abbreviation "Me3SOCl" refers to trimethylsulfoxonium chloride. The abbreviations "MeOH" and "EtOH" refer to methanol and ethanol, respectively.

[0177] The abbreviation "MS" stands for mass spectrometry.

[0178] The abbreviation "MTBE" refers to methyl tert-butyl ether.

[0179] The abbreviation "MTX" refers to methotrexate.

[0180] The abbreviation "NatOBu" or "NaOtBu" refers to sodium tert-butoxide.

[0181] The abbreviation "Ni(acac)2" refers to nickel(II) acetylacetonate.

[0182] The abbreviation "NMM" refers to N-methylmorpholine.

[0183] The abbreviation "Pd / C" refers to palladium on carbon (palladium on carbon).

[0184] The abbreviation "PdCl2(dppf)" refers to [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II).

[0185] The abbreviation "PdCl2(Ph3P)2" refers to bis(triphenylphosphine)palladium(II) dichloride.

[0186] The abbreviation "Pd(OAc)2" refers to palladium(II) acetate.

[0187] The abbreviation "Pd(OH2) / C" refers to palladium hydroxide on carbon (palladium hydroxide on carbon).

[0188] The abbreviation "PFPAA" refers to pentafluoropropionic anhydride.

[0189] The abbreviation "pTsOH" refers to p-toluenesulfonic acid.

[0190] The abbreviation "PVA" refers to polyvinyl acetate.

[0191] The abbreviation "PXRD" stands for powder X-ray diffraction.

[0192] The abbreviation "(S)-Segphos Ru(OAc)2" or "Ru(OAc)2-Segphos" refers to diacetato[(S)-(-)5,5'-bis(diphenylphosphino)-4,4'-bi-1,3-benzodioxole]ruthenium(II).

[0193] As used herein, the term "t" refers to the terminal half-life of a reference drug following oral ingestion of a single dose or a specified number of doses of the reference drug. The term "t" refers to the terminal half-life measured at steady state.

[0194] The abbreviation "TEA" refers to triethylamine.

[0195] The abbreviation "TFAA" refers to trifluoroacetic anhydride.

[0196] The abbreviation "TF2O" refers to trifluoromethanesulfonic anhydride.

[0197] The abbreviation "TGA" stands for thermogravimetric analysis.

[0198] The abbreviation "TGA-MS" stands for Thermogravimetric Analysis-Mass Spectrometer.

[0199] The abbreviation "THF" refers to tetrahydrofuran.

[0200] As used herein, the term "Tmax" refers to the time to peak plasma concentration of a reference drug after oral ingestion of a single dose or a specified number of doses of the reference drug.

[0201] As used herein, the term "Tmax,ss" refers to the time to peak plasma concentration of a reference drug after oral ingestion of the reference drug at steady state.

[0202] The abbreviation "TMS" refers to trimethylsilyl.

[0203] The term "triflate" refers to trifluoromethanesulfonate.

[0204] The abbreviation "v / v" refers to volume / volume.

[0205] The abbreviation "w / w" refers to weight / weight.

[0206] For clarity and convenience only, conventional practice will be used herein to designate the time of drug administration or the start of the dissolution test as time zero (0) (t=0 hr) and the time after administration in appropriate time increments, e.g., t=30 min or t=2 hr.

[0207] II. <Method for producing (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 intermediates> The present disclosure relates to improved 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 (referred to as "Compound 1" or "Compound 1 free base"), pharmaceutically acceptable salts of Compound 1, and intermediates used in the preparation of Compound 1. Compound 1 has the structure shown below.

[0208] [ka] Methods for making and using this compound are described, for example, in International Patent Application WO2011 / 068881A1, which is incorporated herein by reference.

[0209] Previously disclosed methods for preparing Compound 1 and its pharmaceutically acceptable salts have drawbacks. In particular, these methods utilize particularly hazardous reagents, such as trimethylsilyldiazomethane or diazomethane, and / or do not yield crystalline products. The disclosed methods overcome these drawbacks by avoiding the use of these hazardous reagents and yielding crystalline intermediates that are useful for purification.

[0210] The compounds of the present disclosure can be prepared using synthetic transformations such as those depicted in Schemes I to XVI. Starting materials can be commercially available, prepared by procedures described herein, by literature procedures, or by procedures that would be known to one skilled in the art of organic chemistry (see, for example, Larock, RC "Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd edition", 1999, Wiley-VCH or Greene, TW and Wuts, PGM "Protective Groups in Organic Synthesis, 3rd Edition", 1999, Wiley-Interscience).

[0211] A. Preparation of Compound 1 In one aspect, the present disclosure relates to a method for preparing Compound 1, or a pharmaceutically acceptable salt thereof. The method for preparing Compound 1 is depicted in Scheme I. Reaction of protected (3R,4S)-4-ethylpyrrolidine-3-carboxylic acid (I), or a pharmaceutically acceptable salt thereof, with trimethylsulfoxonium chloride provides sulfur ylide (II). Contacting sulfur ylide (II) with LiX and a sulfonic acid provides the corresponding halomethyl ketone (III). Reaction of (III) with (IV) in the presence of a base provides (V). Cyclization of (V) in the presence of a perfluoroanhydride and an organic base provides (VI). Removal of the protecting group and contacting the deprotected compound with an acid provides a pharmaceutically acceptable salt of (VII). Reaction of a pharmaceutically acceptable salt of (VII) with 2,2,2-trifluoroethylamine provides Compound 1.

[0212] [ka] During the ceremony, PG is a protecting group; X is Br or Cl; R1 is selected from the group consisting of alkyl, aryl, and -OR2; R2 is alkyl; Ts is tosyl.

[0213] The protecting group can be any suitable protecting group known in the art. In some embodiments, the protecting group is selected from the group consisting of carboxybenzyl, p-methoxybenzylcarbonyl, benzyl, p-methoxybenzyl, and 3,4-dimethoxybenzyl. In other embodiments, the protecting group is carboxybenzyl.

[0214] In another embodiment, R1 is -OR2 and R2 is methyl or ethyl. In such an embodiment, the compound of formula (IV) is a compound of formula (IVa):

[0215] [ka] and R2 is methyl or ethyl. Surprisingly, it has been found that when R2 is ethyl or methyl, the compound of formula (V) and subsequent downstream compounds can be isolated as crystalline solids, which are useful for purifying these intermediates. In contrast, known methods using compounds in which R2 is t-butyl produce compounds of formula (V) that are isolated as amorphous solids.

[0216] In certain embodiments, a pharmaceutically acceptable salt of a compound of Formula (I) is used in the reaction of step (a). In one embodiment, the pharmaceutically acceptable salt of a compound of Formula (I) is selected from the group consisting of naphthaleneethanamine salt (Ia) and dicyclohexylamine salt (Ib).

[0217] [ka] TIFF2026004431000063.tif29154In the formula, Cbz is carboxybenzyl.

[0218] In one embodiment, the pharmaceutically acceptable salt of compound (VII) is selected from the group consisting of (VIIa), (VIIb), and (VIIc).

[0219] [ka]

[0220] An alternative method for preparing compound 1 is depicted in Scheme Ia. Reaction of (3R,4S)-1-((benzyloxy)carbonyl)-4-ethylpyrrolidine-3-carboxylate dicyclohexylamine salt (Ib) with trimethylsulfoxonium chloride in the presence of carbonyldiimidazole and a strong base provides sulfur ylide (IIa). Contact of sulfur ylide (IIa) with lithium bromide and sulfonic acid provides the corresponding bromomethyl ketone (IIIa). Reaction of (IIIa) with alkyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate (IVa) in the presence of lithium tert-butoxide provides (Va). Cyclization of (Va) in the presence of perfluoroanhydride and an organic base produces (VIa). Removal of the carboxybenzyl protecting group and contacting the deprotected compound with hydrochloric acid provides the pharmaceutically acceptable salt (VIIa). Reaction of the pharmaceutically acceptable salt (VIIa) with 2,2,2-trifluoroethylamine produces compound 1.

[0221] [ka] During the ceremony, Cbz is carboxybenzyl; Ts is tosyl; R2 is methyl or ethyl.

[0222] The reaction in step (a) of Schemes I and Ia is generally carried out in the presence of a coupling agent, such as carbonyldiimidazole (CDI), and a strong base. The strong base can be, for example, potassium tert-butoxide, sodium tert-butoxide, or a combination thereof. The reaction in step (a) can be carried out in any suitable solvent, such as, but not limited to, tetrahydrofuran, water, and methyl tert-butyl ether. In one embodiment, the reaction is carried out in the presence of carbonyldiimidazole and potassium tert-butoxide.

[0223] Specifically, in certain embodiments, a solution of a compound of Formula (I), (Ia), or (Ib) in a solvent is slowly added (e.g., over 30 minutes) to a slurry of CDI in the solvent, and the resulting mixture is stirred at room temperature for 30 minutes to 12 hours, typically about 1 hour. The resulting solution is slowly added (e.g., over 15 minutes) to a suspension of trimethylsulfoxonium chloride, a strong base, and the solvent, while maintaining an internal temperature below -1°C. In another embodiment, the reaction is stopped, and the resulting compound of Formula (II) or (IIa) is isolated prior to step (b).

[0224] In some embodiments, the reaction in step (a) further comprises contacting (Ia) or (Ib) with an acid to extract the amine prior to the reaction with trimethylsulfoxonium chloride to obtain a compound of Formula (I). Suitable acids include any mineral or organic acid, such as phosphoric acid, hydrochloric acid (HCl), acetic acid (HOAc), citric acid, and the like. The compound of Formula (I) can then be taken up in a suitable solvent and reacted with trimethylsulfoxonium chloride according to the methods described herein. In one embodiment, a pharmaceutically acceptable salt of a compound of Formula (I) is used in step (a), and the pharmaceutically acceptable salt is (Ia) or (Ib), and the reaction in step (a) is carried out according to the procedure described in Step A of Example 3.

[0225] In step (b) of Schemes I and Ia, a compound of formula (II) or (IIa) is contacted with LiX and a sulfonic acid to form a compound of formula (III) or (IIIa), respectively. In one embodiment, the sulfonic acid is selected from the group consisting of methanesulfonic acid and p-toluenesulfonic acid. In one embodiment, the sulfonic acid is p-toluenesulfonic acid. LiX can be selected from lithium bromide and lithium chloride. In one embodiment, LiX is lithium bromide. In one embodiment, the reaction is carried out in lithium bromide and p-toluenesulfonic acid. The reaction of step (b) can be carried out in any suitable solvent, such as, but not limited to, tetrahydrofuran, ethyl acetate, heptane, ethanol, water, and combinations thereof.

[0226] Specifically, in certain embodiments, a sulfonic acid is added to a solution of a compound of Formula (II) or (IIa) and LiX in a solvent. The resulting mixture is warmed to about 35° C. to about 65° C. and stirred overnight. In one embodiment, the mixture is warmed to about 40° C. and stirred overnight. The mixture is cooled to room temperature and washed. The compound of Formula (III) or (IIIa) can be isolated or, optionally, used in the next step without purification.

[0227] In step (c) of Schemes I and Ia, a compound of Formula (III) or (IIIa) is reacted with a compound of Formula (IV) or (IVa) (prepared according to the methods described herein). The step (c) reaction is carried out in the presence of a base, such as lithium tert-butoxide, sodium tert-butoxide, or a combination thereof. In one embodiment, the base is lithium tert-butoxide. The step (c) reaction can be carried out in any suitable solvent, such as, but not limited to, dimethylacetamide, tetrahydrofuran, dichloromethane, ethyl acetate, heptane, and combinations thereof.

[0228] Specifically, in certain embodiments, a base is added to a cooled suspension of a compound of Formula (III) or (IIIa) in a solvent. The resulting solution is stirred for about 30 minutes to about 12 hours, or about 30 minutes, and then cooled to about −20° C. to about 0° C., or about −10° C. In one embodiment, the solution is stirred for about 30 minutes and then cooled to about −20° C. to about 0° C. The solution of a compound of Formula (IV) or (IVa) in a solvent is slowly added (e.g., over 30 minutes), and the resulting mixture is stirred at a temperature of about −20° C. to about 0° C., or about −10° C. for about 30 minutes to about 6 hours, or about 30 minutes. In one embodiment, after adding the solution of a compound of Formula (IV) or (IVa) in a solvent, the resulting mixture is stirred at a temperature of about −10° C. for about 30 minutes. In one embodiment, the reaction is stopped, and in some embodiments, the resulting product (V) or (Va) is isolated prior to step (d).

[0229] In step (d) of Schemes I and Ia, a compound of Formula (V) or (Va) is contacted with a perfluoroacid anhydride and an organic base to form a compound of Formula (VI) or (VIa), respectively. Non-limiting examples of suitable organic bases include pyridine, triethylamine, and combinations thereof. Examples of suitable perfluoroacid anhydrides include trifluoroacetic anhydride, pentafluoropropionic anhydride, heptafluorobutyric anhydride, and combinations thereof. In certain embodiments, the organic base is pyridine and the perfluoroacid anhydride is trifluoroacetic anhydride. In other embodiments, the organic base is triethylamine and the perfluoroacid anhydride is pentafluoropropionic anhydride. Suitable solvents for use in step (d) include, but are not limited to, acetonitrile, toluene, and combinations thereof.

[0230] Specifically, in certain embodiments, an organic base and a perfluoroacid anhydride are placed in a solution of a compound of Formula (V) or (Va) in a solvent. The resulting mixture is heated to about 55° C. to about 75° C., or to about 55° C., and stirred for about 4 hours to about 18 hours, or about 6 hours. In one embodiment, the mixture of the perfluoroacid anhydride and a compound of Formula (V) or (Va) is heated to about 55° C. and stirred for about 4 hours to about 18 hours. In one embodiment, the mixture is stirred for about 6 hours. Upon completion of the reaction, in some embodiments, the reaction mixture can be cooled, concentrated, and then contacted with a hydroxide solution to quench excess reagents and remove the tosyl protecting group. Suitable hydroxide solutions include sodium hydroxide (NaOH) solution, potassium hydroxide (KOH) solution, and the like. The resulting mixture can be stirred at room temperature to about 85° C., e.g., at about 55° C., for about 30 minutes to about 8 hours. In one embodiment, the mixture is stirred for about 1 hour. Once complete, the solvent may be removed and replaced with methanol, ethanol, isopropanol or other suitable solvent prior to step (e).

[0231] In step (e) of Schemes I and Ia, the compound of Formula (VI) or (VIa) is deprotected to form a pharmaceutically acceptable salt of compound (VII), e.g., (VIIa), (VIIb), or (VIIc). The protecting group on the compound of Formula (VI) or (VIa) can be removed using any suitable means known in the art. In one embodiment, deprotection is achieved by contacting the compound of Formula (VI) or (VIa) with palladium on carbon (e.g., Pd / C or Pd(OH) / C) under hydrogen pressure. In another embodiment, deprotection is achieved by contacting the compound of Formula (VI) or (VIa) with an acid. Non-limiting examples of suitable acids include hydrochloric acid (HCl), hydrobromic acid (HBr), and hydrobromic acid / acetic acid (e.g., HBr / HOAc). In other embodiments, deprotection is carried out by heating the compound of formula (VI) or (VIa), for example, at a temperature from room temperature to about 85° C., for example, about 50° C. Once deprotected, the compound of formula (VII) is contacted with a suitable acid (e.g., hydrochloric acid or p-toluenesulfonic acid) to form a pharmaceutically acceptable salt.

[0232] Step (e) can be carried out in any suitable solvent, such as, but not limited to, ethanol, isopropyl acetate, ethyl acetate, and combinations thereof.

[0233] Specifically, in some embodiments, palladium on carbon and a compound of Formula (VI) or (VIa) in a solvent are combined under a hydrogen pressure of about 1 psig to about 100 psig. In another embodiment, the hydrogen pressure is about 20 psig. The mixture is stirred at about 20° C. to about 85° C., for example, about 50° C., for about 2 hours to about 24 hours, for example, about 16 hours. In one embodiment, the mixture is stirred at about 20° C. to about 80° C. for about 16 hours. In one embodiment, the mixture is stirred at about 50° C. for about 16 hours. Upon completion of the reaction, the reaction mixture is cooled and filtered, followed by the addition of an appropriate acid. The resulting salt may be isolated prior to step (f).

[0234] In step (f), the salt produced in step (e) is reacted with 2,2,2-trifluoroethylamine to produce compound 1. The step (f) reaction is carried out in the presence of a coupling agent, such as carbonyldiimidazole (CDI), and optionally a buffer, such as dipotassium phosphate, potassium hydroxide, and combinations thereof. In one embodiment, the step (f) reaction is carried out in the presence of CDI, dipotassium phosphate, and potassium hydroxide. The step (f) reaction can be carried out in any suitable solvent, such as, but not limited to, tetrahydrofuran, ethyl acetate, heptane, ethanol, water, and combinations thereof.

[0235] Specifically, in certain embodiments, 2,2,2-trifluoroethylamine is added slowly (e.g., over 20 minutes) to a slurry of CDI in a solvent while maintaining an internal temperature below 30° C. The resulting solution is stirred for about 10 minutes to about 12 hours, and in one embodiment, about 1 hour, to form an imidazolide solution. The pH of the two-phase mixture in the pharmaceutically acceptable salt buffer and solvent from step (e) is adjusted to about 7 to about 11, and in one embodiment, to about 9, by adding a base. The imidazolide solution is added, and the resulting mixture is blended for about 30 minutes to about 18 hours, while maintaining the pH at about 9 by adding a base in small increments. In one embodiment, the mixture formed after adding the imidazolide solution is blended at about 25° C. for about 1 hour, while maintaining the pH at about 9 by adding a base in small increments. In one embodiment, upon completion, the reaction is stopped, and the resulting product is isolated.

[0236] In one embodiment, compound 1 is prepared according to the method described in Scheme Ia. In certain embodiments, the method can further include preparing (Ib) according to the method described in Scheme V herein.

[0237] An alternative preparation of compound 1 is depicted in Scheme II. Reaction of protected (3R,4S)-4-ethylpyrrolidine-3-carboxylic acid (I) or a pharmaceutically acceptable salt thereof with trimethylsulfoxonium chloride provides the sulfur ylide (II). Contact of sulfur ylide (II) with LiX and sulfonic acid provides the corresponding halomethyl ketone (III). Reaction of (III) with (IV) in the presence of a base provides (V). Cyclization of (V) in the presence of a perfluoroanhydride and an organic base produces (VI). Removal of the protecting group and contact of the deprotected compound (VII) (not shown) with hydrochloric acid provides the pharmaceutically acceptable salt (VIIb). Converting the pharmaceutically acceptable salt (VIIb) to the free base (VII) and reacting it with 2,2,2-trifluoroethylamine produces compound 1. Compound 1 is contacted with L-tartaric acid to form the corresponding tartrate salt, which then forms Compound 1 free base.

[0238] [ka] wherein PG, Ts, X, and R1 are as defined above.

[0239] The protecting group can be any suitable protecting group known in the art. In some embodiments, the protecting group is selected from the group consisting of carboxybenzyl, p-methoxybenzylcarbonyl, benzyl, p-methoxybenzyl, and 3,4-dimethoxybenzyl. In one embodiment, the protecting group is carboxybenzyl.

[0240] In one embodiment, R1 is -OR2, and R2 is ethyl or methyl.

[0241] In certain embodiments, a pharmaceutically acceptable salt of a compound of Formula (I) is used in the reaction of step (a). In one embodiment, the pharmaceutically acceptable salt of a compound of Formula (I) is selected from the group consisting of naphthaleneethanamine salt (Ia) and dicyclohexylamine salt (Ib).

[0242] Steps (a) through (e) of Scheme II are carried out in a manner similar to that described above for Scheme I, and after deprotection of the compound of formula (VI), the deprotected compound (VII) is contacted with hydrochloric acid to form the pharmaceutically acceptable salt (VIIb).

[0243] In step (f) of Scheme II, salt (VIIb) is contacted with a base to form the corresponding free base (VII). Suitable bases include, but are not limited to, hydroxides such as sodium hydroxide, potassium hydroxide, and the like, and combinations thereof. In one embodiment, the base is sodium hydroxide. The reaction of step (f) can be carried out in any suitable aqueous solvent, such as, but not limited to, water alone or in combination with THF, 2-methyltetrahydrofuran, ethanol, methanol, and the like.

[0244] In step (g), compound (VII) is reacted with 2,2,2-trifluoroethylamine to produce compound 1. The reaction of step (g) is carried out in the presence of a coupling agent, such as CDI. Step (g) in Scheme II is carried out using similar reagents and under similar conditions as described above for step (f) of Scheme I.

[0245] In step (h) of Scheme II, compound 1 is contacted with L-tartaric acid to form the corresponding tartrate salt (step (h)). Formation of the tartrate salt advantageously aids in the removal of impurities prior to isolation of the free base. In one embodiment, the tartrate salt can be formed using the procedure described in Example 8, Method B, only the tartrate salt is not dried prior to step (i). The tartrate salt is then converted back to the free base form (step (i)) to produce compound 1. In particular, in step (i), the tartrate salt can be contacted with a base, such as an inorganic base, to produce the corresponding free base. Suitable bases include, but are not limited to, sodium bicarbonate, sodium carbonate, sodium hydroxide, potassium carbonate, potassium bicarbonate, potassium hydroxide, or the like, or combinations thereof. In one embodiment, the tartrate salt is contacted with sodium bicarbonate and sodium carbonate to produce the corresponding free base.

[0246] Suitable solvents for use in step (h) include, but are not limited to, isopropyl acetate, methyl tert-butyl ether, water, isopropyl alcohol, and combinations thereof. Suitable solvents for use in step (i) include, but are not limited to, ethyl acetate, ethanol, water, and combinations thereof.

[0247] In some embodiments, the products of steps (d), (e), (g), and (h) of Scheme II are not isolated prior to the next step.

[0248] An alternative method for preparing compound 1 is depicted in Scheme III. Compound (XIa) is hydrogenated to produce (I). Reaction of protected (3R,4S)-4-ethylpyrrolidine-3-carboxylic acid (I) with trimethylsulfoxonium chloride provides the sulfur ylide (II). Contact of sulfur ylide (II) with an anhydrous source of HBr or HCl provides the corresponding halomethyl ketone (III). Reaction of (III) with (IV) in the presence of a base provides (V). Cyclization of (V) in the presence of a perfluoroanhydride and an organic base provides (VI). Removal of the protecting group and contact of the deprotected compound with an acid provides a pharmaceutically acceptable salt of (VII). Reaction of a pharmaceutically acceptable salt of (VII) with 2,2,2-trifluoroethylamine provides compound 1.

[0249] [ka] During the ceremony, PG is a protecting group; X is Br or Cl; R1 is selected from the group consisting of alkyl, aryl, and -OR2; R2 is alkyl; Ts is tosyl.

[0250] The protecting group can be any suitable protecting group known in the art. In some embodiments, the protecting group is selected from the group consisting of carboxybenzyl, p-methoxybenzylcarbonyl, benzyl, p-methoxybenzyl, and 3,4-dimethoxybenzyl. In other embodiments, the protecting group is carboxybenzyl.

[0251] In another embodiment, R1 is -OR2 and R2 is methyl or ethyl. In such an embodiment, the compound of formula (IV) is a compound of formula (IVa):

[0252] [ka] (R2 is methyl or ethyl.) Surprisingly, it has been found that when R2 is ethyl or methyl, the compound of formula (V) and subsequent downstream compounds can be isolated as crystalline solids that aid in the purification of these intermediates. In contrast, known methods using compounds in which R2 is t-butyl produce compounds of formula (V) that are isolated as amorphous solids.

[0253] An alternative method for preparing compound 1 is depicted in Scheme IIIa. 1-((benzyloxy)carbonyl)-4-ethyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid (XI) is hydrogenated to produce (XII). Reaction of (3R,4S)-1-((benzyloxy)carbonyl)-4-ethylpyrrolidine-3-carboxylate (XII) with trimethylsulfoxonium chloride provides the sulfur ylide (IIa). Contact of sulfur ylide (IIa) with a source of anhydrous HBr provides the corresponding bromomethyl ketone (IIIa). Reaction of (IIIa) with alkyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate (IVa) in the presence of lithium tert-butoxide provides (Va). Cyclization of (Va) in the presence of perfluoroanhydride and an organic base provides (VIa). Removal of the carboxybenzyl protecting group and contacting the deprotected compound with hydrochloric acid provides the pharmaceutically acceptable salt (VIIa). Compound 1 is prepared by reaction of the pharmaceutically acceptable salt (VIIa) with 2,2,2-trifluoroethylamine.

[0254] [ka] During the ceremony, Cbz is carboxybenzyl; Ts is tosyl; R2 is methyl or ethyl.

[0255] In step (a) of Schemes III and IIIa, (XIa) or (XI) (which can be prepared according to the method described in Scheme V) is converted to (I) or (XII), respectively. In particular, in step (a), compound (XI) or (XIa) can be contacted with a catalyst, such as a ruthenium catalyst. Any chiral phosphine-containing catalyst can be used. One specific example of a suitable catalyst is diacetato[(S)-(-)5,5'-bis(diphenylphosphino)-4,4'-bi-1,3-benzodioxole]ruthenium(II) (i.e., (S)-SegphosRu(OAc)2). Suitable solvents for use in step (a) include, but are not limited to, methanol, triethylamine, and combinations thereof.

[0256] Specifically, in certain embodiments, a solution of (XI) or (XIa) and the catalyst in a solvent is hydrogenated at about 30° C. to about 100° C. for about 1 hour to about 18 hours. In one embodiment, a solution of (XI) or (XIa) and the catalyst in a solvent is hydrogenated at about 4.00 MPa (about 580 psi). In one embodiment, a solution of (XI) or (XIa) and the catalyst in a solvent is hydrogenated at about 200 psi gauge (psig). In one embodiment, a solution of (XI) or (XIa) and the catalyst in a solvent is hydrogenated at about 80° C. for about 1 hour to about 8 hours, or about 2 hours, or about 4 hours. Upon completion, the reaction mixture is cooled to room temperature, filtered, and concentrated. In one particular embodiment, step (a) of Schemes III and IIIa is carried out according to the method described in Step A of Example 4.

[0257] The reaction in step (b) of Schemes III and IIIa is carried out in the presence of a coupling agent, such as carbonyldiimidazole (CDI), and a strong base. The strong base can be, for example, potassium tert-butoxide, sodium tert-butoxide, or a combination thereof. The step (b) reaction can be carried out in any suitable solvent, such as, but not limited to, tetrahydrofuran, water, and methyl tert-butyl ether. In one embodiment, the reaction is carried out in the presence of carbonyldiimidazole and potassium tert-butoxide.

[0258] Specifically, in certain embodiments, a suspension of trimethylsulfoxonium chloride, a strong base, and a solvent is heated (e.g., from about 35°C to about 65°C, or about 45°C) for about 30 minutes to about 8 hours, or about 1 hour, and then cooled. In one embodiment, the suspension is cooled to a temperature of about -1°C or below, or about -5°C or below. In some embodiments, the concentrated filtrate from step (a) is diluted with a suitable solvent (e.g., tetrahydrofuran), and CDI is slowly added to the solution (e.g., over 30 minutes to 1 hour, or over 30 minutes). The resulting mixture is stirred at room temperature for 30 minutes to 12 hours, typically about 1 hour. The resulting solution is slowly added (e.g., over 15 minutes to 1 hour, or over 1 hour) to the suspension of trimethylsulfoxonium chloride, a strong base, and a solvent, while maintaining an internal temperature of -1°C or below. In examples, the reaction can be stirred at a temperature of about -1°C or below, or about -5°C, for about 30 minutes to about 8 hours, or about 1 hour. In another embodiment, the reaction is stopped and the resulting compound of Formula (II) or (IIa) is isolated prior to step (c). In one particular embodiment, step (b) of Scheme III or IIIa is carried out according to the method described in Step A of Example 4.

[0259] Steps (a) and (b) of Schemes III and IIIa advantageously allow the preparation of protected (3R,4S)-4-ethylpyrrolidine-3-carboxylic acid without the formation and isolation of the naphthaleneethanamine salt (Ia) or dicyclohexylamine salt (Ib) or the isolation of (I) or (XI).

[0260] In step (c) of Schemes III and IIIa, a compound of formula (II) or (IIa) is contacted with an anhydrous source of HBr or HCl to form a compound of formula (III) or (IIIa), respectively. In particular, the anhydrous source of HBr or HCl contains 0.2% or less water (by volume), or about 0.15% or less water (by volume). The reaction of step (c) can be carried out in any suitable solvent, such as tetrahydrofuran.

[0261] Specifically, in certain embodiments, (II) or (IIa) is combined with HBr or HCl in a suitable solvent. In one embodiment, the solvent is tetrahydrofuran and acetic acid. In one embodiment, the solvent contains 0.2% or less water (by volume). In one embodiment, (II) or (IIa) is combined with a solvent (e.g., THF) and a solution of HBr / HOAc. The resulting mixture is warmed to about 35° C. to about 65° C., or about 40° C., and stirred. In one embodiment, the mixture is stirred for about 4 hours to about 12 hours, or about 5 hours. In one embodiment, the mixture is warmed to about 40° C. and stirred (e.g., stirred) for about 5 hours. In one embodiment, the mixture is cooled to room temperature (e.g., about 20° C.), distilled, and then washed. In one particular embodiment, the product (compound (III) or (IIIa)) is concentrated to dryness and resuspended in a solvent (e.g., N,N-dimethylacetamide) to provide a solution of (III) or (IIIa), which is used in step (d). In one embodiment, step (c) of Scheme III or IIIa is carried out according to the method described in Step B of Example 4.

[0262] Advantageously, step (c) produces the halomethyl ketone (III) or (IIIa) in higher purity than Schemes I and Ia.

[0263] In step (d) of Schemes III and IIIa, a compound of Formula (III) or (IIIa) is reacted with a compound of Formula (IV) or (IVa) (prepared according to the methods described herein). The reaction of step (d) is carried out in the presence of a base, such as lithium tert-butoxide, sodium tert-butoxide, or a combination thereof. In one embodiment, the base is lithium tert-butoxide. The reaction of step (d) can be carried out in any suitable solvent, including, but not limited to, dimethylacetamide, tetrahydrofuran, dichloromethane, ethyl acetate, heptane, and combinations thereof.

[0264] Specifically, in certain embodiments, a base is slowly added (e.g., over about 30 minutes) to a cooled suspension of a compound of Formula (IV) or (IVa) in a solvent. In one embodiment, the suspension of a compound of Formula (IV) or (IVa) is cooled to about 0°C. The resulting solution is stirred for about 30 minutes to about 12 hours, or about 30 minutes, and then cooled to about -20°C to about 0°C, or about -10°C. In one embodiment, the solution is stirred for about 30 minutes and then cooled to about -20°C to about 0°C, or about -10°C. The halomethyl ketone solution prepared in step (c) is then slowly added (e.g., over about 1 hour), and the resulting mixture is stirred (e.g., stirred) at a temperature of about -20°C to about 0°C, or about -10°C for about 30 minutes to about 6 hours, or about 30 minutes. In one embodiment, after adding the step (c) solution, the resulting mixture is stirred at a temperature of about -10°C for about 30 minutes. In one embodiment, the reaction is stopped and, in some embodiments, the resulting product (V) or (Va) is isolated prior to step (e). In one embodiment, step (d) of Schemes III and IIIa is carried out according to the method described in Step C of Example 4.

[0265] Steps (e) through (g) of Schemes III and IIIa can be carried out according to the methods described above for steps (d) through (f) of Scheme I, respectively.

[0266] In one embodiment, compound 1 is prepared according to the method described in Scheme IIIa.

[0267] B. Preparation of Compounds of Formulae (I), (Ia), (Ib), and (XIa) The method for preparing Compound 1 disclosed herein can employ a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and / or a compound of Formula (XI) or (XIa). In one embodiment, the method employs either the naphthaleneethanamine salt of Formula (Ia) or the dicyclohexylamine salt of Formula (Ib). Compounds of Formula (I) and (Ia) and their preparation are described, for example, in US 2013 / 0072470, incorporated herein by reference. (Ia) can also be prepared according to the method described in Scheme IV, described below. (Ib) can be prepared according to the method described in Scheme V, described below. Compounds of Formula (I) in which PG is Cbz (i.e., compounds of Formula (XII)) can be prepared using the procedures described in Scheme IV or V. Compounds of Formula (XI) can be prepared using the procedures described in Scheme V. Other protecting groups can be substituted for Cbz using techniques known to those skilled in the art.

[0268] <Formula (Ia)> The preparation of (Ia) has been reported (see, e.g., US 2013 / 0072470, Example 12, incorporated herein by reference). One suitable method for preparing the naphthaleneethanamine salt of the compound of Formula (I) is depicted in Scheme IV. Ethyl pent-2-ynoate is hydrogenated with a Lindlar catalyst to form (Z)-ethyl pent-2-enoate. (Z)-ethyl pent-2-enoate is reacted with N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine to form (XIII). (XIII) is deprotected to form (XIV), which is then hydrolyzed to form (XV). (XV) is reacted with N-(benzyloxycarbonyloxy)succinimide to form (XVI). Protected (XVI) is contacted with (R)-1-(naphthalen-1-yl)ethanamine to form (Ia).

[0269] [ka] During the ceremony, TMS is trimethylsilyl; Cbz is carboxybenzyl; Bn is benzyl.

[0270] In step (a) of Scheme IV, ethyl pent-2-ynoate is hydrogenated over a Lindlar catalyst to form (Z)-ethyl pent-2-enoate. In particular, in certain embodiments, ethyl pent-2-ynoate is added to a slurry of Lindlar's catalyst in a solvent (e.g., THF) and an organic base (e.g., pyridine). Hydrogen is sparged through the reaction mixture (e.g., for about 15 hours). In one embodiment, upon completion of the reaction, the reaction mixture is filtered and the (Z)-ethyl pent-2-enoate is washed prior to step (b).

[0271] In step (b) of Scheme IV, (Z)-ethyl pent-2-enoate is reacted with N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine to form (XIII). Specifically, to a solution of (Z)-ethyl pent-2-enoate and N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine in a solvent (e.g., dichloromethane (DCM)), trifluoroacetic acid (TFA) is added. After about two days, the reaction mixture is concentrated to provide (XIII).

[0272] In steps (c) and (d) of Scheme IV, (XIII) is deprotected to form (XIV), followed by hydrolysis of (XIV) to form (XV). Any suitable means known in the art can be used to deprotect (XIII), such as those described above for step (e) of Scheme I. In one embodiment, (XIII) is deprotected by contacting (XIII) with a catalyst (e.g., a palladium catalyst such as Pd / C or Pd(OH) / C) under hydrogen pressure. In one embodiment, the resulting mixture is filtered to provide (XIV). In step (d), (XIV) is contacted with an acid (e.g., HCl). In one embodiment, the reaction mixture is typically heated (e.g., to about 100° C.) for about 24 hours. The reaction mixture is cooled and concentrated. In step (e), the reaction mixture from step (d) containing (XV) is reacted with N-(benzyloxycarbonyloxy)succinimide (e.g., for about 15 hours) to form (XVI).

[0273] In step (f) of Scheme IV, (XVI) is contacted with (R)-1-(naphthalen-1-yl)ethanamine to form (Ia).

[0274] <Formula (Ib)> In some embodiments, the present disclosure relates to compound (Ib) and a method for preparing compound (Ib). Scheme V depicts a method for preparing the dicyclohexylamine salt of compound of Formula (I). Carboxybenzyl-glycine ethyl ester is reacted with ethyl acrylate to form (VIII). Protection of (VIII) provides (IX). Contact of (IX) with one of ethyl boronate, ethyl magnesium bromide, or ethyl zinc chloride in the presence of a catalyst provides (X). Hydrolysis of (X) provides (XI), which is hydrogenated to provide (XII). Contact of (XII) with dicyclohexylamine provides (Ib).

[0275] [ka] During the ceremony, Cbz is carboxybenzyl; R3 is selected from the group consisting of CF3SO2-, CH3SO2-, and tosyl.

[0276] In step (a) of Scheme V, carboxybenzyl-glycine ethyl ester is reacted with ethyl acrylate to form (VIII). The step (a) reaction is carried out in the presence of a strong base. Suitable bases include, but are not limited to, sodium tert-butoxide, potassium tert-butoxide, and lithium tert-butoxide. In one embodiment, the strong base is sodium tert-butoxide. In one embodiment, the step (a) reaction is carried out in an organic solvent such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 2-methyltetrahydrofuran, and the like, and combinations thereof.

[0277] In particular, in certain embodiments, a base is added slowly (e.g., over 1 hour) to a mixture of carboxybenzyl-glycine ethyl ester and ethyl acrylate in a solvent at about -5°C to about 20°C. In one embodiment, a base is added slowly (e.g., over 1 hour) to a mixture of carboxybenzyl-glycine ethyl ester and ethyl acrylate in a solvent at about 0°C. The resulting mixture is allowed to warm to room temperature and stirred overnight. In one embodiment, upon completion, the reaction is stopped and the product is crystallized. The product may be isolated prior to step (b).

[0278] In step (b) of Scheme V, a compound of formula (VIII) is protected to form (IX). In one embodiment, the compound of formula (VIII) is reacted with a reagent selected from the group consisting of trifluoromethanesulfonic anhydride, methanesulfonyl chloride, and p-toluenesulfonyl chloride to form (IX). In one embodiment, the step (b) reaction is carried out in the presence of an organic base. Suitable organic bases include, but are not limited to, diisopropylethylamine (DIPEA), 4-dimethylaminopyridine (DMAP), triethylamine (TEA), pyridine, N-methylmorpholine (NMM), and combinations thereof. The step (b) reaction can be carried out in any suitable solvent, such as, but not limited to, triethylamine, N-methylmorpholine, pyridine, diisopropyl ether, and combinations thereof.

[0279] In particular, in certain embodiments, trifluoromethanesulfonic anhydride, methanesulfonyl chloride, or p-toluenesulfonyl chloride is added to a mixture of (VIII) in a solvent at about -5°C to about 20°C. In one embodiment, trifluoromethanesulfonic anhydride, methanesulfonyl chloride, or p-toluenesulfonyl chloride is added to a mixture of (VIII) in a solvent at a temperature of about 0°C. An organic base is then added slowly (e.g., over about 30 minutes), and the mixture is allowed to warm to room temperature and stirred for about 30 minutes to about 18 hours. In one embodiment, the mixture is stirred for about 1 hour. Upon completion, the reaction is preferably quenched and the product is washed. In some embodiments, a solution of (IX) in a solvent is prepared and used directly in step (c).

[0280] In step (c) of Scheme V, (IX) is contacted with one of ethylboronic acid, ethylmagnesium bromide, or ethylzinc chloride in the presence of a catalyst to produce (X). Any suitable catalyst known in the art can be used. In certain embodiments, the catalyst is a palladium catalyst, such as PdCl(dppf). In some embodiments, the catalyst is a nickel catalyst, such as Ni(acac). In some embodiments, the catalyst is an iron catalyst, particularly an Fe(III) catalyst, such as FeCl and Fe(acac). Step (c) can be carried out in a buffer solution. Suitable buffers include, but are not limited to, potassium carbonate, sodium carbonate, potassium phosphate tribasic, and combinations thereof. Suitable solvents for use in step (c) include, but are not limited to, toluene, water, dioxane, tetrahydrofuran, and combinations thereof.

[0281] In particular, in certain embodiments, ethylboronic acid and a buffering agent are added to the solution of (IX) in the solvent prepared in step (b). A suitable catalyst can then be added, and the resulting mixture is heated to about 75°C to about 110°C, or about 85°C, and stirred for about 4 hours to about 18 hours, or about 6 hours. In one embodiment, the mixture is heated to about 85°C and stirred for about 6 hours. Upon completion, the reaction mixture is cooled to room temperature, and the product is filtered. In one embodiment, the product is isolated prior to step (d).

[0282] In step (d), (X) is hydrolyzed to produce (XI). (X) can be hydrolyzed using any suitable means known in the art. In one embodiment, (X) is contacted with an alkali metal hydroxide. The alkali metal hydroxide can be selected from the group consisting of sodium hydroxide and lithium hydroxide. In one embodiment, the alkali metal hydroxide is sodium hydroxide. Any suitable solvent can be used in the step (d) reaction, such as, but not limited to, tetrahydrofuran, water, dioxane, and combinations thereof.

[0283] In particular, in certain embodiments, an alkali metal hydroxide is added to a solution of (X) in a solvent. The resulting mixture is warmed to about 20° C. to about 65° C. and stirred for about 2 hours to about 18 hours. In one embodiment, the mixture is warmed to about 50° C. and stirred for about 2 hours to about 18 hours. In one embodiment, the mixture is stirred for about 7 hours. Upon completion, the mixture is cooled to room temperature, the pH is adjusted to about 9, and the solvent is removed. In one embodiment, the product is washed and isolated prior to step (e).

[0284] In steps (e) and (f) of Scheme V, (XI) is converted to (XII), which is then contacted with dicyclohexylamine to form (Ib). In particular, in step (e), compound (XI) can be contacted with a catalyst, such as a ruthenium catalyst. A catalyst containing any chiral phosphine can be used. One specific example of a suitable catalyst is diacetato[(S)-(-)5,5'-bis(diphenylphosphino)-4,4'-bi-1,3-benzodioxole]ruthenium(II) (i.e., (S)-SegphosRu(OAc)2). Suitable solvents for use in step (e) include, but are not limited to, methanol, triethylamine, and combinations thereof.

[0285] Specifically, in certain embodiments, a solution of (XI) and the catalyst in a solvent is hydrogenated at about 30° C. to about 100° C. for about 1 hour to about 18 hours. In one embodiment, a solution of (XI) and the catalyst in a solvent is hydrogenated at about 4.00 MPa (about 580 psi). In one embodiment, a solution of (XI) and the catalyst in a solvent is hydrogenated at about 80° C. for about 1 hour to about 8 hours, or about 2 hours. Upon completion, the reaction mixture is cooled to room temperature, filtered, and concentrated. In one embodiment, prior to step (f), the product is washed and transferred to a suitable solvent, such as acetonitrile. In step (f), additional solvent (e.g., acetonitrile) and dicyclohexylamine are added, and the mixture is heated to about 50° C. to about 80° C. In one embodiment, the mixture is heated to about 80° C. The resulting solution is cooled to room temperature and stirred for about 1 hour to about 18 hours. In one embodiment, the mixture is cooled to room temperature and stirred for about 1 hour. The resulting product (Ib) can be isolated prior to use in the preparation of Compound 1.

[0286] C.<Intermediate compound> In some embodiments, the present disclosure relates to intermediate compounds useful in the preparation of Compound 1, as well as methods for making the intermediate compounds.

[0287] <Formula (IVa)> In one embodiment, the present disclosure relates to a compound of formula (IVa):

[0288] [ka] wherein R2 and Ts are as defined above.

[0289] As described herein and depicted in Schemes I, II, and III, a compound of formula (IVa) can be reacted with a compound of formula (III) or (IIIa) to produce a compound of formula (V) or (Va). Advantageously, reaction of a compound of formula (IVa) with a compound of formula (III) or (IIIa) in Schemes I, II, or III results in a crystalline product due to the methyl carbamate or ethyl carbamate moiety present on the compound of formula (IVa).

[0290] In another aspect, the present disclosure relates to a method for preparing a compound of formula (IVa). One suitable method for preparing a compound of formula (IVa) is depicted in Scheme VI. In particular, (XVII) is reacted with trimethylsilylacetylene in the presence of a catalyst to form (XVIII). (XVIII) is contacted with p-toluenesulfonyl chloride in the presence of a base to form (XIX). (XIX) is reacted with ethyl carbamate or methyl carbamate in the presence of a catalyst and a ligand to form a compound of formula (IVa).

[0291] [ka] During the ceremony, R2 is methyl or ethyl; Ts is tosyl; TMS is trimethylsilyl.

[0292] In step (a) of Scheme VI, commercially available compound (XVII) is reacted with trimethylsilylacetylene in the presence of a catalyst to form (XVIII). Any suitable catalyst known in the art can be used. In some embodiments, the catalyst is a palladium catalyst, such as bis(triphenylphosphine)palladium(II) dichloride (PdCl(PhP)). Step (a) is typically carried out in the presence of copper(I) iodide (CuI). Any suitable solvent can be used in step (a), such as, but not limited to, triethylamine.

[0293] In particular, in certain embodiments, a catalyst is added to a solution of (XVII) and CuI in a solvent. The reaction mixture is cooled (e.g., to about -5 to 0°C), and a solution of trimethylsilylacetylene in a solvent is added slowly (e.g., over about 15 minutes). The reaction mixture is stirred at about -5 to 0°C (e.g., for about 1.5 hours) and allowed to warm to room temperature overnight. In one embodiment, the reaction mixture is filtered and washed to isolate the product prior to step (b).

[0294] In step (b) of Scheme VI, (XVIII) is contacted with p-toluenesulfonyl chloride in the presence of a base to form (XIX). Suitable bases for use in step (b) include, but are not limited to, potassium tert-butoxide, sodium hydride, and the like, and combinations thereof. Suitable solvents for use in step (b) include, but are not limited to, dimethylformamide.

[0295] In particular, in certain embodiments, a base is added to a solution of (XVIII) in a solvent (e.g., at about 0°C). p-Toluenesulfonyl chloride is then added, and the mixture is allowed to warm to room temperature. After reaction (e.g., about 16 hours), the reaction mixture is poured into ice-cold water, and the precipitate is collected. In one embodiment, the product is isolated and purified prior to step (c).

[0296] In step (c) of Scheme VI, (XIX) is reacted with ethyl carbamate or methyl carbamate in the presence of a catalyst and a ligand to form a compound of formula (IVa). The reaction can be carried out in the presence of a buffer, such as potassium carbonate, tetramethylammonium hydroxide, or the like. Any suitable catalyst known in the art can be used in step (c). In one embodiment, the catalyst is a palladium catalyst, such as palladium(II) acetate. Suitable ligands for use in step (c) include bidentate ligands, such as xantphos. In one embodiment, the catalyst is palladium(II) acetate and the ligand is xantphos. Suitable solvents for use in step (c) include, but are not limited to, dioxane, toluene, and tetrahydrofuran.

[0297] Specifically, in certain embodiments, a degassed mixture of catalyst, ligand, (XIX), carbamate, and buffer in a solvent is heated to about 75° C. to about 110° C., or about 95° C., and stirred overnight. Upon completion, the reaction mixture is cooled to about 30° C. to about 60° C. In one embodiment, the reaction mixture is cooled to about 50° C. Optionally, additional solvent can be added, and the resulting solution is filtered. In another embodiment, the product is washed and isolated before use in 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.

[0298] Compound (XVII) used in Scheme VI is commercially available. The preparation of compounds (XVIII) and (XIX) is also described in Example 1 of WO2011 / 068881 (incorporated herein by reference).

[0299] <Formula (II)> In one aspect, the present disclosure relates to a compound of formula (II):

[0300] [ka] In the formula, PG is a protecting group.

[0301] The protecting group can be any suitable protecting group known in the art, hi some embodiments, the protecting group is selected from the group consisting of carboxybenzyl, p-methoxybenzylcarbonyl, benzyl, p-methoxybenzyl, and 3,4-dimethoxybenzyl.

[0302] In one preferred embodiment, the protecting group is carboxybenzyl and the compound of formula (II) is compound (IIa).

[0303] [ka] In the formula, Cbz is carboxybenzyl.

[0304] In another aspect, the present disclosure relates to a method for preparing a compound of Formula (II) or (IIa). One method for preparing a compound of Formula (II) or (IIa) is depicted in Scheme VII. In Scheme VII, a compound of Formula (I) or a pharmaceutically acceptable salt thereof is reacted with trimethylsulfoxonium chloride to form a compound of Formula (II). In one particular embodiment, the pharmaceutically acceptable salt is a compound of Formula (Ib).

[0305] [ka] wherein PG is a protecting group as defined herein.

[0306] The reaction of Scheme VII is typically carried out in the presence of a coupling agent, such as carbonyldiimidazole (CDI), and a strong base. The strong base can be, for example, potassium tert-butoxide, sodium tert-butoxide, or a combination thereof. The reaction of Scheme VII can be carried out in any suitable solvent, including, but not limited to, tetrahydrofuran, water, and methyl tert-butyl ether. In one embodiment, the reaction is carried out in the presence of carbonyldiimidazole and potassium tert-butoxide. In one embodiment, the reaction of Scheme VII is carried out under the conditions described above for step (a) of Scheme I.

[0307] An alternative method for preparing a compound of formula (II) or (IIa) is depicted in Scheme VIII. In step (a) of Scheme VIII, a compound of formula (XIa) is hydrogenated to give a compound of formula (I), and in step (b) of Scheme VIII, the compound of formula (I) is reacted with trimethylsulfoxonium chloride to form a compound of formula (II).

[0308] [ka] wherein PG is a protecting group as defined herein.

[0309] In step (a) of Scheme VIII, the compound of Formula (XIa) can be contacted with a catalyst, such as a ruthenium catalyst. Any chiral phosphine-containing catalyst can be used. One specific example of a suitable catalyst is diacetato[(S)-(-)5,5'-bis(diphenylphosphino)-4,4'-bi-1,3-benzodioxole]ruthenium(II) (i.e., (S)-SegphosRu(OAc)2). Suitable solvents for use in step (a) include, but are not limited to, methanol, triethylamine, and combinations thereof. In one embodiment, the reaction in step (a) of Scheme VIII is carried out under the conditions described above for step (a) of Scheme III.

[0310] The reaction in step (b) of Scheme VIII is typically carried out in the presence of a coupling agent, such as carbonyldiimidazole (CDI), and a strong base. The strong base can be, for example, potassium tert-butoxide, sodium tert-butoxide, or a combination thereof. The reaction in step (b) can be carried out in any suitable solvent, including, but not limited to, tetrahydrofuran, water, and methyl tert-butyl ether. In one embodiment, the reaction is carried out in the presence of carbonyldiimidazole and potassium tert-butoxide. In one embodiment, the reaction in step (b) of Scheme VIII is carried out under the conditions described above for step (b) of Scheme III.

[0311] <Formula (III)> In another embodiment, the present disclosure relates to a method for preparing a compound of formula (III):

[0312] [ka] In the formula, PG is a protecting group and X is Br or Cl.

[0313] The protecting group can be any suitable protecting group known in the art, hi some embodiments, the protecting group is selected from the group consisting of carboxybenzyl, p-methoxybenzylcarbonyl, benzyl, p-methoxybenzyl, and 3,4-dimethoxybenzyl.

[0314] In one preferred embodiment, the protecting group is carboxybenzyl, X is Br, and the compound of formula (III) is compound (IIIa).

[0315] [ka] In the formula, Cbz is carboxybenzyl.

[0316] One method for preparing compounds of formula (III) or (IIIa) is depicted in Scheme IX.

[0317] [ka] wherein PG and X are as defined herein.

[0318] Referring to Scheme IX, in one embodiment, a compound of Formula (II) is contacted with LiX and a sulfonic acid to form a compound of Formula (III). In this embodiment, the sulfonic acid is selected from the group consisting of methanesulfonic acid and p-toluenesulfonic acid. In one embodiment, the sulfonic acid is p-toluenesulfonic acid. LiX can be selected from lithium bromide and lithium chloride. In one embodiment, LiX is lithium bromide. In one embodiment, the reaction is carried out in lithium bromide and p-toluenesulfonic acid. The reaction can be carried out in any suitable solvent, such as, but not limited to, tetrahydrofuran, ethyl acetate, heptane, ethanol, water, and combinations thereof. In one embodiment, the reaction of Scheme XI is carried out under the conditions described above for step (b) of Scheme I.

[0319] Referring to Scheme IX, in another embodiment, a compound of Formula (II) is contacted with an anhydrous source of HBr or HCl to form a compound of Formula (III). The reaction can be carried out in any suitable solvent, such as, but not limited to, tetrahydrofuran, ethyl acetate, acetic acid, N,N-dimethylacetamide, heptane, and combinations thereof. In one embodiment, the reaction of Scheme IX is carried out under the conditions described above for step (c) of Scheme III.

[0320] In some embodiments, the method for preparing a compound of Formula (III) or (IIIa) can further comprise preparing a compound of Formula (II). One such method is depicted in Scheme X.

[0321] [ka] wherein PG and X are as defined above.

[0322] In Scheme X, a compound of Formula (I) or a pharmaceutically acceptable salt thereof is reacted with trimethylsulfoxonium chloride in the presence of carbonyldiimidazole and a strong base (e.g., potassium tert-butoxide, sodium tert-butoxide, and combinations thereof) to form a compound of Formula (II). Following the method described above in Scheme IX, a compound of Formula (II) is contacted with LiX and a sulfonic acid to form a compound of Formula (III). In one embodiment, step (a) of Scheme X is carried out under the conditions described above for step (a) of Scheme I. In one embodiment, the protecting group is carboxybenzyl, and the compound of Formula (II) is compound (IIa). In another embodiment, in step (a) of Scheme X, a pharmaceutically acceptable salt of a compound of Formula (I) is reacted with trimethylsulfoxonium chloride to form a compound of Formula (II). In one embodiment, the salt is (Ia) or (Ib).

[0323] In some embodiments, the method for preparing a compound of Formula (III) or (IIIa) can further comprise preparing a compound of Formula (I) and (II). One such method is depicted in Scheme XI.

[0324] [ka] wherein PG and X are as defined above.

[0325] In step (a) of Scheme XI, a compound of Formula (XIa) is hydrogenated to a compound of Formula (I), and in step (b), the compound of Formula (I) is reacted with trimethylsulfoxonium chloride in the presence of CDI and a strong base (e.g., K0tBu, NatOBu, and combinations thereof) to form a compound of Formula (II). The compound of Formula (II) is then contacted with an anhydrous source of HBr or HCl to form a compound of Formula (III), according to the method described above for Scheme IX. In one embodiment, the protecting group is carboxybenzyl, and the compounds of Formulas (XIa), (I), and (II) are compounds (XI), (XII), and (IIa), respectively. In one embodiment, steps (a), (b), and (c) of Scheme XI are carried out under the conditions described above for steps (a), (b), and (c) of Scheme III, respectively.

[0326] <Formulas (V) and (Va)> In another embodiment, the present disclosure relates to a compound of formula (Va):

[0327] [ka] wherein R2, Cbz, and Ts are as defined above.

[0328] In another aspect, the present disclosure relates to a method for preparing a compound of Formula (V) or (Va). One method for preparing a compound of Formula (V) or (Va) is depicted in Scheme XII. In Scheme XII, a compound of Formula (I) or a pharmaceutically acceptable salt thereof is reacted with trimethylsulfoxonium chloride to form a compound of Formula (II). Contact of the compound of Formula (II) with LiX and a sulfonic acid provides the corresponding halomethyl ketone (III). Reaction of the compound of Formula (III) with a compound of Formula (IV) in the presence of a base provides a compound of Formula (V).

[0329] [ka] wherein PG, Ts, R1, and X are as defined above.

[0330] The protecting group can be any suitable protecting group known in the art, hi some embodiments, the protecting group is selected from the group consisting of carboxybenzyl, p-methoxybenzylcarbonyl, benzyl, p-methoxybenzyl, and 3,4-dimethoxyenzyl.

[0331] In one embodiment, the protecting group is carboxybenzyl and the compound is a compound of formula (Va): In one embodiment, the protecting group is carboxybenzyl and X is Br.

[0332] In one embodiment, R1 is -OR2 and R2 is methyl or ethyl. In such an embodiment, the compound of formula (IV) is a compound of formula (IVa).

[0333] In certain embodiments, the reaction of step (a) of Scheme XII employs a pharmaceutically acceptable salt of a compound of Formula (I). In one embodiment, the pharmaceutically acceptable salt of a compound of Formula (I) is selected from the group consisting of naphthaleneethanamine salts (Ia) and dicyclohexylamine salts (Ib).

[0334] The reaction in step (a) of Scheme XII is typically carried out in the presence of a coupling agent, such as carbonyldiimidazole (CDI), and a strong base. The strong base can be, for example, potassium tert-butoxide, sodium tert-butoxide, or a combination thereof. The step (a) reaction can be carried out in any suitable solvent, such as, but not limited to, tetrahydrofuran, water, and methyl tert-butyl ether. In one embodiment, the reaction is carried out in the presence of carbonyldiimidazole and potassium tert-butoxide.

[0335] In step (b) of Scheme XII, a compound of Formula (II) or (IIa) is contacted with LiX and a sulfonic acid to form a compound of Formula (III) or (IIIa), respectively. In one embodiment, the sulfonic acid is selected from the group consisting of methanesulfonic acid and p-toluenesulfonic acid. In one embodiment, the sulfonic acid is p-toluenesulfonic acid. LiX can be selected from lithium bromide and lithium chloride. In one embodiment, LiX is lithium bromide. In one embodiment, the reaction is carried out in lithium bromide and p-toluenesulfonic acid. The reaction of step (b) can be carried out in any suitable solvent, such as, but not limited to, tetrahydrofuran, ethyl acetate, heptane, ethanol, water, and combinations thereof.

[0336] In step (c) of Scheme XII, a compound of Formula (III) or (IIIa) is reacted with a compound of Formula (IV) or (IVa) (prepared according to the methods described herein). The reaction of step (c) is carried out in the presence of a base, such as lithium tert-butoxide, sodium tert-butoxide, or a combination thereof. In one embodiment, the base is lithium tert-butoxide. The reaction of step (c) can be carried out in any suitable solvent, such as, but not limited to, dimethylacetamide, tetrahydrofuran, dichloromethane, ethyl acetate, heptane, and combinations thereof.

[0337] In one embodiment, steps (a), (b), and (c) of Scheme XII are carried out under the conditions described herein for the corresponding steps of Scheme I.

[0338] In another aspect, the present disclosure relates to an alternative method for preparing a compound of Formula (V) or (Va). One method for preparing a compound of Formula (V) or (Va) is depicted in Scheme XIII. In Scheme XIII, a compound of Formula (XIa) is hydrogenated to provide a compound of Formula (I), which is then reacted with trimethylsulfoxonium chloride to form a compound of Formula (II). Contacting the compound of Formula (II) with an anhydrous source of HBr or HCl provides the corresponding halomethyl ketone (III). Reaction of the compound of Formula (III) with a compound of Formula (IV) in the presence of a base provides a compound of Formula (V).

[0339] [ka] wherein PG, Ts, R1, and X are as defined above.

[0340] The protecting group can be any suitable protecting group, such as those described herein. In one embodiment, the protecting group is carboxybenzyl, and the compounds of formula (XIa), (I), (II), (III), (IV), and (V) are compounds (XI), (XII), (IIa), (IIIa), (IVa), and (Va), respectively. In one embodiment, the protecting group is carboxybenzyl, and X is Br. In one embodiment, R1 is -OR2, and R2 is methyl or ethyl. In such an embodiment, the compound of formula (IV) is a compound of formula (IVa).

[0341] In step (a) of Scheme XIII, the compound of formula (XIa) can be contacted with a catalyst, such as a ruthenium catalyst. Any chiral phosphine-containing catalyst can be used. One specific example of a suitable catalyst is diacetato[(S)-(-)5,5'-bis(diphenylphosphino)-4,4'-bi-1,3-benzodioxole]ruthenium(II) (i.e., (S)-SegphosRu(OAc)2). Suitable solvents for use in step (a) include, but are not limited to, methanol, triethylamine, and combinations thereof.

[0342] In one embodiment, the reaction of step (a) of Scheme XIII is carried out under the conditions described above for step (a) of Scheme III.

[0343] The reaction in step (b) of Scheme XIII is typically carried out in the presence of a coupling agent, such as carbonyldiimidazole (CDI), and a strong base. The strong base can be, for example, potassium tert-butoxide, sodium tert-butoxide, or a combination thereof. The step (b) reaction can be carried out in any suitable solvent, such as, but not limited to, tetrahydrofuran, water, and methyl tert-butyl ether. In one embodiment, the reaction is carried out in the presence of carbonyldiimidazole and potassium tert-butoxide. In one embodiment, the reaction in step (b) of Scheme XIII is carried out under the conditions described above for step (b) of Scheme III.

[0344] In step (c) of Scheme XIII, a compound of Formula (II) is contacted with an anhydrous source of HBr or HCl to form a compound of Formula (III). The reaction can be carried out in any suitable solvent, such as, but not limited to, tetrahydrofuran, ethyl acetate, acetic acid, N,N-dimethylacetamide, heptane, and combinations thereof. In one embodiment, the reaction of step (c) of Scheme XIII is carried out under the conditions described above for step (c) of Scheme III.

[0345] In step (d) of Scheme XIII, a compound of Formula (III) is reacted with a compound of Formula (IV) or (IVa) (prepared according to the methods described herein). The step (d) reaction is carried out in the presence of a base, such as lithium tert-butoxide, sodium tert-butoxide, or a combination thereof. In one embodiment, the base is lithium tert-butoxide. The reaction of step (d) can be carried out in any suitable solvent, such as, but not limited to, dimethylacetamide, tetrahydrofuran, dichloromethane, ethyl acetate, heptane, and combinations thereof. In one embodiment, the reaction of step (d) of Scheme XIII is carried out under the conditions described above for step (d) of Scheme III.

[0346] As described herein, it has surprisingly been discovered that when R1 is -OR2 and R2 is ethyl or methyl, the compound of formula (V) and subsequent downstream compounds can be isolated as crystalline solids that aid in the purification of these intermediates. Accordingly, in another aspect, the present disclosure relates to a method for preparing a crystalline compound of formula (V). The method comprises: a) reacting a compound of formula (III):

[0347] [ka] with a compound of formula (IV):

[0348] [ka] to produce a compound of Formula (V), wherein PG is a protecting group; X is Br or Cl; R is -OR; R is methyl or ethyl; and T is tosyl. In one embodiment, the process is carried out under the conditions described above for step c) in Scheme XII or step (d) in Scheme XIII.

[0349] <Formula (VII)> In another embodiment, the present disclosure provides compound (VII):

[0350] [ka] or a pharmaceutically acceptable salt thereof.

[0351] In one embodiment, the pharmaceutically acceptable salt of (VII) is selected from the group consisting of (VIIa), (VIIb), and (VIIc).

[0352] [ka] TIFF2026004431000090.tif30159

[0353] In some embodiments, any of the methods 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 described herein may further include forming one of the solid forms described herein in Section III.

[0354] III.<Solid type> The present disclosure also relates to solid forms of Compound 1. As with all pharmaceutical compounds and compositions, the chemical and physical properties of Compound 1 are important in its commercial development. These properties include, but are not limited to, (1) packing properties such as molar volume, bulk density, and hygroscopicity; (2) thermodynamic properties such as melting point, vapor pressure, and solubility; (3) mechanical properties such as dissolution rate and stability (including stability under environmental conditions, particularly moisture, and under storage conditions); (4) surface properties such as surface area, wettability, interfacial tension, and shape; (5) mechanical properties such as hardness, tensile strength, compactibility, moldability, flow, and mixing; and (6) filtration properties. These properties can affect, for example, the processing and storage of the compound and pharmaceutical compositions containing the compound.

[0355] It would be desirable to have a solid state form of Compound 1 that improves one or more of these properties compared to other solid state forms of Compound 1. It has been difficult to isolate a pharmaceutically acceptable solid state form of Compound 1 that can be manufactured and formulated on a commercial scale.

[0356] The amorphous free base form of Compound 1 typically has higher solubility and bioavailability than most of the corresponding crystalline forms of the compound. The amorphous free base also has acceptable chemical stability. However, it is hygroscopic, and environmental control may be required to ensure adequate control of potency and water content during storage, formulation, and handling of the amorphous free base. Furthermore, the amorphous free base exhibits an oiling-out limit close to the as-manufactured solubility curve.

[0357] Crystalline hydrochloride solvate form AA, crystalline hydrochloride solvate form BB, and crystalline hydrochloride solvate form CC typically convert to amorphous hydrochloride salts upon ambient drying. The resulting amorphous hydrochloride salts are hygroscopic. Low yields were typically obtained for each crystalline hydrochloride salt. Hydrochloride solvate form AA, hydrochloride solvate form BB, and hydrochloride solvate form CC may not be suitable for large-scale manufacturing.

[0358] The crystalline L-maleate salt form generally has reduced chemical stability compared to the amorphous free base, free base hydrate Form C, and tartrate salt hydrate, and may not exhibit pharmaceutically acceptable stability for use as an active ingredient in pharmaceutical formulations.

[0359] The tartrate hydrate form has acceptable chemical stability, high solubility, fairly good impurity rejection upon isolation, and is not hygroscopic. However, tartrate hydrate presents challenges due to its lack of physical stability, which also impacts manufacturing. Tartrate hydrate dehydrates to an amorphous state at low relative humidity and elevated temperatures, e.g., <10% RH at 25°C. It is unsuitable for compression into tablet form because it can be converted to amorphous tartrate by shear and compression. Furthermore, the filter cake solidifies upon drying, requiring additional drying control.

[0360] Free base hydrate Form B has been manufactured on a large scale without the need for labor-intensive and expensive techniques such as spray drying. It also provided adequate control of the bulk properties of the amorphous free base. However, the amorphous free base, when isolated via free base hydrate Form B, exhibited poor impurity rejection and required a dry environment for storage and relative humidity control during manufacturing and packaging.

[0361] Free base hydrate Form B was not physically stable. It desolvates (or dehydrates) and converts to the amorphous free base upon drying. Free base hydrate Form B generally did not exhibit pharmaceutically acceptable physical stability for use as an active ingredient in pharmaceutical formulations, although it may be a useful intermediate in the preparation of other solid forms, such as the amorphous free base.

[0362] After many years of experimentation, while attempting to scale up the amorphous free base, the free base hydrate Form C was unexpectedly discovered, which offers many surprising and superior properties over the amorphous free base, tartrate salt hydrate, and other forms of Compound 1.

[0363] Free base hydrate Form C generally exhibits excellent chemical stability, physical stability, and solid-state properties, such as low hygroscopicity and columnar morphology. Free base hydrate Form C has improved bulk properties, such as powder flow and bulk density, which are advantageous in formulation processes. Furthermore, free base hydrate Form C offers at least the following unexpected advantages over other forms: 1) efficient purification is achieved because tartrate crystals are not required; 2) the seeding step is simplified because free base hydrate Form C can be stored at standard conditions; 3) the drying step can be performed at standard conditions using standard equipment because no dehydration occurs until around 110°C; and 4) free base hydrate Form C can be crystallized to different particle sizes. Large-scale production of free base hydrate Form C is relatively straightforward due to minimal scale generation, good yield, good impurity rejection, rapid filtration, conventional drying, and minimal grinding issues. Furthermore, free base hydrate Form C can be grown to different particle sizes.

[0364] Free base anhydrous Form D can only be produced when the crystallization solvent has a low water content; at high water contents, it converts to free base hydrate Form C in solution. Therefore, strict control of water content is required for the production of free base anhydrous Form D. Free base anhydrous Form D crystallizes slowly and is difficult to produce in relatively high yields. This anhydrous form is reversibly hygroscopic (up to 1.8% water at 90% RH and 25°C) and is metastable compared to free base hydrate Form C under typical environmental conditions used during storage for downstream processing (e.g., greater than 2.4% RH at 23°C). Free base hydrate Form C converts to free base anhydrous Form D in solution in ethyl acetate with low water content.

[0365] The following sections discuss the solid forms that have been identified and the particular properties of those solid forms.

[0366] A. <Amorphous free base> In one embodiment, the solid form is amorphous Compound 1 ("amorphous free base"). In one embodiment, the amorphous free base contains less than about 13% water by weight. In another embodiment, the amorphous free base contains less than about 12% water by weight. In another embodiment, the amorphous free base contains less than about 10% water by weight. In another embodiment, the amorphous free base contains less than about 9% water by weight. In another embodiment, the amorphous free base contains less than about 8% water by weight. In another embodiment, the amorphous free base contains less than about 7% water by weight. In another embodiment, the amorphous free base contains less than about 6% water by weight. In another embodiment, the amorphous free base contains less than about 5% water by weight. In another embodiment, the amorphous free base contains less than about 4% water by weight. In another embodiment, the amorphous free base contains less than about 3% water by weight. In another embodiment, the amorphous free base contains less than about 2% water by weight. In another embodiment, the amorphous free base contains less than about 1% water by weight. In another embodiment, the amorphous free base has a glass transition onset temperature of about 119° C. In another embodiment, the amorphous free base has a glass transition midpoint temperature of about 122° C. In another embodiment, the amorphous free base has a glass transition onset temperature of about 119° C. and a glass transition midpoint temperature of about 122° C. The amorphous free base is further described in the Examples section of this application.

[0367] Amorphous free base generally has higher solubility and bioavailability than the corresponding crystalline form of the compound. Amorphous free base also has acceptable chemical stability. For example, when chemical stability was evaluated in sealed vials at 30°C / 65% relative humidity and 40°C / 75% relative humidity for 12 weeks and at 50°C / 75% relative humidity for 6 weeks, no decomposition of the amorphous free base was observed in the sealed vial under either of these conditions. Furthermore, amorphous free base exhibits acceptable stability against light and peroxide. However, amorphous free base is hygroscopic and can contain as much as 12% water by weight at 25°C / 90% relative humidity. Environmental controls may be required to ensure adequate control of potency and water content during storage, formulation, and handling of the amorphous free base.

[0368] Amorphous free base can be prepared, for example, by using antisolvent crystallization to produce free base solvate Form A or free base hydrate Form B (described below), followed by dehydration or desolvation to obtain the amorphous free base. This crystallization / dehydration / desolvation method allows for large-scale production of amorphous free base without the need for labor-intensive and expensive techniques such as spray drying. It also provides adequate control over the bulk properties (i.e., particle size, flow characteristics, etc.) of the amorphous free base. When amorphous free base is prepared by desolvation of free base solvate Form A or dehydration of free base hydrate Form B, the amorphous free base typically retains the morphology of free base solvate Form A or free base hydrate Form B (i.e., hexagonal-faced blade shape when prepared by dehydration of free base hydrate Form B, or amorphous shape when desolvated from free base solvate Form A).

[0369] The process volumes required for crystallization during large-scale production of free base solvate Form A or free base hydrate Form B are within conventional process volumes, but impurity rejection may be lower than desired. Drying and dehydration / desolvation of free base hydrate Form B / free base solvate Form A to form amorphous free base can generally be accomplished under conventional conditions using standard equipment, and the isolated amorphous free base can typically be co-milled without adversely affecting the amorphous state.

[0370] B. Crystalline Free Base Solvates and Hydrates In another embodiment, the solid form is a crystalline free base of Compound 1. In one aspect, the crystalline free base is a solvate. In another aspect, the crystalline free base is an isopropyl acetate / water solvate ("Free Base Solvate Form A"). In another aspect, the crystalline free base is a hydrate ("Free Base Hydrate Form B"). Free Base Solvate Form A and Free Base Hydrate Form B are further described in the Examples of this application.

[0371] In one embodiment, the crystalline free base solvate or 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 2θ when measured at about 25° C. with monochromated Kα1 light.

[0372] In one embodiment, the crystalline free base solvate or 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 2θ, and further characterized by one or more peaks at 13.7±0.2, 20.8±0.2, and 25.0±0.2 degrees 2θ, when measured at about 25°C with monochromated Kα1 light.

[0373] In one embodiment, the crystalline free base solvate or hydrate has an X-ray powder diffraction pattern characterized by peaks at 3.1±0.2, 9.3±0.2, 12.0±0.2, and 20.8±0.2 degrees 2θ, measured at about 25°C with monochromated Kα1 light.

[0374] In one embodiment, the crystalline free base solvate or hydrate has an X-ray powder diffraction pattern characterized by peaks at 3.1±0.2, 9.3±0.2, 12.0±0.2, and 25.0±0.2 degrees 2θ, when measured at about 25°C with monochromated Kα1 light.

[0375] In one embodiment, the crystalline free base solvate or hydrate has an X-ray powder diffraction pattern characterized by peaks at 3.1±0.2, 9.3±0.2, 12.0±0.2, 20.8±0.2, and 25.0±0.2 degrees 2θ, measured at about 25°C with monochromated Kα1 light.

[0376] In one embodiment, the crystalline free base solvate or hydrate has an X-ray powder diffraction pattern characterized by peaks at 3.1±0.2, 9.3±0.2, 12.0±0.2, 13.7±0.2, 20.8±0.2, and 25.0±0.2 degrees 2θ, when measured at about 25°C with monochromated Kα1 light.

[0377] In one embodiment, the crystalline free base solvate or hydrate has an X-ray powder diffraction pattern with no significant peaks at or above 15.1±0.2 and 21.7±0.2 degrees 2θ, when measured at about 25°C with monochromated Kα1 light.

[0378] In one embodiment, the crystalline free base solvate or hydrate has an X-ray powder diffraction pattern with no significant peaks at one or more of 3.9±0.2, 6.8±0.2, and 14.1±0.2 degrees 2θ, when measured at about 25°C with monochromated Kα1 light.

[0379] In one embodiment, the crystalline free base solvate or hydrate has an X-ray powder diffraction pattern with no significant peaks at greater than one of 15.1±0.2 and 21.7±0.2 degrees 2θ, and no significant peaks at greater than one of 3.9±0.2, 6.8±0.2, and 14.1±0.2 degrees 2θ, when measured at about 25°C with monochromated Kα1 light.

[0380] In one embodiment, the crystalline free base solvate or 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 2θ, and no significant peaks at one or more of 15.1±0.2 and 21.7±0.2 degrees 2θ, when measured at about 25°C with monochromated Kα1 light.

[0381] In one embodiment, the crystalline free base solvate or 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 2θ, and no significant peaks at one or more of 3.9±0.2, 6.8±0.2, and 14.1±0.2 degrees 2θ, when measured at about 25°C with monochromated Kα1 light.

[0382] In one embodiment, the crystalline free base solvate or 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 2θ, and no significant peaks at one or more of 15.1±0.2, and 21.7±0.2 degrees 2θ, and no significant peaks at one or more of 3.9±0.2, 6.8±0.2, and 14.1±0.2 degrees 2θ, when measured at about 25°C with monochromated Kα1 light.

[0383] In one embodiment, the crystalline free base solvate or 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, 13.7±0.2, 20.8±0.2, and 25.0±0.2 degrees 2θ, and no significant peaks at one or more of 15.1±0.2 and 21.7±0.2 degrees 2θ, when measured at about 25°C with monochromated Kα1 light.

[0384] In one embodiment, the crystalline free base solvate or 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, 13.7±0.2, 20.8±0.2, and 25.0±0.2 degrees 2θ, and no significant peaks at one or more of 3.9±0.2, 6.8±0.2, and 14.1±0.2 degrees 2θ, when measured at about 25°C with monochromated Kα1 light.

[0385] In one embodiment, the crystalline free base solvate or 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, 13.7±0.2, 20.8±0.2, and 25.0±0.2 degrees 2θ, and no significant peaks at one or more of 15.1±0.2 and 21.7±0.2 degrees 2θ, and no significant peaks at one or more of 3.9±0.2, 6.8±0.2, and 14.1±0.2 degrees 2θ, when measured at about 25°C with monochromated Kα1 light.

[0386] In one embodiment, the crystalline free base solvate or hydrate has an X-ray powder diffraction pattern characterized by peaks at locations substantially listed in Table 16-A ±0.2° 2θ when measured at about 25°C with monochromated Kα1 light.

[0387] In one embodiment, the crystalline free base solvate or hydrate has an X-ray powder diffraction pattern characterized by peaks at locations substantially listed in Table 16-B ±0.2° 2θ when measured at about 25° C. with monochromated Kα1 light.

[0388] In one embodiment, the crystalline free base solvate or hydrate has an X-ray powder diffraction pattern characterized by peaks at positions listed in Table 16-B ±0.2° 2θ having a relative intensity of substantially at least 10.0% when measured at about 25°C with monochromated Kα1 light.

[0389] In further aspects of each of the above embodiments, the significant peak values ​​have a variation of ±0.1° 2θ instead of ±0.2° 2θ. In yet other aspects of each of the above embodiments, the significant peak values ​​have a variation of ±0.05° 2θ instead of ±0.2° 2θ.

[0390] In one embodiment, the crystalline free base has an X-ray powder diffraction pattern substantially as shown in Figure 3B.

[0391] In one embodiment, the crystalline free base has a thermogravimetric profile that exhibits a weight loss of about 5% to about 6% between about 100° C. and about 160° C. when heated at a rate of 10° C. / min.

[0392] In one embodiment, the crystalline free base has a thermogravimetric analysis profile substantially as shown in Figure 4D.

[0393] In one embodiment, the crystalline free base has a differential scanning calorimetry profile comprising a first endotherm between about 25° C. and about 100° C. when heated at a rate of 10° C. / min.

[0394] In one embodiment, the crystalline free base has a differential scanning calorimetry profile comprising a first endotherm between about 59.90° C. and about 98.79° C. when heated at a rate of 10° C. / min.

[0395] In one embodiment, the crystalline free base has a differential scanning calorimetry profile comprising a second endotherm between about 100° C. and about 160° C. when heated at a rate of 10° C. / min.

[0396] In one embodiment, the crystalline free base has a differential scanning calorimetry profile comprising a second endotherm between about 109.31° C. and about 132.94° C. when heated at a rate of 10° C. / min.

[0397] In one embodiment, the crystalline free base has a differential scanning calorimetry profile comprising a first endotherm between about 25°C and about 100°C and a second endotherm between about 100°C and about 160°C when heated at a rate of 10°C / min.

[0398] In one embodiment, the crystalline free base has a differential scanning calorimetry profile substantially as shown in Figure 5B.

[0399] In one embodiment, the crystalline free base has a thermogravimetric profile exhibiting a weight loss of about 5% to about 6% between about 100°C and about 160°C when heated at a rate of 10°C / min; and a differential scanning calorimetry profile comprising a first endotherm between about 25°C and about 100°C when heated at a rate of 10°C / min and / or a second endotherm between about 100°C and about 160°C when heated at a rate of 10°C / min. In one aspect, the differential scanning calorimetry profile comprises a first endotherm between about 25°C and about 100°C when heated at a rate of 10°C / min. In another aspect, the differential scanning calorimetry profile comprises a second endotherm between about 100°C and about 160°C when heated at a rate of 10°C / min. In another aspect, the differential scanning calorimetry profile comprises a first endotherm between about 25°C and about 100°C and a second endotherm between about 100°C and about 160°C when heated at a rate of 10°C / min.

[0400] In one embodiment, the crystalline free base has a thermogravimetric profile exhibiting a weight loss of about 5% to about 6% between about 100°C and about 160°C when heated at a rate of 10°C / min; and a differential scanning calorimetry profile comprising a first endotherm between about 59.90°C and about 98.79°C when heated at a rate of 10°C / min and / or a second endotherm between about 109.31°C and about 132.94°C when heated at a rate of 10°C / min. In one aspect, the differential scanning calorimetry profile comprises a first endotherm between about 59.90°C and about 98.79°C when heated at a rate of 10°C / min. In another aspect, the differential scanning calorimetry profile comprises a second endotherm between about 109.31°C and about 132.94°C when heated at a rate of 10°C / min. In another embodiment, the differential scanning calorimetry profile comprises a first endotherm between about 59.90°C and about 98.79°C and a second endotherm between about 109.31°C and about 132.94°C when heated at a rate of 10°C / min.

[0401] In one embodiment, the crystalline free base has the X-ray diffraction pattern previously described above and further has at least one of the following: (a) a thermogravimetric profile exhibiting a weight loss of about 5% to about 6% between about 100° C. and about 160° C. when heated at a rate of 10° C. / min; and (b) a differential scanning calorimetry profile comprising a first endotherm between about 25° C. and about 100° C. when heated at a rate of 10° C. / min, and / or a second endotherm between about 100° C. and about 160° C. when heated at a rate of 10° C. / min. In one aspect, the differential scanning calorimetry profile comprises a first endotherm between about 25° C. and about 100° C. when heated at a rate of 10° C. / min. In another aspect, the differential scanning calorimetry profile comprises a second endotherm between about 100° C. and about 160° C. when heated at a rate of 10° C. / min. In another embodiment, the differential scanning calorimetry profile comprises a first endotherm between about 25°C and about 100°C and a second endotherm between about 100°C and about 160°C when heated at a rate of 10°C / min.

[0402] In one embodiment, the crystalline free base has the X-ray diffraction pattern described above and further has a thermogravimetric analysis profile that exhibits a weight loss of about 5% to about 6% between about 100°C and about 160°C when heated at a rate of 10°C / min.

[0403] In one embodiment, the crystalline free base has the X-ray diffraction pattern previously described above and further has a differential scanning calorimetry profile comprising a first endotherm between about 25° C. and about 100° C. and / or a second endotherm between about 100° C. and about 160° C. when heated at a rate of 10° C. / min. In one aspect, the differential scanning calorimetry profile comprises a first endotherm between about 25° C. and about 100° C. when heated at a rate of 10° C. / min. In another aspect, the differential scanning calorimetry profile comprises a second endotherm between about 100° C. and about 160° C. when heated at a rate of 10° C. / min. In another aspect, the differential scanning calorimetry profile comprises a first endotherm between about 25° C. and about 100° C. and a second endotherm between about 100° C. and about 160° C. when heated at a rate of 10° C. / min.

[0404] In one embodiment, the crystalline free base has the X-ray diffraction pattern previously described above; a thermogravimetric profile exhibiting a weight loss of about 5% to about 6% between about 100° C. and about 160° C. when heated at a rate of 10° C. / min; and a differential scanning calorimetry profile comprising a first endotherm between about 25° C. and about 100° C. when heated at a rate of 10° C. / min and / or a second endotherm between about 100° C. and about 160° C. when heated at a rate of 10° C. / min. In one aspect, the differential scanning calorimetry profile comprises a first endotherm between about 25° C. and about 100° C. when heated at a rate of 10° C. / min. In another aspect, the differential scanning calorimetry profile comprises a second endotherm between about 100° C. and about 160° C. when heated at a rate of 10° C. / min. In another embodiment, the differential scanning calorimetry profile comprises a first endotherm between about 25°C and about 100°C and a second endotherm between about 100°C and about 160°C when heated at a rate of 10°C / min.

[0405] Free base solvate Form A and free base hydrate Form B are not physically stable. As discussed above, they desolvate (or dehydrate) upon drying, converting to the amorphous free base. While free base solvate Form A and free base hydrate Form B generally do not exhibit pharmaceutically acceptable physical stability for use as active ingredients in pharmaceutical formulations, they are useful intermediates in the preparation of other solid forms, such as the amorphous free base.

[0406] C.<Crystalline free base hydrate form C (hemihydrate)> In another embodiment, the solid form is a crystalline hydrate, and the crystalline hydrate is a hemihydrate. In another embodiment, the solid form is a crystalline hemihydrate of Compound 1 having an X-ray powder diffraction pattern corresponding to free base hydrate Form C, which is further described in the Examples section of this application.

[0407] In one embodiment, the free base hydrate form C 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 2θ when measured at about 25° C. with monochromated Kα1 light.

[0408] In one embodiment, the free base hydrate form C is characterized by peaks at 13.4±0.2, 15.1±0.2, and 21.7±0.2 degrees 2θ, and further characterized by peaks at 7.7±0.2, 7.9±0.2, 9.6±0.2, 10.3±0.2, 13.9±0.2, 15.5±0.2, 15.9±0.2, 17.0±0.2, 17.2±0. 2, 17.8±0.2, 18.1±0.2, 18.3±0.2, 19.3±0.2, 19.7±0.2, 20.5±0.2, 20.9±0.2, 21.9±0.2, 22.2±0.2, 23.5±0.2, 24.4±0.2, 24.9±0.2, 28.2±0.2, and 29.5±0.2 degrees 2θ.

[0409] In one embodiment, the free base hydrate form C has an X-ray powder diffraction pattern characterized by peaks at 13.4±0.2, 15.1±0.2, 15.5±0.2, and 21.7±0.2 degrees 2θ, when measured at about 25° C. with monochromated Kα1 light.

[0410] In one embodiment, the free base hydrate form C has an X-ray powder diffraction pattern characterized by peaks at 13.4±0.2, 15.1±0.2, 17.0±0.2, and 21.7±0.2 degrees 2θ, when measured at about 25° C. with monochromated Kα1 light.

[0411] In one embodiment, the free base hydrate form C has an X-ray powder diffraction pattern characterized by peaks at 13.4±0.2, 15.1±0.2, 20.9±0.2, and 21.7±0.2 degrees 2θ, when measured at about 25° C. with monochromated Kα1 light.

[0412] In one embodiment, the free base hydrate form C has an X-ray powder diffraction pattern characterized by peaks at 13.4±0.2, 15.1±0.2, 15.5±0.2, 17.0±0.2, 20.9±0.2, and 21.7±0.2 degrees 2θ, when measured at about 25°C with monochromated Kα1 light.

[0413] In one embodiment, the free base hydrate form C has an X-ray powder diffraction pattern characterized by peaks at 15.5±0.2, 13.4±0.2, 15.1±0.2, 19.3±0.2, 20.5±0.2, and 21.7±0.2 degrees 2θ, when measured at about 25°C with monochromated Kα1 light.

[0414] In one embodiment, the free base hydrate form C has an X-ray powder diffraction pattern with no significant peaks at more than one of 3.1±0.2, 9.3±0.2, and 12.0±0.2 degrees 2θ, when measured at about 25°C with monochromated Kα1 light.

[0415] In one embodiment, the free base hydrate form C has an X-ray powder diffraction pattern with no significant peaks at greater than one of 3.9±0.2, 6.8±0.2, and 14.1±0.2 degrees 2θ, when measured at about 25°C with monochromated Kα1 light.

[0416] In one embodiment, the free base hydrate Form C has an X-ray powder diffraction pattern, measured at about 25°C with monochromated Kα1 light, that has no significant peaks at greater than one of 3.1±0.2, 9.3±0.2, and 12.0±0.2 degrees 2θ, and no significant peaks at greater than one of 3.9±0.2, 6.8±0.2, and 14.1±0.2 degrees 2θ.

[0417] In one embodiment, the free base hydrate Form C 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 2θ, and no significant peaks at one or more of 3.1±0.2, 9.3±0.2, and 12.0±0.2 degrees 2θ, when measured at about 25°C with monochromated Kα1 light.

[0418] In one embodiment, the free base hydrate Form C 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 2θ, and no significant peaks at one or more of 3.9±0.2, 6.8±0.2, and 14.1±0.2 degrees 2θ, when measured at about 25°C with monochromated Kα1 light.

[0419] In one embodiment, the free base hydrate Form C 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, and no significant peaks at greater than or equal to one of 3.1±0.2, 9.3±0.2, and 12.0±0.2 degrees two-theta, and no significant peaks at greater than or equal to one of 3.9±0.2, 6.8±0.2, and 14.1±0.2 degrees two-theta, when measured with monochromated Kα1 light at about 25°C.

[0420] In one embodiment, the free base hydrate Form C has an X-ray powder diffraction pattern characterized by peaks at 15.5±0.2, 13.4±0.2, 15.1±0.2, 19.3±0.2, 20.5±0.2, and 21.7±0.2 degrees 2θ, and no significant peaks at one or more of 3.1±0.2, 9.3±0.2, and 12.0±0.2 degrees 2θ, when measured at about 25°C with monochromated Kα1 light.

[0421] In one embodiment, the free base hydrate Form C has an X-ray powder diffraction pattern characterized by peaks at 15.5±0.2, 13.4±0.2, 15.1±0.2, 19.3±0.2, 20.5±0.2, and 21.7±0.2 degrees 2θ, and no significant peaks at one or more of 3.9±0.2, 6.8±0.2, and 14.1±0.2 degrees 2θ, when measured at about 25°C with monochromated Kα1 light.

[0422] In one embodiment, the free base hydrate Form C has an X-ray powder diffraction pattern characterized by peaks at 15.5±0.2, 13.4±0.2, 15.1±0.2, 19.3±0.2, 20.5±0.2, and 21.7±0.2 degrees 2θ, and with no significant peaks at 3.1±0.2, 9.3±0.2, and 12.0±0.2 degrees 2θ, and no significant peaks at one or more of 3.9±0.2, 6.8±0.2, and 14.1±0.2 degrees 2θ, when measured with monochromated Kα1 light at about 25°C.

[0423] In one embodiment, the free base hydrate form C has an X-ray powder diffraction pattern characterized by peaks at positions substantially listed in Table 16-C ±0.2° 2θ when measured at about 25° C. with monochromated Kα1 light.

[0424] In one embodiment, the free base hydrate form C has an X-ray powder diffraction pattern characterized by peaks at positions listed in Table 16-C ±0.2° 2θ having a relative intensity substantially of at least 10.0% when measured at about 25°C with monochromated Kα1 light.

[0425] In further aspects of each of the above embodiments, the significant peak values ​​have a variation of ±0.1° 2θ instead of ±0.2° 2θ. In yet other aspects of each of the above embodiments, the significant peak values ​​have a variation of ±0.05° 2θ instead of ±0.2° 2θ.

[0426] In one embodiment, the free base hydrate form C has an X-ray powder diffraction pattern substantially as shown in FIG. 3C when measured at about 25° C. with monochromated Kα1 light.

[0427] In one embodiment, free base hydrate Form C has a thermogravimetric analysis profile that exhibits a weight loss of about 2.3% to about 2.6% between about 120° C. and 160° C. when heated at a rate of 10° C. / min.

[0428] In one embodiment, free base hydrate Form C has a thermogravimetric analysis profile that exhibits a weight loss of about 2.3% to about 2.6% between about 114.52°C and 168.15°C when heated at a rate of 10°C / min.

[0429] In one embodiment, free base hydrate Form C has a thermogravimetric analysis profile substantially as shown in FIG. 4E.

[0430] In one embodiment, free base hydrate Form C has a differential scanning calorimetry profile comprising an endotherm between about 120° C. and about 170° C. when heated at a rate of 10° C. / min.

[0431] In one embodiment, free base hydrate Form C has a differential scanning calorimetry profile comprising an endotherm between about 134.70° C. and about 167.53° C. when heated at a rate of 10° C. / min.

[0432] In one embodiment, free base hydrate Form C has a differential scanning calorimetry profile substantially as shown in Figure 5C.

[0433] In one embodiment, free base hydrate Form C has a moisture sorption isotherm profile that exhibits a weight gain of from about 0% to about 0.2% as the relative humidity is increased from about 0% relative humidity to about 90% relative humidity at a temperature of 25° C.

[0434] In one embodiment, free base hydrate Form C has a moisture sorption isotherm profile substantially as shown in Figure 6B.

[0435] In one embodiment, free base hydrate Form C has a thermogravimetric profile that exhibits a weight loss of about 2.3% to about 2.6% when heated between about 120° C. and 160° C. at a rate of 10° C. / min; and a differential scanning calorimetry profile that includes an endotherm between about 120 and about 170° C. when heated at a rate of 10° C. / min.

[0436] In one embodiment, free base hydrate Form C has a thermogravimetric analysis profile that exhibits a weight loss of about 2.3% to about 2.6% between about 120°C and 160°C when heated at a rate of 10°C / min; and a moisture sorption isotherm profile that exhibits a weight gain of about 0% to about 0.2% as the relative humidity is increased from about 0% relative humidity to about 90% relative humidity at a temperature of 25°C.

[0437] In one embodiment, free base hydrate Form C has a differential scanning calorimetry profile that includes an endotherm between about 120 and about 170°C when heated at a rate of 10°C / min; and a moisture sorption isotherm profile that exhibits a weight gain of about 0% to about 0.2% as the relative humidity is increased from about 0% relative humidity to about 90% relative humidity at a temperature of 25°C.

[0438] In one embodiment, free base hydrate Form C has a thermogravimetric analysis profile that exhibits a weight loss of about 2.3% to about 2.6% between about 120°C and 160°C when heated at a rate of 10°C / min; a differential scanning calorimetry profile that includes an endotherm between about 120 and about 170°C when heated at a rate of 10°C / min; and a moisture sorption isotherm profile that exhibits a weight gain of about 0% to about 0.2% when the relative humidity is increased from about 0% relative humidity to about 90% relative humidity at a temperature of 25°C.

[0439] In one embodiment, free base hydrate Form C has a thermogravimetric analysis profile that exhibits a weight loss of about 2.3% to about 2.6% between about 120°C and 160°C when heated at a rate of 10°C / min; a differential scanning calorimetry profile that includes an endotherm between about 134.70 and about 167.53°C when heated at a rate of 10°C / min; and a moisture sorption isotherm profile that exhibits a weight gain of about 0% to about 0.2% as the relative humidity is increased from about 0% relative humidity to about 90% relative humidity at a temperature of 25°C.

[0440] In one embodiment, the free base hydrate form C has an orthorhombic lattice shape.

[0441] In one embodiment, the free base hydrate form C has the P212121 space group.

[0442] In one embodiment, free base hydrate Form C has unit cell a, b, and c values ​​of about 12.7 Å, about 13.1 Å, and about 22.6 Å, respectively.

[0443] In one embodiment, free base hydrate Form C has the X-ray diffraction pattern previously described above and at least one of the following: (a) a thermogravimetric analysis profile that exhibits a weight loss of about 2.3% to about 2.6% between about 120°C and 160°C when heated at a rate of 10°C / min; (b) a differential scanning calorimetry profile that includes an endotherm between about 120 and about 170°C when heated at a rate of 10°C / min; and / or (c) a moisture sorption isotherm profile that exhibits a weight gain of about 0% to about 0.2% when the relative humidity is increased from about 0% relative humidity to about 90% relative humidity at a temperature of 25°C.

[0444] In one embodiment, free base hydrate Form C has the X-ray diffraction pattern previously described above and a thermogravimetric analysis profile that exhibits a weight loss of about 2.3% to about 2.6% between about 120° C. and 160° C. when heated at a rate of 10° C. / min.

[0445] In one embodiment, free base hydrate Form C has the X-ray diffraction pattern previously described above and a differential scanning calorimetry profile comprising an endotherm between about 120 and about 170° C. when heated at a rate of 10° C. / min.

[0446] In one embodiment, free base hydrate Form C has the X-ray diffraction pattern previously described above and a moisture sorption isotherm profile that exhibits a weight gain of from about 0% to about 0.2% as the relative humidity is increased from about 0% relative humidity to about 90% relative humidity at a temperature of 25° C.

[0447] In one embodiment, free base hydrate Form C has the X-ray diffraction pattern previously described above; a thermogravimetric profile that exhibits a weight loss of about 2.3% to about 2.6% between about 120°C and 160°C when heated at a rate of 10°C / min; and a differential scanning calorimetry profile that includes an endotherm between about 120°C and about 170°C when heated at a rate of 10°C / min.

[0448] In one embodiment, free base hydrate Form C has the X-ray diffraction pattern previously described above; a thermogravimetric analysis profile that exhibits a weight loss of about 2.3% to about 2.6% between about 120°C and 160°C when heated at a rate of 10°C / min; and a moisture sorption isotherm profile that exhibits a weight gain of about 0% to about 0.2% as the relative humidity is increased from about 0% relative humidity to about 90% relative humidity at a temperature of 25°C.

[0449] In one embodiment, free base hydrate Form C has the X-ray diffraction pattern previously described above; a differential scanning calorimetry profile that includes an endotherm between about 120 and about 170°C when heated at a rate of 10°C / minute; and a moisture sorption isotherm profile that exhibits a weight gain of about 0% to about 0.2% as the relative humidity is increased from about 0% relative humidity to about 90% relative humidity at a temperature of 25°C.

[0450] In one embodiment, free base hydrate Form C has the X-ray diffraction pattern previously described above; a thermogravimetric analysis profile that exhibits a weight loss of about 2.3% to about 2.6% between about 120°C and 160°C when heated at a rate of 10°C / min; a differential scanning calorimetry profile that includes an endotherm between about 120 and about 170°C when heated at a rate of 10°C / min; and a moisture sorption isotherm profile that exhibits a weight gain of about 0% to about 0.2% when the relative humidity is increased from about 0% relative humidity to about 90% relative humidity at a temperature of 25°C.

[0451] Free base hydrate Form C generally exhibits good chemical stability, physical stability, and solid state properties (such as low hygroscopicity). Large-scale production of free base hydrate Form C is relatively straightforward, with minimal scaling, good yield, good impurity rejection, rapid filtration, drying, and minimal grinding problems (even after high-energy pin milling of the isolate). Furthermore, different particle sizes can be achieved by proper control of the crystallization process.

[0452] D. <Crystalline free base anhydrous form D> In another embodiment, the solid form is the crystalline anhydrous free base of Compound 1 having an X-ray powder diffraction pattern corresponding to free base anhydrous Form D. Free base anhydrous Form D is further described in the Examples of this application.

[0453] In one embodiment, the free base anhydrate Form D has 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 2θ when measured at about 25°C with monochromated Kα1 light.

[0454] In one embodiment, the free base anhydrate Form D has 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, and further characterized by peaks at one or more of 4.0±0.2, 18.4±0.2, 19.0±0.2, 23.0±0.2, and 24.7±0.2 degrees two-theta, when measured with monochromated Kα1 light at about 25°C.

[0455] In one embodiment, the free base anhydrate Form D has an X-ray powder diffraction pattern characterized by peaks at 4.0±0.2, 8.0±0.2, 9.7±0.2, 14.2±0.2, 14.5±0.2, and 20.3±0.2 degrees 2θ, when measured at about 25°C with monochromated Kα1 light.

[0456] In one embodiment, the free base anhydrate Form D has 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, 18.4±0.2, and 20.3±0.2 degrees 2θ, when measured at about 25°C with monochromated Kα1 light.

[0457] In one embodiment, the free base anhydrate Form D has 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, 19.0±0.2, and 20.3±0.2 degrees 2θ, when measured at about 25°C with monochromated Kα1 light.

[0458] In one embodiment, the free base anhydrate Form D has an X-ray powder diffraction pattern characterized by peaks at 4.0±0.2, 8.0±0.2, 9.7±0.2, 14.2±0.2, 14.5±0.2, 19.0±0.2, and 20.3±0.2 degrees 2θ, when measured at about 25°C with monochromated Kα1 light.

[0459] In one embodiment, the free base anhydrate Form D has 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, 20.3±0.2, and 23.0±0.2 degrees 2θ, when measured at about 25°C with monochromated Kα1 light.

[0460] In one embodiment, the free base anhydrate Form D has 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, 20.3±0.2, and 24.7±0.2 degrees 2θ, when measured at about 25°C with monochromated Kα1 light.

[0461] In one embodiment, the free base anhydrate Form D has an X-ray powder diffraction pattern characterized by peaks at 4.0±0.2, 14.5±0.2, and 19.0±0.2 degrees 2θ when measured at about 25° C. with monochromated Kα1 light.

[0462] In one embodiment, the free base anhydrate Form D has an X-ray powder diffraction pattern characterized by peaks at 4.0±0.2, 14.5±0.2, and 19.0±0.2 degrees two-theta, and further characterized by peaks at one or more of 8.0±0.2, 9.7±0.2, 14.2±0.2, 18.4±0.2, 20.3±0.2, 23.0±0.2, and 24.7±0.2 degrees two-theta, when measured with monochromated Kα1 light at about 25°C.

[0463] In one embodiment, the free base anhydrate Form D has an X-ray powder diffraction pattern with no significant peaks at greater than one of 3.1±0.2, 9.3±0.2, and 20.8±0.2 degrees 2θ when measured at about 25°C with monochromated Kα1 light.

[0464] In one embodiment, the free base anhydrate Form D has an X-ray powder diffraction pattern with no significant peaks at greater than one of 6.8±0.2, 15.7±0.2, and 21.9±0.2 degrees 2θ when measured at about 25°C with monochromated Kα1 light.

[0465] In one embodiment, the free base anhydrate Form D has an X-ray powder diffraction pattern with no significant peaks at greater than one of 13.4±0.2, 15.5±0.2, and 21.7±0.2 degrees 2θ when measured at about 25°C with monochromated Kα1 light.

[0466] In one embodiment, the free base anhydrate Form D has an X-ray powder diffraction pattern, measured at about 25° C. with monochromated Kα1 light, of no significant peaks at greater than one of 13.4±0.2, 15.5±0.2, and 21.7±0.2 degrees two-theta, and no significant peaks at greater than one of 6.8±0.2, 15.7±0.2, and 21.9±0.2 degrees two-theta, and no significant peaks at greater than one of 3.1±0.2, 9.3±0.2, and 20.8±0.2 degrees two-theta.

[0467] In one embodiment, the free base anhydrate Form D has 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 2θ, and no significant peaks at one or more of 3.1±0.2, 9.3±0.2, and 20.8±0.2 degrees 2θ, when measured with monochromated Kα1 light at about 25°C.

[0468] In one embodiment, the free base anhydrate Form D has 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 2θ, and no significant peaks at one or more of 6.8±0.2, 15.7±0.2, and 21.9±0.2 degrees 2θ, when measured with monochromated Kα1 light at about 25°C.

[0469] In one embodiment, the free base anhydrate Form D has 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 2θ, and no significant peaks at one or more of 13.4±0.2, 15.5±0.2, and 21.7±0.2 degrees 2θ, when measured with monochromated Kα1 light at about 25°C.

[0470] In one embodiment, the free base anhydrate Form D has 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, and no significant peaks at greater than or equal to one of 3.1±0.2, 9.3±0.2, and 20.8±0.2 degrees two-theta, and no significant peaks at greater than or equal to one of 6.8±0.2, 15.7±0.2, and 21.9±0.2 degrees two-theta, and no significant peaks at greater than or equal to one of 13.4±0.2, 15.5±0.2, and 21.7±0.2 degrees two-theta, when measured with monochromated Kα1 light at about 25°C.

[0471] In one embodiment, the free base anhydrate Form D has an X-ray powder diffraction pattern characterized by peaks at 4.0±0.2, 8.0±0.2, 9.7±0.2, 14.2±0.2, 14.5±0.2, 19.0±0.2, and 20.3±0.2 degrees 2θ, and no significant peaks at one or more of 3.1±0.2, 9.3±0.2, and 20.8±0.2 degrees 2θ, when measured with monochromated Kα1 light at about 25°C.

[0472] In one embodiment, the free base anhydrate Form D has an X-ray powder diffraction pattern characterized by peaks at 4.0±0.2, 8.0±0.2, 9.7±0.2, 14.2±0.2, 14.5±0.2, 19.0±0.2, and 20.3±0.2 degrees 2θ, and no significant peaks at one or more of 6.8±0.2, 15.7±0.2, and 21.9±0.2 degrees 2θ, when measured with monochromated Kα1 light at about 25°C.

[0473] In one embodiment, the free base anhydrate Form D has an X-ray powder diffraction pattern characterized by peaks at 4.0±0.2, 8.0±0.2, 9.7±0.2, 14.2±0.2, 14.5±0.2, 19.0±0.2, and 20.3±0.2 degrees 2θ, and no significant peaks at one or more of 13.4±0.2, 15.5±0.2, and 21.7±0.2 degrees 2θ, when measured with monochromated Kα1 light at about 25°C.

[0474] In one embodiment, the free base anhydrate Form D has an X-ray powder diffraction pattern characterized by peaks at 4.0±0.2, 8.0±0.2, 9.7±0.2, 14.2±0.2, 14.5±0.2, 19.0±0.2, and 20.3±0.2 degrees two-theta, and no significant peaks at greater than one of 3.1±0.2, 9.3±0.2, and 20.8±0.2 degrees two-theta, and no significant peaks at greater than one of 6.8±0.2, 15.7±0.2, and 21.9±0.2 degrees two-theta, and no significant peaks at greater than one of 13.4±0.2, 15.5±0.2, and 21.7±0.2 degrees two-theta, when measured with monochromated Kα1 light at about 25°C.

[0475] In one embodiment, the free base anhydrate Form D has an X-ray powder diffraction pattern characterized by peaks at locations substantially listed in Table 16-J ±0.2° 2θ when measured at about 25° C. with monochromated Kα1 light.

[0476] In one embodiment, the free base anhydrate Form D has an X-ray powder diffraction pattern characterized by peaks at positions listed in Table 16-J ±0.2° 2θ having a relative intensity of substantially at least 10.0% when measured at about 25°C with monochromated Kα1 light.

[0477] In further aspects of each of the above embodiments, the significant peak values ​​have a variation of ±0.1° 2θ instead of ±0.2° 2θ. In yet other aspects of each of the above embodiments, the significant peak values ​​have a variation of ±0.05° 2θ instead of ±0.2° 2θ.

[0478] In one embodiment, the free base anhydrate Form D has an X-ray powder diffraction pattern substantially as shown in Figure 3J when measured at about 25°C using monochromated Kα1 light.

[0479] In one embodiment, the free base anhydrate Form D has a thermogravimetric profile that exhibits a weight loss of about 0.5% to about 0.8% between about 43° C. and 188° C. when heated at a rate of 10° C. / min.

[0480] In one embodiment, the free base anhydrate Form D has a thermogravimetric analysis profile that exhibits a weight loss of about 0.5% to about 0.8% between about 41.36°C and 190.48°C when heated at a rate of 10°C / min.

[0481] In one embodiment, the free base anhydrate Form D has a thermogravimetric analysis profile that exhibits a weight loss of about 0.45% to about 0.55% between about 43° C. and 100° C. when heated at a rate of 10° C. / min.

[0482] In one embodiment, the free base anhydrate Form D has a thermogravimetric profile that exhibits a weight loss of about 0.5% between about 43° C. and 100° C. when heated at a rate of 10° C. / min.

[0483] In one embodiment, the free base anhydrate form D has a thermogravimetric analysis profile substantially as shown in Figure 4I.

[0484] In one embodiment, the free base anhydrate Form D has a differential scanning calorimetry profile that includes an endotherm between about 180° C. and about 220° C. when heated at a rate of 10° C. / min.

[0485] In one embodiment, the free base anhydrate Form D has a differential scanning calorimetry profile comprising an endotherm between about 199.55° C. and about 217.41° C. when heated at a rate of 10° C. / min.

[0486] In one embodiment, free base anhydrate Form D has a differential scanning calorimetry profile comprising an onset melting point of about 199.55° C. and an endotherm with an enthalpy of fusion of about 85.4 J / g.

[0487] In one embodiment, the free base anhydrate form D has a differential scanning calorimetry profile substantially as shown in Figure 5E.

[0488] In one embodiment, the free base anhydrous Form D has a moisture sorption isotherm profile that exhibits a weight gain of about 1.6% to about 2.0% as the relative humidity is increased from about 0% relative humidity to about 90% relative humidity at a temperature of 25° C.

[0489] In one embodiment, the free base anhydrate Form D has a moisture sorption isotherm profile substantially as shown in Figure 6D.

[0490] In one embodiment, the free base anhydrate Form D has a thermogravimetric profile that exhibits a weight loss of about 0.5% to about 0.8% between about 43°C and 188°C when heated at a rate of 10°C / min; and a differential scanning calorimetry profile that includes an endotherm between about 180°C and about 220°C when heated at a rate of 10°C / min.

[0491] In one embodiment, the free base anhydrous Form D has a thermogravimetric analysis profile that exhibits a weight loss of about 0.5% to about 0.8% between about 43°C and 188°C when heated at a rate of 10°C / min; and a moisture sorption isotherm profile that exhibits a weight gain of about 1.6% to about 2.0% when the relative humidity is increased from about 0% relative humidity to about 90% relative humidity at a temperature of 25°C.

[0492] In one embodiment, the free base anhydrate Form D has a differential scanning calorimetry profile that includes an endotherm between about 180°C and about 220°C when heated at a rate of 10°C / min; and a moisture sorption isotherm profile that exhibits a weight gain of about 1.6% to about 2.0% as the relative humidity is increased from about 0% relative humidity to about 90% relative humidity at a temperature of 25°C.

[0493] In one embodiment, the free base anhydrous Form D has a thermogravimetric analysis profile that exhibits a weight loss of about 0.5% to about 0.8% between about 43°C and 188°C when heated at a rate of 10°C / min; a differential scanning calorimetry profile that includes an endotherm between about 180°C and about 220°C when heated at a rate of 10°C / min; and a moisture sorption isotherm profile that exhibits a weight gain of about 1.6% to about 2.0% when the relative humidity is increased from about 0% relative humidity to about 90% relative humidity at a temperature of 25°C.

[0494] In one embodiment, the free base anhydrous Form D has a thermogravimetric analysis profile that exhibits a weight loss of about 0.5% to about 0.8% between about 43°C and 188°C when heated at a rate of 10°C / min; a differential scanning calorimetry profile that includes an endotherm between about 199.55°C and about 217.41°C when heated at a rate of 10°C / min; and a moisture sorption isotherm profile that exhibits a weight gain of about 1.6% to about 2.0% when the relative humidity is increased from about 0% relative humidity to about 90% relative humidity at a temperature of 25°C.

[0495] In one embodiment, the free base anhydrate form D has an orthorhombic lattice shape.

[0496] In one embodiment, the free base anhydrate form D has the P21212 space group.

[0497] In one embodiment, the free base anhydrate form D has unit cell a, b, and c values ​​of about 43.8 Å, about 8.6 Å, and about 9.2 Å, respectively.

[0498] In one embodiment, the free base anhydrous Form D has the X-ray diffraction pattern previously described above and at least one of the following: (a) a thermogravimetric analysis profile that exhibits a weight loss of about 0.5% to about 0.8% between about 43°C and 188°C when heated at a rate of 10°C / min; (b) a differential scanning calorimetry profile that includes an endotherm between about 180°C and about 220°C when heated at a rate of 10°C / min; and / or (c) a moisture sorption isotherm profile that exhibits a weight gain of about 1.6% to about 2.0% when the relative humidity is increased from about 0% relative humidity to about 90% relative humidity at a temperature of 25°C.

[0499] In one embodiment, the free base anhydrous Form D has the X-ray diffraction pattern previously described above and a thermogravimetric analysis profile that exhibits a weight loss of about 0.5% to about 0.8% between about 43°C and 188°C when heated at a rate of 10°C / min.

[0500] In one embodiment, the free base anhydrate Form D has the X-ray diffraction pattern previously described above and a differential scanning calorimetry profile that includes an endotherm between about 180° C. and about 220° C. when heated at a rate of 10° C. / min.

[0501] In one embodiment, the free base anhydrous Form D has the X-ray diffraction pattern previously described above and a moisture sorption isotherm profile that exhibits a weight gain of about 1.6% to about 2.0% as the relative humidity is increased from about 0% relative humidity to about 90% relative humidity at a temperature of 25° C.

[0502] In one embodiment, the free base anhydrous Form D has the X-ray diffraction pattern previously described above; a thermogravimetric profile that exhibits a weight loss of about 0.5% to about 0.8% between about 43°C and 188°C when heated at a rate of 10°C / min; and a differential scanning calorimetry profile that includes an endotherm between about 180°C and about 220°C when heated at a rate of 10°C / min.

[0503] In one embodiment, the free base anhydrous Form D has the X-ray diffraction pattern previously described above; a thermogravimetric analysis profile that exhibits a weight loss of about 0.5% to about 0.8% between about 43°C and 188°C when heated at a rate of 10°C / min; and a moisture sorption isotherm profile that exhibits a weight gain of about 1.6% to about 2.0% as the relative humidity is increased from about 0% relative humidity to about 90% relative humidity at a temperature of 25°C.

[0504] In one embodiment, the free base anhydrous Form D has the X-ray diffraction pattern previously described above; a differential scanning calorimetry profile that includes an endotherm between about 180°C and about 220°C when heated at a rate of 10°C / min; and a moisture sorption isotherm profile that exhibits a weight gain of about 1.6% to about 2.0% as the relative humidity is increased from about 0% relative humidity to about 90% relative humidity at a temperature of 25°C.

[0505] In one embodiment, the free base anhydrous Form D has the X-ray diffraction pattern previously described above; a thermogravimetric analysis profile that exhibits a weight loss of about 0.5% to about 0.8% between about 43°C and 188°C when heated at a rate of 10°C / min; a differential scanning calorimetry profile that includes an endotherm between about 180°C and about 220°C when heated at a rate of 10°C / min; and a moisture sorption isotherm profile that exhibits a weight gain of about 1.6% to about 2.0% when the relative humidity is increased from about 0% relative humidity to about 90% relative humidity at a temperature of 25°C.

[0506] Free base anhydrous Form D is reversibly hygroscopic (up to 1.8% moisture at 90% RH and 25° C.) and metastable compared to free base hydrate Form C under typical environmental conditions used during storage for downstream processing (e.g., greater than 2.4% RH at 23° C.). Production of free base anhydrous Form D requires strict control of water content, as free base anhydrous Form D can only be produced if the water content of the crystallization solvent is low (e.g., less than 0.15% at 23° C., which corresponds to a water activity of 2.4%) and will convert to free base hydrate Form C in solution at high water contents. Free base anhydrous Form D crystallizes slowly and is difficult to produce in relatively high yields.

[0507] E. <Crystalline tartrate> In another embodiment, the solid form is the tartrate salt of Compound 1. In one embodiment, the tartrate salt is amorphous. In another embodiment, the tartrate salt is crystalline. In another embodiment, the crystalline tartrate salt is a solvate. In another embodiment, the crystalline tartrate salt is a hydrate. In another embodiment, the tartrate salt is a crystalline L-tartrate salt. In another embodiment, the crystalline L-tartrate salt is a hydrate. In another embodiment, the crystalline tartrate salt is a tetrahydrate ("tartrate hydrate"). Tartrate hydrate (tetrahydrate) is further described in the Examples of this application.

[0508] In one embodiment, the tartrate salt hydrate 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 2θ when measured at about 25° C. with monochromated Kα1 light.

[0509] In one embodiment, the tartrate salt hydrate has an X-ray powder diffraction pattern characterized by peaks at 3.9±0.2, 6.8±0.2, 14.1±0.2, 15.7±0.2, 21.9±0.2, and 25.9±0.2 degrees 2θ, when measured at about 25°C with monochromated Kα1 light.

[0510] In one embodiment, the tartrate salt hydrate has an X-ray powder diffraction pattern with no significant peaks at or above one of 13.4±0.2 and 15.1±0.2 degrees 2θ when measured at about 25°C with monochromated Kα1 light.

[0511] In one embodiment, the tartrate salt hydrate has an X-ray powder diffraction pattern with no significant peaks at more than one of 3.1±0.2, 9.3±0.2, and 12.0±0.2 degrees 2θ when measured at about 25°C with monochromated Kα1 light.

[0512] In one embodiment, the tartrate salt hydrate has an X-ray powder diffraction pattern, measured at about 25°C with monochromated Kα1 light, with no significant peaks at or above one of 13.4±0.2 and 15.1±0.2 degrees 2θ, and no significant peaks at or above one of 3.1±0.2 and 9.3±0.2 degrees 2θ.

[0513] In one embodiment, the tartrate salt hydrate 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 2θ, and no significant peaks at one or more of 13.4±0.2 and 15.1±0.2 degrees 2θ, when measured at about 25°C with monochromated Kα1 light.

[0514] In one embodiment, the tartrate salt hydrate 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 2θ, and no significant peaks at one or more of 3.1±0.2, 9.3±0.2, and 12.0±0.2 degrees 2θ, when measured at about 25°C with monochromated Kα1 light.

[0515] In one embodiment, the tartrate salt hydrate 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 2θ, and no significant peaks at greater than or equal to 13.4±0.2 and 15.1±0.2 degrees 2θ, and no significant peaks at greater than or equal to 3.1±0.2, 9.3±0.2, and 12.0±0.2 degrees 2θ, when measured with monochromated Kα1 light at about 25°C.

[0516] In one embodiment, the tartrate salt hydrate has an X-ray powder diffraction pattern characterized by peaks at 3.9±0.2, 6.8±0.2, 14.1±0.2, 15.7±0.2, 21.9±0.2 degrees 2θ, and no significant peaks at one or more of 13.4±0.2 and 15.1±0.2 degrees 2θ, when measured with monochromated Kα1 light at about 25°C.

[0517] In one embodiment, the tartrate salt hydrate has an X-ray powder diffraction pattern characterized by peaks at 3.9±0.2, 6.8±0.2, 14.1±0.2, 15.7±0.2, 21.9±0.2 degrees 2θ, and no significant peaks at one or more of 3.1±0.2, 9.3±0.2, and 12.0±0.2 degrees 2θ.

[0518] In one embodiment, the tartrate salt hydrate has an X-ray powder diffraction pattern characterized by peaks at 3.9±0.2, 6.8±0.2, 14.1±0.2, 15.7±0.2, 21.9±0.2 degrees 2θ, and no significant peaks at greater than or equal to 13.4±0.2 and 15.1±0.2 degrees 2θ, and no significant peaks at greater than or equal to 3.1±0.2, 9.3±0.2, and 12.0±0.2 degrees 2θ.

[0519] In further aspects of each of the above embodiments, the significant peak values ​​have a variation of ±0.1° 2θ instead of ±0.2° 2θ. In yet other aspects of each of the above embodiments, the significant peak values ​​have a variation of ±0.05° 2θ instead of ±0.2° 2θ.

[0520] In one embodiment, the tartrate salt hydrate has an X-ray powder diffraction pattern substantially as shown in FIG. 3D when measured at about 25° C. with monochromated Kα1 light.

[0521] In one embodiment, the tartrate salt hydrate has a thermogravimetric profile that exhibits a weight loss of about 11.8% to about 12.2% between about 25°C and 160°C when heated at a rate of 10°C / min.

[0522] In one embodiment, the tartrate salt hydrate has a thermogravimetric profile that exhibits a weight loss of about 11.8% to about 12.2% between about 32.98°C and 159.76°C when heated at a rate of 10°C / min.

[0523] In one embodiment, the tartrate salt hydrate has a thermogravimetric analysis profile substantially as shown in Figure 4F.

[0524] In one embodiment, the tartrate salt hydrate has a differential scanning calorimetry profile that includes an endotherm between about 60° C. and about 100° C. when heated at a rate of 10° C. / min.

[0525] In one embodiment, the tartrate salt hydrate has a differential scanning calorimetry profile that includes an endotherm between about 75.74°C and about 110.26°C when heated at a rate of 10°C / min.

[0526] In one embodiment, the tartrate salt hydrate has a differential scanning calorimetry profile substantially as shown in Figure 5D.

[0527] In one embodiment, the tartrate salt hydrate has a thermogravimetric profile that exhibits a weight loss of about 11.8% to about 12.2% between about 25°C and 160°C when heated at a rate of 10°C / min; and a differential scanning calorimetry profile that includes an endotherm between about 60°C and about 100°C when heated at a rate of 10°C / min.

[0528] In one embodiment, the tartrate salt hydrate has a moisture sorption isotherm profile that exhibits a weight gain of about 1% to about 2% when the relative humidity is increased from about 10% relative humidity to about 90% relative humidity at a temperature of 25°C.

[0529] In one embodiment, the tartrate salt hydrate has a moisture sorption isotherm profile substantially as shown in Figure 6C.

[0530] In one embodiment, the tartrate salt hydrate has a thermogravimetric analysis profile that exhibits a weight loss of about 11.8% to about 12.2% between about 25°C and 160°C when heated at a rate of 10°C / min; a differential scanning calorimetry profile that includes an endotherm between about 60°C and about 100°C when heated at a rate of 10°C / min; and a moisture sorption isotherm profile that exhibits a weight gain of about 1% to about 2% when the relative humidity is increased from about 10% relative humidity to about 90% relative humidity at a temperature of 25°C.

[0531] In one embodiment, the tartrate salt hydrate has the X-ray diffraction pattern described above and at least one of the following: (a) a thermogravimetric analysis profile that exhibits a weight loss of about 11.8% to about 12.2% between about 25°C and 160°C when heated at a rate of 10°C / min; (b) a differential scanning calorimetry profile that includes an endotherm between about 60°C and about 100°C when heated at a rate of 10°C / min; and / or (c) a moisture sorption isotherm profile that exhibits a weight gain of about 1% to about 2% when the relative humidity is increased from about 10% relative humidity to about 90% relative humidity at a temperature of 25°C.

[0532] In one embodiment, the tartrate salt hydrate has the X-ray diffraction pattern described above and a thermogravimetric analysis profile that exhibits a weight loss of about 11.8% to about 12.2% between about 25°C and 160°C when heated at a rate of 10°C / min.

[0533] In one embodiment, the tartrate salt hydrate has the X-ray diffraction pattern previously described above and a differential scanning calorimetry profile that includes an endotherm between about 60°C and about 100°C when heated at a rate of 10°C / min.

[0534] In one embodiment, the tartrate salt hydrate has the X-ray diffraction pattern described above and a moisture sorption isotherm profile that exhibits a weight gain of about 1% to about 2% when the relative humidity is increased from about 10% relative humidity to about 90% relative humidity at a temperature of 25°C.

[0535] In one embodiment, the tartrate salt hydrate has the X-ray diffraction pattern previously described above; a thermogravimetric profile that exhibits a weight loss of about 11.8% to about 12.2% between about 25°C and 160°C when heated at a rate of 10°C / min; and a differential scanning calorimetry profile that includes an endotherm between about 60°C and about 100°C when heated at a rate of 10°C / min.

[0536] In one embodiment, the tartrate salt hydrate has the X-ray diffraction pattern previously described above; a thermogravimetric analysis profile that exhibits a weight loss of about 11.8% to about 12.2% between about 25°C and 160°C when heated at a rate of 10°C / min; and a moisture sorption isotherm profile that exhibits a weight gain of about 1% to about 2% when the relative humidity is increased from about 10% relative humidity to about 90% relative humidity at a temperature of 25°C.

[0537] In one embodiment, the tartrate salt hydrate has the X-ray diffraction pattern previously described above; a differential scanning calorimetry profile that includes an endotherm between about 60°C and about 100°C when heated at a rate of 10°C / min; and a moisture sorption isotherm profile that exhibits a weight gain of about 1% to about 2% when the relative humidity is increased from about 10% relative humidity to about 90% relative humidity at a temperature of 25°C.

[0538] In one embodiment, the tartrate salt hydrate has the X-ray diffraction pattern described above; a thermogravimetric analysis profile that exhibits a weight loss of about 11.8% to about 12.2% between about 25°C and 160°C when heated at a rate of 10°C / min; a differential scanning calorimetry profile that includes an endotherm between about 60°C and about 100°C when heated at a rate of 10°C / min; and a moisture sorption isotherm profile that exhibits a weight gain of about 1% to about 2% when the relative humidity is increased from about 10% relative humidity to about 90% relative humidity at a temperature of 25°C.

[0539] Tartrate hydrate has acceptable chemical stability and exhibits acceptable stability against light and peroxide. For example, when its chemical stability was evaluated in a sealed vial at 30°C / 65% relative humidity and 40°C / 75% relative humidity for 12 weeks and at 50°C / 75% relative humidity for 6 weeks, no decomposition of tartrate hydrate was observed in the sealed vial under either of these conditions. Tartrate hydrate has good solubility (BCS Class I) and is not hygroscopic. However, tartrate hydrate may convert to amorphous tartrate when heated, or when compressed or sheared at less than 10% relative humidity.

[0540] Tartrate hydrate can be produced, for example, using antisolvent crystallization. Although impurity rejection during large-scale production of tartrate hydrate is usually good, scale generation may be greater than desired, and specific antisolvent addition control and process volume limitations may be required. Furthermore, appropriate control of the filtration, washing, and drying steps may be required to reduce wet cake compaction and the formation of hard lumps in the isolate. For example, to reduce the formation of hard lumps in the isolate, control of relative humidity (e.g., greater than 10% and less than 100%), temperature (e.g., crystallization occurs well at about 10°C), and mixing speed during drying may be required. Insufficient control of drying conditions may result in a compacted, harder material, which may be difficult to break down during subsequent processing. As previously mentioned, shear and compression may cause conversion to amorphous tartrate. Dried materials are typically milled by mechanical impact mills (e.g., Fitzmills and pin mills) because shear-based mills (e.g., comills) can cause crystallinity loss. Additionally, pressure or compression forces during formulation (e.g., those that may be required for tableting) can cause crystallinity loss.

[0541] F. <Crystalline hydrochloride> In another embodiment, the solid form is a crystalline hydrochloride salt of Compound 1. In one aspect, the crystalline hydrochloride salt corresponds to crystalline hydrochloride solvate Form AA. In another aspect, the crystalline hydrochloride salt corresponds to crystalline hydrochloride solvate Form BB. In another aspect, the crystalline hydrochloride salt corresponds to crystalline hydrochloride solvate Form CC. Hydrochloride solvate Form AA, hydrochloride solvate Form BB, and hydrochloride solvate Form CC are further described in the Examples of this application.

[0542] Hydrochloride solvate Form AA, Hydrochloride solvate Form BB, and Hydrochloride solvate Form CC appear to be solvates and typically convert to amorphous hydrochloride salts upon ambient drying. The resulting amorphous hydrochloride salts are hygroscopic. Yields obtained for each crystalline hydrochloride salt typically ranged from 10% to 15%.

[0543] G. <Crystalline L-Maleate> In another embodiment, the solid form is a crystalline L-maleate salt of Compound 1. In one aspect, the crystalline L-maleate salt corresponds to crystalline L-maleate form AAA. In another aspect, the crystalline L-maleate salt corresponds to crystalline L-maleate form BBB. L-maleate form AAA and L-maleate form BBB are further described in the Examples section of this application.

[0544] Because L-maleic acid reacts with Compound 1, L-maleate Form AAA and L-maleate Form BBB are generally less chemically stable than the amorphous free base, free base hydrate Form C, and tartrate hydrate and do not exhibit pharmaceutically acceptable stability for use as active ingredients in pharmaceutical formulations.

[0545] H.<Crystal purity> In another embodiment of the solid form discussed above, the solid form has a pharmaceutically acceptable crystalline purity (or, in the case of the amorphous free base, a pharmaceutically acceptable amorphous purity). For example, in one embodiment, Compound 1 comprises at least about 75% by weight of the desired solid form. In another embodiment, at least 80% by weight of the desired solid form. In another embodiment, at least 85% by weight of the desired solid form. In another embodiment, at least 90% by weight of the desired solid form. In another embodiment, at least 95% by weight of the desired solid form. In another embodiment, at least 96% by weight of the desired solid form. In another embodiment, at least 97% by weight of the desired solid form. In another embodiment, at least 98% by weight of the desired solid form. In another embodiment, at least 99% by weight of the desired solid form. In another embodiment, Compound 1 exists as a substantially pure crystalline (or, in the case of the amorphous free base, pure amorphous) solid form. In a preferred embodiment, the solid form is the amorphous free base. In another embodiment, the solid form is free base anhydrous Form D. In a more preferred embodiment, the solid form is free base hydrate form B. In a particularly preferred embodiment, the solid form is free base hydrate form C. In a preferred embodiment, the solid form is the tartrate salt hydrate.

[0546] IV.<Treatment method> The present disclosure also relates to a method for treating a JAK-associated condition in a subject, particularly a human subject suffering from or susceptible to the condition, comprising administering to the subject a therapeutically effective amount of Compound 1 free base or a pharmaceutically acceptable salt thereof, or one or more solid forms of Compound 1, as described herein. Another aspect of the present disclosure relates to Compound 1 free base or a pharmaceutically acceptable salt thereof, or one or more solid forms of Compound 1, as described herein, for use in treating a JAK-associated condition in a subject, particularly a human subject suffering from or susceptible to the condition, comprising administering to the subject a therapeutically effective amount of Compound 1 free base or a pharmaceutically acceptable salt thereof, or one or more solid forms of Compound 1. In one embodiment, the condition is a JAK-1-associated condition. In another embodiment, the solid form is amorphous free base. In another embodiment, the solid form is free base hydrate form B. In another embodiment, the solid form is free base hydrate form C. In another embodiment, the solid form is a tartrate salt hydrate. In another embodiment, the solid form is free base anhydrous Form D.

[0547] In one embodiment, the disclosure relates to a method for treating a condition in a subject selected from the group consisting of immunomodulatory, inflammatory, and proliferative diseases (such as cancer), comprising administering to the subject, particularly a human subject suffering from or susceptible to the condition, a therapeutically effective amount of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a solid form of Compound 1. In another aspect, the disclosure relates to Compound 1 free base or a pharmaceutically acceptable salt thereof, or a solid form of Compound 1 for use in treating a condition in a subject, particularly a human subject suffering from or susceptible to the condition, selected from the group consisting of immunomodulatory, inflammatory, and proliferative diseases (such as cancer), comprising administering to the subject a therapeutically effective amount of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a solid form of Compound 1. In one aspect, the solid form is amorphous free base. In another aspect, the solid form is free base anhydrous form D. In another aspect, the solid form is free base hydrate form B. In another aspect, the solid form is free base hydrate form C. In another embodiment, the solid form is a tartrate salt hydrate.

[0548] In one embodiment, the disclosure provides a method for treating rheumatoid arthritis, multiple sclerosis, experimental allergic encephalomyelitis, systemic lupus erythematosus, Crohn's disease, atopic dermatitis, vasculitis, cardiomyopathy, psoriasis, Reiter's syndrome, glomerulonephritis, ulcerative colitis, allergic asthma, insulin-dependent diabetes mellitus, peripheral neuropathy, uveitis, fibrosing alveolitis, type 1 diabetes, juvenile diabetes, juvenile arthritis, Castleman's disease, neutropenia, endometriosis, autoimmune thyroid disease, resting and testicular autoimmunity, scleroderma, axonal and neuronal neuropathy, allergic rhinitis, Sjogren's syndrome, hemolytic anemia, Graves' disease, The present invention relates to a method for treating a condition selected from the group consisting of Hashimoto's thyroiditis, IgA nephropathy, amyloidosis, ankylosing spondylitis, Behcet's disease, sarcoidosis, vesicular bullous dermatosis, myositis, primary biliary cirrhosis, polymyalgia rheumatica, autoimmune immunodeficiency syndrome, Chagas' disease, Kawasaki syndrome, psoriatic arthritis, celiac disease, myasthenia gravis, autoimmune myocarditis, POEMS syndrome, and chronic fatigue syndrome, comprising administering to a subject, particularly a human subject suffering from or susceptible to the condition, a therapeutically effective amount of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a solid form of Compound 1.In another aspect, the disclosure provides a method for the treatment of rheumatoid arthritis, multiple sclerosis, experimental allergic encephalomyelitis, systemic lupus erythematosus, Crohn's disease, atopic dermatitis, vasculitis, cardiomyopathy, psoriasis, Reiter's syndrome, glomerulonephritis, ulcerative colitis, allergic asthma, insulin-dependent diabetes mellitus, peripheral neuropathy, uveitis, fibrosing alveolitis, type 1 diabetes, juvenile diabetes, juvenile arthritis, Castleman's disease, neutropenia, endometriosis, autoimmune thyroid disease, resting and testicular autoimmunity, scleroderma, axonal and neuronal neuropathy, allergic rhinitis, Sjogren's syndrome, hemolytic anemia, Gleicher's syndrome, glaucoma ... The present invention relates to Compound 1 free base or a pharmaceutically acceptable salt thereof, or a solid form of Compound 1 for use in treating a condition selected from the group consisting of: Beth's disease, Hashimoto's thyroiditis, IgA nephropathy, amyloidosis, ankylosing spondylitis, Behcet's disease, sarcoidosis, vesicular bullous dermatosis, myositis, primary biliary cirrhosis, polymyalgia rheumatica, autoimmune immunodeficiency syndrome, Chagas' disease, Kawasaki syndrome, psoriatic arthritis, celiac disease, myasthenia gravis, autoimmune myocarditis, POEMS syndrome, and chronic fatigue syndrome, comprising administering to a subject a therapeutically effective amount of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a solid form of Compound 1. In one embodiment, the solid form is amorphous free base. In another embodiment, the solid form is free base hydrate form B. In another embodiment, the solid form is free base hydrate form C. In another embodiment, the solid form is tartrate salt hydrate. In another embodiment, the solid form is free base anhydrous Form D.

[0549] In one embodiment, the disclosure relates to a method for treating a condition in a subject selected from the group consisting of rheumatoid arthritis (including moderate to severe rheumatoid arthritis), systemic lupus erythematosus, multiple sclerosis, Crohn's disease (including moderate to severe Crohn's disease), psoriasis (including moderate to severe chronic plaque psoriasis), ulcerative colitis (including moderate to severe ulcerative colitis), ankylosing spondylitis, psoriatic arthritis, juvenile idiopathic arthritis (including moderate to severe polyarticular juvenile idiopathic arthritis), diabetic nephropathy, dry eye syndrome, Sjogren's syndrome, alopecia areata, vitiligo, and atopic dermatitis, comprising administering to the subject, particularly a human subject suffering from or susceptible to the condition, a therapeutically effective amount of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a solid form of Compound 1. In another aspect, the disclosure relates to Compound 1 free base or a pharmaceutically acceptable salt thereof, or a solid form of Compound 1 for use in treating a condition selected from the group consisting of rheumatoid arthritis (including moderate to severe rheumatoid arthritis), systemic lupus erythematosus, multiple sclerosis, Crohn's disease (including moderate to severe Crohn's disease), psoriasis (including moderate to severe chronic plaque psoriasis), ulcerative colitis (including moderate to severe ulcerative colitis), ankylosing spondylitis, psoriatic arthritis, juvenile idiopathic arthritis (including moderate to severe polyarticular juvenile idiopathic arthritis), diabetic nephropathy, dry eye syndrome, Sjögren's syndrome, alopecia areata, vitiligo, and atopic dermatitis in a subject, particularly a human subject suffering from or susceptible to the condition, comprising administering to the subject a therapeutically effective amount of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a solid form of Compound 1. In one embodiment, the solid form is amorphous free base. In another embodiment, the solid form is free base hydrate form B. In another embodiment, the solid form is free base hydrate form C. In another embodiment, the solid form is tartrate salt hydrate. In another embodiment, the solid form is free base anhydrous form D.

[0550] In one embodiment, the disclosure provides a method for treating an ophthalmic condition, systemic inflammatory response syndrome, juvenile rheumatoid arthritis, systemic onset juvenile rheumatoid arthritis, type III hypersensitivity reaction, type IV hypersensitivity, inflammation of the aorta, iridocyclitis / uveitis / optic neuritis, juvenile spinal muscular atrophy, diabetic retinopathy or microangiopathy, chronic inflammation, ulcerative colitis, inflammatory bowel disease, allergic disease, dermatitis scleroderma, acute or chronic immune disorders associated with organ transplant, psoriatic arthropathy, ulcerative colitis arthropathy, autoimmune bullous disease, autoimmune hemolytic anemia, rheumatoid arthritis-associated interstitial lung disease, systemic lupus erythematosus-associated lung disease, dermatomyositis / polymyositis-associated lung disease, Sjogren's syndrome / disease-associated lung disease, ankylosing spondylitis and ankylosing spondylitis in a subject. The present invention relates to a method for treating a condition selected from the group consisting of spondylitis-associated lung disease, autoimmune hepatitis, type 1 autoimmune hepatitis (classical autoimmune or lupoid hepatitis), type 2 autoimmune hepatitis (anti-LKM antibody hepatitis), autoimmune-mediated hypoglycemia, type 1 psoriasis, type 2 psoriasis, plaque psoriasis, moderate to severe chronic plaque psoriasis, autoimmune neutropenia, sperm autoimmunity, multiple sclerosis (all subtypes), acute rheumatic fever, rheumatoid spondylitis, Sjogren's syndrome, and autoimmune thrombocytopenia, comprising administering to a subject, particularly a human subject suffering from or susceptible to the condition, a therapeutically effective amount of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a solid form of Compound 1.In another aspect, the disclosure provides a method for treating ophthalmic conditions, systemic inflammatory response syndrome, juvenile rheumatoid arthritis, systemic onset juvenile rheumatoid arthritis, type III hypersensitivity reactions, type IV hypersensitivity reactions, aortic inflammation, iridocyclitis / uveitis / optic neuritis, juvenile spinal muscular atrophy, diabetic retinopathy or microangiopathy, chronic inflammation, ulcerative colitis, inflammatory bowel disease, allergic diseases, dermatitis scleroderma, acute or chronic immune disorders associated with organ transplant, psoriatic arthropathy, ulcerative colitis arthropathy, autoimmune bullous diseases, autoimmune hemolytic anemia, rheumatoid arthritis-associated interstitial lung disease, systemic lupus erythematosus-associated lung disease, dermatomyositis / polymyositis-associated lung disease, Sjogren's syndrome / disease-associated lung disease, ankylosing spondylitis, and the like in a subject, particularly a human subject suffering from or susceptible to the condition. The present invention relates to Compound 1 free base or a pharmaceutically acceptable salt thereof, or a solid form of Compound 1 for use in treating a condition selected from the group consisting of ankylosing spondylitis-associated lung disease, autoimmune hepatitis, type 1 autoimmune hepatitis (classical or lupoid hepatitis), type 2 autoimmune hepatitis (anti-LKM antibody hepatitis), autoimmune-mediated hypoglycemia, type 1 psoriasis, type 2 psoriasis, plaque psoriasis, moderate to severe chronic plaque psoriasis, autoimmune neutropenia, sperm autoimmunity, multiple sclerosis (all subtypes), acute rheumatic fever, rheumatoid spondylitis, Sjogren's syndrome, and autoimmune thrombocytopenia, the use comprising administering to a subject a therapeutically effective amount of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a solid form of Compound 1. In one embodiment, the solid form is amorphous free base. In another embodiment, the solid form is free base hydrate Form B. In another embodiment, the solid form is free base hydrate form C. In another embodiment, the solid form is tartrate salt hydrate. In another embodiment, the solid form is free base anhydrous form D.

[0551] In one embodiment, the disclosure relates to a method for 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, the method comprising administering to the subject a therapeutically effective amount of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a solid form of Compound 1. In another embodiment, the present disclosure relates to Compound 1 free base or a pharmaceutically acceptable salt thereof, or a solid form of Compound 1 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, particularly a human subject suffering from or susceptible to the condition, comprising administering to the subject a therapeutically effective amount of Compound 1 free base or a solid form of Compound 1. In one embodiment, the solid form is amorphous free base. In another embodiment, the solid form is free base hydrate form B. In another embodiment, the solid form is free base hydrate form C. In another embodiment, the solid form is tartrate salt hydrate. In another embodiment, the solid form is free base anhydrous form D.

[0552] In one embodiment, the disclosure relates to a method for treating a condition selected from the group consisting of rheumatoid arthritis, Crohn's disease, ankylosing spondylitis, psoriatic arthritis, psoriasis, ulcerative colitis, systemic lupus erythematosus, lupus nephritis, diabetic nephropathy, dry eye syndrome, Sjogren's syndrome, alopecia areata, vitiligo, and atopic dermatitis in a subject, comprising administering to the subject a therapeutically effective amount of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a solid form of Compound 1. In another embodiment, the present disclosure relates to Compound 1 free base or a pharmaceutically acceptable salt thereof, or a solid form of Compound 1 for use in treating a condition selected from the group consisting of rheumatoid arthritis, Crohn's disease, ankylosing spondylitis, psoriatic arthritis, psoriasis, ulcerative colitis, systemic lupus erythematosus, lupus nephritis, diabetic nephropathy, dry eye syndrome, Sjögren's syndrome, alopecia areata, vitiligo, and atopic dermatitis in a subject, particularly a human subject suffering from or susceptible to the condition, comprising administering to the subject a therapeutically effective amount of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a solid form of Compound 1. In one embodiment, the solid form is amorphous free base. In another embodiment, the solid form is free base hydrate form B. In another embodiment, the solid form is free base hydrate form C. In another embodiment, the solid form is tartrate salt hydrate. In another embodiment, the solid form is free base anhydrous form D.

[0553] In one embodiment, the disclosure relates to a method of treating arthritis in a subject, comprising administering to the subject a therapeutically effective amount of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a solid form of Compound 1. In another aspect, the disclosure relates to Compound 1 free base or a pharmaceutically acceptable salt thereof, or a solid form of Compound 1 for use in treating arthritis in a subject, particularly a human subject suffering from or susceptible to arthritis, comprising administering to the subject a therapeutically effective amount of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a solid form of Compound 1. In one aspect, the arthritis is selected from the group consisting of rheumatoid arthritis, juvenile idiopathic arthritis, and psoriatic arthritis. In another aspect, the arthritis is rheumatoid arthritis. In another aspect, the arthritis is juvenile idiopathic arthritis. In another aspect, the arthritis is psoriatic arthritis. In another aspect, the solid form is amorphous free base. In another aspect, the solid form is free base hydrate Form B. In another embodiment, the solid form is free base hydrate form C. In another embodiment, the solid form is tartrate salt hydrate. In another embodiment, the solid form is free base anhydrous form D. In another embodiment, the solid form is free base solvate form A. In another embodiment, the solid form is hydrochloride solvate form AA. In another embodiment, the solid form is hydrochloride solvate form BB. In another embodiment, the solid form is hydrochloride solvate form CC. In another embodiment, the solid form is L-maleate salt form AAA. In another embodiment, the solid form is L-maleate salt form BBB.

[0554] In one embodiment, the disclosure relates to a method for treating a spondyloarthropathic disorder in a subject, comprising administering to the subject a therapeutically effective amount of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a solid form of Compound 1. In another aspect, the disclosure relates to Compound 1 free base or a pharmaceutically acceptable salt thereof, or a solid form of Compound 1 for use in treating a spondyloarthropathic disorder, particularly in a human subject suffering from or susceptible to a spondyloarthropathic disorder, comprising administering to the subject a therapeutically effective amount of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a solid form of Compound 1. In one aspect, the spondyloarthropathic disorder is ankylosing spondylitis. In another aspect, the solid form is amorphous free base. In another aspect, the solid form is free base hydrate form B. In another aspect, the solid form is free base hydrate form C. In another aspect, the solid form is tartrate salt hydrate. In another aspect, the solid form is free base anhydrous form D. In another aspect, the solid form is free base solvate form A. In another embodiment, the solid form is hydrochloride solvate form AA. In another embodiment, the solid form is hydrochloride solvate form BB. In another embodiment, the solid form is hydrochloride solvate form CC. In another embodiment, the solid form is L-maleate form AAA. In another embodiment, the solid form is L-maleate form BBB.

[0555] In one embodiment, the disclosure relates to a method of treating a gastrointestinal condition in a subject, comprising administering to the subject a therapeutically effective amount of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a solid form of Compound 1. In another aspect, the disclosure relates to Compound 1 free base or a pharmaceutically acceptable salt thereof, or a solid form of Compound 1 for use in treating a gastrointestinal condition, particularly in a human subject suffering from or susceptible to the gastrointestinal condition, comprising administering to the subject a therapeutically effective amount of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a solid form of Compound 1. In one aspect, the gastrointestinal condition is selected from the group consisting of Crohn's disease and ulcerative colitis. In another aspect, the gastrointestinal condition is Crohn's disease. In another aspect, the gastrointestinal condition is ulcerative colitis. In another aspect, the solid form is amorphous free base. In another aspect, the solid form is free base hydrate Form B. In another aspect, the solid form is free base hydrate Form C. In another aspect, the solid form is tartrate salt hydrate. In another embodiment, the solid form is free base anhydrate form D. In another embodiment, the solid form is free base solvate form A. In another embodiment, the solid form is hydrochloride solvate form AA. In another embodiment, the solid form is hydrochloride solvate form BB. In another embodiment, the solid form is hydrochloride solvate form CC. In another embodiment, the solid form is L-maleate form AAA. In another embodiment, the solid form is L-maleate form BBB.

[0556] In one embodiment, the disclosure relates to a method of treating a skin condition, comprising administering to a subject a therapeutically effective amount of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a solid form of Compound 1. In another aspect, the disclosure relates to Compound 1 free base or a pharmaceutically acceptable salt thereof, or a solid form of Compound 1 for use in treating a skin condition, particularly in a human subject suffering from or susceptible to the skin condition, comprising administering to the subject a therapeutically effective amount of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a solid form of Compound 1. In one aspect, the skin condition is selected from the group consisting of psoriasis, plaque psoriasis, nail psoriasis, and hidradenitis suppurativa. In another aspect, the skin condition is psoriasis. In another aspect, the skin condition is plaque psoriasis. In another aspect, the skin condition is nail psoriasis. In another aspect, the skin condition is hidradenitis suppurativa. In another aspect, the skin condition is atopic dermatitis. In another aspect, the solid form is the amorphous free base. In another embodiment, the solid form is free base hydrate form B. In another embodiment, the solid form is free base hydrate form C. In another embodiment, the solid form is tartrate hydrate. In another embodiment, the solid form is free base anhydrous form D. In another embodiment, the solid form is free base solvate form A. In another embodiment, the solid form is hydrochloride solvate form AA. In another embodiment, the solid form is hydrochloride solvate form BB. In another embodiment, the solid form is hydrochloride solvate form CC. In another embodiment, the solid form is L-maleate form AAA. In another embodiment, the solid form is L-maleate form BBB.

[0557] The therapeutically effective dose level for a particular subject will depend on the specific circumstances and may be determined by a variety of factors, such as the type, age, weight, sex, diet, and condition of the subject being treated; the severity of the pathological condition; the activity of the specific compound used; the specific composition used; the age, weight, general health, sex, and diet of the subject; the route of administration; the duration of treatment; pharmacological considerations, such as the activity, efficacy, pharmacokinetics, and toxicity profile of the specific compound or salt used; whether a drug delivery system is used; drugs used in combination or concomitantly with the specific compound used; and similar factors known in the medical community. A physician of ordinary skill in the art, armed with the disclosure of this application, will be able to determine the appropriate dose and administration method for a therapeutic agent for a subject and adjust such dose and administration method as necessary during the course of treatment, according to methods known in the therapeutic arts. It is within the skill of the art to start the dose of a compound at a level lower than that required to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved. Therefore, the administration method actually employed may vary widely and may be derived from the preferred administration method described below.

[0558] The total daily dose of the solid form (administered in a single dose or divided doses) is typically about 0.001 to about 100 mg / kg, or about 0.001 to about 30 mg / kg, or about 0.001 to about 15 mg / kg. In another embodiment, the total daily dose is about 0.01 to about 10 mg / kg (i.e., mg of compound or salt per kg of body weight). A unit dose composition can contain an amount or fraction thereof that makes up a daily dose. In many cases, the administration of the compound or salt is repeated multiple times. Typically, multiple doses can be used to increase the total daily dose, if desired.

[0559] In one embodiment, the daily dose of the solid form administered to a subject is from about 0.01 mg to about 3000 mg. In one embodiment, the daily dose is from about 0.1 mg to about 1000 mg. In another embodiment, the daily dose is from about 1 mg to about 500 mg. In another embodiment, the daily dose is from about 1 mg to about 250 mg. In another embodiment, the daily dose is from about 1 mg to about 100 mg. In another embodiment, the daily dose is from about 1 mg to about 50 mg. In another embodiment, the daily dose is from about 1 mg to about 45 mg. In another embodiment, the daily dose is from about 1 mg to about 30 mg. In another embodiment, the daily dose is from about 1 mg to about 25 mg. In another embodiment, the daily dose is from about 1 mg to about 24 mg. In another embodiment, the daily dose is from about 1 mg to about 15 mg. In another embodiment, the daily dose is from about 1 mg to about 7.5 mg. In another embodiment, the daily dose is from about 25 mg to about 50 mg. In another embodiment, the daily dose is about 1 mg to about 10 mg. In another embodiment, the daily dose is about 10 mg to about 20 mg. In another embodiment, the daily dose is about 20 mg to about 30 mg. In another embodiment, the daily dose is about 30 mg to about 40 mg. In another embodiment, the daily dose is about 7.5 mg to about 45 mg. In another embodiment, the daily dose is about 15 mg to about 30 mg. In another embodiment, the daily dose is about 3 mg. In another embodiment, the daily dose is about 6 mg. In another embodiment, the daily dose is about 7.5 mg. In another embodiment, the daily dose is about 12 mg. In another embodiment, the daily dose is about 15 mg. In another embodiment, the daily dose is about 18 mg. In another embodiment, the daily dose is about 24 mg. In another embodiment, the daily dose is about 30 mg. In another embodiment, the daily dose is about 36 mg. In another embodiment, the daily dose is about 45 mg.

[0560] In one embodiment, a human subject is orally administered a solid form of Compound 1 in equal amounts BID (twice daily) (e.g., about 3 mg twice daily) at a dose of about 3 mg, about 6 mg, about 12 mg, or about 24 mg per unit formulation (e.g., per tablet or capsule).

[0561] In one embodiment, the disclosure relates to a method of treating a subject with rheumatoid arthritis, comprising administering to the subject about 3 mg per unit dosage form (e.g., per tablet or capsule) of a solid-state form of Compound 1 orally twice daily (e.g., about 3 mg each time). In another aspect, the disclosure relates to a solid-state form of Compound 1 for use in treating rheumatoid arthritis in a subject, particularly a human subject suffering from or susceptible to rheumatoid arthritis, comprising administering to the subject about 3 mg per unit dosage form (e.g., per tablet or capsule) of a solid-state form of Compound 1 orally twice daily (e.g., about 3 mg each time).

[0562] In one embodiment, the disclosure relates to a method of treating a subject with rheumatoid arthritis, comprising administering to the subject about 6 mg per unit dosage form (e.g., per tablet or capsule) of a solid-state form of Compound 1 orally twice daily (e.g., twice daily, about 6 mg each time). In another aspect, the disclosure relates to a solid-state form of Compound 1 for use in treating rheumatoid arthritis in a subject, particularly a human subject suffering from or susceptible to rheumatoid arthritis, comprising administering to the subject about 6 mg per unit dosage form (e.g., per tablet or capsule) of a solid-state form of Compound 1 orally twice daily (e.g., twice daily, about 6 mg each time).

[0563] In one embodiment, the disclosure relates to a method of treating a subject with rheumatoid arthritis, comprising administering to the subject about 12 mg per unit dosage form (e.g., per tablet or capsule) of a solid-state form of Compound 1 orally BID (twice daily) in equal doses (e.g., twice daily, about 12 mg each time). In another aspect, the disclosure relates to a solid-state form of Compound 1 for use in treating a subject with rheumatoid arthritis, particularly a human subject suffering from or susceptible to rheumatoid arthritis, comprising administering to the subject about 12 mg per unit dosage form (e.g., per tablet or capsule) of a solid-state form of Compound 1 orally BID (twice daily) in equal doses (e.g., twice daily, about 12 mg each time).

[0564] In one embodiment, the disclosure relates to a method of treating a subject with rheumatoid arthritis, comprising administering to the subject about 24 mg per unit dosage form (e.g., per tablet or capsule) of a solid-state form of Compound 1 orally BID (twice daily) in equal doses (e.g., twice daily, about 24 mg each time). In another aspect, the disclosure relates to a solid-state form of Compound 1 for use in treating rheumatoid arthritis in a subject, particularly a human subject suffering from or susceptible to rheumatoid arthritis, comprising administering to the subject about 24 mg per unit dosage form (e.g., per tablet or capsule) of a solid-state form of Compound 1 orally BID (twice daily) in equal doses (e.g., twice daily, about 24 mg each time).

[0565] In another embodiment, the methods and uses comprise orally administering to a human subject QD (once daily) a dose of about 7.5 mg per unit formulation (e.g., per tablet or capsule) of Compound 1 free base or a pharmaceutically acceptable salt thereof.

[0566] In another embodiment, the method and use comprises orally administering to a human subject a solid form of Compound 1 at a dose of about 7.5 mg per unit formulation (e.g., per tablet or capsule) QD (once daily). In one embodiment, the method and use comprises orally administering to a human subject a solid form of Compound 1 at a dose of about 7.5 mg per unit formulation (e.g., per tablet or capsule) QD (once daily) in an amount sufficient to deliver to the subject the equivalent of 7.5 mg of Compound 1 free base per unit formulation (e.g., per tablet or capsule). In one embodiment, the solid form is amorphous free base. In one embodiment, the solid form is free base hydrate Form B. In one embodiment, the solid form is free base hydrate Form C. In one embodiment, the solid form is tartrate salt hydrate. In another aspect, the solid form is free base anhydrous Form D.

[0567] In another embodiment, the methods and uses comprise orally administering to a human subject QD (once daily) a dose of about 15 mg per unit formulation (e.g., per tablet or capsule) of Compound 1 free base or a pharmaceutically acceptable salt thereof.

[0568] In another embodiment, the method and use comprises orally administering to a human subject a solid form of Compound 1 at a dose of about 15 mg per unit formulation (e.g., per tablet or capsule) QD (once daily). In one embodiment, the method and use comprises orally administering to a human subject a solid form of Compound 1 at a dose of about 15 mg per unit formulation (e.g., per tablet or capsule) QD (once daily) in an amount sufficient to deliver to the subject the equivalent of 15 mg of Compound 1 free base per unit formulation (e.g., per tablet or capsule). In one embodiment, the solid form is amorphous free base. In one embodiment, the solid form is free base hydrate Form B. In one embodiment, the solid form is free base hydrate Form C. In one embodiment, the solid form is tartrate salt hydrate. In another aspect, the solid form is free base anhydrous Form D.

[0569] In another embodiment, the methods and uses comprise orally administering to a human subject a QD (once daily) dose of about 24 mg of Compound 1 free base or a pharmaceutically acceptable salt thereof. The 24 mg QD dose of Compound 1 free base or a pharmaceutically acceptable salt thereof can be administered either as a single formulation containing about 24 mg per unit formulation (e.g., per tablet or capsule) of Compound 1 free base or a pharmaceutically acceptable salt thereof, or as two formulations administered simultaneously, each containing about 12 mg per unit formulation (e.g., per tablet or capsule) of Compound 1 free base or a pharmaceutically acceptable salt thereof.

[0570] In another embodiment, the method and use comprises orally administering to a human subject a dose of about 24 mg of the solid form of Compound 1 QD (once daily). In one embodiment, the method and use comprises orally administering to a human subject a dose of about 24 mg of the solid form of Compound 1 QD (once daily) in an amount sufficient to deliver to the subject 24 mg of the free base equivalent of Compound 1. The 24 mg QD dose of the solid form of Compound 1 can be administered either as a single formulation containing about 24 mg of the solid form of Compound 1 per unit formulation (e.g., per tablet or capsule), or as two formulations containing about 12 mg of the solid form of Compound 1 per unit formulation (e.g., per tablet or capsule) administered simultaneously. In one embodiment, the solid form is the amorphous free base. In one embodiment, the solid form is free base hydrate Form B. In one embodiment, the solid form is free base hydrate Form C. In one embodiment, the solid form is the tartrate salt hydrate. In another aspect, the solid form is free base anhydrous Form D.

[0571] In another embodiment, the methods and uses comprise orally administering to a human subject QD (once daily) a dose of about 30 mg per unit formulation (e.g., per tablet or capsule) of Compound 1 free base or a pharmaceutically acceptable salt thereof.

[0572] In another embodiment, the method and use comprises orally administering to a human subject a solid form of Compound 1 at a dose of about 30 mg per unit formulation (e.g., per tablet or capsule) QD (once daily). In one embodiment, the method and use comprises orally administering to a human subject a solid form of Compound 1 at a dose of about 30 mg per unit formulation (e.g., per tablet or capsule) QD (once daily) in an amount sufficient to deliver to the subject the equivalent of 30 mg of Compound 1 free base per unit formulation (e.g., per tablet or capsule). In one embodiment, the solid form is amorphous free base. In one embodiment, the solid form is free base hydrate Form B. In one embodiment, the solid form is free base hydrate Form C. In one embodiment, the solid form is tartrate salt hydrate. In another aspect, the solid form is free base anhydrous Form D.

[0573] In another embodiment, the methods and uses comprise orally administering to a human subject QD (once daily) a dose of about 36 mg per unit formulation (e.g., per tablet or capsule) of Compound 1 free base or a pharmaceutically acceptable salt thereof.

[0574] In another embodiment, the method and use comprises orally administering to a human subject a solid form of Compound 1 at a dose of about 36 mg per unit formulation (e.g., per tablet or capsule) QD (once daily). In one embodiment, the method and use comprises orally administering to a human subject a solid form of Compound 1 at a dose of about 36 mg per unit formulation (e.g., per tablet or capsule) QD (once daily) in an amount sufficient to deliver to the subject the equivalent of 36 mg of Compound 1 free base per unit formulation (e.g., per tablet or capsule). In one embodiment, the solid form is amorphous free base. In one embodiment, the solid form is free base hydrate Form B. In one embodiment, the solid form is free base hydrate Form C. In one embodiment, the solid form is tartrate salt hydrate. In another aspect, the solid form is free base anhydrous Form D.

[0575] In another embodiment, the methods and uses comprise orally administering to a human subject QD (once daily) a dose of about 45 mg per unit formulation (e.g., per tablet or capsule) of Compound 1 free base or a pharmaceutically acceptable salt thereof.

[0576] In another embodiment, the method and use comprises orally administering to a human subject a solid form of Compound 1 at a dose of about 45 mg per unit formulation (e.g., per tablet or capsule) QD (once daily). In one embodiment, the method and use comprises orally administering to a human subject a solid form of Compound 1 at a dose of about 45 mg per unit formulation (e.g., per tablet or capsule) QD (once daily) in an amount sufficient to deliver to the subject the equivalent of 45 mg of Compound 1 free base per unit formulation (e.g., per tablet or capsule). In one embodiment, the solid form is amorphous free base. In one embodiment, the solid form is free base hydrate Form B. In one embodiment, the solid form is free base hydrate Form C. In one embodiment, the solid form is tartrate salt hydrate. In another aspect, the solid form is free base anhydrous Form D.

[0577] In certain embodiments, Compound 1 free base or a pharmaceutically acceptable salt thereof and / or a solid form thereof can be used to treat rheumatoid arthritis (RA), for example, to reduce signs and symptoms of RA, induce a major clinical response, inhibit or treat the progression of RA-associated structural damage, and improve physical function in adult subjects, e.g., adult subjects with moderately to severely active RA. In one embodiment, Compound 1 free base or a pharmaceutically acceptable salt thereof and / or a solid form thereof is used to treat RA in an adult subject. In one embodiment, Compound 1 free base or a pharmaceutically acceptable salt thereof and / or a solid form thereof is used to reduce signs and symptoms of RA in an adult subject. In one embodiment, Compound 1 free base or a pharmaceutically acceptable salt thereof and / or a solid form thereof induces a major clinical response in an adult subject with RA. In one embodiment, Compound 1 free base or a pharmaceutically acceptable salt thereof and / or a solid form thereof is used to inhibit the progression of RA-associated structural damage in an adult subject. In one embodiment, Compound 1 free base and / or solid forms thereof are used to treat RA-associated structural damage in an adult subject. In one embodiment, Compound 1 free base or a pharmaceutically acceptable salt thereof and / or solid forms thereof are used to improve physical function in an adult subject. In one embodiment, the adult subject has RA. In another embodiment, the adult subject has moderately to severely active RA.

[0578] Compound 1 free base or a pharmaceutically acceptable salt thereof or solid state forms thereof may be used alone or in combination with methotrexate or other non-biologic disease-modifying antirheumatic drugs (DMARDs), and / or anti-TNFα biologic agents, such as TNF antagonists, e.g., chimeric, humanized, or human TNF antibodies, adalimumab (e.g., HUMIRA® trade name adalimumab), infliximab, e.g., CA2 (REMICADE® trade name infliximab), ximab), golimumab, e.g., SIMPONI™ (golimumab), certolizumab pegol, e.g., CIMZIA™, tocilizumab, e.g., ACTEMRA™, CDP571, and soluble p55 or p75 TNF receptors, derivatives thereof, etanercept, e.g., p75TNFR1gG (ENBREL™ trade name etanercept) or p55TNFR1gG (lenercept).

[0579] Patients with active rheumatoid arthritis (RA) can be diagnosed according to the 1987 revised American College of Rheumatology (ACR) classification criteria or the 2010 ACR / EULAR criteria. In certain embodiments, RA can be diagnosed based on patients having at least 6 swollen and 6 tender joints. In certain embodiments, patients treatable with Compound 1 or a solid form thereof can include patients who have failed therapy with at least one (e.g., at least 1 but not more than 4) DMARD and / or who have had an inadequate response to methotrexate, adalimumab, infliximab, etanercept, other anti-TNFα biologic agents, or non-anti-TNF biologic agents.

[0580] In certain embodiments, Compound 1 free base or a pharmaceutically acceptable salt thereof or solid form thereof halts the progression of the disease and / or at least alleviates the symptoms of the disease, which can be detected or monitored by radiographic findings, such as radiographic progression of joint damage.

[0581] In certain embodiments, therapeutic efficacy can be measured by improvement in ACR20, ACR50, and / or ACR70 in either an individual patient or a patient population in need of treatment. In certain embodiments, a statistically significant improvement (compared to placebo or untreated control) in ACR criteria 1 or greater over the treatment period (e.g., 1 week, 2 weeks, 4 weeks, 6 weeks, 8 weeks, 12 weeks, 2 months, 3 months, 6 months, 1 year, 2 years, 5 years, 10 years or more) is achieved. Statistical significance is represented by a p-value of less than 0.05 or less than 0.01.

[0582] ACR response items are known in the art and may include median tender joint count, median swollen joint count, physician global assessment such as measured by visual analog scale (VAS), patient global assessment such as measured by visual analog scale, pain such as measured by visual analog scale, Health Assessment Questionnaire Disability Index (HAQ-DI score), and C-reactive protein (CRP) (mg / dL).

[0583] In certain embodiments, an ACR20 response is determined based on a 20% or greater improvement in tender joint counts (TJC) and swollen joint counts (SJC) and three or more of the following five scales: patient assessment of pain (VAS), patient global assessment of disease activity (VAS), physician global assessment of disease activity (VAS), HAQ-DI, or high-sensitivity C-reactive protein (hsCRP). In some embodiments, an ACR50 response is determined based on a 50% or greater improvement in TJC and SJC and three or more of the following five scales: patient assessment of pain (VAS), patient global assessment of disease activity (VAS), physician global assessment of disease activity (VAS), HAQ-DI, or hsCRP. An ACR70 response is determined based on a 70% or greater improvement in TJC and SJC, and three or more of the following five scales: patient's pain assessment (VAS), patient's global assessment of disease activity (VAS), physician's global assessment of disease activity (VAS), HAQ-DI, or hsCRP. In certain embodiments, an ACR20, ACR50, or ACR70 response occurs by 12 weeks of treatment.

[0584] In certain embodiments, the DAS28 (Disease Activity Score based on 28 examined joints) score is determined as a composite score derived from four of the following measures: examination of the joints for swelling and tenderness, a global score for pain and overall condition, blood markers of inflammation (e.g., ESR (erythrocyte sedimentation rate) and CRP (C-reactive protein), referred to herein as DAS28(CRP)), questionnaires (e.g., the HAQ (Health Assessment Questionnaire) which assesses function), and other imaging techniques such as x-ray and ultrasound and MRI.

[0585] In certain embodiments, structural joint damage can be assessed radiographically and expressed, for example, as the change in the Total Sharp Score (TSS) and its components, the erosion score and the joint space narrowing (JSN) score, at 12 weeks compared to baseline, or at 24 weeks compared to baseline.

[0586] In certain embodiments, improvement in disease signs and symptoms can be measured by patient physical function responses, such as the disability index of the Health Assessment Questionnaire (HAQ-DI), and / or health outcomes assessed by the Short Form Health Survey (SF36). In one embodiment, improvement in disease signs and symptoms is measured by the HAQ-DI, for example, a minimal clinically important difference (MCID) of -0.22. Improvement can also be measured by one or both of the Physical Component Summary (PCS) and Mental Component Summary (MCS). Improvement can also be measured by the Work Instability Scale of the RA (RA-WIS) (see Gilworth et al., Arthritis & Rheumatism (Arthritis Care & Research) 49(3): 349-354, 2003; incorporated herein by reference).

[0587] In one embodiment, the disclosure relates to a method for treating rheumatoid arthritis in a subject, comprising orally administering to the subject, particularly a human subject suffering from or susceptible to rheumatoid arthritis, about 7.5 mg of Compound 1 free base or a pharmaceutically acceptable salt thereof per unit dosage form (e.g., per tablet or capsule) QD (once per day). In another aspect, the disclosure relates to Compound 1 free base or a pharmaceutically acceptable salt thereof for use in treating rheumatoid arthritis in a subject, particularly a human subject suffering from or susceptible to rheumatoid arthritis, comprising orally administering to the subject about 7.5 mg of Compound 1 free base or a pharmaceutically acceptable salt thereof per unit dosage form (e.g., per tablet or capsule) QD (once per day). In one embodiment, the subject has moderate to severe active rheumatoid arthritis. In one embodiment, the subject is an adult.

[0588] In one embodiment, the disclosure relates to a method for treating rheumatoid arthritis in a subject, comprising orally administering to the subject, particularly a human subject suffering from or susceptible to rheumatoid arthritis, about 7.5 mg of a solid form of Compound 1 per unit dosage form (e.g., per tablet or capsule) QD (once per day). In one embodiment, the method comprises orally administering to the subject a solid form of Compound 1 QD (once per day) in an amount sufficient to deliver to the subject 7.5 mg of Compound 1 free base equivalent per unit dosage form (e.g., per tablet or capsule). In another aspect, the disclosure relates to a solid form of Compound 1 for use in treating rheumatoid arthritis in a subject, particularly a human subject suffering from or susceptible to rheumatoid arthritis, comprising orally administering to the subject about 7.5 mg of a solid form of Compound 1 per unit dosage form (e.g., per tablet or capsule) QD (once per day). In one embodiment, the solid form delivers about 7.5 mg of Compound 1 free base equivalent per dosage unit (e.g., per tablet or capsule) to a subject. In one embodiment, the solid form is free base hydrate Form B. In one embodiment, the solid form is free base hydrate Form C. In one embodiment, the solid form is tartrate salt hydrate. In one embodiment, the solid form is free base anhydrate Form D. In one embodiment, the subject has moderate to severe active rheumatoid arthritis. In another embodiment, the solid form is free base solvate Form A. In another embodiment, the solid form is hydrochloride solvate Form AA. In another embodiment, the solid form is hydrochloride solvate Form BB. In another embodiment, the solid form is hydrochloride solvate Form CC. In another embodiment, the solid form is L-maleate salt Form AAA. In another embodiment, the solid form is L-maleate salt Form BBB. In one embodiment, the subject is an adult.

[0589] In one embodiment, the disclosure relates to a method for treating rheumatoid arthritis in a subject, comprising orally administering to the subject, particularly a human subject suffering from or susceptible to rheumatoid arthritis, about 15 mg of Compound 1 free base or a pharmaceutically acceptable salt thereof per unit dosage form (e.g., per tablet or capsule) QD (once per day). In another aspect, the disclosure relates to Compound 1 free base or a pharmaceutically acceptable salt thereof for use in treating rheumatoid arthritis in a subject, particularly a human subject suffering from or susceptible to rheumatoid arthritis, comprising orally administering to the subject about 15 mg of Compound 1 free base or a pharmaceutically acceptable salt thereof per unit dosage form (e.g., per tablet or capsule) QD (once per day). In one embodiment, the subject has moderate to severe active rheumatoid arthritis. In one embodiment, the subject is an adult.

[0590] In one embodiment, the disclosure relates to a method for treating rheumatoid arthritis in a subject, comprising orally administering to the subject, particularly a human subject suffering from or susceptible to rheumatoid arthritis, about 15 mg of a solid form of Compound 1 per unit dosage form (e.g., per tablet or capsule) QD (once per day). In one embodiment, the method comprises orally administering to the subject a solid form of Compound 1 QD (once per day) in an amount sufficient to deliver to the subject 15 mg of the free base equivalent of Compound 1 per unit dosage form (e.g., per tablet or capsule). In another aspect, the disclosure relates to a solid form of Compound 1 for use in treating rheumatoid arthritis in a subject, particularly a human subject suffering from or susceptible to rheumatoid arthritis, comprising orally administering to the subject about 15 mg of a solid form of Compound 1 per unit dosage form (e.g., per tablet or capsule) QD (once per day). In one embodiment, the solid form delivers to a subject about 15 mg of Compound 1 free base equivalent per unit dosage form (e.g., per tablet or capsule). In one embodiment, the solid form is free base hydrate Form B. In one embodiment, the solid form is free base hydrate Form C. In one embodiment, the solid form is tartrate salt hydrate. In one embodiment, the solid form is free base anhydrate Form D. In one embodiment, the subject has moderate to severe active rheumatoid arthritis. In another embodiment, the solid form is free base solvate Form A. In another embodiment, the solid form is hydrochloride solvate Form AA. In another embodiment, the solid form is hydrochloride solvate Form BB. In another embodiment, the solid form is hydrochloride solvate Form CC. In another embodiment, the solid form is L-maleate salt Form AAA. In another embodiment, the solid form is L-maleate salt Form BBB. In one embodiment, the subject is an adult.

[0591] In one embodiment, the disclosure relates to a method for treating rheumatoid arthritis in a subject, comprising administering to the subject, particularly a human subject suffering from or susceptible to rheumatoid arthritis, about 24 mg of Compound 1 free base or a pharmaceutically acceptable salt thereof, orally QD (once per day). In another aspect, the disclosure relates to Compound 1 free base or a pharmaceutically acceptable salt thereof for use in treating rheumatoid arthritis in a subject, particularly a human subject suffering from or susceptible to rheumatoid arthritis, comprising administering to the subject about 24 mg of Compound 1 free base or a pharmaceutically acceptable salt thereof, orally QD (once per day). A 24 mg dose of Compound 1 free base or a pharmaceutically acceptable salt thereof can be administered either as a single formulation containing about 24 mg of Compound 1 free base or a pharmaceutically acceptable salt thereof per unit formulation (e.g., per tablet or capsule), or as two formulations containing about 12 mg of Compound 1 free base or a pharmaceutically acceptable salt thereof per unit formulation (e.g., per tablet or capsule) administered simultaneously. In one embodiment, the subject has moderate to severe active rheumatoid arthritis. In one embodiment, the subject is an adult.

[0592] In one embodiment, the disclosure relates to a method for treating rheumatoid arthritis in a subject, comprising orally administering to the subject, particularly a human subject suffering from or susceptible to rheumatoid arthritis, about 24 mg of a solid form of Compound 1 QD (once per day). In one embodiment, the method comprises orally administering to the subject a solid form of Compound 1 QD (once per day) in an amount sufficient to deliver to the subject the equivalent of 24 mg of Compound 1 free base. In another aspect, the disclosure relates to a solid form of Compound 1 for use in treating rheumatoid arthritis in a subject, particularly a human subject suffering from or susceptible to rheumatoid arthritis, comprising orally administering to the subject about 24 mg of a solid form of Compound 1 QD (once per day). In one embodiment, the solid form delivers to the subject the equivalent of about 24 mg of Compound 1 free base. A 24 mg dose of the solid form of Compound 1 can be administered either as a single formulation containing about 24 mg of the solid form of Compound 1 per unit formulation (e.g., per tablet or capsule), or as two formulations containing about 12 mg of the solid form of Compound 1 per unit formulation (e.g., per tablet or capsule) administered simultaneously. In one embodiment, the solid form is free base hydrate Form B. In one embodiment, the solid form is free base hydrate Form C. In one embodiment, the solid form is tartrate salt hydrate. In one embodiment, the solid form is free base anhydrate Form D. In another embodiment, the solid form is free base solvate Form A. In another embodiment, the solid form is hydrochloride solvate Form AA. In another embodiment, the solid form is hydrochloride solvate Form BB. In another embodiment, the solid form is hydrochloride solvate Form CC. In another embodiment, the solid form is L-maleate salt Form AAA. In another embodiment, the solid form is L-maleate salt Form BBB. In one embodiment, the subject has moderate to severe active rheumatoid arthritis. In one embodiment, the subject is an adult.

[0593] In one embodiment, the disclosure relates to a method for treating rheumatoid arthritis in a subject, comprising orally administering to the subject, particularly a human subject suffering from or susceptible to rheumatoid arthritis, about 30 mg of Compound 1 free base or a pharmaceutically acceptable salt thereof per unit dosage form (e.g., per tablet or capsule) QD (once per day). In another aspect, the disclosure relates to Compound 1 free base or a pharmaceutically acceptable salt thereof for use in treating rheumatoid arthritis in a subject, particularly a human subject suffering from or susceptible to rheumatoid arthritis, comprising orally administering to the subject about 30 mg of Compound 1 free base or a pharmaceutically acceptable salt thereof per unit dosage form (e.g., per tablet or capsule) QD (once per day). In one embodiment, the subject has moderate to severe active rheumatoid arthritis. In one embodiment, the subject is an adult.

[0594] In one embodiment, the disclosure relates to a method for treating rheumatoid arthritis in a subject, comprising orally administering to the subject, particularly a human subject suffering from or susceptible to rheumatoid arthritis, about 30 mg of a solid form of Compound 1 per unit dosage form (e.g., per tablet or capsule) QD (once per day). In one embodiment, the method comprises orally administering to the subject a solid form of Compound 1 QD (once per day) in an amount sufficient to deliver to the subject 30 mg of the free base equivalent of Compound 1 per unit dosage form (e.g., per tablet or capsule). In another aspect, the disclosure relates to a solid form of Compound 1 for use in treating rheumatoid arthritis in a subject, particularly a human subject suffering from or susceptible to rheumatoid arthritis, comprising orally administering to the subject about 30 mg of a solid form of Compound 1 per unit dosage form (e.g., per tablet or capsule) QD (once per day). In one embodiment, the solid form delivers about 30 mg of Compound 1 free base equivalent per dosage unit (e.g., per tablet or capsule) to a subject. In one embodiment, the solid form is free base hydrate Form B. In one embodiment, the solid form is free base hydrate Form C. In one embodiment, the solid form is tartrate salt hydrate. In one embodiment, the solid form is free base anhydrate Form D. In one embodiment, the subject has moderate to severe active rheumatoid arthritis. In another embodiment, the solid form is free base solvate Form A. In another embodiment, the solid form is hydrochloride solvate Form AA. In another embodiment, the solid form is hydrochloride solvate Form BB. In another embodiment, the solid form is hydrochloride solvate Form CC. In another embodiment, the solid form is L-maleate salt Form AAA. In another embodiment, the solid form is L-maleate salt Form BBB. In one embodiment, the subject is an adult.

[0595] In one embodiment, the disclosure relates to a method for treating rheumatoid arthritis in a subject, comprising orally administering to the subject, particularly a human subject suffering from or susceptible to rheumatoid arthritis, about 36 mg of Compound 1 free base or a pharmaceutically acceptable salt thereof per unit dosage form (e.g., per tablet or capsule) QD (once per day). In another aspect, the disclosure relates to Compound 1 free base or a pharmaceutically acceptable salt thereof for use in treating rheumatoid arthritis in a subject, particularly a human subject suffering from or susceptible to rheumatoid arthritis, comprising orally administering to the subject about 36 mg of Compound 1 free base or a pharmaceutically acceptable salt thereof per unit dosage form (e.g., per tablet or capsule) QD (once per day). In one embodiment, the subject has moderate to severe active rheumatoid arthritis. In one embodiment, the subject is an adult.

[0596] In one embodiment, the disclosure relates to a method for treating rheumatoid arthritis in a subject, comprising orally administering to the subject, particularly a human subject suffering from or susceptible to rheumatoid arthritis, about 36 mg of a solid form of Compound 1 per unit dosage form (e.g., per tablet or capsule) QD (once per day). In one embodiment, the method comprises orally administering to the subject a solid form of Compound 1 QD (once per day) in an amount sufficient to deliver to the subject 36 mg of Compound 1 free base equivalent per unit dosage form (e.g., per tablet or capsule). In another aspect, the disclosure relates to a solid form of Compound 1 for use in treating rheumatoid arthritis in a subject, particularly a human subject suffering from or susceptible to rheumatoid arthritis, comprising orally administering to the subject about 36 mg of a solid form of Compound 1 per unit dosage form (e.g., per tablet or capsule) QD (once per day). In one embodiment, the solid form delivers about 36 mg of Compound 1 free base equivalent per dosage unit (e.g., per tablet or capsule) to a subject. In one embodiment, the solid form is free base hydrate Form B. In one embodiment, the solid form is free base hydrate Form C. In one embodiment, the solid form is tartrate salt hydrate. In one embodiment, the solid form is free base anhydrate Form D. In one embodiment, the subject has moderate to severe active rheumatoid arthritis. In another embodiment, the solid form is free base solvate Form A. In another embodiment, the solid form is hydrochloride solvate Form AA. In another embodiment, the solid form is hydrochloride solvate Form BB. In another embodiment, the solid form is hydrochloride solvate Form CC. In another embodiment, the solid form is L-maleate salt Form AAA. In another embodiment, the solid form is L-maleate salt Form BBB. In one embodiment, the subject is an adult.

[0597] In one embodiment, the disclosure relates to a method for treating rheumatoid arthritis in a subject, comprising orally administering to the subject, particularly a human subject suffering from or susceptible to rheumatoid arthritis, about 45 mg of Compound 1 free base or a pharmaceutically acceptable salt thereof per unit dosage form (e.g., per tablet or capsule) QD (once per day). In another aspect, the disclosure relates to Compound 1 free base or a pharmaceutically acceptable salt thereof for use in treating rheumatoid arthritis in a subject, particularly a human subject suffering from or susceptible to rheumatoid arthritis, comprising orally administering to the subject about 45 mg of Compound 1 free base or a pharmaceutically acceptable salt thereof per unit dosage form (e.g., per tablet or capsule) QD (once per day). In one embodiment, the subject has moderate to severe active rheumatoid arthritis. In one embodiment, the subject is an adult.

[0598] In one embodiment, the disclosure relates to a method for treating rheumatoid arthritis in a subject, comprising orally administering to the subject, particularly a human subject suffering from or susceptible to rheumatoid arthritis, about 45 mg of a solid form of Compound 1 per unit dosage form (e.g., per tablet or capsule) QD (once per day). In one embodiment, the method comprises orally administering to the subject a solid form of Compound 1 QD (once per day) in an amount sufficient to deliver to the subject 45 mg of Compound 1 free base equivalent per unit dosage form (e.g., per tablet or capsule). In another aspect, the disclosure relates to a solid form of Compound 1 for use in treating rheumatoid arthritis in a subject, particularly a human subject suffering from or susceptible to rheumatoid arthritis, comprising orally administering to the subject about 45 mg of a solid form of Compound 1 per unit dosage form (e.g., per tablet or capsule) QD (once per day). In one embodiment, the solid form delivers about 45 mg of Compound 1 free base equivalent per dosage unit (e.g., per tablet or capsule) to a subject. In one embodiment, the solid form is free base hydrate Form B. In one embodiment, the solid form is free base hydrate Form C. In one embodiment, the solid form is tartrate salt hydrate. In one embodiment, the solid form is free base anhydrate Form D. In one embodiment, the subject has moderate to severe active rheumatoid arthritis. In another embodiment, the solid form is free base solvate Form A. In another embodiment, the solid form is hydrochloride solvate Form AA. In another embodiment, the solid form is hydrochloride solvate Form BB. In another embodiment, the solid form is hydrochloride solvate Form CC. In another embodiment, the solid form is L-maleate salt Form AAA. In another embodiment, the solid form is L-maleate salt Form BBB. In one embodiment, the subject is an adult.

[0599] In one embodiment, the disclosure relates to a method for treating moderately to severely active rheumatoid arthritis in an adult subject, particularly a human subject suffering from or susceptible to moderately to severely active rheumatoid arthritis, comprising administering to the subject a therapeutically effective amount of Compound 1 (free base), or a pharmaceutically acceptable salt thereof, or a solid form of Compound 1. In one embodiment, the method comprises administering to the subject about 7.5 mg, or about 15 mg, or about 30 mg, or about 45 mg of Compound 1 (free base) or a pharmaceutically acceptable salt thereof per unit dosage form (e.g., per tablet or capsule), or a solid form of Compound 1 in an amount sufficient to deliver to the subject about 7.5 mg, or about 15 mg, or about 30 mg, or about 45 mg of Compound 1 free base equivalent per unit dosage form (e.g., per tablet or capsule). In one embodiment, the method comprises administering to a subject about 7.5 mg, about 15 mg, about 30 mg, or about 45 mg of Compound 1 (free base), or a pharmaceutically acceptable salt thereof, or a solid form of Compound 1, per unit dosage form (e.g., per tablet or capsule). In one embodiment, Compound 1 (free base), or a pharmaceutically acceptable salt thereof, or a solid form of Compound 1, is administered orally QD (once daily) to a subject. In another aspect, the disclosure relates to Compound 1 free base, or a pharmaceutically acceptable salt thereof, or a solid form of Compound 1 (e.g., a crystalline hydrate or a crystalline anhydrate), as described herein, for use in treating moderately to severely active rheumatoid arthritis in adult subjects, particularly human subjects suffering from or susceptible to moderately to severely active rheumatoid arthritis, comprising administering to the subject a therapeutically effective amount of Compound 1 free base, or a pharmaceutically acceptable salt thereof, or a solid form of Compound 1. In one embodiment, the solid form is a crystalline hydrate. In one embodiment, the crystalline hydrate is free base hydrate form B. In one embodiment, the crystalline hydrate is a hemihydrate. In one embodiment, the hemihydrate is free base hydrate form C. In one embodiment, the solid form is a crystalline anhydrate. In one embodiment, the crystalline anhydrate is free base anhydrate form D. In one embodiment, the solid form is free base solvate form A.In another embodiment, the solid form is hydrochloride solvate form AA. In one embodiment, the solid form is hydrochloride solvate form BB. In one embodiment, the solid form is hydrochloride solvate form CC. In one embodiment, the solid form is L-maleate form AAA. In one embodiment, the solid form is L-maleate form BBB. In one embodiment, Compound 1 (free base) or a pharmaceutically acceptable salt thereof or a solid form of Compound 1 is in a once-daily sustained release formulation. In one embodiment, the formulation delivers about 7.5 mg, about 15 mg, about 30 mg, or about 45 mg per unit formulation (e.g., per tablet or capsule) of Compound 1 (free base equivalent) or a solid form of Compound 1 orally QD (once-daily).

[0600] In one embodiment, a subject with moderately to severely active rheumatoid arthritis has at least one of the following distinguishing features prior to receiving treatment: at least 6 swollen joints (based on a 66-joint count), at least 6 tender joints (based on a 68-joint count), high-sensitivity C-reactive protein (hsCRP) above the upper limit of normal (ULN), or positive test results for both rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP). In one embodiment, a subject with moderately to severely active rheumatoid arthritis has at least 6 swollen joints (based on a 66-joint count) and at least 6 tender joints (based on a 68-joint count) prior to receiving treatment. Methods for assessing tenderness and swollen joints are known and are described, for example, in Scott, et al., Clinical and Experimental Rheumatology, 2014, Vol. 32 (Supp. 85), S7-S12.

[0601] Accordingly, in another embodiment, the present disclosure relates to a method for treating moderately to severely active rheumatoid arthritis in an adult subject, particularly a human subject suffering from or susceptible to moderately to severely active rheumatoid arthritis, comprising administering to the subject a therapeutically effective amount of Compound 1 (free base) as described herein, or a pharmaceutically acceptable salt thereof, or a solid form of Compound 1 (e.g., a crystalline hydrate or a crystalline anhydrate), wherein the subject has, prior to treatment, a symptom selected from the group consisting of at least six swollen joints, at least six tender joints, and combinations thereof. In one embodiment, the method comprises administering to a subject about 7.5 mg, about 15 mg, about 30 mg, or about 45 mg of Compound 1 (free base) or a pharmaceutically acceptable salt thereof per unit dosage form (e.g., per tablet or capsule) per day, or a solid form of Compound 1 in an amount sufficient to deliver to the subject about 7.5, or about 15 mg, or about 30 mg, or about 45 mg of Compound 1 free base equivalent per unit dosage form (e.g., per tablet or capsule) per day, wherein the subject has, prior to treatment, a symptom selected from the group consisting of at least 6 swollen joints, at least 6 tender joints, and combinations thereof. In one embodiment, the method comprises administering to the subject about 7.5 mg, or about 15 mg, or about 30 mg, or about 45 mg of the solid form of Compound 1 per unit dosage form (e.g., per tablet or capsule). In another aspect, the present disclosure relates to Compound 1 free base or a pharmaceutically acceptable salt thereof, or a solid form of Compound 1 (e.g., a crystalline hydrate or a crystalline anhydrate), as described herein, for use in treating moderately to severely active rheumatoid arthritis in adult subjects, particularly human subjects suffering from or susceptible to moderately to severely active rheumatoid arthritis, wherein the subject has, prior to treatment, a symptom selected from the group consisting of at least 6 swollen joints, at least 6 tender joints, and combinations thereof, comprising administering to the subject a therapeutically effective amount of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a solid form of Compound 1.In one embodiment, the therapeutically effective amount of the solid form of Compound 1 is delivered to a subject orally QD (once per day) about 7.5 mg, about 15 mg, about 30 mg, or about 45 mg per unit formulation (e.g., per tablet or capsule) of Compound 1 (free base equivalent) or a solid form of Compound 1. In one embodiment, Compound 1 (free base) or a pharmaceutically acceptable salt thereof or a solid form of Compound 1 is in a once-daily sustained release formulation. In one embodiment, Compound 1 (free base) or a pharmaceutically acceptable salt thereof or a solid form of Compound 1 is administered orally QD (once per day) to a subject. In one embodiment, the solid form is a crystalline hydrate. In one embodiment, the crystalline hydrate is free base hydrate form B. In one embodiment, the crystalline hydrate is free base hydrate form C. In one embodiment, the solid form is a crystalline anhydrate. In one embodiment, the crystalline anhydrate is free base anhydrate form D. In one embodiment, the solid form is the tartrate salt hydrate. In one embodiment, the symptoms are due to progression of structural damage as assessed by radiography.

[0602] In one embodiment, the disclosure relates to a method for treating moderately to severely active rheumatoid arthritis in an adult subject, particularly a human subject suffering from or susceptible to moderately to severely active rheumatoid arthritis, comprising administering to the subject about 7.5 mg of Compound 1 (free base) or a pharmaceutically acceptable salt thereof per unit dosage form (e.g., per tablet or capsule) per day, or a solid form of Compound 1 in an amount sufficient to deliver to the subject about 7.5 mg of Compound 1 free base equivalent per unit dosage form (e.g., per tablet or capsule) per day, wherein the subject has a symptom selected from the group consisting of at least 6 swollen joints, at least 6 tender joints, and combinations thereof prior to treatment. In one embodiment, the method comprises administering to the subject about 7.5 mg of the solid form of Compound 1 per unit dosage form (e.g., per tablet or capsule) per day. In another aspect, the disclosure relates to Compound 1 free base or a pharmaceutically acceptable salt thereof, or a solid form of Compound 1 for use in treating moderately to severely active rheumatoid arthritis in adult subjects, particularly human subjects suffering from or susceptible to moderately to severely active rheumatoid arthritis, wherein the subject has, prior to treatment, a symptom selected from the group consisting of at least six swollen joints, at least six tender joints, and combinations thereof, comprising administering to the subject about 7.5 mg of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a solid form of Compound 1 per unit dosage form (e.g., per tablet or capsule). In one embodiment, the solid form is a crystalline hydrate. In one embodiment, the crystalline hydrate is free base hydrate form B. In one embodiment, the crystalline hydrate is free base hydrate form C. In one embodiment, the solid form is a crystalline anhydrate. In one embodiment, the crystalline anhydrate is free base anhydrate form D. In one embodiment, the solid form is a tartrate salt hydrate. In one embodiment, Compound 1 free base or a pharmaceutically acceptable salt thereof, or a solid form of Compound 1 is administered orally QD (once daily). In one embodiment, Compound 1 free base or a pharmaceutically acceptable salt thereof, or a solid form of Compound 1 is in a once-daily sustained release formulation.In one embodiment, the symptoms are due to progression of structural damage as assessed by radiography.

[0603] In one embodiment, the disclosure relates to a method for treating moderately to severely active rheumatoid arthritis in an adult subject, particularly a human subject suffering from or susceptible to moderately to severely active rheumatoid arthritis, comprising administering to the subject about 15 mg of Compound 1 (free base) or a pharmaceutically acceptable salt thereof per unit dosage form (e.g., per tablet or capsule) per day, or a solid form of Compound 1 in an amount sufficient to deliver to the subject about 15 mg of Compound 1 free base equivalent per unit dosage form (e.g., per tablet or capsule) per day, wherein the subject has, prior to treatment, a symptom selected from the group consisting of at least 6 swollen joints, at least 6 tender joints, and combinations thereof. In one embodiment, the method comprises administering to the subject about 15 mg of a solid form of Compound 1 per unit dosage form (e.g., per tablet or capsule) per day. In another aspect, the disclosure relates to Compound 1 free base or a pharmaceutically acceptable salt thereof, or a solid form of Compound 1 for use in treating moderately to severely active rheumatoid arthritis in adult subjects, particularly human subjects suffering from or susceptible to moderately to severely active rheumatoid arthritis, wherein the subject has, prior to treatment, a symptom selected from the group consisting of at least six swollen joints, at least six tender joints, and combinations thereof, comprising administering to the subject about 15 mg of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a solid form of Compound 1 per unit dosage form (e.g., per tablet or capsule). In one embodiment, the solid form is a crystalline hydrate. In one embodiment, the crystalline hydrate is free base hydrate form B. In one embodiment, the crystalline hydrate is free base hydrate form C. In one embodiment, the solid form is a crystalline anhydrate. In one embodiment, the crystalline anhydrate is free base anhydrate form D. In one embodiment, the solid form is a tartrate salt hydrate. In one embodiment, Compound 1 free base or a pharmaceutically acceptable salt thereof, or a solid form of Compound 1 is administered orally QD (once daily). In one embodiment, Compound 1 free base or a pharmaceutically acceptable salt thereof, or a solid form of Compound 1 is in a once-daily sustained release formulation.In one embodiment, the symptoms are due to progression of structural damage as assessed by radiography.

[0604] In one embodiment, the disclosure relates to a method for treating moderately to severely active rheumatoid arthritis in an adult subject, particularly a human subject suffering from or susceptible to moderately to severely active rheumatoid arthritis, comprising administering to the subject about 30 mg of Compound 1 (free base) or a pharmaceutically acceptable salt thereof per unit dosage form (e.g., per tablet or capsule) per day, or a solid form of Compound 1 in an amount sufficient to deliver to the subject about 30 mg of Compound 1 free base equivalent per unit dosage form (e.g., per tablet or capsule) per day, wherein the subject has, prior to treatment, a symptom selected from the group consisting of at least 6 swollen joints, at least 6 tender joints, and combinations thereof. In one embodiment, the method comprises administering to the subject about 30 mg of a solid form of Compound 1 per unit dosage form (e.g., per tablet or capsule) per day. In another aspect, the disclosure relates to Compound 1 free base or a pharmaceutically acceptable salt thereof, or a solid form of Compound 1 for use in treating moderately to severely active rheumatoid arthritis in adult subjects, particularly human subjects suffering from or susceptible to moderately to severely active rheumatoid arthritis, wherein the subject has, prior to treatment, a symptom selected from the group consisting of at least six swollen joints, at least six tender joints, and combinations thereof, comprising administering to the subject about 30 mg of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a solid form of Compound 1 per unit dosage form (e.g., per tablet or capsule). In one embodiment, the solid form is a crystalline hydrate. In one embodiment, the crystalline hydrate is free base hydrate form B. In one embodiment, the crystalline hydrate is free base hydrate form C. In one embodiment, the solid form is a crystalline anhydrate. In one embodiment, the crystalline anhydrate is free base anhydrate form D. In one embodiment, the solid form is a tartrate salt hydrate. In one embodiment, Compound 1 free base or a pharmaceutically acceptable salt thereof, or a solid form of Compound 1 is administered orally QD (once daily). In one embodiment, Compound 1 free base or a pharmaceutically acceptable salt thereof, or a solid form of Compound 1 is in a once-daily sustained release formulation.In one embodiment, the symptoms are due to progression of structural damage as assessed by radiography.

[0605] In one embodiment, the disclosure relates to a method for treating moderately to severely active rheumatoid arthritis in an adult subject, particularly a human subject suffering from or susceptible to moderately to severely active rheumatoid arthritis, comprising administering to the subject about 45 mg of Compound 1 (free base) or a pharmaceutically acceptable salt thereof per unit dosage form (e.g., per tablet or capsule) per day, or a solid form of Compound 1 in an amount sufficient to deliver to the subject about 45 mg of Compound 1 free base equivalent per unit dosage form (e.g., per tablet or capsule) per day, wherein the subject has, prior to treatment, a symptom selected from the group consisting of at least 6 swollen joints, at least 6 tender joints, and combinations thereof. In one embodiment, the method comprises administering to the subject about 45 mg of a solid form of Compound 1 per unit dosage form (e.g., per tablet or capsule) per day. In another aspect, the disclosure relates to Compound 1 free base or a pharmaceutically acceptable salt thereof, or a solid form of Compound 1 for use in treating moderately to severely active rheumatoid arthritis in adult subjects, particularly human subjects suffering from or susceptible to moderately to severely active rheumatoid arthritis, wherein the subject has, prior to treatment, a symptom selected from the group consisting of at least six swollen joints, at least six tender joints, and combinations thereof, comprising administering to the subject about 45 mg of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a solid form of Compound 1 per unit dosage form (e.g., per tablet or capsule). In one embodiment, the solid form is a crystalline hydrate. In one embodiment, the crystalline hydrate is free base hydrate form B. In one embodiment, the crystalline hydrate is free base hydrate form C. In one embodiment, the solid form is a crystalline anhydrate. In one embodiment, the crystalline anhydrate is free base anhydrate form D. In one embodiment, the solid form is a tartrate salt hydrate. In one embodiment, Compound 1 free base or a pharmaceutically acceptable salt thereof, or a solid form of Compound 1 is administered orally QD (once daily). In one embodiment, Compound 1 free base or a pharmaceutically acceptable salt thereof, or a solid form of Compound 1 is in a once-daily sustained release formulation.In one embodiment, the symptoms are due to progression of structural damage as assessed by radiography.

[0606] In one embodiment, the adult subject receiving the treatment achieves an ACR20 response after treatment. In one embodiment, the adult subject achieves an ACR20 response after at least 12 weeks of treatment (e.g., at week 12 of treatment). In another embodiment, the adult subject receiving the treatment achieves an ACR50 response after treatment. In one embodiment, the adult subject achieves an ACR50 response after at least 12 weeks of treatment (e.g., at week 12 of treatment), or after at least 24 weeks (e.g., at week 24). In another embodiment, the adult subject receiving the treatment achieves an ACR70 response after treatment. In one embodiment, the adult subject achieves an ACR70 response after at least 12 weeks of treatment (e.g., at week 12 of treatment). In certain embodiments, the adult subject achieves an ACR20 response, an ACR50 response, and / or an ACR70 response after at least 12 weeks of treatment (e.g., at week 12 of treatment).

[0607] In one embodiment, the adult subject to be treated achieves an ACR20 response after at least 8 weeks of treatment (e.g., at week 8 of treatment). In another embodiment, the adult subject to be treated achieves an ACR20 response after at least 6 weeks of treatment (e.g., at week 6 of treatment). In another embodiment, the adult subject to be treated achieves an ACR20 response after at least 4 weeks of treatment (e.g., at week 4 of treatment). In another embodiment, the adult subject to be treated achieves an ACR20 response after at least 2 weeks of treatment (e.g., at week 2 of treatment).

[0608] In one embodiment, the adult subject to be treated achieves an ACR50 response after at least 8 weeks of treatment (e.g., at week 8 of treatment). In another embodiment, the adult subject to be treated achieves an ACR50 response after at least 6 weeks of treatment (e.g., at week 6 of treatment). In another embodiment, the adult subject to be treated achieves an ACR50 response after at least 4 weeks of treatment (e.g., at week 4 of treatment). In another embodiment, the adult subject to be treated achieves an ACR50 response after at least 2 weeks of treatment (e.g., at week 2 of treatment).

[0609] In one embodiment, the treated adult subject achieves an ACR70 response after at least 8 weeks of treatment (e.g., at week 8 of treatment). In another embodiment, the treated adult subject achieves an ACR70 response after at least 6 weeks of treatment (e.g., at week 6 of treatment). In another embodiment, the treated adult subject achieves an ACR70 response after at least 4 weeks of treatment (e.g., at week 4 of treatment).

[0610] In one embodiment, the treated adult subject achieves a change in DAS28 score after treatment. In one embodiment, the change in DAS score is a decrease in DAS28(CRP) after treatment compared to baseline (i.e., DAS28(CRP) before treatment). In one embodiment, the adult subject achieves a decrease in DAS28 score compared to baseline after at least 12 weeks of treatment (e.g., at week 12 of treatment). In one embodiment, the adult subject achieves a decrease in DAS28(CRP) compared to baseline after at least 12 weeks of treatment (e.g., at week 12 of treatment). In another embodiment, the adult subject achieves a decrease in DAS28(CRP) compared to baseline after at least 8 weeks of treatment (e.g., at week 8 of treatment). In another embodiment, the adult subject achieves a decrease in DAS28(CRP) compared to baseline after at least 6 weeks of treatment (e.g., at week 6 of treatment). In another embodiment, the adult subject achieves a reduction in DAS28(CRP) compared to baseline after at least 4 weeks of treatment (e.g., at week 4 of treatment). In another embodiment, the adult subject achieves a reduction in DAS28(CRP) compared to baseline after at least 2 weeks of treatment (e.g., at week 2 of treatment).

[0611] In another embodiment, the treated adult subject achieves a low disease activity (LDA) score or clinical remission after treatment. In one embodiment, the LDA score or clinical remission is measured as a DAS28 score (pa...

Claims

1. 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. 2. The crystalline hydrate of claim 1, wherein the hydrate is a hemihydrate.

3. 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 2θ when measured at about 25°C with monochromated Kα1 light.

4. The crystalline hydrate is a) an X-ray powder diffraction pattern substantially as shown in Figure 3C; b) Thermogravimetric profile substantially as shown in Figure 4E; c) a differential scanning calorimetry profile substantially as shown in Figure 5C; d) Moisture sorption isotherm profile substantially as shown in Figure 6B; e) P2 １ 2 １ 2 １ The space group is orthorhombic, with 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).

4. The crystalline hydrate according to any one of claims 1 to 3, having at least one characteristic selected from the group consisting of:

5. 2. 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 2θ when measured at about 25°C with monochromated Kα1 light.

6. The crystalline hydrate is a) an X-ray powder diffraction pattern substantially as shown in Figure 3B; b) Thermogravimetric analysis profile substantially as shown in Figure 4D; c) a differential scanning calorimetry profile substantially as shown in Figure 5B; and d) Any combination of a) to c).

6. The crystalline hydrate of claim 1 or claim 5, having at least one characteristic selected from the group consisting of:

7. Amorphous free base (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. 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. 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 2θ when measured at about 25°C with monochromated Kα1 light.

10. The crystalline anhydrate is a) an X-ray powder diffraction pattern substantially as shown in Figure 3J; b) Thermogravimetric analysis profile substantially as shown in Figure 4I; c) a differential scanning calorimetry profile substantially as shown in Figure 5E; d) Moisture sorption isotherm profile substantially as shown in Figure 6D; e) P2 １ 2 １ 2 space group, an orthorhombic lattice having 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).

10. The crystalline anhydrate of claim 8 or claim 9, having at least one characteristic selected from the group consisting of:

11. 1. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a solid 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 form is a) a crystalline hydrate according to any one of claims 1 to 6; b) the amorphous free base (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 according to any one of claims 8 to 10. A pharmaceutical composition selected from the group consisting of:

12. 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; 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 2θ when measured at about 25°C with monochromated Kα1 light; 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 2θ when measured at about 25°C with monochromated Kα1 light; c) amorphous free base (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 2θ when measured at about 25° C. with monochromated Kα1 light.

12. The pharmaceutical composition of claim 11, selected from the group consisting of:

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, 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. 14. The pharmaceutical composition of claim 13, wherein the tartrate salt 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. 15. The pharmaceutical composition of claim 13 or claim 14, wherein the tartrate salt 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 2θ when measured at about 25°C with monochromated Kα1 light.

16. The tartrate salt is a) an X-ray powder diffraction pattern substantially as shown in Figure 3D; b) Thermogravimetric profile substantially as shown in Figure 4F; c) a differential scanning calorimetry profile substantially as shown in Figure 5D; d) a moisture sorption isotherm profile substantially as shown in FIG. 6C; and e) Any combination of a) to d).

16. The pharmaceutical composition according to any one of claims 13 to 15, having at least one characteristic selected from the group consisting of:

17. 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. 11. A pharmaceutical composition comprising a therapeutically effective amount 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 according to any one of claims 1 to 10 for use in treating a JAK-1 associated condition in a subject suffering from or susceptible to said condition.

19. 11. A pharmaceutical composition comprising a therapeutically effective amount 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 according to 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 said condition.

20. 20. The pharmaceutical composition of claim 18 or 19, wherein the therapeutically effective amount 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 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. 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 free base hydrate form C.

22. 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 said crystalline hydrate.

4. A method for producing the crystalline hydrate according to claim 2 or claim 3, comprising:

23. 23. The method of claim 22, wherein the crystallization initiation step comprises seeding the solvent or mixture of solvents with crystals of the crystalline hydrate of claim 2 or claim 3.

24. 24. The method of claim 22 or claim 23, wherein the crystallization initiation step comprises both admixing 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. 25. The method of any one of claims 22 to 24, comprising 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 admixing the solvent or mixture of solvents.

26. 26. The method of any one of claims 22 to 25, wherein the crystallization occurs in a wet mill.

27. 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 including an anti-solvent; and maintaining the solvent or mixture of solvents at a temperature below 15°C for a time sufficient to initiate crystallization of the crystalline hydrate.

6. A method for producing the crystalline hydrate of claim 5, comprising:

28. 28. The method of claim 27, wherein the method further comprises seeding the solvent or mixture of solvents with crystals of the crystalline hydrate of claim 5.

29. 10. A method for preparing the amorphous free base (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, comprising dehydrating the crystalline hydrate of claim 5 to provide said amorphous free base (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. 8. A method for preparing the amorphous free base (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, 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 greater than about 8 to initiate precipitation of the amorphous free base (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 method comprising:

31. A method for producing the crystalline anhydrate of claim 8 or claim 9, 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 contains less than about 0.15% water by weight; and initiating crystallization to provide said crystalline anhydrate. A method comprising:

32. 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 crystallization initiation stage is a) combining said 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) 33. The method of claim 31 or claim 32, comprising:

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 produced by the method 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 produced by the method of claim 27 or 28.

36. Amorphous free base (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, produced by the method of claim 29 or claim 30.

37. A crystalline anhydrous (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 produced by the method of any one of claims 31 to 33.

38. A method 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, comprising: a) A compound of formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof with trimethylsulfoxonium chloride to give a compound of formula (II): 【Chemistry 2】 (PG is a protecting group); b) contacting a compound of formula (II) with LiX and a sulfonic acid to produce a compound of formula (III): 【Transformation 3】 (X is Br or Cl); c) reacting a compound of formula (III) with a compound of formula (IV): 【Chemistry 4】 to produce a compound of formula (V): 【Transformation 5】 (R １ is alkyl, aryl, and —OR ２ R ２ is alkyl; and Ts is tosyl; d) contacting the compound of formula (V) with a perfluoroanhydride and an organic base to produce a compound of formula (VI): 【Transformation 6】 forming; e) deprotecting the compound of formula (VI) to give a compound of formula (VII): 【Transformation 7】 forming a pharmaceutically acceptable salt of f) reacting a pharmaceutically acceptable salt of the compound of formula (VII) with 2,2,2-trifluoroethylamine to prepare (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 method comprising:

39. 39. The method of claim 38, wherein step e) comprises contacting the compound of formula (VII) with an acid to form a pharmaceutically acceptable salt of the compound of formula (VII).

40. The pharmaceutically acceptable salt of the compound of formula (I) is a compound of formula (Ib): 【Transformation 8】 and The compound of formula (Ib) (i) reacting carboxybenzyl-glycine ethyl ester with ethyl acrylate to give a compound of formula (VIII): 【Chemistry 9】 Forming; (ii) protecting the compound of formula (VIII) to obtain a compound of formula (IX): 【Chemistry 10】 (R ３ is CF ３ SO ２ -;CH ３ SO ２ -; and tosyl; (iii) contacting the compound of formula (IX) with one of ethylboronic acid, ethylmagnesium bromide, or ethylzinc chloride in the presence of a catalyst to produce a compound of formula (X): 【Chemistry 11】 Forming; (iv) hydrolyzing the compound of formula (X) to obtain a compound of formula (XI): 【Chemistry 12】 Manufacture the (v) Reacting the compound of formula (XI) with a compound of formula (XII): 【Chemistry 13】 Transformed into; (vi) contacting said compound of formula (XII) with dicyclohexylamine to form said compound of formula (Ib). Manufactured by 40. The method of claim 38 or claim 39, wherein Cbz is carboxybenzyl.

41. The pharmaceutically acceptable salt of the compound of formula (I) is a compound of formula (Ia): 【Chemistry 14】 and The compound of formula (Ia) (i) hydrogenating ethyl pent-2-ynoate with a Lindlar catalyst to form (Z)-ethyl pent-2-enoate; (ii) (Z)-ethyl pent-2-enoate is reacted with N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine to give a compound of formula (XIII): 【Chemistry 15】 Forming; (iii) deprotecting the compound of formula (XIII) to give a compound of formula (XIV): 【Chemistry 16】 Forming; (iv) hydrolyzing the compound of formula (XIV) to obtain a compound of formula (XV): 【Chemistry 17】 Forming; (v) reacting the compound of formula (XV) with N-benzyloxycarbonyloxysuccinimide to give a compound of formula (XVI): [Chemistry 18] Forming; (vi) contacting the compound of formula (XVI) with (R)-1-(naphthalen-1-yl)ethanamine to form a compound of formula (Ia) Manufactured by 40. The method of claim 38 or 39, wherein Cbz is carboxybenzyl; Bn is benzyl; and Et is ethyl.

42. A method 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, comprising: a) a compound of formula (XIa): 【Chemistry 19】 with a compound of formula (I): 【Chemistry 20】 (PG is a protecting group); b) reacting the compound of formula (I) with trimethylsulfoxonium chloride to give a compound of formula (II): 【Chemistry 21】 forming; c) contacting said compound of formula (II) with an anhydrous source of HBr or HCl to produce a compound of formula (III): 【Chemistry 22】 (X is Br or Cl); d) reacting the compound of formula (III) with a compound of formula (IV): 【Chemistry 23】 to produce a compound of formula (V): 【Chemistry 24】 (R １ is alkyl, aryl, and —OR ２ R ２ is alkyl; and Ts is tosyl; e) contacting the compound of formula (V) with a perfluoroacid anhydride and an organic base to produce a compound of formula (VI): 【Chemistry 25】 forming; f) Deprotecting the compound of formula (VI) to obtain a compound of formula (VII): 【Chemistry 26】 forming a pharmaceutically acceptable salt of g) reacting a 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. 43. The method of claim 42, wherein step f) comprises contacting the compound of formula (VII) with an acid to form a pharmaceutically acceptable salt of the compound of formula (VII).

44. 44. The method of claim 42 or claim 43, wherein the protecting group is carboxybenzyl.

45. 45. The method of any one of claims 42 to 44, wherein the anhydrous source of HBr or HCl contains no more than 0.2% water (by volume).

46. step b) comprises reacting said compound of formula (I) with trimethylsulfoxonium chloride in the presence of carbonyldiimidazole and a strong base to form said compound of formula (II); Step c) is carried out in tetrahydrofuran and comprises contacting said compound of formula (II) with an anhydrous source of HBr to form said compound of formula (III); and 46. ​​The method of any one of claims 42 to 45, wherein step d) comprises reacting said compound of formula (III) with a compound of formula (IV) in the presence of lithium tert-butoxide to produce said compound of formula (V).

47. 47. The method of claim 46, wherein the anhydrous source of HBr is HBr / HOAc.

48. The pharmaceutically acceptable salt of the compound of formula (VII) is 【Chemistry 27】 48. The method of any one of claims 38 to 47, selected from the group consisting of:

49. 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; 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 said crystalline hydrate. Including; 49. The method of any one of claims 38 to 48, wherein the crystalline hydrate is a hemihydrate.

50. 50. The method 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 2θ when measured at about 25°C with monochromated Kα1 light.

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 produced by the method of claim 49 or 50.

52. 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; 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 including an anti-solvent; and maintaining the solvent or mixture of solvents at a temperature below 15°C for an amount of time sufficient to initiate crystallization of the crystalline hydrate. Including; 49. The method of any one of claims 38 to 48, 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 2θ when measured at about 25°C with monochromated Kα1 light.

53. 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 produced by the method of claim 52.

54. 59. The method of any one of claims 38 to 48, further comprising preparing amorphous free base (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, comprising dehydrating the crystalline hydrate produced by the method of claim 52 to provide said amorphous free base (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. preparing amorphous free base (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; 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 greater than about 8 to initiate precipitation of the amorphous free base (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; 49. The method of any one of claims 38 to 48, comprising:

56. 56. Amorphous free base (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 produced by the method of claim 54 or 55.

57. preparing a crystalline anhydrous (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; 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 contains less than about 0.15% by weight of water; and initiating crystallization to provide said crystalline anhydrate.

49. The method of any one of claims 38 to 48, comprising:

58. 58. A crystalline anhydrous (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 produced by the method of claim 57.

59. A method 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, comprising: a) a compound of formula (Ib): 【Chemistry 28】 is reacted with trimethylsulfoxonium chloride in the presence of carbonyldiimidazole and a strong base to give a compound of formula (IIa): 【Chemistry 29】 (Cbz is carboxybenzyl); b) contacting the compound of formula (IIa) with lithium bromide and a sulfonic acid to produce a compound of formula (IIIa): 【Transformation 30】 forming; c) reacting the compound of formula (IIIa) with a compound of formula (IVa): 【Chemistry 31】 in the presence of lithium tert-butoxide to produce a compound of formula (Va): 【Chemistry 32】 (R ２ is methyl or ethyl; and Ts is tosyl; d) contacting the compound of formula (Va) with a perfluoroacid anhydride and an organic base to produce a compound of formula (VIa): 【Transformation 33】 forming; e) deprotecting the compound of formula (VIa) to obtain a compound of formula (VII): 【Transformation 34】 forming; f) contacting the compound of formula (VII) with hydrochloric acid to obtain a compound of formula (VIIa): 【Chemistry 35】 forming; g) reacting the compound of formula (VIIa) with 2,2,2-trifluoroethylamine in the presence of carbonyldiimidazole to prepare (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 method comprising:

60. 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-toluenesulfonic acid; The perfluoroacid anhydride of step d) is trifluoroacetic anhydride; The organic base of step d) is pyridine; The compound of formula (VIa) is reacted with hydrogen gas and Pd(OH ２ ) / C; and 60. The method of claim 59, wherein the reaction of step g) is carried out 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 produced by the method of claim 59 or 60.

62. A compound of formula (II). 【Transformation 36】 (PG is a protecting group.)

63. A compound of formula (V): 【Chemistry 37】 A method for producing a) a compound of formula (XIa): 【Transformation 38】 with a compound of formula (I): 【Chemistry 39】 To be converted into; b) reacting the compound of formula (I) with trimethylsulfoxonium chloride to give a compound of formula (II): 【Chemistry 40】 forming; c) contacting the compound of formula (II) with an anhydrous source of HBr or HCl to produce a compound of formula (III): 【Chemistry 41】 forming; d) reacting the compound of formula (III) with a compound of formula (IV): 【Chemistry 42】 to produce a compound of formula (V). [PG is a protecting group; X is Br or Cl; R １ is alkyl, aryl, and —OR ２ selected from the group consisting of: R ２ is alkyl; Ts is tosyl. A method comprising:

64. 64. The method of claim 63, wherein step c) is carried out in tetrahydrofuran and comprises contacting said compound of formula (II) with an anhydrous source of HBr to form said compound of formula (III).

65. The crystalline compound of formula (V): 【Chemistry 43】 A method for producing a) a compound of formula (III): 【Chemistry 44】 with a compound of formula (IV): 【Chemistry 45】 to prepare the compound of formula (V); [PG is a protecting group; X is Br or Cl; R １ Ha-OR ２ and R ２ is methyl or ethyl; Ts is tosyl. A method comprising:

66. A compound of formula (VII): 【Chemistry 46】 or a pharmaceutically acceptable salt thereof.

67. The pharmaceutically acceptable salt of the compound of formula (VII) is 【Chemistry 47】 【change】 67. The compound of claim 66, selected from the group consisting of:

68. Compound of formula (Ib): 【Chemistry 48】 (Cbz is carboxybenzyl), (i) reacting carboxybenzyl-glycine ethyl ester with ethyl acrylate to give a compound of formula (VIII): 【Chemistry 49】 forming; (ii) protecting the compound of formula (VIII) to obtain a compound of formula (IX): [Transformation 50] (R ３ is CF ３ SO ２ -;CH ３ SO ２ -; and tosyl; (iii) contacting the compound of formula (IX) with one of ethylboronic acid, ethylmagnesium bromide, or ethylzinc chloride in the presence of a catalyst to produce a compound of formula (X): 【Chemistry 51】 forming; (iv) hydrolyzing the compound of formula (X) to obtain a compound of formula (XI): 【Chemistry 52】 Manufacture of; (v) Reacting the compound of formula (XI) with a compound of formula (XII): 【Chemistry 53】 To be converted into; (vi) contacting said compound of formula (XII) with dicyclohexylamine to form said compound of formula (Ib). A method comprising:

69. 1. A pharmaceutical composition for use in treating an adult subject with moderate to severe active rheumatoid arthritis, comprising: 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) free base, or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1 in an amount sufficient to deliver to said subject the equivalent of about 7.5 mg of Compound 1 free base; or b) about 15 mg of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1 in an amount sufficient to deliver to said subject the equivalent of about 15 mg of Compound 1 free base; or c) about 30 mg of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1 in an amount sufficient to deliver to said subject the equivalent of about 30 mg of Compound 1 free base; or d) about 45 mg of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1 in an amount sufficient to deliver to said subject the equivalent of about 45 mg of Compound 1 free base. A pharmaceutical composition comprising:

70. 70. The pharmaceutical composition of claim 69, wherein the adult subject has had an inadequate response to or tolerance of one or more disease-modifying antirheumatic drugs (DMARDS).

71. 1. A pharmaceutical composition for use in treating rheumatoid arthritis-associated structural damage in an adult subject, comprising: a) about 7.5 mg / 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) free base 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 the equivalent of about 7.5 mg / day of Compound 1 free base; or b) about 15 mg / day of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1 in an amount sufficient to deliver to said subject the equivalent of about 15 mg / day of Compound 1 free base; or c) about 30 mg / day of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1 in an amount sufficient to deliver to said subject the equivalent of about 30 mg / day of Compound 1 free base; or d) about 45 mg / day of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1 in an amount sufficient to deliver to said subject the equivalent of about 45 mg / day of Compound 1 free base.

10. A pharmaceutical composition comprising:

72. 1. A pharmaceutical composition for use in the treatment of moderately to severely active rheumatoid arthritis in an adult subject, comprising: a) about 7.5 mg / 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) free base 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 the equivalent of about 7.5 mg / day of Compound 1 free base; or b) about 15 mg / day of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1 in an amount sufficient to deliver to said subject the equivalent of about 15 mg / day of Compound 1 free base; or c) about 30 mg / day of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1 in an amount sufficient to deliver to said subject the equivalent of about 30 mg / day of Compound 1 free base; or d) about 45 mg / day of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1 in an amount sufficient to deliver to said subject the equivalent of about 45 mg / day of Compound 1 free base. Including; The pharmaceutical composition, wherein the subject has, prior to treatment, a symptom selected from the group consisting of at least 6 swollen joints, at least 6 tender joints, and combinations thereof.

73. 1. A pharmaceutical composition for use in alleviating the signs and symptoms of rheumatoid arthritis in an adult subject with moderate to severe active rheumatoid arthritis, comprising: a) about 7.5 mg / 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) free base 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 the equivalent of about 7.5 mg of Compound 1 free base; or b) about 15 mg / day of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1 in an amount sufficient to deliver to said subject the equivalent of about 15 mg of Compound 1 free base; or c) about 30 mg / day of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1 in an amount sufficient to deliver to said subject the equivalent of about 30 mg of Compound 1 free base; or d) about 45 mg / day of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1 in an amount sufficient to deliver to said subject the equivalent of about 45 mg of Compound 1 free base. A pharmaceutical composition comprising:

74. 74. The pharmaceutical composition of any one of claims 69 to 73, wherein the use comprises administering to the subject about 7.5 mg, or about 15 mg, or about 30 mg, or about 45 mg per day of the crystalline hydrate or crystalline anhydrate of Compound 1.

75. 75. The pharmaceutical composition of any one of claims 69 to 74, wherein the crystalline anhydrate is free base anhydrate form D.

76. 75. The pharmaceutical composition of any one of claims 69 to 74, wherein the crystalline hydrate of Compound 1 is administered to the subject in an amount sufficient to deliver the equivalent of about 7.5 mg of Compound 1 free base to the subject.

77. 75. The pharmaceutical composition of any one of claims 69 to 74, wherein the crystalline hydrate of Compound 1 is administered to the subject in an amount sufficient to deliver the equivalent of about 45 mg of Compound 1 free base to the subject.

78. 75. The pharmaceutical composition of any one of claims 69 to 74, wherein the crystalline hydrate of Compound 1 is administered to the subject in an amount sufficient to deliver about 15 mg of Compound 1 free base equivalent.

79. Administration of the crystalline hydrate results in a mean peak plasma concentration (C) of Compound 1 of about 25 to about 70 ng / mL. ｍａｘ 79. The pharmaceutical composition of claim 78, wherein

80. Administration of the crystalline hydrate provides a time to peak plasma concentration (T) for Compound 1 of about 1.0 to about 6.0 hours. ｍａｘ 80. The pharmaceutical composition of claim 78 or claim 79, wherein

81. Administration of the crystalline hydrate results in a mean area under the plasma concentration-time curve (AUC) from time 0 to infinity for Compound 1 of about 220 to about 450 ng·hr / mL. ｉｎｆ 81. The pharmaceutical composition of any one of claims 78 to 80, wherein

82. Administration of the crystalline hydrate results in a harmonic mean terminal half-life (t １／２ 82. The pharmaceutical composition of any one of claims 78 to 81, wherein

83. C for Compound 1 when the crystalline hydrate was administered in the fed vs. fasted state ｍａｘ 83. The pharmaceutical composition of any one of claims 78 to 82, wherein the difference in is selected from the group consisting of about 30% or less, about 20% or less, and about 10% or less.

84. Administration of the crystalline hydrate results in a mean peak steady-state plasma concentration (C) of Compound 1 of about 27 to about 55 ng / mL. ｍａｘ，ｓｓ 84. The pharmaceutical composition of any one of claims 78 to 83, wherein

85. Administration of the crystalline hydrate results in a time to peak plasma concentration at steady state (T) of about 1.5 to about 6.0 hours. ｍａｘ，ｓｓ 85. The pharmaceutical composition of any one of claims 78 to 84, wherein

86. Administration of the crystalline hydrate results in a mean steady-state area under the plasma concentration-time curve (AUC) from time 0 to 24 hours for Compound 1 of about 240 to about 325 ng·hr / mL. ２４，ｓｓ 86. The pharmaceutical composition of any one of claims 78 to 85, wherein

87. Administration of the crystalline hydrate results in a harmonic mean steady-state terminal half-life (t １／２，ｓｓ 87. The pharmaceutical composition of any one of claims 78 to 86, wherein

88. Administration of the crystalline hydrate results in a mean minimum steady-state plasma concentration (C) of Compound 1 of about 2.8 to about 3.2 ng / mL. ｍｉｎ，ｓｓ 88. The pharmaceutical composition of any one of claims 78 to 87, wherein

89. 75. The pharmaceutical composition of any one of claims 69 to 74, wherein the crystalline hydrate of Compound 1 is administered to the subject in an amount sufficient to deliver the equivalent of about 30 mg of Compound 1 free base to the subject.

90. Administration of the crystalline hydrate results in a mean C for Compound 1 of about 55 to about 85 ng / mL. ｍａｘ The pharmaceutical composition of claim 89, which achieves the above.

91. Administration of the crystalline hydrate provides a T for Compound 1 of about 1.0 to about 8.0 hours. ｍａｘ The pharmaceutical composition of claim 89 or claim 90, which achieves the above.

92. Administration of the crystalline hydrate results in a mean AUC for Compound 1 of about 483 to about 660 ng-hr / mL. ｉｎｆ 92. The pharmaceutical composition of any one of claims 89 to 91, wherein

93. Administration of the crystalline hydrate results in a harmonic mean terminal half-life (t １／２ 93. The pharmaceutical composition of any one of claims 89 to 92, wherein

94. C for Compound 1 when the crystalline hydrate is administered in the fed vs. fasted state ｍａｘ 94. The pharmaceutical composition of any one of claims 89 to 93, wherein the difference in 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. Administration of the crystalline hydrate results in a mean C for Compound 1 of about 65 to about 86 ng / mL. ｍａｘ，ｓｓ 95. The pharmaceutical composition of any one of claims 89 to 94, wherein

96. Administration of the crystalline hydrate results in a mean AUC for Compound 1 of about 485 to about 658 ng-hr / mL. ２４，ｓｓ 96. The pharmaceutical composition of any one of claims 89 to 95,

97. The administration of the crystalline hydrate has a T of about 1.5 to about 6.0 hours. ｍａｘ，ｓｓ 97. The pharmaceutical composition of any one of claims 89 to 96, wherein

98. The administration of the crystalline hydrate provides a harmonic mean t for Compound 1 of about 10.0 to about 14.5 hours. １／２，ｓｓ 98. The pharmaceutical composition of any one of claims 89 to 97, wherein

99. Administration of the crystalline hydrate results in a mean C for Compound 1 of about 3.5 to about 5.3 ng / mL. ｍｉｎ，ｓｓ 99. The pharmaceutical composition of any one of claims 89 to 98, wherein

100. 100. The pharmaceutical composition of any one of claims 69-74 and 76-99, wherein the crystalline hydrate is free base hydrate form C.

101. 1. A pharmaceutical composition comprising a crystalline hydrate or 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 free base equivalent, or about 15 mg of Compound 1 free base equivalent, or about 30 mg of Compound 1 free base equivalent, or about 45 mg of Compound 1 free base 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 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. 103. The composition of claim 101 or claim 102, wherein the crystalline hydrate is free base hydrate form C.

104. the composition comprising about 15 mg of free base hydrate Form C, and administering the composition to a subject comprises: (a) Mean C for Compound 1 from about 25 to about 70 ng / mL ｍａｘ ; (b) T for Compound 1 from about 1.0 hour to about 6.0 hours ｍａｘ ; (c) The harmonic mean t for Compound 1 of about 10.0 to about 14.0 hours １／２ ; (d) Mean AUC for Compound 1 from about 220 to about 450 ng-hr / mL ｉｎｆ ; (e) Mean C for Compound 1 from about 27 to about 55 ng / mL ｍａｘ，ｓｓ ; (f) Mean AUC for Compound 1 from about 240 to about 325 ng-hr / mL ２４，ｓｓ ; (g) T for Compound 1 of about 1.5 to about 6.0 hours ｍａｘ，ｓｓ ; (h) Mean C for Compound 1 from about 2.8 to about 3.2 ng / mL ｍｉｎ，ｓｓ ; (i) The harmonic mean t for Compound 1 of about 9.4 to about 10.5 hours １／２，ｓｓ ; or any combination thereof.

105. the composition comprising about 30 mg of free base hydrate Form C, and administering the composition to a subject comprises: (a) Mean C for Compound 1 from about 55 to about 85 ng / mL ｍａｘ ; (b) T for Compound 1 from about 1.0 hour to about 8.0 hours ｍａｘ ; (c) The harmonic mean t for Compound 1 of about 9.0 to about 12.0 hours １／２ ; (d) Mean AUC for Compound 1 from about 483 to about 660 ng-hr / mL ｉｎｆ ; (e) Mean C for Compound 1 from about 65 to about 85 ng / mL ｍａｘ，ｓｓ ; (f) Mean AUC for Compound 1 from about 485 to about 658 ng-hr / mL ２４，ｓｓ ; (g) T for Compound 1 of about 1.5 to about 6.0 hours ｍａｘ，ｓｓ ; (h) Mean C for Compound 1 from about 3.5 to about 5.3 ng / mL ｍｉｎ，ｓｓ ; (i) the harmonic mean t for Compound 1 of about 10.0 to about 14.5 hours １／２、ｓｓ ; or any combination of these 104. The composition of claim 103,

106. 103. The composition of claim 101 or claim 102, wherein the crystalline anhydrate is free base anhydrate form D.

107. 107. The pharmaceutical composition of any one of claims 69-100 or the composition of any one of claims 101-106, wherein the free base, the crystalline hydrate, or the crystalline anhydrate is in a once-daily sustained release formulation.

108. A sustained-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 adjuster, wherein the hydrophilic polymer forms a gel layer upon contact with water, which provides an environment suitable for dissolving Compound 1 and the pH adjuster.

109. The sustained-release formulation of claim 108, wherein the environment suitable for dissolving Compound 1 has a pH of 3.8 or less at 37°C.

110. 110. The sustained release formulation of claim 108 or claim 109, wherein the pH adjuster is selected from the group consisting of tartaric acid, fumaric acid, citric acid, succinic acid, and malic acid, and combinations thereof.

111. 111. The sustained release formulation of any one of claims 108 to 110, wherein the pH adjusting agent is present in an amount of 10 to 35% w / w.

112. 112. The sustained release formulation of any one of claims 108 to 111, wherein the hydrophilic polymer is a cellulose derivative having a viscosity between 1000 and 150,000 mPa-s.

113. 113. The sustained release formulation of claim 112, wherein the hydrophilic polymer is selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylcellulose, and mixtures thereof.

114. 1. A method for producing a pharmaceutical composition, 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 form of Compound 1, and at least a portion of one other composition ingredient 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) grinding the particulate material to form a ground particulate material; (e) combining the ground particulate material with any remaining composition ingredients; and (f) compressing the composition to form the pharmaceutical composition. A method comprising:

115. 1. 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-controlling polymer; and about 20% w / w tartaric acid, wherein the release-controlling polymer comprises hydroxypropyl methylcellulose, and the hydrate is free base hydrate Form C.

116. 1. 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-controlling polymer; and about 20% w / w tartaric acid, wherein the release-controlling polymer comprises hydroxypropyl methylcellulose, and the hydrate is free base hydrate Form C.

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