Method for preparing imidazo [1, 2-a] pyrrolo [2, 3-e] pyrazine compound and solid-state form thereof

Abstract

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

Description

This application is a divisional application of the patent application for invention with the application date of October 17, 2016, application number 202211671688.7, and invention title "Method for Preparing Imidazo[1,2-a]pyrrolo[2,3-e]pyrazine Compounds and Their Solid Forms". Cross - reference to related applications

[0001] This application claims the benefit of U.S. Provisional Application No. 62 / 242,797, filed on October 16, 2015; and claims the benefit of U.S. Provisional Application No. 62 / 267,672, filed on December 15, 2015; and claims the benefit of U.S. Provisional Application No. 62 / 301,537, filed on February 29, 2016; and claims the benefit of U.S. Provisional Application No. 62 / 352,380, filed on June 20, 2016; all of which are hereby incorporated by reference in their entirety. Technical field

[0002] This disclosure relates to: (a) 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 (hereinafter referred to as "Compound 1"), (b) intermediates used in the preparation of Compound 1 and methods for preparing the intermediates; (c) solid forms of Compound 1, (d) pharmaceutical compositions comprising one or more solid forms of Compound 1 and optionally one or more additional therapeutic agents; (e) a method for treating Janus kinase - related disorders (including rheumatoid arthritis) by administering one or more solid forms of Compound 1 to a subject in need thereof; (f) a kit comprising a first pharmaceutical composition and optionally a second pharmaceutical composition, the first pharmaceutical composition comprising a solid form of Compound 1 and the second pharmaceutical composition comprising one or more additional therapeutic agents; (g) a method for preparing a solid form of Compound 1; and (h) solid forms of Compound 1 prepared according to these methods. Background of the invention

[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 Application WO 2011 / 068881A1, which is hereby incorporated by reference in its entirety. The compound has activity as a Janus kinase ("JAK") inhibitor, particularly as a JAK - 1 inhibitor. Clinical trials are underway to evaluate the use of the compound for the treatment of rheumatoid arthritis.

[0004] The isolation and commercial-scale preparation of solid forms of Compound 1 and corresponding pharmaceutical formulations having acceptable solid-state properties (including chemical stability, thermal stability, solubility, hygroscopicity, and / or particle size), the compound manufacturability (including yield, impurity rejection during crystallization, filtration performance, drying properties, and milling properties), and the formulation feasibility (including stability to pressure or compression force during tableting) pose many challenges, which will be discussed in more detail below. Accordingly, there is a current need for one or more solid forms of Compound 1 that have an acceptable balance of these properties and are useful for preparing pharmaceutically acceptable solid dosage forms.

[0005] In addition, currently known methods for preparing Compound 1 involve the use of particularly hazardous reagents such as trimethylsilyldiazomethane or diazomethane and do not form crystalline products. Accordingly, there remains a need for methods for preparing Compound 1 and its pharmaceutically acceptable salts that avoid the use of particularly hazardous reagents and can form crystalline products and crystalline intermediates.

[0006] Additionally, sustained plasma peak concentrations can theoretically be achieved through a sustained-release matrix system. However, when such systems are made of hydrophilic polymers such as HPMC, they rarely provide pH-independent drug release for pH-dependent soluble drugs, and they generally cannot achieve zero-order release except for virtually insoluble drugs. Surprisingly, it has been found that when tartaric acid is used as a pH regulator in the system, it allows Compound 1 to be released at a stable rate regardless of the pH of the environment.

[0007] Surprisingly, as the tablets containing the hydrophilic polymer matrix system erode, Compound 1 reacts with HPMC to produce a thicker gel layer that slows the release of Compound 1 from the tablets. The resulting gel layer provides an environment suitable for the dissolution of Compound 1. SUMMARY OF THE INVENTION

[0008] In one aspect, the present disclosure relates to a method for preparing Compound 1 or a pharmaceutically acceptable salt thereof. The method comprises: a) reacting a compound having formula (I) or a pharmaceutically acceptable salt thereof with trimethylsulfoxonium chloride to form a compound having formula (II) wherein PG is a protecting group; b) reacting the compound having formula (II) with LiX and a sulfonic acid to form a compound having formula (III) wherein X is Br or Cl; c) React the compound of formula (III) with a compound of formula (IV) to produce a compound of formula (V) wherein R1 is selected from the group consisting of: alkyl, aryl, and -OR2; R2 is alkyl; and Ts is tosyl; d) Contact the compound of formula (V) with a perfluoroanhydride and an organic base to form a compound of formula (VI) e) Deprotect the compound of formula (VI) and form a pharmaceutically acceptable salt of the compound of formula (VII): f) React the pharmaceutically acceptable salt of the compound of formula (VII) with 2,2,2-trifluoroethylamine to produce Compound 1.

[0009] In another aspect, the present disclosure relates to a method for preparing Compound 1 or a pharmaceutically acceptable salt thereof. The method comprises: a) React a compound of formula (Ib) with trimethylsulfoxonium chloride in the presence of carbonyldiimidazole and a strong base to form a compound of formula (IIa) wherein Cbz is carboxybenzyl; b) React the compound of formula (IIa) with lithium bromide and a sulfonic acid to form a compound of formula (IIIa) c) React the compound of formula (IIIa) with a compound of formula (IVa) in the presence of lithium tert-butoxide to form a compound of formula (Va) wherein R2 is methyl or ethyl; and Ts is tosyl; d) Contact the compound of formula (Va) with a perfluoroanhydride and an organic base to form a compound of formula (VIa) e) Deprotect the compound of formula (VIa) to form a compound of formula (VII) f) Contacting the compound of formula (VII) with hydrochloric acid to form a compound of formula (VIIa). g) Reacting the compound of formula (VIIa) with 2,2,2-trifluoroethylamine in the presence of carbonyldiimidazole to produce Compound 1.

[0010] In another aspect, the present disclosure relates to a method for preparing Compound 1. The method comprises: a) Reacting a compound of formula (I) or a pharmaceutically acceptable salt thereof with trimethylsulfoxonium chloride to form a compound of formula (II) wherein PG is a protecting group; b) Contacting the compound of formula (II) with LiX and a sulfonic acid to form a compound of formula (III) wherein X is Br or Cl; c) Reacting the compound of formula (III) with a compound of formula (IV) to produce a compound of formula (V) wherein 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 form a compound of formula (VI) e) Deprotecting the compound of formula (VI) to form a compound of formula (VII) and contacting the compound of formula (VII) with hydrochloric acid to form the compound of formula (VIIb) f) Contacting the compound of formula (VIIb) with a base to form the compound of formula (VII); g) Reacting the compound of formula (VII) with 2,2,2-trifluoroethylamine to produce Compound 1; h) Contacting Compound 1 with L-tartaric acid to form the tartrate salt of Compound 1; and i) Contacting a tartrate salt with sodium carbonate and sodium bicarbonate to form Compound 1.

[0011] In another aspect, the present disclosure relates to a method for preparing Compound 1 or a pharmaceutically acceptable salt thereof. The method comprises: a) Converting a compound having the formula (XIa): into a compound having the formula (I): wherein PG is a protecting group; b) Reacting the compound having the formula (I) with trimethylsulfoxonium chloride to form a compound having the formula (II) c) Contacting the compound having the formula (II) with an anhydrous HBr or anhydrous HCl source to form a compound having the formula (III) wherein X is Br or Cl; d) Reacting the compound having the formula (III) with a compound having the formula (IV) to produce a compound having the formula (V) wherein R1 is selected from the group consisting of alkyl, aryl, and -OR2; R2 is alkyl; and Ts is tosyl; e) Contacting the compound having the formula (V) with a perfluoroanhydride and an organic base to form a compound having the formula (VI) f) Deprotecting the compound having the formula (VI) and forming a pharmaceutically acceptable salt of the compound having the formula (VII): and g) Reacting the pharmaceutically acceptable salt of the compound having the formula (VII) with 2,2,2-trifluoroethylamine to produce Compound 1.

[0012] In another aspect, the present disclosure relates to a compound having the formula (II): wherein PG is a protecting group.

[0013] In another aspect, the present invention relates to a method for preparing a compound having the formula (II): where PG is a protecting group, and the method comprises reacting a compound of formula (I) or a pharmaceutically acceptable salt thereof with trimethylsulfoxonium chloride to form a compound of formula (II).

[0014] In another aspect, the present invention is directed to a method for preparing a compound of formula (III): The method comprises contacting a compound of formula (II) with LiX and a sulfonic acid to form the compound of formula (III); where PG is a protecting group; and X is Br or Cl.

[0015] In another aspect, the present disclosure relates to a compound of formula (Va) where R2 is methyl or ethyl; and Ts is tosyl.

[0016] In another aspect, the present disclosure relates to a method for preparing a compound of formula (V) The method comprises:[[]] a) converting a compound of formula (XIa): into a compound of formula (I) b) reacting the compound of formula (I) with trimethylsulfoxonium chloride to form a compound of formula (II) c) contacting the compound of formula (II) with an anhydrous HBr or anhydrous HCl source to form a compound of formula (III) d) reacting the compound of formula (III) with a compound of formula (IV) to produce the compound of formula (V); where:[[]] PG is a protecting group; X is Br or Cl; R1 is selected from the group consisting of alkyl, aryl, and -OR2; R2 is an alkyl group; and Ts is tosyl.

[0017] In another aspect, the present disclosure is directed to a method for preparing a crystalline compound having formula (V) The method comprises: a) reacting a compound having formula (III) with a compound having formula (IV): to produce the compound having formula (V); wherein: PG is a protecting group; X is Br or Cl; R1 is -OR2; R2 is methyl or ethyl; and Ts is tosyl.

[0018] In another aspect, the present disclosure relates to a compound having formula (IVa): wherein R2 is methyl or ethyl; and Ts is tosyl.

[0019] In another aspect, the present disclosure relates to a method for preparing a compound having formula (IVa): wherein R2 is methyl or ethyl; and Ts is tosyl, the method comprising: a) reacting a compound having formula (XVII) with trimethylsilylacetylene in the presence of a catalyst to form a compound having formula (XVIII): wherein TMS is trimethylsilyl; b) reacting the compound having formula (XVIII) with p-toluenesulfonyl chloride in the presence of a base to form a compound having formula (XIX) wherein Ts is tosyl; and c) reacting the compound having formula (XIX) with a carbamate in the presence of a catalyst and a ligand to form a compound having formula (IVa), wherein the carbamate is selected from the group consisting of methyl carbamate and ethyl carbamate.

[0020] In another aspect, the present disclosure relates to compounds of formula (VII): or a pharmaceutically acceptable salt thereof.

[0021] In another aspect, the present disclosure relates to a method for preparing a compound of formula (Ib) wherein Cbz is carboxybenzyl, the method comprising: (i) reacting carboxybenzyl-glycine ethyl ester with ethyl acrylate to form a compound of formula (VIII): (ii) protecting the compound of formula (VIII) to form a compound of formula (IX): wherein R 3 is selected from the group consisting of: 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 form a compound of formula (X): (iv) hydrolyzing the compound of formula (X) to form the compound of formula (XI): (v) converting the compound of formula (XI) to the compound of formula (XII): (vi) contacting the compound of formula (XII) with dicyclohexylamine to form the compound of formula (Ib).

[0022] In another aspect, the present disclosure relates to the dicyclohexylamine salt of (3R,4S)-1-((benzyloxy)carbonyl)-4-ethylpyrrolidine-3-carboxylate.

[0023] In one aspect, the present disclosure relates to a pharmaceutically acceptable solid form of Compound 1.

[0024] In another aspect, the present disclosure relates to the amorphous free base of Compound 1.

[0025] In another aspect, the present disclosure relates to crystalline Compound 1.

[0026] In another aspect, the present disclosure relates to the crystalline hydrate of Compound 1.

[0027] In another aspect, the present disclosure relates to the crystalline tartrate salt of Compound 1.

[0028] In another aspect, the present disclosure relates to the free base hydrate Form C of Compound 1.

[0029] In another aspect, the present disclosure relates to the free base hydrate Form B of Compound 1.

[0030] In another aspect, the present disclosure relates to the crystalline anhydrate of Compound 1.

[0031] In another aspect, the present disclosure relates to the free base anhydrate Form D of Compound 1.

[0032] In another aspect, the present disclosure relates to a pharmaceutical composition comprising one or more solid forms of Compound 1 and a pharmaceutically acceptable carrier.

[0033] In another aspect, the present disclosure is directed to a pharmaceutical composition comprising one or more solid forms of Compound 1, an organic acid selected from tartaric acid, fumaric acid, citric acid, succinic acid, malic acid, and combinations thereof in an amount from about 10 w / w% to about 35 w / w%, and a pharmaceutically acceptable carrier. In one embodiment, the solid form is the tartrate hydrate. In one embodiment, the solid form is the free base hydrate Form C.

[0034] In another aspect, the present disclosure relates to a pharmaceutical composition comprising one or more solid forms of Compound 1 and optionally one or more additional therapeutic agents.

[0035] In another aspect, the present disclosure relates to a method of treating a JAK-related disorder (such as rheumatoid arthritis) in a human subject having or susceptible to such a disorder, the method 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 in the present disclosure for treating a JAK-related disorder (such as rheumatoid arthritis) in a subject, particularly in a human patient having or susceptible to the disorder.

[0036] In another aspect, the present disclosure relates to a method of treating rheumatoid arthritis, wherein the term "rheumatoid arthritis" includes juvenile rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis disease, Sjogren's syndrome, psoriatic arthritis.

[0037] In another aspect, the present disclosure relates to a method of treating inflammatory bowel disease, wherein the term "inflammatory bowel disease" includes Crohn's disease, pediatric Crohn's disease, and ulcerative colitis.

[0038] In another aspect, the present disclosure relates to a method for treating such a disorder in a human subject having or susceptible to a disorder 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, the method 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 the solid form of Compound 1 described herein for treating such a disorder in a subject, particularly a human subject having or susceptible to a disorder 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.

[0039] In another aspect, the present disclosure relates to a method for treating a JAK-related disorder (such as rheumatoid arthritis) in a human subject having or susceptible to such a disorder, the method comprising co-administering to the subject a solid form of Compound 1 and one or more additional therapeutic agents (e.g., a therapeutic agent that is not a JAK inhibitor for treating rheumatoid arthritis). In another aspect, the present disclosure relates to a pharmaceutical composition comprising the solid form of Compound 1 as described herein, in combination with one or more additional therapeutic agents (e.g., a therapeutic agent that is not a JAK inhibitor for treating rheumatoid arthritis), for treating a JAK-related disorder (such as rheumatoid arthritis) in a subject, particularly a human subject having or susceptible to such a disorder.

[0040] In another aspect, the present disclosure relates to a method for treating moderate to severe active rheumatoid arthritis, the method comprising administering to a subject having or susceptible to such a disorder a therapeutically effective amount of one or more forms of Compound 1 disclosed herein. In a particular aspect, such a method may comprise administering Compound 1 to the subject at 7.5 mg once daily, or 15 mg once daily, or 30 mg once daily, or 45 mg once daily in one or more forms disclosed herein. In this or another particular aspect, the subject can administer Compound 1 in the free base form C. In this or another particular aspect, the subject may be insufficiently responsive to methotrexate. In this or another particular aspect, the subject may be insufficiently responsive to a biologic drug approved for rheumatoid arthritis. In this or another particular aspect, the subject may not have been previously administered a biologic drug approved for rheumatoid arthritis.

[0041] In another aspect, the present disclosure relates to a method of treating adult subjects suffering from moderate to severe active rheumatoid arthritis, the method 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 to the subject about 7.5 mg of Compound 1 free base equivalent; 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 the subject about 15 mg of Compound 1 free base equivalent; 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 the subject about 30 mg of Compound 1 free base equivalent; 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 the subject about 45 mg of Compound 1 free base equivalent. In one embodiment, the present disclosure is directed to a pharmaceutical composition for treating adult subjects suffering from moderate to severe active rheumatoid arthritis, the use comprising administering the pharmaceutical composition to a subject, wherein the 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 to the subject about 7.5 mg of Compound 1 free base equivalent; 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 the subject about 15 mg of Compound 1 free base equivalent; 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 the subject about 30 mg of Compound 1 free base equivalent; 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 the subject about 45 mg of Compound 1 free base equivalent.

[0042] In another embodiment, the present disclosure relates to a method for treating structural damage associated with rheumatoid arthritis in adult subjects, the method comprising administering to the subject: a) about 7.5 mg per 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 the subject about 7.5 mg per day of Compound 1 free base equivalent; or b) about 15 mg per 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 the subject about 15 mg per day of Compound 1 free base equivalent; or c) about 30 mg per 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 the subject about 30 mg per day of Compound 1 free base equivalent; or d) about 45 mg per 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 the subject about 45 mg per day of Compound 1 free base equivalent; such that the structural damage in the adult subject is inhibited or reduced. In one embodiment, the present disclosure relates to a pharmaceutical composition for treating structural damage associated with rheumatoid arthritis in adult subjects, the use comprising administering to the subject a pharmaceutical composition, wherein the pharmaceutical composition comprises: a) about 7.5 mg per 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 the subject about 7.5 mg per day of Compound 1 free base equivalent; or b) about 15 mg per 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 the subject about 15 mg per day of Compound 1 free base equivalent; or c) about 30 mg per 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 the subject about 30 mg per day of Compound 1 free base equivalent; or d) about 45 mg per 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 the subject about 45 mg per day of Compound 1 free base equivalent; such that the structural damage in the adult subject is inhibited or reduced.

[0043] In another aspect, the present disclosure is directed to a method for treating moderate to severe active rheumatoid arthritis in adult subjects, the method comprising administering to a subject: a) about 7.5 mg per 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 the subject about 7.5 mg per day of Compound 1 free base equivalents; or b) about 15 mg per 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 the subject about 15 mg per day of Compound 1 free base equivalents; or c) about 30 mg per 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 the subject about 30 mg per day of Compound 1 free base equivalents; or d) about 45 mg per 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 the subject about 45 mg per day of Compound 1 free base equivalents; wherein the subject has symptoms selected from the group consisting of: at least 6 swollen joints, at least 6 tender joints, and combinations thereof, prior to treatment. In one embodiment, the present disclosure is directed to a pharmaceutical composition for treating moderate to severe active rheumatoid arthritis in adult subjects, the use comprising administering the pharmaceutical composition to a subject, wherein the pharmaceutical composition comprises: a) about 7.5 mg per 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 the subject about 7.5 mg per day of Compound 1 free base equivalents; or b) about 15 mg per 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 the subject about 15 mg per day of Compound 1 free base equivalents; or c) about 30 mg per 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 the subject about 30 mg per day of Compound 1 free base equivalents; or d) about 45 mg per 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 the subject about 45 mg per day of Compound 1 free base equivalents; wherein the subject has symptoms selected from the group consisting of: at least 6 swollen joints, at least 6 tender joints, and combinations thereof, prior to treatment.

[0044] In another aspect, the present disclosure is directed to methods for alleviating the signs and symptoms of rheumatoid arthritis in adult subjects with moderate to severe active rheumatoid arthritis, the methods comprising administering to the subject: a) about 7.5 mg per day of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a hydrate or anhydrate crystal of Compound 1, in an amount sufficient to deliver to the subject about 7.5 mg of Compound 1 free base equivalent; or b) about 15 mg per day of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a hydrate or anhydrate crystal of Compound 1, in an amount sufficient to deliver to the subject about 15 mg of Compound 1 free base equivalent; or c) about 30 mg per day of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a hydrate or anhydrate crystal of Compound 1, in an amount sufficient to deliver to the subject about 30 mg of Compound 1 free base equivalent; or d) about 45 mg per day of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a hydrate or anhydrate crystal of Compound 1, in an amount sufficient to deliver to the subject about 45 mg of Compound 1 free base equivalent. In one embodiment, the present disclosure is directed to a pharmaceutical composition for alleviating the signs and symptoms of rheumatoid arthritis in adult subjects with moderate to severe active rheumatoid arthritis, the use comprising administering the pharmaceutical composition to the subject, wherein the pharmaceutical composition comprises: a) about 7.5 mg per day of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a hydrate or anhydrate crystal of Compound 1, in an amount sufficient to deliver to the subject about 7.5 mg of Compound 1 free base equivalent; or b) about 15 mg per day of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a hydrate or anhydrate crystal of Compound 1, in an amount sufficient to deliver to the subject about 15 mg of Compound 1 free base equivalent; or c) about 30 mg per day of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a hydrate or anhydrate crystal of Compound 1, in an amount sufficient to deliver to the subject about 30 mg of Compound 1 free base equivalent; or d) about 45 mg per day of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a hydrate or anhydrate crystal of Compound 1, in an amount sufficient to deliver to the subject about 45 mg of Compound 1 free base equivalent.

[0045] In another aspect, the present disclosure relates to a kit comprising one or more pharmaceutical compositions, the pharmaceutical compositions comprising a solid form of Compound 1. Optionally, the kit may comprise another pharmaceutical composition comprising one or more additional therapeutic agents and / or instructions, such as instructions for using the kit.

[0046] In another aspect, the present disclosure relates to methods for preparing a solid form of Compound 1.

[0047] In another aspect, the present disclosure relates to a solid form of Compound 1 prepared according to these methods.

[0048] In another aspect, the present disclosure relates to a method of treating adult subjects suffering from moderate to severe 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 Compound 1 free base, or a crystalline hydrate 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 equivalents. In this or another particular aspect, the hydrate may be a hemihydrate. In this or another aspect, the hemihydrate may be free base hydrate Form C. In this or another particular aspect, the subject may be insufficiently responsive or intolerant to one or more disease-modifying anti-rheumatic drugs (DMARDs) such as methotrexate. In this or another particular aspect, the subject may not have previously received DMARDs. In this or another particular aspect, the subject may further receive one or more DMARDs.

[0049] In another aspect, the present disclosure relates to a method of treating structural damage associated with rheumatoid arthritis in adult subjects, the method comprising administering to the subject about 7.5 mg per day, or about 15 mg per day, or about 30 mg per day, or about 45 mg per day of Compound 1 free base or a crystalline hydrate of Compound 1, in an amount sufficient to deliver to the subject about 7.5 mg per day, or about 15 mg per day, or about 30 mg per day, or about 45 mg per day of Compound 1 free base equivalents, whereby structural damage in the adult subject is inhibited or reduced. In this or another particular aspect, the hydrate may be a hemihydrate. In this or another aspect, the hemihydrate may be free base hydrate Form C.

[0050] In another aspect, the present disclosure relates to a method of treating moderate to severe active rheumatoid arthritis in adult subjects, the method comprising administering to the subject about 7.5 mg per day, or about 15 mg per day, or about 30 mg per day, or about 45 mg per day of Compound 1 free base or a crystalline hydrate of Compound 1, in an amount sufficient to deliver to the subject about 7.5 mg per day, or about 15 mg per day, or about 30 mg per day, or about 45 mg per day of Compound 1 free base equivalents, wherein the subject has, prior to treatment, symptoms selected from the group consisting of: at least 6 swollen joints, at least 6 tender joints, and combinations thereof. In this or another particular aspect, the hydrate may be a hemihydrate. In this or another aspect, the hemihydrate may be free base hydrate Form C.

[0051] In another aspect, the present disclosure relates to a method for alleviating the signs and symptoms of rheumatoid arthritis in adult subjects suffering from moderate to severe active rheumatoid arthritis, the method comprising administering to the subject about 7.5 mg per day of Compound 1 free base or a crystalline hydrate of Compound 1 in an amount sufficient to deliver to the subject about 7.5 mg of Compound 1 free base equivalent. 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.

[0052] In another aspect, the present disclosure relates to a method for alleviating the signs and symptoms of rheumatoid arthritis in adult subjects suffering from moderate to severe active rheumatoid arthritis, the method comprising administering to the subject about 15 mg per day of Compound 1 free base or a crystalline hydrate of Compound 1 in an amount sufficient to deliver to the subject about 15 mg of Compound 1 free base equivalent. 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.

[0053] In another aspect, the present disclosure relates to a method for alleviating the signs and symptoms of rheumatoid arthritis in adult subjects suffering from moderate to severe active rheumatoid arthritis, the method comprising administering to the subject about 30 mg per day of Compound 1 free base or a crystalline hydrate of Compound 1 in an amount sufficient to deliver to the subject about 30 mg of Compound 1 free base equivalent. 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.

[0054] In another aspect, the present disclosure relates to a method for alleviating the signs and symptoms of rheumatoid arthritis in adult subjects suffering from moderate to severe active rheumatoid arthritis, the method comprising administering to the subject about 45 mg per day of Compound 1 free base or a crystalline hydrate of Compound 1 in an amount sufficient to deliver to the subject about 45 mg of Compound 1 free base equivalent. 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.

[0055] In another aspect, the present disclosure relates to a pharmaceutical composition comprising a crystalline hydrate of Compound 1 and a pharmaceutically acceptable carrier, wherein the composition comprises a crystalline hydrate in an amount sufficient to deliver about 7.5 mg of Compound 1 free base equivalent. 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.

[0056] In another aspect, the present disclosure relates to a pharmaceutical composition comprising a crystalline hydrate of Compound 1 and a pharmaceutically acceptable carrier, wherein the composition comprises a crystalline hydrate sufficient to deliver about 15 mg of Compound 1 free base equivalent. In this or another particular aspect, the hydrate may be a hemihydrate. In this or another aspect, the hemihydrate may be free base hydrate Form C.

[0057] In another aspect, the present disclosure relates to a pharmaceutical composition comprising a crystalline hydrate of Compound 1 and a pharmaceutically acceptable carrier, wherein the composition comprises a crystalline hydrate sufficient to deliver about 30 mg of Compound 1 free base equivalent. In this or another particular aspect, the hydrate may be a hemihydrate. In this or another aspect, the hemihydrate may be free base hydrate Form C.

[0058] In another aspect, the present disclosure relates to a pharmaceutical composition comprising a crystalline hydrate of Compound 1 and a pharmaceutically acceptable carrier, wherein the composition comprises a crystalline hydrate sufficient to deliver about 45 mg of Compound 1 free base equivalent. In this or another particular aspect, the hydrate may be a hemihydrate. In this or another aspect, the hemihydrate may be free base hydrate Form C.

[0059] In another aspect, the present disclosure relates to a method of treating adult subjects suffering from moderate to severe 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 particular aspect, the hydrate may be a hemihydrate. In this or another aspect, the hemihydrate may be free base hydrate Form C.

[0060] In another aspect, the present disclosure relates to a method of treating structural damage associated with rheumatoid arthritis in adult subjects, the method comprising administering to the subject about 7.5 mg per day, or about 15 mg per day, or about 30 mg per day, or about 45 mg per day of a crystalline hydrate of Compound 1, whereby structural damage in the adult subject is inhibited or reduced. In this or another particular aspect, the hydrate may be a hemihydrate. In this or another aspect, the hemihydrate may be free base hydrate Form C.

[0061] In another aspect, the present disclosure relates to a method of treating moderate to severe active rheumatoid arthritis in adult subjects, the method comprising administering to the subject a crystalline hydrate of Compound 1 at about 7.5 mg per day, or about 15 mg per day, or about 30 mg per day, or about 45 mg per day, wherein the subject has, prior to treatment, symptoms selected from the group consisting of at least 6 swollen joints, at least 6 tender joints, and combinations thereof. In this or another particular aspect, the hydrate can be a hemihydrate. In this or another aspect, the hemihydrate can be free base hydrate Form C.

[0062] In another aspect, the present disclosure relates to a method of reducing the signs and symptoms of rheumatoid arthritis in adult subjects with moderate to severe active rheumatoid arthritis, the method comprising administering to the subject a crystalline hydrate of Compound 1 at about 7.5 mg per day, or about 15 mg per day, or about 30 mg per day, or about 45 mg per day. In this or another particular aspect, the hydrate can be a hemihydrate. In this or another aspect, the hemihydrate can be free base hydrate Form C.

[0063] In another aspect, the present disclosure is directed to an extended release formulation for oral administration, the extended release formulation comprising Compound 1 or a pharmaceutically acceptable salt thereof, a hydrophilic polymer, and a pH modifier, wherein the hydrophilic polymer forms a gel layer upon contact with water, the gel layer providing an environment suitable for the dissolution of Compound 1 and the pH modifier.

[0064] In another aspect, the present disclosure is directed to a method of preparing a pharmaceutical composition, the method comprising: (a) combining Compound 1 or a pharmaceutically acceptable salt thereof or a solid form of Compound 1 with at least a portion of an additional composition component to form a dry granulation mixture; (b) contacting the dry granulation mixture with a granulation fluid to form a wet granulation mixture; (c) drying the wet granulation mixture to form a granular material; (d) milling the granular material to form a milled granular material; (e) combining the milled granulated material with any remaining composition components; and (f) compressing the composition to form the pharmaceutical composition. Brief Description of the Drawings

[0065] Figure 1A Schematically illustrates a method of preparing amorphous free base.

[0066] Figure 1B Schematically illustrates a method of preparing free base hydrate Form C.

[0067] Figure 1C Schematically illustrates a method of preparing tartrate hydrate.

[0068] Figure 2A and 2B are the X-ray powder diffraction patterns corresponding to the amorphous free base (via precipitation) and the amorphous free base (via dehydration), respectively.

[0069] Figure 3A is the X-ray powder diffraction pattern corresponding to the free base solvate form A (isopropyl acetate / water solvate).

[0070] Figure 3B is the X-ray powder diffraction pattern corresponding to the free base hydrate form B.

[0071] Figure 3C is the X-ray powder diffraction pattern corresponding to the free base hydrate form C.

[0072] Figure 3D is the X-ray powder diffraction pattern corresponding to the tartrate 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 .

[0073] Figure 3E is the X-ray powder diffraction pattern corresponding to the hydrochloride solvate form AA.

[0074] Figure 3F is the X-ray powder diffraction pattern corresponding to the hydrochloride solvate form BB.

[0075] Figure 3G is the X-ray powder diffraction pattern corresponding to the hydrochloride solvate form CC.

[0076] Figure 3H is the X-ray powder diffraction pattern corresponding to the L-malate form AAA.

[0077] Fig. 3I is the X-ray powder diffraction pattern corresponding to the L-malate form BBB.

[0078] Figure 3J is the X-ray powder diffraction pattern corresponding to the free base anhydrous form D.

[0079] Figure 4A and 4B are the thermogravimetric analysis thermograms corresponding to the amorphous free base (via precipitation) and the amorphous free base (via dehydration), respectively.

[0080] Figure 4C is the thermogravimetric analysis thermogram corresponding to the free base solvate form A.

[0081] Figure 4D is the thermogravimetric analysis thermogram corresponding to the free base hydrate form B.

[0082] Figure 4E It is a thermogravimetric analysis thermogram corresponding to the free base hydrate form C.

[0083] Figure 4F It is a thermogravimetric analysis thermogram corresponding to the tartrate hydrate.

[0084] Figure 4G It is a thermogravimetric analysis thermogram corresponding to the hydrochloride solvate form AA.

[0085] Figure 4H It is a thermogravimetric analysis thermogram corresponding to the L - maleate form BBB.

[0086] Fig. 4I It is a thermogravimetric analysis thermogram corresponding to the free base anhydrous form D.

[0087] Figure 5A It is a differential scanning calorimetry thermogram corresponding to the amorphous free base (via dehydration).

[0088] Figure 5B It is a differential scanning calorimetry thermogram corresponding to the free base hydrate form B.

[0089] Figure 5C It is a differential scanning calorimetry thermogram corresponding to the free base hydrate form C.

[0090] Figure 5D It is a differential scanning calorimetry thermogram corresponding to the tartrate hydrate.

[0091] Figure 5E It is a differential scanning calorimetry thermogram corresponding to the free base anhydrous form D.

[0092] Fig. 6A It is a moisture adsorption isotherm corresponding to the amorphous free base (via dehydration).

[0093] Figure 6B It is a moisture adsorption isotherm corresponding to the free base hydrate form C.

[0094] Figure 6C It is a moisture adsorption isotherm corresponding to the tartrate hydrate.

[0095] Fig.6D It is a moisture adsorption isotherm corresponding to the free base anhydrous form D.

[0096] Figure 7 It is a comparison of the dissolution curves of extended - release tablets from Example 26 (free base hydrate form C) and Example 27 (amorphous free base) at pH 6.8.

[0097] Figure 8Comparison 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.

[0098] Fig. 9 Comparison of the dissolution profiles of extended-release tablets from Example 32 (ER4) and Example 33 (ER4, without mannitol) at pH 1.2, pH 6.8, or in a dual pH system.

[0099] Fig.10 Comparison of the dissolution profiles of extended-release tablets from Example 34 (ER5) at pH 1.2, pH 6.8, and in a dual pH system.

[0100] Fig.11 Comparison of the dissolution profiles of extended-release tablets from Example 35 (ER6) at pH 1.2, pH 6.8, and in a dual pH system.

[0101] Fig.12 Comparison of the dissolution profiles of extended-release tablets from Example 28 (ER7) and Example 32 (ER4) in a dual pH system.

[0102] Fig.13 Comparison of the dissolution profiles of extended-release tablets from Example 31 (ER8) and Example 32 (ER4) in a dual pH system.

[0103] Fig.14 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.

[0104] Figures 15A-15H Comparison of the dissolution profiles of extended-release tablets from Example 43 at pH 1.2 and pH 6.8, which contain HPMC ( Figures 15A-15D ) or ( Figures 15E-15H ) as a controlled-release polymer, and tartaric acid ( Fig.15A and 15E ), citric acid ( Fig. 15B and 15F ), succinic acid ( Fig. 15C and 15G ), or fumaric acid ( Fig.15D and 15H ) as a pH regulator.

[0105] Fig.16A and 16B show the use of linear ( Fig.16A ) or semi-logarithmic ( Fig. 16B)Scale, relationship between the mean plasma concentration of Compound 1 and time after administration of a 12 mg immediate-release capsule (Protocol A) or a 15 mg once-daily extended-release tablet (Protocol B) under fasting conditions.

[0106] Fig.17A and 17B shows the relationship between the mean plasma concentration of Compound 1 and time after administration of a 24 mg dose (2 × 12 mg) immediate-release capsule (Protocol C) or a 30 mg once-daily extended-release tablet (Protocol D) under fasting conditions using a linear ( Fig.17A ) or semi-logarithmic ( Fig. 17B ) scale.

[0107] Fig.18A and 18B shows the relationship between the mean plasma concentration of Compound 1 and time after administration of a 30 mg once-daily extended-release tablet (Protocol D) or a 30 mg once-daily extended-release tablet after a high-fat meal (Protocol E) under fasting conditions using a linear ( Fig.18A ) or semi-logarithmic ( Fig.18B ) scale.

[0108] Fig.19 shows the relationship between the mean plasma concentration of Compound 1 and time after administration of a 15 mg once-daily extended-release tablet (Protocol F) or a 30 mg once-daily extended-release tablet (Protocol G) for 7 days under non-fasting conditions.

[0109] Fig. 20 shows the relationship between the mean plasma concentration of Compound 1 and time after administration of a 6 mg twice-daily immediate-release capsule (Protocol K) or a 15 mg once-daily extended-release tablet (Protocol L) for 7 days under fasting conditions.

[0110] Fig.21 shows the pre-morning dose trough concentration (C 谷 ) of Compound 1 after administration of a 6 mg twice-daily immediate-release capsule or a 15 mg once-daily extended-release tablet for 7 days under fasting conditions.

[0111] Fig. 22 shows the relationship between the mean plasma concentration of Compound 1 and time after administration of a 12 mg twice-daily immediate-release capsule (Protocol M) or a 30 mg once-daily extended-release tablet (Protocol N) for 7 days under fasting conditions.

[0112] Fig.23 shows the pre-morning dose trough concentration (C 谷 ) of Compound 1 after administration of a 12 mg twice-daily immediate-release capsule or a 30 mg once-daily extended-release tablet for 7 days under fasting conditions.

[0113] Fig.24A and 24B show the relationship between the mean plasma concentration of Compound 1 and time after administration of different extended-release tablets with different concentrations of tartaric acid at 30 mg once daily under fasting conditions, using a linear ( Fig.24A ) or log-linear ( Fig. 24B ) scale.

[0114] Fig.25A and 25B show the relationship between the mean plasma concentration of Compound 1 and time after administration of an extended-release tablet (ER10) at 30 mg once daily under fasting conditions or after a high-fat meal (non-fasting), using a linear ( Fig.25A ) or log-linear ( Fig.25B ) scale.

[0115] Fig.26A and 26B show the individual variability of Compound 1 C max ( Fig.26A ) and AUC inf ( Fig.26B ) after administration of an extended-release tablet (ER10) at 30 mg once daily under fasting conditions or after a high-fat meal (non-fasting).

[0116] Fig.27A and 27B show the relationship between the mean plasma concentration of Compound 1 and time after administration of an extended-release tablet (ER11) at 30 mg once daily under fasting conditions or after a high-fat meal (non-fasting), using a linear ( Fig.27A ) or log-linear ( Fig.27B ) scale.

[0117] Fig.28A and 28B show the individual variability of Compound 1 C max ( Fig.28A ) and AUC inf ( Fig.28B ) after administration of an extended-release tablet (ER11) at 30 mg once daily under fasting conditions or after a high-fat meal (non-fasting).

[0118] Fig.29A and 29B show the relationship between the mean plasma concentration of Compound 1 and time after administration of an extended-release tablet (ER12) at 30 mg once daily under fasting conditions or after a high-fat meal (non-fasting), using a linear ( Fig.29A ) or log-linear ( Fig.29B ) scale.

[0119] Fig. 30A and30B Shows compound 1C after administration of an extended-release tablet (ER12) at 30 mg once daily under fasting conditions or after a high-fat meal (non-fasting). max ( Fig. 30A ) and individual variations in AUC inf ( Fig. 30B ).

[0120] Fig.31 Shows the pH curves of gels formed on tablets containing different amounts of tartaric acid.

[0121] Fig.32A And 32B Shows the relationship between the mean plasma concentration of compound 1 and time after administration of a single oral dose of a rapid-release capsule of compound 1 to healthy subjects using a linear ( Fig.32A ) or log-linear ( Fig.32B ) scale.

[0122] Fig.33 Shows the relationship between the mean plasma concentration of compound 1 and time after administration of multiple oral doses of a rapid-release capsule of compound 1 twice daily to healthy subjects.

[0123] Figures 34A-34D Shows the mean C Fig.34A - single dose, C max ; Fig.34C - single dose, AUC ∞ ) of dose-normalized compound 1 after administration of a single dose ( Fig.34B - multiple doses, C max ; Fig.34D - multiple doses, AUC 0-12 ) of the drug to healthy subjects, multiple doses to healthy subjects, and multiple doses ( max ) to subjects with rheumatoid arthritis, and AUC.

[0124] Fig.35A And 35B Shows that concomitant administration of methotrexate has no effect on the AUC of dose-normalized compound 1 ( Fig.35A ), and concomitant administration of compound 1 has no effect on the AUC of dose-normalized methotrexate ( Fig.35B ).

[0125] Fig.36AShows the response rates of ACR20, ACR50, and ACR70 after 12 weeks of administering placebo or various doses of Compound 1 to subjects with active rheumatoid arthritis who were previously insufficiently responsive or intolerant to anti-TNF biologics (*P < 0.05; **P < 0.01; ***P < 0.001, relative to placebo; modified intention-to-treat population (NRI)). Fig.36B Shows the ACR20 response rate at week 12 in the same population, separated by the amount of previous anti-TNF biologics.

[0126] Figures 37A-37D Shows the change over time in ACR20 ( Fig.37A ), ACR50 ( Fig.37B ), and ACR70 ( Fig.37C ) responses or the mean change from baseline in DAS28(CRP) ( Fig.37D ) after administering placebo or various doses of Compound 1 to subjects with active rheumatoid arthritis who were previously insufficiently responsive or intolerant to anti-TNF biologics (*P < 0.05; **P < 0.01; ***P < 0.001, relative to placebo; modified intention-to-treat population (NRI)). Fig.37E Shows the subjects in the same population who had a DAS28(CRP) score of ≤ 3.2 or < 2.6 at week 12. Fig.37F Shows the subjects in the same population who achieved low disease activity (LDA) or clinical remission (CR) based on the Clinical Disease Activity Index (CDAI) criteria at week 12 (LDA is CDAI ≤ 10; CR is CDAI ≤ 2.8).

[0127] Fig.38A Shows the mean hemoglobin levels over time for all subjects after administering placebo or various doses of Compound 1 to subjects with active rheumatoid arthritis who were previously insufficiently responsive or intolerant to anti-TNF biologics (safety population with observed data (no imputation of missing values)). Fig.38B Shows the mean change in hemoglobin from baseline over time in subjects with high-sensitivity C-reactive protein (hsCRP) above the upper limit of normal (ULN) (normal range of hemoglobin: 11.5 - 15.5 g / dL in females and 13.2 - 17.0 g / dL in males; ULN of hsCRP = 5 mg / L).

[0128] Fig.39 Shows the subject disposition of the study described in Example 55.

[0129] Fig.40A and 40B Shows the subject disposition of the study described in Example 56.

[0130] Fig.41 Shows the responses of ACR20, ACR50, and ACR70 (*P < 0.05; **P < 0.01; ***P < 0.001, relative to placebo; modified intention-to-treat population, missing NRI values) after 12 weeks of administering placebo or various doses of Compound 1 to subjects with active rheumatoid arthritis who are insufficient responders to methotrexate.

[0131] Figures 42A-42D Shows the responses of ACR20 ( Fig.42A , NRI analysis), ACR50 ( Fig.42B , NRI analysis), and ACR70 ( Fig.42C , NRI analysis) or the mean change from baseline of DAS28(CRP) ( Fig.42D , observed cases) over time after administering placebo or various doses of Compound 1 to subjects with active rheumatoid arthritis who are insufficient responders to methotrexate (*P < 0.05; **P < 0.01; ***P < 0.001, relative to placebo; modified intention-to-treat population).

[0132] Fig.43A and 43B Shows the subjects whose DAS28(CRP) scores reached ≤ 3.2 or < 2.6 ( Fig.44A ) or CDAI scores reached ≤ 10 or ≤ 2.8 after 12 weeks of administering placebo or various doses of Compound 1 to subjects with active rheumatoid arthritis who are insufficient responders to methotrexate (*P < 0.05; **P < 0.01; ***P < 0.001, relative to placebo; modified intention-to-treat population (NRI)). For Fig.43A and 43B , the bottom numbers represent the percentage of subjects who reached both cut-off values, the middle numbers represent the percentage of subjects who reached the less stringent cut-off value but not the more stringent cut-off value, and the top numbers represent the patients who reached the cut-off value.

[0133] Figures 44A-44C Shows the mean change from baseline of hemoglobin in the treatment groups over time in all subjects ( Fig.44A ), subjects with baseline hsCRP ≤ 5 mg / mL ( Fig.44B ), and subjects with baseline hsCRP > 5 mg / mL ( Fig.44C ) after administering placebo or various doses of Compound 1 to subjects with active rheumatoid arthritis who are insufficient responders to methotrexate (safety population with observed data (no imputation of missing values)). DETAILED DESCRIPTION OF THE INVENTION

[0134] This written description uses examples to disclose the present invention and also enables any person skilled in the art to practice the present invention, including making and using any disclosed solid form or composition, and performing any disclosed method or process. The patentable scope of the present invention is defined by the claims and may include other examples that occur to a person skilled in the art. If these other examples have elements that do not differ from the literal language of the claims, or if they include equivalent elements, they are expected to be within the scope of the claims. I. definition

[0135] As used in this chapter, the chapter headings and the entire disclosure are not intended to be limiting.

[0136] In the case of listing numerical ranges, each intervening number within the range is clearly considered with the same degree of precision. For example, for the range from 6 to 9, the numbers 7 and 8 are considered in addition to 6 and 9, and for the range from 6.0 to 7.0, 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 are clearly considered. In the same manner, all listed ratios also include all sub-ratios that fall within the broader ratio.

[0137] The singular forms "a / an" and "the" include plural referents unless the context clearly dictates otherwise.

[0138] The term "about" generally refers to a numerical range that a person skilled in the art would consider equivalent to the recited value (i.e., having the same function or result). In many cases, the term "about" may include values that are rounded to the nearest significant digit.

[0139] The term "alkyl" refers to a fully saturated straight-chain or branched-chain hydrocarbon. For exemplary purposes (which should not be construed as limiting the scope of the present invention), examples of alkyl include methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, and their isomers.

[0140] The term "alkenyl" refers to a hydrocarbon moiety having two to eight carbons, including a straight-chain or branched-chain hydrocarbon containing one or more double bonds. Non-limiting examples of alkenyl are vinyl, propenyl, and butenyl.

[0141] The term "amorphous" as applied to a compound refers to a state in which the material lacks long-range order at the molecular level and may exhibit physical properties of a solid or a liquid depending on temperature. Typically, such materials do not give a distinct X-ray diffraction pattern and, although exhibiting solid properties, are more formally described as liquids. Upon heating, a change from solid to liquid properties occurs, which is characterized by a change in state, typically second order ("glass transition").

[0142] The term "anhydrate" as applied to a compound refers to a solid state in which the compound contains no water of crystallization within the lattice.

[0143] The term "aryl" refers to a monocyclic, bicyclic, or tricyclic aromatic hydrocarbon group. Examples include phenyl, naphthyl, biphenyl, and 1,2,3,4-tetrahydronaphthyl.

[0144] Unless the context otherwise requires, the terms "comprise", "comprises", and "comprising" are to be interpreted as inclusive rather than exclusive, and the applicant intends that each of those words be used on the basis and with the clear understanding that they will be so interpreted in the context of this patent application, including the claims below.

[0145] The term "crystalline" as applied to a compound refers to a solid phase in which the material has a regular, ordered internal structure at the molecular level and gives a distinct X-ray diffraction pattern with defined peaks. When heated sufficiently, such materials will also exhibit liquid properties, but the change from solid to liquid is characterized by a phase change, typically first order ("melting point").

[0146] The term "crystalline purity" refers to the crystalline purity of a compound relative to a specific crystalline form of the compound as determined by the X-ray powder diffraction analysis method described in this application.

[0147] The term "crystallization" as used throughout this application may refer to crystallization and / or recrystallization depending on the applicable circumstances related to the preparation of the compound.

[0148] The term "pharmaceutically acceptable" (e.g., in the recitation of "pharmaceutically acceptable salt" or "pharmaceutically acceptable diluent") refers to a material that is compatible with administration to a human subject, e.g., the material does not cause undesirable biological effects. Examples of pharmaceutically acceptable salts are described in Stahl and Wermuth's "Handbook of Pharmaceutical Salts: Properties, Selection and Use" (Wiley-VCH, Weinheim, Germany, 2002). Examples of pharmaceutically acceptable excipients are described in "Handbook of Pharmaceutical Excipients" (edited by Rowe et al., Pharmaceutical Press, 7th Edition, 2012).

[0149] The term "subject" refers to a human subject.

[0150] The terms "treating" and "treatment" refer to ameliorating, inhibiting, eradicating a disorder, reducing the severity of a disorder, reducing the frequency of occurrence of a disorder, preventing a disorder, reducing the risk of a disorder, slowing the progression of damage caused by the disorder, or delaying the onset of a disorder, or improving the quality of life of a patient having the disorder.

[0151] The term "Xantphos" refers to 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.

[0152] The abbreviation "2-Me THF" refers to 2-methyltetrahydrofuran.

[0153] The abbreviation "ACN" refers to acetonitrile.

[0154] The abbreviation "AcOH" refers to acetic acid.

[0155] As used herein, the term "AUC 24,ss " refers to the steady-state area under the plasma concentration-time curve from time zero to twenty-four hours after administration of the indicated drug. The term "AUC 12,ss " refers to the steady-state area under the plasma concentration-time curve from time zero to twelve hours after administration of the indicated drug.

[0156] As used herein, the term "AUC inf " 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 inf = AUC t + C最后 / k, where C 最后 is the last measured concentration, and k is the calculated terminal elimination rate constant.

[0157] As used herein, the term "AUC t " refers to the area under the plasma concentration-time curve from the time of administration of the indicated drug to the time of the last measured concentration, calculated using the trapezoidal rule. "AUC 24 " refers to the area under the plasma concentration-time curve from time zero to twenty-four hours after administration of a single dose of the indicated drug.

[0158] The abbreviation "Bn" refers to benzyl.

[0159] As used herein, the term "C 12 " is the plasma concentration of the indicated drug observed 12 hours after administration of a single dose or a specified number of doses of the indicated drug. The term "C 12,ss " refers to C 12 measured at steady state.

[0160] As used herein, the term "C 24 " is the plasma concentration of the indicated drug observed 24 hours after administration of a single dose or a specified number of doses of the indicated drug. The term "C 24,ss " refers to C 24 measured at steady state.

[0161] The abbreviation "Cbz" refers to carboxybenzyl.

[0162] The abbreviation "CDI" refers to carbonyldiimidazole.

[0163] The abbreviation "%CV" refers to the coefficient of variation expressed as a percentage. %CV is calculated according to the following formula: %CV = (SD / x)*100, where x is the mean, and SD is the standard deviation.

[0164] As used herein, the term "C max " refers to the plasma concentration of the indicated drug at T max , expressed herein in ng / mL, generated by oral ingestion of a single dose or a specified number of doses of a dosage form or pharmaceutical composition (such as the dosage forms and compositions disclosed herein). Unless otherwise specified, C max refers to the overall maximum observed concentration.

[0165] As used herein, the term "C max ,ss" refers to the steady-state C max of the indicated drug during the dosing interval.

[0166] As used herein, the term "C min, "Css" refers to the minimum steady-state plasma concentration of the indicated drug during the dosing interval.

[0167] As used herein, the term "C 谷 min" refers to the plasma trough concentration of the indicated drug measured at the end of the dosing interval at steady state.

[0168] The abbreviation "DBU" refers to 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0169] The abbreviation "DCHA" refers to dicyclohexylamine.

[0170] The abbreviation "DCM" refers to dichloromethane.

[0171] The abbreviation "DIPEA" refers to diisopropylethylamine.

[0172] The abbreviation "DMA" refers to dimethylacetamide or N,N-dimethylacetamide.

[0173] The abbreviation "DMAP" refers to 4-dimethylaminopyridine.

[0174] The abbreviation "DSC" refers to differential scanning calorimetry.

[0175] As used herein, the term "exposed to the use environment" means contacting the formulation of the present disclosure with the gastric fluid of the subject to which it is administered or a liquid used to simulate gastric fluid.

[0176] The abbreviation "EtB(OH)2" refers to ethylboronic acid.

[0177] The abbreviation "EtOAc" refers to ethyl acetate.

[0178] The abbreviation "Fe(acac)3" refers to iron(III) acetylacetonate.

[0179] The abbreviation "HDPE" refers to high density polyethylene.

[0180] The abbreviation "HOAc" refers to acetic acid.

[0181] The abbreviation "HPMC" refers to hydroxypropyl methylcellulose.

[0182] The abbreviation "IPAc" refers to isopropyl acetate.

[0183] The abbreviation "KOtBu" refers to potassium tert-butoxide.

[0184] The abbreviation "LiOtBu" refers to lithium tert-butoxide.

[0185] The abbreviation "Me3SOCl" refers to trimethylsulfoxonium chloride.

[0186] The abbreviations "MeOH" and "EtOH" refer to methanol and ethanol, respectively.

[0187] The abbreviation "MS" refers to mass spectrometry.

[0188] The abbreviation "MTBE" refers to methyl tert-butyl ether.

[0189] The abbreviation "MTX" refers to methotrexate.

[0190] The abbreviation "NatOBu" or "NaOtBu" refers to sodium tert-butoxide.

[0191] The abbreviation "Ni(acac)2" refers to nickel(II) acetylacetonate.

[0192] The abbreviation "NMM" refers to N-methylmorpholine.

[0193] The abbreviation "Pd / C" refers to palladium on carbon.

[0194] The abbreviation "PdCl2(dppf)" refers to dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II).

[0195] The abbreviation "PdCl2(Ph3P)2" refers to dichloro[bis(triphenylphosphine)]palladium(II).

[0196] The abbreviation "Pd(OAc)2" refers to palladium(II) acetate.

[0197] The abbreviation "Pd(OH2) / C" refers to palladium hydroxide on carbon.

[0198] The abbreviation "PFPAA" refers to pentafluoropropionic anhydride.

[0199] The abbreviation "pTsOH" refers to p-toluenesulfonic acid.

[0200] The abbreviation "PVA" refers to polyvinyl acetate.

[0201] The abbreviation "PXRD" refers to X-ray powder diffraction.

[0202] 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).

[0203] As used herein, the term "t 1 / 2 " refers to the terminal half-life of the indicated drug after oral ingestion of a single dose or a specified number of doses of the indicated drug. The term "t 1 / 2,ss " refers to the terminal half-life measured at steady state.

[0204] The abbreviation "TEA" refers to triethylamine.

[0205] The abbreviation "TFAA" refers to trifluoroacetic anhydride.

[0206] The abbreviation "TF2O" refers to trifluoromethanesulfonic anhydride.

[0207] The abbreviation "TGA" refers to thermogravimetric analysis.

[0208] The abbreviation "TGA-MS" refers to thermogravimetric analysis-mass spectrometry.

[0209] The abbreviation "THF" refers to tetrahydrofuran.

[0210] As used herein, the term "T max " refers to the time from oral administration of a single dose or a specified number of doses of an indicated drug to the plasma peak concentration of that indicated drug.

[0211] As used herein, the term "T max,ss " refers to the time from oral administration of an indicated drug at steady state to the plasma peak concentration of that indicated drug.

[0212] The abbreviation "TMS" refers to trimethylsilyl.

[0213] The term "triflate" refers to trifluoromethanesulfonate.

[0214] The abbreviation "v / v" refers to volume / volume.

[0215] The abbreviation "w / w" refers to weight / weight.

[0216] For clarity and convenience only, the following convention is used herein: the time of administration or the start time of the dissolution test is designated as zero (0) hours (t = 0 hours) and the time after administration is designated in appropriate time units, e.g., t = 30 minutes or t = 2 hours, etc. II. For the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)- N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (Compound 1) and intermediates

[0217] This disclosure relates to an improved 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 (referred to herein as "Compound 1" or "Compound 1 free base"), to pharmaceutically acceptable salts of Compound 1, and to intermediates for preparing Compound 1. Compound 1 has the structure shown below: For example, methods for preparing and using this compound are described in International Application WO 2011 / 068881 A1, which is incorporated herein by reference.

[0218] Previously disclosed methods for preparing Compound 1 and its pharmaceutically acceptable salts have several disadvantages. Specifically, these methods involve the use of particularly hazardous reagents such as trimethylsilyldiazomethane or diazomethane, and / or do not form crystalline products. The methods of the present disclosure overcome these disadvantages by avoiding the use of these harmful reagents and producing crystalline intermediates that facilitate purification.

[0219] The compounds of the present disclosure can be prepared by using synthetic transformations such as those shown in Schemes I - XVI. The starting materials are commercially available and can be prepared by the procedures described herein, literature procedures, or procedures well known to those of ordinary skill in the art of organic chemistry (see, for example, Larock, R.C., “Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2 nd edition [Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition]”, 1999, Wiley - VCH or Greene, T.W., and Wuts, P.G.M., “Protective Groups in Organic Synthesis, 3 rd Edition [Protective Groups in Organic Synthesis, 3rd Edition]”, 1999, Wiley - Interscience). A. Preparation of compound 1

[0220] In one aspect, the present disclosure relates to a method for preparing Compound 1 or its pharmaceutically acceptable salt. The method for preparing Compound 1 is illustrated in Scheme I. Protected (3R,4S)-4 - ethylpyrrolidine - 3 - carboxylic acid (I) or its pharmaceutically acceptable salt reacts with trimethylsulfoxonium chloride to produce sulfonium ylide (II). Sulfonium ylide (II) is contacted with LiX and a sulfonic acid to produce the corresponding halomethyl ketone (III). (III) reacts with (IV) in the presence of a base to give (V). Cyclization of (V) in the presence of perfluoroanhydride and an organic base produces (VI). Removal of the protecting group and contacting the deprotected compound with an acid produces the pharmaceutically acceptable salt of (VII). The pharmaceutically acceptable salt of (VII) is reacted with 2,2,2 - trifluoroethylamine to produce Compound 1. Scheme I Wherein: 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.

[0221] 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 another embodiment, the protecting group is carboxybenzyl.

[0222] 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): wherein R2 is methyl or ethyl. It has surprisingly 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 facilitates the purification of these intermediates. In contrast, previously known methods using compounds in which R2 is tert-butyl result in the formation of the compound of formula (V), which is isolated as an amorphous solid.

[0223] In certain embodiments, a pharmaceutically acceptable salt of the compound of formula (I) is used in the reaction of step (a). In one embodiment, the pharmaceutically acceptable salt of the compound of formula (I) is selected from the group consisting of the naphthaleneethanamine salt (Ia) and the dicyclohexylamine salt (Ib) where Cbz is carboxybenzyl.

[0224] In one embodiment, the pharmaceutically acceptable salt of compound (VII) is selected from the group consisting of (VIIa), (VIIb), and (VIIc),

[0225] Another method for preparing Compound 1 is described in Scheme Ia. In the presence of carbonyldiimidazole and a strong base, (3R,4S)-1-((benzyloxy)carbonyl)-4-ethylpyrrolidine-3-carboxylate dicyclohexylamine salt (Ib) reacts with trimethylsulfoxonium chloride to produce the sulfonium ylide (IIa). The sulfonium ylide (IIa) is contacted with lithium bromide and a sulfonic acid to produce the corresponding bromomethyl ketone (IIIa). In the presence of lithium tert-butoxide, (IIIa) reacts with alkyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate (IVa) to produce (Va). The 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 produces the pharmaceutically acceptable salt (VIIa). The pharmaceutically acceptable salt (VIIa) is reacted with 2,2,2-trifluoroethylamine to produce Compound 1. Scheme Ia Wherein: Cbz is carboxybenzyl; Ts is tosyl; and R2 is methyl or ethyl.

[0226] The reactions in step (a) of Scheme I and Ia are generally completed 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 (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.

[0227] More specifically, in certain embodiments, a solution of a compound having formula (I), (Ia), or (Ib) in a solvent is slowly added (e.g., over 30 minutes) to a slurry of CDI in a solvent, and the resulting mixture is stirred at room temperature for 30 minutes to 12 hours, and 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 a solvent while maintaining the internal temperature below -1 °C. In another embodiment, the reaction is quenched and the resulting compound having formula (II) or (IIa) is isolated before step (b).

[0228] In some embodiments, the reaction of step (a) may further involve contacting (Ia) or (Ib) with an acid prior to reacting with trimethylsulfoxonium chloride to extract the amine to obtain a compound having formula (I). Suitable acids include any mineral or organic acid such as phosphoric acid, hydrochloric acid (HCl), acetic acid (HOAc), citric acid, etc. Subsequently, the compound having formula (I) can be taken up in a suitable solvent and reacted with trimethylsulfoxonium chloride as described herein. In one embodiment, a pharmaceutically acceptable salt of the compound having formula (I) is used in step (a), wherein the pharmaceutically acceptable salt is (Ia) or (Ib), and the reaction of step (a) is carried out according to the procedure described in Step A of Example 3.

[0229] In step (b) of Schemes I and Ia, a compound having formula (II) or (IIa) is contacted with LiX and a sulfonic acid, respectively, to form a compound having formula (III) or (IIIa). 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 (including but not limited to, tetrahydrofuran, ethyl acetate, heptane, ethanol, water, and combinations thereof).

[0230] More specifically, in certain embodiments, the sulfonic acid is added to a solution of a compound having formula (II) or (IIa) and LiX in a solvent. The resulting mixture is heated to about 35 °C to about 65 °C and stirred overnight. In one embodiment, the mixture is heated to about 40 °C and stirred overnight. The mixture is cooled to room temperature and washed. The compound having formula (III) or (IIIa) can be isolated or can optionally be used in the next step without purification.

[0231] In step (c) of Schemes I and Ia, a compound having formula (III) or (IIIa) is reacted with a compound having formula (IV) or (IVa) (prepared as 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 reaction of step (c) can be carried out in any suitable solvent (including but not limited to, dimethylacetamide, tetrahydrofuran, dichloromethane, ethyl acetate, heptane, and combinations thereof).

[0232] More specifically, in certain embodiments, an alkali 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 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 cooled to about -20 °C to about 0 °C. A solution of a compound of formula (IV) or (IVa) in a solvent is added slowly (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 the 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 quenched and in some embodiments, the resulting product (V) or (Va) is separated before step (d).

[0233] In step (d) of Schemes I and Ia, a compound of formula (V) or (Va) is contacted with a perfluoroanhydride and an organic base, respectively, to form a compound of formula (VI) or (VIa). Non-limiting examples of suitable organic bases include pyridine, triethylamine, and combinations thereof. Examples of suitable perfluoroanhydrides include trifluoroacetic anhydride, pentafluoropropionic anhydride, heptafluorobutyric anhydride, and combinations thereof. In certain embodiments, the organic base is pyridine and the perfluoroanhydride is trifluoroacetic anhydride. In other embodiments, the organic base is triethylamine and the perfluoroanhydride is pentafluoropropionic anhydride. Suitable solvents for use in step (d) include, but are not limited to, acetonitrile, toluene, and combinations thereof.

[0234] More specifically, in certain embodiments, an organic base and a perfluoroanhydride are charged to 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 about 55 °C and stirred for about 4 hours to about 18 hours or about 6 hours. In one embodiment, the mixture of the perfluoroanhydride and the 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. After completion of the reaction, in some embodiments, the reaction mixture can be cooled and concentrated before contacting 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, etc. The resulting mixture can be stirred at room temperature to about 85 °C (including at about 55 °C) for about 30 minutes to about 8 hours. In one embodiment, the mixture is stirred for about 1 hour. After completion, the solvent can be optionally removed and transferred to methanol, ethanol, isopropanol, or other suitable solvents before step (e).

[0235] In step (e) of Schemes I and Ia, the compound of formula (VI) or (VIa) is deprotected and a pharmaceutically acceptable salt of the compound (VII) (e.g., (VIIa), (VIIb), or (VIIc)) is formed. The protecting group on the compound of formula (VI) or (VIa) can be removed using any suitable manner known in the art. In one embodiment, deprotection occurs by contacting the compound of formula (VI) or (VIa) with palladium on carbon (e.g., Pd / C or Pd(OH2) / C) under hydrogen pressure. In other embodiments, deprotection occurs 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), hydrobromic acid in acetic acid (e.g., HBr / HOAc), etc. In other embodiments, deprotection occurs by heating the compound of formula (VI) or (VIa), e.g., at a temperature from room temperature to about 85 °C, including about 50 °C. After deprotection, the compound of formula (VII) is contacted with a suitable acid (such as hydrochloric acid or p-toluenesulfonic acid) to form a pharmaceutically acceptable salt.

[0236] Step (e) can occur in any suitable solvent (including but not limited to, ethanol, isopropyl acetate, ethyl acetate, and combinations thereof).

[0237] More specifically, in some embodiments, palladium on carbon and the compound of formula (VI) or (VIa) are mixed in a solvent 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 (including about 50 °C) for about 2 hours to about 24 hours (including 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. After completion of the reaction, the reaction mixture is cooled and filtered, and then a suitable acid is added. Optionally, the resulting salt is isolated before step (f).

[0238] 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 an optional buffer (such as dipotassium hydrogen phosphate, potassium hydroxide, and combinations thereof). In one embodiment, the step (f) reaction is carried out in the presence of CDI, dipotassium hydrogen phosphate, and potassium hydroxide. The step (f) reaction can be carried out in any suitable solvent (including but not limited to, tetrahydrofuran, ethyl acetate, heptane, ethanol, water, and combinations thereof).

[0239] More specifically, in certain embodiments, 2,2,2-trifluoroethylamine is slowly added (e.g., over 20 minutes) to a slurry of CDI in a solvent while maintaining the internal temperature below 30 °C. The resulting solution is stirred for about 10 minutes to about 12 hours, and in one embodiment, for about 1 hour, to form an imidazole solution. By adding a base, the pH of the two-phase mixture of the pharmaceutically acceptable salt from step (e) in a buffer and a solvent is adjusted to about 7 to about 11, and in one embodiment, to about 9. The imidazole solution is added, and the resulting mixture is mixed at about 25 °C while maintaining the pH at about 9 by adding the base in portions over about 30 minutes to about 18 hours. In one embodiment, the mixture formed after adding the imidazole solution is mixed at about 25 °C while maintaining the pH at about 9 by adding the base in portions over about 1 hour. In one embodiment, after completion, the reaction is quenched and the resulting product is isolated.

[0240] In one embodiment, Compound 1 is prepared according to the method described in Scheme Ia. In certain embodiments, the method may further comprise preparing (Ib) according to the method described in Scheme V herein.

[0241] An alternative method for preparing Compound 1 is illustrated in Scheme II. Protected (3R,4S)-4-ethylpyrrolidine-3-carboxylic acid (I) or a pharmaceutically acceptable salt thereof is reacted with trimethylsulfoxonium chloride to produce a sulfonium ylide (II). The sulfonium ylide (II) is contacted with LiX and a sulfonic acid to produce the corresponding halomethyl ketone (III). (III) is reacted with (IV) in the presence of a base to obtain (V). Cyclization of (V) in the presence of a perfluoroanhydride and an organic base produces (VI). The protecting group is removed and the deprotected compound (VII) (not shown) is contacted with hydrochloric acid to produce the pharmaceutically acceptable salt (VIIb). The pharmaceutically acceptable salt (VIIb) is converted to the free base (VII), which is reacted with 2,2,2-trifluoroethylamine to produce Compound 1. Compound 1 is contacted with L-tartaric acid to form the corresponding tartrate salt, followed by formation of the free base of Compound 1. Solution II Wherein PG, Ts, X, and R1 are as defined above.

[0242] 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.

[0243] In one embodiment, R1 is -OR2 and R2 is ethyl or methyl.

[0244] In certain embodiments, a pharmaceutically acceptable salt of a compound having formula (I) is used in the reaction of step (a). In one embodiment, the pharmaceutically acceptable salt of the compound having formula (I) is selected from the group consisting of naphthaleneethanamine salt (Ia) and dicyclohexylamine salt (Ia).

[0245] Steps (a)-(e) of Scheme II are carried out as described above for Scheme I, wherein after deprotecting the compound having formula (VI), the deprotected compound (VII) is contacted with hydrochloric acid to form a pharmaceutically acceptable salt (VIIb).

[0246] In step (f) of Scheme II, the 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, etc., 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 (including but not limited to, water alone or a combination of water with THF, 2-methyltetrahydrofuran, ethanol, methanol, etc.).

[0247] 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 conditions similar to those described for step (f) of Scheme I above.

[0248] In step (h) of Scheme II, compound 1 is contacted with L-tartaric acid to form the corresponding tartrate salt (step (h)). The formation of the tartrate salt facilitates the removal of impurities before separating the free base. In one embodiment, the tartrate salt can be formed using the procedure described in Example 8 Method B, without drying the tartrate salt only before step (i). Subsequently, the tartrate salt is converted back to the free base form (step (i)) to produce compound 1. Specifically, 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, etc., or combinations thereof. In one embodiment, the tartrate salt is contacted with sodium bicarbonate and sodium carbonate to produce the corresponding free base.

[0249] 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.

[0250] In some embodiments, the products of steps (d), (e), (g), and (h) of Scheme II are not separated before a subsequent step.

[0251] Alternative methods for preparing Compound 1 are illustrated in Scheme III. Hydrogenating compound (XIa) to produce (I). Protected (3R,4S)-4-ethylpyrrolidine-3-carboxylic acid (I) reacts with trimethylsulfoxonium chloride to produce the sulfur ylide (II). Contacting the sulfur ylide (II) with an anhydrous HBr or anhydrous HCl source produces the corresponding halomethyl ketone (III). (III) reacts with (IV) in the presence of a base to give (V). Cyclization of (V) in the presence of perfluoroanhydride and an organic base produces (VI). Removing the protecting group and contacting the deprotected compound with an acid produces the pharmaceutically acceptable salt of (VII). Reacting the pharmaceutically acceptable salt of (VII) with 2,2,2-trifluoroethylamine produces Compound 1. Scheme III Wherein: 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.

[0252] 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 another embodiment, the protecting group is carboxybenzyl.

[0253] In another embodiment, R1 is -OR2, and R2 is methyl or ethyl. In such an embodiment, the compound having the formula (IV) is a compound having the formula (IVa): Wherein R2 is methyl or ethyl. It has surprisingly been found that when R2 is ethyl or methyl, the compound having the formula (V) and subsequent downstream compounds can be isolated as crystalline solids, which aids in the purification of these intermediates. In contrast, previously known methods using compounds in which R2 is tert-butyl result in the formation of the compound having the formula (V), which is isolated as an amorphous solid.

[0254] Another method for preparing Compound 1 is illustrated in Scheme IIIa. Hydrogenate 1-((benzyloxy)carbonyl)-4-ethyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid (XI) to produce (XII). React (3R,4S)-1-((benzyloxy)carbonyl)-4-ethylpyrrolidine-3-carboxylate (XII) with trimethylsulfoxonium chloride to produce the sulfonium ylide (IIa). Contact the sulfonium ylide (IIa) with an anhydrous HBr source to produce the corresponding bromomethyl ketone (IIIa). In the presence of lithium tert-butoxide, react (IIIa) with alkyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate (IVa) to produce (Va). Cyclization of (Va) in the presence of perfluoroacid anhydride and an organic base produces (VIa). Remove the carboxybenzyl protecting group and contact the deprotected compound with hydrochloric acid to produce the pharmaceutically acceptable salt (VIIa). React the pharmaceutically acceptable salt (VIIa) with 2,2,2-trifluoroethylamine to produce Compound 1. Scheme IIIa Wherein: Cbz is carboxybenzyl; Ts is tosyl; and R2 is methyl or ethyl.

[0255] In step (a) of Schemes III and IIIa, (XIa) or (XI), which can be prepared as described in Scheme V, is respectively converted to (I) or (XII). Specifically, in step (a), Compound (XI) or (XIa) can be contacted with a catalyst such as a ruthenium catalyst. Any catalyst containing a chiral phosphine can be used. A specific example of a suitable catalyst is diacetato[(S)-(-)5,5'-bis(diphenylphosphino)-4,4'-di-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 a 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 a catalyst in a solvent is hydrogenated at about 580 psi. In one embodiment, a solution of (XI) or (XIa) and a catalyst in a solvent is hydrogenated at about 200 psi gauge (psig). In one embodiment, a solution of (XI) or (XIa) and a 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. After completion, the reaction mixture is cooled to room temperature, filtered, and concentrated. In a specific embodiment, step (a) of Schemes III and IIIa is carried out as described in Step A of Example 4.

[0257] The reaction in step (b) of Schemes III and IIIa is generally completed 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 (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.

[0258] More specifically, in certain embodiments, a suspension of trimethylsulfoxonium chloride, a strong base, and a solvent is heated (e.g., to 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 lower, or to about -5 °C or lower. In some embodiments, the concentrated filtrate from step (a) is diluted with a suitable solvent (e.g., tetrahydrofuran), and CDI (e.g., over 30 minutes to 1 hour, or over 30 minutes) is slowly added to the solution. The resulting mixture is stirred at room temperature for 30 minutes to 12 hours, and 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 the internal temperature below -1 °C. In an embodiment, the reaction can be stirred at a temperature below about -1 °C or at about -5 °C for about 30 minutes to about 8 hours, or about 1 hour. In another embodiment, the reaction is quenched and the resulting compound of formula (II) or (IIa) is isolated before step (c). In a specific embodiment, step (b) of Scheme III or IIIa is carried out as described in Step A of Example 4.

[0259] Steps (a) and (b) of Schemes III and IIIa advantageously allow for the preparation of protected (3R,4S)-4-ethylpyrrolidine-3-carboxylic acid without the formation and isolation of the naphthylethylamine 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 HBr or anhydrous HCl source to form a compound of formula (III) or (IIIa), respectively. Specifically, the anhydrous HBR or anhydrous HCl source contains no more than 0.2% water (by volume) or no more than about 0.15% water (by volume). The reaction of step (c) can be carried out in any suitable solvent including tetrahydrofuran.

[0261] More 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 no more than 0.2% water (by volume). In one embodiment, (II) or (IIa) is combined with a solvent (such as THF) and a solution of HBr in 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 to about 12 hours, or about 5 hours. In one embodiment, the mixture is warmed to about 40 °C and stirred (e.g., agitated) for about 5 hours. In one embodiment, the mixture is cooled to room temperature (e.g., about 20 °C) and distilled, followed by washing. In a specific embodiment, the product (compound (III) or (IIIa)) is concentrated to dryness and resuspended in a solvent (such as N,N-dimethylacetamide) to form a solution of (III) or (IIIa) for use in step (d). In one embodiment, step (c) of Scheme III or IIIa is carried out as described in Step B of Example 4.

[0262] Step (c) advantageously produces a higher purity halo-methyl ketone (III) or (IIIa) than Scheme I or 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 as 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] More specifically, in certain embodiments, the 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 the 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 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 cooled to about -20 °C to about 0 °C, or about -10 °C. Then the solution of the halomethyl ketone prepared in step (c) is slowly added (e.g., over about 1 hour), and the resulting mixture is stirred (e.g., agitated) 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 quenched and in some embodiments, the resulting product (V) or (Va) is isolated before step (e). In one embodiment, step (d) of Schemes III and IIIa is carried out as described in step C of Example 4.

[0265] Steps (e)-(g) of Schemes III and IIIa can be carried out respectively as described in steps (d)-(f) of Scheme I above.

[0266] In one embodiment, Compound 1 is prepared according to the method described in Scheme IIIa. B. Preparation of compounds of formula (I), (Ia), (Ib), and (XIa)

[0267] The methods for preparing Compound 1 disclosed herein can use a compound of formula (I) or a pharmaceutically acceptable salt thereof, and / or a compound of formula (XI) or (XIa). In one embodiment, these methods use a naphthaleneethanamine salt of formula (Ia) or a dicyclohexylamine salt of formula (Ib). Compounds of formula (I) and (Ia) and their preparation are described, for example, in US2013 / 0072470, which is incorporated herein by reference. (Ia) can also be prepared as described in Scheme IV below. (Ib) can be prepared as described in Scheme V below. Compounds of formula (I) wherein 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. Formula (Ia)

[0268] The preparation of (Ia) has been described previously (see, for example, US2013 / 0072470, Example 12, which is incorporated herein by reference). A suitable method for preparing the naphthylethylamine salt of the compound of formula (I) is illustrated in Scheme IV. Ethyl pent-2-ynoate is hydrogenated using a Lindlar catalyst to form ethyl (Z)-pent-2-enoate. Ethyl (Z)-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). The deprotected (XVI) is contacted with (R)-1-(naphthalen-1-yl)ethylamine to form (Ia). Scheme IV Wherein: TMS is trimethylsilyl; Cbz is carboxybenzyl; and Bn is benzyl.

[0269] In step (a) of Scheme IV, ethyl pent-2-ynoate is hydrogenated using a Lindlar catalyst to form ethyl (Z)-pent-2-enoate. Specifically, in certain embodiments, ethyl pent-2-ynoate is added to a slurry of Lindlar catalyst in a solvent (such as THF) and an organic base (such as pyridine). The reaction mixture is bubbled with hydrogen (for example, for about 15 hours). In one embodiment, after completion of the reaction, the reaction mixture is filtered and ethyl (Z)-pent-2-enoate is washed before step (b).

[0270] In step (b) of Scheme IV, ethyl (Z)-pent-2-enoate is reacted with N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine to form (XIII). Specifically, trifluoroacetic acid (TFA) is added to a solution of ethyl (Z)-pent-2-enoate and N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine in a solvent (such as dichloromethane (DCM)). After about 2 days, the reaction mixture is concentrated to afford (XIII).

[0271] In steps (c) and (d) of Scheme IV, (XIII) is deprotected to form (XIV), which is then hydrolyzed to form (XV). (XIII) can be deprotected using any suitable means known in the art, including those methods described above for step (e) of Scheme I. In one embodiment, (XIII) is deprotected by contacting it with a catalyst (such as a palladium catalyst, e.g., Pd / C or Pd(OH2) / C) under hydrogen pressure. In one embodiment, the resulting mixture is filtered to afford (XIV). In step (d), (XIV) is contacted with an acid (such as HCl). In one embodiment, the reaction mixture is heated (e.g., to about 100 °C), typically for about 24 hours. The reaction mixture is cooled and concentrated. In step (e), the reaction mixture containing (XV) from step (d) is reacted with N-(benzyloxycarbonyloxy)succinimide (e.g., for about 15 hours) to form (XVI).

[0272] In step (f) of Scheme IV, (XVI) is contacted with (R)-1-(naphthalen-1-yl)ethylamine to form (Ia). Formula (Ib)

[0273] In some embodiments, the present disclosure relates to compound (Ib) and a method for preparing compound (Ib). A method for preparing the dicyclohexylamine salt of the compound of formula (I) is illustrated in Scheme V. Carboxybenzyl-glycine ethyl ester is reacted with ethyl acrylate to form (VIII). Protecting (VIII) gives (IX). Contacting (IX) with one of ethylboronic acid, ethylmagnesium bromide, or ethylzinc chloride in the presence of a catalyst gives (X). Hydrolyzing (X) gives (XI), which is hydrogenated to give (XII). Contacting (XII) with dicyclohexylamine forms (Ib). Scheme V wherein Cbz is carboxybenzyl; and R 3 is selected from the group consisting of CF3SO2-, CH3SO2-, and tosyl.

[0274] 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, etc., and combinations thereof).

[0275] Specifically, in certain embodiments, at about -5°C to about 20°C, a base is slowly added (e.g., over 1 hour) to a mixture of carboxybenzyl-glycine ethyl ester and ethyl acrylate in a solvent. In one embodiment, at about 0°C, a base is slowly added (e.g., over 1 hour) to a mixture of carboxybenzyl-glycine ethyl ester and ethyl acrylate in a solvent. The resulting mixture is warmed to room temperature and stirred overnight. In one embodiment, after completion, the reaction is quenched and the product is crystallized. Optionally, the product can be isolated before step (b).

[0276] In step (b) of Scheme V, the 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 (including, but not limited to, triethylamine, N-methylmorpholine, pyridine, diisopropyl ether, and combinations thereof).

[0277] Specifically, in certain embodiments, at about -5°C to about 20°C, trifluoromethanesulfonic anhydride, methanesulfonyl chloride, or p-toluenesulfonyl chloride is added to a mixture of (VIII) in a solvent. In one embodiment, at a temperature of about 0°C, trifluoromethanesulfonic anhydride, methanesulfonyl chloride, or p-toluenesulfonyl chloride is added to a mixture of (VIII) in a solvent. Subsequently, an organic base is slowly added (e.g., over about 30 minutes), and the mixture is warmed to room temperature and stirred for about 30 minutes to about 18 hours. In one embodiment, the mixture is stirred for about 1 hour. After completion, preferably the reaction is quenched and the product is washed. In some embodiments, a solution of (IX) in a solvent is prepared and used directly in step (c).

[0278] 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 PdCl2(dppf). In some embodiments, the catalyst is a nickel catalyst, such as Ni(acac)2. In some embodiments, the catalyst is an iron catalyst, and specifically an Fe(III) catalyst, such as FeCl3 and Fe(acac)3. Step (c) can be carried out in a buffer. Suitable buffers include, but are not limited to, potassium carbonate, sodium carbonate, tripotassium phosphate, and combinations thereof. Suitable solvents for use in step (c) include, but are not limited to, toluene, water, dioxane, tetrahydrofuran, and combinations thereof.

[0279] Specifically, in certain embodiments, ethylboronic acid and a buffer are added to a 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. After completion, the reaction mixture is cooled to room temperature and the product is filtered. In one embodiment, the product is separated before step (d).

[0280] In step (d), (X) is hydrolyzed to produce (XI). Any suitable means known in the art can be used to hydrolyze (X). 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 that can be used in the step (d) reaction includes, but is not limited to, tetrahydrofuran, water, dioxane, and combinations thereof.

[0281] Specifically, in certain embodiments, the alkali metal hydroxide is added to a solution of (X) in a solvent. The resulting mixture is heated to about 20 °C to about 65 °C and stirred for about 2 hours to about 18 hours. In one embodiment, the mixture is heated 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. After 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 separated before step (e).

[0282] In steps (e) and (f) of Scheme V, (XI) is converted to (XII), and (XII) is contacted with dicyclohexylamine to form (Ib). Specifically, in step (e), compound (XI) can be contacted with a catalyst such as a ruthenium catalyst. Any catalyst containing a chiral phosphine can be used. A specific example of a suitable catalyst is diacetato[(S)-(-)5,5'-bis(diphenylphosphino)-4,4'-di-1,3-benzodioxole]ruthenium(II) (i.e., (S)-Segphos Ru(OAc)2). Suitable solvents for step (e) include, but are not limited to, methanol, triethylamine, and combinations thereof.

[0283] 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, the solution of (XI) and the catalyst in a solvent is hydrogenated at about 580 psi. In one embodiment, the 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. After 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. C. Intermediate Compounds

[0284] In some embodiments, the present disclosure relates to intermediate compounds for the preparation of compound 1, and methods for the preparation of these intermediate compounds. Formula (IVa)

[0285] In one embodiment, the present disclosure relates to a compound having formula (IVa). Wherein R2 and Ts are as defined above.

[0286] As discussed herein and depicted in Schemes I, II, and III, a compound having formula (IVa) can react with a compound having formula (III) or (IIIa) to produce a compound having formula (V) or (Va). Advantageously, when the compound having formula (IVa) reacts with the compound having formula (III) or (IIIa) in Schemes I, II, or III, the methyl carbamate or ethyl carbamate moiety present on the compound having formula (IVa) produces a crystalline product.

[0287] In another aspect, the present disclosure relates to a method for preparing a compound having formula (IVa). A suitable method for preparing a compound having formula (IVa) is illustrated in Scheme VI. Specifically, (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). In the presence of a catalyst and a ligand, (XIX) is reacted with ethyl carbamate or methyl carbamate to form a compound having formula (IVa). Solution VI wherein: R2 is methyl or ethyl; Ts is toluenesulfonyl; and TMS is trimethylsilyl.

[0288] In step (a) of Scheme VI, a 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) chloride (PdCl2(Ph3P)2). Step (a) is typically carried out in the presence of copper(I) iodide (CuI). Any suitable solvent can be used in step (a), including but not limited to triethylamine.

[0289] Specifically, in certain embodiments, the catalyst is added to a solution of (XVII) and CuI in a solvent. The reaction mixture is cooled (e.g., to about -5 °C to 0 °C), and a solution of trimethylsilylacetylene in a solvent is slowly added (e.g., over about 15 minutes). The reaction mixture is stirred at about -5 °C 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, and the product is isolated before step (b).

[0290] 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 step (b) include, but are not limited to, potassium tert-butoxide, sodium hydride, etc., and combinations thereof. Suitable solvents for step (b) include, but are not limited to, dimethylformamide.

[0291] Specifically, in certain embodiments, the base is added to a solution of (XVIII) in a solvent (e.g., at about 0 °C). Subsequently, p-toluenesulfonyl chloride is added, and the mixture is warmed to room temperature. After the 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 separated and purified before step (c).

[0292] 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 having formula (IVa). The reaction can be carried out in the presence of a buffer (e.g., potassium carbonate, tetramethylammonium hydroxide, etc.). 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 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 step (c) include, but are not limited to, dioxane, toluene, and tetrahydrofuran.

[0293] Specifically, in certain embodiments, an evacuated mixture of the 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. After 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 separated before 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.

[0294] Compound (XVII) used in Scheme VI is commercially available. The preparation of compounds (XVIII) and (XIX) is also described in Example 1 of WO 2011 / 068881, which is incorporated herein by reference. Chemical formula (II)

[0295] In one aspect, the present disclosure relates to a compound having formula (II): Wherein PG is a protecting group.

[0296] 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.

[0297] In a preferred embodiment, the protecting group is carboxybenzyl, and the compound having formula (II) is compound (IIa): Wherein Cbz is carboxybenzyl.

[0298] In another aspect, the present disclosure relates to a method for preparing a compound having formula (II) or (IIa). A method for preparing a compound having formula (II) or (IIa) is illustrated in Scheme VII. In Scheme VII, a compound having formula (I) or a pharmaceutically acceptable salt thereof is reacted with trimethylsulfoxonium chloride to form a compound having formula (II). In a specific embodiment, the pharmaceutically acceptable salt is a compound having formula (Ib). Scheme VII Wherein PG is a protecting group as defined herein.

[0299] The reaction of Scheme VII is generally completed 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.

[0300] Another method for preparing a compound having formula (II) or (IIa) is illustrated in Scheme VIII. In step (a) of Scheme VIII, a compound having formula (XIa) is hydrogenated to a compound having formula (I), and in step (b) of Scheme VIII, a compound having formula (I) is reacted with trimethylsulfoxonium chloride to form a compound having formula (II). Scheme VIII Wherein PG is a protecting group as defined herein.

[0301] In step (a) of Scheme VIII, a compound having the formula (XIa) can be contacted with a catalyst, such as a ruthenium catalyst. Any catalyst containing a chiral phosphine can be used. A specific example of a suitable catalyst is diacetato[(S)-(-)5,5'-bis(diphenylphosphino)-4,4'-di-1,3-benzodioxole]ruthenium(II) (i.e., (S)-Segphos Ru(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 of step (a) of Scheme VIII is carried out under the conditions described above for step (a) of Scheme III.

[0302] The reaction in step (b) of Scheme VIII is generally completed 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 combinations thereof. The step (b) reaction 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 step (b) of Scheme VIII is carried out under the conditions described above for step (b) of Scheme III. Formula (III)

[0303] In another embodiment, the present disclosure relates to a method for preparing a compound having the formula (III). Wherein PG is a protecting group and X is Br or Cl.

[0304] 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.

[0305] In a preferred embodiment, the protecting group is carboxybenzyl and X is Br, and the compound having the formula (III) is compound (IIIa), Wherein Cbz is carboxybenzyl.

[0306] A method for preparing a compound having the formula (III) or (IIIa) is illustrated in Scheme IX. Scheme IX Wherein PG and X are as defined herein.

[0307] Referring to Scheme IX, in one embodiment, a compound having formula (II) is contacted with LiX and a sulfonic acid to form a compound having 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 (including 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.

[0308] Referring to Scheme IX, in an alternative embodiment, a compound having formula (II) is contacted with an anhydrous HBr or anhydrous HCl source to form a compound having formula (III). The reaction can be carried out in any suitable solvent (including 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.

[0309] In some embodiments, the method for preparing a compound having formula (III) or (IIIa) may further include preparing a compound having formula (II). One such method is illustrated in Scheme X. Plan X Wherein PG and X are as defined above.

[0310] In Scheme X, a compound having formula (I) or a pharmaceutically acceptable salt thereof is reacted with trimethylsulfoxonium chloride in the presence of carbonyldiimidazole and a strong base (such as potassium tert-butoxide, sodium tert-butoxide, and combinations thereof) to form a compound having formula (II). Then the compound having formula (II) is contacted with LiX and a sulfonic acid to form a compound having formula (III), as described above in Scheme IX. 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 having formula (II) is compound (IIa). In another embodiment, in step (a) of Scheme X, a pharmaceutically acceptable salt of the compound having formula (I) is reacted with trimethylsulfoxonium chloride to form a compound having formula (II). In one embodiment, the salt is (Ia) or (Ib).

[0311] In some embodiments, a method for preparing a compound of formula (III) or (IIIa) may further comprise preparing compounds of formulas (I) and (II). One such method is illustrated in Scheme XI. Scheme XI wherein PG and X are as defined above.

[0312] 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 (such as KOtBu, NatOBu, and combinations thereof) to form a compound of formula (II). The compound of formula (II) is then contacted with an anhydrous HBr or anhydrous HCl source to form a compound of formula (III), as described in Scheme IX above. 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. Formula (V) and (Va)

[0313] In another embodiment, the present disclosure relates to a compound of formula (Va): wherein R2, Cbz, and Ts are as defined above.

[0314] In another aspect, the present disclosure relates to a method for preparing a compound of formula (V) or (Va). A method for preparing a compound of formula (V) or (Va) is illustrated 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). The compound of formula (II) is contacted with LiX and a sulfonic acid to produce the corresponding halomethyl ketone (III). The compound of formula (III) is reacted with a compound of formula (IV) in the presence of a base to produce a compound of formula (V). Scheme XII wherein PG, Ts, R1, and X are as defined above.

[0315] 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.

[0316] In one embodiment, the protecting group is carboxybenzyl, and the compound is a compound having formula (Va). In one embodiment, the protecting group is carboxybenzyl, and X is Br.

[0317] In one embodiment, R1 is -OR2, and R2 is methyl or ethyl. In such an embodiment, the compound having formula (IV) is a compound having formula (IVa).

[0318] In certain embodiments, a pharmaceutically acceptable salt of the compound having formula (I) is used in the reaction of step (a) of Scheme XII. In one embodiment, the pharmaceutically acceptable salts of the compound having formula (I) are selected from the group consisting of naphthaleneethanamine salt (Ia) and dicyclohexylamine salt (Ia).

[0319] The reaction in step (a) of Scheme XII is generally completed 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 (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.

[0320] In step (b) of Scheme XII, the compound having formula (II) or (IIa) is contacted with LiX and a sulfonic acid, respectively, to form the compound having formula (II) or (IIa). 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 (including but not limited to, tetrahydrofuran, ethyl acetate, heptane, ethanol, water, and combinations thereof).

[0321] In step (c) of Scheme XII, the compound having formula (III) or (IIIa) is reacted with the compound having formula (IV) or (IVa) (prepared as 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 reaction of step (c) can be carried out in any suitable solvent (including but not limited to, dimethylacetamide, tetrahydrofuran, dichloromethane, ethyl acetate, heptane, and combinations thereof).

[0322] 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.

[0323] In another aspect, the present disclosure relates to an alternative method for preparing a compound having formula (V) or (Va). A method for preparing a compound having formula (V) or (Va) is illustrated in Scheme XIII. In Scheme XIII, a compound having formula (XIa) is hydrogenated to a compound having formula (I), and the compound having formula (I) is reacted with trimethylsulfoxonium chloride to form a compound having formula (II). Contacting the compound having formula (II) with an anhydrous HBr or anhydrous HCl source produces the corresponding halomethyl ketone (III). Reacting the compound having formula (III) with a compound having formula (IV) in the presence of a base produces a compound having formula (V). Scheme XIII wherein PG, Ts, R1, and X are as defined above.

[0324] The protecting group can be any suitable protecting group as described herein. In one embodiment, the protecting group is carboxybenzyl, and the compounds having formulae (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 having formula (IV) is a compound having formula (IVa).

[0325] In step (a) of Scheme XIII, the compound having formula (XIa) can be contacted with a catalyst such as a ruthenium catalyst. Any catalyst containing a chiral phosphine can be used. A specific example of a suitable catalyst is diacetato[(S)-(-)5,5'-bis(diphenylphosphino)-4,4'-di-1,3-benzodioxole]ruthenium(II) (i.e., (S)-Segphos Ru(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 of step (a) of Scheme XIII is carried out under the conditions described above for step (a) of Scheme III.

[0326] 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 (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 step (b) of Scheme XIII is carried out under the conditions described above for step (b) of Scheme III.

[0327] In step (c) of Scheme XIII, the compound having formula (II) is contacted with a source of anhydrous HBr or anhydrous HCl to form a compound having formula (III). This reaction can be carried out in any suitable solvent (including 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.

[0328] In step (d) of Scheme XIII, the compound having formula (III) is reacted with a compound having formula (IV) or (IVa) (prepared as 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 (including 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.

[0329] As discussed herein, it has surprisingly been found that when R1 is -OR2 and R2 is ethyl or methyl, the compound having formula (V) and subsequent downstream compounds can be isolated as crystalline solids, which aids in the purification of these intermediates. Thus, in another aspect, the present disclosure is directed to a method for preparing a crystalline compound having formula (V). The method comprises a) reacting a compound having formula (III): with a compound having formula (IV): to produce the compound having formula (V); wherein: PG is a protecting group; X is Br or Cl; R1 is -OR2; R2 is methyl or ethyl; and Ts is tosyl. In one embodiment, the method is carried out under the conditions described above for step (c) in Scheme XII or step (d) in Scheme XIII. Formula (VII)

[0330] In another embodiment, the present disclosure relates to compound (VII):

[0331] or a pharmaceutically acceptable salt thereof.

[0332] In one embodiment, the pharmaceutically acceptable salts of (VII) are selected from the group consisting of (VIIa), (VIIb), and (VIIc),

[0333] In some embodiments, any of the methods disclosed herein 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 may further comprise forming one of the solid forms described in Part III herein. III. Solid form

[0334] 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) packaging properties such as molar volume, bulk density, and hygroscopicity, (2) thermodynamic properties such as melting temperature, vapor pressure, and solubility, (3) kinetic properties such as dissolution rate and stability (including stability under environmental conditions, especially humidity and storage conditions), (4) surface properties such as surface area, wettability, interfacial tension, and shape, (5) mechanical properties such as hardness, tensile strength, formability, handleability, flowability, and blendability; and (6) filtration properties. These properties can affect, for example, the processing and storage of the compound and pharmaceutical compositions containing the compound.

[0335] Solid forms of the compound that improve one or more of these properties relative to other solid forms of Compound 1 are desirable. Isolating pharmaceutically acceptable solid forms of the compound that can be produced and formulated on a commercial scale has been a challenge.

[0336] The amorphous free base form of Compound 1 generally has greater solubility and improved bioavailability relative to most corresponding crystalline forms of the compound. The amorphous free base also has acceptable chemical stability. However, it is hygroscopic and potentially requires environmental control to ensure proper control of potency and water content during storage, distribution, and handling of the amorphous free base. In addition, the amorphous free base exhibits an oiling-out limit near the solubility curve during the manufacturing process.

[0337] The crystalline hydrochloride solvate Form AA, the crystalline hydrochloride solvate Form BB, and the crystalline hydrochloride solvate Form CC generally convert to the amorphous hydrochloride when the environment is dry. The resulting amorphous hydrochloride is hygroscopic. The yield of each crystalline hydrochloride obtained is generally low. The hydrochloride solvate Form AA, the hydrochloride solvate Form BB, and the hydrochloride solvate Form CC may not be suitable for large-scale production.

[0338] The crystalline L-malate form may generally be more chemically stable than the amorphous free base, the free base hydrate Form C, and the tartrate hydrate and may not exhibit pharmaceutically acceptable stability as an active ingredient in a pharmaceutical dosage form.

[0339] The tartrate hydrate form has acceptable chemical stability, high solubility, overall good impurity rejection during isolation, and non-hygroscopicity. However, the tartrate hydrate presents challenges due to a lack of physical stability (which also affects manufacturing). The tartrate hydrate dehydrates to the amorphous form at relatively low humidity and high temperature (e.g., at 25 °C, <10% RH). Shearing and compression potentially lead to conversion to the amorphous tartrate, and thus it is not suitable for compression into tablet form. In addition, the filter cake solidifies during drying, resulting in a need for additional control during the drying process.

[0340] The free base hydrate Form B has been produced on a large scale without labor-intensive and expensive techniques such as spray drying. It also provides suitable control of the bulk properties of the amorphous free base. However, when isolated via the free base hydrate Form B, the amorphous free base shows poor impurity rejection and requires a dry environment for storage and control of relative humidity during manufacturing and packaging.

[0341] The free base hydrate Form B is physically unstable. It desolvates (or dehydrates) and converts to the amorphous free base upon drying. Although the free base hydrate Form B generally does not exhibit pharmaceutically acceptable physical stability as an active ingredient in a pharmaceutical dosage form, it may be a useful intermediate for preparing other solid forms (such as the amorphous free base).

[0342] After years of experimentation, the free base hydrate Form C was serendipitously discovered while attempting to scale up the amorphous free base. It offers many surprising and superior properties over the amorphous free base, the tartrate hydrate, and other forms of Compound 1.

[0343] The free base hydrate Form C generally exhibits excellent chemical stability, physical stability, and solid-state properties, including low hygroscopicity and a prismatic morphology. The free base hydrate Form C has improved overall properties such as powder flowability and bulk density, which are advantageous during formulation. In addition, the free base hydrate Form C offers at least the following unexpected advantages compared to other forms: 1) efficient purification can be achieved since the use of tartrate crystals is not required; 2) the seeding step is simple since the free base hydrate Form C can be stored under normal conditions; 3) the drying step can be carried out under normal conditions using standard equipment since dehydration does not occur until about 110 °C; and 4) the free base hydrate Form C can crystallize in different particle sizes. The large-scale production of the free base hydrate Form C is relatively simple, with minimal fouling, good yields, good impurity rejection, rapid filtration, conventional drying, and minimal milling problems. In addition, the free base hydrate Form C can have different particle sizes.

[0344] The free base hydrate Form D can only be produced when the water content of the crystallization solvent is low and is converted to the free base hydrate Form C in solutions with high water content. Therefore, strict control of the water content is required for the production of the free base anhydrate Form D. The free base anhydrate Form D crystallizes slowly and is difficult to produce in higher yields. This anhydrate is reversibly hygroscopic (up to 1.8% water at 25 °C and 90% RH) and is metastable relative to the free base hydrate Form C under the typical environmental conditions used during storage for downstream processing (e.g., above 2.4% RH at 23 °C). The free base hydrate Form C will convert to the free base anhydrate Form D in ethyl acetate solutions with low water content.

[0345] The following sections discuss the identified solid forms and selected properties of these solid forms. A. Amorphous free base

[0346] In one embodiment, the solid form is amorphous Compound 1 (“amorphous free base”). In one aspect, the amorphous free base comprises less than about 13% water by weight. In another aspect, the amorphous free base comprises less than about 12% water by weight. In another aspect, the amorphous free base comprises less than about 10% water by weight. In another aspect, the amorphous free base comprises less than about 9% water by weight. In another aspect, the amorphous free base comprises less than about 8% water by weight. In another aspect, the amorphous free base comprises less than about 7% water by weight. In another aspect, the amorphous free base comprises less than about 6% water by weight. In another aspect, the amorphous free base comprises less than about 5% water by weight. In another aspect, the amorphous free base comprises less than about 4% water by weight. In another aspect, the amorphous free base comprises less than about 3% water by weight. In another aspect, the amorphous free base comprises less than about 2% water by weight. In another aspect, the amorphous free base comprises less than about 1% water by weight. In another aspect, the onset glass transition temperature of the amorphous free base is about 119 °C. In another aspect, the midpoint glass transition temperature of the amorphous free base is about 122 °C. In another aspect, the onset glass transition temperature of the amorphous free base is about 119 °C and the midpoint glass transition temperature is about 122 °C. The amorphous free base is further described in the examples of this application.

[0347] The amorphous free base generally has greater solubility and improved bioavailability relative to the corresponding crystalline form of the compound. The amorphous free base also has acceptable chemical stability. For example, when chemical stability was evaluated in a closed 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 degradation of the amorphous free base was observed in the closed vial under any of these conditions. Additionally, the amorphous free base shows acceptable stability to light and peroxide. However, the amorphous free base is hygroscopic and can contain up to 12% water by weight at 25 °C / 90% relative humidity. Environmental control may potentially be required to ensure proper control of potency and water content during storage, distribution, and handling of the amorphous free base.

[0348] For example, anti-solvent crystallization can be used to prepare the amorphous free base to prepare the free base solvate form A or the free base hydrate form B (as described below), and then dehydrated or desolvated to produce the amorphous free base. This crystallization / dehydration / desolvation method allows for the large-scale manufacture of the amorphous free base without the need for labor-intensive and expensive techniques such as spray drying. It also provides for the proper control of the overall properties of the amorphous free base (i.e., particle size, flowability, etc.). When the amorphous free base is prepared by the desolvation of the free base solvate form A or the dehydration of the free base hydrate form B, the amorphous free base typically retains the morphology of the free base solvate form A or the free base hydrate form B (i.e., blades with hexagonal facets when prepared by the dehydration of the free base hydrate form B, or irregular when desolvated from the free base solvate form A).

[0349] The process volume required for crystallization during the large-scale production of the free base solvate form A or the free base hydrate form B is typically within the conventional processing volume, but the impurity rejection may potentially be lower than desired. The drying and dehydration / desolvation of the free base hydrate form B / free base solvate form A to the amorphous free base can generally be carried out under conventional conditions using standard equipment, and the separated amorphous free base can typically be co-ground without adversely affecting the amorphous state. B. Crystalline free base solvates and hydrates

[0350] In another embodiment, the solid form is the 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"). The free base solvate form A and the free base hydrate form B are further described in the examples of the present application.

[0351] 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 degrees 2θ, 9.3 ± 0.2 degrees 2θ, and 12.0 ± 0.2 degrees 2θ when measured using monochromatic Kα1 radiation at about 25°C.

[0352] 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 degrees 2θ, 9.3 ± 0.2 degrees 2θ, and 12.0 ± 0.2 degrees 2θ when measured using monochromatic Kα1 radiation at about 25°C, and is further characterized by peaks at one or more of 13.7 ± 0.2 degrees 2θ, 20.8 ± 0.2 degrees 2θ, and 25.0 ± 0.2 degrees 2θ.

[0353] 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 degrees 2θ, 9.3 ± 0.2 degrees 2θ, 12.0 ± 0.2 degrees 2θ, and 20.8 ± 0.2 degrees 2θ when measured at about 25 °C using monochromatic Kα1 radiation.

[0354] 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 degrees 2θ, 9.3 ± 0.2 degrees 2θ, 12.0 ± 0.2 degrees 2θ, and 25.0 ± 0.2 degrees 2θ when measured at about 25 °C using monochromatic Kα1 radiation.

[0355] 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 degrees 2θ, 9.3 ± 0.2 degrees 2θ, 12.0 ± 0.2 degrees 2θ, 20.8 ± 0.2 degrees 2θ, and 25.0 ± 0.2 degrees 2θ when measured at about 25 °C using monochromatic Kα1 radiation.

[0356] 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 degrees 2θ, 9.3 ± 0.2 degrees 2θ, 12.0 ± 0.2 degrees 2θ, 13.7 ± 0.2 degrees 2θ, 20.8 ± 0.2 degrees 2θ, and 25.0 ± 0.2 degrees 2θ when measured at about 25 °C using monochromatic Kα1 radiation.

[0357] In one embodiment, the crystalline free base solvate or hydrate has an X-ray powder diffraction pattern that does not have a significant peak at one or more of 15.1 ± 0.2 degrees 2θ and 21.7 ± 0.2 degrees 2θ when measured at about 25 °C using monochromatic Kα1 radiation.

[0358] In one embodiment, the crystalline free base solvate or hydrate has an X-ray powder diffraction pattern that does not have a significant peak at one or more of 3.9 ± 0.2 degrees 2θ, 6.8 ± 0.2 degrees 2θ, and 14.1 ± 0.2 degrees 2θ when measured at about 25 °C using monochromatic Kα1 radiation.

[0359] In one embodiment, the crystalline free base solvate or hydrate has an X-ray powder diffraction pattern that does not have a significant peak at one or more of 15.1 ± 0.2 degrees 2θ and 21.7 ± 0.2 degrees 2θ, and does not have a significant peak at one or more of 3.9 ± 0.2 degrees 2θ, 6.8 ± 0.2 degrees 2θ, and 14.1 ± 0.2 degrees 2θ when measured at about 25 °C using monochromatic Kα1 radiation.

[0360] 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 degrees 2θ, 9.3 ± 0.2 degrees 2θ, and 12.0 ± 0.2 degrees 2θ when measured at about 25 °C using monochromatic Kα1 radiation, and having no significant peak at one or more of 15.1 ± 0.2 degrees 2θ and 21.7 ± 0.2 degrees 2θ.

[0361] 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 degrees 2θ, 9.3 ± 0.2 degrees 2θ, and 12.0 ± 0.2 degrees 2θ when measured at about 25 °C using monochromatic Kα1 radiation, and having no significant peak at one or more of 3.9 ± 0.2 degrees 2θ, 6.8 ± 0.2 degrees 2θ, and 14.1 ± 0.2 degrees 2θ.

[0362] 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 degrees 2θ, 9.3 ± 0.2 degrees 2θ, and 12.0 ± 0.2 degrees 2θ when measured at about 25 °C using monochromatic Kα1 radiation, and having no significant peak at one or more of 15.1 ± 0.2 degrees 2θ and 21.7 ± 0.2 degrees 2θ, and having no significant peak at one or more of 3.9 ± 0.2 degrees 2θ, 6.8 ± 0.2 degrees 2θ, and 14.1 ± 0.2 degrees 2θ.

[0363] 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 degrees 2θ, 9.3 ± 0.2 degrees 2θ, 12.0 ± 0.2 degrees 2θ, 13.7 ± 0.2 degrees 2θ, 20.8 ± 0.2 degrees 2θ, and 25.0 ± 0.2 degrees 2θ when measured at about 25 °C using monochromatic Kα1 radiation, and having no significant peak at one or more of 15.1 ± 0.2 degrees 2θ and 21.7 ± 0.2 degrees 2θ.

[0364] 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 degrees 2θ, 9.3 ± 0.2 degrees 2θ, 12.0 ± 0.2 degrees 2θ, 13.7 ± 0.2 degrees 2θ, 20.8 ± 0.2 degrees 2θ, and 25.0 ± 0.2 degrees 2θ when measured at about 25 °C using monochromatic Kα1 radiation, and having no significant peak at one or more of 3.9 ± 0.2 degrees 2θ, 6.8 ± 0.2 degrees 2θ, and 14.1 ± 0.2 degrees 2θ.

[0365] 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 degrees 2θ, 9.3 ± 0.2 degrees 2θ, 12.0 ± 0.2 degrees 2θ, 13.7 ± 0.2 degrees 2θ, 20.8 ± 0.2 degrees 2θ, and 25.0 ± 0.2 degrees 2θ when measured at about 25 °C using monochromatic Kα1 radiation, and does not have a significant peak at one or more of 15.1 ± 0.2 degrees 2θ and 21.7 ± 0.2 degrees 2θ, and does not have a significant peak at one or more of 3.9 ± 0.2 degrees 2θ, 6.8 ± 0.2 degrees 2θ, and 14.1 ± 0.2 degrees 2θ.

[0366] In one embodiment, the crystalline free base solvate or hydrate has an X-ray powder diffraction pattern characterized by peaks at substantially the positions ± 0.2 degrees 2θ listed in Table 16-A when measured at about 25 °C using monochromatic Kα1 radiation.

[0367] In one embodiment, the crystalline free base solvate or hydrate has an X-ray powder diffraction pattern characterized by peaks at substantially the positions ± 0.2 degrees 2θ listed in Table 16-B when measured at about 25 °C using monochromatic Kα1 radiation.

[0368] In one embodiment, the crystalline free base solvate or hydrate has an X-ray powder diffraction pattern characterized by peaks at substantially the positions ± 0.2 degrees 2θ listed in Table 16-B when measured at about 25 °C using monochromatic Kα1 radiation, and having a relative intensity of at least 10.0%.

[0369] In a further aspect of each of the above embodiments, the significant peaks have a variation of ± 0.1 degrees 2θ rather than ± 0.2 degrees 2θ. In yet a further aspect of each of the above embodiments, the significant peaks have a variation of ± 0.05 degrees 2θ rather than ± 0.2 degrees 2θ.

[0370] In one embodiment, the crystalline free base has substantially as Figure 3B the X-ray powder diffraction pattern shown in.

[0371] In one embodiment, the crystalline free base has a thermogravimetric analysis profile that shows 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 / minute.

[0372] In one embodiment, the crystalline free base has substantially as Figure 4D the thermogravimetric analysis profile shown in.

[0373] In one embodiment, the crystalline free base has a differential scanning calorimetry (DSC) thermogram that, when heated at a rate of 10 °C / minute, between about 25 °C and about 100 °C, contains a first endotherm.

[0374] In one embodiment, the crystalline free base has a differential scanning calorimetry (DSC) thermogram that, when heated at a rate of 10 °C / minute, between about 59.90 °C and about 98.79 °C, contains a first endotherm.

[0375] In one embodiment, the crystalline free base has a differential scanning calorimetry (DSC) thermogram that, when heated at a rate of 10 °C / minute, between about 100 °C and about 160 °C, contains a second endotherm.

[0376] In one embodiment, the crystalline free base has a differential scanning calorimetry (DSC) thermogram that, when heated at a rate of 10 °C / minute, between about 109.31 °C and about 132.94 °C, contains a second endotherm.

[0377] In one embodiment, the crystalline free base has a differential scanning calorimetry (DSC) thermogram that, when heated at a rate of 10 °C / minute, between about 25 °C and about 100 °C, contains a first endotherm and, between about 100 °C and about 160 °C, contains a second endotherm.

[0378] In one embodiment, the crystalline free base has a differential scanning calorimetry (DSC) thermogram that is substantially as Figure 5B shown therein.

[0379] In one embodiment, the crystalline free base has a thermogravimetric analysis (TGA) thermogram that, when heated at a rate of 10 °C / minute, between about 100 °C and about 160 °C, shows a weight loss of about 5% to about 6%; and has a differential scanning calorimetry (DSC) thermogram that, when heated at a rate of 10 °C / minute, between about 25 °C and about 100 °C, contains a first endotherm and / or, between about 100 °C and about 160 °C, contains a second endotherm. In one aspect, when heated at a rate of 10 °C / minute, the DSC thermogram includes a first endotherm between about 25 °C and about 100 °C. In another aspect, when heated at a rate of 10 °C / minute, the DSC thermogram includes a second endotherm between about 100 °C and about 160 °C. In yet another aspect, when heated at a rate of 10 °C / minute, the DSC thermogram includes a first endotherm between about 25 °C and about 100 °C and includes a second endotherm between about 100 °C and about 160 °C.

[0380] In one embodiment, the crystalline free base has a thermogravimetric analysis (TGA) profile that shows 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 per minute; and has a differential scanning calorimetry (DSC) profile that, when heated at a rate of 10 °C per minute, contains a first endothermic peak between about 59.90 °C and about 98.79 °C, and / or a second endothermic peak between about 109.31 °C and about 132.94 °C. In one aspect, the DSC profile, when heated at a rate of 10 °C per minute, includes a first endothermic peak between about 59.90 °C and about 98.79 °C. In another aspect, the DSC profile, when heated at a rate of 10 °C per minute, includes a second endothermic peak between about 109.31 °C and about 132.94 °C. In yet another aspect, the DSC profile, when heated at a rate of 10 °C per minute, includes a first endothermic peak between about 59.90 °C and about 98.79 °C and a second endothermic peak between about 109.31 °C and about 132.94 °C.

[0381] In one embodiment, the crystalline free base has an X-ray diffraction pattern as described above and further has at least one of the following: (a) a thermogravimetric analysis (TGA) profile that shows 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 per minute; and (b) a differential scanning calorimetry (DSC) profile that, when heated at a rate of 10 °C per minute, contains a first endothermic peak between about 25 °C and about 100 °C, and / or a second endothermic peak between about 100 °C and about 160 °C. In one aspect, the DSC profile includes a first endothermic peak between about 25 °C and about 100 °C when heated at a rate of 10 °C per minute. In another aspect, the DSC profile includes a second endothermic peak between about 100 °C and about 160 °C when heated at a rate of 10 °C per minute. In yet another aspect, the DSC profile includes a first endothermic peak between about 25 °C and about 100 °C and a second endothermic peak between about 100 °C and about 160 °C when heated at a rate of 10 °C per minute.

[0382] In one embodiment, the crystalline free base has an X-ray diffraction pattern as described above and further has a thermogravimetric analysis (TGA) profile that shows 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 per minute.

[0383] In one embodiment, the crystalline free base has the X-ray diffraction pattern as described above and further has a differential scanning calorimetry (DSC) thermogram which, when heated at a rate of 10 °C / minute, includes a first endothermic peak between about 25 °C and about 100 °C, and / or between about 100 °C and about 160 °C, the DSC thermogram includes a second endothermic peak. In one aspect, when heated at a rate of 10 °C / minute, the DSC thermogram includes a first endothermic peak between about 25 °C and about 100 °C. In another aspect, when heated at a rate of 10 °C / minute, the DSC thermogram includes a second endothermic peak between about 100 °C and about 160 °C. In yet another aspect, when heated at a rate of 10 °C / minute, the DSC thermogram includes a first endothermic peak between about 25 °C and about 100 °C and a second endothermic peak between about 100 °C and about 160 °C.

[0384] In one embodiment, the crystalline free base has the X-ray diffraction pattern as described above; a thermogravimetric analysis (TGA) thermogram which, when heated at a rate of 10 °C / minute, shows a weight loss of about 5% to about 6% between about 100 °C and about 160 °C; and a differential scanning calorimetry (DSC) thermogram which, when heated at a rate of 10 °C / minute, includes a first endothermic peak between about 25 °C and about 100 °C, and / or between about 100 °C and about 160 °C, the DSC thermogram includes a second endothermic peak. In one aspect, when heated at a rate of 10 °C / minute, the DSC thermogram includes a first endothermic peak between about 25 °C and about 100 °C. In another aspect, when heated at a rate of 10 °C / minute, the DSC thermogram includes a second endothermic peak between about 100 °C and about 160 °C. In yet another aspect, when heated at a rate of 10 °C / minute, the DSC thermogram includes a first endothermic peak between about 25 °C and about 100 °C and a second endothermic peak between about 100 °C and about 160 °C.

[0385] The free base solvate Form A and the free base hydrate Form B are physically unstable. As described above, they desolvate (or dehydrate) and convert to the amorphous free base upon drying. Although the free base solvate Form A and the free base hydrate Form B generally do not exhibit pharmaceutically acceptable physical stability as the active ingredient in a pharmaceutical dosage form, they are useful intermediates for preparing other solid forms such as the amorphous free base. C. Crystalline Free Base Hydrate Form C (Hemihydrate)

[0386] In another embodiment, the solid form is a crystalline hydrate, wherein the crystalline hydrate is a hemihydrate. In another embodiment, the solid form is the crystalline hemihydrate of Compound 1, which has an X-ray powder diffraction pattern corresponding to the free base hydrate Form C. The free base hydrate Form C is further described in the examples of the present application.

[0387] In one embodiment, the free base hydrate Form C has an X-ray powder diffraction pattern characterized by peaks at 13.4 ± 0.2 degrees 2θ, 15.1 ± 0.2 degrees 2θ, and 21.7 ± 0.2 degrees 2θ when measured using monochromatic Kα1 radiation at about 25°C.

[0388] In one embodiment, the free base hydrate Form C has an X-ray powder diffraction pattern characterized by peaks at 13.4 ± 0.2 degrees 2θ, 15.1 ± 0.2 degrees 2θ, and 21.7 ± 0.2 degrees 2θ when measured using monochromatic Kα1 radiation at about 25°C, and is further characterized by peaks at one or more of 7.7 ± 0.2 degrees 2θ, 7.9 ± 0.2 degrees 2θ, 9.6 ± 0.2 degrees 2θ, 10.3 ± 0.2 degrees 2θ, 13.9 ± 0.2 degrees 2θ, 15.5 ± 0.2 degrees 2θ, 15.9 ± 0.2 degrees 2θ, 17.0 ± 0.2 degrees 2θ, 17.2 ± 0.2 degrees 2θ, 17.8 ± 0.2 degrees 2θ, 18.1 ± 0.2 degrees 2θ, 18.3 ± 0.2 degrees 2θ, 19.3 ± 0.2 degrees 2θ, 19.7 ± 0.2 degrees 2θ, 20.5 ± 0.2 degrees 2θ, 20.9 ± 0.2 degrees 2θ, 21.9 ± 0.2 degrees 2θ, 22.2 ± 0.2 degrees 2θ, 23.5 ± 0.2 degrees 2θ, 24.4 ± 0.2 degrees 2θ, 24.9 ± 0.2 degrees 2θ, 28.2 ± 0.2 degrees 2θ, and 29.5 ± 0.2 degrees 2θ.

[0389] In one embodiment, the free base hydrate Form C has an X-ray powder diffraction pattern characterized by peaks at 13.4 ± 0.2 degrees 2θ, 15.1 ± 0.2 degrees 2θ, 15.5 ± 0.2 degrees 2θ, and 21.7 ± 0.2 degrees 2θ when measured using monochromatic Kα1 radiation at about 25°C.

[0390] In one embodiment, the free base hydrate Form C has an X-ray powder diffraction pattern characterized by peaks at 13.4 ± 0.2 degrees 2θ, 15.1 ± 0.2 degrees 2θ, 17.0 ± 0.2 degrees 2θ, and 21.7 ± 0.2 degrees 2θ when measured using monochromatic Kα1 radiation at about 25°C.

[0391] In one embodiment, the free base hydrate Form C has an X-ray powder diffraction pattern characterized by peaks at 13.4 ± 0.2 degrees 2θ, 15.1 ± 0.2 degrees 2θ, 20.9 ± 0.2 degrees 2θ, and 21.7 ± 0.2 degrees 2θ when measured at about 25 °C using monochromatic Kα1 radiation.

[0392] In one embodiment, the free base hydrate Form C has an X-ray powder diffraction pattern characterized by peaks at 13.4 ± 0.2 degrees 2θ, 15.1 ± 0.2 degrees 2θ, 15.5 ± 0.2 degrees 2θ, 17.0 ± 0.2 degrees 2θ, 20.9 ± 0.2 degrees 2θ, and 21.7 ± 0.2 degrees 2θ when measured at about 25 °C using monochromatic Kα1 radiation.

[0393] In one embodiment, the free base hydrate Form C has an X-ray powder diffraction pattern characterized by peaks at 15.5 ± 0.2 degrees 2θ, 13.4 ± 0.2 degrees 2θ, 15.1 ± 0.2 degrees 2θ, 19.3 ± 0.2 degrees 2θ, 20.5 ± 0.2 degrees 2θ, and 21.7 ± 0.2 degrees 2θ when measured at about 25 °C using monochromatic Kα1 radiation.

[0394] In one embodiment, the free base hydrate Form C has an X-ray powder diffraction pattern that does not have a significant peak at one or more of 3.1 ± 0.2 degrees 2θ, 9.3 ± 0.2 degrees 2θ, and 12.0 ± 0.2 degrees 2θ when measured at about 25 °C using monochromatic Kα1 radiation.

[0395] In one embodiment, the free base hydrate Form C has an X-ray powder diffraction pattern that does not have a significant peak at one or more of 3.9 ± 0.2 degrees 2θ, 6.8 ± 0.2 degrees 2θ, and 14.1 ± 0.2 degrees 2θ when measured at about 25 °C using monochromatic Kα1 radiation.

[0396] In one embodiment, the free base hydrate Form C has an X-ray powder diffraction pattern that does not have a significant peak at one or more of 3.1 ± 0.2 degrees 2θ, 9.3 ± 0.2 degrees 2θ, and 12.0 ± 0.2 degrees 2θ and does not have a significant peak at one or more of 3.9 ± 0.2 degrees 2θ, 6.8 ± 0.2 degrees 2θ, and 14.1 ± 0.2 degrees 2θ when measured at about 25 °C using monochromatic Kα1 radiation.

[0397] In one embodiment, the free base hydrate Form C has an X-ray powder diffraction pattern characterized by peaks at 13.4 ± 0.2 degrees 2θ, 15.1 ± 0.2 degrees 2θ, and 21.7 ± 0.2 degrees 2θ when measured using monochromatic Kα1 radiation at about 25°C, and having no significant peak at one or more of 3.1 ± 0.2 degrees 2θ, 9.3 ± 0.2 degrees 2θ, and 12.0 ± 0.2 degrees 2θ.

[0398] In one embodiment, the free base hydrate Form C has an X-ray powder diffraction pattern characterized by peaks at 13.4 ± 0.2 degrees 2θ, 15.1 ± 0.2 degrees 2θ, and 21.7 ± 0.2 degrees 2θ when measured using monochromatic Kα1 radiation at about 25°C, and having no significant peak at one or more of 3.9 ± 0.2 degrees 2θ, 6.8 ± 0.2 degrees 2θ, and 14.1 ± 0.2 degrees 2θ.

[0399] In one embodiment, the free base hydrate Form C has an X-ray powder diffraction pattern characterized by peaks at 13.4 ± 0.2 degrees 2θ, 15.1 ± 0.2 degrees 2θ, and 21.7 ± 0.2 degrees 2θ when measured using monochromatic Kα1 radiation at about 25°C, and having no significant peak at one or more of 3.1 ± 0.2 degrees 2θ, 9.3 ± 0.2 degrees 2θ, and 12.0 ± 0.2 degrees 2θ, and having no significant peak at one or more of 3.9 ± 0.2 degrees 2θ, 6.8 ± 0.2 degrees 2θ, and 14.1 ± 0.2 degrees 2θ.

[0400] In one embodiment, the free base hydrate Form C has an X-ray powder diffraction pattern characterized by peaks at 15.5 ± 0.2 degrees 2θ, 13.4 ± 0.2 degrees 2θ, 15.1 ± 0.2 degrees 2θ, 19.3 ± 0.2 degrees 2θ, 20.5 ± 0.2 degrees 2θ, and 21.7 ± 0.2 degrees 2θ when measured using monochromatic Kα1 radiation at about 25°C, and having no significant peak at one or more of 3.1 ± 0.2 degrees 2θ, 9.3 ± 0.2 degrees 2θ, and 12.0 ± 0.2 degrees 2θ.

[0401] In one embodiment, the free base hydrate Form C has an X-ray powder diffraction pattern characterized by peaks at 15.5 ± 0.2 degrees 2θ, 13.4 ± 0.2 degrees 2θ, 15.1 ± 0.2 degrees 2θ, 19.3 ± 0.2 degrees 2θ, 20.5 ± 0.2 degrees 2θ, and 21.7 ± 0.2 degrees 2θ when measured using monochromatic Kα1 radiation at about 25°C, and having no significant peak at one or more of 3.9 ± 0.2 degrees 2θ, 6.8 ± 0.2 degrees 2θ, and 14.1 ± 0.2 degrees 2θ.

[0402] In one embodiment, the free base hydrate Form C has an X-ray powder diffraction pattern characterized by peaks at 15.5 ± 0.2 degrees 2θ, 13.4 ± 0.2 degrees 2θ, 15.1 ± 0.2 degrees 2θ, 19.3 ± 0.2 degrees 2θ, 20.5 ± 0.2 degrees 2θ, and 21.7 ± 0.2 degrees 2θ when measured using monochromatic Kα1 radiation at about 25°C, and does not have a significant peak at one or more of 3.1 ± 0.2 degrees 2θ, 9.3 ± 0.2 degrees 2θ, and 12.0 ± 0.2 degrees 2θ, and does not have a significant peak at one or more of 3.9 ± 0.2 degrees 2θ, 6.8 ± 0.2 degrees 2θ, and 14.1 ± 0.2 degrees 2θ.

[0403] In one embodiment, the free base hydrate Form C has an X-ray powder diffraction pattern characterized by peaks at positions ± 0.2 degrees 2θ substantially as listed in Table 16-C when measured using monochromatic Kα1 radiation at about 25°C.

[0404] In one embodiment, the free base hydrate Form C has an X-ray powder diffraction pattern characterized by peaks at positions ± 0.2 degrees 2θ substantially as listed in Table 16-C when measured using monochromatic Kα1 radiation at about 25°C, with a relative intensity of at least 10.0%.

[0405] In a further aspect of each of the above embodiments, the significant peaks have a variation of ± 0.1 degree 2θ rather than ± 0.2 degrees 2θ. In yet a further aspect of each of the above embodiments, the significant peaks have a variation of ± 0.05 degree 2θ rather than ± 0.2 degrees 2θ.

[0406] In one embodiment, when measured using monochromatic Kα1 radiation at about 25°C, the free base hydrate Form C has an X-ray powder diffraction pattern substantially as Figure 3C shown therein.

[0407] In one embodiment, the free base hydrate Form C has a thermogravimetric analysis pattern that shows 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 / minute.

[0408] In one embodiment, the free base hydrate Form C has a thermogravimetric analysis pattern that shows 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 / minute.

[0409] In one embodiment, the free base hydrate Form C has a thermogravimetric analysis pattern substantially as Figure 4E shown therein.

[0410] In one embodiment, the free base hydrate Form C has a differential scanning calorimetry (DSC) thermogram that exhibits an endothermic peak between approximately 120 °C and approximately 170 °C when heated at a rate of 10 °C per minute.

[0411] In one embodiment, the free base hydrate Form C has a differential scanning calorimetry (DSC) thermogram that exhibits an endothermic peak between approximately 134.70 °C and approximately 167.53 °C when heated at a rate of 10 °C per minute.

[0412] In one embodiment, the free base hydrate Form C has a differential scanning calorimetry (DSC) thermogram that is substantially as Figure 5C shown therein.

[0413] In one embodiment, the free base hydrate Form C has a moisture sorption isotherm that shows 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.

[0414] In one embodiment, the free base hydrate Form C has a moisture sorption isotherm that is substantially as Figure 6B shown therein.

[0415] In one embodiment, the free base hydrate Form C has a thermogravimetric analysis (TGA) thermogram that shows a weight loss of from about 2.3% to about 2.6% between approximately 120 °C and 160 °C when heated at a rate of 10 °C per minute; and has a differential scanning calorimetry (DSC) thermogram that exhibits an endothermic peak between approximately 120 °C and approximately 170 °C when heated at a rate of 10 °C per minute.

[0416] In one embodiment, the free base hydrate Form C has a thermogravimetric analysis (TGA) thermogram that shows a weight loss of from about 2.3% to about 2.6% between approximately 120 °C and 160 °C when heated at a rate of 10 °C per minute; and has a moisture sorption isotherm that shows 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.

[0417] In one embodiment, the free base hydrate Form C has a differential scanning calorimetry (DSC) thermogram that exhibits an endothermic peak between approximately 120 °C and approximately 170 °C when heated at a rate of 10 °C per minute; and has a moisture sorption isotherm that shows 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.

[0418] In one embodiment, the free base hydrate Form C has a thermogravimetric analysis (TGA) plot that shows 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 per minute; a differential scanning calorimetry (DSC) plot that contains an endothermic peak between about 120 °C and about 170 °C when heated at a rate of 10 °C per minute; and a water adsorption isotherm plot that shows a weight gain from 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.

[0419] In one embodiment, the free base hydrate Form C has a thermogravimetric analysis (TGA) plot that shows 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 per minute; a differential scanning calorimetry (DSC) plot that contains an endothermic peak between about 134.70 °C and about 167.53 °C when heated at a rate of 10 °C per minute; and a water adsorption isotherm plot that shows a weight gain from 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.

[0420] In one embodiment, the free base hydrate Form C has an orthorhombic lattice type.

[0421] In one embodiment, the free base hydrate Form C has a P212121 space group.

[0422] In one embodiment, the unit cell a, b, and c values of the free base hydrate Form C are approximately about and about

[0423] In one embodiment, the free base hydrate Form C has an X-ray diffraction pattern as described above and at least one of the following: (a) a thermogravimetric analysis (TGA) plot that shows 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 per minute; (b) a differential scanning calorimetry (DSC) plot that contains an endothermic peak between about 120 °C and about 170 °C when heated at a rate of 10 °C per minute; and / or (c) a water adsorption isotherm plot that shows a weight gain from 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.

[0424] In one embodiment, the free base hydrate Form C has the X-ray diffraction pattern and thermogravimetric analysis pattern as described above. When heated at a rate of 10 °C / minute, between about 120 °C and 160 °C, the thermogravimetric analysis pattern shows a weight loss of about 2.3% to about 2.6%.

[0425] In one embodiment, the free base hydrate Form C has the X-ray diffraction pattern and differential scanning calorimetry pattern as described above. When heated at a rate of 10 °C / minute, between about 120 °C and about 170 °C, the differential scanning calorimetry pattern contains an endothermic peak.

[0426] In one embodiment, the free base hydrate Form C has the X-ray diffraction pattern and moisture sorption isotherm pattern as described above. When the relative humidity is increased from about 0% relative humidity to about 90% relative humidity at a temperature of 25 °C, the moisture sorption isotherm pattern shows a weight increase of about 0% to about 0.2%.

[0427] In one embodiment, the free base hydrate Form C has the X-ray diffraction pattern as described above; a thermogravimetric analysis pattern, which shows 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 / minute; and a differential scanning calorimetry pattern, which contains an endothermic peak between about 120 °C and about 170 °C when heated at a rate of 10 °C / minute.

[0428] In one embodiment, the free base hydrate Form C has the X-ray diffraction pattern as described above; a thermogravimetric analysis pattern, which shows 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 / minute; and a moisture sorption isotherm pattern, which shows a weight increase from 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.

[0429] In one embodiment, the free base hydrate Form C has the X-ray diffraction pattern as described above; a differential scanning calorimetry pattern, which contains an endothermic peak between about 120 °C and about 170 °C when heated at a rate of 10 °C / minute; and a moisture sorption isotherm pattern, which shows a weight increase from 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.

[0430] In one embodiment, the free base hydrate Form C has an X-ray diffraction pattern as described above; a thermogravimetric analysis pattern that shows 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 per minute; a differential scanning calorimetry pattern that contains an endothermic peak between about 120 °C and about 170 °C when heated at a rate of 10 °C per minute; and has a moisture sorption isotherm pattern that shows a weight gain 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.

[0431] The free base hydrate Form C generally exhibits good chemical stability, physical stability, and solid-state properties (including low hygroscopicity). The large-scale production of the free base hydrate Form C is relatively simple, with minimal fouling, good yields, good impurity rejection, rapid filtration, conventional drying, and minimal milling problems (even after high-energy pinmilling of the separated material). Additionally, different particle sizes can be obtained by appropriately controlling the crystallization process. D. Crystalline free base anhydrate form D

[0432] In another embodiment, the solid form is the crystalline anhydrous free base of Compound 1, which has 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.

[0433] In one embodiment, the free base anhydrous Form D has an X-ray powder diffraction pattern characterized by peaks at 8.0 ± 0.2 degrees 2θ, 9.7 ± 0.2 degrees 2θ, 14.2 ± 0.2 degrees 2θ, 14.5 ± 0.2 degrees 2θ, and 20.3 ± 0.2 degrees 2θ when measured at about 25 °C using monochromatic Kα1 radiation.

[0434] In one embodiment, the free base anhydrous Form D has an X-ray powder diffraction pattern characterized by peaks at 8.0 ± 0.2 degrees 2θ, 9.7 ± 0.2 degrees 2θ, 14.2 ± 0.2 degrees 2θ, 14.5 ± 0.2 degrees 2θ, and 20.3 ± 0.2 degrees 2θ when measured at about 25 °C using monochromatic Kα1 radiation, and is further characterized by peaks at one or more of 4.0 ± 0.2 degrees 2θ, 18.4 ± 0.2 degrees 2θ, 19.0 ± 0.2 degrees 2θ, 23.0 ± 0.2 degrees 2θ, and 24.7 ± 0.2 degrees 2θ.

[0435] In one embodiment, the free base anhydrous Form D has an X-ray powder diffraction pattern characterized by peaks at 4.0 ± 0.2 degrees 2θ, 8.0 ± 0.2 degrees 2θ, 9.7 ± 0.2 degrees 2θ, 14.2 ± 0.2 degrees 2θ, 14.5 ± 0.2 degrees 2θ, and 20.3 ± 0.2 degrees 2θ when measured using monochromatic Kα1 radiation at about 25 °C.

[0436] In one embodiment, the free base anhydrous Form D has an X-ray powder diffraction pattern characterized by peaks at 8.0 ± 0.2 degrees 2θ, 9.7 ± 0.2 degrees 2θ, 14.2 ± 0.2 degrees 2θ, 14.5 ± 0.2 degrees 2θ, 18.4 ± 0.2 degrees 2θ and 20.3 ± 0.2 degrees 2θ when measured using monochromatic Kα1 radiation at about 25 °C.

[0437] In one embodiment, the free base anhydrous Form D has an X-ray powder diffraction pattern characterized by peaks at 8.0 ± 0.2 degrees 2θ, 9.7 ± 0.2 degrees 2θ, 14.2 ± 0.2 degrees 2θ, 14.5 ± 0.2 degrees 2θ, 19.0 ± 0.2 degrees 2θ and 20.3 ± 0.2 degrees 2θ when measured using monochromatic Kα1 radiation at about 25 °C.

[0438] In one embodiment, the free base anhydrous Form D has an X-ray powder diffraction pattern characterized by peaks at 4.0 ± 0.2 degrees 2θ, 8.0 ± 0.2 degrees 2θ, 9.7 ± 0.2 degrees 2θ, 14.2 ± 0.2 degrees 2θ, 14.5 ± 0.2 degrees 2θ, 19.0 ± 0.2 degrees 2θ and 20.3 ± 0.2 degrees 2θ when measured using monochromatic Kα1 radiation at about 25 °C.

[0439] In one embodiment, the free base anhydrous Form D has an X-ray powder diffraction pattern characterized by peaks at 8.0 ± 0.2 degrees 2θ, 9.7 ± 0.2 degrees 2θ, 14.2 ± 0.2 degrees 2θ, 14.5 ± 0.2 degrees 2θ, 20.3 ± 0.2 degrees 2θ and 23.0 ± 0.2 degrees 2θ when measured using monochromatic Kα1 radiation at about 25 °C.

[0440] In one embodiment, the free base anhydrous Form D has an X-ray powder diffraction pattern characterized by peaks at 8.0 ± 0.2 degrees 2θ, 9.7 ± 0.2 degrees 2θ, 14.2 ± 0.2 degrees 2θ, 14.5 ± 0.2 degrees 2θ, 20.3 ± 0.2 degrees 2θ and 24.7 ± 0.2 degrees 2θ when measured using monochromatic Kα1 radiation at about 25 °C.

[0441] In one embodiment, the free base anhydrous Form D has an X-ray powder diffraction pattern characterized by peaks at 4.0 ± 0.2 degrees 2θ, 14.5 ± 0.2 degrees 2θ, and 19.0 ± 0.2 degrees 2θ when measured using monochromatic Kα1 radiation at about 25°C.

[0442] In one embodiment, the free base anhydrous Form D has an X-ray powder diffraction pattern characterized by peaks at 4.0 ± 0.2 degrees 2θ, 14.5 ± 0.2 degrees 2θ, and 19.0 ± 0.2 degrees 2θ when measured using monochromatic Kα1 radiation at about 25°C, and is further characterized by peaks at one or more of 8.0 ± 0.2 degrees 2θ, 9.7 ± 0.2 degrees 2θ, 14.2 ± 0.2 degrees 2θ, 18.4 ± 0.2 degrees 2θ, 20.3 ± 0.2 degrees 2θ, 23.0 ± 0.2 degrees 2θ, and 24.7 ± 0.2 degrees 2θ.

[0443] In one embodiment, the free base anhydrous Form D has an X-ray powder diffraction pattern that does not have significant peaks at one or more of 3.1 ± 0.2 degrees 2θ, 9.3 ± 0.2 degrees 2θ, and 20.8 ± 0.2 degrees 2θ when measured using monochromatic Kα1 radiation at about 25°C.

[0444] In one embodiment, the free base anhydrous Form D has an X-ray powder diffraction pattern that does not have significant peaks at one or more of 6.8 ± 0.2 degrees 2θ, 15.7 ± 0.2 degrees 2θ, and 21.9 ± 0.2 degrees 2θ when measured using monochromatic Kα1 radiation at about 25°C.

[0445] In one embodiment, the free base anhydrous Form D has an X-ray powder diffraction pattern that does not have significant peaks at one or more of 13.4 ± 0.2 degrees 2θ, 15.5 ± 0.2 degrees 2θ, and 21.7 ± 0.2 degrees 2θ when measured using monochromatic Kα1 radiation at about 25°C.

[0446] In one embodiment, the free base anhydrous Form D has an X-ray powder diffraction pattern that does not have significant peaks at one or more of 13.4 ± 0.2 degrees 2θ, 15.5 ± 0.2 degrees 2θ, and 21.7 ± 0.2 degrees 2θ when measured using monochromatic Kα1 radiation at about 25°C, and does not have significant peaks at one or more of 6.8 ± 0.2 degrees 2θ, 15.7 ± 0.2 degrees 2θ, and 21.9 ± 0.2 degrees 2θ, and does not have significant peaks at one or more of 3.1 ± 0.2 degrees 2θ, 9.3 ± 0.2 degrees 2θ, and 20.8 ± 0.2 degrees 2θ.

[0447] In one embodiment, the free base anhydrous form D has an X-ray powder diffraction pattern characterized by peaks at 8.0 ± 0.2 degrees 2θ, 9.7 ± 0.2 degrees 2θ, 14.2 ± 0.2 degrees 2θ, 14.5 ± 0.2 degrees 2θ, and 20.3 ± 0.2 degrees 2θ when measured at about 25 °C using monochromatic Kα1 radiation, and does not have significant peaks at one or more of 3.1 ± 0.2 degrees 2θ, 9.3 ± 0.2 degrees 2θ, and 20.8 ± 0.2 degrees 2θ.

[0448] In one embodiment, the free base anhydrous form D has an X-ray powder diffraction pattern characterized by peaks at 8.0 ± 0.2 degrees 2θ, 9.7 ± 0.2 degrees 2θ, 14.2 ± 0.2 degrees 2θ, 14.5 ± 0.2 degrees 2θ, and 20.3 ± 0.2 degrees 2θ when measured at about 25 °C using monochromatic Kα1 radiation, and does not have significant peaks at one or more of 6.8 ± 0.2 degrees 2θ, 15.7 ± 0.2 degrees 2θ, and 21.9 ± 0.2 degrees 2θ.

[0449] In one embodiment, the free base anhydrous form D has an X-ray powder diffraction pattern characterized by peaks at 8.0 ± 0.2 degrees 2θ, 9.7 ± 0.2 degrees 2θ, 14.2 ± 0.2 degrees 2θ, 14.5 ± 0.2 degrees 2θ, and 20.3 ± 0.2 degrees 2θ when measured at about 25 °C using monochromatic Kα1 radiation, and does not have significant peaks at one or more of 13.4 ± 0.2 degrees 2θ, 15.5 ± 0.2 degrees 2θ, and 21.7 ± 0.2 degrees 2θ.

[0450] In one embodiment, the free base anhydrous form D has an X-ray powder diffraction pattern characterized by peaks at 8.0 ± 0.2 degrees 2θ, 9.7 ± 0.2 degrees 2θ, 14.2 ± 0.2 degrees 2θ, 14.5 ± 0.2 degrees 2θ, and 20.3 ± 0.2 degrees 2θ when measured at about 25 °C using monochromatic Kα1 radiation, and does not have significant peaks at one or more of 3.1 ± 0.2 degrees 2θ, 9.3 ± 0.2 degrees 2θ, and 20.8 ± 0.2 degrees 2θ, and does not have significant peaks at one or more of 6.8 ± 0.2 degrees 2θ, 15.7 ± 0.2 degrees 2θ, and 21.9 ± 0.2 degrees 2θ, and does not have significant peaks at one or more of 13.4 ± 0.2 degrees 2θ, 15.5 ± 0.2 degrees 2θ, and 21.7 ± 0.2 degrees 2θ.

[0451] In one embodiment, the free base anhydrous form D has an X-ray powder diffraction pattern characterized by peaks at 4.0 ± 0.2 degrees 2θ, 8.0 ± 0.2 degrees 2θ, 9.7 ± 0.2 degrees 2θ, 14.2 ± 0.2 degrees 2θ, 14.5 ± 0.2 degrees 2θ, 19.0 ± 0.2 degrees 2θ, and 20.3 ± 0.2 degrees 2θ when measured at about 25 °C using monochromatic Kα1 radiation, and does not have a significant peak at one or more of 3.1 ± 0.2 degrees 2θ, 9.3 ± 0.2 degrees 2θ, and 20.8 ± 0.2 degrees 2θ.

[0452] In one embodiment, the free base anhydrous form D has an X-ray powder diffraction pattern characterized by peaks at 4.0 ± 0.2 degrees 2θ, 8.0 ± 0.2 degrees 2θ, 9.7 ± 0.2 degrees 2θ, 14.2 ± 0.2 degrees 2θ, 14.5 ± 0.2 degrees 2θ, 19.0 ± 0.2 degrees 2θ, and 20.3 ± 0.2 degrees 2θ when measured at about 25 °C using monochromatic Kα1 radiation, and does not have a significant peak at one or more of 6.8 ± 0.2 degrees 2θ, 15.7 ± 0.2 degrees 2θ, and 21.9 ± 0.2 degrees 2θ.

[0453] In one embodiment, the free base anhydrous form D has an X-ray powder diffraction pattern characterized by peaks at 4.0 ± 0.2 degrees 2θ, 8.0 ± 0.2 degrees 2θ, 9.7 ± 0.2 degrees 2θ, 14.2 ± 0.2 degrees 2θ, 14.5 ± 0.2 degrees 2θ, 19.0 ± 0.2 degrees 2θ, and 20.3 ± 0.2 degrees 2θ when measured at about 25 °C using monochromatic Kα1 radiation, and does not have a significant peak at one or more of 13.4 ± 0.2 degrees 2θ, 15.5 ± 0.2 degrees 2θ, and 21.7 ± 0.2 degrees 2θ.

[0454] In one embodiment, the free base anhydrous form D has an X-ray powder diffraction pattern characterized by peaks at 4.0 ± 0.2 degrees 2θ, 8.0 ± 0.2 degrees 2θ, 9.7 ± 0.2 degrees 2θ, 14.2 ± 0.2 degrees 2θ, 14.5 ± 0.2 degrees 2θ, 19.0 ± 0.2 degrees 2θ, and 20.3 ± 0.2 degrees 2θ when measured at about 25 °C using monochromatic Kα1 radiation, and does not have a significant peak at one or more of 3.1 ± 0.2 degrees 2θ, 9.3 ± 0.2 degrees 2θ, and 20.8 ± 0.2 degrees 2θ, and does not have a significant peak at one or more of 6.8 ± 0.2 degrees 2θ, 15.7 ± 0.2 degrees 2θ, and 21.9 ± 0.2 degrees 2θ, and does not have a significant peak at one or more of 13.4 ± 0.2 degrees 2θ, 15.5 ± 0.2 degrees 2θ, and 21.7 ± 0.2 degrees 2θ.

[0455] In one embodiment, the free base anhydrous Form D has an X-ray powder diffraction pattern characterized by peaks at positions ±0.2 degrees 2θ substantially as listed in Table 16-J when measured using monochromatic Kα1 radiation at about 25°C.

[0456] In one embodiment, the free base anhydrous Form D has an X-ray powder diffraction pattern characterized by peaks at positions ±0.2 degrees 2θ substantially as listed in Table 16-J when measured using monochromatic Kα1 radiation at about 25°C, with a relative intensity of at least 10.0%.

[0457] In a further aspect of each of the above embodiments, the prominent peaks have a variation of ±0.1 degree 2θ rather than ±0.2 degrees 2θ. In yet a further aspect of each of the above embodiments, the prominent peaks have a variation of ±0.05 degree 2θ rather than ±0.2 degrees 2θ.

[0458] In one embodiment, when measured using monochromatic Kα1 radiation at about 25°C, the free base anhydrous Form D has an X-ray powder diffraction pattern substantially as Figure 3J shown therein.

[0459] In one embodiment, the free base anhydrous Form D has a thermogravimetric analysis plot which, when heated at a rate of 10°C per minute, shows a weight loss of about 0.5% to about 0.8% between about 43°C and 188°C.

[0460] In one embodiment, the free base anhydrous Form D has a thermogravimetric analysis plot which, when heated at a rate of 10°C per minute, shows a weight loss of about 0.5% to about 0.8% between about 41.36°C and 190.48°C.

[0461] In one embodiment, the free base anhydrous Form D has a thermogravimetric analysis plot which, when heated at a rate of 10°C per minute, shows a weight loss of about 0.45% to about 0.55% between about 43°C and 100°C.

[0462] In one embodiment, the free base anhydrous Form D has a thermogravimetric analysis plot which, when heated at a rate of 10°C per minute, shows a weight loss of about 0.5% between about 43°C and 100°C.

[0463] In one embodiment, the free base anhydrous Form D has a thermogravimetric analysis plot substantially as Fig. 4I shown therein.

[0464] In one embodiment, the free base anhydrous Form D has a differential scanning calorimetry plot which, when heated at a rate of 10°C per minute, contains an endothermic peak between about 180°C and about 220°C.

[0465] In one embodiment, the free base anhydrous form D has a differential scanning calorimetry (DSC) thermogram that, when heated at a rate of 10 °C / minute, has an endothermic peak between approximately 199.55 °C and approximately 217.41 °C.

[0466] In one embodiment, the free base anhydrous form D has a differential scanning calorimetry (DSC) thermogram with an endothermic peak having an onset melting point of approximately 199.55 °C and a melting enthalpy of approximately 85.4 J / g.

[0467] In one embodiment, the free base anhydrous form D has a differential scanning calorimetry (DSC) thermogram substantially as Figure 5E shown therein.

[0468] In one embodiment, the free base anhydrous form D has a moisture sorption isotherm that shows a weight gain of approximately 1.6% to approximately 2.0% when the relative humidity is increased from approximately 0% relative humidity to approximately 90% relative humidity at a temperature of 25 °C.

[0469] In one embodiment, the free base anhydrous form D has a moisture sorption isotherm substantially as Fig.6D shown therein.

[0470] In one embodiment, the free base anhydrous form D has a thermogravimetric analysis (TGA) thermogram that shows a weight loss of approximately 0.5% to approximately 0.8% between approximately 43 °C and 188 °C when heated at a rate of 10 °C / minute; and a differential scanning calorimetry (DSC) thermogram that has an endothermic peak between approximately 180 °C and approximately 220 °C when heated at a rate of 10 °C / minute.

[0471] In one embodiment, the free base anhydrous form D has a thermogravimetric analysis (TGA) thermogram that shows a weight loss of approximately 0.5% to approximately 0.8% between approximately 43 °C and 188 °C when heated at a rate of 10 °C / minute; and a moisture sorption isotherm that shows a weight gain of approximately 1.6% to approximately 2.0% when the relative humidity is increased from approximately 0% relative humidity to approximately 90% relative humidity at a temperature of 25 °C.

[0472] In one embodiment, the free base anhydrous form D has a differential scanning calorimetry (DSC) thermogram that has an endothermic peak between approximately 180 °C and approximately 220 °C when heated at a rate of 10 °C / minute; and a moisture sorption isotherm that shows a weight gain of approximately 1.6% to approximately 2.0% when the relative humidity is increased from approximately 0% relative humidity to approximately 90% relative humidity at a temperature of 25 °C.

[0473] In one embodiment, the free base anhydrous Form D has a thermogravimetric analysis (TGA) plot that shows 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 per minute; a differential scanning calorimetry (DSC) plot that contains an endothermic peak between about 180 °C and about 220 °C when heated at a rate of 10 °C per minute; and a water adsorption isotherm plot that shows 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.

[0474] In one embodiment, the free base anhydrous Form D has a thermogravimetric analysis (TGA) plot that shows 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 per minute; a differential scanning calorimetry (DSC) plot that contains an endothermic peak between about 199.55 °C and about 217.41 °C when heated at a rate of 10 °C per minute; and a water adsorption isotherm plot that shows 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.

[0475] In one embodiment, the free base anhydrous Form D has an orthorhombic lattice type.

[0476] In one embodiment, the free base anhydrous Form D has a P21212 space group.

[0477] In one embodiment, the unit cell a, b, and c values of the free base anhydrous Form D are approximately about and about

[0478] In one embodiment, the free base anhydrous Form D has an X-ray diffraction pattern as described above and at least one of the following: (a) a thermogravimetric analysis (TGA) plot that shows 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 per minute; (b) a differential scanning calorimetry (DSC) plot that contains an endothermic peak between about 180 °C and about 220 °C when heated at a rate of 10 °C per minute; and / or (c) a water adsorption isotherm plot that shows 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.

[0479] In one embodiment, the free base anhydrous form D has the X-ray diffraction pattern and thermogravimetric analysis pattern as described above. When heated at a rate of 10 °C / minute, between about 43 °C and 188 °C, the thermogravimetric analysis pattern shows a weight loss of about 0.5% to about 0.8%.

[0480] In one embodiment, the free base anhydrous form D has the X-ray diffraction pattern and differential scanning calorimetry pattern as described above. When heated at a rate of 10 °C / minute, between about 180 °C and about 220 °C, the differential scanning calorimetry pattern contains an endothermic peak.

[0481] In one embodiment, the free base anhydrous form D has the X-ray diffraction pattern and moisture sorption isotherm pattern as described above. When the relative humidity is increased from about 0% relative humidity to about 90% relative humidity at a temperature of 25 °C, the moisture sorption isotherm pattern shows a weight increase of about 1.6% to about 2.0%.

[0482] In one embodiment, the free base anhydrous form D has the X-ray diffraction pattern as described above; a thermogravimetric analysis pattern that shows 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 / minute; and a differential scanning calorimetry pattern that contains an endothermic peak between about 180 °C and about 220 °C when heated at a rate of 10 °C / minute.

[0483] In one embodiment, the free base anhydrous form D has the X-ray diffraction pattern as described above; a thermogravimetric analysis pattern that shows 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 / minute; and a moisture sorption isotherm pattern that shows a weight increase 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.

[0484] In one embodiment, the free base anhydrous form D has the X-ray diffraction pattern as described above; a differential scanning calorimetry pattern that contains an endothermic peak between about 180 °C and about 220 °C when heated at a rate of 10 °C / minute; and a moisture sorption isotherm pattern that shows a weight increase 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.

[0485] In one embodiment, the free base anhydrous Form D has an X-ray diffraction pattern as described above; a thermogravimetric analysis pattern that shows 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 per minute; a differential scanning calorimetry pattern that includes an endothermic peak between about 180 °C and about 220 °C when heated at a rate of 10 °C per minute; and a moisture sorption isotherm pattern that shows 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.

[0486] The free base anhydrous Form D is reversibly hygroscopic (up to 1.8% water at 90% RH at 25 °C) and is metastable relative to the free base hydrate Form C under typical environmental conditions used during storage for downstream processing (e.g., above 2.4% RH at 23 °C). Since the free base anhydrous Form D can only be produced in the presence of low water content in the crystallization solvent (e.g., less than 0.15% at 23 °C, corresponding to a water activity of 2.4%) and converts to the free base hydrate Form C in solutions with high water content, strict control of water is required for the production of the free base anhydrous Form D. The free base anhydrous Form D crystallizes slowly and is difficult to produce in higher yields. E. Crystalline tartrate

[0487] In another embodiment, the solid form is the tartrate salt of Compound 1. In one aspect, the tartrate salt is amorphous. In another aspect, the tartrate salt is crystalline. In another aspect, the crystalline tartrate salt is a solvate. In another aspect, the crystalline tartrate salt is a hydrate. In another aspect, the tartrate salt is the crystalline L-tartrate. In another aspect, the crystalline L-tartrate is a hydrate. In another aspect, the crystalline tartrate salt is the tetrahydrate ("tartrate hydrate"). The tartrate hydrate (tetrahydrate) is further described in the examples of this application.

[0488] In one embodiment, the tartrate hydrate has an X-ray powder diffraction pattern characterized by peaks at 3.9 ± 0.2 degrees 2θ, 6.8 ± 0.2 degrees 2θ, and 14.1 ± 0.2 degrees 2θ when measured using monochromatic Kα1 radiation at about 25 °C.

[0489] In one embodiment, the tartrate hydrate has an X-ray powder diffraction pattern characterized by peaks at 3.9 ± 0.2 degrees 2θ, 6.8 ± 0.2 degrees 2θ, 14.1 ± 0.2 degrees 2θ, 15.7 ± 0.2 degrees 2θ, 21.9 ± 0.2 degrees 2θ, and 25.9 ± 0.2 degrees 2θ when measured using monochromatic Kα1 radiation at about 25 °C.

[0490] In one embodiment, the tartrate hydrate has an X-ray powder diffraction pattern that, when measured using monochromatic Kα1 radiation at about 25 °C, does not have a significant peak at one or more of 13.4 ± 0.2 degrees 2θ and 15.1 ± 0.2 degrees 2θ.

[0491] In one embodiment, the tartrate hydrate has an X-ray powder diffraction pattern that, when measured using monochromatic Kα1 radiation at about 25 °C, does not have a significant peak at one or more of 3.1 ± 0.2 degrees 2θ, 9.3 ± 0.2 degrees 2θ, and 12.0 ± 0.2 degrees 2θ.

[0492] In one embodiment, the tartrate hydrate has an X-ray powder diffraction pattern that, when measured using monochromatic Kα1 radiation at about 25 °C, does not have a significant peak at one or more of 13.4 ± 0.2 degrees 2θ and 15.1 ± 0.2 degrees 2θ, and does not have a significant peak at one or more of 3.1 ± 0.2 degrees 2θ and 9.3 ± 0.2 degrees 2θ.

[0493] In one embodiment, the tartrate hydrate has an X-ray powder diffraction pattern characterized by peaks at 3.9 ± 0.2 degrees 2θ, 6.8 ± 0.2 degrees 2θ, and 14.1 ± 0.2 degrees 2θ when measured using monochromatic Kα1 radiation at about 25 °C, and does not have a significant peak at one or more of 13.4 ± 0.2 degrees 2θ and 15.1 ± 0.2 degrees 2θ.

[0494] In one embodiment, the tartrate hydrate has an X-ray powder diffraction pattern characterized by peaks at 3.9 ± 0.2 degrees 2θ, 6.8 ± 0.2 degrees 2θ, and 14.1 ± 0.2 degrees 2θ when measured using monochromatic Kα1 radiation at about 25 °C, and does not have a significant peak at one or more of 3.1 ± 0.2 degrees 2θ, 9.3 ± 0.2 degrees 2θ, and 12.0 ± 0.2 degrees 2θ.

[0495] In one embodiment, the tartrate hydrate has an X-ray powder diffraction pattern characterized by peaks at 3.9 ± 0.2 degrees 2θ, 6.8 ± 0.2 degrees 2θ, and 14.1 ± 0.2 degrees 2θ when measured using monochromatic Kα1 radiation at about 25 °C, and does not have a significant peak at one or more of 13.4 ± 0.2 degrees 2θ and 15.1 ± 0.2 degrees 2θ, and does not have a significant peak at one or more of 3.1 ± 0.2 degrees 2θ, 9.3 ± 0.2 degrees 2θ, and 12.0 ± 0.2 degrees 2θ.

[0496] In one embodiment, the tartrate hydrate has an X-ray powder diffraction pattern characterized by peaks at 3.9 ± 0.2 degrees 2θ, 6.8 ± 0.2 degrees 2θ, 14.1 ± 0.2 degrees 2θ, 15.7 ± 0.2 degrees 2θ, 21.9 ± 0.2 degrees 2θ when measured using monochromatic Kα1 radiation at about 25 °C, and does not have a significant peak at one or more of 13.4 ± 0.2 degrees 2θ and 15.1 ± 0.2 degrees 2θ.

[0497] In one embodiment, the tartrate hydrate has an X-ray powder diffraction pattern characterized by peaks at 3.9 ± 0.2 degrees 2θ, 6.8 ± 0.2 degrees 2θ, 14.1 ± 0.2 degrees 2θ, 15.7 ± 0.2 degrees 2θ, 21.9 ± 0.2 degrees 2θ, and does not have a significant peak at one or more of 3.1 ± 0.2 degrees 2θ, 9.3 ± 0.2 degrees 2θ, and 12.0 ± 0.2 degrees 2θ.

[0498] In one embodiment, the tartrate hydrate has an X-ray powder diffraction pattern characterized by peaks at 3.9 ± 0.2 degrees 2θ, 6.8 ± 0.2 degrees 2θ, 14.1 ± 0.2 degrees 2θ, 15.7 ± 0.2 degrees 2θ, 21.9 ± 0.2 degrees 2θ, and does not have a significant peak at one or more of 13.4 ± 0.2 degrees 2θ and 15.1 ± 0.2 degrees 2θ, and does not have a significant peak at one or more of 3.1 ± 0.2 degrees 2θ, 9.3 ± 0.2 degrees 2θ, and 12.0 ± 0.2 degrees 2θ.

[0499] In a further aspect of each of the above embodiments, the significant peaks have a variation of ±0.1 degree 2θ rather than ±0.2 degree 2θ. In yet a further aspect of each of the above embodiments, the significant peaks have a variation of ±0.05 degree 2θ rather than ±0.2 degree 2θ.

[0500] In one embodiment, when measured using monochromatic Kα1 radiation at about 25 °C, the tartrate hydrate has substantially the Figure 3D X-ray powder diffraction pattern as shown in

[0501] In one embodiment, the tartrate hydrate has a thermogravimetric analysis profile that shows 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 / minute.

[0502] In one embodiment, the tartrate hydrate has a thermogravimetric analysis profile that shows 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 / minute.

[0503] In one embodiment, the tartrate hydrate has substantially the Figure 4F The thermogravimetric analysis chart shown in

[0504] In one embodiment, the tartrate hydrate has a differential scanning calorimetry chart that, when heated at a rate of 10 °C / minute, between approximately 60 °C and approximately 100 °C, the differential scanning calorimetry chart includes an endothermic peak.

[0505] In one embodiment, the tartrate hydrate has a differential scanning calorimetry chart that, when heated at a rate of 10 °C / minute, between approximately 75.74 °C and approximately 110.26 °C, the differential scanning calorimetry chart includes an endothermic peak.

[0506] In one embodiment, the tartrate hydrate has substantially as Figure 5D the differential scanning calorimetry chart shown in

[0507] In one embodiment, the tartrate hydrate has a thermogravimetric analysis chart that, when heated at a rate of 10 °C / minute, between approximately 25 °C and 160 °C, the thermogravimetric analysis chart shows a weight loss of approximately 11.8% to approximately 12.2%; and a differential scanning calorimetry chart that, when heated at a rate of 10 °C / minute, between approximately 60 °C and approximately 100 °C, the differential scanning calorimetry chart includes an endothermic peak.

[0508] In one embodiment, the tartrate hydrate has a moisture adsorption isotherm chart that, when the relative humidity increases from approximately 10% relative humidity to approximately 90% relative humidity at a temperature of 25 °C, the moisture adsorption isotherm chart shows a weight increase of approximately 1% to approximately 2%.

[0509] In one embodiment, the tartrate hydrate has substantially as Figure 6C the moisture adsorption isotherm chart shown in

[0510] In one embodiment, the tartrate hydrate has a thermogravimetric analysis chart that, when heated at a rate of 10 °C / minute, between approximately 25 °C and 160 °C, the thermogravimetric analysis chart shows a weight loss of approximately 11.8% to approximately 12.2%; a differential scanning calorimetry chart that, when heated at a rate of 10 °C / minute, between approximately 60 °C and approximately 100 °C, the differential scanning calorimetry chart includes an endothermic peak; and a moisture adsorption isotherm chart that, when the relative humidity increases from approximately 10% relative humidity to approximately 90% relative humidity at a temperature of 25 °C, the moisture adsorption isotherm chart shows a weight increase of approximately 1% to approximately 2%.

[0511] In one embodiment, the tartrate hydrate has an X-ray diffraction pattern as described above and at least one of the following: (a) a thermogravimetric analysis pattern that shows 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 per minute; (b) a differential scanning calorimetry pattern that contains an endothermic peak between about 60°C and about 100°C when heated at a rate of 10°C per minute; and / or (c) a moisture adsorption isotherm pattern that shows 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.

[0512] In one embodiment, the tartrate hydrate has an X-ray diffraction pattern as described above and a thermogravimetric analysis pattern that shows 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 per minute.

[0513] In one embodiment, the tartrate hydrate has an X-ray diffraction pattern as described above and a differential scanning calorimetry pattern that contains an endothermic peak between about 60°C and about 100°C when heated at a rate of 10°C per minute.

[0514] In one embodiment, the tartrate hydrate has an X-ray diffraction pattern as described above and a moisture adsorption isotherm pattern that shows 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.

[0515] In one embodiment, the tartrate hydrate has an X-ray diffraction pattern as described above; a thermogravimetric analysis pattern that shows 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 per minute; and a differential scanning calorimetry pattern that contains an endothermic peak between about 60°C and about 100°C when heated at a rate of 10°C per minute.

[0516] In one embodiment, the tartrate hydrate has an X-ray diffraction pattern as described above; a thermogravimetric analysis pattern that shows 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 per minute; and a moisture adsorption isotherm pattern that shows 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.

[0517] In one embodiment, the tartrate hydrate has an X-ray diffraction pattern as described above; a differential scanning calorimetry (DSC) thermogram that, when heated at a rate of 10 °C / minute, between about 60 °C and about 100 °C, contains endothermic peaks; and a water adsorption isotherm that, when the relative humidity is increased from about 10% relative humidity to about 90% relative humidity at a temperature of 25 °C, shows a weight gain of about 1% to about 2%.

[0518] In one embodiment, the tartrate hydrate has an X-ray diffraction pattern as described above; a thermogravimetric analysis (TGA) thermogram that, when heated at a rate of 10 °C / minute, between about 25 °C and 160 °C, shows a weight loss of about 11.8% to about 12.2%; a differential scanning calorimetry (DSC) thermogram that, when heated at a rate of 10 °C / minute, between about 60 °C and about 100 °C, contains endothermic peaks; and a water adsorption isotherm that, when the relative humidity is increased from about 10% relative humidity to about 90% relative humidity at a temperature of 25 °C, shows a weight gain of about 1% to about 2%.

[0519] The tartrate hydrate has acceptable chemical stability and shows acceptable stability to light and peroxides. For example, when the 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 degradation of the tartrate hydrate was observed in the sealed vials under any of these conditions. The tartrate hydrate has good solubility (BCS class I) and is non-hygroscopic. However, the tartrate hydrate, when heated, or when compressed or under shear, potentially converts to an amorphous tartrate at a relative humidity below 10%.

[0520] The tartrate hydrate can be produced, for example, using anti-solvent crystallization. Impurity rejection during large-scale production of the tartrate hydrate is generally good, but fouling can be greater than expected and may require specific anti-solvent addition control and process volume limitations. Additionally, appropriate control of the filtration, washing, and drying steps may be required to minimize consolidation of the wet cake and formation of hard lumps in the separated material. For example, during drying, it may be necessary to control the relative humidity (e.g., a relative humidity greater than 10% and less than 100%), temperature (e.g., good crystallization at about 10 °C), and mixing rate to minimize the formation of hard lumps in the separated material. Inadequate control of the drying conditions will potentially result in consolidated, harder material that is difficult to break down during subsequent processing. As previously mentioned, shear and compression will potentially lead to conversion to the amorphous tartrate. The dried material is typically milled using mechanical impact mills (e.g., Fitzmills and pin mills) because shear-based mills (e.g., co-mills) will cause loss of crystallinity. Additionally, pressure or compressive force during formulation (e.g., required for tableting) can potentially cause loss of crystallinity. F. Crystalline hydrochloride

[0521] In another embodiment, the solid form is the crystalline hydrochloride salt of Compound 1. In one aspect, the crystalline hydrochloride salt corresponds to the crystalline hydrochloride salt solvate form AA. In another aspect, the crystalline hydrochloride salt corresponds to the crystalline hydrochloride salt solvate form BB. In yet another aspect, the crystalline hydrochloride salt corresponds to the crystalline hydrochloride salt solvate form CC. The hydrochloride salt solvate forms AA, BB, and CC are further described in the examples of this application.

[0522] The hydrochloride salt solvate forms AA, BB, and CC appear to be solvates and generally convert to the amorphous hydrochloride salt upon ambient drying. The resulting amorphous hydrochloride salt is hygroscopic. The yield of each crystalline hydrochloride salt obtained is generally in the range of 10% to 15%. G. Crystalline L-maleate

[0523] In another embodiment, the solid form is the crystalline L-malate salt of Compound 1. In one aspect, the crystalline L-malate corresponds to the crystalline L-malate form AAA. In another aspect, the crystalline L-malate corresponds to the crystalline L-malate form BBB. The L-malate forms AAA and BBB are further described in the examples of this application.

[0524] Since L-maleic acid will react with Compound 1, L-maleate form AAA and L-maleate form BBB are generally chemically less stable than the amorphous free base, free base hydrate form C, and tartrate hydrate, and do not exhibit pharmaceutically acceptable stability as an active ingredient in a pharmaceutical dosage form. H. Crystal purity

[0525] In further embodiments of the solid forms discussed above, the solid form has pharmaceutically acceptable crystalline purity (or pharmaceutically acceptable amorphous purity in the case of the amorphous free base). For example, in one aspect, Compound 1 comprises at least about 75% by weight of the desired solid form. In another aspect, at least 80% by weight is the desired solid form. In another aspect, at least 85% by weight is the desired solid form. In another aspect, at least 90% by weight is the desired solid form. In another aspect, at least 95% by weight is the desired solid form. In another aspect, at least 96% by weight is the desired solid form. In another aspect, at least 97% by weight is the desired solid form. In another aspect, at least 98% by weight is the desired solid form. In another aspect, at least 99% by weight is the desired solid form. In another aspect, Compound 1 exists as a substantially crystalline pure (or amorphous pure in the case of the amorphous free base) solid form. In a preferred aspect, the solid form is the amorphous free base. In another aspect, the solid form is free base anhydrate form D. In a more preferred aspect, the solid form is free base hydrate form B. In a particularly preferred aspect, the solid form is free base hydrate form C. In a preferred aspect, the solid form is tartrate hydrate. IV. Treatment

[0526] This disclosure relates to methods of treating a disorder in a subject, particularly a human subject suffering from or susceptible to a JAK-related disorder, 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 in this disclosure. Another aspect of this disclosure relates to Compound 1 free base or a pharmaceutically acceptable salt thereof or one or more solid forms of Compound 1 as described in this disclosure for treating a disorder in a subject, particularly a human subject suffering from or susceptible to a JAK-related disorder, the use 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 aspect, the disorder is a JAK-1 related disorder. 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 hydrate. In another aspect, the solid form is free base anhydrate Form D.

[0527] In one embodiment, this disclosure relates to methods of treating a disorder selected from the group consisting of immunomodulatory, inflammatory, and proliferative diseases (such as cancer) in a subject, the method comprising administering to the subject, particularly a subject suffering from or susceptible to the disorder, a therapeutically effective amount of Compound 1 free base or a pharmaceutically acceptable salt thereof or a solid form of Compound 1. Another aspect of this disclosure relates to Compound 1 free base or a pharmaceutically acceptable salt thereof or a solid form of Compound 1 for treating a disorder selected from the group consisting of immunomodulatory, inflammatory, and proliferative diseases (such as cancer) in a subject, particularly a human subject suffering from or susceptible to a disorder selected from the group consisting of immunomodulatory, inflammatory, and proliferative diseases (such as cancer), the use 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 anhydrate 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 aspect, the solid form is tartrate hydrate.

[0528] In one embodiment, the present disclosure relates to a method of treating a disorder selected from the group consisting 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, peripheral neuropathy, uveitis, fibrosing alveolitis, type I diabetes, juvenile diabetes, juvenile arthritis, Castleman disease, neutropenia, endometriosis, autoimmune thyroid disease, sperm and testicular autoimmunity, scleroderma, axonal and neuronal neuropathy, allergic rhinitis, Sjogren's syndrome, hemolytic anemia, Graves' disease, Hashimoto's thyroiditis, IgA nephropathy, amyloidosis, ankylosing spondylitis, Behcet's disease, sarcoidosis, vesicular dermatosis, myositis, primary biliary cirrhosis, polymyalgia rheumatica, autoimmune immunodeficiency, Chagas disease, Kawasaki syndrome, psoriatic arthritis, celiac disease, myasthenia gravis, autoimmune myocarditis, POEMS syndrome, and chronic fatigue syndrome in a subject, particularly a subject suffering from or susceptible to said disorder, wherein the method comprises 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 present disclosure relates to the free base of Compound 1 or a pharmaceutically acceptable salt thereof or a solid form of Compound 1 for treating a disorder selected from the group consisting 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, peripheral neuropathy, uveitis, fibrosing alveolitis, type I diabetes, juvenile diabetes, juvenile arthritis, Castleman disease, neutropenia, endometriosis, autoimmune thyroid disease, sperm and testicular autoimmunity, scleroderma, axonal and neuronal neuropathy, allergic rhinitis, Sjogren's syndrome, hemolytic anemia, Graves' disease, Hashimoto's thyroiditis, IgA nephropathy, amyloidosis, ankylosing spondylitis, Behcet's disease, sarcoidosis, vesicular dermatosis, myositis, primary biliary cirrhosis, polymyalgia rheumatica, autoimmune immunodeficiency, Chagas disease, Kawasaki syndrome, psoriatic arthritis, celiac disease, myasthenia gravis, autoimmune myocarditis, POEMS syndrome, and chronic fatigue syndrome in a subject, particularly a human subject suffering from or predisposed to a disorder selected from the group consisting of the foregoing, the use comprising administering to the subject a therapeutically effective amount of the free base of Compound 1 or a pharmaceutically acceptable salt thereof or a solid form of Compound 1. In one aspect, the solid form is the amorphous free base. In another aspect, the solid form is the free base hydrate Form B. In another aspect, the solid form is the free base hydrate Form C. In another aspect, the solid form is the tartrate hydrate. In another aspect, the solid form is the free base anhydrate Form D.

[0529] In one embodiment, the present disclosure relates to a method of treating a disorder 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 in a subject, especially a subject suffering from or susceptible to said disorder, wherein the method comprises 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 present disclosure relates to the use of Compound 1 free base or a pharmaceutically acceptable salt thereof or a solid form of Compound 1 for treating a disorder 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 in a subject, especially a human subject suffering from or susceptible to a disorder selected from the group, wherein the use comprises 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 hydrate Form B. In another aspect, the solid form is free base hydrate Form C. In another aspect, the solid form is tartrate hydrate. In another aspect, the solid form is free base anhydrate Form D.

[0530] In one embodiment, the present disclosure relates to a method for treating a disorder selected from the group consisting of: ocular disorders, systemic inflammatory response syndrome, juvenile rheumatoid arthritis, systemic-onset juvenile rheumatoid arthritis, type III hypersensitivity, type IV hypersensitivity, aortic inflammation, iritis / uveitis / optic neuritis, juvenile spinal muscular atrophy, diabetic retinopathy or microangiopathy, chronic inflammation, ulcerative colitis, inflammatory bowel disease, allergic diseases, scleroderma, acute or chronic immune diseases associated with organ transplantation, psoriatic arthropathy, ulcerative colonic 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( syndrome / disease)-associated lung disease, ankylosing spondylitis and ankylosing spondylitis-associated lung disease, autoimmune hepatitis, type 1 autoimmune hepatitis (classic autoimmune or lupoid hepatitis), type 2 autoimmune hepatitis (anti-LKM antibody hepatitis), autoimmune-mediated hypoglycemia, psoriasis vulgaris type 1, psoriasis vulgaris type 2, plaque psoriasis, moderate to severe chronic plaque psoriasis, autoimmune neutropenia, sperm autoimmunity, multiple sclerosis (all subtypes), acute rheumatic fever, rheumatoid spondylitis, Sjogren's syndrome( syndrome) and autoimmune thrombocytopenia, wherein the method comprises administering to the subject (especially a subject suffering from or susceptible to said disorder) 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 present disclosure relates to compound 1 free base or a pharmaceutically acceptable salt thereof or a solid form of compound 1 for treating a disorder selected from the group consisting of: ocular disorders, systemic inflammatory response syndrome, juvenile rheumatoid arthritis, systemic-onset juvenile rheumatoid arthritis, type III hypersensitivity, type IV hypersensitivity, aortic inflammation, iritis / uveitis / optic neuritis, juvenile spinal muscular atrophy, diabetic retinopathy or microangiopathy, chronic inflammation, ulcerative colitis, inflammatory bowel disease, allergic diseases, scleroderma, acute or chronic immune diseases associated with organ transplantation, psoriatic arthropathy, ulcerative colonic 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( syndrome / disease)-related lung diseases, ankylosing spondylitis and ankylosing spondylitis-related lung diseases, autoimmune hepatitis, type 1 autoimmune hepatitis (classical autoimmune or lupoid hepatitis), type 2 autoimmune hepatitis (anti-LKM antibody hepatitis), autoimmunity-mediated hypoglycemia, psoriasis vulgaris type 1, psoriasis vulgaris type 2, plaque psoriasis, moderate to severe chronic plaque psoriasis, autoimmune neutropenia, sperm autoimmunity, multiple sclerosis (all subtypes), acute rheumatic fever, rheumatoid spondylitis, Sjogren's syndrome( 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 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 hydrate. In another aspect, the solid form is free base anhydrate Form D.

[0531] In one embodiment, the present disclosure relates to a method of treating a disorder 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 aspect, the present disclosure relates to Compound 1 free base or a pharmaceutically acceptable salt thereof or a solid form of Compound 1 for treating the disorder in a subject (especially a human subject suffering from or susceptible to a disorder 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), the use comprising administering to the subject a therapeutically effective amount of Compound 1 free base 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 hydrate Form B. In another aspect, the solid form is free base hydrate Form C. In another aspect, the solid form is tartrate hydrate. In another aspect, the solid form is free base anhydrate Form D.

[0532] In one embodiment, the present disclosure relates to a method of treating a disorder 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, wherein the method comprises 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 present disclosure relates to Compound 1 free base or a pharmaceutically acceptable salt thereof or a solid form of Compound 1 for treating the disorder in a subject (especially a human subject suffering from or susceptible to a disorder 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), the use 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 an amorphous free base. In another aspect, the solid form is hydrate form B of the free base. In another aspect, the solid form is hydrate form C of the free base. In another aspect, the solid form is a tartrate hydrate. In another aspect, the solid form is anhydrous form D of the free base.

[0533] In one embodiment, the present disclosure relates to a method of treating arthritis 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 aspect, the present disclosure relates to Compound 1 free base or a pharmaceutically acceptable salt thereof or a solid form of Compound 1 for treating arthritis in a subject (especially a human subject suffering from or prone to arthritis), the use 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 aspect, the solid form is free base hydrate Form C. In another aspect, the solid form is tartrate hydrate. In another aspect, the solid form is free base anhydrate Form D. In another aspect, the solid form is free base solvate Form A. In another aspect, the solid form is hydrochloride solvate Form AA. In another aspect, the solid form is hydrochloride solvate Form BB. In another aspect, the solid form is hydrochloride solvate Form CC. In another aspect, the solid form is L-malate Form AAA. In another aspect, the solid form is L-malate Form BBB.

[0534] In one embodiment, the present disclosure relates to a method of treating spondyloarthropathy in a subject, wherein the method comprises 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 present disclosure relates to Compound 1 free base or a pharmaceutically acceptable salt thereof or a solid form of Compound 1, particularly for use in treating spondyloarthropathy in human subjects suffering from or prone to spondyloarthropathy, the use 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 spondyloarthropathy 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 hydrate. In another aspect, the solid form is free base anhydrate Form D. In another aspect, the solid form is free base solvate Form A. In another aspect, the solid form is hydrochloride solvate Form AA. In another aspect, the solid form is hydrochloride solvate Form BB. In another aspect, the solid form is hydrochloride solvate Form CC. In another aspect, the solid form is L-malate Form AAA. In another aspect, the solid form is L-malate Form BBB.

[0535] In one embodiment, the present disclosure relates to a method of treating gastrointestinal disorders in a subject, wherein the method comprises 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 present disclosure relates to Compound 1 free base or a pharmaceutically acceptable salt thereof or a solid form of Compound 1, particularly for use in treating gastrointestinal disorders in human subjects suffering from or prone to gastrointestinal disorders, the use 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 disorder is selected from Crohn's disease and ulcerative colitis. In another aspect, the gastrointestinal disease is Crohn's disease. In another aspect, the gastrointestinal disorder 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 hydrate. In another aspect, the solid form is free base anhydrate Form D. In another aspect, the solid form is free base solvate Form A. In another aspect, the solid form is hydrochloride solvate Form AA. In another aspect, the solid form is hydrochloride solvate Form BB. In another aspect, the solid form is hydrochloride solvate Form CC. In another aspect, the solid form is L-malate Form AAA. In another aspect, the solid form is L-malate Form BBB.

[0536] In one embodiment, the present disclosure relates to a method of treating a skin disorder, the method 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 present disclosure relates to Compound 1 free base or a pharmaceutically acceptable salt thereof or a solid form of Compound 1, particularly for use in treating a skin disorder in a human subject suffering from or prone to a skin disorder, the use 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 disorder is selected from the group consisting of: psoriasis, plaque psoriasis, nail psoriasis, and hidradenitis suppurativa. In another aspect, the skin disorder is psoriasis. In another aspect, the skin disorder is plaque psoriasis. In another aspect, the skin disorder is nail psoriasis. In another aspect, the skin disorder is hidradenitis suppurativa. In another aspect, the skin disorder is atopic dermatitis. 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 hydrate. In another aspect, the solid form is free base anhydrate Form D. In another aspect, the solid form is free base solvate Form A. In another aspect, the solid form is hydrochloride solvate Form AA. In another aspect, the solid form is hydrochloride solvate Form BB. In another aspect, the solid form is hydrochloride solvate Form CC. In another aspect, the solid form is L-malate Form AAA. In another aspect, the solid form is L-malate Form BBB.

[0537] The therapeutically effective dosage level for any particular subject will depend upon the circumstances and can depend on a variety of factors, including the type, age, weight, sex, diet, and disorder of the subject being treated; the severity of the pathological condition; the activity of the particular compound employed; the particular composition employed; the age, weight, general health, sex, and diet of the subject; the route of administration; the duration of the treatment; pharmacological considerations, such as the activity, efficacy, pharmacokinetic, and toxicological characteristics of the particular compound or salt being used; whether a drug delivery system is used; drugs used in combination with or concurrently with the particular compound employed; and other factors well known in the medical arts. One of ordinary skill in the art to which this application pertains will be able to determine the appropriate dosage and regimen for administering a therapeutic agent to a subject and will be able to adjust such dosage and regimen as needed during the course of treatment according to methods well known in the art of treatment. It is within the skill of the art to initiate a lower level of the compound dosage than that required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. Accordingly, the actual dosage regimen employed may vary widely and thus may be derived from the preferred dosage regimens set forth below.

[0538] The total daily dose of the solid form (administered as a single dose or divided doses) is typically from about 0.001 to about 100 mg / kg or from about 0.001 to about 30 mg / kg or from about 0.001 to about 15 mg / kg. In another embodiment, the total daily dose is from about 0.01 to about 10 mg / kg (i.e., mg of compound or salt / kg of body weight). The dosage unit composition may contain such amounts or a fraction thereof to constitute the daily dose. In many cases, administration of the compound or salt will be repeated multiple times. If desired, multiple daily doses may typically be used to increase the total daily dose.

[0539] 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 aspect, the daily dose is from about 0.1 mg to about 1000 mg. In another aspect, the daily dose is from about 1 mg to about 500 mg. In another aspect, the daily dose is from about 1 mg to about 250 mg. In another aspect, the daily dose is from about 1 mg to about 100 mg. In another aspect, the daily dose is from about 1 mg to about 50 mg. In another aspect, the daily dose is from about 1 mg to about 45 mg. In another aspect, the daily dose is from about 1 mg to about 30 mg. In another aspect, the daily dose is from about 1 mg to about 25 mg. In another aspect, the daily dose is from about 1 mg to about 24 mg. In another aspect, the daily dose is from about 1 mg to about 15 mg. In another aspect, the daily dose is from about 1 mg to about 7.5 mg. In another aspect, the daily dose is from about 25 mg to about 50 mg. In another aspect, the daily dose is from about 1 mg to about 10 mg. In another aspect, the daily dose is from about 10 mg to about 20 mg. In another aspect, the daily dose is from about 20 mg to about 30 mg. In another aspect, the daily dose is from about 30 mg to about 40 mg. In another aspect, the daily dose is from about 7.5 mg to about 45 mg. In another aspect, the daily dose is from about 15 mg to about 30 mg. In another aspect, the daily dose is about 3 mg. In another aspect, the daily dose is about 6 mg. In another aspect, the daily dose is about 7.5 mg. In another aspect, the daily dose is about 12 mg. In another aspect, the daily dose is about 15 mg. In another aspect, the daily dose is about 18 mg. In another aspect, the daily dose is about 24 mg. In another aspect, the daily dose is about 30 mg. In another aspect, the daily dose is about 36 mg. In another aspect, the daily dose is about 45 mg.

[0540] In one embodiment, a solid form of Compound 1 at a dose of about 3 mg, about 6 mg, about 12 mg, or about 24 mg per unit dosage form (e.g., per tablet or per capsule) is administered (orally, BID (twice daily)) in equal amounts (e.g., about 3 mg twice daily) to human subjects.

[0541] In one embodiment, the present disclosure relates to a method of treating a subject having rheumatoid arthritis, the method comprising administering (orally, BID (twice daily)) to the subject in equal amounts (e.g., about 3 mg twice daily) a solid form of Compound 1 at about 3 mg per unit dosage form (e.g., per tablet or per capsule). In another aspect, the present disclosure relates to a solid form of Compound 1 for treating rheumatoid arthritis in a subject (especially a human subject having or susceptible to rheumatoid arthritis), the use comprising administering (orally, BID (twice daily)) to the subject in equal amounts (e.g., about 3 mg twice daily) a solid form of Compound 1 at about 3 mg per unit dosage form (e.g., per tablet or per capsule).

[0542] In one embodiment, the present disclosure relates to a method of treating a subject having rheumatoid arthritis, the method comprising administering (orally, BID (twice daily)) to the subject in equal amounts (e.g., about 6 mg twice daily) a solid form of Compound 1 at about 6 mg per unit dosage form (e.g., per tablet or per capsule). In another aspect, the present disclosure relates to a solid form of Compound 1 for treating rheumatoid arthritis in a subject (especially a human subject having or susceptible to rheumatoid arthritis), the use comprising administering (orally, BID (twice daily)) to the subject in equal amounts (e.g., about 6 mg twice daily) a solid form of Compound 1 at about 6 mg per unit dosage form (e.g., per tablet or per capsule).

[0543] In one embodiment, the present disclosure relates to a method of treating a subject having rheumatoid arthritis, the method comprising administering (orally, BID (twice daily)) to the subject in equal amounts (e.g., about 12 mg twice daily) a solid form of Compound 1 at about 12 mg per unit dosage form (e.g., per tablet or per capsule). In another aspect, the present disclosure relates to a solid form of Compound 1 for treating rheumatoid arthritis in a subject (especially a human subject having or susceptible to rheumatoid arthritis), the use comprising administering (orally, BID (twice daily)) to the subject in equal amounts (e.g., about 12 mg twice daily) a solid form of Compound 1 at about 12 mg per unit dosage form (e.g., per tablet or per capsule).

[0544] In one embodiment, the present disclosure relates to a method of treating a subject having rheumatoid arthritis, the method comprising administering (orally, BID (twice daily)) to the subject a solid form of Compound 1 at an equivalent amount (e.g., about 24 mg twice daily), wherein each unit dosage form (e.g., each tablet or each capsule) contains about 24 mg of the solid form of Compound 1. In another aspect, the present disclosure relates to a solid form of Compound 1 for treating rheumatoid arthritis in a subject (especially a human subject having or susceptible to rheumatoid arthritis), the use comprising administering (orally, BID (twice daily)) to the subject a solid form of Compound 1 at an equivalent amount (e.g., about 24 mg twice daily), wherein each unit dosage form (e.g., each tablet or each capsule) contains about 24 mg of the solid form of Compound 1.

[0545] In another embodiment, these methods or uses comprise administering (orally, QD (once daily)) to a human subject a dose of about 7.5 mg of Compound 1 free base or a pharmaceutically acceptable salt thereof per unit dosage form (e.g., each tablet or each capsule).

[0546] In another embodiment, these methods or uses comprise administering (orally, QD (once daily)) to a human subject a dose of about 7.5 mg of a solid form of Compound 1 per unit dosage form (e.g., each tablet or each capsule). In one embodiment, these methods or uses comprise administering (orally, QD (once daily)) to a human subject 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., each tablet or each capsule). In one embodiment, the solid form is the amorphous free base. In one embodiment, the solid form is the free base hydrate form B. In one embodiment, the solid form is the free base hydrate form C. In one embodiment, the solid form is the tartrate hydrate. In another aspect, the solid form is the free base anhydrate form D.

[0547] In another embodiment, these methods or uses comprise administering (orally, QD (once daily)) to a human subject a dose of about 15 mg of Compound 1 free base or a pharmaceutically acceptable salt thereof per unit dosage form (e.g., each tablet or each capsule).

[0548] In another embodiment, these methods or uses include administering (orally, QD (once daily)) a dose of about 15 mg of a solid form of Compound 1 per unit dosage form (e.g., per tablet or per capsule) to a human subject. In one embodiment, these methods or uses include administering (orally, QD (once daily)) a solid form of Compound 1 to a human subject in an amount sufficient to deliver 15 mg of Compound 1 free base equivalent per unit dosage form (e.g., per tablet or per capsule) to the subject. 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 hydrate. In another aspect, the solid form is free base anhydrate Form D.

[0549] In another embodiment, these methods or uses include administering (orally, QD (once daily)) a dose of about 24 mg of Compound 1 free base or a pharmaceutically acceptable salt thereof to a human subject. The 24 mg QD dose of Compound 1 free base or a pharmaceutically acceptable salt thereof can be administered as a single dosage form containing about 24 mg of Compound 1 free base or a pharmaceutically acceptable salt thereof per unit dosage form (e.g., per tablet or per capsule), or as two dosage forms containing about 12 mg of Compound 1 free base or a pharmaceutically acceptable salt thereof per unit dosage form (e.g., per tablet or per capsule) administered simultaneously.

[0550] In another embodiment, these methods or uses include administering (orally, QD (once daily)) a dose of about 24 mg of a solid form of Compound 1 to a human subject. In one embodiment, these methods or uses include administering (orally, QD (once daily)) a solid form of Compound 1 to a human subject in an amount sufficient to deliver 24 mg of Compound 1 free base equivalent. The 24 mg QD dose of the solid form of Compound 1 can be administered as a single dosage form containing about 24 mg of the solid form of Compound 1 per unit dosage form (e.g., per tablet or per capsule), or as two dosage forms containing about 12 mg of the solid form of Compound 1 per unit dosage form (e.g., per tablet or per capsule) administered simultaneously. 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 hydrate. In another aspect, the solid form is free base anhydrate Form D.

[0551] In another embodiment, these methods or uses include administering (orally, QD (once daily)) to a human subject a dose of about 30 mg of Compound 1 free base or a pharmaceutically acceptable salt thereof per unit dosage form (e.g., per tablet or per capsule).

[0552] In another embodiment, these methods or uses include administering (orally, QD (once daily)) to a human subject a solid form of Compound 1 at a dose of about 30 mg per unit dosage form (e.g., per tablet or per capsule). In one embodiment, these methods or uses include administering (orally, QD (once daily)) to a human subject a solid form of Compound 1 in an amount sufficient to deliver 30 mg of Compound 1 free base equivalent per unit dosage form (e.g., per tablet or per capsule) to the subject. 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 hydrate. In another aspect, the solid form is free base anhydrate Form D.

[0553] In another embodiment, these methods or uses include administering (orally, QD (once daily)) to a human subject a dose of about 36 mg of Compound 1 free base or a pharmaceutically acceptable salt thereof per unit dosage form (e.g., per tablet or per capsule).

[0554] In another embodiment, these methods or uses include administering (orally, QD (once daily)) to a human subject a solid form of Compound 1 at a dose of about 36 mg per unit dosage form (e.g., per tablet or per capsule). In one embodiment, these methods or uses include administering (orally, QD (once daily)) to a human subject a solid form of Compound 1 in an amount sufficient to deliver 36 mg of Compound 1 free base equivalent per unit dosage form (e.g., per tablet or per capsule) to the subject. 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 hydrate. In another aspect, the solid form is free base anhydrate Form D.

[0555] In another embodiment, these methods or uses include administering (orally, QD (once daily)) to a human subject a dose of about 45 mg of Compound 1 free base or a pharmaceutically acceptable salt thereof per unit dosage form (e.g., per tablet or per capsule).

[0556] In another embodiment, the methods or uses include administering (orally, QD (once daily)) to a human subject a dose of about 45 mg of a solid form of Compound 1 per unit dosage form (e.g., per tablet or per capsule). In one embodiment, the methods or uses include administering (orally, QD (once daily)) to a human subject a solid form of Compound 1 in an amount sufficient to deliver 45 mg of Compound 1 free base equivalent per unit dosage form (e.g., per tablet or per capsule). In one embodiment, the solid form is the amorphous free base. In one embodiment, the solid form is the free base hydrate Form B. In one embodiment, the solid form is the free base hydrate Form C. In one embodiment, the solid form is the tartrate hydrate. In another aspect, the solid form is the free base anhydrate Form D.

[0557] In certain embodiments, Compound 1 free base or a pharmaceutically acceptable salt and / or a solid form thereof can be used to treat rheumatoid arthritis (RA), including alleviating the signs and symptoms of RA, inducing a major clinical response, inhibiting the progression of or treating the structural damage associated with RA, and improving the physical function of adult subjects (e.g., adult subjects with moderate to severe active RA). In one embodiment, Compound 1 free base or a pharmaceutically acceptable salt 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 and / or a solid form thereof is used to reduce the signs and symptoms of RA in an adult subject. In one embodiment, Compound 1 free base or a pharmaceutically acceptable salt 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 and / or a solid form thereof is used to inhibit the progression of the structural damage associated with RA in an adult subject. In one embodiment, Compound 1 free base and / or a solid form thereof is used to treat the structural damage associated with RA in an adult subject. In one embodiment, Compound 1 free base or a pharmaceutically acceptable salt and / or a solid form thereof is used to improve the physical function of an adult subject. In one embodiment, the adult subject has RA. In another embodiment, the adult subject has moderate to severe active RA.

[0558] Compound 1 free base or a pharmaceutically acceptable salt or a solid form thereof can be used alone or in combination with methotrexate or other non - biologic disease - modifying antirheumatic drugs (DMARDs), and / or with anti - TNFα biologic agents (e.g., TNF antagonists such as chimeric, humanized or human TNF antibodies, adalimumab (e.g., HUMIRA TM brand adalimumab), infliximab (e.g., CA2 (REMICADE TMBrand infliximab), golimumab (e.g., SIMPONI TM (golimumab)), certolizumab (e.g., CIMZIA TM ), tocilizumab (e.g., ACTEMRA TM ), CDP 571 and soluble p55 or p75 TNF receptor, its derivatives, etanercept (e.g., p75TNFR1gG (ENBREL TM Brand etanercept) or p55TNFR1gG (lenalidomide))) are used in combination.

[0559] Patients with active rheumatoid arthritis (RA) can be diagnosed according to the American College of Rheumatology (ACR) classification criteria revised in 1987 or the 2010 ACR / EULAR criteria. In certain embodiments, RA can be diagnosed based on a patient having at least 6 swollen joints and 6 tender joints. In certain embodiments, patients who can be treated with Compound 1 or its solid form can include those who have failed treatment with at least one (e.g., at least one but no more than four) DMARD and / or are insufficiently responsive to methotrexate, adalimumab, infliximab, etanercept or other anti-TNFα biologics or non-anti-TNF biologics.

[0560] In certain embodiments, Compound 1 free base or its pharmaceutically acceptable salt or its solid form prevents disease progression and / or alleviates disease symptoms that can be detected or monitored at least by X-ray results (including radiographic progression of joint damage).

[0561] In certain embodiments, in either an individual patient in need of treatment or a patient population, treatment efficacy can be measured by improvement in ACR20, ACR50 and / or ACR70. In certain embodiments, achieve a statistically significant improvement (compared to placebo or untreated control) during the treatment period in one or more ACR criteria (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 longer). Statistical significance is manifested as a p-value less than 0.05 or less than 0.01.

[0562] The components of ACR response are well known in the art and can include the median of tender joints, the median of swollen joints, physician's global assessment (e.g., assessment measured by visual analogue scale (VAS)), patient's global assessment (e.g., assessment measured by visual analogue scale), pain measured by visual analogue scale, health assessment questionnaire dysfunction index (HAQ-DI score) and C-reactive protein (CRP) (mg / dL).

[0563] In certain embodiments, an ACR20 response is determined based on a 20% or greater improvement in the tender joint count (TJC) and the swollen joint count (SJC), and a 20% or greater improvement in 3 or more of the 5 metrics of the patient's pain assessment (VAS), the patient's overall assessment of disease activity (VAS), the physician's overall assessment of disease activity (VAS), the HAQ-DI, or the high-sensitivity C-reactive protein (hsCRP). In some embodiments, an ACR50 response is determined based on a 50% or greater improvement in the TJC and the SJC, and a 50% or greater improvement in 3 or more of the 5 metrics of the patient's pain assessment (VAS), the patient's overall assessment of disease activity (VAS), the physician's overall assessment of disease activity (VAS), the HAQ-DI, or the hsCRP. An ACR70 response is determined based on a 70% or greater improvement in the TJC and the SJC, and a 70% or greater improvement in 3 or more of the 5 metrics of the patient's pain assessment (VAS), the patient's overall assessment of disease activity (VAS), the physician's overall assessment of disease activity (VAS), the HAQ-DI, or the hsCRP. In certain embodiments, an ACR20, ACR50, or ACR70 response occurs at week 12 of treatment.

[0564] In certain embodiments, the DAS28 (disease activity score based on 28 joints examined) score is determined as a composite score from four of the following measurements: examination of joint swelling and tenderness, overall scores of pain and general 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., HAQ (health assessment questionnaire) assessing function), and x-rays and other imaging techniques (e.g., ultrasound and MRI).

[0565] In certain embodiments, structural joint damage can be assessed radiographically and is expressed as, for example, a change in the total Sharp score (TSS) and its components, the erosion score, and the joint space narrowing (JSN) score at week 12 (compared to baseline) or at week 24 (compared to baseline).

[0566] In certain embodiments, improvements in the signs and symptoms of the disease can be measured by the patient's physical function response (e.g., the Health Assessment Questionnaire Disability Index (HAQ-DI) and / or health outcomes as assessed by the Short Form-36 Health Survey (SF 36)). In one embodiment, improvements in the signs and symptoms of the disease are measured by the HAQ-DI (including a minimal clinically important difference (MCID) of -0.22). Improvements can also be measured by one or both of the Physical Component Summary (PCS) and the Mental Component Summary (MCS). Improvements can be further measured by the Rheumatoid Arthritis Work Instability Scale (RA-WIS) (see Gilworth et al., Arthritis & Rheumatism (Arthritis Care & Research) 49(3):349-354, 2003, incorporated by reference).

[0567] In one embodiment, the present disclosure relates to a method of treating rheumatoid arthritis in a subject, the method comprising administering (orally, QD (once daily)) about 7.5 mg of free base of Compound 1 or a pharmaceutically acceptable salt thereof per unit dosage form (e.g., per tablet or per capsule) to the subject, particularly a human subject suffering from or susceptible to rheumatoid arthritis. In another aspect, the present disclosure relates to free base of Compound 1 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, the use comprising administering (orally, QD (once daily)) about 7.5 mg of free base of Compound 1 or a pharmaceutically acceptable salt thereof per unit dosage form (e.g., per tablet or per capsule) to the subject. In one embodiment, the subject has moderate to severe active rheumatoid arthritis. In one embodiment, the subject is an adult.

[0568] In one embodiment, the present disclosure relates to a method of treating rheumatoid arthritis in a subject, the method comprising administering (orally, QD (once daily)) a solid form of Compound 1 at about 7.5 mg per unit dosage form (e.g., per tablet or per capsule) to a subject, particularly a human subject suffering from or prone to rheumatoid arthritis. In one embodiment, the method comprises administering (orally, QD (once daily)) a solid form of Compound 1 to the subject in an amount sufficient to deliver 7.5 mg of Compound 1 free base equivalent per unit dosage form (e.g., per tablet or per capsule) to the subject. In another aspect, the present disclosure relates to a solid form of Compound 1 for treating rheumatoid arthritis in a subject, particularly a human subject suffering from or prone to rheumatoid arthritis, the use comprising administering (orally, QD (once daily)) a solid form of Compound 1 at about 7.5 mg per unit dosage form (e.g., per tablet or per capsule) to the subject. In one embodiment, the solid form delivers about 7.5 mg of Compound 1 free base equivalent per unit dosage form (e.g., per tablet or per capsule) to the 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 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 aspect, the solid form is free base solvate Form A. In another aspect, the solid form is hydrochloride solvate Form AA. In another aspect, the solid form is hydrochloride solvate Form BB. In another aspect, the solid form is hydrochloride solvate Form CC. In another aspect, the solid form is L-malate Form AAA. In another aspect, the solid form is L-malate Form BBB. In one embodiment, the subject is an adult.

[0569] In one embodiment, the present disclosure relates to a method of treating rheumatoid arthritis in a subject, the method comprising administering (orally, QD (once daily)) about 15 mg of Compound 1 free base or a pharmaceutically acceptable salt thereof per unit dosage form (e.g., per tablet or per capsule) to a subject, particularly a human subject suffering from or prone to rheumatoid arthritis. In another aspect, the present disclosure relates to Compound 1 free base or a pharmaceutically acceptable salt thereof for treating rheumatoid arthritis in a subject, particularly a human subject suffering from or prone to rheumatoid arthritis, the use comprising administering (orally, QD (once daily)) about 15 mg of Compound 1 free base or a pharmaceutically acceptable salt thereof per unit dosage form (e.g., per tablet or per capsule) to the subject. In one embodiment, the subject has moderate to severe active rheumatoid arthritis. In one embodiment, the subject is an adult.

[0570] In one embodiment, the present disclosure relates to a method for treating rheumatoid arthritis in a subject, the method comprising administering (orally, QD (once daily)) a solid form of Compound 1 at about 15 mg per unit dosage form (e.g., per tablet or per capsule) to a subject, particularly a human subject suffering from or susceptible to rheumatoid arthritis. In one embodiment, the method comprises administering (orally, QD (once daily)) a solid form of Compound 1 to the subject in an amount sufficient to deliver 15 mg of Compound 1 free base equivalent per unit dosage form (e.g., per tablet or per capsule) to the subject. In another aspect, the present disclosure relates to a solid form of Compound 1 for treating rheumatoid arthritis in a subject, particularly a human subject suffering from or susceptible to rheumatoid arthritis, the use comprising administering (orally, QD (once daily)) a solid form of Compound 1 at about 15 mg per unit dosage form (e.g., per tablet or per capsule) to the subject. In one embodiment, the solid form delivers about 15 mg of Compound 1 free base equivalent per unit dosage form (e.g., per tablet or per capsule) to the 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 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 aspect, the solid form is free base solvate Form A. In another aspect, the solid form is hydrochloride solvate Form AA. In another aspect, the solid form is hydrochloride solvate Form BB. In another aspect, the solid form is hydrochloride solvate Form CC. In another aspect, the solid form is L-malate Form AAA. In another aspect, the solid form is L-malate Form BBB. In one embodiment, the subject is an adult.

[0571] In one embodiment, the present disclosure relates to a method for treating rheumatoid arthritis in a subject, the method comprising administering (orally, QD (once daily)) about 24 mg of Compound 1 free base or a pharmaceutically acceptable salt thereof to a subject, particularly a human subject suffering from or susceptible to rheumatoid arthritis. In another aspect, the present 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, the use comprising administering (orally, QD (once daily)) about 24 mg of Compound 1 free base or a pharmaceutically acceptable salt thereof to the subject. The 24 mg dose of Compound 1 free base or a pharmaceutically acceptable salt thereof can be administered as a single dosage form comprising about 24 mg of Compound 1 free base or a pharmaceutically acceptable salt thereof per unit dosage form (e.g., per tablet or per capsule), or as two dosage forms comprising about 12 mg of Compound 1 free base or a pharmaceutically acceptable salt thereof per unit dosage form (e.g., per tablet or per capsule) administered simultaneously. In one embodiment, the subject has moderate to severe active rheumatoid arthritis. In one embodiment, the subject is an adult.

[0572] In one embodiment, the present disclosure relates to a method of treating rheumatoid arthritis in a subject, the method comprising administering (orally, QD (once daily)) a solid form of Compound 1 to the subject, particularly a human subject suffering from or susceptible to rheumatoid arthritis, in an amount of about 24 mg. In one embodiment, the method comprises administering (orally, QD (once daily)) a solid form of Compound 1 to the subject in an amount sufficient to deliver 24 mg of Compound 1 free base equivalent to the subject. In another aspect, the present 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, the use comprising administering (orally, QD (once daily)) a solid form of Compound 1 to the subject in an amount of about 24 mg. In one embodiment, the solid form delivers to the subject about 24 mg of Compound 1 free base equivalent. The 24 mg dose of the solid form of Compound 1 can be administered as a single dosage form comprising about 24 mg of the solid form of Compound 1 per unit dosage form (e.g., per tablet or per capsule), or as two dosage forms comprising about 12 mg of the solid form of Compound 1 per unit dosage form (e.g., per tablet or per 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 hydrate. In one embodiment, the solid form is free base anhydrate Form D. In another aspect, the solid form is free base solvate Form A. In another aspect, the solid form is hydrochloride solvate Form AA. In another aspect, the solid form is hydrochloride solvate Form BB. In another aspect, the solid form is hydrochloride solvate Form CC. In another aspect, the solid form is L-malate Form AAA. In another aspect, the solid form is L-malate Form BBB. In one embodiment, the subject has moderate to severe active rheumatoid arthritis. In one embodiment, the subject is an adult.

[0573] In one embodiment, the present disclosure relates to a method for treating rheumatoid arthritis in a subject, the method comprising administering (orally, QD (once daily)) about 30 mg of free base of Compound 1 or a pharmaceutically acceptable salt thereof per unit dosage form (e.g., per tablet or per capsule) to a subject (especially a human subject suffering from or susceptible to rheumatoid arthritis). In another aspect, the present disclosure relates to free base of Compound 1 or a pharmaceutically acceptable salt thereof for treating rheumatoid arthritis in a subject (especially a human subject suffering from or susceptible to rheumatoid arthritis), the use comprising administering (orally, QD (once daily)) about 30 mg of free base of Compound 1 or a pharmaceutically acceptable salt thereof per unit dosage form (e.g., per tablet or per capsule) to a subject. In one embodiment, the subject has moderate to severe active rheumatoid arthritis. In one embodiment, the subject is an adult.

[0574] In one embodiment, the present disclosure relates to a method for treating rheumatoid arthritis in a subject, the method comprising administering (orally, QD (once daily)) a solid form of Compound 1 at an amount per unit dosage form (e.g., per tablet or per capsule) of about 30 mg to a subject (especially a human subject suffering from or susceptible to rheumatoid arthritis). In one embodiment, the method comprises administering (orally, QD (once daily)) the solid form of Compound 1 to the subject in an amount sufficient to deliver 30 mg of free base equivalent of Compound 1 per unit dosage form (e.g., per tablet or per capsule) to the subject. In another aspect, the present disclosure relates to a solid form of Compound 1 for treating rheumatoid arthritis in a subject (especially a human subject suffering from or susceptible to rheumatoid arthritis), the use comprising administering (orally, QD (once daily)) a solid form of Compound 1 at an amount per unit dosage form (e.g., per tablet or per capsule) of about 30 mg to a subject. In one embodiment, the solid form delivers about 30 mg of free base equivalent of Compound 1 per unit dosage form (e.g., per tablet or per capsule) to the 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 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 aspect, the solid form is free base solvate Form A. In another aspect, the solid form is hydrochloride solvate Form AA. In another aspect, the solid form is hydrochloride solvate Form BB. In another aspect, the solid form is hydrochloride solvate Form CC. In another aspect, the solid form is L - malate Form AAA. In another aspect, the solid form is L - malate Form BBB. In one embodiment, the subject is an adult.

[0575] In one embodiment, the present disclosure relates to a method of treating rheumatoid arthritis in a subject, the method comprising administering (orally, QD (once daily)) to the subject, particularly a human subject suffering from or susceptible to rheumatoid arthritis, about 36 mg of free base of Compound 1 or a pharmaceutically acceptable salt thereof per unit dosage form (e.g., per tablet or per capsule). In another aspect, the present disclosure relates to free base of Compound 1 or a pharmaceutically acceptable salt thereof for treating rheumatoid arthritis in a subject, particularly a human subject suffering from or susceptible to rheumatoid arthritis, the use comprising administering (orally, QD (once daily)) to the subject about 36 mg of free base of Compound 1 or a pharmaceutically acceptable salt thereof per unit dosage form (e.g., per tablet or per capsule). In one embodiment, the subject has moderate to severe active rheumatoid arthritis. In one embodiment, the subject is an adult.

[0576] In one embodiment, the present disclosure relates to a method of treating rheumatoid arthritis in a subject, the method comprising administering (orally, QD (once daily)) to the subject, particularly a human subject suffering from or susceptible to rheumatoid arthritis, a solid form of Compound 1 in an amount sufficient to deliver to the subject about 36 mg of free base equivalent of Compound 1 per unit dosage form (e.g., per tablet or per capsule). In another aspect, the present disclosure relates to a solid form of Compound 1 for treating rheumatoid arthritis in a subject, particularly a human subject suffering from or susceptible to rheumatoid arthritis, the use comprising administering (orally, QD (once daily)) to the subject a solid form of Compound 1 in an amount sufficient to deliver to the subject about 36 mg of free base equivalent of Compound 1 per unit dosage form (e.g., per tablet or per capsule). In one embodiment, the solid form delivers to the subject about 36 mg of free base equivalent of Compound 1 per unit dosage form (e.g., per tablet or per 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 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 aspect, the solid form is free base solvate Form A. In another aspect, the solid form is hydrochloride solvate Form AA. In another aspect, the solid form is hydrochloride solvate Form BB. In another aspect, the solid form is hydrochloride solvate Form CC. In another aspect, the solid form is L - malate Form AAA. In another aspect, the solid form is L - malate Form BBB. In one embodiment, the subject is an adult.

[0577] In one embodiment, the present disclosure relates to a method of treating rheumatoid arthritis in a subject, the method comprising administering (orally, QD (once daily)) about 45 mg of free base of Compound 1 or a pharmaceutically acceptable salt thereof per unit dosage form (e.g., per tablet or per capsule) to a subject (especially a human subject suffering from or susceptible to rheumatoid arthritis). In another aspect, the present disclosure relates to free base of Compound 1 or a pharmaceutically acceptable salt thereof for treating rheumatoid arthritis in a subject (especially a human subject suffering from or susceptible to rheumatoid arthritis), the use comprising administering (orally, QD (once daily)) about 45 mg of free base of Compound 1 or a pharmaceutically acceptable salt thereof per unit dosage form (e.g., per tablet or per capsule) to a subject. In one embodiment, the subject has moderate to severe active rheumatoid arthritis. In one embodiment, the subject is an adult.

[0578] In one embodiment, the present disclosure relates to a method of treating rheumatoid arthritis in a subject, the method comprising administering (orally, QD (once daily)) a solid form of Compound 1 to a subject (especially a human subject suffering from or susceptible to rheumatoid arthritis) in an amount sufficient to deliver 45 mg of free base equivalent of Compound 1 per unit dosage form (e.g., per tablet or per capsule). In another aspect, the present disclosure relates to a solid form of Compound 1 for treating rheumatoid arthritis in a subject (especially a human subject suffering from or susceptible to rheumatoid arthritis), the use comprising administering (orally, QD (once daily)) a solid form of Compound 1 to a subject in an amount sufficient to deliver about 45 mg of free base equivalent of Compound 1 per unit dosage form (e.g., per tablet or per capsule). In one embodiment, the solid form delivers about 45 mg of free base equivalent of Compound 1 per unit dosage form (e.g., per tablet or per capsule) to the 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 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 aspect, the solid form is free base solvate Form A. In another aspect, the solid form is hydrochloride solvate Form AA. In another aspect, the solid form is hydrochloride solvate Form BB. In another aspect, the solid form is hydrochloride solvate Form CC. In another aspect, the solid form is L-malate Form AAA. In another aspect, the solid form is L-malate Form BBB. In one embodiment, the subject is an adult.

[0579] In one embodiment, the present disclosure relates to a method of treating moderate to severe active rheumatoid arthritis in adult subjects, particularly human subjects suffering from or prone to moderate to severe active rheumatoid arthritis, 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 one embodiment, the method comprises administering to the subject an amount of 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 or a solid form of Compound 1 per unit dosage form (e.g., per tablet or per capsule), 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 per capsule). In one embodiment, the method comprises administering to the subject an amount of 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 or a solid form of Compound 1 per unit dosage form (e.g., per tablet or per capsule). In one embodiment, Compound 1 (free base) or a pharmaceutically acceptable salt thereof or a solid form of Compound 1 is administered to the subject (orally, QD (once daily)). 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., crystalline hydrate or crystalline anhydrate) as described in the present disclosure for treating moderate to severe active rheumatoid arthritis in adult subjects, particularly human subjects suffering from or prone to moderate to severe active rheumatoid arthritis, the use 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 aspect, 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-malate Form AAA. In one embodiment, the solid form is L-malate 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 extended release formulation.In one embodiment, the formulation is delivered (orally, QD (once daily)) about 7.5 mg or about 15 mg or about 30 mg or about 45 mg of Compound 1 (free base equivalent) or a solid form of Compound 1 per unit dosage form (e.g., per tablet or per capsule).

[0580] In one embodiment, a subject with moderate to severe active rheumatoid arthritis has at least one of the following identified characteristics prior to treatment: at least 6 swollen joints (based on 66 joint counts), at least 6 tender joints (based on 68 joint counts), 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 moderate to severe active rheumatoid arthritis has at least 6 swollen joints (based on 66 joint counts) and at least 6 tender joints (based on 68 joint counts) prior to treatment. Methods for assessing tender and swollen joints are known and are described, for example, in: Scott et al., Clinical and Experimental Rheumatology, 2014, Vol. 32 (Suppl 85), S7-S12.

[0581] Accordingly, in another embodiment, the present disclosure relates to a method of treating moderate to severe active rheumatoid arthritis in adult subjects, particularly human subjects suffering from or prone to moderate to severe active rheumatoid arthritis, the method 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, symptoms 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, per unit dosage form (e.g., per tablet or per capsule), 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 or a solid form of Compound 1 per day, an amount sufficient to deliver to the subject, per unit dosage form (e.g., per tablet or per capsule), about 7.5 mg or about 15 mg or about 30 mg or about 45 mg of Compound 1 free base equivalent per day, wherein the subject has, prior to treatment, symptoms 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, per unit dosage form (e.g., per tablet or per capsule), about 7.5 mg or about 15 mg or about 30 mg or about 45 mg of a solid form of Compound 1. 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 in the present disclosure for treating moderate to severe active rheumatoid arthritis in adult subjects, particularly human subjects suffering from or prone to moderate to severe active rheumatoid arthritis, wherein the subject has, prior to treatment, symptoms selected from the group consisting of: at least 6 swollen joints, at least 6 tender joints, and combinations thereof, the use 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 delivers (orally, QD (once daily)) to the subject, per unit dosage form (e.g., per tablet or per capsule), about 7.5 mg or about 15 mg or about 30 mg or about 45 mg 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 an extended release formulation once daily. 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 the 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 the free base anhydrate Form D. In one embodiment, the solid form is the tartrate hydrate. In one embodiment, these symptoms are caused by the progression of structural damage as evaluated by radiographs.

[0582] In one embodiment, the present disclosure relates to a method for treating moderate to severe active rheumatoid arthritis in adult subjects, particularly human subjects suffering from or prone to moderate to severe active rheumatoid arthritis, the method comprising administering to the subject daily an amount of 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 per capsule), the amount being 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 per capsule) per day, wherein the subject has symptoms selected from the group consisting of: at least 6 swollen joints, at least 6 tender joints, and combinations thereof, prior to treatment. In one embodiment, the method comprises administering to the subject a solid form of Compound 1 in an amount of about 7.5 mg per unit dosage form (e.g., per tablet or per 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 for treating moderate to severe active rheumatoid arthritis in adult subjects, particularly human subjects suffering from or prone to moderate to severe active rheumatoid arthritis, wherein the subject has symptoms selected from the group consisting of: at least 6 swollen joints, at least 6 tender joints, and combinations thereof, prior to treatment, the use comprising administering to the subject an amount of 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 per capsule). In one embodiment, the solid form is a crystalline hydrate. In one embodiment, the crystalline hydrate is the free base hydrate Form B. In one embodiment, the crystalline hydrate is the free base hydrate Form C. In one embodiment, the solid form is a crystalline anhydrate. In one embodiment, the crystalline anhydrate is the free base anhydrate Form D. In one embodiment, the solid form is the tartrate 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 extended release formulation. In one embodiment, these symptoms are caused by the progression of structural damage as evaluated by radiographs.

[0583] In one embodiment, the present disclosure relates to a method of treating moderate to severe active rheumatoid arthritis in adult subjects, particularly human subjects suffering from or susceptible to moderate to severe active rheumatoid arthritis, the method comprising administering to the subject daily an amount of 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 per capsule), the amount being sufficient to deliver to the subject daily about 15 mg of Compound 1 free base equivalent per unit dosage form (e.g., per tablet or per capsule), wherein the subject has symptoms selected from the group consisting of: at least 6 swollen joints, at least 6 tender joints, and combinations thereof prior to treatment. In one embodiment, the method comprises administering to the subject a solid form of Compound 1 at about 15 mg per unit dosage form (e.g., per tablet or per 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 for treating moderate to severe active rheumatoid arthritis in adult subjects, particularly human subjects suffering from or susceptible to moderate to severe active rheumatoid arthritis, wherein the subject has symptoms selected from the group consisting of: at least 6 swollen joints, at least 6 tender joints, and combinations thereof prior to treatment, the use 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 per 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 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 extended release formulation. In one embodiment, these symptoms are caused by the progression of radiographic evidence of structural damage.

[0584] In one embodiment, the present disclosure relates to a method for treating moderate to severe active rheumatoid arthritis in adult subjects, particularly human subjects suffering from or prone to moderate to severe active rheumatoid arthritis, the method comprising administering to the subject daily an amount of 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 per capsule), the amount being sufficient to deliver to the subject per day an amount of about 30 mg of Compound 1 free base equivalent per unit dosage form (e.g., per tablet or per capsule), wherein the subject has symptoms selected from the group consisting of: at least 6 swollen joints, at least 6 tender joints, and combinations thereof, prior to treatment. In one embodiment, the method comprises administering to the subject a solid form of Compound 1 in an amount of about 30 mg per unit dosage form (e.g., per tablet or per 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 for treating moderate to severe active rheumatoid arthritis in adult subjects, particularly human subjects suffering from or prone to moderate to severe active rheumatoid arthritis, wherein the subject has symptoms selected from the group consisting of: at least 6 swollen joints, at least 6 tender joints, and combinations thereof, prior to treatment, the use comprising administering to the subject an amount of 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 per 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 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 an extended release formulation once daily. In one embodiment, these symptoms are caused by the progression of radiographic evidence of structural damage.

[0585] In one embodiment, the present disclosure relates to a method for treating moderate to severe active rheumatoid arthritis in adult subjects, particularly human subjects suffering from or prone to moderate to severe active rheumatoid arthritis, the method comprising administering to the subject daily an amount of 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 per capsule), the amount being sufficient to deliver to the subject about 45 mg of Compound 1 free base equivalent per unit dosage form (e.g., per tablet or per capsule) per day, wherein the subject has symptoms selected from the group consisting of: at least 6 swollen joints, at least 6 tender joints, and combinations thereof, prior to treatment. In one embodiment, the method comprises administering to the subject a solid form of Compound 1 in an amount of about 45 mg per unit dosage form (e.g., per tablet or per 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 for treating moderate to severe active rheumatoid arthritis in adult subjects, particularly human subjects suffering from or prone to moderate to severe active rheumatoid arthritis, wherein the subject has symptoms selected from the group consisting of: at least 6 swollen joints, at least 6 tender joints, and combinations thereof, prior to treatment, the use comprising administering to the subject an amount of 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 per 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 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 an extended release formulation once daily. In one embodiment, the symptoms are caused by progression of radiographic evidence of structural damage.

[0586] In one embodiment, an adult subject being treated achieves an ACR20 response after treatment. In one embodiment, an adult subject achieves an ACR20 response after at least 12 weeks of treatment (e.g., at the 12th week of treatment). In another embodiment, an adult subject being treated achieves an ACR50 response after treatment. In one embodiment, an adult subject achieves an ACR50 response after at least 12 weeks of treatment (e.g., at the 12th week of treatment) or after at least 24 weeks of treatment (e.g., at the 24th week). In another embodiment, an adult subject being treated achieves an ACR70 response after treatment. In one embodiment, an adult subject achieves an ACR70 response after at least 12 weeks of treatment (e.g., at the 12th week of treatment). In certain embodiments, an adult subject achieves an ACR20 response, an ACR50 response, and / or an ACR70 response after at least 12 weeks of treatment (e.g., at the 12th week of treatment).

[0587] In one embodiment, an adult subject being treated achieves an ACR20 response after at least 8 weeks of treatment (e.g., at the 8th week of treatment). In another embodiment, an adult subject being treated achieves an ACR20 response after at least 6 weeks of treatment (e.g., at the 6th week of treatment). In another embodiment, an adult subject being treated achieves an ACR20 response after at least 4 weeks of treatment (e.g., at the 4th week of treatment). In another embodiment, an adult subject being treated achieves an ACR20 response after at least 2 weeks of treatment (e.g., at the 2nd week of treatment).

[0588] In one embodiment, an adult subject being treated achieves an ACR50 response after at least 8 weeks of treatment (e.g., at the 8th week of treatment). In another embodiment, an adult subject being treated achieves an ACR50 response after at least 6 weeks of treatment (e.g., at the 6th week of treatment). In another embodiment, an adult subject being treated achieves an ACR50 response after at least 4 weeks of treatment (e.g., at the 4th week of treatment). In another embodiment, an adult subject being treated achieves an ACR50 response after at least 2 weeks of treatment (e.g., at the 2nd week of treatment).

[0589] In one embodiment, an adult subject being treated achieves an ACR70 response after at least 8 weeks of treatment (e.g., at the 8th week of treatment). In another embodiment, an adult subject being treated achieves an ACR70 response after at least 6 weeks of treatment (e.g., at the 6th week of treatment). In another embodiment, an adult subject being treated achieves an ACR70 response after at least 4 weeks of treatment (e.g., at the 4th week of treatment).

[0590] In one embodiment, the adult subject being treated achieves a change in the DAS28 score after treatment. In one embodiment, the change in the DAS score is a decrease in DAS28(CRP) after treatment as compared to baseline (i.e., DAS28(CRP) before treatment). In one embodiment, the adult subject achieves a decrease in the DAS28 score as 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) as 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) as 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) as 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 decrease in DAS28(CRP) as 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 decrease in DAS28(CRP) as compared to baseline after at least 2 weeks of treatment (e.g., at week 2 of treatment).

[0591] In another embodiment, the adult subject being treated 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 (specifically, DAS28(CRP)) of 3.2 or lower. In another embodiment, the LDA score or clinical remission is measured as a DAS28(CRP) of less than 2.6. In another embodiment, the clinical disease activity index (CDAI) criteria are used to evaluate the LDA score or clinical remission. In one embodiment, the adult subject achieves a CDAI score of 10 or less after treatment. In another embodiment, the adult subject achieves a CDAI score of 2.8 or lower after treatment. In one embodiment, the adult subject achieves an LDA score or clinical remission after at least 12 weeks of treatment (e.g., at week 12 of treatment). In one embodiment, the adult subject achieves an LDA score or clinical remission after at least 8 weeks of treatment (e.g., at week 8 of treatment). In one embodiment, the adult subject achieves an LDA score or clinical remission after at least 6 weeks of treatment (e.g., at week 6 of treatment). In one embodiment, the adult subject achieves an LDA score or clinical remission after at least 4 weeks of treatment (e.g., at week 4 of treatment). In one embodiment, the adult subject achieves an LDA score or clinical remission after at least 2 weeks of treatment (e.g., at...

Claims

1. 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.

2. The amorphous free base according to claim 1, which has an X-ray powder diffraction pattern substantially as shown in Figure 2A.

3. The amorphous free base according to claim 1, which has an X-ray powder diffraction pattern substantially as shown in Figure 2B.

4. The amorphous free base according to claim 1, which has a thermogravimetric analysis graph substantially as shown in Figure 4A.

5. The amorphous free base according to claim 1, which has a thermogravimetric analysis graph substantially as shown in Figure 4B.

6. The amorphous free base according to claim 1, which has a differential scanning calorimetry graph substantially as shown in Figure 5A.

7. The amorphous free base according to claim 1, the onset of its glass transition temperature is about 119 °C.

8. The amorphous free base according to claim 1, the midpoint of its glass transition temperature is about 122 °C.

9. The amorphous free base according to claim 1, which has a water adsorption isotherm graph substantially as shown in Figure 6A.

10. The amorphous free base according to claim 1, which contains less than 13% water by weight.

Images