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 invention patent application with application date of October 17, 2016, application number 202211671688.7, and invention name “Method for preparing imidazo[1,2-a]pyrrolo[2,3-e]pyrazine compounds and their solid form”. CROSS-REFERENCE TO RELATED APPLICATIONS

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

[0002] The present disclosure relates to: (a) methods for preparing (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (referred to herein as "Compound 1"), (b) intermediates used in the preparation of Compound 1 and methods for preparing intermediates; (c) solid-state forms of Compound 1, (d) pharmaceutical compositions comprising one or more solid-state forms of Compound 1 and, optionally, one or more additional therapeutic agents; (e) methods for treating Janus kinase-related disorders (including rheumatoid arthritis) by administering one or more solid-state forms of Compound 1 to a subject in need thereof; (f) kits comprising a first pharmaceutical composition and, optionally, a second pharmaceutical composition, the first pharmaceutical composition comprising a solid-state form of Compound 1 and the second pharmaceutical composition comprising one or more additional therapeutic agents; (g) methods for preparing solid-state forms of Compound 1; and (h) solid-state 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 incorporated herein by reference in its entirety. This compound has activity as a Janus kinase ("JAK") inhibitor, particularly as a JAK-1 inhibitor. Clinical trials are underway to evaluate the compound for the treatment of rheumatoid arthritis.

[0004] The isolation and commercial-scale preparation of solid-state forms of Compound 1 and corresponding pharmaceutical formulations with acceptable solid-state properties (including chemical stability, thermal stability, solubility, hygroscopicity, and / or particle size), compound manufacturability (including yield, impurity rejection during crystallization, filterability, drying properties, and milling properties), and formulation feasibility (including stability to pressure or compression forces during tableting) present many challenges, which will be discussed in more detail below. Therefore, there is a need for one or more solid-state forms of Compound 1 that have an acceptable balance of these properties and can be used to prepare pharmaceutically acceptable solid dosage forms.

[0005] Furthermore, 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. Therefore, 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] In addition, sustained peak plasma concentrations can theoretically be achieved through sustained-release matrix systems. However, when such systems are made from hydrophilic polymers such as HPMC, they rarely provide pH-independent drug release of pH-dependent soluble drugs, and, except for virtually insoluble drugs, they generally cannot achieve zero-order release. Surprisingly, it was discovered that when tartaric acid was used as a pH modifier in this system, it allowed compound 1 to be released at a stable rate regardless of the pH of the environment.

[0007] It was unexpectedly discovered that as tablets containing a 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 tablet. 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) making a compound having formula (I) or a pharmaceutically acceptable salt thereof is reacted with trimethylsulfoxonium chloride to form a compound having formula (II) Wherein PG is a protecting group; b) contacting the compound of formula (II) with LiX and 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 perfluoroanhydride and an organic base to form a compound of formula (VI) e) deprotecting the compound of formula (VI) and forming a pharmaceutically acceptable salt of the compound of formula (VII): f) reacting a pharmaceutically acceptable salt of a compound having 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) making a compound of formula (Ib) Reacting with trimethylsulfoxonium chloride in the presence of carbonyldiimidazole and a strong base to form a compound having formula (IIa) wherein Cbz is carboxybenzyl; b) contacting the compound of formula (IIa) with lithium bromide and sulfonic acid to form a compound of formula (IIIa) c) reacting the compound of formula (IIIa) with the compound of formula (IVa) Reaction in the presence of lithium tert-butoxide to form a compound having formula (Va) wherein R2 is methyl or ethyl; and Ts is toluenesulfonyl; d) contacting the compound of formula (Va) with perfluoroanhydride and an organic base to form a compound of formula (VIa) e) deprotecting the compound of formula (VIa) to form a compound of formula (VII) f) contacting the compound of formula (VII) with hydrochloric acid to form a compound of formula (VIIa) g) reacting the compound of formula (VIIa) with 2,2,2-trifluoroethylamine in the presence of carbonyldiimidazole to produce compound 1.

[0010] In another aspect, the present disclosure relates to a method for preparing Compound 1. The method comprises: a) making a compound having formula (I) or a pharmaceutically acceptable salt thereof is reacted with trimethylsulfoxonium chloride to form a compound having formula (II) Wherein PG is a protecting group; b) contacting the compound of formula (II) with LiX and 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 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 a tartrate salt of Compound 1; and i) contacting the 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) making a compound having the formula (XIa): is converted into a compound of formula (I): Wherein PG is a protecting group; b) reacting the compound of formula (I) with trimethylsulfoxonium chloride to form a compound of formula (II) c) contacting the compound of formula (II) with a source of anhydrous HBr or anhydrous HCl to form a compound of formula (III) wherein X is Br or Cl; d) reacting the compound of formula (III) with a compound of formula (IV) To produce a compound of formula (V) wherein R1 is selected from the group consisting of: alkyl, aryl, and -OR2; R2 is alkyl; and Ts is tosyl; e) contacting the compound of formula (V) with perfluoroanhydride and an organic base to form a compound of formula (VI) f) deprotecting the compound of formula (VI) and forming a pharmaceutically acceptable salt of the compound of formula (VII): and g) reacting a pharmaceutically acceptable salt of a compound having formula (VII) with 2,2,2-trifluoroethylamine to produce Compound 1.

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

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

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

[0015] In another aspect, the present disclosure relates to compounds having formula (Va) wherein R2 is methyl or ethyl; and Ts is tosyl.

[0016] In another aspect, the present disclosure relates to a method for preparing a compound having formula (V) The method includes: a) making a compound having the formula (XIa): Converted 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 a source of anhydrous HBr or anhydrous HCl to form a compound of formula (III) d) reacting the compound of formula (III) with a compound of formula (IV) to produce the compound of formula (V); in: 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.

[0017] In another aspect, the present disclosure is directed to a method of preparing a crystalline compound having formula (V) The method includes: a) making a compound having formula (III) Reaction with a compound of formula (IV): to produce the compound of formula (V); in: 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 disclosure relates to compounds having formula (IVa): wherein R2 is methyl or ethyl; and Ts is tosyl.

[0019] In another aspect, the disclosure relates to a method of preparing a compound having formula (IVa): wherein R2 is methyl or ethyl; and Ts is tosyl, the method comprising: a) making a compound having formula (XVII) and reacting with trimethylsilylacetylene in the presence of a catalyst to form a compound having formula (XVIII): Wherein TMS is trimethylsilyl; b) reacting the compound of formula (XVIII) with p-toluenesulfonyl chloride in the presence of a base to form a compound of formula (XIX) wherein Ts is tosyl; and c) reacting a 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 having formula (VII): or a pharmaceutically acceptable salt thereof.

[0021] In another aspect, the present disclosure relates to a method for preparing a compound having formula (Ib) Wherein Cbz is carboxybenzyl, the method comprises: (i) reacting carboxybenzyl-glycine ethyl ester with ethyl acrylate to form a compound having formula (VIII): (ii) protecting the compound of formula (VIII) to form a compound of formula (IX): where R 3 is selected from the group consisting of CF3SO2-, CH3SO2-, and tosyl; (iii) contacting the compound of formula (IX) with one of ethylboric 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) into 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 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 state form of Compound 1.

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

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

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

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

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

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

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

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

[0032] In another aspect, the present disclosure relates to pharmaceutical compositions comprising one or more solid state 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, from about 10 w / w% to about 35 w / w% of an organic acid selected from tartaric acid, fumaric acid, citric acid, succinic acid, malic acid, and combinations thereof, and a pharmaceutically acceptable carrier. In one embodiment, the solid form is a tartrate hydrate. In one embodiment, the solid form is the free base hydrate Form C.

[0034] In another aspect, the disclosure relates to pharmaceutical compositions comprising one or more solid state 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-associated disorder (e.g., rheumatoid arthritis) in a human subject suffering from or susceptible to such a disorder, the method comprising administering to the subject a therapeutically effective amount of a solid-state form of Compound 1. In another aspect, the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a solid-state form of Compound 1 as described herein for treating a JAK-associated disorder (e.g., rheumatoid arthritis) in a subject, particularly in a human patient suffering from or susceptible to the disorder.

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

[0037] In another aspect, the disclosure relates to methods 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 disclosure relates to a method for treating a disorder in a human subject suffering from or susceptible to such 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, comprising administering to the subject a therapeutically effective amount of a solid state form of Compound 1. In another aspect, the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a solid state form of Compound 1 as described herein for treating a condition in a subject, particularly a human subject suffering from or susceptible to a condition selected from the group consisting of rheumatoid arthritis, juvenile idiopathic arthritis, Crohn's disease, ulcerative colitis, psoriasis, plaque psoriasis, nail psoriasis, psoriatic arthritis, ankylosing spondylitis, alopecia areata, hidradenitis suppurativa, atopic dermatitis, and systemic lupus erythematosus.

[0039] In another aspect, the present disclosure relates to a method for treating a JAK-associated disorder (e.g., rheumatoid arthritis) in a human subject suffering from or susceptible to such a disorder, the method comprising administering to the subject a solid form of Compound 1 in combination with one or more additional therapeutic agents (e.g., a therapeutic agent other than a JAK inhibitor for treating rheumatoid arthritis). In another aspect, the present disclosure relates to a pharmaceutical composition comprising a solid form of Compound 1 as described herein, in combination with one or more additional therapeutic agents (e.g., a therapeutic agent other than a JAK inhibitor for treating rheumatoid arthritis) for treating a subject, particularly a JAK-associated disorder (e.g., rheumatoid arthritis) in a human subject suffering from or susceptible to the disorder.

[0040] In another aspect, the disclosure relates to a method for treating moderate to severe active rheumatoid arthritis, comprising administering a therapeutically effective amount of one or more forms of compound 1 disclosed herein to a subject suffering from or susceptible to the condition. In a specific aspect, such a method may comprise administering compound 1 in one or more forms disclosed herein 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 this or another specific aspect, the subject can administer compound 1 in free base form C. In this or another specific aspect, the subject may have an insufficient response to methotrexate. In this or another specific aspect, the subject may have an insufficient response to a biologic drug approved for rheumatoid arthritis. In this or another specific aspect, the subject may not have been administered a biologic drug approved for rheumatoid arthritis before.

[0041] In another aspect, the disclosure relates to a method of treating an adult subject with moderately to severely active rheumatoid arthritis, comprising administering to the subject: a) about 7.5 mg of Compound 1 free base, or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1, in an amount sufficient to deliver to the subject an amount equivalent to about 7.5 mg of Compound 1 free base; or b) about 15 mg of Compound 1 free base, or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1. anhydrate, in an amount sufficient to deliver to a subject approximately 15 mg of the equivalent of Compound 1 free base; or c) approximately 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 a subject approximately 30 mg of the equivalent of Compound 1 free base; or d) approximately 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 a subject approximately 45 mg of the equivalent of Compound 1 free base. In one embodiment, the present disclosure is directed to a pharmaceutical composition for treating adult subjects with moderately to severely active rheumatoid arthritis, the use 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 an amount equivalent to about 7.5 mg of Compound 1 free base; or b) about 15 mg of Compound 1 free base, or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1. or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1, in an amount sufficient to deliver to a subject approximately 15 mg of the equivalent of Compound 1 free base; or c) about 30 mg of Compound 1 free base, or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1, in an amount sufficient to deliver to a subject approximately 30 mg of the equivalent of Compound 1 free base; or d) about 45 mg of Compound 1 free base, or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or crystalline anhydrate of Compound 1, in an amount sufficient to deliver to a subject approximately 45 mg of the equivalent of Compound 1 free base.

[0042] In another embodiment, the present disclosure relates to a method of treating structural damage associated with rheumatoid arthritis in an adult subject, 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 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 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 structural damage to 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 an adult subject, 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 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, An amount sufficient to deliver to the subject approximately 15 mg per day of Compound 1 free base equivalents; or c) approximately 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 approximately 30 mg per day of Compound 1 free base equivalents; or d) approximately 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 approximately 45 mg per day of Compound 1 free base equivalents; such that structural damage to the adult subject is inhibited or reduced.

[0043] In another aspect, the disclosure is directed to a method of treating moderately to severely active rheumatoid arthritis in an adult subject, 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 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 a symptom selected from the group consisting of at least 6 swollen joints, at least 6 tender joints, and combinations thereof prior to treatment. In one embodiment, the present disclosure is directed to a pharmaceutical composition for treating moderately to severely active rheumatoid arthritis in an adult subject, the use comprising administering to the subject the 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 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. g 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; wherein the subject has a symptom selected from the group consisting of at least 6 swollen joints, at least 6 tender joints, and combinations thereof prior to treatment.

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

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

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

[0047] In another aspect, the disclosure relates to solid-state forms of Compound 1 prepared according to these methods.

[0048] In another aspect, present disclosure relates to a method for treating an adult subject with moderate to severe active rheumatoid arthritis, 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 alkali, or a crystalline hydrate of compound 1 in an amount sufficient to deliver about 7.5 mg, or about 15 mg, or about 30 mg, or about 45 mg of compound 1 free alkali equivalent to the subject. In this or another specific aspect, the hydrate may be a hemihydrate. In this or another specific aspect, the hemihydrate may be a free alkali hydrate form C. In this or another specific aspect, the subject may respond insufficiently or with tolerance to one or more disease-modifying antirheumatic drugs (DMARDS) such as methotrexate. In this or another specific aspect, the subject may not have previously administered DMARDS. In this or another specific aspect, the subject may further administer one or more DMARDs.

[0049] In another aspect, the disclosure relates to a method for treating structural damage associated with rheumatoid arthritis in an adult subject, 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, such that the structural damage in the adult subject is inhibited or alleviated. 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.

[0050] In another aspect, the disclosure relates to a method for treating moderate to severe active rheumatoid arthritis in an adult subject, 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 a symptom selected from the group consisting of at least 6 swollen joints, at least 6 tender joints, and combinations thereof before treatment. 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.

[0051] In another aspect, the disclosure relates to a method for alleviating the signs and symptoms of rheumatoid arthritis in an adult subject with moderate to severe active rheumatoid arthritis, the method comprising administering to the subject about 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 equivalents. 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 disclosure relates to a method for alleviating the signs and symptoms of rheumatoid arthritis in an adult subject with moderate to severe active rheumatoid arthritis, the method comprising administering to the subject about 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 equivalents. 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 disclosure relates to a method for alleviating the signs and symptoms of rheumatoid arthritis in an adult subject with moderate to severe active rheumatoid arthritis, the method comprising administering to the subject about 30 mg 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 equivalents. 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 disclosure relates to a method for alleviating the signs and symptoms of rheumatoid arthritis in an adult subject with moderate to severe active rheumatoid arthritis, the method comprising administering to the subject about 45 mg 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 equivalents. 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 sufficient crystalline hydrate to deliver approximately 7.5 mg of the free base equivalent of Compound 1. 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 sufficient crystalline hydrate to deliver about 15 mg of the free base equivalent of Compound 1. 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.

[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 sufficient crystalline hydrate to deliver about 30 mg of the free base equivalent of Compound 1. 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.

[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 sufficient crystalline hydrate to deliver about 45 mg of the free base equivalent of Compound 1. 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.

[0059] In another aspect, the disclosure relates to a method for treating an adult subject with moderate to severe active rheumatoid arthritis, comprising administering to the subject about 7.5 mg, or about 15 mg, or about 30 mg, or about 45 mg of a crystalline hydrate of Compound 1. In this or another specific aspect, the hydrate can be a hemihydrate. In this or another aspect, the hemihydrate can be the free base hydrate Form C.

[0060] In another aspect, the disclosure relates to a method for treating structural damage associated with rheumatoid arthritis in an adult subject, 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, such that the structural damage in the adult subject is inhibited or reduced. In this or another specific aspect, the hydrate can be a hemihydrate. In this or another aspect, the hemihydrate can be the free base hydrate Form C.

[0061] In another aspect, the disclosure relates to a method of treating moderate to severe active rheumatoid arthritis in an adult subject, 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, wherein the subject has a symptom selected from the group consisting of at least 6 swollen joints, at least 6 tender joints, and combinations thereof prior to treatment. In this or another specific aspect, the hydrate can be a hemihydrate. In this or another aspect, the hemihydrate can be the free base hydrate Form C.

[0062] In another aspect, the disclosure relates to a method for 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 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. In this or another specific aspect, the hydrate can be a hemihydrate. In this or another aspect, the hemihydrate can be the free base hydrate Form C.

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

[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 state 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 granulated material; (d) grinding the granulated material to form a milled granulated 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 One method for preparing the amorphous free base is schematically shown.

[0066] Figure 1B One method for preparing the free base hydrate Form C is schematically shown.

[0067] Figure 1C One method for preparing tartrate hydrate is schematically shown.

[0068] Figure 2A and 2B 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 tartaric acid salt hydrate. Figure 3D The calculated PXRD pattern is shown at the bottom of Figure 3D top.

[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-maleate salt form of AAA.

[0077] Figure 3I is the X-ray powder diffraction pattern corresponding to the L-maleate salt form of BBB.

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

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

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

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

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

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

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

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

[0086] Figure 4I is the thermogravimetric analysis thermogram corresponding to the free base anhydrate Form D.

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

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

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

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

[0091] Figure 5E is a differential scanning calorimetry thermogram corresponding to the free base anhydrate Form D.

[0092] Figure 6A is the water sorption isotherm corresponding to the amorphous free base (via dehydration).

[0093] Figure 6B is the water sorption isotherm corresponding to the free base hydrate Form C.

[0094] Figure 6C is the water adsorption isotherm corresponding to tartrate hydrate.

[0095] Figure 6D is the water adsorption isotherm corresponding to the anhydrate form D of the free base.

[0096] Figure 7 Comparison of the dissolution profiles of the 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] Figure 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 the dual pH system.

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

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

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

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

[0103] Figure 14 Comparison of the dissolution profiles of extended-release tablets from Example 24 (ER1), Example 26 (ER3), and Example 32 (ER4) under a dual pH system.

[0104] Figures 15A-15H is a comparison of the dissolution profiles at pH 1.2 and pH 6.8 for the extended release tablet from Example 43, which contains HPMC ( Figures 15A-15D )or ( Figures 15E-15H ) as a controlled release polymer, and tartaric acid ( Figure 15A and 15E ), citric acid ( Figure 15B and 15F ), succinic acid ( Figure 15C and 15G ) or fumaric acid ( Figure 15D and 15H ) as a pH adjuster.

[0105] Figure 16A and 16B shows the use of linear ( Figure 16A ) or semi-logarithmic ( Figure 16B) scale, the relationship between the mean plasma concentration of Compound 1 and time after administration of 12 mg immediate-release capsules (Regimen A) or 15 mg once-daily extended-release tablets (Regimen B) under fasting conditions.

[0106] Figure 17A and 17B shows the use of linear ( Figure 17A ) or semi-logarithmic ( Figure 17B ) scale, mean plasma concentration versus time of Compound 1 after administration of a 24 mg dose (2×12 mg) of immediate-release capsules (Schedule C) or a 30 mg once-daily extended-release tablet (Schedule D) under fasting conditions.

[0107] Figure 18A and 18B shows the use of linear ( Figure 18A ) or semi-logarithmic ( Figure 18B ) scale, mean plasma concentration versus time of Compound 1 after administration of a 30 mg once daily extended-release tablet under fasting conditions (Regimen D) or after administration of a 30 mg once daily extended-release tablet after consumption of a high-fat meal (Regimen E).

[0108] Figure 19 Shown are the mean plasma concentrations of Compound 1 versus time after 7 days of administration of either a 15 mg once daily extended-release tablet (Schedule F) or a 30 mg once daily extended-release tablet (Schedule G) under non-fasting conditions.

[0109] Figure 20 Shown are the mean plasma concentrations of Compound 1 versus time after 7 days of administration of 6 mg twice daily immediate-release capsules (Regimen K) or 15 mg once daily extended-release tablets (Regimen L) under fasting conditions.

[0110] Figure 21 Shown are the pre-morning dose trough concentrations (C) of Compound 1 after 7 days of administration of 6 mg twice daily immediate-release capsules or 15 mg once daily extended-release tablets under fasting conditions. 谷 ).

[0111] Figure 22 Shown are the mean plasma concentrations of Compound 1 versus time after 7 days of administration of 12 mg twice daily immediate-release capsules (Regimen M) or 30 mg once daily extended-release tablets (Regimen N) under fasting conditions.

[0112] Figure 23 Shown are the morning pre-dose trough concentrations (C) of Compound 1 after 7 days of administration of 12 mg twice daily immediate-release capsules or 30 mg once daily extended-release tablets under fasting conditions. 谷 ).

[0113] Figure 24A and 24B shows the use of linear ( Figure 24A ) or log-linear ( Figure 24B ) scale, mean plasma concentration of Compound 1 versus time after administration of 30 mg once daily of different extended-release tablets with different tartaric acid concentrations under fasting conditions.

[0114] Figure 25A and 25B shows the use of linear ( Figure 25A ) or log-linear ( Figure 25B ) scale, mean plasma concentration versus time of Compound 1 after administration of 30 mg once daily extended-release tablets (ER10) under fasting conditions or after a high-fat meal (non-fasting).

[0115] Figure 26A and 26B Compound 1C is shown after administration of a 30 mg once daily extended release tablet (ER10) under fasting conditions or after a high fat meal (non-fasting) max ( Figure 26A ) and AUC inf ( Figure 26B ) individual changes.

[0116] Figure 27A and 27B shows the use of linear ( Figure 27A ) or log-linear ( Figure 27B ) scale, mean plasma concentration versus time of Compound 1 after administration of 30 mg once daily extended-release tablets (ER11) under fasting conditions or after a high-fat meal (non-fasting).

[0117] Figure 28A and 28B Compound 1C is shown after administration of a 30 mg once daily extended release tablet (ER11) under fasting conditions or after a high fat meal (non-fasting) max ( Figure 28A ) and AUC inf ( Figure 28B ) individual changes.

[0118] Figure 29A and 29B shows the use of linear ( Figure 29A ) or log-linear ( Figure 29B ) scale, mean plasma concentration versus time of Compound 1 after administration of 30 mg once daily extended-release tablets (ER12) under fasting conditions or after a high-fat meal (non-fasting).

[0119] Figure 30A and30B Compound 1C is shown after administration of a 30 mg once daily extended release tablet (ER12) under fasting conditions or after a high fat meal (non-fasting) max ( Figure 30A ) and AUC inf ( Figure 30B ) individual changes.

[0120] Figure 31 Shown are the pH profiles of gels formed on tablets containing different amounts of tartaric acid.

[0121] Figure 32A and 32B shows the use of linear ( Figure 32A ) or log-linear ( Figure 32B ) scale, the relationship between the mean plasma concentration of Compound 1 and time after a single oral dose of Compound 1 immediate-release capsules to healthy subjects.

[0122] Figure 33 Shown are the mean plasma concentrations of Compound 1 as a function of time following administration of multiple twice daily oral doses of Compound 1 immediate-release capsules to healthy subjects.

[0123] Figures 34A-34D Shown is the administration of a single dose ( Figure 34A - Single dose, C max ; Figure 34C -Single dose, AUC ∞ ), multiple doses administered to healthy subjects, and multiple doses administered to subjects with rheumatoid arthritis ( Figure 34B -Multiple doses, C max ; Figure 34D -Multiple doses, AUC 0-12 ) after administration of the drug, the dose-normalized mean C max and AUC.

[0124] Figure 35A and 35B The AUC ( Figure 35A ) had no effect, and concomitant administration of Compound 1 had no effect on the methotrexate dose-normalized AUC ( Figure 35B ).

[0125] Figure 36AShown are ACR20, ACR50, and ACR70 response rates 12 weeks after administration of placebo or various doses of Compound 1 to subjects with active rheumatoid arthritis and a previous inadequate response to or intolerance to anti-TNF biologics (*P<0.05; **P<0.01; ***P<0.001 vs. placebo; modified intention-to-treat population (NRI)). Figure 36B Shown are ACR20 response rates at week 12 in the same cohort, separated by the amount of prior anti-TNF biologics.

[0126] Figures 37A-37D The ACR20 ( Figure 37A )、ACR50( Figure 37B ) and ACR70( Figure 37C ) response or mean change from baseline in DAS28(CRP) ( Figure 37D )(*P < 0.05; **P < 0.01; ***P < 0.001, vs. placebo; modified intention-to-treat population (NRI)). Figure 37E Shown are subjects in the same cohort who achieved a DAS28 (CRP) score of ≤3.2 or <2.6 at Week 12. Figure 37F Shown are subjects who achieved low disease activity (LDA) or clinical remission (CR) at week 12 based on the Clinical Disease Activity Index (CDAI) criteria (LDA is CDAI ≤ 10; CR is CDAI ≤ 2.8) in the same cohort.

[0127] Figure 38A Shown are mean hemoglobin levels over time for all subjects following administration of placebo or various doses of Compound 1 to subjects with active rheumatoid arthritis who had a previous inadequate response to or were intolerant to anti-TNF biologics (safety population with observed data (no imputation of missing values)). Figure 38B Shown are mean hemoglobin changes from baseline over time in subjects whose high-sensitivity C-reactive protein (hsCRP) was above the upper limit of normal (ULN) (normal range for hemoglobin: 11.5-15.5 g / dL in women and 13.2-17.0 g / dL in men; ULN for hsCRP = 5 mg / L).

[0128] Figure 39 Subject disposition for the study described in Example 55 is shown.

[0129] Figure 40A and 40B Subject disposition for the study described in Example 56 is shown.

[0130] Figure 41 Shown are ACR20, ACR50, and ACR70 responses after 12 weeks of administration of placebo or various doses of Compound 1 to subjects with active rheumatoid arthritis and an inadequate response to methotrexate (*P<0.05; **P<0.01; ***P<0.001 vs. placebo; modified intention-to-treat population, NRI value missing).

[0131] Figures 42A-42D Shown are the changes in ACR20 ( Figure 42A , NRI analysis), ACR50( Figure 42B , NRI analysis) and ACR70 ( Figure 42C , NRI analysis) response or mean change from baseline in DAS28 (CRP) ( Figure 42D , observed cases) (*P < 0.05; **P < 0.01; ***P < 0.001, versus placebo; modified intention-to-treat population).

[0132] Figure 43A and 43B The results showed that after 12 weeks of administration of placebo or various doses of Compound 1 to subjects with active rheumatoid arthritis and an inadequate response to methotrexate, DAS28 (CRP) scores reached ≤3.2 or <2.6 ( Figure 44A ) or CDAI score ≤10 or ≤2.8 (*P<0.05; **P<0.01; ***P<0.001, vs. placebo; modified intention-to-treat population (NRI)). Figure 43A and 43B , the bottom number represents the percentage of subjects who achieved both cutoffs, the middle number represents the percentage of subjects who achieved the less stringent cutoff but not the more stringent cutoff, and the top number represents the patients who achieved the cutoff.

[0133] Figures 44A-44C Shown are the changes in the overall response rate over time in all subjects ( Figure 44A ), subjects with baseline hsCRP ≤ 5 mg / mL ( Figure 44B ) and subjects with baseline hsCRP>5mg / mL ( Figure 44C ), mean change from baseline in hemoglobin by treatment group (safety population with observed data (no imputation of missing values)). Detailed Description of the Invention

[0134] This written description uses examples to disclose the invention and also to enable any person skilled in the art to practice the invention, including making and using any disclosed solid forms or compositions and performing any disclosed methods or processes. The patentable scope of the invention is defined by the claims, and may include other examples that occur to those skilled in the art. If such other examples have elements that do not differ from the literal language of the claims, or if they include equivalent elements, they are intended to be within the scope of the claims. I. definition

[0135] The section headings as used in this section and the overall disclosure are not intended to be limiting.

[0136] Where a numerical range is recited, each intervening number within that range is expressly contemplated with the same degree of precision. For example, for the range 6 to 9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 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 expressly contemplated. In like manner, all recited ratios also include all sub-ratios falling 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 range of values that one skilled in the art considers equivalent to the recited value (ie, having the same function or result). In many cases, the term "about" can include values that are rounded to the nearest significant figure.

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

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

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

[0142] The term "anhydrate" as applied to a compound refers to the solid state in which the compound contains no structural water within the crystal 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 requires otherwise, the terms "comprise," "comprises," and "comprising" are to be construed as inclusive rather than exclusive, and applicant intends that each of those words be used with the basic and clear understanding that they will be so construed in reading 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 regularly ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials will also exhibit the properties of a liquid when heated sufficiently, but the change from solid to liquid is characterized by a phase transition, usually first order ("melting point").

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

[0147] As used throughout this application, the term "crystallization" may refer to crystallization and / or recrystallization depending on the applicable circumstances associated with the preparation of the compound.

[0148] The term "pharmaceutically acceptable" (e.g., in the description of "pharmaceutically acceptable salt" or "pharmaceutically acceptable diluent") refers to a material that is compatible with administration to human subjects, e.g., the material does not cause an undesirable biological effect. Examples of pharmaceutically acceptable salts are described in Stahl and Wermuth, "The 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" (Rowe et al., eds., 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, reducing the severity of, decreasing the frequency of, preventing, reducing the risk of, slowing the progression of damage caused by, or delaying the onset of a disorder, or improving the quality of life of a patient suffering from the disorder.

[0151] The term "Xantphos" refers to 4,5-bis(diphenylphosphine)-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 " is 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 "AUC" 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. 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 the C measured at steady state 12 .

[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 the C measured at steady state 24 .

[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 ” means that in T max The plasma concentration of the indicated drug under , expressed herein in ng / mL, resulting from 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 indicated, C max is the overall maximum observed concentration.

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

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

[0167] As used herein, the term "C 谷 ” 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 "entering the environment of use" 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" stands for 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 [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride.

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

[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 diacetate[(S)-(-)5,5'-bis(diphenylphosphine)-4,4'-bis-1,3-benzodioxole]ruthenium(II).

[0203] As used herein, the term " 1 / 2 ” refers to the terminal half-life of the indicated drug after oral administration 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 " max ” refers to the time from oral administration of a single dose or a specified number of doses of the indicated drug to the peak plasma concentration of the indicated drug.

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

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

[0213] The term "triflate" refers to a trifluoromethanesulfonic acid ester.

[0214] The abbreviation "v / v" means volume / volume.

[0215] The abbreviation "w / w" means weight / weight.

[0216] For purposes of clarity and convenience only, the following convention is used herein: the time of administration or the start of the dissolution test is designated as zero (0) hour (t=0 hour) 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] The present disclosure relates to improved methods for preparing (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (referred to herein as "Compound 1" or "Compound 1 free base"), pharmaceutically acceptable salts of Compound 1, and intermediates for preparing Compound 1. Compound 1 has the structure shown below: Methods for preparing and using the compounds are described, for example, in the 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 disclosed herein overcome these disadvantages by avoiding the use of these hazardous reagents and producing a crystalline intermediate that is amenable to purification.

[0219] The compounds of the present disclosure can be prepared by using synthetic transformations such as those shown in Schemes I-XVI. Starting materials are commercially available and can be prepared by the procedures described herein, literature procedures, or by procedures that will be familiar to one of ordinary skill in the art of organic chemistry (see, for example, Larock, RC, "Comprehensive Organic Transformations: A Guide to Functional Group Preparations," 2 nd ed., Comprehensive Organic Transformations: A Guide to Functional Group Preparation, 2nd ed., 1999, Wiley-VCH or Greene, TW Publishers, and Wuts, PGM, "Protective Groups in Organic Synthesis, 3 rd Edition [Protective Groups in Organic Synthesis, 3rd Edition]", 1999, Wiley-Interscience Publishers). A. Preparation of compound 1

[0220] In one aspect, the present disclosure relates to a method for preparing compound 1 or a pharmaceutically acceptable salt thereof. The preparation method of compound 1 is illustrated in Scheme 1. Protected (3R, 4S)-4-ethylpyrrolidine-3-carboxylic acid (I) or a pharmaceutically acceptable salt thereof is reacted with trimethylsulfoxonium chloride to produce a sulfur ylide (II). The sulfur 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 produce (V). Cyclization of (V) in the presence of a perfluoroanhydride and an organic base produces (VI). Removal of the protecting group and contacting the deprotected compound with an acid produces a pharmaceutically acceptable salt of (VII). Reacting a pharmaceutically acceptable salt of (VII) with 2,2,2-trifluoroethylamine produces compound 1. Plan I in: 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 this embodiment, the compound of formula (IV) is a compound of formula (IVa): Wherein R is methyl or ethyl. Surprisingly found that when R is ethyl or methyl, there is the compound of formula (V) and subsequent downstream compounds can be separated as crystalline solids, which helps the purification of these intermediates. On the contrary, the previously known method using the compound in which R is tert-butyl leads to the formation of the compound with formula (V), which is separated as an amorphous solid.

[0223] In certain embodiments, a pharmaceutically acceptable salt of a compound of formula (I) is used in the reaction of step (a). In one embodiment, the pharmaceutically acceptable salt of a compound of formula (I) is selected from the group consisting of naphthyl ethylamine salt (Ia) and dicyclohexylamine salt (Ib). wherein 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 illustrated in Scheme Ia. (3R,4S)-1-((benzyloxy)carbonyl)-4-ethylpyrrolidine-3-carboxylate dicyclohexylamine salt (Ib) is reacted with trimethylsulfoxonium chloride in the presence of carbonyldiimidazole and a strong base to produce the sulfur ylide (IIa). The sulfur ylide (IIa) is contacted with lithium bromide and sulfonic acid to produce the corresponding bromomethyl ketone (IIIa). In the presence of lithium tert-butoxide, (IIIa) is reacted with alkyl 5-toluenesulfonyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate (IVa) to produce (Va). Cyclization of (Va) in the presence of perfluoroanhydride and an organic base produces (VIa). Removal of the carboxybenzyl protecting group and contacting the deprotected compound with hydrochloric acid produces a pharmaceutically acceptable salt (VIIa). Reaction of the pharmaceutically acceptable salt (VIIa) with 2,2,2-trifluoroethylamine produces compound 1. Plan Ia in: Cbz is carboxybenzyl; Ts is tosyl; and R2 is methyl or ethyl.

[0226] The reaction in step (a) of Schemes I and Ia is typically carried out in the presence of a coupling agent such as carbonyldiimidazole (CDI) and a strong base. The strong base can be, for example, potassium tert-butoxide, sodium tert-butoxide, or a combination thereof. The step (a) reaction can be carried out in any suitable solvent 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 of 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 of formula (II) or (IIa) is isolated prior to step (b).

[0228] In some embodiments, the reaction of step (a) may further involve contacting (Ia) or (Ib) with an acid before reacting with trimethylsulfoxonium chloride to obtain a compound of formula (I) with extractive amine. Suitable acid includes any mineral acid or organic acid, such as phosphoric acid, hydrochloric acid (HCl), acetic acid (HOAc), citric acid, etc. The compound of formula (I) may then be absorbed in a suitable solvent and reacted with trimethylsulfoxonium chloride as described herein. In one embodiment, a pharmaceutically acceptable salt of a compound of 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 Scheme I and Ia, a compound of formula (II) or (IIa) is contacted with LiX and a sulfonic acid to form a compound of formula (III) or (IIIa). 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, a sulfonic acid is added to a solution of a compound of formula (II) or (IIa) and LiX in a solvent. The resulting mixture is warmed to about 35°C to about 65°C and stirred overnight. In one embodiment, the mixture is warmed to about 40°C and stirred overnight. The mixture is cooled to room temperature and washed. The compound of formula (III) or (IIIa) can be isolated or can be optionally used in the next step without purification.

[0231] In step (c) of Schemes I and Ia, a compound of formula (III) or (IIIa) is reacted with a compound of formula (IV) or (IVa) (prepared as described herein). The reaction of step (c) is carried out in the presence of a base such as lithium tert-butoxide, sodium tert-butoxide, or a combination thereof. In one embodiment, the base is lithium tert-butoxide. The reaction of step (c) can be carried out in any suitable solvent, including but not limited to dimethylacetamide, tetrahydrofuran, dichloromethane, ethyl acetate, heptane, and combinations thereof.

[0232] More specifically, in certain embodiments, a base is added to a cooled suspension of a compound of formula (III) or (IIIa) in a solvent. The resulting solution is stirred for about 30 minutes to about 12 hours or about 30 minutes, and 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 slowly added (e.g., over 30 minutes), and the resulting mixture is stirred for about 30 minutes to about 6 hours or about 30 minutes at a temperature of about -20°C to about 0°C or about -10°C. In one embodiment, after adding a solution of a compound of formula (IV) or (IVa) in a solvent, the resulting mixture is stirred for about 30 minutes at a temperature of about -10°C. In one embodiment, the reaction is quenched, and in some embodiments, the resulting product (V) or (Va) is separated before step (d).

[0233] In the step (d) of Scheme I and Ia, a compound with formula (V) or (Va) is contacted with perfluoroanhydride and an organic base to form a compound with formula (VI) or (VIa). The limiting examples of suitable organic bases include pyridine, triethylamine and combinations thereof. The example of suitable perfluoroanhydride includes 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. The suitable solvent for step (d) includes but is not limited to acetonitrile, toluene and combinations thereof.

[0234] More specifically, in certain embodiments, an organic base and perfluoroanhydride are loaded into 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, a mixture of perfluoroanhydride and a compound of formula (V) or (Va) is heated to about 55°C and stirred for about 4 hours to about 18 hours. In one embodiment, the mixture is stirred for about 6 hours. After the reaction is complete, in some embodiments, the reaction mixture can be cooled and concentrated to quench excess reagent and remove the tosyl protecting group before contacting with a hydroxide solution. Suitable hydroxide solutions include sodium hydroxide (NaOH) solution, potassium hydroxide (KOH) solution, and the like. The resulting mixture can be stirred at room temperature to about 85°C (including 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 converted 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 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 means 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., heating at a temperature from room temperature to about 85°C, including about 50°C. After deprotection, the compound having 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, under a hydrogen pressure of about 1psig to about 100psig, palladium on carbon and a compound with formula (VI) or (VIa) are mixed in a solvent. In another embodiment, the hydrogen pressure is about 20psig. 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 the reaction is complete, the reaction mixture is cooled and filtered, and then an appropriate acid is added. Before step (f), the resulting salt is optionally separated.

[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 (e.g., over 20 minutes) added 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. The pH of the two-phase mixture of the pharmaceutically acceptable salt from step (e) in the buffer and the solvent is adjusted to about 7 to about 11 by adding a base, 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 a base in batches for 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 a base in batches for 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 1a. In certain embodiments, the method can 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 sulfur ylide (II). The sulfur ylide (II) is contacted with LiX and sulfonic acid to produce the corresponding halomethyl ketone (III). (III) is reacted with (IV) in the presence of a base to produce (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 (VII) (not shown) with hydrochloric acid produces a 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, followed by formation of compound 1 free base. Option 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 of formula (I) is used in the reaction of step (a). In one embodiment, the pharmaceutically acceptable salt of a compound of formula (I) is selected from the group consisting of naphthyl ethylamine salt (Ia) and dicyclohexylamine salt (Ia).

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

[0246] In step (f) of scheme II, salt (VIIb) is contacted with a base to form the corresponding free base (VII). Suitable bases include, but are not limited to, hydroxides such as sodium hydroxide, potassium hydroxide, and 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, a combination of single water or 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 step (g) reaction is carried out in the presence of a coupling agent such as CDI. Step (g) in Scheme II is carried out using similar reagents and under similar conditions as described in step (f) of Scheme I above.

[0248] In the step (h) of scheme II, compound 1 is contacted with L-tartaric acid to form corresponding tartrate (step (h)). The formation of tartrate is conducive to removing impurities before separating free alkali. In one embodiment, tartrate can be formed using the program described in example 8 method B, only tartrate is not dried before step (i). Subsequently tartrate is converted back into free alkali form (step (i)) to produce compound 1. Specifically, in step (i), tartrate can be contacted with alkali (such as inorganic base) to produce corresponding free alkali. Suitable alkali includes but is not limited to sodium bicarbonate, sodium carbonate, sodium hydroxide, potassium carbonate, potassium bicarbonate, potassium hydroxide etc., or its combination. In one embodiment, tartrate is contacted with sodium bicarbonate and sodium carbonate to produce corresponding free alkali.

[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 isolated prior to the subsequent step.

[0251] An alternative method for preparing compound 1 is illustrated in Scheme III. Compound (XIa) is hydrogenated to produce (I). Protected (3R,4S)-4-ethylpyrrolidine-3-carboxylic acid (I) is reacted with trimethylsulfoxonium chloride to produce the sulfur ylide (II). The sulfur ylide (II) is contacted with anhydrous HBr or anhydrous HCl source to produce the corresponding halomethyl ketone (III). (III) is reacted with (IV) in the presence of a base to produce (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 a pharmaceutically acceptable salt of (VII). Reaction of a pharmaceutically acceptable salt of (VII) with 2,2,2-trifluoroethylamine produces compound 1. Option III in: 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 this embodiment, the compound of formula (IV) is a compound of formula (IVa): Wherein R is methyl or ethyl. Surprisingly found that when R is ethyl or methyl, there is the compound of formula (V) and subsequent downstream compounds can be separated as crystalline solids, which helps the purification of these intermediates. On the contrary, the previously known method using the compound in which R is tert-butyl leads to the formation of the compound with formula (V), which is separated as an amorphous solid.

[0254] Another method for preparing compound 1 is illustrated in Scheme IIIa. 1-((Benzyloxy)carbonyl)-4-ethyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid (XI) is hydrogenated to produce (XII). (3R,4S)-1-((Benzyloxy)carbonyl)-4-ethylpyrrolidine-3-carboxylate (XII) is reacted with trimethylsulfoxonium chloride to produce the sulfur ylide (IIa). The sulfur ylide (IIa) is contacted with an anhydrous HBr source to produce the corresponding bromomethyl ketone (IIIa). (IIIa) is reacted with an alkyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate (IVa) in the presence of lithium tert-butoxide to produce (Va). Cyclization of (Va) in the presence of perfluoroanhydride and an organic base produces (VIa). Removal of the carboxybenzyl protecting group and contacting the deprotected compound with hydrochloric acid produces a pharmaceutically acceptable salt (VIIa). The pharmaceutically acceptable salt (VIIa) is reacted with 2,2,2-trifluoroethylamine to produce compound 1. Scheme IIIa in: Cbz is a carboxylic acid benzyl group; 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 converted to (I) or (XII), respectively. Specifically, in step (a), compound (XI) or (XIa) can be contacted with a catalyst, such as a ruthenium catalyst. Any catalyst comprising a chiral phosphine can be used. A specific example of a suitable catalyst is diacetate [(S)-(-)5,5'-bis(diphenylphosphine)-4,4'-di-1,3-benzodioxole]ruthenium (II) (i.e., (S)-SegphosRu(OAc)2). Suitable solvents for step (a) include, but are not limited to, methanol, triethylamine, and combinations thereof.

[0256] In certain embodiments, (XI) or (XIa) and a solution of catalyst in a solvent are hydrogenated at about 30°C to about 100°C for about 1 hour to about 18 hours. In one embodiment, (XI) or (XIa) and a solution of catalyst in a solvent are hydrogenated at about 580psi. In one embodiment, (XI) or (XIa) and a solution of catalyst in a solvent are hydrogenated at about 200psi gauge pressure (psig). In one embodiment, (XI) or (XIa) and a solution of catalyst in a solvent are 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, the step (a) of scheme III and IIIa is carried out as described in the steps A of example 4.

[0257] The reaction in step (b) of scheme III and IIIa is usually completed in the presence of a coupling agent such as carbonyl diimidazole (CDI) and a strong base. The strong base can be, for example, potassium tert-butoxide, sodium tert-butoxide or a combination thereof. 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 carbonyl diimidazole 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 a temperature of 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 is slowly added to the solution (e.g., over 30 minutes to 1 hour, or over 30 minutes). The resulting mixture is stirred at room temperature for 30 minutes to 12 hours, and typically for about 1 hour. The resulting solution is slowly added (e.g., over 15 minutes to 1 hour, or over 1 hour) to a suspension of trimethylsulfoxonium chloride, a strong base, and a solvent while maintaining an 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 prior to step (c). In a specific embodiment, step (b) of Scheme III or IIIa is performed 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 need for forming and isolating the naphthylethaneamine salt (Ia) or the dicyclohexylamine salt (Ib), or isolating (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 an 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 (e.g., 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 (e.g., 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 the halomethyl ketone (III) or (IIIa) in higher purity than in Schemes 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, a base is slowly added (e.g., over about 30 minutes) to a cooled suspension of a compound of formula (IV) or (IVa) in a solvent. In one embodiment, a suspension of a compound of formula (IV) or (IVa) is cooled to about 0°C. The resulting solution is stirred for about 30 minutes to about 12 hours or about 30 minutes and 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. The halomethyl ketone solution prepared in step (c) is then slowly added (e.g., over about 1 hour), and the resulting mixture is stirred (e.g., agitated) for about 30 minutes to about 6 hours, or about 30 minutes at a temperature of about -20°C to about 0°C, or about -10°C. 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 performed as described in Step C of Example 4.

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

[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 naphthyl ethylamine salt of formula (Ia) or a dicyclohexylamine salt of formula (Ib). Compounds of formula (I) and (Ia) and their preparation are described in, for example, 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) (i.e., compounds of formula (XII)) wherein PG is Cbz 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. Cbz can be substituted with other protecting groups using techniques known to those skilled in the art. Formula (Ia)

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

[0269] In step (a) of Scheme IV, ethyl pent-2-ynoate is hydrogenated with 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 (e.g., THF) and an organic base (e.g., pyridine). The reaction mixture is sparged with hydrogen (e.g., for about 15 hours). In one embodiment, after the reaction is complete, the reaction mixture is filtered and the ethyl (Z)-pent-2-enoate is washed prior to 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 provide (XIII).

[0271] In steps (c) and (d) of scheme IV, (XIII) is deprotected to form (XIV), followed by hydrolysis of (XIV) to form (XV). Any suitable means known in the art can be used to deprotect (XIII), including those methods described above for step (e) of scheme I. In one embodiment, under hydrogen pressure, (XIII) is deprotected by contacting with a catalyst (e.g., a palladium catalyst, such as Pd / C or Pd(OH2) / C). In one embodiment, the resulting mixture is filtered to provide (XIV). In step (d), (XIV) is contacted with an acid (e.g., HCl). In one embodiment, the reaction mixture is 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., 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). Scheme V illustrates a method for preparing a dicyclohexylamine salt of a compound of formula (I). Carboxybenzyl-glycine ethyl ester is reacted with ethyl acrylate to form (VIII). Protecting (VIII) produces (IX). In the presence of a catalyst, (IX) is contacted with one of ethylboric acid, ethylmagnesium bromide, or ethylzinc chloride to produce (X). (X) is hydrolyzed to produce (XI), which is hydrogenated to produce (XII). (XII) is contacted with dicyclohexylamine to form (Ib). Plan V in Cbz is carboxybenzyl; and R 3 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). 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, step (a) reaction is carried out in an organic solvent (such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 2-methyltetrahydrofuran, and the like, and combinations thereof).

[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. Before step (b), the product can be optionally separated.

[0276] In the step (b) of scheme V, the compound with formula (VIII) is protected to form (IX). In one embodiment, the compound with 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 DEG C to about 20 DEG C, trifluoromethanesulfonic anhydride, methanesulfonyl chloride or p-toluenesulfonyl chloride are added to the mixture of (VIII) in a solvent. In one embodiment, at a temperature of about 0 DEG C, trifluoromethanesulfonic anhydride, methanesulfonyl chloride or p-toluenesulfonyl chloride are added to the mixture of (VIII) in a solvent. Subsequently, an organic base is slowly added (for example, over about 30 minutes), and the mixture is warming 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, the reaction is preferably quenched and the product is washed. In certain embodiments, a solution of (IX) in a solvent is prepared and directly used in step (c).

[0278] In step (c) of scheme V, (IX) is contacted with one of ethylboric 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 certain embodiments, the catalyst is a nickel catalyst, such as Ni(acac)2. In certain 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 step (c) include, but are not limited to, toluene, water, dioxane, tetrahydrofuran, and combinations thereof.

[0279] Specifically, in certain embodiments, ethylboric acid and buffer are added to the solution of (IX) in the solvent prepared in step (b). Suitable catalysts can then be added, and the resulting mixture is warmed 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 warmed 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, an alkali metal hydroxide is added to a solution of (X) in a solvent. The resulting mixture is warmed to about 20°C to about 65°C and stirred for about 2 hours to about 18 hours. In one embodiment, the mixture is warmed to about 50°C and stirred for about 2 hours to about 18 hours. In one embodiment, the mixture is stirred for about 7 hours. 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 the steps (e) and (f) of scheme V, (XI) is converted into (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 comprising a chiral phosphine can be used. A specific example of a suitable catalyst is diacetate and [(S)-(-)5,5'-bis(diphenylphosphine)-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 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) and a catalyst in a solvent is hydrogenated at about 580psi. In one embodiment, a solution of (XI) and a 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, before step (f), the product is washed and transferred to a suitable solvent such as acetonitrile. In step (f), another solvent (such as 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 separated before being used to prepare compound 1. C. Intermediate compounds

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

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

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

[0287] On the other hand, the present disclosure relates to a method for preparing a compound of formula (IVa). A suitable method for preparing a compound of formula (IVa) is described in Scheme VI. Specifically, (XVII) is reacted with trimethylsilyl acetylene 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 of formula (IVa). Plan VI in: R2 is methyl or ethyl; Ts is tosyl; and TMS is trimethylsilyl.

[0288] In step (a) of Scheme VI, commercially available compound (XVII) is reacted with trimethylsilyl acetylene in the presence of a catalyst to form (XVIII). Any suitable catalyst known in the art can be used. In certain 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, a 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 slowly added (e.g., over about 15 minutes) a solution of trimethylsilyl acetylene in a solvent. The reaction mixture is stirred at about -5°C to 0°C (e.g., 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 use in step (b) include, but are not limited to, potassium tert-butoxide, sodium hydride, and the like, and combinations thereof. Suitable solvents for use in step (b) include, but are not limited to, dimethylformamide.

[0291] Specifically, in certain embodiments, a base is added to a solution of (XVIII) in a solvent (e.g., at about 0° C.). p-Toluenesulfonyl chloride is subsequently added and the mixture is allowed to warm 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 isolated and purified before step (c).

[0292] In the 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 with formula (IVa). The reaction can be carried out in the presence of a buffer (such as 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 acetate (II). The suitable ligand for step (c) includes a bidentate ligand, such as Xantphos. In one embodiment, the catalyst is palladium acetate (II), and the ligand is Xantphos. The suitable solvent for step (c) includes but is not limited to dioxane, toluene and tetrahydrofuran.

[0293] Specifically, in certain embodiments, a degassed mixture of a catalyst, a ligand, (XIX), a carbamate, and a 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 being used in the preparation of (3S, 4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-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 compounds 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 of formula (II) or (IIa). A method for preparing a compound of formula (II) or (IIa) is described in Scheme VII. In Scheme VII, a compound of formula (I) or a pharmaceutically acceptable salt thereof is reacted with trimethylsulfoxonium chloride to form a compound of formula (II). In a specific embodiment, the pharmaceutically acceptable salt is a compound of formula (Ib). Scheme VII wherein PG is a protecting group as defined herein.

[0299] The reaction of Scheme VII is typically 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 compounds of formula (II) or (IIa) is illustrated in Scheme VIII. In step (a) of Scheme VIII, a compound of formula (XIa) is hydrogenated to a compound of formula (I), and in step (b) of Scheme VIII, the compound of formula (I) is reacted with trimethylsulfoxonium chloride to form a compound of formula (II). Scheme VIII wherein PG is a protecting group as defined herein.

[0301] In step (a) of scheme VIII, the compound of formula (XIa) can be contacted with a catalyst (such as a ruthenium catalyst). Any catalyst comprising a chiral phosphine can be used. A specific example of a suitable catalyst is diacetate and [(S)-(-)5,5'-bis(diphenylphosphine)-4,4'-di-1,3-benzodioxole]ruthenium (II) (i.e., (S)-Segphos Ru(OAc) 2). Suitable solvents for 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 typically 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. 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 process for preparing a compound having 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 of formula (III) is compound (IIIa), wherein Cbz is carboxybenzyl.

[0306] A method for preparing compounds of formula (III) or (IIIa) is illustrated in Scheme IX. Plan IX wherein PG and X are as defined herein.

[0307] With reference to Scheme IX, in one embodiment, a compound of formula (II) is contacted with LiX and a sulfonic acid to form a compound of formula (III). In this embodiment, the sulfonic acid is selected from the group consisting of methanesulfonic acid and p-toluenesulfonic acid. In one embodiment, the sulfonic acid is p-toluenesulfonic acid. LiX can be selected from lithium bromide and lithium chloride. In one embodiment, LiX is lithium bromide. In one embodiment, the reaction is carried out in lithium bromide and p-toluenesulfonic acid. The reaction can be carried out in any suitable solvent (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] With reference to Scheme IX, in an alternative embodiment, a compound of formula (II) is contacted with anhydrous HBr or anhydrous HCl source to form a compound of 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 of preparing a compound of formula (III) or (Ilia) can further comprise preparing a compound of 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 of formula (I) or a pharmaceutically acceptable salt thereof is reacted with trimethylsulfoxonium chloride in the presence of carbonyldiimidazole and a strong base (e.g., potassium tert-butoxide, sodium tert-butoxide, and combinations thereof) to form a compound of formula (II). The compound of formula (II) is then contacted with LiX and a sulfonic acid to form a compound of 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 of formula (II) is compound (IIa). In another embodiment, in step (a) of Scheme X, a pharmaceutically acceptable salt of a compound of formula (I) is reacted with trimethylsulfoxonium chloride to form a compound of formula (II). In one embodiment, the salt is (Ia) or (Ib).

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

[0312] In the step (a) of scheme XI, the compound with formula (XIa) is hydrogenated to a compound with formula (I), and in step (b), in the presence of CDI and a strong base (such as KOtBu, NatOBu and combinations thereof), the compound with formula (I) is reacted with trimethylsulfoxonium chloride to form a compound with formula (II). The compound with formula (II) is then contacted with anhydrous HBr or anhydrous HCl source to form a compound with formula (III), as described in scheme IX above. In one embodiment, the protecting group is a carboxybenzyl group, and the compound with formula (XIa), (I) and (II) is compound (XI), (XII) and (IIa) respectively. In one embodiment, the steps (a), step (b) and step (c) of scheme XI are carried out under the conditions described in the above steps (a), step (b) and step (c) for scheme III, respectively. Formula (V) and (Va)

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

[0314] On the other hand, 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 described 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). Plan 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 this embodiment, the compound of formula (IV) is a compound of formula (IVa).

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

[0319] The reaction in step (a) of Scheme XII is typically carried out in the presence of a coupling agent such as carbonyldiimidazole (CDI) and a strong base. The strong base can be, for example, potassium tert-butoxide, sodium tert-butoxide, or a combination thereof. The step (a) reaction can be carried out in any suitable solvent 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, a compound of formula (II) or (IIa) is contacted with LiX and a sulfonic acid to form a compound of 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, 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 (c) is carried out in the presence of a base such as lithium tert-butoxide, sodium tert-butoxide, or a combination thereof. In one embodiment, the base is lithium tert-butoxide. The reaction of step (c) can be carried out in any suitable solvent, 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 performed under the conditions described herein for the corresponding steps of Scheme I.

[0323] On the other hand, present disclosure relates to an alternative method for preparing a compound with formula (V) or (Va). A method for preparing a compound with formula (V) or (Va) is described in Scheme XIII. In Scheme XIII, the compound with formula (XIa) is hydrogenated to a compound with formula (I), and the compound with formula (I) is reacted with trimethylsulfoxonium chloride to form a compound with formula (II). The compound with formula (II) is contacted with anhydrous HBr or anhydrous HCl source to produce corresponding halomethyl ketone (III). The compound with formula (III) is reacted with a compound with formula (IV) in the presence of a base to produce a compound with formula (V). Plan 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 of formula (XIa), (I), (II), (III), (IV), and (V) are compounds (XI), (XII), (IIa), (IIIa), (IVa), and (Va), respectively. In one embodiment, the protecting group is carboxybenzyl, and X is Br. In one embodiment, R1 is -OR2 and R2 is methyl or ethyl. In this embodiment, the compound of formula (IV) is a compound of formula (IVa).

[0325] In the step (a) of scheme XIII, the compound with formula (XIa) can be contacted with a catalyst (such as a ruthenium catalyst). Any catalyst comprising a chiral phosphine can be used. A specific example of a suitable catalyst is diacetate and [(S)-(-)5,5'-bis(diphenylphosphine)-4,4'-di-1,3-benzodioxole]ruthenium (II) (i.e., (S)-Segphos Ru(OAc) 2). Suitable solvents for 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 completed in the presence of a coupling agent (such as carbonyl diimidazole (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 carbonyl diimidazole 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, a compound of formula (II) is contacted with anhydrous HBr or anhydrous HCl source to form a compound of 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 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, a compound of formula (III) 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. 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 was surprisingly found that when R1 is -OR2 and R2 is ethyl or methyl, the compound of formula (V) and subsequent downstream compounds can be isolated as crystalline solids, which facilitates the purification of these intermediates. Therefore, in another aspect, the present disclosure is directed to a method for preparing a crystalline compound of formula (V). The method comprises a) allowing a compound of formula (III): Reaction with a compound of formula (IV): To produce the compound of 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 disclosure relates to compound (VII):

[0331] or a pharmaceutically acceptable salt thereof.

[0332] In one embodiment, the pharmaceutically acceptable salt of (VII) is 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 can further comprise forming one of the solid state forms described in Section 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 ambient 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, handling, flowability, and miscibility; and (6) filterability. These properties can affect, for example, the processing and storage of the compound and pharmaceutical compositions containing the compound.

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

[0336] The amorphous free alkali form of compound 1 has larger solubility conventionally, and relative to most of the corresponding crystal forms of this compound, has the bioavailability of improvement.Amorphous free alkali also has acceptable chemical stability.Yet it is hygroscopic, and needs environmental control potentially to guarantee during storage, distribution and processing amorphous free alkali, suitably control effectiveness and water content.In addition, amorphous free alkali shows the oiling-out limit (oiling-out) near solubility curve in manufacturing process.

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

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

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

[0340] Free base hydrate Form B has been produced on a large scale without the need for labor-intensive and expensive techniques such as spray drying. It also provides adequate control of the bulk properties of the amorphous free base. However, when isolated by free base hydrate Form B, the amorphous free base exhibits 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 for use as an active ingredient in a pharmaceutical dosage form, it may be a useful intermediate for preparing other solid-state forms (e.g., the amorphous free base).

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

[0343] Free base hydrate Form C generally exhibits excellent chemical and physical stability, and solid-state properties, including low hygroscopicity and a prismatic morphology. Free base hydrate Form C has improved overall properties, such as powder flowability and bulk density, which are advantageous during formulation. Furthermore, free base hydrate Form C offers at least the following unexpected advantages over other forms: 1) efficient purification is possible because tartrate crystals are not required; 2) the inoculation step is simple because free base hydrate Form C can be stored under normal conditions; 3) the drying step can be performed under normal conditions using standard equipment because dehydration does not occur until approximately 110°C; and 4) free base hydrate Form C can be crystallized in various particle sizes. Large-scale production of free base hydrate Form C is relatively straightforward, with minimal scaling, good yields, good impurity rejection, rapid filtration, routine drying, and minimal milling issues. Furthermore, free base hydrate Form C can be produced in various particle sizes.

[0344] Free base hydrate form D can only be produced when the crystallization solvent has a low water content and is converted into free base hydrate form C in a solution with a high water content. Therefore, the production of free base anhydrate form D requires strict control of water content. 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, at 90% RH) and is metastable relative to free base hydrate form C under typical environmental conditions used during storage for downstream processing (e.g., at 23°C, more than 2.4% RH). Free base hydrate form C will be converted into free base anhydrate form D in an ethyl acetate solution with a low water content.

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

[0346] In one embodiment, the solid state 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 amorphous free base has a glass transition temperature onset of about 119°C. In another aspect, the amorphous free base has a glass transition temperature midpoint of about 122°C. In another aspect, the amorphous free base has a glass transition temperature onset of about 119°C and a glass transition temperature midpoint of about 122°C. Amorphous free base is further described in the Examples of this application.

[0347] The amorphous free base generally has greater solubility and, relative to the corresponding crystalline form of the compound, has improved bioavailability. Amorphous free base also has acceptable chemical stability. For example, when chemical stability was assessed 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 amorphous free base was observed in the sealed vials under any of these conditions. In addition, the amorphous free base showed acceptable stability to light and peroxides. However, the amorphous free base is hygroscopic and can contain up to 12% water by weight at 25°C / 90% relative humidity. Environmental control is potentially required to ensure that efficacy and water content are properly controlled during storage, distribution, and handling of the amorphous free base.

[0348] For example, antisolvent crystallization can be used to prepare amorphous free alkali to prepare free alkali solvate form A or free alkali hydrate form B (as described below), then dehydration or desolvation are to produce amorphous free alkali.This crystallization / dehydration / desolvation method allows large-scale manufacturing of amorphous free alkali, and does not need labor-intensive and expensive technology, such as spray drying.It also provides the appropriate control (that is, granularity, mobility etc.) of the overall property of amorphous free alkali.When amorphous free alkali is prepared by the desolvation of free alkali solvate form A or the dehydration of free alkali hydrate form B, this amorphous free alkali retains the form of free alkali solvate form A or free alkali hydrate form B usually (that is, when prepared by the dehydration of free alkali hydrate form B, for the blade with hexagonal crystal face, or when being irregular from free alkali solvate form A desolvation).

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

[0350] In another embodiment, the solid state form is a crystalline free base of Compound 1. In one aspect, the crystalline free base is a solvate. In another aspect, the crystalline free base is an isopropyl acetate / water solvate ("free base solvate Form A"). In another aspect, the crystalline free base is a hydrate ("free base hydrate Form B"). The free base solvate Form A and free base hydrate Form B are further described in the Examples herein.

[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 at about 25°C using monochromatic Kα1 radiation.

[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 at about 25°C using monochromatic Kα1 radiation, 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 without significant peaks 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 having no significant peaks 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 having no significant peaks at one or more of 15.1±0.2 degrees 2θ and 21.7±0.2 degrees 2θ, and no significant peaks 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, and lacking significant peaks 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.

[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, and lacks significant peaks 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.

[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, and lacking significant peaks at one or more of 15.1±0.2 degrees 2θ and 21.7±0.2 degrees 2θ, and lacking significant peaks 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.

[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, and 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, and lacks 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.

[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, and 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, and lacks significant peaks 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.

[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, and 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, and lacking significant peaks at one or more of 15.1±0.2 degrees 2θ and 21.7±0.2 degrees 2θ, and lacking significant peaks 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.

[0366] In one embodiment, the crystalline free base solvate or hydrate has an X-ray powder diffraction pattern characterized by peaks at ±0.2 degrees 2Θ substantially at the positions 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 ±0.2 degrees 2Θ substantially at the positions 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 a peak at ±0.2 degrees 2Θ substantially at the positions listed in Table 16-B when measured at about 25°C using monochromatic Kα1 radiation, with a relative intensity of at least 10.0%.

[0369] In further aspects of each of the above embodiments, the significant peak has a variation of ±0.1 degrees 2Θ instead of ±0.2 degrees 2Θ. In still further aspects of each of the above embodiments, the significant peak has a variation of ±0.05 degrees 2Θ instead of ±0.2 degrees 2Θ.

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

[0371] In one embodiment, the crystalline free base has a thermogravimetric analysis chart showing a weight loss of about 5% to about 6% when heated at a rate of 10°C / minute between about 100°C and about 160°C.

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

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

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

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

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

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

[0378] In one embodiment, the crystalline free base has substantially Figure 5B The differential scanning calorimetry diagram is shown in .

[0379] In one embodiment, the crystalline free base has a thermogravimetric analysis pattern showing a weight loss of about 5% to about 6% when heated at a rate of 10°C / minute between about 100°C and about 160°C; and a differential scanning calorimetry pattern comprising a first endotherm between about 25°C and about 100°C and / or a second endotherm between about 100°C and about 160°C when heated at a rate of 10°C / minute. In one aspect, the differential scanning calorimetry pattern comprises a first endotherm between about 25°C and about 100°C when heated at a rate of 10°C / minute. In another aspect, the differential scanning calorimetry pattern comprises a second endotherm between about 100°C and about 160°C when heated at a rate of 10°C / minute. In another aspect, the differential scanning calorimetry plot includes a first endotherm between about 25°C and about 100°C, and a second endotherm between about 100°C and about 160°C when heated at a rate of 10°C / minute.

[0380] In one embodiment, the crystalline free base has a thermogravimetric analysis pattern showing a weight loss of about 5% to about 6% when heated at a rate of 10°C / minute between about 100°C and about 160°C; and a differential scanning calorimetry pattern comprising a first endotherm at about 59.90°C to about 98.79°C and / or a second endotherm at about 109.31°C to about 132.94°C when heated at a rate of 10°C / minute. In one aspect, the differential scanning calorimetry pattern comprises a first endotherm at about 59.90°C to about 98.79°C when heated at a rate of 10°C / minute. In another aspect, the differential scanning calorimetry pattern comprises a second endotherm at about 109.31°C to about 132.94°C when heated at a rate of 10°C / minute. In another aspect, the differential scanning calorimetry plot includes a first endotherm between about 59.90°C and about 98.79°C, and a second endotherm between about 109.31°C and about 132.94°C, when heated at a rate of 10°C / minute.

[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 pattern showing a weight loss of about 5% to about 6% when heated at a rate of 10°C / minute between about 100°C and about 160°C; and (b) a differential scanning calorimetry pattern comprising a first endotherm between about 25°C and about 100°C and / or a second endotherm between about 100°C and about 160°C when heated at a rate of 10°C / minute. In one aspect, the differential scanning calorimetry pattern comprises a first endotherm between about 25°C and about 100°C when heated at a rate of 10°C / minute. In another aspect, the differential scanning calorimetry pattern comprises a second endotherm between about 100°C and about 160°C when heated at a rate of 10°C / minute. In another aspect, the differential scanning calorimetry plot includes a first endotherm between about 25°C and about 100°C, and a second endotherm between about 100°C and about 160°C when heated at a rate of 10°C / minute.

[0382] In one embodiment, the crystalline free base has an X-ray diffraction pattern as described above, and further has a thermogravimetric analysis pattern showing a weight loss of about 5% to about 6% when heated between about 100°C and about 160°C at a rate of 10°C / minute.

[0383] In one embodiment, the crystalline free base has an X-ray diffraction pattern as described above and further has a differential scanning calorimetry pattern comprising a first endotherm between about 25°C and about 100°C and / or a second endotherm between about 100°C and about 160°C when heated at a rate of 10°C / minute. In one aspect, the differential scanning calorimetry pattern comprises a first endotherm between about 25°C and about 100°C when heated at a rate of 10°C / minute. In another aspect, the differential scanning calorimetry pattern comprises a second endotherm between about 100°C and about 160°C when heated at a rate of 10°C / minute. In another aspect, the differential scanning calorimetry pattern comprises a first endotherm between about 25°C and about 100°C and a second endotherm between about 100°C and about 160°C when heated at a rate of 10°C / minute.

[0384] In one embodiment, the crystalline free base has an X-ray diffraction pattern as described above; a thermogravimetric analysis pattern showing a weight loss of about 5% to about 6% when heated at a rate of 10°C / minute between about 100°C and about 160°C; and a differential scanning calorimetry pattern comprising a first endotherm between about 25°C and about 100°C and / or a second endotherm between about 100°C and about 160°C when heated at a rate of 10°C / minute. In one aspect, the differential scanning calorimetry pattern comprises a first endotherm between about 25°C and about 100°C when heated at a rate of 10°C / minute. In another aspect, the differential scanning calorimetry pattern comprises a second endotherm between about 100°C and about 160°C when heated at a rate of 10°C / minute. In another aspect, the differential scanning calorimetry plot includes a first endotherm between about 25°C and about 100°C, and a second endotherm between about 100°C and about 160°C when heated at a rate of 10°C / minute.

[0385] Free base solvate Form A and free base hydrate Form B are physically unstable. As described above, after drying, they desolvate (or dehydrate) and are converted to amorphous free base. Although free base solvate Form A and free base hydrate Form B generally do not exhibit pharmaceutically acceptable physical stability for use as active ingredients in pharmaceutical dosage forms, they are useful intermediates for preparing other solid forms (e.g., amorphous free base). C. Crystalline free base hydrate Form C (hemihydrate)

[0386] In another embodiment, the solid state form is a crystalline hydrate, wherein the crystalline hydrate is a hemihydrate. In another embodiment, the solid state form is a crystalline hemihydrate of compound 1 having an X-ray powder diffraction pattern corresponding to free base hydrate Form C. 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 at about 25°C using monochromatic Kα1 radiation.

[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 at about 25°C using monochromatic Kα1 radiation, and is further characterized by peaks at 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, and 19.1±0.2 degrees 2θ. 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 at about 25°C using monochromatic Ka1 radiation.

[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 at about 25°C using monochromatic Kα1 radiation.

[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 without significant peaks 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 without significant peaks 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 having no significant peaks 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 no significant peaks 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, and lacks significant peaks 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.

[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, and lacks significant peaks 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.

[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, and lacks significant peaks 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 lacks significant peaks 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.

[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, and lacks significant peaks 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.

[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, and lacks significant peaks 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.

[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, and lacks significant peaks 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 lacks significant peaks 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.

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

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

[0405] In further aspects of each of the above embodiments, the significant peak has a variation of ±0.1 degrees 2Θ instead of ±0.2 degrees 2Θ. In still further aspects of each of the above embodiments, the significant peak has a variation of ±0.05 degrees 2Θ instead of ±0.2 degrees 2Θ.

[0406] In one embodiment, the free base hydrate Form C has substantially the following properties when measured at about 25°C using monochromatic Kα1 radiation: Figure 3C The X-ray powder diffraction pattern is shown in .

[0407] In one embodiment, the free base hydrate Form C has a thermogravimetric analysis pattern showing a weight loss of about 2.3% to about 2.6% when heated between about 120°C and 160°C at a rate of 10°C / minute.

[0408] In one embodiment, the free base hydrate Form C has a thermogravimetric analysis pattern showing a weight loss of about 2.3% to about 2.6% when heated between about 114.52°C and 168.15°C at a rate of 10°C / minute.

[0409] In one embodiment, the free base hydrate Form C has substantially Figure 4E Thermogravimetric analysis diagram shown in .

[0410] In one embodiment, the free base hydrate Form C has a differential scanning calorimetry plot comprising endotherms between about 120°C and about 170°C when heated at a rate of 10°C / minute.

[0411] In one embodiment, the free base hydrate Form C has a differential scanning calorimetry plot comprising endotherms between about 134.70°C and about 167.53°C when heated at a rate of 10°C / minute.

[0412] In one embodiment, the free base hydrate Form C has substantially Figure 5C The differential scanning calorimetry diagram is shown in .

[0413] In one embodiment, the free base hydrate Form C has a moisture sorption isotherm showing a weight gain of about 0% to about 0.2% when the relative humidity is increased from about 0% relative humidity to about 90% relative humidity at a temperature of 25°C.

[0414] In one embodiment, the free base hydrate Form C has substantially Figure 6B The water adsorption isotherm diagram shown in .

[0415] In one embodiment, the free base hydrate Form C has a thermogravimetric analysis pattern showing a weight loss of about 2.3% to about 2.6% when heated at a rate of 10°C / minute between about 120°C and 160°C; and a differential scanning calorimetry pattern comprising an endotherm when heated at a rate of 10°C / minute between about 120°C and about 170°C.

[0416] In one embodiment, the free base hydrate Form C has a thermogravimetric analysis plot showing a weight loss of about 2.3% to about 2.6% when heated between about 120°C and 160°C at a rate of 10°C / minute; and a moisture sorption isotherm plot showing a weight gain of 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.

[0417] In one embodiment, the free base hydrate Form C has a differential scanning calorimetry plot comprising an endotherm between about 120°C and about 170°C when heated at a rate of 10°C / minute, and a water sorption isotherm plot showing 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.

[0418] In one embodiment, the free base hydrate Form C has a thermogravimetric analysis plot showing a weight loss of about 2.3% to about 2.6% when heated between about 120°C and 160°C at a heating rate of 10°C / minute; a differential scanning calorimetry plot containing an endotherm when heated between about 120°C and about 170°C at a heating rate of 10°C / minute; and a water sorption isotherm plot showing a weight gain of 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 plot showing a weight loss of about 2.3% to about 2.6% when heated between about 120°C and 160°C at a heating rate of 10°C / minute; a differential scanning calorimetry plot containing an endotherm between about 134.70°C and about 167.53°C when heated at a rate of 10°C / minute; and a water sorption isotherm plot showing a weight gain of 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, 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 about about peace treaty

[0423] In one embodiment, the free base hydrate Form C has an X-ray diffraction pattern as described above, and at least one of: (a) a thermogravimetric analysis pattern showing a weight loss of about 2.3% to about 2.6% when heated between about 120°C and 160°C at a rate of 10°C / minute; (b) a differential scanning calorimetry pattern containing an endotherm when heated between about 120°C and about 170°C at a rate of 10°C / minute; and / or (c) a water sorption isotherm pattern showing a weight gain of 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 an X-ray diffraction pattern as described above, and a thermogravimetric analysis pattern showing a weight loss of about 2.3% to about 2.6% when heated between about 120°C and 160°C at a rate of 10°C / minute.

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

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

[0427] In one embodiment, the free base hydrate Form C has an X-ray diffraction pattern as described above; a thermogravimetric analysis pattern showing a weight loss of about 2.3% to about 2.6% when heated at a rate of 10°C / minute between about 120°C and 160°C; and a differential scanning calorimetry pattern comprising an endotherm when heated at a rate of 10°C / minute between about 120°C and about 170°C.

[0428] In one embodiment, the free base hydrate Form C has an X-ray diffraction pattern as described above; a thermogravimetric analysis pattern showing a weight loss of about 2.3% to about 2.6% when heated between about 120°C and 160°C at a rate of 10°C / minute; and a moisture sorption isotherm plot showing a weight gain of 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 an X-ray diffraction pattern as described above; a differential scanning calorimetry pattern comprising an endotherm between about 120°C and about 170°C when heated at a rate of 10°C / minute; and a water sorption isotherm plot showing 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.

[0430] In one embodiment, the free base hydrate Form C has an X-ray diffraction pattern as described above; a thermogravimetric analysis pattern showing a weight loss of about 2.3% to about 2.6% when heated between about 120°C and 160°C at a rate of 10°C / minute; a differential scanning calorimetry pattern containing an endotherm when heated between about 120°C and about 170°C at a rate of 10°C / minute; and a water sorption isotherm pattern showing a weight gain of 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.

[0431] The free base hydrate Form C generally exhibits good chemical stability, physical stability, and solid-state properties (including low hygroscopicity). Large-scale production of the free base hydrate Form C is relatively simple, with minimal scaling, good yields, good impurity rejection, rapid filtration, conventional drying, and minimal grinding problems (even after high-energy pin milling of the isolated material). In addition, different particle sizes can be obtained by appropriate control of the crystallization process. D. Crystalline free base anhydrate form D

[0432] In another embodiment, the solid state form is a crystalline anhydrate free base of Compound 1 having an X-ray powder diffraction pattern corresponding to the free base anhydrate Form D. The free base anhydrate Form D is further described in the Examples herein.

[0433] In one embodiment, the free base anhydrate 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 anhydrate 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 anhydrate 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 at about 25°C using monochromatic Kα1 radiation.

[0436] In one embodiment, the free base anhydrate 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 at about 25°C using monochromatic Kα1 radiation.

[0437] In one embodiment, the free base anhydrate 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 at about 25°C using monochromatic Kα1 radiation.

[0438] In one embodiment, the free base anhydrate 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.

[0439] In one embodiment, the free base anhydrate 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 at about 25°C using monochromatic Kα1 radiation.

[0440] In one embodiment, the free base anhydrate 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 at about 25°C using monochromatic Kα1 radiation.

[0441] In one embodiment, the free base anhydrate 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 at about 25°C using monochromatic Kα1 radiation.

[0442] In one embodiment, the free base anhydrate 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 at about 25°C using monochromatic Kα1 radiation, 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 anhydrate Form D has an X-ray powder diffraction pattern without 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 at about 25°C using monochromatic Kα1 radiation.

[0444] In one embodiment, the free base anhydrate Form D has an X-ray powder diffraction pattern without 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 at about 25°C using monochromatic Kα1 radiation.

[0445] In one embodiment, the free base anhydrate Form D has an X-ray powder diffraction pattern without 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 at about 25°C using monochromatic Kα1 radiation.

[0446] In one embodiment, the free base anhydrate Form D has an X-ray powder diffraction pattern having no 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, and no 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 no 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 at about 25°C using monochromatic Kα1 radiation.

[0447] In one embodiment, the free base anhydrate 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, and lacks 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 at about 25°C using monochromatic Kα1 radiation.

[0448] In one embodiment, the free base anhydrate 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, and lacks 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 at about 25°C using monochromatic Kα1 radiation.

[0449] In one embodiment, the free base anhydrate 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, and lacks 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 when measured at about 25°C using monochromatic Kα1 radiation.

[0450] In one embodiment, the free base anhydrate 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, and lacking 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 lacking 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 lacking 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 at about 25°C using monochromatic Kα1 radiation.

[0451] In one embodiment, the free base anhydrate 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, and lacks 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 at about 25°C using monochromatic Kα1 radiation.

[0452] In one embodiment, the free base anhydrate 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, and lacks 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 at about 25°C using monochromatic Kα1 radiation.

[0453] In one embodiment, the free base anhydrate 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, and lacks 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 when measured at about 25°C using monochromatic Kα1 radiation.

[0454] In one embodiment, the free base anhydrate 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, and a peak at 3.1±0. The invention also has no significant peaks at one or more of 2 degrees 2θ, 9.3±0.2 degrees 2θ, and 20.8±0.2 degrees 2θ, and has no 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 has no 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.

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

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

[0457] In further aspects of each of the above embodiments, the significant peak has a variation of ±0.1 degrees 2Θ instead of ±0.2 degrees 2Θ. In still further aspects of each of the above embodiments, the significant peak has a variation of ±0.05 degrees 2Θ instead of ±0.2 degrees 2Θ.

[0458] In one embodiment, the free base anhydrate Form D has substantially the following properties when measured at about 25°C using monochromatic Kα1 radiation: Figure 3J The X-ray powder diffraction pattern is shown in .

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

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

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

[0462] In one embodiment, the free base anhydrate Form D has a thermogravimetric analysis pattern showing a weight loss of about 0.5% when heated between about 43°C and 100°C at a rate of 10°C / minute.

[0463] In one embodiment, the free base anhydrate Form D has substantially Figure 4I Thermogravimetric analysis diagram shown in .

[0464] In one embodiment, the free base anhydrate Form D has a differential scanning calorimetry plot comprising endotherms between about 180°C and about 220°C when heated at a rate of 10°C / minute.

[0465] In one embodiment, the free base anhydrate Form D has a differential scanning calorimetry plot comprising endotherms between about 199.55°C and about 217.41°C when heated at a rate of 10°C / minute.

[0466] In one embodiment, the free base anhydrate Form D has a differential scanning calorimetry pattern having an endotherm with an onset melting point of about 199.55°C and a melting enthalpy of about 85.4 J / g.

[0467] In one embodiment, the free base anhydrate Form D has substantially Figure 5E The differential scanning calorimetry diagram is shown in .

[0468] In one embodiment, the free base anhydrate Form D has a moisture sorption isotherm showing 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.

[0469] In one embodiment, the free base anhydrate Form D has substantially Figure 6D The water adsorption isotherm diagram shown in .

[0470] In one embodiment, the free base anhydrate Form D has a thermogravimetric analysis pattern showing a weight loss of about 0.5% to about 0.8% when heated at a rate of 10°C / minute between about 43°C and 188°C; and a differential scanning calorimetry pattern comprising an endotherm when heated at a rate of 10°C / minute between about 180°C and about 220°C.

[0471] In one embodiment, the free base anhydrate Form D has a thermogravimetric analysis plot showing a weight loss of about 0.5% to about 0.8% when heated between about 43°C and 188°C at a rate of 10°C / minute; and a moisture sorption isotherm plot showing 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.

[0472] In one embodiment, the free base anhydrate Form D has a differential scanning calorimetry plot comprising an endotherm between about 180°C and about 220°C when heated at a rate of 10°C / minute; and a water sorption isotherm plot showing 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.

[0473] In one embodiment, the free base anhydrate Form D has a thermogravimetric analysis plot showing a weight loss of about 0.5% to about 0.8% when heated between about 43°C and 188°C at a heating rate of 10°C / minute; a differential scanning calorimetry plot comprising an endotherm when heated between about 180°C and about 220°C at a heating rate of 10°C / minute; and a moisture sorption isotherm plot showing 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 anhydrate Form D has a thermogravimetric analysis plot showing a weight loss of about 0.5% to about 0.8% when heated at a rate of 10°C / minute between about 43°C and 188°C; a differential scanning calorimetry plot comprising an endotherm when heated at a rate of 10°C / minute between about 199.55°C and about 217.41°C; and a moisture sorption isotherm plot showing 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 anhydrate Form D has an orthorhombic crystal lattice type.

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

[0477] In one embodiment, the unit cell a, b, and c values of the free base anhydrate form D are about about peace treaty

[0478] In one embodiment, the free base anhydrate Form D has an X-ray diffraction pattern as described above, and at least one of: (a) a thermogravimetric analysis pattern showing a weight loss of about 0.5% to about 0.8% when heated between about 43°C and 188°C at a rate of 10°C / minute; (b) a differential scanning calorimetry pattern containing an endotherm when heated between about 180°C and about 220°C at a rate of 10°C / minute; and / or (c) a moisture sorption isotherm pattern showing 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 anhydrate Form D has an X-ray diffraction pattern as described above, and a thermogravimetric analysis pattern showing a weight loss of about 0.5% to about 0.8% when heated between about 43°C and 188°C at a rate of 10°C / minute.

[0480] In one embodiment, the free base anhydrate Form D has an X-ray diffraction pattern as described above, and a differential scanning calorimetry pattern comprising an endotherm between about 180°C and about 220°C when heated at a rate of 10°C / minute.

[0481] In one embodiment, the free base anhydrate Form D has an X-ray diffraction pattern as described above, and a moisture sorption isotherm plot showing 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.

[0482] In one embodiment, the free base anhydrate Form D has an X-ray diffraction pattern as described above; a thermogravimetric analysis pattern showing a weight loss of about 0.5% to about 0.8% when heated at a rate of 10°C / minute between about 43°C and 188°C; and a differential scanning calorimetry pattern containing an endotherm when heated at a rate of 10°C / minute between about 180°C and about 220°C.

[0483] In one embodiment, the free base anhydrate Form D has an X-ray diffraction pattern as described above; a thermogravimetric analysis pattern showing a weight loss of about 0.5% to about 0.8% when heated between about 43°C and 188°C at a rate of 10°C / minute; and a moisture sorption isotherm pattern showing 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.

[0484] In one embodiment, the free base anhydrate Form D has an X-ray diffraction pattern as described above; a differential scanning calorimetry pattern comprising an endotherm between about 180° C. and about 220° C. when heated at a rate of 10° C. / minute; and a moisture sorption isotherm pattern showing 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.

[0485] In one embodiment, the free base anhydrate Form D has an X-ray diffraction pattern as described above; a thermogravimetric analysis pattern showing a weight loss of about 0.5% to about 0.8% when heated at a rate of 10°C / minute between about 43°C and 188°C; a differential scanning calorimetry pattern containing an endotherm when heated at a rate of 10°C / minute between about 180°C and about 220°C; and a moisture sorption isotherm pattern showing 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 anhydrate 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 ambient conditions used during storage for downstream processing (e.g., above 2.4% RH at 23° C.). The production of the free base anhydrate Form D requires strict water control because the free base anhydrate Form D can only be produced when the crystallization solvent has a low water content (e.g., less than 0.15% at 23° C., corresponding to a water activity of 2.4%) and will convert to the free base hydrate Form C in solutions with high water content. The free base anhydrate Form D crystallizes slowly and is difficult to produce in higher yields. E. Crystalline tartrate

[0487] In another embodiment, the solid state form is a 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 a crystalline L-tartrate salt. In another aspect, the crystalline L-tartrate salt is a hydrate. In another aspect, the crystalline tartrate salt is a tetrahydrate ("tartrate hydrate"). Tartrate hydrate (tetrahydrate) is further described in the Examples of this application.

[0488] In one embodiment, the tartrate salt 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 at about 25°C using monochromatic Kα1 radiation.

[0489] In one embodiment, the tartrate salt 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 at about 25°C using monochromatic Kα1 radiation.

[0490] In one embodiment, the tartrate salt hydrate has an X-ray powder diffraction pattern having no significant peaks at one or more of 13.4±0.2 degrees 2Θ and 15.1±0.2 degrees 2Θ when measured at about 25°C using monochromatic Kα1 radiation.

[0491] In one embodiment, the tartrate salt hydrate has an X-ray powder diffraction pattern having no significant peaks 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.

[0492] In one embodiment, the tartrate hydrate has an X-ray powder diffraction pattern having no significant peaks at one or more of 13.4±0.2 degrees 2θ and 15.1±0.2 degrees 2θ, and no significant peaks at one or more of 3.1±0.2 degrees 2θ and 9.3±0.2 degrees 2θ, when measured at about 25°C using monochromatic Kα1 radiation.

[0493] In one embodiment, the tartrate salt 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, and lacks a significant peak at one or more of 13.4±0.2 degrees 2θ and 15.1±0.2 degrees 2θ when measured at about 25°C using monochromatic Kα1 radiation.

[0494] In one embodiment, the tartrate salt 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, and lacks significant peaks 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.

[0495] In one embodiment, the tartrate salt 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, and lacking significant peaks at one or more of 13.4±0.2 degrees 2θ and 15.1±0.2 degrees 2θ, and lacking significant peaks 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.

[0496] In one embodiment, the tartrate salt 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 no significant peak at one or more of 13.4±0.2 degrees 2θ and 15.1±0.2 degrees 2θ when measured at about 25°C using monochromatic Kα1 radiation.

[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 no significant peaks 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 no significant peaks at one or more of 13.4±0.2 degrees 2θ and 15.1±0.2 degrees 2θ, and no significant peaks 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 further aspects of each of the above embodiments, the significant peak has a variation of ±0.1 degrees 2Θ instead of ±0.2 degrees 2Θ. In still further aspects of each of the above embodiments, the significant peak has a variation of ±0.05 degrees 2Θ instead of ±0.2 degrees 2Θ.

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

[0501] In one embodiment, the tartrate salt hydrate has a thermogravimetric analysis chart showing a weight loss of about 11.8% to about 12.2% when heated between about 25°C and 160°C at a rate of 10°C / minute.

[0502] In one embodiment, the tartrate salt hydrate has a thermogravimetric analysis chart showing a weight loss of about 11.8% to about 12.2% when heated between about 32.98°C and 159.76°C at a rate of 10°C / minute.

[0503] In one embodiment, the tartrate hydrate has substantially Figure 4F Thermogravimetric analysis diagram shown in .

[0504] In one embodiment, the tartrate salt hydrate has a differential scanning calorimetry plot comprising an endotherm between about 60°C and about 100°C when heated at a rate of 10°C / minute.

[0505] In one embodiment, the tartrate salt hydrate has a differential scanning calorimetry plot comprising endotherms between about 75.74°C and about 110.26°C when heated at a rate of 10°C / minute.

[0506] In one embodiment, the tartrate hydrate has substantially Figure 5D The differential scanning calorimetry diagram is shown in .

[0507] In one embodiment, the tartrate salt hydrate has a thermogravimetric analysis pattern showing a weight loss of about 11.8% to about 12.2% when heated at a rate of 10°C / minute between about 25°C and 160°C; and a differential scanning calorimetry pattern comprising an endotherm when heated at a rate of 10°C / minute between about 60°C and about 100°C.

[0508] In one embodiment, the tartrate hydrate has a moisture sorption isotherm showing a weight increase 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.

[0509] In one embodiment, the tartrate hydrate has substantially Figure 6C The water adsorption isotherm diagram shown in .

[0510] In one embodiment, the tartrate salt hydrate has a thermogravimetric analysis plot showing a weight loss of about 11.8% to about 12.2% when heated at a rate of 10°C / minute between about 25°C and 160°C; a differential scanning calorimetry plot comprising an endotherm when heated at a rate of 10°C / minute between about 60°C and about 100°C; and a moisture sorption isotherm plot showing 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.

[0511] In one embodiment, the tartrate hydrate has an X-ray diffraction pattern as described above, and at least one of: (a) a thermogravimetric analysis pattern showing a weight loss of about 11.8% to about 12.2% when heated at a rate of 10°C / minute between about 25°C and 160°C; (b) a differential scanning calorimetry pattern containing an endotherm when heated at a rate of 10°C / minute between about 60°C and about 100°C; and / or (c) a moisture sorption isotherm pattern showing 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 salt hydrate has an X-ray diffraction pattern as described above, and a thermogravimetric analysis pattern showing a weight loss of about 11.8% to about 12.2% when heated between about 25°C and 160°C at a rate of 10°C / minute.

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

[0514] In one embodiment, the tartrate hydrate has an X-ray diffraction pattern as described above, and a water sorption isotherm plot showing a weight increase 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 showing a weight loss of about 11.8% to about 12.2% when heated at a rate of 10°C / minute between about 25°C and 160°C; and a differential scanning calorimetry pattern comprising an endotherm when heated at a rate of 10°C / minute between about 60°C and about 100°C.

[0516] In one embodiment, the tartrate hydrate has an X-ray diffraction pattern as described above; a thermogravimetric analysis pattern showing a weight loss of about 11.8% to about 12.2% when heated at a rate of 10°C / minute between about 25°C and 160°C; and a moisture sorption isotherm pattern showing 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 pattern comprising an endotherm between about 60° C. and about 100° C. when heated at a rate of 10° C. / minute; and a moisture sorption isotherm plot showing 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.

[0518] In one embodiment, the tartrate hydrate has an X-ray diffraction pattern as described above; a thermogravimetric analysis pattern showing a weight loss of about 11.8% to about 12.2% when heated at a rate of 10°C / minute between about 25°C and 160°C; a differential scanning calorimetry pattern containing an endotherm when heated at a rate of 10°C / minute between about 60°C and about 100°C; and a moisture sorption isotherm pattern showing 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.

[0519] The tartrate hydrate has acceptable chemical stability and demonstrates acceptable stability to light and peroxide. For example, when in a closed bottle at 30°C / 65% relative humidity and 40°C / 75% relative humidity through 12 weeks and under 50°C / 75% relative humidity through 6 weeks of assessing chemical stability, under any of these conditions, no degradation of the tartrate hydrate was observed in the closed bottle. The tartrate hydrate has good solubility (BCS Class I) and is not hygroscopic. However, the tartrate hydrate, when heated, or when compressed or in shearing, will potentially be converted into an amorphous tartrate lower than 10% relative humidity.

[0520] The tartrate hydrate can be produced, for example, using antisolvent crystallization. Impurity rejection during large-scale production of tartrate hydrate is generally good, but scaling may be greater than expected and may require specific antisolvent addition controls and process volume limitations. In addition, appropriate control of the filtration, washing, and drying steps may be required to minimize the consolidation of the wet cake and the formation of hard lumps in the separated material. For example, relative humidity (e.g., greater than 10% and less than 100% relative humidity), temperature (e.g., crystallization is good at about 10°C), and mixing rate may need to be controlled during drying to minimize the formation of hard lumps in the separated material. Inadequate control of drying conditions potentially will produce a solidified, harder material that is difficult to decompose during subsequent processing. As previously mentioned, shearing and compression will potentially lead to conversion to an amorphous tartrate. The dried material is typically ground with a mechanical impact grinder (e.g., Fitzmills and pin mill) because shear-based grinders (e.g., co-grinding machines) can result in a loss of crystallinity. Additionally, pressure or compression forces during formulation (such as required for tableting) can potentially lead to a loss of crystallinity. F. Crystalline hydrochloride

[0521] In another embodiment, the solid state form is a crystalline hydrochloride salt of Compound 1. In one aspect, the crystalline hydrochloride salt corresponds to crystalline hydrochloride solvate Form AA. In another aspect, the crystalline hydrochloride salt corresponds to crystalline hydrochloride solvate Form BB. In another aspect, the crystalline hydrochloride salt corresponds to crystalline hydrochloride solvate Form CC. Hydrochloride solvate Form AA, hydrochloride solvate Form BB, and hydrochloride solvate Form CC are further described in the Examples herein.

[0522] Hydrochloride solvate form AA, hydrochloride solvate form BB and hydrochloride solvate form CC appear to be solvates and are generally converted to amorphous hydrochloride salts when the environment is dry. The amorphous hydrochloride salts obtained are 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 state form is a crystalline L-maleate salt of compound 1. In one aspect, the crystalline L-maleate salt corresponds to crystalline L-maleate salt Form AAA. In another aspect, the crystalline L-maleate salt corresponds to crystalline L-maleate salt Form BBB. L-maleate salt Form AAA and L-maleate salt Form BBB are further described in the Examples of this application.

[0524] Because L-maleic acid reacts with Compound 1, L-maleate salt Form AAA and L-maleate salt 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 for use as an active ingredient in a pharmaceutical dosage form. H. Crystal purity

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

[0526] The present disclosure relates to a method for treating a JAK-related disorder in a subject (especially a human subject suffering from or susceptible to a JAK-related disorder), comprising administering to the subject a therapeutically effective amount of a free base of compound 1 or a pharmaceutically acceptable salt thereof or one or more solid forms of compound 1 as described in the present disclosure. Another aspect of the present disclosure relates to a free base of compound 1 or a pharmaceutically acceptable salt thereof or one or more solid forms of compound 1 as described in the present disclosure, for treating the disorder in a subject (especially a human subject suffering from or susceptible to a JAK-related disorder), the use comprising administering to the subject a therapeutically effective amount of a free base of compound 1 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 an amorphous free base. In another aspect, the solid form is a free base hydrate form B. In another aspect, the solid form is a free base hydrate form C. In another aspect, the solid form is a tartrate hydrate. In another aspect, the solid form is a free base anhydrate form D.

[0527] In one embodiment, the present disclosure relates to a method for treating a condition selected from the group consisting of immunomodulation, inflammation, and proliferative diseases (e.g., cancer) in a subject, wherein the method comprises administering to the subject (particularly a subject suffering from or susceptible to the condition) a therapeutically effective amount of compound 1 free base, or a pharmaceutically acceptable salt thereof, or a solid form of compound 1. On the other hand, 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 condition selected from the group consisting of immunomodulation, inflammation, and proliferative diseases (e.g., cancer) in a subject (particularly a human subject suffering from or susceptible to a condition selected from the group consisting of immunomodulation, inflammation, and proliferative diseases (e.g., 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 an 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 condition in a subject 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 mellitus, peripheral neuropathy, uveitis, fibrosing alveolitis, type I diabetes, juvenile diabetes, juvenile arthritis, Castleman's disease, disease), neutropenia, endometriosis, autoimmune thyroid disease, sperm and testicular autoimmunity, scleroderma, axonal and neuronal neuropathy, allergic rhinitis, Sjögren's syndrome, hemolytic anemia, Graves' disease, Hashimoto's thyroiditis, IgA nephropathy, amyloidosis, ankylosing spondylitis, Behçet's disease, sarcoidosis, cystic dermatosis, myositis, primary biliary cirrhosis, polymyalgia rheumatica, autoimmune immunodeficiency, Chagas disease, Kawasaki syndrome syndrome), psoriatic arthritis, celiac disease, myasthenia gravis, autoimmune myocarditis, POEMS syndrome and chronic fatigue syndrome, wherein the method comprises administering to the subject (especially a subject suffering from or susceptible to the condition) a therapeutically effective amount of Compound 1 free base or a pharmaceutically acceptable salt thereof or a solid form of Compound 1.In another aspect, the present disclosure relates to a free base of Compound 1 or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1 for use in treating a condition 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 mellitus, peripheral neuropathy, uveitis, fibrosing alveolitis, type I diabetes, juvenile diabetes, juvenile arthritis, Castleman's disease, and the like in a subject, particularly a human subject suffering from or susceptible to a condition 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 mellitus, peripheral neuropathy, uveitis, fibrosing alveolitis, type I diabetes, juvenile diabetes, juvenile arthritis, Castleman's disease, and the like. 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, cystic 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, the use comprising administering to the subject a therapeutically effective amount of a free base of Compound 1 or a pharmaceutically acceptable salt thereof or a solid form of Compound 1. In one aspect, the solid state form is amorphous free alkali. In another aspect, the solid state form is free alkali hydrate Form B. In another aspect, the solid state form is free alkali hydrate Form C. In another aspect, the solid state form is tartrate hydrate. In another aspect, the solid state form is free alkali anhydrate Form D.

[0529] In one embodiment, the present disclosure relates to a method for treating a condition in a subject selected from the group consisting of rheumatoid arthritis (including moderate to severe rheumatoid arthritis), systemic lupus erythematosus, multiple sclerosis, Crohn's disease (including moderate to severe Crohn's disease), psoriasis (including moderate to severe chronic plaque psoriasis), ulcerative colitis (including moderate to severe ulcerative colitis), ankylosing spondylitis, psoriatic arthritis, juvenile idiopathic arthritis (including moderate to severe polyarticular juvenile idiopathic arthritis), diabetic nephropathy, dry eye syndrome, Sjögren's syndrome, alopecia areata, vitiligo and atopic dermatitis, wherein the method comprises administering to the subject (especially a subject suffering from or susceptible to the condition) a therapeutically effective amount of Compound 1 free base or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1. In another aspect, the present disclosure relates to the use of a free base of Compound 1 or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1 for treating a condition selected from the group consisting of rheumatoid arthritis (including moderate to severe rheumatoid arthritis), systemic lupus erythematosus, multiple sclerosis, Crohn's disease (including moderate to severe Crohn's disease), psoriasis (including moderate to severe chronic plaque psoriasis), ulcerative colitis (including moderate to severe ulcerative colitis), ankylosing spondylitis, psoriatic arthritis, juvenile idiopathic arthritis (including moderate to severe polyarticular juvenile idiopathic arthritis), diabetic nephropathy, dry eye syndrome, Sjögren's syndrome, alopecia areata, vitiligo, and atopic dermatitis in a subject (particularly a human subject suffering from or susceptible to a condition selected from the group consisting of rheumatoid arthritis (including moderate to severe rheumatoid arthritis), systemic lupus erythematosus, multiple sclerosis, Crohn's disease (including moderate to severe Crohn's disease), psoriasis (including moderate to severe chronic plaque psoriasis), ulcerative colitis (including moderate to severe ulcerative colitis), ankylosing spondylitis, psoriatic arthritis, juvenile idiopathic arthritis (including moderate to severe polyarticular juvenile idiopathic arthritis), diabetic nephropathy, dry eye syndrome, Sjögren's syndrome, alopecia areata, vitiligo, and atopic dermatitis, the use comprising administering to the subject a therapeutically effective amount of a free base of Compound 1 or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1. In one aspect, the solid state form is an amorphous free base. In another aspect, the solid state form is the free base hydrate Form B. In another aspect, the solid state form is the free base hydrate Form C. In another aspect, the solid state form is the tartrate hydrate. In another aspect, the solid state form is the free base anhydrate Form D.

[0530] In one embodiment, the disclosure relates to a method of treating a condition in a subject selected from the group consisting of an ocular condition, a systemic inflammatory response syndrome, juvenile rheumatoid arthritis, systemic onset juvenile rheumatoid arthritis, type III hypersensitivity reaction, type IV hypersensitivity reaction, aortic inflammation, iridocyclitis / uveitis / optic neuritis, juvenile spinal muscular atrophy, diabetic retinopathy or microangiopathy, chronic inflammation, ulcerative colitis, inflammatory bowel disease, allergic disease, dermatitis scleroderma, acute or chronic immune disease associated with organ transplantation, psoriatic arthropathy, ulcerative colitis, autoimmune bullous disease, autoimmune hemolytic anemia, interstitial lung disease associated with rheumatoid arthritis, lung disease associated with systemic lupus erythematosus, lung disease associated with dermatomyositis / polymyositis, Sjögren's syndrome / disease ( syndrome / disease)-related lung disease, ankylosing spondylitis and ankylosing spondylitis-related lung disease, autoimmune hepatitis, autoimmune hepatitis type 1 (classic autoimmune or lupus-like hepatitis), autoimmune hepatitis type 2 (anti-LKM antibody hepatitis), autoimmune-mediated hypoglycemia, psoriasis type 1, psoriasis type 2, plaque psoriasis, moderate to severe chronic plaque psoriasis, autoimmune neutropenia, sperm autoimmunity, multiple sclerosis (all subtypes), acute rheumatic fever, rheumatoid spondylitis, Sjögren's syndrome ( syndrome) and autoimmune thrombocytopenia, wherein the method comprises administering to the subject (especially a subject suffering from or susceptible to the condition) a therapeutically effective amount of Compound 1 free base or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1. In another aspect, the present disclosure relates to a free base of Compound 1 or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1 for use in treating a condition selected from the group consisting of an ocular condition, a systemic inflammatory response syndrome, juvenile rheumatoid arthritis, systemic onset juvenile rheumatoid arthritis, type III hypersensitivity reaction, type IV hypersensitivity reaction, aortic inflammation, iridocyclitis / uveitis / optic neuritis, juvenile spinal muscular atrophy, diabetic retinopathy or microangiopathy, chronic inflammation, ulcerative colitis, inflammatory bowel disease, allergic disease, dermatitis scleroderma, acute or chronic immune disease associated with organ transplantation, psoriatic arthropathy, ulcerative colitis, autoimmune bullous disease, autoimmune hemolytic anemia, interstitial lung disease associated with rheumatoid arthritis, lung disease associated with systemic lupus erythematosus, lung disease associated with dermatomyositis / polymyositis, Sjögren's syndrome / disease ( syndrome / disease)-related lung disease, ankylosing spondylitis and ankylosing spondylitis-related lung disease, autoimmune hepatitis, autoimmune hepatitis type 1 (classic autoimmune or lupus-like hepatitis), autoimmune hepatitis type 2 (anti-LKM antibody hepatitis), autoimmune-mediated hypoglycemia, psoriasis type 1, psoriasis type 2, plaque psoriasis, moderate to severe chronic plaque psoriasis, autoimmune neutropenia, sperm autoimmunity, multiple sclerosis (all subtypes), acute rheumatic fever, rheumatoid spondylitis, Sjögren's syndrome ( syndrome) and autoimmune thrombocytopenia, 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 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 condition selected from the group consisting of rheumatoid arthritis, juvenile idiopathic arthritis, Crohn's disease, ulcerative colitis, psoriasis, plaque psoriasis, nail psoriasis, psoriatic arthritis, ankylosing spondylitis, alopecia areata, hidradenitis suppurativa, atopic dermatitis, and systemic lupus erythematosus in a subject, 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 state form of Compound 1. On the other hand, present disclosure relates to compound 1 free alkali or its pharmaceutically acceptable salt or the solid form of compound 1, for treating the disease in a subject (especially a human subject suffering from or susceptible to a disease 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 purposes including administering a therapeutically effective amount of compound 1 free alkali or the solid form of compound 1 to the subject. In one aspect, the solid form is amorphous free alkali. On the other hand, the solid form is free alkali hydrate form B. On the other hand, the solid form is free alkali hydrate form C. In another aspect, the solid form is tartrate hydrate. In another aspect, the solid form is free alkali anhydrate form D.

[0532] In one embodiment, the present disclosure relates to a method of treating a condition selected from the group consisting of rheumatoid arthritis, Crohn's disease, ankylosing spondylitis, psoriatic arthritis, psoriasis, ulcerative colitis, systemic lupus erythematosus, lupus nephritis, diabetic nephropathy, dry eye syndrome, Sjögren's syndrome, alopecia areata, vitiligo, and atopic dermatitis in a subject, 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 state form of Compound 1. On the other hand, present disclosure relates to compound 1 free alkali or its pharmaceutically acceptable salt or the solid form of compound 1, for treating the disease in a subject (especially a human subject suffering from or susceptible to a disease selected from the group consisting of rheumatoid arthritis, Crohn's disease, ankylosing spondylitis, psoriatic arthritis, psoriasis, ulcerative colitis, systemic lupus erythematosus, lupus nephritis, diabetic nephropathy, dry eye syndrome, Sjögren's syndrome, alopecia areata, vitiligo and atopic dermatitis, the purposes including administering a therapeutically effective amount of compound 1 free alkali or its pharmaceutically acceptable salt or the solid form of compound 1 to the subject. In one aspect, the solid form is amorphous free alkali. On the other hand, the solid form is free alkali hydrate form B. On the other hand, the solid form is free alkali hydrate form C. In another aspect, the solid form is tartrate hydrate. In another aspect, the solid form is free alkali anhydrate form D.

[0533] In one embodiment, the present disclosure relates to a method for treating arthritis 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. On the other hand, 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 susceptible 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 state form is the free base anhydrate Form D. In another aspect, the solid state form is the free base solvate Form A. In another aspect, the solid state form is the hydrochloride solvate Form AA. In another aspect, the solid state form is the hydrochloride solvate Form BB. In another aspect, the solid state form is the hydrochloride solvate Form CC. In another aspect, the solid state form is the L-maleate salt Form AAA. In another aspect, the solid state form is the L-maleate salt Form BBB.

[0534] In one embodiment, the present disclosure relates to a method for treating spondyloarthropathies 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-state 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-state form of Compound 1, particularly for treating spondyloarthropathies in a human subject suffering from or susceptible to spondyloarthropathies, 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-state form of Compound 1. In one aspect, the spondyloarthropathies are ankylosing spondylitis. In another aspect, the solid-state form is the amorphous free base. In another aspect, the solid-state form is the free base hydrate Form B. In another aspect, the solid-state form is the free base hydrate Form C. In another aspect, the solid-state form is the tartrate hydrate. In another aspect, the solid-state form is the free base anhydrate Form D. In another aspect, the solid-state form is the free base solvate Form A. In another aspect, the solid-state form is the hydrochloride solvate Form AA. In another aspect, the solid-state form is the hydrochloride solvate Form BB. In another aspect, the solid state form is the hydrochloride solvate Form CC. In another aspect, the solid state form is the L-maleate salt Form AAA. In another aspect, the solid state form is the L-maleate salt Form BBB.

[0535] In one embodiment, the present disclosure relates to a method for treating a gastrointestinal disorder 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-state 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-state form of Compound 1, particularly for treating a gastrointestinal disorder in a human subject suffering from or susceptible to a gastrointestinal 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-state form of Compound 1. In one aspect, the gastrointestinal disorder is selected from Crohn's disease and ulcerative colitis. In another aspect, the gastrointestinal disorder is Crohn's disease. In another aspect, the gastrointestinal disorder is ulcerative colitis. In another aspect, the solid-state form is an amorphous free base. In another aspect, the solid-state form is free base hydrate Form B. In another aspect, the solid-state form is free base hydrate Form C. In another aspect, the solid-state form is tartrate hydrate. In another aspect, the solid-state form is free base anhydrate Form D. In another aspect, the solid state form is the free base solvate Form A. In another aspect, the solid state form is the hydrochloride solvate Form AA. In another aspect, the solid state form is the hydrochloride solvate Form BB. In another aspect, the solid state form is the hydrochloride solvate Form CC. In another aspect, the solid state form is the L-maleate salt Form AAA. In another aspect, the solid state form is the L-maleate salt Form BBB.

[0536] In one embodiment, the present disclosure relates to a method for treating a skin disorder, wherein the method comprises administering to a subject a therapeutically effective amount of Compound 1 free base, or a pharmaceutically acceptable salt thereof, or a solid-state 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-state form of Compound 1, particularly for treating a skin disorder in a human subject suffering from or susceptible 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-state 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-state form is an amorphous free base. In another aspect, the solid-state form is free base hydrate Form B. In another aspect, the solid state form is the free base hydrate Form C. In another aspect, the solid state form is the tartrate hydrate. In another aspect, the solid state form is the free base anhydrate Form D. In another aspect, the solid state form is the free base solvate Form A. In another aspect, the solid state form is the hydrochloride solvate Form AA. In another aspect, the solid state form is the hydrochloride solvate Form BB. In another aspect, the solid state form is the hydrochloride solvate Form CC. In another aspect, the solid state form is the L-maleate salt Form AAA. In another aspect, the solid state form is the L-maleate salt Form BBB.

[0537] The therapeutically effective dosage level for any particular subject will depend on the specific circumstances and may depend on a variety of factors, including the type, age, weight, sex, diet, and condition of the subject being treated; the severity of the pathological condition; the activity of the specific compound employed; the specific composition employed; the age, weight, general health, sex, and diet of the subject; the route of administration; the duration of treatment; pharmacological considerations, such as the activity, efficacy, pharmacokinetic, and toxicological profile of the specific compound or salt employed; whether a drug delivery system is used; drugs used in combination with or concurrently with the specific compound employed; and other factors well known in the medical field. A person of ordinary skill, provided the disclosure of this application, will be able to determine the appropriate dosage and regimen for administering the 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 therapeutic field. It is within the skill of the art to start a compound dosage at a lower level than required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. Therefore, the dosage regimen actually employed may vary widely and may therefore be derived from the preferred dosage regimen listed below.

[0538] The total daily dose (given in single doses or divided doses) of solid-state forms 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 (that is, mg compound or salt / kg body weight). Dosage unit compositions can contain such amounts or factors thereof to constitute a daily dose. In many cases, the administration of a compound or salt will be repeated multiple times. If desired, typically multiple doses can be used every day 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 capsule) is administered (orally, BID (twice daily)) to a human subject in equal amounts (e.g., about 3 mg twice daily).

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

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

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

[0544] In one embodiment, the present disclosure relates to a method for treating a subject with rheumatoid arthritis, the method comprising administering to the subject (orally, BID (twice daily)) about 24 mg of a solid form of compound 1 per unit dosage form (e.g., per tablet or per capsule) in equal amounts (e.g., about 24 mg twice daily). In another aspect, the present disclosure relates to a solid form of compound 1 for use in treating rheumatoid arthritis in a subject (especially a human subject suffering from or susceptible to rheumatoid arthritis), the use comprising administering to the subject (orally, BID (twice daily)) about 24 mg of a solid form of compound 1 per unit dosage form (e.g., per tablet or per capsule) in equal amounts (e.g., about 24 mg twice daily).

[0545] In another embodiment, the 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., per tablet or per capsule).

[0546] In another embodiment, the methods or uses include administering (orally, QD (once a day)) a solid form of Compound 1 to a human subject at a dose of about 7.5 mg per unit dosage form (e.g., per tablet or capsule). In one embodiment, the methods or uses include administering (orally, QD (once a day)) a solid form of Compound 1 to a human 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 capsule) to the subject. In one embodiment, the solid form is an 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.

[0547] In another embodiment, the 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., per tablet or per capsule).

[0548] In another embodiment, the methods or uses include administering (orally, QD (once a day)) a solid form of Compound 1 to a human subject at a dose of about 15 mg per unit dosage form (e.g., per tablet or capsule). In one embodiment, the methods or uses include administering (orally, QD (once a day)) 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 capsule) to the subject. In one embodiment, the solid form is an 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, the methods or uses comprise 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 comprising about 24 mg of Compound 1 free base or a pharmaceutically acceptable salt thereof per unit dosage form (e.g., per tablet or 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 capsule) administered simultaneously.

[0550] In another embodiment, the methods or uses include administering (orally, QD (once daily)) a solid form of compound 1 at a dose of about 24 mg to a human subject. In one embodiment, the 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 to the subject. The 24 mg QD 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 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 capsule) simultaneously. In one embodiment, the solid form is an 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, the methods or uses comprise administering (orally, QD (once daily)) to a human subject a dose of about 30 mg per unit dosage form (e.g., per tablet or per capsule) of Compound 1 free base or a pharmaceutically acceptable salt thereof.

[0552] In another embodiment, the methods or uses include administering (orally, QD (once a day)) a solid form of compound 1 to a human subject at a dose of about 30 mg per unit dosage form (e.g., per tablet or per capsule). In one embodiment, the methods or uses include administering (orally, QD (once a day)) a solid form of compound 1 to a human subject 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 an 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, the methods or uses comprise 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, the methods or uses include administering (orally, QD (once a day)) a solid form of Compound 1 to a human subject at a dose of about 36 mg per unit dosage form (e.g., per tablet or capsule). In one embodiment, the methods or uses include administering (orally, QD (once a day)) a solid form of Compound 1 to a human subject in an amount sufficient to deliver 36 mg of Compound 1 free base equivalent per unit dosage form (e.g., per tablet or capsule) to the subject. In one embodiment, the solid form is an 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, the methods or uses comprise 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 a day)) a solid form of Compound 1 to a human subject at a dose of about 45 mg per unit dosage form (e.g., per tablet or per capsule). In one embodiment, the methods or uses include administering (orally, QD (once a day)) a solid form of Compound 1 to a human subject 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) to the subject. In one embodiment, the solid form is an 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.

[0557] In certain embodiments, compound 1 free base or its pharmaceutically acceptable salt and / or its solid form 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 structural damage associated with RA or treating it, 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 its pharmaceutically acceptable salt and / or its solid form is used to treat RA in adult subjects. In one embodiment, compound 1 free base or its pharmaceutically acceptable salt and / or its solid form is used to reduce the signs and symptoms of RA in adult subjects. In one embodiment, compound 1 free base or its pharmaceutically acceptable salt and / or its solid form induces a major clinical response in adult subjects with RA. In one embodiment, compound 1 free base or its pharmaceutically acceptable salt and / or its solid form is used to inhibit the progression of structural damage associated with RA in adult subjects. In one embodiment, compound 1 free base and / or its solid form is used to treat structural damage associated with RA in adult subjects. In one embodiment, Compound 1 free base or a pharmaceutically acceptable salt thereof and / or a solid form thereof is used to improve physical function in an adult subject. In one embodiment, the adult subject suffers from RA. In another embodiment, the adult subject suffers from 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-biological disease-modifying antirheumatic drugs (DMARDs), and / or with anti-TNFα biological agents (e.g., TNF antagonists (e.g., chimeric, humanized or human TNF antibodies), adalimumab (e.g., HUMIRA TM Brands adalimumab), infliximab (eg, CA2 (REMICADE TMBrands: infliximab), golimumab (eg, SIMPONI TM (golimumab)), certolizumab pegol (eg, CIMZIA TM ), tocilizumab (eg, ACTEMRA TM ), CDP 571 and soluble p55 or p75 TNF receptors, their derivatives, etanercept (e.g. p75TNFR1gG (ENBREL TM Brand etanercept) or p55TNFR1gG (linecept))) used in combination.

[0559] Patients with active rheumatoid arthritis (RA) can be diagnosed according to the 1987 revised American College of Rheumatology (ACR) classification criteria or the 2010 ACR / EULAR criteria. In certain embodiments, RA can be diagnosed based on the patient having at least 6 swollen joints and 6 tender joints. In certain embodiments, patients who can be treated with Compound 1 or a solid form thereof may include those who have failed treatment with at least one (e.g., at least one but not more than four) DMARDs and / or have an inadequate response to methotrexate, adalimumab, infliximab, etanercept, or other anti-TNFα biologics or non-anti-TNF biologics.

[0560] In certain embodiments, Compound 1 free base or a pharmaceutically acceptable salt thereof or a solid state form thereof prevents disease progression and / or alleviates at least disease symptoms detectable or monitored by X-ray findings, including radiological progression of joint damage.

[0561] In certain embodiments, whether in individual patients or patient populations for which treatment is desired, therapeutic efficacy can be measured by improving ACR20, ACR50, and / or ACR70. In certain embodiments, statistically significant improvements (compared to placebo or untreated controls) are achieved during the treatment period (e.g., 1 week, 2 weeks, 4 weeks, 6 weeks, 8 weeks, 12 weeks, 2 months, 3 months, 6 months, 1 year, 2 years, 5 years, 10 years, or longer) in one or more ACR standards. Statistically significant improvements are shown as p values being less than 0.05 or less than 0.01.

[0562] The components of an ACR response are well known in the art and can include the median number of tender joints, the median number of swollen joints, physician global assessment (e.g., assessment measured by a visual analog scale (VAS)), patient global assessment (e.g., assessment measured by a visual analog scale), such as pain measured by a visual analog scale, Health Assessment Questionnaire Disability 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 tender joint count (TJC) and swollen joint count (SJC), and a 20% or greater improvement in three or more of the following five metrics: patient assessment of pain (VAS), patient global assessment of disease activity (VAS), physician global assessment of disease activity (VAS), HAQ-DI, or high-sensitivity C-reactive protein (hsCRP). In some embodiments, an ACR50 response is determined based on a 50% or greater improvement in TJC and SJC, and a 50% or greater improvement in three or more of the following five metrics: patient assessment of pain (VAS), patient global assessment of disease activity (VAS), physician global assessment of disease activity (VAS), HAQ-DI, or hsCRP. An ACR70 response is determined based on a 70% or greater improvement in TJC and SJC, and a 70% or greater improvement in three or more of the five measures: patient assessment of pain (VAS), patient global assessment of disease activity (VAS), physician global assessment of disease activity (VAS), HAQ-DI, or 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, a global score of pain and overall condition, blood markers of inflammation such as ESR (erythrocyte sedimentation rate) and CRP (C-reactive protein) (referred to herein as DAS28(CRP)), questionnaires such as the HAQ (Health Assessment Questionnaire) that assesses function, and X-rays and other imaging techniques such as ultrasound and MRI.

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

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

[0567] In one embodiment, the present disclosure relates to a method for treating rheumatoid arthritis in a subject, comprising administering (orally, QD (once daily)) about 7.5 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 (especially a human subject suffering from or susceptible to rheumatoid arthritis). On the other hand, the present disclosure relates to compound 1 free base or a pharmaceutically acceptable salt thereof for treating rheumatoid arthritis in a subject (especially a human subject suffering from or susceptible to rheumatoid arthritis), comprising administering (orally, QD (once daily)) about 7.5 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 suffers from 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 for treating rheumatoid arthritis in a subject, the method comprising administering (orally, QD (once daily)) about 7.5 mg of a solid form of compound 1 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 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. On the other hand, 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)) about 7.5 mg of a solid form of compound 1 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 suffers from moderate to severe active rheumatoid arthritis. On the other hand, the solid form is free base solvate form A. On the other hand, the solid form is hydrochloride solvate form AA. On the other hand, the solid form is hydrochloride solvate form BB. On the other hand, the solid form is hydrochloride solvate form CC. On the other hand, the solid form is L-maleate salt form AAA. On the other hand, the solid form is L-maleate salt form BBB. In one embodiment, the subject is an adult.

[0569] In one embodiment, the present disclosure relates to a method for treating rheumatoid arthritis in a subject, the method comprising administering (orally, QD (once a day)) 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 (especially a human subject suffering from or susceptible to rheumatoid arthritis). On the other hand, the present disclosure relates to compound 1 free base 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 a day)) 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 suffers from 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)) about 15 mg of a solid form of compound 1 per unit dosage form (e.g., per tablet or per capsule) to the subject (especially 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. On the other hand, 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)) about 15 mg of a solid form of compound 1 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 state form is free base hydrate Form B. In one embodiment, the solid state form is free base hydrate Form C. In one embodiment, the solid state form is tartrate hydrate. In one embodiment, the solid state form is free base anhydrate Form D. In one embodiment, the subject has moderate to severe active rheumatoid arthritis. In another aspect, the solid state form is free base solvate Form A. In another aspect, the solid state form is hydrochloride solvate Form AA. In another aspect, the solid state form is hydrochloride solvate Form BB. In another aspect, the solid state form is hydrochloride solvate Form CC. In another aspect, the solid state form is L-maleate salt Form AAA. In another aspect, the solid state form is L-maleate salt 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 the subject (especially a human subject suffering from or susceptible to rheumatoid arthritis). On the other hand, the present disclosure relates to compound 1 free base 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 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 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 capsule) simultaneously. In one embodiment, the subject has moderately to severely active rheumatoid arthritis. In one embodiment, the subject is an adult.

[0572] 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 a solid form of compound 1 to the subject, especially 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 24 mg of compound 1 free base equivalents to the subject. On the other hand, 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)) about 24 mg of a solid form of compound 1 to the subject. In one embodiment, the solid form delivers about 24 mg of compound 1 free base equivalents to the subject. A 24 mg dose of the solid form of compound 1 can be administered as a single dosage form containing approximately 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 approximately 12 mg of the solid form 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. On the other hand, the solid form is free base solvate form A. On the other hand, the solid form is hydrochloride solvate form AA. On the other hand, the solid form is hydrochloride solvate form BB. On the other hand, the solid form is hydrochloride solvate form CC. On the other hand, the solid form is L-maleate salt form AAA. On the other hand, the solid form is L-maleate salt form BBB. In one embodiment, the subject suffers from 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 a day)) 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) to the subject (especially a human subject suffering from or susceptible to rheumatoid arthritis). On the other hand, the present disclosure relates to compound 1 free base 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 a day)) 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) to the subject. In one embodiment, the subject suffers from 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)) about 30 mg of a solid form of compound 1 per unit dosage form (e.g., per tablet or per capsule) to the subject (especially 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 30 mg of compound 1 free base equivalents per unit dosage form (e.g., per tablet or per capsule) to the subject. On the other hand, 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)) about 30 mg of a solid form of compound 1 per unit dosage form (e.g., per tablet or per capsule) to the subject. In one embodiment, the solid form delivers about 30 mg of compound 1 free base equivalents 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-maleate salt Form AAA. In another aspect, the solid form is L-maleate salt Form BBB. In one embodiment, the subject is an adult.

[0575] In one embodiment, the present disclosure relates to a method for treating rheumatoid arthritis in a subject, the method comprising administering (orally, QD (once a day)) 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) to the subject (especially a human subject suffering from or susceptible to rheumatoid arthritis). On the other hand, the present disclosure relates to compound 1 free base 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 a day)) 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) to the subject. In one embodiment, the subject suffers from 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 for treating rheumatoid arthritis in a subject, the method comprising administering (orally, QD (once daily)) about 36 mg of a solid form of compound 1 per unit dosage form (e.g., per tablet or per capsule) to the subject (especially 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 36 mg of compound 1 free base equivalents per unit dosage form (e.g., per tablet or per capsule) to the subject. On the other hand, 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)) about 36 mg of a solid form of compound 1 per unit dosage form (e.g., per tablet or per capsule) to the subject. In one embodiment, the solid form delivers about 36 mg of compound 1 free base equivalents 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-maleate salt Form AAA. In another aspect, the solid form is L-maleate salt Form BBB. In one embodiment, the subject is an adult.

[0577] In one embodiment, the present disclosure relates to a method for treating rheumatoid arthritis in a subject, the method comprising administering (orally, QD (once a day)) 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) to the subject (especially a human subject suffering from or susceptible to rheumatoid arthritis). On the other hand, the present disclosure relates to compound 1 free base 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 a day)) 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) to the subject. In one embodiment, the subject suffers from 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 for treating rheumatoid arthritis in a subject, the method comprising administering (orally, QD (once daily)) about 45 mg of a solid form of compound 1 per unit dosage form (e.g., per tablet or per capsule) to the subject (especially 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 45 mg of compound 1 free base equivalents per unit dosage form (e.g., per tablet or per capsule) to the subject. On the other hand, 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)) about 45 mg of a solid form of compound 1 per unit dosage form (e.g., per tablet or per capsule) to the subject. In one embodiment, the solid form delivers about 45 mg of compound 1 free base equivalents per unit dosage form (e.g., per tablet or per capsule) to the subject. In one embodiment, the solid state form is free base hydrate Form B. In one embodiment, the solid state form is free base hydrate Form C. In one embodiment, the solid state form is tartrate hydrate. In one embodiment, the solid state form is free base anhydrate Form D. In one embodiment, the subject has moderate to severe active rheumatoid arthritis. In another aspect, the solid state form is free base solvate Form A. In another aspect, the solid state form is hydrochloride solvate Form AA. In another aspect, the solid state form is hydrochloride solvate Form BB. In another aspect, the solid state form is hydrochloride solvate Form CC. In another aspect, the solid state form is L-maleate salt Form AAA. In another aspect, the solid state form is L-maleate salt Form BBB. In one embodiment, the subject is an adult.

[0579] In one embodiment, the present disclosure relates to a method for treating moderately to severely active rheumatoid arthritis in an adult subject, particularly a human subject having or susceptible to moderately to severely active rheumatoid arthritis, comprising administering to the subject a therapeutically effective amount of Compound 1 (free base) or a pharmaceutically acceptable salt thereof, or a solid state form of Compound 1. In one embodiment, the method comprises administering to the subject about 7.5 mg, or about 15 mg, or about 30 mg, or about 45 mg of Compound 1 (free base), or a pharmaceutically acceptable salt thereof, or a solid state form of Compound 1 per unit dosage form (e.g., per tablet or 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 capsule). In one embodiment, the method comprises administering to the subject about 7.5 mg, or about 15 mg, or about 30 mg, or about 45 mg of compound 1 (free base) or a pharmaceutically acceptable salt thereof, or a solid form of compound 1 per unit dosage form (e.g., per tablet or capsule). In one embodiment, compound 1 (free base) or a pharmaceutically acceptable salt thereof, or a solid form of compound 1, is administered (orally, QD (once daily)) to the subject. On the other hand, the present disclosure relates to a solid form (e.g., a crystalline hydrate or a crystalline anhydrate) of compound 1 free base or a pharmaceutically acceptable salt thereof, or compound 1 as described herein, for treating moderate to severe active rheumatoid arthritis in adult subjects (especially human subjects suffering from or susceptible 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 state form is a crystalline anhydrate. In one embodiment, the crystalline anhydrate is free base anhydrate Form D. In one embodiment, the solid state form is free base solvate Form A. On the other hand, the solid state form is hydrochloride solvate Form AA. In one embodiment, the solid state form is hydrochloride solvate Form BB. In one embodiment, the solid state form is hydrochloride solvate Form CC. In one embodiment, the solid state form is L-maleate salt Form AAA. In one embodiment, the solid state form is L-maleate salt Form BBB. In one embodiment, compound 1 (free base) or a pharmaceutically acceptable salt thereof, or a solid state form of compound 1 is in a once-daily extended release formulation.In one embodiment, the formulation delivers (oral, 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 state 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 identifying features before treatment: at least 6 swollen joints (based on a 66 joint count), at least 6 tender joints (based on a 68 joint count), high-sensitivity C-reactive protein (hsCRP) above the upper limit of normal (ULN), or a positive test result 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 a 66 joint count) and at least 6 tender joints (based on a 68 joint count) before treatment. Methods for assessing tender and swollen joints are known and described, for example, in Scott et al., Clinical and Experimental Rheumatology, 2014, Vol. 32 (Suppl. 85), S7-S12.

[0581] Thus, in another embodiment, the present disclosure relates to a method for treating moderately to severely active rheumatoid arthritis in an adult subject, particularly a human subject having or susceptible to moderately to severely active rheumatoid arthritis, comprising administering to the subject a therapeutically effective amount of Compound 1 (free base) as described herein, or a pharmaceutically acceptable salt thereof, or a solid state form of Compound 1 (e.g., a crystalline hydrate or crystalline anhydrate), wherein the subject has a symptom prior to treatment selected from the group consisting of at least 6 swollen joints, at least 6 tender joints, and combinations thereof. In one embodiment, the method comprises administering to the subject about 7.5 mg or about 15 mg or about 30 mg or about 45 mg of Compound 1 (free base) or a pharmaceutically acceptable salt thereof, or a solid state form of Compound 1 per unit dosage form (e.g., per tablet or capsule) per day, 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 per unit dosage form (e.g., per tablet or capsule) per day, wherein the subject has a symptom selected from the group consisting of at least 6 swollen joints, at least 6 tender joints, and combinations thereof before treatment. In one embodiment, the method comprises administering to the subject about 7.5 mg or about 15 mg or about 30 mg or about 45 mg of a solid state form of Compound 1 per unit dosage form (e.g., per tablet or capsule). In another aspect, the present disclosure relates to a free base of Compound 1 or a pharmaceutically acceptable salt thereof, or a solid state form of Compound 1 (e.g., a crystalline hydrate or a crystalline anhydrate) as described herein for use in treating moderately to severely active rheumatoid arthritis in an adult subject (particularly a human subject suffering from or susceptible to moderately to severely active rheumatoid arthritis), wherein the subject has a symptom selected from the group consisting of at least 6 swollen joints, at least 6 tender joints, and combinations thereof prior to treatment, the use comprising administering to the subject a therapeutically effective amount of a free base of Compound 1 or a pharmaceutically acceptable salt thereof, or a solid state form of Compound 1. In one embodiment, the therapeutically effective amount of the solid state form of Compound 1 delivers (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 the solid state form of Compound 1 to the subject per unit dosage form (e.g., per tablet or capsule). In one embodiment, compound 1 (free base) or its pharmaceutically acceptable salt or the solid form of compound 1 is in a once-daily extended release formulation. In one embodiment, the subject is given (oral, QD (once a day)) compound 1 (free base) or its pharmaceutically acceptable salt or the 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 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 state form is the tartrate salt hydrate. In one embodiment, the symptoms are caused by progression of structural damage as assessed by radiographs.

[0582] In one embodiment, the present disclosure relates to a method for treating moderately to severely active rheumatoid arthritis in an adult subject, particularly a human subject having or susceptible to moderately to severely active rheumatoid arthritis, comprising administering to the subject daily about 7.5 mg of compound 1 (free base) or a pharmaceutically acceptable salt thereof, or a solid state form of compound 1 per unit dosage form (e.g., per tablet or capsule), an amount sufficient to deliver to the subject about 7.5 mg of compound 1 free base equivalent per unit dosage form (e.g., per tablet or capsule) per day, wherein the subject has a symptom selected from the group consisting of at least 6 swollen joints, at least 6 tender joints, and combinations thereof prior to treatment. In one embodiment, the method comprises administering to the subject about 7.5 mg of a solid state form of compound 1 per unit dosage form (e.g., per tablet or capsule). On the other hand, the present disclosure relates to a solid form of compound 1 free base or a pharmaceutically acceptable salt thereof or compound 1 for treating moderate to severe active rheumatoid arthritis in an adult subject (especially a human subject suffering from or susceptible to moderate to severe active rheumatoid arthritis), wherein the subject has a symptom selected from the group consisting of at least 6 swollen joints, at least 6 tender joints, and a combination thereof before treatment, the use comprising administering to the subject about 7.5 mg of compound 1 free base or a pharmaceutically acceptable salt thereof or compound 1 solid form 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 structural damage assessed by radiographs.

[0583] In one embodiment, the present disclosure relates to a method for treating moderate to severe active rheumatoid arthritis in an adult subject, particularly a human subject having or susceptible to moderate to severe active rheumatoid arthritis, comprising administering to the subject daily about 15 mg of compound 1 (free base) or a pharmaceutically acceptable salt thereof, or a solid form of compound 1 per unit dosage form (e.g., per tablet or capsule), an amount sufficient to deliver to the subject about 15 mg of compound 1 free base equivalent per unit dosage form (e.g., per tablet or capsule) per day, wherein the subject has a symptom selected from the group consisting of at least 6 swollen joints, at least 6 tender joints, and combinations thereof prior to treatment. In one embodiment, the method comprises administering to the subject about 15 mg of a solid form of compound 1 per unit dosage form (e.g., per tablet or capsule). On the other hand, the present disclosure relates to a solid form of compound 1 free base or a pharmaceutically acceptable salt thereof or compound 1 for treating moderate to severe active rheumatoid arthritis in an adult subject (especially a human subject suffering from or susceptible to moderate to severe active rheumatoid arthritis), wherein the subject has a symptom selected from the group consisting of at least 6 swollen joints, at least 6 tender joints, and a combination thereof before treatment, the use comprising administering to the subject about 15 mg of compound 1 free base or a pharmaceutically acceptable salt thereof or compound 1 solid form 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 structural damage assessed by radiographs.

[0584] In one embodiment, the present disclosure relates to a method for treating moderately to severely active rheumatoid arthritis in an adult subject, particularly a human subject having or susceptible to moderately to severely active rheumatoid arthritis, comprising administering to the subject daily about 30 mg of compound 1 (free base) or a pharmaceutically acceptable salt thereof, or a solid form of compound 1 per unit dosage form (e.g., per tablet or capsule), an amount sufficient to deliver to the subject about 30 mg of compound 1 free base equivalent per unit dosage form (e.g., per tablet or capsule) per day, wherein the subject has a symptom selected from the group consisting of at least 6 swollen joints, at least 6 tender joints, and combinations thereof prior to treatment. In one embodiment, the method comprises administering to the subject about 30 mg of a solid form of compound 1 per unit dosage form (e.g., per tablet or capsule). On the other hand, the present disclosure relates to a solid form of compound 1 free base or a pharmaceutically acceptable salt thereof or compound 1 for treating moderate to severe active rheumatoid arthritis in an adult subject (especially a human subject suffering from or susceptible to moderate to severe active rheumatoid arthritis), wherein the subject has a symptom selected from the group consisting of at least 6 swollen joints, at least 6 tender joints, and a combination thereof before treatment, the use comprising administering to the subject about 30 mg of compound 1 free base or a pharmaceutically acceptable salt thereof or compound 1 solid form 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 structural damage assessed by radiographs.

[0585] In one embodiment, the present disclosure relates to a method for treating moderately to severely active rheumatoid arthritis in an adult subject, particularly a human subject having or susceptible to moderately to severely active rheumatoid arthritis, comprising administering to the subject daily about 45 mg of compound 1 (free base) or a pharmaceutically acceptable salt thereof, or a solid form of compound 1 per unit dosage form (e.g., per tablet or capsule), an amount sufficient to deliver to the subject about 45 mg of compound 1 free base equivalent per unit dosage form (e.g., per tablet or capsule) per day, wherein the subject has a symptom selected from the group consisting of at least 6 swollen joints, at least 6 tender joints, and combinations thereof prior to treatment. In one embodiment, the method comprises administering to the subject about 45 mg of a solid form of compound 1 per unit dosage form (e.g., per tablet or capsule). On the other hand, the present disclosure relates to a solid form of compound 1 free base or a pharmaceutically acceptable salt thereof or compound 1 for treating moderate to severe active rheumatoid arthritis in an adult subject (especially a human subject suffering from or susceptible to moderate to severe active rheumatoid arthritis), wherein the subject has a symptom selected from the group consisting of at least 6 swollen joints, at least 6 tender joints, and a combination thereof before treatment, the use comprising administering to the subject about 45 mg of compound 1 free base or a pharmaceutically acceptable salt thereof or compound 1 solid form 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 structural damage assessed by radiographs.

[0586] In one embodiment, the adult subject for treatment realizes ACR20 responses after treatment.In one embodiment, adult subject realizes ACR20 responses after treatment (for example, at the 12th week for treatment) after at least 12 weeks.In another embodiment, the adult subject for treatment realizes ACR50 responses after treatment.In one embodiment, adult subject realizes ACR50 responses after treatment (for example, at the 12th week for treatment) or at least 24 weeks (for example, at the 24th week).In another embodiment, the adult subject for treatment realizes ACR70 responses after treatment.In one embodiment, adult subject realizes ACR70 responses after treatment (for example, at the 12th week for treatment) after at least 12 weeks.In certain embodiments, adult subject realizes ACR20 responses, ACR50 responses and / or ACR70 responses after treatment (for example, at the 12th week for treatment) after at least 12 weeks.

[0587] In one embodiment, the adult subject receiving treatment achieves ACR20 responses after treatment for at least 8 weeks (e.g., in the 8th week of treatment). In another embodiment, the adult subject receiving treatment achieves ACR20 responses after treatment for at least 6 weeks (e.g., in the 6th week of treatment). In another embodiment, the adult subject receiving treatment achieves ACR20 responses after treatment for at least 4 weeks (e.g., in the 4th week of treatment). In another embodiment, the adult subject receiving treatment achieves ACR20 responses after treatment for at least 2 weeks (e.g., in the 2nd week of treatment).

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

[0589] In one embodiment, the adult subject receiving treatment achieves ACR70 responses after treatment for at least 8 weeks (e.g., in the 8th week for treatment). In another embodiment, the adult subject receiving treatment achieves ACR70 responses after treatment for at least 6 weeks (e.g., in the 6th week for treatment). In another embodiment, the adult subject receiving treatment achieves ACR70 responses after treatment for at least 4 weeks (e.g., in the 4th week for treatment).

[0590] In one embodiment, the adult subject receiving treatment achieves a change in DAS28 score after treatment. In one embodiment, the change in DAS score is a decrease in DAS28 (CRP) after treatment compared to baseline (i.e., DAS28 (CRP) before treatment). In one embodiment, the adult subject achieves a decrease in DAS28 score compared to baseline after at least 12 weeks of treatment (e.g., in week 12 of treatment). In one embodiment, the adult subject achieves a decrease in DAS28 (CRP) compared to baseline after at least 12 weeks of treatment (e.g., in week 12 of treatment). In another embodiment, the adult subject achieves a decrease in DAS28 (CRP) compared to baseline after at least 8 weeks of treatment (e.g., in week 8 of treatment). In another embodiment, the adult subject achieves a decrease in DAS28 (CRP) compared to baseline after at least 6 weeks of treatment (e.g., in week 6 of treatment). In another embodiment, the adult subject achieves a decrease in DAS28 (CRP) compared to baseline after at least 4 weeks of treatment (e.g., in week 4 of treatment). In another embodiment, the adult subject achieves a decrease in DAS28 (CRP) compared to baseline after at least 2 weeks of treatment (eg, in week 2 of treatment).

[0591] In another embodiment, the adult subject receiving treatment realizes low disease activity (LDA) scores or clinical remission after treatment. In one embodiment, LDA scores or clinical remission are measured as 3.2 or lower DAS28 scores (particularly, DAS28 (CRP)). In another embodiment, LDA scores or clinical remission are measured as less than 2.6 DAS28 (CRP). In another embodiment, clinical disease activity index (CDAI) standards are used to assess LDA scores or clinical remission. In one embodiment, adult subjects realize 10 or less CDAI scores after treatment. In another embodiment, adult subjects realize 2.8 or lower CDAI scores after treatment. In one embodiment, adult subjects realize LDA scores or clinical remission after treatment for at least 12 weeks (for example, at the 12th week for treatment). In one embodiment, adult subjects realize LDA scores or clinical remission after treatment for at least 8 weeks (for example, at the 8th week for treatment). In one embodiment, adult subjects realize LDA scores or clinical remission after treatment for at least 6 weeks (for example, at the 6th week for treatment). In one embodiment, the adult subject achieves an LDA score or clinical remission after at least 4 weeks of treatment (e.g., in 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., in week 2 of treatment).

[0592] In one embodiment, the treated adult subjects achieve a change in mean modified Total Sharp Score (mTSS). In one embodiment, the treated adult subjects achieve a change in mTSS at least 12 weeks after treatment (e.g., at week 12 of treatment) or at least 24 weeks after treatment (e.g., at week 24 of treatment). In one embodiment, mTSS can be determined by scoring x-rays of the hand / wrist and foot joints for erosion and joint space narrowing. The erosion score and the narrowing score are added to determine a total score.

[0593] In one embodiment, the treated adult subject achieves a change in HAQ-DI score. In one embodiment, the treated adult subject achieves a change in HAQ-DI score after at least 12 weeks of treatment (eg, at week 12 of treatment).

[0594] In one embodiment, the treated adult subject achieves a change in the Short Form Questionnaire 36 (SF-36) physical component score (PCS). In one embodiment, the treated adult subject achieves a change in the SF-36 PCS after at least 12 weeks of treatment (e.g., at week 12 of treatment). The SF-36 is a 36-item participant questionnaire that includes questions related to the participant's health and daily activities.

[0595] In one embodiment, the treated adult subject achieves clinical remission (CR). In one embodiment, the treated adult subject achieves CR after at least 12 weeks of treatment (e.g., at week 12 of treatment). In one embodiment, CR is determined based on the DAS28 C-reactive protein (DAS28 (CRP)) response rate. In one embodiment, CR is a DAS28 (CRP) score of less than 2.6.

[0596] In one embodiment, the adult subjects receiving treatment achieve changes in the Functional Assessment of Chronic Illness Therapy (FACIT-F). In one embodiment, the adult subjects receiving treatment achieve changes in FACIT-F after at least 12 weeks of treatment (e.g., in the 12th week of treatment). FACIT-F is a participant questionnaire that includes 13 indicators and is scored on a 5-point scale. These indicators are related to the fatigue level of the participant over the past seven days.

[0597] In one embodiment, the treated adult subject achieves a change on the Rheumatoid Arthritis Work Instability Scale (RA-WIS). In one embodiment, the treated adult subject achieves a change on the RA-WIS after at least 12 weeks of treatment (e.g., at week 12 of treatment). The RA-WIS is a participant questionnaire that contains 23 questions related to the participant's functioning in their work environment.

[0598] In one embodiment, the treated adult subject achieves a change in severity of morning stiffness. In one embodiment, the treated adult subject achieves a change in se...

Claims

1. An extended-release pharmaceutical tablet comprising: (a) 15 mg of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide; (b) an acidic pH adjuster; and (c) Controlled release polymers.

2. The tablet of claim 1, wherein the release-controlling polymer is a hydrophilic polymer and wherein the acidic pH adjuster is an organic acid.

3. The tablet of claim 2, wherein the organic acid is present in an amount of about 10 w / w% to about 35 w / w%.

4. The tablet of claim 3, wherein the organic acid is tartaric acid.

5. The tablet of claim 2, wherein the extended-release formulation releases (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 upon entry into an environment of use at a rate that is substantially independent of the pH of the environment of use, wherein the environment of use has a pH range of about 1.2 to about 6.

8.

6. The tablet of claim 5, wherein the organic acid is present in an amount of about 10 w / w% to about 35 w / w%.

7. The tablet of claim 6, wherein the organic acid is tartaric acid.

8. The tablet of claim 2, wherein the extended-release solid dosage form dissolves from about 50% to about 90% 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 after about 8 hours when added to a test medium comprising 900 mL of 50 mM sodium phosphate buffer, pH 6.8, in a standard USP rotating paddle apparatus at 37°C ± 0.5°C with the paddle rotating at 75 rpm ± 4%.

9. The tablet of claim 8, wherein the organic acid is present in an amount of about 10 w / w% to about 35 w / w%.

10. The tablet of claim 9, wherein the organic acid is tartaric acid.

Images