BR112018007677B1 - CRYSTALLINE HEMIHYDRATE OF THE COMPOUND (3S,4R)-3-ETHYL-4-(3H-IMIDAZO[1,2-A] PYRROLO[2,3-E]PYRAZIN-8-YL)-N-(2,2 ,2-TRIFLUOROETHYL)PYRROLI-DINE-1-CARBOXAMIDE - Google Patents

Abstract

PROCESSES FOR THE PREPARATION OF (3S,4R)-3-ETHYL-4-(3HIMIDAZO[1,2-a] PYRROL[2,3-e]-PYRAZIN-8-IL)-N-(2,2,2 -TRIFLUOROETHYL)PYRROLIDINE-1-CARBOXAMIDE AND ITS SOLID STATE FORMS. The present disclosure relates to processes for preparing (3S, 4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-( 2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, its solid state forms and corresponding pharmaceutical compositions, treatment methods (including treatment of rheumatoid arthritis), kits, synthesis methods and products-by-process.

Description

CROSS REFERENCE TO RELATED ORDERS

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

FIELD OF INVENTION

[002] The present disclosure relates to: (a) processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e ]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (herein referred to as "Compound 1"), (b) intermediates used in the preparation of Compound 1 and processes for preparation of intermediaries; (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 of treating conditions associated with Janus kinase (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 comprising a solid state form of Compound 1 and, optionally, a second pharmaceutical composition comprising one or more additional therapeutic agents; (g) methods of preparing solid state forms of Compound 1; and (h) solid state forms of Compound 1 prepared in accordance with such methods.

BACKGROUND OF THE INVENTION

[003] (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 WO2011/068881A1, which is incorporated herein by reference in its entirety. The compound has activity as a Janus kinase (“JAK”) inhibitor, in particular as a JAK-1 inhibitor. Clinical trials are underway to evaluate the use of the compound to treat rheumatoid arthritis.

[004] The isolation and preparation on a commercial scale of a solid state form of Compound 1 and corresponding pharmaceutical formulations having acceptable solid state properties (including chemical stability, thermal stability, solubility, hygroscopicity and/or particle size), compound manufacturability (including yield, rejection of impurities during crystallization, filtration properties, drying properties and grinding properties), and formulation feasibility (including stability in relation to pressure or compression forces during tablet production) presents several challenges which are discussed in greater detail below. Accordingly, there is a current need for one or more solid state forms of Compound 1 that have an acceptable balance of these properties and can be used in the preparation of pharmaceutically acceptable solid dosage forms.

[005] Additionally, currently known processes for the preparation of compound 1 involve the use of particularly dangerous reagents, such as trimethylsilyldiazomethane or diazomethane and do not produce a crystalline product. There is also a need for a process for preparing Compound 1 and its pharmaceutically acceptable salts that avoids the use of particularly hazardous reagents and can produce a crystalline product and crystalline intermediates.

[006] Additionally, sustained peak plasma concentrations can theoretically be achieved through sustained release matrix systems. However, when such systems are made of hydrophilic polymers, such as HPMC, they rarely provide pH-independent drug release from pH-dependent soluble drugs, and are typically unable to achieve zero-order release except for practically insoluble drugs. Unexpectedly, it was discovered that when tartaric acid is used as a pH modifier in such a system, it allows Compound 1 to be released at a constant rate regardless of the pH of the environment.

[007] In an unexpected discovery, it was discovered that as a tablet containing the hydrophilic polymer matrix system erodes, Compound 1 reacts with HPMC, creating a thicker gel layer that slows the release of Compound 1 of the tablet. The resulting gel layer provided a suitable environment for the dissolution of Compound 1.

SUMMARY OF THE INVENTION

[008] In one aspect, the present disclosure relates to a process for preparing Compound 1 or a pharmaceutically acceptable salt thereof. The process comprises: a) reacting a compound of formula (I) or a pharmaceutically acceptable salt thereof with trimethylsulfoxonium chloride to form a compound of formula (II) where PG is a protecting group; b) contacting the compound of formula (II) with LiX and a sulfonic acid to form a compound of formula (III) where 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 Ri 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 an anhydrous perfluoro acid and an organic base to form a compound of formula (VI) e) deprotecting the compound of formula (VI) and forming a pharmaceutically acceptable salt of the compound of formula (VII): f) reacting the pharmaceutically acceptable salt of the compound of formula (VII) with 2,2,2-trifluoroethylamine to produce Compound 1.

[009] In another aspect, the present disclosure relates to a process for preparing Compound 1 or a pharmaceutically acceptable salt thereof. The process comprises: a) reacting a compound of formula (Ib) with trimethylsulfoxonium chloride in the presence of carbonyldiimidazole and a strong base to form the compound of formula (IIa) wherein Cbz is carboxybenzyl; b) contacting the compound of formula (IIa) with lithium bromide and a sulfonic acid to form a compound of formula (IIIa) c) reacting the compound of formula (IIIa) with a compound of formula (IVa) in the presence of lithium tert-butoxide to produce a compound of formula (Va) wherein R2 is methyl or ethyl; and Ts is tosyl; d) contacting the compound of formula (Va) with an anhydrous perfluoro acid 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.

[010] In another aspect, the present disclosure relates to a process for preparing Compound 1. The process comprises: a) reacting a compound of formula (I) or a pharmaceutically acceptable salt thereof with trimethylsulfoxonium chloride to form a compound of formula (II) where PG is a protecting group; b) contacting the compound of formula (II) with LiX and a sulfonic acid to form a compound of formula (III) where 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 Ri 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 an anhydrous perfluoro acid and an organic base to produce 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 produce a tartrate salt of Compound 1; and i) contacting the tartrate salt with sodium carbonate and sodium bicarbonate to produce Compound 1.

[011] In another aspect, the present disclosure relates to a process for preparing Compound 1 or a pharmaceutically acceptable salt thereof. The process comprises: a) converting a compound of formula (XIa): for a compound of formula (I): where PG is a protecting group; b) reacting the compound of formula (I) with trimethylsulfoxonium chloride to form a compound of formula (II) c) contacting the compound of formula (II) with an anhydrous source of HBr or HCl to form a compound of formula (III) where 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 Ri 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 an anhydrous perfluoro acid 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): g) reacting the pharmaceutically acceptable salt of the compound of formula (VII) with 2,2,2-trifluoroethylamine to produce Compound i.

[012] In another aspect, the present disclosure relates to a compound of formula (II): where PG is a protecting group.

[013] In another aspect, the disclosure relates to a process for preparing a compound of formula (II): wherein PG is a protecting group, the process comprising reacting a compound of formula (I) or a pharmaceutically acceptable salt thereof with trimethylsulfoxonium chloride to form the compound of formula (II).

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

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

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

[017] In another aspect, the disclosure is directed to a process for preparing a crystalline compound of formula (V) the process comprising: a) reacting a compound of formula (III) with a compound of formula (IV): to produce the compound of formula (V); where: PG is a protecting group; X is Br or Cl; Ri is -OR2; R2 is methyl or ethyl; and Ts is tosila.

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

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

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

[021] In another aspect, the present disclosure relates to a process for preparing a compound of formula (Ib) wherein Cbz is carboxybenzyl, the process comprising: (i) reacting carboxybenzyl-glycine ethyl ester with ethyl acrylate to form a compound of formula (VIII): (ii) protect the compound of formula (VIII) to form a compound of formula (IX): wherein R3 is selected from the group consisting of CF3SO2-; CH3SO2-; and tosila; (iii) contacting the compound of formula (IX) with one of ethylboronic acid, ethylmagnesium bromide or ethylzinc chloride in the presence of a catalyst to form a compound of formula (X): (iv) hydrolyze the compound of formula (X) to produce the compound of formula (XI): (v) convert the compound of formula (XI) to the compound of formula (XII): (vi) contacting the compound of formula (XII) with dicyclohexylamine to form a compound of formula (Ib).

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

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

[024] In another aspect, the present disclosure relates to Amorphous Free Base of Compound 1,

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

[026] In another aspect, the present disclosure relates to crystalline hydrates of Compound 1,

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

[028] In another aspect, the present disclosure relates to Free Base Hydrate Form C of Compound 1,

[029] In another aspect, the present disclosure relates to Free Base Hydrate Form B of Compound 1,

[030] In another aspect, the present disclosure relates to crystalline anhydrous compounds of Compound 1,

[031] In another aspect, the present disclosure relates to Free Base Anhydrous Form D of Compound 1,

[032] 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.

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

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

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

[036] In another aspect, the present disclosure relates to methods of treating rheumatoid arthritis, wherein the term “rheumatoid arthritis” includes juvenile rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, Sjogren's syndrome, psoriatic arthritis.

[037] In another aspect, the present 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.

[038] In another aspect, 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, psoriasis of the nails, psoriatic arthritis, ankylosing spondylitis, alopecia areata, hidradenitis suppurativa, atopic dermatitis and systemic lupus erythematosus in a human subject suffering from, or susceptible to, such condition, the method comprising administering to the subject a therapeutically effective amount of a solid state form of Compound 1. In another aspect, the disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a solid state form of Compound 1, as defined in the present disclosure, for use in treating a condition selected from the group consisting in 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 one subject, in particular in a human subject suffering from, or susceptible to, the condition.

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

[040] In another aspect, the present disclosure relates to a method of treating moderately to severely active rheumatoid arthritis, the method comprising administering a therapeutically effective amount of Compound 1 in one or more forms as disclosed herein to a subject suffering from, or susceptible to, condition. In a particular aspect, such a method may comprise administering 7.5 mg once per day, or 15 mg once per day, or 30 mg once per day, or 45 mg once per day of Compound 1, in one or more more forms as revealed here, to the subject. In this or another particular aspect, the subject may be administered Compound 1 in Free Base Form C. In this or in yet another particular aspect, the subject may have an inadequate response to methotrexate. In this or another particular aspect, the subject may have an inadequate response to biological medications approved for rheumatoid arthritis. In this or another particular aspect, the subject may not have previously been administered biological medications approved for rheumatoid arthritis.

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

[042] 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 free base of Compound 1 or a pharmaceutically acceptable salt thereof, or a crystalline or anhydrous crystalline hydrate of Compound 1 in an amount sufficient to provide the subject with about 7.5 mg per day of free base equivalent of Compound 1; or b) about 15 mg per day of free base of Compound 1, or a pharmaceutically acceptable salt thereof, or a crystalline or crystalline anhydrous hydrate of Compound 1 in an amount sufficient to provide the subject with about 15 mg per day of equivalent of free base of Compound 1; or c) about 30 mg per day of free base of Compound 1, or a pharmaceutically acceptable salt thereof, or a crystalline or crystalline anhydrous hydrate of Compound 1 in an amount sufficient to provide the subject with about 30 mg per day of equivalent of free base of Compound 1; or d) about 45 mg per day of free base of Compound 1 or a pharmaceutically acceptable salt thereof, or a crystalline or crystalline anhydrous hydrate of Compound 1 in an amount sufficient to provide the subject with about 45 mg per day of base equivalent free of Compound 1; so that structural damage to the adult subject is inhibited or attenuated. In one embodiment, the disclosure relates to a pharmaceutical composition for use in treating structural damage associated with rheumatoid arthritis in an adult subject, the use comprising administering the pharmaceutical composition to the subject, wherein the pharmaceutical composition comprises: a) about 7 .5 mg per day of free base of Compound 1 or a pharmaceutically acceptable salt thereof, or a crystalline or anhydrous crystalline hydrate of Compound 1 in an amount sufficient to provide the subject with about 7.5 mg per day of free base equivalent of Compound 1; or b) about 15 mg per day of free base of Compound 1, or a pharmaceutically acceptable salt thereof, or a crystalline or crystalline anhydrous hydrate of Compound 1 in an amount sufficient to provide the subject with about 15 mg per day of equivalent of free base of Compound 1; or c) about 30 mg per day of free base of Compound 1, or a pharmaceutically acceptable salt thereof, or a crystalline or crystalline anhydrous hydrate of Compound 1 in an amount sufficient to provide the subject with about 30 mg per day of equivalent of free base of Compound 1; or d) about 45 mg per day of free base of Compound 1 or a pharmaceutically acceptable salt thereof, or a crystalline or anhydrous crystalline hydrate of Compound 1 in an amount sufficient to provide the subject with about 45 mg per day of base equivalent free of Compound 1; so that structural damage to the adult subject is inhibited or attenuated.

[043] 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 free base Compound 1 or a pharmaceutically acceptable salt thereof, or a crystalline or anhydrous crystalline hydrate of Compound 1 in an amount sufficient to provide the subject with about 7.5 mg per day of free base equivalent of Compound 1; or b) about 15 mg per day of free base of Compound 1, or a pharmaceutically acceptable salt thereof, or a crystalline or crystalline anhydrous hydrate of Compound 1 in an amount sufficient to provide the subject with about 15 mg per day of equivalent of free base of Compound 1; or c) about 30 mg per day of free base of Compound 1, or a pharmaceutically acceptable salt thereof, or a crystalline or crystalline anhydrous hydrate of Compound 1 in an amount sufficient to provide the subject with about 30 mg per day of equivalent of free base of Compound 1; or d) about 45 mg per day of free base of Compound 1 or a pharmaceutically acceptable salt thereof, or a crystalline or crystalline anhydrous hydrate of Compound 1 in an amount sufficient to provide the subject with about 45 mg per day of base equivalent free of Compound 1; wherein, prior to treatment, the subject has symptoms selected from the group consisting of at least 6 swollen joints, at least 6 tender joints, and combinations thereof. In one embodiment, the disclosure is directed to a pharmaceutical composition for use in treating moderately to severely active rheumatoid arthritis in an adult subject, the use comprising administering the pharmaceutical composition to the subject, wherein the pharmaceutical composition comprises a) about 7, 5 mg per day of free base of Compound 1 or a pharmaceutically acceptable salt thereof, or a crystalline or anhydrous crystalline hydrate of Compound 1 in an amount sufficient to provide the subject with about 7.5 mg per day of free base equivalent of Compound 1; or b) about 15 mg per day of free base of Compound 1 or a pharmaceutically acceptable salt thereof, or a crystalline or crystalline anhydrous hydrate of Compound 1 in an amount sufficient to provide the subject with about 15 mg per day of base equivalent free of Compound 1; or c) about 30 mg per day of free base of Compound 1 or a pharmaceutically acceptable salt thereof, or a crystalline or crystalline anhydrous hydrate of Compound 1 in an amount sufficient to provide the subject with about 30 mg per day of base equivalent free of Compound 1; or d) about 45 mg per day of free base of Compound 1 or a pharmaceutically acceptable salt thereof, or a crystalline or crystalline anhydrous hydrate of Compound 1 in an amount sufficient to provide the subject with about 45 mg per day of equivalent free base of Compound 1; wherein, prior to treatment, the subject has symptoms selected from the group consisting of at least 6 swollen joints, at least 6 tender joints, and combinations thereof.

[044] In another aspect, the disclosure is directed to a method of reducing 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 free base of Compound 1 or a pharmaceutically acceptable salt thereof, or a crystalline or anhydrous crystalline hydrate of Compound 1 in an amount sufficient to provide the subject with about 7.5 mg of 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 or crystalline anhydrous hydrate of Compound 1 in an amount sufficient to provide the subject with about 15 mg of free base equivalent. Compound 1; or c) about 30 mg per day of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a crystalline or crystalline anhydrous hydrate of Compound 1 in an amount sufficient to provide the subject with about 30 mg of free base equivalent. Compound 1; or d) about 45 mg per day of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a crystalline or crystalline anhydrous hydrate of Compound 1 in an amount sufficient to provide the subject with about 45 mg of free base equivalent. Compound 1. In one embodiment, the disclosure is directed to a pharmaceutical composition for use in reducing signs and symptoms of rheumatoid arthritis in an adult subject with moderately to severely active rheumatoid arthritis, the use comprising administering the pharmaceutical composition to the subject, wherein the pharmaceutical composition comprises: a) about 7.5 mg per day of free base of Compound 1 or a pharmaceutically acceptable salt thereof, or a crystalline or crystalline anhydrous hydrate of Compound 1 in an amount sufficient to provide the subject with about 7, 5 mg 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 or crystalline anhydrous hydrate of Compound 1 in an amount sufficient to provide the subject with about 15 mg of free base equivalent. Compound 1; or c) about 30 mg per day of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a crystalline or crystalline anhydrous hydrate of Compound 1 in an amount sufficient to provide the subject with about 30 mg of free base equivalent. Compound 1; or d) about 45 mg per day of free base of Compound 1 or a pharmaceutically acceptable salt thereof, or a crystalline or anhydrous crystalline hydrate of Compound 1 in an amount sufficient to provide the subject with about 45 mg of base equivalent free of Compound 1.

[045] In another aspect, the present disclosure relates to kits comprising one or more pharmaceutical compositions comprising a solid state form of Compound 1. The kit may further comprise another pharmaceutical composition comprising one or more additional therapeutic agents and /or instructions, for example instructions for using the kit.

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

[047] In another aspect, the present disclosure relates to solid state forms of Compound 1 prepared in accordance with such methods.

[048] In another aspect, the present disclosure relates to a method of treating an adult subject with moderately to severely active rheumatoid arthritis, the method comprising administering to the subject about 7.5 mg, or about 15 mg, or about 30 mg, or about 45 mg of free base of Compound 1, or a crystalline hydrate of Compound 1 in an amount sufficient to provide the subject with about 7.5 mg, or about 15 mg, or about 30 mg, or about 45 mg free base equivalent of Compound 1. In this or another particular aspect, the hydrate may be a hemihydrate. In this or another particular aspect, the hemihydrate may be Free Base Hydrate Form C. In this or another particular aspect, the subject may have an inadequate response or tolerance to one or more disease-modifying antirheumatic drugs (DMARDS). In this or another particular aspect, the subject may not have previously been administered DMARDS. In this or another particular aspect, the subject may also be administered one or more DMARDS.

[049] In another aspect, 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 about 7.5 mg, or about 15 mg, or about 30 mg, or about 45 mg per day of free base of Compound 1 or a crystalline hydrate of Compound 1 in an amount sufficient to provide the subject with about 7.5 mg, or about 15 mg, or about 30 mg, or about 45 mg per day of free base equivalent of Compound 1, such that structural damage in the adult subject is inhibited or attenuated. In this or another particular aspect, the hydrate may be a hemihydrate. In this or still another aspect, the hemihydrate may be Free Base Hydrate Form C.

[050] In another aspect, the present disclosure relates to a method of treating moderately to severely active rheumatoid arthritis in an adult subject, the method comprising administering to the subject about 7.5 mg, or about 15 mg, or about 30 mg, or about 45 mg per day of free base of Compound 1 or a crystalline hydrate of Compound 1 in an amount sufficient to provide the subject with about 7.5 mg, or about 15 mg, or about 30 mg, or about 45 mg per day of free base equivalent of Compound 1, wherein, prior to treatment, the subject has symptoms selected from the group consisting of at least 6 swollen joints, at least 6 tender joints, and combinations thereof . In this or another particular aspect, the hydrate may be a hemihydrate. In this or still another aspect, the hemihydrate may be Free Base Hydrate Form C.

[051] In another aspect, the present disclosure relates to a method of reducing signs and symptoms of rheumatoid arthritis in an adult subject with moderately to severely active rheumatoid arthritis, the method comprising administering to the subject about 7.5 mg per day of free base of Compound 1 or a crystalline hydrate of Compound 1 in an amount sufficient to provide the subject with about 7.5 mg of free base equivalent of Compound 1. In this or another particular aspect, the hydrate may be a hemihydrate . In this or still another aspect, the hemihydrate may be Free Base Hydrate Form C.

[052] In another aspect, the present disclosure relates to a method of reducing signs and symptoms of rheumatoid arthritis in an adult subject with moderately to severely active rheumatoid arthritis, the method comprising administering to the subject about 15 mg per day of free base of Compound 1 or a crystalline hydrate of Compound 1 in an amount sufficient to provide the subject with about 15 mg of free base equivalent of Compound 1. In this or another particular aspect, the hydrate may be a hemihydrate. In this or still another aspect, the hemihydrate may be Free Base Hydrate Form C.

[053] In another aspect, the present disclosure relates to a method of reducing signs and symptoms of rheumatoid arthritis in an adult subject with moderately to severely active rheumatoid arthritis, the method comprising administering to the subject about 30 mg per day of free base of Compound 1 or a crystalline hydrate of Compound 1 in an amount sufficient to provide the subject with about 30 mg of free base equivalent of Compound 1. In this or another particular aspect, the hydrate may be a hemihydrate. In this or still another aspect, the hemihydrate may be Free Base Hydrate Form C.

[054] In another aspect, the present disclosure relates to a method of reducing signs and symptoms of rheumatoid arthritis in an adult subject with moderately to severely active rheumatoid arthritis, the method comprising administering to the subject about 45 mg per day of free base of Compound 1 or a crystalline hydrate of Compound 1 in an amount sufficient to provide the subject with about 45 mg of free base equivalent of Compound 1. In this or another particular aspect, the hydrate may be a hemihydrate. In this or still another aspect, the hemihydrate may be Free Base Hydrate Form C.

[055] 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 the crystalline hydrate in an amount sufficient to provide the subject with about 7.5 mg free base equivalent of Compound 1. In this or another particular aspect, the hydrate may be a hemihydrate. In this or still another aspect, the hemihydrate may be Free Base Hydrate Form C.

[056] 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 the crystalline hydrate in an amount sufficient to provide the subject with about 15 mg of free base equivalent of Compound 1. In this or another particular aspect, the hydrate may be a hemihydrate. In this or still another aspect, the hemihydrate may be Free Base Hydrate Form C.

[057] 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 the crystalline hydrate in an amount sufficient to provide the subject with about 30 mg of free base equivalent of Compound 1. In this or another particular aspect, the hydrate may be a hemihydrate. In this or still another aspect, the hemihydrate may be Free Base Hydrate Form C.

[058] 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 the crystalline hydrate in an amount sufficient to provide the subject with about 45 mg of free base equivalent of Compound 1. In this or another particular aspect, the hydrate may be a hemihydrate. In this or still another aspect, the hemihydrate may be Free Base Hydrate Form C.

[059] In another aspect, the present disclosure relates to a method of treating an adult subject with moderately to severely active rheumatoid arthritis, the method comprising administering to the subject about 7.5 mg, or about 15 mg, or about 30 mg, or about 45 mg of a crystalline hydrate of Compound 1. In this or another particular aspect, the hydrate may be a hemihydrate. In this or still another aspect, the hemihydrate may be Free Base Hydrate Form C.

[060] In another aspect, 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 about 7.5 mg, or about 15 mg, or about 30 mg, or about 45 mg per day of a crystalline hydrate of Compound 1, so that structural damage in the adult subject is inhibited or attenuated. In this or another particular aspect, the hydrate may be a hemihydrate. In this or still another aspect, the hemihydrate may be Free Base Hydrate Form C.

[061] In another aspect, the present disclosure relates to a method of treating moderately to severely active rheumatoid arthritis in an adult subject, the method comprising administering to the subject about 7.5 mg, or about 15 mg, or about 30 mg, or about 45 mg per day of a crystalline hydrate of Compound 1, wherein, prior to treatment, the subject has symptoms selected from the group consisting of at least 6 swollen joints, at least 6 tender joints, and their combinations. In this or another particular aspect, the hydrate may be a hemihydrate. In this or still another aspect, the hemihydrate may be Free Base Hydrate Form C.

[062] In another aspect, the present disclosure relates to a method of reducing signs and symptoms of rheumatoid arthritis in a subject with moderately to severely active rheumatoid arthritis, the method comprising administering to the subject about 7.5 mg, or about 15 mg, or about 30 mg, or about 45 mg per day of a crystalline hydrate of Compound 1. In this or another particular aspect, the hydrate may be a hemihydrate. In this or still another aspect, the hemihydrate may be Free Base Hydrate Form C.

[063] In another aspect, the present disclosure is directed to a sustained-release formulation for oral administration comprising Compound 1 or a pharmaceutically acceptable salt thereof, a hydrophilic polymer and a pH modifier, wherein the hydrophilic polymer, in contact with water it forms a gel layer that provides a suitable environment for Compound 1 and the pH modifier to dissolve.

[064] In another aspect, the present disclosure is directed to a process for preparing a pharmaceutical composition, the process comprising: (a) combining Compound 1 or a pharmaceutically acceptable salt thereof, or a solid state form of Compound 1, and 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 ground granulated material; (e) combining the ground granulation material with any remaining composition components; and (f) compressing the composition to form the pharmaceutical composition.

BRIEF DESCRIPTION OF FIGURES

[065] Figure 1A schematically illustrates a method for preparing the Amorphous Free Base.

[066] Figure 1B schematically illustrates a method of preparing Free Base Hydrate Form C.

[067] Figure 1C schematically illustrates a method of preparing Tartrate Hydrate.

[068] Figures 2A and 2B are X-ray diffraction patterns by the powder method corresponding to the Amorphous Free Base (via precipitation) and the Amorphous Free Base (via dehydration), respectively.

[069] Figure 3A is an X-ray diffraction pattern by the powder method corresponding to Free Base Solvate Form A (Isopropyl Acetate Solvate/Water).

[070] Figure 3B is an X-ray diffraction pattern by the powder method corresponding to Free Base Hydrate Form B.

[071] Figure 3C is an X-ray diffraction pattern by the powder method corresponding to Free Base Hydrate Form C.

[072] Figure 3D is an X-ray diffraction pattern by the powder method corresponding to Tartrate Hydrate. The experimental PXRD pattern is shown at the bottom of Figure 3D, and the calculated PXRD pattern is shown at the top of Figure 3D.

[073] Figure 3E is an X-ray diffraction pattern by the powder method corresponding to Form AA of Hydrochloride Solvate.

[074] Figure 3F is an X-ray diffraction pattern by the powder method corresponding to Form BB of Hydrochloride Solvate.

[075] Figure 3G is an X-ray diffraction pattern by the powder method corresponding to Form CC of Hydrochloride Solvate.

[076] Figure 3H is an X-ray diffraction pattern by the powder method corresponding to Form AAA of L-Maleate.

[077] Figure 3I is an X-ray diffraction pattern by the powder method corresponding to the BBB Form of L-Maleate.

[078] Figure 3J is an X-ray diffraction pattern by the powder method corresponding to Free Base Anhydrous Form D.

[079] Figures 4A and 4B are thermograms from thermogravimetric analysis corresponding to the Amorphous Free Base (via precipitation) and the Amorphous Free Base (via dehydration), respectively.

[080] Figure 4C is a thermogravimetric analysis thermogram corresponding to Free Base Solvate Form A.

[081] Figure 4D is a thermogravimetric analysis thermogram corresponding to Free Base Hydrate Form B.

[082] Figure 4E is a thermogravimetric analysis thermogram corresponding to Free Base Hydrate Form C.

[083] Figure 4F is a thermogravimetric analysis thermogram corresponding to Tartrate Hydrate.

[084] Figure 4G is a thermogravimetric analysis thermogram corresponding to Form AA of Hydrochloride Solvate.

[085] Figure 4H is a thermogravimetric analysis thermogram corresponding to the BBB Form of L-Maleate.

[086] Figure 4I is a thermogravimetric analysis thermogram corresponding to Free Base Anhydrous Form D.

[087] Figure 5A is a differential scanning calorimetry thermogram corresponding to the Amorphous Free Base (via dehydration).

[088] Figure 5B is a differential scanning calorimetry thermogram corresponding to Free Base Hydrate Form B.

[089] Figure 5C is a differential scanning calorimetry thermogram corresponding to Free Base Hydrate Form C.

[090] Figure 5D is a differential scanning calorimetry thermogram corresponding to Tartrate Hydrate.

[091] Figure 5E is a differential scanning calorimetry thermogram corresponding to Free Base Anhydrous Form D.

[092] Figure 6A is a moisture sorption isotherm corresponding to the Amorphous Free Base (via dehydration).

[093] Figure 6B is a moisture sorption isotherm corresponding to Free Base Hydrate Form C.

[094] Figure 6C is a moisture sorption isotherm corresponding to Tartrate Hydrate.

[095] Figure 6D is a moisture sorption isotherm corresponding to Free Base Anhydrous Form D.

[096] Figure 7 is a comparison of the dissolution profile of the extended-release tablets of Example 26 (Free Base Hydrate Form C) and Example 27 (Amorphous Free Base) at pH 6.8.

[097] Figure 8 is a comparison of the dissolution profile of the extended-release tablets of Example 24 (ER1), Example 25 (ER2) and Example 26 (ER3) in a dual pH system and at pH 6.8.

[098] Figure 9 is a comparison of the dissolution profile of the extended release tablet of Example 32 (ER4) and Example 33 (ER4, without mannitol) at pH 1.2, pH 6.8 or a dual pH system.

[099] Figure 10 is a comparison of the dissolution profile of the extended release tablet of Example 34 (ER5) at pH 1.2, pH 6.8 and a dual pH system.

[0100] Figure 11 is a comparison of the dissolution profile of the extended release tablet of Example 35 (ER6) at pH 1.2, pH 6.8 and a dual pH system.

[0101] Figure 12 is a comparison of the dissolution profile of the extended release tablet of Example 28 (ER7) and Example 32 (ER4) in a dual pH system.

[0102] Figure 13 is a comparison of the dissolution profile of the extended release tablet of Example 31 (ER8) and Example 32 (ER4) in a dual pH system.

[0103] Figure 14 is a comparison of the dissolution profile of the extended-release tablets of Example 24 (ER1), Example 26 (ER3) and Example 32 (ER4) in a dual pH system.

[0104] Figures 15A to 15H are comparisons of the dissolution profile at pH 1.2 and 6.8 for the extended-release tablets of Example 43, which contain HPMC (Figs. 15A to 15D) or Carbopol® (Figs. 15E to 15H) as release control polymers, and tartaric acid (Figs. 15A and 15E), citric acid (Figs. 15B and 15F), succinic acid (Figs. 15C and 15G), or fumaric acid (Figs. 15D and 15H ) as a pH modifier.

[0105] Figures 16A and 16B show the mean plasma concentration of Compound 1 versus time following administration of a 12 mg immediate-release capsule (Regimen A) or a 15 mg extended-release tablet once daily (Regimen B) under fasting conditions using a linear (Figure 16A) or semi-log (Figure 16B) scale.

[0106] Figures 17A and 17B show the mean plasma concentration of Compound 1 versus time following administration of a 24 mg (2 x 12 mg) immediate-release capsule (Regimen C) or a 30 mg extended-release tablet once daily (Regimen D) under fasting conditions using a linear (Figure 17A) or semi-log (Figure 17B) scale.

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

[0108] Figure 19 shows the mean plasma concentration of Compound 1 versus time following administration of a 15 mg extended-release tablet once daily (Regimen F) or a 30 mg extended-release tablet once daily (Regimen G) for seven days under non-fasting conditions.

[0109] Figure 20 shows the mean plasma concentration of Compound 1 versus time following administration of a 6 mg immediate-release capsule twice daily (Regimen K) or a 15 mg extended-release tablet once daily ( Regime L) for seven days under fasting conditions.

[0110] Figure 21 shows the trough concentration before the morning dose of Compound 1 (Cmin) following administration of 6 mg immediate-release capsules twice daily or a 15 mg extended-release tablet once daily for seven days under fasting conditions.

[0111] Figure 22 shows the mean plasma concentration of Compound 1 versus time following administration of a 12 mg immediate-release capsule twice daily (Regimen M) or a 30 mg extended-release tablet once daily (Regimen M) Regime N) for seven days under fasting conditions.

[0112] Figure 23 shows the trough concentration before the morning dose of Compound 1 (Cmin) following administration of 12 mg immediate-release capsules twice daily or a 30 mg extended-release tablet once daily for seven days under fasting conditions.

[0113] Figures 24A and 24B show the mean plasma concentration of Compound 1 versus time following administration under fasting conditions of various once-daily 30 mg extended-release tablets having different concentrations of tartaric acid, using a linear scale. (Figure 24A) or log-linear (Figure 24B).

[0114] Figures 25A and 25B show the mean plasma concentration of Compound 1 versus time following administration under fasting conditions or after a high-fat meal (non-fasting) of a 30 mg extended-release tablet once per day (ER10) using a linear (Figure 25A) or log-linear (Figure 25B) scale.

[0115] Figures 26A and 26B show the individual change in Cmax (Figure 26A) and AUCinf (Figure 26B) of Compound 1 following administration under fasting conditions or after a high-fat meal (non-fasting) of a 30 mg extended-release tablet once daily (ER10).

[0116] Figures 27A and 27B show the mean plasma concentration of Compound 1 versus time following administration under fasting conditions or after a high-fat meal (non-fasting) of a 30 mg extended-release tablet once per day (ER11) using a linear (Figure 27A) or log-linear (Figure 27B) scale.

[0117] Figures 28A and 28B show the individual change in Cmax (Figure 28A) and AUCinf (Figure 28B) of Compound 1 following administration under fasting conditions or after a high-fat meal (non-fasting) of a 30 mg once daily extended-release tablet (ER11).

[0118] Figures 29A and 29B show the mean plasma concentration of Compound 1 versus time following administration under fasting conditions or after a high-fat meal (non-fasting) of a 30 mg extended-release tablet once per day (ER12) using a linear (Figure 29A) or log-linear (Figure 29B) scale.

[0119] Figures 30A and 30B show the individual change in Cmax (Figure 30A) and AUCinf (Figure 30B) of Compound 1 following administration under fasting conditions or after a high-fat meal (non-fasting) of a 30 mg once daily extended-release tablet (ER12).

[0120] Figure 31 shows a graph of the pH of the gel formed in tablets comprising different amounts of tartaric acid.

[0121] Figures 32A and 32B show mean plasma concentrations of Compound 1 versus time following administration of single oral doses of Compound 1 immediate-release capsules to healthy subjects using a linear (Figure 32A) or log-linear (Figure 32B).

[0122] Figure 33 shows the profiles of mean plasma concentration of Compound 1 versus time following administration of multiple twice-daily oral doses of Compound 1 immediate-release capsules to healthy subjects.

[0123] Figure 34A-34D shows the mean dose-normalized Cmax and AUC of Compound 1 after administration of single doses in healthy subjects (Figure 34A - single dose, Cmax; Figure 34C - single dose, AUC~) and multiple doses in healthy subjects and subjects with rheumatoid arthritis (Figure 34B - multiple doses, Cmax; Figure 34D - multiple doses, AUC0-12).

[0124] Figures 35A and 35B show the lack of effect of concomitant administration of methotrexate on AUC of dose-normalized Compound 1 (Figure 35A) and the lack of effect of concomitant administration of Compound 1 on AUC of methotrexate. normalized dose (Figure 35B).

[0125] Figure 36A shows the response rate of ACR20, ACR50, and ACR70 at week 12 following administration of placebo or various doses of Compound 1 to subjects with active rheumatoid arthritis and prior inadequate response or intolerance to an anti-inflammatory biological agent. -TNF (*P<0.05; **P<0.01; ***P<0.001 relative to placebo; modified intention-to-treat (NRI) population). Figure 36B shows the ACR20 response rate at week 12 in the same population, broken down by the number of prior anti-TNF biologics.

[0126] Figures 37A to 37D show the ACR20 (Figure 37A), ACR50 (Figure 37B), and ACR70 (Figure 37C) responses or mean DAS28(CRP) change from baseline (Figure 37D) over the following time to administration of placebo or multiple doses of Compound 1 to subjects with active rheumatoid arthritis and prior inadequate response or intolerance to an anti-TNF biologic agent (*P<0.05; **P<0.01; ***P< 0.001 relative to placebo; modified intention-to-treat (NRI) population. Figure 37E shows subjects achieving a DAS28(CRP) score of <3.2 or <2.6 at week 12 in the same population. Figure 37F shows subjects achieving low disease activity (LDA) or clinical remission (CR) based on clinical disease activity index (CDAI) criteria (LDA is CDAI <10; CR is CDAI <2, 8) at week 12 in the same population.

[0127] Figure 38A shows mean hemoglobin levels over time for all subjects following administration of placebo or various doses of Compound 1 to subjects with active rheumatoid arthritis and prior inadequate response or intolerance to a biological agent anti-TNF (safety population with observed data (no imputation of missing values). Figure 38B shows the mean hemoglobin change from baseline over time in subjects with higher high-sensitivity C-reactive protein (hsCRP) to the upper limit of normal (ULN) (normal ranges for hemoglobin: 11.5-15.5 g/dL in females and 13.2-17.0 g/dL in males; ULN for hsCRP = 5 mg/L).

[0128] Figure 39 shows the arrangement of subjects for the study described in Example 55.

[0129] Figures 40A and 40B show the arrangement of subjects for the study described in Example 56.

[0130] Figure 41 shows the ACR20, ACR50, and ACR70 responses at week 12 following administration of placebo or various doses of Compound 1 to subjects with active rheumatoid arthritis and inadequate response to methotrexate (*P<0. 05; **P<0.01; ***P<0.001 relative to placebo; modified intention-to-treat population with missing values).

[0131] Figures 42A to 42D show the ACR20 (Figure 42A, NRI analysis), ACR50 (Figure 42B, NRI analysis) and ACR70 (Figure 42C, NRI analysis) responses or mean DAS28(CRP) change from the line of baseline (Figure 42D, observed cases) over time following administration of placebo or multiple doses of Compound 1 to subjects with active rheumatoid arthritis and inadequate response to methotrexate (*P<0.05; **P<0.01 ; ***P<0.001 relative to placebo; modified intention-to-treat population).

[0132] Figures 43A and 43B show subjects achieving a DAS28(CRP) score of <3.2 or <2.6 (Figure 44A) or CDAI of <10 or <2.8) at week 12 following administration of placebo or various doses of Compound 1 to subjects with active rheumatoid arthritis and inadequate response to methotrexate (*P<0.05; **P<0.01; ***P<0.001 relative to placebo; population intending to modified treatment (NRI)). For Figures 43A and 43B, the bottom number indicates the percentage of subjects who reached both minimum threshold values, the middle number indicates the percentage of subjects who achieved the less stringent minimum threshold value but not the stricter minimum threshold value, and the top number indicates the percentage of patients who achieved any of the minimum threshold values.

[0133] Figures 44A to 44C show the average change in hemoglobin from baseline over time by treatment group (Figure 44A), subjects with hsCRP < 5 mg/mL at baseline (Figure 44B) , and subjects with hsCRP >5 mg/mL at baseline (Figure 44C) following administration of placebo or multiple doses of Compound 1 to subjects with active rheumatoid arthritis and inadequate response to methotrexate (safety population with observed data (no imputation of missing values)).

DETAILED DESCRIPTION OF THE INVENTION

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

I. Definitions

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

[0136] Where a numerical range is mentioned, each number within the range is explicitly considered with the same degree of precision. For example, for the range 6 to 9, the numbers 7 and 8 are covered, 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 explicitly covered. Likewise, all proportions cited also include all sub-proportions that fall within the broader ratio.

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

[0138] The term “about” generally refers to a range of numbers that one skilled in the art would consider equivalent to the cited value (i.e., having the same function or result). In many cases, the term “about” may include numbers that are rounded to the nearest significant figure.

[0139] The term “alkyl” refers to straight or branched chain hydrocarbons that are completely saturated. For exemplary purposes, which should not be understood as limiting the scope of this invention, examples of alkyls include methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl and their isomers.

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

[0141] The term “amorphous” as applied to a compound refers to a state in which the material lacks long-range order at the molecular level and, depending on temperature, can exhibit the physical properties of a solid or liquid. Typically, such materials do not give distinctive x-ray diffraction patterns and, although they exhibit the properties of a solid, they are more formally described as a liquid. After heating, there is a change in properties from solids to liquids, characterized by a change of state, typically of second order (“glass transition”).

[0142] The term “anhydrous” as applied to a compound refers to a solid state in which the compound does not contain any structural water within the crystalline lattice.

[0143] The term “aryl” refers to a mono, bi- or tricyclic aromatic hydrocarbon radical. Examples include phenyl, naphthyl, biphenyl and 1,2,3,4-tetrahydronaphthyl.

[0144] Unless the context requires another interpretation, the terms “understand”, “understand” and “understanding” are used on the basis of a clear understanding that they are to be interpreted inclusively, not exclusively, and that Applicant intends that each of these words be so construed in the interpretation of this patent, including the claims below.

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

[0146] The term “crystalline purity” means the crystalline purity of a compound with respect to a particular crystalline form of the compound, as determined by the powder method X-ray diffraction analytical methods described in this application.

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

[0148] The term “pharmaceutically acceptable” (such as in citing a “pharmaceutically acceptable salt” or a “pharmaceutically acceptable diluent”) refers to a material compatible with administration to a human subject, for example the material does not cause a undesirable biological effect. Examples of pharmaceutically acceptable salts are described in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002). Examples of pharmaceutically acceptable excipients are described in "Handbook of Pharmaceutical Excipients," Rowe et al., Ed. (Pharmaceutical Press, 7th ed., 2012).

[0149] The term “subject” refers to a human subject.

[0150] The terms “treat” and “treatment” refer to improving, suppressing, eradicating, reducing the severity of, decreasing the frequency of incidence of, preventing, reducing the risk of, slowing the progression of damage caused by or delay the onset of the condition or improve the quality of life of a patient suffering from the condition.

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

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

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

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

[0155] As used herein, the term "AUC24,ss" refers to the steady-state area under the plasma concentration time curve extrapolated from 0 to 24 hours after administration of the reference drug. The term "AUC12,ss" refers to the steady-state area under the ex-trapolated plasma concentration time curve from zero to twelve hours after administration of the reference drug.

[0156] As used herein, the term "AUCinf” refers to the area under the plasma concentration time curve extrapolated from zero to infinity after a single dose, calculated using the trapezoidal rule. AUCinf = AUCt + Clast/k, where Clast is the last measured concentration and k is the calculated terminal elimination rate constant.

[0157] As used herein, the term "AUCt” refers to the area under the plasma concentration time curve extrapolated from administration of the reference drug to the time of the last measured concentration calculated using the trapezoidal rule. "AUC24" refers to the area under the plasma concentration time curve extrapolated from 0 to 24 hours after administration of the reference drug after a single dose.

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

[0159] As used herein, the term "C12" is the plasma concentration of the reference drug observed 12 hours after administration of a single dose, or the indicated number of doses, of the reference drug. The term "C12,ss" refers to C12 as measured at steady state.

[0160] As used herein, the term "C24" is the plasma concentration of the reference drug observed 24 hours after administration of a single dose, or the indicated number of doses, of the reference drug. The term "C24,ss" refers to C24 as measured at steady state.

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

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

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

[0164] As used herein, the term "Cmax" refers to the plasma concentration of the drug reference Tmax, expressed herein as ng/mL, produced by oral ingestion of a single dose, or indicated number of doses, of the dosage form or pharmaceutical composition, such as the dosage forms and compositions of the present disclosure. Unless otherwise stated, Cmax refers to the overall maximum observed concentration.

[0165] As used herein, the term "Cmax,ss" refers to the steady-state Cmax of the reference drug during a dosage interval.

[0166] As used herein, the term "Cmin,ss" refers to the minimum steady-state plasma concentration of the reference drug during a dosing interval.

[0167] As used herein, the term "Cmin" refers to the minimum plasma concentration of the reference drug, as measured at the end of a 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" stands for differential scanning calorimetry.

[0175] As used herein, the term “entry into an environment of use” means contact of a formulation of the disclosure with the gastric fluids of the subject to which it is administered, or with a fluid intended 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" stands for mass spectrometry.

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

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

[0190] The abbreviations "NatOBu" or "NaOtBu" refer to sodium tert-butoxide.

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

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

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

[0194] The abbreviation "PdCl2(dppf)" refers to [1,1'-Bis(diphenylphosphine)ferrocene]dichloropalladium(II).

[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 anhydrous.

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

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

[0201] The abbreviation "PXRD" stands for 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'-bi-1,3-benzodioxole]ruthenium(II).

[0203] As used herein, the term "t1/2” refers to the terminal half-life of the reference drug after oral ingestion of a single dose, or the indicated number of doses, of the reference drug. The term "t1/ 2.ss" refers to the terminal half-life as measured at steady state.

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

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

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

[0207] The abbreviation "TGA" stands for thermogravimetric analysis.

[0208] The abbreviation "TGA-MS" stands for thermogravimetric analysis-mass spectrometry.

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

[0210] As used herein, the term "Tmax" refers to the time to reach peak plasma concentration of the reference drug after oral ingestion of a single dose, or the indicated number of doses, of the reference drug.

[0211] As used herein, the term "Tmax,ss" refers to the time to reach peak plasma concentration of the reference drug after oral ingestion of the reference drug at steady state.

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

[0213] The term “triflate” refers to trifluoromethanesulfonate.

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

[0215] The abbreviation “w/w” refers to weight/weight.

[0216] For purposes of clarity and convenience only, the convention of designating the time of drug administration or start of dissolution test as zero (0) hours (t=0 hours) and times following administration in units appropriate time periods, for example, t=30 minutes or t=2 hours, etc.

II. Processes for preparing (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3- e]pyrazin-8-yl)-N-(2,2,2- trifluoroethyl)pyrrolidine-1-carboxamide (Compound 1) and Intermediates

[0217] The present disclosure relates to improved processes for preparing (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl) -N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (referred to herein as "Compound 1" or as "free base of Compound 1"), pharmaceutically acceptable salts of Compound 1, and intermediates used in preparation of Compound 1. Compound 1 has the structure shown below: Methods for making and using this compound are described, for example, in International Application WO 2011/068881A1, which is incorporated into this application by reference.

[0218] Previously disclosed processes for preparing Compound 1 and its pharmaceutically acceptable salts suffer from several drawbacks. In particular, these processes involve the use of particularly hazardous reagents such as trimethylsilyldiazomethane or diazomethane and do not produce a crystalline product. The processes of the present disclosure overcome these drawbacks by avoiding the use of these dangerous reagents and producing crystalline intermediates that aid in purification.

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

A. Preparation of Compound 1

[0220] In one aspect, the present disclosure is directed to a process for preparing Compound 1 or a pharmaceutically acceptable salt thereof. A process for preparing Compound 1 is illustrated in Scheme I. Acid reaction (3R,4S)- 4- protected ethylpyrrolidine-3-carboxylic acid (I) or a pharmaceutically acceptable salt thereof with trimethylsulfoxonium chloride gives sulfur ylide (II). Contacting sulfur ylide (II) with LiX and a sulfonic acid gives rise to the corresponding halomethyl ketone (III). The reaction of (III) with (IV) in the presence of a base gives (V). Cyclization of (V) in the presence of an anhydrous perfluoro acid and an organic base produces (VI). Removal of the protecting group and contact of the unprotected compound with an acid yields a pharmaceutically acceptable salt of (VII). Reacting the pharmaceutically acceptable salt of (VII) with 2,2,2-trifluoroethylamine produces Compound 1. where: PG is a protecting group; X is Br or Cl; Ri is selected from the group consisting of alkyl, aryl and -OR2; R2 is alkyl; and Ts is tosila.

[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-methoxybenzyl carbonyl, benzyl, p-methoxybenzyl, and 3,4-dimethoxybenzyl. In another embodiment, the protecting group is carboxybenzyl.

[0222] In another embodiment, Ri is -OR2, and R2 is methyl or ethyl. In such embodiments, the compound of formula (VI) is a compound of formula (IVa): where R2 is methyl or ethyl. It was surprisingly discovered that when R2 is ethyl or methyl, the compound of formula (V) and subsequent downstream compounds can be isolated as crystalline solids, which helps in the purification of these intermediates. In contrast, previously known processes, which use compounds where R2 is t-butyl, result in the formation of compounds of formula (V) that are isolated as amorphous solids.

[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 the compound of formula (I) is selected from the group consisting of the naphthaleneethane amine salt (Ia) and the dicyclohexylamine salt (Ib). where Cbz is carboxybenzyl.

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

[0225] Another process for preparing Compound 1 is illustrated in Scheme 1a. The reaction of (3R,4S)-1-((benzyloxy)carbonyl)-4-ethylpyrrolidine-3-carboxylate dicyclohexylamine (ib) salt with trimethylsulfoxonium chloride in the presence of carbonyldiimidazole and a base strong gives rise to (iia). Contacting sulfur ylide (iia) with lithium bromide and a sulfonic acid gives the corresponding bromomethyl ketone (iiia). Reaction of (iiia) with alkyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate (iVa) in the presence of lithium tert-butoxide gives (Va). Cyclization of (Va) in the presence of an anhydrous perfluoro acid and an organic base produces (Via). Removal of the carboxybenzyl protecting group and contact of the deprotected compound with hydrochloric acid gives rise to the pharmaceutically acceptable salt (Viia). Reacting the pharmaceutically acceptable salt of (Viia) with 2,2,2-trifluoroethylamine produces Compound 1. where: Cbz is carboxybenzyl; Ts is tosila; and R2 is methyl or ethyl.

[0226] The reaction in step (a) of Schemes I and Ia is generally carried out in the presence of a coupling agent, such as carbonyldiimidazole (CDI) and a strong base. The strong base may be, for example, potassium tert-butoxide, sodium tert-butoxide or combinations thereof. The reaction of step (a) 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 particularly, in some embodiments, a solution of a compound of formula (I), (Ia), or (Ib) in solvent is slowly added (e.g., over 30 minutes) to a CDI paste in solvent, and 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 a suspension of trimethylsulfoxonium chloride, strong base and solvent, simultaneously maintaining the internal temperature below -1 °C. In another embodiment, the reaction is cooled and the resulting compound of formula (II) or (IIa) is isolated before step (b).

[0228] In some embodiments, the reaction of step (a) may also involve contact of (Ia) or (Ib) with an acid before the reaction with trimethylsulfoxonium chloride, in order to extract the amine to obtain a compound of formula ( I). Suitable acids include any mineral acid or organic acid, such as phosphoric acid, hydrochloric acid (HCl), acetic acid (HOAc), citric acid and the like. The compound of formula (I) can subsequently be absorbed into 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 presented in Step A of Example 3.

[0229] In step (b) of Schemes I and Ia, a compound of formula (II) or (IIa) is contacted with LiX and a sulfonic acid to form a compound of formula (III) or (IIIa), respectively. In one embodiment, the sulfonic acid is selected from the group consisting of methanesulfonic acid and p-toluenesulfonic acid. In one embodiment, the sulfonic acid is p-toluenesulfonic acid. LiX can be selected from lithium bromide and lithium chloride. In one embodiment, LiX is lithium bromide. In one embodiment, the reaction is conducted in lithium bromide and p-toluenesulfonic acid. The reaction of step (b) can be conducted in any suitable solvent, including, but not limited to, tetrahydrofuran, ethyl acetate, heptanes, ethanol, water and combinations thereof.

[0230] More particularly, in some embodiments, sulfonic acid is added to a solution of the compound of formula (II) or (IIa) and LiX in a solvent. The resulting mixture is heated to about 35°C to about 65°C and stirred overnight. In one embodiment, the mixture is heated to about 40°C and stirred overnight. The mixture is cooled to room temperature and washed. The compound of formula (III) or (IIIa) can be isolated or 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). Step (c) is conducted in the presence of a base, such as lithium tert-butoxide, sodium tert-butoxide or combinations thereof. In one embodiment, the base is lithium tert-butoxide. The reaction of step (c) can be conducted in any suitable solvent, including, but not limited to, dimethylacetamide, tetrahydrofuran, dichloromethane, ethyl acetate, heptanes and combinations thereof.

[0232] More particularly, in some embodiments, the base is added to a cooled suspension of the 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°, or about -10°C. In one embodiment, the solution is stirred for about 30 minutes and cooled to about -20°C to about 0°. 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, following addition of the solution of the 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 cooled, and, in some embodiments, the resulting product (V) or (Va) is isolated before step (d).

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

[0234] More particularly, in some embodiments, the organic base and perfluoro acid anhydrous are charged in a solution of a compound of formula (V) or (Va) in solvent. The resulting mixture is heated to about 55°C to about 75°C, or about 55°C, and stirred for about 4 hours to about 18 hours, or about 6 hours. In one embodiment, the mixture of anhydrous perfluoro acid and the compound of formula (V) or (Va) is heated to about 55 ° C and stirred for about 4 hours to about 18 hours. In one embodiment, the mixture is stirred for about 6 hours. After completion of the reaction, in some embodiments, the reaction mixture may be cooled and concentrated before contacting with a hydroxide solution to quench excess reactants and remove the tosyl protecting group. Suitable hydroxide solutions include a sodium hydroxide solution (NaOH), a potassium hydroxide solution (KOH) and the like. The resulting mixture may 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. Upon completion, the solvent may optionally be removed and exchanged for methanol, ethanol, isopropanol or other suitable solvents prior to step (e).

[0235] In step (e) of Schemes I and Ia, a compound of formula (VI) or (VIa) is deprotected, and a pharmaceutically acceptable salt of compound (VII) is formed, such as (VIIa), (VIIb) , or (VIIc). The protecting group in 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), and the like. In other embodiments, deprotection occurs by subjecting the compound of formula (VI) or (VIa) to heating, for example to a temperature between room temperature and about 85 °C, including about 50 °C. After deprotection, the compound of formula (VII) is contacted with the appropriate acid (for example, hydrochloric acid or p-toluenesulfonic acid) to form the pharmaceutically acceptable salt.

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

[0237] More particularly, in some embodiments, palladium on carbon and the compound of formula (VI) or (VIa) in solvent are mixed under hydrogen pressure at about 1 psig to about 100 psig. In another embodiment, the hydrogen pressure is about 20 psig. The mixture is stirred for about 2 hours to about 24 hours, including about 16 hours, at about 20°C to about 85°C, including about 50°C. In one embodiment, the mixture is stirred for about 16 hours at about 20°C to about 80°C. In one embodiment, the mixture is stirred for about 16 hours at about 50°C. After completion of the reaction, the reaction mixture is cooled and filtered, followed by addition of the appropriate acid. The resulting salt is optionally isolated before step (f).

[0238] In step (f), the salt produced in step (e) is reacted with 2,2,2-trifluoroethylamine to produce Compound 1. The reaction of step (f) is conducted in the presence of a coupling agent , such as carbonyldiimidazole (CDI), and optionally buffers, such as dipotassium phosphate, potassium hydroxide and combinations thereof. In one embodiment, the reaction of step (f) is conducted in the presence of CDI, dipotassium phosphate and potassium hydroxide. The reaction of step (f) can be conducted in any suitable solvent, including, but not limited to, tetrahydrofuran, ethyl acetate, heptanes, ethanol, water and combinations thereof.

[0239] More particularly, in some embodiments, 2,2,2-trifluoroethyl amine is added slowly (e.g., over 20 minutes) to a CDI paste in solvent, simultaneously maintaining an 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 a biphasic mixture of the pharmaceutically acceptable salt of step (e) in buffer and solvent is adjusted to about 7 to about 11, and in one embodiment to about 9, by adding a base. The imidazolide solution is added and the resulting mixture is mixed at about 25°C while maintaining a pH of about 9 by adding base in portions for about 30 minutes to about 18 hours. In one embodiment, the mixture formed after addition of the imidazolide solution is mixed at about 25 ° C while maintaining a pH of about 9 by adding base in portions for about 1 hour. In one embodiment, upon completion, the reaction is quenched and the resulting product is isolated.

[0240] In one embodiment, Compound 1 is prepared according to the process presented in Scheme Ia. In some embodiments, the process may further comprise the preparation of (Ib) according to the process presented herein in Scheme V.

[0241] An alternative process for preparing Compound 1 is illustrated in Scheme II. Reaction of (3R,4S)-4-ethylpyrrolidine-3-carboxylic acid (I) or a pharmaceutically acceptable salt thereof with trimethylsulfoxonium chloride gives sulfur ylide (II). Contacting sulfur ylide (II) with LiX and a sulfonic acid gives rise to the corresponding halomethyl ketone (III). The reaction of (III) with (IV) in the presence of a base gives (V). Cyclization of (V) in the presence of an anhydrous perfluoro acid and an organic base produces (VI). Removal of the protecting group and contacting the unprotected compound (VII) (not shown) with hydrochloric acid gives the pharmaceutically acceptable salt (VIIb). The pharmaceutically acceptable salt (VIIb) is converted to the free base (VII), which is reacted with 2,2,2-trifluoroethylamine to produce Compound 1. Compound 1 is contacted with L-tartaric acid to form the corresponding tartaric salt. tarate, followed by formation of the free base of Compound 1. where 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-methoxybenzyl carbonyl, benzyl, p-methoxybenzyl, and 3,4-dimethoxybenzyl. In one embodiment, the protecting group is carboxybenzyl.

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

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

[0245] Steps (a)-(e) of Scheme II are conducted as described above for Scheme I, in which following deprotection of the compound of formula (VI), the deprotected compound (VII) is contacted with hydrochloric acid to form 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 the like, and combinations thereof. In one embodiment, the base is sodium hydride. The reaction of step (f) can be conducted in any water-containing solvent including, but not limited to, water alone or a combination with THF, 2-methyl tetrahydrofuran, ethanol, methanol and the like.

[0247] In step (g), compound (VII) is reacted with 2,2,2-trifluoroethylamine to produce Compound 1. The reaction of step (g) is conducted in the presence of a coupling agent, such as CDI. Step (g) in Scheme II is conducted using similar reagents and under similar conditions as presented above for step (f) of Scheme I.

[0248] In step (h) of Scheme II, Compound 1 is contacted with L-tartaric acid to form the corresponding tartrate salt (step (h)). The formation of the tartrate salt advantageously aids in the removal of impurities prior to isolation of the free base. In one embodiment, the tartrate salt can be formed using the procedure described in Example 8, Method B, only without drying the tartrate salt before step (i). The tartrate salt is subsequently converted back to the free base form (i) to produce Compound 1. In particular, in step (i) the tartrate salt may be contacted with a base, such as an inorganic base, to produce the corresponding free base. Suitable bases include, but are not limited to, sodium bicarbonate, sodium carbonate, sodium hydroxide, potassium carbonate, potassium bicarbonate, potassium hydroxide and the like, or combinations thereof. In one embodiment, the tartrate salt is contacted with sodium bicarbonate and sodium carbonate to produce the corresponding free base.

[0249] Solvents suitable for use in step (h), but not limited to, isopropyl acetate, tert-butyl methyl 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 before the subsequent step.

[0251] An alternative process for preparing Compound 1 is illustrated in Scheme III. Compound (XIa) is hydrogenated to produce (I). Reaction of protected (3R,4S)-4-ethylpyrrolidine-3-carboxylic acid (I) with trimethylsulfoxonium chloride gives rise to sulfur ylide (II). Contacting sulfur ylide (II) with an anhydrous source of HBr or HCl gives rise to the corresponding halomethyl ketone (III). The reaction of (III) with (IV) in the presence of a base gives (V). Cyclization of (V) in the presence of an anhydrous perfluoro acid and an organic base produces (VI). Removal of the protecting group and contact of the unprotected compound with an acid yields a pharmaceutically acceptable salt of (VII). Reacting the pharmaceutically acceptable salt of (VII) with 2,2,2-trifluoroethylamine produces Compound 1. where: PG is a protecting group; X is Br or Cl; Ri is selected from the group consisting of alkyl, aryl and -OR2; R2 is alkyl; and Ts is tosila.

[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-methoxybenzyl carbonyl, benzyl, p-methoxybenzyl, and 3,4-dimethoxybenzyl. In another embodiment, the protecting group is carboxybenzyl.

[0253] In another embodiment, Ri is -OR2, and R2 is methyl or ethyl. In such embodiments, the compound of formula (VI) is a compound of formula (IVa): where R2 is methyl or ethyl. It was surprisingly discovered that when R2 is ethyl or methyl, the compound of formula (V) and subsequent downstream compounds can be isolated as crystalline solids, which helps in the purification of these intermediates. In contrast, previously known processes, which use compounds where R2 is t-butyl, result in the formation of compounds of formula (V) that are isolated as amorphous solids.

[0254] Another process for preparing Compound i is illustrated in Scheme IIIa. i-((Benzyloxy)carbonyl)-4-ethyl-2,5-dihydro-iH-pyrrole-3-carboxylic acid (XI) is hydrogenated to produce (XII). Reaction of (3R,4S)-i-((benzyloxy)carbonyl)-4-ethylpyrrolidine-3-carboxylate (XII) with trimethylsulfoxonium chloride gives sulfur ylide (IIa). Contacting sulfur ylide (IIa) with an anhydrous source of HBr gives rise to the corresponding bromomethyl ketone (IIIa). Reaction of (IIIa) with alkyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-ylcarbamate (IVa) in the presence of lithium tert-butoxide gives (Va). Cyclization of (Va) in the presence of an anhydrous perfluoro acid and an organic base produces (VIa). Removal of the carboxybenzyl protecting group and contact of the unprotected compound with hydrochloric acid gives the pharmaceutically acceptable salt (VIIa). Reacting the pharmaceutically acceptable salt of (VIIa) with 2,2,2-trifluoroethylamine produces Compound i. where: Cbz is carboxybenzyl; Ts is tosila; 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. In particular, in step (a), the compound (XI) or (XIa) can be contacted with a catalyst, such as a ruthenium catalyst. Any catalyst comprising a chiral phosphine may be used. A particular example of a suitable catalyst is diacetate[(S)-(-)5,5'-bis(diphenylphosphine)-4,4'-bi-1,3-benzodioxol]ruthenium(II) (i.e. (S )-Segphos Ru(OAc)2). Suitable solvents for use in step (a) include, but are not limited to, methanol, triethylamine and combinations thereof.

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

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

[0258] More particularly, in some embodiments, a suspension of trimethylsulfoxonium chloride, strong base and solvent is heated (e.g., at about 35°C to about 65°C, or at about 45°C) for about 30 minutes to about 8 hours, or for about 1 hour, followed by cooling. In one embodiment, the suspension is cooled to a temperature of about -1°C or less, or to about -5°C or less. In some embodiments, the concentrated filtrate from step (a) is diluted with a suitable solvent (e.g., tetrahydrofuran), and to this solution is slowly added CDI (e.g., over 30 minutes to 1 hour, or during 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 the suspension of trimethylsulfoxonium chloride, strong base and solvent, simultaneously maintaining the internal temperature below -1°C. In embodiments, the reaction may be stirred for about 30 minutes to about 8 hours, or for about 1 hour at a temperature below about -1°C, or at about -5°C. In another embodiment, the reaction is quenched and the resulting compound of formula (II) or (IIa) is isolated before step (c). In a particular embodiment, step (b) of Schemes 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 the preparation of a protected (3R,4S)-4-ethylpyrrolidine-3-carboxylic acid without formation and isolation of the naphthaleneethane amine salt ( Ia) or the dicyclohexylamine salt (Ib), or isolation of (I) or (XI).

[0260] In step (c) of Schemes III and IIIa, a compound of formula (II) or (IIa) is contacted with an anhydrous source of HBr or HCl to form a compound of formula (III) or (IIIa), respectively . In particular, the anhydrous source of HBR or HCl comprises no more than about 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 particularly, in some embodiments, (II) or (IIa) is combined with HBr or HCl in a suitable solvent. In one embodiment, the solvents are tetrahydrofuran and acetic acid. In one embodiment, the solvent comprises 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 heated 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 for about 5 hours. In one embodiment, the mixture is heated to about 40°C and stirred (e.g., mixed) 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 particular embodiment, the product (compound (III) or (IIIa)) is concentrated to dryness and resuspended in a solvent (N,N-dimethylacetamide) to form a solution of (III) or (IIIa) for use in step (d). In one embodiment, step (c) of Schemes III or IIIa is performed as described in Step B of Example 4.

[0262] Step (c) advantageously produces the halomethyl ketone (III) or (IIIa) with greater purity than in Scheme I or Ia.

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

[0264] More particularly, in some embodiments, the base is slowly added (e.g., over about 30 minutes) to a cooled suspension of the compound of formula (IV) or (IVa) in a solvent. In one embodiment, the suspension of the compound of formula (IV) or (IVa) is cooled to about 0 °C. The resulting solution is stirred for about 30 minutes to about 12 hours, or about 30 minutes and cooled to about -20°C to about 0°C, or about -10°C. In one embodiment, the solution is stirred for about 30 minutes and cooled to about -20°C to about 0°C, or about -10°C. 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. mixed) 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, following addition of the solution from step (c), 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 isolated before step (e). In one embodiment, step (d) of Schemes III or IIIa is performed as described in Step C of Example 4.

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

[0266] In one embodiment, Compound 1 is prepared according to the process presented in Scheme IIIa.

B. Preparation of compounds of formula (I), (Ia), (Ib) and (XIa)

[0267] The processes for preparing Compound 1 disclosed herein may use a compound of formula (I) or a pharmaceutically acceptable salt thereof, and/or a compound of formula (XI) or (XIa). In one embodiment, the processes use the naphthaleneethane amine salt of formula (Ia), or the dicyclohexylamine salt of formula (Ib). Compounds of formula (I) and (Ia) and their preparation are described, for example, in US 2013/0072470, which is incorporated herein by reference. (Ia) can also be prepared as described in Scheme IV, shown below. (Ib) can be prepared as described in Scheme V, shown below. Compounds of formula (I) where PG is Cbz (i.e., compounds of formula (XII)) can be prepared using the procedure shown in Scheme IV or V. Compounds of formula (XI) can be prepared using the procedure shown in Scheme V. Other protecting groups can be substituted for Cbz using techniques known to those skilled in the art.

Formula (Ia)

[0268] The preparation of (Ia) has been previously described (see, for example, US 2013/0072470, Example 12, incorporated herein by reference). A suitable process for preparing the naphthaleneethane amine salt of the compound of formula (I) is illustrated in Scheme IV. Ethyl pent-2-enoate is hydrogenated with a Lindlar catalyst to form (Z)-ethyl pent-2-enoate. (Z)-ethyl pent-2-enoate is reacted with N-(methoxymethyl)-N-(trimethylsilyl methyl)benzylamine to form (XIII). (XIII) is deprotected to form (XIV), followed by hydrolysis of (XIV) to form (XV). (XV) is reacted with N-(benzyloxycarbonyloxy)succinimide to form (XVI). The protected (XVI) is contacted with (R)-1-(naphthalene-1-yl)ethanamine to form (Ia). where: TMS is trimethylsilyl; Cbz is carboxybenzyl; and Bn is benzyl.

[0269] In step (a) of Scheme IV, ethyl pent-2-inoate is hydrogenated with a Lindlar catalyst to form (Z)-ethyl pent-2-enoate. In particular, in some embodiments, ethyl pent-2-inoate is added to a slurry of Lindlar catalyst in solvent (e.g., THF) and organic base (e.g., pyridine). The reaction mixture is sprayed with hydrogen (e.g. for about 15 hours). In one embodiment, after completion of the reaction, the reaction mixture is filtered and the (Z)-ethyl pent-2-enoate washed before step (b).

[0270] In step (b) of Scheme IV, (Z)-ethyl pent-2-enoate is reacted with N-(methoxymethyl)-N-(trimethylsilyl methyl)benzylamine to form (XIII). In particular, trifluoroacetic acid (TFA) is added to a solution of (Z)-ethyl pent-2-enoate and N-(methoxymethyl)-N-(trimethylsilyl methyl)benzylamine in solvent (e.g. 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). (XIII) may be deprotected using any suitable means known in the art, including those set forth above for step (e) of Scheme I. In one embodiment, (XIII) is deprotected by contacting (XIII) with a catalyst (e.g. a palladium such as Pd/C or Pd(OH2)/C) under hydrogen pressure. In one embodiment, the resulting mixture is filtered to provide (XIV). In step (d), (XIV) is contacted with an acid (e.g. HCl). In one embodiment, the reaction mixture is 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 from step (d) containing (XV) is reacted with N-(benzyloxycarbonyloxy) succinimide (e.g., for about 15 hours) to form (XVI).

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

Formula (Ib)

[0273] In some embodiments, the present disclosure is directed to compound (Ib) and a process for preparing compound (Ib). A process for preparing the dicyclohexylamine salt of the compound of formula (I) is illustrated in Scheme V. Carboxybenzyl glycine ethyl ester is reacted with ethyl acrylate to form (VIII). Protection of (VIII) gives rise to (IX). Contacting (IX) with one of ethylboronic acid, ethylmagnesium bromide or ethylzinc chloride in the presence of a catalyst results in (X). (X) is hydrolyzed to produce (XI), which is hydrogenated to produce (XII). (XII) is contacted with dicyclohexylamine to form (Ib). wherein Cbz is carboxybenzyl; and R3 is selected from the group consisting of CF3SO2-; CH3SO2-; and cough.

[0274] In step (a) of Scheme V, carboxybenzyl-glycine ethyl ester is reacted with ethyl acrylate to form (VIII). The reaction in step (a) is conducted in the presence of a strong base. Suitable bases include, but are not limited to, sodium tert-butoxide, potassium tert-butoxide and lithium tert-butoxide. In one embodiment, the strong base is sodium tert-butoxide. In one embodiment, the reaction of step (a) is conducted in an organic solvent, such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 2-methyl tetrahydrofuran, and the like, and combinations thereof.

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

[0276] In step (b) of Scheme V, the compound of formula (VIII) is protected to form (IX). In one embodiment, the compound of formula (III) is reacted with a reagent selected from the group consisting of trifluoromethanesulfonic anhydrous, methanesulfonyl chloride and p-toluenesulfonyl chloride to form (IX). In one embodiment, the reaction of step (b) is conducted in the presence of an organic base. Suitable organic bases include, but are not limited to, diisopropylethylamine (DIPEA), 4-dimethylamino pyridine (DMAP), triethylamine (TEA), pyridine, N-methylmorpholine (NMM), and combinations thereof. The reaction of step (b) can be conducted in any suitable solvent, including, but not limited to, triethylamine, N-methylmorpholine, pyridine, diisopropyl ether and combinations thereof.

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

[0278] In step (c) of Scheme V, (IX) is contacted with one of ethylboronic acid, ethylmagnesium bromide or ethylzinc chloride in the presence of a catalyst to produce (X). Any suitable catalyst known in the art may be used. In some embodiments, the catalyst is a palladium catalyst, such as PdCl2(dppf). In some embodiments, the catalyst is a nickel catalyst, such as Ni(acac)2. In some embodiments, the catalyst is an iron catalyst, and in particular a Fe(III) catalyst, such as FeCl3 and Fe(acac)3. Step (c) can be conducted in a buffer. Some buffers include, but are not limited to, potassium carbonate, sodium carbonate, tribasic potassium phosphate, and combinations thereof. Suitable solvents for use in step (c) include, but are not limited to, toluene, water, dioxane, tetrahydrofuran and combinations thereof.

[0279] In particular, in some embodiments, ethylboronic acid and buffer are added to the solution of (IX) in solvent prepared in step (b). A suitable catalyst may then be added and the resulting mixture heated to about 75°C to about 110°C, or about 85°C, and stirred for about 4 hours to about 18 hours, or about 6 hours. . In one embodiment, the mixture is heated to about 85°C and stirred for about 6 hours. Upon completion, the reaction mixture is cooled to room temperature and the product is filtered. In one embodiment, the product is isolated prior to step (d).

[0280] In step (d), (X) is hydrolyzed to produce (XI). (X) can be hydrolyzed using any suitable means known in the art. In one embodiment, (X) is contacted with an alkali metal hydroxide. 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 may be used in the reaction of step (d) including, but not limited to, tetrahydrofuran, water, dioxane and combinations thereof.

[0281] In particular, in some embodiments, alkali metal hydroxide is added to a solution of (X) in solvent. The resulting mixture is heated to about 20°C to about 65°C and stirred for about 2 hours to about 18 hours. In one embodiment, the mixture is heated to about 50°C and stirred for about 2 hours to about 18 hours. In one embodiment, the mixture is stirred for about 7 hours. Upon completion, the mixture is cooled to room temperature, the pH adjusted to about 9 and the solvent removed. In one embodiment, the product is washed and isolated prior to step (e).

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

[0283] In particular, in some embodiments, a solution of (XI) and the catalyst in solvent is hydrogenated at about 30 °C to about 100 °C for between about 1 hour and about 18 hours. In one embodiment, the solution of (XI) and the catalyst in solvent is hydrogenated at about 580 psi. In one embodiment, the solution of (XI) and the catalyst in solvent is hydrogenated at about 80 ° C for about 1 hour to about 8 hours, or for about 2 hours. Upon completion, the reaction mixture is cooled to room temperature, filtered and concentrated. In one embodiment, the product is washed and transferred to a suitable solvent, such as acetonitrile, prior to step (f). In step (f), additional solvent (e.g., acetonitrile) and dicyclohexylamine are added, and the mixture is heated to about 50°C to about 80°C. In one embodiment, the mixture is heated to about 80 °C. The resulting solution is cooled to room temperature and stirred for about 1 hour to about 18 hours. In one embodiment, the mixture is cooled to room temperature and stirred for about 1 hour. The resulting product (Ib) can be isolated before being used to prepare Compound 1.

C. Intermediate Compounds

[0284] In some embodiments, the present disclosure is directed to intermediate compounds useful in preparing compound 1, as well as to processes for preparing the intermediate compounds.

Formula (IVa)

[0285] In one embodiment the present disclosure is directed to a compound of formula (IVa). where R2 and Ts are as defined above.

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

[0287] In another aspect, the present disclosure is directed to a process for preparing a compound of formula (IVa). A suitable process for preparing a compound of formula (IVa) is illustrated in Scheme VI. In particular, (XVII) is reacted with trimethylsilylacetylene in the presence of a catalyst to form (XVIII). (XVIII) is contacted with p-toluenesulfonyl chloride in the presence of a base to form (XIX). (XIX) is reacted with an ethyl or methyl carbamate in the presence of a catalyst and a ligand to form a compound of formula (IVa). where: R2 is methyl or ethyl; Ts is tosila; and TMS is trimethylsilyl.

[0288] In step (a) of Scheme VI, the commercially available compound (XVII) is reacted with trimethylsilylacetylene in the presence of a catalyst to form (XVIII). Any suitable catalyst known in the art may be used. In some embodiments, the catalyst is a palladium catalyst, such as bis(triphenylphosphine) palladium (II) dichloride (PdCl2(Ph3P)2). Step (a) is typically conducted in the presence of copper(I) iodide (CuI). Any solvent may be used in step (a), including, but not limited to, triethylamine.

[0289] In particular, in some embodiments, the catalyst is added to a solution of (XVII) and CuI in solvent. The reaction mixture is cooled (e.g., to about -5 to 0 °C), and a solution of trimethylsilylacetylene in solvent is slowly added (e.g., over about 15 minutes). The reaction mixture is stirred at about -5°C to 0°C (e.g., for about 1.5 hours), allowing it 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] In particular, in some embodiments, the base is added to a solution of (XVIII) in solvent (for example, at about 0 °C). p-Toluenesulfonyl chloride is subsequently added and the mixture is allowed to warm to room temperature. After reaction (e.g. for about 16 hours), the reaction mixture is poured into ice water and the precipitate is collected. In one embodiment, the product is isolated and purified prior to step (c).

[0292] In step (c) of Scheme VI, (XIX) is reacted with an ethyl or methyl carbamate in the presence of a catalyst and a ligand to form a compound of formula (IVa). The reaction can be carried out in the presence of buffers, such as potassium carbonate, tetramethylammonium hydroxide and the like. In step (c) any suitable catalyst known in the art may be used. In one embodiment, the catalyst is a palladium catalyst, such as palladium (II) acetate. Suitable ligands for use in step (c) include bidentate ligands, such as Xantphos. In one embodiment, the catalyst is palladium (II) acetate and the ligand is Xantphos. Suitable solvents for use in step (c) include, but are not limited to, dioxane, toluene and tetrahydrofuran.

[0293] In particular, in some embodiments, a degassed mixture of the catalyst, ligand, (XIX), carbamate and the buffer in solvent is heated to about 75 °C to about 110 °C, or about 95 °C, and restless during the night. Upon completion, the reaction mixture is cooled to about 30 °C to about 60 °C. In one embodiment, the reaction mixture is cooled to about 50 °C. Optionally, additional solvent may be added, and the resulting solution is filtered. In another embodiment, the product is washed and isolated before being used in the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e] pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide.

[0294] The 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, incorporated herein by reference.

Formula (II)

[0295] In one aspect, the present disclosure is directed to a compound of formula (II): where 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-methoxybenzyl carbonyl, benzyl, p-methoxybenzyl, and 3,4-dimethoxybenzyl.

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

[0298] In another aspect, the present disclosure is directed to a process for preparing a compound of formula (II) or (IIa). A process for preparing a compound of formula (II) or (IIa) is illustrated 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 particular embodiment, the pharmaceutically acceptable salt is a compound of formula (Ib). where PG is a protecting group as defined herein.

[0299] The reaction of Scheme VII is generally carried out in the presence of a coupling agent, such as carbonyldiimidazole (CDI) and a strong base. The strong base may be, for example, potassium tert-butoxide, sodium tert-butoxide or combinations thereof. The reaction of Scheme VII can be carried out in any suitable solvent, including, but not limited to, tetrahydrofuran, water and tert-butyl methyl 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 conducted under the conditions described above for step (a) of Scheme I.

[0300] Another process for preparing a compound 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). where PG is a protecting group as defined herein.

[00301] 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 may be used. A particular example of a suitable catalyst is diacetate[(S)-(-)5,5'-bis(diphenylphosphine)-4,4'-bi-1,3-benzodioxol]ruthenium(II) (i.e. (S)-Segphos Ru(OAc)2). Suitable solvents for use in step (a) include, but are not limited to, methanol, triethylamine and combinations thereof. In one embodiment, the reaction of step (a) of Scheme VIII is conducted under the conditions described above for step (a) of Scheme III.

[0302] The reaction in step (b) of Scheme VIII is generally carried out in the presence of a coupling agent, such as carbonyldiimidazole (CDI) and a strong base. The strong base may be, for example, potassium tert-butoxide, sodium tert-butoxide or combinations thereof. The reaction of step (b) can be carried out in any suitable solvent, including, but not limited to, tetrahydrofuran, water and tert-butyl methyl 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 conducted under the conditions described above for step (b) of Scheme III.

Formula (III)

[0303] In another embodiment, the present disclosure is directed to a process for preparing a compound of formula (III): where 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-methoxybenzyl carbonyl, 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) where Cbz is carboxybenzyl.

[0306] A process for preparing a compound of formula (III) or (IIIa) is illustrated in Scheme IX. where PG and X are as defined herein.

[0307] With reference to Scheme IX, in one embodiment, the 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 conducted in lithium bromide and p-toluenesulfonic acid. The reaction can be conducted in any suitable solvent, including, but not limited to, tetrahydrofuran, ethyl acetate, heptanes, ethanol, water and combinations thereof. In one embodiment, the reaction of Scheme XI is conducted under the conditions described above for step (b) of Scheme I.

[0308] With reference to Scheme IX, in an alternative embodiment, the compound of formula (II) is contacted with an anhydrous source of HBr or HCl to form the compound of formula (III). The reaction can be conducted in any suitable solvent, including, but not limited to, tetrahydrofuran, ethyl acetate, acetic acid, N,N-dimethylacetamide, heptanes and combinations thereof. In one embodiment, the reaction of Scheme IX is conducted under the conditions described above for step (c) of Scheme III.

[0309] In some embodiments, the process for preparing a compound of formula (III) or (IIIa) may further comprise preparing a compound of formula (II). One such process is illustrated in Scheme X. where PG and X are as defined above.

[0310] In Scheme 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 conducted 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 process for preparing a compound of formula (III) or (IIIa) may further comprise preparing a compound of formula (I) or (II). One such process is illustrated in Scheme XI. where PG and X are as defined above.

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

Formulas (V) and (Va)

[0313] In another embodiment, the present disclosure is directed to a compound of formula (Va): where R2, CBz and Ts are as defined above.

[0314] In another aspect, the present disclosure is directed to a process for preparing a compound of formula (V) or (Va). A process for preparing a compound of formula (V) or (Va) is illustrated in Scheme XII. In Scheme XII, a compound of formula (I) or a pharmaceutically acceptable salt thereof is reacted with trimethylsulfoxonium chloride to form a compound of formula (II). Contacting the compound of formula (II) with LiX and a sulfonic acid gives rise to the corresponding halomethyl ketone (III). The reaction of a compound of formula (III) with a compound of formula (IV) in the presence of a base gives rise to a compound of formula (V). where 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-methoxybenzyl carbonyl, benzyl, p-methoxybenzyl, and 3,4-dimethoxybenzyl.

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

[0317] In one embodiment, Ri is -OR2, and R2 is methyl or ethyl. In such embodiments, the compound of formula (VI) 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 the compound of formula (I) is selected from the group consisting of naphthaleneethane amine salt (Ia) and the dicyclohexylamine salt (Ib).

[0319] The reaction in step (a) of Scheme XII is generally carried out in the presence of a coupling agent, such as carbonyldiimidazole (CDI) and a strong base. The strong base may be, for example, potassium tert-butoxide, sodium tert-butoxide or combinations thereof. The reaction of step (a) 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 (III) or (IIIa), respectively. In one embodiment, the sulfonic acid is selected from the group consisting of methanesulfonic acid and p-toluenesulfonic acid. In one embodiment, the sulfonic acid is p-toluenesulfonic acid. LiX can be selected from lithium bromide and lithium chloride. In one embodiment, LiX is lithium bromide. In one embodiment, the reaction is conducted in lithium bromide and p-toluenesulfonic acid. The reaction of step (b) can be conducted in any suitable solvent, including, but not limited to, tetrahydrofuran, ethyl acetate, heptanes, 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). Step (c) is conducted in the presence of a base, such as lithium tert-butoxide, sodium tert-butoxide or combinations thereof. In one embodiment, the base is lithium tert-butoxide. The reaction of step (c) can be conducted in any suitable solvent, including, but not limited to, dimethylacetamide, tetrahydrofuran, dichloromethane, ethyl acetate, heptanes and combinations thereof.

[0322] In one embodiment, steps (a), (b) and (c) of Scheme XII are conducted under the conditions presented here for the corresponding step of Scheme I.

[0323] In another aspect, the present disclosure is directed to an alternative process for preparing a compound of formula (V) or (Va). A process for preparing a compound of formula (V) or (Va) is illustrated in Scheme XIII. In Scheme XIII, a compound of formula (XIa) is hydrogenated to a compound of formula (I), and the compound of formula (I) is reacted with trimethylsulfoxonium chloride to form a compound of formula (II). Contacting the compound of formula (II) with an anhydrous source of HBr or HCl gives rise to the corresponding halomethyl ketone (III). The reaction of a compound of formula (III) with a compound of formula (IV) in the presence of a base gives rise to a compound of formula (V). where 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 compound of formula (XIa), (I), (II), (III), (IV) and (V) is compound (XI), (XII), (IIa ), (IIIa), (IVa) and (Va), respectively. In one embodiment, the protecting group is carboxybenzyl and X is Br. In one embodiment, Ri is -OR2 and R2 is methyl or ethyl. In such embodiments, the compound of formula (VI) is a compound of formula (IVa).

[0325] In step (a) of Scheme XIII, the compound of formula (XIa) can be contacted with a catalyst, such as a ruthenium catalyst. Any catalyst comprising a chiral phosphine may be used. A particular example of a suitable catalyst is diacetate[(S)-(-)5,5'-bis(diphenylphosphine)-4,4'-bi-i,3-benzodioxol]ruthenium(II) (i.e. (S)-Segphos Ru(OAc)2). Suitable solvents for use in step (a) include, but are not limited to, methanol, triethylamine and combinations thereof. In one embodiment, the reaction of step (a) of Scheme XIII is conducted under the conditions described above for step (a) of Scheme III.

[0326] The reaction in step (b) of Scheme XIII is generally carried out in the presence of a coupling agent, such as carbonyldiimidazole (CDI) and a strong base. The strong base may be, for example, potassium tert-butoxide, sodium tert-butoxide or combinations thereof. The reaction of step (b) can be carried out in any suitable solvent, including, but not limited to, tetrahydrofuran, water and tert-butyl methyl ether. In one embodiment, the reaction is carried out in the presence of carbonyldiimidazole and potassium tert-butoxide. In one embodiment, the reaction of step (b) of Scheme XIII is conducted under the conditions described above for step (b) of Scheme III.

[0327] In step (c) of Scheme IX, the compound of formula (II) is contacted with an anhydrous source of HBr or HCl to form the compound of formula (III). The reaction can be conducted in any suitable solvent, including, but not limited to, tetrahydrofuran, ethyl acetate, acetic acid, N,N-dimethylacetamide, heptanes and combinations thereof. In one embodiment, the reaction of step (c) of Scheme XIII is conducted under the conditions described above for step (c) of Scheme III.

[0328] In step (d) of Scheme XIII, the compound of formula (III) is reacted with a compound of formula (IV) or (IVa) (prepared as described herein). Step (d) is conducted in the presence of a base, such as lithium tert-butoxide, sodium tert-butoxide or combinations thereof. In one embodiment, the base is lithium tert-butoxide. The reaction of step (d) can be conducted in any suitable solvent, including, but not limited to, dimethylacetamide, tetrahydrofuran, dichloromethane, ethyl acetate, heptanes and combinations thereof. In one embodiment, the reaction of step (d) of Scheme XIII is conducted under the conditions described above for step (d) of Scheme III.

[0329] As discussed herein, it was surprisingly discovered that when R1 is -OR2, and R2 is ethyl or methyl, the compound of formula (V) and subsequent downstream compounds can be isolated as crystalline solids, which aids in purification of these intermediaries. Thus, in another aspect, the present disclosure is directed to a process for preparing a crystalline compound of formula (V). The process comprises a) reacting a compound of formula (III): with a compound of formula (IV): to produce the compound of formula (V); where: PG is a protecting group; X is Br or Cl; Ri is-OR2; R2 is methyl or ethyl; and Ts is tosila. In one embodiment, the process is conducted under the conditions set forth above for step c) in Scheme XII or step (d) in Scheme XIII.

Formula (VII)

[0330] In another modality, the present disclosure is directed to the 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 processes for preparing (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl) -N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide which are disclosed herein may further comprise forming one or more of the solid state forms described herein in Section III.

III. Solid State Forms

[0334] The present disclosure also relates to solid state forms of Compound 1. As with all pharmaceutical compositions and compounds, the chemical and physical properties of Compound 1 are important in its commercial development. These properties include, but are not limited to: (1) packaging properties such as molar volume, bulk density and hygroscopicity, (2) thermodynamic properties such as melting temperature, vapor pressure and solubility, (3 ) kinetic properties such as dissolution rate and stability (including stability under environmental conditions, especially humidity and under storage conditions), (4) surface properties such as surface area, wettability, interfacial tension and shape (5) properties mechanics such as hardness, tensile strength, compactability, handling, fluidity and mixing; and (6) filtration properties. These properties may affect, for example, the processing and storage of the compound and pharmaceutical compositions comprising the compound.

[0335] Solid-state forms of Compound 1 are desirable that improve one or more of these properties over other solid-state forms of the compound. Isolating pharmaceutically acceptable solid-state forms of the compound that can be manufactured and formulated on a commercial scale has been challenging.

[0336] The Amorphous Free Base form of Compound 1 generally has greater solubility and greater bioavailability compared to most of the corresponding crystalline forms of the compound. Amorphous Free Base also has acceptable chemical stability. However, it is hygroscopic and environmental controls are potentially required to ensure appropriate control of potency and water content during storage, distribution and handling of Amorphous Free Base. Furthermore, Amorphous Free Base exhibits an oiling-out limit close to the solubility curve during manufacturing.

[0337] Crystalline Hydrochloride Solvate Form AA, Crystalline Hydrochloride Solvate Form BB and Crystalline Hydrochloride Solvate Form CC generally convert to an amorphous hydrochloride after ambient drying. The resulting amorphous hydrochloride is hygroscopic. The yields obtained for each of the crystalline hydrochlorides have generally been low. Form AA of Hydrochloride Solvate, Form BB of Hydrochloride Solvate and Form CC of Hydrochloride Solvate may not be suitable for large-scale manufacturing.

[0338] Crystalline L-maleate forms generally may be less chemically stable than Amorphous Free Base, Free Base Hydrate Form C, and Tartrate Hydrate and may not exhibit pharmaceutically acceptable stability for use as an ingredient active in a pharmaceutical dosage form.

[0339] The Tartrate Hydrate form has acceptable chemical stability, high solubility, generally good rejection of impurities during isolation and is not hygroscopic. However, Tartrate Hydrate presented challenges due to lack of physical stability which also affected manufacturing. Tartrate Hydrate dehydrated in Amorphous at low relative humidity and high temperature, e.g. <10% RH at 25°C. Shear and compression potentially cause conversion to the amorphous tartrate, and as such, it is not suitable for compression into tablet form. Additionally, the filter cake solidified during drying, resulting in the need for additional controls during drying.

[0340] Free Base Hydrate Form B was manufactured on a large scale without the need for laborious and expensive techniques such as spray drying. It also provided appropriate control over the global properties of the Amorphous Free Base. However, Amorphous Free Base exhibited poor impurity rejection when isolated via Free Base Hydrate Form B and required a dry environment for storage and relative humidity control during manufacturing and packaging.

[0341] Free Base Hydrate Form B was not physically stable. It desolvated (or dehydrated) and became the Amorphous Free Base after drying. Although 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 in the preparation of other solid state forms such as Amorphous Free Base. .

[0342] After years of experimentation, Free Base Hydrate Form C was fortuitously discovered when trying to increase Amorphous Free Base. It offers many superior and surprising properties over Amorphous Free Base, Tartrate Hydrate and other forms of Compound 1.

[0343] Free Base Hydrate Form C generally exhibits excellent chemical stability, physical stability and solid state properties, including low hygroscopicity and prismatic morphology. Freebase Hydrate Form C has improved general properties such as powder product flow and bulk density, which are beneficial in the formulation process. Furthermore, Free Base Hydrate Form C offers at least the following unexpected advantages over other forms: 1) efficient purification is obtained since there is no need to use tartrate crystal; 2) the seeding step is simple since Free Base Hydrate Form C can be stored under normal conditions; 3) the drying step can be carried out under normal conditions with standard equipment since dehydration does not occur up to around 110 °C; 4) Free Base Hydrate Form C can be crystallized in different particle sizes. Large-scale manufacture of Free Base Hydrate Form C is relatively simple with minimal organic precipitation, good yield, good impurity rejection, rapid filtration, conventional drying and minimal milling problems. Furthermore, Free Base Hydrate Form C can be grown into different particle sizes.

[0344] Free Base Hydrate Form D can be manufactured only when the water content of the crystallization solvent is low, and will convert to Free Base Hydrate Form C in solutions with high water content. The manufacture of Freebase Anhydrous Form D thus requires strict control of the water content. Free Base Anhydrous Form D is slow to crystallize, and difficult to manufacture in higher yields. This anhydrous is reversibly hygroscopic (up to 1.8% water at 90% RH at 25°C), and is metastable relative to Free Base Hydrate Form C under typical environmental conditions (e.g., above 2.4 %RH at 23°C) used during storage for downstream processing. Free Base Hydrate Form C will convert to Free Base Anhydrous Form D in a low water ethyl acetate solution.

[0345] The sections below discuss 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 (the “Amorphous Free Base”). In one aspect, the Amorphous Free Base comprises less than about 13% by weight of water. In another aspect, the Amorphous Free Base comprises less than about 12% by weight of water. In another aspect, the Amorphous Free Base comprises less than about 10% by weight of water. In another aspect, the Amorphous Free Base comprises less than about 9% by weight of water. In another aspect, the Amorphous Free Base comprises less than about 8% by weight of water. In another aspect, the Amorphous Free Base comprises less than about 7% by weight of water. In another aspect, the Amorphous Free Base comprises less than about 6% by weight of water. In another aspect, the Amorphous Free Base comprises less than about 5% by weight of water. In another aspect, the Amorphous Free Base comprises less than about 4% by weight of water. In another aspect, the Amorphous Free Base comprises less than about 3% by weight of water. In another aspect, the Amorphous Free Base comprises less than about 2% by weight of water. In another aspect, the Amorphous Free Base comprises less than about 1% by weight of water. In another aspect, the Amorphous Free Base has an onset glass transition temperature of about 119 °C. In another aspect, the Amorphous Free Base has a midpoint glass transition temperature of about 122 °C. In another aspect, the Amorphous Free Base has an onset glass transition temperature of about 119 °C and a midpoint glass transition temperature of about 122 °C. The Amorphous Free Base is further described in the Application Examples.

[0347] Amorphous Free Base generally has greater solubility and greater bioavailability in relation to the corresponding crystalline forms of the compound. Amorphous Free Base also has acceptable chemical stability. For example, when chemical stability was evaluated in unopened vials at 30°C/65% relative humidity and 40°C/75% relative humidity over 12 weeks, and at 50°C/75% relative humidity over Over 6 weeks, no degradation was observed in the unopened vials under any of these conditions. Furthermore, Amorphous Free Base exhibits acceptable stability to light and peroxide. Amorphous Free Base, however, is hygroscopic and can comprise up to 12% by weight of water at 25°C/90% relative humidity. Environmental controls are potentially required to ensure appropriate control of potency and water content during storage, distribution and handling of Amorphous Free Base.

[0348] Amorphous Free Base can be prepared, for example, using antisolvent crystallization to prepare Free Base Solvate Form A or Free Base Hydrate Form B (described below) followed by dehydration or desolvation to give rise to Amorphous Free Base. The crystallization/dehydration/desolvation method allows the large-scale manufacture of Amorphous Free Base without the need for laborious and expensive techniques such as spray drying. It also provides appropriate control of the global properties of the Amorphous Free Base (i.e. particle size, flow properties, etc.). When Amorphous Free Base is prepared by desolvation of Free Base Solvate Form A or dehydration of Free Base Hydrate Form B it generally retains the morphology of Free Base Solvate Form A or Free Base Hydra Form B (i.e. , sheets with hexagonal crystal faces when prepared by dehydration from Free Base Hydrate Form B or irregular when desolvated from Free Base Solvate Form A).

[0349] The process volumes required for crystallization during large-scale manufacture of Free Base Solvate Form A or Free Base Hydrate Form B are generally within conventional processing volumes, but impurity rejection may potentially be lower. to the desired. Drying and dehydration/desolvation of Free Base Hydrate Form B/Free Base Solvate Form A to the Amorphous Free Base can generally be accomplished without standard equipment under conventional conditions and the isolated Amorphous Free Base typically can be co-milled without adversely affect 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 (the "Free Base Solvate Form A"). In another aspect, the crystalline free base is a hydrate (the "Free Base Hydrate Form B"). Free"). Free Base Solvate Form A and Free Base Hydra Form B are further described in the Application Examples.

[0351] In one embodiment, the crystalline free base solvate or hydrate has a powder method X-ray diffraction pattern characterized by peaks at 3.1 ± 0.2, 9.3 ± 0.2, and 12. 0 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Kα1 radiation.

[0352] In one embodiment, the crystalline free base solvate or hydrate has a powder method X-ray diffraction pattern characterized by peaks at 3.1 ± 0.2, 9.3 ± 0.2, and 12. 0 ± 0.2 degrees two theta and which is additionally characterized by a peak at one or more of 13.7 ± 0.2, 20.8 ± 0.2 and 25.0 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Kα1 radiation.

[0353] In one embodiment, the crystalline free base solvate or hydrate has a powder method X-ray diffraction pattern characterized by peaks at 3.1 ± 0.2, 9.3 ± 0.2, 12.0 ± 0.2 and 20.8 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Kα1 radiation.

[0354] In one embodiment, the crystalline free base solvate or hydrate has a powder method X-ray diffraction pattern characterized by peaks at 3.1 ± 0.2, 9.3 ± 0.2, 12.0 ± 0.2 and 25.0 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Kα1 radiation.

[0355] In one embodiment, the crystalline free base solvate or hydrate has a powder method X-ray diffraction pattern characterized by peaks at 3.1 ± 0.2, 9.3 ± 0.2, 12.0 ± 0.2, 20.8 ± 0.2, and 25.0 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Kα1 radiation.

[0356] In one embodiment, the crystalline free base solvate or hydrate has a powder method X-ray diffraction pattern characterized by peaks at 3.1 ± 0.2, 9.3 ± 0.2, 12.0 ± 0.2, 13.7 ± 0.2, 20.8 ± 0.2 and 25.0 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Kα1 radiation.

[0357] In one embodiment, the crystalline free base solvate or hydrate has a powder X-ray diffraction pattern without a significant peak at one or more of 15.1 ± 0.2, and 21.7 ± 0 .2 degrees two theta when measured at about 25°C with monochromatic Kα1 radiation.

[0358] In one embodiment, the crystalline free base solvate or hydrate has a powder X-ray diffraction pattern without a significant peak at one or more of 3.9 ± 0.2, 6.8 ± 0, 2 and 14.1 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Kα1 radiation.

[0359] In one embodiment, the crystalline free base solvate or hydrate has a powder X-ray diffraction pattern without a significant peak at one or more of 15.1 ± 0.2, and 21.7 ± 0 .2 degrees two theta and without a significant peak at one or more of 3.9 ± 0.2, 6.8 ± 0.2 and 14.1 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Kα1 radiation.

[0360] In one embodiment, the crystalline free base solvate or hydrate has a powder method X-ray diffraction pattern characterized by peaks at 3.1 ± 0.2, 9.3 ± 0.2, and 12. 0 ± 0.2 degrees two theta and without a significant peak at one or more of 15.1 ± 0.2, and 21.7 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Kα1 radiation.

[0361] In one embodiment, the crystalline free base solvate or hydrate has a powder method X-ray diffraction pattern characterized by peaks at 3.1 ± 0.2, 9.3 ± 0.2, and 12. 0 ± 0.2 degrees two theta and without a significant peak at one or more of 3.9 ± 0.2, 6.8 ± 0.2 and 14.1 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Kα1 radiation.

[0362] In one embodiment, the crystalline free base solvate or hydrate has a powder method X-ray diffraction pattern characterized by peaks at 3.1 ± 0.2, 9.3 ± 0.2, and 12. 0 ± 0.2 degrees two theta and without a significant peak at one or more of 15.1 ± 0.2, and 21.7 ± 0.2 degrees two theta and without a significant peak at one or more of 3.9 ± 0.2, 6.8 ± 0.2 and 14.1 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Kα1 radiation.

[0363] In one embodiment, the crystalline free base solvate or hydrate has a powder method X-ray diffraction pattern characterized by peaks at 3.1 ± 0.2, 9.3 ± 0.2, and 12. 0 ± 0.2, 13.7 ± 0.2, 20.8 ± 0.2 degrees and 25.0 ± 0.2 two theta and without a significant peak at one or more of 15.1 ± 0.2, and 21.7 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Ka1 radiation.

[0364] In one embodiment, the crystalline free base solvate or hydrate has a powder method X-ray diffraction pattern characterized by peaks at 3.1 ± 0.2, 9.3 ± 0.2, and 12. 0 ± 0.2, 13.7 ± 0.2, 20.8 ± 0.2 and 25.0 ± 0.2 degrees two theta and without a significant peak at one or more of 3.9 ± 0.2, 6.8 ± 0.2 and 14.1 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Ka1 radiation.

[0365] In one embodiment, the crystalline free base solvate or hydrate has a powder method X-ray diffraction pattern characterized by peaks at 3.1 ± 0.2, 9.3 ± 0.2 and 12.0 ± 0.2, 13.7 ± 0.2, 20.8 ± 0.2, and 25.0 ± 0.2 degrees two theta and without a significant peak at one or more of 15.1 ± 0.2, and 21.7 ± 0.2 degrees two theta and without a significant peak at one or more of 3.9 ± 0.2, 6.8 ± 0.2 and 14.1 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Ka1 radiation.

[0366] In one embodiment, the crystalline free base solvate or hydrate has a powder method X-ray diffraction pattern characterized by peaks substantially at the positions listed in Table 16-A ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Ka1 radiation.

[0367] In one embodiment, the crystalline free base solvate or hydrate has a powder method X-ray diffraction pattern characterized by peaks substantially at the positions listed in Table 16-B ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Ka1 radiation.

[0368] In one embodiment, the crystalline free base solvate or hydrate has a powder method X-ray diffraction pattern characterized by peaks substantially at the positions listed in Table 16-B ± 0.2 degrees two theta that have a relative intensity of at least 10.0% when measured at about 25 °C with monochromatic Ka1 radiation.

[0369] In additional aspects of each of the above embodiments, the significant peak values have a variation of ± 0.1 degrees two theta instead of ± 0.2 degrees theta. In still further aspects of each of the above embodiments, the significant peak values have a variation of ±0.05 degrees two theta rather than ±0.2 degrees theta.

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

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

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

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

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

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

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

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

[0378] In one embodiment, the crystalline free base has a differential scanning calorimetry profile substantially as shown in Figure 5B.

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

[0380] In one embodiment, the crystalline free base has a thermogravimetric analysis profile showing a weight loss of about 5% to about 6% between about 100°C and about 160°C when heated at a rate of 10 °C/minute; and a differential scanning calorimetry profile comprising a first endotherm between about 59.90°C to about 98.79°C, and/or a second endotherm between about 109.31°C to about 132.94°C. °C, when heated at a rate of 10 °C/minute. In one aspect, the differential scanning calorimetry profile comprises a first endotherm between about 59.90 °C and about 98.79 °C when heated at a rate of 10 °C/minute. In another aspect, the differential scanning calorimetry profile comprises a second endotherm between about 109.31 °C and about 132.94 °C when heated at a rate of 10 °C/minute. In one aspect, the differential scanning calorimetry profile comprises a first endotherm between about 59.90°C to about 98.79°C, and a second endotherm between about 109.31°C to about 132.94°C. 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 previously described above, and additionally has at least one of the following: (a) a thermogravimetric analysis profile showing a weight loss of about 5 % to about 6% between about 100°C and about 160°C when heated at a rate of 10°C/minute; and (b) a differential scanning calorimetry profile comprising a first endotherm between about 25°C to about 100°C, and/or a second endotherm between about 100°C to about 160°C, when heated to a rate of 10 °C/minute. In one aspect, the differential scanning calorimetry profile comprises a first endotherm between about 25 °C and about 100 °C when heated at a rate of 10 °C/minute. In another aspect, the differential scanning calorimetry profile comprises a second endotherm between about 100 °C and about 160 °C when heated at a rate of 10 °C/minute. In one aspect, the differential scanning calorimetry profile comprises a first endotherm between about 25°C to about 100°C, and a second endotherm between about 100°C to 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 previously described above, and additionally has a thermogravimetric analysis profile showing a weight loss of about 5% to about 6% between about 100°C and about 160°C when heated at a rate of 10°C/minute.

[0383] In one embodiment, the crystalline free base has an X-ray diffraction pattern as previously described above, and additionally has a differential scanning calorimetry profile comprising a first endotherm between about 25°C to about 100° C, and a second endotherm between about 100 °C to about 160 °C when heated at a rate of 10 °C/minute. In one aspect, the differential scanning calorimetry profile comprises a first endotherm between about 25 °C and about 100 °C when heated at a rate of 10 °C/minute. In another aspect, the differential scanning calorimetry profile comprises a second endotherm between about 100 °C and about 160 °C when heated at a rate of 10 °C/minute. In one aspect, the differential scanning calorimetry profile comprises a first endotherm between about 25°C to about 100°C, and a second endotherm between about 100°C to 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 previously described above; a thermogravimetric analysis profile showing a weight loss of about 5% to about 6% between about 100°C and about 160°C when heated at a rate of 10°C/minute; and a differential scanning calorimetry profile comprising a first endotherm between about 25°C to about 100°C, and/or a second endotherm between about 100°C to about 160°C when heated at a rate of 10° C/minute. In one aspect, the differential scanning calorimetry profile comprises a first endotherm between about 25 °C and about 100 °C when heated at a rate of 10 °C/minute. In another aspect, the differential scanning calorimetry profile comprises a second endotherm between about 100 °C and about 160 °C when heated at a rate of 10 °C/minute. In one aspect, the differential scanning calorimetry profile comprises a first endotherm between about 25°C to about 100°C, and a second endotherm between about 100°C to 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 not physically stable. As discussed above, they desolvate (or dehydrate) and convert to Amorphous Free Base upon drying. Although Free Base Solvate Form A and Free Base Hydra Form B generally do not exhibit pharmaceutically acceptable physical stability for use as an active ingredient in a pharmaceutical dosage form, they are useful intermediates in the preparation of other forms in solid state such as Amorphous Free Base.

C. Form C of Crystalline Free Base Hydrate (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 crystalline hemihydrate of Compound 1 having a powder method X-ray diffraction pattern corresponding to Free Base Hydrate Form C. Freebase Hydrate Form C is further described in the Application Examples.

[0387] In one embodiment, Free Base Hydrate Form C has an X-ray powder diffraction pattern characterized by peaks at 13.4 ± 0.2, 15.1 ± 0.2, and 21.7 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Kα1 radiation.

[0388] In one embodiment, Free Base Hydrate Form C has an X-ray powder diffraction pattern characterized by peaks at 13.4 ± 0.2, 15.1 ± 0.2, and 21.7 ± 0.2 degrees two theta, and which is additionally characterized by a peak at one or more of 7.7 ± 0.2, 7.9 ± 0.2, 9.6 ± 0.2, 10, 3 ± 0.2, 13.9 ± 0.2, 15.5 ± 0.2, 15.9 ± 0.2, 17.0 ± 0.2, 17.2 ± 0.2, 17.8 ± 0.2, 18.1 ± 0.2, 18.3 ± 0.2, 19.3 ± 0.2, 19.7 ± 0.2, 20.5 ± 0.2, 20.9 ± 0, 2, 21.9 ± 0.2, 22.2 ± 0.2, 23.5 ± 0.2, 24.4 ± 0.2, 24.9 ± 0.2, 28.2 ± 0.2, and 29.5 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Kα1 radiation.

[0389] In one embodiment, Free Base Hydrate Form C has a powder X-ray diffraction pattern that is characterized by peaks at 13.4 ± 0.2, 15.1 ± 0.2 , 15.5 ± 0.2, and 21.7 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Kα1 radiation.

[0390] In one embodiment, Free Base Hydrate Form C has a powder X-ray diffraction pattern that is characterized by peaks at 13.4 ± 0.2, 15.1 ± 0.2 , 17.0 ± 0.2, and 21.7 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Kα1 radiation.

[0391] In one embodiment, Free Base Hydrate Form C has a powder X-ray diffraction pattern that is characterized by peaks at 13.4 ± 0.2, 15.1 ± 0.2 , 20.9 ± 0.2, and 21.7 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Kα1 radiation.

[0392] In one embodiment, Free Base Hydrate Form C has a powder X-ray diffraction pattern that is characterized by peaks at 13.4 ± 0.2, 15.1 ± 0.2 , 15.5 ± 0.2, 17.0 ± 0.2, 20.9 ± 0.2, and 21.7 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Kα1 radiation.

[0393] In one embodiment, Free Base Hydrate Form C has an X-ray powder diffraction pattern characterized by peaks at 15.5 ± 0.2, 13.4 ± 0.2, 15 .1 ± 0.2, 19.3 ± 0.2, 20.5 ± 0.2 and 21.7 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Kα1 radiation.

[0394] In one embodiment, Free Base Hydrate Form C has an X-ray powder diffraction pattern without a significant peak at one or more of 3.1 ± 0.2, 9.3 ± 0.2 and 12.0 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Kα1 radiation.

[0395] In one embodiment, Free Base Hydrate Form C has a powder X-ray diffraction pattern without a significant peak at one or more of 3.9 ± 0.2, 6.8 ± 0.2 and 14.1 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Kα1 radiation.

[0396] In one embodiment, Free Base Hydrate Form C has a powder X-ray diffraction pattern without a significant peak at one or more of 3.1 ± 0.2, 9.3 ± 0.2, and 12.0 ± 0.2 degrees two theta and without a significant peak at one or more of 3.9 ± 0.2, 6.8 ± 0.2, and 14.1 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Kα1 radiation.

[0397] In one embodiment, Free Base Hydrate Form C has an X-ray powder diffraction pattern characterized by peaks at 13.4 ± 0.2, 15.1 ± 0.2, and 21.7 ± 0.2 degrees two theta and without a significant peak at one or more of 3.1 ± 0.2, 9.3 ± 0.2 and 12.0 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Kα1 radiation.

[0398] In one embodiment, Free Base Hydrate Form C has an X-ray powder diffraction pattern characterized by peaks at 13.4 ± 0.2, 15.1 ± 0.2, and 21.7 ± 0.2 degrees two theta and without a significant peak at one or more of 3.9 ± 0.2, 6.8 ± 0.2 and 14.1 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Kα1 radiation.

[0399] In one embodiment, Free Base Hydrate Form C has an X-ray powder diffraction pattern characterized by peaks at 13.4 ± 0.2, 15.1 ± 0.2, and 21.7 ± 0.2 degrees two theta and without a significant peak at one or more of 3.1 ± 0.2, 9.3 ± 0.2, and 12.0 ± 0.2 degrees two theta and without a significant peak at one or more of 3.9 ± 0.2, 6.8 ± 0.2 and 14.1 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Ka1 radiation.

[0400] In one embodiment, Free Base Hydrate Form C has an X-ray powder diffraction pattern characterized by peaks at 15.5 ± 0.2, 13.4 ± 0.2, 15 .1 ± 0.2, 19.3 ± 0.2, 20.5 ± 0.2 and 21.7 ± 0.2 degrees two theta and without a significant peak at one or more of 3.1 ± 0.2 , 9.3 ± 0.2 and 12.0 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Ka1 radiation.

[0401] In one embodiment, Free Base Hydrate Form C has an X-ray powder diffraction pattern characterized by peaks at 15.5 ± 0.2, 13.4 ± 0.2, 15 .1 ± 0.2, 19.3 ± 0.2, 20.5 ± 0.2 and 21.7 ± 0.2 degrees two theta and without a significant peak at one or more of 3.9 ± 0.2 , 6.8 ± 0.2 and 14.1 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Ka1 radiation.

[0402] In one embodiment, Free Base Hydrate Form C has an X-ray powder diffraction pattern characterized by peaks at 15.5 ± 0.2, 13.4 ± 0.2, 15 .1 ± 0.2, 19.3 ± 0.2, 20.5 ± 0.2, and 21.7 ± 0.2 degrees two theta and without a significant peak at one or more of 3.1 ± 0, 2, 9.3 ± 0.2, and 12.0 ± 0.2 degrees two theta and without a significant peak at one or more of 3.9 ± 0.2, 6.8 ± 0.2, and 14.1 ±0.2 degrees two theta when measured at about 25°C with monochromatic Ka1 radiation.

[0403] In one embodiment, Free Base Hydrate Form C has a powder method X-ray diffraction pattern characterized by peaks substantially at the positions listed in Table 16-C ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Ka1 radiation.

[0404] In one embodiment, Free Base Hydrate Form C has a powder method X-ray diffraction pattern characterized by peaks substantially at the positions listed in Table 16-C ± 0.2 degrees two theta which have a relative intensity of at least 10.0% when measured at about 25 °C with monochromatic Ka1 radiation.

[0405] In additional aspects of each of the above embodiments, the significant peak values have a variation of ± 0.1 degrees two theta instead of ± 0.2 degrees theta. In still further aspects of each of the above embodiments, the significant peak values have a variation of ±0.05 degrees two theta rather than ±0.2 degrees theta.

[0406] In one embodiment, Free Base Hydrate Form C has an X-ray powder diffraction pattern substantially as shown in Figure 3C when measured at about 25 ° C with monochromatic Ka1 radiation.

[0407] In one embodiment, Free Base Hydrate Form C has a thermogravimetric analysis profile showing a weight loss of about 2.3% to about 2.6% between about 120°C and 160°C when heated at a rate of 10 °C/minute.

[0408] In one embodiment, Free Base Hydrate Form C has a thermogravimetric analysis profile showing a weight loss of about 2.3% to about 2.6% between about 114.52°C and 168°C. .15°C when heated at a rate of 10°C/minute.

[0409] In one embodiment, Free Base Hydrate Form C has a thermogravimetric analysis profile substantially as shown in Figure 4E.

[0410] In one embodiment, Free Base Hydrate Form C has a differential scanning calorimetry profile comprising an endotherm between about 120 °C and about 170 °C when heated at a rate of 10 °C/minute.

[0411] In one embodiment, Free Base Hydrate Form C has a differential scanning calorimetry profile comprising an endotherm between about 134.70°C and about 167.53°C when heated at a rate of 10°C /minute.

[0412] In one embodiment, Free Base Hydrate Form C has a differential scanning calorimetry profile substantially as shown in Figure 5C.

[0413] In one embodiment, Free Base Hydrate Form C has a moisture sorption isotherm profile showing a weight increase 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, Free Base Hydrate Form C has a moisture sorption isotherm profile substantially as shown in Figure 6B.

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

[0416] In one embodiment, Free Base Hydrate Form C has a thermogravimetric analysis profile showing a weight loss of about 2.3% to about 2.6% between about 120°C and 160°C when heated at a rate of 10 °C/minute; and a profile of moisture sorption isotherms showing a weight increase of about 0% to about 0.2% when the relative humidity is increased from about 0% relative humidity to about 90% relative humidity. a temperature of 25 °C.

[0417] In one embodiment, Free Base Hydrate Form C has a differential scanning calorimetry profile comprising an endotherm between about 120 and about 170 °C when heated at a rate of 10 °C/minute; and a profile of moisture sorption isotherms showing a weight increase 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.

[0418] In one embodiment, Free Base Hydrate Form C has a thermogravimetric analysis profile showing a weight loss of about 2.3% to about 2.6% between about 120°C and 160°C when heated at a rate of 10 °C/minute; a differential scanning calorimetry profile comprising an endotherm between about 120°C to about 170°C when heated at a rate of 10°C/minute; and a profile of moisture sorption isotherms showing a weight increase 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.

[0419] In one embodiment, Free Base Hydrate Form C has a thermogravimetric analysis profile showing a weight loss of about 2.3% to about 2.6% between about 120°C and 160°C when heated at a rate of 10 °C/minute; a differential scanning calorimetry profile comprising an endotherm between about 134.70 and about 167.53°C, when heated at a rate of 10°C/minute; and a profile of moisture sorption isotherms showing a weight increase of about 0% to about 0.2% when the relative humidity is increased from about 0% relative humidity to about 90% relative humidity. a temperature of 25 °C.

[0420] In one embodiment, Free Base Hydrate Form C has an orthorhombic network type.

[0421] In one embodiment, Free Base Hydrate Form C has a space group P212121.

[0422] In one embodiment, Free Base Hydrate Form C has unit cell values a, b and c of about 12.7 Á, about 13.1 Á and about 22.6 Á, respectively.

[0423] In one embodiment, Free Base Hydrate Form C has an X-ray diffraction pattern as previously described above, and at least one of the following: (a) thermogravimetric analysis profile showing a weight loss of about 2.3% to about 2.6% between about 120°C and 160°C when heated at a rate of 10°C/minute; (b) a differential scanning calorimetry profile comprising an endotherm between about 120 °C to about 170 °C, when heated at a rate of 10 °C/minute; and/or (c) a moisture sorption isotherm profile showing a weight increase of about 0% to about 0.2% when the relative humidity is increased from about 0% relative humidity to about 90% of relative humidity at a temperature of 25 °C.

[0424] In one embodiment, Free Base Hydrate Form C has an X-ray diffraction pattern as previously described above, and a thermogravimetric analysis profile showing a weight loss of about 2.3% at about of 2.6% between about 120°C and 160°C when heated at a rate of 10°C/minute.

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

[0426] In one embodiment, Free Base Hydrate Form C has an X-ray powder diffraction pattern as described above, and a moisture sorption isotherm profile showing a weight increase 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, Free Base Hydrate Form C has an X-ray diffraction pattern by the powder method as described above; a thermogravimetric analysis profile showing a weight loss of about 2.3% to about 2.6% between about 120°C and 160°C when heated at a rate of 10°C/minute; and a differential scanning calorimetry profile comprising an endotherm between about 120°C to about 170°C when heated at a rate of 10°C/minute.

[0428] In one embodiment, Free Base Hydrate Form C has an X-ray diffraction pattern by the powder method as described above; a thermogravimetric analysis profile showing a weight loss of about 2.3% to about 2.6% between about 120°C and 160°C when heated at a rate of 10°C/minute; and a profile of moisture sorption isotherms showing a weight increase of about 0% to about 0.2% when the relative humidity is increased from about 0% relative humidity to about 90% relative humidity. a temperature of 25 °C.

[0429] In one embodiment, Free Base Hydrate Form C has an X-ray diffraction pattern by the powder method as described above; a differential scanning calorimetry profile comprising an endotherm between about 120 and about 170°C when heated at a rate of 10°C/minute; and a profile of moisture sorption isotherms showing a weight increase 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.

[0430] In one embodiment, Free Base Hydrate Form C has an X-ray diffraction pattern by the powder method as described above; a thermogravimetric analysis profile showing a weight loss of about 2.3% to about 2.6% between about 120°C and 160°C when heated at a rate of 10°C/minute; a differential scanning calorimetry profile comprising an endotherm between about 120°C to about 170°C when heated at a rate of 10°C/minute; and a profile of moisture sorption isotherms showing a weight increase 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.

[0431] Free Base Hydrate Form C generally exhibits good chemical stability, physical stability and solid state properties (including low hygroscopicity). Large-scale manufacture of Free Base Hydrate Form C is relatively simple with minimal organic precipitation, good yield, good impurity rejection, rapid filtration, conventional drying, and minimal milling problems (even after subjecting the isolated material to milling). by high-energy pins). Furthermore, different particle sizes can be achieved through appropriate control of the crystallization process.

D. Crystalline Free Base Anhydrous D Form

[0432] In another embodiment, the solid state form is a crystalline free base anhydrous of Compound 1 having an X-ray diffraction pattern by the powder method corresponding to Free Base Anhydrous Form D. Freebase Anhydrous Form D is further described in the Application Examples.

[0433] In one embodiment, Free Base Anhydrous Form D has a powder method X-ray diffraction pattern characterized by peaks at 8.0 ± 0.2, 9.7 ± 0.2, 14 .2 ± 0.2, 14.5 ± 0.2, and 20.3 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Ka1 radiation.

[0434] In one embodiment, Free Base Anhydrous Form D has a powder method X-ray diffraction pattern characterized by peaks at 8.0 ± 0.2, 9.7 ± 0.2, 14 .2 ± 0.2, 14.5 ± 0.2, and 20.3 ± 0.2 degrees two theta and which is additionally characterized by a peak at one or more of 4.0 ± 0.2, 18.4 ± 0.2, 19.0 ± 0.2, 23.0 ± 0.2 and 24.7 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Ka1 radiation.

[0435] In one embodiment, Free Base Anhydrous Form D has a powder method X-ray diffraction pattern characterized by peaks at 4.0 ± 0.2, 8.0 ± 0.2, 9 .7 ± 0.2, 14.2 ± 0.2, 14.5 ± 0.2 and 20.3 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Kα1 radiation.

[0436] In one embodiment, Free Base Anhydrous Form D has a powder method X-ray diffraction pattern characterized by peaks at 8.0 ± 0.2, 9.7 ± 0.2, 14 .2 ± 0.2, 14.5 ± 0.2, 18.4 ± 0.2 and 20.3 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Kα1 radiation.

[0437] In one embodiment, Free Base Anhydrous Form D has a powder method X-ray diffraction pattern characterized by peaks at 8.0 ± 0.2, 9.7 ± 0.2, 14 .2 ± 0.2, 14.5 ± 0.2, 19.0 ± 0.2, and 20.3 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Kα1 radiation.

[0438] In one embodiment, Free Base Anhydrous Form D has a powder method X-ray diffraction pattern characterized by peaks at 4.0 ± 0.2, 8.0 ± 0.2, 9 .7 ± 0.2, 14.2 ± 0.2, 14.5 ± 0.2, 19.0 ± 0.2 and 20.3 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Kα1 radiation.

[0439] In one embodiment, Free Base Anhydrous Form D has a powder method X-ray diffraction pattern characterized by peaks at 8.0 ± 0.2, 9.7 ± 0.2, 14 .2 ± 0.2, 14.5 ± 0.2, 20.3 ± 0.2 and 23.0 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Kα1 radiation.

[0440] In one embodiment, Free Base Anhydrous Form D has a powder method X-ray diffraction pattern characterized by peaks at 8.0 ± 0.2, 9.7 ± 0.2, 14 .2 ± 0.2, 14.5 ± 0.2, 20.3 ± 0.2 and 24.7 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Kα1 radiation.

[0441] In one embodiment, Free Base Anhydrous Form D has a powder method X-ray diffraction pattern characterized by peaks at 4.0 ± 0.2, 14.5 ± 0.2, and 19.0 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Kα1 radiation.

[0442] In one embodiment, Free Base Anhydrous Form D has a powder method X-ray diffraction pattern characterized by peaks at 4.0 ± 0.2, 14.5 ± 0.2, and 19.0 ± 0.2 degrees two theta and which is additionally characterized by a peak at one or more of 8.0 ± 0.2, 9.7 ± 0.2, 14.2 ± 0.2, 18.4 ± 0.2, 20.3 ± 0.2, 23.0 ± 0.2 and 24.7 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Ka1 radiation.

[0443] In one embodiment, Free Base Anhydrous Form D has a powder X-ray diffraction pattern without a significant peak at one or more of 3.1 ± 0.2, 9.3 ± 0.2 and 20.8 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Ka1 radiation.

[0444] In one embodiment, Free Base Anhydrous Form D has a powder X-ray diffraction pattern without a significant peak at one or more of 6.8 ± 0.2, 15.7 ± 0.2 and 21.9 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Ka1 radiation.

[0445] In one embodiment, Free Base Anhydrous Form D has a powder X-ray diffraction pattern without a significant peak at one or more of 13.4 ± 0.2, 15.5 ± 0.2 and 21.7 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Ka1 radiation.

[0446] In one embodiment, Free Base Anhydrous Form D has a powder X-ray diffraction pattern without a significant peak at one or more of 13.4 ± 0.2, 15.5 ± 0.2, and 21.7 ± 0.2 degrees two theta and without a significant peak at one or more of 6.8 ± 0.2, 15.7 ± 0.2, and 21.9 ± 0.2 degrees two theta and without a significant peak at one or more of 3.1 ± 0.2, 9.3 ± 0.2 and 20.8 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Ka1 radiation .

[0447] In one embodiment, Free Base Anhydrous Form D has a powder method X-ray diffraction pattern characterized by peaks at 8.0 ± 0.2, 9.7 ± 0.2, 14 .2 ± 0.2, 14.5 ± 0.2 and 20.3 ± 0.2 degrees two theta and without a significant peak at one or more of 3.1 ± 0.2, 9.3 ± 0.2 and 20.8 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Kα1 radiation.

[0448] In one embodiment, Free Base Anhydrous Form D has a powder method X-ray diffraction pattern characterized by peaks at 8.0 ± 0.2, 9.7 ± 0.2, 14 .2 ± 0.2, 14.5 ± 0.2 and 20.3 ± 0.2 degrees two theta and without a significant peak at one or more of 6.8 ± 0.2, 15.7 ± 0.2 and 21.9 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Kα1 radiation.

[0449] In one embodiment, Free Base Anhydrous Form D has a powder method X-ray diffraction pattern characterized by peaks at 8.0 ± 0.2, 9.7 ± 0.2, 14 .2 ± 0.2, 14.5 ± 0.2 and 20.3 ± 0.2 degrees two theta and without a significant peak at one or more of 13.4 ± 0.2, 15.5 ± 0.2 and 21.7 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Kα1 radiation.

[0450] In one embodiment, Free Base Anhydrous Form D has a powder method X-ray diffraction pattern characterized by peaks at 8.0 ± 0.2, 9.7 ± 0.2, 14 .2 ± 0.2, 14.5 ± 0.2, and 20.3 ± 0.2 degrees two theta, and without a significant peak at one or more of 3.1 ± 0.2, 9.3 ± 0 .2, and 20.8 ± 0.2 degrees two theta and without a significant peak at one or more of 6.8 ± 0.2, 15.7 ± 0.2, and 21.9 ± 0.2 degrees two theta and without a significant peak at one or more of 13.4 ± 0.2, 15.5 ± 0.2 and 21.7 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Ka1 radiation.

[0451] In one embodiment, Free Base Anhydrous Form D has a powder method X-ray diffraction pattern characterized by peaks at 4.0 ± 0.2, 8.0 ± 0.2, 9 .7 ± 0.2, 14.2 ± 0.2, 14.5 ± 0.2, 19.0 ± 0.2 and 20.3 ± 0.2 degrees two theta and without a significant peak in one or more of 3.1 ± 0.2, 9.3 ± 0.2 and 20.8 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Ka1 radiation.

[0452] In one embodiment, Free Base Anhydrous Form D has a powder method X-ray diffraction pattern characterized by peaks at 4.0 ± 0.2, 8.0 ± 0.2, 9 .7 ± 0.2, 14.2 ± 0.2, 14.5 ± 0.2, 19.0 ± 0.2 and 20.3 ± 0.2 degrees two theta and without a significant peak in one or more of 6.8 ± 0.2, 15.7 ± 0.2 and 21.9 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Ka1 radiation.

[0453] In one embodiment, Free Base Anhydrous Form D has a powder method X-ray diffraction pattern characterized by peaks at 4.0 ± 0.2, 8.0 ± 0.2, 9 .7 ± 0.2, 14.2 ± 0.2, 14.5 ± 0.2, 19.0 ± 0.2 and 20.3 ± 0.2 degrees two theta and without a significant peak in one or more of 13.4 ± 0.2, 15.5 ± 0.2 and 21.7 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Ka1 radiation.

[0454] In one embodiment, Free Base Anhydrous Form D has a powder method X-ray diffraction pattern characterized by peaks at 4.0 ± 0.2, 8.0 ± 0.2, 9 .7 ± 0.2, 14.2 ± 0.2, 14.5 ± 0.2, 19.0 ± 0.2, and 20.3 ± 0.2 degrees two theta, and without a significant peak at one or more than 3.1 ± 0.2, 9.3 ± 0.2, and 20.8 ± 0.2 degrees two theta and without a significant peak at one or more of 6.8 ± 0.2, 15, 7 ± 0.2, and 21.9 ± 0.2 degrees two theta and without a significant peak at one or more of 13.4 ± 0.2, 15.5 ± 0.2, and 21.7 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Ka1 radiation.

[0455] In one embodiment, Free Base Anhydrous Form D has a powder X-ray diffraction pattern characterized by peaks substantially at the positions listed in Table 16-J ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Ka1 radiation.

[0456] In one embodiment, Free Base Anhydrous Form D has a powder X-ray diffraction pattern characterized by peaks substantially at the positions listed in Table 16-J ± 0.2 degrees two theta which have a relative intensity of at least 10.0% when measured at about 25 °C with monochromatic Ka1 radiation.

[0457] In additional aspects of each of the above embodiments, the significant peak values have a variation of ± 0.1 degrees two theta instead of ± 0.2 degrees theta. In still further aspects of each of the above embodiments, the significant peak values have a variation of ±0.05 degrees two theta rather than ±0.2 degrees theta.

[0458] In one embodiment, Free Base Anhydrous Form D has an X-ray powder diffraction pattern substantially as shown in Figure 3J when measured at about 25 ° C with monochromatic Ka1 radiation.

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

[0460] In one embodiment, Free Base Anhydrous Form D has a thermogravimetric analysis profile showing a weight loss of about 0.5% to about 0.8% between about 41.36°C and 190°C. .48°C when heated at a rate of 10°C/minute.

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

[0462] In one embodiment, Free Base Anhydrous Form D has a thermogravimetric analysis profile showing a weight loss of about 0.5% between about 43°C and 100°C when heated at a rate of 10 °C/minute.

[0463] In one embodiment, Free Base Anhydrous Form D has a thermogravimetric analysis profile substantially as shown in Figure 4I.

[0464] In one embodiment, Free Base Anhydrous Form D has a differential scanning calorimetry profile comprising an endotherm between about 180 °C and about 220 °C when heated at a rate of 10 °C/minute.

[0465] In one embodiment, Free Base Anhydrous Form D has a differential scanning calorimetry profile comprising an endotherm between about 199.55°C and about 217.41°C when heated at a rate of 10°C /minute.

[0466] In one embodiment, Free Base Anhydrous Form D has a differential scanning calorimetry profile comprising an endotherm with an onset melting point of about 199.55°C and an enthalpy of fusion of about 85. 4 J/g.

[0467] In one embodiment, Free Base Anhydrous Form D has a differential scanning calorimetry profile substantially as shown in Figure 5E.

[0468] In one embodiment, Free Base Anhydrous Form D has a moisture sorption isotherm profile showing a weight increase of about 1.6% to about 2.0% when the relative humidity is increased from from about 0% relative humidity to about 90% relative humidity at a temperature of 25°C.

[0469] In one embodiment, Free Base Anhydrous Form D has a moisture sorption isotherm profile substantially as shown in Figure 6D.

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

[0471] In one embodiment, Free Base Anhydrous Form D has a thermogravimetric analysis profile showing a weight loss of about 0.5% to about 0.8% between about 43°C and 188°C when heated at a rate of 10 °C/minute; and a profile of moisture sorption isotherms showing a weight increase of about 1.6°C to about 2.0°C when the relative humidity is increased from about 0% relative humidity to about 90% of relative humidity at a temperature of 25 °C.

[0472] In one embodiment, Free Base Anhydrous Form D has a differential scanning calorimetry profile comprising an endotherm between about 180 °C and about 220 °C when heated at a rate of 10 °C/minute; and a profile of moisture sorption isotherms showing a weight increase of about 1.6% to about 2.0% when the relative humidity is increased from about 0% relative humidity to about 90% relative humidity at a temperature of 25 °C.

[0473] In one embodiment, Free Base Anhydrous Form D has a thermogravimetric analysis profile showing a weight loss of about 0.5% to about 0.8% between about 43°C and 188°C when heated at a rate of 10 °C/minute; a differential scanning calorimetry profile comprising an endotherm between about 180°C and about 220°C when heated at a rate of 10°C/minute; and a profile of moisture sorption isotherms showing a weight increase of about 1.6°C to about 2.0°C when the relative humidity is increased from about 0% relative humidity to about 90% of relative humidity at a temperature of 25 °C.

[0474] In one embodiment, Free Base Anhydrous Form D has a thermogravimetric analysis profile showing a weight loss of about 0.5% to about 0.8% between about 43°C and 188°C when heated at a rate of 10 °C/minute; a differential scanning calorimetry profile comprising an endotherm between about 199.55°C and about 217.41°C, when heated at a rate of 10°C/minute; and a profile of moisture sorption isotherms showing a weight increase of about 1.6°C to about 2.0°C when the relative humidity is increased from about 0% relative humidity to about 90% of relative humidity at a temperature of 25 °C.

[0475] In one embodiment, Free Base Anhydrous Form D has an orthorhombic lattice type.

[0476] In one embodiment, Free Base Anhydrous Form D has a space group P21212.

[0477] In one embodiment, Free Base Anhydrous Form D has unit cell values a, b and c of about 43.8 Á, about 8.6 Á and about 9.2 Á, respectively.

[0478] In one embodiment, Free Base Anhydrous Form D has an X-ray diffraction pattern as previously described above, and at least one of the following: (a) thermogravimetric analysis profile showing a weight loss of about 0.5% to about 0.8% between about 43°C and 188°C when heated at a rate of 10°C/minute; (b) a differential scanning calorimetry profile comprising an endotherm between about 180°C to about 220°C when heated at a rate of 10°C/minute; and/or (c) a moisture sorption isotherm profile showing a weight increase of about 1.6% to about 2.0% when the relative humidity is increased from about 0% relative humidity to about 90% relative humidity at a temperature of 25 °C.

[0479] In one embodiment, Free Base Anhydrous Form D has an X-ray diffraction pattern as previously described above, and a thermogravimetric analysis profile showing a weight loss of about 0.5% to about of 0.8% between about 43°C and 188°C when heated at a rate of 10°C/minute.

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

[0481] In one embodiment, Free Base Anhydrous Form D has an X-ray powder diffraction pattern as described above, and a moisture sorption isotherm profile showing a weight increase of about 1.6% to about 2.0% when the relative humidity is increased from about 0% relative humidity to about 90% relative humidity at a temperature of 25°C.

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

[0483] In one embodiment, Free Base Anhydrous Form D has an X-ray diffraction pattern by the powder method as described above; a thermogravimetric analysis profile showing a weight loss of about 0.5% to about 0.8% between about 43°C and 188°C when heated at a rate of 10°C/minute; and a profile of moisture sorption isotherms showing a weight increase of about 1.6°C to about 2.0°C when the relative humidity is increased from about 0% relative humidity to about 90% of relative humidity at a temperature of 25 °C.

[0484] In one embodiment, Free Base Anhydrous Form D has an X-ray diffraction pattern by the powder method as described above; a differential scanning calorimetry profile comprising an endotherm between about 180°C and about 220°C when heated at a rate of 10°C/minute; and a profile of moisture sorption isotherms showing a weight increase of about 1.6% to about 2.0% when the relative humidity is increased from about 0% relative humidity to about 90% relative humidity at a temperature of 25 °C.

[0485] In one embodiment, Free Base Anhydrous Form D has an X-ray diffraction pattern by the powder method as described above; a thermogravimetric analysis profile showing a weight loss of about 0.5% to about 0.8% between about 43°C and 188°C when heated at a rate of 10°C/minute; a differential scanning calorimetry profile comprising an endotherm between about 180°C to about 220°C when heated at a rate of 10°C/minute; and a profile of moisture sorption isotherms showing a weight increase of about 1.6% to about 2.0% when the relative humidity is increased from about 0% relative humidity to about 90% relative humidity at a temperature of 25 °C.

[0486] Free Base Anhydrous Form D is reversibly hygroscopic (up to 1.8% water at 90% RH at 25°C), and is metastable relative to Free Base Hydrate Form C under typical environmental conditions (e.g. above 2.4% RH at 23°C) used during storage for downstream processing. The manufacture of Freebase Anhydrous Form D requires strict water control, since Freebase Anhydrous Form D can be manufactured only when the water content of the crystallization solvent is low (e.g., less than 0. 15% at 23 °C, corresponding to a water activity of 2.4%), and will convert to Free Base Hydrate Form C in solutions with high water content. Free Base Anhydrous Form D is slow to crystallize and difficult to manufacture in higher yields.

E. Crystalline Tartrate

[0487] In another embodiment, the solid state form is a tartrate of Compound 1. In one aspect, the tartrate is amorphous. In another aspect, the tartrate is crystalline. In another aspect, crystalline tartrate is a solvate. In another aspect, crystalline tartrate is a hydrate. In another aspect, the tartrate is crystalline L-tartrate. In another aspect, crystalline L-tartrate is a hydrate. In another aspect, crystalline tartrate is a tetrahydrate (the “Tartrate Hydrate”. Tartrate Hydrate (a tetrahydrate) is further described in the Application Examples.

[0488] In one embodiment, Tartrate Hydrate has a powder method X-ray diffraction pattern characterized by peaks at 3.9 ± 0.2, 6.8 ± 0.2, and 14.1 ± 0. 2 degrees two theta when measured at about 25 °C with monochromatic Ka1 radiation.

[0489] In one embodiment, the Tartrate Hydrate has a powder method X-ray diffraction pattern characterized by peaks at 3.9 ± 0.2, 6.8 ± 0.2, 14.1 ± 0.2 , 15.7 ± 0.2, 21.9 ± 0.2 and 25.9 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Kα1 radiation.

[0490] In one embodiment, the Tartrate Hydrate has an X-ray powder diffraction pattern without a significant peak at one or more of 13.4 ± 0.2, and 15.1 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Ka1 radiation.

[0491] In one embodiment, the Tartrate Hydrate has a powder X-ray diffraction pattern without a significant peak at one or more of 3.1 ± 0.2, 9.3 ± 0.2 and 12, 0 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Ka1 radiation.

[0492] In one embodiment, the Tartrate Hydrate has an X-ray powder diffraction pattern without a significant peak at one or more of 13.4 ± 0.2, and 15.1 ± 0.2 degrees two theta and without a significant peak at one or more of 3.1 ± 0.2 and 9.3 ± 0.2 degrees two theta when measured at about 25 °C with mono-chromatic Ka1 radiation.

[0493] In one embodiment, Tartrate Hydrate has a powder method X-ray diffraction pattern characterized by peaks at 3.9 ± 0.2, 6.8 ± 0.2, and 14.1 ± 0. 2 degrees two theta and without a significant peak at one or more of 13.4 ± 0.2 and 15.1 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Ka1 radiation.

[0494] In one embodiment, Tartrate Hydrate has a powder method X-ray diffraction pattern characterized by peaks at 3.9 ± 0.2, 6.8 ± 0.2, and 14.1 ± 0. 2 degrees two theta and without a significant peak at one or more of 3.1 ± 0.2, 9.3 ± 0.2 and 12.0 ± 0.2 degrees two theta when measured at about 25 °C with radiation Ka1 monochromatic.

[0495] In one embodiment, Tartrate Hydrate has a powder method X-ray diffraction pattern characterized by peaks at 3.9 ± 0.2, 6.8 ± 0.2, and 14.1 ± 0. 2 degrees two theta and without a significant peak at one or more of 13.4 ± 0.2, and 15.1 ± 0.2 degrees two theta and without a significant peak at one or more of 3.1 ± 0.2 , 9.3 ± 0.2 and 12.0 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Ka1 radiation.

[0496] In one embodiment, the Tartrate Hydrate has a powder method X-ray diffraction pattern characterized by peaks at 3.9 ± 0.2, 6.8 ± 0.2, 14.1 ± 0.2 , 15.7 ± 0.2, 21.9 ± 0.2 degrees two theta and without a significant peak at one or more of 13.4 ± 0.2 and 15.1 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Ka1 radiation.

[0497] In one embodiment, the Tartrate Hydrate has a powder method X-ray diffraction pattern characterized by peaks at 3.9 ± 0.2, 6.8 ± 0.2, 14.1 ± 0.2 , 15.7 ± 0.2 and 21.9 ± 0.2 degrees two theta and without a significant peak at one or more of 3.1 ± 0.2, 9.3 ± 0.2 and 12.0 ± 0 .2 degrees two theta.

[0498] In one embodiment, Tartrate Hydrate has a powder method X-ray diffraction pattern characterized by peaks at 3.9 ± 0.2, 6.8 ± 0.2, 14.1 ± 0.2 , 15.7 ± 0.2 and 21.9 ± 0.2 degrees two theta and without a significant peak at one or more of 13.4 ± 0.2, and 15.1 ± 0.2 degrees two theta and without a significant peak at one or more of 3.1 ± 0.2, 9.3 ± 0.2 and 12.0 ± 0.2 degrees two theta.

[0499] In additional aspects of each of the above embodiments, the significant peak values have a variation of ± 0.1 degrees two theta instead of ± 0.2 degrees theta. In still further aspects of each of the above embodiments, the significant peak values have a variation of ±0.05 degrees two theta rather than ±0.2 degrees theta.

[0500] In one embodiment, the Tartrate Hydrate has an X-ray powder diffraction pattern substantially as shown in Figure 3D when measured at about 25 ° C with monochromatic Ka1 radiation.

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

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

[0503] In one embodiment, Tartrate Hydrate has a thermogravimetric analysis profile substantially as shown in Figure 4F.

[0504] In one embodiment, Tartrate Hydrate has a differential scanning calorimetry profile comprising an endotherm between about 60 °C and about 100 °C when heated at a rate of 10 °C/minute.

[0505] In one embodiment, Tartrate Hydrate has a differential scanning calorimetry profile comprising an endotherm between about 75.74°C and about 110.26°C when heated at a rate of 10°C/minute .

[0506] In one embodiment, Tartrate Hydrate has a differential scanning calorimetry profile substantially as shown in Figure 5D.

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

[0508] In one embodiment, the Tartrate Hydrate has a moisture sorption isotherm profile 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, Tartrate Hydrate has a moisture sorption isotherm profile substantially as shown in Figure 6C.

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

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

[0512] In one embodiment, the Tartrate Hydrate has an X-ray diffraction pattern as previously described above, and a thermogravimetric analysis profile showing a weight loss of about 11.8% to about 12.2% between about 25°C and 160°C when heated at a rate of 10°C/minute.

[0513] In one embodiment, the Tartrate Hydrate has an X-ray diffraction pattern by the powder method as described above, and a differential scanning calorimetry profile 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 powder diffraction pattern as described above, and a moisture sorption isotherm profile 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 by the powder method as described above; a thermogravimetric analysis profile showing a weight loss of about 11.8% to about 12.2% between about 25°C and 160°C when heated at a rate of 10°C/minute; and a differential scanning calorimetry profile comprising an endotherm between about 60°C to about 100°C when heated at a rate of 10°C/minute.

[0516] In one embodiment, the Tartrate Hydrate has an X-ray diffraction pattern by the powder method as described above; a thermogravimetric analysis profile showing a weight loss of about 11.8% to about 12.2% between about 25°C and 160°C when heated at a rate of 10°C/minute; and a profile of moisture sorption isotherms 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 25°C.

[0517] In one embodiment, the Tartrate Hydrate has an X-ray diffraction pattern by the powder method as described above; a differential scanning calorimetry profile comprising an endotherm between about 60 °C and about 100 °C when heated at a rate of 10 °C/minute; and a profile of moisture sorption isotherms 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.

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

[0519] Tartrate Hydrate has acceptable chemical stability and exhibits acceptable stability to light and peroxide. For example, when chemical stability was evaluated in unopened vials at 30°C/65% relative humidity and 40°C/75% relative humidity over 12 weeks, and at 50°C/75% relative humidity relative to 6 weeks, no degradation of Tartrate Hydrate was observed in the closed vials under any of the conditions. Tartrate Hydrate has good solubility (BCS Class I) and is not hygroscopic. Tartrate Hydrate, however, will potentially convert to an amorphous tartrate below 10% relative humidity when heated, or when compressed or under shear.

[0520] Tartrate Hydrate can be manufactured, for example, using anti-solvent crystallization. Rejection of impurities during large-scale manufacture of Tartrate Hydrate is generally good, but organic precipitation may be higher than desired and specific anti-solvent addition controls and process volume restrictions may potentially be required. In addition, appropriate control of the filtration, washing and drying steps may be required to minimize consolidation of the wet agglutinate and formation of hard granules in the isolated material. For example, control of relative humidity (e.g., more than 10% and less than 100% relative humidity), temperature (e.g., crystallization at about 10°C is advantageous), and the rate of mixing during drying to minimize the formation of hard granules in the insulated material. Insufficient control of drying conditions will potentially produce a harder, consolidated material that may be difficult to separate during subsequent processing. As previously mentioned, shearing and compression will potentially cause conversion to amorphous tartrate. The dry material is typically milled with mechanical impact mills (e.g., Fitzmill mills and pin mills) because shear-based mills (e.g., comills) can lead to loss of crystallinity. Additionally, loss of crystallinity can potentially occur through pressure or compression forces during formulation (such as would be required for tablet production).

F. Crystalline Hydrochloride

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

[0522] Form AA of Hydrochloride Solvate, Form BB of Hydrochloride Solvate and Form CC of Hydrochloride Solvate appear to be solvates and generally convert to an amorphous hydrochloride upon ambient drying. The resulting amorphous hydrochloride is hygroscopic. The yields obtained for each of the crystalline hydrochlorides are generally in the range of 10% to 15%.

G. L-Crystalline Maleate

[0523] In another embodiment, the solid state form is a crystalline L-maleate of Compound 1. In one aspect, the crystalline L-maleate corresponds to Form AAA of crystalline L-Maleate. In another aspect, crystalline L-maleate corresponds to the BBB Form of crystalline L-Maleate. Form AAA of L-Maleate and Form BBB of L-Maleate are further described in the Application Examples.

[0524] Since L-maleic acid will react with Compound 1, Form AAA of L-Maleate and Form BBB of L-Maleate are less chemically stable than the Amorphous Free Base, Form C of Base Hydrate Free and Tartrate Hydrate and do not exhibit pharmaceutically acceptable stability for use as an active ingredient in a pharmaceutical dosage form.

H. Crystalline Purity

[0525] In additional 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 the 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 99% by weight is the desired solid state form. In another aspect, Compound 1 is present as the pure substantially crystalline (or pure amorphous 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 Free Base Anhydrous Form D. In a more preferred aspect, the solid state form is Free Base Hydrate Form B. In a particularly preferred aspect, the solid state form is Free Base Hydrate Form C. In a preferred aspect, the solid state form is Tartrate Hydrate.

IV. Treatment Methods

[0526] The present disclosure also relates to methods of treating a condition associated with JAK in a subject, in particular a human subject suffering from, or susceptible to, the condition, comprising administering to the subject a therapeutically effective amount of free base. Compound 1 or a pharmaceutically acceptable salt thereof or one or more solid state forms of Compound 1 as described in the present disclosure. Another aspect of the disclosure relates to free base of Compound 1 or a pharmaceutically acceptable salt thereof or one or more solid state forms of Compound 1 as described in the present disclosure for use in treating a condition associated with JAK in a subject, in particular in a human subject suffering from, or susceptible to, the condition, the use comprising administering to the subject a therapeutically effective amount of free base of Compound 1 or a pharmaceutically acceptable salt thereof or one or more solid state forms of Compound 1. In one aspect , the condition is a condition associated with JAK-1. In another preferred aspect, the solid state form is the 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 Hydra Form C. In another aspect, the solid state form is Free Base Hydrate of Tartrate. In another aspect, the solid state form is Free Base Anhydrous Form D.

[0527] In one embodiment, the present disclosure relates to methods of treating a condition selected from the group consisting of immunomodulation, inflammation and proliferative disorders (such as cancer) in a subject, wherein the method comprises administering to the subject , in particular a human subject suffering from, or susceptible to, the condition, a therapeutically effective amount of Compound 1 free base or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1. In another aspect, the present disclosure relates with a free base of Compound 1 or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1 for use in the treatment of a condition selected from the group consisting of immunomodulation, inflammation and proliferative disorders (such as cancer) in a subject, wherein the method comprises administering to the subject, in particular in a human subject suffering from, or susceptible to, the condition, the use comprising administering to the subject a therapeutically effective amount of Compound 1 free base or a salt thereof pharmaceutically acceptable or a solid state form of Compound 1. In one aspect, the solid state form is the Amorphous Free Base. In one aspect, the solid state form is Free Base Anhydrous Form D. 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.

[0528] In one embodiment, the present disclosure relates to methods of 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, peripheral neuropathy, uveitis, fibrosing alveolitis, type I diabetes, juvenile diabetes, juvenile arthritis, Castleman's disease, neutropenia, endometriosis, disease thyroid autoimmunity, testicular and sperm 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, vesiculobullous dermatosis, myositis, primary biliary cirrhosis, polymyalgia rheumatica, autoimmune immunodeficiency, Chagas disease, Kawasaki syndrome, psoriatic arthritis, celiac disease, myasthenia gravis, autoimmune myocarditis, POEMS syndrome, and chronic fatigue syndrome in one subject, in that the method comprises administering to the subject, in particular a human subject suffering from, or susceptible to, the condition, a therapeutically effective amount of Compound 1 free base or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1. In another In this 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, allergic encephalomyelitis experimental, systemic lupus erythematosus, Crohn's disease, atopic dermatitis, vasculitis, cardiomyopathy, psoriasis, Reiter's syndrome, glomerulonephritis, ulcerative colitis, allergic asthma, insulin-dependent diabetes, peripheral neuropathy, uveitis, fibrosing alveolitis, type I diabetes, juvenile diabetes, juvenile arthritis, Castleman's disease, neutropenia, endometriosis, autoimmune thyroid disease, testicular and sperm autoimmunity, scleroderma, axonal and neuronal neuropathy, allergic rhinitis, Sjogren's syndrome, hemolytic anemia, Graves' disease, Hashimoto's roiditis, IgA nephropathy, amyloidosis, ankylosing spondylitis, Behcet's disease, sarcoidosis, vesiculobullous dermatosis, myositis, primary biliary cirrhosis, polymyalgia rheumatica, autoimmune immunodeficiency, Chagas disease, Kawasaki syndrome, psoriatic arthritis, celiac disease, myasthenia gravis, autoimmune myocarditis, POEMS syndrome and chronic fatigue syndrome in a subject, in particular in a human subject suffering from, or susceptible to, the condition, the use comprising administering to the subject a therapeutically effective amount of free base Compound 1 or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1. In one aspect, the solid state form is the 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 Anhydrous Form D.

[0529] In one embodiment, the present disclosure relates to methods of 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). severe), diabetic nephropathy, dry eye syndrome, Sjogren's syndrome, alopecia areata, vitiligo and atopic dermatitis in a subject, wherein the method comprises administering to the subject, in particular a human subject suffering from, or susceptible to, the condition, a therapeutically effective amount of Compound 1 free base or a pharmaceutically acceptable salt or solid state form thereof. In another aspect, the present disclosure relates to Compound 1 free base or a pharmaceutically acceptable salt or solid state form thereof. solid state of Compound 1 for use in the treatment of 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, Sjogren's syndrome, alopecia areata, vitiligo and atopic dermatitis in a subject, in particular in a human subject suffering from, or susceptible to, the condition, the use comprising administering to the subject a therapeutically effective amount of free base Compound 1 or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1. In one aspect, the solid state form is the 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 Anhydrous Form D.

[0530] In one embodiment, the present disclosure relates to methods of treating a condition selected from the group consisting of an ocular condition, systemic inflammatory response syndrome, juvenile rheumatoid arthritis, systemic onset juvenile rheumatoid arthritis, hypersensitivity reactions type III, type IV hypersensitivity, inflammation of the aorta, iridocyclitis/uveitis/optic neuritis, juvenile spinal muscular atrophy, diabetic retinopathy or microangiopathy, chronic inflammation, ulcerative colitis, inflammatory bowel disease, allergic diseases, scleroderma dermatitis, severe immune disease or chronic disease associated with organ transplantation, psoriatic arthropathy, ulcerative colitic arthropathy, 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, lung disease associated with Sjogren's syndrome/disease, ankylosing spondylitis and lung disease associated with ankylosing spondylitis, autoimmune hepatitis, autoimmune hepatitis type 1 (classic or lupoid autoimmune 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, Sjogren's syndrome and thrombocytopenia autoimmune disease in a subject, wherein the method comprises administering to the subject, in particular a human subject suffering from, or susceptible to, the condition, a therapeutically effective amount of free base of Compound 1 or a pharmaceutically acceptable salt thereof or a solid state form thereof. 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 a condition ocular, systemic inflammatory response syndrome, juvenile rheumatoid arthritis, systemic onset juvenile rheumatoid arthritis, type III hypersensitivity reactions, type IV hypersensitivity, aortic inflammation, iridocyclitis/uveitis/optic neuritis, juvenile spinal muscular atrophy, retinopathy or diabetic microangiopathy, chronic inflammation, ulcerative colitis, inflammatory bowel disease, allergic diseases, scleroderma dermatitis, severe or chronic immune disease associated with organ transplantation, psoriatic arthropathy, ulcerative colitic arthropathy, autoimmune bullous disease, autoimmune hemolytic anemia, disease interstitial lung disease associated with rheumatoid arthritis, lung disease associated with systemic lupus erythematosus, lung disease associated with dermatomyositis/polymyositis, lung disease associated with Sjogren's syndrome/disease, ankylosing spondylitis and lung disease associated with ankylosing spondylitis, autoimmune hepatitis, autoimmune hepatitis type 1 (classic autoimmune or lupoid 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, autoimmunity of sperm, multiple sclerosis (all subtypes), acute rheumatic fever, rheumatoid spondylitis, Sjogren's syndrome and autoimmune thrombocytopenia in a subject, in particular a human subject suffering from, or susceptible to, the condition, the use comprising administering to the subject a therapeutically effective amount of 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 the 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 Anhydrous Form D.

[0531] In one embodiment, the present disclosure relates to methods 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. 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 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, in particular a human subject suffering from, or susceptible to, the condition, the use comprising administering to the subject a therapeutically effective amount of free base of Compound 1 or a solid state form of Compound 1. In one aspect, the form in solid state is the 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 Anhydrous Form D.

[0532] In one embodiment, the present disclosure relates to methods 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, nephritis lupus, diabetic nephropathy, dry eye syndrome, Sjogren's syndrome, alopecia areata, vitiligo and atopic dermatitis in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of Compound 1 free base or a pharmaceutically available salt thereof. acceptable 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 rheumatoid arthritis, Crohn's disease, ankylosing spondylitis, psoriatic arthritis, psoriasis, ulcerative colitis, systemic lupus erythematosus, lupus nephritis, diabetic nephropathy, dry eye syndrome, Sjogren's syndrome, alopecia areata, vitiligo and atopic dermatitis in a subject, in particular in a human subject suffering from, or susceptible to, the condition, the use comprising administering to the subject a therapeutically effective amount of 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 the 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 Anhydrous Form D.

[0533] In one embodiment, the present disclosure relates to methods of treating arthritis in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of free base of Compound 1 or a pharmaceutically acceptable salt thereof or an in-state form. solid 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 arthritis in a subject, in particular in 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 state form of Compound 1. In one aspect, Arthritis is selected from the group consisting of rheumatoid arthritis, juvenile idiopathic arthritis, and psoriatic arthritis. In another aspect, arthritis is rheumatoid arthritis. In another aspect, the arthritis is juvenile idiopathic arthritis. In another aspect, arthritis is psoriatic arthritis. In another preferred aspect, the solid state form is the 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 Anhydrous Form D. 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 Form AAA of L-Maleate. In another aspect, the solid state form is the BBB Form of L-Maleate.

[0534] In one embodiment, the present disclosure relates to methods of treating a spondyloarthropathy in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of Compound 1 free base or a pharmaceutically acceptable salt thereof. or a solid 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 the treatment of spondyloarthropathy, in particular in a human subject suffering from, or susceptible to, spondyloarthropathy, the use comprising administering to the subject a therapeutically effective amount of Compound 1 free base or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1. In one aspect, spondyloarthropathy is ankylosing spondylitis. In another preferred aspect, the solid state form is the 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 Anhydrous Form D. 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 Form AAA of L-Maleate. In another aspect, the solid state form is the BBB Form of L-Maleate.

[0535] In one embodiment, the present disclosure relates to methods of treating a gastrointestinal condition in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of free base of Compound 1 or a pharmaceutically acceptable salt thereof or a form in a solid state 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 gastrointestinal condition, in particular in a human subject suffering from, or susceptible to, a gastrointestinal condition, the use comprising administering to the subject a therapeutically effective amount of free base of Compound 1 or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1. In one aspect , the gastrointestinal condition is selected from the group consisting of Crohn's disease and ulcerative colitis. In another aspect, the gastrointestinal condition is Crohn's disease. In another aspect, the gastrointestinal condition is ulcerative colitis. In another preferred aspect, the solid state form is the 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 Anhydrous Form D. 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 Form AAA of L-Maleate. In another aspect, the solid state form is the BBB Form of L-Maleate.

[0536] In one embodiment, the present disclosure relates to methods of treating a skin condition, wherein the method comprises administering to the subject a therapeutically effective amount of free base of Compound 1 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 skin condition, in particular in a human subject suffering from of, or susceptible to, a skin condition, 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 condition is selected from the group consisting of psoriasis, plaque psoriasis and hidradenitis suppurativa. In another aspect, the skin condition is psoriasis. In another aspect, the skin condition is plaque psoriasis. In another aspect, the skin condition is nail psoriasis. In another aspect, the skin condition is hidradenitis suppurativa. In another aspect, the skin condition is atopic dermatitis. In another preferred aspect, the solid state form is the 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 Anhydrous Form D. 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 Form AAA of L-Maleate. In another aspect, the solid state form is the BBB Form of L-Maleate.

[0537] The therapeutically effective dose level for a particular subject will depend on the specific situation and may depend on several factors including the type, age, weight, sex, diet and condition of the subject being treated; the severity of the pathological condition; activity of the specific compound used; the specific composition used; the subject's age, body weight, general health, sex, and diet; administration route; duration of treatment; pharmacological considerations, such as the activity, efficacy, pharmacokinetic and toxicological profiles of the particular compound or salt used; whether a drug delivery system is used; drugs used in combination or coincident with the specific compound used; and similar factors well known in the medical field. A physician of ordinary skill to whom disclosure of the present application is provided will be able to determine appropriate regimens and doses for administration of the therapeutic agent to the subject, and adjust such doses and regimens as necessary during the course of treatment, in accordance with methods well known in the therapeutic field. It is well within the skill of the art to begin doses of the compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dose until the desired effect is achieved. Therefore, the dosage regimen actually employed may vary greatly and, as such, may differ from the preferred dosage regimen presented below.

[0538] The total daily dose of the solid state form (administered in single or divided doses) is typically from about 0.001 to about 100 mg/kg, or from about 0.001 to about 30 mg/kg, or about from 0.001 to about 15 mg/kg. In another embodiment, the total daily dose is about 0.01 to about 10 mg/kg (i.e., mg of compound or salt per kg of body weight). Dosage unit compositions may contain such amounts or submultiples thereof to make up the daily dose. In many cases, administration of the compound or salt will be repeated several times. Multiple doses per day may be used to increase the total daily dose if desired.

[0539] In one embodiment, the daily dose of the solid state form administered to the 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 about 1 mg to about 100 mg. In another aspect, the daily dose is 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 about 1 mg to about 30 mg. In another aspect, the daily dose is 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 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 about 25 mg to about 50 mg. In another aspect, the daily dose is about 1 mg to about 10 mg. In another aspect, the daily dose is about 10 mg to about 20 mg. In another aspect, the daily dose is about 20 mg to about 30 mg. In another aspect, the daily dose is about 30 mg to about 40 mg. In another aspect, the daily dose is about 7.5 mg to about 45 mg. In another aspect, the daily dose is 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 one 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 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) in a solid state form of Compound 1 is administered orally BID (twice per day) in equal amounts (e.g., twice per day, about 3 mg each time) to a human subject.

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

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

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

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

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

[0546] In another embodiment, the methods or uses comprise orally administering QD (once per day) to a human subject a dose of about 7.5 mg per unit dosage form (e.g., per tablet or capsule) of a solid state form of Compound 1. In one embodiment, the methods or uses comprise orally administering QD (once per day) to a human subject a solid state form of Compound 1 in an amount sufficient to provide 7.5 mg per form of unit dosage (e.g., per tablet or capsule) of free base equivalent of Compound 1 to the subject. In one embodiment, the solid state form is the Amorphous Free Base. 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 another aspect, the solid state form is Free Base Anhydrous Form D.

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

[0548] In another embodiment, the methods or uses comprise orally administering QD (once per day) to a human subject a dose of about 15 mg per unit dosage form (e.g., per tablet or capsule) in a form in solid state of Compound 1. In one embodiment, the methods or uses comprise orally administering QD (once per day) to a human subject a solid state form of Compound 1 in an amount sufficient to provide 15 mg per unit dosage form ( e.g., per tablet or capsule) of free base equivalent of Compound 1 to the subject. In one embodiment, the solid state form is the Amorphous Free Base. 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 another aspect, the solid state form is Free Base Anhydrous Form D.

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

[0550] In another embodiment, the methods or uses comprise orally administering QD (once per day) to a human subject a dose of about 24 mg of a solid state form of Compound 1. In one embodiment, the methods or uses comprise orally administering QD (once per day) to a human subject a solid state form of Compound 1 in an amount sufficient to provide 24 mg of free base equivalent of Compound 1 to the subject. The 24 mg QD dose of the solid state form of Compound 1 may be administered as a single dosage form comprising about 24 mg per unit dosage form (e.g., per tablet or capsule) of the solid state form of Compound 1. or two dosage forms comprising about 12 mg per unit dosage form (e.g., per tablet or capsule) of the solid state form of Compound 1 administered simultaneously. In one embodiment, the solid state form is the Amorphous Free Base. 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 another aspect, the solid state form is Free Base Anhydrous Form D.

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

[0552] In another embodiment, the methods or uses comprise orally administering QD (once per day) to a human subject a dose of about 30 mg per unit dosage form (e.g., per tablet or capsule) in a form in solid state of Compound 1. In one embodiment, the methods or uses comprise orally administering QD (once per day) to a human subject a solid state form of Compound 1 in an amount sufficient to provide 30 mg per unit dosage form ( e.g., per tablet or capsule) of free base equivalent of Compound 1 to the subject. In one embodiment, the solid state form is the Amorphous Free Base. 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 another aspect, the solid state form is Free Base Anhydrous Form D.

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

[0554] In another embodiment, the methods or uses comprise orally administering QD (once per day) to a human subject a dose of about 36 mg per unit dosage form (e.g., per tablet or capsule) in a form in solid state of Compound 1. In one embodiment, the methods or uses comprise orally administering QD (once per day) to a human subject a solid state form of Compound 1 in an amount sufficient to provide 36 mg per unit dosage form ( e.g., per tablet or capsule) of free base equivalent of Compound 1 to the subject. In one embodiment, the solid state form is the Amorphous Free Base. 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 another aspect, the solid state form is Free Base Anhydrous Form D.

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

[0556] In another embodiment, the methods or uses comprise orally administering QD (once per day) to a human subject a dose of about 45 mg per unit dosage form (e.g., per tablet or capsule) in a form in solid state of Compound 1. In one embodiment, the methods or uses comprise orally administering QD (once per day) to a human subject a solid state form of Compound 1 in an amount sufficient to provide 45 mg per unit dosage form ( e.g., per tablet or capsule) of free base equivalent of Compound 1 to the subject. In one embodiment, the solid state form is the Amorphous Free Base. 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 another aspect, the solid state form is Free Base Anhydrous Form D.

[0557] In certain embodiments, free base of Compound 1 or a pharmaceutically acceptable salt thereof and/or solid state forms thereof can be used to treat rheumatoid arthritis (RA), including reducing signs and symptoms of RA, inducing an important clinical response, inhibit the progression of or treat structural damage associated with RA, and improve physical function in adult subjects, such as adult subjects with moderately to severely active RA. In one embodiment, the free base of Compound 1 or a pharmaceutically acceptable salt thereof and/or solid state forms thereof are used to treat RA in adult subjects. In one embodiment, the free base of Compound 1 or a pharmaceutically acceptable salt thereof and/or solid state forms thereof are used to treat signs and symptoms of RA in adult subjects. In one embodiment, the free base of Compound 1 or a pharmaceutically acceptable salt thereof and/or solid state forms thereof induce an important clinical response in adult subjects with RA. In one embodiment, the free base of Compound 1 or a pharmaceutically acceptable salt thereof and/or solid state forms thereof are used to inhibit the progression of structural damage associated with RA in adult subjects. In one embodiment, the free base of Compound 1 and/or its solid state forms are used to treat structural damage associated with RA in adult subjects. In one embodiment, the free base of Compound 1 or a pharmaceutically acceptable salt thereof and/or solid state forms thereof are used to improve physical function in adult subjects. In one embodiment, adult subjects have RA. In another embodiment, adult subjects have moderately to severely active AR.

[0558] Free base of Compound 1 or a pharmaceutically acceptable salt thereof or solid state forms thereof can be used alone or in combination with methotrexate or non-biological disease-modifying antirheumatic drugs (DMARDs), and/or in combination with biological anti-rheumatic agents. -TNFα, such as TNF antagonists such as chimeric, humanized or human TNF antibodies, adalimumab (such as adalimumab brand HUMIRA™), infliximab such as CA2 (infliximab brand name REMICADE™), golimumab such as SIMPONI™ (golimumab), Certolizumab pe - gol such as CIMZIA™, tocilizumab such as ACTEMRA™, CDP 571, and soluble TNF receptors p55 or p75, derivatives thereof, etanercept such as p75TNFR1gG (etanercept brand ENBREL™) or p55TNFR1gG (lenercept).

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

[0560] In some embodiments, the free base of Compound 1 or a pharmaceutically acceptable salt thereof or solid state forms thereof halt the progression of the disease, and/or alleviate at least one symptom of the disease, which can be detected or monitored by results X-rays, including radiographic progression of joint damage.

[0561] In some embodiments, therapeutic efficacy can be measured by improvements in ACR20, ACR50, and/or ACR70, in individual patients or in a population of patients in need of treatment. In some embodiments, a statistically significant improvement (compared to placebo or untreated control) is achieved over a period of time (e.g., 1 week, 2 weeks, 4 weeks, 6 weeks, 8 weeks, 12 weeks, 2 months, 3 months, 6 months, 1 year, 2 years, 5 years, 10 years or more) in one or more of the ACR criteria. Statistical significance is manifested by a p-value less than 0.05 or less than 0.01.

[0562] Components of ACR responses are well known in the art and may include the median number of tender joints, the median number of swollen joints, clinical global assessment as measured by visual analogue scale (VAS), patient global assessment as measured visual analogue scale, pain as measured by visual analogue scale, Health Assessment Questionnaire disability index (HAQ-DI score), and C-reactive protein (CRP) (mg/dL).

[0563] In some embodiments, an ACR20 response is determined based on a 20% or greater improvement in swollen joint count (TJC) and swollen joint count (SJC) and greater than or equal to 3 of the 5 measurements of the Assessment of Patient Global 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 greater than or equal to 3 of 5 Patient Assessment of Pain (VAS) measurements, Patient Global Assessment for Disease Activity (VAS), Physician's 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 greater than or equal to 3 of the 5 Patient Assessment of Pain (VAS) measurements, Patient Global Assessment of Disease Activity (VAS), Physician's Global Assessment of Disease Activity (VAS), HAQ-DI, or hsCRP. In certain modalities, the ACR20, ACR50 or ACR70 response occurs by week 12 of treatment.

[0564] In certain embodiments, the DAS28 score (disease activity score based on the 28 joints examined) is determined as a composite score derived from four of the following measurements: examination of joints for swelling and tenderness, global pain scores, and general status, blood markers of inflammation (e.g. ESR (erythrocyte sedimentation rate) and CRP (C-reactive protein), herein referred to as DAS28(CRP)), questionnaires (e.g. the HAQ (Health Assessment Questionnaire) that assess function) and X-rays and other imaging techniques such as ultrasound and MRI.

[0565] In certain embodiments, structural damage to joints can be assessed by radiography and expressed as change in Total Sharp Score (TSS) and its components, the erosion score and Joint Space Reduction score (JSN), e.g. 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 the patient's physical function response, such as the Health Assessment Questionnaire disability index (HAQ-DI), and/or health outcomes. assessed by The Short Form Health Survey (SF 36). In one embodiment, improvement in disease signs and symptoms is measured by HAQ-DI, including the minimum clinically important difference (MCID) of -0.22. Improvement can also be measured by one or both of the Physical Component Summary (PCS) and Mental Component Summary (MCS). Improvements can further be measured by the RA Work Instability Scale (RA-WIS) (see Gilworth et al., Arthritis & Rheumatism (Arthritis Care & Research) 49(3): 349-354, 2003, incorporated herein by reference ).

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

[0568] In one embodiment, the disclosure relates to a method of treating rheumatoid arthritis in a subject, the method comprising orally administering QD (once a day) to the subject, in particular a human subject suffering from, or susceptible to, arthritis rheumatoid, about 7.5 mg per unit dosage form (e.g., per tablet or capsule) of a solid state form of Compound 1. In one embodiment, the method comprises orally administering QD (once per day) to the subject a solid state form of Compound 1 in an amount sufficient to provide 7.5 mg per unit dosage form (e.g., per tablet or capsule) of free base equivalent of Compound 1 to the subject. In another aspect, the present disclosure relates to a solid state form of Compound 1 for use in treating rheumatoid arthritis in a subject, in particular a human subject suffering from, or susceptible to, rheumatoid arthritis, the use comprising administering orally QD (once daily) to the subject about 7.5 mg per unit dosage form (e.g., per tablet or capsule) of a solid state form of Compound 1. In one embodiment, the solid state form provides about of 7.5 mg per unit dosage form (e.g., per tablet or capsule) of free base equivalent of Compound 1 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 Anhydrous Form D. In one embodiment, the subject has moderately to severely 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 Form AAA of L-Maleate. In another aspect, the solid state form is the BBB Form of L-Maleate. In one embodiment, the subject is an adult.

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

[0570] In one embodiment, the disclosure relates to a method of treating rheumatoid arthritis in a subject, the method comprising orally administering QD (once per day) to the subject, in particular a human subject suffering from, or susceptible to, arthritis rheumatoid, about 15 mg per unit dosage form (e.g., per tablet or capsule) of a solid state form of Compound 1. In one embodiment, the method comprises orally administering QD (once per day) to the subject of a form solid state of Compound 1 in an amount sufficient to provide 15 mg per unit dosage form (e.g., per tablet or capsule) of free base equivalent of Compound 1 to the subject. In another aspect, the present disclosure relates to a solid state form of Compound 1 for use in treating rheumatoid arthritis in a subject, in particular a human subject suffering from, or susceptible to, rheumatoid arthritis, the use comprising administering orally QD (once daily) to the subject about 15 mg per unit dosage form (e.g., per tablet or capsule) of a solid state form of Compound 1. In one embodiment, the solid state form provides about 15 mg per unit dosage form (e.g., per tablet or capsule) of free base equivalent of Compound 1 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 Anhydrous Form D. In one embodiment, the subject has moderately to severely 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 Form AAA of L-Maleate. In another aspect, the solid state form is the BBB Form of L-Maleate. In one embodiment, the subject is an adult.

[0571] In one embodiment, the disclosure relates to a method of treating rheumatoid arthritis in a subject, the method comprising orally administering QD (once a day) to the subject, in particular a human subject suffering from, or susceptible to, arthritis rheumatoid, about 24 mg per unit dosage form of Compound 1 free base or a pharmaceutically acceptable salt thereof. In another aspect, the present disclosure relates to a free base of Compound 1 or a pharmaceutically acceptable salt thereof for use in treating rheumatoid arthritis in a subject, in particular a human subject suffering from, or susceptible to, rheumatoid arthritis. the use comprising administering orally QD (once per day) to the subject about 24 mg of Compound 1 free base or a pharmaceutically acceptable salt thereof. The 24 mg dose of Compound 1 free base or a pharmaceutically acceptable salt thereof may be administered as a single dosage form comprising about 24 mg per unit dosage form (e.g., per tablet or capsule) of Compound 1 free base. or a pharmaceutically acceptable salt thereof, or two dosage forms comprising about 12 mg per unit dosage form (e.g., per tablet or capsule) of Compound 1 free base or a pharmaceutically acceptable salt thereof administered 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 disclosure relates to a method of treating rheumatoid arthritis in a subject, the method comprising orally administering QD (once a day) to the subject, in particular a human subject suffering from, or susceptible to, arthritis rheumatoid, about 24 mg of a solid state form of Compound 1. In one embodiment, the method comprises orally administering QD (once per day) to the subject a solid state form of Compound 1 in an amount sufficient to provide 24 mg of free base equivalent of Compound 1 to the subject. In another aspect, the present disclosure relates to a solid state form of Compound 1 for use in treating rheumatoid arthritis in a subject, in particular a human subject suffering from, or susceptible to, rheumatoid arthritis, the use comprising orally administer QD (once per day) to the subject about 24 mg of a solid state form of Compound 1. In one embodiment, the solid state form provides about 24 mg of free base equivalent of Compound 1 to the subject. The 24 mg dose of the solid state form of Compound 1 may be administered as a single dosage form comprising about 24 mg per unit dosage form (e.g., per tablet or capsule) of the solid state form of Compound 1, or two dosage forms comprising about 12 mg per unit dosage form (e.g., per tablet or capsule) of the solid state form of Compound 1 administered simultaneously. 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 Anhydrous Form D. 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 Form AAA of L-Maleate. In another aspect, the solid state form is the BBB Form of L-Maleate. In one embodiment, the subject has moderately to severely active rheumatoid arthritis. In one embodiment, the subject is an adult.

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

[0574] In one embodiment, the disclosure relates to a method of treating rheumatoid arthritis in a subject, the method comprising orally administering QD (once per day) to the subject, in particular a human subject suffering from, or susceptible to, arthritis rheumatoid, about 30 mg per unit dosage form (e.g., per tablet or capsule) of a solid state form of Compound 1. In one embodiment, the method comprises orally administering QD (once per day) to the subject of a form solid state of Compound 1 in an amount sufficient to provide 30 mg per unit dosage form (e.g., per tablet or capsule) of free base equivalent of Compound 1 to the subject. In another aspect, the present disclosure relates to a solid state form of Compound 1 for use in treating rheumatoid arthritis in a subject, in particular a human subject suffering from, or susceptible to, rheumatoid arthritis, the use comprising administering orally QD (once daily) to the subject about 30 mg per unit dosage form (e.g., per tablet or capsule) of a solid-state form of Compound 1. In one embodiment, the solid-state form provides about 30 mg per unit dosage form (e.g., per tablet or capsule) of free base equivalent of Compound 1 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 Anhydrous Form D. In one embodiment, the subject has moderately to severely 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 Form AAA of L-Maleate. In another aspect, the solid state form is the BBB Form of L-Maleate. In one embodiment, the subject is an adult.

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

[0576] In one embodiment, the disclosure relates to a method of treating rheumatoid arthritis in a subject, the method comprising orally administering QD (once a day) to the subject, in particular a human subject suffering from, or susceptible to, arthritis rheumatoid, about 36 mg per unit dosage form (e.g., per tablet or capsule) of a solid state form of Compound 1. In one embodiment, the method comprises orally administering QD (once per day) to the subject of a form solid state of Compound 1 in an amount sufficient to provide 36 mg per unit dosage form (e.g., per tablet or capsule) of free base equivalent of Compound 1 to the subject. In another aspect, the present disclosure relates to a solid state form of Compound 1 for use in treating rheumatoid arthritis in a subject, in particular a human subject suffering from, or susceptible to, rheumatoid arthritis, the use comprising administering orally QD (once daily) to the subject about 36 mg per unit dosage form (e.g., per tablet or capsule) of a solid state form of Compound 1. In one embodiment, the solid state form provides about 36 mg per unit dosage form (e.g., per tablet or capsule) of free base equivalent of Compound 1 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 Anhydrous Form D. In one embodiment, the subject has moderately to severely 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 Form AAA of L-Maleate. In another aspect, the solid state form is the BBB Form of L-Maleate. In one embodiment, the subject is an adult.

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

[0578] In one embodiment, the disclosure relates to a method of treating rheumatoid arthritis in a subject, the method comprising orally administering QD (once a day) to the subject, in particular a human subject suffering from, or susceptible to, arthritis rheumatoid, about 45 mg per unit dosage form (e.g., per tablet or capsule) of a solid state form of Compound 1. In one embodiment, the method comprises orally administering QD (once per day) to the subject of a form solid state of Compound 1 in an amount sufficient to provide 45 mg per unit dosage form (e.g., per tablet or capsule) of free base equivalent of Compound 1 to the subject. In another aspect, the present disclosure relates to a solid state form of Compound 1 for use in treating rheumatoid arthritis in a subject, in particular a human subject suffering from, or susceptible to, rheumatoid arthritis, the use comprising administering orally QD (once daily) to the subject about 45 mg per unit dosage form (e.g., per tablet or capsule) of a solid state form of Compound 1. In one embodiment, the solid state form provides about 45 mg per unit dosage form (e.g., per tablet or capsule) of free base equivalent of Compound 1 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 Anhydrous Form D. In one embodiment, the subject has moderately to severely 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 Form AAA of L-Maleate. In another aspect, the solid state form is the BBB Form of L-Maleate. In one embodiment, the subject is an adult.

[0579] In one embodiment, the disclosure relates to a method of treating moderately to severely active rheumatoid arthritis in an adult subject, in particular a human subject suffering from, or susceptible to, moderately to severely active rheumatoid arthritis, the method comprising administering to the subject a therapeutically effective amount of Compound 1 (free base) or a pharmaceutically acceptable salt thereof or a solid 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, per unit dosage form (e.g., per tablet or capsule) of Compound 1 (free base), or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1 in an amount sufficient to provide the subject with about 7.5 mg or about 15 mg or about 30 mg or about 45 mg, per unit dosage form (e.g., per tablet or capsule) of free base equivalent 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, per unit dosage form (e.g., per tablet or capsule). of Compound 1 (free base), or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1. In one embodiment, Compound 1 (free base), or a pharmaceutically acceptable salt thereof or solid state form of Compound 1 is administered to the subject orally QD (once daily). In another aspect, the 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 or anhydrous crystalline hydrate), as described in the present disclosure, for use in treating moderately to severely active rheumatoid arthritis in an adult subject, in particular in a human subject suffering from, or susceptible to, moderately to severely active rheumatoid arthritis, the use comprising administering to the subject a therapeutically effective amount of free base Compound 1 or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1. In one embodiment, the solid state 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 an anhydrous crystalline. In one embodiment, the crystalline anhydrous is Free Base Anhydrous Form D. In one embodiment, the solid state form is Free Base Solvate Form A. In another aspect, 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 CC Form. In one embodiment, the solid state form is Form AAA of L-Maleate. In one embodiment, the solid state form is the BBB Form of L-Maleate. In one embodiment, Compound 1 (free base), or a pharmaceutically acceptable salt thereof or the solid state form of Compound 1 is presented in the form of a once-daily extended release formulation. In one embodiment, the formulation orally provides QD (once daily) about 7.5 mg or about 15 mg or about 30 mg or about 45 mg per unit dosage form (e.g., per tablet or capsule). of Compound 1 (free base equivalent) or a solid state form of Compound 1.

[0580] In one embodiment, the subject having moderately to severely active rheumatoid arthritis has, prior to treatment, at least one of the following identifying characteristics: at least 6 swollen joints (based on 66 joint counts), at least 6 tender joints (based on 68 joint counts), high-sensitivity C-reactive protein (hsCRP) greater than the upper limit of normal (ULN), or positive test results for rheumatoid factor (RF) and anticyclic citrullinated peptide (CCP ). In one embodiment, the subject with moderately to severely active rheumatoid arthritis has, prior to treatment, at least 6 swollen joints (based on 66 joint counts) and at least 6 tender joints (based on 68 joint counts). Methods for evaluating swollen and tender joints are known, and described, for example, in Scott, et al., Clinical and Experimental Rheumatology, 2014, Vol. 32 (Sup. 85), S7-S12.

[0581] Thus, in another embodiment, the present disclosure is directed to a method of treating moderately to severely active rheumatoid arthritis in an adult subject, in particular a human subject suffering from, or susceptible to, moderately to severely active rheumatoid arthritis. , the method comprising administering to the subject a therapeutically effective amount of Compound 1 (free base), or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1 (e.g., a crystalline hydrate or anhydrous crystalline) as described herein, wherein the subject has symptoms selected from the group consisting of at least 6 swollen joints, at least 6 tender joints, and combinations thereof prior to treatment. In one embodiment, the method comprises administering to the subject about 7.5 mg or about 15 mg or about 30 mg or about 45 mg, per unit dosage form (e.g., per tablet or capsule) per day of Compound. 1 (free base), or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1 in an amount sufficient to provide the subject with about 7.5 mg or about 15 mg or about 30 mg or about 45 mg , per unit dosage form (e.g., per tablet or capsule) per day of free base equivalent of Compound 1, wherein the subject has symptoms selected from the group consisting of at least 6 swollen joints, at least 6 tender joints and their combinations 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, per unit dosage form (e.g., per tablet or capsule) in a mass form. solid state of Compound 1. In another aspect, the 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 or anhydrous crystalline hydrate), as described in present disclosure, for use in treating moderately to severely active rheumatoid arthritis in an adult subject, in particular in a human subject suffering from, or susceptible to, moderately to severely active rheumatoid arthritis, wherein the subject has symptoms selected from the group consisting of at least 6 swollen joints, at least 6 tender joints and combinations thereof prior to treatment, the use comprising administering to the subject a therapeutically effective amount of free base of Compound 1 or a pharmaceutically acceptable salt thereof or a solid state form of the Compound 1. In one embodiment, the therapeutically effective amount of the solid state form of Compound 1 orally provides QD (once per day) to the subject about 7.5 mg or about 15 mg or about 30 mg or about 45 mg per unit dosage form (e.g., per tablet or capsule) of Compound 1 (free base equivalent) or a solid state form of Compound 1. In one embodiment, Compound 1 (free base), or a pharmaceutically available salt thereof acceptable or the solid state form of Compound 1 is presented in the form of a once-daily extended-release formulation. In one embodiment, Compound 1 (free base), or a pharmaceutically acceptable salt thereof or solid state form of Compound 1 is administered to the subject orally QD (once per day). In one embodiment, the solid state 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 state form is an anhydrous crystalline. In one embodiment, the crystalline anhydrous is Free Base Anhydrous Form D. In one embodiment, the solid state form is Tartrate Hydrate. In one embodiment, symptoms result from the progression of structural damage assessed by radiography.

[0582] In one embodiment, the present disclosure is directed to a method of treating moderately to severely active rheumatoid arthritis in an adult subject, in particular a human subject suffering from, or susceptible to, moderately to severely active rheumatoid arthritis, the method comprising administer to the subject about 7.5 mg, per unit dosage form (e.g., per tablet or capsule) per day of Compound 1 (free base), or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1, in an amount sufficient to provide the subject with about 7.5 mg, per unit dosage form (e.g., per tablet or capsule) per day of free base equivalent of Compound 1, wherein the subject has symptoms 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, per unit dosage form (e.g., per tablet or capsule) per day of a solid state form of Compound 1. In another aspect, the disclosure is 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 the treatment of moderately to severely active rheumatoid arthritis in an adult subject, in particular in a human subject suffering from, or susceptible to, moderately to severely active rheumatoid arthritis, wherein the subject has symptoms selected from the group consisting of at least 6 swollen joints, at least 6 tender joints, and combinations thereof prior to treatment, the use comprising administering to the subject about of 7.5 mg per unit dosage form (e.g., per tablet or capsule) of free base of Compound 1 or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1. In one embodiment, the solid state 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 state form is an anhydrous crystalline. In one embodiment, the crystalline anhydrous is Free Base Anhydrous Form D. In one embodiment, the solid state form is Tartrate Hydrate. In one embodiment, the free base of Compound 1 or a pharmaceutically acceptable salt thereof or the solid state form of Compound 1 is administered orally QD (once per day). In one embodiment, the free base of Compound 1 or a pharmaceutically acceptable salt thereof or the solid state form of Compound 1 is in the form of a once-daily extended release formulation. In one embodiment, symptoms result from the progression of structural damage assessed by radiography.

[0583] In one embodiment, the present disclosure is directed to a method of treating moderately to severely active rheumatoid arthritis in an adult subject, in particular a human subject suffering from, or susceptible to, moderately to severely active rheumatoid arthritis, the method comprising administering to the subject about 15 mg, per unit dosage form (e.g., per tablet or capsule) per day of Compound 1 (free base), or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1, in an amount sufficient to provide the subject with about 15 mg, per unit dosage form (e.g., per tablet or capsule) per day of free base equivalent of Compound 1, wherein the subject has symptoms 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 15 mg, per unit dosage form (e.g., per tablet or capsule) per day of a solid state form of Compound 1. In another aspect, the disclosure relates to free base of Compound 1 or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1 for use in treating moderately to severely active rheumatoid arthritis in an adult subject, in particular in a human subject suffering from, or susceptible to, arthritis moderately to severely active rheumatoid disease, wherein the subject has symptoms selected from the group consisting of at least 6 swollen joints, at least 6 tender joints, and combinations thereof prior to treatment, the use comprising administering to the subject about 15 mg per form of unit dosage (e.g., per tablet or capsule) of free base of Compound 1 or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1. In one embodiment, the solid state 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 state form is an anhydrous crystalline. In one embodiment, the crystalline anhydrous is Free Base Anhydrous Form D. In one embodiment, the solid state form is Tartrate Hydrate. In one embodiment, the free base of Compound 1 or a pharmaceutically acceptable salt thereof or the solid state form of Compound 1 is administered orally QD (once per day). In one embodiment, the free base of Compound 1 or a pharmaceutically acceptable salt thereof or the solid state form of Compound 1 is presented in the form of a once-daily extended release formulation. In one embodiment, symptoms result from the progression of structural damage assessed by radiography.

[0584] In one embodiment, the present disclosure is directed to a method of treating moderately to severely active rheumatoid arthritis in an adult subject, in particular a human subject suffering from, or susceptible to, moderately to severely active rheumatoid arthritis, the method comprising administer to the subject about 30 mg, per unit dosage form (e.g., per tablet or capsule) per day of Compound 1 (free base), or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1, in a amount sufficient to provide the subject with about 30 mg, per unit dosage form (e.g., per tablet or capsule) per day of free base equivalent of Compound 1, wherein the subject has symptoms selected from the group consisting of at least 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 30 mg, per unit dosage form (e.g., per tablet or capsule) per day of a solid state form of Compound 1. In another aspect, the disclosure relates to free base of Compound 1 or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1 for use in treating moderately to severely active rheumatoid arthritis in an adult subject, in particular in a human subject suffering from, or susceptible to, arthritis moderately to severely active rheumatoid disease, wherein the subject has symptoms selected from the group consisting of at least 6 swollen joints, at least 6 tender joints, and combinations thereof prior to treatment, the use comprising administering to the subject about 30 mg per form of unit dosage (e.g., per tablet or capsule) of free base of Compound 1 or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1. In one embodiment, the solid state 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 state form is an anhydrous crystalline. In one embodiment, the crystalline anhydrous is Free Base Anhydrous Form D. In one embodiment, the solid state form is Tartrate Hydrate. In one embodiment, the free base of Compound 1 or a pharmaceutically acceptable salt thereof or the solid state form of Compound 1 is administered orally QD (once per day). In one embodiment, the free base of Compound 1 or a pharmaceutically acceptable salt thereof or the solid state form of Compound 1 is in the form of a once-daily extended release formulation. In one embodiment, symptoms result from the progression of structural damage assessed by radiography.

[0585] In one embodiment, the present disclosure is directed to a method of treating moderately to severely active rheumatoid arthritis in an adult subject, in particular a human subject suffering from, or susceptible to, moderately to severely active rheumatoid arthritis, the method comprising administer to the subject about 45 mg, per unit dosage form (e.g., per tablet or capsule) per day of Compound 1 (free base), or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1, in a amount sufficient to provide the subject with about 45 mg, per unit dosage form (e.g., per tablet or capsule) per day of free base equivalent of Compound 1, wherein the subject has symptoms selected from the group consisting of at least 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 45 mg, per unit dosage form (e.g., per tablet or capsule) per day of a solid state form of Compound 1. In another aspect, the disclosure relates to free base of Compound 1 or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1 for use in treating moderately to severely active rheumatoid arthritis in an adult subject, in particular in a human subject suffering from, or susceptible to. , moderately to severely active rheumatoid arthritis, wherein the subject has symptoms selected from the group consisting of at least 6 swollen joints, at least 6 tender joints, and combinations thereof prior to treatment, the use comprising administering to the subject about 45 mg per unit dosage form (e.g., per tablet or capsule) of free base of Compound 1 or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1. In one embodiment, the solid state 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 state form is an anhydrous crystalline. In one embodiment, the crystalline anhydrous is Free Base Anhydrous Form D. In one embodiment, the solid state form is Tartrate Hydrate. In one embodiment, the free base of Compound 1 or a pharmaceutically acceptable salt thereof or the solid state form of Compound 1 is administered orally QD (once per day). In one embodiment, the free base of Compound 1 or a pharmaceutically acceptable salt thereof or the solid state form of Compound 1 is in the form of a once-daily extended release formulation. In one embodiment, symptoms result from the progression of structural damage assessed by radiography.

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

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

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

[0589] In one embodiment, the adult subject receiving treatment achieves an ACR70 response after treatment for at least 8 weeks (e.g., at week 8 of treatment). In another embodiment, the adult subject receiving treatment achieves an ACR70 response after treatment for at least 6 weeks (e.g., at week 6 of treatment). In another embodiment, the adult subject receiving treatment achieves an ACR70 response after treatment for at least 4 weeks (e.g., at week 4 of 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 when compared to baseline (i.e., DAS28(CRP) before treatment). In one embodiment, the adult subject achieves a decrease in DAS28 score when compared to baseline after treatment for at least twelve weeks (e.g., at week 12 of treatment). In one embodiment, the adult subject achieves a decreased DAS28(CRP) when compared to baseline after treatment for at least 12 weeks (e.g., at week 12 of treatment). In another embodiment, the adult subject achieves a decrease in DAS28(CRP) when compared to baseline after treatment for at least 8 weeks (e.g., at week 8 of treatment). In another embodiment, the adult subject achieves a decrease in DAS28(CRP) when compared to baseline after treatment for at least 6 weeks (e.g., at week 6 of treatment). In another embodiment, the adult subject achieves a decrease in DAS28(CRP) when compared to baseline after treatment for at least 4 weeks (e.g., at week 4 of treatment). In another embodiment, the adult subject achieves a decrease in DAS28(CRP) when compared to baseline after treatment for at least 2 weeks (e.g., in week 2 of treatment).

[0591] In another embodiment, the adult subject receiving treatment achieves a low disease activity (LDA) score or clinical remission after treatment. In one embodiment, the LDA or clinical remission score is measured as a DAS28 score (in particular, DAS28(CRP)) of 3.2 or less. In another embodiment, the LDA or clinical remission score is measured as a DAS28(CRP) of less than 2.6. In another embodiment, the LDA score or clinical remission is assessed using Clinical Disease Activity Index (CDAI) criteria. In one embodiment, the adult subject achieves a CDAI score of 10 or less after treatment. In another embodiment, the adult subject achieves a CDAI score of 2.8 or less after treatment. In one embodiment, the adult subject achieves an LDA score or clinical remission after treatment for at least 12 weeks (e.g., at week 12 of treatment). In one embodiment, the adult subject achieves an LDA score or clinical remission after treatment for at least 8 weeks (e.g., at week 8 of treatment). In one embodiment, the adult subject achieves an LDA score or clinical remission after treatment for at least 6 weeks (e.g., at week 6 of treatment). In one embodiment, the adult subject achieves an LDA score or clinical remission after treatment for at least 4 weeks (e.g., at week 4 of treatment). In one embodiment, the adult subject achieves an LDA score or clinical remission after treatment for at least 2 weeks (e.g., in week 2 of treatment).

[0592] In one embodiment, the adult subject receiving the treatment achieves a change in the average modified Total Sharp Score (mTSS). In one embodiment, the adult subject receiving treatment achieves a change in mTSS after treatment for at least twelve weeks (e.g., at week 12 of treatment), or after treatment for at least twenty-four weeks (e.g., at week 24 of treatment). In one embodiment, mTSS can be determined by scoring X-rays of the hand/wrist joints and feet for erosions and joint space reduction. The erosion score and reduction score are added to determine the total score.

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

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

[0595] In one embodiment, the adult subject receiving the treatment achieves a clinical remission (CR). In one embodiment, the adult subject receiving treatment achieves a CR after treatment for at least twelve weeks (e.g., at week 12 of treatment). In one embodiment, CR is determined based on a 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 subject receiving treatment achieves a change in functional assessment of chronic disease therapy (FACIT-F). In one embodiment, the adult subject receiving treatment achieves a change in FACIT-F after treatment for at least twelve weeks (e.g., at week 12 of treatment). FACIT-F is a participant questionnaire with 13 indices rated on a 5-point scale. The indices relate to the participant's level of fatigue during the last seven days.

[0597] In one embodiment, the adult subject receiving treatment achieves a change in the rheumatoid arthritis work instability score (RA-WIS). In one embodiment, the adult subject receiving treatment achieves a change in RA-WIS after treatment for at least twelve weeks (e.g., at week 12 of treatment). RA-WIS is a participant questionnaire containing 23 questions related to participants' functioning in their work environment.

[0598] In one embodiment, the adult subject receiving the treatment achieves a change in the severity of morning stiffness. In one embodiment, the adult subject receiving treatment achieves a change in the severity of morning stiffness after treatment for at least twelve weeks (e.g., at week 12 of treatment). The severity of morning stiffness is determined by the Patient Assessment of Severity and Duration of Morning Stiffness questionnaire.

[0599] In one embodiment, the method or use comprises administering to the subject about 7.5 mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1 (free base), or one thereof. pharmaceutically acceptable salt or solid state form of Compound 1 in an amount sufficient to provide the subject with about 7.5 mg per unit dosage form (e.g., per tablet or capsule) of free base equivalent of Compound 1, wherein the subject achieves an ACR20 response at week 12 of treatment. In another embodiment, the subject achieves an ACR20 response at week 8 of treatment. In another embodiment, the subject achieves an ACR20 response at week 6 of treatment. In another embodiment, the subject achieves an ACR20 response at week 4 of treatment. In another embodiment, the subject achieves an ACR20 response at week 2 of treatment. In one embodiment, the method or use comprises administering to the subject about 7.5 mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1 (free base), or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1 in an amount sufficient to provide the subject with about 7.5 mg per unit dosage form (e.g., per tablet or capsule), of free base equivalent of Compound 1, where the subject achieves an ACR50 response at week 12 of treatment. In another embodiment, the subject achieves an ACR50 response at week 8 of treatment. In another embodiment, the subject achieves an ACR50 response at week 6 of treatment. In another embodiment, the subject achieves an ACR50 response at week 4 of treatment. In one embodiment, the method or use comprises administering to the subject about 7.5 mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1 (free base), or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1 in an amount sufficient to provide the subject with about 7.5 mg per unit dosage form (e.g., per tablet or capsule), of free base equivalent of Compound 1, where the subject achieves an ACR70 response at week 12 of treatment. In one embodiment, the method or use comprises administering to the subject about 7.5 mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1 (free base), or a pharmaceutically acceptable salt thereof. or a solid state form of Compound 1 in an amount sufficient to provide the subject with about 7.5 mg per unit dosage form (e.g., per tablet or capsule), of free base equivalent of Compound 1, wherein the subject achieves a decrease in DAS28(CRP) when compared to baseline at week 12 of treatment. In another embodiment, the subject achieves a decrease in DAS28(CRP) when compared to baseline at week 8 of treatment. In another embodiment, the subject achieves a decrease in DAS28(CRP) when compared to baseline at week 6 of treatment. In another embodiment, the subject achieves a decrease in DAS28(CRP) when compared to baseline at week 4 of treatment. In another embodiment, the subject achieves a decrease in DAS28(CRP) when compared to baseline at week 2 of treatment. In one embodiment, the method or use comprises administering to the subject about 7.5 mg, per unit dosage form (e.g., per tablet or capsule) of the solid state form. In one embodiment, Compound 1 (free base) or a pharmaceutically acceptable salt or solid state form thereof is in the form of a once-daily extended release formulation. In one embodiment, the solid state 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 state form is an anhydrous crystalline. In one embodiment, the crystalline anhydrous is Free Base Anhydrous Form D. In one embodiment, the solid state form is Tartrate Hydrate.

[0600] In one embodiment, the method or use comprises administering to the subject about 15 mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1 (free base), or a pharmaceutically available salt thereof. acceptable or a solid state form of Compound 1 in an amount sufficient to provide the subject with about 15 mg per unit dosage form (e.g., per tablet or capsule), of free base equivalent of Compound 1, wherein the subject achieves an ACR20 response at week 12 of treatment. In another embodiment, the subject achieves an ACR20 response at week 8 of treatment. In another embodiment, the subject achieves an ACR20 response at week 6 of treatment. In another embodiment, the subject achieves an ACR20 response at week 4 of treatment. In another embodiment, the subject achieves an ACR20 response at week 2 of treatment. In one embodiment, the method or use comprises administering to the subject about 15 mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1 (free base), or a pharmaceutically acceptable salt or form thereof. solid state of Compound 1 in an amount sufficient to provide the subject with about 15 mg per unit dosage form (e.g., per tablet or capsule) of free base equivalent of Compound 1, wherein the subject achieves an ACR50 response at week 12 of treatment. In another embodiment, the subject achieves an ACR50 response at week 8 of treatment. In another embodiment, the subject achieves an ACR50 response at week 6 of treatment. In another embodiment, the subject achieves an ACR50 response at week 4 of treatment. In one embodiment, the method or use comprises administering to the subject about 15 mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1 (free base), or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1 in an amount sufficient to provide the subject with about 15 mg per unit dosage form (e.g., per tablet or capsule), of free base equivalent of Compound 1, wherein the subject achieves a response ACR70 at week 12 of treatment. In another embodiment, the subject achieves an ACR70 response at week 8 of treatment. In another embodiment, the subject achieves an ACR70 response at week 6 of treatment. In one embodiment, the method or use comprises administering to the subject about 15 mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1 (free base), or a pharmaceutically acceptable salt or form thereof. solid state of Compound 1 in an amount sufficient to provide the subject with about 15 mg per unit dosage form (e.g., per tablet or capsule), of free base equivalent of Compound 1, wherein the subject achieves a decrease in DAS28 (CRP) when compared to baseline at week 12 of treatment. In another embodiment, the subject achieves a decrease in DAS28(CRP) when compared to baseline at week 8 of treatment. In another embodiment, the subject achieves a decrease in DAS28(CRP) when compared to baseline at week 6 of treatment. In another embodiment, the subject achieves a decrease in DAS28(CRP) when compared to baseline at week 4 of treatment. In another embodiment, the subject achieves a decrease in DAS28(CRP) when compared to baseline at week 2 of treatment. In one embodiment, the method or use comprises administering to the subject about 15 mg, per unit dosage form (e.g., per tablet or capsule) of the solid state form. In one embodiment, Compound 1 (free base) or a pharmaceutically acceptable salt or solid state form thereof is in the form of a once-daily extended release formulation. In one embodiment, the solid state 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 state form is an anhydrous crystalline. In one embodiment, the crystalline anhydrous is Free Base Anhydrous Form D. In one embodiment, the solid state form is Tartrate Hydrate.

[0601] In one embodiment, the method or use comprises administering to the subject about 24 mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1 (free base), or a pharmaceutically available salt thereof. acceptable or a solid state form of Compound 1 in an amount sufficient to provide the subject with about 24 mg per unit dosage form (e.g., per tablet or capsule), of free base equivalent of Compound 1, wherein the subject achieves an ACR20 response at week 12 of treatment. In another embodiment, the subject achieves an ACR20 response at week 8 of treatment. In another embodiment, the subject achieves an ACR20 response at week 6 of treatment. In another embodiment, the subject achieves an ACR20 response at week 4 of treatment. In another embodiment, the subject achieves an ACR20 response at week 2 of treatment. In one embodiment, the method or use comprises administering to the subject about 24 mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1 (free base), or a pharmaceutically acceptable salt or form thereof. solid state of Compound 1 in an amount sufficient to provide the subject with about 24 mg per unit dosage form (e.g., per tablet or capsule) of free base equivalent of Compound 1, wherein the subject achieves an ACR50 response at week 12 of treatment. In another embodiment, the subject achieves an ACR50 response at week 8 of treatment. In another embodiment, the subject achieves an ACR50 response at week 6 of treatment. In another embodiment, the subject achieves an ACR50 response at week 4 of treatment. In one embodiment, the method or use comprises administering to the subject about 24 mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1 (free base), or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1 in an amount sufficient to provide the subject with about 24 mg per unit dosage form (e.g., per tablet or capsule), of free base equivalent of Compound 1, wherein the subject achieves a response ACR70 at week 12 of treatment. In another embodiment, the subject achieves an ACR70 response at week 8 of treatment. In another embodiment, the subject achieves an ACR70 response at week 6 of treatment. In one embodiment, the method or use comprises administering to the subject about 24 mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1 (free base), or a pharmaceutically acceptable salt or form thereof. solid state of Compound 1 in an amount sufficient to provide the subject with about 24 mg per unit dosage form (e.g., per tablet or capsule), of free base equivalent of Compound 1, wherein the subject achieves a decrease in DAS28 (CRP) when compared to baseline at week 12 of treatment. In another embodiment, the subject achieves a decrease in DAS28(CRP) when compared to baseline at week 8 of treatment. In another embodiment, the subject achieves a decrease in DAS28(CRP) when compared to baseline at week 6 of treatment. In another embodiment, the subject achieves a decrease in DAS28(CRP) when compared to baseline at week 4 of treatment. In another embodiment, the subject achieves a decrease in DAS28(CRP) when compared to baseline at week 2 of treatment. In one embodiment, the method or use comprises administering to the subject about 24 mg, per unit dosage form (e.g., per tablet or capsule) of the solid state form. In one embodiment, Compound 1 (free base) or a pharmaceutically acceptable salt or solid state form thereof is in the form of a once-daily extended release formulation. In one embodiment, the solid state 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 state form is an anhydrous crystalline. In one embodiment, the crystalline anhydrous is Free Base Anhydrous Form D. In one embodiment, the solid state form is Tartrate Hydrate.

[0602] In one embodiment, the method or use comprises administering to the subject about 30 mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1 (free base), or a pharmaceutically available salt thereof. acceptable or a solid state form of Compound 1 in an amount sufficient to provide the subject with about 30 mg per unit dosage form (e.g., per tablet or capsule), of free base equivalent of Compound 1, wherein the subject achieves an ACR20 response at week 12 of treatment. In another embodiment, the subject achieves an ACR20 response at week 8 of treatment. In another embodiment, the subject achieves an ACR20 response at week 6 of treatment. In another embodiment, the subject achieves an ACR20 response at week 4 of treatment. In another embodiment, the subject achieves an ACR20 response at week 2 of treatment. In one embodiment, the method or use comprises administering to the subject about 30 mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1 (free base), or a pharmaceutically acceptable salt or form thereof. solid state of Compound 1 in an amount sufficient to provide the subject with about 30 mg per unit dosage form (e.g., per tablet or capsule), of free base equivalent of Compound 1, wherein the subject achieves an ACR50 response at week 12 of treatment. In another embodiment, the subject achieves an ACR50 response at week 8 of treatment. In another embodiment, the subject achieves an ACR50 response at week 6 of treatment. In another embodiment, the subject achieves an ACR50 response at week 4 of treatment. In another embodiment, the subject achieves an ACR50 response in week 2 of treatment. In one embodiment, the method or use comprises administering to the subject about 30 mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1 (free base), or a pharmaceutically acceptable salt or form thereof. solid state of Compound 1 in an amount sufficient to provide the subject with about 30 mg per unit dosage form (e.g., per tablet or capsule) of free base equivalent of Compound 1, wherein the subject achieves an ACR70 response at week 12 of treatment. In another embodiment, the subject achieves an ACR70 response at week 8 of treatment. In one embodiment, the method or use comprises administering to the subject about 30 mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1 (free base), or a pharmaceutically acceptable salt or form thereof. solid state of Compound 1 in an amount sufficient to provide the subject with about 30 mg per unit dosage form (e.g., per tablet or capsule), of free base equivalent of Compound 1, wherein the subject achieves a decrease in DAS28 (CRP) when compared to baseline at week 12 of treatment. In another embodiment, the subject achieves a decrease in DAS28(CRP) when compared to baseline at week 8 of treatment. In another embodiment, the subject achieves a decrease in DAS28(CRP) when compared to baseline at week 6 of treatment. In another embodiment, the subject achieves a decrease in DAS28(CRP) when compared to baseline at week 4 of treatment. In another embodiment, the subject achieves a decrease in DAS28(CRP) when compared to baseline at week 2 of treatment. In one embodiment, the method or use comprises administering to the subject about 30 mg, per unit dosage form (e.g., per tablet or capsule) of the solid state form. In one embodiment, Compound 1 (free base) or a pharmaceutically acceptable salt or solid state form thereof is in the form of a once-daily extended release formulation. In one embodiment, the solid state 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 state form is an anhydrous crystalline. In one embodiment, the crystalline anhydrous is Free Base Anhydrous Form D. In one embodiment, the solid state form is Tartrate Hydrate.

[0603] In one embodiment, the method or use comprises administering to the subject about 45 mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1 (free base), or a pharmaceutically available salt thereof. acceptable or a solid state form of Compound 1 in an amount sufficient to provide the subject with about 45 mg per unit dosage form (e.g., per tablet or capsule) of free base equivalent of Compound 1, wherein the subject achieves an ACR20 response at week 12 of treatment. In another embodiment, the subject achieves an ACR20 response at week 8 of treatment. In another embodiment, the subject achieves an ACR20 response at week 6 of treatment. In another embodiment, the subject achieves an ACR20 response at week 4 of treatment. In another embodiment, the subject achieves an ACR20 response at week 2 of treatment. In one embodiment, the method or use comprises administering to the subject about 45 mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1 (free base), or a pharmaceutically acceptable salt or form thereof. solid state of Compound 1 in an amount sufficient to provide the subject with about 45 mg per unit dosage form (e.g., per tablet or capsule) of free base equivalent of Compound 1, wherein the subject achieves an ACR50 response at week 12 of treatment. In another embodiment, the subject achieves an ACR50 response at week 8 of treatment. In another embodiment, the subject achieves an ACR50 response at week 6 of treatment. In another embodiment, the subject achieves an ACR50 response at week 4 of treatment. In one embodiment, the method or use comprises administering to the subject about 45 mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1 (free base), or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1 in an amount sufficient to provide the subject with about 45 mg per unit dosage form (e.g., per tablet or capsule), of free base equivalent of Compound 1, wherein the subject achieves a response ACR70 at week 12 of treatment. In another embodiment, the subject achieves an ACR70 response at week 8 of treatment. In another embodiment, the subject achieves an ACR70 response at week 6 of treatment. In another embodiment, the subject achieves an ACR70 response at week 4 of treatment. In one embodiment, the method or use comprises administering to the subject about 45 mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1 (free base), or a pharmaceutically acceptable salt or form thereof. solid state of Compound 1 in an amount sufficient to provide the subject with about 45 mg per unit dosage form (e.g., per tablet or capsule), of free base equivalent of Compound 1, wherein the subject achieves a decrease in DAS28 (CRP) when compared to baseline at week 12 of treatment. In another embodiment, the subject achieves a decrease in DAS28(CRP) when compared to baseline at week 8 of treatment. In another embodiment, the subject achieves a decrease in DAS28(CRP) when compared to baseline at week 6 of treatment. In another embodiment, the subject achieves a decrease in DAS28(CRP) when compared to baseline at week 4 of treatment. In another embodiment, the subject achieves a decrease in DAS28(CRP) when compared to baseline at week 2 of treatment. In one embodiment, the method or use comprises administering to the subject about 45 mg, per unit dosage form (e.g., per tablet or capsule) of the solid state form. In one embodiment, Compound 1 (free base) or a pharmaceutically acceptable salt or solid state form thereof is in the form of a once-daily extended release formulation. In one embodiment, the solid state 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 state form is an anhydrous crystalline. In one embodiment, the crystalline anhydrous is Free Base Anhydrous Form D. In one embodiment, the solid state form is Tartrate Hydrate.

[0604] In another embodiment, the adult subject is a subject who has had an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs (DMARDS). In one embodiment, the DMARD is a conventional synthetic DMARD (csDMARD). In one embodiment, the DMARD is a biological DMARD (bDMARD). Examples of csDMARDs include, but are not limited to, methotrexate (MTX), sulfasalazine, hydroxychloroquine, chloroquine, leflunomide, and azathioprine. Examples of bDMARDs include, but are not limited to, tocilizumab such as ACTEMRA™, etanercept such as p75TNFR1gG (etanercept brand ENBREL™), adalimumab (such as adalimumab brand HUMIRA™), and golimumab such as SIMPONI™ (golimumab). In one embodiment, the csDMARD is MTX. In one embodiment, the bDMARD is an anti-TNF biological agent. An inadequate response or intolerance to one or more DMARDs can be measured using any of the indices described herein (e.g., failure to achieve an ACR20 response). In one embodiment, a subject having an inadequate response to a DMARD is a subject who does not achieve reduced disease activity, does not achieve an improvement in physical function, does not exhibit evidence of arrest of disease progression, or who enters into disease relapse following treatment with the DMARD. In one embodiment, a subject having an inadequate response to a DMARD is a subject who does not achieve an ACR20 response after treatment with the DMARD. In one embodiment, a subject having an inadequate tolerance (intolerance) to a DMARD is a subject who experiences toxicity or co-morbidities following treatment with the DMARD.

[0605] In one embodiment, the adult subject is a subject who has demonstrated an inadequate response to stable methotrexate therapy. In one embodiment, the adult subject has received methotrexate therapy for at least three months prior to treatment. In another embodiment, the adult subject received a stable dose of methotrexate of about 7.5 to about 25 mg per week for at least four weeks prior to treatment. In another embodiment, the adult subject is administered a stable dose of methotrexate (e.g., from about 7.5 to about 25 mg per week) during treatment with Compound 1. In one embodiment, the adult subject receives an acid supplement. folic acid for at least four weeks before treatment. In another embodiment, a folic acid supplement is administered to the adult subject during treatment.

[0606] In one embodiment, the adult subject is a subject who has exhibited an inadequate response or intolerance to at least one anti-TNF therapy. Anti-TNF biologic agents are described elsewhere herein, and include TNF antagonists such as chimeric, humanized or human TNF antibodies, adalimumab (as adalimumab brand HUMIRA™), infliximab as CA2 (infliximab brand REMICADE™), golimumab as SIMPONI™ (golimumab), Certolizumab pegol as CIMZIA™, tocilizumab as ACTEMRA™, CDP 571, and soluble p55 or p75 TNF receptors, derivatives thereof, etanercept as p75TNFR1gG (etanercept brand ENBREL™) or p55TNFR1gG (lenercept). In one embodiment, the adult subject has received methotrexate therapy for at least three months prior to treatment. In another embodiment, the adult subject received a stable dose of methotrexate of about 7.5 to about 25 mg per week for at least four weeks prior to treatment. In another embodiment, the adult subject is administered a stable dose of methotrexate (e.g., from about 7.5 to about 25 mg per week) during treatment with Compound 1. In another embodiment, the adult subject is treated with at least an anti-TNF biological agent for at least three months prior to treatment with Compound 1. In one embodiment, the adult subject received a folic acid supplement for at least four weeks prior to treatment. In another embodiment, a folic acid supplement is administered to the adult subject during treatment.

[0607] In certain embodiments, the adult subject, who has had an inadequate response or tolerance to one or more DMARDS (including methotrexate and/or an anti-TNF biological agent), achieves an ACR20 response, an ACR50 response, an ACR70 and/or a decrease in DAS28(CRP) compared to baseline following treatment for at least twelve weeks (e.g., at week 12 of treatment), and/or following treatment for at least 8 weeks (e.g., at week 8 of treatment), and/or following treatment for at least 6 weeks (e.g., at week 6 of treatment), and/or following treatment for at least 4 weeks (e.g., in week 4 of treatment), and/or following treatment for at least 2 weeks (e.g. in week 2 of treatment).

[0608] For example, in one embodiment, the method or use comprises administering to the subject about 7.5 mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1 (free base), or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1 in an amount sufficient to provide the subject with about 7.5 mg per unit dosage form (e.g., per tablet or capsule) of base equivalent Compound 1-free, wherein the subject has had an inadequate response or intolerance to one or more DMARDS, and the subject achieves an ACR20 response at week 12 of treatment. In another embodiment, the subject achieves an ACR20 response at week 8 of treatment. In another embodiment, the subject achieves an ACR20 response at week 6 of treatment. In another embodiment, the subject achieves an ACR20 response at week 4 of treatment. In another embodiment, the subject achieves an ACR20 response at week 2 of treatment. In one embodiment, the method or use comprises administering to the subject about 7.5 mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1 (free base), or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1 in an amount sufficient to provide the subject with about 7.5 mg per unit dosage form (e.g., per tablet or capsule), of free base equivalent of Compound 1, wherein the subject has had an inadequate response or intolerance to one or more DMARDS, and the subject achieves an ACR50 response at week 12 of treatment. In another embodiment, the subject achieves an ACR50 response at week 8 of treatment. In another embodiment, the subject achieves an ACR50 response at week 6 of treatment. In another embodiment, the subject achieves an ACR50 response at week 4 of treatment. In one embodiment, the method or use comprises administering to the subject about 7.5 mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1 (free base), or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1 in an amount sufficient to provide the subject with about 7.5 mg per unit dosage form (e.g., per tablet or capsule), of free base equivalent of Compound 1, wherein the subject has had an inadequate response or intolerance to one or more DMARDS, and the subject achieves an ACR70 response at week 12 of treatment. In one embodiment, the method or use comprises administering to the subject about 7.5 mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1 (free base), or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1 in an amount sufficient to provide the subject with about 7.5 mg per unit dosage form (e.g., per tablet or capsule), of free base equivalent of Compound 1, wherein the subject has had an inadequate response or intolerance to one or more DMARDS, and the subject achieves a decrease in DAS28(CRP) when compared to baseline at week 12 of treatment. In another embodiment, the subject achieves a decrease in DAS28(CRP) when compared to baseline at week 8 of treatment. In another embodiment, the subject achieves a decrease in DAS28(CRP) when compared to baseline at week 6 of treatment. In another embodiment, the subject achieves a decrease in DAS28(CRP) when compared to baseline at week 4 of treatment. In another embodiment, the subject achieves a decrease in DAS28(CRP) when compared to baseline at week 2 of treatment. In one embodiment, the method or use comprises administering to the subject about 7.5 mg, per unit dosage form (e.g., per tablet or capsule) of the solid state form. In one embodiment, Compound 1 (free base) or a pharmaceutically acceptable salt or solid state form thereof is in the form of a once-daily extended release formulation. In one embodiment, the solid state 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 state form is an anhydrous crystalline. In one embodiment, the crystalline anhydrous is Free Base Anhydrous Form D. In one embodiment, the solid state form is Tartrate Hydrate.

[0609] In one embodiment, the method or use comprises administering to the subject about 15 mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1 (free base), or a pharmaceutically available salt thereof. acceptable or a solid state form of Compound 1 in an amount sufficient to provide the subject with about 15 mg per unit dosage form (e.g., per tablet or capsule), of free base equivalent of Compound 1, wherein the subject has had an inadequate response or intolerance to one or more DMARDS, and the subject achieves an ACR20 response at week 12 of treatment. In another embodiment, the subject achieves an ACR20 response at week 8 of treatment. In another embodiment, the subject achieves an ACR20 response at week 6 of treatment. In another embodiment, the subject achieves an ACR20 response at week 4 of treatment. In another embodiment, the subject achieves an ACR20 response at week 2 of treatment. In one embodiment, the method or use comprises administering to the subject about 15 mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1 (free base), or a pharmaceutically acceptable salt or form thereof. solid state of Compound 1 in an amount sufficient to provide the subject with about 15 mg per unit dosage form (e.g., per tablet or capsule), of free base equivalent of Compound 1, in which the subject had an inadequate response or intolerance to one or more DMARDS, and the subject achieves an ACR50 response at week 12 of treatment. In another embodiment, the subject achieves an ACR50 response at week 8 of treatment. In another embodiment, the subject achieves an ACR50 response at week 6 of treatment. In another embodiment, the subject achieves an ACR50 response at week 4 of treatment. In one embodiment, the method or use comprises administering to the subject about 15 mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1 (free base), or a pharmaceutically acceptable salt or form thereof. solid state of Compound 1 in an amount sufficient to provide the subject with about 15 mg per unit dosage form (e.g., per tablet or capsule), of free base equivalent of Compound 1, in which the subject had an inadequate response or intolerance to one or more DMARDS, and the subject achieves an ACR70 response at week 12 of treatment. In another embodiment, the subject achieves an ACR70 response at week 8 of treatment. In another embodiment, the subject achieves an ACR70 response at week 6 of treatment. In one embodiment, the method or use comprises administering to the subject about 15 mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1 (free base), or a pharmaceutically acceptable salt or form thereof. solid state of Compound 1 in an amount sufficient to provide the subject with about 15 mg per unit dosage form (e.g., per tablet or capsule), of free base equivalent of Compound 1, in which the subject had an inadequate response or intolerance to one or more DMARDS, and the subject achieves a decrease in DAS28(CRP) when compared to baseline at week 12 of treatment. In another embodiment, the subject achieves a decrease in DAS28(CRP) when compared to baseline at week 8 of treatment. In another embodiment, the subject achieves a decrease in DAS28(CRP) when compared to baseline at week 6 of treatment. In another embodiment, the subject achieves a decrease in DAS28(CRP) when compared to baseline at week 4 of treatment. In another embodiment, the subject achieves a decrease in DAS28(CRP) when compared to baseline at week 2 of treatment. In one embodiment, the method or use comprises administering to the subject about 15 mg, per unit dosage form (e.g., per tablet or capsule) of the solid state form. In one embodiment, Compound 1 (free base) or a pharmaceutically acceptable salt or solid state form thereof is in the form of a once-daily extended release formulation. In one embodiment, the solid state 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 state form is an anhydrous crystalline. In one embodiment, the crystalline anhydrous is Free Base Anhydrous Form D. In one embodiment, the solid state form is Tartrate Hydrate.

[0610] In one embodiment, the method or use comprises administering to the subject about 24 mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1 (free base), or a pharmaceutically available salt thereof. acceptable or a solid state form of Compound 1 in an amount sufficient to provide the subject with about 24 mg per unit dosage form (e.g., per tablet or capsule), of free base equivalent of Compound 1, wherein the subject has had an inadequate response or intolerance to one or more DMARDS, and the subject achieves an ACR20 response at week 12 of treatment. In another embodiment, the subject achieves an ACR20 response at week 8 of treatment. In another embodiment, the subject achieves an ACR20 response at week 6 of treatment. In another embodiment, the subject achieves an ACR20 response at week 4 of treatment. In another embodiment, the subject achieves an ACR20 response at week 2 of treatment. In one embodiment, the method or use comprises administering to the subject about 24 mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1 (free base), or a pharmaceutically acceptable salt or form thereof. solid state of Compound 1 in an amount sufficient to provide the subject with about 24 mg per unit dosage form (e.g., per tablet or capsule), of free base equivalent of Compound 1, in which the subject had an inadequate response or intolerance to one or more DMARDS, and the subject achieves an ACR50 response at week 12 of treatment. In another embodiment, the subject achieves an ACR50 response at week 8 of treatment. In another embodiment, the subject achieves an ACR50 response at week 6 of treatment. In another embodiment, the subject achieves an ACR50 response at week 4 of treatment. In another embodiment, the subject achieves an ACR50 response at week 2 of treatment. In one embodiment, the method or use comprises administering to the subject about 24 mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1 (free base), or a pharmaceutically acceptable salt or form thereof. solid state of Compound 1 in an amount sufficient to provide the subject with about 24 mg per unit dosage form (e.g., per tablet or capsule), of free base equivalent of Compound 1, in which the subject had an inadequate response or intolerance to one or more DMARDS, and the subject achieves an ACR70 response at week 12 of treatment. In one embodiment, the method or use comprises administering to the subject about 24 mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1 (free base), or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1 in an amount sufficient to provide the subject with about 24 mg per unit dosage form (e.g., per tablet or capsule), of free base equivalent of Compound 1, in which the subject had a response inadequate or intolerance to one or more DMARDS, and the subject achieves a decrease in DAS28(CRP) when compared to baseline at week 12 of treatment. In another embodiment, the subject achieves a decrease in DAS28(CRP) when compared to baseline at week 8 of treatment. In another embodiment, the subject achieves a decrease in DAS28(CRP) when compared to baseline at week 6 of treatment. In another embodiment, the subject achieves a decrease in DAS28(CRP) when compared to baseline at week 4 of treatment. In another embodiment, the subject achieves a decrease in DAS28(CRP) when compared to baseline at week 2 of treatment. In one embodiment, the method or use comprises administering to the subject about 24 mg, per unit dosage form (e.g., per tablet or capsule) of the solid state form. In one embodiment, Compound 1 (free base) or a pharmaceutically acceptable salt or solid state form thereof is in the form of a once-daily extended release formulation. In one embodiment, the solid state 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 state form is an anhydrous crystalline. In one embodiment, the crystalline anhydrous is Free Base Anhydrous Form D. In one embodiment, the solid state form is Tartrate Hydrate.

[0611] In one embodiment, the method or use comprises administering to the subject about 30 mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1 (free base), or a pharmaceutically available salt thereof. acceptable or a solid state form of Compound 1 in an amount sufficient to provide the subject with about 30 mg per unit dosage form (e.g., per tablet or capsule), of free base equivalent of Compound 1, wherein the subject has had an inadequate response or intolerance to one or more DMARDS, and the subject achieves an ACR20 response at week 12 of treatment. In another embodiment, the subject achieves an ACR20 response at week 8 of treatment. In another embodiment, the subject achieves an ACR20 response at week 6 of treatment. In another embodiment, the subject achieves an ACR20 response at week 4 of treatment. In another embodiment, the subject achieves an ACR20 response at week 2 of treatment. In one embodiment, the method or use comprises administering to the subject about 30 mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1 (free base), or a pharmaceutically acceptable salt or form thereof. solid state of Compound 1 in an amount sufficient to provide the subject with about 30 mg per unit dosage form (e.g., per tablet or capsule), of free base equivalent of Compound 1, in which the subject had an inadequate response or intolerance to one or more DMARDS, and the subject achieves an ACR50 response at week 12 of treatment. In another embodiment, the subject achieves an ACR50 response at week 8 of treatment. In another embodiment, the subject achieves an ACR50 response at week 6 of treatment. In another embodiment, the subject achieves an ACR50 response at week 4 of treatment. In another embodiment, the subject achieves an ACR50 response in week 2 of treatment. In one embodiment, the method or use comprises administering to the subject about 30 mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1 (free base), or a pharmaceutically acceptable salt or form thereof. solid state of Compound 1 in an amount sufficient to provide the subject with about 30 mg per unit dosage form (e.g., per tablet or capsule), of free base equivalent of Compound 1, in which the subject had an inadequate response or intolerance to one or more DMARDS, and the subject achieves an ACR70 response at week 12 of treatment. In one embodiment, the method or use comprises administering to the subject about 30 mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1 (free base), or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1 in an amount sufficient to provide the subject with about 30 mg per unit dosage form (e.g., per tablet or capsule), of free base equivalent of Compound 1, in which the subject had a response inadequate or intolerance to one or more DMARDS, and the subject achieves a decrease in DAS28(CRP) when compared to baseline at week 12 of treatment. In another embodiment, the subject achieves a decrease in DAS28(CRP) when compared to baseline at week 8 of treatment. In another embodiment, the subject achieves a decrease in DAS28(CRP) when compared to baseline at week 6 of treatment. In another embodiment, the subject achieves a decrease in DAS28(CRP) when compared to baseline at week 4 of treatment. In another embodiment, the subject achieves a decrease in DAS28(CRP) when compared to baseline at week 2 of treatment. In one embodiment, the method or use comprises administering to the subject about 30 mg, per unit dosage form (e.g., per tablet or capsule) of the solid state form. In one embodiment, Compound 1 (free base) or a pharmaceutically acceptable salt or solid state form thereof is in the form of a once-daily extended release formulation. In one embodiment, the solid state 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 state form is an anhydrous crystalline. In one embodiment, the crystalline anhydrous is Free Base Anhydrous Form D. In one embodiment, the solid state form is Tartrate Hydrate.

[0612] In one embodiment, the method or use comprises administering to the subject about 45 mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1 (free base), or a pharmaceutically available salt thereof. acceptable or a solid state form of Compound 1 in an amount sufficient to provide the subject with about 45 mg per unit dosage form (e.g., per tablet or capsule) of free base equivalent of Compound 1, wherein the subject has had an inadequate response or intolerance to one or more DMARDS, and the subject achieves an ACR20 response at week 12 of treatment. In another embodiment, the subject achieves an ACR20 response at week 8 of treatment. In another embodiment, the subject achieves an ACR20 response at week 6 of treatment. In another embodiment, the subject achieves an ACR20 response at week 4 of treatment. In another embodiment, the subject achieves an ACR20 response at week 2 of treatment. In one embodiment, the method or use comprises administering to the subject about 45 mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1 (free base), or a pharmaceutically acceptable salt or form thereof. solid state of Compound 1 in an amount sufficient to provide the subject with about 45 mg per unit dosage form (e.g., per tablet or capsule), of free base equivalent of Compound 1, in which the subject had an inadequate response or intolerance to one or more DMARDS, and the subject achieves an ACR50 response at week 12 of treatment. In another embodiment, the subject achieves an ACR50 response at week 8 of treatment. In another embodiment, the subject achieves an ACR50 response at week 6 of treatment. In another embodiment, the subject achieves an ACR50 response at week 4 of treatment. In one embodiment, the method or use comprises administering to the subject about 45 mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1 (free base), or a pharmaceutically acceptable salt or form thereof. solid state of Compound 1 in an amount sufficient to provide the subject with about 45 mg per unit dosage form (e.g., per tablet or capsule), of free base equivalent of Compound 1, in which the subject had an inadequate response or intolerance to one or more DMARDS, and the subject achieves an ACR70 response at week 12 of treatment. In another embodiment, the subject achieves an ACR70 response at week 8 of treatment. In another embodiment, the subject achieves an ACR70 response at week 6 of treatment. In another embodiment, the subject achieves an ACR70 response at week 4 of treatment. In one embodiment, the method or use comprises administering to the subject about 45 mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1 (free base), or a pharmaceutically acceptable salt or form thereof. solid state of Compound 1 in an amount sufficient to provide the subject with about 45 mg per unit dosage form (e.g., per tablet or capsule), of free base equivalent of Compound 1, in which the subject had an inadequate response or intolerance to one or more DMARDS, and the subject achieves a decrease in DAS28(CRP) when compared to baseline at week 12 of treatment. In another embodiment, the subject achieves a decrease in DAS28(CRP) when compared to baseline at week 8 of treatment. In another embodiment, the subject achieves a decrease in DAS28(CRP) when compared to baseline at week 6 of treatment. In another embodiment, the subject achieves a decrease in DAS28(CRP) when compared to baseline at week 4 of treatment. In another embodiment, the subject achieves a decrease in DAS28(CRP) when compared to baseline at week 2 of treatment. In one embodiment, the method or use comprises administering to the subject about 45 mg, per unit dosage form (e.g., per tablet or capsule) of the solid state form. In one embodiment, Compound 1 (free base) or a pharmaceutically acceptable salt or solid state form thereof is in the form of a once-daily extended release formulation. In one embodiment, the solid state 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 state form is an anhydrous crystalline. In one embodiment, the crystalline anhydrous is Free Base Anhydrous Form D. In one embodiment, the solid state form is Tartrate Hydrate.

[0613] In another embodiment, the adult subject is also administered a csDMARD or a bDMARD in a combination therapy, as described below. In certain embodiments, the DMARD is MTX. In certain embodiments, the adult subject receiving the combination therapy achieves an ACR20 response, an ACR50 response, an ACR70 response and/or a decrease in DAS28 (CRP) when compared to baseline following treatment. In particular embodiments, the adult subject receiving the combination therapy achieves an ACR20 response, an ACR50 response, an ACR70 response and/or a decrease in DAS28(CRP) when compared to baseline at week 12 of treatment and/or at week 8 of treatment, and/or week 6 of treatment, and/or week 4 of treatment and/or week 2 of treatment. In one embodiment, the adult subject receiving the combination therapy is administered about 7.5 mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1 (free base), or a pharmaceutically acceptable salt thereof. or a solid state form of Compound 1 in an amount sufficient to provide the subject with about 7.5 mg per unit dosage form (e.g., per tablet or capsule), of free base equivalent of Compound 1. In one embodiment , the adult subject receiving combination therapy is administered about 15 mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1 (free base), or a pharmaceutically acceptable salt or form thereof. in a solid state of Compound 1 in an amount sufficient to provide the subject with about 15 mg per unit dosage form (e.g., per tablet or capsule) of free base equivalent of Compound 1. In one embodiment, the adult subject receiving In combination therapy, about 30 mg per unit dosage form (e.g., per tablet or capsule) of Compound 1 (free base) or a pharmaceutically acceptable salt or solid state form thereof are administered. of Compound 1 in an amount sufficient to provide the subject with about 30 mg per unit dosage form (e.g., per tablet or capsule) of free base equivalent of Compound 1. In one embodiment, the adult subject receiving compound 1 therapy combination are administered about 45 mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1 (free base), or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1 in a sufficient amount to provide the subject with about 45 mg per unit dosage form (e.g., per tablet or capsule), of free base equivalent of Compound 1. In one embodiment, the method comprises administering to the subject about 7.5 mg or about of 15 mg or about 30 mg or about 45 mg, per unit dosage form (e.g., per tablet or capsule) of the solid state form. In one embodiment, Compound 1 (free base) or a pharmaceutically acceptable salt or solid state form thereof is in the form of a once-daily extended release formulation. In one embodiment, the solid state 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 state form is an anhydrous crystalline. In one embodiment, the crystalline anhydrous is Free Base Anhydrous Form D. In one embodiment, the solid state form is Tartrate Hydrate.

[0614] In another embodiment, any of the methods described herein of treating an adult subject having moderately to severely active rheumatoid arthritis may further comprise alleviating at least one symptom selected from the group consisting of bone erosion, cartilage erosion, inflammation and vascularization. In another embodiment, arthritis is further treated by relieving at least one symptom selected from the group consisting of joint distortion, swelling, joint deformity, flexion ankylosis, and severely affected movement.

[0615] In another embodiment, the present disclosure relates to a method of treating structural damage associated with rheumatoid arthritis in an adult subject, in particular a human subject suffering from, or susceptible to, structural damage associated with rheumatoid arthritis. 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 (e.g., a crystalline hydrate or anhydrous crystalline) as described herein. , so that structural damage in the adult subject is inhibited or attenuated. 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, per unit dosage form (e.g., per tablet or capsule) per day of Compound. 1 (free base), or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1 in an amount sufficient to provide the subject with about 7.5 mg or about 15 mg or about 30 mg or about 45 mg, per unit dosage form (e.g., per tablet or capsule) per day of free base equivalent of Compound 1, such that structural damage in the adult subject is inhibited or attenuated. 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, per unit dosage form (e.g., per tablet or capsule) in a mass form. solid state of Compound 1, so that structural damage in the adult subject is inhibited or attenuated. In one embodiment, Compound 1 (free base), or a pharmaceutically acceptable salt thereof or solid state form of Compound 1 is administered to the subject orally QD (once per day). In one embodiment, structural damage is selected from the group consisting of bone and/or cartilage loss, bone erosion, joint space reduction as measured by radiography, and combinations thereof. In one embodiment, structural damage is inhibited or mitigated when structural damage is reduced by at least 20%, or at least 25%, or at least 30%, or at least 50%. In other embodiments, structural damage is inhibited or attenuated when there is no further radiographic progression of structural damage. In certain embodiments, structural damage to joints can be assessed by radiography and expressed as change in Total Sharp Score (TSS) and its components, erosion score, and Joint Space Reduction score (JSN), for example at week 12. compared to the baseline. In another aspect, the disclosure relates to a solid state form (and in particular, a crystalline hydrate) of Compound 1, as described in the present disclosure, for use in treating structural damage associated with rheumatoid arthritis in an adult subject, in particularly a human subject suffering from, or susceptible to, rheumatoid arthritis. In one embodiment, the solid state 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 an anhydrous crystalline. In one embodiment, the crystalline anhydrous is Free Base Anhydrous Form D. In one embodiment, the solid state form is Tartrate Hydrate. In one embodiment, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof is in the form of a once-daily extended release formulation. In one embodiment, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof is in the form of a once-daily extended-release formulation and the formulation orally delivers QD (once a day). day) about 7.5 mg or about 15 mg or about 30 mg or about 45 mg per unit dosage form (e.g., per tablet or capsule) of Compound 1 (free base equivalent).

[0616] In another aspect, the 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 or anhydrous crystalline hydrate), as described herein. disclosure, for use in treating structural damage associated with rheumatoid arthritis in an adult subject, in particular a human subject suffering from, or susceptible to, structural damage associated with rheumatoid arthritis, such that the structural damage in the adult subject is inhibited or attenuated, 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 embodiment, the solid state 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 an anhydrous crystalline. In one embodiment, the crystalline anhydrous is Free Base Anhydrous Form D. In one embodiment, Compound 1 (free base), or a pharmaceutically acceptable salt thereof or the solid state form of Compound 1 is presented in the form of a once-daily extended release formulation. In one embodiment, the formulation orally provides QD (once daily) about 7.5 mg or about 15 mg or about 30 mg or about 45 mg per unit dosage form (e.g., per tablet or capsule). of Compound 1 (free base equivalent) or a solid state form of Compound 1.

[0617] In one embodiment, the present disclosure is directed to a method of treating structural damage associated with rheumatoid arthritis in an adult subject, in particular a human subject suffering from, or susceptible to, structural damage associated with rheumatoid arthritis, the method comprising administer to the subject about 7.5 mg, per unit dosage form (e.g., per tablet or capsule) per day of Compound 1 (free base), or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1, in an amount sufficient to provide the subject with about 7.5 mg, per unit dosage form (e.g., per tablet or capsule) per day of free base equivalent of Compound 1, such that structural damage in the adult subject is inhibited or attenuated. In one embodiment, the method comprises administering to the subject about 7.5 mg, per unit dosage form (e.g., per tablet or capsule) per day of a solid state form of Compound 1. In another aspect, the disclosure is 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 structural damage associated with rheumatoid arthritis in an adult subject, in particular in a human subject suffering from, or susceptible to a, structural damage associated with rheumatoid arthritis, such that structural damage in the adult subject is inhibited or attenuated, the use comprising administering to the subject about 7.5 mg, per unit dosage form (e.g., per tablet or capsule) of Compound 1 free base or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1. In one embodiment, the solid state 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 state form is an anhydrous crystalline. In one embodiment, the crystalline anhydrous is Free Base Anhydrous Form D. In one embodiment, the solid state form is Tartrate Hydrate. In one embodiment, the free base of Compound 1 or a pharmaceutically acceptable salt thereof or the solid state form of Compound 1 is administered orally QD (once per day). In one embodiment, the free base of Compound 1 or a pharmaceutically acceptable salt thereof or the solid state form of Compound 1 is in the form of a once-daily extended release formulation. In one embodiment, structural damage is selected from the group consisting of bone and/or cartilage loss, bone erosion, joint space reduction as measured by radiography, and combinations thereof.

[0618] In one embodiment, the present disclosure is directed to a method of treating structural damage associated with rheumatoid arthritis in an adult subject, in particular a human subject suffering from, or susceptible to, structural damage associated with rheumatoid arthritis, the method comprising administer to the subject about 15 mg, per unit dosage form (e.g., per tablet or capsule) per day of Compound 1 (free base), or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1, in a sufficient amount to provide the subject with about 15 mg, per unit dosage form (e.g., per tablet or capsule) per day of free base equivalent of Compound 1, such that structural damage in the adult subject is inhibited or attenuated. In one embodiment, the method comprises administering to the subject about 15 mg, per unit dosage form (e.g., per tablet or capsule) per day of a solid state form of Compound 1. In another aspect, the disclosure relates to free base of Compound 1 or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1, for use in treating structural damage associated with rheumatoid arthritis in an adult subject, in particular in a human subject suffering from, or susceptible to, structural damage associated with rheumatoid arthritis, so that structural damage in the adult subject is inhibited or attenuated, the use comprising administering to the subject about 15 mg, per unit dosage form (e.g., per tablet or capsule) of base free of Compound 1 or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1. In one embodiment, the solid state 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 state form is an anhydrous crystalline. In one embodiment, the crystalline anhydrous is Free Base Anhydrous Form D. In one embodiment, the solid state form is Tartrate Hydrate. In one embodiment, the free base of Compound 1 or a pharmaceutically acceptable salt thereof or the solid state form of Compound 1 is administered orally QD (once per day). In one embodiment, the free base of Compound 1 or a pharmaceutically acceptable salt thereof or the solid state form of Compound 1 is in the form of a once-daily extended release formulation. In one embodiment, structural damage is selected from the group consisting of bone and/or cartilage loss, bone erosion, joint space reduction as measured by radiography, and combinations thereof.

[0619] In one embodiment, the present disclosure is directed to a method of treating structural damage associated with rheumatoid arthritis in an adult subject, in particular a human subject suffering from, or susceptible to, structural damage associated with rheumatoid arthritis, the method comprising administer to the subject about 30 mg, per unit dosage form (e.g., per tablet or capsule) per day of Compound 1 (free base), or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1, in a sufficient amount to provide the subject with about 30 mg, per unit dosage form (e.g., per tablet or capsule) per day of free base equivalent of Compound 1, such that structural damage in the adult subject is inhibited or attenuated. In one embodiment, the method comprises administering to the subject about 30 mg, per unit dosage form (e.g., per tablet or capsule) per day of a solid state form of Compound 1. In another aspect, the disclosure relates to free base of Compound 1 or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1, for use in treating structural damage associated with rheumatoid arthritis in an adult subject, in particular in a human subject suffering from, or susceptible to, structural damage associated with rheumatoid arthritis, so that structural damage in the adult subject is inhibited or attenuated, the use comprising administering to the subject about 30 mg, per unit dosage form (e.g., per tablet or capsule) of free base Compound 1 or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1. In one embodiment, the solid state 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 state form is an anhydrous crystalline. In one embodiment, the crystalline anhydrous is Free Base Anhydrous Form D. In one embodiment, the solid state form is Tartrate Hydrate. In one embodiment, the free base of Compound 1 or a pharmaceutically acceptable salt thereof or the solid state form of Compound 1 is administered orally QD (once per day). In one embodiment, the free base of Compound 1 or a pharmaceutically acceptable salt thereof or the solid state form of Compound 1 is in the form of a once-daily extended release formulation. In one embodiment, structural damage is selected from the group consisting of bone and/or cartilage loss, bone erosion, joint space reduction as measured by radiography, and combinations thereof.

[0620] In one embodiment, the present disclosure is directed to a method of treating structural damage associated with rheumatoid arthritis in an adult subject, in particular a human subject suffering from, or susceptible to, structural damage associated with rheumatoid arthritis, the method comprising administering to the subject about 45 mg, per unit dosage form (e.g., per tablet or capsule) per day of Compound 1 (free base), or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1, in an amount sufficient to provide the subject with about 45 mg, per unit dosage form (e.g., per tablet or capsule) per day of free base equivalent of Compound 1, such that structural damage in the adult subject is inhibited or attenuated. In one embodiment, the method comprises administering to the subject about 45 mg, per unit dosage form (e.g., per tablet or capsule) per day of a solid state form of Compound 1. In another aspect, the disclosure relates to free base of Compound 1 or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1, for use in treating structural damage associated with rheumatoid arthritis in an adult subject, in particular in a human subject suffering from, or susceptible to, structural damage associated with rheumatoid arthritis, such that structural damage in the adult subject is inhibited or attenuated, the use comprising administering to the subject 45 mg, per unit dosage form (e.g., per tablet or capsule) of free base of Compound 1 or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1. In one embodiment, the solid state 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 state form is an anhydrous crystalline. In one embodiment, the crystalline anhydrous is Free Base Anhydrous Form D. In one embodiment, the solid state form is Tartrate Hydrate. In one embodiment, the free base of Compound 1 or a pharmaceutically acceptable salt thereof or the solid state form of Compound 1 is administered orally QD (once per day). In one embodiment, the free base of Compound 1 or a pharmaceutically acceptable salt thereof or the solid state form of Compound 1 is in the form of a once-daily extended release formulation. In one embodiment, structural damage is selected from the group consisting of bone and/or cartilage loss, bone erosion, joint space reduction as measured by radiography, and combinations thereof.

[0621] In another embodiment, the present disclosure is directed to a method of reducing signs and symptoms of rheumatoid arthritis in an adult subject, in particular a human subject suffering from, or susceptible to, moderately to severely active rheumatoid arthritis. 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 (e.g., a crystalline hydrate or anhydrous crystalline) as described herein. . 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, per unit dosage form (e.g., per tablet or capsule) per day of Compound. 1 (free base), or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1 in an amount sufficient to provide the subject with about 7.5 mg or about 15 mg or about 30 mg or about 45 mg , per unit dosage form (e.g., per tablet or capsule) per day of free base equivalent 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, per unit dosage form (e.g., per tablet or capsule) of a solid state form of Compound 1. In one embodiment, Compound 1 (free base), or a pharmaceutically acceptable salt thereof or the solid state form of Compound 1 is administered to the subject orally QD (once daily). In another aspect, the disclosure relates to a free base of Compound 1 or a pharmaceutically acceptable salt thereof or a solid state form (and in particular a crystalline hydrate) of Compound 1, as described in the present disclosure, for use in reducing of signs and symptoms of rheumatoid arthritis in an adult subject, in particular in a human subject suffering from, or susceptible to, moderately to severely active rheumatoid arthritis, the use comprising administering to the subject a therapeutically effective amount of Compound 1 free base or a its pharmaceutically acceptable salt or a solid state form (and in particular a crystalline hydrate) of Compound 1. In one embodiment, the free base of Compound 1 or a pharmaceutically acceptable salt thereof or the solid state form of Compound 1 has It is in the form of a once-daily extended-release formulation. In one embodiment, the formulation orally provides QD (once per day) to the subject about 7.5 mg or about 15 mg or about 30 mg or about 45 mg per unit dosage form (e.g., per tablet or capsule) of Compound 1 (free base equivalent) or the solid state form of Compound 1. In one embodiment, the solid state 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 state form is an anhydrous crystalline. In one embodiment, the crystalline anhydrous is Free Base Anhydrous Form D. In one embodiment, the solid state form is Tartrate Hydrate.

[0622] In one embodiment, the present disclosure is directed to a method of reducing the signs and symptoms of rheumatoid arthritis in an adult subject, in particular a human subject suffering from, or susceptible to, moderately to severely active rheumatoid arthritis, the method comprising administering to the subject about 7.5 mg, per unit dosage form (e.g., per tablet or capsule) per day of Compound 1 (free base), or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1 , in an amount sufficient to provide the subject with about 7.5 mg, per unit dosage form (e.g., per tablet or capsule) per day of free base equivalent of Compound 1. In one embodiment, the method comprises administer to the subject about 7.5 mg, per unit dosage form (e.g., per tablet or capsule) per day of a solid state form of Compound 1. In another aspect, the disclosure relates to free base of Compound 1 or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1, for use in reducing signs and symptoms of rheumatoid arthritis in an adult subject, in particular in a human subject suffering from, or susceptible to, moderately to severely rheumatoid arthritis active, use comprising administering to the subject about 7.5 mg, per unit dosage form (e.g., per tablet or capsule) of free base of Compound 1 or a pharmaceutically acceptable salt thereof or a solid state form of the Compound 1. In one embodiment, the solid state 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 an anhydrous crystalline. In one embodiment, the crystalline anhydrous is Free Base Anhydrous Form D. In one embodiment, the solid state form is Tartrate Hydrate. In one embodiment, the free base of Compound 1 or a pharmaceutically acceptable salt thereof or the solid state form of Compound 1 is administered orally QD (once per day). In one embodiment, the free base of Compound 1 or a pharmaceutically acceptable salt thereof or the solid state form of Compound 1 is presented in the form of a once-daily extended release formulation. In one embodiment, Compound 1 (free base), or a pharmaceutically acceptable salt thereof or solid state form of Compound 1 is in the form of a once-daily extended-release formulation and the formulation orally provides QD (a once per day) to the subject about 7.5 mg per unit dosage form (e.g., per tablet or capsule) of Compound 1 (free base equivalent) or the solid state form of Compound 1.

[0623] In one embodiment, the present disclosure is directed to a method of reducing the signs and symptoms of rheumatoid arthritis in an adult subject, in particular a human subject suffering from, or susceptible to, moderately to severely active rheumatoid arthritis, the method comprising administering to the subject about 15 mg, per unit dosage form (e.g., per tablet or capsule) per day of Compound 1 (free base), or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1, in an amount sufficient to provide the subject with about 15 mg, per unit dosage form (e.g., per tablet or capsule) per day of free base equivalent of Compound 1. In one embodiment, the method comprises administering to the subject about 15 mg, per unit dosage form (e.g., per tablet or capsule) per day of a solid state form of Compound 1. In another aspect, the disclosure relates to free base of Compound 1 or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1, for use in reducing signs and symptoms of rheumatoid arthritis in an adult subject, in particular in a human subject suffering from, or susceptible to, moderately to severely active rheumatoid arthritis, the use comprising administering to the subject about 15 mg, per unit dosage form (e.g., per tablet or capsule) of free base of Compound 1 or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1. In one embodiment, the solid state form is a crystalline hydrate. In one embodiment, the crystalline hydrate is a hemihydrate. In one embodiment, the hemihydrate is Free Base Hydrate Form C. In one embodiment, the crystalline hydrate is Free Base Hydrate Form B. In one embodiment, the solid state form is an anhydrous crystalline. In one embodiment, the crystalline anhydrous is Free Base Anhydrous Form D. In one embodiment, the solid state form is Tartrate Hydrate. In one embodiment, the free base of Compound 1 or the solid state form of Compound 1 is administered orally QD (once per day). In one embodiment, Compound 1 (free base), or a pharmaceutically acceptable salt thereof or the solid state form of Compound 1 is presented in the form of a once-daily extended release formulation. In one embodiment, Compound 1 (free base), or a pharmaceutically acceptable salt thereof or solid state form of Compound 1 is in the form of a once-daily extended-release formulation and the formulation orally provides QD (a once daily) to the subject about 15 mg per unit dosage form (e.g., per tablet or capsule) of Compound 1 (free base equivalent) or the solid state form of Compound 1.

[0624] In another embodiment, the present disclosure is directed to a method of reducing signs and symptoms of rheumatoid arthritis in an adult subject, in particular a human subject suffering from, or susceptible to, moderately to severely active rheumatoid arthritis. The method comprises administering to the subject about 30 mg, per unit dosage form (e.g., per tablet or capsule) per day of Compound 1 (free base), or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1. in an amount sufficient to provide the subject with about 30 mg, per unit dosage form (e.g., per tablet or capsule) per day of free base equivalent of Compound 1. In one embodiment, the method comprises administering to the subject about 30 mg per unit dosage form (e.g., per tablet or capsule) per day of a solid state form of Compound 1. In another aspect, the disclosure relates to free base of Compound 1 or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1, for use in reducing signs and symptoms of rheumatoid arthritis in an adult subject, in particular in a human subject suffering from, or susceptible to, moderately to severely active rheumatoid arthritis, the use comprising administering to the subject to about 30 mg, per unit dosage form (e.g., per tablet or capsule) of free base of Compound 1 or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1. In one embodiment, the form in solid state it is a crystalline hydrate. In one embodiment, the crystalline hydrate is a hemihydrate. In one embodiment, the hemihydrate is Free Base Hydrate Form C. In one embodiment, the crystalline hydrate is Free Base Hydrate Form B. In one embodiment, the solid state form is an anhydrous crystalline. In one embodiment, the crystalline anhydrous is Free Base Anhydrous Form D. In one embodiment, the solid state form is Tartrate Hydrate. In one embodiment, the free base of Compound 1 or a pharmaceutically acceptable salt thereof or the solid state form of Compound 1 is administered orally QD (once per day). In one embodiment, Compound 1 (free base) or crystalline hydrate is presented in the form of a once-daily extended-release formulation. In one embodiment, Compound 1 (free base), or a pharmaceutically acceptable salt thereof or solid state form of Compound 1 is in the form of a once-daily extended-release formulation and the formulation orally provides QD (a once daily) to the subject about 30 mg per unit dosage form (e.g., per tablet or capsule) of Compound 1 (free base equivalent) or the solid state form of Compound 1.

[0625] In one embodiment, the present disclosure is directed to a method of reducing the signs and symptoms of rheumatoid arthritis in an adult subject, in particular a human subject suffering from, or susceptible to, moderately to severely active rheumatoid arthritis, the method comprising administering to the subject about 45 mg, per unit dosage form (e.g., per tablet or capsule) per day of Compound 1 (free base), or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1, in an amount sufficient to provide the subject with about 45 mg, per unit dosage form (e.g., per tablet or capsule) per day of free base equivalent of Compound 1. In one embodiment, the method comprises administering to the subject about 45 mg per unit dosage form (e.g., per tablet or capsule) per day of a solid state form of Compound 1. In another aspect, the disclosure relates to free base of Compound 1 or a pharmaceutically acceptable salt thereof. or a solid state form of Compound 1, for use in reducing signs and symptoms of rheumatoid arthritis in an adult subject, in particular in a human subject suffering from, or susceptible to, moderately to severely active rheumatoid arthritis, the use comprising administering to the subject about 45 mg, per unit dosage form (e.g., per tablet or capsule) of free base of Compound 1 or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1. In one embodiment, the solid state 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 an anhydrous crystalline. In one embodiment, the crystalline anhydrous is Free Base Anhydrous Form D. In one embodiment, the solid state form is Tartrate Hydrate. In one embodiment, the free base of Compound 1 or a pharmaceutically acceptable salt thereof or the solid state form of Compound 1 is administered orally QD (once per day). In one embodiment, the free base of Compound 1 or a pharmaceutically acceptable salt thereof or the solid state form of Compound 1 is presented in the form of a once-daily extended release formulation. In one embodiment, Compound 1 (free base), or a pharmaceutically acceptable salt thereof or solid state form of Compound 1 is in the form of a once-daily extended-release formulation and the formulation orally provides QD (a once per day) to the subject about 45 mg per unit dosage form (e.g., per tablet or capsule) of Compound 1 (free base equivalent) or the solid state form of Compound 1.

[0626] In another aspect, the disclosure relates to a solid state form (and in particular, a crystalline hydrate) of Compound 1, as described in the present disclosure, for use in reducing signs and symptoms of rheumatoid arthritis in a subject. adult, in particular a human subject suffering from, or susceptible to, rheumatoid arthritis.

[0627] In another embodiment, any of the methods described herein of reducing signs and symptoms of rheumatoid arthritis may further comprise alleviating at least one symptom selected from the group consisting of bone erosion, cartilage erosion, inflammation and vascularization. In another embodiment, arthritis is further treated by alleviating at least one symptom selected from the group consisting of joint distortion, swelling, joint deformity, ankylosis in flexion, and severely affected movement.

[0628] In another embodiment, the free base of Compound 1 or a pharmaceutically acceptable salt thereof and/or solid state form of Compound 1 used in any of the methods presented herein can be administered to the subject in an oral dosage form. extended-release solid once daily. In particular, in one embodiment, the methods comprise administering once daily to the subject an extended-release (e.g., modified release) solid oral dosage form comprising the free base of Compound 1 or a pharmaceutically acceptable salt thereof. or the solid state form of Compound 1, and a pharmaceutically acceptable polymeric carrier substantially contributing to modifying the release of the free base of Compound 1 or a pharmaceutically acceptable salt thereof or the solid state form of Compound 1. In one aspect , the dosage form sustains release of the free base of Compound 1 or a pharmaceutically acceptable salt thereof or the solid state form of Compound 1 for about 4 hours to about 24 hours following entry of the dosage form into an environment of use. In one embodiment, the dosage form has a release rate of no more than about 60% after the passage of about 4 hours following entry of the dosage form into an environment of use. The term “entry into an environment of use” relates to the contact of the dosage form with gastric fluids of the subject to whom it is administered. As used herein, the term “release rate” relates to the percentage of active ingredient (e.g., Compound 1 or a solid-state form of Compound 1) in the dosage form that is released over the period of time in question and under the specified conditions. In one embodiment, the dosage form comprises about 7.5 mg or about 15 mg or about 30 mg or about 45 mg, per unit dosage form (e.g., per tablet or capsule) of Compound 1 (base free), or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1 in an amount sufficient to provide the subject with about 7.5 mg or about 15 mg or about 30 mg or about 45 mg, per form unit dosage (e.g., per tablet or capsule) per day of free base equivalent of Compound 1. In one embodiment, the dosage form comprises about 7.5 mg or about 15 mg or about 30 mg or about of 45 mg, per unit dosage form (e.g., per tablet or capsule) per day of a solid state form of Compound 1. 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 Free Base Anhydrous Form D. In one embodiment, the solid state form is Tartrate Hydrate. In one embodiment, the pharmaceutically acceptable polymeric carrier is a release control polymer, as set forth herein.

[0629] Thus, in one aspect, the dosage form sustains release of the free base of Compound 1 or a pharmaceutically acceptable salt thereof or the solid state form of Compound 1 for about 4 hours to about 24 hours. In one embodiment, the dosage form releases the active ingredient (i.e., Compound 1 or a solid state form of Compound 1), at a release rate no greater than about 25%, or from about 10% to about 25%, or from about 15% to about 20%, or about 20% after about 1 hour after entering the use environment. In one embodiment, the dosage form releases the active ingredient at a release rate of no more than about 40%, or about 20% to about 40%, or about 25% to about 35% after passing approximately 2 hours after entering the use environment. In one embodiment, the dosage form releases the active ingredient at a release rate of no more than about 60%, or from about 30% to about 60%, or from about 40% to about 60%. , or from about 45% to about 55% after about 4 hours have passed after entering the environment of use. In one embodiment, the dosage form releases the active ingredient at a release rate of no more than about 70%, or about 40% to about 70%, or about 55% to about 70%, after approximately 6 hours pass after entering the use environment. In one embodiment, the dosage form releases the active ingredient at a release rate of no more than about 80%, or from about 55% to about 80%, or from about 60% to about 80%, after approximately 6 hours pass after entering the use environment. In one embodiment, the dosage form releases the active ingredient at a release rate of not more than about 80%, or not less than about 50%, or not less than about 60%, or not less than about 70%. %, or not less than about 75%, or from about 50% to about 80%, or from about 60% to about 80%, or from about 65% to about 80% after passing about 8 hours after entering the use environment. In one embodiment, the dosage form releases the active ingredient at a release rate of not less than about 55%, or not less than about 60%, or not less than about 70%, or not less than about 80%. %, or not less than about 85%, or from about 55% to about 90%, or from about 70% to about 90% after about 10 hours pass after entering the environment of use. In one embodiment, the dosage form releases the active ingredient at a release rate of not less than about 65%, or not less than about 70%, or not less than about 80%, or not less than about 90%. %, or from about 65% to about 99%, or from about 80% to about 99%, or from about 90% to about 99% after about 16 hours have passed following entry into the environment. use. In one embodiment, the dosage form releases the active ingredient at a release rate of not less than about 70%, or not less than about 80%, or not less than about 90%, or from about 70% to about 100%, or from about 80% to about 100% after about 20 hours pass after entering the environment of use. In one aspect, the dosage form has a release rate of no more than about 60% after about 4 hours after entering the dosage form into a use environment, from about 50% to about 80%. after about 8 hours have passed following the entry of the dosage form into an environment of use, from about 55% to about 90% after about 10 hours have passed following the entry of the dosage form into an environment of use, and from about 70% to 100% after about 20 hours have passed following entry of the dosage form into a use environment.

[0630] In one embodiment, the present disclosure is directed 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, psoriasis of the nails, psoriatic arthritis, ankylosing spondylitis, alopecia areata, hidradenitis suppurativa, atopic dermatitis and systemic lupus erythematosus, the method comprising administering once daily to a subject suffering from, or susceptible to, the condition, a solid release dosage form prolonged period comprising about 7.5 mg or about 15 mg or about 30 mg or about 45 mg, per unit dosage form (e.g., per tablet or capsule), of free base of Compound 1 or a pharmaceutically available salt thereof acceptable or the solid state form of Compound 1 in an amount sufficient to provide the subject with about 7.5 mg or about 15 mg or about 30 mg or about 45 mg, per unit dosage form (e.g., per tablet or capsule), of equivalent free base of Compound 1, and a pharmaceutically acceptable polymeric carrier contributing substantially to modifying the release of the free base of Compound 1 or a pharmaceutically acceptable salt thereof or the solid state form of Compound 1 , wherein the dosage form sustains release of the free base of Compound 1 or a pharmaceutically acceptable salt thereof or the solid state form of Compound 1 for about 4 to about 24 hours following entry of the dosage form into a environment of use, wherein the dosage form has a release rate of no more than about 60% after about 4 hours have passed following said entry into said environment of use. In one embodiment, the dosage form comprises about 7.5 mg or about 15 mg or about 30 mg or about 45 mg, per unit dosage form (e.g., per tablet or capsule) in an in-state form. solid of Compound 1. 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 Free Base Anhydrous Form D. In one embodiment, the solid state form is Tartrate Hydrate. In one embodiment, the dosage form further has a release rate of about 50% to about 80% after about 8 hours following entry of the dosage form into an environment of use, from about 55% to about 80%. about 90% after about 10 hours pass after the dosage form enters a use environment, and/or about 70% to 100% after about 20 hours passes after the dosage form enters a a usage environment.

[0631] In another aspect, the disclosure is directed to a sustained-release solid oral dosage form comprising free base of Compound 1 or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1 for use in treating of 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, the use comprising administering once daily to a subject suffering from, or susceptible to, the condition, the extended-release solid dosage form, wherein the solid dosage form comprises about 7 5 mg or about 15 mg or about 30 mg or about 45 mg, per unit dosage form (e.g., per tablet or capsule), of free base of Compound 1 or a pharmaceutically acceptable salt thereof or the form in solid state of Compound 1 in an amount sufficient to provide the subject with about 7.5 mg or about 15 mg or about 30 mg or about 45 mg, per unit dosage form (e.g., per tablet or capsule), of equivalent free base of Compound 1, and a pharmaceutically acceptable polymeric carrier substantially contributing to modifying the release of the free base of Compound 1 or a pharmaceutically acceptable salt thereof or the solid state form of Compound 1, wherein the dosage form sustains the release of the free base of Compound 1 or a pharmaceutically acceptable salt thereof or the solid state form of Compound 1 for about 4 to about 24 hours following entry of the dosage form into an environment of use, in which the The dosage form has a release rate of no more than about 60% after about 4 hours have passed following said entry into said environment of use. In one embodiment, the dosage form comprises about 7.5 mg or about 15 mg or about 30 mg or about 45 mg, per unit dosage form (e.g., per tablet or capsule) in an in-state form. solid of Compound 1. 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 Free Base Anhydrous Form D. In one embodiment, the solid state form is Tartrate Hydrate. In one embodiment, the dosage form further has a release rate of about 50% to about 80% after about 8 hours following entry of the dosage form into an environment of use, from about 55% to about 80%. about 90% after about 10 hours pass after the dosage form enters a use environment, and/or about 70% to 100% after about 20 hours passes after the dosage form enters a a usage environment.

[0632] In another embodiment, the disclosure is directed to a method of treating an adult subject having moderately to severely active rheumatoid arthritis, the method comprising administering once daily to the subject, in particular a human subject suffering from, or susceptible to, rheumatoid arthritis, of an extended-release solid dosage form comprising about 7.5 mg or about 15 mg or about 30 mg or about 45 mg, per unit dosage form (e.g., per tablet or capsule), free base of Compound 1 or a pharmaceutically acceptable salt thereof or the solid state form of Compound 1 in an amount sufficient to provide the subject with about 7.5 mg or about 15 mg or about 30 mg or about 45 mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1 free base equivalent, and a pharmaceutically acceptable polymeric carrier substantially contributing to modifying the release of Compound 1 free base or a pharmaceutically acceptable salt thereof or the solid state form of Compound 1, wherein the dosage form sustains the release of the free base of Compound 1 or a pharmaceutically acceptable salt thereof or the solid state form of Compound 1 for about 4 to about 24 hours following entry of the dosage form into an environment of use, wherein the dosage form has a release rate of no more than about 60% after about 4 hours have passed following said entry into said environment of use. In one embodiment, the dosage form comprises about 7.5 mg or about 15 mg or about 30 mg or about 45 mg, per unit dosage form (e.g., per tablet or capsule) in an in-state form. solid of Compound 1. 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 Free Base Anhydrous Form D. In one embodiment, the solid state form is Tartrate Hydrate. In one embodiment, the dosage form further has a release rate of about 50% to about 80% after about 8 hours following entry of the dosage form into an environment of use, from about 55% to about 80%. about 90% after about 10 hours pass after the dosage form enters a use environment, and/or about 70% to 100% after about 20 hours passes after the dosage form enters a a usage environment. In one embodiment, the subject has symptoms selected from the group consisting of at least 6 swollen joints, at least 6 tender joints, and combinations thereof prior to treatment.

[0633] In another aspect, the disclosure is directed to a sustained-release solid dosage form comprising free base of Compound 1 or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1 for use in treating a subject adult having moderately to severely active rheumatoid arthritis, the use comprising administering once daily to the subject, in particular a subject suffering from, or susceptible to, moderately to severely active rheumatoid arthritis, the extended-release solid dosage form, wherein the solid dosage form comprises about 7.5 mg or about 15 mg or about 30 mg or about 45 mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1 free base or a pharmaceutically acceptable salt thereof or solid state form of Compound 1 in an amount sufficient to provide the subject with about 7.5 mg or about 15 mg or about 30 mg or about 45 mg, per unit dosage form ( for example, per tablet or capsule), of equivalent free base of Compound 1, and a pharmaceutically acceptable polymeric carrier contributing substantially to modifying the release of the free base of Compound 1 or a pharmaceutically acceptable salt thereof or the form solid-state form of Compound 1, wherein the dosage form sustains release of the free base of Compound 1 or a pharmaceutically acceptable salt thereof or the solid-state form of Compound 1 for about 4 to about 24 hours following entry of the dosage form in an environment of use, wherein the dosage form has a release rate of no more than about 60% after about 4 hours have passed following said entry into said environment of use. In one embodiment, the dosage form comprises about 7.5 mg or about 15 mg or about 30 mg or about 45 mg, per unit dosage form (e.g., per tablet or capsule) in an in-state form. solid of Compound 1. 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 Free Base Anhydrous Form D. In one embodiment, the solid state form is Tartrate Hydrate. In one embodiment, the dosage form further has a release rate of about 50% to about 80% after about 8 hours following entry of the dosage form into an environment of use, from about 55% to about 80%. about 90% after about 10 hours pass after the dosage form enters a use environment, and/or about 70% to 100% after about 20 hours passes after the dosage form enters a a usage environment. In one embodiment, the subject has symptoms selected from the group consisting of at least 6 swollen joints, at least 6 tender joints, and combinations thereof prior to treatment.

[0634] In one embodiment, the disclosure is directed to a method of treating structural damage associated with rheumatoid arthritis in an adult subject, the method comprising administering once daily to the subject, in particular a human subject suffering from, or susceptible to, rheumatoid arthritis, of an extended-release solid dosage form comprising about 7.5 mg or about 15 mg or about 30 mg or about 45 mg, per unit dosage form (e.g., per tablet or capsule), free base of Compound 1 or a pharmaceutically acceptable salt thereof or the solid state form of Compound 1 in an amount sufficient to provide the subject with about 7.5 mg or about 15 mg or about 30 mg or about 45 mg, per unit dosage form (e.g., per tablet or capsule), of free base equivalent of Compound 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable polymeric carrier substantially contributing to modification of release of free base of Compound 1 or a pharmaceutically acceptable salt thereof or the solid state form of Compound 1, wherein the dosage form sustains the release of the free base of Compound 1 or a pharmaceutically acceptable salt thereof or the solid state form of the Compound 1 for about 4 to about 24 hours following entry of the dosage form into a use environment, wherein the dosage form has a release rate of no more than about 60% after about 4 hours pass to said entry into said use environment. In one embodiment, the dosage form comprises about 7.5 mg or about 15 mg or about 30 mg or about 45 mg, per unit dosage form (e.g., per tablet or capsule) in a form solid state form of Compound 1. 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 Free Base Anhydrous Form D. In one embodiment, the solid state form is Tartrate Hydrate. In one embodiment, the dosage form further has a release rate of about 50% to about 80% after about 8 hours following entry of the dosage form into an environment of use, from about 55% to about 80%. about 90% after about 10 hours pass after the dosage form enters a use environment, and/or about 70% to 100% after about 20 hours passes after the dosage form enters a a usage environment.

[0635] In another aspect, the disclosure is directed to a sustained-release solid dosage form comprising free base of Compound 1 or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1 for use in treating structural damage associated with rheumatoid arthritis in an adult subject, the use comprising administering once daily to the subject, in particular a subject suffering from, or susceptible to, structural damage associated with rheumatoid arthritis, the extended-release solid dosage form, wherein the solid dosage form comprises about 7.5 mg or about 15 mg or about 30 mg or about 45 mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1 free base or a pharmaceutically acceptable salt thereof or solid state form of Compound 1 in an amount sufficient to provide the subject with about 7.5 mg or about 15 mg or about 30 mg or about 45 mg, per unit dosage form ( for example, per tablet or capsule), of equivalent free base of Compound 1, and a pharmaceutically acceptable polymeric carrier contributing substantially to modifying the release of the free base of Compound 1 or a pharmaceutically acceptable salt thereof or the solid state form of the Compound 1, wherein the dosage form sustains release of the free base of Compound 1 or a pharmaceutically acceptable salt thereof or the solid state form of Compound 1 for about 4 to about 24 hours following entry of the dosage form in an environment of use, wherein the dosage form has a release rate of no more than about 60% after about 4 hours have passed following said entry into said environment of use. In one embodiment, the dosage form comprises about 7.5 mg or about 15 mg or about 30 mg or about 45 mg, per unit dosage form (e.g., per tablet or capsule) in a form solid state form of Compound 1. 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 Free Base Anhydrous Form D. In one embodiment, the solid state form is Tartrate Hydrate. In one embodiment, the dosage form further has a release rate of about 50% to about 80% after about 8 hours following entry of the dosage form into an environment of use, from about 55% to about 80%. about 90% after about 10 hours pass after the dosage form enters a use environment, and/or about 70% to 100% after about 20 hours passes after the dosage form enters a a usage environment.

[0636] In one embodiment, the disclosure is directed to a method of reducing signs and symptoms of rheumatoid arthritis in an adult subject, the method comprising administering once daily to the subject, in particular a human subject suffering from , or susceptible to, moderately to severely active rheumatoid arthritis, of an extended-release solid dosage form comprising about 7.5 mg or about 15 mg or about 30 mg or about 45 mg, per dosage form unit (e.g., per tablet or capsule) of free base of Compound 1 or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1 in an amount sufficient to provide the subject with about 7.5 mg or about of 15 mg or about 30 mg or about 45 mg, per unit dosage form (e.g., per tablet or capsule), of free base equivalent of Compound I, and a pharmaceutically acceptable polymeric carrier contributing substantially to the modification of release of the free base of Compound 1 or a pharmaceutically acceptable salt thereof or the solid state form of Compound 1, wherein the dosage form sustains the release of the free base of Compound 1 or a pharmaceutically acceptable salt thereof or the solid state form of Compound 1 for about 4 to about 24 hours following entry of the dosage form into an environment of use, wherein the dosage form has a release rate of no more than about 60% after passing through approximately 4 hours following said entry into said use environment. In one embodiment, the dosage form comprises about 7.5 mg or about 15 mg or about 30 mg or about 45 mg, per unit dosage form (e.g., per tablet or capsule) in an in-state form. solid of Compound 1. 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 Free Base Anhydrous Form D. In one embodiment, the solid state form is Tartrate Hydrate. In one embodiment, the dosage form further has a release rate of about 50% to about 80% after about 8 hours following entry of the dosage form into an environment of use, from about 55% to about 80%. about 90% after about 10 hours pass after the dosage form enters a use environment, and/or about 70% to 100% after about 20 hours passes after the dosage form enters a a usage environment.

[0637] In another aspect, the disclosure is directed to a sustained-release solid dosage form comprising free base of Compound 1 or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1 for use in reducing signs and symptoms. symptoms associated with rheumatoid arthritis in an adult subject, the use comprising administering once daily to the subject, in particular a subject suffering from, or susceptible to, rheumatoid arthritis, the extended-release solid dosage form, wherein the Solid dosage comprises about 7.5 mg or about 15 mg or about 30 mg or about 45 mg, per unit dosage form (e.g., per tablet or capsule), of free base of Compound 1 or a salt thereof. pharmaceutically acceptable or solid state form of Compound 1 in an amount sufficient to provide the subject with about 7.5 mg or about 15 mg or about 30 mg or about 45 mg, per unit dosage form (e.g., per tablet or capsule), of equivalent free base of Compound 1, and a pharmaceutically acceptable polymeric carrier contributing substantially to modifying the release of the free base of Compound 1 or a pharmaceutically acceptable salt thereof or the solid state form of Compound 1, wherein the dosage form sustains release of the free base of Compound 1 or a pharmaceutically acceptable salt thereof or the solid state form of Compound 1 for about 4 to about 24 hours following entry of the dosage form into an environment of use, wherein the dosage form has a release rate of no more than about 60% after about 4 hours have passed following said entry into said environment of use. In one embodiment, the dosage form comprises about 7.5 mg or about 15 mg or about 30 mg or about 45 mg, per unit dosage form (e.g., per tablet or capsule) in an in-state form. solid of Compound 1. 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 Free Base Anhydrous Form D. In one embodiment, the solid state form is Tartrate Hydrate. In one embodiment, the dosage form further has a release rate of about 50% to about 80% after about 8 hours following entry of the dosage form into an environment of use, from about 55% to about 80%. about 90% after about 10 hours pass after the dosage form enters a use environment, and/or about 70% to 100% after about 20 hours passes after the dosage form enters a a usage environment.

[0638] In prior methods, in one embodiment, the pharmaceutically acceptable polymeric carrier comprises a release control polymer. In one embodiment, the release controlling polymer is hydroxypropylmethyl cellulose. In one embodiment, the dosage form comprises a pH modifier. In one embodiment, the pH modifier is tartaric acid. In one embodiment, the dosage form comprises from about 10% w/w to about 35% w/w tartaric acid. In one embodiment, the dosage form comprises about 10% w/w tartaric acid. In one embodiment, the dosage form comprises about 20% w/w tartaric acid. In one embodiment, the dosage form comprises about 30% w/w tartaric acid.

[0639] In another embodiment, the methods of the present disclosure further comprise administering Compound 1 or a solid state form thereof for at least 8 weeks. In another embodiment, the methods of the present disclosure comprise administering Compound 1 or a solid state form thereof for at least 12 weeks.

[0640] In another embodiment, the present disclosure relates to the use of a solid state form of Compound 1 to treat a condition as described in various embodiments of the present disclosure.

[0641] In another embodiment, the present disclosure relates to a solid state form of Compound 1 for use in treating a condition as described in various embodiments of the present disclosure.

V. Combination Therapy and Fixed Dose Combinations

[0642] The present disclosure further relates to (i) treatment methods and uses as previously described which further comprise the administration of one or more additional therapeutic agents (i.e., combination therapies), and (ii) pharmaceutical compositions as previously described which further comprise one or more additional therapeutic agents (i.e., fixed dose combinations). When administered to a subject in combination with one or more additional therapeutic agents, the solid state form of Compound 1 and the additional therapeutic agent(s) may be administered as separate dosage forms or as a single dosage form comprising the solid state form of Compound 1 and the additional therapeutic agent(s). If administered as a separate dosage form, the additional therapeutic agent may be administered simultaneously or sequentially with the dosage form comprising the solid state form of Compound 1.

[0643] For example, the solid state forms of the present disclosure can be administered in a pharmaceutically acceptable form alone or in combination with one or more additional agents that modulate a mammal's immune system or with anti-inflammatory agents. These agents may include, but are not limited to, cyclosporin A (e.g., SANDIMMUNE® or NEORAL®, rapamycin, FK-506 (tacrolimus), leflunomide, deoxyspergualin, mycophenolate (e.g., CELLCEPT®), azathioprine (e.g., e.g., IMURAN®), daclizumab (e.g., ZENAPAX®), OKT3 (e.g., ORTHOCLONE®), AtGam, aspirin, acetaminophen, aminosalicylate, ciprofloxacin, corticosteroid, metronidazole, probiotic, tacrolimus, ibuprofen, naproxen, piroxicam and anti-inflammatory steroids (e.g., prednisolone or dexamethasone). In certain embodiments, the one or more additional agents are selected from the group consisting of aspirin, acetaminophen, aminosalicylate, ciprofloxacin, corticosteroid, cyclosporine, metronidazole, probiotic, tacrolimus, ibuprofen). , naproxen, piroxicam, prednisolone, dexamethasone, anti-inflammatory steroid, methotrexate, chloroquine, azathioprine, hydroxychloroquine, penicillamine, sulfasalazine, leflunomide, tocilzumab, anakinra, abatacept, Certolizumab pegol, golimumab, vedolizumab, natalizumab, ustekinumab, , efalizumab , belimumab, etanercept, infliximab, adalimumab and immunomodulator (e.g. activator) for CD4+CD25+ Treg cells.

[0644] Non-limiting examples of therapeutic agents for rheumatoid arthritis with which a compound of the invention can be combined include the following: cytokine suppressive anti-inflammatory drug(s) (CSAIDs); antibodies to or antagonists of other human cytokines or growth factors, e.g., TNF, LT, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL- 8, IL-12, IL-15, IL-16, IL-21, IL-23, interferons, EMAP-II, GM-CSF, FGF and PDGF. The compounds of the invention can be combined with antibodies to cell surface molecules such as CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD80 (B7.1), CD86 (B7.2), CD90, CTLA or their ligands including CD154 (gp39 or CD40L). Combinations of therapeutic agents can interfere at different points in autoimmunity and the subsequent inflammatory cascade. Such examples may include TNF antagonists such as chimeric, humanized or human TNF antibodies, adalimumab (brand name adalimumab HUMIRA™), infliximab such as CA2 (brand name infliximab REMICADE™), golimumab such as SIMPONI™ (golimumab), Certolizumab pegol such as CIMZIA™, tocilizumab such as ACTEMRA™, CDP 571, and soluble TNF receptors p55 or p75, derivatives thereof, etanercept such as p75TNFR1gG (brand name etanercept ENBREL™) or p55TNFR1gG (lenercept) and also TNFα-converting enzyme (TACE) inhibitors; Similarly IL-1 inhibitors (interleukin-1 converting enzyme inhibitors, IL-1RA etc.) may be effective for the same reason. Other combinations include Interleukin 11.

[0645] The solid state form can also be combined with non-biological DMARDS or other agents, such as methotrexate, 6-mercaptopurine, azathioprine, sulfasalazine, mesalazine, olsalazine, chloroquinine / hydroxychloroquine, pencilamine, aurothiomalate (intramuscular and oral), azathioprine , colchicine, corticosteroids (oral, inhaled and local injection), beta-2 adrenoreceptor agonists (salbutamol, terbutaline, salmeteral), xanthines (theophylline, aminophylline), cromolyn, nedocromil, ketotifen, ipratropium and oxitropium, cyclosporine, FK506, rapamycin, mycophenolate mofetil, leflunomide, NSAIDs, e.g. ibuprofen, corticosteroids such as prednisolone, phosphodiesterase inhibitors, adenosine agonists, antithrombotic agents, complement inhibitors, adrenergic agents, agents that interfere with pro-cytokine signaling. inflammatory drugs such as IL-1 (e.g., NIK, IKK, p38 or MAP kinase inhibitors), IL-1 β-converting enzyme inhibitors, T cell signaling inhibitors such as kinase inhibitors, metalloproteinase inhibitors, sulfasalazine, 6-mercaptopurines. The solid state form can also be combined with methotrexate.

[0646] Non-limiting examples of therapeutic agents for inflammatory bowel disease (IBD) with which the solid state form can be combined may include (but are not limited to) the following: budenoside; epidermal growth factor; corticosteroids; cyclosporine, sulfasalazine; aminosalicylates; 6-mercaptopurine; azathioprine; metronidazole; lipoxygenase inhibitors; mesalamine; ol- salazine; balsalazide; antioxidants; thromboxane inhibitors; IL-1 receptor antagonists; anti-IL-1 β monoclonal antibodies; anti-IL-6 monoclonal antibodies; growth factors; elastase inhibitors; pyridinyl-imidazole compounds; antibodies to or antagonists of other human cytokines or growth factors, e.g., TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-15, IL- 16, IL-23, EMAP-II, GM-CSF, FGF, and PDGF; cell surface molecules such as CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD90 or their ligands; methotrexate; cyclosporin; FK506; rapamycin; mycophenolate mofetil; leflunomide; NSAIDs, e.g. ibuprofen; corticosteroids such as prednisolone; phosphodiesterase inhibitors; adenosine agonists; antithrombotic agents; complement inhibitors; adrenergic agents; agents that interfere with pro-inflammatory cytokine signaling, such as TNFa or IL-1 (e.g., NIK, IKK or MAP kinase inhibitors); IL-1 β-converting enzyme inhibitors; TNFa-converting enzyme inhibitors; inhibitors of T cell signaling such as kinase inhibitors; metalloproteinase inhibitors; sulfasalazine; azathioprine; 6-mercaptopurines; angiotensin-converting enzyme inhibitors; soluble cytokine receptors and their derivatives (e.g., soluble p55 or p75 TNF receptors, sIL-1RI, sIL-1RII, sIL-6R) and anti-inflammatory cytokines (e.g., IL-4, IL-10, IL- 11, IL-13 and TGFβ). The solid state form can also be combined with methotrexate.

[0647] Examples of therapeutic agents for Crohn's disease with which the solid state form can be combined include the following: TNF antagonists, for example anti-TNF antibodies, adalimumab (as adalimumab brand name HUMIRA™), infliximab as CA2 ( infliximab REMICADE™ brand), Certolizumab pegal as CIMZIA™, golimumab as SIMPONI™ (golimumab), CDP 571, TNFR-Ig constructs, etanercept as p75TNFRIgG (etanercept brand ENBREL™) and lenercept as p55TNFRIgG inhibitors (Lenercept™) and PDE4 inhibitors.

[0648] The solid state form can be combined with corticosteroids, for example, budenoside and dexamethasone; sulfasalazine, 5-aminosalicylic acid; olsalazine; and agents that interfere with the synthesis or action of pro-inflammatory cytokines such as IL-1, for example, IL-1 β and IL-1 ra converting enzyme inhibitors; inhibitors of T cell signaling, for example, tyrosine kinase inhibitors; 6-mercaptopurine; IL-11; mesalamine; prednisone; azathioprine; mercaptopurine; methylprednisolone sodium succinate; diphenoxylate/atrop sulfate; loperamide hydrochloride; methotrexate; omeprazole; folate; ciprofloxacin/dextrose-water; hydrocodone bitartrate/apap; tetracycline hydrochloride; fluocinonide; metronidazole; thimerosal/boric acid; cholestyramine/sucrose; ciprofloxacin hydrochloride; hyoscyamine sulfate; meperidine hydrochloride; midazolam hydrochloride; oxycodone HCl/acetaminophen; promethazine hydrochloride; sodium phosphate; sulfamethoxazole/trimethoprim; celecoxib; polycarbophil; propoxyphene napsilate; hydrocortisone; multivitamins; disodium balsalazide; codeine phosphate/apap; colesevelam HCl; cyanocobalamin; folic acid; levofloxacin; methylprednisolone; natalizumab and interferon-gamma.

[0649] Non-limiting examples of therapeutic agents for multiple sclerosis (MS) with which the solid state form can be combined include the following: corticosteroids; prednisolone; methylprednisolone; azathioprine; cyclophosphamide; cyclosporine; methotrexate; 4-aminopyridine; tizanidine; interferon-β1a (AVONEX®; Biogen); interferon-βlb (BETASERON®; Chiron/Berlex); interferon α-n3) (Interferon Sciences/Fujimoto), interferon-a (Alfa Wassermann/J&J), interferon β1A-IF (Serono/Inhale Therapeutics), Peginterferon α 2b (Enzon/Schering-Plough), Co-polymer 1 (Cop -1; COPAXONE®; Teva Pharmaceutical Industries, Inc.); hyperbaric oxygen; intravenous immunoglobulin; cladribine; antibodies to or antagonists of other human cytokines or growth factors and their receptors, e.g., TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-23 , IL-15, IL-16, EMAP-II, GM-CSF, FGF and PDGF. A compound of the invention can be combined with antibodies to cell surface molecules such as CD2, CD3, CD4, CD8, CD19, CD20, CD25, CD28, CD30, CD40, CD45, CD69, CD80, CD86, CD90 or their ligands. The solid state form can also be combined with agents such as methotrexate, cyclosporine, FK506, rapamycin, mycophenolate mofetil, leflunomide, an S1P1 agonist, NSAIDs, e.g. ibuprofen, corticosteroids such as prednisolone, phosphodiesterase inhibitors, adenosine agonists. , antithrombotic agents, complement inhibitors, adrenergic agents, agents that interfere with signaling by pro-inflammatory cytokines such as TNFα or IL-1 (e.g., NIK, IKK, p38, or MAP kinase inhibitors), IL-converting enzyme inhibitors 1 β, TACE inhibitors, T-cell signaling inhibitors such as kinase inhibitors, metalloproteinase inhibitors, sulfasalazine, azathioprine, 6-mercaptopurines, angiotensin-converting enzyme inhibitors, soluble cytokine receptors and their derivatives (e.g. soluble p55 or p75 TNF receptors, sIL-1RI, sIL-1RII, sIL-6R) and anti-inflammatory cytokines (e.g., IL-4, IL-10, IL-13 and TGFβ). Examples of therapeutic agents for multiple sclerosis with which a compound of the invention can be combined include interferon-β, for example, IFNβ1a and IFNβ1b; copaxone, corticosteroids, caspase inhibitors, for example, caspase-1 inhibitors, IL-1 inhibitors, TNF inhibitors, and antibodies to CD40 and CD80 ligand.

[0650] The solid state form can also be combined with agents such as alemtuzumab, dronabinol, daclizumab, mitoxantrone, xaliproden hydrochloride, fampridine, glatiramer acetate, natalizumab, sinabidol, α-immunocin NNSO3, ABR- 215062, AnergiX.MS , chemokine receptor antagonists, BBR-2778, calagualin, CPI-1189, LEM (liposome-encapsulated mitoxantrone), THC.CBD (cannabinoid agonist), MBP-8298, mesopram (PDE4 inhibitor), MNA -715, anti-IL-6 receptor antibody, neurovax, pirfenidone allotrap 1258 (RDP-1258), sTNF-R1, talampanel, teriflunomide, TGF-beta2, tiplimotide, VLA-4 antagonists (e.g., TR-14035, VLA4 Ultrahaler , Antegran-ELAN/Biogen), interferon gamma antagonists and IL-4 agonists.

[0651] Non-limiting examples of therapeutic agents for ankylosing spondylitis (AS) with which the solid state form can be combined include the following: ibuprofen, diclofenac, misoprostol, naproxen, meloxicam, indomethacin, diclofenac, celecoxib, rofecoxib, sulfasalazine, methotrexate, azathioprine, minocycline, prednisone, and anti-TNF antibodies, adalimumab (brand name adalimumab HUMIRA™), infliximab as CA2 (brand name infliximab REMICADE™), CDP 571, TNFR-Ig constructs, etanercept as p75TNFRIgG (brand name etanercept ENBREL™) and lenercept as p55TNFRIgG (LENERCEPT™).

[0652] Non-limiting examples of therapeutic agents for psoriasis (Ps, such as moderate to severe plaque psoriasis) with which the solid state form can be combined include the following: calcipotriene, clobetasol propionate, triamcinolone acetonide, propionate halobetasol, tazarotene, methotrexate, fluocinonide, betamethasone increased diprop, fluocinolone acetonide, acitretin, tar shampoo, betamethasone valerate, mometasone furoate, ketoconazole, pramoxine/fluocinolone, hydrocortisone valerate, flurandrenolide, urea, betamethasone, propionate clobetasol/emol, fluticasone propionate, azithromycin, hydrocortisone, moisturizing formula, folic acid, desonide, pimecrolimus, mineral tar, diflorasone diacetate, etanercept folate, lactic acid, methoxsalen, bismuth hc/subgal /znox/resor, methylprednisolone acetate, prednisone, sunscreen, halcinonide, salicylic acid, anthralin, clocortolone pivalate, coal extract, mineral tar/salicylic acid, mineral tar/salicylic acid/sulfur, desoximethasone, diazepam, emollient , fluocinonide/emollient, mineral oil/castor oil/na lact, mineral oil/peanut oil, petroleum/isopropyl myristate, psoralen, salicylic acid, soap/tribromsalan, thimerosal/boric acid, celecoxib, infliximab, cyclosporine, alefa -cept, efalizumab, tacrolimus, pimecrolimus, PUVA, UVB, sulfasalazine, ABT-874, ustekinamab and adalimumab (brand name adalimumab HUMIRA™).

[0653] Non-limiting examples of therapeutic agents for psoriatic arthritis (PsA) with which the solid state form can be combined include the following: methotrexate, etanercept, rofecoxib, celecoxib, folic acid, sulfasalazine, naproxene, leflunomide, acetate methylprednisolone, indomethacin, hydroxychloroquine sulfate, prednisone, sulindac, betamethasone increased diprop, infliximab, methotrexate, folate, triamcinolone acetonide, diclofenac, dimethylsulfoxide, piroxicam, diclofenac sodium, ketoprofen, meloxicam, methylprednisolone, nabumetone, tolmetin only - tip, calcipotriene, cyclosporine, diclofenac sodium/misoprostol, fluocinonide, glucosamine sulfate, gold sodium thiomalate, hydrocodone bitartrate/apap, ibuprofen, risedronate sodium, sulfadiazine, thioguanine, valdecoxib, alefacept, adalimumab (brand name adalimumab HUMIRA™) and efalizumab.

[0654] Examples of therapeutic agents for SLE (lupus) with which the solid state form can be combined include the following: NSAIDS, for example, diclofenac, naproxen, ibuprofen, piroxicam, indomethacin; COX2 inhibitors, e.g. celecoxib, rofecoxib, valdecoxib; antimalarials, for example, hydroxychloroquine; steroids, e.g. prednisone, prednisolone, budenoside, dexamethasone; cytotoxics, for example, azathioprine, cyclophosphamide, mycophenolate mofetil, methotrexate; PDE4 inhibitors or purine synthesis inhibitor, for example CELLCEPT®. A solid state form can also be combined with agents such as sulfasalazine, 5-aminosalicylic acid, olsalazine, IMURAN® and agents that interfere with the synthesis, production or action of pro-inflammatory cytokines such as IL-1, e.g. caspases as IL-1β and IL-1ra converting enzyme inhibitors. The solid state form can also be used with inhibitors of T cell signaling, for example, tyrosine kinase inhibitors; or molecules that target T cell activation molecules, e.g. CTLA-4-IgG or anti-B7 family antibodies, anti-PD-1 family antibodies. The solid state form can be combined with IL-11 or anti-cytokine antibodies, e.g., fonotolizumab (anti-IFNg antibody), or anti-receptor antibodies, e.g., anti-IL-6 receptor antibody and antibodies to cell surface molecules. B. The solid state form can also be used with LJP 394 (abetimus), agents that deplete or inactivate B cells, e.g., Rituximab (anti-CD20 antibody), lymphostat-B (anti-BlyS antibody), TNF antagonists, for example, anti-TNF antibodies, adalimumab (brand name adalimumab HUMIRA™), infliximab as CA2 (brand name infliximab REMICADE™), CDP 571, TNFR-Ig constructs, etanercept as p75TNFRIgG (brand name etanercept ENBREL™) and lenercept as p55TNFRIgG (LENERCEPT ™).

[0655] The solid state form can also be combined with a CD4+CD25+ Treg cell immunomodulator. Treg cells are essential for maintaining normal immune homeostasis. In patients with autoimmune diseases, a reduced number or functional incapacity of Treg cells has been observed, leading to the loss of this finely tuned mechanism. A humanized agonistic monoclonal antibody, BT-061, binds to a unique epitope of human CD4, and induces Treg-specific signaling events that lead to its functional activation. Preclinical data using isolated Treg cells and rheumatoid arthritis synovial fluid indicate that BT-061 leads to suppression of CD4+ and CD8+ T effector cell proliferation, reduced expression of pro-inflammatory cytokines, and increased production of the anti-inflammatory cytokine. inflammatory TGFβ. Thus, similar immunomodulators for CD4+CD25+ Treg cells may also be co-administered with a compound of the invention to treat any of the inflammatory diseases/disorders, or an autoimmune disease/disorder described herein, including, but not limited to, rheumatoid arthritis, Crohn's disease, ankylosing spondylitis, psoriatic arthritis, psoriasis, ulcerative colitis, systemic lupus erythematosus, lupus nephritis, diabetic nephropathy, dry eye syndrome, Sjogren's syndrome, alopecia areata, vitiligo or atopic dermatitis. In certain embodiments, the combination treats rheumatoid arthritis, Crohn's disease, psoriasis, or psoriatic arthritis, including moderately to severely active rheumatoid arthritis, Crohn's disease, psoriasis, or psoriatic arthritis. In certain embodiments, the patient with rheumatoid arthritis, Crohn's disease, or psoriatic arthritis being treated has responded inadequately or has therapy discontinued due to loss of response or intolerance to a first-line therapy (such as a DMARD, including methotrexate) or an anti-TNFα therapy.

[0656] In certain embodiments, the immunomodulator has one or more (or all) of the following properties: (1) activates a subset of CD4+ T cells comprising CD4+CD25+ regulatory T cells (Treg), or CD4 Treg cells +CD25+; (2) binds only to a special epitope of the human CD4 antigen (such as the IgG type 1 C2 domain of CD4), this epitope of human CD4 that can be bound by an anti-CD4 monoclonal B-F5 antibody IgG1 or a humanized version thereof, such as the hB-F5 antibody BT-061 tregalizumab as described in U.S. Pat. U.S. No. 7,452,981 (incorporated herein by reference, including all VH and VL chain sequences disclosed therein); (3) provides an activation signal to naturally occurring Treg cells but does not activate conventional T cells (e.g., CD4+ T cells that are not activated in (1), CD8+ cytotoxic T cells, etc.); and (4) is not a depleting anti-CD4 antibody that depletes CD4+ T cells, and/or does not appreciably trigger ADCC or CDC.

SAW. Pharmaceutical Compositions

[0657] The present disclosure further relates, in part, to compositions comprising Compound 1 or a pharmaceutically acceptable salt thereof, or one or more solid state forms of Compound 1. Although the solid state form may be administered alone or in the form of a pharmaceutical composition, administration will generally occur in the form of a pharmaceutical composition. In some embodiments, the composition comprises Compound 1 or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1 in association with a pharmaceutically acceptable carrier. The preferred composition depends on the method of administration, and typically comprises one or more pharmaceutically acceptable vehicles, adjuvants and/or carriers (collectively referred to as “excipients”). Such compositions may be formulated for various routes of systemic or local delivery, for example by oral administration, topical administration, transmucosal administration, rectal administration, intravaginal administration, or administration by subcutaneous, intrathecal, intravenous, intramuscular, intraperitoneal, intranasal, intraocular or intraventricular.

[0658] Solid dosage forms for oral administration include, for example, capsules, tablets, pills, powders and granules. In such solid dosage forms, the compounds or salts are normally combined with one or more excipients. If administered orally, the compounds or salts may be mixed with, for example, lactose, sucrose, starch powder, cellulose esters of alkanoic acids, alkyl esters of cellulose, talc, stearic acid, magnesium stearate, oxide of magnesium, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, gum acacia, sodium alginate, polyvinylpyrrolidone and/or polyvinyl alcohol and then processed into tablets or encapsulated for convenience of administration. Such capsules or tablets may contain a controlled release formulation, as may be provided in, for example, a compound or salt dispersion in hydroxypropylmethyl cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise pH modifiers such as sodium citrate; magnesium or calcium carbonate or bicarbonate; tartaric acid, fumaric acid, citric acid, succinic acid, malic acid and phosphoric acid and combinations thereof. Tablets and pills can additionally be prepared with enteric coatings.

[0659] Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions (including oil-in-water and water-in-oil emulsions), solutions (including aqueous and non-aqueous solutions), suspensions (including aqueous and non-aqueous suspensions), syrups and elixirs containing inert diluents commonly used in the art (e.g. water). Such compositions may also comprise, for example, wetting, emulsifying, suspending, sweetening and flavoring agents.

[0660] Parenteral administration includes subcutaneous injections, intravenous injections, intramuscular injections, intrasternal injections and infusion. Injectable preparations (e.g., aqueous or oleaginous injectable sterile suspensions) may be formulated in accordance with known art using dispersing agents, wetting agents and/or suspending agents. Acceptable vehicles and solvents include, for example, water, 1,3-butanediol, Ringer's solution, isotonic sodium chloride solution, bland fixed oils (e.g., synthetic mono- or diglycerides), fatty acids (e.g., oleic acid). ), dimethyl acetamide, surfactants (for example, ionic and non-ionic detergents), and/or polyethylene glycols.

[0661] Formulations for parenteral administration can, for example, be prepared from sterilized powders or granules having one or more excipients mentioned for use in formulations for oral administration. A compound or salt of the invention can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride and/or various salt modifiers. pH. The pH can be adjusted, if necessary, with a suitable acid, base or pH modifier.

[0662] Suppositories for rectal administration can be prepared by example, mixing a compound or salt of the invention with a suitable non-irritating excipient which is solid at normal temperatures, but liquid at rectal temperature, and will therefore melt in the rectum to release the drug. Suitable excipients include, for example, cocoa butter, synthetic mono-, di- or triglycerides, fatty acids and/or polyethylene glycols.

[0663] Compound 1 or the solid state forms of the present disclosure can be formulated for topical administration to the skin or mucosa, that is, in dermal or transdermal form. Such administration may include the use, for example, of transdermal patches or iontophoresis devices.

[0664] In addition to the representative dosage forms described above, pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are thus included in the present invention. Drug formulation is generally discussed in, for example, Hoover, J., Remington's Pharmaceutical Sciences (Mack Publishing Co., 1975) and Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems (Lippincott Williams & Wilkins, 2005).

[0665] Depending on the route and frequency of administration, the pharmaceutical compositions of the present invention may contain, for example, from about 0.1 percent by weight to about 99 percent or more by weight of the active ingredient. The amount of active ingredient contained in the dosage unit composition employed for adult treatment may generally be in the range of, for example, about 0.01 mg to about 3000 mg. For the therapeutic uses described in this application, the amount of active ingredient contained in the unit dosage composition will generally be in the range of, for example, about 0.1 mg to about 1000 mg. In one embodiment, the amount of active ingredient contained in the dosage unit composition is in the range of about 1 mg to about 500 mg. In another embodiment, the amount of active ingredient contained in the dosage unit composition is in the range of about 1 mg to about 250 mg. In another embodiment, the amount of active ingredient contained in the dosage unit composition is in the range of about 1 mg to about 100 mg. In another embodiment, the amount of active ingredient contained in the dosage unit composition is in the range of about 1 mg to about 50 mg. In another embodiment, the amount of active ingredient contained in the dosage unit composition is in the range of about 1 mg to about 45 mg. In another embodiment, the amount of active ingredient contained in the dosage unit composition is in the range of about 1 mg to about 30 mg. In another embodiment, the amount of active ingredient contained in the dosage unit composition is in the range of about 1 mg to about 25 mg. In another embodiment, the amount of active ingredient contained in the dosage unit composition is in the range of about 1 mg to about 24 mg. In another embodiment, the amount of active ingredient contained in the dosage unit composition is in the range of about 1 mg to about 15 mg. In another embodiment, the amount of active ingredient contained in the dosage unit composition is in the range of about 1 mg to about 10 mg. In another embodiment, the amount of active ingredient contained in the dosage unit composition is in the range of about 1 mg to about 7.5 mg. In another embodiment, the amount of active ingredient contained in the dosage unit composition is in the range of about 10 mg to about 20 mg. In another embodiment, the amount of active ingredient contained in the dosage unit composition is in the range of about 20 mg to about 30 mg. In another embodiment, the amount of active ingredient contained in the dosage unit composition is in the range of about 30 mg to about 40 mg. In another embodiment, the amount of active ingredient contained in the dosage unit composition is in the range of about 7.5 mg to about 45 mg. In another embodiment, the amount of active ingredient contained in the dosage unit composition is in the range of about 15 mg to about 30 mg. In another embodiment, the amount of active ingredient contained in the dosage unit composition is about 3 mg. In another embodiment, the amount of active ingredient contained in the dosage unit composition is about 6 mg. In another embodiment, the amount of active ingredient contained in the dosage unit composition is about 7.5 mg. In another embodiment, the amount of active ingredient contained in the dosage unit composition is about 12 mg. In another embodiment, the amount of active ingredient contained in the dosage unit composition is about 15 mg. In another embodiment, the amount of active ingredient contained in the dosage unit composition is about 18 mg. In another embodiment, the amount of active ingredient contained in the dosage unit composition is about 24 mg. In another embodiment, the amount of active ingredient contained in the dosage unit composition is about 30 mg. In another embodiment, the amount of active ingredient contained in the dosage unit composition is about 36 mg. In another embodiment, the amount of active ingredient contained in the dosage unit composition is about 45 mg.

[0666] In one embodiment, the active ingredient contained in the dosage unit composition is Compound 1 or a pharmaceutically acceptable salt thereof. In one embodiment, the target or label amount of active ingredient (e.g., Compound 1) provided for inclusion in the compositions of the present disclosure relates to the amount of free base of Compound 1. For example, as discussed herein, the Compound 1 can be prepared in various solid state forms including Amorphous Free Base, crystalline solvates and hydrates (e.g. Free Base Solvate Form A, Free Base Hydra Form B), crystalline hemihydrates (e.g. Form C of Free Base Hydrate), crystalline anhydrous (e.g. Form D of Free Base Anhydrous), crystalline tartrate (e.g. Tartrate Hydrate), crystalline hydrochloride (e.g. Form AA of Hydrochloride Solvate, Form BB of Hydrochloride Solvate, CC Form Hydrochloride Solvate) and crystalline L-maleate (e.g., AAA Form of L-Maleate, BBB Form of L-Maleate, CCC Form of L-Maleate). It should be understood that in embodiments wherein the dosage unit composition comprises, for example, a solvate, hydrate, hemihydrate, tartrate, hydrochloride or L-maleate of Compound 1, the amount of solvate, hydrate, hemihydrate, tartrate, hydrochloride or L-maleate of Compound 1 present in the dosage unit composition may be slightly greater than the target amount of Compound 1 (active ingredient), and preferably will be present in the dosage unit composition in an amount sufficient to provide the target amount of free base equivalent of Compound 1 to a subject. For example, if the target amount of Compound 1 (active ingredient) in a dosage unit composition is 15 mg, a dosage unit composition comprising, for example, Free Base Hydrate Form C may comprise Hydrate Form C of Free Base in an amount sufficient to provide 15 mg of the free base equivalent of Compound 1.

[0667] In one embodiment, the pharmaceutical composition is a tablet dosage form. In one aspect, the tablet is coated with a pharmaceutically acceptable polymer.

[0668] In one embodiment, the tablet is a controlled-release formulation, such as a controlled-release dosage form (also referred to herein as a modified-release or sustained-release formulation). Such formulations allow for sustained release of the active ingredient over an extended period of time, as compared to immediate-release solid dosage forms, which allow for the release of most or all of the active ingredient over a short period of time ( for example, typically about 60 minutes or less). In one aspect, the tablet comprises an active ingredient and at least one additive selected from the group consisting of a release controlling polymer, a filler, a fluidizer, a lubricant (e.g., for use in compacting granules) , a pH modifier, a surfactant and combinations thereof. In one aspect, the tablet comprises an active ingredient, a release controlling polymer, a filler, a fluidizer, and a lubricant. In one aspect, the tablet comprises an active ingredient, a release controlling polymer, a filler, a fluidizer, a lubricant and a pH modifier.

[0669] In certain embodiments, the release control polymer will be a hydrophilic polymer. Examples of suitable release control polymers include, but are not limited to, a cellulose derivative with a viscosity between 1000 and 150,000 mPA-s, hydroxypropylmethyl cellulose (e.g., Hypromellose 2208 or controlled release grades of hydroxypropylmethyl cellulose, including series E, F and K), copolymers of acrylic acid cross-linked with a polyalkenyl polyether (e.g. Carbopol® polymers), hydroxypropyl cellulose, hydroxyethyl cellulose, non-ionic homopolymers of ethylene oxide (e.g. Polyox™ ), natural water-soluble gums of polysaccharides (e.g., xanthan gum, alginate, carob seed flour, etc.), cross-linked starch, polyvinyl acetates, polyvinylpyrrolidone, mixtures of polyvinyl acetates and polyvinylpyrrolidone, and combinations thereof. In one embodiment, the release controlling polymer is selected from the group consisting of hydroxypropylmethyl cellulose, acrylic acid copolymers cross-linked with a polyalkenyl polyether (e.g., Carbopol® polymers), and combinations thereof. Examples of suitable fillers ("bulking agents") include, but are not limited to, microcrystalline cellulose (e.g., Avicel® PH 101; Avicel® PH 102;), mannitol (e.g., Pearlitol® 100 SD or Pearlitol® 200 SD), lactose, sucrose, sorbitol, and the like. In one embodiment, the filler is selected from the group consisting of microcrystalline cellulose, mannitol and a combination thereof. Examples of suitable fluidizers include, but are not limited to, silicone dioxide (e.g., colloidal silicon dioxide), calcium silicate, magnesium silicate, talc and combinations thereof. In one embodiment, the fluidizer is colloidal silicon dioxide. Examples of suitable lubricants include, but are not limited to, polyethylene glycol (e.g., having a molecular weight of 1000 to 6000), magnesium and calcium stearates, sodium stearyl fumarate, talc and the like. In one embodiment, the lubricant is magnesium stearate. Examples of suitable pH modifiers include, but are not limited to, organic acids, such as tartaric acid, citric acid, succinic acid, fumaric acid; sodium citrate; magnesium or calcium carbonate or bicarbonate; and their combinations. In one embodiment, the pH modifier is tartaric acid. Examples of suitable surfactants include sodium lauryl sulfate.

[0670] In one embodiment, the pharmaceutical composition comprises from about 10% w/w to about 35% w/w of a pH modifier and in particular, tartaric acid, fumaric acid, citric acid, succinic acid, malic acid or their combinations. In other embodiments, the formulation comprises from about 20% w/w to about 35% w/w, or from about 20% w/w to about 30% w/w, or from about 20% w/w to about 25% w/w, or about 10% w/w, about 15% w/w, about 20% w/w, about 25% w/w or about 30% w/w pH modifier . In one embodiment, the pH modifier is tartaric acid.

[0671] As discussed herein, sustained peak plasma concentrations can be achieved through sustained release matrix systems. However, when such systems are made of hydrophilic polymers, such as HPMC, they rarely provide pH-independent drug release of pH-dependent soluble drugs, and are typically unable to achieve zero-order release except for practically insoluble drugs. . Unexpectedly, it has now been discovered that when a pH modifier, such as tartaric acid, fumaric acid, citric acid, succinic acid, malic acid or combinations thereof, is used in a hydrophilic sustained release matrix system, it allows the Compound 1 or a pharmaceutically acceptable salt or solid state form thereof are released at a constant rate regardless of the pH of the environment. In an unexpected discovery, it was discovered that as a tablet containing the hydrophilic polymer matrix system erodes, Compound 1 reacts with the HPMC, creating a thicker gel layer that slows the release of Compound 1 from the tablet. The resulting gel layer provides a suitable environment for the dissolution of Compound 1.

[0672] Thus, in one embodiment, the pharmaceutical composition of the present disclosure exhibits a pH-independent release of the active ingredient (Compound 1). Advantageously, it has been found that including organic acids, such as tartaric acid, in the composition as a pH modifier improves the release profile, and results in a pH-independent release of the active ingredient. Without wishing to be bound by any particular theory, it is believed that the pH modifier and hydrophilic polymer create a microenvironment in which the active ingredient dissolves, and is then released. Release from the microenvironment occurs at approximately the same rate regardless of pH. This is particularly advantageous since the pH of the gastrointestinal tract can vary significantly from the stomach (e.g., pH of about 1.5 to 3), to the duodenum (e.g., pH of about 4 to 5), to to the lower part of the small intestine (e.g. pH of about 6.5 to 7.5).

[0673] Thus, in one embodiment, the pharmaceutical composition is a sustained-release formulation comprising Compound 1, or a pharmaceutically acceptable salt or solid state form thereof, a hydrophilic polymer and a pH modifier, wherein the Hydrophilic polymer, in contact with water, forms a gel layer that provides a suitable environment for Compound 1, or a pharmaceutically acceptable salt or solid state form thereof, to dissolve. In some embodiments, the suitable environment for Compound 1, or a pharmaceutically acceptable salt or solid state form thereof to dissolve, has a pH equal to or less than about 3.8 at 37 °C. In some such embodiments, the environment has a pH of from about 1.5 to about 3.7, or from about 2.0 to about 3.7, or from about 2.5 to about 3.6. , or from about 3.0 to about 3.6, or from about 3.0 to about 3.5.

[0674] In such an embodiment, the suitable environment for Compound 1, or a pharmaceutically acceptable salt or solid state form thereof to dissolve is as set forth above, and the sustained release formulation comprises from about 10% w/w to about 35% w/w of a pH modifier, and in particular, tartaric acid, fumaric acid, citric acid, succinic acid, malic acid or combinations thereof. In other embodiments, the formulation comprises from about 20% w/w to about 35% w/w, or from about 20% w/w to about 30% w/w, or from about 20% w/w to about of 25% w/w, or about 10% w/w, about 15% w/w, about 20% w/w, about 25% w/w or about 30% w/w modifier pH. In any of these embodiments, the pH modifier may be selected from the group consisting of tartaric acid, fumaric acid, citric acid, succinic acid, malic acid, and combinations thereof. In such an embodiment, the pH modifier is selected from the group consisting of tartaric acid, fumaric acid, citric acid, succinic acid and combinations thereof. In one such embodiment, the pH modifier is selected from the group consisting of tartaric acid and fumaric acid. In one embodiment, the pH modifier is tartaric acid. In one embodiment, the pH modifier is fumaric acid or citric acid. The % by weight of tartaric acid presented here is by weight of the uncoated composition (e.g., uncoated tablet). In any of the above embodiments, the hydrophilic polymer may be a cellulose derivative with a viscosity between 1000 and 150,000 mPA-s. In one embodiment, the hydrophilic polymer is selected from the group consisting of hydroxypropylmethyl cellulose, hydroxyethyl cellulose, and mixtures and combinations thereof. In one embodiment, the hydrophilic polymer is hydroxypropylmethyl cellulose. In one embodiment, the hydrophilic polymer is hydroxypropylmethyl cellulose of grade E, F or K. In one embodiment, the hydrophilic polymer is Hypromellose 2208.

[0675] In one embodiment, the tablet is a compressed and/or ground tablet. For example, in some embodiments, the tablet is formed by mixing the composition components (e.g., including the active ingredient and at least one pharmaceutically acceptable carrier). The composition may be compressed directly or one or more of the components of the composition may be granulated prior to compression. In one embodiment, grinding is performed using a mill equipped with a suitable screen size (e.g., equipped with a screen size of about 600 to about 1400 μm or about 610 μm or about 1397 μm). Compression can be done in a tablet press, such as in a steel die between two moving punches.

[0676] In other embodiments, the compressed and/or ground tablet is formulated using a wet granulation process. The use of wet granulation reduces and/or eliminates stickiness that may occur when compression without wet granulation is used for tablet formulation (for example, direct compression). In one embodiment, the wet granulation process may include the following steps: (a) combining the active ingredient (e.g., Compound 1 or a pharmaceutically acceptable salt thereof, or a solid state form of Compound 1) and 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 ground granulated material; (e) combining the ground granulation material with the remaining composition components; and (f) compressing the composition to form the solid dosage unit (e.g., a tablet).

[0677] In step (a) of this process, the active ingredient can be combined with, for example, a portion of the release control polymer (e.g., HPMC), a portion of the filler (e.g., a microcrispy cellulose). - talin, such as Avicel® PH101), or the assembly of a release control polymer portion and a filler portion to form the dry granulation mixture. In step (a) any suitable portion of the release control polymer may be used. In one embodiment, in step (a) about 5 to 10% by weight or about 6 to 8% by weight of the total amount of release control polymer in the composition is used.

[0678] In certain embodiments, the granulation fluid used in step (b) may comprise water, a suitable solvent (e.g., ethanol, isopropanol, etc.) or combinations thereof. In one embodiment, the granulation fluid comprises water. In one embodiment, the active ingredient may be combined with a portion of the filler, while a portion of the release controlling polymer (e.g. HPMC) is dissolved in a liquid, such as water, to form the granulation fluid. In one embodiment, the granulation fluid is sprayed onto the dry granulation mixture.

[0679] The dry granulation material can be milled using, for example, a conical mill (comill) equipped with any suitable screen size. In one embodiment, the screen size is from about 600 to about 900 microns, or from about 610 to about 813 microns. In one embodiment, the granulated material is milled using a conical mill equipped with a 610 μm screen. In one embodiment, the granulated material is ground using a conical mill equipped with an 813 μm screen.

[0680] In step (e), the ground granulation material is combined with any remaining composition components, such as any remaining fillers (e.g., microcrystalline cellulose, such as Avicel® PH102), any polymers release control, fluidizers, lubricants, pH modifiers, surfactants and the like. In one embodiment, the filler and/or release controlling polymer included in the granulated material may be the same or different from the filler and/or release controlling polymer added in step (e). For example, in one embodiment, the filler included in the granulated material (e.g., Avicel®PH101) may have a smaller particle size distribution than the filler added in step (e) (e.g., Avicel® PH102).

[0681] In one embodiment, the composition may be sieved and the sieved composition may be mixed, for example after step (e) and before compression of the composition (step (f). In one embodiment, the formulation is sieved before adding any lubricant. In one embodiment, the pH modifier (e.g., tartaric acid) is optionally milled before combining with the granulated material.

[0682] In one embodiment, the present disclosure is directed to a process for preparing a pharmaceutical composition, the process comprising: (a) combining an active ingredient (e.g., Compound 1 or a pharmaceutically acceptable salt thereof, or a form solid state of Compound 1) and 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 ground granulated material; (e) combine the ground granulation material with the remaining composition components; and (f) compressing the composition to form the pharmaceutical composition. In one embodiment, the method further comprises optionally coating the pharmaceutical composition. In one embodiment, the disclosure is directed to a pharmaceutical composition prepared by this wet granulation process. In one embodiment, the pharmaceutical composition is a tablet. In one embodiment, the pH modifier (e.g., tartaric acid) is optionally ground before compression. In one embodiment, the solid state form is Free Base Hydrate Form C.

[0683] In some embodiments, the compressed and/or ground tablet comprises a crystalline solid state form of Compound 1. In one embodiment, the crystalline solid state form is a crystalline hydrate. In one embodiment, the crystalline solid state form is Free Base Hydrate Form C. Advantageously, it has been found that crystalline Free Base Hydrate Form C is stable to mechanical processing and presents minimal problems during milling. In other embodiments, the crystalline solid state form is an anhydrous crystalline. In one embodiment, the crystalline anhydrous is Free Base Anhydrous Form D

[0684] In some embodiments, the pharmaceutical composition is a compressed and/or ground tablet comprising Compound 1, wherein at least about 75% by weight of Compound 1 present in the tablet is Free Base Hydrate Form C. In one aspect, at least 80% by weight is Free Base Hydrate Form C. In another aspect, at least 85% by weight is Free Base Hydrate Form C. In another aspect, at least 90% by weight is Free Base Hydrate Form C. In another aspect, at least 95% by weight is Free Base Hydrate Form C. In another aspect, at least 96% by weight is Free Base Hydrate Form C. In another aspect, at least 97% by weight is Free Base Hydrate Form C. In another aspect, at least 98% by weight is Free Base Hydrate Form C. In another aspect, at least 99% by weight is Free Base Hydrate Form C.

[0685] In some embodiments, the pharmaceutical composition is a compressed and/or ground tablet comprising Compound 1, wherein at least about 75% by weight of Compound 1 present in the tablet is Amorphous Free Base. In one aspect, at least 80% by weight is Amorphous Free Base. In another aspect, at least 85% by weight is Amorphous Free Base. In another aspect, at least 90% by weight is Amorphous Free Base. In another aspect, at least 95% by weight is Amorphous Free Base. In another aspect, at least 96% by weight is Amorphous Free Base. In another aspect, at least 97% by weight is Amorphous Free Base. In another aspect, at least 98% by weight is Amorphous Free Base. In another aspect, at least 99% by weight is Amorphous Free Base.

[0686] In some embodiments, the pharmaceutical composition is a compressed and/or ground tablet comprising Compound 1, wherein at least about 75% by weight of Compound 1 present in the tablet is Free Base Hydrate Form B. In one aspect, at least 80% by weight is Free Base Hydrate Form B. In another aspect, at least 85% by weight is Free Base Hydrate Form B. In another aspect, at least 90% by weight is Free Base Hydrate Form B. In another aspect, at least 95% by weight is Free Base Hydrate Form B. In another aspect, at least 96% by weight is Free Base Hydrate Form B. In another aspect, at least 97% by weight is Free Base Hydrate Form B. In another aspect, at least 98% by weight is Free Base Hydrate Form B. In another aspect, at least 99% by weight is Free Base Hydrate Form B.

[0687] In some embodiments, the pharmaceutical composition is a compressed and/or ground tablet comprising Compound 1, wherein at least about 75% by weight of Compound 1 present in the tablet is Free Base Anhydrous Form D. In one aspect, at least 80% by weight is Free Base Anhydrous Form D. In another aspect, at least 85% by weight is Free Base Anhydrous Form D. In another aspect, at least 90% by weight is Free Base Anhydrous Form D. In another aspect, at least 95% by weight is Free Base Anhydrous Form D. In another aspect, at least 96% by weight is Free Base Anhydrous Form D. In another aspect, at least 97% by weight is Free Base Anhydrous Form D. In another aspect, at least 98% by weight is Free Base Anhydrous Form D. In another aspect, at least 99% by weight is Free Base Anhydrous Form D.

[0688] In some embodiments, the pharmaceutical composition is a compressed and/or ground tablet comprising Compound 1, wherein at least about 75% by weight of Compound 1 present in the tablet is crystalline tartrate. In one aspect, at least 80% by weight is crystalline tartrate. In another aspect, at least 85% by weight is crystalline tartrate. In another aspect, at least 90% by weight is crystalline tartrate. In another aspect, at least 95% by weight is crystalline tartrate. In another aspect, at least 96% by weight is crystalline tartrate. In another aspect, at least 97% by weight is crystalline tartrate. In another aspect, at least 98% by weight is crystalline tartrate. In another aspect, at least 99% by weight is crystalline tartrate.

[0689] In one embodiment, the pharmaceutical composition is a tablet comprising a solid state form of Compound 1 and a pharmaceutically acceptable carrier, wherein the tablet is prepared by compressing the solid state form of Compound 1 and the carrier pharmaceutically acceptable. In one embodiment, the solid state form of Compound 1 is milled prior to compression. In one embodiment, the solid state form is Free Base Hydrate Form C.

[0690] In some embodiments, the tablet further comprises a film coating. A film coating on the tablet may further contribute to the ease with which it can be swallowed. A film coating can also improve flavor and provide an elegant appearance. In certain embodiments, the film coating includes a polymeric film-forming material, such as hydroxypropyl methylcellulose, hydroxypropylcellulose, and acrylate or methacrylate copolymers. In addition to a film-forming polymer, the film coating may further comprise a plasticizer, e.g. polyethylene glycol, a surfactant, e.g. polysorbates, and optionally a pigment, e.g. titanium dioxide or iron oxides. The film coating may also comprise talc, as an anti-adhesive. In one embodiment, the film coating accounts for at least 5% by weight of a pharmaceutical composition of the present invention.

[0691] In another embodiment, the pharmaceutical composition is a capsule dosage form.

[0692] In another embodiment, the pharmaceutical composition comprises a crystalline hydrate of Compound 1, wherein at least about 75% by weight of Compound 1 present in the tablet is the crystalline hydrate of Compound 1. In one aspect, at least 80% by weight is crystalline hydrate. In another aspect, at least 85% by weight is crystalline hydrate. In another aspect, at least 90% by weight is crystalline hydrate. In another aspect, at least 95% by weight is crystalline hydrate. In another aspect, at least 96% by weight is crystalline hydrate. In another aspect, at least 97% by weight is crystalline hydrate. In another aspect, at least 98% by weight is crystalline hydrate. In another aspect, at least 99% by weight is crystalline hydrate. In another aspect, the crystalline hydrate is Free Base Hydrate Form C.

[0693] In another embodiment, the pharmaceutical composition comprises a crystalline tartrate of Compound 1, wherein at least about 75% by weight of Compound 1 present in the tablet is the crystalline tartrate of Compound 1. In one as- percent, at least 80% by weight is crystalline tartrate. In another aspect, at least 85% by weight is crystalline tartrate. In another aspect, at least 90% by weight is crystalline tartrate. In another aspect, at least 95% by weight is cristalino tartrate. In another aspect, at least 96% by weight is crystalline tartrate. In another aspect, at least 97% by weight is crystalline tartrate. In another aspect, at least 98% by weight is crystalline tartrate. In another aspect, at least 99% by weight is crystalline tartrate. In another aspect, the crystalline hydrate is Tartrate Hydrate. In one embodiment, the pharmaceutical composition comprises a crystalline tartrate of Compound 1, from about 10% w/w to about 35% w/w of an organic acid selected from the group consisting of tartaric acid, fumaric acid, acid citric acid, succinic acid and malic acid and combinations thereof, and a pharmaceutically acceptable carrier. In one embodiment, the crystalline hydrate is Tartrate Hydrate.

[0694] In another embodiment, the pharmaceutical composition comprises the Amorphous Free Base, wherein at least about 75% by weight of Compound 1 present in the composition is the Amorphous Free Base. In one aspect, at least 80% by weight is Amorphous Free Base. In another aspect, at least 85% by weight is Amorphous Free Base. In another aspect, at least 90% by weight is Amorphous Free Base. In another aspect, at least 95% by weight is Amorphous Free Base. In another aspect, at least 96% by weight is Amorphous Free Base. In another aspect, at least 97% by weight is Amorphous Free Base. In another aspect, at least 98% by weight is Amorphous Free Base. In another aspect, at least 99% by weight is Amorphous Free Base.

[0695] In another embodiment, the pharmaceutical composition comprises a crystalline anhydrous of Compound 1, wherein at least about 75% by weight of Compound 1 present in the tablet is the crystalline anhydrous of Compound 1. In one aspect, at least 80% by weight is crystalline anhydrous. In another aspect, at least 85% by weight is crystalline anhydrous. In another aspect, at least 90% by weight is crystalline anhydrous. In another aspect, at least 95% by weight is crystalline anhydrous. In another aspect, at least 96% by weight is crystalline anhydrous. In another aspect, at least 97% by weight is crystalline anhydrous. In another aspect, at least 98% by weight is crystalline anhydrous. In another aspect, at least 99% by weight is crystalline anhydrous. In another aspect, the crystalline anhydrous is Free Base Anhydrous Form D.

[0696] In one embodiment, the present disclosure is directed to a pharmaceutical composition comprising about 15 mg of free base of Compound 1 or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1, and a pharmaceutically acceptable carrier, in that the solid state form of Compound 1 is selected from the group consisting of Amorphous Free Base, Free Base Hydrate Form B, Free Base Hydrate Form C, and Free Base Anhydrous Form D. In some such embodiments, the pharmaceutical composition is a once-daily extended-release dosage form (e.g., tablet or capsule).

[0697] In one embodiment, the present disclosure is directed to a pharmaceutical composition comprising about 15 mg of free base of Compound 1 or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1, a pharmaceutically acceptable carrier, and a pH modifier, wherein the solid state form of Compound 1 is selected from the group consisting of Amorphous Free Base, Free Base Hydrate Form B, Free Base Hydrate Form C, and Free Base Anhydrous Form D. In one embodiment, the pharmaceutical composition comprises from about 10% by weight to about 30% by weight of the pH modifier. In one embodiment, the pH modifier is tartaric acid. In some such embodiments, the pharmaceutical composition is a once-daily extended-release dosage form (e.g., tablet or capsule).

[0698] In one embodiment, the present disclosure is directed to a pharmaceutical composition comprising about 15 mg of a solid state form of Compound 1, a pharmaceutically acceptable carrier, and from about 10% w/w to about 35% w/w /p of tartaric acid, wherein the solid state form of Compound 1 is selected from the group consisting of Amorphous Free Base, Free Base Hydrate Form B, Free Base Hydrate Form C, and Anhydrous Form D Free Base. In some such embodiments, the pharmaceutical composition is a once-daily extended-release dosage form (e.g., tablet or capsule).

[0699] In one embodiment, the present disclosure is directed to a pharmaceutical composition comprising about 15 mg of Free Base Hydrate Form B, a pharmaceutically acceptable carrier, and from about 10% w/w to about 35% w/w of tartaric acid. In some such embodiments, the pharmaceutical composition is a once-daily extended-release dosage form (e.g., tablet or capsule).

[0700] In one embodiment, the present disclosure is directed to a pharmaceutical composition comprising about 15 mg of Amorphous Free Base, a pharmaceutically acceptable carrier and from about 10% w/w to about 35% w/w tartaric acid. In some such embodiments, the pharmaceutical composition is a once-daily extended-release dosage form (e.g., tablet or capsule).

[0701] In one embodiment, the present disclosure is directed to a pharmaceutical composition comprising about 15 mg of Free Base Anhydrous Form D, a pharmaceutically acceptable carrier, and from about 10% w/w to about 35% w/w of tartaric acid. In some such embodiments, the pharmaceutical composition is a once-daily extended-release dosage form (e.g., tablet or capsule).

[0702] In one embodiment, the present disclosure is directed to a pharmaceutical composition comprising about 15 mg of Free Base Hydrate Form C, a pharmaceutically acceptable carrier, and from about 10% w/w to about 35% w/w of tartaric acid. In some such embodiments, the pharmaceutical composition is a once-daily extended-release dosage form (e.g., tablet or capsule).

[0703] In one embodiment, the present disclosure is directed to a pharmaceutical composition comprising about 15 mg of Free Base Hydrate Form C, a pharmaceutically acceptable carrier and about 10% w/w tartaric acid. In some such embodiments, the pharmaceutical composition is a once-daily extended-release dosage form (e.g., tablet or capsule).

[0704] In one embodiment, the present disclosure is directed to a pharmaceutical composition comprising about 15 mg of Free Base Hydrate Form C, a pharmaceutically acceptable carrier and about 20% w/w tartaric acid. In some such embodiments, the pharmaceutical composition is a once-daily extended-release dosage form (e.g., tablet or capsule).

[0705] In one embodiment, the present disclosure is directed to a pharmaceutical composition comprising about 15 mg of Free Base Hydrate Form C, a pharmaceutically acceptable carrier and about 30% w/w tartaric acid. In some such embodiments, the pharmaceutical composition is a once-daily extended-release dosage form (e.g., tablet or capsule).

[0706] In one embodiment, the present disclosure is directed to a pharmaceutical composition comprising about 30 mg of free base of Compound 1 or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1, and a pharmaceutically acceptable carrier, in that the solid state form of Compound 1 is selected from the group consisting of Amorphous Free Base, Free Base Hydrate Form B, Free Base Hydrate Form C, and Free Base Anhydrous Form D. In some such embodiments, the pharmaceutical composition is a once-daily extended-release dosage form (e.g., tablet or capsule).

[0707] In one embodiment, the present disclosure is directed to a pharmaceutical composition comprising about 30 mg of free base of Compound 1 or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1, a pharmaceutically acceptable carrier, and a pH modifier, wherein the solid state form of Compound 1 is selected from the group consisting of Amorphous Free Base, Free Base Hydrate Form B, Free Base Hydrate Form C, and Free Base Anhydrous Form D. In one embodiment, the pharmaceutical composition comprises from about 10% by weight to about 30% by weight of the pH modifier. In one embodiment, the pH modifier is tartaric acid. In some such embodiments, the pharmaceutical composition is a once-daily extended-release dosage form (e.g., tablet or capsule).

[0708] In one embodiment, the present disclosure is directed to a pharmaceutical composition comprising about 30 mg of a solid state form of Compound 1, a pharmaceutically acceptable carrier, and from about 10% w/w to about 35% w/w /p of tartaric acid, wherein the solid state form of Compound 1 is selected from the group consisting of Amorphous Free Base, Free Base Hydrate Form B, Free Base Hydrate Form C, and Anhydrous Form D Free Base. In some such embodiments, the pharmaceutical composition is a once-daily extended-release dosage form (e.g., tablet or capsule).

[0709] In one embodiment, the present disclosure is directed to a pharmaceutical composition comprising about 30 mg of Free Base Hydrate Form B, a pharmaceutically acceptable carrier, and from about 10% w/w to about 35% w/w of tartaric acid. In some such embodiments, the pharmaceutical composition is a once-daily extended-release dosage form (e.g., tablet or capsule).

[0710] In one embodiment, the present disclosure is directed to a pharmaceutical composition comprising about 30 mg of Amorphous Free Base, a pharmaceutically acceptable carrier and from about 10% w/w to about 35% w/w tartaric acid. In some such embodiments, the pharmaceutical composition is a once-daily extended-release dosage form (e.g., tablet or capsule).

[0711] In one embodiment, the present disclosure is directed to a pharmaceutical composition comprising about 30 mg of Free Base Anhydrous Form D, a pharmaceutically acceptable carrier, and from about 10% w/w to about 35% w/w of tartaric acid. In some such embodiments, the pharmaceutical composition is a once-daily extended-release dosage form (e.g., tablet or capsule).

[0712] In one embodiment, the present disclosure is directed to a pharmaceutical composition comprising about 30 mg of Free Base Hydrate Form C, a pharmaceutically acceptable carrier, and from about 10% w/w to about 35% w/w of tartaric acid. In some such embodiments, the pharmaceutical composition is a once-daily extended-release dosage form (e.g., tablet or capsule).

[0713] In one embodiment, the present disclosure is directed to a pharmaceutical composition comprising about 30 mg of Free Base Hydrate Form C, a pharmaceutically acceptable carrier and about 10% w/w tartaric acid. In some such embodiments, the pharmaceutical composition is a once-daily extended-release dosage form (e.g., tablet or capsule).

[0714] In one embodiment, the present disclosure is directed to a pharmaceutical composition comprising about 30 mg of Free Base Hydrate Form C, a pharmaceutically acceptable carrier and about 20% w/w tartaric acid. In some such embodiments, the pharmaceutical composition is a once-daily extended-release dosage form (e.g., tablet or capsule).

[0715] In one embodiment, the present disclosure is directed to a pharmaceutical composition comprising about 30 mg of Free Base Hydrate Form C, a pharmaceutically acceptable carrier and about 30% w/w tartaric acid. In some such embodiments, the pharmaceutical composition is a once-daily extended-release dosage form (e.g., tablet or capsule).

[0716] In one embodiment, the present disclosure is directed to a pharmaceutical composition comprising about 7.5 mg or about 15 mg or about 30 mg or about 45 mg of Compound 1 free base or a pharmaceutical salt thereof. pharmaceutical composition or a solid state form of Compound 1, and pharmaceutically acceptable carrier, wherein the pharmaceutical composition is a once-daily extended-release dosage form (e.g., tablet or capsule) that sustains release of the free base of Compound 1 or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1 for about 4 hours to about 24 hours following entry of the dosage form into an environment of use, and wherein the dosage form dosage has a release rate of no more than about 60% after about 4 hours have passed following entry of the dosage form into a use environment. In some such embodiments, the dosage form has a release rate of no more than about 60% after about 4 hours have passed following entry of the dosage form into an environment of use, from about 50% to about 80%. % after about 8 hours pass after entering the dosage form into an environment of use, from about 55% to about 90% after about 10 hours pass after entering the dosage form into an environment of use, and from about 70% to 100% after about 20 hours pass after the dosage form enters a use environment. In some embodiments, the solid state form of Compound 1 is selected from the group consisting of Amorphous Free Base, Free Base Hydrate Form B, Free Base Hydrate Form C, and Free Base Anhydrous Form D.

[0717] In one embodiment, the present disclosure is directed to a pharmaceutical composition comprising about 15 mg of a solid state form of Compound 1, a pharmaceutically acceptable carrier, and from about 10% w/w to about 35% w/w /p of tartaric acid, wherein the solid state form of Compound 1 is selected from the group consisting of Amorphous Free Base, Free Base Hydrate Form B, Free Base Hydrate Form C, and Anhydrous Form D of Free Base, and the pharmaceutical composition is a once-daily extended-release dosage form (e.g., tablet or capsule) that sustains release of the free base of Compound 1 or the solid-state form of Compound 1 for about from 4 hours to about 24 hours following entry of the dosage form into an environment of use, and wherein the dosage form has a release rate of no more than about 60% after about 4 hours have passed following release. entry of the dosage form into an environment of use. In some such embodiments, the dosage form has a release rate of no more than about 60% after about 4 hours have passed following entry of the dosage form into an environment of use, from about 50% to about 80%. % after about 8 hours have passed following the entry of the dosage form into an environment of use, from about 55% to about 90% after about 10 hours have passed following the entry of the dosage form into an environment of use, and from about 70% to 100% after about 20 hours pass after the dosage form enters a use environment.

[0718] In one embodiment, the present disclosure is directed to a pharmaceutical composition comprising about 15 mg of Free Base Hydrate Form C, a pharmaceutically acceptable carrier and from about 10% w/w to about 35% w/w of tartaric acid, wherein the pharmaceutical composition is a once-daily extended-release dosage form (e.g., tablet or capsule) that sustains release of the free base of Compound 1 or the solid-state form of Compound 1 during about 4 hours to about 24 hours following entry of the dosage form into an environment of use, and wherein the dosage form has a release rate of no more than about 60% after about 4 hours pass thereafter upon entry of the dosage form into an environment of use, from about 50% to about 80% after about 8 hours pass following entry of the dosage form into an environment of use, from about 55% to about 90% after about 10 hours pass after the dosage form enters a use environment and from about 70% to about 100% after about 20 hours passes after the dosage form enters a usage environment.

[0719] In one embodiment, the present disclosure is directed to a pharmaceutical composition comprising about 30 mg of a solid state form of Compound 1, a pharmaceutically acceptable carrier, and from about 10% w/w to about 35% w/w /p of tartaric acid, wherein the solid state form of Compound 1 is selected from the group consisting of Amorphous Free Base, Free Base Hydrate Form B, Free Base Hydrate Form C, and Anhydrous Form D of Free Base, and the pharmaceutical composition is a once-daily extended-release dosage form (e.g., tablet or capsule) that sustains release of the free base of Compound 1 or the solid-state form of Compound 1 for about from 4 hours to about 24 hours following entry of the dosage form into an environment of use, and wherein the dosage form has a release rate of no more than about 60% after about 4 hours have passed following release. entry of the dosage form into an environment of use. In some such embodiments, the dosage form has a release rate of no more than about 60% after about 4 hours have passed following entry of the dosage form into an environment of use, from about 50% to about 80%. % after about 8 hours pass after the dosage form enters a use environment, from about 55% to about 90% after about 10 hours passes after the dosage form enters a use environment , and from about 70% to 100% after about 20 hours pass after the dosage form enters a use environment.

[0720] In one embodiment, the present disclosure is directed to a pharmaceutical composition comprising about 30 mg of Free Base Hydrate Form C, a pharmaceutically acceptable carrier, and from about 10% w/w to about 35% w/w of tartaric acid, wherein the pharmaceutical composition is a once-daily extended-release dosage form (e.g., tablet or capsule) that sustains release of the free base of Compound 1 or the solid-state form of Compound 1 during about 4 hours to about 24 hours following entry of the dosage form into an environment of use, and wherein the dosage form has a release rate of no more than about 60% after about 4 hours pass thereafter upon entry of the dosage form into an environment of use, from about 50% to about 80% after about 8 hours pass following entry of the dosage form into an environment of use, from about 55% to about 90% after about 10 hours pass after the dosage form enters a use environment and from about 70% to about 100% after about 20 hours passes after the dosage form enters a usage environment.

[0721] In some of the above embodiments, the dosage form releases the active ingredient (i.e., free base of Compound 1 or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1), at a release rate not exceeding to about 25%, or from about 10% to about 25%, or from about 15% to about 20%, or about 20% after about 1 hour after entering the use environment. In one embodiment, the dosage form releases the active ingredient at a release rate of no more than about 40%, or about 20% to about 40%, or about 25% to about 35% after passing approximately 2 hours after entering the use environment. In one embodiment, the dosage form releases the active ingredient at a release rate of no more than about 60%, or from about 30% to about 60%, or from about 40% to about 60%, or from about 45% to about 55% after about 4 hours pass after entering the use environment. In one embodiment, the dosage form releases the active ingredient at a release rate of no more than about 70%, or about 40% to about 70%, or about 55% to about 70%, after approximately 6 hours pass after entering the use environment. In one embodiment, the dosage form releases the active ingredient at a release rate of no more than about 80%, or from about 55% to about 80%, or from about 60% to about 80%, after approximately 6 hours pass after entering the use environment. In one embodiment, the dosage form releases the active ingredient at a release rate of not more than about 80%, or not less than about 50%, or not less than about 60%, or not less than about 70%. %, or not less than about 75%, or from about 50% to about 80%, or from about 60% to about 80%, or from about 65% to about 80% after passing about 8 hours after entering the use environment. In one embodiment, the dosage form releases the active ingredient at a release rate of not less than about 55%, or not less than about 60%, or not less than about 70%, or not less than about 80%. %, or not less than about 85%, or from about 55% to about 90%, or from about 70% to about 90% after about 10 hours pass after entering the environment of use. In one embodiment, the dosage form releases the active ingredient at a release rate of not less than about 65%, or not less than about 70%, or not less than about 80%, or not less than about 90%. %, or from about 65% to about 99%, or from about 80% to about 99%, or from about 90% to about 99% after about 16 hours have passed following entry into the environment. use. In one embodiment, the dosage form releases the active ingredient at a release rate of not less than about 70%, or not less than about 80%, or not less than about 90%, or from about 70% to about 100%, or from about 80% to about 100% after about 20 hours pass after entering the environment of use. In one aspect, the dosage form has a release rate of no more than about 60% after about 4 hours after entering the dosage form into a use environment, from about 50% to about 80%. after about 8 hours have passed following the entry of the dosage form into an environment of use, from about 55% to about 90% after about 10 hours have passed following the entry of the dosage form into an environment of use, and from about 70% to 100% after about 20 hours have passed following entry of the dosage form into a use environment.

[0722] In one embodiment, the present disclosure is directed to a pharmaceutical composition comprising about 7.5 mg or about 15 mg or about 30 mg or about 45 mg of Compound 1 free base or a pharmaceutical salt thereof. ketically acceptable or a solid state form of Compound 1, and pharmaceutically acceptable carrier, wherein the solid state form of Compound 1 is selected from the group consisting of Amorphous Free Base, Free Base Hydrate Form B , Freebase Hydrate Form C and Freebase Anhydrous Form D, wherein the pharmaceutical composition is a once-daily extended-release dosage form (e.g., tablet or capsule) that, when added to a delivery medium test comprising 900 mL of 50 mM sodium phosphate buffer pH 6.8 at 37 °C ± 0.5 °C in a standard USP rotating paddle device when the paddles are rotated at 75 rpm ± 4%, dissolves no more than 60% free base of Compound 1 or the solid state form of Compound 1 after about 4 hours have passed, from about 50% to about 80% free base of Compound 1 or the solid state form of Compound 1 after about 8 hours have passed, from about 55% to about 90% free base of Compound 1 or the solid state form of Compound 1 after about 10 hours has passed, and from about 70% to 100% free base of Compound 1 or the solid state form of Compound 1 after about 20 hours have passed.

[0723] In one embodiment, the present disclosure is directed to a pharmaceutical composition comprising about 15 mg of a solid state form of Compound 1, a pharmaceutically acceptable carrier, and from about 10% by weight to about 30% by weight. weight of tartaric acid, wherein the solid state form of Compound 1 is selected from the group consisting of Amorphous Free Base, Free Base Hydrate Form B, Free Base Hydrate Form C, and Free Base Anhydrous Form D , wherein the pharmaceutical composition is a once-daily extended-release dosage form (e.g., tablet or capsule) that, when added to a test medium comprising 900 mL of 50 mM sodium phosphate buffer, pH 6 .8 to 37 °C ± 0.5 °C in a standard USP rotating paddle device when the paddles are rotated at 75 rpm ± 4%, dissolves no more than 60% of Compound 1 free base or the state form solid state of Compound 1 after about 4 hours has passed, from about 50% to about 80% free base of Compound 1 or the solid state form of Compound 1 after about 8 hours has passed, from about 55% to about of 90% free base of Compound 1 or the solid state form of Compound 1 after about 10 hours have passed, and from about 70% to 100% free base of Compound 1 or the solid state form of Compound 1 after about 20 hours pass.

[0724] In one embodiment, the present disclosure is directed to a pharmaceutical composition comprising about 15 mg of Free Base Hydrate Form C, a pharmaceutically acceptable carrier, and from about 10% by weight to about 30% by weight of tartaric acid, wherein the pharmaceutical composition is a once-daily extended-release dosage form (e.g., tablet or capsule) which, when added to a test medium comprising 900 mL of 50 mM sodium phosphate buffer and pH 6.8 at 37 °C ± 0.5 °C in a standard USP rotary paddle device when the paddles are rotated at 75 rpm ± 4%, dissolves no more than 60% free base of Compound 1 or the solid state form of Compound 1 after about 4 hours has passed, from about 50% to about 80% free base of Compound 1 or the solid state form of Compound 1 after about 8 hours has passed, from about 55% free base. % to about 90% free base of Compound 1 or the solid state form of Compound 1 after about 10 hours have passed, and from about 70% to 100% free base of Compound 1 or the solid state form of Compound 1 after about 20 hours have passed.

[0725] In one embodiment, the present disclosure is directed to a pharmaceutical composition comprising about 30 mg of a solid state form of Compound 1, a pharmaceutically acceptable carrier, and from about 10% by weight to about 30% by weight. weight of tartaric acid, wherein the solid state form of Compound 1 is selected from the group consisting of Amorphous Free Base, Free Base Hydrate Form B, Free Base Hydrate Form C, and Free Base Anhydrous Form D , wherein the pharmaceutical composition is a once-daily extended-release dosage form (e.g., tablet or capsule) that, when added to a test medium comprising 900 mL of 50 mM sodium phosphate buffer, pH 6 .8 to 37 °C ± 0.5 °C in a standard USP rotating paddle device when the paddles are rotated at 75 rpm ± 4%, dissolves no more than 60% of Compound 1 free base or the state form solid state of Compound 1 after about 4 hours, from about 50% to about 80% free base of Compound 1 or the solid state form of Compound 1 after about 8 hours, from about 55% to about 90% free base of Compound 1 or the solid state form of Compound 1 after about 10 hours have passed, and from about 70% to 100% free base of Compound 1 or the solid state form of Compound 1 after approximately 20 hours have passed.

[0726] In one embodiment, the present disclosure is directed to a pharmaceutical composition comprising about 30 mg of Free Base Hydrate Form C, a pharmaceutically acceptable carrier, and from about 10% by weight to about 30% by weight of tartaric acid, wherein the pharmaceutical composition is a once-daily extended-release dosage form (e.g., tablet or capsule) which, when added to a test medium comprising 900 mL of 50 mM sodium phosphate buffer and pH 6.8 at 37 °C ± 0.5 °C in a standard USP rotary paddle device when the paddles are rotated at 75 rpm ± 4%, dissolves no more than 60% free base of Compound 1 or the solid state form of Compound 1 after about 4 hours has passed, from about 50% to about 80% free base of Compound 1 or the solid state form of Compound 1 after about 8 hours has passed, from about 55% free base. % to about 90% free base of Compound 1 or the solid state form of Compound 1 after about 10 hours have passed, and from about 70% to 100% free base of Compound 1 or the solid state form of Compound 1 after about 20 hours have passed.

VII. Pharmacokinetic Parameters

[0727]15 mg Dosage Formulations

[0728] In certain embodiments, the methods of the present disclosure comprise administering to an adult subject (e.g., a human subject) Compound 1 (free base), or a pharmaceutically acceptable salt thereof, or a crystalline hydrate of Compound 1 in an amount sufficient to provide the subject with 15 mg of free base equivalent of Compound 1. In one embodiment, the free base or hydrate is in the form of a once-daily extended-release formulation.

[0729] Unless otherwise indicated, the following pharmacokinetic parameters are achieved after administration of a single 15 mg dose of Compound 1 (free base) or a pharmaceutically acceptable salt thereof or the crystalline hydrate (e.g., Hydrate Form C of Free Base) to the adult subject, or after administration of a sufficient number of 15 mg doses once daily to achieve steady state. By a single dose of 15 mg is meant a single dosage unit containing an amount of free base or pharmaceutically acceptable salt or crystalline hydrate sufficient to provide the subject with 15 mg of free base equivalent of Compound 1. In one embodiment, the one unit Single dosage is presented in the form of a once-daily extended-release formulation.

[0730] In certain embodiments, administration of Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof to the adult subject achieves an average Cmax for Compound 1 of about 25 to about 70 ng/mL, after a single dose of 15 mg. In some embodiments, when administered to the adult subject, Compound 1 (free base) or the crystalline hydrate achieves an average Cmax for Compound 1 of about 25.0 to about 60.0 ng/mL, or from about 25.0 to about 40.0 ng/mL, about 25.0 to about 30.0 ng/mL, or about 25.0 to about 28.0 ng/mL, after a single dose of 15 mg. In some embodiments, when administered to the adult subject, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves an average Cmax for Compound 1 of about 26.0 to about 26.4 ng / mL, or from about 26.2 to about 26.6 ng/mL, or from about 26.4 to about 26.8 ng/mL, or from about 26.6 to about 27.0 ng /mL, or from about 26.8 to about 27.2 ng/mL, or from about 27.0 to about 27.4 ng/mL, or from about 27.2 to about 27.6 ng/mL, or from about 27.4 to about 27.8 ng/mL, or from about 27.6 to about 28.0 ng/mL, or from about 27.8 to about 28, 2 ng/mL, or from about 28.0 to about 28.4 ng/mL, or from about 28.2 to about 28.6 ng/mL, or from about 28.4 to about 28 .8 ng/mL, or from about 28.6 to about 29.0 ng/mL, or from about 28.8 to about 29.2 ng/mL, or from about 29.0 to about 29.4 ng/mL, or from about 29.2 to about 29.6 ng/mL, or from about 29.4 to about 29.8 ng/mL, or from about 29.6 to about from 30.0 ng/mL, or from about 29.8 to about 30.2 ng/mL, or from about 30.0 to about 30.4 ng/mL, or from about 30.2 to about 30.6 ng/mL, or from about 30.4 to about 30.8 ng/mL, or from about 30.6 to about 31.0 ng/mL, or from about 30.8 to about 31.2 ng/mL, or from about 31.0 to about 31.4 ng/mL, or from about 31.2 to about 31.6 ng/mL, or from about 31. 4 to about 31.8 ng/mL, or from about 31.6 to about 32.0 ng/mL, after a single 15 mg dose.

[0731] In some embodiments, when administered to the adult subject under fasting conditions, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves an average Cmax for Compound 1 of about 26 ng/mL or about of 32 ng/mL, after a single dose of 15 mg. In other embodiments, when administered to the adult subject under non-fasting conditions, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves an average Cmax for Compound 1 of about 37 ng/mL or about 40 ng/mL, after a single dose of 15 mg.

[0732] In certain embodiments, when Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof is administered to the adult subject, the difference in Cmax for Compound 1 after a single dose of 15 mg in the fed state versus Fasting state is selected from about 30% or less, about 20% or less, and about 10% or less. As used herein, a subject in a “fed” state (also referred to herein as “non-fasting” state or “non-fasting conditions”) is a subject who has consumed a normal or high-fat meal within about 30 minutes before of drug administration. As used herein, a subject in a “fasted” state (also referred to herein as “fasting conditions”) refers to a subject who has been fasting for at least 10 hours prior to initial drug administration or, if the drug is being administered to the subject by various routes, refers to a subject who has been fasting for at least two hours before each subsequent administration of the drug.

[0733] When administered to the adult subject, in some embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves a Tmax for Compound 1 of about 1.0 to about 6.0 hours after a single dose of 15 mg. In some embodiments, when administered to the adult subject, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves a Tmax for Compound 1 of about 1.0 to about 5.0 hours, or about from 1.0 to about 4.0 hours, or from about 1.0 to about 3.0 hours, or from about 1.0 to about 2.0 hours, or from about 2.0 to about 6.0 hours, or from about 3.0 to about 6.0 hours, or from about 4.0 to about 6.0 hours, or from about 5.0 to about 6.0 hours, or from about 2.0 to about 5.0 hours, or from about 2.0 to about 4.0 hours, or from about 2.0 to about 3.0 hours, or from about from 3.0 to about 4.0 hours, or from about 3.0 to about 5.0 hours, or from about 4.0 to about 5.0 hours, after a single 15 mg dose. In some embodiments, when administered to the adult subject, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves a Tmax for Compound 1 of about 2.6 to about 3.0 hours, or about from 2.8 to about 4.4 hours after a single dose of 15 mg.

[0734] In other embodiments, when administered to the adult subject under fasting conditions, Compound 1 (free base) or a pharmaceutically acceptable salt thereof or crystalline hydrate achieve a Tmax for Compound 1 of about 1.0 to about of 4.0 hours after a single dose of 15 mg, or achieve a Tmax for Compound 1 of about 1.5 to about 6.0 hours after a single dose of 15 mg, or achieve a median Tmax for Compound 1 of approximately 3.0 hours after a single dose of 15 mg. In other embodiments, when administered to the adult subject under non-fasting conditions, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves a Tmax for Compound 1 of about 3.0 to about 6.0 hours after a single 15 mg dose, or achieve a median Tmax for Compound 1 of about 4.0 hours after a single 15 mg dose.

[0735] When administered to the adult subject, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt thereof or crystalline hydrate achieve a harmonic mean t1/2 for Compound 1 of about 10.0 to about of 14.0 hours after a single dose of 15 mg. In other embodiments, when administered to the adult subject, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves a harmonic mean t1/2 for Compound 1 of about 10.0 to about 13.0 hours, or from about 10.0 to about 12.0 hours, or from about 10.0 to about 11.0 hours, or from about 11.0 to about 14.0 hours, or from about 11.0 to about 13.0 hours, or from about 11.0 to about 12.0 hours, or from about 12.0 to about 14.0 hours, or from about 12.0 hours .0 to about 13.0 hours, or from about 13.0 to about 14.0 hours, after a single 15 mg dose. In other embodiments, when administered to an adult subject, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves a harmonic mean t1/2 for Compound 1 of about 12.0 to about 12. .4 hours, or from about 12.2 to about 12.6 hours, or from about 12.4 to about 12.8 hours, or from about 12.6 to about 13.0 hours, or from about 12.8 to about 13.2 hours, or from about 13.0 to about 13.4 hours, or from about 13.4 to about 13.8 hours, or from about 13. 6 to approximately 14.0 hours after a single dose of 15 mg. In other embodiments, when administered to the adult subject, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves a harmonic mean t1/2 for Compound 1 of about 12.5 hours after a single dose of 15 mg.

[0736] When administered to the adult subject, in some embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves an average AUCinf for Compound 1 of about 220 to about 450 ng^hours /mL after a single dose of 15 mg. When administered to the adult subject, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves an average AUCinf for Compound 1 of about 220 to about 320 ng^hours/mL, or of about 220 to about 260 ng^hours/mL, or from about 220 to about 250 ng^hours/mL, or from about 220 to about 245 ng^hours/mL, or from about 230 to about from 260 ng^hours/mL, or from about 230 to about 250 ng^hours/mL, or from about 230 to about 245 ng^hours/mL, or from about 240 to about 260 ng^hours /mL, or from about 240 to about 250 ng^hours/mL, or from about 242 to about 250 ng^hours/mL, or from about 240 to about 245 ng^hours/mL, after a single dose of 15 mg. When administered to the adult subject, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves an average AUCinf for Compound 1 of about 238 to about 240 ng^hours/mL. or from about 239 to about 241 ng^hours/mL, or from about 240 to about 242 ng^hours/mL, or from about 242 to about 244 ng^hours/mL, or from about 243 to about 245 ng^hours/mL, or from about 244 to about 246 ng^hours/mL, or from about 245 to about 247 ng^hours/mL, or from about 246 to about 248 ng^hours/mL, or from about 247 to about 249 ng^hours/mL, after a single 15 mg dose.

[0737] When administered to the adult subject under fasting conditions, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves an average AUCinf for Compound 1 of about 240 to about 245 ng ^hours/mL, or about 242 ng^hours/mL after a single 15 mg dose.

[0738] When administered to the adult subject under fasting conditions, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves an average AUCt for Compound 1 of about 227 ng^hours/mL after a single dose of 15 mg, or achieve a mean AUC24 for Compound 1 of about 249 ng^hours/mL after a single dose of 15 mg. When administered to the adult subject under non-fasting conditions, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves an average AUC24 for Compound 1 of about 305 ng^hours/mL or about of 318 ng^hours/mL, after a single dose of 15 mg.

[0739] In certain embodiments, when Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof is administered to the subject, the difference in AUCinf for Compound 1 following a 15 mg dose in the fed state versus the fed state Fasting is selected from about 30% or less, about 20% or less, and about 10% or less.

[0740] When administered to the adult subject, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves an average C24 for Compound 1 of about 1.4 to about 2. 5 ng/mL after a single dose of 15 mg. When administered to the adult subject under fasting conditions, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves an average C24 for Compound 1 of about 1.5 ng/mL or about 1.9 ng/mL, after a single dose of 15 mg. When administered to the adult subject under non-fasting conditions, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves an average C24 for Compound 1 of about 2.4 ng/mL.

[0741] When administered QD (once a day) to the adult subject, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt thereof or crystalline hydrate achieve an average Cmax, ss for Compound 1 from about 27 to about 55 ng/mL. When administered QD (once daily) to the adult subject, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves an average Cmax,ss for Compound 1 of about 27 to about 38 ng/mL, or from about 27 to about 36 ng/mL, or from about 27 to about 34 ng/mL, or from about 27 to about 32 ng/mL, or from about 27 to about 30 ng/mL, or from about 29 to about 38 ng/mL, or from about 29 to about 36 ng/mL, or from about 29 to about 34 ng/mL, or from about 29 to about 32 ng/mL, or from about 30 to about 36 ng/mL, or from about 30 to about 34 ng/mL. When administered QD (once daily) to the adult subject, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves an average Cmax,ss for Compound 1 of about 31.0 to about 31.4 ng/mL, or from about 31.2 to about 31.6 ng/mL, or from about 31.4 to about 31.8 ng/mL, or from about 31.6 to about 32.0 ng/mL, or from about 31.8 to about 32.2 ng/mL, or from about 32.0 to about 32.4 ng/mL, or from about 32. 2 to about 32.6 ng/mL, or from about 32.4 to about 32.8 ng/mL, or from about 32.6 to about 33.0 ng/mL, or from about 32 .8 to about 33.2 ng/mL, or from about 33.0 to about 33.4 ng/mL, or from about 33.2 to about 33.6 ng/mL, or from about 33.4 to about 33.8 ng/mL, or from about 33.6 to about 34.0 ng/mL, or from about 33.8 to about 34.2 ng/mL, or from about from 34.0 to about 34.4 ng/mL, or from about 34.2 to about 34.6 ng/mL, or from about 34.4 to about 34.8 ng/mL, or from about 34.6 to about 35.0 ng/mL, or from about 34.8 to about 35.2 ng/mL, or from about 35.0 to about 35.4 ng/mL, or from about 35.2 to about 35.6 ng/mL, or from about 35.4 to about 35.8 ng/mL, or from about 35.6 to about 36.0 ng/mL, or from about 35.8 to about 36.2 ng/mL, or from about 36.0 to about 36.4 ng/mL, or from about 36.2 to about 36.6 ng/mL , or from about 36.4 to about 36.8 ng/mL, or from about 36.6 to about 37.0 ng/mL, or from about 36.8 to about 37.2 ng/mL, or from about 36.8 to about 37.2 ng/mL mL, or from about 37.0 to about 37.4 ng/mL, or from about 37.2 to about 37.6 ng/mL, or from about 37.4 to about 37.8 ng /mL, or from about 37.6 to about 38.0 ng/mL.

[0742] When administered QD (once per day) to the adult subject under fasting conditions, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt thereof or crystalline hydrate achieves an average Cmax,ss for Compound 1 of about 32 ng/mL. When administered QD (once daily) to the adult subject under non-fasting conditions, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt thereof or crystalline hydrate achieves an average Cmax, ss for Compound 1 of about 36 ng/mL or about 37 ng/mL.

[0743] When administered QD (once a day) to the adult subject, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt thereof or crystalline hydrate achieve a Tmax,ss for Compound 1 of about 1.5 to about 6.0 hours. When administered QD (once daily) to the adult subject, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves a Tmax,ss for Compound 1 of about 1.5 to about from 5.0 hours, or from about 1.5 to about 4.0 hours, or from about 1.5 to about 3.0 hours, or from about 1.5 to about 2.0 hours , or from about 2.0 to about 6.0 hours, or from about 3.0 to about 6.0 hours, or from about 4.0 to about 6.0 hours, or from about 2.0 to about 5.0 hours, or from about 2.0 to about 4.0 hours, or from about 2.0 to about 3.0 hours, or from about 3.0 to about from 5.0 hours, or from about 3.0 to about 4.0 hours, or from about 4.0 to about 5.0 hours. In some embodiments, when administered QD (once daily) to the adult subject, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves a Tmax,ss for Compound 1 of about 2.6 to about from 3.0 hours, or from about 2.8 to about 3.2 hours, or from about 3.0 to about 3.4 hours, or from about 3.2 to about 3.6 hours , or from about 3.4 to about 3.8 hours, or from about 3.6 to about 4.0 hours, or from about 3.8 to about 4.2 hours, or from about 4.0 to about 4.4 hours.

[0744] When administered QD (once per day) to the adult subject under fasting conditions, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt thereof or crystalline hydrate achieves a Tmax,ss for Compound 1 of about 1.5 to about 4.0 hours, or achieve a median Tmax,ss for Compound 1 of about 2.5 hours. When administered QD (once daily) to the adult subject under non-fasting conditions, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt thereof or crystalline hydrate achieves a Tmax,ss for Compound 1 of about 2.0 to about 6.0 hours, or achieve a median Tmax,ss for Compound 1 of about 4.0 hours.

[0745] When administered QD (once per day) to the adult subject, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt thereof or crystalline hydrate achieve an average Cmin for Compound 1 of about from 2.5 to about 5.1 ng/mL. When administered QD (once daily) to the adult subject under fasting conditions, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves an average Cmin for Compound 1 of about 2. 8 ng/mL. When administered QD (once daily) to the adult subject under non-fasting conditions, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt thereof or crystalline hydrate achieves an average Cmin for Compound 1 of about from 2.5 to about 5.1 ng/mL, or from about 2.5 to about 3.6 ng/mL, or achieve an average Cmin for Compound 1 of about 2.6 ng/mL or from about 3.2 ng/mL or about 3.6 ng/mL, or about 5.0 ng/mL.

[0746] When administered QD (once per day) to the adult subject, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt thereof or crystalline hydrate achieve an average AUC24.ss for Compound 1 from about 240 to about 325 ng^hours/mL. When administered QD (once daily) to the adult subject, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves an average AUC24,ss for Compound 1 of about 240 to about 290 ng^hours/mL, or from about 240 to about 280 ng^hours/mL, or from about 240 to about 260 ng^hours/mL, or from about 250 to about 290 ng^ hours/mL, or from about 250 to about 280 ng^hours/mL, or from about 260 to about 280 ng^hours/mL, or from about 270 to about 280 ng^hours/mL, or from about 275 to about 280 ng^hours/mL, or from about 279 to about 280 ng^hours/mL. When administered QD (once daily) to the adult subject, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves an average AUC24,ss for Compound 1 of about 240 to about 244 ng^hours/mL, or from about 241 to about 245 ng^hours/mL, or from about 242 to about 246 ng^hours/mL, or from about 244 to about 248 ng^ hours/mL, or from about 246 to about 250 ng^hours/mL, or from about 248 to about 252 ng^hours/mL, or from about 250 to about 254 ng^hours/mL , or from about 252 to about 256 ng^hours/mL, or from about 254 to about 258 ng^hours/mL, or from about 256 to about 260 ng^hours/mL, or from about 258 to about 262 ng^hours/mL, or from about 260 to about 264 ng^hours/mL, or from about 262 to about 266 ng^hours/mL, or from about 264 to about 268 ng^hours/mL, or from about 266 to about 270 ng^hours/mL, or from about 268 to about 272 ng^hours/mL, or from about 270 to about 274 ng^hours/mL , or from about 272 to about 276 ng^hours/mL, or from about 274 to about 278 ng^hours/mL, or from about 276 to about 280 ng^hours/mL.

[0747] When administered QD (once daily) to the adult subject under fasting conditions, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt thereof or crystalline hydrate achieves an average AUC24.ss for Compound 1 of about 241 ng^hours/mL or about 279 ng^hours/mL. When administered QD (once daily) to the adult subject under non-fasting conditions, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves an average AUC24.ss for Compound 1 of about of 317 ng^hours/mL or about 322 ng^hours/mL.

[0748] When administered QD (once a day) to the adult subject, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt thereof or crystalline hydrate achieve an average Cmin,ss for Compound 1 from about 2.8 to about 3.2 ng/mL. When administered QD (once daily) to the adult subject, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves an average Cmin,ss for Compound 1 of about 2.8 to about 3.1 ng/mL, or about 2.8 to about 3.0 ng/mL, or about 2.8 to about 2.9 ng/mL, or about 2.9 to about 3.2 ng/mL, or from about 2.9 to about 3.0 ng/mL, or from about 3.0 to about 3.2 ng/mL, or from about 3. 0 to about 3.1 ng/mL, or from about 3.1 to about 3.2 ng/mL. When administered QD (once daily) to the adult subject, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves an average Cmin,ss for Compound 1 of about 2.8 ng /mL, or about 3.0 ng/mL, or about 3.1 ng/mL.

[0749] When administered QD (once a day) to the adult subject, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt thereof or crystalline hydrate achieves an average C24,ss for Compound 1 from about 2.9 to about 3.2 hours. When administered QD (once daily) to the adult subject under fasting conditions, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves an average C24,ss for Compound 1 of about 3.1 ng/mL. When administered QD (once daily) to the adult subject under fasting conditions, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves an average C24,ss for Compound 1 of about 3.2 ng/mL.

[0750] When administered QD (once a day) to the adult subject, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt thereof or crystalline hydrate achieve a harmonic mean t1/2,ss for Compound 1 from about 9.4 to about 10.5 hours. When administered QD (once daily) to the adult subject, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt thereof or crystalline hydrate achieve a harmonic mean t1/2,ss for Compound 1 of about from 9.4 to about 10.4 hours, or from about 9.4 to about 10.3 hours, or from about 9.4 to about 10.1 hours, or from about 9.4 to about about 9.9 hours, or from about 9.5 to about 10.4 hours. When administered QD (once daily) to the adult subject, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves a harmonic mean t1/2,ss for Compound 1 of about 9 4 to about 9.8 hours, or from about 9.6 to about 10.0 hours, or from about 9.8 to about 10.2 hours, or from about 10.0 to about 10.4 hours, or from about 10.1 to about 10.5 hours. When administered QD (once daily) to the adult subject, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves a harmonic mean t1/2,ss for Compound 1 of about 10 .3 hours to about 9.4 hours or about 9.5 hours.

[0751] In certain embodiments, when administered to the adult subject, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof provides: (a) an average Cmax for Compound 1 of about 25 to about 70 ng/mL; (b) a Tmax for Compound 1 of about 1.0 hour to about 6.0 hours; (c) a harmonic mean t1/2 for Compound 1 of about 10.0 to about 14.0 hours; (d) an average AUCinf for Compound 1 of about 220 to about 450 ng-hours/mL; (e) an average Cmax,ss for Compound 1 of about 27 to about 55 ng/mL; (f) an average AUC24.ss for Compound 1 of about 240 to about 325 ng-hours/mL; (g) a Tmax,ss for Compound 1 of about 1.5 to about 6.0 hours; (h) an average Cmin,ss for Compound 1 of about 2.8 to about 3.2 ng/mL; (i) a harmonic mean t1/2,ss for Compound 1 of about 9.4 to about 10.5 hours; or combinations thereof.

[0752] In certain embodiments, when administered to the adult subject, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt thereof or crystalline hydrate provide: (a) an average Cmax for Compound 1 of about 25 to about 70 ng/mL; (b) a Tmax for Compound 1 of about 1.0 hour to about 6.0 hours; (c) a harmonic mean t1/2 for Compound 1 of about 10.0 to about 14.0 hours; (d) an average AUCinf for Compound 1 of about 220 to about 450 ng-hours/mL; or their combinations, after a single dose of 15 mg.

[0753] In certain embodiments, when administered QD (once daily) to the adult subject, Compound 1 (free base) or a pharmaceutically acceptable salt thereof or crystalline hydrate provides: (a) an average Cmax,ss for Compound 1 from about 27 to about 55 ng/mL; (b) an average AUC24.ss for Compound 1 of about 240 to about 325 ng-hours/mL; (c) a Tmax,ss for Compound 1 of about 1.5 to about 6.0 hours; (d) an average Cmin,ss for Compound 1 of about 2.8 to about 3.2 ng/mL; (e) a harmonic mean t1/2,ss for Compound 1 of about 9.4 to about 10.5 hours; or combinations thereof.

[0754] In certain embodiments, when administered to the adult subject under fasting conditions, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof provides: (a) an average Cmax for Compound 1 of about 26 ng /mL or about 32 ng/mL; (b) a Tmax for Compound 1 of about 1.0 to about 4.0 hours, or of about 1.5 to about 6.0 hours, or a median Tmax for Compound 1 of about 3.0 hours; (c) a harmonic mean t1/2 for Compound 1 of about 12.5 hours; (d) an average AUCinf for Compound 1 of about 242 ng^hours/mL; or their combinations, after a single dose of 15 mg.

[0755] In certain embodiments, when administered to the adult subject under non-fasting conditions, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof provides: (a) an average Cmax for Compound 1 of about 40 ng/mL; (b) a Tmax for Compound 1 of about 3.0 hours to about 6.0 hours or a median Tmax for Compound 1 of about 4.0 hours; (c) a harmonic mean t1/2 for Compound 1 of about 12.5 hours; or their combinations, after a single dose of 15 mg.

[0756] In certain embodiments, when administered QD (once per day) to the adult subject under fasting conditions, Compound 1 (free base) or a pharmaceutically acceptable salt thereof or the crystalline hydrate alternatively or additionally may provide: ( a) an average Cmax,ss for Compound 1 of about 32 ng/mL; (b) an average AUC24.ss for Compound 1 of about 279 ng-hours/mL; (c) a Tmax,ss for Compound 1 of about 1.5 to about 4.0 hours, or a median Tmax,ss for Compound 1 of about 2.5 hours; (d) an average Cmin,ss for Compound 1 of about 3.0 ng/mL or about 3.1 ng/mL; (e) a harmonic mean t1/2,ss for Compound 1 of about 9.5 hours or about 10.3 hours; or combinations thereof.

[0757] In certain embodiments, when administered QD (once daily) to the adult subject under non-fasting conditions, Compound 1 (free base) or a pharmaceutically acceptable salt thereof or the crystalline hydrate alternatively or additionally may provide: (a ) an average Cmax,ss for Compound 1 of about 36 ng/mL or about 37 ng/mL; (b) an average AUC24,ss for Compound 1 of about 317 ng-hours/mL or about 322 ng-hours/mL; (c) a Tmax,ss for Compound 1 of about 2.0 to about 6.0 hours or a median Tmax,ss for Compound 1 of about 4.0 hours; (d) an average Cmin,ss for Compound 1 of about 2.8 ng/mL or about 3.0 ng/mL; (e) a harmonic mean t1/2,ss for Compound 1 of about 9.4 hours or about 9.5 hours or 10.3 hours; or combinations thereof.

[0758] In certain embodiments, the present disclosure is directed to pharmaceutical compositions comprising a crystalline hydrate of Compound 1 in an amount sufficient to provide the subject with 15 mg of free base equivalent of Compound 1. In certain embodiments, the crystalline hydrate is the Free Base Hydrate Form C. In one embodiment, the crystalline hydrate is a once-daily extended-release formulation. In one embodiment, after oral administration of the pharmaceutical composition to an adult subject, the composition provides (a) an average Cmax for Compound 1 of about 25 to about 70 ng/mL; (b) a Tmax for Compound 1 of about 1.0 hour to about 6.0 hours; (c) a harmonic mean t1/2 for Compound 1 of about 10.0 to about 14.0 hours; (d) an average AUCinf for Compound 1 of about 220 to about 450 ng-hours/mL; (e) an average Cmax,ss for Compound 1 of about 27 to about 55 ng/mL; (f) an average AUC24.ss for Compound 1 of about 240 to about 325 ng-hours/mL; (g) a Tmax,ss for Compound 1 of about 1.5 to about 6.0 hours; (h) an average Cmin,ss for Compound 1 of about 2.8 to about 3.2 ng/mL; (i) a harmonic mean t1/2,ss for Compound 1 of about 9.4 to about 10.5 hours; or combinations thereof.

[0759] In one embodiment, after oral administration of the pharmaceutical composition to an adult subject, the composition provides (a) an average Cmax for Compound 1 of about 25 to about 70 ng/mL; (b) a Tmax for Compound 1 of about 1.0 hour to about 6.0 hours; (c) a harmonic mean t1/2 for Compound 1 of about 10.0 to about 14.0 hours; (d) an average AUCinf for Compound 1 of about 220 to about 450 ng-hours/mL; or their combinations, after a single dose of 15 mg.

[0760] In one embodiment, when administered QD (once per day) to the adult subject, the pharmaceutical composition provides (a) an average Cmax,ss for Compound 1 of about 27 to about 55 ng/mL; (b) an average AUC24.ss for Compound 1 of about 240 to about 325 ng-hours/mL; (c) a Tmax,ss for Compound 1 of about 1.5 to about 6.0 hours; (d) an average Cmin,ss for Compound 1 of about 2.8 to about 3.2 ng/mL; (e) a harmonic mean t1/2,ss for Compound 1 of about 9.4 to about 10.5 hours; or combinations thereof.

[0761] In one embodiment, after oral administration of the pharmaceutical composition to an adult subject under fasting conditions, the composition provides (a) an average Cmax for Compound 1 of about 26 ng/mL or about 32 ng/mL ; (b) a Tmax for Compound 1 of about 1.0 to about 4.0 hours, or of about 1.5 to about 6.0 hours, or a median Tmax for Compound 1 of about 3.0 hours; (c) a harmonic mean t1/2 for Compound 1 of about 12.5 hours; (d) an average AUCinf for Compound 1 of about 242 ng^hours/mL; or their combinations, after a single dose of 15 mg. In one embodiment, after oral administration of the pharmaceutical composition to an adult subject under non-fasting conditions, the composition provides (a) an average Cmax for Compound 1 of about 40 ng/mL; (b) a Tmax for Compound 1 of about 3.0 hours to about 6.0 hours or a median Tmax for Compound 1 of about 4.0 hours; (c) a harmonic mean t1/2 for Compound 1 of about 12.5 hours; or their combinations, after a single dose of 15 mg.

[0762] In one embodiment, after oral administration of the pharmaceutical composition to an adult subject QD (once per day) under fasting conditions, the composition, alternatively or additionally, provides (a) an average Cmax, ss for Compound 1 of about 32 ng/mL; (b) an average AUC24.ss for Compound 1 of about 279 ng-hours/mL; (c) a Tmax,ss for Compound 1 of about 1.5 to about 4.0 hours, or a median Tmax,ss for Compound 1 of about 2.5 hours; (d) an average Cmin,ss for Compound 1 of about 3.0 ng/mL or about 3.1 ng/mL; (e) a harmonic mean t1/2,ss for Compound 1 of about 9.5 hours or about 10.3 hours; or their combinations. In one embodiment, following oral administration of the pharmaceutical composition to an adult subject QD (once per day) under non-fasting conditions, the composition alternatively or additionally provides (a) an average Cmax,ss for Compound 1 of about 36 ng/mL or about 37 ng/mL; (b) an average AUC24,ss for Compound 1 of about 317 ng-hours/mL or about 322 ng-hours/mL; (c) a Tmax,ss for Compound 1 of about 2.0 to about 6.0 hours or a median Tmax,ss for Compound 1 of about 4.0; (d) an average Cmin,ss for Compound 1 of about 2.8 ng/mL or about 3.0 ng/mL; (e) a harmonic mean t1/2,ss for Compound 1 of about 9.4 hours or about 9.5 hours or about 10.3 hours; or combinations thereof.

[0763] In one embodiment, the present disclosure is directed to a pharmaceutical composition comprising about 15 mg of Free Base Hydrate Form C, a pharmaceutically acceptable carrier, and from about 10% w/w to about 35% w/w of tartaric acid, wherein the pharmaceutical composition is a once-daily extended-release dosage form (e.g., tablet or capsule) and, following oral administration of the pharmaceutical composition to an adult subject, the composition provides (a) an average Cmax for Compound 1 of about 25 to about 70 ng/mL; (b) a Tmax for Compound 1 of about 1.0 hour to about 6.0 hours; (c) a harmonic mean t1/2 for Compound 1 of about 10.0 to about 14.0 hours; (d) an average AUCinf for Compound 1 of about 220 to about 450 ng-hours/mL; (e) an average Cmax,ss for Compound 1 of about 27 to about 55 ng/mL; (f) an average AUC24.ss for Compound 1 of about 240 to about 325 ng-hours/mL; (g) a Tmax,ss for Compound 1 of about 1.5 to about 6.0 hours; (h) an average Cmin,ss for Compound 1 of about 2.8 to about 3.2 ng/mL; (i) a harmonic mean t1/2,ss for Compound 1 of about 9.4 to about 10.5 hours; or combinations thereof.

[0764] In one embodiment, the present disclosure is directed to a pharmaceutical composition comprising about 15 mg Free Base Hydrate Form C, a pharmaceutically acceptable carrier, and about 10% w/w or about 20% w/w or about 30% w/w tartaric acid, wherein the pharmaceutical composition is a once-daily extended-release dosage form (e.g., tablet or capsule) and, following oral administration of the pharmaceutical composition to an adult subject, the composition provides (a) an average Cmax for Compound 1 of about 25 to about 70 ng/mL; (b) a Tmax for Compound 1 of about 1.0 hour to about 6.0 hours; (c) a harmonic mean t1/2 for Compound 1 of about 10.0 to about 14.0 hours; (d) an average AUCinf for Compound 1 of about 220 to about 450 ng-hours/mL; or their combinations, after a single dose of 15 mg.

[0765] In one embodiment, the present disclosure is directed to a pharmaceutical composition comprising about 15 mg Free Base Hydrate Form C, a pharmaceutically acceptable carrier, and about 10% w/w or about 20% w/w or about 30% w/w tartaric acid, wherein the pharmaceutical composition is a once-daily extended-release dosage form (e.g., tablet or capsule) and, following oral administration of the pharmaceutical composition to an adult subject QD (once daily), the composition provides (a) an average Cmax,ss for Compound 1 of about 27 to about 55 ng/mL; (b) an average AUC24.ss for Compound 1 of about 240 to about 325 ng-hours/mL; (c) a Tmax,ss for Compound 1 of about 1.5 to about 6.0 hours; (d) an average Cmin,ss for Compound 1 of about 2.8 to about 3.2 ng/mL; (e) a harmonic mean t1/2,ss for Compound 1 of about 9.4 to about 10.5 hours; or combinations thereof.

[0766]30 mg Dosage Formulations

[0767] In certain embodiments, the methods of the present disclosure comprise administering to an adult subject (e.g., a human subject) 30 mg of Compound 1 (free base), or a pharmaceutically acceptable salt thereof, or a crystalline hydrate of Compound 1 in an amount sufficient to provide the subject with 30 mg of free base equivalent of Compound 1. In one embodiment, the free base or hydrate is in the form of a once-daily extended-release formulation.

[0768] Unless otherwise indicated, the following pharmacokinetic parameters are achieved after administration of a single dose of 30 mg of Compound 1 (free base) or a pharmaceutically acceptable salt thereof or the crystalline hydrate (e.g., Form C of Free Base Hydrate) to the adult subject, or after administration of a sufficient number of 30 mg doses once daily to achieve steady state. By a single dose of 30 mg is meant a single dosage unit containing an amount of free base or pharmaceutically acceptable salt or crystalline hydrate sufficient to provide the subject with 30 mg of free base equivalent of Compound 1. In one embodiment, the unit of Single dosage is presented in the form of a once-daily extended-release formulation.

[0769] In certain embodiments, when administered to the adult subject, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves an average Cmax for Compound 1 of about 55 to about 85 ng/mL , after a single dose of 30 mg. In certain embodiments, when administered to the adult subject, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves an average Cmax for Compound 1 of about 55 to about 70 ng/mL, or about 55 to about 67 ng/mL, or from about 55 to about 66 ng/mL, or from about 70 to about 85 ng/mL, or from about 72 to about 85 ng/mL, or from about 74 to about 85 ng/mL after a single 30 mg dose.

[0770] In certain embodiments, when administered to the subject under fasting conditions, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves an average Cmax for Compound 1 of about 55 ng/mL at about 66 ng/mL, or about 55 ng/mL, or about 56 ng/mL, or about 57 ng/mL, or about 59 ng/mL, or about 61 ng/mL, or about 64 ng/mL, or about 66 ng/mL after a single 30 mg dose. In other embodiments, when administered to the subject under non-fasting conditions, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves an average Cmax for Compound 1 of about 74 ng/mL to about 85 ng /mL, or about 74 ng/mL, or about 76 ng/mL, or about 77 ng/mL, or about 79 ng/mL, about 82 ng/mL, or about 84 ng/mL after a single dose of 30 mg.

[0771] In certain embodiments, when Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof is administered to the subject, the difference in Cmax for Compound 1 after a dose of 30 mg in the fed state versus the fed state fasting is about 55% or less, or about 53% or less, or about 30% or less, or about 20% or less, or about 10% or less. In one embodiment, the difference in Cmax for Compound 1 after a 30 mg dose in the fed state versus the fed state is from about 3% to about 40%, or from about 15% to about 55%.

[0772] When administered to the adult subject, in some embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves a Tmax for Compound 1 of about 1.0 to about 8.0 hours after a single dose of 30 mg. When administered to the adult subject, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves a Tmax for Compound 1 of about 2.0 to about 6.0 hours, or from about 1.0 to about 4.0 hours, or from about 1.5 to about 4.0 hours, or from about 1.5 to about 8.0 hours, or from about 2. 0 to about 4.0 hours, or from about 2.0 to about 3.0 hours, after a single 30 mg dose.

[0773] In other embodiments, when administered to the adult subject under fasting conditions, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves a Tmax for Compound 1 of about 1.0 to about 4 .0 hours, or from about 1.5 to about 4.0 hours, or a median Tmax for Compound 1 of about 2.0 hours, or about 2.5 hours, or about 3.0 hours, after a single dose of 30 mg. In other embodiments, when administered to the adult subject under non-fasting conditions, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves a Tmax for Compound 1 of about 1.5 to about 8 .0 hours, or about 2.0 hours to about 6.0 hours, or a median Tmax for Compound 1 of about 4.0 hours after a single 30 mg dose.

[0774] When administered to the adult subject, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt thereof or crystalline hydrate achieve a harmonic mean t1/2 for Compound 1 of about 9.0 to about 12.0 hours after a single dose of 30 mg. When administered to the adult subject, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves a harmonic mean t1/2,ss for Compound 1 of about 9.0 to about 11.0 hours, or from about 9.0 to about 10.0 hours, or from about 10.0 to about 12.0 hours, or from about 10.0 to about 11.5 hours, after a single dose of 30 mg.

[0775] When administered to the adult subject, in some embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt thereof or crystalline hydrate achieve a harmonic mean t1/2 for Compound 1 of about 9.0 hours, or about 9.5 hours, or about 10.0 hours, or about 10.5 hours, or about 11.0 hours, or about 11.5 hours, or about 12.0 hours, after a single dose of 30 mg.

[0776] When administered to the adult subject, in some embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves an average AUCinf for Compound 1 of about 453 to about 660 ng^hours /mL after a single dose of 30 mg. When administered to the adult subject, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves an average AUCinf for Compound 1 of about 483 to about 660 ng^hours/mL, or of about 483 to about 550 ng^hours/mL, or from about 484 to about 515 ng^hours/mL, or from about 484 to about 513 ng^hours/mL, or from about 560 to about from 660 ng^hours/mL, or from about 570 to about 660 ng^hours/mL, or from about 577 to about 657 ng^hours/mL, after a single 30 mg dose.

[0777] When administered to the adult subject under fasting conditions, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves an average AUCinf for Compound 1 of about 484 to about 550 ng ^hours/mL, or about 484 ng^hours/mL, or about 491 ng^hours/mL, or about 495 ng^hours/mL, or about 499 ng^hours/mL, or about 513 ng ^hours/mL after a single dose of 30 mg. When administered to the adult subject under fasting conditions, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves an average AUCt for Compound 1 of about 473 ng^hours/mL, or about of 477 ng^hours/mL, about 481 ng^hours/mL, or about 487 ng^hours/mL, or about 495 ng^hours/mL, or a mean AUC24 of about 454 ng^hours /mL, after a single dose of 30 mg. When administered to the adult subject under non-fasting conditions, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves a mean AUCinf for Compound 1 of about 560 to about 660 ng^hours. /mL, or about 577 ng^hours/mL, or about 609 ng^hours/mL, or about 622 ng^hours/mL, or about 657 ng^hours/mL, after a single dose of 30 mg. When administered to the adult subject under non-fasting conditions, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves an average AUC24 for Compound 1 of about 517 ng^hours/mL or about of 563 ng^hours/mL, or an average AUCt of about 564 ng^hours/mL, or about 605 ng^hours/mL, or about 615 ng^hours/mL, or about 648 ng^hours/mL after a single dose of 30 mg.

[0778] In certain embodiments, when Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof is administered to the subject, the difference in AUCinf for Compound 1 following a 30 mg dose in the fed state versus the fed state fasting is about 30% or less, or about 20% or less, or about 10% or less.

[0779] When administered to the adult subject, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves an average C24 for Compound 1 of about 2.3 to about 4. 5 ng/mL after a single dose of 30 mg. When administered to the adult subject under fasting conditions, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves an average C24 for Compound 1 of about 2.7 ng/mL, or about 3.2 ng/mL, or about 2.8 ng/mL, or about 3.5 ng/mL, or about 3.7 ng/mL, or about 3.9 ng/mL, after a single dose of 30 mg. When administered to the adult subject under non-fasting conditions, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves an average C24 for Compound 1 of about 2.4 ng/mL, or about 2.6 ng/mL, or about 2.8 ng/mL, or about 2.9 ng/mL, or about 4.3 ng/mL, after a single 30 mg dose.

[0780] When administered QD (once per day) to the adult subject, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt thereof or crystalline hydrate achieve an average Cmax, ss for Compound 1 from about 65 to about 86 ng/mL. When administered QD (once daily) to the adult subject, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves an average Cmax,ss for Compound 1 of about 65 to about 70 ng/mL, or from about 67 to about 68 ng/mL, or from about 78 to about 86 ng/mL, or from about 80 to about 84 ng/mL.

[0781] When administered QD (once daily) to the adult subject under fasting conditions, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt thereof or crystalline hydrate achieves an average Cmax,ss for Compound 1 of about 67 ng/mL or about 68 ng/mL. When administered QD (once daily) to the adult subject under non-fasting conditions, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt thereof or crystalline hydrate achieves an average Cmax,ss for Compound 1 of about 80 ng/mL or about 84 ng/mL.

[0782] When administered QD (once a day) to the adult subject, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt thereof or crystalline hydrate achieve a Tmax, ss of about 1 .5 to about 6.0 hours. When administered QD (once daily) to the adult subject, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt thereof or crystalline hydrate achieves a Tmax,ss of about 1.5 to about 4.0 hours, or from about 2.0 to about 4.0 hours, or from about 3.0 to about 4.0 hours, or from about 3.5 to about 4.0 hours.

[0783] When administered QD (once per day) to the adult subject under fasting conditions, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt thereof or crystalline hydrate achieves a Tmax, ss of about 2 .0 to about 4.0 hours, or a median Tmax,ss for Compound 1 of about 3.0 hours. When administered QD (once daily) to the adult subject under non-fasting conditions, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt thereof or crystalline hydrate achieves a Tmax,ss of about 1 5 to about 6.0 hours, or a median Tmax,ss for Compound 1 of about 3.5 hours to about 4.0 hours.

[0784] When administered QD (once per day) to the adult subject, in certain embodiments, Compound 1 (free base) or the crystalline hydrate achieves an average Cmin for Compound 1 of about 2.8 to about 6 .1ng/mL. When administered QD (once daily) to the adult subject under fasting conditions, in certain embodiments, Compound 1 (free base) or crystalline hydrate achieves an average Cmin for Compound 1 of about 4.9 ng/mL . When administered QD (once daily) to the adult subject under non-fasting conditions, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt thereof or crystalline hydrate achieves an average Cmin for Compound 1 of about from 2.8 to about 6.1 ng/mL, or from about 4.6 to about 6.1 ng/mL, or about 3.0 ng/mL, or about 4.7 ng/mL or about 5.3 ng/mL or about 6.1 ng/mL.

[0785] When administered QD (once per day) to the adult subject, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt thereof or crystalline hydrate achieve an average AUC24.ss for Compound 1 from about 485 to about 658 ng^hours/mL. When administered QD (once daily) to the adult subject, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves an average AUC24,ss for Compound 1 of about 520 to about 640 ng^hours/mL, or from about 520 to about 630 ng^hours/mL, or from about 525 to about 620 ng^hours/mL, or from about 525 to about 585 ng^ hours/mL, or from about 580 to about 630 ng^hours/mL, or from about 582 to about 620 ng^hours/mL.

[0786] When administered to the adult subject under fasting conditions, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves an average AUC24,ss for Compound 1 of about 525 ng^hours /mL. When administered to the adult subject under non-fasting conditions, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves an average AUC24.ss for Compound 1 of about 582 ng^hours /mL or about 620 ng^hours/mL.

[0787] When administered QD (once a day) to the adult subject, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt thereof or crystalline hydrate achieve an average Cmin, ss for Compound 1 from about 3.5 to about 5.3 ng/mL. When administered QD (once daily) to the adult subject, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves an average Cmin,ss for Compound 1 of about 3.6 to about 5.2 ng/mL, or from about 3.8 to about 5.2 ng/mL, or from about 4.6 to about 5.2 ng/mL.

[0788] When administered QD (once per day) to the adult subject under fasting conditions, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt thereof or crystalline hydrate achieve an average Cmin,ss for Compound 1 of about 3.8 ng/mL. When administered QD (once daily) to the adult subject under non-fasting conditions, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt thereof or crystalline hydrate achieves an average Cmin,ss for Compound 1 of about 4.6 ng/mL or about 5.2 ng/mL.

[0789] When administered QD (once a day) to the adult subject, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt thereof or crystalline hydrate achieves an average C24,ss for Compound 1 from about 4.0 to about 5.3 hours. When administered QD (once daily) to the adult subject under fasting conditions, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves an average C24,ss for Compound 1 of about 4.3 ng/mL or about 4.4 ng/mL. When administered QD (once daily) to the adult subject under fasting conditions, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves an average C24.ss for Compound 1 of about 5.3 ng/mL.

[0790] When administered QD (once a day) to the adult subject, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt thereof or crystalline hydrate achieve a harmonic mean t1/2,ss for Compound 1 from about 10.0 to about 14.5 hours. When administered QD (once daily) to the adult subject, in certain embodiments, Compound 1 (free base) or crystalline hydrate achieves a harmonic mean t1/2,ss for Compound 1 of about 10.1 to about 14 .4 hours, or from about 10.1 to about 10.4 hours, or from about 10.4 hours to about 14.4 hours. When administered QD (once daily) to the adult subject, in certain embodiments, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof achieves a harmonic mean t1/2,ss for Compound 1 of about 14 .4 hours to about 10.1 hours or about 10.4 hours.

[0791] In certain embodiments, when administered to the adult subject, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof provides: (a) an average Cmax for Compound 1 of about 55 to about 85 ng/mL; (b) a Tmax for Compound 1 of about 1.0 hour to about 8.0 hours; (c) a harmonic mean t1/2 for Compound 1 of about 9.0 to about 12.0 hours; (d) an average AUCinf for Compound 1 of about 483 to about 660 ng-hours/mL; (e) an average Cmax,ss for Compound 1 of about 65 to about 85 ng/mL; (f) an average AUC24,ss for Compound 1 of about 485 to about 658 ng-hours/mL; (g) a Tmax,ss for Compound 1 of about 1.5 to about 6.0 hours; (h) an average Cmin,ss for Compound 1 of about 3.5 to about 5.3 ng/mL; (i) a harmonic mean t1/2,ss for Compound 1 of about 10.0 to about 14.5 hours; or combinations thereof.

[0792] In certain embodiments, when administered to the adult subject, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof provides: (a) an average Cmax for Compound 1 of about 55 to about 85 ng/mL; (b) a Tmax for Compound 1 of about 1.0 hour to about 8.0 hours; (c) a harmonic mean t1/2 for Compound 1 of about 9.0 to about 12.0 hours; (d) an average AUCinf for Compound 1 of about 483 to about 660 ng-hours/mL; or their combinations, after a single dose of 30 mg.

[0793] In certain embodiments, when administered QD (once daily) to the adult subject, Compound 1 (free base) or a pharmaceutically acceptable salt thereof or crystalline hydrate provides: (a) an average Cmax,ss for Compound 1 from about 65 to about 85 ng/mL; (b) an average AUC24.ss for Compound 1 of about 485 to about 658 ng-hours/mL; (c) a Tmax,ss for Compound 1 of about 1.5 to about 6.0 hours; (d) an average Cmin,ss for Compound 1 of about 3.5 to about 5.3 ng/mL; (e) a harmonic mean t1/2,ss for Compound 1 of about 10.0 to about 14.5 hours; or combinations thereof.

[0794] In certain embodiments, when administered to the adult subject under fasting conditions, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof provides: (a) an average Cmax for Compound 1 of about 55 ng /mL to about 66 ng/mL, or about 55 ng/mL, or about 56 ng/mL, or about 57 ng/mL, or about 59 ng/mL, or about 61 ng/mL, or about 64 ng/mL or about 66 ng/mL; (b) a Tmax for Compound 1 of about 1.0 hour to about 4.0 hours, or about 1.5 hours to about 4.0 hours, or a median Tmax for Compound 1 of about 2.0 hours, or about 2.5 hours, or about 3.0 hours; (c) a harmonic mean t1/2 for Compound 1 of about 9.0 hours, or about 9.5 hours, or about 10.0 hours, or about 10.5 hours, or about 11.0 hours , or about 11.5 hours, or about 12.0 hours; (d) an average AUCinf for Compound 1 of about 484 to about 550 ng^hours/mL, or about 484 ng^hours/mL, or about 491 ng^hours/mL, or about 495 ng^hours/mL mL, or about 499 ng^hours/mL, or about 513 ng^hours/mL; or their combinations, after a single dose of 30 mg.

[0795] In certain embodiments, when administered to the adult subject under non-fasting conditions, Compound 1 (free base) or a pharmaceutically acceptable salt thereof or crystalline hydrate alternatively or additionally provide: (a) an average Cmax for Compound 1 of about 76 ng/mL to about 85 ng/mL, or about 76 ng/mL, or about 77 ng/mL, or about 79 ng/mL, about 82 ng/mL, or about 84 ng /mL; (b) a Tmax for Compound 1 of about 1.5 hours to about 8.0 hours, or from about 2.0 hours to about 6.0 hours, or a median Tmax for Compound 1 of about 4.0 hours; (c) a harmonic mean t1/2 for Compound 1 of about 9.0 hours, or about 9.5 hours, or about 10.0 hours, or about 10.5 hours, or about 11.0 hours, or about 11.5 hours, or about 12.0 hours; (d) an average AUCinf for Compound 1 of about 577 ng^hours/mL, or about 609 ng^hours/mL, or about 622 ng^hours/mL, or about 657 ng^hours/mL; or adult subject, after a single dose of 30 mg.

[0796] In one embodiment, when administered QD (once daily) to the adult subject under non-fasting conditions, Compound 1 (free base) or a pharmaceutically acceptable salt thereof or crystalline hydrate alternatively or additionally provides (a) a Average Cmax,ss for Compound 1 of about 67 ng/mL or about 68 ng/mL; (b) an average AUC24.ss for Compound 1 of about 525 ng-hours/mL; (c) a Tmax,ss for Compound 1 of about 2.0 to about 4.0 hours or a median Tmax,ss for Compound 1 of about 3.0 hours; (d) an average Cmin,ss for Compound 1 of about 3.8 ng/mL; (e) a harmonic mean t1/2,ss for Compound 1 of about 10.1 hours or about 10.4 hours or 14.4 hours; or combinations thereof.

[0797] In one embodiment, when administered QD (once daily) to the adult subject under non-fasting conditions, Compound 1 (free base) or a pharmaceutically acceptable salt thereof or crystalline hydrate alternatively or additionally provides (a) a Average Cmax,ss for Compound 1 of about 80 ng/mL or about 84 ng/mL; (b) an average AUC24,ss for Compound 1 of about 582 ng-hours/mL or about 620 ng-hours/mL; (c) a Tmax,ss for Compound 1 of about 1.5 to about 6.0 hours or a median Tmax,ss for Compound 1 of about 3.5 hours to about 4.0 hours; (d) a Cmin,ss for Compound 1 of about 4.6 ng/mL or about 5.2 ng/mL; (e) a harmonic mean t1/2,ss for Compound 1 of about 10.1 hours or about 10.4 hours or about 14.4 hours; or combinations thereof.

[0798] In certain embodiments, the present disclosure is directed to pharmaceutical compositions comprising a crystalline hydrate of Compound 1 in an amount sufficient to provide the subject with 30 mg of free base equivalent of Compound 1. In certain embodiments, the crystalline hydrate is the Free Base Hydrate Form C. In one embodiment, the crystalline hydrate is a once-daily extended-release formulation. In one embodiment, after oral administration of the pharmaceutical composition to an adult subject, the composition provides (a) an average Cmax for Compound 1 of about 55 to about 85 ng/mL; (b) a Tmax for Compound 1 of about 1.0 hour to about 8.0 hours; (c) a harmonic mean t1/2 for Compound 1 of about 9.0 to about 12.0 hours; (d) an average AUCinf for Compound 1 of about 483 to about 660 ng-hours/mL; (e) an average Cmax,ss for Compound 1 of about 65 to about 85 ng/mL; (f) an average AUC24,ss for Compound 1 of about 485 to about 658 ng-hours/mL; (g) a Tmax,ss for Compound 1 of about 1.5 to about 6.0 hours; (h) an average Cmin,ss for Compound 1 of about 3.5 to about 5.3 ng/mL; (i) a harmonic mean t1/2,ss for Compound 1 of about 10.0 to about 14.5 hours; or combinations thereof.

[0799] In one embodiment, after oral administration of the pharmaceutical composition to an adult subject, the composition provides (a) an average Cmax for Compound 1 of about 55 to about 85 ng/mL; (b) a Tmax for Compound 1 of about 1.0 hour to about 8.0 hours; (c) a harmonic mean t1/2 for Compound 1 of about 9.0 to about 12.0 hours; (d) an average AUCinf for Compound 1 of about 483 to about 660 ng-hours/mL; or their combinations, after a single dose of 30 mg.

[0800] In one embodiment, after oral administration of the pharmaceutical composition to an adult subject QD (once per day), the composition provides (a) an average Cmax, ss for Compound 1 of about 65 to about 85 ng /mL; (b) an average AUC24.ss for Compound 1 of about 485 to about 658 ng-hours/mL; (c) a Tmax,ss for Compound 1 of about 1.5 to about 6.0 hours; (d) an average Cmin,ss for Compound 1 of about 3.5 to about 5.3 ng/mL; (e) a harmonic mean t1/2,ss for Compound 1 of about 10.0 to about 14.5 hours; or combinations thereof.

[0801] In one embodiment, after oral administration of the pharmaceutical composition to an adult subject under fasting conditions, the composition provides (a) an average Cmax for Compound 1 of about 55 ng/mL to about 66 ng/mL , or about 55 ng/mL, or about 56 ng/mL, or about 57 ng/mL, or about 59 ng/mL, or about 61 ng/mL, or about 64 ng/mL, or about 66 ng/mL; (b) a Tmax for Compound 1 of about 1.0 hour to about 4.0 hours, or from about 1.5 hours to about 4.0 hours, or a median Tmax for Compound 1 of about 2, 0 hours, or about 2.5 hours, or about 3.0 hours; (c) a harmonic mean t1/2 for Compound 1 of about 9.0 hours, or about 9.5 hours, or about 10.0 hours, or about 10.5 hours, or about 11.0 hours , or about 11.5 hours, or about 12.0 hours; (d) an average AUCinf for Compound 1 of about 484 to about 550 ng^hours/mL, or about 484 ng^hours/mL, or about 491 ng^hours/mL, or about 495 ng^hours/mL mL, or about 499 ng^hours/mL, or about 513 ng^hours/mL; or their combinations, after a single dose of 30 mg.

[0802] In one embodiment, following oral administration of the pharmaceutical composition to an adult subject under non-fasting conditions, the composition provides (a) an average Cmax for Compound 1 of about 76 ng/mL to about 85 ng/mL mL, or about 76 ng/mL, or about 77 ng/mL, or about 79 ng/mL, about 82 ng/mL, or about 84 ng/mL; (b) a Tmax for Compound 1 of about 1.5 hours to about 8.0 hours, or from about 2.0 hours to about 6.0 hours, or a median Tmax for Compound 1 of about 4 .0 hours; (c) a harmonic mean t1/2 for Compound 1 of about 9.0 hours, or about 9.5 hours, or about 10.0 hours, or about 10.5 hours, or about 11.0 hours, or about 11.5 hours, or about 12.0 hours; (d) an average AUCinf for Compound 1 of about 577 ng^hours/mL, or about 609 ng^hours/mL, or about 622 ng^hours/mL, or about 657 ng^hours/mL; or adult subject, after a single dose of 30 mg.

[0803] In one embodiment, after oral administration of the pharmaceutical composition to an adult subject QD (once per day) under fasting conditions, the composition, alternatively or additionally, provides (a) an average Cmax, ss for Compound 1 of about 67 ng/mL or about 68 ng/mL; (b) an average AUC24.ss for Compound 1 of about 525 ng-hours/mL; (c) a Tmax,ss for Compound 1 of about 2.0 to about 4.0 hours, or a median Tmax,ss for Compound 1 of about 3.0 hours; (d) an average Cmin,ss for Compound 1 of about 3.8 ng/mL; (e) a harmonic mean t1/2,ss for Compound 1 of about 10.1 hours or about 10.4 hours or about 14.4 hours; or combinations thereof.

[0804] In one embodiment, following oral administration of the pharmaceutical composition to an adult subject QD (once per day) under non-fasting conditions, the composition, alternatively or additionally, provides (a) an average Cmax,ss for Compound 1 about 80 ng/mL or about 84 ng/mL; (b) an average AUC24,ss for Compound 1 of about 582 ng-hours/mL or about 620 ng-hours/mL; (c) a Tmax,ss for Compound 1 of about 1.5 to about 6.0 hours or a median Tmax,ss for Compound 1 of about 3.5 hours to about 4.0 hours; (d) a Cmin,ss for Compound 1 of about 4.6 ng/mL or about 5.2 ng/mL; (e) a harmonic mean t1/2,ss for Compound 1 of about 10.1 hours or about 10.4 hours or about 14.4 hours; or combinations thereof.

[0805] In one embodiment, the present disclosure is directed to pharmaceutical compositions comprising about 30 mg of Free Base Hydrate Form C, a pharmaceutically acceptable carrier, and from about 10% w/w to about 35% w/w. p of tartaric acid, wherein the pharmaceutical composition is a once-daily extended-release formulation and wherein, following oral administration of the pharmaceutical composition to an adult subject, the composition provides (a) an average Cmax for Compound 1 of about 55 to about 85 ng/mL; (b) a Tmax for Compound 1 of about 1.0 hour to about 8.0 hours; (c) a harmonic mean t1/2 for Compound 1 of about 9.0 to about 12.0 hours; (d) an average AUCinf for Compound 1 of about 483 to about 660 ng-hours/mL; (e) an average Cmax,ss for Compound 1 of about 65 to about 85 ng/mL; (f) an average AUC24,ss for Compound 1 of about 485 to about 658 ng-hours/mL; (g) a Tmax,ss for Compound 1 of about 1.5 to about 6.0 hours; (h) an average Cmin,ss for Compound 1 of about 3.5 to about 5.3 ng/mL; (i) a harmonic mean t1/2,ss for Compound 1 of about 10.0 to about 14.5 hours; or combinations thereof.

[0806] In one embodiment, the present disclosure is directed to pharmaceutical compositions comprising about 30 mg of Free Base Hydrate Form C, a pharmaceutically acceptable carrier, and about 10% w/w or about 20% w/w p or about 30% w/w tartaric acid, wherein the pharmaceutical composition is a once-daily extended-release formulation and wherein, following oral administration of the pharmaceutical composition to an adult subject, the composition provides (a ) an average Cmax for Compound 1 of about 55 to about 85 ng/mL; (b) a Tmax for Compound 1 of about 1.0 hour to about 8.0 hours; (c) a harmonic mean t1/2 for Compound 1 of about 9.0 to about 12.0 hours; (d) an average AUCinf for Compound 1 of about 483 to about 660 ng-hours/mL; or their combinations, after a single dose of 30 mg.

[0807] In one embodiment, the present disclosure is directed to pharmaceutical compositions comprising about 30 mg of Free Base Hydrate Form C, a pharmaceutically acceptable carrier and about 10% w/w or about 20% w/w p or about 30% w/w tartaric acid, wherein the pharmaceutical composition is a once-daily extended-release formulation and wherein, following oral administration of the pharmaceutical composition to an adult subject QD (once-a-day ), the composition provides (a) an average Cmax,ss for Compound 1 of about 65 to about 85 ng/mL; (b) an average AUC24.ss for Compound 1 of about 485 to about 658 ng-hours/mL; (c) a Tmax,ss for Compound 1 of about 1.5 to about 6.0 hours; (d) an average Cmin,ss for Compound 1 of about 3.5 to about 5.3 ng/mL; (e) a harmonic mean t1/2,ss for Compound 1 of about 10.0 to about 14.5 hours; or their combinations.

VIII. Extended Release Tablets

[0808] In one embodiment, Compound 1 (free base) or a pharmaceutically acceptable salt thereof or the crystalline hydrate used in the methods of the present disclosure is in the form of a once-daily extended release formulation. In one embodiment, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof is in the form of a once-daily extended-release formulation and the formulation provides orally QD (once-a-day). about 7.5 mg or about 15 mg or about 30 mg or about 45 mg per unit dosage form (e.g., per tablet or capsule) of Compound 1 (free base equivalent). In a particular embodiment, the crystalline hydrate is Free Base Hydrate Form C.

[0809] In one embodiment, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof is in the form of a once-daily extended-release formulation and the formulation provides QD (once a day). day) 7.5 mg of Compound 1 (free base equivalent). In some such embodiments, the once-daily extended-release formulation will have a relative bioavailability approximately equivalent to that of an immediate-release capsule comprising Compound 1 (free base) or a pharmaceutically acceptable salt thereof or a solid state form thereof that provides 3 mg of Compound 1 (free base equivalent) and is administered twice daily (BID). In one embodiment, the immediate-release capsule comprises a crystalline hydrate of Compound 1. In one embodiment, the immediate-release capsule comprises Free Base Hydrate Form C. In one embodiment, the immediate release capsule comprises Tartrate Hydrate.

[0810] In one embodiment, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof is in the form of a once-daily extended-release formulation and the formulation provides QD (once a day). day) 15 mg of Compound 1 (free base equivalent). In some such embodiments, the once-daily extended-release formulation will have a relative bioavailability approximately equivalent to that of an immediate-release capsule comprising Compound 1 (free base) or a pharmaceutically acceptable salt thereof or a solid state form thereof that provides 6 mg of Compound 1 (free base equivalent) and is administered twice daily (BID). In one embodiment, the immediate-release capsule comprises a crystalline hydrate of Compound 1. In one embodiment, the immediate-release capsule comprises Free Base Hydrate Form C. In one embodiment, the immediate release capsule comprises Tartrate Hydrate.

[0811] In one embodiment, Compound 1 (free base) or a pharmaceutically acceptable salt or crystalline hydrate thereof is in the form of a once-daily extended-release formulation and the formulation provides QD (once a day). day) 30 mg of Compound 1 (free base equivalent). In some such embodiments, the once-daily extended-release formulation will have a relative bioavailability approximately equivalent to that of an immediate-release capsule comprising Compound 1 (free base) or a pharmaceutically acceptable salt thereof or a solid state form thereof that provides 12 mg of Compound 1 (free base equivalent) and is administered twice daily (BID). In one embodiment, the immediate-release capsule comprises a crystalline hydrate of Compound 1. In one embodiment, the immediate-release capsule comprises Free Base Hydrate Form C. In one embodiment, the immediate release capsule comprises Tartrate Hydrate.

[0812] In one embodiment, Compound 1 (free base) or a pharmaceutically acceptable salt thereof or crystalline hydrate is presented in the form of a once-daily extended-release formulation and the formulation provides QD (once a day). day) 45 mg of Compound 1 (free base equivalent). In some such embodiments, the once-daily extended-release formulation will have a relative bioavailability approximately equivalent to that of an immediate-release capsule comprising Compound 1 (free base) or a pharmaceutically acceptable salt thereof or a solid state form thereof that provides 18 mg of Compound 1 (free base equivalent) and is administered twice daily (BID). In one embodiment, the immediate-release capsule comprises a crystalline hydrate of Compound 1. In one embodiment, the immediate-release capsule comprises Free Base Hydrate Form C. In one embodiment, the immediate release capsule comprises Tartrate Hydrate.

[0813] In one embodiment, the present disclosure is directed to a pharmaceutical composition comprising about 15 mg of free base of Compound 1 or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1, and a pharmaceutically acceptable carrier, in that the pharmaceutical composition is a once-daily sustained-release formulation, and the solid state form of Compound 1 is selected from the group consisting of Amorphous Free Base, Free Base Hydrate Form B, Free Base Hydrate Form C Free and Free Base Anhydrous Form D.

[0814] In one embodiment, the present disclosure is directed to a pharmaceutical composition comprising about 15 mg of free base of Compound 1 or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1, a pharmaceutically acceptable carrier and a modifier of pH, wherein the pharmaceutical composition is a once-daily extended release formulation, and the solid state form of Compound 1 is selected from the group consisting of Amorphous Free Base, Free Base Hydrate Form B, Form C of Free Base Hydrate and Free Base Anhydrous Form D. In one embodiment, the pharmaceutical composition comprises from about 10% by weight to about 30% by weight of the pH modifier. In one embodiment, the pH modifier is tartaric acid.

[0815] In one embodiment, the present disclosure is directed to a pharmaceutical composition comprising about 15 mg of a solid state form of Compound 1, a pharmaceutically acceptable carrier, and from about 10% w/w to about 35% w/w /p of tartaric acid, wherein the pharmaceutical composition is a once-daily extended-release formulation, and the solid state form of Compound 1 is selected from the group consisting of Amorphous Free Base, Free Base Hydrate Form B , Free Base Hydrate Form C and Free Base Anhydrous Form D.

[0816] In one embodiment, the present disclosure is directed to a pharmaceutical composition comprising about 15 mg of Free Base Hydrate Form B, a pharmaceutically acceptable carrier, and from about 10% w/w to about 35% w/w of tartaric acid, wherein the pharmaceutical composition is a once-daily extended-release formulation.

[0817] In one embodiment, the present disclosure is directed to a pharmaceutical composition comprising about 15 mg of Amorphous Free Base, a pharmaceutically acceptable carrier and from about 10% w/w to about 35% w/w tartaric acid in that the pharmaceutical composition is a once-daily extended-release formulation.

[0818] In one embodiment, the present disclosure is directed to a pharmaceutical composition comprising about 15 mg of Free Base Anhydrous Form D, a pharmaceutically acceptable carrier, and from about 10% w/w to about 35% w/w of tartaric acid wherein the pharmaceutical composition is a once-daily extended-release formulation.

[0819] In one embodiment, the present disclosure is directed to a pharmaceutical composition comprising about 15 mg of Free Base Hydrate Form C, a pharmaceutically acceptable carrier, and from about 10% w/w to about 35% w/w of tartaric acid, wherein the pharmaceutical composition is a once-daily extended-release formulation.

[0820] In one embodiment, the present disclosure is directed to a pharmaceutical composition comprising about 15 mg of Free Base Hydrate Form C, a pharmaceutically acceptable carrier and about 10% w/w tartaric acid, wherein The pharmaceutical composition is a once-daily extended-release formulation.

[0821] In one embodiment, the present disclosure is directed to a pharmaceutical composition comprising about 15 mg of Free Base Hydrate Form C, a pharmaceutically acceptable carrier and about 20% w/w tartaric acid, wherein The pharmaceutical composition is a once-daily extended-release formulation.

[0822] In one embodiment, the present disclosure is directed to a pharmaceutical composition comprising about 15 mg of Free Base Hydrate Form C, a pharmaceutically acceptable carrier and about 30% w/w tartaric acid, wherein The pharmaceutical composition is a once-daily extended-release formulation.

[0823] In one embodiment, the present disclosure is directed to a pharmaceutical composition comprising about 30 mg of free base of Compound 1 or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1, and a pharmaceutically acceptable carrier, in that the pharmaceutical composition is a once-daily sustained-release formulation, and the solid state form of Compound 1 is selected from the group consisting of Amorphous Free Base, Free Base Hydrate Form B, Free Base Hydrate Form C Free and Free Base Anhydrous Form D.

[0824] In one embodiment, the present disclosure is directed to a pharmaceutical composition comprising about 30 mg of free base of Compound 1 or a pharmaceutically acceptable salt thereof or a solid state form of Compound 1, a pharmaceutically acceptable carrier and a modifier of pH, wherein the pharmaceutical composition is a once-daily extended release formulation, and the solid state form of Compound 1 is selected from the group consisting of Amorphous Free Base, Free Base Hydrate Form B, Form C of Free Base Hydrate and Free Base Anhydrous Form D. In one embodiment, the pharmaceutical composition comprises from about 10% by weight to about 30% by weight of the pH modifier. In one embodiment, the pH modifier is tartaric acid.

[0825] In one embodiment, the present disclosure is directed to a pharmaceutical composition comprising about 30 mg of a solid state form of Compound 1, a pharmaceutically acceptable carrier, and from about 10% w/w to about 35% w/w /p of tartaric acid, wherein the pharmaceutical composition is a once-daily extended-release formulation, and the solid state form of Compound 1 is selected from the group consisting of Amorphous Free Base, Free Base Hydrate Form B , Free Base Hydrate Form C and Free Base Anhydrous Form D.

[0826] In one embodiment, the present disclosure is directed to a pharmaceutical composition comprising about 30 mg of Free Base Hydrate Form B, a pharmaceutically acceptable carrier, and from about 10% w/w to about 35% w/w of tartaric acid, wherein the pharmaceutical composition is a once-daily extended-release formulation.

[0827] In one embodiment, the present disclosure is directed to a pharmaceutical composition comprising about 30 mg of Amorphous Free Base, a pharmaceutically acceptable carrier, and from about 10% w/w to about 35% w/w tartaric acid in that the pharmaceutical composition is a once-daily extended-release formulation.

[0828] In one embodiment, the present disclosure is directed to a pharmaceutical composition comprising about 30 mg of Free Base Anhydrous Form D, a pharmaceutically acceptable carrier, and from about 10% w/w to about 35% w/w of tartaric acid wherein the pharmaceutical composition is a once-daily extended-release formulation.

[0829] In one embodiment, the present disclosure is directed to a pharmaceutical composition comprising about 30 mg of Free Base Hydrate Form C, a pharmaceutically acceptable carrier, and from about 10% w/w to about 35% w/w of tartaric acid, wherein the pharmaceutical composition is a once-daily extended-release formulation.

[0830] In one embodiment, the present disclosure is directed to a pharmaceutical composition comprising about 30 mg of Free Base Hydrate Form C, a pharmaceutically acceptable carrier and about 10% w/w tartaric acid, wherein The pharmaceutical composition is a once-daily extended-release formulation.

[0831] In one embodiment, the present disclosure is directed to a pharmaceutical composition comprising about 30 mg of Free Base Hydrate Form C, a pharmaceutically acceptable carrier and about 20% w/w tartaric acid, wherein The pharmaceutical composition is a once-daily extended-release formulation.

[0832] In one embodiment, the present disclosure is directed to a pharmaceutical composition comprising about 30 mg of Free Base Hydrate Form C, a pharmaceutically acceptable carrier and about 30% w/w tartaric acid, wherein The pharmaceutical composition is a once-daily extended-release formulation.

IX. Kits

[0833] The present disclosure also relates to kits comprising one or more solid pharmaceutical dosage units (such as tablets or capsules) comprising a solid state form of the present disclosure. The kit may optionally comprise one or more additional therapeutic agents and/or instructions, for example instructions for using the kit. In one aspect, the kit comprises one or more solid pharmaceutical dosage units (such as tablets or capsules) comprising a solid state form of the present disclosure and instructions for administering the one or more dosage forms to a subject.

[0834] In one embodiment, the kit comprises a first dosage unit and a second dosage unit, wherein the first dosage unit is a solid pharmaceutical dosage unit comprising a solid state form of the present disclosure, and the second unit dosage form comprises a second therapeutic agent. In one aspect, the second therapeutic agent is one of the therapeutic agents identified in the prior discussion relating to combination therapies. In another aspect, the second therapeutic agent is an immunosuppressant. In another aspect, the second therapeutic agent is a therapeutic agent for treating systemic lupus erythematosus. In another aspect, the second therapeutic agent is acetaminophen. In another aspect, the second therapeutic agent is methotrexate. In another aspect, the second therapeutic agent is a TNF antagonist, such as a humanized or human anti-TNF antibody (e.g., adalimumab, infliximab, golimumab, Certolizumab pegol, tocilizumab or enteracept).

X. Preparation Methods

[0835] The present disclosure also relates to methods of preparing a solid state form of Compound 1. In one aspect, the prepared solid state form is the Amorphous Free Base. In another aspect, the solid state form prepared is Free Base Hydrate Form B. In another aspect, the solid state form prepared is Free Base Hydrate Form C. In another aspect, the prepared solid state form is Tartrate Hydrate. In another aspect, the solid state form prepared is Free Base Anhydrous Form D.

A. Preparation of Amorphous Free Base

[0836] The present disclosure relates to methods for preparing the Amorphous Free Base. In one embodiment, the method comprises dehydrating the Free Base Hydrate Form B to provide the Amorphous Free Base. In another embodiment, the method comprises desolvating the Free Base Solvate Form A to provide the Amorphous Free Base. A wide range of process conditions can be employed for dehydration/desolvation. Dehydration can be conducted, for example, under ambient conditions or in a vacuum oven. Figure 1A schematically illustrates a method of preparing Amorphous Free Base by dehydrating Free Base Hydrate Form B.

[0837] In another embodiment, the method comprises dissolving Compound 1 in a solvent or mixture of solvents; and adjusting the pH of the solvent or solvent mixture to a pH greater than about 8 to initiate precipitation of the Amorphous Free Base. In one aspect, the solvent or mixture of solvents comprises water. In another aspect, the pH is adjusted to a pH greater than about 9. In another aspect, the pH is adjusted to a pH greater than about 10. In another aspect, the pH is adjusted to a pH greater than about 11 In another aspect, the pH is adjusted to a pH of at least about 9.

[0838] In still other embodiments, the method comprises preparing the Amorphous Free Base using a method selected from the group consisting of convergent injection, spray drying and hot melt extrusion.

B. Preparation of Crystalline Freebase Solvate Form A and Crystalline Freebase Hydrate Form B

[0839] The present disclosure further relates to methods for preparing Free Base Solvate Form A and Free Base Hydra Form B. In one embodiment, the method comprises dissolving Compound 1 in a solvent or mixture of solvents comprising an antisolvent; and maintaining the solvent or solvent mixture at a temperature below about 15 ° C for an amount of time sufficient to initiate crystallization of Free Base Solvate Form A and Free Base Hydra Form B. The antisolvent may comprise, for example, water. The solvent or mixture of solvents may comprise a polar solvent such as a solvent selected from the group consisting of methanol, ethanol, n-butylamine, acetone, acetonitrile, ethyl formate, methyl acetate, ethyl acetate, methyl ethyl ketone , methyl isobutyl ketone, methyl isobutyl ketone, methyl tert-butyl ether and isopropyl acetate. Freebase Solvate Form A and Freebase Hydrate Form B exhibit similar PXRD patterns and are as such isostructural. The method is generally conducted at subambient temperatures, for example, less than about 10 °C, less than about 5 °C, or less than about 0 °C. In certain aspects, the process further comprises seeding the solvent or mixture of solvents with crystals of Free Base Solvate Form A or Free Base Hydra Form B.

C. Preparation of Crystalline Free Base Hydrate Form C

[0840] The present disclosure further relates to methods for preparing Free Base Hydrate Form C. In one embodiment, the method comprises dissolving Compound 1 in a solvent or mixture of solvents; and initiating crystallization to provide Free Base Hydrate Form C. The solvent or mixture of solvents will generally comprise an antisolvent (such as water) which may be present in the solvent or mixture of solvents before, or added to the solvent or mixture of solvents after, Compound 1 is dissolved in the solvent or mixture of solvents. The solvent or mixture of solvents may comprise, for example, one or more polar solvents (such as a polar solvent selected from the group consisting of ethanol and ethyl acetate); one or more non-polar solvents (such as a non-polar solvent selected from the group consisting of hexane and heptane); or at least one polar solvent and at least one non-polar solvent. In one aspect, the solvent or solvent mixture is a ternary solvent mixture comprising ethyl acetate, heptane and water. The method is generally conducted at temperatures less than about 30°C, less than about 20°C, or less than about 10°C. In certain aspects, the step of initiating crystallization comprises mixing the solvent or mixture of solvents to provide sufficient agitation to initiate crystallization. In certain aspects, the crystallization initiation step comprises seeding the solvent or solvent mixture with Free Base Hydrate Form C crystals. In certain aspects, the crystallization initiation step comprises mixing the solvent or solvent mixture and seeding the solvent or solvent mixture with Free Base Hydrate Form C crystals.

[0841] In one embodiment, Compound 1 is first prepared according to any of the methods presented herein, a reaction mixture comprising Compound 1 is filtered, and the resulting solution is suspended in a solvent or mixture of solvents. The solvent or mixture of solvents may comprise, for example, one or more polar solvents (such as a polar solvent selected from the group consisting of ethanol and ethyl acetate); one or more non-polar solvents (such as a non-polar solvent selected from the group consisting of hexane and heptane); or at least one polar solvent and at least one non-polar solvent. In a particular embodiment, the solvent is ethyl acetate, or a mixture of ethyl acetate and water. In certain aspects, the crystallization initiation step comprises seeding the solvent or solvent mixture with Free Base Hydrate Form C crystals. In a particular aspect, crystallization occurs in a wet grinding mill.

[0842] Figure 1B schematically illustrates a method of preparing Free Base Hydrate Form C.

D. Preparation of Crystalline Free Base Anhydrous Form D

[0843] The present disclosure further relates to methods for preparing Free Base Anhydrous Form D. In one embodiment, the method comprises dissolving Compound 1 in a solvent or mixture of solvents; and initiating crystallization to provide Free Base Anhydrous Form D. The solvent or mixture of solvents will be anhydrous or close to it. In embodiments, the solvent or solvent mixture will have a water content of less than about 0.15% by weight, or less than about 0.10% by weight, or less than about 0.05% by weight, or about 0% by weight at 23°C. In one embodiment, the solvent or mixture of solvents will have a water activity of about 2.4% or less, or about 2.2% or less, or about 2.0% or less, or about 1.5 % or less. The solvent or mixture of solvents may comprise, for example, ethyl acetate (EtOAc), heptane and combinations thereof. In one embodiment, the solvent system comprises a mixture of heptane in ethyl acetate. In some embodiments, the solvent system comprises about 10% by weight, or about 20% by weight, or about 30% by weight, or about 40% by weight heptane in ethyl acetate. The method is generally conducted at temperatures of at least about 7°C, at least about 23°C, at least about 25°C or less, or at least about 30°C. In one embodiment, the method is conducted at about 23 °C. In certain aspects, the step of initiating crystallization comprises mixing the solvent or mixture of solvents to provide sufficient agitation to initiate crystallization. In certain aspects, the crystallization initiation step comprises seeding the solvent or solvent mixture with Free Base Anhydrous Form D crystals. In certain aspects, the crystallization initiation step comprises mixing the solvent or solvent mixture and seeding the solvent or solvent mixture with Free Base Anhydrous Form D crystals.

E. Preparation of Crystalline Tartrate Hydrate

[0844] The present disclosure further relates to methods for preparing Tartrate Hydrate. In one embodiment, the method comprises dissolving Compound 1 and L-tartaric acid in a solvent or mixture of solvents to form a crystallization solution; and crystallizing the Tartrate Hydrate from the crystallization solution. The solvent or mixture of solvents may comprise, for example, water and/or, for example, one or more polar solvents (such as isopropyl acetate). The solvent or solvent mixture may also comprise an antisolvent (such as isopropyl acetate). In certain aspects, the process further comprises seeding the solvent or solvent mixture with Tartrate Hydrate crystals.

[0845] Crystallization is generally conducted at a temperature below about 40 °C. When an antisolvent is used, a moderate rate of addition is employed for the antisolvent, since a faster rate of addition typically results in the precipitation of an amorphous tartrate and a slower rate of addition allows the resulting paste to thicken. Adequate control of filtration, washing and drying may be necessary to avoid potential problems associated with filter cake consolidation, including solvent entrapment, solids properties (e.g., hard and bulky solids) and handling, and equipment damage. Depending on the properties of the dry Tartrate Hydrate material, grinding may require a mechanical impact type mill rather than a shear-based mill (such as a co-mill).

[0846] Figure 1C schematically illustrates a method of preparing Tartrate Hydrate.

XI. Product-by-Process

[0847] The present disclosure also relates to a solid state form of Compound 1 prepared according to any of the methods described in the disclosure.

[0848] In one embodiment, the solid state form prepared is the Amorphous Free Base.

[0849] In one embodiment, the solid state form prepared is Free Base Hydrate Form B.

[0850] In one embodiment, the solid state form prepared is Free Base Hydrate Form C.

[0851] In one embodiment, the solid state form prepared is Tartrate Hydrate.

[0852] In one embodiment, the solid state form prepared is Free Base Anhydrous Form D.

XII. Additional Modalities

[0853]In some aspects, disclosure is directed to the following additional modalities:

[0854] Modality A: A crystalline hydrate of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)- N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide.

[0855] Modality A1: The crystalline hydrate of Modality A, where the hydrate is a hemihydrate.

[0856] Modality A2: The crystalline hydrate of Modality A or Modality A1 having an X-ray diffraction pattern by the powder method characterized by peaks at 13.4 ± 0.2, 15.1 ± 0.2 and 21.7 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Kα1 radiation.

[0857] Modality A3: The crystalline hydrate of Modality A2, in which the X-ray diffraction pattern by the powder method is additionally characterized by peaks at 15.5 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Ka1 radiation.

[0858] Modality A4: The crystalline hydrate of Modality A3, in which the X-ray diffraction pattern by the powder method is additionally characterized by peaks at 17.0 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Ka1 radiation.

[0859] Modality A5: The crystalline hydrate of Modality A4, in which the X-ray diffraction pattern by the powder method is additionally characterized by peaks at 20.9 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Ka1 radiation.

[0860] Modality A6: The crystalline hydrate of any one of Modalities A to A5, wherein the crystalline hydrate has an X-ray diffraction pattern by the powder method substantially as shown in Figure 3C.

[0861] Modality A7: The crystalline hydrate of any of Modalities A to A6, wherein the crystalline hydrate has a thermogravimetric analysis profile substantially as shown in Figure 4E.

[0862] Modality A8: The crystalline hydrate of any one of Modalities A to A7, wherein the crystalline hydrate has a differential scanning calorimetry profile substantially as shown in Figure 5C.

[0863] Modality A9: The crystalline hydrate of any of Modalities A to A8, wherein the crystalline hydrate has a moisture sorption isotherm profile substantially as shown in Figure 6B.

[0864]Modality A10: The crystalline hydrate of any of Modalities A to A9, wherein the crystalline hydrate has a thermogravimetric analysis profile showing a weight loss of about 2.3% to about 2.6% between about 120°C and 160°C when heated at a rate of 10°C/minute; and a differential scanning calorimetry profile comprising an endotherm between about 120°C to about 170°C when heated at a rate of 10°C/minute.

[0865] Modality A11: The crystalline hydrate of any of Modalities A to A10, wherein the crystalline hydrate has an orthorhombic lattice type.

[0866] Modality A12: The crystalline hydrate of Modality A11, wherein the crystalline hydrate has a space group P212121.

[0867] Modality A13: The crystalline hydrate of Modality A11 or A12, wherein the crystalline hydrate has unit cell a, b and c values of about 12.7 Á, about 13.1 Á and about 22.6 Á, respectively.

[0868] Modality A14: The crystalline hydrate of Modality A having an X-ray diffraction pattern by the powder method characterized by peaks at 3.1 ± 0.2, 9.3 ± 0.2, and 12.0 ± 0 .2 degrees two theta when measured at about 25 °C with monochromatic Ka1 radiation.

[0869]Modality A15: The crystalline hydrate of Modality A14, in which the X-ray diffraction pattern by the powder method is further characterized by peaks at 20.8 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Ka1 radiation.

[0870]Modality A16: The crystalline hydrate of Modality A15, in which the X-ray diffraction pattern by the powder method is further characterized by peaks at 25.0 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Ka1 radiation.

[0871] Modality A17: The crystalline hydrate of any one of Modalities A or A14 to A16, wherein the crystalline hydrate has an X-ray diffraction pattern by the powder method substantially as shown in Figure 3B.

[0872] Modality A18: The crystalline hydrate of any one of Modalities A or A14 to A17, wherein the crystalline hydrate has a thermogravimetric analysis profile substantially as shown in Figure 4D.

[0873]Modality A19: The crystalline hydrate of any one of Modalities A or A14 to A18, wherein the crystalline hydrate has a differential scanning calorimetry profile substantially as shown in Figure 5B.

[0874] Modality A20: A pharmaceutical composition comprising a crystalline hydrate according to any one of embodiments A to A19 and a pharmaceutically acceptable carrier.

[0875] Modality A21: The pharmaceutical composition of Modality A20, in which more than about 90% by weight 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 in the composition is a crystalline hydrate of (3S,4R)-3-ethyl-4-( 3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide having an X-ray diffraction pattern by powder method characterized by peaks at 13.4 ± 0.2, 15.1 ± 0.2, and 21.7 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Ka1 radiation.

[0876] Modality A22: The pharmaceutical composition of Modality A20, in which more than about 90% by weight 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 in the composition is a crystalline hydrate of (3S,4R)-3-ethyl-4-( 3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide having an X-ray diffraction pattern by powder method comprising peaks at 3.1 ± 0.2, 9.3 ± 0.2 and 12.0 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Ka1 radiation.

[0877] Modality B: (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2 Amorphous free base ,2,2-trifluoroethyl)pyrrolidine-1-carboxamide.

[0878] Modality B1: A (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-( Amorphous free base 2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide of Modality B comprising less than about 12% by weight of water.

[0879] Modality B2: A (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-( Amorphous free base 2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide of Modality B or B1 having an onset glass transition temperature of about 119 °C.

[0880] Modality B3: A (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-( Amorphous free base 2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide of any one of Embodiments B to B22 having a glass transition temperature midpoint of about 122 ° C.

[0881] Modality B4: A pharmaceutical composition comprising (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N -(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide amorphous free base according to any one of Embodiments B to B3 and a pharmaceutically acceptable carrier.

[0882] Modality B5: The pharmaceutical composition of Modality B4, in which more than about 90% by weight of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyr- rolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide in the composition is (3S,4R)-3-ethyl-4-(3H-imidazo Amorphous free base [1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide.

[0883] Modality C: A crystalline anhydrous 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.

[0884]Modality C1: The anhydrous crystalline of Modality C having an X-ray diffraction pattern by the powder method characterized by peaks at 8.0 ± 0.2, 9.7 ± 0.2, 14.2 ± 0, 2, 14.5 ± 0.2 and 20.3 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Kα1 radiation.

[0885]Modality C2: The anhydrous crystalline of Modality C1, in which the X-ray diffraction pattern by the powder method is additionally characterized by peaks at 4.0 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Ka1 radiation.

[0886]Modality C3: The anhydrous crystalline of Modality C2, in which the X-ray diffraction pattern by the powder method is additionally characterized by peaks at 19.0 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Ka1 radiation.

[0887]Modality C4: The anhydrous crystalline of Modality C3 in which the X-ray diffraction pattern by the powder method is further characterized by peaks at 18.4 ± 0.2, 23.0 ± 0.2, and 24, 7 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Kα1 radiation.

[0888] Modality C5: The anhydrous crystalline of any one of Modalities C to C4, wherein the anhydrous crystalline has an X-ray diffraction pattern by the powder method substantially as shown in Figure 3J.

[0889]Modality C6: The crystalline anhydrous of any of Modalities C to C5, wherein the crystalline anhydrous has a thermogravimetric analysis profile substantially as shown in Figure 4I.

[0890] Modality C7: The anhydrous crystalline of any of Modalities C to C6, wherein the anhydrous crystalline has a differential scanning calorimetry profile substantially as shown in Figure 5E.

[0891] Modality C8: The crystalline anhydrous of any of Modalities C to C7, wherein the crystalline anhydrous has a moisture sorption isotherm profile substantially as shown in Figure 6D.

[0892] Modality C9: The crystalline anhydrous of any of Modalities C to C8, in which the crystalline anhydrous has an orthorhombic lattice type.

[0893] Modality C10: The crystalline anhydrous of any of Modalities C to C9, wherein the crystalline anhydrous has a space group P21212.

[0894] Modality C11: The crystalline anhydrous of any of Modalities C to C10, wherein the crystalline anhydrous has unit cell a, b, and c values of about 43.8 Á, about 8.6 Á, and about 9 ,2 Á, respectively.

[0895] Modality C12: The crystalline anhydrous of any of Modalities C to C11, wherein the crystalline hydrate has a thermogravimetric analysis profile showing a weight loss of about 0.5% to about 0.8% between about 43°C and 188°C when heated at a rate of 10°C/minute; and a differential scanning calorimetry profile comprising an endotherm between about 180°C to about 220°C when heated at a rate of 10°C/minute.

[0896] Modality C13: The crystalline anhydrous of any of Modalities C to C12, wherein the crystalline anhydrous has an initial melting point at about 199.6 °C.

[0897] Modality C14: A pharmaceutical composition comprising a crystalline anhydrous according to any one of claims C to C13 and a pharmaceutically acceptable carrier.

[0898] Modality C15: The pharmaceutical composition of Modality C14, in which more than about 90% by weight 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 in the composition is a crystalline anhydrous of (3S,4R)-3-ethyl-4-(3H- imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide having an X-ray diffraction pattern by the method of powder characterized by peaks at 8.0 ± 0.2, 9.7 ± 0.2, 14.2 ± 0.2, 14.5 ± 0.2 and 20.3 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Ka1 radiation.

[0899]Modality D: A pharmaceutical composition comprising (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl tartrate )-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, between 10% w/w to about 35% w/w of an organic acid selected from the group consisting of tartaric acid, fumaric acid , citric acid, succinic acid, malic acid and combinations thereof, and a pharmaceutically acceptable carrier.

[0900]Modality D1: The pharmaceutical composition of Modality D, in which the tartrate is crystalline tartrate tetrahydrate of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrole[2 ,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide.

[0901] Modality D2: The pharmaceutical composition of Modality D or Modality D1, in which the tartrate has an X-ray diffraction pattern by the powder method characterized by peaks at 3.9 ± 0.2, 6.8 ± 0.2, and 14.1 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Kα1 radiation.

[0902] Modality D3: The pharmaceutical composition of any of Modalities D to D2, in which the tartrate has an X-ray diffraction pattern by the powder method substantially as shown in Figure 3D.

[0903]Modality D4: The pharmaceutical composition of any of Modalities D to D3, wherein the tartrate has a thermogravimetric analysis profile substantially as shown in Figure 4F.

[0904] Modality D5: The pharmaceutical composition of any of Modalities D to D4, wherein the tartrate has a differential scanning calorimetry profile substantially as shown in Figure 5D.

[0905] Modality D6: The pharmaceutical composition of any of Modalities D to D5, in which the tartrate has a moisture sorption isotherm profile substantially as shown in Figure 6C.

[0906]Modality D7: The pharmaceutical composition of any one of Modality D to D6, in which more than about 90% by weight 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 in the composition is crystalline tartrate tetrahydrate 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.

[0907] Modality E: The pharmaceutical composition of any of Modalities A20 to A22, B4, B5, C14, C15, or D to D7, wherein the composition comprises a release control polymer.

[0908] Modality E1: The pharmaceutical composition of Modality E, in which the release controlling polymer is a hydrophilic polymer.

[0909]Modality E2: The pharmaceutical composition of Modality E or E1, in which the release control polymer is a cellulose derivative with a viscosity between 1000 and 150,000 mPa-s.

[0910]Modality E3: The pharmaceutical composition of any of Modalities E to E2, in which the release controlling polymer is selected from the group consisting of hydroxypropylmethyl cellulose, hydroxyethyl cellulose and acrylic acid copolymers cross-linked with a polyether polyalkenyl and its combinations.

[0911]Modality E4: The pharmaceutical composition of any of Modalities E to E3, in which the release controlling polymer is selected from the group consisting of hydroxypropylmethyl cellulose, hydroxyethyl cellulose and combinations thereof.

[0912]Modality E5: The pharmaceutical composition of any of Modalities E to E4, in which the release controlling polymer is hydroxypropylmethyl cellulose.

[0913] Modality E6: The pharmaceutical composition of Modality E5, in which the hydroxypropylmethyl cellulose is grade E, F or K.

[0914]Modality E6: The pharmaceutical composition of Modality E5, in which the hydroxypropylmethyl cellulose is Hypromellose 2208.

[0915] Modality E7: The pharmaceutical composition of any of Modalities E to E6, wherein the composition comprises a filler.

[0916]Modality E8: The pharmaceutical composition of Modality E7, in which the filler is selected from the group consisting of microcrystalline cellulose, mannitol and a combination thereof.

[0917]Modality E9: The pharmaceutical composition of any of Modalities E to E8, wherein the composition comprises a lubricant.

[0918] Modality E10: The pharmaceutical composition of any of Modalities E to E9, wherein the composition comprises a fluidizer.

[0919]Modality E11: The pharmaceutical composition of any of Modalities E to E10, wherein the composition comprises a pH modifier.

[0920] Modality E12: The pharmaceutical composition of Modality E11, in which the pH modifier is selected from the group consisting of tartaric acid, fumaric acid, citric acid, succinic acid, malic acid and combinations thereof.

[0921]Modality E13: The pharmaceutical composition of Modalities E11 to E12, in which the pH modifier is selected from the group consisting of tartaric acid, fumaric acid, citric acid, succinic acid and combinations thereof.

[0922]Modality E14: The pharmaceutical composition of any of Modalities E11 to E13, in which the pH modifier is selected from the group consisting of tartaric acid, fumaric acid and combinations thereof.

[0923] Modality E15: The pharmaceutical composition of any of Modalities E11 to E14, in which the pH modifier is tartaric acid.

[0924]Modality E16: The pharmaceutical composition of any of Modalities E11 to E14, in which the pH modifier is fumaric acid or citric acid.

[0925]Modality E17: The pharmaceutical composition of any of Modalities E11 to E16, in which the pH modifier is present in an amount of about 10 to about 35% w/w.

[0926]Modality E18: The pharmaceutical composition of any of Modalities E11 to E17, in which the pH modifier is present in an amount of about 20 to about 35% w/w.

[0927]Modality E19: The pharmaceutical composition of any of Modalities E11 to E18, in which the pH modifier is present in an amount of about 20 to about 30% w/w.

[0928] Modality E20: The pharmaceutical composition of any of Modalities E11 to E19, in which the pH modifier is present in an amount of about 20 to about 25% w/w.

[0929]Modality E21: The pharmaceutical composition of any of Modalities E11 to E20, in which the pH modifier is present in an amount of about 10% w/w.

[0930]Modality E22: The pharmaceutical composition of any of Modalities E11 to E20, in which the pH modifier is present in an amount of about 20% w/w.

[0931]Modality E23: The pharmaceutical composition of any of Modalities E11 to E20, in which the pH modifier is present in an amount of about 30% w/w.

[0932]Modality F: A method of treating a condition associated with JAK-1, the method comprising administering a therapeutically effective amount of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a] pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide according to any one of Embodiments A to A19, B to B3, or C to C13, to a subject suffering from, or susceptible to, the condition.

[0933]Modality F1: The method of Modality F, in which the therapeutically effective amount of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3- e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide is selected from the group consisting of 7.5 mg once a day, 15 mg once a day , 30 mg once a day and 45 mg once a day.

[0934]Modality F2: A method of treating a condition associated with JAK-1, the method comprising administering the pharmaceutical composition of any of Modalities A20 to A22, B4, B5, C14, C15, D to D7 or E to E23 to a subject suffering from, or susceptible to, the condition.

[0935]Modality F2a: The method of any of Modalities F to F2, in which the condition is selected from the group consisting of immunomodeling, inflammation and proliferative diseases.

[0936]Modality F2b: The method of any of Modalities F to F2a, in which the (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e ]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide is Form C of Free Base Hydrate.

[0937]Modality F3: A (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2, 2,2-trifluoroethyl)pyrrolidine-1-carboxamide according to any one of Embodiments A to A19, B to B3, or C to C13, for use in treating a condition associated with JAK-1. In certain aspects of Modality E3, use comprises administering a therapeutically effective amount of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e ]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide according to any one of Embodiments A to A19, B to B3, or C to C13, to a subject suffering from, or susceptible to, condition. In one embodiment, the condition is selected from the group consisting of immunomodulation, inflammation and proliferative diseases. In certain aspects, in Embodiment F3, (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-( 2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide may be Free Base Hydrate Form C. In some aspects, in Embodiment F3, the therapeutically effective amount of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8- il)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide is selected from the group consisting of 7.5 mg once daily, 15 mg once daily, 30 mg once daily and 45 mg once a day.

[0938]Modality F4: The pharmaceutical composition of any of Modalities A20 to A22, B4, B5, C14, C15, D to D7, or E to E23, for use in treating a condition associated with JAK-1. In certain aspects of Embodiment F4, use comprises administering the pharmaceutical composition to a subject suffering from, or susceptible to, the condition. In one embodiment, the condition is selected from the group consisting of immunomodulation, inflammation, and proliferative diseases. In certain aspects, in Embodiment F4, the composition comprises Free Base Hydrate Form C.

[0939]Modality G: 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, the method comprising administering a therapeutically effective amount of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3- e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide of any of Embodiments A to A19, B to B3, or C to C13 to a subject suffering from, or susceptible to the condition.

[0940]Modality G1: The method of Modality G, in which the therapeutically effective amount of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e] pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide is selected from the group consisting of 7.5 mg once a day, 15 mg once a day, 30 mg once a day and 45 mg once a day.

[0941] Modality G2: 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, the method comprising administering the pharmaceutical composition of any of Modalities A20 to A22, B4, B5, C14, C15, D to D7, or E to E23 to a subject suffering from, or susceptible to, the condition.

[0942]Modality G3: The method of any of Modalities G to G2, in which the condition is rheumatoid arthritis.

[0943]Modality G3a: The method of any of Modalities G to G3, in which the (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e ]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide is Form C of Free Base Hydrate.

[0944] Modality G4: A (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-( 2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide of any one of Modalities A to A19, B to B3, or C to C13, for use in the treatment of a condition selected from the group consisting of 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 certain aspects of Embodiment G4, use comprises administering a therapeutically effective amount of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8 -yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide according to any of Embodiments A to A19, B to B3, or C to C13, to a subject suffering from, or susceptible to the condition. In one embodiment, the condition is rheumatoid arthritis. In some cases, in Modality G4, the therapeutically effective amount of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8- il)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide can be selected from the group consisting of 7.5 mg once a day, 15 mg once a day, 30 mg once a day and 45 mg once a day. In certain aspects, in Embodiment G4, (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-( 2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide may be Free Base Hydrate Form C.

[0945] Modality G5: A pharmaceutical composition of any of Modalities A20 to A22, B4, B5, C14, C15, D to D7, or E to E23 for use in treating a condition selected from the group consisting of 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 certain aspects of Embodiment G5, use comprises administering the pharmaceutical composition to a subject suffering from, or susceptible to, the condition. In one embodiment, the condition is rheumatoid arthritis. In certain aspects, in Embodiment G5, the composition comprises Free Base Hydrate Form C.

[0946]Modality H: A method of treating moderately to severely active rheumatoid arthritis, the method comprising administering a therapeutically effective amount of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a ]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide according to any one of Embodiments A to A19, B to B3, or C to C13, to a subject suffering from, or susceptible to, the condition.

[0947]Modality H1: The method of Modality H, in which the therapeutically effective amount of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3- e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide is about 7.5 mg once a day.

[0948]Modality H2: The method of Modality H, in which the therapeutically effective amount of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3- e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide is about 15 mg once a day.

[0949]Modality H3: The method of Modality H, in which the therapeutically effective amount of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3- e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide is about 30 mg once a day.

[0950]Modality H4: The method of Modality H, in which the therapeutically effective amount of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3- e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide is about 45 mg once a day.

[0951]Modality H5: A method of treating moderately to severely active rheumatoid arthritis, the method comprising administering the pharmaceutical composition of any of Modalities A20 to A22, B4, B5, C14, C15, D to D7 or E to E23 to a subject suffering from, or susceptible to, the condition.

[0952]Modality H6: The method of any of Modalities H to H5, in which the (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e ]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide is Form C of Free Base Hydrate.

[0953] Modality H7: The method according to any one of Modalities H to H6, in which the subject had an inadequate response to methotrexate.

[0954]Modality H8: The method according to any of Modalities H to H7, in which the subject has had an inadequate response to biological medicines approved for rheumatoid arthritis.

[0955]Modality H9: The method according to any of Modalities H to H8, in which the subject has not previously been administered biological drugs approved for rheumatoid arthritis.

[0956] Modality H10: A (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2, 2,2-trifluoroethyl)pyrrolidine-1-carboxamide according to any of Modalities A to A19, B to B3, or C to C13, for use in the treatment of moderately to severely active rheumatoid arthritis. In certain aspects of Embodiment H10, use comprises administering a therapeutically effective amount of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8 -yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide according to any of Embodiments A to A19, B to B3, or C to C13, to a subject suffering from, or susceptible to the condition. In one aspect, in Embodiment H10, the therapeutically effective amount of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8- il)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide is about 7.5 or about 15 mg or about 30 mg or about 45 mg once a day.

[0957]Modality H11: The pharmaceutical composition of any of Modalities A20 to A22, B4, B5, C14, C15, D to D7, or E to E23, for use in the treatment of moderately to severely active rheumatoid arthritis. In certain aspects of Embodiment H11, use comprises administering the pharmaceutical composition to a subject suffering from, or susceptible to, the condition.

[0958]Modality I: A method of treating a subject having rheumatoid arthritis, the method comprising administering to the subject about 7.5 mg, in unit dosage form, of (3S,4R)-3-ethyl-4-( 3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide orally once a day.

[0959]Modality I1: A method of treating a subject having moderate rheumatoid arthritis, the method comprising administering to the subject about 7.5 mg per unit dosage form of (3S,4R)-3-ethyl-4-( 3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide of any of Embodiments A to A19, B to B3, or C to C13, orally once a day.

[0960]Modality I1a: A (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2, 2,2-trifluoroethyl)pyrrolidine-1-carboxamide of any one of Modalities A to A19, B to B3, or C to C13, for use in treating a subject having rheumatoid arthritis. In certain aspects of Modality E1a, use comprises administering to the subject about 7.5 mg per unit dosage form of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[ 2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide of any of Modalities A to A19, B to B3, or C to C13, orally once a day.

[0961]Modality I2: A method of treating a subject having rheumatoid arthritis, the method comprising administering to the subject orally once a day the pharmaceutical composition of any of Modalities A20 to A22, B4, B5, C14, C15, D to D7, or E to E23, wherein the composition comprises about 7.5 mg, per unit dosage form of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrole [2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide.

[0962]Modality I3: The pharmaceutical composition of any of Modalities A20 to A22, B4, B5, C14, C15, D to D7, or E to E23, for use in treating a subject with rheumatoid arthritis. In certain aspects of Modality I3, the use comprises administering to the subject orally once a day the pharmaceutical composition, wherein the composition comprises about 7.5 mg, per unit dosage form of (3S,4R)-3- ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide.

[0963]Modality I4: A method of treating a subject having rheumatoid arthritis, the method comprising administering to the subject about 15 mg, per unit dosage form, of (3S,4R)-3-ethyl-4-(3H- imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide orally once daily.

[0964]Modality I5: A method of treating a subject having moderate rheumatoid arthritis, the method comprising administering to the subject about 15 mg per unit dosage form of (3S,4R)-3-ethyl-4-(3H- imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide of any of Embodiments A to A19, B to B3, or C to C13, orally once a day.

[0965]Modality I6: A (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2, 2,2-trifluoroethyl)pyrrolidine-1-carboxamide according to any one of Embodiments A to A19, B to B3, or C to C13, for use in treating a subject having rheumatoid arthritis. In certain aspects of Modality I6, use comprises administering to the subject about 15 mg per unit dosage form of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[ 2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide of any of Modalities A to A19, B to B3, or C to C13, orally once per day.

[0966]Modality I7: A method of treating a subject having rheumatoid arthritis, the method comprising administering to the subject orally once a day the pharmaceutical composition of any of Modalities A20 to A22, B4, B5, C14, C15, D to D7, or E to E23, wherein the composition comprises about 15 mg, per unit dosage form of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2 ,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide.

[0967]Modality I8: The pharmaceutical composition of any of Modalities A20 to A22, B4, B5, C14, C15, D to D7, or E to E23, for use in treating a subject with rheumatoid arthritis. In certain aspects of Modality I8, the use comprises administering to the subject orally once a day the pharmaceutical composition, wherein the composition comprises about 15 mg, per unit dosage form of (3S,4R)-3-ethyl- 4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide.

[0968]Modality I9: A method of treating a subject having rheumatoid arthritis, the method comprising administering to the subject about 30 mg, per unit dosage form, of (3S,4R)-3-ethyl-4-(3H- imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide orally once daily.

[0969]Modality I10: A method of treating a subject having moderate rheumatoid arthritis, the method comprising administering to the subject about 30 mg per unit dosage form of (3S,4R)-3-ethyl-4-(3H- imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide of any of Embodiments A to A19, B to B3, or C to C13, orally once a day.

[0970]Modality I11: A (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2, 2,2-trifluoroethyl)pyrrolidine-1-carboxamide according to any one of Embodiments A to A19, B to B3, or C to C13, for use in treating a subject having rheumatoid arthritis. In certain aspects of Modality I11, use comprises administering to the subject about 30 mg per unit dosage form of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[ 2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide of any of Modalities A to A19, B to B3, or C to C13, orally once a day.

[0971]Modality I12: A method of treating a subject having rheumatoid arthritis, the method comprising administering to the subject orally once a day the pharmaceutical composition of any of Modalities A20 to A22, B4, B5, C14, C15, D to D7, or E to E23, wherein the composition comprises about 30 mg, per unit dosage form of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2 ,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide.

[0972]Modality I13: The pharmaceutical composition of any of Modalities A20 to A22, B4, B5, C14, C15, D to D7, or E to E23, for use in treating a subject with rheumatoid arthritis. In certain aspects of Modality I13, the use comprises administering to the subject orally once a day the pharmaceutical composition, wherein the composition comprises about 30 mg, per unit dosage form of (3S,4R)-3-ethyl- 4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide.

[0973]Modality I14: A method of treating a subject having rheumatoid arthritis, the method comprising administering to the subject about 45 mg, per unit dosage form, of (3S,4R)-3-ethyl-4-(3H- imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide orally once daily.

[0974]Modality I15: A method of treating a subject having moderate rheumatoid arthritis, the method comprising administering to the subject about 45 mg, per unit dosage form, of (3S,4R)-3-ethyl-4-(3H -imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide of any of Embodiments A to A19, B to B3, or C to C13, orally once a day.

[0975]Modality I16: A (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2, 2,2-trifluoroethyl)pyrrolidine-1-carboxamide of any one of Modalities A to A19, B to B3, or C to C13, for use in treating a subject having rheumatoid arthritis. In certain aspects of Embodiment I16, use comprises administering to the subject about 45 mg per unit dosage form of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2, 3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide of any of Modalities A to A19, B to B3, or C to C13, orally once per day.

[0976]Modality I17: A method of treating a subject having rheumatoid arthritis, the method comprising administering to the subject orally once a day the pharmaceutical composition of any of Modalities A20 to A22, B4, B5, C14, C15, D to D7, or E to E23, wherein the composition comprises about 45 mg, per unit dosage form of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2 ,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide.

[0977]Modality I18: The pharmaceutical composition of any of Modalities A20 to A22, B4, B5, C14, C15, D to D7, or E to E23, for use in treating a subject with rheumatoid arthritis. In certain aspects of Modality I18, the use comprises administering to the subject orally once a day the pharmaceutical composition, wherein the composition comprises about 45 mg, per unit dosage form of (3S,4R)-3-ethyl- 4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide.

[0978]Modality J: A method for preparing the crystalline hydrate of Modality A1 or A2, the method comprising: dissolving (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[ 2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide in a solvent or mixture of solvents; and initiating crystallization to provide the crystalline hydrate.

[0979]Modality J1: The method of Modality J, in which the solvent or mixture of solvents comprises an antisolvent.

[0980]Modality J2: The method of Modality J or J1, in which the solvent or mixture of solvents comprises a polar solvent.

[0981]Modality J3: The method of Modality J or J1, in which the solvent or mixture of solvents comprises a non-polar solvent.

[0982]Modality J4: The method of any of Modalities J to J3, in which the crystallization initiation step comprises mixing the solvent or mixture of solvents.

[0983]Modality J5: The method of any of Modalities J to J4, in which the crystallization initiation step comprises seeding the solvent or mixture of solvents with crystals of the crystalline hydrate of Modality A1 or A2.

[0984]Modality J6: The method of any of Modalities J to J5, in which the crystallization initiation step comprises mixing the solvent or mixture of solvents and seeding the solvent or mixture of solvents with crystals of the crystalline hydrate of the Modality A1 or A2.

[0985]Modality J7: The method of Modality J, wherein the method comprises adding an antisolvent to the solvent or mixture of solvents, and the solvent or mixture of solvents comprises a polar solvent.

[0986]Modality J8: The method of Modalities J, wherein the method comprises adding an antisolvent to the solvent or mixture of solvents, and the solvent or mixture of solvents comprises a non-polar solvent.

[0987]Modality J9: The method of any of Modalities J, J7 to J8, wherein the method comprises adding an antisolvent to the solvent or mixture of solvents and seeding the solvent or mixture of solvents with crystals of the crystalline hydrate of Modality A1 or A2.

[0988]Modality J10: The method of any of Modalities J, J7 or J8, wherein the method comprises adding an antisolvent to the solvent or mixture of solvents, and mixing the solvent or mixture of solvents.

[0989] Modality J11: The method of any of Modalities J, J7 or J8, wherein the method comprises adding an antisolvent to the solvent or mixture of solvents and seeding the solvent or mixture of solvents with crystals of the crystalline hydrate in accordance with the claim 2 and mixing the solvent or mixture of solvents.

[0990] Modality J12: The method of any of Modalities J to J11, in which crystallization occurs in a wet grinding mill.

[0991] Modality K: A method for preparing the crystalline hydrate of Modality A14, the method comprising: dissolving (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2, 3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide in a solvent or mixture of solvents comprising an antisolvent; and maintaining the solvent or mixture of solvents at a temperature below about 15 ° C for an amount of time sufficient to initiate crystallization of the crystalline hydrate.

[0992]Modality K1: The method of Modality K, in which the solvent or mixture of solvents comprises a polar solvent.

[0993]Mode K2: The method of Mode K or K11, in which the temperature is lower than about 10 °C.

[0994]Modality K3: The method of any of Modalities K to K2, wherein the process further comprises seeding the solvent or mixture of solvents with crystals of the crystalline hydrate of Modality A14.

[0995]Modality L: A method for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)- Amorphous free base N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide of Embodiment B, the method comprising dehydrating the crystalline hydrate of Embodiment A14 to provide the (3S,4R)-3-ethyl-4-( Amorphous free base 3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide.

[0996]Modality L1: A method for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)- Amorphous free base N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide of Embodiment B, the method comprising: dissolving (3S,4R)-3-ethyl-4-(3H-imidazo[1,2- a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide in a solvent or mixture of solvents; and adjusting the pH of the solvent or solvent mixture to a pH greater than about 8 to initiate precipitation 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 amorphous free base.

[0997]Modality L2: The method of Modality L1, in which the solvent or mixture of solvents comprises water.

[0998]Mode L3: The method of Mode L1 or L2, in which the pH of the solvent or mixture of solvents is adjusted to a pH equal to or greater than about 12.

[0999]Modality M: A method for preparing the crystalline anhydrous of Modality C, the method comprising: dissolving (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2, 3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide in a solvent or mixture of solvents, wherein the solvent or mixture of solvents comprises less than about 0 .15% by weight of water; and initiating crystallization to provide the crystalline anhydrous.

[01000]Modality M1: The method of Modality M, in which the solvent or mixture of solvents has a water activity of about 2.4% or less.

[01001]Modality M2: The method of Modality M to M1, in which the crystallization initiation step comprises mixing the solvent or mixture of solvents.

[01002]Mode M3: The method of Mode M2, in which mixing occurs at a temperature of at least 23 °C.

[01003]Modality M4: The method of any of Modalities M to M3, in which the crystallization initiation step comprises seeding the solvent or mixture of solvents with crystalline anhydrous crystals of Modality C or C1.

[01004]Modality N: A crystalline hydrate of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)- N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide prepared by the process of any one of Embodiments J to J12.

[01005] Modality N1: A crystalline hydrate of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)- N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide prepared by the process of any of Embodiments K to K3.

[01006] Modality N2: (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2 Amorphous free base ,2,2-trifluoroethyl)pyrrolidine-1-carboxamide prepared by the process of any of Embodiments L to L3.

[01007]Modality N3: A crystalline anhydrous of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)- N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide prepared by the process of any of Embodiments M to M4.

[01008]Modality O: A process for preparing (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)- N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide or a pharmaceutically acceptable salt thereof, the process comprising: a). react a compound of formula (I) or a pharmaceutically acceptable salt thereof with trimethylsulfoxonium chloride to form a compound of formula (II) where PG is a protecting group; B). contacting the compound of formula (II) with LiX and a sulfonic acid to form a compound of formula (III) where X is Br or Cl; w). react the compound of formula (III) with a compound of formula (IV) to produce a compound of formula (V) wherein Ri 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 an anhydrous perfluoro acid and an organic base to form a compound of formula (VI) It is). deprotect the compound of formula (VI) and form a pharmaceutically acceptable salt of the compound of formula (VII): f). react the pharmaceutically acceptable salt of the compound of formula (VII) with 2,2,2-trifluoroethylamine to produce (3S,4R)-3-ethyl-4-(3H-imidazo[i,2-a]pyrrole[2 ,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-i-carboxamide.

[01009] Modality Oi: The process of Modality O, in which the pharmaceutically acceptable salt of the compound of formula (I) is selected from the group consisting of a compound of formula (Ia) and a compound of formula (Ib) where Cbz is carboxybenzyl.

[01010]Modality O2: The process of Modality O1, further comprising contacting the compound of formula (Ia) or (Ib) with an acid before reacting to trimethylsulfoxonium chloride.

[01011]Modality O3: The Modality O2 process, in which the acid is selected from the group consisting of a mineral acid or an organic acid.

[01012]Mode O4: The process of Mode O3, in which the acid is selected from the group consisting of phosphoric acid, hydrochloric acid, acetic acid, citric acid and combinations thereof.

[01013]Mode O5: The process of Mode O4, in which the acid is phosphoric acid.

[01014] Modality O6: The process of any of Modalities O to O5, in which the reaction of step a) is conducted in the presence of carbonyldiimidazole and a strong base.

[01015] Modality O7: The process of any of Modalities O to O6, in which the reaction of step a) is conducted in a solvent selected from the group consisting of tetrahydrofuran, water and tert-butyl methyl ether.

[01016]Modality O8: The process of any of Modalities O to O7, in which the reaction of step a) is conducted in a solvent selected from the group consisting of tetrahydrofuran, ethyl acetate, heptanes, ethanol and water.

[01017] Modality O9: The process of any of Modalities O to O8, in which the reaction of step c) is conducted in the presence of a base.

[01018] Modality O10: The process of any of Modalities O to O9, in which the reaction of step c) is conducted in a solvent selected from the group consisting of dimethylacetamide, tetrahydrofuran, dichloromethane, ethyl acetate and heptanes, and their combinations.

[01019] Modality O11: The process of any of Modalities O to O10, in which the reaction of step d) is conducted in a solvent selected from the group consisting of acetonitrile, toluene and combinations thereof.

[01020] Modality O12: The process of any of Modalities O to O11, further comprising contacting the reaction mixture formed in step d) with a hydroxide.

[01021]Mode O13: The process of Mode O12, in which the hydroxide is sodium hydroxide.

[01022] Modality O14: The process of any of Modalities O to O13, in which the reaction of step e) is conducted in a solvent selected from the group consisting of ethanol, isopropyl acetate and combinations thereof.

[01023] Modality O15: The process of any of Modalities O to O14, wherein step e) comprises contacting the compound of formula (VII) with an acid to form the pharmaceutically acceptable salt of the compound of formula (VII).

[01024] Modality O16: The process of any of Modalities O to O15, in which the pharmaceutically acceptable salt of the compound of formula (VII) is selected from the group consisting of:

[01025] Modality O17: The process of any of Modalities O to O16, wherein step e) comprises contacting the compound of formula (Vi) with an acid to form the pharmaceutically acceptable salt of the compound of formula (Vii).

[01026] Modality O18: The process of any of Modalities O to O17, in which the pharmaceutically acceptable salt of the compound of formula (Vii) in step f) is selected from the group consisting of a compound of formula (Viia), a compound of formula (Viib) and a compound of formula (Viic).

[01027] Modality O19: The process of any of Modalities O to O18, in which the reaction of step f) is conducted in the presence of carbonyldiimidazole, dipotassium phosphate and potassium hydroxide.

[01028] Modality O20: The process of any of Modalities O to O19, further comprising preparing a crystalline hydrate of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrole [2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, the process comprising: dissolving (3S,4R)-3-ethyl-4-(3H -imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide in a solvent or mixture of solvents; and initiating crystallization to provide the crystalline hydrate; wherein the crystalline hydrate is a hemihydrate.

[01029] Modality O21: A crystalline hydrate of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)- N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide prepared by the Mode O20 process.

[01030] Modality O22: The process of any of Modalities O to O19, further comprising preparing a crystalline hydrate of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2 ,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, the process comprising: dissolving (3S,4R)-3-ethyl-4-(3H-imidazo [1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide in a solvent or mixture of solvents comprising an antisolvent; and maintaining the solvent or mixture of solvents at a temperature below about 15°C for an amount of time sufficient to initiate crystallization of the crystalline hydrate; in which the crystalline hydrate has an X-ray diffraction pattern by the powder method characterized by peaks at 3.1 ± 0.2, 9.3 ± 0.2, and 12.0 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Ka1 radiation.

[01031] Modality O23: A crystalline hydrate of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)- N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide prepared by the Method O22 process.

[01032] Modality O24: The process of any of Modalities O to O19, further comprising preparing a (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrole[2, 3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide of amorphous free base, the process comprising dehydrating the crystalline hydrate produced in the Modality O22 process to provide the (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrole[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl )pyrrolidine-1-carboxamide amorphous free base.

[01033] Modality O25: The process of any of Modalities O to O19, further comprising preparing a (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrole[2, 3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide amorphous free base, the process comprising: dissolving (3S,4R)-3-ethyl-4-( 3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide in a solvent or mixture of solvents; and adjusting the pH of the solvent or solvent mixture to a pH greater than about 8 to initiate precipitation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2, Amorphous free base 3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide.

[01034]Modality O26: A (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2, Amorphous free base 2,2-trifluoroethyl)pyrrolidine-1-carboxamide prepared by the Mode O24 or O25 process.

[01035] Modality O27: The process of any of Modalities O to O19, further comprising preparing an anhydrous crystalline (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrole [2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, the process comprising: dissolving (3S,4R)-3-ethyl-4-(3H -imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide in a solvent or mixture of solvents, wherein the solvent or mixture of solvents comprises less than about 0.15% by weight of water; and initiating crystallization to provide the crystalline anhydrous.

[01036] Modality O28: A crystalline anhydrous of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)- N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide prepared by the Method O27 process.

[01037] Modality O29: The process of any of Modalities O to O19, in which the pharmaceutically acceptable salt of the compound of formula (I) is the compound of formula (Ib): wherein the compound of formula (Ib) is prepared by: (i) reacting carboxybenzyl glycine ethyl ester with ethyl acrylate to form a compound of formula (VIII): (ii) protecting the compound of formula (VIII) to form a compound of formula (IX): wherein R3 is selected from the group consisting of CF3SO2-; CH3SO2-; and tosila; (iii) contacting the compound of formula (IX) with ethylboronic acid, ethylmagnesium bromide or ethylzinc chloride in the presence of a catalyst to form a compound of formula (X): (iv) hydrolyze the compound of formula (X) to produce the compound of formula (XI): (v) convert the compound of formula (XI) to the compound of formula (XII): (vi) contacting the compound of formula (XII) with dicyclohexylamine to form a compound of formula (Ib); where Cbz is carboxybenzyl.

[01038]Modality O29a: The process of Modality O29, in which the reaction of step (i) is conducted in the presence of a strong base.

[01039] Modality O29b: The process from Modality O29 to O29a, in which the reaction of step (ii) is conducted in the presence of diisopropylethylamine.

[01040] Modality O29c: The process of any of Modalities O29 to O29b, wherein the catalyst in step (iii) is a palladium catalyst.

[01041] Modality O29d: The process of any of Modalities O29 to O29c, in which the compound of formula (X) is contacted with an alkali metal hydroxide to form the compound of formula (XI).

[01042] Modality O29e: The process of any of Modalities O29 to O29d, in which the compound of formula (XI) is contacted with a ruthenium catalyst to form the compound of formula (XII).

[01043] Modality O30: The process of any one of Modalities O to O19, in which the pharmaceutically acceptable salt of the compound of formula (I) is the compound of formula (Ia): wherein the compound of formula (Ia) is prepared by: (i) hydrogenating ethyl pent-2-enoate with a Lindlar catalyst to form (Z)-ethyl pent-2-enoate; (ii) reacting (Z)-ethyl pent-2-enoate with N-(methoxymethyl)-N-(trimethylsilyl methyl)benzylamine to form a compound of formula (XIII) (iii) deprotecting the compound of formula (XIII) to form a compound of formula (XIV) (iv) hydrolyze the compound of formula (XIV) to form a compound of formula (XV) (v) reacting the compound of formula (XV) with N-benzyloxycarbonyloxy succinimide to form a compound of formula (XVI) (vi) contacting the compound of formula (XVI) with (R)-1-(naphthalene-1-yl)ethanamine to form the compound of formula (Ia); wherein Cbz is carboxybenzyl; Bn is benzyl; and Et is ethyl.

[01044] Modality O30a: The Modality O30 process, in which the reaction of step (i) is conducted in a solvent selected from pyridine, tetrahydrofuran and combinations thereof.

[01045] Modality O30b: The process of modality O30 or O30a, in which the compound of formula (XIII) is deprotected by hydrogenation with a catalyst and hydrogen gas.

[01046] Modality O30c: The process of any of Modalities O30 to O30b, in which the compound of formula (XIV) is contacted with hydrochloric acid to form the compound of formula (XV).

[01047]Mode P: A process for preparing (3S,4R)-3-ethyl-4-(3H-imi-dazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)- N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide or a pharmaceutically acceptable salt thereof, the process comprising: a) reacting a compound of formula (Ib) with trimethylsulfoxonium chloride in the presence of carbonyldiimidazole and a strong base to form the compound of formula (IIa) wherein Cbz is carboxybenzyl; b) contacting the compound of formula (IIa) with lithium bromide and a sulfonic acid to form a compound of formula (IIIa) c) reacting the compound of formula (IIIa) with a compound of formula (IVa) in the presence of lithium tert-butoxide to produce a compound of formula (Va) wherein R2 is methyl or ethyl; and Ts is tosyl; d) contacting the compound of formula (Va) with an anhydrous perfluoro acid and an organic base to form a compound of formula (VIa) e) deprotecting the compound of formula (VIa) to form a compound of formula (VII) f) contacting the compound of formula (VII) with hydrochloric acid to form a compound of formula (VIIa) g) reacting the compound of formula (VIIa) with 2,2,2-trifluoroethylamine in the presence of carbonyldiimidazole to produce (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a ]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide.

[01048]Mode P1: The process of Mode P, in which: the strong base of step a) is potassium tert-butoxide; the sulfonic acid of step b) is selected from the group consisting of methanesulfonic acid and p-toluenesulfonic acid; the perfluoro acid anhydrous from step d) is trifluoroacetic anhydrous; the organic base of step d) is pyridine; the compound of formula (VIa) is deprotected using hydrogen gas and Pd(OH2)/C; and the reaction of step g) is conducted in the presence of dipotassium phosphate and potassium hydroxide.

[01049]Modality P2: The process of Modality P or P1, further comprising contacting the compound of formula (Ib) with an acid before reacting to trimethylsulfoxonium chloride.

[01050] Mode P3: The process of Mode P2, in which the acid is selected from the group consisting of a mineral acid or an organic acid.

[01051]Mode P4: The process of Mode P3, in which the acid is selected from the group consisting of phosphoric acid, hydrochloric acid, acetic acid, citric acid and combinations thereof.

[01052]Mode P5: The process of Mode P4, in which the acid is phosphoric acid.

[01053]Modality P6: The process of any of Modalities P to P5, further comprising preparing a crystalline hydrate of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrole [2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, the process comprising: dissolving (3S,4R)-3-ethyl-4-(3H -imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide in a solvent or mixture of solvents; and initiating crystallization to provide the crystalline hydrate; wherein the crystalline hydrate is a hemihydrate.

[01054]Modality P7: A crystalline hydrate of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)- N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide prepared by the Method P6 process.

[01055]Modality P8: The process of any of Modalities P to P5, further comprising preparing a crystalline hydrate of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrole [2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, the process comprising: dissolving (3S,4R)-3-ethyl-4-(3H -imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide in a solvent or mixture of solvents comprising an antisolvent ; and maintaining the solvent or mixture of solvents at a temperature below about 15°C for an amount of time sufficient to initiate crystallization of the crystalline hydrate; in which the crystalline hydrate has an X-ray diffraction pattern by the powder method characterized by peaks at 3.1 ± 0.2, 9.3 ± 0.2, and 12.0 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Ka1 radiation.

[01056]Modality P9: A crystalline hydrate of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)- N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide prepared by the Method P8 process.

[01057] Modality P10: The process of any of Modalities P to P5, further comprising preparing a (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrole[2, 3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide of amorphous free base, the process comprising dehydrating the crystalline hydrate produced in the process of Modality P8 to provide the (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrole[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl )pyrrolidine-1-carboxamide amorphous free base.

[01058] Modality P11: The process of any of Modalities P to P5, further comprising preparing a (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrole[2, 3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide amorphous free base, the process comprising: dissolving (3S,4R)-3-ethyl-4-( 3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide in a solvent or mixture of solvents; and adjusting the pH of the solvent or solvent mixture to a pH greater than about 8 to initiate precipitation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2, Amorphous free base 3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide.

[01059]Modality P12: A (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2, Amorphous free base 2,2-trifluoroethyl)pyrrolidine-1-carboxamide prepared by the process of Mode P10 or P11.

[01060]Modality P13: The process of any of Modalities P to P5, further comprising preparing a crystalline anhydrous of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrole [2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, the process comprising: dissolving (3S,4R)-3-ethyl-4-(3H -imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide in a solvent or mixture of solvents, wherein the solvent or mixture of solvents comprises less than about 0.15% by weight of water; and initiating crystallization to provide the crystalline anhydrous.

[01061] Modality P14: A crystalline anhydrous of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)- N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide prepared by the Method P13 process.

[01062] Modality Q: A process for preparing (3S,4R)-3-ethyl-4-(3H-imi-dazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)- N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide or a pharmaceutically acceptable salt thereof, the process comprising: a) converting a compound of formula (XIa): for a compound of formula (I): where PG is a protecting group; b) reacting the compound of formula (I) with trimethylsulfoxonium chloride to form a compound of formula (II) c) contacting the compound of formula (II) with an anhydrous source of HBr or HCl to form a compound of formula (III) where 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 Ri 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 an anhydrous perfluoro acid 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): g) reacting the pharmaceutically acceptable salt of the compound of formula (VII) with 2,2,2-trifluoroethylamine to produce (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrole [2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide.

[01063]Modality Q1: The process of Modality Q, wherein step f) comprises contacting the compound of formula (VII) with an acid to form the pharmaceutically acceptable salt of the compound of formula (VII).

[01064]Modality Q2: The process of Modality Q or Q1, in which the protecting group is carboxybenzyl.

[01065]Modality Q3: The process of any of Modalities Q to Q2, in which the anhydrous source of HBr or HCl does not comprise more than 0.2% water (by volume).

[01066] Modality Q4: The process of any of Modalities Q to Q3, in which step a) is conducted in a solvent selected from the group consisting of methanol, trimethylamine and combinations thereof.

[01067] Modality Q5: The process of any of Modalities Q to Q4, wherein step b) comprises reacting the compound of formula (I) with trimethylsulfoxonium chloride in the presence of carbonyldiimidazole and a strong base to form the compound of formula (II).

[01068]Mode Q6: The process of Mode Q5, in which the base is selected from the group consisting of potassium tert-butoxide, sodium tert-butoxide and combinations thereof.

[01069] Modality Q7: The process of any of Modalities Q to Q6, in which step b) is conducted in a solvent selected from the group consisting of tetrahydrofuran, water, methyl tert-butyl ether and combinations thereof.

[01070] Modality Q8: The process of any of Modalities Q to Q7, in which step c) is conducted in tetrahydrofuran and comprises contacting the compound of formula (II) with an anhydrous source of HBr to form a compound of formula (III).

[01071]Mode Q9: The process of Mode Q8, in which the anhydrous source of HBr is HBr/HOAc.

[01072] Modality Q10: The process of any of Modalities Q to Q9, wherein step d) comprises reacting the compound of formula (III) with the compound of formula (IV) in the presence of lithium tert-butoxide to produce the compound of formula (V).

[01073] Modality Q11: The process of any of Modalities Q to Q10, in which the reaction of step e) is conducted in a solvent selected from the group consisting of acetonitrile, toluene and combinations thereof.

[01074] Modality Q12: The process of any of Modalities Q to Q11, further comprising contacting the reaction mixture formed in step d) with a hydroxide.

[01075]Mode Q13: The process of Mode Q12, in which the hydroxide is sodium hydroxide.

[01076] Modality Q14: The process of any of Modalities Q to Q13, in which the reaction of step f) is conducted in a solvent selected from the group consisting of ethanol, isopropyl acetate and combinations thereof.

[01077] Modality Q15: The process of any of Modalities Q to Q14, wherein step f) comprises contacting the compound of formula (VII) with an acid to form the pharmaceutically acceptable salt of the compound of formula (VII).

[01078] Modality Q16: The process of any of Modalities Q to O14, wherein step f) comprises contacting the compound of formula (VI) with an acid to form the pharmaceutically acceptable salt of the compound of formula (VII).

[01079] Modality Q17: The process of any of Modalities Q to Q16, in which the pharmaceutically acceptable salt of the compound of formula (VII) is selected from the group consisting of:

[01080] Modality Q18: The process of any of Modalities Q to Q17, further comprising preparing a crystalline hydrate of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrole [2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, the process comprising: dissolving (3S,4R)-3-ethyl-4-(3H -imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide in a solvent or mixture of solvents; and initiating crystallization to provide the crystalline hydrate; wherein the crystalline hydrate is a hemihydrate.

[01081]Modality Q19: A crystalline hydrate of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)- N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide prepared by the process of Embodiment Q18.

[01082] Modality Q20: The process of any of Modalities Q to Q17, further comprising preparing a crystalline hydrate of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2 ,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, the process comprising: dissolving (3S,4R)-3-ethyl-4-(3H-imidazo [1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide in a solvent or mixture of solvents comprising an antisolvent; and maintaining the solvent or mixture of solvents at a temperature below about 15°C for an amount of time sufficient to initiate crystallization of the crystalline hydrate; in which the crystalline hydrate has an X-ray diffraction pattern by the powder method characterized by peaks at 3.1 ± 0.2, 9.3 ± 0.2, and 12.0 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Ka1 radiation.

[01083]Modality Q21: A crystalline hydrate of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)- N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide prepared by the Method Q20 process.

[01084] Modality Q22: The process of any of Modalities Q to Q17, further comprising preparing a (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrole[2, 3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide of amorphous free base, the process comprising dehydrating the crystalline hydrate produced in the process of Modality Q20 to provide the (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrole[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl )pyrrolidine-1-carboxamide amorphous free base.

[01085] Modality Q23: The process of any of Modalities Q to Q17, further comprising preparing a (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrole[2, 3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide amorphous free base, the process comprising: dissolving (3S,4R)-3-ethyl-4-( 3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide in a solvent or mixture of solvents; and adjusting the pH of the solvent or solvent mixture to a pH greater than about 8 to initiate precipitation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2, Amorphous free base 3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide.

[01086]Modality Q24: A (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2, Amorphous free base 2,2-trifluoroethyl)pyrrolidine-1-carboxamide prepared by the process of Mode Q22 or Q23.

[01087] Modality Q25: The process of any of Modalities Q to Q17, further comprising preparing an anhydrous crystalline (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrole [2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, the process comprising: dissolving (3S,4R)-3-ethyl-4-(3H -imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide in a solvent or mixture of solvents, wherein the solvent or mixture of solvents comprises less than about 0.15% by weight of water; and initiating crystallization to provide the crystalline anhydrous.

[01088]Modality Q26: A crystalline anhydrous of (3S,4R)-3-ethyl-4-(3H-imi-dazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)- N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide prepared by the Method Q25 process.

[01089] Modality R: Compound of formula (II): where PG is a protecting group.

[01090] Modality R1: The compound of Modality R, in which the protecting group is selected from the group consisting of carboxybenzyl, p-methoxybenzyl carbonyl, benzyl, p-methoxybenzyl and 3,4-dimethoxybenzyl.

[01091] Modality R2: A process for preparing a compound of formula (II): the process comprising reacting a compound of formula (I) or a pharmaceutically acceptable salt thereof with trimethylsulfoxonium chloride to form the compound of formula (II), wherein PG is a protecting group.

[01092]Modality R2a: The process of Modality R2, in which the protecting group is selected from the group consisting of carboxybenzyl, p-methoxybenzyl carbonyl, benzyl, p-methoxybenzyl and 3,4-dimethoxybenzyl.

[01093]Modality R2b: The process of Modality R2 or R2a, in which the pharmaceutically acceptable salt of the compound of formula (I) is selected from the group consisting of a compound of formula (Ia) and a compound of formula (Ib)

[01094] Modality R2c: The process of any of the modalities R2 to R2b, in which the reaction is conducted in the presence of carbonyldiimidazole and a strong base.

[01095] Modality R2d: The process of any of Modalities R2 to R2c, in which the reaction is conducted in the presence of phosphoric acid.

[01096]Modality R2e: The process of any of Modalities R2 to R2d, in which the reaction is conducted in a solvent selected from the group consisting of tetrahydrofuran, water and methyl tert-butyl ether.

[01097] Modality R3: A process for preparing a compound of formula (II): the process comprising a) converting a compound of formula (XIa): for a compound of formula (I): where PG is a protecting group; and b) reacting the compound of formula (I) with trimethylsulfoxonium chloride to form the compound of formula (II).

[01098]Modality R3a: The process of Modality R3, in which the reaction in step b) is conducted in the presence of carbonyldiimidazole and a strong base.

[01099] Modality S: A process for preparing a compound of formula (III): the process comprising contacting a compound of formula (II) with LiX and a sulfonic acid to form the compound of formula (III); where PG is a protecting group; and X is Br or Cl.

[01100]Modality S1: The process of Modality S, in which the compound of formula (II) is formed by reaction of a compound of Formula (I) or a pharmaceutically acceptable salt thereof with trimethylsulfoxonium chloride.

[01101]Modality S2: The process of Modality S1, in which the pharmaceutically acceptable salt of the compound of formula (I) is selected from the group consisting of a compound of formula (Ia) and a compound of formula (Ib)

[01102]Modality S3: The process of Modality S1 or S2, in which the compound or pharmaceutically acceptable salt of formula (I) is reacted with trimethylsulfoxonium chloride in the presence of carbonyldiimidazole and a strong base.

[01103] Modality S4: A process for preparing a compound of formula (III): the process comprising contacting a compound of formula (II) with an anhydrous source of HBr or HCl to form a compound of formula (III), wherein PG is a protecting group, and X is Br or Cl.

[01104]Modality S4a: The process of Modality S4, in which the compound of formula (II) is formed by converting a compound of formula (XIa): for a compound of formula (I): where PG is a protecting group; and reacting the compound of formula (I) with trimethylsulfoxonium chloride to form the compound of formula (II).

[01105]Modality S4b: The process of Modality S4 or S4a, in which the compound of formula (II) is contacted with an anhydrous source of HBr to form the compound of formula (III).

[01106]Modality S4c: The process of Modality S4b, in which the anhydrous source of HBr is HBr/HOAc.

[01107] Modality T: A compound of formula (Va) wherein R2 is methyl or ethyl; Ts is tosila; and Cbz is carboxybenzyl.

[01108] Modality T1: A process for preparing a compound of formula (V) the process comprising: a) reacting a compound of formula (I) or a pharmaceutically acceptable salt thereof with trimethylsulfoxonium chloride to form a compound of formula (II) b) contacting the compound of formula (II) with LiX and a sulfonic acid to form a compound of formula (III) c) reacting the compound of formula (III) with a compound of formula (IV) to produce the compound of formula (V); where: PG is a protecting group; X is Br or Cl; Ri is selected from the group consisting of alkyl, aryl and -OR2; R2 is alkyl; and Ts is tosila.

[01109] Modality Tia: The process of Modality Ti, in which the pharmaceutically acceptable salt of the compound of formula (I) is selected from the group consisting of a compound of formula (Ia) and a compound of formula (Ib)

[01110] Tib Modality: The Ti or Tia Modality process, in which the reaction in step a) is conducted in the presence of carbonyldiimidazole and a strong base.

[01111] Tic Mode: The process of any of the Ti to Tib Modalities, in which the reaction of step c) is conducted in the presence of a base selected from the group consisting of lithium tert-butoxide, sodium tert-butoxide and their combinations.

[01112] Modality T2: A process for preparing a compound of formula (V) the process comprising: a) converting a compound of formula (XIa): for a compound of formula (I): where PG is a protecting group; b) reacting the compound of formula (I) with trimethylsulfoxonium chloride to form a compound of formula (II) c) contacting the compound of formula (II) with an anhydrous source of HBr or HCl to form a compound of formula (III) where 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 Ri is selected from the group consisting of alkyl, aryl and -OR2; R2 is alkyl; and Ts is tosila.

[01113]Modality T2a: The process of Modality T2, in which the compound of formula (II) is contacted with an anhydrous source of HBr to form the compound of formula (III).

[01114]Modality T2b: The process of Modality T2a, in which the anhydrous source of HBr is HBr/HOAc.

[01115] Modality T3: A process for preparing a crystalline compound of formula (V) the process comprising: a) reacting a compound of formula (III) with a compound of formula (IV): to produce the compound of formula (V); where: PG is a protecting group; X is Br or Cl; Ri is -OR2; R2 is methyl or ethyl; and Ts is tosila.

[01116] Modality U: A compound of formula (IVa): where R2 is methyl or ethyl, and Ts is tosyl.

[01117] Modality V: A compound of formula (VII): or a pharmaceutically acceptable salt thereof.

[01118] Modality Vi: The compound of Modality V, in which the pharmaceutically acceptable salt of the compound of formula (VII) is selected from the group consisting of:

[01119] Modality W: A process for preparing a compound of formula (Ib) wherein Cbz is carboxybenzyl, the process comprising: (i) reacting carboxybenzyl-glycine ethyl ester with ethyl acrylate to form a compound of formula (VIII): (ii) protecting the compound of formula (VIII) to form a compound of formula (IX): wherein R3 is selected from the group consisting of CF3SO2-; CH3SO2-; and tosila; (iii) contacting the compound of formula (IX) with ethylboronic acid, ethylmagnesium bromide or ethylzinc chloride in the presence of a catalyst to form a compound of formula (X): (iv) hydrolyze the compound of formula (X) to produce the compound of formula (XI): (v) convert the compound of formula (XI) to the compound of formula (XII): (vi) contacting the compound of formula (XII) with dicyclohexylamine to form a compound of formula (Ib).

[01120]Mode W1: The process of Mode W, in which the reaction of step (i) is conducted in the presence of a strong base.

[01121]Modality W2: The process of Modality W or W1, in which the re-action of step (i) is conducted in an organic solvent.

[01122] Modality W3: The process of any of Modalities W to W2, in which the reaction of step (ii) is conducted in the presence of diisopropylethylamine.

[01123] Modality W4: The process of any of Modalities W to W3, in which the reaction of step (ii) is conducted in a solvent selected from the group consisting of triethylamine, N-methylmorpholine, pyridine, diisopropyl ether and their combinations.

[01124] Modality W5: The process of any of Modalities W to W4, in which the reaction of step (iii) is conducted in a buffer selected from the group consisting of potassium carbonate, sodium carbonate, tribasic potassium phosphate and their combinations.

[01125] Modality W6: The process of any of Modalities W to W5, in which the reaction of step (iii) is conducted in a solvent selected from the group consisting of toluene, water, dioxane, tetrahydrofuran and combinations thereof.

[01126] Modality W7: The process of any of Modalities W to W6, in which the compound of formula (X) is contacted with an alkali metal hydroxide to form the compound of formula (XI).

[01127] Modality W8: The process of any of Modalities W to W7, in which the compound of formula (XI) is contacted with a ruthenium catalyst to form the compound of formula (XII).

[01128] Modality W9: The process of any of Modalities W to W8, in which: the reaction of step (i) is conducted in the presence of sodium tert-butoxide; the reaction of step (ii) is conducted in the presence of diisopropylethylamine; the catalyst from step (iii) is PdCl2(dppf); the reaction of step (iii) is carried out in potassium carbonate; the compound of formula (X) is contacted with sodium hydroxide to form the compound of formula (XI); and the compound of formula (XI) is contacted with a ruthenium catalyst to form the compound of formula (XII).

[01129]Modality X: The dicyclohexylamine salt of (3R,4S)-1-((benzyloxy)carbonyl)-4-ethylpyrrolidine-3-carboxylate.

[01130]Modality Y: A method of treating an adult subject with moderately to severely active rheumatoid arthritis, the method comprising administering to the subject: a) about 7.5 mg of free base of Compound 1, or one thereof pharmaceutically acceptable salt, or a crystalline or anhydrous crystalline hydrate of Compound 1 in an amount sufficient to provide the subject with about 7.5 mg of free base equivalent of Compound 1; or b) about 15 mg of free base of Compound 1, or a pharmaceutically acceptable salt thereof, or a crystalline or crystalline anhydrous hydrate of Compound 1 in an amount sufficient to provide the patient with about 15 mg of free base equivalent of Compound 1; or c) about 30 mg of free base of Compound 1, or a pharmaceutically acceptable salt thereof, or a crystalline or crystalline anhydrous hydrate of Compound 1 in an amount sufficient to provide the subject with about 30 mg of free base equivalent of Compound 1; or d) about 45 mg of free base of Compound 1, or a pharmaceutically acceptable salt thereof, or a crystalline or crystalline anhydrous hydrate of Compound 1 in an amount sufficient to provide the subject with about 45 mg of free base equivalent of Compound 1.

[01131]Modality Y1: The method of Modality Y, in which the crystalline hydrate is a hemihydrate.

[01132] Modality Y2: The method of Modality Y1, in which the crystalline hydrate is Free Base Hydrate Form C.

[01133]Modality Y3: The method of Modality Y, in which the crystalline anhydrous is Form D of Free Base Anhydrous.

[01134]Modality Y4: The method of any of Modalities Y to Y3, in which the free base, or its pharmaceutically acceptable salt, or the hydrate, or the anhydrous is a once-daily extended-release formulation.

[01135] Modality Y5: A pharmaceutical composition for use in treating an adult subject with moderately to severely active rheumatoid arthritis, wherein the pharmaceutical composition comprises: a) about 7.5 mg of free base of Compound 1, or a pharmaceutically acceptable salt thereof, or a crystalline or anhydrous crystalline hydrate of Compound 1 in an amount sufficient to provide the subject with about 7.5 mg of free base equivalent of Compound 1; or b) about 15 mg of free base of Compound 1, or a pharmaceutically acceptable salt thereof, or a crystalline or crystalline anhydrous hydrate of Compound 1 in an amount sufficient to provide the patient with about 15 mg of free base equivalent of Compound 1; or c) about 30 mg of free base of Compound 1, or a pharmaceutically acceptable salt thereof, or a crystalline or crystalline anhydrous hydrate of Compound 1 in an amount sufficient to provide the subject with about 30 mg of free base equivalent of Compound 1; or d) about 45 mg of free base of Compound 1, or a pharmaceutically acceptable salt thereof, or a crystalline or crystalline anhydrous hydrate of Compound 1 in an amount sufficient to provide the subject with about 45 mg of free base equivalent of Compound 1. In certain aspects of Modality Y5, use comprises administering to the subject the pharmaceutical composition.

[01136]Modality Y6: The method or pharmaceutical composition of any of Modalities Y to Y5, in which the adult subject achieves ACR20 response in week 12 of said treatment.

[01137]Modality Y7: The method or pharmaceutical composition of any of Modalities Y to Y6, in which the adult subject achieves ACR20 response in week 8 of said treatment.

[01138]Modality Y8: The method or pharmaceutical composition of any of Modalities Y to Y7, in which the adult subject achieves ACR20 response in week 6 of said treatment.

[01139]Modality Y9: The method or pharmaceutical composition of any of Modalities Y to Y8, in which the adult subject achieves ACR20 response in week 4 of said treatment.

[01140]Modality Y10: The method or pharmaceutical composition of any of Modalities Y to Y9, in which the adult subject achieves ACR20 response in week 2 of said treatment.

[01141] Modality Y11: The method or pharmaceutical composition of any of Modalities Y to Y10, in which the adult subject achieves ACR50 response in week 12 of said treatment.

[01142]Modality Y12: The method or pharmaceutical composition of any of Modalities Y to Y11, in which the adult subject achieves ACR50 response in week 8 of said treatment.

[01143]Modality Y13: The method or pharmaceutical composition of any of Modalities Y to Y12, in which the adult subject achieves ACR50 response in week 6 of said treatment.

[01144]Modality Y14: The method or pharmaceutical composition of any of Modalities Y to Y13, in which the adult subject achieves ACR50 response in week 4 of said treatment.

[01145]Modality Y15: The method or pharmaceutical composition of any of Modalities Y to Y14, in which the adult subject achieves ACR50 response in week 2 of said treatment.

[01146]Modality Y16: The method or pharmaceutical composition of any of Modalities Y to Y15, in which the adult subject achieves ACR70 response in week 12 of said treatment.

[01147]Modality Y17: The method or pharmaceutical composition of any of Modalities Y to Y16, in which the adult subject achieves ACR70 response in week 8 of said treatment.

[01148]Modality Y18: The method or pharmaceutical composition of any of Modalities Y to Y17, in which the adult subject achieves ACR70 response in week 6 of said treatment.

[01149]Modality Y19: The method or pharmaceutical composition of any of Modalities Y to Y18, in which the adult subject achieves ACR70 response in week 4 of said treatment.

[01150] Modality Y20: The method or pharmaceutical composition of any of Modalities Y to Y19, in which the adult subject achieves a decrease in DAS28 (CRP) when compared to the baseline in week 12 of said treatment.

[01151] Modality Y21: The method or pharmaceutical composition of any of Modalities Y to Y20, in which the adult subject achieves a decrease in DAS28 (CRP) when compared to the baseline in week 8 of said treatment.

[01152] Modality Y22: The method or pharmaceutical composition of any of Modalities Y to Y21, in which the adult subject achieves a decrease in DAS28 (CRP) when compared to the baseline in week 6 of said treatment.

[01153] Modality Y23: The method or pharmaceutical composition of any of Modalities Y to Y22, in which the adult subject achieves a decrease in DAS28 (CRP) when compared to the baseline in week 4 of said treatment.

[01154] Modality Y24: The method or pharmaceutical composition of any of Modalities Y to Y23, in which the adult subject achieves a decrease in DAS28 (CRP) when compared to the baseline in week 2 of said treatment.

[01155]Modality Y25: The method or pharmaceutical composition of any of Modalities Y to Y5, in which the adult subject has had an inadequate response or tolerance to one or more disease-modifying antirheumatic drugs (DMARDS).

[01156] Modality Y26: The pharmaceutical method or composition of Modality Y25, wherein the DMARD is a conventional synthetic DMARD or a biological DMARD.

[01157] Modality Y27: The pharmaceutical method or composition of Modality Y25, wherein the DMARD is an anti-TNF biological DMARD.

[01158]Modality Y28: The method or pharmaceutical composition of Modality Y27, in which the adult subject received the anti-TNF biological DMARD for at least three months before said treatment.

[01159] Modality Y29: The method or pharmaceutical composition of any of Modalities Y25 to Y28, wherein the DMARD is methotrexate.

[01160] Modality Y30: The method or pharmaceutical composition of Modality Y29, in which the adult subject received methotrexate for at least three months before said treatment.

[01161]Modality Y31: The method or pharmaceutical composition of any of Modalities Y25 to Y30, in which the adult subject is administered stable background methotrexate for at least three months before said treatment.

[01162]Modality Y32: The method or pharmaceutical composition of any of Modalities Y25 to Y31, in which the adult subject is administered stable background methotrexate during said treatment.

[01163]Modality Y33: The method or pharmaceutical composition of any of Modalities Y25 to Y32, in which the adult subject receives a folic acid supplement for at least four weeks prior to said treatment.

[01164]Modality Y34: The method or pharmaceutical composition of any of Modalities Y25 to Y33, in which the adult subject is administered a folic acid supplement during said treatment.

[01165]Modality Y35: The method or pharmaceutical composition of any of Modalities Y25 to Y34, in which the adult subject achieves ACR20 response in week 12 of said treatment.

[01166]Modality Y36: The method or pharmaceutical composition of any of Modalities Y25 to Y35, in which the adult subject achieves ACR20 response in week 8 of said treatment.

[01167]Modality Y37: The method or pharmaceutical composition of any of Modalities Y25 to Y36, in which the adult subject achieves ACR20 response in week 6 of said treatment.

[01168]Modality Y38: The method or pharmaceutical composition of any of Modalities Y25 to Y37, in which the adult subject achieves ACR20 response in week 4 of said treatment.

[01169]Modality Y39: The method or pharmaceutical composition of any of Modalities Y25 to Y38, in which the adult subject achieves ACR20 response in week 2 of said treatment.

[01170]Modality Y40: The method or pharmaceutical composition of any of Modalities Y25 to Y39, in which the adult subject achieves ACR50 response in week 12 of said treatment.

[01171]Modality Y41: The method or pharmaceutical composition of any of Modalities Y25 to Y40, in which the adult subject achieves ACR50 response in week 8 of said treatment.

[01172]Modality Y42: The method or pharmaceutical composition of any of Modalities Y25 to Y41, in which the adult subject achieves ACR50 response in week 6 of said treatment.

[01173]Modality Y43: The method or pharmaceutical composition of any of Modalities Y25 to Y42, in which the adult subject achieves ACR50 response in week 4 of said treatment.

[01174]Modality Y44: The method or pharmaceutical composition of any of Modalities Y25 to Y43, in which the adult subject achieves ACR50 response in week 2 of said treatment.

[01175]Modality Y45: The method or pharmaceutical composition of any of Modalities Y25 to Y44, in which the adult subject achieves ACR70 response in week 12 of said treatment.

[01176]Modality Y46: The method or pharmaceutical composition of any of Modalities Y25 to Y45, in which the adult subject achieves ACR70 response in week 8 of said treatment.

[01177]Modality Y47: The method or pharmaceutical composition of any of Modalities Y25 to Y46, in which the adult subject achieves ACR70 response in week 6 of said treatment.

[01178]Modality Y48: The method or pharmaceutical composition of any of Modalities Y25 to Y47, in which the adult subject achieves an ACR70 response in week 4 of said treatment.

[01179]Modality Y49: The method or pharmaceutical composition of any of Modalities Y25 to Y48, in which the adult subject achieves a decrease in DAS28(CRP) when compared to baseline in week 12 of said treatment.

[01180]Modality Y50: The method or pharmaceutical composition of any of Modalities Y25 to Y49, in which the adult subject achieves a decrease in DAS28(CRP) when compared to baseline in week 8 of said treatment.

[01181] Modality Y51: The method or pharmaceutical composition of any of Modalities Y25 to Y50, in which the adult subject achieves a decrease in DAS28 (CRP) when compared to baseline in week 6 of said treatment.

[01182] Modality Y52: The method or pharmaceutical composition of any of Modalities Y25 to Y51, in which the adult subject achieves a decrease in DAS28 (CRP) when compared to baseline in week 4 of said treatment.

[01183] Modality Y53: The method or pharmaceutical composition of any of Modalities Y25 to Y52, in which the adult subject achieves a decrease in DAS28 (CRP) when compared to baseline in week 2 of said treatment.

[01184] Modality Y54: The method or pharmaceutical composition of any of Modalities Y25 to Y53, in which the adult subject is also administered a conventional synthetic or biological DMARD.

[01185] Modality Y55: The method or pharmaceutical composition of Modality Y54, in which the DMARD is methotrexate.

[01186]Modality Y56: The method or pharmaceutical composition of Modality Y54 to Y55, in which the adult subject achieves ACR20 response in week 12 of said treatment.

[01187]Modality Y57: The method or pharmaceutical composition of any of Modalities Y54 to Y56, in which the adult subject achieves ACR20 response in week 8 of said treatment.

[01188]Modality Y58: The method or pharmaceutical composition of any of Modalities Y54 to Y57, in which the adult subject achieves ACR20 response in week 6 of said treatment.

[01189]Modality Y59: The method or pharmaceutical composition of any of Modalities Y54 to Y58, in which the adult subject achieves ACR20 response in week 4 of said treatment.

[01190]Modality Y60: The method or pharmaceutical composition of any of Modalities Y54 to Y59, in which the adult subject achieves ACR20 response in week 2 of said treatment.

[01191] Modality Y61: The method or pharmaceutical composition of any of Modalities Y54 to Y60, in which the adult subject achieves an ACR50 response following said treatment.

[01192]Modality Y62: The method or pharmaceutical composition of any of Modalities Y54 to Y61, in which the adult subject achieves ACR50 response in week 12 of said treatment.

[01193]Modality Y63: The method or pharmaceutical composition of any of Modalities Y54 to Y62, in which the adult subject achieves ACR50 response in week 8 of said treatment.

[01194]Modality Y64: The method or pharmaceutical composition of any of Modalities Y54 to Y63, in which the adult subject achieves ACR50 response in week 6 of said treatment.

[01195]Modality Y65: The method or pharmaceutical composition of any of Modalities Y54 to Y64, in which the adult subject achieves ACR50 response in week 4 of said treatment.

[01196]Modality Y66: The method or pharmaceutical composition of any of Modalities Y54 to Y65, in which the adult subject achieves ACR50 response in week 2 of said treatment.

[01197]Modality Y67: The method or pharmaceutical composition of any of Modalities Y54 to Y66, in which the adult subject achieves an ACR70 response following said treatment.

[01198]Modality Y68: The method or pharmaceutical composition of any of Modalities Y54 to Y67, in which the adult subject achieves ACR70 response in week 12 of said treatment.

[01199]Modality Y69: The method or pharmaceutical composition of any of Modalities Y54 to Y68, in which the adult subject achieves ACR70 response in week 8 of said treatment.

[01200]Modality Y70: The method or pharmaceutical composition of any of Modalities Y54 to Y69, in which the adult subject achieves ACR70 response in week 6 of said treatment.

[01201]Modality Y71: The method or pharmaceutical composition of any of Modalities Y54 to Y70, in which the adult subject achieves ACR70 response in week 4 of said treatment.

[01202]Modality Y72: The method or pharmaceutical composition of any of Modalities Y54 to Y71, in which the adult subject achieves ACR70 response in week 2 of said treatment.

[01203]Modality Y73: The method or pharmaceutical composition of any of Modalities Y to Y72, in which arthritis is additionally treated by relieving at least one symptom selected from the group consisting of bone erosion, cartilage erosion, inflammation and vascularity.

[01204]Modality Y74: The pharmaceutical method or composition of Modality Y73, wherein arthritis is further treated by alleviating at least one symptom selected from the group consisting of joint distortion, swelling, joint deformation, ankyloses in flexion and movement seriously affected.

[01205]Modality Y75: The method or pharmaceutical composition of any of Modalities Y to Y74, in which the crystalline or crystalline anhydrous hydrate of Compound 1 is administered in an amount sufficient to provide the subject with 7.5 mg of free base equivalent of Compound 1.

[01206]Modality Y76: The method or pharmaceutical composition of any of Modalities Y to Y74, in which the crystalline hydrate or crystalline anhydrous of Compound 1 is administered in an amount sufficient to provide the subject with 15 mg of free base equivalent. Compound 1.

[01207]Modality Y77: The method or pharmaceutical composition of any of Modalities Y to Y74, in which the crystalline hydrate or crystalline anhydrous of Compound 1 is administered in an amount sufficient to provide the subject with 30 mg of free base equivalent. Compound 1.

[01208]Modality Y78: The method or pharmaceutical composition of any of Modalities Y to Y74, in which the crystalline hydrate or crystalline anhydrous of Compound 1 is administered in an amount sufficient to provide the subject with 45 mg of free base equivalent. Compound 1.

[01209]Modality Z: 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 (3S,4R)-3-ethyl-4- Li-base (3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (Compound 1) vre, or a pharmaceutically acceptable salt thereof, or a crystalline or anhydrous crystalline hydrate of Compound 1 in an amount sufficient to provide the subject with about 7.5 mg per day of free base equivalent of Compound 1; or b) about 15 mg per day of free base of Compound 1 or a pharmaceutically acceptable salt thereof, or a crystalline or crystalline anhydrous hydrate of Compound 1 in an amount sufficient to provide the patient with about 15 mg per day of equivalent free base of Compound 1; or c) about 30 mg per day of free base of Compound 1 or a pharmaceutically acceptable salt thereof, or a crystalline or crystalline anhydrous hydrate of Compound 1 in an amount sufficient to provide the subject with about 30 mg per day of equivalent free base of Compound 1; or d) about 45 mg per day of free base of Compound 1 or a pharmaceutically acceptable salt thereof, or a crystalline or crystalline anhydrous hydrate of Compound 1 in an amount sufficient to provide the subject with about 45 mg per day of equivalent free base of Compound 1; so that structural damage to the adult subject is inhibited or attenuated.

[01210]Modality Z1: Pharmaceutical composition for use in the treatment of structural damage associated with rheumatoid arthritis in an adult subject, wherein the pharmaceutical composition comprises: a) about 7.5 mg per day of free base of Compound 1 or a pharmaceutically acceptable salt thereof, or a crystalline or anhydrous crystalline hydrate of Compound 1 in an amount sufficient to provide the subject with about 7.5 mg per day of free base equivalent of Compound 1; or b) about 15 mg per day of free base of Compound 1 or a pharmaceutically acceptable salt thereof, or a crystalline or crystalline anhydrous hydrate of Compound 1 in an amount sufficient to provide the patient with about 15 mg per day of equivalent free base of Compound 1; or c) about 30 mg per day of free base of Compound 1 or a pharmaceutically acceptable salt thereof, or a crystalline or crystalline anhydrous hydrate of Compound 1 in an amount sufficient to provide the subject with about 30 mg per day of equivalent free base of Compound 1; or d) about 45 mg per day of free base of Compound 1 or a pharmaceutically acceptable salt thereof, or a crystalline or crystalline anhydrous hydrate of Compound 1 in an amount sufficient to provide the subject with about 45 mg per day of equivalent free base of Compound 1; so that structural damage to the adult subject is inhibited or attenuated. In certain aspects of Embodiment Z1, use comprises administering the pharmaceutical composition to the subject.

[01211]Modality Z2: A method of treating structural damage associated with rheumatoid arthritis in an adult subject, the method comprising administering to the subject about 7.5 mg per day of Compound 1 free base or a pharmaceutical salt thereof acceptable, or a crystalline or anhydrous crystalline hydrate of Compound 1 in an amount sufficient to provide the subject with about 15 mg per day of free base equivalent of Compound 1 such that structural damage in the adult subject is inhibited or attenuated.

[01212]Modality Z3: The method of Modality Z2, comprising administering the crystalline or crystalline anhydrous hydrate of Compound 1 in an amount sufficient to provide the subject with 7.5 mg of free base equivalent of Compound 1.

[01213]Modality Z4: A method of treating structural damage associated with rheumatoid arthritis in an adult subject, the method comprising administering to the subject about 15 mg per day of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a crystalline or crystalline anhydrous hydrate of Compound 1 in an amount sufficient to provide the subject with about 15 mg per day of free base equivalent of Compound 1 such that structural damage in the adult subject is inhibited or attenuated.

[01214]Modality Z5: The method of Modality Z4, comprising administering the crystalline or crystalline anhydrous hydrate of Compound 1 in an amount sufficient to provide the subject with 15 mg of free base equivalent of Compound 1.

[01215]Modality Z6: A method of treating structural damage associated with rheumatoid arthritis in an adult subject, the method comprising administering to the subject about 30 mg per day of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a crystalline or crystalline anhydrous hydrate of Compound 1 in an amount sufficient to provide the subject with about 30 mg per day of free base equivalent of Compound 1 such that structural damage in the adult subject is inhibited or attenuated.

[01216]Modality Z7: The method of Modality Z6, comprising administering the crystalline or crystalline anhydrous hydrate of Compound 1 in an amount sufficient to provide the subject with 30 mg of free base equivalent of Compound 1.

[01217]Modality Z8: A method of treating structural damage associated with rheumatoid arthritis in an adult subject, the method comprising administering to the subject about 45 mg per day of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a crystalline or crystalline anhydrous hydrate of Compound 1 in an amount sufficient to provide the subject with about 45 mg per day of free base equivalent of Compound 1 such that structural damage in the adult subject is inhibited or attenuated.

[01218]Modality Z9: The method of Modality Z8, comprising administering the crystalline or crystalline anhydrous hydrate of Compound 1 in an amount sufficient to provide the subject with 45 mg of free base equivalent of Compound 1.

[01219] Modality Z10: The method or composition of any of Modalities Z to Z9, in which the hydrate is a hemihydrate.

[01220] Modality Z11: The method or composition of Modality Z10, in which the hydrate is Free Base Hydrate Form C.

[01221]Modality Z12: The method or composition of any of Modalities Z to Z9, in which the anhydrous is Form D of Free Base Anhydrous.

[01222]Modality Z13: The method or composition of any of Modalities Z to Z12, in which the free base or hydrate or anhydrous is presented in a prolonged release formulation once a day.

[01223]Modality AA: 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 (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) from free base, or a pharmaceutically acceptable salt thereof, or a crystalline or anhydrous crystalline hydrate of Compound 1 in an amount sufficient to provide the subject with about 7.5 mg per day of free base equivalent of Compound 1; or b) about 15 mg per day of free base of Compound 1 or a pharmaceutically acceptable salt thereof, or a crystalline or crystalline anhydrous hydrate of Compound 1 in an amount sufficient to provide the patient with about 15 mg per day of equivalent free base of Compound 1; or c) about 30 mg per day of free base of Compound 1 or a pharmaceutically acceptable salt thereof, or a crystalline or crystalline anhydrous hydrate of Compound 1 in an amount sufficient to provide the subject with about 30 mg per day of equivalent free base of Compound 1; or d) about 45 mg per day of free base of Compound 1 or a pharmaceutically acceptable salt thereof, or a crystalline or crystalline anhydrous hydrate of Compound 1 in an amount sufficient to provide the subject with about 45 mg per day of equivalent free base of Compound 1; and wherein the subject has symptoms selected from the group consisting of at least 6 swollen joints, at least 6 tender joints, and combinations thereof prior to treatment.

[01224]Modality AA1: Pharmaceutical composition for use in the treatment of moderately to severely active rheumatoid arthritis in an adult subject, wherein the pharmaceutical composition comprises: a) about 7.5 mg per day of (3S,4R)- 3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (Compound 1) free base, or a pharmaceutically acceptable salt thereof, or a crystalline or anhydrous crystalline hydrate of Compound 1 in an amount sufficient to provide the subject with about 7.5 mg per day of free base equivalent of Compound 1; or b) about 15 mg per day of free base of Compound 1 or a pharmaceutically acceptable salt thereof, or a crystalline or crystalline anhydrous hydrate of Compound 1 in an amount sufficient to provide the patient with about 15 mg per day of equivalent free base of Compound 1; or c) about 30 mg per day of free base of Compound 1 or a pharmaceutically acceptable salt thereof, or a crystalline or crystalline anhydrous hydrate of Compound 1 in an amount sufficient to provide the subject with about 30 mg per day of equivalent free base of Compound 1; or d) about 45 mg per day of free base of Compound 1 or a pharmaceutically acceptable salt thereof, or a crystalline or crystalline anhydrous hydrate of Compound 1 in an amount sufficient to provide the subject with about 45 mg per day of equivalent free base of Compound 1; and wherein the subject has symptoms selected from the group consisting of at least 6 swollen joints, at least 6 tender joints, and combinations thereof prior to treatment. In certain aspects of Embodiment AA1, use comprises administering the pharmaceutical composition to the subject.

[01225]Modality AA2: A method of treating moderately to severely active rheumatoid arthritis in an adult subject, the method comprising administering to the subject about 7.5 mg per day of Compound 1 free base or a pharmaceutically acceptable salt thereof, or a crystalline or crystalline anhydrous hydrate of Compound 1 in an amount sufficient to provide the subject with about 7.5 mg per day of free base equivalent of Compound 1, wherein the subject has symptoms selected from the group consisting of at least 6 swollen joints, at least 6 tender joints and combinations thereof before treatment.

[01226]Modality AA3: The method of Modality AA2, comprising administering the crystalline or crystalline anhydrous hydrate of Compound 1 in an amount sufficient to provide the subject with 7.5 mg of free base equivalent of Compound 1.

[01227]Modality AA4: A method of treating moderately to severely active rheumatoid arthritis in an adult subject, the method comprising administering to the subject about 15 mg per day of free base of Compound 1 or a pharmaceutically acceptable salt thereof, or a crystalline or crystalline anhydrous hydrate of Compound 1 in an amount sufficient to provide the subject with about 15 mg per day of free base equivalent of Compound 1, wherein the subject has symptoms selected from the group consisting of at least 6 swollen joints, at least 6 sensitive joints and their combinations before treatment.

[01228]Modality AA5: The method of Modality AA4, comprising administering the crystalline or crystalline anhydrous hydrate of Compound 1 in an amount sufficient to provide the subject with 15 mg of free base equivalent of Compound 1.

[01229]Modality AA6: A method of treating moderately to severely active rheumatoid arthritis in an adult subject, the method comprising administering to the subject about 30 mg per day of free base of Compound 1 or a pharmaceutically acceptable salt thereof, or a crystalline or crystalline anhydrous hydrate of Compound 1 in an amount sufficient to provide the subject with about 30 mg per day of free base equivalent of Compound 1, wherein the subject has symptoms selected from the group consisting of at least 6 swollen joints, at least 6 sensitive joints and their combinations before treatment.

[01230]Modality AA7: The method of Modality AA6, comprising administering the crystalline or crystalline anhydrous hydrate of Compound 1 in an amount sufficient to provide the subject with 30 mg of free base equivalent of Compound 1.

[01231]Modality AA8: A method of treating moderately to severely active rheumatoid arthritis in an adult subject, the method comprising administering to the subject about 45 mg per day of free base of Compound 1 or a pharmaceutically acceptable salt thereof, or a crystalline or crystalline anhydrous hydrate of Compound 1 in an amount sufficient to provide the subject with about 45 mg per day of free base equivalent of Compound 1, wherein the subject has symptoms selected from the group consisting of at least 6 swollen joints, at least 6 sensitive joints and their combinations before treatment.

[01232]Modality AA9: The method of Modality AA8, comprising administering the crystalline or crystalline anhydrous hydrate of Compound 1 in an amount sufficient to provide the subject with 45 mg of free base equivalent of Compound 1.

[01233]Modality AA10: The method or composition of any of Modalities AA to AA9, in which said symptoms result from the progression of structural damage assessed by radiography.

[01234] BB Modality: A method of reducing 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 (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) of free base, or a pharmaceutically acceptable salt thereof, or a crystalline or anhydrous crystalline hydrate of Compound 1 in an amount sufficient to provide the subject with about 7.5 mg of free base equivalent of Compound 1; or b) about 15 mg per day of free base of Compound 1 or a pharmaceutically acceptable salt thereof, or a crystalline or anhydrous crystalline hydrate of Compound 1 in an amount sufficient to provide the patient with about 15 mg equivalent free base of Compound 1; or c) about 30 mg per day of free base of Compound 1 or a pharmaceutically acceptable salt thereof, or a crystalline or anhydrous crystalline hydrate of Compound 1 in an amount sufficient to provide the subject with about 30 mg of base equivalent free of Compound 1; or d) about 45 mg per day of free base of Compound 1 or a pharmaceutically acceptable salt thereof, or a crystalline or crystalline anhydrous hydrate of Compound 1 in an amount sufficient to provide the subject with about 45 mg of base equivalent free of Compound 1.

[01235] Embodiment BB1: A pharmaceutical composition for reducing signs and symptoms of rheumatoid arthritis in an adult subject with moderately to severely active rheumatoid arthritis, wherein the pharmaceutical composition comprises: a) about 7.5 mg per day of ( 3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine- free base 1-carboxamide (Compound 1), or a pharmaceutically acceptable salt thereof, or a crystalline or crystalline anhydrous hydrate of Compound 1 in an amount sufficient to provide the subject with about 7.5 mg of free base equivalent. Compound 1; or b) about 15 mg per day of free base of Compound 1 or a pharmaceutically acceptable salt thereof, or a crystalline or anhydrous crystalline hydrate of Compound 1 in an amount sufficient to provide the patient with about 15 mg equivalent free base of Compound 1; or c) about 30 mg per day of free base of Compound 1 or a pharmaceutically acceptable salt thereof, or a crystalline or anhydrous crystalline hydrate of Compound 1 in an amount sufficient to provide the subject with about 30 mg of base equivalent free of Compound 1; or d) about 45 mg per day of free base of Compound 1 or a pharmaceutically acceptable salt thereof, or a crystalline or crystalline anhydrous hydrate of Compound 1 in an amount sufficient to provide the subject with about 45 mg of base equivalent free of Compound 1. In certain aspects of Embodiment BB1, use comprises administering the pharmaceutical composition to the subject.

[01236] BB2 Modality: A method of reducing signs and symptoms of rheumatoid arthritis in an adult subject with moderately to severely active rheumatoid arthritis, the method comprising administering to the subject about 7.5 mg per day of Compound 1 free base or a its pharmaceutically acceptable salt or a crystalline or anhydrous crystalline hydrate of Compound 1 in an amount sufficient to provide the subject with about 7.5 mg of free base equivalent of Compound 1.

[01237] BB3 Modality: The BB2 Modality method, in which the free base or hydrate or anhydrous is presented in a prolonged release formulation once a day.

[01238]Modality BB4: The method of Modality BB2 or BB3, in which the hydrate is a hemihydrate.

[01239]Modality BB5: The method of Modality BB4, in which the hemihydrate is Free Base Hydrate Form C.

[01240]Modality BB6: The method of Modality BB2 or BB3, in which the anhydrous is Form D of Free Base Anhydrous.

[01241]Modality BB7: The method of any of Modalities BB2 to BB6, in which the crystalline hydrate or crystalline anhydrous of Compound 1 is administered in an amount sufficient to provide the subject with 7.5 mg of free base equivalent of Compound 1.

[01242] Modality BB8: A method of reducing signs and symptoms of rheumatoid arthritis in an adult subject with moderately to severely active rheumatoid arthritis, the method comprising administering to the subject about 15 mg per day of free base of Compound 1 or a salt thereof pharmaceutically acceptable or a crystalline or anhydrous crystalline hydrate of Compound 1 in an amount sufficient to provide the subject with about 15 mg of free base equivalent of Compound 1.

[01243] BB9 Modality: The BB8 Modality method, in which the free base or hydrate or anhydrous is presented in a prolonged release formulation once a day.

[01244]Modality BB10: The method of Modality BB8 or BB9, in which the hydrate is a hemihydrate.

[01245]Modality BB11: The method of Modality BB10, in which the hemihydrate is Free Base Hydrate Form C.

[01246]Modality BB12: The method of Modality BB8 or BB9, in which the anhydrous is Form D of Free Base Anhydrous.

[01247]Modality BB13: The method of any of Modalities BB8 to BB12, in which the crystalline or crystalline anhydrous hydrate of Compound 1 is administered in an amount sufficient to provide the subject with 15 mg of free base equivalent of Compound 1.

[01248] Modality BB14: A method of reducing signs and symptoms of rheumatoid arthritis in an adult subject with moderately to severely active rheumatoid arthritis, the method comprising administering to the subject about 30 mg per day of Compound 1 free base or a salt thereof pharmaceutically acceptable or a crystalline or anhydrous crystalline hydrate of Compound 1 in an amount sufficient to provide the subject with about 30 mg of free base equivalent of Compound 1.

[01249]Modality BB15: The method of Modality BB14, in which the free base or hydrate or anhydrous is presented in a prolonged release formulation once a day.

[01250]Modality BB16: The method of Modality BB14 or BB15, in which the hydrate is a hemihydrate.

[01251]Modality BB17: The method of Modality BB16, in which the hemihydrate is Free Base Hydrate Form C.

[01252] Modality BB18: The method of Modality BB14 or BB15, in which the anhydrous is Form D of Free Base Anhydrous.

[01253]Modality BB19: The method of any of Modalities BB14 to BB17, in which the crystalline or crystalline anhydrous hydrate of Compound 1 is administered in an amount sufficient to provide the subject with 30 mg of free base equivalent of Compound 1 .

[01254] BB20 Modality: A method of reducing signs and symptoms of rheumatoid arthritis in an adult subject with moderately to severely active rheumatoid arthritis, the method comprising administering to the subject about 45 mg per day of Compound 1 free base or a salt thereof pharmaceutically acceptable or a crystalline or anhydrous crystalline hydrate of Compound 1 in an amount sufficient to provide the subject with about 45 mg of free base equivalent of Compound 1.

[01255] BB21 Modality: The BB20 Modality method, in which the free base or hydrate or anhydrous is presented in a prolonged release formulation once a day.

[01256]Modality BB22: The method of Modality BB20 or BB21, in which the hydrate is a hemihydrate.

[01257]Modality BB23: The method of Modality BB22, in which the hemihydrate is Free Base Hydrate Form C.

[01258]Modality BB24: The method of Modality BB20 or BB21, in which the anhydrous is Form C of Free Base Anhydrous.

[01259]Modality BB25: The method of any of Modalities BB20 to BB24, in which the crystalline or anhydrous crystalline hydrate of Compound 1 is administered in an amount sufficient to provide the subject with 45 mg of free base equivalent of Compound 1 .

[01260] Modality BB26: The method or composition of any of Modalities BB to BB25, wherein the method or use further comprises relieving at least one symptom of arthritis selected from the group consisting of bone erosion, cartilage erosion, inflammation and vascularity.

[01261] Modality BB27: The method or composition of Modality B26, wherein the method or use further comprises relieving at least one symptom of arthritis selected from the group consisting of joint distortion, swelling, joint deformation, ankylosis in Severely affected flexion and movement.

[01262]Modality BB28: The method or composition of any of Modalities Y to Y78, Z to Z13, AA to AA10, or BB to BB27, in which the free base or hydrate or anhydrous is administered for at least 8 weeks.

[01263]Modality BB29: The method or composition of Modality BB28, in which the free base or hydrate is administered for at least 12 weeks.

[01264] Modality CC: The method or pharmaceutical composition of any of Modalities Y to Y78, Z to Z13, AA to AA10, or BB to BB29, comprising administering to the subject about 7.5 mg or about 15 mg or about of 30 mg or about 45 mg per day of a crystalline or anhydrous crystalline hydrate of Compound 1.

[01265] Modality CC1: The method or pharmaceutical composition of any of Modalities Y to Y78, Z to Z13, AA to AA10, or BB to BB29, in which the crystalline anhydrous is Form D of Free Base Anhydrous.

[01266] Modality CC2: The method or pharmaceutical composition of any of Modalities Y to Y78, Z to Z13, AA to AA10, or BB to BB29, in which the crystalline hydrate of Compound 1 is administered in an amount sufficient to provide the subject about 7.5 mg free base equivalent of Compound 1.

[01267] Modality CC2a: The pharmaceutical method or composition of Modality CC2, in which the hydrate is a hemihydrate.

[01268] Modality CC2b: The method or pharmaceutical composition of Modality CC2a, in which the hydrate is Free Base Hydrate Form C.

[01269]Modality CC2c: The method or pharmaceutical composition of any of Modalities CC2 to CC2b, in which the crystalline hydrate is presented in a prolonged release formulation once a day.

[01270] Modality CC3: The method or pharmaceutical composition of any of Modalities Y to Y78, Z to Z13, AA to AA10, or BB to BB29, in which the crystalline hydrate of Compound 1 is administered in an amount sufficient to provide the subject about 45 mg of free base equivalent of Compound 1.

[01271] Modality CC3a: The method or pharmaceutical composition of Modality CC3, in which the hydrate is a hemihydrate.

[01272] Modality CC3b: The method or pharmaceutical composition of Modality CC3a, in which the hydrate is Free Base Hydrate Form C.

[01273]Modality CC3c: The method or pharmaceutical composition of any of Modalities CC3 to CC3b, in which the crystalline hydrate is presented in a prolonged release formulation once a day.

[01274] Modality CC4: The method or pharmaceutical composition of any of Modalities Y to Y78, Z to Z13, AA to AA10, or BB to BB29, in which the crystalline hydrate of Compound 1 is administered in an amount sufficient to provide the subject about 15 mg of free base equivalent of Compound 1.

[01275] Modality CC4a: The method or pharmaceutical composition of Modality CC4, in which the hydrate is a hemihydrate.

[01276] Modality CC4b: The method or pharmaceutical composition of Modality CC4a, in which the hydrate is Free Base Hydrate Form C.

[01277]Modality CC4c: The method or pharmaceutical composition of any of Modalities CC4 to CC4b, in which the crystalline hydrate is presented in a prolonged release formulation once a day.

[01278] Modality CC4d: The method or pharmaceutical composition of any of Modalities CC4 to CC4c, in which administration of the crystalline hydrate achieves an average peak plasma concentration (Cmax) for Compound 1 of about 25 to about of 70 ng/mL.

[01279] Modality CC4e: The method or pharmaceutical composition of any of Modalities CC4 to CC4d, in which administration of the crystalline hydrate achieves an average peak plasma concentration (Cmax) for Compound 1 of about 25 to about of 40 ng/mL.

[01280] Modality CC4f: The method or pharmaceutical composition of any of Modalities CC4 to CC4e, in which administration of the hydrate under fasting conditions achieves an average Cmax for Compound 1 of about 26.0 ng/mL.

[01281]Modality CC4g: The method or pharmaceutical composition of any of Modalities CC4 to CC4e, in which administration of the hydrate under fasting conditions achieves an average Cmax for Compound 1 of about 32 ng/mL.

[01282] Modality CC4h: The method or pharmaceutical composition of any of Modalities CC4 to CC4g, in which administration of the hydrate under non-fasting conditions achieves an average Cmax for Compound 1 of about 37 ng/mL.

[01283]Modality CC4i: The method or pharmaceutical composition of any of Modalities CC4 to CC4g, in which administration of the hydrate under non-fasting conditions achieves an average Cmax for Compound 1 of about 40 ng/mL.

[01284] Modality CC4j: The method or pharmaceutical composition of any of Modalities CC4 or CC4i, in which the difference in Cmax for Compound 1 when the hydrate is administered in the fed state versus in the fasted state is selected from from the group consisting of about 30% or less, about 20% or less, and about 10% or less.

[01285] Modality CC4k: The method or pharmaceutical composition of any of Modalities CC4 to CC4j, in which administration of the crystalline hydrate achieves a time to reach peak plasma concentration (Tmax) for Compound 1 of about 1. 0 to about 6.0 hours.

[01286] Modality CC4l: The method or pharmaceutical composition of any of Modalities CC4 to CC4k, in which administration of the hydrate under fasting conditions achieves a Tmax for Compound 1 of about 1.0 to about 4. 0 hours.

[01287] Modality CC4m: The method or pharmaceutical composition of any of Modalities CC4 to CC4k, in which administration of the hydrate under fasting conditions achieves a Tmax for Compound 1 of about 1.5 to about 6, 0 hours.

[01288] Modality CC4n: The method or pharmaceutical composition of any of Modalities CC4 to CC4m, in which administration of the hydrate under fasting conditions achieves a median Tmax for Compound 1 of about 3.0 hours.

[01289] Modality CC4o: The method or pharmaceutical composition of any of Modalities CC4 to CC4n, in which administration of the hydrate under non-fasting conditions achieves a Tmax for Compound 1 of about 3.0 to about 6 ,0 hours.

[01290] Modality CC4p: The method or pharmaceutical composition of any of Modalities CC4 to CC4o, in which administration of the hydrate under non-fasting conditions achieves a median Tmax for Compound 1 of about 4.0 hours.

[01291] Modality CC4q: The method or pharmaceutical composition of any of the Modalities CC4 to CC4p, in which the administration of the crystalline hydrate achieves an average area under the plasma concentration time curve extrapolated from 0 to infinity (AUCinf) for Compound 1 from about 220 to about 450 ng^hours/mL.

[01292]Modality CC4r: The method or pharmaceutical composition of any of Modalities CC4 to CC4q, in which administration of the hydrate under fasting conditions achieves an average AUCinf for Compound 1 of about 242 ng^hours/ mL.

[01293]Modality CC4s: The method or pharmaceutical composition of any of Modalities CC4 to CC4r, in which administration of the crystalline hydrate achieves a harmonic mean terminal half-life (t1/2) for Compound 1 of about 10, 0 to about 14.0 hours.

[01294] Modality CC4t: The method or pharmaceutical composition of any of Modalities CC4 to CC4s, in which the administration of the crystalline hydrate achieves a harmonic mean t1/2 for Compound 1 of about 12.5 hours.

[01295] Modality CC4u: The method or pharmaceutical composition of any of Modalities CC4 to CC4t, in which the administration of the crystalline hydrate achieves an average of the peak plasma concentration at steady state (Cmax, ss) for Compound 1 of about 27 to about 55 ng/mL.

[01296] Modality CC4v: The method or pharmaceutical composition of any of Modalities CC4 to CC4u, in which administration of the hydrate under fasting conditions achieves an average Cmax, ss for Compound 1 of about 32 ng/mL.

[01297] Modality CC4w: The method or pharmaceutical composition of any of Modalities CC4 to CC4v, in which administration of the hydrate under non-fasting conditions achieves an average Cmax, ss for Compound 1 of about 37 or about 37 ng/mL.

[01298] Modality CC4x: The method or pharmaceutical composition of any of the Modalities CC4 to CC4w, in which the administration of the crystalline hydrate achieves a time to reach peak plasma concentration at steady state (Tmax,ss) of about 1 .5 to about 6.0 hours.

[01299] Modality CC4y: The method or pharmaceutical composition of any of Modalities CC4 to CC4x, in which administration of the hydrate under fasting conditions achieves a Tmax,ss of about 1.5 to about 4.0 hours .

[01300] Modality CC4z: The method or pharmaceutical composition of any of Modalities CC4 to CC4y, in which administration of the hydrate under fasting conditions achieves a median Tmax,ss of about 2.5 hours.

[01301] Modality CC4aa: The method or pharmaceutical composition of any of Modalities CC4 to CC4z, in which administration of the hydrate under non-fasting conditions achieves a Tmax,ss of about 2.0 to about 6.0 hours.

[01302] Modality CC4bb: The method or pharmaceutical composition of any of Modalities CC4 to CC4aa, in which administration of the hydrate under non-fasting conditions achieves a median Tmax,ss of about 4.0 hours.

[01303] Modality CC4cc: The method or pharmaceutical composition of any of Modalities CC4 to CC4bb, in which administration of the crystalline hydrate achieves a mean steady-state area under the plasma concentration time curve extrapolated from 0 to 24 hours (AUC24,ss) for Compound 1 of about 240 to about 325 ng^hours/mL.

[01304] Modality CC4dd: The method or pharmaceutical composition of any of Modalities CC4 to CC4cc, in which administration of the hydrate under fasting conditions achieves an average AUC24,ss for Compound 1 of about 241 ng^hours/ mL.

[01305] Modality CC4ee: The method or pharmaceutical composition of any of Modalities CC4 to CC4cc, in which administration of the hydrate under fasting conditions achieves an average AUC24,ss for Compound 1 of about 279 ng^hours/ mL.

[01306] Modality CC4ff: The method or pharmaceutical composition of any of Modalities CC4 to CC4ee, in which administration of the hydrate under non-fasting conditions achieves an average AUC24,ss for Compound 1 of about 317 ng^hours /mL.

[01307] Modality CC4gg: The method or pharmaceutical composition of any of Modalities CC4 to CC4ee, in which administration of the hydrate under non-fasting conditions achieves an average AUC24,ss for Compound 1 of about 322 ng^hours /mL.

[01308] Modality CC4hh: The method or pharmaceutical composition of any of Modalities CC4 to CC4gg, in which administration of the crista-line hydrate achieves a harmonic mean steady state terminal half-life (t1/2,ss) for the Compound 1 from about 9.4 to about 10.5 hours.

[01309] Modality CC4ii: The method or pharmaceutical composition of any of Modalities CC4 to CC4hh, in which administration of the crystalline hydrate achieves a harmonic mean t1/2,ss for Compound 1 of about 9.4 hours or about 9.5 hours or about 10.3 hours.

[01310] Modality CC4jj: The method or pharmaceutical composition of any of Modalities CC4 to CC4ii, in which administration of the crystalline hydrate achieves an average minimum plasma concentration (Cmin, ss) for Compound 1 of about 2. 8 to about 3.2 ng/mL.

[01311] Modality CC4kk: The method or pharmaceutical composition of any of Modalities CC4 to CC4jj, in which administration of the crystalline hydrate achieves an average minimum plasma concentration (Cmin, ss) for Compound 1 of about 2. 8 to about 3.0 ng/mL.

[01312] Modality CC5: The method or pharmaceutical composition of any of Modalities Y to Y78, Z to Z13, AA to AA10, or BB to BB29, in which the crystalline hydrate of Compound 1 is administered in an amount sufficient to provide the subject about 30 mg of free base equivalent of Compound 1.

[01313] Modality CC5a: The method or pharmaceutical composition of Modality CC5, in which the hydrate is a hemihydrate.

[01314] Modality CC5b: The method or pharmaceutical composition of Modality CC5a, in which the hydrate is Free Base Hydrate Form C.

[01315] Modality CC5c: The method or pharmaceutical composition of any of Modalities CC5 to CC5b, in which the crystalline hydrate is presented in a prolonged release formulation once a day.

[01316] Modality CC5d: The method or pharmaceutical composition of any of Modalities CC5 to CC5c, in which administration of the crystalline hydrate achieves an average Cmax for Compound 1 of about 55 to about 85 ng/mL.

[01317] Modality CC5e: The method or pharmaceutical composition of any of Modalities CC5 to CC5d, in which administration of the hydrate under fasting conditions achieves an average Cmax for Compound 1 of about 55 ng/mL to about 66 ng/mL.

[01318] Modality CC5f: The method or pharmaceutical composition of any of Modalities CC5 to CC5e, in which administration of the hydrate under fasting conditions achieves an average Cmax for Compound 1 of about 55 ng/mL, or about of 56 ng/mL, or about 57 ng/mL, or about 59 ng/mL, or about 61 ng/mL, or about 64 ng/mL, or about 66 ng/mL.

[01319] Modality CC5g: The method or pharmaceutical composition of any of Modalities CC5 to CC5f, in which administration of the hydrate under non-fasting conditions achieves an average Cmax for Compound 1 of about 74 ng/mL at about 85 ng/mL.

[01320] Modality CC5h: The method or pharmaceutical composition of any of Modalities CC5 to CC5g, in which administration of the hydrate under non-fasting conditions achieves an average Cmax for Compound 1 of about 74 ng/mL, or about 76 ng/mL, or about 77 ng/mL, or about 79 ng/mL, about 82 ng/mL, or about 84 ng/mL.

[01321] Modality CC5i: The method or pharmaceutical composition of any of Modalities CC5 or CC5h, in which the difference in Cmax for Compound 1 when the hydrate is administered in the fed state versus in the fasted state is selected from from the group consisting of about 55% or less, about 53% or less, about 20% or less, about 10% or less, from about 3% or less to about 40%, and from about 15 % to about 55%.

[01322] Modality CC5j: The method or pharmaceutical composition of any one of Modalities CC5 to CC5i, in which administration of the crystalline hydrate achieves a Tmax for Compound 1 of about 1.0 to about 8.0 hours.

[01323] Modality CC5k: The method or pharmaceutical composition of any one of Modalities CC5 to CC5j, in which administration of the hydrate under fasting conditions achieves a Tmax for Compound 1 of about 1.0 to about 4.0 hours.

[01324] Modality CC5l: The method or pharmaceutical composition of any of Modalities CC5 to CC5k, in which administration of the hydrate under fasting conditions achieves a median Tmax for Compound 1 of about 2.0 hours to about 2.5 hours, or about 3.0 hours.

[01325] Modality CC5m: The method or pharmaceutical composition of any of Modalities CC5 to CC5l, in which administration of the hydrate under non-fasting conditions achieves a Tmax for Compound 1 of about 1.5 to about of 8.0 hours.

[01326] Modality CC5n: The method or pharmaceutical composition of any of Modalities CC5 to CC5m, in which administration of the hydrate under non-fasting conditions achieves a median Tmax for Compound 1 of about 4.0 hours.

[01327] Modality CC5o: The method or pharmaceutical composition of any of Modalities CC5 to CC5n, in which administration of the crystalline hydrate achieves an average AUCinf for Compound 1 of about 483 to about 660 ng-hours/mL .

[01328] Modality CC5p: The method or pharmaceutical composition of any of Modalities CC5 to CC5o, in which administration of the hydrate under fasting conditions achieves an average AUC24inf for Compound 1 of about 484 to about 550 ng^hours /mL.

[01329] Modality CC5q: The method or pharmaceutical composition of any of Modalities CC5 to CC5p, in which administration of the hydrate under fasting conditions achieves an average AUCinf for Compound 1 of about 484 ng^hours/ mL, or about 491 ng^hours/mL, or about 495 ng^hours/mL, or about 499 ng^hours/mL, or about 513 ng^hours/mL.

[01330] Modality CC5r: The method or pharmaceutical composition of any of Modalities CC5 to CC5q, in which administration of the hydrate under non-fasting conditions achieves an average AUCinf for Compound 1 of about 560 to about 660 ng ^hours/mL.

[01331] Modality CC5s: The method or pharmaceutical composition of any of Modalities CC5 to CC5r, in which administration of the hydrate under non-fasting conditions achieves an average AUCinf for Compound 1 of about 577 ng^hours /mL, or about 609 ng^hours/mL, or about 622 ng^hours/mL, or about 657 ng^hours/mL.

[01332] Modality CC5t: The method or pharmaceutical composition of any of Modalities CC5 to CC5s, in which administration of the crystalline hydrate achieves a harmonic mean t1/2 for Compound 1 of about 9.0 to about 12 ,0 hours.

[01333] Modality CC5u: The method or pharmaceutical composition of any of Modalities CC5 to CC5t, in which administration of the crystalline hydrate achieves an average Cmax, ss for Compound 1 of about 65 to about 86 ng/mL .

[01334] Modality CC5v: The method or pharmaceutical composition of any of Modalities CC5 to CC5u, in which administration of the hydrate under fasting conditions achieves an average Cmax, ss for Compound 1 of about 67 ng/mL.

[01335] Modality CC5w: The method or pharmaceutical composition of any of Modalities CC5 to CC5u, in which administration of the hydrate under fasting conditions achieves an average Cmax, ss for Compound 1 of about 68 ng/mL.

[01336] Modality CC5x: The method or pharmaceutical composition of any of Modalities CC5 to CC5w, in which administration of the hydrate under non-fasting conditions achieves an average Cmax,ss for Compound 1 of about 80 ng/mL .

[01337] Modality CC5y: The method or pharmaceutical composition of any of Modalities CC5 to CC5w, in which administration of the hydrate under non-fasting conditions achieves an average Cmax,ss for Compound 1 of about 84 ng/mL .

[01338] Modality CC5z: The method or pharmaceutical composition of any of Modalities CC5 to CC5y, in which administration of the crystalline hydrate achieves an average AUC24,ss for Compound 1 of about 485 to about 658 ng-hours /mL.

[01339] Modality CC5aa: The method or pharmaceutical composition of any of Modalities CC5 to CC5z, in which administration of the hydrate under fasting conditions achieves an average AUC24,ss for Compound 1 of about 525 ng-hours/mL .

[01340]Modality CC5bb: The method or pharmaceutical composition of any of Modalities CC5 to CC5aa, in which administration of the hydrate under non-fasting conditions achieves an average AUC24,ss for Compound 1 of about 582 ng-hours /mL.

[01341] Modality CC5cc: The method or pharmaceutical composition of any of Modalities CC5 to CC5aa, in which administration of the hydrate under non-fasting conditions achieves an average AUC24,ss for Compound 1 of about 620 ng-hours /mL.

[01342] Modality CC5dd: The method or pharmaceutical composition of any of Modalities CC5 to CC5cc, in which the administration of the crystalline hydrate achieves a Tmax,ss of about 1.5 to about 6.0 hours.

[01343] Modality CC5ee: The method or pharmaceutical composition of any of Modalities CC5 to CC5dd, in which administration of the hydrate under fasting conditions achieves a Tmax,ss of about 2.0 to about 4.0 hours .

[01344] Modality CC5ff: The method or pharmaceutical composition of any of Modalities CC5 to CC5ee, in which administration of the hydrate under fasting conditions achieves a median Tmax,ss of about 3.0 hours.

[01345] Modality CC5gg: The method or pharmaceutical composition of any of Modalities CC5 to CC5ff, in which administration of the hydrate under non-fasting conditions achieves a median Tmax,ss of about 3.5 hours or about 4 ,0 hours.

[01346]Modality CC5hh: The method or pharmaceutical composition of any of Modalities CC5 to CC5gg, in which administration of the crystalline hydrate achieves a harmonic mean t1/2,ss for Compound 1 of about 10.0 to about 14.5 hours.

[01347]Modality CC5ii: The method or pharmaceutical composition of any of Modalities CC5 to CC5hh, in which administration of the crystalline hydrate achieves a harmonic mean t1/2,ss for Compound 1 of about 10.1 hours or about 10.4 hours or about 14.4 hours.

[01348] Modality CC5jj: The method or pharmaceutical composition of any of Modalities CC5 to CC5ii, in which administration of the crystalline hydrate achieves an average Cmin, ss for Compound 1 of about 3.5 to about 5, 3 ng/mL.

[01349] Modality CC5kk: The method or pharmaceutical composition of any of Modalities CC5 to CC5jj, in which administration of the crystalline hydrate under fasting conditions achieves an average Cmin, ss for Compound 1 of about 3.8 ng /mL.

[01350] Modality CC5ll: The method or pharmaceutical composition of any of Modalities CC5 to CC5jj, in which administration of the crystalline hydrate under non-fasting conditions achieves an average Cmin, ss for Compound 1 of about 4.6 ng/mL or about 5.2 ng/mL.

[01351] DD Modality: A pharmaceutical composition comprising a crystalline hydrate or a crystalline anhydrous of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrole[2,3-e ]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (Compound 1) and a pharmaceutically acceptable carrier, wherein the composition comprises the crystalline hydrate or crystalline anhydrous in a sufficient amount to provide about 7.5 mg free base equivalent of Compound 1 or about 15 mg free base equivalent of Compound 1 or about 30 mg free base equivalent of Compound 1 or about 45 mg equivalent of free base of Compound 1.

[01352] Modality DD1: A pharmaceutical composition comprising about 7.5 mg, or about 15 mg, or about 30 mg, or about 45 mg of a crystalline hydrate or anhydrous crystalline of (3S,4R)- 3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (Compound 1), and a pharmaceutically acceptable carrier.

[01353] Embodiment DD2: A pharmaceutical composition comprising a crystalline hydrate of Compound 1 and a pharmaceutically acceptable carrier, wherein the composition comprises the crystalline hydrate in an amount sufficient to provide the subject with about 15 mg of free base equivalent of Compound 1 .

[01354] Embodiment DD3: A pharmaceutical composition comprising a crystalline hydrate of Compound 1 and a pharmaceutically acceptable carrier, wherein the composition comprises the crystalline hydrate in an amount sufficient to provide the subject with about 30 mg of free base equivalent of Compound 1 .

[01355]Modality DD4: The composition of any of Modalities DD to DD3, in which the hydrate is Free Base Hydrate Form C.

[01356]Modality DD5: The composition of any of Modalities DD to DD4, in which the hydrate or anhydrous is presented in a prolonged release formulation once a day.

[01357]Modality DD6: The composition of Modality DD4 or DD5, wherein the composition comprises about 15 mg of Free Base Hydrate Form C, and administration of the composition to a subject provides: (a) an average Cmax for the Compound 1 from about 25 to about 70 ng/mL; (b) a Tmax for Compound 1 of about 1.0 hour to about 6.0 hours; (c) a harmonic mean t1/2 for Compound 1 of about 10.0 to about 14.0 hours; (d) an average AUCinf for Compound 1 of about 220 to about 450 ng-hours/mL; (e) an average Cmax,ss for Compound 1 of about 27 to about 55 ng/mL; (f) an average AUC24,ss for Compound 1 of about 240 to about 325 ng-hours/mL; (g) a Tmax,ss for Compound 1 of about 1.5 to about 6.0 hours; (h) an average Cmin,ss for Compound 1 of about 2.8 to about 3.2 ng/mL; (i) a harmonic mean t1/2,ss for Compound 1 of about 9.4 to about 10.5 hours; or any combination of these.

[01358]Modality DD7: The composition of Modality DD4 or DD5, wherein the composition comprises about 30 mg of Free Base Hydrate Form C, and administration of the composition to a subject provides: (a) an average Cmax for the Compound 1 from about 55 to about 85 ng/mL; (b) a Tmax for Compound 1 of about 1.0 hour to about 8.0 hours; (c) a harmonic mean t1/2 for Compound 1 of about 9.0 to about 12.0 hours; (d) an average AUCinf for Compound 1 of about 483 to about 660 ng-hours/mL; (e) an average Cmax,ss for Compound 1 of about 65 to about 85 ng/mL; (f) an average AUC24,ss for Compound 1 of about 485 to about 658 ng-hours/mL; (g) a Tmax,ss for Compound 1 of about 1.5 to about 6.0 hours; (h) an average Cmin,ss for Compound 1 of about 3.5 to about 5.3 ng/mL; (i) a harmonic mean t1/2,ss for Compound 1 of about 10.0 to about 14.5 hours; or any combination of these.

[01359] Embodiment DD8: A pharmaceutical composition comprising a crystalline hydrate of Compound 1 and a pharmaceutically acceptable carrier, wherein the composition comprises the crystalline hydrate in an amount sufficient to provide the subject with about 7.5 mg of free base equivalent. Compound 1.

[01360] Modality DD9: The composition of Modality DD8, in which the hydrate is Free Base Hydrate Form C.

[01361] Modality DD10: The composition of Modality DD8 or DD9, in which the hydrate is presented as a once-daily extended-release formulation.

[01362] Modality DD11: The composition of any of Modalities DD8 to DD10, wherein the composition comprises the hydrate in an amount sufficient to provide 7.5 mg of free base equivalent of Compound 1.

[01363] Embodiment DD12: A pharmaceutical composition comprising a crystalline hydrate of Compound 1 and a pharmaceutically acceptable carrier, wherein the composition comprises the crystalline hydrate in an amount sufficient to provide the subject with about 45 mg of free base equivalent of Compound 1 .

[01364] Modality DD13: The composition of Modality DD12, in which the hydrate is Free Base Hydrate Form C.

[01365]Modality DD14: The composition of Modality DD12 or DD13, in which the hydrate is presented as a once-daily extended-release formulation.

[01366] Modality DD15: The composition of any of Modalities DD12 to DD14, wherein the composition comprises the hydrate in an amount sufficient to provide 45 mg of free base equivalent of Compound 1.

[01367] EE Modality: A method of treating an adult subject with moderately to severely active rheumatoid arthritis, the method comprising administering to the subject about 7.5 mg, or about 15 mg, or about 30 mg, or about 45 mg of a crystalline hydrate of Compound 1.

[01368]Modality EE1: A method of treating structural damage associated with rheumatoid arthritis in an adult subject, the method comprising administering to the subject about 7.5 mg, or about 15 mg, or about 30 mg, or about 45 mg per day of a crystalline hydrate of Compound 1, so that structural damage in the adult subject is inhibited or attenuated.

[01369]Modality EE2: A method of treating moderately to severely active rheumatoid arthritis in an adult subject, the method comprising administering to the subject about 7.5 mg, or about 15 mg, or about 30 mg, or about 45 mg per day of a crystalline hydrate of Compound 1, wherein the subject has symptoms selected from the group consisting of at least 6 swollen joints, at least 6 tender joints, and combinations thereof prior to treatment.

[01370]Modality EE3: A method of reducing signs and symptoms of rheumatoid arthritis in a subject with moderately to severely active rheumatoid arthritis, the method comprising administering to the subject about 7.5 mg, or about 15 mg, or about 30 mg, or about 45 mg per day of a crystalline hydrate of Compound 1.

[01371]Modality EE4: The method of any of Modalities EE to EE3, in which the hydrate is a hemihydrate.

[01372] Modality EE5: The method of Modality EE4, in which the hydrate is Free Base Hydrate Form C.

[01373]Modality EE6: The method of any of Modalities EE to EE5, in which the hydrate is presented as a once-daily extended-release formulation.

[01374] Modality FF: A pharmaceutical composition comprising about 7.5 mg, or about 15 mg, or about 30 mg, or about 45 mg of a crystalline hydrate of Compound 1 and a pharmaceutically acceptable salt.

[01375] Modality FF1: The composition of Modality FF, in which the hydrate is a hemihydrate.

[01376] Modality FF2: The composition of Modality FF1, in which the hydrate is Free Base Hydrate Form C.

[01377]Modality FF3: The composition of any of Modalities FF to FF2, in which the free base or hydrate is presented as a once-daily extended release formulation.

[01378] Modality GG: A sustained-release formulation for oral administration comprising Compound 1 or a pharmaceutically acceptable salt thereof, a hydrophilic polymer and a pH modifier, in which the hydrophilic polymer, in contact with water, forms a layer of gel that provides a suitable environment for Compound 1 and the pH modifier to dissolve.

[01379] Modality GG1: A sustained-release formulation for oral administration comprising a solid state form of Compound 1, a hydrophilic polymer and a pH modifier, in which the hydrophilic polymer, in contact with water, forms a gel layer which provides a suitable environment for the solid state form of Compound 1 and the pH modifier to dissolve.

[01380] Modality GG1a: The extended release formulation of Modality GG1, in which the solid state form is a crystalline hydrate.

[01381] Modality GG1b: The prolonged release formulation of Modality GG1a, in which the crystalline hydrate is a hemihydrate.

[01382] Modality GG1c: The extended release formulation of Modality GG1b, in which the hemihydrate is Free Base Hydrate Form C.

[01383] Modality GG1d: The extended release formulation of Modality GG1a, in which the crystalline hydrate is Free Base Hydrate Form B.

[01384] Modality GG1e: The extended release formulation of Modality GG1, in which the solid state form is an anhydrous crystalline.

[01385] Modality GG1f: The prolonged release formulation of Modality GG1e, in which the crystalline anhydrous is Form D of Free Base Anhydrous.

[01386]Modality GG2: The sustained-release formulation of any of Modalities GG through GG1f, wherein the suitable environment for Compound 1 or the solid state form to dissolve has a pH of 3.8 or less at 37° W.

[01387]Modality GG2a: The sustained-release formulation of any of Modalities GG to GG2, in which the suitable environment for Compound 1 or the solid state form to dissolve has a pH of 1.5 to 3 ,7.

[01388]Modality GG3: The sustained-release formulation of any of Modalities GG to GG2a, in which the suitable environment for Compound 1 or the solid state form to dissolve has a pH of 2.0 to 3.7.

[01389]Modality GG4: The sustained-release formulation of any of Modalities GG to GG3, in which the suitable environment for Compound 1 or the solid state form to dissolve has a pH of 2.5 to 3.6.

[01390]Modality GG5: The sustained-release formulation of any of Modalities GG to GG4, in which the suitable environment for Compound 1 or the solid state form to dissolve has a pH of 3.0 to 3.6.

[01391]Modality GG6: The sustained-release formulation of any of Modalities GG to GG5, in which the suitable environment for Compound 1 or the solid state form to dissolve has a pH of 3.0 to 3.5.

[01392]Modality GG7: The sustained-release formulation of any of Modalities GG to GG6, in which the pH modifier is selected from the group consisting of tartaric acid, fumaric acid, citric acid, succinic acid, malic acid and combinations of the same.

[01393]Modality GG8: The extended release formulation of any of Modalities GG to GG7, in which the pH modifier is selected from the group consisting of tartaric acid, fumaric acid, citric acid, succinic acid and combinations thereof.

[01394]Modality GG9: The sustained release formulation of any of Modalities GG to GG8, in which the pH modifier is selected from the group consisting of tartaric acid, fumaric acid and combinations thereof.

[01395]Modality GG10: The sustained-release formulation of any of Modalities GG to GG9, in which the pH modifier is tartaric acid.

[01396]Modality GG11: The sustained-release formulation of any of Modalities GG to GG10, in which the pH modifier is fumaric acid or citric acid.

[01397]Modality GG12: The sustained-release formulation of any of Modalities GG to GG11, in which the pH modifier is present in an amount of about 10 to about 35% w/w.

[01398]Modality GG13: The sustained-release formulation of any of Modalities GG to GG12, in which the pH modifier is present in an amount of about 20 to about 35% w/w.

[01399]Modality GG14: The sustained-release formulation of any of Modalities GG to GG13, in which the pH modifier is present in an amount of about 20 to about 30% w/w.

[01400] Modality GG15: The extended release formulation of any of Modalities GG to GG14, in which the pH modifier is present in an amount of about 20 to about 25% w/w.

[01401]Modality GG16: The sustained-release formulation of any of Modalities GG to GG15, in which the pH modifier is present in an amount of about 30% w/w.

[01402] Modality GG17: The extended release formulation of any of Modalities GG to GG16, in which the pH modifier is present in an amount of about 20% w/w.

[01403] Modality GG18: The extended release formulation of any of Modalities GG to GG17, in which the pH modifier is present in an amount of about 10% w/w.

[01404]Modality GG19: The sustained release formulation of any of Modalities GG to GG18, in which the hydrophilic polymer is a cellulose derivative with a viscosity between 1000 and 150000 mPa-s.

[01405]Modality GG20: The sustained-release formulation of any of Modalities GG to GG19, in which the hydrophilic polymer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxyethylcellulose and mixtures thereof

[01406]Modality GG21: The sustained-release formulation of any of Modalities GG to GG20, in which the hydrophilic polymer is hydroxypropyl methylcellulose.

[01407] Modality GG22: The extended release formulation of Modality GG21, in which the hydroxypropyl methylcellulose is grade E, F or K.

[01408] Modality GG22: The extended release formulation of Modality GG21, in which the hydroxypropyl methylcellulose is Hypromellose 2208.

[01409] HH Modality: A process for preparing a pharmaceutical composition, the process comprising: (a) combining (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2 ,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (Compound 1) or a pharmaceutically acceptable salt thereof, or a solid state form of Compound 1 , and at least a portion of 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 ground granulated material; (e) combining the ground granulation material with any remaining composition components; and (f) compressing the composition to form the pharmaceutical composition.

XIII. EXAMPLES Example 1: Preparation of (3R,4S)-1-((benzyloxy)carbonyl)-4-ethylpyrrolidine-3-carboxylate dicyclohexylamine salt

[01410] Dicyclohexylamine salt of (3R,4S)-1-((benzyloxy)carbonyl)-4-ethylpyrrolidine-3-carboxylate was prepared according to the following reaction scheme: Scheme XIV

[01411] A mixture of carboxybenzyl glycine ethyl ester (5.5 g, 23.2 mmol) and ethyl acrylate (2.3 g, 23.2 mmol) in THF (55 mL) at 0 °C was Added NatOBu (2.2 g, 23.2 mmol) in portions over 1 hour. The resulting mixture was warmed to room temperature and stirred overnight. After completion, the reaction was quenched with water (30 mL), the pH adjusted to 4.0 with concentrated HCl, and the THF removed by distillation. The product was extracted into DCM (40 mL) and the organic layer washed with water (15 mL). After removing the DCM, the product was crystallized from diisopropyl ether/heptane (30 mL/60 mL). The solids were collected by filtration and washed with heptane (6 mL). The wet material (5.5 g of adjusted power, 82%) is used directly in the next step.B. Step B: Preparation of 1-benzyl 3-ethyl 4-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrrole-1,3(2H,5H)-dicarboxylate

[01412] A mixture of 1-benzyl 3-ethyl 4-hydroxy-1H-pyrrole-1,3(2H,5H)-dicarboxylate (16.2 g dry weight, 55.6 mmol) in di ether -isopropyl (150 mL) was added at 0 °C trifluoromethanesulfonic anhydrous (17.3 g, 61.2 mmol) followed by a slow addition of DIPEA (8.6 g, 66.7 mmol) over 30 min. The resulting mixture was warmed to room temperature and stirred for 1 hour. Upon completion, the reaction was carefully quenched with 0.5 M HCl (200 mL), additional diisopropyl ether (50 mL) was added, and the layers were separated. The organic layer was washed twice with water (30 mL) and concentrated. The residue was chased with toluene, absorbed into toluene to provide a 30% solution by weight (21.7 g adjusted strength, 92%), and used directly in the next step.

[01413]1H NMR (400 MHz, CDCI3) δ 7.48 - 7.28 (m, 5H), 5.20 (s, 2H), 4.60 - 4.42 (m, 4H), 4.42 - 4.23 (m, 2H), 1.40 - 1.31 (m, 3H) in a purified sample. C. Step C: Preparation of 1-benzyl 3-ethyl 4-ethyl-1H-pyrrole-1,3(2H,5H)-dicarboxylate

[01414] To the previous triflate toluene solution (21.3 g of triflate, 50.3 mmol) was added additional toluene (170 mL), water (20 mL), ethylboronic acid (EtB(OH)2) (5, 6 g, 75.4 mmol), potassium carbonate (10.4 g, 75.4 mmol) and the resulting mixture was purged with nitrogen. PdCl2(dppf) (735 mg, 1.0 mmol) was added, the resulting mixture was heated to 85°C and stirred for 6 hours. Upon completion, the mixture was cooled to room temperature, filtered and the layers separated. The organic layer was washed with water, concentrated to approximately 15% volume (30 mL) and diluted with heptane (120 mL). The product solution was treated with activated carbon, filtered and concentrated to dryness to give the desired product (13.9 g, 91%)

[01415]1H NMR (400 MHz, CDCI3) δ 7.50 - 7.31 (m, 5H), 5.20 (s, 2H), 4.54 - 4.30 (m, 4H), 4.24 (q, J = 7.2 Hz, 2H), 2.68 (p, J = 7.8 Hz, 2H), 1.36 - 1.30 (m, 3H), 1.22 - 1.00 ( m, 3H). D. Step D: Preparation of 1-((benzyloxy)carbonyl)-4-ethyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid

[01416] To a THF solution (90 mL) of 1-benzyl 3-ethyl 4-ethyl-1H-pyrrole-1,3(2H,5H)-dicarboxylate (13.9 g, 46.0 mmol) was added 30% aqueous NaOH (61.3 g, 460 mmol). The resulting mixture was heated to 50°C and stirred for 7 h. Upon completion, the mixture was cooled to room temperature, additional water (50mL) was added and the pH was adjusted to 9 with concentrated HCl. THF was removed by distillation and the aqueous layer washed at 50°C twice with toluene (2 x 50mL). The aqueous layer was cooled to room temperature and the pH was adjusted to 4 with concentrated HCl. The resulting product slurry was stirred for 2 hours before collecting the solids by filtration. The cake was washed with water (50 mL) and dried in a vacuum oven. The product was then dissolved in EtOAc (275 mL) at 75 °C, treated with activated carbon and filtered. The crystallized product after cooling to 0 °C was collected by filtration, washed with EtOAc (2 x 10 mL) and dried in a vacuum oven to give the desired compound (10.3 g, 83%)

[01417]1H NMR (400 MHz, CDCI3) δ 7.63 - 7.33 (m, 5H), 5.20 (s, 2H), 4.51 - 4.37 (m, 4H), 2.78 - 2.58 (m, 2H), 1.17 - 1.08 (m, 3H).E. Step E: Preparation of (3R,4S)-1-((benzyloxy)carbonyl)-4-ethylpyrrolidine-3-carboxylate dicyclohexylamine salt

[01418] A MeOH solution (100 mL) of 1-((benzyloxy)carbonyl)-4-ethyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid (9.9 g, 36 mmol), TEA (4.2 g, 41.4 mmol) and (S)-segphos Ru(OAc)2 (29.8 mg, 0.04 mmol) was hydrogenated at 580 psi and 80 °C for 2 hours. Upon completion, the reaction mixture was cooled to room temperature, filtered and concentrated by distillation. The residue was taken up in water (50 mL) and water (50 mL) and the pH of the aqueous layer was adjusted to 11 with 30% aqueous NaOH. The layers were separated, the pH of the aqueous layer was adjusted to 3 with concentrated HCl, and the product extracted with EtOAc (50 mL). The EtOAc was distilled off, the residue taken up in ACN (75 mL) and filtered. Additional ACN (100 mL) and dicyclohexylamine (6.3 g, 34.6 mmol) were added and the mixture heated to 80 °C. The resulting solution was slowly cooled to room temperature and stirred for 1 hour. The resulting solids were collected by filtration, washed with ACN (50 mL), and dried in a vacuum oven to provide the desired product (14.9 g, 90%, >99% ee).

[01419]1H NMR (400 MHz, CDCI3) δ 7.47 - 7.18 (m, 5H), 5.14 (ddd, J = 15.5, 12.6, 3.7 Hz, 2H), 3 .67 (td, J = 10.5, 4.8 Hz, 1H), 3.61 - 3.47 (m, 2H), 3.34 (ddd, J = 13.4, 10.1, 7, 5 Hz, 1H), 3.02 - 2.77 (m, 3H), 2.33 - 2.14 (m, 1H), 1.96 (t, J = 8.0 Hz, 4H), 1, 77 (d, J = 10.0 Hz, 4H), 1.69 - 1.53 (m, 3H), 1.49 - 1.30 (m, 5H), 1.29 - 1.05 (m, 6H), 0.98 (td, J = 7.3, 2.5 Hz, 3H). Example 2: Preparation of ethyl (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl) carbamate

[01420] A degassed mixture of 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (100 g, 284 mmol), K2CO3 (118 g, 852 mmol), ethyl carbamate (50 .6 g, 568 mmol), palladium(II) acetate (Pd(OAc)2) (640 mg, 2.8 mmol) and Xantphos (3.3 g, 5.7 mmol) in toluene (1 L) was heated to 95°C and stirred overnight. The resulting mixture was cooled to 50°C and THF (1 L) was added and the solids removed by filtration by rinsing the cake with THF (2 L). The resulting solution was mixed with a solution of cysteine (50 g) in saturated aqueous sodium bicarbonate (1 L) for two hours. After separating the layers, the organic layer was washed with saturated aqueous sodium bicarbonate (1 L) and brine (500 mL), treated with activated carbon, filtered and concentrated. The resulting solid was triturated with EtOAc (500 mL), the solid was collected, washed with EtOAc (100 mL) and dried in a vacuum oven at 50 °C to yield 85 g (83%).

[01421]1H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 8.86 (s, 1H), 8.22 (d, J = 4.0 Hz, 1H), 7, 99 (d, J = 8.5 Hz, 2H), 7.55 - 7.29 (m, 2H), 6.88 (d, J = 4.0 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 2.35 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H).

Example 3: 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)

[01422] Compound 1 was prepared according to the following reaction scheme: Scheme XV

[01423] (3R,4S)-1-((benzyloxy)carbonyl)-4-ethylpyrrolidine-3-carboxylate salt, (R)-1-(naphthalen-1-yl)ethanamine (150 g, 334 mmol) was partitioned between MTBE (1.5 L) and 0.5 M H3PO4 (750 mL) and stirred for 30 minutes. After separating the layers, the organic layer was washed with 0.25 H3PO4 (750 mL) and saturated aqueous NaCl (500 mL). After concentration to an oil, the free acid is collected in THF (250 mL) and stored for later.

[01424] To a paste of CDI (81 g, 501 mmol) in THF (400 mL) was added the THF solution of (3R,4S)-1-(benzyloxycarbonyl)-4-ethylpyrrolidine-3-carboxylic acid from above ( 93 g, 334 mmol) for 30 minutes. The resulting mixture was stirred at room temperature for 1 hour. A suspension of trimethylsulfoxonium chloride (86 g, 668 mmol) and KOtBu (77 g, 685 mmol) in THF (1 L) was heated to reflux for 2 hours and then cooled to -5 °C. The solution of (3S,4R)-benzyl 3-ethyl-4-(1H-imidazol-1-carbonyl)pyrrolidine-1-carboxylate (109 g, 334 mmol) prepared above was added dropwise over 15 minutes, simultaneously maintaining internal temperature below -1 °C. After the addition was complete, the solution was quenched with 5% NaCl (1.2 L). The layers were separated and the aqueous layer was extracted with EtOAc (1 mL). The combined organic layers were washed with 12% NaCl (600 mL) and concentrated to near dryness. The crude yellow oil was chased with water (3 x 400 mL), concentrating to dryness each time, during which time solids formed. The residue was taken up in water (1.5 L) and heated to 70 °C. The suspension was allowed to cool to room temperature. The solids were collected by filtration, washed with water (2 x 200 mL) and dried in a vacuum oven. The product was isolated (96.1 g) (82%) as a white solid.

[01425]1H NMR (400 MHz, DMSO) δ 7.41 - 7.25 (m, 5H), 5.11 - 4.93 (m, 2H), 4.76 (s, 1H), 3.54 - 3.23 (m, 9H), 3.15 (dd, J = 18.0, 9.6 Hz, 1H), 2.91 - 2.72 (m, 1H), 2.26 - 2.02 (m, 1H), 1.57 - 1.39 (m, 1H), 1.20 (tq, J = 14.1, 7.3 Hz, 1H), 0.88 (td, J = 7.4 , 2.7Hz, 3H). MS (ESI+): 352.0 m/e (M+H).B. Step B: Preparation of (3R,4S)-benzyl 3-(2-bromoacetyl)-4-ethylpyrrolidine-1-carboxylate

[01426] To a THF solution (100 mL) of dimethylsulfoxonium 2-((3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidin-3-yl)-2-oxo-ethylide (10.0 g, 28, 5 mmol) and lithium bromide (LiBr) (2.97 g, 34.1 mmol) p-toluenesulfonic acid monohydrate (5.95 g, 31.3 mmol) was added. The resulting mixture was heated to 40 °C and stirred for overnight. After cooling to room temperature, the reaction mixture was diluted with EtOAc (100 mL), washed with water (100 mL), saturated aqueous sodium bicarbonate (100 mL) and brine (50 mL). was concentrated and used without purification.

[01427]1H NMR (400 MHz, CDCL3) δ 7.41 - 7.27 (m, 5H), 5.22 - 5.03 (m, 2H), 3.98 - 3.83 (m, 2H) , 3.76 - 3.65 (m, 1H), 3.65 - 3.49 (m, 3H), 3.46 - 3.27 (m, 1H), 2.47 - 2.32 (m, 1H), 1.48 - 1.21 (m, 2H), 0.99 - 0.89 (m, 3H). MS (ESI+): 353.9 m/e (M+H).C. Step C: Preparation of (3S,4R)-benzyl 3-ethyl-4-(2-((ethoxycarbonyl)(5-to-sil-5H-pyrrolo[2,3-b]pyrazin-2-yl)amino) acetyl)pyrrolidine-1-carboxylate

[01428] To a DMA suspension (40 mL) of ethyl (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)carbamate (8.25 g, 22.9 mmol) (prepared as described in Example 2) cooled to 5 ° C, a solution of N,N-dimethylacetamide (DMA) (20 mL) of LiOtBu (1.75 g, 21.9 mmol) was added. The resulting solution was stirred 30 minutes and cooled to -10 °C. A DMA solution (20 mL) of (3R,4S)-benzyl 3-(2-bromoacetyl)-4-ethylpyrrolidine-1-carboxylate from above (approximately 7.1 g, 19.9 mmol) was added for 30 minutes and stirred at -10 °C for 30 minutes. The resulting mixture was quenched with HOAc (2.3 mL, 40 mmol) and heated to 25 °C. EtOH (40 mL) was added and the mixture seeded with the desired product (500 mg). After stirring for a further 2 hours, a mixture of EtOH (40 ml) and water (20 ml) was added over 8 hours. The product was then collected, washed with ethanol (2 x 40 mL) and dried to give 10.7 g (88% by weight pure with 12% of the initial carbamate). A purified sample was prepared by recrystallizing from EtOAc.

[01429]1H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.20 (dd, J = 9.0, 4.1 Hz, 1H), 8.06 - 7.86 (m, 2H), 7.51 - 7.35 (m, 2H), 7.33 - 7.23 (m, 5H), 6.74 (dd, J = 36.1, 4.1 Hz, 1H ), 5.02 (d, J = 4.1 Hz, 2H), 4.80 (s, 2H), 4.14 (qd, J = 7.1, 4.5 Hz, 2H), 3.64 - 3.34 (m, 4H), 3.21 - 3.08 (m, 1H), 2.46 - 2.34 (m, 1H), 2.32 (s, 3H), 1.41 (d , J = 13.3 Hz, 1H), 1.29 - 1.08 (m, 4H), 0.86 (td, J = 7.3, 4.8 Hz, 3H).D. Step D: Preparation of (3S,4R)-benzyl 3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)pyrrolidine-1-carboxylate

[01430] To a solution of (3S,4R)-benzyl 3-ethyl-4-(2-(ethoxycarbonyl(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)amino)acetyl) pyrrolidine-1-carboxylate (27.0 g, 42.6 mmol) in ACN (140 mL) pyridine (9.3 mL, 115 mmol) and trifluoroacetic anhydrous (24.1 mL, 170 mmol) were charged and the mixture was heated to 75°C and stirred for 2 hours. Upon completion, the reaction mixture was cooled to room temperature and concentrated on the rotary evaporator. The residue was taken up in 2-methyl tetrahydrofuran (2-MeTHF) (200 mL) and poured into a 20% NaOH solution (200 g) and the mixture stirred at 55 °C for 1 hour. Upon completion, the reaction mixture was cooled to room temperature and the layers separated. The organic layer was washed with 20% NaOH (100 g) and brine (100 g) and the solvent changed to EtOH. The EtOH solution was evaluated for product (15.2 g, 92%) and taken to the Cbz removal step as a solution.E. Step E: Preparation of 8-((3R,4S)-4-ethylpyrrolidin-3-yl)- 3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine bishydrochloride

[01431] A mixture of 10% Pd(OH)2/C (1 g) and (3S,4R)-benzyl 3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3 -e]pyrazin-8-yl)pyrrolidine-1-carboxylate (5.13 g, 13.2 mmol) in EtOH (70 mL) was mixed under hydrogen pressure at 20 psig. The mixture was stirred for 16 hours at 50 °C. Upon completion, the reaction was cooled to room temperature and filtered through a short plug of diatomaceous earth. To this solution was added 35% aqueous HCl (2.6 mL, 31.1 mmol) and the mixture concentrated. The resulting residue was suspended in EtOH (17mL) and EtOAc (34mL), and stirred for 1 hour. The crystalline solids were collected, washed with EtOAc/ethanol (2/1, 15 mL) and EtOAc (15 mL), and dried in a vacuum oven to obtain the product (3.63 g, 83%).

[01432]1H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 10.32 - 9.91 (m, 2H), 8.91 (s, 1H), 8.60 (s , 1H), 7.89 (t, J = 3.3 Hz, 1H), 7.29 (dd, J = 3.5, 1.9 Hz, 1H), 4.58 (q, J = 7, 4 Hz, 1H), 3.80 - 3.67 (m, 1H), 3.67 - 3.55 (m, 2H), 3.20 - 3.02 (m, 1H), 2.75 - 2 .59 (m, 1H), 1.16 - 1.01 (m, 1H), 1.01 - 0.87 (m, 1H), 0.65 (t, J = 7.3 Hz, 3H). F1. Step F1: Preparation of Compound 1

[01433] To a THF paste (60 mL) of CDI (8.7 g, 53.7 mmol) was added dropwise 2,2,2-trifluoroethyl amine (4.52 mL, 57.5 mmol) for 20 minutes, simultaneously maintaining an internal temperature below 30 °C. The resulting solution was stirred for 1 hour.

[01434] A biphasic mixture of 8-((3R,4S)-4-ethylpyrrolidin-3-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine bishydrochloride (12 .7 g, 38.7 mmol) and dibasic potassium phosphate (K2HPO4) (7.4 g, 42.6 mmol) in THF (60 mL) and water (30 mL) 10% KOH was added to adjust the pH to 9. The imidazolide from above was added and the resulting mixture was mixed at 25°C while maintaining a pH of 9 by the portionwise addition of 10% KOH over 1 hour. After completion, the reaction was quenched with 20% aqueous citric acid (50 mL), stirred for 1 hour and the product extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with 15% aqueous KH2PO4 (50 mL), saturated aqueous sodium bicarbonate (50 mL) and brine (25 mL). The product solution was treated with activated carbon and concentrated by distillation. The residue was taken up in 2% water in EtOAc (70 ml), seeded and stirred for 1 hour. Heptane (35 mL) was added, stirred for 1 hour and the solids were collected by filtration. The wet cake was washed with 1% water in EtOAc/heptane (2/1, 2 x 25 mL) and dried in a vacuum oven to give the desired product (12.8 g, 87%).

[01435]1H NMR (400 MHz, DMSO-d6) δ 12.24 (s, 1H), 8.54 (s, 1H), 7.47 - 7.35 (m, 2H), 7.02 - 6 .85 (m, 2H), 4.31 (q, J = 6.4 Hz, 1H), 3.91 - 3.68 (m, 4H), 3.65 (dd, J = 10.2, 6 .9 Hz, 1H), 3.23 (dd, J = 10.3, 6.1 Hz, 1H), 2.59 - 2.48 (m, 1H), 1.06 (dtd, J = 14, 7, 7.4, 4.7 Hz, 1H), 0.84 - 0.70 (m, 1H), 0.60 (t, J = 7.4 Hz, 3H).F2. Step F2: Alternative Compound Preparation 1

[01436] As an alternative to the Step F1 procedure, Compound 1 was prepared according to Step F2.

[01437] To a THF paste (500 mL) of CDI (67.1 g, 414 mmol) 2,2,2-trifluoroethylamine (34.6 mL, 441 mmol) was added dropwise over 20 minutes, simultaneously maintaining an internal temperature below 30 °C. The resulting solution was stirred for 1 hour.

[01438] A biphasic mixture of 8-((3R,4S)-4-ethylpyrrolidin-3-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine bishydrochloride (91 .0 g, 276 mmol) and dibasic potassium phosphate (K2HPO4) (48.0 g, 276 mmol) in THF (500 mL) and water (500 mL) and 20% KOH was added to adjust the pH to 9 The imidazolide from above was added and the resulting mixture was mixed at 25°C while maintaining a pH of 9 by the portionwise addition of 20% KOH over 1 hour. After completion, the reaction was quenched with 50% aqueous citric acid (200 g), stirred for 1 hour and the product extracted with 2-MeTHF (2 x 500 mL). The combined organic layers were treated with 20% KOH at 50°C for 30 minutes and after cooling to 25°C, the layers were separated, the organic layer was washed with 15% aqueous KH2PO4 (2 x 500 mL) and brine. (250 mL). The product solution was treated with activated carbon.

G. Alternative Process for Crystallization and Isolation 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)

[01439] Following carbon filtration of the solution containing 50 g of Compound 1 dissolved in Step F2 of Example 3, the solution was distilled to dryness. Two consecutive 250 mL portions of EtOAc were added and distilled to approximately 100 mL to bring the water content of the solution to less than 1% w/w (as determined by coulometric Karl Fischer titration). This solution was brought to a total weight by adding EtOH 200 at 25% w/w of 100% alcohol content (75 g) and EtOAc (to give 500 g of solution). This solution was then treated with a 20 μm Teflon polishing filter to remove residual salts from the reaction process. After filtration, the solution was distilled again to approximately 100 mL, followed by the addition of 2 consecutive 250 mL portions of EtOAc that were each distilled to a minimum volume (achieving a water content no greater than 0.05% w/w of water and not more than 1% w/w EtOH after final distillation). The final solution was adjusted to approximately 250 mL, and a sample was analyzed by HPLC to assess the concentration of Compound 1 (with a target concentration of no less than 18% w/w Compound 1).

[01440]Crystallization

[01441] The distillation product solution (250 g of total solution) was separated into two portions: 15% (37.5 g) and 85% (212.5 g) of the total volume. The 15% portion was added to the crystallization vessel and diluted with a pre-mixed solution of EtOAc (353 g) and water (3.95 g) to achieve a final solution of approximately 1.9% w/w. p of Compound 1 and 1% w/w of water. This solution was allowed to recirculate from the crystallization vessel via a pump through an IKA wet grinding mill (medium-fine-fine rotor-stator configuration) and return to the top of the crystallization vessel. The wet grinding mill was set to a rotor tip speed of 9 meters/sec. and the crystallization solution was seeded with the desired crystal form, Free Base Hydrate Form C, of Compound 1. The crystal slurry was allowed to undergo continuous wet milling for not less than 2 hours at a recirculation rate. giving at least 10 revolutions of the crystallization solution through the wet grinding mill configuration. Upon completion, the tip speed of the wet grinding mill was reduced to 4 meters/sec, and the remaining 85% product solution of Compound 1 was slowly added to the crystallization vessel over no less than 4 hours. . After addition of the entire product solution, the antisolvent, n-heptane, was slowly added over no less than 4 hours to achieve approximately 30% w/w (260 g) n-heptane in the final crystallization liquor (while maintaining a wet grinding mill tip speed of 4 meters/second). Upon completion, wet grinding was discontinued, the crystal paste contents were recirculated in the crystallization vessel and the crystal paste was allowed to mix for no less than 1 hour.

[01442] I soloing and drying

[01443] The crystal slurry was filtered under reduced pressure (approximately 10 psig nitrogen) simultaneously collecting the liquor and continuing until the resulting crystal cake was completely free of liquor. A wash solution (69.4% w/w EtOAc, 30% w/w n-heptane, and 0.4% w/w water; 5 wash volumes in total, 250 mL) was applied to the wet cake in two portions, removing the liquor from the cake completely after each portion. The wet cake was purged with a stream of nitrogen for at least 3 hours and then heated slowly (~10°C/hour) to a target temperature of 50°C, not more than 55°C and allowed to dry for at least 12 hours. After 12 hours, a sample was taken to analyze the cake for residual ethyl acetate by gas chromatography and water content by Karl Fischer titration. The final dry product was additionally analyzed for product identity, impurity profile, water content and Compound 1 potency.

Example 4: Alternative Process for 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)

[01444] In this example, Steps AC of the Example 3 process were modified to eliminate certain processing steps and salt isolation, and to improve the purity of the bromo methyl ketone. Specifically, Compound 1 was prepared according to the following reaction scheme: Scheme XVI

[01445] 1-((Benzyloxy)carbonyl)-4-ethyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid (prepared as described in Example 1) (10 g, 36.3 mmol) and Ru( OAc)2-Segphos (0.030 g, 0.036 mmol) were charged to a stirred 300 mL SS Parr reactor, and transferred to the controlled atmosphere glovebox. A solution of TEA (5.82 mL, 41.8 mmol) in MeOH (60 mL) was added and then the reactor was closed and removed from the glove box. The reactor was placed in a reactor station, and was first purged with inert gas and then pressurized with hydrogen (200 psig). The mixture was stirred and heated at 80°C for 4 hours. The reaction is monitored by HPLC for conversion.

[01446] The reaction mixture was filtered through a propylene filter funnel with diatomaceous earth/fried polyethylene disc, (Chemglass part# OP-6603-12) to remove the catalyst, and MeOH (10 mL) was used as a rinse. The combined filtrate obtained was a clear amber solution.

[01447] The combined filtrate from step 1 was concentrated in vacuo to approximately 20 mL. The concentrate was diluted with THF (10 g) and concentrated in vacuo to approximately 20 mL. This was repeated four additional times. The concentrate was then diluted with THF (40 mL). To this solution was added CDI (8.62 g, 53.2 mmol) in portions over 30 minutes. The reaction was stirred at room temperature for 1 hour. The reaction was monitored by HPLC (derivatized with MeOH and DBU) for conversion.

[01448] A suspension of trimethylsulfoxonium chloride (9.29 g, 72.2 mmol) and KOtBu (7.18 g, 64.0 mmol) in THF (70 mL) was heated to 45 ° C for 1 hour and then cooled to -5°C. The solution of (3S,4R)-benzyl 3-ethyl-4-(1H-imidazol-1-carbonyl)pyrrolidine-1-carboxylate (prepared above) was added dropwise over 1 hour, simultaneously maintaining the internal temperature below -1°C. After the addition was complete, the reaction was stirred for 1 hour at -5°C. The reaction was monitored by HPLC for conversion.

[01449] The paste was adjusted to 0 °C and quenched with water (16 mL). The mixture was then concentrated in vacuo to approximately 170 mL. The concentrate was diluted with water (22 mL) and concentrated in vacuo to approximately 170 mL. This was repeated five additional times. At the last concentration, the internal temperature was approximately 45 °C. The solution was reduced to 5°C for 6 hours. During this time, the product precipitated. The slurry was kept at 5°C for 1 hour, and the product was collected by vacuum filtration. The solid was washed with water (100 mL) and dried in a vacuum oven at 45 °C for 24 hours. Dimethylsulfoxonium 2-((3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidin-3-yl)-2-oxo-ethylide (9.62 g, 27.4 mmol) was isolated in 77% yield.

[01450]1H NMR (400 MHz, DMSO) δ 7.41 - 7.25 (m, 5H), 5.11 - 4.93 (m, 2H), 4.76 (s, 1H), 3.54 - 3.23 (m, 9H), 3.15 (dd, J = 18.0, 9.6 Hz, 1H), 2.91 - 2.72 (m, 1H), 2.26 - 2.02 (m, 1H), 1.57 - 1.39 (m, 1H), 1.20 (tq, J = 14.1, 7.3 Hz, 1H), 0.88 (td, J = 7.4 , 2.7Hz, 3H). MS (ESI+): 352.0 m/e (M+H).B. Step B: Preparation of (3R,4S)-benzyl 3-(2-bromoacetyl)-4-ethylpyrrolidine-1-carboxylate

[01451] Dimethylsulfoxonium 2-((3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidin-3-yl)-2-oxo-ethylide (10.0 g, 28.5 mmol, 1.0 equivalents), THF ( 100 mL), and 33% HBr in AcOH (8.37 g, 34.1 mmol, 1.2 equivalents) were charged sequentially and heated to 40 °C. The reaction mixture was stirred for 5 hours, cooled to 20 °C, and then distilled under vacuum to approximately 65 mL. EtOAc (20 mL) and heptane (50 mL) were charged and the reaction mixture was washed with water (5 x 50 mL). The organic layer was concentrated in vacuo and chased with EtOAc (2 x 50 mL) concentrating to dryness each time. N,N-dimethylacetamide (20 mL) was then charged to provide 30.8 g of a 24.0% w/w solution of (3R,4S)-benzyl 3-(2-bromoacetyl)-4-ethylpyrrolidine-1 -carboxylate (73% yield). The solution was transported to the next step.C. Step C: Preparation of (3S,4R)-benzyl 3-ethyl-4-(2-((ethoxycarbonyl)(5-to-sil-5H-pyrrolo[2,3-b]pyrazin-2-yl)amino) acetyl)pyrrolidine-1-carboxylate

[01452] To a suspension of ethyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate (5.0 g, 13.9 mmol, 1.0 equivalents) and N,N- dimethylacetamide (20 mL) at 0 °C a solution of LiOtBu (1.3 g, 16.0 mmol, 1.15 equivalents) and N,N-dimethylacetamide (10 mL) was charged for 30 minutes. After stirring for 30 minutes, the reaction mixture was cooled to -10 °C. A portion of the bromo methyl ketone solution (23.6 g, 24% w/w in DMA, 16.0 mmol, 1.15 equivalents) from Step B above was then added over 1 hour. After addition, the reaction mixture was stirred at -10 °C for 30 minutes, quenched with acetic acid (0.4 mL, 6.9 mmol, 0.5 equivalents), and warmed to 20 °C. EtOH (40 mL) was then charged followed by seeding (25 mg). The resulting paste was aged at 20°C for 1 hour, heated to 50°C for 1 hour, and cooled to 20°C for 3 hours. The heating cycle was performed 5 times in total. After the heating cycle was completed, water (10 mL) was charged to 50 °C for 2 hours and the slurry was cooled to 20 °C for 3 hours. The slurry was aged at 20 °C for 2 hours, filtered and then washed with EtOH (2 x 25 mL). The isolated solids were dried under vacuum at 45°C to provide 7.4 g of (3S,4R)-benzyl 3-ethyl-4-(2-((ethoxycarbonyl)(5-tosyl-5H-pyrrolo[2,3 -b]pyrazin-2-yl)amino)acetyl)pyrrolidine-1-carboxylate in 84% yield (99.6% purity).

[01453]1H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.20 (dd, J = 9.0, 4.1 Hz, 1H), 8.06 - 7.86 (m, 2H), 7.51 - 7.35 (m, 2H), 7.33 - 7.23 (m, 5H), 6.74 (dd, J = 36.1, 4.1 Hz, 1H ), 5.02 (d, J = 4.1 Hz, 2H), 4.80 (s, 2H), 4.14 (qd, J = 7.1, 4.5 Hz, 2H), 3.64 - 3.34 (m, 4H), 3.21 - 3.08 (m, 1H), 2.46 - 2.34 (m, 1H), 2.32 (s, 3H), 1.41 (d , J = 13.3 Hz, 1H), 1.29 - 1.08 (m, 4H), 0.86 (td, J = 7.3, 4.8 Hz, 3H).

[01454] Compound 1 can be prepared from (3S,4R)-benzyl 3-ethyl-4-(2- ((ethoxycarbonyl)(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2- yl)amino)acetyl)pyrrolidine-1-carboxylate according to the procedure described in Steps D to F of Example 3, and Compound 1 can be isolated and crystallized according to the procedure described in Example 3G.

Example 5: Amorphous Free Base Preparation A. Method A: Water Precipitation

[01455] Compound 1 (approximately 300 g) was dissolved in water (10 L) and 50% sodium hydroxide (160 g) was added dropwise over a period of 2 hours to adjust the pH to greater than 12. Immediately solids formed. The solids were filtered, washed with two 500 mL aliquots of water and then dried in a vacuum oven. Solids were equilibrated for a short period of time at room temperature before characterization. Conversion to Amorphous Free Base of Compound 1 was confirmed by PXRD analysis.

B. Method B: Dehydration of Free Base Hydrate Form B

[01456] A sample of Free Base Hydrate Form B of Compound 1 (crystallized from ethanol/water at sub-ambient temperatures as described in Example 5, Method C below) was placed in a vacuum oven at 40 °C during the night. Solids removed from the vacuum oven were equilibrated for a short period of time at 23 °C before characterization. Conversion to Amorphous Free Base of Compound 1 was confirmed by PXRD analysis.

Example 6: Preparation of Free Base Solvate Form A and Free Base Hydra Form B A. Method A: Free Base Solvate Form A (Isopropyl Acetate Solvate/Water)

[01457] A sample of Compound 1 Amorphous Free Base (25 mg) was added to a vial followed by isopropyl acetate (125 μL) and water (10 μL). All solids dissolved at room temperature. The solution was placed in a freezer at -16 °C for 4 days. The liquor was decanted and the crystallized solids were isolated. The isolated crystals were analyzed by PXRD while still wet. Conversion to Free Base Solvate Form A (isopropyl acetate/water solvate) of Compound 1 was confirmed by PXRD analysis.

B. Method B: Free Base Hydrate Form B from Methanol/Water

[01458] A sample of the Amorphous Free Base of Compound 1 (164 mg) and MeOH (621 mg) was added to a vial. The components were mixed at room temperature until the solids dissolved. Water (approximately 680 μL) was added to the vial and the vial was placed in an ice/sodium chloride bath at approximately −3°C. Crystal seeds comprising Free Base Hydrate Form B were added to the vial and the vial was placed in a -16 °C freezer. The sample was removed from the crystallized suspension and the solids were immediately analyzed with PXRD and TGA-MS. Conversion to Free Base Hydrate Form B of Compound 1 was confirmed by PXRD and TGA-MS analysis.

C. Method C: Free Base Hydrate Form B from Ethanol/Water

[01459] A sample of Compound 1 Amorphous Free Base (4.2 g) was dissolved in EtOH (15.3 g) in a jacketed reactor. Water (23.3 g) was slowly added to the reactor. The reactor solution was cooled to approximately 2 °C. A small portion of a seed solution comprising Free Base Hydrate Form B was charged to the reactor. The suspension was mixed at approximately 2 ° C for 3 hours and water (36 g) was charged to the reactor in small aliquots over several hours, simultaneously maintaining the suspension at a temperature of approximately 2 ° C. The crystallized suspension was mixed at approximately 2°C and the solids were isolated via filtration. Conversion to Free Base Hydrate Form B of Compound 1 was confirmed by PXRD analysis. * **

[01460] Free Base Solvate Form A and Free Base Hydrate Form B do not readily crystallize from solution. In general, subambient temperatures and sufficient water activity are required to crystallize Free Base Solvate Form A and Free Base Hydrate Form B from solution.

[01461] Crystalline free base hydrates and solvates have been isolated from various solvent systems through primary nucleation (without seeding) or through seeding. In addition to crystallization from isopropyl acetate/water (as described in Method A above), crystalline free base hydrates or solvates are also isolated through primary nucleation (without seeding) from, for example, non-solvent systems. -butylamine/water and ethanol/water. In addition to crystallization from methanol/water (as described in Method B above) and ethanol/water (as described in Method C above), crystalline free base hydrates or solvates are also isolated by seeding from, e.g. example, acetone/water solvent systems; acetonitrile/water; ethyl/water formate; methyl acetate/water; ethyl acetate/water; methyl ethyl ketone/water; methyl isobutyl ketone/water, methyl isobutyl ketone/methyl tert-butyl ether/water; and isopropyl acetate/methyl tert-butyl ether/water. The Free Base Solvate Form A (isopropyl acetate/water solvate) prepared in Method A above, the Free Base Hydrate Form B prepared in Methods B and C above, and these other free base solvates or hydrates crystallins that were prepared are isostructural and exhibit similar PXRD patterns. Notably, these crystalline free base solvates and hydrates can be distinguished, and exhibit a PXRD pattern different from that of Free Base Hydrate Form C (a hemihydrate), which is described below.

[01462] The Free Base Solvate Form A and Free Base Hydrate Form B that were prepared were not stable after isolation to environmental conditions and readily dehydrated to the Amorphous Free Base.

Example 7: Preparation of Free Base Hydrate Form C A. Method A: Freebase Hydrate Form C from Ethanol/Water

[01463] A sample of Compound 1 Amorphous Free Base (2 g) was transferred to a 500 mL beaker equipped with a stir bar. EtOH (50 g) was added to the beaker and stirred until all solids dissolved. The solution was transferred to a 250 mL jacketed flask equipped with a dispersion device. The solution was cooled to 6 °C. Water (150 g) was added to the solution and the solution was subjected to high shear for two hours using the dispersion device. After solid formation was observed, an additional amount of water (50 g) was added to the resulting suspension. The suspension was kept overnight at room temperature. The solids were isolated and examined the following day. Conversion to Free Base Hydrate Form C of Compound 1 was confirmed by PXRD analysis.

B. Method B: Free Base Hydrate Form C from Ethyl Acetate/Heptane/Water

[01464] A crude reaction mixture analysis for 11.1 g of Compound 1 was collected in 2% water in EtOAc (70 g) and seeded with Free Base Hydrate Form C (100 mg). The suspension was stirred overnight and heptane (70 g) was added. The solids were collected by filtration, washed with water-saturated EtOAc/heptane (1/1, 100 mL), and dried under vacuum at 50 °C. Conversion to Base Hydrate Form C of Compound 1 was confirmed by PXRD analysis. * **

[01465] As observed with Free Base Solvate Form A and Free Base Hydrate Form B, Free Base Hydra Form C also does not readily crystallize from solution.

Example 8: Preparation of Tartrate Hydrate

[01466] Three methods for preparing tartrate tetrahydrate of Compound 1 (the “Tartrate Hydrate”) are described below. Method A describes an initial procedure that was used to prepare tartrate tetrahydrate. Method B describes a modified procedure used to prepare tartrate tetrahydrate on a larger scale. Method C describes another modified procedure used to prepare tartrate tetrahydrate. The modified Method C procedure relative to the Method B procedure further reduces filter cake solidification, a potential problem that can potentially influence manufacturing capacity and downstream processing.

A. Method A

[01467] A sample of Compound 1 Amorphous Free Base (28.2 mg) was transferred to an amber vial. Water (200 μL) and L-tartaric acid (34.5 mg (approximately 3 equivalents)) were added to the vial. The suspension was vortexed under ambient conditions until all solids dissolved. The solution in the flask was magnetically stirred at 0 °C. The following day, the solids were isolated from the solution and left at room temperature for a short period of time before characterization. Conversion to Compound 1 Tartrate Hydrate (tetrahydrate) was confirmed by PXRD analysis.

B. Method B

[01468] Compound 1 (4.6 g) was added to a jacketed reactor followed by addition of isopropanol (6.5 mL) and IPAc (7.8 mL). The slurry was mixed at ambient conditions until the solids dissolved. In a separate vial, L-tartaric acid (1.96 g) was dissolved in deionized water (3.92 mL). Tartaric acid solution was added to the reactor followed by addition of tartrate tetrahydrate seed crystals (28 mg). The suspension was mixed for 30 minutes under ambient conditions. IPAc (71 mL) was added in small aliquots over 2 hours. The crystallized suspension was cooled to 5°C and equilibrated at 5°C overnight. The suspension was discharged onto a filter and the filter cake rinsed with 20 mL of IPAc saturated with water. The filtered solids were air dried for two days. Conversion to Compound 1 Tartrate Hydrate (tetrahydrate) was confirmed by PXRD analysis.

C. Method C

[01469] Crystallization: Compound 1 (104 g) was added to a flask along with isopropanol (222.7 g) and IPAc (375.8 g). The components were mixed under ambient conditions until the solids dissolved. In a separate flask, L-tartaric acid (61.6 g) was dissolved in water (98.3 g). The contents of the two flasks were then added to a jacketed reactor. Tartrate tetrahydrate seed crystals (1.55 g) were added to the reactor solution. The resulting suspension was mixed overnight under ambient conditions. IPAc (2542 g) was charged to the reactor suspension over a period of 8 hours.

[01470] Filtration, Washing and Drying: Approximately half of the crystallized tartrate suspension was charged to a jacketed agitated filter dryer. The suspension was cooled inside the filter dryer to approximately 11 °C. The suspension was filtered using positive pressure until a wet cake was obtained. Water-saturated IPAc (438 g) was charged to the filter dryer and the suspension was mixed overnight at approximately 11 °C. The suspension was filtered using positive pressure until a wet cake was obtained. Water-saturated MTBE (110 g) was charged to the filter dryer. After 10 minutes, the suspension was filtered with positive pressure until a moist cake was obtained. Water-saturated MTBE (261 g) was charged to the filter dryer and the suspension was mixed at approximately 11 °C for 3.5 hours. The suspension was filtered with stirring using positive pressure until a wet cake was obtained. The wet cake was dried with constant stirring at a temperature of approximately 11 °C under humidified nitrogen and positive pressure for two days. Conversion to Compound 1 Tartrate Hydrate (tetrahydrate) was confirmed by PXRD analysis.

Example 9: Preparation of Form AA of Hydrochloride Solvate

[01471] Initial Preparation: A sample of Compound 1 Amorphous Free Base (23.8 mg), EtOAc (200 μL), and concentrated HCl (5 μL) was added to a vial. A viscous solution was heated on a hot plate to 50 °C. MeOH (20 μL) was added to the solution and stirring was continued. EtOH (10 μL) was added and stirring continued at 50 °C. The resulting solution was biphasic. The flask was placed in a 0 °C bath while simultaneously continuing mixing with a magnetic stirrer. A white solid was obtained after approximately 1.5 hours.

[01472] Preparation on a Larger Scale: The procedure described above was repeated on a larger scale to generate additional solids for characterization. A sample of Compound 1 Amorphous Free Base (50.3 mg), EtOAc (500 μL), and concentrated HCl (11 μL) was added to a vial. The solution was heated on a hot plate and the same viscous phase was obtained as observed in the procedure described above. EtOH (40 μL) was added to the solution and stirring continued. MeOH (40 μL) was added and the flask was placed in a 0 °C bath while simultaneously continuing mixing with a magnetic stirrer. Once the solution had cooled, a drop of the seed paste from the initial preparation was added. The suspension was mixed for 30 minutes in the cooling bath. The vial was placed in a -16°C freezer overnight. The solids in the flask were isolated via vacuum filtration. The filtered solids were equilibrated for a short period of time before characterization. Conversion to Compound 1 Hydrochloride (Form AA of Hydrochloride Solvate) was confirmed by PXRD analysis.

Example 10: Preparation of BB Form of Hydrochloride Solvate

[01473] A sample of Compound 1 Amorphous Free Base (76 mg) and THF (approximately 228 μL) was added to a vial. The paste was sonicated until a clear solution was obtained. Concentrated HCl (12 μL) was added to the clear solution. Some precipitation immediately occurred. The vial was placed in a freezer at -16°C for 4 hours. More precipitation occurred. Solids were isolated from the flask after a few days and equilibrated for a short period of time at ambient conditions before characterization. Conversion to Compound 1 Hydrochloride (BB Form of Hydrochloride Solvate) was confirmed by PXRD analysis.

Example 11: Preparation of CC Form of Hydrochloride Solvate

[01474] A sample of Compound 1 Amorphous Free Base (50 mg) was dissolved in 0.2 mL of 50/50 v/v EtOAc/EtOH. Concentrated HCl (40 μL) and 0.8 mL of 50/50 v/v EtOAc/EtOH were added to the solution. EtOAc was slowly diffused into the product solution via the gas phase (i.e., vapor diffusion procedure). Solids were obtained after approximately three weeks. Solids were isolated via centrifugal filtration and equilibrated for a short period of time before characterization. Conversion to Compound 1 Hydrochloride (CC Form of Hydrochloride Solvate) was confirmed by PXRD analysis.

Example 12: Preparation of AAA Form of L-Maleate

[01475] Compound 1 (78.5 mg), L-maleic acid (32 mg), and water-saturated methyl isobutyl ketone (630 μL) were added to a vial. A thick paste quickly formed after addition of the solvents. Additional methyl isobutyl ketone was added and the suspension mixed for three days. The isolated wet solids were equilibrated for a short period of time before characterization. Conversion to Form AAA of L-Maleate of Compound 1 was confirmed by PXRD analysis.

Example 13: Preparation of BBB Form of L-Maleate

[01476] Form BBB of L-Maleate can be obtained by drying Form AAA of L-Maleate under vacuum. The BBB Form of L-Maleate can also be obtained as described below.

[01477] Compound 1 (500 mg), L-maleic acid (150 mg), and water-saturated methyl isobutyl ketone (4 mL) were added to a vial. The contents of the vial were mixed overnight. Approximately 10 mg of L-Maleate BBB Form crystal seeds were added to the vial. Another 2 mL of methyl isobutyl ketone saturated with water was added to the flask. Solids were isolated after crystallization and dried at 50 °C/75% relative humidity. Conversion to the L-Maleate BBB Form of Compound 1 was confirmed by PXRD analysis.

Example 14: Preparation of Free Base Anhydrous Form D

[01478] A sample of Compound 1 Amorphous Free Base was dissolved in anhydrous EtOAc at a concentration of 19.6% (w/w). An aliquot comprising approximately 1 mL was transferred to a 4 mL flask equipped with a magnetic stirrer. The vial was sealed with parafilm and mixed at 400 rpm on a magnetic stir plate at about 23 °C for almost 8 weeks. The resulting slurry was removed by filtration and left at ambient conditions for a short period of time before characterization. Conversion to Free Base Anhydrous Form D was confirmed by PXRD analysis.

Example 15: Microscopy/Crystal Morphology

[01479] Solid state forms of Compound 1 were evaluated by microscopy. Samples were examined by visual microscopic examination using a polarizing microscope (model Eclipse E-600 POL, Nikon Corp., Garden City, NI). A color video camera was used to record digital images (model DXC 390, Fryer Co., Inc., Huntley, IL). Images were captured using MetaMorph Imaging System (version 4.6R8, Universal Imaging Corporation, Downingtown, PA). Observations regarding the crystal morphology of the samples are reported in Table 15-A below. Those skilled in the art will recognize that variation in crystal shape and size may be observed depending on the specific crystallization conditions used. The solvation states and PXRD profiles reported in Table 15-A correspond to the information presented in the figures and subsequent examples of this application. TABLE 15-A:

Example 16: PXRD Analysis

[01480] The Solid State forms of Compound 1 listed in Table 15-A were analyzed by powder X-ray diffraction ("PXRD"). PXRD data were collected with a G3000 diffractometer (Inel Corp., Artenay, France) equipped with a position-sensitive curved detector and parallel-beam optics. The diffractometer was operated with a copper anode tube (1.5 kW fine focus) at 40 kV and 30 mA. An incident beam germanium monochromator provided monochromatic Kα1 radiation À = 1.540562 Á). A diffractometer was calibrated using the direct beam attenuated at one degree intervals. Calibration was verified using a silicone powder line position reference standard (NIST 640c). Samples were prepared by spreading sample powder in a thin layer on an aluminum sample holder and gently leveling with a glass microscope slide. The instrument was computer controlled using Symphonix software (Inel Corp., Artenay, France) and data were analyzed using Jade software (version 6.5, Materials Data, Inc., Livermore, CA). The aluminum sample holder was mounted on the rotating sample holder of the G3000 diffractometer and the diffraction data was collected under ambient conditions.

[01481] Tables 16-A to 16-J define the parameters of the main peaks in terms of values and intensities for the crystalline forms analyzed. It is known in the art that an X-ray diffraction pattern can be obtained by the powder method that has one or more measurement errors depending on measurement conditions (such as equipment, sample preparation or machine used). In particular, it is generally known that intensities in an X-ray powder diffraction pattern can fluctuate depending on measurement conditions and sample preparation. For example, those skilled in the technique of X-ray powder diffraction will understand that relative peak intensities may vary according to the orientation of the sample under test and the type and configuration of the instrument. Those skilled in the art will understand that the position of reflections can be affected by the precise weight at which the sample is placed in the diffractometer and the zero calibration of the diffractometer. The surface flatness of the sample may also have an effect on the results. One of skill in the art will understand that the diffraction pattern data presented below should not be construed as absolute and that any crystalline form that provides a powder diffraction pattern substantially identical to that disclosed below will fall within the scope of the present disclosure (for more information, see Jenkins, R & Snyder, R.L. 'Introduction to X-Ray Powder Diffractometry', John Wiley & Sons, 1996).

[01482] The PXRD patterns corresponding to the Amorphous Free Base (via precipitation) and the Amorphous Free Base (via dehydration) are shown in Figures 2A and 2B, respectively.

[01483] The PXRD pattern corresponding to Free Base Solvate Form A is shown in Figure 3A. The experimental PXRD pattern peak listing with relative intensities is presented in Table 16-A below.Table 16-A: PXRD Peak Listing Free Base Solvate Form A (Isopropyl Acetate Solvate/Water)

[01484] The PXRD pattern corresponding to Free Base Hydrate Form B is shown in Figure 3B. The experimental PXRD pattern peak listing with relative intensities is presented in Table 16-B below.Table 16-B: PXRD Peak Listing Free Base Hydrate Form B

[01485] The PXRD pattern corresponding to Free Base Hydrate Form C is shown in Figure 3C. The experimental PXRD pattern peak listing with relative intensities is presented in Table 16-C below.Table 16-C: PXRD Peak Listing Free Base Hydrate Form C

[01486] The PXRD pattern corresponding to Tartrate Hydrate is shown in Figure 3D. The list of peaks of the experimental PXRD pattern with relative intensities is presented in Table 16-D below. The experimental PXRD pattern is shown at the bottom of Figure 3D, and the calculated PXRD pattern is shown at the top of Figure 3D. Table 16-D: Tartrate Hydrate PXRD Peak Listing

[01487] The PXRD pattern corresponding to Form AA of Hydrochloride Solvate is shown in Figure 3E. The peak listing of the experimental PXRD pattern with relative intensities is presented in Table 16-E below.Table 16-E: PXRD Peak Listing Form AA of Hydrochloride Solvate

[01488] The PXRD pattern corresponding to Form BB of Hydrochloride Solvate is shown in Figure 3F. The peak listing of the experimental PXRD pattern with relative intensities is presented in Table 16-F below.Table 16-F: PXRD Peak Listing BB Form of Hydrochloride Solvate

[01489] The PXRD pattern corresponding to Form CC of Hydrochloride Solvate is shown in Figure 3G. The peak listing of the experimental PXRD pattern with relative intensities is presented in Table 16-G below.Table 16-G: PXRD Peak Listing CC Form of Hydrochloride Solvate

[01490] The PXRD pattern corresponding to Form AAA of L-Maleate is shown in Figure 3H. The peak listing of the experimental PXRD pattern with relative intensities is presented in Table 16-H below. Table 16-H: PXRD Peak Listing AAA Form of L-Maleate

[01491] The PXRD pattern corresponding to the BBB Form of L-Maleate is shown in Figure 3I. The list of peaks of the experimental PXRD pattern with relative intensities is presented in Table 16-I below Table 16-I: List of PXRD Peaks BBB Form of L-Maleate

[01492] The PXRD pattern corresponding to Free Base Anhydrous Form D is shown in Figure 3J. The experimental PXRD pattern peak listing with relative intensities is presented in Table 16-J below.Table 16-J: Free Base Anhydrous Form D PXRD Peak Listing

Example 17: Unit Cell Parameters

[01493] Unit cell parameters were determined for Free Base Hydrate Form C in a single crystal X-ray diffraction study and are reported below in Table 17-A. Single-crystal X-ray diffraction data were collected using a Bruker Apex II diffractometer (Bruker AXS, Madison, WI) equipped with an Apex II CCD area detector. The diffractometer was operated with a molybdenum anode tube (2.0 kW fine focus) at 50 kV and 40 mA. An incident beam silicon monochromator provided Mo-Ka1 monochromatic radiation. Data were collected under flow of cold nitrogen gas at 100 K using a Kryoflex low-temperature device (Bruker AXS, Madison, WI). The beam diameter for data collection was 5 mm and the detector distance was 6 cm. Goniometer alignment was checked using a 2-Dimethylsufuranilidene-1,3-indanedione (YLID) spherical crystal. The instrument was computer controlled using the BIS and Apex 2 software programs (Bruker AXS, Madison, WI). Data was analyzed using Apex 2 software (Version 2011.2-0, Bruker AXS, Madison, WI). Table 17-A: Free Base Hydrate Form C Unit Cell Parameters

[01494] Unit cell parameters were also determined for Tartrate Hydrate based on data from a PXRD study and are reported below in Table 17-B. The unit cell parameters for Tartrate Hydrate, however, have not been confirmed in a single crystal X-ray diffraction study. The asymmetric unit contains one molecule of Compound 1, one molecule of L-tartaric acid and 4 molecules of water. Table 17-B: Tartrate Hydrate Unit Cell Parameters

[01495] Unit cell parameters were also determined for Free Base Anhydrous Form D based on a single crystal X-ray diffraction study, performed using the method as described above for Free Base Hydra Form C, and are reported below in Table 17-C.Table 17-C: Free Base Anhydrous Form D Unit Cell Parameters

Example 18: Thermogravimetric Analysis

[01496] The Solid State forms of Compound 1 listed in Table 15-A were analyzed in a thermogravimetric analysis (“TGA”) study. TGA thermograms were collected with a Mettler TGA/sDTA 851e (Mettler-Toledo International Incorporated, Schwerzenbach , Switzerland) equipped with a TSO801RO robotic autosampler. The instrument was operated and data evaluated with Stare software (V9.01, Mettler-Toledo International Incorporated, Schwerzenbach, Switzerland). The sample powders were encapsulated in an appropriate container and screened at a certain rate as specified in TGA thermogram charts. Nitrogen at 50 mL/minute was used to purge the sample chamber. TA, data were collected on a thermal balance (Q-500 or Q-5000, TA Instruments, New Castle, DE) equipped with a data analyzer (Universal Analysis 2000, version 4.5A, TA Instruments, New Castle, IN). During the experiments, the furnace was purged with nitrogen at 60 mL/minute, while the balance chamber was purged at 40 mL/minute. The TGA furnace temperature was calibrated using aluminum and nickel Curie points. The sample size was between 2 mg and 20 mg, and a heating rate of 10 °C/minute was used.

[01497] For TGA-MS, the thermogravimetric analysis part was the same as above. The mass of gas released was analyzed with PFEIFFER GSD 301 T3 ThermoStar (PFEIFFER Vacuum, Asslar, Germany). The instrument was operated and data evaluated with Quadstar 32-bit Software (V7.01, Inficon, LI-9496 Balzers, Liechtenstein).

[01498] For thermogravimetric analyzes carried out with Mettler TGA/sDTA 851e (Mettler-Toledo International Incorporated, Schwerzenbach, Switzerland), Differential Thermal Analysis (sDTA) signals were also recorded and the data were analyzed with the Stare software ( V9.01, Mettler-Toledo International Incorporated, Schwerzenbach, Switzerland).

[01499] The TGA thermograms corresponding to the Amorphous Free Base (via precipitation) and the Amorphous Free Base (via dehydration of Free Base Hydrate Form B) are shown in Figures 4A and 4B, respectively.

[01500] The TGA thermogram corresponding to Free Base Solvate Form A is shown in Figure 4C.

[01501] The TGA thermogram corresponding to Free Base Hydrate Form B is shown in Figure 4D.

[01502] The TGA thermogram corresponding to Free Base Hydrate Form C is shown in Figure 4E.

[01503] The TGA thermogram corresponding to Tartrate Hydrate is shown in Figure 4F.

[01504] The TGA thermogram corresponding to Hydrochloride Solvate Form AA is shown in Figure 4G.

[01505] The TGA thermogram corresponding to the BBB Form of L-Maleate is shown in Figure 4H.

[01506] The TGA thermogram corresponding to Free Base Anhydrous Form D is shown in Figure 4I. * **

[01507] Amorphous Free Base: TGA indicates that the Amorphous Free Base loses most of its water at or before 100 °C at a heating rate of 10 °C/minute.

[01508] Free Base Hydrate Form B: TGA indicates that Free Base Hydrate Form B is a labile hydrate. The exact stoichiometry has not been confirmed. Available data suggest a higher hydrate, possibly 4 to 5 water molecules per Free Base molecule.

[01509] Free Base Hydrate Form C: TGA indicates that Free Base Hydra Form C is a hemihydrate consistent with single crystal X-ray diffraction data. In general, TGA at a heating rate of 10°C/minute (ambient relative humidity) shows dehydration of Free Base Hydrate Form C between approximately 120°C and 160°C with a weight loss of approximately 2.3% to 2.6% between these temperatures.

[01510] Tartrate Hydrate: TGA indicates that Tartrate Hydrate is a tetrahydrate. In general, TGA at a heating rate of 10°C/minute (ambient relative humidity) shows dehydration of Tartrate Hydrate between approximately 25°C and 160°C with a weight loss of approximately 12% between these temperatures.

[01511] Freebase Anhydrous Form D: In general, TGA at a heating rate of 10°C/minute (ambient relative humidity) shows dehydration of Freebase Anhydrous Form D between about 43°C and 188° C with a weight loss of approximately 0.5% between these temperatures.

Example 19: Differential Scanning Calorimetry (DSC):

[01512] The Solid State forms of Compound 1 listed in Table 15-A were analyzed by differential scanning calorimetry ("DSC"). DSC data were collected with a Mettler DSC 823e (Mettler-Toledo International Incorporated, Schwerzenbach, Switzerland) equipped with a TSO801RO robotic autosampler. The instrument was operated and data evaluated using Stare software (V9.01, Mettler-Toledo International Incorporated, Schwerzenbach, Switzerland). The temperature axis was calibrated with indium and aluminum standards. Unless otherwise stated, the sample (2 mg to 5 mg) was encapsulated in a vented aluminum container, punctured immediately before loading into the measuring cell, and heated at a rate of 10 °C/minute under a stream of nitrogen gas. of 50 mL/minute during the study.

[01513] The DSC thermogram corresponding to the Amorphous Free Base (via dehydration) is shown in Figure 5A.

[01514] The DSC thermogram corresponding to Free Base Hydrate Form B is shown in Figure 5B.

[01515] The DSC thermogram corresponding to Free Base Hydrate Form C is shown in Figure 5C.

[01516] The DSC thermogram corresponding to Tartrate Hydrate is shown in Figure 5D.

[01517] The DSC thermogram corresponding to Free Base Anhydrous Form D is shown in Figure 5E. * **

[01518] Amorphous Free Base: DSC indicates that the Amorphous Free Base has a glass transition onset temperature of about 119 °C with a midpoint of about 122 °C.

[01519] Free Base Hydrate Form B: The DSC thermogram for Free Base Hydrate Form B, at a heating rate of 10 °C/minute (ambient relative humidity), shows two endotherms. The first endotherm relates to water loss (12.3%) and the second endotherm relates to water loss (5.5%) and incongruent melting.

[01520] Free Base Hydrate Form C: The DSC thermogram for Free Base Hydra Form C, at a heating rate of 10 °C/minute (ambient relative humidity), shows an endotherm between approximately 120 and 170 °C , with an onset temperature of 134.7 °C and a peak temperature of 149.9 °C.

[01521] Tartrate Hydrate: The DSC thermogram for Tartrate Hydrate, at a heating rate of 10 °C/minute (ambient relative humidity), shows an endotherm corresponding to dehydration at approximately 60 °C to 100 °C.

[01522] Freebase Anhydrous Form D: The DSC thermogram for Freebase Anhydrous Form D, at a heating rate of 10 °C/minute (ambient relative humidity), shows an endotherm between about 180 and 220 °C, with a melting point of about 199.55 °C and an enthalpy of fusion of 85.4 J/g.

[01523] As with thermal analysis, one skilled in the art will understand that the DSC thermogram may change to some extent depending on factors such as heating rate, particle size, sample size, sample purity, moisture content of the sample, ambient relative humidity, etc.

Example 20: Moisture Sorption Isotherms

[01524] The Solid State forms of Compound 1 listed in Table 15-A were analyzed in a water vapor isotherm study. Water vapor isotherm data were collected with a DVS Advantage (Surface Measurement Systems Ltd, Alperton, United Kingdom). Sample powder (5 mg to 20 mg) was loaded into a tared DVS Advantage container. Moisture sorption isotherm data were collected from 30-0-90-0-30% relative humidity at intervals of 10% relative humidity. For each step, the dm/dt criteria were 0.001% for 5 minutes, a minimum dm/dt time of 30 minutes, and a maximum dm/dt of 120 minutes. Data were collected isothermally at 25 °C with a nitrogen flow rate of 200 cm3/minute. The post DVS sample was maintained at approximately 30% relative humidity prior to PXRD analysis.

[01525] The moisture sorption isotherm corresponding to the Amorphous Free Base (via dehydration) is shown in Figure 6A.

[01526] The moisture sorption isotherm corresponding to Form C of Free Base Hydrate (Hemi-Hydrate) is shown in Figure 6B.

[01527] The moisture sorption isotherm corresponding to Tartrate Hydrate is shown in Figure 6C.

[01528] The moisture sorption isotherm corresponding to Free Base Anhydrous Form D is shown in Figure 6D. * **

[01529]Amorphous Free Base: Analysis of moisture sorption isotherms indicates that the Amorphous Free Base obtained through dehydration of Free Base Hydrate Form B absorbs up to 13% to 90% relative humidity at 25 °C.

[01530] Free-Base Hydrate Form B: No moisture sorption isotherm could be obtained for Free-Base Hydrate Form B. Free Base Hydrate Form B is not stable under environmental conditions and rapidly dehydrates to Amorphous Free Base.

[01531] Free Base Hydrate Form C: The moisture sorption isotherm indicates that Free Base Hydrate Form C is not hygroscopic.

[01532] Tartrate Hydrate: Moisture sorption isotherm analysis indicates that Tartrate Hydrate dehydrates to an amorphous tartrate below 10% relative humidity at 25 °C. If the analysis of moisture sorption isotherms is restricted to a relative humidity range of 10% to 90%, the appearance of the moisture sorption isotherm will generally correspond to the Moisture sorption shown in Figure 6C for Tartrate Hydrate.

[01533] Free Base Anhydrous Form D: Analysis of moisture sorption isotherms indicates that Free Base Anhydrous Form D absorbs up to 1.8% water at 90% relative humidity at 25 °C.

Example 21: Solid State Accelerated Stability Study

[01534] The Solid State forms of Compound 1 listed in Table 15-A were analyzed in an accelerated solid state stability study. Samples (approximately 1 mg to 2 mg) of the solid state form were weighed into glass vials and tested as described below. Chemical stability was acceptable for Amorphous Free Base, Free Base Hydrate Form C and Tartrate Hydrate. The L-maleate salt, however, showed a tendency to chemical degradation.

[01535] Amorphous Free Base: The Amorphous Free Base did not exhibit any growth of degradation products after storage at 50 °C/75% relative humidity (open and closed glass vials) for up to six weeks and after storage at 40 °C/75% relative humidity (open and closed glass bottles) for up to 24 weeks. No change of material was observed for any of the attributes evaluated (description, crystal form, test, impurities and water content).

[01536] Free Base Hydrate Form C: Surprisingly, Free Base Hydra Form C did not exhibit any growth of degradation products under the conditions listed in Table 16-A below (open and closed vials): Table 21-A : Test Conditions No change of material was observed for any of the attributes evaluated (description, crystal form, test, impurities and water content).

[01537] Tartrate Hydrate: Tartrate Hydrate did not exhibit any growth of degradation products after storage at 25 °C/60% relative humidity (open and closed glass vials) for up to 24 months after storage at 40 °C/75% relative humidity (open and closed glass bottles) for at least one month, and after storage at 50 °C/75% relative humidity (open and closed glass bottles) for up to six weeks. No change of material was observed for any of the attributes evaluated (description, crystal shape, test, impurities and water content).

[01538] BBB Form of L-Maleate: When stored at 50 °C/75% relative humidity (open and closed bottles), the L-maleate salt degraded into products that were not observed for the Form C of Free Base Hydrate or Tartrate Hydrate.

Example 22: Thermal Degradation Study

[01539] The Solid State forms of Compound 1 listed in Table 15-A were analyzed in a thermal degradation study. The following pH solutions were prepared: 0.1N hydrochloric acid (HCl); 50 mM sodium phosphate buffer (pH 7.4, adjusted to 0.155 M ionic strength with sodium chloride) and FasSIF (pH 6.5). For each buffer, a target concentration of about 100 μg/mL was prepared by accurately weighing about 1 mg of the solid-state form using a microanalytical balance in a scintillation vial. Water (1 mL) was added to dissolve the solid as a stock solution. The stock solution was diluted 10 times in the various buffers to prepare reaction solutions. The peak area of the compound in these reaction solutions was monitored at 37 °C by HPLC every two hours for a total of 32 hours.

Example 23: Solubility Stability

[01540] For equilibrium solubility, enough solid was added to 3-4 mL of liquid medium in triplicate so that the excess solid remained undissolved. The mixtures were equilibrated for 24 to 48 hours at 25 rpm in a model 30-1200 vertical drum mixer (Vankel, Cary, NC) in a constant temperature water bath. After equilibration, the mixtures were inspected to ensure that the amount of excess solid was sufficient to allow re-characterization. If not, solid was added and the mixtures were equilibrated again for 24 to 48 hours. The pH of the aqueous suspensions was determined after equilibration. The solid phase was separated from the liquid phase by centrifugation at 3300 rpm at equilibrium temperatures (i.e., 25 °C or 37 °C). The supernatant was then filtered (Acrodisc® 13 mm syringe filter with 0.45 μ GHP membrane, Pall® Life Sciences, Ann Arbor, MI) to discard the initial 2 mL (to saturate the filter) and capture the last 1 mL. mL for analysis. The filtrate was diluted as necessary for quantification of the material studied by the HPLC method (as detailed elsewhere in this document). The physical form of the recovered solid was characterized by powder method X-ray diffraction to examine whether or not phase change occurred.

[01541]The results are presented in Table 23-A.Table 23-A

Examples 24 to 27: Extended Release Tablets

[01542] Free Base Hydrate Form C and Amorphous Free Base solid state form of Compound 1 listed in Table 15-A were formulated into 24 mg extended release tablets in accordance with the formulations presented in Table 24-A .Table 24-A: Extended-release tablets (without pH modifier)

[01543] The formulations were prepared by combining and mixing the active ingredient, microcrystalline cellulose, hydroxypropylmethyl methyl cellulose (HPMC) and colloidal silicon dioxide. The mixture was milled using a Mobil mill equipped with a 610 micron screen. Magnesium stearate was passed through #30 mesh and added to the conjugate and mixed.

[01544] The lubricated granulation was compressed into tablets weighing 480 mg using a rotary tablet press. The tablets may optionally be coated with any suitable film coating.

[01545] The effect of the solid state form on the dissolution profile of the tablets was evaluated. In particular, the dissolution profile of Example 26 (containing Free Base Hydrate Form C as active) and Example 27 (containing Amorphous Free Base as active) was evaluated at pH 6.8 (representative of the pH in the large intestine). Dissolution testing was performed using the following parameters and dissolution conditions:

[01546] The medium used for the study was a 0.05 M sodium phosphate buffer solution, pH 6.8 ± 0.05. The medium was prepared using an acid step medium (0.1 N hydrochloric acid solution) and a buffer step concentrate (0.05 M sodium phosphate buffer concentrate solution prepared by dissolving about 41.4 g of sodium phosphate, monobasic, monohydrate and approximately 14.4 g of sodium hydroxide pellets in approximately 4 L of water, dilute to 6 L with water and mix well). The medium was prepared by mixing 500 mL of the acid step medium and 400 mL of buffer step concentrate in an appropriately sized container or directly in the dissolution vessel and adjusting the pH with 1 N phosphoric acid or 1 N sodium hydroxide. N, if the pH was not in the range of 6.8 ± 0.05.

[01547] For the dissolution test, one tablet each was added to a dissolution vessel containing 900 mL of 0.05 M sodium phosphate buffer solution maintained at 37 °C. The dissolution apparatus blades were operated at 75 RPM, with 1.5 mL samples from the dissolution vessel being obtained at the designated time periods. The sample filtrate was the sample preparation.

[01548] For sample analysis, conventional liquid chromatography methods were used, in which the % of the identified amount of released active ingredient was calculated (% of LA released). The results are presented in Figure 7.

[01549] As can be seen from Figure 7, the formulation containing Free Base Hydrate Form C (Example 26) as the active showed a slower rate of dissolution than the formulation containing Amorphous Free Base (Example 27) as the active at pH 6.8.

[01550] The dissolution profile of formulations comprising Free Base Hydrate Form C as an active was further evaluated at pH 6.8 and in a dual pH system. In particular, the dissolution profile of the tablets of Example 24 (ER1), Example 25 (ER2) and Example 26 (ER3) at pH 6.8 was carried out as described above. The dissolution profile of the tablets of Examples 24 to 26 was also carried out in a dual pH system using the following parameters and dissolution conditions:

[01551] The acid step medium is a 0.1 N hydrochloric acid solution. A buffer step medium for the study was prepared using a buffer step concentrate (0.05 N sodium phosphate buffer concentrate solution). M prepared by dissolving approximately 41.4 g of sodium phosphate, monobasic, monohydrate and approximately 14.4 g of sodium hydroxide pellets in approximately 4 L of water, dilute to 6 L with water and mix well). The buffer stage medium of a 0.05 M sodium phosphate buffer solution, pH 6.8 ± 0.05, was prepared by mixing 500 mL of the acidic stage medium and 400 mL of buffer stage medium concentrate in a appropriate size container or directly into the dissolution vessel and adjusting the pH of the buffer cap medium concentrate with 1 N phosphoric acid or 1 N sodium hydroxide, if the pH was not in the range of 6.8 ± 0, 05.

[01552] For the dissolution test, one tablet each was added to a dissolution vessel containing 500 mL of a 0.1 N hydrochloric acid solution maintained at 37 °C. The dissolution apparatus blades were operated at 75 RPM for 1 hour, after which a 1.5 ML sample was automatically obtained from the dissolution vessel. After the acid stage sample was obtained, 400 mL of buffer stage medium concentrate was added, maintained at 37 °C. The dissolution test was continued, with the blades remaining at a speed of 75 RPM. The sample filtrate was the sample preparation.

[01553] For sample analysis, conventional liquid chromatography methods were used, in which the % relative standard deviation (RSD) of peak areas was calculated for each set of six standard injections. The results are presented in Figure 8.

[01554] As can be seen in Figure 8, after initial release at low pH (representative of pH in the stomach), drug release is slowed at higher pH (representative of pH in the large intestine). As such, in order to achieve the desired bioavailability, a formulation that allowed pH-independent release was necessary.

Examples 28-35: Extended Release Tablets

[01555] The solid state form of Compound 1 Free Base Hydrate Form C listed in Table 15-A was formulated into 15 mg, 24 mg or 30 mg extended release tablets, according to the formulations presented in Table 28-A, using direct compression. Table 28-A: Extended Release Tablets (tartaric acid pH modifier) a Provides 15 mg free base equivalent of Compound 1.b Provides 30 mg free base equivalent of Compound 1.c Provides 24 mg free base equivalent of Compound 1.

[01556] The formulations were prepared by first grinding the tartaric acid through a Fitz Model M5A mill, equipped with a 1512-0027 screen. Free Base Hydrate Form C, microcrystalline cellulose, mannitol (when present), ground tartaric acid, release control polymer and colloidal silicon dioxide (when present) were combined and mixed. The mixture was milled using a Mobil mill equipped with a 610 or 1397 micron screen. The magnesium stearate was passed through #30 mesh and was then added to the conjugate and mixed. The lubricated granulation was compressed into tablets weighing about 480 mg using a rotary tablet press.

[01557] The tablets of Example 28 and 31 were coated using a film coating device, which sprayed a solution containing the Opadry® II Yellow film coating and purified water until 14.40 mg of coating had been applied to the tablets .

[01558] The dissolution profile of the tablets of Example 32 (ER4, 24 mg active), Example 33 (ER4, without mannitol, 24 mg active), Example 34 (ER5, 24 mg active) and Example 35 (ER6, 24 mg active) was evaluated at pH 1.2, at pH 6.8, and in a dual pH system. The pH 6.8 study was performed as described above for Examples 26 and 27. For the dual pH study, it was prepared an acid step medium of 0.05 M sodium phosphate solution, pH 3.5 ± 0.05, dissolving about 41.4 g of sodium phosphate, monobasic, monohydrate in about 4 L of water, Measure the pH and add phosphoric acid, 85%, dropwise as needed to adjust the target pH. The mixture was diluted to 6 L with water and mixed. A buffer stage medium for the study was prepared using a buffer stage concentrate (0.05 M sodium phosphate buffer concentrate solution prepared by dissolving about 41.4 g of sodium phosphate, monobasic, monohydrate and about 14.4 g of sodium hydroxide pellets in about 4 L of water, dilute to 6 L with water and mix well). The buffer stage medium of a 0.05 M sodium phosphate buffer solution, pH 6.8 ± 0.05, was prepared by mixing 500 mL of the acidic stage medium and 400 mL of buffer stage medium concentrate in a appropriate size container or directly into the dissolution vessel and adjusting the pH of the buffer cap medium concentrate with 1 N phosphoric acid or 1 N sodium hydroxide, if the pH was not in the range of 6.8 ± 0, 05.

[01559] The dissolution test was performed using the following parameters and dissolution conditions:

[01560] For the dissolution test, one tablet each was added to a dissolution vessel containing 500 mL of the acid step medium, maintained at 37 °C. The dissolution apparatus blades were operated at 75 RPM for 1 hour, after which a 1.5 mL sample was automatically obtained from the dissolution vessel. After the acid step sample was obtained, 400 mL of buffer step medium concentrate was added, and then the mixture was maintained at 37 °C. The dissolution test was continued, with the blades remaining at a speed of 75 RPM. The sample filtrate was the sample preparation.

[01561] For the pH 1.2 study, the dissolution test was performed using the following parameters and dissolution conditions:

[01562] For this study, an acidic medium of 0.05 M sodium phosphate solution, pH 3.5 ± 0.05, was prepared, dissolving about 41.4 g of sodium phosphate, monobasic, monohydrate in about of 4 L of water, measure the pH and add phosphoric acid, 85%, dropwise as needed to adjust the target pH to 1.2. The mixture was diluted to 6 L with water and mixed.

[01563] For the dissolution test, one tablet each was added to a dissolution container containing 500 mL of the acidic medium maintained at 37 °C. The dissolution apparatus blades were operated at 75 RPM, with 1.5 mL samples from the dissolution vessel being obtained at the designated time periods. The sample filtrate was the sample preparation.

[01564] For sample analysis, conventional liquid chromatography methods were used, in which the % relative standard deviation (RSD) of peak areas was calculated for each set of six standard injections. The results are shown in Figure 9 (Example 32 and 33 tablets), Figure 10 (Example 34 tablet) and Figure 11 (Example 35 tablet). As can be seen in Figures 9 to 11, pH independence is achieved in the once-a-day formulations.

[01565] The dissolution profile of the tablets of Example 28 (ER7), Example 31 (ER8) and Example 32 (ER4) was evaluated in a dual pH system, as described above. The results are presented in Figures 12 and 13. As can be seen in Figures 12 and 13, the formulations provide an 80 to 100% sustained release profile over a period of 8 to 10 hours.

[01566] The formulations of Examples 28 and 31 to 35 all exhibit pH-independent release of the active ingredient. In contrast, as can be seen in Figure 8, after the initial release at the low pH, the release of the active is slowed at the higher pH for the formulations of Examples 24 to 26. Without wishing to be bound by any particular theory, it is believed It is clear that the inclusion of tartaric acid as a pH modifier in the formulations of Example 28 and 31 to 35 contributed to the pH-independent release observed for these tablets. A comparison of the dissolution profile of Example 24 (no pH modifier), Example 26 (no pH modifier), and Example 32 (tartaric acid pH modifier) tablets in a dual pH system is depicted in Figure 14.

Example 36: Extended Release Tablet

[01567] The solid state form of Compound 1 Free Base Hydrate Form C listed in Table 15-A was formulated into a 7.5 mg extended-release tablet according to the formulation presented in Table 36-A. Table 36-A: Extended Release Tablets (tartaric acid pH modifier) a Provides 7.5 mg of free base equivalent of Compound 1.

[01568] The formulation was prepared by first grinding tartaric acid through a Fitz Model M5A mill, equipped with a 1512-0027 screen. Free Base Hydrate Form C, microcrystalline cellulose, mannitol, ground tartaric acid, release control polymer and colloidal silicon dioxide were combined and mixed. The mixture was milled using a Mobil mill equipped with a 610 micron screen. The magnesium stearate was passed through #30 mesh and was then added to the conjugate and mixed. The lubricated granulation was compressed into tablets weighing about 480 mg using a rotary tablet press.

[01569] The tablets were coated using a film coating device, which sprayed a solution containing the Opadry® II Yellow film coating and purified water until 14.4 mg of coating had been applied to the tablets.

Examples 37-42: Extended Release Tablets

[01570] The solid state form of Compound 1 Free Base Hydrate Form C listed in Table 15-A was formulated into 15 mg or 30 mg extended release tablets according to the formulations presented in Table 37- A. The tablets were prepared using a wet granulation process and were compressed into tablets with a core weight of about 480 mg. Table 37-A: Extended Release Tablets (tartaric acid pH modifier) a Provides 30 mg free base equivalent of Compound 1.b Provides 15 mg free base equivalent of Compound 1.c Film coating weight is approximate.

[01571] The formulation was prepared by first grinding tartaric acid through a Fitz Model M5A mill, equipped with a 1512-0027 screen. The intragranular portion of the hydroxypropylmethyl cellulose release control polymer, the Free Base Hydrate Form C, and the intragranular portion of the microcrystalline cellulose filler were added to a granulator and mixed. Water was sprayed to granulate. The granulated material was then dried and milled using a conical mill equipped with a 610 micron screen. The milled granulation was then added to the extragranular tablet components other than magnesium stearate and sieved using a conical mill equipped with a 1397 micron screen, followed by mixing. Magnesium stearate was then added to the conjugate and mixed. The lubricated granulation was compressed into tablets weighing about 480 mg using a rotary tablet press.

[01572] The tablets were coated using a film coating device, which sprayed a solution containing the Opadry® II Yellow film coating and purified water until 14.4 mg of coating had been applied to the tablets.

Example 43: Evaluation of the Effect of Organic Acids on the Dissolution Profile of Extended Release Tablets

[01573] In this example, the effect of various organic acid pH modifiers (e.g., tartaric acid, citric acid, succinic acid, and fumaric acid) on the release rate of Free Base Hydrate Form C from tablets of 24 mg extended release (ER) once daily. Free Base Hydrate Form C was formulated into 24 mg extended-release tablets in accordance with the formulations presented in Table 43-A. Table 43-A: Extended-Release Tablets

[01574] The formulations were prepared by first grinding the organic acid through a Fitz Model M5A mill, equipped with a 1512-0027 screen. The active ingredient, microcrystalline cellulose, ground organic acid and release control polymer were combined and mixed. The mixture was milled using a Mobil mill equipped with a 610 micron screen. Magnesium stearate was passed through #30 mesh and added to the conjugate and mixed. The lubricated granulation was compressed into tablets weighing 480 mg using a rotary tablet press.

[01575] The effect of organic acids on the dissolution profile of the tablets was evaluated at 1.2 and pH 6.8. Dissolution tests were performed using the dissolution parameters and conditions as described above in Examples 26 and 27 and 32 to 35. For sample analysis, conventional liquid chromatography methods were used, in which the % of the identified amount of asset released (% of LA released). The results are shown in Figures 15A-15H.

[01576] As can be seen from these results, organic acids improved the dissolution rate at high pH, with tartaric acid showing the best improvement. Formulations comprising Carbopol® release control polymer with tartaric acid provided nearly linear release at pH 6.8.

Example 44: Measuring pH of gel for Tablets with Different Amounts of Tartaric Acid

[01577] To measure the pH of the environment created when Compound 1 reacts with HPMC, the following experiment was carried out.

[01578] The solid state form of Compound 1 Free Base Hydrate Form C was formulated into 30 mg extended-release tablets according to the formulations presented in Table 44-A. Tablets were prepared using a wet granulation process as described in Examples 37 to 42.

[01579] At 37 °C, 0.01 N HCl dissolution medium (pH 2) and 113 mM sodium phosphate buffer (pH 6.8) were prepared. One tablet was added to 500 mL of 0.01 N HCl medium at 75 rpm at 37 °C for one hour in a Vankel VK 7010 dissolution bath. 400 mL of sodium phosphate buffer were then added. The solution was stirred for a further 3 hours. The tablet was removed, rinsed with water and dried using laboratory tissues. The gel that formed on the tablet was separated from the dry nucleus for pH measurement. This procedure was repeated three times for each formulation. The pH of the gel formed in the tablets is shown in Table 44-B. The pH results are represented graphically in Figure 31.Table 44-A: Formulations Table 44-B: pH results

Example 45: Assessment of the In Vivo Pharmacokinetic Profile of 15 mg Extended Release Tablets (Fasted)

[01580] The pharmacokinetic profile of the 15 mg once-daily extended release (ER) tablets prepared in Example 28 was evaluated and compared with that of a 12 mg immediate release (IR) capsule comprising Tartrate Hydrate as the active .

[01581] Healthy human subjects (n=11) were administered a single dose of the 12 mg IR capsule (regimen A) and the 15 mg ER tablet (once per day) of Example 28 (regimen B) under conditions of fasting in a randomized, two-period, crossover study design. Subjects were administered Regimen A in the first study period and Regimen B in the second study period, or Regimen B in the first study period and Regimen A in the second study period. Serial blood samples were collected from each subject before dosing and for 72 hours after dosing in each study period. After collection, the samples were promptly placed in an ice bath, and within two hours of sample collection they were centrifuged at approximately 4 °C. The resulting plasma samples were placed in clean polypropylene tubes and stored in a freezer until analysis. Plasma samples were evaluated for Compound 1 using appropriate liquid chromatography/mass spectrometry procedures. Pharmacokinetic parameters were estimated using non-compartmental methods and summary statistics were computed.

[01582]The results are summarized in Table 45-A. The average concentration of Compound 1 at each time point using linear (Figure 16A) and semi-log (Figure 16B) scales for each of the two regimes is presented in Figures 16A and 16B. Table 45-A: Average Pharmacokinetic Parameters (%CV )c for Compound 1 Following Administration of 15 mg ER Tablet and 12 mg IR Capsule Formulations Under Fasting Conditions a - Median (minimum, maximum) b - Harmonic mean (pseudo-%CV) c - Data in parentheses are the coefficient of variance of the PK parameter (%CV), unless otherwise indicated.

[01583] As can be seen from these data, the 15 mg ER tablet provided a lower Cmax and AUC comparable to that of the 12 mg IR capsule under fasting conditions.

[01584] The relative bioavailability for a single dose of the once daily (ER) tablet formulation (Regimen B) versus the IR capsule formulation (Regimen A) was also determined based on analysis of the natural logarithms of Cmax and AUC . The results are summarized in Table 45-B below: Table 45-B: Relative Bioavailability and 90% Confidence Intervals for Bioequivalence Assessment

[01585] For Regimen B versus Regimen A, the point estimates for the proportions of AUCt and AUCinf were close to unity and the 90% confidence intervals were in the range 0.86-1.09.

Example 46: Assessment of the In Vivo Pharmacokinetic Profile of 30 mg Extended Release Tablets (Fasted)

[01586] The pharmacokinetic profile of the once-daily 30 mg extended-release (ER) tablets prepared in Example 31 was evaluated and compared with that of a 24 mg dose of an immediate-release (IR) capsule comprising Hydrate of Tartrate as the active.

[01587] Healthy human subjects (n=12) were administered a single dose of 24 mg (two 12 mg IR capsules) (Regimen C) and the 30 mg ER tablet (once per day) of Example 31 (Regimen D) under fasting conditions in a randomized, two-period, crossover study design. Half of the subjects were administered Regimen C in the first study period and Regimen D in the second study period, while the other half were administered Regimen D in the first study period and Regimen C in the second study period. Serial blood samples were collected from each subject before dosing and for 72 hours after dosing in each study period. After collection, the samples were promptly placed in an ice bath, and within two hours of sample collection they were centrifuged at approximately 4 °C. The resulting plasma samples were placed in clean polypropylene tubes and stored in a freezer until analysis. Plasma samples were evaluated for Compound 1 using appropriate liquid chromatography/mass spectrometry procedures. Pharmacokinetic parameters were estimated using non-compartmental methods and summary statistics were computed.

[01588]The results are summarized in Table 46-A. The average concentration of Compound 1 at each time point using linear (Figure 17A) and semi-log (Figure 17B) scales for each of the two regimes is presented in Figures 17A and 17B. Table 46-A: Average Pharmacokinetic Parameters (%CV )c for Compound 1 following administration of 30 mg ER Tablet and 24 mg dose IR Capsule Formulations (2 x 12 mg) Under Fasting Conditions a - Median (minimum - maximum) b - Harmonic mean (pseudo %CV) c - Data in parentheses are the coefficient of variance of the PK parameter (%CV), unless otherwise indicated.

[01589] As can be seen from these data, the 30 mg ER tablet provided a lower Cmax and AUC comparable to that of the 24 mg dose IR capsule (2 x 12 mg) under fasting conditions.

[01590] The relative bioavailability for a single dose of the once daily (ER) tablet formulation (Regimen D) relative to the IR capsule formulations (Regimen C) was also determined based on analysis of the natural logarithms of Cmax and AUC . The results are summarized in Table 46-B below: Table 46-B: Relative Bioavailability and 90% Confidence Intervals for Bioequivalence Assessment

[01591] For Regimen D versus Regimen C, the point estimates for the proportions of AUCt and AUCinf were close to unity and the 90% confidence intervals were in the range 0.82-1.03.

Example 47: Comparison of the In Vivo Pharmacokinetic Profile of 30 mg Extended Release Tablets Under Fasted Versus Fed Conditions

[01592] The pharmacokinetic profile of the 30 mg extended-release tablets prepared in Example 31 after a high-fat meal was evaluated and compared with the pharmacokinetic profile of the 30 mg extended-release tablets under fasting conditions (see Example 46 ).

[01593] Following completion of the study of Example 46, healthy human subjects (n=12) were administered single doses of the 30 mg ER tablet (once per day) of Example 31 following a high-fat meal (Regimen E ). Serial blood samples were collected from each subject before dosing and for 72 hours after dosing. After collection, the samples were promptly placed in an ice bath, and within two hours of sample collection they were centrifuged at approximately 4 °C. The resulting plasma samples were placed in clean polypropylene tubes and stored in a freezer until analysis. Plasma samples were evaluated for Compound 1 using appropriate liquid chromatography/mass spectrometry procedures.

[01594] Pharmacokinetic parameters were estimated using non-compartmental methods, and summary statistics were computed for each parameter and compared with the pharmacokinetic parameters for the 30 mg tablets administered under fasting conditions (see Example 46, Regimen D). The results are summarized in Table 47-A. The average concentration of Compound 1 at each time point using linear (Figure 18A) and semi-log (Figure 18B) scales for each of the two regimes is presented in Figures 18A and 18B. Table 47-A: Average Pharmacokinetic Parameters ( %CV)c for Compound 1 Following Administration of 30 mg ER Tablet Under Fasting Conditions or After a High-Fat Meal a - Median (minimum - maximum) b - Harmonic mean (pseudo-%CV) c - Data in parentheses are the coefficient of variance of the PK parameter (%CV), unless otherwise indicated.

[01595] The relative bioavailability for a single dose of the 30 mg once daily (ER) tablet formulation following a high-fat meal (Regimen E) relative to the bioavailability of the 30 mg ER tablet under conditions of fasting (Regimen D) was also determined based on analysis of the natural logarithms of Cmax and AUC. The results are summarized in Table 47-B below Table 47-B: Relative Bioavailability and 90% Confidence Intervals for Bioequivalence Assessment

[01596] As can be seen from Tables 47-A and 47-B, there is no clinically significant food effect for the 30 mg ER tablets. Administration following the high-fat meal increased the mean AUC and Cmax of Compound 1 by 17% and 20%, respectively.

Example 48: Steady-State Exposures Observed for 15 mg and 30 mg Extended-Release Tablets Under Non-Fasting Conditions

[01597] The steady-state pharmacokinetic profile of the 15 mg once-daily extended-release (ER) tablets (prepared in Example 28) and the 30 mg once-daily ER tablets (prepared in Example 31) was evaluated.

[01598] Healthy human subjects (n=24) were assigned to one of two regimens. Subjects on Regimen F (n=12) were administered the 15 mg ER tablet of Example 28 once daily for seven days under non-fasting conditions. Subjects on Regimen G (n=12) were administered the 30 mg ER tablet of Example 31 once daily for seven days under non-fasting conditions. On days one and seven, serial blood samples were collected from each subject before daily dosing and for 24 hours after dosing. After collection, the samples were promptly placed in an ice bath, and within two hours of sample collection they were centrifuged at approximately 4 °C. The resulting plasma samples were placed in clean polypropylene tubes and stored in a freezer until analysis. Plasma samples were evaluated for Compound 1 using appropriate liquid chromatography/mass spectrometry procedures. Pharmacokinetic parameters were estimated using non-compartmental methods and summary statistics were computed.

[01599]The results are summarized in Table 48-A. The mean plasma concentration of Compound 1 at each time point measured for each of the two regimens is presented in Figure 19. Table 48-A: Mean Pharmacokinetic Parameters (%CV) for Compound 1 following ER Tablet administration 15 mg or 30 mg ER Tablet QD for Seven Days (Non-Fasting) a - Median (minimum - maximum) b - Harmonic mean (pseudo-%CV) c - RAUC = AUC24Day7/AUC24Day 1; median (range) d - RCmax = CmaxDay 7/CmaxDay 1; median (range) e- Data in parentheses are the coefficient of variance of the PK parameter (% CV), unless otherwise indicated.

[01600] As can be seen from these data, the steady-state Cmax and AUC24 observed following administration of 15 mg QD and 30 mg QD are generally consistent with the single dose and food effect results obtained in Examples 45 -47. The bioavailability of the 15 mg and 30 mg ER tablets is 70% to 80% relative to the same dose of IR capsules.

Example 49: Steady-State Exposures Observed for 15 mg Extended-Release Tablets and 6 mg Immediate-Release Capsules Under Fasting Conditions

[01601] The steady-state pharmacokinetic profile of the once-daily 15 mg extended-release (ER) tablets (prepared in Example 28) under fasting conditions was evaluated and compared to that of an immediate-release (IR) capsule of 6 mg twice daily (BID) comprising Tartrate Hydrate as the active ingredient.

[01602] Healthy human subjects were assigned to one of two regimens under fasting conditions in a randomized, two-period, crossover study design. Subjects on Regimen K (n=12 at baseline; n=11 on Day 7) were administered the 6 mg IR capsule twice daily for seven days under fasting conditions. Subjects on Regimen L (n=12) were administered the 15 mg ER tablet of Example 28 once daily for seven days under fasting conditions. On days one and seven, serial blood samples were collected from each subject before daily dosing and for 24 hours after dosing. Blood samples were also collected at 48, 72, 96 and 120 hours after initial dosing. After collection, the samples were promptly placed in an ice bath, and within two hours of sample collection they were centrifuged at approximately 4 °C. The resulting plasma samples were placed in clean polypropylene tubes and stored in a freezer until analysis. Plasma samples were evaluated for Compound 1 using appropriate liquid chromatography/mass spectrometry procedures. Pharmacokinetic parameters were estimated using non-compartmental methods and summary statistics were computed.

[01603]The results are summarized in Table 49-A. The mean plasma concentration of Compound 1 at each time point measured for each of the two regimens is presented in Figure 20. Table 49-A: Mean Pharmacokinetic Parameters (%CV) for Compound 1 following administration of Compound 1 Capsules. 6 mg BID (IR) and 15 mg Tablets QD (ER) for Seven Days (Fasting Conditions) a - Median (minimum - maximum) b - Harmonic mean (pseudo-%CV) c - RAUC = AUC24Day7/AUC24Day 1; median (range) d - RCmax = CmaxDay 7/CmaxDay 1; median (range) e- Data in parentheses are the coefficient of variance of the PK parameter (%CV), unless otherwise indicated.

[01604] The relative bioavailability for the once-daily (ER) tablet formulation (Regimen L) versus the twice-daily (IR) capsule formulation (Regimen K) at steady state was also determined based on analysis of natural logarithms of Cmax, AUC24, Cmin, and C24. The results are summarized in Table 49-B below. Table 49-B: Relative Bioavailability Estimates and 90% Confidence Interval for 15 mg QD Tablets Versus 6 mg BID Capsules at Steady State Fast

[01605] The steady-state AUC ratio for the 15 mg QD tablets relative to the 6 mg BID capsules was approximately 1, with 90% confidence intervals within the limits of equivalence. The steady-state Cmin ratio was approximately 1 for the 15 mg QD tablet relative to the 6 mg BID capsules.

[01606] The minimum concentration before the morning dose (Cmin) for the 6 mg BID capsules and 15 mg QD tablets was determined before the morning dose on Days 2 to 8. The results are presented in Figure 21.

[01607] As can be seen from these data, at steady state under fasting conditions, the 15 mg QD tablets provided equivalent AUC24 and comparable Cmax and Cmin relative to the 6 mg BID capsules. Steady-state Cmax was 10% lower for the 15 mg QD tablet compared to the 6 mg BID capsule.

Example 50: Steady-State Exposures Observed for 30 mg Extended-Release Tablets and 12 mg Immediate-Release Capsules Under Fasting Conditions

[01608] The steady-state pharmacokinetic profile of the 30 mg once-daily extended-release (ER) tablets (prepared in Example 31) under fasting conditions was evaluated and compared to that of an immediate-release (IR) capsule of 12 mg twice daily (BID) comprising Tartrate Hydrate as the active ingredient.

[01609] Healthy human subjects were assigned to one of two regimens under fasting conditions in a randomized, two-period, crossover study design. Subjects on Regimen M (n=11) were administered the 12 mg IR capsule twice daily for seven days under fasting conditions. Subjects on Regimen N (n=12 at baseline; n=11 on Day 7) were administered the 30 mg ER tablet of Example 31 once daily for seven days under fasting conditions. On days one and seven, serial blood samples were collected from each subject before daily dosing and for 24 hours after dosing. Blood samples were also collected at 48, 72, 96 and 120 hours after initial dosing. After collection, the samples were promptly placed in an ice bath, and within two hours of sample collection they were centrifuged at approximately 4 °C. The resulting plasma samples were placed in clean polypropylene tubes and stored in a freezer until analysis. Plasma samples were evaluated for Compound 1 using appropriate liquid chromatography/mass spectrometry procedures. Pharmacokinetic parameters were estimated using noncompartmental methods and summary statistics were computed.

[01610]The results are summarized in Table 50-A. The mean plasma concentration of Compound 1 at each time point measured for each of the two regimens is presented in Figure 22. Table 50-A: Mean Pharmacokinetic Parameters (%CV) for Compound 1 following administration of Compound 1 Capsules. 12 mg BID (IR) and 30 mg Tablets QD (ER) for Seven Days (Fasting Conditions) a - Median (minimum - maximum) b - Harmonic mean (pseudo-%CV) c - RAUC = AUC24Day7/AUC24Day 1; median (range) d - RCmax = CmaxDay 7/CmaxDay 1; median (range) e- Data in parentheses are the coefficient of variance of the PK parameter (% CV), unless otherwise indicated.

[01611] The relative bioavailability for a single dose of the once-daily (ER) tablet formulation (Regimen N) versus the twice-daily (IR) capsule formulation (Regimen M) was also determined based on analysis of the natural logarithms of Cmax, AUC24, Cmin, and C24. The results are summarized in Table 50-B below. Table 50-B: Relative Bioavailability Estimates and 90% Confidence Interval for 30 mg QD Tablets Versus 12 mg BID Capsules at Steady State under Conditions of Fast

[01612] The steady-state AUC ratio for the 30 mg QD tablets relative to the 12 mg BID capsules was approximately 1, with 90% confidence intervals within the limits of equivalence. The steady-state Cmin of the 30 mg QD tablet was approximately 13% lower than that of the 12 mg BID capsules. Extreme values with high Cmin at the BID dose of 12 mg may have contributed to this difference.

[01613] The minimum concentration before the morning dose (Cmin) for the 12 mg BID capsules and 30 mg QD tablets was determined before the morning dose on Days 2 to 8. The results are presented in Figure 23. As can be seen from these data, at steady state under fasting conditions, the 30 mg QD tablets provided equivalent AUC24 and comparable Cmax and Cmin relative to the 12 mg BID capsules. Steady-state Cmax was 10% lower for the 30 mg QD tablet compared to the 12 mg BID capsules.

Example 51: Comparison of the Pharmacokinetic Profile of AM vs. PM Following Administration of 6 mg or 12 mg Immediate Release Capsules Under Fasting Conditions

[01614] The pharmacokinetic profile of the 6 mg immediate release (IR) twice daily (BID) capsules and the 12 mg twice daily IR capsules was determined on Day 7 of Regimen K (Example 49) and Regimen M (Example 50), respectively, after administration in the morning (AM dose) and in the evening (PM dose). The results are summarized in Table 51-A. Table 51-A: Mean Pharmacokinetic Parameters (%CV)b for Compound 1 following administration of AM and PM Doses of 6 mg and 12 mg Immediate Release Capsules on the Day 7 (Fasting Conditions) a - Median (Minimum - Maximum) b- Data in parentheses are the coefficient of variance of the PK parameter (% CV), unless otherwise indicated. c - The PM dose was administered 3 hours after the start of dinner and 4 hours before a snack.

Example 52: Assessment of the In Vivo Pharmacokinetic Profile of 30 mg Extended Release Tablets

[01615] The pharmacokinetic profiles of the once-daily 30 mg extended-release (ER) tablets that were prepared in Examples 37 (ER10, 30% tartaric acid), 38 (ER11, 20% tartaric acid), and 39 ( ER12, 10% tartaric acid) using wet granulation were evaluated and compared with those of the 30 mg ER tablet that was prepared in Example 31 (ER8, 30% tartaric acid) using direct compression (without wet granulation). The effect of a high-fat meal in the formulations of Example 37, 38 and 39 was also evaluated.

[01616] Healthy human subjects (n=36) were administered a single dose of the ER tablet (once per day) of 30 mg of Example 31 (ER8), Example 37 (ER10), Example 38 (ER11) and Example 39 (ER12) under fasting conditions or after a high-fat meal (non-fasting), in an incomplete, four-period, randomized, open-label crossover study. Doses in the four periods were at least four days apart. Dosage regimens were as presented in Table 52-A.Table 52-A: Dosage Regimens

[01617] Serial blood samples were collected from each subject before dosing and for 72 hours after dosing in each study period. After collection, the samples were promptly placed in an ice bath, and within 1 hour of sample collection they were centrifuged at approximately 4 °C. The resulting plasma samples were placed in clean polypropylene tubes and stored in a freezer until analysis. Plasma samples were evaluated for Compound 1 using appropriate liquid chromatography/mass spectrometry procedures. Pharmacokinetic parameters were estimated using noncompartmental methods and summary statistics were computed.

[01618]Bioavailability Under Fasting Conditions

[01619] Results for administration under fasting conditions are summarized in Table 52-B. The mean plasma concentration of Compound 1 at each time point using linear (Figure 24A) and log-linear (Figure 24B) scales for each of the four fasting regimens is presented in Figures 24A and 24B. Table 52-B: Pharmacokinetic Parameters Averages (%CV)c for Compound 1 following Administration of a Single 30 mg Dose of Various Compound 1 Once Daily Formulations prepared using Wet Granulation compared to Administration of a Single 30 mg Dose of a Once Daily Formulation per Day of Compound 1 Prepared by Direct Compression Under Fasting Conditions a - Median (minimum - maximum) b - Harmonic mean (pseudo-%CV) c - Data in parentheses are the coefficient of variance of the PK parameter (%CV), unless otherwise indicated.

[01620]The relative bioavailability for a single dose of the three once-daily (ER) tablet formulations prepared using wet granulation (Regimens B, D, and F) relative to the ER tablet prepared by direct compression (without wet granulation) ( Regimen A) was also determined based on analysis of the natural logarithms of Cmax, AUCt, and AUCinf. The results are summarized in Table 52-C below. Table 52-C: Bioavailability for Three Once-Daily Formulations of Compound 1 prepared using Wet Granulation (30 mg; ER10, ER11, ER12) relative to a Formulation Prepared by Compression Direct (30 mg, ER8) under Fasting Conditions

[01621] As can be seen from these data, the three 30 mg tablets prepared using wet granulation (ER10, ER11 and ER12) were bioequivalent, under fasting conditions, to the tablet prepared by direct compression (without wet granulation). .

[01622] Effect of a High-Fat Meal on the Formulation of Example 37 (ER10)

[01623] The effect of a high-fat meal on the pharmacokinetic parameters of the formulation of Example 37 (ER10, 30 mg active, 30% tartaric acid) is summarized in Table 52-D. The mean plasma concentration of Compound 1 at each time point using linear (Figure 25A) and log-linear (Figure 25B) scales for each of Regimen B (ER10, fasting) and Regimen C (ER10, high-fat meal ) is shown in Figures 25A and 25B. The change in Cmax and AUCinf of Compound 1 following administration of a single 30 mg dose of the ER10 tablet under fasting conditions and after a high-fat meal is shown in Figures 26A (Cmax) and 26B (AUCinf). Table 52-D: Mean Pharmacokinetic Parameters (%CV)c for Compound 1 following administration of a Single 30 mg Dose of ER10 Tablet Formulation Once Daily under Fasting Conditions and after a High-Fat Meal a - Median (minimum - maximum) b - Harmonic mean (pseudo-%CV) c - Data in parentheses are the coefficient of variance of the PK parameter (%CV), unless otherwise indicated.

[01624] The relative bioavailability for a single dose of the formulation of Example 37 (ER10) administered after a high-fat meal relative to administration under fasting conditions was also determined based on analysis of the natural logarithms of Cmax, AUCt, and AUCinf. The results are summarized in Table 52-E below. Table 52-E: Single Dose Bioavailability of ER10 30 mg Tablet Once Daily Administered After High-Fat Meal vs. Under Fasting Conditions

[01625] As can be seen from these data, a high-fat meal increased Cmax and AUCinf for the ER10 formulation (30 mg active, 30% tartaric acid) by about 32% and 28%, respectively. .

[01626] Effect of a High-Fat Meal on the Formulation of Example 38 (ER11)

[01627] The effect of a high-fat meal on the pharmacokinetic parameters of the formulation of Example 38 (ER11, 30 mg, 20% tartaric acid) is summarized in Table 52-F. The mean plasma concentration of Compound 1 at each time point using linear (Figure 27A) and log-linear (Figure 27B) scales for each of Regimen D (ER11, fasting) and Regimen E (ER11, high-fat meal ) is shown in Figures 27A and 27B. The change in Cmax and AUCinf of Compound 1 following administration of a single 30 mg dose of ER11 tablet under fasting conditions and after a high-fat meal is shown in Figures 28A (Cmax) and 28B (AUCinf). .Table 52-F: Mean Pharmacokinetic Parameters (%CV)c for Compound 1 following administration of a Single 30 mg Dose of ER11 Tablet Formulation Once Daily under Fasting Conditions and after a High-Fat Meal a - Median (minimum - maximum) b - Harmonic mean (pseudo-%CV) c - Data in parentheses are the coefficient of variance of the PK parameter (%CV), unless otherwise indicated.

[01628] The relative bioavailability for a single dose of the formulation of Example 38 (ER11) administered after a high-fat meal relative to administration under fasting conditions was also determined based on analysis of the natural logarithms of Cmax, AUCt, and AUCinf. The results are summarized in Table 52-G below. Table 52-G: Single Dose Bioavailability of ER11 30 mg Tablet Once Daily Administered After High-Fat Meal vs. Under Fasting Conditions

[01629] As can be seen from these data, a high-fat meal increased Cmax and AUCinf for the ER11 formulation (30 mg active, 20% tartaric acid) by about 34% and 29%, respectively. , which was a similar dietary effect to that observed for the tablet of Example 37 (ER10).

[01630] Effect of a High-Fat Meal on the Formulation of Example 39 (ER12)

[01631] The effect of a high-fat meal on the pharmacokinetic parameters of the formulation of Example 39 (ER12, 30 mg active, 10% tartaric acid) is summarized in Table 52-H. The mean plasma concentration of Compound 1 at each time point using linear (Figure 29A) and log-linear (Figure 29B) scales for each of Regimen F (ER12, fasting) and Regimen G (ER12, high-fat meal ) is shown in Figures 29A and 29B. The change in Cmax and AUCinf of Compound 1 following administration of a single 30 mg dose of the ER12 tablet under fasting conditions and after a high-fat meal is shown in Figures 30A (Cmax) and 30B (AUCinf). Table 52-H: Mean Pharmacokinetic Parameters (%CV)c for Compound 1 following administration of a Single 30 mg Dose of ER12 Tablet Formulation Once Daily under Fasting Conditions and after a High-Fat Meal a - Median (minimum - maximum) b - Harmonic mean (pseudo-%CV) c - Data in parentheses are the coefficient of variance of the PK parameter (%CV), unless otherwise indicated.

[01632] The relative bioavailability for a single dose of the formulation of Example 39 (ER12) administered after a high-fat meal relative to administration under fasting conditions was also determined based on analysis of the natural logarithms of Cmax, AUCt, and AUCinf. The results are summarized in Table 52-I below. Table 52-I: Single Dose Bioavailability of ER12 30 mg Tablet Once Daily Administered after High-Fat Meal vs. Under Fasting Conditions

[01633] As can be seen from these data, a high-fat meal increased Cmax and AUCinf for the ER12 formulation (30 mg active, 10% tartaric acid) by about 53% and 27%, respectively. .

Example 53: Predicted Pharmacokinetic Parameters for 15 mg Extended Release Tablets

[01634] The average pharmacokinetic parameters under fasting conditions for the 15 mg once daily (QD) extended release tablets prepared in Examples 40 (ER13), 41 (ER14) and 42 (ER15) using wet granulation were extrapolated to from the single dose data obtained in Example 52 for the formulations of Examples 37 (ER10), 38 (ER11) and 39 (ER12), respectively, under fasting conditions. The results are presented in Table 53-A.Table 53-A: Predicted Mean Pharmacokinetic Parameters under Fasting Conditions for Compound 1 following administration of Once Daily 15 mg Single Dose Formulations (extrapolated from Single Dose Profiles in Example 52 for 30 mg Doses) a - Median (minimum - maximum)

Example 54: Preliminary Data from a Phase 1 Study in Healthy Volunteers and Patients with Rheumatoid Arthritis

[01635] Compound 1 was studied in 2 Phase 1 studies, first in a single ascending dose study in humans (Study Ml3-401, described in WO 2015/061665, and referred to herein as Study 1), and then in a multiple ascending dose study (Study Ml3-845, also generally referred to in WO 2015/061665, and referred to herein as Study 2).

[01636] In Study 1, a total of 42 healthy volunteers received a single dose of Compound 1. In Study 2, a total of 32 healthy volunteers received multiple doses of Compound 1 over 14 days (Study 2, Part 1). Additionally, 14 patients with RA were enrolled and completed the double-blind Part 2 of Study 2. The study was designed as a multicenter, randomized, multiple-dose trial with the primary objective of evaluating the safety, tolerability, and PK of multiple ascending doses of Compound 1 in healthy adult volunteers and evaluate the safety, tolerability and PK of multiple doses of Compound 1 in patients with RA who are on a stable methotrexate regimen.

[01637] Details of Study 1 and Study 2 and results obtained therein are provided below.

[01638] Study 1 - Single Dose Escalation in Healthy Subjects

[01639] Study 1 was a single dose escalation evaluation of Compound 1. Study 1 was designed as a double-blind, randomized, single-site, placebo-controlled study. Fifty-six subjects in good general health were randomized to receive single doses of Compound 1 immediate-release capsules comprising Tartrate Hydrate (1, 3, 6, 12, 24, 36, and 48 mg) or placebo in a 3:1 ratio. with 8 subjects at each dose level. Study drug was administered following at least 10 hours of fasting. The study was conducted at PPD Development (Austin, TX). The subjects were confined to the study site and supervised for approximately 8 consecutive days. The study protocol and informed consent were approved by the RCRC Institutional Review Board (IRB) (Austin, TX).

[01640] Study 2 - Multiple Dose Escalation

[01641] In Study 2, multiple twice-daily (BID) doses of immediate-release capsules comprising Tartrate Hydrate were administered to healthy subjects (Part 1) or to subjects with rheumatoid arthritis (RA) receiving stable doses of methotrexate (Part 2). Both evaluations followed placebo-controlled, double-blind, randomized designs. Part 1 was performed at PPD Deve-lopment (Austin, TX) and Part 2 was performed at two sites: Aspen Clinical Research (Orem, UT) and Altoona Center for Clinical Research (Duncansville, PA). The study protocol and informed consent were approved by RCRC IRB (Austin, TX) and Quorum Review IRB (Seattle, WA).

[01642] Study 2 - Part 1 - Multiple Dose Escalation in Healthy Subjects

[01643] The objective of Part 1 of the multiple dose study was to characterize the pharmacokinetics, safety and tolerability of multiple oral doses of immediate release capsules of Compound 1 comprising Tartrate Hydrate in healthy subjects. Four escalating dosage regimens were evaluated (3, 6, 12 and 24 mg of Compound 1 or matching placebo twice daily for 13 consecutive days and once on the morning of day 14). The study drug was administered approximately 30 minutes after a normal breakfast (in the morning) or a snack (in the evening). Forty-four healthy subjects participated in this part of the study with 11 subjects per dose group (Compound 1:placebo ratio of 8:3). The subjects were confined to the study site and supervised for approximately 18 days.

[01644] Study 2 - Part 2 - Multiple dose evaluation in subjects with RA

[01645] The objective of Part 2 of the multiple dose study was to evaluate the pharmacokinetics, safety and tolerability of multiple oral doses of immediate release capsules of Compound 1 comprising Tartrate Hydrate in subjects with moderate to severe RA who were on stable methotrexate treatment. This evaluation was designed to enroll approximately 32 subjects randomized in a 1:1:1:1 ratio to one of four parallel twice-daily regimens (6, 12, and 24 mg of Compound 1 and placebo). Subjects received study drug for 26 consecutive days (Study Days 3 to 28) and a single morning dose of study drug on Study Day 29. Compound 1 was administered following breakfast for the dose of morning, and after dinner or snack, for the evening dose. Subjects had been on methotrexate therapy for at least 3 months and on a stable dose of 10 to 25 mg/week of methotrexate for at least 4 weeks before the first dose of study drug was administered on Study Day 3, and continued their weekly stable dose of methotrexate on Study Days 1, 8, 15, 22, and 29. Subjects were confined to the study site for a total of 10 days - from Day 1 to Day 4 and from Day 27 to Day 31.

[01646] Study Participants

[01647] Subjects underwent screening procedures within 30 days prior to initial study drug administration. Subjects signed written informed consent before beginning any screening or study-specific procedures. Subjects were eligible for study participation if they were men or women between 18 to 55 years of age (Study 1 and Study 2, - Part 1) or 18 to 75 years of age (Study 2, - Part 2); if they were considered to be in good general health based on the results of the medical history, laboratory profile, physical examination, chest x-ray and 12-lead electrocardiogram (ECG); and if your body mass index (BMI) was in the range of 19 to 29 kg/m2 (Study 1 and Study 2 - Part 1) or 19 to 39 kg/m2 (Study 2 - Part 2) at screening. Subjects were considered eligible to participate in Study 2 - Part 2 if they had been diagnosed as having RA based on the 2010 American College of Rheumatology/European League against Rheumatism criteria > 6 months, if they had been on methotrexate therapy > 3 months ( and folate or equivalent for at least 2 weeks prior to Study Day 1), at a stable methotrexate dose of 10 to 25 mg/week for at least 4 weeks prior to the first dose of study drug administered on Study Day 3.

[01648] In both studies, subjects were excluded if they had any clinically significant abnormalities, infection, severe febrile illness, hospitalization, or if they had undergone any clinically relevant surgery within 30 days prior to the first dose of study drug, if they had resulted in positive for hepatitis A virus immunoglobulin M, hepatitis B surface antigen or hepatitis C virus antibody, or HIV antibodies at Screening; if they had a history or evidence of active or latent tuberculosis; if they had a history of diabetes or lymphoproliferative disease or evidence of immunosuppression (except for methotrexate use in Study 2- Part 2); or if they had clinically significant findings at Screening as determined by the principal investigator. Additionally, subjects in Study 2 - Part 2 were excluded if they had a history of acute inflammatory joint disease of origin other than RA or had a current or expected need for oral prednisone > 10 mg/day or equivalent corticosteroid therapy.

[01649] Pharmacokinetic Sampling

[01650] In healthy subjects, serial blood samples were collected for 72 hours after a single dosage (Study 1) or for 12 hours after the first dose (Study Day 1) and for 72 hours after the last dose (Study Day 1) Study Day 14) of study drug (Study 2-Part 1). In subjects with RA, serial blood samples were collected over 48 hours on Study Day 1 for the methotrexate trial, for 12 hours following the first dose of study drug on Study Day 3 for the Compound 1 trial, for 12 hours following the morning dose of study drug on Study Day 28 for Compound 1 trials and for 48 hours following the last dose of study drug on Study Day 29 for Compound 1 and methotrexate trials. Minimum pre-dose samples were collected prior to the morning dose on Study Days 5, 6, 7, 13, and 14 in Study 2 - Part 1 to assess achievement of steady state.

[01651] Urine for Compound 1 assay was collected during a 12 hour interval after the last dose was administered on Study Day 14 in Study 2 - Part 1 and on Study Days 28 and 29 in Study 2 - Part 2. It was Urine for methotrexate assay was collected for 48 hours on Study Day 1 and Study Day 29.

[01652] Plasma and urine concentrations of Compound 1 and methotrexate were determined using a liquid chromatography method validated with mass spectrometry detection methods. The lower limits of quantitation (LLOQ) for Compound 1 and methotrexate in plasma were set at 0.0503 ng/mL and 1.00 ng/mL, respectively. The LLOQ for Compound 1 and methotrexate in urine were set at 1.01 ng/mL and 0.0500 μg/mL, respectively. Samples quantified below LLOQ were reported as zero. For Compound 1 assays, interassay variability (measured as % coefficient of variation [%CV]) was < 9.5% for plasma < 8.4% for urine and the mean absolute deviation was < 6.7% for plasma and < 5.9% for urine. For methotrexate assay, interassay variability (%CV) was < 3.9% for plasma and < 5.2% for urine and mean absolute deviation was < 5.4% in plasma and < 13.1% in urine .

[01653] Pharmacokinetic Analysis

[01654] The pharmacokinetic parameters of Compound 1 and methotrexate were determined using non-compartmental analyzes with Phoenix software (Version 6.3, Certara, Princeton, NJ, USA). The calculated pharmacokinetic parameters included the maximum observed plasma concentration (Cmax), time to Cmax (Tmax), minimum plasma concentration (Cmin), the apparent terminal phase elimination rate constant (β), the elimination half-life of terminal phase (t1/2), the area under the plasma concentration-time curve (AUC) [from time 0 to time of last measurable concentration (AUCt), from time 0 to infinity (AUC~) for single dosing, and at over a 12 hour dosing interval (AUC0-12, or AUC12,ss) for multiple dosing and apparent oral elimination (CL/F). The functional half-life of Compound 1 (t1/2F) following multiple dosing was calculated as ln(2)/(ln[Cmax/Cmin]/T) at steady state, where T is the dosing interval of 12 hours (Dutta et al., Clin. Drug Investig., 2006, Vol. 26(12), pp. 681-690). Accumulation ratio (Rac) was calculated as the ratio of AUC0-12 of Compound 1 on Day 14 to Day 1 (Study 2 - Part 1) or Day 28 to Day 3 (Study 2 - Part 2). The percentage of Compound 1 dose recovered unchanged in urine (fe%) at steady state was calculated as the amount of Compound 1 recovered in urine during the 0 to 12 hour interval (Au, 0-12), divided by the administered dose and multiplied by 100. Renal clearance (CLr) was calculated as Au, 0-12/ AUC0-12 at steady state. Methotrexate Fe%e% was calculated as the amount of methotrexate recovered in urine during the 0 to 48 hour interval (Au, 0-48), divided by the administered dose and multiplied by 100. CLr or methotrexate was calculated as Au, 0 -48/ AUC0-48. The effect of co-administration of methotrexate on exposure to Compound 1 was evaluated from the ratios of AUC0-12 and Cmax of Compound 1 on Study Day 29 to Study Day 28. The effect of Compound 1 on exposure to methotrexate was evaluated from the ratios of methotrexate AUC~ and Cmax on Study Day 29 to Study Day 1.

[01655] Safety and Tolerability Assessment

[01656]Safety was evaluated based on assessment of adverse events, vital signs, physical examination, laboratory measurements and 12-lead electrocardiogram (ECG). All subjects who received at least one dose of study drug were included in the safety analyses. Subjects administered placebo were grouped into a single group within each study or study part. Laboratory test values and vital sign measurements that were above or below the reference range were identified. Subjects were followed for a total of 7 days in Study 1, 35 days in Study 2 - Part 1, and 57 days in Study 2 - Part 2. In healthy subjects, adverse clinical events were graded as described in Guidance for Industry Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (September 2007). In subjects with RA, the severity of adverse events was classified by investigators as mild (temporary and easily tolerated by the subject), moderate (cause discomfort to the subject and interrupt the subject's normal activities), or severe (cause considerable interference with the subject's normal activities). and may be disabling or life-threatening). One subject in Study 2 - Part 2 was randomized to the placebo group, but received Compound 1 in error on Study Days 10 to 16. As such, the subject was included in the Compound 1 cohort for safety assessments.

[01657]Statistical Analysis

[01658] Dose proportionality for Compound 1 in healthy subjects was tested using the natural logarithms of dose-normalized Cmax and AUC following single dosing (Study 1) or for dose-normalized Cmax, Cmin, and AUC at steady state following to multiple dosing assessments (Study 2 - Part 1). The achievement of steady state following multiple doses in healthy volunteers was assessed by testing the logarithmic transformation of pre-dose morning concentrations of Compound 1 for Study Days 5, 6, 7, 13 and 14 by repeated measurement analysis. Statistical analyzes were performed using SAS software (Version 9.3; SAS Institute Inc., Cary, NC, USA).

[01659] Results

[01660] Demographics and Subject Disposition

[01661] A total of 56 healthy subjects were enrolled and completed the single dose evaluation (Study 1) and 44 healthy subjects were enrolled and completed the multiple dose evaluation (Study 2 - Part 1). Enrollment in the multiple dose evaluation of RA subjects (Study 2 - Part 2) was discontinued early due to slow recruitment rate and 14 RA subjects were actually enrolled and completed this evaluation. There were no early dropouts in any of the assessments. Table 54-A presents a summary of demographic data.Table 54-A: Baseline Demographics of Study Participants

[01662] Single and Multiple Dose Pharmacokinetics of Compound 1 in Healthy Volunteers

[01663] Plasma concentrations of Compound 1 reached peak levels approximately 1 to 2 hours after oral dosing of the immediate-release capsule formulation. Plasma concentrations of Compound 1 subsequently decreased bi-exponentially with a terminal t1/2 elimination of approximately 6 to 15 hours after single dosing (Figures 32A and 32B, Table 54-B) and 8 to 16 hours after multiple twice-daily dosing. day (Figure 33, Table 54-C). The functional half-life of Compound 1, estimated from the ratio of Cmax to Cmin at steady state, was approximately 3 hours. After multiple dosing, there was a small but statistically significant difference (p < 0.05) between pre-dose concentrations of Compound 1 on Study Day 13 (13% lower) compared to Study Day 5. There were no statistically significant differences at Compound 1 pre-dose concentration on Study Day 13 and Study Day 14, indicating that steady state was achieved on Study Day 13. At steady state, the median accumulation ratios for AUC0-12 of Compound 1 were approximately 1 .0 over the evaluated dose range (Table 54-C).

[01664] The relationships of Cmax and AUC values of normalized dose versus dose following single and multiple dosing are shown in Figures 34A-34D. In the single dose evaluation, the 1 mg dose group was excluded from statistical analyzes for AUC~ since the majority of samples collected in the terminal phase were below the limit of quantification for all subjects. There was no statistically significant difference in dose-normalized Cmax between the highest (48 mg) and lowest dose (1 mg) of Compound 1, and there was no statistically significant trend for change in dose-normalized Cmax values. There was no trend for change in dose-normalized AUC of Compound 1 with doses in the dose range of 3 to 36 mg (P>0.05); however, dose-normalized AUC following the single 48 mg dose was 40% lower than that following the 3 mg dose (p < 0.05).

[01665] Following multiple dosing in healthy subjects, there was no statistically significant difference (p > 0.05) in Cmax, Cmin, or AUC at steady-state dose-normalized Compound 1 for the 24 mg twice a day regimen. day compared to 3, 6, or 12 mg twice daily regimens.

[01666] Overall, exposures to Compound 1 appeared to be dose proportional, in particular in the single dose range of 3 to 36 mg and the multiple dose range of 3 mg to 24 mg BID. Table 54-B: Pharmacokinetic Parameters (mean ± standard deviation) of Compound 1 after administration of single doses of the immediate-release formulation to healthy subjects The. Median (range) b. Terminal elimination half-life, presented as harmonic mean ± pseudo-standard deviation Table 54-C: Steady-state pharmacokinetic parameters (Day 14) (mean ± standard deviation) of Compound 1 after administration of multiple twice-daily oral doses of immediate release formulation to healthy subjects The. Terminal elimination half-life. B. Functional half-life calculated from the ratio Cmax to Cmin at steady state. w. Accumulation ratio for AUC0-12. Harmonic mean ± pseudo standard deviation are presented for t1/2 and t1/2F. Median and range (minimum to maximum) are presented for Tmax and Rac AUC0-12. BID: twice a day.

[01667] Multiple dose pharmacokinetics of Compound 1 in subjects with RA

[01668] In subjects with RA who were on stable doses of methotrexate, plasma concentrations of Compound 1 reached peak levels 1 to 2 hours after dosing (Table 54-D). The mean terminal elimination half-life of Compound 1 was approximately 10 to 14 hours and the functional half-life was approximately 4 hours. The median accumulation ratio of Compound 1 after 26 days of twice daily dosing was 0.8 to 1.4. The median ratio of Cmax and AUC0-12 of Compound 1 when administered with methotrexate (on Study Day 29) compared to that administered without methotrexate (Study Day 28) was 0.9 to 1.2, indicating a lack of significant effect of methotrexate co-administration on the pharmacokinetics of Compound 1 (Figure 35A). The steady-state dose-normalized Cmax and AUC0-12 of Compound 1 in subjects with RA compared to healthy subjects are shown in Figures 34B and 34D. The ratio of exposure to Compound 1 in subjects with rheumatoid arthritis to exposure to Compound 1 in healthy subjects was 1.1 (24 mg dose twice a day) to 1.6 (6 mg dose twice a day ) for AUC0-12 and from 1.2 (dose of 24 mg twice a day) to 1.7 (dose of 6 mg twice a day) for Cmax.Table 54-D: Pharmacokinetic parameters (mean ± standard deviation) of Compound 1 following administration of multiple oral doses twice daily to subjects with mild to moderate rheumatoid arthritis on stable doses of methotrexate The. Terminal elimination half-life. B. Functional half-life calculated from the ratio Cmax to Cmin at steady state. w. Accumulation ratio for AUC0-12. Harmonic mean ± pseudo standard deviation are presented for t1/2 and t1/2F. Median and range (minimum to maximum) are presented for Tmax accumulation ratios and Day 29/Day 28 ratios. BID: twice daily

[01669] Effect of co-administration of Compound 1 on exposure to methotrexate

[01670] Pharmacokinetic parameters of methotrexate when administered before (Study Day 1) and after administration of multiple doses of Compound 1 (Day 29) are summarized in Table 54-E. Since methotrexate was administered weekly and has a short plasma half-life, plasma accumulation was not expected with repeated dosing and AUC~ was calculated for Days 1 and 29. The median ratio for AUC~ and Cmax of methotrexate when administered after multiple doses of Compound 1 (on Study Day 29) to that administered without Compound 1 (on Study Day 1) from 0.9 to 1.1 and from 0.8 to 1.2, respectively. No change in AUC~ of normalized dose of methotrexate was observed when administered with or without Compound 1 (Figure 35B). Table 54-E: Pharmacokinetic parameters (mean ± standard deviation) of methotrexate following administration to subjects with RA alone (Day 1) or concomitant with Compound 1 (Day 29) The. Terminal elimination half-life, presented as harmonic mean ± pseudo-standard deviation. B. The proportion of methotrexate exposure (AUC~) on Study Day 29 compared to that on Study Day 1 is shown; median and range (minimum to maximum).

[01671 ] Safety and Tolerability In the three evaluations, a total of 74 healthy subjects and 11 subjects with RA received Compound 1 and a total of 26 healthy subjects and 3 subjects with RA received placebo. There were no dose-limiting toxicities or safety issues with Compound 1 from single doses up to 48 mg or multiple doses up to 24 mg twice daily. Notably, the safety and tolerability profile of Compound 1 was comparable between subjects receiving Compound 1 or placebo, and between healthy subjects and subjects with RA on background methotrexate treatment, although the number of subjects with RA was limited. There was no evidence of a dose or time dependence for the incidence of adverse events in healthy subjects or subjects with RA. There were no study discontinuations due to adverse events, there were no serious adverse events, nor clinically significant changes in ECG parameters, or laboratory measurements in any of the subjects or treatment groups. The maximum tolerated dose of Compound 1 was not reached in the multiple or single dose studies. Adverse events that were reported by at least two subjects and Compound 1 or placebo groups in Study 1 or Study 2 - Part 1 are presented in Table 54-F. Table 54-F: Treatment-emergent adverse events reported by two or more healthy subjects administered Compound 1 or placebo in multiple and single ascending dose assessments *The two cases of pre-syncope were associated with venipuncture. In healthy subjects who were administered single doses of Compound 1 (1, 3, 6, 12, 24, 36 and 48 mg) or placebo in Study 1, 14.3% (6/42) and 21.4% (3/14) of subjects, respectively, reported having one or more treatment-emergent adverse events (TEAEs). All TEAEs were assessed as mild in severity. Adverse events reported by more than one subject who received Compound 1 were headache and presyncope (1 subject in the 6 mg dose group and 1 subject in the 24 mg dose group) in association with venipuncture (see Table 54-F).

[01672] In healthy subjects administered multiple doses of Compound 1 (3, 6, 12 and 24 mg BID) or placebo for 14 consecutive days in Study 2 - Part 1, 34% (11/32) and 58% ( 7/12) of subjects, respectively, reported one or more TEAEs. The overall incidences of TEAEs were numerically higher at higher doses of Compound 1; 2 (25.0%), 2 (25.0%), 3(37.5%) and 4 (50%) subjects in the 3 mg, 6 mg, 12 mg and 24 mg dose groups, respectively; however, these rates were lower than those observed in the placebo group (58%). All TEAEs were reported to be mild in severity. Four events occurred in at least two subjects receiving Compound 1: headache, abdominal pain, diarrhea, and nasopharyngitis; three of these events also occurred in subjects receiving placebo: headache, diarrhea, and nasopharyngitis (Table 54-F).

[01673] There were no clinically significant changes in any hematological parameters after multiple dose administration in healthy subjects for 14 days. With increasing doses of Compound 1, there were statistically significant decreasing trends in mean hemoglobin, RBCs, WBCs, and neutrophil levels; however, even at the 24 mg dose, mean levels were within the normal reference range. The mean changes in reticulocyte counts with increasing dose of Compound 1 compared to placebo were not statistically significant, suggesting no evidence of a drug-related effect on reticulocyte counts after 14 days of treatment with Compound 1. Total cholesterol, HDL cholesterol and LDL cholesterol showed a statistically significant upward trend with increasing dose of Compound 1 compared to placebo; however, the final mean values for these lipid parameters in the Compound 1 dose groups remained within the normal reference range.

[01674] Subjects with mild to moderate RA on stable background doses of methotrexate in Study 2-Part 2 were administered multiple doses of Compound 1 (a total of 11 subjects) or placebo (a total of 3 subjects). Five subjects in the Compound 1 dose groups and two subjects in the placebo group experienced at least one TEAE. In the Compound 1 dose groups, 7 TEAEs were reported: nausea, vomiting, viral gastroenteritis, upper respiratory tract infection, post-traumatic neck syndrome, back pain, and insomnia. All TEAEs were reported by investigators to be mild or moderate in severity and no adverse events were reported in more than one subject in any treatment group. There was no evidence of a dose relationship with any of these events. Notably, since these subjects with RA received a stable background dose of methotrexate, there were no changes in hepatobiliary measurements for those receiving Compound 1. There was also no evidence of a dose-related effect of Compound 1 on renal function in these subjects with RA, as assessed by serum creatinine and blood urea nitrogen values.

[01675] Discussion

[01676] Compound 1 was well tolerated after single doses up to 48 mg and multiple twice daily doses up to 24 mg of immediate release formulation of Compound 1. All adverse events that occurred following multiple or single dose administrations were mild to moderate in nature with comparable frequency among subjects receiving Compound 1 or placebo. No anemia, serious infections, or clinically significant changes in hematologic, hepatobiliary, or renal laboratory measurements were observed with 14 days of repeat dosing of Compound 1 in healthy volunteers or 27 days of dosing in patients with RA.

[01677] Compound 1 exhibited multi-exponential plasma disposition with a functional half-life of 3 to 4 hours over the dose range of 3 to 24 mg twice daily of the immediate release formulation in healthy volunteers and subjects with RA. The terminal elimination half-life of Compound 1 was 6 to 16 hours at the different dose levels. However, given the multi-exponential arrangement of Compound 1, the longer terminal half-life is clinically less relevant than the functional half-life (Dutta et al., Clin. Drug Investig., 2006, Vol. 26(12), pp 681- 690; Sahin, Pharm., 2008, Vol. 25(12), pp. 2869-77). Consistent with a shorter functional half-life, there was no accumulation over the evaluated twice-daily dose range of 3 to 24 mg. Although there are no reliable clinical data to suggest that prolonged exposure is necessary for JAK inhibitor efficacy (i.e., to determine whether efficacy is driven by concentration or AUC), the pharmacokinetic profile of the immediate-release formulation of JAK Compound 1 appears to be generally more suitable for twice-daily dosing than for once-daily dosing.

[01678] Compound 1 exhibited dose-proportional pharmacokinetics in particular over the dose range 3 to 36 mg (Figure 34), which encompasses the dose ranges evaluated in Phase 2b clinical trials in RA (3 to 18 mg BID and 24 mg QD), or currently being evaluated in Crohn's disease (3 to 24 mg BID).

[01679] The JAK inhibitors tofacitinib and filgotinib have previously been reported to have higher exposures in subjects with RA than in healthy volunteers (see FDA, "Clinical Pharmacology and Biopharmaceutics Review(s) - Tofacitinib", Application Number 203214Orig1s000, Center for Drug Evaluation and Research, 2011; Namour et al., Clin. Pharmacokinet., 2015, Vol. 54, pages 859-874). The apparent oral elimination of Compound 1 was 23% lower in subjects with RA (leading to approximately 30% higher exposure), on average across all dose groups, compared to healthy subjects. In general, older subjects are expected to have lower renal and metabolic capacity compared to younger subjects (Mangoni, Br. J. Clin. Pharmacol., 2004, Vol. 57(1), pages 6-14). RA subjects who received multiple doses of Compound 1 were 26 years older, on average, than healthy subjects evaluated in Study 2 (Table 54-A); as such, age cannot be excluded as a potential contributor to the apparently 30% higher exposure of Compound 1 in RA subjects than in healthy subjects.

[01680] Methotrexate remains the first-line therapy for treating RA and is often used with biologic DMARDs or in combination with other csDMARDs (see Ma, et al., Rheumatology (Oxford), 2010, Vol. 49(1) , pp. 918; Singh, et al., Arthritis Care Res. (Hoboken), 2012, Vol. 64(5), pp. 625-39; (3), pp. 492-509). As such, at least in a subset of RA patients, Compound 1 is expected to be added to the first-line therapy, methotrexate; therefore, it was important to confirm the lack of any potential interaction between Compound 1 and methotrexate. The ratios of AUC and Cm values of Compound 1 when administered with methotrexate to those administered alone indicate lack of significant effect of methotrexate on Compound 1 (Table 54-D; Figure 35A). Similarly, Compound 1 had no significant effect on methotrexate exposures (Table 54-E; Figure 35B). This was consistent with the safety and tolerability profiles observed in these two populations.

[01681] In summary, Compound 1 exhibited favorable safety and tolerability profiles in single doses up to 48 mg and multiple doses up to 24 mg twice daily for 14 days in healthy subjects and for 27 days in subjects with RA. Compound 1 demonstrated a pharmacokinetic profile suitable for twice daily dosing with the immediate-release formulation. There was no pharmacokinetic interaction between methotrexate and Compound 1 and there was no accumulation of Compound 1 with repeated administration. Example 55: Treatment of Moderately to Severely Active Rheumatoid Arthritis in Patients Who Have Responded Inadequately to or Are Intolerant to Anti-TNF Therapy

[01682] The following example briefly describes the results of a placebo-controlled, parallel-group, double-blind, randomized, twelve-week, Phase 2b study in which adult subjects with moderately to severely active rheumatoid arthritis (RA) who responded inadequately to or are intolerant to anti-tumor necrosis factor (TNF) therapy were treated with Compound 1.

[01683] The study was conducted in accordance with the guidelines of the International Conference on Harmonization, applicable regulations and the principles of the Declaration of Helsinki. The study protocol was approved by an independent ethics committee or institutional review board. All patients provided informed consent before participating in any study-related procedures.

[01684] Participants

[01685] Adult men and women aged 18 or over diagnosed with RA and who met the American College of Rheumatology (ACR) classification criteria revised in 1987 (Arnett et al, Arthritis Rheum.,) were enrolled in the study. 1988, Vol. 31(3), pp. 315-324) or the 2010 ACR/European League Against Rheumatism (EULAR) criteria (Smolen et al, Ann. Rheum. Dis., 2010, Vol. 69(6) ), pp. 964-975). Active RA was defined as subjects having >6 swollen joints (based on a count of 66 joints); >6 tender joints (based on 68 joint count); and high-sensitivity C-reactive protein (hsCRP) > the upper limit of normal (ULN = 5 mg/L), or seropositivity for rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP). Eligible subjects had to have been treated with >1 anti-TNF biologic for >3 months but continued to experience active AR, or discontinued anti-TNF biologic therapy because of intolerance or toxicity. Additionally, subjects with previous exposure to non-anti-TNF biological therapy were allowed to enroll, as long as they had failed >1 anti-TNF biological therapy. All biological therapies had to be eliminated from the body prior to randomization: >4 weeks for etanercept, >8 weeks for adalimumab, infliximab, Certolizumab, and golimumab, >8 weeks for abatacept, >12 weeks for tocilizumab, and >1 year for rituximab. A stable dose of methotrexate (7.5-25 mg/week) was required throughout the study. Key exclusion criteria were prior exposure to a JAK inhibitor, or a need for any immunosuppressant other than methotrexate. Subjects with serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 1.5 x ULN or absolute neutrophil count (ANC) < 1,200/μL or absolute lymphocyte count < 750/μL at screening were excluded.

[01686] Study Design and Treatment

[01687] The study was a placebo-controlled, parallel-group, double-blind, randomized, twelve-week, Phase 2b study conducted at 123 sites, enrolling patients in the United States of America (176 patients, 64%) and Porto. Rich (11 patients, 4%); Australia and New Zealand (6 patients, 2%); Western Europe including Belgium, Spain and Great Britain (29 patients, 11%); Eastern Europe including Czech Republic, Hungary, Poland (54 patients, 20%) .

[01688] Subjects were equally randomized to receive immediate-release oral doses of Compound 1 (immediate-release capsules comprising Tartrate Hydrate) at 3 mg BID, 6 mg BID, 12 mg BID, or 18 mg BID, or matching placebo BID, for 12 weeks. Randomization was carried out centrally, according to a block randomization schedule, by investigators making enrollments via an interactive voice response system. Subjects, caregivers, investigators, joint evaluators, and study staff were blinded to which treatment was being administered. The placebo and Compound 1 capsules looked identical. Subjects must have been taking an oral folic acid supplement (or equivalent) since four weeks prior to baseline and throughout the study. Subjects were allowed to continue taking stable doses of methotrexate and nonsteroidal anti-inflammatory drugs (NSAIDS), acetaminophen, or oral corticosteroids (prednisone equivalent < 10 mg).

[01689] Reviews

[01690] The primary efficacy endpoint was the proportion of subjects achieving an ACR20 response at Week 12. Secondary endpoints included the proportions of subjects achieving an ACR50/ACR70 response and the proportion of subjects achieving a disease activity score of 28 joint counts based on C-reactive protein (DAS28(CRP)) <3.2, or <2.6, at Week 12. Among the other endpoints were the proportion of subjects achieving low disease activity ( LDA) or clinical remission (CR) based on Clinical Disease Activity Index (CDAI) criteria (LDA, CDAI <10; CR, £2.8); change in DAS28(CRP), and change in the Health Assessment Questionnaire (HAQ-DI) disability index (Anderson et al, Arthritis Care Res. (Hoboken), 2012, Vol. 64(5), pages 640- 647), including the proportion of subjects achieving a minimum clinically important difference (MCID) of -0.22 (Strand et al, Rheumatology (Oxford), 2006, Vol. 45(12), pp. 1505-1513). An a posteriori analysis was performed to determine the proportion of subjects who had a sustained ACR20 response, defined as meeting ACR20 criteria at each visit (at Weeks 2, 4, 6, 8, and 12).

[01691] Safety was assessed at each scheduled visit during treatment and for 30 days after the last dose of study drug based on AEs, serious AEs, vital signs, and laboratory tests (hematology, blood chemistry analysis and urine analysis). Adverse events were coded according to the Medical Dictionary for Regulatory Activities (MedDRA, version 17.1). Descriptions of AE severity and post-baseline laboratory changes were based on the Rheumatology Common Toxicity v.2.0 criteria developed by the OMERACT Drug Safety Working Group (Woodworth et al., 2007, J. Rheumatol., Vol. 34( 6), pages 140114).

[01692]Statistical Methods

[01693] All efficacy analyzes were conducted in a modified intention-to-treat population that consisted of all randomized patients who received >1 dose of study drug. For ACR response rates, last observation carried forward (LOCF) was the primary method of imputation for missing data, and non-responder imputation (NRI) was also used to assess the robustness of results. For continuous endpoints including DAS28 (CRP), LOCF missing data imputation was implemented; NRI is reported for binary endpoints. Binary scores including ACR response rates were analyzed using chi-square test with normal approximation when comparing each Compound 1 treatment group to the placebo group. Continuous end points were analyzed using an Analysis of Covariance (ANCOVA) model with treatment group as a factor and baseline measurement as the covariate. The Multiple Comparison and Modeling Procedure (MCPMod) method was implemented to detect any non-flat dose-response relationships by evaluating multiple non-linear dose-response models at the same time. P values were not corrected for multiple comparisons.

[01694] Assuming ACR20 response rates of 25% in the placebo group and 55% in either Compound 1 group, a sample size of 50 subjects per group (250 patients total) was estimated to provide at least 80% power to detect a 30% difference in response rates between the placebo group and a Compound 1 group when using a one-tailed test with an alpha level of 0.05.

[01695] Results

[01696] Subject disposition and baseline characteristics

[01697] A total of 276 subjects were randomized; everyone received their intended treatment. The overall study completion rate was 88% (Figure 39). Subject baseline characteristics and disease activity were generally similar between treatment groups (see Table 55-A). The average duration since RA diagnosis was 12 years. Seventy-two percent of subjects had prior exposure to only one anti-TNF, 28% to >2 anti-TNF, and 20% of subjects had also been exposed to non-anti-TNF biological agents. At baseline, subjects had mean swollen and tender joint counts of 18 (from 66 joints) and 28 (from 68 joints), respectively; 60% of subjects had an elevated hsCRP and the mean DAS28(CRP) was 5.8. Table 55-A: Characteristics and Disease Activity of Patients at Baseline Abbreviations: BID – twice a day; CDAI – Clinical Disease Activity Index; DAS28(CRP) – Disease Activity Score-28 joints using C-reactive protein; HAQ-DI – Health Assessment Questionnaire disability index; hsCRP – high sensitivity C-reactive protein; RA – rheumatoid arthritis; SJC66 – swollen joint count using 66 joints; TJC68 – sensitive joint count using 68 joints; TNF – tumor necrosis factor; ULN – upper limit of normal. *Non-TNF biological agents.†ULN = 5 mg/L.‡Subjects with normal hsCRP could be enrolled as long as they were positive for rheumatoid factor and anti-cyclic citrullinated peptide. Modified intention-to-treat population. Percentages were calculated using non-missing values. Effectiveness

[01698] The LOCF-based primary analysis revealed that an ACR20 response of 55.6% (P=0.033), 63.5% (P=0.004), 72.7% (P<0.001), and 70. 9% (P<0.001) in subjects treated with Compound 1 at 3, 6, 12 and 18 mg BID, respectively, compared to 35.2% in subjects receiving placebo. NRI-based analysis also demonstrated a statistically significant improvement in the ACR20 response rate in subjects receiving any dose of Compound 1 compared to those receiving placebo (Figure 36A). A significant dose-response relationship was observed for all doses of Compound 1 (P < 0.01). ACR20 response rates (NRI) at Week 12 were similar between patients who had received 1 versus >2 prior anti-TNFs (Figure 36B). ACR50 and ACR70 response rates were significantly higher at Compound 1 doses of >6 mg BID versus placebo (Figure 36A).

[01699] Significant differences in ACR20 response rates (NRI) were observed at the first post-baseline assessment (Week 2) in subjects with Compound 1 at 12 mg BID and 18 mg BID versus placebo (P<0.007; Figure 37A) ; the maximum response rate (71%) was observed with the 12 mg BID dose at Week 8 and stabilized thereafter. Starting at Week 4, there were significantly higher ACR50 response rates with Compound 1 doses >6 mg BID versus placebo; the maximum response rate (42%) was observed at the 18 mg BID dose at week 8 and stabilized thereafter (Figure 37B). Improvements in ACR70 response rates better than placebo were observed from Week 6, with peak response of up to 25% at Week 12 (Figure 37C). A sustained ACR20 response (at each visit between Weeks 2 to 12, NRI) of 13%, 22%, 40% and 27% was achieved in subjects in the 3 mg, 6 mg, 12 mg and 18 mg Compound BID groups 1, respectively, versus 4% in the placebo group. There were significant improvements in DAS28(CRP) (LOCF) at the Week 2 assessment with Compound 1 at >6 mg BID versus placebo (P<0.001; Figure 37D).

[01700] A greater percentage of subjects receiving Compound 1 (any dose) achieved DAS28(CRP) <3.2 or <2.6, versus placebo at Week 12 (NRI, Figure 37E and 37F with the difference being statistically significant for the Compound 1 group at 12 mg BID (DAS28(CRP) <3.2, 49%; DAS28(CRP) <2.6, 33%, P<0.01) compared to placebo (25% and 13 %, respectively). Similarly, a greater percentage of patients treated with any dose of Compound 1 achieved CDAI LDA or CR criteria versus placebo at Week 12 (NRI, Figure 37F, Compound 1 treatment at 12 mg BID). also resulted in statistically significant mean changes from baseline in individual components of the ACR score compared to placebo (Table 55-B). Additionally, a significantly greater proportion of patients achieved the MCID for HAQ-DI with Compound 1 >. 6 mg BID (58%-64%) compared to placebo (44%). Table 55-B: Mean Changes from Baseline in ACR Components at Week 12 Data are averages (95% CI) unless otherwise noted. Abbreviations: ACR - American College of Rheumatology; BID - twice a day; HAQ-DI - Disability Index - Health Assessment Questionnaire; hsCRP - high sensitivity C-reactive protein; LOCF - last observation carried forward; MCID - minimum clinically important difference; PhGA - physician's global assessment of disease activity; PtGA - patient's global assessment of disease activity; RA - rheumatoid arthritis; SJC66 - swollen joint count using 66 joints; TJC68 - sensitive joint count using 68 joints. *P<0.05;**P<0.01;***P<0.001 compared to placebo. |1 patient with missing data. f2 patients with missing data. §MCID = -0.22. Modified Intent to Treat (LOCF) population.

[01701] Security

[01702] The percentage of subjects with any treatment-emergent AEs was numerically higher in a dose-dependent manner for the 6, 12, and 18 mg BID Compound 1 treatment groups compared to placebo (Table 55-C) . The majority of reported AEs were considered mild to moderate in severity. The most commonly observed AEs were headache, nausea, upper respiratory tract infection, and urinary tract infection. The incidences of serious AEs and severe AEs were low, without an apparent dose-response relationship (Table 55-C). Five subjects in the Compound 1 dose groups reported seven serious AEs (3 mg BID; one subject each with pancreatitis and pulmonary embolism, 6 mg BID; one subject each with pulmonary embolism and deep vein thrombosis; one subject each with TIA and benign hyperplasia prostate, dose 18 mg BID; one subject with acute respiratory failure). One subject on placebo experienced a serious AE of bronchiectasis. Overall infection rates were similar for the 3 and 6 mg BID dose groups of Compound 1 and placebo (20%, 22%, and 23%, respectively), but were higher in the 12 and 18 mg BID dose groups. of Compound 1 (40% and 38%). No serious infections were reported in any of the Compound 1 treatment groups. Herpes zoster occurred in two subjects in the placebo group (4%) and in three subjects receiving Compound 1 (1%, one case each in groups 3, 12 and 18 mg BID; were all isolated to a single dermatome). The two reported events of liver disorders in the 18 mg BID dose group and one event in the placebo group were attributed to increased transaminases; none were serious. There was one case declared to be a transient ischemic attack (left ventricular hypertrophy, classified as mild) in a subject in the Compound 1 6 mg BID group. One patient in the 6 mg BID group had an event of basal cell carcinoma and scaly. There were no opportunistic infections or deaths during the study period.

[01703] Dose-dependent increases in low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were observed; however, LDL-C/HDL-C ratios remained the same through Week 12. Of subjects with normal AST or ALT at baseline, 6 to 18% of patients on Compound 1 had elevated AST at least twice. and 4 to 11% had elevated ALT at least twice, versus 2% and 6% on placebo, respectively. The number of these subjects was greater in groups with a higher dose. Most elevations were Grade 1 (for AST and ALT, >1.2-<1.6 x ULN) and Grade 2 (1.6-3.0 x ULN). One subject each (2%) in the Compound 1 3 mg BID group and placebo group (2%) had a Grade 3 ALT elevation (3.0-8.0 x ULN). Of subjects with normal creatinine at baseline, 4 to 14% of subjects in Compound 1 had creatinine elevated at least twice versus none in the placebo group. One subject in the 18 mg BID group had a Grade 3 elevation (>1.9-<3.0 xULN). The elevations did not result in discontinuation of any subject from the study.

[01704] Reductions from baseline in mean hemoglobin levels were observed in a dose-dependent manner with Compound 1 despite mean hemoglobin levels continuing in the normal range in all dose groups during the study (Figure 38A). Twenty-six of 219 subjects (11.9%) in the Compound 1 groups had a Grade 2 reduction in hemoglobin (from 15 to 20 g/L); 14/219 subjects (6.4%) had a Grade 3 reduction (from 21 to 29 g/L); 8/219 subjects (3.7%) had a Grade 4 reduction (>30 g/L). The majority (79%) of these reductions were transient (only one occurrence) and one subject discontinued the study due to reported AE of low hemoglobin. However, in subjects with underlying systemic inflammation, as measured by elevated baseline hsCRP, treatment with Compound 1 at 3 or 6 mg BID resulted in mean increases from baseline in hemoglobin levels compared to placebo. (Figure 38B).

[01705] Reductions in mean circulating leukocytes, neutrophils (Table 55-D) and natural killer (NK) cells were also observed and one subject discontinued the study drug due to leukopenia. Only NK cell reductions appeared to be dose related. The mean percentage change in NK cells was +16.5±46.6 in the placebo group; A dose-dependent reduction was seen in subjects treated with Compound 1 (-15.8±25.3 in the 3 mg BID group, -18.3±47.4 in the 6 mg BID group, -28.0±37 .3 in the 12 mg BID group, and -42.6±31.7 in the 18 mg BID group). At all doses of Compound 1 there was a transient mean increase in total lymphocytes, which returned to baseline at Week 12, except in the 18 mg dose group. There were two subjects in the 18 mg dose group with Grade 4 lymphocyte reduction; one subject reported having a vaginal and urinary tract infection and the other herpes zoster. One subject had a Grade 4 neutrophil reduction that was not associated with a serious infection. Table 55-C: Summary of Adverse Events Abbreviations: AE - adverse event; BID - twice a day. * AEs as reported by the investigator. fThe cardiovascular event was declared to be a transient ischemic attack. * A patient with basal cell carcinoma and squamous cell carcinoma. Safety population Table 55-D: Mean Change Over Time in Selected Hematological Parameters and Incidence of Patients with Anomalies BID - twice a day. * 1 subject with missing data. Security population. Assignment of grades based on the OMERACT Rheumatology Common Toxicity Criteria v.2.0

[01706] Discussion

[01707] In this study, a wide dose range of Compound 1 (dosed up to 18 mg BID) was studied to evaluate efficacy and safety in subjects with an inadequate response or intolerance to anti-TNF biological therapies. At all doses, Compound 1 demonstrated rapid and robust efficacy as shown by significant improvements in clinical and functional outcomes compared to placebo. The onset of improvement with Compound 1 treatment was rapid with up to 58% of subjects achieving an ACR20 response as early as 2 weeks after treatment. The proportion of ACR20 responders reached a maximum at 8 weeks and stabilized at 71% through Week 12. Improvements in ACR50 (up to 42%) and ACR70 (up to 25%) response rates in the Compound 1 groups also reached a maximum before of Week 12. The rapidity of response contrasts with the 3 to 6 months seen for many biologic therapies (Bathon, et al., The New England Journal of Medicine, 2000, Vol. 343(22), pp. 1586-93; Keystone , et al., Arthritis and Rheumatism, 2008, Vol. 58(11), pp. 3319-29; It is comparable to those observed for other JAK inhibitors, baracitinib and tofacitinib in TNF-IR patients. (Burmester, et al., Lancet (London, England), 2013, Vol. 381(9865), pp. 451-60; Genovese, et al., European League Against Rheumatism, 2015; 2015). Furthermore, the ACR20 response rate was comparable between subjects with two or more prior anti-TNF therapies and those with only one prior anti-TNF therapy. In general, maximum efficacy was observed at a dose of 12 mg BID.

[01708] Despite producing significant clinical improvement in different spectrums of RA patients, there are safety concerns with JAK inhibitors, predominantly related to impairing the body's ability to fight infections, viral reactivation, as well as altering hematopoietic homeostasis that may be linked to anemia. The most commonly reported adverse events with JAK inhibitors are infections, herpes zoster, pulmonary tuberculosis, cryptococcal pneumonia (Fleisch-mann, et al., Arthritis Rheumatol., 2015, Vol. 67(2), pp. 334-43; Genovese, et al., Arthritis Rheumatol., 2016, Vol. 68(1), pp. 46-55). Furthermore, increases in total cholesterol, elevation of transaminase and serum creatinine, reductions in neutrophil counts and anemia are also observed (Burmester, et al., Lancet (London, England), 2013, Vol. 381(9865 ), pp. 451-60; Genovese, et al., Arthritis Rheumatol., 2016, Vol. 68(1), pp. 46-55; 74(2), pp. 333-40).

[01709] In the current study, a wide range of doses of Compound 1 was tested to evaluate the selectivity of Compound 1 in vivo. Overall, Compound 1 demonstrated an acceptable safety and tolerability profile at all doses in this refractory RA population. There were no serious infections, although the proportion of overall infection rates was higher at the two highest doses of Compound 1 (12 mg and 18 mg BID). The most common infections observed with Compound 1 were bronchitis, upper respiratory tract and urinary tract infections. The incidence of herpes zoster was similar in the placebo group (two subjects, 4%) and the Compound 1 treatment groups (three subjects, 1%), and were all non-disseminated.

[01710] At doses of 12 mg BID and 18 mg BID, there was a modest reduction in mean hemoglobin levels by Week 12, although mean hemoglobin levels continued to be within the normal range. Notably, in subjects with elevated hsCRP at baseline who were receiving 3 or 6 mg BID of Compound 1, hemoglobin levels increased compared to placebo treatment, possibly due to a reduction in systemic inflammation at the same time. which minimized the inhibitory effects on JAK2.

[01711] Circulating NK cells, which function as the critical mediator of host immunity against malignancies and infections, were measured as a pharmacodynamic readout of IL-15 inhibition. With higher doses of Compound 1, there was a greater reduction in circulating NK cell counts. At the maximally effective dose, 12 mg BID, NK cells decreased by 28% from baseline, with proportionally smaller decreases in NK cells observed at lower doses. Given the fact that IL-15 signaling involves a heterodimer of JAK1 and JAK3, this was expected at higher doses of Compound 1. It is unclear how much each of the heterodimeric components (JAK1 and JAK3) contributes to IL-15 signaling. 15 overall. However, it is possible that at higher exposure of Compound 1, the threshold for in vivo selectivity for Jak1 compared to JAK3 is lowered in the context of the JAK1/JAK3 heterodimer. Of note, for tofacitinib at 5 mg BID, the reported median reduction in NK cells at week 24 was ~35%, with greater reduction at doses of 10 mg BID or greater of ofacitinib (van Vollenhoven, et al., Annals of the Rheumatic Diseases, 2015, pp. 258-9; Addendum to Primary Clinical Review, NDA 203,214, Center for Drug Evaluation and Research). However, it is important to note that the significance of NK cell reduction is lacking, especially what is considered clinically significant reduction in NK cells in terms of predicting clinical events (i.e., onset of viral reactivation). A significant association was observed with changes in NK cell nadir and infection rates treated with tofacitinib treatment (van Vollenhoven, et al., Annals of the Rheumatic Diseases, 2015, pp. 258-9). In the present study, no association between reduced NK cells and clinical events was observed.

[01712] As reported with other JAK inhibitors, with Compound 1 a dose-dependent elevation of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol levels was observed; however, the LDL-C/HDL-C ratio remained unchanged. For the other laboratory parameters of interest, i.e., serum transaminases, WBC, neutrophils, or lymphocytes, the mean changes were irrelevant and showed no apparent relationship to dose, with only one subject discontinuing the study early due to leukopenia.

[01713] In summary, the results of the present study demonstrated the safety and efficacy of a selective JAK1 inhibitor, Compound 1, in a difficult-to-treat population of RA patients who had an inadequate response or intolerance to anti-TNF biologic therapies. .

Example 56: Treatment of Moderately to Severely Active Rheumatoid Arthritis in Patients Who Responded Inadequately to Methotrexate

[01714] The following example briefly describes the results of a placebo-controlled, parallel-group, double-blind, randomized, twelve-week, Phase 2b study in which adult subjects with moderately to severely active rheumatoid arthritis (RA) who responded inadequately to stable methotrexate therapy were treated with Compound 1.

[01715] Patients

[01716] Men and women >18 years of age with active RA and inadequate response to methotrexate were included in the study. The diagnosis of RA was based on the American College of Rheumatology (ACR) classification criteria revised in 1987 (Arnett et al, Arthritis Rheum., 1988, Vol. 31(3), pages 315-324) or the ACR/ European League Against Rheumatism (EULAR) 2010 (Smolen et al, Ann. Rheum. Dis., 2010, Vol. 69(6), pp. 964-975). Active RA was defined by minimal disease criteria of >6 swollen joints (based on counts of 66 joints) at screening and baseline; >6 tender joints (based on 68 joint counts) at screening and baseline; and high-sensitivity C-reactive protein (hsCRP) greater than the upper limit of normal (ULN) or positive test results for rheumatoid factor and anti-cyclic citrullinated peptide (CCP) at screening. Eligible patients had received methotrexate for >3 months on a stable prescription (7.5-25 mg/week) for >4 weeks prior to baseline. Stable doses of methotrexate were continued throughout the study. In addition, all patients were asked to take a dietary supplement of oral folic acid (or equivalent) from 4 weeks before baseline and throughout study participation. All other oral disease-modifying antirheumatic drugs (DMARDs) were discontinued before baseline for >5 times the mean terminal elimination half-life of the specific DMARD to ensure elimination from the organism (washout). >4 weeks prior to baseline high potency opioids (e.g., oxycodone, methadone, morphine) were discontinued. All patients had a negative tuberculosis screening evaluation or, if there was evidence of a latent tuberculosis infection, completed >2 weeks of tuberculosis prophylaxis or had documented completion of a complete tuberculosis prophylaxis prior to the line of base. Patients were permitted to receive nonsteroidal anti-inflammatory drugs, acetaminophen, oral/nasal corticosteroids, and low-potency opioids. Patients were excluded if they had received JAK inhibitor therapy or any other investigational or approved biologic RA therapy.

[01717]Treatment

[01718] Patients were randomized in a 1:1:1:1:1:1 ratio in a double-blind fashion to oral doses of Compound 1 (immediate-release capsules comprising Tartrate Hydrate) at 3 mg BID, 6 mg BID , 12 mg BID, 18 mg BID, or 24 mg QD (two 12 mg tablets administered at the same time), or placebo BID for 12 weeks. Patients were randomized using a voice/web response system according to a block randomization schedule. Investigators, patients, and other study personnel were blinded to treatment assignments throughout the study. To maintain this lack of knowledge, the placebo and active treatments looked identical. Patients were instructed to take their doses (6 capsules in total, divided into 2 batches of 3) at approximately the same time each day.

[01719] Reviews

[01720] The primary efficacy endpoint was a >20% improvement in ACR criteria (ACR20) at week 12. Other endpoints included ACR50 and ACR70 response rates; change in Disease Activity Score of 28 joints using C-reactive protein (DAS28(CRP)); change in the Clinical Disease Activity Index (CDAI); the proportion of patients achieving low disease activity (LDA) or clinical remission based on DAS28(CRP) and CDAI criteria; and change in the Health Assessment Questionnaire Disability Index (HAQ-DI). The minimum clinically important difference (MCID) in HAQ-DI, which is a reduction of >0.22, (Strand et al, 2006), was also assessed.

[01721] Safety was assessed during treatment and for 30 days after the last dose of study drug based on adverse events (AEs), vital signs, physical examinations, and laboratory tests. AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA, version 17.1).

[01722]Statistical analysis

[01723] Per-protocol primary efficacy analysis was conducted in a modified intention-to-treat population, including all randomized patients who took at least 1 dose of study drug, with last observation carried forward (LOCF) imputation; the data were also analyzed with non-responder imputation (NRI). Statistical tests were one-tailed with a significance level of 0.05 for efficacy analyzes and two-tailed with a significance level of 0.05 for all other analyses. A sample size of 270 patients (45 per randomized treatment group) was targeted giving 80% power to establish a true 30% difference in the primary efficacy endpoint (ACR20 response rate at week 12), assuming that the rate of response would be 30% in the placebo group and 60% in at least 1 of the Compound 1 dose groups.

[01724] Results

[01725] Patients

[01726] A total of 300 patients were randomized and 299 received placebo (n=50) or Compound 1 at 3 mg BID (n=50), 6 mg BID (n=50), 12 mg BID (n=50), 18 mg BID (n=50) or 24 mg QD (n=49). Overall, 91% of patients completed the study, with similar discontinuation rates across all treatment groups and no apparent relationship between Compound 1 dose and discontinuation (Figures 40A and 40B). Demographic and clinical characteristics at baseline were balanced between treatment groups (Table 56-A). Patients were from Eastern Europe (61%), Central/South America (18%), United States of America (10%), Western Europe (8%), or other regions (4%). Patients had a minimum disease duration of 6.9 years and 17.7% had used >1 prior non-methotrexate DMARD. Of note, patients with normal hsCRP could be enrolled if they were positive for rheumatoid factor and anti-CCP antibody. Approximately 43% of patients had hsCRP values < ULN at baseline. Table 56-A: Baseline Characteristics and Disease Activity in Patients with Inadequate Response to Methotrexate

[01727] Effectiveness

[01728] The per-protocol primary endpoint, ACR20 at week 12 (LOCF imputation), was met at all doses of Compound 1, with the exception of the lowest dose of 3 mg BID. The proportion of patients with ACR20 was 65% (P=0.153), 73% (P=0.18), 82% (P=0.001), 77% (P=0.008) and 82% (P=0.001) a 3 mg BID, 6 mg BID, 12 mg BID, 18 mg BID, and 24 mg QD, respectively, versus the placebo response rate (50%). ACR20 (NRI) responses were significantly higher with Compound 1 at 6 mg BID (68%), 12 mg BID (80%), and 24 mg QD (76%) versus placebo (46%; Figure 41). More stringent criteria responses, i.e., ACR50 and ACR70, were achieved at week 12 by significantly higher percentages of patients receiving Compound 1 versus placebo at all doses except 12 mg BID for ACR70 response (NRI; Figure 41). ACR20 response rates increased over time with Compound 1 to reach maximum mean values at weeks 6 to 12 (Figure 42A). ACR50 responses were significant from week 4 onwards and stabilized by week 8 (Figure 42B); ACR70 responses also appeared to stabilize by week 8, with some further improvements by week 12 (Figure 42C). At the first assessment (week 2), ACR20 responses with Compound 1 were 30% to 44% and were significantly higher at all doses in patients receiving Compound 1 versus placebo (12%). Mean reductions in DAS28(CRP) improved over time from baseline, going from -2.2 to -2.6 with Compound 1 at week 12, and were significantly lower compared to placebo (-1. 3) at all doses of Compound 1 and at all time points (Figure 42D).

[01729] Higher percentages of patients receiving Compound 1 achieved DAS28(CRP) <3.2 or <2.6 compared to placebo. The DAS28(CRP) minimum threshold value <3.2 was achieved by a significantly higher percentage of patients (41% to 52%) across all doses of Compound 1 compared to placebo (20%); the minimum threshold value <2.6 was achieved by significantly higher proportions (34% to 40%) with Compound 1 compared to placebo (14%) at all doses except 24 mg QD (22%; Figure 43A). Similarly, CDAI <10 was achieved by a significantly higher percentage of patients (40%-46%) compared to placebo (20%) with Compound 1 at all doses except 24 mg QD (35%; Figure 43B).

[01730] Improvements from baseline in ACR component scores were greater with Compound 1 compared to placebo, reaching statistical significance for most doses of 6 mg BID and higher (Table 56-B). Changes from baseline in HAQ-DI at week 12 with Compound 1 ranged from -0.6 to -0.8 and were significantly greater than those seen with placebo (-0.4) for all but the dose of Compound 1 24 mg QD (-0.6). Numerically, more patients in the Compound 1 >6 mg BID dose groups (69% to 88%) achieved the MCID at week 12 compared to placebo (67%); The study was not powered for this analysis and comparisons versus placebo were mostly not statistically significant. Table 56-B: Mean Changes from Baseline in ACR Components at Week 12 Abbreviations: ACR - American College of Rheumatology; BID - twice a day; HAQ-DI - Health Assessment Questionnaire Disability Index; hsCRP - high sensitivity C-reactive protein; LOCF - last observation carried forward; MCID - minimum clinically important difference; QD - once a day; RA - rheumatoid arthritis; SJC66 - count of swollen joints using 66 joints; TJC68 - sensitive joint count using 68 joints. *P<0.05;**P<0.01;***P<0.001 compared to placebo. §MCID = -0.22. Modified intent-to-treat population with LOCF imputation of missing values. 95% CIs were calculated based on a normal approximation to the binomial distribution.

[01731] As can be seen from the results, Compound 1 had an early onset of action in subjects who had demonstrated a prior inadequate response to methotrexate. In particular, ACR20 response rates improved from week 2, with a maximum effect reached as early as week 6, with continued improvement in some dose groups until week 12. ACR50 response rates (maximum efficacy up to 50%) and ACR70 (maximum efficacy up to 28%) were also rapidly stabilized by week 8. Compound 1 showed dose-dependent efficacy that appeared to reach a maximum at 12 mg BID.

[01732]Security

[01733] The safety and tolerability profile of Compound 1 at various doses was acceptable (Table 56-C). The incidence of any AE was statistically significantly higher with Compound 1 overall versus placebo (45% vs 26%; P=0.012), with a trend towards dose dependence. Among common AEs, those occurring in >3% of patients in any group were abdominal pain, upper abdominal pain, back pain, elevated blood creatine phosphokinase, cough, diarrhea, dyslipidemia, dyspepsia, gastroenteritis, chest pain, headache, shingles, flu, leukopenia, nasopharyngitis, upper respiratory tract infection, urinary tract infection, low white blood cell count and sores. The majority of AEs in the Compound 1 treatment groups were mild to moderate in severity. Serious AEs occurred in 1 patient each on Compound 1 at 6 mg BID (lung cancer on post-treatment day 10 in a 79-year-old male patient with family and smoking history; patient died 3 months later) , 12 mg BID (pyrexia), 18 mg BID (hyperbilirubinemia), and 24 mg QD (head injury). There were 2 serious AEs with Compound 1 that were considered possibly related to the study drug: community-acquired pneumonia at 12 mg BID and syncope at 24 mg QD. In general, infections occurred in 20% of patients who received Compound 1 and in 14% who received placebo, with no tendency for higher rates at higher doses. Three herpes zoster infections, 1 with Compound 1 at 3 mg BID and 2 at 24 mg QD, involving 1 dermatome per patient. One patient in the Compound 1 at 6 mg BID group, aged 79 years and with a history of smoking, was diagnosed with lung cancer 10 days after stopping study treatment and died 3 months later.

[01734] At week 12, mean values for alanine aminotransferase (ALT) were significantly higher with Compound 1 at 18 mg BID than with placebo; mean values for aspartate aminotransferase (AST) were significantly higher than placebo at all doses of Compound 1 >3 mg BID (Table 56-D). However, grade 3/4 ALT or AST abnormalities during the study were sporadic, without clear dose dependence (Table 56-E). Creatinine and creatine phosphokinase levels were significantly higher in all Compound 1 dose groups compared to placebo. Compound 1 was associated with elevations in high-density and low-density lipoprotein cholesterol (HDL-C; LDL-C); HDL-C elevation was statistically significant at 6 mg BID, while LDL-C values were significantly higher than placebo for all doses of Compound 1; however, LDL-C/HDL-C ratios remained the same through week 12. There were no significant increases in lymphocyte or neutrophil levels between placebo and Compound 1 dose groups through week 12. grade 3 with placebo and all doses of Compound 1; Grade 4 values occurred in one patient each with Compound 1 at 3 mg BID and 18 mg BID (Table 56-E). Grade 3 neutrophil values occurred with Compound 1 at 12 mg BID (1 patient), 18 mg BID (3 patients), and 24 mg QD (1 patient). Natural killer (NK) cell percentages were significantly lower with Compound 1 doses >6 mg BID than placebo (Table 56-D).

[01735] The average changes in hemoglobin over time in all patients, patients with hsCRP values <5 mg/mL, and patients with hsCRP values >5 mg/mL are shown in Figures 44A-44C. Mean hemoglobin values remained stable or increased at lower doses, most notably in patients with elevated CRP at baseline. Dose-dependent reductions in hemoglobin were observed at higher doses without clinical impact. Table 56-C: Summary of Adverse Events Abbreviations: AE - adverse event; BID - twice a day; QD - once a day. *The cardiovascular event was a cerebrovascular accident and was declared an ischemic stroke. fHerpes zoster events involved one dermatome per patient. * Lung cancer on day 10 post-treatment in a 79-year-old male patient with a family and smoking history. The patient died 3 months later. Security analysis population. Table 56-D: Average Changes in Laboratory Values at Week 12 Abbreviations: ALT - alanine aminotransferase; AST - aspartate aminotransferase; BID - twice a day; HDL-C - high-density lipoprotein cholesterol; LDL-C - low-density lipoprotein cholesterol; NK - natural killer; QD - once a day. * P<0.05;**P<0.01 compared to placebo; P value for difference between treatment groups at baseline and mean change from baseline using a contrast within one-way analysis of variance. fMean percentage change from baseline to week 12. Safety analysis population. Table 56-E: Incidence of Patients with Laboratory Abnormalities at Week 12 Abbreviations: ALT - alanine aminotransferase; AST - aspartate aminotransferase; BID - twice a day; QD - once a day; ULN - upper limit of normal.

[01736] As can be seen from these results, the safety and tolerability profile of Compound 1 was acceptable at all doses.

[01737] All references (patent and non-patent) cited above are incorporated by reference in this patent application. The discussion of these references is intended merely to summarize the statements made by the authors. No admission is made that any reference (or a portion of any reference) is relevant prior art (or is even prior art). Applicants reserve the right to question the accuracy and relevance of cited references.

Claims (14)

1. Crystalline hemihydrate of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2, 2,2-trifluoroethyl)pyrrolidine-1-carboxamide CHARACTERIZED by the fact that it has: a powder X-ray diffraction pattern defined by peaks at 13.4 ± 0.2, 15.1 ± 0.2 and 21.7 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Kα1 radiation; and at least one additional feature selected from: a thermogravimetric analysis profile showing a weight loss of about 2.3% to about 2.6% between about 120°C and 160°C when heated at a rate of 10 °C/minute, or a weight loss of about 2.3% to about 2.6% between about 114.52°C and 168.15°C when heated at a rate of 10°C/minute; a differential scanning calorimetry profile comprising an endotherm between about 134.70°C and about 167.53°C when heated at a rate of 10°C/minute, or an endotherm between about 120°C and about 170°C when heated at a rate of 10°C/minute; a moisture sorption isotherm profile 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 25°C; and a type of orthorhombic lattice having a space group P212121, a unit cell value a of about 12.7 A, a unit cell value b of about 13.1 A, and a unit cell value c of about of 22.6 A. 2. Crystalline hemihydrate, according to claim 1, CHARACTERIZED by the fact that it has a powder X-ray diffraction pattern defined by peaks at 13.4 ± 0.2, 15.1 ± 0.2, 17 .0 ± 0.2 and 21.7 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Kα1 radiation. 3. Crystalline hemihydrate according to claim 1, CHARACTERIZED by the fact that it has a powder X-ray diffraction pattern defined by peaks at 13.4 ± 0.2, 15.1 ± 0.2, 20 .9 ± 0.2 and 21.7 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Kα1 radiation. 4. Crystalline hemihydrate according to claim 1, CHARACTERIZED by the fact that it has a powder X-ray diffraction pattern defined by peaks at 13.4 ± 0.2, 15.1 ± 0.2, 15 .5 ± 0.2, 17.0 ± 0.2, 20.9 ± 0.2 and 21.7 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Kα1 radiation. 5. Crystalline hemihydrate, according to claim 1, CHARACTERIZED by the fact that it has an X-ray powder diffraction pattern defined by peaks at 7.9 ± 0.2, 10.3 ± 0.2 and 13 .4 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Kα1 radiation. 6. Crystalline hemihydrate, according to claim 5, CHARACTERIZED by the fact that it has a powder X-ray diffraction pattern defined by peaks at 7.9 ± 0.2, 10.3 ± 0.2 and 13 .4 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Kα1 radiation, and further defined by at least one additional peak selected from the group consisting of 15.1 ± 0.2, 15.5 ± 0.2, 17.0 ± 0.2, 17.2 ± 0.2, 18.3 ± 0.2, 19.3 ± 0.2, 20.5 ± 0.2, 20.9 ± 0, 2, 21.7 ± 0.2, 21.9 ± 0.2, and 24.9 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Kα1 radiation. 7. Crystalline hemihydrate according to claim 1, CHARACTERIZED by the fact that it has an X-ray powder diffraction pattern defined by at least one peak at 21.7 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Kα1 radiation. 8. Crystalline hemihydrate according to claim 1, CHARACTERIZED by the fact that it has an X-ray powder diffraction pattern defined by at least one peak at 15.5 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Kα1 radiation. 9. Crystalline hemihydrate according to claim 1, CHARACTERIZED by the fact that it has an X-ray powder diffraction pattern defined by at least one peak at 17.0 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Kα1 radiation. 10. Crystalline hemihydrate according to claim 1, CHARACTERIZED by the fact that it has an X-ray powder diffraction pattern defined by at least one peak at 15.1 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Kα1 radiation. 11. Crystalline hemihydrate according to claim 1, CHARACTERIZED by the fact that it has an X-ray powder diffraction pattern defined by at least one peak at 13.4 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Kα1 radiation. 12. Crystalline hemihydrate according to claim 1, CHARACTERIZED by the fact that it has an X-ray powder diffraction pattern defined by at least one peak at 20.9 ± 0.2 degrees two theta when measured at about of 25 °C with monochromatic Kα1 radiation. 13. Crystalline hemihydrate according to claim 1, CHARACTERIZED by the fact that it has an X-ray powder diffraction pattern defined by at least one peak at 17.2 ± 0.2 degrees two theta when measured at about of 25 °C with monochromatic Kα1 radiation. 14. Crystalline hemihydrate according to claim 1, CHARACTERIZED by the fact that it has an X-ray powder diffraction pattern defined by at least one peak at 7.9 ± 0.2 degrees two theta when measured at about 25 °C with monochromatic Kα1 radiation.