HIBITORS OF APOL1 AND METHOD OF USE OF THEM

Description

[0001] The invention is defined in the appended claims. This disclosure provides compounds that may inhibit apolipoprotein L1 (APOL1) and pharmaceutical compositions and compounds for use in methods of treating focal segmental glomerulosclerosis (FSGS) and / or non-diabetic kidney disease (NDKD). In some embodiments, the FSGS and / or NDKD is associated with at least one of the 2 common APOL1 genetic variants (G1: S342G:I384M and G2: N388del:Y389del). WO 2008 / 092231 A1 discloses compounds which are useful for regulating the expression of apolipoprotein A-I (ApoA-1), and their use for the treatment and prevention of cardiovascular disease and related disease states, including cholesterol- or lipid-related disorders, such as, for example, atherosclerosis. WO 2015 / 048301 A1 discloses compounds that are autotaxin inhibitors, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders associated with autotaxin activity. Ryoko Takasawa et al. (Bioorganic & Medicinal Chemistry Letters, Pergamon, Amsterdam, NL, vol. 21, no. 14, page 4337-4342, 16th May 2011) discloses a new type of compound, which has a unique benzothiazole ring with a carboxyl group, named TLSC702, which was found to inhibit hGLO I more effectively than S-p-bromobenzylglutathione (BBG), a well-known GSH analog inhibitor. WO 03 / 104180 A1 discloses an improved process for the preparation of 4-(4-Fluorobenzoyl)butyric acid, which is prepared on a commercial scale using normal quality fluorobenzene (benzene content 300-700ppm) with the desfluoro analogue impurity at an acceptable level (less than 0.1 % by HPLC). The 4-(4-fluorobenzoyl)butyric acid is a key raw material for the synthesis of anti-hyperlipoproteinemetic drug ezetimibe.

[0002] FSGS is a disease of the podocyte (glomerular visceral epithelial cells) responsible for proteinuria and progressive decline in kidney function. NDKD is a disease characterized by hypertension and progressive decline in kidney function. Human genetics support a causal role for the G1 and G2 APOL1 variants in inducing kidney disease. Individuals with 2 APOL1 risk alleles are at increased risk of developing primary (idiopathic) FSGS, human immunodeficiency virus (HIV)-associated FSGS, and NDKD. Currently, FSGS and NDKD are managed with symptomatic treatment (including blood pressure control using blockers of the renin angiotensin system), and patients with FSGS and heavy proteinuria may be offered high dose steroids. Corticosteroids induce remission in a minority of patients and are associated with numerous side effects. These patients, in particular individuals of recent sub-Saharan African ancestry with 2 APOL1 risk alleles, experience rapid disease progression leading to end-stage renal disease (ESRD). Thus, there is an unmet medical need for treatment for FSGS and NDKD.

[0003] The invention is set out in the appended claims. One aspect of the disclosure provides at least one entity chosen from compounds of Formulae (I), (II), (IIIa), (IIIb), and (IIIc), pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing, which can be employed in the treatment of diseases mediated by APOL1, such as FSGS and NDKD. The invention provides: at least one entity chosen from compounds of Formula (I): wherein: (i) each R 1 is independently chosen from halogen groups, hydroxy, cyano, C 1 -C 4 linear, branched, and cyclic alkyl groups, C 2 -C 4 linear, branched, and cyclic alkenyl groups, C 1 -C 4 linear, branched, and cyclic hydroxyalkyl groups, C 1 -C 4 linear, branched, and cyclic alkoxy groups, C 1 -C 4 linear, branched, and cyclic haloalkyl groups, C 1 -C 4 linear, branched, and cyclic haloalkoxy groups, benzyloxy groups, 3 to 6-membered heterocycloalkenyl groups, 3 to 6-membered heterocycloalkyl groups, and 5 and 6-membered heteroaryl groups; (ii) each R 2 is independently chosen from halogen groups, cyano, C 1 -C 4 linear, branched, and cyclic alkoxy groups, C 1 -C 4 linear, branched, and cyclic haloalkoxy groups, C 1 -C 4 linear, branched, and cyclic alkyl groups, and C 1 -C 4 linear, branched, and cyclic haloalkyl groups; (iii) m is chosen from 0 to 4; (iv) n is chosen from 0 to 5; (v) Y is chosen from divalent C 1 -C 4 linear and branched alkyl groups and divalent C 1 -C 4 linear and branched thioalkyl groups, wherein the divalent alkyl groups and divalent thioalkyl groups are optionally substituted with at least one group chosen from C 1 -C 4 alkyl groups, halogen groups, and hydroxy; (vi) each of R 3 and R 4 is independently chosen from hydrogen, C 1 -C 3 linear, branched, and cyclic alkyl groups, C 1 -C 3 linear, branched, and cyclic hydroxyalkyl groups, and C 1 -C 3 linear, branched, and cyclic haloalkyl groups, or R 3 and R 4 , together with the carbon atom to which they are attached, form a C 3 -C 6 cycloalkyl group or carbonyl group; (vii) each of R 5 and R 6 is independently chosen from hydrogen, hydroxy, C 1 -C 4 linear, branched, and cyclic alkyl groups, C 1 -C 4 linear, branched, and cyclic haloalkyl groups, and -OC(O)C 1 -C 4 linear, branched, and cyclic alkyl groups; and (viii) each of R 7 , R 8 , and R 9 is independently chosen from hydrogen, C 1 -C 4 linear, branched, and cyclic alkyl groups, and C 1 -C 4 linear, branched, and cyclic haloalkyl groups.

[0004] In one aspect of the disclosure, the compounds of Formula I are chosen from Compounds 1 to 135 such that the at least one entity is chosen from Compounds 1 to 135, pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing.

[0005] In some embodiments, the disclosure provides pharmaceutical compositions comprising at least one entity chosen from compounds of Formulae (I), (II), (IIIa), (IIIb), and (IIIc), pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing. In some embodiments, the pharmaceutical compositions may comprise at least one compound chosen from Compounds 1 to 135, pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing. These compositions may further include at least one additional active pharmaceutical ingredient and / or at least one carrier.

[0006] Another aspect of the disclosure provides pharmaceutical compositions and compounds for use in methods of treating FSGS and / or NDKD, the methods comprising administering to a subject in need thereof, at least one entity chosen from compounds of Formulae (I), (II), (IIIa), (IIIb), and (IIIc), pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing or a pharmaceutical composition comprising the at least one entity. In some embodiments, the pharmaceutical compositions and compounds are for use in methods of treatment, wherein the methods comprise administering at least one entity chosen from Compounds 1 to 135, pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing.

[0007] In some embodiments, the pharmaceutical compositions and compounds are for use in methods of treatment, wherein the methods of treatment include administration of at least one additional active agent to the subject in need thereof, either in the same pharmaceutical composition as the at least one entity chosen from compounds of Formulae (I), (II), (IIIa), (IIIb), and (IIIc), pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing, or as separate compositions. In some embodiments, the pharmaceutical compositions and compounds are for use in methods of treatment, wherein the methods comprise administering at least one entity chosen from Compounds 1 to 135, pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing with at least one additional active agent either in the same pharmaceutical composition or in a separate composition.

[0008] Also provided are pharmaceutical compositions and compounds for use in methods of inhibiting APOL1, the methods comprising administering to a subject in need thereof, at least one entity chosen from compounds of Formulae (I), (II), (IIIa), (IIIb), and (IIIc), pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing or a pharmaceutical composition comprising the at least one entity. In some embodiments, the pharmaceutical compositions and compounds are for use in methods of inhibiting APOL1, wherein the methods of inhibiting APOL1 comprise administering at least one entity chosen from Compounds 1 to 135, pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing or a pharmaceutical composition comprising the at least one entity.Brief Description of the Drawings

[0009] FIG. 1 depicts an XRPD diffractogram of Form A of Compound 2. FIG. 2 depicts a solid state 13< C NMR spectrum for Form A of Compound 2. FIG. 3 depicts a 19< F MAS (magnetic angle spinning) spectrum for Form A of Compound 2. FIG. 4 depicts a TGA thermogram of Form A of Compound 2. FIG. 5 depicts a DSC curve of Form A of Compound 2. FIG. 6 depicts an IR spectrum of Form A of Compound 2. FIG. 7 depicts an XRPD diffractogram of Hydrate Form A of Compound 2. FIG. 8 depicts a solid state 13< C NMR spectrum for Hydrate Form A of Compound 2. FIG. 9 depicts a 19< F MAS (magnetic angle spinning) spectrum for Hydrate Form A of Compound 2. FIG. 10 depicts a TGA thermogram of Hydrate Form A of Compound 2. FIG. 11 depicts a DSC curve of Hydrate Form A of Compound 2. FIG. 12 depicts an XRPD spectrum of Hydrate Form B of Compound 2. FIG. 13 depicts a 19< F MAS (magnetic angle spinning) spectrum for a mixture of Hydrate Form A and Hydrate Form B of Compound 2. FIG. 14 depicts an XRPD diffractogram of Hydrate Form C of Compound 2. FIG. 15 depicts a solid state 13< C NMR spectrum for Hydrate Form C of Compound 2. FIG. 16 depicts a 19< F MAS (magnetic angle spinning) spectrum for Hydrate Form C of Compound 2. FIG. 17 depicts a TGA thermogram of Hydrate Form C of Compound 2, FIG. 18 depicts a DSC curve of Hydrate Form C of Compound 2. FIG. 19 depicts an XRPD diffractogram of Hydrate Form D of Compound 2. FIG. 20 depicts a TGA thermogram of Hydrate Form D of Compound 2, FIG. 21 depicts a DSC curve of Hydrate Form D of Compound 2. FIG. 22 depicts an XRPD diffractogram of Hydrate Form E of Compound 2. FIG. 23 depicts a TGA thermogram of Hydrate Form E of Compound 2, FIG. 24 depicts a DSC curve of Hydrate Form E of Compound 2. FIG. 25 depicts an XRPD diffractogram of Hydrate Form F of Compound 2. FIG. 26 depicts a TGA thermogram of Hydrate Form F of Compound 2, FIG. 27 depicts a DSC curve of Hydrate Form F of Compound 2. FIG. 28 depicts an XRPD diffractogram of MTBE solvate of Compound 2. FIG. 29 depicts a TGA thermogram of MTBE solvate of Compound 2, FIG. 30 depicts a DSC curve of MTBE solvate of Compound 2. FIG. 31 depicts an XRPD diffractogram of DMFsolvate of Compound 2. FIG. 32 depicts a TGA thermogram of DMF solvate of Compound 2, FIG. 33 depicts a DSC curve of DMF solvate of Compound 2. FIG. 34 depicts an XRPD diffractogram of amorphous form of Compound 2. FIG. 35 depicts a solid state 13< C NMR spectrum for amorphous form of Compound 2. FIG. 36 depicts a 19< F MAS (magnetic angle spinning) spectrum for amorphous form of Compound 2. FIG. 37 depicts a DSC curve of amorphous form of Compound 2. FIG. 38 depicts an XRPD diffractogram of Form A of Compound 87. FIG. 39 depicts a solid state 13< C NMR spectrum for Form A of Compound 87. FIG. 40 depicts a 19< F MAS (magnetic angle spinning) spectrum for Form A of Compound 87. FIG. 41 depicts a TGA thermogram of Form A of Compound 87. FIG. 42 depicts a DSC curve of Form A of Compound 87. FIG. 43 depicts an XRPD diffractogram of Hydrate Form A of Compound 87. FIG. 44 depicts a solid state 13< C NMR spectrum for Hydrate Form A of Compound 87. FIG. 45 depicts a 19< F MAS (magnetic angle spinning) spectrum for Hydrate Form A of Compound 87. FIG. 46 depicts a TGA thermogram of Hydrate Form A of Compound 87. FIG. 47 depicts a DSC curve of Hydrate Form A of Compound 87. FIG. 48 depicts an XRPD diffractogram of wet sample of IPAc Solvate of Compound 87. FIG. 49 depicts an XRPD diffractogram of vacuum dried sample of IPAc Solvate of Compound 87. FIG. 50 depicts a solid state 13< C NMR spectrum for IPAc Solvate of Compound 87. FIG. 51 depicts a 19< F MAS (magnetic angle spinning) spectrum for IPAc Solvate of Compound 87. FIG. 52 depicts a TGA thermogram of shortly vacuum dried sample of IPAc Solvate of Compound 87. FIG. 53 depicts a TGA thermogram of vacuum dried sample of IPAc Solvate of Compound 87. FIG. 54 depicts a DSC curve of shortly vacuum dried sample of IPAc Solvate of Compound 87. FIG. 55 depicts a DSC curve of vacuum dried sample of IPAc Solvate of Compound 87. FIG. 56 depicts an XRPD diffractogram of amorphous form of Compound 87. FIG. 57 depicts a solid state 13< C NMR spectrum for amorphous form of Compound 87. FIG. 58 depicts a 19< F MAS (magnetic angle spinning) spectrum for amorphous form of Compound 87. FIG. 59 depicts a plate map used in Example 3. Definitions

[0010] The term "APOL1" as used herein means apolipoprotein L1 protein and the term "APOL1" means apolipoprotein L1 gene.

[0011] The term "FSGS" as used herein means focal segmental glomerulosclerosis, which is a disease of the podocyte (glomerular visceral epithelial cells) responsible for proteinuria and progressive decline in kidney function, and associated with 2 common APOL1 genetic variants (G1: S342G:I384M and G2: N388del:Y389del).

[0012] The term "NDKD" as used herein means non-diabetic kidney disease, which is characterized by severe hypertension and progressive decline in kidney function, and associated with 2 common APOL1 genetic variants (G1: S342G:I384M and G2: N388del:Y389del).

[0013] The term "compound," when referring to a compound of this disclosure, refers to a collection of molecules having an identical chemical structure unless otherwise indicated as a collection of stereoisomers (for example, a collection of racemates, a collection of cis / trans stereoisomers, or a collection of (E) and (Z) stereoisomers), except that there may be isotopic variation among the constituent atoms of the molecules. Thus, it will be clear to those of skill in the art that a compound represented by a particular chemical structure containing indicated deuterium atoms, will also contain lesser amounts of isotopologues having hydrogen atoms at one or more of the designated deuterium positions in that structure. The relative amount of such isotopologues in a compound of this disclosure will depend upon a number of factors including the isotopic purity of reagents used to make the compound and the efficiency of incorporation of isotopes in the various synthesis steps used to prepare the compound. However, as set forth above the relative amount of such isotopologues in toto will be less than 49.9% of the compound. In other embodiments, the relative amount of such isotopologues in toto will be less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, less than 3%, less than 1%, or less than 0.5% of the compound.

[0014] As used herein, "optionally substituted" is interchangeable with the phrase "substituted or unsubstituted." In general, the term "substituted", whether preceded by the term "optionally" or not, refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. Unless otherwise indicated, an "optionally substituted" group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent chosen from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this disclosure are those that result in the formation of stable or chemically feasible compounds.

[0015] The term "isotopologue" refers to a species in which the chemical structure differs from only in the isotopic composition thereof. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13< C or 14< C are within the scope of this disclosure.

[0016] Unless otherwise indicated, structures depicted herein are also meant to include all isomeric forms of the structure, e.g., racemic mixtures, cis / trans isomers, geometric (or conformational) isomers, such as (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, geometric and conformational mixtures of the present compounds are within the scope of the disclosure. Unless otherwise stated, all tautomeric forms of the compounds of the disclosure are within the scope of the disclosure.

[0017] The term "tautomer," as used herein, refers to one of two or more isomers of compound that exist together in equilibrium, and are readily interchanged by migration of an atom, e.g., a hydrogen atom, or group within the molecule.

[0018] "Stereoisomer" as used herein refers to enantiomers and diastereomers.

[0019] As used herein, "deuterated derivative" refers to a compound having the same chemical structure as a reference compound, but with one or more hydrogen atoms replaced by a deuterium atom ("D" or " 2< H"). It will be recognized that some variation of natural isotopic abundance occurs in a synthesized compound depending on the origin of chemical materials used in the synthesis. The concentration of naturally abundant stable hydrogen isotopes, notwithstanding this variation is small and immaterial as compared to the degree of stable isotopic substitution of deuterated derivatives described herein. Thus, unless otherwise stated, when a reference is made to a "deuterated derivative" of compound of the disclosure, at least one hydrogen is replaced with deuterium at well above its natural isotopic abundance (which is typically about 0.015%). In some embodiments, the deuterated derivatives of the disclosure have an isotopic enrichment factor for each deuterium atom, of at least 3500 (52.5% deuterium incorporation at each designated deuterium) at least 4500, (67.5 % deuterium incorporation), at least 5000 (75% deuterium incorporation) at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation, at least 6466.7 (97% deuterium incorporation, or at least 6600 (99% deuterium incorporation).

[0020] The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope.

[0021] The term "alkyl" or "aliphatic" as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic that has a single point of attachment to the rest of the molecule. Unless otherwise specified, alkyl groups contain 1 to 20 alkyl carbon atoms. In some embodiments, alkyl groups contain 1 to 10 aliphatic carbon atoms. In some embodiments, alkyl groups contain 1 to 8 aliphatic carbon atoms. In some embodiments, alkyl groups contain 1 to 6 alkyl carbon atoms, and in some embodiments, alkyl groups contain 1 to 4 alkyl carbon atoms, and in yet other embodiments alkyl groups contain 1 to 3 alkyl carbon atoms. Nonlimiting examples of alkyl groups include, but are not limited to, linear or branched, and substituted or unsubstituted alkyl. Suitable cycloaliphatic groups include cycloalkyl, bicyclic cycloalkyl (e.g., decalin), bridged bicycloalkyl such as norbornyl or [2.2.2]bicyclo-octyl, or bridged tricyclic such as adamantyl. In some embodiments, alkyl groups are substituted. In some embodiments, alkyl groups are unsubstituted. In some embodiments, alkyl groups are straight-chain. In some embodiments, alkyl groups are branched.

[0022] The terms "cycloalkyl," "carbocycle," "cycloaliphatic," or "cyclic alkyl" refer to a spirocyclic or monocyclic C 3-8 hydrocarbon or a spirocyclic, bicyclic, bridged bicyclic, tricyclic, or bridged tricyclic C 8-14 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, wherein any individual ring in said bicyclic ring system has 3 to 7 members. In some embodiments, cyclogroups are substituted. In some embodiments, cyclogroups are unsubstituted.

[0023] The term "heteroalkyl," or "heteroaliphatic" as used herein, means aliphatic groups wherein one or two carbon atoms are independently replaced by one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon. Heteroaliphatic groups may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and include "heterocycle", "heterocyclyl", "heterocycloaliphatic", or "heterocyclic" groups.

[0024] The term "alkenyl" as used herein, means a straight-chain (i.e., unbranched), branched, substituted or unsubstituted hydrocarbon chain that contains one or more units of saturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that contains one or more units of unsaturation, but which is not aromatic (referred to herein as, "cyclic alkenyl"). In some embodiments, alkenyl groups are substituted. In some embodiments, alkenyl groups are unsubstituted. In some embodiments, alkenyl groups are straight-chain. In some embodiments, alkenyl groups are branched.

[0025] The term "heterocycle", "heterocyclyl", "heterocycloaliphatic", or "heterocyclic" as used herein means non-aromatic, monocyclic, bicyclic, or tricyclic ring systems in which one or more ring members is an independently chosen heteroatom. In some embodiments, the "heterocycle", "heterocyclyl", "heterocycloaliphatic", or "heterocyclic" group has 3 to 14 ring members in which one or more ring members is a heteroatom independently chosen from oxygen, sulfur, nitrogen, and phosphorus. In some embodiments, each ring in a bicyclic or tricyclic ring system contains 3 to 7 ring members. In some embodiments the heterocycle has at least one unsaturated carbon-carbon bond. In some embodiments, the heterocycle has at least one unsaturated carbon-nitrogen bond. In some embodiments, the heterocycle has one heteroatom independently chosen from oxygen, sulfur, nitrogen, and phosphorus. In some embodiments, the heterocycle has one heteroatom that is a nitrogen atom. In some embodiments, the heterocycle has one heteroatom that is an oxygen atom. In some embodiments, the heterocycle has two heteroatoms that are each independently selected from nitrogen and oxygen. In some embodiments, the heterocycle has three heteroatoms that are each independently selected from nitrogen and oxygen. In some embodiments, heterocycles are substituted. In some embodiments, heterocycles are unsubstituted.

[0026] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR +< (as in N-substituted pyrrolidinyl)).

[0027] The term "unsaturated", as used herein, means that a moiety has one or more units or degrees of unsaturation. Unsaturation is the state in which not all of the available valance bonds in a compound are satisfied by substituents and thus the compound contains double or triple bonds.

[0028] The term "alkoxy", or "thioalkyl", as used herein, refers to an alkyl group, as previously defined, wherein one carbon of the alkyl group is replaced by an oxygen ("alkoxy") or sulfur ("thioalkyl") atom, respectively, provided that the oxygen and sulfur atoms are linked between two carbon atoms. A "cyclic alkoxy" refers to a monocyclic, spirocyclic, bicyclic, bridged bicyclic, tricyclic, or bridged tricyclic hydrocarbon that contains at least one alkoxy group, but is not aromatic. Non-limiting examples of cyclic alkoxy groups include tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, 8-oxabicyclo[3.2.1]octanyl, and oxepanyl. In some embodiments, "alkoxy" and / or "thioalkyl" groups are substituted. In some embodiments, "alkoxy" and / or "thioalkyl" groups are unsubstituted.

[0029] The terms "haloalkyl" and "haloalkoxy," as used herein, means a linear or branched alkyl or alkoxy, as the case may be, which is substituted with one or more halogen atoms. Non-limiting examples of haloalkyl groups include -CHF 2 , -CH 2 F, -CF 3 , -CF 2 -, and perhaloalkyls, such as -CF 2 CF 3 . Non-limiting examples of haloalkoxy groups include -OCHF 2 , -OCH 2 F, -OCF 3 , -OCF 2 -.

[0030] The term "halogen" includes F, Cl, Br, and I, i.e., fluoro, chloro, bromo, and iodo, respectively.

[0031] The term "aminoalkyl" means an alkyl group which is substituted with or contains an amino group.

[0032] As used herein, an "amino" refers to a group which is a primary, secondary, or tertiary amine.

[0033] As used herein, a "carbonyl" group refers to C=O.

[0034] As used herein, a "cyano" or "nitrile" group refer to -C≡N.

[0035] As used herein, a "hydroxy" group refers to -OH.

[0036] As used herein, a "thiol" group refers to -SH.

[0037] As used herein, "tert" and "t-" each refer to tertiary.

[0038] As used herein, "aromatic groups" or "aromatic rings" refer to chemical groups that contain conjugated, planar ring systems with delocalized pi electron orbitals comprised of [4n+2] p orbital electrons, wherein n is an integer ranging from 0 to 6. Nonlimiting examples of aromatic groups include aryl and heteroaryl groups.

[0039] The term "aryl" used alone or as part of a larger moiety as in "arylalkyl", "arylalkoxy", or "aryloxyalkyl", refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in a bicyclic or tricyclic ring system contains 3 to 7 ring members. The term "aryl" also refers to heteroaryl ring systems as defined herein below. Nonlimiting examples of aryl groups include phenyl rings. In some embodiments, aryl groups are substituted. In some embodiments, aryl groups are unsubstituted.

[0040] The term "heteroaryl", used alone or as part of a larger moiety as in "heteroarylalkyl" or "heteroarylalkoxy", refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and wherein each ring in a bicyclic or tricyclic ring system contains 3 to 7 ring members. In some embodiments, heteroaryl groups are substituted. In some embodiments, heteroaryl groups have one or more heteroatoms chosen from nitrogen, oxygen, and sulfur. In some embodiments, heteroaryl groups have one heteroatom. In some embodiments, heteroaryl groups have two heteroatoms. In some embodiments, heteroaryl groups are monocyclic ring systems having five ring members. In some embodiments, heteroaryl groups are monocyclic ring systems having six ring members. In some embodiments, heteroaryl groups are unsubstituted.

[0041] Non-limiting examples of useful protecting groups for nitrogen-containing groups, such as amine groups, include, for example, t-butyl carbamate (Boc), benzyl (Bn), tetrahydropyranyl (THP), 9-fluorenylmethyl carbamate (Fmoc) benzyl carbamate (Cbz), acetamide, trifluoroacetamide, triphenylmethylamine, benzylideneamine, and p-toluenesulfonamide. Methods of adding (a process generally referred to as "protecting") and removing (process generally referred to as "deprotecting") such amine protecting groups are well-known in the art and available, for example, in P. J. Kocienski, Protecting Groups, Thieme, 1994, and in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Edition (John Wiley & Sons, New York, 1999) and 4 th< Edition (John Wiley & Sons, New Jersey, 2014).

[0042] Non-limiting examples of suitable solvents that may be used in this disclosure include, but are not limited to, water, methanol (MeOH), ethanol (EtOH), dichloromethane or "methylene chloride" (CH 2 Cl 2 ), toluene, acetonitrile (MeCN), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methyl acetate (MeOAc), ethyl acetate (EtOAc), heptanes, isopropyl acetate (IPAc), tert-butyl acetate (t-BuOAc), isopropyl alcohol (IPA), tetrahydrofuran (THF), 2-methyl tetrahydrofuran (2-Me THF), methyl ethyl ketone (MEK), tert-butanol, diethyl ether (Et 2 O), methyl-tert-butyl ether (MTBE), 1,4-dioxane, and N-methyl pyrrolidone (NMP).

[0043] Non-limiting examples of suitable bases that may be used in this disclosure include, but are not limited to, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), potassium tert-butoxide (KOtBu), potassium carbonate (K 2 CO 3 ), N-methylmorpholine (NMM), triethylamine (Et 3 N; TEA), diisopropyl-ethyl amine (i-Pr 2 EtN; DIPEA), pyridine, potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH) and sodium methoxide (NaOMe; NaOCH 3 ).

[0044] The disclosure includes pharmaceutically acceptable salts of the disclosed compounds. A salt of a compound is formed between an acid and a basic group of the compound, such as an amino functional group, or a base and an acidic group of the compound, such as a carboxyl functional group.

[0045] The term "pharmaceutically acceptable," as used herein, refers to a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. A "pharmaceutically acceptable salt" means any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this disclosure. Suitable pharmaceutically acceptable salts are, for example, those disclosed in S. M. Berge, et al. J. Pharmaceutical Sciences, 1977, 66, 1 to 19.

[0046] Acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids such as paratoluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, as well as related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and other salts. In some embodiments, pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid.

[0047] Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N +< (C 1-4 alkyl) 4 salts. This disclosure also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Suitable non-limiting examples of alkali and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. Other suitable, non-limiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts.

[0048] The terms "patient" and "subject" are used interchangeably and refer to an animal including a human.

[0049] The terms "effective dose" and "effective amount" are used interchangeably herein and refer to that amount of compound that produces the desired effect for which it is administered (e.g., improvement in symptoms of FSGS and / or NDKD, lessening the severity of FSGS and / NDKD or a symptom of FSGS and / or NDKD, and / or reducing progression of FSGS and / or NDKD or a symptom of FSGS and / or NDKD). The exact amount of an effective dose will depend on the purpose of the treatment and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0050] As used herein, the term "treatment" and its cognates refer to slowing or stopping disease progression. "Treatment" and its cognates as used herein, include, but are not limited to the following: complete or partial remission, lower risk of kidney failure (e.g. ESRD), and disease-related complications (e.g. edema, susceptibility to infections, or thrombo-embolic events). Improvements in or lessening the severity of any of these symptoms can be readily assessed according to methods and techniques known in the art or subsequently developed.

[0051] The terms "about" and "approximately", when used in connection with doses, amounts, or weight percent of ingredients of a composition or a dosage form, include the value of a specified dose, amount, or weight percent or a range of the dose, amount, or weight percent that is recognized by one of ordinary skill in the art to provide a pharmacological effect equivalent to that obtained from the specified dose, amount, or weight percent.

[0052] The at least one entity chosen from compounds of Formulae (I), (II), (IIIa), (IIIb), and (IIIc), pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and / or deuterated derivatives of any of the foregoing may be administered once daily, twice daily, or three times daily, for example, for the treatment of FSGS. In some embodiments, the compounds of Formulae (I), (II), (IIIa), (IIIb), and (IIIc) are chosen from Compounds 1 to 135, pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing. In some embodiments, at least one entity chosen from compounds of Formulae (I), (II), (IIIa), (IIIb), and (IIIc), pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and / or deuterated derivatives of any of the foregoing is administered once daily. In some embodiments, at least one entity chosen from Compounds 1 to 135, pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing is administered once daily. In some embodiments, at least one entity chosen from compounds of Formulae (I), (II), (IIIa), (IIIb), and (IIIc), pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and / or deuterated derivatives of any of the foregoing is administered twice daily. In some embodiments, at least one entity chosen from Compounds 1 to 135, pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and / or deuterated derivatives of any of the foregoing is administered twice daily. In some embodiments, at least one entity chosen from compounds of Formulae (I), (II), (IIIa), (IIIb), and (IIIc), pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and / or deuterated derivatives of any of the foregoing are administered three times daily. In some embodiments, at least one entity chosen from Compounds 1 to 135, pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and / or deuterated derivatives of any of the foregoing is administered three times daily.

[0053] In some embodiments, 2 mg to 1500 mg, 5 mg to 1000 mg, 10 mg to 500 mg, 20 mg to 300 mg, 20 mg to 200 mg, 30 mg to 150 mg, 50 mg to 150 mg, 60 mg to 125 mg, or 70 mg to 120 mg, 80 mg to 115 mg, 90 mg to 110 mg, 95 mg to 110 mg, or 100 mg to 105 mg of at least one entity chosen from compounds of Formulae (I), (II), (IIIa), (IIIb), and (IIIc), pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing are administered once daily, twice daily, or three times daily. In some embodiments, 2 mg to 1500 mg, 5 mg to 1000 mg, 10 mg to 500 mg, 20 mg to 300 mg, 20 mg to 200 mg, 30 mg to 150 mg, 50 mg to 150 mg, 60 mg to 125 mg, or 70 mg to 120 mg, 80 mg to 115 mg, 90 mg to 110 mg, 95 mg to 110 mg, or 100 mg to 105 mg of at least one entity chosen from Compounds 1 to 135, pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing are administered once daily, twice daily, or three times daily.

[0054] One of ordinary skill in the art would recognize that, when an amount of compound is disclosed, the relevant amount of a pharmaceutically acceptable salt form of the compound is an amount equivalent to the concentration of the free base of the compound. The amounts of the compounds, pharmaceutically acceptable salts, solvates, and deuterated derivatives disclosed herein are based upon the free base form of the reference compound. For example, "10 mg of at least one compound chosen from compounds of Formula (I) and pharmaceutically acceptable salts thereof" includes 10 mg of compound of Formula (I) and a concentration of a pharmaceutically acceptable salt of compounds of Formula (I) equivalent to 10 mg of compounds of Formula (I).

[0055] As used herein, the term "ambient conditions" means room temperature, open air condition and uncontrolled humidity condition.

[0056] As used herein, the terms "crystalline form" and "Form" interchangeably refer to a crystal structure (or polymorph) having a particular molecular packing arrangement in the crystal lattice. Crystalline forms can be identified and distinguished from each other by one or more characterization techniques including, for example, X-ray powder diffraction (XRPD), single crystal X-ray diffraction, solid state nuclear magnetic resonance (SSNMR), differential scanning calorimetry (DSC), dynamic vapor sorption (DVS), and / or thermogravimetric analysis (TGA). Accordingly, as used herein, the terms "crystalline Form [X] of Compound ([Y])" and "crystalline Form [C] of a [pharmaceutically acceptable] salt of Compound ([Y])" refer to unique crystalline forms that can be identified and distinguished from each other by one or more characterization techniques including, for example, X-ray powder diffraction (XRPD), single crystal X-ray diffraction, SSNMR, differential scanning calorimetry (DSC), dynamic vapor sorption (DVS), and / or thermogravimetric analysis (TGA). In some embodiments, the novel crystalline forms are characterized by an X-ray powder diffractogram having one or more signals at one or more specified two-theta values (° 2θ).

[0057] As used herein, the terms "solvate" refers to a crystal form comprising one or more molecules of compound of the present disclosure and, incorporated into the crystal lattice, one or more molecules of a solvent or solvents in stoichiometric or nonstoichiometric amounts. When the solvent is water, the solvate is referred to as a "hydrate".

[0058] As used herein, the term "SSNMR" refers to the analytical characterization method of solid state nuclear magnetic resonance. SSNMR spectra can be recorded at ambient conditions on any magnetically active isotope present in the sample. The typical examples of active isotopes for small molecule active pharmaceutical ingredients include 1< H, 2< H, 13< C, 19< F, 31< P, 15< N, 14< N, 35< Cl, 11< B, 7< Li, 17< O, 23< Na, 79< Br, and 195< pt.

[0059] As used herein, the term "XRPD" refers to the analytical characterization method of X-ray powder diffraction. XRPD patterns can be recorded at ambient conditions in transmission or reflection geometry using a diffractometer.

[0060] As used herein, the terms "X-ray powder diffractogram," "X-ray powder diffraction pattern," "XRPD pattern" interchangeably refer to an experimentally obtained pattern plotting signal positions (on the abscissa) versus signal intensities on the ordinate). For an amorphous material, an X-ray powder diffractogram may include one or more broad signals; and for a crystalline material, an X-ray powder diffractogram may include one or more signals, each identified by its angular value as measured in degrees 2θ (° 2θ), depicted on the abscissa of an X-ray powder diffractogram, which may be expressed as "a signal at ... degrees two-theta," "a signal at [a] two-theta value(s)of ..." and / or "a signal at at least ... two-theta value(s) chosen from ...."

[0061] A "signal" or "peak" as used herein refers to a point in the XRPD pattern where the intensity as measured in counts is at a local maximum. One of ordinary skill in the art would recognize that one or more signals (or peaks) in an XRPD pattern may overlap and may, for example, not be apparent to the naked eye. Indeed, one of ordinary skill in the art would recognize that some art-recognized methods are capable of and suitable for determining whether a signal exists in a pattern, such as Rietveld refinement.

[0062] As used herein, "a signal at ... degrees two-theta," "a signal at [a] two-theta value[] of ..." and / or "a signal at at least ... two-theta value(s) chosen from ...." refer to X-ray reflection positions as measured and observed in X-ray powder diffraction experiments (° 2θ).

[0063] The repeatability of the angular values is in the range of ± 0.2° 2θ, i.e., the angular value can be at the recited angular value + 0.2 degrees two-theta, the angular value - 0.2 degrees two-theta, or any value between those two end points (angular value +0.2 degrees two-theta and angular value -0.2 degrees two-theta).

[0064] The terms "signal intensities" and "peak intensities" interchangeably refer to relative signal intensities within a given X-ray powder diffractogram. Factors that can affect the relative signal or peak intensities include sample thickness and preferred orientation (e.g., the crystalline particles are not distributed randomly).

[0065] The term "X-ray powder diffractogram having a signal at ... two-theta values" as used herein refers to an XRPD pattern that contains X-ray reflection positions as measured and observed in X-ray powder diffraction experiments (° 2θ).

[0066] As used herein, the term "amorphous" refers to a solid material having no long range order in the position of its molecules. Amorphous solids are generally supercooled liquids in which the molecules are arranged in a random manner so that there is no well-defined arrangement, e.g., molecular packing, and no long range order.

[0067] For example, an amorphous material is a solid material having no sharp characteristic signal(s) in its X-ray power diffractogram (i.e., is not crystalline as determined by XRPD). Instead, one or more broad peaks (e.g., halos) appear in its diffractogram. Broad peaks are characteristic of an amorphous solid. See, e.g., US 2004 / 0006237 for a comparison of diffractograms of an amorphous material and crystalline material. In addition, the widths of signals in 13< C NMR and 19< F NMR spectra of amorphous material are typically substantially broader than those in 13< C NMR and 19< F NMR spectra of crystalline material.

[0068] As used herein, an X-ray powder diffractogram is "substantially similar to that in [a particular] Figure" when at least 90%, such as at least 95%, at least 98%, or at least 99%, of the signals in the two diffractograms overlap. In determining "substantial similarity," one of ordinary skill in the art will understand that there may be variation in the intensities and / or signal positions in XRPD diffractograms even for the same crystalline form. Thus, those of ordinary skill in the art will understand that the signal maximum values in XRPD diffractograms (in degrees two-theta (° 2θ) referred to herein) generally mean that value reported ±0.2 degrees 2θ of the reported value, an art-recognized variance.

[0069] As used herein, an SSNMR spectrum is "substantially similar to that in [a particular] Figure" when at least 90%, such as at least 95%, at least 98%, or at least 99%, of the signals in the two spectra overlap. In determining "substantial similarity," one of ordinary skill in the art will understand that there may be variation in the intensities and / or signal positions in SSNMR spectra even for the same crystalline form. Thus, those of ordinary skill in the art will understand that the signal maximum values in SSNMR spectra (in ppm) referred to herein generally mean that value reported ±0.2 ppm of the reported value, an art-recognized variance.

[0070] As used herein, a crystalline form is "substantially pure" when it accounts for an amount by weight equal to or greater than 90% of the sum of all solid form(s) in a sample as determined by a method in accordance with the art, such as quantitative XRPD. In some embodiments, the solid form is "substantially pure" when it accounts for an amount by weight equal to or greater than 95% of the sum of all solid form(s) in a sample. In some embodiments, the solid form is "substantially pure" when it accounts for an amount by weight equal to or greater than 99% of the sum of all solid form(s) in a sample.

[0071] As used herein, the term "DSC" refers to the analytical method of Differential Scanning Calorimetry.

[0072] As used herein, the term "TGA" refers to the analytical method of Thermo Gravimetric (or thermogravimetric) Analysis.Compounds and Compositions

[0073] In some embodiments, at least one entity of the disclosure is chosen from compounds of Formula (I): pharmaceutically acceptable salts thereof, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing, wherein: (i) each R 1 is independently chosen from halogen groups, hydroxy, cyano, C 1 -C 4 linear, branched, and cyclic alkyl groups, C 2 -C 4 linear, branched, and cyclic alkenyl groups, C 1 -C 4 linear, branched, and cyclic hydroxyalkyl groups, C 1 -C 4 linear, branched, and cyclic alkoxy groups, C 1 -C 4 linear, branched, and cyclic haloalkyl groups, C 1 -C 4 linear, branched, and cyclic haloalkoxy groups, benzyloxy groups, 3 to 6-membered heterocycloalkenyl groups, 3 to 6-membered heterocycloalkyl groups, and 5 and 6-membered heteroaryl groups; (ii) each R 2 is independently chosen from halogen groups, cyano, C 1 -C 4 linear, branched, and cyclic alkoxy groups, C 1 -C 4 linear, branched, and cyclic haloalkoxy groups, C 1 -C 4 linear, branched, and cyclic alkyl groups, and C 1 -C 4 linear, branched, and cyclic haloalkyl groups; (iii) m is chosen from 0, 1, 2, 3, and 4; (iv) n is chosen from 0, 1, 2, 3, 4, and 5; (v) Y is chosen from divalent C 1 -C 4 linear and branched alkyl groups, wherein the divalent alkyl groups are optionally substituted with at least one group chosen from C 1 -C 4 alkyl groups, halogen groups, and hydroxy; (vi) each of R 3 and R 4 is independently chosen from hydrogen, C 1 -C 3 linear, branched, and cyclic alkyl groups, C 1 -C 3 linear, branched, and cyclic hydroxyalkyl groups, and C 1 -C 3 linear, branched, and cyclic haloalkyl groups, or R 3 and R 4 , together with the carbon atom to which they are attached, form a C 3 -C 6 cycloalkyl group or carbonyl group; (vii) each of R 5 and R 6 is independently chosen from hydrogen, hydroxy, C 1 -C 4 linear, branched, and cyclic alkyl groups, C 1 -C 4 linear, branched, and cyclic haloalkyl groups, and -OC(O)C 1 -C 4 linear, branched, and cyclic alkyl groups; and (viii) each of R 7 , R 8 , and R 9 is independently chosen from hydrogen, C 1 -C 4 linear, branched, and cyclic alkyl groups, and C 1 -C 4 linear, branched, and cyclic haloalkyl groups.

[0074] In some embodiments, each of R 3 and R 4 is hydrogen.

[0075] In some embodiments, each of R 5 and R 6 is independently chosen from hydrogen and hydroxy.

[0076] In some embodiments, one of R 5 and R 6 is hydrogen and the other is hydroxy.

[0077] In some embodiments, each R 1 is independently chosen from halogen groups.

[0078] In some embodiments, each R 1 is fluoro.

[0079] In some embodiments, each R 2 is independently chosen from halogen groups and methyl.

[0080] In some embodiments, each R 2 is independently chosen from fluoro and methyl.

[0081] In some embodiments, each R 2 is independently fluoro.

[0082] In some embodiments, each R 2 is independently methyl.

[0083] In some embodiments, m is 0, 1, or 2.

[0084] In some embodiments, m is 0.

[0085] In some embodiments, m is 1 or 2.

[0086] In some embodiments, m is 1.

[0087] In some embodiments, m is 2.

[0088] In some embodiments, n is 0, 1, or 2.

[0089] In some embodiments, n is 0.

[0090] In some embodiments, n is 1 or 2.

[0091] In some embodiments, n is 1.

[0092] In some embodiments, n is 2.

[0093] In some embodiments, Y is divalent ethyl optionally substituted with at least one group chosen from C 1 -C 4 alkyl groups, halogen groups, and hydroxy.

[0094] In some embodiments, Y is -CH 2 CH 2 -, also referred to herein as "divalent ethyl".

[0095] In some embodiments, Y is -CH 2 CH(CH 3 )-.

[0096] In some embodiments, Y is divalent ethyl substituted with one or two groups chosen from halogen groups and hydroxy.

[0097] In some embodiments, Y is divalent ethyl substituted with one halogen.

[0098] In some embodiments, Y is divalent ethyl substituted with one fluoro.

[0099] In some embodiments, Y is divalent ethyl substituted with one chloro.

[0100] In some embodiments, Y is divalent ethyl substituted with two halogen groups.

[0101] In some embodiments, Y is divalent ethyl substituted with two fluoro groups.

[0102] In some embodiments, Y is divalent ethyl substituted with two chloro groups.

[0103] In some embodiments, Y is divalent ethyl substituted with one fluoro and one chloro.

[0104] In some embodiments, Y is divalent ethyl substituted with one hydroxy.

[0105] In some embodiments, m is 2, n is 1, and Y is divalent ethyl. In some embodiments, m is 2, n is 1, one of R 5 and R 6 is hydrogen and the other is hydroxy, and Y is divalent ethyl. In some embodiments, m is 2, n is 1, each R 1 is independently chosen from halogen groups, R 2 is chosen from halogen groups, and Y is divalent ethyl. In some embodiments, m is 2, n is 1, each R 1 is independently chosen from halogen groups, R 2 is chosen from halogen groups, one of R 5 and R 6 is hydrogen and the other is hydroxyl, and Y is divalent ethyl.

[0106] In some embodiments, m is 0, n is 1, and Y is divalent ethyl. In some embodiments, m is 0, n is 1, one of R 5 and R 6 is hydrogen and the other is hydroxy, and Y is divalent ethyl. In some embodiments, m is 0, n is 1, R 2 is chosen from halogen groups, and Y is divalent ethyl. In some embodiments, m is 0, n is 1, R 2 is chosen from halogen groups, one of R 5 and R 6 is hydrogen and the other is hydroxy, and Y is divalent ethyl.

[0107] In some embodiments, the at least one entity is chosen from compounds of Formula (II): pharmaceutically acceptable salts thereof, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing, wherein: (i) each R 1 is independently chosen from halogen groups, cyano, methyl, cyclopropyl, ispropyl, C 2 -C 3 linear and branched alkenyl groups, hydroxypropyl groups, methoxy, dihydrofuran groups, and furan groups; (ii) each R 2 is independently chosen from fluoro, cyano, and methyl; (iii) m is chosen from 0. 1, 2, and 3; (iv) n is chosen from 0, 1, and 2; and (v) Y is divalent ethyl optionally substituted with at least one group chosen from fluoro, methyl, and hydroxy.

[0108] In some embodiments, the at least one entity of the disclosure is chosen from compounds of Formula (IIIa), compounds of Formula (IIIb), compounds of Formula (IIIc): pharmaceutically acceptable salts of any of the foregoing, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing, wherein: (i) each R 1 is independently chosen from fluoro, chloro, bromo, cyano, methyl, cyclopropyl, ethyl, hydroxypropyl, isopropyl, propen-2-yl, dihydrofuran, furan, and methoxy; (ii) each R 2 is independently chosen from fluoro, bromo, cyano, and methyl; and (iii) Y is divalent ethyl optionally substituted with at least one group chosen from fluoro, methyl, and hydroxy.

[0109] In some embodiments, the at least one entity of the disclosure is chosen from Compounds 1 to 135 depicted in Table 1. A wavy line in a compound in Table 1 (i.e., ) depicts a bond between two atoms and indicates a position of mixed stereochemistry for a collection of molecules, such as a racemic mixture, cis / trans isomers, or (E) / (Z) isomers. An asterisk adjacent to an atom (e.g., ) in a compound in Table 1, indicates a chiral position in the molecule. Table 1. Compounds 1 to 135 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135

[0110] Some embodiments of the disclosure include derivatives of Compounds 1 to 135 or compounds of Formulae (I), (II), (IIIa), (IIIb), and (IIIc). In some embodiments not claimed in the appended claims, the derivatives are silicon derivatives in which at least one carbon atom in a compound chosen from Compounds 1 to 135 or compounds of Formulae (I), (II), (IIIa), (IIIb), and (IIIc), has been replaced by silicon. In some embodiments not claimed in the appended claims, the derivatives are boron derivatives, in which at least one carbon atom in a compound chosen from Compounds 1 to 135 or compounds of Formulae (I), (II), (IIIa), (IIIb), and (IIIc), has been replaced by boron. In other embodiments not claimed in the appended claims, the derivatives are phosphorus derivatives, in which at least one carbon atom in a compound chosen from Compounds 1 to 135 or compounds of Formulae (I), (II), (IIIa), (IIIb), and (IIIc) has been replaced by phosphorus. Because the general properties of silicon, boron, and phosphorus are similar to those of carbon, replacement of carbon by silicon, boron, or phosphorus can result in compounds with similar biological activity to a carbon containing original compound.

[0111] In some embodiments not claimed in the appended claims, the derivative is a silicon derivative in which one carbon atom in a compound chosen from Compounds 1 to 135 or compounds of Formulae (I), (II), (IIIa), (IIIb), and (IIIc) has been replaced by silicon or a silicon derivative (e.g. -Si(CH 3 ) 2 - or -Si(OH) 2 -). The carbon replaced by silicon may be a non-aromatic carbon. In other embodiments not claimed in the appended claims, a fluorine has been replaced by silicon derivative (e.g. -Si(CH 3 ) 3 ). In some embodiments not claimed in the appended claims, the silicon derivatives of the disclosure may include one or more hydrogen atoms replaced by deuterium. In some embodiments not claimed in the appended claims, a silicon derivative of compound chosen from Compounds 1 to 135 or compounds of Formulae (I), (II), (IIIa), (IIIb), and (IIIc) may have silicon incorporated into a heterocycle ring.

[0112] In some embodiments not claimed in the appended claims, examples of silicon derivatives of Compounds 1 to 135 or compounds of Formulae (I), (II), (IIIa), (IIIb), and (IIIc) include the following compounds:

[0113] In some embodiments not claimed in the appended claims, examples of boron derivatives of Compounds 1 to 135 or compounds of Formulae (I), (II), (IIIa), (IIIb), and (IIIc) include the following compound:

[0114] In some embodiments not claimed in the appended claims, examples of phosphorus derivatives of Compounds 1 to 135 or compounds of Formulae (I), (II), (IIIa), (IIIb), and (IIIc) include the following compounds:

[0115] Another aspect of the disclosure provides pharmaceutical compositions comprising at least one compound according to any one formula chosen from Formulae (I), (II), (IIIa), (IIIb), and (IIIc) and Compounds 1 to 135, pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing. In some embodiments, the pharmaceutical composition comprising at least one compound chosen from Formulae (I), (II), (IIIa), (IIIb), and (IIIc) and Compounds 1 to 135, pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing is administered to a patient in need thereof.

[0116] A pharmaceutical composition may further comprise at least one pharmaceutically acceptable carrier. In some embodiments, the at least one pharmaceutically acceptable carrier is chosen from pharmaceutically acceptable vehicles and pharmaceutically acceptable adjuvants. In some embodiments, the at least one pharmaceutically acceptable is chosen from pharmaceutically acceptable fillers, disintegrants, surfactants, binders, lubricants.

[0117] It will also be appreciated that a pharmaceutical composition of this disclosure can be employed in combination therapies; that is, the pharmaceutical compositions described herein can further include at least one additional active therapeutic agent. Alternatively, a pharmaceutical composition comprising at least one compound chosen from compounds of Formulae (I), (II), (IIIa), (IIIb), and (IIIc), pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing can be administered as a separate composition concurrently with, prior to, or subsequent to, a composition comprising at least one other active therapeutic agent. In some embodiments, a pharmaceutical composition comprising at least one compound chosen from Compounds 1 to 135, pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing can be administered as a separate composition concurrently with, prior to, or subsequent to, a composition comprising at least one other active therapeutic agent.

[0118] As described above, pharmaceutical compositions disclosed herein may optionally further comprise at least one pharmaceutically acceptable carrier. The at least one pharmaceutically acceptable carrier may be chosen from adjuvants and vehicles. The at least one pharmaceutically acceptable carrier, as used herein, includes any and all solvents, diluents, other liquid vehicles, dispersion aids, suspension aids, surface active agents, isotonic agents, thickening agents, emulsifying agents, preservatives, solid binders, and lubricants, as suited to the particular dosage form desired. Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988 to 1999, Marcel Dekker, New York discloses various carriers used in formulating pharmaceutical compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier is incompatible with the compounds of this disclosure, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition, its use is contemplated to be within the scope of this disclosure. Non-limiting examples of suitable pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates, glycine, sorbic acid, and potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts, and electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars (such as lactose, glucose and sucrose), starches (such as corn starch and potato starch), cellulose and its derivatives (such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (such as cocoa butter and suppository waxes), oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil), glycols (such as propylene glycol and polyethylene glycol), esters (such as ethyl oleate and ethyl laurate), agar, buffering agents (such as magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer solutions, non-toxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), coloring agents, releasing agents, coating agents, sweetening agents, flavoring agents, perfuming agents, preservatives, and antioxidants.

[0119] In some embodiments of the disclosure, the compounds and the pharmaceutical compositions described herein are for use in treating FSGS and / or NDKD. In some embodiments, FSGS is mediated by APOL1. In some embodiments, NDKD is mediated by APOL1.

[0120] In some embodiments, the disclosure provides pharmaceutical compositions and compounds for use in methods, the methods comprising administering to a patient in need thereof at least one entity chosen from compounds of Formulae (I), (II), (IIIa), (IIIb), and (IIIc), pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing. In some embodiments, the compound of Formula I is chosen from Compounds 1 to 135, pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing. In some embodiments, said patient in need thereof possesses APOL1 genetic variants, i.e., G1: S342G:I384M and G2: N388del:Y389del.

[0121] Another aspect of the disclosure provides pharmaceutical compositions and compounds for use in methods of inhibiting APOL1 activity, the methods comprising contacting said APOL1 with at least one entity chosen from compounds of Formulae (I), (II), (IIIa), (IIIb), and (IIIc), pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing. In some embodiments, the methods of inhibiting APOL1 activity comprise contacting said APOL1 with at least one entity chosen from Compounds 1 to 135, pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing.Solid forms of Compound 2

[0122] In some embodiments, the at least one entity chosen from compounds of Formula (I) is Compound 2. Compound 2 can be depicted as follows:

[0123] In some embodiments, Compound 2 is an amorphous solid. In some embodiments, Compound 2 is a crystalline solid. In some embodiments, Compound 2 is in the form of Form A, Hydrate Form A, Hydrate Form B, Hydrate Form C, Hydrate Form C, Hydrate Form D, Hydrate Form E, Compound 2 MTBE solvate, Compound 2 DMF solvate, or a mixture of any two or more of the foregoing.Form A of Compound 2

[0124] In some embodiments, Compound 2 is in the form of Form A. In some embodiments, Compound 2 is in the form of substantially pure Form A. In some embodiments, Form A is characterized by an X-ray powder diffractogram substantially similar to that in FIG. 1. In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at at least two two-theta values chosen from 9.5 ± 0.2, 13.2 ± 0.2, 14.4 ± 0.2, 19.2 ± 0.2, 19.5 ± 0.2, 19.8 ± 0.2, 26.3 ± 0.2, 26.7 ± 0.2, and 28.6 ± 0.2. In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 9.5 ± 0.2, 13.2 ± 0.2, 14.4 ± 0.2, 19.2 ± 0.2, 19.5 ± 0.2, 19.8 ± 0.2, 26.3 ± 0.2, 26.7 ± 0.2, and 28.6 ± 0.2. In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at at least four two-theta values chosen from 9.5 ± 0.2, 13.2 ± 0.2, 14.4 ± 0.2, 19.2 ± 0.2, 19.5 ± 0.2, 19.8 ± 0.2, 26.3 ± 0.2, 26.7 ± 0.2, and 28.6 ± 0.2. In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at at least five two-theta values chosen from 9.5 ± 0.2, 13.2 ± 0.2, 14.4 ± 0.2, 19.2 ± 0.2, 19.5 ± 0.2, 19.8 ± 0.2, 26.3 ± 0.2, 26.7 ± 0.2, and 28.6 ± 0.2. In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at at least six two-theta values chosen from 9.5 ± 0.2, 13.2 ± 0.2, 14.4 ± 0.2, 19.2 ± 0.2, 19.5 ± 0.2, 19.8 ± 0.2, 26.3 ± 0.2, 26.7 ± 0.2, and 28.6 ± 0.2. In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at at least seven two-theta values chosen from 9.5 ± 0.2, 13.2 ± 0.2, 14.4 ± 0.2, 19.2 ± 0.2, 19.5 ± 0.2, 19.8 ± 0.2, 26.3 ± 0.2, 26.7 ± 0.2, and 28.6 ± 0.2. In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at at least eight two-theta values chosen from 9.5 ± 0.2, 13.2 ± 0.2, 14.4 ± 0.2, 19.2 ± 0.2, 19.5 ± 0.2, 19.8 ± 0.2, 26.3 ± 0.2, 26.7 ± 0.2, and 28.6 ± 0.2. In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at the following two-theta values 9.5 ± 0.2, 13.2 ± 0.2, 14.4 ± 0.2, 19.2 ± 0.2, 19.5 ± 0.2, 19.8 ± 0.2, 26.3 ± 0.2, 26.7 ± 0.2, and 28.6 ± 0.2.

[0125] In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at at least one two-theta values chosen from 9.5 ± 0.2, 13.2 ± 0.2, 14.4 ± 0.2, 16.1 ± 0.2, 17.7 ± 0.2, 18.8 ± 0.2, 19.2 ± 0.2, 19.5 ± 0.2, 19.8:!: 0.2, 20.7 ± 0.2, 21.4 ± 0.2, 21.7 ± 0.2, 22.4 ± 0.2, 22.9 ± 0.2, 23.3 ± 0.2, 24.0 ± 0.2, 26.3 ± 0.2, 26.7 ± 0.2, 27.1 ± 0.2, 27.7 ± 0.2, 28.6 ± 0.2, 29.1 ± 0.2, and 29.5 ± 0.2. In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at at least two two-theta values chosen from 9.5 ± 0.2, 13.2 ± 0.2, 14.4 ± 0.2, 16.1 ± 0.2, 17.7 ± 0.2, 18.8 ± 0.2, 19.2 ± 0.2, 19.5 ± 0.2, 19.8 ± 0.2, 20.7 ± 0.2, 21.4 ± 0.2, 21.7 ± 0.2, 22.4 ± 0.2, 22.9 ± 0.2, 23.3 ± 0.2, 24.0 ± 0.2, 26.3 ± 0.2, 26.7 ± 0.2, 27.1:!: 0.2, 27.7 ± 0.2, 28.6 ± 0.2, 29.1 ± 0.2, and 29.5 ± 0.2. In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 9.5 ± 0.2, 13.2 ± 0.2, 14.4 ± 0.2, 16.1 ± 0.2, 17.7 ± 0.2, 18.8 ± 0.2, 19.2 ± 0.2, 19.5 ± 0.2, 19.8 ± 0.2, 20.7 ± 0.2, 21.4 ± 0.2, 21.7 ± 0.2, 22.4 ± 0.2, 22.9 ± 0.2, 23.3 ± 0.2, 24.0 ± 0.2, 26.3 ± 0.2, 26.7 ± 0.2, 27.1 ± 0.2, 27.7 ± 0.2, 28.6 ± 0.2, 29.1 ± 0.2, and 29.5 ± 0.2. In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at at least four two-theta values chosen from 9.5 ± 0.2, 13.2 ± 0.2, 14.4 ± 0.2, 16.1 ± 0.2, 17.7 ± 0.2, 18.8 ± 0.2, 19.2 ± 0.2, 19.5 ± 0.2, 19.8 ± 0.2, 20.7 ± 0.2, 21.4 ± 0.2, 21.7 ± 0.2, 22.4 ± 0.2, 22.9 ± 0.2, 23.3 ± 0.2, 24.0 ± 0.2, 26.3 ± 0.2, 26.7 ± 0.2, 27.1 ± 0.2, 27.7 ± 0.2, 28.6 ± 0.2, 29.1 ± 0.2, and 29.5 ± 0.2. In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at at least five two-theta values chosen from 9.5 ± 0.2, 13.2 ± 0.2, 14.4 ± 0.2, 16.1 ± 0.2, 17.7 ± 0.2, 18.8 ± 0.2, 19.2 ± 0.2, 19.5 ± 0.2, 19.8 ± 0.2, 20.7 ± 0.2, 21.4 ± 0.2, 21.7 ± 0.2, 22.4 ± 0.2, 22.9 ± 0.2, 23.3 ± 0.2, 24.0 ± 0.2, 26.3 ± 0.2, 26.7 ± 0.2, 27.1 ± 0.2, 27.7 ± 0.2, and 28.6 ± 0.2. In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at at least six two-theta values chosen from 9.5 ± 0.2, 13.2 ± 0.2, 14.4 ± 0.2, 16.1 ± 0.2, 17.7 ± 0.2, 18.8 ± 0.2, 19.2 ± 0.2, 19.5 ± 0.2, 19.8 ± 0.2, 20.7 ± 0.2, 21.4 ± 0.2, 21.7 ± 0.2, 22.4 ± 0.2, 22.9 ± 0.2, 23.3 ± 0.2, 24.0 ± 0.2, 26.3 ± 0.2, 26.7 ± 0.2, 27.1 ± 0.2, 27.7 ± 0.2, and 28.6 ± 0.2. In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at at least seven two-theta values chosen from 9.5 ± 0.2, 13.2 ± 0.2, 14.4 ± 0.2, 16.1 ± 0.2, 17.7 ± 0.2, 18.8 ± 0.2, 19.2 ± 0.2, 19.5 ± 0.2, 19.8 ± 0.2, 20.7 ± 0.2, 21.4 ± 0.2, 21.7 ± 0.2, 22.4 ± 0.2, 22.9 ± 0.2, 23.3 ± 0.2, 24.0 ± 0.2, 26.3 ± 0.2, 26.7 ± 0.2, 27.1 ± 0.2, 27.7 ± 0.2, and 28.6 ± 0.2. In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at at least eight two-theta values chosen from 9.5 ± 0.2, 13.2 ± 0.2, 14.4 ± 0.2, 16.1 ± 0.2, 17.7 ± 0.2, 18.8 ± 0.2, 19.2 ± 0.2, 19.5 ± 0.2, 19.8 ± 0.2, 20.7 ± 0.2, 21.4 ± 0.2, 21.7 ± 0.2, 22.4 ± 0.2, 22.9 ± 0.2, 23.3 ± 0.2, 24.0 ± 0.2, 26.3 ± 0.2, 26.7 ± 0.2, 27.1 ± 0.2, 27.7 ± 0.2, and 28.6 ± 0.2. In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at at least nine two-theta values chosen from 9.5 ± 0.2, 13.2 ± 0.2, 14.4 ± 0.2, 16.1 ± 0.2, 17.7 ± 0.2, 18.8 ± 0.2, 19.2 ± 0.2, 19.5 ± 0.2, 19.8 ± 0.2, 20.7 ± 0.2, 21.4 ± 0.2, 21.7 ± 0.2, 22.4 ± 0.2, 22.9 ± 0.2, 23.3 ± 0.2, 24.0 ± 0.2, 26.3 ± 0.2, 26.7 ± 0.2, 27.1 ± 0.2, 27.7 ± 0.2, and 28.6 ± 0.2. In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at at least ten two-theta values chosen from 9.5 ± 0.2, 13.2 ± 0.2, 14.4 ± 0.2, 16.1 ± 0.2, 17.7 ± 0.2, 18.8 ± 0.2, 19.2 ± 0.2, 19.5 ± 0.2, 19.8 ± 0.2, 20.7 ± 0.2, 21.4 ± 0.2, 21.7 ± 0.2, 22.4 ± 0.2, 22.9 ± 0.2, 23.3 ± 0.2, 24.0 ± 0.2, 26.3 ± 0.2, 26.7 ± 0.2, 27.1 ± 0.2, 27.7 ± 0.2, and 28.6 ± 0.2. In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at at least eleven two-theta values chosen from 9.5 ± 0.2, 13.2 ± 0.2, 14.4 ± 0.2, 16.1 ± 0.2, 17.7 ± 0.2, 18.8 ± 0.2, 19.2 ± 0.2, 19.5 ± 0.2, 19.8 ± 0.2, 20.7 ± 0.2, 21.4 ± 0.2, 21.7 ± 0.2, 22.4 ± 0.2, 22.9 ± 0.2, 23.3 ± 0.2, 24.0 ± 0.2, 26.3 ± 0.2, 26.7 ± 0.2, 27.1 ± 0.2, 27.7 ± 0.2, and 28.6 ± 0.2. In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at at least twelve two-theta values chosen from 9.5 ± 0.2, 13.2 ± 0.2, 14.4 ± 0.2, 16.1 ± 0.2, 17.7 ± 0.2, 18.8 ± 0.2, 19.2 ± 0.2, 19.5 ± 0.2, 19.8 ± 0.2, 20.7 ± 0.2, 21.4 ± 0.2, 21.7 ± 0.2, 22.4 ± 0.2, 22.9 ± 0.2, 23.3 ± 0.2, 24.0 ± 0.2, 26.3 ± 0.2, 26.7 ± 0.2, 27.1 ± 0.2, 27.7 ± 0.2, and 28.6 ± 0.2. In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at at least thirteen two-theta values chosen from 9.5 ± 0.2, 13.2 ± 0.2, 14.4 ± 0.2, 16.1 ± 0.2, 17.7 ± 0.2, 18.8 ± 0.2, 19.2 ± 0.2, 19.5 ± 0.2, 19.8 ± 0.2, 20.7 ± 0.2, 21.4 ± 0.2, 21.7 ± 0.2, 22.4 ± 0.2, 22.9 ± 0.2, 23.3 ± 0.2, 24.0 ± 0.2, 26.3 ± 0.2, 26.7 ± 0.2, 27.1 ± 0.2, 27.7 ± 0.2, and 28.6 ± 0.2. In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at at least fourteen two-theta values chosen from 9.5 ± 0.2, 13.2 ± 0.2, 14.4 ± 0.2, 16.1 ± 0.2, 17.7 ± 0.2, 18.8 ± 0.2, 19.2 ± 0.2, 19.5 ± 0.2, 19.8 ± 0.2, 20.7 ± 0.2, 21.4 ± 0.2, 21.7 ± 0.2, 22.4 ± 0.2, 22.9 ± 0.2, 23.3 ± 0.2, 24.0 ± 0.2, 26.3 ± 0.2, 26.7 ± 0.2, 27.1 ± 0.2, 27.7 ± 0.2, and 28.6 ± 0.2. In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at at least fifteen two-theta values chosen from 9.5 ± 0.2, 13.2 ± 0.2, 14.4 ± 0.2, 16.1 ± 0.2, 17.7 ± 0.2, 18.8 ± 0.2, 19.2 ± 0.2, 19.5 ± 0.2, 19.8 ± 0.2, 20.7 ± 0.2, 21.4 ± 0.2, 21.7 ± 0.2, 22.4 ± 0.2, 22.9 ± 0.2, 23.3 ± 0.2, 24.0 ± 0.2, 26.3 ± 0.2, 26.7 ± 0.2, 27.1 ± 0.2, 27.7 ± 0.2, and 28.6 ± 0.2. In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at at least sixteen two-theta values chosen from 9.5 ± 0.2, 13.2 ± 0.2, 14.4 ± 0.2, 16.1 ± 0.2, 17.7 ± 0.2, 18.8 ± 0.2, 19.2 ± 0.2, 19.5 ± 0.2, 19.8 ± 0.2, 20.7 ± 0.2, 21.4 ± 0.2, 21.7 ± 0.2, 22.4 ± 0.2, 22.9 ± 0.2, 23.3 ± 0.2, 24.0 ± 0.2, 26.3 ± 0.2, 26.7 ± 0.2, 27.1 ± 0.2, 27.7 ± 0.2, and 28.6 ± 0.2. In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at at least seventeen two-theta values chosen from 9.5 ± 0.2, 13.2 ± 0.2, 14.4 ± 0.2, 16.1 ± 0.2, 17.7 ± 0.2, 18.8 ± 0.2, 19.2 ± 0.2, 19.5 ± 0.2, 19.8 ± 0.2, 20.7 ± 0.2, 21.4 ± 0.2, 21.7 ± 0.2, 22.4 ± 0.2, 22.9 ± 0.2, 23.3 ± 0.2, 24.0 ± 0.2, 26.3 ± 0.2, 26.7 ± 0.2, 27.1 ± 0.2, 27.7 ± 0.2, and 28.6 ± 0.2. In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at at least eighteen two-theta values chosen from 9.5 ± 0.2, 13.2 ± 0.2, 14.4 ± 0.2, 16.1 ± 0.2, 17.7 ± 0.2, 18.8 ± 0.2, 19.2 ± 0.2, 19.5 ± 0.2, 19.8 ± 0.2, 20.7 ± 0.2, 21.4 ± 0.2, 21.7 ± 0.2, 22.4 ± 0.2, 22.9 ± 0.2, 23.3 ± 0.2, 24.0 ± 0.2, 26.3 ± 0.2, 26.7 ± 0.2, 27.1 ± 0.2, 27.7 ± 0.2, and 28.6 ± 0.2. In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at at least nineteen two-theta values chosen from 9.5 ± 0.2, 13.2 ± 0.2, 14.4 ± 0.2, 16.1 ± 0.2, 17.7 ± 0.2, 18.8 ± 0.2, 19.2 ± 0.2, 19.5 ± 0.2, 19.8 ± 0.2, 20.7 ± 0.2, 21.4 ± 0.2, 21.7 ± 0.2, 22.4 ± 0.2, 22.9 ± 0.2, 23.3 ± 0.2, 24.0 ± 0.2, 26.3 ± 0.2, 26.7 ± 0.2, 27.1 ± 0.2, 27.7 ± 0.2, and 28.6 ± 0.2. In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at at least twenty two-theta values chosen from 9.5 ± 0.2, 13.2 ± 0.2, 14.4 ± 0.2, 16.1 ± 0.2, 17.7 ± 0.2, 18.8 ± 0.2, 19.2 ± 0.2, 19.5 ± 0.2, 19.8 ± 0.2, 20.7 ± 0.2, 21.4 ± 0.2, 21.7 ± 0.2, 22.4 ± 0.2, 22.9 ± 0.2, 23.3 ± 0.2, 24.0 ± 0.2, 26.3 ± 0.2, 26.7 ± 0.2, 27.1 ± 0.2, 27.7 ± 0.2, and 28.6 ± 0.2. In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at 9.5 ± 0.2, 13.2 ± 0.2, 14.4 ± 0.2, 16.1 ± 0.2, 17.7 ± 0.2, 18.8 ± 0.2, 19.2 ± 0.2, 19.5 ± 0.2, 19.8 ± 0.2, 20.7 ± 0.2, 21.4 ± 0.2, 21.7 ± 0.2, 22.4 ± 0.2, 22.9 ± 0.2, 23.3 ± 0.2, 24.0 ± 0.2, 26.3 ± 0.2, 26.7 ± 0.2, 27.1 ± 0.2, 27.7 ± 0.2, and 28.6 ± 0.2, two-theta.

[0126] In some embodiments, disclosed herein is a composition comprising Form A of Compound 2. In some embodiments, disclosed herein is a composition comprising Compound 2 in substantially pure Form A. In some embodiments, disclosed herein is a composition comprising at least one active compound consisting essentially of Compound 2 in Form A.

[0127] In some embodiments, Form A is characterized by a DSC curve substantially similar to that in FIG. 5. In some embodiments, Form A is characterized by a DSC curve having a peak at 202°C.

[0128] In some embodiments, Form A is characterized by a 13< C NMR spectrum having a signal at at least one ppm value chosen from 178.7 ± 0.2 ppm, 154.4 ± 0.2 ppm, 127.8 ± 0.2 ppm, 125.2 ± 0.2 ppm, 102.0 ± 0.2 ppm, 59.3 ± 0.2 ppm, 38.9 ± 0.2 ppm, and 24.4 ± 0.2 ppm. In some embodiments, Form A is characterized by a 13< C NMR spectrum having a signal at at least two ppm values chosen from 178.7 ± 0.2 ppm, 154.4 ± 0.2 ppm, 127.8 ± 0.2 ppm, 125.2 ± 0.2 ppm, 102.0 ± 0.2 ppm, 59.3 ± 0.2 ppm, 38.9 ± 0.2 ppm, and 24.4 ± 0.2 ppm. In some embodiments, Form A is characterized by a 13< C NMR spectrum having a signal at at least three ppm values chosen from 178.7 ± 0.2 ppm, 154.4 ± 0.2 ppm, 127.8 ± 0.2 ppm, 125.2 ± 0.2 ppm, 102.0 ± 0.2 ppm, 59.3 ± 0.2 ppm, 38.9 ± 0.2 ppm, and 24.4 ± 0.2 ppm. In some embodiments, Form A is characterized by a 13< C NMR spectrum having a signal at at least four ppm values chosen from 178.7 ± 0.2 ppm, 154.4 ± 0.2 ppm, 127.8 ± 0.2 ppm, 125.2 ± 0.2 ppm, 102.0 ± 0.2 ppm, 59.3 ± 0.2 ppm, 38.9 ± 0.2 ppm, and 24.4 ± 0.2 ppm. In some embodiments, Form A is characterized by a 13< C NMR spectrum having a signal at 178.7 ± 0.2 ppm, 154.4 ± 0.2 ppm, 127.8 ± 0.2 ppm, 125.2 ± 0.2 ppm, 102.0 ± 0.2 ppm, 59.3 ± 0.2 ppm, 38.9 ± 0.2 ppm, and 24.4 ± 0.2 ppm.

[0129] In some embodiments, Form A is characterized by a 19< F NMR spectrum having a signal at least at one ppm value chosen from -116.0 ± 0.2 ppm, -119.7 ± 0.2 ppm, and -138.1 ± 0.2 ppm. In some embodiments, Form A is characterized by a 19< F NMR spectrum having a signal at least at two ppm value chosen from -116.0 ± 0.2 ppm, -119.7 ± 0.2 ppm, and -138.1 ± 0.2 ppm. In some embodiments, Form A is characterized by a 19< F NMR spectrum having a signal at -116.0 ± 0.2 ppm, -119.7 ± 0.2 ppm, and -138.1 ± 0.2 ppm.

[0130] In some embodiments, Compound 2 is a crystalline solid. In some embodiments, Compound 2 is a crystalline solid. In some embodiments, the crystalline solid consists of 1% to 99% Form A relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 2% to 99% Form A relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 5% to 99% Form A relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 10% to 99% Form A relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 15% to 99% Form A relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 20% to 99% Form A relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 25% to 99% Form A relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 30% to 99% Form A relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 35% to 99% Form A relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 45% to 99% Form A relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 50% to 99% Form A relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 55% to 99% Form A relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 60% to 99% Form A relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 65% to 99% Form A relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 70% to 99% Form A relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 75% to 99% Form A relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 80% to 99% Form A relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 85% to 99% Form A relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 90% to 99% Form A relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 95% to 99% Form A relative to the total weight of the crystalline solid Compound 2.Hydrate Form A of Compound 2

[0131] In some embodiments, Compound 2 is in the form of Hydrate Form A. In some embodiments, Compound 2 is in the form of substantially pure Hydrate Form A. In some embodiments, Hydrate Form A is characterized by an X-ray powder diffractogram substantially similar to that in FIG. 7. In some embodiments, Hydrate Form A is characterized by an X-ray powder diffractogram having a signal at at least two two-theta values chosen from 12.2 ± 0.2, 19.0 ± 0.2, 19.1 ± 0.2, 19.6 ± 0.2, 20.2 ± 0.2, 22.7 ± 0.2, 24.2 ± 0.2, 25.4 ± 0.2, and 25.5 ± 0.2. In some embodiments, Hydrate Form A is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 12.2 ± 0.2, 19.0 ± 0.2, 19.1 ± 0.2, 19.6 ± 0.2, 20.2 ± 0.2, 22.7 ± 0.2, 24.2 ± 0.2, 25.4 ± 0.2, and 25.5 ± 0.2. In some embodiments, Hydrate Form A is characterized by an X-ray powder diffractogram having a signal at at least four two-theta values chosen from 12.2 ± 0.2, 19.0 ± 0.2, 19.1 ± 0.2, 19.6 ± 0.2, 20.2 ± 0.2, 22.7 ± 0.2, 24.2 ± 0.2, 25.4 ± 0.2, and 25.5 ± 0.2. In some embodiments, Hydrate Form A is characterized by an X-ray powder diffractogram having a signal at at least five two-theta values chosen from 12.2 ± 0.2, 19.0 ± 0.2, 19.1 ± 0.2, 19.6 ± 0.2, 20.2 ± 0.2, 22.7 ± 0.2, 24.2 ± 0.2, 25.4 ± 0.2, and 25.5 ± 0.2. In some embodiments, Hydrate Form A is characterized by an X-ray powder diffractogram having a signal at at least six two-theta values chosen from 12.2 ± 0.2, 19.0 ± 0.2, 19.1 ± 0.2, 19.6 ± 0.2, 20.2 ± 0.2, 22.7 ± 0.2, 24.2 ± 0.2, 25.4 ± 0.2, and 25.5 ± 0.2.

[0132] In some embodiments, Hydrate Form A is characterized by an X-ray powder diffractogram having a signal at at least two two-theta values chosen from 6.2 ± 0.2, 12.2 ± 0.2, 12.4 ± 0.2, 18.3 ± 0.2, 19.0 ± 0.2, 19.1 ± 0.2, 19.6 ± 0.2, 19.9 ± 0.2 and 25.5 ± 0.2. In some embodiments, Hydrate Form A is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 6.2 ± 0.2, 12.2 ± 0.2, 12.4 ± 0.2, 18.3 ± 0.2, 19.0 ± 0.2, 19.1 ± 0.2, 19.6 ± 0.2, 19.9 ± 0.2 and 25.5 ± 0.2. In some embodiments, Hydrate Form A is characterized by an X-ray powder diffractogram having a signal at at least four two-theta values chosen from 6.2 ± 0.2, 12.2 ± 0.2, 12.4 ± 0.2, 18.3 ± 0.2, 19.0 ± 0.2, 19.1 ± 0.2, 19.6 ± 0.2, 19.9 ± 0.2 and 25.5 ± 0.2. In some embodiments, Hydrate Form A is characterized by an X-ray powder diffractogram having a signal at at least five two-theta values chosen from 6.2 ± 0.2, 12.2 ± 0.2, 12.4 ± 0.2, 18.3 ± 0.2, 19.0 ± 0.2, 19.1 ± 0.2, 19.6 ± 0.2, 19.9 ± 0.2 and 25.5 ± 0.2. In some embodiments, Hydrate Form A is characterized by an X-ray powder diffractogram having a signal at at least six two-theta values chosen from 6.2 ± 0.2, 12.2 ± 0.2, 12.4 ± 0.2, 18.3 ± 0.2, 19.0 ± 0.2, 19.1 ± 0.2, 19.6 ± 0.2, 19.9 ± 0.2 and 25.5 ± 0.2. In some embodiments, Hydrate Form A is characterized by an X-ray powder diffractogram having a signal at at least seven two-theta values chosen from 6.2 ± 0.2, 12.2 ± 0.2, 12.4 ± 0.2, 18.3 ± 0.2, 19.0 ± 0.2, 19.1 ± 0.2, 19.6 ± 0.2, 19.9 ± 0.2 and 25.5 ± 0.2. In some embodiments, Hydrate Form A is characterized by an X-ray powder diffractogram having a signal at at least eight two-theta values chosen from 6.2 ± 0.2, 12.2 ± 0.2, 12.4 ± 0.2, 18.3 ± 0.2, 19.0 ± 0.2, 19.1 ± 0.2, 19.6 ± 0.2, 19.9 ± 0.2 and 25.5 ± 0.2. In some embodiments, Hydrate Form A is characterized by an X-ray powder diffractogram having a signal at at least nine two-theta values chosen from 6.2 ± 0.2, 12.2 ± 0.2, 12.4 ± 0.2, 18.3 ± 0.2, 19.0 ± 0.2, 19.1 ± 0.2, 19.6 ± 0.2, 19.9 ± 0.2 and 25.5 ± 0.2.

[0133] In some embodiments, Hydrate Form A is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 6.2 ± 0.2, 12.2 ± 0.2, 12.4 ± 0.2, 18.3 ± 0.2, 19.0 ± 0.2, 19.1 ± 0.2, 19.6 ± 0.2, 19.9 ± 0.2, 20.2 ± 0.2, 22.7 ± 0.2, 24.2 ± 0.2, 25.4 ± 0.2, 25.5 ± 0.2, and 27.2 ± 0.2. In some embodiments, Hydrate Form A is characterized by an X-ray powder diffractogram having a signal at at least four two-theta values chosen from 6.2 ± 0.2, 12.2 ± 0.2, 12.4 ± 0.2, 18.3 ± 0.2, 19.0 ± 0.2, 19.1 ± 0.2, 19.6 ± 0.2, 19.9 ± 0.2, 20.2 ± 0.2, 22.7 ± 0.2, 24.2 ± 0.2, 25.4 ± 0.2, 25.5 ± 0.2, and 27.2 ± 0.2. In some embodiments, Hydrate Form A is characterized by an X-ray powder diffractogram having a signal at at least five two-theta values chosen from 6.2 ± 0.2, 12.2 ± 0.2, 12.4 ± 0.2, 18.3 ± 0.2, 19.0 ± 0.2, 19.1 ± 0.2, 19.6 ± 0.2, 19.9 ± 0.2, 20.2 ± 0.2, 22.7 ± 0.2, 24.2 ± 0.2, 25.4 ± 0.2, 25.5 ± 0.2, and 27.2 ± 0.2. In some embodiments, Hydrate Form A is characterized by an X-ray powder diffractogram having a signal at at least six two-theta values chosen from 6.2 ± 0.2, 12.2 ± 0.2, 12.4 ± 0.2, 18.3 ± 0.2, 19.0 ± 0.2, 19.1 ± 0.2, 19.6 ± 0.2, 19.9 ± 0.2, 20.2 ± 0.2, 22.7 ± 0.2, 24.2 ± 0.2, 25.4 ± 0.2, 25.5 ± 0.2, and 27.2 ± 0.2. In some embodiments, Hydrate Form A is characterized by an X-ray powder diffractogram having a signal at at least seven two-theta values chosen from 6.2 ± 0.2, 12.2 ± 0.2, 12.4 ± 0.2, 18.3 ± 0.2, 19.0 ± 0.2, 19.1 ± 0.2, 19.6 ± 0.2, 19.9 ± 0.2, 20.2 ± 0.2, 22.7 ± 0.2, 24.2 ± 0.2, 25.4 ± 0.2, 25.5 ± 0.2, and 27.2 ± 0.2. In some embodiments, Hydrate Form A is characterized by an X-ray powder diffractogram having a signal at at least eight two-theta values chosen from 6.2 ± 0.2, 12.2 ± 0.2, 12.4 ± 0.2, 18.3 ± 0.2, 19.0 ± 0.2, 19.1 ± 0.2, 19.6 ± 0.2, 19.9 ± 0.2, 20.2 ± 0.2, 22.7 ± 0.2, 24.2 ± 0.2, 25.4 ± 0.2, 25.5 ± 0.2, and 27.2 ± 0.2. In some embodiments, Hydrate Form A is characterized by an X-ray powder diffractogram having a signal at at least nine two-theta values chosen from 6.2 ± 0.2, 12.2 ± 0.2, 12.4 ± 0.2, 18.3 ± 0.2, 19.0 ± 0.2, 19.1 ± 0.2, 19.6 ± 0.2, 19.9 ± 0.2, 20.2 ± 0.2, 22.7 ± 0.2, 24.2 ± 0.2, 25.4 ± 0.2, 25.5 ± 0.2, and 27.2 ± 0.2. In some embodiments, Hydrate Form A is characterized by an X-ray powder diffractogram having a signal at at least ten two-theta values chosen from 6.2 ± 0.2, 12.2 ± 0.2, 12.4 ± 0.2, 18.3 ± 0.2, 19.0 ± 0.2, 19.1 ± 0.2, 19.6 ± 0.2, 19.9 ± 0.2, 20.2 ± 0.2, 22.7 ± 0.2, 24.2 ± 0.2, 25.4 ± 0.2, 25.5 ± 0.2, and 27.2 ± 0.2. In some embodiments, Hydrate Form A is characterized by an X-ray powder diffractogram having a signal at at least eleven two-theta values chosen from 6.2 ± 0.2, 12.2 ± 0.2, 12.4 ± 0.2, 18.3 ± 0.2, 19.0 ± 0.2, 19.1 ± 0.2, 19.6 ± 0.2, 19.9 ± 0.2, 20.2 ± 0.2, 22.7 ± 0.2, 24.2 ± 0.2, 25.4 ± 0.2, 25.5 ± 0.2, and 27.2 ± 0.2. In some embodiments, Hydrate Form A is characterized by an X-ray powder diffractogram having a signal at at least twelve two-theta values chosen from 6.2 ± 0.2, 12.2 ± 0.2, 12.4 ± 0.2, 18.3 ± 0.2, 19.0 ± 0.2, 19.1 ± 0.2, 19.6 ± 0.2, 19.9 ± 0.2, 20.2 ± 0.2, 22.7 ± 0.2, 24.2 ± 0.2, 25.4 ± 0.2, 25.5 ± 0.2, and 27.2 ± 0.2. In some embodiments, Hydrate Form A is characterized by an X-ray powder diffractogram having a signal at at least thirteen two-theta values chosen from 6.2 ± 0.2, 12.2 ± 0.2, 12.4 ± 0.2, 18.3 ± 0.2, 19.0 ± 0.2, 19.1 ± 0.2, 19.6 ± 0.2, 19.9 ± 0.2, 20.2 ± 0.2, 22.7 ± 0.2, 24.2 ± 0.2, 25.4 ± 0.2, 25.5 ± 0.2, and 27.2 ± 0.2. In some embodiments, Hydrate Form A is characterized by an X-ray powder diffractogram having a signal at at least fourteen two-theta values chosen from 6.2 ± 0.2, 12.2 ± 0.2, 12.4 ± 0.2, 18.3 ± 0.2, 19.0 ± 0.2, 19.1 ± 0.2, 19.6 ± 0.2, 19.9 ± 0.2, 20.2 ± 0.2, 22.7 ± 0.2, 24.2 ± 0.2, 25.4 ± 0.2, 25.5 ± 0.2, and 27.2 ± 0.2. In some embodiments, Hydrate Form A is characterized by an X-ray powder diffractogram having a signal at at least fifteen two-theta values chosen from 6.2 ± 0.2, 12.2 ± 0.2, 12.4 ± 0.2, 18.3 ± 0.2, 19.0 ± 0.2, 19.1 ± 0.2, 19.6 ± 0.2, 19.9 ± 0.2, 20.2 ± 0.2, 22.7 ± 0.2, 24.2 ± 0.2, 25.4 ± 0.2, 25.5 ± 0.2, and 27.2 ± 0.2. In some embodiments, Hydrate Form A is characterized by an X-ray powder diffractogram having a signal at at least sixteen two-theta values chosen from 6.2 ± 0.2, 12.2 ± 0.2, 12.4 ± 0.2, 18.3 ± 0.2, 19.0 ± 0.2, 19.1 ± 0.2, 19.6 ± 0.2, 19.9 ± 0.2, 20.2 ± 0.2, 22.7 ± 0.2, 24.2 ± 0.2, 25.4 ± 0.2, 25.5 ± 0.2, and 27.2 ± 0.2. In some embodiments, Hydrate Form A is characterized by an X-ray powder diffractogram having a signal at at least seventeen two-theta values chosen from 6.2 ± 0.2, 12.2 ± 0.2, 12.4 ± 0.2, 18.3 ± 0.2, 19.0 ± 0.2, 19.1 ± 0.2, 19.6 ± 0.2, 19.9 ± 0.2, 20.2 ± 0.2, 22.7 ± 0.2, 24.2 ± 0.2, 25.4 ± 0.2, 25.5 ± 0.2, and 27.2 ± 0.2. In some embodiments, Hydrate Form A is characterized by an X-ray powder diffractogram having a signal at at least eighteen two-theta values chosen from 6.2 ± 0.2, 12.2 ± 0.2, 12.4 ± 0.2, 18.3 ± 0.2, 19.0 ± 0.2, 19.1 ± 0.2, 19.6 ± 0.2, 19.9 ± 0.2, 20.2 ± 0.2, 22.7 ± 0.2, 24.2 ± 0.2, 25.4 ± 0.2, 25.5 ± 0.2, and 27.2 ± 0.2. In some embodiments, Hydrate Form A is characterized by an X-ray powder diffractogram having a signal at at least nineteen two-theta values chosen from 6.2 ± 0.2, 12.2 ± 0.2, 12.4 ± 0.2, 18.3 ± 0.2, 19.0 ± 0.2, 19.1 ± 0.2, 19.6 ± 0.2, 19.9 ± 0.2, 20.2 ± 0.2, 22.7 ± 0.2, 24.2 ± 0.2, 25.4 ± 0.2, 25.5 ± 0.2, and 27.2 ± 0.2. In some embodiments, Hydrate Form A is characterized by an X-ray powder diffractogram having a signal at 6.2 ± 0.2, 12.2 ± 0.2, 12.4 ± 0.2, 18.3 ± 0.2, 19.0 ± 0.2, 19.1 ± 0.2, 19.6 ± 0.2, 19.9 ± 0.2, 20.2 ± 0.2, 22.7 ± 0.2, 24.2 ± 0.2, 25.4 ± 0.2, 25.5 ± 0.2, and 27.2 ± 0.2 two-theta.

[0134] In some embodiments, disclosed herein is a composition comprising Hydrate Form A of Compound 2. In some embodiments, disclosed herein is a composition comprising Compound 2 in substantially pure Hydrate Form A. In some embodiments, disclosed herein is a composition comprising at least one active compound consisting essentially of Compound 2 in Hydrate Form A.

[0135] In some embodiments, Hydrate Form A is characterized by a DSC curve substantially similar to that in FIG. 11. In some embodiments, Hydrate Form A is characterized by a DSC curve having a peak at at least one temperature chosen from 97°C, 137°C, 164°C, 185°C, and 222°C.

[0136] In some embodiments, Hydrate Form A is characterized by a 13< C NMR spectrum having a signal at at least one ppm value chosen from 177.5 ± 0.2 ppm, 157.7 ± 0.2 ppm, 128.9 ± 0.2 ppm, 95.4 ± 0.2 ppm, 36.9 ± 0.2 ppm, 23.0 ± 0.2 ppm, and 22.3 ± 0.2 ppm. In some embodiments, Hydrate Form A is characterized by a 13< C NMR spectrum having a signal at at least two ppm values chosen from 177.5 ± 0.2 ppm, 157.7 ± 0.2 ppm, 128.9 ± 0.2 ppm, 95.4 ± 0.2 ppm, 36.9 ± 0.2 ppm, 23.0 ± 0.2 ppm, and 22.3 ± 0.2 ppm. In some embodiments, Hydrate Form A is characterized by a 13< C NMR spectrum having a signal at at least three ppm values chosen from 177.5 ± 0.2 ppm, 157.7 ± 0.2 ppm, 128.9 ± 0.2 ppm, 95.4 ± 0.2 ppm, 36.9 ± 0.2 ppm, 23.0 ± 0.2 ppm, and 22.3 ± 0.2 ppm. In some embodiments, Hydrate Form A is characterized by a 13< C NMR spectrum having a signal at at least four ppm values chosen from 177.5 ± 0.2 ppm, 157.7 ± 0.2 ppm, 128.9 ± 0.2 ppm, 95.4 ± 0.2 ppm, 36.9 ± 0.2 ppm, 23.0 ± 0.2 ppm, and 22.3 ± 0.2 ppm. In some embodiments, Hydrate Form A is characterized by a 13< C NMR spectrum having a signal at at least five ppm values chosen from 177.5 ± 0.2 ppm, 157.7 ± 0.2 ppm, 128.9 ± 0.2 ppm, 95.4 ± 0.2 ppm, 36.9 ± 0.2 ppm, 23.0 ± 0.2 ppm, and 22.3 ± 0.2 ppm. In some embodiments, Hydrate Form A is characterized by a 13< C NMR spectrum having a signal at at least six ppm values chosen from 177.5 ± 0.2 ppm, 157.7 ± 0.2 ppm, 128.9 ± 0.2 ppm, 95.4 ± 0.2 ppm, 36.9 ± 0.2 ppm, 23.0 ± 0.2 ppm, and 22.3 ± 0.2 ppm. In some embodiments, Hydrate Form A is characterized by a 13< C NMR spectrum having a signal at 177.5 ± 0.2 ppm, 157.7 ± 0.2 ppm, 128.9 ± 0.2 ppm, 95.4 ± 0.2 ppm, 36.9 ± 0.2 ppm, 23.0 ± 0.2 ppm, and 22.3 ± 0.2 ppm.

[0137] In some embodiments, Hydrate Form A is characterized by a 19< F NMR spectrum having a signal at at least one ppm value chosen from -113.8 ± 0.2 ppm, - 125.8 ± 0.2 ppm, and -132.8 ± 0.2 ppm. In some embodiments, Hydrate Form A is characterized by a 19< F NMR spectrum having a signal at at least two ppm values chosen from -113.8 ± 0.2 ppm, -125.8 ± 0.2 ppm, and -132.8 ± 0.2 ppm. In some embodiments, Hydrate Form A is characterized by a 19< F NMR spectrum having signals at at -113.8 ± 0.2 ppm, -125.8 ± 0.2 ppm, and -132.8 ± 0.2 ppm.

[0138] In some embodiments, Compound 2 is a crystalline solid. In some embodiments, the crystalline solid consists of 1% to 99% Hydrate Form A relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 2% to 99% Hydrate Form A relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 5% to 99% Hydrate Form A relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 10% to 99% Hydrate Form A relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 15% to 99% Hydrate Form A relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 20% to 99% Hydrate Form A relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 25% to 99% Hydrate Form A relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 30% to 99% Hydrate Form A relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 35% to 99% Hydrate Form A relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 45% to 99% Hydrate Form A relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 50% to 99% Hydrate Form A relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 55% to 99% Hydrate Form A relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 60% to 99% Hydrate Form A relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 65% to 99% Hydrate Form A relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 70% to 99% Hydrate Form A relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 75% to 99% Hydrate Form A relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 80% to 99% Hydrate Form A relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 85% to 99% Hydrate Form A relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 90% to 99% Hydrate Form A relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 95% to 99% Hydrate Form A relative to the total weight of the crystalline solid Compound 2.Hydrate Form B of Compound 2

[0139] In some embodiments, Compound 2 is in the form of Hydrate Form B. In some embodiments, Compound 2 is in the form of substantially pure Hydrate Form B. In some embodiments, Hydrate Form B is characterized by an X-ray powder diffractogram substantially similar to that in FIG. 12. In some embodiments, Hydrate Form B is characterized by an X-ray powder diffractogram having a signal at at least two two-theta values chosen from 3.8 ± 0.2, 9.0 ± 0.2, 9.3 ± 0.2, 18.7 ± 0.2, 19.1 ± 0.2, 20.8 ± 0.2, 21.1 ± 0.2, 24.6 ± 0.2, and 26.8 ± 0.2. In some embodiments, Hydrate Form B is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 3.8 ± 0.2, 9.0 ± 0.2, 9.3 ± 0.2, 18.7 ± 0.2, 19.1 ± 0.2, 20.8 ± 0.2, 21.1 ± 0.2, 24.6 ± 0.2, and 26.8 ± 0.2. In some embodiments, Hydrate Form B is characterized by an X-ray powder diffractogram having a signal at at least four two-theta values chosen from 3.8 ± 0.2, 9.0 ± 0.2, 9.3 ± 0.2, 18.7 ± 0.2, 19.1 ± 0.2, 20.8 ± 0.2, 21.1 ± 0.2, 24.6 ± 0.2, and 26.8 ± 0.2. In some embodiments, Hydrate Form B is characterized by an X-ray powder diffractogram having a signal at at least five two-theta values chosen from 3.8 ± 0.2, 9.0 ± 0.2, 9.3 ± 0.2, 18.7 ± 0.2, 19.1 ± 0.2, 20.8 ± 0.2, 21.1 ± 0.2, 24.6 ± 0.2, and 26.8 ± 0.2. In some embodiments, Hydrate Form B is characterized by an X-ray powder diffractogram having a signal at at least six two-theta values chosen from 3.8 ± 0.2, 9.0 ± 0.2, 9.3 ± 0.2, 18.7 ± 0.2, 19.1 ± 0.2, 20.8 ± 0.2, 21.1 ± 0.2, 24.6 ± 0.2, and 26.8 ± 0.2. In some embodiments, Hydrate Form B is characterized by an X-ray powder diffractogram having a signal at at least seven two-theta values chosen from 3.8 ± 0.2, 9.0 ± 0.2, 9.3 ± 0.2, 18.7 ± 0.2, 19.1 ± 0.2, 20.8 ± 0.2, 21.1 ± 0.2, 24.6 ± 0.2, and 26.8 ± 0.2. In some embodiments, Hydrate Form B is characterized by an X-ray powder diffractogram having a signal at at least eight two-theta values chosen from 3.8 ± 0.2, 9.0 ± 0.2, 9.3 ± 0.2, 18.7 ± 0.2, 19.1 ± 0.2, 20.8 ± 0.2, 21.1 ± 0.2, 24.6 ± 0.2, and 26.8 ± 0.2. In some embodiments, Hydrate Form B is characterized by an X-ray powder diffractogram having a signal at 3.8 ± 0.2, 9.0 ± 0.2, 9.3 ± 0.2, 18.7 ± 0.2, 19.1 ± 0.2, 20.8 ± 0.2, 21.1 ± 0.2, 24.6 ± 0.2, and 26.8 ± 0.2 two-theta.

[0140] In some embodiments, Hydrate Form B is characterized by an X-ray powder diffractogram having a signal at at least two two-theta values chosen from 3.8 ± 0.2, 7.6 ± 0.2, 9.0 ± 0.2, 9.3 ± 0.2, 18.7 ± 0.2, and 19.1 ± 0.2. In some embodiments, Hydrate Form B is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 3.8 ± 0.2, 7.6 ± 0.2, 9.0 ± 0.2, 9.3 ± 0.2, 18.7 ± 0.2, and 19.1 ± 0.2. In some embodiments, Hydrate Form B is characterized by an X-ray powder diffractogram having a signal at at least four two-theta values chosen from 3.8 ± 0.2, 7.6 ± 0.2, 9.0 ± 0.2, 9.3 ± 0.2, 18.7 ± 0.2, and 19.1 ± 0.2. In some embodiments, Hydrate Form B is characterized by an X-ray powder diffractogram having a signal at at least five two-theta values chosen from 3.8 ± 0.2, 7.6 ± 0.2, 9.0 ± 0.2, 9.3 ± 0.2, 18.7 ± 0.2, and 19.1 ± 0.2. In some embodiments, Hydrate Form B is characterized by an X-ray powder diffractogram having a signal at 3.8 ± 0.2, 7.6 ± 0.2, 9.0 ± 0.2, 9.3 ± 0.2, 18.7 ± 0.2, and 19.1 ± 0.2 two-theta.

[0141] In some embodiments, Hydrate Form B is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 3.8 ± 0.2, 7.6 ± 0.2, 9.0 ± 0.2, 9.3 ± 0.2, 10.2 ± 0.2, 11.0 ± 0.2, 12.5 ± 0.2, 13.7 ± 0.2, 15.4 ± 0.2, 16.7 ± 0.2, 18.7 ± 0.2, 19.1 ± 0.2, 20.2 ± 0.2, 20.8 ± 0.2, 21.1 ± 0.2, 21.7 ± 0.2, 22.0 ± 0.2, 22.9 ± 0.2, 24.6 ± 0.2, 26.4 ± 0.2, 26.8 ± 0.2, and 29.4 ± 0.2. In some embodiments, Hydrate Form B is characterized by an X-ray powder diffractogram having a signal at at least four two-theta values chosen from 3.8 ± 0.2, 7.6 ± 0.2, 9.0 ± 0.2, 9.3 ± 0.2, 10.2 ± 0.2, 11.0 ± 0.2, 12.5 ± 0.2, 13.7 ± 0.2, 15.4 ± 0.2, 16.7 ± 0.2, 18.7 ± 0.2, 19.1 ± 0.2, 20.2 ± 0.2, 20.8 ± 0.2, 21.1 ± 0.2, 21.7 ± 0.2, 22.0 ± 0.2, 22.9 ± 0.2, 24.6 ± 0.2, 26.4 ± 0.2, 26.8 ± 0.2, and 29.4 ± 0.2. In some embodiments, Hydrate Form B is characterized by an X-ray powder diffractogram having a signal at at least five two-theta values chosen from 3.8 ± 0.2, 7.6 ± 0.2, 9.0 ± 0.2, 9.3 ± 0.2, 10.2 ± 0.2, 11.0 ± 0.2, 12.5 ± 0.2, 13.7 ± 0.2, 15.4 ± 0.2, 16.7 ± 0.2, 18.7 ± 0.2, 19.1 ± 0.2, 20.2 ± 0.2, 20.8 ± 0.2, 21.1 ± 0.2, 21.7 ± 0.2, 22.0 ± 0.2, 22.9 ± 0.2, 24.6 ± 0.2, 26.4 ± 0.2, 26.8 ± 0.2, and 29.4 ± 0.2. In some embodiments, Hydrate Form B is characterized by an X-ray powder diffractogram having a signal at at least six two-theta values chosen from 3.8 ± 0.2, 7.6 ± 0.2, 9.0 ± 0.2, 9.3 ± 0.2, 10.2 ± 0.2, 11.0 ± 0.2, 12.5 ± 0.2, 13.7 ± 0.2, 15.4 ± 0.2, 16.7 ± 0.2, 18.7 ± 0.2, 19.1 ± 0.2, 20.2 ± 0.2, 20.8 ± 0.2, 21.1 ± 0.2, 21.7 ± 0.2, 22.0 ± 0.2, 22.9 ± 0.2, 24.6 ± 0.2, 26.4 ± 0.2, 26.8 ± 0.2, and 29.4 ± 0.2. In some embodiments, Hydrate Form B is characterized by an X-ray powder diffractogram having a signal at at least seven two-theta values chosen from 3.8 ± 0.2, 7.6 ± 0.2, 9.0 ± 0.2, 9.3 ± 0.2, 10.2 ± 0.2, 11.0 ± 0.2, 12.5 ± 0.2, 13.7 ± 0.2, 15.4 ± 0.2, 16.7 ± 0.2, 18.7 ± 0.2, 19.1 ± 0.2, 20.2 ± 0.2, 20.8 ± 0.2, 21.1 ± 0.2, 21.7 ± 0.2, 22.0 ± 0.2, 22.9 ± 0.2, 24.6 ± 0.2, 26.4 ± 0.2, 26.8 ± 0.2, and 29.4 ± 0.2. In some embodiments, Hydrate Form B is characterized by an X-ray powder diffractogram having a signal at at least eight two-theta values chosen from 3.8 ± 0.2, 7.6 ± 0.2, 9.0 ± 0.2, 9.3 ± 0.2, 10.2 ± 0.2, 11.0 ± 0.2, 12.5 ± 0.2, 13.7 ± 0.2, 15.4 ± 0.2, 16.7 ± 0.2, 18.7 ± 0.2, 19.1 ± 0.2, 20.2 ± 0.2, 20.8 ± 0.2, 21.1 ± 0.2, 21.7 ± 0.2, 22.0 ± 0.2, 22.9 ± 0.2, 24.6 ± 0.2, 26.4 ± 0.2, 26.8 ± 0.2, and 29.4 ± 0.2. In some embodiments, Hydrate Form B is characterized by an X-ray powder diffractogram having a signal at at least nine two-theta values chosen from 3.8 ± 0.2, 7.6 ± 0.2, 9.0 ± 0.2, 9.3 ± 0.2, 10.2 ± 0.2, 11.0 ± 0.2, 12.5 ± 0.2, 13.7 ± 0.2, 15.4 ± 0.2, 16.7 ± 0.2, 18.7 ± 0.2, 19.1 ± 0.2, 20.2 ± 0.2, 20.8 ± 0.2, 21.1 ± 0.2, 21.7 ± 0.2, 22.0 ± 0.2, 22.9 ± 0.2, 24.6 ± 0.2, 26.4 ± 0.2, 26.8 ± 0.2, and 29.4 ± 0.2. In some embodiments, Hydrate Form B is characterized by an X-ray powder diffractogram having a signal at at least ten two-theta values chosen from 3.8 ± 0.2, 7.6 ± 0.2, 9.0 ± 0.2, 9.3 ± 0.2, 10.2 ± 0.2, 11.0 ± 0.2, 12.5 ± 0.2, 13.7 ± 0.2, 15.4 ± 0.2, 16.7 ± 0.2, 18.7 ± 0.2, 19.1 ± 0.2, 20.2 ± 0.2, 20.8 ± 0.2, 21.1 ± 0.2, 21.7 ± 0.2, 22.0 ± 0.2, 22.9 ± 0.2, 24.6 ± 0.2, 26.4 ± 0.2, 26.8 ± 0.2, and 29.4 ± 0.2. In some embodiments, Hydrate Form B is characterized by an X-ray powder diffractogram having a signal at at least eleven two-theta values chosen from 3.8 ± 0.2, 7.6 ± 0.2, 9.0 ± 0.2, 9.3 ± 0.2, 10.2 ± 0.2, 11.0 ± 0.2, 12.5 ± 0.2, 13.7 ± 0.2, 15.4 ± 0.2, 16.7 ± 0.2, 18.7 ± 0.2, 19.1 ± 0.2, 20.2 ± 0.2, 20.8 ± 0.2, 21.1 ± 0.2, 21.7 ± 0.2, 22.0 ± 0.2, 22.9 ± 0.2, 24.6 ± 0.2, 26.4 ± 0.2, 26.8 ± 0.2, and 29.4 ± 0.2. In some embodiments, Hydrate Form B is characterized by an X-ray powder diffractogram having a signal at at least twelve two-theta values chosen from 3.8 ± 0.2, 7.6 ± 0.2, 9.0 ± 0.2, 9.3 ± 0.2, 10.2 ± 0.2, 11.0 ± 0.2, 12.5 ± 0.2, 13.7 ± 0.2, 15.4 ± 0.2, 16.7 ± 0.2, 18.7 ± 0.2, 19.1 ± 0.2, 20.2 ± 0.2, 20.8 ± 0.2, 21.1 ± 0.2, 21.7 ± 0.2, 22.0 ± 0.2, 22.9 ± 0.2, 24.6 ± 0.2, 26.4 ± 0.2, 26.8 ± 0.2, and 29.4 ± 0.2. In some embodiments, Hydrate Form B is characterized by an X-ray powder diffractogram having a signal at at least thirteen two-theta values chosen from 3.8 ± 0.2, 7.6 ± 0.2, 9.0 ± 0.2, 9.3 ± 0.2, 10.2 ± 0.2, 11.0 ± 0.2, 12.5 ± 0.2, 13.7 ± 0.2, 15.4 ± 0.2, 16.7 ± 0.2, 18.7 ± 0.2, 19.1 ± 0.2, 20.2 ± 0.2, 20.8 ± 0.2, 21.1 ± 0.2, 21.7 ± 0.2, 22.0 ± 0.2, 22.9 ± 0.2, 24.6 ± 0.2, 26.4 ± 0.2, 26.8 ± 0.2, and 29.4 ± 0.2. In some embodiments, Hydrate Form B is characterized by an X-ray powder diffractogram having a signal at at least fourteen two-theta values chosen from 3.8 ± 0.2, 7.6 ± 0.2, 9.0 ± 0.2, 9.3 ± 0.2, 10.2 ± 0.2, 11.0 ± 0.2, 12.5 ± 0.2, 13.7 ± 0.2, 15.4 ± 0.2, 16.7 ± 0.2, 18.7 ± 0.2, 19.1 ± 0.2, 20.2 ± 0.2, 20.8 ± 0.2, 21.1 ± 0.2, 21.7 ± 0.2, 22.0 ± 0.2, 22.9 ± 0.2, 24.6 ± 0.2, 26.4 ± 0.2, 26.8 ± 0.2, and 29.4 ± 0.2. In some embodiments, Hydrate Form B is characterized by an X-ray powder diffractogram having a signal at at least fifteen two-theta values chosen from 3.8 ± 0.2, 7.6 ± 0.2, 9.0 ± 0.2, 9.3 ± 0.2, 10.2 ± 0.2, 11.0 ± 0.2, 12.5 ± 0.2, 13.7 ± 0.2, 15.4 ± 0.2, 16.7 ± 0.2, 18.7 ± 0.2, 19.1 ± 0.2, 20.2 ± 0.2, 20.8 ± 0.2, 21.1 ± 0.2, 21.7 ± 0.2, 22.0 ± 0.2, 22.9 ± 0.2, 24.6 ± 0.2, 26.4 ± 0.2, 26.8 ± 0.2, and 29.4 ± 0.2.

[0142] In some embodiments, disclosed herein is a composition comprising Hydrate Form B of Compound 2. In some embodiments, disclosed herein is a composition comprising Compound 2 in substantially pure Hydrate Form B. In some embodiments, disclosed herein is a composition comprising at least one active compound consisting essentially of Compound 2 in Hydrate Form B.

[0143] In some embodiments, Hydrate Form B is characterized by a 19< F NMR spectrum having a signal at at least one ppm value chosen from -117.0 ± 0.2 ppm, - 119.1 ± 0.2 ppm, and -137.7 ± 0.2 ppm. In some embodiments, Hydrate Form B is characterized by a 19< F NMR spectrum having a signal at at least two ppm values chosen from -117.0 ± 0.2 ppm, -119.1 ± 0.2 ppm, and -137.7 ± 0.2 ppm. In some embodiments, Hydrate Form B is characterized by a 19< F NMR spectrum having signals at at -117.0 ± 0.2 ppm, -119.1 ± 0.2 ppm, and -137.7 ± 0.2 ppm.

[0144] In some embodiments, Compound 2 is a crystalline solid. In some embodiments, the crystalline solid consists of 1% to 99% Hydrate Form B relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 2% to 99% Hydrate Form B relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 5% to 99% Hydrate Form B relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 10% to 99% Hydrate Form B relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 15% to 99% Hydrate Form B relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 20% to 99% Hydrate Form B relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 25% to 99% Hydrate Form B relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 30% to 99% Hydrate Form B relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 35% to 99% Hydrate Form B relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 45% to 99% Hydrate Form B relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 50% to 99% Hydrate Form B relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 55% to 99% Hydrate Form B relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 60% to 99% Hydrate Form B relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 65% to 99% Hydrate Form B relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 70% to 99% Hydrate Form B relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 75% to 99% Hydrate Form B relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 80% to 99% Hydrate Form B relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 85% to 99% Hydrate Form B relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 90% to 99% Hydrate Form B relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 95% to 99% Hydrate Form B relative to the total weight of the crystalline solid Compound 2.

[0145] In some embodiments, Compound 2 is a crystalline solid. In some embodiments, Compound 2 is a crystalline solid comprising 60% to 99.9% Hydrate Form A relative to the total weight of the crystalline solid Compound 2 and 0.1% to 40% Hydrate Form B relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid comprises 70% to 95% Hydrate Form A relative to the total weight of the crystalline solid Compound 2 and 5% to 30% Hydrate Form B relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid comprises 80% to 90% Hydrate Form A relative to the total weight of the crystalline solid Compound 2 and 10% to 20% Hydrate Form B relative to the total weight of the crystalline solid Compound 2.Hydrate Form C of Compound 2

[0146] In some embodiments, Compound 2 is in the form of Hydrate Form C. In some embodiments, Compound 2 is in the form of substantially pure Hydrate Form C. In some embodiments, Hydrate Form C is characterized by an X-ray powder diffractogram substantially similar to that in FIG. 14. In some embodiments, Hydrate Form C is characterized by an X-ray powder diffractogram having a signal at at least two two-theta values chosen from 3.7 ± 0.2, 10.4 ± 0.2, 10.7 ± 0.2, 13.2 ± 0.2, 14.6 ± 0.2, 15.7 ± 0.2, 18.3 ± 0.2, 21.8 ± 0.2, and 24.9 ± 0.2. In some embodiments, Hydrate Form C is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 3.7 ± 0.2, 10.4 ± 0.2, 10.7 ± 0.2, 13.2 ± 0.2, 14.6 ± 0.2, 15.7 ± 0.2, 18.3 ± 0.2, 21.8 ± 0.2, and 24.9 ± 0.2. In some embodiments, Hydrate Form C is characterized by an X-ray powder diffractogram having a signal at at least four two-theta values chosen from 3.7 ± 0.2, 10.4 ± 0.2, 10.7 ± 0.2, 13.2 ± 0.2, 14.6 ± 0.2, 15.7 ± 0.2, 18.3 ± 0.2, 21.8 ± 0.2, and 24.9 ± 0.2. In some embodiments, Hydrate Form C is characterized by an X-ray powder diffractogram having a signal at at least five two-theta values chosen from 3.7 ± 0.2, 10.4 ± 0.2, 10.7 ± 0.2, 13.2 ± 0.2, 14.6 ± 0.2, 15.7 ± 0.2, 18.3 ± 0.2, 21.8 ± 0.2, and 24.9 ± 0.2. In some embodiments, Hydrate Form C is characterized by an X-ray powder diffractogram having a signal at at least six two-theta values chosen from 3.7 ± 0.2, 10.4 ± 0.2, 10.7 ± 0.2, 13.2 ± 0.2, 14.6 ± 0.2, 15.7 ± 0.2, 18.3 ± 0.2, 21.8 ± 0.2, and 24.9 ± 0.2. In some embodiments, Hydrate Form C is characterized by an X-ray powder diffractogram having a signal at at least seven two-theta values chosen from 3.7 ± 0.2, 10.4 ± 0.2, 10.7 ± 0.2, 13.2 ± 0.2, 14.6 ± 0.2, 15.7 ± 0.2, 18.3 ± 0.2, 21.8 ± 0.2, and 24.9 ± 0.2. In some embodiments, Hydrate Form C is characterized by an X-ray powder diffractogram having a signal at at least eight two-theta values chosen from 3.7 ± 0.2, 10.4 ± 0.2, 10.7 ± 0.2, 13.2 ± 0.2, 14.6 ± 0.2, 15.7 ± 0.2, 18.3 ± 0.2, 21.8 ± 0.2, and 24.9 ± 0.2. In some embodiments, Hydrate Form C is characterized by an X-ray powder diffractogram having a signal at 3.7 ± 0.2, 10.4 ± 0.2, 10.7 ± 0.2, 13.2 ± 0.2, 14.6 ± 0.2, 15.7 ± 0.2, 18.3 ± 0.2, 21.8 ± 0.2, and 24.9 ± 0.2 two-theta.

[0147] In some embodiments, Hydrate Form C is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 3.7 ± 0.2, 10.4 ± 0.2, 10.7 ± 0.2, 11.3 ± 0.2, 12.2 ± 0.2, 13.2 ± 0.2, 14.6 ± 0.2, 15.7 ± 0.2, 18.3 ± 0.2, 18.6 ± 0.2, 21.0 ± 0.2, 21.8 ± 0.2, 22.0 ± 0.2, 24.0 ± 0.2, 24.6 ± 0.2, and 24.9 ± 0.2. In some embodiments, Hydrate Form C is characterized by an X-ray powder diffractogram having a signal at at least four two-theta values chosen from 3.7 ± 0.2, 10.4 ± 0.2, 10.7 ± 0.2, 11.3 ± 0.2, 12.2 ± 0.2, 13.2 ± 0.2, 14.6 ± 0.2, 15.7 ± 0.2, 18.3 ± 0.2, 18.6 ± 0.2, 21.0 ± 0.2, 21.8 ± 0.2, 22.0 ± 0.2, 24.0 ± 0.2, 24.6 ± 0.2, and 24.9 ± 0.2. In some embodiments, Hydrate Form C is characterized by an X-ray powder diffractogram having a signal at at least five two-theta values chosen from 3.7 ± 0.2, 10.4 ± 0.2, 10.7 ± 0.2, 11.3 ± 0.2, 12.2 ± 0.2, 13.2 ± 0.2, 14.6 ± 0.2, 15.7 ± 0.2, 18.3 ± 0.2, 18.6 ± 0.2, 21.0 ± 0.2, 21.8 ± 0.2, 22.0 ± 0.2, 24.0 ± 0.2, 24.6 ± 0.2, and 24.9 ± 0.2. In some embodiments, Hydrate Form C is characterized by an X-ray powder diffractogram having a signal at at least six two-theta values chosen 3.7 ± 0.2, 10.4 ± 0.2, 10.7 ± 0.2, 11.3 ± 0.2, 12.2 ± 0.2, 13.2 ± 0.2, 14.6 ± 0.2, 15.7 ± 0.2, 18.3 ± 0.2, 18.6 ± 0.2, 21.0 ± 0.2, 21.8 ± 0.2, 22.0 ± 0.2, 24.0 ± 0.2, 24.6 ± 0.2, and 24.9 ± 0.2. In some embodiments, Hydrate Form C is characterized by an X-ray powder diffractogram having a signal at at least seven two-theta values chosen 3.7 ± 0.2, 10.4 ± 0.2, 10.7 ± 0.2, 11.3 ± 0.2, 12.2 ± 0.2, 13.2 ± 0.2, 14.6 ± 0.2, 15.7 ± 0.2, 18.3 ± 0.2, 18.6 ± 0.2, 21.0 ± 0.2, 21.8 ± 0.2, 22.0 ± 0.2, 24.0 ± 0.2, 24.6 ± 0.2, and 24.9 ± 0.2. In some embodiments, Hydrate Form C is characterized by an X-ray powder diffractogram having a signal at at least eight two-theta values chosen 3.7 ± 0.2, 10.4 ± 0.2, 10.7 ± 0.2, 11.3 ± 0.2, 12.2 ± 0.2, 13.2 ± 0.2, 14.6 ± 0.2, 15.7 ± 0.2, 18.3 ± 0.2, 18.6 ± 0.2, 21.0 ± 0.2, 21.8 ± 0.2, 22.0 ± 0.2, 24.0 ± 0.2, 24.6 ± 0.2, and 24.9 ± 0.2. In some embodiments, Hydrate Form C is characterized by an X-ray powder diffractogram having a signal at at least nine two-theta values chosen 3.7 ± 0.2, 10.4 ± 0.2, 10.7 ± 0.2, 11.3 ± 0.2, 12.2 ± 0.2, 13.2 ± 0.2, 14.6 ± 0.2, 15.7 ± 0.2, 18.3 ± 0.2, 18.6 ± 0.2, 21.0 ± 0.2, 21.8 ± 0.2, 22.0 ± 0.2, 24.0 ± 0.2, 24.6 ± 0.2, and 24.9 ± 0.2. In some embodiments, Hydrate Form C is characterized by an X-ray powder diffractogram having a signal at at least ten two-theta values chosen 3.7 ± 0.2, 10.4 ± 0.2, 10.7 ± 0.2, 11.3 ± 0.2, 12.2 ± 0.2, 13.2 ± 0.2, 14.6 ± 0.2, 15.7 ± 0.2, 18.3 ± 0.2, 18.6 ± 0.2, 21.0 ± 0.2, 21.8 ± 0.2, 22.0 ± 0.2, 24.0 ± 0.2, 24.6 ± 0.2, and 24.9 ± 0.2. In some embodiments, Hydrate Form C is characterized by an X-ray powder diffractogram having a signal at at least eleven two-theta values chosen 3.7 ± 0.2, 10.4 ± 0.2, 10.7 ± 0.2, 11.3 ± 0.2, 12.2 ± 0.2, 13.2 ± 0.2, 14.6 ± 0.2, 15.7 ± 0.2, 18.3 ± 0.2, 18.6 ± 0.2, 21.0 ± 0.2, 21.8 ± 0.2, 22.0 ± 0.2, 24.0 ± 0.2, 24.6 ± 0.2, and 24.9 ± 0.2. In some embodiments, Hydrate Form C is characterized by an X-ray powder diffractogram having a signal at at least twelve two-theta values chosen 3.7 ± 0.2, 10.4 ± 0.2, 10.7 ± 0.2, 11.3 ± 0.2, 12.2 ± 0.2, 13.2 ± 0.2, 14.6 ± 0.2, 15.7 ± 0.2, 18.3 ± 0.2, 18.6 ± 0.2, 21.0 ± 0.2, 21.8 ± 0.2, 22.0 ± 0.2, 24.0 ± 0.2, 24.6 ± 0.2, and 24.9 ± 0.2. In some embodiments, Hydrate Form C is characterized by an X-ray powder diffractogram having a signal at at least thirteen two-theta values chosen 3.7 ± 0.2, 10.4 ± 0.2, 10.7 ± 0.2, 11.3 ± 0.2, 12.2 ± 0.2, 13.2 ± 0.2, 14.6 ± 0.2, 15.7 ± 0.2, 18.3 ± 0.2, 18.6 ± 0.2, 21.0 ± 0.2, 21.8 ± 0.2, 22.0 ± 0.2, 24.0 ± 0.2, 24.6 ± 0.2, and 24.9 ± 0.2. In some embodiments, Hydrate Form C is characterized by an X-ray powder diffractogram having a signal at at least fourteen two-theta values chosen 3.7 ± 0.2, 10.4 ± 0.2, 10.7 ± 0.2, 11.3 ± 0.2, 12.2 ± 0.2, 13.2 ± 0.2, 14.6 ± 0.2, 15.7 ± 0.2, 18.3 ± 0.2, 18.6 ± 0.2, 21.0 ± 0.2, 21.8 ± 0.2, 22.0 ± 0.2, 24.0 ± 0.2, 24.6 ± 0.2, and 24.9 ± 0.2. In some embodiments, Hydrate Form C is characterized by an X-ray powder diffractogram having a signal at at least fifteen two-theta values chosen 3.7 ± 0.2, 10.4 ± 0.2, 10.7 ± 0.2, 11.3 ± 0.2, 12.2 ± 0.2, 13.2 ± 0.2, 14.6 ± 0.2, 15.7 ± 0.2, 18.3 ± 0.2, 18.6 ± 0.2, 21.0 ± 0.2, 21.8 ± 0.2, 22.0 ± 0.2, 24.0 ± 0.2, 24.6 ± 0.2, and 24.9 ± 0.2. In some embodiments, Hydrate Form C is characterized by an X-ray powder diffractogram having a signal at 6.2 ± 0.2, 12.2 ± 0.2, 12.4 ± 0.2, 18.3 ± 0.2, 19.0 ± 0.2, 19.1 ± 0.2, 19.6 ± 0.2, 19.9 ± 0.2, 20.2 ± 0.2, 22.7 ± 0.2, 24.2 ± 0.2, 25.4 ± 0.2, 25.5 ± 0.2, and 27.2 ± 0.2 two-theta.

[0148] In some embodiments, disclosed herein is a composition comprising Hydrate Form C of Compound 2. In some embodiments, the composition further comprises Hydrate Form A of Compound 2. In some embodiments, disclosed herein is a composition comprising Compound 2 in substantially pure Hydrate Form C. In some embodiments, disclosed herein is a composition comprising at least one active compound consisting essentially of Compound 2 in Hydrate Form C.

[0149] In some embodiments, Hydrate Form C is characterized by a DSC curve substantially similar to that in FIG. 18. In some embodiments, Hydrate Form C is characterized by a DSC curve having a peak at at least one temperature chosen from 112°C, 145°C, and 189°C.

[0150] In some embodiments, Hydrate Form C is characterized by a 13< C NMR spectrum having a signal at at least one ppm value chosen from 178.2 ± 0.2 ppm, 127.2 ± 0.2 ppm, 116.9 ± 0.2 ppm, 71.6 ± 0.2 ppm, 57.6 ± 0.2 ppm, 49.6 ± 0.2 ppm, 35.5 ± 0.2 ppm, and 20.0 ± 0.2 ppm. In some embodiments, Hydrate Form C is characterized by a 13< C NMR spectrum having a signal at at least two ppm values chosen from 178.2 ± 0.2 ppm, 127.2 ± 0.2 ppm, 116.9 ± 0.2 ppm, 71.6 ± 0.2 ppm, 57.6 ± 0.2 ppm, 49.6 ± 0.2 ppm, 35.5 ± 0.2 ppm, and 20.0 ± 0.2 ppm. In some embodiments, Hydrate Form C is characterized by a 13< C NMR spectrum having a signal at at least three ppm values chosen from 178.2 ± 0.2 ppm, 127.2 ± 0.2 ppm, 116.9 ± 0.2 ppm, 71.6 ± 0.2 ppm, 57.6 ± 0.2 ppm, 49.6 ± 0.2 ppm, 35.5 ± 0.2 ppm, and 20.0 ± 0.2 ppm. In some embodiments, Hydrate Form C is characterized by a 13< C NMR spectrum having a signal at at least four ppm values chosen from 178.2 ± 0.2 ppm, 127.2 ± 0.2 ppm, 116.9 ± 0.2 ppm, 71.6 ± 0.2 ppm, 57.6 ± 0.2 ppm, 49.6 ± 0.2 ppm, 35.5 ± 0.2 ppm, and 20.0 ± 0.2 ppm. In some embodiments, Hydrate Form C is characterized by a 13< C NMR spectrum having a signal at 178.2 ± 0.2 ppm, 127.2 ± 0.2 ppm, 116.9 ± 0.2 ppm, 71.6 ± 0.2 ppm, 57.6 ± 0.2 ppm, 49.6 ± 0.2 ppm, 35.5 ± 0.2 ppm, and 20.0 ± 0.2 ppm.

[0151] In some embodiments, Hydrate Form C is characterized by a 19< F NMR spectrum having a signal at at least one ppm value chosen -109.9 ± 0.2 ppm, -111.5 ± 0.2 ppm, -113.0 ± 0.2, -120.9 ± 0.2, -121.8 ± 0.2 and -123.4 ± 0.2 ppm. In some embodiments, Hydrate Form C is characterized by a 19F NMR spectrum having a signal at at least two ppm values chosen from -109.9 ± 0.2 ppm, -111.5 ± 0.2 ppm, - 113.0 ± 0.2, -120.9 ± 0.2, -121.8 ± 0.2 and -123.4 ± 0.2 ppm. In some embodiments, Hydrate Form C is characterized by a 19< F NMR spectrum having a signal at at least three ppm values chosen from -109.9 ± 0.2 ppm, -111.5 ± 0.2 ppm, -113.0 ± 0.2, -120.9 ± 0.2, -121.8 ± 0.2 and -123.4 ± 0.2 ppm. In some embodiments, Hydrate Form C is characterized by a 19< F NMR spectrum having a signal at at least four ppm values chosen from -109.9 ± 0.2 ppm, -111.5 ± 0.2 ppm, -113.0 ± 0.2, -120.9 ± 0.2, -121.8 ± 0.2 and -123.4 ± 0.2 ppm. In some embodiments, Hydrate Form C is characterized by a 19< F NMR spectrum having a signal at at least five ppm values chosen from -109.9 ± 0.2 ppm, -111.5 ± 0.2 ppm, -113.0 ± 0.2, -120.9 ± 0.2, -121.8 ± 0.2 and -123.4 ± 0.2 ppm. In some embodiments, Hydrate Form C is characterized by a 19< F NMR spectrum having signals at -109.9 ± 0.2 ppm, -111.5 ± 0.2 ppm, -113.0 ± 0.2, -120.9 ± 0.2, -121.8 ± 0.2 and -123.4 ± 0.2 ppm.

[0152] In some embodiments, Compound 2 is a crystalline solid. In some embodiments, the crystalline solid consists of 1% to 99% Hydrate Form C relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 2% to 99% Hydrate Form C relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 5% to 99% Hydrate Form C relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 10% to 99% Hydrate Form C relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 15% to 99% Hydrate Form C relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 20% to 99% Hydrate Form C relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 25% to 99% Hydrate Form C relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 30% to 99% Hydrate Form C relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 35% to 99% Hydrate Form C relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 45% to 99% Hydrate Form C relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 50% to 99% Hydrate Form C relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 55% to 99% Hydrate Form C relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 60% to 99% Hydrate Form C relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 65% to 99% Hydrate Form C relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 70% to 99% Hydrate Form C relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 75% to 99% Hydrate Form C relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 80% to 99% Hydrate Form C relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 85% to 99% Hydrate Form C relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 90% to 99% Hydrate Form C relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 95% to 99% Hydrate Form C relative to the total weight of the crystalline solid Compound 2.Hydrate Form D of Compound 2

[0153] In some embodiments, Compound 2 is in the form of Hydrate Form D. In some embodiments, Compound 2 is in the form of substantially pure Hydrate Form D. In some embodiments, Hydrate Form D is characterized by an X-ray powder diffractogram substantially similar to that in FIG. 19. In some embodiments, Hydrate Form D is characterized by an X-ray powder diffractogram having a signal at at least two two-theta values chosen from 4.1 ± 0.2, 5.0 ± 0.2, 7.7 ± 0.2, 8.2 ± 0.2, and 15.2 ± 0.2. In some embodiments, Hydrate Form D is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 4.1 ± 0.2, 5.0 ± 0.2, 7.7 ± 0.2, 8.2 ± 0.2, and 15.2 ± 0.2. In some embodiments, Hydrate Form D is characterized by an X-ray powder diffractogram having a signal at at least four two-theta values chosen from 4.1 ± 0.2, 5.0 ± 0.2, 7.7 ± 0.2, 8.2 ± 0.2, and 15.2 ± 0.2. In some embodiments, Hydrate Form D is characterized by an X-ray powder diffractogram having a signal at 4.1 ± 0.2, 5.0 ± 0.2, 7.7 ± 0.2, 8.2 ± 0.2, and 15.2 ± 0.2 two-theta.

[0154] In some embodiments, Hydrate Form D is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 4.1 ± 0.2, 5.0 ± 0.2, 7.6 ± 0.2, 7.7 ± 0.2, 8.2 ± 0.2, 15.2 ± 0.2, 15.5 ± 0.2, 16.5 ± 0.2, and 19.0 ± 0.2. In some embodiments, Hydrate Form D is characterized by an X-ray powder diffractogram having a signal at at least four two-theta values chosen from 4.1 ± 0.2, 5.0 ± 0.2, 7.6 ± 0.2, 7.7 ± 0.2, 8.2 ± 0.2, 15.2 ± 0.2, 15.5 ± 0.2, 16.5 ± 0.2, and 19.0 ± 0.2. In some embodiments, Hydrate Form D is characterized by an X-ray powder diffractogram having a signal at at least five two-theta values chosen from 4.1 ± 0.2, 5.0 ± 0.2, 7.6 ± 0.2, 7.7 ± 0.2, 8.2 ± 0.2, 15.2 ± 0.2, 15.5 ± 0.2, 16.5 ± 0.2, and 19.0 ± 0.2. In some embodiments, Hydrate Form D is characterized by an X-ray powder diffractogram having a signal at at least six two-theta values chosen from 4.1 ± 0.2, 5.0 ± 0.2, 7.6 ± 0.2, 7.7 ± 0.2, 8.2 ± 0.2, 15.2 ± 0.2, 15.5 ± 0.2, 16.5 ± 0.2, and 19.0 ± 0.2. In some embodiments, Hydrate Form D is characterized by an X-ray powder diffractogram having a signal at at least seven two-theta values chosen from 4.1 ± 0.2, 5.0 ± 0.2, 7.6 ± 0.2, 7.7 ± 0.2, 8.2 ± 0.2, 15.2 ± 0.2, 15.5 ± 0.2, 16.5 ± 0.2, and 19.0 ± 0.2. In some embodiments, Hydrate Form D is characterized by an X-ray powder diffractogram having a signal at at least eight two-theta values chosen from 4.1 ± 0.2, 5.0 ± 0.2, 7.6 ± 0.2, 7.7 ± 0.2, 8.2 ± 0.2, 15.2 ± 0.2, 15.5 ± 0.2, 16.5 ± 0.2, and 19.0 ± 0.2. In some embodiments, Hydrate Form D is characterized by an X-ray powder diffractogram having a signal at 4.1 ± 0.2, 5.0 ± 0.2, 7.6 ± 0.2, 7.7 ± 0.2, 8.2 ± 0.2, 15.2 ± 0.2, 15.5 ± 0.2, 16.5 ± 0.2, and 19.0 ± 0.2 two-theta.

[0155] In some embodiments, disclosed herein is a composition comprising Hydrate Form D of Compound 2. In some embodiments, disclosed herein is a composition comprising Compound 2 in substantially pure Hydrate Form D. In some embodiments, disclosed herein is a composition comprising at least one active compound consisting essentially of Compound 2 in Hydrate Form D.

[0156] In some embodiments, Hydrate Form D is characterized by a DSC curve substantially similar to that in FIG. 21. In some embodiments, Hydrate Form D is characterized by a DSC curve having a peak at at least one temperature chosen from 121°C, 148°C, 176°C, and 196°C.

[0157] In some embodiments, Compound 2 is a crystalline solid. In some embodiments, the crystalline solid consists of 1% to 99% Hydrate Form D relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 2% to 99% Hydrate Form D relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 5% to 99% Hydrate Form D relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 10% to 99% Hydrate Form D relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 15% to 99% Hydrate Form D relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 20% to 99% Hydrate Form D relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 25% to 99% Hydrate Form D relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 30% to 99% Hydrate Form D relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 35% to 99% Hydrate Form D relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 45% to 99% Hydrate Form D relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 50% to 99% Hydrate Form D relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 55% to 99% Hydrate Form D relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 60% to 99% Hydrate Form D relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 65% to 99% Hydrate Form D relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 70% to 99% Hydrate Form D relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 75% to 99% Hydrate Form D relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 80% to 99% Hydrate Form D relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 85% to 99% Hydrate Form D relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 90% to 99% Hydrate Form D relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 95% to 99% Hydrate Form D relative to the total weight of the crystalline solid Compound 2.Hydrate Form E of Compound 2

[0158] In some embodiments, Compound 2 is in the form of Hydrate Form E. In some embodiments, Compound 2 is in the form of substantially pure Hydrate Form E. In some embodiments, Hydrate Form E is characterized by an X-ray powder diffractogram substantially similar to that in FIG. 22. In some embodiments, Hydrate Form E is characterized by an X-ray powder diffractogram having a signal at at least two two-theta values chosen from 6.5 ± 0.2, 7.7 ± 0.2, 11.4 ± 0.2, 14.3 ± 0.2, and 18.9 ± 0.2. In some embodiments, Hydrate Form E is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 6.5 ± 0.2, 7.7 ± 0.2, 11.4 ± 0.2, 14.3 ± 0.2, and 18.9 ± 0.2. In some embodiments, Hydrate Form E is characterized by an X-ray powder diffractogram having a signal at at least four two-theta values chosen from 6.5 ± 0.2, 7.7 ± 0.2, 11.4 ± 0.2, 14.3 ± 0.2, and 18.9 ± 0.2. In some embodiments, Hydrate Form E is characterized by an X-ray powder diffractogram having a signal at 6.5 ± 0.2, 7.7 ± 0.2, 11.4 ± 0.2, 14.3 ± 0.2, and 18.9 ± 0.2 two-theta.

[0159] In some embodiments, Hydrate Form E is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 6.5 ± 0.2, 7.7 ± 0.2, 11.4 ± 0.2, 11.8 ± 0.2, 12.8 ± 0.2, 14.3 ± 0.2, 15.8 ± 0.2, 16.4 ± 0.2, 18.9 ± 0.2, and 22.1 ± 0.2. In some embodiments, Hydrate Form E is characterized by an X-ray powder diffractogram having a signal at at least four two-theta values chosen from 6.5 ± 0.2, 7.7 ± 0.2, 11.4 ± 0.2, 11.8 ± 0.2, 12.8 ± 0.2, 14.3 ± 0.2, 15.8 ± 0.2, 16.4 ± 0.2, 18.9 ± 0.2, and 22.1 ± 0.2. In some embodiments, Hydrate Form E is characterized by an X-ray powder diffractogram having a signal at at least five two-theta values chosen from 6.5 ± 0.2, 7.7 ± 0.2, 11.4 ± 0.2, 11.8 ± 0.2, 12.8 ± 0.2, 14.3 ± 0.2, 15.8 ± 0.2, 16.4 ± 0.2, 18.9 ± 0.2, and 22.1 ± 0.2. In some embodiments, Hydrate Form E is characterized by an X-ray powder diffractogram having a signal at at least six two-theta values chosen from 6.5 ± 0.2, 7.7 ± 0.2, 11.4 ± 0.2, 11.8 ± 0.2, 12.8 ± 0.2, 14.3 ± 0.2, 15.8 ± 0.2, 16.4 ± 0.2, 18.9 ± 0.2, and 22.1 ± 0.2. In some embodiments, Hydrate Form E is characterized by an X-ray powder diffractogram having a signal at at least seven two-theta values chosen from 6.5 ± 0.2, 7.7 ± 0.2, 11.4 ± 0.2, 11.8 ± 0.2, 12.8 ± 0.2, 14.3 ± 0.2, 15.8 ± 0.2, 16.4 ± 0.2, 18.9 ± 0.2, and 22.1 ± 0.2. In some embodiments, Hydrate Form E is characterized by an X-ray powder diffractogram having a signal at at least eight two-theta values chosen from 6.5 ± 0.2, 7.7 ± 0.2, 11.4 ± 0.2, 11.8 ± 0.2, 12.8 ± 0.2, 14.3 ± 0.2, 15.8 ± 0.2, 16.4 ± 0.2, 18.9 ± 0.2, and 22.1 ± 0.2. In some embodiments, Hydrate Form E is characterized by an X-ray powder diffractogram having a signal at at least nine two-theta values chosen from 6.5 ± 0.2, 7.7 ± 0.2, 11.4 ± 0.2, 11.8 ± 0.2, 12.8 ± 0.2, 14.3 ± 0.2, 15.8 ± 0.2, 16.4 ± 0.2, 18.9 ± 0.2, and 22.1 ± 0.2. In some embodiments, Hydrate Form E is characterized by an X-ray powder diffractogram having a signal at 6.5 ± 0.2, 7.7 ± 0.2, 11.4 ± 0.2, 11.8 ± 0.2, 12.8 ± 0.2, 14.3 ± 0.2, 15.8 ± 0.2, 16.4 ± 0.2, 18.9 ± 0.2, and 22.1 ± 0.2 two-theta.

[0160] In some embodiments, disclosed herein is a composition comprising Hydrate Form E of Compound 2. In some embodiments, disclosed herein is a composition comprising Compound 2 in substantially pure Hydrate Form E. In some embodiments, disclosed herein is a composition comprising at least one active compound consisting essentially of Compound 2 in Hydrate Form E.

[0161] In some embodiments, Hydrate Form E is characterized by a DSC curve substantially similar to that in FIG. 24. In some embodiments, Hydrate Form E is characterized by a DSC curve having a peak at at least one temperature chosen from 107°C, 127°C, 150°C, 177°C, and 195°C.

[0162] In some embodiments, Compound 2 is a crystalline solid. In some embodiments, the crystalline solid consists of 1% to 99% Hydrate Form E relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 2% to 99% Hydrate Form E relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 5% to 99% Hydrate Form E relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 10% to 99% Hydrate Form E relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 15% to 99% Hydrate Form E relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 20% to 99% Hydrate Form E relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 25% to 99% Hydrate Form E relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 30% to 99% Hydrate Form E relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 35% to 99% Hydrate Form E relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 45% to 99% Hydrate Form E relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 50% to 99% Hydrate Form E relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 55% to 99% Hydrate Form E relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 60% to 99% Hydrate Form E relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 65% to 99% Hydrate Form E relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 70% to 99% Hydrate Form E relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 75% to 99% Hydrate Form E relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 80% to 99% Hydrate Form E relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 85% to 99% Hydrate Form E relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 90% to 99% Hydrate Form E relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 95% to 99% Hydrate Form E relative to the total weight of the crystalline solid Compound 2.Hydrate Form F of Compound 2

[0163] In some embodiments, Compound 2 is in the form of Hydrate Form F. In some embodiments, Compound 2 is in the form of substantially pure Hydrate Form F. In some embodiments, Hydrate Form F is characterized by an X-ray powder diffractogram substantially similar to that in FIG. 25. In some embodiments, Hydrate Form F is characterized by an X-ray powder diffractogram having a signal at at least two two-theta values chosen from 3.8 ± 0.2, 7.6 ± 0.2, and 11.4 ± 0.2. In some embodiments, Hydrate Form F is characterized by an X-ray powder diffractogram having a signal at 3.8 ± 0.2, 7.6 ± 0.2, and 11.4 ± 0.2 two-theta.

[0164] In some embodiments, disclosed herein is a composition comprising Hydrate Form F of Compound 2. In some embodiments, disclosed herein is a composition comprising Compound 2 in substantially pure Hydrate Form F. In some embodiments, disclosed herein is a composition comprising at least one active compound consisting essentially of Compound 2 in Hydrate Form F.

[0165] In some embodiments, Hydrate Form F is characterized by a DSC curve substantially similar to that in FIG. 27. In some embodiments, Hydrate Form F is characterized by a DSC curve having a peak at at least one temperature chosen from 174°C, 177°C, and 197°C.

[0166] In some embodiments, Compound 2 is a crystalline solid. In some embodiments, the crystalline solid consists of 1% to 99% Hydrate Form F relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 2% to 99% Hydrate Form F relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 5% to 99% Hydrate Form F relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 10% to 99% Hydrate Form F relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 15% to 99% Hydrate Form F relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 20% to 99% Hydrate Form F relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 25% to 99% Hydrate Form F relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 30% to 99% Hydrate Form F relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 35% to 99% Hydrate Form F relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 45% to 99% Hydrate Form F relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 50% to 99% Hydrate Form F relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 55% to 99% Hydrate Form F relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 60% to 99% Hydrate Form F relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 65% to 99% Hydrate Form F relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 70% to 99% Hydrate Form F relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 75% to 99% Hydrate Form F relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 80% to 99% Hydrate Form F relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 85% to 99% Hydrate Form F relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 90% to 99% Hydrate Form F relative to the total weight of the crystalline solid Compound 2. In some embodiments, the crystalline solid consists of 95% to 99% Hydrate Form F relative to the total weight of the crystalline solid Compound 2.MTBE Solvate Form of Compound 2

[0167] In some embodiments, Compound 2 is in the form of an MTBE Solvate Form. In some embodiments, Compound 2 is in the form of substantially pure MTBE Solvate Form. In some embodiments, MTBE Solvate Form is characterized by an X-ray powder diffractogram substantially similar to that in FIG. 28.

[0168] In some embodiments, MTBE Solvate Form is characterized by an X-ray powder diffractogram having a signal at at least two two-theta values chosen from 6.0 ± 0.2, 6.8 ± 0.2, 8.4 ± 0.2, 18.0 ± 0.2, 19.4 ± 0.2, and 20.2 ± 0.2. In some embodiments, MTBE Solvate Form is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 6.0 ± 0.2, 6.8 ± 0.2, 8.4 ± 0.2, 18.0 ± 0.2, 19.4 ± 0.2, and 20.2 ± 0.2. In some embodiments, MTBE Solvate Form is characterized by an X-ray powder diffractogram having a signal at at least four two-theta values chosen from 6.0 ± 0.2, 6.8 ± 0.2, 8.4 ± 0.2, 18.0 ± 0.2, 19.4 ± 0.2, and 20.2 ± 0.2. In some embodiments, MTBE Solvate Form is characterized by an X-ray powder diffractogram having a signal at at least five two-theta values chosen from 6.0 ± 0.2, 6.8 ± 0.2, 8.4 ± 0.2, 18.0 ± 0.2, 19.4 ± 0.2, and 20.2 ± 0.2. In some embodiments, MTBE Solvate Form is characterized by an X-ray powder diffractogram having a signal at at least 6.0 ± 0.2, 6.8 ± 0.2, 8.4 ± 0.2, 18.0 ± 0.2, 19.4 ± 0.2, and 20.2 ± 0.2 two-theta.

[0169] In some embodiments, disclosed herein is a composition comprising MTBE Solvate Form of Compound 2. In some embodiments, disclosed herein is a composition comprising Compound 2 in substantially pure MTBE Solvate Form. In some embodiments, disclosed herein is a composition comprising at least one active compound consisting essentially of Compound 2 in MTBE Solvate Form.

[0170] In some embodiments, MTBE Solvate Form is characterized by a DSC curve substantially similar to that in FIG. 30. In some embodiments, MTBE Solvate Form is characterized by a DSC curve having a peak at at least one temperature chosen from 131°C, 148°C, and 193°C.DMF Solvate Form of Compound 2

[0171] In some embodiments, Compound 2 is in the form of a DMF Solvate Form. In some embodiments, Compound 2 is in the form of substantially pure DMF Solvate Form. In some embodiments, DMF Solvate Form is characterized by an X-ray powder diffractogram substantially similar to that in FIG. 31.

[0172] In some embodiments, DMF Solvate Form is characterized by an X-ray powder diffractogram having a signal at at least two two-theta values chosen from 15.3 ± 0.2, 18.0 ± 0.2, and 20.1 ± 0.2. In some embodiments, DMF Solvate Form is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 15.3 ± 0.2, 18.0 ± 0.2, and 20.1 ± 0.2. In some embodiments, DMF Solvate Form is characterized by an X-ray powder diffractogram having a signal at at least two two-theta values chosen from 5.6 ± 0.2, 9.3 ± 0.2, 15.3 ± 0.2, 18.0 ± 0.2, and 20.1 ± 0.2. In some embodiments, DMF Solvate Form is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 5.6 ± 0.2, 9.3 ± 0.2, 15.3 ± 0.2, 18.0 ± 0.2, and 20.1 ± 0.2. In some embodiments, DMF Solvate Form is characterized by an X-ray powder diffractogram having a signal at at least four two-theta values chosen from 5.6 ± 0.2, 9.3 ± 0.2, 15.3 ± 0.2, 18.0 ± 0.2, and 20.1 ± 0.2. In some embodiments, DMF Solvate Form is characterized by an X-ray powder diffractogram having a signal at at least 5.6 ± 0.2, 9.3 ± 0.2, 15.3 ± 0.2, 18.0 ± 0.2, and 20.1 ± 0.2 two-theta.

[0173] In some embodiments, disclosed herein is a composition comprising DMF Solvate Form of Compound 2. In some embodiments, disclosed herein is a composition comprising Compound 2 in substantially pure DMF Solvate Form. In some embodiments, disclosed herein is a composition comprising at least one active compound consisting essentially of Compound 2 in DMF Solvate Form.

[0174] In some embodiments, DMF Solvate Form is characterized by a DSC curve substantially similar to that in FIG. 33. In some embodiments, DMF Solvate Form is characterized by a DSC curve having a peak at at least one temperature chosen from 101°C, 110°C, and 190°C.Amorphous Form of Compound 2

[0175] In some embodiments, Compound 2 is in an amorphous Form. In some embodiments, Compound 2 is in the form of substantially pure amorphous Form. In some embodiments, amorphous Form of Compound 2 is characterized by an X-ray powder diffractogram substantially similar to that in FIG. 34.

[0176] In some embodiments, disclosed herein is a composition comprising amorphous Form of Compound 2. In some embodiments, disclosed herein is a composition comprising Compound 2 in substantially pure amorphous Form. In some embodiments, disclosed herein is a composition comprising at least one active compound consisting essentially of Compound 2 in amorphous Form.

[0177] In some embodiments, amorphous Form is characterized by a DSC curve substantially similar to that in FIG. 37. In some embodiments, amorphous Form is characterized by a DSC curve having a glass transition of 87 °C.

[0178] In some embodiments, amorphous Form is characterized by a 13< C NMR spectrum having a signal at at least one ppm value chosen from 174.7 ± 0.2 ppm, 161.3 ± 0.2 ppm, 130.2 ± 0.2 ppm, 120.9 ± 0.2 ppm, 74.7 ± 0.2 ppm, and 20.5 ± 0.2 ppm. In some embodiments, amorphous Form is characterized by a 13< C NMR spectrum having a signal at at least two ppm values chosen from 174.7 ± 0.2 ppm, 161.3 ± 0.2 ppm, 130.2 ± 0.2 ppm, 120.9 ± 0.2 ppm, 74.7 ± 0.2 ppm, and 20.5 ± 0.2 ppm. In some embodiments, amorphous Form is characterized by a 13< C NMR spectrum having a signal at at least three ppm values chosen from 174.7 ± 0.2 ppm, 161.3 ± 0.2 ppm, 130.2 ± 0.2 ppm, 120.9 ± 0.2 ppm, 74.7 ± 0.2 ppm, and 20.5 ± 0.2 ppm. In some embodiments, amorphous Form is characterized by a 13< C NMR spectrum having a signal at at least four ppm values chosen from 174.7 ± 0.2 ppm, 161.3 ± 0.2 ppm, 130.2 ± 0.2 ppm, 120.9 ± 0.2 ppm, 74.7 ± 0.2 ppm, and 20.5 ± 0.2 ppm. In some embodiments, amorphous Form is characterized by a 13< C NMR spectrum having a signal at at least five ppm values chosen from 174.7 ± 0.2 ppm, 161.3 ± 0.2 ppm, 130.2 ± 0.2 ppm, 120.9 ± 0.2 ppm, 74.7 ± 0.2 ppm, and 20.5 ± 0.2 ppm. In some embodiments, amorphous Form is characterized by a 13< C NMR spectrum having a signal at 174.7 ± 0.2 ppm, 161.3 ± 0.2 ppm, 130.2 ± 0.2 ppm, 120.9 ± 0.2 ppm, 74.7 ± 0.2 ppm, and 20.5 ± 0.2 ppm.

[0179] In some embodiments, amorphous Form is characterized by a 19< F NMR spectrum having a signal at at least one ppm value chosen from -122.4 ± 0.2 ppm and - 131.1 ± 0.2 ppm. In some embodiments, amorphous Form is characterized by a 19< F NMR spectrum having a signal at -122.4 ± 0.2 ppm and -131.1 ± 0.2 ppm.Solid forms of Compound 87

[0180] In some embodiments, the at least one entity chosen from compounds of Formula (I) is Compound 87. Compound 87 can be depicted as follows:

[0181] In some embodiments, Compound 87 is an amorphous solid. In some embodiments, Compound 87 is a crystalline solid. In some embodiments, Compound 87 is in the form of Form A, Hydrate Form, IPAc solvate, or a mixture of any two or more of the foregoing.Form A of Compound 87

[0182] In some embodiments, Compound 87 is in the form of Form A. In some embodiments, Compound 87 is in the form of substantially pure Form A. In some embodiments, Form A is characterized by an X-ray powder diffractogram substantially similar to that in FIG. 38. In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at at least two two-theta values chosen from 4.7 ± 0.2, 9.0 ± 0.2, 14.2 ± 0.2, 16.7 ± 0.2, 21.0 ± 0.2, 21.2 ± 0.2, 22.9 ± 0.2, 23.1 ± 0.2 and 24.5 ± 0.2. In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 4.7 ± 0.2, 9.0 ± 0.2, 14.2 ± 0.2, 16.7 ± 0.2, 21.0 ± 0.2, 21.2 ± 0.2, 22.9 ± 0.2, 23.1 ± 0.2 and 24.5 ± 0.2. In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at at least four two-theta values chosen from 4.7 ± 0.2, 9.0 ± 0.2, 14.2 ± 0.2, 16.7 ± 0.2, 21.0 ± 0.2, 21.2 ± 0.2, 22.9 ± 0.2, 23.1 ± 0.2 and 24.5 ± 0.2. In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at at least five two-theta values chosen from 4.7 ± 0.2, 9.0 ± 0.2, 14.2 ± 0.2, 16.7 ± 0.2, 21.0 ± 0.2, 21.2 ± 0.2, 22.9 ± 0.2, 23.1 ± 0.2 and 24.5 ± 0.2. In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at at least six two-theta values chosen 4.7 ± 0.2, 9.0 ± 0.2, 14.2 ± 0.2, 16.7 ± 0.2, 21.0 ± 0.2, 21.2 ± 0.2, 22.9 ± 0.2, 23.1 ± 0.2 and 24.5 ± 0.2. In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at at least seven two-theta values chosen from 4.7 ± 0.2, 9.0 ± 0.2, 14.2 ± 0.2, 16.7 ± 0.2, 21.0 ± 0.2, 21.2 ± 0.2, 22.9 ± 0.2, 23.1 ± 0.2 and 24.5 ± 0.2. In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at at least eight two-theta values chosen from 4.7 ± 0.2, 9.0 ± 0.2, 14.2 ± 0.2, 16.7 ± 0.2, 21.0 ± 0.2, 21.2 ± 0.2, 22.9 ± 0.2, 23.1 ± 0.2 and 24.5 ± 0.2. In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at the following two-theta values 4.7 ± 0.2, 9.0 ± 0.2, 14.2 ± 0.2, 16.7 ± 0.2, 21.0 ± 0.2, 21.2 ± 0.2, 22.9 ± 0.2, 23.1 ± 0.2 and 24.5 ± 0.2.

[0183] In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at at least one two-theta values chosen from 4.7 ± 0.2, 9.0 ± 0.2, 9.5 ± 0.2, 14.2 ± 0.2, 16.7 ± 0.2, 18.1 ± 0.2, 18.9 ± 0.2, 20.0 ± 0.2, 21.0 ± 0.2, 21.9 ± 0.2, 22.1 ± 0.2, 22.9 ± 0.2, 23.1 ± 0.2, 24.3 ± 0.2, 24.5 ± 0.2, 25.2 ± 0.2, 25.6 ± 0.2, 26.0 ± 0.2, 26.1 ± 0.2, and 27.8 ± 0.2. In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at at least two two-theta values chosen from 4.7 ± 0.2, 9.0 ± 0.2, 9.5 ± 0.2, 14.2 ± 0.2, 16.7 ± 0.2, 18.1 ± 0.2, 18.9 ± 0.2, 20.0 ± 0.2, 21.0 ± 0.2, 21.9 ± 0.2, 22.1 ± 0.2, 22.9 ± 0.2, 23.1 ± 0.2, 24.3 ± 0.2, 24.5 ± 0.2, 25.2 ± 0.2, 25.6 ± 0.2, 26.0 ± 0.2, 26.1 ± 0.2, and 27.8 ± 0.2. In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 4.7 ± 0.2, 9.0 ± 0.2, 9.5 ± 0.2, 14.2 ± 0.2, 16.7 ± 0.2, 18.1 ± 0.2, 18.9 ± 0.2, 20.0 ± 0.2, 21.0 ± 0.2, 21.9 ± 0.2, 22.1 ± 0.2, 22.9 ± 0.2, 23.1 ± 0.2, 24.3 ± 0.2, 24.5 ± 0.2, 25.2 ± 0.2, 25.6 ± 0.2, 26.0 ± 0.2, 26.1 ± 0.2, and 27.8 ± 0.2. In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at at least four two-theta values chosen from 4.7 ± 0.2, 9.0 ± 0.2, 9.5 ± 0.2, 14.2 ± 0.2, 16.7 ± 0.2, 18.1 ± 0.2, 18.9 ± 0.2, 20.0 ± 0.2, 21.0 ± 0.2, 21.9 ± 0.2, 22.1 ± 0.2, 22.9 ± 0.2, 23.1 ± 0.2, 24.3 ± 0.2, 24.5 ± 0.2, 25.2 ± 0.2, 25.6 ± 0.2, 26.0 ± 0.2, 26.1 ± 0.2, and 27.8 ± 0.2. In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at at least five two-theta values chosen from 4.7 ± 0.2, 9.0 ± 0.2, 9.5 ± 0.2, 14.2 ± 0.2, 16.7 ± 0.2, 18.1 ± 0.2, 18.9 ± 0.2, 20.0 ± 0.2, 21.0 ± 0.2, 21.9 ± 0.2, 22.1 ± 0.2, 22.9 ± 0.2, 23.1 ± 0.2, 24.3 ± 0.2, 24.5 ± 0.2, 25.2 ± 0.2, 25.6 ± 0.2, 26.0 ± 0.2, 26.1 ± 0.2, and 27.8 ± 0.2. In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at at least six two-theta values chosen from 4.7 ± 0.2, 9.0 ± 0.2, 9.5 ± 0.2, 14.2 ± 0.2, 16.7 ± 0.2, 18.1 ± 0.2, 18.9 ± 0.2, 20.0 ± 0.2, 21.0 ± 0.2, 21.9 ± 0.2, 22.1 ± 0.2, 22.9 ± 0.2, 23.1 ± 0.2, 24.3 ± 0.2, 24.5 ± 0.2, 25.2 ± 0.2, 25.6 ± 0.2, 26.0 ± 0.2, 26.1 ± 0.2, and 27.8 ± 0.2. In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at at least seven two-theta values chosen from 4.7 ± 0.2, 9.0 ± 0.2, 9.5 ± 0.2, 14.2 ± 0.2, 16.7 ± 0.2, 18.1 ± 0.2, 18.9 ± 0.2, 20.0 ± 0.2, 21.0 ± 0.2, 21.9 ± 0.2, 22.1 ± 0.2, 22.9 ± 0.2, 23.1 ± 0.2, 24.3 ± 0.2, 24.5 ± 0.2, 25.2 ± 0.2, 25.6 ± 0.2, 26.0 ± 0.2, 26.1 ± 0.2, and 27.8 ± 0.2, and 27.8 ± 0.2. In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at at least eight two-theta values chosen from 4.7 ± 0.2, 9.0 ± 0.2, 9.5 ± 0.2, 14.2 ± 0.2, 16.7 ± 0.2, 18.1 ± 0.2, 18.9 ± 0.2, 20.0 ± 0.2, 21.0 ± 0.2, 21.9 ± 0.2, 22.1 ± 0.2, 22.9 ± 0.2, 23.1 ± 0.2, 24.3 ± 0.2, 24.5 ± 0.2, 25.2 ± 0.2, 25.6 ± 0.2, 26.0 ± 0.2, 26.1 ± 0.2, and 27.8 ± 0.2. In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at at least nine two-theta values chosen from 4.7 ± 0.2, 9.0 ± 0.2, 9.5 ± 0.2, 14.2 ± 0.2, 16.7 ± 0.2, 18.1 ± 0.2, 18.9 ± 0.2, 20.0 ± 0.2, 21.0 ± 0.2, 21.9 ± 0.2, 22.1 ± 0.2, 22.9 ± 0.2, 23.1 ± 0.2, 24.3 ± 0.2, 24.5 ± 0.2, 25.2 ± 0.2, 25.6 ± 0.2, 26.0 ± 0.2, 26.1 ± 0.2, and 27.8 ± 0.2. In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at at least ten two-theta values chosen from 4.7 ± 0.2, 9.0 ± 0.2, 9.5 ± 0.2, 14.2 ± 0.2, 16.7 ± 0.2, 18.1 ± 0.2, 18.9 ± 0.2, 20.0 ± 0.2, 21.0 ± 0.2, 21.9 ± 0.2, 22.1 ± 0.2, 22.9 ± 0.2, 23.1 ± 0.2, 24.3 ± 0.2, 24.5 ± 0.2, 25.2 ± 0.2, 25.6 ± 0.2, 26.0 ± 0.2, 26.1 ± 0.2, and 27.8 ± 0.2. In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at at least eleven two-theta values chosen from 4.7 ± 0.2, 9.0 ± 0.2, 9.5 ± 0.2, 14.2 ± 0.2, 16.7 ± 0.2, 18.1 ± 0.2, 18.9 ± 0.2, 20.0 ± 0.2, 21.0 ± 0.2, 21.9 ± 0.2, 22.1 ± 0.2, 22.9 ± 0.2, 23.1 ± 0.2, 24.3 ± 0.2, 24.5 ± 0.2, 25.2 ± 0.2, 25.6 ± 0.2, 26.0 ± 0.2, 26.1 ± 0.2, and 27.8 ± 0.2. In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at at least twelve two-theta values chosen from 4.7 ± 0.2, 9.0 ± 0.2, 9.5 ± 0.2, 14.2 ± 0.2, 16.7 ± 0.2, 18.1 ± 0.2, 18.9 ± 0.2, 20.0 ± 0.2, 21.0 ± 0.2, 21.9 ± 0.2, 22.1 ± 0.2, 22.9 ± 0.2, 23.1 ± 0.2, 24.3 ± 0.2, 24.5 ± 0.2, 25.2 ± 0.2, 25.6 ± 0.2, 26.0 ± 0.2, 26.1 ± 0.2, and 27.8 ± 0.2. In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at at least thirteen two-theta values chosen from 4.7 ± 0.2, 9.0 ± 0.2, 9.5 ± 0.2, 14.2 ± 0.2, 16.7 ± 0.2, 18.1 ± 0.2, 18.9 ± 0.2, 20.0 ± 0.2, 21.0 ± 0.2, 21.9 ± 0.2, 22.1 ± 0.2, 22.9 ± 0.2, 23.1 ± 0.2, 24.3 ± 0.2, 24.5 ± 0.2, 25.2 ± 0.2, 25.6 ± 0.2, 26.0 ± 0.2, 26.1 ± 0.2, and 27.8 ± 0.2. In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at at least fourteen two-theta values chosen from 4.7 ± 0.2, 9.0 ± 0.2, 9.5 ± 0.2, 14.2 ± 0.2, 16.7 ± 0.2, 18.1 ± 0.2, 18.9 ± 0.2, 20.0 ± 0.2, 21.0 ± 0.2, 21.9 ± 0.2, 22.1 ± 0.2, 22.9 ± 0.2, 23.1 ± 0.2, 24.3 ± 0.2, 24.5 ± 0.2, 25.2 ± 0.2, 25.6 ± 0.2, 26.0 ± 0.2, 26.1 ± 0.2, and 27.8 ± 0.2. In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at at least fifteen two-theta values chosen from 4.7 ± 0.2, 9.0 ± 0.2, 9.5 ± 0.2, 14.2 ± 0.2, 16.7 ± 0.2, 18.1 ± 0.2, 18.9 ± 0.2, 20.0 ± 0.2, 21.0 ± 0.2, 21.9 ± 0.2, 22.1 ± 0.2, 22.9 ± 0.2, 23.1 ± 0.2, 24.3 ± 0.2, 24.5 ± 0.2, 25.2 ± 0.2, 25.6 ± 0.2, 26.0 ± 0.2, 26.1 ± 0.2, and 27.8 ± 0.2. In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at at least sixteen two-theta values chosen from 4.7 ± 0.2, 9.0 ± 0.2, 9.5 ± 0.2, 14.2 ± 0.2, 16.7 ± 0.2, 18.1 ± 0.2, 18.9 ± 0.2, 20.0 ± 0.2, 21.0 ± 0.2, 21.9 ± 0.2, 22.1 ± 0.2, 22.9 ± 0.2, 23.1 ± 0.2, 24.3 ± 0.2, 24.5 ± 0.2, 25.2 ± 0.2, 25.6 ± 0.2, 26.0 ± 0.2, 26.1 ± 0.2, and 27.8 ± 0.2. In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at at least seventeen two-theta values chosen from 4.7 ± 0.2, 9.0 ± 0.2, 9.5 ± 0.2, 14.2 ± 0.2, 16.7 ± 0.2, 18.1 ± 0.2, 18.9 ± 0.2, 20.0 ± 0.2, 21.0 ± 0.2, 21.9 ± 0.2, 22.1 ± 0.2, 22.9 ± 0.2, 23.1 ± 0.2, 24.3 ± 0.2, 24.5 ± 0.2, 25.2 ± 0.2, 25.6 ± 0.2, 26.0 ± 0.2, 26.1 ± 0.2, and 27.8 ± 0.2. In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at at least eighteen two-theta values chosen from 4.7 ± 0.2, 9.0 ± 0.2, 9.5 ± 0.2, 14.2 ± 0.2, 16.7 ± 0.2, 18.1 ± 0.2, 18.9 ± 0.2, 20.0 ± 0.2, 21.0 ± 0.2, 21.9 ± 0.2, 22.1 ± 0.2, 22.9 ± 0.2, 23.1 ± 0.2, 24.3 ± 0.2, 24.5 ± 0.2, 25.2 ± 0.2, 25.6 ± 0.2, 26.0 ± 0.2, 26.1 ± 0.2, and 27.8 ± 0.2. In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at at least nineteen two-theta values chosen from 4.7 ± 0.2, 9.0 ± 0.2, 9.5 ± 0.2, 14.2 ± 0.2, 16.7 ± 0.2, 18.1 ± 0.2, 18.9 ± 0.2, 20.0 ± 0.2, 21.0 ± 0.2, 21.9 ± 0.2, 22.1 ± 0.2, 22.9 ± 0.2, 23.1 ± 0.2, 24.3 ± 0.2, 24.5 ± 0.2, 25.2 ± 0.2, 25.6 ± 0.2, 26.0 ± 0.2, 26.1 ± 0.2, and 27.8 ± 0.2. In some embodiments, Form A is characterized by an X-ray powder diffractogram having a signal at 4.7 ± 0.2, 9.0 ± 0.2, 9.5 ± 0.2, 14.2 ± 0.2, 16.7 ± 0.2, 18.1 ± 0.2, 18.9 ± 0.2, 20.0 ± 0.2, 21.0 ± 0.2, 21.9 ± 0.2, 22.1 ± 0.2, 22.9 ± 0.2, 23.1 ± 0.2, 24.3 ± 0.2, 24.5 ± 0.2, 25.2 ± 0.2, 25.6 ± 0.2, 26.0 ± 0.2, 26.1 ± 0.2, and 27.8 ± 0.2 two-theta.

[0184] In some embodiments, disclosed herein is a composition comprising Form A of Compound 87. In some embodiments, disclosed herein is a composition comprising Compound 87 in substantially pure Form A. In some embodiments, disclosed herein is a composition comprising at least one active compound consisting essentially of Compound 87 in Form A.

[0185] In some embodiments, Form A is characterized by a DSC curve substantially similar to that in FIG. 42. In some embodiments, Form A is characterized by a DSC curve having a melting onset of 157 °C with a peak at 160 °C.

[0186] In some embodiments, Form A is characterized by a 13< C NMR spectrum having a signal at at least one ppm value chosen from 128.3 ± 0.2 ppm, 122.0 ± 0.2 ppm, 58.4 ± 0.2 ppm, and 38.4 ± 0.2 ppm. In some embodiments, Form A is characterized by a 13< C NMR spectrum having a signal at at least two ppm values chosen from 128.3 ± 0.2 ppm, 122.0 ± 0.2 ppm, 58.4 ± 0.2 ppm, and 38.4 ± 0.2 ppm. In some embodiments, Form A is characterized by a 13< C NMR spectrum having a signal at at least three ppm values chosen from 128.3 ± 0.2 ppm, 122.0 ± 0.2 ppm, 58.4 ± 0.2 ppm, and 38.4 ± 0.2 ppm. In some embodiments, Form A is characterized by a 13< C NMR spectrum having a signal at 128.3 ± 0.2 ppm, 122.0 ± 0.2 ppm, 58.4 ± 0.2 ppm, and 38.4 ± 0.2 ppm.

[0187] In some embodiments, Form A is characterized by a 19< F NMR spectrum having a signal at -110.9 ± 0.2 ppm.

[0188] In some embodiments, Compound 87 is a crystalline solid. In some embodiments, Compound 87 is a crystalline solid. In some embodiments, the crystalline solid consists of 1% to 99% Form A relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 2% to 99% Form A relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 5% to 99% Form A relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 10% to 99% Form A relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 15% to 99% Form A relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 20% to 99% Form A relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 25% to 99% Form A relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 30% to 99% Form A relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 35% to 99% Form A relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 45% to 99% Form A relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 50% to 99% Form A relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 55% to 99% Form A relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 60% to 99% Form A relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 65% to 99% Form A relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 70% to 99% Form A relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 75% to 99% Form A relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 80% to 99% Form A relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 85% to 99% Form A relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 90% to 99% Form A relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 95% to 99% Form A relative to the total weight of the crystalline solid Compound 87.Hydrate Form of Compound 87

[0189] In some embodiments, Compound 87 is in the form of Hydrate Form. In some embodiments, Compound 87 is in the form of substantially pure Hydrate Form. In some embodiments, Hydrate Form is characterized by an X-ray powder diffractogram substantially similar to that in FIG. 43. In some embodiments, Hydrate Form is characterized by an X-ray powder diffractogram having a signal at at least two two-theta values chosen from 9.3 ± 0.2, 10.0 ±0.2, 10.9 ± 0.2, 12.1 ± 0.2, 20.0 ± 0.2, 20.5 ± 0.2, 20.8 ± 0.2, 21.3 ± 0.2, and 24.8 ± 0.2. In some embodiments, Hydrate Form is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 9.3 ± 0.2, 10.0 ±0.2, 10.9 ± 0.2, 12.1 ± 0.2, 20.0 ± 0.2, 20.5 ± 0.2, 20.8 ± 0.2, 21.3 ± 0.2, and 24.8 ± 0.2. In some embodiments, Hydrate Form is characterized by an X-ray powder diffractogram having a signal at at least four two-theta values chosen from 9.3 ± 0.2, 10.0 ±0.2, 10.9 ± 0.2, 12.1 ± 0.2, 20.0 ± 0.2, 20.5 ± 0.2, 20.8 ± 0.2, 21.3 ± 0.2, and 24.8 ± 0.2. In some embodiments, Hydrate Form is characterized by an X-ray powder diffractogram having a signal at at least five two-theta values chosen from 9.3 ± 0.2, 10.0 ±0.2, 10.9 ± 0.2, 12.1 ± 0.2, 20.0 ± 0.2, 20.5 ± 0.2, 20.8 ± 0.2, 21.3 ± 0.2, and 24.8 ± 0.2. In some embodiments, Hydrate Form is characterized by an X-ray powder diffractogram having a signal at at least six two-theta values chosen from 9.3 ± 0.2, 10.0 ±0.2, 10.9 ± 0.2, 12.1 ± 0.2, 20.0 ± 0.2, 20.5 ± 0.2, 20.8 ± 0.2, 21.3 ± 0.2, and 24.8 ± 0.2.

[0190] In some embodiments, Hydrate Form is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 9.3 ± 0.2, 10.0 ± 0.2, 10.9 ± 0.2, 11.8 ± 0.2, 12.1 ± 0.2, 15.0 ± 0.2, 15.8 ± 0.2, 18.3 ± 0.2, 19.3 ± 0.2, 20.0 ± 0.2, 20.1 ± 0.2, 20.5 ± 0.2, 20.8 ± 0.2, 20.9 ± 0.2, 21.3 ± 0.2, 21.8 ± 0.2, 22.0 ± 0.2, 22.7 ± 0.2, 22.8 ± 0.2, 23.7 ± 0.2, 24.8 ± 0.2, 26.0 ± 0.2, 26.1 ± 0.2, 26.3 ± 0.2, 26.4 ± 0.2, 26.7 ± 0.2, 26.8 ± 0.2, 27.3 ± 0.2, 28.6 ± 0.2, and 28.7 ± 0.2. In some embodiments, Hydrate Form is characterized by an X-ray powder diffractogram having a signal at at least four two-theta values chosen from 9.3 ± 0.2, 10.0 ± 0.2, 10.9 ± 0.2, 11.8 ± 0.2, 12.1 ± 0.2, 15.0 ± 0.2, 15.8 ± 0.2, 18.3 ± 0.2, 19.3 ± 0.2, 20.0 ± 0.2, 20.1 ± 0.2, 20.5 ± 0.2, 20.8 ± 0.2, 20.9 ± 0.2, 21.3 ± 0.2, 21.8 ± 0.2, 22.0 ± 0.2, 22.7 ± 0.2, 22.8 ± 0.2, 23.7 ± 0.2, 24.8 ± 0.2, 26.0 ± 0.2, 26.1 ± 0.2, 26.3 ± 0.2, 26.4 ± 0.2, 26.7 ± 0.2, 26.8 ± 0.2, 27.3 ± 0.2, 28.6 ± 0.2, and 28.7 ± 0.2. In some embodiments, Hydrate Form is characterized by an X-ray powder diffractogram having a signal at at least five two-theta values chosen from 9.3 ± 0.2, 10.0 ± 0.2, 10.9 ± 0.2, 11.8 ± 0.2, 12.1 ± 0.2, 15.0 ± 0.2, 15.8 ± 0.2, 18.3 ± 0.2, 19.3 ± 0.2, 20.0 ± 0.2, 20.1 ± 0.2, 20.5 ± 0.2, 20.8 ± 0.2, 20.9 ± 0.2, 21.3 ± 0.2, 21.8 ± 0.2, 22.0 ± 0.2, 22.7 ± 0.2, 22.8 ± 0.2, 23.7 ± 0.2, 24.8 ± 0.2, 26.0 ± 0.2, 26.1 ± 0.2, 26.3 ± 0.2, 26.4 ± 0.2, 26.7 ± 0.2, 26.8 ± 0.2, 27.3 ± 0.2, 28.6 ± 0.2, and 28.7 ± 0.2. In some embodiments, Hydrate Form is characterized by an X-ray powder diffractogram having a signal at at least six two-theta values chosen from 9.3 ± 0.2, 10.0 ± 0.2, 10.9 ± 0.2, 11.8 ± 0.2, 12.1 ± 0.2, 15.0 ± 0.2, 15.8 ± 0.2, 18.3 ± 0.2, 19.3 ± 0.2, 20.0 ± 0.2, 20.1 ± 0.2, 20.5 ± 0.2, 20.8 ± 0.2, 20.9 ± 0.2, 21.3 ± 0.2, 21.8 ± 0.2, 22.0 ± 0.2, 22.7 ± 0.2, 22.8 ± 0.2, 23.7 ± 0.2, 24.8 ± 0.2, 26.0 ± 0.2, 26.1 ± 0.2, 26.3 ± 0.2, 26.4 ± 0.2, 26.7 ± 0.2, 26.8 ± 0.2, 27.3 ± 0.2, 28.6 ± 0.2, and 28.7 ± 0.2. In some embodiments, Hydrate Form is characterized by an X-ray powder diffractogram having a signal at at least seven two-theta values chosen from 9.3 ± 0.2, 10.0 ± 0.2, 10.9 ± 0.2, 11.8 ± 0.2, 12.1 ± 0.2, 15.0 ± 0.2, 15.8 ± 0.2, 18.3 ± 0.2, 19.3 ± 0.2, 20.0 ± 0.2, 20.1 ± 0.2, 20.5 ± 0.2, 20.8 ± 0.2, 20.9 ± 0.2, 21.3 ± 0.2, 21.8 ± 0.2, 22.0 ± 0.2, 22.7 ± 0.2, 22.8 ± 0.2, 23.7 ± 0.2, 24.8 ± 0.2, 26.0 ± 0.2, 26.1 ± 0.2, 26.3 ± 0.2, 26.4 ± 0.2, 26.7 ± 0.2, 26.8 ± 0.2, 27.3 ± 0.2, 28.6 ± 0.2, and 28.7 ± 0.2. In some embodiments, Hydrate Form is characterized by an X-ray powder diffractogram having a signal at at least eight two-theta values chosen from 9.3 ± 0.2, 10.0 ± 0.2, 10.9 ± 0.2, 11.8 ± 0.2, 12.1 ± 0.2, 15.0 ± 0.2, 15.8 ± 0.2, 18.3 ± 0.2, 19.3 ± 0.2, 20.0 ± 0.2, 20.1 ± 0.2, 20.5 ± 0.2, 20.8 ± 0.2, 20.9 ± 0.2, 21.3 ± 0.2, 21.8 ± 0.2, 22.0 ± 0.2, 22.7 ± 0.2, 22.8 ± 0.2, 23.7 ± 0.2, 24.8 ± 0.2, 26.0 ± 0.2, 26.1 ± 0.2, 26.3 ± 0.2, 26.4 ± 0.2, 26.7 ± 0.2, 26.8 ± 0.2, 27.3 ± 0.2, 28.6 ± 0.2, and 28.7 ± 0.2. In some embodiments, Hydrate Form is characterized by an X-ray powder diffractogram having a signal at at least nine two-theta values chosen from 9.3 ± 0.2, 10.0 ± 0.2, 10.9 ± 0.2, 11.8 ± 0.2, 12.1 ± 0.2, 15.0 ± 0.2, 15.8 ± 0.2, 18.3 ± 0.2, 19.3 ± 0.2, 20.0 ± 0.2, 20.1 ± 0.2, 20.5 ± 0.2, 20.8 ± 0.2, 20.9 ± 0.2, 21.3 ± 0.2, 21.8 ± 0.2, 22.0 ± 0.2, 22.7 ± 0.2, 22.8 ± 0.2, 23.7 ± 0.2, 24.8 ± 0.2, 26.0 ± 0.2, 26.1 ± 0.2, 26.3 ± 0.2, 26.4 ± 0.2, 26.7 ± 0.2, 26.8 ± 0.2, 27.3 ± 0.2, 28.6 ± 0.2, and 28.7 ± 0.2. In some embodiments, Hydrate Form is characterized by an X-ray powder diffractogram having a signal at at least ten two-theta values chosen from 9.3 ± 0.2, 10.0 ± 0.2, 10.9 ± 0.2, 11.8 ± 0.2, 12.1 ± 0.2, 15.0 ± 0.2, 15.8 ± 0.2, 18.3 ± 0.2, 19.3 ± 0.2, 20.0 ± 0.2, 20.1 ± 0.2, 20.5 ± 0.2, 20.8 ± 0.2, 20.9 ± 0.2, 21.3 ± 0.2, 21.8 ± 0.2, 22.0 ± 0.2, 22.7 ± 0.2, 22.8 ± 0.2, 23.7 ± 0.2, 24.8 ± 0.2, 26.0 ± 0.2, 26.1 ± 0.2, 26.3 ± 0.2, 26.4 ± 0.2, 26.7 ± 0.2, 26.8 ± 0.2, 27.3 ± 0.2, 28.6 ± 0.2, and 28.7 ± 0.2. In some embodiments, Hydrate Form is characterized by an X-ray powder diffractogram having a signal at at least eleven two-theta values chosen from 9.3 ± 0.2, 10.0 ± 0.2, 10.9 ± 0.2, 11.8 ± 0.2, 12.1 ± 0.2, 15.0 ± 0.2, 15.8 ± 0.2, 18.3 ± 0.2, 19.3 ± 0.2, 20.0 ± 0.2, 20.1 ± 0.2, 20.5 ± 0.2, 20.8 ± 0.2, 20.9 ± 0.2, 21.3 ± 0.2, 21.8 ± 0.2, 22.0 ± 0.2, 22.7 ± 0.2, 22.8 ± 0.2, 23.7 ± 0.2, 24.8 ± 0.2, 26.0 ± 0.2, 26.1 ± 0.2, 26.3 ± 0.2, 26.4 ± 0.2, 26.7 ± 0.2, 26.8 ± 0.2, 27.3 ± 0.2, 28.6 ± 0.2, and 28.7 ± 0.2. In some embodiments, Hydrate Form is characterized by an X-ray powder diffractogram having a signal at at least twelve two-theta values chosen from 9.3 ± 0.2, 10.0 ± 0.2, 10.9 ± 0.2, 11.8 ± 0.2, 12.1 ± 0.2, 15.0 ± 0.2, 15.8 ± 0.2, 18.3 ± 0.2, 19.3 ± 0.2, 20.0 ± 0.2, 20.1 ± 0.2, 20.5 ± 0.2, 20.8 ± 0.2, 20.9 ± 0.2, 21.3 ± 0.2, 21.8 ± 0.2, 22.0 ± 0.2, 22.7 ± 0.2, 22.8 ± 0.2, 23.7 ± 0.2, 24.8 ± 0.2, 26.0 ± 0.2, 26.1 ± 0.2, 26.3 ± 0.2, 26.4 ± 0.2, 26.7 ± 0.2, 26.8 ± 0.2, 27.3 ± 0.2, 28.6 ± 0.2, and 28.7 ± 0.2. In some embodiments, Hydrate Form is characterized by an X-ray powder diffractogram having a signal at at least thirteen two-theta values chosen from 9.3 ± 0.2, 10.0 ± 0.2, 10.9 ± 0.2, 11.8 ± 0.2, 12.1 ± 0.2, 15.0 ± 0.2, 15.8 ± 0.2, 18.3 ± 0.2, 19.3 ± 0.2, 20.0 ± 0.2, 20.1 ± 0.2, 20.5 ± 0.2, 20.8 ± 0.2, 20.9 ± 0.2, 21.3 ± 0.2, 21.8 ± 0.2, 22.0 ± 0.2, 22.7 ± 0.2, 22.8 ± 0.2, 23.7 ± 0.2, 24.8 ± 0.2, 26.0 ± 0.2, 26.1 ± 0.2, 26.3 ± 0.2, 26.4 ± 0.2, 26.7 ± 0.2, 26.8 ± 0.2, 27.3 ± 0.2, 28.6 ± 0.2, and 28.7 ± 0.2. In some embodiments, Hydrate Form is characterized by an X-ray powder diffractogram having a signal at at least fourteen two-theta values chosen from 9.3 ± 0.2, 10.0 ± 0.2, 10.9 ± 0.2, 11.8 ± 0.2, 12.1 ± 0.2, 15.0 ± 0.2, 15.8 ± 0.2, 18.3 ± 0.2, 19.3 ± 0.2, 20.0 ± 0.2, 20.1 ± 0.2, 20.5 ± 0.2, 20.8 ± 0.2, 20.9 ± 0.2, 21.3 ± 0.2, 21.8 ± 0.2, 22.0 ± 0.2, 22.7 ± 0.2, 22.8 ± 0.2, 23.7 ± 0.2, 24.8 ± 0.2, 26.0 ± 0.2, 26.1 ± 0.2, 26.3 ± 0.2, 26.4 ± 0.2, 26.7 ± 0.2, 26.8 ± 0.2, 27.3 ± 0.2, 28.6 ± 0.2, and 28.7 ± 0.2. In some embodiments, Hydrate Form is characterized by an X-ray powder diffractogram having a signal at at least fifteen two-theta values chosen from 9.3 ± 0.2, 10.0 ± 0.2, 10.9 ± 0.2, 11.8 ± 0.2, 12.1 ± 0.2, 15.0 ± 0.2, 15.8 ± 0.2, 18.3 ± 0.2, 19.3 ± 0.2, 20.0 ± 0.2, 20.1 ± 0.2, 20.5 ± 0.2, 20.8 ± 0.2, 20.9 ± 0.2, 21.3 ± 0.2, 21.8 ± 0.2, 22.0 ± 0.2, 22.7 ± 0.2, 22.8 ± 0.2, 23.7 ± 0.2, 24.8 ± 0.2, 26.0 ± 0.2, 26.1 ± 0.2, 26.3 ± 0.2, 26.4 ± 0.2, 26.7 ± 0.2, 26.8 ± 0.2, 27.3 ± 0.2, 28.6 ± 0.2, and 28.7 ± 0.2. In some embodiments, Hydrate Form is characterized by an X-ray powder diffractogram having a signal at at least sixteen two-theta values chosen from 9.3 ± 0.2, 10.0 ± 0.2, 10.9 ± 0.2, 11.8 ± 0.2, 12.1 ± 0.2, 15.0 ± 0.2, 15.8 ± 0.2, 18.3 ± 0.2, 19.3 ± 0.2, 20.0 ± 0.2, 20.1 ± 0.2, 20.5 ± 0.2, 20.8 ± 0.2, 20.9 ± 0.2, 21.3 ± 0.2, 21.8 ± 0.2, 22.0 ± 0.2, 22.7 ± 0.2, 22.8 ± 0.2, 23.7 ± 0.2, 24.8 ± 0.2, 26.0 ± 0.2, 26.1 ± 0.2, 26.3 ± 0.2, 26.4 ± 0.2, 26.7 ± 0.2, 26.8 ± 0.2, 27.3 ± 0.2, 28.6 ± 0.2, and 28.7 ± 0.2. In some embodiments, Hydrate Form is characterized by an X-ray powder diffractogram having a signal at at least seventeen two-theta values chosen from 9.3 ± 0.2, 10.0 ± 0.2, 10.9 ± 0.2, 11.8 ± 0.2, 12.1 ± 0.2, 15.0 ± 0.2, 15.8 ± 0.2, 18.3 ± 0.2, 19.3 ± 0.2, 20.0 ± 0.2, 20.1 ± 0.2, 20.5 ± 0.2, 20.8 ± 0.2, 20.9 ± 0.2, 21.3 ± 0.2, 21.8 ± 0.2, 22.0 ± 0.2, 22.7 ± 0.2, 22.8 ± 0.2, 23.7 ± 0.2, 24.8 ± 0.2, 26.0 ± 0.2, 26.1 ± 0.2, 26.3 ± 0.2, 26.4 ± 0.2, 26.7 ± 0.2, 26.8 ± 0.2, 27.3 ± 0.2, 28.6 ± 0.2, and 28.7 ± 0.2. In some embodiments, Hydrate Form is characterized by an X-ray powder diffractogram having a signal at at least eighteen two-theta values chosen from 9.3 ± 0.2, 10.0 ± 0.2, 10.9 ± 0.2, 11.8 ± 0.2, 12.1 ± 0.2, 15.0 ± 0.2, 15.8 ± 0.2, 18.3 ± 0.2, 19.3 ± 0.2, 20.0 ± 0.2, 20.1 ± 0.2, 20.5 ± 0.2, 20.8 ± 0.2, 20.9 ± 0.2, 21.3 ± 0.2, 21.8 ± 0.2, 22.0 ± 0.2, 22.7 ± 0.2, 22.8 ± 0.2, 23.7 ± 0.2, 24.8 ± 0.2, 26.0 ± 0.2, 26.1 ± 0.2, 26.3 ± 0.2, 26.4 ± 0.2, 26.7 ± 0.2, 26.8 ± 0.2, 27.3 ± 0.2, 28.6 ± 0.2, and 28.7 ± 0.2. In some embodiments, Hydrate Form is characterized by an X-ray powder diffractogram having a signal at at least nineteen two-theta values chosen from 9.3 ± 0.2, 10.0 ± 0.2, 10.9 ± 0.2, 11.8 ± 0.2, 12.1 ± 0.2, 15.0 ± 0.2, 15.8 ± 0.2, 18.3 ± 0.2, 19.3 ± 0.2, 20.0 ± 0.2, 20.1 ± 0.2, 20.5 ± 0.2, 20.8 ± 0.2, 20.9 ± 0.2, 21.3 ± 0.2, 21.8 ± 0.2, 22.0 ± 0.2, 22.7 ± 0.2, 22.8 ± 0.2, 23.7 ± 0.2, 24.8 ± 0.2, 26.0 ± 0.2, 26.1 ± 0.2, 26.3 ± 0.2, 26.4 ± 0.2, 26.7 ± 0.2, 26.8 ± 0.2, 27.3 ± 0.2, 28.6 ± 0.2, and 28.7 ± 0.2. In some embodiments, Hydrate Form is characterized by an X-ray powder diffractogram having a signal at at least twenty two-theta values chosen from 9.3 ± 0.2, 10.0 ± 0.2, 10.9 ± 0.2, 11.8 ± 0.2, 12.1 ± 0.2, 15.0 ± 0.2, 15.8 ± 0.2, 18.3 ± 0.2, 19.3 ± 0.2, 20.0 ± 0.2, 20.1 ± 0.2, 20.5 ± 0.2, 20.8 ± 0.2, 20.9 ± 0.2, 21.3 ± 0.2, 21.8 ± 0.2, 22.0 ± 0.2, 22.7 ± 0.2, 22.8 ± 0.2, 23.7 ± 0.2, 24.8 ± 0.2, 26.0 ± 0.2, 26.1 ± 0.2, 26.3 ± 0.2, 26.4 ± 0.2, 26.7 ± 0.2, 26.8 ± 0.2, 27.3 ± 0.2, 28.6 ± 0.2, and 28.7 ± 0.2. In some embodiments, Hydrate Form is characterized by an X-ray powder diffractogram having a signal at at least twenty one two-theta values chosen from 9.3 ± 0.2, 10.0 ± 0.2, 10.9 ± 0.2, 11.8 ± 0.2, 12.1 ± 0.2, 15.0 ± 0.2, 15.8 ± 0.2, 18.3 ± 0.2, 19.3 ± 0.2, 20.0 ± 0.2, 20.1 ± 0.2, 20.5 ± 0.2, 20.8 ± 0.2, 20.9 ± 0.2, 21.3 ± 0.2, 21.8 ± 0.2, 22.0 ± 0.2, 22.7 ± 0.2, 22.8 ± 0.2, 23.7 ± 0.2, 24.8 ± 0.2, 26.0 ± 0.2, 26.1 ± 0.2, 26.3 ± 0.2, 26.4 ± 0.2, 26.7 ± 0.2, 26.8 ± 0.2, 27.3 ± 0.2, 28.6 ± 0.2, and 28.7 ± 0.2. In some embodiments, Hydrate Form is characterized by an X-ray powder diffractogram having a signal at at least twenty two two-theta values chosen from 9.3 ± 0.2, 10.0 ± 0.2, 10.9 ± 0.2, 11.8 ± 0.2, 12.1 ± 0.2, 15.0 ± 0.2, 15.8 ± 0.2, 18.3 ± 0.2, 19.3 ± 0.2, 20.0 ± 0.2, 20.1 ± 0.2, 20.5 ± 0.2, 20.8 ± 0.2, 20.9 ± 0.2, 21.3 ± 0.2, 21.8 ± 0.2, 22.0 ± 0.2, 22.7 ± 0.2, 22.8 ± 0.2, 23.7 ± 0.2, 24.8 ± 0.2, 26.0 ± 0.2, 26.1 ± 0.2, 26.3 ± 0.2, 26.4 ± 0.2, 26.7 ± 0.2, 26.8 ± 0.2, 27.3 ± 0.2, 28.6 ± 0.2, and 28.7 ± 0.2. In some embodiments, Hydrate Form is characterized by an X-ray powder diffractogram having a signal at at least twenty three two-theta values chosen from 9.3 ± 0.2, 10.0 ± 0.2, 10.9 ± 0.2, 11.8 ± 0.2, 12.1 ± 0.2, 15.0 ± 0.2, 15.8 ± 0.2, 18.3 ± 0.2, 19.3 ± 0.2, 20.0 ± 0.2, 20.1 ± 0.2, 20.5 ± 0.2, 20.8 ± 0.2, 20.9 ± 0.2, 21.3 ± 0.2, 21.8 ± 0.2, 22.0 ± 0.2, 22.7 ± 0.2, 22.8 ± 0.2, 23.7 ± 0.2, 24.8 ± 0.2, 26.0 ± 0.2, 26.1 ± 0.2, 26.3 ± 0.2, 26.4 ± 0.2, 26.7 ± 0.2, 26.8 ± 0.2, 27.3 ± 0.2, 28.6 ± 0.2, and 28.7 ± 0.2. In some embodiments, Hydrate Form is characterized by an X-ray powder diffractogram having a signal at at least twenty four two-theta values chosen from 9.3 ± 0.2, 10.0 ± 0.2, 10.9 ± 0.2, 11.8 ± 0.2, 12.1 ± 0.2, 15.0 ± 0.2, 15.8 ± 0.2, 18.3 ± 0.2, 19.3 ± 0.2, 20.0 ± 0.2, 20.1 ± 0.2, 20.5 ± 0.2, 20.8 ± 0.2, 20.9 ± 0.2, 21.3 ± 0.2, 21.8 ± 0.2, 22.0 ± 0.2, 22.7 ± 0.2, 22.8 ± 0.2, 23.7 ± 0.2, 24.8 ± 0.2, 26.0 ± 0.2, 26.1 ± 0.2, 26.3 ± 0.2, 26.4 ± 0.2, 26.7 ± 0.2, 26.8 ± 0.2, 27.3 ± 0.2, 28.6 ± 0.2, and 28.7 ± 0.2. In some embodiments, Hydrate Form is characterized by an X-ray powder diffractogram having a signal at at least twenty five two-theta values chosen from 9.3 ± 0.2, 10.0 ± 0.2, 10.9 ± 0.2, 11.8 ± 0.2, 12.1 ± 0.2, 15.0 ± 0.2, 15.8 ± 0.2, 18.3 ± 0.2, 19.3 ± 0.2, 20.0 ± 0.2, 20.1 ± 0.2, 20.5 ± 0.2, 20.8 ± 0.2, 20.9 ± 0.2, 21.3 ± 0.2, 21.8 ± 0.2, 22.0 ± 0.2, 22.7 ± 0.2, 22.8 ± 0.2, 23.7 ± 0.2, 24.8 ± 0.2, 26.0 ± 0.2, 26.1 ± 0.2, 26.3 ± 0.2, 26.4 ± 0.2, 26.7 ± 0.2, 26.8 ± 0.2, 27.3 ± 0.2, 28.6 ± 0.2, and 28.7 ± 0.2. In some embodiments, Hydrate Form is characterized by an X-ray powder diffractogram having a signal at at least twenty six two-theta values chosen from 9.3 ± 0.2, 10.0 ± 0.2, 10.9 ± 0.2, 11.8 ± 0.2, 12.1 ± 0.2, 15.0 ± 0.2, 15.8 ± 0.2, 18.3 ± 0.2, 19.3 ± 0.2, 20.0 ± 0.2, 20.1 ± 0.2, 20.5 ± 0.2, 20.8 ± 0.2, 20.9 ± 0.2, 21.3 ± 0.2, 21.8 ± 0.2, 22.0 ± 0.2, 22.7 ± 0.2, 22.8 ± 0.2, 23.7 ± 0.2, 24.8 ± 0.2, 26.0 ± 0.2, 26.1 ± 0.2, 26.3 ± 0.2, 26.4 ± 0.2, 26.7 ± 0.2, 26.8 ± 0.2, 27.3 ± 0.2, 28.6 ± 0.2, and 28.7 ± 0.2. In some embodiments, Hydrate Form is characterized by an X-ray powder diffractogram having a signal at at least twenty seven two-theta values chosen from 9.3 ± 0.2, 10.0 ± 0.2, 10.9 ± 0.2, 11.8 ± 0.2, 12.1 ± 0.2, 15.0 ± 0.2, 15.8 ± 0.2, 18.3 ± 0.2, 19.3 ± 0.2, 20.0 ± 0.2, 20.1 ± 0.2, 20.5 ± 0.2, 20.8 ± 0.2, 20.9 ± 0.2, 21.3 ± 0.2, 21.8 ± 0.2, 22.0 ± 0.2, 22.7 ± 0.2, 22.8 ± 0.2, 23.7 ± 0.2, 24.8 ± 0.2, 26.0 ± 0.2, 26.1 ± 0.2, 26.3 ± 0.2, 26.4 ± 0.2, 26.7 ± 0.2, 26.8 ± 0.2, 27.3 ± 0.2, 28.6 ± 0.2, and 28.7 ± 0.2. In some embodiments, Hydrate Form is characterized by an X-ray powder diffractogram having a signal at at least twenty eight two-theta values chosen from 9.3 ± 0.2, 10.0 ± 0.2, 10.9 ± 0.2, 11.8 ± 0.2, 12.1 ± 0.2, 15.0 ± 0.2, 15.8 ± 0.2, 18.3 ± 0.2, 19.3 ± 0.2, 20.0 ± 0.2, 20.1 ± 0.2, 20.5 ± 0.2, 20.8 ± 0.2, 20.9 ± 0.2, 21.3 ± 0.2, 21.8 ± 0.2, 22.0 ± 0.2, 22.7 ± 0.2, 22.8 ± 0.2, 23.7 ± 0.2, 24.8 ± 0.2, 26.0 ± 0.2, 26.1 ± 0.2, 26.3 ± 0.2, 26.4 ± 0.2, 26.7 ± 0.2, 26.8 ± 0.2, 27.3 ± 0.2, 28.6 ± 0.2, and 28.7 ± 0.2. In some embodiments, Hydrate Form is characterized by an X-ray powder diffractogram having a signal at at least twenty nine two-theta values chosen from 9.3 ± 0.2, 10.0 ± 0.2, 10.9 ± 0.2, 11.8 ± 0.2, 12.1 ± 0.2, 15.0 ± 0.2, 15.8 ± 0.2, 18.3 ± 0.2, 19.3 ± 0.2, 20.0 ± 0.2, 20.1 ± 0.2, 20.5 ± 0.2, 20.8 ± 0.2, 20.9 ± 0.2, 21.3 ± 0.2, 21.8 ± 0.2, 22.0 ± 0.2, 22.7 ± 0.2, 22.8 ± 0.2, 23.7 ± 0.2, 24.8 ± 0.2, 26.0 ± 0.2, 26.1 ± 0.2, 26.3 ± 0.2, 26.4 ± 0.2, 26.7 ± 0.2, 26.8 ± 0.2, 27.3 ± 0.2, 28.6 ± 0.2, and 28.7 ± 0.2. In some embodiments, Hydrate Form is characterized by an X-ray powder diffractogram having a signal at 9.3 ± 0.2, 10.0 ± 0.2, 10.9 ± 0.2, 11.8 ± 0.2, 12.1 ± 0.2, 15.0 ± 0.2, 15.8 ± 0.2, 18.3 ± 0.2, 19.3 ± 0.2, 20.0 ± 0.2, 20.1 ± 0.2, 20.5 ± 0.2, 20.8 ± 0.2, 20.9 ± 0.2, 21.3 ± 0.2, 21.8 ± 0.2, 22.0 ± 0.2, 22.7 ± 0.2, 22.8 ± 0.2, 23.7 ± 0.2, 24.8 ± 0.2, 26.0 ± 0.2, 26.1 ± 0.2, 26.3 ± 0.2, 26.4 ± 0.2, 26.7 ± 0.2, 26.8 ± 0.2, 27.3 ± 0.2, 28.6 ± 0.2, and 28.7 ± 0.2 two-theta.

[0191] In some embodiments, Hydrate Form of Compound 87 has a single crystal unit cell characterized as follows: Crystal SystemOrthorhombicSpace GroupP2 1 2 1 2 1 a (Å)4.9 ± 0.1b (Å)9.5 ± 0.1c (Å)44.6 ± 0.1α (°)90β (°)90γ (°)90V (Å 3< )2064.3 ± 0.2Z / Z'4 / 1

[0192] In some embodiments, disclosed herein is a composition comprising Hydrate Form of Compound 87. In some embodiments, disclosed herein is a composition comprising Compound 87 in substantially pure Hydrate Form. In some embodiments, disclosed herein is a composition comprising at least one active compound consisting essentially of Compound 87 in Hydrate Form.

[0193] In some embodiments, Hydrate Form is characterized by a DSC curve substantially similar to that in FIG. 47. In some embodiments, Hydrate Form is characterized by a DSC curve having a peak at at least one temperature chosen from 86 °C and 158 °C.

[0194] In some embodiments, Hydrate Form is characterized by a 13< C NMR spectrum having a signal at at least one ppm value chosen from 133.5 ± 0.2 ppm, 119.8 ± 0.2 ppm, 74.2 ± 0.2 ppm, 56.4 ± 0.2 ppm, and 18.7 ± 0.2 ppm. In some embodiments, Hydrate Form is characterized by a 13< C NMR spectrum having a signal at at least two ppm values chosen from 133.5 ± 0.2 ppm, 119.8 ± 0.2 ppm, 74.2 ± 0.2 ppm, 56.4 ± 0.2 ppm, and 18.7 ± 0.2 ppm. In some embodiments, Hydrate Form is characterized by a 13< C NMR spectrum having a signal at at least three ppm values chosen from 133.5 ± 0.2 ppm, 119.8 ± 0.2 ppm, 74.2 ± 0.2 ppm, 56.4 ± 0.2 ppm, and 18.7 ± 0.2 ppm. In some embodiments, Hydrate Form is characterized by a 13< C NMR spectrum having a signal at at least four ppm values chosen from 133.5 ± 0.2 ppm, 119.8 ± 0.2 ppm, 74.2 ± 0.2 ppm, 56.4 ± 0.2 ppm, and 18.7 ± 0.2 ppm. In some embodiments, Hydrate Form is characterized by a 13< C NMR spectrum having a signal at 133.5 ± 0.2 ppm, 119.8 ± 0.2 ppm, 74.2 ± 0.2 ppm, 56.4 ± 0.2 ppm, and 18.7 ± 0.2 ppm.

[0195] In some embodiments, Hydrate Form is characterized by a 19< F NMR spectrum having a signal at -113.6 ± 0.2 ppm.

[0196] In some embodiments, Compound 87 is a crystalline solid. In some embodiments, the crystalline solid consists of 1% to 99% Hydrate Form relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 2% to 99% Hydrate Form relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 5% to 99% Hydrate Form relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 10% to 99% Hydrate Form relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 15% to 99% Hydrate Form relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 20% to 99% Hydrate Form relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 25% to 99% Hydrate Form relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 30% to 99% Hydrate Form relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 35% to 99% Hydrate Form relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 45% to 99% Hydrate Form relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 50% to 99% Hydrate Form relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 55% to 99% Hydrate Form relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 60% to 99% Hydrate Form relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 65% to 99% Hydrate Form relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 70% to 99% Hydrate Form relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 75% to 99% Hydrate Form relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 80% to 99% Hydrate Form relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 85% to 99% Hydrate Form relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 90% to 99% Hydrate Form relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 95% to 99% Hydrate Form relative to the total weight of the crystalline solid Compound 87.IPAc Solvate of Compound 87

[0197] In some embodiments, Compound 87 is in the form of an IPAc Solvate Form. In some embodiments, Compound 87 is in the form of substantially pure IPAc Solvate Form. In some embodiments, IPAc Solvate Form is characterized by an X-ray powder diffractogram substantially similar to that in FIG. 49. In some embodiments, IPAc Solvate Form is characterized by an X-ray powder diffractogram having a signal at at least two two-theta values chosen from 5.0 ± 0.2, 9.9 ± 0.2, 11.5 ± 0.2, 11.7 ± 0.2, 12.0 ± 0.2, 16.0 ± 0.2, 18.8 ± 0.2, 22.0 ± 0.2, and 23.1 ± 0.2. In some embodiments, IPAc Solvate Form is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 5.0 ± 0.2, 9.9 ± 0.2, 11.5 ± 0.2, 11.7 ± 0.2, 12.0 ± 0.2, 16.0 ± 0.2, 18.8 ± 0.2, 22.0 ± 0.2, and 23.1 ± 0.2. In some embodiments, IPAc Solvate Form is characterized by an X-ray powder diffractogram having a signal at at least four two-theta values chosen from 5.0 ± 0.2, 9.9 ± 0.2, 11.5 ± 0.2, 11.7 ± 0.2, 12.0 ± 0.2, 16.0 ± 0.2, 18.8 ± 0.2, 22.0 ± 0.2, and 23.1 ± 0.2. In some embodiments, IPAc Solvate Form is characterized by an X-ray powder diffractogram having a signal at at least five two-theta values chosen from 5.0 ± 0.2, 9.9 ± 0.2, 11.5 ± 0.2, 11.7 ± 0.2, 12.0 ± 0.2, 16.0 ± 0.2, 18.8 ± 0.2, 22.0 ± 0.2, and 23.1 ± 0.2. In some embodiments, IPAc Solvate Form is characterized by an X-ray powder diffractogram having a signal at at least six two-theta values chosen from 5.0 ± 0.2, 9.9 ± 0.2, 11.5 ± 0.2, 11.7 ± 0.2, 12.0 ± 0.2, 16.0 ± 0.2, 18.8 ± 0.2, 22.0 ± 0.2, and 23.1 ± 0.2.

[0198] In some embodiments, IPAc Solvate Form is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 5.0 ± 0.2, 9.9 ± 0.2, 11.5 ± 0.2, 11.7 ± 0.2, 12.0 ± 0.2, 12.5 ± 0.2, 13.0 ± 0.2, 13.7 ± 0.2, 14.4 ± 0.2, 16.0 ± 0.2, 16.9 ± 0.2, 18.8 ± 0.2, 19.9 ± 0.2, 20.4 ± 0.2, 22.0 ± 0.2, 23.1 ± 0.2, 23.6 ± 0.2, 24.2 ± 0.2, 25.2 ± 0.2, 26.2 ± 0.2, and 27.5 ± 0.2. In some embodiments, IPAc Solvate Form is characterized by an X-ray powder diffractogram having a signal at at least four two-theta values chosen from 5.0 ± 0.2, 9.9 ± 0.2, 11.5 ± 0.2, 11.7 ± 0.2, 12.0 ± 0.2, 12.5 ± 0.2, 13.0 ± 0.2, 13.7 ± 0.2, 14.4 ± 0.2, 16.0 ± 0.2, 16.9 ± 0.2, 18.8 ± 0.2, 19.9 ± 0.2, 20.4 ± 0.2, 22.0 ± 0.2, 23.1 ± 0.2, 23.6 ± 0.2, 24.2 ± 0.2, 25.2 ± 0.2, 26.2 ± 0.2, and 27.5 ± 0.2. In some embodiments, IPAc Solvate Form is characterized by an X-ray powder diffractogram having a signal at at least five two-theta values chosen from 5.0 ± 0.2, 9.9 ± 0.2, 11.5 ± 0.2, 11.7 ± 0.2, 12.0 ± 0.2, 12.5 ± 0.2, 13.0 ± 0.2, 13.7 ± 0.2, 14.4 ± 0.2, 16.0 ± 0.2, 16.9 ± 0.2, 18.8 ± 0.2, 19.9 ± 0.2, 20.4 ± 0.2, 22.0 ± 0.2, 23.1 ± 0.2, 23.6 ± 0.2, 24.2 ± 0.2, 25.2 ± 0.2, 26.2 ± 0.2, and 27.5 ± 0.2. In some embodiments, IPAc Solvate Form is characterized by an X-ray powder diffractogram having a signal at at least six two-theta values chosen from 5.0 ± 0.2, 9.9 ± 0.2, 11.5 ± 0.2, 11.7 ± 0.2, 12.0 ± 0.2, 12.5 ± 0.2, 13.0 ± 0.2, 13.7 ± 0.2, 14.4 ± 0.2, 16.0 ± 0.2, 16.9 ± 0.2, 18.8 ± 0.2, 19.9 ± 0.2, 20.4 ± 0.2, 22.0 ± 0.2, 23.1 ± 0.2, 23.6 ± 0.2, 24.2 ± 0.2, 25.2 ± 0.2, 26.2 ± 0.2, and 27.5 ± 0.2. In some embodiments, IPAc Solvate Form is characterized by an X-ray powder diffractogram having a signal at at least seven two-theta values chosen from 5.0 ± 0.2, 9.9 ± 0.2, 11.5 ± 0.2, 11.7 ± 0.2, 12.0 ± 0.2, 12.5 ± 0.2, 13.0 ± 0.2, 13.7 ± 0.2, 14.4 ± 0.2, 16.0 ± 0.2, 16.9 ± 0.2, 18.8 ± 0.2, 19.9 ± 0.2, 20.4 ± 0.2, 22.0 ± 0.2, 23.1 ± 0.2, 23.6 ± 0.2, 24.2 ± 0.2, 25.2 ± 0.2, 26.2 ± 0.2, and 27.5 ± 0.2. In some embodiments, IPAc Solvate Form is characterized by an X-ray powder diffractogram having a signal at at least eight two-theta values chosen from 5.0 ± 0.2, 9.9 ± 0.2, 11.5 ± 0.2, 11.7 ± 0.2, 12.0 ± 0.2, 12.5 ± 0.2, 13.0 ± 0.2, 13.7 ± 0.2, 14.4 ± 0.2, 16.0 ± 0.2, 16.9 ± 0.2, 18.8 ± 0.2, 19.9 ± 0.2, 20.4 ± 0.2, 22.0 ± 0.2, 23.1 ± 0.2, 23.6 ± 0.2, 24.2 ± 0.2, 25.2 ± 0.2, 26.2 ± 0.2, and 27.5 ± 0.2. In some embodiments, IPAc Solvate Form is characterized by an X-ray powder diffractogram having a signal at at least nine two-theta values chosen from 5.0 ± 0.2, 9.9 ± 0.2, 11.5 ± 0.2, 11.7 ± 0.2, 12.0 ± 0.2, 12.5 ± 0.2, 13.0 ± 0.2, 13.7 ± 0.2, 14.4 ± 0.2, 16.0 ± 0.2, 16.9 ± 0.2, 18.8 ± 0.2, 19.9 ± 0.2, 20.4 ± 0.2, 22.0 ± 0.2, 23.1 ± 0.2, 23.6 ± 0.2, 24.2 ± 0.2, 25.2 ± 0.2, 26.2 ± 0.2, and 27.5 ± 0.2. In some embodiments, IPAc Solvate Form is characterized by an X-ray powder diffractogram having a signal at at least ten two-theta values chosen from 5.0 ± 0.2, 9.9 ± 0.2, 11.5 ± 0.2, 11.7 ± 0.2, 12.0 ± 0.2, 12.5 ± 0.2, 13.0 ± 0.2, 13.7 ± 0.2, 14.4 ± 0.2, 16.0 ± 0.2, 16.9 ± 0.2, 18.8 ± 0.2, 19.9 ± 0.2, 20.4 ± 0.2, 22.0 ± 0.2, 23.1 ± 0.2, 23.6 ± 0.2, 24.2 ± 0.2, 25.2 ± 0.2, 26.2 ± 0.2, and 27.5 ± 0.2. In some embodiments, IPAc Solvate Form is characterized by an X-ray powder diffractogram having a signal at at least eleven two-theta values chosen from 5.0 ± 0.2, 9.9 ± 0.2, 11.5 ± 0.2, 11.7 ± 0.2, 12.0 ± 0.2, 12.5 ± 0.2, 13.0 ± 0.2, 13.7 ± 0.2, 14.4 ± 0.2, 16.0 ± 0.2, 16.9 ± 0.2, 18.8 ± 0.2, 19.9 ± 0.2, 20.4 ± 0.2, 22.0 ± 0.2, 23.1 ± 0.2, 23.6 ± 0.2, 24.2 ± 0.2, 25.2 ± 0.2, 26.2 ± 0.2, and 27.5 ± 0.2. In some embodiments, IPAc Solvate Form is characterized by an X-ray powder diffractogram having a signal at at least twelve two-theta values chosen from 5.0 ± 0.2, 9.9 ± 0.2, 11.5 ± 0.2, 11.7 ± 0.2, 12.0 ± 0.2, 12.5 ± 0.2, 13.0 ± 0.2, 13.7 ± 0.2, 14.4 ± 0.2, 16.0 ± 0.2, 16.9 ± 0.2, 18.8 ± 0.2, 19.9 ± 0.2, 20.4 ± 0.2, 22.0 ± 0.2, 23.1 ± 0.2, 23.6 ± 0.2, 24.2 ± 0.2, 25.2 ± 0.2, 26.2 ± 0.2, and 27.5 ± 0.2. In some embodiments, IPAc Solvate Form is characterized by an X-ray powder diffractogram having a signal at at least thirteen two-theta values chosen from 5.0 ± 0.2, 9.9 ± 0.2, 11.5 ± 0.2, 11.7 ± 0.2, 12.0 ± 0.2, 12.5 ± 0.2, 13.0 ± 0.2, 13.7 ± 0.2, 14.4 ± 0.2, 16.0 ± 0.2, 16.9 ± 0.2, 18.8 ± 0.2, 19.9 ± 0.2, 20.4 ± 0.2, 22.0 ± 0.2, 23.1 ± 0.2, 23.6 ± 0.2, 24.2 ± 0.2, 25.2 ± 0.2, 26.2 ± 0.2, and 27.5 ± 0.2. In some embodiments, IPAc Solvate Form is characterized by an X-ray powder diffractogram having a signal at at least fourteen two-theta values chosen from 5.0 ± 0.2, 9.9 ± 0.2, 11.5 ± 0.2, 11.7 ± 0.2, 12.0 ± 0.2, 12.5 ± 0.2, 13.0 ± 0.2, 13.7 ± 0.2, 14.4 ± 0.2, 16.0 ± 0.2, 16.9 ± 0.2, 18.8 ± 0.2, 19.9 ± 0.2, 20.4 ± 0.2, 22.0 ± 0.2, 23.1 ± 0.2, 23.6 ± 0.2, 24.2 ± 0.2, 25.2 ± 0.2, 26.2 ± 0.2, and 27.5 ± 0.2. In some embodiments, IPAc Solvate Form is characterized by an X-ray powder diffractogram having a signal at at least fifteen two-theta values chosen from 5.0 ± 0.2, 9.9 ± 0.2, 11.5 ± 0.2, 11.7 ± 0.2, 12.0 ± 0.2, 12.5 ± 0.2, 13.0 ± 0.2, 13.7 ± 0.2, 14.4 ± 0.2, 16.0 ± 0.2, 16.9 ± 0.2, 18.8 ± 0.2, 19.9 ± 0.2, 20.4 ± 0.2, 22.0 ± 0.2, 23.1 ± 0.2, 23.6 ± 0.2, 24.2 ± 0.2, 25.2 ± 0.2, 26.2 ± 0.2, and 27.5 ± 0.2. In some embodiments, IPAc Solvate Form is characterized by an X-ray powder diffractogram having a signal at at least sixteen two-theta values chosen from 5.0 ± 0.2, 9.9 ± 0.2, 11.5 ± 0.2, 11.7 ± 0.2, 12.0 ± 0.2, 12.5 ± 0.2, 13.0 ± 0.2, 13.7 ± 0.2, 14.4 ± 0.2, 16.0 ± 0.2, 16.9 ± 0.2, 18.8 ± 0.2, 19.9 ± 0.2, 20.4 ± 0.2, 22.0 ± 0.2, 23.1 ± 0.2, 23.6 ± 0.2, 24.2 ± 0.2, 25.2 ± 0.2, 26.2 ± 0.2, and 27.5 ± 0.2. In some embodiments, IPAc Solvate Form is characterized by an X-ray powder diffractogram having a signal at at least seventeen two-theta values chosen from 5.0 ± 0.2, 9.9 ± 0.2, 11.5 ± 0.2, 11.7 ± 0.2, 12.0 ± 0.2, 12.5 ± 0.2, 13.0 ± 0.2, 13.7 ± 0.2, 14.4 ± 0.2, 16.0 ± 0.2, 16.9 ± 0.2, 18.8 ± 0.2, 19.9 ± 0.2, 20.4 ± 0.2, 22.0 ± 0.2, 23.1 ± 0.2, 23.6 ± 0.2, 24.2 ± 0.2, 25.2 ± 0.2, 26.2 ± 0.2, and 27.5 ± 0.2. In some embodiments, IPAc Solvate Form is characterized by an X-ray powder diffractogram having a signal at at least eighteen two-theta values chosen from 5.0 ± 0.2, 9.9 ± 0.2, 11.5 ± 0.2, 11.7 ± 0.2, 12.0 ± 0.2, 12.5 ± 0.2, 13.0 ± 0.2, 13.7 ± 0.2, 14.4 ± 0.2, 16.0 ± 0.2, 16.9 ± 0.2, 18.8 ± 0.2, 19.9 ± 0.2, 20.4 ± 0.2, 22.0 ± 0.2, 23.1 ± 0.2, 23.6 ± 0.2, 24.2 ± 0.2, 25.2 ± 0.2, 26.2 ± 0.2, and 27.5 ± 0.2. In some embodiments, IPAc Solvate Form is characterized by an X-ray powder diffractogram having a signal at at least nineteen two-theta values chosen from 5.0 ± 0.2, 9.9 ± 0.2, 11.5 ± 0.2, 11.7 ± 0.2, 12.0 ± 0.2, 12.5 ± 0.2, 13.0 ± 0.2, 13.7 ± 0.2, 14.4 ± 0.2, 16.0 ± 0.2, 16.9 ± 0.2, 18.8 ± 0.2, 19.9 ± 0.2, 20.4 ± 0.2, 22.0 ± 0.2, 23.1 ± 0.2, 23.6 ± 0.2, 24.2 ± 0.2, 25.2 ± 0.2, 26.2 ± 0.2, and 27.5 ± 0.2. In some embodiments, IPAc Solvate Form is characterized by an X-ray powder diffractogram having a signal at at least twenty two-theta values chosen from 5.0 ± 0.2, 9.9 ± 0.2, 11.5 ± 0.2, 11.7 ± 0.2, 12.0 ± 0.2, 12.5 ± 0.2, 13.0 ± 0.2, 13.7 ± 0.2, 14.4 ± 0.2, 16.0 ± 0.2, 16.9 ± 0.2, 18.8 ± 0.2, 19.9 ± 0.2, 20.4 ± 0.2, 22.0 ± 0.2, 23.1 ± 0.2, 23.6 ± 0.2, 24.2 ± 0.2, 25.2 ± 0.2, 26.2 ± 0.2, and 27.5 ± 0.2. In some embodiments, IPAc Solvate Form is characterized by an X-ray powder diffractogram having a signal at 5.0 ± 0.2, 9.9 ± 0.2, 11.5 ± 0.2, 11.7 ± 0.2, 12.0 ± 0.2, 12.5 ± 0.2, 13.0 ± 0.2, 13.7 ± 0.2, 14.4 ± 0.2, 16.0 ± 0.2, 16.9 ± 0.2, 18.8 ± 0.2, 19.9 ± 0.2, 20.4 ± 0.2, 22.0 ± 0.2, 23.1 ± 0.2, 23.6 ± 0.2, 24.2 ± 0.2, 25.2 ± 0.2, 26.2 ± 0.2, and 27.5 ± 0.2 degrees two-theta.

[0199] In some embodiments, disclosed herein is a composition comprising IPAc Solvate Form of Compound 87. In some embodiments, disclosed herein is a composition comprising Compound 87 in substantially pure IPAc Solvate Form. In some embodiments, disclosed herein is a composition comprising at least one active compound consisting essentially of Compound 87 in IPAc Solvate Form.

[0200] In some embodiments, IPAc Solvate Form is characterized by a DSC curve substantially similar to that in FIG. 54. In some embodiments, IPAc Solvate Form is characterized by a DSC curve having at least one peak at 116 °C.

[0201] In some embodiments, IPAc Solvate Form is characterized by a 13< C NMR spectrum having a signal at at least one ppm value chosen from 178.3 ± 0.2 ppm, 178.0 ± 0.2 ppm, 177.5 ± 0.2 ppm, 173.2 ± 0.2 ppm, 171.5 ± 0.2 ppm, 138.1 ± 0.2 ppm, 137.9 ± 0.2 ppm, 135.9 ± 0.2 ppm, 132.2 ± 0.2 ppm, 131.4 ± 0.2 ppm, 119.1 ± 0.2 ppm, 118.7 ± 0.2 ppm, 109.8 ± 0.2 ppm, 108.9 ± 0.2 ppm, 107.4 ± 0.2 ppm, 77.1 ± 0.2 ppm, 76.8 ± 0.2 ppm, 76.0 ± 0.2 ppm, 68.5 ± 0.2 ppm, 33.9 ± 0.2 ppm, and 20.8 ± 0.2 ppm. In some embodiments, IPAc Solvate Form is characterized by a 13< C NMR spectrum having a signal at at least two ppm values chosen from 178.3 ± 0.2 ppm, 178.0 ± 0.2 ppm, 177.5 ± 0.2 ppm, 173.2 ± 0.2 ppm, 171.5 ± 0.2 ppm, 138.1 ± 0.2 ppm, 137.9 ± 0.2 ppm, 135.9 ± 0.2 ppm, 132.2 ± 0.2 ppm, 131.4 ± 0.2 ppm, 119.1 ± 0.2 ppm, 118.7 ± 0.2 ppm, 109.8 ± 0.2 ppm, 108.9 ± 0.2 ppm, 107.4 ± 0.2 ppm, 77.1 ± 0.2 ppm, 76.8 ± 0.2 ppm, 76.0 ± 0.2 ppm, 68.5 ± 0.2 ppm, 33.9 ± 0.2 ppm, and 20.8 ± 0.2 ppm. In some embodiments, IPAc Solvate Form is characterized by a 13< C NMR spectrum having a signal at at least three ppm values chosen from 178.3 ± 0.2 ppm, 178.0 ± 0.2 ppm, 177.5 ± 0.2 ppm, 173.2 ± 0.2 ppm, 171.5 ± 0.2 ppm, 138.1 ± 0.2 ppm, 137.9 ± 0.2 ppm, 135.9 ± 0.2 ppm, 132.2 ± 0.2 ppm, 131.4 ± 0.2 ppm, 119.1 ± 0.2 ppm, 118.7 ± 0.2 ppm, 109.8 ± 0.2 ppm, 108.9 ± 0.2 ppm, 107.4 ± 0.2 ppm, 77.1 ± 0.2 ppm, 76.8 ± 0.2 ppm, 76.0 ± 0.2 ppm, 68.5 ± 0.2 ppm, 33.9 ± 0.2 ppm, and 20.8 ± 0.2 ppm. In some embodiments, IPAc Solvate Form is characterized by a 13< C NMR spectrum having a signal at at least four ppm values chosen from 178.3 ± 0.2 ppm, 178.0 ± 0.2 ppm, 177.5 ± 0.2 ppm, 173.2 ± 0.2 ppm, 171.5 ± 0.2 ppm, 138.1 ± 0.2 ppm, 137.9 ± 0.2 ppm, 135.9 ± 0.2 ppm, 132.2 ± 0.2 ppm, 131.4 ± 0.2 ppm, 119.1 ± 0.2 ppm, 118.7 ± 0.2 ppm, 109.8 ± 0.2 ppm, 108.9 ± 0.2 ppm, 107.4 ± 0.2 ppm, 77.1 ± 0.2 ppm, 76.8 ± 0.2 ppm, 76.0 ± 0.2 ppm, 68.5 ± 0.2 ppm, 33.9 ± 0.2 ppm, and 20.8 ± 0.2 ppm. In some embodiments, IPAc Solvate Form is characterized by a 13< C NMR spectrum having a signal at at least five ppm values chosen from 178.3 ± 0.2 ppm, 178.0 ± 0.2 ppm, 177.5 ± 0.2 ppm, 173.2 ± 0.2 ppm, 171.5 ± 0.2 ppm, 138.1 ± 0.2 ppm, 137.9 ± 0.2 ppm, 135.9 ± 0.2 ppm, 132.2 ± 0.2 ppm, 131.4 ± 0.2 ppm, 119.1 ± 0.2 ppm, 118.7 ± 0.2 ppm, 109.8 ± 0.2 ppm, 108.9 ± 0.2 ppm, 107.4 ± 0.2 ppm, 77.1 ± 0.2 ppm, 76.8 ± 0.2 ppm, 76.0 ± 0.2 ppm, 68.5 ± 0.2 ppm, 33.9 ± 0.2 ppm, and 20.8 ± 0.2 ppm. In some embodiments, IPAc Solvate Form is characterized by a 13< C NMR spectrum having a signal at at least six ppm values chosen from 178.3 ± 0.2 ppm, 178.0 ± 0.2 ppm, 177.5 ± 0.2 ppm, 173.2 ± 0.2 ppm, 171.5 ± 0.2 ppm, 138.1 ± 0.2 ppm, 137.9 ± 0.2 ppm, 135.9 ± 0.2 ppm, 132.2 ± 0.2 ppm, 131.4 ± 0.2 ppm, 119.1 ± 0.2 ppm, 118.7 ± 0.2 ppm, 109.8 ± 0.2 ppm, 108.9 ± 0.2 ppm, 107.4 ± 0.2 ppm, 77.1 ± 0.2 ppm, 76.8 ± 0.2 ppm, 76.0 ± 0.2 ppm, 68.5 ± 0.2 ppm, 33.9 ± 0.2 ppm, and 20.8 ± 0.2 ppm. In some embodiments, IPAc Solvate Form is characterized by a 13< C NMR spectrum having a signal at at least seven ppm values chosen from 178.3 ± 0.2 ppm, 178.0 ± 0.2 ppm, 177.5 ± 0.2 ppm, 173.2 ± 0.2 ppm, 171.5 ± 0.2 ppm, 138.1 ± 0.2 ppm, 137.9 ± 0.2 ppm, 135.9 ± 0.2 ppm, 132.2 ± 0.2 ppm, 131.4 ± 0.2 ppm, 119.1 ± 0.2 ppm, 118.7 ± 0.2 ppm, 109.8 ± 0.2 ppm, 108.9 ± 0.2 ppm, 107.4 ± 0.2 ppm, 77.1 ± 0.2 ppm, 76.8 ± 0.2 ppm, 76.0 ± 0.2 ppm, 68.5 ± 0.2 ppm, 33.9 ± 0.2 ppm, and 20.8 ± 0.2 ppm. In some embodiments, IPAc Solvate Form is characterized by a 13< C NMR spectrum having a signal at at least eight ppm values chosen from 178.3 ± 0.2 ppm, 178.0 ± 0.2 ppm, 177.5 ± 0.2 ppm, 173.2 ± 0.2 ppm, 171.5 ± 0.2 ppm, 138.1 ± 0.2 ppm, 137.9 ± 0.2 ppm, 135.9 ± 0.2 ppm, 132.2 ± 0.2 ppm, 131.4 ± 0.2 ppm, 119.1 ± 0.2 ppm, 118.7 ± 0.2 ppm, 109.8 ± 0.2 ppm, 108.9 ± 0.2 ppm, 107.4 ± 0.2 ppm, 77.1 ± 0.2 ppm, 76.8 ± 0.2 ppm, 76.0 ± 0.2 ppm, 68.5 ± 0.2 ppm, 33.9 ± 0.2 ppm, and 20.8 ± 0.2 ppm. In some embodiments, IPAc Solvate Form is characterized by a 13< C NMR spectrum having a signal at at least nine ppm values chosen from 178.3 ± 0.2 ppm, 178.0 ± 0.2 ppm, 177.5 ± 0.2 ppm, 173.2 ± 0.2 ppm, 171.5 ± 0.2 ppm, 138.1 ± 0.2 ppm, 137.9 ± 0.2 ppm, 135.9 ± 0.2 ppm, 132.2 ± 0.2 ppm, 131.4 ± 0.2 ppm, 119.1 ± 0.2 ppm, 118.7 ± 0.2 ppm, 109.8 ± 0.2 ppm, 108.9 ± 0.2 ppm, 107.4 ± 0.2 ppm, 77.1 ± 0.2 ppm, 76.8 ± 0.2 ppm, 76.0 ± 0.2 ppm, 68.5 ± 0.2 ppm, 33.9 ± 0.2 ppm, and 20.8 ± 0.2 ppm. In some embodiments, IPAc Solvate Form is characterized by a 13< C NMR spectrum having a signal at at least ten ppm values chosen from 178.3 ± 0.2 ppm, 178.0 ± 0.2 ppm, 177.5 ± 0.2 ppm, 173.2 ± 0.2 ppm, 171.5 ± 0.2 ppm, 138.1 ± 0.2 ppm, 137.9 ± 0.2 ppm, 135.9 ± 0.2 ppm, 132.2 ± 0.2 ppm, 131.4 ± 0.2 ppm, 119.1 ± 0.2 ppm, 118.7 ± 0.2 ppm, 109.8 ± 0.2 ppm, 108.9 ± 0.2 ppm, 107.4 ± 0.2 ppm, 77.1 ± 0.2 ppm, 76.8 ± 0.2 ppm, 76.0 ± 0.2 ppm, 68.5 ± 0.2 ppm, 33.9 ± 0.2 ppm, and 20.8 ± 0.2 ppm. In some embodiments, IPAc Solvate Form is characterized by a 13< C NMR spectrum having a signal at at least eleven ppm values chosen from 178.3 ± 0.2 ppm, 178.0 ± 0.2 ppm, 177.5 ± 0.2 ppm, 173.2 ± 0.2 ppm, 171.5 ± 0.2 ppm, 138.1 ± 0.2 ppm, 137.9 ± 0.2 ppm, 135.9 ± 0.2 ppm, 132.2 ± 0.2 ppm, 131.4 ± 0.2 ppm, 119.1 ± 0.2 ppm, 118.7 ± 0.2 ppm, 109.8 ± 0.2 ppm, 108.9 ± 0.2 ppm, 107.4 ± 0.2 ppm, 77.1 ± 0.2 ppm, 76.8 ± 0.2 ppm, 76.0 ± 0.2 ppm, 68.5 ± 0.2 ppm, 33.9 ± 0.2 ppm, and 20.8 ± 0.2 ppm. In some embodiments, IPAc Solvate Form is characterized by a 13< C NMR spectrum having a signal at at least twelve ppm values chosen from 178.3 ± 0.2 ppm, 178.0 ± 0.2 ppm, 177.5 ± 0.2 ppm, 173.2 ± 0.2 ppm, 171.5 ± 0.2 ppm, 138.1 ± 0.2 ppm, 137.9 ± 0.2 ppm, 135.9 ± 0.2 ppm, 132.2 ± 0.2 ppm, 131.4 ± 0.2 ppm, 119.1 ± 0.2 ppm, 118.7 ± 0.2 ppm, 109.8 ± 0.2 ppm, 108.9 ± 0.2 ppm, 107.4 ± 0.2 ppm, 77.1 ± 0.2 ppm, 76.8 ± 0.2 ppm, 76.0 ± 0.2 ppm, 68.5 ± 0.2 ppm, 33.9 ± 0.2 ppm, and 20.8 ± 0.2 ppm. In some embodiments, IPAc Solvate Form is characterized by a 13< C NMR spectrum having a signal at at least thirteen ppm values chosen from 178.3 ± 0.2 ppm, 178.0 ± 0.2 ppm, 177.5 ± 0.2 ppm, 173.2 ± 0.2 ppm, 171.5 ± 0.2 ppm, 138.1 ± 0.2 ppm, 137.9 ± 0.2 ppm, 135.9 ± 0.2 ppm, 132.2 ± 0.2 ppm, 131.4 ± 0.2 ppm, 119.1 ± 0.2 ppm, 118.7 ± 0.2 ppm, 109.8 ± 0.2 ppm, 108.9 ± 0.2 ppm, 107.4 ± 0.2 ppm, 77.1 ± 0.2 ppm, 76.8 ± 0.2 ppm, 76.0 ± 0.2 ppm, 68.5 ± 0.2 ppm, 33.9 ± 0.2 ppm, and 20.8 ± 0.2 ppm. In some embodiments, IPAc Solvate Form is characterized by a 13< C NMR spectrum having a signal at at least fourteen ppm values chosen from 178.3 ± 0.2 ppm, 178.0 ± 0.2 ppm, 177.5 ± 0.2 ppm, 173.2 ± 0.2 ppm, 171.5 ± 0.2 ppm, 138.1 ± 0.2 ppm, 137.9 ± 0.2 ppm, 135.9 ± 0.2 ppm, 132.2 ± 0.2 ppm, 131.4 ± 0.2 ppm, 119.1 ± 0.2 ppm, 118.7 ± 0.2 ppm, 109.8 ± 0.2 ppm, 108.9 ± 0.2 ppm, 107.4 ± 0.2 ppm, 77.1 ± 0.2 ppm, 76.8 ± 0.2 ppm, 76.0 ± 0.2 ppm, 68.5 ± 0.2 ppm, 33.9 ± 0.2 ppm, and 20.8 ± 0.2 ppm. In some embodiments, IPAc Solvate Form is characterized by a 13< C NMR spectrum having a signal at at least fifteen ppm values chosen from 178.3 ± 0.2 ppm, 178.0 ± 0.2 ppm, 177.5 ± 0.2 ppm, 173.2 ± 0.2 ppm, 171.5 ± 0.2 ppm, 138.1 ± 0.2 ppm, 137.9 ± 0.2 ppm, 135.9 ± 0.2 ppm, 132.2 ± 0.2 ppm, 131.4 ± 0.2 ppm, 119.1 ± 0.2 ppm, 118.7 ± 0.2 ppm, 109.8 ± 0.2 ppm, 108.9 ± 0.2 ppm, 107.4 ± 0.2 ppm, 77.1 ± 0.2 ppm, 76.8 ± 0.2 ppm, 76.0 ± 0.2 ppm, 68.5 ± 0.2 ppm, 33.9 ± 0.2 ppm, and 20.8 ± 0.2 ppm. In some embodiments, IPAc Solvate Form is characterized by a 13< C NMR spectrum having a signal at at least sixteen ppm values chosen from 178.3 ± 0.2 ppm, 178.0 ± 0.2 ppm, 177.5 ± 0.2 ppm, 173.2 ± 0.2 ppm, 171.5 ± 0.2 ppm, 138.1 ± 0.2 ppm, 137.9 ± 0.2 ppm, 135.9 ± 0.2 ppm, 132.2 ± 0.2 ppm, 131.4 ± 0.2 ppm, 119.1 ± 0.2 ppm, 118.7 ± 0.2 ppm, 109.8 ± 0.2 ppm, 108.9 ± 0.2 ppm, 107.4 ± 0.2 ppm, 77.1 ± 0.2 ppm, 76.8 ± 0.2 ppm, 76.0 ± 0.2 ppm, 68.5 ± 0.2 ppm, 33.9 ± 0.2 ppm, and 20.8 ± 0.2 ppm. In some embodiments, IPAc Solvate Form is characterized by a 13< C NMR spectrum having a signal at at least seventeen ppm values chosen from 178.3 ± 0.2 ppm, 178.0 ± 0.2 ppm, 177.5 ± 0.2 ppm, 173.2 ± 0.2 ppm, 171.5 ± 0.2 ppm, 138.1 ± 0.2 ppm, 137.9 ± 0.2 ppm, 135.9 ± 0.2 ppm, 132.2 ± 0.2 ppm, 131.4 ± 0.2 ppm, 119.1 ± 0.2 ppm, 118.7 ± 0.2 ppm, 109.8 ± 0.2 ppm, 108.9 ± 0.2 ppm, 107.4 ± 0.2 ppm, 77.1 ± 0.2 ppm, 76.8 ± 0.2 ppm, 76.0 ± 0.2 ppm, 68.5 ± 0.2 ppm, 33.9 ± 0.2 ppm, and 20.8 ± 0.2 ppm. In some embodiments, IPAc Solvate Form is characterized by a 13< C NMR spectrum having a signal at at least eighteen ppm values chosen from 178.3 ± 0.2 ppm, 178.0 ± 0.2 ppm, 177.5 ± 0.2 ppm, 173.2 ± 0.2 ppm, 171.5 ± 0.2 ppm, 138.1 ± 0.2 ppm, 137.9 ± 0.2 ppm, 135.9 ± 0.2 ppm, 132.2 ± 0.2 ppm, 131.4 ± 0.2 ppm, 119.1 ± 0.2 ppm, 118.7 ± 0.2 ppm, 109.8 ± 0.2 ppm, 108.9 ± 0.2 ppm, 107.4 ± 0.2 ppm, 77.1 ± 0.2 ppm, 76.8 ± 0.2 ppm, 76.0 ± 0.2 ppm, 68.5 ± 0.2 ppm, 33.9 ± 0.2 ppm, and 20.8 ± 0.2 ppm. In some embodiments, IPAc Solvate Form is characterized by a 13< C NMR spectrum having a signal at at least nineteen ppm values chosen from 178.3 ± 0.2 ppm, 178.0 ± 0.2 ppm, 177.5 ± 0.2 ppm, 173.2 ± 0.2 ppm, 171.5 ± 0.2 ppm, 138.1 ± 0.2 ppm, 137.9 ± 0.2 ppm, 135.9 ± 0.2 ppm, 132.2 ± 0.2 ppm, 131.4 ± 0.2 ppm, 119.1 ± 0.2 ppm, 118.7 ± 0.2 ppm, 109.8 ± 0.2 ppm, 108.9 ± 0.2 ppm, 107.4 ± 0.2 ppm, 77.1 ± 0.2 ppm, 76.8 ± 0.2 ppm, 76.0 ± 0.2 ppm, 68.5 ± 0.2 ppm, 33.9 ± 0.2 ppm, and 20.8 ± 0.2 ppm. In some embodiments, IPAc Solvate Form is characterized by a 13< C NMR spectrum having a signal at at least twenty ppm values chosen from 178.3 ± 0.2 ppm, 178.0 ± 0.2 ppm, 177.5 ± 0.2 ppm, 173.2 ± 0.2 ppm, 171.5 ± 0.2 ppm, 138.1 ± 0.2 ppm, 137.9 ± 0.2 ppm, 135.9 ± 0.2 ppm, 132.2 ± 0.2 ppm, 131.4 ± 0.2 ppm, 119.1 ± 0.2 ppm, 118.7 ± 0.2 ppm, 109.8 ± 0.2 ppm, 108.9 ± 0.2 ppm, 107.4 ± 0.2 ppm, 77.1 ± 0.2 ppm, 76.8 ± 0.2 ppm, 76.0 ± 0.2 ppm, 68.5 ± 0.2 ppm, 33.9 ± 0.2 ppm, and 20.8 ± 0.2 ppm. In some embodiments, IPAc Solvate Form is characterized by a 13< C NMR spectrum having a signal at 178.3 ± 0.2 ppm, 178.0 ± 0.2 ppm, 177.5 ± 0.2 ppm, 173.2 ± 0.2 ppm, 171.5 ± 0.2 ppm, 138.1 ± 0.2 ppm, 137.9 ± 0.2 ppm, 135.9 ± 0.2 ppm, 132.2 ± 0.2 ppm, 131.4 ± 0.2 ppm, 119.1 ± 0.2 ppm, 118.7 ± 0.2 ppm, 109.8 ± 0.2 ppm, 108.9 ± 0.2 ppm, 107.4 ± 0.2 ppm, 77.1 ± 0.2 ppm, 76.8 ± 0.2 ppm, 76.0 ± 0.2 ppm, 68.5 ± 0.2 ppm, 33.9 ± 0.2 ppm, and 20.8 ± 0.2 ppm.

[0202] In some embodiments, IPAc Solvate Form is characterized by a 19< F NMR spectrum having a signal at least at one ppm value chosen from -107.1 ± 0.2 ppm, - 107.4 ± 0.2 ppm, -108.0 ± 0.2 ppm, -114.5 ± 0.2 ppm, -115.0 ± 0.2 ppm, and -116.2 ± 0.2 ppm. In some embodiments, Form A is characterized by a 19< F NMR spectrum having a signal at least at two ppm value chosen from -107.1 ± 0.2 ppm, -107.4 ± 0.2 ppm, -108.0 ± 0.2 ppm, -114.5 ± 0.2 ppm, -115.0 ± 0.2 ppm, and -116.2 ± 0.2 ppm. In some embodiments, Form A is characterized by a 19< F NMR spectrum having a signal at least at three ppm value chosen from -107.1 ± 0.2 ppm, -107.4 ± 0.2 ppm, -108.0 ± 0.2 ppm, -114.5 ± 0.2 ppm, -115.0 ± 0.2 ppm, and -116.2 ± 0.2 ppm. In some embodiments, Form A is characterized by a 19< F NMR spectrum having a signal at least at four ppm value chosen from -107.1 ± 0.2 ppm, -107.4 ± 0.2 ppm, -108.0 ± 0.2 ppm, -114.5 ± 0.2 ppm, -115.0 ± 0.2 ppm, and -116.2 ± 0.2 ppm. In some embodiments, Form A is characterized by a 19< F NMR spectrum having a signal at least at five ppm value chosen from -107.1 ± 0.2 ppm, -107.4 ± 0.2 ppm, -108.0 ± 0.2 ppm, -114.5 ± 0.2 ppm, -115.0 ± 0.2 ppm, and -116.2 ± 0.2 ppm. In some embodiments, Form A is characterized by a 19< F NMR spectrum having a signal at -107.1 ± 0.2 ppm, -107.4 ± 0.2 ppm, -108.0 ± 0.2 ppm, -114.5 ± 0.2 ppm, -115.0 ± 0.2 ppm, and -116.2 ± 0.2 ppm.

[0203] In some embodiments, Compound 87 is a crystalline solid. In some embodiments, the crystalline solid consists of 1% to 99% IPAc Solvate Form relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 2% to 99% IPAc Solvate Form relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 5% to 99% IPAc Solvate Form relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 10% to 99% IPAc Solvate Form relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 15% to 99% IPAc Solvate Form relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 20% to 99% IPAc Solvate Form relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 25% to 99% IPAc Solvate Form relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 30% to 99% IPAc Solvate Form relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 35% to 99% IPAc Solvate Form relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 45% to 99% IPAc Solvate Form relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 50% to 99% IPAc Solvate Form relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 55% to 99% IPAc Solvate Form relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 60% to 99% IPAc Solvate Form relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 65% to 99% IPAc Solvate Form relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 70% to 99% IPAc Solvate Form relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 75% to 99% IPAc Solvate Form relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 80% to 99% IPAc Solvate Form relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 85% to 99% IPAc Solvate Form relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 90% to 99% IPAc Solvate Form relative to the total weight of the crystalline solid Compound 87. In some embodiments, the crystalline solid consists of 95% to 99% IPAc Solvate Form relative to the total weight of the crystalline solid Compound 87.Amorphous Form of Compound 87

[0204] In some embodiments, Compound 87 is in an amorphous form. In some embodiments, Compound 87 is in the form of substantially pure amorphous form. In some embodiments, amorphous form of Compound 87 is characterized by an X-ray powder diffractogram substantially similar to that in FIG. 56.

[0205] In some embodiments, disclosed herein is a composition comprising amorphous form of Compound 87. In some embodiments, disclosed herein is a composition comprising Compound 87 in substantially pure amorphous form. In some embodiments, disclosed herein is a composition comprising at least one active compound consisting essentially of Compound 87 in amorphous form.

[0206] In some embodiments, amorphous form is characterized by a 13< C NMR spectrum having a signal at at least one ppm value chosen from 119.5 ± 0.2 ppm, 37.2 ± 0.2 ppm, and 21.2 ± 0.2 ppm. In some embodiments, amorphous form is characterized by a 13< C NMR spectrum having a signal at at least two ppm values chosen from 119.5 ± 0.2 ppm, 37.2 ± 0.2 ppm, and 21.2 ± 0.2 ppm. In some embodiments, amorphous form is characterized by a 13< C NMR spectrum having a signal at 119.5 ± 0.2 ppm, 37.2 ± 0.2 ppm, and 21.2 ± 0.2 ppm.

[0207] In some embodiments, amorphous form is characterized by a 19< F NMR spectrum having a signal at -114.1 ppm.EXAMPLES

[0208] In order that the disclosure described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this disclosure in any manner.

[0209] The compounds of the disclosure may be made according to standard chemical practices or as described herein. Throughout the following synthetic schemes and in the descriptions for preparing compounds of Formulae (I), (II), (IIIa), (IIIb), and (IIIc), Compounds 1 to 135, pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing, the following abbreviations are used:Abbreviations

[0210] AIBN = Azobisisobutyronitrile ARP = assay ready plate BBBPY = 4,4'-Di-tert-butyl-2,2'-dipyridyl CBzCl = Benzyl chloroformate CDMT = 2-Chloro-4,6-dimethoxy-1,3,5-triazine DIPEA = N,N-Diisopropylethylamine or N-ethyl-N-isopropyl-propan-2-amine DMAP = dimethylamino pyridine DMA = dimethyl acetamide DME = dimethoxyethane DMEM = Dulbecco's modified Eagle's medium DMF = dimethylformamide DMSO = dimethyl sulfoxide DPPA = diphenylphosphoryl azide EtOAc = Ethyl Acetate EtOH = ethanol FBS = fetal bovine serum FLU = fluorescent values HATU = [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethylammonium (Phosphorus Hexafluoride Ion) HDMC =N-[(5-Chloro-3-oxido-1H-benzotriazol-1-yl)-4-morpholinylmethylene]-N-methylmethanaminium hexafluorophosphate HEPES = 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid HBSS = Hank's balanced salt solution IPA = isopropyl alcohol LDA = lithium diisopropyl amide LED = light emitting diode MeOH = methanol MTBE = Methyl tert-butyl ether NMM = N-methyl morpholine NMP = N-methyl pyrrolidine PBS = phosphate-buffered saline Pd(dppf) 2 Cl 2 = [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) PdCl 2 (PPh 3 ) 2 = Bis(triphenylphosphine)palladium(II) dichloride PP = polypropylene PTSA = p-Toluenesulfonic acid monohydrate T3P = 2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide TEA = triethylamine Tet = tetracycline TFA = trifluoroacetic acid THF = tetrahydrofuran THP = tetrahydropyran TMSS = Tris(trimethylsilyl)silane Example 1. Synthesis of Compounds

[0211] All the specific and generic compounds, and the intermediates disclosed for making those compounds, are considered to be part of the disclosure disclosed herein.Synthesis of Starting Materials

[0212] Preparations of describe synthetic routes to intermediates used in the synthesis of compounds 1 to 135. General Schemes

[0213] In some embodiments, processes for preparing compounds of formula I comprise reacting a compound of formula 1-1 with an amine of formula 1-2 in the presence of an amide coupling agent (e.g. HATU, CDMT, HDMC, or T3P) and a suitable base (e.g. DIPEA or TEA), as depicted in Scheme 1. Any suitable conditions for amide bond formation may be used.

[0214] Scheme 2 provides processes for preparing compounds of formula 2-3, 2-4, 2-5 and 2-6; wherein variables R 1< , R 2< , R 3< , R 4< , R 5< , R 6< , R 7< , R 8< , R 9< , m, and n are as defined in formula I above; Z 1< is an acetal protecting group (e.g. Me or Et); R 10< is any suitable group such that a compound of Formula 2-6 may also be a compound of Formula I (e.g. alkyl, halogen, alkoxy). R 11< is selected from C1-C6 linear, branched and cyclic alkyl groups;

[0215] In some embodiments, a compound of formula 2-3 may be prepared by reacting indoles 2-1 with acetals of formula 2-2 in the presence of an acid such as TFA or methanesulfonic acid in a suitable solvent (e.g. dichloromethane or toluene). Compounds of formula 2-4 may be prepared from compounds of formula 2-3 using reduction methods such as those for hydrogenation of an olefin. For example, in some embodiments the reaction is performed in the presence of hydrogenation reagents such as H 2 and palladium on carbon catalyst. In other embodiments, transfer hydrogenation conditions may be used (e.g. Pd(OH) 2 catalyst and NH 4 HCO 2 ). Alternatively, a compound of formula 2-4 may be prepared directly from a compound of formula 2-1 by reaction with an aldehyde of formula 2-7. The reaction may be performed in the presence of an acid such as methanesulfonic acid, and a reducing agent such as Et 3 SiH. Any suitable conditions, such as those for the hydrolysis of an ester, may be used for converting a compound of formula 2-4 to formula 2-5. For example, the reaction may be performed in the presence of a base (e.g. LiOH or NaOH) in an aqueous solvent mixture (e.g. THF and water). Compounds of formula 2-5 may be used as a compound of formula 1-1 in Scheme 1. Any suitable conditions, such as those for formation of an amide from a carboxylic acid can be used for reacting a compound of formula 2-5 with an amine of Formula 1-2 to provide compounds of formula 2-6.

[0216] Scheme 3 depicts processes for preparation of compounds of Formula 3-5 (wherein variables R 1< , R 2< , m and n are defined as in Formula I above; X 1< is a halogen e.g. I, Br or Cl; R 14< is any suitable alkyl e.g. Me or Et. Compounds of Formula 3-2 may be prepared from compounds of formula 3-1 using a suitable halogenating reagent (e.g. N-iodosuccinimide). Any suitable alkyne coupling reactions can be used for converting compounds of formula 3-2 to such as those 3-4. For example, the reaction is performed in the presence of catalysts such as Pd(PPh 3 ) 2 Cl 2 and CuI, and a base (e.g. DIPEA or TEA). In some embodiments, hydrogenation conditions can be used to convert 3-4 to compounds of formula 3-5 (e.g. hydrogen and palladium on carbon catalyst) in a suitable solvent, such as MeOH or EtOH.

[0217] Scheme 4 refers to a process for the preparation of compounds of Formula 4-4 which may be used as a compound of Formula 1-1 in Scheme 1 above. R 1< , R 2< , m and n are defined as in scheme 1. R 15< and R 16< may be alkyls, halogens, or alkoxy. R 17< is any suitable alkyl forming an ester group (e.g. Me or Et). Any suitable conditions for a performing a Fischer indole synthesis may be used in the reaction of a diketone of formula 4-1 with a hydrazine of Formula 4-2. For example, ZnCl 2 in a solvent such as AcOH and toluene at elevated temperature (110 °C). In an alternative embodiment, BF 3 ·OEt 2 in xylene solvent in the presence of added heat may be used. Any suitable conditions for the hydrolysis of an ester may be used in the preparation of 4-4 from 4-3. A compound of formula 4-4 may be prepared from a compound of formula 4-5 and a hydrazine of formula 4-3 using any suitable Fischer indole synthesis conditions. In some embodiments, ZnCl 2 and AcOH may be used. The reaction may be performed in the presence of added heat. Hydrazines of formula 4-2 may be used as free bases or as salts, such as the hydrochloride salt.

[0218] Scheme 5 provides processes for preparation of compounds of formula 5-3. X 2< is a halogen (e.g. Br). A compound of Formula 5-3 may be prepared by reaction of compound of formula 5-1 with an alkyl halide of Formula 5-2 under suitable photochemical coupling conditions. For example, in some embodiments a catalyst system containing NiCl 2 .(OMeCH 2 ) 2 , Iridium photocatalyst and TMSS, in the presence of a ligand such as BBBPY and under irradiation with blue LED light may be used.

[0219] Scheme 6 provides a process for preparation of compounds of Formula 6-3 from compounds of Formula 6-1 and 6-2. Any suitable conditions for ring opening of an epoxide may be used. In some embodiments, the reaction is performed in the presence of a reagent such as SnCl 4 .

[0220] Scheme 7 refers to processes for preparation of compounds of Formula 7-4 from compounds of formula 7-1 or 7-5. X 3< and X 4< are halogens such are Cl, I, or Br. Any suitable conditions for coupling an alkyne can be used to convert aryl halides of Formula 7-1 and alkynes of formula 7-2 to an alkyne of Formula 7-3. For example, the coupling may be performed in the presence of a CuI and Pd(PPh 3 ) 2 Cl 2 catalyst system. The reaction may be performed in the presence of a base (e.g. NEt 3 ). Conversion of compounds of formula 7-3 to indoles of Formula 7-4 may be accomplished by treatment with CuI or PdCl 2 in a polar solvent (e.g. DMF or MeCN) in the presence of added heat (>100 °C). A compound of formula 7-3 may also be prepared from a compound of formula 7-5 and an aryl halide of formula 7-6. Any suitable Sonagashira coupling condition may be used. For example, Pd(PPh 3 ) 2 Cl 2 and CuI in the presence of a base such as DIPEA or NEt 3 .

[0221] Scheme 8 refers to a process for preparation of compounds of Formula 8-3 from an indole such as that represented by Formula 8-1, and an alkyl halide of formula 8-2, where X 4< is a halogen (e.g. I or Br).R 20< is an alkyl group such as Me or Et. The two R 20< groups may be linked by a carbon carbon bond to form a cyclic boronate ester. In some embodiments, the reaction is performed in the presence of a catalyst such as PdCl 2 CN 2 , a ligand such as norbornylene, and a base (e.g. K 2 CO 3 ). The reaction may be performed in a solvent such as dimethylacetamide at elevated temperature (e.g. 90 °C). Compounds of formula 8-3 may also be prepared from indoles of formula 8-1 and aryl boronic acids or esters of formula 8-5. In some embodiments, the reaction is performed in the presence of a palladium catalyst (e.g. Pd(OAc) 2 .trimer in a solvent such as AcOH. The reaction is performed in the presence of oxygen.

[0222] Scheme 9 provides processes for preparing compounds of Formula 9-5 wherein variables depicted in scheme 9 are as defined in Formula I. X 5< is a halogen (e.g. I, Br or Cl) and R 21< is an alkyl group (e.g. Me, Et or tBu). In some embodiments, the conversion of 9-1 to an epoxide of Formula 9-2 may be performed in the presence of a base (e.g. K 2 CO 3 or Cs 2 CO 3 ). Any suitable conditions for displacement of a halide with an azide group may be employed to obtain compounds of Formula 9-3 from 9-2 (e.g. NaN 3 ). In some embodiments, the reaction generating a compound of Formula 9-4 from 9-3 is performed in the presence of a reducing system (e.g. AIBN, nBuSnH). In some embodiments, a reaction generating a compound of Formula 9-5 from 9-4 may be performed in the presence of an amine source (e.g. liquid NH 3 ). In an alternative embodiment, compounds of Formula 9-5 may be obtained from 9-2 by treatment with an amine source (e.g. NH 3 gas) under conditions of elevated pressure and temperature (e.g. autoclave conditions).

[0223] Scheme 10 describes processes for the preparation of compounds of Formula 10-5, wherein variables R 3< , R 4< , R 6< , R 7< , are as defined in Formula I. R 22< is any alkyl group that forms a suitable ester (e.g. Me or Et). PG 1< is a suitable amine protecting group such as t-butyl carbamate (Boc), Benzyl carbamate (CBz) or 9-fluorenylmethyl carbamate (Fmoc). In some embodiments, as shown in scheme 10, epoxides of Formula 10-2 may be prepared from compounds of Formula 10-1 in the presence of a reagent such as mCPBA. Compounds of formula 10-3 may be prepared from compounds of formula 10-2 by treatment with an azide source (e.g. NaN 3 ) in a polar solvent (e.g. DMF) in the presence of additional heat. As depicted in scheme 10, a compound of Formula 10-4 may be prepared from 10-3 in the presence of a suitable reducing agent (e.g. PPh 3 ). Any suitable conditions for the removal of a nitrogen atom protecting group may be used in the conversion of compounds of Formula 10-4 to compounds of Formula 10-5. For example, in some embodiments where PG 1< is CBz, hydrogenation conditions (e.g. H 2 and a palladium on carbon catalyst) may be used.

[0224] Scheme 11 shows processes for preparation of compounds of Formula 11-6. R 4< , R 5< , R 6< and R 7< are defined as in formula I. R 23< is a suitable alkyl group which forms an appropriate ester (e.g. Me or Et). PG 2< is an alcohol protecting group (e.g. TBDMS) Compounds of Formula 11-1 may be converted to compounds of Formula 11-2 by heating in the presence of a suitable solvent (e.g. toluene at 110 °C). Any suitable conditions for the reduction of ester groups to alcohols may be used to prepare compounds 11-3 from compounds of Formula 11-2. For example, in some embodiments, sodium borohydride in protic solvent (e.g. IPA) may be used. In some embodiments, compounds of Formula 11-4 may be prepared from Formula 11-3 by the treatment with a silylating reagent (e.g. tButyldimethyl silyl chloride) in the presence of imidazole or other suitable base. Amination of compounds of Formula 11-4 to give compounds of Formula 11-5 may be achieved by any suitable aminating reagents known to those in the art. For example, deprotonation using a base such as LDA and treatment with diphenylphosphoryl azide, followed by Boc protecting of the resulting amine with Boc 2 O affords compounds of Formula 11-5 where PG 3< is a Boc group. In some embodiments, where PG 2< is an acid labile group such as TBDMS, and PG 3< is a group such as Boc, compounds of Formula 11-6 may be prepared by treatment of 11-5 with suitable deprotection reagents (e.g. HCl).

[0225] A process for preparation of compounds of formula 12-4 from amino alkynes of formula 7-3 is shown in scheme 12. R 24< may be any suitable alkyl group that forms an ester (e.g. Et, Me, tBu). Formula 7-3 compounds may react with compounds of formula 12-1 to afford compounds of formula 12-2. In some embodiments, the reaction is performed in the presence of PdCl 2 and KI under an air atmosphere. A polar solvent such as DMF may be used. The reaction may be performed in the presence of added heat (e.g. 100 °C). A compound of formula 12-4 may be prepared from compounds of formula 12-2 by reduction of the alkene, and then ester hydrolysis. In one embodiment, hydrogenation with a palladium on carbon catalyst under an atmosphere of hydrogen gas, then ester hydrolysis with sodium hydroxide in a solvent such as THF and water. Preparation S1 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]-N-[(3S,4S)-4-hydroxy-2-oxopyrrolidin-3-yl]propanamide (S1)

[0226] Step 1. Synthesis of methyl (2S)-2-(benzyloxycarbonylamino)-2-[(2S)-oxiran-2-yl]acetate (C2)

[0227] To a solution of methyl (2S)-2-(benzyloxycarbonylamino)but-3-enoate C1 (6.4 g, 25.8 mmol) in CH 2 Cl 2 (200 mL) was added mCPBA (18.6 g of 70% w / w, 75.5 mmol). The mixture was heated at reflux for 18 h. A saturated aqueous solution of sodium bisulfite (100 mL) and CH 2 Cl 2 was added. The combined organic layers were washed with NaHCO 3 and brine, and then dried to afford the product as approx.1:4 mixture of diastereomers (by NMR). Methyl (2S)-2-(benzyloxycarbonylamino)-2-[(2S)-oxiran-2-yl]acetate is assumed to be the major diastereomer (7.04 g, 98%). LCMS m / z 266.2 [M+H] +< .Step 2. Synthesis of methyl (2S, 3R)-4-azido-2-(benzyloxycarbonylamino)-3-hydroxybutanoate (C3)

[0228] A mixture of methyl (2S)-2-(benzyloxycarbonylamino)-2-[(2S)-oxiran-2-yl]acetate C2 (1.0 g, 3.7 mmol), sodium azide (2.4 g, 36.9 mmol) and NH 4 Cl (206 mg, 3.9 mmol) in DMF (10 mL) was heated at 60 °C overnight. Water (60 mL) was added and the mixture extracted with EtOAc. The organic phase was dried and concentrated to afford the product which was used in the subsequent step without purification. (1.1 g, 91%). LCMS m / z 309.2 [M+H] +< .Step 3. Synthesis of benzyl N-[(3S,4R)-4-hydroxy-2-oxo-pyrrolidin-3-yl]carbamate (C4) and benzyl N-[(3S,4S)-4-hydroxy-2-oxo-pyrrolidin-3-yl]carbamate (C5)

[0229] A solution of methyl (2S,3R)-4-azido-2-(benzyloxycarbonylamino)-3-hydroxy-butanoate C3 (221 mg, 0.22 mmol) and PPh 3 (200 mg, 0.8 mmol) in MeOH (5 mL), water (1 mL) and THF (4 mL) was heated at 100 °C for 18 h. Purification by reverse phase chromatography (column: C18 column; Gradient: MeCN in water with 0.2 % formic acid) afforded two diastereomeric products in an 8:1 ratio.

[0230] C4 is the major diastereomer and is presumed to have 3S,4R stereochemistry. benzyl N-[(3S,4R)-4-hydroxy-2-oxo-pyrrolidin-3-yl]carbamate (55 mg, 28 %). 1< H NMR (300 MHz, CD 3 OD) δ 7.51 - 7.27 (m, 5H), 5.12 (s, 2H), 4.42 (q, J = 7.8 Hz, 1H), 4.06 (d, J = 8.3 Hz, 1H), 3.56 (dd, J = 9.8, 7.7 Hz, 1H), 3.10 (dd, J = 9.9, 7.4 Hz, 1H). LCMS m / z 251.2 [M+H] +< .

[0231] C5 is the minor diastereomer and is presumed to have 3S,4S stereochemistry. benzyl N-[(3S,4S)-4-hydroxy-2-oxo-pyrrolidin-3-yl]carbamate (8.8 mg, 8 %). 1< H NMR (300 MHz, CD 3 OD) δ 7.37 (dddd, J = 16.2, 8.6, 6.7, 3.5 Hz, 5H), 5.15 (s, 2H), 4.52 - 4.34 (m, 2H), 3.69 - 3.53 (m, 1H), 3.25 (d, J= 11.3 Hz, 1H). LCMS m / z 251.1 [M+H] +< .Step 4. Synthesis of 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]-N-[(3S,4S)-4-hydroxy-2-oxo-pyrrolidin-3-yl]propanamide (S1)

[0232] To a solution of benzyl N-[(3S,4S)-4-hydroxy-2-oxo-pyrrolidin-3-yl]carbamate C5 (8.8 mg, 0.03 mmol) in MeOH (8 mL) was added 5% Palladium on carbon (10 mg). The mixture was subjected to hydrogenation conditions (50 psi H 2 ) for 4 h. The mixture was filtered through Celite ®< , washing with MeOH, then concentrated in vacuo to afford the product which was used directly in the synthesis of compound 1. 1< H NMR(300 MHz, CD 3 OD) δ 4.34 (dd, J = 5.1, 3.8 Hz, 1H), 3.57 - 3.49 (m, 1H), 3.45 (d, J= 5.1 Hz, 1H), 3.23 (d, J= 11.2 Hz, 1H).Preparation S2 (3S,4R)-3-amino-4-hydroxy-pyrrolidin-2-one (S2)

[0233] Step 1. Synthesis of methyl (2S,3R)-2,4-dibromo-3-hydroxy-butanoate (C7)

[0234] Potassium (2R,3R)-2,3,4-trihydroxybutanoate C6 (10 g, 57.1 mmol) was stirred with HBr in Acetic acid (154 g, 103 mL of 30% w / w, 570.8 mmol) for 16 h. Anhydrous MeOH (250 mL) was added and the mixture heated at reflux for 4 h. The mixture was concentrated dryness and the residue dissolved in EtOAc (100 mL). The solution was washed with water (50 mL) and brine (50 mL), then dried over Na 2 SO 4 , and concentrated in vacuo. Purification by silica gel chromatography (Gradient: 15-20 % EtOAc in hexane) afforded the product as a colorless liquid (13 g, 83%). 1< H NMR (400 MHz, CDCl 3 ) δ 4.71 (d, J = 3.4 Hz, 1H), 4.17-4.14 (m, 1H), 3.82 (s, 3H), 3.53 - 3.44 (m, 2H).Step 1. Alternative procedure for synthesis of methyl (2S,3R)-2,4-dibromo-3-hydroxybutanoate (C7)

[0235] Potassium (2R,3R)-2,3,4-trihydroxybutanoate C6 (280 g) was stirred with a 33% solution of HBr in acetic acid (1 L) at room temperature for 24 h. The reaction mixture was then poured into MeOH (5 L). The mixture was stirred at room temperature for 8 h, then at 65 °C for 4 h. The mixture was concentrated, the residue was dissolved in MeOH (1.2 L) and then concentrated sulfuric acid (30 mL) was slowly added. The mixture was heated under reflux for 6 h, then concentrated. The residue was taken up with EtOAc (400 mL). The resulting solution was washed with water (250 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuo to give the product as an oil which solidified upon storage at 4 °C (375g, 74%).Step 2. Synthesis of methyl (2R, 3S)-3-(bromomethyl)oxirane-2-carboxylate (C8)

[0236] Methyl (2R,3R)-2,4-dibromo-3-hydroxy-butanoate C7 (524.8 g, 1.9 mol) was dissolved in acetone (4.5 L) in a 12 L round-bottomed flask equipped with an overhead stirrer. The reaction was cooled to 0 °C in an ice-bath and Cs 2 CO 3 (994 g, 3.1 mol) was added. The reaction was stirred for 30 minutes at 0 °C and then for 2 h at room temperature. The mixture was filtered, washing with acetone, and then concentrated in vacuo to afford a dark grey oil residue. The product was dissolved in CH 2 Cl 2 and filtered over a short plug of silica gel, eluting with CH 2 Cl 2 (approx. 1 L). The filtrate was concentrated in vacuo to afford the product as a clear yellow oil (377.3 g, quantitative). 1< H NMR (300 MHz, CDCl 3 ) δ 3.83 (s, 3H), 3.71 - 3.61 (m, 2H), 3.61 - 3.53 (m, 1H), 3.46 (dd, J = 9.9, 6.6 Hz, 1H) ppm. 13< C NMR (75 MHz, CDCl 3 ) δ 167.58, 55.89, 53.52, 52.77, 26.83 ppm.Step 2. Alternative procedure for synthesis of methyl (2R,3S)-3-(bromomethyl)oxirane-2-carboxylate (C8)

[0237] To a solution of methyl (2R,3R)-2,4-dibromo-3-hydroxy-butanoate C7 (200 g, 0.73 mol) in acetone (2.0 L) was added anhydrous K2CO3 (151.1 g, 1.1 mol), while the reaction temperature was maintained at 0-5 °C. The reaction was stirred at 0-5 °C for 2 h, then gradually warmed to room temperature over 4 h The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was distilled under vacuum 75-80 °C / 200-300 Pa to give the product as a colorless liquid (105 g, 74%).Step 3. Synthesis of methyl (2R,3R)-3-(azidomethyl)oxirane-2-carboxylate (C9)

[0238] Methyl (2R,3S)-3-(bromomethyl)oxirane-2-carboxylate C8 (52.6 g, 269.7 mmol) was dissolved in DMF (500 mL) in a 3L round-bottomed flask equipped with a magnetic stir bar. NaN 3 (25.3 g, 388.4 mmol) was added and the mixture was stirred at room temperature for 1 h. The reaction was poured into water, and extracted with EtOAc. The extract was washed with water, dried over MgSO 4 , and concentrated in vacuo to afford a dark red oil. The oil residue was dissolved in CH 2 Cl 2 , and filtered over a plug of silica gel eluting with CH 2 Cl 2 . The filtrate was concentrated in vacuo to afford the product as a clear, light red oil (40.8 g, 96%). 1< H NMR (300 MHz, CDCl 3 ) δ 3.87 - 3.74 (m, 3H), 3.67 - 3.55 (m, 2H), 3.47 (dd, J = 13.3, 5.1 Hz, 1H), 3.38 (ddd, J = 6.3, 5.0, 4.4 Hz, 1H). 13< C NMR (75 MHz, CDCl 3 ) δ 167.76, 54.81, 52.67, 51.32, 48.74.Step 4. Synthesis of (1R,5R)-6-oxa-3-azabicyclo[3.1.0]hexan-2-one (C10)

[0239] A 2L 3-neck flask with overhead stirrer was charged with methyl (2R,3R)-3-(azidomethyl)oxirane-2-carboxylate C9 (67 g, 402.5 mmol) in toluene (500 mL), stirred for 10 minutes, and then warmed to 80 °C. Bu 3 SnH (220 mL, 817.8 mmol) and AIBN (2 g, 12.2 mmol) were dissolved in toluene (500 mL) and then added to the reaction over 3 h using an additional funnel. The resulting reaction mixture was stirred at 80-87 °C for 1 h, then cooled to ambient temperature, and concentrated under reduced pressure. The residue was partitioned between acetonitrile (2 L) and pentane (1 L), stirred for 10 minutes and then the acetonitrile phase (bottom) was separated. The acetonitrile phase was washed with pentane (2 x 500 mL) and concentrated in vacuo to afford a light yellow solid. The solid residue was triturated with pentane (~200 mL) to afford the product as a yellow solid which was used without further purification (52 g, 98%). 1< H NMR (300 MHz, CDCl 3 ) δ 5.89 (s, 1H), 4.00 (q, J = 2.5 Hz, 1H), 3.74 - 3.50 (m, 2H), 3.44 (dd, J = 12.4, 2.4 Hz, 1H). 13< C NMR (75 MHz, CDCl 3 ) δ 173.24, 53.28, 52.18, 44.00.Step 5. Synthesis of (3S, 4R)-3-amino-4-hydroxy-pyrrolidin-2-one (S2)

[0240] A parr vessel containing (1R,5R)-6-oxa-3-azabicyclo[3.1.0]hexan-2-one C10 (60 g, 605.5 mmol) and NH 3 (1.5 L, 58.6 mol) was pressurized to 200 psi and allowed to stir at 18 °C for 2 days. NH 3 was released from the vessel to provide a grey solid. Heptane was added and the mixture stirred for 30 min. The solid was filtered, and then the filter cake was isolated, and then EtOAc and heptane to the solid. The mixture was concentrated in vacuo to afford the product (55 g, 78%). 1< H NMR (300 MHz, D 2 O) δ 4.13 (q, J = 7.2 Hz, 1H), 3.53 (dd, J = 10.4, 7.4 Hz, 1H), 3.36 (d, J = 7.5 Hz, 1H), 3.05 (dd, J = 10.4, 6.8 Hz, 1H).Alternative Preparation S2 (3S, 4R)-3-amino-4-hydroxypyrrolidin-2-one hydrochloride (S2)

[0241] Step 1 & 2. Synthesis of N-Boc-(3S,4R)-3-amino-4-hydroxypyrrolidin-2-one (C12 )

[0242] At -60 °C, ammonia gas was condensed into an autoclave containing a frozen solution of methyl (2R,3S)-3-(bromomethyl)oxirane-2-carboxylate C8 (81 g, 0.42 mol) in 1,4-dioxane (160 mL) until approx. 400 mL of liquid was collected. The autoclave was closed, allowed to warm gradually to room temperature and then heated at 50-60 °C for 2 h. The autoclave was then cooled back to -60 °C and depressurized. The reaction mixture was warmed gradually to allow the liquid ammonia to evaporate, leaving a viscous residue. The residue was taken up with MeOH (500 mL) and the suspension was treated with a 28 % solution of sodium methoxide in MeOH (86g, 0.42 mol). The mixture was stirred at room temperature for 30 min then concentrated. The residue was dissolved in water (500 mL), then Na 2 CO 3 (89g, 0.84 mol) and a solution of Boc 2 O (110 g, 0.5 mol) in THF (200 mL) was added. The mixture was stirred at room temperature for 10 h. The aqueous phase was then saturated with NaCl, and extracted THF (3 × 200 mL). The combined organic phases were dried over Na 2 SO 4 and concentrated in vacuo. The residue was triturated with warm MTBE (200 mL) and the precipitated solid was collected by filtration, washed with MTBE and dried under vacuum to afford the product as a white solid (28 g, 31% yield).Step 3. Synthesis of (3S, 4R)-3-amino-4-hydroxypyrrolidin-2-one hydrochloride (S2)

[0243] To solution of N-Boc-(3S,4R)-3-amino-4-hydroxypyrrolidin-2-one C12 (28 g, 129 mmol) in EtOH (300 mL) heated at 50-60 °C was added a solution of HCl in EtOH (5.0M, 75 mL). The reaction mixture was kept at 50-60 °C for 2 h. The suspension was cooled to room temperature and the solid was collected by filtration, washed with EtOH and dried in vacuo to afford the product as an off-white solid (18 g, 90%). 1< H NMR (500 MHz, DMSO-d 6 ) δ 8.73 (brs, 3H), 8.28 (s, 1H), 6.03 (s, 1H), 4.42-4.37 (m, 1H), 3.74 (d, J = 6.8 Hz, 1H), 3.48-3.39 (m, 1H), 3.03-3.00 (m, 1H).Preparation S3 (3S)-3-amino-5-methyl-pyrrolidin-2-one (S3)

[0244] Step 1. Synthesis of tert-butyl (S)-(5-methylene-2-oxotetrahydrofuran-3-yl)carbamate (C14)

[0245] CuBr (6723 mg, 4.7 mmol) was added to a solution of (2S)-2-(tert-butoxycarbonylamino)pent-4-ynoic acid C13 (5 g, 23.5 mmol) in tBuOH (50 mL) and water (50 mL) and stirred at room temperature for 24 h. The mixture was concentrated in vacuo to afford the product as an off-white solid (4.5 g, 80%). 1< H NMR (400 MHz, DMSO-d 6 ): δ 7.56 (d, 1H, J = 7.88), 4.64 (s, 1H), 4.49-4.43 (m, 1H), 4.34 (s, 1H), 3.12-3.05 (m, 1H), 2.78-2.72 (m, 1H), 1.38 (s, 9H). LCMS m / z 214.3 [M+H] +< .Step 2. Synthesis of methyl (2S)-2-(tert-butoxycarbonylamino)-4-oxo-pentanoate (C15 )

[0246] A solution of tert-butyl (S)-(5-methylene-2-oxotetrahydrofuran-3-yl)carbamate C14 (500 mg, 2.4 mmol) in MeOH (100 mL) was stirred at room temperature for 24 h. The solvent was evaporated under reduced pressure and the residue purified by silica gel chromatography (Gradient: 10% EtOAc in hexane) to afford the product as a colorless oil (300 mg, 51%). 1< H NMR (400 MHz, DMSO-d 6 ) δ 7.16 (d, 1H J = 7.64 Hz), 4.37-4.31 (m, 1H), 3.60 (s, 3H), 2.89-2.73 (m, 2H), 2.09 (s, 3H), 1.38 (s, 9H). LCMS m / z 246.0 [M+H] +< .Step 3. Synthesis of methyl (2S)-4-amino-2-(tert-butoxycarbonylamino)pentanoate (C16)

[0247] To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-4-oxo-pentanoate C15 (2.5 g, 10.2 mmol) in MeOH (30 mL) was added ammonium acetate (6.3 g, 81.5 mmol) and NaCNBH 3 (6.4 g, 101.9 mmol) at 0 °C. The mixture was stirred at room temperature for 24 h. The mixture was concentrated in vacuo and the residue was quenched with sat. solution of NH 4 Cl (25 mL). The aqueous layer was extracted with 10% MeOH in CH 2 Cl 2 (4 x 25 mL). The combined organic layers were washed sequentially with water (10 mL) and brine (10 mL), then dried over magnesium sulfate, and concentrated in vacuo to afford the product which was used without further purification (2.5 g, 100%). LCMS m / z 247.3 [M+H] +< .Step 4. Synthesis of tert-butyl N-[(3S)-5-methyl-2-oxo-pyrrolidin-3-yl]carbamate (C17 )

[0248] A solution of methyl (2S)-4-amino-2-(tert-butoxycarbonylamino)pentanoate C16 (2.5 g, 10.2 mmol) in 1,4-dioxane (100 mL) was heated at 90 °C for 24 h. The solvent was evaporated under reduced pressure. Purification by silica gel column chromatography (Gradient: 5% MeOH / DCM) afforded the product. (2 g, 92%) 1< H NMR (400MHz, DMSO-d 6 ): δ 7.82 (d, J =11.68 Hz, 1H), 7.00 (q, 1H), 4.09-4.01 (m, 1H), 3.56-3.45 (m, 2H), 1.90-1.87 (m, 1H), 1.37 (s, 9H), 1.08 (s, 3H). LCMS m / z 214.9 [M+H] +< .Step 5. Synthesis of (3S)-3-amino-5-methyl-pyrrolidin-2-one hydrochloride (S3)

[0249] To a solution of tert-butyl N-[(3S)-5-methyl-2-oxo-pyrrolidin-3-yl]carbamate C17 (2 g, 9.3 mmol) in 1,4-dioxane (10 mL) was added HCl in 1,4-dioxane (23.3 mL of 4 M, 93.3 mmol). The mixture was stirred at room temperature for 6 h. The reaction mixture was concentrated under reduced pressure and the residue was triturated with diethylether and n-pentane. Lyophilization afforded the product mixture of two diastereomers as an off white solid (927 mg, 65%). 1< H NMR (300 MHz, DMSO-d 6 ) δ 8.61 (brs), 8.42 (d, J = 9.9 Hz, 1H), 4.02-3.82 (m, 1H), 3.70 - 3.57 (m, 1H), 2.60 - 2.51 (m, 1H of one diastereomer), 2.29-2.16 (m, 1H of one diastereomer), 2.02 (ddd, J = 13.0, 8.8, 2.2 Hz, 1H of one diastereomer), 1.57 (ddd, J = 12.2, 11.0, 9.0 Hz, 1H of one diastereomer), 1.14 (dd, J = 6.3, 3.5 Hz, 3H).LCMS m / z 115.0 [M+H] +< .Preparation S4 (3S,5S)-3-amino-5-(hydroxymethyl)pyrrolidin-2-one (S4)

[0250] Step 1. Synthesis of methyl (2S)-5-oxopyrrolidine-2-carboxylate (C19 )

[0251] A solution of dimethyl (2S)-2-aminopentanedioate C18 (16 g, 91.3 mmol) in toluene (150 mL) was refluxed at 110 °C for 6 h. The reaction mixture was concentrated in vacuo. Silica gel chromatography (Gradient: 5% MeOH in CH 2 Cl 2 ) afforded the product as a colorless liquid (4.2 g, 32%). 1< H NMR (400 MHz, CDCl 3 ) δ 6.14 (s, 1H), 4.32 (s, 1H), 3.78 (s, 3H), 2.52 (s, 1H), 2.40 (s, 2H), 2.29 (s, 1H).Step 2. Synthesis of (5S)-5-(hydroxymethyl)pyrrolidin-2-one (C20)

[0252] To a solution of methyl (2S)-5-oxopyrrolidine-2-carboxylate C19 (4.2 g, 29.3 mmol) in IPA (40 mL) was added NaBH 4 (6.7 g, 7.0 mL, 176 mmol), the reaction was allowed to stirred at room temperature for 20 h. The mixture was then quenched with MeOH and concentrated in vacuo. Purification by column chromatography (Gradient: 5% MeOH in CH 2 Cl 2 ) afforded the product as a colorless liquid (3.3 g, 98%). 1< H NMR (400 MHz, CDCl 3 ) δ 7.29 (s,1H), 4.25 (s,1H), 3.79-3.74 (m,1H), 3.64 (d, J =11.8 Hz,1H), 3.43 (t, J =10.2 Hz,1H), 2.35-2.30 (m, 2H), 2.27-2.20 (m, 1H), 1.81-1.73 (m, 1H).Step 3. Synthesis of (3R, 7aS)-3-phenyl-3,6, 7, 7a-tetrahydro-1H-pyrrolo[1,2-c]oxazol-5-one (C21)

[0253] To a solution of (5S)-5-(hydroxymethyl)pyrrolidin-2-one C20 (4.7 g, 40.8 mmol) in toluene (75 mL) was added benzaldehyde (6.9 g, 6.7 mL, 65.3 mmol) and PTSA (388 mg, 2.0 mmol) and the reaction mixture was allowed to stirred at same temperature for 17 h. The mixture was then refluxed for 6 h with a Dean-Stark apparatus to remove water. The mixture was concentrated in vacuo and purified by silica gel chromatography (Eluent: 30% Ethyl acetate in hexane) to afford the product as a light yellow liquid (4.8 g, 48%). 1< H NMR (400 MHz, CDCl3) δ 7.43 (d, J =7 Hz, 2H), 7.37-7.29 (m, 3H), 6.32 (s, 1H), 4.24-4.17 (m, 1H), 4.15-4.11 (m,1H), 3.48 (t, J = 8.04 Hz,1H), 2.85-2.76 (m, 1H), 2.59-2.51 (m, 1H), 2.42-2.33 (m, 1H), 1.98-1.91 (m, 1H). LCMS m / z 204.0 [M+H] +< .Step 4. Synthesis of tert-butyl N-[(3R, 6S, 7αS)-5-oxo-3-phenyl-3,6,7,7a-tetrahydro-1H-pyrrolo[1,2-c]oxazol-6-yl]carbamate(C22 )

[0254] LDA (5.1 mL of 2 M, 10.3 mmol) was cooled to -78 0< C then a solution of (3R,7αS)-3-phenyl-3,6,7,7α-tetrahydro-1H-pyrrolo[1,2-c]oxazol-5-one C21 (1.75 g, 8.6 mmol) in THF (20 mL) was added and the reaction mixture was stirred at -78 °C for 30 minutes. DPPA (4.7 g, 3.7 mL, 17.2 mmol) was then added, and reaction mixture was stirred for a further 10 minutes. Boc-anhydride (3.8 g, 3.9 mL, 17.2 mmol) was added to the mixture and the reaction allowed to stir for 17 h. Ethyl acetate (125 mL) was added and the mixture was washed with brine solution (2 x 200 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. Purification by silica gel chromatography (Eluent: 22% Ethyl acetate in hexanes) afforded the product (750 mg, 25%) 1< H NMR (400 MHz, CDCl 3 ) δ 7.46 - 7.28 (m, 5H), 6.34 (s, 1H), 5.18 (s, 1H), 4.62 (s, 1H), 4.30- 4.21 (m, 1H), 4.06 (p, J = 6.8 Hz, 1H), 3.62 (t, J = 7.6 Hz, 1H), 3.00 (s, 1H), 1.75 (q, J = 11.8, 11.3 Hz,1H), 1.45 (s, 9H). LCMS m / z 319.0 [M+H] +< .Step 5. Synthesis of (3S, 5S)-3-amino-5-(hydroxymethyl)pyrrolidin-2-one hydrochloride (S4)

[0255] TFA (11.1 g, 7.5 mL, 97.3 mmol) was added to a solution of tert-butyl N-[(3R,6S,7αS)-5-oxo-3-phenyl-3,6,7,7α-tetrahydro-1H-pyrrolo[1,2-c]oxazol-6-yl]carbamate C22 (1.5 g, 4.7 mmol) in CH 2 Cl 2 (15 mL) cooled to 0 0< C. The mixture was allowed to stir at room temperature for 2 h, and then concentrated in vacuo. 4M HCl in 1,4-dioxane was added and the mixture was washed with pentane to afford the product as the hydrochloride salt (750 mg, 96%). 1< H NMR (400 MHz, DMSO-d 6 and D 2 O) δ 3.89 (t, 9.3 Hz, 3H), 3.63-3.56 (m, 1H), 3.43-3.32 (dd, J = 10.9, 4.5 Hz, 2H), 2.45-2.38 (m, 1H), 1.67-1.59 (m, 1H). LCMS m / z 131.0 [M+H] +< .Preparation S5 (3S,5R)-3-amino-5-(hydroxymethyl)pyrrolidin-2-one (S5)

[0256] Step 1. Synthesis of methyl (2R)-5-oxopyrrolidine-2-carboxylate (C24)

[0257] A solution of dimethyl (2R)-2-aminopentanedioate hydrochloride salt C23 (25 g, 118.2 mmol) in Toluene (300 mL) was heated under reflux for 4 h. The solvent was removed and purification by silica gel column chromatography (Eluent: 5-6% MeOH in CH 2 Cl 2 ) afforded the product as a light brown oil (12 g, 71%). 1< H NMR (400 MHz, CDCl 3 ) δ: 6.39 (s, 1H), 4.26 (s,1H), 3.76 (s, 3H), 2.46 (m,1H), 2.36 (m, 2H), 2.02 (m, 1H).Step 2. Synthesis of (SR)-5-(hydroxymethyl)pyrrolidin-2-one (C25)

[0258] NaBH 4 (5.3 g, 5.6 mL, 140.8 mmol) was added to a solution of methyl (2R)-5-oxopyrrolidine-2-carboxylate C24 (5 g, 34.9 mmol) in IPA (50 mL). The mixture was allowed to stir at room temperature for 20 h. Methanol (5 mL) was added drop-wise to the reaction mixture, which was then concentrated in vacuo. Purification by silica gel chromatography (2-4% MeOH in CH 2 Cl 2 ) afforded the product which was used in the subsequent step without further purification (3 g, 75%).Step 3. Synthesis of (5R)-5-[[tert-butyl(dimethyl)silyl]oxymethyl]pyrrolidin-2-one (C26)

[0259] To a solution of (SR)-5-(hydroxymethyl)pyrrolidin-2-one C25 (10 g, 86.9 mmol) in CH 2 Cl 2 (100 mL) was added imidazole (14.8 g, 217.2 mmol) and TBDMSCl (15.7 g, 104.2 mmol). The reaction mixture was stirred at room temperature for 6 h. Water (50 mL) was added and the reaction mixture extracted with CH 2 Cl 2 (100 mL). The organic layer was dried over Na 2 SO 4 and concentrated in vacuo afford the product (18 g, 90%) 1< H NMR(400 MHz, CDCl 3 ) δ 6.02 (s, 1H), 3.73-3.71 (m, 1H), 3.60 (dd, J =10.08, 10.08 Hz,1H), 3.44-3.40 (m, 1H), 2.34-2.29 (m, 2H), 2.17-2.12 (m, 1H), 1.73-1.71 (m,1H), 0.88 (s, 9H), 0.04 (s, 6H). LCMS m / z 230.2 [M+H] +< .Step 4. Synthesis of tert-butyl (2R)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-oxo-pyrrolidine-1-carboxylate (C27)

[0260] To a solution of (5R)-5-[[tert-butyl(dimethyl)silyl]oxymethyl]pyrrolidin-2-one C26 (12.5 g, 54.5 mmol) in CH 2 Cl 2 (50 mL) at 0 °C was added Boc anhydride (23.8 g, 109 mmol) , DMAP (6.7 g, 54.5 mmol) and triethyl amine (5.5 g, 7.6 mL, 54.5 mmol) and the mixture allowed to stir at room temperature for 16 h. Water (50 mL) was added to the reaction mixture and extracted with CH 2 Cl 2 (50 mL x 3). Combined organic layers were dried over Na 2 SO 4 and concentrated in vacuo. Purification by silica gel chromatography (Gradient: 10% EtOAc in hexane) provided the product as a light yellow oil (15 g, 82%). 1< H NMR (400 MHz, CDCl 3 ) δ 4.16-4.14 (m, 1H), 3.90 (dd, J = 10.4, 4.0 Hz, 1H), 3.68 (dd, J = 10.5, 2.3 Hz, 1H), 2.69 (dt, J = 17.5, 10.4 Hz, 1H), 2.36 (ddd, J = 17.6, 9.7, 2.3 Hz, 1H), 2.04 (dq, J = 22.6, 11.9, 11.4 Hz, 2H), 1.52 (s, 9H), 0.87 (s, 9H), 0.03 (s, 6H). LCMS m / z 330.0 [M+H] +< .Step 5. Synthesis of tert-butyl (3S,5R)-3-(tert-butoxycarbonylamino)-5-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-oxo-pyrrolidine-1-carboxylate (C28)

[0261] A solution of LDA (13.6 mL of 2 M in THF, 27.0 mmol) was cooled to -78 °C, and a solution of tert-butyl (2R)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-oxo-pyrrolidine-1-carboxylate C27 (6 g, 18.2 mmol) in THF (80 mL) was added. After 30 minutes, DPPA (12.5 g, 9.8 mL, 45.5 mmol) was added and the mixture was stirred for 5 minutes. Boc anhydride (9.9 g, 10.5 mL, 45.5 mmol) was then added and the mixture stirred for 16 h. Water (100 mL) was added and the mixture extracted with EtOAc (100 mL x 3). The combined organic layers were dried over Na 2 SO 4 , and concentrated in vacuo. Purification by silica gel chromatography (Eluent: 5-6% EtOAc in hexane) afforded the product as a light yellow oil (2.7 g, 24%). 1< H NMR (400 MHz, DMSO-d 6 ) δ 7.08 (d, J = 8.76 Hz, 1H), 4.41 (d, J = 11.12 Hz, 1H), 4.06 (d, J = 8.48 Hz, 1H), 3.89 (dd, J = 10.56, 10.6Hz, 1H), 3.66 (d, J = 9.96 Hz, 1H), 2.15-2.02 (m, 2H), 1.45-1.34 (m, 18H), 0.85 (s, 9H), 0.03 (d, J = 6.8, 6H). LCMS m / z 445.3 [M+H] +< .Step 6. Synthesis of (3S,5R)-3-amino-5-(hydroxymethyl)pyrrolidin-2-one hydrochloride (S5)

[0262] To a solution of tert-butyl (3S,5R)-3-(tert-butoxycarbonylamino)-5-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-oxo-pyrrolidine-1-carboxylate C28 (1.5 g, 3.4 mmol) at 0 °C was added in HCl in 1,4-dioxane (20 mL of 4 M, 80 mmol). The mixture was allowed to stir at room temperature for 1.5 h. The mixture was concentrated in vacuo, and the residue washed with diethyl ether to afford the product as the hydrochloride salt (500 mg, 80%). 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.42-8.35 (m, 4H), 3.88 (d, J = 4.88 Hz, 1H), 3.57 (d, J = 8.0 Hz, 1H), 3.40-3.36 (m, 2H), 2.28-2.23 (m, 1H), 2.11-1.98 (m, 1H). LCMS m / z 131.0 [M+H] +< .Preparation S6 (3S,5S)-3-amino-5-(fluoromethyl)pyrrolidin-2-one (S6)

[0263] Step 1. Synthesis of 9H-fluoren-9-ylmethyl N-[(3S, 5S)-5-(hydroxymethyl)-2-oxopyrrolidin-3-yl]carbamate (C29)

[0264] A solution of Fmoc-oSu (746 mg, 2.2 mmol) in MeCN (4 mL)was added to a solution of (3S,5S)-3-amino-5-(hydroxymethyl)pyrrolidin-2-one S4 (320 mg, 2.5 mmol) in aqueous NaHCO 3 (6 mL). Then reaction was stirred at room temperature for 2 h. The reaction mixture was then filtered, washed with water and hexane, then dried under vacuum to afford the product as an off-white solid (410 mg, 32%). 1< H NMR (400 MHz, DMSO-d 6 ) δ 7.95 - 7.86 (m, 2H), 7.80 (s, 1H), 7.70 (t, J = 8.6 Hz, 2H), 7.54 (t, J =10.4 Hz, 1H), 7.39 (ddt, J = 35.4, 14.4, 7.4 Hz, 4H), 4.85 - 4.76 (m, 1H), 4.25 (dd, J = 17.6, 6.4 Hz, 2H),3.46 (s, 1H), 2.75 (s, 1H). LCMS m / z 353.0 [M+H] +< .Step 2. Synthesis of 9H-fluoren-9-ylmethyl N-[(3S, 5S)-5-(fluoromethyl)-2-oxopyrrolidin-3-yl]carbamate (C30 )

[0265] To a solution of 9H-fluoren-9-ylmethyl N-[(3S,5S)-5-(hydroxymethyl)-2-oxo-pyrrolidin-3-yl]carbamate C29 (100 mg, 0.28 mmol) in CH 2 Cl 2 (2.8 mL) was cooled to 0 0< C, then Deoxo-Fluor ®< (0.14 mL of 50 %w / w, 0.31 mmol) was added. The mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with water and extracted with CH 2 Cl 2 . The organic layer was dried over anhydrous magnesium sulfate, then concentrated in vacuo. Purification by silica gel chromatography (Eluent: 2% MeOH in CH 2 Cl 2 ) afforded the product as an off-white solid which was used directly in the subsequent step (50 mg, 48%). LCMS m / z 355.0 [M+H] +< .Step 3. Synthesis of (3S,5S)-3-amino-5-(fluoromethyl)pyrrolidin-2-one (S6)

[0266] To a solution of 9H-fluoren-9-ylmethyl N-[(3S,5S)-5-(fluoromethyl)-2-oxopyrrolidin-3-yl]carbamate C30 (70 mg, 0.20 mmol) in THF (3 mL) was added diethyl amine (0.01 mL of 4 M, 0.04 mmol) and the reaction mixture was allowed to stir at room temperature for 2 h. The mixture was evaporated under reduced pressure, then diethyl ether-HCl was added and the mixture stirred for an additional 30 minutes. The mixture was concentrated in vacuo with pentane to afford the product as an off-white solid (20 mg, 60%). 1< H NMR (400 MHz, DMSO-d 6 ) 8.68 (s,1H), 8.36 (brs, 2H), 4.57-4.43 (m,1H), 4.38-4.24 (m,1H), 4.00-3.98 (m,1H), 3.87 (s,1H), 2.43-2.32 (m,1H), 1.69-1.66 (m,1H).Preparation S7 (3S,5R)-3-amino-5-(fluoromethyl)pyrrolidin-2-one (S7)

[0267] Step 1. Synthesis of 9H-fluoren-9-ylmethyl N-[(3S,5R)-5-(hydroxymethyl)-2-oxopyrrolidin-3-yl]carbamate (C31)

[0268] 9H-fluoren-9-ylmethyl N-[(3S,5R)-5-(hydroxymethyl)-2-oxo-pyrrolidin-3-yl]carbamate C31 was prepared from (3S,5R)-3-amino-5-(hydroxymethyl)pyrrolidin-2-one S5 (100 mg, 0.7684 mmol) as described in preparation S6 (130 mg, 47%). 1< H NMR (400 MHz, DMSO-d 6 ) δ7.89 (d, J =7.52 Hz, 2H), 7.80 (s, 1H), 7.71 (d, J = 7.32 Hz, 2H), 7.52 (d, J = 9.0 Hz, 2H), 7.41 (t, J = 7.2 Hz, 2H), 7.33 (t, J = 7.32 Hz, 2H), 4.88-4.86 (m, 1H), 4.29-4.28 (m, 2H), 4.23-4.12 (m, 2H), 3.44 (s, 1H), 3.32 (s, 1H), 2.16-2.11 (m, 1H), 1.95-1.92 (m, 1H). LCMS m / z 353.1 [M+H] +< .Step 2. Synthesis of 9H-fluoren-9-ylmethyl N-[(3S,5R)-5-(fluoromethyl)-2-oxopyrrolidin-3-yl]carbamate (C32)

[0269] 9H-fluoren-9-ylmethyl N-[(3S,5R)-5-(fluoromethyl)-2-oxo-pyrrolidin-3-yl]carbamate C32 was prepared from 9H-fluoren-9-ylmethyl N-[(3S,5R)-5-(hydroxymethyl)-2-oxo-pyrrolidin-3-yl]carbamate C31 (600 mg, 1.7 mmol) as described in preparation S6 (170 mg, 27%). 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.08 (s, 1H), 7.98 (d, J = 7.44 Hz, 2H), 7.70 (d, J = 7.36 Hz, 2H), 7.58 (d, J = 8.68 Hz, 1H), 7.41 (t, J = 7.28 Hz, 2H), 7.33 (t, J = 7.4 Hz,2H), 4.43 (d, J = 3.88 Hz,1H), 4.31-4.20 (m, 4H), 4.11 (d, J = 9.24 Hz,1H), 3.76-3.69 (m, 2H), 2.17-1.98 (m, 2H). LCMS m / z 355.2 [M+H] +< .Step 3. Synthesis of (3S,5R)-3-amino-5-(fluoromethyl)pyrrolidin-2-one hydrochloride (S7)

[0270] (3S,5R)-3-amino-5-(fluoromethyl)pyrrolidin-2-one hydrochloride salt S7 was prepared from 9H-fluoren-9-ylmethyl N-[(3S,5R)-5-(fluoromethyl)-2-oxo-pyrrolidin-3-yl]carbamate C32 (170 mg, 0.5 mmol) as described in preparation S6. (49 mg, 61%) 1< H NMR (400 MHz, DMSO-d 6 ) δ8.58 (s, 1H), 8.10-7.85 (m, 2H), 4.46 (d, J = 3.8 Hz, 1H), 4.34 (d, J = 3.76Hz, 1H), 3.83 (t, J = 9.4 Hz, 2H), 2.32-2.11 (m, 2H). LCMS m / z 133.0 [M+H] +< .Preparation S8 (3S,4S)-3-amino-4-methyl-pyrrolidin-2-one (S8)

[0271] Step 1. Synthesis of (2R)-2-isopropyl-3, 6-dimethoxy-2, 5-dihydropyrazine (C34)

[0272] To a mixture of (3R)-3-isopropylpiperazine-2,5-dione C33 (2g, 12.8 mmol) and trimethyloxonium tetrafluoroborate (6.6 g, 44.8 mmol) was added CH 2 Cl 2 (50 mL). The mixture was stirred at room temperature for 24 h. The resulting solid was collected by filtration under a nitrogen atmosphere, and washed with CH 2 Cl 2 (300 mL). The solid was added in portions to a vigorously stirred mixture of saturated aqueous NaHCO 3 and CH 2 Cl 2 at 4 °C, while maintaining the pH between 8-9 with simultaneous addition of 3 M aqueous NaOH as required. The mixture was separated, and the aqueous phase was extracted with CH 2 Cl 2 . The combined organic phases were washed with brine, dried, and concentrated under in vacuo. Purification by silica gel chromatography afforded the product (1.5 g, 64%). 1< H NMR (400 MHz, DMSO-d 6 ) 3.99 - 3.89 (m, 3H), 3.63 (s, 3H), 3.60 (s, 3H, 2.15 (dtt, J =10.3, 6.9, 3.5 Hz, 1H), 0.98 (d, J = 6.9 Hz, 3H), 0.67 (d,J = 6.8 Hz, 3H). LCMS m / z 185.0 [M+H] +< .Step 2. Synthesis of (2R,5S)-2-isopropyl-3,6-dimethoxy-5-[(1S)-1-methyl-2-nitroethyl]-2,5-dihydropyrazine (C35)

[0273] n-Butyllithium (5.2 mL of 2.5 M, 13.0 mmol) was added to a solution of (2R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine C34 (2 g, 10.9 mmol) in THF (25 mL) at -78 °C. Upon stirring for 15 minutes, TiCl(OiPr) 3 (11.9 mL of 1 M, 11.9 mmol) was added and stirring continued for 1 h. This solution was then added to a precooled solution (-78 °C) of (Z)-1-nitroprop-1-ene (1.1 g, 13.0 mmol) in THF and stirring continued for 12 h. Phosphate buffer (25 mL, pH 7) was added and the reaction mixture was allowed to warm up to -40 °C. Water (25 mL) was added, the aqueous layer was extracted with diethyl ether (4 x 50 mL) and the combined organic layers were dried over Na 2 SO 4 . Silica gel chromatography afforded the product (1.6 g, 54%). 1< H NMR (400 MHz, CDCl 3 ) d 4.72 (ddd, J = 12.6, 6.8, 3.2 Hz, 1H), 4.47 - 4.27 (m, 1H), 4.22 - 4.03 (m, 1H), 4.01 - 3.84 (m, 2H), 3.73 - 3.61 (m, 6H), 2.23 (dtq, J = 9.8, 6.8, 3.0 Hz, 1H), 1.17 - 1.07 (m, 2H), 1.11 - 0.99 (m, 3H), 0.79 - 0.66 (m, 3H), 0.69 - 0.62 (m, 2H).Step 3. Synthesis of methyl (2S, 3S)-2-amino-3-methyl-4-nitro-butanoate (C36)

[0274] A suspension of (2R,5S)-2-isopropyl-3,6-dimethoxy-5-[(1 S)-1-methyl-2-nitro-ethyl]-2,5-dihydropyrazine C35 (630 mg, 2.3 mmol) in HCl (18.6 mL of 0.25 M, 4.6 mmol) and THF (2 mL) was allowed to stir at room temperature for 24 h. The mixture was concentrated in vacuo and the aqueous solution was washed with diethyl ether (25 mL). Diethyl ether (25 mL) was then added to the aqueous layer and the mixture was adjusted to pH 8-10 with aqueous ammonia. The layers were separated and the aqueous layer was extracted with diethyl ether (2 x 25 mL). The combined diethyl ether layers were dried with Na 2 SO 4 and concentrated in vacuo. Purification by silica gel chromatography afforded the product (300 mg, 73%). 1< H NMR (400 MHz, CDCl 3 ) δ 4.62-4.66 (m, 1H), 4.32 - 4.38 (m, 1H), 3.76 (s, 3H), 3.49 (d, J = 6 Hz, 1H), 2.70 (brs, 1H), 1.06 (d, J = 6.8 Hz, 3H).Step 4. Synthesis of (3S, 4S)-3-amino-4-methyl-pyrrolidin-2-one (S8)

[0275] To a suspension of methyl (2S,3 S)-2-amino-3-methyl-4-nitro-butanoate C36 (310 mg, 1.76 mmol) in MeOH was added 10 % Pd on carbon (132.9 mg, 0.62 mmol). The mixture was stirred under an atmosphere of hydrogen at room temperature for 3 h. Then the reaction mixture was filtered through Celite ®< , washed with MeOH and concentrated in vacuo. Purification by chromatography on neutral alumina (Eluent: 1-2% MeOH in CH 2 Cl 2 ) afforded the product as a hydrochloride salt (80 mg, 30%) 1< H NMR (400 MHz, CD 3 OD) δ 3.64 (d, J= 10.6 Hz, 1H), 3.51 (t, J= 8.44 Hz, 1H), 3.02 (t, J= 9.6 Hz, 1H), 2.48 -2.45 (m, 1H), 1.28 (d, J= 2.84 Hz, 3H).Preparation S9 and S10 3-[5, 7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]-N-[(3R,4S)-4-hydroxy-2-oxopyrrolidin-3-yl]propanamide (S9) and of 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]-N-[(3R,4R)-4-hydroxy-2-oxo-pyrrolidin-3-yl]propanamide (S10)

[0276] Step 1. Synthesis of methyl (2R)-2-(((benzyloxy)carbonyl)amino)-2-(oxiran-2-yl)acetate (C38)

[0277] To methyl (2R)-2-(benzyloxycarbonylamino)but-3-enoate C37 (2.4 g, 9.7 mmol) in CH 2 Cl 2 (40 mL) was added mCPBA (4.8 g of 70 %w / w, 19.5 mmol). The mixture was heated at reflux for 5 h. Additional mCPBA (2.4 g of 70 %w / w, 9.7 mmol) was added and the mixture allowed to stir for a further 30 minutes. A saturated solution of Na 2 HSO 3 (sodium bisulfite) and then 100 mL CH 2 Cl 2 were added. The CH 2 Cl 2 layer was washed with NaHCO 3 and brine. Purification by chromatography on silica gel (Gradient: 0 to 100% Ethyl acetate in heptane) afforded methyl (2R)-2-(((benzyloxy)carbonyl)amino)-2-(oxiran-2-yl)acetate as a mixture of diastereomers which were used in the subsequent step without separation (1.6 g, 60%). 1< H NMR (300 MHz, CDCl 3 ) δ 7.48 - 7.30 (m, 5H), 5.27 (d, J = 8.9 Hz, 1H), 5.14 (d, J = 1.2 Hz, 2H), 4.82 - 4.68 (m, 1H), 3.83 (d, J = 4.4 Hz, 3H), 3.49 (d, J = 3.7 Hz, 1H), 2.90 - 2.75 (m, 1H), 2.70 (dd, J = 4.7, 2.6 Hz, 1H). LCMS m / z 266.2 [M+H] +< .Step 2. Synthesis of methyl (2R, 3S)-4-azido-2-(benzyloxycarbonylamino)-3-hydroxybutanoate (C39) and methyl (2R, 3R)-4-azido-2-(((benzyloxy)carbonyl)amino)-3-hydroxybutanoate (C40 )

[0278] A mixture of methyl (2R)-2-(benzyloxycarbonylamino)-2-(oxiran-2-yl)acetate C38 (476 mg, 1.7 mmol), sodium azide (1.1 g, 17.1 mmol) and NH 4 Cl (100 mg, 1.9 mmol) in DMF (4 mL) was heated at 60 °C overnight. Water (60 mL) was added and the mixture extracted with EtOAc (120 mL). The organic phase was dried and concentrated in vacuo to afford the product as a mixture of major and minor diastereomers, methyl (2R, 3S)-4-azido-2-(((benzyloxy)carbonyl)amino)-3-hydroxybutanoate C39 and methyl (2R, 3R)-4-azido-2-(((benzyloxy)carbonyl)amino)-3-hydroxybutanoate C40 which were progressed, without separation, to the subsequent step. The 2R,3S diastereomer C39 is presumed to be the major component. LCMS m / z 308.9 [M+H] +< .Step 3. Synthesis of benzyl N-[(3R,4S)-4-hydroxy-2-oxo-pyrrolidin-3-yl]carbamate (C41) and benzyl N-[(3R,4R)-4-hydroxy-2-oxo-pyrrolidin-3-yl]carbamate (C42)

[0279] To a solution of methyl (2R,3S)-4-azido-2-(benzyloxycarbonylamino)-3-hydroxy-butanoate C39 and (2R, 3R)-4-azido-2-(((benzyloxy)carbonyl)amino)-3-hydroxybutanoate C40 (543 mg, 1.708 mmol) in a mixture of MeOH (8 mL),THF (6 mL), and water (4 mL), was added PPh 3 (1.56 g, 5.9 mmol). The mixture was heated at 90 °C for 5 days. Purification by reverse phase HPLC (C18 Column; Gradient: Acetonitrile in water with 0.1 % TFA) to provide the two diastereomers C41 and C42.

[0280] C41 is the major peak and is presumed to be benzyl N-[(3R,4S)-4-hydroxy-2-oxo-pyrrolidin-3-yl]carbamate (86 mg, 20%). 1< H NMR (300 MHz, CD 3 OD) δ 7.51 - 7.23 (m, 5H), 5.12 (s, 2H), 4.41 (q, J = 7.8 Hz, 1H), 4.06 (d, J = 8.3 Hz, 1H), 3.56 (dd, J = 9.8, 7.7 Hz, 1H), 3.10 (dd, J = 9.9, 7.3 Hz, 1H). LCMS m / z 251.07 [M+H] +< .

[0281] C42 is the minor peak and is presumed to be benzyl N-[(3R,4R)-4-hydroxy-2-oxo-pyrrolidin-3-yl]carbamate (15 mg, 3%). 1< H NMR (300 MHz, CD 3 OD) δ 7.51 - 7.15 (m, 5H), 5.15 (s, 2H), 4.53 - 4.32 (m, 2H), 3.60 (dd, J= 11.2, 3.7 Hz, 1H), 3.25 (d, J = 11.3 Hz, 1H). LCMS m / z 251.1 [M+H] +< .Step 4. Synthesis of 3-[5, 7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]-N-[(3R, 4S)-4-hydroxy-2-oxo-pyrrolidin-3-yl]propanamide (S9)

[0282] To a suspension of benzyl N-[(3R,4S)-4-hydroxy-2-oxo-pyrrolidin-3-yl]carbamate C41 (86 mg, 0.34 mmol) in 20 mL MeOH was added 5% Palladium on carbon catalyst (20 mg). The mixture was subjected to hydrogenation conditions of 50 psi H 2 for 4 h. Filtration through a pad of Celite ®< , washing with MeOH and CH 2 Cl 2 , then concentration of the filtrate in vacuo afforded hydroxy lactam S9 which was used in subsequent step without further purification. 1< H NMR (300 MHz, CD 3 OD) δ 4.26 - 4.18 (m, 1H), 3.42 (dd, J = 11.2, 3.9 Hz, 1H), 3.33 (d, J = 5.1 Hz, 1H), 3.11 (d, J = 11.2 Hz, 1H).Step 5. Synthesis of 3-[5, 7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]-N-[(3R,4R)-4-hydroxy-2-oxo-pyrrolidin-3-yl]propanamide (S10)

[0283] To a suspension of benzyl N-[(3R,4R)-4-hydroxy-2-oxo-pyrrolidin-3-yl]carbamate C42 (15 mg, 0.06 mmol) in MeOH (10 mL) was added 5% Palladium on carbon catalyst (10 mg). The mixture was subjected to hydrogenation conditions of 50 psi H 2 for 4 h. Filtration through a pad of Celite ®< , washing with MeOH and CH 2 Cl 2 , then concentration of the filtrate in vacuo afforded hydroxy lactam S10 which was used in subsequent steps without further purification.Preparation S11 6-amino-4-azaspiro[2.4]heptan-5-one (S11 )

[0284] Step 1. Synthesis of benzyl N-(1-formylcyclopropyl)carbamate (C44)

[0285] To a solution of benzyl N-[1-(hydroxymethyl)cyclopropyl]carbamate C43 (7.8 g, 35.3 mmol) in CH 2 Cl 2 (160 mL) was added Dess Martin Periodinane (22.4 g, 52.9 mmol) at 0 °C and the reaction mixture stirred at room temperature for 3 h. Upon completion, the reaction was quenched with mixture of saturated NaHCO 3 (100 mL) and sodium thiosulfate solution (100 mL). The mixture was extracted with CH 2 Cl 2 and combined organic layers were dried over anhydrous sodium sulfate. Purification by silica gel chromatography (Eluent: 15% EtOAc in hexane) afforded the product as a light yellow solid (7.5 g, 78%). 1< H NMR (400 MHz, CDCl 3 ) δ 9.12 (s, 1H), 7.35 (m, 5H), 5.35 (s, 1H), 5.13 (s, 2H), 1.53 (m, 2H), 1.38 (s, 2H). LCMS m / z 220.0 [M+H] +< .Step 2.Synthesis of methyl (Z)-3-[1-(benzyloxycarbonylamino)cyclopropyl]-2-(tert-butoxycarbonylamino)prop-2-enoate (C45)

[0286] To a solution of benzyl N-(1-formylcyclopropyl)carbamate C44 (7.5 g, 34.2 mmol) in CH 2 Cl 2 (350 mL) was added N-Boc-2-Phosphonoglycine trimethyl ester (20.3 g, 68.4 mmol) and DBU (10.4 g, 10.2 mL, 68.4 mmol) and the mixture was stirred at room temperature overnight. The reaction mixture was quenched with saturated aqueous NH 4 Cl and extracted into CH 2 Cl 2 (2 x 100 mL). The organic layer was dried over anhydrous sodium sulfate and evaporated. Purification by silica gel chromatography (Eluent: 20% EtOAc in hexane) afforded the product as white solid. (10 g, 75%). 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.21 (s, 1H), 7.73 (s, 1H), 7.38 - 7.31 (m, 5H), 5.98 (s, 1H), 4.99 (s, 2H), 3.71 - 3.68 (m, 3H), 1.38 (d, J = 11.1 Hz, 9H), 1.02 (d, J = 4.6 Hz, 4H). LCMS m / z 391.0 [M+H] +< .Step 3. tert-butyl N-(5-oxo-4-azaspiro[2.4]heptan-6-yl)carbamate (C46) and tert-butyl N-(5-oxo-4-azaspiro[2.4]heptan-6-yl)carbamate (C47)

[0287] Mg (8.7 g, 358.6 mmol) was added to a solution of methyl (Z)-3-[1-(benzyloxycarbonylamino)cyclopropyl]-2-(tert-butoxycarbonylamino)prop-2-enoate C45 (14 g, 35.9 mmol) in MeOH (140 mL) and the mixture allowed to stir at 0 °C for 4 h, then at 25 °C for 8 h. Upon completion, the reaction mixture was neutralized with NH 4 Cl solution, and extracted with EtOAc (3 x 100 mL). The organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product mixture was purified by silica gel chromatography (Eluent: 50% EtOAc in hexane) to afford the racemic product. Purification by chiral HPLC [Chiralpak IA column (21.0 x 250 mm), 5µ Mobile phase: n-Hexane / EtOH / Dichloromethane: 50 / 25 / 25 Flow rate: 21.0 mL / min] afforded single enantiomers C46 and C47, both as white solids.

[0288] C46 was the first eluting enantiomer. (Yield 2 g, 24%) 1< H NMR (400 MHz, DMSO-d 6 ) δ 7.78 (s, 1H), 7.11 (d, J = 8.9 Hz, 1H), 4.23 (q, J = 9.3 Hz, 1H), 2.15 (t, J = 11.4 Hz, 1H), 2.06 - 1.97 (m, 1H), 1.39 (s, 9H), 0.74 (m, 1H), 0.64 (m, 1H), 0.53 (m, 2H). LCMS m / z 227.0 [M+H] +< .

[0289] C47 was the second eluting enantiomer. (2 g, 24%) 1< H NMR (400 MHz, DMSO-d 6 ) δ 7.78 (s, 1H), 7.11 (d, J = 8.9 Hz, 1H), 4.23 (q, J = 9.4 Hz, 1H), 2.15 (t, J = 11.4 Hz, 1H), 2.02 (m, 1H), 1.39 (s, 9H), 0.81 - 0.59 (m, 2H), 0.53 (m, 2H). LCMS m / z 227.0 [M+H] +< .Step 4. Synthesis of 6-amino-4-azaspiro[2.4]heptan-5-one hydrochloride (S11)

[0290] To a stirred solution of tert-butyl N-(5-oxo-4-azaspiro[2.4]heptan-6-yl)carbamate C47 (850 mg, 3.8 mmol) in CH 2 Cl 2 (8 mL) at 0 °C was added TFA (12.8 g, 8.9 mL, 112.7 mmol). The reaction mixture was stirred at room temperature for 2 h. The mixture was then concentrated in vacuo. 4 M HCl in 1,4-dioxane (8 mL) was added and upon stirring for 30 min at room temperature, reaction mixture was concentrated in vacuo. The resulting solid was washed with ether to afford the product as a hydrochloride salt (180 mg, 18%). 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.51 (s, 3H), 8.39 (s, 1H), 4.15-4.10 (m, 1H), 2.31 (dd, J = 12.6,10.2 Hz, 1H), 2.20 (dd, J = 12.7, 8.8 Hz, 1H), 0.86 - 0.84 (m, 1H), 0.77 - 0.74 (m, 1H), 0.72 - 0.66 (m, 2H). LCMS m / z 127.0 [M+H] +< .Preparation S12 (3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]propanoic acid) (S12 )

[0291] Step 1. Synthesis of 2, 4-difluoro-6-[2-(4-fluorophenyl)ethynyl]aniline (C49)

[0292] Method A: Sonagashira Coupling Method. To a flask containing 2,4-difluoro-6-iodo-aniline C48 (134 g, 525.5 mmol) was added NEt 3 (1.3 L), followed by DMF (250 mL), 1-ethynyl-4-fluoro-benzene (83.5 g, 695.1 mmol), CuI (20.5 g, 107.6 mmol), and PdCl 2 (PPh 3 ) 2 (25 g, 35.6 mmol). The mixture was allowed to stir at room temperature for 2 h. Solvent was removed under reduced pressure and water (500 mL) was added. The mixture was extracted with Ethyl acetate, filtered and concentrated in vacuo. The product mixture was filtered through a silica gel plug (Eluent: CH 2 Cl 2 ), followed by a second silica plug filtration (Eluent: 30-40% EtOAc in Heptane). Silica gel chromatography (Gradient: 0-20% EtOAc in heptane) afforded the product as a pale yellow solid. (87 g, 60%). 1< H NMR (300 MHz, CDCl 3 ) δ 7.58 - 7.45 (m, 2H), 7.14 - 7.02 (m, 2H), 6.92 (ddd, J = 8.8, 2.8, 1.7 Hz, 1H), 6.87 - 6.71 (m, 1H), 4.15 (s, 2H). LCMS m / z 248.0 [M+H] +< .Step 2. Synthesis of 5, 7-difluoro-2-(4-fluorophenyl)-1H-indole (C50 )

[0293] Method B: Amine-Alkyne cyclization Method (CuI promoted). To a solution of 2,4-difluoro-6-[2-(4-fluorophenyl)ethynyl] aniline C49 (46 g, 167.5 mmol) in DMF (600 mL) was added CuI (1.9 g, 10.0 mmol) and the reaction was heated at reflux. Water (800 mL) was added and the mixture extracted with MTBE. The mixture was then washed with sat. NaCl solution, dried over Na 2 SO 4 and then concentrated in vacuo to afford the product, which was used in subsequent steps without further purification (41 g, 87%). 1< H NMR (300 MHz, CDCl 3 ) δ 8.43 (s, 1H), 7.72 - 7.58 (m, 2H), 7.27 - 7.15 (m, 2H), 7.09 (dd, J = 9.0, 2.1 Hz, 1H), 6.85 - 6.63 (m, 2H). LCMS m / z 248.0 [M+H] +< .Step 3.Synthesis of methyl (E)-3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]prop-2-enoate (C51)

[0294] Method C: Reductive Alkylation Method (TFA promoted). A 12 L flask with overhead stirrer was charged with 5,7-difluoro-2-(4-fluorophenyl)-1H-indole C50 (300 g, 1.2 mol), CH 2 Cl 2 (3 L), methyl 3,3-dimethoxypropanoate (195 mL, 1.4 mol) and TFA (300 mL, 3.9 mol).The reaction was heated to reflux for 4 h. Additional CH 2 Cl 2 was added to facilitate stirring. Upon cooling to room temperature, the solid product was filtered, washed with minimal CH 2 Cl 2 and dried to afford the product (388 g, 96%). 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.66 (s, 1H), 7.77 - 7.57 (m, 4H), 7.56 - 7.37 (m, 2H), 7.19 (ddd, J = 11.0, 9.7, 2.1 Hz, 1H), 6.47 (d, J = 16.1 Hz, 1H), 3.69 (s, 3H). LCMS m / z 332.4 [M+H] +< .Step 4. Synthesis of methyl 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]propanoate (C52)

[0295] Method D: Pd(OH) 2 Catalyzed Transfer Hydrogenation .To a suspension of methyl (E)-3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]prop-2-enoate C51 (80 g, 236.5 mmol) in EtOH (1.5 L) under a nitrogen atmosphere was added Pd(OH) 2 (6 g of 20 % w / w 8.5mmol) and ammonium formate (160 g, 2.5 mol). The mixture was heated at reflux for ~3 h, then filtered to remove catalyst. The filtrate was concentrated in vacuo to afford the product as an off-white solid which was used without further purification (82 g, 100%). 1< H NMR (300 MHz, CDCl 3 ) δ 8.18 (s, 1H), 7.65 - 7.47 (m, 2H), 7.27 - 7.14 (m, 2H), 7.14 - 7.00 (m, 1H), 6.76 (ddd, J = 10.8, 9.4, 2.2 Hz, 1H), 3.65 (s, 3H), 3.27 - 3.04 (m, 2H), 2.75 - 2.49 (m, 2H). LCMS m / z 334.3 [M+H] +< .Step 5. Synthesis of 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]propanoic acid (S12)

[0296] Method E: Ester hydrolysis with LiOH. LiOH (67 g, 2.8 mol) was added to a solution of methyl 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]propanoate C52 (217 g, 651.1 mmol) in THF (1 L) and water (100 mL). The mixture was heated at reflux for 2 h, and then allowed to cool overnight. THF was removed by concentration under reduced pressure, and water was added (approx. 1 L). The mixture was cooled on an ice bath and HCl (250 mL of 11.7 M, 2.9 mol) was added to adjust pH to ~ 4. EtOAc (300 mL) was added, and the aqueous layer extracted with further EtOAc (100 mL). Combined organic extracts were dried over sodium sulfate (Na 2 SO 4 ), filtered through a plug of silica gel rinsing with EtOAc. The filtrate was concentrated in vacuo to afford an orange oil (50-75 mL). Heptanes (~ 50 mL) were added and the mixture chilled on dry ice. Upon agitation, a crystalline solid formed. The mixture was allowed to stir on an ice-bath until to allow completion of the crystallization process. The solid was filtered, washed with heptane and air dried to afford the product (208 g, 96%). 1< H NMR (300 MHz, CDCl 3 ) δ 8.15 (s, 1H), 7.60 - 7.46 (m, 2H), 7.27 - 7.15 (m, 2H), 7.09 (dd, J = 9.1, 2.2 Hz, 1H), 6.77 (ddd, J = 10.8, 9.4, 2.2 Hz, 1H), 3.26 - 3.05 (m, 2H), 2.78 - 2.57 (m, 2H). LCMS m / z 320.0 [M+H] +< .Alternative Preparation S12 Step 3. Synthesis of methyl (E)-3-[5, 7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]prop-2-enoate (C51)

[0297] A reactor was charged with 5,7-difluoro-2-(4-fluorophenyl)-1H-indole C50 (4.0 kg, 16.5 mol), CH 2 Cl 2 (37 L) and methyl 3,3-dimethoxypropanoate (2.6 L, 18.1 mol) followed by TFA (3.9 L, 51.0 mol) at ambient temperature. The resulting mixture was heated to reflux for 6 h. The batch was then cooled to 20 °C, charged with n-heptane (2 vol) and filtered. The filter cake was dried under vacuum at 45 °C to afford the product in ~90% yield. 1< H NMR (300 MHz, DMSO-d 6 ) δ 12.63 (s, 1H), 7.76 - 7.54 (m, 4H), 7.55 - 7.39 (m, 2H), 7.18 (ddd, J = 11.1, 9.7, 2.2 Hz, 1H), 6.46 (d, J = 16.1 Hz, 1H), 3.69 (s, 3H). LCMS m / z 332.1 [M+H] +< .Step 4. Synthesis of methyl 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]propanoate (C52)

[0298] Methyl (E)-3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]prop-2-enoate C51 (1.5 kg, 9.06 mol) was slurried with THF (7 L) in a vessel. Pd(OH) 2 (10 g of 20 %w / w, ~50% water, 0.014 mol) was charged. The mixture was purged with N 2 three times, then once with H 2 and the vessel pressurized to 50 psi with H 2 . The mixture was agitated at 20 °C until H 2 uptake ceased. After 1.5 h, the mixture was purged with N 2 (x 3) and filtered through Solka-Floc using a THF (2 vol) rinse. The resulting filtrate was concentrated in vacuo at 45 °C (to 1.5 vol), charged with cyclohexane (1 vol), and concentrated again (to 1.5 vol) at 45 °C. The slurry was cooled to 15-20 °C and filtered. The filter cake was then washed with cold cyclohexane (1 vol), and dried under vacuum at 45 °C to afford the product in 95% yield.Step 5. Synthesis of 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]propanoic acid (S12)

[0299] A mixture of methyl 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]propanoate C52 (9 kg, 27 mmol) in 2-MeTHF (54 L, 6 vol) and MeOH (8.1 L, 0.9 vol) was charged with 20% KOH (2 equiv, 54 mol). The mixture was stirred at 35 °C for 6 h. The mixture was then distilled under vacuum to 27 L (3 vol) and cooled to 10 - 15 °C. Water (7.5 L) and 2-MeTHF (16 L) were charged and the resulting biphasic mixture was pH adjusted with 6 M HCl to a pH ~2. The temperature was adjusted to 20 °C and the phases separated. The organic phase was washed with water (15 L), filtered through celite ®< with 2-MeTHF rinse (18 L, 2 vol), and concentrated under vacuum to 18 L (2 vol). 18 L (2 vol) of n-heptane was charged and the batch again concentrated under vacuum to 18 L (3 vol). This cycle was repeated once more and the batch was seeded. 16 L (1.8 vol) n-heptane was charged and the temperature adjusted to 20 °C. The slurry was stirred for 2 h, filtered and the cake washed with 2 x 18 L (2 x 2 vol) n-heptane. The filter cake was dried under vacuum at 45 °C to afford the desired product in 90% yield. 1< H NMR (300 MHz, CDCl 3 ) δ 8.28 (s, 1H), 7.53 (ddd, J = 8.7, 5.4, 2.8 Hz, 2H), 7.27 - 7.13 (m, 2H), 7.08 (dd, J = 9.1, 2.1 Hz, 1H), 6.76 (ddd, J = 11.3, 9.4, 2.2 Hz, 1H), 3.91 - 3.69 (m, 4H), 3.28 - 3.07 (m, 2H), 2.79 - 2.53 (m, 2H), 2.00 - 1.74 (m, 3H). LCMS m / z 320.4 [M+H] +< .

[0300] Method F: Amide Coupling with HATU. To a solution of 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]-N-[(3S,4S)-4-hydroxy-2-oxo-pyrrolidin-3-yl]propanamide S1 in DMSO (1 mL) was added 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]propanoic acid S12 (25 mg, 0.08 mmol), HATU (33 mg, 0.09 mmol) and NEt 3 (30 µL, 0.22 mmol). The mixture was allowed to stir at room temperature for 2 h. The mixture was then purified by reversed phase chromatography (C18 column; Gradient: MeCN in H 2 O with 0.2 % formic acid) to afford the product (6 mg, 40%). 1< H NMR (300 MHz, CD 3 OD) δ 7.68 (ddd, J = 9.2, 5.1, 2.3 Hz, 2H), 7.37 - 7.19 (m, 3H), 6.75 (ddt, J = 11.4, 9.6, 1.9 Hz, 1H), 4.68 (d, J = 5.1 Hz, 1H), 4.40 (dd, J = 5.1, 3.9 Hz, 1H), 3.65 - 3.57 (m, 1H), 3.26 (d, J = 11.3 Hz, 1H), 3.20 - 3.08 (m, 2H), 2.75 - 2.64 (m, 2H). LCMS m / z 418.1 [M+H] +< . Synthesis of 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]-N-[(3S, 4R)-4-hydroxy-2-oxo-pyrrolidin-3-yl]propanamide (2)

[0301] Method G: Amide Coupling with CDMT. A 2 L 3-neck RB flask with magnetic stirrer, temperature probe and nitrogen inlet was charged with 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]propanoic acid S12 (90.5 g, 283.5 mmol) and (3S,4R)-3-amino-4-hydroxy-pyrrolidin-2-one S2 (39.9 g, 343.6 mmol) in DMF (1.65 L), and stirred for 15 minutes. CDMT (61.1 g, 348 mmol) was added. The mixture was then cooled to ~2 °C on an ice bath. N-methylmorpholine was added (131 mL, 1.2 mol) dropwise over 20 minutes and the mixture was heated at 30 °C overnight. The reaction mixture was added into approx. 4.5 L of ice water, and extracted with EtOAc (1.2 L x 4). The combined organic layers, were washed with 1.2 L of 1 M HCl (x 3) and then water (1.2 L) and brine (1.2 L). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated. The mixture was washed through a silica gel plug (1.8 L of silica gel), first eluting with 25% EtOAc in dichloromethane (8 L) to remove impurities, followed by hot EtOAc (8 L), to elute the product. The EtOAc filtrate was concentrated in vacuo. TBME was then added (400 mL), and the mixture allowed to stirred for overnight. Filtration of the resulting solid afforded the product as a white solid. 62 g, 52%) 1< H NMR (300 MHz, CD 3 OD) δ 7.70 - 7.58 (m, 2H), 7.29 - 7.13 (m, 3H), 6.73 (ddd, J = 11.1, 9.6, 2.2 Hz, 1H), 4.34 (td, J = 7.6, 6.8 Hz, 1H), 4.21 (d, J = 7.8 Hz, 1H), 3.56 (dd, J = 9.9, 7.6 Hz, 1H), 3.20 - 3.04 (m, 3H), 2.65 - 2.53 (m, 2H). LCMS m / z 418.2 [M+H] +< . Optical rotation: [α] D 20.7< = -14.01 (c = 1.0, 10 mg in 1 mL of MeOH).Alternative procedure for synthesis of compound (2) Step 1. Synthesis of methyl (E)-3-[5, 7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]prop-2-enoate (C51)

[0302] A solution of 5,7-difluoro-2-(4-fluorophenyl)-1H-indole C50 (100 g, 1.0 equiv) in dichloromethane (850 mL, 8.5 vol) was agitated at 22 °C. Methyl 3,3-dimethoxypropionate (63 mL, 1.1 equiv) was charged followed by trifluoroacetic acid (96 mL, 3.1 equiv), which was rinsed forward with dichloromethane (25 mL, 0.25 vol). The batch was heated to 38 °C and stirred at that temperature. After 4h, the batch was cooled to 22 °C and charged with n-heptane (200 mL, 2 vol). The mixture was stirred for no less than 1 h at 22 °C. The slurry was filtered, and the reactor and the filter cake were washed with n-heptane (1 x 2 vol (200 mL) and 1 x 3 vol (300 mL)). The resulting solid was dried under vacuum with nitrogen bleed at 45 °C to afford the product C51 (127.7 g, 95% yield).Step 2. Synthesis of methyl 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]propanoate (C52)

[0303] To a hydrogenator was charged methyl (E)-3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]prop-2-enoate C51 (100.4 g, 1.0 equiv) followed by Pd(OH) 2 / C (0.014 equiv). The vessel was sealed and three vacuum / purge cycles with N 2 were performed. 2-MeTHF (2000 mL, 20 vol) was charged using residual vacuum and the resulting mixture was stirred at 22 °C. The vessel was sealed and three vacuum / purge cycles with N 2 were performed followed by one vacuum purge cycle with hydrogen (H 2 ). The temperature was adjusted to 22 °C, and the vessel pressurized with 20 psi H 2 . The mixture was agitated at 22 °C for 4 h. Three vacuum / purge cycles with nitrogen N 2 were performed. The batch was filtered through a pad of Hyflo ®< and the filter cake was rinsed with 2-MeTHF (2 x 300 mL, 2 x 3 vol). The combined filtrates were placed under vacuum and distilled at ≤45.0 °C to 2.0 to 3.0 total volumes. The batch temperature was adjusted to 22 °C and the vessel was charge with n-heptane (1000 mL, 10 vol) over at least 1 h. A vacuum was applied and the filtrate distilled at ≤45.0 °C to 3.5 to 4.5 total volumes. The slurry was cooled to 22 °C and allowed to stir for no less than 1 h. The slurry was filtered and the filter cake was washed with n-heptane (1 x 1 vol (100 mL) and 1 x 0.5 vol (50 mL)). The solids were dried under vacuum with nitrogen bleed at 45 °C to afford the product C52 (91.9 g, 91% yield).Step 3. Synthesis of 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]propanoic acid (S12)

[0304] A mixture of methyl 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]propanoate C52 (80.0 g, 1.0 equiv) and 2-MeTHF (480 mL, 6 vol) was agitated at 22 °C and treated with methanol (72 mL, 0.9 vol). A solution of KOH (27.1 g, 2.0 equiv) in water (107 mL, 1.3 vol) was charged over approximately 20 min. The resulting mixture was heated to an internal temperature of 35 °C and stirred for 3 h. The temperature was adjusted to 22 °C. A vacuum was applied and the mixture was distilled at ≤45 °C to 3.0 total volumes. The internal temperature was adjusted to 12 °C. The mixture was then charged with water (64 mL, 0.8 vol) and 2-MeTHF (304 mL, 3.8 vol). 6 N HCl (75 mL, 0.9 vol) was slowly charged into the mixture with vigorous agitation until the batch attained a pH <3. The internal temperature was adjusted to 22 °C, and the biphasic mixture was stirred for no less than 0.5 h. The stirring was stopped and the phases were allowed to separate for no less than 0.5 h. The lower aqueous phase was removed. Water (160 mL, 2 vol) was charged to the reactor at 22 °C, and the biphasic mixture stirred for no less than 0.5 h. The stirring was stopped, and the phases allowed separated over no less than 0.5 h. The lower aqueous phase was removed and the batch was filtered through a pad of Hyflo ®< . The reactor and filter cake were rinsed with 2-MeTHF (160 mL, 2 vol). A vacuum was applied and the combined filtrates distilled at ≤40.0 °C to 2 - 3 total volumes. The vessel was charged with n-heptane (160 mL, 2 vol), a vacuum was applied and the filtrate distilled at ≤40.0 °C to 2 total volumes (this step was repeated one additional time). The mixture was then charged with additional n-heptane (144 mL, 1.8 vol). The internal temperature was adjusted to 40 °C and stirred for no less than 2 h. The internal temperature was adjusted to 22 °C over a minimum of 5 h and stirred for no less than 16 hours. The slurry was filtered. The filter cake was washed with n-heptane (3 x 40 mL, 3 x 0.5 vol). The solids were dried under vacuum with nitrogen bleed at 45 °C to afford product S12 (72.6 g, 95% yield).Step 4. Synthesis of 3-[5, 7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]-N-[(3S, 4R)-4-hydroxy-2-oxo-pyrrolidin-3-yl]jpropanamide (2)

[0305] A mixture of S12 (50.0 g, 1.0 equiv), (3S,4R)-3-amino-4-hydroxypyrrolidin-2-one hydrochloride S2 (25.1 g, 1.05 equiv), and CDMT (30.3 g, 1.1 equiv) in DMF (250 mL, 5 vol) was agitated and cooled to 0 °C. The reactor was charged with NMM (60 mL, 3.5 equiv) over no less than 1 h, while maintaining the internal temperature at ≤5 °C. The batch was stirred at ~5 °C for no less than 1 h. The batch was warmed to 22 °C over at least 1 h and stirred at 22 °C for 16 h. The batch was cooled to 0 °C. Water (250 mL, 5 vol) was charged, while keeping the internal temperature <20 °C. The mixture was charged with a 90 / 10 mixture of EtOAc / IPA (1000 mL, 20 vol). 6 N HCl (40 mL, 0.8 vol) was then charged, while maintaining an internal temperature <10 °C, until a pH ~1-3 was achieved. The internal temperature was adjusted to 22 °C and the biphasic mixture stirred for no less than 0.5 h. Stirring was stopped and the phases allowed to separate for no less than 0.5 h. The lower aqueous phase was removed. The aqueous layer was back extracted with a 90 / 10 mixture of EtOAc / IPA (2 x 250 mL, 2 x 5 vol) at 22 °C. The combined organic phases from extractions were washed with water (5 x 500 mL, 5 x 10 vol) at 22 °C, by mixing for no less than 0.5 h and settling for no less than 0.5 h for each wash. The batch was polish filtered. A vacuum was applied and the organic phase distilled at <50 °C to 9.5-10.5 total volumes. The mixture was charged with EtOAc (500 mL, 10 vol), vacuum was applied and the organic phase distilled at <50 °C to 9.5-10.5 total volumes (this step was repeated one more time). The mixture was charged with EtOAc (300 mL, 6 vol) and n-heptane (200 mL, 4 vol). The resulting slurry was heated to 50 °C and stirred for no less than 17 h. The mixture was then cooled to 22 °C over 2 h, and stirred for no less than 1 h. The slurry was filtered. The filter cake was washed with 1:1 EtOAc / n-heptane (2 x 150 mL, 2 x 3 vol). The solids were dried under vacuum with nitrogen bleed at ≤45 °C to afford Compound 2 (52.6 g, 80% yield).Re-crystallization of Compound 2

[0306] Compound 2 (37.6 g, 1.0 equiv) was charged to a reactor followed by a 3:1 mixture of IPA / water (240 mL, 6.4 vol). The slurry was heated to an internal temperature of 75 °C. The batch was cooled to an internal temperature of 55 °C and stirred at that temperature for at least 0.5 h. The batch was seeded with 0.5 wt % of a previously generated batch of Compound 2, as a suspension in a mixture of 3:1 IPA / water (4 mL, 0.1 vol). The mixture was stirred at 55 °C for no less than 1.5 h. Water (218 mL, 5.8 vol) was added over minimum period of 5 h while maintaining the temperature at 55 °C. The slurry was cooled to 22 °C over no less than 5 h and stirred for no less than 2 h. The slurry was filtered. The filter cake was washed with 2:3 IPA / water (2 x 114 mL, 2 x 3 vol). The solids were dried under vacuum with nitrogen bleed at ≤45 °C to afford Compound 2 (34.5 g, 92% yield).Form A of Compound 2

[0307] 12.3 kg of Compound 2 was charged to the reactor follow by a 3:1 mixture of 2-propanol / water. Agitation was initiated and the mixture was heated to 75 °C to achieve complete dissolution. The mixture was cooled to 55 °C over 1 hour and agitated at that temperature for 30 minutes. Agitation was continued for 1.5 hours. Water (5.8 vol) was charged over 5 h at 55 °C, after which the mixture was cooled to 22 °C over 6 hours. The mixture was agitated at 22 °C for 2 hours then filtered under vacuum. The resulting wet cake was washed with a 3:1 mixture of 2-propanol / water (2.74 vol x 2) and pulled dry under vacuum. The wet cake was further dried under vacuum with nitrogen bleed at 45°C to yield 11.2 kg of Form A.Hydrate Form A of Compound 2

[0308] 200mg of Compound 2 was charged with 10 mL of water. The slurry was cooled to 5°C and allowed to stir. Hydrate A was observed after 3 days of stirring.Hydrate Form B of Compound 2 Form A

[0309] 1g of Compound 2 was charged with 50 mL of water. The slurry was cooled to 5°C and allowed to stir. Hydrate B was observed after 18 hours of stirring.Hydrate Form C of Compound 2 Form A

[0310] A solution of Compound 2 in MeOH was sealed into a system with water vapor, allowing the vapor to interact with the solution. The precipitate was isolated and analyzed to be Hydrate Form C.Hydrate Form D of Compound 2 Form A

[0311] A suspension of Form A was magnetically stirred at 50°C for 2~5 days in EtOH before the solid was isolated and analyzed. The resulted solid was Hydrate Form D.Hydrate Form E of Compound 2 Form A

[0312] A clear solution of Compound 2 in MeOH was covered using parafilm with 3~4 pinholes, and kept at room temperature allowing the solvent to evaporate slowly. The resulted form was Hydrate Form E.Hydrate Form F of Compound 2 Form A

[0313] A saturated solution of Compound 2 in ACN was cooled from 50 °C to 5 °C at a rate of 0.1 °C / min. The precipitate was equilibrated at 5 °C before isolation and analysis. The resulted solid was Hydrate Form F.MTBE Solvate of Compound 2 Form A

[0314] MTBE was added into a clear solution of Compound 2 in MeOH. The precipitate was stirred at RT / 5 °C before isolated and analyzed. The resulted solid was the MTBE solvate.DMF Solvate of Compound 2 Form A

[0315] Water was added into a clear solution of Compound 2 in DMF. The precipitate was stirred at RT / 5 °C before isolated and analyzed. The resulted solid was the DMF solvate.Amorphous Form of Compound 2 Form A

[0316] The amorphous form was made by spray drying a solution of Compound 2 at ~ 7% solid load in 95:5 w / w acetone: water. Synthesis of 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]-N-[(3S)-2-oxopyrrolidin-3-yl]propanamide (3)

[0317] Method H: Amide coupling with T3P. A 3L flask was charged with 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]propanoic acid S12 (41 g, 128.4 mmol), (3S)-3-aminopyrrolidin-2-one (16.5 g, 164.8 mmol), 4-methylmorpholine (48 mL, 436.6 mmol) and DMF (450 mL). 2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide solution (92 mL of 50 %w / w, 154.5 mmol) was added and the reaction allowed to stir for 24 h at room temperature. The reaction was diluted with water (2 L) and the resultant precipitate filtered off, and dried under vacuum to afford a tan solid which was then recrystallized from hot EtOH (2 L) to afford the product (43.9 g, 84%). 1< H NMR (300 MHz, DMSO-d 6 ) δ 11.68 (s, 1H), 8.19 (d, J = 8.0 Hz, 1H), 7.83 (s, 1H), 7.76 - 7.63 (m, 2H), 7.44 - 7.32 (m, 2H), 7.27 (dd, J = 9.6, 2.2 Hz, 1H), 6.97 (ddd, J = 11.7, 9.8, 2.2 Hz, 1H), 4.28 (dt, J = 10.3, 8.3 Hz, 1H), 3.16 (dd, J = 9.2, 4.3 Hz, 2H), 3.04 - 2.92 (m, 2H), 2.50 - 2.39 (m, 2H), 2.27 (ddt, J = 12.6, 8.5, 4.2 Hz, 1H), 1.78 - 1.58 (m, 1H).LCMS m / z 402.4 [M+H] +< . Synthesis of [(3R, 4S)-4-[3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]propanoylamino]-5-oxo-pyrrolidin-3-yl] acetate (4)

[0318] To 3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]-N-[(3S,4R)-4-hydroxy-2-oxo-pyrrolidin-3-yl]propanamide 2 (25 mg, 0.06 mmol) in CH 2 Cl 2 (1 mL) was added pyridine (1 mL, 12.36 mmol) and Ac 2 O (100 µL, 1.1 mmol). The mixture was allowed to stir overnight at room temperature. The reaction was concentrated in vacuo and purified by reversed phase chromatography to afford the product (21 mg, 76%). 1< H NMR (300 MHz, CD 3 OD) δ 7.64 - 7.41 (m, 2H), 7.23 - 7.01 (m, 3H), 6.63 (ddd, J = 11.1, 9.6, 2.2 Hz, 1H), 5.13 (ddd, J = 7.9, 6.9, 5.9 Hz, 1H), 4.22 (d, J = 6.9 Hz, 1H), 3.67 (dd, J = 10.5, 7.9 Hz, 1H), 3.19 - 3.10 (m, 1H), 3.08 - 2.94 (m, 2H), 2.55 - 2.35 (m, 2H), 1.94 (s, 3H). LCMS m / z 460.0 [M+H] +< .Compounds 5-17

[0319] Compounds 5-17 (see Table 2) were prepared in a single step from intermediate S12 using the appropriate reagent, and using the amide formation methods as described for compounds 1-3 (using coupling reagents such as HATU, CDMT, or T3P). Amines were prepared by methods described above or obtained from commercial sources. Any modifications to methods are noted in Table 2 and accompanying footnotes. Table 2. Method of preparation, structure and physicochemical data for compounds 5-17 Compound Product Amine Reagent Amine Coupling Method 1< H NMR; LCMS m / z [M+H] +< 5 Method F. 1< 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.71 (s, 1H), 11.23 (s, 1H), 8.53 (d, J= 7.6 Hz, 1H), 7.71 - 7.63 (m, 2H), 7.37 (t, J = 8.9 Hz, 2H), 7.24 (dd, J= 9.6, 2.2 Hz, 1H), 6.98 (ddd, J = 11.6, 9.7, 2.2 Hz, 1H), 4.42 - 4.32 (m, 1H), 3.02 - 2.93 (m, 2H), 2.79 (dd, J = 17.6, 9.3 Hz, 1H), 2.46 - 2.32 (m, 3H). LCMS m / z 416.1 [M+H] +< .6 Method F. 1< 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.69 (s, 1H), 8.20 (dd, J = 10.2, 8.1 Hz, 1H), 7.96 (d, J= 10.2 Hz, 1H), 7.73 - 7.64 (m, 2H), 7.37 (t, J= 8.9 Hz, 2H), 7.27 (dt, J = 9.7, 2.2 Hz, 1H), 6.98 (ddd, J = 11.7, 9.8, 2.2 Hz, 1H), 4.40 - 4.28 (m, 1H), 3.07 - 2.84 (m, 3H), 2.47 - 2.37 (m, 2H), 1.95 - 1.80 (m, 1H), 1.21 (q, J= 11.0 Hz, 1H), 1.10 (d,J = 6.0 Hz, 3H). LCMS m / z 446.3 [M+H] +< .7 Method F. 1< 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.69 (s, 1H), 8.20 (d, J = 8.1 Hz, 1H), 7.87 (s, 1H), 7.73 - 7.65 (m, 2H), 7.37 (t, J = 8.8 Hz, 2H), 7.28 (dd, J = 9.6, 2.2 Hz, 1H), 6.98 (ddd, J = 11.6, 9.7, 2.2 Hz, 1H), 4.82 (t, J = 5.4 Hz, 1H), 4.35 (q, J = 9.2 Hz, 1H), 3.02 - 2.92 (m, 3H), 2.48 - 2.39 (m, 2H), 2.36 - 2.25 (m, 1H), 1.44 - 1.32 (m, 1H). LCMS m / z 416.3 [M+H] +< .8 Method F. 1< 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.69 (s, 1H), 8.16 (d, J = 8.1 Hz, 1H), 7.88 (s, 1H), 7.73 - 7.65 (m, 2H), 7.37 (t, J= 8.9 Hz, 2H), 7.27 (dd, J = 9.6, 2.2 Hz, 1H), 6.98 (ddd, J = 11.7, 9.9, 2.3 Hz, 1H), 4.92 (t, J = 5.3 Hz, 1H), 4.38 (q, J= 9.0 Hz, 1H), 3.34 (s, 1H), 3.02 - 2.93 (m, 3H), 2.55 (s, 14H), 2.43 (dd, J= 9.4, 6.6 Hz, 2H), 2.16 (dd, J = 12.7, 9.0 Hz, 1H), 1.77 (dt, J = 12.5, 9.0 Hz, 1H). LCMS m / z 432.0 [M+H] +< .9 Method F. 1< 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.69 (s, 1H), 8.28 - 8.18 (m, 2H), 7.73 - 7.65 (m, 2H), 7.37 (t, J = 8.9 Hz, 2H), 7.27 (dd, J = 9.5, 2.2 Hz, 1H), 6.98 (ddd, J = 11.6, 9.8, 2.2 Hz, 1H), 4.54 - 4.13 (m, 4H), 3.75 (d, J = 20.9 Hz, 1H), 3.02 - 2.93 (m, 2H), 2.44 (t, J = 8.1 Hz, 2H), 2.37 - 2.28 (m, 1H), 1.47 - 1.35 (m, 1H). LCMS m / z 434.0 [M+H] +< .10 Method F. 1< 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.71 (s, 1H), 8.23 (d, J= 8.3 Hz, 1H), 8.16 (s, 1H), 7.73 - 7.65 (m, 2H), 7.42 - 7.32 (m, 2H), 7.27 (dd, J = 9.7, 2.2 Hz, 1H), 6.98 (ddd, J = 11.6, 9.7, 2.2 Hz, 1H), 4.43 (d, J = 4.2 Hz, 1H), 4.38 - 4.27 (m, 2H), 3.77 (d, J = 8.7 Hz, 1H), 3.71 (s, 1H), 3.02 - 2.93 (m, 2H), 2.44 (dd, J = 9.5, 6.5 Hz, 2H), 2.23 - 2.02 (m, 1H), 1.94 - 1.81 (m, 1H). LCMS m / z 434.0 [M+H] +< .11 Method F. 1< 1< H NMR (300 MHz, CD 3 OD) δ 8.18 (d, J = 8.7 Hz, 1H), 7.81 - 7.53 (m, 2H), 7.38 - 7.11 (m, 3H), 6.74 (ddd, J = 11.1, 9.6, 2.2 Hz, 1H), 4.22 - 4.07 (m, 1H), 3.40 (dd, J = 9.8, 8.0 Hz, 1H), 3.17 (ddd, J = 8.9, 6.2, 1.4 Hz, 2H),2.93 (t, J= 9.5 Hz, 1H), 2.68 - 2.57 (m, 2H), 2.39 - 2.19 (m, 1H), 1.02 (d, J= 6.7 Hz, 3H). LCMS m / z 416.3 [M+H] +< .12 Method F. 1< 1< H NMR (300 MHz, CD 3 OD) δ 7.73 - 7.57 (m, 2H), 7.30 - 7.15 (m, 3H), 6.75 (ddd, J = 11.1, 9.6, 2.2 Hz, 1H), 4.36 (td, J = 7.6, 6.9 Hz, 1H), 4.23 (d, J = 7.8 Hz, 1H), 3.58 (dd, J = 9.9, 7.6 Hz, 1H), 3.21 - 2.98 (m, 3H), 2.68 - 2.46 (m, 2H). LCMS m / z 418.0[M+H] +< .13 Method F. 1< 1< H NMR (300 MHz, CDCl 3 ) δ 8.16 (s, 1H), 7.56 (dd, J = 8.7, 5.3 Hz, 2H), 7.22 (t, J = 8.6 Hz, 2H), 7.11 (dd,J = 9.1, 2.1 Hz, 1H), 6.84 - 6.67 (m, 1H), 5.93 (d, J= 15.8 Hz, 2H), 4.38 - 4.21 (m, 1H), 3.39 (dd, J = 9.6, 3.8 Hz, 2H), 3.19 (dd, J = 8.5, 6.9 Hz, 2H), 2.78 (tt, J = 8.5, 3.9 Hz, 1H), 2.56 (td, J = 7.6, 3.9 Hz, 2H). LCMS m / z 402.2 [M+H] +< .14 Method F 1< 1< H NMR (300 MHz, CD 3 OD) δ 7.71 - 7.48 (m, 2H), 7.31 - 7.07 (m, 3H), 6.79 - 6.60 (m, 1H), 3.38 (td, J = 9.8, 2.4 Hz, 1H), 3.28 - 3.22 (m, 1H), 3.15 - 3.01 (m, 2H), 2.61 - 2.38 (m, 3H), 1.95 (ddd, J = 12.7, 7.6, 2.4 Hz, 1H), 1.30 (s, 3H). LCMS m / z 416.1 [M+H] +< .15 Method . 1< 1< H NMR (300 MHz, CD 3 OD) δ 7.73 - 7.58 (m, 2H), 7.25 (td, J = 9.0, 2.3 Hz, 3H), 6.74 (ddd, J = 11.1, 9.6, 2.2 Hz, 1H), 4.68 (d, J = 5.0 Hz, 1H), 4.44 - 4.33 (m, 1H), 3.61 (dd, J = 11.3, 4.0 Hz, 1H), 3.26 (d, J = 11.3 Hz, 1H), 3.23 - 3.05 (m, 2H), 2.77 - 2.59 (m, 2H). LCMS m / z 418.1 [M+H] +< 16 Method F 1< 1< H NMR (400 MHz, DMSO-d6) δ 11.71 (s, 1H), 11.23 (s, 1H), 8.53 (d, J = 7.6 Hz, 1H), 7.71 - 7.63 (m, 2H), 7.37 (t, J = 8.9 Hz, 2H), 7.24 (dd, J = 9.6, 2.2 Hz, 1H), 6.98 (ddd, J = 11.6, 9.6, 2.1 Hz, 1H), 4.37 (ddd, J = 9.1, 7.5, 5.5 Hz, 1H), 3.02 - 2.92 (m, 2H), 2.79 (dd, J = 17.6, 9.3 Hz, 1H), 2.42 (s, 1H), 2.47 - 2.32 (m, 2H). LCMS m / z 416.2 [M+H] +< .17 Method F 1< 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.69 (s, 1H), 8.31 (d, J = 8.0 Hz, 1H), 7.93 (s, 1H), 7.74 - 7.64 (m, 2H), 7.37 (t, J = 8.9 Hz, 2H), 7.27 (dd, J = 9.6, 2.2 Hz, 1H), 6.98 (ddd, J = 11.6, 9.7, 2.2 Hz, 1H), 4.49 (q, J = 8.9 Hz, 1H), 2.99 - 2.94 (m, 2H), 2.45 (dd, J = 9.3, 6.7 Hz, 2H), 2.09 (dd, J = 12.4, 8.8 Hz, 1H), 1.99 (dd, J = 12.4, 10.1 Hz, 1H), 0.77 (dt, J = 10.8, 5.4 Hz, 1H), 0.67 (dt, J = 10.5, 5.1 Hz, 1H), 0.55 (ddt, J = 21.1, 9.9, 6.0 Hz, 2H).LCMS m / z 428.0 [M+H] +< .1. Purification by reversed-phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: 10-100% MeCN in H 2 O with 0.2 % formic acid. Step 1. Synthesis of 1-Bromo-4-fluorobenzene-2, 3, 5, 6-d 4 (C54)

[0320] A solution of bromine (34.8g, 218 mmol, 1.1 equiv) in CH 2 Cl 2 (40 mL) was added dropwise to a solution of 1-fluorobenzene-2,3,4,5,6-d 5 C53 (20 g, 200 mol, 1 equiv) and FeCl 3 (0.6 g, 3.7 mmol, 0.02 equiv) in CH 2 Cl 2 (40 mL) at 18-20 °C. After stirring at room temperature for 1.5 h, the mixture was washed with water (3 x 50 mL), sodium thiosulfate solution (0.72 M, 50 mL) and additional water (50 mL). The organic layer was dried over sodium sulfate and filtered. A small scale run of this reaction (5 g of 1-fluorobenzene-2,3,4,5,6-ds) which was processed in same manner was combined for distillation to remove solvent. The combined organic layers were evaporated under atmospheric distillation to remove dichloromethane and then distilled to afford the product (33.3 g, 75% yield, b.p. 150-152 °C) as a colorless oil.Step 2. ((4-Fluorophenyl-2,3,5,6-d 4 )ethynyl)trimethylsilane (C55 )

[0321] (Trimethylsilyl) acetylene (32.9 mL, 232.5 mmol, 1.3 equiv), copper(I) iodide (3.5 g, 18.6 mmol, 0.1 equiv) and PdCl 2 (PPh 3 ) 2 (6.5 g, 9.3 mmol, 0.05 equiv) were added to a mixture of 1-Bromo-4-fluorobenzene-2,3,5,6-d 4 C54 (33.3 g, 186.0 mmol, 1 equiv) in NEt 3 (310 mL) at room temperature. The mixture was purged with nitrogen for 10 minutes, then stirred at 70-80 °C for 18 h. After cooling to room temperature, the mixture was diluted with EtOAc (300 mL), filtered through celite ®< , which was washed with EtOAc (2 x 100 mL). The filtrate was concentrated under reduced pressure at 30 °C to afford the product (45.3 g) as a dark-brown oil, which was used subsequently.Step 3. 1-Ethynyl-4-fluorobenzene-2,3,5,6-d 4 (C56 )

[0322] Potassium carbonate (128.5 g, 930 mmol, 5 equiv) was added to a mixture of ((4-Fluorophenyl-2,3,5,6-d 4 )ethynyl)trimethylsilane C55 (45.3 g, 186 mmol, 1 equiv) in MeOH (620 mL) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was filtered through celite ®< , washing with MeOH (50 mL) and hexanes (3 x 50 mL). The filtrate was diluted with water (2000 mL) and separated. The aqueous layer was extracted with hexanes (3 x 500 mL). The combined organic layers were washed with water (200 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure (50 mbar, 5 °C) to give the product (30 g, theoretical yield 23.09 g) as a dark oil. (Note: 1-Ethynyl-4-fluorobenzene-2,3,5,6-d 4 is volatile, and it was co-distilled with other solvents (MeOH, hexanes) under reduced pressure or under atmospheric distillation. The crude 1-Ethynyl-4-fluorobenzene-2,3,5,6-d 4 C56 was used in next step without column purification in order to minimize the loss during evaporation of solvents.)Step 4. 2, 4-Difluoro-6-((4-fluorophenyl-2,3, 5, 6-d 4 )ethynyl)aniline (C58 )

[0323] A mixture of crude 2,4-difluoro-6-iodoaniline C57 (59.7 g, 58% purity, 135.8 mmol, 1 equiv) and crude 1-Ethynyl-4-fluorobenzene-2,3,5,6-d4 C56 (28.1 g, 60% purity, 135.80 mmol, 1 equiv) in NEt3 (550 mL) was purged with nitrogen for 10 minutes. CuI (5.2 g, 27.2 mmol, 0.2 equiv) and Pd(PPh 3 )Cl 2 (9.5 g, 13.6 mmol, 0.1 equiv) were added. The mixture was stirred at room temperature for 20 h, and then the mixture was concentrated under reduced pressure at 40°C. The residue was purified twice over silica gel (800 g silica gel, dry-loading, eluting each time with a gradient of 0 to 10% dichloromethane in heptanes) to give the product C58 (40.5 g) as a brown solid which was used in subsequent steps without further purification. (This material still contained some unreacted 2,4-difluoro-6-iodoaniline (40% based on LCMS)).Step 5. 5, 7-Difluoro-2-(4fluorophenyl-2,3,5,6-d 4 )-1H-indole (C59 )

[0324] A solution of 2,4-Difluoro-6-((4-fluorophenyl-2,3,5,6-d 4 )ethynyl)aniline C58 (39.5 g, 60% purity, 157.2 mmol, 1 equiv) in DMF (400 mL) was purged with nitrogen for 10 minutes. CuI (3.0 g, 15.7 mmol, 0.1 equiv) was added, and the mixture was purged with nitrogen for an additional 10 minutes. The mixture was heated at 145 °C for 20 h and cooled to room temperature. The mixture was concentrated under reduced pressure at 60 °C to remove most of DMF. The residue was diluted with water (500 mL) and t-butyl methyl ether (300 mL). The mixture was filtered through Celite ®< , which was washed with t-butyl methyl ether (100 mL). The layers of the filtrate were separated and the aqueous layer was extracted with t-butyl methyl ether (2 x 200 mL). The combined organic layers were washed with saturated brine (500 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure at 40 °C. Purification by silica gel chromatography (Gradient: 0-10% EtOAc in heptanes) afforded 5,7-Difluoro-2-(4-fluorophenyl-2,3,5,6-d 4 )-1H-indole as an orange-brown solid (19 g, 80% yield).Step 6. Methyl (E)-3-(5, 7-difluoro-2-(4-fluorophenyl-2,3,5,6-d 4 )-1H-indol-3-yl)acrylate (C60 )

[0325] Methyl 3,3-dimethoxypropanoate (11.8 mL, 83.2 mmol, 1.1 equiv) and TFA (31.9 mL, 415.9 mmol, 5.5 equiv) were added to a solution of 5,7-Di...

Claims

1. At least one entity chosen from compounds of Formula (I): pharmaceutically acceptable salts thereof, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing, wherein: (i) each R1 is independently chosen from halogen groups, hydroxy, cyano, C1-C4 linear, branched, and cyclic alkyl groups, C2-C4 linear, branched, and cyclic alkenyl groups, C1-C4 linear, branched, and cyclic hydroxyalkyl groups, C1-C4 linear, branched, and cyclic alkoxy groups, C1-C4 linear, branched, and cyclic haloalkyl groups, C1-C4 linear, branched, and cyclic haloalkoxy groups, benzyloxy groups, 3 to 6-membered heterocycloalkenyl groups, 3 to 6-membered heterocycloalkyl groups, and 5 and 6-membered heteroaryl groups, (ii) each R2 is independently chosen from halogen groups, cyano, C1-C4 linear, branched, and cyclic alkoxy groups, C1-C4 linear, branched, and cyclic haloalkoxy groups, C1-C4 linear, branched, and cyclic alkyl groups, and C1-C4 linear, branched, and cyclic haloalkyl groups; (iii) m is chosen from 0, 1, 2, 3, and 4; (iv) n is chosen from 0, 1, 2, 3, 4, and 5; (v) Y is chosen from divalent C1-C4 linear and branched alkyl groups and divalent C1-C4 linear and branched thioalkyl groups, wherein the divalent alkyl groups and divalent thioalkyl groups are optionally substituted with at least one group chosen from C1-C4 alkyl groups, halogen groups, and hydroxy; (vi) each of R3 and R4 is independently chosen from hydrogen, C1-C3 linear, branched, and cyclic alkyl groups, C1-C3 linear, branched, and cyclic hydroxyalkyl groups, and C1-C3 linear, branched, and cyclic haloalkyl groups, or R3 and R4, together with the carbon atom to which they are attached, form a C3-C6 cycloalkyl group or carbonyl group; (vii) each of R5 and R6 is independently chosen from hydrogen, hydroxy, C1-C4 linear, branched, and cyclic alkyl groups, C1-C4 linear, branched, and cyclic haloalkyl groups, and -OC(O)C1-C4 linear, branched, and cyclic alkyl groups; and (viii) each of R7, R8, and R9 is independently chosen from hydrogen, C1-C4 linear, branched, and cyclic alkyl groups, and C1-C4 linear, branched, and cyclic haloalkyl groups.

2. The at least one entity according to claim 1, wherein Y is chosen from divalent C1-C3 linear and branched alkyl groups and divalent C1-C3 linear and branched thioalkyl groups, wherein the divalent alkyl groups and divalent thioalkyl groups are optionally substituted with at least one group chosen from C1-C4 alkyl groups, halogen groups, and hydroxy.

3. The at least one entity according to claim 1 or claim 2, wherein Y is divalent ethyl optionally substituted with at least one group chosen from C1-C4 alkyl groups, halogen groups, and hydroxy.

4. The at least one entity according to claim 1 or claim 2, wherein Y is divalent thiomethyl optionally substituted with at least one group chosen from C1-C4 alkyl groups, halogen groups, and hydroxy.

5. The at least one entity according to any one of claims 1 to 4, wherein the at least one entity is chosen from compounds of Formula II: pharmaceutically acceptable salts thereof, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing, wherein: (i) each R1 is independently chosen from halogen groups, cyano, methyl, cyclopropyl, ispropyl, C2-C3 linear and branched alkenyl groups, hydroxypropyl groups, methoxy, dihydrofuran groups, and furan groups; (ii) each R2 is independently chosen from fluoro, cyano, and methyl; (iii) m is chosen from 0, 1, 2, and 3; (iv) n is chosen from 0, 1, and 2; and (v) Y is divalent ethyl or divalent thiomethyl optionally substituted with at least one group chosen from fluoro, methyl, and hydroxy.

6. The at least one entity according to any one of claims 1 to 4 chosen from compounds of Formula IIIa, IIIb or IIIc: pharmaceutically acceptable salts thereof, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing, wherein: (i) each R1 is independently chosen from fluoro, chloro, bromo, cyano, methyl, cyclopropyl, ethyl, hydroxypropyl, isopropyl, propen-2-yl, dihydrofuran, furan, and methoxy; (ii) each R2 is independently chosen from fluoro, bromo, cyano, and methyl; and (iii) Y is divalent ethyl or divalent thiomethyl optionally substituted with at least one group chosen from fluoro, methyl, and hydroxy.

7. The at least one entity according to claim 1, wherein the at least one entity is chosen from: 123 456 789 101112 131415 161718 192021 222324 252627 282930 313233 343536 373839 404142 434445 464748 495051 525354 555657 585960 616263 646566 676869 707172 737475 767778 798081 828384 858687 888990 919293 949596 979899 100101102 103104105 106107108 109110111 112113114 115116117 118119120 121122123 124125126 127128129 130131132 133134135 pharmaceutically acceptable salts thereof, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing.

8. The at least one entity according to claim 7, wherein the at least one entity is chosen from Compound 2 pharmaceutically acceptable salts thereof, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing.

9. The at least one entity according to claim 7 or claim 8, wherein the at least one entity is chosen from Compound 2 and pharmaceutically acceptable salts thereof.

10. The at least one entity according to any one of claims 7 to 9, wherein the at least one entity is Compound 2 11. The at least one entity according to claim 7, wherein the at least one entity is chosen from Compound 87 pharmaceutically acceptable salts thereof, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing.

12. The at least one entity according to claim 7 or claim 11, wherein the at least one entity is chosen from Compound 87 and pharmaceutically acceptable salts thereof.

13. The at least one entity according to any one of claims 7, 11, and 12, wherein the at least one entity is Compound 87 14. The at least one entity according to any one of claims 8 to 10, wherein the at least one entity is Form A of Compound 2: characterized by: (i) an X-ray powder diffractogram having a signal at at least two two-theta values chosen from 9.5 ± 0.2, 13.2 ± 0.2, 14.4 ± 0.2, 19.2 ± 0.2, 19.5 ± 0.2, 19.8 ± 0.2, 26.3 ± 0.2, 26.7 ± 0.2, and 28.6 ± 0.2; or (ii) a 13C NMR spectrum having a signal at at least three ppm values chosen from 178.7 ± 0.2 ppm, 154.4 ± 0.2 ppm, 127.8 ± 0.2 ppm, 125.2 ± 0.2 ppm, 102.0 ± 0.2 ppm, 59.3 ± 0.2 ppm, 38.9 ± 0.2 ppm, and 24.4 ± 0.2 ppm; or (iii) a 19F NMR spectrum having a signal at at least one ppm value chosen from - 116.0 ± 0.2 ppm, -119.7 ± 0.2 ppm, and -138.1 ± 0.2 ppm.

15. The at least one entity according to any one of claims 8 to 10, wherein the at least one entity is selected from: Form A of Compound 2, according to claim 14; Hydrate Form A of Compound 2, characterized by an X-ray powder diffractogram having a signal at at least two two-theta values chosen from 12.2 ± 0.2, 19.0 ± 0.2, 19.1 ± 0.2, 19.6 ± 0.2, 20.2 ± 0.2, 22.7 ± 0.2, 24.2 ± 0.2, 25.4 ± 0.2, and 25.5 ± 0.2; Hydrate Form B of Compound 2, characterized by an X-ray powder diffractogram having a signal at at least two two-theta values chosen from 3.8 ± 0.2, 9.0 ± 0.2, 9.3 ± 0.2, 18.7 ± 0.2, 19.1 ± 0.2, 20.8 ± 0.2, 21.1 ± 0.2, 24.6 ± 0.2, and 26.8 ± 0.2; Hydrate Form C of Compound 2, characterized by an X-ray powder diffractogram having a signal at at least two two-theta values chosen from 3.7 ± 0.2, 10.4 ± 0.2, 10.7 ± 0.2, 13.2 ± 0.2, 14.6 ± 0.2, 15.7 ± 0.2, 18.3 ± 0.2, 21.8 ± 0.2, and 24.9 ± 0.2; Hydrate Form D of Compound 2, characterized by an X-ray powder diffractogram having a signal at at least two two-theta values chosen from 4.1 ± 0.2, 5.0 ± 0.2, 7.7 ± 0.2, 8.2 ± 0.2, and 15.2 ± 0.2; Hydrate Form E of Compound 2, characterized by an X-ray powder diffractogram having a signal at at least two two-theta values chosen from 6.5 ± 0.2, 7.7 ± 0.2, 11.4 ± 0.2, 14.3 ± 0.2, and 18.9 ± 0.2; Hydrate Form F of Compound 2, characterized by an X-ray powder diffractogram having a signal at at least two two-theta values chosen from 3.8 ± 0.2, 7.6 ± 0.2, and 11.4 ± 0.2; MTBE Solvate Form of Compound 2, characterized by an X-ray powder diffractogram having a signal at at least two two-theta values chosen from 6.0 ± 0.2, 6.8 ± 0.2, 8.4 ± 0.2, 18.0 ± 0.2, 19.4 ± 0.2, and 20.2 ± 0.2; DMF Solvate Form of Compound 2, characterized by an X-ray powder diffractogram having a signal at at least two two-theta values chosen from 5.6 ± 0.2, 9.3 ± 0.2, 15.3 ± 0.2, 18.0 ± 0.2, and 20.1 ± 0.2; and Amorphous Form of Compound 2, characterized by a 13C NMR spectrum having a signal at at least three ppm values chosen from 174.7 ± 0.2 ppm, 161.3 ± 0.2 ppm, 130.2 ± 0.2 ppm, 120.9 ± 0.2 ppm, 74.7 ± 0.2 ppm, and 20.5 ± 0.2 ppm.

16. The at least one entity according to any one of claims 11 to 13, wherein the at least one entity is selected from: Form A of Compound 87, characterized by an X-ray powder diffractogram having a signal at at least two two-theta values chosen from 4.7 ± 0.2, 9.0 ± 0.2, 14.2 ± 0.2, 16.7 ± 0.2, 21.0 ± 0.2, 21.2 ± 0.2, 22.1 ± 0.2, 22.9 ± 0.2, 23.1 ± 0.2, and 24.5 ± 0.2; Hydrate Form of Compound 87, characterized by an X-ray powder diffractogram having a signal at at least two two-theta values chosen from 9.3 ± 0.2, 10.0 ± 0.2, 10.9 ± 0.2, 12.1 ± 0.2, 15.0 ± 0.2, 20.0 ± 0.2, 20.5 ± 0.2, 20.8 ± 0.2, 21.3 ± 0.2, and 24.8 ± 0.2; IPAc Solvate Form of Compound 87, characterized by an X-ray powder diffractogram having a signal at at least two two-theta values chosen from 5.0 ± 0.2, 9.9 ± 0.2, 11.5 ± 0.2, 11.7 ± 0.2, 12.0 ± 0.2, 16.0 ± 0.2, 18.8 ± 0.2, 22.0 ± 0.2, and 23.1 ± 0.2; and Amorphous Form of Compound 87, characterized by a 13C NMR spectrum having a signal at at least one ppm value chosen from 119.5 ± 0.2 ppm, 37.2 ± 0.2 ppm, and 21.2 ± 0.2 ppm.

17. A pharmaceutical composition comprising at least one entity according to any one of claims 1 to 16 and a pharmaceutically acceptable carrier.

18. The at least one entity according to any one of claims 1 to 16, or the pharmaceutical composition according to claim 17, for use in a method of treating focal segmental glomerulosclerosis and / or non-diabetic kidney disease, the method comprising administering to a patient in need thereof the at least one entity according to any one of claims 1 to 12 or the pharmaceutical composition according to claim 13.

19. A method of preparing a compound of formula C51 a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, comprising reacting a compound of formula C50 with methyl 3,3-dimethoxypropionate and at least one acid.

20. A method of preparing a compound of formula C52 a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, comprising: reacting a compound of formula 51 with at least one catalytic reducing agent.

21. A method of preparing a compound of formula S12 a salt thereof, or a deuterated derivative of any of the foregoing, comprising reacting a compound of formula C52 with at least one base or at least one acid.

22. A method of preparing Compound 2 a salt thereof, or a deuterated derivative of any of the foregoing, comprising heating a solution comprising a compound of formula S12 with at least one compound of formula S2 and at least one peptide bond forming reagent.

23. A method of preparing a compound of formula C99 a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, comprising reacting a compound of formula C98 with methyl 3,3-dimethoxypropionate and at least one acid.

24. A method of preparing a compound of formula C100 a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, comprising: reacting a compound of formula C99 with at least one catalytic reducing agent.

25. A method of preparing a compound of formula C101 a salt thereof, or a deuterated derivative of any of the foregoing, comprising reacting a compound of formula C100 with at least one base or at least one acid.

26. A method of preparing Compound 87 a salt thereof, or a deuterated derivative of any of the foregoing, comprising heating a solution comprising a compound of formula C101 with at least one compound of formula S2 and at least one peptide bond forming reagent.

27. A method of preparing a compound of formula C101 a salt thereof, or a deuterated derivative of any of the foregoing, comprising reacting a compound of formula C104 with phenyl hydrazine and at least one acid, optionally wherein the at least one acid is chosen from mineral acids, sulfonic acids, and Lewis acids.