WO2025218772A1

WO2025218772A1 - Solid forms comprising a bruton's tyrosine kinase degrader and uses therefor

Info

Publication number: WO2025218772A1
Application number: PCT/CN2025/089757
Authority: WO
Inventors: Mengyuan XIA; Zhi Zhong; Xianzhao Kuang; Zhiyu Yin; Juntao Liu; Zilong ZHANG; Huaqing Liu; Zhiwei Wang; Hexiang Wang
Original assignee: BeiGene Switzerland GmbH; Beigene Suzhou Co Ltd
Current assignee: BeiGene Switzerland GmbH; Beigene Suzhou Co Ltd
Priority date: 2024-04-19
Filing date: 2025-04-18
Publication date: 2025-10-23
Anticipated expiration: 2026-10-19

Abstract

Provided herein are solid forms and methods of prepapation relating to (R) -3- (tert-butyl) -N-(1- (4- (6- (6- (4- ( (1- (4- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) phenyl) piperidin-4-yl) methyl) piperazin-1-yl) pyridin-3-yl) -7H-pyrrolo [2, 3-d] pyrimidin-4-yl) -2-methylphenyl) ethyl) -1,2,4-oxadiazole-5-carboxamide.

Description

SOLID FORMS COMPRISING A BRUTON’S TYROSINE KINASE DEGRADER AND USES THEREFOR

1. FIELD

Provided herein are solid forms comprising (R) -3- (tert-butyl) -N- (1- (4- (6- (6- (4- ( (1- (4- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) phenyl) piperidin-4-yl) methyl) piperazin-1-yl)pyridin-3-yl) -7H-pyrrolo [2, 3-d] pyrimidin-4-yl) -2-methylphenyl) ethyl) -1, 2, 4-oxadiazole-5-carboxamide ( “Compound 1” ) and the method for preparation thereof.

2. BACKGROUND

Bruton’s tyrosine kinase (BTK) belongs to the Tec tyrosine kinase family primarily expressed in most hematopoietic cells such as B cells. BTK plays an important role in B-cell receptor (BCR) and FcR signaling pathways, which involve in B cell development, differentiation (Khan, Immunol. Res. 23: 147, 2001) .

Inhibition of BTK has been shown to affect cancer development (B cell malignancies) . Inhibition of BTK has also been reported via alternative strategies, such as through degradation of BTK. WO2021219070 discloses BTK degraders including Compound 1 having the following structure for use in treating cancer.

Provided here are unexpected discoveries of novel solid forms of Compound 1, having surprising and useful properties such as good bioavailability and chemical and physical stability.

Citation or identification of any reference in this application is not to be construed as an admission that the reference is prior art to the present application.

3. SUMMARY

Provided herein are solid forms comprising Compound 1:

including tautomers thereof. Also provided are methods of using, preparing,
isolating, and characterizing the solid forms.

4. BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1A depicts a schematic diagram of interconversion relationship of polymorphs Form A, B, C, E, F, G, H, I, J, K, L, M, or N.

Figure 1B depitcts a schematic diagram of interconversion relationship of polymorphs Form B, X, F, K, O, P, Q, R, or S.

Figure 2 depicts an XRPD pattern of Form A.

Figure 3 depicts a DSC thermogram of Form A.

Figure 4 depicts a TGA thermogram of Form A.

Figure 5 depicts an XRPD pattern of Form B.

Figure 6 depicts DSC thermogram of Form B.

Figure 7 depicts a TGA thermogram of Form B.

Figure 8 depicts an XRPD pattern of Form C.

Figure 9 depicts a DSC thermogram of Form C.

Figure 10 depicts a TGA thermogram of Form C.

Figure 11 depicts an XRPD pattern of Form E.

Figure 12 depicts a DSC thermogram of Form E.

Figure 13 depicts a TGA thermogram of Form E.

Figure 14 depicts an XRPD pattern of Form F.

Figure 15 depicts a DSC thermogram of Form F.

Figure 16 depicts a TGA thermogram of Form F.

Figure 17 depicts an XRPD pattern of Form G.

Figure 18 depicts a DSC thermogram of Form G.

Figure 19 depicts a TGA thermogram of Form G.

Figure 20 depicts a XRPD Pattern of Form H.

Figure 21 depicts a DSC thermogram of Form H.

Figure 22 depicts an XRPD Pattern of Form I.

Figure 23 depicts an XRPD pattern of Form J.

Figure 24A depicts an XRPD pattern of Form K.

Figure 25A depicts a DSC thermogram of Form K.

Figure 26A depicts a TGA thermogram of Form K.

Figure 24B depicts another XRPD pattern of Form K.

Figure 25B depicts another DSC thermogram of Form K.

Figure 26B depicts another TGA thermogram of Form K.

Figure 27 depicts an XRPD pattern of Form L.

Figure 28 depicts a DSC thermogram of Form L.

Figure 29 depicts a TGA thermogram of Form L.

Figure 30 depicts an XRPD pattern of Form M.

Figure 31 depicts an XRPD pattern of Form N.

Figure 32 depicts an XRPD overlay of polymorphs and pseudo-polymorphs.

Figure 33 depicts an XRPD overlay of solids obtained from equilibration experiments at 25℃. The bottom pattern depicts the XRPD pattern of Form B, the 2^nd pattern from the bottom depicts the XRPD pattern of an amorphous form of Compound 1 obtained from equilibration experiment EQ10, and the 3^rd, 4^th, and 5^th patterns from the bottom depict the XRPD patterns of Form B obtained from equilibration experiments EQ14, EQ15, and EQ16, respectively.

Figure 34 depicts an XRPD overlay of solids obtained from addition of antisolvent experiments. The bottom, middle, and top patterns depict the XRPD patterns of the amorphous forms obtained from antisolvent experiments AS1, AS2, and AS3, respectively.

Figure 35 depicts an XRPD overlay of the solid forms obtained from slow evaporation experiments. The bottom pattern depicts the XRPD pattern of Form B. The 2^nd, 3^rd, 4^th, and 5^th patterns depict the XRPD patterns of the amorphous forms obtained from slow evaporation experiments SE1, SE2, SE3, and SE4, respectively.

Figure 36 depicts an XRPD overlay of solids obtained from slow evaporation experiments. The bottom, middle, and top patterns depict the XRPD patterns of the amorphous forms obtained from slow evaporation experiments SE5, SE6, and SE7, respectively.

Figure 37 depicts an XRPD overlay of solids obtained from fast cooling experiments. The top pattern depicts the XRPD pattern of the amorphous form obtained from fast cooling experiment FC1, and the botttom pattern depicts the XRPD pattern of the amorphous form obtained from fast cooling experiment FC5.

Figure 38 depicts a DVS isotherm plot of Form B at 25℃.

Figure 39 depicts an XRPD overlay of Form B before and after DVS test. The top pattern depicts the XRPD pattern of Form B, and the bottom pattern depicts the XRPD pattern of Form B after the DVS test.

Figure 40 depicts a DVS isotherm plot of Form K at 25℃.

Figure 41 depicts an XRPD overlay of Form K before and after DVS test. The top pattern depicts the XRPD pattern of Form K, and the bottom pattern depicts the XRPD pattern of Form K after the DVS test.

Figure 42 depicts an XRPD pattern of Form X.

Figure 43 depicts a DSC thermogram of Form X.

Figure 44 depicts a TGA thermogram of Form X.

Figure 45 depicts an XRPD pattern of Form O

Figure 46 depcits an XRPD pattern of Form P.

Figure 47 depicts an XRPD pattern of Form Q.

Figure 48 depicts an XRPD pattern of Form R.

Figure 49 depcits a DSC thermogram of Form R.

Figure 50 depicts a TGA thermogram of Form R.

Figure 51 depicts an XRPD pattern of Form S.

Figure 52 depicts a DSC thermogram of Form S.

Figure 53 depicts a TGA thermogram of Form S.

Figure 54 depicts an XRPD overlay pattern of the amorphous forms obtained from rotary evaporation in MeOH: DCM.

Figure 55 depicts an XRPD pattern of Mesylate Pattern A.

Figure 56 depicts an XRPD pattern of Mesylate Pattern F.

Figure 57 depcits an XRPD pattern of L-Tartrate Pattern B.

Figure 58 depicts an XRPD pattern of L-Tartrate Pattern D.

Figure 59 depicts an XRPD pattern of Glycolate Pattern A.

Figure 60 depicts an XRPD pattern of Glycolate Pattern B.

Figure 61 depicts an XRPD pattern of Fumarate Pattern B.

Figure 62 depicts an XRPD pattern of Tosylate Pattern E.

Figure 63 depicts a DSC thermogram and a TGA thermogram of Mesylate Pattern A.

Figure 64 depicts a DSC thermogram and a TGA thermogram of Mesylate Pattern F.

Figure 65 depicts a DSC thermogram and a TGA thermogram of L-Tartrate Pattern B.

Figure 66 depicts a DSC thermogram and a TGA thermogram of L-Tartrate Pattern D.

Figure 67 depicts a DSC thermogram and a TGA thermogram of Glycolate Pattern A.

Figure 68 depicts a DSC thermogram and a TGA thermogram of Glycolate Pattern B.

Figure 69 depicts a DSC thermogram and a TGA thermogram of Fumarate Pattern B.

Figure 70 depcits a DSC thermogram and a TGA thermogram of Tosylate Pattern E.

5. DETAILED DESCRIPTION

5.1 DEFINITIONS

As used herein, and in the specification and the accompanying claims, the indefinite articles “a” and “an” and the definite article “the” include plural as well as single referents, unless the context clearly indicates otherwise.

As used herein, and unless otherwise specified, the terms “about” and “approximately, ” when used in connection with a numeric value or range of values which is provided to characterize a particular solid form, e.g., a specific temperature or temperature range, such as, for example, that describes a melting, dehydration, desolvation, or glass transition temperature; a mass change, such as, for example, a mass change as a function of temperature or humidity; a solvent or water content, in terms of, for example, mass or a percentage; or a peak position, such as, for example, in analysis by, for example, infrared radiation (IR) or Raman spectroscopy or X-ray powder diffraction (XRPD) ; indicate that the value or range of values may deviate to an extent deemed reasonable to one of ordinary skill in the art while still describing the solid form. Techniques for characterizing crystal forms and amorphous forms include, but are not limited to, thermal gravimetric analysis (TGA) , differential scanning calorimetry (DSC) , XRPD, single-crystal X-ray diffractometry, and solubility studies. In certain embodiments, the terms “about” and “approximately, ” when used in this context, indicate that the numeric value or range of values may vary within 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1.5%, 1%, 0.5%, or 0.25%of the recited value or range of values, particularly within 10%of the recited value or range of values. For example, in some embodiments, the value of an XRPD peak position may vary by up to ±0.2 degrees two theta while still describing the particular XRPD peak. In one embodiment, the XRPD is measured using an incident beam of Cu radiation, e.g., Cu Ka radiation, e.g., wherein the XRPD is measured using radiation of wavelength 1.54059 A. In one embodiment, the value of the d-spacing of an XRPD peak position may vary within a few hundredths of a percent (e.g., ±0.02%) . In some embodiments, the value of the d-spacing of an XRPD peak position may vary by up to while still describing the particular XRPD peak.

As used herein and unless otherwise indicated, the term “substantially pure” when used to describe a polymorph of a compound, i.e., a crystal form or an amorphous form of a compound, means a crystal form or an amourphous form of the compound that comprises that crystal form or amorphous form and is substantially free of other polymorphs of the compound. In certain embodiments, a form that is substantially pure contains less than about 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or 0.01%of one or more other polymorphs on a weight basis.

Unless otherwise specified, the terms “solvate” and “solvated, ” as used herein, refer to a solid form of a substance which contains solvent. The terms “hydrate” and “hydrated” refer to a solvate wherein the solvent is water. The terms “solvate” and “solvated, ” as used herein, can also refer to a solvate of a salt, cocrystal, or molecular complex. The terms “hydrate” and “hydrated, ” as used herein, can also refer to a hydrate of a salt, cocrystal, or molecular complex.

“Tautomers” refers to isomeric forms of a compound that are in equilibrium with each other. The concentrations of the isomeric forms will depend on the environment the compound is found in and may be different depending upon, for example, whether the compound is a solid or is in an organic or aqueous solution.

As readily understood by one skilled in the art, a wide variety of functional groups and other structures may exhibit tautomerism and all tautomers of Compound 1 are within the scope of the present disclosure.

The term “pharmaceutically acceptable excipient” means a diluent, excipient, or carrier in a formulation that is compatible with the other ingredient (s) of the formulation and not deleterious to the recipient thereof.

The term “solid form” refers to a physical form which is not predominantly in a liquid or a gaseous state. As used herein and unless otherwise specified, the term “solid form” refers to a physical form comprising Compound 1 which is not predominantly in a liquid or a gaseous state. A solid form may be a crystalline form or a mixture thereof. In certain embodiments, a solid form may be an amorphous form. In certain embodiments, the term “asolid form comprising Compound 1” includes a solid form comprising Compound 1. In one embodiment, the solid form is Forms A, B, C, E, F, G, H, I, J, K, L, M, N, X, O, P, Q, R, or S, or the amorphous form provided herein. In another embodiment, the solid form is Mesylate Pattern A, Mesylate Pattern F, L-tartrate Pattern B, L-tartrate Pattern D, Glycolate Pattern A, Glycolate Pattern B, Fumarate Pattern B, Tosylate Pattern E, Sulfate Pattern B, Maleate Pattern B, Besylate Pattern B, Oxalate Pattern C, or Hydrobromide Pattern A.

As used herein and unless otherwise specified, the term “crystalline” when used to describe a compound, substance, modification, material, component, or product, unless otherwise specified, means that the compound, substance, modification, material, component, or product is substantially crystalline as determined by XRPD.

The term “crystal form” or “crystalline form” refers to a solid form that is crystalline. In certain embodiments, crystal forms include salts. In certain embodiments, a crystal form of a substance may be substantially free of amorphous forms and/or other crystal forms. In certain embodiments, a crystal form of a substance may contain less than about 1%, less than about 2%, less than about 3%, less than about 4%, less than about 5%, less than about 6%, less than about 7%, less than about 8%, less than about 9%, less than about 10%, less than about 15%, less than about 20%, less than about 25%, less than about 30%, less than about 35%, less than about 40%, less than about 45%, or less than about 50%by weight of one or more amorphous forms and/or other crystal forms.

The term “crystallinity” as applied to a compound refers to a solid phase in which the material has a well-ordered internal structure at the molecular level, giving a characteristic X-ray diffraction pattern with predetermined peaks. Such materials also exhibit liquid properties when sufficiently heated, but the solid-to-liquid change is typically characterized by a primary phase change ( “melting point” ) . Crystallinity can be estimated by conventional X-ray diffraction techniques. Methods of determining the degree of crystallinity are known to those of skill in the art, including, for example, X-ray powder diffraction, which are fully incorporated herein by reference. In some embodiments, the substantially crystalline forms described herein are about 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100%crystalline.

Unless otherwise specified, the terms “polymorph, ” “polymorphic form, ” “polymorphs, ” “polymorphic forms, ” and related terms herein refer to two or more crystal forms that consist essentially of the same molecule, molecules or ions. Different polymorphs may have different physical properties, such as, for example, melting temperatures, heats of fusion, solubilities, dissolution rates, and/or vibrational spectra as a result of a different arrangement or conformation of the molecules or ions in the crystal lattice. The differences in physical properties exhibited by polymorphs may affect pharmaceutical parameters, such as storage stability, compressibility and density (important in formulation and product manufacturing) , and dissolution rate (an important factor in bioavailability) . Differences in stability can result from changes in chemical reactivity (e.g., differential oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph) or mechanical changes (e.g., tablets crumble on storage as a kinetically favored polymorph converts to thermodynamically a more stable polymorph) or both (e.g., tablets of one polymorph are more susceptible to breakdown at high humidity) . As a result of solubility/dissolution differences, in the extreme case, some polymorphic transitions may result in lack of potency or, at the other extreme, toxicity. In addition, the physical properties of the crystal may be important in processing; for example, one polymorph might be more likely to form solvates or might be difficult to filter and wash free of impurities (e.g., particle shape and size distribution might be different between polymorphs) .

Unless otherwise specified, the term “amorphous” or “amorphous form” means that the substance, component, or product in question is not substantially crystalline as determined by X-ray diffraction. In particular, the term “amorphous form” describes a disordered solid form, i.e., a solid form lacking long range crystalline order. In certain embodiments, an amorphous form of a substance may be substantially free of other amorphous forms and/or crystal forms. In certain embodiments, an amorphous form of a substance may contain less than about 1%, less than about 2%, less than about 3%, less than about 4%, less than about 5%, less than about 10%, less than about 15%, less than about 20%, less than about 25%, less than about 30%, less than about 35%, less than about 40%, less than about 45%, or less than about 50%by weight of one or more other amorphous forms and/or crystal forms on a weight basis.

“Treating” as used herein, means an alleviation, in whole or in part, of the disease or disorder, or symptoms associated with the disease or disorder, or slowing, or halting of further progression or worsening of the disease or disorder, or symptoms associated with the disease or disorder.

“Patient” as used herein, means a human.

Unless otherwise specified, to the extent that there is a discrepancy between a depicted chemical structure of a compound provided herein and a chemical name of a compound provided herein, the chemical structure shall control.
5.2 SOLID FORMS OF COMPOUND 1

While not intending to be bound by any particular theory, certain solid forms (e.g., crystals) are characterized by physical properties, e.g., stability, solubility, and dissolution rate, appropriate for pharmaceutical and therapeutic dosage forms. Moreover, while not wishing to be bound by any particular theory, certain solid forms (e.g., crystals) are characterized by physical properties (e.g., density, compressibility, hardness, morphology, cleavage, stickiness, solubility, water uptake, electrical properties, thermal behavior, solid-state reactivity, physical stability, and chemical stability) affecting particular processes (e.g., yield, filtration, washing, drying, milling, mixing, tableting, flowability, dissolution, formulation, and lyophilization) which make certain solid forms (e.g., crystals) suitable for the manufacture of a solid dosage form. Such properties can be determined using particular analytical chemical techniques, including solid-state analytical techniques (e.g., X-ray diffraction, microscopy, spectroscopy, and thermal analysis) , as described herein and known in the art.

The solid form crystals provided herein (e.g., Forms A, B, C, E, F, G, H, I, J, K, L, M, N, X, O, P, Q, R, S, Mesylate Pattern A, Mesylate Pattern F, L-tartrate Pattern B, L-tartrate Pattern D, Glycolate Pattern A, Glycolate Pattern B, Fumarate Pattern B, Tosylate Pattern E, Sulfate Pattern B, Maleate Pattern B, Besylate Pattern B, Oxalate Pattern C, or Tosylate Pattern E) may be characterized using a number of methods known to a person having ordinary skill in the art, including, but not limited to, single crystal X-ray diffraction, XRPD , microscopy (e.g., scanning electron microscopy (SEM) ) , thermal analysis (e.g., DSC, TGA, and hot-stage microscopy) , spectroscopy (e.g., infrared, Raman, and solid-state nuclear magnetic resonance) , single differential thermal analysis (SDTA) , high performance liquid chromatography coupled with mass spectroscopy (HPLC-MS) , thermogravimetrical analysis coupled with single differential thermal analysis (TGA-SDTA) , and thermogravimetric analysis coupled with mass spectroscopy (TGA-MS) . The particle size and size distribution of the solid forms provided herein may be determined by conventional methods, such as laser light scattering technique.

The purity of the solid forms provided herein may be determined by standard analytical methods, such as thin layer chromatography (TLC) , gel electrophoresis, gas chromatography, high performance liquid chromatography (HPLC) , and mass spectrometry (MS) .

Unless instructed otherwise, the XRPD provided herein is obtained by Cu/K-Alpha1 or Cu/Kα (Kα1 1.540598, Kα2 1.544426) .
5.2.1 Form A

Provided herein is solid Form A, comprising Compound 1. In one embodiment, Form A is a crystal form. In one embodiment, Form A is a physical mixture of Form B and Form F.

In another embodiment, Form A is a metastable form. In another embodiment, Form A is converted into Form B. In another embodiment, Form A is converted into Form C. In another embodiment, Form A is converted into Form F. In another embodiment, Form A is converted into Form G. In another emobidment, Form A is converted into Form L.

In certain embodiments, a solid form provided herein, e.g., Form A, is substantially crystalline, as indicated by, e.g., XRPD measurements. In one embodiment, Form A has one, two, three, four, five, six, seven, eight, nine, or more characteristic XRPD peaks as set forth in Figure 2.

In one embodiment, provided herein is Form A having a DSC thermogram as depicted in Figure 3 comprising an endothermic event with a maximum at about 221.7 ℃ with onset temperature at about 216.4 ℃. In one embodiment, Form A has a DSC comprising an endothermic event with a maximum at about 221.7 ℃. In one embodiment, Form A has a DSC thermogram comprising an endothermic event with an onset temperature at approximately 216.4 ℃. In one embodiment, Form A has a DSC thermogram comprising an endothermic event with enthalpy (normalized) of about 2.8 J/g.

In one embodiment, provided herein is Form A having a DSC thermogram as depicted in Figure 3 comprising an exothermic event with a maximum at about 279.8 ℃ with onset temperature at about 276.1 ℃. In one embodimentForm A has a DSC thermogram comprising an exothermic event with a maximum at about 279.8 ℃. In one embodiment, Form A has a DSC thermogram comprising an exothermic event with an onset temperature at approximately 276.1 ℃. In one embodiment, Form A has a DSC thermogram comprising an exothermic event with enthalpy (normalized) of about 89.8 J/g.

In one embodiment, provided herein is Form A having a TGA thermograph corresponding substantially to the representative TGA thermogram as depicted in Figure 4. In certain embodiments, Form A exhibits a TGA thermogram comprising a total mass loss of approximately 1.3 %of the total mass of the sample between approximately 33.7 ℃ and approximately 200.0 ℃. Thus, in certain embodiments, Form A loses about 3.7 %of the total mass when heated from about 33 ℃ to about 200 ℃.

In one embodiment, provided herein is a method of making Form A comprising slurring Compound 1 in methyl tert-butyl ether. In one embodiment, the method comprises recrytallizing Compound 1 in isopropanol and water (about 10: 1; v/v) . In one embodiment, provided herein is a method of making Form A comprising equilibrating Compound 1 in a solvent. In one embodiment, the solvent is water, acetone, methyl ethyl ketone (MEK) , Isopropyl Acetate (IPAc) , or MeOH/water (20: 80, v/v) . In one embodiment, the equilibrating takes place at about 25℃ or about 50℃ for about 4 days, about 1 week, or about 2 weeks.
5.2.2 Form B

Provided herein is solid Form B, comprising Compound 1. In one embodiment, Form B is an anhydrous form. In another embodiment, Form B is crystalline. In one embodiment, Form B is substantially crystalline. In one embodiment, Form B is substantially pure. In another embodiment, Form B is a metastable form. In another embodiment, Form B is converted into Form K.

In one embodiment, Form B has an XRPD pattern substantially as shown in Figure 5. In one embodiment, Form B has one or more characteristic XRPD peaks at a two-theta angle of approximately 5.1, 13.1, or 16.9 degrees (see Table 1) . In another embodiment, Form B has one or more characteristic XRPD peaks at a two-theta angle of approximately 5.1, 8.4, 13.1, 13.7, 16.9, or 21.1 degrees. In another embodiment, Form B has one or more characteristic XRPD peaks at a two-theta angle of approximately 5.1, 8.4, 12.7, 13.1, 13.7, 14.3 16.9, 21.1, or 21.5 degrees. In another embodiment, Form B of has one, two, three, four, five, six, seven, eight, nine, or more characteristic XRPD peaks at a two-theta angle selected from the peaks listed in Table 1. In another embodiment, Form B has one, two, three, four, five, six, seven, eight, nine, or more characteristic XRPD peaks as set forth in Figure 5.

In one embodiment, provided herein is Form B having a DSC thermogram as depicted in Figure 6 comprising an endothermic event with a maximum at about 281.8 ℃ with onset temperature at about 279.3 ℃. In one embodiment, Form B has a DSC thermogram comprising an endothermic event with a maximum at about 281.8 ℃. In one embodiment, Form B has a DSC thermogram comprising an endothermic event with an onset temperature at approximately 279.3 ℃. In one embodiment, Form B has a DSC thermogram comprising an endothermic event with enthalpy (normalized) of about 81.3 J/g.

In one embodiment, provided herein is Form B having a TGA thermograph corresponding substantially to the representative TGA thermogram as depicted in Figure 7. In certain embodiments, Form B exhibits a TGA thermogram comprising a total mass loss of approximately 1.3 %of the total mass of the sample between approximately 35 ℃ and approximately 200.0 ℃. Thus, in certain embodiments, Form B loses about 1.3 %of the total mass when heated from about 35 ℃ to about 200 ℃.

In certain embodiments, provided herein are methods for making Form B. In one embodiment, Form B is prepared by an equilibration experiment using Compound 1. In one embodiment, Form B is prepared by an equilibration experiment from a solvent or a mixture of solvents at about 50 ℃ for about 1 day, about 2 days, or about 3 days. In one embodiment, Form B is prepared by an equilibration experiment from a solvent or a mixture of solvents at about 25 ℃. In one embodiment, the solvent is water, methanol, ethanol, isopropanol, acetone, MEK, ethyl acetate (EA) , isopropyl acetate, acentonitrile (ACN) , dichloromethane (DCM) , heptane, T-butyl methyl ether, tetrahydrofuran (THF) , toluene, 1, 4-dioxane, or a mixture thereof. In one embodiment, Form B is prepared by an equilibration experiment, wherein the solvent is a mixture of acetonitrile and water. In one embodiment, the ratio of acetonitrile and water is about 80:20 by volume. In one embodiment, Form B is prepared by an equilibration experiment, wherein the solvent is ethyl acetate. In one embodiment, Form B is prepared by an equilibration experiment, wherein the solvent is acetonitrile. In one embodiment, Form B is prepared by an equilibration experiment, wherein the solvent is EtOH. In one embodiment, Form B is prepared by an equilibration experiment, wherein the solvent is a mixture of acetone and water. In one embodiment, the ratio of aceton and water is about 30: 70 by volume. In one embodiment, Form B is prepared from Form G by air drying in fume hood for about 4 days. In one embodiment, Form B is prepared by slow evaporation experiment, wherein the solvent is 1, 4-dioxane.
5.2.3 Form C

Provided herein is solid Form C, comprising Compound 1. In one embodiment, Form C is a crystal form. In one embodiment, Form C is a solvate. In one embodiment, Form C is a THF solvate of Compound 1. In one embodiment, Form C is substantially pure.

In one embodiment, Form C is a solvated form comprising Compound 1. In another embodiment, Form C is a metastable form. In another embodiment, Form C is converted into Form I.

In one embodiment, the molar ratio of THF to Compound 1 of Form C is 0.25 ±0.1, 0.25 ± 0.05, 0.25 ± 0.01, or about 0.25.

In one embodiment, Form C has an XRPD pattern substantially as shown in Figure 8. In one embodiment, Form C has one or more characteristic XRPD peaks at a two-theta angle of approximately 4.6, 6.0, or 14.2 degrees (see Table 2) . In another embodiment, Form C has one or more characteristic XRPD peaks at a two-theta angle of approximately 4.6, 6.0, 15.6, 17.0, or 19.8 degrees. In another embodiment, Form C has one or more characteristic XRPD peaks at a two-theta angle of approximately 4.6, 6.0, 9.1, 11.9, 14.2, 15.6, 17.0, or 19.8 degrees. In another embodiment, Form C has one, two, three, four, five, six, seven, eight, nine, or more characteristic XRPD peaks at a two-theta angle selected from the peaks listed in Table 2. In another embodiment, Form C has one, two, three, four, five, six, seven, eight, nine, or more characteristic XRPD peaks as set forth in Figure 8.

In one embodiment, provided herein is Form C having a DSC thermogram as depicted in Figure 9 comprising an endothermic event with a maximum at about 33.1 ℃ with onset temperature at about 30.6 ℃. In one embodiment, Form C has a DSC thermogram comprising an endothermic event with a maximum at about 33.1 ℃. In one embodiment, Form C has a DSC thermogram comprising an endothermic event with an onset temperature at approximately 30.6 ℃. In one embodiment, Form C has a DSC thermogram comprising an endothermic event with enthalpy (normalized) of about 5.7 J/g.

In one embodiment, provided herein is Form C having a DSC thermogram as depicted in Figure 9 comprising an exothermic event with a maximum at about 73.8 ℃ with onset temperature at about 60.9 ℃. In one embodiment, Form C has a DSC thermogram comprising an exothermic event with a maximum at about 73.8 ℃. In one embodiment, Form C has a DSC thermogram comprising an exothermic event with an onset temperature at approximately 60.9 ℃. In one embodiment, Form C has a DSC thermogram comprising an exothermic event with enthalpy (normalized) of about 7.1 J/g.

In one embodiment, provided herein is Form C having a DSC thermogram as depicted in Figure 9 comprising an exothermic event with a maximum at about 213 ℃ with onset temperature at about 201 ℃. In one embodiment, Form C has a DSC thermogram comprising an exothermic event with a maximum at about 213 ℃. In one embodiment, Form C has a DSC thermogram comprising an exothermic event with an onset temperature at approximately 201 ℃. In one embodiment, Form C has a DSC thermogram comprising an exothermic event with enthalpy (normalized) of about 33.0 J/g.

In one embodiment, provided herein is Form C having a DSC thermogram as depicted in Figure 9 comprising an exothermic event with a maximum at about 248.5 ℃ with onset temperature at about 233.7 ℃. In one embodiment, Form C has a DSC thermogram comprising an exothermic event with a maximum at about 248.5 ℃. In one embodiment, Form C has a DSC thermogram comprising an exothermic event with an onset temperature at approximately 233.7 ℃. In one embodiment, Form C has a DSC thermogram comprising an exothermic event with enthalpy (normalized) of about 24.3 J/g.

In one embodiment, provided herein is Form C having a DSC thermogram as depicted in Figure 9 comprising an exothermic event with a maximum at about 277.9 ℃ with onset temperature at about 272.3 ℃. In one embodiment, Form C has a DSC thermogram comprising an exothermic event with a maximum at about 277.9 ℃. In one embodiment, Form C has a DSC thermogram comprising an exothermic event with an onset temperature at approximately 272.3 ℃. In one embodiment, Form C has a DSC thermogram comprising an exothermic event with enthalpy (normalized) of about 34.0 J/g.

In one embodiment, provided herein is Form C having a TGA thermograph corresponding substantially to the representative TGA thermogram as depicted in Figure 10. In certain embodiments, Form C exhibits a TGA thermogram comprising a total mass loss of approximately 2.7 %of the total mass of the sample between approximately 35 ℃ and approximately 200.0 ℃. Thus, in certain embodiments, Form C loses about 2.7 %of the total mass when heated from about 35 ℃ to about 200 ℃.

In certain embodiments, provided herein are methods for making Form C. In one embodiment, the method comprises equilibrating Compound 1 in a solvent or a mixture of solvents. In one embodiment, the equilibrating takes place at about 50 ℃ or about 25 ℃. In one embodiment, the equilibrating takes place for about 2 hours or about 18 hours. In one embodiment, the solvent is water, methanol, ethanol, isopropanol, acetone, MEK, ethyl acetate, isopropyl acetate, ACN, DCM, heptane, T-butyl methyl ether, THF, toluene, 1, 4-dioxane, or a mixture thereof. In one embodiment, the solvent is THF.
5.2.4 Form E

Provided herein is solid Form E, comprising Compound 1. In one embodiment, Form E is a crystal form. In one embodiment, Form E is a solvate of Compound 1. In one embodiment, Form E is substantially pure.

In one embodiment, Form E is a solvated form comprising Compound 1. In one embodiment, Form E is a 1, 4-dioxane and water hetero solvate of Compuond A. In another embodiment, Form E is a metastable form. In another embodiment, Form E is converted into Form H.

In one embodiment, the molar ratio of 1, 4-dioxane to Compound 1 of Form E is 0.79 ± 0.1, 0.79 ± 0.05, 0.79 ± 0.01, or about 0.79.

In one embodiment, the molar ratio of water to Compound 1 of Form E is 2.1 ±0.1, 2.1 ± 0.05, 2.1 ± 0.01, or about 2.1.

In one embodiment, Form E has an XRPD pattern substantially as shown in Figure 11. In one embodiment, Form E has one or more characteristic XRPD peaks at a two-theta angle of approximately 2.5, 3.2, or 19.6 degrees (Table ) . In another embodiment, Form E has one or more characteristic XRPD peaks at a two-theta angle of approximately 2.5, 3.2, 19.0, 19.6 or 21.3 degrees. In another embodiment, Form E has one or more characteristic XRPD peaks at a two-theta angle of approximately 2.5, 3.2, 3.8, 15.7, 19.0, 19.6, or 21.3 degrees. In another embodiment, Form E has one, two, three, four, five, six, seven, eight, nine, or more characteristic XRPD peaks at a two-theta angle selected from the peaks listed in Table 3. In another embodiment, Form E has one, two, three, four, five, six, seven, eight, nine, or more characteristic XRPD peaks as set forth in Figure 11.

In one embodiment, provided herein is Form E having a DSC thermogram as depicted in Figure 12 comprising an endothermic event with a maximum at about 33.3 ℃ with onset temperature at about 30.7 ℃. In one embodiment, Form E has a DSC thermogram comprising an endothermic event with a maximum at about 33.3 ℃. In one embodiment, Form E has a DSC thermogram comprising an endothermic event with onset temperature at about 30.7 ℃. In one embodiment, Form E has a DSC thermogram comprising an endothermic event with enthalpy (normalized) of about 2.3 J/g.

In one embodiment, provided herein is Form E having a DSC thermogram as depicted in Figure 12 comprising an endothermic event with a maximum at about 62.5 ℃ with onset temperature at about 48.4 ℃. In one embodiment, Form E has a DSC thermogram comprising an endothermic event with a maximum at about 62.5 ℃. In one embodiment, Form E has a DSC thermogram comprising an endothermic event with onset temperature at about 48.4 ℃. In one embodiment, Form E has a DSC thermogram comprising an endothermic event with enthalpy (normalized) of about 10.6 J/g.

In one embodiment, provided herein is Form E having a DSC thermogram as depicted in Figure 12 comprising an endothermic event with a maximum at about 126.6 ℃ with onset temperature at about 105.1 ℃. In one embodiment, Form E has a DSC thermogram comprising an endothermic event with a maximum at about 126.6 ℃. In one embodiment, Form E has a DSC thermogram comprising an endothermic event with onset temperature at about 105.1 ℃. In one embodiment, Form E has a DSC thermogram comprising an endothermic event with enthalpy (normalized) of about 48.6 J/g.

In one embodiment, provided herein is Form E having a DSC thermogram as depicted in Figure 12 comprising an endothermic event with a maximum at about 172.8 ℃ with onset temperature at about 167.0 ℃. In one embodiment, Form E has a DSC thermogram comprising an endothermic event with a maximum at about 172.8 ℃. In one embodiment, Form E has a DSC thermogram comprising an endothermic event with onset temperature at about 167.0 ℃. In one embodiment, Form E has a DSC thermogram comprising an endothermic event with enthalpy (normalized) of about 4.1 J/g.

In one embodiment, provided herein is Form E having a DSC thermogram as depicted in Figure 12 comprising an endothermic event with a maximum at about 243.0 ℃ with onset temperature at about 232.7 ℃. In one embodiment, Form E has a DSC thermogram comprising an endothermic event with a maximum at about 243.0 ℃. In one embodiment, Form E has a DSC thermogram comprising an endothermic event with onset temperature at about 232.7 ℃. In one embodiment, Form E has a DSC thermogram comprising an endothermic event with enthalpy (normalized) of about 59.3 J/g.

In one embodiment, provided herein is Form E having a DSC thermogram as depicted in Figure 12 comprising an endothermic event with a maximum at about 279.5 ℃ with onset temperature at about 277.7 ℃. In one embodiment, Form E has a DSC thermogram comprising an endothermic event with a maximum at about 279.5 ℃. In one embodiment, Form E has a DSC thermogram comprising an endothermic event with onset temperature at about 277.7 ℃. In one embodiment, Form E has a DSC thermogram comprising an endothermic event with enthalpy (normalized) of about 63.3 J/g.

In one embodiment, provided herein is Form E having a TGA thermograph corresponding substantially to the representative TGA thermogram as depicted in Figure 13. In certain embodiments, Form E exhibits a TGA thermogram comprising a total mass loss of approximately 2.6 %of the total mass of the sample between approximately 35 ℃ and approximately 80.0 ℃. Thus, in certain embodiments, Form E loses about 2.6 %of the total mass when heated from about 35 ℃ to about 80 ℃.

In one embodiment, provided herein is Form E having a TGA thermograph corresponding substantially to the representative TGA thermogram as depicted in Figure 13. In certain embodiments, Form E exhibits a TGA thermogram comprising a total mass loss of approximately 5.4 %of the total mass of the sample between approximately 80 ℃ and approximately 200.0 ℃. Thus, in certain embodiments, Form E loses about 5.4 %of the total mass when heated from about 80 ℃ to about 200 ℃.

In certain embodiments, provided herein are methods for making Form E by an antisolvent addition experiment using Compound 1. In one embodiment, the method comprises dissolving Compound 1 in a solvent to get a clear solution; adding an antisolvent into the solution; stirring at 25℃ for 1 day; and optionally collecting the solids by centrifugal filtration. In one embodiment, the solvent and antisolvent are 1, 4-dioxane and water, respectively. In one embodiment, the solvent and antisolvent are 1, 4-dioxane and water in the ratio of about 5: 4 by volumn, respectively.
5.2.5 Form F

Provided herein is solid Form F, comprising Compound 1. In one embodiment, Form F is a crystal form. In one embodiment, Form F is a hydrate. In one embodiment, Form F is substantially pure. In one embodiment, Form F is a channel hydrate. In another embodiment, Form F is a channel monohydrate.

In one embodiment, Form F has one or more characteristic XRPD peaks at a two-theta angle of approximately 5.9, 16.7, or 18.5 degrees (Table 44) . In another embodiment, Form F has one or more characteristic XRPD peaks at a two-theta angle of approximately 5.9, 7.3, 15.6, 16.7, 17.2, or 18.5 degrees. In another embodiment, Form F has one or more characteristic XRPD peaks at a two-theta angle of approximately 5.9, 7.3, 15.6, 16.7, 17.2, 18.5, 20.6, 22.5, or 23.0 degrees. In another embodiment, Form F has one, two, three, four, five, six, seven, eight, nine, or more characteristic XRPD peaks at a two-theta angle selected from the peaks listed in Table 4. In another embodiment, Form F has one, two, three, four, five, six, seven, eight, nine, or more characteristic XRPD peaks as set forth in Figure 14.

In one embodiment, provided herein is Form F having a DSC thermogram as depicted in Figure 15 comprising an endothermic event with a maximum at about 33.1 ℃ with onset temperature at about 30.6 ℃. In one embodiment, Form F has a DSC thermogram comprising an endothermic event with a maximum at about 33.1 ℃. In one embodiment, Form F has a DSC thermogram comprising an endothermic event with onset temperature at about 30.6 ℃. In one embodiment, Form F has a DSC thermogram comprising an endothermic event with enthalpy (normalized) of about 3.2 J/g.

In one embodiment, provided herein is Form F having a DSC thermogram as depicted in Figure 15 comprising an endothermic event with a maximum at about 91.1 ℃ with onset temperature at about 90.0 ℃. In one embodiment, Form F has a DSC thermogram comprising an endothermic event with a maximum at about 91.1 ℃. In one embodiment, Form F has a DSC thermogram comprising an endothermic event with onset temperature at about 90.0 ℃. In one embodiment, Form F has a DSC thermogram comprising an endothermic event with enthalpy (normalized) of about 8.1 J/g.

In one embodiment, provided herein is Form F having a DSC thermogram as depicted in Figure 15 comprising an endothermic event with a maximum at about 149.3 ℃ with onset temperature at about 149.0 ℃. In one embodiment, Form F has a DSC thermogram comprising an endothermic event with a maximum at about 149.3 ℃. In one embodiment, Form F has a DSC thermogram comprising an endothermic event with onset temperature at about 149.0 ℃. In one embodiment, Form F has a DSC thermogram comprising an endothermic event with enthalpy (normalized) of about 0.8 J/g.

In one embodiment, provided herein is Form F having a DSC thermogram as depicted in Figure 15 comprising an endothermic event with a maximum at about 212.2 ℃ with onset temperature at about 204.8 ℃. In one embodiment, Form F has a DSC thermogram comprising an endothermic event with a maximum at about 212.2 ℃. In one embodiment, Form F has a DSC thermogram comprising an endothermic event with onset temperature at about 204.8 ℃. In one embodiment, Form F has a DSC thermogram comprising an endothermic event with enthalpy (normalized) of about 35.5 J/g.

In one embodiment, provided herein is Form F having a DSC thermogram as depicted in Figure 15 comprising an endothermic event with a maximum at about 225.2 ℃ with onset temperature at about 217.6 ℃. In one embodiment, Form F has a DSC thermogram comprising an endothermic event with a maximum at about 225.2 ℃. In one embodiment Form F has a DSC thermogram comprising an endothermic event with onset temperature at about 217.6 ℃. In one embodiment, Form F has a DSC thermogram comprising an endothermic event with enthalpy (normalized) of about 47.5 J/g.

In one embodiment, provided herein is Form F having a DSC thermogram as depicted in Figure 15 comprising an endothermic event with a maximum at about 281.0 ℃ with onset temperature at about 276.0 ℃. In one embodiment, Form F has a DSC thermogram comprising an endothermic event with a maximum at about 281.0 ℃. In one embodiment, Form F has a DSC thermogram comprising an endothermic event with onset temperature at about 276.0 ℃. In one embodiment, Form F has a DSC thermogram comprising an endothermic event with enthalpy (normalized) of about 82.3 J/g.

In one embodiment, provided herein is Form F having a TGA thermograph corresponding substantially to the representative TGA thermogram as depicted in Figure 16. In certain embodiments, Form F exhibits a TGA thermogram comprising a total mass loss of approximately 2.7 %of the total mass of the sample between approximately 35 ℃ and approximately 200.0 ℃. Thus, in certain embodiments, Form F loses about 2.7 %of the total mass when heated from about 35 ℃ to about 200 ℃.

In certain embodiments, provided herein are methods for making Form F by an equilibration experiment using Compound 1. In one embodiment, Form F is prepared from major solvents at about 25 ℃ for about two weeks. In one embodiment, the solvent is water, methanol, ethanol, isopropanol, acetone, MEK, ethyl acetate, isopropyl acetate, ACN, DCM, heptane, T-butyl methyl ether, THF, toluene, 1, 4-dioxane, or a mixture thereof. In one embodiment, the solvent is MEK. In one embodiment, the solvent is acetone.
5.2.6 Form G

Provided herein is solid Form G, comprising Compound 1. In one embodiment, Form G is a crystal form. In one embodiment, Form G is substantially pure.

In one embodiment, Form G is a solvated form comprising Compound 1. In one embodiment, Form G is a 1, 4-dioxane solvate of Compuond A. In another embodiment, Form G is a metastable form. In another embodiment, Form G is converted into Form B.

In one embodiment, Form G has an XRPD pattern substantially as shown in Figure 17. In one embodiment, Form G of Compound 1 has one or more characteristic XRPD peaks at a two-theta angle of approximately 16.8, 18, and 21.3 degrees (Table 5) . In another embodiment, Form G of Compound 1 has one or more characteristic XRPD peaks at a two-theta angle of approximately 5.1, 13.1, 16.9, 18, 21.3, or 22.5 degrees. In another embodiment, Form G of Compound 1 has one or more characteristic XRPD peaks at a two-theta angle of approximately 5.1, 8.4, 13.1, 15, 16.9, 17.2, 18, 21.3, or 22.5 degrees. In another embodiment, Form G of Compound 1 has one, two, three, four, five, six, seven, eight, nine, or more characteristic XRPD peaks at a two-theta angle selected from the peaks listed in Table 55. In another embodiment, Form G has one, two, three, four, five, six, seven, eight, nine, or more characteristic XRPD peaks as set forth in Figure 17.

In one embodiment, provided herein is Form G having a DSC thermogram as depicted in Figure 18 comprising an endothermic event with a maximum at about 84.8 ℃ with onset temperature at about 60.8 ℃. In one embodiment, Form G has a DSC thermogram comprising an endothermic event with a maximum at about 84.8 ℃. In one embodiment, Form G has a DSC thermogram comprising an endothermic event with onset temperature at about 60.8 ℃. In one embodiment, Form G has a DSC thermogram comprising an endothermic event with enthalpy (normalized) of about 23.9 J/g.

In one embodiment, provided herein is Form G having a DSC thermogram as depicted in Figure 18 comprising an endothermic event with a maximum at about 278.2 ℃ with onset temperature at about 272.4 ℃. In one embodiment, Form G has a DSC thermogram comprising an endothermic event with a maximum at about 278.2 ℃. In one embodiment, Form G has a DSC thermogram comprising an endothermic event with onset temperature at about 272.4 ℃. In one embodiment, Form G has a DSC thermogram comprising an endothermic event with enthalpy (normalized) of about 60.6 J/g.

In one embodiment, provided herein is Form G having a TGA thermograph corresponding substantially to the representative TGA thermogram as depicted in Figure 19. In certain embodiments, Form G exhibits a TGA thermogram comprising a total mass loss of approximately 5.3 %of the total mass of the sample between approximately 35 ℃ and approximately 200.0 ℃. Thus, in certain embodiments, Form G loses about 5.3 %of the total mass when heated from about 35 ℃ to about 200 ℃.

In certain embodiments, provided herein are methods for making Form G. In one embodiment, Form G is prepared from multiple solvents by an equilibration experiment using Compound 1. In one embodiment, Form G is prepared from a solvent or a mixture of solvents at about 25 ℃ for two weeks.

In one embodiment, the solvent is water, methanol, ethanol, isopropanol, acetone, MEK, ethyl acetate, isopropyl acetate, ACN, DCM, heptane, T-butyl methyl ether, THF, toluene, 1,4-dioxane, or a mixture thereof.

In one embodiment, provided here is a method of making Form G by an equilibration experiment, wherein the solvent is 1, 4-dioxane. In one embodiment, the method comprises equilibrating Compound 1 in 1, 4-dioxane at 25℃ for 2 weeks.
5.2.7 Form H

Provided herein is solid Form H, comprising Compound 1. In another embodiment, Form H is a metastable form. In another embodiment, Form H is a metastable form. In another embodiment, Form H is substantially pure.

In one embodiment, Form H has an XRPD pattern substantially as shown in Figure 20. In one embodiment, Form H has one or more characteristic XRPD peaks at a two-theta angle of approximately 3.3, 19.6, or 21.4 degrees (Table 66) . In another embodiment, Form H has one or more characteristic XRPD peaks at a two-theta angle of approximately 3.3, 18.1, 18.9, 19.6, 20.4, or 21.4 degrees. In another embodiment, Form H of Compound 1 has one or more characteristic XRPD peaks at a two-theta angle of approximately 3.3, 10.7, 15.3, 16.3, 18.1, 18.9, 19.6, 20.4, or 21.4 degrees. In another embodiment, Form H of Compound 1 has one, two, three, four, five, six, seven, eight, nine, or more characteristic XRPD peaks at a two-theta angle selected from the peaks listed in Table 6. In another embodiment, Form H has one, two, three, four, five, six, seven, eight, nine, or more characteristic XRPD peaks as set forth in Figure 20.

In one embodiment, provided herein is Form H having a DSC thermogram as depicted in Figure 21. comprising an endothermic event with a maximum at about 58.7 ℃ with onset temperature at about 39.3 ℃. In one embodiment, Form H has a DSC thermogram comprising an endothermic event with a maximum at about 58.7 ℃. In one embodiment, Form H has a DSC thermogram comprising an endothermic event with onset temperature at about 39.3 ℃. In one embodiment, Form H has a DSC thermogram comprising an endothermic event with enthalpy (normalized) of about 33.9 J/g.

In one embodiment, provided herein is Form H having a DSC thermogram as depicted in Figure 21 comprising an endothermic event with a maximum at about 118.8 ℃ with onset temperature at about 93.8 ℃. In one embodiment, Form H has a DSC thermogram comprising an endothermic event with a maximum at about 118.8 ℃. In one embodiment, Form H has a DSC thermogram comprising an endothermic event with onset temperature at about 93.8 ℃. In one embodiment, Form H has a DSC thermogram comprising an endothermic event with enthalpy (normalized) of about 41.1 J/g.

In one embodiment, provided herein is Form H having a DSC thermogram as depicted in Figure 21 comprising an endothermic event with a maximum at about 172 ℃ with onset temperature at about 166.2 ℃. In one embodiment, Form H has a DSC thermogram comprising an endothermic event with a maximum at about 172 ℃. In one embodiment, Form H has a DSC thermogram comprising an endothermic event with onset temperature at about 166.2 ℃. In one embodiment, Form H has a DSC thermogram comprising an endothermic event with enthalpy (normalized) of about 2.2 J/g.

In one embodiment, provided herein is Form H having a DSC thermogram as depicted in Figure 21. comprising an endothermic event with a maximum at about 237.8 ℃ with onset temperature at about 228.2 ℃. In one embodiment, Form H has a DSC thermogram comprising an endothermic event with a maximum at about 237.8 ℃. In one embodiment, Form H has a DSC thermogram comprising an endothermic event with onset temperature at about 228.2 ℃. In one embodiment, Form H has a DSC thermogram comprising an endothermic event with enthalpy (normalized) of about 46.4 J/g.

In one embodiment, provided herein is Form H having a DSC thermogram as depicted in Figure 21. comprising an endothermic event with a maximum at about 275.8 ℃ with onset temperature at about 267.5 ℃. In one embodiment, Form H has a DSC thermogram comprising an endothermic event with a maximum at about 275.8 ℃. In one embodiment, Form H has a DSC thermogram comprising an endothermic event with onset temperature at about 267.5 ℃. In one embodiment, Form H has a DSC thermogram comprising an endothermic event with enthalpy (normalized) of about 45.4 J/g.

In certain embodiments, provided herein is a method for making Form H comprising air drying Form E in fume hood at about 25℃ for about 1 month.
5.2.8 Form I

Provided herein is solid Form I, comprising Compound 1. In one embodiment, Form I is a crystal form. In one embodiment, Form I is an anhydrous form. In one embodiment, Form I is substantially pure.

In another embodiment, Form I is a metastable form. In another embodiment, Form I is converted into Form B.

In one embodiment, Form I has an XRPD pattern substantially as shown in Figure 22. In one embodiment, Form I has one or more characteristic XRPD peaks at a two-theta angle of approximately 4.6, 5.0, or 15.8 degrees (Table 7) . In another embodiment, Form I has one or more characteristic XRPD peaks at a two-theta angle of approximately 4.6, 5.0, 15.8, 16.3, 16.6, or 18.1 degrees. In another embodiment, Form I has one or more characteristic XRPD peaks at a two-theta angle of approximately 4.6, 5.0, 5.4, 15.8, 16.3, 16.6, 17.0, 18.1, or 18.7 degrees. In another embodiment, Form I has one, two, three, four, five, six, seven, eight, nine, or more characteristic XRPD peaks at a two-theta angle selected from the peaks listed in Table 7. In another embodiment, Form I has one, two, three, four, five, six, seven, eight, nine, or more characteristic XRPD peaks as set forth in Figure 22.

In one embodiment, provided herein is a method for making Form I comprising heating Form C to about 150℃.
5.2.9 Form J

Provided herein is solid Form J, comprising Compound 1.

In one embodiment, Form J has an XRPD pattern substantially as shown in Figure 23. In another embodiment, Form J has one, two, three, four, five, six, seven, eight, nine, or more characteristic XRPD peaks as set forth in Figure 26. In still another embodiment, Form J is substantially pure.

In one embodiment, Form J is prepared by an equilibration experiment using Compound 1at about 25℃, wherein the solvent is a mixture of DMSO, IPA, and water. In one embodiment, Form J is prepared by an equilibration experiment at about 25℃, wherein the solvent is a mixture of DMSO, IPA, and water (about 5: 8: 1 by volume) .
5.2.10 Form K

Provided herein is solid Form K, comprising Compound 1. In one embodiment, Form K is a crystal form. In one embodiment, Form K is an anhydrous form. In one embodiment, Form K is substantially pure. In another embodiment, Form K is a metastable form. In another embodiment, Form K is converted into Form L.

In one embodiment, Form K has an XRPD pattern substantially as shown in Figure 24A. In one embodiment, Form K has one or more characteristic XRPD peaks at a two-theta angle of approximately 3.9, 4.4, or 15.9 degrees (Table A) . In another embodiment, Form K has one or more characteristic XRPD peaks at a two-theta angle of approximately 3.9, 4.4, 5.5, 11.0, 15.9 or 17.9 degrees. In another embodiment, Form K has one or more characteristic XRPD peaks at a two-theta angle of approximately 3.9, 4.4, 5.5, 10.3, 11.0, 14.0, 15.3, 15.9 or 17.9 degrees. In another embodiment, Form K has one, two, three, four, five, six, seven, eight, nine, or more characteristic XRPD peaks at a two-theta angle selected from the peaks listed in Table . In another embodiment, Form K has one, two, three, four, five, six, seven, eight, nine, or more characteristic XRPD peaks as set forth in Figure 24A.

In one embodiment, provided herein is Form K having a DSC thermogram as depicted in Figure 25A comprising an endothermic event with a maximum at about 231.4 ℃with onset temperature at about 225.8 ℃. In one embodiment, Form K has a DSC thermogram comprising an endothermic event with a maximum at about 231.4 ℃. In one embodiment, Form K has a DSC thermogram comprising an endothermic event with onset temperature at about 225.8 ℃. In one embodiment, Form K has a DSC thermogram comprising an endothermic event with enthalpy (normalized) of about 59.1 J/g.

In one embodiment, provided herein is Form K having a DSC thermogram as depicted in Figure 25A comprising an endothermic event with a maximum at about 256.0 ℃with onset temperature at about 245.4 ℃. In one embodiment, Form K has a DSC thermogram comprising an endothermic event with a maximum at about 256.0 ℃. In one embodiment, Form K has a DSC thermogram comprising an endothermic event with onset temperature at about 245.4 ℃. In one embodiment, Form K has a DSC thermogram comprising an endothermic event with enthalpy (normalized) of about 6.2 J/g.

In one embodiment, provided herein is Form K having a DSC thermogram as depicted in Figure 25A comprising an endothermic event with a maximum at about 282.5 ℃with onset temperature at about 279.7 ℃. In one embodiment, Form K has a DSC thermogram comprising an endothermic event with a maximum at about 282.5 ℃. In one embodiment, Form K has a DSC thermogram comprising an endothermic event with onset temperature at about 279.7 ℃. In one embodiment, Form K has a DSC thermogram comprising an endothermic event with enthalpy (normalized) of about 8.7 J/g.

In one embodiment, provided herein is Form K having a TGA thermograph corresponding substantially to the representative TGA thermogram as depicted in Figure 26A. In certain embodiments, Form K exhibits a TGA thermogram comprising a total mass loss of approximately 1.0 %of the total mass of the sample between approximately 35.3 ℃ and approximately 200.0 ℃. Thus, in certain embodiments, Form K loses about 1.0 %of the total mass when heated from about 35 ℃ to about 200 ℃.

In one embodiment, Form K is prepared from multiple solvents by an equilibration experiment using Compound 1. In one embodiment, Form K is prepared from a solvent or a mixture of solvents at about 60 ℃.

In one embodiment, Form K is prepared by an equilibration experiment, wherein the solvent is a mixture of THF and and water. In one embodiment, Form K is prepared by an equilibration experiment, wherein the solvent is a mixture of THF and and water (about 90: 10 by volume) . In one embodiment, Form K is prepared by an equilibration experiment at about 60 ℃, wherein the solvent is a mixture of THF and and water (about 90: 10 by volume) .

In one embodiment, Form K has an XRPD pattern substantially as shown in Figure 24B. In one embodiment, Form K has one or more characteristic XRPD peaks at a two-theta angle of approximately 4.4, 11.0, or 15.8 degrees (Table 8B) . In another embodiment, Form K has one or more characteristic XRPD peaks at a two-theta angle of approximately 3.8, 4.4, 5.5, 11.0, 15.8, or 17.9 degrees. In another embodiment, Form K has one or more characteristic XRPD peaks at a two-theta angle of approximately, 3.8, 4.4, 5.5, 10.3, 11.0, 14.1, 15.2, 15.8, or 17.9 degrees. In another embodiment, Form K has one, two, three, four, five, six, seven, eight, nine, or more characteristic XRPD peaks at a two-theta angle selected from the peaks listed in Table B. In another embodiment, Form K has one, two, three, four, five, six, seven, eight, nine, or more characteristic XRPD peaks as set forth in Figure 24B.

In one embodiment, provided herein is Form K having a DSC thermogram as depicted in Figure 25B comprising an endothermic event with a maximum at about 229.8℃ with oneset temperature at about 223.3℃. In one embodiment, Form K has a DSC thermogram comprising an endothermic event with a maximum at about 229.8℃. In one embodiment, Form K has a DSC thermogram comprising an endothermic event with onset temperature at about 223.3℃. In one embodiment, Form K has a DSC thermogram comprising an endothermic event with enthalpy (normalized) of about 66.2 J/g.

In one embodiment, provided herein is Form K having a TGA thermograph corresponding substantially to the representative TGA thermogram as depicted in Figure 26B. In certain embodiment, Form K exhibit a TGA thermogram comprising a total mass loss of approximately 2.8%of the total mass of the sample between approximately 26.1℃ and approximately 200.0℃. Thus, in certain embodiment, Form K loses about 2.8%of the total mass when heated from about 26℃ to about 200℃.
5.2.11 Form L

Provided herein is solid Form L, comprising Compound 1. In one embodiment, Form L is a crystal form. In one embodiment, Form L is a hydrate. In one embodiment, Form L is substantially pure. In one embodiment, Form L is converted into Form M.

In one embodiment, the molar ratio of water to Compound 1 of Form L is 1.5 ±0.1, 1.5 ± 0.05, 1.5 ± 0.01, or about 1.5.

In one embodiment, Form L has an XRPD pattern substantially as shown in Figure 27. In one embodiment, Form L has one or more characteristic XRPD peaks at a two-theta angle of approximately 10.6, 21.2, or 22.0 degrees (Table ) . In another embodiment, Form L has one or more characteristic XRPD peaks at a two-theta angle of approximately 10.6, 12.2, 16.9, 21.2, 22.0 or 26.5 degrees. In another embodiment, Form L has one or more characteristic XRPD peaks at a two-theta angle of approximately 10.6, 12.2, 16.9, 17.3, 18.7, 21.2, 22.0, 26.3, 26.5 or 28.6 degrees. In another embodiment, Form L has one, two, three, four, five, six, seven, eight, nine, or more characteristic XRPD peaks at a two-theta angle selected from the peaks listed in Table . In another embodiment, Form L has one, two, three, four, five, six, seven, eight, nine, or more characteristic XRPD peaks as set forth in Figure 27.

In one embodiment, provided herein is Form L having a DSC thermogram as depicted in Figure 28 comprising an endothermic event with a maximum at about 58.9 ℃ with onset temperature at about 24.2 ℃. In one embodiment, Form L has a DSC thermogram comprising an endothermic event with a maximum at about 58.9 ℃. In one embodiment, Form L has a DSC thermogram comprising an endothermic event with an onset temperature at approximately 24.2 ℃. In one embodiment Form L has a DSC thermogram comprising an endothermic event with enthalpy (normalized) of about 48.8 J/g.

In one embodiment, provided herein is Form L having a DSC thermogram as depicted in Figure 28 comprising an exothermic event with a maximum at about 205.1 ℃ with onset temperature at about 195.1 ℃. In one embodiment, Form L has a DSC thermogram comprising an exothermic event with a maximum at about 205.1 ℃. In one embodiment, Form L has a DSC thermogram comprising an exothermic event with an onset temperature at approximately 195.1 ℃. In one embodiment, Form L has a DSC thermogram comprising an endothermic event with enthalpy (normalized) of about 44.2 J/g.

In one embodiment, provided herein is Form L having a TGA thermograph corresponding substantially to the representative TGA thermogram as depicted in Figure 29. In certain embodiments, Form L exhibits a TGA thermogram comprising a total mass loss of approximately 1.9 %of the total mass of the sample between approximately 35.6 ℃ and approximately 151.1 ℃. Thus, in certain embodiments, Form L loses about 1.9 %of the total mass when heated from about 35.6 ℃ to about 151.1 ℃.

In one embodiment, Form L is prepared by an equilibration experiment using Compound 1 at about 50℃, wherein the solvent is MeOH.
5.2.12 Form M

Provided herein is solid Form M, comprising Compound 1. In one embodiment, Form M is a crystal form. In another embodiment, Form M is a solvate. In another embodiment, Form M is a hydrate. In one embodiment, Form M is substantially pure. In another embodiment, Form M is a metastable form.

In one embodiment, Form M has an XRPD pattern substantially as shown in Figure 30. In one embodiment, Form M has one or more characteristic XRPD peaks at a two-theta angle of approximately 10.4, 17.4, or 20.9 degrees (Table 3) . In another embodiment, Form M has one or more characteristic XRPD peaks at a two-theta angle of approximately 10.4, 17.4, 20.9, 23.6, 25, or 26.5 degrees. In another embodiment, Form M of Compound 1 has one or more characteristic XRPD peaks at a two-theta angle of approximately10.4, 11.4, 13.1, 17.4, 20.9, 23.6, 25, 26.2, or 26.5 degrees. In another embodiment, Form M of Compound 1 has one, two, three, four, five, six, seven, eight, nine, or more characteristic XRPD peaks at a two-theta angle selected from the peaks listed in Table 3. In another embodiment, Form M has one, two, three, four, five, six, seven, eight, nine, or more characteristic XRPD peaks as set forth in Figure 30.

In one embodiment, Form M is prepared by an equilibration experiment using Compound 1, wherein the solvent is MeOH and water. In one embodiment, Form M is prepared by an equilibration experiment at about 25℃, wherein the solvent is MeOH and water (about 20:80 by volume) .
5.2.13 Form N

Provided herein is solid Form N, comprising Compound 1.

In one embodiment, Form N has an XRPD pattern substantially as shown in Figure 31. In another embodiment, Form N has one, two, three, four, five, six, seven, eight, nine, or more characteristic XRPD peaks as set forth in Figure 31. In still another embodiment, Form N is substantially pure.

In one embodiment, Form N is prepared by slurring Form B in THF/water/isopropal alcohol (IPA) at about 25℃. In one embodiment, Form N is prepared by slurring Form B in THF/water/IPA (about 36/4/1 by volume) at about 25℃
5.2.14 Form X

Provided herein is solid Form X, comprising Compound 1. In one embodiment, Form X is a crystal form. In one embodiment, Form X is a hydrate. In still another embodiment, Form X is substantially pure.

In one embodiment, Form X has an XRPD pattern sustantailly as shown in Figure 45. In one embodiment, Form X has one or more characteristic XRPD peaks at a two-theta angle of approximately 4.7, 16.8, or 19.2 degrees (Table 11) . In another embodiment, Form X has one or more characteristic XRPD peaks at a two-theta angle of approximately 4.7, 14.6, 16.9, 19.1, 19.2, or 19.9 degrees. In another embodiment, Form X has one or more characteristic XRPD peaks at a two-theta angle of approximately 4.7, 14.6, 16.9, 18.1, 19.1, 19.2, 19.9, 21.2, or 21.5 degrees. In another embodiment, Form X has one, two, three, four, five, six, seven, eight, nine, or more characteristic XRPD peaks as set forth in Table 11. In another embodiment, Form X has one, two, three, four, five, six, seven, eight, nine, or more characteristic XRPD peaks as set forth in Figure 42.

In one embodiment, provided herein is Form X having a DSC thermogram as depicted in Figure 43 comprising an endothermic event with a maximum at about 53.3℃ with one set temperature at about 38.3℃. In one embodiment, Form X has a DSC thermogram comprising an endothermic event with a maximum at about 53.3℃. In one embodment, Form X has a DSC thermogram comprising an endothermic event with an onest temperature at about 38.3℃. In one embodiment, Form X has a DSC thermogram comprising an endothermic event with enthalpy (normalized) of about 79.7J/g.

In one embodiment, provided herein is Form X having a DSC thermogram as depicted in Figure 43 comprising an endothermic event with a maximum at about 190.7℃ with one set temperature at about 181.8℃. In one embodiment, Form X has a DSC thermogram comprising an endothermic event with a maximum at about 190.7℃. In one embodment, Form X has a DSC thermogram comprising an endothermic event with an onest temperature at about 181.8℃. In one embodiment, Form X has a DSC thermogram comprising an endothermic event with enthalpy (normalized) of about 6.5J/g.

In one embodiment, provided herein is Form X having a TGA thermograph corresponding substantially to the representative TGA thermogram as depicted in Figure 44. In certain embodiments, Form X exhibits a TGA thermogram comprising a total mass loss of approximately 5.5%of the total mass of the sample between approximately 26.6℃ and approximately 150.0℃. Thus, in certain embodiment, Form X loses about 5.5%of the total mass when heated from about 27℃ to about 150℃.

In another embodiment, Form X is prepared from Form K by anti-solvent addition in THF/ACN to obtain a solid part (wet cake) , then air drying the solid part (wet cake) for about 10 min to obtain Form X.
5.2.15 Form O

Provided herein is solid Form O, comprising Compound 1. In one embodiment, Form O is a crystal form. In one embodiment, Formd O is substantially pure. In another embodiment, Form O is a metastable form.

In one embodiment, Form O has an XRPD pattern sustantailly as shown in Figure 45. In one embodiment, Form O has one or more characteristic XRPD peaks at a two-theta angle of approximately 3.8, 5.8, or 8.8 degrees (see Table 12) . In another embodiment, Form O has one or more characteristic XRPD peaks at a two-theta angle of approximately 3.8, 5.8, 8.8, 17.6, 19.4, or 22.7 degrees. In another embodiment, Form O has one or more characteristic XRPD peaks at a two-theta angle of approximately 3.8, 5.8, 7.5, 8.8, 17.6, 18.9, 19.4, 22.7, or 23.5 degrees. In another embodiment, Form O has one, two, three, four, five, six, seven, eight, nine, or more characteristic XRPD peaks as set forth in Table 12. In another embodiment, Form O has one, two, three, four, five, six, seven, eight, nine, or more characteristic XRPD peaks as set forth in Figure 45.

In one embodiment, Form O is prepared from Form K by anti-solvent addition in MeOH/DCM/ACN to obtain a slurry which was air dried for about 1 hour then stirred to obtain Form O. In another embodiment, Form O is converted to Form X after air drying for 10 minutes. In one embodiment, Form O is a metastable form.
5.2.16 Form P

Provided herein is solid Form P, comprising Compound 1. In one embodiment, Form P is a crystal form. In one embodiment, Form P is substantially pure. In another embodiment, Form P is a metastable form.

In one embodiment, Form P has an XRPD pattern substantially as shown in Figure 46. In one embodiment, Form P has one or more characteristic XRPD peaks at a two-theta angle of approximately 5.8, 7.1, or 23.2 degrees (Table 13) . In another embodment, Form P has one or more characteristic XRPD peaks at a two-theta angle of approximately 5.8, 7.1, 8.7, 11.2, 11.6, or 23.2 degress. In another embodiment, Form P has one or more characteristic XRPD peaks at a two-theta angle of approximately 5.8, 7.1, 8.7, 11.2, 11.6, 22.4, 22.6, 223.2, or 24.1 degress. In another embodiment, Form P has one, two, three, four, five, six, seven, eight, nine, or more characteristic XRPD peaks as set forth in Table 13. In another embodiment, Form P has one, two, three, four, five, six, seven, eight, nine, or more characteristic XRPD peaks as set forth in Figure 46.

In another embodiment, Form O prepared as described above is converted to Form P after slurrying for about 1 day. In another embodiment, Form P is converted to Form F after air drying for about 4 hours.
5.2.17 Form Q

Provided herein is solid Form Q, comprising compound 1. In one embodiment, Form Q is a crystal form. In one embodiment, Form Q is substantially pure. In another embodiment, Form Q is a hydrate.

In one embodiment, Form Q has an XRPD pattern substantially as shown in Figure 47. In one embodiment, Form Q has one or more characteristic XRPD peaks at a two-theta angle of approximately 5.9, 6.3, or 9.4 degress (Table 14) . In one embodiment, Form Q has one or more characteristic XRPD peaks at a two-theta angle of approximately 3.2, 5.9, 6.3, 7.4, 9.4, or 17.1 degrees. In one embodiment, Form Q has one or more characteristic XRPD peaks at a two-theta angle of approximately 3.2, 5.9, 6.3, 7.4, 9.4, 16.9, 17.1, 17.3, or 22.8 degrees. In another embodiment, Form Q has one, two, three, four, five, six, seven, eight, nine, or more characteristic XRPD peaks as set forth in Figure 47. In another embodiment, Form Q has one, two, three, four, five, six, seven, eight, nine, or more characteristic XRPD peaks as set forth in Table 14.

In one embodiment, Form Q is prepared by purging Form F under N₂ protection for 20 minutes, heating to 120℃ under N₂ protection and then cooling to 25℃.
5.2.18 Form R

Provided herein is solid Form R, comprising compound 1. In one embodiment, Form R is a crystal form. In another embodiment, Form R is substantially pure. In another embodiment, Form R is anhydrate.

In one embodiment, Form R has an XRPD pattern substantially as shown in Figure 48. In one embodiment, Form R has one or more characteristic XRPD peaks at a two-theta angle of approximately 4.8, 15.2, or 17.6 degrees (Table 15) . In one embodiment, Form R has one or more characteristic XRPD peaks at a two-theta angle of approximately 4.8, 15.2, 16.8, 17.6, 18.1, or 20.0 degrees. In one embodiment, Form R has one or more characteristic XRPD peaks at a two-theta angle of approximately 4.8, 15.2, 16.0, 16.8, 17.6, 18.1, 18.6, 20.0, or 20.6 degrees. In another embodiment, Form R has one, two, three, four, five, six, seven, eight, nine, or more characteristic XRPD peaks as set forth in Figure 48. In another embodiment, Form R has one, two, three, four, five, six, seven, eight, nine, or more characteristic XRPD peaks as set forth in Table 15.

In one embodiment, provided herein is Form R having a DSC thermogram as depicted in Figure 49 comprising an exothermic event with a maximum at about 38.7 ℃ with onset temperature at about 25.6 ℃. In one embodiment, Form R has a DSC thermogram comprising an endothermic event with enthalpy (normalized) of about 36.5J/g.

In one embodiment, provided herein is Form R having a DSC thermogram as depicted in Figure 49 comprising an exothermic event with a maximum at about 191.3℃ with onset temperature at about 179.7℃. In one embodiment, Form R has a DSC thermogram comprising an endothermic event with a maximum at about 191.3℃. In one embodiment, Form R has a DSC thermogram comprising an endothermic event with an onset temperature at about 179.7℃. In one embodiment, Form R has a DSC thermogram comprising an endothermic event with enthalpy (normalized) of about 14.6J/g.

In one embodiment, provided herein is Form R having a TGA thermograph corresponding substantially to the representative TGA thermogram as depicted in Figure 50. In certain embodiments, Form R exhibits a TGA thermogram comprising a total mass loss of approximately 2.5%of the total mass of the sample between approximately 27.2℃ and approximately 150.0℃. Thus, in certain embodiment, Form R loses about 2.5%of the total mass when heated from about 27℃ to about 150℃.

In one embodiment, Form R is prepared by heating Form X prepared as described above to 150℃ under N₂ protection and cooling to ambient.
5.2.19 Form S

Provided herein is solid Form S, comprising compound 1. In one embodiment, Form S is a crystal form. In another embodiment, Form S is substantially pure. In another embodiment, Form S is a hydrate.

In one embodiment, Form S has an XRPD pattern substantially as shown in Figure 51. In one embodiment, Form S has one or more characteristic XRPD peaks at a two-theta angle of approximately 4.2, 6.8, or 10.5 degrees (Table 16) . In one embodiment, Form S has one or more characteristic XRPD peaks at a two-theta angle of approximately 4.2, 6.8, 10.5, 13.4, 8.5, or 12.9 degrees. In one embodiment, Form S has one or more characteristic XRPD peaks at a two-theta angle of approximately 4.2, 5.1, 6.8, 8.5, 10.5, 12.9, 13.4, 16.9, or 17.9 degrees. In another embodiment, Form S has one, two, three, four, five, six, seven, eight, nine, or more characteristic XRPD peaks as set forth in Figure 51. In another embodiment, Form S has one, two, three, four, five, six, seven, eight, nine, or more characteristic XRPD peaks as set forth in Table 16.

In one embodiment, provided herein is Form S having a DSC thermogram as depicted in Figure 52 comprising an exothermic event with a maximum at about 57.2℃ with onset temperature at about 25.9℃. In one embodiment, Form S has a DSC thermogram comprising an endothermic event with a maximum at about 57.2℃. In one embodiment, Form S has a DSC thermogram comprising an endothermic event with an onset temperature at about 25.9℃. In one embodiment, Form S has a DSC thermogram comprising an endothermic event with enthalpy (normalized) of about 94.9J/g.

In one embodiment, provided herein is Form S having a DSC thermogram as depicted in Figure 52 comprising an exothermic event with a maximum at about 174.5℃ with onset temperature at about 168.6℃. In one embodiment, Form S has a DSC thermogram comprising an endothermic event with a maximum at about 174.5℃. In one embodiment, Form S has a DSC thermogram comprising an endothermic event with an onset temperature at about 168.6℃. In one embodiment, Form S has a DSC thermogram comprising an endothermic event with enthalpy (normalized) of about 5.0J/g.

In one embodiment, provided herein is Form S having a DSC thermogram as depicted in Figure 52 comprising an exothermic event with a maximum at about 259.1℃ with onset temperature at about 247.2℃. In one embodiment, Form S has a DSC thermogram comprising an endothermic event with a maximum at about 259.1℃. In one embodiment, Form S has a DSC thermogram comprising an endothermic event with an onset temperature at about 247.2℃. In one embodiment, Form S has a DSC thermogram comprising an endothermic event with enthalpy (normalized) of about 58.3J/g.

In one embodiment, provided herein is Form S having a DSC thermogram as depicted in Figure 52 comprising an exothermic event with a maximum at about 285.0℃ with onset temperature at about 281.1℃. In one embodiment, Form S has a DSC thermogram comprising an endothermic event with a maximum at about 285.0℃. In one embodiment, Form S has a DSC thermogram comprising an endothermic event with an onset temperature at about 281.1℃. In one embodiment, Form S has a DSC thermogram comprising an endothermic event with enthalpy (normalized) of about 69.9J/g.

In one embodiment, provided herein is Form S having a TGA thermograph corresponding substantially to the representative TGA thermogram as depicted in Figure 53. In certain embodiments, Form S exhibits a TGA thermogram comprising a total mass loss of approximately 4.0%of the total mass of the sample between approximately 26.6℃ and approximately 120℃. Thus, in certain embodiment, Form S loses about 4.0%of the total mass when heated from about 27℃ to about 120℃.

In one embodiment, Form S is prepared from Form K by anti-solvent addition in THF/ACN and air drying at RT.
5.2.20 Amorphous form

Provided herein is an amorphous form of Compound 1.

In one embodiment, the amorphous form has an XRPD pattern substantially as shown in Figure 33. In one embodiment, the amorphous form has an XRPD pattern substantially as shown in Figure 34. In one embodiment, the amorphous form has an XRPD pattern substantially as shown in Figure 35. In one embodiment, the amorphous form has an XRPD pattern substantially as shown in Figure 36. In one embodiment, the amorphous form has an XRPD pattern substantially as shown in Figure 37.

In yet another embodiment, the amorphous form has an XRPD pattern substantially as shown in Figure 54.

In still another embodiment, the amorphous form is substantially pure. In certain embodiments, the substantially pure amorphous form is substantially free of other solid forms, e.g., crystalline amorphous forms.

In one embodiment, the amorphous form is prepared by slurring Form A in dichloromethane at about 25℃. In one embodiment, the amorphous form is prepared by slurring Form A in dichloromethane at about 25℃ for about 2 weeks. In one embodiment, the amorphous form is prepared by slurring Form A in dichloromethane at about 25℃ for about 4 days. In one embodiment, the amorphous form is prepared by an equilibration experiment at about 25℃ for a period of time (e.g., about 2 weeks or about 4 days) , wherein the solvent is dichloromethane.

In one embodiment, the amorphous form is prepared by an antisolvent addition experiment. In one embodiment, the solvent and antisolvent are dichloromethane and heptane, respectively. In one embodiment, the solvent and antisolvent are dichloromethane and ACN, respectively. In one embodiment, the solvent and antisolvent are dichloromethane and ethyl acetate, respectively.

In one embodiment, the amorphous form is prepared by a slow evaporation experiment. In one embodiment, the solvent is dichloromethane. In one embodiment, the solvent is THF. In one embodiment, the solvent is a mixture of dichloromethane and MeOH (about 1: 1 by volume) . In one embodiment, the solvent is a mixture of dichloromethane and EtOH (about 1: 1 by volume) . In one embodiment, the solvent is a mixture of THF and EtOAc (about 1: 1 by volume) . In one embodiment, the solvent is a mixture of THF and MeOH (about 1: 1 by volume) .

In one embodiment, the amorphous form is prepared by a fast cooling experiment. In one embodiment, the solvent is dichloromethane. In one embodiment, the solvent is a mixture of THF and acetone (about 1: 1 by volume) .

In one embodiment, the amorphous form is obtained by rotary evaporation in MeOH: DCM (1: 1 by volume) .
5.2.21 Mesylate Pattern A

Provided herein is Mesylate Pattern A, comprising compound 1. In one embodiment, Mesylate Pattern A is a crystal form. In another embodiment, Mesylate Pattern A is substantially pure.

In one embodiment, Mesylate Pattern A has an XRPD pattern substantially as shown in Figure 55. In one embodiment, Mesylate Pattern A has one or more characteristic XRPD peaks at a two-theta angle of approximately 4.9, 19.3, or 21.7 degress (Table 17) . In one embodiment, Mesylate Pattern A has one or more characteristic XRPD peaks at a two-theta angle of approximately 4.8, 15.5, 17.4, 19.3, 20.1, or 21.7 degrees. In one embodiment, Mesylate Pattern A has one or more characteristic XRPD peaks at a two-theta angle of approximately 3.9, 4.8, 14.4, 15.5, 17.4, 17.8, 19.3, 20.1, or 21.7 degrees. In another embodiment, Mesylate Pattern A has one, two, three, four, five, six, seven, eight, nine, or more characteristic XRPD peaks as set forth in Figure 55. In another embodiment, Mesylate Pattern A has one, two, three, four, five, six, seven, eight, nine, or more characteristic XRPD peaks as set forth in Table 17.

In one embodiment, Mesylate Pattern A is prepared by slurring Form X and 1.0 eq. methanesulfonic acid in acetone at RT for about 2 days, followed by centrifugation and vacuum drying.
5.2.22 Mesylate Pattern F

Provided herein is Mesylate Pattern F, comprising compound 1. In one embodiment, Mesylate Pattern F is a crystal form. In another embodiment, Mesylate Pattern F is substantially pure.

In one embodiment, Mesylate Pattern F has an XRPD pattern substantially as shown in Figure 56. In one embodiment, Mesylate Pattern F has one or more characteristic XRPD peaks at a two-theta angle of approximately 4.6, 5.0, or 20.0 degress (Table 18) . In one embodiment, Mesylate Pattern F has one or more characteristic XRPD peaks at a two-theta angle of approximately 4.6, 5.0, 13.7, 19.4, 20.0, or 20.8 degrees. In one embodiment, Mesylate Pattern F has one or more characteristic XRPD peaks at a two-theta angle of approximately 4.6, 5.0, 13.7, 16.1, 17.7, 18.9, 19.4, 20.0, or 20.8 degrees. In another embodiment, Mesylate Pattern F has one, two, three, four, five, six, seven, eight, nine, or more characteristic XRPD peaks as set forth in Figure 56. In another embodiment, Mesylate Pattern A has one, two, three, four, five, six, seven, eight, nine, or more characteristic XRPD peaks as set forth in Table 18.

In one embodiment, Mesylate Pattern F is prepared by slurring about 60 mg of Form K of compound 1 and 1.0 eq. methanesulfonic acid in 1.0mL acetone at RT for about 3 days, followed by centrifugation and vacuum drying.
5.2.23 L-Tartrate Pattern B

Provided herein is L-Tartrate Pattern B, comprising compound 1. In one embodiment, L-Tartrate Pattern B is a crystal form. In another embodiment, L-Tartrate Pattern B is substantially pure.

In one embodiment, L-Tartrate Pattern B has an XRPD pattern substantially as shown in Figure 57. In one embodiment, L-Tartrate Pattern B has one or more characteristic XRPD peaks at a two-theta angle of approximately 4.8, 14.2, or 17.4 degress (Table 19) . In one embodiment, L-Tartrate Patter B has one or more characteristic XRPD peaks at a two-theta angle of approximately 4.8, 14.0, 14.2, 14.5, 17.4, or 19.0 degrees. In one embodiment, L-Tartrate Pattern B has one or more characteristic XRPD peaks at a two-theta angle of approximately 4.8, 14.0, 14.2, 14.5, 16.8, 17.4, 19.0, 19.4, or 20.4 degrees. In another embodiment, L-Tartrate Pattern B has one, two, three, four, five, six, seven, eight, nine, or more characteristic XRPD peaks as set forth in Figure 57. In another embodiment, L-Tartrate Pattern B has one, two, three, four, five, six, seven, eight, nine, or more characteristic XRPD peaks as set forth in Table 19.

In one embodiment, L-Tartrate Pattern B is prepared by slurring Form K of compound 1 and 2.0 eq. L-Tartaric acid in acetone and THF/H₂O (19: 1, v/v) at RT about 2 days, followed by centrifugation and vacuum
5.2.24 L-Tartrate Pattern D

Provided herein is L-Tartrate Pattern D, comprising compound 1. In one embodiment, L-Tartrate Pattern D is a crystal form. In another embodiment, L-Tartrate Pattern D is substantially pure.

In one embodiment, L-Tartrate Pattern D has an XRPD pattern substantially as shown in Figure 58. In one embodiment, L-Tartrate Pattern B has one or more characteristic XRPD peaks at a two-theta angle of approximately 4.4, 5.1, or 20.0 degress (Table 20) . In one embodiment, L-Tartrate Patter D has one or more characteristic XRPD peaks at a two-theta angle of approximately 4.4, 5.1, 7.9, 17.3, 19.6, or 20.0 degrees. In one embodiment, L-Tartrate Pattern D has one or more characteristic XRPD peaks at a two-theta angle of approximately 4.4, 5.1, 7.9, 12.9, 17.3, 8.1, 19.6, 20.0, or 20.5 degrees. In another embodiment, L-Tartrate Pattern D has one, two, three, four, five, six, seven, eight, nine, or more characteristic XRPD peaks as set forth in Figure 58. In another embodiment, L-Tartrate Pattern D has one, two, three, four, five, six, seven, eight, nine, or more characteristic XRPD peaks as set forth in Table 20.

In one embodiment, L-Tartrate Pattern D is prepared slurrying about 60 mg of Form K of compound 1 and 2.4 eq. L-Tartaric acid in 1.0 mL acetone at RT for about 5 days, followed by centrifugation and vacuum drying.
5.2.25 Glycolate Pattern A

Provided herein is Glycolate Pattern A, comprising compound 1. In one embodiment, Glycolate Pattern A is a crystal form. In another embodiment, Glycolate Pattern A is substantially pure.

In one embodiment, Glycolate Pattern A has an XRPD pattern substantially as shown in Figure 59. In one embodiment, Glycolate Pattern A has one or more characteristic XRPD peaks at a two-theta angle of approximately 18.8, 21.9, or 23.3 degrees (Table 21) . In one embodiment, Glycolate Pattern A has one or more characteristic XRPD peaks at a two-theta angle of approximately 15.0, 16.9, 18.8, 20.2, 21.9, or 23.3 degrees. In one embodiment, Glycolate Pattern A has one or more characteristic XRPD peaks at a two-theta angle of approximately 7.5, 15.0, 16.9, 18.8, 20.2, 21.4, 21.9, 23.3, or 25.6 degrees. In another embodiment, Glycolate Pattern A has one, two, three, four, five, six, seven, eight, nine, or more characteristic XRPD peaks as set forth in Figure 59. In another embodiment, Glycolate Pattern A has one, two, three, four, five, six, seven, eight, nine, or more characteristic XRPD peaks as set forth in Table 21.

In one embodiment, Glycolate Pattern A is prepared slurrying Form K of compound 1 and 2.0 eq. glycolic acid in EtOH at RT for about 2 days, followed by centrifugation and vacuum drying.
5.2.26 Glycolate Pattern B

Provided herein is Glycolate Pattern B, comprising compound 1. In one embodiment, Glycolate Pattern B is a crystal form. In another embodiment, Glycolate Pattern B is substantially pure.

In one embodiment, Glycolate Pattern B has an XRPD pattern substantially as shown in Figure 60. In one embodiment, Glycolate Pattern B has one or more characteristic XRPD peaks at a two-theta angle of approximately 4.8, 5.1, or 15.4 degrees (Table 22) . In one embodiment, Glycolate Pattern B has one or more characteristic XRPD peaks at a two-theta angle of approximately 4.8, 5.1, 15.4, 19.3, 20.33, or 20.6 degrees. In one embodiment, Glycolate Pattern B has one or more characteristic XRPD peaks at a two-theta angle of approximately 4.8, 5.1, 15.4, 19.0, 19.3, 19.6, 20.3, 20.6, or 21.5 degrees. In another embodiment, Glycolate Pattern B has one, two, three, four, five, six, seven, eight, nine, or more characteristic XRPD peaks as set forth in Figure 60. In another embodiment, Glycolate Pattern B has one, two, three, four, five, six, seven, eight, nine, or more characteristic XRPD peaks as set forth in Table 22.

In one embodiment, Glycolate Pattern B is prepared slurrying about 60 mg of Form K of compound 1 and 2.0 eq. glycolic acid in 1.5 mL EtOH at RT for about 3 days, followed by centrifugation and vacuum drying.
5.2.27 Fumarate Pattern B

Provided herein is Fumarate Pattern B, comprising compound 1. In one embodiment, Fumarate Pattern B is a crystal form. In another embodiment, Fumarate Pattern B is substantially pure.

In one embodiment, Fumarate Pattern B has an XRPD pattern substantially as shown in Figure 61. In one embodiment, Fumarate Pattern B has one or more characteristic XRPD peaks at a two-theta angle of approximately 4.3, 17.6, or 18.1 degrees (Table 23) . In one embodiment, Fumarate Pattern B has one or more characteristic XRPD peaks at a two-theta angle of approximately 4.3, 13.8, 17.3, 17.6, 18.2, or 26.0 degrees. In one embodiment, Fumarate Pattern B has one or more characteristic XRPD peaks at a two-theta angle of approximately 4.3, 8.2, 13.8, 17.3, 17.6, 18.2, 18.8, 24.3, or 26.0 degrees. In another embodiment, Fumarate Pattern B has one, two, three, four, five, six, seven, eight, nine, or more characteristic XRPD peaks as set forth in Figure 61. In another embodiment, Fumarate Pattern B has one, two, three, four, five, six, seven, eight, nine, or more characteristic XRPD peaks as set forth in Table 23.

In one embodiment, Fumarate Pattern B is prepared slurrying Form K of compound 1 and 2.0 eq. Fumaric acid in EtOAc at RT for about 2 days, followed by centrifugation and vacuum drying.
5.2.28 Tosylate Pattern E

Provided herein is Tosylate Pattern E, comprising compound 1. In one embodiment, Tosylate Pattern E is a crystal form. In another embodiment, Tosylate Pattern E is substantially pure.

In one embodiment, Tosylate Pattern E has an XRPD pattern substantially as shown in Figure 62. In one embodiment, Tosylate Pattern E has one or more characteristic XRPD peaks at a two-theta angle of approximately 4.5, 14.7, or 17.6 degrees (Table 24) . In one embodiment, Tyosylate Pattern E has one or more characteristic XRPD peaks at a two-theta angle of approximately 4.5, 10.1, 114.7, 15.6, 17.6, or 22.1 degrees. In one embodiment, Tosylate Pattern E has one or more characteristic XRPD peaks at a two-theta angle of approximately 4.5, 8.7, 10.1, 14.7, 15.6, 17.6, 18.1, 20.6, or 22.1 degrees. In another embodiment, Tosylate Pattern E has one, two, three, four, five, six, seven, eight, nine, or more characteristic XRPD peaks as set forth in Figure 62. In another embodiment, Tosylate Pattern E has one, two, three, four, five, six, seven, eight, nine, or more characteristic XRPD peaks as set forth in Table 24.

In one embodiment, Tosylate Pattern E is prepared slurrying about 60 mg of Form K of compound 1 and 2.0 eq. p-Toluenesulfonic acid in 1.5mL acetone at RT for about 3 days, and at 50-5℃ cyclying for about 2 days, followed by centrifugation and vacuum drying.
5.3 METHODS OF MAKING

The solid forms provided herein can be prepared by the methods described herein, or by techniques, including, but not limited to, heating, cooling, freeze drying, spray drying, temperature cycling, lyophilization, quench cooling the melt, rapid solvent evaporation, slow solvent evaporation, solvent recrystallization, antisolvent addition, slurry recrystallization, crystallization from the melt, desolvation, recrystallization in confined spaces, such as, e.g., in nanopores or capillaries, recrystallization on surfaces or templates, such as, e.g., on polymers, recrystallization in the presence of additives, such as, e.g., salt counter-molecules, cocrystal counter-molecules, desolvation, dehydration, rapid cooling, slow cooling, exposure to solvent and/or water, drying, including, e.g., vacuum drying, solid vapor diffusion, liquid vapor diffusion, sublimation, grinding (including, e.g., cryo-grinding and solvent-drop grinding) , microwave-induced precipitation, sonication-induced precipitation, laser-induced precipitation, and precipitation from a supercritical fluid. The particle size of the resulting solid forms, which can vary (e.g., from nanometer dimensions to millimeter dimensions) , can be controlled, e.g., by varying crystallization conditions, such as, e.g., the rate of crystallization and/or the crystallization solvent system, or by particle-size reduction techniques, e.g., grinding, milling, micronizing, or sonication.

In certain embodiments, reverse antisolvent addition crystallization is a process that involves the addition of an antisolvent to a solution containing the solute. The controlled addition of antisolvent reduces solubility in the mixture and triggers recrystallization. Two common ways of operation are either antisolvent addition to product solution or product solution addition to antisolvent (reverse addition) .

In certain embodiments, provided herein are antisolvent addition methods for making a solid form of Compound 1, comprising 1) obtaining a close-to saturated or saturated solution of Compound 1 in a polar solvent; 2) slowly adding a non-polar solvent into the solution at a temperature (e.g., about 22 ℃ to about 26 ℃) for a period of time (e.g., about 5 days) ; 3) filtering the solution to yield a solid if there is precipitation; and 4) evaporating the solvent to collect a solid if there is no precipitation after step 2. In one embodiment, the solution may be seeded.

In certain embodiments, provided herein are reverse antisolvent addition methods for making a solid form of Compound 1, comprising 1) obtaining a close-to saturated or saturated solution of Compound 1 in a polar solvent; 2) slowly adding the solution into a non-polar solvent at a temperature (e.g., about 22 ℃ to about 26 ℃) for a period of time (e.g., about 5 days) ; 3) filtering the solution to yield a solid if there is precipitation; and 4) evaporating the solvent to collect a solid if there is no precipitation after step 2. In one embodiment, the solution may be seeded.

In certain embodiments, equilibrium crystallization is a process where crystals form from a cooling melt in a closed system. Chemical equilibrium is maintained until the melt has completely crystallized. Crystal growth is a dynamic process occurring in equilibrium where solute molecules or atoms precipitate out of solution, and dissolve back into solution. A system in which crystallization and dissolution occur at the same rate is in dynamic equilibrium.

In certain embodiments, crystallization is a natural process that happens when the materials solidify from a liquid, it can also occur when a solid precipitates from a liquid or gas. The crystallization process occurs resulting in a change in the physical property of the liquid, such as the change in temperature, change in its acidity. The three major stages in the process of Crystallization are: 1) Supersaturation of Solution: It can be done in three ways: Heating the solution, Cooling the solution, and Salting it out. 2) Nucleation: This takes place in several steps. During their random motion, the atoms/molecules/ions will come closer to one another, and form aggregates called Clusters. 3) Crystal Growth: Once the crystals are formed, nuclei formation stops, and crystal growth begins.

In certain embodiments, provided herein are slow evaporation methods for making a solid form of Compound 1, comprising 1) obtaining a close-to saturated or saturated solution of Compound 1 in a solvent; 2) slowly evaporating the solution at a temperature (e.g., about 22 ℃ to about 26 ℃) for a period of time (e.g., about 5 days) ; 3) filtering the solution to yield a solid if there is precipitation; and 4) evaporating the solvent to collect a solid if there is no precipitation after step 2. In one embodiment, the solution may be seeded.

In certain embodiments, provided herein are slurry methods for making a solid form of Compound 1, comprising 1) obtaining a slurry of Compound 1 in a solvent; 2) stirring the slurry for a period of time; 3) collecting a solid from the slurry by filtration (e.g., centrifuge filtration) . In one embodiment, the solution may be seeded.

In certain embodiments, provided herein are equilibration methods for making a solid form of Compound 1, comprising 1) obtaining a slurry of Compound 1 in a solvent; 2) stirring the slurry for a period of time (e.g., about 2 weeks or about 4 days) , wherein the slurry is optionally protected from light; 3) collecting a solid from the slurry by filtration (e.g., centrifuge filtration) . In one embodiment, the solution may be seeded.

In certain embodiments, provided herein are thermo conversion methods for making a solid form of Compound 1, comprising heating a starting solid form of Compound 1 to a temperature for a period of time.
5.4 PHARMACEUTICAL COMPOSITIONS

Solid forms of Compound 1 provided herein are useful for the preparation of pharmaceutical compositions, comprising an effective amount of a solid form of Compound 1 and a pharmaceutically acceptable excipient.

In certain embodiments, provided herein are compositions comprising one or more solid forms of Compound 1. Also provided herein are compositions comprising: (i) one or more solid forms of Compound 1 provided herein, and (ii) other active or inactive ingredient (s) .

In one embodiment, the pharmaceutical compositions provided herein comprise a solid form of Compound 1 and one or more pharmaceutically acceptable excipients.

In certain embodiments, the pharmaceutical composition provided herein comprise one of Forms A, B, C, E, F, G, H, I, J, K, L, M, N, X, O, P, Q, R, or S of Compound 1. In certain embodiments, the pharmaceutical compositions provided herein comprise Form K of Compound 1.

In certain embodiments, the pharmaceutical composition provided hereine comprise salts selected from Mesylate Pattern A, Mesylate Pattern F, L-tartrate Pattern B, L-tartrate Pattern D, Glycolate Pattern A, Glycolate Pattern B, Fumarate Pattern B, Tosylate Pattern E, Sulfate Pattern B, Maleate Pattern B, Besylate Pattern B, Oxalate Pattern C, or Hydrobromide Pattern A. In certain embodiments, the pharmaceutical composition provided herein comprise Mesylate Pattern A.

Another embodiment provided herein is a process for preparing a pharmaceutical composition comprising Compound 1, the process comprising mixing one of Forms A, B, C, E, F, G, H, I, J, K, L, M, N, X, O, P, Q, R, S, or an amorphous form of Compound 1 with a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition provided herein comprise Mesylate Pattern A, Mesylate Pattern F, L-tartrate Pattern B, L-tartrate Pattern D, Glycolate Pattern A, Glycolate Pattern B, Fumarate Pattern B, Tosylate Pattern E, Sulfate Pattern B, Maleate Pattern B, Besylate Pattern B, Oxalate Pattern C, or Hydrobromide Pattern A of Compound 1 with a pharmaceutically acceptable excipient. Another embodiment provided herein is a process for preparing a pharmaceutical composition comprising Compound 1, the process comprising mixing Form K of Compound 1 with a pharmaceutically acceptable excipient. Another embodiment provided herein is a process for preparing a pharmaceutical composition comprising Compound 1, the process comprising mixing an amorphous form of Compound 1 with a pharmaceutically acceptable excipient.

The present embodiments can be understood more fully by reference to the detailed description and examples, which are intended to exemplify non-limiting embodiments.
6 EXAMPLES

The following Examples are presented by way of illustration, not limitation.

In the following examples, the following abbreviations are used:

6.2 Preparation of polymorphs
6.2.21 Form A

Form A is a physical mixture of Form B and Form F with high crystallainity. DSC of Form A showed an exothermic peak at T_onset of 216.4 ℃ with an enthalpy of about 3J/g, followed by a melting peak at T_onset of 276.1 ℃ with a melting enthalpy of about 90J/g (Figure 3) . TGA showed about 1.3%weight loss at about 200 ℃ (Figure 4) . ¹H-NMR showed about 0.7%isopropanol by weight, which is about 0.1 equivalent by molar ratio.

The crude product of Compound 1 was prepared by the process in Example 14 of WO2021219070, i.e., paragraph [0209] , which is incorporated herein by reference in its entirety. Form A was prepared by one of the following procedures from the crude product of Compound 1:

(1) Form A was made by slurring the crude product in methyl tert-butyl ether and then recrystallization in isopropyal and water (10: 1; v/v) .

(2) About 50mg of the crude product of Compound 1 was equilibrated in a suitable amount of solvent (e.g., water, IPAc, or MeOH/water (20: 80, v/v) ) at 25℃ for 2 weeks or 4 days on a stirring plate and protected from light by covering with aluminum foil. The obtained suspension was filtered to provide Form A.

(3) About 50mg or 100 mg of the crude product of Compound 1 was equilibrated in a suitable amount of solvent (e.g., water, acetone, or MEK) at 50℃ for 1 week on a stirring plate and protected from light by covering with aluminum foil. The obtained suspension was filtered to provide Form A.

Figure 2 describes the XRPD pattern of Form A.
6.2.22 Form B

Form B is an anhydrate. Form B was crystalline and also showed a sharp melting peak at T_onset of 279.3℃ with a melting enthalpy of about 81J/g (Figure 6) . TGA shows about 1.3%weight loss at about 200℃ (Figure 7) . ¹H-NMR showed no residual solvent.

Form B was obtained from majority of the solvents in equilibration experiments at 25℃ and 50℃. In particular, Form B was prepared by one of the following procedures:

(1) About 300 mg of Compound 1 was equilibrated in 3mL of EtOH at 50℃ for 2 days. Solids were isolated by centrifugal filtration. After drying at 50℃ under vacuum for 2h, obtained dry cake was analyzed by XRPD. Form B was obtained, and the yield is about 77%. No residual solvent was detected by ¹H-NMR.

(2) About 300mg of Compound 1 was equilibrated in 4mL of ACN/water (80: 20, v: v) at 50℃ for 3 days. The suspension was cooled to 5℃ under agitation for 6h. Solids were isolated by centrifugal filtration. After drying at 50℃ under vacuum for 3 days, obtained dry cake was analyzed by XRPD, DSC, TGA and ¹H-NMR. Form B was obtained and the yield is about 80%. No residual solvent was detected by ¹H-NMR.

(3) Form B was prepared by air drying Form G in fume hood over 4 days;

(4) Form B was prepared by slow evaporation from 1, 4-dioxane.

Figure 5 described the XRPD pattern of Compound 1 free base Form B

Table 1. XRPD peaks table of Form B

6.2.23 Form C

Form C is a THF solvate. Form C was crystalline. TGA showed about 2.7%weight loss at about 200℃ (Figure 10) . 1H-NMR showed about 2.1%THF by weight, which was about 0.25 equivalent by molar ratio. Form C showed no form change under ambient condition over 1 week.

Form C was prepared by the following procedure: About 300mg of Compound 1 was equilibrated in 1.5mL of THF at 50℃ for 2 h to give suspension. Then the suspension was cooled to 25℃. After the suspension was stirred at 25℃ for 18h, the solid was isolated by centrifugal filtration and analyzed by XRPD. Form C was obtained.

The DSC thermogram of Form C showed multiple thermal events (Figure 9) . The DSC thermogram of Form C as depicted in Figure 9 comprises an endothermic event with a maximum at about 33.1 ℃ with onset temperature at about 30.6 ℃ with enthalpy (normalized) of about 5.7 J/g, an exothermic event with a maximum at about 73.8 ℃ with onset temperature at about 60.9 ℃ with enthalpy (normalized) of about 7.1 J/g, an exothermic event with a maximum at about 213 ℃ with onset temperature at about 201 ℃ with enthalpy (normalized) of about 33.0 J/g, an exothermic event with a maximum at about 248.5 ℃ with onset temperature at about 233.7 ℃ with enthalpy (normalized) of about 24.3 J/g, and an exothermic event with a maximum at about 277.9 ℃ with onset temperature at about 272.3 ℃ with enthalpy (normalized) of about 34.0 J/g.

Figure 8 described the XRPD pattern of Form C.

Table 2. XRPD peaks table of Form C

6.2.24 Form E

Form E is a 1, 4-dioxane and water hetero solvate. Form E was crystalline. TGA showed two weight loss steps, i.e., about 2.6%up to about 80℃ and about 5.4%from 80℃ to about 200℃ (Figure 13) . 1H-NMR showed about 7.6%1, 4-dioxane by weight which is about 0.79 equivalent by molar ratio. KF showed that Form E contained about 4.1%water by weight which was about 2.1 equivalent by molar ratio. After air drying in fume hood over 1 month, Form E converted to a metastable form, Form H.

The DSC of Form E showed multiple thermal events (Figure 12) . The DSC thermogram of Form E as depicted in Figure 12 comprises an endothermic event with a maximum at about 33.3 ℃ with onset temperature at about 30.7 ℃ with enthalpy (normalized) of about 2.3 J/g, an endothermic event with a maximum at about 62.5 ℃ with onset temperature at about 48.4 ℃ with enthalpy (normalized) of about 10.6 J/g, an endothermic event with a maximum at about 126.6 ℃ with onset temperature at about 105.1 ℃ with enthalpy (normalized) of about 48.6 J/g, an endothermic event with a maximum at about 172.8 ℃ with onset temperature at about 167.0 ℃ with enthalpy (normalized) of about 4.1 J/g, an endothermic event with a maximum at about 243.0 ℃ with onset temperature at about 232.7 ℃ with enthalpy (normalized) of about 59.3 J/g, and an endothermic event with a maximum at about 279.5 ℃with onset temperature at about 277.7 ℃ with enthalpy (normalized) of about 63.3 J/g.

Form E was obtained by an antisolvent experiment from 1, 4-dioxane/water (5: 4, v/v) . In particular, about 300mg of Compound 1 was dissolved in 6.0 mL of 1, 4-dioxane to get a clear solution. 4.8 mL water was added into the clear solution dropwise. At first, oily substance was obtained. After stirring at 25℃ for 1 day, suspension was obtained. Solids were isolated by centrifugal filtration and analyzed by XRPD. Form E was obtained.

Figure 11 described the XRPD pattern of Form E

Table 3. XRPD peaks table of Form E

6.2.25 Form F

Form F is a hydrate or a channel hydrate. Form F was crystalline. TGA showed about 2.7%weight loss at about 200℃ (Figure 16) . ¹H-NMR showed about 1.1%acetone by weight which was about 0.11 equivalent by molar ratio. KF results showed that Form F contained about 2.0%water which was about 1.0 equivalent by molar ratio.

The DSC thermogram of Form F showed multiple thermal events (Figure 15) . The DSC thermogram of Form F as depicted in Figure 15 comprises an endothermic event with a maximum at about 33.1 ℃ with onset temperature at about 30.6 ℃ with enthalpy (normalized) of about 3.2 J/g, an endothermic event with a maximum at about 91.1 ℃ with onset temperature at about 90.0 ℃ with enthalpy (normalized) of about 8.1 J/g, an endothermic event with a maximum at about 149.3 ℃ with onset temperature at about 149.0 ℃ with enthalpy (normalized) of about 0.8 J/g, an endothermic event with a maximum at about 212.2 ℃ with onset temperature at about 204.8 ℃ with enthalpy (normalized) of about 35.5 J/g, an endothermic event with a maximum at about 225.2 ℃ with onset temperature at about 217.6 ℃with enthalpy (normalized) of about 47.5 J/g, and an endothermic event with a maximum at about 281.0 ℃ with onset temperature at about 276.0 ℃ with enthalpy (normalized) of about 82.3 J/g.

Competitive equilibration experiments between Form B and Form F were conducted on Form A, as Form A is the physical mixture of the two polymorphs. In most solvents, Form B was obtained, suggesting Form B is more stable than Form F. Meanwhile, the appearance of Form F solely in acetone and MEK may be via transient solvates.

Form F was obtained from acetone and MEK by equilibration at 25℃. In particular, about 50mg of Compound 1 was equilibrated in a suitable amount of acetone or MEK at 25℃ for 2 weeks on a stirring plate and protected from light by covering with aluminum foil. The obtained suspension was filtered. The solid part (wet cakes) was investigated by XRPD. Form F was obtained.

Figure 14 describes the XRPD pattern of Form F

Table 4. XRPD peaks table of Form F

6.2.26 Form G

Form G is a metastable solid form. Form G is a 1, 4-dioxane solvate. Form G was crystalline. DSC showed an endothermic peak at T_onset of 60.8℃ with an enthalpy of about 24J/g, and a melting peak at T_onset of 272.4℃ with a melting enthalpy of about 61J/g (Figure 18) . TGA showed about 5.3%weight loss at about 200℃ (Figure 19) . ¹H-NMR showed about 13.4%1, 4-dioxane by weight which is about 1.5 equivalent by molar ratio. After air drying in fume hood over 2 days, ¹H-NMR showed about 1.8%1, 4-dioxane by weight which is about 0.2 equivalent by molar ratio. After air drying in fume hood over 4 days, Form G converted to Form B, suggesting that Form G is a metastable 1, 4-dioxane solvate.

Fom G was obtained from 1, 4-dioxane by equilibration at 25℃. In particular, about 50mg of Compound 1 was equilibrated in a suitable amount of 1, 4-dioxane at 25℃ for 2 weeks on a stirring plate and protected from light by covering with aluminum foil. The obtained suspension was filtered. The solid part (wet cakes) was investigated by XRPD. Form G was obtained.

Figure 17 described the XRPD pattern of Form G

Table 5. XRPD peaks table of Form G

6.2.27 Form H

Form H is a metastable form. Form H was crystalline. The XRPD pattern of Form H had only one peak before 10 degree in 2theta. ¹H-NMR showed about 0.4%1, 4-dioxane by weight which is about 0.04 equivalent by molar ratio.

The DSC thermogram of Form H showed multiple thermal events (Figure 21) . The DSC thermogram of Form H as depicted in Figure 21 comprises an endothermic event with a maximum at about 58.7 ℃ with onset temperature at about 39.3 ℃ with enthalpy (normalized) of about 33.9 J/g, an endothermic event with a maximum at about 118.8 ℃ with onset temperature at about 93.8 ℃ with enthalpy (normalized) of about 41.1 J/g, an endothermic event with a maximum at about 172 ℃ with onset temperature at about 166.2 ℃ with enthalpy (normalized) of about 2.2 J/g, an endothermic event with a maximum at about 237.8 ℃ with onset temperature at about 228.2 ℃ with enthalpy (normalized) of about 46.4 J/g, and an endothermic event with a maximum at about 275.8 ℃ with onset temperature at about 267.5 ℃with enthalpy (normalized) of about 45.4 J/g.

Form H was obtained by air drying Form E in fume hood at 25℃ over 1 month. Form H was obtained.

Figure 20 described the XRPD pattern of Form H.

Table 6. XRPD peaks table of Form H

6.2.28 Form I

Form I is an anhydrate. Form I was crystalline. Competitive equilibration experiments in ACN and EA at 5℃ and 25℃ showed that Form I is less stable than Form B.

Form I was prepared by heating Form C to 150℃ and then cooling down to ambient temperature.

Figure 22 described the XRPD pattern of Form I.

Table 7. XRPD peaks table of Form I

6.2.29 Form J

Form J is a crystalline form. Form J was prepared by the following procedure:
About 50mg of Compound 1 was equilibrated in a suitable amount of solvent (e.g.,
DMSO/IPA/water (5: 8: 1, v/v/v) , or DMSO) at 25℃ for 2 weeks or 4 days on a stirring plate and protected from light by covering with aluminum foil. The obtained suspension was filtered. The solid part (wet cakes) was investigated by XRPD. Form J was obtained.

Figure 23 describes the XRPD pattern of Form J.
6.2.30 Form K

Form K is an anhydrate. Form K was crystalline. DSC showed a melting peak at T_onset of 225.8℃ with an enthalpy of about 59J/g, followed by an exothermic recrystallization peak at T_onset of 245.4℃ with an enthalpy of about 6J/g, and then a melting peak of T_onset of 279.7℃ with a melting enthalpy of about 9J/g appears (Figure 25A) . TGA showed about 1.0%weight loss at about 200℃ (Figure 26A) . No residual solvent was detected by ¹H-NMR.

The crude product of Compound 1 was prepared by the process in Example 14 of WO2021219070, i.e., paragraph [0209] . Form K was prepared by one of the following two procedures:

(1) About 50mg of the crude product of Compound 1 was equilibrated in a suitable amount of THF and water (9: 1; v/v) at 25℃ for 2 weeks on a stirring plate and protected from light by covering with aluminum foil. The obtained suspension was filtered. The solid part (wet cake) was investigated by XRPD. Form K was obtained.

(2) About 50mg of the crude product of Compound 1 was equilibrated in a suitable amount of THF and water (9: 1; v/v) at 60℃ for 1 week on a stirring plate and protected from light by covering with aluminum foil. The obtained suspension was filtered, and then dried at 50℃ for 12h under vacuum to remove excessive THF residue. Form K was obtained.

Figure 24A described the XRPD pattern of Form K.

Table 8A. XRPD peaks table of Form K.

Figure 24B described the XRPD pattern of Form K that was used as the starting material to prepare polymorph Forms X, O, P, Q, R, or S. Form K was anhydrate.

Table 8B. XRPD peaks table of Form K

6.2.31 Form L

Form L is a hydrate. Form L was crystalline. The DSC showed dehydration peak at T_onset of 24.2℃ with an enthalpy of about 49J/g, followed by a melting peak at T_onset of 195.1℃ with a melting enthalpy of about 44J/g (Figure 28) . No residual solvent was detected by 1H-NMR. TGA shows about 1.9%weight loss at about 150℃ (Figure 29) . The KF result showed Form L contained about 3.3%water which was about 1.5 equivalent by molar ratio.

Form L was obtained by equilibration in MeOH at 50℃. In particular, about 100 mg of Compound 1 was equilibrated in 1 mL of MeOH at 50℃ for 12 days on a stirring plate and protected from light by covering with aluminum foil. The resulted suspension was filtered. The solid part (wet cake) was investigated by XRPD. Form L was obtained.

Figure 27 described the XRPD pattern of Form L.

Table 9. XRPD peaks table of Form L

6.2.32 Form M

Form M is a hydrate/solvate. Form M was crystalline. The appearance of Form M may be via a transient solvate.

Form M was obtained from MeOH/water (20: 80, v/v, a. w. =0.9) during water activity experiment. Inparticular, Form K of Compound 1 was used to prepare a saturated solution in MeOH/water (20: 80, v/v, a. w. = 0.9) at 25 ℃. Then 5 mg of Form K of Compound 1 and 5 mg of Form L of Compound 1 were added to the saturated solutions. The obtained suspensions were stirred at 25℃ for 1 week. Wet solids were isolated by centrifugal filtration, and Form M was obtained.

Figure 30 describes the XRPD pattern of Form M.

Table 3. XRPD peaks table of Form M

6.2.33 Form N

Form N was crystalline.

Fomr N was obtained by slurrying Form B in (THF/water=9v/1v) /IPA=4v/1v at 25℃. In particular, Form N was prepared by equilibrating about 50mg of Compound 1 in a suitable amount of solvent (e.g., (THF/water=9v/1v) /IPA=4v/1v) at 25℃ for 2 weeks or 4 days on a stirring plate and protected from light by covering with aluminum foil. The obtained suspension was filtered. The solid part (wet cake) was investigated by XRPD.

Figure 31 describes the XRPD pattern of Compound 1 Form N.
6.2.34 Form X

Form X was hydrate. Form X was crystalline. Form X was prepared from Form K by anti-solvent addition in THF/ACN to obtain a solid part (wet cake) , then air drying the solid part (wet cake) for about 10 min to obtain Form X.

Figure 42 described the XRPD pattern of Compund 1 Form X.

Table 11. XRPD peaks table of Form X

6.1.16. Form O

Form O was crystalline. Form O was metastable form. Form O was prepared from Form K by anti-solvent addition of MeOH/DCM/ACN to obtain a slurry; air dried the slurry for about 1 hour then stirred to obtain Form O.

Figure 45 described the XRPD pattern of Compound 1 Form O.

Table 12. XRPD peaks table of Form O

6.2.35 Form P

Form P was a metastable form. Form P was crystalline. Form P was obtained from Form O prepared above after slurrying for about 1 day.

Figure 46 described the XRPD pattern of Compound 1 Form P.

Table 13. XRPD peaks table of Form P.

6.2.36 Form Q

Form Q is a metastable form. Form Q was crystalline. Form Q was prepared by purging Form F prepared above under N₂ protection for about 20 minutes, then heated to 120℃ under N₂ protection and then cooled to 25℃.

Figure 47 described the XRPD pattern of Compound 1 Form Q.

Table 14. XRPD peaks table of Form Q

6.2.37 Form R

Form R was an anydrate. Form R was crystalline. Form R was prepared by heating Form X prepared above to 150^oc under N₂ protection and cooling to ambient.

Figure 48 depicts the XRPD pattern of Form R.

Table 15. XRPD peaks table of Compound 1 Form R

6.2.38 Form S

Form S wasa hydrate. Form S was crystalline. Form S was prepared from Form K by anti-solvent addition in THF/ACN and air dried at RT.

Figure 51 depicts the XRPD pattern of Compound 1 Form S.

Table 16. The XRPD peaks table of Form S

6.2.39 Amorphous Form

Amorphous form was prepared by the procedure below.

About 50mg of Compound 1 was equilibrated in a suitable amount of solvent (e.g., dichloromethane) at 25℃ for 2 weeks or 4 days on a stirring plate and protected from light by covering with aluminum foil. The obtained suspension was filtered to produce the amorphous form. Figure 33 described the XRPD pattern of the amorphous form of Compund 1.

The amorphous form was also prepared by dissolving about 50mg of Compound 1 in a good solvent, and adding an antisolvent slowly into the obtained solution. Precipitates were collected by filtration. The solid part (wet cake) was investigated by XRPD. Figure 34 described the XRPD pattern of the amorphous forms of Compound 1 obtained from this procedure. The good solvent and the antisolvent were one of the following three pairs: (1) DCM and Heptane (0.5V) , (2) DCM and ACN (0.5V) , and (3) THF and ethyl acetate.

The amorphous forms were also prepared by a slow evaporation experiment. About 30 mg of Compound 1 was dissolved at 25℃ in DCM, THF, DCM: MeOH (1: 1, v/v) , DCM: EtOH (1: 1, v/v) , THF: EA (1: 1, v/v) , or THF: MeOH (1: 1, v/v) . After filtration, a clear solution was obtained and was put into an ice bath (0 ℃) and agitated. Precipitates were collected by filtration to give the amorphous form. Figures 35 and 36 described the XRPD patterns of the amorphous forms of Compound 1 obtained from this procedure.

The amorphous form was also prepared by fast cooling experiment. Approximately 50mg of Compund 1 was dissolved in DCM or THF: acetone (1: 1, v/v) at 25℃ or 50℃. After filtration, a clear solution was obtained and was put on ice bath (0 ℃) and agitated. Precipitates were collected by filtration. When no precipitation was obtained, the solution was put in -20 ℃ for crystallization. Figure 37 described the amorphous forms of Compound 1 obtained from this procedure.

The amourphous form was also obtained by rotary evaporation in MeOH: DCM (1: 1, v/v) at 40℃.

Figure 54 described the XRPD of Compound 1 amorphous form prepared by the rotary evaporation method.

Polymorphic behaviors of Compound 1 were investigated by equilibration at 25 ℃ and 50 ℃, crystallization from hot saturated solutions by fast cooling, slow evaporation, and precipitation by addition of antisolvent. Relative stability of relevant polymorphs was investigated by competitive slurry experiments.
6.3 INTERRELATIONSHIP INVESTIGATION OF POLYMORPHS
6.3.21 Competitive equilibration experiments of Form B and Form I

Competitive experiments were conducted to determine thermodynamic relationships of Form B and Form I. Form B was used to prepare saturated solutions in different solvents at 5℃ and 25℃. Then 5mg of Form B and 5mg of Form I were respectively added to the saturated solutions. Obtained suspensions were stirred at 25℃ and 5℃ for 12 days. Wet solids were isolated by centrifugal filtration and investigated by XRPD.

Table 25. Competitive equilibration experiments of Form B and Form I at 5℃and 25℃

6.3.22 Competitive equilibration experiments of Form B and Form K

Competitive experiments were conducted to determine thermodynamic relationships of Form B and Form K. Form B were used to prepare saturated solutions in different solvents at 5℃, 25℃ 50℃, 70℃, 90℃ and 100℃. Then 5mg of Form B and 5mg of Form K were added to the saturated solutions respectively. Obtained suspensions were stirred at 5℃, 25℃, 50℃, 70℃, 90℃ and 100℃ for 3-5 days. Wet solids were isolated by centrifugal filtration and investigated by XRPD.

Table 26. Competitive equilibration experiments of Form B and Form K at 5℃, 25℃ and 50℃

Explanation “//” : Not carried out

Table 27 Competitive equilibration experiments of Form B and Form K at 70℃, 90℃ and 100℃

Explanation “//” : Not carried out
6.3.23 Water activity experiments of Form K and Form L at 25℃

Water activity experiments were conducted at 25℃ in MeOH/water, IPA/water, and ACN/water systems to determine critical water activity between Form K and Form L. Form K was used to prepare saturated solutions in MeOH/water, IPA/water, and ACN/water with different water activities at 25℃. Then 5mg of Form K and 5mg of Form L were added to the saturated solutions. Obtained suspensions were stirred at 25℃ for 1 week. Wet solids were isolated by centrifugal filtration and analyzed by XRPD.

Table 28. Water activity study of Form K and Form L at 25℃

Explanation: The water activity of a binary solvent system is calculated based on UNIFAC
method (UNIQUAC Functional-group Activity Coefficients) .
6.3.24 Water sorption and desorption experiments

Water sorption and desorption behavior of Form B.

Form B was obtained by equilibrating the starting materials in Form A in Acetone/water (30: 70, v/v) a. w. =0.9. Form B was investigated by DVS at 25℃ with a cycle of 40-0-95-0-40%RH. dm/dt is 0.002. Min equilibration time is 60 min. Max equilibration time is 360 min. XRPD was measured after the DVS test to determine form change.

Table 29. Water sorption and desorption experiments of Form B

Explanation “//” Not carried out

Hygroscopicity of Form B was evaluated by dynamic vapor sorption (DVS) test at 25℃. Form B was slightly hygroscopic. It absorbed about 1.3%water from 40%RH to 95%RH at 25℃. No form changed after the DVS test.

Water sorption and desorption behavior of Form K

Form K was investigated by DVS at 25℃ with a cycle of 40-0-95-0-40%RH. dm/dt is 0.002. Min equilibration time is 60 min. Max equilibration time is 360 min. XRPD was measured after DVS test to determine form change.

Table 30. Water sorption and desorption experiments of Form K

Explanation “//” Not carried out

Hygroscopicity of Form K was evaluated by dynamic vapor soprtioin (DVS) test at 25℃. It absorbed about 1.5%water up to 60%RH and about 4.0%water up to 80%RH at 25℃.

Form K is the most stable anhydrate identified, except in acetonitrile at 70℃, where conversion from Form K to Form B favored, based on the competitive equilibration experiments between Form B and Form I (Table 14) and Form B and Form K (Tables 15 and 16) . Form K has high melting point. Form K is hygroscopic and only abosorbs about 1.5%water up to 60%RH at 25 ℃.
6.3.25 Experiment conditions
6.3.25.1 Approximate solubility at 25℃ and 50℃

About 5mg of Compound 1 was weighed into a 2mL glass vial and aliquots of 20μL of each solvent were added to determine solubility at 25℃ and 50℃. Max. volume of each solvent added was 1mL. Approximate solubility was determined by visual observation. 6.3.25.2 Equilibration with solvents at 25℃

About 50mg of Compound 1 was equilibrated in a suitable amount of solvent at 25℃ for 2 weeks or 4 days on a stirring plate and protected from light by covering with aluminum foil. Obtained suspensions were filtered. The solid parts (wet cakes) were investigated by XRPD. When differences are observed, additional investigations are performed (e.g., DSC, TGA, NMR, KF) .
6.3.25.3 Equilibration with solvents at 50℃

About 50mg or 100 mg of Compound 1 was equilibrated in a suitable amount of solvent at 50℃ for 1 week on a stirring plate and protected from light by covering with aluminum foil. Obtained suspension were filtered. The solid part (wet cake) was investigated by XRPD. When differences were observed, additional investigations were performed (e.g., DSC, TGA, NMR) .
6.3.25.4 Precipitation by addition of antisolvent

About 50mg of Compound 1 was dissolved in a good solvent. Antisolvent was added into the obtained solutions slowly. Precipitates were collected by filtration. The solid part (wet cake) was investigated by XRPD. When differences were observed, additional investigations were performed (e.g. DSC, TGA, NMR) .
6.3.25.5 Crystallization at room temperature by slow evaporation

Based on approximate solubility results, about 30mg of Compound 1 was dissolved in a suitable amount of solvent. Obtained clear solutions were slowly evaporated at ambient condition. Solid residues were examined for their polymorphic form by XRPD.
6.3.25.6 Crystallization from hot saturated solutions by fast cooling

Approximate 50 mg of Compound 1 was dissolved in the minimal amount of selected solvet at 50℃ or 25℃. After filtration, the obtained clear solution was put into an ice bath (0℃) and agitated. Precipitates were collected by filtration. The solid part (wet cake) was investigated by XRPD. When no precipitation was obtained, the solution was put in -20℃ for crystallization.
6.2.5.7 Inter-conversion Relationship Experiment of Form K/R/S

Slurry competition experiments were performed were performed at 5℃/25℃/50 ℃ in EtOAc and under different water activity in IPA/H2O at RT. Form K was weighed into a HPLC vial, added corresponding solvents to prepare suspensions under RT condition. After slurrying for 4 hours, filtered the suspension by 0.45 μm PTFE membrane to obtain saturated solution. Weighed about 1～2 mg of Form K, Form R, and Form S into a new HPLC vial and added pre-saturated solution. Transferred the mixtures to slurry at corresponding temperature. The results of competitive slurry experiments were summarized in Table 32.

Table 31, Summary of competitive slurry experiments

6.3 Preparation of Salts
6.3.1 Summary of Salt Screening Experiments

About of 20 mg of Form K was magnetically stirred at RT with 1.0 eq. or 2.0 eq. acids and 0.5 mL solvent. For the obtained suspension, isolated solids by centrifugation and analyzed by XRPD. For potential salt hits, isolated the solids by centrifugation and dried at 50 ℃ under vacuum for characterization.

As the XRPD comparison results in Table 32 showed, a total of 13 salt hits (27 crystal forms) were obtained, including HCl salt Pattern A/B, Sulfate Pattern A/B, Maleate Pattern A/B, Fumarate Pattern B, Tartrate Pattern B/C, Glycolate Pattern A, Tosylate Pattern A/B/C/D, Mesylate Pattern A/B/E, Besylate Pattern A/B/C, Oxalate Pattern A/B, Isethionate Pattern A/B, Esylate Pattern A and HBr salt Pattern A/B. The characterization data of these forms were summarized in Table 32.

Table 32 Characterization summary of salt forms

Note: the purity of starting material Form K of Compound 1 was 99.59 area%.
^#: measured by ¹H NMR.
^##: measured by HPLC/IC.
*: The crystallinity of the sample decreased after vacuum drying at 50 ℃.

Kinetic solubility of 10 salt hits (Sulfate Pattern B, Maleate Pattern B, Fumarate Pattern B, Tartrate Pattern D, Glycolate Pattern B, Tosylate Pattern E, Mesylate Pattern F, Besylate Pattern B, Oxalate Pattern C, and HBr salt Pattern A) and Form K were selected and evaluated in water at 37 ℃. As results summarized in

Table 33, all salts showed improved solubility in water compared with Freebase Form K, and Mesylate Pattern F showed the highest solubility (～3 mg/mL) . XRPD results showed no form change was observed for all samples after solubility test expect for Tartrate Pattern D/Oxalate Pattern C after 1/2/24 hrs and Tosylate Pattern E/Besylate Pattern B after 24 hrs.

Table 33. Summary of kinetic solubility results of freebase Form K and ten salts in H2O at 37 ℃.

S: solubility (mg/mL) . FC: form change.
*: limited sample for XRPD test.
6.3.2 Preparation of Salt Leads

Based on the results of characterization and kinetic solubility in H2O, Mesylate Pattern F, Tartrate Pattern D, Fumarate Pattern B, Glycolate Pattern A and Tosylate Pattern E were selected for re-preparation on 300-mg scale for evaluation (hygroscopicity/solid stability/kinetic solubility) . In addition, it was observed that the polymorphism of mesylate and tartrate was complicated, so Mesylate Pattern F and Tartrate Pattern D were re-prepared on 200 mg scale for small scale polymorph screening.

Re-preparation results were summarized in Table 34. For re-preparation of Mesylate Pattern F and Tartrate Pattern D on 300 mg scale, Mesylate Pattern A and Tartrate Pattern B with high crystallinity were obtained. For re-preparation of Mesylate Pattern F and Tartrate Pattern D on 200 mg scale, Mesylate Pattern A and Tartrate Pattern D were obtained. For re-preparation of Fumarate Pattern B, Tosylate Pattern E and Glycolate Pattern A on 300 mg scale, Fumarate Pattern B with improved crystallinity, Tosylate Pattern E and Glycolate Pattern A with high crystallinity were obtained.

Table 34. Summary of re-preparation results

^#: measured by ¹H NMR. ND: not detected.
Note: seeds were added in the re-preparation of all salts.

6.3.2.1 Mesylate Pattern AMesylate Pattern F was re-prepared according to the 60 mg scale re-preparation method. Slurried ～200 mg Form K and 1.0 eq. Methanesulfonic acid in 5.5 mL Acetone at RT for ～3 days, followed by centrifugation and vacuum drying. As XRPD results showed in Figure 55, Mesylate Pattern A was obtained. The XRPD peaks table of Mesylate Pattern A is shown in Table 17. For Mesylate Pattern A, TGA/DSC results (Figure 63) showed a weight loss of 6.9%up to 150 ℃ and two endotherms at 66.7 ℃ and 231.8 ℃ (peak temperature) . ¹H NMR result showed the molar ratio of Methanesulfonic acid to freebase was 1.0: 1, and the molar ratio of Acetone to freebase Form X was 0.07: 1 (0.4 wt%) . HPLC test revealed that the purity was 99.57%.

Table 17. The XRPD peaks table of Mesylate Pattern A

6.3.2.2 Mesylate Pattern F

Mesylate Pattern F was prepared by slurring about 60 mg of Form K of compound 1 and 1.0 eq. methanesulfonic acid in 1.0mL acetone at RT for about 3 days, followed by centrifugation and vacuum drying. XRPD results are shown in Figure 56. The XRPD peaks table of Mesyalte Pattern F is shown in Table 18. TGA/DSC results (Figure 64) of Mesylate Pattern F showed a weight loss of 5.2%up to 150 ℃ and two endotherms at 48.0 ℃ and 238.4 ℃ (peak temperature) . ¹H NMR result showed the molar ratio of Methanesulfonic acid to freebase was 1.2: 1, and no Acetone was detected. HPLC test revealed that the purity was 99.36%.

Table 18. The XRPD peaks table of Mesylate Pattern F

6.3.2.3 L-Tartrate Pattern B

L-Tartrate Pattern B was obtained by slurrying freebase Form K and 2.0 eq. L-Tartaric acid in acetone and THF/H2O (19: 1, v/v) at RT for about 2 days, followed by centrifugation and vacuum drying. XRPD results are shown in Figure 57. The XRPD peaks table of L-Tartrate Pattern B is shown in Table 19. TGA/DSC results (Figure 65) of L-Tartrate Pattern B showed a weight loss of 3.14%up to 150 ℃ and two endotherms at 43.5 ℃ and 199.2 ℃ (peak temperature) . ¹H NMR result showed the molar ratio of L-Tartaric acid to freebase was 2.0: 1, and the molar ratio of Acetone to freebase was 0.02: 1 (0.1 wt%) . HPLC test revealed that the purity was 98.70%.

Table 19. XRPD peaks table of L-Tartrate Pattern B

6.3.2.4 L-Tartrate Pattern D

L-Tartrate Pattern D was obtained by slurrying ～200 mg Form K and 2.4 eq. L-Tartaric acid in 3.5 mL Acetone at RT for ～3 days and at 50 ℃ overnight followed by centrifugation and vacuum drying. XRPD results are showed in Figure 58. The XRPD peaks table of L-Tartrate Pattern D is shown in Table 20. TGA/DSC results (Figure 66) showed a weight loss of 5.46%up to 140 ℃ and three endotherms at 55.7 ℃, 142.9 ℃ and 193.3 ℃ (peak temperature) . ¹H NMR result showed the molar ratio of L-Tartaric acid to freebase was 2.0: 1, and the molar ratio of Acetone to freebase was 0.02: 1 (0.1 wt%) . HPLC test revealed that the purity was 98.70%.

Table 20. XRPD peaks table of L-Tartrate Pattern D

6.3.2.5 Gycolate Pattern A

Glycolate Pattern A was obtained by slurrying Form K and 2.0 eq. Glycolic acid in EtOH at RT for about 4 days, followed by centrifugation and vacuum drying. XRPD results are shown in Figure 59. The XRPD peaks table is shown in Table 21. TGA/DSC curves in Figure 67 showed a weight loss of 4.39%up to 150 ℃, two endotherms at 120.3 ℃ and 195.8 ℃(peak temperature) . 1H NMR result showed the molar ratio of Glycolic acid to freebase was 2.0: 1, and the molar ratio of EtOH to freebase was 0.44: 1 (2.0 wt%) . HPLC test revealed that the purity was 97.29%.

Table 21. XRPD peaks table of Glycoate Pattern A

6.3.2.6 Glycolate Pattern B

Glycolate Pattern B was obtained by slurrying about 60 mg of Form K and 2.0 eq. Glycolic acid in 1.5 mL EtOH at RT for about 3 days, followed by centrifugation and vacuum drying. XRPD results are shown in Figure 60. The XRPD peaks table is shown in Table 22. TGA/DSC curves in Figure 68. TGA/DSC curves (Figure 68) of Glycolate Pattern B showed a weight loss of 6.47%up to 140 ℃, three endotherms at 66.5 ℃, 166.7 ℃ and 196.6 ℃ (peak temperature) . ¹H NMR result showed the molar ratio of Glycolic acid to freebase was 1.0: 1, and no EtOH was detected. HPLC test revealed that the purity was 99.35%

Table 22. XRPD peaks table of Glycoate Pattern B

6.3.2.7 Fumarate Pattern B

Fumarate Pattern B was obtained by slurrying Form K and 2.0 eq. Fumaric acid in EtOAc at RT for ～2 days, followed by centrifugation and vacuum drying. XRPD results showed in Figure 61. The XRPD peaks table is shown in Table 23. TGA/DSC results in Figure 69 showed a weight loss of 1.60%up to 90 ℃, and a weight loss of 1.04%from 90 ℃ to 140 ℃, three endotherms at 38.2 ℃, 111.0 ℃ and 207.0 ℃ (peak temperature) . ¹H NMR result showed the molar ratio of Fumaric acid to freebase was 1.9: 1, and the molar ratio of EtOAc to freebase was 0.19: 1 (1.5 wt%) . HPLC test revealed that the purity was 98.81%.

Table 23. XRPD peaks table of Fumarate Pattern B

6.3.2.8 Tosylate Pattern E

Tosylate Pattern E was obtained by slurrying about 60 mg of Form K of compound 1 and 2.0 eq. p-Toluenesulfonic acid in 1.5mL acetone at RT for about 3 days, and at 50-5℃ cyclying for about 2 days, followed by centrifugation and vacuum drying. XRPD results are shown in Figure 62. The XRPD peaks table is shown in Table 24. TGA/DSC curves (Figure 70) of Tosylate Pattern E showed a weight loss of 5.51%up to 150 ℃, three endotherms at 54.3 ℃, 137.1 ℃ and 210.9 ℃ (peak temperature) . ¹H NMR result showed the molar ratio of p-Toluenesulfonic acid to freebase was 2.0: 1, and the molar ratio of Acetone to freebase was 0.08: 1 (0.4 wt%) . HPLC test revealed that the purity was 99.49%

Table 24. XRPD peaks table of Tosylate Pattern E

6.3.3 Evaluation of salts
6.3.3.1 Kinetic solubility

The kinetic solubility of Form K, Amorphous freebase form, Fumarate Pattern B, Tosylate Pattern E, Glycolate Pattern A, Mesylate Pattern A and Tartrate Pattern B were tested in H₂O, SGF, FaSSIF and FeSSIF with solid loading of ～5 mg/mL (calculated by freebase) . Solids were suspended into media and the suspensions were agitated on a rolling incubator with 25 rpm at 37 ℃. Sampled at 1, 2 and 24 hrs, respectively. Supernatant was extracted via centrifugation before filtration through a 0.45 μm PTFE membrane and used for solubility and pH measurement. Residual solids were collected for XRPD characterization. Results were summarized in Table 35. As a result, all salts showed improved solubility in H₂O compared with Freebase Form K and Amorphous freebase form. All salts and freebase samples showed similar solubility in SGF and FeSSIF. Fumarate Pattern B, Mesylate Pattern A and Tartrate Pattern B showed improved solubility in H₂O, and Fumarate Pattern B showed improved solubility in FaSSIF compared with other samples.

Table 35. Kinetic solubility test summary

S: solubility (mg/mL) . FC: form change. LOQ: 0.00017 mg/mL.
*: limited sample for XRPD test. ^: The sample was gel-like. ^#: peak shift was observed.
6.3.3.2 Hygroscopicity

DVS test was performed to investigate the hygroscopicity of Freebase Form K, Amorphous freebase Form, Fumarate Pattern B, Tosylate Pattern E, Glycolate Pattern A, Mesylate Pattern A and Tartrate Pattern B. Results were summarized in Table 36.

Table 36 Summary of hygroscopicity evaluation

Results showed that Freebase Form K has a water uptake of 2.381%in the first adsorption curve at 80%RH, and no form change was observed after the test; Amorphous freebase form has a water uptake of 5.196%in the first adsorption curve at 80%RH, and no form change was observed after the test; Fumarate Pattern B has a water uptake of 3.220%in the first adsorption curve at 80%RH, and peak shift was observed after the test; Glycolate Pattern A has a water uptake of 1.558%in the first adsorption curve at 80%RH, and no form change was observed after the test; Tosylate Pattern E has a water uptake of 7.049%in the first adsorption curve at 80%RH, and no form change was observed after the test; Mesylate Pattern A (peak shift) has a water uptake of 8.921%in the first adsorption curve at 80%RH, and peak shift was observed after the test; Tartrate Pattern B has a water uptake of 12.270%in the first adsorption curve at 80%RH, and form change to low crystallinity sample was observed after the test.
6.3.3.3

Solid-state stability of Amorphous freebase form, Fumarate Pattern B, Tosylate Pattern E, Glycolate Pattern A, Mesylate Pattern A and Tartrate Pattern B were evaluated under the conditions of 25 ℃/60%RH, 40 ℃/75%RH for 1 week. The solids were tested by XRPD and HPLC to study the physical and chemical stability before and after storage. The stability results were summarized in Table 37..

Table 37. Solid-state stability evaluation summary

Results showed that all samples showed no purity or form change expect for Fumarate Pattern B and Tartrate Pattern B. Crystallinity decrease with slightly purity decrease was observed for Fumarate Pattern B and Tartrate Pattern B after storage under 40 ℃/75%RH for 1 week.

The embodiments disclosed herein are not to be limited in scope by the specific embodiments disclosed in the examples which are intended as illustrations of a few aspects of the disclosed embodiments and any embodiments that are functionally equivalent are encompassed by the present disclosure. Indeed, various modifications of the embodiments disclosed herein are in addition to those shown and described herein will become apparent to those skilled in the art and are intended to fall within the scope of the appended claims.

A number of references have been cited, the disclosures of which are incorporated herein by reference in their entirety.

Claims

A solid form of Compound 1, which is polymorph Form B, polymorph Form I, or polymorph Form K.
The solid form of claim 1, which is polymorph Form B.
The solid form of claim 2, which has an XRPD pattern comprising a peak at about 16.9 °2θ.
The solid form of claim 3, which has an XRPD pattern comprising peaks at about 5.1, about 13.1, and about 16.9 °2θ.
The solid form of any of claims 2-4, which has a DSC thermogram comprising an endothermic event with an onset temperature at about 279.3 ℃ and a peak temperature at about 281.8 ℃.
The solid form of any of claims 2-5, which has a TGA thermogram comprising a total mass loss of about 1.3 %when heated from about 35.0 ℃ to about 200 ℃.
The solid form of claim 1, which is polymorph Form K.
The solid form of claim 7, which has an XRPD pattern comprising a peak at about 3.9 °2θ.
The solid form of claim 8, which has an XRPD pattern comprising peaks at about 3.9, about 4.4, and about 15.9 °2θ.
The solid form of any of claims 7-9, which has a DSC thermogram comprising an endothermic event with an onset temperature at about 225.8 ℃ and a peak temperature at about 231.4 ℃, an onset temperature at about 245.4 ℃ and a peak temperature at about 256.0 ℃, or an onset temperature at about 279.7 ℃ and a peak temperature at about 282.5 ℃.
The solid form of any of claims 7-10, which has a TGA thermogram comprising a total mass loss of about 1 %when heated from about 35.3 ℃ to about 200 ℃.
The solid form of claim 7, which has an XRPD pattern comprising a peak at about15.8^o2θ.
The solid form of claim 12, which has an XRPD pattern comprising peaks at about 4.4, about 11.0, or about 15.8 ^o2θ.
The solid form of any one of claims 7, 12, or 13, which has a DSC thermogram comprising an endothermic event with an onset temperature at about 223.3℃ and a peak temperature at about 229.8℃.
The solid form of claim 14, which has a DSC themorgram comprising an endothermic event with entahlypy of about 66.2J/g.
The solid form of any one of claims 7 or 12-16, which has a TGA thermogram comprising a total mass loss of about 2.8%when heated from about 26℃ to about 200℃.
An amorphous form of Compound 1, which has an XRPD pattern substantially as shown in Figure 34-37 or 54.
A pharmaceutical composition comprising the solidform of any one of claims 1-17 and at least one pharmaceutically acceptable excipient.
A process for preparing a pharmaceutical composition comprising Compound 1, comprising mixing the solid form of any one of claims 1-18 with at least one pharmaceutically acceptable excipient.