Salts and polymorphs of specific MCL-1 inhibitors

Abstract

The present disclosure relates to salts and crystalline forms of specific 3 ', 4, 4', 5-tetrahydro-2H, 2 'H-spiro [benzo [b] [1, 4] oxaza # imgabs0 #-3, 1'-naphthalene] derivatives as well as pharmaceutical formulations and therapeutic uses thereof. The present disclosure also relates to the preparation of such salts, crystalline forms, and pharmaceutical formulations.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 338,119, filed on May 4, 2022, the contents of which are incorporated herein by reference in their entirety for all purposes. Technical Field

[0003] The present disclosure relates to specific 3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazepine -3,1'-naphthalene] derivatives and their salts and crystalline forms and their pharmaceutical preparations and therapeutic uses. The present disclosure also relates to the preparation of such salts, crystalline forms and pharmaceutical preparations. Background Art

[0004] Apoptosis (programmed cell death) is the process of eliminating unwanted or potentially dangerous cells from an organism. Avoiding apoptosis is essential for the development and continued growth of tumors. Myeloid cell leukemia 1 protein (MCL-1) is an anti-apoptotic member of the Bcl-2 protein family. MCL-1 is necessary to maintain the growth of a variety of tumors, including acute myeloid leukemia (AML), MYC or BCR-ABL driven pre-B / B lymphomas, and certain breast cancers. See, for example, "Discovery of S64315, a Potent and Selective Mcl-1 Inhibitor" by Z. Szlavik, J. Med. Chem., 2020, 63 (22): 13762-13795.

[0005] Studies have shown that MCL-1 inhibitors can be used to treat a variety of cancers. See, for example, “The MCL1inhibitor S63845 is tolerable and effective in diverse cancer models” A. Kotschy et al., Nature, 2016(538):477-482; “Structure Based Design of Non-Natural Peptidic Macrocyclic Mcl-1 Inhibitors” J. Johannes et al., ACS Med. Chem. Lett., 2017, 8(2):239-244 & ACS Med. Chem. Lett., 2017, 8(11):1204; “Synergistic action of the MCL-1inhibitor S63845 with current therapies in preclinical models of triple-negative and HER2-amplified breast cancer” D. Merino et al., Sci. Transl. Med., August 2, 2017, 9(401):eaam7049; “Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia" A. Tron et al., Nature Comm. 2018(9): Article No. 5341; "AMG 176, a Selective MCL1 Inhibitor, Is Effective in Hematologic Cancer Models Alone and in Combination with Established Therapies" S. Caenepeel et al., Cancer Discov., December 2018, 8(12):1582-1597; "Discovery of S64315, a Potent and Selective Mcl-1 Inhibitor" by Z. Szlavik et al., J. Med. Chem., 2020, 63(22): 13762-13795.

[0006] WO 2019 / 222112 discloses novel 3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazepine -3,1'-naphthalene] derivatives that are active against MCL-1. For example, compound 1 (below) has been shown to be a potent MCL-1 inhibitor.

[0007]

[0008] Although WO 2019 / 222112 provides the synthesis of compound 1, the synthesis therein provides an amorphous free base product. Amorphous products tend to be more unstable than their crystalline counterparts, which may cause problems for the manufacture and stability of pharmaceutical formulations. Therefore, it is necessary to develop a more stable form of compound 1. Summary of the invention

[0009] In certain embodiments, the present disclosure relates to a crystalline form of Compound 1:

[0010]

[0011] In certain embodiments, the present disclosure relates to crystalline Form I of Compound 1. In certain embodiments, the present disclosure relates to crystalline Form II of Compound 1. In certain embodiments, the present disclosure relates to crystalline Form III of Compound 1. In certain embodiments, the present disclosure relates to crystalline Form IV of Compound 1.

[0012] In certain embodiments, the present disclosure relates to a crystalline form of a pharmaceutically acceptable salt of Compound 1:

[0013]

[0014] In certain embodiments, the present disclosure relates to a crystalline form of a sodium salt of Compound 1. In certain embodiments, the present disclosure relates to a crystalline form 1 of a sodium salt of Compound 1. In certain embodiments, the present disclosure relates to a crystalline form 2 of a sodium salt of Compound 1. In certain embodiments, the present disclosure relates to a crystalline form 3 of a sodium salt of Compound 1. In certain embodiments, the present disclosure relates to a crystalline form 4 of a sodium salt of Compound 1. In certain embodiments, the present disclosure relates to a crystalline form 5 of a sodium salt of Compound 1.

[0015] In certain embodiments, the present disclosure relates to a crystalline form of the potassium salt of Compound 1. In certain embodiments, the present disclosure relates to a crystalline Form 1 of the potassium salt of Compound 1.

[0016] In certain embodiments, the present disclosure relates to a crystalline form of the diethylamine salt of Compound 1. In certain embodiments, the present disclosure relates to a crystalline Form 1 of the diethylamine salt of Compound 1.

[0017] In certain embodiments, the present disclosure relates to a crystalline form of a choline salt of Compound 1. In certain embodiments, the present disclosure relates to a crystalline Form 1 of a choline salt of Compound 1.

[0018] In certain embodiments, the present disclosure relates to a pharmaceutical composition comprising a crystalline form of Compound 1 or a crystalline form of a pharmaceutically acceptable salt of Compound 1 and a pharmaceutically acceptable carrier or excipient.

[0019] In certain embodiments, the present disclosure relates to a method for inhibiting MCL-1 in a patient, the method comprising administering to the patient a crystalline form of Compound 1, a crystalline form of a pharmaceutically acceptable salt of Compound 1, or a pharmaceutical composition comprising a crystalline form of Compound 1 or a crystalline form of a pharmaceutically acceptable salt of Compound 1 and a pharmaceutically acceptable carrier or excipient.

[0020] In certain embodiments, the present disclosure relates to a method for treating cancer in a patient, comprising administering to the patient a crystalline form of Compound 1, a crystalline form of a pharmaceutically acceptable salt of Compound 1, or a pharmaceutical composition comprising a crystalline form of Compound 1 or a crystalline form of a pharmaceutically acceptable salt of Compound 1 and a pharmaceutically acceptable carrier or excipient.

[0021] In certain embodiments, the present disclosure relates to the use of a crystalline form of Compound 1, a crystalline form of a pharmaceutically acceptable salt of Compound 1, or a pharmaceutical composition comprising a crystalline form of Compound 1 or a crystalline form of a pharmaceutically acceptable salt of Compound 1 and a pharmaceutically acceptable carrier or excipient for treating cancer.

[0022] In certain embodiments, the present disclosure relates to the use of a crystalline form of Compound 1, a crystalline form of a pharmaceutically acceptable salt of Compound 1, or a pharmaceutical composition comprising a crystalline form of Compound 1 or a crystalline form of a pharmaceutically acceptable salt of Compound 1 and a pharmaceutically acceptable carrier or excipient in the manufacture of a medicament for treating cancer.

[0023] In certain embodiments, the present disclosure relates to a crystalline form of Compound 1, a crystalline form of a pharmaceutically acceptable salt of Compound 1, or a pharmaceutical composition comprising a crystalline form of Compound 1 or a crystalline form of a pharmaceutically acceptable salt of Compound 1 and a pharmaceutically acceptable carrier or excipient, for use in a method of treating cancer.

[0024] Other purposes and advantages will be explained in part in the following detailed description, and will be understood in part from the detailed description, or may be learned through practice. These purposes and advantages will be realized and obtained by the elements and combinations particularly pointed out in the appended claims.

[0025] It should be understood that the above invention summary and the following detailed description are only exemplary and illustrative, rather than limiting the claims. The headings used throughout this disclosure are provided for convenience only and should not be construed as limiting the claims in any way.

[0026] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments and, together with the detailed description, serve to explain the principles described herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 An XRPD pattern of the Na salt Form 1 is provided.

[0028] Figure 2 A DSC thermogram of the Na salt form 1 is provided.

[0029] Figure 3 A TGA thermogram of the Na salt form 1 is provided.

[0030] Figure 4 A DVS analysis of the Na salt form 1 is provided.

[0031] Figure 5 An XRPD pattern of Na salt Form 2 is provided.

[0032] Figure 6 A DSC thermogram of the Na salt form 2 is provided.

[0033] Figure 7 A TGA thermogram of the Na salt form 2 is provided.

[0034] Figure 8 An XRPD pattern of the Na salt form 3 is provided.

[0035] Fig. 9 A DSC thermogram of the Na salt form 3 is provided.

[0036] Fig.10 A TGA thermogram of the Na salt form 3 is provided.

[0037] Fig.11 An XRPD pattern of the Na salt form 4 is provided.

[0038] Fig.12 An XRPD pattern of the Na salt form 5 is provided.

[0039] Fig.13 A DSC thermogram of the Na salt form 5 is provided.

[0040] Fig.14 A TGA thermogram of the Na salt form 5 is provided.

[0041] Fig.15 An XRPD pattern of K Salt Form 1 is provided.

[0042] Fig.16 A comparison of the XRPD pattern of the Na Salt Form 1 with the XRPD pattern of the K Salt Form 1 is provided.

[0043] Fig.17 A DSC thermogram of K salt Form 1 is provided.

[0044] Fig.18 A TGA thermogram of K salt Form 1 is provided.

[0045] Fig.19 A DVS analysis of the K salt form 1 is provided.

[0046] Fig. 20 An XRPD pattern of the K salt IPA solvate is provided.

[0047] Fig.21 An XRPD pattern of the K salt THF solvate is provided.

[0048] Fig. 22 An XRPD pattern of the DEA salt toluene solvate is provided.

[0049] Fig.23 An XRPD pattern of DEA Salt Form 1 is provided.

[0050] Fig.24 A DSC thermogram of DEA Salt Form 1 is provided.

[0051] Fig.25 A TGA thermogram of DEA salt Form 1 is provided.

[0052] Fig.26 A DVS analysis of DEA salt Form 1 is provided.

[0053] Fig. 27 An XRPD pattern of choline salt Form 1 is provided.

[0054] Fig.28 A DSC thermogram of choline salt Form 1 is provided.

[0055] Fig.29 A TGA thermogram of choline salt Form 1 is provided.

[0056] Fig.30 An XRPD pattern of amorphous Compound 1 is provided.

[0057] Fig.31 An XRPD pattern of Compound 1 - Polymorph Form I is provided.

[0058] Fig.32A DSC thermogram of Compound 1 - Polymorph Form I is provided.

[0059] Fig.33 A TGA thermogram of Compound 1 - Polymorph Form I is provided.

[0060] Fig.34 A DVS analysis of Compound 1 - polymorph Form I is provided.

[0061] Fig.35 Provided is the single crystal X-ray structure of Compound 1 - Polymorph Form I. C = carbon atom, Cl = chlorine atom, O = oxygen atom, N = nitrogen atom.

[0062] Fig.36 An XRPD pattern of Compound 1 - polymorph Form II is provided.

[0063] Fig.37 A DSC thermogram of Compound 1 - polymorph Form II is provided.

[0064] Fig.38 A TGA thermogram of Compound 1 - polymorph Form II is provided.

[0065] Fig.39 A DVS analysis of Compound 1 - polymorph Form II is provided.

[0066] Fig.40 An XRPD pattern of Compound 1 - polymorph Form III is provided.

[0067] Fig.41 A DSC thermogram of Compound 1 - polymorph Form III is provided.

[0068] Fig.42 A TGA thermogram of Compound 1 - polymorph Form III is provided.

[0069] Fig.43 Provided is a DVS analysis of Compound 1 - polymorph Form III.

[0070] Fig.44 An XRPD pattern of Compound 1 - polymorph Form IV is provided.

[0071] Fig.45 A DSC thermogram of Compound 1 - polymorph Form IV is provided.

[0072] Fig.46 A TGA thermogram of Compound 1 - polymorph Form IV is provided.

[0073] Fig.47 An XRPD pattern of Compound 1-MeCN solvate is provided.

[0074] Fig.48 An XRPD pattern of Compound 1-MeOH solvate is provided.

[0075] Fig.49 An XRPD pattern of Compound 1 - EtOAc solvate is provided.

[0076] Fig.50 An XRPD pattern of partially converted Compound 1 - EtOAc solvate is provided.

[0077] Fig.51 An XRPD pattern of Compound 1 - MeTHF solvate is provided.

[0078] Fig.52 An XRPD pattern of Compound 1 - toluene solvate is provided.

[0079] Fig.53 An XRPD pattern of Compound 1-n-BuOAc solvate is provided.

[0080] Fig.54 An XRPD pattern of Compound 1 -MTBE Solvate 1 is provided.

[0081] Fig.55 The XRPD pattern of Compound 1 -MTBE Solvate 2 is provided.

[0082] Fig.56 An XRPD pattern of Compound 1-isopropanol hemisolvate is provided.

[0083] Fig.57 XRPD patterns of Compound 1-Form I and various isostructural forms of Compound 1 are provided.

[0084] Fig.58 Provided Fig.57 An enlarged view of a portion of the XRPD pattern disclosed in . DETAILED DESCRIPTION

[0085] I. Definitions

[0086] Unless the context requires otherwise, throughout this specification and claims, the word "comprise" and variations such as "include" and "comprising" are to be interpreted in an open, inclusive sense, ie, to mean "including, but not limited to."

[0087] Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in conjunction with the embodiment is included in at least one embodiment of the present invention. Thus, the phrases "in one embodiment" or "in an embodiment" appearing in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, in one or more embodiments, the particular features, structures, or characteristics may be combined in any suitable manner.

[0088] It should be understood that salts and polymorphs of Compound 1 include all isotopically labeled compounds having one or more atoms replaced by atoms having a different atomic mass or mass number. Examples of isotopes that may be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, and chlorine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 35 S and 36 Cl. These radiolabeled compounds can be used to help determine or measure the effectiveness of a compound by characterizing, for example, the site or mode of action or the binding affinity for a pharmacologically important site of action. Certain isotopically labeled compounds, such as those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotope tritium (i.e. 3 H) and carbon-14 (i.e. 14 C) may be particularly suitable for this purpose due to their ease of incorporation and convenient means of detection.

[0089] Using heavier isotopes such as deuterium (i.e. 2 H) substitution may offer certain therapeutic advantages due to greater metabolic stability. For example, the in vivo half-life may be increased or dosage requirements may be reduced. Therefore, in some cases, heavier isotopes may be preferred.

[0090] Using positron emitting isotopes such as 11 C. 18 F. 15 O and 13 N substitution can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described in the Examples listed below, using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously employed.

[0091] The terms "crystalline" or "crystal" refer to a form of matter in which the atoms, molecules or ions are arranged in a highly ordered three-dimensional lattice.

[0092] The term "substantially as shown" when referring to, for example, an XRPD pattern, a DSC thermogram, or a TGA graph, includes patterns, thermograms, or graphs that are not necessarily the same as those depicted herein, but that fall within the limits of experimental error or deviation when considered by one of ordinary skill in the art.

[0093] "Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and / or formulation into an efficacious therapeutic agent.

[0094] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not occur.

[0095] The phrase "pharmaceutically acceptable carrier or excipient" includes, but is not limited to, any additive acceptable for use in humans or animals. Such additives include, for example, any and all types of adjuvants, carriers, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavor enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers.

[0096] "Pharmaceutical composition" refers to a formulation of a compound for delivery to an animal, such as a human.

[0097] An "effective amount" or "therapeutically effective amount" refers to an amount of a compound that is sufficient to achieve treatment of a disease, condition, and / or disorder when the amount is administered to a patient in need thereof. Such an amount will be sufficient to elicit a biological or medical response of a tissue system or patient. An "effective amount" or "therapeutically effective amount" will vary depending on factors such as the compound and its biological activity, the composition used for administration, the time of administration, the route of administration, the excretion rate of the compound, the duration of treatment, the type of disease, condition, and / or disorder being treated and its severity, the drugs used in combination or concomitantly with the compounds of the invention, and the patient's age, weight, general health, sex, and diet. An "effective amount" or "therapeutically effective amount" can be routinely determined by those of ordinary skill in the art taking into account their own knowledge, the prior art, and the present disclosure.

[0098] As used herein, the term "inhibit" refers to blocking a specific biological pathway. In some embodiments, the term "inhibit" refers to administering a compound or composition to block MCL-1 activity.

[0099] As used herein, the term "treating" refers to the administration of a compound or composition in an attempt to cure or heal a patient's disease, condition, and / or disorder, or to alleviate or eliminate the symptoms of such disease, condition, and / or disorder.

[0100] "Prevention" means any treatment of a disease, condition, and / or disorder that results in the clinical symptoms of the disease, condition, and / or disorder not developing.

[0101] The term "subject" or "patient" refers to an animal, such as a mammal (including a human). The methods or uses described herein can be used for human therapy and / or veterinary applications. In some embodiments, the subject is a mammal (or patient). In some embodiments, the subject (or patient) is a human, livestock (e.g., dogs and cats), farm animals (e.g., cattle, horses, sheep, goats and pigs), and / or laboratory animals (e.g., mice, rats, hamsters, guinea pigs, pigs, rabbits, dogs and monkeys). In one embodiment, the subject (or patient) is a human. "A person (or patient) in need thereof" refers to a person (or patient) who may suffer from or is suspected of suffering from a disease, condition and / or illness that would benefit from certain treatments.

[0102] "Tautomer" refers to a proton migration from one atom of a molecule to another atom of the same molecule. Salts and crystalline forms of Compound 1 include tautomers of any of the compounds.

[0103] As used herein, the term "about" refers to numerical values, including, for example, integers, fractions, and percentages, whether or not explicitly stated. The term "about" generally refers to a numerical range (e.g., + / - 5%-10% of the range) that one of ordinary skill in the art would consider equivalent to the value (e.g., having the same function or result). When a term such as "about" precedes a list of numerical values ​​or ranges, the term modifies all values ​​or ranges provided in the list. In some cases, the term "about" may include numerical values ​​rounded to the nearest significant figure.

[0104] Furthermore, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" may refer to a plurality of such compounds.

[0105] "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other substances that are acceptable for use in humans or animals.

[0106] "Unit dosage forms" are physically discrete units suitable as unitary dosages for subjects (eg, human subjects and other mammals), each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect.

[0107] abbreviation :

[0108]

[0109]

[0110]

[0111] II.Compounds

[0112] One aspect of the present disclosure relates to a crystalline form of Compound 1:

[0113]

[0114] Another aspect of the present disclosure relates to a crystalline form of a solvate of Compound 1.

[0115] One aspect of the present disclosure relates to a pharmaceutically acceptable salt of Compound 1:

[0116]

[0117] Another aspect of the present disclosure relates to solvates of pharmaceutically acceptable salts of Compound 1.

[0118] One aspect of the present disclosure relates to a crystalline form of a pharmaceutically acceptable salt of Compound 1:

[0119]

[0120] Another aspect of the present disclosure relates to a crystalline form of a solvate of a pharmaceutically acceptable salt of Compound 1.

[0121] A. Crystalline Form of Compound 1

[0122] One aspect of the present disclosure relates to a crystalline form of Compound 1:

[0123]

[0124] In some embodiments, the crystalline form is Form I. In some embodiments, the crystalline form is Form II. In some embodiments, the crystalline form is Form III. In some embodiments, the crystalline form is Form IV.

[0125] In some embodiments, the crystalline form of Compound 1 is characterized by an x-ray powder diffraction pattern comprising peaks at about 4.9°±0.2°, 8.6°±0.2°, and 14.3°±0.2° 2-θ. In some embodiments, the x-ray powder diffraction pattern comprises one or more additional peaks selected from the peaks at about 16.2°±0.2°, 18.3°±0.2°, and 22.1°±0.2° 2-θ. In some embodiments, the x-ray powder diffraction pattern comprises one or more additional peaks selected from the peaks at about 17.8°±0.2°, 19.3°±0.2°, and 21.5°±0.2° 2-θ. In some embodiments, the x-ray powder diffraction pattern comprises one or more additional peaks selected from peaks at about 13.5°±0.2°, 14.6°±0.2°, 16.0°±0.2°, 17.5°±0.2°, 18.8°±0.2°, 20.2°±0.2°, 20.7°±0.2°, 23.0°±0.2°, 24.6°±0.2°, 26.3°±0.2°, and 26.8°±0.2° 2-theta. In some embodiments, the crystalline form is characterized by being substantially as Fig.31 The x-ray powder diffraction pattern shown in .

[0126] In some embodiments, the crystalline form of Compound 1 is Form I. In some embodiments, Form I is characterized by having a differential scanning calorimetry thermogram comprising an endothermic peak with an onset temperature at about 180°C. In some embodiments, the differential scanning calorimetry thermogram is substantially as follows Fig.32 as shown in .

[0127] In some embodiments, Form I is characterized by having a thermogravimetric thermogram showing a weight loss of about 1.0% at a temperature between ambient temperature and about 170° C. In some embodiments, the thermogravimetric thermogram is substantially as follows Fig.33 as shown in .

[0128] In some embodiments, Form I is characterized by absorbing about 1.4 wt % water at about 25°C and between about 0% and 90% relative humidity. In some embodiments, the dynamic vapor sorption mass absorption curve is substantially as follows Fig.34 as shown in .

[0129] In some embodiments, Form I is prepared by a method comprising the following steps: (1) contacting Compound 1 or a salt thereof with a solvent selected from acetone, ethyl acetate, alcohol, methyl ethyl ketone, methyl isobutyl ketone, tetrahydrofuran, dichloromethane and dibutyl ether, and mixtures of such solvents; and (2) isolating the solid product. In some embodiments, the solvent comprises acetone. In some embodiments, the solvent comprises ethyl acetate. In some embodiments, the solvent comprises an alcohol selected from ethanol and isopropanol. In some embodiments, the solvent comprises ethanol.

[0130] In some embodiments, the method further comprises filtering the mixture of compound 1 or its salt and solvent before isolating the solid product. In some embodiments, the method further comprises heating the mixture of compound 1 or its salt and solvent. In some embodiments, the mixture is heated to about 50°C-70°C, for example, about 60°C. In some embodiments, the filtration is performed before heating. In some embodiments, the filtration is performed before and after heating. In some embodiments, the method further comprises drying the solid product and / or the filtrate.

[0131] In some embodiments, the method further comprises washing the solid product with a second solvent selected from acetone, ethyl acetate, an alcohol or a mixture of such solvents and / or crystallizing the solid product and optionally drying. In some embodiments, washing comprises washing the solid product with ethyl acetate and an alcohol mixture.

[0132] In some embodiments, washing comprises washing the solid product with a mixture of ethyl acetate and ethanol.

[0133] In some embodiments, Form I is prepared by a process comprising the steps of: (1) contacting Compound 1 or a salt thereof with a buffer to produce a mixture; (2) adding a solvent selected from acetonitrile and an acetonitrile / water mixture to the mixture to produce a slurry; (3) mixing the slurries; and (4) isolating the solid product. In some embodiments, the salt is a sodium salt of Compound 1. In some embodiments, the pH of the buffer is from about 1 to about 6. In some embodiments, the pH of the buffer is from about 2 to about 4. In some embodiments, the pH of the buffer is about 2.

[0134] In some embodiments, Form I is prepared by a process comprising the steps of: (1) contacting Form II of Compound 1, Form III of Compound 1, or Form IV of Compound 1, or a salt thereof, with an alcohol; and (2) isolating the solid product. In some embodiments, the alcohol is selected from ethanol and isopropanol. In some embodiments, the alcohol is ethanol.

[0135] In some embodiments, the crystalline form of Compound 1 is characterized by an x-ray powder diffraction pattern comprising peaks at about 6.1°±0.2°, 15.7°±0.2°, and 16.1°±0.2° 2-θ. In some embodiments, the x-ray powder diffraction pattern comprises one or more additional peaks selected from the peaks at about 15.4°±0.2°, 16.9°±0.2°, and 19.9°±0.2° 2-θ. In some embodiments, the x-ray powder diffraction pattern comprises one or more additional peaks selected from the peaks at about 12.8°±0.2°, 13.9°±0.2°, and 22.8°±0.2° 2-θ. In some embodiments, the x-ray powder diffraction pattern comprises one or more selected from about 10.5°±0.2°, 12.2°±0.2°, 13.3°±0.2°, 18.2°±0.2°, 19.0°±0.2°, 19.4°±0.2°, 20.3°±0.2°, 21.1°±0.2°, 23.4°±0.2°, 25.2°±0.2°, 25.7°±0.2°, 26.8°±0.2°, 27.9°±0.2°, 28.1°±0.2°, 29.2°±0.2°, 30.

[0136] In some embodiments, the crystalline form is characterized by being substantially as follows Fig.36 The x-ray powder diffraction pattern shown in .

[0137] In some embodiments, the crystalline form of Compound 1 is Form II. In some embodiments, Form II is characterized by having a differential scanning calorimetry thermogram comprising an endothermic peak with an onset temperature at about 163°C. In some embodiments, the differential scanning calorimetry thermogram is substantially as follows Fig.37 as shown in .

[0138] In some embodiments, Form II is characterized by having a thermogravimetric thermogram showing a weight loss of about 0.6% at a temperature between ambient temperature and about 210° C. In some embodiments, the thermogravimetric thermogram is substantially as follows Fig.38 as shown in .

[0139] In some embodiments, Form II is characterized by absorbing up to about 1.1% by weight of water at about 25°C between about 0% and 90% relative humidity. In some embodiments, Form II is characterized by having substantially Fig.39 The dynamic vapor adsorption mass absorption curve shown in .

[0140] In some embodiments, Form II is prepared by a method comprising the steps of: (1) contacting Compound 1 or a salt thereof with acetonitrile and optionally an acid; and (2) isolating the solid product. In some embodiments, the acid is HCl. In some embodiments, the method further comprises drying the solid product. In some embodiments, the salt of Compound 1 is a sodium salt.

[0141] In some embodiments, the crystalline form of Compound 1 is characterized by an x-ray powder diffraction pattern comprising peaks at about 8.0°±0.2°, 15.0°±0.2°, and 18.4°±0.2° 2-θ. In some embodiments, the x-ray powder diffraction pattern comprises one or more additional peaks selected from the peaks at about 16.5°±0.2°, 22.1°±0.2°, and 22.9°±0.2° 2-θ. In some embodiments, the x-ray powder diffraction pattern comprises one or more additional peaks selected from the peaks at about 12.5°±0.2°, 19.5°±0.2°, and 23.6°±0.2° 2-θ. In some embodiments, the x-ray powder diffraction pattern comprises one or more additional peaks selected from peaks at about 6.5°±0.2°, 12.3°±0.2°, 12.9°±0.2°, 13.6°±0.2°, 14.3°±0.2°, 16.0°±0.2°, 18.1°±0.2°, 20.7°±0.2°, 24.1°±0.2°, 24.7°±0.2°, 26.8°±0.2°, and 28.3°±0.2° 2-theta. In some embodiments, the crystalline form is characterized by being substantially as Fig.40 The x-ray powder diffraction pattern shown in .

[0142] In some embodiments, the crystalline form of Compound 1 is Form III. In some embodiments, Form III is characterized by having a differential scanning calorimetry thermogram comprising at least one endothermic peak selected from peaks with onset temperatures at about 20°C, 133°C, and 153°C. In some embodiments, the differential scanning calorimetry thermogram is substantially as follows Fig.41 as shown in .

[0143] In some embodiments, Form III is characterized by having a thermogravimetric thermogram showing a weight loss of about 2.9% at a temperature of about ambient temperature to about 90°C. In some embodiments, Form III is characterized by having a thermogravimetric thermogram showing a weight loss of about 1.1% at a temperature of about 90°C to about 175°C. In some embodiments, Form III is characterized by having a thermogravimetric thermogram showing a weight loss of about 1.6% at a temperature of about 175°C to about 225°C. In some embodiments, the thermogravimetric thermogram is substantially as Fig.42 as shown in .

[0144] In some embodiments, Form III is characterized by absorbing up to about 5% by weight of water at about 25°C between about 0% and 90% relative humidity. In some embodiments, Form III is characterized by having substantially Fig.43 The dynamic vapor adsorption mass absorption curve shown in .

[0145] In some embodiments, Form III is prepared by a method comprising the steps of: (1) contacting Compound 1 or a salt thereof with methanol and optionally an acid; and (2) isolating a solid product. In some embodiments, the acid is selected from oxalic acid, phosphoric acid, citric acid, malic acid, and malonic acid. In some embodiments, the method further comprises drying the solid product. In some embodiments, the salt of Compound 1 is a sodium salt.

[0146] In some embodiments, the crystalline form of Compound 1 is characterized by an x-ray powder diffraction pattern comprising peaks at about 0.1°±0.2°, 8.7°±0.2°, and 10.6°±0.2° 2-θ. In some embodiments, the x-ray powder diffraction pattern comprises one or more additional peaks selected from the peaks at about 10.3°±0.2°, 11.2°±0.2°, and 18.2°±0.2° 2-θ. In some embodiments, the x-ray powder diffraction pattern comprises one or more additional peaks selected from the peaks at about 14.2°±0.2°, 20.5°±0.2°, and 24.9°±0.2° 2-θ. In some embodiments, the x-ray powder diffraction pattern comprises one or more additional peaks selected from peaks at about 3.3°±0.2°, 13.2°±0.2°, 15.4°±0.2°, 16.2°±0.2°, 17.9°±0.2°, 19.0°±0.2°, 21.3°±0.2°, 21.9°±0.2°, 23.3°±0.2°, 26.1°±0.2°, and 28.3°±0.2° 2-theta. In some embodiments, the crystalline form is characterized by being substantially as Fig.44 The x-ray powder diffraction pattern shown in .

[0147] In some embodiments, the crystalline form of Compound 1 is Form IV. In some embodiments, Form IV is characterized by having a differential scanning calorimetry thermogram comprising at least one endothermic peak selected from peaks with onset temperatures at about 119° C. and 166° C. In some embodiments, the differential scanning calorimetry thermogram is substantially as follows Fig.45 as shown in .

[0148] In some embodiments, Form IV is characterized by having a thermogravimetric thermogram showing a weight loss of about 0.6% at temperatures ranging from ambient temperature to about 200° C. In some embodiments, the thermogravimetric thermogram is substantially as follows Fig.46 as shown in .

[0149] In some embodiments, Form IV is prepared by a process comprising the steps of: (1) contacting Compound 1 or a salt thereof with ethanol and / or heptane; and (2) isolating the solid product.

[0150] One aspect of the present disclosure relates to a crystalline form of a solvate of Compound 1.

[0151] In some embodiments, the crystalline form of the solvate of Compound 1 is characterized by being substantially as follows Fig.47 The x-ray powder diffraction pattern shown in . In some embodiments, the crystalline form is a MeCN solvate of Compound 1.

[0152] In some embodiments, the crystalline form of the solvate of Compound 1 is characterized by being substantially as follows Fig.48 The x-ray powder diffraction pattern shown in . In some embodiments, the crystalline form is a MeOH solvate of Compound 1.

[0153] In some embodiments, the crystalline form of the solvate of Compound 1 is characterized by being substantially as follows Fig.49 The x-ray powder diffraction pattern shown in . In some embodiments, the crystalline form is an EtOAC solvate of Compound 1.

[0154] In some embodiments, the crystalline form of the solvate of Compound 1 is characterized by being substantially as follows Fig.50 The x-ray powder diffraction pattern shown in . In some embodiments, the crystalline form is a partially desolvated EtOAC solvate of Compound 1.

[0155] In some embodiments, the crystalline form of the solvate of Compound 1 is characterized by being substantially as follows Fig.51 The x-ray powder diffraction pattern shown in . In some embodiments, the crystalline form is a MeTHF solvate of Compound 1.

[0156] In some embodiments, the crystalline form of the solvate of Compound 1 is characterized by being substantially as follows Fig.52 The x-ray powder diffraction pattern shown in . In some embodiments, the crystalline form is a toluene solvate of Compound 1.

[0157] In some embodiments, the crystalline form of the solvate of Compound 1 is characterized by being substantially as follows Fig.53 The x-ray powder diffraction pattern shown in . In some embodiments, the crystalline form is an nBuOAc solvate of Compound 1.

[0158] In some embodiments, the crystalline form of the solvate of Compound 1 is characterized by being substantially as follows Fig.54The x-ray powder diffraction pattern shown in . In some embodiments, the crystalline form is MTBE solvate 1 of Compound 1.

[0159] In some embodiments, the crystalline form of the solvate of Compound 1 is characterized by being substantially as follows Fig.55 The x-ray powder diffraction pattern shown in . In some embodiments, the crystalline form is MTBE solvate 2 of Compound 1.

[0160] In some embodiments, the crystalline form of the solvate of Compound 1 is characterized by being substantially as follows Fig.56 The x-ray powder diffraction pattern shown in . In some embodiments, the crystalline form is an isopropanol hemisolvate of Compound 1.

[0161] B. Salts of Compound 1

[0162] One aspect of the present disclosure relates to a pharmaceutically acceptable salt of Compound 1:

[0163]

[0164] In some embodiments, the pharmaceutically acceptable salt is selected from sodium salt, potassium salt, diethylamine salt, and choline salt.

[0165] Another aspect of the present disclosure relates to a crystalline form of a pharmaceutically acceptable salt of Compound 1:

[0166]

[0167] In some embodiments, the pharmaceutically acceptable salt is selected from sodium salt, potassium salt, diethylamine salt, and choline salt.

[0168] In some embodiments, the pharmaceutically acceptable salt of Compound 1 is a sodium salt. In some embodiments, the sodium salt of Compound 1 is characterized by an x-ray powder diffraction pattern comprising peaks at about 7.6°±0.2°, 8.4°±0.2°, and 12.8°±0.2° 2-θ. In some embodiments, the x-ray powder diffraction pattern comprises one or more additional peaks selected from the peaks at about 15.3°±0.2°, 18.4°±0.2°, and 20.4°±0.2° 2-θ. In some embodiments, the x-ray powder diffraction pattern comprises one or more additional peaks selected from the peaks at about 12.3°±0.2°, 13.4°±0.2°, and 24.0°±0.2° 2-θ. In some embodiments, the x-ray powder diffraction pattern comprises one or more additional peaks selected from peaks at about 6.7°±0.2°, 13.7°±0.2°, 14.0°±0.2°, 15.7°±0.2°, 17.1°±0.2°, 17.4°±0.2°, 17.9°±0.2°, 19.2°±0.2°, 22.0°±0.2°, 22.2°±0.2°, 23.6°±0.2°, 24.3°±0.2°, and 24.8°±0.2° 2-θ. In some embodiments, the pharmaceutically acceptable Na salt form 1 of Compound 1 is characterized by being substantially as Figure 1 The x-ray powder diffraction pattern shown in .

[0169] In some embodiments, the crystalline form of the pharmaceutically acceptable salt of Compound 1 is Na salt Form 1. In some embodiments, Na salt Form 1 is characterized by having a differential scanning calorimetry thermogram comprising at least one endothermic peak selected from peaks with onset temperatures at about 14° C., 83° C., and 232° C. In some embodiments, the differential scanning calorimetry thermogram is substantially as follows Figure 2 as shown in .

[0170] In some embodiments, Na salt Form 1 is characterized by having a thermogravimetric analysis thermogram showing a weight loss of about 4.2% at temperatures ranging from ambient temperature to about 200° C. In some embodiments, the thermogravimetric analysis thermogram is substantially as Figure 3 as shown in .

[0171] In some embodiments, Na Salt Form 1 is characterized by absorbing about 7.5% by weight of water at about 25°C between about 0% and 90% relative humidity. In some embodiments, Na Salt Form 1 is characterized by having substantially Figure 4 The dynamic vapor adsorption mass absorption curve shown in .

[0172] In some embodiments, the sodium salt of Compound 1 is characterized by an x-ray powder diffraction pattern comprising peaks at about 7.2°±0.2°, 14.7°±0.2°, and 19.3°±0.2° 2-θ. In some embodiments, the x-ray powder diffraction pattern comprises one or more additional peaks selected from the peaks at about 11.1°±0.2°, 17.1°±0.2°, and 20.7°±0.2° 2-θ. In some embodiments, the x-ray powder diffraction pattern comprises one or more additional peaks selected from the peaks at about 13.1°±0.2°, 14.5°±0.2°, and 16.9°±0.2° 2-θ. In some embodiments, the x-ray powder diffraction pattern comprises one or more additional peaks selected from peaks at about 6.7°±0.2°, 9.1±0.2°, 9.7°±0.2°, 12.1°±0.2°, 15.2°±0.2°, 17.3°±0.2°, 17.5°±0.2°, 17.8°±0.2°, 18.2°±0.2°, 19.1°±0.2°, 21.6°±0.2°, 22.0°±0.2°, 22.8°±0.2°, 24.4°±0.2°, and 25.1°±0.2° 2-theta. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is characterized by being substantially as Figure 5 The x-ray powder diffraction pattern shown in .

[0173] In some embodiments, the crystalline form of the pharmaceutically acceptable salt of Compound 1 is Na Salt Form 2. In some embodiments, Na Salt Form 2 is characterized by having a differential scanning calorimetry thermogram comprising at least one endothermic peak selected from peaks with an onset temperature at about 21°C and 224°C. In some embodiments, Na Salt Form 2 is characterized by having a differential scanning calorimetry thermogram comprising an exothermic peak with an onset temperature at about 109°C. In some embodiments, the differential scanning calorimetry thermogram is substantially as follows Figure 6 as shown in .

[0174] In some embodiments, Na salt Form 2 is characterized by having a thermogravimetric thermogram showing a weight loss of about 4.8% at temperatures ranging from ambient temperature to about 200° C. In some embodiments, the thermogravimetric thermogram is substantially as Figure 7 as shown in .

[0175] In some embodiments, the sodium salt of Compound 1 is characterized by an x-ray powder diffraction pattern comprising peaks at about 4.1°±0.2°, 13.2°±0.2°, and 18.8°±0.2° 2-θ. In some embodiments, the x-ray powder diffraction pattern comprises one or more additional peaks selected from the peaks at about 12.1°±0.2°, 20.0°±0.2°, and 24.2°±0.2° 2-θ. In some embodiments, the x-ray powder diffraction pattern comprises one or more additional peaks selected from the peaks at about 14.8°±0.2°, 20.9°±0.2°, and 22.9°±0.2° 2-θ. In some embodiments, the x-ray powder diffraction pattern comprises one additional peak at about 8.2°±0.2° 2-θ. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is characterized by being substantially as Figure 8 The x-ray powder diffraction pattern shown in .

[0176] In some embodiments, the crystalline form of the pharmaceutically acceptable salt of Compound 1 is Na salt Form 3. In some embodiments, Na salt Form 3 is characterized by having a differential scanning calorimetry thermogram comprising at least one endothermic peak selected from peaks with onset temperatures at about 19° C. and 219° C. In some embodiments, the differential scanning calorimetry thermogram is substantially as follows Fig. 9 as shown in .

[0177] In some embodiments, Na salt Form 3 is characterized by having a thermogravimetric analysis thermogram showing a weight loss of about 5.1% at temperatures ranging from ambient temperature to about 200° C. In some embodiments, the thermogravimetric analysis thermogram is substantially as Fig.10 as shown in .

[0178] In some embodiments, the sodium salt form of Compound 1 is characterized by an x-ray powder diffraction pattern comprising peaks at about 6.7°±0.2°, 13.3°±0.2°, and 20.2°±0.2° 2-θ. In some embodiments, the x-ray powder diffraction pattern comprises one or more additional peaks selected from the peaks at about 16.0°±0.2°, 21.0°±0.2°, and 23.4°±0.2° 2-θ. In some embodiments, the x-ray powder diffraction pattern comprises one or more additional peaks selected from the peaks at about 7.2°±0.2°, 21.5°±0.2°, and 22.8°±0.2° 2-θ. In some embodiments, the x-ray powder diffraction pattern comprises one or more additional peaks selected from peaks at about 7.5°±0.2°, 8.3°±0.2°, 9.4°±0.2°, 11.9°±0.2°, 12.8°±0.2°, 14.8°±0.2°, 15.5°±0.2°, 16.5°±0.2°, 16.8°±0.2°, 18.2°±0.2°, 18.9°±0.2°, 24.2°±0.2°, 25.9°±0.2°, and 26.8°±0.2° 2-θ. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is characterized by being substantially as Fig.11 The x-ray powder diffraction pattern shown in .

[0179] In some embodiments, the crystalline form of the pharmaceutically acceptable salt of Compound 1 is Na Salt Form 4.

[0180] In some embodiments, the sodium salt of Compound 1 is characterized by an x-ray powder diffraction pattern comprising peaks at about 7.6°±0.2°, 13.9°±0.2°, and 15.4°±0.2° 2-θ. In some embodiments, the x-ray powder diffraction pattern comprises one or more additional peaks selected from the peaks at about 6.0°±0.2°, 8.9°±0.2°, and 12.1°±0.2° 2-θ. In some embodiments, the x-ray powder diffraction pattern comprises one or more additional peaks selected from the peaks at about 17.0°±0.2°, 21.7°±0.2°, and 23.0°±0.2° 2-θ. In some embodiments, the x-ray powder diffraction pattern comprises one or more additional peaks selected from the group consisting of peaks at about 5.2°±0.2°, 12.7°±0.2°, 14.5°±0.2°, 17.3°±0.2°, 17.7°±0.2°, 18.6°±0.2°, 18.9°±0.2°, 19.7°±0.2°, 20.2°±0.2°, 22.1°±0.2°, 22.4°±0.2°, 23.5°±0.2°, 24.3°±0.2°, 25.4°±0.2°, 28.0°±0.2°, 29.5°±0.2°, and 37.2°±0.2° 2-theta. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is characterized by being substantially as Fig.12 The x-ray powder diffraction pattern shown in .

[0181] In some embodiments, the crystalline form of the pharmaceutically acceptable salt of Compound 1 is Na salt Form 5. In some embodiments, Na salt Form 5 is characterized by having a differential scanning calorimetry thermogram comprising at least one endothermic peak selected from peaks with an onset temperature at about 29°C and 143°C. In some embodiments, Na salt Form 5 is characterized by having a differential scanning calorimetry thermogram comprising an exothermic peak with an onset temperature at about 198°C. In some embodiments, the differential scanning calorimetry thermogram is substantially as follows Fig.13 as shown in .

[0182] In some embodiments, Na salt form 5 is characterized by having a thermogravimetric thermogram showing a weight loss of about 4.2% at temperatures ranging from ambient temperature to about 200° C. In some embodiments, the thermogravimetric thermogram is substantially as Fig.14 as shown in .

[0183] In some embodiments, the pharmaceutically acceptable salt of Compound 1 is a potassium salt. In some embodiments, the potassium salt of Compound 1 is characterized by an x-ray powder diffraction pattern comprising peaks at about 7.6°±0.2°, 8.2°±0.2°, and 12.7°±0.2° 2-θ. In some embodiments, the x-ray powder diffraction pattern comprises one or more additional peaks selected from the peaks at about 13.4°±0.2°, 18.2°±0.2°, and 21.9°±0.2° 2-θ. In some embodiments, the x-ray powder diffraction pattern comprises one or more additional peaks selected from the peaks at about 12.3°±0.2°, 15.3°±0.2°, and 20.1°±0.2° 2-θ. In some embodiments, the x-ray powder diffraction pattern comprises one or more additional peaks selected from peaks at about 6.7°±0.2°, 9.3°±0.2°, 11.1°±0.2°, 13.7°±0.2°, 14.0°±0.2°, 16.2°±0.2°, 17.1°±0.2°, 17.7°±0.2°, 19.2°±0.2°, 22.2°±0.2°, 23.5°±0.2°, 24.1°±0.2°, and 24.7°±0.2° 2-θ. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is characterized by being substantially as Fig.15 The x-ray powder diffraction pattern shown in .

[0184] In some embodiments, the crystalline form of the pharmaceutically acceptable salt of Compound 1 is K salt Form 1. In some embodiments, K salt Form 1 is characterized by having a differential scanning calorimetry thermogram comprising at least one endothermic peak selected from peaks with onset temperatures at about 14°C, 182°C, and 233°C. In some embodiments, the differential scanning calorimetry thermogram is substantially as follows Fig.17 as shown in .

[0185] In some embodiments, K salt Form 1 is characterized by having a thermogravimetric thermogram showing a weight loss of about 4.2% at temperatures ranging from ambient temperature to about 200° C. In some embodiments, the thermogravimetric thermogram is substantially as Fig.18 as shown in .

[0186] In some embodiments, K salt Form 1 is characterized by absorbing about 11% by weight of water at about 25°C between about 0% and 90% relative humidity. In some embodiments, K salt Form 1 is characterized by having substantially Fig.19 The dynamic vapor adsorption mass absorption curve shown in .

[0187] In some embodiments, the pharmaceutically acceptable salt of Compound 1 is a diethylamine salt. In some embodiments, the diethylamine salt of Compound 1 is characterized by an x-ray powder diffraction pattern comprising peaks at about 9.0°±0.2°, 9.5°±0.2°, and 12.7°±0.2° 2-θ. In some embodiments, the x-ray powder diffraction pattern comprises one or more additional peaks selected from the peaks at about 6.2°±0.2°, 12.5°±0.2°, and 13.1°±0.2° 2-θ. In some embodiments, the x-ray powder diffraction pattern comprises one or more additional peaks selected from the peaks at about 4.3°±0.2°, 14.1°±0.2°, and 17.0°±0.2° 2-θ. In some embodiments, the x-ray powder diffraction pattern comprises one or more additional peaks selected from the group consisting of peaks at about 5.2°±0.2°, 8.5°±0.2°, 10.5°±0.2°, 16.1°±0.2°, 19.5°±0.2°, 21.1°±0.2°, and 26.4°±0.2° 2-θ. In some embodiments, the x-ray powder diffraction pattern is substantially as Fig.23 as shown in .

[0188] In some embodiments, the crystalline form of the pharmaceutically acceptable salt of Compound 1 is a diethylamine salt Form 1. In some embodiments, the diethylamine salt Form 1 is characterized by having a differential scanning calorimetry thermogram comprising at least one endothermic peak selected from peaks with onset temperatures at about 17°C and 145°C. In some embodiments, the differential scanning calorimetry thermogram is substantially as follows Fig.24 In some embodiments, the diethylamine salt form 1 is characterized by having a thermogravimetric analysis thermogram showing a weight loss of about 8.4% at a temperature between ambient temperature and about 170°C. In some embodiments, the thermogravimetric analysis thermogram is substantially as shown in Fig.25 In some embodiments, the diethylamine salt form 1 is characterized by absorbing about 5.5% by weight of water at about 25°C between about 0% and 90% relative humidity. In some embodiments, the diethylamine salt form 1 is characterized by having substantially Fig.26 The dynamic vapor adsorption mass absorption curve shown in .

[0189] In some embodiments, the pharmaceutically acceptable salt of Compound 1 is a choline salt. In some embodiments, the choline salt of Compound 1 is characterized by an x-ray powder diffraction pattern comprising peaks at about 10.4°±0.2°, 20.9°±0.2°, and 22.9°±0.2° 2-θ. In some embodiments, the x-ray powder diffraction pattern comprises one or more additional peaks selected from the peaks at about 14.0°±0.2°, 15.7°±0.2°, and 24.0°±0.2° 2-θ. In some embodiments, the x-ray powder diffraction pattern comprises one or more additional peaks selected from the peaks at about 14.4°±0.2°, 16.8°±0.2°, and 25.1°±0.2° 2-θ. In some embodiments, the x-ray powder diffraction pattern comprises one or more additional peaks selected from peaks at about 4.8°±0.2°, 11.0°±0.2°, 11.4°±0.2°, 13.2°±0.2°, 15.6°±0.2°, 16.1°±0.2°, 17.2°±0.2°, 18.2°±0.2°, 18.9°±0.2°, 19.4°±0.2°, 20.2°±0.2°, 27.0°±0.2°, and 28.0°±0.2° 2-θ. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is characterized by being substantially as Fig. 27 The x-ray powder diffraction pattern shown in .

[0190] In some embodiments, the crystalline form of the pharmaceutically acceptable salt of Compound 1 is choline salt Form 1. In some embodiments, wherein choline salt Form 1 is characterized by having a differential scanning calorimetry thermogram comprising at least one endothermic peak selected from peaks with onset temperatures at about 23°C, 99°C, and 156°C. In some embodiments, the differential scanning calorimetry thermogram is substantially as Fig.28 In some embodiments, choline salt form 1 is characterized by having a thermogravimetric thermogram showing a weight loss of about 8.8% at a temperature ranging from ambient temperature to about 200° C. In some embodiments, the thermogravimetric thermogram is substantially as shown in Fig.29 as shown in .

[0191] One aspect of the present disclosure relates to a crystalline form of a solvate of a pharmaceutically acceptable salt of Compound 1.

[0192] In some embodiments, the solvate is a potassium salt solvate. In some embodiments, the potassium salt solvate is characterized by being substantially as Fig. 20 The x-ray powder diffraction pattern shown in . In some embodiments, the solvate is a potassium salt IPA solvate.

[0193] In some embodiments, the potassium salt solvate is characterized by being substantially as Fig.21The x-ray powder diffraction pattern is shown in . In some embodiments, the solvate is a potassium salt THF solvate.

[0194] In some embodiments, the solvate is a diethylamine salt solvate. In some embodiments, the diethylamine salt solvate is characterized by being substantially as Fig. 20 The x-ray powder diffraction pattern is shown in . In some embodiments, the solvate is a diethylamine salt toluene solvate.

[0195] III. Pharmaceutical Compositions

[0196] One aspect of the present disclosure relates to a pharmaceutical composition comprising a crystalline form of Compound 1. Another aspect of the present disclosure relates to a pharmaceutical composition comprising a crystalline form of a solvate of Compound 1.

[0197] One aspect of the present disclosure relates to a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1. Another aspect of the present disclosure relates to a pharmaceutical composition comprising a solvate of a pharmaceutically acceptable salt of Compound 1.

[0198] One aspect of the present disclosure relates to a pharmaceutical composition comprising a crystalline form of a pharmaceutically acceptable salt of Compound 1. Another aspect of the present disclosure relates to a pharmaceutical composition comprising a crystalline form of a solvate of a pharmaceutically acceptable salt of Compound 1.

[0199] The pharmaceutical compositions herein contain any compound in Part II for treating or preventing a disease, condition and / or illness in a therapeutically effective amount. The therapeutically effective amount may vary according to a variety of factors, including the activity of the specific compound employed; the metabolic stability and duration of action of the compound; the age, weight, general health, sex and diet of the patient; the mode and time of administration; the rate of excretion; the combination of drugs; the severity of a particular condition or illness; and the subject being treated. One skilled in the art can determine appropriate concentrations and dosages.

[0200] In some embodiments, the dose of Compound 1 is in the range of about 1 mg / kg to 24 mg / kg, but lower or higher doses may be administered as needed. A dose of 1 mg / kg to 20 mg / kg for a 70 kg patient is, for example, 70 mg to 1,400 mg. The dose may be repeated as needed, for example, once a week for 4 to 10 weeks, once a week for 8 weeks, or once a week for 4 weeks. Depending on the need for maintenance therapy, the dose may also be administered at a lower frequency, such as every other week for several months, or monthly or quarterly for several months. In some embodiments, the dosage is 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, 20 mg / kg, 22 mg / kg, 24 mg / kg, 26 mg / kg, 28 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 55 mg / kg, 6 5mg / kg, 70mg / kg, 75mg / kg, 80mg / kg, 85mg / kg, 90mg / kg, 95mg / kg, 100mg / kg, 120mg / kg, 140mg / kg, 160mg / kg, 180mg / kg, 200mg / kg, 220mg / kg, 240m g / kg, 260mg / kg, 280mg / kg, 300mg / kg, 350mg / kg, 400mg / kg, 450mg / kg, 500mg / kg, 550mg / kg, 600mg / kg, 650mg / kg, 700mg / kg, 750mg / kg or 800mg / kg.

[0201] In some embodiments, the compound is present in the pharmaceutical composition in an amount of about 5 mg to about 1000 mg. In some embodiments, the compound is present in the pharmaceutical composition in an amount of about 5 mg to about 300 mg. In some embodiments, the compound is present in the pharmaceutical composition in an amount of about 5 mg to about 200 mg. In some embodiments, the compound is present in the pharmaceutical composition in an amount of about 5 mg to about 100 mg. In some embodiments, the compound is present in the pharmaceutical composition in an amount of about 5 mg to about 100 mg. In some embodiments, the compound is present in the pharmaceutical composition in an amount of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 1 20 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg or about 1000 mg is present in the pharmaceutical composition.

[0202] In some embodiments, the compound is present in the pharmaceutical composition in an amount of about 5 mg. In some embodiments, the compound is present in the pharmaceutical composition in an amount of about 15 mg. In some embodiments, the compound is present in the pharmaceutical composition in an amount of about 25 mg. In some embodiments, the compound is present in the pharmaceutical composition in an amount of about 50 mg.

[0203] In some embodiments, the compound is administered in a 21 day cycle with 2 days of administration followed by 5 days of rest. In some embodiments, the compound is administered on days 1, 2, 8, 9, 15, and 16 of each 21 day cycle for up to 105 weeks.

[0204] In some embodiments, the compound is administered once a week, with one day of administration followed by six days of rest. In some embodiments, the compound is administered twice every three weeks.

[0205] The pharmaceutical compositions disclosed herein can be prepared by combining the compounds disclosed herein with appropriate pharmaceutically acceptable carriers or excipients, and can be formulated into solid, semisolid, liquid or gaseous preparations, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols. In some embodiments, the pharmaceutical compositions disclosed herein are formulated into preparations in the form of tablets or capsules.

[0206] The pharmaceutical compositions disclosed herein can be prepared by methods well known in the pharmaceutical field. For example, a solid pharmaceutical composition intended for oral administration can be prepared by mixing the compound disclosed herein with at least one pharmaceutical carrier or excipient to form a solid preformulation composition, which can then be easily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules. The method of preparing the dosage form is known or will be apparent to those skilled in the art; for example, see Remington: The Science and Practice of Pharmacy, 20th edition (Philadelphia College of Pharmacy and Science, 2000). In some embodiments, the composition is in the form of a unit dosage form. In some embodiments, the unit dosage form is a tablet.

[0207] In some embodiments, the pharmaceutical composition disclosed herein further comprises at least one additional therapeutic compound. In some embodiments, at least one additional therapeutic compound is a drug for treating cancer. In some embodiments, at least one additional therapeutic compound is selected from docetaxel, sacituzumab govitecan and gemcitabine.

[0208] The pharmaceutical compositions disclosed herein can be formulated to allow the active ingredients contained therein to be bioavailable when the composition is administered to a patient. Typical routes of administration of such pharmaceutical compositions include, but are not limited to, oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal, and intranasal. In some embodiments, the pharmaceutical composition is prepared for oral administration.

[0209] In some embodiments, the pharmaceutical compositions disclosed herein are administered with at least one additional therapeutic compound. Administration of at least one additional therapeutic compound may be performed before, after, or simultaneously with administration of the pharmaceutical compositions disclosed herein. In some embodiments, at least one additional therapeutic compound is a drug for treating cancer. In some embodiments, at least one additional therapeutic compound is selected from docetaxel, gosartuzumab, and gemcitabine.

[0210] IV. Methods and Uses

[0211] One aspect of the present disclosure relates to methods and uses of any of the compounds and pharmaceutical compositions disclosed herein.

[0212] In one aspect, the present disclosure relates to a method of inhibiting MCL-1 in a patient, the method comprising administering to the patient any of the compounds or pharmaceutical compositions disclosed herein.

[0213] In some embodiments, the method of inhibiting MCL-1 in a patient comprises administering to the patient a crystalline form of Compound 1 and / or a crystalline form of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the method of inhibiting MCL-1 in a patient comprises administering to the patient a pharmaceutical composition comprising a crystalline form of Compound 1 and / or a crystalline form of a pharmaceutically acceptable salt of Compound 1 and a pharmaceutically acceptable carrier or excipient.

[0214] In one aspect, the present disclosure relates to a method of treating cancer in a patient, the method comprising administering to the patient any of the compounds or pharmaceutical compositions disclosed herein.

[0215] In some embodiments, the method of treating cancer in a patient comprises administering to the patient a crystalline form of Compound 1 and / or a crystalline form of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the method of treating cancer in a patient comprises administering to the patient a pharmaceutical composition comprising a crystalline form of Compound 1 and / or a crystalline form of a pharmaceutically acceptable salt of Compound 1 and a pharmaceutically acceptable carrier or excipient.

[0216] In one aspect, the present disclosure relates to the use of any of the compounds or pharmaceutical compositions disclosed herein for treating cancer. In some embodiments, the compound is a crystalline form of Compound 1 and / or a crystalline form of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the pharmaceutical composition comprises a crystalline form of Compound 1 and / or a crystalline form of a pharmaceutically acceptable salt of Compound 1 and a pharmaceutically acceptable carrier or excipient.

[0217] In one aspect, the present disclosure relates to the use of any of the compounds or pharmaceutical compositions disclosed herein in the manufacture of a medicament for treating cancer. In some embodiments, the compound is a crystalline form of Compound 1 and / or a crystalline form of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the pharmaceutical composition comprises a crystalline form of Compound 1 and / or a crystalline form of a pharmaceutically acceptable salt of Compound 1 and a pharmaceutically acceptable carrier or excipient.

[0218] In some embodiments, in any of the above methods or uses, the cancer is a hematological malignancy. In some embodiments, the cancer is relapsed refractory multiple myeloma or relapsed refractory myeloma. In some embodiments, the cancer is a solid malignancy. In some embodiments, the cancer is triple-negative breast cancer, colorectal cancer, skin cancer, melanoma, ovarian cancer, renal cancer, small cell lung cancer, non-small cell lung cancer, lymphoma, leukemia, or metastatic soft tissue sarcoma.

[0219] In one aspect, the present disclosure relates to any of the compounds or pharmaceutical compositions disclosed herein for use in a method for treating cancer. In some embodiments, the compound is a crystalline form of Compound 1 and / or a crystalline form of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the pharmaceutical composition comprises a crystalline form of Compound 1 and / or a crystalline form of a pharmaceutically acceptable salt of Compound 1 and a pharmaceutically acceptable carrier or excipient.

[0220] In some embodiments, the cancer is a hematological malignancy. In some embodiments, the cancer is relapsed refractory multiple myeloma or relapsed refractory myeloma. In some embodiments, the cancer is triple negative breast cancer, colorectal cancer, skin cancer, melanoma, ovarian cancer, kidney cancer, small cell lung cancer, non-small cell lung cancer, lymphoma, leukemia, or metastatic soft tissue sarcoma. In some embodiments, the cancer is a solid malignancy.

[0221] In some embodiments, in any of the above methods or uses, the method further comprises administering to the patient an additional therapeutic compound. In some embodiments, the additional therapeutic compound is selected from docetaxel, gosartuzumab, and gemcitabine.

[0222] List of implementation plans

[0223] Embodiment 1: A crystalline form of compound 1:

[0224]

[0225] Embodiment 2: The crystalline form according to Embodiment 1, wherein the crystalline form of Compound 1 is Form I.

[0226] Embodiment 3: The crystalline form of Embodiment 1 or Embodiment 2, wherein the crystalline form of Compound 1 is characterized by an x-ray powder diffraction pattern comprising peaks at approximately 4.9°±0.2°, 8.6°±0.2°, and 14.3°±0.2° 2-θ.

[0227] Embodiment 4: The crystalline form of Embodiment 3, wherein the x-ray powder diffraction pattern comprises one or more additional peaks selected from the group consisting of peaks at approximately 16.2°±0.2°, 18.3°±0.2°, and 22.1°±0.2° 2-θ.

[0228] Embodiment 5: The crystalline form of Embodiment 3 or Embodiment 4, wherein the x-ray powder diffraction pattern comprises one or more additional peaks selected from the peaks at approximately 17.8°±0.2°, 19.3°±0.2°, and 21.5°±0.2° 2-θ.

[0229] Embodiment 6: The crystalline form of Embodiment 5, wherein the x-ray powder diffraction pattern comprises one or more additional peaks selected from peaks at approximately 13.5°±0.2°, 14.6°±0.2°, 16.0°±0.2°, 17.5°±0.2°, 18.8°±0.2°, 20.2°±0.2°, 20.7°±0.2°, 23.0°±0.2°, 24.6°±0.2°, 26.3°±0.2°, and 26.8°±0.2° 2-θ.

[0230] Embodiment 7: The crystalline form according to any one of Embodiments 1 to 6, wherein the crystalline form of Compound 1 is characterized by being substantially Fig.31 The x-ray powder diffraction pattern shown in .

[0231] Embodiment 8: The crystalline form according to any one of Embodiments 2 to 7, wherein Form I is characterized by having a differential scanning calorimetry thermogram comprising an endothermic peak with an onset temperature at about 180°C.

[0232] Embodiment 9: The crystalline form of Embodiment 8, wherein the differential scanning calorimetry thermogram is substantially as follows Fig.32 as shown in .

[0233] Embodiment 10: The crystalline form according to any one of Embodiments 2 to 9, wherein Form I is characterized by having a thermogravimetric analysis thermogram showing a weight loss of about 1.0% at temperatures from ambient temperature to about 170°C.

[0234] Embodiment 11: The crystalline form of Embodiment 10, wherein the thermogravimetric thermogram is substantially as follows: Fig.33 as shown in .

[0235] Embodiment 12: The crystalline form of any one of Embodiments 2 to 11, wherein Form I is characterized by absorbing about 1.4 wt% water at about 25°C and between about 0% and 90% relative humidity.

[0236] Embodiment 13: A crystalline form according to any one of Embodiments 2 to 12, wherein Form I is characterized by having substantially Fig.34 The dynamic vapor adsorption mass absorption curve shown in .

[0237] Embodiment 14: The crystalline form according to Embodiment 1, wherein the crystalline form of Compound 1 is Form II.

[0238] Embodiment 15: A crystalline form according to Embodiment 1 or Embodiment 14, wherein the crystalline form of Compound 1 is characterized by an x-ray powder diffraction pattern comprising peaks at approximately 6.1°±0.2°, 15.7°±0.2°, and 16.1°±0.2° 2-θ.

[0239] Embodiment 16: The crystalline form of Embodiment 15, wherein the x-ray powder diffraction pattern comprises one or more additional peaks selected from the group consisting of peaks at approximately 15.4°±0.2°, 16.9°±0.2°, and 19.9°±0.2° 2-θ.

[0240] Embodiment 17: The crystalline form of Embodiment 15 or Embodiment 16, wherein the x-ray powder diffraction pattern comprises one or more additional peaks selected from the peaks at approximately 12.8°±0.2°, 13.9°±0.2°, and 22.8°±0.2° 2-θ.

[0241] Embodiment 18: A crystalline form according to Embodiment 17, wherein the x-ray powder diffraction pattern comprises one or more additional peaks selected from peaks at approximately 10.5°±0.2°, 12.2°±0.2°, 13.3°±0.2°, 18.2°±0.2°, 19.0°±0.2°, 19.4°±0.2°, 20.3°±0.2°, 21.1°±0.2°, 23.4°±0.2°, 25.2°±0.2°, 25.7°±0.2°, 26.7°±0.2° and 27.9°±0.2° 2-θ.

[0242] Embodiment 19: A crystalline form according to any one of Embodiments 1 or 14 to 18, wherein the crystalline form of Compound 1 is characterized by being substantially Fig.36 The x-ray powder diffraction pattern shown in .

[0243] Embodiment 20: The crystalline form of any one of Embodiments 14 to 19, wherein Form II is characterized by having a differential scanning calorimetry thermogram comprising an endothermic peak with an onset temperature at about 163°C.

[0244] Embodiment 21: The crystalline form of Embodiment 20, wherein the differential scanning calorimetry thermogram is substantially as follows Fig.37 as shown in .

[0245] Embodiment 22: The crystalline form of any one of Embodiments 14 to 21, wherein Form II is characterized by having a thermogravimetric analysis thermogram showing a weight loss of about 0.6% at temperatures from ambient temperature to about 210°C.

[0246] Embodiment 23: The crystalline form of Embodiment 22, wherein the thermogravimetric thermogram is substantially as follows: Fig.38 as shown in .

[0247] Embodiment 24: The crystalline form of any one of Embodiments 14 to 23, wherein Form II is characterized by absorbing up to about 1.1 wt% water at about 25°C between about 0% and 90% relative humidity.

[0248] Embodiment 25: A crystalline form according to any one of Embodiments 14 to 24, wherein Form II is characterized by having substantially Fig.39 The dynamic vapor adsorption mass absorption curve shown in .

[0249] Embodiment 26: The crystalline form according to Embodiment 1, wherein the crystalline form of Compound 1 is Form III.

[0250] Embodiment 27: The crystalline form of Embodiment 1 or Embodiment 26, wherein the crystalline form of Compound 1 is characterized by an x-ray powder diffraction pattern comprising peaks at approximately 8.0°±0.2°, 15.0°±0.2°, and 18.4°±0.2° 2-θ.

[0251] Embodiment 28: The crystalline form of Embodiment 27, wherein the x-ray powder diffraction pattern comprises one or more additional peaks selected from the group consisting of peaks at approximately 16.5°±0.2°, 22.1°±0.2°, and 22.9°±0.2° 2-θ.

[0252] Embodiment 29: A crystalline form according to Embodiment 27 or Embodiment 28, wherein the x-ray powder diffraction pattern comprises one or more additional peaks selected from the peaks at approximately 12.5°±0.2°, 19.5°±0.2° and 23.6°±0.2° 2-θ.

[0253] Embodiment 30: A crystalline form according to Embodiment 29, wherein the x-ray powder diffraction pattern comprises one or more additional peaks selected from the peaks at approximately 6.5°±0.2°, 12.3°±0.2°, 12.9°±0.2°, 13.6°±0.2°, 14.3°±0.2°, 16.0°±0.2°, 18.1°±0.2°, 20.7°±0.2°, 24.1°±0.2°, 24.7°±0.2°, 26.8°±0.2° and 28.3°±0.2° 2-θ.

[0254] Embodiment 31: A crystalline form according to any one of Embodiments 1 or 26 to 30, wherein the crystalline form of Compound 1 is characterized by being substantially Fig.40The x-ray powder diffraction pattern shown in .

[0255] Embodiment 32: The crystalline form of any one of Embodiments 26 to 31, wherein Form III is characterized by having a differential scanning calorimetry thermogram comprising at least one endothermic peak selected from peaks with onset temperatures at about 20°C, 133°C, and 153°C.

[0256] Embodiment 33: The crystalline form of Embodiment 32, wherein the differential scanning calorimetry thermogram is substantially as follows: Fig.41 as shown in .

[0257] Embodiment 34: The crystalline form of any one of Embodiments 26 to 33, wherein Form III is characterized by having a thermogravimetric analysis thermogram showing a weight loss of about 2.9% at a temperature from about ambient temperature to about 90°C.

[0258] Embodiment 35: The crystalline form of any one of Embodiments 26 to 34, wherein Form III is characterized by having a thermogravimetric analysis thermogram showing a weight loss of about 1.1% at a temperature of about 90°C to about 175°C.

[0259] Embodiment 36: The crystalline form of any one of Embodiments 26 to 35, wherein Form III is characterized by having a thermogravimetric analysis thermogram showing a weight loss of about 1.6% at a temperature of about 175°C to about 225°C.

[0260] Embodiment 37: A crystalline form according to any one of Embodiments 34 to 36, wherein the thermogravimetric thermogram is substantially as follows Fig.42 as shown in .

[0261] Embodiment 38: The crystalline form of any one of Embodiments 26 to 37, wherein Form III is characterized by absorbing up to about 5% by weight of water at about 25°C between about 0% and 90% relative humidity.

[0262] Embodiment 39: A crystalline form according to any one of Embodiments 26 to 38, wherein Form III is characterized by having substantially Fig.43 The dynamic vapor adsorption mass absorption curve shown in .

[0263] Embodiment 40: The crystalline form of Embodiment 1, wherein the crystalline form of Compound 1 is Form IV.

[0264] Embodiment 41: A crystalline form according to Embodiment 1 or Embodiment 40, wherein the crystalline form of Compound 1 is characterized by an x-ray powder diffraction pattern comprising peaks at approximately 7.1°±0.2°, 8.7°±0.2°, and 10.6°±0.2° 2-θ.

[0265] Embodiment 42: The crystalline form of Embodiment 41, wherein the x-ray powder diffraction pattern comprises one or more additional peaks selected from the group consisting of peaks at approximately 10.3°±0.2°, 11.2°±0.2°, and 18.2°±0.2° 2-θ.

[0266] Embodiment 43: A crystalline form according to Embodiment 41 or Embodiment 42, wherein the x-ray powder diffraction pattern comprises one or more additional peaks selected from the peaks at approximately 14.2°±0.2°, 20.5°±0.2° and 24.9°±0.2° 2-θ.

[0267] Embodiment 44: A crystalline form according to Embodiment 43, wherein the x-ray powder diffraction pattern comprises one or more additional peaks selected from peaks at approximately 3.3°±0.2°, 13.2°±0.2°, 15.4°±0.2°, 16.2°±0.2°, 17.9°±0.2°, 19.0°±0.2°, 21.3°±0.2°, 21.9°±0.2°, 23.3°±0.2°, 26.1°±0.2° and 28.3°±0.2° 2-θ.

[0268] Embodiment 45: A crystalline form according to any one of Embodiments 1 or 40 to 41, wherein the crystalline form of Compound 1 is characterized by being substantially Fig.44 The x-ray powder diffraction pattern shown in .

[0269] Embodiment 46: The crystalline form of any one of Embodiments 40 to 45, wherein Form IV is characterized by having a differential scanning calorimetry thermogram comprising at least one endothermic peak selected from peaks with onset temperatures at about 119°C and 166°C.

[0270] Embodiment 47: The crystalline form of Embodiment 46, wherein the differential scanning calorimetry thermogram is substantially as follows Fig.45 as shown in .

[0271] Embodiment 48: The crystalline form of any one of Embodiments 40 to 47, wherein Form IV is characterized by having a thermogravimetric analysis thermogram showing a weight loss of about 0.6% at temperatures from ambient temperature to about 200°C.

[0272] Embodiment 49: The crystalline form of Embodiment 48, wherein the thermogravimetric thermogram is substantially as follows: Fig.46 as shown in .

[0273] Embodiment 50: A crystalline form of a pharmaceutically acceptable salt of Compound 1:

[0274]

[0275] Embodiment 51: The crystalline form according to Embodiment 50, wherein the pharmaceutically acceptable salt of Compound 1 is a sodium salt.

[0276] Embodiment 52: The crystalline form of Embodiment 51, wherein the sodium salt is Na Salt Form 1.

[0277] Embodiment 53: A crystalline form according to Embodiment 51 or Embodiment 52, wherein the sodium salt of Compound 1 is characterized by an x-ray powder diffraction pattern comprising peaks at approximately 7.6°±0.2°, 8.4°±0.2°, and 12.8°±0.2° 2-θ.

[0278] Embodiment 54: The crystalline form of Embodiment 53, wherein the x-ray powder diffraction pattern comprises one or more additional peaks selected from the group consisting of peaks at approximately 15.3°±0.2°, 18.4°±0.2°, and 20.4°±0.2° 2-θ.

[0279] Embodiment 55: A crystalline form according to Embodiment 53 or Embodiment 54, wherein the x-ray powder diffraction pattern comprises one or more additional peaks selected from the peaks at approximately 12.3°±0.2°, 13.4°±0.2°, and 24.0°±0.2° 2-θ.

[0280] Embodiment 56: A crystalline form according to Embodiment 55, wherein the x-ray powder diffraction pattern comprises one or more additional peaks selected from the peaks at approximately 6.7°±0.2°, 13.7°±0.2°, 14.0°±0.2°, 15.7°±0.2°, 17.1°±0.2°, 17.4°±0.2°, 17.9°±0.2°, 19.2°±0.2°, 22.0°±0.2°, 22.2°±0.2°, 23.6°±0.2°, 24.3°±0.2°, and 24.8°±0.2° 2-θ.

[0281] Embodiment 57: A crystalline form according to any one of Embodiments 50 to 56, wherein the pharmaceutically acceptable salt of Compound 1 is characterized by being substantially as follows Figure 1 The x-ray powder diffraction pattern shown in .

[0282] Embodiment 58: The crystalline form of any one of Embodiments 52 to 57, wherein the Na salt form 1 is characterized by having a differential scanning calorimetry thermogram comprising at least one endothermic peak selected from peaks with onset temperatures at about 14°C, 83°C, and 232°C.

[0283] Embodiment 59: The crystalline form of Embodiment 58, wherein the differential scanning calorimetry thermogram is substantially as follows Figure 2 as shown in .

[0284] Embodiment 60: The crystalline form according to any one of Embodiments 52 to 59, wherein the Na salt Form 1 is characterized by having a thermogravimetric analysis thermogram showing a weight loss of about 4.2% at temperatures from ambient temperature to about 200°C.

[0285] Embodiment 61: The crystalline form of Embodiment 60, wherein the thermogravimetric thermogram is substantially as follows: Figure 3 as shown in .

[0286] Embodiment 62: The crystalline form of any one of Embodiments 52 to 61, wherein the Na salt Form 1 is characterized by absorbing about 7.5 wt% water at about 25°C between about 0% and 90% relative humidity.

[0287] Embodiment 63: A crystalline form according to any one of Embodiments 52 to 62, wherein the Na salt form 1 is characterized by having substantially Figure 4 The dynamic vapor adsorption mass absorption curve shown in .

[0288] Embodiment 64: The crystalline form according to Embodiment 51, wherein the sodium salt of Compound 1 is Na Salt Form 2.

[0289] Embodiment 65: The crystalline form of Embodiment 51 or Embodiment 64, wherein the sodium salt of Compound 1 is characterized by an x-ray powder diffraction pattern comprising peaks at approximately 7.2°±0.2°, 14.7°±0.2°, and 19.3°±0.2° 2-θ.

[0290] Embodiment 66: A crystalline form according to Embodiment 65, wherein the x-ray powder diffraction pattern comprises one or more additional peaks selected from the group consisting of peaks at approximately 11.1°±0.2°, 17.1°±0.2°, and 20.7°±0.2° 2-θ.

[0291] Embodiment 67: The crystalline form of Embodiment 65 or Embodiment 66, wherein the x-ray powder diffraction pattern comprises one or more additional peaks selected from the peaks at approximately 13.1°±0.2°, 14.5°±0.2°, and 16.9°±0.2° 2-θ.

[0292] Embodiment 68: A crystalline form according to Embodiment 67, wherein the x-ray powder diffraction pattern comprises one or more additional peaks selected from the peaks at approximately 6.7°±0.2°, 9.1±0.2°, 9.7°±0.2°, 12.1°±0.2°, 15.2°±0.2°, 17.3°±0.2°, 17.5°±0.2°, 17.8°±0.2°, 18.2°±0.2°, 19.1°±0.2°, 21.6°±0.2°, 22.0°±0.2°, 22.8°±0.2°, 24.4°±0.2°, and 25.1°±0.2° 2-θ.

[0293] Embodiment 69: A crystalline form according to any one of Embodiments 50 to 52 or 64 to 68, wherein the pharmaceutically acceptable salt of Compound 1 is characterized by being substantially Figure 5 The x-ray powder diffraction pattern shown in .

[0294] Embodiment 70: The crystalline form of any one of Embodiments 64 to 69, wherein the Na salt form 2 is characterized by having a differential scanning calorimetry thermogram comprising at least one endothermic peak selected from peaks with onset temperatures at about 21°C and 224°C.

[0295] Embodiment 71: The crystalline form of any one of Embodiments 64 to 70, wherein the Na salt form 2 is characterized by having a differential scanning calorimetry thermogram comprising an exothermic peak with an onset temperature at about 109°C.

[0296] Embodiment 72: The crystalline form of Embodiment 70 or Embodiment 71, wherein the differential scanning calorimetry thermogram is substantially as follows Figure 6 as shown in .

[0297] Embodiment 73: The crystalline form of any one of Embodiments 64 to 72, wherein the Na salt Form 2 is characterized by having a thermogravimetric analysis thermogram showing a weight loss of about 4.8% at temperatures from ambient temperature to about 200°C.

[0298] Embodiment 74: The crystalline form of Embodiment 73, wherein the thermogravimetric thermogram is substantially as follows: Figure 7 as shown in .

[0299] Embodiment 75: The crystalline form of Embodiment 51, wherein the sodium salt is Na salt Form 3.

[0300] Embodiment 76: The crystalline form of Embodiment 51 or Embodiment 75, wherein the sodium salt of Compound 1 is characterized by an x-ray powder diffraction pattern comprising peaks at approximately 4.1°±0.2°, 13.2°±0.2°, and 18.8°±0.2° 2-θ.

[0301] Embodiment 77: The crystalline form of Embodiment 76, wherein the x-ray powder diffraction pattern comprises one or more additional peaks selected from the peaks at approximately 12.1°±0.2°, 20.0°±0.2°, and 24.2°±0.2° 2-θ.

[0302] Embodiment 78: The crystalline form of Embodiment 76 or Embodiment 77, wherein the x-ray powder diffraction pattern comprises one or more additional peaks selected from the peaks at approximately 14.8°±0.2°, 20.9°±0.2°, and 22.9°±0.2° 2-θ.

[0303] Embodiment 79: The crystalline form of Embodiment 78, wherein the x-ray powder diffraction pattern comprises an additional peak at about 8.2°±0.2° 2-θ.

[0304] Embodiment 80: A crystalline form according to any one of Embodiments 50 to 51 or 75 to 79, wherein the pharmaceutically acceptable salt of Compound 1 is characterized by being substantially Figure 8 The x-ray powder diffraction pattern shown in .

[0305] Embodiment 81: The crystalline form of any one of Embodiments 75 to 80, wherein the Na salt form 3 is characterized by having a differential scanning calorimetry thermogram comprising at least one endothermic peak selected from peaks with onset temperatures at about 19°C and 219°C.

[0306] Embodiment 82: The crystalline form of Embodiment 81, wherein the differential scanning calorimetry thermogram is substantially as follows Fig. 9 as shown in .

[0307] Embodiment 83: The crystalline form of any one of Embodiments 75 to 82, wherein the Na salt form 3 is characterized by having a thermogravimetric analysis thermogram showing a weight loss of about 5.1% at temperatures from ambient temperature to about 200°C.

[0308] Embodiment 84: The crystalline form of Embodiment 83, wherein the thermogravimetric thermogram is substantially as follows: Fig.10 as shown in .

[0309] Embodiment 85: The crystalline form of Embodiment 51, wherein the sodium salt is Na salt Form 4.

[0310] Embodiment 86: The crystalline form of Embodiment 51 or Embodiment 85, wherein the sodium salt of Compound 1 is characterized by an x-ray powder diffraction pattern comprising peaks at approximately 6.7°±0.2°, 13.3°±0.2°, and 20.2°±0.2° 2-θ.

[0311] Embodiment 87: The crystalline form of Embodiment 86, wherein the x-ray powder diffraction pattern comprises one or more additional peaks selected from the group consisting of peaks at approximately 16.0°±0.2°, 21.0°±0.2°, and 23.4°±0.2° 2-θ.

[0312] Embodiment 88: The crystalline form of Embodiment 87, wherein the x-ray powder diffraction pattern comprises one or more additional peaks selected from the group consisting of peaks at approximately 7.2°±0.2°, 21.5°±0.2°, and 22.8°±0.2° 2-θ.

[0313] Embodiment 89: The crystalline form of Embodiment 87 or Embodiment 88, wherein the x-ray powder diffraction pattern comprises one or more additional peaks selected from peaks at approximately 7.5°±0.2°, 8.3°±0.2°, 9.4°±0.2°, 11.9°±0.2°, 12.8°±0.2°, 14.8°±0.2°, 15.5°±0.2°, 16.5°±0.2°, 16.8°±0.2°, 18.2°±0.2°, 18.9°±0.2°, 24.2°±0.2°, 25.9°±0.2°, and 26.8°±0.2° 2-θ.

[0314] Embodiment 90: A crystalline form according to any one of Embodiments 50 to 51 or 85 to 89, wherein the pharmaceutically acceptable salt of Compound 1 is characterized by being substantially Fig.11 The x-ray powder diffraction pattern shown in .

[0315] Embodiment 91: The crystalline form of Embodiment 51, wherein the sodium salt is Na salt Form 5.

[0316] Embodiment 92: The crystalline form of Embodiment 51 or Embodiment 91, wherein the sodium salt of Compound 1 is characterized by an x-ray powder diffraction pattern comprising peaks at approximately 7.6°±0.2°, 13.9°±0.2°, and 15.4°±0.2° 2-θ.

[0317] Embodiment 93: The crystalline form of Embodiment 92, wherein the x-ray powder diffraction pattern comprises one or more additional peaks selected from the group consisting of peaks at approximately 6.0°±0.2°, 8.9°±0.2°, and 12.1°±0.2° 2-θ.

[0318] Embodiment 94: A crystalline form according to Embodiment 92 or Embodiment 93, wherein the x-ray powder diffraction pattern comprises one or more additional peaks selected from the peaks at approximately 17.0°±0.2°, 21.7°±0.2°, and 23.0°±0.2° 2-θ.

[0319] Embodiment 95: A crystalline form according to Embodiment 94, wherein the x-ray powder diffraction pattern comprises one or more additional peaks selected from the peaks at approximately 5.2°±0.2°, 12.7°±0.2°, 14.5°±0.2°, 17.3°±0.2°, 17.7°±0.2°, 18.6°±0.2°, 18.9°±0.2°, 19.7°±0.2°, 20.2°±0.2°, 22.1°±0.2°, 22.4°±0.2°, 23.5°±0.2°, 24.3°±0.2°, 25.4°±0.2°, 28.0°±0.2°, 29.5°±0.2°, and 37.2°±0.2° 2-θ.

[0320] Embodiment 96: A crystalline form according to any one of Embodiments 50 to 51 and 91 to 95, wherein the pharmaceutically acceptable salt of Compound 1 is characterized by being substantially as Fig.12 The x-ray powder diffraction pattern shown in .

[0321] Embodiment 97: The crystalline form of any one of Embodiments 91 to 96, wherein the Na salt form 5 is characterized by having a differential scanning calorimetry thermogram comprising at least one endothermic peak selected from peaks with onset temperatures at about 29°C and 143°C.

[0322] Embodiment 98: The crystalline form of any one of Embodiments 91 to 97, wherein the Na salt form 5 is characterized by having a differential scanning calorimetry thermogram comprising an exothermic peak with an onset temperature at about 198°C.

[0323] Embodiment 99: The crystalline form of Embodiment 97 or Embodiment 98, wherein the differential scanning calorimetry thermogram is substantially as follows Fig.13 as shown in .

[0324] Embodiment 100: The crystalline form according to any one of Embodiments 91 to 99, wherein the Na salt form 5 is characterized by having a thermogravimetric analysis thermogram showing a weight loss of about 4.2% at temperatures from ambient temperature to about 200°C.

[0325] Embodiment 101: The crystalline form of Embodiment 100, wherein the thermogravimetric thermogram shows substantially Fig.14 as shown in .

[0326] Embodiment 102: The crystalline form according to Embodiment 50, wherein the pharmaceutically acceptable salt of Compound 1 is a potassium salt.

[0327] Embodiment 103: A crystalline form according to Embodiment 102, wherein the potassium salt is K salt form 1.

[0328] Embodiment 104: A crystalline form according to Embodiment 102 or Embodiment 103, wherein the potassium salt of Compound 1 is characterized by an x-ray powder diffraction pattern comprising peaks at approximately 7.6°±0.2°, 8.2°±0.2°, and 12.7°±0.2° 2-θ.

[0329] Embodiment 105: A crystalline form according to Embodiment 104, wherein the x-ray powder diffraction pattern comprises one or more additional peaks selected from the peaks at approximately 13.4°±0.2°, 18.2°±0.2°, and 21.9°±0.2° 2-θ.

[0330] Embodiment 106: The crystalline form of Embodiment 104 or Embodiment 105, wherein the x-ray powder diffraction pattern comprises one or more additional peaks selected from the peaks at approximately 12.3°±0.2°, 15.3°±0.2°, and 20.1°±0.2° 2-θ.

[0331] Embodiment 107: A crystalline form according to Embodiment 106, wherein the x-ray powder diffraction pattern comprises one or more additional peaks selected from peaks at approximately 6.7°±0.2°, 9.3°±0.2°, 11.1°±0.2°, 13.7°±0.2°, 14.0°±0.2°, 16.2°±0.2°, 17.1°±0.2°, 17.7°±0.2°, 19.2°±0.2°, 22.2°±0.2°, 23.5°±0.2°, 24.1°±0.2° and 24.7°±0.2° 2-θ.

[0332] Embodiment 108: A crystalline form according to any one of Embodiments 50 or 102 to 107, wherein the pharmaceutically acceptable salt of Compound 1 is characterized by being substantially as follows Fig.15The x-ray powder diffraction pattern shown in .

[0333] Embodiment 109: The crystalline form of any one of Embodiments 103 to 108, wherein the K salt form 1 is characterized by having a differential scanning calorimetry thermogram comprising at least one endothermic peak selected from peaks with onset temperatures at about 14°C, 182°C, and 233°C.

[0334] Embodiment 110: The crystalline form of Embodiment 109, wherein the differential scanning calorimetry thermogram is substantially as follows Fig.17 as shown in .

[0335] Embodiment 111: The crystalline form of any one of Embodiments 103 to 110, wherein the K salt form 1 is characterized by having a thermogravimetric analysis thermogram showing a weight loss of about 4.2% at temperatures from ambient temperature to about 200°C.

[0336] Embodiment 112: The crystalline form of Embodiment 111, wherein the thermogravimetric thermogram is substantially as follows: Fig.18 as shown in .

[0337] Embodiment 113: The crystalline form of any one of Embodiments 103 to 112, wherein the K salt form 1 is characterized by absorbing about 11 wt % water at about 25°C between about 0% and 90% relative humidity.

[0338] Embodiment 114: A crystalline form according to any one of Embodiments 103 to 113, wherein the K salt form 1 is characterized by having substantially Fig.19 The dynamic vapor adsorption mass absorption curve shown in .

[0339] Embodiment 115: The crystalline form according to Embodiment 50, wherein the pharmaceutically acceptable salt of Compound 1 is a diethylamine salt.

[0340] Embodiment 116: The crystalline form of Embodiment 115, wherein the diethylamine salt is diethylamine salt Form 1.

[0341] Embodiment 117: A crystalline form according to Embodiment 115 or Embodiment 116, wherein the diethylamine salt of Compound 1 is characterized by an x-ray powder diffraction pattern comprising peaks at approximately 9.0°±0.2°, 9.5°±0.2°, and 12.7°±0.2° 2-θ.

[0342] Embodiment 118: The crystalline form of Embodiment 117, wherein the x-ray powder diffraction pattern comprises one or more additional peaks selected from the group consisting of peaks at approximately 6.2°±0.2°, 12.5°±0.2°, and 13.1°±0.2° 2-θ.

[0343] Embodiment 119: A crystalline form according to Embodiment 117 or Embodiment 118, wherein the x-ray powder diffraction pattern comprises one or more additional peaks selected from the peaks at approximately 4.3°±0.2°, 14.1°±0.2°, and 17.0°±0.2° 2-θ.

[0344] Embodiment 120: A crystalline form according to Embodiment 119, wherein the x-ray powder diffraction pattern comprises one or more additional peaks selected from peaks at approximately 5.2°±0.2°, 8.5°±0.2°, 10.5°±0.2°, 16.1°±0.2°, 19.5°±0.2°, 21.1°±0.2° and 26.4°±0.2° 2-θ.

[0345] Embodiment 121: A crystalline form according to any one of Embodiments 50 or 115 to 120, wherein the pharmaceutically acceptable salt of Compound 1 is characterized by being substantially Fig.23 The x-ray powder diffraction pattern shown in .

[0346] Embodiment 122: The crystalline form of any one of Embodiments 116 to 121, wherein the diethylamine salt form 1 is characterized by having a differential scanning calorimetry thermogram comprising at least one endothermic peak selected from peaks with onset temperatures at about 17°C and 145°C.

[0347] Embodiment 123: The crystalline form of Embodiment 122, wherein the differential scanning calorimetry thermogram is substantially as follows: Fig.24 as shown in .

[0348] Embodiment 124: The crystalline form of any one of Embodiments 116 to 123, wherein the diethylamine salt Form 1 is characterized by having a thermogravimetric analysis thermogram showing a weight loss of about 8.4% at temperatures from ambient temperature to about 170°C.

[0349] Embodiment 125: The crystalline form of Embodiment 124, wherein the thermogravimetric thermogram is substantially as follows: Fig.25 as shown in .

[0350] Embodiment 126: The crystalline form of any one of Embodiments 116 to 125, wherein the diethylamine salt Form 1 is characterized by absorbing about 5.5 wt% water at about 25°C between about 0% and 90% relative humidity.

[0351] Embodiment 127: A crystalline form according to any one of Embodiments 116 to 126, wherein the diethylamine salt form 1 is characterized by having substantially Fig.26 The dynamic vapor adsorption mass absorption curve shown in .

[0352] Embodiment 128: The crystalline form according to Embodiment 50, wherein the pharmaceutically acceptable salt of Compound 1 is a choline salt.

[0353] Embodiment 129: The crystalline form of Embodiment 128, wherein the choline salt is choline salt form 1.

[0354] Embodiment 130: The crystalline form of Embodiment 128 or Embodiment 129, wherein the choline salt of Compound 1 is characterized by an x-ray powder diffraction pattern comprising peaks at approximately 10.4°±0.2°, 20.9°±0.2°, and 22.9°±0.2° 2-θ.

[0355] Embodiment 131: A crystalline form according to Embodiment 130, wherein the x-ray powder diffraction pattern comprises one or more additional peaks selected from the peaks at approximately 14.0°±0.2°, 15.7°±0.2°, and 24.0°±0.2° 2-θ.

[0356] Embodiment 132: A crystalline form according to Embodiment 130 or Embodiment 131, wherein the x-ray powder diffraction pattern comprises one or more additional peaks selected from the peaks at approximately 14.4°±0.2°, 16.8°±0.2°, and 25.1°±0.2° 2-θ.

[0357] Embodiment 133: A crystalline form according to Embodiment 132, wherein the x-ray powder diffraction pattern comprises one or more additional peaks selected from peaks at approximately 4.8°±0.2°, 11.0°±0.2°, 11.4°±0.2°, 13.2°±0.2°, 15.6°±0.2°, 16.1°±0.2°, 17.2°±0.2°, 18.2°±0.2°, 18.9°±0.2°, 19.4°±0.2°, 20.2°±0.2°, 27.0°±0.2°, and 28.0°±0.2° 2-θ.

[0358] Embodiment 134: A crystalline form according to any one of Embodiments 50 or 128 to 133, wherein the pharmaceutically acceptable salt of Compound 1 is characterized by being substantially Fig. 27 The x-ray powder diffraction pattern shown in .

[0359] Embodiment 135: The crystalline form of any one of Embodiments 129 to 134, wherein the choline salt form 1 is characterized by having a differential scanning calorimetry thermogram comprising at least one endothermic peak selected from peaks with onset temperatures at about 23°C, 99°C, and 156°C.

[0360] Embodiment 136: The crystalline form of Embodiment 135, wherein the differential scanning calorimetry thermogram is substantially as follows Fig.28 as shown in .

[0361] Embodiment 137: The crystalline form of any one of Embodiments 129 to 136, wherein the choline salt form 1 is characterized by having a thermogravimetric analysis thermogram showing a weight loss of about 8.8% at temperatures from ambient temperature to about 200°C.

[0362] Embodiment 138: The crystalline form of Embodiment 128, wherein the thermogravimetric thermogram is substantially as follows: Fig.29 as shown in .

[0363] Embodiment 139: A pharmaceutical composition comprising a crystalline form of Compound 1 according to any one of Embodiments 1 to 49 or a crystalline form of a pharmaceutically acceptable salt of Compound 1 according to any one of Claims 50 to 138 and a pharmaceutically acceptable carrier or excipient.

[0364] Embodiment 140: A pharmaceutical composition according to Embodiment 139, wherein the composition is in the form of a unit dosage form.

[0365] Embodiment 141: A pharmaceutical composition according to Embodiment 140, wherein the unit dosage form is a tablet.

[0366] Embodiment 142: A method for inhibiting MCL-1 in a patient, comprising administering to the patient a crystalline form of Compound 1 according to any one of Embodiments 1 to 49, or a crystalline form of a pharmaceutically acceptable salt of Compound 1 according to any one of Embodiments 50 to 138, or a pharmaceutical composition according to any one of Embodiments 139 to 141.

[0367] Embodiment 143: A method for treating cancer in a patient, comprising administering to the patient a crystalline form of Compound 1 according to any one of Embodiments 1 to 49, or a crystalline form of a pharmaceutically acceptable salt of Compound 1 according to any one of Embodiments 50 to 138, or a pharmaceutical composition according to any one of Embodiments 139 to 141.

[0368] Embodiment 144: Use of the crystalline form of Compound 1 of any one of Embodiments 1 to 49, or the crystalline form of the pharmaceutically acceptable salt of Compound 1 of any one of Embodiments 50 to 138, or the pharmaceutical composition of any one of Embodiments 139 to 141 for treating cancer.

[0369] Embodiment 145: Use of the crystalline form of Compound 1 described in any one of Embodiments 1 to 49, or the crystalline form of the pharmaceutically acceptable salt of Compound 1 described in any one of Embodiments 50 to 138, or the pharmaceutical composition described in any one of Embodiments 139 to 141 in the manufacture of a medicament for treating cancer.

[0370] Embodiment 146: The method or use according to any one of Embodiments 143 to 145, wherein the cancer is a hematological malignancy.

[0371] Embodiment 147: The method or use according to any one of Embodiments 143 to 145, wherein the cancer is relapsed refractory multiple myeloma or relapsed refractory myeloma.

[0372] Embodiment 148: The method or use according to any one of Embodiments 143 to 145, wherein the cancer is a solid malignancy.

[0373] Embodiment 149: The method or use of any one of Embodiments 143 to 145, wherein the cancer is triple-negative breast cancer, colorectal cancer, skin cancer, melanoma, ovarian cancer, renal cancer, small cell lung cancer, non-small cell lung cancer, lymphoma, leukemia, or metastatic soft tissue sarcoma.

[0374] Embodiment 150: The method or use according to any one of Embodiments 142 to 149, wherein the method further comprises administering an additional therapeutic compound to the patient.

[0375] Embodiment 151: The method of Embodiment 150, wherein the additional therapeutic compound is selected from docetaxel, gosartuzumab, and gemcitabine.

[0376] Embodiment 152: A crystalline form of Compound 1 according to any one of Embodiments 1 to 49, or a crystalline form of a pharmaceutically acceptable salt of Compound 1 according to any one of Embodiments 50 to 138, or a pharmaceutical composition according to any one of Embodiments 139 to 141, for use in a method of treating cancer.

[0377] Embodiment 153: The crystalline form of Embodiment 152, wherein the cancer is a hematological malignancy.

[0378] Embodiment 154: The crystalline form according to Embodiment 152, wherein the cancer is relapsed refractory multiple myeloma or relapsed refractory myeloma.

[0379] Embodiment 155: The crystalline form of Embodiment 152, wherein the cancer is triple-negative breast cancer, colorectal cancer, skin cancer, melanoma, ovarian cancer, renal cancer, small cell lung cancer, non-small cell lung cancer, lymphoma, leukemia, or metastatic soft tissue sarcoma.

[0380] Embodiment 156: The crystalline form of Embodiment 152, wherein the cancer is a solid malignancy.

[0381] Embodiment 157: The crystalline form according to any one of Embodiments 152 to 156, wherein the method further comprises administering an additional therapeutic compound to the patient.

[0382] Embodiment 158: The crystalline form of Embodiment 157, wherein the additional therapeutic compound is selected from docetaxel, gosartuzumab and gemcitabine.

[0383] Embodiment 159: A crystalline form of Compound 1 according to any one of Embodiments 2 to 13, prepared by a method comprising the following steps: (1) contacting Compound 1 or a salt thereof with a solvent selected from acetone, ethyl acetate, alcohol, methyl ethyl ketone, methyl isobutyl ketone, tetrahydrofuran, dichloromethane and dibutyl ether, and a mixture of such solvents; and (2) isolating the solid product.

[0384] Embodiment 160: The crystalline form of Embodiment 159, wherein the solvent comprises acetone.

[0385] Embodiment 161: The crystalline form of Embodiment 159 or 160, wherein the method further comprises heating the mixture of Compound 1 or its salt and the solvent.

[0386] Embodiment 162: The crystalline form of any one of Embodiments 159 to 161, wherein the method further comprises drying the solid product.

[0387] Embodiment 163: A crystalline form according to any one of Embodiments 159 to 162, wherein the method further comprises washing the solid product with a second solvent selected from acetone, ethyl acetate, alcohol or a mixture of such solvents and / or crystallizing the solid product and optionally drying.

[0388] Embodiment 164: A crystalline form of Compound 1 according to any one of Embodiments 2 to 13, prepared by a method comprising the following steps: (1) contacting Compound 1 or a salt thereof with a buffer to produce a mixture; (2) adding a solvent selected from acetonitrile and an acetonitrile / water mixture to the mixture to produce a slurry; (3) mixing the slurries; and (4) isolating the solid product.

[0389] Embodiment 165: The crystalline form of Embodiment 164, wherein the pH of the buffer is about 2.

[0390] Embodiment 166: A crystalline form of compound 1 according to any one of Embodiments 2 to 13, prepared by a method comprising the following steps: (1) contacting Form II according to claims 14 to 25, Form III according to claims 26 to 39, or Form IV according to claims 40 to 49, or a salt thereof, with an alcohol; and (2) isolating the solid product.

[0391] Embodiment 167: The crystalline form of Compound 1 according to any one of Embodiments 159 to 163 or 166, wherein the alcohol is selected from ethanol and isopropanol.

[0392] Embodiment 168: The crystalline form of Compound 1 according to any one of Embodiments 159 to 163 or 166 to 167, wherein the alcohol is ethanol.

[0393] Example

[0394] equipment : The following equipment was used to study the salts and polymorphs in the following examples.

[0395] X-ray powder diffraction (XRPD) analysis is carried out using copper radiation (Cu Kα, λ=1.541874) on a diffractometer (PANalytical XPERT-PRO, PANalytical B.V., Almelo, Netherlands). The sample is spread evenly on a zero background sample plate. The generator is operated at a voltage of 45kV and a current intensity of 40mA. The slit is a Soller slit 0.02rad, an anti-scattering slit 1.0°, and a divergent slit. Scanning is performed from 2° to 40°2-θ with a step length of 0.0167. Data analysis is performed using X'Pert Data Viewer V1.2d (PANalytical BV, Almelo, Netherlands).

[0396] Differential scanning calorimetry (DSC) was run on a Q2000 (TA Instruments, New Castle, DE) by loading 1 mg to 5 mg of material into a Tzero standard aluminum pan with a lid (with or without a pinhole) and heating the sample from about 20° C. to 250° C. or higher at 10° C. / min. The sample and reference pans were under a 50 mL / min nitrogen purge. Data analysis was completed using UniversalAnalysis 2000 Version 4.5A (TA Instruments, New Castle, DE).

[0397] Thermogravimetric analysis (TGA) was used to evaluate the sample weight loss as a function of temperature on a Q5000 or Q500 (TA Instruments, New Castle, DE) by loading 1 mg-10 mg of material onto a weighing pan and heating the sample to 350° C. at a rate of 10° C. / min. The sample and reference pans were under a nitrogen purge of 60 mL / min and 40 mL / min, respectively. Data analysis was completed using Universal Analysis 2000 Version 4.5A (TA Instruments, New Castle, DE).

[0398] Thermogravimetric analysis and mass spectrometry (TA Discovery Series TGA and MS) were used to determine what is associated with the sample weight loss as a function of temperature (TA Instruments, New Castle). The sample (approximately 2 mg-5 mg) was placed in a platinum pan and heated to 350° C. at a heating rate of 10° C. / min-20° C. / min. The sample and reference pans were under a 25 mL / min and 10 mL / min nitrogen purge, respectively. Data analysis was completed using TA Instruments Trios software version 4.0 (TA Instruments, New Castle, DE).

[0399] Hygroscopicity was studied using dynamic vapor sorption (DVS, TA Q5000 SA, TA Instruments, New Castle, DE or DVS, DVS Intrinsic, Surface Measurement Systems, London, UK). The sample (2 mg-20 mg) was placed in an aluminum DVS pan and loaded on the sample side of a double pan balance. The adsorption and desorption of water as a function of relative humidity (RH) were studied at 25 °C. The relative humidity was increased from 40% RH to 90% RH in increments of 10% RH, then dropped back to 0%, and then the entire cycle from 0% RH to 90% RH and back to 0% RH was repeated. Each relative humidity increment had an equilibrium time of 180 minutes unless the weight change% was less than 0.002% within 30 minutes. Data analysis was performed using UniversalAnalysis 2000 4.5A version (A Instruments, New Castle, DE) for TA DVS operation and Microsoft Excel for SMSDVS operation.

[0400] Proton NMR spectra were collected on a Varian 400-MR 400 MHz instrument with a 7620AS sample exchanger. 1 HNMR) spectra. The default proton parameters were as follows: spectral width: 14 ppm to -2 ppm (6397.4 Hz); relaxation delay: 1 s; pulse: 45 degrees; acquisition time: 2.049 s; number of scans or repetitions: 8; temperature: 25°C. Unless otherwise stated, samples were prepared in dimethyl sulfoxide-d6. Offline analysis was performed using MNova software.

[0401] Amounts: All amounts provided in the following examples should be understood to mean "about" the exact number listed, whether or not the word "about" is explicitly cited. For example, "600 mg" and "about 600 mg" should be understood to mean "about 600 mg".

[0402] Example 1. Study on the salt of compound 1

[0403] Compound 1 was subjected to salt studies as described below.

[0404]

[0405] More specifically, salt studies were performed on Compound 1 using the following basic coformers: NaOH, KOH, choline hydroxide, tert-butylamine, TRIS, meglumine, L-lysine, benzathine, and diethylamine. Only four crystalline salts of Compound 1 were obtained: sodium, potassium, diethylamine, and choline salts. Cocrystal studies with nine acids (oxalic, fumaric, citric, adipic, glutaric, succinic, malic, mandelic, and glycolic) did not yield any crystalline material.

[0406] A. Sodium Salt - Overview

[0407] The sodium salt of compound 1 was initially obtained during the sodium bicarbonate washing of the compound 1 reaction mixture. Studies using about 25 organic solvents to the Na salt provided four desolvated forms (form 1, form 2, form 3 and form 4) and a variety of potential solvates with the following solvents: MeCN, EtOH, IPA, acetone, THF, DCM, DMF, DMAc / water and BuCN. All solvated forms appear to be unstable and desolvated when dried. Sodium salt form 1 was also obtained from the polymorph form I (discussed below) of compound 1 using NaOH.

[0408] B. Sodium Salt of Compound 1 - Form 1 ("Na Salt Form 1")

[0409] The form 1 of the sodium salt of compound 1 is a desolvated / dehydrated form initially obtained during the sodium bicarbonate washing of the reaction mixture of compound 1. More specifically, the crude reaction mixture of compound 1 described in Example 154 of PCT Publication WO 2019 / 222112 in DCM is concentrated in vacuo. The remaining material is distributed between ethyl acetate (about 300mL) and saturated aqueous ammonium chloride solution (about 40mL). The organic phase is washed twice with saturated aqueous ammonium chloride solution (about 40mL each time), then washed once with saturated aqueous sodium bicarbonate solution (about 40mL), and then washed once with brine (about 40mL). The organic phase is dried over sodium sulfate, filtered, and concentrated in vacuo to a crude brown solid.

[0410] The crude solid was azeotroped once with dichloromethane (about 30 mL) and then suspended in acetonitrile (about 270 mL) and N,N-dimethylformamide (about 5 mL). The resulting mixture was warmed to about 80°C for about 1 hour and then filtered to collect the undissolved solids, which were washed with acetonitrile. The resulting filter cake was dried in air and then further dried in a vacuum oven at about 50°C for about 4 days to obtain 6.72 g of Na salt form 1. The XRPD pattern is at Figure 1 0.04-0.06-0.08-0.06 % 1.03-0.06-0.08 % 1.02-0.06-0.08 % 1.03 ...

[0411] Table 1a - Characteristic peaks of Na salt form 1

[0412] Position [°2θ] Relative strength [%] 7.6 100 8.4 88 12.8 62 15.3 48 18.4 53 20.4 53 12.3 36 13.4 41 24.0 44

[0413] Table 1b - Expanded Peak List for Na Salt Form 1

[0414]

[0415]

[0416] The DSC thermogram of the Na salt form 1 is Figure 2 The DSC data showed two broad endothermic events with an onset temperature of about 14°C and at about 83°C, which were attributed to the loss of water and residual solvent, followed by a third endothermic event with an onset temperature of about 232°C, which was attributed to the melting of the salt. The TGA thermogram of the Na salt form 1 is shown in Figure 3 The TGA weight loss of about 4.2 wt% observed from ambient temperature to about 200°C corresponds to the loss of water (about 2.2 wt% by KF) and residual MeCN (about 0.5 eq. by NMR). DVS analysis of Na salt form 1 is shown in Figure 4 It is shown and demonstrated in Figure 1 that Na salt Form 1 is moderately hygroscopic and absorbs about 7.5 wt% water between 0% and 90% RH and at about 25° C. XRPD analysis of the post-DVS sample showed no form change.

[0417] C. Sodium Salt of Compound 1 - Form 2 ("Na Salt Form 2")

[0418] Na Salt Form 2 was obtained by slurrying Na Salt Form 1 with dichloromethane and then drying the DCM solvate at about 50°C. The XRPD pattern of Na Salt Form 2 is Figure 5 2a shows the characteristic peaks of Na salt form 2. Table 2b shows an expanded peak list of Na salt form 2.

[0419] Table 2a - Characteristic Peaks of Na Salt Form 2

[0420] Position [°2θ] Relative strength [%] 7.2 76 14.7 100 19.3 92 11.1 63 17.1 56 20.7 73 13.1 47 14.5 44 16.9 50

[0421] Table 2b - Expanded Peak List for Na Salt Form 2

[0422]

[0423]

[0424] The DSC thermogram of the Na salt form 2 is Figure 6The DSC data showed a broad endothermic event with an onset temperature of about 21°C, followed by a broad exothermic event with an onset temperature of about 109°C, and then an endothermic event with an onset temperature of about 224°C, which was attributed to the melting of the salt. The TGA thermogram of the Na salt form 2 is shown in Figure 7 The TGA continuous weight loss of about 4.8 wt% observed from ambient temperature up to about 200°C most likely corresponds to the loss of surface water.

[0425] D. Sodium Salt of Compound 1 - Form 3 ("Na Salt Form 3")

[0426] Na Salt Form 3 was obtained by slurrying Na Salt Form 1 with isopropanol and then drying the IPA solvate at about 50°C. The XRPD pattern of Na Salt Form 3 is Figure 8 3a shows the characteristic peaks of Na salt form 3. Table 3b shows an expanded peak list of Na salt form 3.

[0427] Table 3a - Characteristic peaks of Na salt form 3

[0428]

[0429]

[0430] Table 3b - Expanded Peak List for Na Salt Form 3

[0431] Position [°2θ] Relative strength [%] 4.1 100 8.2 4 12.1 14 13.2 63 14.8 7 18.8 44 20.0 21 20.9 14 22.9 11 24.2 31

[0432] The DSC thermogram of the Na salt form 3 is Fig. 9 The DSC data showed a broad endothermic event with an onset temperature of about 19°C, followed by a second broad endothermic event with an onset temperature of about 219°C, which was attributed to the melting and decomposition of the salt. The TGA thermogram of the Na salt form 3 is shown in Fig.10 The TGA continuous weight loss of about 5.1 wt % observed from ambient temperature up to about 200° C. most likely corresponds to the loss of residual solvent or water.

[0433] E. Sodium Salt of Compound 1 - Form 4 ("Na Salt Form 4")

[0434] Na Salt Form 4 was obtained by slurrying Na Salt Form 1 with dimethylacetamide followed by drying under vacuum at about 50°C. The XRPD pattern of Na Salt Form 4 is Fig.11 4a shows the characteristic peaks of Na salt form 4. Table 4b shows an expanded peak list of Na salt form 4.

[0435] Table 4a - Characteristic Peaks of Na Salt Form 4

[0436] Position [°2θ] Relative strength [%] 6.7 80 13.3 100 20.2 81 16.0 66 21.0 71 23.4 67 7.2 61 21.5 58 22.8 63

[0437] Table 4b - Expanded Peak List for Na Salt Form 4

[0438]

[0439]

[0440] F. Sodium Salt of Compound 1 - Form 5 ("Na Salt Form 5")

[0441] The solvated form separated from THF / water is dried under vacuum at about 50°C to obtain Na salt form 5. More specifically, about 500mg of Form I (synthesis described below) of compound 1 and about 4mL THF and about 0.1mL water are loaded into a 20mL vial, followed by the addition of about 1.1 equivalents of NaOH. The mixture is stirred at about 50°C for about 30 minutes, then stirred at ambient temperature for about two days. The separated solid is analyzed by XRPD, then dried under vacuum at about 50°C for about 16 hours. The XRPD pattern of the dried solid is different from that of the wet solid, which indicates that the dried solvated form is converted into the desolvated Na salt form 5.

[0442] The XRPD pattern of Na salt form 5 is Fig.12 5a shows the characteristic peaks of Na salt form 5. Table 5b shows an expanded peak list of Na salt form 5.

[0443] Table 5a - Characteristic Peaks of Na Salt Form 5

[0444]

[0445]

[0446] Table 5b - Expanded Peak List for Na Salt Form 5

[0447]

[0448]

[0449] The DSC thermogram of the Na salt form 5 is Fig.13 The DSC data showed a broad endothermic event with an onset temperature of about 29°C, followed by a small second broad endothermic event with an onset temperature of about 143°C, and then an exotherm with an onset temperature of about 198°C. The TGA thermogram of the Na salt form 5 is shown in Fig.14 The TGA continuous weight loss of about 4.2 wt% observed from ambient temperature up to about 200°C most likely corresponds to the loss of residual solvent or water.

[0450] G. Potassium Salt - Form 1 ("K Salt Form 1") and IPA Solvate ("K Salt IPA Solvate") of Compound 1

[0451] The potassium salt of compound 1 was obtained during the salt conversion of the Na salt of compound 1. More specifically, a 4 mL vial was charged with Na salt form 1 (about 100 mg) and about 1 mL of IPA, followed by the addition of about 2.1 equivalents of KOH in the form of an about 50% aqueous solution, sonicated, and stirred at about 50° C. for about 30 minutes, and then stirred at ambient temperature for about 3 days. The obtained solid was separated by filtration and dried under vacuum at about 50° C. for about 16 hours. Two crystalline forms of the K salt were observed: (1) K salt form 1; and (2) IPA solvate, which was converted to desolvated form 1 upon drying.

[0452] The XRPD pattern of K salt form 1 is Fig.15 The XRPD pattern of K salt form 1 is very similar to that of Na salt form 1, as shown in Table 6a. Fig.16 (above and below, respectively).

[0453] Table 6a-Characteristic peaks of K salt form 1

[0454]

[0455]

[0456] Table 6b - Expanded Peak List for K Salt Form 1

[0457]

[0458]

[0459] The DSC thermogram of K salt form 1 is Fig.17 The DSC data showed three broad endothermic events with onset temperatures at about 14°C, about 182°C, and about 233°C, which were attributed to the loss of residual solvent or water, potential form conversion, and melting, respectively. The TGA thermogram of K salt form 1 is shown in Fig.18 The TGA thermogram shows a continuous weight loss of about 4.2 wt% observed from ambient temperature up to about 200°C, which most likely corresponds to the loss of residual solvent or water. Fig.19 The K salt Form 1 is shown and indicated to be moderately hygroscopic, with about 11 wt % moisture absorption between 0% and 90% RH and about 25° C. The K salt Form 1 rapidly absorbs up to about 4 wt %-6 wt % moisture under ambient conditions. XRPD analysis of the post-DVS sample showed no form change.

[0460] The XRPD pattern of K salt IPA solvate is Fig. 20 is shown in and is characterized by sharp reflections, indicating crystallinity.

[0461] H. Potassium salt-THF solvate of compound 1 ("K salt THF solvate")

[0462] The K salt THF solvate is obtained during the formation of the potassium salt in THF. More specifically, a 20 mL vial is charged with about 500 mg of polymorph Form I of Compound 1 (preparation described below) and about 2 mL of THF, followed by the addition of about 1.1 equivalents of KOH in the form of an approximately 50% aqueous solution. The mixture is stirred at about 50° C. for about 15 minutes and then stirred at ambient temperature for about 16 hours. The obtained solid is separated by filtration and dried under vacuum at about 50° C. for about 24 hours to obtain the K salt THF solvate. The XRPD pattern is Fig.21 is shown in and is characterized by sharp reflections, indicating crystallinity.

[0463] I. Diethylamine salt-toluene solvate of compound 1 ("DEA salt toluene solvate")

[0464] DEA salt toluene solvate was prepared by charging about 1.1 molar equivalents of diethylamine into a slurry of Form I of Compound 1 in 1 mL of EtOH at about 50° C., followed by cooling to ambient temperature. No crystalline solid was formed. The mixture was concentrated to dryness. The remaining oil was redissolved in toluene, followed by slow addition of heptane as an antisolvent. After stirring overnight at ambient temperature, a crystalline solid was formed. Based on XRPD analysis, the wet solid was most likely a toluene solvate, which was converted to a desolvated disordered form (Form I) upon drying. The XRPD pattern of the DEA salt toluene solvate is shown in FIG. Fig. 22 is shown in and is characterized by sharp reflections, indicating crystallinity.

[0465] J. Diethylamine Salt of Compound 1 - Form 1 ("DEA Salt Form 1")

[0466] As described above, DEA salt form 1 is a desolvated form obtained after drying the DEA salt toluene solvate. The XRPD pattern of DEA salt form 1 is Fig.23 7a shows the characteristic peaks of DEA Salt Form 1. Table 7b shows an expanded peak list of DEA Salt Form 1.

[0467] Table 7a-Characteristic peaks of DEA salt form 1

[0468] Position [°2θ] Relative strength [%] 9.0 99 9.5 81 12.7 100 6.2 61 12.5 52 13.1 46 4.3 31 14.1 30 17.0 29

[0469] Table 7b - Expanded Peak List for DEA Salt Form 1

[0470]

[0471]

[0472] The DSC thermogram of DEA salt form 1 is Fig.24 The DSC data showed a small, broad endotherm with an onset temperature of about 17°C, followed by an endotherm with an onset temperature of about 145°C. The TGA thermogram of DEA salt form 1 is shown in Fig.25 The TGA weight loss of about 8.4 wt % observed from ambient temperature up to about 170° C. corresponds to the dissociation of the salt. The DVS analysis of DEA salt form 1 is shown in Fig.26 % water between 0% and 90% RH at about 25° C. However, XRPD analysis of the post-DVS sample showed no form change.

[0473] K. Choline Salt of Compound 1 - Form 1 ("Choline Salt Form 1")

[0474] Choline salt form 1 was obtained from a slurry in an EtOAc / heptane solvent mixture. More specifically, a 4 mL vial was charged with Form I of compound 1 (about 45 mg) and about 0.5 mL of EtOH, followed by the addition of about 1.1 equivalents of choline hydroxide (as about 45% MeOH solution) to give a solution. The solution was concentrated to dryness. EtOH / heptane (about 1.25 mL of a 3:2 mixture) was added to the remaining oil, followed by stirring at about 50° C. for about 1 hour, and then stirring at ambient temperature. The obtained solid was separated by filtration and dried under vacuum at about 50° C. for about 24 hours. No form change was observed before and after drying. The XRPD pattern of choline salt form 1 is shown in FIG. Fig. 27 8a shows the characteristic peaks of choline salt form 1. Table 8b shows an expanded peak list of choline salt form 1.

[0475] Table 8a - Characteristic Peaks of Choline Salt Form 1

[0476] Position [°2θ] Relative strength [%] 10.4 100 20.9 77 22.9 68 14.0 39 15.7 57 24.0 59 14.4 34 16.8 31 25.1 27

[0477] Table 8b - Expanded Peak List for Choline Salt Form 1

[0478]

[0479]

[0480] The DSC thermogram of choline salt form 1 is Fig.28The DSC data showed three broad endothermic events with onset temperatures at about 23°C, about 99°C, and about 156°C, which were attributed to the loss of residual solvent or water and melt, respectively. The TGA thermogram of choline salt form 1 is shown in Fig.29 The TGA thermogram shows a stepwise weight loss totaling about 8.8 wt% observed from ambient temperature up to about 200°C, which most likely corresponds to the loss of residual solvent or water.

[0481] Example 2. Study on polymorphs of compound 1

[0482] Polymorph studies of Compound 1 were performed as described below.

[0483]

[0484] More specifically, studies were performed on an amorphous form of Compound 1. Hydrate studies were also performed in MeCN / water at ambient conditions and at 50°C, but did not provide any hydrated forms. Certain polymorphs were also obtained starting from one or more of the salts found above.

[0485] Based on these studies, four unsolvated / desolvated forms were found, eight solvates with unique XRPD patterns were identified, and eight isostructural solvated forms were found with XRPD patterns that were largely consistent with Form I, with some peak shifts and sometimes small additional peaks. Single crystal X-ray analysis showed that the unit cell parameters of crystals isolated from MeCN, acetone, and EtOH were nearly identical.

[0486] A. Amorphous Form of Compound 1

[0487] The amorphous form of compound 1 can be prepared according to WO 2019 / 222112. It is also prepared by converting the Na salt form 1 of compound 1 into an amorphous free acid in a DCM / water system at about pH 5.5 adjusted with HCl. The organic layer was evaporated to dryness using a rotary evaporator. The XRPD pattern of amorphous compound 1 is Fig.30 is shown in and is characterized by an amorphous halo.

[0488] B. Compound 1 - Polymorph Form I ("Form I")

[0489] Method 1: The crude compound 1 (600 mg) prepared according to WO 2019 / 222112 was suspended in acetone (20 mL) and heated to about 60 ° C in a thermowell. After the solution was observed, the contents were filtered into a clean flask through a 0.45 μm syringe filter and heated to about 60 ° C. Once at this temperature, the heating was stopped. The contents were cooled to ambient temperature under stirring. After reaching ambient temperature, the contents were aged for about 24 hours. The solid was collected by vacuum filtration and washed with 2x acetone (1.2 mL). The solid was dried under reduced pressure at about 70 ° C for about 24 hours to obtain Form I.

[0490] Method 2 : The crude compound 1 (about 3 g) prepared according to WO 2019 / 222112 was dissolved in EtOAc (about 24 mL) at about 60 ° C, followed by slow addition (in about 2 hours) of EtOH (about 36 mL), and then cooled to about 20 ° C in about 4 hours. The obtained slurry was stirred at about 20 ° C for about 20 hours. The solid was separated by vacuum filtration, washed with 2: 3 EtOAc / EtOH (about 6 mL), and dried under vacuum at about 60 ° C with nitrogen purge for about 24 hours to obtain Form I (about 2.6 g).

[0491] Method 3 Crystallization of crude compound 1 in acetone provided the elimination of the Z-isomer of compound 1, followed by crystallization from EtOAc / EtOH (2:3) to afford purified Form I.

[0492] Method 4 :Form I was also obtained from the slurry experiment of the Na salt of Compound 1. For example, the Na salt Form 1 of Compound 1 (about 10 mg) and about 2 mL of pH 2 sodium phosphate buffer (50 mM sodium dihydrogen phosphate solution adjusted to pH 2 with phosphoric acid) were added to a scintillation vial, followed by the slow addition of about 2 mL of acetonitrile. A slurry was formed and stirred overnight with a magnetic stirring bar. The solid was separated by centrifugal filtration and dried at ambient temperature to obtain Form I. Form I was also prepared from a slurry of the Na salt of Compound 1 in MeCN / water (pH 2) using different acids for pH adjustment (such as HCl, phosphoric acid, MSA and p-TSA).

[0493] Method 5 Form I was also obtained from EtOH, IPA, acetone, MEK, MIBK, THF, DCM, and dibutyl ether by slurrying amorphous Compound 1 (about 20 mg-30 mg) in about 0.5 mL of the selected solvent at ambient temperature for up to about 2 weeks. The isolated wet solid is an isostructural solvated form, which converts to Form I upon drying under vacuum at about 50° C.-100° C. It is noted that Form I tends to retain non-stoichiometric amounts of residual solvent or water due to the void volume in the crystal lattice.

[0494] Slurry method Competitive slurries of Form I in EtOH with other polymorphs discussed and prepared below (i.e., Form II, Form III, and Form IV) showed complete conversion to Form I in all cases, indicating that Form I has higher stability under these conditions compared to all other unsolvated / desolvated forms.

[0495] Characterization : The XRPD pattern of Form I is Fig.31 9a shows the characteristic peaks of Form I. Table 9b shows an expanded peak list of Form I.

[0496] Table 9a - List of characteristic peaks of Form I

[0497] Position [°2θ] Relative strength [%] 4.9 36 8.6 86 14.3 100 18.3 48 16.2 47 22.1 43 17.8 42 19.3 40 21.5 39

[0498] Table 9b - Expanded Peak List for Form I

[0499]

[0500]

[0501] The DSC thermogram of Form I is Fig.32 The DSC data showed an endothermic event with an onset temperature of about 180°C. The TGA thermogram of Form I is shown in Fig.33 A continuous weight loss of about 1.0% was observed from ambient temperature to about 170°C, most likely corresponding to residual solvent.

[0502] DVS Analysis Fig.34 ) showed that Form I was slightly hygroscopic, absorbing about 1.4 wt% water at about 25°C and between 0% and 90% RH. XRPD analysis of the post-DVS sample showed no form change.

[0503] The single crystal structure of Form I was solved and confirmed the presence of one Compound 1 molecule and half a water molecule. However, the water molecule is disordered on and around the 2-fold axis. No intermolecular hydrogen bonding was observed. The N2 hydrogen forms intramolecular hydrogen bonds with O4 and O5, and water does not appear to form hydrogen bonds. The orthorhombic crystal unit cell dimensions at room temperature are shown in Table 9c, and a diagram of the single crystal structure is shown in Fig.35 The calculated XRPD pattern is shown in Figure 1. Figure 1 To.

[0504] Table 9c - Unit cell dimensions of Form I single crystal structure at room temperature

[0505]

[0506] C. Compound 1 - Polymorph Form II ("Form II")

[0507] Method 1 :Form II is a desolvated form. This form is prepared by adding a solution of about 1.1 equivalents of HCl in about 0.5 mL of water to a slurry of the Na salt form 1 of compound 1 (about 100 mg) in about 0.5 mL of MeCN. The slurry is stirred at ambient conditions for about 16 hours. The obtained solid is separated by filtration and dried under vacuum at about 50 ° C for about 24 hours to obtain Form II.

[0508] Method 2 Form II was also obtained after drying the MeCN solvate of Compound 1 (prepared below) under vacuum at about 50 °C.

[0509] Characterization : The XRPD pattern of Form II is Fig.36 10a shows the characteristic peaks of Form II. Table 10b shows an expanded peak list of Form II.

[0510] Table 10a - List of characteristic peaks of Form II

[0511]

[0512]

[0513] Table 10b - Expanded Peak List for Form II

[0514] Position [°2θ] Relative strength [%] 6.1 100 10.5 8 12.2 8 12.8 13 13.3 5 13.9 16 15.4 27 15.7 31 16.1 31 16.9 21 18.2 9 19.0 7 19.4 5 19.9 18 20.3 7 21.1 7 22.8 15 23.4 8 25.2 9 25.7 5 26.7 5 27.9 5

[0515] The DSC thermogram of Form II is Fig.37 The DSC data showed an endothermic event with an onset temperature of about 163°C, which was attributed to the melting of Form II. The TGA thermogram of Form II is shown in Fig.38 A continuous weight loss of about 0.6% was observed from ambient temperature to about 210°C and most likely corresponds to residual solvent. DVS analysis ( Fig.39 ) showed that Form II was slightly hygroscopic, absorbing up to about 1.1 wt% water at about 25°C and between 0% and 90% RH. XRPD analysis of the post-DVS sample showed no form change.

[0516] D. Compound 1 - Polymorph Form III ("Form III")

[0517] Method 1:Form III is a desolvated form. Form III was prepared during co-crystal studies of the Na salt Form 1 of Compound 1 with oxalic acid, phosphoric acid, citric acid, malic acid, and malonic acid in MeOH. Each vial was charged with the Na salt (about 60 mg-70 mg) and about 1 mL of MeOH, followed by the addition of about 1.1 equivalents of the co-former, followed by stirring at about 50° C. for about 30 minutes, and then stirring at ambient temperature for about 16 hours. The solid was isolated by filtration and dried under vacuum at about 50° C. to give Form III.

[0518] Method 2: Form III was also obtained after drying the MeOH solvate of Compound 1 (prepared below) under vacuum at about 50°C. The XRPD pattern of Form III is Fig.40 14. The peaks of Form III are shown in Table 11a and are characterized by sharp reflections, indicating crystallinity. Table 11a shows the characteristic peaks of Form III. Table 11b shows an expanded peak list of Form III.

[0519] Table 11a - List of characteristic peaks of Form III

[0520] Position [°2θ] Relative strength [%] 8.0 46 15.0 100 18.4 60 16.5 31 22.1 46 22.9 33 12.5 24 19.5 26 23.6 27

[0521] Table 11b - Expanded Peak List for Form III

[0522] Position [°2θ] Relative strength [%] 6.5 10 8.0 46 12.3 12 12.5 24 12.9 11 13.6 17 14.3 12 15.0 100 16.0 9 16.5 31 18.1 19 18.4 60 19.5 26 20.7 10 22.1 46 22.9 33 23.6 27 24.1 9 24.7 17 26.8 10 28.3 15

[0523] The DSC thermogram of Form III is Fig.41 The DSC data showed three endothermic events with onset temperatures at about 20°C, about 133°C, and about 153°C. The TGA thermogram of Form III is shown in Fig.42 The TGA thermogram shows a weight loss of about 2.9% below about 90°C, a weight loss of about 1.1% at about 90°C-175°C, and a weight loss of about 1.6% at about 175°C-225°C, which most likely corresponds to residual solvent. DVS analysis ( Fig.43 ) showed that Form III was moderately hygroscopic, absorbing up to about 5 wt% water at about 25°C and between 0% and 90% RH. XRPD analysis of Form III after DVS showed no form change.

[0524] E. Compound 1 - Polymorph Form IV ("Form IV")

[0525] Form IV is a desolvated form and is prepared by slurrying amorphous Compound 1 in EtOH for about 16 hours or in heptane for about 2 weeks at ambient temperature. The XRPD pattern of Form IV is Fig.4414.4-14.7 ...

[0526] Table 12a - List of characteristic peaks of Form IV

[0527] Position [°2θ] Relative strength [%] 7.1 35 8.7 62 10.6 100.0 10.3 76 11.2 62 18.2 79 14.2 53 20.5 46 24.9 59

[0528] Table 12b - Expanded Peak List for Form IV

[0529]

[0530]

[0531] The DSC thermogram of Form IV is Fig.45 The DSC data showed two endothermic events with onset temperatures at about 119°C and about 166°C. The TGA thermogram of Form IV is shown in Fig.46 The TGA thermogram shows a continuous weight loss of about 0.6% below about 200°C, which most likely corresponds to residual solvent.

[0532] F. Compound 1-MeCN Solvate

[0533] The MeCN solvate of compound 1 was obtained by slurrying amorphous compound 1 (prepared according to WO 2021 / 108254) in MeCN. The XRPD pattern of the MeCN solvate is shown in Fig.47 is shown in and is characterized by sharp reflections, indicating crystallinity.

[0534] G. Compound 1-MeOH Solvate

[0535] The MeOH solvate of Compound 1 was obtained by slurrying amorphous Compound 1 (prepared according to WO 2021 / 108254) in MeOH. The XRPD pattern of the MeOH solvate is shown in Fig.48 is shown in and is characterized by sharp reflections, indicating crystallinity.

[0536] H. Compound 1-EtOAc Solvate

[0537] The EtOAc solvate of Compound 1 was obtained by slurrying Form I in EtOAc. The XRPD pattern of the EtOAc solvate is Fig.49 and characterized by sharp reflections, indicating crystallinity. After drying at about 50°C for about 24 hours, the EtOAc solvate partially converted to the latent desolvated form, such as Fig.50 as shown in .

[0538] I. Compound 1-MeTHF Solvate

[0539] The MeTHF solvate of Compound 1 was obtained by slurrying Form I in 2-MeTHF at ambient temperature. The XRPD pattern of the 2-MeTHF solvate is Fig.51 is shown in and is characterized by sharp reflections, indicating crystallinity.

[0540] J. Compound 1-Toluene Solvate

[0541] The toluene solvate of Compound 1 was obtained by slurrying Form I in toluene at ambient temperature. The XRPD pattern of the toluene solvate is Fig.52 ] is shown in and is characterized by sharp reflections, indicating crystallinity. Upon drying under vacuum at about 50°C, the toluene solvate converts to a disordered, desolvated form.

[0542] K. Compound 1-nBuOAc Solvate

[0543] The n-BuOAc solvate of Compound 1 was obtained by slurrying Form I in n-BuOAc at ambient temperature. The XRPD pattern of the n-BuOAc solvate is Fig.53 ] is shown in and is characterized by sharp reflections, indicating crystallinity. Upon drying under vacuum at about 50°C, the n-BuOAc solvate converts to a disordered, desolvated form.

[0544] L. Compound 1-MTBE Solvate 1

[0545] The first MTBE solvate ("MTBE Solvate 1") was obtained by slurrying Form I in MTBE. The XRPD pattern of MTBE Solvate 1 is Fig.54 is shown in and is characterized by sharp reflections, indicating crystallinity.

[0546] M. Compound 1-MTBE solvate 2

[0547] A second MTBE solvate ("MTBE Solvate 2") was obtained by slurrying Form I in MTBE. The XRPD pattern of MTBE Solvate 2 is Fig.55 is shown in and is characterized by sharp reflections, indicating crystallinity.

[0548] N. Compound 1-isopropanol hemisolvate

[0549] The isopropanol hemisolvate of compound 1 is obtained by dissolving Form I in EtOAc (about 24 mL) at about 65°C. EtOAc / iPrOH (4:1, about 10 mL) is added, followed by the slow addition (over about 2.5 hours) of iPrOH (about 46 mL). The reactants are cooled to about 20°C over about 4 hours, followed by cooling to about 0°C over about 1.5 hours. The obtained slurry is stirred at about 0°C for about 4 hours. The solid is separated by vacuum filtration, washed with EtOAc / iPrOH (1:2, about 12 mL), and dried under vacuum at about 65°C with a nitrogen purge for about 45 hours to give compound 1-isopropanol hemisolvate. The XRPD pattern of the isopropanol hemisolvate is shown in Fig.56 is shown in and is characterized by sharp reflections, indicating crystallinity.

[0550] Example 3. Isostructural Solvated Forms of Form I

[0551] Slurries of Form I of Compound 1 in several solvents such as acetone, MEK, MIBK, butyl ether (BuO), THF, DCM, EtOH, and IPA provided solids with an XRPD pattern very similar to Form I with some peak shifts and additional small peaks, indicating the formation of an isostructural solvated form ( Fig.57 and Fig.58 ). These isostructural solvates retain non-stoichiometric amounts of residual solvent after drying. However, thorough drying at elevated temperatures and particle size reduction (by grinding and milling) yields Form I, which may still retain small amounts of residual solvent.

[0552] Single crystal X-ray analysis of the EtOH solvate and the acetone solvate provided unit cell parameters similar to Form I (Table 13), confirming the isostructural nature of these solvates with Form I, which retains some water within the void volume of the lattice even after drying due to some hygroscopicity.

[0553] Table 13 - Single crystal X-ray data

[0554]

[0555] Equivalent

[0556] The foregoing written description is considered sufficient to enable those skilled in the art to implement these embodiments. The foregoing specific embodiments and examples detail certain embodiments and describe the best mode contemplated by the inventors. However, it should be understood that no matter how the details of the foregoing may appear in the text, the embodiment can be practiced in many ways and should be interpreted according to the appended claims and any equivalents thereof.

Claims

1. A crystalline form of Compound 1:

2. The crystalline form of claim 1, wherein the crystalline form of Compound 1 is Form I.

3. The crystalline form of claim 1 or claim 2, wherein the crystalline form of Compound 1 is characterized by an x-ray powder diffraction pattern comprising peaks at approximately 4.9°±0.2°, 8.6°±0.2°, and 14.3°±0.2° 2-θ.

4. The crystalline form of claim 3, wherein the x-ray powder diffraction pattern comprises one or more additional peaks selected from the group consisting of peaks at about 16.2°±0.2°, 18.3°±0.2°, and 22.1°±0.2° 2-θ.

5. The crystalline form of claim 3 or claim 4, wherein the x-ray powder diffraction pattern comprises one or more additional peaks selected from the group consisting of peaks at about 17.8°±0.2°, 19.3°±0.2°, and 21.5°±0.2° 2-θ.

6. The crystalline form of claim 5, wherein the x-ray powder diffraction pattern comprises one or more additional peaks selected from peaks at about 13.5°±0.2°, 14.6°±0.2°, 16.0°±0.2°, 17.5°±0.2°, 18.8°±0.2°, 20.2°±0.2°, 20.7°±0.2°, 23.0°±0.2°, 24.6°±0.2°, 26.3°±0.2°, and 26.8°±0.2° 2-θ.

7. The crystalline form of claim 1, wherein the crystalline form of Compound 1 is Form II.

8. The crystalline form of claim 1 or claim 7, wherein the crystalline form of Compound 1 is characterized by an x-ray powder diffraction pattern comprising peaks at approximately 6.1°±0.2°, 15.7°±0.2°, and 16.1°±0.2° 2-θ.

9. The crystalline form of claim 8, wherein the x-ray powder diffraction pattern comprises one or more additional peaks selected from the group consisting of peaks at about 15.4°±0.2°, 16.9°±0.2°, and 19.9°±0.2° 2-θ.

10. The crystalline form of claim 8 or claim 9, wherein the x-ray powder diffraction pattern comprises one or more additional peaks selected from the group consisting of peaks at about 12.8°±0.2°, 13.9°±0.2°, and 22.8°±0.2° 2-θ.

11. The crystalline form of claim 10, wherein the x-ray powder diffraction pattern comprises one or more selected from the group consisting of about 10.5°±0.2°, 12.2°±0.2°, 13.3°±0.2°, 18.2°±0.2°, 19.0°±0.2°, 19.4°±0.2°, 20.3°±0.2°, 21.1°±0.2°, 23.4°±0.2°, Additional peaks are at 25.2°±0.2°, 25.7°±0.2°, 26.7°±0.2°, and 27.9°±0.2° 2-theta.

12. The crystalline form of claim 1, wherein the crystalline form of Compound 1 is Form III.

13. The crystalline form of claim 1 or claim 12, wherein the crystalline form of Compound 1 is characterized by an x-ray powder diffraction pattern comprising peaks at approximately 8.0°±0.2°, 15.0°±0.2°, and 18.4°±0.2° 2-θ.

14. The crystalline form of claim 13, wherein the x-ray powder diffraction pattern comprises one or more additional peaks selected from the group consisting of peaks at about 16.5°±0.2°, 22.1°±0.2°, and 22.9°±0.2° 2-θ.

15. The crystalline form of claim 13 or claim 14, wherein the x-ray powder diffraction pattern comprises one or more additional peaks selected from peaks at about 12.5°±0.2°, 19.5°±0.2°, and 23.6°±0.2° 2-θ.

16. The crystalline form of claim 15, wherein the x-ray powder diffraction pattern comprises one or more selected from the group consisting of about 6.5°±0.2°, 12.3°±0.2°, 12.9°±0.2°, 13.6°±0.2°, 14.3°±0.2°, 16.0°±0.2°, 18.1°±0.2°, 20.7°±0.2°, 24.1°±0.2°, Additional peaks at 24.7°±0.2°, 26.8°±0.2°, and 28.3°±0.2° 2-θ.

17. The crystalline form of claim 1, wherein the crystalline form of Compound 1 is Form IV.

18. The crystalline form of claim 1 or claim 17, wherein the crystalline form of Compound 1 is characterized by an x-ray powder diffraction pattern comprising peaks at approximately 7.1°±0.2°, 8.7°±0.2°, and 10.6°±0.2° 2-θ.

19. The crystalline form of claim 18, wherein the x-ray powder diffraction pattern comprises one or more additional peaks selected from the group consisting of peaks at about 10.3°±0.2°, 11.2°±0.2°, and 18.2°±0.2° 2-θ.

20. The crystalline form of claim 18 or claim 19, wherein the x-ray powder diffraction pattern comprises one or more additional peaks selected from the group consisting of peaks at about 14.2°±0.2°, 20.5°±0.2°, and 24.9°±0.2° 2-θ.

21. The crystalline form of claim 20, wherein the x-ray powder diffraction pattern comprises one or more selected from the group consisting of about 3.3°±0.2°, 13.2°±0.2°, 15.4°±0.2°, 16.2°±0.2°, 17.9°±0.2°, 19.0°±0.2°, 21.3°±0.2°, 21.9°±0.2°, 23.3°±0.2°, Additional peaks are at 26.1°±0.2° and 28.3°±0.2° 2-θ.

22. A pharmaceutical composition comprising the crystalline form of Compound 1 according to any one of claims 1 to 21 and a pharmaceutically acceptable carrier or excipient.

23. A method for inhibiting MCL-1 in a patient, comprising administering to the patient a crystalline form of Compound 1 according to any one of claims 1 to 21 or a pharmaceutical composition according to claim 22.

24. A crystalline form of a pharmaceutically acceptable salt of Compound 1:

25. The crystalline form of claim 24, wherein the pharmaceutically acceptable salt of Compound 1 is a sodium salt, and wherein the sodium salt of Compound 1 is characterized by an x-ray powder diffraction pattern comprising peaks at approximately 7.6°±0.2°, 8.4°±0.2°, and 12.8°±0.2° 2-θ.

26. The crystalline form of claim 24, wherein the pharmaceutically acceptable salt of Compound 1 is a potassium salt, and wherein the potassium salt of Compound 1 is characterized by an x-ray powder diffraction pattern comprising peaks at approximately 7.6°±0.2°, 8.2°±0.2°, and 12.7°±0.2° 2-θ.

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