Salts and polymorphs of certain MCL-1 inhibitors

Abstract

The present disclosure relates to salts and crystalline forms of certain 3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazepine-3,1'-naphthalene] derivatives, and pharmaceutical formulations and therapeutic uses thereof. The present disclosure also relates to the preparation of such salts, crystalline forms and pharmaceutical formulations. Apoptosis (programmed cell death) is a process for ridding the body of unwanted or potentially dangerous cells. Evasion of apoptosis is important for the development and sustained growth of tumors.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 63 / 338,119, filed May 4, 2022, the contents of which are incorporated herein by reference in their entirety for all purposes.

[0002] The present disclosure relates to salts and crystalline forms of certain 3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazepine-3,1'-naphthalene] derivatives, and pharmaceutical formulations and therapeutic uses thereof. The present disclosure also relates to the preparation of such salts, crystalline forms, and pharmaceutical formulations. [Background technology]

[0003] Apoptosis (programmed cell death) is a process used to remove unnecessary or potentially dangerous cells from the body. Avoiding apoptosis is important for tumor development and sustained growth. Myeloid cell leukemia 1 protein (MCL-1) is an anti-apoptotic member of the Bcl-2 family of proteins. MCL-1 is required for the sustained growth of various tumors, including acute myeloid leukemia (AML), MYC- or BCR-ABL-driven pre-B / B lymphoma, and certain breast cancers. See, for example, "Discovery of S64315, a Potent and Selective Mcl-1 Inhibitor," Z. Szlavik, J. Med. Chem., 2020, 63(22):13762-13795.

[0004] Studies have shown that MCL-1 inhibitors can be used to treat a variety of cancers.For example, see the following: 「The MCL1 inhibitor 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 and ACS Med.Chem.Lett., 2017, 8(11):1204, 「Synergistic action of the MCL-1 inhibitor S63845 with current therapies in preclinical models of triple-negative and HER2-amplified breast cancer」, D. Merino et al., Sci.Transl.Med., 2017 Aug. 2, 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., 2018 Dec 8(12):1582-1597, 「Discovery of S64315, a Potent and Selective Mcl-1 Inhibitor」, Z. Szlavik at al., J.Med.Chem., 2020, 63(22):13762-13795. WO 2019 / 222112 discloses novel 3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazepine-3,1'-naphthalene] derivatives active against MCL-1. For example, compound 1 (below) has been shown to be an effective MCL-1 inhibitor. [ka] WO 2019 / 222112 presents a synthesis of Compound 1, but the synthesis results in an amorphous free base product. Amorphous products tend to be less stable than crystalline products, which can cause problems with the manufacturing and stability of pharmaceutical formulations. Therefore, there is a need to develop a more stable form of Compound 1. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] International Publication No. 2019 / 222112 [Non-patent literature]

[0006] [Non-Patent Document 1] Z.Szlavik,J.Med.Chem.,2020,63(22):13762-13795 [Non-patent document 2] A. Kotschy et al.,Nature,2016(538):477-482 [Non-patent document 3] J.Johannes et al.,ACS Med.Chem.Lett.,2017,8(2):239-244 [Non-patent document 4] J.Johannes et al.,ACS Med.Chem.Lett.,2017,8(11):1204 [Non-Patent Document 5] D.Merino et al.,Sci.Transl.Med.,2017 Aug.2,9(401):eaam7049 [Non-patent document 6] A.Tron et al.,Nature Comm.2018(9):Article No.5341 [Non-Patent Document 7] S. Caenepeel et al., Cancer Discov.,2018 Dec 8(12):1582-1597 Summary of the Invention [Means for solving the problem]

[0007] In certain embodiments, the present disclosure provides Compound 1: [ka] This relates to the crystalline form of

[0008] 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.

[0009] In certain embodiments, the present disclosure provides Compound 1: [ka] The present invention relates to a crystalline form of a pharmaceutically acceptable salt of

[0010] In certain embodiments, the present disclosure relates to crystalline forms of the sodium salt of Compound 1. In certain embodiments, the present disclosure relates to crystalline Form 1 of the sodium salt of Compound 1. In certain embodiments, the present disclosure relates to crystalline Form 2 of the sodium salt of Compound 1. In certain embodiments, the present disclosure relates to crystalline Form 3 of the sodium salt of Compound 1. In certain embodiments, the present disclosure relates to crystalline Form 4 of the sodium salt of Compound 1. In certain embodiments, the present disclosure relates to crystalline Form 5 of the sodium salt of Compound 1.

[0011] In certain embodiments, the present disclosure relates to crystalline Form 1 of the potassium salt of Compound 1. In certain embodiments, the present disclosure relates to crystalline Form 1 of the potassium salt of Compound 1.

[0012] In certain embodiments, the present disclosure relates to crystalline Form 1 of the diethylamine salt of Compound 1. In certain embodiments, the present disclosure relates to crystalline Form 1 of the diethylamine salt of Compound 1.

[0013] In certain embodiments, the present disclosure relates to crystalline Form 1 of the choline salt of Compound 1. In certain embodiments, the present disclosure relates to crystalline Form 1 of the choline salt of Compound 1.

[0014] 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.

[0015] 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.

[0016] In certain embodiments, the present disclosure relates to a method for treating cancer 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 according to, 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.

[0017] 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 the treatment of cancer.

[0018] 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 the manufacture of a medicament for treating cancer.

[0019] 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.

[0020] Additional objects and advantages will be set forth in part in the description which follows, and in part will be understood from the description, or may be learned by practice. These objects and advantages will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.

[0021] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not intended to limit the scope of the claims. Headings used throughout this disclosure are provided for convenience only and should not be construed as limiting the scope of the claims in any way.

[0022] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments and, together with the description, serve to explain the principles described herein. [Brief explanation of the drawings]

[0023] [Figure 1] 1 presents the XRPD pattern of Na salt Form 1.

[0024] [Figure 2] 1 presents a DSC thermogram of Na salt Form 1.

[0025] [Figure 3] 1 presents the TGA thermogram of Na salt Form 1.

[0026] [Figure 4] DVS analysis of Na salt form 1 is presented.

[0027] [Figure 5] The XRPD pattern of Na salt Form 2 is presented.

[0028] [Figure 6] 1 presents the DSC thermogram of Na salt Form 2.

[0029] [Figure 7] 1 presents the TGA thermogram of Na salt Form 2.

[0030] [Figure 8] The XRPD pattern of Na salt Form 3 is presented.

[0031] [Figure 9] 1 presents the DSC thermogram of Na salt form 3.

[0032] [Figure 10] 1 presents the TGA thermogram of Na salt Form 3.

[0033] [Figure 11] The XRPD pattern of Na salt Form 4 is presented.

[0034] [Figure 12] 1 presents the XRPD pattern of Na salt Form 5.

[0035] [Figure 13] 1 presents the DSC thermogram of the Na salt form 5.

[0036] [Figure 14] 1 presents the TGA thermogram of Na salt form 5.

[0037] [Figure 15] 1 presents the XRPD pattern of K salt Form 1.

[0038] [Figure 16] A comparison of the XRPD patterns of Na salt Form 1 and K salt Form 1 is presented.

[0039] [Figure 17] 1 presents a DSC thermogram of K salt form 1.

[0040] [Figure 18] 1 presents the TGA thermogram of K salt Form 1.

[0041] [Figure 19] A DVS analysis of the K salt form 1 is presented.

[0042] [Figure 20] The XRPD pattern of the K salt IPA solvate is presented.

[0043] [Figure 21] The XRPD pattern of the K salt THF solvate is presented.

[0044] [Figure 22] The XRPD pattern of the DEA salt toluene solvate is presented.

[0045] [Figure 23] 1 presents the XRPD pattern of DEA salt Form 1.

[0046] [Figure 24] 1 presents the DSC thermogram of DEA salt Form 1.

[0047] [Figure 25] 1 presents the TGA thermogram of DEA salt Form 1.

[0048] [Figure 26] A DVS analysis of DEA salt form 1 is presented.

[0049] [Figure 27] 1 presents the XRPD pattern of choline salt Form 1.

[0050] [Figure 28] 1 presents a DSC thermogram of choline salt Form 1.

[0051] [Figure 29] 1 presents a TGA thermogram of choline salt Form 1.

[0052] [Figure 30] 1 presents the XRPD pattern of amorphous Compound 1.

[0053] [Figure 31] 1 presents the XRPD pattern of Compound 1—Polymorphic Form I.

[0054] [Figure 32] 1 presents the DSC thermogram of Compound 1 - Polymorphic Form I.

[0055] [Figure 33] 1 presents the TGA thermogram of Compound 1—Polymorphic Form I.

[0056] [Figure 34] 1 presents a DVS analysis of Compound 1 - Polymorphic Form I.

[0057] [Figure 35] Presented is the single crystal X-ray structure of Compound 1 - Polymorphic Form I. C = carbon atom, Cl = chlorine atom, O = oxygen atom, N = nitrogen atom.

[0058] [Figure 36] 1 presents the XRPD pattern of Compound 1 - Polymorph Form II.

[0059] [Figure 37] 1 presents a DSC thermogram of Compound 1 - Polymorph Form II.

[0060] [Figure 38] 1 presents the TGA thermogram of Compound 1 - Polymorph Form II.

[0061] [Figure 39] 1 presents a DVS analysis of Compound 1 - Polymorph Form II.

[0062] [Figure 40] 1 presents the XRPD pattern of Compound 1 - Polymorphic Form III.

[0063] [Figure 41] 1 presents a DSC thermogram of Compound 1 - Polymorphic Form III.

[0064] [Figure 42] 1 presents the TGA thermogram of Compound 1 - Polymorphic Form III.

[0065] [Figure 43] 1 presents a DVS analysis of Compound 1 - polymorphic Form III.

[0066] [Figure 44] 1 presents the XRPD pattern of Compound 1 - Polymorphic Form IV.

[0067] [Figure 45] 1 presents a DSC thermogram of Compound 1 - Polymorphic Form IV.

[0068] [Figure 46] 1 presents the TGA thermogram of Compound 1—Polymorphic Form IV.

[0069] [Figure 47] 1 presents the XRPD pattern of compound 1-MeCN solvate.

[0070] [Figure 48] 1 presents the XRPD pattern of compound 1-MeOH solvate.

[0071] [Figure 49] 1 presents the XRPD pattern of compound 1-EtOAc solvate.

[0072] [Figure 50] 1 presents the XRPD pattern of partially converted Compound 1-EtOAc solvate.

[0073] [Figure 51] 1 presents the XRPD pattern of compound 1-MeTHF solvate.

[0074] [Figure 52] 1 presents the XRPD pattern of compound 1-toluene solvate.

[0075] [Figure 53] 1 presents the XRPD pattern of compound 1-n-BuOAc solvate.

[0076] [Figure 54]1 shows the XRPD pattern of Compound 1-MTBE solvate 1.

[0077] [Figure 55] 1 shows the XRPD pattern of compound 1-MTBE solvate 2.

[0078] [Figure 56] 1 shows the XRPD pattern of compound 1-isopropanol hemi-solvate.

[0079] [Figure 57] 1 presents the XRPD patterns of Compound 1—Form I as well as various isostructural forms of Compound 1.

[0080] [Figure 58] A magnified view of a portion of the XRPD pattern disclosed in Figure 57 is presented. DETAILED DESCRIPTION OF THE INVENTION

[0081] I. Definition Unless the context otherwise requires, throughout this specification and claims, the word "comprise" and variations thereof, such as "comprises" and "comprising," are to be interpreted in an open and inclusive sense, i.e., "including but not limited to."

[0082] Throughout this specification, references to "one embodiment" or "an embodiment" mean that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment of the invention. Thus, the appearances of the phrase "in one embodiment" or "in an embodiment" in various places throughout this specification do not necessarily all refer to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0083] It should be understood that salts and polymorphs of Compound 1 encompass all isotopically labeled compounds having one or more atoms replaced with an atom having a different atomic mass or mass number. Examples of isotopes that may be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, and chlorine, e.g., 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 35 S, and 36 These radiolabeled compounds may be useful, for example, to determine or measure the effectiveness of a compound by characterizing its site or mechanism of action, or its binding affinity to a pharmacologically important site of action. Certain isotopically labeled compounds, for example, those incorporating a radioisotope, may be useful in drug and / or substrate tissue distribution studies. The radioisotope tritium, i.e., 3 H, and carbon-14, i.e., 14 C may be particularly useful for this purpose given their ease of incorporation and convenient means of detection.

[0084] Deuterium, i.e., 2 Substitution with heavier isotopes, such as H, may offer certain therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life or reduced required dosage. Thus, in some situations, heavier isotopes may be preferred.

[0085] 11 C. 18 F, 15 O, and 13Substitution with positron-emitting isotopes, such as N, can be useful in Positron Emission Topography (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 processes analogous to those described in the Examples below, using appropriately isotopically labeled reagents in place of conventionally employed non-labeled reagents.

[0086] The terms "crystalline" or "crystal" refer to a form of matter in which atoms, molecules, or ions are arranged in a highly ordered three-dimensional lattice.

[0087] The term "substantially as shown in," when referring to, for example, an XRPD pattern, DSC thermogram, or TGA graph, includes patterns, thermograms, or graphs that are not necessarily identical to those shown herein, but that fall within the limits of experimental error or variation as would be considered by one of ordinary skill in the art.

[0088] "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.

[0089] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where the event or circumstance does not occur.

[0090] The expression "pharmaceutically acceptable carrier or excipient" includes, but is not limited to, any additive acceptable for use in humans or animals, such as, for example, any or all types of adjuvants, carriers, flow agents, sweeteners, diluents, preservatives, dyes / colorants, flavor enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonicity agents, solvents, or emulsifiers.

[0091] A "pharmaceutical composition" refers to a formulation of a compound for delivery to an animal, e.g., a human.

[0092] An "effective amount" or "therapeutically effective amount" refers to an amount of a compound sufficient to effect treatment of a disease, condition, and / or disorder when administered to a patient in need thereof. Such an amount would be sufficient to elicit a biological or medical response in 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 and severity of the disease, condition, and / or disorder being treated, drugs used in combination with 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 determined routinely by one of ordinary skill in the art having regard to their own knowledge, the prior art, and this disclosure.

[0093] As used herein, the terms "inhibit" and "inhibiting" refer to blocking a particular biological pathway. In some embodiments, the term "inhibiting" refers to administering a compound or composition that blocks MCL-1 activity.

[0094] As used herein, the terms "treatment" and "treating" refer to the administration of a compound or composition to attempt to cure or cure a disease, condition, and / or disorder in a patient or to attempt to alleviate or eliminate the symptoms of such disease, condition, and / or disorder.

[0095] "Prevention" or "preventing" refers to any treatment of a disease, condition, and / or disorder that prevents the clinical symptoms of the disease, condition, and / or disorder from developing.

[0096] The term "subject" or "patient" refers to an animal, such as a mammal (including a human). The methods and uses described herein may be useful in 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, a domestic animal (e.g., dog and cat), a livestock animal (e.g., cows, horses, sheep, goats, and pigs), and / or a laboratory animal (e.g., mouse, rat, hamster, guinea pig, pig, rabbit, dog, and monkey). In one embodiment, the subject (or patient) is a human. A "human (or patient) in need thereof" refers to a human (or patient) who may have or is suspected of having a disease, condition, and / or disorder that would benefit from a particular treatment.

[0097] "Tautomer" refers to the migration of a proton from one atom of a molecule to another atom of the same molecule. Salts and crystalline forms of Compound 1 include all tautomers of the compound.

[0098] 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 range of numbers (e.g., + / - 5 to 10% of the recited range) that one of ordinary skill in the art would consider equivalent to the recited value (e.g., having the same function or result). When a term such as "about" precedes a list of numbers or ranges, the term modifies all of the values ​​or ranges set forth in the list. In some cases, the term "about" may include numbers that are rounded to the nearest significant figure.

[0099] Also, the singular forms "a" and "the" include plural references unless the context clearly indicates otherwise. Thus, for example, a reference to "the compound" may refer to a plurality of such compounds.

[0100] "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms and other materials that are acceptable for use in humans or animals.

[0101] A "unit dosage form" is a physically discrete unit suitable as a unitary dosage for subjects (e.g., human subjects and other mammals), each unit containing a predetermined quantity of active material calculated to produce a desired therapeutic effect.

[0102] [Table 1-1] [Table 1-2]

[0103] II. Compounds One aspect of the present disclosure is Compound 1: [ka] This relates to the crystalline form of Another aspect of the present disclosure relates to crystalline forms of solvates of Compound 1.

[0104] One aspect of the present disclosure is Compound 1: [ka] The present invention relates to a pharmaceutically acceptable salt of Another aspect of the present disclosure relates to solvates of pharmaceutically acceptable salts of Compound 1.

[0105] One aspect of the present disclosure is Compound 1: [ka] The present invention relates to a crystalline form of a pharmaceutically acceptable salt of Another aspect of the present disclosure relates to crystalline forms of solvates of pharmaceutically acceptable salts of Compound 1.

[0106] A. Crystalline Form of Compound 1 One aspect of the present disclosure is Compound 1: [ka] This relates to the crystalline form of 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.

[0107] 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 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 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-θ. In some embodiments, the crystalline form is characterized by an X-ray powder diffraction pattern substantially as shown in FIG.

[0108] 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 at about 180° C. In some embodiments, the differential scanning calorimetry thermogram is substantially as shown in FIG.

[0109] In some embodiments, Form I is characterized by having a thermogravimetric analysis thermogram that exhibits a weight loss of about 1.0% over a temperature range from ambient temperature to about 170° C. In some embodiments, the thermogravimetric analysis thermogram is substantially as shown in FIG.

[0110] In some embodiments, Form I is characterized by absorbing about 1.4% water by weight at about 25° C. and about 0% to 90% relative humidity. In some embodiments, the dynamic water vapor sorption mass uptake profile is substantially as shown in FIG.

[0111] In some embodiments, Form I is prepared by a process comprising: (1) contacting Compound 1 or a salt thereof with a solvent selected from acetone, ethyl acetate, an 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 isopropyl alcohol. In some embodiments, the solvent comprises ethanol.

[0112] In some embodiments, the process further comprises filtering the mixture of Compound 1 or a salt thereof and the solvent prior to isolating the solid product. In some embodiments, the process further comprises heating the mixture of Compound 1 or a salt thereof and the solvent. In some embodiments, the mixture is heated to about 50-70°C, e.g., about 60°C. In some embodiments, the filtration occurs before heating. In some embodiments, the filtration occurs before or after heating. In some embodiments, the process further comprises drying the solid product and / or the filtrate.

[0113] In some embodiments, the process further comprises washing and / or crystallizing the solid product with a second solvent selected from acetone, ethyl acetate, an alcohol, or a mixture of such solvents, and optionally drying. In some embodiments, washing comprises washing the solid product with a mixture of ethyl acetate and an alcohol. In some embodiments, washing comprises washing the solid product with a mixture of ethyl acetate and ethanol.

[0114] In some embodiments, Form I is prepared by a process comprising: (1) contacting Compound 1 or a salt thereof with a buffer to form a mixture; (2) adding a solvent selected from acetonitrile and an acetonitrile / water mixture to the mixture to form a slurry; (3) mixing the slurry; and (4) isolating the solid product. In some embodiments, the salt is the sodium salt of Compound 1. In some embodiments, the pH of the buffer is about 1 to about 6. In some embodiments, the pH of the buffer is about 2 to about 4. In some embodiments, the pH of the buffer is about 2.

[0115] In some embodiments, Form I is prepared by a process comprising: (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 isopropyl alcohol. In some embodiments, the alcohol is ethanol.

[0116] 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 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 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 additional peaks selected from peaks at 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°, 26.7°±0.2°, and 27.9°±0.2° 2-θ. In some embodiments, the crystalline form is characterized by an X-ray powder diffraction pattern substantially as shown in FIG. 36.

[0117] 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 at about 163° C. In some embodiments, the differential scanning calorimetry thermogram is substantially as shown in FIG.

[0118] In some embodiments, Form II is characterized by having a thermogravimetric analysis thermogram that exhibits a weight loss of about 0.6% over a temperature range from ambient temperature to about 210° C. In some embodiments, the thermogravimetric analysis thermogram is substantially as shown in FIG.

[0119] In some embodiments, Form II is characterized by absorbing up to about 1.1% by weight of water at about 0% to 90% relative humidity at about 25° C. In some embodiments, Form II is characterized by having a dynamic water vapor sorption mass uptake profile substantially as shown in FIG.

[0120] In some embodiments, Form II is prepared by a process comprising: (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 process further comprises drying the solid product. In some embodiments, the salt of Compound 1 is a sodium salt.

[0121] 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 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 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-θ. In some embodiments, the crystalline form is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 40.

[0122] 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 onsets at about 20° C., 133° C., and 153° C. In some embodiments, the differential scanning calorimetry thermogram is substantially as shown in FIG.

[0123] In some embodiments, Form III is characterized by having a thermogravimetric analysis thermogram that exhibits a weight loss of about 2.9% over a temperature range from about ambient temperature to about 90° C. In some embodiments, Form III is characterized by having a thermogravimetric analysis thermogram that exhibits a weight loss of about 1.1% over a temperature range from about 90° C. to about 175° C. In some embodiments, Form III is characterized by having a thermogravimetric analysis thermogram that exhibits a weight loss of about 1.6% over a temperature range from about 175° C. to about 225° C. In some embodiments, the thermogravimetric analysis thermogram is substantially as shown in FIG.

[0124] In some embodiments, Form III is characterized by absorbing up to about 5% by weight of water at about 0% to 90% relative humidity at about 25° C. In some embodiments, Form III is characterized by having a dynamic water vapor sorption mass uptake profile substantially as shown in FIG.

[0125] In some embodiments, Form III is prepared by a process comprising: (1) contacting Compound 1 or a salt thereof with methanol and optionally an acid; and (2) isolating the 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 process further comprises drying the solid product. In some embodiments, the salt of Compound 1 is a sodium salt.

[0126] 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 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 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-θ. In some embodiments, the crystalline form is characterized by an X-ray powder diffraction pattern substantially as shown in FIG. 44.

[0127] 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 onsets at about 119° C. and 166° C. In some embodiments, the differential scanning calorimetry thermogram is substantially as shown in FIG.

[0128] In some embodiments, Form IV is characterized by having a thermogravimetric analysis thermogram that exhibits a weight loss of about 0.6% over a temperature range from ambient temperature to about 200° C. In some embodiments, the thermogravimetric analysis thermogram is substantially as shown in FIG.

[0129] In some embodiments, Form IV is prepared by a process comprising: (1) contacting Compound 1 or a salt thereof with ethanol and / or heptane; and (2) isolating the solid product.

[0130] One aspect of the present disclosure relates to crystalline forms of solvates of Compound 1.

[0131] In some embodiments, the crystalline form of the solvate of Compound 1 is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 47. In some embodiments, the crystalline form is a MeCN solvate of Compound 1.

[0132] In some embodiments, the crystalline form of the solvate of Compound 1 is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 48. In some embodiments, the crystalline form is a MeOH solvate of Compound 1.

[0133] In some embodiments, the crystalline form of the solvate of Compound 1 is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 49. In some embodiments, the crystalline form is an EtOAc solvate of Compound 1.

[0134] In some embodiments, the crystalline form of the solvate of Compound 1 is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 50. In some embodiments, the crystalline form is a partially desolvated EtOAc solvate of Compound 1.

[0135] In some embodiments, the crystalline form of the solvate of Compound 1 is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 51. In some embodiments, the crystalline form is a MeTHF solvate of Compound 1.

[0136] In some embodiments, the crystalline form of the solvate of Compound 1 is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 52. In some embodiments, the crystalline form is a toluene solvate of Compound 1.

[0137] In some embodiments, the crystalline form of the solvate of Compound 1 is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 53. In some embodiments, the crystalline form is an nBuOAc solvate of Compound 1.

[0138] In some embodiments, the crystalline form of the solvate of Compound 1 is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 54. In some embodiments, the crystalline form is MTBE solvate 1 of Compound 1.

[0139] In some embodiments, the crystalline form of the solvate of Compound 1 is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 55. In some embodiments, the crystalline form is MTBE solvate 2 of Compound 1.

[0140] In some embodiments, the crystalline form of the solvate of Compound 1 is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 56. In some embodiments, the crystalline form is an isopropanol hemisolvate of Compound 1.

[0141] B. Salt of Compound 1 One aspect of the present disclosure is Compound 1: [ka] The present invention relates to a pharmaceutically acceptable salt of In some embodiments, the pharmaceutically acceptable salt is selected from sodium salts, potassium salts, diethylamine salts, and choline salts.

[0142] Another aspect of the present disclosure is Compound 1: [ka] The present invention relates to a crystalline form of a pharmaceutically acceptable salt of In some embodiments, the pharmaceutically acceptable salt is selected from sodium salts, potassium salts, diethylamine salts, and choline salts.

[0143] 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 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 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 an X-ray powder diffraction pattern substantially as shown in FIG.

[0144] In some embodiments, the crystalline form of a 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 onsets at about 14° C., 83° C., and 232° C. In some embodiments, the differential scanning calorimetry thermogram is substantially as shown in FIG.

[0145] In some embodiments, Na salt Form 1 is characterized by having a thermogravimetric analysis thermogram that exhibits a weight loss of about 4.2% over temperatures from ambient to about 200° C. In some embodiments, the thermogravimetric analysis thermogram is substantially as shown in FIG.

[0146] In some embodiments, Na salt Form 1 is characterized by absorbing about 7.5% water by weight at about 25° C. and about 0% to 90% relative humidity. In some embodiments, Na salt Form 1 is characterized by having a dynamic water vapor sorption mass uptake profile substantially as shown in FIG.

[0147] 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 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 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-θ. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is characterized by an X-ray powder diffraction pattern substantially as shown in FIG.

[0148] In some embodiments, the crystalline form of a 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 onsets 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 onset at about 109° C. In some embodiments, the differential scanning calorimetry thermogram is substantially as shown in FIG.

[0149] In some embodiments, Na salt Form 2 is characterized by having a thermogravimetric analysis thermogram that exhibits a weight loss of about 4.8% over temperatures from ambient to about 200° C. In some embodiments, the thermogravimetric analysis thermogram is substantially as shown in FIG.

[0150] 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 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 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, a pharmaceutically acceptable salt of Compound 1 is characterized by an X-ray powder diffraction pattern substantially as shown in FIG. 8.

[0151] In some embodiments, the crystalline form of a 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 onsets at about 19° C. and 219° C. In some embodiments, the differential scanning calorimetry thermogram is substantially as shown in FIG.

[0152] In some embodiments, Na salt Form 3 is characterized by having a thermogravimetric analysis thermogram that exhibits a weight loss of about 5.1% over temperatures from ambient to about 200° C. In some embodiments, the thermogravimetric analysis thermogram is substantially as shown in FIG.

[0153] 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 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 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 an X-ray powder diffraction pattern substantially as shown in FIG.

[0154] In some embodiments, the crystalline form of a pharmaceutically acceptable salt of Compound 1 is Na salt form 4.

[0155] 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 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 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 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-θ. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is characterized by an X-ray powder diffraction pattern substantially as shown in FIG.

[0156] In some embodiments, the crystalline form of a 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 onsets 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 onset at about 198° C. In some embodiments, the differential scanning calorimetry thermogram is substantially as shown in FIG.

[0157] In some embodiments, Na salt Form 5 is characterized by having a thermogravimetric analysis thermogram that exhibits a weight loss of about 4.2% over temperatures from ambient to about 200° C. In some embodiments, the thermogravimetric analysis thermogram is substantially as shown in FIG.

[0158] 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 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 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, a pharmaceutically acceptable salt of Compound 1 is characterized by an X-ray powder diffraction pattern substantially as shown in FIG.

[0159] In some embodiments, the crystalline form of a 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 onsets at about 14° C., 182° C., and 233° C. In some embodiments, the differential scanning calorimetry thermogram is substantially as shown in FIG.

[0160] In some embodiments, K salt Form 1 is characterized by having a thermogravimetric analysis thermogram that exhibits a weight loss of about 4.2% over temperatures from ambient to about 200° C. In some embodiments, the thermogravimetric analysis thermogram is substantially as shown in FIG.

[0161] In some embodiments, K salt Form 1 is characterized by absorbing about 11% water by weight at about 25° C. and about 0%-90% relative humidity. In some embodiments, K salt Form 1 is characterized by having a dynamic water vapor sorption mass uptake profile substantially as shown in FIG.

[0162] 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 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 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 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, hi some embodiments, the X-ray powder diffraction pattern is substantially as shown in FIG.

[0163] In some embodiments, the crystalline form of a pharmaceutically acceptable salt of Compound 1 is diethylamine salt Form 1. In some embodiments, diethylamine salt Form 1 is characterized by having a differential scanning calorimetry thermogram comprising at least one endothermic peak selected from peaks with onsets at about 17° C. and 145° C. In some embodiments, the differential scanning calorimetry thermogram is substantially as shown in FIG. 24. In some embodiments, diethylamine salt Form 1 is characterized by having a thermogravimetric analysis thermogram exhibiting a weight loss of about 8.4% over a temperature range from ambient temperature to about 170° C. In some embodiments, the thermogravimetric analysis thermogram is substantially as shown in FIG. 25. In some embodiments, diethylamine salt Form 1 is characterized by absorbing about 5.5% water by weight at about 25° C. and from about 0% to 90% relative humidity. In some embodiments, diethylamine salt Form 1 is characterized by having a dynamic water vapor sorption mass uptake profile substantially as shown in FIG. 26.

[0164] 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 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 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, a pharmaceutically acceptable salt of Compound 1 is characterized by an X-ray powder diffraction pattern substantially as shown in FIG.

[0165] In some embodiments, the crystalline form of a pharmaceutically acceptable salt of Compound 1 is choline salt Form 1. In some embodiments, choline salt Form 1 is characterized by having a differential scanning calorimetry thermogram comprising at least one endothermic peak selected from peaks with onsets at about 23° C., 99° C., and 156° C. In some embodiments, the differential scanning calorimetry thermogram is substantially as shown in FIG. 28. In some embodiments, choline salt Form 1 is characterized by having a thermogravimetric analysis thermogram exhibiting a weight loss of about 8.8% over a temperature range from ambient to about 200° C. In some embodiments, the thermogravimetric analysis thermogram is substantially as shown in FIG. 29.

[0166] One aspect of the present disclosure relates to a crystalline form of a solvate of a pharmaceutically acceptable salt of Compound 1.

[0167] In some embodiments, the solvate is a potassium salt solvate. In some embodiments, the potassium salt solvate is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 20. In some embodiments, the solvate is a potassium salt IPA solvate.

[0168] In some embodiments, the potassium salt solvate is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 21. In some embodiments, the solvate is a potassium salt THF solvate.

[0169] In some embodiments, the solvate is a diethylamine salt solvate. In some embodiments, the diethylamine salt solvate is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 20. In some embodiments, the solvate is a diethylamine salt toluene solvate.

[0170] III. Pharmaceutical Compositions 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.

[0171] 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.

[0172] 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.

[0173] The pharmaceutical compositions herein contain a therapeutically effective amount of any of the compounds in Section II for treating or preventing a disease, condition, and / or disorder. The therapeutically effective amount may vary depending on a variety of factors, such as the activity of the specific compound used, the metabolic stability and length of action of that compound, the patient's age, weight, general health, sex, and diet, the method and time of administration, excretion rate, drug combination, the severity of the specific disorder or condition, and the subject being treated. Appropriate concentrations and dosages can be determined by one of ordinary skill in the art.

[0174] In some embodiments, the dose of Compound 1 ranges from about 1 mg / kg to 24 mg / kg, although lower or higher doses may be administered as appropriate. For example, a dose of 1 to 20 mg / kg for a 70 kg patient would be 70 to 1,400 mg. Dosages may be repeated as needed, for example, once weekly for 4 to 10 weeks, once weekly for 8 weeks, or once weekly for 4 weeks. Maintenance therapy may also be administered less frequently, for example, every other week for several months, or monthly or quarterly for many 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, 60 mg / kg, 65 mg / kg, 66 mg / kg, 67 mg / kg, 68 mg / kg, 69 mg / kg, 70 mg / kg, 71 mg / kg, 72 mg / kg, 73 mg / kg, 74 mg / kg, 75 mg / kg, 76 mg / kg, 77 mg / kg, 78 mg / kg, 79 mg / kg, 80 mg / kg, 81 mg / kg, 82 mg / kg, 83 mg / kg, 84 mg / kg, 85 mg / kg, 86 mg / kg, 87 mg / kg, 88 mg / kg, 89 mg / kg, 90 mg / kg, 91 mg / kg, 92 mg / kg, 93 mg / kg, 94 mg / kg, 95 mg / kg, 96 mg / kg, 97 mg / kg, 98 mg / kg, 99 mg / kg, 100 mg / kg, 101 mg / kg, 102 mg / kg, 103 mg / kg, 104 mg / kg, 105 mg / kg, 10 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, 240mg / kg 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.

[0175] 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, 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 120 mg, about 130 mg, about 140 mg, about 155 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 450 mg, about 4 The compound is present in the pharmaceutical composition in an amount of about 0 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.

[0176] 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.

[0177] In some embodiments, the compound is administered in a 21-day cycle with 2 days on medication followed by 5 days off medication, hi 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.

[0178] In some embodiments, the compound is administered once a week with one day on and six days off, hi some embodiments, the compound is administered twice every three weeks.

[0179] The pharmaceutical compositions disclosed herein can be prepared by combining the compounds disclosed herein with a suitable pharmaceutically acceptable carrier or excipient, and can be formulated into solid, semi-solid, liquid, or gaseous formulations such as tablets, capsules, powders, granules, ointments, liquids, suppositories, injections, inhalants, gels, microspheres, and aerosols. In some embodiments, the pharmaceutical compositions disclosed herein are formulated into tablet or capsule formulations.

[0180] The pharmaceutical compositions disclosed herein can be prepared by methods well known in the pharmaceutical art. For example, solid pharmaceutical compositions intended for oral administration can be prepared by mixing the compounds disclosed herein with at least one pharmaceutical carrier or excipient to form a solid preformulation composition, which can then be easily divided into equally effective unit dosage forms, such as tablets, pills, and capsules. Methods for preparing dosage forms are known or apparent to those skilled in the art. See, for example, 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.

[0181] In some embodiments, the pharmaceutical compositions disclosed herein further comprise at least one additional therapeutic compound. In some embodiments, the at least one additional therapeutic compound is a drug used to treat cancer. In some embodiments, the at least one additional therapeutic compound is selected from docetaxel, sacituzumab govitecan, and gemcitabine.

[0182] The pharmaceutical compositions disclosed herein can be formulated so that the active ingredients contained therein become bioavailable upon administration of the composition 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 compositions are prepared for oral administration.

[0183] In some embodiments, the pharmaceutical compositions disclosed herein are administered together with at least one additional therapeutic compound. The administration of the at least one additional therapeutic compound may occur before, after, or simultaneously with the administration of the pharmaceutical compositions disclosed herein. In some embodiments, the at least one additional therapeutic compound is a drug used to treat cancer. In some embodiments, the at least one additional therapeutic compound is selected from docetaxel, sacituzumab govitecan, and gemcitabine.

[0184] IV. Methods and Uses One aspect of the present disclosure relates to methods and uses of any of the compounds and pharmaceutical compositions disclosed herein.

[0185] In one aspect, the 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.

[0186] 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.

[0187] In one aspect, the 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.

[0188] 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.

[0189] In one aspect, the disclosure relates to the use of any of the compounds or pharmaceutical compositions disclosed herein to treat 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.

[0190] In one aspect, the disclosure relates to the use of any of the compounds or pharmaceutical compositions disclosed herein for 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.

[0191] In any of the above methods or uses, in some embodiments, the cancer is a hematological cancer. 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, colon cancer, skin cancer, melanoma, ovarian cancer, renal cancer, small cell lung cancer, non-small cell lung cancer, lymphoma, leukemia, or metastatic soft tissue sarcoma.

[0192] In one aspect, the disclosure relates to any of the compounds or pharmaceutical compositions disclosed herein for use in a method of 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.

[0193] In some embodiments, the cancer is a hematological cancer. In some embodiments, the cancer is relapsed / refractory multiple myeloma or relapsed / refractory myeloma. In some embodiments, the cancer is triple-negative breast cancer, colon cancer, skin cancer, melanoma, ovarian cancer, renal 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.

[0194] In any of the above methods or uses, in some embodiments, the method further comprises administering to the patient an additional therapeutic compound, in some embodiments, the additional therapeutic compound is selected from docetaxel, sacituzumab govitecan, and gemcitabine.

[0195] Enumerated Embodiments Embodiment 1: Compound 1: [ka] Crystalline form of.

[0196] Embodiment 2: The crystalline form of embodiment 1, wherein the crystalline form of Compound 1 is Form I.

[0197] 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 about 4.9°±0.2°, 8.6°±0.2°, and 14.3°±0.2° 2-θ.

[0198] Embodiment 4: The crystalline form of embodiment 3, wherein the X-ray powder diffraction pattern comprises one or more additional peaks selected from peaks at about 16.2°±0.2°, 18.3°±0.2°, and 22.1°±0.2° 2-θ.

[0199] 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 peaks at about 17.8°±0.2°, 19.3°±0.2°, and 21.5°±0.2° 2-θ.

[0200] 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 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.

[0201] Embodiment 7: The crystalline form of any one of embodiments 1-6, wherein the crystalline form of Compound 1 is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 31.

[0202] Embodiment 8: The crystalline form of any one of embodiments 2-7, wherein Form I is characterized by having a differential scanning calorimetry thermogram comprising an endothermic peak with an onset at about 180° C.

[0203] Embodiment 9: The crystalline form of embodiment 8, wherein the differential scanning calorimetry thermogram is substantially as shown in Figure 32.

[0204] Embodiment 10: The crystalline form of any one of embodiments 2-9, wherein Form I is characterized by having a thermogravimetric analysis thermogram exhibiting a weight loss of about 1.0% over a temperature range from ambient temperature to about 170°C.

[0205] Embodiment 11: The crystalline form of embodiment 10, wherein the thermogravimetric analysis thermogram is substantially as shown in Figure 33.

[0206] Embodiment 12: The crystalline form of any one of embodiments 2-11, wherein Form I is characterized by absorbing about 1.4% by weight of water at about 25° C. and about 0% to 90% relative humidity.

[0207] Embodiment 13: The crystalline form of any one of embodiments 2-12, wherein Form I is characterized by having a dynamic vapor sorption mass uptake profile substantially as shown in FIG. 34.

[0208] Embodiment 14: The crystalline form of embodiment 1, wherein the crystalline form of Compound 1 is Form II.

[0209] Embodiment 15: The crystalline form of embodiment 1 or embodiment 14, wherein 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.

[0210] Embodiment 16: The crystalline form of embodiment 15, wherein the X-ray powder diffraction pattern comprises one or more additional peaks selected from peaks at about 15.4°±0.2°, 16.9°±0.2°, and 19.9°±0.2° 2-θ.

[0211] 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 peaks at about 12.8°±0.2°, 13.9°±0.2°, and 22.8°±0.2° 2-θ.

[0212] Embodiment 18: The crystalline form of embodiment 17, wherein the X-ray powder diffraction pattern comprises one or more additional peaks selected from peaks at 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°, 26.7°±0.2°, and 27.9°±0.2° 2-θ.

[0213] Embodiment 19: The crystalline form of any one of embodiments 1 or 14-18, wherein the crystalline form of Compound 1 is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 36.

[0214] Embodiment 20: The crystalline form of any one of embodiments 14-19, wherein Form II is characterized by having a differential scanning calorimetry thermogram comprising an endothermic peak with an onset at about 163°C.

[0215] Embodiment 21: The crystalline form of embodiment 20, wherein the differential scanning calorimetry thermogram is substantially as shown in Figure 37.

[0216] Embodiment 22: The crystalline form of any one of embodiments 14-21, wherein Form II is characterized by having a thermogravimetric analysis thermogram exhibiting a weight loss of about 0.6% over a temperature range from ambient temperature to about 210°C.

[0217] Embodiment 23: The crystalline form of embodiment 22, wherein the thermogravimetric analysis thermogram is substantially as shown in Figure 38.

[0218] Embodiment 24: The crystalline form of any one of embodiments 14-23, wherein Form II is characterized by absorbing up to about 1.1% by weight of water at about 25° C. and about 0% to 90% relative humidity.

[0219] Embodiment 25: The crystalline form of any one of embodiments 14-24, wherein Form II is characterized by having a dynamic vapor sorption mass uptake profile substantially as shown in Figure 39.

[0220] Embodiment 26: The crystalline form of embodiment 1, wherein the crystalline form of Compound 1 is Form III.

[0221] 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 about 8.0°±0.2°, 15.0°±0.2°, and 18.4°±0.2° 2-θ.

[0222] Embodiment 28: The crystalline form of embodiment 27, wherein the X-ray powder diffraction pattern comprises one or more additional peaks selected from peaks at about 16.5°±0.2°, 22.1°±0.2°, and 22.9°±0.2° 2-θ.

[0223] Embodiment 29: The crystalline form of embodiment 27 or embodiment 28, 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.

[0224] Embodiment 30: The crystalline form of embodiment 29, wherein 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-θ.

[0225] Embodiment 31: The crystalline form of any one of embodiments 1 or 26-30, wherein the crystalline form of Compound 1 is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 40.

[0226] Embodiment 32: The crystalline form of any one of embodiments 26-31, wherein Form III is characterized by having a differential scanning calorimetry thermogram comprising at least one endothermic peak selected from peaks with onsets at about 20°C, 133°C, and 153°C.

[0227] Embodiment 33: The crystalline form of embodiment 32, wherein the differential scanning calorimetry thermogram is substantially as shown in Figure 41.

[0228] Embodiment 34: The crystalline form of any one of embodiments 26-33, wherein Form III is characterized by having a thermogravimetric analysis thermogram exhibiting a weight loss of about 2.9% over a temperature range from about ambient temperature to about 90°C.

[0229] Embodiment 35: The crystalline form of any one of embodiments 26-34, wherein Form III is characterized by having a thermogravimetric analysis thermogram exhibiting a weight loss of about 1.1% over a temperature range from about 90°C to about 175°C.

[0230] Embodiment 36: The crystalline form of any one of embodiments 26-35, wherein Form III is characterized by having a thermogravimetric analysis thermogram exhibiting a weight loss of about 1.6% over a temperature range of about 175°C to about 225°C.

[0231] Embodiment 37: The crystalline form of any one of embodiments 34-36, wherein the thermogravimetric analysis thermogram is substantially as shown in Figure 42.

[0232] Embodiment 38: The crystalline form of any one of embodiments 26-37, wherein Form III is characterized by absorbing up to about 5% by weight of water at about 25° C. and about 0% to 90% relative humidity.

[0233] Embodiment 39: The crystalline form of any one of embodiments 26-38, wherein Form III is characterized by having a dynamic vapor sorption mass uptake profile substantially as shown in Figure 43.

[0234] Embodiment 40: The crystalline form of embodiment 1, wherein the crystalline form of Compound 1 is Form IV.

[0235] Embodiment 41: The crystalline form of embodiment 1 or embodiment 40, wherein the crystalline form of Compound 1 is characterized by an X-ray powder diffraction pattern comprising peaks at about 7.1°±0.2°, 8.7°±0.2°, and 10.6°±0.2° 2-θ.

[0236] Embodiment 42: The crystalline form of embodiment 41, wherein the X-ray powder diffraction pattern comprises one or more additional peaks selected from peaks at about 10.3°±0.2°, 11.2°±0.2°, and 18.2°±0.2° 2-θ.

[0237] Embodiment 43: The crystalline form of embodiment 41 or embodiment 42, wherein the X-ray powder diffraction pattern comprises one or more additional peaks selected from peaks at about 14.2°±0.2°, 20.5°±0.2°, and 24.9°±0.2° 2-θ.

[0238] Embodiment 44: The crystalline form of embodiment 43, wherein 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-θ.

[0239] Embodiment 45: The crystalline form of any one of embodiments 1 or 40-41, wherein the crystalline form of Compound 1 is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 44.

[0240] Embodiment 46: The crystalline form of any one of embodiments 40-45, wherein Form IV is characterized by having a differential scanning calorimetry thermogram comprising at least one endothermic peak selected from peaks with onsets at about 119°C and 166°C.

[0241] Embodiment 47: The crystalline form of embodiment 46, wherein the differential scanning calorimetry thermogram is substantially as shown in Figure 45.

[0242] Embodiment 48: The crystalline form of any one of embodiments 40-47, wherein Form IV is characterized by having a thermogravimetric analysis thermogram exhibiting a weight loss of about 0.6% over a temperature range from ambient temperature to about 200°C.

[0243] Embodiment 49: The crystalline form of embodiment 48, wherein the thermogravimetric analysis thermogram is substantially as shown in Figure 46.

[0244] Embodiment 50: Compound 1: [ka] A crystalline form of a pharmaceutically acceptable salt of

[0245] Embodiment 51: The crystalline form of embodiment 50, wherein the pharmaceutically acceptable salt of Compound 1 is a sodium salt.

[0246] Embodiment 52: The crystalline form of embodiment 51, wherein the sodium salt is Na salt form 1.

[0247] Embodiment 53: The crystalline form of embodiment 51 or embodiment 52, wherein 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.

[0248] Embodiment 54: The crystalline form of embodiment 53, wherein the X-ray powder diffraction pattern comprises one or more additional peaks selected from peaks at about 15.3°±0.2°, 18.4°±0.2°, and 20.4°±0.2° 2-θ.

[0249] Embodiment 55: The crystalline form of embodiment 53 or embodiment 54, wherein the X-ray powder diffraction pattern comprises one or more additional peaks selected from peaks at about 12.3°±0.2°, 13.4°±0.2°, and 24.0°±0.2° 2-θ.

[0250] Embodiment 56: The crystalline form of embodiment 55, wherein 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.

[0251] Embodiment 57: The crystalline form of any one of embodiments 50-56, wherein the pharmaceutically acceptable salt of Compound 1 is characterized by an X-ray powder diffraction pattern substantially as shown in FIG. 1.

[0252] Embodiment 58: The crystalline form of any one of embodiments 52-57, wherein Na Salt Form 1 is characterized by having a differential scanning calorimetry thermogram comprising at least one endothermic peak selected from peaks with onsets at about 14°C, 83°C, and 232°C.

[0253] Embodiment 59: The crystalline form of embodiment 58, wherein the differential scanning calorimetry thermogram is substantially as shown in FIG. 2.

[0254] Embodiment 60: The crystalline form of any one of embodiments 52-59, wherein Na salt Form 1 is characterized by having a thermogravimetric analysis thermogram exhibiting a weight loss of about 4.2% over a temperature range from ambient temperature to about 200°C.

[0255] Embodiment 61: The crystalline form of embodiment 60, wherein the thermogravimetric analysis thermogram is substantially as shown in FIG. 3.

[0256] Embodiment 62: The crystalline form of any one of embodiments 52-61, wherein the Na salt Form 1 is characterized by absorbing about 7.5% by weight of water at about 25° C. and about 0% to 90% relative humidity.

[0257] Embodiment 63: The crystalline form of any one of embodiments 52-62, wherein the Na salt Form 1 is characterized by having a dynamic vapor sorption mass uptake profile substantially as shown in FIG.

[0258] Embodiment 64: The crystalline form of embodiment 51, wherein the sodium salt of Compound 1 is Na salt form 2.

[0259] 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 about 7.2°±0.2°, 14.7°±0.2°, and 19.3°±0.2° 2-θ.

[0260] Embodiment 66: The crystalline form of embodiment 65, wherein the X-ray powder diffraction pattern comprises one or more additional peaks selected from peaks at about 11.1°±0.2°, 17.1°±0.2°, and 20.7°±0.2° 2-θ.

[0261] 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 about 13.1°±0.2°, 14.5°±0.2°, and 16.9°±0.2° 2-θ.

[0262] Embodiment 68: The crystalline form of embodiment 67, wherein 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-θ.

[0263] Embodiment 69: The crystalline form of any one of embodiments 50-52 or 64-68, wherein the pharmaceutically acceptable salt of Compound 1 is characterized by an X-ray powder diffraction pattern substantially as shown in FIG. 5.

[0264] Embodiment 70: The crystalline form of any one of embodiments 64-69, 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 onsets at about 21°C and 224°C.

[0265] Embodiment 71: The crystalline form of any one of embodiments 64-70, wherein the Na salt Form 2 is characterized by having a differential scanning calorimetry thermogram comprising an exothermic peak with an onset at about 109°C.

[0266] Embodiment 72: The crystalline form of embodiment 70 or embodiment 71, wherein the differential scanning calorimetry thermogram is substantially as shown in Figure 6.

[0267] Embodiment 73: The crystalline form of any one of embodiments 64-72, wherein the Na salt Form 2 is characterized by having a thermogravimetric analysis thermogram exhibiting a weight loss of about 4.8% over a temperature range from ambient temperature to about 200°C.

[0268] Embodiment 74: The crystalline form of embodiment 73, wherein the thermogravimetric analysis thermogram is substantially as shown in Figure 7.

[0269] Embodiment 75: The crystalline form of embodiment 51, wherein the sodium salt is Na salt form 3.

[0270] 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 about 4.1°±0.2°, 13.2°±0.2°, and 18.8°±0.2° 2-θ.

[0271] Embodiment 77: The crystalline form of embodiment 76, wherein the X-ray powder diffraction pattern comprises one or more additional peaks selected from peaks at about 12.1°±0.2°, 20.0°±0.2°, and 24.2°±0.2° 2-θ.

[0272] 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 peaks at about 14.8°±0.2°, 20.9°±0.2°, and 22.9°±0.2° 2-θ.

[0273] Embodiment 79: The crystalline form of embodiment 78, wherein the X-ray powder diffraction pattern comprises one additional peak at about 8.2°±0.2° 2-θ.

[0274] Embodiment 80: The crystalline form of any one of embodiments 50-51 or 75-79, wherein the pharmaceutically acceptable salt of Compound 1 is characterized by an X-ray powder diffraction pattern substantially as shown in FIG. 8.

[0275] Embodiment 81: The crystalline form of any one of embodiments 75-80, 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 onsets at about 19°C and 219°C.

[0276] Embodiment 82: The crystalline form of embodiment 81, having a differential scanning calorimetry thermogram substantially as shown in Figure 9.

[0277] Embodiment 83: The crystalline form of any one of embodiments 75-82, wherein the Na salt Form 3 is characterized by having a thermogravimetric analysis thermogram exhibiting a weight loss of about 5.1% over a temperature range from ambient temperature to about 200°C.

[0278] Embodiment 84: The crystalline form of embodiment 83, wherein the thermogravimetric analysis thermogram is substantially as shown in Figure 10.

[0279] Embodiment 85: The crystalline form of embodiment 51, wherein the sodium salt is Na salt form 4.

[0280] 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 about 6.7°±0.2°, 13.3°±0.2°, and 20.2°±0.2° 2-theta.

[0281] Embodiment 87: The crystalline form of embodiment 86, wherein the X-ray powder diffraction pattern comprises one or more additional peaks selected from peaks at about 16.0°±0.2°, 21.0°±0.2°, and 23.4°±0.2° 2-θ.

[0282] Embodiment 88: The crystalline form of embodiment 87, wherein the X-ray powder diffraction pattern comprises one or more additional peaks selected from peaks at about 7.2°±0.2°, 21.5°±0.2°, and 22.8°±0.2° 2-θ.

[0283] 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 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.

[0284] Embodiment 90: The crystalline form of any one of embodiments 50-51 or 85-89, wherein the pharmaceutically acceptable salt of Compound 1 is characterized by an X-ray powder diffraction pattern substantially as shown in FIG. 11.

[0285] Embodiment 91: The crystalline form of embodiment 51, wherein the sodium salt is Na salt form 5.

[0286] 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 about 7.6°±0.2°, 13.9°±0.2°, and 15.4°±0.2° 2-θ.

[0287] Embodiment 93: The crystalline form of embodiment 92, wherein the X-ray powder diffraction pattern comprises one or more additional peaks selected from peaks at about 6.0°±0.2°, 8.9°±0.2°, and 12.1°±0.2° 2-θ.

[0288] Embodiment 94: The crystalline form of embodiment 92 or embodiment 93, wherein the X-ray powder diffraction pattern comprises one or more additional peaks selected from peaks at about 17.0°±0.2°, 21.7°±0.2°, and 23.0°±0.2° 2-θ.

[0289] Embodiment 95: The crystalline form of embodiment 94, wherein the X-ray powder diffraction pattern comprises one or more additional peaks selected from 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-θ.

[0290] Embodiment 96: The crystalline form of any one of embodiments 50-51 and 91-95, wherein the pharmaceutically acceptable salt of Compound 1 is characterized by an X-ray powder diffraction pattern substantially as shown in FIG. 12.

[0291] Embodiment 97: The crystalline form of any one of embodiments 91-96, 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 onsets at about 29°C and 143°C.

[0292] Embodiment 98: The crystalline form of any one of embodiments 91-97, wherein the Na salt Form 5 is characterized by having a differential scanning calorimetry thermogram comprising an exothermic peak with an onset at about 198°C.

[0293] Embodiment 99: The crystalline form of embodiment 97 or embodiment 98, wherein the differential scanning calorimetry thermogram is substantially as shown in Figure 13.

[0294] Embodiment 100: The crystalline form of any one of embodiments 91-99, wherein the Na salt form 5 is characterized by having a thermogravimetric analysis thermogram exhibiting a weight loss of about 4.2% over a temperature range from ambient temperature to about 200°C.

[0295] Embodiment 101: The crystalline form of embodiment 100, wherein the presented thermogravimetric analysis thermogram is substantially as shown in Figure 14.

[0296] Embodiment 102: The crystalline form of embodiment 50, wherein the pharmaceutically acceptable salt of Compound 1 is a potassium salt.

[0297] Embodiment 103: The crystalline form of embodiment 102, wherein the potassium salt is K salt form 1.

[0298] Embodiment 104: The crystalline form of embodiment 102 or embodiment 103, wherein 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.

[0299] Embodiment 105: The crystalline form of embodiment 104, wherein the X-ray powder diffraction pattern comprises one or more additional peaks selected from peaks at about 13.4°±0.2°, 18.2°±0.2°, and 21.9°±0.2° 2-θ.

[0300] 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 peaks at about 12.3°±0.2°, 15.3°±0.2°, and 20.1°±0.2° 2-θ.

[0301] Embodiment 107: The crystalline form of embodiment 106, wherein 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.

[0302] Embodiment 108: The crystalline form of any one of embodiments 50 or 102-107, wherein the pharmaceutically acceptable salt of Compound 1 is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 15.

[0303] Embodiment 109: The crystalline form of any one of embodiments 103-108, wherein K Salt Form 1 is characterized by having a differential scanning calorimetry thermogram comprising at least one endothermic peak selected from peaks with onsets at about 14°C, 182°C, and 233°C.

[0304] Embodiment 110: The crystalline form of embodiment 109, having a differential scanning calorimetry thermogram substantially as shown in Figure 17.

[0305] Embodiment 111: The crystalline form of any one of embodiments 103-110, wherein K Salt Form 1 is characterized by having a thermogravimetric analysis thermogram exhibiting a weight loss of about 4.2% over a temperature range from ambient temperature to about 200°C.

[0306] Embodiment 112: The crystalline form of embodiment 111, wherein the thermogravimetric analysis thermogram is substantially as shown in Figure 18.

[0307] Embodiment 113: The crystalline form of any one of embodiments 103-112, wherein the K Salt Form 1 is characterized by absorbing about 11% by weight of water at about 25° C. and about 0% to 90% relative humidity.

[0308] Embodiment 114: The crystalline form of any one of embodiments 103-113, wherein the K Salt Form 1 is characterized by having a dynamic vapor sorption mass uptake profile substantially as shown in FIG.

[0309] Embodiment 115: The crystalline form of embodiment 50, wherein the pharmaceutically acceptable salt of Compound 1 is a diethylamine salt.

[0310] Embodiment 116: The crystalline form of embodiment 115, wherein the diethylamine salt is diethylamine salt Form 1.

[0311] Embodiment 117: The crystalline form of embodiment 115 or embodiment 116, wherein 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.

[0312] Embodiment 118: The crystalline form of embodiment 117, wherein the X-ray powder diffraction pattern comprises one or more additional peaks selected from peaks at about 6.2°±0.2°, 12.5°±0.2°, and 13.1°±0.2° 2-θ.

[0313] Embodiment 119: The crystalline form of embodiment 117 or embodiment 118, wherein the X-ray powder diffraction pattern comprises one or more additional peaks selected from peaks at about 4.3°±0.2°, 14.1°±0.2°, and 17.0°±0.2° 2-θ.

[0314] Embodiment 120: The crystalline form of embodiment 119, wherein the X-ray powder diffraction pattern comprises one or more additional peaks selected from 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.

[0315] Embodiment 121: The crystalline form of any one of embodiments 50 or 115-120, wherein the pharmaceutically acceptable salt of Compound 1 is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 23.

[0316] Embodiment 122: The crystalline form of any one of embodiments 116-121, wherein diethylamine salt Form 1 is characterized by having a differential scanning calorimetry thermogram comprising at least one endothermic peak selected from peaks with onsets at about 17°C and 145°C.

[0317] Embodiment 123: The crystalline form of embodiment 122, having a differential scanning calorimetry thermogram substantially as shown in Figure 24.

[0318] Embodiment 124: The crystalline form of any one of embodiments 116-123, wherein the diethylamine salt Form 1 is characterized by having a thermogravimetric analysis thermogram exhibiting a weight loss of about 8.4% over a temperature range from ambient temperature to about 170°C.

[0319] Embodiment 125: The crystalline form of embodiment 124, wherein the thermogravimetric analysis thermogram is substantially as shown in Figure 25.

[0320] Embodiment 126: The crystalline form of any one of embodiments 116-125, wherein the diethylamine salt Form 1 is characterized by absorbing about 5.5% by weight of water at about 25° C. and about 0% to 90% relative humidity.

[0321] Embodiment 127: The crystalline form of any one of embodiments 116-126, wherein the diethylamine salt Form 1 is characterized by having a dynamic vapor sorption mass uptake profile substantially as shown in FIG. 26.

[0322] Embodiment 128: The crystalline form of embodiment 50, wherein the pharmaceutically acceptable salt of Compound 1 is a choline salt.

[0323] Embodiment 129: The crystalline form of embodiment 128, wherein the choline salt is choline salt Form 1.

[0324] 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 about 10.4°±0.2°, 20.9°±0.2°, and 22.9°±0.2° 2-θ.

[0325] Embodiment 131: The crystalline form of embodiment 130, wherein the X-ray powder diffraction pattern comprises one or more additional peaks selected from peaks at about 14.0°±0.2°, 15.7°±0.2°, and 24.0°±0.2° 2-θ.

[0326] Embodiment 132: The crystalline form of embodiment 130 or embodiment 131, wherein 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.

[0327] Embodiment 133: The crystalline form of embodiment 132, wherein 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.

[0328] Embodiment 134: The crystalline form of any one of embodiments 50 or 128-133, wherein the pharmaceutically acceptable salt of Compound 1 is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 27.

[0329] Embodiment 135: The crystalline form of any one of embodiments 129-134, 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 onsets at about 23°C, 99°C, and 156°C.

[0330] Embodiment 136: The crystalline form of embodiment 135, having a differential scanning calorimetry thermogram substantially as shown in Figure 28.

[0331] Embodiment 137: The crystalline form of any one of embodiments 129-136, wherein the choline salt Form 1 is characterized by having a thermogravimetric analysis thermogram exhibiting a weight loss of about 8.8% over a temperature range from ambient temperature to about 200°C.

[0332] Embodiment 138: The crystalline form of embodiment 128, wherein the thermogravimetric analysis thermogram is substantially as shown in Figure 29.

[0333] Embodiment 139: A pharmaceutical composition comprising a crystalline form of compound 1 as defined in any one of embodiments 1 to 49 or a crystalline form of a pharmaceutically acceptable salt of compound 1 as defined in any one of claims 50 to 138, and a pharmaceutically acceptable carrier or excipient.

[0334] Embodiment 140: The pharmaceutical composition of embodiment 139, wherein the composition is in unit dosage form.

[0335] Embodiment 141: The pharmaceutical composition of embodiment 140, wherein the unit dosage form is a tablet.

[0336] Embodiment 142: A method for inhibiting MCL-1 in a patient, comprising administering to the patient a crystalline form of compound 1 as defined in any one of embodiments 1 to 49, or a crystalline form of a pharmaceutically acceptable salt of compound 1 as defined in any one of embodiments 50 to 138, or a pharmaceutical composition as defined in any one of embodiments 139 to 141.

[0337] Embodiment 143: A method for treating cancer in a patient, comprising administering to the patient a crystalline form of compound 1 as defined in any one of embodiments 1 to 49, or a crystalline form of a pharmaceutically acceptable salt of compound 1 as defined in any one of embodiments 50 to 138, or a pharmaceutical composition as defined in any one of embodiments 139 to 141.

[0338] Embodiment 144: Use of 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 treating cancer.

[0339] Embodiment 145: Use of 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 the manufacture of a medicament for treating cancer.

[0340] Embodiment 146: The method or use according to any one of embodiments 143 to 145, wherein the cancer is a blood cancer.

[0341] 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.

[0342] Embodiment 148: The method or use according to any one of embodiments 143 to 145, wherein the cancer is a solid malignant tumor.

[0343] Embodiment 149: The method or use according to any one of embodiments 143 to 145, wherein the cancer is triple-negative breast cancer, colon cancer, skin cancer, melanoma, ovarian cancer, renal cancer, small cell lung cancer, non-small cell lung cancer, lymphoma, leukemia, or metastatic soft tissue sarcoma.

[0344] Embodiment 150: The method or use according to any one of embodiments 142 to 149, wherein the method further comprises administering to the patient an additional therapeutic compound.

[0345] Embodiment 151: The method of embodiment 150, wherein the additional therapeutic compound is selected from docetaxel, sacituzumab govitecan, and gemcitabine.

[0346] Embodiment 152: A crystalline form of compound 1 as defined in any one of embodiments 1 to 49 or a crystalline form of a pharmaceutically acceptable salt of compound 1 as defined in any one of embodiments 50 to 138, or a pharmaceutical composition as defined in any one of embodiments 139 to 141, for use in a method for treating cancer.

[0347] Embodiment 153: The crystalline form of embodiment 152, wherein the cancer is a blood cancer.

[0348] Embodiment 154: The crystalline form of embodiment 152, wherein the cancer is relapsed / refractory multiple myeloma or relapsed / refractory myeloma.

[0349] Embodiment 155: The crystalline form of embodiment 152, wherein the cancer is triple-negative breast cancer, colon cancer, skin cancer, melanoma, ovarian cancer, renal cancer, small cell lung cancer, non-small cell lung cancer, lymphoma, leukemia, or metastatic soft tissue sarcoma.

[0350] Embodiment 156: The crystalline form of embodiment 152, wherein the cancer is a solid malignant tumor.

[0351] Embodiment 157: The crystalline form of any one of embodiments 152 to 156, wherein the method further comprises administering to the patient an additional therapeutic compound.

[0352] Embodiment 158: The crystalline form of embodiment 157, wherein the additional therapeutic compound is selected from docetaxel, sacituzumab govitecan, and gemcitabine.

[0353] Embodiment 159: A crystalline form of Compound 1 of any one of Embodiments 2-13, prepared by a process comprising: (1) contacting Compound 1 or a salt thereof with a solvent selected from acetone, ethyl acetate, an alcohol, methyl ethyl ketone, methyl isobutyl ketone, tetrahydrofuran, dichloromethane, and dibutyl ether, and mixtures of such solvents; and (2) isolating the solid product.

[0354] Embodiment 160: The crystalline form of embodiment 159, wherein the solvent comprises acetone.

[0355] Embodiment 161: The crystalline form of embodiment 159 or 160, wherein the process further comprises heating a mixture of Compound 1 or a salt thereof and a solvent.

[0356] Embodiment 162: The crystalline form of any one of embodiments 159 to 161, wherein the process further comprises drying the solid product.

[0357] Embodiment 163: The crystalline form of any one of embodiments 159 to 162, wherein the process further comprises washing and / or crystallizing the solid product with a second solvent selected from acetone, ethyl acetate, an alcohol, or a mixture of such solvents, and optionally drying.

[0358] Embodiment 164: A crystalline form of Compound 1 of any one of embodiments 2-13, prepared by a process comprising: (1) contacting Compound 1 or a salt thereof with a buffer to form a mixture; (2) adding a solvent selected from acetonitrile and an acetonitrile / water mixture to the mixture to form a slurry; (3) mixing the slurry; and (4) isolating the solid product.

[0359] Embodiment 165: The crystalline form of embodiment 164, wherein the pH of the buffer is about 2.

[0360] Embodiment 166: A crystalline form of Compound 1 according to any one of embodiments 2 to 13, prepared by a process comprising: (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.

[0361] Embodiment 167: A crystalline form of Compound 1 according to any one of embodiments 159-163 or 166, wherein the alcohol is selected from ethanol and isopropyl alcohol.

[0362] Embodiment 168: A crystalline form of compound 1 according to any one of embodiments 159-163 or 166-167, wherein the alcohol is ethanol. [Example]

[0363] Instruments: The following instruments were used to study the salts and polymorphs in the examples below.

[0364] X-ray powder diffraction (XRPD) analysis was performed using copper radiation (Cu Kα, γ = 1.541874) on a diffractometer (PANalytical XPERT-PRO, PANalytical BV, Almelo, Netherlands). Samples were uniformly spread on a zero-background sample plate. The generator was operated at a voltage of 45 kV and an amperage of 40 mA. The slits were a 0.02 rad solar slit, a 1.0° anti-scatter slit, and a divergence slit. Scans were performed from 2 to 40° 2-θ with a step size of 0.0167. Data analysis was performed using X'Pert Data Viewer V1.2d (PANalytical BV, Almelo, Netherlands).

[0365] Differential scanning calorimetry (DSC) was performed on a Q2000 (TA Instruments, New Castle, DE) by placing 1–5 mg of material in a Tzero standard aluminum pan with a lid (with or without a pinhole) and heating the sample at 10°C / min from approximately 20°C to over 250°C. The sample and reference pans were under a 50 mL / min nitrogen purge. Data analysis was completed using Universal Analysis 2000 Version 4.5A (TA Instruments, New Castle, DE).

[0366] Thermogravimetric analysis (TGA) was performed on either a Q5000 or Q500 (TA Instruments, New Castle, DE) by placing 1–10 mg of material in a weigh pan and heating the sample to 350°C at a rate of 10°C / min to evaluate the sample weight loss as a function of temperature. The sample and reference pans were under nitrogen purges at 60 and 40 mL / min, respectively. Data analysis was completed using Universal Analysis 2000 Version 4.5A (TA Instruments, New Castle, DE).

[0367] Thermogravimetric analysis (TA Discovery Series TGA and MS) with mass spectrometry was used to determine the weight loss of the samples as a function of temperature (TA Instruments, New Castle). Samples (approximately 2-5 mg) were placed in platinum pans and heated to 350 °C at a heating rate of 10-20 °C / min. The sample and reference pans were under a nitrogen purge of 25 mL / min and 10 mL / min, respectively. Data analysis was completed using TA Instruments Trios Software v.4.0 (TA Instruments, New Castle, DE).

[0368] Hygroscopicity was studied by dynamic water vapor sorption (DVS, TA Q5000 SA, TA Instruments, New Castle, DE, or DVS, DVS Intrinsic, Surface Measurement Systems, London, UK). Samples (2–20 mg) were placed in aluminum DVS pans and placed on the sample side of a twin-pan balance. Water sorption and desorption were studied as a function of relative humidity (RH) at 25°C. The relative humidity was increased from 40% RH to 90% RH in 10% RH increments, then decreased back to 0%, and the entire cycle of increasing from 0% RH to 90% RH and returning to 0% RH was repeated. Each RH increment had a 180-minute equilibration time unless the weight change was less than 0.002% in 30 minutes. Data analysis was performed using Universal Analysis 2000 Version 4.5A (TA Instruments, New Castle, DE) for TA DVS implementations and Microsoft Excel for SMS DVS implementations.

[0369] Proton nuclear magnetic resonance ( 1 H NMR spectra were collected on a Varian 400-MR 400 MHz instrument equipped with a 7620AS sample changer. Default proton parameters were as follows: spectral width: 14-2 ppm (6397.4 Hz), relaxation delay: 1 s, pulse: 45°C, acquisition time: 2.049 s, number of scans or repeats: 8, temperature: 25°C. Samples were prepared in dimethyl sulfoxide-d6 unless otherwise noted. Offline analysis was performed using MNova software.

[0370] Amounts: All amounts given in the following examples should be understood to be "about" the exact recited number, whether or not the word "about" is explicitly stated. For example, "600 mg" and "about 600 mg" should be understood to mean "about 600 mg."

[0371] Example 1. Examination of salts of Compound 1 Salts of Compound 1 were investigated as described below. [ka]

[0372] More specifically, salts of Compound 1 were investigated using the following basic coformers: NaOH, KOH, choline hydroxide, t-butylamine, TRIS, meglumine, L-lysine, benzathine, and diethylamine. Only four crystalline salts of Compound 1 were obtained: sodium, potassium, diethylamine, and choline. Co-crystal studies with nine acids (oxalic, fumaric, citric, adipic, glutaric, succinic, malic, mandelic, and glycolic) did not yield any crystalline material.

[0373] A. Sodium Salts - Overview The sodium salt of Compound 1 was first obtained during sodium bicarbonate washes of the Compound 1 reaction mixture. Investigation of the Na salt with approximately 25 organic solvents yielded four desolvated forms (Forms 1, 2, 3, and 4) and several potential solvates with the following solvents: MeCN, EtOH, IPA, acetone, THF, DCM, DMF, DMAc / water, and BuCN. All solvated forms were unstable and appeared to desolvate upon drying. Additionally, sodium salt Form 1 was obtained from polymorphic Form I of Compound 1 (discussed below) using NaOH.

[0374] B. Sodium Salt of Compound 1 - Form 1 ("Na Salt Form 1") Form 1 of the sodium salt of Compound 1 is a desolvated / dehydrated form initially obtained during the sodium bicarbonate wash of the Compound 1 reaction mixture. More specifically, the crude reaction mixture of Compound 1 in DCM described in Example 154 of WO 2019 / 222112 was concentrated in vacuo. The residual material was partitioned between ethyl acetate (approximately 300 mL) and saturated aqueous ammonium chloride (approximately 40 mL). The organic phase was washed twice with saturated aqueous ammonium chloride (approximately 40 mL each), then once with saturated aqueous sodium bicarbonate (approximately 40 mL), and then once with saturated brine (approximately 40 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo to yield a crude brown solid.

[0375] This crude solid was azeotroped once with dichloromethane (approximately 30 mL) and then suspended in acetonitrile (approximately 270 mL) and N,N-dimethylformamide (approximately 5 mL). The resulting mixture was warmed to approximately 80°C for approximately 1 hour, then filtered to collect the undissolved solid and washed with acetonitrile. The resulting cake was dried under air and then further dried in a vacuum oven at approximately 50°C for approximately 4 days to yield 6.72 g of Na salt Form 1. The XRPD pattern is shown in Figure 1. It is characterized by sharp reflections, indicating crystalline nature. Table 1a below lists the characteristic peaks. Table 1b shows an expanded peak list. It was observed that Na salt Form 1 tends to retain some residual solvent and water after drying. [Table 1a] [Table 1b]

[0376] The DSC thermogram of Na salt Form 1 is shown in Figure 2. The DSC data show two broad endothermic events with onsets at approximately 14 °C and approximately 83 °C, which are due to the loss of water and residual solvent, followed by a third endothermic event with onset at approximately 232 °C, which is due to melting of the salt. The TGA thermogram of Na salt Form 1 is shown in Figure 3. The TGA weight loss of approximately 4.2 wt% observed from ambient to approximately 200 °C corresponds to the loss of water (approximately 2.2 wt% by KF) and residual MeCN (approximately 0.5 equivalents by NMR). The DVS analysis of Na salt Form 1 is shown in Figure 4. This indicates that Na salt Form 1 is moderately hygroscopic, absorbing approximately 7.5 wt% water at 0% to 90% RH and approximately 25 °C. XRPD analysis of the sample after DVS showed no morphological changes.

[0377] C. Sodium Salt of Compound 1 - Form 2 ("Na Salt Form 2") Na salt Form 2 was obtained by slurrying Na salt Form 1 in dichloromethane and then drying the DCM solvate at about 50°C. The XRPD pattern of Na salt Form 2 is shown in Figure 5. It is characterized by sharp reflections, indicating crystallinity. Table 2a shows the characteristic peaks of Na salt Form 2. Table 2b shows an expanded peak list for Na salt Form 2. [Table 2a] [Table 2b]

[0378] The DSC thermogram of Na salt Form 2 is shown in Figure 6. The DSC data shows a broad endothermic event with an onset of approximately 21°C, followed by a broad exothermic event with an onset of approximately 109°C, and then an endothermic event with an onset of approximately 224°C due to melting of the salt. The TGA thermogram of Na salt Form 2 is shown in Figure 7. The sequential weight loss of approximately 4.8 wt% observed in the TGA from ambient to approximately 200°C most likely corresponds to loss of surface water.

[0379] D. Sodium Salt of Compound 1 - Form 3 ("Na Salt Form 3") Na salt Form 3 was obtained by slurrying Na salt Form 1 in isopropanol and then drying the IPA solvate at about 50°C. The XRPD pattern of Na salt Form 3 is shown in Figure 8. It is characterized by a mixture of sharp and broad reflections, indicating low crystallinity. Table 3a shows the characteristic peaks of Na salt Form 3. Table 3b shows an expanded peak list for Na salt Form 3. [Table 3a] [Table 3b]

[0380] A DSC thermogram of Na salt Form 3 is shown in Figure 9. The DSC data shows a broad endothermic event with an onset of approximately 19°C, followed by a second broad endothermic event with an onset of approximately 219°C, which is attributed to melting and decomposition of the salt. A TGA thermogram of Na salt Form 3 is shown in Figure 10. The continuous TGA weight loss of approximately 5.1 wt% observed from ambient to approximately 200°C most likely corresponds to the loss of residual solvent or water.

[0381] E. Sodium Salt of Compound 1 - Form 4 ("Na Salt Form 4") Na salt Form 4 was obtained by slurrying Na salt Form 1 in dimethylacetamide, followed by drying under vacuum at about 50°C. The XRPD pattern of Na salt Form 4 is shown in Figure 11. It is characterized by a mixture of sharp and broad reflections, indicating low crystallinity. Table 4a shows the characteristic peaks of Na salt Form 4. Table 4b shows an expanded peak list for Na salt Form 4. [Table 4a] [Table 4b]

[0382] F. Sodium Salt of Compound 1 - Form 5 ("Na Salt Form 5") Na salt Form 5 was obtained after drying the solvated form isolated from THF / water under vacuum at about 50°C. More specifically, about 500 mg of Compound 1 Form I (synthesis described below) was placed in a 20 mL vial with about 4 mL of THF and about 0.1 mL of water, followed by the addition of about 1.1 equivalents of NaOH. The mixture was stirred at about 50°C for about 30 minutes and then at ambient temperature for about 2 days. The isolated solid was analyzed by XRPD and then dried under vacuum at about 50°C for about 16 hours. The XRPD pattern of this solid after drying was different compared to that of the wet solid, suggesting that the solvated form was converted to the desolvated Na salt Form 5 after drying.

[0383] The XRPD pattern of Na salt Form 5 is shown in Figure 12. It is characterized by a mixture of sharp and broad reflections, indicating low crystallinity. Table 5a shows the characteristic peaks of Na salt Form 5. Table 5b shows an expanded peak list for Na salt Form 5. [Table 5a] [Table 5b]

[0384] A DSC thermogram of Na salt Form 5 is shown in Figure 13. The DSC data shows a broad endothermic event with an onset of about 29°C, followed by a second, smaller, broad endothermic event with an onset of about 143°C, and then an exotherm with an onset of about 198°C. A TGA thermogram of Na salt Form 5 is shown in Figure 14. The continuous TGA weight loss of about 4.2 wt% observed from ambient temperature to about 200°C most likely corresponds to the loss of residual solvent or water.

[0385] G. Potassium Salt of Compound 1—Form 1 (“K Salt Form 1”) and IPA Solvate (“K Salt IPA Solvate”) The potassium salt of Compound 1 was obtained during the 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 as an about 50% aqueous solution, sonication, and stirring at about 50° C. for about 30 minutes, and then at ambient temperature for about 3 days. The resulting solid was isolated 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) an IPA solvate, which converted to the desolvated Form 1 upon drying.

[0386] The XRPD pattern of K salt Form 1 is shown in Figure 15. It is characterized by sharp reflections, indicating crystallinity. Table 6a shows the characteristic peaks of K salt Form 1. Table 6b shows the expanded peak list for K salt Form 1. As shown in Figure 16 (top and bottom, respectively), the XRPD pattern of K salt Form 1 is very similar to that of Na salt Form 1. [Table 6a] [Table 6b]

[0387] The DSC thermogram of K salt Form 1 is shown in Figure 17. The DSC data show three broad endothermic events with onset temperatures of approximately 14 °C, approximately 182 °C, and approximately 233 °C, which are attributed to residual solvent or water loss, potential form transformation, and melting, respectively. The TGA thermogram of K salt Form 1 is shown in Figure 18. This TGA thermogram shows a continuous weight loss of approximately 4.2 wt% observed from ambient to approximately 200 °C, which most likely corresponds to residual solvent or water loss. The DVS analysis is shown in Figure 19. This indicates that K salt Form 1 is moderately hygroscopic, taking up approximately 11 wt% water at 0% to 90% RH and approximately 25 °C. K salt Form 1 rapidly absorbs water up to approximately 4 to 6 wt% at ambient conditions. XRPD analysis of the sample after DVS showed no morphological change.

[0388] The XRPD pattern of the K salt IPA solvate is shown in Figure 20. It is characterized by sharp reflections, indicating crystalline nature.

[0389] H. Potassium Salt-THF Solvate of Compound 1 ("K Salt THF Solvate") The K salt THF solvate was obtained during potassium salt formation in THF. More specifically, about 500 mg of polymorphic Form I of Compound 1 (preparation described below) and about 2 mL of THF were placed in a 20 mL vial, followed by the addition of about 1.1 equivalents of KOH as an approximately 50% aqueous solution. The mixture was stirred at about 50° C. for about 15 minutes and then at ambient temperature for about 16 hours. The resulting solid was isolated 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 shown in FIG. 21. It is characterized by sharp reflections, indicating crystalline nature.

[0390] I. Diethylamine Salt-Toluene Solvate of Compound 1 ("DEA Salt Toluene Solvate") DEA salt toluene solvate was prepared by adding approximately 1.1 molar equivalents of diethylamine to a slurry of Compound 1 Form I in 1 mL of EtOH at approximately 50°C, followed by cooling to ambient temperature. No crystalline solid formed. The mixture was concentrated to dryness. The residual oil was redissolved in toluene, followed by the slow addition of heptane as an antisolvent. After stirring overnight at ambient temperature, a crystalline solid formed. XRPD analysis indicated that this wet solid was most likely a toluene solvate, which converted to the desolvated, disordered form (Form I) upon drying. The XRPD pattern of the DEA salt toluene solvate is shown in Figure 22. It is characterized by sharp reflections, indicating crystallinity.

[0391] J. Diethylamine Salt of Compound 1 - Form 1 ("DEA Salt Form 1") As noted above, DEA salt Form 1 is a desolvated form obtained after drying of the DEA salt toluene solvate. The XRPD pattern of DEA salt Form 1 is shown in Figure 23. It is characterized by a mixture of sharp and broad reflections, indicating low crystallinity. Table 7a shows the characteristic peaks of DEA salt Form 1. Table 7b shows an expanded peak list for DEA salt Form 1. [Table 7a] [Table 7b]

[0392] The DSC thermogram of DEA salt Form 1 is shown in Figure 24. The DSC data show a small, broad endotherm with an onset of approximately 17°C, followed by an endotherm with an onset of approximately 145°C. The TGA thermogram of DEA salt Form 1 is shown in Figure 25. The TGA weight loss of approximately 8.4 wt% observed from ambient to approximately 170°C corresponds to dissociation of the salt. The DVS analysis of DEA salt Form 1 is shown in Figure 26. This indicates that DEA salt Form 1 is moderately hygroscopic, absorbing approximately 5.5 wt% water at 0% to 90% RH and approximately 25°C. However, XRPD analysis after DVS showed that the sample did not exhibit any morphological changes.

[0393] K. Choline Salt of Compound 1 - Form 1 ("Choline Salt Form 1") Choline salt Form 1 was obtained from a slurry in an EtOAc / heptane solvent mixture. More specifically, a 4 mL vial was charged with Compound 1 Form I (approximately 45 mg) and approximately 0.5 mL of EtOH, followed by the addition of approximately 1.1 equivalents of choline hydroxide (as an approximately 45% solution in MeOH) to obtain a solution. The solution was concentrated to dryness. EtOH / heptane (approximately 1.25 mL of a 3:2 mixture) was added to the residual oil, followed by stirring at approximately 50°C for approximately 1 hour and then at ambient temperature. The resulting solid was isolated by filtration and dried under vacuum at approximately 50°C for approximately 24 hours. No change in morphology was observed before and after drying. The XRPD pattern of choline salt Form 1 is shown in Figure 27. It is characterized by sharp reflections, indicating crystalline nature. Table 8a shows the characteristic peaks of choline salt Form 1. Table 8b shows an expanded peak list for choline salt Form 1. [Table 8a] [Table 8b]

[0394] A DSC thermogram of choline salt Form 1 is shown in Figure 28. The DSC data shows three broad endothermic events with onset temperatures of about 23°C, about 99°C, and about 156°C, which are attributed to residual solvent or water loss and melting, respectively. A TGA thermogram of choline salt Form 1 is shown in Figure 29. The TGA thermogram shows a gradual weight loss of a total of about 8.8 wt% observed from ambient temperature to about 200°C, which most likely corresponds to residual solvent or water loss.

[0395] Example 2. Examination of polymorphism of Compound 1 A polymorphic study of Compound 1 was carried out as described below. [ka]

[0396] More specifically, the amorphous form of Compound 1 was investigated. Hydration in MeCN / water at ambient conditions and at 50° C. was also investigated, but no hydrated forms were obtained. Specific polymorphs were also obtained from one or more of the salts discovered above.

[0397] Based on these studies, four unsolvated / desolvated forms were discovered, eight solvates with unique XRPD patterns were identified, and eight isostructural solvated forms were discovered with XRPD patterns nearly identical to Form I but showing some peak shifts and occasionally small additional peaks. Single-crystal X-ray analysis showed that crystals isolated from MeCN, acetone, and EtOH showed nearly identical lattice parameters.

[0398] A. Amorphous Form of Compound 1 The amorphous form of Compound 1 can be prepared according to WO 2019 / 222112. The amorphous form of Compound 1 was also prepared by converting the Na salt Form 1 of Compound 1 to the amorphous free acid in a DCM / water system adjusted to about pH 5.5 with HCl. The organic layer was evaporated to dryness using a rotary evaporator. The XRPD pattern of amorphous Compound 1 is shown in Figure 30 and is characterized by an amorphous halo.

[0399] B. Compound 1 - Polymorphic Form I (“Form I”) Method 1: Crude Compound 1 (600 mg), which can be prepared according to WO 2019 / 222112, was suspended in acetone (20 mL) and heated to approximately 60°C in a thermowell. After a solution was observed, the contents were filtered through a 0.45 μm syringe filter into a clean flask and heated to approximately 60°C. Once this temperature was reached, the heat was turned off. The contents were allowed to cool to ambient temperature with stirring. After reaching ambient temperature, the contents were aged for approximately 24 hours. The solid was collected by vacuum filtration and washed twice with acetone (1.2 mL). The solid was dried under reduced pressure at approximately 70°C for approximately 24 hours to obtain Form I.

[0400] Method 2: Crude Compound 1 (about 3 g), which can be prepared according to WO 2019 / 222112, was dissolved in EtOAc (about 24 mL) at about 60° C., followed by the slow addition (over about 2 hours) of EtOH (about 36 mL), and then cooled to about 20° C. over about 4 hours. The resulting slurry was stirred at about 20° C. for about 20 hours. The solid was isolated by vacuum filtration, washed with 2:3 EtOAc / EtOH (about 6 mL), and dried under vacuum at about 60° C. with a nitrogen sweep for about 24 hours to provide Form I (about 2.6 g).

[0401] Method 3: Crude Compound 1 was crystallized in acetone to remove the Z-isomer of Compound 1, followed by crystallization from EtOAc / EtOH (2:3) to give purified Form I.

[0402] Method 4: Form I was also obtained from a slurry experiment of the Na salt of Compound 1. For example, about 10 mg of Compound 1 Na salt Form 1 and about 2 mL of pH 2 sodium phosphate buffer (50 mM sodium phosphate monobasic 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 stir bar. The solid was isolated 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 at pH 2 using various acids for pH adjustment, including HCl, phosphoric acid, MSA, and p-TSA.

[0403] Method 5: Form I was also obtained by slurrying amorphous Compound 1 (about 20-30 mg) in about 0.5 mL of the selected solvent from EtOH, IPA, acetone, MEK, MIBK, THF, DCM, and dibutyl ether at ambient temperature for up to about 2 weeks. The isolated wet solid was an isostructural solvate form, which was converted to Form I after vacuum drying at about 50-100°C. Form I was observed to have a tendency to retain non-stoichiometric amounts of residual solvent or water due to void volume in the crystal lattice.

[0404] Slurry Method: Competitive slurries of Form I in EtOH with the other polymorphic forms discussed and prepared below (i.e., Form II, Form III, and Form IV) showed complete conversion to Form I in all cases, suggesting the greater stability of Form I compared to all other unsolvated / desolvated forms under these conditions.

[0405] Characterization: The XRPD pattern of Form I is shown in Figure 31. It is characterized by sharp reflections, indicating crystallinity. Table 9a shows the characteristic peaks of Form I. Table 9b shows the expanded peak list for Form I. [Table 9a] [Table 9b]

[0406] A DSC thermogram of Form I is shown in Figure 32. The DSC data shows an endothermic event with an onset temperature of approximately 180°C. A TGA thermogram of Form I is shown in Figure 33. A progressive weight loss of approximately 1.0% is observed from ambient temperature to approximately 170°C, which most likely corresponds to residual solvent.

[0407] DVS analysis (Figure 34) shows that Form I is slightly hygroscopic, absorbing about 1.4 wt% water at about 25°C and about 0% to 90% RH. XRPD analysis of the sample after DVS showed no change in form.

[0408] The single crystal structure of Form I was solved, confirming the presence of one molecule of Compound 1 and half a molecule of water. However, the water molecule is disordered at and around the two-fold axis. No intermolecular hydrogen bonds are observed. The N2 hydrogen forms intramolecular hydrogen bonds with O4 and O5, and water appears to form no hydrogen bonds. The orthorhombic lattice dimensions at room temperature are shown in Table 9c, and a diagram of the single crystal structure is shown in Figure 35. The calculated XRPD pattern is consistent with the experimental XRPD pattern of Form I. [Table 9c]

[0409] C. Compound 1 - Polymorphic Form II (“Form II”) Method 1: Form II is a desolvated form. Form II was prepared by adding a solution of about 1.1 equivalents of HCl in about 0.5 mL of water to a slurry of about 100 mg of the Na salt Form 1 of Compound 1 in about 0.5 mL of MeCN. The slurry was stirred at ambient conditions for about 16 hours. The resulting solid was isolated by filtration and dried under vacuum at about 50° C. for about 24 hours to obtain Form II.

[0410] Method 2: Form II was also obtained after drying the MeCN solvate of Compound 1 (prepared below) under vacuum at about 50°C.

[0411] Characterization: The XRPD pattern of Form II is shown in Figure 36. It is characterized by sharp reflections, indicating crystalline nature. Table 10a shows the characteristic peaks of Form II. Table 10b shows the expanded peak list for Form II. [Table 10a] [Table 10b]

[0412] The DSC thermogram of Form II is shown in Figure 37. The DSC data show an endothermic event with an onset temperature of approximately 163°C, which is attributed to the melting of Form II. The TGA thermogram of Form II is shown in Figure 38. A progressive weight loss of approximately 0.6% was observed from ambient temperature to approximately 210°C, which most likely corresponds to residual solvent. DVS analysis (Figure 39) indicates that Form II is slightly hygroscopic, absorbing up to approximately 1.1 wt% water at approximately 25°C and from approximately 0% to 90% RH. XRPD analysis of the sample after DVS showed no morphological change.

[0413] D. Compound 1 - Polymorphic Form III (“Form III”) Method 1: Form III is a desolvated form. Form III was prepared in a co-crystal study 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 (approximately 60-70 mg) and approximately 1 mL of MeOH, followed by the addition of approximately 1.1 equivalents of coformer. This was followed by stirring at approximately 50°C for approximately 30 minutes and then at ambient temperature for approximately 16 hours. The solid was isolated by filtration and dried under vacuum at approximately 50°C to obtain Form III.

[0414] 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 shown in Figure 40. It is characterized by sharp reflections, indicating crystalline nature. Table 11a shows the characteristic peaks of Form III. Table 11b shows the expanded peak list for Form III. [Table 11a] [Table 11b]

[0415] The DSC thermogram of Form III is shown in Figure 41. The DSC data show three endothermic events with onset temperatures of about 20°C, about 133°C, and about 153°C. The TGA thermogram of Form III is shown in Figure 42. The TGA thermogram shows a weight loss of about 2.9% below about 90°C, a weight loss of about 1.1% between about 90 and 175°C, and a weight loss of about 1.6% between about 175 and 225°C, most likely corresponding to residual solvent. DVS analysis (Figure 43) shows that Form III is moderately hygroscopic, absorbing up to about 5% by weight of water at about 25°C and about 0% to 90% RH. XRPD analysis of Form III after DVS showed no morphological change.

[0416] E. Compound 1 - Polymorphic Form IV (“Form IV”) Form IV is a desolvated form and was 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 shown in Figure 44. It is characterized by sharp reflections, indicating crystallinity. Table 12a shows the characteristic peaks of Form IV. Table 12b shows the expanded peak list for Form IV. [Table 12a] [Table 12b]

[0417] A DSC thermogram of Form IV is shown in Figure 45. The DSC data shows two endothermic events with onset temperatures of about 119°C and about 166°C. A TGA thermogram of Form IV is shown in Figure 46. The TGA thermogram shows a continuous weight loss of about 0.6% below about 200°C, which most likely corresponds to residual solvent.

[0418] F. Compound 1-MeCN Solvate 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 Figure 47. It is characterized by sharp reflections, indicating crystallinity.

[0419] G. Compound 1-MeOH Solvate 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 Figure 48. It is characterized by sharp reflections, indicating crystallinity.

[0420] H. Compound 1 - EtOAc solvate The EtOAc solvate of Compound 1 was obtained by slurrying Form I with EtOAc. The XRPD pattern of the EtOAc solvate is shown in Figure 49. It is characterized by sharp reflections, indicating crystalline nature. After drying at about 50°C for about 24 hours, the EtOAc solvate was partially converted to the latent desolvated form, as shown in Figure 50.

[0421] I. Compound 1-MeTHF solvate 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 shown in Figure 51. It is characterized by sharp reflections, indicating crystalline nature.

[0422] J. Compound 1 - Toluene Solvate 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 shown in Figure 52. It is characterized by sharp reflections, indicating crystalline nature. The toluene solvate was converted to the desolvated disordered form after drying under vacuum at about 50°C.

[0423] K. Compound 1-nBuOAc solvate 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 shown in Figure 53. It is characterized by sharp reflections, indicating crystalline nature. The n-BuOAc solvate was converted to the desolvated disordered form after drying under vacuum at about 50°C.

[0424] L. Compound 1-MTBE solvate 1 The first MTBE solvate ("MTBE Solvate 1") was obtained by slurrying Form I in MTBE. The XRPD pattern of MTBE Solvate 1 is shown in Figure 54. It is characterized by sharp reflections, indicating crystalline nature.

[0425] M. Compound 1-MTBE solvate 2 A second MTBE solvate ("MTBE solvate 2") was obtained by slurrying Form I in MTBE. The XRPD pattern of MTBE solvate 2 is shown in Figure 55. It is characterized by sharp reflections, indicating crystalline nature.

[0426] N. Compound 1-isopropanol hemisolvate The isopropanol hemisolvate of Compound 1 was obtained by dissolving Form I in EtOAc (about 24 mL) at about 65° C. EtOAc / iPrOH (4:1, about 10 mL) was added, followed by the slow addition (over about 2.5 hours) of iPrOH (about 46 mL). The reaction was cooled to about 20° C. over about 4 hours, and then cooled to about 0° C. over about 1.5 hours. The resulting slurry was stirred at about 0° C. for about 4 hours. The solid was isolated by vacuum filtration, washed with EtOAc / iPrOH (1:2, about 12 mL), and dried under vacuum at about 65° C. with a nitrogen sweep for about 45 hours to obtain Compound 1-isopropanol hemisolvate. The XRPD pattern of the isopropanol hemisolvate is shown in Figure 56. It is characterized by sharp reflections, indicating crystalline nature.

[0427] Example 3. Isostructural solvated forms of Form I Slurrying Form I of Compound 1 in several solvents, including acetone, MEK, MIBK, butyl ether (BuO), THF, DCM, EtOH, and IPA, yielded solids with XRPD patterns very similar to Form I but showing some peak shifts and small additional peaks. This suggests the formation of isostructural solvate forms (Figures 57 and 58). These isostructural solvates retain non-stoichiometric amounts of residual solvent even after drying. However, extensive drying at elevated temperatures and particle size reduction (by grinding and milling) gives Form I, which may still retain small amounts of residual solvent.

[0428] Single crystal X-ray analysis of the EtOH and acetone solvates yielded unit cell dimensions similar to Form I (Table 13), confirming the isostructural nature of these solvates with Form I, which is somewhat hygroscopic and retains some water within the void volume of the crystal lattice even after drying. [Table 13]

[0429] equivalent weight The foregoing written specification is considered sufficient to enable one skilled in the art to practice the embodiments. The foregoing description and examples detail certain embodiments and set forth the best mode contemplated by the inventors. However, it will be understood that no matter how detailed the above appears in text, the embodiments can be practiced in many ways and should be construed in accordance with the appended claims and any equivalents thereof.

Claims

1. Compound 1: 【Chemistry 14】 Crystalline form of.

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

3. 3. The crystalline form of claim 1 or 2, wherein 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-theta.

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

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

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

8. 10. The crystalline form of claim 1 or 7, wherein 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-theta.

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

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

11. 11. The crystalline form of claim 10, wherein the X-ray powder diffraction pattern comprises one or more additional peaks selected from peaks at 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°, 26.7°±0.2°, and 27.9°±0.2° 2-θ.

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

13. 13. The crystalline form of claim 1 or 12, wherein 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-theta.

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

15. 15. The crystalline form of claim 13 or 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. 16. The crystalline form of claim 15, wherein 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-θ.

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

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

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

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

21. 21. The crystalline form of claim 20, wherein 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-θ.

22. A pharmaceutical composition comprising a crystalline form of compound 1 according to any one of claims 1 to 21, and a pharma- ceutically acceptable carrier or excipient.

23. A method for inhibiting MCL-1 in a patient comprising administering to said 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. Compound 1: 【Chemistry 15】 A crystalline form of a pharma- ceutically acceptable salt of.

25. 25. The crystalline form of claim 24, wherein the pharma- ceutically acceptable salt of Compound 1 is a sodium salt, and 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.

26. 25. The crystalline form of claim 24, wherein the pharma- ceutically 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 about 7.6°±0.2°, 8.2°±0.2°, and 12.7°±0.2° 2-θ.

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