Crystalline forms of Menin inhibitors

Abstract

Described herein are crystalline forms of (S)-4-methyl-5-((4-((2-(methylamino)-6-(2, 2, 2-trifluoroethyl) thieno [2, 3-d] pyrimidin-4-yl) amino) piperidin-1-yl) methyl)-1-(2-(4-(methylsulfonyl) piperazin-1-yl) propyl)-1H-indole-2-formonitrile or a solvate thereof.

Description

Cross-references

[0001] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 514,089, filed July 17, 2023, and U.S. Provisional Application Serial No. 63 / 655,384, filed June 3, 2024, each of which is incorporated herein by reference in its entirety. Background Technology

[0002] Mixed lineage leukemia (MLL) proteins are histone methyltransferases crucial for the epigenetic regulation of gene transcription. Many acute leukemias, including acute myeloblastic leukemia (AML), acute lymphoblastic leukemia (ALL), and mixed lineage leukemia (MLL), are characterized by the presence of chimeric MLL fusion proteins, which arise from chromosomal translocations of the MLL gene located at the q23 band of chromosome 11 (11q23). Chimeric MLL fusion proteins retain approximately 1,400 amino acids from the N-terminus of MLL but fuse with one of approximately 80 chaperone proteins (e.g., AF4, AF9, ENL, AF10, ELL, AF6, AF1p, GAS7). Lacking the original histone methyltransferase activity of the C-terminus of MLL, MLL fusion proteins acquire the ability to regulate the transcription of multiple oncogenes (including HOX and MEIS1), leading to increased cell proliferation and decreased cell differentiation, ultimately resulting in leukemia.

[0003] The menin protein, encoded by the multiple endocrine neoplasia (MEN) gene, is a universally expressed nuclear protein involved in interactions with DNA processing and repair proteins, chromatin modification proteins, and various transcription factors (Agarwal et al., Horm. Metab. Res. 2005, 37(6), 369-374). Binding of menin to the N-terminus of the MLL fusion protein is essential for the observed oncogenic activity of the MLL fusion protein. This binding has been shown to constitutively upregulate the expression of the HOX and MEIS1 oncogenes and impair hematopoietic cell proliferation and differentiation, leading to leukemia. Given that menin has been shown to function as a universal oncogenic cofactor in MLL-related leukemia, the interaction between menin and the MLL fusion protein and MLL represents a potential chemotherapeutic target. Summary of the Invention

[0004] In one aspect, this paper describes the crystalline form of (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carboxynitrile (compound 1) or its solvates.

[0005] In one embodiment of the crystalline form of (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methanesulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carboxynitrile (compound 1) or a solvate thereof, the crystalline form of (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methanesulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carboxynitrile (compound 1) or a solvate thereof is form 1, which has at least one of the following properties:

[0006] (a) and Figure 1 The X-ray powder diffraction (XRPD) patterns shown are essentially similar to those shown.

[0007] (b) An XRPD spectrum having at least three characteristic peaks selected from the following: 4.1° 2θ, 5.4° 2θ, 6.6° 2θ, 8.2° 2θ, 9.5° 2θ, 12.3° 2θ, 13.1° 2θ, 13.9° 2θ, 15.9° 2θ, 16.4° 2θ, 17.0° 2θ, 17.5° 2θ, 19.7° 2θ, and 22.6° 2θ;

[0008] (c) and Figure 2 The differential scanning calorimetry (DSC) thermograms shown are essentially similar to those of the DSC thermograms shown.

[0009] (d) Endothermic DSC thermograms with an onset point of about 136 °C and / or a peak value of about 149 °C;

[0010] (e) and Figure 3 The thermogravimetric analysis (TGA) curves shown are essentially similar to those of the thermogravimetric analysis (TGA) curves; or

[0011] (f) Their combinations.

[0012] In one embodiment of the crystalline form of (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carboxynitrile (compound 1) or a solvate thereof, the crystalline form of (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carboxynitrile (compound 1) or a solvate thereof is form 2, which has at least one of the following properties:

[0013] (a) and Figure 4 The X-ray powder diffraction (XRPD) patterns shown are essentially similar to those shown.

[0014] (b) An XRPD spectrum having at least three characteristic peaks selected from the following: 3.8° 2θ, 5.6° 2θ, 6.4° 2θ, 7.1° 2θ, 8.8° 2θ, 9.9° 2θ, 11.9° 2θ, and 14.8° 2θ; or

[0015] (c) Their combination.

[0016] In one embodiment of the crystalline form of (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carboxynitrile (compound 1) or a solvate thereof, the crystalline form of (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carboxynitrile (compound 1) or a solvate thereof is form 3, which has at least one of the following properties:

[0017] (a) and Figure 5 The X-ray powder diffraction (XRPD) patterns shown are essentially similar to those shown.

[0018] (b) An XRPD spectrum having at least three characteristic peaks selected from the following: 7.9° 2θ, 9.5° 2θ, 11.0° 2θ, 15.7° 2θ, 16.5° 2θ, 18.0° 2θ, 19.0° 2θ and 21.9° 2θ;

[0019] (c) and Figure 6A The differential scanning calorimetry (DSC) thermograms shown are essentially similar to those of the DSC thermograms shown.

[0020] (d) Endothermic DSC thermograms with an onset point of about 117 °C and / or a peak value of about 135 °C;

[0021] (e) and Figure 6B The thermogravimetric analysis (TGA) curves shown are essentially similar to those of the thermogravimetric analysis (TGA) curves; or

[0022] (f) Their combinations.

[0023] In one embodiment of the crystalline form of (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carboxynitrile (compound 1) or a solvate thereof, the crystalline form of (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carboxynitrile (compound 1) or a solvate thereof is form 4, which has at least one of the following properties:

[0024] (a) and Figure 7 The X-ray powder diffraction (XRPD) patterns shown are essentially similar to those shown.

[0025] (b) An XRPD spectrum having at least three characteristic peaks selected from the following: 8.1° 2θ, 9.4° 2θ, 10.8° 2θ, 13.5° 2θ, 15.7° 2θ, 16.3° 2θ, 17.5° 2θ, 18.3° 2θ, 18.7° 2θ, 20.1° 2θ, 21.6° 2θ, 21.8° 2θ, 25.2° 2θ, and 25.7° 2θ;

[0026] (c) and Figure 8 The differential scanning calorimetry (DSC) thermograms shown are essentially similar to those of the DSC thermograms shown.

[0027] (d) A DSC thermogram showing a first endothermic reaction with an onset point of about 127°C and / or a peak value of about 138°C and an optional second endothermic reaction with an onset point of about 45°C and / or a peak value of about 75°C; or

[0028] (e) Their combination.

[0029] In another embodiment of the crystalline form of (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carboxynitrile (compound 1) or a solvate thereof, the crystalline form of (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carboxynitrile (compound 1) or a solvate thereof is form 5, which has at least one of the following properties:

[0030] (a) and Figure 9 The X-ray powder diffraction (XRPD) patterns shown are essentially similar to those shown.

[0031] (b) An XRPD spectrum having at least three characteristic peaks selected from the following: 7.9° 2θ, 8.5° 2θ, 9.6° 2θ, 11.1° 2θ, 15.8° 2θ, 16.9° 2θ, 18.4° 2θ, 19.1° 2θ, 22.1° 2θ, 25.5° 2θ, and 27.4° 2θ;

[0032] (c) and Figure 10 The differential scanning calorimetry (DSC) thermograms shown are essentially similar to those of the DSC thermograms shown.

[0033] (d) An endothermic DSC thermogram with an onset point of approximately 122°C and / or a peak temperature of approximately 132°C; or

[0034] (e) and Figure 11 The thermogravimetric analysis (DVS) curves shown are essentially similar to those of the thermogravimetric analysis (DVS) curves; or

[0035] (f) Their combinations.

[0036] On the other hand, this article describes a pharmaceutical composition comprising (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carboxynitrile or a solvation thereof in crystalline form and a pharmaceutically acceptable excipient.

[0037] On the other hand, this article describes a method for treating a disease or condition in a subject, comprising administering to the subject a therapeutically effective amount of the (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methanesulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carboxynitrile or a solvation thereof as described herein, wherein the disease or condition includes leukemia, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), hematologic malignancies, myelodysplastic syndromes, myelodysplastic / myeloproliferative neoplasms, solid tumors, prostate cancer, breast cancer, liver cancer, brain tumors, or diabetes.

[0038] In some embodiments, the method of inhibiting the interaction of menin with one or more of the MLL1, MLL2, MLL fusion proteins, and MLL partial tandem repeats includes contacting menin with an effective amount of the crystalline form of (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carboxynitrile or a solvate thereof.

[0039] Incorporate by reference

[0040] To the extent applicable and relevant, all publications, patents and patent applications mentioned in this specification are incorporated herein by reference to the extent that each individual publication, patent or patent application is specifically and individually indicated to be incorporated by reference. Attached Figure Description

[0041] Figure 1 The XRPD spectrum of crystalline (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thiopheno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carboxynitrile (compound 1) or its solvate form 1 is shown.

[0042] Figure 2The DSC thermograms of crystalline (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carboxynitrile (compound 1) or its solvate form 1 are shown.

[0043] Figure 3 TGA curves of crystalline (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carboxynitrile (compound 1) or its solvate form 1 are shown.

[0044] Figure 4 The XRPD spectrum of crystalline (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carboxynitrile (compound 1) or its solvate form 2 is shown.

[0045] Figure 5 The XRPD spectrum of crystalline (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thiopheno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carboxynitrile (compound 1) or its solvate form 3 is shown.

[0046] Figures 6A-6B The DSC thermograms of crystalline (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thiopheno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carboxynitrile (compound 1) or its solvate form 3 are shown. Figure 6A ) and TGA curve ( Figure 6B (The curve marked with an asterisk).

[0047] Figure 7The XRPD spectrum of crystalline (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thiopheno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carboxynitrile (compound 1) or its solvate form 4 is shown.

[0048] Figure 8 The DSC thermograms of crystalline (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carboxynitrile (compound 1) or its solvate form 4 are shown.

[0049] Figure 9 The XRPD spectrum of crystalline (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thiopheno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carboxynitrile (compound 1) or its solvate form 5 is shown.

[0050] Figure 10 The DSC thermograms of crystalline (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carboxynitrile (compound 1) or its solvate form 5 are shown.

[0051] Figure 11 The DVS curves of crystalline (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thiopheno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carboxynitrile (compound 1) or its solvate form 5 are shown. Detailed Implementation

[0052] Specific terms

[0053] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains. It should be understood that the general description above and the detailed description below are exemplary and explanatory only, and not intended to limit any of the claimed subject matter. In this application, the singular is used to include the plural unless expressly stated otherwise. It must be noted that, as used in this specification and the appended claims, the singular forms “a” and “the” include the plural referents unless the context clearly specifies otherwise. In this application, the use of “or” means “and / or” unless expressly stated otherwise. Furthermore, the use of the term “comprising” and other forms such as “including” is not restrictive. The term “comprising” (and related terms such as “containing” or “having” or “including”) is not intended to exclude the following: in some other embodiments, for example, embodiments of any of the material compositions, compositions, methods, or processes described herein may “consist of the described features” or “consist substantially of the described features.” When referring to a number or range of values, the term “approximately” means that the number or range of values ​​mentioned is an approximation within experimental variability (or within statistical experimental error), and therefore the number or range of values ​​may vary between 1% and 15% of the specified number or range of values.

[0054] The chapter headings used herein are for organizational purposes only and should not be construed as limiting the subject matter. All references or portions thereof cited in this application, including but not limited to patents, patent applications, articles, books, manuals, and monographs, are expressly incorporated herein by reference in their entirety.

[0055] As used herein, the terms “acceptable” or “pharmaceutically acceptable” with respect to formulations, compositions or ingredients mean that they do not have a lasting harmful effect on the overall health of the subject receiving treatment, or do not eliminate the biological activity or properties of the compound, and are relatively non-toxic.

[0056] As used herein, “improvement” of symptoms of a particular disease, condition or symptom by application of a particular compound or pharmaceutical composition means any reduction in severity, delay in onset, slowing of progression or shortening of duration attributable to or related to the application of the compound or composition, whether permanent or temporary, lasting or transient.

[0057] As used herein, the terms “combined administration” and the like are intended to cover the administration of selected therapeutic agents to a single patient and are intended to include treatment regimens in which the agents are administered via the same or different routes of administration or at the same or different times.

[0058] As used herein, the term "effective amount" or "therapeutic effective amount" refers to an adequate amount of a drug or compound administered that will, to a certain extent, alleviate one or more of the symptoms of the disease or condition being treated. The result may be a reduction and / or relief of the signs, symptoms, or cause of the disease, or any other desired alteration of the biological system. For example, an "effective amount" for therapeutic use is the amount of composition (containing compounds as disclosed herein) required to provide a clinically significant reduction in the symptoms of a disease without excessively producing adverse side effects. In any specific case, techniques such as dose-escalation studies may be used to determine the appropriate "effective amount." The term "therapeutic effective amount" includes, for example, a prophylactic effective amount. The "effective amount" of the compounds disclosed herein is the amount that effectively achieves the desired pharmacological effect or therapeutic improvement without excessively producing adverse side effects. It should be understood that the "effective amount" or "therapeutic effective amount" may vary from subject to subject due to variations in the metabolism of compound 1, the subject's age, weight, general condition, the condition being treated, the severity of the condition being treated, and the prescribing physician's judgment. By way of example only, a therapeutic effective amount may be determined through dose-escalation clinical trials.

[0059] The term "enhancement" refers to increasing or prolonging the potency or duration of a desired effect. For example, "enhancement" of a therapeutic agent means increasing or prolonging its potency or duration of action during the treatment of a disease, condition, or symptom. As used herein, "enhancing effective amount" refers to an amount sufficient to enhance the therapeutic effect of the agent in treating a disease, condition, or symptom. When used on a patient, the effective amount for this purpose will depend on the severity and progression of the disease, condition, or symptom, prior treatments, the patient's health status and response to the medication, and the judgment of the treating physician.

[0060] As used herein, the term "preventative effective dose" refers to the amount of a composition administered to a patient that will, to a certain extent, alleviate one or more of the symptoms of the disease, condition, or ailment being treated. In such preventative applications, this dose may depend on the patient's health status, weight, etc. As an example, such a preventative effective dose can be determined through dose-escalation clinical trials.

[0061] As used herein, the term "subject" refers to an animal that is the object of treatment, observation, or experimentation. By way of example only, a subject can be, but is not limited to, mammals, including but not limited to humans.

[0062] As used herein, the term "target activity" refers to a biological activity that can be modulated by selective modulators. Some exemplary target activities include, but are not limited to, binding affinity, signal transduction, enzyme activity, tumor growth, inflammation or inflammation-related processes, and improvement of one or more symptoms associated with a disease or symptom.

[0063] As used herein, the term "treatment" includes reducing, alleviating, or improving symptoms of a disease or condition; preventing the development of new symptoms; improving or preventing underlying metabolic causes of symptoms; inhibiting a disease or condition (e.g., preventing the development of a disease or condition); relieving a disease or condition; causing the remission of a disease or condition; alleviating the condition caused by a disease or condition; or terminating the symptoms of a disease or condition. The term "treatment" includes, but is not limited to, preventive and / or therapeutic treatments.

[0064] Compound 1

[0065] In one embodiment, (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carboxynitrile (compound 1) or a solvation thereof. “Compound 1” or “(S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carboxynitrile” refers to a free base compound having the following structure:

[0066] .

[0067] Compound 1 is a menin inhibitor and inhibits the menin-MLL interaction.

[0068] In some embodiments, this document describes the crystalline form of compound 1 or its solvates. The solvate contains stoichiometric or non-stoichiometric amounts of solvent and is formed in combination with pharmaceutically acceptable solvents such as water, ethanol (EtOH), methanol (MeOH), tert-butyl methyl ether (MTBE), diisopropyl ether, ethyl acetate (EtOAc), isopropyl acetate, isopropanol (IPA), methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), acetone, nitromethane, tetrahydrofuran (THF), dichloromethane (DCM), dioxane, heptane, toluene, anisole, acetonitrile (ACN), etc. In some embodiments, solvents of, but not limited to, three classes are used to form the solvate. In some embodiments, solvents of, but not limited to, two classes are used to form the solvate. The solvent classes are defined, for example, by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), “Impurities: Residual Solvents Guidance Q3C(R6)” (October 2016). When the solvent is water, a hydrate is formed; or when the solvent is an alcohol (such as EtOH or IPA), an alcohol is formed.

[0069] In other embodiments, compound 1 or its solvates are prepared in various forms, including but not limited to amorphous phases and crystalline forms.

[0070] While not intended to be bound by any particular theory, certain solid forms are characterized by physical properties (e.g., stability, solubility, and dissolution rate) suitable for pharmaceutical and therapeutic dosage forms. Furthermore, while not wishing to be bound by any particular theory, certain solid forms are characterized by physical properties (e.g., density, compressibility, hardness, morphology, pyrolysis, viscosity, solubility, hygroscopicity, electrical properties, thermal behavior, solid-state reactivity, physical stability, and chemical stability) that affect specific processes (e.g., yield, filtration, washing, drying, grinding, mixing, tableting, flowability, dissolution, formulation, and lyophilization), thus making certain solid forms suitable for the preparation of solid dosage forms. Such properties can be determined using specific analytical chemistry techniques, including solid-state analysis techniques (e.g., X-ray diffraction, microscopy, spectroscopy, and thermal analysis), as described herein.

[0071] Crystalline form

[0072] The identification and selection of solid forms for pharmaceutical compounds is complex because variations in solid form can affect a wide range of physical and chemical properties, potentially offering benefits or drawbacks in important drug characteristics such as processing (e.g., flowability, bulk density), formulation, stability, bioavailability, storage, and disposal (e.g., transportation). Useful pharmaceutical solids include crystalline and amorphous solids, depending on the product and its administration method. Amorphous solids are characterized by a lack of long-range structural order, while crystalline solids are characterized by periodic structures. The desired class of pharmaceutical solids depends on the specific application; amorphous solids are sometimes selected based on, for example, enhanced dissolution properties, while crystalline solids may be desired due to properties such as physical or chemical stability.

[0073] Whether crystalline or amorphous, the solid forms of pharmaceutical compounds include single-component solids and multi-component solids. Single-component solids consist primarily of the pharmaceutical compound or active ingredient, with no other compounds present. The diversity among single-component crystalline materials may potentially be caused by polymorphism, where multiple three-dimensional arrangements exist for a particular pharmaceutical compound.

[0074] It is noteworthy that it is impossible to predict a priori whether a compound exists in a crystalline form, let alone the physicochemical and biological properties of any one or more of such substances, or how they can be successfully prepared (see, for example, Braga and Grepioni, Chem. Commun. 2005, 29, 3635-3645 (“With regard to crystal engineering, the results may be unpredictable if the guidance is not very precise and / or if there are other external factors affecting the process”); Jones et al., MRSBull. 2006, 31, 875-879 (“Currently, it is generally impossible to predict by calculation the number of observable polymorphs of even the simplest molecules”); Price, Adv. Drug Deliv. Rev. 2004, 56(3), 301-319; and Bernstein, ACA Transactions 2004, 39, 14-23 (“There is much work to be learned and done before we can confidently predict crystal structures, let alone polymorphic forms”).

[0075] For a given drug compound, the diversity of its solid forms can lead to a potential diversity in its physical and chemical properties. The discovery and selection of solid forms is crucial in the development of effective, stable, and marketable drug products.

[0076] Crystalline compound 1, form 1

[0077] In some embodiments, compound 1 or its solvate is in crystalline form 1, characterized by having at least one of the following properties:

[0078] (a) and Figure 1 The XRPD spectra shown are basically similar to those of other XRPD spectra.

[0079] (b) An XRPD spectrum having at least three characteristic peaks selected from the following: 4.1° 2θ, 5.4° 2θ, 6.6° 2θ, 8.2° 2θ, 9.5° 2θ, 12.3° 2θ, 13.1° 2θ, 13.9° 2θ, 15.9° 2θ, 16.4° 2θ, 17.0° 2θ, 17.5° 2θ, 19.7° 2θ, and 22.6° 2θ;

[0080] (c) and Figure 2 The differential scanning calorimetry (DSC) thermograms shown are essentially similar to those of the DSC thermograms shown.

[0081] (d) Endothermic DSC thermograms with an onset point of about 136 °C and / or a peak value of about 149 °C;

[0082] (e) and Figure 3 The TGA curve shown is basically similar to the TGA curve shown; or

[0083] (f) Their combinations.

[0084] In some embodiments, crystalline compound form 1 is characterized by having at least two of the properties selected from (a) to (e). In some embodiments, crystalline compound form 1 is characterized by having at least three of the properties selected from (a) to (e). In some embodiments, crystalline compound form 1 is characterized by having at least four of the properties selected from (a) to (e). In some embodiments, crystalline compound form 1 is characterized by having properties (a) to (e).

[0085] In some embodiments, crystalline compound 1 in form 1 has the same properties as... Figure 1The XRPD spectra shown are substantially similar to those of the XRPD spectra. In some embodiments, the XRPD spectrum of crystalline compound 1 in form 1 has at least four characteristic peaks selected from the following: 4.1° 2θ, 5.4° 2θ, 6.6° 2θ, 8.2° 2θ, 9.5° 2θ, 12.3° 2θ, 13.1° 2θ, 13.9° 2θ, 15.9° 2θ, 16.4° 2θ, 17.0° 2θ, 17.5° 2θ, 19.7° 2θ, and 22.6° 2θ. In some embodiments, the XRPD spectrum of crystalline compound 1, form 1, has at least five characteristic peaks selected from the following: 4.1° 2θ, 5.4° 2θ, 6.6° 2θ, 8.2° 2θ, 9.5° 2θ, 12.3° 2θ, 13.1° 2θ, 13.9° 2θ, 15.9° 2θ, 16.4° 2θ, 17.0° 2θ, 17.5° 2θ, 19.7° 2θ, and 22.6° 2θ. In some embodiments, the XRPD spectrum of crystalline compound 1 in form 1 has at least six characteristic peaks selected from the following: 4.1° 2θ, 5.4° 2θ, 6.6° 2θ, 8.2° 2θ, 9.5° 2θ, 12.3° 2θ, 13.1° 2θ, 13.9° 2θ, 15.9° 2θ, 16.4° 2θ, 17.0° 2θ, 17.5° 2θ, 19.7° 2θ, and 22.6° 2θ. In some embodiments, the XRPD spectrum of crystalline compound 1 in form 1 has at least seven characteristic peaks selected from the following: 4.1° 2θ, 5.4° 2θ, 6.6° 2θ, 8.2° 2θ, 9.5° 2θ, 12.3° 2θ, 13.1° 2θ, 13.9° 2θ, 15.9° 2θ, 16.4° 2θ, 17.0° 2θ, 17.5° 2θ, 19.7° 2θ, and 22.6° 2θ. In some embodiments, the XRPD spectrum of crystalline compound 1 in form 1 has at least eight, or at least nine, or at least ten, or at least eleven, or at least twelve characteristic peaks selected from the following: 4.1° 2θ, 5.4° 2θ, 6.6° 2θ, 8.2° 2θ, 9.5° 2θ, 12.3° 2θ, 13.1° 2θ, 13.9° 2θ, 15.9° 2θ, 16.4° 2θ, 17.0° 2θ, 17.5° 2θ, 19.7° 2θ, and 22.6° 2θ. In some embodiments, the XRPD spectrum of crystalline compound 1, form 1, has characteristic peaks at 5.4° 2θ, 6.6° 2θ, 8.2° 2θ, 9.5° 2θ, 15.9° 2θ, 16.4° 2θ, 17.5° 2θ, and 22.6° 2θ.In some embodiments, the XRPD spectrum of crystalline compound 1, form 1, has characteristic peaks at 4.1° 2θ, 5.4° 2θ, 6.6° 2θ, 8.2° 2θ, 9.5° 2θ, 12.3° 2θ, 13.1° 2θ, 13.9° 2θ, 15.9° 2θ, 16.4° 2θ, 17.0° 2θ, 17.5° 2θ, 19.7° 2θ, and 22.6° 2θ. In some embodiments, crystalline compound 1, form 1, has [the characteristic peaks at 4.1° 2θ, 5.4° 2θ, 6.6° 2θ, 8.2° 2θ, 9.5° 2θ, 12.3° 2θ, 13.1° 2θ, 13.9° 2θ, 15.9° 2θ, 16.4° 2θ, 17.0° 2θ, 17.5° 2θ, 19.7° 2θ, and 22.6° 2θ.] Figure 2 The DSC thermograms shown are substantially similar to those of the DSC thermograms. In some embodiments, the DSC thermogram of crystalline compound 1 in form 1 has an endothermic onset point of approximately 136°C. In some embodiments, the DSC thermogram of crystalline compound 1 in form 1 has an endothermic peak of approximately 149°C. In some embodiments, crystalline compound 1 in form 1 has a similar... Figure 3 The TGA curves shown are substantially similar to those of the TGA curves in the embodiments shown. In some embodiments, the TGA curve of crystalline compound form 1 exhibits approximately 0.60% weight loss in the range of approximately 29°C to approximately 150°C. In some embodiments, crystalline compound form 1 is anhydrous. In some embodiments, crystalline compound form 1 is obtained from a mixture of MEK and n-heptane. In some embodiments, crystalline compound form 1 is obtained from toluene. In some embodiments, crystalline compound form 1 is obtained from MTBE.

[0086] Crystalline compound 1, form 2

[0087] In some embodiments, compound 1 or its solvate is in crystalline form 2, characterized by having at least one of the following properties:

[0088] (a) and Figure 4 The XRPD spectra shown are basically similar to those of other XRPD spectra.

[0089] (b) An XRPD spectrum having at least three characteristic peaks selected from the following: 3.8° 2θ, 5.6° 2θ, 6.4° 2θ, 7.1° 2θ, 8.8° 2θ, 9.9° 2θ, 11.9° 2θ, and 14.8° 2θ; or

[0090] (c) Their combination.

[0091] In some embodiments, the crystalline compound 1 form 2 is characterized by having both properties (a) and (b).

[0092] In some embodiments, crystalline compound 1 in form 2 has the same properties as... Figure 4The XRPD spectra shown are substantially similar to those of other XRPD spectra. In some embodiments, the XRPD spectrum of crystalline compound 1 in form 2 has at least four characteristic peaks selected from the following: 3.8° 2θ, 5.6° 2θ, 6.4° 2θ, 7.1° 2θ, 8.8° 2θ, 9.9° 2θ, 11.9° 2θ, and 14.8° 2θ. In some embodiments, the XRPD spectrum of crystalline compound 1 in form 2 has at least five characteristic peaks selected from the following: 3.8° 2θ, 5.6° 2θ, 6.4° 2θ, 7.1° 2θ, 8.8° 2θ, 9.9° 2θ, 11.9° 2θ, and 14.8° 2θ. In some embodiments, the XRPD spectrum of crystalline compound 1, form 2, has at least six or at least seven characteristic peaks selected from the following: 3.8° 2θ, 5.6° 2θ, 6.4° 2θ, 7.1° 2θ, 8.8° 2θ, 9.9° 2θ, 11.9° 2θ, and 14.8° 2θ. In some embodiments, the XRPD spectrum of crystalline compound 1, form 2, has peaks at 5.6° 2θ, 6.4° 2θ, 7.1° 2θ, 8.8° 2θ, 11.9° 2θ, and 14.8° 2θ. In some embodiments, the XRPD spectrum of crystalline compound 1, form 2, has peaks at 3.8° 2θ, 5.6° 2θ, 6.4° 2θ, 7.1° 2θ, 8.8° 2θ, 9.9° 2θ, 11.9° 2θ, and 14.8° 2θ. In some embodiments, crystalline compound 1 form 2 is obtained from ACN. In some embodiments, crystalline compound 1 form 2 is an acetonitrile solvate.

[0093] Crystalline compound 1, form 3

[0094] In some embodiments, compound 1 or its solvate is in crystalline form 3, characterized by having at least one of the following properties:

[0095] (a) and Figure 5 The XRPD spectra shown are basically similar to those of other XRPD spectra.

[0096] (b) An XRPD spectrum having at least three characteristic peaks selected from the following: 7.9° 2θ, 9.5° 2θ, 11.0° 2θ, 15.7° 2θ, 16.5° 2θ, 18.0° 2θ, 19.0° 2θ and 21.9° 2θ;

[0097] (c) and Figure 6A The DSC thermograms shown are basically similar to those shown in the images.

[0098] (d) Endothermic DSC thermograms with an onset point of about 117 °C and / or a peak value of about 135 °C;

[0099] (e) and Figure 6B The TGA curve shown is basically similar to the TGA curve shown; or

[0100] (f) Their combinations.

[0101] In some embodiments, crystalline compound form 3 is characterized by having at least two of the properties selected from (a) to (e). In some embodiments, crystalline compound form 3 is characterized by having at least three of the properties selected from (a) to (e). In some embodiments, crystalline compound form 3 is characterized by having at least four of the properties selected from (a) to (e). In some embodiments, crystalline compound form 3 is characterized by having properties (a) to (e).

[0102] In some embodiments, crystalline compound 1 in form 3 has the same properties as... Figure 5 The XRPD spectra shown are substantially similar to those of other XRPD spectra. In some embodiments, the XRPD spectrum of crystalline compound 1 in form 3 has at least four characteristic peaks selected from the following: 7.9° 2θ, 9.5° 2θ, 11.0° 2θ, 15.7° 2θ, 16.5° 2θ, 18.0° 2θ, 19.0° 2θ, and 21.9° 2θ. In some embodiments, the XRPD spectrum of crystalline compound 1 in form 3 has at least five characteristic peaks selected from the following: 7.9° 2θ, 9.5° 2θ, 11.0° 2θ, 15.7° 2θ, 16.5° 2θ, 18.0° 2θ, 19.0° 2θ, and 21.9° 2θ. In some embodiments, the XRPD spectrum of crystalline compound 1, form 3, has at least six characteristic peaks selected from the following: 7.9° 2θ, 9.5° 2θ, 11.0° 2θ, 15.7° 2θ, 16.5° 2θ, 18.0° 2θ, 19.0° 2θ, and 21.9° 2θ. In some embodiments, the XRPD spectrum of crystalline compound 1, form 3, has at least seven characteristic peaks selected from the following: 7.9° 2θ, 9.5° 2θ, 11.0° 2θ, 15.7° 2θ, 16.5° 2θ, 18.0° 2θ, 19.0° 2θ, and 21.9° 2θ. In some embodiments, the XRPD spectrum of crystalline compound 1, form 3, exhibits characteristic peaks at 7.9° 2θ, 9.5° 2θ, 11.0° 2θ, 15.7° 2θ, 16.5° 2θ, 18.0° 2θ, 19.0° 2θ, and 21.9° 2θ. In some embodiments, crystalline compound 1, form 3, has... Figure 6AThe DSC thermograms shown are substantially similar to those of the DSC thermograms. In some embodiments, the DSC thermogram of crystalline compound 1 in form 3 has an endothermic onset point of approximately 117°C. In some embodiments, the DSC thermogram of crystalline compound 1 in form 3 has an endothermic peak of approximately 135°C. In some embodiments, crystalline compound 1 in form 3 has a similar... Figure 6B The TGA curves shown are substantially similar to those of the TGA curves in the embodiments shown. In some embodiments, the TGA curve of crystalline compound form 3 exhibits a weight loss of approximately 1.33% in the range of approximately 29°C to approximately 150°C. In some embodiments, crystalline compound form 3 is obtained from EtOH. In some embodiments, crystalline compound form 3 is an EtOH solvate.

[0103] Crystalline compound 1, form 4

[0104] In some embodiments, compound 1 or its solvate is in crystalline form 4, characterized by having at least one of the following properties:

[0105] (a) and Figure 7 The XRPD spectra shown are basically similar to those of other XRPD spectra.

[0106] (b) An XRPD spectrum having at least three characteristic peaks selected from the following: 8.1° 2θ, 9.4° 2θ, 10.8° 2θ, 13.5° 2θ, 15.7° 2θ, 16.3° 2θ, 17.5° 2θ, 18.3° 2θ, 18.7° 2θ, 20.1° 2θ, 21.6° 2θ, 21.8° 2θ, 25.2° 2θ, and 25.7° 2θ;

[0107] (c) and Figure 8 The DSC thermograms shown are basically similar to those shown in the images.

[0108] (d) A DSC thermogram showing a first endothermic reaction with an onset point of about 128°C and / or a peak value of about 138°C and an optional second endothermic reaction with an onset point of about 45°C and / or a peak value of about 75°C; or

[0109] (e) Their combination.

[0110] In some embodiments, crystalline compound form 4 is characterized by having at least two of the properties selected from (a) to (d). In some embodiments, crystalline compound form 4 is characterized by having at least three of the properties selected from (a) to (d). In some embodiments, crystalline compound form 4 is characterized by having properties (a) to (d).

[0111] In some embodiments, crystalline compound 1 in form 4 has the same properties as... Figure 7The XRPD spectra shown are substantially similar to those of the XRPD spectra. In some embodiments, the XRPD spectrum of crystalline compound 1, form 4, has at least four characteristic peaks selected from the following: 8.1° 2θ, 9.4° 2θ, 10.8° 2θ, 13.5° 2θ, 15.7° 2θ, 16.3° 2θ, 17.5° 2θ, 18.3° 2θ, 18.7° 2θ, 20.1° 2θ, 21.6° 2θ, 21.8° 2θ, 25.2° 2θ, and 25.7° 2θ. In some embodiments, the XRPD spectrum of crystalline compound 1, form 4, has at least five characteristic peaks selected from the following: 8.1° 2θ, 9.4° 2θ, 10.8° 2θ, 13.5° 2θ, 15.7° 2θ, 16.3° 2θ, 17.5° 2θ, 18.3° 2θ, 18.7° 2θ, 20.1° 2θ, 21.6° 2θ, 21.8° 2θ, 25.2° 2θ, and 25.7° 2θ. In some embodiments, the XRPD spectrum of crystalline compound 1, form 4, has at least six characteristic peaks selected from the following: 8.1° 2θ, 9.4° 2θ, 10.8° 2θ, 13.5° 2θ, 15.7° 2θ, 16.3° 2θ, 17.5° 2θ, 18.3° 2θ, 18.7° 2θ, 20.1° 2θ, 21.6° 2θ, 21.8° 2θ, 25.2° 2θ, and 25.7° 2θ. In some embodiments, the XRPD spectrum of crystalline compound 1, form 4, has at least seven characteristic peaks selected from the following: 8.1° 2θ, 9.4° 2θ, 10.8° 2θ, 13.5° 2θ, 15.7° 2θ, 16.3° 2θ, 17.5° 2θ, 18.3° 2θ, 18.7° 2θ, 20.1° 2θ, 21.6° 2θ, 21.8° 2θ, 25.2° 2θ, and 25.7° 2θ. In some embodiments, the XRPD spectrum of crystalline compound 1, form 4, has at least eight, or at least nine, or at least ten, or at least eleven, or at least twelve, or at least thirteen characteristic peaks selected from the following: 8.1° 2θ, 9.4° 2θ, 10.8° 2θ, 13.5° 2θ, 15.7° 2θ, 16.3° 2θ, 17.5° 2θ, 18.3° 2θ, 18.7° 2θ, 20.1° 2θ, 21.6° 2θ, 21.8° 2θ, 25.2° 2θ, and 25.7° 2θ. In some embodiments, the XRPD spectrum of crystalline compound 1, form 4, has characteristic peaks at 10.8° 2θ, 15.7° 2θ, 16.3° 2θ, 17.5° 2θ, 18.3° 2θ, 18.7° 2θ, 21.6° 2θ, and 21.8° 2θ.In some embodiments, the XRPD spectrum of crystalline compound 1, form 4, has characteristic peaks at 8.1° 2θ, 9.4° 2θ, 10.8° 2θ, 13.5° 2θ, 15.7° 2θ, 16.3° 2θ, 17.5° 2θ, 18.3° 2θ, 18.7° 2θ, 20.1° 2θ, 21.6° 2θ, 21.8° 2θ, 25.2° 2θ, and 25.7° 2θ. In some embodiments, crystalline compound 1, form 4, has [the characteristic peaks at 8.1° 2θ, 9.4° 2θ, 10.8° 2θ, 13.5° 2θ, 15.7° 2θ, 16.3° 2θ, 17.5° 2θ, 18.3° 2θ, 18.7° 2θ, 20.1° 2θ, 21.6° 2θ, 21.8° 2θ, 25.2° 2θ, and 25.7° 2θ.] Figure 8 The DSC thermograms shown are substantially similar. In some embodiments, the DSC thermogram of crystalline compound form 4 has a first endothermic onset point of about 127°C and / or a peak of about 138°C, and optionally a second endothermic onset point of about 45°C and / or a peak of about 75°C. In some embodiments, crystalline compound form 4 is obtained from EtOH, propanol, or IPA, or mixtures thereof. In some embodiments, crystalline compound form 4 is obtained from EtOH. In some embodiments, crystalline compound form 4 is obtained from propanol. In some embodiments, crystalline compound form 4 is obtained from IPA. In some embodiments, crystalline compound form 4 is obtained from a mixture of two or more of EtOH, propanol, and IPA. In some embodiments, crystalline compound form 4 is a hydrate.

[0112] Crystalline compound 1, form 5

[0113] In some embodiments, compound 1 is in crystalline form 5, characterized by having at least one of the following properties:

[0114] (a) and Figure 9 The XRPD spectra shown are basically similar to those of other XRPD spectra.

[0115] (b) An XRPD spectrum having at least three characteristic peaks selected from the following: 7.9° 2θ, 8.5° 2θ, 9.6° 2θ, 11.1° 2θ, 15.8° 2θ, 16.9° 2θ, 18.4° 2θ, 19.1° 2θ, 22.1° 2θ, 25.5° 2θ, and 27.4° 2θ;

[0116] (c) and Figure 10 The DSC thermograms shown are basically similar to those shown in the images.

[0117] (d) DSC thermograms with an onset point of approximately 122°C and / or a peak value of approximately 132°C;

[0118] (e) and Figure 11 The DVS curve shown is basically similar to the DVS curve shown; or

[0119] (f) Their combinations.

[0120] In some embodiments, crystalline compound form 5 is characterized by having at least two of the properties selected from (a) to (e). In some embodiments, crystalline compound form 5 is characterized by having at least three of the properties selected from (a) to (e). In some embodiments, crystalline compound form 5 is characterized by having at least four of the properties selected from (a) to (e). In some embodiments, crystalline compound form 5 is characterized by having properties (a) to (e).

[0121] In some embodiments, crystalline compound 1 in form 5 has the same properties as... Figure 9The XRPD spectra shown are substantially similar to those of the XRPD spectra. In some embodiments, the XRPD spectrum of crystalline compound 1 in form 5 has at least four characteristic peaks selected from the following: 7.9° 2θ, 8.5° 2θ, 9.6° 2θ, 11.1° 2θ, 15.8° 2θ, 16.9° 2θ, 18.4° 2θ, 19.1° 2θ, 22.1° 2θ, 25.5° 2θ, and 27.4° 2θ. In some embodiments, the XRPD spectrum of crystalline compound 1 in form 5 has at least five characteristic peaks selected from the following: 7.9° 2θ, 8.5° 2θ, 9.6° 2θ, 11.1° 2θ, 15.8° 2θ, 16.9° 2θ, 18.4° 2θ, 19.1° 2θ, 22.1° 2θ, 25.5° 2θ, and 27.4° 2θ. In some embodiments, the XRPD spectrum of crystalline compound 1 in form 5 has at least six characteristic peaks selected from the following: 7.9° 2θ, 8.5° 2θ, 9.6° 2θ, 11.1° 2θ, 15.8° 2θ, 16.9° 2θ, 18.4° 2θ, 19.1° 2θ, 22.1° 2θ, 25.5° 2θ, and 27.4° 2θ. In some embodiments, the XRPD spectrum of crystalline compound 1, form 5, has at least seven characteristic peaks selected from the following: 7.9° 2θ, 8.5° 2θ, 9.6° 2θ, 11.1° 2θ, 15.8° 2θ, 16.9° 2θ, 18.4° 2θ, 19.1° 2θ, 22.1° 2θ, 25.5° 2θ, and 27.4° 2θ. In some embodiments, the XRPD spectrum of crystalline compound 1, form 5, has at least eight, at least nine, or at least ten characteristic peaks selected from the following: 7.9° 2θ, 8.5° 2θ, 9.6° 2θ, 11.1° 2θ, 15.8° 2θ, 16.9° 2θ, 18.4° 2θ, 19.1° 2θ, 22.1° 2θ, 25.5° 2θ, and 27.4° 2θ. In some embodiments, the XRPD spectrum of crystalline compound 1, form 5, has characteristic peaks at 8.5° 2θ, 9.6° 2θ, 15.8° 2θ, 16.9° 2θ, 18.4° 2θ, 19.2° 2θ, 22.2° 2θ, and 25.5° 2θ. In some embodiments, the XRPD spectrum of crystalline compound 1, form 5, exhibits characteristic peaks at 7.9° 2θ, 8.5° 2θ, 9.6° 2θ, 11.1° 2θ, 15.8° 2θ, 16.9° 2θ, 18.4° 2θ, 19.1° 2θ, 22.1° 2θ, 25.5° 2θ, and 27.4° 2θ. In some embodiments, crystalline compound 1, form 5, has... Figure 10The DSC thermograms shown are substantially similar to those of the DSC thermograms. In some embodiments, the DSC thermogram of crystalline compound 1 in form 5 has an endothermic onset point of approximately 122°C. In some embodiments, the DSC thermogram of crystalline compound 1 in form 5 has an endothermic peak of approximately 132°C. In some embodiments, crystalline compound 1 in form 5 has a similar... Figure 11 The DVS curves shown are substantially similar to those shown. In some embodiments, crystalline compound form 5 is obtained from EtOH, optionally followed by drying. In some embodiments, crystalline compound form 5 is anhydrous. In some embodiments, crystalline compound form 5 has a residual EtOH content of less than 0.1% or about 0.05%, and a residual water content of about 0.5% as measured by KF analysis.

[0122] Preparation of crystalline compound 1

[0123] In some embodiments, compound 1 or its solvates are prepared in crystalline form as outlined in the examples. It should be noted that the solvents, temperatures, and other reaction conditions presented herein may vary.

[0124] In another embodiment, crystalline compound 1, form 1, is substantially pure. In some embodiments, the substantially pure crystalline compound 1, form 1, is substantially free of other solid forms (e.g., amorphous solids). In some embodiments, the substantially pure crystalline compound 1, form 1, has a purity of not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 98.5%, not less than about 99%, not less than about 99.5%, or not less than about 99.8%.

[0125] In another embodiment, crystalline compound 1 form 2 is substantially pure. In some embodiments, the substantially pure crystalline compound 1 form 2 is substantially free of other solid forms (e.g., amorphous solids). In some embodiments, the substantially pure crystalline compound 1 form 2 has a purity of not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 98.5%, not less than about 99%, not less than about 99.5%, or not less than about 99.8%.

[0126] In another embodiment, crystalline compound 1 form 3 is substantially pure. In some embodiments, the substantially pure crystalline compound 1 form 3 is substantially free of other solid forms (e.g., amorphous solids). In some embodiments, the substantially pure crystalline compound 1 form 3 has a purity of not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 98.5%, not less than about 99%, not less than about 99.5%, or not less than about 99.8%.

[0127] In another embodiment, crystalline compound 1 form 4 is substantially pure. In some embodiments, the substantially pure crystalline compound 1 form 4 is substantially free of other solid forms (e.g., amorphous solids). In some embodiments, the substantially pure crystalline compound 1 form 4 has a purity of not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 98.5%, not less than about 99%, not less than about 99.5%, or not less than about 99.8%.

[0128] In another embodiment, crystalline compound 1 form 5 is substantially pure. In some embodiments, the substantially pure crystalline compound 1 form 5 is substantially free of other solid forms (e.g., amorphous solids). In some embodiments, the substantially pure crystalline compound 1 form 5 has a purity of not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 98.5%, not less than about 99%, not less than about 99.5%, or not less than about 99.8%.

[0129] Suitable solvents

[0130] Therapeutic agents applicable to mammals, such as humans, must be manufactured in accordance with regulatory guidelines. These government-regulated guidelines are known as Good Manufacturing Practices (GMP). GMP guidelines outline acceptable levels of contamination for active therapeutic agents, such as the amount of residual solvents in the final product. In some embodiments, the solvents disclosed herein are those applicable to GMP facilities and consistent with industrial safety concerns. The categories of solvents are defined, for example, by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), “Impurities: Residual Solvents Guidance Principle Q3C(R6)” (October 2016).

[0131] Solvents are classified into three categories. Category 1 solvents are toxic and should therefore be avoided. Category 2 solvents are those whose use is restricted during the manufacture of therapeutic agents. Category 3 solvents are solvents with low potential toxicity and a low risk to human health. Data on Category 3 solvents indicate that they have low toxicity in acute or short-term studies and are negative in genotoxicity studies.

[0132] Solvents to be avoided in Class 1 include: benzene; carbon tetrachloride; 1,2-dichloroethane; 1,1-dichloroethylene; and 1,1,1-trichloroethane.

[0133] Examples of Class 2 solvents are: ACN, chlorobenzene, chloroform, isopropylbenzene, cyclohexane, 1,2-dichloroethylene, DCM, 1,2-dimethoxyethane, N,N-dimethylacetamide (DMA), N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, MeOH, 2-methoxyethanol, methyl butyl ketone, methylcyclohexane, MIBK, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, THF, tetrahydronaphthalene, toluene, 1,1,2-trichloroethylene, and xylene.

[0134] The three classes of solvents with low toxicity include: acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, MTBE, dimethyl sulfoxide (DMSO), EtOH, EtOAc, diethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, MEK, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, IPA, propyl acetate, and triethylamine.

[0135] Residual solvents in active pharmaceutical ingredients (APIs) originate from the manufacturing process of the API. In some cases, the solvent cannot be completely removed by actual manufacturing techniques. Appropriate selection of the solvent used to synthesize the API can improve yield or determine characteristics such as crystal form, purity, and solubility. Therefore, the solvent is a critical parameter in the synthesis process.

[0136] In some embodiments, the composition comprising the crystalline form of compound 1 or its solvate comprises an organic solvent. In some embodiments, the composition comprising the crystalline form of compound 1 or its solvate comprises a residual amount of an organic solvent. In some embodiments, the composition comprising the crystalline form of compound 1 or its solvate comprises a residual amount of a Class 3 solvent. In some embodiments, the organic solvent is a Class 3 solvent, such as the Class 3 solvents listed above. In some embodiments, the Class 3 solvent is selected from the group consisting of acetone, EtOAc, isopropyl acetate, MTBE, heptane, IPA, and EtOH. In some embodiments, the organic solvent is a Class 2 solvent, such as the Class 2 solvents listed above. In some embodiments, the Class 2 solvent is ACN, THF, or toluene. In some embodiments, the Class 2 solvent is ACN. In some embodiments, the organic solvent is 2-butanone or 2-methyltetrahydrofuran (2-MeTHF).

[0137] Pharmaceutical Compositions / Formulations

[0138] In some embodiments, the pharmaceutical composition comprises crystalline compound 1 and a pharmaceutically acceptable excipient. In some embodiments, it is a pharmaceutical composition comprising form 2, 3, 4, or 5 of compound 1 and a pharmaceutically acceptable excipient. Pharmaceutical compositions comprising crystalline compound 1 or form 2, 3, 4, or 5 of compound 1 can be formulated in a conventional manner. Pharmaceutically acceptable excipients may include, for example, diluents, fillers, binders, disintegrants, glidants, lubricants, carriers, stabilizers, dispersants, suspending agents, surfactants, and thickeners, as well as capsule shells or tablet coatings.

[0139] method

[0140] In some embodiments, this is a method of treating a subject for a disease or condition, including leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, hematologic malignancies, myelodysplastic syndromes, myelodysplastic / myeloproliferative neoplasms, solid tumors, prostate cancer, breast cancer, liver cancer, brain tumors, or diabetes. The method involves administering to the subject a crystalline form of Compound 1 or a solvation thereof described herein, or a pharmaceutical composition containing Compound 1 or a solvation thereof, or a crystalline form of Compound 1 or a solvation thereof, such as a therapeutically effective amount of such compounds or pharmaceutical compositions as described herein. In some embodiments, the crystalline form of Compound 1 is Compound 1 Form 1, or Compound 1 Form 2, or Compound 1 Form 3, or Compound 1 Form 4, or Compound 1 Form 5. In practicing the treatment methods or uses provided herein, a therapeutically effective amount of Compound 1 or a solvation thereof is administered, for example, in the form of a pharmaceutical composition, to a mammal suffering from the disease, condition, or symptom to be treated. In some embodiments, the mammal is a human. The therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health status of the subject, the potency of the compound used, and other factors. In some embodiments, this is a method for treating leukemia, optionally wherein the leukemia is AML or ALL, the method comprising administering to a subject in need a therapeutically effective amount of the compound 1 described herein or a solvent thereof in crystalline form. In some embodiments, the AML is menin-dependent AML, KMT2A rearranged AML, or NPM1-mutated AML. In some embodiments, the ALL is KMT2A rearranged ALL.

[0141] Example

[0142] I. Characterization of Polymorphs

[0143] Example 1: X-ray powder diffraction (XRPD)

[0144] X-ray powder diffraction studies were performed using a Bruker D8 Advance with the following instrument parameters: X-ray wavelength: Cu: K-α (l=1.54179); X-ray tube settings: voltage: 40 kV; current: 40 mA; scanning range: 4° (2θ) to 40° (2θ); sample rotation speed: 15 rpm; scanning rate: 10 degrees / min.

[0145] XRPD analysis of compound 1 in form 1 ( Figure 1 The results show that form 1 is crystalline, with characteristic peaks at 4.1° 2θ, 5.4° 2θ, 6.6° 2θ, 8.2° 2θ, 9.5° 2θ, 12.3° 2θ, 13.1° 2θ, 13.9° 2θ, 15.9° 2θ, 16.4° 2θ, 17.0° 2θ, 17.5° 2θ, 19.7° 2θ, and 22.6° 2θ.

[0146] XRPD analysis of compound 1 in form 2 ( Figure 4 The results show that form 2 is crystalline, with characteristic peaks at 3.8° 2θ, 5.6° 2θ, 6.4° 2θ, 7.1° 2θ, 8.8° 2θ, 9.9° 2θ, 11.9° 2θ and 14.8° 2θ.

[0147] XRPD analysis of compound 1 in form 3 ( Figure 5 The results show that form 3 is crystalline, with characteristic peaks at 7.9° 2θ, 9.5° 2θ, 11.0° 2θ, 15.7° 2θ, 16.5° 2θ, 18.0° 2θ, 19.0° 2θ and 21.9° 2θ.

[0148] XRPD analysis of compound 1 in form 4 ( Figure 7 Form 4 is shown to be crystalline, with characteristic peaks at 8.1° 2θ, 9.4° 2θ, 10.8° 2θ, 13.5° 2θ, 15.7° 2θ, 16.3° 2θ, 17.5° 2θ, 18.3° 2θ, 18.7° 2θ, 20.1° 2θ, 21.6° 2θ, 21.8° 2θ, 25.2° 2θ, and 25.7° 2θ.

[0149] XRPD analysis of compound 1 in form 5 ( Figure 9 Form 5 is shown to be crystalline, with characteristic peaks at 7.9° 2θ, 8.5° 2θ, 9.6° 2θ, 11.1° 2θ, 15.8° 2θ, 16.9° 2θ, 18.4° 2θ, 19.1° 2θ, 22.1° 2θ, 25.5° 2θ, and 27.4° 2θ.

[0150] Example 2: Differential Scanning Calorimetry (DSC)

[0151] DSC studies were performed using a TA Discovery Q2000 or DSC250. The sample was weighed in a rolled aluminum pan and the accurate weight was recorded. Under nitrogen purging, the sample was heated from room temperature or 30°C to 250°C or 300°C at a heating rate of 10°C / min.

[0152] DSC analysis of compound 1 in form 1 ( Figure 2 The results showed an endothermic onset point of approximately 136 °C. DSC analysis of compound 1 in form 1 (…) Figure 2 The results show that the endothermic effect peaks at approximately 149°C.

[0153] DSC analysis of compound 1 in form 3 ( Figure 6A The results show an endothermic start point of approximately 117°C and / or a peak value of approximately 135°C.

[0154] DSC analysis of compound 1 in form 4 ( Figure 8 The results show endothermic events with an initial temperature of approximately 45°C and a peak temperature of approximately 75°C, as well as endothermic events with an initial temperature of approximately 127°C and a peak temperature of approximately 138°C.

[0155] DSC analysis of compound 1 in form 5 ( Figure 10 The results show that the melting endothermic effect started at approximately 122°C and peaked at approximately 132°C.

[0156] Example 3: Thermogravimetric Analysis / Dynamic Vapor Adsorption

[0157] Thermogravimetric analysis of solids was performed using a TA Q5000IR. The sample was placed in an open platinum pan and its mass was automatically weighed. The sample was heated from 30°C to 300°C at a heating rate of 10°C / min.

[0158] TGA in form 1 of compound 1 ( Figure 3 The results showed a weight loss of approximately 0.6% in the range of approximately 29°C to approximately 150°C.

[0159] TGA in form 3 of compound 1 ( Figure 6B The results showed a weight loss of approximately 1.33% in the range of approximately 29°C to approximately 150°C.

[0160] Dynamic vapor adsorption tests were conducted at 25℃ using 10mg-15mg samples, under N2 flow rate of 200mL / min, and dried at 0% relative humidity for 120min.

[0161] DVS of compound 1 in form 5 was obtained. Figure 11Compound 1, form 5, contains less than 0.1% or about 0.05% residual EtOH, and KF analysis shows a residual water content of about 0.5%.

[0162] II. Polymorph Screening

[0163] Example 4: Solid vapor diffusion

[0164] Solid vapor diffusion experiments were conducted using 14 different solvents. Approximately 10 mg of amorphous compound 1 (free base) was weighed into a 4 mL vial and placed in a 40 mL vial containing 3 mL of volatile solvent. The 40 mL vial was sealed and placed under laboratory conditions for one day to allow the solvent vapor to interact with the sample. For clear solutions, slow evaporation was allowed under laboratory conditions to induce crystallization. The obtained solids were tested by XRPD. The results are summarized in Table 1. Compound 1 form 1 and compound 1 form 2 were generated via solid vapor diffusion in toluene and ACN, respectively.

[0165]

[0166] Example 5: Slurry at 25°C

[0167] Slurry conversion experiments were conducted at 25 °C in various solvent systems. Approximately 10-20 mg of amorphous compound 1 was weighed into 0.5 mL of solvent in 2 mL glass vials and then vortexed for approximately 2 min to ensure thorough mixing. After shaking at 25 °C for two days, clear solutions were obtained for all solvents except MeOH / H₂O (3:1, v / v), IPA, MTBE, and toluene. The 12 solvent systems with clear solutions were stored at 4 °C to induce crystallization. No precipitate was observed. The solid was obtained by slow evaporation under laboratory conditions and tested by XRPD. The results are summarized in Table 2. Compound 1 was generated in form 1 as shown below. EtOH experiments yielded crystalline form 3 as indicated by XRPD, with DSC showing a broad endothermic peak in the range of approximately 95 °C to 150 °C, starting at approximately 117 °C and peaking at approximately 135 °C, and TGA showing approximately 1.3% weight loss in the range of approximately 29 °C to 150 °C (DSC and TGA not shown). Compound 1, form 3, was characterized as an EtOH solvate. Form 3 was heated to 90 °C and then dried under vacuum to obtain form 5. Form 5 was characterized as an anhydrous product. Compound 1 was crystallized from EtOH solution, and the resulting solid was dried, yielding form 5 upon drying.

[0168]

[0169] Example 6: Slow Evaporation

[0170] Amorphous compound 1 samples (10 mg each) were weighed into clean glass vials, and the selected solvent was added to dissolve the samples. If the samples were not completely dissolved, the solids were removed by filtration, and the filtrate was collected in another vial. Each vial was sealed with Parafilm with several pinholes. The solvent was allowed to evaporate at ambient temperature. Any solid precipitates from the resulting suspensions were collected and analyzed by XRPD. The results are summarized in Table 3, showing that no crystalline material was obtained.

[0171]

[0172] Example 7: Solution vapor diffusion

[0173] Solution vapor diffusion experiments were conducted under laboratory conditions using 14 different solvents. Approximately 10 mg of amorphous compound 1 was dissolved in 0.5 mL of solvent (Table 4) to obtain a clear solution in a 4 mL vial. Each vial was then placed in a 40 mL glass vial containing 4 mL of a volatile antisolvent (Table 4). The 40 mL vials were sealed and kept under ambient conditions to allow sufficient time for the organic vapors to interact with the solution. For the clear solution, it was allowed to evaporate slowly to induce crystallization under laboratory conditions. Any precipitates were separated for XRPD analysis. As summarized in Table 4, no crystalline solids formed.

[0174]

[0175] Example 8: Preparation of compound 1, form 4

[0176] Samples of compound 1 form 3 were exposed to 35°C to 40°C and 65% to 75% relative humidity to provide compound 1 form 4 (1.2% water as determined by Karl Fischer analysis).

[0177] Example 9: Preparation of compound 1, form 5

[0178] A solution of compound 1 (free base) in 11.5V EtOH was heated to 55°C, then cooled to 30°C, and three crystals were added at 1 wt% each. The mixture was stirred at 30°C for 15 h, cooled to -5°C over 7 h, and stirred at -5°C for 19 h. The resulting solid was filtered, washed with 2V EtOH, and dried under vacuum at 50°C to produce compound 1 in form 5 (0.05% residual EtOH and 0.5% water as determined by Karl Fischer analysis).

[0179] Example 10: Study on the interconversion of compound 1 form 1 and compound 1 form 5

[0180] Saturated solutions of compound form 1 in EtOH, MTBE, and isopropyl acetate were prepared at 50 °C. Approximately 6 mg of compound form 1 and compound form 5 were weighed into each saturated solution, and the resulting suspensions were slurried at the corresponding temperatures for 2 days. Samples of the resulting solids were taken for XRPD analysis. As shown in Table 5, compound form 1 is a thermodynamically stable crystalline form.

[0181]

[0182] Example 11: Study on the interconversion of compound 1 in forms 1, 4 and 5

[0183] Treatment of a 1:1 mixture of Form 1 and Form 4 at 5°C or 50°C in IPA, IPA / water, MTBE or CPME for up to 20 h, or at 25°C in acetone / water for up to 24 h, yielded Form 1 predominantly or completely, and treatment in water at 5°C or 50°C for up to 20 h, yielded a mixture of Form 1 and Form 4.

[0184] Form 1 was produced by treating a 1:1 mixture of Form 1 and Form 5 at 25°C in IPAc, IPA, n-PrOH or toluene for up to 24 h.

[0185] A 1:1:1 mixture of Form 1, Form 4 and Form 5 was treated at 25°C in a mixture of water and IPA for up to 24 hours to produce Form 1.

[0186] Form 5 was treated at 40℃ and 75% relative humidity for 6 days, which mainly provided the results for Form 4.

[0187] Form 4 was treated at 50°C in a vacuum and inert atmosphere for 5 days, which mainly provided Form 4.

[0188] II. Biological Data

[0189] Example 12: Fluorescence Polarization Measurement

[0190] Fluorescence polarization (FP) competition experiments were performed to determine the effectiveness of compound 1 in inhibiting the menin-MLL interaction, and the results were reported as IC50. 50Value. A fluorescein-labeled peptide containing a high-affinity menin-binding motif present in MLL was prepared according to Yokoyama et al. (Cell, 2005, 123(2): 207-218). The binding of the labeled peptide (1.7 kDa) to the much larger menin (approximately 67 kDa) was accompanied by a significant change in the rotation-related time of the fluorophore, resulting in a significant increase in fluorescence polarization and fluorescence anisotropy (excitation at 500 nm, emission at 525 nm). The effectiveness of compound 1 in inhibiting the menin-MLL interaction was measured in FP competition experiments, where the decrease in fluorescence anisotropy was correlated with the inhibition of the interaction, and was used as an IC. 50 Measured readings: IC50 of compound 1 50 (Half-maximum inhibition concentration) <50 nM.

Claims

1. A crystalline form of (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carboxynitrile or a solvate thereof.

2. The crystalline form according to claim 1, wherein the crystalline form of (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thiopheno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carboxynitrile is form 1 having at least one of the following properties: (a) An X-ray powder diffraction (XRPD) pattern that is substantially similar to the X-ray powder diffraction (XRPD) pattern shown in Figure 1. (b) An XRPD spectrum having at least three characteristic peaks selected from the following: 4.1° 2θ, 5.4° 2θ, 6.6° 2θ, 8.2° 2θ, 9.5° 2θ, 12.3° 2θ, 13.1° 2θ, 13.9° 2θ, 15.9° 2θ, 16.4° 2θ, 17.0° 2θ, 17.5° 2θ, 19.7° 2θ, and 22.6° 2θ; (c) A differential scanning calorimetry (DSC) thermogram that is substantially similar to the differential scanning calorimetry (DSC) thermogram shown in Figure 2; (d) Endothermic DSC thermograms with an onset point of about 136 °C and / or a peak value of about 149 °C; (e) A thermogravimetric analysis (TGA) curve that is substantially similar to the thermogravimetric analysis (TGA) curve shown in Figure 3; or (f) Their combinations.

3. The crystalline form according to claim 2, wherein the crystalline form has an XRPD spectrum substantially similar to the XRPD spectrum shown in FIG1.

4. The crystalline form according to claim 2, wherein the XRPD spectrum of the crystalline form has at least five characteristic peaks selected from the following: 4.1° 2θ, 5.4° 2θ, 6.6° 2θ, 8.2° 2θ, 9.5° 2θ, 12.3° 2θ, 13.1° 2θ, 13.9° 2θ, 15.9° 2θ, 16.4° 2θ, 17.0° 2θ, 17.5° 2θ, 19.7° 2θ, and 22.6° 2θ.

5. The crystalline form according to claim 2, wherein the crystalline form has a DSC thermogram substantially similar to the DSC thermogram shown in FIG2.

6. The crystalline form according to claim 2, wherein the DSC thermogram of the crystalline form has an endothermic start point of about 136°C or a peak value of about 149°C.

7. The crystalline form according to claim 2, wherein the crystalline form has a TGA curve substantially similar to the TGA curve shown in FIG3.

8. The crystalline form according to claim 2, wherein the crystalline form is characterized by having properties (a), (b), (c), (d) and (e).

9. The crystalline form according to claim 1, wherein the crystalline form of (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thiopheno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carboxynitrile is form 3 having at least one of the following properties: (a) An XRPD spectrum that is substantially similar to the XRPD spectrum shown in Figure 5; (b) An XRPD spectrum having at least three characteristic peaks selected from the following: 7.9° 2θ, 9.5° 2θ, 11.0° 2θ, 15.7° 2θ, 16.5° 2θ, 18.0° 2θ, 19.0° 2θ and 21.9° 2θ; (c) A DSC thermogram that is substantially similar to the one shown in Figure 6A; (d) Endothermic DSC thermograms with an onset point of about 117 °C and / or a peak value of about 135 °C; (e) A TGA curve that is substantially similar to the TGA curve shown in Figure 6B; or (f) Their combinations.

10. The crystalline form according to claim 9, wherein the crystalline form has an XRPD spectrum substantially similar to the XRPD spectrum shown in FIG5.

11. The crystalline form according to claim 9, wherein the XRPD spectrum of the crystalline form has at least five characteristic peaks selected from the following: 7.9° 2θ, 9.5° 2θ, 11.0° 2θ, 15.7° 2θ, 16.5° 2θ, 18.0° 2θ, 19.0° 2θ and 21.9° 2θ.

12. The crystalline form according to claim 9, wherein the crystalline form has a DSC thermogram substantially similar to the DSC thermogram shown in FIG. 6A.

13. The crystalline form according to claim 9, wherein the DSC thermogram of the crystalline form has an endothermic onset point of about 117°C and / or a peak value of about 135°C.

14. The crystalline form according to claim 9, wherein the crystalline form has a TGA curve substantially similar to the TGA curve shown in FIG6B.

15. The crystalline form according to claim 9, wherein the crystalline form is characterized by having properties (a), (b), (c), (d) and (e).

16. The crystalline form according to any one of claims 9 to 15, wherein the crystalline form is obtained from ethanol.

17. The crystalline form according to claim 1, wherein the crystalline form of (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thiopheno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carboxynitrile is form 4 having at least one of the following properties: (a) An XRPD spectrum that is substantially similar to the XRPD spectrum shown in Figure 7; (b) An XRPD spectrum having at least three characteristic peaks selected from the following: 8.1° 2θ, 9.4° 2θ, 10.8° 2θ, 13.5° 2θ, 15.7° 2θ, 16.3° 2θ, 17.5° 2θ, 18.3° 2θ, 18.7° 2θ, 20.1° 2θ, 21.6° 2θ, 21.8° 2θ, 25.2° 2θ, and 25.7° 2θ; (c) A DSC thermogram that is basically similar to the DSC thermogram shown in Figure 8; (d) An endothermic DSC thermogram with an onset point of approximately 127 °C and / or a peak temperature of approximately 138 °C; or (e) Their combination.

18. The crystalline form according to claim 17, wherein the crystalline form has an XRPD spectrum substantially similar to the XRPD spectrum shown in FIG7.

19. The crystalline form according to claim 17, wherein the XRPD spectrum of said crystalline form has at least five characteristic peaks selected from the following: 8.1° 2θ, 9.4° 2θ, 10.8° 2θ, 13.5° 2θ, 15.7° 2θ, 16.3° 2θ, 17.5° 2θ, 18.3° 2θ, 18.7° 2θ, 20.1° 2θ, 21.6° 2θ, 21.8° 2θ, 25.2° 2θ, and 25.7° 2θ.

20. The crystalline form according to claim 17, wherein the crystalline form has a DSC thermogram substantially similar to the DSC thermogram shown in FIG8.

21. The crystalline form according to claim 17, wherein the DSC thermogram of the crystalline form has an endothermic onset point of about 127°C and / or a peak value of about 138°C.

22. The crystalline form according to claim 17, wherein the crystalline form is characterized by having properties (a), (b), (c) and (d).

23. The crystalline form according to any one of claims 17 to 22, wherein the crystalline form is obtained from ethanol, propanol, or isopropanol, or a mixture thereof.

24. The crystalline form according to claim 1, wherein the crystalline form of (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thiopheno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carboxynitrile is form 5 having at least one of the following properties: (a) An XRPD spectrum that is substantially similar to the XRPD spectrum shown in Figure 9; (b) An XRPD spectrum having at least three characteristic peaks selected from the following: 7.9° 2θ, 8.5° 2θ, 9.6° 2θ, 11.1° 2θ, 15.8° 2θ, 16.9° 2θ, 18.4° 2θ, 19.1° 2θ, 22.1° 2θ, 25.5° 2θ, and 27.4° 2θ; (c) A DSC thermogram that is substantially similar to the DSC thermogram shown in Figure 10. (d) Endothermic DSC thermograms with an onset point of about 122 °C and / or a peak value of about 132 °C; (e) A DVS curve that is substantially similar to the DVS curve shown in Figure 11; or (f) Their combinations.

25. The crystalline form according to claim 24, wherein the crystalline form has an XRPD spectrum substantially similar to the XRPD spectrum shown in FIG9.

26. The crystalline form according to claim 24, wherein the XRPD spectrum of said crystalline form has at least five characteristic peaks selected from the following: 7.9° 2θ, 8.5° 2θ, 9.6° 2θ, 11.1° 2θ, 15.8° 2θ, 16.9° 2θ, 18.4° 2θ, 19.1° 2θ, 22.1° 2θ, 25.5° 2θ, and 27.4° 2θ.

27. The crystalline form according to claim 24, wherein the crystalline form has a DSC thermogram substantially similar to the DSC thermogram shown in FIG10.

28. The crystalline form according to claim 24, wherein the DSC thermogram of the crystalline form has an endothermic onset point of about 122°C and / or a peak value of about 132°C.

29. The crystalline form according to claim 24, wherein the crystalline form has a DVS curve substantially similar to the DVS curve shown in FIG11.

30. The crystalline form according to claim 24, wherein the crystalline form is characterized by having properties (a), (b), (c), (d) and (e).

31. The crystalline form according to any one of claims 24 to 30, wherein the crystalline form is obtained from ethanol.

32. A pharmaceutical composition comprising a crystalline form according to any one of claims 1 to 30 and a pharmaceutically acceptable excipient.

33. The pharmaceutical composition of claim 32, wherein the pharmaceutical composition comprises: (a) Crystal form 2, whose XRPD spectrum has at least three characteristic peaks selected from the following: 3.8° 2θ, 5.6° 2θ, 6.4° 2θ, 7.1° 2θ, 8.8° 2θ, 9.9° 2θ, 11.9° 2θ and 14.8° 2θ; or (b) Crystal form 3, whose XRPD spectrum has at least three characteristic peaks selected from the following: 7.9° 2θ, 9.5° 2θ, 11.0° 2θ, 15.7° 2θ, 16.5° 2θ, 18.0° 2θ, 19.0° 2θ, and 21.9° 2θ; or (c) Crystal form 4, whose XRPD spectrum has at least three characteristic peaks selected from the following: 8.1° 2θ, 9.4° 2θ, 10.8° 2θ, 13.5° 2θ, 15.7° 2θ, 16.3° 2θ, 17.5° 2θ, 18.3° 2θ, 18.7° 2θ, 20.1° 2θ, 21.6° 2θ, 21.8° 2θ, 25.2° 2θ, and 25.7° 2θ; or (d) Crystal form 5, whose XRPD spectrum has at least three characteristic peaks selected from the following: 7.9° 2θ, 8.5° 2θ, 9.6° 2θ, 11.1° 2θ, 15.8° 2θ, 16.9° 2θ, 18.4° 2θ, 19.1° 2θ, 22.1° 2θ, 25.5° 2θ, and 27.4° 2θ; or (e) Their combination.

34. A method of treating a subject for a disease or condition, comprising administering to the subject a crystalline form according to any one of claims 1 to 31 or a pharmaceutical composition according to claim 32 or 33, wherein the disease or condition includes leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, hematologic malignancies, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasms, solid tumors, prostate cancer, breast cancer, liver cancer, brain tumors, or diabetes.

35. A method for inhibiting the interaction of menin with one or more of MLL1, MLL2, MLL fusion protein and MLL partial tandem repeats, comprising contacting menin with a crystalline form according to any one of claims 1 to 31 or a pharmaceutical composition according to claim 32 or 33.

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