Crystal morphology of menin inhibitors

Abstract

This specification describes the crystalline form of (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazine-1-yl)propyl)-1H-indole-2-carbonitride or its solvate.

Description

Technical Field

[0001] Cross-reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 514,089, filed Jul. 17, 2023, and U.S. Provisional Patent Application No. 63 / 655,384, filed Jun. 3, 2024, which are hereby incorporated by reference in their entirety.

Background Art

[0002] The mixed lineage leukemia (MLL) protein is a histone methyltransferase important for the epigenetic regulation of gene transcription. Many acute leukemias, including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and mixed lineage leukemia (MLL), are characterized by the presence of chimeric MLL fusion proteins resulting from chromosomal translocations of the MLL gene located at band q23 (11q23) of chromosome 11. The chimeric MLL fusion protein retains approximately 1,400 amino acids at the N-terminus of MLL but is fused to one of approximately 80 partner proteins (e.g., AF4, AF9, ENL, AF10, ELL, AF6, AF1p, GAS7). The MLL fusion protein lacks the native histone methyltransferase activity at the C-terminus of MLL and acquires the ability to regulate the transcription of a number of oncogenes, including HOX and MEIS1, resulting in increased cell proliferation and decreased cell differentiation, ultimately leading to leukemia induction.

[0003] Menin protein, encoded by the multiple endocrine neoplasm (MEN) gene, is a ubiquitously expressed nucleoprotein involved in DNA processing and repair proteins, chromatin modification proteins, and interactions with numerous transcription factors (Horm. Metab. Res. 2005, 37(6), pp. 369-374, by Agarwal et al.). The association of menin with the N-terminus of the MLL fusion protein is required for the oncogenic activity observed with the MLL fusion protein. This association has been shown to constitutively upregulate the expression of HOX and MEIS1 oncogenes and impair hematopoietic cell proliferation and differentiation, leading to the development of leukemia. Since menin has been shown to function as a common oncogenic cofactor in MLL-associated leukemia, the interaction between menin and the MLL fusion protein and MLL represents a potential target for chemotherapy. [Overview of the Initiative]

[0004] One embodiment of this specification describes the crystalline form of (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazine-1-yl)propyl)-1H-indole-2-carbonitrile (Compound 1) or its solvate.

[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]pyrimidine-4-yl)amino)piperidine-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazine-1-yl)propyl)-1H-indole-2-carbonitrile (compound 1) or its solvate, the crystalline form of (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazine-1-yl)propyl)-1H-indole-2-carbonitrile (compound 1) or its solvate is form 1 having at least one of the following properties: (a) X-ray powder diffraction (XRPD) pattern substantially similar to that shown in Figure 1, (b) XRPD pattern with at least three characteristic peaks selected from 4.1°²-theta, 5.4°²-theta, 6.6°²-theta, 8.2°²-theta, 9.5°²-theta, 12.3°²-theta, 13.1°²-theta, 13.9°²-theta, 15.9°²-theta, 16.4°²-theta, 17.0°²-theta, 17.5°²-theta, 19.7°²-theta, and 22.6°²-theta, (c) A differential scanning calorimetry (DSC) thermogram substantially similar to that shown in Figure 2, (d) An endothermic DSC thermogram with an onset temperature of approximately 136°C and / or a peak temperature of approximately 149°C. (e) A thermogravimetric analysis (TGA) curve substantially similar to that shown in Figure 3, or (f) combinations of those

[0006] In another embodiment of the crystalline form of (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazine-1-yl)propyl)-1H-indole-2-carbonitrile (compound 1) or its solvate, the crystalline form is form 2 having at least one of the following properties: (a) X-ray powder diffraction (XRPD) pattern substantially similar to that shown in Figure 4, (b) XRPD pattern with at least three characteristic peaks selected from 3.8°²-theta, 5.6°²-theta, 6.4°²-theta, 7.1°²-theta, 8.8°²-theta, 9.9°²-theta, 11.9°²-theta, and 14.8°²-theta, or (c) combinations of those

[0007] In another embodiment of the crystalline form of (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazine-1-yl)propyl)-1H-indole-2-carbonitrile (compound 1) or its solvate, the crystalline form is form 3 having at least one of the following properties: (a) X-ray powder diffraction (XRPD) pattern substantially similar to that shown in Figure 5, (b) XRPD pattern with at least three characteristic peaks selected from 7.9°²-theta, 9.5°²-theta, 11.0°²-theta, 15.7°²-theta, 16.5°²-theta, 18.0°²-theta, 19.0°²-theta, and 21.9°²-theta, (c) A differential scanning calorimetry (DSC) thermogram substantially similar to that shown in Figure 6A, (d) An endothermic DSC thermogram with an onset temperature of approximately 117°C and / or a peak temperature of approximately 135°C. (e) A thermogravimetric analysis (TGA) curve substantially similar to that shown in Figure 6B, or (f) combinations of those

[0008] In another embodiment of the crystalline form of (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazine-1-yl)propyl)-1H-indole-2-carbonitrile (compound 1) or its solvate, the crystalline form is form 4 having at least one of the following properties: (a) X-ray powder diffraction (XRPD) pattern substantially similar to that shown in Figure 7, (b) XRPD pattern with at least three characteristic peaks selected from 8.1°²-theta, 9.4°²-theta, 10.8°²-theta, 13.5°²-theta, 15.7°²-theta, 16.3°²-theta, 17.5°²-theta, 18.3°²-theta, 18.7°²-theta, 20.1°²-theta, 21.6°²-theta, 21.8°²-theta, 25.2°²-theta, and 25.7°²-theta, (c) A differential scanning calorimetry (DSC) thermogram substantially similar to that shown in Figure 8, (d) A DSC thermogram with a first endothermic thermogram having a starting temperature of approximately 127°C and / or a peak temperature of approximately 138°C, and optionally a second endothermic thermogram having a starting temperature of approximately 45°C and / or a peak temperature of approximately 75°C, or (e) combinations of those

[0009] In another embodiment of the crystalline form of (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazine-1-yl)propyl)-1H-indole-2-carbonitrile (compound 1) or its solvate, the crystalline form is form 5 having at least one of the following properties: (a) X-ray powder diffraction (XRPD) pattern substantially similar to that shown in Figure 9, (b) XRPD pattern with at least three characteristic peaks selected from 7.9°²-theta, 8.5°²-theta, 9.6°²-theta, 11.1°²-theta, 15.8°²-theta, 16.9°²-theta, 18.4°²-theta, 19.1°²-theta, 22.1°²-theta, 25.5°²-theta, and 27.4°²-theta, (c) A differential scanning calorimetry (DSC) thermogram substantially similar to that shown in Figure 10, (d) an endothermic DSC thermogram with an onset temperature of approximately 122°C and / or a peak temperature of approximately 132°C, (e) A dynamic vapor sorbation (DVS) curve substantially similar to that shown in Figure 11, or (f) combinations of those

[0010] Another embodiment described herein describes a pharmaceutical composition comprising (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazine-1-yl)propyl)-1H-indole-2-carbonitride or a solvate thereof in crystalline form and a pharmaceutically acceptable excipient.

[0011] Another aspect of this specification describes a method for treating a disease or illness of interest, comprising the step of administering to the subject a therapeutically effective amount of (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazine-1-yl)propyl)-1H-indole-2-carbonitrile or a solvate thereof in crystalline form, wherein the disease or illness is leukemia, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), hematological malignancies, myelodysplastic syndromes, myelodysplastic / myeloproliferative neoplasms, solid tumors, prostate cancer, breast cancer, liver cancer, brain tumors, or diabetes.

[0012] In some embodiments, a method for inhibiting the interaction of menine with one or more of MLL1, MLL2, MLL fusion proteins, and MLL partial tandem duplications comprises the step of contacting menine 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]pyrimidine-4-yl)amino)piperidine-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazine-1-yl)propyl)-1H-indole-2-carbonitrile or a solvate thereof as described herein.

[0013] Reference All publications, patents, and patent applications referenced herein are incorporated herein by reference to the extent applicable and relevant, and to the same extent that each individual publication, patent, or patent application is specifically and individually indicated as being invoked by reference. [Brief explanation of the drawing]

[0014] [Figure 1] This figure shows the XRPD pattern of crystalline (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazine-1-yl)propyl)-1H-indole-2-carbonitride (Compound 1) or its solvate, i.e., Form 1. [Figure 2] This figure shows a DSC thermogram of crystalline (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazine-1-yl)propyl)-1H-indole-2-carbonitrile (Compound 1) or its solvate, i.e., Form 1. [Figure 3] This figure shows the TGA curve for crystalline (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazine-1-yl)propyl)-1H-indole-2-carbonitrile (Compound 1) or its solvate, i.e., Form 1. [Figure 4]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-carbonitrile (Compound 1) or a solvate thereof, that is, a figure showing the XRPD pattern of Form 2. [Figure 5] 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-carbonitrile (Compound 1) or a solvate thereof, that is, a figure showing the XRPD pattern of Form 3. [Figure 6A] 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-carbonitrile (Compound 1) or a solvate thereof, that is, a figure showing the DSC thermogram (Figure 6A) of Form 3. [Figure 6B] 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-carbonitrile (Compound 1) or a solvate thereof, that is, a figure showing the TGA curve (the curve marked with an asterisk in Figure 6B) of Form 3. [Figure 7]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-carbonitrile (Compound 1) or a solvate thereof, namely a figure showing the XRPD pattern of Form 4. [Figure 8] 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-carbonitrile (Compound 1) or a solvate thereof, namely a figure showing the DSC thermogram of Form 4. [Figure 9] 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-carbonitrile (Compound 1) or a solvate thereof, namely a figure showing the XRPD pattern of Form 5. [Figure 10] 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-carbonitrile (Compound 1) or a solvate thereof, namely a figure showing the DSC thermogram of Form 5. [Figure 11]This figure shows the DVS curve for crystalline (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazine-1-yl)propyl)-1H-indole-2-carbonitrile (Compound 1) or its solvate, i.e., Form 5. [Modes for carrying out the invention]

[0015] Specific terms Unless otherwise specified, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art in the field to which the claimed subject matter pertains. The above summary and the following detailed description are illustrative and descriptive only and should not be understood as limiting to any claimed subject matter. In this application, the use of singular nouns includes plural nouns unless specifically stated otherwise. Note that, as used herein and in the appended claims, the singular nouns "a," "an," and "the" include multiple referents unless the context clearly indicates the opposite. In this application, the use of "or" means "and / or" unless otherwise specified. Furthermore, the use of other forms of the term, such as "include," "includes," and "included," in addition to "including," is not limited to these. The term “comprising” (and related terms such as “comprise,” “comprises,” “having,” or “including”) is not intended to exclude the possibility that, in other specific embodiments, for example, any of the compounds, compositions, methods, or processes described herein may “consist of” or “essentially consist of” the described features. The term “about” when referring to numbers or numerical ranges means that the number or numerical range referred to is an approximation within experimental variability (or statistical experimental error), and therefore the number or numerical range may vary between 1% and 5% of the explicitly stated number or numerical range.

[0016] The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described. All documents or parts thereof cited in this application, including but not limited to patents, patent applications, articles, books, manuals, and papers, are expressly invoked herein by reference in their entirety.

[0017] With respect to a formulation, composition, or component, the terms “acceptable” or “pharmaceutically acceptable,” as used herein, mean that it does not cause a sustained adverse effect on the overall health of the subject being treated, nor inhibits the biological activity or properties of the compound, and is relatively non-toxic.

[0018] As used herein, “relief” of symptoms of a particular disease, disorder, or illness by administration of a particular compound or pharmaceutical composition means any reduction in severity, delay in onset, delay in progression, or reduction in duration, whether persistent or temporary, permanent or transient, that may be caused by or associated with the administration of that compound or pharmaceutical composition.

[0019] When used herein, terms such as “co-administration” mean the administration of a selected therapeutic agent to a single patient, and are intended to include treatment regimens in which this therapeutic agent is administered via the same or different routes of administration, or at the same or different times.

[0020] The terms “effective dose” or “therapeutic effective dose,” as used herein, refer to an amount of the drug or compound administered that is sufficient to alleviate, to some extent, one or more symptoms of the disease or illness being treated. As a result, the signs, symptoms, or causes of the disease may be reduced and / or alleviated, or any other desirable changes may occur in the biological system. For example, an “effective dose” for therapeutic use is the amount of a composition containing the compound disclosed herein that is required to clinically and significantly reduce disease symptoms without causing excessive adverse side effects. The appropriate “effective dose” in any individual case may be determined using techniques such as dose escalation studies. The term “therapeutic effective dose” includes, for example, a prophylactic effective dose. An “effective dose” of a compound disclosed herein is an amount that is effective in achieving a desired pharmacological effect or therapeutic improvement without causing excessive adverse side effects. The “effective dose” or “therapeutic effective dose” may vary between subjects due to metabolic variations of compound 1, the subject’s age, weight, general condition, the disease being treated, the severity of the disease being treated, and the judgment of the attending physician. For example, the effective therapeutic dose may be determined by a dose-escalation clinical trial.

[0021] The terms “enhance” or “enhancing” mean increasing or extending a desired effect in terms of either potency or duration. For example, “enhancing” the effect of a therapeutic agent means the ability to increase or extend the effect of the therapeutic agent in terms of either potency or duration during the treatment of a disease, disorder, or illness. “Enhancing effective dose,” as used herein, means an appropriate amount to enhance the effect of the therapeutic agent in the treatment of a disease, disorder, or illness. When used in a patient, the effective dose for this purpose will depend on the severity and course of the disease, disorder, or illness, past treatments, the patient’s health status and response to the drug, and the judgment of the attending physician.

[0022] The term "preventive effective dose," as used herein, refers to the amount of a composition applied to a patient that will alleviate, to some extent, one or more of the symptoms of the disease, illness, or disorder being treated. In such preventive applications, such a dose may depend on the patient's health condition, weight, etc. As an example, such a preventive effective dose can be determined by dose-escalation clinical trials.

[0023] As used herein, the term "subject" refers to an animal that is the subject of treatment, observation, or experimentation. For example, a subject may be, but is not limited to, a mammal, including, but not limited to, humans.

[0024] As used herein, the term “target activity” refers to a biological activity that can be regulated by a selective modulator. Certain exemplary target activities include, but are not limited to, binding affinity, signaling, enzyme activity, tumor growth, inflammation or inflammation-related processes, and relief of one or more symptoms associated with a disease or illness.

[0025] The terms “treat,” “treating,” or “treatment,” as used herein, include alleviating, reducing, or improving the symptoms of a disease or illness; preventing further symptoms; improving or preventing the underlying metabolic causes of symptoms; inhibiting a disease or illness, for example, halting the progression of a disease or illness; easing a disease or illness; reversing a disease or illness; alleviating a condition caused by a disease or illness; or cessating the symptoms of a disease or illness. The terms “treat,” “treating,” or “treatment” include, but are not limited to, preventive and / or therapeutic treatments.

[0026] compound 1 In one embodiment, it is (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazine-1-yl)propyl)-1H-indole-2-carbonitrile (Compound 1) or a solvate thereof. "Compound 1" or "(S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazine-1-yl)propyl)-1H-indole-2-carbonitrile" refers to a free base compound having the following structure.

[0027] [ka] Compound 1 is a menin inhibitor and inhibits the interaction between menin and MLL.

[0028] Some embodiments of this specification describe the crystalline form of compound 1 or its solvate. The solvate contains a stoichiometric or non-stoichiometric amount of solvent and is formed during the process of product formation or isolation using pharmaceutically acceptable solvents such as water, ethanol (EtOH), methanol (MeOH), tert-butyl methyl ether (MTBE), diisopropyl ether, ethyl acetate (siRNA), isopropyl acetate, isopropyl alcohol (IPA), methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), acetone, nitromethane, tetrahydrofuran (THF), dichloromethane (DCM), dioxane, heptane, toluene, anisole, and acetonitrile (ACN). In some embodiments, the solvate is formed using a Class 3 solvent, but is not limited. In some embodiments, the solvate is formed using a Class 2 solvent, but is not limited. The categories of solvents are defined, for example, in the "Impurities: Guidelines for Residual Solvents Q3C(R6)" (October 2016) of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). When the solvent is water, a hydrate is formed, or when the solvent is an alcohol such as ethanol or IPA, an alcoholate is formed.

[0029] In other embodiments, compound 1 or its solvate may be prepared in various forms, including but not limited to amorphous and crystalline phases.

[0030] While not intended to be bound by any particular theory, certain solid forms are characterized by physical properties suitable for pharmaceutical and therapeutic dosage forms, such as stability, solubility, and dissolution rate. Furthermore, while not intended to be bound by any particular theory, certain solid forms are characterized by physical properties (e.g., density, compressibility, hardness, morphology, brittleness, tackiness, solubility, water absorption, electrical properties, thermal behavior, solid-state reactivity, physical stability, and chemical stability) that influence specific processes (e.g., production, filtration, washing, drying, grinding, mixing, tableting, flow, dissolution, formation, and freeze-drying) that produce a particular solid form suitable for the manufacture of a solid dosage form. Such properties can be determined using specific analytical chemistry techniques, including solid-state analysis techniques described herein (e.g., X-ray diffraction, microscopy, spectroscopy, and thermal analysis).

[0031] Crystal morphology The identification and selection of the solid form of a pharmaceutical compound is complex, considering that changes in solid form can affect various physical and chemical properties, potentially leading to advantages or disadvantages in processing (e.g., fluidity, bulk density), formulation, stability, bioavailability, storage, and handling (e.g., transport), among other important pharmaceutical characteristics. Useful pharmaceutical solids include crystalline and amorphous solids, depending on the product and its mode of administration. Amorphous solids are characterized by a lack of long-range structural order, while crystalline solids are characterized by structural periodicity. The preferred classification of pharmaceutical solids depends on the specific application. Amorphous solids may be selected based, for example, on an enhanced solubility profile, while crystalline solids may be preferred for properties such as physical or chemical stability.

[0032] Whether crystalline or amorphous, the solid forms of pharmaceutical compounds include single-component solids and multi-component solids. A single-component solid consists essentially of a pharmaceutical compound or active ingredient in the absence of other compounds. Diversity in single-component crystalline materials can potentially arise from polymorphism, resulting in the existence of multiple three-dimensional arrangements for a particular pharmaceutical compound.

[0033] In particular, it is impossible to predict a priori whether a crystalline form of a compound exists, let alone one or more physicochemical and biological properties of such materials, or methods for successfully preparing them (e.g., Braga and Grepioni, Chem.Commun. 2005, 29, pp. 3635-3645 ("with respect to crystal engineering, if instructions are not very precise and / or if other external factors affect the process, the result can be unpredictable"), Jones et al., MRS Bull. 2006, 31, pp. 875-879 ("At present it is not generally possible to computationally predict the number of observable polymorphs of even the simplest molecules"), Price, Adv.Drug Deliv.Rev. 2004, 56(3), pp. 301-319, and Bernstein, ACA Transactions 2004, 39, pp. 14-23 ("a great deal still needs to be learned and done before one can state with any degree of confidence the ability"). (See "to predict a crystal structure, much less polymorphic forms")

[0034] The various possible solid-state forms lead to potential diversity in the physical and chemical properties of a given pharmaceutical compound. The discovery and selection of solid-state forms are crucial for the development of effective, stable, and marketable pharmaceuticals.

[0035] Crystalline compound 1, form 1 In some embodiments, the crystalline form of compound 1 or its solvate is characterized by having at least one of the following properties: (a) An XRPD pattern substantially similar to that shown in Figure 1, (b) XRPD pattern with at least three characteristic peaks selected from 4.1°²-theta, 5.4°²-theta, 6.6°²-theta, 8.2°²-theta, 9.5°²-theta, 12.3°²-theta, 13.1°²-theta, 13.9°²-theta, 15.9°²-theta, 16.4°²-theta, 17.0°²-theta, 17.5°²-theta, 19.7°²-theta, and 22.6°²-theta, (c) A differential scanning calorimetry (DSC) thermogram substantially similar to that shown in Figure 2, (d) An endothermic DSC thermogram with an onset temperature of approximately 136°C and / or a peak temperature of approximately 149°C. (e) A TGA curve substantially similar to that shown in Figure 3, or (f) combinations of those

[0036] In some embodiments, the crystalline compound 1, i.e., form 1, is characterized by having at least two of the properties selected from (a) to (e). In some embodiments, the crystalline compound 1, i.e., form 1, is characterized by having at least three of the properties selected from (a) to (e). In some embodiments, the crystalline compound 1, i.e., form 1, is characterized by having at least four of the properties selected from (a) to (e). In some embodiments, the crystalline compound 1, i.e., form 1, is characterized by having properties (a) to (e).

[0037] In some embodiments, crystalline compound 1, i.e., form 1, has an XRPD pattern substantially similar to that shown in Figure 1. In some embodiments, crystalline compound 1, i.e., form 1, has an XRPD pattern with at least four characteristic peaks selected from 4.1°2-theta, 5.4°2-theta, 6.6°2-theta, 8.2°2-theta, 9.5°2-theta, 12.3°2-theta, 13.1°2-theta, 13.9°2-theta, 15.9°2-theta, 16.4°2-theta, 17.0°2-theta, 17.5°2-theta, 19.7°2-theta, and 22.6°2-theta. In some embodiments, the crystalline compound 1, i.e., form 1, has an XRPD pattern with at least five characteristic peaks selected from 4.1°2-theta, 5.4°2-theta, 6.6°2-theta, 8.2°2-theta, 9.5°2-theta, 12.3°2-theta, 13.1°2-theta, 13.9°2-theta, 15.9°2-theta, 16.4°2-theta, 17.0°2-theta, 17.5°2-theta, 19.7°2-theta, and 22.6°2-theta. In some embodiments, the crystalline compound 1, i.e., form 1, has an XRPD pattern with at least six characteristic peaks selected from 4.1°2-theta, 5.4°2-theta, 6.6°2-theta, 8.2°2-theta, 9.5°2-theta, 12.3°2-theta, 13.1°2-theta, 13.9°2-theta, 15.9°2-theta, 16.4°2-theta, 17.0°2-theta, 17.5°2-theta, 19.7°2-theta, and 22.6°2-theta. In some embodiments, the crystalline compound 1, i.e., form 1, has an XRPD pattern with at least seven characteristic peaks selected from 4.1°2-theta, 5.4°2-theta, 6.6°2-theta, 8.2°2-theta, 9.5°2-theta, 12.3°2-theta, 13.1°2-theta, 13.9°2-theta, 15.9°2-theta, 16.4°2-theta, 17.0°2-theta, 17.5°2-theta, 19.7°2-theta, and 22.6°2-theta.In some embodiments, the crystalline compound 1, i.e., form 1, has an XRPD pattern with at least eight, or at least nine, or at least ten, or at least eleven, or at least twelve characteristic peaks selected from 4.1°²-theta, 5.4°²-theta, 6.6°²-theta, 8.2°²-theta, 9.5°²-theta, 12.3°²-theta, 13.1°²-theta, 13.9°²-theta, 15.9°²-theta, 16.4°²-theta, 17.0°²-theta, 17.5°²-theta, 19.7°²-theta, and 22.6°²-theta. In some embodiments, the crystalline compound 1, i.e., form 1, has an XRPD pattern with characteristic peaks at 5.4°²-theta, 6.6°²-theta, 8.2°²-theta, 9.5°²-theta, 15.9°²-theta, 16.4°²-theta, 17.5°²-theta, and 22.6°²-theta. In some embodiments, crystalline compound 1, i.e., form 1, has an XRPD pattern with characteristic peaks at 4.1°2-theta, 5.4°2-theta, 6.6°2-theta, 8.2°2-theta, 9.5°2-theta, 12.3°2-theta, 13.1°2-theta, 13.9°2-theta, 15.9°2-theta, 16.4°2-theta, 17.0°2-theta, 17.5°2-theta, 19.7°2-theta, and 22.6°2-theta. In some embodiments, crystalline compound 1, i.e., form 1, has a DSC thermogram substantially similar to that shown in Figure 2. In some embodiments, crystalline compound 1, i.e., form 1, has a DSC thermogram with endothermic activity with a starting temperature of approximately 136°C. In some embodiments, crystalline compound 1, i.e., form 1, has a DSC thermogram with endothermic activity with a peak temperature of approximately 149°C. In some embodiments, crystalline compound 1, i.e., form 1, has a TGA curve substantially similar to that shown in Figure 3. In some embodiments, crystalline compound 1, i.e., form 1, has a TGA curve showing a weight loss of about 0.60% over a range of about 29°C to about 150°C. In some embodiments, crystalline compound 1, i.e., form 1, is an anhydrous. In some embodiments, crystalline compound 1, i.e., form 1, is obtained from a mixture of MEK and n-heptane.In some embodiments, crystalline compound 1, i.e., form 1, is obtained from toluene. In some embodiments, crystalline compound 1, i.e., form 1, is obtained from MTBE.

[0038] Crystalline compound 1, form 2 In some embodiments, the crystalline form of compound 1 or its solvate is characterized by having at least one of the following properties: (a) An XRPD pattern substantially similar to that shown in Figure 4, (b) XRPD pattern with at least three characteristic peaks selected from 3.8°²-theta, 5.6°²-theta, 6.4°²-theta, 7.1°²-theta, 8.8°²-theta, 9.9°²-theta, 11.9°²-theta, and 14.8°²-theta, or (c) combinations of those

[0039] In some embodiments, crystalline compound 1, i.e., form 2, is characterized by having both properties (a) and (b).

[0040] In some embodiments, crystalline compound 1, i.e., form 2, has an XRPD pattern substantially similar to that shown in Figure 4. In some embodiments, crystalline compound 1, i.e., form 2, has an XRPD pattern with at least four characteristic peaks selected from 3.8°2-theta, 5.6°2-theta, 6.4°2-theta, 7.1°2-theta, 8.8°2-theta, 9.9°2-theta, 11.9°2-theta, and 14.8°2-theta. In some embodiments, crystalline compound 1, i.e., form 2, has an XRPD pattern with at least five characteristic peaks selected from 3.8°2-theta, 5.6°2-theta, 6.4°2-theta, 7.1°2-theta, 8.8°2-theta, 9.9°2-theta, 11.9°2-theta, and 14.8°2-theta. In some embodiments, crystalline compound 1, i.e., form 2, has an XRPD pattern with at least six or at least seven characteristic peaks selected from 3.8°²-theta, 5.6°²-theta, 6.4°²-theta, 7.1°²-theta, 8.8°²-theta, 9.9°²-theta, 11.9°²-theta, and 14.8°²-theta. In some embodiments, crystalline compound 1, i.e., form 2, has an XRPD pattern with peaks at 3.8°²-theta, 5.6°²-theta, 6.4°²-theta, 7.1°²-theta, 8.8°²-theta, 9.9°²-theta, 11.9°²-theta, and 14.8°²-theta. In some embodiments, crystalline compound 1, i.e., form 2, is obtained from ACN. In some embodiments, crystalline compound 1, i.e., form 2, is an acetonitrile solvate.

[0041] Crystalline compound 1, form 3 In some embodiments, the crystalline form of compound 1 or its solvate is characterized by having at least one of the following properties: (a) An XRPD pattern substantially similar to that shown in Figure 5, (b) XRPD pattern with at least three characteristic peaks selected from 7.9°²-theta, 9.5°²-theta, 11.0°²-theta, 15.7°²-theta, 16.5°²-theta, 18.0°²-theta, 19.0°²-theta, and 21.9°²-theta, (c) A DSC thermogram substantially similar to the one shown in Figure 6A, (d) An endothermic DSC thermogram with an onset temperature of approximately 117°C and / or a peak temperature of approximately 135°C. (e) A TGA curve substantially similar to that shown in Figure 6B, or (f) combinations of those

[0042] In some embodiments, the crystalline compound 1, i.e., form 3, is characterized by having at least two of the properties selected from (a) to (e). In some embodiments, the crystalline compound 1, i.e., form 3, is characterized by having at least three of the properties selected from (a) to (e). In some embodiments, the crystalline compound 1, i.e., form 3, is characterized by having at least four of the properties selected from (a) to (e). In some embodiments, the crystalline compound 1, i.e., form 3, is characterized by having properties (a) to (e).

[0043] In some embodiments, crystalline compound 1, i.e., form 3, has an XRPD pattern substantially similar to that shown in Figure 5. In some embodiments, crystalline compound 1, i.e., form 3, has an XRPD pattern with at least four characteristic peaks selected from 7.9°²-theta, 9.5°²-theta, 11.0°²-theta, 15.7°²-theta, 16.5°²-theta, 18.0°²-theta, 19.0°²-theta, and 21.9°²-theta. In some embodiments, crystalline compound 1, i.e., form 3, has an XRPD pattern with at least five characteristic peaks selected from 7.9°²-theta, 9.5°²-theta, 11.0°²-theta, 15.7°²-theta, 16.5°²-theta, 18.0°²-theta, 19.0°²-theta, and 21.9°²-theta. In some embodiments, the crystalline compound 1, i.e., form 3, has an XRPD pattern with at least six characteristic peaks selected from 7.9°²-theta, 9.5°²-theta, 11.0°²-theta, 15.7°²-theta, 16.5°²-theta, 18.0°²-theta, 19.0°²-theta, and 21.9°²-theta. In some embodiments, the crystalline compound 1, i.e., form 3, has an XRPD pattern with at least seven characteristic peaks selected from 7.9°²-theta, 9.5°²-theta, 11.0°²-theta, 15.7°²-theta, 16.5°²-theta, 18.0°²-theta, 19.0°²-theta, and 21.9°²-theta. In some embodiments, crystalline compound 1, i.e., form 3, has an XRPD pattern with characteristic peaks at 7.9°²-theta, 9.5°²-theta, 11.0°²-theta, 15.7°²-theta, 16.5°²-theta, 18.0°²-theta, 19.0°²-theta, and 21.9°²-theta. In some embodiments, crystalline compound 1, i.e., form 3, has a DSC thermogram substantially similar to that shown in Figure 6A. In some embodiments, crystalline compound 1, i.e., form 3, has a DSC thermogram with endothermic properties, with a starting temperature of approximately 117°C. In some embodiments, crystalline compound 1, i.e., form 3, has a DSC thermogram with endothermic properties, with a peak temperature of approximately 135°C.In some embodiments, crystalline compound 1, i.e., form 3, has a TGA curve substantially similar to that shown in Figure 6B. In some embodiments, crystalline compound 1, i.e., form 3, has a TGA curve showing a weight loss of about 1.33% over a range of about 29°C to about 150°C. In some embodiments, crystalline compound 1, i.e., form 3, is obtained from EtOH. In some embodiments, crystalline compound 1, i.e., form 3, is an EtOH solvate.

[0044] Crystalline compound 1, form 4 In some embodiments, embodiment 4 is characterized in that the crystalline form of compound 1 or its solvate has at least one of the following properties: (a) An XRPD pattern substantially similar to that shown in Figure 7, (b) XRPD pattern with at least three characteristic peaks selected from 8.1°²-theta, 9.4°²-theta, 10.8°²-theta, 13.5°²-theta, 15.7°²-theta, 16.3°²-theta, 17.5°²-theta, 18.3°²-theta, 18.7°²-theta, 20.1°²-theta, 21.6°²-theta, 21.8°²-theta, 25.2°²-theta, and 25.7°²-theta, (c) A DSC thermogram substantially similar to the one shown in Figure 8, (d) A DSC thermogram with a second endothermic thermogram having a starting temperature of approximately 128°C and / or a peak temperature of approximately 138°C, and optionally a second endothermic thermogram having a starting temperature of approximately 45°C and / or a peak temperature of approximately 75°C, or (e) combinations of those

[0045] In some embodiments, the crystalline compound 1, i.e., form 4, is characterized by having at least two of the properties selected from (a) to (d). In some embodiments, the crystalline compound 1, i.e., form 4, is characterized by having at least three of the properties selected from (a) to (d). In some embodiments, the crystalline compound 1, i.e., form 4, is characterized by having properties (a) to (d).

[0046] In some embodiments, crystalline compound 1, i.e., form 4, has an XRPD pattern substantially similar to that shown in Figure 7. In some embodiments, crystalline compound 1, i.e., form 4, has an XRPD pattern with at least four characteristic peaks selected from 8.1°2-theta, 9.4°2-theta, 10.8°2-theta, 13.5°2-theta, 15.7°2-theta, 16.3°2-theta, 17.5°2-theta, 18.3°2-theta, 18.7°2-theta, 20.1°2-theta, 21.6°2-theta, 21.8°2-theta, 25.2°2-theta, and 25.7°2-theta. In some embodiments, the crystalline compound 1, i.e., form 4, has an XRPD pattern with at least five characteristic peaks selected from 8.1°²-theta, 9.4°²-theta, 10.8°²-theta, 13.5°²-theta, 15.7°²-theta, 16.3°²-theta, 17.5°²-theta, 18.3°²-theta, 18.7°²-theta, 20.1°²-theta, 21.6°²-theta, 21.8°²-theta, 25.2°²-theta, and 25.7°²-theta. In some embodiments, the crystalline compound 1, i.e., form 4, has an XRPD pattern with at least six characteristic peaks selected from 8.1°²-theta, 9.4°²-theta, 10.8°²-theta, 13.5°²-theta, 15.7°²-theta, 16.3°²-theta, 17.5°²-theta, 18.3°²-theta, 18.7°²-theta, 20.1°²-theta, 21.6°²-theta, 21.8°²-theta, 25.2°²-theta, and 25.7°²-theta. In some embodiments, the crystalline compound 1, i.e., form 4, has an XRPD pattern with at least seven characteristic peaks selected from 8.1°²-theta, 9.4°²-theta, 10.8°²-theta, 13.5°²-theta, 15.7°²-theta, 16.3°²-theta, 17.5°²-theta, 18.3°²-theta, 18.7°²-theta, 20.1°²-theta, 21.6°²-theta, 21.8°²-theta, 25.2°²-theta, and 25.7°²-theta.In some embodiments, the crystalline compound 1, i.e., form 4, has an XRPD pattern with at least eight, or at least nine, or at least ten, or at least eleven, or at least 12, or at least 13 characteristic peaks selected from 8.1°²-theta, 9.4°²-theta, 10.8°²-theta, 13.5°²-theta, 15.7°²-theta, 16.3°²-theta, 17.5°²-theta, 18.3°²-theta, 18.7°²-theta, 20.1°²-theta, 21.6°²-theta, 21.8°²-theta, 25.2°²-theta, and 25.7°²-theta. In some embodiments, the crystalline compound 1, i.e., form 4, has an XRPD pattern with characteristic peaks at 10.8°²-theta, 15.7°²-theta, 16.3°²-theta, 17.5°²-theta, 18.3°²-theta, 18.7°²-theta, 21.6°²-theta, and 21.8°²-theta. In some embodiments, crystalline compound 1, i.e., form 4, has an XRPD pattern with characteristic peaks at 8.1°2-theta, 9.4°2-theta, 10.8°2-theta, 13.5°2-theta, 15.7°2-theta, 16.3°2-theta, 17.5°2-theta, 18.3°2-theta, 18.7°2-theta, 20.1°2-theta, 21.6°2-theta, 21.8°2-theta, 25.2°2-theta, and 25.7°2-theta. In some embodiments, crystalline compound 1, i.e., form 4, has a DSC thermogram substantially similar to that shown in Figure 8. In some embodiments, crystalline compound 1, i.e., form 4, has a DSC thermogram with a first endothermic onset temperature of about 127°C and / or a peak temperature of about 138°C, and optionally a second endothermic onset temperature of about 45°C and / or a peak temperature of about 75°C. In some embodiments, crystalline compound 1, i.e., form 4, is obtained from EtOH, propanol, or IPA, or a mixture thereof. In some embodiments, crystalline compound 1, i.e., form 4, is obtained from EtOH. In some embodiments, crystalline compound 1, i.e., form 4, is obtained from propanol. In some embodiments, crystalline compound 1, i.e., form 4, is obtained from IPA.In some embodiments, crystalline compound 1, i.e., form 4, is obtained from a mixture of two or more of EtOH, propanol, and IPA. In some embodiments, crystalline compound 1, i.e., form 4, is a hydrate.

[0047] Crystalline compound 1, form 5 In some embodiments, the crystalline form of compound 1 is characterized by having at least one of the following properties: (a) An XRPD pattern substantially similar to that shown in Figure 9, (b) XRPD pattern with at least three characteristic peaks selected from 7.9°²-theta, 8.5°²-theta, 9.6°²-theta, 11.1°²-theta, 15.8°²-theta, 16.9°²-theta, 18.4°²-theta, 19.1°²-theta, 22.1°²-theta, 25.5°²-theta, and 27.4°²-theta, (c) A DSC thermogram substantially similar to the one shown in Figure 10, (d) A DSC thermogram with an onset temperature of approximately 122°C and / or a peak temperature of approximately 132°C. (e) A DVS curve substantially similar to that shown in Figure 11, or (f) combinations of those

[0048] In some embodiments, the crystalline compound 1, i.e., form 5, is characterized by having at least two of the properties selected from (a) to (e). In some embodiments, the crystalline compound 1, i.e., form 5, is characterized by having at least three of the properties selected from (a) to (e). In some embodiments, the crystalline compound 1, i.e., form 5, is characterized by having at least four of the properties selected from (a) to (e). In some embodiments, the crystalline compound 1, i.e., form 5, is characterized by having properties (a) to (e).

[0049] In some embodiments, crystalline compound 1, i.e., form 5, has an XRPD pattern substantially similar to that shown in Figure 9. In some embodiments, crystalline compound 1, i.e., form 5, has an XRPD pattern with at least four characteristic peaks selected from 7.9°²-theta, 8.5°²-theta, 9.6°²-theta, 11.1°²-theta, 15.8°²-theta, 16.9°²-theta, 18.4°²-theta, 19.1°²-theta, 22.1°²-theta, 25.5°²-theta, and 27.4°²-theta. In some embodiments, the crystalline compound 1, i.e., form 5, has an XRPD pattern with at least five characteristic peaks selected from 7.9°²-theta, 8.5°²-theta, 9.6°²-theta, 11.1°²-theta, 15.8°²-theta, 16.9°²-theta, 18.4°²-theta, 19.1°²-theta, 22.1°²-theta, 25.5°²-theta, and 27.4°²-theta. In some embodiments, the crystalline compound 1, i.e., form 5, has an XRPD pattern with at least six characteristic peaks selected from 7.9°²-theta, 8.5°²-theta, 9.6°²-theta, 11.1°²-theta, 15.8°²-theta, 16.9°²-theta, 18.4°²-theta, 19.1°²-theta, 22.1°²-theta, 25.5°²-theta, and 27.4°²-theta. In some embodiments, the crystalline compound 1, i.e., form 5, has an XRPD pattern with at least seven characteristic peaks selected from 7.9°²-theta, 8.5°²-theta, 9.6°²-theta, 11.1°²-theta, 15.8°²-theta, 16.9°²-theta, 18.4°²-theta, 19.1°²-theta, 22.1°²-theta, 25.5°²-theta, and 27.4°²-theta.In some embodiments, the crystalline compound 1, i.e., form 5, has an XRPD pattern with at least eight, or at least nine, or at least ten characteristic peaks selected from 7.9°²-theta, 8.5°²-theta, 9.6°²-theta, 11.1°²-theta, 15.8°²-theta, 16.9°²-theta, 18.4°²-theta, 19.1°²-theta, 22.1°²-theta, 25.5°²-theta, and 27.4°²-theta. In some embodiments, crystalline compound 1, i.e., form 5, has an XRPD pattern with characteristic peaks at 7.9°²-theta, 8.5°²-theta, 9.6°²-theta, 11.1°²-theta, 15.8°²-theta, 16.9°²-theta, 18.4°²-theta, 19.1°²-theta, 22.1°²-theta, 25.5°²-theta, and 27.4°²-theta. In some embodiments, crystalline compound 1, i.e., form 5, has a DSC thermogram substantially similar to that shown in Figure 10. In some embodiments, crystalline compound 1, i.e., form 5, has a DSC thermogram with endothermic activity with a starting temperature of approximately 122°C. In some embodiments, crystalline compound 1, i.e., form 5, has a DSC thermogram with endothermic activity with a peak temperature of approximately 132°C. In some embodiments, crystalline compound 1, i.e., form 5, has a DVS curve substantially similar to that shown in Figure 11. In some embodiments, crystalline compound 1, i.e., form 5, is obtained from EtOH and is then optionally dried. In some embodiments, crystalline compound 1, i.e., form 5, is an anhydrous form. In some embodiments, crystalline compound 1, i.e., form 5 has a residual EtOH content of less than 0.1% or about 0.05%, and a residual water content measured to be about 0.5% by KF analysis.

[0050] Preparation of crystalline compound 1 In some embodiments, the crystalline form of compound 1 or its solvate is prepared as outlined in the examples. Note that the solvent, temperature, and other reaction conditions presented herein may vary.

[0051] In another embodiment, the crystalline compound 1, i.e., form 1, is substantially pure. In a particular embodiment, the substantially pure crystalline compound 1, i.e., form 1, substantially contains no other solid forms, such as amorphous solids. In a particular embodiment, the purity of the substantially pure crystalline compound 1, i.e., form 1 is about 95% or higher, about 96% or higher, about 97% or higher, about 98% or higher, about 98.5% or higher, about 99% or higher, about 99.5% or higher, or about 99.8% or higher.

[0052] In another embodiment, crystalline compound 1, i.e., form 2, is substantially pure. In a particular embodiment, substantially pure crystalline compound 1, i.e., form 2, substantially contains no other solid forms, such as amorphous solids. In a particular embodiment, the purity of substantially pure crystalline compound 1, i.e., form 2 is about 95% or higher, about 96% or higher, about 97% or higher, about 98% or higher, about 98.5% or higher, about 99% or higher, about 99.5% or higher, or about 99.8% or higher.

[0053] In another embodiment, crystalline compound 1, i.e., form 3, is substantially pure. In a particular embodiment, substantially pure crystalline compound 1, i.e., form 3, substantially contains no other solid forms, such as amorphous solids. In a particular embodiment, the purity of substantially pure crystalline compound 1, i.e., form 3 is about 95% or higher, about 96% or higher, about 97% or higher, about 98% or higher, about 98.5% or higher, about 99% or higher, about 99.5% or higher, or about 99.8% or higher.

[0054] In another embodiment, crystalline compound 1, i.e., form 4, is substantially pure. In a particular embodiment, substantially pure crystalline compound 1, i.e., form 4, substantially contains no other solid forms, such as amorphous solids. In a particular embodiment, the purity of substantially pure crystalline compound 1, i.e., form 4 is about 95% or higher, about 96% or higher, about 97% or higher, about 98% or higher, about 98.5% or higher, about 99% or higher, about 99.5% or higher, or about 99.8% or higher.

[0055] In another embodiment, the crystalline compound 1, i.e., form 5, is substantially pure. In a particular embodiment, the substantially pure crystalline compound 1, i.e., form 5, substantially contains no other solid forms, such as amorphous solids. In a particular embodiment, the purity of the substantially pure crystalline compound 1, i.e., form 5 is about 95% or higher, about 96% or higher, about 97% or higher, about 98% or higher, about 98.5% or higher, about 99% or higher, about 99.5% or higher, or about 99.8% or higher.

[0056] Suitable solvent Therapeutic agents that can be administered to mammals such as humans must be prepared in accordance with regulatory guidelines. Such government regulatory guidelines are called Good Manufacturing Practices (GMP). GMP guidelines outline acceptable levels of contamination of active therapeutic agents, such as the amount of solvent remaining in the final product. In some embodiments, the solvents disclosed herein are suitable for use in GMP facilities and are consistent with industrial safety concerns. Solvent categories are defined, for example, in the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) "Impurities: Guidelines for Residual Solvents Q3C(R6)" (October 2016).

[0057] Solvents are classified into three classes. Class 1 solvents are toxic and must be avoided. Class 2 solvents are limited to use during the manufacture of therapeutic agents. Class 3 solvents have low potential toxicity and pose little risk to human health. Data on Class 3 solvents shows that they have low toxicity in acute or short-term tests and are negative in genotoxicity tests.

[0058] Class 1 solvents to be avoided include benzene, carbon tetrachloride, 1,2-dichloroethane, 1,1-dichloroethene, and 1,1,1-trichloroethane.

[0059] Examples of Class 2 solvents include ACN, chlorobenzene, chloroform, cumene, cyclohexane, 1,2-dichloroethene, 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, tetralin, toluene, 1,1,2-trichloroethene, and xylene.

[0060] Low-toxicity Class 3 solvents include acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, MTBE, dimethyl sulfoxide (DMSO), EtOH, HCl, 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.

[0061] The solvents remaining in active pharmaceutical ingredients (APIs) are a byproduct of API manufacturing. In some cases, these solvents are not completely removed even with actual manufacturing techniques. Appropriate selection of solvents in API synthesis can improve yield or determine characteristics such as crystalline form, purity, and solubility. Therefore, solvents are a crucial parameter in the synthesis process.

[0062] In some embodiments, the composition containing compound 1 or a solvate in crystalline form contains an organic solvent. In some embodiments, the composition containing compound 1 or a solvate in crystalline form contains a residual amount of organic solvent. In some embodiments, the composition containing compound 1 or a solvate in crystalline form contains a residual amount of class 3 solvent. In some embodiments, the organic solvent is a class 3 solvent, for example, the class 3 solvents listed above. In some embodiments, the class 3 solvent is selected from the group consisting of acetone, siRNA, isopropyl acetate, MTBE, heptane, IPA, and EtOH. In some embodiments, the organic solvent is a class 2 solvent, for example, 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).

[0063] Pharmaceutical composition / Pharmaceutical preparation In some embodiments, the pharmaceutical composition comprises crystalline compound 1 and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises compound 1, form 2, form 3, form 4, or form 5 and a pharmaceutically acceptable excipient. The pharmaceutical composition comprising crystalline compound 1, or compound 1, form 2, form 3, form 4, or form 5, can be formulated conventionally. Examples of pharmaceutically acceptable excipients include diluents, fillers, binders, disintegrants, flow enhancers, lubricants, carriers, stabilizers, dispersants, suspending agents, surfactants, and thickeners, as well as capsule shells or tablet coatings.

[0064] method In some embodiments, the method is for treating a disease or illness of interest, the disease or illness of interest including leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, hematological malignancies, myelodysplastic syndromes, myelodysplastic / myeloproliferative neoplasms, solid tumor cancers, prostate cancer, breast cancer, liver cancer, brain tumors, or diabetes, and the method includes administering to the subject a crystalline form of Compound 1 or its solvate as described herein, or a pharmaceutical composition containing Compound 1 or its solvate or a crystalline form of Compound 1 or its solvate, for example, such a compound or pharmaceutical composition as described herein, in a therapeutically effective amount. In some embodiments, the crystalline form of Compound 1 is Form 1 of Compound 1, or Form 2 of Compound 1, or Form 3 of Compound 1, or Form 4 of Compound 1, or Form 5 of Compound 1. When performing the treatment or method of use provided herein, a therapeutically effective amount of Compound 1 or its solvate is administered, for example, in a pharmaceutical composition, to a mammal suffering from the disease, disorder, or illness to be treated. In some embodiments, the mammal is a human. The therapeutically effective dose may vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors. In some embodiments, the method is for treating leukemia, where leukemia is optionally AML or ALL, and the method comprises administering a therapeutically effective dose of compound 1 or a solvate thereof described herein to a subject in need of treatment for leukemia. In some embodiments, AML is menin-dependent AML, KMT2A rearranged AML, or NPM1 mutant AML. In some embodiments, ALL is KTM2A rearranged ALL. [Examples]

[0065] I. Characterization of Polymorphs Example 1: X-ray powder diffraction (XRPD) X-ray powder diffraction tests were performed using a Bruker D8 Advance with the following instrument parameters: X-ray wavelength: Cu: K-alpha (I=1.54179), X-ray tube settings: voltage: 40kV, current: 40mA, scanning range: 4°(2θ)~40°(2θ), sample rotation speed: 15rpm, scanning speed: 10deg / min.

[0066] XRPD analysis of Form 1 of Compound 1 (Figure 1) revealed that Form 1 is a crystal with characteristic peaks at 4.1°2-theta, 5.4°2-theta, 6.6°2-theta, 8.2°2-theta, 9.5°2-theta, 12.3°2-theta, 13.1°2-theta, 13.9°2-theta, 15.9°2-theta, 16.4°2-theta, 17.0°2-theta, 17.5°2-theta, 19.7°2-theta, and 22.6°2-theta.

[0067] XRPD analysis of compound 1, form 2 (Figure 4) revealed that form 2 is a crystal with characteristic peaks at 3.8°²-theta, 5.6°²-theta, 6.4°²-theta, 7.1°²-theta, 8.8°²-theta, 9.9°²-theta, 11.9°²-theta, and 14.8°²-theta.

[0068] XRPD analysis of form 3 of compound 1 (Figure 5) revealed that form 3 is a crystal with characteristic peaks at 7.9°²-theta, 9.5°²-theta, 11.0°²-theta, 15.7°²-theta, 16.5°²-theta, 18.0°²-theta, 19.0°²-theta, and 21.9°²-theta.

[0069] XRPD analysis of form 4 of compound 1 (Figure 7) revealed that form 4 is a crystal with characteristic peaks at 8.1°2-theta, 9.4°2-theta, 10.8°2-theta, 13.5°2-theta, 15.7°2-theta, 16.3°2-theta, 17.5°2-theta, 18.3°2-theta, 18.7°2-theta, 20.1°2-theta, 21.6°2-theta, 21.8°2-theta, 25.2°2-theta, and 25.7°2-theta.

[0070] XRPD analysis of form 5 of compound 1 (Figure 9) revealed that form 5 is a crystal with characteristic peaks at 7.9°²-theta, 8.5°²-theta, 9.6°²-theta, 11.1°²-theta, 15.8°²-theta, 16.9°²-theta, 18.4°²-theta, 19.1°²-theta, 22.1°²-theta, 25.5°²-theta, and 27.4°²-theta.

[0071] Example 2: Differential Scanning Calorimetry (DSC) DSC testing was performed using a TA Discovery Q2000 or DSC250. Samples were weighed in a compressed aluminum pan, and the exact amount was recorded. Samples were heated from room temperature or 30°C to 250°C or 300°C at a heating rate of 10°C / min while purging with nitrogen.

[0072] DSC analysis of compound 1, form 1 (Figure 2) revealed endothermic activity with an onset temperature of approximately 136°C. DSC analysis of compound 1, form 1 (Figure 2) revealed endothermic activity with a peak temperature of approximately 149°C.

[0073] DSC analysis of compound 1 in form 3 (Figure 6A) revealed endothermic activity with an onset temperature of approximately 117°C and / or a peak temperature of approximately 135°C.

[0074] DSC analysis of compound 1, form 4 (Figure 8), revealed endothermic reactions with an onset temperature of approximately 45°C and a peak temperature of approximately 75°C, as well as endothermic reactions with an onset temperature of approximately 127°C and a peak temperature of approximately 138°C.

[0075] DSC analysis of compound 1 in form 5 (Figure 10) revealed endothermic fusion with an onset temperature of approximately 122°C and a peak temperature of approximately 132°C.

[0076] Example 3: Thermogravimetric Analysis / Dynamic Vapor Adsorption Thermogravimetric analysis of the solid was performed using the TA Q5000IR. The sample was placed in an open platinum pan, and its volume was automatically weighed. The sample was heated from 30°C to 300°C at a heating rate of 10°C / min.

[0077] In TGA of compound 1 in form 1 (Figure 3), a weight loss of approximately 0.6% was observed over a temperature range of approximately 29°C to approximately 150°C.

[0078] In the TGA of compound 1 in form 3 (Figure 6B), a weight loss of approximately 1.33% was observed over a temperature range of approximately 29°C to approximately 150°C.

[0079] The dynamic vapor sorbation test was performed at 25°C using 10-15 mg of sample under N2 conditions at a flow rate of 200 mL / min, followed by drying at 0% relative humidity for 120 minutes.

[0080] DVS (Figure 11) was obtained for form 5 of compound 1. Form 5 of compound 1 contained less than 0.1% or about 0.05% residual EtOH, and KF analysis revealed a residual water content of about 0.5%.

[0081] II. Polymorphic Screens Example 4: Solid vapor diffusion Solid vapor diffusion experiments were conducted using 14 different solvents. Approximately 10 mg of amorphous compound 1 (free base) was weighed and placed in a 4 mL vial, which was then added to a 40 mL vial containing 3 mL of volatile solvent. The 40 mL vial was sealed with a cap and maintained under ambient laboratory conditions for 1 day to allow the solvent vapor to interact with the sample. In the case of a clear solution, slow evaporation under ambient laboratory conditions was performed to induce crystallization. The resulting solids were tested by XRPD. The results are summarized in Table 1. Forms 1 and 2 of compound 1 were produced by solid vapor diffusion in toluene and ACN, respectively.

[0082] [Table 1]

[0083] Example 5: Slurry at 25°C Slurry conversion experiments were performed at 25°C in different solvent systems. Approximately 10-20 mg of amorphous compound 1 was weighed and placed in 0.5 mL of solvent in a 2 mL glass vial, then vortexed for approximately 2 minutes to thoroughly mix. After shaking at 25°C for 2 days, clear solutions were obtained in all solvents except MeOH / H2O (3:1, v / v), IPA, MTBE, and toluene. The 12 solvent systems containing the clear solutions were stored in a refrigerator at 4°C to induce crystallization. No precipitate was observed. Solids were obtained under ambient laboratory conditions by slow evaporation and tested by XRPD. The results are summarized in Table 2. Form 1 of compound 1 was produced as shown below. EtOH experiments yielded a crystalline form, namely form 3, as shown by XRPD. The DSC showed broad endothermic activity over a range of approximately 95°C to 150°C, with an onset temperature of approximately 117°C and a peak temperature of approximately 135°C. The TGA showed a weight loss of approximately 1.3% over a range of approximately 29°C to 150°C (DSC and TGA are not shown). Form 3 of compound 1 was characterized as an EtOH solvate. Form 3 was heated at 90°C and then vacuum-dried to obtain form 5. Form 5 was characterized as an anhydrous form. Form 5 was also produced after drying by solution crystallization of compound 1 from EtOH and drying the resulting solid.

[0084] [Table 2]

[0085] Example 6: Slow evaporation Samples of amorphous compound 1 (10 mg each) were weighed and placed in clean glass vials. The selected solvent was added to dissolve the samples. If the samples did not dissolve completely, the solid was removed by filtration, and the filtrate was collected and placed in another vial. Each vial was covered with Parafilm containing several pinholes. The solvent was evaporated at ambient temperature. All solid precipitates were collected from the resulting suspensions and analyzed by XRPD. The results are summarized in Table 3, and it can be seen that no crystalline material was obtained.

[0086] [Table 3]

[0087] Example 7: Solution vapor diffusion Solution vapor diffusion experiments were conducted under ambient laboratory conditions using 14 different solvent conditions. 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 into a 40 mL glass vial containing 4 mL of volatile poor solvent (Table 4). The 40 mL vials were capped and maintained under ambient conditions to allow sufficient time for the organic vapor to interact with the solution. In the case of clear solutions, slow evaporation induced crystallization under ambient laboratory conditions. All precipitates were isolated for XRPD analysis. As summarized in Table 4, no crystalline solids were formed.

[0088] [Table 4]

[0089] Example 8: Preparation of Form 4 of Compound 1 A sample of compound 1 in form 3 was exposed to conditions of 35°C to 40°C and 65°C to 75% relative humidity to obtain compound 1 in form 4 (1.2% water by Karl Fischer analysis).

[0090] Example 9: Preparation of Form 5 of Compound 1 A solution of compound 1 (free base) in 11.5V EtOH was heated at 55°C, then cooled to 30°C, 1% by weight of form 3 was added, and the mixture was stirred at 30°C for 15 hours, cooled to -5°C over 7 hours, and stirred at -5°C for 19 hours. The resulting solid was filtered, washed with 2V EtOH, and dried under vacuum at 50°C to obtain form 5 of compound 1 (0.05% residual EtOH, 0.5% water, as determined by Karl Fischer analysis).

[0091] Example 10: Interconversion test between form 1 and form 5 of compound 1 Saturated solutions of form 1 of compound 1 in EtOH, MTBE, and isopropyl acetate were prepared at 50°C. Approximately 6 mg each of form 1 and form 5 of compound 1 were weighed and added to each saturated solution, and the resulting suspensions were made into slurries at the corresponding temperatures over 2 days. The resulting solids were sampled for XRPD analysis. As shown in Table 5, form 1 of compound 1 is a thermodynamically stable crystalline form.

[0092] [Table 5]

[0093] Example 11: Interconversion test of forms 1, 4, and 5 of compound 1 Treatment of a 1:1 mixture of Form 1 and Form 4 in IPA, IPA / water, MTBE, or CPME at 5 or 50°C for up to 20 hours, or acetone / water at 25°C for up to 24 hours, yielded mostly or completely Form 1, while treatment in water at 5 or 50°C for up to 20 hours yielded a mixture of Form 1 and Form 4.

[0094] Form 1 was obtained by treating a 1:1 mixture of Form 1 and Form 5 in IPAc, IPA, n-PrOH, or toluene at 25°C for up to 24 hours.

[0095] Form 1 was obtained by treating a 1:1:1 mixture of Forms 1, 4, and 5 in a mixture of water and IPA at 25°C for up to 24 hours.

[0096] Form 5 was treated at 40°C and 75% relative humidity for 6 days to mainly obtain Form 4.

[0097] Form 4 was mainly obtained by treating Form 4 under vacuum and in an inert atmosphere at 50°C for 5 days.

[0098] II. Biological Data Example 12: Fluorescence Polarization Assay Fluorescence polarization (FP) competition experiments were conducted to determine the effectiveness of compound 1 in inhibiting the interaction between menine and MLL, and IC 50The values ​​were reported. A fluorescein-labeled peptide containing a high-affinity menine-binding motif found in MLL was generated according to Yokoyama et al. (Cell, 2005, 123(2): pp. 207-218). Binding of the labeled peptide (1.7 kDa) to a larger menine (approximately 67 kDa) was accompanied by a significant change in the rotational correlation time of the fluorophore, and a substantial increase in fluorescence polarization and fluorescence anisotropy (excitation at 500 nm, emission at 525 nm). The effectiveness of compound 1 in inhibiting the interaction between menine and MLL was measured by an FP competition experiment in which a decrease in fluorescence anisotropy correlates with inhibition of the interaction, and this was converted to IC. 50 Used as a readout for the determination of compound 1. IC 50 The maximum half-dose inhibitory concentration is less than 50 nM.

Claims

1. (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazine-1-yl)propyl)-1H-indole-2-carbonitride or its solvate in crystalline form.

2. The crystalline form of (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazine-1-yl)propyl)-1H-indole-2-carbonitrile has the following properties: (a) X-ray powder diffraction (XRPD) pattern substantially similar to that shown in Figure 1, (b) XRPD pattern with at least three characteristic peaks selected from 4.1°²-theta, 5.4°²-theta, 6.6°²-theta, 8.2°²-theta, 9.5°²-theta, 12.3°²-theta, 13.1°²-theta, 13.9°²-theta, 15.9°²-theta, 16.4°²-theta, 17.0°²-theta, 17.5°²-theta, 19.7°²-theta, and 22.6°²-theta, (c) A differential scanning calorimetry (DSC) thermogram substantially similar to that shown in Figure 2, (d) An endothermic DSC thermogram with an onset temperature of approximately 136°C and / or a peak temperature of approximately 149°C. (e) A thermogravimetric analysis (TGA) curve substantially similar to that shown in Figure 3, or (f) combinations of those The crystal form according to claim 1, which is a form 1 having at least one of the above.

3. The crystal morphology according to claim 2, wherein the crystal morphology has an XRPD pattern substantially the same as that shown in Figure 1.

4. The crystal morphology according to claim 2, wherein the crystal morphology has an XRPD pattern with at least five characteristic peaks selected from 4.1°²-theta, 5.4°²-theta, 6.6°²-theta, 8.2°²-theta, 9.5°²-theta, 12.3°²-theta, 13.1°²-theta, 13.9°²-theta, 15.9°²-theta, 16.4°²-theta, 17.0°²-theta, 17.5°²-theta, 19.7°²-theta, and 22.6°²-theta.

5. The crystal morphology according to claim 2, wherein the crystal morphology has a DSC thermogram substantially the same as that shown in Figure 2.

6. The crystal morphology according to claim 2, wherein the crystal morphology has an endothermic DSC thermogram with a starting temperature of approximately 136°C or a peak temperature of approximately 149°C.

7. The crystal morphology according to claim 2, wherein the crystal morphology has a TGA curve substantially the same as that shown in Figure 3.

8. The crystal morphology according to claim 2, characterized in that the crystal morphology has properties (a), (b), (c), (d), and (e).

9. The crystalline form of (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazine-1-yl)propyl)-1H-indole-2-carbonitrile has the following characteristics: (a) An XRPD pattern substantially the same as that shown in Figure 5, (b) XRPD pattern with at least three characteristic peaks selected from 7.9°²-theta, 9.5°²-theta, 11.0°²-theta, 15.7°²-theta, 16.5°²-theta, 18.0°²-theta, 19.0°²-theta, and 21.9°²-theta, (c) A DSC thermogram substantially similar to the one shown in Figure 6A, (d) An endothermic DSC thermogram with an onset temperature of approximately 117°C and / or a peak temperature of approximately 135°C. (e) A TGA curve substantially similar to that shown in Figure 6B, or (f) combinations of those The crystal form according to claim 1, which is form 3 having at least one of the above.

10. The crystal morphology according to claim 9, wherein the crystal morphology has an XRPD pattern substantially the same as that shown in Figure 5.

11. The crystal morphology according to claim 9, wherein the crystal morphology has an XRPD pattern with at least five characteristic peaks selected from 7.9°²-theta, 9.5°²-theta, 11.0°²-theta, 15.7°²-theta, 16.5°²-theta, 18.0°²-theta, 19.0°²-theta, and 21.9°²-theta.

12. The crystal morphology according to claim 9, wherein the crystal morphology has a DSC thermogram substantially the same as that shown in Figure 6A.

13. The crystal morphology according to claim 9, wherein the crystal morphology has an endothermic DSC thermogram with a starting temperature of approximately 117°C and / or a peak temperature of approximately 135°C.

14. The crystal morphology according to claim 9, wherein the crystal morphology has a TGA curve substantially the same as that shown in Figure 6B.

15. The crystal morphology according to claim 9, characterized in that the crystal morphology has 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 of (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazine-1-yl)propyl)-1H-indole-2-carbonitrile has the following characteristics: (a) An XRPD pattern substantially the same as that shown in Figure 7, (b) XRPD pattern with at least three characteristic peaks selected from 8.1°²-theta, 9.4°²-theta, 10.8°²-theta, 13.5°²-theta, 15.7°²-theta, 16.3°²-theta, 17.5°²-theta, 18.3°²-theta, 18.7°²-theta, 20.1°²-theta, 21.6°²-theta, 21.8°²-theta, 25.2°²-theta, and 25.7°²-theta, (c) A DSC thermogram substantially similar to the one shown in Figure 8, (d) an endothermic DSC thermogram with a starting temperature of approximately 127°C and / or a peak temperature of approximately 138°C, (e) combinations of those The crystal form according to claim 1, which is form 4 having at least one of the above.

18. The crystal morphology according to claim 17, wherein the crystal morphology has an XRPD pattern substantially the same as that shown in Figure 7.

19. The crystal morphology according to claim 17, wherein the crystal morphology has an XRPD pattern with at least five characteristic peaks selected from 8.1°²-theta, 9.4°²-theta, 10.8°²-theta, 13.5°²-theta, 15.7°²-theta, 16.3°²-theta, 17.5°²-theta, 18.3°²-theta, 18.7°²-theta, 20.1°²-theta, 21.6°²-theta, 21.8°²-theta, 25.2°²-theta, and 25.7°²-theta.

20. The crystal morphology according to claim 17, wherein the crystal morphology has a DSC thermogram substantially the same as that shown in Figure 8.

21. The crystal morphology according to claim 17, wherein the crystal morphology has an endothermic DSC thermogram with a starting temperature of approximately 127°C and / or a peak temperature of approximately 138°C.

22. The crystal morphology according to claim 17, characterized in that the crystal morphology has 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 isopropyl alcohol, or a mixture thereof.

24. The crystalline form of (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazine-1-yl)propyl)-1H-indole-2-carbonitrile has the following characteristics: (a) An XRPD pattern substantially the same as that shown in Figure 9, (b) XRPD pattern with at least three characteristic peaks selected from 7.9°²-theta, 8.5°²-theta, 9.6°²-theta, 11.1°²-theta, 15.8°²-theta, 16.9°²-theta, 18.4°²-theta, 19.1°²-theta, 22.1°²-theta, 25.5°²-theta, and 27.4°²-theta, (c) A DSC thermogram substantially similar to the one shown in Figure 10, (d) An endothermic DSC thermogram with an onset temperature of approximately 122°C and / or a peak temperature of approximately 132°C. (e) A DVS curve substantially similar to that shown in Figure 11, or (f) combinations of those The crystal form according to claim 1, which is form 5 having at least one of the above.

25. The crystal morphology according to claim 24, wherein the crystal morphology has an XRPD pattern substantially the same as that shown in Figure 9.

26. The crystal morphology according to claim 24, wherein the crystal morphology has an XRPD pattern with at least five characteristic peaks selected from 7.9°²-theta, 8.5°²-theta, 9.6°²-theta, 11.1°²-theta, 15.8°²-theta, 16.9°²-theta, 18.4°²-theta, 19.1°²-theta, 22.1°²-theta, 25.5°²-theta, and 27.4°²-theta.

27. The crystal morphology according to claim 24, wherein the crystal morphology has a DSC thermogram substantially the same as that shown in Figure 10.

28. The crystal morphology according to claim 24, wherein the crystal morphology has an endothermic DSC thermogram with a starting temperature of approximately 122°C and / or a peak temperature of approximately 132°C.

29. The crystal morphology according to claim 24, wherein the crystal morphology has a DVS curve substantially the same as that shown in Figure 11.

30. The crystal morphology according to claim 24, characterized in that the crystal morphology has 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 or 9 to 30 and a pharmaceutically acceptable excipient.

33. (a) Crystal morphology 2 having an XRPD pattern with at least three characteristic peaks selected from 3.8°²-theta, 5.6°²-theta, 6.4°²-theta, 7.1°²-theta, 8.8°²-theta, 9.9°²-theta, 11.9°²-theta, and 14.8°²-theta, or (b) Crystal morphology 3 having an XRPD pattern with at least three characteristic peaks selected from 7.9°²-theta, 9.5°²-theta, 11.0°²-theta, 15.7°²-theta, 16.5°²-theta, 18.0°²-theta, 19.0°²-theta, and 21.9°²-theta, or (c) Crystal morphology 4 having an XRPD pattern with at least three characteristic peaks selected from 8.1°²-theta, 9.4°²-theta, 10.8°²-theta, 13.5°²-theta, 15.7°²-theta, 16.3°²-theta, 17.5°²-theta, 18.3°²-theta, 18.7°²-theta, 20.1°²-theta, 21.6°²-theta, 21.8°²-theta, 25.2°²-theta, and 25.7°²-theta, or (d) Crystal morphology 5 having an XRPD pattern with at least three characteristic peaks selected from 7.9°²-theta, 8.5°²-theta, 9.6°²-theta, 11.1°²-theta, 15.8°²-theta, 16.9°²-theta, 18.4°²-theta, 19.1°²-theta, 22.1°²-theta, 25.5°²-theta, and 27.4°²-theta, or (e) combinations of those The pharmaceutical composition according to claim 32, comprising:

34. A method for treating a target disease or illness, comprising the step of administering to the target a crystalline form described in any one of claims 1 to 31, or a pharmaceutical composition described in claim 32 or claim 33, wherein the disease or illness includes leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, hematological malignancies, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasms, solid tumor carcinoma, prostate cancer, breast cancer, liver cancer, brain tumor, or diabetes.

35. A method for inhibiting the interaction between menine and one or more of MLL1, MLL2, MLL fusion proteins, and MLL partial tandem duplication, comprising the step of contacting menine with the crystalline form described in any one of claims 1 to 31, or the pharmaceutical composition described in claim 32 or claim 33.

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