Pharmaceutical composition containing 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, a method for preparing the crystalline form, and pharmaceutical compositions containing the crystalline form.

Description

[Technical Field]

[0001] cross reference This application claims benefits under U.S. Provisional Patent Application No. 63 / 514,089 filed July 17, 2023, and International Application PCT / CN2024 / 097083 filed June 3, 2024, which are incorporated herein by reference in their entirety. [Background technology]

[0002] Mixed-phenotype 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-phenotype leukemia (MLL), are characterized by the presence of chimeric MLL fusion proteins resulting from a chromosomal translocation of the MLL gene located in band q23 (11q23) of chromosome 11. Chimeric MLL fusion proteins retain approximately 1,400 amino acids from the N-terminus of MLL but are fused with one of approximately 80 partner proteins (e.g., AF4, AF9, ENL, AF10, ELL, AF6, AF1p, GAS7). MLL fusion proteins lack the intrinsic histone methyltransferase activity of the C-terminus of MLL and acquire the ability to regulate the transcription of numerous 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 chemotherapy target. [Overview of the project]

[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), 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) 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] 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.

[0007] 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 pharmaceutical composition comprising 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, wherein the disease or illness is a 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.

[0008] 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.

[0009] 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]

[0010] [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-carbonitride (Compound 1) or its solvate, i.e., Form 1. [Modes for carrying out the invention]

[0011] Specific terms Unless otherwise defined, all technical and scientific terms used herein shall have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any claimed subject matter. In this application, the use of the singular is intended to include the plural unless specifically stated otherwise. It should be noted that, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. In this application, the use of “or” means “and / or” unless otherwise specified further. Additionally, the use of other forms such as “include,” “includes,” and “included” in addition to the term “including” is not limiting. The term “comprising” (and related terms such as “comprise,” “comprises,” “having,” or “including”) is not intended to exclude the possibility that other specific embodiments, for example, embodiments of any composition, mixture, method, or process described herein, may “consist of” or “consist essentially of” the recited features. The term “about” when referring to a number or numerical range means that the recited number or numerical range is an approximation within experimental variation (or within statistical experimental error), and thus the number or numerical range may vary between 1% and 5% of the explicitly recited number or numerical range.

[0012] The section headings used herein are for purposes of organization only and are not to be construed as limiting the subject matter described. All documents or portions thereof cited in this application, including but not limited to patents, patent applications, articles, books, manuals, and papers, are hereby expressly incorporated by reference in their entirety.

[0013] With respect to a formulation, composition, or ingredient, the terms "acceptable" or "pharmaceutically acceptable" as used herein mean that they do not produce a persistent adverse effect on the overall health of the subject being treated or are relatively non-toxic, without inhibiting the biological activity or properties of the compound.

[0014] As used herein, "alleviation" of the symptoms of a particular disease, disorder, or illness by administration of a particular compound or pharmaceutical composition refers to any reduction in severity, delay in onset, retardation of progression, or shortening of duration that may be caused by or associated with the administration of that compound or pharmaceutical composition, whether persistent or transient, permanent or temporary.

[0015] The term "bulk density" means the mass per unit volume of a solid, and the term "tap density" (or "tapped density") means the mass per unit volume of a solid after mechanically tapping a container containing a powder sample, and these can be measured in accordance with United States Pharmacopeia 616.

[0016] Terms such as "co-administration" as used herein are meant to encompass the administration of a selected therapeutic agent to a single patient, and this therapeutic agent is intended to include treatment regimens administered by the same or different routes of administration or at the same or different times.

[0017] 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.

[0018] 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.

[0019] The term "particle size distribution" refers to the proportion of particles of a particular size (or within a particular size range) and can be measured by optical diffraction measurements according to United States Pharmacopeia 786 or United States Pharmacopeia 429.

[0020] 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.

[0021] 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.

[0022] 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.

[0023] 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.

[0024] 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.

[0025] [ka] Compound 1 is a menin inhibitor and inhibits the interaction between menin and MLL.

[0026] 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.

[0027] In other embodiments, compound 1 or its solvate may be prepared in a variety of forms, including but not limited to amorphous phase, crystalline form, pulverized form, and nanoparticle form. In other embodiments, compound 1 or its solvate may be in granular form.

[0028] 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).

[0029] 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.

[0030] 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.

[0031] In particular, it is impossible to predict a priori whether a crystalline form of a compound exists, let alone the 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 to predict a crystal") See "structure, much less polymorphic forms").

[0032] 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.

[0033] 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

[0034] 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).

[0035] 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 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 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 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 properties starting at approximately 136°C. In some embodiments, crystalline compound 1, i.e., form 1, has a DSC thermogram with endothermic properties peaking at 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 MEK and IPA.In some embodiments, crystalline compound 1, i.e., form 1, is obtained from a 1:1 mixture of MEK and IPA. 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.

[0036] 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.

[0037] 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.

[0038] In some embodiments, crystalline compound 1, i.e., form 1, is obtained from MEK and IPA by wet grinding during the crystallization process. In some embodiments, compound 1, i.e., form 1, is at least 0.1 g / cm³ 3 , or approximately 0.1 to 0.15 g / cm³ 3 , or approximately 0.11, 0.12, 0.13, 0.14, or 0.15 g / cm³ 3 It has a bulk density of . In some embodiments, the crystalline compound 1, i.e., form 1, is D 10 1.5~4.5μm, or approximately 2.0~4.0μm, or approximately 3.8~3.9μm, D 50 5-11 μm, or approximately 9.5-10.5 μm, or D 90 It has a particle size distribution of 13-50 μm, or approximately 33-45 μm (measured by optical diffraction method developed in accordance with the United States Pharmacopeia 429). In some embodiments, the particle size distribution D 90 It is 50 μm or less.

[0039] In some embodiments, the method is for preparing 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, and the method is for preparing the crystalline form of (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine-4-yl)amino) The process includes the steps of: heating piperidine-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazine-1-yl)propyl)-1H-indole-2-carbonitride in a mixture of MEK and IPA to a first temperature of about 35-45°C (optionally, the first temperature is about 40°C) to form a diluted suspension; optionally maintaining the diluted suspension at the first temperature for 3-48 hours; wet grinding the diluted suspension at the first temperature; optionally performing a second wet grinding of the diluted suspension at about 25°C; and filtering the diluted suspension to obtain a crystalline form. In some embodiments, the method comprises the steps of: dissolving (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)piperazin-1-yl)propyl)-1H-indole-2-carbonitrile together with MEK to form a solution; heating the solution to a first temperature; and adding IPA to form a diluted suspension, wherein the v / v ratio of MEK / IPA is optionally about 2:3 to about 1:10, or about 1:2 to about 1:8, or about 1:2, 2:5, or 1:7, or about 1:7.

[0040] 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).

[0041] 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.

[0042] Class 1 solvents to be avoided include benzene, carbon tetrachloride, 1,2-dichloroethane, 1,1-dichloroethene, and 1,1,1-trichloroethane.

[0043] 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.

[0044] 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.

[0045] The solvents remaining in active pharmaceutical ingredients (APIs) originate from the API's manufacturing process. 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, the solvent is a crucial parameter in the synthesis process.

[0046] 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).

[0047] Pharmaceutical composition / formulation Pharmaceutical compositions comprising Compound 1 or its solvates as described herein, such as Form 1, can be formulated conventionally by conventional mixing, dissolution, granulation, sugar-coating, powdering, emulsification, encapsulation, encapsulation, or compression processes, using one or more physiologically acceptable carriers, for example, including excipients and adjuvants that facilitate the processing of the active compound into a preparation usable as a pharmaceutical. The appropriate formulation depends on the selected route of administration. An overview of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995), which is incorporated herein by reference in its entirety; Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 1975; Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980, edited by Liberman, H.A. and Lachman, L.; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins, 1999).

[0048] In one aspect of the present specification, there is described 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-carbonitrile (Compound 1) or a solvate thereof, and a pharmaceutically acceptable excipient. Pharmaceutically acceptable excipients 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. The pharmaceutical composition facilitates the administration of the compound to a mammal. The compound can be used as a component of a mixture, alone, or in combination with one or more therapeutic agents.

[0049] In some embodiments, the pharmaceutical composition comprises a crystalline form of Compound 1 or a solvate thereof and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises crystalline Compound 1, i.e., Form 1, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition has a bulk density of at least 0.1 g / cm 3 , or about 0.1 to about 0.15 g / cm 3 , or about 0.11, 0.12, 0.13, 0.14, or 0.15 g / cm 3 , and / or a particle size distribution (measured by a light diffraction method developed in accordance with USP 429) of D 10 of 1.5 to 4.5 μm, or about 2.0 to 4.0 μm, or about 3.8 to 3.9 μm, D 50 of 5 to 11 μm, or about 9.5 to 10.5 μm, or D 90 of 13 to 50 μm, or about 33 to 45 μm, and comprises Compound 1, i.e., Form 1. In some aspects, the particle size distribution D 90 is 50 μm or less.

[0050] In some embodiments, the pharmaceutical composition is an immediate-release pharmaceutical composition. In some embodiments, the pharmaceutical composition is a solid dosage form. In some embodiments, the pharmaceutical composition contains 15 to 800 mg, or 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, or 800 mg of compound 1 or its solvate. In some embodiments, the pharmaceutical composition is a capsule or tablet dosage form. In some embodiments, the pharmaceutical composition is a capsule dosage form. In some embodiments, the pharmaceutical composition is a tablet dosage form.

[0051] Capsule formulation In some embodiments, the capsule dosage form contains 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, or 400 mg of compound 1 or its solvate. In some embodiments, the capsule dosage form contains 25 mg, 50 mg, or 200 mg of compound 1 or its solvate. In some embodiments, the capsule dosage form contains a granular composition comprising compound 1 or its solvate, or a crystalline form of compound 1 or its solvate, in a capsule shell such as a hydroxypropyl methylcellulose (HPMC) capsule shell. In some embodiments, the granular composition comprises compound 1 or its solvate and a pharmaceutically acceptable excipient. In some embodiments, the granular composition comprises a filler, a disintegrant, a surfactant, or a lubricant, or a combination thereof. In some embodiments, the granular composition comprises two fillers, optionally comprising mannitol and / or microcrystalline cellulose. In some embodiments, the disintegrant is croscarmellose sodium. In some embodiments, the surfactant is sodium lauryl sulfate. In some embodiments, the lubricant is magnesium stearate. In some embodiments, pharmaceutically acceptable excipients are selected from mannitol, microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate, magnesium stearate, and combinations thereof. In some embodiments, the granular composition comprises compound 1 or its solvate, mannitol, microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate, and magnesium stearate. In some embodiments, the granular composition comprises compound 1 or its solvate in crystalline form. In some embodiments, the granular composition comprises crystalline compound 1, i.e., form 1. In some embodiments, the quantitative composition for capsule dosage forms comprises compound 1, e.g., form 1 of compound 1, and one or more of the following excipients in relative amounts listed in Table 1.

[0052] [Table 1]

[0053] In some embodiments, the granular composition contains each of these components in the listed %w / w range. In some embodiments, the granular composition contains 25 mg, 50 mg, or 200 mg of compound 1 or its solvate, one or more fillers (e.g., mannitol and / or microcrystalline cellulose (about 35-85% w / w, or about 45-85% w / w, or about 47% w / w, or about 58% w / w)), a disintegrant (e.g., croscarmellose sodium) (about 1-10% w / w, or about 3-10% w / w, or about 4-8% w / w, or about 6% w / w), a surfactant (e.g., lauryl sulfide) The granules contain sodium phosphate (about 0.1-1.0% w / w, or about 0.2-0.8% w / w, or about 0.4-0.6% w / w, or about 0.5% w / w) and a lubricant (e.g., magnesium stearate) (about 0.1-1.0% w / w, or about 0.2-0.8% w / w, or about 0.4-0.6% w / w, or about 0.5% w / w). In some embodiments, the granule composition contains 25 mg, 50 mg, or 200 mg of compound 1 or its solvate, mannitol (about 15-75%) w / w, or about 25-35% w / w, or about 25-30% w / w, or about 28-32% w / w, or about 29% w / w), microcrystalline cellulose (about 10-35% w / w, or about 25-35% w / w, or about 25-30% w / w, or about 28-32% w / w, or about 29% w / w), croscarmellose sodium (about 1-10% w / w, or about 3-10% w / w, or about 4-8% w / w, or about 6% w / w), sodium lauryl sulfate (about 0.1-1.0% w / w, or The capsule composition contains granules containing approximately 0.2–0.8% w / w, or approximately 0.4–0.6% w / w, or approximately 0.5% w / w, and magnesium stearate (approximately 0.1–1.0% w / w, or approximately 0.2–0.8% w / w, or approximately 0.4–0.6% w / w, or approximately 0.5% w / w). In some embodiments, the capsule composition contains granules and an additional extragranular filler (e.g., mannitol). In some embodiments, the capsule composition contains granules and an extragranular lubricant.

[0054] In some embodiments, the granular composition contains one of the components from the following three exemplary lists in the relative amounts listed in Table 2.

[0055] [Table 2]

[0056] Tablet formulation In some embodiments, the pharmaceutical composition is a tablet dosage form containing about 25 to 800 mg, or about 100 mg, or about 200 mg, or about 300 mg, or about 400 mg, or about 500 mg, or about 600 mg of compound 1 or its solvate. In some embodiments, the tablet dosage form contains a pharmaceutically acceptable excipient selected from fillers, disintegrants, surfactants, flow enhancers, or lubricants, or combinations thereof. In some embodiments, the tablet contains a filler, optionally selected from microcrystalline cellulose, lactose (e.g., anhydrous lactose), mannitol, and combinations thereof, or either microcrystalline cellulose and lactose (e.g., anhydrous lactose) or mannitol. In some embodiments, the tablet contains a disintegrant, optionally the disintegrant being croscarmellose sodium or crospovidone. In some embodiments, the tablet contains a binder, optionally the binder being hydroxypropyl cellulose. In some embodiments, the tablet contains a surfactant, optionally the surfactant being sodium lauryl sulfate. In some embodiments, the tablet contains a flow enhancer, optionally being colloidal silicon dioxide. In some embodiments, the tablet contains a lubricant, optionally being magnesium stearate. In some embodiments, the tablet comprises microcrystalline cellulose, lactose (e.g., anhydrous lactose), hydroxypropyl cellulose, croscarmellose sodium, sodium lauryl sulfate, colloidal silicon dioxide, or magnesium stearate, or any combination thereof. In some embodiments, the tablet dosage form comprises microcrystalline cellulose, lactose (e.g., anhydrous lactose), hydroxypropyl cellulose, croscarmellose sodium, sodium lauryl sulfate, colloidal silicon dioxide, and magnesium stearate. In some embodiments, the tablet is prepared from granules (intragranular portion) and extragranular portion. In some embodiments, the tablet dosage form is coated with a non-functional polyvinyl alcohol-based coating (e.g., Opadry II such as Orange or Beige).In some embodiments, the quantitative composition for tablet dosage form comprises compound 1, for example form 1 of compound 1, and one or more of the following excipients, in the %w / w range listed in Table 3.

[0057] [Table 3]

[0058] The tablet content of compound 1 may be in the range of approximately 25 to 800 mg, or approximately 50 to 500 mg, or approximately 50 to 200 mg, or approximately 200 to 500 mg, or approximately 50 mg, 100 mg, 150 mg, 200 mg, 300 mg, 400 mg, 500 mg, or 600 mg. Compound 1 may be used in a %w / w range of approximately 35 to 75, or approximately 45 to 55, or approximately 60 to 75, or approximately 50 or approximately 67% w / w. Compound 1 may be used in crystalline form. Compound 1 may be used in form 1 or in amorphous form of free base. Compound 1 may be used in free base form 1 as described herein.

[0059] One or more fillers may be used in a total %w / w range of about 10–70, or about 17–45, or about 17–25, or about 35–40, or about 19, or about 22, or about 23, or about 37.5, or about 38.5%w / w. Fillers such as microcrystalline cellulose may be used in a %w / w range of about 7–40, or about 20–30, or about 8–15, or about 25–30, or about 9, or about 12, or about 13, or about 29%w / w, or about 30%w / w. Fillers such as lactose (e.g., anhydrous lactose) or mannitol, preferably anhydrous lactose, may be used in a %w / w range of about 5–25, or 5–20, or 7–18, or 5–10, or about 8.5, or about 9.5, or about 10%w / w.

[0060] Binders such as hydroxypropylcellulose may be used in a %w / w range of approximately 2-10, 3-7, or 4-5, or at approximately 3%, 4%, or 5% w / w.

[0061] A granular disintegrant such as croscarmellose sodium or crospovidone, preferably croscarmellose sodium, may be used in a %w / w range of about 1 to 6 or about 2 to 4, or about 2% or about 3% w / w.

[0062] Surfactants such as sodium lauryl sulfate may be used in a %w / w range of approximately 0.3 to 2, or at approximately 1%w / w.

[0063] An extragranular disintegrant such as croscarmellose sodium or crospovidone, preferably croscarmellose sodium, may be used in a %w / w range of about 1 to 4, or about 1 to 3, or about 2%w / w.

[0064] Lubricants such as magnesium stearate may be used in a %w / w range of approximately 0.3 to 2, or approximately 0.5 to 1.5, or approximately 0.75 or 1%w / w. Optionally, the lubricant may be present in the extragranular components.

[0065] Flow accelerators such as colloidal silicon dioxide may be used in a %w / w range of approximately 0.1 to 1, or approximately 0.5%w / w.

[0066] In some embodiments, the tablet dosage form contains the following components in the amounts listed in Tables 4 and 6-12.

[0067] [Table 4]

[0068] method In some embodiments, the method is a method for treating a disease or illness, the disease or illness being 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 therapeutically effective dose of Compound 1 or its solvate in crystalline form, or a pharmaceutical composition containing Compound 1 or its solvate or a pharmaceutical composition containing Compound 1 or its solvate in crystalline form, for example, such a compound or pharmaceutical composition as described herein. When performing the treatment or method of use provided herein, a therapeutically effective dose of Compound 1 or its solvate is administered to a mammal suffering from the disease, disorder, or illness to be treated, for example, in a pharmaceutical composition. 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 requiring 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.

[0069] In some embodiments, the treatment method includes administering to a subject a pharmaceutical composition containing compound 1 or its solvate, or compound 1 or its solvate in crystalline form. In some embodiments, a therapeutically effective dose of the pharmaceutical composition is administered once or multiple times daily in one or more unit dosage forms. In some embodiments, the therapeutically effective dose of compound 1 or its solvate is 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, or 800 mg. In some embodiments, the therapeutically effective dose is administered once daily. In some embodiments, the therapeutically effective dose is 600 mg once daily and can be administered, for example, using three 200 mg tablets or capsules, or two 300 mg tablets or capsules. In some embodiments, the therapeutically effective dose is 400 mg once daily and can be administered, for example, using two 200 mg tablets or capsules, or one 400 mg tablet or capsule. [Examples]

[0070] 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.

[0071] 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.

[0072] XRPD analysis of compound 1, form 2, 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.

[0073] XRPD analysis of compound 1, form 3, revealed that it 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.

[0074] XRPD analysis of form 4 of compound 1 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, and 21.8°2-theta, 25.2°2-theta, and 25.7°2-theta.

[0075] XRPD analysis of form 5 of compound 1 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.

[0076] 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.

[0077] 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.

[0078] DSC analysis of compound 1, form 3, revealed endothermic activity with an onset temperature of approximately 117°C and / or a peak temperature of approximately 135°C.

[0079] DSC analysis of compound 1, form 4, 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.

[0080] DSC analysis of compound 1 in form 5 revealed endothermic fusion with an onset temperature of approximately 122°C and a peak temperature of approximately 132°C.

[0081] 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.

[0082] 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.

[0083] In TGA of compound 1 in form 3, a weight loss of approximately 1.33% was observed over a temperature range of approximately 29°C to approximately 150°C.

[0084] 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.

[0085] DVS 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%.

[0086] II. Synthesis of Polymorphs Example 4: Preparation 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), i.e., Form 1 The crystallization process to produce compound 1, i.e., form 1, generally yielded a material exhibiting a needle-like morphology, resulting in poor bulk properties (e.g., fluidity and mobility when handling the bulk material) that would affect the preparation of pharmaceutical compositions. Several approaches to improve bulk properties were investigated, including modifications to the MEK / IPA crystallization process, evaluation of alternative solvent systems, pH swing experiments, and spherical agglutination analysis. Initial experiments to improve bulk properties by adjusting the conditions of the MEK / IPA crystallization process did not result in significant improvement. Solvent screening failed to deliver form 1 material with bulk properties suitable for large-scale preparation, and pH swing experiments did not yield crystalline solids. Spherical aggregates were prepared in a water / MEK system, but the resulting material exhibited mixed properties (aggregation and needle-like morphology), high residual solvent levels, poor fluidity, and degraded bulk properties after sieving to remove clumps. Wet grinding during MEK / IPA crystallization was investigated at various temperatures and conditions. After cooling to approximately 10°C in MEK / IPA, the suspension exhibited low mobility, hindering wet grinding; therefore, this procedure required higher temperatures and larger volumes of IPA. Wet grinding at 40°C followed by cooling to 5°C resulted in a poorly mobile suspension and ultimately a needle-shaped material, likely due to a low proportion of solids available for wet grinding at 40°C. Wet grinding after heating to 40°C and holding for 21 hours, followed by cooling to 5°C, yielded a suspension with improved mobility. In additional experiments, wet grinding was performed in two stages, the first at 40°C and the second at 25°C. Thermal cycling did not improve the bulk properties of the solid product.

[0087] Preparation A: Amorphous compound 1 (prepared as described in U.S. Patent No. 10,781,218, incorporated herein by reference) was dissolved in 1:1 MEK / IPA v / v (4.5 mL / g) under N2 at approximately 50–65°C. The solution was cooled to 33–37°C. Seed crystals were added (0.8–1.2% by weight relative to compound 1), and the mixture was stirred at 33–37°C for 4–6 hours. The mixture was cooled to 23–27°C over 3–4 hours and stirred for 16–24 hours. Isopropanol (8.6–9.1 mL per g of compound 1) was added at 23–27°C over 9–11 hours, and the mixture was then stirred for 5–6 hours. The mixture was cooled to 3–8°C over 4–6 hours and stirred for at least 24 hours. The resulting solid precipitate was collected at 5°C. The filter cake was rinsed with IPA (1.8-2.1 mL per g of compound 1) at 3-8°C and dried under vacuum at 45-55°C for 24-32 hours. XRPD analysis confirmed the isolated material as crystalline compound 1, i.e., form 1. Purity was 99.5% by HPLC, and the total residual solvent was [value missing]. 1 ¹H NMR determined the concentration to be approximately 0.4 wt%. When compound 1, i.e., form 1, was recrystallized in MEK / IPA (6v / 12v) by dissolving it in MEK, adding IPA in small amounts at 25°C, stirring the suspension after each IPA portion, cooling to 5°C, and stirring at 5°C for 20 hours, a wet cake, a mixture of two crystalline forms other than form 1 (forms 2 and 5), was obtained. Under other recrystallization conditions, the resulting crystalline material had low bulk density, small particle size, and needle-like morphology, resulting in poor fluidity and processability in formulation preparation. It was discovered that form 1 could be obtained by recrystallization from MEK / IPA at high temperature. In this procedure, compound 1 was dissolved in 2.5v MEK, heated to 40°C, and treated in small amounts with 17.5v IPA. After crystallization, the material was filtered at 25°C to obtain form 1, but after standing, the material converted to form 5. Performing this procedure at 50°C yielded material of form 1 (99.5% purity), but the material still exhibited a needle-like morphology. Extensive evaluation of other solvent systems, back addition of solvents, other poor solvents, and pH swing conditions did not yield material with improved morphology and suitable bulk properties. When wet grinding was included in the MEK / IPA crystallization process, the bulk density was approximately 0.1 g / cm³.3 Less than, for example, 0.07 or 0.08 g / cm³ 3 From at least 0.1 g / cm³ 3 or approximately 0.1 to 0.15 g / cm³ 3 , or approximately 0.11, 0.12, 0.13, 0.14, or 0.15 g / cm³ 3 This increased. Wet grinding also improved the mobility of the suspension in the reaction vessel and simplified filtration during production. In this process, compound 1 is diluted with MEK / IPA and heated to 40°C for 21 hours without temperature cycling to obtain form 1 material with improved bulk properties (bulk density 0.12 g / mL). The use of pulverized seed crystals also helps to improve the particle size distribution (D 90 This resulted in improvements in bulk density (from 29.7 μm to 4.1 μm), bulk density (from 0.08 to 0.17 g / mL), and Hausner ratio (from 2.0 to 1.8). In some embodiments, crystalline compound 1, i.e., form 1, D 10 1.5~4.5μm, or approximately 2.0~4.0μm, or approximately 3.8~3.9μm, D 50 5-11 μm, or approximately 9.5-10.5 μm, or D 90 The particles had a particle size distribution of 13–50 μm, or approximately 33–45 μm (measured by optical diffraction measurement according to Section 429 of the United States Pharmacopeia).

[0088] Preparation B: Amorphous compound 1 (1.8 g) was stirred in 30 mL of toluene to form a clear solution, to which 6 mg of compound 1, i.e., form 1, was sprinkled. The resulting mixture was stirred for 1 day to obtain a turbid suspension. The obtained solid was collected by filtration, washed with IPA (50 mL), and vacuum-dried overnight at 30°C to obtain compound 1, i.e., form 1 (1.56 g). Purity was... 1 Confirmed by 1H NMR, HPLC, and XRPD.

[0089] Preparation C: Amorphous compound 1 was diluted with MEK / IPA (2 vol / 5 vol ratio, 5.5 vol), and the resulting mixture was heated to 65-75°C and stirred for 0.5-3 hours until all the solids dissolved and a clear solution was obtained. The solution was filtered by polishing and placed in a container that had been preheated to 65-75°C, stirred for 0.5-3 hours, then cooled to 55-65°C over 0.5-1 hour, and treated with a slurry of seed crystals (0.004-0.006 wt%) in IPA (0.01-0.06 vol). The resulting mixture was stirred at 55-65°C for 1-2 hours, then cooled to 40-50°C over 1-2 hours, and stirred for 12-20 hours. The mixture was heated to 50-60°C over 1-2 hours and stirred for 1-16 hours. The resulting slurry was wet-ground at 50-60°C. Filtered IPA (7.2–8.2 vol) was added over 8–12 hours at 50–60°C, the resulting mixture was cooled to 0–10°C over 4–6 hours, and then stirred at 0–10°C for 16–24 hours. The suspension was filtered at 0–10°C, and the filter cake was washed twice with cold IPA (2 vol). The wet cake was dried under vacuum at 45–55°C, and the dried product was selectively sieved. Yield 90%. Form 1 was confirmed by XRPD analysis.

[0090] Mai. Pharmaceutical composition Example 5: Composition and preparation of capsule composition The active pharmaceutical ingredient of compound 1 has low bulk density, small particle size, and may exhibit a needle-like morphology, all of which contribute to poor flowability. Dry granulation using roller compression improved the powder flowability and bulk density characteristics, enabling capsule filling. Furthermore, while flow enhancers such as talc and colloidal silicon dioxide were not effective in improving the powder flowability and bulk density characteristics, mannitol and microcrystalline cellulose fillers improved the flowability of the formulation in the roller compressor. The formulation exhibited good stability and excipient compatibility, as well as rapid solubility suitable for immediate-release drug products.

[0091] An exemplary capsule formulation contains compound 1 and the excipients shown in Table 5 in the following amounts.

[0092] [Table 5]

[0093] Method A: Compound 1, microcrystalline cellulose, croscarmellose sodium, and sodium lauryl sulfate are mixed together. Mannitol, followed by magnesium stearate, is added. The resulting smoothing mixture is fed into a roller compactor for dry granulation. The resulting ribbon is pulverized by a screen to produce granules. For 25.0 mg strength capsules, granules are prepared using the %w / w amount indicated for the excipient in the 50.0 mg column, and the resulting granules are mixed with mannitol to reach the %w / w amount indicated for the 25.0 mg column. The granules obtained for each strength are filled into capsule shells.

[0094] Method B: Compound 1 is mixed with a mixture of microcrystalline cellulose, mannitol, croscarmellose sodium, and sodium lauryl sulfate. The resulting mixture is pulverized and then mixed with 50% magnesium stearate. The resulting smoothed mixture is fed into a roller compactor for dry granulation. The resulting ribbons are pulverized to produce granules. These granules are mixed with the remaining 50% magnesium stearate, and the resulting mixture is encapsulated.

[0095] The capsule formulation may contain compound 1 in form 1 or amorphous form. Compound 1 may be used in an amount of about 15 to 800 mg. Mannitol may be used in a %w / w range of about 15 to 75, or about 25 to 35, or about 25 to 30, or about 28 to 32, or about 65 to 70, or about 29% w / w, or about 68% w / w. Microcrystalline cellulose may be used in a %w / w range of about 10 to 35, or about 10 to 15, or about 25 to 35, or about 25 to 30, or about 28 to 32, or about 13%, or about 29% w / w. Croscarmellose sodium may be used in a %w / w range of about 1 to 10, or about 3 to 10, or about 1 to 8, or about 4 to 8, or about 3% w / w, or about 6% w / w. Sodium lauryl sulfate may be used in a %w / w range of approximately 0.1–1.0, approximately 0.2–0.8, or approximately 0.4–0.6, or at approximately 0.2 or approximately 0.5% w / w. Magnesium stearate may be used in a %w / w range of approximately 0.1–1.0, approximately 0.2–0.8, or approximately 0.4–0.6, or at approximately 0.2% or approximately 0.5% w / w.

[0096] Example 6: Composition and preparation of tablet composition Excipient compatibility tests for tablet formulations revealed that certain excipients, including mannitol, povidone, hydroxypropyl methylcellulose, and Opadry HPMC, affected the stability of Compound 1. Therefore, special caution may be required when using it, particularly in tablet environments. In particular, these tests showed that the risk of instability in the presence of lactose as a diluent was lower compared to mannitol.

[0097] The components of exemplary tablet compositions are shown in Tables 6(A) and 7(B).

[0098] [Table 6]

[0099] The granular components containing compound 1 (e.g., compound 1, i.e., form 1) were screened and then mixed for 1 minute to obtain a dry formulation in a PMA-1 high-shear granulator. Water (400 g per 1 kg batch) was sprayed at a rate of 100 g / min for 4 minutes at an impeller speed of 350 rpm and a chopper speed of 2200 rpm. Optionally, an additional 50 g of water was sprayed under the same conditions for 30 seconds. Alternatively, hydroxypropyl cellulose was dissolved in water and sprayed onto the formulation during granulation. The resulting wet granules were screened by passing them through a Quadro Comil 197S equipped with a 250 Q screen. The resulting granules were dried in an S-1 fluidized bed dryer and then dry-ground by screening them through an 062 R screen. The dried and ground granules were compounded with colloidal silicon dioxide and croscarmellose sodium, and the resulting mixture was compounded with magnesium stearate. The resulting formulations were compressed on a Korsch XM-12 equipped with D-tooling to a target tablet weight of 800 mg (400 mg for compound 1). The resulting tablets were coated. For the final formulations of the compositions in Table 6, the bulk density was 0.48–0.52 g / mL, the tap density was 0.6–0.65 g / mL, and the Hausner ratio was 1.25–1.28, indicating that the fluidity met the provisional standards. Dissolution tests showed 82% dissolution in 10 minutes, 93–95% in 20 minutes, 97% in 30 minutes, and 99% in 60 minutes.

[0100] [Table 7]

[0101] The granular components containing compound 1 (e.g., compound 1, i.e., form 1) were screened, then mixed to form a pre-formulation. This was then subjected to wet granulation to form granules, which were screened (using a #8 mesh), dried, and screened again (using a #30 mesh) to form dried granules. The dried granules were combined with extragranular components and compressed to form 200 mg and 500 mg tablets, which were then coated. The target hardness range for the tablets was 10-25 kp (e.g., 12 kp for 200 mg tablets and 20 kp for 500 mg tablets).

[0102] Further exemplary tablet compositions (C), (D), and (E) are shown in Table 8.

[0103] [Table 8]

[0104] The granular components were mixed to form a pre-composition, which was then wet-granulated with 25-30% water to form wet granules. The wet granules were screened with a #4 mesh, dried, screened with a #30 mesh, mixed with the extragranular components, and compressed into tablets at 200 mg and 500 mg densities. The bulk density of the final composition ranged from 0.12(E) to 0.18(D) g / mL, the tap density ranged from 0.26(E) to 0.34(D) g / mL, the curl index ranged from 46(D) to 56%(E), and the Hausner ratio ranged from 1.85(D) to 2.30(E). Disintegration time of tablets compressed at 2500 N: (C) 14 seconds, (D) 20 seconds, (E) 32 seconds. Disintegration time of tablets compressed at 6000 N: (C) 32 seconds, (D) 31 seconds, (E) 29 seconds. The bulk density was increased by using components with higher bulk density, such as microcrystalline cellulose (e.g., 0.43 vs. 0.32 g / mL) and lactose (0.72 vs. 0.59 g / mL), removing the microcrystalline cellulose from the outer part of the granules and adding it to the inner part, increasing the binder component, removing mannitol, and adding colloidal silicon dioxide to the outer part of the granules.

[0105] An example composition (F) is shown in Table 9.

[0106] [Table 9]

[0107] The granular components were mixed and subjected to wet granulation using a Key High Shear Granulator at water addition levels ranging from 40% to 60%. The bulk densities of the wet granules after water addition were 40% at 0.34 g / cc, 45% at 0.38 g / cc, 50% at 0.47 g / cc, 55% at 0.52 g / cc, and 60% at 0.59 g / cc. The granules were screened through a #4 mesh screen, the screened granules were dried, and the dried granules were screened using a #20 mesh screen. The dried granules were mixed with the extragranular components to form the final formulation (for the 50% water example, the bulk density was 0.12 g / mL, tap density was 0.26 g / mL, Curl index was 56.5, and Hausner ratio was 2.30), and the final formulations were compressed into tablets of strengths of 200 and 500 mg using forces of 3000 N and 7500 N, respectively. Dissolution (0.01N HCl / 0.5% Tween80): 200 mg tablets (50% aqueous preparation) were 98% dissolved in 10 minutes and 100% in 20 minutes; 500 mg tablets (50% aqueous preparation) were 98% dissolved in 10 minutes and 100% in 20 minutes; and 500 mg tablets (60% aqueous preparation) were 93% dissolved in 10 minutes, 99% in 20 minutes, and 100% in 30 minutes. The 60% aqueous preparation increased the bulk density to 0.59 g / mL, but this material exhibited an excessively granular appearance. In some embodiments, the amount of disintegrant decreased by 1% w / w in the case of 500 mg tablets.

[0108] An example composition (G) is shown in Table 10.

[0109] [Table 10]

[0110] The granular components were mixed (bulk density 0.13 g / mL, tap density 0.33 g / mL, Hausner ratio 2.54), then wet-granulated with 50% water, screened (#8 mesh), dried (bulk density 0.30 g / mL, tap density 0.41 g / mL, Hausner ratio 1.37), screened again (#30 mesh), mixed with the granular excipient (bulk density 0.33 g / mL, tap density 0.44 g / mL, Hausner ratio 1.33, fluidity meets provisional standards), compressed to 200 and 500 mg tablet strengths (good compressibility), and then coated with Opadry II. Dissolution profile of 200 mg tablets: 93% in 10 minutes, 97% in 30 minutes, 99.2% in 90 minutes. Dissolution profile of 500 mg tablets: 91% in 10 minutes, 94% in 30 minutes, and 98% in 90 minutes. To improve the fluidity of the formulation, colloidal silicon dioxide was added to the extragranular portion as a flow enhancer, as shown in the exemplary compositions in Table 7.

[0111] Table 11 shows exemplary compositions (H), (I), and (J) filled with 50% compound 1.

[0112] [Table 11]

[0113] The granular components were formulated, and hydroxypropyl cellulose was added as a drying agent, either with a water spray or with hydroxypropyl cellulose dissolved in the spray water. The formulation was subjected to wet granulation, and the wet granules were screened by passing them through a Quadro Comil 197S equipped with a 250Q screen. The resulting granules were dried. The dried granules were screened by passing them through an 062R screen and formulated with croscarmellose sodium and colloidal silicon dioxide. The resulting mixture was then formulated with magnesium stearate. Data for the final formulation: bulk density 0.43-0.45 g / mL, tap density 0.56-0.57 g / mL, compressibility index 21-23%, and fluidity characteristics met the provisional criteria. The final formulation was compressed into tablets at strengths of 200, 300, or 400 mg and coated with Opadry II. The dissolution profile of (A) (5% HPC, 1% magnesium stearate) was similar to that of (H) and (I) (4% HPC, 0.75 vs 1.0% magnesium stearate), as well as (J) (4% HPC, 0.75% magnesium stearate), and (A) and (J) were similar (the amount of water used during granulation differed, 43% vs 48%). Dissolution of 200, 300, and 400 mg tablets: 66-79% in 10 minutes, 85-93% in 20 minutes, 92-97% in 30 minutes, and 95-99% in 60 minutes.

[0114] IV. Biological Data Example 7: 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. 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-carbonitrile or a solvate thereof 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 pharmaceutical composition according to claim 1, which is a form 1 having at least one of the above.

3. The pharmaceutical composition according to claim 2, wherein the crystalline form has an XRPD pattern substantially the same as that shown in Figure 1.

4. The pharmaceutical composition according to claim 2, wherein the crystalline 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 pharmaceutical composition according to claim 2, wherein the crystalline form has a DSC thermogram substantially the same as that shown in Figure 2.

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

7. The pharmaceutical composition according to claim 2, wherein the crystalline form has a TGA curve substantially the same as that shown in Figure 3.

8. The pharmaceutical composition according to claim 2, characterized in that the crystalline form has properties (a), (b), (c), (d), and (e).

9. The pharmaceutical composition according to any one of claims 2 to 8, wherein the crystalline form is obtained from methyl ethyl ketone (MEK) and isopropanol (IPA).

10. The pharmaceutical composition according to claim 9, wherein the crystalline form is obtained from a 1:1 mixture of methyl ethyl ketone (MEK) and isopropanol (IPA).

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the crystalline form is wet-ground.

12. The crystalline form is at least 0.1 g / cm³ ３ A pharmaceutical composition according to any one of claims 2 to 11, having the following bulk density.

13. The aforementioned crystalline form is approximately 0.1 to approximately 0.15 g / cm³. ３ A pharmaceutical composition according to any one of claims 2 to 11, having the following bulk density.

14. The aforementioned crystal form is D １０ 1.5–4.5 μm, D ５０ 5-11 μm, or D ９０ 13-50 μm, or D ９０ A pharmaceutical composition according to any one of claims 2 to 13, having a particle size distribution of 50 μm or less.

15. A pharmaceutical composition according to any one of claims 1 to 14, comprising 15 to 800 mg 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.

16. A pharmaceutical composition according to any one of claims 1 to 14, further comprising a pharmaceutically acceptable excipient.

17. The pharmaceutical composition according to claim 16, wherein the pharmaceutically acceptable excipient is selected from fillers, disintegrants, surfactants, and lubricants, and combinations thereof, wherein the filler is optionally mannitol and / or microcrystalline cellulose, the disintegrant is optionally croscarmellose sodium, the surfactant is optionally sodium lauryl sulfate, and the lubricant is optionally magnesium stearate.

18. The pharmaceutical composition according to claim 16, wherein the pharmaceutically acceptable excipient is selected from fillers, binders, disintegrants, surfactants, flow promoters, and lubricants, and combinations thereof, wherein the filler is optionally microcrystalline cellulose, lactose, or mannitol, or a combination thereof; optionally the binder is optionally hydroxypropyl cellulose; optionally the disintegrant is optionally croscarmellose sodium or crospovidone; optionally the surfactant is optionally sodium lauryl sulfate; optionally the flow promoter is optionally colloidal silicon dioxide; and optionally the lubricant is optionally magnesium stearate.

19. The pharmaceutical composition according to claim 16, which is a capsule or a tablet.

20. The pharmaceutical composition according to claim 17, which is a capsule.

21. The pharmaceutical composition according to claim 18, which is in the form of a tablet.

22. A method for treating a target disease or illness, comprising the step of administering to the target a pharmaceutical composition according to any one of claims 1 to 21, 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.

23. A method for inhibiting the interaction between menin and one or more of MLL1, MLL2, MLL fusion proteins, and MLL partial tandem duplication, comprising the step of contacting menin with a pharmaceutical composition according to any one of claims 1 to 21.

24. A method for preparing 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, wherein (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine-4-yl)amino)piperidine-1-yl)methyl) A method comprising the steps of: heating -1-(2-(4-(methylsulfonyl)piperazine-1-yl)propyl)-1H-indole-2-carbonitride in a mixture of MEK and IPA to a first temperature of about 35 to 45°C (optionally, the first temperature is about 40°C) to form a diluted suspension; optionally maintaining the diluted suspension at the first temperature for 3 to 48 hours; wet grinding the diluted suspension at the first temperature; optionally performing a second wet grinding of the diluted suspension at about 25°C; and filtering the diluted suspension to obtain a crystalline form.

25. The method according to claim 24, comprising the steps of: dissolving (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 together with MEK to form a solution; heating the solution to the first temperature; and adding IPA to form the diluted suspension, wherein optionally the v / v ratio of MEK / IPA is about 2:3 to about 1:10, or about 1:2 to about 1:8, or about 1:2, 2:5, or 1:7, or about 1:7.

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