Physical forms of PRC2 inhibitors

Abstract

The present disclosure relates to physical forms of PRC2 inhibitor compounds, pharmaceutical compositions comprising the physical forms of the compounds, and methods of treating a subject suffering from cancer by administering to the subject the physical form or a pharmaceutical composition comprising one or more of the physical forms.

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Application No. 63 / 375,582, filed September 14, 2022, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Polycomb repressive complex 2 (PRC2) is a multiprotein complex that contributes to epigenetic silencing of target genes that regulate development and homeostasis. The PRC2 complex is composed of three core subunits: enhancer of zeste homolog 2 (EZH2), embryonic ectoderm development protein (EED), and suppressor of zeste 12 (SUZ12). Two additional nonessential subunits, AEBP2 and RbAp48, function to promote the enzymatic activity of the RRC2 complex (see, e.g., Cao et al., (2002) Science 298:1039-1043). Dysregulation of PRC2 methyltransferase activity can lead to tumorigenesis in a wide range of cancers, including prostate, breast, skin, bladder, liver, pancreatic, head and neck, and hematological malignancies. PRC2 is composed of two druggable subunits, EED and EZ. A pharmacological property of some EZH2 inhibitor compounds is that high doses may be required, yet only achieve partial target inhibition in subjects with cancer. Furthermore, preclinical studies suggest that drug resistance to EZH2 inhibitors may develop through EZH1 bypass compensation or acquired mutations in EZH2. Allosteric inhibition of EED may affect the assembly, stabilization, and activation of PRC2 and may have benefits beyond EZH2-mediated inhibition of PRC2. Therefore, there is a need to develop compounds that exhibit inhibition of the EED subunit of PRC2, and pharmaceutically acceptable compositions containing such compounds, for treating cancer in subjects. Summary of the Invention

[0003] The physical forms of Compound 1 are provided herein.

[0004] [ka]

[0005] Also provided herein are crystalline forms of Compound 1. Additionally provided herein are crystalline forms of Compound 1 that are anhydrous forms. Also provided herein are pharmaceutical compositions comprising an amount of a crystalline form of Compound 1 disclosed herein and at least one pharmaceutically acceptable excipient.

[0006] In another embodiment, there is provided a method of inhibiting PRC2 activity in a subject in need thereof, the method comprising administering to the subject an effective amount of a solid form of Compound 1, including a crystalline form of Compound 1 disclosed herein.

[0007] In other embodiments, there are provided methods of treating cancer in a subject, comprising administering to the subject an effective amount of a solid form of Compound 1, including a crystalline form of Compound 1 disclosed herein. In another embodiment, there is provided such a method of treating cancer in a subject, wherein the cancer is a PRC2-associated cancer. DETAILED DESCRIPTION OF THE INVENTION

[0008] 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. Thus, for example, a reference to "an agent" includes a plurality of such agents and equivalents thereof known to those of skill in the art, and so forth. When ranges are used herein for physical properties such as molecular weight, melting point, or chemical properties such as chemical formula, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about," when referring to a number or numerical range, means that the referenced number or numerical range is an approximation within experimental variation (or within statistical experimental error); thus, in some cases, the number or numerical range may vary by 1% to 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that embodiments, such as, for example, any compositions, compositions, methods, or processes consisting of the substances described herein, "consist of" or "consist essentially of" the described features, in certain other embodiments.

[0009] As used in this specification and the appended claims, unless indicated to the contrary, the following terms have the meanings indicated below.

[0010] "Administering," when used in combination with a therapeutic agent, means administering a therapeutic agent systemically or locally, such as by direct administration into or onto a target tissue, or administering a therapeutic agent to a subject, thereby positively affecting the tissue to which the therapeutic agent is targeted. Thus, as used herein, the term "administering," when used in combination with a composition described herein, can include, but is not limited to, providing the composition into or onto the target tissue, providing the composition systemically to a subject, for example, by oral administration, thereby allowing the therapeutic agent to reach the target tissue or cell. "Administering" a composition can be accomplished by injection, topical administration, oral administration, or other methods alone or in combination with other known techniques.

[0011] The terms "crystalline" and "crystallinity" refer to a solid composition that has some measure of long-range order in the positions of its molecules as determined by analytical techniques known to those skilled in the art, such as x-ray powder diffraction (XRPD).

[0012] The term "differential scanning calorimetry" as used herein means a calorimeter according to the U.S.P. <891> This refers to the method of thermal analysis described in

[0013] The term "pharmaceutically acceptable" means the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0014] The term "pharmaceutical composition" means a composition comprising one or more active ingredients, whereby the composition is suitable for investigation in a mammal (e.g., but not limited to, a human) for a specified efficacious outcome. Those of skill in the art will understand and appreciate the techniques appropriate for determining whether an active ingredient has a desired efficacious outcome based on the needs of the artisan.

[0015] As used herein, the term "therapeutic agent" means an agent utilized to treat, combat, ameliorate, prevent, or ameliorate an unwanted disease or disorder in a subject.

[0016] As used herein, a "therapeutically effective amount" or "effective amount" refers to an amount of an active compound or pharmaceutical agent that elicits the biological or medical response in a tissue, system, animal, individual, or human that is being sought by a researcher, veterinarian, medical physician, or other clinician, including one or more of: (1) preventing a disease, e.g., preventing a disease, illness, or disorder in an individual who may be predisposed to the disease, illness, or disorder but who has not yet experienced or exhibited the pathology or symptomology of the disease; (2) inhibiting a disease, e.g., inhibiting a disease, illness, or disorder (i.e., halting further progression of the pathology and / or symptomology) in an individual who is experiencing or exhibiting the pathology or symptomology of the disease, illness, or disorder; and (3) ameliorating a disease, e.g., ameliorating a disease, illness, or disorder (i.e., reversing the pathology and / or symptomology) in an individual who is experiencing or exhibiting the pathology or symptomology of the disease, illness, or disorder.

[0017] As used herein, the terms "treat," "treated," "treatment," or "treating" refer, in some embodiments, to therapeutic treatment, where the objective is to prevent or delay (alleviate) an undesirable physiological disease, disorder, or condition, or to obtain a beneficial or desired clinical result. For purposes described herein, a beneficial or desired clinical result includes, but is not limited to, alleviation of symptoms, reduction in the extent of the disease, disorder, or condition, stabilization (i.e., not worsening) of the disease, disorder, or condition, delay in the onset or slowing of progression of the disease, disorder, or condition, remission of the disease, disorder, or condition, and remission (whether partial or total), whether detectable or undetectable, or whether enhancement or improvement of the disease, disorder, or condition. Treating includes eliciting a clinically significant response without excessive levels of side effects. Treating also includes prolonging survival compared to expected survival if not receiving treatment.

[0018] As used herein, the term "x-ray powder diffraction (XRPD)" refers to the <941> By use of powder x-ray diffraction as defined in the JIS K 1995 / 10001, we mean a technique for characterizing solids as to their crystallinity or partial crystallinity.

[0019] Crystalline forms of Compound 1 are provided herein.

[0020] [ka]

[0021] Also provided herein is a crystalline form of Compound 1, which is an anhydrous form.

[0022] Further provided herein is a crystalline form of Compound 1 exhibiting a peak in an x-ray powder diffraction (XRPD) pattern at 8.1°±0.2°2θ. In another embodiment, provided is a crystalline form of Compound 1 exhibiting additional peaks in an x-ray powder diffraction (XRPD) pattern at 9.6°±0.2°2θ. A further embodiment provides a crystalline form of Compound 1 exhibiting additional peaks in an x-ray powder diffraction (XRPD) pattern at 5.7°±0.2°2θ, 19.7°±0.2°2θ, and 22.0°±0.2°2θ. In yet a further embodiment, provided is a crystalline form of Compound 1 exhibiting additional peaks in an x-ray powder diffraction (XRPD) pattern at 9.8°±0.2°2θ, 15.2°±0.2°2θ, and 17.7°±0.2°2θ. In yet another embodiment, provided is a crystalline form of Compound 1 comprising a peak in a differential scanning calorimetry pattern at about 172°C. In yet another embodiment, a crystalline form of Compound 1 is provided, which comprises a peak in a differential scanning calorimetry pattern from about 205°C to about 210°C. In yet another embodiment, a crystalline form of Compound 1 is provided, which comprises a peak in a differential scanning calorimetry pattern from about 206°C to about 210°C, or from about 207°C to about 210°C, or from about 208°C to about 210°C, or from about 209°C to about 210°C. In a further embodiment, a crystalline form of Compound 1 is provided, which exhibits less than about 1% mass loss in thermogravimetric analysis when a sample is heated from about 25°C to a temperature below the melting point. In a further embodiment, a crystalline form of Compound 1 is provided, which exhibits less than about 1% mass loss in thermogravimetric analysis when a sample is heated from about 25°C to about 380°C.

[0023] In another embodiment, a crystalline form of Compound 1 is provided that exhibits a peak in an x-ray powder diffraction (XRPD) pattern at 7.7°±0.2°2θ. In yet another embodiment, a crystalline form of Compound 1 is provided that exhibits additional peaks in an x-ray powder diffraction (XRPD) pattern at 13.7°±0.2°2θ and 19.2°±0.2°2θ. In yet a further embodiment, a crystalline form of Compound 1 is provided that exhibits additional peaks in an x-ray powder diffraction (XRPD) pattern at 5.5°±0.2°2θ, 8.6°±0.2°2θ, 15.9°±0.2°2θ, 19.9°±0.2°2θ, and 24.1°±0.2°2θ. Another embodiment provides a crystalline form of Compound 1 that exhibits additional peaks in an x-ray powder diffraction (XRPD) pattern at 10.6°±0.2°2θ, 11.0°±0.2°2θ, 15.4°±0.2°2θ, 21.0°±0.2°2θ, and 26.3°±0.2°2θ. A further embodiment provides a crystalline form of Compound 1 that includes peaks in a differential scanning calorimetry pattern from about 203°C to about 210°C. In yet another embodiment, a crystalline form of Compound 1 is provided that includes peaks in a differential scanning calorimetry pattern from about 203°C to about 208°C, or from about 203°C to about 206°C, or from about 203°C to about 205°C. In another embodiment, a crystalline form of Compound 1 is provided that exhibits less than about 2% mass loss in thermogravimetric analysis when a sample is heated from about 25°C to about 380°C. In another embodiment, a crystalline form of Compound 1 is provided, which exhibits a mass loss of less than about 2% in thermogravimetric analysis when a sample is heated from about 25°C to about 210°C.

[0024] In another embodiment, a crystalline form of Compound 1 is provided, which exhibits a peak in an x-ray powder diffraction (XRPD) pattern at 7.7°±0.2°2θ. In yet another embodiment, a crystalline form of Compound 1 is provided, which exhibits an additional peak in an x-ray powder diffraction (XRPD) pattern at 15.4°±0.2°2θ. In yet another embodiment, a crystalline form of Compound 1 is provided, which exhibits an additional peak in an x-ray powder diffraction (XRPD) pattern at 19.2°±0.2°2θ. In yet another embodiment, a crystalline form of Compound 1 is provided, which exhibits an additional peak in an x-ray powder diffraction (XRPD) pattern at 13.7°±0.2°2θ. In yet a further embodiment, a crystalline form of Compound 1 is provided that exhibits additional peaks in an x-ray powder diffraction (XRPD) pattern at 5.5°±0.2°2θ, 8.6°±0.2°2θ, 15.9°±0.2°2θ, 19.9°±0.2°2θ, and 24.1°±0.2°2θ. Another embodiment provides a crystalline form of Compound 1 that exhibits additional peaks in an x-ray powder diffraction (XRPD) pattern at 10.6°±0.2°2θ, 11.0°±0.2°2θ, 21.0°±0.2°2θ, and 26.3°±0.2°2θ. A further embodiment provides a crystalline form of Compound 1 that includes peaks in a differential scanning calorimetry pattern from about 203°C to about 210°C. A further embodiment provides a crystalline form of Compound 1 that includes peaks in a differential scanning calorimetry pattern from about 206°C to about 210°C. In yet another embodiment, a crystalline form of Compound 1 is provided that includes a peak in a differential scanning calorimetry pattern from about 203°C to about 208°C, or from about 203°C to about 206°C, or from about 203°C to about 205°C. In another embodiment, a crystalline form of Compound 1 is provided that exhibits less than about a 2% mass loss in thermogravimetric analysis when a sample is heated from about 25°C to about 380°C. In another embodiment, a crystalline form of Compound 1 is provided that exhibits less than about a 2% mass loss in thermogravimetric analysis when a sample is heated from about 25°C to about 210°C.

[0025] In another embodiment, a crystalline form of Compound 1 is provided that exhibits peaks in an x-ray powder diffraction (XRPD) pattern at 7.7°±0.2°2θ and 15.4°±0.2°2θ. In another embodiment, a crystalline form of Compound 1 is provided that additionally exhibits a peak in an x-ray powder diffraction (XRPD) pattern at 19.2°±0.2°2θ. In yet another embodiment, a crystalline form of Compound 1 is provided that exhibits additional peaks in an x-ray powder diffraction (XRPD) pattern at 13.7°±0.2°2θ. In yet a further embodiment, a crystalline form of Compound 1 is provided that exhibits additional peaks in an x-ray powder diffraction (XRPD) pattern at 5.5°±0.2°2θ, 8.6°±0.2°2θ, 15.9°±0.2°2θ, 19.9°±0.2°2θ, and 24.1°±0.2°2θ. Another embodiment provides a crystalline form of Compound 1 that exhibits additional peaks in an x-ray powder diffraction (XRPD) pattern at 10.6°±0.2°2θ, 11.0°±0.2°2θ, 21.0°±0.2°2θ, and 26.3°±0.2°2θ. A further embodiment provides a crystalline form of Compound 1 that includes peaks in a differential scanning calorimetry pattern from about 203°C to about 210°C. A further embodiment provides a crystalline form of Compound 1 that includes peaks in a differential scanning calorimetry pattern from about 206°C to about 210°C. Yet another embodiment provides a crystalline form of Compound 1 that includes peaks in a differential scanning calorimetry pattern from about 203°C to about 208°C, or from about 203°C to about 206°C, or from about 203°C to about 205°C. In another embodiment, a crystalline form of Compound 1 is provided that exhibits less than about 2% mass loss in thermogravimetric analysis when a sample is heated from about 25° C. to about 380° C. In another embodiment, a crystalline form of Compound 1 is provided that exhibits less than about 2% mass loss in thermogravimetric analysis when a sample is heated from about 25° C. to about 210° C.

[0026] In another embodiment, a crystalline form of Compound 1 is provided that exhibits peaks in an x-ray powder diffraction (XRPD) pattern at 7.7°±0.2°2θ and 19.2°±0.2°2θ. In another embodiment, a crystalline form of Compound 1 is provided that additionally exhibits a peak in an x-ray powder diffraction (XRPD) pattern at 15.4°±0.2°2θ. In yet another embodiment, a crystalline form of Compound 1 is provided that exhibits additional peaks in an x-ray powder diffraction (XRPD) pattern at 13.7°±0.2°2θ. In yet a further embodiment, a crystalline form of Compound 1 is provided that exhibits additional peaks in an x-ray powder diffraction (XRPD) pattern at 5.5°±0.2°2θ, 8.6°±0.2°2θ, 15.9°±0.2°2θ, 19.9°±0.2°2θ, and 24.1°±0.2°2θ. Another embodiment provides a crystalline form of Compound 1 that exhibits additional peaks in an x-ray powder diffraction (XRPD) pattern at 10.6°±0.2°2θ, 11.0°±0.2°2θ, 21.0°±0.2°2θ, and 26.3°±0.2°2θ. A further embodiment provides a crystalline form of Compound 1 that includes peaks in a differential scanning calorimetry pattern from about 203°C to about 210°C. A further embodiment provides a crystalline form of Compound 1 that includes peaks in a differential scanning calorimetry pattern from about 206°C to about 210°C. Yet another embodiment provides a crystalline form of Compound 1 that includes peaks in a differential scanning calorimetry pattern from about 203°C to about 208°C, or from about 203°C to about 206°C, or from about 203°C to about 205°C. In another embodiment, a crystalline form of Compound 1 is provided that exhibits less than about 2% mass loss in thermogravimetric analysis when a sample is heated from about 25° C. to about 380° C. In another embodiment, a crystalline form of Compound 1 is provided that exhibits less than about 2% mass loss in thermogravimetric analysis when a sample is heated from about 25° C. to about 210° C.

[0027] In further embodiments, there are provided crystalline forms of Compound 1 disclosed herein that exhibit less than about 10% decomposition when stored at 25° C. and 60% relative humidity for at least 7 days, at least 1 month, at least 3 months, and at least 6 months. Other embodiments provide crystalline forms of Compound 1 disclosed herein that exhibit less than about 1%, or less than about 2%, or less than about 3%, or less than about 4%, or less than about 5%, or less than about 6%, or less than about 7%, or less than about 8%, or less than about 9% decomposition when stored at 25° C. and 60% relative humidity for at least 7 days, at least 1 month, at least 3 months, or at least 6 months.

[0028] In a further embodiment, there is provided a crystalline form of Compound 1 that (a) exhibits peaks in an x-ray powder diffraction (XRPD) pattern at 8.1°±0.2°2θ, and (b) exhibits less than about 10% decomposition when stored at 25° C. and 60% relative humidity for at least 7 days, at least 1 month, at least 3 months, or at least 6 months. In a further embodiment, there is provided a crystalline form of Compound 1 that (a) exhibits peaks in an x-ray powder diffraction (XRPD) pattern at 9.6°±0.2°2θ, 5.7°±0.2°2θ, 19.7°±0.2°2θ, and 22.0°±0.2°2θ, and (b) exhibits less than about 10% decomposition when stored at 25° C. and 60% relative humidity for at least 7 days, at least 1 month, at least 3 months, or at least 6 months. Other embodiments provide such crystalline forms of Compound 1 that exhibit less than about 1%, or less than about 2%, or less than about 3%, or less than about 4%, or less than about 5%, or less than about 6%, or less than about 7%, or less than about 8%, or less than about 9% decomposition when stored at 25° C. and 60% relative humidity for at least 7 days, at least 1 month, at least 3 months, or at least 6 months.

[0029] In a further embodiment, there is provided a crystalline form of Compound 1 that (a) exhibits peaks in an x-ray powder diffraction (XRPD) pattern at 7.7°±0.2°2θ, and (b) exhibits less than about 10% decomposition when stored at 25° C. and 60% relative humidity for at least 7 days, at least 1 month, at least 3 months, or at least 6 months. In a further embodiment, there is provided a crystalline form of Compound 1 that (a) exhibits peaks in an x-ray powder diffraction (XRPD) pattern at 7.7°±0.2°2θ, 13.7°±0.2°2θ, and 19.2°±0.2°2θ, and (b) exhibits less than about 10% decomposition when stored at 25° C. and 60% relative humidity for at least 7 days, at least 1 month, at least 3 months, or at least 6 months. Other embodiments provide such crystalline forms of Compound 1 that exhibit less than about 1%, or less than about 2%, or less than about 3%, or less than about 4%, or less than about 5%, or less than about 6%, or less than about 7%, or less than about 8%, or less than about 9% decomposition when stored at 25° C. and 60% relative humidity for at least 7 days, at least 1 month, at least 3 months, or at least 6 months.

[0030] Further embodiments provide crystalline forms of Compound 1 disclosed herein that exhibit less than about 10% decomposition when stored at 40° C. and 75% relative humidity for at least 7 days, at least 1 month, at least 3 months, or at least 6 months. Further embodiments provide crystalline forms of Compound 1 disclosed herein that exhibit less than about 1%, or less than about 2%, or less than about 3%, or less than about 4%, or less than about 5%, or less than about 6%, or less than about 7%, or less than about 8%, or less than about 9% decomposition when stored at 40° C. and 75% relative humidity for at least 7 days, at least 1 month, at least 3 months, or at least 6 months.

[0031] In a further embodiment, there is provided a crystalline form of Compound 1 that (a) exhibits peaks in an x-ray powder diffraction (XRPD) pattern at 8.1°±0.2°2θ, and (b) exhibits less than about 10% decomposition when stored at 40° C. and 75% relative humidity for at least 7 days, at least 1 month, at least 3 months, or at least 6 months. In a further embodiment, there is provided a crystalline form of Compound 1 disclosed herein that (a) exhibits peaks in an x-ray powder diffraction (XRPD) pattern at 9.6°±0.2°2θ, 5.7°±0.2°2θ, 19.7°±0.2°2θ, and 22.0°±0.2°2θ, and (b) exhibits less than about 10% decomposition when stored at 40° C. and 75% relative humidity for at least 7 days, at least 1 month, at least 3 months, or at least 6 months. Other embodiments provide such crystalline forms of Compound 1 that exhibit less than about 1%, or less than about 2%, or less than about 3%, or less than about 4%, or less than about 5%, or less than about 6%, or less than about 7%, or less than about 8%, or less than about 9% decomposition when stored at 40° C. and 75% relative humidity for at least 7 days, at least 1 month, at least 3 months, or at least 6 months.

[0032] In a further embodiment, there is provided a crystalline form of Compound 1 that (a) exhibits peaks in an x-ray powder diffraction (XRPD) pattern at 7.7°±0.2°2θ, and (b) exhibits less than about 10% decomposition when stored at 40° C. and 75% relative humidity for at least 7 days, at least 1 month, at least 3 months, or at least 6 months. In a further embodiment, there is provided a crystalline form of Compound 1 that (a) exhibits peaks in an x-ray powder diffraction (XRPD) pattern at 7.7°±0.2°2θ, 13.7°±0.2°2θ, and 19.2°±0.2°2θ, and (b) exhibits less than about 10% decomposition when stored at 40° C. and 75% relative humidity for at least 7 days, at least 1 month, at least 3 months, or at least 6 months. Other embodiments provide such crystalline forms of Compound 1 that exhibit less than about 1%, or less than about 2%, or less than about 3%, or less than about 4%, or less than about 5%, or less than about 6%, or less than about 7%, or less than about 8%, or less than about 9% decomposition when stored at 40° C. and 75% relative humidity for at least 7 days, at least 1 month, at least 3 months, or at least 6 months.

[0033] Other embodiments provide crystalline forms of Compound 1 disclosed herein that exhibit less than about 10% decomposition when stored at 60° C. for at least one week. Further embodiments provide crystalline forms of Compound 1 that exhibit less than about 1%, or less than about 2%, or less than about 3%, or less than about 4%, or less than about 5%, or less than about 6%, or less than about 7%, or less than about 8%, or less than about 9% decomposition when stored at 60° C. for at least one week.

[0034] Further provided herein are pharmaceutical compositions comprising an amount of any of the crystalline forms of Compound 1 disclosed herein and at least one pharmaceutically acceptable excipient.

[0035] In another embodiment, provided herein is a method of inhibiting PRC2 activity in a subject in need thereof, comprising administering to the subject an effective amount of any of the crystalline forms of Compound 1 disclosed herein. Further provided herein is a method of inhibiting PRC2 activity in a subject in need thereof, comprising administering to the subject an effective amount of a pharmaceutical composition disclosed herein.

[0036] In yet another embodiment, there is provided a crystalline form of Compound 1 disclosed herein for use in a method of inhibiting PRC2 activity in a subject in need thereof. In some uses, the PRC2 activity in a subject in need thereof is associated with a subject suffering from a PRC2-associated cancer.

[0037] In further embodiments, a method of treating cancer in a subject is provided, comprising administering to the subject a therapeutically effective amount of any of the crystalline forms of Compound 1 disclosed herein. In some embodiments, the present invention is directed to treating cancer in a subject with a therapeutically effective amount of any of the following: cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; lung: bronchogenic carcinoma (squamous cell, small undifferentiated cell, large undifferentiated cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (pancreatic ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary tract: kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver: hepatoma (hepatocellular carcinoma) Cancer), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gallbladder carcinoma, ampullary carcinoma, bile duct carcinoma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteochondroma), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma and giant cell tumor; Nervous system: skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meninges (meningiomas, meningeal sarcomas, gliomatosis), brain (astrocytoma, myeloma) Germinoma (pineal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibroma, meningioma, glioma, sarcoma); Gynecology: uterus (endometrial carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecocytoma, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (carcinoma);Such methods are provided for treating a cancer selected from the group consisting of hematology: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles, dysplastic nevi, lipomas, hemangiomas, dermatofibromas, keloids, psoriasis; and adrenal gland: neuroblastoma. In some embodiments, the cancer is a PRC2-associated cancer. In further embodiments, the cancer is prostate cancer, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, or head and neck cancer. In certain embodiments, the cancer is prostate cancer. In some embodiments, the prostate cancer is metastatic prostate cancer, metastatic castration-resistant prostate cancer, high-risk localized prostate cancer, recurrent prostate cancer, non-metastatic CRPC (nmCRPC), non-metastatic castration-sensitive prostate cancer, or metastatic castration-sensitive prostate cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is skin cancer. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is head and neck cancer.

[0038] In yet another embodiment, there is provided a crystalline form of Compound 1 disclosed herein for use in a method of treating cancer in a subject in need thereof. In some uses, the cancer in the subject in need thereof is a PRC2-associated cancer. In further embodiments, the cancer is prostate cancer, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, or head and neck cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the prostate cancer is metastatic prostate cancer, metastatic castration-resistant prostate cancer, high-risk localized prostate cancer, recurrent prostate cancer, non-metastatic CRPC (nmCRPC), non-metastatic castration-sensitive prostate cancer, or metastatic castration-sensitive prostate cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is skin cancer. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is head and neck cancer.

[0039] Also provided herein are pharmaceutical compositions comprising an amount of a crystalline form of Compound 1 disclosed herein and one or more pharmaceutically acceptable excipients. Further provided herein are such pharmaceutical compositions, wherein the one or more pharmaceutically acceptable excipients comprise one or more diluents, binders, disintegrants, lubricants, anti-adherents, glidants, colorants, flavorants, sweeteners, coating agents, plasticizers, wetting agents, buffers, or adsorbents.

[0040] Also provided herein is a pharmaceutical composition comprising an amount of a crystalline form of Compound 1 disclosed herein and one or more pharmaceutically acceptable excipients for use in a method of treating cancer in a subject in need thereof. In some uses, the cancer in the subject in need thereof is a PRC2-associated cancer. In further embodiments, the cancer is prostate cancer, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, or head and neck cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the prostate cancer is metastatic prostate cancer, metastatic castration-resistant prostate cancer, high-risk localized prostate cancer, recurrent prostate cancer, non-metastatic CRPC (nmCRPC), non-metastatic castration-sensitive prostate cancer, or metastatic castration-sensitive prostate cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is skin cancer. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is head and neck cancer.

[0041] Among the one or more diluents that may be used are lactose, mannitol, xylitol, microcrystalline cellulose, calcium hydrogen phosphate, and starch. In some embodiments, the one or more diluents comprise about 1% to about 80%, or about 10% to about 80%, or about 10% to about 70%, or about 15% to about 80%, or about 20% to about 80%, or about 15% to about 75%, or about 20% to about 75%, or about 25% to about 75%, or about 50% to about 80%, or about 50% to about 75%, or about 60% to about 80%, or about 60% to 75% of the total weight of the pharmaceutical composition. In some embodiments, the diluent is lactose. In some embodiments, the diluent is mannitol. In some embodiments, the diluent is xylitol. In some embodiments, the diluent is microcrystalline cellulose. In some embodiments, the diluent is calcium hydrogen phosphate. In some embodiments, the diluent is starch. In some embodiments, the diluent is isomalt. In some embodiments, the diluent is silicified microcrystalline cellulose. In some embodiments, the diluent is pregelatinized starch.

[0042] Also provided herein are pharmaceutical compositions in which the one or more pharmaceutically acceptable excipients comprise one or more binders, the one or more binders comprising about 1% to about 80%, or about 10% to about 80%, or about 10% to about 70%, or about 15% to about 80%, or about 20% to about 80%, or about 15% to about 75%, or about 20% to about 75%, or about 25% to about 75%, or about 50% to about 80%, or about 50% to about 75%, or about 60% to about 80%, or about 60% to about 75% of the total weight of the pharmaceutical composition. In some embodiments, the one or more binders are selected from methylcellulose, microcrystalline cellulose, starch, and gums such as guar gum and tragacanth, or mixtures thereof.

[0043] Also provided herein is a pharmaceutical composition wherein the one or more pharmaceutically acceptable excipients comprise one or more disintegrants, and the one or more disintegrants comprise about 0.1 wt% to about 10 wt%, or about 0.1 wt% to about 5 wt%, or about 0.1 wt% to about 4 wt%, or about 0.1 wt% to about 3 wt%, or about 0.1 wt% to about 2 wt%, or about 0.1 wt% to about 1 wt%, or about 0.1 wt% to about 0.75 wt%, or about 0.2 wt% to about 1 wt%, or about 0.3 wt% to about 1 wt%, or about 0.4 wt% to about 1 wt%, or about 0.2 wt% to about 0.8 wt%, or about 0.3 wt% to about 0.75 wt%, or about 0.3 wt% to about 0.7 wt%, or about 0.3 wt% to about 0.6 wt% of the total weight of the pharmaceutical composition. In some embodiments, the one or more disintegrants are selected from starch, sodium starch glycolate, sodium alginate, sodium carboxymethylcellulose, methylcellulose, croscarmellose sodium, and crospovidone, or mixtures thereof. In some embodiments, the disintegrant is starch. In some embodiments, the disintegrant is sodium starch glycolate. In some embodiments, the disintegrant is sodium alginate. In some embodiments, the disintegrant is sodium carboxymethylcellulose. In some embodiments, the disintegrant is methylcellulose. In some embodiments, the disintegrant is croscarmellose sodium. In some embodiments, the disintegrant is crospovidone. In some embodiments, the disintegrant is methylcellulose. In some embodiments, the disintegrant is sodium carboxymethylcellulose.

[0044] Also provided herein is a pharmaceutical composition wherein the one or more pharmaceutically acceptable excipients comprise one or more lubricants, and the one or more lubricants comprise about 0.1 wt % to about 10 wt %, or about 0.1 wt % to about 5 wt %, or about 0.1 wt % to about 4 wt %, or about 0.1 wt % to about 3 wt %, or about 0.1 wt % to about 2 wt %, or about 0.1 wt % to about 1 wt %, or about 0.1 wt % to about 0.75 wt %, or about 0.2 wt % to about 1 wt %, or about 0.3 wt % to about 1 wt %, or about 0.4 wt % to about 1 wt %, or about 0.2 wt % to about 0.8 wt %, or about 0.3 wt % to about 0.75 wt %, or about 0.3 wt % to about 0.7 wt %, or about 0.3 wt % to about 0.6 wt % of the total weight of the pharmaceutical composition. In further embodiments, the one or more lubricants are selected from magnesium stearate, calcium stearate, sodium stearyl fumarate, and stearic acid, or mixtures thereof. In some embodiments, the lubricant is magnesium stearate. In some embodiments, the lubricant is calcium stearate. In some embodiments, the lubricant is sodium stearyl fumarate. In some embodiments, the lubricant is stearic acid. In some embodiments, the lubricant is glyceryl behenate. In some embodiments, the lubricant is glyceryl monostearate. In some embodiments, the lubricant is magnesium lauryl sulfate.

[0045] In some embodiments, the pharmaceutical compositions disclosed herein may include additional excipients, including, but not limited to, buffers or buffering agents, glidants, preservatives, and colorants. Additional excipients such as bulking agents, tonicity agents, and chelating agents are also within the scope of embodiments.

[0046] Non-limiting examples of buffering agents include, but are not limited to, sodium bicarbonate, potassium bicarbonate, magnesium hydroxide, magnesium lactate, magnesium gluconate, aluminum hydroxide, aluminum hydroxide / sodium bicarbonate coprecipitate, a mixture of an amino acid and a buffer, a mixture of an aluminum glycinate and a buffer, a mixture of an amino acid acid salt and a buffer, and a mixture of an amino acid alkali salt and a buffer. Additional buffering agents include sodium citrate, sodium tartrate, sodium acetate, sodium carbonate, sodium polyphosphate, potassium polyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, trisodium phosphate, tripotassium phosphate, sodium acetate, potassium metaphosphate, magnesium oxide, magnesium hydroxide, magnesium carbonate, magnesium silicate, calcium acetate, calcium glycerophosphate, calcium chloride, calcium hydroxide, calcium lactate, calcium carbonate, calcium bicarbonate, and other calcium salts.

[0047] In some embodiments, the pharmaceutical compositions disclosed herein may include a glidant. Suitable glidants include, but are not limited to, tricalcium phosphate, calcium silicate, cellulose, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, silicon dioxide, starch, talc, etc. In some embodiments, the glidant is tricalcium phosphate. In some embodiments, the glidant is calcium silicate. In some embodiments, the glidant is cellulose. In some embodiments, the glidant is colloidal silicon dioxide. In some embodiments, the glidant is magnesium silicate. In some embodiments, the glidant is magnesium trisilicate. In some embodiments, the glidant is silicon dioxide. In some embodiments, the glidant is starch. In some embodiments, the glidant is talc.

[0048] In some embodiments, the pharmaceutical compositions disclosed herein may contain a preservative. Preservatives include antibacterial agents, antioxidants, and agents that enhance sterility. Exemplary preservatives include ascorbic acid, ascorbyl palmitate, BHA, BHT, citric acid, erythorbic acid, fumaric acid, malic acid, propyl gallate, sodium ascorbate, sodium bisulfate, sodium metabisulfite, sodium sulfite, parabens (methylparaben, ethylparaben, butylparaben), benzoic acid, potassium sorbate, vanillin, etc.

[0049] In some embodiments, the pharmaceutical compositions disclosed herein may contain a coloring agent for identification and / or aesthetic purposes in the resulting liquid form. Suitable coloring agents include, by way of example, FD&C Red No. 3, FD&C Red No. 20, FD&C Red No. 40, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, caramel, iron oxide, and mixtures thereof.

[0050] Additional excipients are contemplated in the pharmaceutical compositions disclosed herein.These additional excipients are selected based on function and compatibility with the pharmaceutical compositions described herein, and can be found in, for example, Remington: The Science and Practice of Pharmacy, Nineteenth Edition (Easton, PA: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, (Easton, PA: Mack Publishing Co 1975); Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms (New York, NY: Marcel Decker 1980) and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Edition (Lippincott Williams & Wilkins 1999), all of which are incorporated herein by reference.

[0051] The pharmaceutical compositions disclosed herein may be in a form suitable for oral administration to a subject in need thereof. Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules made of hard or soft gelatin, methylcellulose, or another suitable material that dissolves easily in the digestive tract. Solid oral dosage forms may be provided, for example, as individual units, such as hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of the crystalline form of Compound 1 disclosed herein and one or more pharmaceutically acceptable excipients. In another embodiment, oral dosage forms may be in powder or granular form. In another embodiment, oral dosage forms are sublingual tablets, such as lozenges. Capsules or tablets may contain a controlled-release formulation. In the case of capsules, tablets, and pills, the dosage forms may include buffers or may be prepared with enteric coatings. In another embodiment, oral dosage forms may be in liquid form. Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art (e.g., water). Such compositions may also contain adjuvants such as wetting agents, emulsifying agents, suspending agents, flavoring agents (e.g., sweeteners), and / or aromatic agents.

[0052] In another embodiment, the pharmaceutical compositions disclosed herein may comprise parenteral dosage forms. "Parenteral administration" includes, for example, subcutaneous injection, intravenous injection, intraperitoneal injection, intramuscular injection, intrasternal injection, and infusion. Injectable preparations (for example, sterile injectable aqueous suspensions or oily suspensions) may be formulated according to known techniques using suitable dispersants, wetting agents, and / or suspending agents.

[0053] In another embodiment, the pharmaceutical compositions disclosed herein may comprise topical dosage forms. "Topical administration" includes, for example, transdermal administration, such as via a transdermal patch or iontophoresis device, intraocular administration, or intranasal or inhalation administration. Compositions for topical administration also include, for example, topical gels, sprays, ointments, and creams. Topical formulations may contain compounds that enhance absorption or penetration of the active ingredient through the skin or other affected areas. When the compositions disclosed herein are administered via a transdermal device, administration is achieved using a patch, either of the reservoir and porous membrane type or of the solid matrix variety. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages, and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Penetration enhancers may be incorporated, see, eg, Finnin and Morgan, J. Pharm. Sci., 88(10), 955-958 (October 1999).

[0054] For intranasal administration or inhalation administration, the pharmaceutical compositions disclosed herein are conveniently delivered in the form of a solution or suspension from a pump spray container that is forced or ejected by the subject, or as an aerosol spray from a pressurized container or nebulizer using a suitable propellant. Formulations suitable for intranasal administration are typically administered in the form of a dry powder from a dry powder inhaler (alone, as a mixture in a dry blend with, for example, lactose, or as mixed-component particles mixed with, for example, a phospholipid such as phosphatidylcholine), or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer that uses electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder may contain a bioadhesive agent, such as chitosan or cyclodextrin.

[0055] Other carrier materials and modes of administration known in the pharmaceutical industry may also be used.The pharmaceutical compositions disclosed herein may be prepared by any known pharmaceutical technology, such as effective formulation and administration procedures.The above considerations regarding effective formulation and administration procedures are well known in the art and are described in standard textbooks.Drug formulations are discussed, for example, in Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 1975; Liberman et al., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Kibbe et al., Eds., Handbook of Pharmaceutical Excipients (3rd Ed.), American Pharmaceutical Association, Washington, 1999.

[0056] The dosage of a composition containing a crystalline form of Compound 1 described herein may vary depending on the condition of the subject (e.g., a human), i.e., the stage of the disease, general health, age, and other factors. The pharmaceutical composition is administered in a manner appropriate to the disease to be treated (or prevented). The appropriate dosage and the suitable duration and frequency of administration are determined by factors such as the subject's condition, the type and severity of the subject's disease, the specific form of the active ingredient, and the method of administration. Generally, an appropriate dosage and treatment regimen provides the composition(s) in an amount sufficient to provide a therapeutic benefit (e.g., improved clinical outcome), such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or a reduction in the severity of symptoms. Optimal dosages are generally determined using experimental models and / or clinical trials. Optimal dosages vary depending on the subject's body type, weight, or blood volume. Oral dosages typically range from about 1.0 mg to about 1000 mg, administered one to four or more times daily.

[0057] Compound 1 may be prepared by methods known to those skilled in the art, including, but not limited to, those methods set forth in U.S. Pat. No. 11,091,495, the contents of which are incorporated herein by reference for such purposes. [Example]

[0058] Example 1: Preparation of Compound 1 Compound 1 can be prepared according to the following scheme: The compounds (5-fluoro-2,3-dihydrobenzofuran-4-yl)methanamine (Compound A), 8-bromo-5-chloroimidazo[1,2-c]pyrimidine-2-carbonitrile (Compound B), and N,N-dimethyl-1-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanamine (Compound D) can be prepared by methods known to those skilled in the art, including, but not limited to, the methods set forth in U.S. Pat. No. 11,091,495, the contents of which are incorporated herein by reference for such purposes.

[0059] [ka]

[0060] Step 1: A mixture of 5-fluoro-2,3-dihydrobenzofuran-4-yl)methanamine (Compound A) and 8-bromo-5-chloroimidazo[1,2-c]pyrimidine-2-carbonitrile (Compound B) in N,N-dimethylformamide (DMF) was treated with diisopropylethylamine (DIPEA), and the mixture was stirred until the reaction was deemed complete. The resulting mixture was treated with ethanol and water, then filtered to give 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carbonitrile) (Compound C).

[0061] Step 2: A mixture of 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carbonitrile (Compound C), N,N-dimethyl-1-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanamine hydrochloride (Compound D), palladium acetate (Pd(OAc)), 2-(dicyclohexylphosphino)-1′,2′,3′-triisopropyl-1,1′-biphenyl (X-Phos), aqueous sodium carbonate (aqueous NaCO), and 2-methyltetrahydrofuran (2-MeTHF) was heated until the reaction was deemed complete. The mixture was then subjected to aqueous workup to 2-MeTHF, and the crude product was isolated by crystallization and filtration from 2-MeTHF / heptane to give crude 8-(4-((dimethylamino)methyl)-2-methylphenyl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carbonitrile (Compound 1).

[0062] Step 3: Crude 8-(4-((dimethylamino)methyl)-2-methylphenyl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carbonitrile (Compound 1) was taken up in 2-MeTHF and passed through a pad of silica gel (SiO), followed by solvent switching to ethyl acetate (EtOAc). The resulting mixture was then treated with acetic acid (HOAc) and filtered to give the acetate salt of 8-(4-((dimethylamino)methyl)-2-methylphenyl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carbonitrile.

[0063] Step 4: The acetate salt of 8-(4-((dimethylamino)methyl)-2-methylphenyl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carbonitrile from Step 3 was converted to the free base by treatment with aqueous NaHCO in ethyl acetate. The resulting EtOAc solution of 8-(4-((dimethylamino)methyl)-2-methylphenyl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carbonitrile was then treated with HOAc, and the resulting mixture was filtered to give the acetate salt of 8-(4-((dimethylamino)methyl)-2-methylphenyl-5-(((5-thiolo-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carbonitrile).

[0064] Step 5: The acetate salt of 8-(4-((dimethylamino)methyl)-2-methylphenyl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carbonitrile from Step 4 was converted to the free base by treatment with aqueous NaHCO in 2-MeTHF, the resulting solution was treated with heptane, and the resulting mixture was filtered to give 8-(4-((dimethylamino)methyl)-2-methylphenyl)-5-(((5-thiolo-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carbonitrile) (Compound 1).

[0065] Example 2A: Preparation of Crystalline Form 1 of Compound 1 150 μL of methanol was added to 50 mg of the free base of Compound 1, and the resulting slurry was stirred at room temperature for 1 day. The resulting solid was vacuum filtered and dried overnight under ambient conditions to obtain Form 1 of Compound 1.

[0066] Example 2B: Preparation of Crystalline Form 2 of Compound 1 400 mg of the free base of Compound 1 was dissolved in 1.5 mL of 2-methyltetrahydrofuran at 50° C., to which 1.5 mL of n-heptane was added at approximately 47° C., and the resulting mixture was cooled to 10° C. The resulting solid was vacuum filtered and air-dried overnight under ambient conditions to provide Form 2 of Compound 1.

[0067] Example 2C: Preparation of Crystalline Form 2 of Compound 1 A quantity of the free base of Compound 1 was dissolved in 2-methyltetrahydrofuran (10 volumes) and then distilled down to 3 volumes. The temperature of the solution was adjusted to approximately 25°C, and the resulting slurry was stirred for 30 minutes or more. n-Heptane (7 volumes) was added to the slurry over 2 hours, and the resulting mixture was stirred for 4 hours or more. The resulting solid was filtered, and the filter cake was washed with 30% 2-methyltetrahydrofuran / heptane (2 volumes) and dried in a vacuum oven to provide Form 2 of Compound 1.

[0068] Example 2D: Preparation of Crystalline Form 2 of Compound 1 The reactor was evacuated and filled with nitrogen to atmospheric pressure. The reactor was then charged with a solution of Compound 1 (approximately 2.41 kg, as determined by HPLC solution assay) in 2-methyltetrahydrofuran (2-MeTHF, 36 kg, 15 volumes), and the batch was concentrated to a batch volume of about 5 L (about 2 volumes) by distillation under reduced pressure. The resulting solution was adjusted to about 25°C, and n-heptane (0.4 kg, 0.2 volumes) was then added in portions over about 3 hours. The resulting solution was then seeded with Compound 1 Form 2 (9 g, 0.4 wt%), and the resulting mixture was stirred for about 1.3 hours, and then additional n-heptane (24 kg, 10 volumes) was added over about 6 hours. The resulting slurry was stirred at 25°C for about 4.25 hours and then filtered. The reactor was then rinsed with n-heptane (5.8 kg, 2.5 V), and this mixture was rinsed forward onto the filter cake, which was deliquored, and the solid was dried under reduced pressure at 40° C. and 50° C. for 19 hours to give 2.48 kg of Compound 1, Form 2.

[0069] Example 3: X-ray powder diffraction (XRPD) analysis of Compound 1 Form 1 and Form 2 Panalytical's X'pert X-ray powder diffractometer 3 XRPD analysis of the crystalline polymorphic forms of Compound 1 was performed using a fluoroscopy. Samples were spread in the center of a zero-background Si holder. The 2θ positions were calibrated against a Si reference standard disk from Panalytical. The parameters used for the analysis are listed in Table 1.

[0070] [Table 1]

[0071] Polymorphic Form 1 of Compound 1 was analyzed by XRPD as described above and exhibited the peaks listed in Table 2. The error associated with each °2θ position was determined to be ±0.2 °θ.

[0072] [Table 2]

[0073] Polymorphic Form 2 of Compound 1 was analyzed by XRPD as described above and exhibited the peaks listed in Table 3. The error associated with each °2θ position was determined to be ±0.2 °θ.

[0074] [Table 3]

[0075] Example 4: Thermogravimetric and Differential Scanning Calorimetry Analysis of Compound 1 Form 1 and Form 2 Thermogravimetric analysis (TGA) data was collected using a TA Instruments TA Discovery TGA 550 TGA, and differential scanning calorimetry (DSC) analysis was performed using a TA Instruments TA Q2000 DSC using the parameters listed in Table 4.

[0076] [Table 4]

[0077] Thermogravimetric analysis (TGA) of a sample of Compound 1 Form 1, when performed under the conditions set forth in Table 4, showed a weight loss of approximately 1% when the sample was heated from room temperature to near the onset of melting (approximately 207°C). Differential scanning calorimetry (DSC) analysis of Compound 1 Form 1, when performed under the conditions set forth in Table 4, showed peaks at approximately 170°C-172°C and approximately 207°C-208°C.

[0078] Thermogravimetric analysis (TGA) of a sample of Form 2 of Compound 1, when performed under the conditions set forth in Table 4, showed a weight loss of approximately 2% when the sample was heated from room temperature to near the onset of melting (approximately 204°C). Differential scanning calorimetry (DSC) analysis of Form 2 of Compound 1, when performed under the conditions set forth in Table 4, showed a peak at approximately 203°C-204°C.

[0079] Example 5: Stability of Form 2 of Compound 1 To determine the stability of Compound 1 Form 2 under storage conditions, samples of Compound 1 Form 2 were placed in double low-density polyethylene bags with a desiccant between the bags, and each was placed in a high-density polyethylene drum. One drum was stored at 25°C and 60% relative humidity (RH), and the other drum was stored at 40°C and 75% RH. Samples of material were taken from both drums at 1 month, 3 months, and 6 months, and the samples were analyzed for the presence of impurities. The amount of Compound 1 Form 2 and any impurities in each sample was measured by ultra-performance liquid chromatography (UPLC) using the test condition sets and solvent gradients described in Tables 5 and 6. The samples were tested to determine the amount of Form 2 remaining at each time point, and the results were analyzed according to the USP <941> Measurements were carried out by x-ray powder diffraction (XRPD) according to the method described above.

[0080] [Table 5]

[0081] [Table 6]

[0082] The results of the stability testing of Compound 1 Form 2 under both storage conditions are shown in Table 7.

[0083] [Table 7]

[0084] The results demonstrated that Form 2 of Compound 1 was stable for up to 6 months when stored at 25°C and 60% RH, and for up to 6 months when stored at 40°C and 75% RH.

[0085] Embodiment Embodiment 1: Compound 1:

[0086] [ka] Crystalline form of.

[0087] Embodiment 2: A crystalline form of Compound 1 of embodiment 1, which is an anhydrous form.

[0088] Embodiment 3: A crystalline form of Compound 1 as described in embodiment 1, exhibiting a peak in an x-ray powder diffraction (XRPD) pattern at 8.1°±0.2° 2θ.

[0089] Embodiment 4: A crystalline form of Compound 1 as described in embodiment 3, which exhibits an additional peak in the x-ray powder diffraction (XRPD) pattern at 9.6°±0.2° 2θ.

[0090] Embodiment 5: A crystalline form of compound 1 of embodiment 4, which exhibits additional peaks in an x-ray powder diffraction (XRPD) pattern at 5.7°±0.2°2θ, 19.7°±0.2°2θ, and 22.0°±0.2°2θ.

[0091] Embodiment 6: A crystalline form of compound 1 of embodiment 5, which exhibits additional peaks in an x-ray powder diffraction (XRPD) pattern at 9.8°±0.2°2θ, 15.2°±0.2°2θ, and 17.7°±0.2°2θ.

[0092] Embodiment 7: A crystalline form of Compound 1 of any one of embodiments 1 to 6, comprising a peak in a differential scanning calorimetry pattern from about 205°C to about 210°C.

[0093] Embodiment 8: A crystalline form of Compound 1 of any one of embodiments 1-7, wherein the crystalline form exhibits less than about 1% mass loss in thermogravimetric analysis when a sample is heated from about 25°C to about 380°C.

[0094] Embodiment 9: A crystalline form of compound 1 as described in embodiment 1, exhibiting a peak in an x-ray powder diffraction (XRPD) pattern at 7.7°±0.2° 2θ.

[0095] Embodiment 10: A crystalline form of compound 1 as described in embodiment 9, which exhibits additional peaks in the x-ray powder diffraction (XRPD) pattern at 13.7°±0.2°2θ and 19.2°±0.2°2θ.

[0096] Embodiment 11: A crystalline form of compound 1 of embodiment 10, which exhibits additional peaks in an x-ray powder diffraction (XRPD) pattern at 5.5°±0.2°2θ, 8.6°±0.2°2θ, 15.9°±0.2°2θ, 19.9°±0.2°2θ, and 24.1°±0.2°2θ.

[0097] Embodiment 12: A crystalline form of Compound 1 of embodiment 11, which exhibits additional peaks in an x-ray powder diffraction (XRPD) pattern at 10.6°±0.2°2θ, 11.0°±0.2°2θ, 15.4°±0.2°2θ, 21.0°±0.2°2θ, and 26.3°±0.2°2θ.

[0098] Embodiment 13: A crystalline form of Compound 1 of any one of embodiments 9 to 12, comprising a peak in a differential scanning calorimetry pattern from about 205°C to about 210°C.

[0099] Embodiment 14: A crystalline form of Compound 1 of any one of embodiments 9-13, wherein the crystalline form exhibits less than about 2% mass loss in thermogravimetric analysis when a sample is heated from about 25°C to about 380°C.

[0100] Embodiment 15: A crystalline form of Compound 1 of any one of embodiments 1 to 14, which exhibits less than about 10% decomposition upon storage at 25° C. and 60% relative humidity for at least 7 days.

[0101] Embodiment 16: A crystalline form of Compound 1 of any one of embodiments 1 to 15, which exhibits less than about 1% decomposition upon storage at 25° C. and 60% relative humidity for at least 7 days.

[0102] Embodiment 17: A crystalline form of Compound 1 of any one of embodiments 1 to 16, which exhibits less than about 10% decomposition upon storage at 40° C. and 75% relative humidity for at least 7 days.

[0103] Embodiment 18: The crystalline form of Compound 1 of embodiment 17, which exhibits less than about 1% decomposition upon storage at 40° C. and 75% relative humidity for at least 7 days.

[0104] Embodiment 19: A crystalline form of Compound 1 of any one of embodiments 1 to 18, which exhibits less than about 10% decomposition upon storage at 60° C. for at least 1 week.

[0105] Embodiment 20: The crystalline form of Compound 1 of embodiment 19, which exhibits less than about 1% decomposition upon storage at 60° C. for at least 1 week.

[0106] Embodiment 21: A crystalline form of compound 1 as described in embodiment 1, exhibiting a peak in an x-ray powder diffraction (XRPD) pattern at 7.7°±0.2° 2θ.

[0107] Embodiment 22: A crystalline form of compound 1 according to embodiment 21, which exhibits an additional peak in the x-ray powder diffraction (XRPD) pattern at 15.4°±0.2° 2θ.

[0108] Embodiment 23: A crystalline form of compound 1 as described in embodiment 21 or embodiment 22, which exhibits an additional peak in the x-ray powder diffraction (XRPD) pattern at 19.2°±0.2° 2θ.

[0109] Embodiment 24: A crystalline form of Compound 1 according to any one of embodiments 21 to 23, which exhibits an additional peak in the x-ray powder diffraction (XRPD) pattern at 13.7°±0.2° 2θ.

[0110] Embodiment 25: A crystalline form of Compound 1 according to any one of embodiments 21 to 24, which exhibits additional peaks in an x-ray powder diffraction (XRPD) pattern at 5.5°±0.2°2θ, 8.6°±0.2°2θ, 15.9°±0.2°2θ, 19.9°±0.2°2θ, and 24.1°±0.2°2θ.

[0111] Embodiment 26: A crystalline form of Compound 1 according to any one of embodiments 21 to 25, which exhibits additional peaks in an x-ray powder diffraction (XRPD) pattern at 10.6°±0.2°2θ, 11.0°±0.2°2θ, 21.0°±0.2°2θ, and 26.3°±0.2°2θ.

[0112] Embodiment 27: A pharmaceutical composition comprising an amount of a crystalline form of Compound 1 according to any one of embodiments 1 to 26 and at least one pharmaceutically acceptable excipient.

[0113] Embodiment 28: A method of inhibiting PRC2 activity in a subject in need thereof, comprising administering to the subject an effective amount of a crystalline form of Compound 1 as described in any one of embodiments 1 to 26.

[0114] Embodiment 29: The method of embodiment 22, wherein the crystalline form of Compound 1 is a form of Compound 1 described in any one of embodiments 2-8.

[0115] Embodiment 30: The method of embodiment 22, wherein the crystalline form of Compound 1 is a form of Compound 1 described in any one of embodiments 9-26.

[0116] Embodiment 31: A method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a crystalline form of Compound 1 according to any one of embodiments 1 to 26.

[0117] Embodiment 32: The method of embodiment 31, wherein the crystalline form of Compound 1 is a form of Compound 1 described in any one of embodiments 2-8.

[0118] Embodiment 33: The method of embodiment 31, wherein the crystalline form of Compound 1 is the form of Compound 1 of any one of embodiments 9-26.

[0119] Embodiment 34: A method of inhibiting PRC2 activity in a subject in need thereof, comprising administering to the subject an effective amount of the pharmaceutical composition of embodiment 27.

[0120] Embodiment 35: A method of treating cancer in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition of embodiment 27.

[0121] Embodiment 36: Cancers include cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; lung: bronchogenic carcinoma (squamous cell, small undifferentiated cell, large undifferentiated cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (pancreatic ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor), , Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colon (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary tract: kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; biliary tract: gallbladder carcinoma, ampullary carcinoma, cholangiocarcinoma; bone: osteogenic sarcoma tumors (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteochondroma), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma and giant cell tumor; nervous system: skull (osteoma, hemangioma, granuloma, xanthomatosis, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibroma, meningioma, nerve Glioma, sarcoma; Gynecology: Uterus (endometrial carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), Vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), Vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), Fallopian tube (carcinoma); Hematology: Blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma);The method of any one of embodiments 31 to 33 and 35, wherein the skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, mole, dysplastic nevi, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland: neuroblastoma.

[0122] Embodiment 37: The method of any one of embodiments 31 to 33, 35, and 36, wherein the cancer is a PRC2-associated cancer.

[0123] Embodiment 38: The method of any one of embodiments 31 to 33, 35, and 36, wherein the cancer is prostate cancer, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, or head and neck cancer.

[0124] Embodiment 39: The method of embodiment 38, wherein the cancer is prostate cancer.

[0125] Embodiment 40: The method of embodiment 39, wherein the prostate cancer is metastatic prostate cancer, metastatic castration-resistant prostate cancer, high-risk localized prostate cancer, recurrent prostate cancer, non-metastatic CRPC (nmCRPC), non-metastatic castration-sensitive prostate cancer, or metastatic castration-sensitive prostate cancer.

[0126] Embodiment 41: The method of embodiment 38, wherein the cancer is breast cancer.

[0127] Embodiment 42: The method of embodiment 38, wherein the cancer is skin cancer.

[0128] Embodiment 43: The method of embodiment 38, wherein the cancer is bladder cancer.

[0129] Embodiment 44: The method of embodiment 38, wherein the cancer is liver cancer.

[0130] Embodiment 45: The method of embodiment 38, wherein the cancer is pancreatic cancer.

[0131] Embodiment 46: The method of embodiment 38, wherein the cancer is head and neck cancer.

[0132] Embodiment 47: A method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of embodiment 27.

[0133] Embodiment 48: Cancers include cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; lung: bronchogenic carcinoma (squamous cell, small undifferentiated cell, large undifferentiated cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (pancreatic ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor), , Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colon (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary tract: kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; biliary tract: gallbladder carcinoma, ampullary carcinoma, cholangiocarcinoma; bone: osteogenic sarcoma tumors (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteochondroma), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma and giant cell tumor; nervous system: skull (osteoma, hemangioma, granuloma, xanthomatosis, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibroma, meningioma, nerve Glioma, sarcoma; Gynecology: Uterus (endometrial carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), Vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), Vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), Fallopian tube (carcinoma); Hematology: Blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma);48. The method of embodiment 47, wherein the skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, mole, dysplastic nevi, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland: neuroblastoma.

[0134] Embodiment 49: The method of any one of embodiments 47 and 48, wherein the cancer is a PRC2-associated cancer.

[0135] Embodiment 50: The method of any one of embodiments 47 to 49, wherein the cancer is prostate cancer, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, or head and neck cancer.

[0136] Embodiment 51: The method of embodiment 50, wherein the cancer is prostate cancer.

[0137] Embodiment 52: The method of embodiment 51, wherein the prostate cancer is metastatic prostate cancer, metastatic castration-resistant prostate cancer, high-risk localized prostate cancer, recurrent prostate cancer, non-metastatic CRPC (nmCRPC), non-metastatic castration-sensitive prostate cancer, or metastatic castration-sensitive prostate cancer.

[0138] Embodiment 53: The method of embodiment 50, wherein the cancer is breast cancer.

[0139] Embodiment 54: The method of embodiment 50, wherein the cancer is skin cancer.

[0140] Embodiment 55: The method of embodiment 50, wherein the cancer is bladder cancer.

[0141] Embodiment 56: The method of embodiment 50, wherein the cancer is liver cancer.

[0142] Embodiment 57: The method of embodiment 50, wherein the cancer is pancreatic cancer.

[0143] Embodiment 58: The method of embodiment 50, wherein the cancer is head and neck cancer.

[0144] While preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. The following claims define the scope of the invention, and it is intended that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

1. Compound 1: 【Chemical 1】 Crystalline form of.

2. 2. The crystalline form of Compound 1 of claim 1, exhibiting a peak in an x-ray powder diffraction (XRPD) pattern at 8.1°±0.2°2θ.

3. 3. The crystalline form of Compound 1 of claim 2, which exhibits an additional peak in its x-ray powder diffraction (XRPD) pattern at 9.6°±0.2° 2θ.

4. 4. The crystalline form of Compound 1 of claim 3, which exhibits additional peaks in an x-ray powder diffraction (XRPD) pattern at 5.7°±0.2°2θ, 19.7°±0.2°2θ, and 22.0°±0.2°2θ.

5. 5. The crystalline form of Compound 1 of claim 4, which exhibits additional peaks in an x-ray powder diffraction (XRPD) pattern at 9.8°±0.2°2θ, 15.2°±0.2°2θ, and 17.7°±0.2°2θ.

6. 2. The crystalline form of Compound 1 of claim 1, exhibiting a peak in an x-ray powder diffraction (XRPD) pattern at 7.7°±0.2°2θ.

7. 7. The crystalline form of Compound 1 of claim 6, which exhibits additional peaks in its x-ray powder diffraction (XRPD) pattern at 13.7°±0.2°2θ and 19.2°±0.2°2θ.

8. 8. The crystalline form of Compound 1 of claim 7, which exhibits additional peaks in an x-ray powder diffraction (XRPD) pattern at 5.5°±0.2°2θ, 8.6°±0.2°2θ, 15.9°±0.2°2θ, 19.9°±0.2°2θ, and 24.1°±0.2°2θ.

9. 9. The crystalline form of Compound 1 of claim 8, which exhibits additional peaks in an x-ray powder diffraction (XRPD) pattern at 10.6°±0.2°2θ, 11.0°±0.2°2θ, 15.4°±0.2°2θ, 21.0°±0.2°2θ, and 26.3°±0.2°2θ.

10. 10. The crystalline form of Compound 1 of any one of claims 1 to 9, which exhibits less than about 10% decomposition upon storage at 25°C and 60% relative humidity for at least 7 days.

11. 10. The crystalline form of Compound 1 of any one of claims 1 to 9, which exhibits less than about 10% decomposition upon storage at 40°C and 75% relative humidity for at least 7 days.

12. A pharmaceutical composition comprising an amount of a crystalline form of Compound 1 according to any one of claims 1 to 11 and at least one pharmaceutically acceptable excipient.

13. 12. A method of inhibiting PRC2 activity in a subject in need thereof, comprising administering to the subject an effective amount of a crystalline form of Compound 1 of any one of claims 1-11.

14. 12. A method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a crystalline form of Compound 1 according to any one of claims 1 to 11.

15. 13. A method of treating cancer in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition of claim 12.

16. 16. The method of claim 14 or 15, wherein the cancer is prostate cancer, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, or head and neck cancer.

17. 17. The method of claim 16, wherein the cancer is prostate cancer.

18. 18. The method of claim 17, wherein the prostate cancer is metastatic prostate cancer, metastatic castration-resistant prostate cancer, high-risk localized prostate cancer, recurrent prostate cancer, non-metastatic CRPC (nmCRPC), non-metastatic castration-sensitive prostate cancer, or metastatic castration-sensitive prostate cancer.

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