Physical forms of PRC2 inhibitors

Abstract

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

Description

[0001] Cross-reference

[0002] This patent application claims the benefit of U.S. Provisional Patent Application Serial No. 63 / 375,582, filed on September 14, 2022, which is hereby incorporated by reference in its entirety. Background Art

[0003] The Polycomb Repressive Complex 2 (PRC2) is a multi - protein complex that contributes to the epigenetic silencing of target genes, thereby regulating development and homeostasis. The PRC2 complex consists of three core subunits: enhancer of zeste homolog 2 (EZH2), extra - embryonic ectoderm development protein (EED), and suppressor of zeste 12 (SUZ12). Two additional non - essential subunits, AEBP2 and RbAp48, play roles in promoting the enzymatic activity of the PRC2 complex (see, for example, 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 cancer, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, head and neck cancer, and hematological malignancies. PRC2 consists of two druggable subunits: EED and EZH2. The pharmacological properties of some EZH2 inhibitor compounds may require high doses to achieve partial target inhibition in subjects with cancer. Additionally, pre - clinical studies have shown that resistance to EZH2 inhibitors can arise through EZH1 bypass compensation or acquired mutations in EZH2. Allosteric inhibition of EED affects the assembly, stability, and activation of PRC2 and may be more beneficial than EZH2 - mediated PRC2 inhibition. 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 the treatment of cancer in subjects. Summary of the Invention

[0004] The present disclosure provides physical forms of Compound 1:

[0005]

[0006] The present disclosure also provides crystalline forms of Compound 1. The present disclosure further provides crystalline forms of Compound 1, wherein the crystalline form is an anhydrous form. The present disclosure also provides pharmaceutical compositions comprising an amount of a crystalline form of Compound 1 as disclosed herein and at least one pharmaceutically acceptable excipient.

[0007] In another embodiment, a method of inhibiting PRC2 activity in a subject in need thereof is provided, comprising administering to the subject an effective amount of a solid form of Compound 1, including a crystalline form of Compound 1 as disclosed herein.

[0008] In other embodiments, methods of treating cancer in a subject are provided, including administering to the subject an effective amount of a solid form of Compound 1, including a crystalline form of Compound 1 as disclosed herein. In another embodiment, such methods of treating cancer in a subject are provided, wherein the cancer is a PRC2-related cancer. Detailed Description

[0009] As used herein and in the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, as well as equivalents known to those of ordinary skill in the art, and the like. 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 the ranges and specific embodiments therein are intended to be included. The term "about" when referring to a number or numerical range means that the recited number or numerical range is an approximation within experimental variability (or within statistical experimental error), and thus in some instances the number or numerical range will vary between 1% and 15% of the recited number or numerical range. The term "comprising" (and related terms such as "including" or "having" or "containing") is not intended to exclude in certain other embodiments (e.g., embodiments of any substance composition, composition, method, or process described herein), "consisting of the recited features" or "consisting essentially of the recited features".

[0010] As used in the specification and the appended claims, unless otherwise specified, the following terms have the meanings set forth below.

[0011] "Administering", when used in connection with a therapeutic means, means systemic or local administration of a therapeutic agent, such as directly into or onto a target tissue, or administration of a therapeutic agent to a subject, whereby the therapeutic agent has a positive effect on the tissue to which it is targeted. Thus, as used herein, the term "administering", when used in connection with the compositions described herein, can include, but is not limited to, providing the composition into or onto a target tissue; providing the composition systemically to a subject, such as by oral administration, whereby the therapeutic agent reaches the target tissue or cell. "Administering" a composition can be accomplished by injection, topical administration, and oral administration, or by other methods alone or in combination with other known techniques.

[0012] The terms "crystallization" and "crystallinity" refer to a degree of long-range order in the molecular positions of a solid composition, as measured by analytical techniques known to those of ordinary skill in the art (such as X-ray powder diffraction (XRPD)).

[0013] The term "differential scanning calorimetry" as used herein refers to the thermal analysis method described in USP <891>.

[0014] The term "pharmaceutically acceptable" means that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and harmless to its recipient.

[0015] The term "pharmaceutical composition" shall mean a composition comprising one or more active ingredients, whereby the composition is suitable for studying a specified effective outcome in mammals (such as but not limited to humans). Those of ordinary skill in the art will understand and recognize the techniques suitable for determining whether an active ingredient has the desired effective outcome based on the needs of the skilled person.

[0016] As used herein, the term "therapeutic agent" means an agent used to treat, counteract, alleviate, prevent or improve an adverse condition or disease in an object.

[0017] As used herein, "therapeutically effective amount" or "effective amount" refers to the amount of an active compound or pharmaceutical agent that elicits a biological or pharmaceutical response in a tissue, system, animal, individual or human, which is sought by a researcher, veterinarian, physician or other clinician, and which includes one or more of the following: (1) preventing a disease; for example, preventing a disease, condition or disorder in an individual who is susceptible to the disease, condition or disorder but has not yet experienced or shown the pathology or symptomatology of the disease, (2) inhibiting a disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or showing the pathology or symptomatology of the disease, condition or disorder (i.e., preventing further development of the pathology and / or symptomatology), and (3) alleviating a disease; for example, alleviating a disease, condition or disorder in an individual who is experiencing or showing the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and / or symptomatology).

[0018] As used herein, the term "treatment" in some embodiments refers to therapeutic treatment, wherein the aim is to prevent or slow down (alleviate) an adverse physiological condition, disorder or disease, or to obtain a beneficial or desired clinical outcome. For the purposes described herein, beneficial or desired clinical outcomes include, but are not limited to, alleviation of symptoms; reduction in the degree of a condition, disorder or disease; stabilization of the state of a condition, disorder or disease (i.e., not worsening); delay in the onset or slowing of the progression of a condition, disorder or disease; reduction in the state of a condition, disorder or disease; and remission (partial or complete), improvement or amelioration of a condition, disorder or disease, whether detectable or undetectable. Treatment includes eliciting a clinically significant response without an excessive level of side effects. Treatment also includes an extended survival period compared to the expected survival period if treatment is not received.

[0019] As used herein, the term "X-ray powder diffraction (XRPD)" means a technique for characterizing the crystallinity or partial crystallinity of a solid using powder X-ray diffraction in accordance with the provisions of USP <941>.

[0020] This text provides the crystal forms of Compound 1:

[0021]

[0022] This text also provides the crystal forms of Compound 1, wherein the crystal form is an anhydrous form.

[0023] This text further provides a crystal form of Compound 1, wherein the crystal form shows a peak at 8.1° ± 0.2° 2-θ in the X-ray powder diffraction (XRPD) pattern. In another embodiment, a crystal form of Compound 1 is provided, wherein the crystal form shows a further peak at 9.6° ± 0.2° 2-θ in the X-ray powder diffraction (XRPD) pattern. A further embodiment provides a crystal form of Compound 1, wherein the crystal form shows further peaks at 5.7° ± 0.2° 2-θ, 19.7° ± 0.2° 2-θ, and 22.0° ± 0.2° 2-θ in the X-ray powder diffraction (XRPD) pattern. In yet a further embodiment, a crystal form of Compound 1 is provided, wherein the crystal form shows further peaks at 9.8° ± 0.2° 2-θ, 15.2° ± 0.2° 2-θ, and 17.7° ± 0.2° 2-θ in the X-ray powder diffraction (XRPD) pattern. In yet another embodiment, a crystal form of Compound 1 is provided, wherein the crystal form contains a peak at approximately 172 °C in the differential scanning calorimetry graph. In yet another embodiment, a crystal form of Compound 1 is provided, wherein the crystal form contains a peak in the range of approximately 205 °C to approximately 210 °C in the differential scanning calorimetry graph. In yet another embodiment, a crystal form of Compound 1 is provided, wherein the crystal form contains a peak in the range of approximately 206 °C to approximately 210 °C, or approximately 207 °C to approximately 210 °C, or approximately 208 °C to approximately 210 °C, or approximately 209 °C to approximately 210 °C in the differential scanning calorimetry graph. In a further embodiment, a crystal form of Compound 1 is provided, wherein when the sample is heated from approximately 25 °C to the temperature before melting, the crystal form shows a mass loss of less than approximately 1% in thermogravimetric analysis. In a further embodiment, a crystal form of Compound 1 is provided, wherein when the sample is heated from approximately 25 °C to approximately 380 °C, the crystal form shows a mass loss of less than approximately 1% in thermogravimetric analysis.

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

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

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

[0027] In another embodiment, a crystalline form of Compound 1 is provided, wherein the crystalline form exhibits peaks at 7.7° ± 0.2° 2-θ and 19.2° ± 0.2° 2-θ in the X-ray powder diffraction (XRPD) pattern. In another embodiment, a crystalline form of Compound 1 is provided, wherein the crystalline form exhibits a further peak at 15.4° ± 0.2° 2-θ in the X-ray powder diffraction (XRPD) pattern. In yet another embodiment, a crystalline form of Compound 1 is provided, wherein the crystalline form exhibits a further peak at 13.7° ± 0.2° 2-θ in the X-ray powder diffraction (XRPD) pattern. In yet a further embodiment, a crystalline form of Compound 1 is provided, wherein the crystalline form exhibits further peaks at 5.5° ± 0.2° 2-θ, 8.6° ± 0.2° 2-θ, 15.9° ± 0.2° 2-θ, 19.9° ± 0.2° 2-θ and 24.1° ± 0.2° 2-θ in the X-ray powder diffraction (XRPD) pattern. Another embodiment provides a crystalline form of Compound 1, wherein the crystalline form exhibits further peaks at 10.6° ± 0.2° 2-θ, 11.0° ± 0.2° 2-θ, 21.0° ± 0.2° 2-θ and 26.3° ± 0.2° 2-θ in the X-ray powder diffraction (XRPD) pattern. A further embodiment provides a crystalline form of Compound 1, wherein the crystalline form comprises a peak at about 203°C to about 210°C in the differential scanning calorimetry (DSC) thermogram. A further embodiment provides a crystalline form of Compound 1, wherein the crystalline form comprises a peak at about 206°C to about 210°C in the differential scanning calorimetry (DSC) thermogram. In yet another embodiment, a crystalline form of Compound 1 is provided, wherein the crystalline form comprises a peak at about 203°C to about 208°C, or about 203°C to about 206°C, or about 203°C to about 205°C in the differential scanning calorimetry (DSC) thermogram. In another embodiment, a crystalline form of Compound 1 is provided, wherein the crystalline form exhibits a mass loss of less than about 2% in thermogravimetric analysis when the sample is heated from about 25°C to about 380°C. In another embodiment, a crystalline form of Compound 1 is provided, wherein the crystalline form exhibits a mass loss of less than about 2% in thermogravimetric analysis when the sample is heated from about 25°C to about 210°C.

[0028] Further embodiments provide crystalline forms of Compound 1 as disclosed herein, wherein the crystalline form shows less than about 10% degradation 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 as disclosed herein, wherein the crystalline form shows 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% degradation 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 further embodiments, there are provided crystalline forms of Compound 1, wherein the crystalline form (a) shows a peak at 8.1° ± 0.2° 2-θ in the X-ray powder diffraction (XRPD) pattern, and (b) shows less than about 10% degradation 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 further embodiments, there are provided crystalline forms of Compound 1, wherein the crystalline form (a) shows peaks at 9.6° ± 0.2° 2-θ, 5.7° ± 0.2° 2-θ, 19.7° ± 0.2° 2-θ, and 22.0° ± 0.2° 2-θ in the X-ray powder diffraction (XRPD) pattern, and (b) shows less than about 10% degradation 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, wherein the crystalline form shows 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% degradation 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] In a further embodiment, a crystalline form of Compound 1 is provided, wherein the crystalline form (a) shows a peak at 7.7° ± 0.2° 2-θ in the X-ray powder diffraction (XRPD) pattern, and (b) shows less than about 10% degradation when the crystalline form is 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, a crystalline form of Compound 1 is provided, wherein the crystalline form (a) shows peaks at 7.7° ± 0.2° 2-θ, 13.7° ± 0.2° 2-θ, and 19.2° ± 0.2° 2-θ in the X-ray powder diffraction (XRPD) pattern, and (b) shows less than about 10% degradation when the crystalline form is 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, wherein when the crystalline form is 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, the crystalline form shows 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% degradation.

[0031] Further embodiments provide a crystalline form of Compound 1 as disclosed herein, wherein when the crystalline form is 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, the crystalline form shows less than about 10% degradation. Further embodiments provide a crystalline form of Compound 1 as disclosed herein, wherein when the crystalline form is 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, the crystalline form shows 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% degradation.

[0032] In a further embodiment, a crystalline form of Compound 1 is provided, wherein the crystalline form (a) shows a peak at 8.1° ± 0.2° 2-θ in the X-ray powder diffraction (XRPD) pattern, and (b) shows less than about 10% degradation when the crystalline form is 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, a crystalline form of Compound 1 as disclosed herein is provided, wherein the crystalline form (a) shows peaks at 9.6° ± 0.2° 2-θ, 5.7° ± 0.2° 2-θ, 19.7° ± 0.2° 2-θ, and 22.0° ± 0.2° 2-θ in the X-ray powder diffraction (XRPD) pattern, and (b) shows less than about 10% degradation when the crystalline form is 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, wherein when the crystalline form is 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, the crystalline form exhibits 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% degradation.

[0033] In a further embodiment, a crystalline form of Compound 1 is provided, wherein the crystalline form (a) shows a peak at 7.7° ± 0.2° 2-θ in the X-ray powder diffraction (XRPD) pattern, and (b) shows less than about 10% degradation when the crystalline form is 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, a crystalline form of Compound 1 is provided, wherein the crystalline form (a) shows peaks at 7.7° ± 0.2° 2-θ, 13.7° ± 0.2° 2-θ, and 19.2° ± 0.2° 2-θ in the X-ray powder diffraction (XRPD) pattern, and (b) shows less than about 10% degradation when the crystalline form is 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, wherein when the crystalline form is 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, the crystalline form shows 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% degradation.

[0034] Other embodiments provide crystalline forms of Compound 1 as disclosed herein, wherein when the crystalline form is stored at 60 °C for at least one week, the crystalline form exhibits less than about 10% degradation. Further embodiments provide crystalline forms of Compound 1, wherein when the crystalline form is stored at 60 °C for at least one week, the crystalline form exhibits 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% degradation.

[0035] The present disclosure further provides pharmaceutical compositions comprising an amount of any crystalline form of Compound 1 as disclosed herein and at least one pharmaceutically acceptable excipient.

[0036] In another embodiment, a method of inhibiting PRC2 activity in a subject in need thereof is provided, comprising administering to the subject an effective amount of any crystalline form of Compound 1 as disclosed herein. The present disclosure also provides a method of inhibiting PRC2 activity in a subject in need thereof, comprising administering to the subject an effective amount of the pharmaceutical composition as disclosed herein.

[0037] In yet another embodiment, a crystalline form of Compound 1 as disclosed herein is provided for use in a method of inhibiting PRC2 activity in a subject in need thereof. In some uses, the PRC2 activity of the subject in need thereof is associated with the subject having a PRC2-related cancer.

[0038] In a further embodiment, there is provided a method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a crystalline form of any of the compounds 1 disclosed herein. In some embodiments, there are provided such methods of treating cancer, wherein the cancer is selected from the heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; lung: bronchial carcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; gastrointestinal tract: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vasoactive intestinal polypeptide tumor), 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, Wilm's 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, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma); liver: liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; biliary tract: gallbladder carcinoma, ampullary carcinoma, cholangiocarcinoma; bone: osteosarcoma (osteogenic sarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteochondral exostosis), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor; nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, Paget's disease), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal cord (neurofibroma, meningioma, glioma, sarcoma); gynecology: uterus (endometrial carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, carcinoma, not otherwise specified), granulosa cell tumor, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, sarcoma botryoides (embryonal rhabdomyosarcoma), fallopian tube (carcinoma);Hematopoietic system: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and Adrenal gland: neuroblastoma. In some embodiments, the cancer is a PRC2-related 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 one embodiment, the cancer is prostate cancer. In one embodiment, the prostate cancer is metastatic prostate cancer, metastatic castration-resistant prostate cancer, locally advanced high-risk 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] In yet another embodiment, there is provided a crystalline form of Compound 1 as 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-related 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 one embodiment, the cancer is prostate cancer. In one embodiment, the prostate cancer is metastatic prostate cancer, metastatic castration-resistant prostate cancer, locally advanced high-risk 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.

[0040] The present invention also provides a pharmaceutical composition comprising an amount of the crystalline form of Compound 1 as disclosed herein and one or more pharmaceutically acceptable excipients. The present invention further provides such a pharmaceutical composition, wherein the one or more pharmaceutically acceptable excipients include one or more diluents, binders, disintegrants, lubricants, anti-adhesives, glidants, colorants, flavorants, sweeteners, coating agents, plasticizers, wetting agents, buffers or adsorbents.

[0041] The present invention also provides a pharmaceutical composition comprising an amount of a crystalline form of Compound 1 as 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-related cancer. In a further embodiment, the cancer is prostate cancer, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer or head and neck cancer. In one embodiment, the cancer is prostate cancer. In one embodiment, the prostate cancer is metastatic prostate cancer, metastatic castration-resistant prostate cancer, locally advanced high-risk 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.

[0042] One or more diluents that can be used include lactose, mannitol, xylitol, microcrystalline cellulose, dibasic calcium phosphate and starch. In some embodiments, the one or more diluents account for 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 dibasic calcium phosphate. In some embodiments, the diluent is starch. In some embodiments, the diluent is isomalt. In some embodiments, the diluent is siliconized microcrystalline cellulose. In some embodiments, the diluent is pregelatinized starch.

[0043] The present invention also provides such a pharmaceutical composition, wherein one or more pharmaceutically acceptable excipients comprise one or more binders, and wherein the one or more binders account for 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 gum) or mixtures thereof.

[0044] The present invention also provides such a pharmaceutical composition, wherein one or more pharmaceutically acceptable excipients include one or more disintegrants, and wherein the one or more disintegrants account for about 0.1% to about 10%, or about 0.1% to about 5%, or about 0.1% to about 4%, or about 0.1% to about 3%, or about 0.1% to about 2%, or about 0.1% to about 1%, or about 0.1% to about 0.75%, or about 0.2% to about 1%, or about 0.3% to about 1%, or about 0.4% to about 1%, or about 0.2% to about 0.8%, or about 0.3% to about 0.75%, or about 0.3% to about 0.7%, or about 0.3% to about 0.6% 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.

[0045] The present invention also provides such a pharmaceutical composition, wherein one or more pharmaceutically acceptable excipients include one or more lubricants, and wherein the one or more lubricants account for about 0.1% to about 10%, or about 0.1% to about 5%, or about 0.1% to about 4%, or about 0.1% to about 3%, or about 0.1% to about 2%, or about 0.1% to about 1%, or about 0.1% to about 0.75%, or about 0.2% to about 1%, or about 0.3% to about 1%, or about 0.4% to about 1%, or about 0.2% to about 0.8%, or about 0.3% to about 0.75%, or about 0.3% to about 0.7%, or about 0.3% to about 0.6% of the total weight of the pharmaceutical composition. In a further embodiment, the one or more lubricants are selected from magnesium stearate, calcium stearate, sodium stearyl fumarate, and stearic acid, or a mixture 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.

[0046] In some embodiments, the pharmaceutical compositions disclosed herein may contain additional excipients including, but not limited to, buffers, glidants, preservatives, and colorants. Additional excipients such as fillers, tonicity agents, and chelating agents are also within the scope of this embodiment.

[0047] Non-limiting examples of buffers include, but are not limited to, sodium bicarbonate, potassium bicarbonate, magnesium hydroxide, magnesium lactate, magnesium gluconate, aluminum hydroxide, aluminum hydroxide / sodium bicarbonate co-precipitate, mixtures of amino acids with buffers, mixtures of aluminum glycinate with buffers, mixtures of amino acid acid salts with buffers, and mixtures of amino acid basic salts with buffers. Additional buffers 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.

[0048] 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, and the like. 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.

[0049] In some embodiments, the pharmaceutical composition disclosed herein may include a preservative. Preservatives include antimicrobial agents, antioxidants, and agents that enhance sterility. Exemplary preservatives include ascorbic acid, ascorbyl palmitate, BHA, BHT, citric acid, isoascorbic acid, fumaric acid, malic acid, propyl gallate, sodium ascorbate, sodium bisulfate, sodium pyrosulfite, sodium sulfite, parabens (methyl, ethyl, butyl), benzoic acid, potassium sorbate, vanillin, etc.

[0050] In some embodiments, the pharmaceutical compositions disclosed herein may include colorants for identification and / or aesthetic purposes of the resulting liquid form. Suitable colorants illustratively include 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.

[0051] Additional excipients of the pharmaceutical compositions disclosed herein are also contemplated. The selection of these additional excipients is based on their function and their compatibility with the pharmaceutical compositions described herein, and reference can be made, for example, to Remington: The Science and Practice of Pharmacy, 19th Edition (Easton, PA: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, (Easton, PA: Mack Publishing Co 1975); Liberman, H.A. and Lachman, L., eds., Pharmaceutical Dosage Forms (New York, NY: Marcel Decker 1980); and Pharmaceutical Dosage Forms and Drug Delivery Systems, 17th Edition (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference in their entireties.

[0052] The pharmaceutical compositions disclosed herein can be in a form suitable for oral administration to a subject in need thereof. Suitable oral dosage forms include, for example, tablets, pills, cachets or capsules, which are made of hard gelatin or soft gelatin, methylcellulose or other suitable materials that are readily soluble in the digestive tract. Oral administration of solid dosage forms can be presented, for example, in discrete units such as hard capsules or soft capsules, pills, cachets, lozenges or tablets, each containing a predetermined amount of a crystalline form of Compound 1 as disclosed herein and one or more pharmaceutically acceptable excipients. In another embodiment, oral administration can be in the form of a powder or granules. In another embodiment, the oral dosage form is sublingual administration, such as, for example, lozenges. Capsules or tablets can contain controlled release formulations. For capsules, tablets and pills, the dosage form can also contain buffering agents or can be prepared with enteric coatings. In another embodiment, oral administration can be in a liquid dosage form. Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs, which contain inert diluents commonly used in the art (such as water). Such compositions can also contain adjuvants such as wetting agents, emulsifying agents, suspending agents, flavoring agents (such as sweeteners) and / or fragrances.

[0053] In another embodiment, the pharmaceutical compositions disclosed herein may comprise a parenteral dosage form. "Parenteral administration" includes, for example, subcutaneous injection, intravenous injection, intraperitoneal injection, intramuscular injection, intracardiac injection, and infusion. Injectable preparations (e.g., sterile injectable aqueous or oily suspensions) may be formulated according to known techniques using suitable dispersing, wetting, and / or suspending agents.

[0054] In another embodiment, the pharmaceutical compositions disclosed herein may comprise a topical dosage form. "Topical administration" includes, for example, transdermal administration (such as via a transdermal patch or iontophoresis device), intraocular administration, or intranasal administration or inhalation administration. Compositions for topical administration also include, for example, topical gels, sprays, ointments, and creams. Topical formulations may include compounds that enhance the 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, the administration will be accomplished using a reservoir and porous membrane type or solid matrix type patch. 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 alcohols, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Penetration enhancers may be added; see, e.g., J. Pharm. Sci., 88(10), 955-958, by Finnin and Morgan (October 1999).

[0055] For intranasal administration or inhalation administration, the pharmaceutical compositions disclosed herein may be conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the subject, or from a pressurized container or nebulizer in the form of an aerosol spray using a suitable propellant. Preparations suitable for intranasal administration are typically administered in dry powder form (used alone, or as a mixture, e.g., a dry blend with lactose, or as mixed component particles, e.g., mixed with a phospholipid such as phosphatidylcholine), via a dry powder inhaler or in the form of an aerosol spray from a pressurized container, pump, sprayer, atomizer (preferably an atomizer that generates fine droplets using electrohydrodynamics), or nebulizer, with or without 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, such as chitosan or cyclodextrin.

[0056] Other carrier materials and modes of administration known in the pharmaceutical art may also be used. The pharmaceutical compositions disclosed herein can be prepared by any well-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. For a discussion of pharmaceutical formulations, see, for example, Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 1975; Liberman et al., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Kibbe et al., eds., Handbook of Pharmaceutical Excipients (3rd Edition Supplement), American Pharmaceutical Association, Washington, 1999.

[0057] The dosage of the composition comprising the crystalline form of Compound 1 described herein may vary depending on the condition of the subject (e.g., human), such as the stage of the disease, general health status, age, and other factors. The pharmaceutical composition is administered in a manner suitable for the disease to be treated (or prevented). The appropriate dosage, as well as the appropriate duration and frequency of administration, will be determined by a variety of factors, such as the condition of the subject, 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 can provide an amount of the composition sufficient to provide a therapeutic benefit (e.g., improved clinical outcomes, such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or reduced severity of symptoms). The optimal dosage is typically determined using experimental models and / or clinical trials. The optimal dosage depends on the body mass, weight, or blood volume of the subject. Oral dosages generally range from about 1.0 mg to about 1000 mg, one to four or more times per day.

[0058] Compound 1 can be prepared by methods known to those of ordinary skill in the art, including but not limited to the methods set forth in U.S. Patent No. 11,091,495, the content of which is incorporated herein by reference for this purpose.

[0059] Examples

[0060] Example 1: Preparation of Compound 1

[0061] Compound 1 can be prepared according to the following scheme. The compound (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 of ordinary skill in the art, including but not limited to the methods set forth in U.S. Patent No. 11,091,495, the content of which is incorporated herein by reference for this purpose.

[0062]

[0063] Step 1: Dissolve (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), treat with diisopropylethylamine (DIPEA), and stir the mixture until the reaction is considered complete. Treat the resulting mixture with ethanol and water and then filter to obtain 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carbonitrile (Compound C).

[0064] Step 2: Heat 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(II) acetate (Pd(OAc)2), 2-(dicyclohexylphosphino)-1’,2’,3’-triisopropyl-1,1’-biphenyl (X-Phos), aqueous sodium carbonate solution (Na2CO3 aqueous solution), and 2-methyltetrahydrofuran (2-MeTHF) until the reaction is considered complete. Then perform an aqueous workup of the mixture in 2-MeTHF and separate the crude product from 2-MeTHF / heptane by crystallization and filtration to obtain 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).

[0065] Step 3: Dissolve the 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) in 2-MeTHF, pass it through a silica gel (SiO2) pad, and then switch the solvent to ethyl acetate (EtOAc). Then treat the resulting mixture with acetic acid (HOAc) and filter to obtain 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.

[0066] Step 4: Treat 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 with an aqueous NaHCO3 solution in ethyl acetate to convert it to the free base. Then treat the resulting 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 in EtOAc with HOAc, and filter the resulting mixture to obtain 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.

[0067] Step 5: Treat 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 with an aqueous NaHCO3 solution in 2-MeTHF to convert it to the free base, treat the resulting solution with heptane, and filter the resulting mixture to obtain 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).

[0068] Example 2A: Preparation of Polymorph 1 of Compound 1

[0069] Add 150 μL of methanol to 50 mg of the free base of Compound 1, and stir the resulting slurry at room temperature for one day. Vacuum filter the resulting solid and dry it overnight under ambient conditions to obtain Form 1 of Compound 1.

[0070] Example 2B: Preparation of Polymorph 2 of Compound 1

[0071] Dissolve 400 mg of the free base of Compound 1 in 1.5 mL of 2-methyltetrahydrofuran at 50 °C. Add 1.5 mL of n-heptane to it at about 47 °C, and cool the resulting mixture to 10 °C. Filter the resulting solid under vacuum and air-dry it overnight under ambient conditions to obtain Form 2 of Compound 1.

[0072] Example 2C: Preparation of Polymorph 2 of Compound 1

[0073] Dissolve a certain amount of the free base of Compound 1 in 2-methyltetrahydrofuran (10 volumes), and then distill it to 3 volumes. Adjust the solution temperature to about 25 °C, and stir the resulting slurry for more than 30 minutes. Add n-heptane (7 volumes) to the slurry within 2 hours, and stir the resulting mixture for more than 4 hours. Filter the resulting solid, wash the filter cake with 30% 2-methyltetrahydrofuran / heptane (2 volumes), and dry it in a vacuum oven to obtain Form 2 of Compound 1.

[0074] Example 2D: Preparation of Polymorph 2 of Compound 1

[0075] Evacuate the reactor and fill it with nitrogen to atmospheric pressure. Then add a solution of Compound 1 (determined by HPLC solution assay, about 2.41 kg) in 2-methyltetrahydrofuran (2-MeTHF, 36 kg, 15 volumes) to the reactor, and concentrate the batch to a batch volume of about 5 L (about 2 volumes) by vacuum distillation. Adjust the resulting solution to about 25 °C, and then add n-heptane (0.4 kg, 0.2 volume) in portions over a period of about 3 hours. Then add seeds of Form 2 of Compound 1 (9 g, 0.4 wt%) to the resulting solution, stir the resulting mixture for about 1.3 hours, and then add additional n-heptane (24 kg, 10 volumes) within about 6 hours. Stir the resulting slurry at 25 °C for about 4.25 hours, and then filter. Subsequently, rinse the reactor with n-heptane (5.8 kg, 2.5V) and rinse this mixture onto the filter cake. Remove the liquid from the filter cake, and dry the solid under reduced pressure at 40 °C and 50 °C for 19 hours to obtain 2.48 kg of Form 2 of Compound 1.

[0076] Example 3: X-ray Powder Diffraction (XRPD) Analysis of Forms 1 and 2 of Compound 1

[0077] Use a Panalytical X'pert 3 X-ray powder diffractometer to perform XRPD analysis on the crystalline polymorphs of Compound 1. Spread the sample in the center of a zero-background Si holder. The 2-θ position is calibrated according to the Panalytical Si reference standard disk. The parameters used for the analysis are shown in Table 1.

[0078] Table 1

[0079]

[0080]

[0081] As described above, Polymorph 1 of Compound 1 was analyzed by XRPD and showed peaks as shown in Table 2. The error associated with each 2-θ position was determined to be ±0.2°θ.

[0082] Table 2

[0083]

[0084] As described above, Polymorph 2 of Compound 1 was analyzed by XRPD and showed peaks as shown in Table 3. The error associated with each 2-θ position was determined to be ±0.2°-θ.

[0085] Table 3

[0086] Position (°2-θ) Relative intensity (%) 5.5 70.17 7.7 100 8.6 62.56 10.6 55.03 11.0 41.46 13.7 85.08 15.4 47.42 15.9 60.49 19.2 78.68 19.9 60.93 21.0 50.16 24.1 68.95 25.3 38.36 26.3 57.53

[0087] Example 4: Thermogravimetric Analysis and Differential Scanning Calorimetry Analysis of Form 1 and Form 2 of Compound 1

[0088] Using the parameters shown in Table 4, thermogravimetric analysis (TGA) data was collected using a TA Discovery TGA 550 TGA from TA Instruments, and differential scanning calorimetry (DSC) analysis was performed using a TA Q2000 DSC from TA Instruments.

[0089] Table 4

[0090]

[0091]

[0092] Under the conditions shown in Table 4, the thermogravimetric analysis (TGA) of a sample of Form 1 of Compound 1 showed a weight loss of approximately 1% when the sample was heated from room temperature to approximately the onset of melting temperature (approximately 207 °C). Under the conditions shown in Table 4, the differential scanning calorimetry (DSC) analysis of Form 1 of Compound 1 showed peaks between approximately 170 °C and 172 °C, and between approximately 207 °C and 208 °C.

[0093] Under the conditions shown in Table 4, thermogravimetric analysis (TGA) of a sample of Form 2 of Compound 1 showed a weight loss of approximately 2% when the sample was heated from room temperature to approximately the onset melting temperature (about 204 °C). Under the conditions shown in Table 4, differential scanning calorimetry (DSC) analysis of Form 2 of Compound 1 showed a peak between approximately 203 °C and 204 °C.

[0094] Example 5: Stability of Form 2 of Compound 1

[0095] To measure the stability of Form 2 of Compound 1 under storage conditions, samples of Form 2 of Compound 1 were placed in double-layer low-density polyethylene bags with a desiccant between the bags, and each sample was placed in a high-density polyethylene bucket. One bucket was stored at 25 °C and a relative humidity (RH) of 60%, and the other bucket was stored at 40 °C and a relative humidity of 75%. Material samples were taken from both buckets at 1 month, 3 months, and 6 months, and the presence of impurities in the samples was analyzed. Using the test conditions and solvent gradients set in Tables 5 and 6, the amount of Form 2 of Compound 1 and the amount of any impurities in each sample were measured by ultra-performance liquid chromatography (UPLC). The samples were tested to determine the remaining amount of Form 2 at each time point and were measured by X-ray powder diffraction (XRPD) according to USP <941>.

[0096] Table 5

[0097]

[0098]

[0099] Table 6

[0100] Time (min) Mobile phase A % Mobile phase B % Initial 98 2 1.00 98 2 30.00 45 55 45.00 5 95 50.00 5 95 50.10 98 2 60.00 98 2

[0101] The results of the stability tests of Form 2 of Compound 1 under the two storage conditions are shown in Table 7.

[0102] Table 7

[0103]

[0104]

[0105] The results showed that Form 2 of Compound 1 was stable for up to 6 months when stored at 25 °C and 60% relative humidity, and was stable for up to 6 months when stored at 40 °C and 75% relative humidity.

[0106] Embodiments

[0107] Embodiment 1: A crystalline form of Compound 1:

[0108]

[0109] Embodiment 2: A crystal form of Compound 1 according to Embodiment 1, wherein the crystal form is the anhydrous form.

[0110] Embodiment 3: A crystal form of Compound 1 according to Embodiment 1, wherein the crystal form shows a peak at 8.1° ± 0.2° 2-θ in the X-ray powder diffraction (XRPD) pattern.

[0111] Embodiment 4: A crystal form of Compound 1 according to Embodiment 3, wherein the crystal form shows a further peak at 9.6° ± 0.2° 2-θ in the X-ray powder diffraction (XRPD) pattern.

[0112] Embodiment 5: A crystal form of Compound 1 according to Embodiment 4, wherein the crystal form shows further peaks at 5.7° ± 0.2° 2-θ, 19.7° ± 0.2° 2-θ, and 22.0° ± 0.2° 2-θ in the X-ray powder diffraction (XRPD) pattern.

[0113] Embodiment 6: A crystal form of Compound 1 according to Embodiment 5, wherein the crystal form shows further peaks at 9.8° ± 0.2° 2-θ, 15.2° ± 0.2° 2-θ, and 17.7° ± 0.2° 2-θ in the X-ray powder diffraction (XRPD) pattern.

[0114] Embodiment 7: A crystal form of Compound 1 according to any one of Embodiments 1 to 6, wherein the crystal form comprises a peak at about 205°C to about 210°C in the differential scanning calorimetry pattern.

[0115] Embodiment 8: A crystal form of Compound 1 according to any one of Embodiments 1 to 7, wherein when the sample is heated from about 25°C to about 380°C, the crystal form shows a mass loss of less than about 1% in thermogravimetric analysis.

[0116] Embodiment 9: A crystal form of Compound 1 according to Embodiment 1, wherein the crystal form shows a peak at 7.7° ± 0.2° 2-θ in the X-ray powder diffraction (XRPD) pattern.

[0117] Embodiment 10: A crystal form of Compound 1 according to Embodiment 9, wherein the crystal form shows further peaks at 13.7° ± 0.2° 2-θ and 19.2° ± 0.2° 2-θ in the X-ray powder diffraction (XRPD) pattern.

[0118] Embodiment 11: A crystalline form of Compound 1 according to Embodiment 10, wherein the crystalline form shows further peaks at 5.5° ± 0.2° 2-θ, 8.6° ± 0.2° 2-θ, 15.9° ± 0.2° 2-θ, 19.9° ± 0.2° 2-θ, and 24.1° ± 0.2° 2-θ in the X-ray powder diffraction (XRPD) pattern.

[0119] Embodiment 12: A crystalline form of Compound 1 according to Embodiment 11, wherein the crystalline form shows further peaks at 10.6° ± 0.2° 2-θ, 11.0° ± 0.2° 2-θ, 15.4° ± 0.2° 2-θ, 21.0° ± 0.2° 2-θ, and 26.3° ± 0.2° 2-θ in the X-ray powder diffraction (XRPD) pattern.

[0120] Embodiment 13: A crystalline form of Compound 1 according to any one of Embodiments 9 to 12, wherein the crystalline form contains a peak at about 205 °C to about 210 °C in the differential scanning calorimetry pattern.

[0121] Embodiment 14: A crystalline form of Compound 1 according to any one of Embodiments 9 to 13, wherein when the sample is heated from about 25 °C to about 380 °C, the crystalline form shows a mass loss of less than about 2% in thermogravimetric analysis.

[0122] Embodiment 15: A crystalline form of Compound 1 according to any one of Embodiments 1 to 14, wherein when the crystalline form is stored at 25 °C and 60% relative humidity for at least 7 days, the crystalline form shows less than about 10% degradation.

[0123] Embodiment 16: A crystalline form of Compound 1 according to any one of Embodiments 1 to 15, wherein when the crystalline form is stored at 25 °C and 60% relative humidity for at least 7 days, the crystalline form shows less than about 1% degradation.

[0124] Embodiment 17: A crystalline form of Compound 1 according to any one of Embodiments 1 to 16, wherein when the crystalline form is stored at 40 °C and 75% relative humidity for at least 7 days, the crystalline form shows less than about 10% degradation.

[0125] Embodiment 18: A crystalline form of Compound 1 according to Embodiment 17, wherein when the crystalline form is stored at 40 °C and 75% relative humidity for at least 7 days, the crystalline form shows less than about 1% degradation.

[0126] Embodiment 19: A crystalline form of Compound 1 according to any one of Embodiments 1 to 18, wherein when the crystalline form is stored at 60 °C for at least one week, the crystalline form shows less than about 10% degradation.

[0127] Embodiment 20: A crystalline form of Compound 1 according to Embodiment 19, wherein when the crystalline form is stored at 60 °C for at least one week, the crystalline form shows less than about 1% degradation.

[0128] Embodiment 21: A crystalline form of Compound 1 according to Embodiment 1, wherein the crystalline form shows a peak at 7.7° ± 0.2° 2-θ in the X-ray powder diffraction (XRPD) pattern.

[0129] Embodiment 22: A crystalline form of Compound 1 according to Embodiment 21, wherein the crystalline form shows a further peak at 15.4° ± 0.2° 2-θ in the X-ray powder diffraction (XRPD) pattern.

[0130] Embodiment 23: A crystalline form of Compound 1 according to Embodiment 21 or Embodiment 22, wherein the crystalline form shows a further peak at 19.2° ± 0.2° 2-θ in the X-ray powder diffraction (XRPD) pattern.

[0131] Embodiment 24: A crystalline form of Compound 1 according to any one of Embodiments 21 to 23, wherein the crystalline form shows a further peak at 13.7° ± 0.2° 2-θ in the X-ray powder diffraction (XRPD) pattern.

[0132] Embodiment 25: A crystalline form of Compound 1 according to any one of Embodiments 21 to 24, wherein the crystalline form shows further peaks at 5.5° ± 0.2° 2-θ, 8.6° ± 0.2° 2-θ, 15.9° ± 0.2° 2-θ, 19.9° ± 0.2° 2-θ, and 24.1° ± 0.2° 2-θ in the X-ray powder diffraction (XRPD) pattern.

[0133] Embodiment 26: A crystalline form of Compound 1 according to any one of Embodiments 21 to 25, wherein the crystalline form shows further peaks at 10.6° ± 0.2° 2-θ, 11.0° ± 0.2° 2-θ, 21.0° ± 0.2° 2-θ, and 26.3° ± 0.2° 2-θ in the X-ray powder diffraction (XRPD) pattern.

[0134] 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.

[0135] 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 according to any one of Embodiments 1 to 26.

[0136] Embodiment 29: The method according to Embodiment 22, wherein the crystalline form of Compound 1 is a form of Compound 1 according to any one of Embodiments 2 to 8.

[0137] Embodiment 30: The method according to Embodiment 22, wherein the crystalline form of Compound 1 is the form of Compound 1 according to any one of Embodiments 9 to 26.

[0138] Embodiment 31: A method for treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of the crystalline form of Compound 1 according to any one of Embodiments 1 to 26.

[0139] Embodiment 32: The method according to Embodiment 31, wherein the crystalline form of Compound 1 is the form of Compound 1 according to any one of Embodiments 2 to 8.

[0140] Embodiment 33: The method according to Embodiment 31, wherein the crystalline form of Compound 1 is the form of Compound 1 according to any one of Embodiments 9 to 26.

[0141] Embodiment 34: A method for inhibiting PRC2 activity in a subject in need thereof, comprising administering to the subject an effective amount of the pharmaceutical composition according to Embodiment 27.

[0142] Embodiment 35: A method for treating cancer in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition according to Embodiment 27.

[0143] Embodiment 36: The method according to any one of Embodiments 31 to 33 and 35, wherein the cancer is selected from the heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; lung: bronchial carcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; gastrointestinal tract: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vasoactive intestinal polypeptide tumor), 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, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma); liver: liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; biliary tract: gallbladder carcinoma, ampullary carcinoma, cholangiocarcinoma; bone: osteosarcoma (osteogenic sarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteochondral exostosis), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor; nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, Paget's disease), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal cord (neurofibroma, meningioma, glioma, sarcoma); gynecology: uterus (endometrial carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, carcinoma, not otherwise specified), granulosa cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, sarcoma botryoides (embryonal rhabdomyosarcoma), fallopian tube (carcinoma); hematopoietic system: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin lymphoma (malignant lymphoma);Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and Adrenal gland: neuroblastoma.

[0144] Embodiment 37: The method according to any one of Embodiments 31 to 33, 35 and 36, wherein the cancer is a PRC2-related cancer.

[0145] Embodiment 38: The method according to 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.

[0146] Embodiment 39: The method according to Embodiment 38, wherein the cancer is prostate cancer.

[0147] Embodiment 40: The method according to Embodiment 39, wherein the prostate cancer is metastatic prostate cancer, metastatic castration-resistant prostate cancer, locally advanced high-risk prostate cancer, recurrent prostate cancer, non-metastatic CRPC (nmCRPC), non-metastatic castration-sensitive prostate cancer or metastatic castration-sensitive prostate cancer.

[0148] Embodiment 41: The method according to Embodiment 38, wherein the cancer is breast cancer.

[0149] Embodiment 42: The method according to Embodiment 38, wherein the cancer is skin cancer.

[0150] Embodiment 43: The method according to Embodiment 38, wherein the cancer is bladder cancer.

[0151] Embodiment 44: The method according to Embodiment 38, wherein the cancer is liver cancer.

[0152] Embodiment 45: The method according to Embodiment 38, wherein the cancer is pancreatic cancer.

[0153] Embodiment 46: The method according to Embodiment 38, wherein the cancer is head and neck cancer.

[0154] Embodiment 47: A method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition according to Embodiment 27.

[0155] Embodiment 48: The method according to Embodiment 47, wherein the cancer is selected from the heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; lung: bronchial carcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar (bronchioloalveolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; gastrointestinal tract: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vasoactive intestinal polypeptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); urogenital 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, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma); liver: liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; biliary tract: gallbladder carcinoma, ampullary carcinoma, cholangiocarcinoma; bone: osteosarcoma (osteogenic sarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteochondral exostosis), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor; nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, Paget's disease), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal cord (neurofibroma, meningioma, glioma, sarcoma); gynecology: uterus (endometrial carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, carcinoma, not otherwise specified), granulosa cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, sarcoma botryoides (embryonal rhabdomyosarcoma), fallopian tube (carcinoma); hematopoietic system: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin lymphoma (malignant lymphoma);Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland: neuroblastoma.

[0156] Embodiment 49: The method according to any one of Embodiments 47 and 48, wherein the cancer is a PRC2-related cancer.

[0157] Embodiment 50: The method according to 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.

[0158] Embodiment 51: The method according to Embodiment 50, wherein the cancer is prostate cancer.

[0159] Embodiment 52: The method according to Embodiment 51, wherein the prostate cancer is metastatic prostate cancer, metastatic castration-resistant prostate cancer, locally advanced high-risk prostate cancer, recurrent prostate cancer, non-metastatic CRPC (nmCRPC), non-metastatic castration-sensitive prostate cancer or metastatic castration-sensitive prostate cancer.

[0160] Embodiment 53: The method according to Embodiment 50, wherein the cancer is breast cancer.

[0161] Embodiment 54: The method according to Embodiment 50, wherein the cancer is skin cancer.

[0162] Embodiment 55: The method according to Embodiment 50, wherein the cancer is bladder cancer.

[0163] Embodiment 56: The method according to Embodiment 50, wherein the cancer is liver cancer.

[0164] Embodiment 57: The method according to Embodiment 50, wherein the cancer is pancreatic cancer.

[0165] Embodiment 58: The method according to Embodiment 50, wherein the cancer is head and neck cancer.

[0166] Although the preferred embodiments of the present invention have been shown and described herein, those skilled in the art should understand that these embodiments are provided by way of example only. Those skilled in the art can now make various changes, alterations and substitutions without departing from the spirit of the present invention. It should be understood that various alternatives to the embodiments of the present invention described herein may be employed in practicing the present invention. The following claims are intended to define the scope of the present invention and cover the methods and structures within the scope of these claims and their equivalents.

Claims

1. Crystal form of Compound 1: Compound 1.

2. The crystal form of Compound 1 according to claim 1, wherein the crystal form shows a peak at 8.1° ± 0.2° 2-θ in the X-ray powder diffraction (XRPD) pattern.

3. The crystal form of Compound 1 according to claim 2, wherein the crystal form shows a further peak at 9.6° ± 0.2° 2-θ in the X-ray powder diffraction (XRPD) pattern.

4. The crystal form of Compound 1 according to claim 3, wherein the crystal form shows further peaks at 5.7° ± 0.2° 2-θ, 19.7° ± 0.2° 2-θ, and 22.0° ± 0.2° 2-θ in the X-ray powder diffraction (XRPD) pattern.

5. The crystal form of Compound 1 according to claim 4, wherein the crystal form shows further peaks at 9.8° ± 0.2° 2-θ, 15.2° ± 0.2° 2-θ, and 17.7° ± 0.2° 2-θ in the X-ray powder diffraction (XRPD) pattern.

6. The crystal form of Compound 1 according to claim 1, wherein the crystal form shows a peak at 7.7° ± 0.2° 2-θ in the X-ray powder diffraction (XRPD) pattern.

7. The crystal form of Compound 1 according to claim 6, wherein the crystal form shows further peaks at 13.7° ± 0.2° 2-θ and 19.2° ± 0.2° 2-θ in the X-ray powder diffraction (XRPD) pattern.

8. The crystal form of Compound 1 according to claim 7, wherein the crystal form shows further peaks at 5.5° ± 0.2° 2-θ, 8.6° ± 0.2° 2-θ, 15.9° ± 0.2° 2-θ, 19.9° ± 0.2° 2-θ, and 24.1° ± 0.2° 2-θ in the X-ray powder diffraction (XRPD) pattern.

9. The crystal form of Compound 1 according to claim 8, wherein the crystal form shows further peaks at 10.6° ± 0.2° 2-θ, 11.0° ± 0.2° 2-θ, 15.4° ± 0.2° 2-θ, 21.0° ± 0.2° 2-θ, and 26.3° ± 0.2° 2-θ in the X-ray powder diffraction (XRPD) pattern.

10. The crystal form of Compound 1 according to any one of claims 1 to 9, wherein when the crystal form is stored at 25 °C and 60% relative humidity for at least 7 days, the crystal form shows less than about 10% degradation.

11. The crystalline form of Compound 1 according to any one of claims 1 to 9, wherein when the crystalline form is stored at 40 °C and 75% relative humidity for at least 7 days, the crystalline form shows less than about 10% degradation.

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

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

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

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

16. The method according to 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. The method according to claim 16, wherein the cancer is prostate cancer.

18. The method according to claim 17, wherein the prostate cancer is metastatic prostate cancer, metastatic castration-resistant prostate cancer, locally advanced high-risk 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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