Crystalline form of 7-chloro-2-(4-(3-methoxyazetidin-1-yl)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide

Abstract

To provide methods for treating diseases or disorders responsive to inhibition of EZH2.SOLUTION: The present disclosure relates to a crystalline form 1 of 7-chloro-2-(4-(3-methoxyazetidin-1-yl)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide, which is useful as a modulator for the activity of histone methyl modifying enzymes.SELECTED DRAWING: None

Description

Related Applications

[0001] This application claims priority to U.S. Provisional Application No. 62 / 878,012, filed Jul. 24, 2019, the entire contents of which are incorporated herein by reference. BACKGROUND OF THE INVENTION

[0002] Eukaryotic chromatin is composed of a macromolecular complex called the nucleosome. The nucleosome has 147 base pairs of DNA that wraps around a protein octamer having two subunits each of the histone proteins H2A, H2B, H3, and H4. The histone proteins are post-translationally modified, which in turn affects chromatin structure and gene expression. One type of post-translational modification found on histones is the methylation of lysine and arginine residues. Histone methylation plays an important role in the regulation of eukaryotic gene expression. Methylation affects chromatin structure and is associated with both the activation and repression of transcription (Zhang and Reinberg, Genes Dev. 15:2343-2360, 2001). Enzymes that catalyze the attachment and removal of methyl groups from histones are involved in gene silencing, embryo development, cell proliferation, and other processes.

[0003] One type of histone methyltransferase is characterized by the presence of a Suppressor of Variegation Enhancer of Zeste Trithorax (SET) domain that contains approximately 130 amino acids. Enhancer of Zeste Homolog 2 (EZH2) is an example of a methyltransferase containing the human SET domain. EZH2 associates with EED (Embryonic Ectoderm Development) and SUZ12 (suppressor of zeste 12 homolog) to form a complex known as PRC2 (Polycomb Group Repressive Complex 2) that has the ability to trimethylate histone H3 at lysine 27 (Cao and Zhang, Mol. Cell 15:57-67, 2004). The PRC2 complex may also include the RBAP46 subunit and the RBAP48 subunit. Another example is the related methyltransferase EZH1.

[0004] Numerous studies have shown the oncogenic activity of EZH2. In cell line experiments, overexpression of EZH2 induces cell invasion, growth in soft agar, and motility, while knockdown of EZH2 inhibits cell proliferation and cell invasion (Kleer et al., 2003, Proc. Nat. Acad. Sci. USA 100:11606-11611, Varambally et al., (2002), “The polycomb group protein EZH2 is involved in progression of prostate cancer,” Nature 419, 624-629). EZH2 has been shown to suppress the expression of several tumor suppressors including, among others, E-cadherin, DAB2IP, and RUNX3. In xenograft models, knockdown of EZH2 suppresses tumor growth and metastasis. In recent years, downregulation of EZH2 in mouse models has been shown to prevent metastasis of prostate cancer (Min et al., “An oncogene-tumor suppressor cascade drives metastatic prostate cancer by coordinately activating Ras and nuclear factor-kappaB,” Nat Med. 2010 Mar;16(3) (:286-94). Overexpression of EZH2 is associated with the aggressiveness of certain cancers such as breast cancer (Kleer et al., Proc. Nat. Acad. Sci. USA 100:11606-11611, 2003). Recent studies have also suggested that the prostate cancer-specific oncogenic fusion gene TMPRSS2-ERG induces a suppressive epigenetic program through direct activation of EZH2 (Yu et al., “An Integrated Network of Androgen Receptor, Polycomb, and TMPRSS2-ERG Gene Fusions in Prostate Cancer Progression,” Cancer Cell. 2010 May 18;17(5):443-454).

[0005] Compound 1, 7-chloro-2-(4-(3-methoxyazetidin-1-yl)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide, is a small molecule inhibitor of EZH2 that shows great therapeutic potential for treating various conditions related to methyl-modifying enzymes, for example, in the treatment of proliferative disorders such as cancer. Compound 1 is exemplified in U.S. Provisional Application No. 62 / 659,408, the content of which is incorporated herein by reference and has the following structure:

[0006]

Chemical formula

[0007] The development of alternative forms of Compound 1 represents an attractive area for further treating diseases or disorders responsive to inhibition of EZH2.

Summary of the Invention

[0008] Provided herein are crystalline forms of Compound 1.

[0009] Also provided herein are pharmaceutical compositions comprising one or more of the crystalline forms of compound 1 disclosed herein.

[0010] Further provided is the use of one or more of the crystalline forms of compound 1 disclosed herein in the treatment of diseases or disorders responsive to EZH2 inhibition, such as cancer. BRIEF DESCRIPTION OF THE DRAWINGS

[0011]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

[0012] Definitions As used herein, "crystalline" refers to a solid form of a compound in which there is long-range atomic order in the positions of the atoms. The crystalline nature of the solid can be confirmed, for example, by examination of an X-ray powder diffraction pattern.

[0013] Unless otherwise specified, the crystalline forms of Compound 1 (Form 1, Form 2, and Form 3) are each in a single crystal form. "Single crystal form" means that the listed compound, i.e., Compound 1, exists as a single crystal or multiple crystals where each crystal has the same crystal form (e.g., Form 1, 2, or 3). The weight percentage of a particular crystal form is calculated by dividing the weight of the particular crystal form by the sum of the weights of the particular crystals, the weights of the other crystal forms present, and the weight of the amorphous form present, and multiplying this by 100%.

[0014] "Form 1", "crystalline form 1", or "single crystal form 1" are used interchangeably. "Form 2", "crystalline form 2", or "single crystal form 2" are used interchangeably. "Form 3", "crystalline form 3", or "single crystal form 3" are used interchangeably.

[0015] Chemical purity refers to the extent to which the disclosed form does not contain substances having different chemical structures. The chemical purity of the compound in the disclosed crystalline form means dividing the weight of the compound by the total weight of the compound and substances / impurities having different chemical structures, and multiplying this by 100% (i.e., weight percentage).

[0016] The term "amorphous" refers to a solid that exists in an amorphous state or form. An amorphous solid is a disordered arrangement of molecules and thus does not have a distinguishable crystal lattice or unit cell and thus does not have a definable long-range order. The solid-state order of a solid can be determined by standard techniques known in the art, such as X-ray powder diffraction (XRPD) or differential scanning calorimetry (DSC).

[0017] The terms "anhydrous" and "anhydrate" are used interchangeably and mean that the referenced crystalline form has substantially no water in the crystal lattice, e.g., less than 1 wt% as determined by Karl Fischer analysis.

[0018] The 2θ values of the X-ray powder diffraction patterns for the crystalline forms described herein may vary slightly depending on the instrument, as well as on variations during sample preparation and batch-to-batch variations due to factors such as temperature fluctuations, sample displacement, and the presence or absence of an internal standard. Accordingly, unless otherwise defined, the XRPD patterns / assignments listed herein should not be construed as absolute and may vary by up to about ±0.2 degrees. It is well known in the art that this variability accounts for the above factors without preventing clear discrimination of the crystalline forms. Unless otherwise specified, the 2θ values provided herein were obtained using Cu Kα1 radiation.

[0019] For example, the temperature values of the DSC peaks in this specification may vary slightly depending on the instrument, as well as on variations during sample preparation, batch-to-batch variations, and environmental factors. Accordingly, Unless otherwise defined, the temperature values listed herein should not be construed as absolute values and may vary by up to about ±5 degrees or ±2 degrees.

[0020] "Substantially the same XRPD pattern" or "X-ray powder diffraction pattern substantially similar to" a defined figure means that at least 90% of the peaks shown are present for comparison purposes. It should be further understood that for comparison purposes, some variation in peak intensity from that shown, such as up to ±0.2 degrees, is acceptable.

[0021] The amount of one crystalline form relative to another in a sample can be evaluated by preparing a series of mixtures of the two crystalline forms in known weight ratios and obtaining XRPD spectra for each. For example, the relative amounts of crystalline forms 1 and 2 in a sample can be evaluated by selecting one or more characteristic peaks of crystalline forms 1 and 2, respectively, as shown in FIGS. 1 and 3, and correlating their relative intensities in the sample XRPD to their relative intensities in the mixture XRPD.

[0022] As used herein, the terms "subject" and "patient" may be used interchangeably and refer to a mammal in need of treatment, such as a companion animal (e.g., dog, cat, etc.), livestock (e.g., cow, pig, horse, sheep, goat, etc.), and laboratory animals (e.g., rat, mouse, guinea pig, etc.). Typically, the subject is a human in need of treatment.

[0023] The term "pharmaceutically acceptable carrier" refers to a non-toxic carrier, adjuvant, or vehicle that does not adversely affect the pharmacological activity of the compound formulated therewith and is safe for human use. Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions of the present disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, magnesium stearate, lecithin, serum proteins such as human serum albumin, buffering substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, dicalcium phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyvinylpyrrolidone-vinyl acetate, cellulose-based substances (e.g., microcrystalline cellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate), starch, lactose monohydrate, mannitol, sodium lauryl sulfate, and croscarmellose sodium, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, polymethacrylate, wax, polyethylene-polyoxypropylene-block polymer, polyethylene glycol, and lanolin.

[0024] The terms "treatment", "treating", and "treatment" refer to restoring, alleviating, reducing the likelihood of occurrence, or suppressing the progression of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be performed after one or more symptoms have occurred (i.e., therapeutic treatment). In other embodiments, treatment may be performed in the absence of symptoms. For example, treatment may be performed on a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or genetic or other susceptibility factors) (i.e., prophylactic treatment). After symptoms have resolved, treatment may also be continued, for example, to prevent or delay recurrence.

[0025] The term "effective amount" or "therapeutically effective amount" refers to the amount of a compound described herein that will induce a biological or medical response in a subject, e.g., a dosage of 0.001 to 100 m g / kg body weight / day of Compound 1.

[0026] Exemplary Forms In a first aspect, the present specification provides a crystalline form 1 of a compound having the following structural formula:

[0027]

Chemical formula

[0028] In a second aspect, crystalline form 1 is characterized by at least 3 X-ray powder diffraction peaks at 2θ angles selected from 10.0°, 13.3°, 14.9°, 20.2°, 20.8°, 22.2°, and 22.5°. Alternatively, as part of the second aspect, crystalline form 1 is characterized by at least 4 X-ray powder diffraction peaks at 2θ angles selected from 10.0°, 13.3°, 14.9°, 20.2°, 20.8°, 22.2°, and 22.5°. In another alternative, as part of the second aspect, crystalline form 1 is characterized by at least 5 X-ray powder diffraction peaks at 2θ angles selected from 10.0°, 13.3°, 14.9°, 20.2°, 20.8°, 22.2°, and 22.5°. In another alternative, as part of the second aspect, crystalline form 1 is characterized by at least 6 X-ray powder diffraction peaks at 2θ angles selected from 10.0°, 13.3°, 14.9°, 20.2°, 20.8°, 22.2°, and 22.5°. In another alternative, as part of the second aspect, crystalline form 1 is characterized by X-ray powder diffraction peaks at 2θ angles selected from 10.0°, 13.3°, 14.9°, 20.2°, 20.8°, 22.2°, and 22.5°. In another alternative, as part of the second aspect, crystalline form 1 is characterized by X-ray powder diffraction peaks at 2θ angles selected from 10.0°, 10.2°, 12.3°, 12.7°, 13.3°, 14.9°, 15.3°, 20.2°, 20.8°, 21.3°, 22.2°, 22.5°, and 23.8°. In another alternative, as part of the second aspect, crystalline form 1 is characterized by X-ray powder diffraction peaks at 2θ angles selected from 10.0°, 10.2°, 11.0°, 11.4°, 11.8°, 12.3°, 12.7°, 13.3°, 14.9°, 15.3°, 16.1°, 17.4°, 20.2°, 20.8°, 21.3°, 22.2°, 22.5°, and 23.8°. In another alternative, as part of the second aspect, crystalline form 1 is characterized by X-ray powder diffraction peaks at 2θ angles selected from 14.9°, 20.2°, and 20.8°. In another alternative, as part of the second aspect, crystalline form 1 is characterized by X-ray powder diffraction peaks at 2θ angles selected from 10.0°, 14.9°, 20.2°, and 20.8°.In another alternative example, as part of the second aspect, crystalline form 1 is characterized by X-ray powder diffraction peaks at 2θ angles selected from 10.0°, 14.9°, 20.2°, 20.8°, and 22.2°. In another alternative example, as part of the second aspect, crystalline form 1 is characterized by X-ray powder diffraction peaks at 2θ angles selected from 10.0°, 13.3°, 14.9°, 20.2°, 20.8°, and 22.2°. In another alternative example, as part of the second aspect, crystalline form 1 is characterized by XRPD (X-ray powder diffraction) substantially similar to FIG. 1.

[0029] In the third aspect, crystalline form 1 has a sharp endotherm at 179.5 °C (starting temperature) in differential scanning calorimetry (DSC), or a thermogravimetric analysis of 1.0% weight loss at 36 °C to 179 °C (TGA), or both, and crystalline form 1 may also include XRPD peaks at 2θ angles selected from any of those described in the second aspect. In other aspects, crystalline form 1 is characterized by differential scanning calorimetry (DSC) substantially similar to FIG. 2, and crystalline form 1 may also include XRPD peaks at 2θ angles selected from any of those described in the second aspect.

[0030] In the fourth aspect, crystalline form 1 is anhydrous, and crystalline form 1 may also include XRPD peaks at 2θ angles selected from any of those described in the second aspect, and / or the TGA or DSC values or figures cited in the third aspect.

[0031] In the fifth aspect, crystalline form 1 described herein (e.g., as in the first, second, third, or fourth aspect) is at least 60 wt% single crystal form, at least 70 wt% single crystal form, at least 80 wt% single crystal form, at least 90 wt% single crystal form, at least 95 wt% single crystal form, or at least 99 wt% single crystal form.

[0032] In a sixth aspect, the crystalline form 1 described herein (such as in the first, second, third, fourth, or fifth aspect) has a chemical purity of at least 60 wt%, at least 70 wt%, at least 80 wt%, at least 90 wt%, at least 95 wt%, or at least 99 wt%.

[0033] In a seventh aspect, a crystalline form 2 of a compound having the following structural formula is provided:

[0034]

Chemical formula

[0035] In an eighth aspect, the crystalline form 2 is characterized by XRPD (X-ray powder diffraction) substantially similar to FIG. 3.

[0036] In a ninth aspect, the crystalline form 2 is characterized by thermogravimetric analysis (TGA) with a weight loss of 3.48% at 46 °C to 114 °C and 0.97% at 114 °C to 156 °C, or differential scanning calorimetry (DSC) with two endotherms at 34.2 °C and 122.6 °C (starting temperature), or both. The crystalline form 2 may also include XRPD peaks at 2θ angles substantially similar to FIG. 3. Alternatively, as part of the ninth aspect, the crystalline form 2 is characterized by thermogravimetric analysis (TGA) or differential scanning calorimetry (DSC) substantially similar to FIG. 4, and the crystalline form 2 may also include XRPD peaks at 2θ angles substantially similar to FIG. 3.

[0037] In a tenth aspect, the crystalline form 2 described herein (such as in the seventh, eighth, or ninth aspect) is at least 60 wt% in single crystal form, at least 70 wt% in single crystal form, at least 80 wt% in single crystal form, at least 90 wt% in single crystal form, at least 95 wt% in single crystal form, or at least 99 wt% in single crystal form.

[0038] In an eleventh aspect, the crystalline form 2 described herein (such as in the seventh, eighth, ninth, Or (such as in the tenth aspect), it has a chemical purity of at least 60 wt%, at least 70 wt%, at least 80 wt%, at least 90 wt%, at least 95 wt%, or at least 99 wt%.

[0039] In the twelfth aspect, crystalline form 3 of a compound having the following structural formula is provided:

[0040]

Chemical formula

[0041] In the thirteenth aspect, crystalline form 3 is characterized by XRPD (X-ray powder diffraction) substantially similar to that in FIG. 5.

[0042] In the fourteenth aspect, crystalline form 3 is characterized by thermogravimetric analysis (TGA) with a weight loss of 5.93% at 43 °C to 143 °C, or differential scanning calorimetry (DSC) having two endotherms at 34.5 °C and 107.0 °C (starting temperatures) and one exotherm at 249.0 °C (starting temperature), or both. Crystalline form 3 may also include XRPD peaks at 2θ angles substantially similar to those in FIG. 5. Alternatively, as part of the fourteenth aspect, crystalline form 3 is characterized by thermogravimetric analysis (TGA) or differential scanning calorimetry (DSC) substantially similar to that in FIG. 6, and crystalline form 3 may also include XRPD peaks at 2θ angles substantially similar to those in FIG. 5.

[0043] In the fifteenth aspect, crystalline form 3 described herein (such as in the twelfth, thirteenth, or fourteenth aspect) is at least 60 wt% in single crystal form, at least 70 wt% in single crystal form, at least 80 wt% in single crystal form, at least 90 wt% in single crystal form, at least 95 wt% in single crystal form, or at least 99 wt% in single crystal form.

[0044] In a 16th aspect, the crystalline form 3 described herein (such as in the 12th, 13th, 14th, or 15th aspect) has a chemical purity of at least 60 wt%, at least 70 wt%, at least 80 wt%, at least 90 wt%, at least 95 wt%, or at least 99 wt%.

[0045] In a 17th aspect, the crystalline form 1 described herein (such as in the 1st, 2nd, 3rd, 4th, or 5th aspect), the crystalline form 2 described herein (such as in the 7th, 8th, 9th, 10th, or 11th aspect), or the crystalline form 3 (such as in the 12th, 13th, 14th, 15th, or 16th aspect) is represented by the following structural formula:

[0046]

Chemical formula

[0047] Alternatively, as part of the 17th aspect, the crystalline form 1 described herein (such as in the 1st, 2nd, 3rd, 4th, or 5th aspect), the crystalline form 2 described herein (such as in the 7th, 8th, 9th, 10th, or 11th aspect), or the crystalline form 3 (such as in the 12th, 13th, 14th, 15th, or 16th aspect) is represented by the following structural formula:

[0048]

Chemical formula

[0049] Alternatively, as part of the 17th aspect, the crystalline form 1 described herein (such as in the 1st, 2nd, 3rd, 4th, or 5th aspect), the crystalline form 2 described herein (such as in the 7th, 8th, 9th, 10th, or 11th aspect), or the crystalline form 3 (such as in the 12th, 13th, 14th, 15th, or 16th aspect) is represented by the following structural formula,

[0050]

Chemical formula

[0051] (2R)-7-chloro-2-(trans-4-(3-methoxyazetidin-1-yl)cyclohexyl)-2,4-dimethyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide.

[0052] Use, formulation, and administration The crystalline forms and compositions thereof described herein are useful for the treatment of diseases or disorders responsive to EZH2 inhibition. Such diseases and disorders include those related to cell proliferation. In some embodiments, the crystalline forms and compositions thereof described herein are useful for the treatment of diseases and / or disorders related to misregulation of the cell cycle or DNA repair. In some embodiments, the crystalline forms and compositions thereof described herein are useful for the treatment of cancer. It is useful for treatment. Exemplary types of cancer include, for example, adrenal cancer, alveolar cell carcinoma, acoustic neuroma, acral lentiginous melanoma, acrospiroma, acute eosinophilic leukemia, acute erythroleukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatoid odontogenic tumor, adenosquamous carcinoma, adipose tissue neoplasm, adrenocortical carcinoma, adult T-cell leukemia / lymphoma, aggressive NK-cell leukemia, AIDS-related lymphoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblastic fibroma, anaplastic large cell lymphoma, anaplastic thyroid cancer, angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma, astrocytoma, atypical teratoid rhabdoid tumor, B-cell chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, B-cell lymphoma, basal cell carcinoma, biliary tract cancer, bladder cancer, blastoma, bone cancer, Brenner tumor, brown tumor, Burkitt lymphoma, breast cancer, brain cancer, carcinoma, non-invasive carcinoma, carcinosarcoma, chondroma, cementoma, chondrosarcoma, chordoma, choriocarcinoma, choroid plexus papilloma, clear cell sarcoma of the kidney, craniopharyngioma, cutaneous T-cell lymphoma, cervical cancer, colorectal cancer, Degos disease, desmoplastic small round cell tumor, diffuse large B-cell lymphoma, embryonal rhabdoid tumor, embryonal carcinoma, fetal carcinoma, endocrine gland neoplasm, endodermal sinus tumor, enteropathy-associated T-cell lymphoma, esophageal cancer, encapsulated fetus, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid cancer, ganglioneuroma, gastrointestinal cancer, germ cell tumor, gestational choriocarcinoma, giant cell fibroblastoma, giant cell tumor of bone, glioma, glioblastoma multiforme, glioma, gliomatosis cerebri, glucagonoma, gonadoblastoma, granulosa cell tumor, germ cell tumor of male, gallbladder cancer, gastric cancer, hairy cell leukemia, hemangioblastoma, head and neck cancer, hemangiopericytoma, hematological malignancy, hepatoblastoma, hepatosplenic T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, invasive lobular carcinoma, intestinal cancer, kidney cancer, laryngeal cancer, malignant melanoma, lethal midline carcinoma, leukemia, Leydig cell tumor, liposarcoma, lung cancer, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, liver cancer, small cell lung cancer, non-small cell lung cancer, MALT lymphoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, malignant triton tumor, mantle cell lymphoma, marginal zone B-cell lymphoma, mast cell leukemiaMedullary cell tumors, medullary breast cancer tumors, medullary thyroid cancer, medulloblastoma, melanoma, meningioma, Merkel cell cancer, mesothelioma, metastatic urothelial cancer tumors, Müllerian duct mixed tumors, mucinous tumors, multiple myeloma, muscle tissue neoplasms, fungating polyps, myxoid liposarcoma, mucocele, myxosarcoma, nasopharyngeal cancer tumors, schwannoma, neuroblastoma, neurofibroma, neuroma, nodular melanoma, eye cancer, anaplastic astrocytoma, anaplastic glioma, oncocytoma, optic nerve sheath meningioma, optic nerve tumors, oral cancer, osteosarcoma, ovarian cancer, Pancoast tumors, papillary thyroid cancer, paraganglioma, pineoblastoma, pineocytoma, pituitary cell tumors, pituitary adenomas, pituitary tumors, plasmacytoma, polyembryoma, precursor T lymphoblastic lymphoma, primary central nervous system lymphoma, primary effusion lymphoma, primary peritoneal cancer, prostate cancer, pancreatic cancer, pharyngeal cancer, peritoneal pseudomyxoma, renal cell cancer tumors, renal medullary cancer tumors, retinoblastoma, rhabdomyoma, rhabdomyosarcoma, Richter transformation, rectal cancer, sarcoma, schwannomatosis, seminoma, Sertoli cell tumors, sex cord-gonadal stromal tumors, signet ring cell cancer tumors, skin cancer, small blue round cell tumors, small cell cancer tumors, soft tissue sarcoma, somatostatinoma, soot wart, spinal cord tumors, splenic marginal zone lymphoma, squamous cell cancer tumors, synovial sarcoma, Sézary disease, small intestine cancer, squamous cell carcinoma, gastric cancer, T cell lymphoma, testicular cancer, capsular cell type, thyroid cancer, transitional epithelial cancer tumors, laryngeal cancer, allantoic duct cancer, urogenital cancer, urothelial cancer tumors, choroidal melanoma, uterine cancer, verrucous cancer tumors, visual pathway glioma, vulvar cancer, vaginal cancer, Waldenström macroglobulinemia, Warthin tumors, and Wilms tumors are mentioned.

[0053] In one aspect, the cancers treated by the crystalline forms and their compositions described herein are selected from breast cancer, prostate cancer, colon cancer, renal cell cancer tumors, glioblastoma multiforme cancer, bladder cancer, melanoma, bronchial cancer, lymphoma, liver cancer, multiple myeloma, lymphoma, ovarian cancer, NSCLC, pancreatic cancer, malignant rhabdoid tumor, synovial sarcoma, and glioma.

[0054] Another aspect of the disclosure is the use of one or more of the crystalline forms described herein in the manufacture of a medicament for use in the treatment of the disorders or diseases herein. Another object of the disclosure is One or more of the crystalline forms or compositions described herein for use in the treatment of disorders or diseases of this specification.

[0055] There is also provided a pharmaceutical composition comprising one or more of the disclosed crystalline forms and a pharmaceutically acceptable carrier.

[0056] The compositions described herein can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implant reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, hepatic, intralesional, and intracranial injection or infusion techniques.

[0057] The amount of the crystalline form provided to be combined with a carrier material to produce a composition in a single dosage form will vary depending on the patient being treated and the particular mode of administration. The compositions provided may be formulated so as to be able to administer a dosage of the inhibitor of 0.001 to 100 mg / kg body weight / day to a patient receiving these compositions.

[0058] It should also be understood that any particular dosage and treatment regimen for a particular patient will depend on a variety of factors, including age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the particular disease being treated. The amount of the crystalline form provided in the composition will also depend on the particular compound in the composition.

[0059] Illustration As shown in the following examples, the crystalline forms were prepared according to the following general procedure.

[0060] Preparation of amorphous Compound 1 The amorphous form of Compound 1 was prepared as a single enantiomer, a single geometric isomer, using the following procedure. The XRPD pattern of the amorphous product by this procedure is shown in Figure 7.

[0061] Intermediate 1: 7-chloro-2,4-dimethyl-2-(4-oxocyclohexyl)benzo[d][1,3]dioxole-5-carboxylate methyl

[0062] [ka]

[0063] Step 1: Synthesis of methyl 5-chloro-3,4-dihydroxy-2-methylbenzoate Methyl 3,4-dihydroxy-2-methylbenzoate (5.11 g, 27.9 mmol) To a solution of in tetrahydrofuran (199 mL) was added sulfuryl chloride (2.45 mL, 30.6 mmol) dropwise at -20°C. The reaction mixture was stirred at -20°C for 3 h and then quenched with a saturated aqueous solution of ammonium chloride (50 mL). The desired product was extracted with ethyl acetate (25 mL x 3). The combined organic layers were washed with brine (25 mL), dried over sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, gradient 0% to 60% ethyl acetate in heptane) to give the title compound (4.117 g, 68% yield) as a beige solid. LCMS [M+H] + m / z: calculated 217.0, found 217.1 (Cl isotope pattern).

[0064] Step 2: Synthesis of methyl 7-chloro-2,4-dimethyl-2-(4-oxocyclohexyl)-2H-1,3-benzodioxole-5-carboxylate A mixture of methyl 5-chloro-3,4-dihydroxy-2-methylbenzoate (1.2 g, 5.53 mmol), tolyltetracarbonylruthenium (176 mg, 276 μmol), and triphenylphosphine (145 mg, 553 μmol) was degassed under vacuum and purged with nitrogen (3 cycles). Toluene (8.1 mL) was added, and the reaction mixture was heated to reflux for 30 minutes. Then, a solution of 4-ethynylcyclohexan-1-one (1.34 g, 11.0 mmol) in toluene (17 mL) was added dropwise, and the reaction was stirred at reflux for 23 hours. Finally, the reaction mixture was cooled to room temperature and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, gradient of 0 - 60% ethyl acetate in heptane) to give the title compound (1.327 g, 70% yield) as a yellow oil. LCMS [M+Na] + m / z: calculated value 361.1, measured value 361.1 (Cl isotope pattern).

[0065] Step 3: Separation of methyl (R)-7-chloro-2,4-dimethyl-2-(4-oxocyclohexyl)benzo[d][1,3]dioxole-5-carboxylate and methyl (S)-7-chloro-2,4-dimethyl-2-(4-oxocyclohexyl)benzo[d][1,3]dioxole-5-carboxylate A racemic mixture of methyl 7-chloro-2,4-dimethyl-2-(4-oxocyclohexyl)benzo[d][1,3]dioxole-5-carboxylate (4.4 g, 13 mmol) was resolved by preparative SFC [column: ChiralPak AY from Daicel chemical industries (inner diameter 250 mm × 50 mm, 10 μm). Mobile phase A: CO 2 / Mobile phase B: 0.1% NH 4 OH in methanol. Isocratic (85% mobile phase A and 15% mobile phase B). Flow rate: 80 mL / min. Column temperature: 40 °C]. Intermediate 1 (peak 1) (undesired enantiomer / diastereomer): retention time = 6.2 minutes. Recovery = 1.4 g, 4.05 mmol, 31% yield, 90% ee, 98% purity (yellow solid). 11H NMR (400 MHz, chloroform-d) δ 7.48 (s, 1H), 3.78 (s, 3H), 2.44 - 2.36 (m, 2H), 2.35 - 2.25 (m, 6H), 2.19 (tdd, J = 2.8, 5.6, 13.1 Hz, 2H), 1.70 - 1.57 (m, 5H). Intermediate 1 (peak 2) (desired enantiomer / eutomer): retention time = 7.0 min. Recovery = 1.1 g, 3.08 mmol, yield 23.75%, 99% ee, purity 95% (yellow solid). 1 1H NMR (400 MHz, chloroform-d) δ 7.49 (s, 1H), 3.78 (s, 3H), 2.44 - 2.36 (m, 2H), 2.36 - 2.25 (m, 6H), 2.20 (tdd, J = 2.8, 5.6, 13.1 Hz, 2H), 1.72 - 1.59 (m, 5H). SFC analysis method: [Column: ChiralPak AY-3 (inner diameter 150 × 4.6 mm, 3 μm). Mobile phase A: CO 2 / Mobile phase B: 0.05% Et in iPrOH 2 NH. Gradient: 5% to 40% mobile phase B (longer than 5.5 min). Flow rate: 2.5 mL / min. Column temperature: 40 °C]. Intermediate 1 (peak 1 - unwanted enantiomer / distomer): retention time = 2.853 min. Intermediate 1 (peak 2 - desired enantiomer / eutomer): retention time = 2.979 min.

[0066] Intermediate 2: 7-chloro-2-(4-(3-methoxyazetidin-1-yl)cyclohexyl)-2,4-dimethylbenzo[d][1,3]dioxole-5-carboxylic acid

[0067]

Chemical Structure

[0068] Step 1: Synthesis of methyl 7-chloro-2-(4-(3-methoxyazetidin-1-yl)cyclohexyl)-2,4-dimethylbenzo[d][1,3]dioxole-5-carboxylate A solution of 3-methoxyazetidine hydrochloride (8 g, 64.75 mmol) and N,N-diisopropylethylamine (12 mL, 68.9 mmol) in methanol (30 mL) was stirred at room temperature for 30 minutes, and then a solution of methyl 7-chloro-2,4-dimethyl-2-(4-oxocyclohexyl)-1,3-benzodioxole-5-carboxylate (Intermediate 1-Peak 2) (4.1 g, 12.10 mmol) in another tetrahydrofuran (30 mL) was added. The reaction mixture was stirred at room temperature for 1 hour and then cooled to -70 °C. Lithium borohydride (500 mg, 22.96 mmol) was added, and the reaction was stirred at -70 °C for 30 minutes [or until complete consumption of the starting material was observed by TLC, ethyl acetate / methanol 5:1]. Next, two batches of the reaction were combined, quenched with a saturated aqueous solution of ammonium chloride (120 mL) at 0 °C, and the desired product was extracted with dichloromethane (200 mL × 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0% to 14% gradient of methanol in dichloromethane) to give the title compound (8.05 g, 67% yield, 83% purity) as a pale yellow oil. The sample (50 mg) was further purified by preparative thin layer chromatography (silica gel, ethyl acetate:methanol 15:1). LCMS [M+H] + m / z: Calculated 410.2, Found 410.1. 1 H NMR (400 MHz, methanol-d 4 ) δ 7.39 (s, 1H), 3.95 - 3.91 (m, 1H), 3.73 (s, 3H), 3.59 - 3.51 (m, 2H), 3.16 (s, 3H), 2.97 (br dd, J = 6.4, 8.0 Hz, 2H), 2.26 (s, 3H), 2.11 - 2.02 (m, 1H), 1.91 - 1.73 (m, 5H), 1.54 (s, 3H), 1.22 - 1.12 (m, 2H), 0.98 - 0.86 (m, 2H).

[0069] Step 2: Synthesis of 7-chloro-2-(4-(3-methoxyazetidin-1-yl)cyclohexyl)-2,4-dimethylbenzo[d][1,3]dioxole-5-carboxylic acid Methyl 7-chloro-2-(4-(3-methoxyazetidin-1-yl)cyclohexyl)-2,4-dimethylbenzo[d][1,3]dioxole-5-carboxylate (4g, 9 .75 mmol) in methanol (48 mL) was added to a solution of lithium hydroxide hydrate (4.03 g, 96.06 mmol) in water (12 mL). The reaction mixture was stirred at 70 °C for 2 h, then the two batches were combined and concentrated under reduced pressure. Water (50 mL) was added and the pH was adjusted to 6 with saturated aqueous citric acid at 0 °C. The desired product was extracted with a 3:1 mixture of dichloromethane and isopropanol (300 mL × 5). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give the title compound (6.1 g, crude product) as an off-white solid, which was used in the next step without further purification. LCMS [M+H] + m / z: calculated 396.2, found 396.1. 1 H NMR (400 MHz, methanol-d 4 ) δ 7.07 (s, 1H), 4.05 - 4.10 (m, 2H), 3.76 - 3.88 (m, 1H), 3.67 (br dd, J = 10, 3.6 Hz, 2H), 3.22 (s, 3H), 2.71 - 2.81 (m, 1H), 2.19 (s, 3H), 1.91 - 1.99 (m, 4H), 1.75 - 1.85 (m, 1H), 1.52 (s, 3H), 1.18 - 1.28 (m, 2H), 1.06 - 1.14 (m, 2H).

[0070] Amorphous Compound 1

[0071]

Chemical Structure

[0072] 7-Chloro-2-(4-(3-methoxyazetidin-1-yl)cyclohexyl)-2,4-dimethylbenzo[d][1,3]dioxole-5-carboxylic acid (Intermediate 2 - single enantiomer and geometric isomers) (5 g, 12.63 mmol) in N,N-dimethylformamide (50 mL) was added with O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (5.7 g, 14 .99 mmol) and N,N-diisopropylethylamine (11 mL, 63.15 mmol). After stirring the mixture at 20 °C for 30 minutes, 3-(aminomethyl)-6-methyl-4-(methylthio)pyridin-2(1H)-one hydrochloride (Intermediate 1) (4.2 g, 19.03 mmol) was added. The reaction mixture was stirred at room temperature for an additional 1.5 hours and then filtered. The filtrate was purified by preparative HPLC [column: Phenomenex Gemini C18 (250 mm × 50 mm, 10 μm), mobile phase A: water (0.04% ammonium hydroxide v / v and 10 mM ammonium bicarbonate) / mobile phase B: acetonitrile. Gradient (75% to 44% mobile phase A / 25% to 56% mobile phase B, over 23 minutes). Column temperature: 30 °C] to obtain the title compound (4.4 g, yield 60%, purity 96%) as a white solid. LCMS [M+H] + m / z: calculated 562.2, found 562.2. 1 H NMR (400 MHz, methanol-d 4 ) δ 6.91 (s, 1H), 6.29 (s, 1H), 4.50 (s, 2H), 4.01 (sextet, J = 6 Hz, 1H), 3.58 (dd, J = 8.8, 6.4 Hz, 2H), 3.26 (s, 3H), 2.92 - 3.02 (m, 2H), 2.54 (s, 3H), 2.31 (s, 3H), 2.21 (s, 3H), 2.01 - 2.11 (m, 1H), 1.79 - 2.00 (m, 5H), 1.62 (s, 3H), 1.19 - 1.34 (m, 2H), 0.91 - 1.08 (m, 2H). The XRPD pattern of the amorphous product by this procedure is shown in Figure 7.

[0073] List of Abbreviations

[0074]

Table 1-1

[0075]

Table 1-2

[0076] 1. Details of Machines and Methodologies X-ray Powder Diffraction (XRPD): XRPD diffractograms were collected on a Bruker AXS C2 GADDS, Bruker AXS D8 Advance, or PANalytical Empyrean as detailed below.

[0077] Bruker AXS C2 GADDS XRPD using a Bruker AXS C2 GADDS diffractometer was carried out using Cu Kα radiation (40 kV, 40 mA), an automatic XYZ stage, a laser video microscope for automatic sample positioning, and a Vantec-500 two-dimensional area detector. The X-ray optics consisted of a single Gobel multilayer mirror coupled with a 0.3 mm pinhole collimator. The beam divergence, i.e., the effective size of the X-ray beam on the sample, was approximately 4 mm. The θ-θ continuous scan mode was used at a sample-detector distance of 20 cm, with an effective 2θ range of 1.5° to 32.5°. Typically, the sample was exposed to the X-ray beam for 120 seconds. The software used for data collection and analysis was GADDS and Diffrac Plus EVA for Win7 / XP, respectively. Samples carried out under ambient conditions were prepared as flat specimens using the as-received powder without grinding. The samples were prepared and analyzed either on a slide glass or a glass frit. The sample was lightly pressed onto the slide glass to obtain a flat surface for analysis. Solid was isolated and analyzed from the suspension by directly adding a small amount of the suspension onto the glass frit using a glass frit filter block prior to filtration under a light vacuum. For variable temperature (VT) experiments, the sample was mounted on an Anton Paar DHS 900 hot stage under ambient conditions. The sample was then heated to the appropriate temperature at 10 °C / min and then held isothermally for 1 minute before starting data collection. The sample was prepared and analyzed on a silicon wafer mounted on the hot stage using a thermal conductive compound.

[0078] Bruker AXS D8 Advance XRPD using a Bruker D8 diffractometer was performed using Cu Kα radiation (40 kV, 40 mA) and a θ-2θ goniometer equipped with a Ge monochromator. The incident beam passed through a 2.0 mm divergence slit, followed by a 0.2 mm anti-scatter slit and a knife edge. The diffracted beam was 8.0 m with a 2.5° Soller slit. It passes through the receiving slit of m and then through the Lynxeye detector. The software used for data collection and analysis was Diffrac Plus XRD Commander and Diffrac Plus EVA, respectively. Using the as-received powder, the sample was run under ambient conditions as a flat sample. The sample was prepared on a polished zero-background (510) silicon wafer by gently pressing it onto a flat surface or packed into a cut cavity. The sample was rotated within the plane of the sample itself.

[0079] PANalytical Empyrean XRPD using a PANalytical Empyrean diffractometer was carried out in transmission geometry using Cu Kα radiation (45 kV, 40 mA). For the incident beam, a 0.5° slit, a 4 mm mask, and a 0.04 rad Soller slit with a focusing mirror were used. A PIXcel3D detector placed on the diffracted beam was equipped with a receiving slit and a 0.04 rad Soller slit. The software used for data collection was X’Pert Data Collector using the X’Pert Operator interface. The data was analyzed and presented using Diffrac Plus EVA or HighScore Plus. The sample was prepared and analyzed in transmission mode either in metal or a Millipore 96-well plate. An X-ray transparent film was used between the metal sheets on the metal well plate, and the powder (approximately 1 - 2 mg) was used as received. Using a Millipore plate, the solid was isolated from the suspension and analyzed by directly adding a small amount of the suspension to the plate before filtering under a light vacuum.

[0080] Differential Scanning Calorimetry (DSC): DSC data was collected on a TA Instruments Q2000 equipped with an autosampler at 50 positions. Typically, each sample of 0.5 - 3 mg in an aluminum pan with a pinhole was heated from 25 °C to 300 °C at 10 °C / min. Dry nitrogen at 50 ml / min was continuously purged over the sample. Temperature-modulated DSC was performed every 60 seconds (period) using a base heating rate of 2 °C / min and a temperature modulation parameter of ±0.318 °C (amplitude). The instrument control software was Advantage for Q Series and Thermal Advantage, and the data was analyzed using Universal Analysis or TRIOS.

[0081] Also, DSC data was collected on a TA Instruments Discovery DSC equipped with an autosampler at 50 positions. Typically, each sample of 0.5 - 3 mg in an aluminum pan with a pinhole was heated from 25 °C to 300 °C at 10 °C / min. Dry nitrogen at 50 ml / min was continuously purged over the sample. The instrument control software was TRIOS, and the data was analyzed using TRIOS or Universal Analysis.

[0082] Thermogravimetric analysis (TGA) TGA data was collected on a TA Instruments Q500 TGA equipped with an autosampler at 16 positions. Typically, each sample of 5 - 10 mg was placed in a pre-weighed aluminum DSC pan and heated from ambient temperature to 300 °C at 10 °C / min. Nitrogen at 60 ml / min was continuously purged over the sample. The instrument control software was Advantage for Q Series and Thermal Advantage, and the data was analyzed using Universal Analysis or TRIOS.

[0083] Also, TGA data was collected on a TA Instruments Discovery TGA equipped with an autosampler at 25 positions. Typically, each sample of 5 - 10 mg The material was placed in a pre-weighed aluminum DSC pan and heated from ambient temperature to 300 °C at 10 °C / min. Nitrogen was continuously purged over the sample at 25 mL / min. The instrument control software was TRIOS, and data was analyzed using TRIOS or Universal Analysis.

[0084] 2. General crystallization methods The screening methods for crystallization are outlined in the methods described below.

[0085] Aging / slurry aging In the aging chamber: The suspension for aging was placed in a platform shaker incubator (Heidolph Titramax / Incubator 1000, Figure 2), and a series of heating-cooling cycles from ambient temperature to approximately 50 °C were performed. This cycle was achieved by switching the heating on and off every 4 hours. Throughout, agitation was maintained.

[0086] In Polar Bear: The suspension was stirred in Polar Bear (Cambridge Reactor Design) at 50 °C for various lengths of time (500 rpm). The sample was then cooled to 25 °C at 0.1 °C / min and stirred for an additional 4 hours. After that, the sample was heated back to 50 °C at 0.1 °C / min. The cycle was then repeated.

[0087] Cooling crystallization In Polar Bear, the solution was cooled to 5 °C at 0.1 °C / min and stirred at this temperature for various lengths of time. All solids were filtered, dried under suction for 10 minutes, and initially analyzed by XRPD. The solution was further cooled to -20 °C over 16 hours, and then any new solids were processed as already shown. The remaining solution was evaporated (see Method 3 below).

[0088] Controlled evaporation The solution placed in the vial was evaporated under ambient conditions by removing the vial cap or inserting a needle into the septum cap of the vial. The sample was slowly evaporated until dry or until a solid appeared under ambient conditions.

[0089] Precipitation / Crystallization by Addition of Poor Solvent The solution was treated by dropwise addition of a poor solvent at 50 °C until turbidity appeared. The sample was then cooled to 5 °C at 0.1 °C / min and maintained isothermally. Additional poor solvent was added to the suspension as needed. The solid was filtered and dried under suction for 10 minutes, and the residue was first analyzed by XRPD.

[0090] 3. Screening Method Amorphous forms of samples of Compound 1 with different purities, one with 95.2% purity (30 mg) and one with 97.6% purity (20 mg), were suspended or dissolved in 10 - 30 volumes of a given solvent at RT. After equilibration at RT for 5 minutes, all samples (solutions and suspensions) were heated to 50 °C in 10 minutes, and the resulting samples were treated as follows. The suspensions were aged at 60 °C to 5 °C for 72 hours (4 hours at each temperature). The solutions were cooled from 50 °C to 5 °C at 0.1 °C / min and maintained at 5 °C for 72 hours. If no solid was obtained, the solution was evaporated at RT. All recovered solids were analyzed by XRPD, followed by appropriate techniques. See Tables 1 - 3 for the screening procedure and analysis results.

[0091] Based on XRPD analysis, the amorphous form of Compound 1 with 95.2% purity was used By polymorph screening, three crystalline forms, designated as Form 1, Form 2, and Form 3 herein, were obtained (Tables 1 and 2). Form 1 was the most abundant form obtained from multiple solvent systems. Form 3 was observed only once from the solvent 2 - butanol. By polymorph screening using the amorphous form of Compound 1 with 97.6% purity, Forms 1 and 2 were obtained, but Form 3 was not obtained (Table 3). Form 1 was more abundant than Form 2. The characterization of Forms 1 - 3 is presented below.

[0092]

Table 2

[0093]

Table 3-1

[0094]

Table 3-2

[0095]

Table 4

[0096] 4. Selection of New Crystal Forms For Form 3, since the XRPD showed insufficient crystal phase, Forms 1 and 2 were selected for further analysis. For Form 1, the sample obtained from acetone had the highest purity (97.4%) and contained only trace amounts of solvent. The scale-up experiment for Form 1 was carried out as follows. For Form 2, the sample obtained from MEK had a higher purity (97.2%) and contained only a small amount of residual MEK. The scale-up experiment for Form 1 was carried out as follows.

[0097] Scale-up of Crystal Forms 1 and 2 The scale-up experiments for Form 1 in acetone and Form 2 in MEK were carried out according to the following procedures respectively. The amorphous form of Compound 1 (1 g) prepared according to the method of U.S.62 / 659,408 was weighed into two 20-ml scintillation vials and dissolved in either 20 volumes (20 ml) of acetone or 20 volumes (20 ml) of MEK at 50 °C with stirring. The solution was then cooled to 5 °C at 0.1 °C / min and held at this temperature for 20 h. Both samples formed a white suspension, which was filtered and dried in a Buchner funnel under vacuum. After air-drying the solid for 1 h, the characterization of both patterns was performed using a variety of techniques (summarized in Tables 4 and 5, and Figures 1-4). The yield was also calculated from the recovered solid.

[0098] For the scale-up of Form 1, the solid sample was confirmed to be in crystalline Form 1 by XRPD (Tables 4 and Figure 1). The purity was determined to be 96.6% by HPLC. This sample 1 According to 1H NMR, it was consistent with the amorphous form of the reference substance of Compound 1, and a small amount of residual acetone (0.04 equivalent) remained in the sample. Thermal analysis showed a small weight loss of 1.0 wt / wt% (equivalent to 0.32 equivalent of water), which was consistent with the KF data. DSC analysis showed a sharp endotherm at 179.5 °C (onset) (Figure 2). From GVS analysis, it was found that the substance was slightly hygroscopic, and 1.7 wt / wt% of water was taken up at 0% RH to 90% RH. The sample remained in Form 1 after GVS analysis or after storage at high RH conditions for 5 days. The morphology of Form 1 by PLM and SEM was aggregates of small crystalline particles. These aggregates may vary in size and shape (20 - 650 μm), and the crystalline particles are small and irregular (up to 20 μm). Generally, Form 1 was determined to be anhydrous. See also Table 5 for a summary of the properties of Form 1.

[0099] Regarding the scale-up of Form 2, the solid sample was confirmed to be in crystalline Form 2 by XRPD (Figure 3). However, further characterization suggested that Form 2 is a less stable crystalline form than Form 1. For example, unlike Form 1, which retains its original crystalline form, XRPD analysis showed that Form 2 became amorphous after GVS analysis or after storage at high RH conditions for 5 days. Unlike Form 1, which shows a sharp endotherm (Figure 2), Form 2 showed two endothermic events in DSC analysis (Figure 4). Form 2 also showed a higher total weight loss than Form 1 in TGA analysis. During polymorph screening and in both competitive slurry experiments, Form 1 was observed more frequently than Form 2, further confirming that Form 1 is more stable than Form 2.

[0100]

Table 5

[0101]

Table 6

[0102] Although some embodiments of the present disclosure have been described, it will be apparent that the basic examples of the inventors can be modified to provide other embodiments that utilize the compounds and methods of the present disclosure. Accordingly, it is to be understood that the scope of the present disclosure is defined not by the specific embodiments represented by way of example, but by the appended claims.

[0103] The contents of all references cited throughout this application (including references, issued patents, published patent applications, and co-pending patent applications) are hereby expressly incorporated by reference in their entirety. Unless otherwise defined, all technical and scientific terms used herein shall have the meanings commonly known to those of ordinary skill in the art. In one aspect, the present invention may be as follows. [Aspect 1] Crystalline Form 1 of a compound having the following structural formula: [Chemical formula] [Aspect 2] The crystal form 1 according to Aspect 1, wherein the crystal form is characterized by at least 3 X-ray powder diffraction peaks at 2θ angles selected from 10.0°, 13.3°, 14.9°, 20.2°, 20.8°, 22.2°, and 22.5°. [Aspect 3] The crystal form 1 according to Aspect 1 or 2, wherein the crystal form is characterized by at least 4 X-ray powder diffraction peaks at 2θ angles selected from 10.0°, 13.3°, 14.9°, 20.2°, 20.8°, 22.2°, and 22.5°. [Aspect 4] The crystal form 1 according to any one of Aspects 1 to 3, wherein the crystal form is characterized by at least 5 X-ray powder diffraction peaks at 2θ angles selected from 10.0°, 13.3°, 14.9°, 20.2°, 20.8°, 22.2°, and 22.5°. [Aspect 5] The crystal form 1 according to any one of Aspects 1 to 4, wherein the crystal form is characterized by at least 6 X-ray powder diffraction peaks at 2θ angles selected from 10.0°, 13.3°, 14.9°, 20.2°, 20.8°, 22.2°, and 22.5°. [Aspect 6] The crystal form 1 according to any one of Aspects 1 to 5, wherein the crystal form is characterized by X-ray powder diffraction peaks at 2θ angles selected from 10.0°, 13.3°, 14.9°, 20.2°, 20.8°, 22.2°, and 22.5°. [Aspect 7] The crystal form 1 according to any one of Aspects 1 to 6, wherein the crystal form is characterized by X-ray powder diffraction peaks at 2θ angles selected from 10.0°, 10.2°, 12.3°, 12.7°, 13.3°, 14.9°, 15.3°, 20.2°, 20.8°, 21.3°, 22.2°, 22.5°, and 23.8°. [Aspect 8] The crystal form 1 according to any one of Aspects 1 to 7, wherein the crystal form is characterized by X-ray powder diffraction peaks at 2θ angles selected from 10.0°, 10.2°, 11.0°, 11.4°, 11.8°, 12.3°, 12.7°, 13.3°, 14.9°, 15.3°, 16.1°, 17.4°, 20.2°, 20.8°, 21.3°, 22.2°, 22.5°, and 23.8°. [Aspect 9] The crystal form 1 according to any one of Aspects 1 to 8, wherein the crystal form is characterized by XRPD substantially similar to FIG. 1. [Aspect 10] The crystal form 1 according to Aspect 1, wherein the crystal form is characterized by X-ray powder diffraction peaks at 2θ angles selected from 14.9°, 20.2°, and 20.8°. [Aspect 11] The crystal form 1 according to Aspect 1 or 10, wherein the crystal form is characterized by X-ray powder diffraction peaks at 2θ angles selected from 10.0°, 14.9°, 20.2°, and 20.8°. [Aspect 12] The crystal form 1 according to any one of Aspects 1, 10, or 11, wherein the crystal form is characterized by X-ray powder diffraction peaks at 2θ angles selected from 10.0°, 14.9°, 20.2°, 20.8°, and 22.2°. [Aspect 13] The crystal form 1 according to Aspect 1 or any one of Aspects 10 to 12, wherein the crystal form is characterized by X-ray powder diffraction peaks at 2θ angles selected from 10.0°, 13.3°, 14.9°, 20.2°, 20.8°, and 22.2°. [Aspect 14] The crystal form 1 according to any one of Aspects 1 to 13, wherein the crystal form is anhydrous. [Aspect 15] The crystal form 1 according to any one of Aspects 1 to 14, wherein at least 90% by weight of the crystal form is in single crystal form. [Aspect 16] The crystal form 1 according to any one of Aspects 1 to 15, wherein at least 95% by weight of the crystal form is in single crystal form. [Aspect 17] The crystal form 1 according to any one of Aspects 1 to 16, wherein the compound has a chemical purity of at least 90% by weight. [Aspect 18] The crystal form 1 according to any one of Aspects 1 to 17, wherein the compound has a chemical purity of at least 95% by weight. [Aspect 19] The crystalline form 1 according to any one of Aspects 1 to 18, wherein the compound has a chemical purity of at least 99% by weight. [Aspect 20] The crystalline form 1 according to any one of Aspects 1 to 19, wherein the compound has the following structural formula: [Chemical formula] [Aspect 21] A pharmaceutical composition comprising the crystalline form according to any one of Aspects 1 to 20 and a pharmaceutically acceptable carrier or diluent. [Aspect 22] A method of performing it in a patient in need of treating a disease or disorder associated with cell proliferation, the method comprising administering to the patient the crystalline form according to any one of Aspects 1 to 20 or the composition according to Aspect 21. [Aspect 23] The method according to Aspect 22, wherein the disease is cancer. [Aspect 24] The method according to Aspect 23, wherein the cancer is selected from breast cancer, prostate cancer, colon cancer, renal cell carcinoma, glioblastoma multiforme, bladder cancer, melanoma, bronchial cancer, lymphoma, liver cancer, multiple myeloma, lymphoma, ovarian cancer, NSCLC, pancreatic cancer, malignant rhabdoid tumor, synovial sarcoma, glioma.

Claims

1. Crystalline Form 1 of a compound having the following structural formula: 【Chemistry 1】 A pharmaceutical composition for treating cancer comprising: the crystalline form is characterized by at least three X-ray powder diffraction peaks at 2θ angles selected from 10.0°, 13.3°, 14.9°, 20.2°, 20.8°, 22.2°, and 22.5°, and the pharmaceutical composition is administered orally. The above pharmaceutical composition.

2. 2. The pharmaceutical composition of claim 1, wherein the crystalline form is characterized by at least four X-ray powder diffraction peaks at 2θ angles selected from 10.0°, 13.3°, 14.9°, 20.2°, 20.8°, 22.2°, and 22.5°.

3. 3. The pharmaceutical composition of claim 1 or 2, wherein the crystalline form is characterized by at least five X-ray powder diffraction peaks at 2θ angles selected from 10.0°, 13.3°, 14.9°, 20.2°, 20.8°, 22.2°, and 22.5°.

4. 4. The pharmaceutical composition of any one of claims 1 to 3, wherein the crystalline form is characterized by at least six X-ray powder diffraction peaks at 2θ angles selected from 10.0°, 13.3°, 14.9°, 20.2°, 20.8°, 22.2°, and 22.5°.

5. 5. The pharmaceutical composition of any one of claims 1 to 4, wherein the crystalline form is characterized by X-ray powder diffraction peaks at 2θ angles of 10.0°, 13.3°, 14.9°, 20.2°, 20.8°, 22.2°, and 22.5°.

6. 6. The pharmaceutical composition of any one of claims 1 to 5, wherein the crystalline form is characterized by X-ray powder diffraction peaks at 2θ angles of 10.0°, 10.2°, 12.3°, 12.7°, 13.3°, 14.9°, 15.3°, 20.2°, 20.8°, 21.3°, 22.2°, 22.5°, and 23.8°.

7. 7. The pharmaceutical composition of any one of claims 1 to 6, wherein the crystalline form is characterized by X-ray powder diffraction peaks at 2θ angles of 10.0°, 10.2°, 11.0°, 11.4°, 11.8°, 12.3°, 12.7°, 13.3°, 14.9°, 15.3°, 16.1°, 17.4°, 20.2°, 20.8°, 21.3°, 22.2°, 22.5°, and 23.8°.

8. The crystalline form has the following XRPD: 【Chemistry 2】 The pharmaceutical composition according to any one of claims 1 to 7, characterized in that

9. 2. The pharmaceutical composition of claim 1, wherein the crystalline form is characterized by X-ray powder diffraction peaks at 2θ angles of 14.9°, 20.2°, and 20.8°.

10. 10. The pharmaceutical composition of claim 1 or 9, wherein the crystalline form is characterized by X-ray powder diffraction peaks at 2θ angles of 10.0°, 14.9°, 20.2°, and 20.8°.

11. 11. The pharmaceutical composition of claim 1, 9 or 10, wherein the crystalline form is characterized by X-ray powder diffraction peaks at 2θ angles of 10.0°, 14.9°, 20.2°, 20.8°, and 22.2°.

12. 12. The pharmaceutical composition of any one of claims 1 or 9-11, wherein the crystalline form is characterized by X-ray powder diffraction peaks at 2θ angles of 10.0°, 13.3°, 14.9°, 20.2°, 20.8°, and 22.2°.

13. The pharmaceutical composition of any one of claims 1 to 12, wherein the crystalline form is anhydrous.

14. 14. The pharmaceutical composition of any one of claims 1 to 13, wherein the crystalline form 1 is at least 90% by weight a single crystalline form.

15. 15. The pharmaceutical composition of any one of claims 1 to 14, wherein the crystalline form 1 is at least 95% by weight a single crystalline form.

16. The pharmaceutical composition of any one of claims 1 to 15, wherein the compound has a chemical purity of at least 90% by weight.

17. The pharmaceutical composition of any one of claims 1 to 16, wherein the compound has a chemical purity of at least 95% by weight.

18. The pharmaceutical composition of any one of claims 1 to 17, wherein the compound has a chemical purity of at least 99% by weight.

19. The pharmaceutical composition of any one of claims 1 to 18, wherein the compound has the following structural formula: 【Chemistry 3】

20. 20. The pharmaceutical composition of any one of claims 1 to 19, wherein the cancer is selected from breast cancer, prostate cancer, colon cancer, renal cell carcinoma, glioblastoma multiforme cancer, bladder cancer, melanoma, bronchial cancer, lymphoma, liver cancer, multiple myeloma, lymphoma, ovarian cancer, NSCL, pancreatic cancer, malignant rhabdoid tumor, synovial sarcoma, and glioma.

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