Crystalline forms 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 July 24, 2019, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Eukaryotic chromatin is composed of macromolecular complexes called nucleosomes. Nucleosomes have 147 base pairs of DNA wrapped around a protein octamer with two subunits each of the histone proteins H2A, H2B, H3, and H4. Histone proteins undergo post-translational modifications that in turn affect chromatin structure and gene expression. One type of post-translational modification found on histones is methylation of lysine and arginine residues. Histone methylation plays an important role in the control of eukaryotic gene expression. Methylation affects chromatin structure and is associated with both 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, embryonic emergence, cell proliferation, and other processes.

[0003] One class of histone methylases is characterized by the presence of a Suppressor of Variegation Enhancer of Zeste Trithorax (SET) domain containing approximately 130 amino acids. EZH2 Homolog 2 (EZH2) is an example of a methylase containing a 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), which has the ability to trimethylate histone H3 at lysine 27 (Cao and Zhang, Mol. Cell 15:57-67, 2004). The PRC2 complex may also contain RBAP46 and RBAP48 subunits. Another example is the related methylase EZH1.

[0004] Many studies have demonstrated the oncogenic activity of EZH2. In cell line experiments, overexpression of EZH2 induces cell invasion, growth in soft agar, and motility, whereas knockdown of EZH2 inhibits cell proliferation and invasion (Kleer et al., 2003, Proc. Nat. Acad. Sci. USA 100:11606-11611; Varambally et al., (2002), “The polycomb “EZH2 is a marker of progression of prostate cancer,” Nature 419, 624-629. EZH2 has been shown to suppress the expression of several tumor suppressors, including E-cadherin, DAB2IP, and RUNX3, among others. In xenograft models, knockdown of EZH2 inhibits tumor growth and metastasis. Recently, downregulation of EZH2 in mouse models has been shown to block prostate cancer metastasis (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 aggressiveness of certain cancers, such as breast cancer (Kleer et al., Proc. Nat. Acad. Sci. USA 100:11606-11611, 2003). Recent studies also suggest 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 a variety of conditions associated with 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 contents of which are incorporated herein by reference, and has the following structure:

[0006] [ka]

[0007] The development of alternative forms of compound 1 represents an attractive area for further treatment of diseases or disorders that respond to inhibition of EZH2. Summary of the Invention

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

[0009] Pharmaceutical compositions comprising one or more of the disclosed crystalline forms of Compound 1 are also provided herein.

[0010] Further provided is the use of one or more of the disclosed crystalline forms of Compound 1 in the treatment of a disease or disorder responsive to inhibition of EZH2, such as cancer. [Brief description of the drawings]

[0011] [Figure 1] 1 shows the X-ray powder diffraction pattern (XRPD) for crystalline Form 1 of Compound 1. [Diagram 2] 1 shows an exemplary differential scanning calorimetry (DSC) thermogram for Form 1 of Compound 1. [Diagram 3] 1 shows the X-ray powder diffraction pattern (XRPD) for crystalline Form 2 of Compound 1. [Figure 4] 1 shows a combination of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms for Form 2 of Compound 1. [Diagram 5] 1 shows the X-ray powder diffraction pattern (XRPD) for crystalline Form 3 of Compound 1. [Figure 6] 1 shows a combination of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms for Form 3 of Compound 1. [Figure 7] FIG. 1 shows the X-ray powder diffraction pattern (XRPD) for the amorphous form of Compound 1, as prepared from the procedure set forth in Example 17 of U.S. Provisional Application No. 62 / 659,408. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] definition 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 a 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 single crystalline forms. By "single crystalline form" is meant that the recited compound, i.e., Compound 1, exists as a single crystal or multiple crystals, each of which has the same crystalline form (e.g., Form 1, 2, or 3). The weight percent of a particular crystalline form is calculated by dividing the weight of the particular crystalline form by the total weight of the particular crystal, plus the weight of any other crystalline forms present, plus the weight of the amorphous form present, and multiplying by 100%.

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

[0015] Chemical purity refers to the degree to which the disclosed forms are free of substances with different chemical structures. The chemical purity of a compound in a disclosed crystalline form means the weight of the compound divided by the sum of the weights of the compound and substances / impurities with different chemical structures, multiplied by 100% (i.e., weight percent).

[0016] The term "amorphous" refers to a solid that exists in a non-crystalline state or form. Amorphous solids are disordered arrangements of molecules and therefore do not have a distinguishable crystal lattice or unit cell and therefore no 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 "anhydrous" are used interchangeably and mean that the referenced crystalline form has substantially no water in the crystal lattice, e.g., less than 1% by weight, 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 from instrument to instrument, depending on the variation during sample preparation and from batch to batch due to factors such as temperature fluctuations, sample displacement, and the presence or absence of internal standards. Therefore, unless otherwise specified, the XRPD patterns / assignments listed herein should not be taken as absolute and may vary by as much as ±0.2 degrees. It is well known in the art that this variability accounts for the above factors without preventing the unambiguous identification of the crystalline forms. Unless otherwise specified, the 2θ values ​​provided herein were obtained using Cu Kα1 radiation.

[0019] For example, the DSC peak temperature values ​​herein may vary slightly from instrument to instrument, and also depending on variations in sample preparation, batch to batch variations, and environmental factors. Unless otherwise defined, temperature values ​​recited herein should not be construed as absolute values ​​and may vary by as much as ±5 degrees or ±2 degrees.

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

[0021] The amount of one crystalline form relative to another in a sample can be assessed by preparing a series of mixtures of the two crystalline forms in known weight ratios and obtaining an XRPD spectrum for each. For example, the relative amounts of crystalline Forms 1 and 2 in a sample can be assessed by selecting one or more characteristic peaks of crystalline Forms 1 and 2 shown in Figures 1 and 3, respectively, 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 companion animals (e.g., dogs, cats, etc.), farm animals (e.g., cows, pigs, horses, sheep, goats, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). Typically, the subject is a human in need of treatment.

[0023] The term "pharmaceutical acceptable carrier" refers to a non-toxic carrier, adjuvant, or vehicle that does not adversely affect the pharmacological activity of the compound with which it is formulated 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, buffer 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, polyvinyl chloride ... Examples of suitable polyvinylpyrrolidone-vinyl acetate include cellulosic substances (e.g., microcrystalline cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate), starch, lactose monohydrate, mannitol, sodium lauryl sulfate, and croscarmellose sodium, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, polymethacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

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

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

[0026] Exemplary Forms In a first aspect, provided herein is crystalline Form 1 of a compound having the following structural formula:

[0027] [ka]

[0028] In a second embodiment, crystalline form 1 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°. Alternatively, as part of the second embodiment, crystalline form 1 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°. In another alternative, as part of the second embodiment, crystalline form 1 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°. In another alternative, as part of the second embodiment, crystalline Form 1 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°. In another alternative, as part of the second embodiment, 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 embodiment, 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 embodiment, crystalline form 1 is characterized by an X-ray powder diffraction peak at a 2θ angle 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 embodiment, crystalline form 1 is characterized by an X-ray powder diffraction peak at a 2θ angle selected from 14.9°, 20.2°, and 20.8°. In another alternative, as part of the second embodiment, crystalline form 1 is characterized by an X-ray powder diffraction peak at a 2θ angle selected from 10.0°, 14.9°, 20.2°, and 20.8°.In another alternative, as part of the second embodiment, 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, as part of the second embodiment, 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, as part of the second embodiment, crystalline Form 1 is characterized by an XRPD (X-ray powder diffraction) substantially similar to FIG. 1.

[0029] In a third embodiment, crystalline Form 1 has a sharp endotherm at 179.5° C. (onset temperature) as determined by differential scanning calorimetry (DSC) or a thermogravimetric analysis of 1.0% weight loss between 36° C. and 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 embodiment. In other embodiments, crystalline Form 1 may also include XRPD peaks at 2θ angles selected from any of those described in the second embodiment. In other embodiments, crystalline Form 1 may also include XRPD peaks at 2θ angles selected from any of those described in the second embodiment.

[0030] In a fourth embodiment, crystalline Form 1 is anhydrous and crystalline Form 1 may also comprise XRPD peaks at 2θ angles selected from any of those described in the second embodiment, and / or TGA or DSC values ​​or diagrams cited in the third embodiment.

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

[0032] In a sixth embodiment, crystalline Form 1 described herein (e.g., as in the first, second, third, fourth, or fifth embodiment) has a chemical purity of at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% by weight.

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

[0034] [ka]

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

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

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

[0038] In an eleventh embodiment, the crystalline form 2 (e.g., the seventh, eighth, ninth, or or the tenth embodiment) has a chemical purity of at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% by weight.

[0039] In a twelfth embodiment, there is provided crystalline Form 3 of a compound having the following structural formula:

[0040] [ka]

[0041] In a thirteenth embodiment, crystalline Form 3 is characterized by an XRPD (X-ray powder diffraction) substantially similar to FIG.

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

[0043] In a fifteenth embodiment, crystalline Form 3 described herein (such as in the twelfth, thirteenth, or fourteenth embodiments) is at least 60% by weight in single crystalline form, at least 70% by weight in single crystalline form, at least 80% by weight in single crystalline form, at least 90% by weight in single crystalline form, at least 95% by weight in single crystalline form, or at least 99% by weight in single crystalline form.

[0044] In a sixteenth embodiment, the crystalline Form 3 described herein (such as in the twelfth, thirteenth, fourteenth, or fifteenth embodiments) has a chemical purity of at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% by weight.

[0045] In a seventeenth embodiment, crystalline form 1 described herein (e.g., as in the first, second, third, fourth, or fifth embodiment), crystalline form 2 described herein (e.g., as in the seventh, eighth, ninth, tenth, or eleventh embodiment), or crystalline form 3 (e.g., as in the twelfth, thirteenth, fourteenth, fifteenth, or sixteenth embodiment) is represented by the following structural formula:

[0046] [ka]

[0047] Alternatively, as part of the seventeenth embodiment, crystalline form 1 described herein (e.g., as in the first, second, third, fourth, or fifth embodiment), crystalline form 2 described herein (e.g., as in the seventh, eighth, ninth, tenth, or eleventh embodiment), or crystalline form 3 (e.g., as in the twelfth, thirteenth, fourteenth, fifteenth, or sixteenth embodiment) is represented by the following structural formula:

[0048] [ka]

[0049] Alternatively, as part of the seventeenth embodiment, crystalline form 1 described herein (e.g., as in the first, second, third, fourth, or fifth embodiment), crystalline form 2 described herein (e.g., as in the seventh, eighth, ninth, tenth, or eleventh embodiment), or crystalline form 3 (e.g., as in the twelfth, thirteenth, fourteenth, fifteenth, or sixteenth embodiment) is represented by the following structural formula:

[0050] [ka]

[0051] It has the chemical name (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 treating diseases or disorders responsive to inhibition of EZH2. Such diseases and disorders include those associated with cell proliferation. In some embodiments, the crystalline forms and compositions thereof described herein are useful for treating diseases and / or disorders associated with misregulation of the cell cycle or DNA repair. In some embodiments, the crystalline forms and compositions thereof described herein are useful for treating cancer. Exemplary types of cancer include, for example, adrenal gland cancer, acinic cell carcinoma, acoustic neuroma, acral lentiginous melanoma, acrohidroma, acute eosinophilic leukemia, acute erythroleukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatous odontogenic tumor, adenosquamous carcinoma, adipose tissue neoplasm, adrenal cortical carcinoma, adult T-cell leukemia / lymphoma, aggressive NK cell leukemia, AIDS-related lymphoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblastoma, anaplastic large cell lymphoma, anaplastic thyroid cancer, hematopoietic carcinoma, and leukemia. Tumor immunoblastic 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, carcinoma in situ, carcinosarcoma, cartilage tumor, cementoma, myeloid sarcoma, chondroma, chordoma, choriocarcinoma, choroid plexus papilloma, clear cell sarcoma of the kidney, craniopharyngioma, cutaneous T-cell lymphoma, cervical cancer, colorectal cancer, Degos disease, desmoplastic small intestine Round cell tumor, Diffuse large B-cell lymphoma, Dysgerminoma, Embryonal carcinoma, Endocrine neoplasm, Endodermal sinus tumor, Enteropathy-associated T-cell lymphoma, Esophageal cancer, Inclusion fetal tumor, Fibroma, Fibrosarcoma, Follicular lymphoma, Follicular thyroid carcinoma, Gangliocytoma, Gastrointestinal cancer, Germ cell tumor, Gestational choriocarcinoma, Giant cell fibroblastoma, Giant cell tumor of bone, Glial tumor, Glioblastoma multiforme, Gliomas, Gliomatosis cerebri, Glucagonoma, Gonadoblastoma, Granulosa cell tumor, Male germinoma, Gallbladder cancer, Gastric cancer, Hairy cell leukemia, Hemangioblastoma, Head and neck cancer, Perivascular hematologic malignancies, hepatoblastoma, hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, invasive lobular carcinoma, intestinal cancer, kidney cancer, laryngeal cancer, lentigo maligna, lethal midline carcinoma, leukemia, Leydig cell tumor, liposarcoma, lung cancer, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphoma, acute lymphocytic 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 leukemia,Mediastinal germ cell tumor, medullary carcinoma of the breast, medullary thyroid carcinoma, medulloblastoma, melanoma, meningioma, Merkel cell carcinoma, mesothelioma, metastatic urothelial carcinoma, mixed Müllerian tumor, mucinous tumor, multiple myeloma, muscle tissue neoplasm, mycosis fungoides, myxoid liposarcoma, myxoma, myxosarcoma, nasopharyngeal carcinoma, schwannoma, neuroblastoma, neurofibroma, neuroma, nodular melanoma, eye cancer, oligoastrocytoma, oligodendroglioma, Oncocytoma, optic nerve sheath meningioma, optic nerve tumor, oral cancer, osteosarcoma, ovarian cancer, Pancoast tumor, papillary thyroid cancer, paraganglioma, pineoblastoma, pineocytoma, pituitary cell tumor, pituitary adenoma, pituitary tumor, plasmacytoma, polyembryomatosis, precursor T-lymphoblastic lymphoma, primary central nervous system lymphoma, primary effusion lymphoma, primary peritoneal cancer, prostate cancer, pancreatic cancer, pharyngeal cancer, peritoneal pseudomucosal tumor These include cystic leukoma, renal cell carcinoma, renal medullary carcinoma, retinoblastoma, rhabdomyoma, rhabdomyosarcoma, Richter transformation, rectal cancer, sarcoma, schwannomatosis, seminoma, Sertoli cell tumor, sex cord-gonadal stromal tumor, signet ring cell carcinoma, skin cancer, small blue round cell tumor, small cell carcinoma, soft tissue sarcoma, somatostatinoma, sooty warts, spinal tumor, splenic marginal zone lymphoma, squamous cell carcinoma, synovial sarcoma, Sézary disease, small intestine cancer, squamous cell carcinoma, gastric cancer, T-cell lymphoma, testicular cancer, thecal cell tumor, thyroid cancer, transitional cell carcinoma, laryngeal cancer, urachal cancer, genitourinary cancer, urothelial carcinoma, uveal melanoma, uterine cancer, verrucous carcinoma, visual pathway glioma, vulvar cancer, vaginal cancer, Waldenstrom's macroglobulinemia, Warthin's tumor, and Wilms' tumor.

[0053] In one aspect, the cancer treated by the crystalline forms and compositions thereof described herein 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.

[0054] Another aspect of the present 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 a disorder or disease herein. One or more of the crystalline forms or compositions described herein for use in the treatment of a disorder or disease herein.

[0055] Also provided are pharmaceutical compositions comprising one or more of the disclosed crystalline forms and a pharma- ceutically acceptable carrier.

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

[0057] The amount of the provided crystalline form that may 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 provided compositions may be formulated so that a dosage of 0.001-100 mg / kg body weight / day of the inhibitor can be administered to a patient receiving these compositions.

[0058] It will also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including age, 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 crystalline form provided in the composition will also depend on the particular compound in the composition.

[0059] Example As shown in the Examples below, the crystalline forms were prepared according to the following general procedures.

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

[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), triruthenium dodecacarbonyl (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 min. A solution of 4-ethynylcyclohexan-1-one (1.34 g, 11.0 mmol) in toluene (17 mL) was then added dropwise and the reaction was stirred at reflux for 23 h. 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, 0-60% gradient of ethyl acetate in heptane) to give the title compound (1.327 g, 70% yield) as a yellow oil. LCMS [M+Na] + m / z: calculated 361.1, found 361.1 (Cl isotope pattern).

[0065] Step 3: Separation of (R)-7-chloro-2,4-dimethyl-2-(4-oxocyclohexyl)benzo[d][1,3]dioxole-5-methyl carboxylate and (S)-7-chloro-2,4-dimethyl-2-(4-oxocyclohexyl)benzo[d][1,3]dioxole-5-methyl 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 (250 mm × 50 mm, 10 μm ID) from Daicel Chemical Industries. Mobile phase A: CO2 / Mobile phase B: 0.1% NH4OH 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) (unwanted enantiomer / distomer): Retention time = 6.2 min. Recovery = 1.4 g, 4.05 mmol, 31% yield, 90% ee, 98% purity (yellow solid). 1H 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 H 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 analytical method: [Column: ChiralPak AY-3 (150 × 4.6 mm i.d., 3 μm). Mobile phase A: CO2 / Mobile phase B: 0.05% Et2NH in iPrOH. Gradient: 5% to 40% mobile phase B (>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] [ka]

[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 min, followed by another solution of 7-chloro-2,4-dimethyl-2-(4-oxocyclohexyl)-1,3-benzodioxole-5-methyl carboxylate (Intermediate 1-Peak 2) (4.1 g, 12.10 mmol) in tetrahydrofuran (30 mL). The reaction mixture was stirred at room temperature for 1 h 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 min [or until complete consumption of starting material was observed by TLC, ethyl acetate / methanol 5:1]. The two batches of reaction were then combined and 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. A 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, measured 410.1. 1 H NMR (400MHz, methanol-d4) δ7.39(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=6.4,8.0Hz,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 7-Chloro-2-(4-(3-methoxyazetidin-1-yl)cyclohexyl)-2,4-dimethylbenzo[d][1,3]dioxole-5-carboxylate methyl ester (4 g, 9 To a solution of 1.75 mmol) of lithium hydroxide hydrate (4.03 g, 96.06 mmol) in methanol (48 mL) was added a solution of lithium hydroxide hydrate (4.03 g, 96.06 mmol) in water (12 mL). The reaction 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) as an off-white solid, which was used in the next step without further purification. LCMS [M+H] + m / z: calculated 396.2, measured 396.1. 1 H NMR (400MHz, methanol-d4) δ7.07(s,1H),4.05-4.10(m,2H),3.76-3.88(m,1H),3.67(br dd,J=10,3.6Hz,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] [ka]

[0072] A solution of 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 isomer) (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) were added. The mixture was stirred at 20° C. for 30 min, after which 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 another 1.5 h 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, >23 min). Column temperature: 30° C.] to give the title compound (4.4 g, 60% yield, 96% purity) as a white solid. LCMS [M+H] + m / z: calculated 562.2, measured 562.2. 1 H NMR (400 MHz, methanol-d4) δ 6.91 (s, 1H), 6.29 (s, 1H), 4.50 (s, 2H), 4.01 (sexlet, 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 from this procedure is shown in Figure 7.

[0073] List of abbreviations

[0074] [Table 1-1]

[0075] [Table 1-2]

[0076] 1. Equipment and Methodology Details X-ray powder diffraction (XRPD): XRPD diffractograms were obtained using a Bruker AXS C2 Acquisition was performed on a GADDS, Bruker AXS D8 Advance, or PANalytical Empyrean.

[0077] Bruker AXS C2 GADDS XRPD using a Bruker AXS C2 GADDS diffractometer was performed using Cu Kα radiation (40 kV, 40 mA), an automated XYZ stage, a laser video microscope for automated sample positioning, and a Vantec-500 2D 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 with a sample-to-detector distance of 20 cm, giving an effective 2θ range of 1.5°-32.5°. Typically, samples were exposed to the X-ray beam for 120 s. The software used for data collection and analysis were GADDS and Diffrac Plus EVA for Win7 / XP, respectively. Samples performed under ambient conditions were prepared as flat specimens using the as-received powder without grinding. Samples were prepared and analyzed on either glass slides or glass frits. The samples were lightly pressed onto a glass slide to obtain a flat surface for analysis. A glass frit filter block was used to isolate and analyze solids from suspension by adding a small amount of the suspension directly to the glass frit before filtering under light vacuum. For variable temperature (VT) experiments, samples were mounted on an Anton Paar DHS 900 hot stage under ambient conditions. The samples were then heated at 10 °C / min to the appropriate temperature and then held isothermal for 1 min before data collection began. Samples were prepared and analyzed on silicon wafers mounted on the hot stage using a thermally 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 fitted with a Ge monochromator. The incident beam passes through a 2.0 mm divergence slit followed by a 0.2 mm anti-scatter slit and a knife edge. The diffracted beam is passed through an 8.0 mm diffractometer with a 2.5° Soller slit. The light passes through a 2000 mm receiving slit and subsequently through a Lynxeye detector. The software used for data collection and analysis was Diffrac Plus XRD Commander and Diffrac Plus EVA, respectively. Samples were run under ambient conditions as flat specimens with the as-received powder. Samples were prepared on polished zero background (510) silicon wafers by gently pressing against a flat surface or packed into cut cavities. Samples were rotated in their own plane.

[0079] PANalytical Empyrean XRPD using a PANalytical Empyrean diffractometer was performed using Cu Kα radiation (45 kV, 40 mA) in transmission geometry. The incident beam used a 0.04 rad Soller slit with a 0.5° slit, a 4 mm mask, and a focusing mirror. A PIXcel3D detector placed on the diffracted beam was fitted 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. Data were analyzed and presented using Diffrac Plus EVA or HighScore Plus. Samples were prepared and analyzed in either metal or Millipore 96-well plates in transmission mode. X-ray transparent films were used between metal sheets on metal well plates and powders (approximately 1-2 mg) were used as received. Millipore plates were used to isolate and analyze solids from suspension by adding a small amount of suspension directly to the plate before filtering under light vacuum.

[0080] Differential Scanning Calorimetry (DSC): DSC data were collected on a TA Instruments Q2000 equipped with a 50-position autosampler. Typically, 0.5-3 mg of each sample in an aluminum pan with a pinhole was heated from 25 °C to 300 °C at 10 °C / min. A 50 ml / min dry nitrogen purge was maintained above the sample. Temperature-controlled DSC was performed with an underlying heating rate of 2 °C / min every 60 s (duration) and temperature control parameters of ±0.318 °C (amplitude). The instrument control software was Advantage for Q Series and Thermal Advantage, and data were analyzed using Universal Analysis or TRIOS.

[0081] DSC data were also collected on a TA Instruments Discovery DSC equipped with a 50-position autosampler. Typically, 0.5-3 mg of each sample in an aluminum pan with a pinhole was heated from 25 °C to 300 °C at 10 °C / min. A 50 ml / min purge of dry nitrogen was maintained above the samples. The instrument control software was TRIOS, and data were analyzed using TRIOS or Universal Analysis.

[0082] Thermogravimetric analysis (TGA) TGA data were collected on a TA Instruments Q500 TGA equipped with a 16-position autosampler. Typically, 5-10 mg of each sample was loaded into a pre-tared aluminum DSC pan and heated from ambient to 300 °C at 10 °C / min. A nitrogen purge of 60 ml / min was maintained above the sample. The instrument control software was Advantage for Q Series and Thermal Advantage, and data were analyzed using Universal Analysis or TRIOS.

[0083] TGA data was also collected on a TA Instruments Discovery TGA equipped with a 25-position autosampler. Typically, 5-10 mg of each sample was used. The sample was loaded into a pre-tared aluminum DSC pan and heated from ambient temperature to 300°C at 10°C / min. A nitrogen purge of 25 ml / min was maintained above the sample. The instrument control software was TRIOS and data were analyzed using TRIOS or Universal Analysis.

[0084] 2. Common crystallization methods Screening methods for crystallization are outlined in the methods described below.

[0085] Aging / Slurry Aging In the maturation chamber: The suspension for maturation was placed in a platform shaker incubator (Heidolph Titramax / Incubator 1000, FIG. 2) and subjected to a series of heating-cooling cycles from ambient temperature to approximately 50° C. This was accomplished by turning the heat on and off every 4 hours. Shaking was maintained throughout.

[0086] In the Polar Bear: The suspensions were stirred (500 rpm) at 50° C. for various lengths of time in a Polar Bear (Cambridge Reactor Design). The samples were then cooled at 0.1° C. / min to 25° C. and stirred for a further 4 hours. After this, the samples were again heated at 0.1° C. / min to 50° C. The cycle was then repeated.

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

[0088] Controlled Evaporation The solution placed in the vial was allowed to evaporate at ambient conditions by removing the vial lid or by inserting a needle into the septum cap of the vial. The sample was allowed to evaporate slowly until dry or until a solid appeared at ambient conditions.

[0089] Precipitation / crystallization by addition of antisolvent The solution was treated with anti-solvent dropwise at 50° C. until cloudy. The sample was then cooled to 5° C. at 0.1° C. / min and held isothermal. Additional anti-solvent was added to the suspension if necessary. The solid was filtered and dried under suction for 10 min, and the residue was initially 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, respectively. After equilibration at RT for 5 min, all samples (solutions and suspensions) were heated to 50 °C in 10 min, and the obtained samples were treated as follows: The suspensions were aged from 60 °C to 5 °C for 72 h (4 h at each temperature). The solutions were cooled from 50 °C to 5 °C at 0.1 °C / min and kept at 5 °C for 72 h. If no solid was obtained, the solutions were evaporated at RT. All recovered solids were analyzed by XRPD followed by the appropriate technique. See Tables 1-3 for screening procedure and analytical results.

[0091] Based on XRPD analysis, an amorphous form of compound 1 was used with a purity of 95.2%. Polymorph screening yielded three crystalline forms, referred to herein as Form 1, Form 2, and Form 3 (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. Polymorph screening using an amorphous form of Compound 1 with a purity of 97.6% yielded Forms 1 and 2, but not Form 3 (Table 3). Form 1 was more abundant than Form 2. 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 morphology Forms 1 and 2 were selected for further analysis since XRPD for Form 3 showed insufficient crystalline phases. For Form 1, the sample obtained from acetone had the highest purity (97.4%) and contained only traces of solvent. Scale-up experiments for Form 1 were carried out as described below. For Form 2, MEK The sample obtained from had a higher purity (97.2%) and contained only small amounts of residual MEK. Scale-up experiments of Form 1 were carried out as described below.

[0097] Scale-up of crystalline Form 1 and Form 2 Scale-up experiments for Form 1 in acetone and Form 2 in MEK were carried out according to the following procedure, respectively. The amorphous form of Compound 1 (1 g), prepared according to the method of US62 / 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 hours. Both samples formed white suspensions, which were filtered and dried in a Buchner funnel under vacuum. The solids were allowed to air dry for 1 hour, after which both patterns were characterized using a wide variety of techniques (summarized in Tables 4 and 5 and Figures 1-4). Yields were also calculated from the recovered solids.

[0098] For the scale-up of Form 1, the solid sample was confirmed to be crystalline Form 1 by XRPD (Table 4 and Figure 1). The purity was determined to be 96.6% by HPLC. 1 H NMR was consistent with the amorphous form of the Compound 1 reference material, with a small amount of residual acetone (0.04 equiv.) remaining in the sample. Thermal analysis showed a small weight loss of 1.0 wt / wt% (corresponding to 0.32 equiv. of water), consistent with the KF data. DSC analysis showed a sharp endotherm at 179.5 °C (onset) (Figure 2). GVS analysis showed the material to be slightly hygroscopic, with 1.7 wt / wt% water uptake from 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). In general, Form 1 was determined to be anhydrous. See also Table 5 for a summary of Form 1 properties.

[0099] For the scale-up of Form 2, the solid samples were confirmed to be 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 retained its original crystalline form, XRPD analysis showed that Form 2 became amorphous after GVS analysis or after 5 days of storage at high RH conditions. Unlike Form 1 (Figure 2), which exhibits a sharp endotherm, Form 2 exhibited two endothermic events in DSC analysis (Figure 4). Form 2 also exhibited a higher total weight loss than Form 1 in TGA analysis. During both polymorph screening and competitive slurry experiments, Form 1 was observed more frequently than Form 2, further supporting that Form 1 is more stable than Form 2.

[0100] [Table 5]

[0101] [Table 6]

[0102] Having described several embodiments of the present disclosure, it is apparent that the inventors' basic examples may be modified to provide other embodiments that utilize the compounds and methods of the present disclosure. It will therefore be appreciated that the scope of the present disclosure is defined by the appended claims, rather than by the specific embodiments represented by way of example.

[0103] The contents of all references cited throughout this application (including literature references, issued patents, published patent applications, and co-pending patent applications) are expressly incorporated herein by reference in their entirety. Unless otherwise defined, all technical and scientific terms used herein are given the meaning commonly known to those of ordinary skill in the art.

Claims

1. Crystalline Form 1 of a compound having the following structural formula: 【Chemistry 1】

2. 2. The crystalline form 1 of claim 1, wherein 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°.

3. 3. Crystalline Form 1 according to claim 1 or 2, 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°.

4. 4. Crystalline Form 1 according to any one of claims 1 to 3, 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°.

5. 5. Crystalline Form 1 according to any one of claims 1 to 4, 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°.

6. 6. Crystalline Form 1 according to any one of claims 1 to 5, wherein the crystalline 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°.

7. 7. Crystalline Form 1 according to any one of claims 1 to 6, wherein the crystalline 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°.

8. 8. Crystalline Form 1 according to any one of claims 1 to 7, wherein the crystalline 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°.

9. 9. Crystalline Form 1 according to any one of claims 1 to 8, wherein the crystalline form is characterized by an XRPD substantially similar to Figure 1.

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

11. 11. Crystalline Form 1 according to claim 1 or 10, wherein the crystalline form is characterized by X-ray powder diffraction peaks at 2θ angles selected from 10.0°, 14.9°, 20.2°, and 20.8°.

12. 12. Crystalline Form 1 according to any one of claims 1, 10 or 11, wherein the crystalline 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°.

13. 13. Crystalline Form 1 according to any one of claims 1 or 10-12, wherein the crystalline 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°.

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

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

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

17. 17. Crystalline Form 1 according to any one of claims 1 to 16, wherein the compound has a chemical purity of at least 90% by weight.

18. 18. Crystalline Form 1 according to any one of claims 1 to 17, wherein the compound has a chemical purity of at least 95% by weight.

19. The crystalline form 1 of any one of claims 1 to 18, wherein the compound has a chemical purity of at least 99% by weight.

20. 20. The crystalline form 1 of any one of claims 1 to 19, wherein the compound has the following structural formula: 【Chemistry 2】

21. A pharmaceutical composition comprising the crystalline form of any one of claims 1 to 20 and a pharma- ceutically acceptable carrier or diluent.

22. 22. A method of treating a disease or disorder associated with cell proliferation in a patient in need thereof, comprising administering to said patient a crystalline form of any one of claims 1 to 20, or a composition of claim 21.

23. 23. The method of claim 22, wherein the disease is cancer.

24. 24. The method of claim 23, 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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