Specific Chemical Entities, Compositions, and Methods

Abstract

Novel compounds, chemical entities, their polymorphs, pharmaceutical compositions, and methods for treating cancer are described.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 144,821, filed February 2, 2021, which is incorporated by reference in its entirety. [Background technology]

[0002] Cancer can be viewed as a communication breakdown between tumor cells and the environment containing their normal neighbors. Both growth stimulatory and growth inhibitory signals are routinely exchanged between cells in tissues. Normally, cells do not divide in the absence of stimulatory signals, and similarly, they stop dividing in the presence of inhibitory signals. In a cancerous or neoplastic state, cells "neutralize" these signals and acquire the ability to grow under conditions in which normal cells do not grow.

[0003] Cardiac steroids such as digoxin and digitoxin inhibit Na + / K + Cardiotonic steroids are a class of naturally occurring compounds that bind and inhibit the ATPase (sodium pump). Members of this family have been used for many years to treat heart failure and arrhythmias. Recent findings have revealed that these compounds may be involved in the regulation of several important cellular processes. Some cardiac steroids, such as digitoxin and oleandrin, have shown inhibitory effects on the proliferation of human tumor cells. Summary of the Invention

[0004] In one aspect, the present disclosure provides a compound comprising (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate maleate (the maleate salt of compound A):

[0005] [ka] or a pharma- ceutically acceptable solvate or hydrate thereof.

[0006] In another aspect, the present disclosure provides a crystalline (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate maleate (the maleate salt of Compound A):

[0007] [ka] or a pharma- ceutically acceptable solvate or hydrate thereof.

[0008] In some embodiments, the crystalline form is crystalline form I. In some embodiments, crystalline form I is (a) an X-ray powder diffraction pattern including peaks at 13.8±0.2°2-θ, 19.5±0.2°2-θ, and 10.3±0.2°2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å; (b) an X-ray powder diffraction pattern substantially the same as that shown in FIG. (c) a differential scanning calorimetry (DSC) thermogram containing an endotherm in the range of about 230-240°C; (d) a differential scanning calorimetry (DSC) thermogram containing an endotherm with an onset of about 234° C. and a peak of about 238° C. (e) A differential scanning calorimetry (DSC) thermogram substantially the same as that shown in FIG. (f) Thermogravimetric analysis (TGA) pattern substantially the same as that shown in FIG. (g) Unchanged XRPD after storage for 6 months at 40°C and 75% relative humidity (RH); (h) XRPD unchanged after storage for 36 months at 25°C and 60% relative humidity (RH); or (i) any combination thereof It is characterized by:

[0009] In some embodiments, crystalline Form I is characterized by an X-ray powder diffraction pattern comprising peaks at 13.8±0.2°2-θ, 19.5±0.2°2-θ, and 10.3±0.2°2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from 25.9±0.2°2-θ, 20.6±0.2°2-θ, and 14.8±0.2°2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from 27.8±0.2°2-θ, 25.2±0.2°2-θ, and 11.4±0.2°2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least five peaks selected from 13.8±0.2°2-θ, 19.5±0.2°2-θ, 10.3±0.2°2-θ, 25.9±0.2°2-θ, 20.6±0.2°2-θ, 14.8±0.2°2-θ, 27.8±0.2°2-θ, 25.2±0.2°2-θ, and 11.4±0.2°2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å. In some embodiments, the X-ray powder diffraction pattern comprises peaks at 13.8±0.1°2-θ, 19.5±0.1°2-θ, 10.3±0.1°2-θ, 25.9±0.1°2-θ, 20.6±0.1°2-θ, 14.8±0.1°2-θ, 27.8±0.1°2-θ, 25.2±0.1°2-θ, and 11.4±0.1°2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å. In some embodiments, crystalline Form I is characterized by an X-ray powder diffraction pattern substantially the same as that shown in FIG.

[0010] In some embodiments, crystalline form I is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm in the range of about 230-240° C. In some embodiments, crystalline form I is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm having an onset of about 234° C. and a peak at about 238° C. In some embodiments, crystalline form I is characterized by a differential scanning calorimetry (DSC) thermogram substantially the same as that shown in FIG.

[0011] In some embodiments, crystalline Form I is characterized by a thermogravimetric analysis (TGA) thermogram substantially similar to that shown in FIG.

[0012] In some embodiments, the crystalline form is crystalline form II. In some embodiments, crystalline form II is (a) an X-ray powder diffraction pattern including peaks at 14.3±0.2°2-θ, 20.1±0.2°2-θ, and 15.2±0.2°2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å; (b) an X-ray powder diffraction pattern substantially the same as that shown in FIG. (c) i) an endotherm in the range of about 75 to 100°C; ii) an endotherm in the range of about 195-210°C; and iii) Endothermic in the range of 215-235°C A differential scanning calorimetry (DSC) thermogram, (d) i) an endotherm with an onset of about 77° C. and a peak of about 94° C.; ii) an endotherm with an onset of about 202° C. and a peak at about 205° C., and iii) an endotherm with an onset of about 220° C. and a peak at about 230° C. A differential scanning calorimetry (DSC) thermogram, (e) A differential scanning calorimetry (DSC) thermogram substantially the same as that shown in FIG. (f) a thermogravimetric analysis (TGA) pattern substantially the same as that shown in FIG. 6; or (g) Combinations thereof It is characterized by:

[0013] In some embodiments, the crystalline form II is characterized by an X-ray powder diffraction pattern comprising peaks at 14.3±0.2°2-θ, 20.1±0.2°2-θ, and 15.2±0.2°2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from 18.4±0.2°2-θ, 26.2±0.2°2-θ, and 16.4±0.2°2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from 20.9±0.2°2-θ, 25.0±0.2°2-θ, and 27.0±0.2°2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least five peaks selected from 14.3±0.2°2-θ, 20.1±0.2°2-θ, 15.2±0.2°2-θ, 18.4±0.2°2-θ, 26.2±0.2°2-θ, 16.4±0.2°2-θ, 20.9±0.2°2-θ, 25.0±0.2°2-θ, and 27.0±0.2°2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å. In some embodiments, the X-ray powder diffraction pattern comprises peaks at 14.3±0.1°2-θ, 20.1±0.1°2-θ, 15.2±0.1°2-θ, 18.4±0.1°2-θ, 26.2±0.1°2-θ, 16.4±0.1°2-θ, 20.9±0.1°2-θ, 25.0±0.1°2-θ, and 27.0±0.1°2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å. In some embodiments, the crystalline Form II is characterized by an X-ray powder diffraction pattern substantially the same as that shown in FIG.

[0014] In some embodiments, crystalline Form II is i) an endotherm in the range of about 75 to 100°C; ii) an endotherm in the range of about 195-210°C; and iii) Endothermic in the range of 215-235°C The material is characterized by a differential scanning calorimetry (DSC) thermogram comprising:

[0015] In some embodiments, crystalline Form II is i) an endotherm with an onset of about 77° C. and a peak of about 94° C. ii) an endotherm with an onset of about 202° C. and a peak at about 205° C., and iii) an endotherm with an onset of about 220° C. and a peak at about 230° C. The material is characterized by a differential scanning calorimetry (DSC) thermogram comprising:

[0016] In some embodiments, crystalline Form II is characterized by a differential scanning calorimetry (DSC) thermogram substantially similar to that shown in FIG.

[0017] In some embodiments, crystalline Form II is characterized by a thermogravimetric analysis (TGA) pattern substantially similar to that shown in FIG.

[0018] In another aspect, the present disclosure provides a pharmaceutical composition comprising crystalline (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate maleate and at least one pharma- ceutically acceptable excipient. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by oral administration. In some embodiments, the pharmaceutical composition is in the form of a solid form pharmaceutical composition. In some embodiments, the pharmaceutical composition is in the form of a tablet, pill, capsule, powder, liquid, suspension, suppository, or aerosol.

[0019] In another aspect, the disclosure provides a packaged pharmaceutical composition comprising a pharmaceutical composition provided herein and instructions for using the composition to treat a subject suffering from cancer.

[0020] In another aspect, the disclosure provides a method for treating a neoplasm in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of crystalline (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate maleate as provided herein, or a pharmaceutical composition as provided herein. In some embodiments, the neoplasm is cancer. In some embodiments, the cancer is head and neck cancer, brain cancer, colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chondroma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovium, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchial carcinoma, renal cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung cancer. , small cell lung cancer, bladder cancer, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, otocytoma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemia, such as acute lymphocytic leukemia and acute myelocytic leukemia (myeloblastic, promyelocytic, myelomonocytic, monocytic, and erythroleukemia), chronic leukemia (chronic myelocytic (granulocytic) leukemia and chronic lymphocytic leukemia), and polycythemia vera, lymphoma (Hodgkin's disease and non-Hodgkin's disease), multiple myeloma, Waldenstrom's macroglobulinemia, and heavy chain disease. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is oral cancer. In some embodiments, the cancer is head and neck cancer, hi some embodiments, the cancer is brain cancer.

[0021] In another aspect, the disclosure provides a method for preparing crystalline Form I of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate maleate, comprising: (a) contacting (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate with maleic acid in a solvent to obtain a solution of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate maleate; (b) crystallizing the solution obtained in step (a) to obtain crystalline form I of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate maleate. The present invention provides a method comprising:

[0022] In some embodiments, the solvent in step (a) comprises ethyl acetate, DCM, ethanol, or isopropanol. In some embodiments, the solvent in step (a) comprises ethanol. In some embodiments, step (a) is performed at a temperature of about 60-90° C. In some embodiments, step (a) is performed at a temperature of about 70° C. In some embodiments, step (a) is performed for a time period of about 1-3 hours. In some embodiments, step (a) is performed for a time period of about 1.5 hours.

[0023] In some embodiments, step (b) comprises cooling the solution obtained in step (a) to room temperature. In some embodiments, step (b) comprises cooling the solution obtained in step (a) to a temperature of about 20-25° C. In some embodiments, the method further comprises filtering the crystallization solution obtained in step (b) to obtain crystalline form I. In some embodiments, the method further comprises drying the obtained crystalline form I. In some embodiments, the drying step is performed under vacuum at room temperature. In some embodiments, the drying step is performed under vacuum at a temperature of about 20-25° C.

[0024] In another aspect, the disclosure provides a method for preparing crystalline Form II of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate maleate, comprising: (a) contacting (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate with maleic acid in a solvent to obtain a solution of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate maleate; (b) crystallizing the solution obtained in step (a) to obtain crystalline form II of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate maleate. The present invention provides a method comprising:

[0025] In some embodiments, the solvent in step (a) comprises ethyl acetate, DCM, ethanol, or isopropanol. In some embodiments, the solvent in step (a) comprises isopropanol. In some embodiments, step (a) is performed at room temperature. In some embodiments, step (a) is performed at a temperature of about 20-25° C.

[0026] In some embodiments, step (b) comprises stirring the solution obtained in step (a) overnight.

[0027] In some embodiments, the method further comprises filtering the crystallization solution obtained in step (b) to obtain crystalline form II. In some embodiments, the method further comprises drying the obtained crystalline form II. In some embodiments, the drying step is performed under vacuum at 35° C.

[0028] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. [Brief description of the drawings]

[0029] The novel features of the invention are set forth with particularity in the appended claims. The features and advantages of the present invention can be understood by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings, in which: [Figure 1] FIG. 2 shows the X-ray powder diffraction (XRPD) pattern for crystalline Form I of the maleate salt of Compound A. [Diagram 2] FIG. 2 shows a differential scanning calorimetry (DSC) thermogram for crystalline Form I of the maleate salt of Compound A. [Diagram 3] FIG. 2 shows a thermogravimetric analysis (TGA) pattern for crystalline Form I of the maleate salt of Compound A. [Figure 4] FIG. 2 shows the X-ray powder diffraction (XRPD) pattern for crystalline Form II of the maleate salt of Compound A. [Diagram 5] FIG. 2 shows a differential scanning calorimetry (DSC) thermogram for crystalline Form II of the maleate salt of Compound A. [Figure 6] FIG. 2 shows a thermogravimetric analysis (TGA) pattern for crystalline Form II of the maleate salt of Compound A. [Figure 7] FIG. 2 shows the X-ray powder diffraction (XRPD) pattern for crystalline Form I of the maleate salt of Compound A stored at 40° C. and 75% relative humidity (RH) for 6 months. [Figure 8] FIG. 2 shows a differential scanning calorimetry (DSC) thermogram for crystalline Form I of the maleate salt of Compound A stored at 40° C. and 75% relative humidity (RH) for 6 months. [Figure 9] FIG. 2 shows the X-ray powder diffraction (XRPD) pattern for crystalline Form I of the maleate salt of Compound A stored at 25° C. and 60% relative humidity (RH) for 36 months. [Figure 10] FIG. 2 shows a differential scanning calorimetry (DSC) thermogram for crystalline Form I of the maleate salt of Compound A stored at 25° C. and 60% relative humidity (RH) for 36 months. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0030] Small molecule inhibitors are often first evaluated for their activity when dissolved in solution, but solid-state characteristics such as polymorphism are also important. Polymorphic forms of a drug substance can have various physical properties, including melting point, apparent solubility, dissolution rate, optical and mechanical properties, vapor pressure, and density. These properties can have a direct impact on the ability to process or manufacture the drug substance and drug product. Furthermore, differences in these properties can often result in different pharmacokinetic profiles of different polymorphic forms of a drug. Polymorphism is therefore often an important factor under regulatory scrutiny of the "identity" of a drug by various manufacturers. For example, polymorphism has been evaluated in multi-million and even billion-dollar drugs, such as warfarin sodium, famotidine, and ranitidine. Polymorphism can affect the quality, safety, and / or efficacy of a drug. Thus, there remains a need for polymorphism of a drug. The present disclosure addresses this need as well as provides related advantages.

[0031] Compound A As used herein, Compound A refers to (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate, having the chemical structure shown below:

[0032] [ka] has.

[0033] Compound A has been previously prepared (see WO 2011 / 085641, U.S. Pat. No. 8,334,376, U.S. Pat. No. 8,993,550, U.S. Pat. No. 9,399,659, U.S. Pat. No. 9,814,735, U.S. Pat. No. 10,179,141, U.S. Pat. No. 10,471,078, and U.S. Pat. No. 16 / 584,263).

[0034] Disclosed herein is (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate maleate (the maleate salt of Compound A).

[0035] In some embodiments disclosed herein, the maleate salt of Compound A is crystalline.

[0036] As used herein, "crystalline form", "polymorph", "form" and "form" may be used interchangeably herein and are intended to include all crystalline and amorphous forms of a compound, including, for example, polymorphs, pseudopolymorphs, salts, solvates, hydrates, nonsolvated polymorphs (including anhydrous), conformational polymorphs, and amorphous polymorphs, as well as mixtures thereof, unless a specific crystalline or amorphous form is mentioned. The compounds of the present invention include all crystalline and amorphous forms of a compound, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, nonsolvated polymorphs (including anhydrous), conformational polymorphs, and amorphous forms of a compound, as well as mixtures thereof. In some embodiments, the crystalline form is a single solid form, such as crystalline form I.

[0037] I. Crystalline Form of the Maleate Salt of Compound A The polymorphs produced by the methods of the present invention can be characterized by any method according to the art. For example, the polymorphs produced by the methods of the present invention can be characterized by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), hot-stage microscopy, and / or spectroscopy (e.g., Raman, solid-state nuclear magnetic resonance (ssNMR), and infrared (IR)). In some embodiments, the crystallinity of the solid form is determined by X-ray powder diffraction (XRPD).

[0038] XRPD: The polymorphs according to the present invention may be characterized by XRPD. The relative intensities of the XRPD peaks may vary depending on particle size, sample preparation technique, sample mounting procedure, and the particular instrument utilized. Additionally, instrumental variation and other factors may affect the 2-Θ values. Thus, the assignments of the XRPD peaks may vary, for example, by plus or minus about 0.2 degrees.

[0039] DSC: Polymorphs according to the present invention can also be identified by their characteristic DSC thermograms, such as those shown in Figures 2 and 5. It is known that in DSC, the temperatures observed depend on the rate of temperature change, as well as the sample preparation technique and the particular instrument employed. Thus, values ​​reported herein relating to DSC thermograms can vary, for example, by plus or minus about 4°C.

[0040] TGA: The polymorphic forms of the present invention may also produce thermal behavior that differs from that of amorphous materials or other polymorphic forms. Thermal behavior can be measured in the laboratory by thermogravimetric analysis (TGA), which can be used to distinguish some polymorphic forms from others. In one aspect, polymorphs can be characterized by thermogravimetric analysis.

[0041] Polymorphic forms of the maleate salt of Compound A are useful for the manufacture of pharmaceutical preparations and can be obtained by a crystallization process to produce crystalline and semi-crystalline forms, or a solidification process to obtain amorphous forms. In various embodiments, crystallization is carried out either by producing the desired compound (e.g., the maleate salt of Compound A) in a reaction mixture and isolating the desired polymorph from the reaction mixture, or by dissolving the raw compound in a solvent, optionally with heat, followed by crystallizing / solidifying the product by lowering the temperature (including active cooling) for a period of time and / or adding an antisolvent. Following crystallization or solidification, drying may be carried out under controlled conditions until the desired moisture content is achieved in the final polymorphic form.

[0042] In various embodiments, the various polymorphic forms disclosed herein (e.g., crystalline Form I and crystalline Form II of the maleate salt of Compound A) are stable at room temperature. In some examples, the various polymorphs can be stored at room temperature for extended periods of time without significant chemical decomposition or change in crystalline form. In some examples, the various polymorphs can be stored at room temperature for periods of at least about 1 month, 2 months, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months, 30 months, or 36 months. In some examples, the various polymorphs can be stored at room temperature for periods of more than about 36 months. In some examples, the various polymorphs may be selected from the group consisting of 1-2 months, 1-3 months, 1-6 months, 1-9 months, 1-12 months, 1-18 months, 1-24 months, 1-30 months, 1-36 months, 2-3 months, 2-6 months, 2-9 months, 2-12 months, 2-18 months, 2-24 months, 2-30 months, 2-36 months, 3-6 months, 3-9 months, 3-12 months, 3-18 months, 3-24 months, 3-30 months, 3-36 months, 6- The polymorphs may be stored at room temperature for periods of 9 months, 6-12 months, 6-18 months, 6-24 months, 6-30 months, 6-36 months, 9-12 months, 9-18 months, 9-24 months, 9-30 months, 9-36 months, 12-18 months, 12-24 months, 12-30 months, 12-36 months, 18-24 months, 18-30 months, 18-36 months, 24-30 months, 24-36 months, or 30-36 months. In some examples, the various polymorphs may be stored at room temperature for periods of at least 1 month, 2 months, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months, 30 months, or 36 months.

[0043] In various embodiments, the various polymorphic forms disclosed herein (e.g., crystalline Form I and Form II of the maleate salt of Compound A) are stable at temperatures above room temperature and / or at high relative humidity (RH). In some examples, the various polymorphic forms disclosed herein (e.g., crystalline Form I and Form II of the maleate salt of Compound A) can be stored at about 40° C. and about 75% RH for extended periods of time without significant chemical decomposition or change in crystalline form. In some examples, the various polymorphic forms disclosed herein (e.g., crystalline Form I and Form II of the maleate salt of Compound A) can be stored at about 40° C. and about 75% RH for periods of about 10, 30, 60, 90, 120, 150, or 180 days. In some examples, the various polymorphic forms disclosed herein (e.g., crystalline Form I and Form II of the maleate salt of Compound A) can be stored at about 40° C. and about 75% RH for periods of more than about 180 days.In some examples, the various polymorphic forms disclosed herein (e.g., crystalline Form I and crystalline Form II of the maleate salt of Compound A) can be incubated at about 40° C. and about 75% RH for 10-14 days, 10-18 days, 10-22 days, 10-26 days, 10-30 days, 10-40 days, 10-50 days, 10-60 days, 10-90 days, 10-120 days, 10-150 days, 10-180 days, 10-200 days, 10-30 ...0 days, 10-50 days, 10-60 days, 10-70 days, 10-70 days, 10-80 days, 10-80 days, 10-90 days, 10-120 days, 10-140 days, 10-160 days, 10-180 days, 10-190 days, 10-200 days, 10-220 days, 10-260 days, 10-30 days, 10-260 days, 10-30 days, 10-40 days, 10-50 days, 10-60 4~18 days, 14~22 days, 14~26 days, 14~30 days, 14~40 days, 14~50 days, 14~60 days, 14~90 days, 14~120 days, 14~150 days, 14~180 days, 18~22 days, 18~26 days, 18~30 days, 18~40 days, 18~50 days, 18~60 days, 18~90 days, 18~120 days, 18~150 days, 18~180 days, 22~26 days, 22~ 30 days, 22~40 days, 22~50 days, 22~60 days, 22~90 days, 22~120 days, 22~150 days, 22~180 days, 26~30 days, 26~40 days, 26~50 days, 26~60 days, 26~90 days, 26~120 days, 26~150 days, 26~180 days, 30~40 days, 30~50 days, 30~60 days, 30~90 days, 30~120 days, 30~150 days, 30~ The storage period may be 180 days, 40-50 days, 40-60 days, 40-90 days, 40-120 days, 40-150 days, 40-180 days, 50-60 days, 50-90 days, 50-120 days, 50-150 days, 50-180 days, 60-90 days, 60-120 days, 60-150 days, 60-180 days, 90-120 days, 90-150 days, or 90-180 days. In some examples, the various polymorphic forms disclosed herein (e.g., crystalline Form I and crystalline Form II of the maleate salt of Compound A) can be stored at about 40° C. and about 75% RH for a period of at least 10 days, 14 days, 18 days, 22 days, 26 days, 30 days, 40 days, 50 days, 60 days, 90 days, 120 days, 150 days, or 180 days.

[0044] Crystal Form I of the Maleate Salt of Compound A FIG. 1 is an X-ray powder diffraction (XRPD) pattern for crystalline Form I of the maleate salt of Compound A.

[0045] FIG. 2 depicts a differential scanning calorimetry (DSC) thermogram for crystalline Form I of the maleate salt of Compound A.

[0046] FIG. 3 is a thermogravimetric analysis (TGA) pattern for crystalline Form I of the maleate salt of Compound A.

[0047] In one aspect, provided herein is (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate maleate crystalline Form I. Some embodiments provide compositions comprising (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate maleate crystalline Form I. In some embodiments, the crystalline form I of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate maleate is (a) an X-ray powder diffraction pattern including peaks at 13.8±0.2°2-θ, 19.5±0.2°2-θ, and 10.3±0.2°2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å; (b) an X-ray powder diffraction pattern substantially the same as that shown in FIG. (c) a differential scanning calorimetry (DSC) thermogram containing an endotherm in the range of about 230-240°C; (d) a differential scanning calorimetry (DSC) thermogram containing an endotherm with an onset of about 234° C. and a peak of about 238° C. (e) A differential scanning calorimetry (DSC) thermogram substantially the same as that shown in FIG. (f) Thermogravimetric analysis (TGA) pattern substantially the same as that shown in FIG. (g) XRPD unchanged after 6 months of storage at 40°C and 75% relative humidity (RH); (h) XRPD unchanged after 36 months of storage at 25°C and 60% relative humidity (RH); or (i) any combination thereof It is characterized as having:

[0048] In some embodiments, crystalline Form I is characterized by an X-ray powder diffraction pattern substantially similar to that shown in FIG.

[0049] In some embodiments, crystalline form I is characterized by an X-ray powder diffraction pattern comprising peaks at 13.8±0.2°2-θ, 19.5±0.2°2-θ, and 10.3±0.2°2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å. In some embodiments, crystalline form I is characterized by an X-ray powder diffraction pattern comprising peaks at 1.8±0.1°2-θ, 19.5±0.1°2-θ, and 10.3±0.1°2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å. In some embodiments, crystalline form I is characterized by an X-ray powder diffraction pattern comprising peaks at about 13.8°2-θ, about 19.5°2-θ, and about 10.3°2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å.

[0050] In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from 25.9±0.2°2-θ, 20.6±0.2°2-θ, and 14.8±0.2°2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from 25.9±0.1°2-θ, 20.6±0.1°2-θ, and 14.8±0.1°2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from about 25.9°2-θ, about 20.6°2-θ, and about 14.8°2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å.

[0051] In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from 27.8±0.2°2-θ, 25.2±0.2°2-θ, and 11.4±0.2°2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from 27.8±0.1°2-θ, 25.2±0.1°2-θ, and 11.4±0.1°2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from about 27.8°2-θ, about 25.2°2-θ, and about 11.4°2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å.

[0052] In some embodiments, the X-ray powder diffraction pattern comprises at least one peak selected from 13.8±0.2°2-θ, 19.5±0.2°2-θ, 10.3±0.2°2-θ, 25.9±0.2°2-θ, 20.6±0.2°2-θ, 14.8±0.2°2-θ, 27.8±0.2°2-θ, 25.2±0.2°2-θ, and 11.4±0.2°2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least two peaks selected from 13.8±0.2°2-θ, 19.5±0.2°2-θ, 10.3±0.2°2-θ, 25.9±0.2°2-θ, 20.6±0.2°2-θ, 14.8±0.2°2-θ, 27.8±0.2°2-θ, 25.2±0.2°2-θ, and 11.4±0.2°2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least three peaks selected from 13.8±0.2°2-θ, 19.5±0.2°2-θ, 10.3±0.2°2-θ, 25.9±0.2°2-θ, 20.6±0.2°2-θ, 14.8±0.2°2-θ, 27.8±0.2°2-θ, 25.2±0.2°2-θ, and 11.4±0.2°2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least four peaks selected from 13.8±0.2°2-θ, 19.5±0.2°2-θ, 10.3±0.2°2-θ, 25.9±0.2°2-θ, 20.6±0.2°2-θ, 14.8±0.2°2-θ, 27.8±0.2°2-θ, 25.2±0.2°2-θ, and 11.4±0.2°2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least five peaks selected from 13.8±0.2°2-θ, 19.5±0.2°2-θ, 10.3±0.2°2-θ, 25.9±0.2°2-θ, 20.6±0.2°2-θ, 14.8±0.2°2-θ, 27.8±0.2°2-θ, 25.2±0.2°2-θ, and 11.4±0.2°2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å.In some embodiments, the X-ray powder diffraction pattern comprises at least six peaks selected from 13.8±0.2°2-θ, 19.5±0.2°2-θ, 10.3±0.2°2-θ, 25.9±0.2°2-θ, 20.6±0.2°2-θ, 14.8±0.2°2-θ, 27.8±0.2°2-θ, 25.2±0.2°2-θ, and 11.4±0.2°2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least seven peaks selected from 13.8±0.2°2-θ, 19.5±0.2°2-θ, 10.3±0.2°2-θ, 25.9±0.2°2-θ, 20.6±0.2°2-θ, 14.8±0.2°2-θ, 27.8±0.2°2-θ, 25.2±0.2°2-θ, and 11.4±0.2°2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least eight peaks selected from 13.8±0.2°2-θ, 19.5±0.2°2-θ, 10.3±0.2°2-θ, 25.9±0.2°2-θ, 20.6±0.2°2-θ, 14.8±0.2°2-θ, 27.8±0.2°2-θ, 25.2±0.2°2-θ, and 11.4±0.2°2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å. In some embodiments, the X-ray powder diffraction pattern comprises peaks at 13.8±0.2°2-θ, 19.5±0.2°2-θ, 10.3±0.2°2-θ, 25.9±0.2°2-θ, 20.6±0.2°2-θ, 14.8±0.2°2-θ, 27.8±0.2°2-θ, 25.2±0.2°2-θ, and 11.4±0.2°2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å. In some embodiments, the X-ray powder diffraction pattern comprises peaks at 13.8±0.1°2-θ, 19.5±0.1°2-θ, 10.3±0.1°2-θ, 25.9±0.1°2-θ, 20.6±0.1°2-θ, 14.8±0.1°2-θ, 27.8±0.1°2-θ, 25.2±0.1°2-θ, and 11.4±0.1°2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å.In some embodiments, the X-ray powder diffraction pattern includes peaks at about 13.8°2-θ, about 19.5°2-θ, about 10.3°2-θ, about 25.9°2-θ, about 20.6°2-θ, about 14.8°2-θ, about 27.8°2-θ, about 25.2°2-θ, and about 11.4°2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å.

[0053] In some embodiments, crystalline Form I is characterized by a differential scanning calorimetry (DSC) thermogram substantially similar to that shown in Figure 2. In some embodiments, crystalline Form I is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm in the range of about 230-240°C. In some embodiments, crystalline Form I is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm having an onset of about 234°C and a peak at about 238°C.

[0054] In some embodiments, crystalline Form I has a crystallinity of about 230-250° C., 232-250° C., 234-250° C., 236-250° C., 238-250° C., 240-250° C., 242-250° C., 244-250° C., 246-250° C., 248-250° C., 230-248° C., 23 ... 248℃, 234~248℃, 236~248℃, 238~248℃, 240~248℃, 242~248℃, 244~248℃, 246~248℃, 230~246℃, 232~246℃, 234~246℃, 236~246℃, 238~246℃, 240~246℃, 242~246℃, 244~2 46℃, 230~244℃, 232~244℃, 234~244℃, 236~244℃, 238~244℃, 240~244℃, 242~244℃, 230~242℃, 232~242℃, 234~242℃, 236~242℃, 238~242℃, 240~242℃, 230~240℃, 232~24 The crystalline form I is characterized by an endotherm at about 230-240°C, e.g., about 230°C, 231°C, 232°C, 233°C, 234°C, 235°C, 236°C, 237°C, 238°C, 239°C, or 240°C in a DSC thermogram. In some embodiments, the melting point of crystalline form I is about 238°C.

[0055] In some embodiments, crystalline form I is characterized by a thermogravimetric analysis (TGA) thermogram substantially similar to that shown in Figure 3. In various embodiments, crystalline form I decomposes above a temperature of about 200°C, about 250°C, about 300°C, about 350°C, about 400°C, about 450°C, about 500°C, about 550°C, or greater than 600°C. In some embodiments, crystalline form I decomposes above a temperature of about 200°C.

[0056] In some embodiments, crystalline form I is characterized by an unchanged XRPD after storage at 40° C. and 75% relative humidity (RH) for 6 months. In some embodiments, crystalline form I is characterized by an unchanged XRPD after storage at 40° C. and 75% relative humidity (RH) for 6 months, substantially the same as that shown in FIG. 7. In some embodiments, crystalline form I is characterized by an unchanged DSC after storage at 40° C. and 75% relative humidity (RH) for 6 months. In some embodiments, crystalline form I is characterized by an unchanged DSC after storage at 40° C. and 75% relative humidity (RH) for 6 months, substantially the same as that shown in FIG. 8.

[0057] In some embodiments, crystalline form I is characterized by an unchanged XRPD after 36 months of storage at 25° C. and 60% relative humidity (RH). In some embodiments, crystalline form I is characterized by an XRPD substantially similar to that shown in FIG. 9 after 36 months of storage at 25° C. and 60% relative humidity (RH). In some embodiments, crystalline form I is characterized by an unchanged DSC after 36 months of storage at 25° C. and 60% relative humidity (RH). In some embodiments, crystalline form I is characterized by a DSC substantially similar to that shown in FIG. 10 after 36 months of storage at 25° C. and 60% relative humidity (RH).

[0058] In various embodiments, crystalline form I is stable at room temperature. In some examples, crystalline form I can be stored at room temperature for a long period of time without significant chemical decomposition or change in crystalline form. In some examples, crystalline form I can be stored at room temperature for at least about 1 month, 2 months, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months, 30 months, or 36 months. In some examples, crystalline form I can be stored at room temperature for more than about 36 months. In some examples, crystalline form I may be present in the form of a crystalline form having a pH of 1-2 months, 1-3 months, 1-6 months, 1-9 months, 1-12 months, 1-18 months, 1-24 months, 1-30 months, 1-36 months, 2-3 months, 2-6 months, 2-9 months, 2-12 months, 2-18 months, 2-24 months, 2-30 months, 2-36 months, 3-6 months, 3-9 months, 3-12 months, 3-18 months, 3-24 months, 3-30 months, 3-36 months, 6- It can be stored at room temperature for a period of 9 months, 6-12 months, 6-18 months, 6-24 months, 6-30 months, 6-36 months, 9-12 months, 9-18 months, 9-24 months, 9-30 months, 9-36 months, 12-18 months, 12-24 months, 12-30 months, 12-36 months, 18-24 months, 18-30 months, 18-36 months, 24-30 months, 24-36 months, or 30-36 months. In some examples, crystalline Form I can be stored at room temperature for a period of at least 1 month, 2 months, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months, 30 months, or 36 months.

[0059] In various embodiments, crystalline form I is stable at temperatures above room temperature and / or at high RH. In some examples, crystalline form I can be stored at about 40° C. and about 75% RH for extended periods of time without significant chemical decomposition or change in crystalline morphology. In some examples, crystalline form I can be stored at about 40° C. and about 75% RH for periods of about 10, 30, 60, 90, 120, 150, or 180 days. In some examples, crystalline form I can be stored at about 40° C. and about 75% RH for periods of more than about 180 days. In some examples, crystalline Form I can be stored at about 40° C. and about 75% RH for 10-14 days, 10-18 days, 10-22 days, 10-26 days, 10-30 days, 10-40 days, 10-50 days, 10-60 days, 10-90 days, 10-120 days, 10-150 days, 10-180 days, 14-18 days, 14-22 days, 14-26 days, 14-30 days, 14-40 days, 14-50 days, 14-60 days, 14-70 days, 14-80 days, 14-90 days, 14-110 days, 14-150 days, 14-260 days, 14-30 days, 14-40 days, 14-50 days, 14-60 days, 14-70 days, 14-80 days, 14-90 days, 14-100 days, 14-110 days, 14-120 days, 14-130 days, 14-140 days, 14-150 days, 14-260 days, 14-30 days, 14-40 days, 14-50 days, 14-60 days, 14-70 days, 14-80 days, 14-90 days, 14-150 days, 14-160 days, 14-170 days, 14-180 days, 14-22 days, 14-26 days, 14-30 days, 14-40 days, 14-50 days, 14-60 days, 14-70 days, 14-80 days, 1 days, 14-50 days, 14-60 days, 14-90 days, 14-120 days, 14-150 days, 14-180 days, 18-22 days, 18-26 days, 18-30 days, 18-40 days, 18-50 days, 18-60 days, 18-90 days, 18-120 days, 18-150 days, 18-180 days, 22-26 days, 22-30 days, 22-40 days, 22-50 days, 22-6 days 0 days, 22-90 days, 22-120 days, 22-150 days, 22-180 days, 26-30 days, 26-40 days, 26-50 days, 26-60 days, 26-90 days, 26-120 days, 26-150 days, 26-180 days, 30-40 days, 30-50 days, 30-60 days, 30-90 days, 30-120 days, 30-150 days, 30-180 days, 40-50 days , 40-60 days, 40-90 days, 40-120 days, 40-150 days, 40-180 days, 50-60 days, 50-90 days, 50-120 days, 50-150 days, 50-180 days, 60-90 days, 60-120 days, 60-150 days, 60-180 days, 90-120 days, 90-150 days, or 90-180 days. In some examples, crystalline Form I can be stored at about 40° C. and about 75% RH for a period of at least 10 days, 14 days, 18 days, 22 days, 26 days, 30 days, 40 days, 50 days, 60 days, 90 days, 120 days, 150 days, or 180 days.

[0060] In various embodiments, crystalline form I is stable at temperatures above room temperature and / or at high RH. In some examples, crystalline form I can be stored at about 25° C. and about 60% RH for extended periods without significant chemical decomposition or change in crystalline form. In some examples, crystalline form I can be stored at about 25° C. and about 60% RH for periods of at least about 1 month, 2 months, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months, 30 months, or 36 months. In some examples, crystalline form I can be stored at about 25° C. and about 60% RH for periods of more than about 36 months. In some examples, crystalline Form I may be soluble in water at about 25° C. and about 60% RH for 1-2 months, 1-3 months, 1-6 months, 1-9 months, 1-12 months, 1-18 months, 1-24 months, 1-30 months, 1-36 months, 2-3 months, 2-6 months, 2-9 months, 2-12 months, 2-18 months, 2-24 months, 2-30 months, 2-36 months, 3-6 months, 3-9 months, 3-12 months, 3-18 months, 3-24 months, 3-30 months, 3-40 months, 3-50 months, 3-60 months, 3-70 months, 3-80 months, 3-90 ... 30 months, 24 months, 30 months, 24 months, 36 months, 6 months, 9 months, 12 ...

[0061] Crystal Form II of the Maleate Salt of Compound A FIG. 4 is an X-ray powder diffraction (XRPD) pattern for crystalline Form II of the maleate salt of Compound A.

[0062] FIG. 5 depicts a differential scanning calorimetry (DSC) thermogram for crystalline Form II of the maleate salt of Compound A.

[0063] FIG. 6 is a thermogravimetric analysis (TGA) pattern for crystalline Form II of the maleate salt of Compound A.

[0064] In one aspect, provided herein is crystalline form II of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate maleate. Some embodiments provide compositions comprising crystalline form II of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate maleate. In some embodiments, the crystalline form II of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate maleate is (a) an X-ray powder diffraction pattern including peaks at 14.3±0.2°2-θ, 20.1±0.2°2-θ, and 15.2±0.2°2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å; (b) an X-ray powder diffraction pattern substantially the same as that shown in FIG. (c) i) an endotherm in the range of about 75 to 100°C; ii) an endotherm in the range of about 195-210°C; and iii) Endothermic in the range of 215-235°C A differential scanning calorimetry (DSC) thermogram, (d) i) an endotherm with an onset of about 77° C. and a peak of about 94° C.; ii) an endotherm with an onset of about 202° C. and a peak at about 205° C., and iii) an endotherm with an onset of about 220° C. and a peak at about 230° C. A differential scanning calorimetry (DSC) thermogram, (e) A differential scanning calorimetry (DSC) thermogram substantially the same as that shown in FIG. (f) a thermogravimetric analysis (TGA) pattern substantially the same as that shown in FIG. 6; or (g) Combinations thereof It is characterized as having:

[0065] In some embodiments, crystalline Form II is characterized by an X-ray powder diffraction pattern substantially similar to that shown in FIG.

[0066] In some embodiments, the crystalline form II is characterized by an X-ray powder diffraction pattern comprising peaks at 14.3±0.2°2-θ, 20.1±0.2°2-θ, and 15.2±0.2°2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å. In some embodiments, the crystalline form II is characterized by an X-ray powder diffraction pattern comprising peaks at 14.3±0.1°2-θ, 20.1±0.1°2-θ, and 15.2±0.1°2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å. In some embodiments, the crystalline form II is characterized by an X-ray powder diffraction pattern comprising peaks at about 14.3°2-θ, about 20.1°2-θ, and about 15.2°2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å.

[0067] In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from 18.4±0.2°2-θ, 26.2±0.2°2-θ, and 16.4±0.2°2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from 18.4±0.1°2-θ, 26.2±0.1°2-θ, and 16.4±0.1°2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from about 18.4°2-θ, about 26.2°2-θ, and about 16.4°2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å.

[0068] In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from 20.9±0.2°2-θ, 25.0±0.2°2-θ, and 27.0±0.2°2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from 20.9±0.1°2-θ, 25.0±0.1°2-θ, and 27.0±0.1°2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from about 20.9°2-θ, about 25.0°2-θ, and about 27.0°2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å.

[0069] In some embodiments, the X-ray powder diffraction pattern comprises at least one peak selected from 14.3±0.2°2-θ, 20.1±0.2°2-θ, 15.2±0.2°2-θ, 18.4±0.2°2-θ, 26.2±0.2°2-θ, 16.4±0.2°2-θ, 20.9±0.2°2-θ, 25.0±0.2°2-θ, and 27.0±0.2°2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least two peaks selected from 14.3±0.2°2-θ, 20.1±0.2°2-θ, 15.2±0.2°2-θ, 18.4±0.2°2-θ, 26.2±0.2°2-θ, 16.4±0.2°2-θ, 20.9±0.2°2-θ, 25.0±0.2°2-θ, and 27.0±0.2°2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least three peaks selected from 14.3±0.2°2-θ, 20.1±0.2°2-θ, 15.2±0.2°2-θ, 18.4±0.2°2-θ, 26.2±0.2°2-θ, 16.4±0.2°2-θ, 20.9±0.2°2-θ, 25.0±0.2°2-θ, and 27.0±0.2°2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least four peaks selected from 14.3±0.2°2-θ, 20.1±0.2°2-θ, 15.2±0.2°2-θ, 18.4±0.2°2-θ, 26.2±0.2°2-θ, 16.4±0.2°2-θ, 20.9±0.2°2-θ, 25.0±0.2°2-θ, and 27.0±0.2°2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least five peaks selected from 14.3±0.2°2-θ, 20.1±0.2°2-θ, 15.2±0.2°2-θ, 18.4±0.2°2-θ, 26.2±0.2°2-θ, 16.4±0.2°2-θ, 20.9±0.2°2-θ, 25.0±0.2°2-θ, and 27.0±0.2°2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å.In some embodiments, the X-ray powder diffraction pattern comprises at least six peaks selected from 14.3±0.2°2-θ, 20.1±0.2°2-θ, 15.2±0.2°2-θ, 18.4±0.2°2-θ, 26.2±0.2°2-θ, 16.4±0.2°2-θ, 20.9±0.2°2-θ, 25.0±0.2°2-θ, and 27.0±0.2°2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least seven peaks selected from 14.3±0.2°2-θ, 20.1±0.2°2-θ, 15.2±0.2°2-θ, 18.4±0.2°2-θ, 26.2±0.2°2-θ, 16.4±0.2°2-θ, 20.9±0.2°2-θ, 25.0±0.2°2-θ, and 27.0±0.2°2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least eight peaks selected from 14.3±0.2°2-θ, 20.1±0.2°2-θ, 15.2±0.2°2-θ, 18.4±0.2°2-θ, 26.2±0.2°2-θ, 16.4±0.2°2-θ, 20.9±0.2°2-θ, 25.0±0.2°2-θ, and 27.0±0.2°2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å. In some embodiments, the X-ray powder diffraction pattern comprises peaks at 14.3±0.2°2-θ, 20.1±0.2°2-θ, 15.2±0.2°2-θ, 18.4±0.2°2-θ, 26.2±0.2°2-θ, 16.4±0.2°2-θ, 20.9±0.2°2-θ, 25.0±0.2°2-θ, and 27.0±0.2°2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å. In some embodiments, the X-ray powder diffraction pattern comprises peaks at 14.3±0.1°2-θ, 20.1±0.1°2-θ, 15.2±0.1°2-θ, 18.4±0.1°2-θ, 26.2±0.1°2-θ, 16.4±0.1°2-θ, 20.9±0.1°2-θ, 25.0±0.1°2-θ, and 27.0±0.1°2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å.In some embodiments, the X-ray powder diffraction pattern includes peaks at about 14.3°2-θ, about 20.1°2-θ, about 15.2°2-θ, about 18.4°2-θ, about 26.2°2-θ, about 16.4°2-θ, about 20.9°2-θ, about 25.0°2-θ, and about 27.0°2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å.

[0070] In some embodiments, crystalline Form II is characterized by a differential scanning calorimetry (DSC) thermogram substantially similar to that shown in Figure 5. In some embodiments, crystalline Form II is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm in the range of about 75-100°C, an endotherm in the range of about 195-210°C, and an endotherm in the range of about 215-235°C. In some embodiments, crystalline Form II is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an onset of about 77°C and a peak at about 94°C, an endotherm with an onset of about 202°C and a peak at about 205°C, and an endotherm with an onset of about 220°C and a peak at about 230°C.

[0071] In some embodiments, crystalline Form II is characterized by an endotherm in a DSC thermogram in the range of about 70-100° C., e.g., about 70-100° C., 70-95° C., 70-90° C., 70-85° C., 70-80° C., 70-75° C., 75-100° C., 75-95° C., 75-90° C., 75-85° C., 75-80° C., 80-100° C., 80-95° C., 80-90° C., 80-85° C., 85-100° C., 85-95° C., 85-90° C., 90-100° C., 90-95° C., or 95-100° C. In some examples, crystalline Form II is characterized by an endotherm in a DSC thermogram in the range of about 94° C.

[0072] In some embodiments, crystalline Form II is characterized by an endotherm in the range of about 190-220°C, e.g., about 190-220°C, 190-215°C, 190-210°C, 190-205°C, 190-200°C, 190-195°C, 195-220°C, 195-215°C, 195-210°C, 195-205°C, 195-200°C, 200-220°C, 200-215°C, 200-210°C, 200-205°C, 205-220°C, 205-215°C, 205-210°C, 210-220°C, 210-215°C, or 215-220°C in a DSC thermogram. In some instances, crystalline Form II is characterized by an endotherm at about 205° C. in a DSC thermogram.

[0073] In some embodiments, crystalline Form II is characterized by an endotherm in the range of about 210-240°C, e.g., about 210-240°C, 210-235°C, 210-230°C, 210-225°C, 210-220°C, 210-215°C, 215-240°C, 215-235°C, 215-230°C, 215-225°C, 215-220°C, 220-240°C, 220-235°C, 220-230°C, 220-225°C, 225-240°C, 225-235°C, 225-230°C, 230-240°C, 230-235°C, or 235-240°C in a DSC thermogram. In some instances, crystalline Form II is further characterized by an endotherm at about 230° C. in a DSC thermogram.

[0074] In some embodiments, crystalline form II is characterized by a thermogravimetric analysis (TGA) pattern substantially similar to that shown in Figure 6. In various embodiments, crystalline form II decomposes above a temperature of about 150°C, about 200°C, about 250°C, about 300°C, about 350°C, about 400°C, about 450°C, about 500°C, about 550°C, or greater than 600°C. In some embodiments, crystalline form II decomposes above a temperature of about 150°C.

[0075] II. Methods of Making the Maleate Salt of Compound A and Its Polymorphic Forms In one aspect, the present invention provides a maleate salt of compound A:

[0076] [ka] The present invention provides a method for making one or more polymorphs of

[0077] In some embodiments, the maleate salt of Compound A is prepared according to the examples herein.

[0078] Polymorphs according to the present invention are not limited to the starting materials used to produce Compound A or the maleate salt of Compound A.

[0079] In one aspect, the present invention relates to a method for producing a polymorph of the maleate salt of compound A or a pharma- ceutically acceptable salt and / or solvate thereof by isolating the desired polymorph as a first solid form following synthesis of the maleate salt of compound A, or alternatively, by isolating the desired polymorph as a transition from a previous solid form of the maleate salt of compound A. Transitions from one form to another are within the scope of the present invention, as they may be alternative manufacturing methods to obtain a form desired for the manufacture of a pharmaceutical preparation.

[0080] The polymorph of the maleate salt of Compound A according to the method of the present invention can be selected from crystalline form I, crystalline form II, and mixtures thereof.

[0081] Isolation and purification of the chemical entities and intermediates described herein can be carried out by any suitable separation or purification procedure, such as, for example, filtration, extraction, crystallization, column chromatography, thin or thick layer chromatography, or a combination of these procedures, as necessary. Specific illustrations of suitable separation and isolation procedures can be obtained by reference to the following examples. However, other equivalent separation or isolation procedures can also be used. Prior to crystallization, the maleate salt of Compound A may be isolated with about 50% chemical purity, 55% chemical purity, 60% chemical purity, 65% chemical purity, 70% chemical purity, 75% chemical purity, 80% chemical purity, 90% chemical purity, 91% chemical purity, 92% chemical purity, 93% chemical purity, 94% chemical purity, 95% chemical purity, 96% chemical purity, 97% chemical purity, 98% chemical purity, 99% chemical purity, about 98% chemical purity, or about 100% chemical purity.

[0082] In some embodiments, the crystalline forms disclosed herein are obtained by crystallizing a maleate salt of Compound A with a chemical purity of less than about 98%, less than about 97%, less than about 96%, less than about 95%, less than about 94%, less than about 93%, less than about 92%, less than about 91%, less than about 90%, less than about 89%, less than about 88%, less than about 87%, less than about 86%, less than about 85%, less than about 84%, less than about 83%, less than about 82%, less than about 81%, less than about 80%, less than about 78%, less than about 76%, less than about 74%, less than about 72%, or less than about 70%. In some embodiments, the crystalline form is obtained by crystallizing the maleate salt of Compound A with a chemical purity in the range of about 70% to about 99%, 80% to about 96%, 85% to about 96%, 90% to about 96%, 80% to about 98%, 85% to about 98%, 90% to about 98%, 92% to about 98%, 94% to 98%, or 96% to about 98%.

[0083] In some embodiments, isolating the desired polymorph of the maleate salt of Compound A comprises crystallization of the crude reaction product from a single solvent system. In various embodiments, isolating the desired polymorph of the maleate salt of Compound A comprises crystallization of the crude product from a secondary, tertiary, or higher solvent system, collectively understood as a multi-solvent system.

[0084] In some embodiments, crystallization is carried out by forming the desired maleate salt of Compound A in the reaction mixture and isolating the desired polymorph from the reaction mixture. In some embodiments, the reaction mixture is formed by adding a solution of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate to maleic acid to form dissolved (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate maleate (the maleate salt of Compound A). In other embodiments, the reaction mixture is formed by dissolving the maleate salt of compound A in a solvent.

[0085] Preparation of Crystalline Form I In some embodiments, the desired polymorph is crystalline Form I of the maleate salt of Compound A, and the isolating step comprises crystallization of the crude reaction product from a single solvent system. In some embodiments, the desired polymorph is crystalline Form I of the maleate salt of Compound A, and the isolating step comprises crystallization of the crude reaction product from a secondary, tertiary, or higher solvent system, collectively understood as a multi-solvent system. In some embodiments, the crude reaction product is formed by contacting (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate with maleic acid to form dissolved (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate maleate (the maleate salt of Compound A).

[0086] In some embodiments, the desired polymorph is crystalline Form I of the maleate salt of Compound A, and isolating the maleate salt of Compound A comprises crystallization from a single solvent or a multi-solvent system, and the crystallization comprises forming the maleate salt of Compound A in situ by contacting (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate with maleic acid at a temperature above ambient temperature. In some examples, reactions in single or multi-solvent systems may be carried out at temperatures between about 40-90°C, 45-90°C, 50-90°C, 55-90°C, 60-90°C, 65-90°C, 70-90°C, 75-90°C, 40-85°C, 45-85°C, 50-85°C, 55-85°C, 60-85°C, 65-85°C, 70-85°C, 75-85°C, 80-85°C, 40-80°C, 45-80°C, 50-80°C, 55-80°C, 60-80°C, 65-80°C, 70-85 ... It is performed at temperatures of ~80°C, 75~80°C, 40~75°C, 45~75°C, 50~75°C, 55~75°C, 60~75°C, 65~75°C, 70~75°C, 40~70°C, 45~70°C, 50~70°C, 55~70°C, 60~70°C, 65~70°C, 40~65°C, 45~65°C, 50~65°C, 55~65°C, 60~65°C, 40~60°C, 45~60°C, 50~60°C, 55~60°C, 40~50°C, or 45~50°C.

[0087] In some examples, the solvent comprises ethyl acetate, DCM, ethanol, or isopropanol. In some examples, the solvent comprises ethanol. In some embodiments, the solvent comprises ethanol and the reaction is carried out at a temperature of about 65-75° C. Any suitable amount of solvent can be used. In some embodiments, the amount of solvent (e.g., ethanol) used is about 40-60 mL per gram of the maleate salt of Compound A. For example, in some embodiments, the amount of solvent used is 50 mL per gram of the maleate salt of Compound A. In some examples, the solvent comprises ethanol and the reaction is carried out at a temperature of about 65-75° C. and the amount of solvent is about 50 mL / g of the maleate salt of Compound A.

[0088] In various embodiments, the crystallization further comprises actively heating the solution in which the maleate salt of compound A is dissolved to a temperature of, for example, about 40-100° C., 40-90° C., 40-80° C., 40-70° C., 40-60° C., 40-50° C., 50-100° C., 50-90° C., 50-80° C., 50-70° C., 50-60° C., 60-100° C., 60-90° C., 60-80° C., 60-70° C., 70-100° C., 70-90° C., 70-80° C., 80-100° C., or 80-90° C. In some embodiments, the solution in which the maleate salt of compound A is dissolved is heated to a temperature of about 65-75° C. In various embodiments, the solution having the maleate salt of Compound A dissolved therein is maintained at an elevated temperature for a period of time, such as, for example, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, or longer.

[0089] In various embodiments, the crystallization further comprises actively lowering the temperature of the heated solution in which the maleate salt of compound A has been dissolved to a temperature of, for example, about 0-40° C., 0-30° C., 0-20° C., 0-10° C., 10-40° C., 10-30° C., 10-20° C., 20-40° C., 20-30° C., 20-10° C., or 30-40° C. In some embodiments, the crystallization further comprises actively lowering the temperature of the heated solution in which the maleate salt of compound A has been dissolved to a temperature of about 20-30° C. In various embodiments, the solution having the dissolved maleate salt of Compound A is further maintained at such low temperature for a period of time, such as, for example, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, or longer.

[0090] In various embodiments, the steps of active heating followed by active cooling are repeated multiple times, for example, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, or at least 10 times. In some embodiments, the steps of active heating followed by active cooling are repeated 2, 3, 4, 5, 6, 7, 8, 9, or 10 times.

[0091] In various embodiments, the crystallization further comprises filtering the solution containing the obtained crystals of the maleate salt of Compound A. In some embodiments, the crystallization optionally comprises washing the obtained crystals with a solvent, e.g., a recrystallization solvent, one or more times. In some embodiments, the crystallization optionally comprises drying the obtained crystals, e.g., under vacuum at a temperature of about 20-30°C.

[0092] In some embodiments, the chemical purity of crystalline form I is greater than 60%, 70%, 80%, 90%, 95%, or 99%. In some embodiments, the chemical purity of crystalline form I is greater than about 90%. In some embodiments, the chemical purity of crystalline form I is greater than about 95%. In some embodiments, the chemical purity of crystalline form I is greater than about 99%. The chemical purity of crystalline form I may be measured by any available analytical technique, for example, HPLC analysis.

[0093] In various embodiments, crystalline form I is dry. In various embodiments, crystalline form I is non-solvated. In various embodiments, crystalline form I is non-hydrated. In various embodiments, crystalline form I is anhydrous.

[0094] Preparation of Crystalline Form II In some embodiments, the desired polymorph is crystalline Form II of the maleate salt of Compound A, and the isolating step comprises crystallization of the crude reaction product from a single solvent system. In some embodiments, the desired polymorph is crystalline Form II of the maleate salt of Compound A, and the isolating step comprises crystallization of the crude reaction product from a secondary, tertiary, or higher solvent system, collectively understood as a multi-solvent system. In some embodiments, the crude reaction product is formed by contacting (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate with maleic acid to form dissolved (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate maleate (the maleate salt of Compound A).

[0095] In some embodiments, the desired polymorph is crystalline Form II of the maleate salt of Compound A, and isolating the maleate salt of Compound A comprises crystallization from a single solvent or a multi-solvent system, and the crystallization comprises forming the maleate salt of Compound A in situ by contacting (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate with maleic acid at a temperature above ambient temperature. In some examples, reactions in single-solvent or multi-solvent systems may be carried out at temperatures between about 10-50° C., 10-45° C., 10-40° C., 10-35° C., 10-30° C., 10-25° C., 10-20° C., 10-15° C., 15-50° C., 15-45° C., 15-40° C., 15-35° C., 15-30° C., 15-25° C., 15-20° C., 20-50° C., 20-45° C. , 20-40°C, 20-35°C, 20-30°C, 20-25°C, 25-50°C, 25-45°C, 25-40°C, 25-35°C, 25-30°C, 30-50°C, 30-45°C, 30-40°C, 30-35°C, 35-50°C, 35-45°C, 35-40°C, 40-50°C, 40-45°C, or 45-50°C.

[0096] In some examples, the solvent comprises ethyl acetate, DCM, ethanol, or isopropanol. In some examples, the solvent comprises isopropanol. In some embodiments, the solvent comprises isopropanol and the reaction is carried out at a temperature of about 20-30° C. Any suitable amount of solvent can be used. In some embodiments, the amount of solvent (e.g., isopropanol) used is about 80-100 mL per gram of the maleate salt of Compound A. For example, in some embodiments, the amount of solvent used is 90 mL per gram of the maleate salt of Compound A. In some examples, the solvent comprises isopropanol and the reaction is carried out at a temperature of about 20-30° C. and the amount of solvent is about 90 mL / g of the maleate salt of Compound A.

[0097] In various embodiments, the crystallization further comprises filtering the solution containing the obtained crystals of the maleate salt of Compound A. In some embodiments, the crystallization optionally comprises washing the obtained crystals with a solvent, e.g., a recrystallization solvent, one or more times. In some embodiments, the crystallization optionally comprises drying the obtained crystals, e.g., under vacuum at a temperature of about 30-40°C.

[0098] In some embodiments, the chemical purity of crystalline form II is greater than 60%, 70%, 80%, 90%, 95%, or 99%. In some embodiments, the chemical purity of crystalline form II is greater than about 90%. In some embodiments, the chemical purity of crystalline form II is greater than about 95%. In some embodiments, the chemical purity of crystalline form II is greater than about 99%. The chemical purity of crystalline form II may be measured by any available analytical technique, for example, HPLC analysis.

[0099] III. Further Definitions As used herein, "active agent" is used to refer to a chemical entity that has biological activity. In certain embodiments, an "active agent" is a compound that has pharmaceutical utility. For example, an active agent can be an anti-cancer therapeutic agent.

[0100] As used herein, "modulation" refers to a change in activity in response to the presence of a chemical entity described herein, either directly or indirectly, compared to the activity in the absence of the chemical entity. This change can be an increase in activity or a decrease in activity, and can be due to the direct interaction of the compound with the target, or due to the interaction of the compound with one or more other factors that affect the activity of the target. For example, the presence of a chemical entity can increase or decrease target activity, for example, by directly binding to the target, by (directly or indirectly) causing another factor to increase or decrease target activity, or by (directly or indirectly) increasing or decreasing the amount of target present in a cell or organism.

[0101] As used herein, a "therapeutically effective amount" of a chemical entity described herein refers to an amount that, when administered to a human or non-human subject, is effective to provide a therapeutic benefit, such as ameliorating symptoms, slowing the progression of a disease, or preventing a disease.

[0102] "Treating" or "treatment" encompasses administration of Compound A, or a pharma- ceutically acceptable salt thereof, to a mammalian subject, particularly a human subject, in need thereof, and includes (i) arresting the onset of clinical symptoms of a disease, such as cancer; (ii) causing regression of clinical symptoms of a disease, such as cancer; and / or (iii) prophylactic treatment to prevent the appearance of a disease, such as cancer.

[0103] As used herein, a "pharmaceutical acceptable" component is one that is suitable for use in humans and / or animals without undue adverse side effects (such as toxicity, irritation, and allergic reactions) commensurate with a reasonable benefit / risk ratio.

[0104] "Pharmaceutically acceptable salts" include salts with inorganic acids, such as hydrochlorides, carbonates, phosphates, hydrogen phosphates, diphosphates, hydrobromides, sulfates, sulfinates, and nitrates, as well as malate, malonate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, gluconate, methanesulfonate, tris(hydroxymethyl-aminomethane), -p-toluenesulfonate, propionate, 2-hydroxyethylsulfonate, benzoate, salicylate, stearate, oxalate, pamoate, and acetate, HOOC-(CH2) salts, where n is 0 to 4. n The salts include, but are not limited to, alkanoates such as -COOH. Other salts include sulfates, metasulfonates, bromides, trifluoroacetates, picrates, sorbates, benzilates, salicylates, nitrates, phthalates, or morpholines. Pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium.

[0105] In addition, if the compounds described herein are obtained as acid addition salts, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, specifically a pharma- ceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art will recognize various synthetic methods that may be used to prepare non-toxic pharma-ceutically acceptable addition salts.

[0106] As used herein, "subject" refers to a mammal that is or will be the object of treatment, observation, or experiment. The methods described herein can be useful for both human therapy and veterinary applications. In some embodiments, the subject is a human.

[0107] The term "mammal" is intended to have its standard meaning and includes, for example, humans, dogs, cats, sheep, and cows.

[0108] A "prodrug" as described herein includes any compound that becomes compound A upon metabolic processing of the prodrug when administered to a subject. Similarly, a "pharmaceutical acceptable salt" includes a "prodrug" of a pharmaceutical acceptable salt. Examples of prodrugs include derivatives of functional groups of compound A, such as carboxylic acid groups. Exemplary prodrugs of carboxylic acid groups include, but are not limited to, carboxylic acid esters, such as alkyl esters, hydroxyalkyl esters, arylalkyl esters, and aryloxyalkyl esters. Other exemplary prodrugs include lower alkyl esters, such as ethyl esters, acyloxyalkyl esters, such as pivaloyloxymethyl (POM), glycosides, and ascorbic acid derivatives. Other exemplary prodrugs include amides of carboxylic acids. A discussion of prodrugs is provided in "Pro-drugs as Novel Delivery Systems" by T. Higuchi and V. Stella, Vol. 14 of the ACS Symposium Series, "Bioreversible Carriers in Drug Design" edited by Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, and "Design of Prodrugs", H. Bundgaard, Elsevier, 1985.

[0109] The compounds disclosed herein may be present in a variety of isotopically enriched forms, e.g. 2 H, 3 H, 11 C. 13 C, and / or 14It can be used in the form that is rich in C content. In a particular embodiment, the compound is deuterated at at least one position. Such deuterated form can be made by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve the efficacy of drugs and increase their duration of action.

[0110] Deuterium substituted compounds can be synthesized using a variety of methods, such as those described in Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, p. 110; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 660, p. 1-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), p. 9-32.

[0111] A "solvate" is formed by the interaction of a solvent with a compound. The term "compound" is intended to include solvates of a compound. Similarly, a "pharmaceutically acceptable salt" includes solvates of a pharmaceutically acceptable salt. Suitable solvates are pharmaceutically acceptable solvates such as hydrates, including monohydrates and hemihydrates. Also included are solvates formed with one or more solvents of crystallization.

[0112] Pharmaceutically acceptable forms of the compounds described herein include pharma- ceutically acceptable salts, chelates, non-covalent complexes, prodrugs, and mixtures thereof.

[0113] A "chelate" is formed by the coordination of a compound to a metal ion at two (or more) points. The term "compound" is intended to include chelates of a compound. Similarly, a "pharmaceutically acceptable salt" includes chelates of a pharmaceutically acceptable salt.

[0114] A "non-covalent complex" is formed by the interaction of a compound with another molecule, where no covalent bond is formed between the compound and the molecule. For example, complexation may occur through van der Waals interactions, hydrogen bonds, and electrostatic interactions (also called ionic bonds). Such non-covalent complexes are included in the term "compound". Similarly, a pharmaceutically acceptable salt includes a "non-covalent complex" of the pharmaceutically acceptable salt.

[0115] When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulas, it is intended that all combinations and subcombinations of the ranges and specific embodiments therein are included.

[0116] The term "about" when referring to a number or numerical range means that the number or numerical range referred to is an approximation within experimental variation (or statistical experimental error), such that the number or numerical range may vary, for example, between 1% and 15% of the stated number or numerical range. In some examples of numerical ranges, "about" means ±10%.

[0117] As used herein, "significant" refers to any detectable change that is statistically significant in a standard parametric test of statistical significance, such as the Student's T-test, where p<0.05.

[0118] As used herein, "cancer" refers to all types of cancer, neoplasms, or malignant tumors found in mammals, including carcinomas and sarcomas. Examples of cancers are cancer of the brain, breast, cervix, colon, head and neck, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterine, and medulloblastoma.

[0119] IV.How to use The polymorphs described herein may be used to treat a variety of neoplasms, including malignant and benign tumors, and cancer. Cancers that may be prevented and / or treated by the polymorphs, compositions, and methods described herein include human sarcomas and carcinomas, such as colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, thyroid cancer, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chondroma, angiosarcoma, endothelioma, lymphangiosarcoma, lymphangioendothelioma, synovium, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchial carcinoma, renal cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung cancer, small cell lung cancer, bladder cancer, epithelial carcinoma, glioma, astrocyt ... Polymorphisms that may be prevented and / or treated by the polymorphisms, compositions, and methods described herein include, but are not limited to, cystoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, otosarcoma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, Langerhans cell histiocytosis (LCH), Erdheim-Chester disease (ECD), leukemias such as acute lymphocytic leukemia and acute myelocytic leukemia (myeloblastic, promyelocytic, myelomonocytic, monocytic, and erythroleukemia), chronic leukemias (chronic myelocytic (granulocytic) leukemia and chronic lymphocytic leukemia), and polycythemia vera, lymphomas (Hodgkin's disease and non-Hodgkin's disease), multiple myeloma, Waldenstrom's macroglobulinemia, and heavy chain disease. Benign tumors that may be prevented and / or treated by the polymorphisms, compositions, and methods described herein include, but are not limited to, craniopharyngioma.

[0120] In some embodiments, the polymorphs described herein have the following structure: i. the digestive system, including but not limited to the esophagus, stomach, small intestine, colon (including the colorectum), liver and intrahepatic bile ducts, gallbladder and other biliary tracts, pancreas, and other digestive organs; ii. The respiratory system, including but not limited to the larynx, lungs and bronchi, and other respiratory organs; iii.Skin, iv. Thyroid gland, v. Breast, vi. The reproductive system, including but not limited to the cervix, ovaries, and prostate; vii. the urinary system, including but not limited to the bladder, kidneys, and renal pelvis; viii. Oral cavity and pharynx, including but not limited to the tongue, mouth, pharynx, and other oral cavity It is used for the treatment of cancer.

[0121] In some embodiments, the polymorphs described herein are used to treat colon cancer, liver cancer, lung cancer, melanoma, thyroid cancer, breast cancer, ovarian cancer, oral cancer, head and neck cancer, and brain cancer.

[0122] The polymorphs described herein may also be used in combination with other known therapeutic agents selected for their particular usefulness against the disease being treated. For example, the polymorphs described herein may be useful in combination with at least one additional anti-cancer and / or cytotoxic agent. Additionally, the polymorphs described herein may be useful in combination with other inhibitors of portions of signal transduction pathways that link cell surface growth factor receptors to nuclear signals that initiate cell proliferation.

[0123] Such known anti-cancer and / or cytotoxic agents that may be used in combination with the polymorphs described herein include: (i) alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan, temozolamide, and nitrosoureas), antimetabolites (e.g., gemcitabine, and fluoropyrimidines such as 5-fluorouracil and tegafur, folate antagonists such as raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea), antitumor antibiotics (e.g., adriamycin, bleomycin, doxorubicin, daunomycin, other antiproliferative / antineoplastic agents used in oncology such as anthracyclines such as epirubicin, idarubicin, mitomycin C, dactinomycin, and mithramycin), antimitotic agents (e.g., vinca alkaloids such as vincristine, vinblastine, vindesine, vinorelbine, taxoids such as taxol and taxotere, polo kinase inhibitors), topoisomerase inhibitors (e.g., epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan, and camptothecin) and combinations thereof; (ii) antiestrogens (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, and iodoxyfene), antiandrogens (e.g., bicalutamide, flutamide, nilutamide, and cyproterone acetate), LHRH antagonists or agonists (e.g., goserelin, leuprorelin, and buserelin), progestogens (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, borazole, and exemestane), and 5α-reductase inhibitors such as finasteride, (iii) anti-invasion agents [e.g., 4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4yloxyquinazoline (AZD0530, WO 01 / 94341), N-(2-chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidine-4-yloxyquinazoline (AZD0530, WO 01 / 94341), c-Src kinase family inhibitors such as arylamino}thiazole-5-carboxamide (dasatinib, BMS-354825, J. Med. Chern., 2004, 47, 66586661), and bosutinib (SK1-606), as well as metalloproteinase inhibitors such as marimastat, inhibitors of urokinase plasminogen activator receptor function, and antibodies against heparanase]. (iv) inhibitors of growth factor function (e.g., such inhibitors include growth factor and growth factor receptor antibodies (e.g., the anti-erbB2 antibody trastuzumab [Herceptin®], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab [Erbitux, C225], and any of the growth factor or growth factor receptor antibodies disclosed in Stem et al., Critical reviews in oncology / haematology, 2005, Vol. 54, pp. 11-29), such inhibitors include tyrosine kinase inhibitors, such as inhibitors of the epidermal growth factor family (e.g., N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZD1839), N-(3-ethynylphenyl)- EGFR family tyrosine kinase inhibitors, such as 6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774), and erbB2 tyrosine kinase inhibitors, such as lapatinib, inhibitors of the hepatocyte growth factor family, inhibitors of the insulin growth factor family, and inhibitors of the imatinib family. Inhibitors of the platelet-derived growth factor family, such as tinib and / or nilotinib (AMN107), inhibitors of serine / threonine kinases (e.g., Ras / Raf signaling inhibitors, such as farnesyltransferase inhibitors, e.g., sorafenib (BAY43-9006), tipifarnib (RI15777), and lonafarnib (SCH66336)), inhibitors of cell signaling through MEK and / or AKT kinases, c-kit inhibitors , abl kinase inhibitors, P13 kinase inhibitors, Plt3 kinase inhibitors, CSF-IR kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors, Aurora kinase inhibitors (e.g., AZD1152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528, and AX39459), and cyclin-dependent kinase inhibitors such as CDK2 and / or CDK4 inhibitors); (v) antiangiogenic agents, such as those that inhibit the effects of vascular endothelial growth factor (e.g., the anti-vascular endothelial growth factor antibody bevacizumab (Avastin™), and, for example, vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SU1l248), axitinib (AG-013736), pazopanib (GW786034), and 4·{4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidinyl)-2-propanediol (PDE21111). VEGF receptor tyrosine kinase inhibitors such as lysine-1-ylpropoxy)quinazoline (AZD2171, Example 240 in WO 00 / 47212), compounds such as those disclosed in WO 97 / 22596, WO 97 / 30035, WO 97 / 32856, and WO 98 / 13354, as well as compounds that act by other mechanisms (e.g., linomide, an inhibitor of integrin av~3 function, and angiostatin), (vi) vascular damaging agents such as combretastatin A4 and the compounds disclosed in WO 99 / 02166, WO 00 / 40529, WO 00 / 41669, WO 01 / 92224, WO 02 / 04434, and WO 02 / 08213; (vii) endothelin receptor antagonists, such as zibotentan (ZD4054) or atrasentan, (viii) antisense therapeutics, e.g., directed to the targets listed above, such as ISIS2503 and anti-ras antisense; (ix) gene therapy approaches, including, for example, approaches to replace abnormal genes, such as abnormal p53 or abnormal BRCA1 or BRCA2, GDEPT (gene-directed enzyme prodrug therapy) approaches, such as those using cytosine deaminase, thymidine kinase, or bacterial nitroreductase enzymes, and approaches to increase a subject's resistance to chemotherapy or radiation therapy, such as multidrug resistance gene therapy; (x) Immunotherapeutic approaches, including, for example, ex-vivo and in-vivo approaches to enhance the immunogenicity of a subject's tumor cells, such as transfection with cytokines, such as interleukin 2, interleukin 4, or granulocyte-macrophage colony-stimulating factor, approaches to reduce T cell energy, approaches using transfected immune cells, such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumor cell lines, and approaches using anti-idiotypic antibodies.

[0124] In certain embodiments, at least one polymorph of Compound A is administered in combination with one or more agents selected from pacilitaxel, bortezomib, dacarbazine, gemcitabine, trastuzumab, bevacizumab, capecitabine, docetaxel, erlotinib, aromatase inhibitors such as AROMASIN™ (exemestane), and estrogen receptor inhibitors such as FASLODEX™ (fulvestrant).

[0125] When a polymorph of Compound A is administered to a human subject, the daily dosage will typically be determined by the prescribing physician, with dosages generally varying depending on the age, weight, and response of the individual subject, as well as the severity of the subject's symptoms.

[0126] In one exemplary application, at least one polymorph of Compound A is administered in a suitable amount to a mammal undergoing treatment for cancer, e.g., breast cancer. Administration is typically performed in an amount between about 0.01 mg / kg of body weight to about 100 mg / kg of body weight per day, such as at least about 0.1 mg / kg of body weight per day (administered in single or divided doses). A particular therapeutic dose may include, for example, about 0.01 mg to about 1000 mg of the polymorph of Compound A, such as about 1 mg to about 1000 mg. The amount of at least one polymorph of Compound A in a unit dose of the preparation may vary or be adjusted in the range of about 0.1 mg to 1000 mg, such as about 1 mg to 300 mg, e.g., 10 mg to 200 mg, depending on the particular application. The amount administered is based on the specific IC of at least one polymorph of Compound A used. 50 The amount of the active ingredient in the at least one polymorph of Compound A may vary depending on the patient's dietary intake and the judgment of the attending physician, taking into account factors such as the patient's health, weight, and age. In combination applications in which at least one polymorph of Compound A described herein is not the only active ingredient, it may be possible to administer a smaller amount of at least one polymorph of Compound A and still achieve a therapeutic or prophylactic effect.

[0127] In some embodiments, the pharmaceutical preparation is in unit dosage form. In such form, the preparation is subdivided into unit doses containing an appropriate amount of a polymorph of Compound A, for example, an effective amount to achieve the desired purpose.

[0128] The actual dosage used may vary depending on the requirements of the subject and the severity of the disease being treated. The determination of the appropriate dosage for a particular situation is within the skill of the art. In general, treatment is initiated with a dosage that is less than the optimal dosage of at least one polymorph of Compound A. This dosage is then increased by small increments until the optimal effect under the circumstances is achieved. For convenience, the total daily dosage may be divided and administered in smaller portions throughout the day as needed.

[0129] The amount and frequency of administration of at least one polymorph of Compound A, and, if applicable, other chemotherapeutic agents and / or radiation therapy, will be adjusted according to the judgment of the attending physician, taking into account factors such as the age, condition, and size of the subject, and the severity of the disease being treated.

[0130] Chemotherapeutic agents and / or radiation therapy can be administered according to treatment protocols well known in the art.It will be clear to those skilled in the art that the administration of chemotherapeutic agents and / or radiation therapy can vary according to the disease being treated and the effect of chemotherapeutic agents and / or radiation therapy known for that disease.Also, according to the thinking of clinicians in the art, treatment protocols (e.g., dosage and administration time) can be varied taking into account the effect observed with the administered therapeutic agent (i.e., antitumor drug or radiation) and the response of the disease observed to the administered therapeutic agent.

[0131] Also, generally, at least one polymorph of compound A does not need to be administered in the same pharmaceutical composition as the chemotherapeutic agent, and may be administered by different routes due to different physical and chemical properties. For example, the polymorph / composition may be administered orally to generate and maintain its good blood level, while the chemotherapeutic agent may be administered intravenously. The determination of the dosage form and the appropriateness of administration in the same pharmaceutical composition is well within the scope of the clinician in the art, if possible. The initial administration may be performed according to established protocols known in the art, and then, based on the observed effect, the dosage, dosage form, and administration time may be modified by the clinician in the art.

[0132] The particular choice of polymorph (and chemotherapeutic agent and / or radiation, if appropriate) will depend on the diagnosis of the attending physician, the attending physician's judgment of the subject's condition, and the appropriate treatment protocol.

[0133] One or more polymorphs of Compound A (and, where appropriate, chemotherapeutic agents and / or radiation) may be administered simultaneously (e.g., simultaneously, substantially simultaneously, or within the same treatment protocol) or sequentially, depending on the nature of the proliferative disease, the condition of the subject, and the actual choice of chemotherapeutic agents and / or radiation to be administered together with the one or more polymorphs / compositions (i.e., within a single treatment protocol).

[0134] In combination applications and uses, the one or more polymorphs / compositions and the chemotherapeutic agent and / or radiation do not need to be administered simultaneously or substantially simultaneously, and the initial administration order of the one or more polymorphs / compositions and the chemotherapeutic agent and / or radiation may not be important. Thus, at least one polymorph of compound A may be administered first, followed by the chemotherapeutic agent and / or radiation, or the chemotherapeutic agent and / or radiation may be administered first, followed by the at least one polymorph of compound A. This alternating administration may be repeated during a single treatment protocol. The determination of the administration order and the number of repetitions of administration of each therapeutic agent during the treatment protocol is well within the purview of the skilled artisan after evaluating the disease being treated and the condition of the subject. For example, the chemotherapeutic agent and / or radiation may be administered first, and then treatment may be continued by administration of at least one polymorph of compound A until the treatment protocol is completed, after which the chemotherapeutic agent and / or radiation, etc. may be administered if deemed advantageous.

[0135] Thus, the physician, according to his experience and knowledge, can modify each protocol for administration of therapeutic Compound A polymorphs / compositions according to the needs of the individual subject as the treatment progresses.

[0136] In determining whether a treatment is effective at a given dosage, the attending clinician will consider not only the subject's overall health, but also more obvious signs such as reduction in disease-related symptoms, inhibition of tumor growth, actual tumor shrinkage, or inhibition of metastasis. Tumor size can be measured by standard methods such as radiological tests, e.g., CAT or MRI scans, and serial measurements can be used to determine whether tumor growth has been slowed or even reversed. Relief of disease-related symptoms, such as pain, and improvement of overall condition can also be used to help determine the effectiveness of treatment.

[0137] V. Compositions and Formulations The present disclosure provides compositions, including pharmaceutical compositions, comprising one or more crystalline forms of the present invention.

[0138] In various embodiments, the ratio of a desired crystalline form, such as crystalline Form I, to all other crystalline forms in the composition is greater than about 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, or more w / w. In other embodiments, the ratio of crystalline Form II to all other crystalline forms is greater than about 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, or more w / w.

[0139] In some embodiments, one or more polymorphs of compound A are formulated into pharmaceutical compositions.In specific embodiments, pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers that contain excipients and auxiliaries that facilitate the processing of active compound / polymorphs into pharma-ceutically usable preparations.The appropriate formulation depends on the route of administration selected. Any pharma- ceutically acceptable technical product, carrier, and excipient may be used as suitable for formulating the pharmaceutical compositions described herein in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995), Remington's Pharmaceutical Sciences by Hoover, John E., Mack Publishing Co., Easton, Pennsylvania 1975, Pharmaceutical Dosage Forms, edited by Liberman, HA, and Lachman, L., Marcel Decker, New York, NY, 1980, and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999).

[0140] Provided herein is a pharmaceutical composition comprising one or more polymorphs of compound A and a pharma- ceutically acceptable diluent, excipient, or carrier. In certain embodiments, one or more polymorphs of compound A are administered as a pharmaceutical composition in which one or more polymorphs are mixed with other active ingredients, such as in combination therapy. This includes all combinations of actives as set forth in the combination therapy section below and throughout this disclosure. In specific embodiments, the pharmaceutical composition comprises one or more polymorphs of compound A.

[0141] Pharmaceutical composition, as used herein, refers to a mixture of one or more polymorphs of Compound A with other chemical components, such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or excipients. In certain embodiments, the pharmaceutical composition facilitates administration of the polymorphs to an organism. In some embodiments, in practicing the methods of treatment or use provided herein, a therapeutically effective amount of one or more polymorphs of Compound A is administered in a pharmaceutical composition to a mammal having a disease or disorder to be treated. In a specific embodiment, the mammal is a human. In certain embodiments, the therapeutically effective amount varies depending on the severity of the disease, the age and relative health of the subject, and other factors. One or more polymorphs of Compound A described herein are used alone or in combination with one or more therapeutic agents as components of a mixture.

[0142] In one embodiment, one or more polymorphs of Compound A are formulated in an aqueous solution. In a specific embodiment, the aqueous solution is selected from physiologically compatible buffers, such as, by way of example only, Hank's solution, Ringer's solution, or saline buffer. In other embodiments, one or more polymorphs of Compound A are formulated for transmucosal administration. In a specific embodiment, the transmucosal formulation comprises a penetrant appropriate for the barrier to be penetrated. In yet other embodiments, one or more polymorphs described herein are formulated for other parenteral injections, suitable formulations include aqueous or non-aqueous solutions. In a specific embodiment, such solutions comprise physiologically compatible buffers and / or excipients.

[0143] In another embodiment, the polymorphs described herein are formulated for oral administration.The polymorphs of Compound A are formulated, for example, by combining with a pharma-ceutically acceptable carrier or excipient.In various embodiments, the polymorphs described herein are formulated in oral dosage forms, including, by way of example only, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions, etc.

[0144] In certain embodiments, pharmaceutical preparations for oral use are obtained by mixing one or more solid excipients with one or more of the polymorphs described herein, optionally grinding the resulting mixture, and processing the granulated mixture after adding suitable auxiliaries as necessary to obtain tablets or dragee cores. Suitable excipients are in particular fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol, cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, or others such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. In certain embodiments, disintegrants are optionally added. Disintegrants include, by way of example only, cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or alginates such as sodium alginate.

[0145] In one embodiment, dosage forms such as dragee cores and tablets are provided with one or more suitable coatings. In a specific embodiment, a concentrated sugar solution is used to coat the dosage form. This sugar solution optionally contains additional components such as, by way of example only, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. For identification purposes, dyes and / or pigments are also optionally added to the coating. In addition, dyes and / or pigments are optionally utilized to characterize different combinations of active compound doses.

[0146] In certain embodiments, at least one therapeutically effective amount of the polymorphs described herein is formulated into other oral dosage forms. Oral dosage forms include push-fit capsules made of gelatin, as well as soft sealed capsules made of gelatin and plasticizers such as glycerol or sorbitol. In specific embodiments, the push-fit capsules contain the active ingredient mixed with one or more fillers. Fillers include, by way of example only, binders such as lactose, starch, and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. In other embodiments, the soft capsules contain one or more active compounds dissolved or suspended in a suitable liquid. Suitable liquids include, by way of example only, one or more fatty oils, liquid paraffin, or liquid polyethylene glycol. In addition, optionally stabilizers are added.

[0147] In other embodiments, at least one therapeutically effective amount of the polymorphs described herein is formulated for buccal or sublingual administration. Formulations suitable for buccal or sublingual administration include, by way of example only, tablets, lozenges, or gels. In yet other embodiments, the polymorphs described herein are formulated for parenteral injection, including formulations suitable for bolus injection or continuous infusion. In specific embodiments, the formulations for injection are provided in unit dosage form (e.g., ampoules) or multi-dose containers. Optionally, a preservative is added to the formulation for injection. In still other embodiments, the pharmaceutical composition of the polymorph of Compound A is formulated in a form suitable for parenteral injection as a sterile suspension, solution, or emulsion in an oily or aqueous vehicle. The parenteral injection formulation optionally contains formulations such as suspending agents, stabilizing agents, and / or dispersing agents. In specific embodiments, the pharmaceutical formulation for parenteral administration comprises an aqueous solution of the active polymorph in water-soluble form. In additional embodiments, a suspension of the active polymorph is prepared as a suitable oily injection suspension. Lipophilic solvents or vehicles suitable for use in the pharmaceutical compositions described herein include, by way of example only, fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. In certain specific embodiments, aqueous injection suspensions contain substances that increase the viscosity of the suspension, such as carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension contains suitable stabilizers or agents that increase the solubility of polymorphs, allowing for the preparation of highly concentrated solutions. Alternatively, in other embodiments, the active ingredient is in powder form prior to use, for constitution with a suitable vehicle, such as sterile pyrogen-free water.

[0148] In yet other embodiments, one or more polymorphs of Compound A are administered topically. One or more polymorphs described herein are formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams, or ointments. Such pharmaceutical compositions optionally contain solubilizers, stabilizers, tonicity enhancing agents, buffers, and preservatives.

[0149] In yet other embodiments, one or more polymorphs of Compound A are formulated for transdermal administration. In specific embodiments, transdermal formulations utilize transdermal delivery devices and transdermal delivery patches, and may be lipophilic emulsions or buffered aqueous solutions dissolved and / or dispersed in polymers or adhesives. In various embodiments, such patches are constructed for continuous, pulsatile, or on-demand delivery of drugs. In additional embodiments, transdermal delivery of one or more polymorphs of Compound A is achieved by iontophoretic patches and the like. In certain embodiments, transdermal patches provide controlled delivery of one or more polymorphs of Compound A. In specific embodiments, the absorption rate is slowed by using a rate-limiting membrane or by trapping the compound within a polymer matrix or gel. In alternative embodiments, absorption enhancers are used to enhance absorption. Absorption enhancers or carriers include absorbable pharma- ceutically acceptable solvents that aid passage through the skin. For example, in one embodiment, the transdermal device is in the form of a bandage that includes a backing, a reservoir containing the compound, optionally with a carrier, and optionally a rate-limiting barrier for delivering the compound to the host's skin at a controlled and predetermined rate over an extended period of time, and a means for securing the device to the skin.

[0150] In other embodiments, one or more polymorphs of Compound A are formulated for administration by inhalation. Various forms suitable for administration by inhalation include, but are not limited to, aerosol, mist, or powder. Pharmaceutical compositions of polymorphs of Compound A are conveniently delivered in the form of providing an aerosol spray from a pressurized pack or nebulizer with the use of a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas). In specific embodiments, the dosage unit of the pressurized aerosol is determined by providing a valve to deliver a metered amount. In certain embodiments, by way of example only, capsules and cartridges of gelatin for use in an inhaler or insufflator are formulated containing a powder mix of the compound and a suitable powder base, such as lactose or starch.

[0151] In yet other embodiments, one or more polymorphs of Compound A are formulated in rectal compositions, such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone or PEG. In suppository forms of the composition, a low melting wax, including, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter, is first melted.

[0152] In certain embodiments, pharmaceutical compositions are formulated in any conventional manner using one or more physiologically acceptable carriers, including excipients and auxiliaries that facilitate the processing of active polymorphs into pharma-ceutically usable preparations.Appropriate formulations depend on the route of administration selected.Any pharma-ceutically acceptable technical product, carrier, and excipient are optionally used as appropriate.The pharmaceutical compositions containing one or more polymorphs of compound A are prepared in a conventional manner, such as by conventional mixing, dissolving, granulating, dragee-making, wet milling, emulsifying, encapsulating, entrapping, or compressing processes, for example only.

[0153] The pharmaceutical composition comprises at least one pharma- ceutically acceptable carrier, diluent, or excipient, and at least one polymorph of Compound A described herein as an active ingredient. The active ingredient is in the form of a free acid or free base, or in the form of a pharma- ceutical acceptable salt. All tautomers of the compounds described herein are included within the scope of the compounds presented herein. In addition, the compounds described herein include unsolvated forms as well as solvated forms with pharma- ceutical acceptable solvents, such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein. In addition, the pharmaceutical composition optionally includes other medicinal or pharmaceutical agents, such as preservatives, stabilizers, wetting agents, or emulsifiers, carriers, adjuvants, solution promoters, salts for regulating osmotic pressure, buffers, and / or other therapeutically valuable substances.

[0154] The method of preparing a pharmaceutical composition comprising one or more polymorphs of Compound A described herein comprises formulating the polymorphs with one or more inert, pharma- ceutically acceptable excipients or carriers to form a solid, semi-solid, or liquid. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include solutions in which the compound is dissolved, emulsions containing the compound, or solutions containing liposomes, micelles, or nanoparticles containing the compounds disclosed herein. Semi-solid compositions include, but are not limited to, gels, suspensions, and creams. The forms of the pharmaceutical compositions described herein include liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to use, or emulsions. These compositions also optionally contain small amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and the like.

[0155] In some embodiments, the pharmaceutical composition comprising at least one polymorph of compound A is illustratively in the form of a liquid in which the drug is in solution, in suspension, or both. Typically, when the composition is administered as a solution or suspension, a first portion of the drug is in solution, and a second portion of the drug is in particulate form in suspension in the liquid matrix of the suspension. In some embodiments, the liquid composition comprises a gel formulation. In other embodiments, the liquid composition is aqueous.

[0156] In certain embodiments, useful aqueous suspensions contain one or more polymers as suspending agents.Useful polymers include water-soluble polymers such as cellulosic polymers, e.g., hydroxypropylmethylcellulose, and water-insoluble polymers such as cross-linked carboxyl-containing polymers.Specific pharmaceutical compositions described herein include mucoadhesive polymers, e.g., selected from carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methyl methacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate, and dextran.

[0157] Useful pharmaceutical compositions also optionally include a solubilizing agent to aid in the solubility of polymorphs of Compound A. The term "solubilizing agent" generally includes agents that result in a micellar solution or a true solution of the drug. Certain acceptable non-ionic surfactants, e.g., polysorbate 80, are useful as solubilizing agents, as are ophthalmically acceptable glycols, polyglycols, e.g., polyethylene glycol 400, and glycol ethers.

[0158] In addition, useful pharmaceutical compositions optionally include one or more pH adjusting or buffering agents, including acids such as acetic acid, boric acid, citric acid, lactic acid, phosphoric acid, and hydrochloric acid, bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, and tris-hydroxymethylaminomethane, and buffers such as citrate / dextrose, sodium bicarbonate, and ammonium chloride. Such acids, bases, and buffers are included in amounts necessary to maintain the pH of the composition in an acceptable range.

[0159] Additionally, useful compositions also optionally contain one or more salts in an amount necessary to bring the osmolality of the composition into an acceptable range.Such salts include salts having sodium, potassium, or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, or bisulfite anions, with suitable salts including sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate.

[0160] Other useful pharmaceutical compositions optionally contain one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as merfen and thiomersal, stabilized chlorine dioxide, and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridinium chloride.

[0161] Still other useful compositions contain one or more surfactants to enhance physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, such as polyoxyethylene (60) hydrogenated castor oil, and polyoxyethylene alkyl ethers and alkyl phenyl ethers, such as Octoxynol 10, Octoxynol 40.

[0162] Yet other useful compositions optionally contain one or more antioxidants to enhance chemical stability. Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite.

[0163] In certain embodiments, aqueous suspension compositions are packaged in single-dose non-reclosable containers. Alternatively, multi-dose reclosable containers are used, in which case it is typical to include a preservative in the composition.

[0164] In alternative embodiments, other delivery systems for hydrophobic pharmaceutical compounds are used. Liposomes and emulsions are examples of delivery vehicles or carriers useful herein. In certain embodiments, organic solvents such as N-methylpyrrolidone are also utilized. In additional embodiments, the polymorphs described herein are delivered using sustained release systems, such as semipermeable matrices of solid hydrophobic polymers containing therapeutic agents. A variety of sustained release materials are useful herein. In some embodiments, sustained release capsules release the polymorphs for several weeks, up to 100 days. Depending on the chemical nature and biological stability of the therapeutic reagent, additional strategies for protein stabilization are employed.

[0165] In certain embodiments, the formulations described herein contain one or more antioxidants, metal chelators, thiol-containing compounds, and / or other general stabilizing agents. Examples of such stabilizers include, but are not limited to, (a) about 0.5% to about 2% w / v glycerol, (b) about 0.1% to about 1% w / v methionine, (c) about 0.1% to about 2% w / v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w / v ascorbic acid, (f) 0.003% to about 0.02% w / v polysorbate 80, (g) 0.001% to about 0.05% w / v polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrin, (l) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc, or (n) combinations thereof.

[0166] VI. Route of Administration Suitable administration routes include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, mucosal, transdermal, vaginal, auricular, nasal, and topical.In addition, parenteral delivery herein includes intramuscular, subcutaneous, intravenous, intramedullary, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.

[0167] In certain embodiments, the polymorph of Compound A is administered locally rather than systemically, for example, by injecting the polymorph directly into an organ, often in a depot preparation or sustained release formulation. In certain embodiments, the long-acting formulation is administered by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, liposomes coated with an antibody specific for the organ. In such embodiments, the liposomes are targeted to and selectively taken up by the organ. In still other embodiments, the polymorph of Compound A is provided in the form of a rapid release formulation, a long-term release formulation, or an intermediate release formulation. In still other embodiments, the polymorph of Compound A is administered locally.

[0168] VII. Kits / Manufactured Products Kits and articles of manufacture are also provided for use in the therapeutic applications described herein.In some embodiments, such kits include a carrier, package, or container that is compartmentalized to receive one or more containers, such as vials or tubes, each of which contains one of the separate elements that will be used in the methods described herein.Suitable containers include, for example, bottles, vials, syringes, and test tubes.Containers are formed from a variety of materials, such as glass and plastic.

[0169] The articles of manufacture provided herein include packaging materials. Packaging materials for use in packaging pharmaceutical products include, for example, those found in U.S. Patent Nos. 5,323,907, 5,052,558, and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for the selected formulation and intended mode of administration and treatment. For example, a container contains one or more polymorphs described herein, optionally in a composition or in combination with another drug disclosed herein. The container optionally has a sterile access port (e.g., the container is an intravenous solution bag or vial with a stopper that can be penetrated by a hypodermic needle). Such kits optionally contain the compound together with an identifying description, label, or instructions related to the use of the kit in the methods described herein.

[0170] For example, the kit typically includes one or more additional containers, each of which has one or more of various materials (such as reagents, optionally in concentrated form, and / or devices) that are desirable from a commercial and user perspective in the use of the compounds described herein. Non-limiting examples of such materials include, but are not limited to, buffers, diluents, filters, needles, syringes, carriers, packages, containers, vials, and / or tube labels that list the contents and / or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included. The label is optionally on or associated with the container. For example, the label is on the container when the letters, numbers, or other characters that form the label are attached, molded, or engraved on the container itself, and the label is associated with the container when it is present, for example, as a package insert, in a receptacle or carrier that also holds the container. In addition, the label is used to indicate that the contents should be used for a particular therapeutic application. In addition, the label indicates instructions for the use of the contents, such as in the methods described herein. In certain embodiments, the pharmaceutical composition is provided in a pack or dispenser device that contains one or more unit dosage forms containing the compound provided herein. The pack includes, for example, metal or plastic foil, such as a blister pack. Alternatively, the pack or dispenser device is accompanied by instructions for administration. Alternatively, the pack or dispenser is accompanied by a notice attached to the container in a manner prescribed by a government agency that regulates the manufacture, use, or sale of pharmaceuticals, which notice reflects the approval by the government agency of the drug form for human or veterinary administration. Such notice is, for example, a label approved by the U.S. Food and Drug Administration for prescriptions, or an approved product insert. In some embodiments, a composition containing a polymorph of Compound A formulated in a compatible pharmaceutical carrier is prepared, placed in a suitable container, and labeled for the treatment of an indication. EXAMPLES

[0171] The following examples will serve to more fully describe the manner of using the present invention. These examples are presented for illustrative purposes and do not serve to limit the true scope of the invention.

[0172] It should be understood that references to specific buffers, media, reagents, cells, culture conditions, and the like in carrying out the procedures of the methods described herein are not intended to be limiting, but should be read to include all relevant material that a person skilled in the art would recognize as being of interest or value in the particular context in which the discussion is presented. For example, it is often possible to replace one buffer system or culture medium with another and still achieve similar, if not identical, results. Those skilled in the art will have sufficient knowledge of such systems and methods to be able to make substitutions that best serve their purposes when using the methods and procedures disclosed herein without undue experimentation.

[0173] The polymorphs described herein can be synthesized from commercially available starting materials and reagents using techniques well known in the art. For example, the polymorphs described herein can be prepared as illustrated below with reference to the Examples and Reaction Schemes.

[0174] Bufalin can be obtained from the skin glands of the Asian toad or Bufo bufo and is commercially available, for example, from Sigma-Aldrich Corp. (St. Louis, Mo.) Other reagents are commercially available, for example, from Sigma-Aldrich Corp. or can be readily prepared by one of skill in the art using commonly employed synthetic methods.

[0175] The polymorphs described herein may be prepared in substantially pure form, typically by standard chromatographic methods, prior to formulation in a pharma- ceutically acceptable form.

[0176] The following abbreviations and terms have the indicated meanings throughout this specification. AcOH = acetic acid Boc = tert-butoxycarbonyl c-=cyclo DCC = dicyclohexylcarbodiimide DCM = dichloromethane DIPEA = N,N-diisopropylethylamine DMAP = 4-dimethylaminopyridine EDC = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide eq = equivalents (plural) Et = ethyl EtOAc or EA = ethyl acetate EtOH = ethanol g = grams h or hr = hours HBTU=O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate HOBt = hydroxybenzotriazole HPLC = High Pressure Liquid Chromatography i-=iso kg or Kg = Kilograms L or l = liters LC / MS = Liquid Chromatography Mass Spectrometry LRMS=low resolution mass spectrometry m / z=mass-to-charge ratio Me = methyl MeOH = methanol mg = milligrams min=minutes mL = milliliters mmol = millimolar n-=normal NaOAc = Sodium Acetate PE=petroleum ether Ph = phenyl Prep quant.=quantitative RP-HPLC = Reversed Phase High Pressure Liquid Chromatography rt or RT = room temperature s-=sec-=secondary t-=tert-=tertiary THF = tetrahydrofuran TLC = Thin Layer Chromatography UV=ultraviolet light

[0177] Example 1: Preparation of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate (Compound A)

[0178] [ka]

[0179] Step 1: To a solution of bufalin (60 mg, 0.15 mmol) and DMAP (16.8 mg, 0.15 mmol) in CHCl (10 mL) was added DIPEA (77.5 mg, 0.6 mmol) and 4-nitrophenyl carbonochloridate (60.6 mg, 0.3 mmol). The mixture was stirred at 37° C. for 16 h and then purified by preparative TLC (PE / EA=1:1) to give (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl 4-nitrophenyl carbonate as a white solid (72 mg, 87.1%).

[0180] Step 2: To a solution of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl 4-nitrophenyl carbonate (29 mg, 0.054 mmol) in CHCl was added piperazine (46.4 mg, 0.54 mmol). The resulting mixture was stirred at room temperature for 16 hours and then purified by preparative TLC to give (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate (18.6 mg, 69.2%) as a white solid. LRMS (M+H + ) m / z 499.5. 1 H NMR(CD3OD,400MHz)δ7.90(dd,J=9.6,2.4Hz,1H),7.33(m,1H),6.18(d,J=9.6Hz,1H),4.89(m,1H) ,3.41(m,4H),2.77-2.80(m,4H),2.44-2.48(m,1H),1.08-2.15(m,21H),0.88(s,3H),0.62(s,3H).

[0181] Example 2. Preparation of crystalline form I of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate maleate (maleate salt of compound A) A solution of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate (2.4 g, 4.81 mmol) in EtOH (120 mL) was stirred at 70 °C for 1 h. A solution of maleic acid in EtOH (21.6 mL, 0.25 M) was added slowly with stirring. The mixture was stirred at 70 °C for about 1.5 h. The suspension was cooled to room temperature and stirred for 15-16 h. The precipitate was filtered, washed with EtOH, and dried under vacuum at room temperature to give crystalline form I of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate maleate.

[0182] Example 3. Preparation of Crystalline Form II of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate maleate (Maleate Salt of Compound A) (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate (1 g, 2 mmol) was dissolved in 90 mL of isopropyl alcohol (IPA) at room temperature. A solution of maleic acid (0.252 g, 2.2 mmol) in IPA (5 mL) was added. The mixture was stirred at room temperature overnight. The precipitate was filtered, washed twice with IPA, and dried in a vacuum oven at 35° C. overnight to give (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate maleate crystalline form II.

[0183] Example 4. X-ray powder diffraction (XRPD) X-ray powder diffraction (XRPD) patterns were obtained on a Bruker D8 Advance, scanning each sample between 3° and 40° 2-theta with a CuK source (=1.54179 Å) operated at 40 kV and 40 mA minimum. The scan rate was 10° 2-theta per minute, and the sample rotation rate was 15 revolutions per minute.

[0184] The XRPD pattern obtained for crystalline Form I of the maleate salt of Compound A is summarized in Table 1 and FIG.

[0185] [Table 1]

[0186] The XRPD pattern obtained for crystalline Form II of the maleate salt of Compound A is summarized in Table 2 and FIG.

[0187] [Table 2]

[0188] Example 5. Thermogravimetric Analysis (TGA) Thermogravimetric analysis was performed on a TA Instruments TGA unit (Q5000IR). Samples were heated in aluminum pans from ambient temperature to 300° C. at 10° C. / min. The TGA pattern obtained for crystalline Form I of the maleate salt of Compound A is summarized in FIG. 3. The TGA pattern obtained for crystalline Form II of the maleate salt of Compound A is summarized in FIG. 6.

[0189] The TGA patterns obtained for the crystalline form of the maleate salt of Compound A are summarized in the table below.

[0190] [Table 3]

[0191] Example 6. Differential Scanning Calorimetry (DSC) Differential scanning calorimetry analysis was performed on a TA Instruments DSC unit (TA Q2000). Samples were heated in non-hermetic aluminum pans from ambient temperature to 260° C. at 10° C. / min. The DSC thermogram obtained for crystalline Form I of the maleate salt of Compound A is summarized in FIG. 2. The DSC thermogram obtained for crystalline Form II of the maleate salt of Compound A is summarized in FIG. 5.

[0192] The DSC thermograms obtained for the crystalline form of the maleate salt of Compound A are summarized in the table below.

[0193] [Table 4]

[0194] Example 7. Stability study of crystalline form I Crystalline form I remained unchanged after storage at 40°C / 75% RH for 6 months or at 25°C / 60% RH for 36 months. The results of crystalline form I in accelerated long-term stability studies are shown in Table 3 and Figures 7-10.

[0195] [Table 5]

[0196] Although several embodiments have been shown and described, various modifications and substitutions may be made to the present invention without departing from the spirit and scope of the present invention. For example, for the purpose of claim construction, the claims set forth below are not intended to be interpreted narrower than their literal language, and thus, the exemplary embodiments from this specification are not intended to be read in the sense of the claims. Therefore, it should be understood that the present invention has been described by way of example and is not limited to the scope of the claims.

Claims

1. (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate maleate (maleate salt of compound A): 【Chemistry 1】 or a pharma- ceutically acceptable solvate or hydrate thereof.

2. Crystalline (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate maleate (Compound A maleate salt): 【Chemistry 2】 or a pharma- ceutically acceptable solvent or hydrate thereof.

3. The crystalline maleate salt of Compound A is in crystalline form I, said crystalline form I comprising: (a) an X-ray powder diffraction pattern including peaks at 13.8±0.2° 2-θ, 19.5±0.2° 2-θ, and 10.3±0.2° 2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å; (b) an X-ray powder diffraction pattern substantially the same as that shown in FIG. (c) a differential scanning calorimetry (DSC) thermogram containing an endotherm in the range of about 230-240° C.; (d) a differential scanning calorimetry (DSC) thermogram containing an endotherm with an onset of about 234° C. and a peak at about 238° C.; (e) a differential scanning calorimetry (DSC) thermogram substantially the same as that shown in FIG. (f) a thermogravimetric analysis (TGA) thermogram substantially the same as that shown in FIG. (g) XRPD unchanged after storage for 6 months at 40° C. and 75% relative humidity (RH); (h) XRPD unchanged after storage for 36 months at 25° C. and 60% relative humidity (RH); or (i) Combinations thereof 3. The crystalline (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate maleate of claim 2, characterized by:

4. The crystalline (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate maleate, or a pharma- ceutically acceptable solvent or hydrate thereof, of claim 2, wherein crystalline Form I is characterized by an X-ray powder diffraction pattern comprising peaks at 13.8±0.2°2-θ, 19.5±0.2°2-θ, and 10.3±0.2°2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å, or an X-ray powder diffraction pattern substantially the same as that shown in FIG.

5. The crystalline (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate maleate, or a pharma- ceutically acceptable solvent or hydrate thereof, of claim 3 or 4, wherein crystalline Form I is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm having an onset of about 234°C and a peak at about 238°C, or a differential scanning calorimetry (DSC) thermogram substantially the same as that shown in Figure 2, and optionally said crystalline Form I is further characterized by a thermogravimetric analysis (TGA) thermogram substantially the same as that shown in Figure 3.

6. The crystalline form is crystalline form II, wherein said crystalline form II is (a) an X-ray powder diffraction pattern including peaks at 14.3±0.2° 2-θ, 20.1±0.2° 2-θ, and 15.2±0.2° 2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å; (b) an X-ray powder diffraction pattern substantially the same as that shown in FIG. (c) i) an endotherm in the range of about 75-100° C.; ii) an endotherm in the range of about 195-210° C., and iii) an endotherm in the range of 215 to 235° C. A differential scanning calorimetry (DSC) thermogram comprising: (d) i) an endotherm with an onset of about 77° C. and a peak at about 94° C.; ii) an endotherm with an onset of about 202° C. and a peak at about 205° C.; and iii) an endotherm with an onset of about 220° C. and a peak at about 230° C. A differential scanning calorimetry (DSC) thermogram comprising: (e) a differential scanning calorimetry (DSC) thermogram substantially the same as that shown in FIG. (f) a thermogravimetric analysis (TGA) thermogram substantially the same as that shown in FIG. 6; or (g) Combinations thereof 3. The crystalline (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate maleate of claim 2, characterized by:

7. The crystalline (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate maleate, or a pharma- ceutically acceptable solvent or hydrate thereof, of claim 6, wherein the crystalline form II is characterized by an X-ray powder diffraction pattern comprising peaks at 14.3±0.2°2-θ, 20.1±0.2°2-θ, and 15.2±0.2°2-θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54179 Å, or an X-ray powder diffraction pattern substantially the same as that shown in FIG.

8. A pharmaceutical composition comprising the crystalline (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate maleate according to any one of claims 2 to 7, and at least one pharma- ceutically acceptable excipient.

9. Use of crystalline (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate maleate according to any one of claims 2 to 7, or the pharmaceutical composition according to claim 8, in the manufacture of a medicament for treating a neoplasm in a subject in need of such treatment.

10. The use of claim 9, wherein the neoplasm is cancer.

11. The cancer is selected from the group consisting of head and neck cancer, brain tumor, colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chondroma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovium, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchial carcinoma, renal cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung cancer, small cell lung cancer, bladder cancer, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, and craniopharynx tumor.

11. The use according to claim 10, wherein the cancer is selected from the group consisting of cranioma, ependymoma, pinealoma, hemangioblastoma, otocytoma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemia, such as acute lymphocytic leukemia and acute myelocytic leukemia (myeloblastic, promyelocytic, myelomonocytic, monocytic and erythroleukemia), chronic leukemia (chronic myelocytic (granulocytic) leukemia and chronic lymphocytic leukemia), and polycythemia vera, lymphoma (Hodgkin's disease and non-Hodgkin's disease), multiple myeloma, Waldenstrom's macroglobulinemia and heavy chain disease, preferably wherein the cancer is colorectal cancer, liver cancer, lung cancer, breast cancer, oral cancer, head and neck cancer or brain cancer.

12. A process for preparing crystalline form I of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate maleate, comprising the steps of: (a) contacting (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate with maleic acid in a solvent to obtain a solution of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate maleate; (b) crystallizing the solution obtained in step (a) to obtain crystalline form I of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate maleate. The method includes:

13. The method of claim 12, wherein the solvent in step (a) comprises ethyl acetate, DCM, ethanol, or isopropanol, preferably ethanol; Step (a) is carried out at a temperature of about 60-90° C., preferably at a temperature of about 70° C.; step (a) is carried out for a period of about 1 to 3 hours, preferably for a period of about 1.5 hours; step (b) comprises lowering the temperature of the solution obtained in step (a) to a temperature of about 20-25° C.; Optionally, the method further comprises: obtaining said crystalline form I by filtering the crystallization solution obtained in step (b); and 13. The process according to claim 12, further comprising the step of drying the obtained crystalline form I, preferably wherein said drying step is carried out under vacuum at a temperature of about 20-25°C.

14. A process for preparing crystalline form II of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate maleate, comprising the steps of: (a) contacting (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate with maleic acid in a solvent to obtain a solution of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate maleate; (b) crystallizing the solution obtained in step (a) to obtain crystalline form II of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate maleate. The method includes:

15. The method of claim 1, wherein the solvent in step (a) comprises ethyl acetate, DCM, ethanol, or isopropanol, preferably isopropanol; Step (a) is carried out at a temperature of about 20-25° C.; step (b) comprises stirring the solution obtained in step (a) overnight; Optionally, the method further comprises: filtering the crystallized solution obtained in step (b) to obtain crystalline form II; and 15. The method according to claim 14, further comprising the step of drying the obtained crystalline form II, preferably wherein said drying step is carried out under vacuum at 35°C.

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