Crystalline forms of a heterobifunctional compound and methods of treating disease

Abstract

The invention provides crystalline forms of a heterobifunctional compound, including crystalline forms comprising a solvent, pharmaceutical compositions, and their use treating disease, such as cancer.

Description

Attorney Docket No. 143839-5029-WOCRYSTALLINE FORMS OF A HETEROBIFUNCTIONAL COMPOUND AND METHODS OF TREATING DISEASECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to International (PCT) Patent Application serial number PCT / CN2025 / 089543, filed April 17, 2025, the contents of which are hereby incorporated by reference in their entirety.FIELD OF THE INVENTION

[0002] The invention provides crystalline forms of a heterobifunctional compound, including crystalline forms comprising a solvent, pharmaceutical compositions, and their use treating disease, such as cancer.BACKGROUND

[0003] Cancer continues to be a significant health problem despite the substantial research efforts and scientific advances reported in the literature for treating this disease. Solid tumors, including prostate cancer, breast cancer, and lung cancer remain highly prevalent among the world population. The incidence of prostate cancer increases with age, and with increasing longevity of human subjects, there continues to be a corresponding rise in the number of patients suffering from prostate cancer. Breast cancer is one of the most common cancers among women and is a leading cause of death for women between ages 50-55. Lung cancer is a leading cause of death among cancer patients, where over 85% of lung cancers are non-small cell lung cancer (NSCLC). Many lung cancers are attributed to tobacco smoking. Current treatment options for these cancers are not effective for all patients and / or can have substantial adverse side effects.

[0004] New therapies are needed to address this unmet need in cancer therapy. In particular, new therapies are needed that achieve an anti -cancer effect through a different mechanism than commonly available therapies. Exemplary mechanisms for common anti -cancer therapies include (a) alkylation of DNA which limits ability of the cell to reproduce, (b) topoisomerase inhibition, in which the therapeutic agent inhibits the activity of a topoisomerase thereby limiting separation of strands of DNA, and (c) mitotic inhibition, where the therapeutic agent reduces ability of the cell to divide. New therapies that achieve an anti-cancer effect through a different mechanismpresent an opportunity to treat cancers more effectively and / or to treat cancers that have become resistant to currently available medicines.

[0005] The present invention addresses the foregoing needs and provides other related advantages.SUMMARY

[0006] The invention provides crystalline forms of a heterobifunctional compound, including crystalline forms comprising a solvent, pharmaceutical compositions, and their use treating disease, such as cancer. In particular, one aspect of the invention provides a compound of Formula II-5 in crystalline form:(II-5).In certain embodiments, the crystalline form further comprises a solvent. The compound may be part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.

[0007] Another aspect of the invention provides a method of treating cancer. The method comprises administering to a patient in need thereof a therapeutically effective amount of a compound described herein to treat the cancer.

[0008] Another aspect of the invention provides a method of causing death of a cancer cell. The method comprises contacting a cancer cell with an effective amount of a compound described herein to cause death of the cancer cell.BRIEF DESCRIPTION OF THE DRAWINGS

[0009] Figure 1 depicts an X-ray powder diffractogram of Compound II- 5 in Crystal Form A, as further described in Example 3.

[0010] Figure 2 depicts a differential scanning calorimetry curve of Compound II-5 in Crystal Form A, as further described in Example 3.

[0011] Figure 3 depicts a thermogravimetric analysis curve of Compound II-5 in Crystal Form A, as further described in Example 3.

[0012] Figure 4 is graph showing cell viability as a function of dose of Compound II-5, as further described in Example 26.

[0013] Figure 5 is a graph that shows the relative total amount of cMYC mRNA present in tumors collected at the end of the PK / PD Aramp, V7+Castrate VcaP Model, for different dose amounts of Compound II-5, as further described in Example 30.

[0014] Figure 6 is a graph that shows the relative total amount of HEXIM1 mRNA present in tumors collected at the end of the PK / PD Aramp, V7+Castrate VcaP Model, for each of the different dose amounts of Compound II-5, as further described in Example 30.

[0015] Figure 7 is a graph that shows the relative total amount of TXNIP mRNA present in tumors collected at the end of the PK / PD Aramp, V7+Castrate VcaP Model, for each of the different dose amounts of Compound II-5, as further described in Example 30.

[0016] Figure 8 is a graph that showing tumor growth in mice treated with either Compound II-5, Compound A, or vehicle, as further described in Example 30.

[0017] Figure 9 is a waterfall plot that shows change in size of tumors at the end of study relative to baseline in mice treated with either Compound II-5, Compound A, or vehicle, as further described in Example 30.

[0018] Figure 10 is a graph that shows PSA plasma levels determined in mice at the end of the study treated with either Compound II-5, Compound A, or vehicle, as further described in Example 30.

[0019] Figure 11 is a graph showing tumor volume in mice treated with (i) vehicle, (ii) Compound II- 5 according to a first dosing regimen in which the dosing frequency was the same as that used for vehicle and for Compound A, (iii) Compound II- 5 according to a second dosing regimen in which the dosing frequency was twice as often as that used for vehicle and for Compound A, or (iv) Compound A, as further described in Example 31

[0020] Figure 12 is a waterfall plot that shows change in size of tumors at the end of study relative to baseline in mice treated with (i) vehicle, (ii) Compound II- 5 according to a first dosing regimen in which the dosing frequency was the same as that used for vehicle and for CompoundA, (iii) Compound II-5 according to a second dosing regimen in which the dosing frequency was twice as often as that used for vehicle and for Compound A, or (iv) Compound A, as further described in Example 31.

[0021] Figure 13 is a graph that shows PSA plasma levels determined in mice at the end of the study treated with (i) vehicle, (ii) Compound II-5 according to a first dosing regimen in which the dosing frequency was the same as that used for vehicle and for Compound A, (iii) Compound II- 5 according to a second dosing regimen in which the dosing frequency was twice as often as that used for vehicle and for Compound A, or (iv) Compound A, as further described in Example 31.

[0022] Figure 14 depicts an X-ray powder diffractogram of Compound II-5 in Crystal Form B, as further described in Example 5.

[0023] Figure 15 depicts a differential scanning calorimetry curve of Compound II- 5 in Crystal Form B, as further described in Example 5.

[0024] Figure 16 depicts a thermogravimetric analysis curve of Compound II-5 in Crystal Form B, as further described in Example 5.

[0025] Figure 17 depicts an X-ray powder diffractogram of Compound II-5 in Crystal Form Cl, as further described in Example 7.

[0026] Figure 18 depicts a differential scanning calorimetry curve of Compound II-5 in Crystal Form Cl, as further described in Example 7.

[0027] Figure 19 depicts a thermogravimetric analysis curve of Compound II-5 in Crystal Form Cl, as further described in Example 7.

[0028] Figure 20 depicts an X-ray powder diffractogram of Compound II-5 in Crystal Form C2, as further described in Example 9.

[0029] Figure 21 depicts a differential scanning calorimetry curve of Compound II- 5 in Crystal Form C2, as further described in Example 9.

[0030] Figure 22 depicts a thermogravimetric analysis curve of Compound II-5 in Crystal Form C2, as further described in Example 9.

[0031] Figure 23 depicts an X-ray powder diffractogram of Compound II-5 in Crystal Form C3, as further described in Example 11.

[0032] Figure 24 depicts a differential scanning calorimetry curve of Compound II- 5 in Crystal Form C3, as further described in Example 11.

[0033] Figure 25 depicts a thermogravimetric analysis curve of Compound II-5 in Crystal Form C3, as further described in Example 11.

[0034] Figure 26 depicts an X-ray powder diffractogram of Compound II-5 in Crystal Form D, as further described in Example 13.

[0035] Figure 27 depicts a differential scanning calorimetry curve of Compound II- 5 in a mixture of Crystal Form D and Crystal Form A, as further described in Example 13.

[0036] Figure 28 depicts a thermogravimetric analysis curve of Compound II-5 in mixture of Crystal Form D and Crystal Form A, as further described in Example 13.

[0037] Figure 29 depicts an X-ray powder diffractogram of Compound II-5 in Crystal Form E, as further described in Example 15.

[0038] Figure 30 depicts a differential scanning calorimetry curve of Compound II-5 in Crystal Form E, as further described in Example 15.

[0039] Figure 31 depicts a thermogravimetric analysis curve of Compound II-5 in Crystal Form E, as further described in Example 15.

[0040] Figure 32 depicts an X-ray powder diffractogram of Compound II-5 in Crystal Form F, as further described in Example 17.

[0041] Figure 33 depicts an X-ray powder diffractogram of Compound II-5 in Crystal Form G, as further described in Example 19.

[0042] Figure 34 depicts a differential scanning calorimetry curve of Compound II- 5 in Crystal Form G, as further described in Example 19.

[0043] Figure 35 depicts a thermogravimetric analysis curve of Compound II-5 in Crystal Form G, as further described in Example 19.

[0044] Figure 36 depicts an X-ray powder diffractogram of Compound II-5 in Crystal Form H, as further described in Example 21.

[0045] Figure 37 depicts a differential scanning calorimetry curve of Compound II- 5 in Crystal Form H, as further described in Example 21.

[0046] Figure 38 depicts a thermogravimetric analysis curve of Compound II-5 in Crystal Form H, as further described in Example 21.

[0047] Figure 39 depicts an X-ray powder diffractogram of Compound II-5 in Crystal Form I, as further described in Example 23.

[0048] Figure 40 depicts an X-ray powder diffractogram of Compound II-5 in Crystal Form J, as further described in Example 25.DETAILED DESCRIPTION

[0049] The invention provides heterobifunctional compounds, pharmaceutical compositions, and their use treating disease, such as cancer. The practice of the present invention employs, unless otherwise indicated, conventional techniques of organic chemistry, pharmacology, molecular biology (including recombinant techniques), cell biology, biochemistry, and immunology. Such techniques are explained in the literature, such as in “Comprehensive Organic Synthesis” (B. M. Trost & I. Fleming, eds., 1991-1992); “Handbook of experimental immunology” (D. M. Weir & C. C. Blackwell, eds ); “Current protocols in molecular biology” (F. M. Ausubel etal., eds., 1987, and periodic updates); and “Current protocols in immunology” (J. E. Coligan etal., eds., 1991), each of which is herein incorporated by reference in its entirety.

[0050] Various aspects of the invention are set forth below in sections; however, aspects of the invention described in one particular section are not to be limited to any particular section. Further, when a variable is not accompanied by a definition, the previous definition of the variable controls.Definitions

[0051] Compounds of the present invention include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. These definitions apply regardlessof whether a term is used by itself or in combination with other terms, unless otherwise indicated. Hence, the definition of “alkyl” applies to “alkyl” as well as the “alkyl” portions of O-alkyl” etc. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5thEd., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0052] Unless otherwise stated or specifically depicted, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers.Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. The invention includes compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a13C- or14C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.

[0053] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to those skilled in the art, such as, for example, by chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Alternatively, a particular enantiomer of a compound of the present invention may be prepared by asymmetric synthesis. Still further, where the molecule contains a basic functional group (such as amino) or an acidic functional group (such as carboxylic acid) diastereomeric salts are formed with an appropriate opticallyactive acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means known in the art, and subsequent recovery of the pure enantiomers.

[0054] Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. In certain embodiments, compounds of the invention have a molar purity of >85%, >90%, >95%, >97%, >98%, >99%, >99.5%, or >99.9% of the depicted stereoisomer relative to all other stereoisomers of the compound. Chiral center(s) in a compound of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. Further, to the extent a compound described herein may exist as an atropisomer (e.g., substituted biaryls), all forms of such atropisomer are considered part of this invention.

[0055] Chemical names, common names, and chemical structures may be used interchangeably to describe the same structure. If a chemical compound is referred to using both a chemical structure and a chemical name, and an ambiguity exists between the structure and the name, the structure predominates. It should also be noted that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences.

[0056] The terms “a” and “an” as used herein mean “one or more” and include the plural unless the context is inappropriate.

[0057] Unless otherwise stated, the term “about” refers to within ±10% of the stated value. In certain embodiments, the term “about” refers to within ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1% of the stated value.

[0058] One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. Unless otherwise stated, it is intended that the invention embrace both solvated and unsolvated forms. “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of thecrystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Nonlimiting examples of suitable solvates include ethanolates, methanolates, and the like. “Hydrate” is a solvate wherein the solvent molecule is H2O.

[0059] As used herein, the terms “subject” and “patient” are used interchangeably and refer to organisms to be treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like), and most preferably includes humans.

[0060] The term “IC50” is art-recognized and refers to the concentration of a compound that is required to achieve 50% inhibition of the target.

[0061] As used herein, the term “effective amount” refers to the amount of a compound sufficient to effect beneficial or desired results (e.g., a therapeutic, ameliorative, inhibitory or preventative result). An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route. As used herein, the term “treating” includes any effect, e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof.

[0062] As used herein, the term “pharmaceutical composition” refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.

[0063] As used herein, the term “pharmaceutically acceptable carrier” refers to any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, emulsions (e.g., such as an oil / water or water / oil emulsions), and various types of wetting agents. The compositions also can include stabilizers and preservatives. For examples of carriers, stabilizers and adjuvants, see e.g., Martin, Remington’s Pharmaceutical Sciences, 17th Ed., Mack Publ. Co., Easton, PA

[1975] ,

[0064] Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions of the present invention that consist essentially of, or consist of, the recitedcomponents, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.

[0065] As a general matter, compositions specifying a percentage are by weight unless otherwise specified.I. Crystalline Forms of the Compound of Formula II-5

[0066] The invention provides crystalline forms ofN-[(lr,3r)-3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro [3.5]nonan-7-yl]pyrimidine-5-carboxamide (i.e., the Compound of Formula II-5). The crystalline forms are described in more detail below, which includes certain crystalline forms that further comprise a solvent. The compounds may be used in the pharmaceutical compositions and therapeutic methods described herein. Exemplary crystalline forms are described in the following sections. Exemplary procedures for making the crystalline forms are described in the Examples.

[0067] One aspect of the invention provides a compound of Formula II-5 in crystalline form:(II-5).

[0068] The crystalline form may be characterized, for example, according to the presence, identity, and / or relative amount of a solvent in the crystalline form. For example, in certain embodiments, the crystalline form further comprises a solvent.

[0069] In certain embodiments, the solvent is one or more of the following: water, cyclopentyl methyl ether, 2-propanol, 1,4-dioxane, ethyl acetate, methanol, methyl isobutyl ketone, ethanol, acetone, or acetonitrile. In certain embodiments, the solvent is (i) water, (ii) an organic compound selected from cyclopentyl methyl ether, 2-propanol, 1,4-dioxane, ethyl acetate, methanol, methyl isobutyl ketone, ethanol, acetone, or acetonitrile, or (iii) a mixture ofwater and an organic compound selected from cyclopentyl methyl ether, 2-propanol, 1,4-dioxane, ethyl acetate, methanol, methyl isobutyl ketone, ethanol, acetone, or acetonitrile.

[0070] In certain embodiments, the solvent is water. In certain embodiments, any water is present at a molar ratio in the range ofabout 0.7:l to about 1.3:1 relative to the compound of Formula II-5.

[0071] In certain embodiments, the solvent is an organic compound selected from cyclopentyl methyl ether, 2-propanol, 1,4-di oxane, ethyl acetate, methanol, methyl isobutyl ketone, ethanol, acetone, or acetonitrile. In certain embodiments, the solvent is cyclopentyl methyl ether. In certain embodiments, the solvent is 2-propanol. In certain embodiments, the solvent is 1,4-dioxane. In certain embodiments, the solvent is ethyl acetate. In certain embodiments, the solvent is methanol. In certain embodiments, the solvent is methyl isobutyl ketone. In certain embodiments, the solvent is ethanol. In certain embodiments, the solvent is acetone. In certain embodiments, the solvent is acetonitrile.

[0072] In certain embodiments, the solvent is a mixture of water and one or more of the following organic compounds: cyclopentyl methyl ether, 2-propanol, 1,4-dioxane, ethyl acetate, methanol, methyl isobutyl ketone, ethanol, acetone, or acetonitrile. In certain embodiments, the solvent is a mixture of water and an organic compound selected from cyclopentyl methyl ether, 2-propanol, 1,4-dioxane, ethyl acetate, methanol, methyl isobutyl ketone, ethanol, acetone, or acetonitrile. In certain embodiments, the solvent is water and methanol. In certain embodiments, the solvent is water and ethanol. In certain embodiments, the solvent is water and 2-propanol. In certain embodiments, the solvent is water and 1,4-dioxane. In certain embodiments, the solvent is water and acetone. In certain embodiments, the solvent is water and acetonitrile.

[0073] In certain embodiments, the molar ratio of solvent relative to the compound of Formula II- 5 is about 0.1:1 to about 0.7:1. In certain embodiments, the molar ratio of solvent relative to the compound of Formula II- 5 is about 0.5:1. In certain embodiments, the molar ratio of solvent relative to the compound of Formula II-5 is about 0.7:1 to about 1.3:1. In certain embodiments, the molar ratio of solvent relative to the compound of Formula II-5 is about 1:1. In certain embodiments, the molar ratio of solvent relative to the compound of Formula II- 5 isabout 1.5:1 to about 2.5:1. In certain embodiments, the molar ratio of solvent relative to the compound of Formula II-5 is about 2:1.

[0074] In certain embodiments, the solvent is cyclopentyl methyl ether, wherein the solvent is present at a molar ratio of about 0.1: 1 to about 0.7:1 relative to the compound of Formula II-5. In certain embodiments, the solvent is cyclopentyl methyl ether, wherein the solvent is present at a molar ratio of about 0.3:1 relative to the compound of Formula II-5.

[0075] In certain embodiments, the solvent is 2-propanol, wherein the solvent is present at a molar ratio in the range of about 0.1: 1 to about 0.7:1 relative to the compound of Formula II-5. In certain embodiments, the solvent is 2-propanol, wherein the solvent is present at a molar ratio of about 0.4: 1 relative to the compound of Formula II-5.

[0076] In certain embodiments, the solvent is 1,4-dioxane, wherein the solvent is present at a molar ratio in the range of about 1.5:1 to about 2.5:1 relative to the compound of Formula II- 5. In certain embodiments, the solvent is 1,4-dioxane, wherein the solvent is present at a molar ratio of about 1.9:1 relative to the compound of Formula II- 5.

[0077] In certain embodiments, the solvent is water, wherein the solvent is present at a molar ratio in the range of about 0.7:1 to about 1.3:1 relative to the compound of Formula II-5. In certain embodiments, the solvent is water, wherein the solvent is present at a molar ratio of about 1.1:1 relative to the compound of Formula II-5.

[0078] In certain embodiments, the solvent is ethyl acetate, wherein the solvent is present at a molar ratio in the range of about 0.1:1 to about 0.7:1 relative to the compound of Formula II-5. In certain embodiments, the solvent is ethyl acetate, wherein the solvent is present at a molar ratio of about 0.5:1 relative to the compound of Formula II-5.

[0079] In certain embodiments, the solvent is a mixture of (i) methanol, wherein the methanol is present at a molar ratio in the range of about 1.5:1 to about 2.5:1 relative to the compound of Formula II-5, and (ii) water, wherein the water is present at a molar ratio in the range of about 0.7:1 to about 1.3:1 relative to the compound of Formula II-5. In certain embodiments, the solvent is a mixture of (i) methanol, wherein the methanol is present at a molar ratio of about 1.9:1 relative to the compound of Formula II-5, and (ii) water, wherein the water is present at a molar ratio of about 0.9: 1 relative to the compound of Formula II-5.

[0080] In certain embodiments, the solvent is methyl isobutyl ketone, wherein the solvent is present at a molar ratio in the range of about 0.7:1 to about 1.3:1 relative to the compound of Formula II-5. In certain embodiments, the solvent is methyl isobutyl ketone, wherein the solvent is present at a molar ratio of about 0.8:1 relative to the compound of Formula II- 5.

[0081] In certain embodiments, the solvent is a mixture of (i) ethanol, wherein the ethanol is present at a molar ratio in the range of about 1.5:1 to about 2.5:1 relative to the compound of Formula II-5, and (ii) water, wherein the water is present at a molar ratio in the range of about 0.7:1 to about 1.3:1 relative to the compound of Formula II-5. In certain embodiments, the solvent is a mixture of (i) ethanol, wherein the ethanol is present at a molar ratio of about 1.6:1 relative to the compound of Formula II-5, and (ii) water, wherein the water is present at a molar ratio of about 1.3:1 relative to the compound of Formula II-5.

[0082] In certain embodiments, the compound has a purity of greater than 98% by weight. In certain embodiments, the compound has a purity of greater than 99% by weight. In certain embodiments, the compound has a purity of greater than 99.5% by weight. In certain embodiments, the purity of the compound is determined by high-performance liquid chromatography (HPLC).Crystal Form Cl

[0083] In certain embodiments, the compound of Formula II- 5 in crystalline form is in Crystal Form Cl. As described above, in certain embodiments, the compound of Formula II- 5 in crystalline form further comprises a solvent. In certain embodiments, the solvent is cyclopentyl methyl ether. In certain embodiments, the solvent is cyclopentyl methyl ether, and the compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (20): 9.8 ± 0.2, 13.0 ± 0.2, 19.2 ± 0.2, 19.5 ± 0.2, 23.6 ± 0.2, 25.4 ± 0.2, and 25.5 ± 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at one or more of the following diffraction angles (29): 8.6 ± 0.2, 18.5 ± 0.2, and 25.1 ± 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at one or more of the following diffraction angles (29): 10.5 ± 0.2, 17.6 ± 0.2, and 18.6 ± 0.2.

[0084] In certain embodiments, the relative intensity of the peak at said diffraction angles (20) is at least 20%. In certain embodiments, the relative intensity of the peak at said diffractionangles (20) is at least 30%. In certain embodiments, the relative intensity of the peak at said diffraction angles (20) is at least 40%.

[0085] In certain embodiments, the compound is characterized by the following X-ray powder diffraction pattern expressed in terms of diffraction angle 20, inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak):

[0086] In certain embodiments, the compound has an X-ray powder diffraction pattern substantially as shown in Figure 17.

[0087] In certain embodiments, the compound has a melting point onset as determined by differential scanning calorimetry in the range of from about 170 degrees Celsius to about 190 degrees Celsius. In certain embodiments, the compound has a melting point onset as determined by differential scanning calorimetry at about 183 degrees Celsius. In certain embodiments, the compound has a melting point onset as determined by differential scanning calorimetry at 183 degrees Celsius. In certain embodiments, the compound has a differential scanning calorimetry curve substantially the same as shown in Figure 18.Crystal Form C2

[0088] In certain embodiments, the compound of Formula II-5 in crystalline form is in Crystal Form C2. As described above, in certain embodiments, the compound of Formula II- 5 in crystalline form further comprises a solvent. In certain embodiments, the solvent is 2-propanol. In certain embodiments, the solvent is 2-propanol, and the compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (20): 8.6 ± 0.2, 9.8 ± 0.2, 10.5 ± 0.2, 19.2 ± 0.2, 19.5 ± 0.2, 23.5 ± 0.2, and 25.5 ± 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at one or more of the following diffraction angles (20): 12.9 ± 0.2, 18.5 ± 0.2, and 25.1 ± 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at one or more of the following diffraction angles (20): 16.5 ± 0.2, 17.3 ± 0.2, and 18.0 ± 0.2.

[0089] In certain embodiments, the relative intensity of the peak at said diffraction angles (20) is at least 30%. In certain embodiments, the relative intensity of the peak at said diffraction angles (20) is at least 35%. In certain embodiments, the relative intensity of the peak at said diffraction angles (20) is at least 40%.

[0090] In certain embodiments, the compound is characterized by the following X-ray powder diffraction pattern expressed in terms of diffraction angle 20, inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak):

[0091] In certain embodiments, the compound has an X-ray powder diffraction pattern substantially as shown in Figure 20.

[0092] In certain embodiments, the compound has a melting point onset as determined by differential scanning calorimetry in the range of from about 170 degrees Celsius to about 200 degrees Celsius. In certain embodiments, the compound has a melting point onset as determined by differential scanning calorimetry at about 186 degrees Celsius. In certain embodiments, the compound has a differential scanning calorimetry curve substantially the same as shown in Figure 21.Crystal Form C3

[0093] In certain embodiments, the compound of Formula II-5 in crystalline form is in Crystal Form C3. As described above, in certain embodiments, the compound of Formula II- 5 in crystalline form further comprises a solvent. In certain embodiments, the solvent is 1,4-di oxane. In certain embodiments, the solvent is 1,4-dioxane, and the compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (20): 8.6 ± 0.2, 10.4 ± 0.2, 13.0 ± 0.2, 17.5 ± 0.2, 19.5 ± 0.2, 23.5 ± 0.2, and 25.5 ± 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at one or more of the following diffraction angles (20): 9.8 ± 0.2, 18.7 ± 0.2, and 19.2 ± 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at one or more of the following diffraction angles (20): 18.5 ± 0.2, 19.8 ± 0.2, and 25.0 ± 0.2.

[0094] In certain embodiments, the relative intensity of the peak at said diffraction angles (20) is at least 30%.

[0095] In certain embodiments, the compound is characterized by the following X-ray powder diffraction pattern expressed in terms of diffraction angle 20, inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak):

[0096] In certain embodiments, the compound has an X-ray powder diffraction pattern substantially as shown in Figure 23.

[0097] In certain embodiments, the compound has a melting point onset as determined by differential scanning calorimetry in the range of from about 180 degrees Celsius to about 200 degrees Celsius. In certain embodiments, the compound has a melting point onset as determined by differential scanning calorimetry at about 188 degrees Celsius. In certain embodiments, the compound has a differential scanning calorimetry curve substantially the same as shown in Figure 24.Crystal Form D

[0098] In certain embodiments, the compound of Formula II- 5 in crystalline form is in Crystal Form D. As described above, in certain embodiments, the compound of Formula II- 5 in crystalline form further comprises a solvent. In certain embodiments, the solvent is water. In certain embodiments, the solvent is water, and the compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (20): 8.7 ± 0.2, 12.7 ± 0.2, 17.3 ± 0.2, 18.0 ± 0.2, 19.0 ± 0.2, 20.8 ± 0.2, and 23.9 ± 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at one or more of the following diffraction angles (20): 11.1 ± 0.2, 19.2 ± 0.2, 24.9 ± 0.2, and 26.3 ± 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at one or more of the following diffraction angles (20): 9.4 ± 0.2, 16.1 ± 0.2, 21.8 ± 0.2, and 25.4 ± 0.2.

[0099] In certain embodiments, the relative intensity of the peak at said diffraction angles (20) is at least 20%. In certain embodiments, the relative intensity of the peak at said diffraction angles (20) is at least 30%.

[0100] In certain embodiments, the compound is characterized by the following X-ray powder diffraction pattern expressed in terms of diffraction angle 20, inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak):

[0101] In certain embodiments, the compound has an X-ray powder diffraction pattern substantially as shown in Figure 26.

[0102] In certain embodiments, the compound has a melting point onset as determined by differential scanning calorimetry in the range of from about 170 degrees Celsius to about 200 degrees Celsius. In certain embodiments, the compound has a melting point onset as determined by differential scanning calorimetry at about 184 degrees Celsius. In certain embodiments, the compound has a melting point onset as determined by differential scanning calorimetry at 184degrees Celsius. In certain embodiments, the compound has a differential scanning calorimetry curve substantially the same as shown in Figure 27.Crystal Form E

[0103] In certain embodiments, the compound of Formula II-5 in crystalline form is in Crystal Form E. As described above, in certain embodiments, the compound of Formula II-5 in crystalline form further comprises a solvent. In certain embodiments, the solvent is ethyl acetate. In certain embodiments, the solvent is ethyl acetate, and the compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (20): 9.8 ± 0.2, 15.6 ± 0.2, 17.3 ± 0.2, 19.2 ± 0.2, 23.6 ± 0.2, 25.2 ± 0.2, and 26.1 ± 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at one or more of the following diffraction angles (20): 8.6 ± 0.2, 12.8 ± 0.2, and 19.6 ± 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at one or more of the following diffraction angles (20): 8.0 ± 0.2, 16.5 ± 0.2, and 24.0 ± 0.2.

[0104] In certain embodiments, the relative intensity of the peak at said diffraction angles (20) is at least 30%.

[0105] In certain embodiments, the compound is characterized by the following X-ray powder diffraction pattern expressed in terms of diffraction angle 20, inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak):

[0106] In certain embodiments, the compound has an X-ray powder diffraction pattern substantially as shown in Figure 29.

[0107] In certain embodiments, the compound has a melting point onset as determined by differential scanning calorimetry in the range of from about 180 degrees Celsius to about 200 degrees Celsius. In certain embodiments, the compound has a melting point onset as determined by differential scanning calorimetry at about 191 degrees Celsius. In certain embodiments, the compound has a differential scanning calorimetry curve substantially the same as shown in Figure 30.Crystal Form F

[0108] In certain embodiments, the compound of Formula II-5 in crystalline form is in Crystal Form F. In certain embodiments, the compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (20): 8.2 ± 0.2, 11.4 ± 0.2, 18.0 ± 0.2, 18.5 ± 0.2, 19.8 ± 0.2, 24.4 ± 0.2, and 25.5 ± 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at one or more of the following diffraction angles (20): 9.0 ± 0.2, 16.5 ± 0.2, and 25.8 ± 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at one or more of the following diffraction angles (20): 7.9 ± 0.2, 12.3 ± 0.2, and 20.7 ± 0.2.

[0109] In certain embodiments, the relative intensity of the peak at said diffraction angles (20) is at least 15%.

[0110] In certain embodiments, the compound is characterized by the following X-ray powder diffraction pattern expressed in terms of diffraction angle 20, inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak):

[0111] In certain embodiments, the compound has an X-ray powder diffraction pattern substantially as shown in Figure 32.Crystal Form G

[0112] In certain embodiments, the compound of Formula II-5 in crystalline form is in Crystal Form G. As described above, in certain embodiments, the compound of Formula II-5 in crystalline form further comprises a solvent. In certain embodiments, the solvent is a mixture of methanol and water. In certain embodiments, the solvent is a mixture of methanol and water, and the compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (26): 8.6 ± 0.2, 13.0 ± 0.2, 17.5 ± 0.2, 18.9 ± 0.2, 19.3 ± 0.2, 19.5 ± 0.2, and 25.5 ± 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at one or more of the following diffraction angles (26): 9.5 ± 0.2, 12.7 ± 0.2, and 18.0 ± 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at one or more of the following diffraction angles (26): 17.4 ± 0.2, 20.1 ± 0.2, and 23.8 ± 0.2.

[0113] In certain embodiments, the relative intensity of the peak at said diffraction angles (26) is at least 30%. In certain embodiments, the relative intensity of the peak at said diffraction angles (20) is at least 35%.

[0114] In certain embodiments, the compound is characterized by the following X-ray powder diffraction pattern expressed in terms of diffraction angle 26, inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak):

[0115] In certain embodiments, the compound has an X-ray powder diffraction pattern substantially as shown in Figure 33.

[0116] In certain embodiments, the compound has a melting point onset as determined by differential scanning calorimetry in the range of from about 170 degrees Celsius to about 200 degrees Celsius. In certain embodiments, the compound has a melting point onset as determined by differential scanning calorimetry at about 185 degrees Celsius. In certain embodiments, the compound has a differential scanning calorimetry curve substantially the same as shown in Figure 34.Crystal Form H

[0117] In certain embodiments, the compound of Formula II-5 in crystalline form is in Crystal Form H. As described above, in certain embodiments, the compound of Formula II-5 in crystalline form further comprises a solvent. In certain embodiments, the solvent is methyl isobutyl ketone. In certain embodiments, the solvent is methyl isobutyl ketone, and the compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (20): 9.7 ± 0.2, 12.8 ± 0.2, 18.4 ± 0.2, 19.1 ± 0.2, 19.5 ± 0.2, 23.5 ± 0.2, and24.9 ± 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at one or more of the following diffraction angles (20): 8.5 ± 0.2, 10.4 ± 0.2, and 15.6 ± 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at one or more of the following diffraction angles (29): 17.2 ± 0.2, 17.9 ± 0.2, and 25.1 ± 0.2.

[0118] In certain embodiments, the relative intensity of the peak at said diffraction angles (29) is at least 30%. In certain embodiments, the relative intensity of the peak at said diffraction angles (20) is at least 35%.

[0119] In certain embodiments, the compound is characterized by the following X-ray powder diffraction pattern expressed in terms of diffraction angle 20, inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak):

[0120] In certain embodiments, the compound has an X-ray powder diffraction pattern substantially as shown in Figure 36.

[0121] In certain embodiments, the compound has a melting point onset as determined by differential scanning calorimetry in the range of from about 180 degrees Celsius to about 200 degrees Celsius. In certain embodiments, the compound has a melting point onset as determined by differential scanning calorimetry at about 188 degrees Celsius. In certain embodiments, the compound has a differential scanning calorimetry curve substantially the same as shown in Figure 37.Crystal Form I

[0122] In certain embodiments, the compound of Formula II-5 in crystalline form is in Crystal Form C2. As described above, in certain embodiments, the compound of Formula II- 5 in crystalline form further comprises a solvent. In certain embodiments, the solvent is a mixture of ethanol and water. In certain embodiments, the solvent is a mixture of ethanol and water, and the compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (20): 11.6 ± 0.2, 15.4± 0.2, 18.1 ± 0.2, 18.6 ± 0.2, 20.0 ± 0.2, 20.2 ± 0.2, and 24.5 ± 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at one or more of the following diffraction angles (29): 9.1 ± 0.2, 16.6 ± 0.2, and 25.6 ± 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at one or more of the following diffraction angles (20): 12.4 ± 0.2, 12.8 ± 0.2, and 25.9 ± 0.2.

[0123] In certain embodiments, the relative intensity of the peak at said diffraction angles (20) is at least 15%. In certain embodiments, the relative intensity of the peak at said diffraction angles (20) is at least 20%.

[0124] In certain embodiments, the compound is characterized by the following X-ray powder diffraction pattern expressed in terms of diffraction angle 20, inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak):

[0125] In certain embodiments, the compound has an X-ray powder diffraction pattern substantially as shown in Figure 39.Crystal Form J

[0126] In certain embodiments, the compound of Formula II-5 in crystalline form is in Crystal Form J. In certain embodiments, the compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (20): 11.4 ± 0.2, 17.9 ± 0.2, 18.1 ± 0.2, 18.5 ± 0.2, 19.0 ± 0.2, 19.9 ± 0.2, and 24.5 ± 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at one or more of the following diffraction angles (20): 12.3 ± 0.2, 17.2 ± 0.2, and 25.5 ± 0.2. In certain embodiments, the X-ray powderdiffraction pattern further comprises a peak at one or more of the following diffraction angles (20): 9.0 ± 0.2, 11.7 ± 0.2, and 16.5 ± 0.2.

[0127] In certain embodiments, the relative intensity of the peak at said diffraction angles (20) is at least 15%.

[0128] In certain embodiments, the compound is characterized by the following X-ray powder diffraction pattern expressed in terms of diffraction angle 20, inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak):

[0129] In certain embodiments, the compound has an X-ray powder diffraction pattern substantially as shown in Figure 40.

[0130] The description above describes multiple embodiments related to crystalline forms of the compound of Formula II-5. The patent application specifically contemplates all combinations of the embodiments.II. Therapeutic Applications

[0131] The crystalline forms of Compound II-5 described herein, such as a compound of Crystal Form D, or other compounds in Section I, provide therapeutic benefits to patients suffering from cancer. Accordingly, one aspect of the invention provides a method of treating cancer. The method comprises administering to a patient in need thereof a therapeutically effective amount of a compound described herein, such as a crystalline form of Compound II-5 described herein, such as a compound of Crystal Form D, or other compound in Section I, to treat the cancer. In certain embodiments, the particular crystalline form of Compound II-5 is a crystalline form defined by one of the embodiments described above.Cancer

[0132] In certain embodiments, the cancer is ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, prostate cancer, testicular cancer, breast cancer, brain cancer, lung cancer, oral cancer, esophageal cancer, head and neck cancer, stomach cancer, colon cancer, rectal cancer, skin cancer, sebaceous gland carcinoma, bile duct and gallbladder cancers, liver cancer, pancreatic cancer, bladder cancer, urinary tract cancer, kidney cancer, eye cancer, thyroid cancer, lymphoma, or leukemia. In certain embodiments, the cancer is prostate cancer.

[0133] In certain embodiments, the cancer is squamous cell cancer, lung cancer including small cell lung cancer, non-small cell lung cancer, vulval cancer, thyroid cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, and head and neck cancer. In certain embodiments, the cancer is at least one selected from the group consisting of ALL, T-lineage Acute lymphoblastic Leukemia (T-ALL), T-lineage lymphoblastic Lymphoma (T-LL), Peripheral T-cell lymphoma, Adult T-cell Leukemia, Pre-B ALL, Pre-B Lymphomas, Large B-cell Lymphoma, Burkitts Lymphoma, B-cell ALL, Philadelphia chromosome positive ALL, Philadelphia chromosome positive CML, lymphoma, leukemia, multiple myeloma myeloproliferative diseases, large B cell lymphoma, or B cell Lymphoma.

[0134] In certain embodiments, the cancer is a solid tumor or leukemia. In certain other embodiments, the cancer is colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, lung cancer, leukemia, bladder cancer, stomach cancer, cervical cancer, testicular cancer, skin cancer, rectal cancer, thyroid cancer, kidney cancer, uterus cancer, espophagus cancer, liver cancer, an acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma, or retinoblastoma. In certain other embodiments, the cancer is small cell lung cancer, non-small cell lung cancer, melanoma, cancer of the central nervous system tissue, brain cancer, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, cutaneous T-Cell lymphoma, cutaneous B-Cell lymphoma, or diffuse large B-Cell lymphoma. In certain other embodiments, the cancer is breast cancer, colon cancer, small-cell lung cancer, non-small cell lung cancer, prostate cancer, renal cancer, ovarian cancer, leukemia, melanoma, or cancer of the central nervous system tissue. In certain other embodiments, the cancer is colon cancer, small-cell lung cancer, non-small cell lung cancer, renal cancer, ovarian cancer, renal cancer, or melanoma.

[0135] In certain embodiments, the cancer is a fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, Ewing’s tumor, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms’ tumor, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, or hemangioblastoma.

[0136] In certain embodiments, the cancer is a neuroblastoma, meningioma, hemangiopericytoma, multiple brain metastase, glioblastoma multiforms, glioblastoma, brain stem glioma, poor prognosis malignant brain tumor, malignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma, neuroendocrine tumor, rectal adeno carcinoma, Dukes C & D colorectal cancer, unresectable colorectal carcinoma, metastatic hepatocellular carcinoma, Kaposi’s sarcoma, karotype acute myeloblastic leukemia, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, cutaneous T-Cell lymphoma, cutaneous B-Cell lymphoma, diffuse large B-Cell lymphoma, low grade follicular lymphoma, metastatic melanoma, localized melanoma, malignant mesothelioma, malignant pleural effusion mesothelioma syndrome, peritonealcarcinoma, papillary serous carcinoma, gynecologic sarcoma, soft tissue sarcoma, scelroderma, cutaneous vasculitis, Langerhans cell histiocytosis, leiomyosarcoma, fibrodysplasia ossificans progressive, hormone refractory prostate cancer, resected high-risk soft tissue sarcoma, unrescectable hepatocellular carcinoma, Waidenstrom’s macroglobulinemia, smoldering myeloma, indolent myeloma, fallopian tube cancer, androgen independent prostate cancer, androgen dependent stage IV non-metastatic prostate cancer, hormone-insensitive prostate cancer, chemotherapy-insensitive prostate cancer, castrate resistant prostate cancer, castrate resistant metastatic prostate cancer, papillary thyroid carcinoma, follicular thyroid carcinoma, medullary thyroid carcinoma, or leiomyoma.

[0137] In certain embodiments, the cancer is bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal (gastric, colorectal, and duodenal), uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, non-Hodgkins's lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, adrenocortical cancer, gall bladder cancer, multiple myeloma, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastoma, or a combination of one or more of the foregoing cancers.

[0138] In certain embodiments, the cancer is hepatocellular carcinoma, ovarian cancer, ovarian epithelial cancer, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatocholangiocarcinoma; soft tissue and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing sarcoma; anaplastic thyroid cancer; adrenocortical adenoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma; gastrointestinal / stomach (GIST) cancer; lymphoma; squamous cell carcinoma of the head and neck (SCCHN); salivary gland cancer; glioma, orbrain cancer; neurofibromatosis- 1 associatedmalignant peripheral nerve sheath tumors (MPNST); Waldenstrom's macroglobulinemia; or medulloblastoma.

[0139] In certain embodiments, the cancer is hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial cancer, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenocortical adenoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis- 1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom's macroglobulinemia, or medulloblastoma.

[0140] In certain embodiments, the cancer is a solid tumor, such as a sarcoma, carcinoma, or lymphoma. In certain embodiments, the cancer is kidney cancer; hepatocellular carcinoma (HCC) or hepatoblastoma, or liver cancer; melanoma; breast cancer; colorectal carcinoma, or colorectal cancer; colon cancer; rectal cancer; anal cancer; lung cancer, such as non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC); ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatocholangiocarcinoma; soft tissue and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing sarcoma; anaplastic thyroid cancer; adrenocortical carcinoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma; gastrointestinal / stomach (GIST) cancer; lymphoma; squamous cell carcinoma of the head and neck (SCCHN); salivary gland cancer; glioma, or brain cancer; neurofibromatosis- 1 associated malignant peripheral nerve sheath tumors (MPNST); Waldenstrom's macroglobulinemia; or medulloblastoma.

[0141] In certain embodiments, the cancer is renal cell carcinoma, hepatocellular carcinoma (HCC), hepatoblastoma, colorectal carcinoma, colorectal cancer, colon cancer, rectal cancer, anal cancer, ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, anaplastic thyroid cancer, adrenocortical carcinoma, pancreaticcancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, brain cancer, neurofibromatosis-1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom's macroglobulinemia, or medulloblastoma.

[0142] In certain embodiments, the cancer is hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis- 1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom's macroglobulinemia, or medulloblastoma.

[0143] In certain embodiments, the cancer is hepatocellular carcinoma (HCC). In some embodiments, the cancer is hepatoblastoma. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is rectal cancer. In some embodiments, the cancer is ovarian cancer, or ovarian carcinoma. In some embodiments, the cancer is ovarian epithelial cancer. In some embodiments, the cancer is fallopian tube cancer. In some embodiments, the cancer is papillary serous cystadenocarcinoma. In some embodiments, the cancer is uterine papillary serous carcinoma (UPSC). In some embodiments, the cancer is hepatocholangiocarcinoma. In some embodiments, the cancer is soft tissue and bone synovial sarcoma. In some embodiments, the cancer is rhabdomyosarcoma. In some embodiments, the cancer is osteosarcoma. In some embodiments, the cancer is anaplastic thyroid cancer. In some embodiments, the cancer is adrenocortical carcinoma. In some embodiments, the cancer is pancreatic cancer, or pancreatic ductal carcinoma. In some embodiments, the cancer is pancreatic adenocarcinoma. In some embodiments, the cancer is glioma. In some embodiments, the cancer is malignant peripheral nerve sheath tumors (MPNST). In some embodiments, the cancer is neurofibromatosis- 1 associated MPNST. In some embodiments, the cancer is Waldenstrom's macroglobulinemia. In some embodiments, the cancer is medulloblastoma.

[0144] Another aspect of the invention provides for the use of a compound described herein (such as a crystalline form of Compound II- 5 described herein, such as a compound of CrystalForm D, or other compounds in Section I) in the manufacture of a medicament. In certain embodiments, the medicament is for treating a disease described herein, such as cancer.

[0145] Another aspect of the invention provides for the use of a compound described herein (such as a crystalline form of Compound II- 5 described herein, such as a compound of Crystal Form D, or other compounds in Section I) for treating a medical disease, such a disease described herein (e.g., cancer).

[0146] Another aspect of the invention provides a compound described herein (such as a crystalline form of Compound II-5 described herein, such as a compound of Crystal Form D, or other compounds in Section I) for use in treating a medical disorder, such as a medical disorder described herein, such as cancer.Causing Death of Cancer Cell

[0147] Another aspect of the invention provides a method of causing death of a cancer cell. The method comprises contacting a cancer cell with an effective amount of a compound described herein, such as a crystalline form of Compound IT-5 described herein, such as a compound of Crystal Form D, or other compounds in Section I, to cause death of the cancer cell. In certain embodiments, the particular crystalline form of Compound II-5 is a crystalline form defined by one of the embodiments described above.

[0148] In certain embodiments, the cancer cell is selected from ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, prostate cancer, testicular cancer, breast cancer, brain cancer, lung cancer, oral cancer, esophageal cancer, head and neck cancer, stomach cancer, colon cancer, rectal cancer, skin cancer, sebaceous gland carcinoma, bile duct and gallbladder cancers, liver cancer, pancreatic cancer, bladder cancer, urinary tract cancer, kidney cancer, eye cancer, thyroid cancer, lymphoma, or leukemia. In certain embodiments, the cancer cell is one or more of the cancers recited in the section above entitled “Cancer.” In certain embodiments, the cancer cell is a prostate cancer cell.Combination Therapies

[0149] The compounds useful within the methods of the invention may be used in combination with one or more additional therapeutic agents useful for treating any disease contemplated herein. These additional therapeutic agents may comprise compounds that are commercially available or synthetically accessible to those skilled in the art. These additionaltherapeutic agents are known to treat, prevent, or reduce the symptoms, of a disease or disorder contemplated herein.

[0150] Accordingly, in certain embodiments, the method further comprises administering to the subject an additional therapeutic agent that treats the disease contemplated herein.

[0151] In certain embodiments, administering the compound of the invention to the subject allows for administering a lower dose of the additional therapeutic agent as compared to the dose of the additional therapeutic agent alone that is required to achieve similar results in treating the disease contemplated herein. For example, in certain embodiments, the compound of the invention enhances the therapeutic activity of the additional therapeutic compound, thereby allowing for a lower dose of the additional therapeutic compound to provide the same effect.

[0152] A synergistic effect may be calculated, for example, using suitable methods such as, for example, the Sigmoid-Emax equation (Holford & Scheiner, 1981, Clin. Pharmacokinet. 6:429-453), the equation of Loewe additivity (Loewe & Muischnek, 1926, Arch. Exp. Pathol Pharmacol. 114:313-326) and the median-effect equation (Chou & Talalay, 1984, Adv. Enzyme Regul. 22:27-55). Each equation referred to above may be applied to experimental data to generate a corresponding graph to aid in assessing the effects of the drug combination. The corresponding graphs associated with the equations referred to above are the concentration-effect curve, isobologram curve and combination index curve, respectively.

[0153] In certain embodiments, the compound of the invention and the therapeutic agent are co-administered to the subject. In other embodiments, the compound of the invention and the therapeutic agent are coformulated and co-administered to the subject.

[0154] In certain embodiments, the compound is administered in combination with a second therapeutic agent having activity against cancer. In certain embodiments, the second therapeutic agent is mitomycin, tretinoin, ribomustin, gemcitabine, vincristine, etoposide, cladribine, mitobronitol, methotrexate, doxorubicin, carboquone, pentostatin, nitracrine, zinostatin, cetrorelix, letrozole, raltitrexed, daunorubicin, fadrozole, fotemustine, thymalfasin, sobuzoxane, nedaplatin, cytarabine, bicalutamide, vinorelbine, vesnarinone, aminoglutethimide, amsacrine, proglumide, elliptinium acetate, ketanserin, doxifluridine, etretinate, isotretinoin, streptozocin, nimustine, vindesine, flutamide, drogenil, butocin, carmofur, razoxane, sizofilan, carboplatin, mitolactol, tegafur, ifosfamide, prednimustine, picibanil, levamisole, teniposide, improsulfan,enocitabine, lisuride, oxymetholone, tamoxifen, progesterone, mepitiostane, epitiostanol, formestane, interferon-alpha, interferon-2 alpha, interferon-beta, interferon-gamma, colony stimulating factor- 1, colony stimulating factor-2, denileukin diftitox, interleukin-2, and leutinizing hormone releasing factor.

[0155] In certain embodiments, the second therapeutic agent is an mTOR inhibitor, which inhibits cell proliferation, angiogenesis and glucose uptake. Approved mTOR inhibitors useful in the present invention include everolimus (Afinitor®, Novartis); temsirolimus (Torisel®, Pfizer); and sirolimus (Rapamune®, Pfizer).

[0156] In certain embodiments, the second therapeutic agent is a Poly ADP ribose polymerase (PARP) inhibitor. Approved PARP inhibitors useful in the present invention include olaparib (Lynparza®, AstraZeneca); rucaparib (Rubraca®, Clovis Oncology); and niraparib (Zejula®, Tesaro). Other PARP inhibitors being studied which may be used in the present invention include talazoparib (MDV3800 / B N 673 / LT00673, Medivation / Pfizer / Biomarin); veliparib (ABT-888, Abb Vie); and BGB-290 (BeiGene, Inc.).

[0157] In certain embodiments, the second therapeutic agent is a phosphatidylinositol 3 kinase (PI3K) inhibitor. Approved PI3K inhibitors useful in the present invention include idelalisib (Zydelig®, Gilead). Other PI3K inhibitors being studied which may be used in the present invention include alpelisib (BYL719, Novartis); taselisib (GDC-0032, Genentech / Roche); pictilisib (GDC-0941, Genentech / Roche); copanlisib (BAY806946, Bayer); duvelisib (formerly IPI-145, Infinity Pharmaceuticals); PQR309 (Piqur Therapeutics, Switzerland); and TGR1202 (formerly RP5230, TG Therapeutics).

[0158] In certain embodiments, the second therapeutic agent is a proteasome inhibitor. Approved proteasome inhibitors useful in the present invention include bortezomib (Velcade®, Takeda); carfilzomib (Kyprolis®, Amgen); and ixazomib (Ninlaro®, Takeda).

[0159] In certain embodiments, the second therapeutic agent is a histone deacetylase (HD AC) inhibitor. Approved HD AC inhibitors useful in the present invention include vorinostat (Zolinza®, Merck); romidepsin (Istodax®, Celgene); panobinostat (Farydak®, Novartis); and belinostat (Beleodaq®, Spectrum Pharmaceuticals). Other HDAC inhibitors being studied which may be used in the present invention include entinostat (SNDX-275, Syndax Pharmaceuticals) (NCT00866333); and chidamide (Epidaza®, HB 1-8000, Chipscreen Biosciences, China).

[0160] In certain embodiments, the second therapeutic agent is a CDK inhibitor, such as a CDK 4 / 6 inhibitor. Approved CDK 4 / 6 inhibitors useful in the present invention include palbociclib (Ibrance®, Pfizer); and ribociclib (Kisqali®, Novartis). Other CDK 4 / 6 inhibitors being studied which may be used in the present invention include abemaciclib (Ly2835219, Eli Lilly); and trilaciclib (G1T28, G1 Therapeutics).

[0161] In certain embodiments, the second therapeutic agent is an indoleamine (2,3)-dioxygenase (IDO) inhibitor. IDO inhibitors being studied which may be used in the present invention include epacadostat (INCB024360, Incyte); indoximod (NLG-8189, NewLink Genetics Corporation); capmanitib (INC280, Novartis); GDC-0919 (Genentech / Roche); PF-06840003 (Pfizer); BMS: F001287 (Bristol-Myers Squibb); Phy906 / KD108 (Phytoceutica); and an enzyme that breaks down kynurenine (Kynase, Kyn Therapeutics).

[0162] In certain embodiments, the second therapeutic agent is a growth factor antagonist, such as an antagonist of platelet-derived growth factor (PDGF), or epidermal growth factor (EGF) or its receptor (EGFR). Approved PDGF antagonists which may be used in the present invention include olaratumab (Lartruvo®; Eli Lilly). Approved EGFR antagonists which may be used in the present invention include cetuximab (Erbitux®, Eli Lilly); necitumumab (Portrazza®, Eli Lilly), panitumumab (Vectibix®, Amgen); and osimertinib (targeting activated EGFR, Tagrisso®, AstraZeneca).

[0163] In certain embodiments, the second therapeutic agent is an aromatase inhibitor.Approved aromatase inhibitors which may be used in the present invention include exemestane (Aromasin®, Pfizer); anastazole (Arimidex®, AstraZeneca) and letrozole (Femara®, Novartis).

[0164] In certain embodiments, the second therapeutic agent is an antagonist of the hedgehog pathway. Approved hedgehog pathway inhibitors which may be used in the present invention include sonidegib (Odomzo®, Sun Pharmaceuticals); and vismodegib (Erivedge®, Genentech), both for treatment of basal cell carcinoma.

[0165] In certain embodiments, the second therapeutic agent is a folic acid inhibitor.Approved folic acid inhibitors useful in the present invention include pemetrexed (Alimta®, Eli Lilly).

[0166] In certain embodiments, the second therapeutic agent is a CC chemokine receptor 4 (CCR4) inhibitor. CCR4 inhibitors being studied that may be useful in the present invention include mogamulizumab (Poteligeo®, Kyowa Hakko Kirin, Japan).

[0167] In certain embodiments, the second therapeutic agent is an isocitrate dehydrogenase (IDH) inhibitor. IDH inhibitors being studied which may be used in the present invention include AG120 (Celgene; NCT02677922); AG221 (Celgene, NCT02677922; NCT02577406);BAY1436032 (Bayer, NCT02746081); IDH305 (Novartis, NCT02987010).

[0168] In certain embodiments, the second therapeutic agent is an arginase inhibitor.Arginase inhibitors being studied which may be used in the present invention include AEB1102 (pegylated recombinant arginase, Aeglea Biotherapeutics), which is being studied in Phase 1 clinical trials for acute myeloid leukemia and myelodysplastic syndrome (NCT02732184) and solid tumors (NCT02561234); and CB-1158 (Calithera Biosciences).

[0169] In certain embodiments, the second therapeutic agent is a glutaminase inhibitor. Glutaminase inhibitors being studied which may be used in the present invention include CB-839 (Calithera Biosciences).

[0170] In certain embodiments, the second therapeutic agent is an antibody that binds to tumor antigens, that is, proteins expressed on the cell surface of tumor cells. Approved antibodies that bind to tumor antigens which may be used in the present invention include rituximab (Rituxan®, Genentech / Biogenldec); ofatumumab (anti-CD20, Arzerra®, GlaxoSmithKline); obinutuzumab (anti-CD20, Gazyva®, Genentech), ibritumomab (anti-CD20 and Yttrium-90, Zevalin®, Spectrum Pharmaceuticals); daratumumab (anti-CD38, Darzalex®, Janssen Biotech), dinutuximab (anti-glycolipid GD2, Unituxin®, United Therapeutics); trastuzumab (anti-HER2, Herceptin®, Genentech); ado-trastuzumab emtansine (anti-HER2, fused to emtansine, Kadcyla®, Genentech); and pertuzumab (anti-HER2, Perjeta®, Genentech); and brentuximab vedotin (anti-CD30-drug conjugate, Adcetris®, Seattle Genetics).

[0171] In certain embodiments, the second therapeutic agent is a topoisomerase inhibitor. Approved topoisomerase inhibitors useful in the present invention include irinotecan (Onivyde®, Merrimack Pharmaceuticals); topotecan (Hycamtin®, GlaxoSmithKline). Topoisomerase inhibitors being studied which may be used in the present invention include pixantrone (Pixuvri®, CTI Biopharma).

[0172] In certain embodiments, the second therapeutic agent is a nucleoside inhibitor, or other therapeutic that interfere with normal DNA synthesis, protein synthesis, cell replication, or will otherwise inhibit rapidly proliferating cells. Such nucleoside inhibitors or other therapeutics include trabectedin (guanidine alkylating agent, Yondelis®, Janssen Oncology), mechlorethamine (alkylating agent, Valchlor®, Aktelion Pharmaceuticals); vincristine (Oncovin®, Eli Lilly; Vincasar®, Teva Pharmaceuticals; Marqibo®, Talon Therapeutics); temozolomide (prodrug to alkylating agent 5-(3-methyltriazen-l-yl)-imidazole-4-carboxamide (MTIC) Temodar®, Merck); cytarabine injection (ara-C, antimetabolic cytidine analog, Pfizer); lomustine (alkylating agent, CeeNU®, Bristol-Myers Squibb; Gleostine®, NextSource Biotechnology); azacitidine (pyrimidine nucleoside analog of cytidine, Vidaza®, Celgene); omacetaxine mepesuccinate (cephalotaxine ester) (protein synthesis inhibitor, Synribo®; Teva Pharmaceuticals); asparaginase Erwinia chiysanthemi (enzyme for depletion of asparagine, Elspar®, Lundbeck; Erwinaze®, EUSA Pharma); eribulin mesylate (microtubule inhibitor, tubulin-based antimitotic, Halaven®, Eisai); cabazitaxel (microtubule inhibitor, tubulin-based antimitotic, Jevtana®, Sanofi-Aventis); capacetrine (thymidylate synthase inhibitor, Xeloda®, Genentech); bendamustine (bifunctional mechlorethamine derivative, believed to form interstrand DNA cross-links, Treanda®, Cephalon / Teva); ixabepilone (semi-synthetic analog of epothilone B, microtubule inhibitor, tubulin-based antimitotic, Ixempra®, Bristol-Myers Squibb); nelarabine (prodrug of deoxyguanosine analog, nucleoside metabolic inhibitor, Arranon®, Novartis); clorafabine (prodrug of ribonucleotide reductase inhibitor, competitive inhibitor of deoxycytidine, Clolar®, Sanofi-Aventis); and trifluridine and tipiracil (thymidine-based nucleoside analog and thymidine phosphorylase inhibitor, Lonsurf®, Taiho Oncology).

[0173] In certain embodiments, the second therapeutic agent is a platinum-based therapeutic, also referred to as platins. Platins cause cross-linking of DNA, such that they inhibit DNA repair and / or DNA synthesis, mostly in rapidly reproducing cells, such as cancer cells. Approved platinum-based therapeutics which may be used in the present invention include cisplatin (Platinol®, Bristol-Myers Squibb); carboplatin (Paraplatin®, Bristol-Myers Squibb; also, Teva; Pfizer); oxaliplatin (Eloxitin® Sanofi -Aventis); and nedaplatin (Aqupla®, Shionogi). Other platinum-based therapeutics which have undergone clinical testing and may be used in the present invention include picoplatin (Poniard Pharmaceuticals); and satraplatin (JM-216, Agennix).

[0174] In certain embodiments, the second therapeutic agent is a taxane compound, which causes disruption of microtubules, which are essential for cell division. Approved taxane compounds which may be used in the present invention include paclitaxel (Taxol®, Bristol-Myers Squibb), docetaxel (Taxotere®, Sanofi -Aventis; Docefrez®, Sun Pharmaceutical), albumin-bound paclitaxel (Abraxane®; Abraxis / Celgene), and cabazitaxel (Jevtana®, Sanofi-Aventis). Other taxane compounds which have undergone clinical testing and may be used in the present invention include SID530 (SK Chemicals, Co.) (NCT00931008).

[0175] In certain embodiments, the second therapeutic agent is an inhibitor of anti-apoptotic proteins, such as BCL-2. Approved anti-apoptotics which may be used in the present invention include venetoclax (Venclexta®, AbbVie / Genentech); and blinatumomab (Blincyto®, Amgen). Other therapeutic agents targeting apoptotic proteins which have undergone clinical testing and may be used in the present invention include navitoclax (ABT-263, Abbott), a BCL-2 inhibitor (NCT02079740).

[0176] In certain embodiments, the second therapeutic agent is a selective estrogen receptor modulator (SERM), which interferes with the synthesis or activity of estrogens. Approved SERMs useful in the present invention include raloxifene (Evista®, Eli Lilly).

[0177] In certain embodiments, the second therapeutic agent is an inhibitor of interaction between the two primary p53 suppressor proteins, MDMX and MDM2. Inhibitors of p53 suppression proteins being studied which may be used in the present invention include ALRN-6924 (Aileron), a stapled peptide that equipotently binds to and disrupts the interaction of MDMX and MDM2 with p53. ALRN-6924 is currently being evaluated in clinical trials for the treatment of AML, advanced myelodysplastic syndrome (MDS) and peripheral T-cell lymphoma (PTCL) (NCT02909972; NCT02264613).

[0178] In certain embodiments, the second therapeutic agent is an inhibitor of transforming growth factor-beta (TGF-beta or TGFP). Inhibitors of TGF-beta proteins being studied which may be used in the present invention include NIS793 (Novartis), an anti-TGF-beta antibody being tested in the clinic for treatment of various cancers, including breast, lung, hepatocellular, colorectal, pancreatic, prostate and renal cancer (NCT 02947165). In some embodiments, the inhibitor of TGF-beta proteins is fresolimumab (GC1008; Sanofi-Genzyme), which is being studied for melanoma (NCT00923169); renal cell carcinoma (NCT00356460); and non-smallcell lung cancer (NCT02581787). Additionally, in some embodiments, the additional therapeutic agent is a TGF-beta trap, such as described in Connolly et al. (2012) Int'l J. Biological Sciences 8:964-978. One therapeutic compound currently in clinical trials for treatment of solid tumors is M7824 (Merck KgaA — formerly MSB0011459X), which is a bispecific, anti-PD-Ll / TGFp trap compound (NCT02699515); and (NCT02517398). M7824 is comprised of a fully human IgGl antibody against PD-L1 fused to the extracellular domain of human TGF-beta receptor II, which functions as a TGFp “trap.”

[0179] In certain embodiments, the second therapeutic agent is a cancer vaccine. In some embodiments, the cancer vaccine is selected from sipuleucel-T (Provenge®, Dendreon / Valeant Pharmaceuticals), which has been approved for treatment of asymptomatic, or minimally symptomatic metastatic castrate-resistant (hormone-refractory) prostate cancer; and talimogene laherparepvec (Imlygic®, BioVex / Amgen, previously known as T-VEC), a genetically modified oncolytic viral therapy approved for treatment of unresectable cutaneous, subcutaneous and nodal lesions in melanoma. In some embodiments, the additional therapeutic agent is selected from an oncolytic viral therapy such as pexastimogene devacirepvec (PexaVec / JX-594, SillaJen / formerly Jennerex Biotherapeutics), a thymidine kinase- (TK-) deficient vaccinia virus engineered to express GM-CSF, for hepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312); pelareorep (Reolysin®, Oncolytics Biotech), a variant of respiratory enteric orphan virus (reovirus) which does not replicate in cells that are not RAS-activated, in numerous cancers, including colorectal cancer (NCTO 1622543); prostate cancer (NCT01619813); head and neck squamous cell cancer (NCTO 1166542); pancreatic adenocarcinoma (NCT00998322); and non-small cell lung cancer (NSCLC) (NCT 00861627); enadenotucirev (NG-348, PsiOxus, formerly known as ColoAdl), an adenovirus engineered to express a full length CD80 and an antibody fragment specific for the T-cell receptor CD3 protein, in ovarian cancer (NCT02028117); metastatic or advanced epithelial tumors such as in colorectal cancer, bladder cancer, head and neck squamous cell carcinoma and salivary gland cancer (NCT02636036); ONCOS-102 (Targovax / formerly Oncos), an adenovirus engineered to express GM-CSF, in melanoma (NCT03003676); and peritoneal disease, colorectal cancer or ovarian cancer (NCT02963831); GL-ONC1 (GLV-lh68 / GLV-lhl53, Genelux GmbH), vaccinia viruses engineered to express beta-galactosidase (beta-gal) / beta-glucoronidase or beta-gal / human sodium iodide symporter (hNIS), respectively, were studied in peritoneal carcinomatosis(NCT01443260); fallopian tube cancer, ovarian cancer (NCT 02759588); or CG0070 (Cold Genesys), an adenovirus engineered to express GM-CSF, in bladder cancer (NCT02365818).

[0180] In certain embodiments, the second therapeutic agent is an immune checkpoint inhibitor selected from a PD-1 antagonist, a PD-L1 antagonist, or a CTLA-4 antagonist. In some embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is administered in combination with nivolumab (anti-PD-1 antibody, Opdivo®, Bristol-Myers Squibb); pembrolizumab (anti-PD-1 antibody, Keytruda®, Merck); ipilimumab (anti-CTLA-4 antibody, Yervoy®, Bristol-Myers Squibb); durvalumab (anti-PD-Ll antibody, Imfinzi®, AstraZeneca); or atezolizumab (anti-PD-Ll antibody, Tecentriq®, Genentech). Other immune checkpoint inhibitors suitable for use in the present invention include REGN2810 (Regeneron), an anti-PD-1 antibody tested in patients with basal cell carcinoma (NCT03132636); NSCLC (NCT03088540); cutaneous squamous cell carcinoma (NCT02760498); lymphoma (NCT02651662); and melanoma (NCT03002376); pidilizumab (CureTech), also known as CT-011, an antibody that binds to PD-1, in clinical trials for diffuse large B-cell lymphoma and multiple myeloma; avelumab (Bavencio®, Pfizer / Merck KGaA), also known as MSB0010718C), a fully human IgGl anti-PD-Ll antibody, in clinical trials for non-small cell lung cancer, Merkel cell carcinoma, mesothelioma, solid tumors, renal cancer, ovarian cancer, bladder cancer, head and neck cancer, and gastric cancer; and PDR001 (Novartis), an inhibitory antibody that binds to PD-1, in clinical trials for non-small cell lung cancer, melanoma, triple negative breast cancer and advanced or metastatic solid tumors. Tremelimumab (CP-675,206; Astrazeneca) is a fully human monoclonal antibody against CTLA-4 that has been in studied in clinical trials for a number of indications, including: mesothelioma, colorectal cancer, kidney cancer, breast cancer, lung cancer and non-small cell lung cancer, pancreatic ductal adenocarcinoma, pancreatic cancer, germ cell cancer, squamous cell cancer of the head and neck, hepatocellular carcinoma, prostate cancer, endometrial cancer, metastatic cancer in the liver, liver cancer, large B-cell lymphoma, ovarian cancer, cervical cancer, metastatic anaplastic thyroid cancer, urothelial cancer, fallopian tube cancer, multiple myeloma, bladder cancer, soft tissue sarcoma, and melanoma. AGEN-1884 (Agenus) is an anti-CTLA4 antibody that is being studied in Phase 1 clinical trials for advanced solid tumors (NCT02694822).TIT. Pharmaceutical Compositions and Dosing Considerations

[0181] As indicated above, the invention provides pharmaceutical compositions, which comprise a therapeutically effective amount of one or more of the compounds described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and / or diluents. The pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g, those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; or (8) nasally. In certain embodiments, the invention provides a pharmaceutical composition comprising a compound described herein (e.g., a crystalline form of Compound II-5 described herein, such as a compound of Crystal Form D, or other compound in Section I) and a pharmaceutically acceptable carrier.

[0182] The phrase “therapeutically effective amount” as used herein means that amount of a compound, material, or composition comprising a compound of the present invention which is effective for producing some desired therapeutic effect in at least a sub-population of cells in an animal at a reasonable benefit / risk ratio applicable to any medical treatment.

[0183] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0184] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[0185] Examples of pharmaceutically acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BEIT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0186] Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and / or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 0.1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.

[0187] In certain embodiments, a formulation of the present invention comprises an excipient selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and polyanhydrides; and a compound of the present invention. In certain embodiments, an aforementioned formulation renders orally bioavailable a compound of the present invention.

[0188] Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0189] Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueousliquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and / or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. A compound of the present invention may also be administered as a bolus, electuary or paste.

[0190] In solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules, trouches and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fdlers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds and surfactants, such as poloxamer and sodium lauryl sulfate; (7) wetting agents, such as, for example, cetyl alcohol, glycerol monostearate, and non-ionic surfactants; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid, and mixtures thereof; (10) coloring agents; and (11) controlled release agents such as crospovidone or ethyl cellulose. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0191] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0192] The tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and / or microspheres. They may be formulated for rapid release, e.g., freeze-dried. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.

[0193] Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, com, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

[0194] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0195] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0196] Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.

[0197] Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.

[0198] Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.

[0199] The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0200] Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0201] Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

[0202] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention.

[0203] Pharmaceutical compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0204] Examples of suitable aqueous and nonaqueous carriers which may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0205] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms upon the subject compounds may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.

[0206] In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[0207] Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.

[0208] When the compounds of the present invention are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99% (more preferably, 10 to 30%) of active ingredient in combination with a pharmaceutically acceptable carrier.

[0209] The preparations of the present invention may be given orally, parenterally, topically, or rectally. They are of course given in forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administrations are preferred.

[0210] The phrases “parenteral administration” and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

[0211] The phrases “systemic administration,” “administered systemically,” “peripheral administration” and “administered peripherally” as used herein mean the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient’s system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.

[0212] These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intraci sternal ly and topically, as by powders, ointments or drops, including buccally and sublingually.

[0213] Regardless of the route of administration selected, the compounds of the present invention, which may be used in a suitable hydrated form, and / or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those of skill in the art.

[0214] Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0215] The selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

[0216] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0217] In general, a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Preferably, the compounds are administered at about 0.01 mg / kg to about 200 mg / kg, more preferably at about 0.1 mg / kg to about 100 mg / kg, even more preferably at about 0.5 mg / kg to about 50 mg / kg. When the compounds described herein are co-administered with another agent (e.g., as sensitizing agents), the effective amount may be less than when the agent is used alone.

[0218] If desired, the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervalsthroughout the day, optionally, in unit dosage forms. Preferred dosing is one administration per day.

[0219] The invention further provides a unit dosage form (such as a tablet or capsule) comprising a heterobifunctional substituted phenylpyrimidinone or related compound described herein in a therapeutically effective amount for the treatment of a medical disorder described herein.IV. MEDICAL KITS

[0220] Another aspect of this invention is a kit comprising (i) a compound described herein, such as a crystalline form of Compound II-5 described herein, such as a compound of Crystal Form D, or other compound in Section I, and (ii) instructions for use, such as treating cancer.EXAMPLES

[0221] The invention now being generally described, will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention.General Methods

[0222] Reactions in Examples 1 and 2 were carried out under an atmosphere of dry nitrogen or argon, unless otherwise indicated. Glassware was oven-dried prior to use. Unless otherwise indicated, common reagents or materials were obtained from commercial sources and used without further purification. Anhydrous. V. A'-Diisopropylethylamine (DIPEA) was obtained by distillation over potassium hydroxide. Tetrahydrofuran (THF), dichloromethane (CH2CI2), and dimethylformamide (DMF) were dried by a PureSolv™ solvent drying system. PTLC refers to preparatory thin layer chromatographic separation. Flash column chromatography was performed using silica gel 60 (230-400 mesh). Analytical thin layer chromatography (TLC) was carried out on Merck silica gel plates with QF-254 indicator and visualized by UV or KMnCU

[0223] rH and13C NMR spectra were recorded on an Agilent DD2500 (500 MHz1H; 125 MHz13C) or Agilent DD2600 (600 MHz ’H; 150 MHz13C) or Agilent DD2400 (400 MHz 'H; 100 MHz13C) spectrometer at room temperature. Chemical shifts were reported in ppm relative to residual CDCI3 (87.26 ppm ’ll; 877.0 ppm13C), CD3OD (83.31 ppm1H; 849.00 ppm13C),ort / <-DMSO (52.50 ppm 'H; 639.52 ppm13C). NMR chemical shifts were expressed in ppm relative to internal solvent peaks, and coupling constants were measured in Hz. (bs = broad signal). In most cases, only peaks of the major rotamer are reported.

[0224] Mass spectra were obtained using Agilent 1100 series LC / MSD spectrometers.Analytical HPLC analyses were carried out on a 250 x 4.6 mm C-18 column using gradient conditions (10-100% B, flow rate = 1.0 mL / min, 20 min).

[0225] Unless indicated otherwise, preparative HPLC was carried out on a 250 x 21.2 mm C-18 column using gradient conditions (10-100% B, flow rate = 10.0 mL / min, 20 min). The eluents used were: solvent A (H2O with 0.1% TFA) and solvent B (CH3CN with 0.1% TFA). Final products were typically purified via reversed-phase HPLC, PTLC, or flash column chromatography.

[0226] The following abbreviations are used herein: ACN or MeCN: acetonitrile; AcO: acetate; AcOH: acetic acid; B2pin: bis(pinacolato)diboron; BINAP: 2,2'-bis(diphenyl-phosphino)-l,l'-binaphthyl; Bn: benzyl; Boc: terZ-butoxycarbonyl; BPD: bis(pinacolato) diboron; BrettPhos Pd G3: [(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'- triisopropyl-1,1'-biphenyl)-2-(2'-amino-l,l' -biphenyl)]palladium(II) methanesulfonate methanesulfonate;DavePhos Pd G3: [2-(dicyclohexyl-phosphino)-2-(N, N-dimethylamino)-l,l-biphenyl]-2-(2-amino-l,l-biphenyl)]palladium(II) methanesulfonate; DCM: dichloromethane; DIAD: diisopropyl azodicarboxylate; DIEA: diisopropylethylamine; DMAC: dimethylacetamide;DMAP: 4-dimethylaminopyridine; DMF: dimethylformamide; DMSO: dimethylsulfoxide;EtOH: ethanol; EA or EtOAc: ethyl acetate; equiv or eq'. molar equivalents; FA: formic acid; Fmoc: fluorenylmethoxycarbonyl; h: hour or hours; HATU: l-[bis(dimethylamino)methylene]-1 7-l,2,3-triazolo[4,5- / >]pyridinium 3-oxide hexafluoro-phosphate; HEPES: 4-(2-hydroxyethyl)-1 -piperazineethanesulfonic acid; HFIP: hexafluoroisopropanol; HPLC: high-pressure liquid chromatography; IPA orz-PrOH: isopropyl alcohol; JQ1: 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-l,8,ll,12-tetrazatricyclo[8.3.0.02-6] trideca-2(6),4,7,10,12-pentaen-9-yl]acetic acid; LCMS or LC-MS: liquid chromatography-mass spectrometry; MeOH: methanol; min: minute or minutes; MS: mass spectrometry; zz-BuLi: zz-butyl lithium; NMM: N-methylmorpholine; NMP: N-methylpyrrolidone; NMR: nuclear magnetic resonance; PCys: tricyclohexylphospine; Pd(dba)2: Palladium(O) bis(dibenzylidene-acetone); Pd2(dba)a:tris(dibenzylideneacetone)dipalladium(0); Pd(dppf)C12: [l,l’-bis(diphenylphosphino)ferrocene] di chloro palladium(II); PE: petroleum ether; PPA: polyphosphoric acid; psi: pounds-per-square-inch; rt: room temperature; SFC: supercritical fluid chromatography; SPhos Pd G3: (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl) [2-(2'-amino-l '-biphenyl)]palladium(II) methanesulfonate; tBuXPhos Pd G3: methanesulfonato(2-di-t-butylphosphino-2',4',6'-tri-i-propyl- 1, 1 '-biphenyl )(2'-amino- 1, 1 '-biphenyl-2-yl)palladium(II); ZczZ-BuO: Zczv-butoxide; tert-BuOH: Zc / 'Z-butanol; TEA: triethylamine; TFA: trifluoroacetic acid; THF: tetrahydrofuran; TMP: tetramethylpiperidine; TMS: trimethyl silyl; Tos or Ts: / J-toluenesulfonyl; T4P: 3-{2,6,8-trioxo-9-[(27?,3^,4A)-2,3,4,5-tetrahydroxypentyl]-l,2,3,6,8,9-hexahydro-7 / / -purin-7-yl}propyl dihydrogen phosphate; XANTPHOS: (9,9-dimethyl-9H-xanthene-4,5-diyl)bis (diphenylphosphane); and XPhos: dicyclohexyl[2’,4’,6’-tris(propan-2-yl)[l,l’-biphenyl]-2-yl]phosphane.EXAMPLE 1 - Synthesis of A-[(lr,3')-3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[2-[4-[(9X)-4,5,13-trimethyl-9-(oxazoI-2-ylmethyl)-3-thia-l,8,ll,12-tetrazatricyclo[8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro[3.5] nonan-7-yl]pyrimidine-5-carboxamide (II-5)

[0227] Step 1: Preparation of 2-[(95)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia- 1.8.11.12-tetrazatricyclo[8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetic acid. To a solution of Zc / V-butyl 2-[(95’)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-l,8,l 1,12-tetrazatri cyclo [8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetate (1.0 g, 2.1 mmol, 1.0 equiv) in DCM (10 mL) was added TFA (7.7 g, 67 mmol, 5.0 mL, 30 equiv). The mixture was stirred at 25 °C for 0.5 hour. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue, 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-l,8,l 1,12-tetrazatri cyclo [8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetic acid (877 mg, 99% yield), was used directly in the next step without purification.

[0228] Step 2: Preparation of 2-[(95)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia- 1.8.11.12-tetrazatricyclo[8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamide. To a solution of 2-[(9 ’)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-l,8,l 1,12-tetrazatri cyclo [8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetic acid (877 mg, 2.19 mmol, 1.0 equiv and NH4CI (351 mg, 6.56 mmol, 3.0 equiv) in DMF (8 mL) was added HATU (915 mg, 2.41 mmol, 1.1 equiv) and DIEA (848 mg, 6.56 mmol, 3.0 equiv). The mixture was stirred at 25 °C for 1 hour. The mixture was filtered and concentrated. The residue was purified by prep-HPLC (column: Waters Xbridge Cl 8 150 mm x 50mm x 10 pm; mobile phase: [water (NH4HCO3)-ACN]; B%: 24%-54%, 10 min) to give 2-[(91S’)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia- 1.8.1 l,12-tetrazatricyclo[8.3.0.026]trideca-2(6), 4, 7,10, 12-pentaen-9-yl]acetamide (740 mg, 84% yield).

[0229] Step 3: Preparation of 2-[[(91)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-l,8,ll,12-tetrazatricyclo[8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole. A solution of l,3-dioxol-2-one (103 mg, 1.20 mmol, 1.2 equiv) and 2-[(95)-7-(4-chlorophenyl)- 4,5,13-trimethyl-3-thia-l, 8,1 l,12-tetrazatricyclo[8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamide (400 mg, 1.00 mmol, 1.0 equiv) in PPA (4 mL) was stirred at 160 °C for 3 hours. The mixture was quenched with H2O (50 mL) at 0°C and then diluted with ethyl acetate (200 mL). The mixture was washed with H2O (15 mL x 2) and then further washed with H2O (10 mL x 3) again to remove PPA. The combined organic layers were washed with H2O (10 mL x 3), dried over Na? SO4, filtered, and concentrated. The residue was purified by column chromatography (SiCh, petroleum etherethyl acetate = 2:1 to 0:1) to give 2-[[(95)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-l,8,ll,12-tetrazatricyclo[8.3.0.02-6]trideca-2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole (260 mg, 61% yield).

[0230] Step 4: Preparation of tert-butyl 2-[4-[(95)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-l,8,ll,12-tetrazatricyclo[8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-7-yl] phenoxy]-7-azaspiro[3.5]nonane-7-carboxylate. To a solution of 2-[[(9S)-7-(4-chlorophenyl)- 4.5.13-trimethyl-3-thia-l, 8,1 l,12-tetrazatricyclo[8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole (300 mg, 707 pmol, 1.0 equiv and tert-butyl 2-hydroxy-7-azaspiro[3.5] nonane-7-carboxylate (853 mg, 3.54 mmol, 5.0 equiv) in dioxane (5 mL) was added tBuXPhos Pd G3 (112 mg, 141 pmol, 0.2 equiv) and CS2CO3 (1.1 g, 3.5 mmol, 5.0 equiv). The mixture was degassed and purged with N23 times, and then the mixture was stirred at 90 °C for 2 hours under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 2 g SepaFlash® Silica Flash Column, eluent of 0~3% methanol / dichloromethanegradient at 18 mL / min) to give tert-butyl 2-[4-[(9 )-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-l,8,ll,12-tetrazatricyclo[8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro[3.5]nonane-7-carboxylate (210 mg, 333 pmol, 47% yield) as a yellow solid.

[0231] Step 5: Preparation of 2-[[(95)-7-[4-(7-azaspiro[3.5]nonan-2-yloxy)phenyl]- 4.5.13-trimethyl-3-thia-l,8,ll,12-tetrazatricyclo[8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-9-yl] methyl] oxazole. A mixture of tert-butyl 2-[4-[(95’)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-l,8,ll,12-tetrazatricyclo[8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro[3.5]nonane-7-carboxylate (210 mg, 333 pmol, 1.0 equiv) in DCM (2 mL) and TFA (0.6mL) was degassed and purged with N23 times. The mixture was stirred at 25 °C for 30 minutes under N2 atmosphere. The mixture was concentrated to give a residue, 2-[[(9S)-7-[4-(7-azaspiro [3.5]nonan-2-yloxy)phenyl]-4,5,13-trimethyl-3-thia-l,8,ll,12-tetrazatricyclo [8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole (214 mg, 332 pmol, 99% yield, TFA), as a brown oil, which was used directly in the next step without purification.

[0232] Step 6: Preparation of A-|(lr.3r)-3-(4-cyano-3-methoxy-phenoxy)-2.2.4.4-tetraniethyl-cyclobutyl]-2-[2-[4-[(95)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-l,8,ll,12-tetrazatricyclo[8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro[3.5] nonan-7-yl]pyrimidine-5-carboxamide (H-5). To a solution of2-[[(95)-7-[4-(7-azaspiro[3.5]nonan-2-yloxy)phenyl]-4,5,13-trimethyl-3-thia-l,8,l l,12-tetrazatricyclo[8.3.0.02’6] trideca-2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole (80 mg, 151 pmol, 1.0 equiv) and 2-chloro-Ar-[(lr,3r)-3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]pyrimidine-5-carboxamide (94 mg, 227 pmol, 1.5 equiv) in NMP (0.5 mL) was added DIEA (60 mg, 460 pmol, 0.1 mL, 3.0 equiv). The mixture was stirred at 25 °C for 8 hours. The reaction mixture was filtered and concentrated to give a residue. The residue was purified by / ?re / ?-HPLC (column: Waters Xbridge C18 150 mm x 50mm x 10 pm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 54%-84% B over 10 min) to giveA-[(l / ',3r)-3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[2-[4-[(95)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-l,8,l 1,12-tetrazatri cyclo[8.3.0.02,6]trideca-2(6), 4, 7, 10, 12-pentaen-7-yl]phenoxy]-7-azaspiro[3.5]nonan-7-yl]pyrimidine-5-carboxamide (63.7 mg, 70.13 pmol, 46% yield, 99.86% purity) as a white solid. ' H NMR (400 MHz, CD3OD) 88.74 (s, 2H), 7.91 (d, J= 0.8 Hz, 1H), 7.54 (d, J= 8.6 Hz, 1H), 7.34 (d, J= 8.8 Hz, 2H), 7.14 (d, J= 0.8 Hz, 1H), 6.85 (d, J= 8.9 Hz, 2H), 6.64 (d, J= 2.1 Hz, 1H), 6.57 (dd, J= 2.1, 8.6 Hz, 1H), 4.79 - 4.71 (m, 2H), 4.27 - 4.25 (m, 1H), 4.16 - 4.12 (m, 1H), 3.95 (s, 7H), 3.90 - 3.83 (m, 2H), 2.72 (s, 3H), 2.61 - 2.50 (m, 2H), 2.48 (s, 3H), 2.03 - 1.92 (m, 2H), 1.72 (s, 7H), 1.30 (s, 6H), 1.24 (s, 6H). LC-MS: MS (ES+): RT = 2.698 min, m / z = 907.4 [M+H]+.EXAMPLE 2 - Synthesis of N-[(lr,3r)-3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-l,8,ll,12-tetrazatricyclo [8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro[3.5]nonan-7-yl]pyrimidine-5-carboxamide Crystal Form A (II-5 in Crystal Form A)Part 1 - Preparation of 2-[[(9X)-7-[4-(7-Azaspiro[3.5]nonan-2-yloxy)phenyl]-4,5,13-trimethyl-3-thia-l,8,ll,12-tetrazatricyclo[8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-9-yl] m ethyl] oxaz ole

[0233] To a solution of / e / 7-butyl 2-[4-[(9, S')-4,5, l3-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,1 l,12-tetrazatricyclo[8.3.0.02-6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro [3.5]nonane-7-carboxylate (22.5 g, 35.78 mmol, 1.0 equiv) in DCM (50 mL) was added TFA (31 mL). The mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched by addition of NaHCCh (300 mL) at 0 °C. The aqueous layer was washed with (DCM / MeOH=10: 1; 300 mL x 3), and then the combined organic layers were dried over Na2SC>4, filtered, and concentrated under reduced pressure to afford 2-[[(9S)-7-[4-(7-azaspiro[3.5]nonan-2-yloxy) phenyl]-4,5,13-trimethyl-3 -thia- 1,8,11,12-tetrazatri cyclo [8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole (18.5 g, 35.0 mmol, 98% yield) as a yellow solid. LC-MS: MS (ES+): RT = 0.686 min, m / z = 529.3 [M + H+],Part 2 - Preparation of Ze / - Butyl N-[(lr, 3r)-3-(4-Cyano-3-methoxy-phenoxy)-2, 2,4,4-tetramethyl-cyclobutyljcarbamate56% yield

[0234] To a solution of Zc / Z-butyl N-((lr,3r)-3-hydroxy-2,2,4,4-tetramethyl-cyclobutyl) carbamate (65.0 g, 267 mmol, 1.0 equiv} in DMF (1 L) was added NaH (10.7 g, 267 mmol, 60% purity, 1.0 equiv at 0°C. The reaction mixture was stirred at 0 °C for 0.5 h. Then 4-fluoro-2-methoxy -benzonitrile (40.4 g, 267 mmol, 1.0 equiv was added. The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched with saturated aqueous NH4CI (20 mb) solution at 0 °C and diluted with water (5 L). The mixture was extracted with ethyl acetate (1 L x 3). The combined organic layers were combined, washed with brine (1 L), dried over anhydrous Na2SO4, fdtered, and concentrated in vacuum. The resulting residue was recrystallized from EtOH (1 L), and the resulting solid was fdtered. The fdter cake was dried to afford ZcvZ-butyl N-[(lr,3r)-3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]carbamate (56.5 g, 151 mmol, 56% yield) as a white solid. LC-MS: MS (ES+): RT = 0.966 min, m / z = 375.3 [M + H+], Part 3 - Preparation of 4-((lr,3r)-3-Amino-2,2,4,4-tetramethyl-cyclobutoxy)-2-methoxy-benzonitrile

[0235] To a solution of ZcvZ-butyl N-[(lr,3r)-3-(4-cyano-3-methoxy-phenoxy)-2, 2,4,4-tetramethyl-cyclobutyl]carbamate (50 g, 133.52 mmol, 1 equiv} in dioxane (125 m ) was added HCI / dioxane (4 M, 125 mb, 3.74 equiv}. The mixture was stirred at 50 °C for 12 h. The reaction mixture was concentrated under reduced pressure to afford crude product 4-((lr,3r)-3-amino-2,2,4,4-tetramethyl-cyclobutoxy)-2-methoxy-benzonitrile (41.5 g, 134 mmol, 100% yield, HC1 salt) as a white solid and it was used in the next step without further purification. LC-MS: MS (ES+): RT = 0.492 min, m / z = 275.2 [M + H+],Part 4 - Preparation of 2-Chloropyrimidine-5-carbonyl Chloride

[0236] To a solution of 2-chloropyrimidine-5-carboxylic acid (32.0 g, 202 mmol, 1.0 equiv) in DCM (240 mL) was added oxalyl dichloride (76.9 g, 606 mmol, 53.0 mL, 3.0 equiv) and DMF (738 mg, 10.1 mmol, 776 pL, 0.1 equiv). The mixture was stirred at 40 °C for 1 h. The reaction mixture was concentrated under reduced pressure to afford 2-chloropyrimidine-5-carbonyl chloride (35.7 g, 202 mmol, 99.94% yield) as a yellow oil, which was used in the next step without further purification.Part 5 - Preparation of 2-Chloro-N-[(lr, 3r)-3-(4-cyano-3-methoxy-phenoxy)-2, 2,4,4-tetramethyl-cyclobutyl]pyrimidine-5-carboxamide

[0237] To a solution of 4-((17',3r)-3-amino-2,2,4,4-tetramethyl-cyclobutoxy)-2-methoxy-benzonitrile (41.5 g, 134 mmol, 1.0 equiv HC1 salt) in THF (215 mL) was added DIEA (86.3 g, 668 mmol, 116 mL, 5.0 equiv), followed by 2-chloropyrimidine-5-carbonyl chloride (35.5 g, 200 mmol, 1.5 equiv) in THF (215 mL) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. The mixture was poured into ice water (2 L), and then extracted with EA (2 L x 3). The combined organic layers were washed with brine (2 L), dried, filtered, and concentrated under reduced pressure to give a residue. The crude product was triturated with EA (500 mL) at 25 °C for 12 min to afford 2-chloro-N-[(lr,3r)-3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]pyrimidine-5-carboxamide (45.0 g, 108 mmol, 81% yield) as a yellow solid.Part 6 - Preparation of N-[(lr,3r)-3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-l,8,ll,12-tetrazatricyclo [8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro[3.5] nonan-7-yl]pyrimidine-5-carboxamide (II-5)

[0238] To a solution of 2-[[(95)-7-[4-(7-azaspiro[3.5]nonan-2-yloxy)phenyl]-4,5,13-trimethyl-3 -thia- 1,8,1 l,12-tetrazatricyclo[8.3.0.02-6]trideca-2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole (13.0 g, 24.6 mmol, 1.0 equiv) and 2-chloro-N-[(lr,3r)-3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]pyrimidine-5-carboxamide (10.7 g, 25.8 mmol, 1.1 equiv) in NMP (30 mL) was added DIEA (9.53 g, 73.8 mmol, 12.9 mL, 3.0 equiv). The mixture was stirred at 25 °C for 8 h. The reaction mixture was diluted with DCM / MeOH (10:1, 300 mL) and washed with H2O (100 mL x 3). The organic phase was dried and concentrated. The crude product was purified by column chromatography (SiCL, Rf = 0.4, EA / MeOH = 10 / 1) to afford N-[(lr,3r)-3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-l, 8,11,12-tetrazatricyclo[8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro[3.5]nonan-7-yl]pyrimidine-5-carboxamide (19.5 g, 21.2 mmol, 87 % yield, 98.5% purity) as a white solid. 'H NMR (400 MHz, CD3OD) 58.74 (s, 2H), 7.91 (d, J= 0.8 Hz, 1H), 7.54 (d, J= 8.6 Hz, 1H), 7.34 (d, J= 8.8 Hz, 2H), 7.14 (d, J= 0.8 Hz, 1H), 6.85 (d, J= 8.9 Hz, 2H), 6.64 (d, J= 2.1 Hz, 1H), 6.57 (dd, J= 2.1, 8.6 Hz, 1H), 4.79 - 4.71 (m, 2H), 4.27 - 4.25 (m, 1H), 4.16 - 4.12 (m, 1H), 3.95 (s, 7H), 3.90 - 3.83 (m,2H), 2.72 (s, 3H), 2.61 - 2.50 (m, 2H), 2.48 (s, 3H), 2.03 - 1.92 (m, 2H),1.72 (s, 7H), 1.30 (s, 6H), 1.24 (s, 6H). LC-MS: MS (ES+): RT = 2.698 min, m / z = 907.4 [M +H+],Part 7 - Preparation of N-[(lr,3r)-3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-l,8,ll,12-tetrazatricyclo [8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-7-yI]phenoxy]-7-azaspiro[3.5] nonan-7-yl]pyrimidine-5-carboxamide Crystal Form A (II-5 in Crystal Form A)

[0239] To N-[(lr,3r)-3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-l,8,ll,12-tetrazatricyclo[8.3.0.02’6] trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro[3.5]nonan-7-yl]pyrimidine-5-carboxamide (90.0 g, 99.2 mmol) was added CH3CN (450 mL), and then it was refluxed for 1 h until the reaction mixture turned clear. The mixture was slowly cooled to 25 °C, and a white precipitate formed. After filtering, the filter cake was washed with CH3CN (50 mL x 2) and dried to afford N-[( l / ',3 / ')-3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-l,8,ll,12-tetrazatricyclo [8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro[3.5] nonan-7-yl]pyrimidine-5-carboxamide Crystal Form A (77.0 g, 84.9 mmol, 86% yield, 99.7% purity) as a white crystalline solid. The filtrate was concentrated to afford a light brown foam (13.0 g, 13.5 mmol, 14% yield, 94% purity). LC-MS: MS (ES+): RT = 0.667 min, m / z = 907.5 [M + H+],1H NMR (400 MHz, CD3OD) 88.75 - 8.70 (m, 2H), 7.92 - 7.89 (m, 1H), 7.53 (d, J= 8.6 Hz, 1H), 7.32 (d, J= 8.7 Hz, 2H), 7.13 (s, 1H), 6.84 (d, J= 8.8 Hz, 2H), 6.63 (d, J= 2.2 Hz, 1H), 6.56 (dd, J= 2.1, 8.6 Hz, 1H), 4.84 - 4.81 (m, 1H), 4.77 - 4.71 (m, 1H), 4.25 (s, 1H), 4.13 (s, 1H), 3.99 - 3.89 (m,7H), 3.88 - 3.82 (m, 2H), 2.71 (s, 3H), 2.58 - 2.50 (m, 2H), 2.46 (s, 3H), 2.02 - 1.93 (m, 2H), 1.74 - 1.66 (m, 7H), 1.28 (s, 6H), 1.23 (s, 6H).EXAMPLE 3 - Physical Characterization ofN-[(lr,3r)-3-(4-Cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetrazatricyclo [8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro [3.5]nonan-7-yl]pyrimidine-5-carboxamide Crystal Form A (II-5 in Crystal Form A)

[0240] X-ray powder diffraction was performed using a LYNXEYE_XE_T detector operated in reflection mode. Samples were prepared on monocrystalline silicon, flat surface sample holders. Parameters for XRPD were:

[0241] An X-ray powder diffractogram taken on the title compound is provided in Figure 1. Tabulated characteristics of the X-ray powder diffractogram in Figure 1 are provided in the following table, which lists diffraction angle 20, inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak):X-Ray Powder Diffractogram Data

[0242] Differential scanning calorimetry analysis was performed on the title compound using a TA Discovery 2500 instrument with nitrogen gas flow of 50 mL / min. The sample (1-2 mg)was weighed into Tzero sample pan with a Tzero hermetic lid with a pinhole (0.7 mm diameter) and analyzed according to the following parameters: ramp method, heating rate 10 °C / min, temperature range 30 to 250 °C or before decomposition. A differential scanning calorimetry curve of the title compound obtained according to this procedure is provided in Figure 2. A melting peak was observed with an onset temperature of 192.0 °C and 38 J / g.

[0243] Thermogravimetric analysis on the title compound was performed using a TA Discovery 5500 instrument. Nitrogen flow rate was 10 mL / min at the balance and 25 mL / min in the sample chamber. The sample (2-10 mg) was weighed directly into an open aluminum pan and analyzed according to the following parameters: ramp method, heating rate 10.0 °C / min, and temperature range ambient temperature (below 35 °C) to 300 °C (or until weight <80%). A thermogravimetric analysis curve of the title compound is provided in Figure 3. A weight loss of 0.2% w / w was observed at 180 °C.

[0244] The title compound was determined to be 99.7% pure by high-pressure liquid chromatography (HPLC).Stability to Storage

[0245] To investigate the influence of relative humidity on the physical stability of Compound II- 5 in Crystal Form A, a sample of Compound II- 5 in Crystal Form A was held at a temperature of 23-25 °C in an environment with relative humidity levels (RH) ranging from 23% RH to 53% RH. After storage of Compound II-5 in Crystal Form A under the preceding conditions for a period of one week, no change in crystalline form was observed.EXAMPLE 4 - Synthesis of N-[(lr,3r)-3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-l,8,ll,12-tetrazatricyclo [8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro [3.5]nonan-7-yl]pyrimidine-5-carboxamide Crystal Form B (II-5 in Crystal Form B)

[0246] About 50 mg of amorphous N-[(lr,3r)-3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-l,8,l 1,12-tetrazatri cyclo[8.3.0.02,6]trideca-2(6), 4, 7, 10, 12-pentaen-7-yl]phenoxy]-7-azaspiro[3.5]nonan-7-yl]pyrimidine-5-carboxamide was equilibrated in 0.15-0.35 mb of solvent that was EtOAc / MTBE (1 / 4, v / v) at 50°C for 24 days with a stirring bar on a magnetic stirring plate at a rate of 600 rpm. On the sixth day, about 1 mg of a nucleating agent was added to the mixture toassist crystallization. On day 20, about 1 mg ofN-[(lr,3r)-3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetrazatricyclo [8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro[3.5]nonan-7-yl]pyrimidine-5-carboxamide Crystal Form A was added to the mixture. On day 24, the resulting suspension was fdtered through a 0.45 pm membrane fdter by centrifugation. The isolated solid was collected and determined to be the title compound, Compound II- 5 in Crystal Form B.EXAMPLE 5 - Physical Characterization ofN-[(lr,3r)-3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetrazatricyclo [8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro[3.5]nonan-7-yl]pyrimidine-5-carboxamide Crystal Form B (II-5 in Crystal Form B)

[0247] An X-ray powder diffractogram taken on the title compound, using the method described in Example 3, is provided in Figure 14. Tabulated characteristics of the X-ray powder diffractogram in Figure 14 are provided in the following table, which lists diffraction angle 20, inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak):X-Ray Powder Diffractogram Data

[0248] Differential scanning calorimetry analysis was performed on the title compound using the method described in Example 3. A differential scanning calorimetry curve of the title compound obtained according to this procedure is provided in Figure 15. A melting peak, which presented with a shoulder, was observed with an onset temperature of191.7 °C and 37 J / g.

[0249] Therm ogravimetric analysis on the title compound was performed using the method described in Example 3. A thermogravimetric analysis curve of the title compound is provided in Figure 16. A weight loss of 1.4% w / w was observed at 180 °C.

[0250] The title compound was determined to be 99.6% pure by high-pressure liquid chromatography (HPLC).EXAMPLE 6 - Synthesis of N-[(lr,3r)-3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-l,8,ll,12-tetrazatricyclo [8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro [3.5]nonan-7-yl]pyrimidine-5-carboxamide Crystal Form Cl (II-5 in Crystal Form Cl)

[0251] About 50 mg of amorphous N-[(lr,3r)-3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-l,8,l 1,12-tetrazatricyclo[8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro[3.5]nonan-7-yl]pyrimidine-5-carboxamide was equilibrated in 0.15-0.35 mb of solvent that was2-methyltetrahydrofuran / cyclopentyl methyl ether (1 / 4, v / v) at 50°C for 24 days with a stirring bar on a magnetic stirring plate at a rate of 600 rpm. On the sixth day, about 1 mg of a nucleating agent was added to the mixture to assist crystallization. On day 20, about 1 mg of Crystal Form A of Compound II-5 was added to the mixture. On day 24, the resulting suspension was filtered through a 0.45 pm membrane filter by centrifugation at 14,000 rpm. The isolated solid was collected and determined to be the title compound, Compound II- 5 in Crystal Form Cl.EXAMPLE 7 - Physical Characterization ofN-[(lr,3r)-3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetrazatricyclo [8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro[3.5]nonan-7-yl]pyrimidine-5-carboxamide Crystal Form Cl (II-5 in Crystal Form ci)

[0252] The title compound was determined to contain 0.3 molar equivalents of cyclopentyl methyl ether (relative to Compound II-5) by 'H NMR in <75-DMSO.

[0253] An X-ray powder diffractogram taken on the title compound, using the method described in Example 3, is provided in Figure 17. Tabulated characteristics of the X-ray powder diffractogram in Figure 17 are provided in the following table, which lists diffraction angle 20, inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak):X-Ray Powder Diffractogram Data

[0254] Differential scanning calorimetry analysis was performed on the title compound using the method described in Example 3. A differential scanning calorimetry curve of the title compound obtained according to this procedure is provided in Figure 18. A first endothermicpeak was observed with an onset temperature of 101.5 °C and 1 J / g, and a melting peak was observed with an onset temperature of 183.0 °C and 34 J / g.

[0255] Thermogravimetric analysis on the title compound was performed using the method described in Example 3. A thermogravimetric analysis curve of the title compound is provided in Figure 19. A weight loss of 3.2% w / w was observed at 130 °C, and an additional weight loss of 0.4% w / w was observed from 130 °C to 170 °C.EXAMPLE 8 - Synthesis of N-[(lr,3r)-3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-l,8,ll,12-tetrazatricyclo [8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro [3.5]nonan-7-yl]pyrimidine-5-carboxamide Crystal Form C2 (II-5 in Crystal Form C2)

[0256] About 50 mg of amorphous N-[(l / -,3 / ')-3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-l,8,l 1,12-tetrazatricyclo[8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro[3.5]nonan-7-yl]pyrimidine-5-carboxamide was equilibrated in 0.15-0.35 mb of solvent that was 2-propanol / water (1 / 1, v / v) at 50°C for 24 days with a stirring bar on a magnetic stirring plate at a rate of 600 rpm. On the sixth day, about 1 mg of a nucleating agent was added to the mixture to assist crystallization. On day 20, about 1 mg of Crystal Form A of Compound II- 5 was added to the mixture. On day 24, the resulting suspension was fdtered through a 0.45 pm membrane fdter by centrifugation at 14,000 rpm. The isolated solid was collected and determined to be the title compound, Compound 11-5 in Crystal Form C2.EXAMPLE 9 - Physical Characterization ofN-[(lr,3r)-3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetrazatricyclo [8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro[3.5]nonan-7-yl]pyrimidine-5-carboxamide Crystal Form C2 (IT-5 in Crystal Form C2)

[0257] The title compound was determined to contain 0.4 molar equivalents of 2-propanol (relative to Compound I

[0258] An X-ray powder diffractogram taken on the title compound, using the method described in Example 3, is provided in Figure 20. Tabulated characteristics of the X-ray powderdiffractogram in Figure 20 are provided in the following table, which lists diffraction angle 20, inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak):X-Ray Powder Diffractogram Data

[0259] Differential scanning calorimetry analysis was performed on the title compound using the method described in Example 3. A differential scanning calorimetry curve of the title compound obtained according to this procedure is provided in Figure 21. Endothermic peaks were observed with an onset temperature of 33.9 °C and 0.3 J / g and an onset temperature of 67.8 °C and 4 J / g. A melting peak was observed with an onset temperature of 185.5 °C and 68 J / g.

[0260] Therm ogravimetric analysis on the title compound was performed using the method described in Example 3. A thermogravimetric analysis curve of the title compound is provided in Figure 22. A weight loss of 2.0% w / w was observed at 120 °C, and an additional weight loss of 0.3% w / w was observed from 120 °C to 175 °C.EXAMPLE 10 - Synthesis of N-[(lr,3r)-3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia- 1.8.11.12-tetrazatricyclo [8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro [3.5]nonan-7-yl]pyrimidine-5-carboxamide Crystal Form C3 (II-5 in Crystal Form C3)

[0261] About 40 mg of Crystal Form A ofN-[(lr,3r)-3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia- 1.8.11.12-tetrazatricyclo[8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro[3.5]nonan-7-yl]pyrimidine-5-carboxamide was equilibrated in 0.15-0.25 m of solvent that was 1,4-dioxane / water (1 / 3, v / v) at 50°C for one week with a stirring bar on a magnetic stirring plate at a rate of 600 rpm. The resulting suspension was filtered through a 0.45 pm membrane filter by centrifugation at 14,000 rpm. The isolated solid was collected and determined to be the title compound, Compound II-5 in Crystal Form C3.EXAMPLE 11 - Physical Characterization ofN-[(lr,3r)-3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetrazatricyclo [8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro[3.5]nonan-7-yI]pyrimidine-5-carboxamide Crystal Form C3 (II-5 in Crystal Form C3)

[0262] The title compound was determined to contain 1.9 molar equivalents of 1,4-dioxane (relative to Compound 11-5) byNMR in t / ^-DMSO. The title compound was determined to contain 0.2% w / w water (0.1 molar equivalent relative to Compound II-5) by Karl-Fischer titration.

[0263] An X-ray powder diffractogram taken on the title compound, using the method described in Example 3, is provided in Figure 23. Tabulated characteristics of the X-ray powder diffractogram in Figure 23 are provided in the following table, which lists diffraction angle 29, inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak):X-Ray Powder Diffractogram Data

[0264] Differential scanning calorimetry analysis was performed on the title compound using the method described in Example 3. A differential scanning calorimetry curve of the title compound obtained according to this procedure is provided in Figure 24. A first endothermic peak was observed with an onset temperature of 98.6 °C and 2 J / g, and a melting peak was observed with an onset temperature of 187.8 °C and 31 J / g.

[0265] Therm ogravimetric analysis on the title compound was performed using the method described in Example 3. A thermogravimetric analysis curve of the title compound is provided in Figure 25. A weight loss of 1.8% w / w was observed at 130 °C, and an additional weight loss of 0.2% w / w was observed from 130 °C to 175 °C.EXAMPLE 12 - Synthesis of N-[(lr,3r)-3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetrazatricyclo [8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro [3.5]nonan-7-yl]pyrimidine-5-carboxamide Crystal Form D (II-5 in Crystal Form D)

[0266] Step 1: About 40 mg of Crystal Form A ofN-[(lr,3r)-3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-l,8,l l,12-tetrazatricyclo[8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro[3.5]nonan-7-yl]pyrimidine-5-carboxamide was equilibrated in 0.15-0.25 m of water at 50°C for one week with a stirring bar on a magnetic stirring plate at a rate of 600 rpm. The resulting suspension was filtered through a 0.45 pm membrane filter by centrifugation at 14,000 rpm. The isolated solid was collected and determined to be a mixture of the title compound, Compound 11-5 in Crystal Form D, and the starting material, Compound 11-5 in Crystal Form A.

[0267] Step 2: A saturated solution of Compound II-5 in acetone / water (85 / 15, v / v) was prepared. To 0.15-0.4 mb of the solution was added about 3 mg of Crystal Form A of Compound 11-5, about 3 mg of Crystal Form B of Compound 11-5, and about 3 mg of the product of the prior step (a mixture of Crystal Forms A and D of Compound II-5). The resulting suspension was stirred at 25°C for one week. The suspension was filtered through a 0.45 pm membrane filter by centrifugation. The isolated solid was collected and determined to be the title compound, Compound 11-5 in Crystal Form D.EXAMPLE 13 - Physical Characterization ofN-[(lr,3r)-3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetrazatricyclo [8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro[3.5]nonan-7-yl]pyrimidine-5-carboxamide Crystal Form D (II-5 in Crystal Form D)

[0268] The product of Step 1 of Example 12 was determined to contain no detectable residual solvent by1H NMR in d6-DMSO. The product of Step 1 of Example 12 was determined to contain 2.2% w / w water (1.1 molar equivalent relative to Compound II-5) by Karl -Fischer titration.

[0269] An X-ray powder diffractogram taken on the product of Step 2 of Example 12, using the method described in Example 3, is provided in Figure 26. Tabulated characteristics of the X-ray powder diffractogram in Figure 26 are provided in the following table, which lists diffraction angle 20, inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak):X-Ray Powder Diffractogram Data

[0270] Differential scanning calorimetry analysis was performed on the product of Step 1 of Example 12 using the method described in Example 3. A differential scanning calorimetry curve of the compound is provided in Figure 27. A dehydration peak was observed with an onsettemperature of 27.4 °C and 13 J / g, and a melting peak was observed with an onset temperature of 184.1 °C and 29 J / g.

[0271] Thermogravimetric analysis on the product of Step 1 of Example 12 was performed using the method described in Example 3. A thermogravimetric analysis curve of the compound is provided in Figure 28. A weight loss of 0.8% w / w was observed at 60 °C, and an additional weight loss of 0.3% w / w was observed from 60 °C to 170 °C.EXAMPLE 14 - Synthesis of N-[(lr,3r)-3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetrazatricyclo [8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro [3.5]nonan-7-yl]pyrimidine-5-carboxamide Crystal Form E (II-5 in Crystal Form E)

[0272] About 40 mg of Crystal Form A of N-[(l / -,3 / ')-3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,1 l,12-tetrazatricyclo[8.3.0.02-6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro[3.5]nonan-7-yl]pyrimidine-5-carboxamide was equilibrated in 0.15-0.25 mL of EtOAc at 50°C for one week with a stirring bar on a magnetic stirring plate at a rate of 600 rpm. The resulting suspension was filtered through a 0.45 pm membrane filter by centrifugation at 14,000 rpm. The isolated solid was collected and determined to be the title compound, Compound II- 5 in Crystal Form E.EXAMPLE 15 - Physical Characterization ofN-[(lr,3r)-3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetrazatricyclo [8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro[3.5]nonan-7-yl]pyrimidine-5-carboxamide Crystal Form E (II-5 in Crystal Form E)

[0273] The title compound was determined to contain 0.5 molar equivalents of ethyl acetate (relative to Compound I.

[0274] An X-ray powder diffractogram taken on the title compound, using the method described in Example 3, is provided in Figure 29. Tabulated characteristics of the X-ray powder diffractogram in Figure 29 are provided in the following table, which lists diffraction angle 20,inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak):X-Ray Powder Diffractogram Data

[0275] Differential scanning calorimetry analysis was performed on the title compound using the method described in Example 3. A differential scanning calorimetry curve of the title compound obtained according to this procedure is provided in Figure 30. Two endothermic peaks were observed with an onset temperature of 27.3 °C and 4 J / g and with an onset temperature of 74.3 °C and 2 J / g. A melting peak was observed with an onset temperature of 190.6 °C and 40 J / g.

[0276] Therm ogravi metric analysis on the title compound was performed using the method described in Example 3. A thermogravimetric analysis curve of the title compound is provided in Figure 31. A weight loss of 0.8% w / w was observed at 60 °C, and an additional weight loss of 0.3% w / w was observed from 60 °C to 170 °C.EXAMPLE 16 - Synthesis of N-[(lr,3r)-3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetrazatricyclo [8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro [3.5]nonan-7-yI]pyrimidine-5-carboxamide Crystal Form F (II-5 in Crystal Form F)

[0277] A saturated solution of Compound II- 5 in acetonitrile / water (98 / 2, v / v) was prepared. To 0.15-0.4 mL of the solution was added about 3 mg of Crystal Form A of Compound II-5, about 3 mg of Crystal Form B of Compound 11-5, and 3 mg of the product Step 1 of Example 12 (a mixture of Crystal Forms A and D of Compound II-5). The resulting suspension was stirred at 25°C for 3 days. The suspension was filtered through a 0.45 pm membrane filter by centrifugation. The isolated solid was collected and determined to be Compound II-5 in Crystal Form A. The solid was stirred at 25°C for an additional 7 days in acetonitrile / water (98 / 2, v / v), then the sample was analyzed by XRPD with a Kapton film covering. The material was determined to be the title compound, Compound II-5 in Crystal Form F. After removal of the Kapton film and exposure for 24 hours to ambient conditions (~25 °C and -30% RH), the material converted to a mixture of Crystal Forms A and D of Compound TT-5.EXAMPLE 17 - Physical Characterization ofN-[(lr,3r)-3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetrazatricyclo [8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro[3.5]nonan-7-yI]pyrimidine-5-carboxamide Crystal Form F (II-5 in Crystal Form F)

[0278] An X-ray powder diffractogram taken on the title compound, using Kapton film as described in Example 16, and using the method described in Example 3, is provided in Figure 32. Tabulated characteristics of the X-ray powder diffractogram in Figure 32 are provided in the following table, which lists diffraction angle 20, inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak):X-Ray Powder Diffractogram DataEXAMPLE 18 - Synthesis of N-[(lr,3r)-3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cydobutyl]-2-[2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia- 1.8.11.12-tetrazatricyclo [8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro [3.5]nonan-7-yl]pyrimidine-5-carboxamide Crystal Form G (II-5 in Crystal Form G)

[0279] About 40 mg of Crystal Form A ofN-[(lr,3r)-3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia- 1.8.11.12-tetrazatricyclo[8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro[3.5]nonan-7-yl]pyrimidine-5-carboxamide was equilibrated in 0.15-0.25 mL of solvent that was methanol / water (1 / 3, v / v) at 50°C for one week with a stirring bar on a magnetic stirring plate at a rate of 600 rpm. The resulting suspension was fdtered through a 0.45 pm membrane filter by centrifugation at 14,000 rpm. The isolated solid was collected and determined to be the title compound, Compound 11-5 in Crystal Form G.EXAMPLE 19 - Physical Characterization ofN-[(lr,3r)-3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia- 1.8.11.12-tetrazatricyclo [8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro[3.5]nonan-7-yl]pyrimidine-5-carboxamide Crystal Form G (II-5 in Crystal Form G)

[0280] The title compound was determined to contain 1.9 molar equivalents of methanol (relative to Compound II-5) byNMR in t / e-DMSO. The title compound was determined to contain 1.6% w / w water (0.9 molar equivalent relative to Compound II-5) by Karl-Fischer titration.

[0281] An X-ray powder diffractogram taken on the title compound, using the method described in Example 3, is provided in Figure 33. Tabulated characteristics of the X-ray powder diffractogram in Figure 33 are provided in the following table, which lists diffraction angle 20, inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak):X-Ray Powder Diffractogram Data

[0282] Differential scanning calorimetry analysis was performed on the title compound using the method described in Example 3. A differential scanning calorimetry curve of the title compound obtained according to this procedure is provided in Figure 34. A desolvation peak was observed with an onset temperature of 57.2 °C and 3 J / g, and a melting peak was observed with an onset temperature of 185.1 °C and 21 J / g.

[0283] Therm ogravi metric analysis on the title compound was performed using the method described in Example 3. A thermogravimetric analysis curve of the title compound is provided in Figure 35. A weight loss of 0.7% w / w was observed at 70 °C, and an additional weight loss of 1.2% w / w was observed from 70 °C to 175 °C.EXAMPLE 20 - Synthesis of N-[(lr,3r)-3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia- 1.8.11.12-tetrazatricyclo [8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro [3.5]nonan-7-yI]pyrimidine-5-carboxamide Crystal Form H (II-5 in Crystal Form H)

[0284] About 40 mg of Crystal Form A ofN-[(lr,3r)-3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia- 1.8.11.12-tetrazatricyclo[8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro[3.5]nonan-7-yl]pyrimidine-5-carboxamide was equilibrated in 0.25-0.4 mL of methyl isobutyl ketone at 25°C for two weeks with a stirring bar on a magnetic stirring plate at a rate of 600 rpm. The resulting suspension was fdtered through a 0.45 pm membrane fdter by centrifugation at 14,000 rpm. The isolated solid was collected and determined to be the title compound, Compound 11-5 in Crystal Form H.EXAMPLE 21 - Physical Characterization ofN-[(lr,3r)-3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia- 1.8.11.12-tetrazatricyclo [8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro[3.5]nonan-7-yl]pyrimidine-5-carboxamide Crystal Form H (II-5 in Crystal Form H)

[0285] The title compound was determined to contain 0.8 molar equivalents of methyl isobutyl ketone (relative to Compound II-5) byNMR in tfc-DMSO.

[0286] An X-ray powder diffractogram taken on the title compound, using the method described in Example 3, is provided in Figure 36. Tabulated characteristics of the X-ray powder diffractogram in Figure 36 are provided in the following table, which lists diffraction angle 20, inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak):X-Ray Powder Diffractogram Data

[0287] Differential scanning calorimetry analysis was performed on the title compound using the method described in Example 3. A differential scanning calorimetry curve of the title compound obtained according to this procedure is provided in Figure 37. A desolvation peak was observed with an onset temperature of 96.5 °C and 5 J / g, and a melting peak was observed with an onset temperature of 187.7 °C and 30 J / g.

[0288] Therm ogravimetric analysis on the title compound was performed using the method described in Example 3. A thermogravimetric analysis curve of the title compound is providedin Figure 38. A weight loss of 3.0% w / w was observed at 150 °C, and an additional weight loss of 0.2% w / w was observed from 150 °C to 175 °C.EXAMPLE 22 - Synthesis of N-[(lr,3r)-3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetrazatricyclo [8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro [3.5]nonan-7-yl]pyrimidine-5-carboxamide Crystal Form I (II-5 in Crystal Form I)

[0289] A saturated solution of Compound II- 5 in ethanol / water (70 / 30, v / v) was prepared. To 0.15-0.4 mL of the solution was added about 3 mg of Crystal Form A of Compound II-5, about 3 mg of Crystal Form B of Compound II-5, and 3 mg of the product Step 1 of Example 12 (a mixture of Crystal Forms A and D of Compound II-5). The resulting suspension was stirred at 25°C for 3 days. The suspension was filtered through a 0.45 pm membrane filter by centrifugation. The isolated solid was collected and determined to be the title compound, Compound II- 5 in Crystal Form I.EXAMPLE 23 - Physical Characterization ofN-[(lr,3r)-3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetrazatricyclo [8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro[3.5]nonan-7-yl]pyrimidine-5-carboxamide Crystal Form I (II-5 in Crystal Form I)

[0290] The title compound was determined to contain 1.6 molar equivalents of ethanol (relative to Compound II-5) by1H NMR in d6-DMSO. The title compound was determined to contain 2.4% w / w water (1.3 molar equivalents relative to Compound II-5) by Karl-Fischer titration.

[0291] An X-ray powder diffractogram taken on the title compound, using the method described in Example 3, is provided in Figure 39. Tabulated characteristics of the X-ray powder diffractogram in Figure 39 are provided in the following table, which lists diffraction angle 29, inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak):X-Ray Powder Diffractogram DataEXAMPLE 24 - Synthesis of N-[(lr,3r)-3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetrazatricyclo [8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro [3.5]nonan-7-yl]pyrimidine-5-carboxamide Crystal Form J (II-5 in Crystal Form J)

[0292] A saturated solution of Compound II- 5 in acetone / water (60 / 40, v / v) was prepared. To 0.15-0.4 mL of the solution was added about 3 mg of Crystal Form A of Compound II-5, about 3 mg of Crystal Form B of Compound II-5, and 3 mg of the product Step 1 of Example 12 (a mixture of Crystal Forms A and D of Compound II-5). The resulting suspension was stirred at 25°C for one week. The suspension was filtered through a 0.45 pm membrane filter by centrifugation. The isolated solid was collected and determined to be Compound II-5 as amixture of Crystal Form A and D. The solid was stirred at 25°C for an additional 10 days in acetone / water (60 / 40, v / v), then the sample was analyzed by XRPD with a Kapton film covering. The material was determined to be the title compound, Compound II- 5 in Crystal Form J. After removal of the Kapton film and exposure for one hour to ambient conditions (~25 °C and -30% RH), the material converted to a mixture of Crystal Forms A and D of Compound II-5.EXAMPLE 25 - Physical Characterization ofN-[(lr,3r)-3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[2-[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1,8,11,12-tetrazatricyclo [8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro[3.5]nonan-7-yl]pyrimidine-5-carboxamide Crystal Form J (II-5 in Crystal Form J)

[0293] An X-ray powder diffractogram taken on the title compound, using Kapton film as described in Example 24, and using the method described in Example 3, is provided in Figure 40. Tabulated characteristics of the X-ray powder diffractogram in Figure 40 are provided in the following table, which lists diffraction angle 20, inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak):X-Ray Powder Diffractogram DataEXAMPLE 26 - Cellular Growth Inhibition Assay Using T-Rex 293 Cells

[0294] Exemplary compounds were tested for ability to inhibit the proliferation of the following types of cells: (i) a T-Rex 293 cell line having increased expression of androgen receptor protein due to exposure to doxycycline and (ii) a T-Rex 293 cell line lacking increased expression of androgen receptor protein. Experimental procedures and results are provided below.Part I - Experimental Procedure

[0295] The following types of cells were prepared for this experiment: (i) a T-Rex 293 cell line having increased expression of androgen receptor protein due to exposure to doxycycline and (ii) a T-Rex 293 cell line lacking increased expression of androgen receptor protein. Ability of the test compounds to inhibit proliferation of the foregoing cell types was evaluated according to the procedures set forth below.

[0296] The doxycycline-inducible androgen receptor protein expressing cell line was established using the following protocol: T-Rex 293 cells were purchased from Invitrogen (Cat#R71007) and transfected using Lipofectamine 2000 with the wild-type androgen receptor protein sequence cloned into the pcDNA4 / TO vector. Transfected cells were selected using 400 pg / mL Zeocin (Invitrogen Cat#R25001). Following selection, single clones were raised and maintained in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% w / w Tetracycline-free fetal bovine serum (FBS) and 250 pg / mL Zeocin. Clones were analyzed for expression of androgen receptor protein in the presence and absence of 10 ng / mL doxycycline (Sigma Cat#D9891), and a single doxycycline-inducible clone (hereinafter “SC3”) was selected for use in downstream assays.

[0297] The SC3 cells were seeded on poly-D-lysine coated, black clear-bottom 384-well plates at 2500 / well, in 25 pL Phenol Red Free Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% w / w charcoal-dextran treated fetal bovine serum (FBS) and 1% w / w pen-strep, with or without 10 ng / mL doxycycline. Pen-Strep is a commercially available mixture of penicillin G and streptomycin, which is used in mammalian cell culture media to prevent bacterial contamination. Phenol Red Free Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% w / w charcoal-dextran treated fetal bovine serum (FBS) and 1% w / w pen-strep, with or without 10 ng / mL doxycycline is herein referred to as Treatment Medium.Following seeding of cells in the plates, the plates were spun at 300 x gfor 30 seconds, then equilibrated to room temperature for 30 minutes, and then deposited in a humidified tissue culture incubator maintained at 37 °C with 5% CO2.

[0298] At 24 hours after seeding of the cells, dilutions of test compound were prepared in DMSO and dissolved in Treatment Medium, to achieve a final DMSO concentration of 0.5% w / w, thereby providing the Test Compound Solution. A 25 pL aliquot of the Test Compound Solution was added to cells in the well plates. An equal volume of a solution containing DMSO and Treatment Medium was used as a negative control. Following treatment of cells with Test Compound Solution or said equal volume of a solution containing DMSO and Treatment Medium, the plates were spun at 300 x g for 30 seconds, and then left in an incubator for 72 hours.

[0299] At the end of the treatment duration, cell viability was quantified with CellTiter-Glo 2.0 reagent (Promega Cat#G9243). For this purpose, plates were equilibrated to room temperature for 30 minutes, and then 25 pL of CellTiter-Glo 2.0 reagent was added to cells in the plate wells. Plates were then agitated on a shaker for two minutes at 500 rpm and subsequently incubated at room temperature for 10 minutes. Following incubation, the plates were spun at 3000 x g for 30 seconds, then sealed with an optical adhesive cover, and luminescence readings were measured with an EnVision Plate Reader.

[0300] Data was normalized using zero luminescence for baseline. A four-parameter nonlinear regression curve fit was applied to dose-response data in GraphPad Prism data analysis software to determine the half-maximal growth inhibitory concentration (GI50) for each test compound.Part II - Results

[0301] Compound II-5 was found to have a growth inhibitory concentration (GI50) of less than 0.5 pM in both types of cells tested: (i) a T-Rex 293 cell line having increased expression of androgen receptor protein due to exposure to doxycycline and (ii) a T-Rex 293 cell line lacking increased expression of androgen receptor protein.EXAMPLE 27 - Cellular Growth Inhibition Assay for VCaP Cells

[0302] Exemplary compounds were tested for ability to inhibit the proliferation of VCaP cells. VCap cells are a commercially available human prostate cancer cell line. Experimental procedures and results are provided below.Part I - Experimental Procedure

[0303] VCaP cells were purchased from American Type Cell Culture (ATCC Cat#CRL2876) and then seeded on poly-D-lysine coated, black clear-bottom 384-well plates at 5000 / well in 25 L Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% w / w Fetal bovine serum (FBS) and 1% w / w Pen-Strep. Pen-Strep is a commercially available mixture of penicillin G and streptomycin, which is used in mammalian cell culture media to prevent bacterial contamination. Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% w / w fetal bovine serum (FBS) and 1% w / w Pen-Strep is herein referred to as Treatment Medium.Following seeding of cells in the plates, the plates were spun at 300 x g for 30 seconds, then equilibrated to room temperature for 30 minutes, and then deposited in a humidified tissue culture incubator maintained at 37 °C with 5% CO2.

[0304] At 24 hours after seeding of the cells, dilutions of test compound were prepared in DMSO and dissolved in Treatment Medium, to achieve a final DMSO concentration of 0.5% w / w, thereby providing the Test Compound Solution. A 25 pL aliquot of the Test Compound Solution was added to cells in the well plates. An equal volume of a solution containing DMSO and Treatment Medium was used as a negative control. Following treatment of cells with Test Compound Solution or said equal volume of a solution containing DMSO and Treatment Medium, the plates were spun at 300 x g for 30 seconds, and then left in an incubator for 72 hours.

[0305] At the end of the treatment duration, cell viability was quantified with CellTiter-Glo 2.0 reagent (Promega Cat#G9243). For this purpose, plates were equilibrated to room temperature for 30 minutes, and then 25 pL of CellTiter-Glo 2.0 reagent was added to cells in the plate wells. Plates were then agitated on a shaker for two minutes at 500 rpm and subsequently incubated at room temperature for 10 minutes. Following incubation, the plates were spun at 3000 x g for 30 seconds, then sealed with an optical adhesive cover, and luminescence readings were measured with an EnVision Plate Reader.

[0306] Data was normalized using zero luminescence for baseline. A four-parameter nonlinear regression curve fit was applied to dose-response data in GraphPad Prism data analysis software to determine the half-maximal growth inhibitory concentration (GI50) for each test compound.Part II - Results

[0307] Compound II- 5 was found to have a growth inhibitory concentration (GI50) of less than 0.5 pM in this experiment.EXAMPLE 28 - Cellular Growth Inhibition Assay for T47D Cells

[0308] Exemplary compounds were tested for ability to inhibit the proliferation of T47D cells. T47D cells are a commercially available human breast cancer cell line. Experimental procedures and results are provided below.Part I - Experimental Procedure

[0309] T47D cells were purchased from American Type Cell Culture (ATCC Cat# HTB-133) and then seeded on poly-D-lysine coated, black clear-bottom 384-well plates at 3000 / well in 25 pL Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% w / w Fetal bovine serum (FBS), 0.2 units / mL recombinant human insulin (Gibco Cat# 12585014), and 1% w / w Pen-Strep. Pen-Strep is a commercially available mixture of penicillin G and streptomycin, which is used in mammalian cell culture media to prevent bacterial contamination. Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% w / w fetal bovine serum (FBS), 0.2 units / mL recombinant human insulin, and 1% w / w Pen-Strep is herein referred to as Treatment Medium. Following seeding of cells in the plates, the plates were spun at 300 x g for 30 seconds, then equilibrated to room temperature for 30 minutes, and then deposited in a humidified tissue culture incubator maintained at 37 °C with 5% CO2.

[0310] At 24 hours after seeding of the cells, dilutions of test compound were prepared in DMSO and dissolved in Treatment Medium, to achieve a final DMSO concentration of 0.5% w / w, thereby providing the Test Compound Solution. A 25 pL aliquot of the Test Compound Solution was added to cells in the well plates. An equal volume of a solution containing DMSO and Treatment Medium was used as a negative control. Following treatment of cells with Test Compound Solution or said equal volume of a solution containing DMSO and TreatmentMedium, the plates were spun at 300 x g for 30 seconds, and then left in an incubator for 72 hours.

[0311] At the end of the treatment duration, cell viability was quantified with CellTiter-Glo 2.0 reagent (Promega Cat#G9243). For this purpose, plates were equilibrated to room temperature for 30 minutes, and then 25 pL of CellTiter-Glo 2.0 reagent was added to cells in the plate wells. Plates were then agitated on a shaker for two minutes at 500 rpm and subsequently incubated at room temperature for 10 minutes. Following incubation, the plates were spun at 3000 x g for 30 seconds, then sealed with an optical adhesive cover, and luminescence readings were measured with an EnVision Plate Reader (Perkin Elmer).

[0312] Data was normalized using zero luminescence for baseline. A four-parameter nonlinear regression curve fit was applied to dose-response data in GraphPad Prism data analysis software to determine the half-maximal growth inhibitory concentration (GI50) for each test compound.Part II - Results

[0313] Compound II-5 was found to have a growth inhibitory concentration (GI50) of less than 0.5 pM in this experiment.EXAMPLE 29 - Assay for Inhibition of Growth of VCaP Cells

[0314] Compound II- 5 was tested for ability to inhibit growth of VCaP cells. Experimental procedures and results are provided below.Part I - Experimental Procedure

[0315] VCaP cells were maintained in standard culture media (ATCC DMEM plus 10% ATCC fetal bovine serum, and 1% pen-strep). Cells were seeded in 25 pL standard culture media in poly-D-lysine coated black clear-bottom 384-well plates at 3000 cells / well for continuous treatment. An additional plate under the same conditions was seeded as a Day 0 plate. Following seeding, plates were spun at 300 x g for 30 seconds and cultured at 37°C with 5% CO2 in a humidified tissue culture incubator.

[0316] At 24 hours after seeding, Compound II-5 was titrated in 100% DMSO and diluted in standard culture media. 25 pL of the compound / media mixture was added to cells, bringing the total volume in each well to 50 pL. DMSO without Compound II-5 was used as a negativecontrol. The day 0 plate was treated with the same percent DMSO as was used in the compound / media mixture but contained no compound. After treatment, plates were spun at 300 x g for 30 seconds, then cultured at 37 °C with 5% CO2 for 7 days in a humidified tissue culture incubator. The day 0 plate cell viability was quantified with CellTiter-Glo 2.0 reagent immediately following treatment under the same conditions as used below for measuring cell viability. On Day 7 of treatment, cell viability was quantified with CellTiter-Glo 2.0 reagent (Promega). Plates were equilibrated to room temperature for 30 minutes, then 25 pL of CellTiter-Glo 2.0 reagent was added to cells, bringing the total volume in each well to 75 pL. After reagent was added, plates were spun at 3000 x g for 30 seconds then mixed on a shaker for two minutes at 500 rpm and then incubated at room temperature for 10 minutes. Following incubation, plates were spun at 300 x g for 30 seconds, sealed with an optical adhesive cover, and luminescence was measured with an EnVision Plate Reader.

[0317] Data was normalized to the average Day 0 luminescence signal for a baseline. A four-parameter non-linear regression curve fit was applied to dose-response data in GraphPad Prism data analysis software to determine the half maximal growth inhibitory concentration (GI50) for Compound 11-5.Part II - Results

[0318] A cell viability dose-response curve obtained for Compound II- 5 following the procedures above is provided in Figure 4.EXAMPLE 30 - Analysis of In Vivo Performance of Compound II-5 in VCaP Cell Tumors

[0319] Compound II- 5 was evaluated for in vivo performance when administered to CB17. SCID mice bearing VCaP cell tumors. Experimental procedures and results are provided below.Part I - Experimental ProcedureA. VCaP Tumor Xenograft Studies

[0320] 5M VCaP cells were subcutaneously implanted into CB17. SCID mice in 50% Matrigel (Corning). Mice were castrated under anesthesia once tumor volumes reached 100 mm3. Tumors were then allowed to reach an average of approximately 150 mm3before randomization into efficacy arms. Tumors were measured twice weekly for Tumor Growth Inhibition (TGI)calculation. For PK / PD analysis, tumors were allowed to reach an average of 400 mm3, before dosing the mice with test compound by oral gavage (n=5) for seven days. Mice were sacrificed 24 hours following the final dose, and tumors were harvested for downstream analysis. Plasma samples were collected from all dosed mice 2 hours following the final dose to determine test compound exposure by LC-MS / MS. Test compounds used in the experiment were (i) Compound II- 5 and (ii) a commercially available nonsteroidal antiandrogen medication that has been approved by the United States Food and Drug Administration for treatment of prostate cancer (hereinafter “Compound A”).B. Determination of Amount of RNA by In Vivo qPCR

[0321] Tumors were lysed in 1.5 mb buffer RLT from the RNeasy Mini Kit (#74104, Qiagen) and pelleted. Total RNA was isolated using RNeasy Mini kit according to the manufacturers’ instructions. After quantification, 1 pg RNA of each sample was used as a template for first strand C-DNA synthesis with Verso cDNA synthesis kit (#AB1453B, ThermoFisher) and the qRT-PCR reaction was performed using TaqMan Fast Advanced Master Mix (#4444964, ThermoFisher) with QuantStudio 5 Real Time PCR System (#A28570, Thermofisher) according to the manufacturers’ instructions. The gene-specific TaqMan probes used in qRT-PCR were all purchased from Thermofisher and are HEXIM1 (#Hs00538918_sl), HPRT (#Hs99999909_ml), cMYC (#HsOO1534O8_ml), and TXNIP (#Hs00197750_ml). All PCR reactions were performed in technical triplicates.C. Plasma PSA Analysis

[0322] All assay reagents were provided in the Human Prostate Specific Antigen (PSA) ELISA Kit (abl 13327, Abeam). Plasma samples were collected at the end of the abovedescribed Castrate VCaP Tumor Xenograft Model and diluted in assay diluent A for the absorbance signal to be in the linear range of the recombinant human PSA standard curve.Diluted samples and PSA standard were loaded into a pre-coated assay plate and incubated for 2.5 hours at ambient temperature. Samples and standards were flicked out, plate was washed, and biotinylated PSA detection antibody was added and incubated for 1 hour. Detection antibody was flicked out, plate was washed, and HRP- Streptavidin was added and incubated for 45 minutes. HRP- Streptavidin was flicked out, plate was washed, and TMB Substrate was added and incubated for 30 minutes while reading absorbance at 620 nm on the SpectraMax M5e, for up to30 minutes. Stop solution was added directly on top of TMB Substrate. Endpoint read was obtained at an absorbance of 450 nm. During analysis, sample absorbances were multiplied by the dilution factor to calculate the concentration of PSA.Part II -Results

[0323] The relative total amount of cMYC mRNA present in tumors collected at the end of the PK / PD Aramp, V7+Castrate VcaP Model, for each of the different dose amounts of Compound II-5, is provided in Figure 5. In Figure 5, Dose Amount 2 is two times greater than Dose Amount 1, and Dose Amount 3 is two times greater than Dose Amount 2.

[0324] The relative total amount of HEXIM 1 mRNA present in tumors collected at the end of the PK / PD Aramp, V7+Castrate VcaP Model, for each of the different dose amounts of Compound II-5, is provided in Figure 6. In Figure 6, Dose Amount 2 is two times greater than Dose Amount 1, and Dose Amount 3 is two times greater than Dose Amount 2. In Figure 7, Dose Amount 2 is two times greater than Dose Amount 1, and Dose Amount 3 is two times greater than Dose Amount 2.

[0325] The relative total amount of TXNIP mRNA present in tumors collected at the end of the PK / PD Aramp, V7+Castrate VcaP Model, for each of the different dose amounts of Compound II-5, is provided in Figure 7.

[0326] Ability of Compound II-5 to inhibit tumor growth is demonstrated by results in Figure 8, which is a graph showing tumor volume in mice that had been administered either Compound II-5, Compound A, or vehicle. The data in Figure 8 were collected on mice in which the dose amount in mg / kg of Compound II- 5 used in the experiment was the same dose amount used for Compound A, and the frequency of dosing was the same for each of Compound II-5 and Compound A. The results in Figure 8 show that Compound II- 5 was more effective in reducing tumor growth in this experiment than Compound A. A graph showing the change in size of tumors at the end of the study relative to baseline is shown in Figure 9. The data in Figure 9 were collected on mice in which the dose amount in mg / kg of Compound II- 5 used in the experiment was the same dose amount used for Compound A, and the frequency of dosing was the same for each of Compound II-5 and Compound A.

[0327] PSA plasma levels determined in mice at the end of the study are shown in Figure 10 for mice treated with either Compound II-5, Compound A, or vehicle. The data in Figure 10were collected on mice in which the dose amount in mg / kg of Compound II-5 used in the experiment was the same dose amount used for Compound A, and the frequency of dosing was the same for each of Compound II-5 and Compound A.EXAMPLE 31 - Analysis of In Vivo Performance of Compound II-5 in LNCaP95 Cell Tumors

[0328] Compound II- 5 was evaluated for in vivo performance when administered to NSG mice bearing LNCaP95 cell tumors. Experimental procedures and results are provided below.Part I - Experimental ProcedureA. LNCaP95 Tumor Xenograft Studies

[0329] Male NSG mice were castrated under anesthesia, and then 7 days later 5M LNCaP95 cells in 50% Matrigel (Coming) were subcutaneously implanted into the right flank of the mice. Tumors were then allowed to reach an average of approximately 150 mm3before randomization into efficacy arms. Tumors were measured twice weekly for Tumor Growth Inhibition (TGI) calculation. Test compound was administered by mice by oral gavage. Test compounds used in the experiment were (i) Compound II- 5 and (ii) a commercially available nonsteroidal antiandrogen medication that has been approved by the United States Food and Drug Administration for treatment of prostate cancer (hereinafter “Compound A”).

[0330] In a first arm of the experiment, Compound II- 5 was administered to mice according to a first dosing regimen in which the dosing frequency was the same as that used for vehicle and for Compound A. In a second arm of the experiment, Compound II- 5 was administered to mice according to a second dosing regimen in which the dosing frequency was twice as often as that used for vehicle and for Compound A. In both the first arm and the second arm of the experiment, the amount of Compound II-5 administered at each dose event was 50% greater in mg / kg than the amount of Compound A administered at each dose event.B. Plasma PSA Analysis

[0331] All assay reagents were provided in the Human Prostate Specific Antigen (PSA) ELISA Kit (abl 13327, Abeam). Plasma samples were collected at the end of the abovedescribed Tumor Xenograft Model and diluted in assay diluent A for the absorbance signal to be in the linear range of the recombinant human PSA standard curve. Diluted samples and PSAstandard were loaded into a pre-coated assay plate and incubated for 2.5 hours at ambient temperature. Samples and standards were flicked out, plate was washed, and biotinylated PSA detection antibody was added and incubated for 1 hour. Detection antibody was flicked out, plate was washed, and HRP-Streptavidin was added and incubated for 45 minutes. HRP-Streptavidin was flicked out, plate was washed, and TMB Substrate was added and incubated for 30 minutes while reading absorbance at 620 nm on the SpectraMax M5e, for up to 30 minutes. Stop solution was added directly on top of TMB Substrate. Endpoint read was obtained at an absorbance of 450 nm. During analysis, sample absorbances were multiplied by the dilution factor to calculate the concentration of PSA.Part II - Results

[0332] Results are provided in Figures 11, 12, and 13. Figure 11 provides a graph showing tumor volume in mice treated with (i) vehicle, (ii) Compound II- 5 according to a first dosing regimen in which the dosing frequency was the same as that used for vehicle and for Compound A, (iii) Compound II-5 according to a second dosing regimen in which the dosing frequency was twice as often as that used for vehicle and for Compound A, or (iv) Compound A.

[0333] A graph showing the change in size of tumors at the end of the study relative to baseline is shown in Figure 12 for mice treated with (i) vehicle, (ii) Compound II-5 according to a first dosing regimen in which the dosing frequency was the same as that used for vehicle and for Compound A, (iii) Compound II-5 according to a second dosing regimen in which the dosing frequency was twice as often as that used for vehicle and for Compound A, or (iv) Compound A.

[0334] PSA plasma levels determined in mice at the end of the study are shown in Figure 13 for mice treated with (i) vehicle, (ii) Compound II- 5 according to a first dosing regimen in which the dosing frequency was the same as that used for vehicle and for Compound A, (iii) Compound II-5 according to a second dosing regimen in which the dosing frequency was twice as often as that used for vehicle and for Compound A, or (iv) Compound A.INCORPORATION BY REFERENCE

[0335] The entire disclosure of each of the patent documents and scientific articles referred to herein is incorporated by reference for all purposes.EQUIVALENTS

[0336] The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting the invention described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

Claims:

1. A compound of Formula II-5 in crystalline form:(II-5).

2. The compound of claim 1, wherein the crystalline form further comprises a solvent.

3. The compound of claim 2, wherein the solvent is (i) water, (ii) an organic compound selected from cyclopentyl methyl ether, 2-propanol, 1,4-di oxane, ethyl acetate, methanol, methyl isobutyl ketone, ethanol, acetone, or acetonitrile, or (iii) a mixture of water and an organic compound selected from cyclopentyl methyl ether, 2-propanol, 1,4-di oxane, ethyl acetate, methanol, methyl isobutyl ketone, ethanol, acetone, or acetonitrile.

4. The compound of any one of claims 1-3, wherein any water is present at a molar ratio in the range of about 0.7:1 to about 1.3:1 relative to the compound of Formula II-5.

5. The compound of claim 2, wherein the solvent is water, and the compound exhibits an X- ray powder diffraction pattern comprising peaks at the following diffraction angles (20): 8.7 ± 0.2, 12.7 ± 0.2, 17.3 ± 0.2, 18.0 ± 0.2, 19.0 ± 0.2, 20.8 ± 0.2, and 23.9 ± 0.2.

6. The compound of claim 5, wherein the X-ray powder diffraction pattern further comprises a peak at one or more of the following diffraction angles (29): 11.1 ± 0.2, 19.2 ± 0.2, 24.9 ± 0.2, and 26.3 ± 0.2.

7. The compound of claim 5 or 6, wherein the X-ray powder diffraction pattern further comprises a peak at one or more of the following diffraction angles (29): 9.4 ± 0.2, 16.1 ± 0.2, 21.8 ± 0.2, and 25.4 ± 0.2.

8. The compound of any one of claims 5-7, wherein the relative intensity of the peak at said diffraction angles (29) is at least 20%.

9. The compound of claim 5, characterized by the following X-ray powder diffraction pattern expressed in terms of diffraction angle 20, inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak):

10. The compound of claim 5, wherein the compound has an X-ray powder diffraction pattern substantially as shown in Figure 26.

11. The compound of any one of claims 4- 10, wherein the compound has a melting point onset as determined by differential scanning calorimetry at about 184 degrees Celsius.

12. The compound of any one of claims 4-10, wherein the compound has a differential scanning calorimetry curve substantially the same as shown in Figure 27.

13. The compound of claim 2, wherein the solvent is cyclopentyl methyl ether, wherein the solvent is present at a molar ratio of about 0.1:1 to about 0.7:1 relative to the compound of Formula II- 5.

14. The compound of claim 2, wherein the solvent is cyclopentyl methyl ether, and the compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (20): 9.8 ± 0.2, 13.0 ± 0.2, 19.2 ± 0.2, 19.5 ± 0.2, 23.6 ± 0.2, 25.4 ± 0.2, and 25.5 ± 0.2.

15. The compound of claim 14, wherein the X-ray powder diffraction pattern further comprises a peak at one or more of the following diffraction angles (29): 8.6 ± 0.2, 18.5 ± 0.2, and 25.1 ± 0.2.

16. The compound of claim 14 or 15, wherein the relative intensity of the peak at said diffraction angles (29) is at least 30%.

17. The compound of claim 14, characterized by the following X-ray powder diffraction pattern expressed in terms of diffraction angle 20, inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak):

18. The compound of claim 14, wherein the compound has an X-ray powder diffraction pattern substantially as shown in Figure 17.

19. The compound of any one of claims 13-18, wherein the compound has a melting point onset as determined by differential scanning calorimetry at about 183 degrees Celsius.

20. The compound of any one of claims 13-18, wherein the compound has a differential scanning calorimetry curve substantially the same as shown in Figure 18.

21. The compound of claim 2, wherein the solvent is 2-propanol, wherein the solvent is present at a molar ratio in the range of about 0.1:1 to about 0.7:1 relative to the compound of Formula II-5.

22. The compound of claim 2, wherein the solvent is 2-propanol, and the compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (26): 8.6 ± 0.2, 9.8 ± 0.2, 10.5 ± 0.2, 19.2 ± 0.2, 19.5 ± 0.2, 23.5 ± 0.2, and 25.5 ± 0.2.

23. The compound of claim 22, wherein the X-ray powder diffraction pattern further comprises a peak at one or more of the following diffraction angles (20): 12.9 ± 0.2, 18.5 ± 0.2, and 25.1 ± 0.2.

24. The compound of claim 22 or 23, wherein the X-ray powder diffraction pattern further comprises a peak at one or more of the following diffraction angles (29): 16.5 ± 0.2, 17.3 ± 0.2, and 18.0 ± 0.2.

25. The compound of any one of claims 22-24, wherein the relative intensity of the peak at said diffraction angles (29) is at least 30%.

26. The compound of claim 22, characterized by the following X-ray powder diffraction pattern expressed in terms of diffraction angle 20, inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak):

27. The compound of claim 22, wherein the compound has an X-ray powder diffraction pattern substantially as shown in Figure 20.

28. The compound of any one of claims 21-27, wherein the compound has a melting point onset as determined by differential scanning calorimetry at about 186 degrees Celsius.

29. The compound of any one of claims 21-27, wherein the compound has a differential scanning calorimetry curve substantially the same as shown in Figure 21.

30. The compound of claim 2, wherein the solvent is 1,4-dioxane, wherein the solvent is present at a molar ratio in the range of about 1.5:1 to about 2.5:1 relative to the compound of Formula II-5.

31. The compound of claim 2, wherein the solvent is 1,4-dioxane, and the compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (20): 8.6 ± 0.2, 10.4 ± 0.2, 13.0 ± 0.2, 17.5 ± 0.2, 19.5 ± 0.2, 23.5 ± 0.2, and 25.5 ± 0.2.

32. The compound of claim 31, wherein the X-ray powder diffraction pattern further comprises a peak at one or more of the following diffraction angles (20): 9.8 ± 0.2, 18.7 ± 0.2, and 19.2 ± 0.2.

33. The compound of claim 31 or 32, wherein the relative intensity of the peak at said diffraction angles (20) is at least 30%.

34. The compound of claim 31, characterized by the following X-ray powder diffraction pattern expressed in terms of diffraction angle 20, inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak):

35. The compound of claim 31, wherein the compound has an X-ray powder diffraction pattern substantially as shown in Figure 23.

36. The compound of any one of claims 30-35, wherein the compound has a melting point onset as determined by differential scanning calorimetry at about 188 degrees Celsius.

37. The compound of any one of claims 30-35, wherein the compound has a differential scanning calorimetry curve substantially the same as shown in Figure 24.

38. The compound of claim 2, wherein the solvent is ethyl acetate, wherein the solvent is present at a molar ratio in the range of about 0.1:1 to about 0.7:1 relative to the compound of Formula II-5.

39. The compound of claim 2, wherein the solvent is ethyl acetate, and the compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (20): 9.8 ± 0.2, 15.6 ± 0.2, 17.3 ± 0.2, 19.2 ± 0.2, 23.6 ± 0.2, 25.2 ± 0.2, and 26.1 ± 0.2.

40. The compound of claim 39, wherein the X-ray powder diffraction pattern further comprises a peak at one or more of the following diffraction angles (20): 8.6 ± 0.2, 12.8 ± 0.2, and 19.6 ± 0.2.

41. The compound of claim 38 or 39, wherein the relative intensity of the peak at said diffraction angles (20) is at least 30%.

42. The compound of claim 39, characterized by the following X-ray powder diffraction pattern expressed in terms of diffraction angle 29, inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak):

43. The compound of claim 39, wherein the compound has an X-ray powder diffraction pattern substantially as shown in Figure 29.

44. The compound of any one of claims 38-43, wherein the compound has a melting point onset as determined by differential scanning calorimetry at about 191 degrees Celsius.

45. The compound of any one of claims 38-43, wherein the compound has a differential scanning calorimetry curve substantially the same as shown in Figure 30.

46. The compound of any one of claims 1-3, wherein the compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (20): 8.2 ± 0.2, 11.4 ± 0.2, 18.0 ± 0.2, 18.5 ± 0.2, 19.8 ± 0.2, 24.4 ± 0.2, and 25.5 ± 0.2.

47. The compound of claim 46, wherein the X-ray powder diffraction pattern further comprises a peak at one or more of the following diffraction angles (29): 9.0 ± 0.2, 16.5 ± 0.2, and 25.8 ± 0.2.

48. The compound of claim 46 or 47, wherein the relative intensity of the peak at said diffraction angles (29) is at least 15%.

49. The compound of any one of claims 1-3, characterized by the following X-ray powder diffraction pattern expressed in terms of diffraction angle 20, inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak):

50. The compound of any one of claims 1-3, wherein the compound has an X-ray powder diffraction pattern substantially as shown in Figure 32.

51. The compound of claim 2, wherein the solvent is a mixture of (i) methanol, wherein the methanol is present at a molar ratio in the range of about 1.5:1 to about 2.5:1 relative to the compound of Formula II-5, and (ii) water, wherein the water is present at a molar ratio in the range of about 0.7:1 to about 1.3:1 relative to the compound of Formula II-5.

52. The compound of claim 2, wherein the solvent is a mixture of methanol and water, and the compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (20): 8.6 ± 0.2, 13.0 ± 0.2, 17.5 ± 0.2, 18.9 ± 0.2, 19.3 ± 0.2, 19.5 ± 0.2, and 25.5 ± 0.2.

53. The compound of claim 52, wherein the X-ray powder diffraction pattern further comprises a peak at one or more of the following diffraction angles (29): 9.5 ± 0.2, 12.7 ± 0.2, and 18.0 ± 0.2.

54. The compound of claim 52 or 53, wherein the relative intensity of the peak at said diffraction angles (20) is at least 30%.

55. The compound of claim 52, characterized by the following X-ray powder diffraction pattern expressed in terms of diffraction angle 20, inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak):

56. The compound of claim 52, wherein the compound has an X-ray powder diffraction pattern substantially as shown in Figure 33.

57. The compound of any one of claims 51-56, wherein the compound has a melting point onset as determined by differential scanning calorimetry at about 185 degrees Celsius.

58. The compound of any one of claims 51-56, wherein the compound has a differential scanning calorimetry curve substantially the same as shown in Figure 34.

59. The compound of claim 2, wherein the solvent is methyl isobutyl ketone, and the solvent is present at a molar ratio in the range of about 0.7: 1 to about 1.3:1 relative to the compound of Formula II-5.

60. The compound of claim 2, wherein the solvent is methyl isobutyl ketone, and the compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (20): 9.7 ± 0.2, 12.8 ± 0.2, 18.4 ± 0.2, 19.1 ± 0.2, 19.5 ± 0.2, 23.5 ± 0.2, and 24.9 ± 0.2.

61. The compound of claim 60, wherein the X-ray powder diffraction pattern further comprises a peak at one or more of the following diffraction angles (29): 8.5 ± 0.2, 10.4 ± 0.2, and 15.6 ± 0.2.

62. The compound of claim 60 or 61, wherein the relative intensity of the peak at said diffraction angles (29) is at least 30%.

63. The compound of claim 60, characterized by the following X-ray powder diffraction pattern expressed in terms of diffraction angle 20, inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak):

64. The compound of claim 60, wherein the compound has an X-ray powder diffraction pattern substantially as shown in Figure 36.

65. The compound of any one of claims 59-64, wherein the compound has a melting point onset as determined by differential scanning calorimetry at about 188 degrees Celsius.

66. The compound of any one of claims 59-64, wherein the compound has a differential scanning calorimetry curve substantially the same as shown in Figure 37.

67. The compound of claim 2, wherein the solvent is a mixture of (i) ethanol, wherein the ethanol is present at a molar ratio in the range of about 1.5:1 to about 2.5:1 relative to the compound of Formula II-5, and (ii) water, wherein the water is present at a molar ratio in the range of about 0.7:1 to about 1.3:1 relative to the compound of Formula II-5.

68. The compound of claim 2, wherein the solvent is a mixture of ethanol and water, and the compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (26): 11.6 ± 0.2, 15.4 ± 0.2, 18.1 ± 0.2, 18.6 ± 0.2, 20.0 ± 0.2, 20.2 ± 0.2, and 24.5 ± 0.2.

69. The compound of claim 68, wherein the X-ray powder diffraction pattern further comprises a peak at one or more of the following diffraction angles (26): 9.1 ± 0.2, 16.6 ± 0.2, and 25.6 ± 0.2.

70. The compound of claim 68 or 69, wherein the relative intensity of the peak at said diffraction angles (20) is at least 20%.

71. The compound of claim 68, characterized by the following X-ray powder diffraction pattern expressed in terms of diffraction angle 29, inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak):

72. The compound of claim 68, wherein the compound has an X-ray powder diffraction pattern substantially as shown in Figure 39.

73. The compound of any one of claims 1-3, wherein the compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (29): 11.4 ± 0.2, 17.9 ± 0.2, 18.1 ± 0.2, 18.5 ± 0.2, 19.0 ± 0.2, 19.9 ± 0.2, and 24.5 ± 0.2.

74. The compound of claim 73, wherein the X-ray powder diffraction pattern further comprises a peak at one or more of the following diffraction angles (20): 12.3 ± 0.2, 17.2 ± 0.2, and 25.5 ± 0.2.

75. The compound of claim 73 or 74, wherein the relative intensity of the peak at said diffraction angles (20) is at least 15%.

76. The compound of any one of claims 1-3, characterized by the following X-ray powder diffraction pattern expressed in terms of diffraction angle 20, inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak):

77. The compound of any one of claims 1-3, wherein the compound has an X-ray powder diffraction pattern substantially as shown in Figure 40.

78. The compound of any one of claims 1-77, wherein the compound has a purity of greater than 98% by weight.

79. The compound of any one of claims 1-77, wherein the compound has a purity of greater than 99% by weight.

80. The compound of any one of claims 1-77, wherein the compound has a purity of greater than 99.5% by weight.

81. A pharmaceutical composition comprising a compound of any one of claims 1-80, and a pharmaceutically acceptable carrier.

82. A method of treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1-80, to treat the cancer.

83. The method of claim 82, wherein the cancer is ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, prostate cancer, testicular cancer, breast cancer, brain cancer, lung cancer, oral cancer, esophageal cancer, head and neck cancer, stomach cancer, colon cancer, rectal cancer, skin cancer, sebaceous gland carcinoma, bile duct cancer, gallbladder cancer, liver cancer, pancreatic cancer, bladder cancer, urinary tract cancer, kidney cancer, eye cancer, thyroid cancer, lymphoma, or leukemia.

84. The method of claim 82, wherein the cancer is prostate cancer.

85. The method of any one of claims 82-84, wherein the patient is a human.

86. A method of causing death of a cancer cell, comprising contacting a cancer cell with an effective amount of a compound of any one of claims 1-80, to cause death of the cancer cell.

87. The method of claim 86, wherein the cancer cell is selected from an ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, prostate cancer, testicular cancer, breast cancer, brain cancer, lung cancer, oral cancer, esophageal cancer, head and neck cancer, stomach cancer, colon cancer, rectal cancer, skin cancer, sebaceous gland carcinoma, bile duct cancer, gallbladder cancer, liver cancer, pancreatic cancer, bladder cancer, urinary tract cancer, kidney cancer, eye cancer, thyroid cancer, lymphoma, or leukemia cell.

88. The method of claim 86, wherein the cancer cell is a prostate cancer cell.

Images