Crystalline form of 2-methoxy-n-{4-methoxy-6-[(1h-pyrazol-1-YL)methyl]-1,2-benzoxazol-3-YL}benzene-1-sulfonamide

Abstract

The invention relates to anhydrous crystalline Form 5 of 2-methoxy-N-{4-methoxy-6-[(1H- pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-sulfonamide (Compound A) and to pharmaceutical compositions comprising anhydrous crystalline Form 5 of Compound A and methods of treatment thereof.

Description

[0001] PC073003A

[0002] 1

[0003] CRYSTALLINE FORM OF 2-METHOXY-N-{4-METHOXY-6-[(1H-PYRAZOL-1-YL)METHYL]- 1,2-BENZOXAZOL-3-YL}BENZENE-1-SULFONAMIDE

[0004] This application claims the benefit of U. S. Provisional Application No. 63 / 614,797 filed December 26, 2023, and U. S. Provisional Application No. 63 / 733,223 filed December 12, 2024, the contents of which are hereby incorporated by reference in their entireties.

[0005] Background of the Invention

[0006] This invention relates to a novel polymorphic form of 2-methoxy- / V-{4-methoxy-6-[(1 / 7- pyrazol-1-yl)methyl]-1 ,2-benzoxazol-3-yl}benzene-1-sulfonamide, also known by its synonym / V- (6-((1 H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamide (referred to herein as “Compound A”), having the following structure: that is useful in the treatment of cancer. Compound A is a potent and selective catalytic inhibitor of KAT6 histone acetyltransferases, KAT6A and KAT6B. Compound A is currently in phase I clinical trials for the treatment of cancers.

[0007] Preparation of Compound A, including an anhydrous crystalline Form 1 of Compound A free acid, is described in International Publication No. WO 2020 / 254946 and in U.S. Patent No. 11 ,492,346. Combination therapies including Compound A are described in International Publication No. WO 2022 / 013369. The contents of each of the foregoing documents are incorporated herein by reference in their entireties.

[0008] Polymorphs are different crystalline forms of the same compound. Crystalline polymorphs typically have different crystal structures due to a different packing of the molecules in the lattice. This results in a different crystal symmetry and / or unit cell parameters which directly influences its physical properties such as the X-ray diffraction characteristics of crystals or powders.

[0009] Polymorphic forms are of interest to the pharmaceutical industry and especially to those involved in the development of suitable dosage forms. If the polymorphic form is not held constant during clinical or stability studies, the exact dosage form used or studied may not be comparable from one lot to another. It is also desirable to have processes for producing a compound with the selected polymorphic form in high purity when the compound is used in clinical studies or commercial products since impurities present may produce undesired toxicological effects. Certain polymorphic forms may also exhibit enhanced stability or may be more readily manufactured in high purity in large quantities, and thus are more suitable for inclusion in pharmaceutical formulations. Certain polymorphic forms may display other advantageous physical properties such as lack of hygroscopic tendencies, improved filterability, improved solubility, and enhanced rates of dissolution due to different lattice energies.

[0010] Summary of the Invention

[0011] A polymorphic form, anhydrous crystalline Form 5 of 2-methoxy-N-{4-methoxy-6-[(1H- pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-sulfonamide (“Compound A”), is disclosed herein. The polymorphic form may be uniquely identified by several different analytical techniques, alone or in combination, such as, but not limited to powder X-ray diffraction (“PXRD”) pattern;13C solid state NMR; and Raman spectroscopy.

[0012] Brief Description of the Drawings

[0013] Figure 1 is a PXRD pattern of anhydrous crystalline Form 5 of 2-methoxy-N-{4-methoxy-6-[(1H- pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-sulfonamide.

[0014] Figure 2 is a13C solid state NMR spectrum of anhydrous crystalline Form 5 of 2-methoxy-N-{4- methoxy-6-[(1 H-pyrazol-1-yl)methyl]-1 ,2-benzoxazol-3-yl}benzene-1 -sulfonamide.

[0015] Figure 3 is a Raman spectrum of anhydrous crystalline Form 5 of 2-methoxy-N-{4-methoxy-6- [(1H-pyrazol-1-yl)methyl]-1 ,2-benzoxazol-3-yl}benzene-1 -sulfonamide.

[0016] Detailed Description of the Invention

[0017] The present invention may be understood more readily by reference to the following detailed description of the embodiments of the invention and the Examples included herein. It is to be also understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be limiting.

[0018] The present invention describes a form of anhydrous crystalline 2-methoxy-N-{4- methoxy-6-[(1 H-pyrazol-1-yl)methyl]-1 ,2-benzoxazol-3-yl}benzene-1-sulfonamide, which is designated herein as Form 5. Form 5 is a particularly advantageous form of anhydrous crystalline form of 2-methoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3- yl}benzene-1 -sulfonamide which exhibits good stability and low hygroscopicity and therefore is suitable for use in pharmaceutical compositions. E1 An anhydrous crystalline form of 2-methoxy-N-{4-methoxy-6-[(1 H-pyrazol-1-yl)methyl]-

[0019] 1 ,2-benzoxazol-3-yl}benzene-1 -sulfonamide, having a powder X-ray diffraction pattern measured using copper wavelength radiation comprising peaks at diffraction angles (20) of 8.6 and 10.4 °20 ± 0.2 °20.

[0020] E2 An anhydrous crystalline form of 2-methoxy-N-{4-methoxy-6-[(1 H-pyrazol-1-yl)methyl]-

[0021] 1 ,2-benzoxazol-3-yl}benzene-1-sulfonamide, having a13C solid state NMR spectrum comprising resonance (ppm) values of: 156.7, 137.6, 130.1 , and 129.0 ppm ± 0.2 ppm.

[0022] E3 An anhydrous crystalline form of 2-methoxy-N-{4-methoxy-6-[(1 H-pyrazol-1-yl)methyl]-

[0023] 1 ,2-benzoxazol-3-yl}benzene-1 -sulfonamide, having a Raman spectrum comprising wavenumber (cnr1) values of: 329, 527, 1257, 1320, and 3104 cm'1± 2 cm'1.

[0024] E4 An anhydrous crystalline form of 2-methoxy-N-{4-methoxy-6-[(1 H-pyrazol-1-yl)methyl]-

[0025] 1 ,2-benzoxazol-3-yl}benzene-1-sulfonamide, having:

[0026] (a) a powder X-ray diffraction pattern measured using copper wavelength radiation comprising peaks at diffraction angles (20) of 8.6 and 10.4 °20 ± 0.2 °20;

[0027] (b) a13C solid state NMR spectrum comprising one or more resonance (ppm) values of: 156.7, 137.6, 130.1 , and 129.0 ppm ± 0.2 ppm; or

[0028] (c) a Raman spectrum comprising one or more wavenumber (cm'1) values of: 329, 527, 1257, 1320, and 3104 cm'1± 2 cm'1; or

[0029] (d) a combination of two or more of (a), (b), and (c).

[0030] E5 The anhydrous crystalline form of embodiment 1 , having a powder X-ray diffraction pattern measured using copper wavelength radiation further comprising at least one set of peaks at diffraction angles (20) selected from:

[0031] (a) 13.6 and 13.9 °20 ± 0.2 °20;

[0032] (b) 18.0 and 20.0 °20 ± 0.2 °20; and

[0033] (c) 24.0 and 24.2 °20 ± 0.2 °20.

[0034] E6 The anhydrous crystalline form of embodiment 1 , having a powder X-ray diffraction pattern measured using copper wavelength radiation further comprising peaks at diffraction angles (20) of 13.6, 13.9, 18.0, 20.0, 24.0, and 24.2 °20 ± 0.2 °20.

[0035] E7 The anhydrous crystalline form of any one of embodiments 1 to 6, which is substantially pure 2-methoxy-N-{4-methoxy-6-[(1 H-pyrazol-1-yl)methyl]-1 ,2-benzoxazol-3-yl}benzene-1- sulfonamide. E8 The anhydrous crystalline form of embodiment 7, wherein the anhydrous crystalline form comprises less than 10%, less than 5%, less than 3%, or less than 1% by weight of any other physical form of 2-methoxy-N-{4-methoxy-6-[(1 H-pyrazol-1-yl)methyl]-1 ,2-benzoxazol-3- yl}benzene-1 -sulfonamide.

[0036] E9 The anhydrous crystalline form of embodiment 8, wherein the anhydrous crystalline form comprises less than 10% by weight of any other physical form of 2-methoxy-N-{4-methoxy-6- [(1 H-pyrazol-1-yl)methyl]-1 ,2-benzoxazol-3-yl}benzene-1 -sulfonamide.

[0037] E10 The anhydrous crystalline form of embodiment 8, wherein the anhydrous crystalline form comprises less than 5% by weight of any other physical form of 2-methoxy-N-{4-methoxy-6- [(1 H-pyrazol-1-yl)methyl]-1 ,2-benzoxazol-3-yl}benzene-1 -sulfonamide.

[0038] E11 The anhydrous crystalline form of embodiment 8, wherein the anhydrous crystalline form comprises less than 3% by weight of any other physical form of 2-methoxy-N-{4-methoxy-6- [(1 H-pyrazol-1-yl)methyl]-1 ,2-benzoxazol-3-yl}benzene-1 -sulfonamide.

[0039] E12 The anhydrous crystalline form of embodiment 8, wherein the crystalline form comprises less than 1% by weight of any other physical form of 2-methoxy-N-{4-methoxy-6-[(1 H-pyrazol-1- yl)methyl]-1 ,2-benzoxazol-3-yl}benzene-1 -sulfonamide.

[0040] E13 An anhydrous crystalline form of 2-methoxy-N-{4-methoxy-6-[(1 H-pyrazol-1-yl)methyl]-

[0041] 1 ,2-benzoxazol-3-yl}benzene-1 -sulfonamide, wherein the anhydrous crystalline form has a powder X-ray diffraction pattern that is essentially the same as shown in Figure 1.

[0042] E14 An anhydrous crystalline form of 2-methoxy-N-{4-methoxy-6-[(1 H-pyrazol-1-yl)methyl]-

[0043] 1 ,2-benzoxazol-3-yl}benzene-1 -sulfonamide, wherein the anhydrous crystalline form has a13C solid state NMR spectrum that is essentially the same as shown in Figure 2.

[0044] E15 An anhydrous crystalline form of 2-methoxy-N-{4-methoxy-6-[(1 H-pyrazol-1-yl)methyl]-

[0045] 1 ,2-benzoxazol-3-yl}benzene-1 -sulfonamide, wherein the anhydrous crystalline form has a Raman spectrum that is essentially the same as shown in Figure 3.

[0046] E16 A pharmaceutical composition comprising the anhydrous crystalline form of 2-methoxy- N-{4-methoxy-6-[(1 H-pyrazol-1-yl)methyl]-1 ,2-benzoxazol-3-yl}benzene-1 -sulfonamide according to any one of embodiments 1 to 15, and at least one pharmaceutically acceptable excipient. E17 The pharmaceutical composition of embodiment 16, comprising about 0.1 mg to about

[0047] 15 mg of the anhydrous crystalline form of 2-methoxy-N-{4-methoxy-6-[(1H-pyrazol-1- yl)methyl]-1 ,2-benzoxazol-3-yl}benzene-1 -sulfonamide.

[0048] E18 The pharmaceutical composition of embodiment 17, comprising about 0.1 mg to about 5 mg of the anhydrous crystalline form of 2-methoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-

[0049] 1.2-benzoxazol-3-yl}benzene-1-sulfonamide.

[0050] E19 The pharmaceutical composition of embodiment 18, comprising about 0.1 mg, about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, or about 5 mg of the anhydrous crystalline form of 2-methoxy-N-{4-methoxy-6-[(1 H-pyrazol-1-yl)methyl]-1 ,2-benzoxazol-3- yl}benzene-1 -sulfonamide.

[0051] E20 A method for treating cancer comprising administering to a subject in need thereof, a therapeutically effective amount of anhydrous crystalline form of 2-methoxy-N-{4-methoxy-6- [(1H-pyrazol-1-yl)methyl]-1 ,2-benzoxazol-3-yl}benzene-1-sulfonamide according to any one of embodiments 1 to 15, or the pharmaceutical composition according to any one of embodiments

[0052] 16 to 19.

[0053] E21 The method of embodiment 20, wherein the cancer is breast cancer.

[0054] E22 The method of embodiment 21 , wherein the breast cancer is HR+ HER2- breast cancer.

[0055] E23 The method of embodiment 21 , wherein the breast cancer is ER+ HER2- breast cancer.

[0056] E24 The method of embodiment 21, wherein the breast cancer is HR+ HER2- metastatic breast cancer.

[0057] E25 The method of embodiment 21 , wherein the breast cancer is ER+ HER2- metastatic breast cancer.

[0058] E26 The method of embodiment 20 or 21 , wherein the cancer is metastatic breast cancer.

[0059] E27 The anhydrous crystalline form of 2-methoxy-N-{4-methoxy-6-[(1 H-pyrazol-1-yl)methyl]-

[0060] 1.2-benzoxazol-3-yl}benzene-1 -sulfonamide according to any one of embodiments 1 to 15 or the pharmaceutical composition according to any one of embodiments 16 to 19 for use in the treatment of cancer. E28 The anhydrous crystalline form or pharmaceutical composition for use of embodiment

[0061] 27, wherein the cancer is breast cancer.

[0062] E29 The anhydrous crystalline form or pharmaceutical composition for use of embodiment

[0063] 28, wherein the breast cancer is HR+ HER2- breast cancer.

[0064] E30 The anhydrous crystalline form or pharmaceutical composition for use of embodiment 28, wherein the breast cancer is ER+ HER2- breast cancer.

[0065] E31 The anhydrous crystalline form or pharmaceutical composition for use of embodiment 28, wherein the breast cancer is HR+ HER2- metastatic breast cancer.

[0066] E32 The anhydrous crystalline form or pharmaceutical composition for use of embodiment 28, wherein the breast cancer is ER+ HER2- metastatic breast cancer.

[0067] E33 The anhydrous crystalline form or pharmaceutical composition for use of embodiment 27 or 28, wherein the cancer is metastatic breast cancer.

[0068] The polymorphic form of the present invention, anhydrous crystalline Form 5 of Compound A has desirable properties, such as high crystallinity, high purity, low hygroscopicity (non-hydroscopic), low risk of hydration / dehydration events, favorable mechanical properties, manufacturability, favorable physical stability, favorable chemical stability, favorable thermal stability, favorable thermodynamic stability, and / or favorable photostability.

[0069] Manufacturability of Form 5 of Compound A is favorable with respect to physical properties, such as filterability, stickiness, cohesion, and ease of drying. Form 5 of Compound A has beneficial properties over Form 1 of Compound A, which may result in easier milling and less sticking, as evidenced for example by the brittle fraction index measurement.

[0070] Other polymorphic forms of Compound A may not have the same balance of favorable properties as Form 5 of Compound A.

[0071] Definitions

[0072] Unless otherwise defined herein, scientific and technical terms used in connection with the present invention have the meanings that are commonly understood by those of ordinary skill in the art.

[0073] The invention described herein suitably may be practiced in the absence of any element(s) not specifically disclosed herein. As used herein, the term “about” when used to modify a numerically defined parameter (e.g., the dose of a KAT6 inhibitor) means that the parameter may vary by as much as 10% below or above the stated numerical value for that parameter. For example, a dose of about 5 mg means 5 mg ± 10%, i.e. , it may vary between 4.5 mg and 5.5 mg.

[0074] As used herein, the term “substantially pure” with reference to a particular crystalline form means that the crystalline form includes less than 10%, preferably less than 5%, preferably less than 3%, or preferably less than 1% by weight of any other physical forms of a compound, such as Form 5 of Compound A.

[0075] The term "treating", "treat" or "treatment" as used herein embraces both preventative, i.e., prophylactic, and palliative treatment, i.e., relieve, alleviate, or slow the progression of the patient’s disease (or condition) or any tissue damage associated with the disease.

[0076] As used herein, the term, “subject” or “patient,” used interchangeably, refers to any animal, including mammals. Mammals according to the invention include canine, feline, bovine, caprine, equine, ovine, porcine, rodents, lagomorphs, primates, humans and the like, and encompass mammals in utero. In an embodiment, humans are suitable subjects. Human subjects may be of any gender and at any stage of development.

[0077] As used herein, the phrase “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which may include one or more of the following:

[0078] (1) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting (or slowing) further development of the pathology or symptomatology or both); and

[0079] (2) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology or symptomatology or both).

[0080] Cyclin-dependent kinases (CDKs) and related serine / threonine kinases are important cellular enzymes that perform essential functions in regulating cell division and proliferation. CDK inhibitors include Pan-CDK inhibitors that target a broad spectrum of CDKs or selective CDK inhibitors that target specific CDK(s).

[0081] As used herein, a “CDK4 inhibitor” includes a CDK4 selective inhibitor and a CDK4 / 6 inhibitor. CDK4 selective inhibitors are disclosed in International Publication No. WO 2019 / 207463. Examples of CDK4 / 6 inhibitors include, but are not limited to, abemaciclib, ribociclib and palbociclib. Additional examples of CDK4 / 6 inhibitors include lerociclib (also known as G1T38) and trilaciclib (also known as GTI128). In an embodiment, CDK4 selective inhibitors of the present invention include 1,5- anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan-2-yl)-1 / 7-benzimidazol-6- yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-t / 7reo-pentitol, or a pharmaceutically acceptable salt thereof.

[0082] In an embodiment, a CDK4 / 6 inhibitor of the present invention includes palbociclib. Unless otherwise indicated herein, palbociclib (also referred to herein as “palbo” or “Palbo”) refers to 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8 / 7-pyrido[2,3- d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof.

[0083] As used herein, “endocrine therapy” means an aromatase inhibitor, a selective estrogen receptor degrader (SERD), or a selective estrogen receptor modulator (SERM). In certain embodiments, endocrine therapy includes fulvestrant, tamoxifen, toremifene, anastrozole, exemestane, or letrozole.

[0084] Pharmaceutical Compositions

[0085] A "pharmaceutical composition" refers to a compound, such as Form 5 of Compound A, and one or more pharmaceutically acceptable excipients. Form 5 of Compound A may be present in a pharmaceutical composition which includes one or more pharmaceutically acceptable excipients.

[0086] "Pharmaceutically acceptable excipient" refers to a component that may be included in the compositions described herein, is physiologically suitable for pharmaceutical use, and causes no significant adverse effects nor therapeutic effects to a subject.

[0087] The term “excipient” is used herein to describe any ingredient other than Form 5 of Compound A. The choice of excipient will to a large extent depend on factors such as the mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

[0088] The amount of Compound A, or a pharmaceutically acceptable salt, in the pharmaceutical compositions may be in any amounts disclosed herein.

[0089] The compounds of the method, use or combination of the present invention may be formulated prior to administration. The formulation will preferably be adapted to the particular mode of administration. These compounds may be formulated with pharmaceutically acceptable excipients as known in the art and administered in a wide variety of dosage forms as known in the art. Dosage unit forms or pharmaceutical compositions suitable for oral administration include, but are not limited to tablets, capsules, such as gelatin capsules, pills, powders, granules, aqueous and nonaqueous oral solutions and suspensions, packaged in containers adapted for subdivision into individual doses. As used herein, "excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, carriers, diluents and the like that are physiologically compatible. Examples of excipients include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, as well as combinations thereof, and may include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol, or sorbitol in the composition. Examples of excipients also include various organic solvents (such as hydrates and solvates). The pharmaceutical compositions may, if desired, contain additional excipients such as flavorings, binders / binding agents, lubricating agents, disintegrants, sweetening or flavoring agents, coloring matters or dyes, and the like. For example, for oral administration, tablets containing various excipients, such as citric acid may be employed together with various disintegrants such as starch, alginic acid and certain complex silicates and with binding agents such as sucrose, gelatin and acacia. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes. Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules. Non-limiting examples of excipients, therefore, also include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration the active compound therein may be combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with additional excipients such as water, ethanol, propylene glycol, glycerin, or combinations thereof.

[0090] Examples of excipients also include pharmaceutically acceptable substances such as wetting agents or minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives, or buffers, which enhance the shelf life or effectiveness of the compound.

[0091] The composition of Form 5 of Compound A may be in a variety of forms. These include, for example, semi-solid and solid dosage forms, such as dispersions or suspensions, tablets, capsules, and pills. The form depends on the intended mode of administration and therapeutic application.

[0092] Oral administration of a solid dose form may be, for example, presented in discrete units, such as hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of at least one compound of the invention. In another embodiment, the oral administration may be in a powder or granule form. In another embodiment, the oral dose form is sub-lingual, such as, for example, a lozenge. In such solid dosage forms, the compounds of the invention are ordinarily combined with one or more adjuvants. Such capsules or tablets may contain a controlled release formulation. In the case of capsules, tablets, and pills, the dosage forms also may comprise buffering agents or may be prepared with enteric coatings.

[0093] In another embodiment, oral administration may be in a liquid dose form. Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art (e.g., water). Such compositions also may comprise adjuvants, such as wetting, emulsifying, suspending, flavoring (e.g., sweetening), and / or perfuming agents.

[0094] Other excipients and modes of administration known in the pharmaceutical art may also be used. Pharmaceutical compositions of the invention may be prepared by any of the well- known techniques of pharmacy, such as effective formulation and administration procedures.

[0095] The above considerations in regard to effective formulations and administration procedures are well known in the art and are described in standard textbooks. Formulation of drugs is discussed in, for example, Ansel, Howard C., et al., Ansel’s Pharmaceutical Dosage Forms and

[0096] Drug Delivery Systems Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams &

[0097] Wilkins, 2000; Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago,

[0098] Pharmaceutical Press, 2005; Stahl, P. Heinrich and Camilli G. Wermuth, Eds. Handbook of

[0099] Pharmaceutical Salts: Selection, and Use. New York: Wiley-VCH, 2011 ; and

[0100] Brittain, Harry G., Ed. Polymorphism in Pharmaceutical Solids. New York: Informa Healthcare USA, Inc., 2016.

[0101] Acceptable excipients are nontoxic to recipients at the dosages and concentrations employed, and may comprise buffers such as phosphate, citrate, and other organic acids; salts such as sodium chloride; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens, such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or Igs; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or non-ionic surfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG).

[0102] For oral administration, the compositions may be provided in the form of tablets or capsules containing 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg or 8 mg of Form 5 of Compound A for the symptomatic adjustment of the dosage to the patient. A medicament typically contains from about 0.1 mg to about 15 mg of Form 5 of Compound A, or in another embodiment, from about 0.1 mg to about 8 mg of Form 5 of Compound A or from about 0.5 mg to above 5 mg of Form 5 of Compound A.

[0103] Administration and Dosing

[0104] Typically, Form 5 of Compound A is administered in an amount effective to treat a condition as described herein.

[0105] Form 5 of Compound A is administered by any suitable route in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended.

[0106] Embodiments of the present invention provide a dose, dosage and dosing regimen comprising administering to a subject an amount, or a therapeutically effective amount, of Compound A or a pharmaceutically acceptable salt thereof. The amount, or the therapeutically effective amount, may be a daily dose in the range of from about 0.1 mg, about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg or about 8 mg of Form 5 of Compound A for the symptomatic adjustment of the dosage to the patient. A medicament typically contains from about 0.1 mg to about 15 mg of Form 5 of Compound A, or in another embodiment, from about 0.1 mg to about 8 mg of Form 5 of Compound A or from about 0.5 mg to above 5 mg of Form 5 of Compound A.

[0107] Compound A may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the bloodstream directly from the mouth.

[0108] The dosage regimen for Compound A or compositions containing Compound A is based on a variety of factors, including the type, age, weight, sex and medical condition of the patient; the severity of the condition; the route of administration; and the activity of the particular compound employed. Thus, the dosage regimen may vary widely.

[0109] Therapeutic Methods and Uses

[0110] Form 5 of Compound A acts as a Lysine Acetyl Transferase (KAT) inhibitor of the MYST family and is useful in the treatment of abnormal cell growth, such as cancer. In particular, Form 5 of Compound A acts as an inhibitor of KAT6 and / or KAT7.

[0111] “Abnormal cell growth” or “cancer” as used herein, unless otherwise indicated, refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes the abnormal growth of: (1) tumor cells (tumors) that proliferate by expressing a mutated tyrosine kinase or overexpression of a receptor tyrosine kinase; (2) benign and malignant cells of other proliferative diseases in which aberrant tyrosine kinase activation occurs; (3) any tumors that proliferate by receptor tyrosine kinases; (4) any tumors that proliferate by aberrant serine / threonine kinase activation; (5) benign and malignant cells of other proliferative diseases in which aberrant serine / threonine kinase activation occurs; (6) any tumors that proliferate by aberrant signaling, metabolic, epigenetic and transcriptional mechanism; and (7) benign and malignant cells of other proliferative diseases in which aberrant signaling, metabolic, epigenetic and transcriptional mechanism occur.

[0112] For convenience, certain well-known abbreviations, may be used herein, including: hormone receptor positive (HR+), estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-), non-small cell lung cancer (NSCLC) and castration resistant prostate cancer (CRPC).

[0113] Additional embodiments relate to methods of treating cancer in a subject in need thereof comprising administering to the subject an amount of Form 5 of Compound A that is effective in treating cancer.

[0114] In another embodiment, the cancer is selected from the group consisting of lung cancer, mesothelioma, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, hepatic carcinoma, colon cancer, breast cancer, 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, hematology malignancy, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, glioblastoma, brain stem glioma, and pituitary adenoma, or a combination of two or more of the foregoing cancers.

[0115] In another embodiment, the cancer is breast, lung, colon, brain, prostate, stomach, pancreatic, ovarian, melanoma, endocrine, uterine, testicular, or bladder.

[0116] In another embodiment, the cancer is breast, lung, prostate, pancreatic, or ovarian.

[0117] In another embodiment, the cancer is breast cancer.

[0118] In another embodiment, the breast cancer is HR+ breast cancer.

[0119] In another embodiment, the breast cancer is ER+ breast cancer.

[0120] In another embodiment, the breast cancer is HR+ HER2- breast cancer.

[0121] In another embodiment, the breast cancer is ER+ HER2- breast cancer.

[0122] In another embodiment, the breast cancer is locally advanced or metastatic HR+ HER2- breast cancer. In another embodiment, the breast cancer is locally advanced or metastatic ER+ HER2- breast cancer.

[0123] In another embodiment, the breast cancer is HR+ HER2- metastatic breast cancer.

[0124] In another embodiment, the breast cancer is ER+ HER2- metastatic breast cancer.

[0125] In another embodiment, the lung cancer is non-small cell lung cancer.

[0126] In another embodiment, the lung cancer is locally advanced or metastatic non-small cell lung cancer.

[0127] In another embodiment, the prostate cancer is castration resistant prostate cancer.

[0128] In another embodiment, the prostate cancer is locally advanced or metastatic castration resistant prostate cancer.

[0129] Additional embodiments relate to methods of treating hematologic tumors in a subject. Some embodiments relate to the treatment of hematologic tumors in a subject in need thereof comprising administering to the subject an amount of Form 5 of Compound A that is effective in treating the hematologic tumor.

[0130] In another embodiment, the hematologic tumor is leukemia, lymphoma or multiple myeloma.

[0131] In another embodiment, the hematologic tumor is leukemia or lymphoma.

[0132] Another embodiment relates to methods of treating cancer in a patient with locally advanced or metastatic HR+HER2- breast cancer, locally advanced or metastatic ER+HER2- breast cancer, CRPC, or NSCLC whose disease progressed on or is intolerant to standard therapy.

[0133] Another embodiment relates to methods of treating cancer in a patient with locally advanced or metastatic HR+HER2- breast cancer, locally advanced or metastatic ER+HER2- breast cancer, CRPC, or NSCLC whose disease progressed on or is intolerant to standard therapy.

[0134] Another embodiment relates to methods of treating cancer in a patient with locally advanced or metastatic 2L+ HR+HER2- breast cancer or locally advanced or metastatic 2L+ ER+HER2 breast cancer who has progressed after at least 1 prior line of treatment with an endocrine therapy and CDK4 / 6 inhibitor. In an embodiment thereof, the patient is administered a combination of Form 5 of Compound A and fulvestrant.

[0135] Another embodiment relates to methods of treating cancer in a patient with locally advanced or metastatic 2L+ HR+HER2- breast cancer or locally advanced or metastatic 2L+ ER+HER2 breast cancer who has progressed after at least 1 prior line of treatment with an endocrine therapy and CDK4 / 6 inhibitor. In an embodiment thereof, the patient is administered a combination of Form 5 of Compound A with letrozole and palbociclib. Another embodiment relates to methods of treating cancer in a patient with advanced or metastatic 2L+ HR+HER2- breast cancer or advanced or metastatic 2L+ ER+HER2- breast cancer who has progressed after at least 1 prior line of CDK4 / 6 inhibitor and 1 line of endocrine therapy. In an embodiment thereof, the patient is administered Form 5 of Compound A.

[0136] Another embodiment relates to methods of treating cancer in a patient with advanced or metastatic 2-4L fulvestrant-naive HR+HER2- breast cancer or advanced or metastatic 2-4L fulvestrant-naive ER+HER2- breast cancer whose disease has progressed after 1 line of a CDK4 / 6 inhibitor and 1 line of endocrine therapy and who must not have received more than 3 lines of systemic therapies in advanced or metastatic setting. In an embodiment thereof, the patient is administered Form 5 of Compound A and fulvestrant.

[0137] Further embodiments relate to methods of treating cancer in a patient which comprises administering to the patient an amount of Form 5 of Compound A that is effective in treating cancer in combination with an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, radiation, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxics, anti-hormones, and anti-androgens.

[0138] More embodiments relate to pharmaceutical compositions for treating cancer in a patient comprising an amount of Form 5 of Compound A that is effective in treating cancer, and a pharmaceutically acceptable carrier.

[0139] Yet more embodiments relate to a method of treating a disorder associated with angiogenesis in a patient, including a human, comprising administering to said patient an amount of Form 5 of Compound A that is effective in treating said disorder in combination with one or more anti-tumor agents listed above. Such disorders include cancerous tumors such as melanoma; ocular disorders such as age-related macular degeneration, presumed ocular histoplasmosis syndrome, and retinal neovascularization from proliferative diabetic retinopathy; rheumatoid arthritis; bone loss disorders such as osteoporosis, Paget’s disease, humoral hypercalcemia of malignancy, hypercalcemia from tumors metastatic to bone, and osteoporosis induced by glucocorticoid treatment; coronary restenosis; and certain microbial infections including those associated with microbial pathogens selected from adenovirus, hantaviruses, Borrelia burgdorferi, Yersinia spp., Bordetella pertussis, and group A Streptococcus.

[0140] Some embodiments relate to a method of (and to a pharmaceutical composition for) treating cancer in a patient which comprise an amount of Form 5 of Compound A, in combination with an amount of one or more substances selected from anti-angiogenesis agents, signal transduction inhibitors (e.g., inhibiting the means by which regulatory molecules that govern the fundamental processes of cell growth, differentiation, and survival communicated within the cell), and antiproliferative agents, which amounts are together effective in treating said abnormal cell growth.

[0141] Anti-angiogenesis agents, such as MMP-2 (matrix-metalloprotienase 2) inhibitors, MMP- 9 (matrix-metalloprotienase 9) inhibitors, and COX-II (cyclooxygenase II) inhibitors, may be used in conjunction with Form 5 of Compound A in the methods and pharmaceutical compositions described herein.

[0142] Tyrosine kinase inhibitors may also be combined with Form 5 of Compound A.

[0143] VEGF inhibitors, for example, sutent and axitinib, may also be combined with Form 5 of Compound A.

[0144] ErbB2 receptor inhibitors may be administered in combination with Form 5 of Compound A. Various other compounds, such as styrene derivatives, have also been shown to possess tyrosine kinase inhibitory properties, and some of tyrosine kinase inhibitors have been identified as erbB2 receptor inhibitors.

[0145] Epidermal growth factor receptor (EGFR) inhibitors may be administered in combination with Form 5 of Compound A.

[0146] PI3K inhibitors, such as PI3K alpha or PI3K beta inhibitors, may be administered in combination with Form 5 of Compound A.

[0147] Mammalian target of rapamycin (mTOR) inhibitors may be administered in combination with Form 5 of Compound A. c-Met inhibitors may be administered in combination with Form 5 of Compound A.

[0148] CDK inhibitors may be administered in combination with Form 5 of Compound A.

[0149] MEK inhibitors may be administered in combination with Form 5 of Compound A.

[0150] PARP inhibitors may be administered in combination with Form 5 of Compound A.

[0151] JAK inhibitors may be administered in combination with Form 5 of Compound A.

[0152] An antagonist of a Programmed Death 1 protein (PD-1) may be administered in combination with Form 5 of Compound A.

[0153] An antagonist of Programmed Death-Ligand 1 (PD-L1) may be administered in combination with Form 5 of Compound A.

[0154] Other antiproliferative agents that may be used with Form 5 of Compound A include inhibitors of the enzyme farnesyl protein transferase and inhibitors of the receptor tyrosine kinase PDGFr.

[0155] Form 5 of Compound A may also be used with other agents useful in treating abnormal cell growth or cancer, including, but not limited to, agents capable of enhancing antitumor immune responses, such as CTLA4 (cytotoxic lymphocyte antigen 4) antibodies, and other agents capable of blocking CTLA4; and anti-proliferative agents such as other farnesyl protein transferase inhibitors, for example the farnesyl protein transferase. Form 5 of Compound A may be applied as a sole therapy or may involve one or more other anti-tumor substances, for example those selected from, for example, mitotic inhibitors, alkylating agents, anti-metabolites, growth factor inhibitors, cell cycle inhibitors, intercalating antibiotics, enzymes, and anti-hormones.

[0156] Form 5 of Compound A may be used alone or in combination with one or more of a variety of anti-cancer agents or supportive care agents. For example, Form 5 of Compound A may be used with cytotoxic agents. Some embodiments also contemplate the use of Form 5 of Compound A with hormonal therapy. Further, some embodiments provide Form 5 of Compound A alone or in combination with one or more supportive care products, e.g., a product selected from the group consisting of Filgrastim (Neupogen), ondansetron (Zofran), Fragmin, Procrit, Aloxi, Emend, or combinations thereof. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment.

[0157] Form 5 of Compound A may be used with antitumor agents, alkylating agents, antimetabolites, antibiotics, plant-derived antitumor agents, camptothecin derivatives, tyrosine kinase inhibitors, antibodies, interferons, and / or biological response modifiers. In this regard, the following is a non-limiting list of examples of secondary agents that may be used with Form 5 of Compound A.

[0158] Kits

[0159] Another aspect of the invention provides kits comprising Form 5 of Compound A or pharmaceutical compositions comprising Form 5 of Compound A. A kit may include, in addition to Form 5 of Compound A or a pharmaceutical composition thereof, diagnostic or therapeutic agents. A kit may also include instructions for use in a diagnostic or therapeutic method. In some embodiments, the kit includes Form 5 of Compound A or a pharmaceutical composition thereof and a diagnostic agent.

[0160] In yet another embodiment, the invention comprises kits that are suitable for use in performing the methods of treatment described herein. In one embodiment, the kit contains a first dosage form comprising Form 5 of Compound A in quantities sufficient to carry out the methods of the invention. In another embodiment, the kit comprises Form 5 of Compound A in quantities sufficient to carry out the methods of the invention and a container for the dosage.

[0161] GENERAL EXPERIMENTAL METHODS

[0162] Powder X-Ray Diffraction (PXRD) Method Powder X-Ray Diffraction (PXRD) was determined for 2-methoxy- / V-{4-methoxy-6-[(1H- pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-sulfonamide, Form 5 according to the method below.

[0163] The powder X-ray diffraction pattern for 2-methoxy-N-{4-methoxy-6-[(1 H-pyrazol-1- yl)methyl]-1 ,2-benzoxazol-3-yl}benzene-1 -sulfonamide, Form 5 was generated using a Bruker AXS D8 Endeavor diffractometer equipped with a copper (Cu) radiation source. The tube voltage and amperage were set to 40 kV and 40 mA, respectively. The motorized divergence slits were set at constant illumination of 11 mm. Diffracted radiation was detected using a LYNXEYE XET energy dispersive X-ray detector, with the position sensitive detector (PSD) opening set at 4.00°. Data were collected on the theta-theta goniometer at the Cu wavelength from 2.0 to 55.0 degrees 2-theta (°20) using a step size of 0.019 °20 and a time per step of 0.2 s. Samples were prepared for analysis by placing them in a silicon low background small divot holder and rotated at 15 rpm during data collection.

[0164] Data were analyzed in DIFFRAC.EVA V5.0 software. The collected powder pattern of 2- methoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-sulfonamide Form 5 was aligned to the simulated powder pattern from the crystal structure. Peak lists were prepared using reflections with a relative intensity > 2 % of the most intense band. A typical variability of ± 0.2 °20 in peak positions (USP-941) applies to this data.

[0165] Solid State Nuclear Magnetic Resonance (ssNMR) Method

[0166] Solid state NMR analysis was conducted on a Bruker AVANCE NEO 400 MHz (1H frequency) NMR spectrometer using a MAS probe at a magic angle spinning rate of 14 kHz. The temperature was unregulated in each case and a phase modulated proton decoupling field of 80-100 kHz was applied during spectral acquisition.

[0167] 13C cross-polarization (CP) spectra were recorded with a 1.75 ms CP contact time and recycle delay of 12 s. Carbon spectral referencing is relative to neat tetramethylsilane, carried out by setting the high-frequency signal from an external sample of L-alanine to 177.8 ppm.

[0168] Peak positions and relative intensities were obtained using ACD Labs 2020.2.1 Spectrus Processor software with the threshold for peak selection set to 3% relative intensity. The automated peak picking was visually checked to ensure validity and adjustments were made if necessary. A variability of ±0.2 ppm applies to the reported13C shifts. ssNMR intensities may vary depending on the experimental setup and the thermal history of the sample.

[0169] Raman Spectroscopy Raman spectra were collected using a Bruker RAM II FT-Raman module attached to a Vertex 70 spectrometer. The instrument was equipped with a 1064 nm solid-state (Nd:YAG) laser and a liquid nitrogen cooled germanium detector. Prior to data acquisition, instrument performance and calibration verifications were conducted using a white light source, and polystyrene and naphthalene references.

[0170] Samples were prepared and analyzed in truncated NMR tubes. A sample rotator (Ventacon, UK) was used during measurement to maximize the volume of material analyzed during data collection, to minimize relative intensity variations caused by preferred orientation. The backscattered Raman signal from the sample collected at a spectral resolution of 2 cm-1using a laser power of 500 mW. A Blackmann-Harris 4-term apodization function was applied to minimize spectral aberrations. Spectra were generated between 3500 and 50 cm'1with the number of scans adjusted accordingly to ensure adequate signal to noise.

[0171] Spectra were normalized to the intensity of the most intense peak. Peak positions and relative intensities were obtained using the automatic peak picking function in the OPUS v8.2 software with the sensitivity set to 3.0%. The variability in the peak positions with this experimental configuration is within ±2 cm'1.

[0172] One of ordinary skill in the art would expect that, since FT-Raman and dispersive Raman are similar techniques, peak positions for FT-Raman spectra would be consistent with those that would be observed using a dispersive Raman measurement, assuming appropriate instrument calibration.

[0173] EXAMPLES

[0174] EXAMPLE 1

[0175] Preparation of 2-methoxy- / V-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3- yl}benzene-1 -sulfonamide, Form 5 - Requires No Seed

[0176] The synthesis of 2-methoxy- / V-{4-methoxy-6-[(1 H-pyrazol-1-yl)methyl]-1 ,2-benzoxazol-3- yl}benzene-1 -sulfonamide Form 1 was described in International Publication No. WO 2020 / 254946 and in U.S. Patent No. 11 ,492,346.

[0177] 2-Methoxy- / V-{4-methoxy-6-[(1 H-pyrazol-1-yl)methyl]-1 ,2-benzoxazol-3-yl}benzene-1- sulfonamide, Form 1 (about 6.0 g) and 120 mL acetonitrile were added to a suitable round bottom vessel, such as a EasyMax® vessel with overhead stirrer and agitated at 460 revolutions per minute (RPM) to give a white slurry. The mixture was heated to 78 °C over 10 minutes and held at this temperature until a yellow solution was seen. Solution was cooled to 70°C at 0.5 K / min and held for 1 hour, during which spontaneous nucleation was observed. The slurry was cooled to -10°C at 0.1 K / min and held at this temperature overnight. A 5 mL aliquot of slurry was filtered through a Buchner funnel, washed with 2 x 0.5 mL acetonitrile and put into a vacuum oven at 50°C to dry. The result was dried solid, 2-methoxy- / V-{4-methoxy-6-[(1H- pyrazol-1-yl)methyl]-1 ,2-benzoxazol-3-yl}benzene-1-sulfonamide, Form 5.

[0178] EXAMPLE 2

[0179] Preparation of 2-methoxy- / V-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3- yl}benzene-1 -sulfonamide, Form 5 (anhydrous free form) - Seeded Recrystalization 2-Methoxy- / V-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1 ,2-benzoxazol-3-yl}benzene-1- sulfonamide, Form 1 (89.70 g), 540 mL toluene and 1260 mL acetonitrile were added to a suitable vessel, such as a 2 L Reactor-Ready™ vessel equipped with overhead stirrer. The vessel was agitated at 370 RPM and a white slurry formed. The slurry was heated rapidly to 74°C and held until dissolution was observed. The resulting solution was cooled to 65°C at 0.2 K / min and seeded with 898 mg 2-methoxy- / V-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2- benzoxazol-3-yl}benzene-1 -sulfonamide, Form 5 to give a thin slurry. The mixture was held at 65°C for 1 hour, cooled to 0°C at 0.1 K / min and held at this temperature overnight. The resulting solid material was 2-methoxy- / V-{4-methoxy-6-[(1 H-pyrazol-1-yl)methyl]-1 ,2- benzoxazol-3-yl}benzene-1 -sulfonamide, Form 5.

[0180] EXAMPLE 3 Physical Characterization of 2-methoxy- / V-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2- benzoxazol-3-yl}benzene-1 -sulfonamide, Form 5

[0181] Powder X-Ray Diffraction

[0182] PXRD was determined for 2-methoxy- / V-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2- benzoxazol-3-yl}benzene-1 -sulfonamide, Form 5 and the PXRD pattern is provided in Figure 1.

[0183] Table 1. PXRD peak list with relative intensities for 2-methoxy- / V-{4-methoxy-6-[(1H-pyrazol-1- yl)methyl]-1 ,2-benzoxazol-3-yl}benzene-1 -sulfonamide, Form 5. PXRD peaks are in degrees 20 each ± 0.20.

[0184] 13C solid-state NMR was determined for 2-methoxy- / V-{4-methoxy-6-[(1 H-pyrazol-1-yl)methyl]- 1 ,2-benzoxazol-3-yl}benzene-1 -sulfonamide, Form 5.

[0185] Table 2.13C solid-state NMR peak list for 2-methoxy- / V-{4-methoxy-6-[(1 H-pyrazol-1-yl)methyl]- 1 ,2-benzoxazol-3-yl}benzene-1 -sulfonamide, Form 5. Each peak is ± 0.2 ppm.

[0186] Raman spectra was collected for 2-methoxy- / V-{4-methoxy-6-[(1H-pyrazol-1-yl)rnethyl]-1 ,2- benzoxazol-3-yl}benzene-1 -sulfonamide, Form 5.

[0187] Table 3. Raman peak list with relative intensities for 2-methoxy- / V-{4-methoxy-6-[(1 H-pyrazol- 1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-sulfonamide, Form 5. Each wavenumber is ± 0.2 cm'1.

[0188] EXAMPLE 4 Physical and Chemical Properties of Anhydrous Crystalline Form 5 of 2- Methoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1- sulfonamide (“Compound A”) compared to Anhydrous Crystalline Form 1 of 2-Methoxy- N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1 -sulfonamide (“Compound A”)

[0189] Chemical Stability Studies

[0190] Accelerated chemical stability studies revealed that Form 5 of Compound A was chemically stable for 21 days at 50°C / 75% relative humidity (RH), 60°C / 40% RH and 70°C / 10% RH, 14 days at 70°C / 40% RH and 7 days at 70°C / 75% RH and no change in appearance or growth of impurity was detected with respect to 5°C control sample. Form 1 of Compound A also demonstrated good chemical stability under accelerated conditions. Compared to a control sample stored between 2-8°C, there was no significant appearance change at 70°C / 5% RH and 70°C / 75% RH after one week. No individual impurity grew by more than 0.1% at 70°C / 75% RH for one week. In addition, a photostability study was set up at 2 times the conditions according to the guidelines of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). No appearance changed compared with the control sample. One photo-degradation impurity at 8.13% level was present in the 2xlCH stressed Form 1 of Compound A sample. Chemical stability studies indicated that both Form 5 of Compound A and Form 1 of Compound A had very similar chemical stability.

[0191] Moisture Sorption Analysis

[0192] Water sorption and desorption studies were conducted with a Form 5 of Compound A sample. The material was exposed to relative humidity progressively increased to 90% in increments of 10% followed by a decrease to a final RH of 10% in 10% RH increments. The water gain was calculated with respect to the mass of the dried sample. Results showed that Form 5 of Compound A absorbed about 0.01% water at 90%RH at 25°C and Form 1 of Compound A absorbed about 0.05% water at 90% RH at 25°C. Moisture sorption analysis studies indicated that Form 5 of Compound A and Form 1 of Compound A have very similar water sorption behavior, and both are non-hygroscopic.

[0193] Table 4. Water sorption and desorption analysis for 2-methoxy- / V-{4-methoxy-6-[(1 H-pyrazol-1- yl)methyl]-1 ,2-benzoxazol-3-yl}benzene-1-sulfonamide, Form 5.

[0194] Table 5. Water sorption and desorption analysis for 2-methoxy- / V-{4-methoxy-6-[(1 H-pyrazol-1- yl)methyl]-1 ,2-benzoxazol-3-yl}benzene-1-sulfonamide, Form 1. Thermal Stability

[0195] Thermal stability analysis was performed using differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) tests via heating a sample of Form 5 or Form 1 to temperatures in the range of 220°C - 300°C with a heating rate of 10°C / min. The change of heat flow and the change of mass were monitored to measure thermal events by DSC and TGA respectively. The thermal profiles for Form 5 showed a melting event at about 201 ,5°C and a decomposition event at 230°C. A small mass change of 0.2% was measured up to 150°C. The thermal profiles for Form 1 showed a melting event at about 204.0°C and a decomposition event at 230°C. A small mass change of 0.3% was measured up to 225°C. Thermal analysis indicated that both polymorphs have very similar thermal stability. (Table 6)

[0196] Relative Physical Stability Experiments

[0197] The relative physical stability between Form 1 and Form 5 was studied via competitive slurries executed at several different conditions. A mixture of Form 1 and Form 5 samples were suspended in acetone and acetonitrile and left stirring for 10 days at 4°C and 7 days at 25°C and 40°C. Following these equilibration periods, samples were isolated by micro-centrifugation and analyzed by PXRD. All samples demonstrated a complete conversion to Form 5 indicating that Form 5 is more stable than Form 1 at 4°C, 25°C and 40°C. (Table 7)

Claims

CLAIMSWe claim:

1. An anhydrous crystalline form of 2-methoxy-N-{4-methoxy-6-[(1 H-pyrazol-1-yl)methyl]-1 ,2-benzoxazol-3-yl}benzene-1 -sulfonamide, having a powder X-ray diffraction pattern measured using copper wavelength radiation comprising peaks at diffraction angles (20) of 8.6 and 10.4 °20 ± 0.2 °20.

2. The anhydrous crystalline form of claim 1 , having a powder X-ray diffraction pattern measured using copper wavelength radiation further comprising at least one set of peaks at diffraction angles (20) selected from:(a) 13.6 and 13.9 °20 ± 0.2 °20;(b) 18.0 and 20.0 °20 ± 0.2 °20; and(c) 24.0 and 24.2 °20 ± 0.2 °20.

3. The anhydrous crystalline form of claim 1 , having a powder X-ray diffraction pattern measured using copper wavelength radiation further comprising peaks at diffraction angles (20) of 13.6, 13.9, 18.0, 20.0, 24.0, and 24.2 °20 ± 0.2 °20.

4. An anhydrous crystalline form of 2-methoxy-N-{4-methoxy-6-[(1 H-pyrazol-1-yl)methyl]-1 ,2-benzoxazol-3-yl}benzene-1-sulfonamide, having a13C solid state NMR spectrum comprising resonance (ppm) values of: 156.7, 137.6, 130.1 , and 129.0 ppm ± 0.2 ppm.

5. An anhydrous crystalline form of 2-methoxy-N-{4-methoxy-6-[(1 H-pyrazol-1-yl)methyl]-1 ,2-benzoxazol-3-yl}benzene-1 -sulfonamide, having a Raman spectrum comprising wavenumber (cnr1) values of: 329, 527, 1257, 1320, and 3104 cm'1± 2 cm'1.

6. An anhydrous crystalline form of 2-methoxy-N-{4-methoxy-6-[(1 H-pyrazol-1-yl)methyl]-1 ,2-benzoxazol-3-yl}benzene-1-sulfonamide, having:(a) a powder X-ray diffraction pattern measured using copper wavelength radiation comprising peaks at diffraction angles (20) of 8.6 and 10.4 °20 ± 0.2 °20;(b) a13C solid state NMR spectrum comprising one or more resonance (ppm) values of: 156.7, 137.6, 130.1 , and 129.0 ppm ± 0.2 ppm; or(c) a Raman spectrum comprising one or more wavenumber (cm'1) values of: 329, 527, 1257, 1320, and 3104 cm'1± 2 cm'1; or(d) a combination of two or more of (a), (b), and (c).

7. The anhydrous crystalline form of any one of claims 1 to 6, which is substantially pure 2- methoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1- sulfonamide.

8. The anhydrous crystalline form of claim 7, wherein the anhydrous crystalline form comprises less than 10%, less than 5%, less than 3%, or less than 1% by weight of any other physical form of 2-methoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3- yl}benzene-1 -sulfonamide.

9. An anhydrous crystalline form of 2-methoxy-N-{4-methoxy-6-[(1 H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1 -sulfonamide, wherein the anhydrous crystalline form has a powder X-ray diffraction pattern that is essentially the same as shown in Figure 1.

10. An anhydrous crystalline form of 2-methoxy-N-{4-methoxy-6-[(1 H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1 -sulfonamide, wherein the anhydrous crystalline form has a13C solid state NMR spectrum that is essentially the same as shown in Figure 2.

11. An anhydrous crystalline form of 2-methoxy-N-{4-methoxy-6-[(1 H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1 -sulfonamide, wherein the anhydrous crystalline form has a Raman spectrum that is essentially the same as shown in Figure 3.

12. A pharmaceutical composition comprising the anhydrous crystalline form of 2-methoxy- N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1 ,2-benzoxazol-3-yl}benzene-1 -sulfonamide according to any one of claims 1 to 11, and at least one pharmaceutically acceptable excipient.

13. The pharmaceutical composition of claim 12, comprising about 0.1 mg to about 15 mg of the anhydrous crystalline form of 2-methoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1 ,2- benzoxazol-3-yl}benzene-1-sulfonamide.

14. The pharmaceutical composition of claim 13, comprising about 0.1 mg to about 5 mg of the anhydrous crystalline form of 2-methoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1 ,2- benzoxazol-3-yl}benzene-1-sulfonamide.

15. The pharmaceutical composition of claim 14, comprising about 0.1 mg, about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, or about 5 mg of the anhydrous crystalline form of 2-methoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1 ,2-benzoxazol-3-yl}benzene-1- sulfonamide.

16. A method for treating cancer comprising administering to a subject in need thereof, a therapeutically effective amount of anhydrous crystalline form of 2-methoxy-N-{4-methoxy-6- [(1H-pyrazol-1-yl)methyl]-1 ,2-benzoxazol-3-yl}benzene-1-sulfonamide according to any one of claims 1 to 11, or the pharmaceutical composition according to any one of claims 12 to 15.

17. The method of claim 16, wherein the cancer is breast cancer.

18. The method of claim 16 or 17, wherein the cancer is metastatic breast cancer.

19. The anhydrous crystalline form of 2-methoxy-N-{4-methoxy-6-[(1 H-pyrazol-1-yl)methyl]- 1,2-benzoxazol-3-yl}benzene-1-sulfonamide according to any one of claims 1 to 11 or the pharmaceutical composition according to any one of claims 12 to 15 for use in the treatment of cancer.

20. The anhydrous crystalline form or pharmaceutical composition for use of claim 19, wherein the cancer is breast cancer.

21. The anhydrous crystalline form or pharmaceutical composition for use of claim 19 or 20, wherein the cancer is metastatic breast cancer.

Images