Crystalline form of 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile

Abstract

The present disclosure provides crystalline forms of androgen receptor modulators of the formula, as well as methods of making and using these forms. JPEG2025501399000023.jpg99170

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 299,678, filed January 14, 2022, the entire contents of which are incorporated by reference in their entirety. [Background technology]

[0002] Prostate cancer is the second leading cause of cancer-related deaths in men in Western countries (Damber, JE and Aus, G. Lancet (2008) 371:1710-1721). Numerous studies have shown that the androgen receptor (AR) is not only important in the development of prostate cancer, but also in the progression of the disease to castration-resistant state (Taplin, ME et al. J. Clin. Oncol. (2003) 21:2673-8, and Tilley, WD et al. Cancer Res. (1994) 54:4096-4102). Therefore, effective inhibition of human AR remains one of the most effective therapeutic approaches to the treatment of advanced metastatic prostate cancer.

[0003] Spinal-bulbar muscular atrophy (SBMA), or Kennedy disease, is an X-linked recessive neuromuscular disorder. The primary symptoms are weakness and atrophy of bulbar and limb muscles due to reduced motor degeneration of the brainstem and spinal cord along with transient muscle involvement. At onset, patients often present with limb weakness, spasms, tremors, and fasciculations, especially prominent in the face and tongue. Dysarthria is also common with hypernasality, laryngospasm, and swallowing dysfunction, often resulting in aspiration pneumonia as the disease progresses. More than half of patients die from respiratory infections. The disease is caused by a CAG expansion in exon 1 of the androgen receptor (AR), and androgens are required for pathogenesis. Currently, there is no cure for Kennedy disease. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Lancet(2008)371:1710-1721 [Non-Patent Document 2] J. Clin. Oncol. (2003) 21:2673-8 [Non-Patent Document 3] Cancer Res. (1994) 54: 4096-4102 Summary of the Invention [Means for solving the problem]

[0005] Provided herein are crystalline forms useful for treating disorders such as Kennedy's disease in subjects in need of such treatment. In certain embodiments, the crystalline forms have the formula: [ka] Provided herein is a crystalline form of 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile free base having the formula: In another aspect, provided herein is a method of treating Kennedy's disease in a subject in need thereof, comprising administering to the subject a crystalline form of 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile free base. [Brief description of the drawings]

[0006] [Figure 1] FIG. 1 shows the XRPD diffractogram of 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile anhydrous crystalline form C. [Diagram 2] 1 shows a DSC thermogram of 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile anhydrous crystalline form C. [Diagram 3]1 shows a TGA thermogram of 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile anhydrous crystalline form C. [Figure 4] 1H NMR spectrum of 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile anhydrous crystalline form C. [Diagram 5] FIG. 1 is a schematic diagram of the interconversion relationship of polymorphs of 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile. [Figure 6] FIG. 1 shows the XRPD diffractogram of 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile form O. [Figure 7] FIG. 1 shows the XRPD diffractogram of 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile anhydrate form A. [Figure 8] FIG. 1 shows the XRPD diffractogram of 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile hydrate form B. [Figure 9] FIG. 1 shows the XRPD diffractogram of 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile solvate form D. [Figure 10] FIG. 1 shows the XRPD diffractogram of 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile solvate form E. [Figure 11] FIG. 1 shows the XRPD diffractogram of 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile hydrate form F. [Figure 12]FIG. 1 shows the XRPD diffractogram of 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile form G. [Figure 13] FIG. 1 shows the XRPD diffractogram of 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile anhydrate form H. [Figure 14] FIG. 1 shows the XRPD diffractogram of 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile solvate form I. [Figure 15] FIG. 1 shows the XRPD diffractogram of 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile anhydrate form J. [Figure 16] FIG. 1 shows the XRPD diffractogram of 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile anhydrate form K. [Figure 17] FIG. 1 shows the XRPD diffractogram of 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile anhydrate form L. [Figure 18] FIG. 1 shows the XRPD diffractogram of 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile form M. [Figure 19] FIG. 1 shows the XRPD diffractogram of 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile hydrate form N. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0007] When a compound is used for pharmaceutical purposes, the solid state of the compound may be important.The physical properties of the compound may change from one solid form to another, which may affect the suitability of the form for pharmaceutical use.For example, a certain crystalline solid compound may overcome the disadvantages of other solid forms of the compound, such as instability and / or reduced purity.

[0008] Provided herein is a solid, crystalline form of 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile. [ka]

[0009] The compounds are useful for treating a variety of indications, including Kennedy's disease, in a subject.

[0010] Specifically provided herein is a crystalline form of 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile, or a solvate or hydrate thereof.

[0011] The compound 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile is disclosed in PCT Application No. PCT / US2021 / 042355 and U.S. Patent Application No. 17 / 380,736, the entire contents of which are incorporated herein by reference.

[0012] The crystalline forms provided herein may be characterized by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA).

[0013] definition Listed below are definitions of the various terms used to describe the crystalline forms provided herein. These definitions apply to the terms as they are used throughout the specification and claims, unless limited in specific instances either individually or as part of a larger group.

[0014] Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which the compound and its crystalline form belongs. Generally, the nomenclature used herein and laboratory procedures in cell culture, molecular genetics, organic chemistry, and peptide chemistry are well known and commonly used in the art.

[0015] As used herein, the articles "a" and "an" refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one or more than one element. Furthermore, use of the term "including," as well as other forms such as "include," "includes," and "included," are not limiting.

[0016] As used herein, "EC 50 " refers to the concentration of a compound required to achieve an effect that is 50% of the maximum observed effect of the compound.

[0017] As used herein, the term "pharmaceutically acceptable carrier" refers to a pharma- ceutically acceptable material, composition, or carrier, such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent, or encapsulating material, that may carry or transport a compound useful within the present disclosure into or to a patient, thereby serving its intended function. Typically, such constructs are carried or transported from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation, including the compound provided herein, and not harmful to the patient.

[0018] Some examples of materials which can function as pharma- ceutically acceptable carriers include sugars such as lactose, glucose, and sucrose, starches such as corn starch and potato starch, cellulose and cellulose derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt, gelatin, talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol, polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; surfactants; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffers; and other non-toxic compatible substances used in other pharmaceutical preparations.

[0019] As used herein, "pharmaceutical acceptable carrier" also includes any and all coatings, antibacterial and antifungal agents, absorption delaying agents, and the like, that are compatible with the activity of the compounds provided herein and are physiologically acceptable to the patient. Supplementary active compounds can also be incorporated into the composition. Other additional components that can be included in the pharmaceutical compositions used to implement the present disclosure are known in the art and are described, for example, in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

[0020] As used herein, the phrases "therapeutically effective dose" and "therapeutically effective amount" refer to that amount of a compound that prevents the onset, alleviates symptoms, halts the progression of a disease, or brings about another desired biological outcome, such as, for example, amelioration of clinical signs.

[0021] The terms "treat," "treated," "treating," or "treatment" include the relief or alleviation of at least one symptom associated with or caused by the condition, disorder, or disease being treated. In certain embodiments, treatment includes contacting an opioid receptor with an effective amount of a compound provided herein for a condition associated with the androgen receptor.

[0022] As used herein, the term "prevent" or "prevention" refers to the absence of onset of a disorder or disease if the disorder or disease has not occurred, or the absence of further onset of a disorder or disease if the disorder or disease has already occurred. Also contemplated is the ability to prevent some or all of the symptoms associated with the disorder or disease.

[0023] As used herein, the terms "patient," "individual," or "subject" refer to a human or non-human mammal. Non-human mammals include, for example, farm animals and pets, such as ovine, bovine, porcine, canine, feline, and murine mammals. In one embodiment, the patient, subject, or individual is a human.

[0024] Terms such as "administering" or "administration" refer to providing a therapeutic agent, such as the crystalline forms disclosed herein, to a subject in need of treatment. In one embodiment, the subject is a mammal. In another embodiment, the subject is a human.

[0025] As used herein, the term "about" will be understood by those of skill in the art and will vary to some extent depending on the context in which it is used. As used herein, when referring to a measurable value, such as an amount, a temporal duration, and the like, the term "about" is meant to encompass variations of ±10%, including ±5%, ±1%, and ±0.1% from the specified value, as such variations are appropriate for performing the disclosed methods.

[0026] Solvents can be broadly classified as polar (hydrophilic) and non-polar (lipophilic). Polarity can be measured as the dielectric constant or dipole moment of a compound.

[0027] Non-polar solvents include alkanes such as pentane, hexane, heptane, and cyclohexane. Additional examples of non-polar solvents include benzene, toluene, chloroform, and diethyl ether, petroleum ether.

[0028] Examples of polar solvents include pyridine, isopropyl acetate, dichloromethane (DCM), acetone, dimethylformamide (DMF), t-butyl alcohol, dimethylsulfoxide (DMSO), acetonitrile, isopropanol, benzyl alcohol, acetic acid, ethanol, methanol, and water.

[0029] Aprotic solvents are organic solvents that do not contain OH or NH bonds or exchange protons with substances dissolved therein. Examples of aprotic solvents include dimethylsulfoxide (DMSO), isopropyl acetate, dimethylformamide (DMF), dichloromethane (DCM), acetonitrile, acetone, methyl ethyl ketone (MEK), methyl t-butyl ether (MBTE), 2-methyltetrahydrofuran, 1,4-dioxane, ethyl acetate, tetrahydrofuran (THF), heptane, methylcyclohexane, and toluene. Additional non-limiting examples include N-methylpyrrolidone, pyridine, piperidine, dimethyl ether, and methyldodecylsulfoxide.

[0030] Protic solvents are solvents that contain OH or NH bonds.Typical protic solvents that can be used herein include various types of glycols, such as tripropylene glycol methyl ether, dipropylene glycol, and propylene glycol.Other examples of protic solvents include water, ammonia, acetic acid, formic acid, and alcohols such as methanol, ethanol, isopropanol, propanol, and butanol.

[0031] Characterization of crystal morphology In certain embodiments, the crystalline forms described herein are distinguishable based on characteristic peaks in X-ray powder diffraction analysis. X-ray powder diffraction (XRPD) is a scientific technique that uses X-ray, neutron, or electron diffraction on powders, microcrystals, or other solid materials for structural characterization of solid materials. Descriptions of the methods used to obtain certain XRPD diffractograms in connection with the crystalline forms provided herein can be found in the Examples below. In one embodiment, the X-ray powder diffraction data provided herein is obtained by a method that utilizes Cu Kα radiation.

[0032] In one aspect, provided herein is a crystalline form of 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile.

[0033] In one embodiment, the crystalline form is anhydrous.

[0034] In another embodiment, the crystalline form is characterized by an XRPD diffractogram having peaks expressed in 2θ angles at 23.8, 20.7, and 11.7 angles (±0.2 degrees).

[0035] In yet another embodiment, the crystalline form is characterized by an XRPD diffractogram having peaks expressed in 2θ angles at 23.8, 20.7, 11.7, and 24.6 angles (±0.2 degrees).

[0036] In yet another embodiment, the crystalline form is characterized by an XRPD diffractogram having peaks, expressed in 2θ angles, at angles 23.8, 20.7, 11.7, 24.6, and 15.8 (±0.2 degrees).

[0037] In another embodiment, the crystalline form is characterized by an XRPD diffractogram having peaks expressed in 2θ angles at the following angles (±0.2 degrees): 23.8, 20.7, 11.7, 24.6, 15.8, 11.5, 12.2, 12.5, 16.3, 22.5, 22.9, and 30.0.

[0038] In one embodiment, the crystalline form is characterized by an XRPD diffractogram having peaks selected from Table 1 (Form C). [Table 1]

[0039] In another embodiment, the crystalline form has an XRPD diffractogram substantially as depicted in FIG.

[0040] In another embodiment, the crystalline form has a DSC thermogram characterized by an endotherm with an onset temperature of about 179° C. In yet another embodiment, the crystalline form has a DSC thermogram characterized by an endotherm with an onset temperature of 179.3° C.

[0041] Treatment method Provided herein are methods for the treatment of diseases comprising administering a crystalline form of 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile, or a pharmaceutical composition comprising the crystalline form and a pharma- ceutically acceptable carrier.

[0042] In one aspect, provided herein is a method of treating a neurodegenerative disorder in a subject in need thereof, comprising administering to the subject a crystalline form or a pharmaceutical composition comprising the crystalline form and a pharma- ceutically acceptable carrier.

[0043] In one embodiment, the neurodegenerative disorder is spinal and bulbar muscular atrophy (SBMA).

[0044] In one embodiment of this method, the crystalline form is anhydrous.

[0045] In another embodiment of the method, the crystalline form is characterized by an XRPD diffractogram having peaks expressed in 2θ angles at 23.8, 20.7, and 11.7 angles (±0.2 degrees).

[0046] In yet another embodiment of the method, the crystalline form is characterized by an XRPD diffractogram having peaks expressed in 2θ angles at 23.8, 20.7, 11.7, and 24.6 angles (±0.2 degrees).

[0047] In yet another embodiment of the method, the crystalline form is characterized by an XRPD diffractogram having peaks expressed in 2θ angles at 23.8, 20.7, 11.7, 24.6, and 15.8 angles (±0.2 degrees).

[0048] In another embodiment, the crystalline form is characterized by an XRPD diffractogram having peaks expressed in 2θ angles at the following angles (±0.2 degrees): 23.8, 20.7, 11.7, 24.6, 15.8, 11.5, 12.2, 12.5, 16.3, 22.5, 22.9, and 30.0.

[0049] In another embodiment of the method, the crystalline form is characterized by an XRPD diffractogram having peaks selected from Table 1.

[0050] In another aspect, provided herein is a method of treating modulation of androgen receptor (AR) activity in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising the crystalline form or the crystalline form and a pharma- ceutically acceptable carrier.

[0051] In one embodiment, the androgen receptor (AR) is allosterically regulated. In another embodiment, the modulation of androgen receptor (AR) activity treats spinal and bulbar muscular atrophy (SBMA) in a subject.

[0052] In another embodiment, the crystalline form selectively binds to the binding function-3 (BF3) domain of the androgen receptor.

[0053] In another embodiment of the method of modulating AR activity, the crystalline form is characterized by an XRPD diffractogram having peaks expressed in 2θ angles at 23.8, 20.7, and 11.7 angles (±0.2 degrees).

[0054] In yet another embodiment of the method, the crystalline form is characterized by an XRPD diffractogram having peaks expressed in 2θ angles at 23.8, 20.7, 11.7, and 24.6 angles (±0.2 degrees).

[0055] In another embodiment of the method, the crystalline form is characterized by an XRPD diffractogram having peaks expressed in 2θ angles at 23.8, 20.7, 11.7, 24.6, and 15.8 angles (±0.2 degrees).

[0056] In yet another embodiment of the method, the crystalline form is characterized by an XRPD diffractogram having peaks selected from Table 1.

[0057] In yet another aspect, provided herein is a method of treating spinal and bulbar muscular atrophy (SBMA) in a subject in need thereof, comprising administering to the subject a crystalline form of 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile.

[0058] In yet another aspect, provided herein is a method of treating spinal and bulbar muscular atrophy (SBMA) in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a crystalline form of 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile and a pharma- ceutical acceptable carrier.

[0059] In one embodiment of this method, the crystalline form is anhydrous.

[0060] In one aspect, provided herein is a method of treating spinal and bulbar muscular atrophy (SBMA) in a subject in need thereof, comprising administering to the subject a crystalline form of 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile, wherein the crystalline form is characterized by an XRPD diffractogram having peaks expressed in 2θ angles at 23.8, 20.7, and 11.7 degrees (±0.2 degrees).

[0061] In one embodiment of this method, the crystalline form is anhydrous.

[0062] In one embodiment of this method, the crystalline form is characterized by an XRPD diffractogram having peaks expressed in 2θ angles at 23.8, 20.7, 11.7, and 24.6 angles (±0.2 degrees).

[0063] In another embodiment of the method, the crystalline form is characterized by an XRPD diffractogram having peaks expressed in 2θ angles at 23.8, 20.7, 11.7, 24.6, and 15.8 angles (±0.2 degrees).

[0064] In yet another embodiment of the method, the crystalline form is characterized by an XRPD diffractogram having peaks selected from Table 1.

[0065] In yet another aspect, provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising the crystalline form or the crystalline form and a pharma- ceutically acceptable carrier.

[0066] In one embodiment of this method, the crystalline form is anhydrous.

[0067] In another embodiment of the method of treating cancer, the crystalline form is characterized by an XRPD diffractogram having peaks expressed in 2θ angles at 23.8, 20.7, and 11.7 angles (±0.2 degrees).

[0068] In yet another embodiment of the method, the crystalline form is characterized by an XRPD diffractogram having peaks expressed in 2θ angles at 23.8, 20.7, 11.7, and 24.6 angles (±0.2 degrees).

[0069] In another embodiment of the method, the crystalline form is characterized by an XRPD diffractogram having peaks expressed in 2θ angles at 23.8, 20.7, 11.7, 24.6, and 15.8 angles (±0.2 degrees).

[0070] In yet another embodiment, the crystalline form is characterized by an XRPD diffractogram having peaks selected from Table 1.

[0071] In one embodiment, the cancer is selected from hematological cancer, sarcoma, lung cancer, gastrointestinal cancer, genitourinary cancer, liver cancer, bone cancer, nervous system cancer, gynecological cancer, and skin cancer.

[0072] In another embodiment, the lung cancer is selected from non-small cell lung cancer (NSCLC), small cell lung carcinoma, bronchogenic carcinoma, bronchogenic squamous cell carcinoma, bronchogenic undifferentiated small cell carcinoma, bronchogenic undifferentiated large cell carcinoma, adenocarcinoma, bronchogenic carcinoma, alveolar adenocarcinoma, bronchiolar carcinoma, bronchial adenoma, chondroitin hamartoma, mesothelioma, small cell and non-small cell carcinoma, bronchial adenoma, and pleuropulmonary blastoma.

[0073] In yet another embodiment, the lung cancer is non-small cell lung cancer (NSCLC). In yet another embodiment, the lung cancer is adenocarcinoma.

[0074] In one embodiment, the gastrointestinal cancer is selected from esophageal squamous cell carcinoma, esophageal adenocarcinoma, esophageal leiomyosarcoma, esophageal lymphoma, gastric carcinoma, gastric lymphoma, gastric leiomyosarcoma, pancreatic exocrine carcinoma, pancreatic ductal adenocarcinoma, pancreatic insulinoma, pancreatic glucagonoma, pancreatic gastrinoma, pancreatic carcinoid tumor, VIP-producing pancreatic tumor, small intestinal adenocarcinoma, small intestinal lymphoma, small intestinal carcinoid tumor, Kaposi's sarcoma, small intestinal leiomyoma, small intestinal hemangioma, small intestinal lipoma, small intestinal neurofibroma, small intestinal fibroma, colon adenocarcinoma, colon tubular adenoma, colon villous adenoma, colon hamartoma, colon leiomyoma, colorectal carcinoma, gallbladder carcinoma, and anal carcinoma.

[0075] In one embodiment, the gastrointestinal cancer is colorectal cancer.

[0076] In another embodiment, the cancer is a carcinoma. In yet another embodiment, the carcinoma is selected from pancreatic cancer, colorectal cancer, lung cancer, bladder cancer, gastric cancer, esophageal cancer, breast cancer, head and neck cancer, cervical skin cancer, and thyroid cancer.

[0077] In yet another embodiment, the cancer is a hematopoietic malignancy, hi one embodiment, the hematopoietic malignancy is selected from multiple myeloma, acute myeloid leukemia, and myeloproliferative disorders.

[0078] In another embodiment, the cancer is a neoplasm. In yet another embodiment, the neoplasm is a glioblastoma or a sarcoma.

[0079] In one embodiment, the cancer is selected from the group consisting of hematological cancer, sarcoma, lung cancer, gastrointestinal cancer, genitourinary cancer, liver cancer, bone cancer, nervous system cancer, gynecological cancer, and skin cancer.

[0080] In one embodiment, the cancer is selected from the group consisting of pancreatic cancer, cervical cancer, colon cancer, ovarian cancer, breast cancer, pancreatic cancer, pancreatic carcinoma, and pancreatic adenocarcinoma.

[0081] In another embodiment, the cancer is pancreatic cancer, hi yet another embodiment, the cancer is a solid tumor.

[0082] In one embodiment of the methods described herein, the subject is a human.

[0083] Process for preparing Form C In one aspect, a process for preparing a crystalline form of 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile is provided, comprising the steps of: a) combining 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile with a first solvent to form a mixture; b) seeding the mixture with 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile crystals; c) stirring the mixture; and d) collecting the solid 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile; e) washing the solid with a second solvent; f) collecting and drying the crystalline form of 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile.

[0084] In one embodiment, the first solvent is a polar solvent and the second solvent is a non-polar solvent.

[0085] In another embodiment, the first solvent is a non-polar solvent and the second solvent is a non-polar solvent.

[0086] In yet another embodiment, the first solvent is an aprotic solvent and the second solvent is an aprotic solvent.

[0087] In yet another embodiment, the first solvent is a protic solvent and the second solvent is an aprotic solvent.

[0088] In one embodiment, the first solvent is selected from the group consisting of acetone, 2-methyltetrahydrofuran, tetrahydrofuran, ethyl acetate, methyl ethyl ketone, isopropanol, methyl isobutyl ketone, ethanol, and isopropyl acetate, or a combination thereof.

[0089] In another embodiment, the second solvent is selected from the group consisting of heptane, methylcyclohexane, and toluene, or a combination thereof.

[0090] In yet another embodiment, the first solvent is 2-methyltetrahydrofuran and the second solvent is heptane.

[0091] In another aspect, a process for preparing a crystalline form of 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile, comprising: a) combining 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile with a polar aprotic solvent to form a mixture; b) seeding the mixture with 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile crystals; c) stirring the mixture; and d) collecting the solid 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile; e) re-equilibrating the solid in a polar aprotic solvent under a temperature cycle of about 5° C. to about 50° C.; f) collecting and drying the crystalline form of 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile.

[0092] In one embodiment, the polar aprotic solvent in step a) is acetone. In another embodiment, the polar aprotic solvent in step e) is acetone.

[0093] In one embodiment of the aforementioned process, the starting material is amorphous.

[0094] In another embodiment, the 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile crystalline seeds in step b) are characterized by an XRPD diffractogram having peaks expressed in 2θ angles at 23.8, 20.7, and 11.7 angles (±0.2 degrees).

[0095] In yet another embodiment, the 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile crystalline seeds in step b) are characterized by an XRPD diffractogram having peaks expressed in 2θ angles at 23.8, 20.7, 11.7, and 24.6 angles (±0.2 degrees).

[0096] In yet another embodiment, the 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile crystalline seeds in step b) are characterized by an XRPD diffractogram having peaks expressed in 2θ angles at 23.8, 20.7, 11.7, 24.6, and 15.8 angles (±0.2 degrees).

[0097] In another embodiment, the 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile crystalline seeds in step b) are characterized by an XRPD diffractogram having peaks expressed in 2θ angles at 23.8, 20.7, 11.7, 24.6, 15.8, 11.5, 12.2, 12.5, 16.3, 22.5, 22.9, and 30.0 angles (±0.2 degrees).

[0098] In one embodiment, the 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile crystalline seeds in step b) are characterized by an XRPD diffractogram having peaks selected from Table 1 (Form C).

[0099] In another embodiment, the mixture in step c) is stirred at room temperature. In yet another embodiment, the mixture in step c) is stirred at 25° C. In yet another embodiment, the mixture in step c) is stirred for 10 days.

[0100] In a further embodiment, the temperature cycle of step e) is a cycle of 5° C. to 50° C. In one embodiment, the temperature cycle of step e) is carried out for 3 cycles.

[0101] In another embodiment, the crystalline form of 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile in step f) is dried at about 50° C. under vacuum.

[0102] In another aspect, provided herein is a process for preparing a crystalline form disclosed herein, comprising dissolving 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile in a first solvent, adding a second solvent to form a slurry, and filtering the slurry to isolate the crystalline form of 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile.

[0103] In one embodiment, the first solvent is selected from the group consisting of acetone, ethyl acetate, methyl tert-butyl ether (MTBE), and 2-methyltetrahydrofuran (MeTHF), or a combination thereof. In another embodiment, the first solvent is ethyl acetate. In yet another embodiment, the first solvent is acetone. In yet another embodiment, the first solvent is 2-methyltetrahydrofuran (MeTHF). In one embodiment, the second solvent is heptane. In one embodiment, the second solvent is methyl tert-butyl ether (MTBE).

[0104] In another embodiment, the crystalline form is characterized by an XRPD diffractogram having peaks expressed in 2θ angles at 23.8, 20.7, and 11.7 angles (±0.2 degrees).

[0105] In yet another embodiment, the crystalline form is characterized by an XRPD diffractogram having peaks expressed in 2θ angles at 23.8, 20.7, 11.7, and 24.6 angles (±0.2 degrees).

[0106] In yet another embodiment, the crystalline form is characterized by an XRPD diffractogram having peaks, expressed in 2θ angles, at angles 23.8, 20.7, 11.7, 24.6, and 15.8 (±0.2 degrees).

[0107] In another embodiment, the crystalline form is characterized by an XRPD diffractogram having peaks expressed in 2θ angles at the following angles (±0.2 degrees): 23.8, 20.7, 11.7, 24.6, 15.8, 11.5, 12.2, 12.5, 16.3, 22.5, 22.9, and 30.0.

[0108] In one embodiment, the crystalline form is characterized by an XRPD diffractogram having peaks selected from Table 1 (Form C).

[0109] Pharmaceutical Compositions In one aspect, provided herein is a pharmaceutical composition comprising a crystalline form provided herein and a pharma- ceutically acceptable carrier.

[0110] In one embodiment, the pharmaceutical composition comprises a crystalline form substantially free of other crystalline forms.

[0111] In another embodiment, the crystalline form is characterized by an XRPD diffractogram having peaks expressed in 2θ angles at 23.8, 20.7, and 11.7 angles (±0.2 degrees).

[0112] In yet another embodiment, the crystalline form is characterized by an XRPD diffractogram having peaks expressed in 2θ angles at 23.8, 20.7, 11.7, and 24.6 angles (±0.2 degrees).

[0113] In another embodiment, the crystalline form is characterized by an XRPD diffractogram having peaks, expressed in 2θ angles, at angles 23.8, 20.7, 11.7, 24.6, and 15.8 (±0.2 degrees).

[0114] In yet another embodiment, the crystalline form is characterized by an XRPD diffractogram having peaks selected from Table 1.

[0115] The pharmaceutical compositions may be formulated for oral, intravenous, intramuscular, subcutaneous, or parenteral administration for the therapeutic or prophylactic treatment of Kennedy's Disease.

[0116] The pharmaceutical formulations disclosed herein can be prepared according to standard procedures and administered in dosages selected to reduce, prevent, or eliminate disease. For a general description of how to administer various agents for human therapy, see, e.g., Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA and Goodman and Gilman's "The Pharmaceutical Basis of Therapeutics," Pergamon Press, New York, NY, the contents of which are incorporated herein by reference.

[0117] The pharmaceutical compositions described herein can include the crystalline forms disclosed herein in association with one or more non-toxic pharma- ceutically acceptable carriers and / or diluents and / or adjuvants and / or excipients.

[0118] For oral or parenteral administration, the crystalline forms disclosed herein can be mixed with conventional pharmaceutical carriers and excipients and used in the form of tablets, capsules, elixirs, suspensions, syrups, wafers, etc. Compositions containing the crystalline forms disclosed herein can contain from about 0.1% to about 99% by weight, such as from about 10% to about 30%, of the active compound.

[0119] For oral use, solid formulations such as tablets and capsules are useful. Preparations with sustained release or enteric coating can also be devised. For pediatric and geriatric use, an embodiment provides suspensions, syrups, and chewable tablets. For oral administration, pharmaceutical compositions are in the form of, for example, tablets, capsules, suspensions, or liquids.

[0120] Pharmaceutical compositions can be prepared in the form of dosage units that contain therapeutically effective amounts of active ingredients.Examples of such dosage units are tablets and capsules.For therapeutic purposes, tablets and capsules can contain, in addition to active ingredients, conventional carriers such as binding agents, fillers, lubricants, disintegrating agents, or acceptable wetting agents.Oral liquid preparations are generally in the form of aqueous or oily solutions, suspensions, emulsions, syrups, or elixirs.

[0121] The pharmaceutical compositions disclosed herein can be placed in a pharma- ceutically acceptable carrier and delivered to a recipient subject (e.g., human) according to known drug delivery methods.Generally, the method of delivering pharmaceutical compositions in vivo utilizes art-recognized protocols for delivering drugs, and the only substantial procedural modification is the substitution of the crystalline form of the present disclosure for the drug in art-recognized protocols.

[0122] Administration / Dosage / Formulation In another aspect, provided herein is a pharmaceutical composition comprising a crystalline form provided herein in association with a pharma- ceutically acceptable carrier.

[0123] Actual dosage levels of the active ingredients in the pharmaceutical compositions described herein may be varied for a particular patient, composition, and mode of administration, to achieve an amount of the active ingredient that is effective to achieve the desired therapeutic response without being toxic to the patient.

[0124] In particular, the selected dosage level will depend on a variety of factors, including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of treatment, other drugs, compounds, or materials used in combination with the crystalline form, the age, sex, weight, condition, general health, and prior medical history of the patient being treated, and similar factors well known in the medical arts.

[0125] A medical practitioner, e.g., 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 can begin administration of the pharmaceutical composition at a level of the disclosed crystalline forms lower than that required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved.

[0126] In certain embodiments, formulating the crystalline form in unit dosage form is especially advantageous for ease of administration and uniformity of dosage.

[0127] As used herein, "unit dosage form" refers to a physically discrete unit suitable as a unitary dosage for a patient to be treated, each unit containing a predetermined amount of the disclosed compound calculated to produce a desired therapeutic effect in association with the necessary pharmaceutical vehicle. The unit dosage form of the crystalline form disclosed herein is governed by and directly dependent on (a) the unique characteristics of the disclosed compound and the specific therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding / formulating the disclosed compound for the treatment of Kennedy's disease (SBMA) in patients.

[0128] In one embodiment, the crystalline forms provided herein are formulated using one or more pharma- ceutically acceptable excipients or carriers. In one embodiment, a pharmaceutical composition comprises a therapeutically effective amount of the disclosed crystalline forms and a pharma- ceutically acceptable carrier.

[0129] In some embodiments, the dosage of the disclosed compounds is from about 1 mg to about 1,000 mg. In some embodiments, the dosage of the disclosed compounds used in the compositions described herein is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 20 mg, or less than about 10 mg. For example, the dosage is about 10 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, or about 600 mg.

[0130] The route of administration of any of the compositions disclosed herein includes oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual, or topical. The compounds for use provided herein can be formulated for administration by any suitable route, such as oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, ​​intravaginal (e.g., vaginal and perivaginal), (intra)nasal and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastric, intrathecal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation, and topical administration. In one embodiment, the preferred route of administration is oral.

[0131] Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gelatin capsules, troches, dispersions, suspensions, liquids, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, patches, lotions, disks, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosol formulations for inhalation, compositions and formulations for intravesical administration, etc. It is understood that the formulations and compositions that would be useful in the present disclosure are not limited to the specific formulations and compositions described herein.

[0132] For oral application, particularly suitable are tablets, dragees, liquids, drops, suppositories, or capsules, caplets, and gel capsules. Compositions intended for oral use can be prepared according to any method known in the art, and such compositions may contain one or more agents selected from the group consisting of inert and non-toxic pharmaceutical excipients suitable for the manufacture of tablets. Such excipients include, for example, inert diluents such as lactose, granulating and disintegrating agents such as cornstarch, binding agents such as starch, and lubricants such as magnesium stearate. Tablets may be uncoated or may be coated by known techniques for aesthetics or delayed release of the active ingredient. Oral preparations may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert diluent.

[0133] For parenteral administration, the disclosed compounds can be formulated for injection or infusion, for example, intravenous, intramuscular or subcutaneous injection or infusion, or for administration as a bolus dose or continuous infusion. Suspensions, solutions or emulsions in oily or aqueous vehicles may be used, optionally containing other formulatory agents such as suspending, stabilizing or dispersing agents.

[0134] Those skilled in the art will recognize or be able to ascertain, without more than routine experimentation, many equivalents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents are considered to be within the scope of this disclosure and the appended claims. For example, it should be understood that it is within the scope of this application to vary reaction conditions, including but not limited to reaction times, reaction sizes / volumes, and experimental reagents, such as solvents, catalysts, pressures, atmospheric conditions, such as nitrogen atmosphere, and reducing / oxidizing agents, with art-recognized substitutes, without more than routine experimentation.

[0135] When values ​​and ranges are provided herein, it is to be understood that all values ​​and ranges encompassed by those values ​​and ranges are encompassed within the scope of the disclosure. Moreover, all values ​​that fall within those ranges, as well as the upper or lower limits of a range of values, are also contemplated by the application.

[0136] The following examples further illustrate aspects of the present disclosure, but are not intended to limit the teachings of the disclosure in any way. EXAMPLES

[0137] The present disclosure is further illustrated by the following examples, which should not be construed as further limiting. The practice of the present disclosure will employ, unless otherwise indicated, conventional techniques of organic synthesis, cell biology, cell culture, and molecular biology, which are within the skill of the art.

[0138] Synthesis of 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile Step 1: To a degassed mixture of 5-iodo-3-methyl-2-[2-methyl-2-(oxan-2-yloxy)propoxy]pyrazine (150 mg, 0.38 mmol) and tert-butyl 7-cyano-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indole-1-carboxylate (140 mg, 0.38 mmol) in dioxane (2 mL) and water (0.2 mL), potassium carbonate (105 mg, 0.76 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (27 mg, 0.04 mmol) were added at room temperature. The mixture was stirred at 100° C. for 2 hours. The reaction mixture was diluted using water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash column chromatography using 0-35% ethyl acetate in petroleum ether to give 3-[6-methyl-5-[2-methyl-2-(oxan-2-yloxy)propoxy]pyrazin-2-yl]-1H-indole-7-carbonitrile (67 mg, 43%) as a white solid. MS m / z 407.1 [M+1] + .

[0139] Step 2: To a solution of 3-[6-methyl-5-[2-methyl-2-(oxan-2-yloxy)propoxy]pyrazin-2-yl]-1H-indole-7-carbonitrile (62 mg, 0.15 mmol) in dichloromethane (2.1 mL) was added trifluoroacetic acid (0.7 mL) at room temperature. The mixture was stirred at room temperature for 3 h. The mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash column chromatography using 10-80% acetonitrile in water (10 mmol / L ammonium bicarbonate) to give 3-[5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl]-1H-indole-7-carbonitrile (21.3 mg, 43%) as a white solid. 1H NMR(400MHz,DMSO-d6)δ12.35(s,1H),8.73(d,J=8.0Hz,1H),8.56(s,1H),8.19(d,J=2.4Hz,1H), 7.69-7.67(m,1H),7.28(t,J=8.0Hz,1H),4.70(br,1H),4.10(s,2H),2.54(s,3H),1.24(s,6H);C 18 H 18 N4O2[M+1] + MS(ESI) calculated for: 323.1; found: 323.0.

[0140] Biological assays LNCaP cells expressing ARR2PB-FireflyLuc and CMV-RenillaLuc were treated with the indicated concentrations of test compounds, enzalutamide (negative control), or DHT (positive control) + / - 0.5 nM DHT for 48 hours at 37°C. Fluorescent signals were read on an ImageXpress Micro Confocal System. Residual activity (antagonist mode) was calculated as % remaining activity = 100 x [(reading value 試料 -LC 平均 ) / (HC 平均 -LC 平均 Activation (agonist mode) was calculated as % activation = 100 x [(reading sample - LC 平均 ) / (HC 平均 -LC 平均 ) where HC is the cells treated with 1 uM DHT and LC is the cells treated with DMSO. Dose-response curves and IC 50 Values ​​were calculated using nonlinear regression analysis in XLfit. 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile had an IC of 50 nM. 50 It has been found to have value.

[0141] Analytical methods for polymorph studies Unless otherwise indicated, X-ray powder diffraction (XRPD) was performed on a Bruker D8 Advance diffractometer in reflector mode using quasi-linear Cu Kα radiation operated at 40 kV and 40 mA. Scans were performed from 2θ angles of 2 to 40 with an angular step size of 0.02 and a scan time of 0.3 s per step.

[0142] Differential scanning calorimetry (DSC) was performed on a TA Discovery 2500 with a Tzero pan with a 0.7 mm diameter pinhole and a Tzero airtight lid. DSC analysis was performed by heating from 30 to 250°C or 0 to 250°C at 10°C / min or 20°C / min.

[0143] Thermogravimetric analysis (TGA) was performed on a Discovery 5500 or Q5000 with a starting temperature at ambient conditions (<35° C.) and a final temperature of 300° C. with heating at 10° C. / min (or the next segment was aborted if the weight was <80% (w / w)).

[0144] Nuclear magnetic resonance (NMR) analysis was performed on a Bruker Avance-AV400M at a frequency of 400 MHz for eight scans.

[0145] Dynamic Vapor Sorption (DVS) was performed on an Intrinsic, Advantage or Adventure using water as the solvent with an oven temperature of 25° C. Sample mass was approximately 5-10 mg using the following method. Cycle: 40-0-95-0-40% RH Stage process: 10% Equilibrium: 0.002dm / dt(% / min) Minimum DM / DT stability period: 60 minutes Maximum dm / dt stage time: 360 minutes

[0146] Polymorph analysis 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile free form exhibits complex polymorphic behavior. In total, 15 forms were identified that are polymorphs or pseudopolymorphs of the free form, including seven anhydrates, forms A, C, H, J, K, L, and O; four hydrates, forms B, F, M, and N; and three solvates, forms D, E, and I. In addition, a metastable form, form G, and an amorphous form were also obtained.

[0147] Form A is anhydrous. It has been obtained from many solvent systems by equilibration, slow cooling, fast cooling, evaporation, vapor diffusion, and antisolvent addition experiments. Form A is highly crystalline. DSC shows a T of 170.2 °C. 開始 It shows a melting point peak at 178.9 ° C. 開始 This is followed by another endothermic peak at about 160° C. TGA shows a weight loss of about 0.2% at about 160° C. 1 H-NMR shows no detectable residual solvent. Form A converts to Form C at both 25° C. and 50° C., suggesting that Form A is thermodynamically less stable than Form C. The XRPD diffractogram of Form A is shown in FIG.

[0148] Form B is a hydrate. It was obtained only from methanol systems by temperature cycling, slow cooling, slow evaporation, and fast evaporation. Form B is highly crystalline. DSC shows a T at 16.7°C with an enthalpy of about 22 J / g. 開始 It shows a dehydration peak at T 開始 Then, a small exothermic peak at T 開始 and T of 173.1°C 開始 Two unresolved endothermic peaks at T 開始 and T of 179.0°C 開始 It shows two small unresolved endothermic peaks at about 150° C. and 2.1% weight loss at about 150° C., respectively. KF shows it contains about 3.8% water by weight, corresponding to 0.7 water molecules. 1H-NMR shows no detectable residual solvent. Form B exhibits reversible dehydration-hydration behavior. After dehydration, it transforms into form K, which reverts to form B after exposure to 25° C. at 40-70% RH for 6 days. Form B is a metastable hydrate, which transforms into anhydrous form C over the entire range of water activity (0≦aw≦1). The XRPD diffractogram of form B is shown in FIG. 8.

[0149] Form C is anhydrous. It has been obtained from several solvent systems by equilibration, slow cooling, fast cooling, slow evaporation, and vapor diffusion. Form C is highly crystalline. DSC shows a T of 179.3° C. with an enthalpy of about 114 J / g. 開始 (Figure 2). TGA shows a weight loss of about 0.8% at about 150°C (Figure 3). 1H-NMR shows no detectable residual solvent (Figure 4). Form C is the most stable polymorph compared to the other polymorphs described herein. Competition equilibrium experiments show that Form C is a thermodynamically stable anhydrate at both 25°C and 50°C. Water activity studies show that Form C is stable over the entire range of water activity (0 < aw < 1). The XRPD diffractogram of Form C is shown in Figure 1.

[0150] Form D is a 1,4-dioxane solvate. It was obtained exclusively from 1,4-dioxane systems by equilibration, slow cooling, fast cooling, slow evaporation, fast evaporation, and vapor diffusion experiments. Form D is highly crystalline. DSC shows a T of 88.0° C. with an enthalpy of approximately 27 J / g. 開始 T of 138.6°C, where the time and enthalpy are about 41 J / g. 開始 It shows two desolvation peaks at 179.1 °C with an enthalpy of about 111 J / g, suggesting that the 1,4-dioxane molecule has two types of intermolecular interaction formats with the API molecule in the crystal structure of Form D. 開始 TGA shows a weight loss of about 9.1% at about 130°C, and a weight loss of about 2.8% between about 130°C and 160°C. 1H-NMR indicates 0.5 equivalents (13.6%) of 1,4-dioxane residues by weight. Form D converts to Form C after desolvation. The XRPD diffractogram of Form D is shown in FIG.

[0151] Form E is an EtOH / water solvate. It was obtained from an ethanol system by fast evaporation experiments. Form E is highly crystalline. DSC shows a T of 80.4°C with an enthalpy of about 8 J / g. 開始 and Ts of 165.2 °C and 170.2 °C, respectively. 開始 This unresolved melting peak is followed by a T 開始 After recrystallization, it exhibits a T of 177.9 °C, which is close to the melting point of Form C. 開始 The TGA shows a weight loss of about 2.1% at about 120°C. 1 H-NMR shows 1.4 wt% EtOH. KF shows it contains about 0.6 wt% water. Form E converts to a physical mixture of Forms F and G after heating to 100° C. and cooling to room temperature by TGA. The XRPD diffractogram of Form E is shown in FIG.

[0152] Form F is a hydrate. It was obtained from THF or MEK systems by fast evaporation experiments. Form F is highly crystalline. DSC shows T 開始 The two unresolved melting peaks at T 開始 After recrystallization, it has a T of 177.9 °C, close to the melting point of Form C. 開始 Form F exhibits a melting point at about 140° C. TGA shows a weight loss of about 0.5% at about 140° C. and a weight loss of about 0.7% between about 140° C. and 180° C. 1H-NMR shows 0.5% THF residue by weight. KF shows it contains about 1.7% water by weight. Form F is a metastable hydrate, which converts to Form C over the entire range of water activity (0≦aw≦1). The XRPD diffractogram of Form F is shown in FIG.

[0153] Form G is a metastable form. It was obtained from DMSO / water system by antisolvent addition experiments. Form G is highly crystalline. It converts to anhydrous form H after equilibration in DMSO / water system at 25° C. for 6 days. The XRPD diffractogram of Form G is shown in FIG.

[0154] Form H is anhydrous. It was obtained from acetone or acetone / water (v:v=20:80) by slow cooling experiments. Form H is highly crystalline. DSC showed T of 169.3 °C and 173.2 °C, respectively. 開始 It then shows an unresolved melting peak at T 開始 The TGA shows a small endothermic peak at about 150° C. and a weight loss of about 1.2%. 1 H-NMR shows no detectable residual solvent. Form H is a metastable anhydrate. It converts to form C at both 25° C. and 50° C., suggesting that form H is more thermodynamically unstable than form C. The XRPD diffractogram of form H is shown in FIG.

[0155] Form I is a THF solvate. It was obtained from the THF / heptane system by anti-solvent addition experiments. Form I is highly crystalline. DSC shows a T of 92.8° C. with an enthalpy of about 73 J / g. 開始 It then shows a desolvation peak at T of 178.5 °C, with an enthalpy of about 114 J / g. 開始 TGA shows a weight loss of about 10.0% at about 130°C. 1 H-NMR indicates 0.5 equivalents (10.1%) of THF residues by weight. Form I was converted by TGA to a physical mixture of Form C, Form N, and an unknown peak after heating to 140° C. and cooling to room temperature. The XRPD diffractogram of Form I is shown in FIG.

[0156] Form J is anhydrous. It was obtained by heat-cool DSC. Form J is highly crystalline. DSC shows an onset of 94.0° C., a T of 172.1° C. 開始 A melting peak at 177.4°C, followed by a T 開始The TGA shows a small exothermic event with another endothermic peak at about 150° C. and a weight loss of about 0.6%. 1 H-NMR shows no detectable residual solvent. Form J is a metastable anhydrate that converts to form C at both 25° C. and 50° C., suggesting that form J is more thermodynamically unstable than form C. The XRPD diffractogram of form J is shown in FIG.

[0157] Form K is anhydrous. It was obtained from equilibration, fast cooling experiments, and dehydration of Form B in a methanol system. Form K is highly crystalline. DSC shows T values ​​of 168.7 °C and 171.9 °C. 開始 The two unresolved melting peaks at T 開始 After recrystallization, the peaks are shown in combination with the recrystallization peaks at 177.3°C and 178.8°C, respectively. 開始 Form K shows two unresolved melting peaks at 0.05° C. Form K is unstable and it converts to the hydrate form B after exposure to 25° C. / 92% RH for 6 days. The XRPD diffractogram of form K is shown in FIG.

[0158] Form L is anhydrous. It was obtained after heating Form B to 160° C. and cooling to room temperature. Form L is highly crystalline. Based on the DSC thermogram and VT-XRPD results, Form K is converted to Form L after melting and recrystallization. Form L has a T of 173.5° C. with an enthalpy of about 86 J / g. 開始 Form L is a metastable anhydrate that converts to form C at both 25° C. and 50° C., suggesting that form L is more thermodynamically unstable than form C. The XRPD diffractogram of form L is shown in FIG.

[0159] Form M is an intermediate crystalline form. It was obtained by equilibration from a methanol system. Form M is highly crystalline. It converts to form B after further equilibration in MeOH at 25° C. for 1 day. Therefore, complete characterization data for form M is not available. The XRPD diffractogram of form M is shown in FIG.

[0160] Form N is a hydrate. It was obtained by exposing the amorphous form to 25° C. / 92% RH in an open container for 3 days. Form N is highly crystalline. DSC shows a T of 47.1° C. 開始 Dehydration peak at 81.1°C, T 開始 An exothermic peak at 128.5° C., and an enthalpy of about 11 J / g. 開始 It then shows an endothermic peak at T of 171.6 °C, with an enthalpy of about 76 J / g. 開始 It dissolves at T 開始 Two small endothermic peaks with a C=177.3° C. and C=178.8° C. are shown after melting. KF shows that it contains about 8.7% water by weight, corresponding to 1.5 water molecules. Form N is a metastable hydrate, which converts to form C over the entire range of water activity (0≦aw≦1). The XRPD diffractogram of form N is shown in FIG. 19.

[0161] Form O is anhydrous. It was obtained from temperature cycling, slow evaporation, and fast evaporation in several solvent systems. Form O is highly crystalline. DSC showed T values ​​of 170.1 °C and 178.5 °C, respectively. 開始 Form O shows an unresolved melting peak at 0.7%. TGA shows a weight loss of about 0.7% at about 180° C. 1H-NMR shows no detectable residual solvent. The XRPD of Form O is shown in FIG.

[0162] The amorphous form was prepared by heat-cool TGA using the free form, which crystallized to form N after exposure to high humidity.

[0163] Table 2 outlines the screening conditions for the polymorphs discussed above. [Table 2]

[0164] Preparation of Form C Form C was prepared using the following procedure: 200 mg of the free form was weighed into a 4 mL glass vial. Under stirring at 25° C., 200 μL of acetone was added to the vial. Approximately 3 mg of Form C seeds were added to the solution. After stirring for 10 days at 25° C., the solids were collected by suction filtration and then dried under vacuum at 25° C. for approximately 4 hours. The dried solids were re-equilibrated in 100 μL of acetone under temperature cycles from 5° C. to 50° C. at a heating / cooling rate of 0.1° C. / min. After three cycles, the solids were collected by suction filtration at 5° C. and then dried under vacuum at 50° C. for approximately 2 hours. 136 mg of Form C was obtained as an off-white solid in 67% yield.

[0165] Alternative Preparation of Form C Purification: A total of 11.5 kg of 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile was purified in one batch from the crude product 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile (17.0 kg) using 2-MeTHF / n-heptane. The desired product was isolated as a white solid with 100% HPLC purity. The following procedure was used to prepare the purification: 1. Charge 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile (1X (0.95-1.05X)) into the first reactor. Charge 2.2-MeTHF (3.3-3.9 volumes) to the reactor. 3. Adjust the reactor temperature to 45-55℃. 4. Stir the above solution in a reactor at 45-55°C for 0.5-2 hours to obtain a clear solution. 5. Pass the organic layer through a charcoal filter and decolorize at 45-55°C for 5-15 hours. 8. Take samples for analysis. 9. The liquid is transferred to a second reactor through a cartridge filter. 10. Rinse the first reactor and charcoal filter twice with 2-MeTHF (1.5-3.0 vol). 11. The rinse liquid is transferred to the second reactor through a cartridge filter. 12. Adjust the temperature of the second reactor to 55-65°C. 13. Concentrate the second reactor to 2-4 volumes under vacuum at <65°C. 14.2-MeTHF (1.0-5.0 vol) is charged to the second reactor through the spray ball. 15. Adjust the temperature of the second reactor to 55-65°C. 16. Charge N-heptane (1.5-2.8 vol) to the second reactor at 55-65 °C over 1-5 hours. 17. Charge the seeds (0.001-0.10 vol) into the second reactor at 55-65 °C. 18. Stir the second reactor at 55-65°C for 1-4 hours. 22. Collect samples for analysis. 23. Charge N-heptane (4.1-9.0 vol) to the second reactor at 55-65 °C over 7-12 hours. 24. Stir the second reactor at 55-65°C for 1-5 hours. 25. Condition the second reactor at 20-30°C for 7-12 hours. 26. Stir the second reactor at 20-30°C for 5-15 hours. 27. Collect samples for analysis. 28. Filter and wash the cake twice with 2-MeTHF / n-heptane solution (1.5-2.9 vol). 29. Take a sample of the mother liquor for analysis. 30. Take a sample of the wet cake for analysis. 31. Dry the wet cake at 40-50°C for 15-35 hours. 32. Collect samples for analysis. 33. Sifting and packaging. 34. 3-(5-(2-Hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile is obtained. 35. Collect samples for analysis.

[0166] Polymorphic Interrelationships The interconversion relationships of the identified polymorphs are outlined in FIG.

[0167] The relative stability of anhydrous forms A, C, H, and J was investigated by competitive equilibrium experiments. Form C was obtained in all selected solvents at both 25° C. and 50° C., except for MeOH, where form B was obtained. An intermediate crystalline form, form M, was obtained from methanol as a wet cake and readily further transformed to form B once exposed to air. The presence of intermediate form M influenced the competitive equilibrium experiments, which cannot reflect the actual thermodynamic relationship between anhydrous forms in methanol. In the other selected solvent systems, form C is the most stable form.

[0168] The relative stability of the anhydrate forms C, K, and L was investigated by competitive equilibrium experiments. Form C was obtained in IPAc at both 25° C. and 50° C.

[0169] Thus, Form C is an anhydrate that is thermodynamically stable at both 25°C and 50°C.

[0170] The relative stability of anhydrous form C, hydrate form B, and hydrate form F was investigated by competitive water activity experiments. The relative stability of anhydrous form C and hydrate form N was also investigated by water activity experiments in acetone / water solvent mixture (aw=0.95). The results show that form C is the thermodynamically stable form in the entire range of water activity (0≦aw≦1). Thus, anhydrous form C is the optimal polymorph of 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile free form.

[0171] competitive equilibrium To determine the relative stability of the anhydrates, competitive equilibrium experiments were performed in different solvent systems.

[0172] Approximately 2 mg of each anhydride was added to 0.3–0.4 mL of a saturated solution of the selected solvent. The resulting suspensions were stirred at 25 °C for 3–10 days, respectively. The solid portion (wet cake) was isolated by centrifugal filtration and examined by XRPD. The results are shown in Table 3. [Table 3-1] [Table 3-2]

[0173] Physicochemical characteristics The physicochemical characteristics of Form C are summarized in Table 4. [Table 4]

[0174] Bulk Stability The bulk stability of Form C was evaluated over one week at 25° C. / 92% RH in an open container, 40° C. / 75% RH in an open container, and 60° C. in a closed container. Form C is physically and chemically stable after stress under these conditions, as shown in Table 5. [Table 5]

[0175] The stability of Form C was further investigated under the following conditions, and the results are summarized in Tables 5A-5F. [Table 6] [Table 7] [Table 8] [Table 9] [Table 10] [Table 11]

[0176] As can be seen above, Form C is stable under varying conditions of temperature and relative humidity.

[0177] solubility Anhydrous Form C (equivalent to 8 mg of free form) was weighed into a 20 mL glass vial. 4 mL of solubility medium was added. The resulting suspension was stirred at 400 rpm at 37° C. Some of the suspensions were removed at 2 hours and 24 hours, respectively. They were then centrifuged at 14,000 rpm for 5 minutes at 37° C. The supernatant was analyzed for solubility and pH by HPLC and pH meter, respectively. The residual solid (wet cake) was characterized by XRPD to determine the physical form. [Table 12]

[0178] The results of additional solubility studies are shown in Table 7. [Table 13]

[0179] These data indicate that Form C has high solubility in acetone, THF, 2-MeTHF, and MEK, but low solubility in water, n-heptane, and MCH. The use of water and THF was avoided in the following studies, since polymorph screening reports indicate that potential Forms A / H (anhydrate) or Form I (THF solvate) may exist in water or THF systems. To achieve high yields in the crystallization process, additional solubilities were measured in acetone, 2-MeTHF, and MEK in combination with anti-solvents n-hep and MCH at 25° C., as shown in Table 8. [Table 14]

[0180] These data show that in MEK, 2-MeTHF, and acetone solvents, the solubility decreased as more antisolvent was added.

[0181] Additional solubility studies were carried out in 2-MeTHF in combination with the antisolvent n-hep at 50° C., as shown in Table 9. [Table 15]

[0182] Solution state chemical stability was performed in acetone, MEK, and 2-MeTHF solvent systems at 50° C. and 55° C. The results are summarized in Table 10. The data show that the compound was stable after 48 hours of storage in both acetone and 2-MeTHF systems. The purity of the compound decreased from 99.43% to 98.27% after 48 hours of storage at 55° C. in the MEK solvent system. [Table 16]

[0183] 2-MeTHF / n-hep was selected as a potential solvent system for crystallization. Solution state chemical stability was performed at higher temperatures (60°C and 70°C) in the 2-MeTHF solvent system. Data shows that the compound was stable after 48 hours in 2-MeTHF at 60°C and 70°C. Solution state chemical stability was performed at 70°C in the 2-MeTHF / n-hep=1v / 1v solvent system, and data shows that the compound was stable after 48 hours in the system at 70°C. [Table 17]

[0184] Antisolvent crystallization According to the solubility and chemical stability data, anti-solvent crystallization experiments were carried out in acetone / n-hep and 2-MeTHF / n-hep systems as shown below. Preparative anti-solvent crystallization in 2-MeTHF / n-hep: 1. Dissolve in 8v 2-MeTHF at 50°C. 2. Adjust to 25℃ in 0.5 hours 3. Seeds (10mg) 4. Stir at 25°C for 1 hour. 5. Load with 24v n-hep at 25℃ for 4 hours 6. Take sample for XRPD-1 and PLM-1 analysis. 7. Stir at 25°C for 15 hours. 8. Take samples for XRPD-2, PLM-2, and Assay-1 analysis. 9. Stir at 25°C for 8 hours. 10. Filter and wash the cake with 2v 2-MeTHF / n-hep=1v / 3v. 11. Dry the wet cake under vacuum at 50°C. 12. Get materials

[0185] After addition of n-hep, XRPD showed Form C (approximately 6% mother liquor (ML) loss) even after holding at 25° C. The dried product showed a purity of 99.41% with 0.46% residual 2-MeTHF and 0.07% residual n-hep.

[0186] Preparative anti-solvent crystallization in acetone / n-hep: 1. Dissolves in 9v acetone at 50℃. 2.Adjust to 45℃. 3. Seeds (10mg) 4. Stir at 45°C for 0.5 hours (thin suspension). 5.Adjust to 42℃. 6. Stir at 42°C for 1 hour (suspension with more solids) 7. Adjust to 25℃ in about 3.5 hours. 8. Take sample for XRPD-1 and PLM-1 analysis. 9. Load 27v n-hep at 25°C for 4.5 hours 10. Stir at 25°C for 12 hours. 11. Take samples for XRPD-2, PLM-2, and Assay-1 analysis. 12. Stir at 25°C for 6 hours. Adjust to 5°C in 13.4 hours. Stir for 14 hours at 14.5°C. 15. Take samples for XRPD-3, PLM-3, and Assay-2 analysis. 16. Filter and wash cake with 2v acetone / n-hep=1v / 3v. 17. Dry the wet cake under vacuum at 50°C. 18. Get materials.

[0187] Prior to the addition of n-hep, the XRPD indicated Form C. After the addition of n-hep, the XRPD reflected Form C even after holding at 25° C. (approximately 17% ML loss). Before filtration, the ML loss was approximately 12%. The dried product had a purity of 99.61% with 0.03% residual acetone and 0.04% residual n-hep.

[0188] Process optimization for 2-MeTHF / n-heptane According to the preliminary anti-solvent crystallization results in 2-MeTHF / n-hep and acetone / n-hep, 2-MeTHF / n-hep system was determined as the main crystallization system. Two use test experiments were carried out, achieving 11 g of crystallization product. The results can be seen in Table 12. [Table 18]

[0189] Using the results of the above experiment, an 11 g scale-up experiment was carried out using the following procedure. 1. Dissolve in 8v 2-MeTHF at 50°C. 2. Load 1.5v n-hep at 50℃ for 1 hour 3. Seeds (110mg) 4. Stir at 50°C for 1.5 hours. 5. Load 22.2v n-hep at 50℃ for 7 hours 6. Take a sample for XRPD-1. 7. Stir at 50°C for 15 hours. 8. Take sample for XRPD-2. 9. Stir at 50°C for 20 hours. 10. Take sample for XRPD-3. 11. Load 0.3v n-hep at 50℃ for 1 hour 12. Stir at 50°C for 1 hour. Adjust to 25℃ in 13.5 hours 14. Stir at 25°C for 17 hours. 15. Take sample for XRPD-4, Purity and Assay-1 analysis. 16. Filter and wash the cake with 2v 2-MeTHF / n-hep=1v / 3v. 17. Dry the wet cake under vacuum at 50°C. 18. Get materials

[0190] After addition of n-hep, XRPD shows Form C with additional peaks. After holding at 50° C. for 15 and 35 hours, XRPD again showed Form C with additional peaks (approximately 4% ML loss). Since additional peaks were observed in the XRPD, the process was further optimized using the following procedure. 1. Dissolve in 8v 2-MeTHF at 50°C. 2. Load with 2v n-hep at 50℃ for 1-3 hours 3. Seeds (150mg) 4. Stir at 50℃ for 1 to 18 hours (thin suspension) 5. Charge with 2v n-hep at 50°C for 2-3 hours. 6. Take a sample for XRPD analysis. 7. Stir at 50℃ for 2 to 4 hours. 8. Take a sample for XRPD analysis. 9. Charge with 20v n-hep at 50°C for 6-8 hours. 10. Stir at 50°C for 2 hours. Adjust to 25℃ in 11.5 hours 12.Stir at 25°C for 2 hours. 13. Take a sample for XRPD analysis. 14. Stir at 25°C for 6 to 15 hours. 15. Filter and wash the cake with 2v 2-MeTHF / n-hep=1v / 3v. 16. Dry the wet cake under vacuum at 50°C. 17. Materials obtained

[0191] This procedure was performed twice and XRPD both times showed Form C. Purity was measured at 99.24% and 97.86%.

[0192] Hygroscopic The hygroscopicity of Form C was evaluated by dynamic vapor sorption (DVS) test at 25° C. Form C is non-hygroscopic below 90% relative humidity (RH). Form C absorbs about 0.2% water at 95% RH at 25° C. After the DVS test, the obtained sample was still Form C.

[0193] Evaluation of Form C Form C is the optimal polymorph identified. Its stability, solubility, hygroscopicity, and formulation process feasibility were evaluated as described above.

[0194] In addition to those described herein, various modifications of the present disclosure will be apparent to those skilled in the art from the above description. Such modifications are also intended to fall within the scope of the appended claims. Each reference, including but not limited to all patents, patent applications, and publications cited in this application, is incorporated herein by reference in its entirety.

Claims

1. A crystalline form of 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile.

2. 2. The crystalline form of claim 1, wherein the crystalline form is anhydrous.

3. 3. The crystalline form of claim 1 or 2, wherein the crystalline form is characterized by an XRPD diffractogram having peaks expressed in 2θ angles at 23.8, 20.7, and 11.7 angles (±0.2 degrees).

4. 4. The crystalline form of any one of claims 1-3, wherein the crystalline form is characterized by an XRPD diffractogram having peaks expressed in 2θ angles at 23.8, 20.7, 11.7, and 24.6 angles (±0.2 degrees).

5. 5. The crystalline form of any one of claims 1-4, wherein the crystalline form is characterized by an XRPD diffractogram having peaks expressed in 2θ angles at 23.8, 20.7, 11.7, 24.6, and 15.8 angles (±0.2 degrees).

6. 6. The crystalline form of any one of claims 1-5, wherein the crystalline form is characterized by an XRPD diffractogram having peaks expressed in 2θ angles at 23.8, 20.7, 11.7, 24.6, and 15.8 angles (±0.2 degrees).

7. 2. The crystalline form of claim 1, wherein the crystalline form has an XRPD diffractogram substantially as depicted in FIG.

8. 8. The crystalline form of any one of claims 1-7, having a DSC thermogram characterized by an endotherm with an onset temperature of about 179°C.

9. 9. The crystalline form of any one of claims 1-8, having a DSC thermogram characterized by an endotherm with an onset temperature of 179.3°C.

10. A pharmaceutical composition comprising the crystalline form of any one of claims 1-9 and a pharma- ceutically acceptable carrier.

11. A method of treating a neurodegenerative disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-9 or a pharmaceutical composition according to claim 10.

12. 12. The method of claim 11, wherein the neurodegenerative disorder is an X-linked recessive disorder.

13. 13. The method of claim 11 or 12, wherein the neurodegenerative disorder is spinal-bulbar muscular atrophy (SBMA).

14. A method of treating modulation of androgen receptor (AR) activity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-9 or a pharmaceutical composition of claim 10.

15. 15. The method of claim 14, wherein the androgen receptor (AR) is subject to allosteric regulation.

16. 16. The method of claim 14 or 15, wherein modulating androgen receptor (AR) activity treats spinal-bulbar muscular atrophy (SBMA) in the subject.

17. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-9 or a pharmaceutical composition according to claim 10.

18. 18. The method of claim 17, wherein the cancer is prostate cancer.

19. A process for preparing the crystalline form of any one of claims 1 to 9, comprising the steps of: a) combining 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile with a polar aprotic solvent to form a mixture; b) seeding the mixture with 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile crystals; c) stirring the mixture; and d) collecting the solid 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile; e) re-equilibrating the solid in the polar aprotic solvent under a temperature cycle of about 5° C. to about 50° C.; f) collecting and drying the crystalline form of 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile.

20. Dissolving 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile in a first solvent; adding a second solvent to form a slurry; filtering the slurry to isolate the crystalline form of 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile; 10. A process for preparing the crystalline form of any one of claims 1-9, comprising:

21. 21. The process of claim 20, wherein the first solvent is selected from the group consisting of acetone, ethyl acetate, methyl tert-butyl ether (MTBE), and 2-methyltetrahydrofuran (MeTHF), or a combination thereof.

22. 22. The process of claim 20 or 21, wherein the first solvent is acetone.

23. 22. The process of claim 20 or 21, wherein the first solvent is 2-methyltetrahydrofuran (MeTHF).

24. 22. The process of claim 20 or 21, wherein the first solvent is ethyl acetate.

25. 25. The process of any one of claims 20-24, wherein the second solvent is heptane.

26. A process for preparing a crystalline form of 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile, comprising: a) combining 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile with a first solvent to form a mixture; b) seeding the mixture with 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile crystals; c) stirring the mixture; and d) collecting the solid 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile; e) washing the solid with a second solvent; f) collecting and drying the crystalline form of 3-(5-(2-hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile; The process includes:

27. 27. The process of claim 26, wherein the crystalline form is characterized by an XRPD diffractogram having peaks expressed in 2θ angles at 23.8, 20.7, and 11.7 angles (±0.2 degrees).

28. 28. The process of claim 26 or 27, wherein the crystalline form is characterized by an XRPD diffractogram having peaks expressed in 2θ angles at 23.8, 20.7, 11.7, 24.6, and 15.8 angles (±0.2 degrees).

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