Crystal and salt forms of NLRP3 inhibitors

Abstract

This disclosure provides crystalline forms of NLRP3 inhibitors, as well as methods for preparing and using these forms.

Description

[Technical Field]

[0001] Related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 582,161, filed on 12 September 2023, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Age-related frailty is characterized as a syndrome of multi-system physiological dysregulation that causes highly concerning problems with the overall health and well-being of individuals. Age-related frailty is a geriatric syndrome characterized by weakness, low physical activity, delayed motor function, wasting, and unintentional weight loss (Yao, X. et al., Clinics in Geriatric Medicine 27(1):79-87 (2011)). Furthermore, many studies have shown a direct correlation between age-related frailty and inflammation (Hubbard, RE, et al., Biogerontology 11(5):635-641 (2010)). Immunosening is characterized by a low-grade chronic systemic inflammatory state known as inflammatory senescence (Franceshi, C. et al., Annals of the New York Academy of Sciences 908:244-254 (2000)). The increased inflammatory state or chronic inflammation seen in aging and age-related frailty leads to immunomodulation abnormalities and complex remodeling of both innate and adaptive immunity.

[0003] Inhibiting the NLRP3 inflammasome, an oligomeric protein complex containing ASC and caspase-1, mediates inflammation in numerous preclinical models (Schwaid, AG, J. Med. Chem. 2021, 64(1), 101-122). Simultaneously, the NLRP3 inflammasome is part of a larger pro-inflammatory pathway, and its regulation is also being studied. NLRP3 is a well-studied inflammasome sensor protein in the context of numerous diseases. A wide variety of indications are associated with the NLRP3 inflammasome, including age-related disorders, cryopyrin-associated periodic syndromes (CAPS), non-alcoholic steatohepatitis (NASH), gout, coronary artery disease, Crohn's disease, osteoarthritis, rheumatoid arthritis, Alzheimer's disease, Parkinson's disease, bowel disorders, acute respiratory distress syndrome (ARDS), amyotrophic lateral sclerosis (ALS), cancer, and skin diseases.

[0004] Inflammation and activation of the NLRP3 inflammasome have also been shown to cause hearing loss (Nakanishi, H., et al., Frontiers in Neurology, 2020, 11, 1-7; Nakanishi, H., et al., PNAS, 2017, E7766-E7775). Inflammation-related hearing loss is age-dependent (Fischer, N., et al., Gerontology, 2019, 1-7), noise-induced (Le Prell, CG, et al., Current Opinion in Physiology, 2020, 18, 32-36), and may be a result of viral infections, such as Zika virus and coronavirus (Yee, KT, et al., Hearing Research, 2020, 395, 1-15).

[0005] Therefore, the NLRP3 inflammasome is a promising drug target. The broad range of indications related to the NLRP3 inflammasome highlights the need for therapeutic agents that target it. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Yao, X. et al., Clinics in Geriatric Medicine 27(1):79-87(2011) [Non-Patent Document 2] Hubbard, RE, et al., Biogerontology 11(5):635-641(2010) [Non-Patent Document 3] Franceshi, C. et al., Annals of the New York Academy of Sciences 908:244-254(2000) [Non-Patent Document 4] Schwaid, AG, J.Med.Chem.2021,64(1),101-122 [Non-Patent Document 5] Nakanishi, H., et al., Frontiers in Neurology,2020,11,1-7; Nakanishi, H., et al., PNAS,2017,E7766-E7775 [Non-Patent Document 6] Fischer,N.,et al.,Gerontology,2019,1-7 [Non-Patent Document 7] Le Prell,CG,et al.Current Opinion in Physiology,2020,18,32-36 [Non-Patent Document 8] Yee,KT,et al.,Hearing Research,2020,395,1-15 [Overview of the project] [Problems that the invention aims to solve]

[0007] The present invention provides a crystalline form that inhibits the NLRP3 inflammasome. Therefore, these compounds are useful in the treatment of a variety of indications, including inflammatory senescence and inflammation.

[0008] In certain embodiments, provided herein by the present invention is a crystalline form of 2-ethoxy-3',5'-difluoro-N-((4-(hydroxymethyl)-1H-pyrazolo[4,3-c]pyridin-7-yl)methyl)-N-methyl-[1,1'-biphenyl]-4-carboxamide (referred to herein as Compound 1).

Chemical Formula

[0009] In another embodiment, provided herein by the present invention is a method of treating diseases and disorders associated with the NLRP3 inflammasome in a subject in need of the treatment, comprising administering to the subject a crystalline form of 2-ethoxy-3',5'-difluoro-N-((4-(hydroxymethyl)-1H-pyrazolo[4,3-c]pyridin-7-yl)methyl)-N-methyl-[1,1'-biphenyl]-4-carboxamide.

Brief Description of the Drawings

[0010] [Figure 1] Shows the XRPD diffractogram of crystalline Compound 1 (Pattern B). [Figure 2] Shows the DSC thermogram of crystalline Compound 1 (Pattern B). [Figure 3] Shows the XRPD diffractogram of the monohydrate of crystalline Compound 1 (Pattern A). [Figure 4] Shows the DSC thermogram of the monohydrate of crystalline Compound 1 (Pattern A). [Figure 5] Shows the TGA thermogram of the monohydrate of crystalline Compound 1 (Pattern A). [Figure 6] Shows the XRPD diffractogram of the HCl salt of crystalline Compound 1 (Pattern A). [Figure 7] Shows the DSC thermogram of the HCl salt of crystalline Compound 1 (Pattern A). [Figure 8] Shows the XRPD diffractogram of the phosphate salt of crystalline Compound 1 (Pattern A). [Figure 9]The DSC thermogram of the phosphate (pattern A) of crystalline compound 1 is shown. [Figure 10] The TGA thermogram of the phosphate (pattern A) of crystalline compound 1 is shown. [Figure 11] The XRPD diffraction pattern of the sodium salt (pattern A) of crystalline compound 1 is shown. [Figure 12] The DSC thermogram of the sodium salt (pattern A) of crystalline compound 1 is shown. [Figure 13] The TGA thermogram of the sodium salt (pattern A) of crystalline compound 1 is shown. [Modes for carrying out the invention]

[0011] When a compound is used for pharmaceutical purposes, its solid state can be important. The physical properties of a compound can change from one solid state to another, and this change can affect the suitability of that state for pharmaceutical applications. For example, certain crystalline solid compounds can overcome the drawbacks of other solid states of the compound, such as instability and / or reduced purity.

[0012] The present invention provides the following solid crystalline form of 2-ethoxy-3',5'-difluoro-N-((4-(hydroxymethyl)-1H-pyrazolo[4,3-c]pyridine-7-yl)methyl)-N-methyl-[1,1'-biphenyl]-4-carboxamide (compound 1): [ka] or a pharmaceutically acceptable salt or hydrate thereof.

[0013] This compound is disclosed in International Application No. PCT / US2022 / 021461, the entire contents of which are incorporated herein by reference.

[0014] The crystal morphology provided in this invention can be characterized by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA).

[0015] definition The following are definitions of various terms used to describe the crystalline forms provided in this invention. These definitions, as used throughout this specification and the claims, apply individually or as part of a larger group of terms, unless otherwise limited in specific examples.

[0016] Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as those commonly understood by those skilled in the art to the extent of the compounds and crystalline forms of the present invention. Generally, the nomenclature used herein, as well as the testing procedures in cell culture, molecular genetics, organic chemistry, and peptide chemistry, are well known and commonly used in the art.

[0017] As used herein, the articles “a” and “an” refer to one or more than one (i.e., at least one) of the grammatical objects of the article. For example, “an element” means one or more elements. Furthermore, the use of the term “including,” as well as other forms such as “include,” “includes,” and “included,” is not limited to these.

[0018] When used in this specification, "EC 50 The term "the concentration of a compound required to achieve an effect that is 50% of the compound's maximum observed effect" refers to the compound concentration required to achieve that effect.

[0019] As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable substance, composition, or carrier, such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent, or encapsulant, that is involved in transporting or delivering a useful compound in or to a patient so that the compound can perform its intended function. Typically, such a construct transports or delivers from one organ or body part to another. Each carrier must be “acceptable” in the sense that it is compatible with the other components of a formulation containing the compound provided in the present invention and is not harmful to the patient.

[0020] Some examples of substances that can function as pharmaceutically acceptable carriers include sugars, e.g., lactose, glucose, and sucrose; starches, e.g., corn starch and potato starch; cellulose and its derivatives, e.g., sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; tragacanth powder; malt; gelatin; talc; excipients, e.g., cocoa butter and suppository waxes; oils, e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, e.g., propylene glycol; polyols, e.g., glycerin, sorbitol, mannitol, and polyethylene glycol; esters, e.g., ethyl oleate and ethyl laurate; agar; buffers, e.g., magnesium hydroxide and aluminum hydroxide; surfactants, alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer; and other non-toxic and suitable substances used in pharmaceutical formulations.

[0021] As used herein, “pharmaceutically acceptable carriers” include any coatings, antimicrobial and antifungal agents, and absorption retarders that are compatible with the activity and suitability of the compounds provided in this invention and are physiologically acceptable to the patient. Auxiliary active compounds may also be incorporated into the compositions of this invention. Other additional components that may be included in the pharmaceutical compositions used in the practice of this 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.

[0022] As used herein, the phrases “therapeutic dose” and “therapeutic amount” refer to the amount of compound that prevents the onset of a disease, alleviates symptoms, halts its progression, or produces another desired biological outcome, such as improvement of clinical signs.

[0023] The terms “to treat,” “to be treated,” “the act of treating,” or “treatment” include the reduction or alleviation of at least one symptom associated with or caused by the condition, disorder or disease being treated.

[0024] As used herein, the terms “prevent” or “prevention” mean, if nothing has occurred, the absence of the onset of a disability or disease, or, if the onset of a disability or disease has already occurred, the absence of further onset of the disability or disease. Furthermore, consideration is given to the ability to prevent some or all of the symptoms associated with the disability or disease.

[0025] As used herein, the terms “patient,” “individual,” or “subject” refer to a human or a non-human mammal. Examples of non-human mammals include livestock and pets, such as sheep, cattle, pigs, dogs, cats, and mice. In embodiments, the patient, subject, or individual is a human.

[0026] Terms such as "administering" or "dosing" refer to providing a therapeutic agent, for example, the crystalline form disclosed in this invention, to a subject in need of treatment. In one embodiment, the subject is a mammal. In another embodiment, the subject is a human.

[0027] As used herein, the term “about” is to be understood by those skilled in the art and will vary to some extent depending on the context in which it is used. As used herein when referring to measurable values, such as quantities or periods of time, the term “about” is intended to include a variation of ±10% from the specified value (including ±5%, ±1%, and ±0.1%), but such variation is appropriate for carrying out the disclosed method.

[0028] Characterization of crystal morphology In certain embodiments, the crystalline morphologies described herein can be identified based on characteristic peaks in X-ray powder diffraction analysis. X-ray powder diffraction (XRPD) is a scientific technique that uses the diffraction of X-rays, neutrons, or electrons on powders, microcrystals, or other solid materials to structurally characterize solid materials. A description of the method used to obtain specific XRPD diffraction patterns with respect to the crystalline morphologies provided in the present invention can be found in the following examples. In embodiments, the X-ray powder diffraction data provided in the present invention is obtained by a method using Cu Kα irradiation.

[0029] In some embodiments, the present invention provides 2-ethoxy-3',5'-difluoro-N-((4-(hydroxymethyl)-1H-pyrazolo[4,3-c]pyridine-7-yl)methyl)-N-methyl-[1,1'-biphenyl]-4-carboxamide, or a crystalline form of a pharmaceutically acceptable salt or hydrate thereof.

[0030] In one embodiment, the crystalline form is a monohydrate. In another embodiment, the crystalline form is an anhydrous.

[0031] In yet another embodiment, the crystalline form is a pharmaceutically acceptable salt. In yet another embodiment, the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride salts, phosphate salts, and sodium salts.

[0032] Free anhydrous form In this embodiment, the crystalline form of compound 1 is anhydrous.

[0033] In one embodiment, the crystal morphology is characterized by an XRPD diffraction pattern having peaks at angles 2θ of 7.2, 20.4, and 20.6 with a degree of ±0.2 degrees. In another embodiment, the crystal morphology is characterized by an XRPD diffraction pattern having peaks at angles 2θ of 7.2, 20.4, 20.6, and 21.6 with a degree of ±0.2 degrees. In yet another embodiment, the crystal morphology is characterized by an XRPD diffraction pattern having peaks at angles 2θ of 7.2, 11.1, 11.8, 20.4, 20.6, and 21.6 with a degree of ±0.2 degrees. In yet another embodiment, the crystal morphology is characterized by an XRPD diffraction pattern having peaks at angles 2θ of 5.5, 7.2, 11.1, 11.8, 15.3, 20.4, 20.6, 21.6, 26.7, and 30.9 with a degree of ±0.2 degrees.

[0034] In this embodiment, the crystal morphology is characterized by an XRPD diffraction pattern having peaks selected from Table 1 (Pattern B). [Table 1]

[0035] In another embodiment, the crystalline morphology has an XRPD diffraction pattern substantially as shown in Figure 1.

[0036] In yet another embodiment, the crystalline form is a monohydrate having a DSC thermogram characterized by endothermicity with an onset temperature of 177.3°C. In yet another embodiment, the crystalline form has a DSC thermogram substantially as depicted in Figure 2.

[0037] Free form, which is a monohydrate. In one embodiment, the crystalline form is a monohydrate characterized by an XRPD diffraction pattern having peaks at angles 2θ of 6.5, 12.9, and 16.1 with a degree of ±0.2 degrees. In another embodiment, the crystalline form is characterized by an XRPD diffraction pattern having peaks at angles 2θ of 6.5, 11.2, 12.9, and 16.1 with a degree of ±0.2 degrees. In yet another embodiment, the crystalline form is characterized by an XRPD diffraction pattern having peaks at angles 2θ of 6.5, 11.2, 12.9, 16.1, 22.7, 24.8, and 32.6 with a degree of ±0.2 degrees.

[0038] In this embodiment, the crystal morphology is characterized by an XRPD diffraction pattern having peaks selected from Table 2 (Pattern A). [Table 2-1] [Table 2-2]

[0039] In another embodiment, the crystalline morphology has an XRPD diffraction pattern substantially as shown in Figure 3.

[0040] In yet another embodiment, the crystalline form is a monohydrate having a DSC thermogram characterized by endothermicity with an onset temperature of 139.6°C. In yet another embodiment, the crystalline form has a DSC thermogram substantially as shown in Figure 4. In yet another embodiment, the crystalline form has a TGA thermogram substantially as shown in Figure 5.

[0041] Hydrochloride In one embodiment, the crystalline form is 2-ethoxy-3',5'-difluoro-N-((4-(hydroxymethyl)-1H-pyrazolo[4,3-c]pyridine-7-yl)methyl)-N-methyl-[1,1'-biphenyl]-4-carboxamide hydrochloride. In another embodiment, the crystalline form of the HCl salt is characterized by an XRPD diffraction pattern having peaks at angles 12.3, 18.1, and 18.2 with a degree of ±0.2 degrees. In yet another embodiment, the crystalline form of the HCl salt is characterized by an XRPD diffraction pattern having peaks at angles 12.3, 12.8, 18.1, 18.2, and 28.7 with a degree of ±0.2 degrees. In yet another embodiment, the crystalline form of the HCl salt is characterized by an XRPD diffraction pattern having peaks represented by degrees (±0.2 degrees) at angles 2θ of 12.3, 12.8, 18.1, 18.2, 26.0, and 28.7.

[0042] In this embodiment, the crystalline form is characterized by an XRPD diffraction pattern having peaks selected from Table 3 (HCl salt of pattern A). [Table 3-1] [Table 3-2]

[0043] In another embodiment, the crystalline morphology has an XRPD diffraction pattern substantially as shown in Figure 6.

[0044] In yet another embodiment, the crystalline form is an HCl salt having a DSC thermogram characterized by endothermicity with an onset temperature of 218.3°C. In yet another embodiment, the crystalline form has a DSC thermogram substantially as depicted in Figure 7.

[0045] Phosphate In this embodiment, the crystalline form is 2-ethoxy-3',5'-difluoro-N-((4-(hydroxymethyl)-1H-pyrazolo[4,3-c]pyridine-7-yl)methyl)-N-methyl-[1,1'-biphenyl]-4-carboxamidphosphate.

[0046] In another embodiment, the crystalline form of the phosphate is characterized by an XRPD diffraction pattern having peaks at angles 2θ of 3.1, 9.2, and 16.4 with a degree of ±0.2 degrees. In yet another embodiment, the crystalline form of the phosphate is characterized by an XRPD diffraction pattern having peaks at angles 2θ of 3.1, 9.2, 11.7, 13.9, 15.4, 16.4, and 24.7 with a degree of ±0.2 degrees. In yet another embodiment, the crystalline form of the phosphate is characterized by an XRPD diffraction pattern having peaks at angles 2θ of 3.1, 9.2, 11.7, 13.9, 15.4, 16.4, 18.1, 19.0, 16.4, and 24.7 with a degree of ±0.2 degrees.

[0047] In this embodiment, the crystalline morphology is characterized by an XRPD diffraction pattern having peaks selected from Table 4 (Phosphate of Pattern A). [Table 4]

[0048] In another embodiment, the crystalline morphology has an XRPD diffraction pattern substantially as shown in Figure 8.

[0049] In another embodiment, the crystalline form is a phosphate having a DSC thermogram characterized by endothermicity with an onset temperature of 223.9°C. In yet another embodiment, the crystalline form has a DSC thermogram substantially as shown in Figure 9. In yet another embodiment, the crystalline form has a TGA thermogram substantially as shown in Figure 10.

[0050] sodium salt In this embodiment, the crystalline form is 2-ethoxy-3',5'-difluoro-N-((4-(hydroxymethyl)-1H-pyrazolo[4,3-c]pyridine-7-yl)methyl)-N-methyl-[1,1'-biphenyl]-4-carboxamide sodium salt.

[0051] In another embodiment, the crystalline form of the sodium salt is characterized by an XRPD diffraction pattern having peaks at angles 2θ of 10.3, 21.1, and 25.8 degrees (±0.2 degrees). In yet another embodiment, the crystalline form of the sodium salt is characterized by an XRPD diffraction pattern having peaks at angles 2θ of 10.3, 17.3, 20.6, 21.1, 23.3, and 25.8 degrees (±0.2 degrees). In yet another embodiment, the crystalline form of the sodium salt is characterized by an XRPD diffraction pattern having peaks at angles 2θ of 10.3, 14.9, 17.2, 17.3, 18.8, 20.6, 20.0, 21.1, 23.3, and 25.8 degrees (±0.2 degrees).

[0052] In this embodiment, the crystalline morphology is characterized by an XRPD diffraction pattern having peaks selected from Table 5 (sodium salt of pattern A). [Table 5-1] [Table 5-2]

[0053] In another embodiment, the crystalline morphology has an XRPD diffraction pattern substantially as shown in Figure 11.

[0054] In another embodiment, the crystalline morphology has a DSC thermogram substantially as shown in Figure 12. In yet another embodiment, the crystalline morphology has a TGA thermogram substantially as shown in Figure 13.

[0055] Pharmaceutically acceptable salts In another embodiment, the present invention provides a crystalline form of a pharmaceutically acceptable salt of 2-ethoxy-3',5'-difluoro-N-((4-(hydroxymethyl)-1H-pyrazolo[4,3-c]pyridine-7-yl)methyl)-N-methyl-[1,1'-biphenyl]-4-carboxamide, the pharmaceutically acceptable salt being selected from the group consisting of hydrochloride, phosphate, and sodium salts.

[0056] In one embodiment, the pharmaceutically acceptable salt is a hydrochloride salt. In another embodiment, the pharmaceutically acceptable salt is a phosphate salt. In yet another embodiment, the pharmaceutically acceptable salt is a sodium salt.

[0057] In one embodiment, the crystalline form of the present invention is measured by X-ray powder diffraction (XRPD) using Cu Kα irradiation operating at 40 kV and 40 mA. In another embodiment of the XRPD, the scan is performed at 2θ from 2 to 40 degrees, with a step size of 0.02 degrees and a scan time of 0.3 seconds per step.

[0058] In yet another aspect, the present invention provides a pharmaceutical composition comprising the crystalline form of the present disclosure and a pharmaceutically acceptable carrier.

[0059] The pharmaceutical preparations disclosed herein can be prepared according to standard procedures and administered in doses selected to alleviate, prevent, or resolve a disease. For example, for a general description of how various drugs are administered for therapeutic purposes in humans, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA and Goodman and Gilman's “The Pharmaceutical Basis of Therapeutics,” Pergamon Press, New York, NY (these contents are incorporated herein by reference).

[0060] The pharmaceutical compositions described herein may contain the crystalline form disclosed herein in combination with one or more non-toxic, pharmaceutically acceptable carriers and / or diluents and / or adjuvants and / or excipients.

[0061] For oral or parenteral administration, the crystalline form disclosed in this invention can be mixed with conventional pharmaceutical carriers and excipients and can be used in the form of tablets, capsules, elixirs, suspensions, syrups, wafers, and the like. Compositions containing the crystalline form disclosed in this invention may contain the active compound in an amount of about 0.1% to about 99% by weight, for example, about 10% to about 30%.

[0062] For oral use, solid formulations, such as tablets and capsules, are useful. Preparations with sustained-release or enteric coatings can also be devised. For use in children and the elderly, one embodiment provides suspensions, syrups, and chewable tablets. For oral administration, the pharmaceutical composition may be in the form of, for example, tablets, capsules, suspensions, or liquids.

[0063] The pharmaceutical composition can be prepared in the form of a dosage unit containing the active ingredient in a therapeutically effective amount. Examples of such dosage units are tablets and capsules. For therapeutic purposes, the tablets and capsules may contain, in addition to the active ingredient, conventional carriers, such as binders, fillers, lubricants, disintegrants, or acceptable wetting agents. Oral liquid preparations generally take the form of aqueous or oily solutions, suspensions, emulsions, syrups, or elixirs.

[0064] The pharmaceutical compositions disclosed herein can be placed on pharmaceutically acceptable carriers and delivered to subjects (e.g., humans) according to known drug delivery methods. Generally, the methods for delivering the pharmaceutical compositions in vivo utilize protocols recognized in the art for drug delivery, and consist only of substantial procedural modifications that replace the drugs in those protocols with the crystalline forms of the disclosure.

[0065] Treatment method The present invention provides a method for treating a disease, comprising administering a pharmaceutical composition comprising the crystalline form of 2-ethoxy-3',5'-difluoro-N-((4-(hydroxymethyl)-1H-pyrazolo[4,3-c]pyridine-7-yl)methyl)-N-methyl-[1,1'-biphenyl]-4-carboxamide, or the crystalline form thereof and a pharmaceutically acceptable carrier.

[0066] In one embodiment, the present invention provides a method for inhibiting the NLRP3 inflammasome in a target subject requiring inhibition, the method comprising administering to the target subject a therapeutically effective dose of the crystalline form disclosed herein.

[0067] In another embodiment, the present invention provides a method for treating inflammation in a subject requiring treatment, comprising administering to the subject a therapeutically effective amount of the crystalline form disclosed herein.

[0068] In another embodiment, the present invention provides a method for treating inflammatory senescence in a subject requiring treatment, comprising administering to the subject a therapeutically effective amount of the crystalline form disclosed herein.

[0069] In yet another embodiment, the present invention provides a method for treating cryopyrin-associated periodic syndromes (CAPS) in a subject requiring treatment, comprising administering to the subject a therapeutically effective dose of the crystalline form disclosed herein.

[0070] In this embodiment, the CAPS is selected from the group consisting of familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and neonatal multiorgan inflammatory disease.

[0071] In one embodiment, the present invention provides a method for treating a disease or disorder of the inner ear in a subject requiring treatment, the method comprising administering to the subject a therapeutically effective amount of the crystalline form disclosed herein.

[0072] In this embodiment, the inner ear disorder or impairment is selected from the group consisting of hearing loss, hearing impairment, dizziness, Meniere's disease, and tinnitus.

[0073] In another aspect, the present invention provides a method for treating a skin disease in a subject requiring treatment, comprising administering to that subject a therapeutically effective amount of the crystalline form disclosed in the present invention.

[0074] In the embodiment, the skin disease is selected from the group consisting of psoriasis, urticaria, photoaging of the skin, and eczema.

[0075] The present invention provides a method of using the crystalline form provided in the present invention to treat or improve aging or age-related conditions that adversely affect lifespan or quality of life, wherein the aging or age-related conditions that adversely affect lifespan or quality of life are inflammation, anemia, hyperglycemia, dyslipidemia, hyperinsulinemia, insulin resistance, immunosuppression, liver disease, iron overload, hypertriglyceridemia, skin integrity disorders, wound healing, scarring, pain, allergies, sleep disorders and problems, gastrointestinal disorders and problems, Th1 inflammation, Th2 inflammation, T cell-dependent B Cell proliferation, inflammatory diseases with T cell-dependent B cell proliferation, T cell-dependent B cell proliferation, allergies, asthma, atherosclerosis, autoimmunity, hypercholesterolemia, chronic inflammation, chronic obstructive pulmonary disease (COPD), Crohn's disease, skin reactions to tissue damage, fibrosis, hematological cancers, metabolic diseases, cardiovascular diseases, organ transplantation, psoriasis, hepatic fibrosis, dermatitis, pulmonary fibrosis, pulmonary reactions to respiratory infections, restenosis, rheumatoid arthritis, sarcoidosis, interstitial biological phenomena in tumors, systemic lupus erythematosus (SLE), ulcerative colitis, vasculitis, and alpha-14. Smooth muscle actin (αSMA), CD40, CD69, collagen I, collagen III, decorin, e-selectin, eotaxin 3 (CCL26), fibroblast proliferation, human leukocyte antigen-DR isotype (HLA-DR), immunoglobulin G, interferon-gamma-inducible protein 10 (IP-10 / CXCL10), interferon-inducible T cell alpha chemoattractant (I-TAC / CXCL11), interleukin (IL)-1, IL-1 alpha, IL-2, IL-6, IL-8 (CXCL8), IL-10, IL-17A, IL-17 F, keratin 8 / 81, macrophage colony-stimulating factor (M-CSF), matrix metalloproteinase (MMP)-1, MMP-9, monocyte chemotactic protein 1 (MCP-1), gamma interferon-induced monokine (MIG / CXCL9), plasminogen activator inhibitor 1 (PAI-1), prostaglandin E2 (PGE2), serum amyloid A, T cell or B cell proliferation, tissue plasminogen activator (tPA), tumor necrosis factor alpha (TNF-alpha), vascular cell adhesion molecule (VCAM-1),The present invention also includes a method comprising administering the crystalline form provided in this invention to a subject in need of treatment or improvement of a disease selected from the group consisting of one or more factors selected from the group consisting of vascular endothelial growth factor 2 (VEGFR2), which is induced by or exacerbated by such a disease.

[0076] In some embodiments, the present invention provides a method for reversing the normal aging process in a subject, comprising administering to the subject a therapeutically effective dose of the crystalline form or a pharmaceutically acceptable salt thereof provided in the present invention.

[0077] In another aspect, the present invention provides a method for reversing the normal aging process in a subject, comprising administering to the subject a pharmaceutical composition containing a therapeutically effective amount of the crystalline form or a pharmaceutically acceptable salt thereof provided for in the present invention.

[0078] In yet another aspect, the present invention provides a method for extending the lifespan of a subject, comprising administering to the subject a therapeutically effective dose of the crystalline form or a pharmaceutically acceptable salt thereof provided for in the present invention.

[0079] In yet another embodiment, the present invention provides a method for extending the lifespan of a subject, comprising administering to the subject a pharmaceutical composition containing a therapeutically effective amount of the crystalline form or a pharmaceutically acceptable salt thereof provided for in the present invention.

[0080] In another embodiment, the present invention provides a method for slowing and mitigating the aging process in a subject, comprising administering to the subject a therapeutically effective dose of the crystalline form or a pharmaceutically acceptable salt thereof provided in the present invention.

[0081] In another aspect, the present invention provides a method for inhibiting or modulating a pro-inflammatory pathway in cells, comprising contacting the cells with the crystalline form provided in the present invention or a pharmaceutically acceptable salt thereof. In yet another aspect, the present invention provides a method for inhibiting or modulating NLRP3 in cells, comprising contacting the cells with the crystalline form provided in the present invention or a pharmaceutically acceptable salt thereof.

[0082] When cells expressing the NLRP3 inflammasome (in vitro or in vivo) are treated with the crystalline form provided in this invention, it is possible to inhibit the pro-inflammatory pathway and, as a result, inhibit downstream events related to that signaling pathway, such as inflammation or inflammatory senescence.

[0083] In another aspect, the present invention provides a method for treating a sensory nerve disorder in a person in need of treatment, comprising administering to that person a therapeutically effective dose of the crystalline form disclosed in the present invention.

[0084] In the embodiment, the sensory nerve disorder is selected from the group consisting of hearing loss, hearing impairment, and eye disorders. In the embodiment, the eye disorder is retinal nerve injury and optic nerve injury.

[0085] In another aspect, the present invention provides a method for treating an inflammatory disorder in a subject requiring treatment, comprising administering to the subject a therapeutically effective amount of the crystalline form disclosed in the present invention.

[0086] In the embodiments, the inflammatory disorder is selected from the group consisting of allergies, asthma, atopic dermatitis, atherosclerosis, autoimmune diseases, celiac disease, chronic inflammation, glomerulonephritis, hepatitis, inflammatory bowel disease, reperfusion injury, SARS-CoV-2 infection, transplant rejection, heart disease, diabetes, arthritis, Crohn's disease, ulcerative colitis, non-alcoholic steatohepatitis (NASH), gout, coronary artery disease, rheumatoid arthritis, intestinal disorders, and acute respiratory distress syndrome (ARDS).

[0087] In another embodiment, the inflammatory disorder is a neuroinflammatory disease. In yet another embodiment, the inflammatory disorder is otitis cochlea.

[0088] In one embodiment, chronic inflammation includes inflammation of tissues. Tissue inflammation is chronic inflammation limited to a specific tissue or organ. In one embodiment, tissue inflammation includes, for example, inflammation of the skin, inflammation of the eyes, inflammation of muscles, inflammation of tendons, inflammation of ligaments, inflammation of bones, inflammation of cartilage, inflammation of the lungs, inflammation of the heart, inflammation of the liver, inflammation of the pancreas, inflammation of the kidneys, inflammation of the bladder, inflammation of the stomach, inflammation of the intestines, inflammation of neurons, and inflammation of the brain.

[0089] In another embodiment, chronic inflammation includes systemic inflammation. Although the processes involved are identical to those of tissue inflammation, systemic inflammation is not limited to specific tissues, but in fact damages the body, including the endothelium and other organ systems. When the inflammation is caused by an infection, the term sepsis is applied, with bacteremia specifically applied to bacterial sepsis and viremia specifically applied to viral sepsis. Vasodilation and organ dysfunction are significant problems associated with widespread infections that can lead to septic shock and death.

[0090] In yet another embodiment, chronic inflammation includes arthritis. Arthritis is a group of conditions involving damage to the joints of the body due to inflammation of the synovial membrane, and includes, but is not limited to, osteoarthritis, rheumatoid arthritis, juvenile idiopathic arthritis, spondyloarthritis-like ankylosing spondylitis, reactive arthritis (Reiter's syndrome), psoriatic arthritis, enteroarthritis associated with inflammatory bowel disease, Whipple's disease and Behçet's disease, septic arthritis, gout (also known as gouty arthritis, crystalline synovitis, or metabolic arthritis), pseudogout (calcium pyrophosphate deposition disease), and Still's disease. Arthritis may affect one joint (monoarthritis), two to four joints (oligoarthritis), or five or more joints (polyarthritis), and may be either an autoimmune or non-autoimmune disease.

[0091] In yet another embodiment, the present invention provides a method for treating age-related disorders in a subject requiring treatment, comprising administering to that subject a therapeutically effective dose of the crystalline form disclosed herein.

[0092] In the embodiment, the age-related disorders are selected from the group consisting of neurodegeneration, cardiovascular disease, insulin resistance, diabetes, osteoporosis, osteoarthritis, cognitive decline, dementia, frailty, cataracts, arthritis, obesity, hypertension, angina pectoris, congestive heart failure, dyslipidemia, myocardial infarction, vascular disease, respiratory disease, kidney disease, cerebrovascular disease, peripheral vascular disease, Alzheimer's disease, cardiac diastolic dysfunction, benign prostatic hyperplasia, aortic aneurysm, and pulmonary emphysema.

[0093] In another aspect, the present invention provides a method for treating a metabolic disorder in a subject requiring treatment, comprising administering to that subject a therapeutically effective dose of the crystalline form disclosed in the present invention.

[0094] In this embodiment, the metabolic pathology is selected from the group consisting of diabetes mellitus, obesity, cystic fibrosis, and hyperthyroidism.

[0095] In another aspect, the present invention provides a method for treating neurodegenerative diseases in subjects requiring treatment, comprising administering to the subject a therapeutically effective dose of the crystalline form disclosed herein.

[0096] In this embodiment, the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and Batten's disease.

[0097] In one embodiment, the present invention provides a method for treating a disease or disorder of the inner ear in a person in need of treatment, the method comprising administering to the person a therapeutically effective amount of the crystalline form disclosed in the present invention.

[0098] In one embodiment, the inner ear disorder or impairment is selected from the group consisting of hearing loss, hearing impairment, dizziness, Meniere's disease, and tinnitus. In another embodiment, the inner ear disorder is hearing loss. In yet another embodiment, the inner ear disorder is hearing impairment.

[0099] In another embodiment, the hearing loss is the result of aging, noise exposure, or a viral infection. In yet another embodiment, the viral infection is the Zika virus or a coronavirus.

[0100] In another aspect, the disclosure provides the crystalline form disclosed herein or a pharmaceutically acceptable salt thereof for use in the manufacture of pharmaceuticals for treating or preventing diseases in which the NLRP3 inflammasome plays a role.

[0101] In some embodiments, the present invention provides a method for treating a condition selected from the group consisting of autoimmune diseases, inflammatory diseases, proliferative and hyperproliferative diseases, immune-mediated diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cardiovascular diseases, hormone-related diseases, allergies, asthma, and Alzheimer's disease. In other embodiments, the condition is selected from proliferative disorders and neurodegenerative disorders.

[0102] One aspect of this disclosure provides crystalline forms of compounds useful for treating diseases, disorders, and conditions characterized by excessive or abnormal cell proliferation. Such diseases include, but are not limited to, proliferative disorders or hyperproliferative disorders and neurodegenerative diseases. Examples of proliferative disorders and hyperproliferative disorders include, but are not limited to, cancer.

[0103] Therefore, in certain embodiments, the present invention provides a method for treating cancer in a subject requiring treatment, comprising administering to the subject a therapeutically effective amount of the crystalline form disclosed in the present invention or a pharmaceutically acceptable salt thereof.

[0104] In the embodiment, the cancer is selected from the group consisting of breast, ovary, cervix, prostate, testis, urogenital tract, esophagus, larynx, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma, bone, colon, colorectal, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma, anaplastic carcinoma, papillary carcinoma, seminomas, melanoma, sarcoma, bladder cancer, liver cancer and biliary tract cancer, kidney cancer, bone marrow disorders, lymphatic disorders, Hodgkin's cancer, hair cell cancer, oral cavity and pharynx (oral), lips, tongue, oral cavity, pharynx, small intestine, colon, rectum, large intestine, rectum, brain and central nervous system cancer, chronic myeloid leukemia (CML), and leukemia.

[0105] In another embodiment, the cancer is selected from myeloma, lymphoma, or from a group consisting of cancers selected from gastric cancer, kidney cancer, head and neck cancer, oropharyngeal cancer, non-small cell lung cancer (NSCLC), endometrial cancer, hepatocellular carcinoma, non-Hodgkin lymphoma, and lung cancer.

[0106] In this embodiment, the cancer is selected from the group consisting of prostate cancer, colon cancer, lung cancer, squamous cell carcinoma of the head and neck, esophageal cancer, hepatocellular carcinoma, melanoma, sarcoma, gastric cancer, pancreatic cancer, ovarian cancer, and breast cancer.

[0107] In embodiments, the cancer is selected from the group consisting of tumors, neoplasms, carcinomas, sarcomas, leukemias, lymphomas, etc. For example, cancers include, but are not limited to, mesothelioma, leukemia and lymphoma, such as cutaneous T-cell lymphoma (CTCL), non-cutaneous peripheral T-cell lymphoma, lymphoma associated with human T-lymphotropic virus (HTLV), such as adult T-cell leukemia / lymphoma (ATLL), B-cell lymphoma, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, acute myeloid leukemia, lymphoma and multiple myeloma, non-Hodgkin lymphoma, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), Hodgkin lymphoma, Burkitt lymphoma, adult T-cell leukemia / lymphoma, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), or hepatocellular carcinoma. Further examples include myelodysplastic syndromes, pediatric solid tumors such as brain tumors, neuroblastomas, retinoblastomas, Wilms' tumors, bone tumors and soft tissue sarcomas, common solid tumors in adults such as head and neck cancers (e.g., oral cavity, larynx, nasopharynx and esophagus), genitourinary cancers (e.g., prostate, bladder, kidney, uterus, ovaries, testes), lung cancers (e.g., small cell and non-small cell), breast cancer, pancreatic cancer, melanoma and other skin cancers, gastric cancer, brain tumors, tumors associated with Gorin syndrome (e.g., medulloblastoma, meningioma, etc.), and liver cancer. Additional exemplary forms of cancer that can be treated by this crystalline form include, but are not limited to, cancers of skeletal muscle or smooth muscle, gastric cancer, small intestine cancer, rectal cancer, salivary gland cancer, endometrial cancer, adrenal cancer, anal cancer, rectal cancer, parathyroid cancer and pituitary cancer.

[0108] Additional cancers for which the crystalline forms described herein may be therapeutically useful include, for example, colorectal cancer, familial adenomatous polyposis carcinoma, hereditary nonpolyposis colorectal cancer, or melanoma. Furthermore, cancers include, but are not limited to, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, thyroid cancer (medullary thyroid carcinoma and papillary thyroid carcinoma), kidney cancer, renal parenchymal cancer, cervical cancer, uterine cancer, endometrial cancer, choriocarcinoma, testicular cancer, urinary tract cancer, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral nerve ectoderm tumors, gallbladder cancer, bronchial cancer, multiple myeloma, basal cell tumor, teratoma, retinoblastoma, choroidal melanoma, seminomas, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma, and plasmacytoma.

[0109] In another aspect, the present invention provides the use of one or more crystalline forms of the present disclosure in the manufacture of drugs for the treatment of cancer, including, but not limited to, the various types of cancer disclosed in the present invention.

[0110] In some embodiments, the crystalline form of the Disclosure is useful for treating cancers, such as colorectal cancer, thyroid cancer, breast cancer, and lung cancer, as well as myeloproliferative disorders, such as polycythemia vera, thrombocythemia, myelometaplasia with myelofibrosis, chronic myeloid leukemia, chronic myelomonocytic leukemia, eosinophilic syndrome, juvenile myelomonocytic leukemia, and systemic mastocytosis. In some embodiments, the crystalline form of the Disclosure is useful for treating hematopoietic disorders, particularly acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute promyelocytic leukemia, and acute lymphoblastic leukemia (ALL).

[0111] Dosage / Prescription The actual dose levels of the active ingredients in the pharmaceutical compositions described herein may vary for specific patients, compositions, and modes of administration to achieve an effective amount of the active ingredient that is not toxic to the patient and is sufficient to achieve a desired therapeutic response.

[0112] In particular, the dosage level to be selected will depend on a variety of factors, including the activity of the specific compound to be employed, the time of administration, the excretion rate of the compound, the duration of treatment, other drugs, compounds, or materials used in combination with the crystalline form of the present invention, the age, sex, weight, condition, overall health, and medical history of the patient being treated, as well as similar factors well known in the medical field.

[0113] A physician with ordinary skill in the art, such as an internist or veterinarian, can easily determine and prescribe the effective amount of the required pharmaceutical composition. For example, an internist or veterinarian may start administering the pharmaceutical composition in a dose of the disclosed crystalline form at a level lower than the level required to achieve the desired therapeutic effect, and gradually increase the dose until the desired effect is achieved.

[0114] In certain embodiments, it is particularly beneficial to prepare the crystalline form in dose unit form for ease of administration and uniformity of dosage.

[0115] As used herein, “dosage unit form” refers to physically separate units suitable as a unit dose for a patient receiving treatment, each unit comprising a predetermined amount of the disclosed compound calculated to produce the desired therapeutic effect in combination with the necessary medicinal vehicle. The crystalline dosage unit forms disclosed herein are determined and directly depend on (a) the inherent characteristics of the disclosed compound and the specific therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding / formulating such compounds for the treatment of a patient's Kennedy disease (SBMA).

[0116] In one embodiment, the crystalline form provided in the present invention is formulated using one or more pharmaceutically acceptable excipients or carriers. In one embodiment, the pharmaceutical composition comprises a therapeutically effective amount of the disclosed crystalline form and a pharmaceutically acceptable carrier.

[0117] In some embodiments, the dose of the disclosed compound is about 1 mg to about 1,000 mg. In some embodiments, the dose of the disclosed compound used in the compositions described herein is less than about 1,000 mg, less than about 800 mg, less than about 600 mg, less than about 500 mg, less than about 300 mg, less than about 200 mg, less than about 100 mg, less than about 50 mg, less than about 20 mg, or about 10 mg. For example, the dose 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.

[0118] Any of the compositions disclosed in this invention may be administered via oral, nasal, rectal, vaginal, parenteral, oral, sublingual, or topical routes. The compounds for use provided in this invention may be formulated for administration via any suitable route, e.g., via or parenteral routes, e.g., transdermal, transmucosal (e.g., sublingual, lingual, oral, urethral, ​​vaginal (e.g., transvaginal and perivaginal), nasal and rectal), intravesical, intrapulmonary, duodenal, gastric, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration. In one embodiment, the preferred route of administration is the oral route.

[0119] Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gelatin capsules, lozenges, dispersants, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magma preparations, lozenges, creams, pastes, transdermal patches, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powders or aerosol preparations for inhalation, and compositions and preparations for intravesical administration. It should be understood that the preparations and compositions that may be useful in this disclosure are not limited to the specific preparations and compositions described herein.

[0120] Particularly suitable for oral administration are tablets, sugar-coated tablets, liquids, drops, suppositories or capsules, caplets, and gel capsules. Compositions intended for oral use may be prepared according to any method known in the art, and such compositions may contain one or more substances selected from the group consisting of inert and non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. Such excipients include inert diluents, e.g., lactose; granulators and disintegrants, e.g., corn starch; binders, e.g., starch; and lubricants, e.g., magnesium stearate. The tablets may be uncoated or coated by known techniques for refinement or delay of release of the active ingredient. Formulations for oral use may be provided as hard gelatin capsules in which the active ingredient is mixed with an inert diluent.

[0121] For parenteral administration, the disclosed compounds may be formulated for injection or infusion, for example, intravenous, intramuscular, or subcutaneous injection or infusion, or for administration by bolus or continuous infusion. A suspension, solution, or emulsion in an oily or aqueous vehicle may be used, optionally containing other formulation agents, such as suspending agents, stabilizers, or dispersants.

[0122] Those skilled in the art will recognize or be able to identify many equivalents to the specific procedures, embodiments, claims, and examples described herein using conventional experiments. Such equivalents are deemed to be within the scope of this disclosure and are included in the claims appended herein. For example, it should be understood that modifying reaction conditions (including, but not limited to, reaction time, reaction size / volume, and experimental reagents, e.g., solvent, catalyst, pressure, atmospheric conditions, e.g., nitrogen atmosphere, and reducing / oxidizing agent) using conventional experiments with substitutes recognized in the art is within the scope of this application.

[0123] Where values ​​and ranges are shown herein, it should be understood that all values ​​and ranges included within those values ​​and ranges are intended to be within the scope of this disclosure. Furthermore, all values ​​that fall within these ranges, and any upper or lower limits on the ranges of values, are also contemplated in this application.

[0124] The following embodiments further illustrate aspects of the present disclosure. However, these embodiments do not in any way limit the teachings of the present disclosure described herein. [Examples]

[0125] This disclosure is further illustrated by the following examples, which should not be construed as limiting the scope of this disclosure. Unless otherwise specified, the practices of this disclosure utilize conventional techniques of organic synthesis, cell biology, cell culture and molecular biology, which are within the scope of the art.

[0126] Synthesis of Compound 1 The synthesis of compound 1 is disclosed in international application PCT / US2022 / 021461, which is incorporated herein by reference in its entirety. This compound is referred to in PCT / US2022 / 021461 as Example 239 and was obtained as a grayish-white solid ("Pattern A"). LCMS: m / z = 453.1 (M + H + ) 1 ¹H NMR: (400MHz, chloroform-d) δ = 8.69-8.29 (m, 2H), 7.35 (br d, J=7.1Hz, 1H), 7.08 (br d, J=7.1Hz, 4H), 6.89-6.73 (m, 1H), 5.31 (br s, 2H), 5.00 (br s, 2H), 4.08 (br d, J=6.5Hz, 2H), 3.09 (br s, 3H), 1.39 (br t, J=5.9Hz, 3H). This compound showed IC50 for NLRP3. 50 The value was shown to be less than 1 μM.

[0127] Analytical methods for polymorphism studies Unless otherwise specified, X-ray powder diffraction (XRPD) was performed using a Bruker D8 Advance diffractometer in reflection mode with collimated Cu Kα irradiation operating at 40 kV and 40 mA. Scans were performed at 2θ from 2 to 40 degrees, with a step size of 0.02 degrees and a scan time of 0.3 seconds per step.

[0128] Differential scanning fluorescence (DSC) quantification was performed using a TA Discovery 2500 with a Tzero Pan and Tzero Hermetic Lid, at a pinhole diameter of 0.7 mm. DSC analysis was performed by increasing the temperature from 0°C to 250°C at a rate of 10°C / min.

[0129] Thermogravimetric analysis (TGA) was performed using a Discovery 5500 or Q5000 with ambient starting temperature (below 35°C) and final temperature of 300°C (or the next segment was stopped if the weight was less than 80% (w / w)), with heating at 10°C / min.

[0130] Nuclear magnetic resonance (NMR) analysis was performed using a Bruker Avance-AV 400M at a frequency of 400 MHz, with eight scans.

[0131] Dynamic water adsorption (DVS) was performed using Intrinsic's Advantage or Adventure oven at an oven temperature of 25°C, with water as the solvent. The sample mass was approximately 5–10 mg using the following method. Cycle: 40% → 0% → 95% → 0% → 40% RH Stage Step: 10% Equilibrium: 0.002dm / dt(% / min) Minimum dm / dt stable duration: 60 minutes Maximum DM / DT stage time: 360 minutes

[0132] Example 1. Preparation of crystal morphology Polymorphic behavior is observed in the free form of compound 1. In total, three crystalline forms were identified as polymorphs of its free form, including one hydrate (pattern A) and two anhydrides (patterns B and C). In addition, amorphous forms were identified by hot-collapse DSC cycles and variable-temperature XRPD experiments. Successful scale-ups were achieved for the HCl salt (pattern A), phosphate salt (pattern A), and sodium salt (pattern A). These scale-up batches exhibited the same polymorphisms as the screening sample.

[0133] Preparation of patterns A, B, and C of compound 1 Pattern A is a monohydrate. This monohydrate can be obtained in water and solvent water / solvent systems by equilibration and addition of a poor solvent. This monohydrate can also be obtained in organic solvents by slow evaporation. Pattern A has a high degree of crystallinity. According to the KF results, Pattern A contains 1.0 equivalent (3.8 wt%) of water. In DSC, the dehydration peak is approximately 8°C (enthalpy is approximately 114 J / g), and the melting peak is T onset It was observed at 134.2°C (enthalpy approximately 66 J / g). TGA showed a weight loss of approximately 3.8% at approximately 100°C. 1H-NMR showed no detectable residual solvent. After dehydration, pattern A was converted to anhydrous pattern C. Pattern C was unstable and converted back to pattern A when exposed to ambient conditions (approximately 23°C, approximately 27% RH). Water activity experiments showed that pattern A was converted to pattern B with water activity in the range of 0-0.4 at 5°C and 0-0.6 at 25°C.

[0134] Pattern B is the anhydride. This anhydride was obtained from most organic solvents by equilibration and slow cooling. This anhydride can also be obtained from acetonitrile / MTBE and THF / MTBE by adding a poor solvent. Pattern B is highly crystallin. In DSC, the melting peak is T onsetIt was observed at 174.8°C, with an enthalpy of approximately 117 J / g. TGA showed a weight loss of approximately 0.4% at around 150°C. ¹H-NMR revealed no detectable residual solvent. Water activity experiments showed that pattern B was thermodynamically stable with water activity in the range of 0-0.4 at 5°C and 0-0.6 at 25°C.

[0135] Pattern C is an anhydrous material. This anhydrous material was obtained by heating Pattern A to 100°C in a nitrogen atmosphere using a variable temperature XRPD experiment. Pattern C has a high degree of crystallinity. According to the DSC thermogram of Pattern A, Pattern C is T onset A melting peak is observed at 134.2°C. Pattern C represents a metastable form. After exposure under ambient conditions (23°C, 27%RH), pattern C was converted to pattern A.

[0136] Experiments on competitive equilibrium and water activity of the free form of compound 1 The relative stability of hydrate pattern A and anhydrous pattern B was investigated by competitive equilibrium and water activity experiments at 5°C and 25°C.

[0137] After equilibration for 5 days, hydrate pattern A was converted to anhydrous pattern B with water activity ranging from 0 to 0.4 at 5°C and 0 to 0.6 at 25°C. With water activity ranging from 0.6 to 1.0 at 5°C and 0.8 to 1.0 at 25°C, the resulting sample was maintained as a physical mixture of pattern A and pattern B. The slow morphological transition rate was presumed to be due to low solubility.

[0138] Based on the above results, pattern B, with water activity in the range of 0-0.4 at 5°C and 0-0.6 at 25°C, is considered to be the thermodynamically stable form and the best polymorph of the free form.

[0139] Evaluation of Pattern B Bulk stability The bulk stability of free morphology pattern B was evaluated over one week in an open container at 25°C / 92.5%RH, in an open container at 40°C / 75%RH, and in an airtight container at 60°C.

[0140] Free morphology pattern B was physically and chemically stable under these conditions. No significant degradation was observed by HPLC. No morphological changes were observed by XRPD.

[0141] solubility The solubility of free form pattern B, BAL-0748, was investigated at 37°C for 2 hours and 24 hours in HCl buffer at pH 1.2, 50 mM acetate buffer at pH 4.5, 50 mM phosphate buffer at pH 6.8, water, FaSSGF at pH 1.6, FaSSIF-v1 at pH 6.5, FeSSIF-v1 at pH 5.0, and 2% HPMC + 1% Pluronic F68 in 50 mM acetate buffer at pH 4.5. The residual solid after these solubility tests was analyzed by XRPD.

[0142] In free form pattern B, solubility was good (0.1–0.6 mg / mL) in HCl buffer at pH 1.2, FaSSGF at pH 1.6, and FeSSIF-v1 at pH 5.0. In other media, free form pattern B showed poor solubility (2–80 μg) at 2 hours and 24 hours.

[0143] After this solubility test, free morphology pattern B showed no morphological change in most media, or was partially converted to free morphology pattern A. However, salt formation occurred in HCl buffer at pH 1.2 and FaSSGF at pH 1.6. MonoHCl salt pattern A and hemiHCl salt pattern A were obtained in HCl buffer at pH 1.2 and FaSSGF at pH 1.6, respectively.

[0144] Hygroscopic The hygroscopicity of free form pattern B was evaluated by dynamic moisture adsorption (DVS) testing at 25°C. Free form pattern B was slightly hygroscopic. This form absorbed approximately 0.8% water at 80% RH and 25°C. After this DVS test, the obtained sample was still pattern B.

[0145] Preparation of pattern A of the HCl salt of compound 1 Pattern A of the HCl salt was prepared using the following procedure.

[0146] 300.3 mg of compound 1, free form pattern A, was weighed into a 20 mL glass vial. 4 mL of IPA was added to the vial at 50°C. Subsequently, 0.57 mL (approximately 1.05 equivalents in molar ratio) of 1.2 N aqueous HCl solution was added to the above solution. After stirring at 50°C for approximately 2 minutes, a suspension was obtained (suspension).

[0147] Approximately 10 mg of HCl salt pattern A seed was added to the above solution (suspension). After stirring at 50°C for about 2 hours, the solution was cooled to 25°C by natural cooling (suspension). The suspension was then stirred at 25°C for about 5 days.

[0148] The solid was collected by centrifugal filtration using a 0.45 μm nylon membrane filter, and then dried at 50°C under vacuum for approximately 2 hours. 295 mg of the HCl salt pattern A was obtained as a white solid with a 90% yield. The characterization of the HCl salt pattern A of compound 1 is reported in Table 9 below.

[0149] Preparation of pattern A of the phosphate of compound 1 The following procedure was used to prepare phosphate pattern A.

[0150] 300.0 mg of free form pattern A, BAL-0748, was weighed into a 20 mL glass vial. 7 mL of IPA was added to the vial at 50°C. Subsequently, 0.48 mL of diluted phosphoric acid solution (approximately 1.05 equivalents in molar ratio, 0.1 mL of phosphoric acid diluted with 0.9 mL of IPA) was added to the above solution. A suspension was obtained. Approximately 10 mg of phosphate pattern A seed was added to the above solution (suspension). After stirring at 50°C for about 2 hours, the solution was cooled to 25°C by natural cooling. The suspension was stirred at 25°C for about 5 days.

[0151] The solid was collected by centrifugal filtration and then dried at 50°C under vacuum for approximately 2 hours. 336 mg of phosphate pattern A was obtained as a white solid in 91% yield. The characterization of phosphate pattern A of compound 1 is reported in Table 9 below.

[0152] Preparation of pattern A of the sodium salt of compound 1 Pattern A of the sodium salt was prepared using the following procedure.

[0153] 300.3 mg of free form pattern A of compound 1 and approximately 29 mg of NaOH (approximately 1.05 molar equivalents) were weighed into a 20 mL glass vial. 3 mL of IPA was added to the vial at 50°C. A suspension was obtained (a nearly clear solution). Approximately 10 mg of sodium salt pattern A seed was added to the above solution. After stirring at 50°C for approximately 10 minutes, the solution was gradually converted to a suspension (nearly clear solution → suspension).

[0154] After stirring at 50°C for approximately 2 hours, the solution was cooled to 25°C by natural cooling (suspension). The suspension was stirred at 25°C for approximately 5 days. The solid was collected by centrifugal filtration and dried at 50°C under vacuum for approximately 2 hours. 283 mg of sodium salt pattern A was obtained as a white solid in 89% yield. The characterization of sodium salt pattern A of compound 1 is reported in Table 9.

[0155] Example 2. Screening of salts / cocrystals Compound 1 is a small molecule with a molecular weight of 452.46 g / mol. As predicted by Marvin Sketch v21.3, the compound contains one basic pKa of 5.16, one acidic pKa of 9.29, two H-bond donors, and five H-bond acceptors. In this salt / cocrystal screening test, pattern A of the free form of compound 1 was used as the starting material. Pattern A is the monohydrate.

[0156] Based on the pKa(s) of compound 1, seven Class I acids, two Class II acids, and two Class I bases were selected as salt-forming agents. These were hydrochloric acid, sulfuric acid, phosphoric acid, L-aspartic acid, maleic acid, L-glutamic acid, fumaric acid, methanesulfonic acid, p-toluenesulfonic acid, sodium hydroxide, and potassium hydroxide. Based on the in silico cocrystal prediction results for compound 1, and considering the preference for H-bond synthons, two cocrystal-forming agents (coformers), namely choline and oxalic acid, were selected to explore the possibility of cocrystallization. IPA, EA, and acetonitrile / water (95:5 (v / v)) were used as screening solvents. A predetermined counterion / coformer in 1.0 equivalent or 0.5 equivalent amounts was applied in this screening. Slurry equilibration, cooling, and poor solvent addition were used as crystallization methods. A total of 53 screening experiments were conducted.

[0157] According to the screening results for salts / cocrystals (Tables 6-8), 18 salts / cocrystals and their polymorphs were identified, including HCl salt pattern A, hemisulfate pattern A, hemisulfate pattern B, monosulfate pattern A, phosphate pattern A, maleate pattern A, hemifumarate pattern A, hemifumarate pattern B, monofumarate pattern A, mesylate pattern A, mesylate pattern B, mesylate pattern C, p-tosylate pattern A, p-tosylate pattern B, oxalate pattern A, sodium salt pattern A, potassium salt pattern A, and potassium salt pattern B. All of these salt / cocrystal hits were DSC, TGA, 1 Further characterization was performed using 1H-NMR, IC, KF, HPLC, and PLM.

[0158] Approximately 50 mg of compound 1 (free form pattern A) and 0.5 or 1.0 equivalent of acid or base were added to a screening solvent in a 2 mL glass vial. The resulting mixture was stirred at 50°C for 2 hours, and then stirred at 25°C for approximately 3 days. [Table 6-1] [Table 6-2]

[0159] The clear solution obtained in the slurry equilibration experiment was cooled to 5°C to precipitate the solid. After stirring at 5°C for approximately 3 days, the suspension was cooled and filtered through a 0.45 μm nylon membrane filter by centrifugation at 14,000 rpm. After drying at 50°C under vacuum for 2 hours, the solid was analyzed by XRPD. [Table 7]

[0160] The clear solution or turbid suspension obtained from the cooling experiment was further treated by adding a poor solvent. The suspension obtained after adding the poor solvent was filtered through a 0.45 μm nylon membrane filter by centrifugation at 14,000 rpm. After drying at 50°C under vacuum for 2 hours, the solid was analyzed by XRPD. [Table 8]

[0161] Among these salt / cocrystal hits, the HCl salt pattern A, the phosphate salt pattern A, and the sodium salt pattern A showed favorable properties, including high purity, high crystallinity, high melting point, reasonable stoichiometric composition, and good counterion safety. Therefore, these were selected as salt / cocrystal candidates for scale-up and for a complete evaluation comparing free morphology pattern A with bulk stability, solubility, hygroscopicity, and morphological properties.

[0162] Free form pattern A (monohydrate), HCl salt pattern A (anhydrous), phosphate pattern A (anhydrous), and sodium salt pattern A (anhydrous) were scaled up and fully evaluated. The results are summarized below. [Table 9]

[0163] Pattern A of the free form is a monohydrate with high crystallinity. By DSC, the dehydration peak is at about 8°C (enthalpy is about 114 J / g), and the melting peak is T onset observed at 134.2°C (enthalpy is about 66 J / g). By TGA, the weight loss is about 3.8% at about 100°C. By HPLC, the chemical purity is 97.8%. By KF, the water content is 3.8% by weight, which corresponds to 1.0 water molecule. 1 By H-NMR, no residual solvent is detected.

[0164] Pattern A of the HCl salt is an anhydrate with high crystallinity. By DSC, the melting peak is T onset observed at 211.2°C. Decomposition occurs upon melting. By TGA, the weight loss is about 1.0% at 180°C. By HPLC, the chemical purity is 98.8%. By IC, the stoichiometric ratio of the free form to HCl is 1:0.94. 1 By H-NMR, the residual IPA is 0.6% by weight (corresponding to 0.05 equivalent in molar ratio).

[0165] Pattern A of the phosphate salt is an anhydrate with high crystallinity. By DSC, the endothermic peak is T onset observed at 153.0°C, its enthalpy is 2 J / g, and the melting peak is T onset observed at 221.1°C. Decomposition occurs upon melting. By TGA, the weight loss is about 0.5% at 195°C. By HPLC, the chemical purity is 98.1%. By IC, the stoichiometric ratio of the free form to H3PO4 is 1:1.06. 1 By H-NMR, the residual IPA is 0.2% by weight (corresponding to 0.02 equivalent in molar ratio).

[0166] Pattern A of the sodium salt is an anhydrate with high crystallinity. By DSC, no melting appears before decomposition. By TGA, the weight loss is about 1.5% at 250°C. By HPLC, the chemical purity is 98.8%. By IC, the stoichiometric ratio of the free form to NaOH is 1:1.06. 1¹H-NMR analysis revealed that the residual IPA was 0.4% by weight (equivalent to 0.03 equivalents in molar ratio).

[0167] Example 3. Bulk Stability The free form pattern A, HCl salt pattern A, and phosphate pattern A of the present invention remained chemically and physically stable for one week under these conditions. No morphological changes were observed by XRPD. No significant degradation was observed by HPLC.

[0168] Pattern A of the sodium salt was chemically stable but physically unstable. No obvious degradation was observed by HPLC. While no morphological change was observed at 60°C for pattern A of the sodium salt, it dissociated into free morphology pattern A after one week at 25°C / 92.5%RH and 40°C / 75%RH. This result suggests that the dissociation of the sodium salt is associated with high humidity.

[0169] The results of these tests are summarized in Table 10. [Table 10]

[0170] Example 4. Solubility The solubility of the free form pattern A, HCl salt pattern A, phosphate pattern A, and sodium salt pattern A of the present invention was measured at 37°C for 2 hours and 24 hours in 2% HPMC + 1% Pluronic F68 in HCl buffer at pH 1.2, acetate buffer (50 mM) at pH 4.5, phosphate buffer (50 mM) at pH 6.8, water, FaSSGF at pH 1.6, FaSSIF-v1 at pH 6.5, FeSSIF-v1 at pH 5.0, and acetate buffer (50 mM) at pH 4.5. The residual solid after 24 hours in this solubility test was analyzed by XRPD.

[0171] In pure water, the solubility of HCl salts (pattern A) and phosphates (pattern A) is clearly higher compared to the free form (pattern A), which must be due to a pH shift.

[0172] At pH 5.0 in FeSSIF-v1, the HCl salt pattern A showed 1x higher solubility after 2 hours compared to the free form pattern A. After 24 hours, all three salts showed solubility equivalent to that of the free form pattern A.

[0173] In HCl buffer at pH 1.2, acetate buffer at pH 4.5, phosphate buffer at pH 6.8, and FaSSIF-v1 at pH 6.5, these three salts showed solubility equivalent to that of free form pattern A.

[0174] In 2% HPMC + 1% Pluronic F68 in acetate buffer (pH 4.5), the solubility of the sodium salt (pattern A) was clearly improved, while the solubility of the HCl salt (pattern A) and the phosphate salt (pattern A) was comparable to that of the free form (pattern A).

[0175] Following this solubility test, these three candidate salts partially or completely dissociated into free form pattern A in all media except pH 1.2 HCl buffer and pH 1.6 FaSSGF. Pattern A of the monoHCl salt or pattern A of the hemiHCl salt was obtained in pH 1.2 HCl buffer or pH 1.6 FaSSGF.

[0176] 10.4 mg of free form pattern A, 10.0 mg of free form pattern B, 10.8 mg of HCl salt pattern A, 12.2 mg of phosphate pattern A, or 10.5 mg of sodium salt pattern A were each weighed into 20 mL glass vials. 5 mL of soluble medium was added. The amount of salt used corresponded to 10 mg of anhydrous free form. The resulting suspensions were stirred at 37°C and 400 rpm, and samples were taken at 2 hours and 24 hours. The samples were centrifuged at 37°C and 14,000 rpm for 5 minutes. The supernatants were analyzed for solubility and pH using HPLC and a pH meter, respectively. The residual solid (wet cake) obtained from the 24-hour sample was also characterized by XRPD to determine its physical form. The results of this test are shown in Table 11. [Table 11-1] [Table 11-2] [Table 11-3] [Table 11-4]

[0177] Example 5. Hygroscopic The hygroscopic properties of the free form pattern A, HCl salt pattern A, phosphate pattern A, and sodium salt pattern A of the present invention were evaluated at 25°C by dynamic moisture adsorption (DVS) testing.

[0178] Free form pattern A, HCl salt pattern A, and phosphate pattern A were slightly hygroscopic, and no morphological changes were observed after DVS testing at 25°C.

[0179] In sodium salt pattern A, the hygroscopicity was moderate. At 80% RH and 25°C, sodium salt pattern A absorbed 2.7% water. No morphological changes were observed in sodium salt pattern A after the DVS test. These results are shown in Table 12. [Table 12-1] [Table 12-2]

[0180] Example 6. Polymorph This salt screening identified one polymorph (pattern A) of the HCl salt, one polymorph (pattern A) of the phosphate salt, and one polymorph (pattern A) of the sodium salt. The polymorph screening yielded three free polymorphs (patterns A, B, and C).

[0181] From the foregoing description, various modifications of this disclosure, in addition to those described herein, will be apparent to those skilled in the art. Such modifications are also intended to fall within the scope of the appended claims. All references cited herein (including, but not limited to, all patents, patent applications and publications) are incorporated herein by reference in their entirety.

Claims

1. 2-ethoxy-3',5'-difluoro-N-((4-(hydroxymethyl)-1H-pyrazolo[4,3-c]pyridine-7-yl)methyl)-N-methyl-[1,1'-biphenyl]-4-carboxamide, or a crystalline form of its pharmaceutically acceptable salt or hydrate.

2. The crystalline form according to claim 1, which is a monohydrate.

3. The crystalline form according to claim 1, which is an anhydrous substance.

4. The crystalline form according to any one of claims 1 to 3, which is a pharmaceutically acceptable salt.

5. The crystalline form according to claim 4, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride salts, phosphate salts, and sodium salts.

6. The crystal morphology according to claim 3, characterized by an XRPD diffraction pattern having peaks represented by degrees (±0.2 degrees) at angles 2θ of 7.2, 20.4, and 20.

6.

7. The crystal morphology according to claim 3 or 6, characterized by an XRPD diffraction pattern having peaks represented by degrees (±0.2 degrees) at angles 2θ of 7.2, 20.4, 20.6, and 21.

6.

8. The crystal morphology according to any one of claims 3, 6, and 7, characterized by an XRPD diffraction pattern having peaks represented by degrees (±0.2 degrees) at angles 2θ of 7.2, 11.1, 11.8, 20.4, 20.6, and 21.

6.

9. The crystal morphology according to any one of claims 3 and 6 to 8, characterized by an XRPD diffraction pattern having peaks represented by degrees (±0.2 degrees) at angles 2θ of 5.5, 7.2, 11.1, 11.8, 15.3, 20.4, 20.6, 21.6, 26.7, and 30.

9.

10. The crystal morphology according to any one of claims 3 and 6 to 9, having a DSC thermogram characterized by endothermic activity with a starting temperature of 177.3°C.

11. The crystal morphology according to claim 2, characterized by an XRPD diffraction pattern having peaks represented by degrees (±0.2 degrees) at angles 2θ of 6.5, 12.9, and 16.

1.

12. The crystal morphology according to claim 2 or 11, characterized by an XRPD diffraction pattern having peaks represented by degrees (±0.2 degrees) at angles 2θ of 6.5, 11.2, 12.9, and 16.

1.

13. The crystal morphology according to any one of claims 2, 11, and 12, characterized by an XRPD diffraction pattern having peaks represented by degrees (±0.2 degrees) at angles 2θ of 6.5, 11.2, 12.9, 16.1, 22.7, 24.8, and 32.

6.

14. A crystal morphology according to any one of claims 2 and 11 to 13, having a DSC thermogram characterized by endothermic properties with a starting temperature of 139.6°C.

15. The crystalline form according to any one of claims 1 to 5, wherein it is 2-ethoxy-3',5'-difluoro-N-((4-(hydroxymethyl)-1H-pyrazolo[4,3-c]pyridine-7-yl)methyl)-N-methyl-[1,1'-biphenyl]-4-carboxamide hydrochloride.

16. The crystal morphology according to claim 15, characterized by an XRPD diffraction pattern having peaks represented by degrees (±0.2 degrees) at angles 2θ of 12.3, 18.1, and 18.

2.

17. The crystal morphology according to claim 15 or 16, characterized by an XRPD diffraction pattern having peaks represented by degrees (±0.2 degrees) at angles 2θ of 12.3, 12.8, 18.1, 18.2, and 28.

7.

18. The crystal morphology according to any one of claims 15 to 17, characterized by an XRPD diffraction pattern having peaks represented by degrees (±0.2 degrees) at angles 2θ of 12.3, 12.8, 18.1, 18.2, 26.0, and 28.

7.

19. The crystal morphology according to any one of claims 15 to 18, having a DSC thermogram characterized by endothermic activity with a starting temperature of 218.3°C.

20. The crystalline form according to any one of claims 1 to 5, wherein it is 2-ethoxy-3',5'-difluoro-N-((4-(hydroxymethyl)-1H-pyrazolo[4,3-c]pyridine-7-yl)methyl)-N-methyl-[1,1'-biphenyl]-4-carboxamid phosphate.

21. The crystal morphology according to claim 20, characterized by an XRPD diffraction pattern having peaks represented by degrees (±0.2 degrees) at angles 2θ of 3.1, 9.2, and 16.

4.

22. The crystal morphology according to claim 20 or 21, characterized by an XRPD diffraction pattern having peaks represented by degrees (±0.2 degrees) at angles 2θ of 3.1, 9.2, 11.7, 13.9, 15.4, 16.4, and 24.

7.

23. The crystal morphology according to any one of claims 20 to 22, characterized by an XRPD diffraction pattern having peaks represented by degrees (±0.2 degrees) at angles 2θ of 3.1, 9.2, 11.7, 13.9, 15.4, 16.4, 18.1, 19.0, 16.4 and 24.

7.

24. The crystal morphology according to any one of claims 20 to 23, having a DSC thermogram characterized by endothermic activity with a starting temperature of 223.9°C.

25. The crystalline form according to any one of claims 1 to 5, wherein it is 2-ethoxy-3',5'-difluoro-N-((4-(hydroxymethyl)-1H-pyrazolo[4,3-c]pyridine-7-yl)methyl)-N-methyl-[1,1'-biphenyl]-4-carboxamide sodium salt.

26. The crystal morphology according to claim 25, characterized by an XRPD diffraction pattern having peaks represented by degrees (±0.2 degrees) at angles 2θ of 10.3, 21.1, and 25.

8.

27. The crystal morphology according to claim 25 or 26, characterized by an XRPD diffraction pattern having peaks represented by degrees (±0.2 degrees) at angles 2θ of 10.3, 17.3, 20.6, 21.1, 23.3, and 25.

8.

28. The crystal morphology according to any one of claims 25 to 27, characterized by an XRPD diffraction pattern having peaks represented by degrees (±0.2 degrees) at angles 2θ of 10.3, 14.9, 17.2, 17.3, 18.8, 20.6, 20.0, 21.1, 23.3, and 25.

8.

29. A crystalline form of a pharmaceutically acceptable salt of 2-ethoxy-3',5'-difluoro-N-((4-(hydroxymethyl)-1H-pyrazolo[4,3-c]pyridine-7-yl)methyl)-N-methyl-[1,1'-biphenyl]-4-carboxamide, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, phosphate, and sodium salts.

30. A pharmaceutical composition comprising a crystalline form according to any one of claims 1 to 29 and a pharmaceutically acceptable carrier.

31. A method for inhibiting the NLRP3 inflammasome in a subject requiring treatment, comprising administering to the subject a therapeutically effective amount of the crystalline form described in any one of claims 1 to 29, or the pharmaceutical composition described in claim 30.

32. A method for treating inflammation in a subject requiring treatment, comprising administering to the subject a therapeutically effective amount of a crystalline form according to any one of claims 1 to 29, or a pharmaceutical composition according to claim 30.

33. A method for treating inflammatory aging in a subject requiring treatment, comprising administering to the subject a therapeutically effective amount of a crystalline form described in any one of claims 1 to 29, or a pharmaceutical composition described in claim 30.

34. A method for treating cryopyrin-associated periodic syndrome (CAPS) in a subject requiring treatment, comprising administering to the subject a therapeutically effective amount of the crystalline form described in any one of claims 1 to 29, or the pharmaceutical composition described in claim 30.

35. A method for treating a disease or disorder of the inner ear in a subject requiring treatment, comprising administering to the subject a therapeutically effective amount of the crystalline form described in any one of claims 1 to 29, or the pharmaceutical composition described in claim 30.

36. The method according to claim 35, wherein the inner ear disorder or disability is selected from the group consisting of hearing loss, hearing impairment, dizziness, Meniere's disease, and tinnitus.

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