Solid forms of complement factor B inhibitors

Abstract

The present disclosure relates to crystalline forms and pharmaceutical compositions of (S)-4-(2, 2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl) methyl)-7-azaspiro [3.5] nonane-6-yl) benzoic acid, and uses thereof.

Description

[0001] This application is a divisional application of Chinese Patent Application No. 202380078053.2, filed on November 13, 2023, entitled "Solid Form of Complement Factor B Inhibitor". Priority requirements

[0002] This application claims priority to U.S. Patent Application Serial No. 63 / 425,206, filed November 14, 2022, the entire contents of which (including any figures) are hereby incorporated by reference. Technical Field

[0003] This article discloses ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H The crystalline form of (-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid, and ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H p-Toluenesulfonate of 1-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid. Background Technology

[0004] The complement system is a key component of the innate immune system, with two main functions: host defense against microbial pathogens and clearance of apoptotic cells. Since its initial discovery by Jules Bordet and Paul Ehrlich in the 1890s, over a century of research on complement has revealed its diverse roles in immune responses, surveillance, homeostasis, and metabolism (Hajishengallis, Nat Immunol [Nature Immunology] 2017 18: 1288-1298; Sim, Immunobiology [Immunobiology] 2016 221(10):1037-1045; Ricklin, Nat Immunol [Nature Immunology] 2010 11(9): 785-797). The complement system contains a large number of soluble proteins, which are found in circulation and tissues as inactive zymogens activated upon cleavage by serine proteases. Activation of complement is tightly regulated by plasma and membrane-bound regulators. Tissue damage has been found to result from gene mutations, autoantibodies, or dysregulation of complement activity in chronic inflammation under a variety of pathological conditions, including autoimmune diseases, inflammatory diseases, neurodegenerative diseases, and widespread kidney diseases (Zipfel, Nat Rev Immunol [Nature Reviews Immunology] 2009 9: 729-749; Holers, Annu Rev Immunol [Annual Review of Immunology] 2014 32: 433-459).

[0005] There are three activation pathways: the classical pathway (CP), the lectin pathway (LP), and the alternative pathway (AP) (Merle, Front Immunol 2015 6: 262). CP is activated by immunoglobulins (IgG and IgM) and immune complexes through the binding of C1q to the Fc domain (Botto, Annu Rev Immunol 2002 205:395-406). LP is activated by a group of proteins that bind to sugars on the bacterial surface, such as mannose-binding lectin (MBL) (Garred, Immunol Rev 2016 274(1): 74-97). Compared to the other two pathways that require specific stimuli for activation, AP maintains low levels of activation in plasma through a spontaneous hydrolysis process called "tickover," and can also be secondary activated by the other two complement pathways (Lachmann, Adv Immunol 2009 104: 115-149). AP forms a rapid self-amplifying loop unless inactivated by factors H and I. These three activation pathways generate protease complexes (C3bBb and C4b2a) called "C3 convertases" to cleave C3, forming C3bBbC3b as a C5 convertase. The terminal complement pathway assembles C5b with other complement proteins to form the C5b-9 membrane attachment complex (MAC), mediating the lysis of pathogens or apoptotic cells (Bhakdi, Immunol Today 1991 12: 318-320). The two soluble fragments C3a and C5a of the C3 and C5 cleavage products, also known as "anaphylactic toxins," are potent chemical inducers that trigger pro-inflammatory responses through their receptors (Klos, Mol Immunol [Molecular Immunology] 2009 46(14): 2753-2766).

[0006] Complement overactivation and renal deposition have been observed in a variety of chronic kidney diseases (CKDs), including atypical hemolytic uremic syndrome (aHUS), C3 glomerulonephropathy (C3G), IgA nephropathy (IgAN), membranous nephropathy (MN), ANCA-associated vasculitis (AAV), focal segmental glomerulosclerosis (FSGS), and lupus nephritis (LN) (Harris, Semin Immunopathol [Immunopathology Symposium] 2018 40(1): 125-140; Willows, Clin Med [Clinical Medicine] 2020 20(2): 156-160). Preclinical and clinical evidence supports the role of complement (especially AP) in disease development and progression. Genetic defects in complement genes (such as CFH, CFI, CFHRs, CFB, C3, and MCP / CD46) are directly associated with aHUS and C3G (Bu, J Am Soc Nephrol [American Journal of Nephrology] 2014 25(1): 55-64; Marinozzi, J AmSoc Nephrol [American Journal of Nephrology] 2015 25: 2053-2065; Xiao, Semin Thromb Hemost [Thrombosis and Hemostasis Symposium] 2014 40(4): 465-471). Activation of complement through autoantibodies and immune complexes in the kidneys can lead to kidney damage and disease progression in various glomerular diseases (Corvillo, Front Immunol 2019 10: 886; Marinozzi, J Am Soc Nephrol 2017 28(5): 1603-1613; Seikrit, N Engl J Med 2018 379(25): 2479-2481). Recent studies have provided evidence of the local production and activation of complement proteins in CKDs such as IgAN and diabetic nephropathy (Mühlig, Front Immunol 2020 11: 1833; Zhou, Clin J Am Soc Nephrol 2021 16(2): 213-224; Kelly Am J Nephrol 2015 41: 48-56). It is believed that the local production of complement and the unique microenvironment within the kidney make this organ more susceptible to complement overactivation (Thurman, Clin J Am Soc Nephrol 2020 11:1856).

[0007] Significant efforts have been invested in developing complement-targeted therapies. Eculizumab, a C5 monoclonal antibody, has been approved for the treatment of aHUS. However, when tested in C3G, only a fraction of patients with higher C5b-9 (MAC) levels showed disease improvement. This may be due to the action of activating fragments at the upstream C3 level of the terminal pathway (Vivarelli, Semin Thromb Hemost [Thrombosis and Hemostasis Symposium] 2014 40(4): 472-477). Multiple therapeutic agents targeting different complement pathways are currently under development, each with its own advantages and limitations (Zipfel, Front Immunol [Frontiers in Immunology] 2019 10: 2166; Thurman, Kidney Int [International Journal of Kidney] 2016 90(4): 746-752). Nevertheless, there is still a need for potent therapeutic compounds that block the C3 and C5 levels of the complement system.

[0008] CFB, as a key enzyme in AP, provides an ideal target for blocking the central amplification loop and the terminal complement pathway. CFB knockout has been shown to have a protective effect in the following rodent models: C3G (Pickering, Nat Genet [Nature Genetics] 2002 31(4): 424-428), MN (Luo, Front Immunol [Immunology Frontiers] 2018 9:1433), ANCA-associated vasculitis (Xiao, Am J Pathol [American Journal of Pathology] 2007 170(1): 52-64), LN (Watanabe, J Immunol [Immunology Journal] 2000 164(2): 786-794), and multiple kidney injury models (Thurman, Am J Physiol Renal Physiol [American Journal of Physiology - Renal Physiology] 2012 302:F1529-F1536; Casiraghi, Am J Transplant [American Journal of Transplantation] 2017 17: 2312-2325; Morigi, Sci Rep [Scientific Reports] 2016 6:8445). In these models, genetic defects in CFB lead to reduced proteinuria, prevent kidney damage, and prolong survival. Like many complement proteins, CFB circulates in its natural form at high plasma concentrations of 300-400 µg / mL. Recently, the selective CFB inhibitor iptacopan (LNP023) has been shown to bind to active CFB (Schubart Proc Natl Acad Sci US A. [Proceedings of the National Academy of Sciences] 2019 116(16):7926-7931). In a phase II clinical trial of C3G, iptacopan showed encouraging efficacy in reducing proteinuria after 12 weeks of treatment (Wong, J Am Soc Nephrol [American Journal of Nephrology] 2020 31: 55A).

[0009] However, variability in complement activity and patient response has also been observed, suggesting that potent compounds with stronger and more durable complement inhibition in vivo could provide greater therapeutic benefit to patients with C3G and a wide range of CKD conditions. Therefore, it is desirable to provide compounds that inhibit complement factor B.

[0010] The following compound, which was filed on June 3, 2022, and is entitled “SUBSTITUTED INDOLE COMPOUNDS AND METHODSOF USE THEREOF [Substituted Indole Compounds and Methods of Using Them Thereof]” (incorporated herein by reference in its entirety), discloses a compound having the following formula I: S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H -indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid.

[0011] I The solid form of the active pharmaceutical ingredient (API) of a particular drug is often a crucial determinant of its ease of preparation, hygroscopicity, stability, solubility, storage stability, ease of formulation, dissolution rate in gastrointestinal fluids, and bioavailability in vivo. Salt forms are a technique for optimizing the aforementioned properties of ionizable drug candidates. Crystalline forms arise where the same composition of substances crystallizes in different lattice arrangements, regardless of the presence of counterions, resulting in different thermodynamic properties and stability specific to a particular crystalline form. Crystalline forms can also include different hydrates or solvates of the same compound. In determining which form is preferred, many properties of the forms are compared, and the preferred form is selected based on many physical property variables. It is entirely possible that in some cases, certain aspects such as ease of preparation and stability are considered crucial, and a particular form may be preferred. In other cases, different forms may be preferred for greater dissolution rates and / or superior bioavailability. It is not possible to predict whether a particular compound or a salt of a compound will form a polymorph, whether any such polymorph will be suitable for commercial use in a therapeutic composition, or which polymorph will exhibit such desired properties. Summary of the Invention

[0012] This article discloses ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H Crystalline form of (-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid.

[0013] In some embodiments, the crystalline form is form A as described herein.

[0014] In some embodiments, form A is prepared by the following method, which includes: (a) With stirring, at about 40°C to about 50°C, ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H-Indo-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid was added to isopropanol to form a solution with a concentration of about 0.44 moles; (b) Cool the solution to approximately 20°C and stir for approximately 72 hours to form a suspension; (c) Filter the suspension to obtain a solid; (d) Wash the solid with isopropanol; and (e) Dry the solid to provide form A.

[0015] This article discloses ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H The crystalline form of p-toluenesulfonate of (-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid.

[0016] In some embodiments, the crystalline form is form B as described herein.

[0017] In some embodiments, form B is prepared by the following method, which includes: (a) Add ethanol to ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H -indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid and p-toluenesulfonic acid to form a suspension, wherein ethanol is relative to ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H -Indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid is about 3.5 vol; (b) Heat the suspension to approximately 50°C and stir for approximately 15 minutes to form a solution; (c) Cool the solution to approximately 25°C over approximately 15 minutes, then add approximately 2.5 volumes of ethyl acetate; (d) Add about 7.5 volumes of ethyl acetate over 2 hours at about 25°C to form a slurry, and then allow the slurry to stand at about 25°C for about 1 hour; (e) Filter the slurry to obtain solids; (f) Wash the solid with a binary mixture of ethanol and ethyl acetate in a volume ratio of about 1:3; (g) Drying the solid to provide it in solid form; (h) Add solid form to a binary mixture of isopropanol and water in a volume ratio of about 9:1, and then heat at about 50°C for about 16 hours to form a slurry; (i) Cooling the slurry to approximately 25°C and filtering to obtain solids; and (j) Dry the solid at about 50°C to provide form B.

[0018] In some embodiments, the crystalline form is form C as described herein.

[0019] In some embodiments, form C is prepared by the following method, which includes: (a) Add ethanol to ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H -indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid and p-toluenesulfonic acid to form a suspension, wherein ethanol is relative to ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H -Indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid is about 3.5 vol; (b) Heat the suspension to approximately 50°C and stir for approximately 15 minutes to form a solution; (c) Cool the solution to approximately 25°C over approximately 15 minutes, then add approximately 2.5 volumes of ethyl acetate; (d) Add about 7.5 volumes of ethyl acetate over 2 hours at about 25°C to form a slurry, and then allow the slurry to stand at about 25°C for about 1 hour; (e) Filter the slurry to obtain solids; (f) Wash the solid with a binary mixture of ethanol and ethyl acetate in a volume ratio of approximately 1:3; and (g) Dry the solid to provide form C.

[0020] This article discloses ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H Crystalline form of hydrochloride of (-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid.

[0021] In some embodiments, the crystalline form is form D as described herein.

[0022] In some embodiments, form D is prepared by the following method, which includes: (a) Preparation ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 HA solution of -indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid in about 5.5 volumes of ethyl acetate; (b) Add approximately 0.55 equivalents of a 1-molar concentration of hydrogen chloride in ethyl acetate; (c) Add crystals ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H -Indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoate salt in ethyl acetate to form a suspension; (d) Add approximately 1.65 equivalents of a 1-molar concentration solution of hydrogen chloride in ethyl acetate to form a slurry; (e) Stir the slurry at approximately 24°C for approximately 16 hours; (f) Filter the slurry to obtain solids; (g) Wash the solid with ethyl acetate; and (h) Dry the solid to provide form D.

[0023] Some embodiments provide pharmaceutical compositions comprising one of form A, form B, form C or form D, and a pharmaceutically acceptable carrier.

[0024] Some embodiments provide pharmaceutical compositions comprising form A and a pharmaceutically acceptable carrier.

[0025] Some embodiments provide pharmaceutical compositions comprising form B, form C, or form D, and a pharmaceutically acceptable carrier.

[0026] This article discloses a method for treating a disease or condition associated with complement factor B (CFB), the method comprising administering to a subject suffering from such a disease or condition a therapeutically effective amount of form A, form B, form C, or form D, or a pharmaceutical composition comprising form A, form B, form C, or form D and a pharmaceutically acceptable carrier.

[0027] This article discloses a method for treating a disease or condition associated with complement factor B (CFB), the method comprising administering to a subject suffering from such a disease or condition a therapeutically effective amount of form A, form B, form C, or form D, or a pharmaceutical composition comprising form B, form C, or form D and a pharmaceutically acceptable carrier.

[0028] Some embodiments provide methods for treating or preventing diseases or conditions selected from the group consisting of: autoimmune diseases or conditions, inflammatory diseases or conditions, metabolic diseases or conditions, nervous system diseases or disorders, lung diseases, respiratory diseases or conditions, eye diseases, cardiovascular diseases, and kidney diseases, the method comprising administering to a subject suffering from such a disease or condition a therapeutically effective amount of form A, form B, form C, or form D, or a pharmaceutical composition comprising form A, form B, form C, or form D and a pharmaceutically acceptable carrier.

[0029] Some embodiments provide methods for treating or preventing diseases or conditions selected from the group consisting of: autoimmune diseases or conditions, inflammatory diseases or conditions, metabolic diseases or conditions, nervous system diseases or disorders, lung diseases, respiratory diseases or conditions, eye diseases, cardiovascular diseases, and kidney diseases, the method comprising administering to a subject suffering from such a disease or condition a therapeutically effective amount of form A, form B, form C, or form D, or a pharmaceutical composition comprising form B, form C, or form D and a pharmaceutically acceptable carrier.

[0030] As used in this article, when referring to modifying numerical values, the term "about" covers a range of uncertainty of 0% to 10% of the numerical value.

[0031] The terms "polymorph" and "polymorphic form" refer to different crystalline forms of a single compound. That is, polymorphs are different solids with the same molecular formula, but each polymorph can have different solid-state physical properties. Therefore, a single compound can produce multiple polymorphic forms, each with different solid-state physical properties, such as different solubility profiles, dissolution rates, melting temperatures, fluidity, and / or different X-ray diffraction peaks.

[0032] The term "amorphous" refers to a solid in a non-crystalline state. Amorphous solids are a disordered arrangement of molecules, and therefore have no distinguishable crystal lattice or unit cell, and thus no definable long-range ordering. The solid form of a solid can be determined by polarized optical microscopy, X-ray powder diffraction ("XRPD"), differential scanning calorimetry ("DSC"), or other standard techniques known to those skilled in the art.

[0033] As used herein, a compound is considered "substantially pure" if it contains trace amounts of other components. Such components may include, for example, starting materials, residual solvents, other polymorphs or crystalline forms, opposite enantiomers, other salt forms, other solvates, or any other impurities that may arise from the preparation, separation, and / or recrystallization of the compounds provided herein. In some embodiments, other components may include, for example, starting materials, residual solvents, other polymorphs or crystalline forms, opposite enantiomers, other salt forms, or any other impurities that may arise from the preparation, separation, and / or recrystallization of the compounds provided herein. In some embodiments, if ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H The solid form of (e.g., a particular crystalline form or salt) of benzoic acid is "substantially pure" if it consists of at least about 95% by weight of the solid form. In some embodiments, if ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H If the solid form of indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid constitutes at least about 97%, about 98%, about 99%, or about 99.5% by weight of the solid form, then the solid form is "substantially pure".

[0034] The terms “effective amount” and “therapeutic effective amount” are used interchangeably herein and refer to the amount of an active compound or agent that elicits a biological or pharmaceutical response (including relief of symptoms of the treated disease or condition) in an tissue system, animal, or human sought by an investigator, veterinarian, physician, or other clinician. Specifically, when administered to a subject requiring such treatment, an effective amount is sufficient to (i) treat or prevent a particular disease, condition, or condition that can be treated with a CFB inhibitor, (ii) reduce, improve, or eliminate one or more symptoms of a particular disease, condition, or condition, or (iii) prevent or delay the onset of one or more symptoms of a particular disease, condition, or condition described herein. The amount of crystalline form corresponding to such a therapeutically effective amount described herein will depend on factors such as the disease condition and its severity, the identity of the mammal requiring treatment (e.g., weight), etc.

[0035] The term "free form" refers to a compound that exists in a non-salt form.

[0036] The term "hydrate" means a compound or salt thereof that further includes stoichiometric or non-stoichiometric water bound by non-covalent intermolecular forces. The term "anhydrous" means a compound or salt thereof that does not include stoichiometric or non-stoichiometric water bound by non-covalent intermolecular forces.

[0037] As used herein, the term "pharmaceutical composition" is intended to cover a product comprising one or more active ingredients and one or more inert ingredients constituting a carrier, and any product directly or indirectly produced by combination, compounding, or aggregation of any two or more of these ingredients, or by dissociation of one or more of these ingredients, or by other types of reactions or interactions of one or more of these ingredients. Therefore, the pharmaceutical compositions disclosed herein cover any composition prepared by mixing the disclosed compounds or pharmaceutically acceptable salts thereof with a pharmaceutically acceptable carrier.

[0038] The term "pharmaceutically acceptable carrier" refers to a carrier or adjuvant that can be administered to a patient together with the compounds disclosed herein or their pharmaceutically acceptable salts, and which, when administered in a dose sufficient to deliver a therapeutic amount of the compound, does not impair its pharmacological activity and is non-toxic.

[0039] The term "subject" refers to an animal, including but not limited to primates (e.g., humans), monkeys, cattle, pigs, sheep, goats, horses, dogs, cats, rabbits, rats, or mice. The terms "subject" and "patient" are used interchangeably in this document, for example, with respect to mammalian subjects (such as humans).

[0040] In the context of treating a disease or condition, the term "treatment" means the relief or elimination of a disease, condition, or illness, or one or more symptoms associated with such disease, condition, or illness; or the slowing of the progression, spread, or worsening of a disease, condition, or illness or one or more symptoms thereof.

[0041] Detailed descriptions of one or more embodiments of this disclosure are set forth in the accompanying drawings and the following description. Other features and advantages of this disclosure will be apparent from the specification, the drawings, and the claims. Attached Figure Description

[0042] Figure 1 It is amorphous ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H X-ray powder diffraction pattern of indole-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid.

[0043] Figure 2 This is the X-ray powder diffraction pattern of form A.

[0044] Figure 3 This is the thermogravimetric analysis pyrometry spectrum of form A.

[0045] Figure 4 It is a differential scanning calorimeter of form A.

[0046] Figure 5 This is the X-ray powder diffraction pattern for form A (alternative preparation).

[0047] Figure 6 This is a differential scanning calorimeter of form A (alternative preparation).

[0048] Figure 7 This is the thermogravimetric analysis pyrometry spectrum of form A (alternative preparation).

[0049] Figure 8 It is form A (alternative preparation) 1 H NMR spectrum.

[0050] Figure 9 This is a scanning electron microscope image of form A (alternative preparation).

[0051] Figure 10 This is the intrinsic solubility rate curve of form A (alternative preparation) in pH 2.0 HCl buffer.

[0052] Figure 11 This is the intrinsic solubility rate curve of form A (alternative preparation) in pH 6.5 phosphate buffer.

[0053] Figure 12 This is the X-ray powder diffraction pattern for form B.

[0054] Figure 13 This is the thermogravimetric analysis pyrometry spectrum of form B.

[0055] Figure 14 The differential scanning calorimetry plot of form B is shown.

[0056] Figure 15 This is the X-ray powder diffraction pattern for form B (alternative preparation).

[0057] Figure 16 This is a differential scanning calorimeter of form B (alternative preparation).

[0058] Figure 17 This is the thermogravimetric analysis pyrometry spectrum of form B (alternative preparation).

[0059] Figure 18 It is form B (alternative preparation) 1 H NMR spectrum.

[0060] Figure 19 This is a scanning electron microscope image of form B (alternative preparation).

[0061] Figure 20 It is the intrinsic solubility rate of form B in pH 2 buffer.

[0062] Figure 21 It is the intrinsic solubility rate of form B in pH 6.5 buffer.

[0063] Figure 22 It is the dissolution curve of the capsule containing form B.

[0064] Figure 23 This is the X-ray powder diffraction pattern of form C.

[0065] Figure 24 This is the thermogravimetric analysis pyrometry spectrum of form C.

[0066] Figure 25 It is a differential scanning calorimeter of form C.

[0067] Figure 26 This is an X-ray powder diffraction pattern of form D.

[0068] Figure 27 It is a thermogravimetric analysis pyrograph of form D.

[0069] Figure 28 It is a differential scanning calorimeter of form D. Detailed Implementation

[0070] The characteristic of this article is ( S Crystallized forms of 4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid (Formula I) and its salts.

[0071] I This article also provides amorphous ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H -indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid. In some embodiments, amorphous ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H -Indole-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid is characterized by its relationship with Figure 1 The XRPD diagram shown is essentially the same.

[0072] Form A This disclosure provides ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 HThe crystalline form of the free form of (indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid (a compound having formula I). ​​In one embodiment, the free form is the anhydrous form. The crystalline form of the free form (i.e., the anhydrous form) of the compound having formula I is referred to herein as form A. Form A is described and characterized herein.

[0073] In some embodiments, the crystalline form is form A, and the XRPD plot is consistent with... Figure 2 The two are essentially the same.

[0074] In some embodiments, the crystalline form is form A, and the XRPD plot is consistent with... Figure 5 The two are essentially the same.

[0075] In some embodiments, the crystalline form is form A, and the XRPD plot is represented by the peaks shown in the table below:

[0076] In some embodiments, the crystalline form is characterized by an X-ray powder diffraction (XRPD) pattern with a peak at 10.7 ± 0.2 degrees 2θ. The X-ray powder diffraction pattern of form A may also include one or more additional characteristic peaks.

[0077] In some embodiments, the X-ray powder diffraction pattern of form A may also include one or more of the following additional characteristic peaks, which may also be used to identify (e.g., in a sample) form A.

[0078] For example, the XRPD plot has a peak at 20.5 ± 0.2 degrees 2θ.

[0079] For example, the XRPD plot has a peak at 18.8 ± 0.2 degrees 2θ.

[0080] For example, the XRPD plot has a peak at 21.7 ± 0.2 degrees 2θ.

[0081] For example, the XRPD plot has a peak at 19.6 ± 0.2 degrees 2θ.

[0082] For example, the XRPD plot has a peak at 19.8 ± 0.2 degrees 2θ.

[0083] For example, the XRPD plot has a peak at 12.5 ± 0.2 degrees 2θ.

[0084] For example, the XRPD plot has a peak at 21.7 ± 0.2 degrees 2θ.

[0085] For example, the XRPD plot has a peak at 23.3 ± 0.2 degrees 2θ.

[0086] For example, the XRPD plot has a peak at 22.5 ± 0.2 degrees 2θ.

[0087] For example, the XRPD plot has a peak at 27.3 ± 0.2 degrees 2θ.

[0088] For example, the XRPD plot has a peak at 15.5 ± 0.2 degrees 2θ.

[0089] The X-ray powder diffraction pattern of type A may also include one or more lower intensity characteristic peaks. The relative intensities of these additional peaks are generally lower than the relative intensities associated with the characteristic peaks described above.

[0090] For example, the XRPD plot has a peak at 5.3 ± 0.2 degrees 2θ.

[0091] For example, the XRPD plot has a peak at 13.7 ± 0.2 degrees 2θ.

[0092] For example, the XRPD plot has a peak at 16.5 ± 0.2 degrees 2θ.

[0093] For example, the XRPD plot has a peak at 15.6 ± 0.2 degrees 2θ.

[0094] For example, the XRPD plot has a peak at 23.5 ± 0.2 degrees 2θ.

[0095] For example, the XRPD plot has a peak at 16.1 ± 0.2 degrees 2θ.

[0096] For example, the XRPD plot has a peak at 28.9 ± 0.2 degrees 2θ.

[0097] For example, the XRPD plot has a peak at 11.3 ± 0.2 degrees 2θ.

[0098] For example, the XRPD plot has a peak at 26.7 ± 0.2 degrees 2θ.

[0099] For example, the XRPD plot has a peak at 25.6 ± 0.2 degrees 2θ.

[0100] For example, the XRPD plot has a peak at 29.2 ± 0.2 degrees 2θ.

[0101] In some embodiments, the crystalline form is form A, and the XRPD plot has peaks at 10.7, 20.5, and 18.8 (± 0.2 degrees 2θ).

[0102] In some embodiments, the crystalline form is form A, and the XRPD plot has peaks at 10.7, 20.5, 18.8, and 21.7 (±0.2 degrees 2θ).

[0103] In some embodiments, the crystalline form is form A, and the XRPD plot has peaks at 10.7, 20.5, 18.8, 21.7, 19.6, 19.8, 12.5, 21.1, 23.3, 22.5, 27.3, and 15.55 (± 0.2 degrees 2θ).

[0104] In some embodiments, the crystalline form is form A, and the XRPD plot has peaks at 10.7, 20.5, 18.8, 21.7, 19.6, 19.8, 12.5, 21.1, 23.3, 22.5, 27.3, 15.5, 5.3, 13.7, 16.5, 15.6, 23.5, 16.1, 28.7, 11.3, 26.7, 25.6, and 29.2 (± 0.2 degrees 2θ).

[0105] In some embodiments, the crystalline form is form A, and the XRPD plot has a peak at 10.7 (± 0.2 degrees 2θ).

[0106] In some embodiments, the crystalline form is form A, and the XRPD plot has peaks at 10.7 and 20.5 (± 0.2 degrees 2θ).

[0107] In some embodiments, the crystalline form is form A, and the XRPD plot has peaks at 10.7, 20.5, and 19.5 (± 0.2 degrees 2θ).

[0108] In some embodiments, the crystalline form is form A, and the XRPD plot has peaks at 10.7, 20.5, 19.5, and 21.6 (±0.2 degrees 2θ).

[0109] In some embodiments, the crystalline form is form A, and the XRPD plot has peaks at 10.7, 20.5, 19.5, 21.6, and 18.8 (± 0.2 degrees 2θ).

[0110] In some embodiments, the crystalline form is form A, and the XRPD plot has peaks at 10.7, 20.5, 19.5, 21.6, 18.8, and 12.4 (± 0.2 degrees 2θ).

[0111] In some embodiments, the crystalline form is form A, and the XRPD plot has peaks at 10.7, 20.5, 19.5, 21.6, 18.8, 12.4, and 22.5 (± 0.2 degrees 2θ).

[0112] In some embodiments, the crystalline form is form A, and the XRPD plot has peaks at 10.7, 20.5, 19.5, 21.6, 18.8, 12.4, 22.5, and 15.5 (± 0.2 degrees 2θ).

[0113] In some embodiments, the crystalline form is form A, and the XRPD plot has peaks at 10.7, 20.5, 19.5, 21.6, 18.8, 12.4, 22.5, 15.5, and 21.2 (± 0.2 degrees 2θ).

[0114] In some embodiments, the crystalline form is form A, and the XRPD plot has peaks at 10.7, 20.5, 19.5, 21.6, 18.8, 12.4, 22.5, 15.5, 21.2, and 15.9 (± 0.2 degrees 2θ).

[0115] In some embodiments, the crystalline form is form A, and the XRPD plot has peaks at 10.7, 20.5, 19.5, 21.6, 18.8, 12.4, 22.5, 15.5, 21.2, 15.9, and 16.3 (± 0.2 degrees 2θ).

[0116] In some embodiments, the crystalline form is form A, and the XRPD plot has peaks at 10.7, 20.5, 19.5, 21.6, 18.8, 12.4, 22.5, 15.5, 21.2, 15.9, 16.3, and 23.2 (± 0.2 degrees 2θ).

[0117] In some embodiments, the crystalline form is form A, and the XRPD plot has peaks at 10.7, 20.5, 19.5, 21.6, 18.8, 12.4, 22.5, 15.5, 21.2, 15.9, 16.3, 23.2, and 20.9 (± 0.2 degrees 2θ).

[0118] In some embodiments, the crystalline form is form A, and the XRPD plot has peaks at 10.7, 20.5, 19.5, 21.6, 18.8, 12.4, 22.5, 15.5, 21.2, 15.9, 16.3, 23.2, 20.9, and 13.6 (± 0.2 degrees 2θ).

[0119] In some embodiments, the crystalline form is form A, and the XRPD plot has peaks at 10.7, 20.5, 19.5, 21.6, 18.8, 12.4, 22.5, 15.5, 21.2, 15.9, 16.3, 23.2, 20.9, 13.6, and 5.3 (± 0.2 degrees 2θ).

[0120] Those skilled in the art will recognize that the relative intensities of peaks in an X-ray powder diffraction pattern can vary depending on sample preparation techniques, crystal size distributions, the various filters used, sample preparation procedures, and the specific instrument employed. Therefore, depending on the type of instrument and the settings employed (including filters), new peaks may be observed in subsequently obtained patterns; or peaks observed in previously obtained patterns may have negligible relative intensities in subsequently obtained patterns (and thus may not be observed). Thus, the absence of one or more of the lower relative intensity peaks described above does not in itself determine the absence of form A (e.g., in the sample). However, the presence of the lower relative intensity peaks described above is generally useful for further determining the presence of form A in the sample.

[0121] Form A may also have one or more of the following characteristics.

[0122] In some embodiments, the crystalline form is form A with a thermogravimetric analysis (TGA) curve characterized by a weight loss of about 0.5% to about 4% (e.g., about 1% to about 3%, or about 2%) at about 150°C to about 220°C (e.g., about 150°C to about 190°C, about 165°C to about 205°C, about 170°C to about 220°C, about 180°C to about 200°C, about 185°C to about 195°C, about 187°C to about 191°C, or about 189°C). In some embodiments, the crystalline form is form A with a thermogravimetric analysis (TGA) curve characterized by a weight loss of about 2% at about 189°C.

[0123] In some embodiments, the crystalline form is form A with a TGA curve characterized by a weight loss of about 15% to about 35% (e.g., about 20% to about 27%, about 23% to about 35%, about 20% to about 30%, or about 23% to about 25%) at about 270°C to about 330°C (e.g., about 280°C to about 320°C, about 290°C to about 310°C, about 295°C to about 305°C, or about 300°C). In some embodiments, the crystalline form is form A with a TGA curve characterized by a weight loss of about 25% at about 300°C.

[0124] In some embodiments, the crystalline form is having the same Figure 3 The TGA curve shown is essentially the same as form A.

[0125] In some embodiments, the crystalline form is having the same Figure 7 The TGA curve shown is essentially the same as form A.

[0126] In some embodiments, the crystalline form is form A with a differential scanning calorimetry (DSC) curve characterized by a melting initiation (endothermic) of about 185°C to about 220°C, about 190°C to about 215°C, about 195°C to about 208°C, about 198°C to about 207°C, about 200°C to about 204°C, about 201°C to about 203°C, or about 201.9°C. In some embodiments, the crystalline form is form A with a differential scanning calorimetry (DSC) curve characterized by a melting initiation (endothermic) of about 201.9°C.

[0127] In some embodiments, the crystalline form is having the same Figure 4 The form A of the DSC curve shown is essentially the same.

[0128] In some embodiments, the crystalline form is having the same Figure 6 The form A of the DSC curve shown is essentially the same.

[0129] In some embodiments, the TGA plot of Form A shows a weight loss of approximately 0.51% at 150°C when heated from 30°C to 300°C at a rate of 10 K / min.

[0130] In some embodiments, Form A absorbs up to 0.45% moisture via DVS at 25°C and 95% RH.

[0131] In some embodiments, the crystalline form is form A, characterized by a solubility of about 1.8 mg / mL to about 2.8 mg / mL (e.g., about 1.8 mg / mL, about 1.9 mg / mL, about 2.0 mg / mL, about 2.1 mg / mL, about 2.2 mg / mL, about 2.3 mg / mL, about 2.4 mg / mL, about 2.5 mg / mL, about 2.6 mg / mL, about 2.7 mg / mL, about 2.8 mg / mL, or any value between these) in fasting-state simulated gastric juice (FaSSGF) at about 37°C after about 30 minutes. In some embodiments, form A is characterized by a solubility of about 2.2 mg / mL to about 2.5 mg / mL in fasting-state simulated gastric juice (FaSSGF) at about 37°C after about 30 minutes. In some embodiments, form A is characterized by a solubility of 2.2 mg / mL to 2.5 mg / mL in fasting-state simulated gastric juice (FaSSGF) at about 37°C after about 30 minutes. In some embodiments, form A is characterized by a solubility of about 2.3 mg / mL in fasting-state simulated gastric juice (FaSSGF) at about 37°C after about 30 minutes.

[0132] In some embodiments, the crystalline form is form A, characterized by a solubility in fasting-state simulated gastric juice (FaSSGF) at about 37°C for about 24 hours from a value greater than about 1.7 mg / mL to a value greater than about 2 mg / mL (e.g., greater than about 1.7 mg / mL, greater than about 1.8 mg / mL, greater than about 1.9 mg / mL, or greater than about 2.0 mg / mL, such as about 2.1 mg / mL, about 2.2 mg / mL, about 2.3 mg / mL, about 2.4 mg / mL, about 2.5 mg / mL, about 2.6 mg / mL, about 2.7 mg / mL, about 2.8 mg / mL, about 2.9 mg / mL, or about 3.0 mg / mL). In some embodiments, form A is characterized by a solubility in fasting-state simulated gastric juice (FaSSGF) at about 37°C for about 24 hours from a value greater than about 1.8 mg / mL to a value greater than about 1.9 mg / mL. In some embodiments, form A is characterized by having a solubility greater than about 1.9 mg / mL to greater than about 2 mg / mL in fasting-state simulated gastric juice (FaSSGF) at about 37°C after about 24 hours. In some embodiments, form A is characterized by having a solubility greater than about 2 mg / mL in fasting-state simulated gastric juice (FaSSGF) at about 37°C after about 24 hours.

[0133] In some embodiments, the crystalline form is form A, characterized by having a solubility greater than 2 mg / mL in fasting simulated gastric juice (FaSSGF) at about 25°C and an initial pH of 1.6 after about 24 hours.

[0134] In some embodiments, the crystalline form is form A, characterized by a solubility of about 0.26 mg / mL to about 0.36 mg / mL (e.g., about 0.26 mg / mL, about 0.27 mg / mL, about 0.28 mg / mL, about 0.29 mg / mL, about 0.30 mg / mL, about 0.31 mg / mL, about 0.32 mg / mL, about 0.33 mg / mL, about 0.34 mg / mL, about 0.35 mg / mL, about 0.36 mg / mL, or any value between these) in a fed-state simulated intestinal fluid (FeSSIF) at about 37°C after about 30 minutes. In some embodiments, form A is characterized by a solubility of about 0.29 mg / mL to about 0.33 mg / mL in a fed-state simulated intestinal fluid (FeSSIF) at about 37°C after about 30 minutes. In some embodiments, form A is characterized by having a solubility of 0.30 mg / mL to 0.32 mg / mL in a fed-state simulated intestinal fluid (FeSSIF) at about 37°C after about 30 minutes. In some embodiments, form A is characterized by having a solubility of about 0.31 mg / mL in a fed-state simulated intestinal fluid (FeSSIF) at about 37°C after about 30 minutes.

[0135] In some embodiments, the crystalline form is form A, characterized by a solubility of about 0.26 mg / mL to about 0.36 mg / mL (e.g., about 0.26 mg / mL, about 0.27 mg / mL, about 0.28 mg / mL, about 0.29 mg / mL, about 0.30 mg / mL, about 0.31 mg / mL, about 0.32 mg / mL, about 0.33 mg / mL, about 0.34 mg / mL, about 0.35 mg / mL, about 0.36 mg / mL, or any value between these) in a fed-state simulated intestinal fluid (FeSSIF) at about 37°C after about 24 hours. In some embodiments, form A is characterized by a solubility of about 0.30 mg / mL to about 0.32 mg / mL in a fed-state simulated intestinal fluid (FeSSIF) at about 37°C after about 24 hours. In some embodiments, form A is characterized by having a solubility of 0.30 mg / mL to 0.32 mg / mL in a fed-state simulated intestinal fluid (FeSSIF) at about 37°C after about 24 hours. In some embodiments, form A is characterized by having a solubility of about 0.31 mg / mL in a fed-state simulated intestinal fluid (FeSSIF) at about 37°C after about 24 hours.

[0136] In some embodiments, the crystalline form is form A, characterized by a solubility of about 0.18 mg / mL to about 0.28 mg / mL (e.g., about 0.18 mg / mL, about 0.19 mg / mL, about 0.20 mg / mL, about 0.21 mg / mL, about 0.22 mg / mL, about 0.23 mg / mL, about 0.24 mg / mL, about 0.25 mg / mL, about 0.26 mg / mL, about 0.27 mg / mL, about 0.28 mg / mL, or any value between these) in a fasting-state simulated intestinal fluid (FaSSIF) at about 37°C after about 30 minutes. In some embodiments, form A is characterized by a solubility of about 0.20 mg / mL to about 0.26 mg / mL in a fasting-state simulated intestinal fluid (FaSSIF) at about 37°C after about 30 minutes. In some embodiments, form A is characterized by having a solubility of 0.23 mg / mL to 0.25 mg / mL in fasting-state simulated intestinal fluid (FaSSIF) at about 37°C after about 30 minutes. In some embodiments, the crystalline form is form A, characterized by having a solubility of about 0.24 mg / mL in fasting-state simulated intestinal fluid (FaSSIF) at about 37°C after about 30 minutes.

[0137] In some embodiments, the crystalline form is form A, characterized by a solubility of about 0.13 mg / mL to about 0.23 mg / mL (e.g., about 0.13 mg / mL, about 0.14 mg / mL, about 0.15 mg / mL, about 0.16 mg / mL, about 0.17 mg / mL, about 0.18 mg / mL, about 0.19 mg / mL, about 0.20 mg / mL, about 0.21 mg / mL, about 0.22 mg / mL, about 0.23 mg / mL, or any value between these) in a fasting-state simulated intestinal fluid (FaSSIF) at about 37°C after about 24 hours. In some embodiments, form A is characterized by a solubility of about 0.15 mg / mL to about 0.20 mg / mL in a fasting-state simulated intestinal fluid (FaSSIF) at about 37°C after about 24 hours. In some embodiments, form A is characterized by having a solubility of 0.17 mg / mL to 0.19 mg / mL in fasting-state simulated intestinal fluid (FaSSIF) at about 37°C after about 24 hours. In some embodiments, the crystalline form is form A, characterized by having a solubility of about 0.18 mg / mL in fasting-state simulated intestinal fluid (FaSSIF) at about 37°C after about 24 hours.

[0138] In some embodiments, the crystalline form is form A, characterized by a solubility of about 0.07 mg / mL in a fasting-state simulated intestinal fluid (FaSSIF) with an initial pH of 6.5 at about 25°C after about 24 hours. In some embodiments, the fasting-state simulated intestinal fluid (FaSSIF) comprises phosphate-buffered saline (PBS).

[0139] In some embodiments, the crystalline form is form A, characterized by a solubility of about 0.07 mg / mL in phosphate-buffered saline (PBS) at about 25°C and an initial pH of 6.5 after about 24 hours. In some embodiments, the phosphate-buffered saline (PBS) contains sodium taurocholate (NaTC). In some embodiments, the phosphate-buffered saline (PBS) contains 3 mM sodium taurocholate (NaTC).

[0140] In some embodiments, the crystalline form is form A, characterized by a solubility of about 0.16 mg / mL to about 0.26 mg / mL (e.g., about 0.16 mg / mL, about 0.17 mg / mL, about 0.18 mg / mL, about 0.19 mg / mL, about 0.20 mg / mL, about 0.21 mg / mL, about 0.22 mg / mL, about 0.23 mg / mL, about 0.24 mg / mL, about 0.25 mg / mL, about 0.26 mg / mL, or any value between these) in water at about 37°C and an initial pH of about 7.0 after about 30 minutes. In some embodiments, form A is characterized by a solubility of about 0.17 mg / mL to about 0.23 mg / mL in water at about 37°C and an initial pH of about 7.0 after about 30 minutes. In some embodiments, form A is characterized by having a solubility of 0.20 mg / mL to 0.22 mg / mL in water at about 37°C and an initial pH of about 7.0 after about 30 minutes. In some embodiments, the crystalline form is form A, characterized by having a solubility of about 0.21 mg / mL in water at about 37°C and an initial pH of about 7.0 after about 30 minutes.

[0141] In some embodiments, the crystalline form is form A, characterized by a solubility of about 0.17 mg / mL to about 0.27 mg / mL (e.g., about 0.17 mg / mL, about 0.18 mg / mL, about 0.19 mg / mL, about 0.20 mg / mL, about 0.21 mg / mL, about 0.22 mg / mL, about 0.23 mg / mL, about 0.24 mg / mL, about 0.25 mg / mL, about 0.26 mg / mL, about 0.27 mg / mL, or any value between these) in water at about 37°C and an initial pH of about 7.0 after about 24 hours. In some embodiments, form A is characterized by a solubility of about 0.20 mg / mL to about 0.24 mg / mL in water at about 37°C and an initial pH of about 7.0 after about 30 minutes. In some embodiments, form A is characterized by having a solubility of 0.20 mg / mL to 0.23 mg / mL in water at about 37°C and an initial pH of about 7.0 after about 30 minutes. In some embodiments, the crystalline form is form A, characterized by having a solubility of about 0.22 mg / mL in water at about 37°C and an initial pH of about 7.0 after about 24 hours.

[0142] In some embodiments, the crystalline form is form A, characterized by having a solubility of about 0.05 mg / mL in water at about 25°C and an initial pH of about 7.0 after 24 hours.

[0143] In some embodiments, the crystalline form is form A in a substantially pure form. In some embodiments, the crystalline form is form A, wherein form A is at least 99%, 99.3%, 99.5%, 99.7%, or 99.9% pure (w / w). In some embodiments, the crystalline form is form A, wherein form A is at least 99%, 99.3%, 99.5%, 99.7%, or 99.9% pure (w / w) after being exposed to about 10% relative humidity at about 50°C for one week. In some embodiments, the crystalline form is form A, wherein form A is at least 99%, 99.3%, 99.5%, 99.7%, or 99.9% pure (w / w) after being exposed to about 10% relative humidity at about 80°C for one week. In some embodiments, the crystalline form is form A, wherein form A is at least 99%, 99.3%, 99.5%, 99.7%, or 99.9% pure (w / w) after being exposed to about 75% relative humidity at about 50°C for one week. In some embodiments, the crystalline form is form A, wherein form A is at least 99%, 99.3%, 99.5%, 99.7%, or 99.9% pure (w / w) after being exposed to about 75% relative humidity at about 80°C for 1 week.

[0144] Form B This disclosure provides ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H -indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid p-toluenesulfonate (Formula II). The term "(S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid p-toluenesulfonate" p -toluene sulfonate) and (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid p-toluenesulfonate ( p "-toluene sulfonic acid salt" can be used interchangeably in this article.

[0145] II This disclosure provides ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H The crystalline form of p-toluenesulfonate of (-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid (referred to herein as form B). In some embodiments, form B comprises water, wherein the amount of water is 0% to 2.7% w / w relative to the total weight of form B. The water content may vary depending on drying conditions and ambient humidity. In some embodiments, the amount of water is 1.5% to 2.5% w / w under ambient conditions. In some embodiments, the amount of water is 1.5% to 2% w / w under ambient conditions.

[0146] Form B is a highly crystalline form with a thick, plate-like morphology. Form B is likely a non-stoichiometric hydrate form, characterized by channel hydrates and exhibiting reversible water adsorption and desorption behavior without hysteresis. The XRPD plot of form B remains unchanged under a wide range of conditions, including ambient humidity and temperature.

[0147] In some embodiments, the crystalline form is form B, and the XRPD diagram is consistent with... Figure 12 The two are essentially the same.

[0148] In some embodiments, the crystalline form is form B, and the XRPD diagram is consistent with... Figure 15 The two are essentially the same.

[0149] In some embodiments, the crystalline form is form B, and the XRPD plot is represented by the peaks shown in the table below:

[0150] In some embodiments, the crystalline form is characterized by an XRPD pattern with a peak at 11.8 ± 0.2 degrees 2θ. The X-ray powder diffraction pattern of form B may also include one or more additional characteristic peaks.

[0151] In some embodiments, the X-ray powder diffraction pattern of form B may also include one or more of the following additional characteristic peaks, which may also be used to identify (e.g., in a sample) form B.

[0152] For example, the XRPD plot has a peak at 9.3 ± 0.2 degrees 2θ.

[0153] For example, the XRPD plot has a peak at 19.9 ± 0.2 degrees 2θ.

[0154] For example, the XRPD plot has a peak at 22.9 ± 0.2 degrees 2θ.

[0155] For example, the XRPD plot has a peak at 17.2 ± 0.2 degrees 2θ.

[0156] For example, the XRPD plot has a peak at 10.2 ± 0.2 degrees 2θ.

[0157] For example, the XRPD plot has a peak at 20.4 ± 0.2 degrees 2θ.

[0158] For example, the XRPD plot has a peak at 21.3 ± 0.2 degrees 2θ.

[0159] For example, the XRPD plot has a peak at 14.2 ± 0.2 degrees 2θ.

[0160] Form B X-ray powder diffraction patterns may also include one or more lower intensity characteristic peaks. The relative intensities of these additional peaks are typically lower than the relative intensities associated with the characteristic peaks described above.

[0161] For example, the XRPD plot has a peak at 18.2 ± 0.2 degrees 2θ.

[0162] For example, the XRPD plot has a peak at 20.7 ± 0.2 degrees 2θ.

[0163] For example, the XRPD plot has a peak at 15.4 ± 0.2 degrees 2θ.

[0164] For example, the XRPD plot has a peak at 24.4 ± 0.2 degrees 2θ.

[0165] For example, the XRPD plot has a peak at 20.2 ± 0.2 degrees 2θ.

[0166] For example, the XRPD plot has a peak at 23.7 ± 0.2 degrees 2θ.

[0167] For example, the XRPD plot has a peak at 15.3 ± 0.2 degrees 2θ.

[0168] For example, the XRPD plot has a peak at 25.2 ± 0.2 degrees 2θ.

[0169] For example, the XRPD plot has a peak at 18.7 ± 0.2 degrees 2θ.

[0170] For example, the XRPD plot has a peak at 18.5 ± 0.2 degrees 2θ.

[0171] For example, the XRPD plot has a peak at 16.9 ± 0.2 degrees 2θ.

[0172] For example, the XRPD plot has a peak at 13.8 ± 0.2 degrees 2θ.

[0173] In some embodiments, the crystalline form is form B, and the XRPD plot has peaks at 11.8, 9.3, and 19.9 (± 0.2 degrees 2θ).

[0174] In some embodiments, the crystalline form is form B, and the XRPD plot has peaks at 11.8, 9.3, 19.9, and 22.9 (± 0.2 degrees 2θ).

[0175] In some embodiments, the crystalline form is form B, and the XRPD plot has peaks at 11.8, 9.3, 19.9, 22.9, 17.2, 10.2, 20.4, 21.3, and 14.2 (±0.2 degrees 2θ).

[0176] In some embodiments, the crystalline form is form B, and the XRPD plot has peaks at 11.8, 9.3, 19.9, 22.9, 17.2, 10.2, 20.4, 21.3, 14.2, 18.2, 20.7, 15.4, 24.4, 20.2, 23.7, 15.3, 25.2, 18.7, 18.5, 16.9, and 13.8 (±0.2 degrees 2θ).

[0177] In some embodiments, the crystalline form is form B, and the XRPD plot has a peak at 11.7 (± 0.2 degrees 2θ).

[0178] In some embodiments, the crystalline form is form B, and the XRPD plot has peaks at 11.7 and 19.9 (± 0.2 degrees 2θ).

[0179] In some embodiments, the crystalline form is form B, and the XRPD plot has peaks at 11.7, 19.9, and 9.3 (± 0.2 degrees 2θ).

[0180] In some embodiments, the crystalline form is form B, and the XRPD plot has peaks at 11.7, 19.9, and 9.3 (± 0.2 degrees 2θ).

[0181] In some embodiments, the crystalline form is form B, and the XRPD plot has peaks at 11.7, 19.9, 9.3, and 10.1 (± 0.2 degrees 2θ).

[0182] In some embodiments, the crystalline form is form B, and the XRPD plot has peaks at 11.7, 19.9, 9.3, 10.1, and 22.9 (± 0.2 degrees 2θ).

[0183] In some embodiments, the crystalline form is form B, and the XRPD plot has peaks at 11.7, 19.9, 9.3, 10.1, 22.9, and 17.2 (± 0.2 degrees 2θ).

[0184] In some embodiments, the crystalline form is form B, and the XRPD plot has peaks at 11.7, 19.9, 9.3, 10.1, 22.9, 17.2, and 20.4 (± 0.2 degrees 2θ).

[0185] In some embodiments, the crystalline form is form B, and the XRPD plot has peaks at 11.7, 19.9, 9.3, 10.1, 22.9, 17.2, 20.4, and 14.2 (± 0.2 degrees 2θ).

[0186] In some embodiments, the crystalline form is form B, and the XRPD plot has peaks at 11.7, 19.9, 9.3, 10.1, 22.9, 17.2, 20.4, 14.2, and 21.3 (± 0.2 degrees 2θ).

[0187] In some embodiments, the crystalline form is form B, and the XRPD plot has peaks at 11.7, 19.9, 9.3, 10.1, 22.9, 17.2, 20.4, 14.2, 21.3, and 18.2 (± 0.2 degrees 2θ).

[0188] In some embodiments, the crystalline form is form B, and the XRPD plot has peaks at 11.7, 19.9, 9.3, 10.1, 22.9, 17.2, 20.4, 14.2, 21.3, 18.2, and 25.5 (± 0.2 degrees 2θ).

[0189] In some embodiments, the crystalline form is form B, and the XRPD plot has peaks at 11.7, 19.9, 9.3, 10.1, 22.9, 17.2, 20.4, 14.2, 21.3, 18.2, 25.5, and 15.4 (± 0.2 degrees 2θ).

[0190] In some embodiments, the crystalline form is form B, and the XRPD plot has peaks at 11.7, 19.9, 9.3, 10.1, 22.9, 17.2, 20.4, 14.2, 21.3, 18.2, 25.5, 15.4, and 20.7 (± 0.2 degrees 2θ).

[0191] In some embodiments, the crystalline form is form B, and the XRPD plot has peaks at 11.7, 19.9, 9.3, 10.1, 22.9, 17.2, 20.4, 14.2, 21.3, 18.2, 25.5, 15.4, 20.7, and 27.6 (± 0.2 degrees 2θ).

[0192] In some embodiments, the crystalline form is form B, and the XRPD plot has peaks at 11.7, 19.9, 9.3, 10.1, 22.9, 17.2, 20.4, 14.2, 21.3, 18.2, 25.5, 15.4, 20.7, 27.6, and 24.4 (± 0.2 degrees 2θ).

[0193] When the humidity decreased from 30% RH to 0% RH and then back to 30% RH, the variable humidity XRPD of form B showed a reversible peak shift. The XRPD plot of form B remained almost unchanged between 30% RH and 90% RH. When form B was exposed to low humidity conditions, only minor differences in the XRPD plot were observed, but these plots could also be explained by the crystal structure of form B (hta02a). This suggests that the dehydrated form can be an isomorphic or isomorphic phase of form B.

[0194] Those skilled in the art will recognize that the relative intensities of peaks in an X-ray powder diffraction pattern can vary depending on sample preparation techniques, crystal size distribution, the various filters used, sample installation procedures, and the specific instrument employed. Therefore, depending on the type of instrument and the settings employed (including filters), new peaks may be observed in subsequently obtained patterns; or peaks observed in previously obtained patterns may have negligible relative intensities in subsequently obtained patterns (and thus may not be observed). Thus, the absence of one or more of the lower relative intensity peaks described above does not in itself determine the absence of form B (e.g., in the sample). However, the presence of the lower relative intensity peaks described above is generally useful for further determining the presence of form B in the sample.

[0195] Form B may also have one or more of the following characteristics.

[0196] In some embodiments, the crystalline form is form B with a TGA curve characterized by a weight loss of about 0.5% to about 10% at about 60°C to about 100°C (e.g., about 0.5% to about 8%, about 0.5% to about 6%, about 0.5% to about 4%, about 0.5% to about 3%, about 0.5% to about 2%, about 0.5% to about 1.5%, or about 1%). In some embodiments, the crystalline form is form B with a TGA curve characterized by a weight loss of about 1% at about 60°C to about 100°C.

[0197] In some embodiments, the crystalline form is having the same Figure 13 The form B of the TGA curve shown is essentially the same.

[0198] In some embodiments, the crystalline form is having the same Figure 17 The form B of the TGA curve shown is essentially the same.

[0199] In some embodiments, the crystalline form is having the same Figure 14 The form B of the DSC curve shown is essentially the same.

[0200] In some embodiments, the crystalline form is having the same Figure 16 The form B of the DSC curve shown is essentially the same.

[0201] In some embodiments, form B has a DSC thermogram characterized in that when heated from 30°C to 300°C at a rate of 10 K / min, at T 起始 = 29.8℃ and T 峰 = A broad endothermic peak at 65℃.

[0202] In some embodiments, form B has a DSC thermogram showing the temperature at T when heated from 30°C to 300°C at a rate of 10 K / min. 起始 = 29.8℃ (enthalpy of 41.9 J / g) and T 峰 = A broad endothermic peak at 65℃.

[0203] In some embodiments, the TGA plot of Form B shows a weight loss of approximately 1.9% to 2.0% at 100°C when heated from 30°C to 300°C at 10 K / min.

[0204] In some embodiments, form B absorbs up to 2.7% moisture via DVS at 25°C and 95% RH. In some embodiments, the crystalline form is form B in a substantially pure form. In some embodiments, the crystalline form is form B, wherein form B is at least 99%, 99.3%, 99.5%, 99.7%, or 99.9% pure (w / w). In some embodiments, the crystalline form is form B, wherein form B is at least 99%, 99.3%, 99.5%, 99.7%, or 99.9% pure (w / w) after being exposed to about 10% relative humidity for 1 week at about 50°C. In some embodiments, the crystalline form is form B, wherein form B is at least 99%, 99.3%, 99.5%, 99.7%, or 99.9% pure (w / w) after being exposed to about 10% relative humidity for 1 week at about 80°C. In some embodiments, the crystalline form is form B, wherein form B is at least 99%, 99.3%, 99.5%, 99.7%, or 99.9% pure (w / w) after exposure to about 75% relative humidity at about 50°C for one week. In some embodiments, the crystalline form is form B, wherein form B is at least 99%, 99.3%, 99.5%, 99.7%, or 99.9% pure (w / w) after exposure to about 75% relative humidity at about 80°C for one week.

[0205] In some embodiments, the crystalline form is form B, characterized by a solubility of about 0.32 mg / mL to about 0.45 mg / mL (e.g., about 0.32 mg / mL, about 0.33 mg / mL, about 0.34 mg / mL, about 0.35 mg / mL, about 0.36 mg / mL, about 0.37 mg / mL, about 0.38 mg / mL, about 0.39 mg / mL, about 0.40 mg / mL, about 0.41 mg / mL, about 0.42 mg / mL, about 0.43 mg / mL, about 0.44 mg / mL, about 0.45 mg / mL, or any value between these) in fasting simulated gastric juice (FaSSGF) at about 37°C after about 30 minutes. In some embodiments, form B is characterized by a solubility of about 0.36 mg / mL to about 0.42 mg / mL in fasting simulated gastric juice (FaSSGF) at about 37°C after about 30 minutes. In some embodiments, the crystalline form is form B, characterized by a solubility of 0.39 mg / mL to 0.41 mg / mL in fasting-state simulated gastric juice (FaSSGF) at about 37°C after about 30 minutes. In some embodiments, the crystalline form is form B, characterized by a solubility of about 0.40 mg / mL in fasting-state simulated gastric juice (FaSSGF) at about 37°C after about 30 minutes.

[0206] In some embodiments, the crystalline form is form B, characterized by a solubility of about 0.49 mg / mL to about 0.59 mg / mL (e.g., about 0.49 mg / mL, about 0.50 mg / mL, about 0.51 mg / mL, about 0.52 mg / mL, about 0.53 mg / mL, about 0.54 mg / mL, about 0.55 mg / mL, about 0.56 mg / mL, about 0.57 mg / mL, about 0.58 mg / mL, about 0.59 mg / mL, or any value between these) in fasting-state simulated gastric juice (FaSSGF) at about 37°C after about 24 hours. In some embodiments, form B is characterized by a solubility of about 0.50 mg / mL to about 0.56 mg / mL in fasting-state simulated gastric juice (FaSSGF) at about 37°C after about 24 hours. In some embodiments, the crystalline form is form B, characterized by a solubility of 0.53 mg / mL to 0.55 mg / mL in fasting-state simulated gastric juice (FaSSGF) at about 37°C after about 24 hours. In some embodiments, the crystalline form is form B, characterized by a solubility of about 0.54 mg / mL in fasting-state simulated gastric juice (FaSSGF) at about 37°C after about 24 hours.

[0207] In some embodiments, the crystalline form is form B, characterized by a solubility of about 0.45 mg / mL to about 0.52 mg / mL (e.g., about 0.49 mg / mL) in fasting simulated gastric juice (FaSSGF) at an initial pH of 1.6 at about 25°C after about 24 hours.

[0208] In some embodiments, the crystalline form is form B, characterized by a solubility greater than about 1.5 mg / mL to greater than about 2 mg / mL (e.g., greater than about 1.6 mg / mL, greater than about 1.7 mg / mL, greater than about 1.8 mg / mL, greater than about 1.9 mg / mL, or greater than about 2 mg / mL) in a fed-state simulated intestinal fluid (FeSSIF) at about 37°C after about 30 minutes. In some embodiments, the crystalline form is form B, characterized by a solubility greater than about 2 mg / mL in a fed-state simulated intestinal fluid (FeSSIF) at about 37°C after about 30 minutes.

[0209] In some embodiments, the crystalline form is form B, characterized by a solubility greater than about 1.5 mg / mL to greater than about 2 mg / mL (e.g., greater than about 1.6 mg / mL, greater than about 1.7 mg / mL, greater than about 1.8 mg / mL, greater than about 1.9 mg / mL, or greater than about 2 mg / mL) in a fed-state simulated intestinal fluid (FeSSIF) at about 37°C after about 24 hours. In some embodiments, the crystalline form is form B, characterized by a solubility greater than about 2 mg / mL in a fed-state simulated intestinal fluid (FeSSIF) at about 37°C after about 24 hours.

[0210] In some embodiments, the crystalline form is form B, characterized by a solubility greater than about 1.5 mg / mL to greater than about 2 mg / mL (e.g., greater than about 1.5 mg / mL, greater than about 1.6 mg / mL, greater than about 1.7 mg / mL, greater than about 1.8 mg / mL, greater than about 1.9 mg / mL, or greater than about 2 mg / mL) in a fasting-state simulated intestinal fluid (FaSSIF) at about 37°C after about 30 minutes. In some embodiments, form B is characterized by a solubility greater than 1.8 mg / mL to greater than 1.9 mg / mL in a fasting-state simulated intestinal fluid (FaSSIF) at about 37°C after about 30 minutes. In some embodiments, form B is characterized by a solubility greater than about 2 mg / mL in a fasting-state simulated intestinal fluid (FaSSIF) at about 37°C after about 30 minutes.

[0211] In some embodiments, the crystalline form is form B, characterized by a solubility of about 0.48 mg / mL to about 0.58 mg / mL (e.g., about 0.48 mg / mL, about 0.49 mg / mL, about 0.50 mg / mL, about 0.51 mg / mL, about 0.52 mg / mL, about 0.53 mg / mL, about 0.54 mg / mL, about 0.55 mg / mL, about 0.56 mg / mL, about 0.57 mg / mL, about 0.58 mg / mL, or any value between these) in a fasting-state simulated intestinal fluid (FaSSIF) at about 37°C after about 24 hours. In some embodiments, form B is characterized by a solubility of about 0.51 mg / mL to about 0.54 mg / mL in a fasting-state simulated intestinal fluid (FaSSIF) at about 37°C after about 24 hours. In some embodiments, form B is characterized by a solubility of 0.52 mg / mL to 0.54 mg / mL in fasting-state simulated intestinal fluid (FaSSIF) at about 37°C after about 24 hours. In some embodiments, the crystalline form is form B, characterized by a solubility of about 0.53 mg / mL in fasting-state simulated intestinal fluid (FaSSIF) at about 37°C after about 24 hours.

[0212] In some embodiments, the crystalline form is form B, characterized by a solubility greater than 2 mg / mL in fasting-state simulated intestinal fluid (FaSSIF) at an initial pH of 6.5 at about 25°C after about 24 hours. In some embodiments, the fasting-state simulated intestinal fluid (FaSSIF) comprises phosphate-buffered saline (PBS).

[0213] In some embodiments, the crystalline form is form B, characterized by a solubility greater than 2 mg / mL in phosphate-buffered saline (PBS) at an initial pH of 6.5 at about 25°C after about 24 hours. In some embodiments, the phosphate-buffered saline (PBS) contains sodium taurocholate (NaTC). In some embodiments, the phosphate-buffered saline (PBS) contains 3 mM sodium taurocholate (NaTC).

[0214] In some embodiments, the crystalline form is form B, characterized by a solubility of about 0.42 mg / mL to about 0.51 mg / mL (e.g., about 0.42 mg / mL, about 0.43 mg / mL, about 0.44 mg / mL, about 0.45 mg / mL, about 0.46 mg / mL, about 0.47 mg / mL, about 0.48 mg / mL, about 0.49 mg / mL, about 0.50 mg / mL, about 0.51 mg / mL, or any value between these) in water at about 37°C and an initial pH of about 7.0 after about 30 minutes. In some embodiments, form B is characterized by a solubility of about 0.46 mg / mL to about 0.50 mg / mL in water at about 37°C and an initial pH of about 7.0 after about 30 minutes. In some embodiments, form B is characterized by a solubility of 0.47 mg / mL to 0.49 mg / mL in water at about 37°C and an initial pH of about 7.0 after about 30 minutes. In some embodiments, the crystalline form is form B, characterized by a solubility of about 0.48 mg / mL in water at about 37°C and an initial pH of about 7.0 after about 30 minutes.

[0215] In some embodiments, the crystalline form is form B, characterized by a solubility in water at about 37°C for about 24 hours of osmosis of about 0.51 mg / mL to about 0.61 mg / mL (e.g., about 0.51 mg / mL, about 0.52 mg / mL, about 0.53 mg / mL, about 0.54 mg / mL, about 0.55 mg / mL, about 0.56 mg / mL, about 0.57 mg / mL, about 0.58 mg / mL, about 0.59 mg / mL, about 0.60 mg / mL, about 0.61 mg / mL, or any value between these values). In some embodiments, form B is characterized by a solubility in water at about 37°C and an initial pH of about 7.0 for about 24 hours of osmosis of about 0.53 mg / mL to about 0.58 mg / mL. In some embodiments, form B is characterized by a solubility in water at about 37°C and an initial pH of about 7.0 for about 24 hours of osmosis of 0.55 mg / mL to 0.57 mg / mL. In some embodiments, the crystalline form is form B, characterized by a solubility of about 0.56 mg / mL in water at about 37°C after about 24 hours.

[0216] In some embodiments, the crystalline form is form B, characterized by a solubility of about 0.38 mg / mL to about 0.42 mg / mL (e.g., about 0.39 mg / mL) in water at about 25°C and an initial pH of about 7.0 after 24 hours.

[0217] In some embodiments, the crystalline form is form B, characterized by having a concentration of approximately 0.15 mg / min / cm³ in a buffer solution at pH 6.5. 2 To approximately 0.2 mg / min / cm 2 (For example, 0.18 mg / min / cm) 2 The inherent dissolution rate of ). In some embodiments, the buffer is a phosphate buffer.

[0218] Form C Some embodiments provide ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H The p-toluenesulfonate crystalline form of (-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid. In some embodiments, ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H The p-toluenesulfonate form of (-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid is an anhydrous form. In some embodiments, the crystalline form is characterized by an XRPD pattern with a peak at 22.3 ± 0.2 degrees 2θ. For ease of interpretation, the aforementioned polymorph is referred to herein as "Form C". The X-ray powder diffraction pattern of Form C may also include one or more additional characteristic peaks.

[0219] In some embodiments, the crystalline form is form C, and the XRPD plot is represented by the peaks shown in the table below:

[0220] In some embodiments, the crystalline form is form C, and the XRPD plot is consistent with... Figure 23 The two are essentially the same.

[0221] In some embodiments, the X-ray powder diffraction pattern of form C may also include one or more of the following additional characteristic peaks, which may also be used to identify (e.g., in a sample) form C.

[0222] For example, the XRPD plot has a peak at 17.3 ± 0.2 degrees 2θ.

[0223] For example, the XRPD plot has a peak at 17.5 ± 0.2 degrees 2θ.

[0224] For example, the XRPD plot has a peak at 21.8 ± 0.2 degrees 2θ.

[0225] For example, the XRPD plot has a peak at 11.5 ± 0.2 degrees 2θ.

[0226] For example, the XRPD plot has a peak at 15.3 ± 0.2 degrees 2θ.

[0227] For example, the XRPD plot has a peak at 10.2 ± 0.2 degrees 2θ.

[0228] For example, the XRPD plot has a peak at 10.7 ± 0.2 degrees 2θ.

[0229] For example, the XRPD plot has a peak at 26.6 ± 0.2 degrees 2θ.

[0230] The X-ray powder diffraction pattern of form C may also include one or more lower intensity characteristic peaks. The relative intensities of these additional peaks are generally lower than the relative intensities associated with the characteristic peaks described above.

[0231] For example, the XRPD plot has a peak at 19.8 ± 0.2 degrees 2θ.

[0232] For example, the XRPD plot has a peak at 5.3 ± 0.2 degrees 2θ.

[0233] For example, the XRPD plot has a peak at 11.3 ± 0.2 degrees 2θ.

[0234] For example, the XRPD plot has a peak at 19.7 ± 0.2 degrees 2θ.

[0235] For example, the XRPD plot has a peak at 18.6 ± 0.2 degrees 2θ.

[0236] For example, the XRPD plot has a peak at 24.7 ± 0.2 degrees 2θ.

[0237] For example, the XRPD plot has a peak at 24.1 ± 0.2 degrees 2θ.

[0238] For example, the XRPD plot has a peak at 20.4 ± 0.2 degrees 2θ.

[0239] For example, the XRPD plot has a peak at 18.2 ± 0.2 degrees 2θ.

[0240] For example, the XRPD plot has a peak at 25.6 ± 0.2 degrees 2θ.

[0241] For example, the XRPD plot has a peak at 21.5 ± 0.2 degrees 2θ.

[0242] For example, the XRPD plot has a peak at 13.3 ± 0.2 degrees 2θ.

[0243] For example, the XRPD plot has a peak at 19.1 ± 0.2 degrees 2θ.

[0244] For example, the XRPD plot has a peak at 9.5 ± 0.2 degrees 2θ.

[0245] For example, the XRPD plot has a peak at 13.6 ± 0.2 degrees 2θ.

[0246] For example, the XRPD plot has a peak at 27.3 ± 0.2 degrees 2θ.

[0247] For example, the XRPD plot has a peak at 19.4 ± 0.2 degrees 2θ.

[0248] For example, the XRPD plot has a peak at 16.3 ± 0.2 degrees 2θ.

[0249] For example, the XRPD plot has a peak at 37.9 ± 0.2 degrees 2θ.

[0250] For example, the XRPD plot has a peak at 24.5 ± 0.2 degrees 2θ.

[0251] For example, the XRPD plot has a peak at 22.6 ± 0.2 degrees 2θ.

[0252] For example, the XRPD plot has a peak at 39.6 ± 0.2 degrees 2θ.

[0253] For example, the XRPD plot has a peak at 23.2 ± 0.2 degrees 2θ.

[0254] For example, the XRPD plot has a peak at 37.0 ± 0.2 degrees 2θ.

[0255] For example, the XRPD plot has a peak at 28.8 ± 0.2 degrees 2θ.

[0256] For example, the XRPD plot has a peak at 30.9 ± 0.2 degrees 2θ.

[0257] For example, the XRPD plot has a peak at 29.3 ± 0.2 degrees 2θ.

[0258] In some embodiments, the crystalline form is form C, and the XRPD plot has peaks at 22.3, 17.3, and 17.5 (± 0.2 degrees 2θ).

[0259] In some embodiments, the crystalline form is form C, and the XRPD plot has peaks at 22.3, 17.3, 17.5, and 21.8 (±0.2 degrees 2θ).

[0260] In some embodiments, the crystalline form is form C, and the XRPD plot has peaks at 22.3, 17.3, 17.5, 21.8, 11.5, 15.3, 10.2, 10.7, and 26.6 (± 0.2 degrees 2θ).

[0261] In some embodiments, the crystalline form is form C, and the XRPD plot has peaks at 22.3, 17.3, 17.5, 21.8, 11.5, 15.3, 10.2, 10.7, 26.6, 19.8, 5.3, 11.3, 19.7, 18.6, 24.7, 24.1, 20.4, 18.2, 25.6, 21.5, 13.3, 19.1, 9.5, 13.6, 27.3, 19.4, 16.3, 37.9, 24.5, 22.6, 39.6, 23.2, 37.0, 28.8, 30.9, and 29.3 (± 0.2 degrees 2θ).

[0262] Those skilled in the art will recognize that the relative intensities of peaks in an X-ray powder diffraction pattern can vary depending on sample preparation techniques, crystal size distributions, the various filters used, sample installation procedures, and the specific instrument employed. Therefore, depending on the type of instrument and the settings employed (including filters), new peaks may be observed in subsequently obtained patterns; or peaks observed in previously obtained patterns may have negligible relative intensities in subsequently obtained patterns (and thus may not be observed). Thus, the absence of one or more of the lower relative intensity peaks described above does not in itself determine the absence of form C (e.g., in the sample). However, the presence of the lower relative intensity peaks described above is generally useful for further determining the presence of form C in the sample.

[0263] Form C may also have one or more of the following characteristics.

[0264] In some embodiments, the crystalline form is form C with a TGA curve characterized by a weight loss of about 0.1% to about 10% (e.g., about 0.1% to about 7%, about 0.1% to about 4%, about 0.1% to about 2%, about 0.1% to about 1%, about 0.2% to about 0.6%, or about 0.4%) at about 210°C to about 240°C. In some embodiments, the crystalline form is form C with a TGA curve characterized by a weight loss of about 0.4% at about 210°C to about 240°C.

[0265] In some embodiments, the crystalline form is having the same Figure 24 The form C of the TGA curve shown is essentially the same.

[0266] In some embodiments, the crystalline form is having the same Figure 25 The form C is essentially the same DSC curve shown. In some embodiments, the crystalline form is form C with a DSC curve characterized by a melting initiation at approximately 187°C.

[0267] In some embodiments, the crystalline form is form C in a substantially pure form. In some embodiments, the crystalline form is form C, wherein form C is at least 99%, 99.3%, 99.5%, 99.7%, or 99.9% pure (w / w). In some embodiments, the crystalline form is form C, wherein form C is at least 99%, 99.3%, 99.5%, 99.7%, or 99.9% pure (w / w) after being exposed to about 10% relative humidity at about 50°C for one week. In some embodiments, the crystalline form is form C, wherein form C is at least 99%, 99.3%, 99.5%, 99.7%, or 99.9% pure (w / w) after being exposed to about 10% relative humidity at about 80°C for one week. In some embodiments, the crystalline form is form C, wherein form C is at least 99%, 99.3%, 99.5%, 99.7%, or 99.9% pure (w / w) after being exposed to about 75% relative humidity at about 50°C for one week. In some embodiments, the crystalline form is form C, wherein form C is at least 99%, 99.3%, 99.5%, 99.7%, or 99.9% pure (w / w) after being exposed to about 75% relative humidity at about 80°C for 1 week.

[0268] In some embodiments, the TGA plot of Form C shows approximately 0.2% weight loss at 180°C when heated from 30°C to 300°C at 10 K / min.

[0269] In some embodiments, form C absorbs up to 0.4% moisture via DVS at 25°C and 95% RH.

[0270] In some embodiments, the crystalline form is form C, characterized by a solubility of about 0.82 mg / mL to about 0.91 mg / mL (e.g., about 0.82 mg / mL, about 0.83 mg / mL, about 0.84 mg / mL, about 0.85 mg / mL, about 0.86 mg / mL, about 0.87 mg / mL, about 0.88 mg / mL, about 0.89 mg / mL, about 0.90 mg / mL, about 0.91 mg / mL, or any value between these) in fasting-state simulated gastric juice (FaSSGF) at about 37°C after about 30 minutes. In some embodiments, form C is characterized by a solubility of about 0.85 mg / mL to about 0.89 mg / mL in fasting-state simulated gastric juice (FaSSGF) at about 37°C after about 30 minutes. In some embodiments, form C is characterized by a solubility of 0.86 mg / mL to 0.88 mg / mL in fasting-state simulated gastric juice (FaSSGF) at about 37°C after about 30 minutes. In some embodiments, form C is characterized by a solubility of about 0.87 mg / mL in fasting-state simulated gastric juice (FaSSGF) at about 37°C after about 30 minutes. In some embodiments, the crystalline form is form C, characterized by a solubility of about 0.8 mg / mL to about 0.9 mg / mL (e.g., about 0.8 mg / mL, about 0.81 mg / mL, about 0.82 mg / mL, about 0.83 mg / mL, about 0.84 mg / mL, about 0.85 mg / mL, about 0.86 mg / mL, about 0.87 mg / mL, about 0.88 mg / mL, about 0.89 mg / mL, about 0.90 mg / mL, or any value between these) in fasting-state simulated gastric juice (FaSSGF) at about 37°C after about 24 hours. In some embodiments, form C is characterized by a solubility of about 0.83 mg / mL to about 0.88 mg / mL in fasting-state simulated gastric juice (FaSSGF) at about 37°C after about 24 hours. In some embodiments, form C is characterized by a solubility of 0.84 mg / mL to 0.87 mg / mL in fasting-state simulated gastric juice (FaSSGF) at about 37°C after about 24 hours. In some embodiments, the crystalline form is form C, characterized by a solubility of about 0.85 mg / mL in fasting-state simulated gastric juice (FaSSGF) at about 37°C after about 24 hours.In some embodiments, the crystalline form is form C, characterized by a solubility of about 1.58 mg / mL to about 1.70 mg / mL (e.g., about 1.58 mg / mL, about 1.59 mg / mL, about 1.60 mg / mL, about 1.61 mg / mL, about 1.62 mg / mL, about 1.63 mg / mL, about 1.64 mg / mL, about 1.65 mg / mL, about 1.66 mg / mL, about 1.67 mg / mL, about 1.68 mg / mL, about 1.69 mg / mL, about 1.70 mg / mL, or any value between these) in a fed-state simulated intestinal fluid (FeSSIF) at about 37°C after about 30 minutes. In some embodiments, the crystalline form is form C, characterized by a solubility of about 1.60 mg / mL to about 1.65 mg / mL in a fed-state simulated intestinal fluid (FeSSIF) at about 37°C after about 30 minutes. In some embodiments, the crystalline form is form C, characterized by a solubility of 1.62 mg / mL to 1.64 mg / mL in a fed-state simulated intestinal fluid (FeSSIF) at about 37°C after about 30 minutes. In some embodiments, the crystalline form is form C, characterized by a solubility of about 1.63 mg / mL in a fed-state simulated intestinal fluid (FeSSIF) at about 37°C after about 30 minutes.

[0271] In some embodiments, the crystalline form is form C, characterized by a solubility of about 1.64 mg / mL to about 1.74 mg / mL (e.g., about 1.64 mg / mL, about 1.65 mg / mL, about 1.66 mg / mL, about 1.67 mg / mL, about 1.68 mg / mL, about 1.69 mg / mL, about 1.70 mg / mL, about 1.71 mg / mL, about 1.72 mg / mL, about 1.73 mg / mL, about 1.74 mg / mL, or any value between these) in a fed-state simulated intestinal fluid (FeSSIF) at about 37°C after about 24 hours. In some embodiments, the crystalline form is form C, characterized by a solubility of about 1.67 mg / mL to about 1.71 mg / mL in a fed-state simulated intestinal fluid (FeSSIF) at about 37°C after about 24 hours. In some embodiments, the crystalline form is form C, characterized by a solubility of 1.68 mg / mL to 1.70 mg / mL in a fed-state simulated intestinal fluid (FeSSIF) at about 37°C after about 24 hours. In some embodiments, the crystalline form is form C, characterized by a solubility of about 1.69 mg / mL in a fed-state simulated intestinal fluid (FeSSIF) at about 37°C after about 24 hours.

[0272] In some embodiments, the crystalline form is form C, characterized by a solubility of about 1.62 mg / mL to about 1.72 mg / mL (e.g., about 1.62 mg / mL, about 1.63 mg / mL, about 1.64 mg / mL, about 1.65 mg / mL, about 1.66 mg / mL, about 1.67 mg / mL, about 1.68 mg / mL, about 1.69 mg / mL, about 1.70 mg / mL, about 1.71 mg / mL, or any value between these) in a fasting-state simulated intestinal fluid (FaSSIF) at about 37°C after about 30 minutes. In some embodiments, the crystalline form is form C, characterized by a solubility of about 1.66 mg / mL to about 1.70 mg / mL in a fasting-state simulated intestinal fluid (FaSSIF) at about 37°C after about 30 minutes. In some embodiments, the crystalline form is form C, characterized by a solubility of 1.67 mg / mL to 1.69 mg / mL after about 30 minutes in a fasting-state simulated intestinal fluid (FaSSIF) at about 37°C. In some embodiments, the crystalline form is form C, characterized by a solubility of about 1.68 mg / mL after about 30 minutes in a fasting-state simulated intestinal fluid (FaSSIF) at about 37°C.

[0273] In some embodiments, the crystalline form is form C, characterized by a solubility of about 0.08 mg / mL to about 0.18 mg / mL (e.g., about 0.08 mg / mL, about 0.09 mg / mL, about 0.10 mg / mL, about 0.11 mg / mL, about 0.12 mg / mL, about 0.13 mg / mL, about 0.14 mg / mL, about 0.15 mg / mL, about 0.16 mg / mL, about 0.17 mg / mL, about 0.18 mg / mL, or any value between these) in a fasting-state simulated intestinal fluid (FaSSIF) at about 37°C after about 24 hours. In some embodiments, the crystalline form is form C, characterized by a solubility of about 0.11 mg / mL to about 0.15 mg / mL in a fasting-state simulated intestinal fluid (FaSSIF) at about 37°C after about 24 hours. In some embodiments, the crystalline form is form C, characterized by a solubility of 0.12 mg / mL to 0.14 mg / mL in fasting-state simulated intestinal fluid (FaSSIF) at about 37°C after about 24 hours. In some embodiments, the crystalline form is form C, characterized by a solubility of about 0.13 mg / mL in fasting-state simulated intestinal fluid (FaSSIF) at about 37°C after about 24 hours. In some embodiments, the crystalline form is form C, characterized by a solubility of about 0.82 mg / mL to about 0.92 mg / mL (e.g., about 0.82 mg / mL, about 0.83 mg / mL, about 0.84 mg / mL, about 0.85 mg / mL, about 0.86 mg / mL, about 0.87 mg / mL, about 0.88 mg / mL, about 0.89 mg / mL, about 0.90 mg / mL, about 0.91 mg / mL, about 0.92 mg / mL, or any value between these) in water at about 37°C and an initial pH of about 7.0 after about 30 minutes. In some embodiments, form C is characterized by a solubility of about 0.86 mg / mL to about 0.90 mg / mL in water at about 37°C and an initial pH of about 7.0 after about 30 minutes. In some embodiments, form C is characterized by a solubility of 0.87 mg / mL to 0.89 mg / mL in water at about 37°C and an initial pH of about 7.0 after about 30 minutes. In some embodiments, the crystalline form is form C, characterized by a solubility of about 0.88 mg / mL in water at about 37°C and an initial pH of about 7.0 after about 30 minutes.

[0274] In some embodiments, the crystalline form is form C, characterized by a solubility of about 0.8 mg / mL to about 1.4 mg / mL (e.g., about 0.8 mg / mL, about 0.85 mg / mL, about 0.9 mg / mL, about 0.95 mg / mL, about 1.0 mg / mL, about 1.05 mg / mL, about 1.1 mg / mL, about 1.15 mg / mL, about 1.2 mg / mL, about 1.25 mg / mL, about 1.3 mg / mL, about 1.35 mg / mL, about 1.4 mg / mL, or any value between these) in water at about 37°C and an initial pH of about 7.0 after about 24 hours. In some embodiments, form C is characterized by a solubility of about 0.86 mg / mL to about 0.90 mg / mL in water at about 37°C and an initial pH of about 7.0 after about 24 hours. In some embodiments, form C is characterized by a solubility of 1.10 mg / mL to 1.14 mg / mL in water at about 37°C and an initial pH of about 7.0 after about 24 hours. In some embodiments, the crystalline form is form C, characterized by a solubility of about 1.12 mg / mL in water at about 37°C and an initial pH of about 7.0 after about 24 hours.

[0275] Form D Some embodiments provide ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H Crystalline form of hydrochloride of (-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid.

[0276] In some embodiments, the crystalline form is form D, and the XRPD diagram is consistent with... Figure 26 The two are essentially the same.

[0277] In some embodiments, the crystalline form is characterized by an XRPD pattern containing a peak at 13.1 ± 0.2 degrees 2θ. For ease of interpretation, the aforementioned polymorph is referred to herein as "Form D". The X-ray powder diffraction pattern of Form D may also include one or more additional characteristic peaks.

[0278] Form D X-ray powder diffraction patterns may also include one or more lower intensity characteristic peaks. The relative intensities of these additional peaks are typically lower than the relative intensities associated with the characteristic peaks described above.

[0279] For example, the XRPD plot has a peak at 16.4 ± 0.2 degrees 2θ.

[0280] For example, the XRPD plot has a peak at 10.4 ± 0.2 degrees 2θ.

[0281] For example, the XRPD plot has a peak at 16.6 ± 0.2 degrees 2θ.

[0282] For example, the XRPD plot has a peak at 23.4 ± 0.2 degrees 2θ.

[0283] For example, the XRPD plot has a peak at 18.2 ± 0.2 degrees 2θ.

[0284] For example, the XRPD plot has a peak at 15.9 ± 0.2 degrees 2θ.

[0285] For example, the XRPD plot has a peak at 24.9 ± 0.2 degrees 2θ.

[0286] For example, the XRPD plot has a peak at 17.5 ± 0.2 degrees 2θ.

[0287] Form D X-ray powder diffraction patterns may also include one or more lower intensity characteristic peaks. The relative intensities of these additional peaks are typically lower than the relative intensities associated with the characteristic peaks described above.

[0288] For example, the XRPD plot has a peak at 20.6 ± 0.2 degrees 2θ.

[0289] For example, the XRPD plot has a peak at 24.1 ± 0.2 degrees 2θ.

[0290] For example, the XRPD plot has a peak at 27.9 ± 0.2 degrees 2θ.

[0291] For example, the XRPD plot has a peak at 22.4 ± 0.2 degrees 2θ.

[0292] For example, the XRPD plot has a peak at 8.2 ± 0.2 degrees 2θ.

[0293] For example, the XRPD plot has a peak at 19.9 ± 0.2 degrees 2θ.

[0294] For example, the XRPD plot has a peak at 15.2 ± 0.2 degrees 2θ.

[0295] For example, the XRPD plot has a peak at 27.3 ± 0.2 degrees 2θ.

[0296] For example, the XRPD plot has a peak at 15.7 ± 0.2 degrees 2θ.

[0297] For example, the XRPD plot has a peak at 26.8 ± 0.2 degrees 2θ.

[0298] For example, the XRPD plot has a peak at 19.7 ± 0.2 degrees 2θ.

[0299] For example, the XRPD plot has a peak at 22.6 ± 0.2 degrees 2θ.

[0300] For example, the XRPD plot has a peak at 26.3 ± 0.2 degrees 2θ.

[0301] For example, the XRPD plot has a peak at 25.4 ± 0.2 degrees 2θ.

[0302] For example, the XRPD plot has a peak at 9.9 ± 0.2 degrees 2θ.

[0303] For example, the XRPD plot has a peak at 9.6 ± 0.2 degrees 2θ.

[0304] For example, the XRPD plot has a peak at 24.4 ± 0.2 degrees 2θ.

[0305] For example, the XRPD plot has a peak at 12.4 ± 0.2 degrees 2θ.

[0306] For example, the XRPD plot has a peak at 31.6 ± 0.2 degrees 2θ.

[0307] For example, the XRPD plot has a peak at 20.9 ± 0.2 degrees 2θ.

[0308] For example, the XRPD plot has a peak at 14.9 ± 0.2 degrees 2θ.

[0309] For example, the XRPD plot has a peak at 11.0 ± 0.2 degrees 2θ.

[0310] For example, the XRPD plot has a peak at 33.2 ± 0.2 degrees 2θ.

[0311] For example, the XRPD plot has a peak at 30.3 ± 0.2 degrees 2θ.

[0312] For example, the XRPD plot has a peak at 26.0 ± 0.2 degrees 2θ.

[0313] For example, the XRPD plot has a peak at 11.2 ± 0.2 degrees 2θ.

[0314] For example, the XRPD plot has a peak at 34.0 ± 0.2 degrees 2θ.

[0315] For example, the XRPD plot has a peak at 32.5 ± 0.2 degrees 2θ.

[0316] For example, the XRPD plot has a peak at 39.3 ± 0.2 degrees 2θ.

[0317] For example, the XRPD plot has a peak at 35.3 ± 0.2 degrees 2θ.

[0318] For example, the XRPD plot has a peak at 37.6 ± 0.2 degrees 2θ.

[0319] For example, the XRPD plot has a peak at 35.5 ± 0.2 degrees 2θ.

[0320] For example, the XRPD plot has a peak at 32.1 ± 0.2 degrees 2θ.

[0321] For example, the XRPD plot has a peak at 29.8 ± 0.2 degrees 2θ.

[0322] In some embodiments, the crystalline form is form D, and the XRPD plot has peaks at 13.1, 16.4, and 10.4 (± 0.2 degrees 2θ).

[0323] In some embodiments, the crystalline form is form D, and the XRPD plot has peaks at 13.1, 16.4, 10.4, 16.6, and 23.4 (± 0.2 degrees 2θ).

[0324] In some embodiments, the crystalline form is form D, and the XRPD plot has peaks at 13.1, 16.4, 10.4, 16.6, 23.4, 18.2, 15.9, 24.9, and 17.5 (± 0.2 degrees 2θ).

[0325] In some embodiments, the crystalline form is form D, and the XRPD plot has peaks at 13.1, 16.4, 10.4, 16.6, 23.4, 18.2, 15.9, 24.9, 17.5, 20.6, 24.1, 27.91, 22.4, 8.2, 19.9, 15.2, 27.3, 15.7, 26.8, 19.7, 22.6, 26.3, 25.4, 9.9, 9.6, 24.4, 12.4, 31.6, 20.9, 14.9, 11.0, 33.2, 30.3, 26.0, 11.2, 34.0, 32.5, 39.3, 35.3, 37.6, 35.5, 32.1, and 29.8 (± 0.2 degrees 2θ).

[0326] Those skilled in the art will recognize that the relative intensities of peaks in an X-ray powder diffraction pattern can vary depending on sample preparation techniques, crystal size distributions, the various filters used, sample preparation procedures, and the specific instrument employed. Therefore, depending on the type of instrument and the settings employed (including filters), new peaks may be observed in subsequently obtained patterns; or peaks observed in previously obtained patterns may have negligible relative intensities in subsequently obtained patterns (and thus may not be observed). Thus, the absence of one or more of the lower relative intensity peaks described above does not in itself determine the absence of form D (e.g., in the sample). However, the presence of the lower relative intensity peaks described above is generally useful for further determining the presence of form D in the sample.

[0327] Form D may also have one or more of the following characteristics.

[0328] In some embodiments, the crystalline form is form D, characterized by a TGA curve showing a weight loss of about 0.1% to about 10% (e.g., about 0.1% to about 5%, about 0.1% to about 4%, about 0.1% to about 3%, about 0.1% to about 2%, about 0.1% to about 1.3%, about 0.4% to about 1%, about 0.6% to about 0.8%, or about 0.7%) at about 210°C to about 230°C. In some embodiments, the crystalline form is form D, characterized by a TGA curve showing a weight loss of about 0.7% at about 210°C to about 230°C.

[0329] In some embodiments, the crystalline form is form D, characterized by being consistent with... Figure 27 The TGA curve shown is essentially the same.

[0330] In some embodiments, the crystalline form is form D, characterized by being consistent with... Figure 28 The DSC curves shown are essentially the same.

[0331] In some embodiments, the crystalline form is form D in a substantially pure form. In some embodiments, the crystalline form is form D, wherein form D is at least 99%, 99.3%, 99.5%, 99.7%, or 99.9% pure (w / w). In some embodiments, the crystalline form is form D, wherein form D is at least 99%, 99.3%, 99.5%, 99.7%, or 99.9% pure (w / w) after being exposed to about 10% relative humidity at about 50°C for one week. In some embodiments, the crystalline form is form D, wherein form D is at least 99%, 99.3%, 99.5%, 99.7%, or 99.9% pure (w / w) after being exposed to about 10% relative humidity at about 80°C for one week. In some embodiments, the crystalline form is form D, wherein form D is at least 99%, 99.3%, 99.5%, 99.7%, or 99.9% pure (w / w) after being exposed to about 75% relative humidity at about 50°C for one week. In some embodiments, the crystalline form is form D, wherein form D is at least 99%, 99.3%, 99.5%, 99.7%, or 99.9% pure (w / w) after being exposed to about 75% relative humidity at about 80°C for 1 week.

[0332] In some embodiments, the crystalline form is form D, characterized by a solubility of about 2.2 mg / mL to about 2.3 mg / mL (e.g., about 2.2 mg / mL, about 2.22 mg / mL, about 2.24 mg / mL, about 2.26 mg / mL, about 2.28 mg / mL, about 2.30 mg / mL, or any value between these) in fasting simulated gastric juice (FaSSGF) at about 37°C after about 30 minutes. In some embodiments, form D is characterized by a solubility of about 2.22 mg / mL to about 2.28 mg / mL in fasting simulated gastric juice (FaSSGF) at about 37°C after about 30 minutes. In some embodiments, form D is characterized by a solubility of 2.24 mg / mL to 2.26 mg / mL in fasting simulated gastric juice (FaSSGF) at about 37°C after about 30 minutes. In some embodiments, the crystalline form is form D, characterized by a solubility of about 2.25 mg / mL in fasting-state simulated gastric juice (FaSSGF) at about 37°C after about 30 minutes.

[0333] In some embodiments, the crystalline form is form D, characterized by a solubility greater than about 1.5 mg / mL to greater than about 2 mg / mL (e.g., greater than about 1.6 mg / mL, greater than about 1.7 mg / mL, greater than about 1.8 mg / mL, greater than about 1.9 mg / mL, or greater than about 2 mg / mL) in fasting simulated gastric juice (FaSSGF) at about 37°C after about 24 hours. In some embodiments, form D is characterized by a solubility greater than about 1.8 mg / mL to greater than about 2 mg / mL in fasting simulated gastric juice (FaSSGF) at about 37°C after about 24 hours. In some embodiments, form D is characterized by a solubility greater than 1.9 mg / mL in fasting simulated gastric juice (FaSSGF) at about 37°C after about 24 hours. In some embodiments, the crystalline form is form D, characterized by a solubility greater than about 2 mg / mL in fasting simulated gastric juice (FaSSGF) at about 37°C after about 24 hours.

[0334] In some embodiments, the crystalline form is form D, characterized by a solubility of about 1.95 mg / mL to about 2.25 mg / mL (e.g., about 1.95 mg / mL, about 2.0 mg / mL, about 2.05 mg / mL, about 2.10 mg / mL, about 2.15 mg / mL, about 2.2 mg / mL, about 2.25 mg / mL, or any value between these) in a fed-state simulated intestinal fluid (FeSSIF) at about 37°C after about 30 minutes. In some embodiments, form D is characterized by a solubility of about 2.16 mg / mL to about 2.22 mg / mL in a fed-state simulated intestinal fluid (FeSSIF) at about 37°C after about 30 minutes. In some embodiments, form D is characterized by a solubility of 2.18 mg / mL to 2.20 mg / mL in a fed-state simulated intestinal fluid (FeSSIF) at about 37°C after about 30 minutes. In some embodiments, the crystalline form is form D, characterized by a solubility of about 2.19 mg / mL in a fed-state simulated intestinal fluid (FeSSIF) at about 37°C after about 30 minutes.

[0335] In some embodiments, the crystalline form is form D, characterized by a solubility of about 2.28 mg / mL to about 2.38 mg / mL (e.g., about 2.28 mg / mL, about 2.29 mg / mL, about 2.30 mg / mL, about 2.31 mg / mL, about 2.32 mg / mL, about 2.33 mg / mL, about 2.34 mg / mL, about 2.35 mg / mL, about 2.36 mg / mL, about 2.37 mg / mL, about 2.38 mg / mL, or any value between these) in a fed-state simulated intestinal fluid (FeSSIF) at about 37°C after about 24 hours. In some embodiments, form D is characterized by a solubility of about 2.31 mg / mL to about 2.35 mg / mL in a fed-state simulated intestinal fluid (FeSSIF) at about 37°C after about 24 hours. In some embodiments, form D is characterized by a solubility of 2.32 mg / mL to 2.34 mg / mL in a fed-state simulated intestinal fluid (FeSSIF) at about 37°C after about 24 hours. In some embodiments, the crystalline form is form D, characterized by a solubility of about 2.33 mg / mL in a fed-state simulated intestinal fluid (FeSSIF) at about 37°C after about 24 hours.

[0336] In some embodiments, the crystalline form is form D, characterized by a solubility of about 2.14 mg / mL to about 2.24 mg / mL (e.g., about 2.14 mg / mL, about 2.15 mg / mL, about 2.16 mg / mL, about 2.17 mg / mL, about 2.18 mg / mL, about 2.19 mg / mL, about 2.20 mg / mL, about 2.21 mg / mL, about 2.22 mg / mL, about 2.23 mg / mL, about 2.24 mg / mL, or any value between these) in a fasting-state simulated intestinal fluid (FaSSIF) at about 37°C after about 30 minutes. In some embodiments, form D is characterized by a solubility of about 2.16 mg / mL to about 2.22 mg / mL in a fasting-state simulated intestinal fluid (FaSSIF) at about 37°C after about 30 minutes. In some embodiments, form D is characterized by a solubility of 2.18 mg / mL to 2.20 mg / mL in fasting-state simulated intestinal fluid (FaSSIF) at about 37°C after about 30 minutes. In some embodiments, the crystalline form is form D, characterized by a solubility of about 2.19 mg / mL in fasting-state simulated intestinal fluid (FaSSIF) at about 37°C after about 30 minutes.

[0337] In some embodiments, the crystalline form is form D, characterized by a solubility greater than about 1.5 mg / mL to greater than about 2 mg / mL (e.g., greater than about 1.5 mg / mL, greater than about 1.6 mg / mL, greater than about 1.7 mg / mL, greater than about 1.8 mg / mL, greater than about 1.9 mg / mL, or greater than about 2 mg / mL) in a fasting-state simulated intestinal fluid (FaSSIF) at about 37°C after about 24 hours. In some embodiments, form D is characterized by a solubility greater than about 1.8 mg / mL to greater than about 2 mg / mL in a fasting-state simulated intestinal fluid (FaSSIF) at about 37°C after about 24 hours. In some embodiments, form D is characterized by a solubility greater than 1.9 mg / mL to greater than 2 mg / mL in a fasting-state simulated intestinal fluid (FaSSIF) at about 37°C after about 24 hours. In some embodiments, the crystalline form is form D, characterized by having a solubility greater than about 2 mg / mL in fasting-state simulated intestinal fluid (FaSSIF) at about 37°C after about 24 hours.

[0338] In some embodiments, the crystalline form is form D, characterized by a solubility of about 2.03 mg / mL to about 2.13 mg / mL (e.g., about 2.03 mg / mL, about 2.04 mg / mL, about 2.05 mg / mL, about 2.06 mg / mL, about 2.07 mg / mL, about 2.08 mg / mL, about 2.09 mg / mL, about 2.10 mg / mL, about 2.11 mg / mL, about 2.12 mg / mL, about 2.13 mg / mL, or any value between these) in water at about 37°C and an initial pH of about 7.0 after about 30 minutes. In some embodiments, form D is characterized by a solubility of about 2.06 mg / mL to about 2.10 mg / mL in water at about 37°C and an initial pH of about 7.0 after about 30 minutes. In some embodiments, form D is characterized by a solubility of 2.07 mg / mL to 2.09 mg / mL in water at about 37°C and an initial pH of about 7.0 after about 30 minutes. In some embodiments, the crystalline form is form D, characterized by a solubility of about 2.08 mg / mL in water at about 37°C after about 30 minutes.

[0339] In some embodiments, the crystalline form is form D, characterized by a solubility greater than about 1.5 mg / mL to greater than about 2 mg / mL (e.g., greater than about 1.5 mg / mL, greater than about 1.6 mg / mL, greater than about 1.7 mg / mL, greater than about 1.8 mg / mL, greater than about 1.9 mg / mL, or greater than about 2 mg / mL) in water at about 37°C and an initial pH of about 7.0 after about 24 hours. In some embodiments, form D is characterized by a solubility greater than about 1.8 mg / mL to greater than about 2 mg / mL in water at about 37°C and an initial pH of about 7.0 after about 24 hours. In some embodiments, form D is characterized by a solubility greater than 1.9 mg / mL to 2 mg / mL in water at about 37°C and an initial pH of about 7.0 after about 24 hours. In some embodiments, the crystalline form is form D, characterized by a solubility greater than about 2 mg / mL in water at about 37°C and an initial pH of about 7.0 after about 24 hours.

[0340] In some embodiments, the crystalline form or crystalline form (e.g., form A, form B, form C, or form D) comprises about 1% to about 99% of the corresponding solvate. For example, about 1% to about 5%, about 6% to about 10%, about 10% to about 15%, about 15% to about 20%, about 25% to about 30%, about 30% to about 35%, about 35% to about 40%, about 45% to about 50%, about 50% to about 55%, about 55% to about 60%, about 60% to about 65%, about 65% to about 70%, about 70% to about 75%, about 75% to about 80%, about 80% to about 85%, about 85% to about 90%, about 90% to about 95%, about 95% to about 99%, about 1% to about 10%, about 10% to about 20%, about 20% to about 30%, about 30% to about 40%, about 4% to about 50%, about 6 ...50%, about 6% to about 50%, about 6% to about 50%, about 6% to about 50%, about 6% to about 50%, about 6% to about 50%, about 6% to about 50%, about 6% to about 50%, about 6% The crystalline form comprises 0% to about 50%, about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, about 90% to about 99%, about 1% to about 30%, about 30% to about 60%, about 60% to about 99%, about 1%, about 2%, about 3%, about 5%, about 10%, about 12%, about 15%, about 17%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 99% of the corresponding solvate. In some embodiments, the solvate is a methanol solvate, an ethyl acetate solvate, an ethanol solvate, an isopropanol solvate, a tetrahydrofuran solvate, an acetonitrile solvate, or a diethyl ether solvate. In some embodiments, the solvate is an isopropanol solvate.

[0341] Methods for preparing forms A, B, C, and D As those skilled in the art will understand, synthesis ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H (-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid, its crystalline form, and other methods for the synthesis of crystalline forms (e.g., p-toluenesulfonate and hydrochloride forms) will be apparent to those skilled in the art. S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H The synthesis of -indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid through chemical transformation and protecting group methods (protection and deprotection) are known in the art, and include, for example, methods described in the following literature: R. Larock, Comprehensive Organic Transformations [Comprehensive Organic Transformation], VCH Publishers (1989); TW Greene and PGM Uts, Protective Groups in Organic Synthesis [Protecting Groups in Organic Synthesis], 2nd Edition, John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis [Fieser and Fieser's Organic Synthetic Reagents], John Wiley and Sons (1994); and L. Paquette (ed.), Encyclopedia of Reagents for Organic Synthesis [Encyclopedia of Organic Synthesis Reagents], John Wiley and Sons (1995), and subsequent editions.

[0342] Method for preparing form A In some embodiments, the crystalline form is form A, which is prepared by a method comprising: (a) will ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H -Indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid is added to the alcohol to form a solution; (b) Cool the solution to form a suspension; (c) Filter the suspension to provide a crystalline form.

[0343] In some embodiments, in step (a) ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H -Indole-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid is amorphous ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid.

[0344] In some embodiments, the alcohol comprises methanol, ethanol, and / or isopropanol. For example, the alcohol comprises isopropanol. In some embodiments, the alcohol is methanol, ethanol, or isopropanol. For example, the alcohol is isopropanol. In some embodiments, ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H The addition of (-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid to an alcohol to form a solution is carried out under agitation. In some embodiments, agitation includes stirring. In some embodiments, agitation is stirring. In some embodiments, ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H The addition of (-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid to an alcohol to form a solution is carried out at a temperature of about 25°C to about 70°C. In some embodiments, ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H The addition of (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid to an alcohol to form a solution is carried out at temperatures of about 25°C to about 50°C, 50°C to about 70°C, 30°C to about 60°C, 35°C to about 55°C, 40°C to about 50°C, 40°C to about 45°C, and 45°C to about 50°C. In some embodiments, the concentration of (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid in the solution is about 0.05 M to about 0.8 M, for example, about 0.05 M to about 0.4 M, about 0.4 M to about 0.8 M, about 0.2 M to about 0.6 M, about 0.4 M to about 0.5 M, about 0.42 M to about 0.46 M, or about 0.44 M. For example,( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 HThe concentration of (-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid in solution is approximately 0.44 M.

[0345] In some embodiments, cooling the solution includes cooling the solution to at least about 5°C, for example, at least about 10°C or at least about 20°C. In some embodiments, cooling the solution includes cooling the solution to about 15°C to about 25°C, for example, cooling to about 18°C ​​to about 22°C. For example, cooling to about 20°C. In some embodiments, the solution is agitated (e.g., stirred) during and after cooling. In some embodiments, the agitation is performed for at least about 1 hour, for example, at least about 6, 12, 18, 24, 36, 48, 60, or 72 hours. In some embodiments, the agitation is performed for about 1 hour to about 96 hours, about 1 hour to about 24 hours, about 24 hours to about 48 hours, about 48 hours to about 72 hours, about 72 hours to about 96 hours, about 48 hours to about 96 hours, about 54 hours to about 90 hours, about 60 hours to about 84 hours, about 66 hours to about 78 hours, about 70 hours to about 74 hours, or about 72 hours. In some embodiments, the solution becomes a suspension after cooling.

[0346] In some embodiments, filtering the suspension to provide a crystalline form includes filtering the suspension to form a solid, washing the solid with a solvent, and drying the solid to provide a crystalline form. In some embodiments, the solvent comprises ethyl acetate, ethanol, diethyl ether, methyl tert-butyl ether, acetonitrile, tetrahydrofuran, isopropanol, methanol, or combinations thereof. In some embodiments, the solvent is ethyl acetate, ethanol, diethyl ether, methyl tert-butyl ether, acetonitrile, tetrahydrofuran, isopropanol, methanol, or combinations thereof. In some embodiments, the solvent comprises methanol, ethanol, and / or isopropanol. For example, the solvent comprises isopropanol. In some embodiments, the solvent is methanol, ethanol, or isopropanol. For example, the solvent is isopropanol.

[0347] In some embodiments, the crystalline form is form A, which is prepared by a method comprising: (a) With stirring, at about 40°C to about 50°C, ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H -Indo-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid was added to isopropanol to form a solution with a concentration of about 0.44 moles; (b) Cool the solution to approximately 20°C and stir for approximately 72 hours to form a suspension; (c) Filter the suspension to obtain a solid; (d) Wash the solid with isopropanol; and (e) Dry the solid to provide a crystalline form.

[0348] Method for preparing form B In some embodiments, the crystalline form is form B, which is prepared by a method comprising: (a) Add alcohol to ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H -indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid and p-toluenesulfonic acid to form a suspension; (b) Heating the suspension to form a solution; (c) Cool the solution and then add ethyl acetate; (d) Optional addition of crystals ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H -Indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid p-toluenesulfonate suspension in a binary mixture of ethanol and ethyl acetate to form a mixture; (e) Add ethyl acetate to form a slurry; (f) Filtering the slurry to form a solid; (g) Wash the solid with solvent; (h) Drying the solid to provide a crystalline form; (i) Add solid form to a binary mixture of isopropanol and water, and then heat to form a slurry; (j) Cooling and filtering the slurry to form a solid; and (k) Dry the solid to provide a crystalline form.

[0349] In some embodiments, in step (a) ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H -Indole-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid is amorphous ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H -indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid.

[0350] In some embodiments, the alcohol comprises methanol, ethanol, and / or isopropanol. For example, the alcohol comprises ethanol. In some embodiments, the alcohol is methanol, ethanol, or isopropanol. For example, the alcohol is ethanol. In some embodiments, step (a) includes adding relative to ( S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H -indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid in about 1 to about 6 (e.g., about 2 to about 5, about 3 to about 4, or about 3.5) volumes of alcohol. In some embodiments, step (a) includes adding relative to ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H Approximately 3.5 volumes of alcohol of indole-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid.

[0351] In some embodiments, step (b) includes heating the suspension to about 30°C to about 70°C (e.g., about 40°C to about 60°C, about 45°C, about 50°C, or about 55°C). In some embodiments, step (b) includes agitating the suspension. For example, step (b) includes stirring the suspension. In some embodiments, step (b) includes heating the suspension for about 1 minute to about 2 hours (e.g., about 5 minutes to about 1 hour, about 5 minutes to about 45 minutes, about 5 minutes to about 30 minutes, about 5 minutes to about 25 minutes, about 10 minutes to about 20 minutes, about 12 minutes to about 17 minutes, or about 15 minutes). For example, step (b) includes heating the suspension for about 15 minutes.

[0352] In some embodiments, step (c) includes cooling the solution to about 15°C to about 50°C (e.g., about 20°C to about 30°C, about 22°C to about 28°C, or about 25°C). In some embodiments, step (c) includes cooling the solution to about 25°C. In some embodiments, step (c) includes agitating the solution. For example, step (c) includes stirring the solution. In some embodiments, step (c) includes cooling the solution to about 1 minute to about 2 hours (e.g., about 5 minutes to about 1 hour, about 5 minutes to about 45 minutes, about 5 minutes to about 30 minutes, about 5 minutes to about 25 minutes, about 10 minutes to about 20 minutes, about 12 minutes to about 17 minutes, or about 15 minutes). For example, step (c) includes cooling the solution to about 15 minutes. In some embodiments, the ethyl acetate added to the solution is about 1 to about 4 (e.g., about 1 to about 3, about 2 to about 4, about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, or about 4) volumes relative to the suspension. In some embodiments, the ethyl acetate added to the solution is about 2.5 volumes relative to the suspension.

[0353] In some embodiments, step (d) is not performed. In some embodiments, step (d) is performed. In some embodiments, the ratio of ethanol to ethyl acetate in the binary mixture in step (d) is about 3:1 to about 1:4 by volume (e.g., about 2:1 to about 1:4, about 1:1 to about 1:4, about 1:2 to about 1:4, or about 1:3). For example, the ratio of ethanol to ethyl acetate in the binary mixture in step (d) is about 1:3 by volume. In some embodiments, the addition of the binary mixture in step (d) is carried out at about 15°C to about 50°C (e.g., about 20°C to about 30°C, about 22°C to about 28°C, or about 25°C). In some embodiments, the addition of the binary mixture in step (d) is carried out at about 25°C.

[0354] In some embodiments, the addition of ethyl acetate in step (d) is carried out over a period of about 15 minutes to about 4 hours (e.g., about 15 minutes to about 3 hours, about 1 hour to about 2.5 hours, about 1.5 hours to about 2.5 hours, about 1.75 hours to about 2.25 hours, or about 2 hours). For example, the addition of ethyl acetate in step (d) is carried out over about 2 hours. In some embodiments, the addition of ethyl acetate in step (d) is carried out at a temperature of about 15°C to about 50°C (e.g., about 20°C to about 30°C, about 22°C to about 28°C, or about 25°C). In some embodiments, the addition of ethyl acetate in step (d) is carried out at about 25°C. In some embodiments, about 1 to about 12 volumes (e.g., about 2 to about 10, about 4 to about 9, about 5 to about 9, about 7 to about 8, or about 7.5 volumes) of ethyl acetate relative to the volume of the mixture before the addition of ethyl acetate is carried out. In some embodiments, the addition of ethyl acetate is carried out relative to the volume used in step (a) S Approximately 7.5 volumes of ethyl acetate in the volume of 4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid.

[0355] In some embodiments, the solvent in step (g) comprises ethanol, ethyl acetate, or both. In some embodiments, the solvent in step (g) comprises ethanol. In some embodiments, the solvent in step (g) comprises ethyl acetate. In some embodiments, the solvent in step (g) is a binary mixture of ethanol and ethyl acetate. In some embodiments, the ratio of ethanol to ethyl acetate in the binary mixture is about 3:1 to about 1:4 by volume (e.g., about 2:1 to about 1:4, about 1:1 to about 1:4, about 1:2 to about 1:4, or about 1:3). For example, the ratio of ethanol to ethyl acetate in the binary mixture is about 1:3 by volume. In some embodiments, the solid is used relative to the solvent used in step (a). S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H The solid is washed with about 1 to about 4 volumes (e.g., about 1 to about 3, about 1.5 to about 2.5, or about 2 volumes) of solvent relative to the volume of the solid. In some embodiments, the solid is washed with about 2 volumes of solvent relative to the volume of the solid.

[0356] In some embodiments, the ratio of isopropanol to water in the binary mixture in step (i) is about 1:1 to about 20:1 by volume (e.g., about 2:1 to about 20:1, about 5:1 to about 20:1, or about 9:1). In some embodiments, the ratio of isopropanol to water in the binary mixture in step (i) is about 9:1 by volume. In some embodiments, heating is performed at about 30°C to about 70°C (e.g., about 40°C to about 60°C, about 45°C, about 50°C, or about 55°C) after the solid form is added to the binary mixture of isopropanol. In some embodiments, heating is performed at about 50°C after the solid form is added to the binary mixture of isopropanol. In some embodiments, after adding the solid form to the binary mixture of isopropanol, heating is performed for about 1 hour to about 48 hours (e.g., about 5 hours to about 36 hours, about 12 hours to about 20 hours, about 14 hours to about 18 hours, about 15 hours to about 17 hours, or about 16 hours). In some embodiments, after adding the solid form to the binary mixture of isopropanol, heating is performed for about 16 hours.

[0357] In some embodiments, the slurry cooling in step (j) is performed at about 0°C to about 35°C (e.g., about 0°C to about 30°C, about 5°C to about 30°C, about 10°C to about 30°C, about 15°C to about 30°C, about 20°C to about 30°C, about 22°C to about 28°C, or about 25°C). In some embodiments, the slurry cooling in step (j) is performed at about 25°C.

[0358] In some embodiments, the drying of the solids in step (k) is performed at about 30°C to about 70°C (e.g., about 35°C to about 65°C, about 40°C to about 60°C, about 45°C to about 55°C, or about 50°C). In some embodiments, the drying of the solids in step (k) is performed at about 50°C.

[0359] In some embodiments, the crystalline form is form B, which is prepared by a method comprising: (a) Add ethanol to ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H -indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid and p-toluenesulfonic acid to form a suspension, wherein ethanol is relative to ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H -Indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid is about 3.5 vol; (b) Heat the suspension to approximately 50°C and stir for approximately 15 minutes to form a solution; (c) Cool the solution to approximately 25°C over approximately 15 minutes, then add approximately 2.5 volumes of ethyl acetate; (d) Add about 7.5 volumes of ethyl acetate over 2 hours at about 25°C to form a slurry, and then allow the slurry to stand at about 25°C for about 1 hour; (e) Filter the slurry to obtain solids; (f) Wash the solid with a binary mixture of ethanol and ethyl acetate in a volume ratio of about 1:3; (g) Drying the solid to provide it in solid form; (h) Add solid form to a binary mixture of isopropanol and water in a volume ratio of about 9:1, and then heat at about 50°C for about 16 hours to form a slurry; (i) Cooling the slurry to approximately 25°C and filtering to obtain solids; and (j) Dry the solid at about 50°C to provide a crystalline form.

[0360] In some embodiments, the crystalline form is form B, which is prepared by a method comprising: (a) Add water and acetone to ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H -indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid and p-toluenesulfonic acid to form a suspension; (b) Heat the suspension to about 50°C and stir to form a solution, then cool the solution to room temperature; (c) Add seed crystals of form B to the solution to form a suspension; (d) Add approximately 2.2 volumes of water to the suspension from step (c) over several hours to form a suspension; (e) Cool the suspension from step (d) and maintain it below room temperature for several hours, then filter it to obtain solids; and (f) Dry the solid at about 40°C to 50°C to provide a crystalline form.

[0361] Method for preparing form C In some embodiments, the crystalline form is form C, which is prepared by a method comprising: (a) Add alcohol to ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H -indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid and p-toluenesulfonic acid to form a suspension; (b) Heating the suspension to form a solution; (c) Cool the solution and then add ethyl acetate; (d) Optional addition of crystals ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H -Indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid p-toluenesulfonate suspension in a binary mixture of ethanol and ethyl acetate to form a mixture; (e) Add ethyl acetate to form a slurry; (f) Filtering the slurry to form a solid; (g) Washing the solid with a solvent; and (h) Dry the solid to provide a crystalline form.

[0362] In some embodiments, (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid in step (a) is amorphous ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid.

[0363] In some embodiments, the alcohol comprises methanol, ethanol, and / or isopropanol. For example, the alcohol comprises ethanol. In some embodiments, the alcohol is methanol, ethanol, or isopropanol. For example, the alcohol is ethanol. In some embodiments, step (a) includes adding relative to ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H -indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid in about 1 to about 6 (e.g., about 2 to about 5, about 3 to about 4, or about 3.5) volumes of alcohol. In some embodiments, step (a) includes adding relative to ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H Approximately 3.5 volumes of alcohol of indole-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid.

[0364] In some embodiments, step (b) includes heating the suspension to about 30°C to about 70°C (e.g., about 40°C to about 60°C, about 45°C, about 50°C, or about 55°C). In some embodiments, step (b) includes agitating the suspension. For example, step (b) includes stirring the suspension. In some embodiments, step (b) includes heating the suspension for about 1 minute to about 2 hours (e.g., about 5 minutes to about 1 hour, about 5 minutes to about 45 minutes, about 5 minutes to about 30 minutes, about 5 minutes to about 25 minutes, about 10 minutes to about 20 minutes, about 12 minutes to about 17 minutes, or about 15 minutes). For example, step (b) includes heating the suspension for about 15 minutes.

[0365] In some embodiments, step (c) includes cooling the solution to about 15°C to about 50°C (e.g., about 20°C to about 30°C, about 22°C to about 28°C, or about 25°C). In some embodiments, step (c) includes cooling the solution to about 25°C. In some embodiments, step (c) includes agitating the suspension. For example, step (c) includes stirring the solution. In some embodiments, step (c) includes cooling the solution to about 1 minute to about 2 hours (e.g., about 5 minutes to about 1 hour, about 5 minutes to about 45 minutes, about 5 minutes to about 30 minutes, about 5 minutes to about 25 minutes, about 10 minutes to about 20 minutes, about 12 minutes to about 17 minutes, or about 15 minutes). For example, step (c) includes cooling the solution to about 15 minutes. In some embodiments, the ethyl acetate added to the solution is about 1 to about 4 (e.g., about 1 to about 3, about 2 to about 4, about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, or about 4) volumes relative to the solution. In some embodiments, the ethyl acetate added to the solution is about 2.5 times the volume of the solution.

[0366] In some embodiments, step (d) is not performed. In some embodiments, step (d) is performed. In some embodiments, the ratio of ethanol to ethyl acetate in the binary mixture in step (d) is about 3:1 to about 1:4 by volume (e.g., about 2:1 to about 1:4, about 1:1 to about 1:4, about 1:2 to about 1:4, or about 1:3). For example, the ratio of ethanol to ethyl acetate in the binary mixture in step (d) is about 1:3 by volume. In some embodiments, the addition of the binary mixture in step (d) is carried out at about 15°C to about 50°C (e.g., about 20°C to about 30°C, about 22°C to about 28°C, or about 25°C). In some embodiments, the addition of the binary mixture in step (d) is carried out at about 25°C.

[0367] In some embodiments, the addition of ethyl acetate in step (d) is carried out over a period of about 15 minutes to about 4 hours (e.g., about 15 minutes to about 3 hours, about 1 hour to about 2.5 hours, about 1.5 hours to about 2.5 hours, about 1.75 hours to about 2.25 hours, or about 2 hours). For example, the addition of ethyl acetate in step (d) is carried out over about 2 hours. In some embodiments, the addition of ethyl acetate in step (d) is carried out at a temperature of about 15°C to about 50°C (e.g., about 20°C to about 30°C, about 22°C to about 28°C, or about 25°C). In some embodiments, the addition of ethyl acetate in step (e) is carried out at about 25°C. In some embodiments, the addition is relative to the amount used in step (a) SEthyl acetate of about 1 to about 12 volumes (e.g., about 2 to about 10, about 4 to about 9, about 5 to about 9, about 7 to about 8, or about 7.5 volumes) of the volume of 4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid. In some embodiments, about 7.5 volumes of ethyl acetate are added relative to the volume of the mixture before the addition of ethyl acetate.

[0368] In some embodiments, the solvent in step (g) comprises ethanol, ethyl acetate, or both. In some embodiments, the solvent in step (g) comprises ethanol. In some embodiments, the solvent in step (g) comprises ethyl acetate. In some embodiments, the solvent in step (g) is a binary mixture of ethanol and ethyl acetate. In some embodiments, the ratio of ethanol to ethyl acetate in the binary mixture is about 3:1 to about 1:4 by volume (e.g., about 2:1 to about 1:4, about 1:1 to about 1:4, about 1:2 to about 1:4, or about 1:3). For example, the ratio of ethanol to ethyl acetate in the binary mixture is about 1:3 by volume. In some embodiments, the solid is used relative to the solvent used in step (a). S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H The solid is washed with about 1 to about 4 volumes (e.g., about 1 to about 3, about 1.5 to about 2.5, or about 2 volumes) of solvent relative to the volume of the solid. In some embodiments, the solid is washed with about 2 volumes of solvent relative to the volume of the solid.

[0369] In some embodiments, the crystalline form is form C, which is prepared by a method comprising: (a) Add ethanol to ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H -indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid and p-toluenesulfonic acid to form a suspension, wherein ethanol is relative to ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H -Indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid is about 3.5 vol; (b) Heat the suspension to approximately 50°C and stir for approximately 15 minutes to form a solution; (c) Cool the solution to approximately 25°C over approximately 15 minutes, then add approximately 2.5 volumes of ethyl acetate; (d) Add ethyl acetate at about 25°C over 2 hours to form a slurry, and then let the slurry stand at about 25°C for about 1 hour; (e) Filter the slurry to obtain solids; (f) Wash the solid with a binary mixture of ethanol and ethyl acetate in a volume ratio of approximately 1:3; and (g) Dry the solid to provide a crystalline form.

[0370] In some embodiments, the crystalline form is form C, which is prepared by a method comprising: (a) Add ethanol to ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H -indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid and p-toluenesulfonic acid to form a suspension, wherein ethanol is relative to ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H -Indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid is about 3.5 vol; (b) Heat the suspension to approximately 50°C and stir for approximately 15 minutes to form a solution; (c) Cool the solution to approximately 25°C over approximately 15 minutes, then add ethyl acetate; (d) Add ethyl acetate at about 25°C over 2 hours to form a slurry, and then let the slurry stand at about 25°C for about 1 hour; (e) Filter the slurry to form a solid; (f) Wash the solid with a binary mixture of ethanol and ethyl acetate in a volume ratio of approximately 1:3; and (g) Dry the solid to provide a crystalline form.

[0371] Method for preparing form D In some embodiments, the crystalline form is form D, which is prepared by a method comprising: (a) Preparation ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H -Indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid solution in solvent; (b) A solution containing hydrogen chloride in ethyl acetate or diethyl ether; (c) Add crystals ( S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H -Indo-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoate salt in solvent to form a slurry to form a suspension; (d) Add a solution of hydrogen chloride in ethyl acetate or diethyl ether to form a slurry; (e) Aging the slurry; (f) Filtering the slurry to form a solid; (g) Washing the solid with a solvent; and (h) Dry the solid to provide a crystalline form.

[0372] In some embodiments, in step (a) ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H -Indole-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid is amorphous ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H -indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid.

[0373] In some embodiments, the solvent in step (a) comprises ethyl acetate, ethanol, diethyl ether, methyl tert-butyl ether, acetonitrile, tetrahydrofuran, isopropanol, methanol, or combinations thereof. In some embodiments, the solvent in step (a) comprises ethyl acetate. In some embodiments, the solvent in step (a) is ethyl acetate. In some embodiments, the amount of solvent relative to the volume of the starting material is about 2 to about 11 (e.g., about 3 to about 10, about 4 to about 7, about 5 to about 6, or about 5.5) volumes. In some embodiments, the amount of solvent relative to the volume of the starting material is about 5.5 volumes.

[0374] In some embodiments, the solution of hydrogen chloride in ethyl acetate or diethyl ether is a solution of hydrogen chloride in ethyl acetate. In some embodiments, the concentration of the hydrogen chloride solution is about 0.5 M to about 2 M (e.g., about 0.5 to about 1.5 M, about 0.7 M to about 2 M, about 0.8 M to about 1.2 M, or about 1 M). In some embodiments, the concentration of the hydrogen chloride solution is about 1 M.

[0375] In some embodiments, the hydrogen chloride added in step (b) is relative to ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 HThe amount of (-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid is about 0.1 to about 2.2 (e.g., about 0.2 to about 2, about 0.4 to about 1.2, about 0.4 to about 0.7, or about 0.55) equivalents. In some embodiments, the hydrogen chloride added in step (b) is relative to ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H The amount of -indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid is about 0.55 equivalents.

[0376] In some embodiments, crystallization is used to form the suspension in step (c). S (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoate is formed by combining a solution of (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid in ethyl acetate with a solution of 1 M hydrogen chloride in ethyl acetate to form a precipitate, and then filtering the precipitate to provide crystals. S (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid salt. In some embodiments, the solution of (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid in ethyl acetate contains less than 1% by weight (e.g., less than 0.1%, less than 0.01%, less than 0.001%, less than 0.0001%, less than 0.00001%, or less than 0.000001%) of water. In some embodiments, the 1 M hydrogen chloride solution in ethyl acetate contains less than 1% by weight (e.g., less than 0.1%, less than 0.01%, less than 0.001%, less than 0.0001%, less than 0.00001%, or less than 0.000001%) of water. In some embodiments, the solvent in step (c) comprises ethyl acetate, ethanol, diethyl ether, methyl tert-butyl ether, acetonitrile, tetrahydrofuran, isopropanol, methanol, or combinations thereof. In some embodiments, the solvent in step (c) comprises ethyl acetate. In some embodiments, the solvent in step (c) is ethyl acetate.

[0377] In some embodiments, the hydrogen chloride added in step (d) is relative to ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H The amount of (-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid is about 0.1 to about 2.2 (e.g., about 0.2 to about 2.2, about 0.8 to about 2, about 1 to about 2, about 1.3 to about 2, about 1.5 to about 1.8, or about 1.65) equivalents. In some embodiments, the hydrogen chloride added in step (b) is relative to ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H The amount of (-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid is about 1.65 equivalents.

[0378] In some embodiments, aging the slurry in step (e) includes agitating the slurry. In some embodiments, agitating the slurry in step (e) includes stirring the slurry. In some embodiments, the slurry is aged for about 1 hour to about 48 hours (e.g., about 5 hours to about 36 hours, about 12 hours to about 20 hours, about 14 hours to about 18 hours, about 15 hours to about 17 hours, or about 16 hours). In some embodiments, the slurry is aged for about 16 hours. In some embodiments, the slurry is aged at about 0°C to about 35°C (e.g., about 0°C to about 30°C, about 5°C to about 30°C, about 10°C to about 30°C, about 15°C to about 30°C, about 20°C to about 30°C, about 22°C to about 28°C, or about 24°C). In some embodiments, the slurry is aged at about 24°C.

[0379] In some embodiments, the solvent in step (g) comprises ethyl acetate, ethanol, diethyl ether, methyl tert-butyl ether, acetonitrile, tetrahydrofuran, isopropanol, methanol, or a combination thereof. In some embodiments, the solvent in step (g) comprises ethyl acetate. In some embodiments, the solvent in step (g) is ethyl acetate.

[0380] In some embodiments, the crystalline form is form D, which is prepared by a method comprising: (a) Preparation ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H A solution of -indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid in about 5.5 volumes of ethyl acetate; (b) Add approximately 0.55 equivalents of a 1-molar concentration of hydrogen chloride in ethyl acetate; (c) Add crystals ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H-Indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid in ethyl acetate hydrochloride slurry to form a suspension; (d) Add approximately 1.65 equivalents of a 1-molar concentration solution of hydrogen chloride in ethyl acetate to form a slurry; (e) Stir the slurry at approximately 24°C for approximately 16 hours; (f) Filter the slurry to obtain solids; (g) Wash the solid with ethyl acetate; and (h) Dry the solid to provide a crystalline form.

[0381] Preparations In another aspect, this document provides pharmaceutical compositions comprising the crystalline forms described herein. In some embodiments, the pharmaceutical composition comprises form A and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises form B and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises form C and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises form D and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises any combination of forms A, B, C, and D, and a pharmaceutically acceptable carrier.

[0382] For example, a pharmaceutical composition may comprise form A and form B, as well as a pharmaceutically acceptable carrier.

[0383] For example, a pharmaceutical composition may contain form A and form C as well as a pharmaceutically acceptable carrier.

[0384] For example, a pharmaceutical composition may comprise form A and form D, as well as a pharmaceutically acceptable carrier.

[0385] For example, a pharmaceutical composition may contain form B and form C as well as a pharmaceutically acceptable carrier.

[0386] For example, a pharmaceutical composition may contain form B and form D, as well as a pharmaceutically acceptable carrier.

[0387] For example, a pharmaceutical composition may contain form C and form D, as well as a pharmaceutically acceptable carrier.

[0388] For example, a pharmaceutical composition may comprise form A, form B, form C, and a pharmaceutically acceptable carrier.

[0389] For example, a pharmaceutical composition may comprise form A, form B, form D, and a pharmaceutically acceptable carrier.

[0390] For example, a pharmaceutical composition may comprise form B, form C, form D, and a pharmaceutically acceptable carrier.

[0391] For example, a pharmaceutical composition may comprise form A, form C, form D, and a pharmaceutically acceptable carrier.

[0392] For example, a pharmaceutical composition may comprise form A, form B, form C, form D, and a pharmaceutically acceptable carrier.

[0393] In some embodiments, the pharmaceutical composition comprises at least about 0.5% by weight (e.g., at least about 1%, at least about 2%, 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 99%) of form A, form B, form C, or form D, or any combination thereof (e.g., any two, three, or four combinations of crystalline forms A, B, C, or D).

[0394] Some embodiments provide compositions (e.g., pharmaceutical compositions or pharmaceutical formulations) comprising one or more (e.g., 1 or 2, e.g., 1) active ingredients, wherein the active ingredient (or at least one active ingredient): (i) is form A, form B, form C, or form D, or any combination thereof (e.g., any two, three, or four combinations of forms A, B, C, or D); or (ii) Including at least about 0.5% by weight (e.g., at least about 1% by weight, at least about 2% by weight, at least about 5% by weight, at least about 10% by weight, at least about 20% by weight, at least about 30% by weight, at least about 40% by weight, at least about 50% by weight, at least about 60% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 95% by weight, at least about 99% by weight) one or more of the following forms (e.g., one or two, e.g., one) of the following (e.g., any two, three or four of the crystalline forms A, B, C or D).

[0395] The composition may include one or more of the following features.

[0396] The composition may include one or more pharmaceutically acceptable carriers.

[0397] Solid dosage forms of the pharmaceutical compositions of the present invention for oral administration include capsules, tablets, pills, powders, and granules. In one embodiment, the solid dosage form is a capsule. In another embodiment, the solid dosage form is a capsule filled with pure form A, form B, form C, form D, or any combination thereof. In some embodiments, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier (e.g., sodium citrate or dicalcium phosphate) and / or the following substances: a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silica; b) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; c) humectants, such as glycerin; d) disintegrants, such as agar-agar, calcium carbonate, potato or cassava starch, alginic acid, certain silicates, and sodium carbonate; e) solution blockers, such as paraffin; f) absorption enhancers, such as quaternary ammonium compounds; g) wetting agents, such as cetyl alcohol and glyceryl monostearate; h) absorbents, such as kaolin and bentonite; and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, and mixtures thereof. For capsules, tablets, and pills, dosage forms may also include buffers. Excipients such as lactose (or milk sugar) and high molecular weight polyethylene glycol may also be used as fillers in soft-filled and hard-filled gelatin capsules, allowing similar types of solid pharmaceutical compositions to be used.

[0398] Solid dosage forms of the pharmaceutical compositions of the present invention, including tablets, sugar-coated pills, capsules, pellets, and granules, can be prepared using coatings and shells (e.g., enteric coatings and other pharmaceutical coatings). The solid dosage forms may optionally contain light-blocking agents and may also be formulations that optionally release one or more active ingredients in a delayed manner only, or preferably in a portion of the intestine. Examples of usable embedded pharmaceutical compositions include polymeric substances and waxes.

[0399] The active compound may also be in microencapsulated form and, where appropriate, may contain one or more of the excipients described above.

[0400] Liquid dosage forms of the pharmaceutical compositions of the present invention for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof.

[0401] In addition to containing active compounds, the suspensions of the compounds of the present invention may also contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol (e.g., polyoxyethylene (20) dehydrated sorbitol monooleate, i.e., polysorbate 80 or "Tween 80"), microcrystalline cellulose, aluminum hydroxide, bentonite, agar-agar and astragalus gum, and mixtures thereof.

[0402] The pharmaceutical compositions disclosed herein for injection comprise pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, as well as sterile powders reconstituted into sterile injectable solutions or dispersions prior to use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or media include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate). Appropriate flowability can be maintained, for example, by using coating materials (e.g., lecithin), by maintaining the desired particle size in the case of dispersions, and by using surfactants. Other excipients or carriers include, for example, kleptose (hydroxypropyl β-cyclodextrin) and water-soluble polymers derived from cellulose (e.g., methylcellulose (e.g., methocel and hydroxypropyl methylcellulose)).

[0403] In some embodiments, the pH of the liquid (e.g., injectable) composition is about 5 to about 12 (e.g., about 6 to about 11, about 7 to about 11, about 7 to about 10, about 7 to about 9, about 7.5 to about 8.0, about 8 to about 10.5, about 8.5 to about 10, about 8.5, about 9, about 9.5, or about 10). For example, the pH of the liquid composition is about 8.5 to about 10.

[0404] In addition to inert diluents, these pharmaceutical compositions may also contain adjuvants such as preservatives, wetting agents, emulsifiers, dispersants, sweeteners, flavoring agents, and aromatizers. Inhibition of microbial activity can be ensured by including various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenolic sorbic acid, etc.). It is also desirable to include isotonic agents such as sugars and sodium chloride. Extended absorption of injectable drug forms can be achieved by including agents with delayed absorption (e.g., aluminum monostearate and gelatin). Compounds can be incorporated into sustained-release or targeted delivery systems (e.g., polymer matrices, liposomes, and microspheres). Such formulations can provide more efficient compound distribution.

[0405] Pharmaceutical compositions that are injectable preparations can be sterilized, for example, by filtering through a bacterial retention filter or by incorporating a sterilizing agent into the form of sterile solid pharmaceutical compositions (which can be dissolved or dispersed in sterile water or other sterile injectable media before use).

[0406] Dosage forms for topical application of the disclosed compounds or pharmaceutical compositions include powders, patches, sprays, ointments, and inhalers. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.

[0407] The compounds and compositions described herein can be administered, for example, orally, parenterally (e.g., subcutaneously, intradermally, intravenously, or intramuscularly), topically, rectally, nasally, sublingually, or orally, at doses ranging from about 0.01 mg / kg to about 1000 mg / kg every 4 to 120 hours (e.g., about 0.01 to about 100 mg / kg, about 0.1 to about 100 mg / kg), or as required by the specific drug, dosage form, and / or route of administration. Other routes of administration include enteric, intra-arterial, intraperitoneal, and intrathecal administration. Freireich et al., Cancer Chemother. Rep. 50, 219-244 (1966) described dose relationships in animals and humans (based on mg / m² body surface area). Body surface area can be roughly determined by the patient's height and weight. See, for example, Scientific Tables, Geigy Pharmaceuticals, Adsley, NY, 537 (1970).

[0408] In some embodiments, the composition comprises form A, form B, form C, or form D; hydroxypropyl β-cyclodextrin; and water. In some embodiments, the composition comprises form A; hydroxypropyl β-cyclodextrin; and water. In some embodiments, the composition comprises form B; hydroxypropyl β-cyclodextrin; and water. In some embodiments, the composition comprises form C; hydroxypropyl β-cyclodextrin; and water. In some embodiments, the composition comprises form D; hydroxypropyl β-cyclodextrin; and water.

[0409] In some embodiments, the composition comprises form A, form B, form C, or form D; methocel; between 80; and water. In some embodiments, the composition comprises form A; methocel; between 80; and water. In some embodiments, the composition comprises form B; methocel; between 80; and water. In some embodiments, the composition comprises form C; methocel; between 80; and water. In some embodiments, the composition comprises form D; methocel; between 80; and water.

[0410] In some embodiments, the grain size (D) of the crystalline form (e.g., form A, form B, form C, or form D) 50The particle size (D) is from about 1 µm to about 100 µm, for example, about 1 µm, about 2 µm, about 3 µm, about 4 µm, about 5 µm, about 10 µm, about 15 µm, about 20 µm, about 25 µm, about 30 µm, about 35 µm, about 40 µm, about 45 µm, about 50 µm, about 55 µm, about 60 µm, about 65 µm, about 70 µm, about 75 µm, about 80 µm, about 85 µm, about 90 µm, about 95 µm, or about 100 µm. In some embodiments, the particle size (D) of the crystalline form (e.g., form A, form B, form C, or form D) is... 50 The particle size is from about 1 µm to about 50 µm. In some embodiments, the particle size (D) of the crystalline form (e.g., form A, form B, form C, or form D) is... 50 The particle size is from about 1 µm to about 25 µm. In some embodiments, the particle size (D) of the crystalline form (e.g., form A, form B, form C, or form D) is... 50 The diameter is approximately 1 µm to approximately 5 µm.

[0411] How to use This document provides methods for treating, preventing, or improving diseases or conditions mediated by or otherwise affected by the alternative complement pathway, using the crystalline forms disclosed herein or pharmaceutical compositions thereof. In certain embodiments, this document provides methods for treating, preventing, or improving diseases or conditions mediated by or otherwise affected by complement factor B (CFB), using the crystalline forms disclosed herein or pharmaceutical compositions thereof. In certain embodiments, this document provides methods for treating, preventing, or improving diseases or conditions mediated by or otherwise affected by inhibition of the alternative complement pathway, using the crystalline forms disclosed herein or pharmaceutical compositions thereof. In certain other embodiments, this document provides methods for treating, preventing, or improving diseases or conditions mediated by or otherwise affected by inhibition of complement factor B, using the crystalline forms disclosed herein or pharmaceutical compositions thereof.

[0412] In some embodiments, the crystalline form is form A. In some embodiments, the crystalline form is form B. In some embodiments, the crystalline form is form C. In some embodiments, the crystalline form is form D.

[0413] Some embodiments provide methods for treating or preventing diseases or conditions as described herein (e.g., complement-related diseases or conditions) in a subject in need, the method comprising administering to the subject a therapeutically effective amount of form A, form B, form C, or form D, or a pharmaceutical composition comprising form A, form B, form C, or form D and a pharmaceutically acceptable carrier.

[0414] Known examples of complement-related disorders or conditions include: neurological disorders, multiple sclerosis, stroke, and Guillain-Barré syndrome. Syndrome, traumatic brain injury, Parkinson's disease, inappropriate or unintended complement activation, complications of hemodialysis, hyperacute allogeneic graft rejection, xenograft rejection, interleukin-2 induced toxicity during IL-2 therapy, inflammatory conditions, inflammation in autoimmune diseases, Crohn's disease, adult respiratory distress syndrome, thermal injuries including burns or frostbite, myocarditis, ischemia-reperfusion conditions, myocardial infarction, balloon angioplasty, post-pump syndrome during cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis, renal ischemia, mesenteric artery reperfusion after aortic reconstruction, infectious diseases or sepsis, immune complex disorders and autoimmune diseases, rheumatoid arthritis, systemic lupus erythematosus (SLE), SLE nephritis, proliferative nephritis, liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration and nerve regeneration. In addition, other known complement-related diseases include lung diseases and conditions such as dyspnea, hemoptysis, ARDS, asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and infarction, pneumonia, fibrotic dust diseases, inert dust and minerals (e.g., silicon, coal dust, beryllium, and asbestos), pulmonary fibrosis, organic dust diseases, chemical injuries (due to irritating gases and chemicals such as chlorine, phosgene, sulfur dioxide, hydrogen sulfide, nitrogen dioxide, ammonia, and hydrochloric acid), smoke injuries, thermal injuries (e.g., burns, frostbite), asthma, allergic reactions, bronchoconstriction, allergic pneumonia, parasitic diseases, and pulmonary hemorrhage nephritis syndrome (Goodpasture's syndrome). Syndrome, pulmonary vasculitis, microimmune vasculitis, immune complex-related inflammation; eye diseases including age-related macular degeneration, diabetic retinopathy, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyanagi-Harada syndrome, intermediate uveitis, shotgun retinal choroiditis, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigoid, non-arteritis-ischemic optic neuropathy, postoperative inflammation, and retinal vein occlusion uveitis (including Behcet's disease and other subtypes of uveitis), antiphospholipid syndrome.

[0415] In some embodiments, the disease or condition is selected from the group consisting of: age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyanagi-Harada syndrome, intermediate uveitis, shotgun retinal choroiditis, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigoid, non-arteritis-associated ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, glaucoma, Doyne's honeycomb retinal dystrophy / familial dominant drusen, and Sorsby fundus. dystrophy), delayed-onset macular dystrophy, North Carolina macular dystrophy, macular degeneration, corneal inflammation, neurological disorders such as multiple sclerosis, stroke, Guillain-Barré syndrome, spinal cord injury, traumatic brain injury, Parkinson's disease, Alzheimer's disease, schizophrenia, amyotrophic lateral sclerosis (ALS), Huntington's disease, multifocal motor neuropathy, autism spectrum disorder, schizophrenia, drug-induced neurotoxicity, and conditions of inappropriate or unintended complement activation (e.g., complications of hemodialysis, hyperacute allogeneic graft rejection, xenotransplantation). Rejection, IL-2-induced toxicity during interleukin-2 therapy, inflammatory symptoms, paroxysmal nocturnal hemoglobinuria, C3 glomerulonephritis (including dense deposit disease and C3 glomerulonephritis), immune complex membrane proliferative glomerulonephritis (IC-MPGN), IgA nephropathy, membranous nephropathy (including idiopathic membranous nephropathy), diabetic nephropathy, atypical hemolytic uremic syndrome (aHUS), hemolytic uremic syndrome, STEC-HUS (Shiga toxin-producing Escherichia coli hemolytic uremic syndrome), periodontitis, CD55 deficiency with complement hyperactivation (CD55... Deficiency with hyperactivation of complement, angiopathic thrombosis, protein-losing enteropathy (CHAPLE syndrome), inflammatory or autoimmune diseases (such as Crohn's disease, neuromyelitis optica (NMO), IgA vasculitis (formerly known as allergic purpura or HSP), hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA), adult respiratory distress syndrome (ARDS), myocarditis, ischemia-reperfusion condition, myocardial infarction, post-pump syndrome after balloon angioplasty, cardiopulmonary bypass or renal bypass, atherosclerosis, renal ischemia, acute kidney injury, mesenteric artery reperfusion after aortic reconstruction, infectious diseases or sepsis);COVID-19, immune complex disorders and autoimmune diseases, rheumatoid arthritis, osteoarthritis, spondyloarthritis, psoriatic arthritis, systemic lupus erythematosus (SLE), lupus nephritis, SLE nephritis, proliferative nephritis, myasthenia gravis, liver fibrosis, hemolytic anemia, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, acute respiratory distress syndrome (ARDS), asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and infarction, pneumonia, fibrotic dust disease, pulmonary fibrosis, asthma, allergic reactions, bronchoconstriction, allergic pneumonia, parasitic diseases, pulmonary hemorrhage nephritis syndrome, pulmonary vasculitis, microimmune vasculitis, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), Buerger's vasculitis, cryoglobulinemia, Kawasaki disease. Diseases including: aortitis, cryoglobulinemia, immune complex-related inflammation, antiphospholipid syndrome, glomerulonephritis, and obesity; immune thrombocytopenic purpura, cold agglutinin disease, warm antibody-type autoimmune hemolytic anemia (wAIHA), thrombotic thrombocytopenic purpura (TTP), abdominal aortic aneurysm, Graves' disease, and hidradenitis suppurativa.

[0416] In some embodiments, the disease or condition is selected from the group consisting of: multiple sclerosis, Guillain-Barré syndrome, traumatic brain injury, Parkinson's disease, age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyanagi-Harada syndrome, intermediate uveitis, shotgun retinochoroiditis, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigoid, non-arteritis-related ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, hemodialysis complications, hyperacute allogeneic graft rejection, xenograft rejection, IL-2-induced toxicity during interleukin-2 therapy, inflammatory conditions, inflammation in autoimmune diseases, Crohn's disease, adult respiratory distress syndrome, myocarditis, ischemia-reperfusion condition, myocardial infarction. Stroke, post-pump syndrome following balloon angioplasty, cardiopulmonary bypass, or renal bypass, atherosclerosis, hemodialysis, renal ischemia, mesenteric artery reperfusion after aortic reconstruction, infectious diseases or sepsis, immune complex disorders and autoimmune diseases, rheumatoid arthritis, systemic lupus erythematosus (SLE), SLE nephritis, proliferative nephritis, liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, ARDS, asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and infarction, pneumonia, fibrotic dust disease, pulmonary fibrosis, asthma, allergic reactions, bronchoconstriction, allergic pneumonia, parasitic diseases, pulmonary hemorrhage nephritis syndrome, pulmonary vasculitis, microimmune vasculitis, immune complex-related inflammation, antiphospholipid syndrome, glomerulonephritis, obesity, metabolic syndrome, and hidradenitis suppurativa.

[0417] In some embodiments, the disease or condition is immune complex membrane proliferative glomerulonephritis (IC-MPGN).

[0418] In some embodiments, the disease or condition is neuromyelitis optica (NMO).

[0419] In some embodiments, the disease or condition is hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA).

[0420] Some embodiments provide methods for treating or preventing kidney diseases or conditions selected from the group consisting of: chronic kidney disease, diabetic nephropathy, glomerular nephropathy, complement C3 glomerulonephropathy (C3G), IgA nephropathy (IgAN), membranous nephropathy (MN), focal segmental glomerulosclerosis (FSGS), atypical hemolytic uremic syndrome (aHUS), dense deposit disease (DDD), minimal change disease (MCD), paroxysmal nocturnal hemoglobinuria (PNH), ANCA-associated vasculitis, lupus nephritis, and polycystic kidney disease (PKD), the method comprising administering to a subject suffering from such disease or condition a therapeutically effective amount of form A, form B, form C, or form D, or a pharmaceutical composition comprising form A, form B, form C, or form D and a pharmaceutically acceptable carrier.

[0421] In some embodiments, the kidney disease is selected from the group consisting of: chronic kidney disease, diabetic nephropathy, glomerular nephropathy, complement C3 glomerulonephropathy (C3G), IgA nephropathy (IgAN), membranous nephropathy (MN), focal segmental glomerulosclerosis (FSGS), atypical hemolytic uremic syndrome (aHUS), dense deposit disease (DDD), minimal change disease (MCD), paroxysmal nocturnal hemoglobinuria (PNH), ANCA-associated vasculitis, lupus nephritis, polycystic kidney disease (PKD), and immune complex membrane proliferative glomerulonephritis (IC-MPGN).

[0422] In some embodiments, kidney disease is chronic kidney disease.

[0423] In some embodiments, kidney disease is diabetic nephropathy.

[0424] In some embodiments, kidney disease is glomerular kidney disease.

[0425] In some embodiments, the kidney disease is complement C3 glomerulonephropathy (C3G).

[0426] In some embodiments, the kidney disease is IgA nephropathy (IgAN).

[0427] In some embodiments, the kidney disease is membranous nephropathy (MN).

[0428] In some embodiments, the kidney disease is focal segmental glomerulosclerosis (FSGS).

[0429] In some embodiments, the kidney disease is atypical hemolytic uremic syndrome (aHUS).

[0430] In some embodiments, kidney disease is dense deposit disease (DDD).

[0431] In some embodiments, the kidney disease is minimal change disease (MCD).

[0432] In some embodiments, kidney disease is paroxysmal nocturnal hemoglobinuria (PNH).

[0433] In some embodiments, kidney disease is ANCA-associated vasculitis.

[0434] In some embodiments, the kidney disease is lupus nephritis.

[0435] In some embodiments, the kidney disease is polycystic kidney disease (PKD).

[0436] In some embodiments, the kidney disease is immune complex membrane proliferative glomerulonephritis (IC-MPGN).

[0437] This disclosure will be further described in the following examples. It should be understood that these examples are for illustrative purposes only and should not be construed as limiting this disclosure in any way.

[0438] Other embodiments 1. A kind of ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H Crystalline form of (-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid.

[0439] 2. The crystalline form as described in Example 1, wherein the crystalline form is form A, characterized by an X-ray powder diffraction (XRPD) pattern having a peak at 10.7 ± 0.2 degrees 2θ.

[0440] 3. The crystalline form as described in Example 2, wherein the XRPD plot has a peak at 20.5 ± 0.2 degrees 2θ.

[0441] 4. The crystalline form as described in any one of Examples 2-3, wherein the XRPD plot has a peak at 18.8 ± 0.2 degrees 2θ.

[0442] 5. The crystalline form as described in any one of Examples 2-4, wherein the XRPD plot has a peak at 21.7 ± 0.2 degrees 2θ.

[0443] 6. The crystalline form as described in any one of Examples 2-5, wherein the XRPD plot has a peak at 19.6 ± 0.2 degrees 2θ.

[0444] 7. The crystalline form as described in any one of Examples 2-6, wherein the XRPD plot has a peak at 19.8 ± 0.2 degrees 2θ.

[0445] 8. The crystalline form as described in any one of Examples 2-7, wherein the XRPD plot has a peak at 12.5 ± 0.2 degrees 2θ.

[0446] 9. The crystalline form as described in any one of Examples 2-8, wherein the XRPD plot has a peak at 21.1 ± 0.2 degrees 2θ.

[0447] 10. The crystalline form as described in any one of Examples 2-9, wherein the XRPD plot has a peak at 23.3 ± 0.2 degrees 2θ.

[0448] 11. The crystalline form as described in any one of Examples 2-10, wherein the XRPD plot has a peak at 22.6 ± 0.2 degrees 2θ.

[0449] 12. The crystalline form as described in any one of Examples 2-11, wherein the XRPD plot has a peak at 27.3 ± 0.2 degrees 2θ.

[0450] 13. The crystalline form as described in any one of Examples 2-12, wherein the XRPD plot has a peak at 15.6 ± 0.2 degrees 2θ.

[0451] 14. The crystalline form as described in Example 1, wherein the crystalline form is form A, and wherein the XRPD plot has peaks at 10.7, 20.5, and 18.8 (± 0.2 degrees 2θ).

[0452] 15. The crystalline form as described in Example 1, wherein the crystalline form is form A, and wherein the XRPD plot has peaks at 10.7, 20.5, 18.8, and 21.7 (± 0.2 degrees 2θ).

[0453] 16. The crystalline form as described in Example 1, wherein the crystalline form is form A, and wherein the XRPD peaks have peaks at 10.7, 20.5, 18.8, 21.7, 19.6, 19.8, 12.5, 21.1, 23.3, 22.5, 27.3 and 15.5 (± 0.2 degrees 2θ).

[0454] 17. The crystalline form as described in Example 1, wherein the crystalline form is form A, ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H -Indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid is in free form, further wherein the free form is anhydrous.

[0455] 18. The crystalline form as described in Example 1, wherein the crystalline form is form A, and wherein the XRPD pattern is consistent with... Figure 2The two are essentially the same.

[0456] 19. The crystalline form as described in any one of Examples 1-18, wherein the crystalline form is form A having a thermogravimetric analysis (TGA) curve characterized by a weight loss of about 2% at about 189°C.

[0457] 20. The crystalline form as described in any one of Examples 1-19, wherein the crystalline form is Form A having a TGA curve characterized by a weight loss of about 25% at about 300°C.

[0458] 21. The crystalline form as described in any one of Examples 1-20, wherein the crystalline form has the same characteristics as... Figure 3 The TGA curve shown is essentially the same as form A.

[0459] 22. The crystalline form as described in any one of Examples 1-21, wherein the crystalline form is Form A having a differential scanning calorimetry (DSC) curve characterized by a melting initiation (endothermic) of about 201.9°C.

[0460] 23. The crystalline form as described in any one of Examples 1-22, wherein the crystalline form has the same characteristics as... Figure 4 The form A of the DSC curve shown is essentially the same.

[0461] 24. The crystalline form as described in any one of Examples 1-23, wherein the crystalline form is form A, characterized in that it has a solubility of about 2.3 mg / mL in fasting simulated gastric juice (FaSSGF) at about 37°C after about 30 minutes.

[0462] 25. The crystalline form as described in any one of Examples 1-24, wherein the crystalline form is form A, characterized in that it has a solubility of about 0.31 mg / mL in a fed-state simulated intestinal fluid (FeSSIF) at about 37°C after about 24 hours.

[0463] 26. The crystalline form as described in any one of Examples 1-25, wherein the crystalline form is form A, characterized in that it has a solubility of about 0.18 mg / mL in fasting simulated intestinal fluid (FaSSIF) at about 37°C after about 24 hours.

[0464] 27. The crystalline form as described in any one of Examples 1-26, wherein the crystalline form is form A, characterized in that it has a solubility of about 0.22 mg / mL in water at about 37°C after about 24 hours.

[0465] 28. The crystalline form as described in any one of Examples 1-27, wherein the crystalline form is form A, prepared by a method comprising: (a) With stirring, at about 40°C to about 50°C, ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H -Indo-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid was added to isopropanol to form a solution with a concentration of about 0.44 moles; (b) Cool the solution to approximately 20°C and stir for approximately 72 hours to form a suspension; (c) Filter the suspension to obtain a solid; (d) Wash the solid with isopropanol; and (e) Dry the solid to provide a crystalline form.

[0466] 29. A kind of ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H The crystalline form of p-toluenesulfonate of (-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid.

[0467] 30. The crystalline form as described in Example 29, wherein the crystalline form is form B, characterized by an XRPD plot showing a peak at 11.8 ± 0.2 degrees 2θ.

[0468] 31. The crystalline form as described in Example 30, wherein the XRPD plot has a peak at 9.3 ± 0.2 degrees 2θ.

[0469] 32. The crystalline form as described in any one of Examples 29-31, wherein the XRPD plot has a peak at 19.9 ± 0.2 degrees 2θ.

[0470] 33. The crystalline form as described in any one of Examples 29-32, wherein the XRPD plot has a peak at 22.9 ± 0.2 degrees 2θ.

[0471] 34. The crystalline form as described in any one of Examples 29-33, wherein the XRPD plot has a peak at 17.2 ± 0.2 degrees 2θ.

[0472] 35. The crystalline form as described in any one of Examples 29-34, wherein the XRPD plot has a peak at 10.2 ± 0.2 degrees 2θ.

[0473] 36. The crystalline form as described in any one of Examples 29-35, wherein the XRPD plot has a peak at 20.4 ± 0.2 degrees 2θ.

[0474] 37. The crystalline form as described in any one of Examples 29-36, wherein the XRPD plot has a peak at 21.3 ± 0.2 degrees 2θ.

[0475] 38. The crystalline form as described in any one of Examples 29-37, wherein the XRPD plot has a peak at 14.2 ± 0.2 degrees 2θ.

[0476] 39. The crystalline form as described in Example 29, wherein the crystalline form is form B, and wherein the XRPD plot is at 11.8. 0 9.3 0 It has a peak at 19.9 (± 0.2 degrees 2θ).

[0477] 40. The crystalline form as described in Example 29, wherein the crystalline form is form B, and wherein the XRPD plot has peaks at 11.8, 9.3, 19.9, and 22.9 (± 0.2 degrees 2θ).

[0478] 41. The crystalline form as described in Example 29, wherein the crystalline form is form B, and wherein the XRPD plot has peaks at 11.8, 9.3, 19.9, 22.9, 17.2, 10.2, 20.4, 21.3 and 14.2 (± 0.2 degrees 2θ).

[0479] 42. The crystalline form as described in Example 29, wherein the crystalline form is form B, and wherein the XRPD pattern is consistent with... Figure 12 or Figure 15 The two are essentially the same.

[0480] 43. The crystalline form as described in any one of Examples 29-42, wherein the crystalline form is Form B having a TGA curve characterized by a weight loss of about 1% at about 60°C to about 100°C.

[0481] 44. The crystalline form as described in any one of Examples 29-43, wherein the crystalline form has the same characteristics as... Figure 13 or Figure 17 The form B of the TGA curve shown is essentially the same.

[0482] 45. The crystalline form as described in any one of Examples 29-44, wherein the crystalline form has the same characteristics as... Figure 14 or Figure 16 The form B of the DSC curve shown is essentially the same.

[0483] 46. ​​The crystalline form as described in any one of Examples 29-45, wherein the crystalline form is form B, characterized in that it has a solubility of about 0.54 mg / mL in fasting simulated gastric juice (FaSSGF) at about 37°C after about 24 hours.

[0484] 47. The crystalline form as described in any one of Examples 29-46, wherein the crystalline form is form B, characterized in that it has a solubility greater than about 2 mg / mL in a fed state simulated intestinal fluid (FeSSIF) at about 37°C after about 24 hours.

[0485] 48. The crystalline form as described in any one of Examples 29-47, wherein the crystalline form is form B, characterized in that it has a solubility of about 0.53 mg / mL in fasting simulated intestinal fluid (FaSSIF) at about 37°C after about 24 hours.

[0486] 49. The crystalline form as described in any one of Examples 29-48, wherein the crystalline form is form B, characterized in that it has a solubility of about 0.56 mg / mL in water at about 37°C after about 24 hours.

[0487] 50. The crystalline form as described in any one of Examples 29-49, wherein the crystalline form is form B, prepared by a method comprising: (a) Add ethanol to ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H -indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid and p-toluenesulfonic acid to form a suspension, wherein ethanol is relative to ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H -Indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid is about 3.5 vol; (b) Heat the suspension to approximately 50°C and stir for approximately 15 minutes to form a solution; (c) Cool the solution to approximately 25°C over approximately 15 minutes, then add approximately 2.5 volumes of ethyl acetate; (d) Add about 7.5 volumes of ethyl acetate over 2 hours at about 25°C to form a slurry, and then allow the slurry to stand at about 25°C for about 1 hour; (e) Filter the slurry to obtain solids; (f) Wash the solid with a binary mixture of ethanol and ethyl acetate in a volume ratio of about 1:3; (g) Drying the solid to provide it in solid form; (h) Add solid form to a binary mixture of isopropanol and water in a volume ratio of about 9:1, and then heat at about 50°C for about 16 hours to form a slurry; (i) Cooling the slurry to approximately 25°C and filtering to obtain solids; and (j) Dry the solid at about 50°C to provide a crystalline form.

[0488] 51. The crystalline form as described in Example 29, wherein the crystalline form is form C, characterized by an XRPD plot showing a peak at 22.3 ± 0.2 degrees 2θ.

[0489] 52. The crystalline form as described in Example 51, wherein the XRPD plot has a peak at 17.3 ± 0.2 degrees 2θ.

[0490] 53. The crystalline form as described in any one of Examples 51-52, wherein the XRPD plot has a peak at 17.5 ± 0.2 degrees 2θ.

[0491] 54. The crystalline form as described in any one of Examples 51-53, wherein the XRPD plot has a peak at 21.8 ± 0.2 degrees 2θ.

[0492] 55. The crystalline form as described in any one of Examples 51-54, wherein the XRPD plot has a peak at 11.5 ± 0.2 degrees 2θ.

[0493] 56. The crystalline form as described in any one of Examples 51-55, wherein the XRPD plot has a peak at 15.3 ± 0.2 degrees 2θ.

[0494] 57. The crystalline form as described in any one of Examples 51-56, wherein the XRPD plot has a peak at 10.2 ± 0.2 degrees 2θ.

[0495] 58. The crystalline form as described in any one of Examples 51-57, wherein the XRPD plot has a peak at 10.7 ± 0.2 degrees 2θ.

[0496] 59. The crystalline form as described in any one of Examples 51-58, wherein the XRPD plot has a peak at 26.6 ± 0.2 degrees 2θ.

[0497] 60. The crystalline form as described in any one of Examples 29-59, wherein form B comprises water, and the amount of water is 0 to 2.7% w / w relative to the total weight of form B.

[0498] 61. The crystalline form as described in Example 29, wherein the crystalline form is form C, and wherein the XRPD plot has peaks at 22.3, 17.3, and 17.5 (± 0.2 degrees 2θ).

[0499] 62. The crystalline form as described in Example 29, wherein the crystalline form is form C, and wherein the XRPD plot has peaks at 22.3, 17.3, 17.5 and 21.8 (± 0.2 degrees 2θ).

[0500] 63. The crystalline form as described in Example 29, wherein the crystalline form is form C, and wherein the XRPD plot has peaks at 22.3, 17.3, 17.5, 21.8, 11.5, 15.3, 10.2, 10.7 and 26.6 (± 0.2 degrees 2θ).

[0501] 64. The crystalline form as described in Example 29, wherein the crystalline form is form C, and wherein the XRPD pattern is consistent with... Figure 23 The two are essentially the same.

[0502] 65. The crystalline form as described in Example 29, wherein ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H The p-toluenesulfonate form of -indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid is in anhydrous form.

[0503] 66. The crystalline form as described in any one of Examples 29 and 61-65, wherein the crystalline form is form C having a TGA curve characterized by a weight loss of about 0.4% at about 210°C to about 240°C.

[0504] 67. The crystalline form as described in any one of Examples 29 and 61-66, wherein the crystalline form has the same characteristics as... Figure 24 The form C of the TGA curve shown is essentially the same.

[0505] 68. The crystalline form as described in any one of Examples 29 and 61-67, wherein the crystalline form is form C having a DSC curve characterized by a melting initiation at about 187°C.

[0506] 69. The crystalline form as described in any one of Examples 29 and 61-68, wherein the crystalline form has the same characteristics as... Figure 25 The form C of the DSC curve shown is essentially the same.

[0507] 70. The crystalline form as described in any one of Examples 29 and 61-69, wherein the crystalline form is form C, characterized by having a solubility of about 0.85 mg / mL in fasting-state simulated gastric juice (FaSSGF) at about 37°C after about 24 hours.

[0508] 71. The crystalline form as described in any one of Examples 29 and 61-70, wherein the crystalline form is form C, characterized by having a solubility of about 1.69 mg / mL in a fed-state simulated intestinal fluid (FeSSIF) at about 37°C after about 24 hours.

[0509] 72. The crystalline form as described in any one of Examples 29 and 61-71, wherein the crystalline form is form C, characterized by having a solubility of about 0.13 mg / mL in fasting-state simulated intestinal fluid (FaSSIF) at about 37°C after about 24 hours.

[0510] 73. The crystalline form as described in any one of Examples 29 and 61-72, wherein the crystalline form is form C, characterized by having a solubility of about 1.12 mg / mL in water at about 37°C after about 24 hours.

[0511] 74. The crystalline form as described in any one of Examples 29 and 61-73, wherein the crystalline form is form C, prepared by a method comprising: (a) Add ethanol to ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H -indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid and p-toluenesulfonic acid to form a suspension, wherein ethanol is relative to ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H -Indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid is about 3.5 vol; (b) Heat the suspension to approximately 50°C and stir for approximately 15 minutes to form a solution; (c) Cool the solution to approximately 25°C over approximately 15 minutes, then add approximately 2.5 volumes of ethyl acetate; (d) Add about 7.5 volumes of ethyl acetate over 2 hours at about 25°C to form a slurry, and then allow the slurry to stand at about 25°C for about 1 hour; (e) Filter the slurry to obtain solids; (f) Wash the solid with a binary mixture of ethanol and ethyl acetate in a volume ratio of approximately 1:3; and (g) Dry the solid to provide a crystalline form.

[0512] 75. A kind of ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H Crystalline form of hydrochloride of (-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid.

[0513] 76. The crystalline form as described in Example 75, wherein the crystalline form is form D, characterized by an XRPD plot containing a peak at 13.1 ± 0.2 degrees 2θ.

[0514] 77. The crystalline form as described in Example 75, wherein the XRPD plot has a peak at 16.4 ± 0.2 degrees 2θ.

[0515] 78. The crystalline form as described in any one of Examples 75-77, wherein the XRPD plot has a peak at 10.4 ± 0.2 degrees 2θ.

[0516] 79. The crystalline form as described in any one of Examples 75-78, wherein the XRPD plot has a peak at 16.6 ± 0.2 degrees 2θ.

[0517] 80. The crystalline form as described in any one of Examples 75-79, wherein the XRPD plot has a peak at 23.4 ± 0.2 degrees 2θ.

[0518] 81. The crystalline form as described in any one of Examples 75-80, wherein the XRPD plot has a peak at 18.2 ± 0.2 degrees 2θ.

[0519] 82. The crystalline form as described in any one of Examples 75-81, wherein the XRPD plot has a peak at 15.9 ± 0.2 degrees 2θ.

[0520] 83. The crystalline form as described in any one of Examples 75-82, wherein the XRPD plot has a peak at 24.9 ± 0.2 degrees 2θ.

[0521] 84. The crystalline form as described in any one of Examples 75-83, wherein the XRPD plot has a peak at 17.5 ± 0.2 degrees 2θ.

[0522] 85. The crystalline form as described in Example 75, wherein the crystalline form is form D, and wherein the XRPD plot has peaks at 13.1, 16.4, and 10.4 (± 0.2 degrees 2θ).

[0523] 86. The crystalline form as described in Example 75, wherein the crystalline form is form D, and wherein the XRPD plot has peaks at 13.1, 16.4, 10.4, 16.6, and 23.4 (± 0.2 degrees 2θ).

[0524] 87. The crystalline form as described in Example 75, wherein the crystalline form is form D, and wherein the XRPD plot has peaks at 13.1, 16.4, 10.4, 16.6, 23.4, 18.2, 15.9, 24.9 and 17.5 (± 0.2 degrees 2θ).

[0525] 88. The crystalline form as described in Example 75, wherein the crystalline form is form D, and wherein the XRPD plot is consistent with... Figure 26 The two are essentially the same.

[0526] 89. The crystalline form as described in any one of Examples 75-88, wherein the crystalline form is form D, characterized by a TGA curve showing a weight loss of about 0.7% at about 210°C to about 230°C.

[0527] 90. The crystalline form as described in any one of Examples 75-89, wherein the crystalline form is form D, characterized by being consistent with... Figure 27 The TGA curve shown is essentially the same.

[0528] 91. The crystalline form as described in any one of Examples 75-90, wherein the crystalline form is form D, characterized by being consistent with... Figure 28 The DSC curves shown are essentially the same.

[0529] 92. The crystalline form as described in any one of Examples 75-91, wherein the crystalline form is form D, characterized in that it has a solubility of about 2.25 mg / mL in fasting simulated gastric juice (FaSSGF) at about 37°C after about 30 minutes.

[0530] 93. The crystalline form as described in any one of Examples 75-92, wherein the crystalline form is form D, characterized in that it has a solubility of about 2.33 mg / mL in a fed state simulated intestinal fluid (FeSSIF) at about 37°C after about 24 hours.

[0531] 94. The crystalline form as described in any one of Examples 75-93, wherein the crystalline form is form D, characterized in that it has a solubility of about 2.19 mg / mL after about 30 minutes in fasting simulated intestinal fluid (FaSSIF) at about 37°C.

[0532] 95. The crystalline form as described in any one of Examples 75-94, wherein the crystalline form is form D, characterized in that it has a solubility of about 2.08 mg / mL in water at about 37°C after about 30 minutes.

[0533] 96. The crystalline form as described in any one of Examples 75-95, wherein the crystalline form is form D, prepared by a method comprising: (a) Preparation ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H A solution of -indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid in about 5.5 volumes of ethyl acetate; (b) Add approximately 0.55 equivalents of a 1-molar concentration of hydrogen chloride in ethyl acetate; (c) Add crystals ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H -Indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoate salt in ethyl acetate to form a suspension; (d) Add approximately 1.65 equivalents of a 1-molar concentration solution of hydrogen chloride in ethyl acetate to form a slurry; (e) Stir the slurry at approximately 24°C for approximately 16 hours; (f) Filter the slurry to obtain solids; (g) Wash the solid with ethyl acetate; and (h) Dry the solid to provide a crystalline form.

[0534] 97. A pharmaceutical composition comprising a crystalline form as described in any one of Examples 1-96, and a pharmaceutically acceptable carrier.

[0535] 98. A method for treating a disease or condition associated with complement factor B (CFB), the method comprising administering to a subject suffering from such a disease or condition a therapeutically effective amount of a crystalline form as described in any one of Examples 1-96, or a pharmaceutical composition as described in Example 94.

[0536] 99. A method for treating or preventing diseases or conditions selected from the group consisting of autoimmune diseases or conditions, inflammatory diseases or conditions, metabolic diseases or conditions, nervous system diseases or disorders, lung diseases, respiratory diseases or conditions, ophthalmic diseases, cardiovascular diseases, and kidney diseases, the method comprising administering to a subject suffering from such diseases or conditions a therapeutically effective amount of a crystalline form as described in any one of Examples 1-96, or a pharmaceutical composition as described in Example 97.

[0537] 100. A method for treating or preventing diseases or conditions selected from the following: multiple sclerosis, Guillain-Barré syndrome, traumatic brain injury, Parkinson's disease, age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyanagi-Harada syndrome, intermediate uveitis, shotgun retinal choroiditis, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigoid, non-arteritis-related ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, hemodialysis complications, hyperacute allogeneic graft rejection, xenograft rejection, IL-2-induced toxicity during interleukin-2 therapy, inflammatory conditions, inflammation of autoimmune diseases, Crohn's disease, adult respiratory distress syndrome, myocarditis, ischemia-reperfusion condition, myocardial infarction, stroke, post-pump syndrome during balloon angioplasty, cardiopulmonary bypass, or renal bypass, atherosclerosis. This method involves administering a therapeutically effective amount of the crystalline form as described in any one of Examples 1-96, or the pharmaceutical composition as described in Example 97, to a subject suffering from such diseases or conditions. The treatment includes conditions such as sclerosis, hemodialysis, renal ischemia, mesenteric artery reperfusion after aortic reconstruction, infectious diseases or sepsis, immune complex disorders and autoimmune diseases, rheumatoid arthritis, systemic lupus erythematosus (SLE), SLE nephritis, proliferative nephritis, liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, ARDS, asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and infarction, pneumonia, fibrotic dust disease, pulmonary fibrosis, asthma, allergic reactions, bronchoconstriction, allergic pneumonia, parasitic diseases, pulmonary hemorrhage nephritis syndrome, pulmonary vasculitis, microimmune vasculitis, immune complex-related inflammation, antiphospholipid syndrome, glomerulonephritis, obesity, metabolic syndrome, and hidradenitis suppurativa.

[0538] 101. A method for treating or preventing diseases or conditions selected from the following: kidney disease, chronic kidney disease, diabetic nephropathy, glomerular nephropathy, complement C3 glomerulonephropathy (C3G), IgA nephropathy (IgAN), membranous nephropathy (MN), focal segmental glomerulosclerosis (FSGS), atypical hemolytic uremic syndrome (aHUS), dense deposit disease (DDD), minimal change disease (MCD), paroxysmal nocturnal hemoglobinuria (PNH), ANCA-associated vasculitis, lupus nephritis, and polycystic kidney disease (PKD), the method comprising administering to a subject suffering from such disease or condition a therapeutically effective amount of the crystalline form as described in any one of Examples 1-96, or the pharmaceutical composition as described in Example 97.

[0539] 102. The crystalline form as described in any one of Examples 1-96, or the pharmaceutical composition as described in Example 97, for use in treating the disease or condition of Example 99 or 100 in a subject requiring such treatment.

[0540] Example Materials and Methods X-ray powder diffraction (XRPD) XRPD analysis was performed using copper Kα1 and Kα2 radiation at 1.5418 Å, a nickel filter, and a LynxEye silicon strip detector (40 kV, 40 mA) on a Bruker D8-Advance X-ray diffractometer in a Bragg-Brentano configuration. The slit was set to 0.6 mm divergence, 8 mm antiscattering, and 2.5˚ Soler, and XRPDs were obtained from 1 to 60 2θ degrees.

[0541] Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) Using Mettler Toledo TGA / DSC 3+ TGA and DSC were performed simultaneously on the same sample. Nitrogen was used as the protective and purge gas at flow rates of 20-30 mL / min and 50-100 mL / min, respectively. The required sample volume (5-10 mg) was weighed directly into a sealed aluminum dish with a pinhole and analyzed according to the following parameters:

[0542] Alternative TGA and DSC methods

[0543] Dynamic vapor adsorption (DVS) method

[0544] Solubility Study Solubility was measured at room temperature (RT, 20℃-24℃) by addition and gravimetric methods.

[0545] For the addition method, add approximately 20 mg of the solid to a 2 mL vial, and then slowly add the appropriate solvent until complete dissolution is observed.

[0546] For the gravimetric method, approximately 30 mg of solid was added to a 2 mL vial, followed by 0.75 mL of solvent. The slurry was stirred at a constant temperature for two days. After two days of stirring, the slurry was filtered using a syringe filter, and the supernatant was transferred to a tare vial. The supernatant solution was evaporated to dryness on a hot plate at 50°C, then placed under vacuum at approximately -29 inHg for 3 hours at 50°C, and finally weighed.

[0547] PBS-V1 + 3 mM NaTC Purchase sodium taurocholate (NaTC) from the supplier. Instructions for assaying are provided. Add the equivalent of 3 mM to PBS V1. Stir until dissolved. Equilibrate at 25°C or 37°C for 1 h before use. Discard after 48 h.

[0548] PBS-V1 + FaSSIF-V2 (simulated intestinal fluid during fasting) Purchase FaSSIF-V2 from the supplier (biorelevant.com). Determine the amount to add to PBS-V1 according to Table 1. Stir until dissolved. Equilibrate at 25°C or 37°C for 1 h before use. Discard after 48 h.

[0549] PBS-V1 + 0.3 FeSSIF-V2 (simulated intestinal fluid during feeding) Purchase FeSSIF-V2 from the supplier (biorelevant.com). Determine the amount to add to PBS-V1 according to Table 1. Stir until dissolved. Equilibrate at 25°C or 37°C for 1 h before use. Discard after 48 h.

[0550] PBS-V1 + FeSSIF-V2 (simulated intestinal fluid during feeding) Purchase FeSSIF-V2 from the supplier (biorelevant.com). Determine the amount to add to PBS-V1 according to Table 1. Stir until dissolved. Equilibrate at 25°C or 37°C for 1 h before use. Discard after 48 h.

[0551] PBS-V1 + 2 FeSSIF-V2 (simulated intestinal fluid during feeding) Purchase FeSSIF-V2 from the supplier (biorelevant.com). Determine the amount to add to PBS-V1 according to Table 1. Stir until dissolved. Equilibrate at 25°C or 37°C for 1 h before use. Discard after 48 h.

[0552] Table 1 Summary of the composition of biologically related media

[0553] abbreviation ACN: Acetonitrile THF: Tetrahydrofuran MeOH: Methanol EtOH: Ethanol EA or EtOAc: Ethyl acetate DMSO: Dimethyl sulfoxide IPAc: Isopropyl acetate MEK: Methyl Ethyl Ketone MTBE: tert-butyl methyl ether 2-MeTHF: 2-Methyltetrahydrofuran MIBK: Methyl isobutyl ketone NaTC: Sodium taurocholate NMP: N 2-Methyl-2-pyrrolidone DCM: Dichloromethane XRPD: X-ray powder diffraction TSA: p-Toluenesulfonic acid Tosylate: p-Toluenesulfonate FaSSGF: Simulated gastric juices during fasting FeSSIF: Simulated intestinal fluid during feeding FaSSIF: Simulated intestinal fluid during fasting Kleptose: Hydroxypropyl β-cyclodextrin K value: Vapor-liquid balance ratio Methocel: Hydroxypropyl methylcellulose D 50 Average particle size diameter determined based on particle size distribution Experimental procedures and characterization data Form A Amorphous and Form A crystals ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H Preparation of -indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid Towards( S )-4-((2,2-difluoro-6-(4-(methoxycarbonyl)phenyl)-7-azaspiro[3.5]nonane-7-yl)methyl)-5-methoxy-7-methyl-1 H1 M LiOH aqueous solution (5.0 equivalents) was added to a solution of tert-butyl indole-1-carboxylic acid (1.0 equivalent) in a 1:1 v / v THF / MeOH (0.09 M) mixture. The mixture was heated to 45 °C with stirring for 16 hours. The resulting reaction mixture was diluted with water (to 0.1 M), concentrated to one volume under reduced pressure, and then acidified to pH 6 with citric acid (5% aqueous). The resulting suspension was filtered, washed with one volume of water, and then dried to give an amorphous, off-white solid (87% yield). Figure 1 It is amorphous ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H X-ray powder diffraction pattern of indole-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid.

[0554] At 40-50°C, an amorphous solid was added to a stirred solution of isopropanol (to 0.44 M). After the addition was complete, the solution was cooled to 20°C and the resulting suspension was stirred for 72 hours. The suspension was filtered, washed with one volume of isopropanol, and then dried to produce a grayish-white crystalline solid (94% yield). 1 H-NMR (400 MHz, DMSO-d6): δ 10.82 (s,1H), 7.97 (d, J = 7.9 Hz, 2H), 7.68 (d, J = 7.8 Hz, 2H), 7.25 (t, J = 2.9 Hz, 1H), 6.65 (s, 1H), 6.45 (s, 1H), 3.70 (s, 3H), 3.53 (d, J = 11.8 Hz, 1H), 3.23 (s,1H), 3.16 (d, J = 11.9 Hz, 1H), 2.67 (d, J = 12.4 Hz, 1H), 2.59 (d, J = 13.1 Hz,1H), 2.46 (s, 1H), 2.43 (s, 3H), 2.29 (t, J = 13.3 Hz, 2H), 1.98 (s, 1H), 1.70(d, J = 9.0 Hz, 2H), 1.53 (d, J = 9.5 Hz, 2H). LCMS (ESI) m / z 455 (M+1)+. The obtained form is A crystal ( S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H The X-ray powder diffraction pattern of indole-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid is depicted on Figure 2 middle.

[0555] Table 2. List of XRPD peaks for form A.

[0556] Thermogravimetric analysis (TGA) spectral plots depicted on Figure 3 The differential scanning calorimetry (DSC) image is displayed in the image. Figure 4 middle.

[0557] Form A crystals ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H Alternative preparation of (-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid Approximately 3.0 g of amorphous ( S )-4-((2,2-difluoro-6-(4-(methoxycarbonyl)phenyl)-7-azaspiro[3.5]nonane-7-yl)methyl)-5-methoxy-7-methyl-1 H 1-Indole-1-carboxylic acid tert-butyl ester was weighed into a 50 mL LeasyMax reactor, and then 20 mL of MeOH was added. The suspension was heated to 50 °C and stirred at 500 rpm for 20 min, then inoculated with previously prepared form A crystals. After holding at 50 °C for 3 h, the suspension was cooled to 25 °C over 250 min, and then heated to 50 °C over 30 min. After aging again at 50 °C for 3 h, the suspension was cooled to 5 °C and stirred overnight. The suspension was filtered, and the filter cake was dried under vacuum at 50 °C overnight. 2.4 g of dried solid was obtained, with a yield of 80%. The molecular formula of the anhydrous free form is C1. 26 H 28 F₂N₂O₃ (454.52 g / mol). The solid's... 1 H NMR (400 MHz, DMSO-d6) was characterized in Figure 8 middle.

[0558] The X-ray powder diffraction pattern of Form A (alternative preparation) is depicted in Figure 5 middle.

[0559] Differential scanning calorimetry (DSC) of Form A (alternative preparation) is shown in Figure 6 Thermogravimetric analysis pyrograph of form A (alternative preparation) is depicted in... Figure 7 middle.

[0560] Form A shows as follows Figure 9 The plate-like shape in the middle.

[0561] Form B Form B ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H Preparation of p-toluenesulfonate of indole-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid amorphous ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H 5 g of indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid was added to a 100 mL EasyMax container, followed by p-toluenesulfonic acid monohydrate (TSA•H2O) (2.30 g, 1.1 equivalents). Ethanol (EtOH) (17.5 mL, 3.5 vol.) was then added, and the resulting suspension was stirred (240 rpm) and heated to 50 °C for 15 min, then cooled to 25 °C over 15 min to produce a clear, dark brown solution. Ethyl acetate (12.5 mL, 2.5 vol.) was added, and the mixture was allowed to stand at 25 °C for 30 min. Ethyl acetate (37.5 mL, 7.5 vol.) was then added to the reactor via a feed pump over 2 hours. After the antisolvent addition was complete, the purple slurry was allowed to stand at 25 °C for 1 h.

[0562] The final slurry was filtered, washed twice with 2 volumes of EtOH:EtOAc (26:74 v / v), and drained until a transferable powder was obtained. Filtration was advantageous, with a K value of 10.4 cm² / (min•bar).

[0563] The solids were transferred to tare bottles and dried in a vacuum oven at 50 °C (approximately -29 in Hg) for 16 h. The solids were separated in a yield of 79 mol%.

[0564] Form B was prepared by heating an initial p-toluenesulfonate (300 mg) in IPA:water (9:1 vol., 1.5 mL) at 50 °C for 16 h. The resulting slurry was sampled by XRPD, then cooled to room temperature and filtered. The resulting wet filter cake solids were dried in a vacuum oven at 50 °C under active vacuum. The yield was 237 mg (79% w / w).

[0565] The X-ray powder diffraction pattern of form B is shown in Figure 12 The XRPD peak table is shown below.

[0566] Table 3. List of XRPD peaks in Form B

[0567] Thermogravimetric analysis (TGA) spectral plots depicted on Figure 13 The differential scanning calorimetry (DSC) image is displayed in the image. Figure 14 middle.

[0568] Form B ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H Alternative Preparation of p-Toluenesulfonate of Indole-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic Acid Approximately 10 g of (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid and 1.05 eq of p-TsOH monohydrate (approximately 4.45 g) were weighed into a 400 mL LeasyMax reactor. 10 mL of water and 90 mL of acetone were added to the reactor, and the solution was heated to 50 °C. The solution was stirred at 300 rpm for 20 min, then cooled to 25 °C. The solution was seeded with 50 mg of previously prepared form B crystals. The temperature was maintained for 1 h, and then 220 mL of water was added over 5 h. After maintaining for 2 h, the reaction was cooled to 5 °C over 2 h and stirred overnight. The suspension was filtered and the filter cake was dried under vacuum at 40°C for 24 hours to produce 11.59 g of p-toluenesulfonate of B(S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid (80%). 1 H-NMR (400 MHz, DMSO-d6): δ 11.19 (s, 1H), 8.14 (d, 2H), 7.84 (d, 1H), 7.49 (m, 3H), 7.11 (d, 2H), 6.77 (s, 1H), 6.39(t, 1H), 4.63 (m, 1H), 4.23 (m, 1H), 4.08 (d, 1H), 3.69 (s, 3H), 3.41 (m,2H), 2.67-2.82 (m, 2H), 2.48 (s, 3H), 2.45 (m, 2H), 2.28 (s, 3H), 1.98-2.23(m, 2H), 1.79 (d, 2H)( Figure 18 The molecular formula of anhydrous p-toluenesulfonate is C2. 26 H28 F2N2O3·C7H8O3S (626.72 g / mol).

[0569] The obtained X-ray powder diffraction pattern of form B (alternative preparation) is depicted in Figure 15 middle.

[0570] Table 4. List of XRPD peaks for Form B (alternative preparation I)

[0571] Thermogravimetric analysis (TGA) spectral plots depicted on Figure 17 The differential scanning calorimetry (DSC) image is displayed in the image. Figure 16 In the middle. Form B shows as follows: Figure 19 The plate-like shape in the middle.

[0572] Form B ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H Alternative Preparation of p-Toluenesulfonate of Indole-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic Acid II 2.0 g of (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid and 0.89 g of p-toluenesulfonic acid were weighed into a 100 mL reactor. 16.2 g of acetone / water (9 / 1, v / v) was added, and the solution was stirred at 250 rpm at 25 °C. 10 mL of water was added, followed by 5 mg of seed, and the mixture was kept in this state for 2 h. 30 mL of water was added over 4 h, and the solution was cooled to 5 °C over 2 h. After keeping the mixture at 5 °C overnight, the suspension was filtered, and the filter cake was dried under vacuum at 50 °C overnight. 2.2 g of dried solid was obtained, with a yield of 80%.

[0573] Water content in forms A and B Under ambient conditions, by Karl Fischer titration, form B contains 2.3% w / w water relative to the total weight of p-toluenesulfonate, while form A contains 0.15% w / w water relative to the total weight of the free form.

[0574] The mass changes measured by the DVS isotherm (2 cycles, 40-0-95-0-40% RH) are shown in the table below. Mass changes are based on the dry weight of each.

[0575] Table 5. Mass changes of forms A and B measured by DVS at 25℃.

[0576] After the DVS experiment, the XRPD curve did not change.

[0577] In DVS, at 95% RH and 25°C, the maximum water absorption rate of form B is 2.67%.

[0578] Table 6. Mass changes of Form B measured by DVS at 25℃ and 40℃

[0579] Stability of forms A and B In bulk, form A exhibits chemical stability after one week of storage at 50°C and 11% or 75% RH. When stored at 80°C and 11% or 75% RH, approximately 0.1% to 0.3% degradation occurs, with slight to moderate discoloration observed. Form A demonstrates chemical and physical stability after two weeks of storage in HPMC and HGC capsules at 50°C and 11% and 75% RH. Approximately 0.9% degradation occurs upon exposure to 1200 kLux light stress. Under stress conditions, the polymorphic form remains unchanged.

[0580] In bulk, form B exhibits chemical stability after one week of storage at 50°C and 11% RH, 50°C / 75% RH, and 80°C / 11% RH. However, approximately 0.1% degradation and slight discoloration were observed when stored at 80°C and 75% RH. Form B demonstrates chemical and physical stability after two weeks of storage in HPMC and HGC capsules at 50°C and 11% and 75% RH. Approximately 0.2% degradation and slight discoloration were observed upon exposure to 1200 kLux light stress. Under stress conditions, this form remains unchanged.

[0581] When exposed to 80% or 92% RH for 24 hours, there was no change in form A or B as shown by XRPD.

[0582] Solubility of forms A and B The solubility of forms A and B in water and bio-associated buffers at 25 °C was collected at 24 h. Form B showed a significantly increased solubility than form A in all media at 24 h.

[0583] Table 7. Solubility (mg / mL) in water and biologically relevant buffer solutions at 25°C

[0584] " / / ": No test was performed due to solution clarification or limited residual material. "-": No formal changes Inherent solubility of forms A and B The intrinsic solubility rate of form A in 0.01 M HCl at pH 2.0 is 0.081 mg / min / cm. 2 ( Figure 10 The dissolution rate of form B in the same medium is 0.015 mg / min / cm³, which is higher than the inherent dissolution rate of form B. 2 ( Figure 20 In PBS-V1 (pH 6.5), the intrinsic dissolution rate of form A is 0.0028 mg / min / cm. 2 ( Figure 11 Form B showed a much higher dissolution rate (0.18 mg / min / cm³), while form B showed a much higher dissolution rate (0.18 mg / min / cm³). 2 () Figure 21 ).

[0585] Compression stability of forms A and B When form A or B is subjected to 4 tons of compression for 5 minutes, there is no form change in XRPD.

[0586] Methods: Approximately 100 mg of the active pharmaceutical ingredient (API) was compressed for 5 min at 4 t using a hydraulic press (tablet diameter 8 mm). The sample was then characterized by XRPD to detect any changes in solid state.

[0587] Grinding and wet granulation of forms A and B Dry milling (2 min and 5 min) and wet granulation (water and ethanol) did not cause any change in form A and B. However, a decrease in crystallinity was observed in the XRPD plot after milling.

[0588] Method: Obtain particles in solid form. Add granulation solvent dropwise until the solid is fully wetted. Grind the wet solid for about 2 min. Dry the wet filter cake under vacuum or atmospheric pressure. Evaluate the solid form and crystallinity by, for example, XRPD and / or DSC.

[0589] Flow characteristics of form B Form B exhibits good flowability and good bulk density, both of which are suitable for precision pharmaceutical processing filler formulations (ultrasonic processing and vibration modules). See U.S. Patent No. 11,642,315.

[0590] Dissolution of Form B in Capsules Capsules containing form B showed 100% solubility in FaSSGF and FeSSIF within 40 min. Figure 22 The particle size of the material used was characterized as 53.2 µm (x50). The test conditions were as follows: - Dosage / Specification, 25 mg (calculated in free form) HGC capsules, No. 3 - 450 mL FaSSGF (pH 1.6) + 450 mL FaSSIF (2x, pH 7.5) - Temperature 37℃ - Paddle technique, 75 rpm - Spiral settling plate Add FaSSIF (2x, pH 7.5) after 30 min. - Repeated testing Summary of Forms A and B Forms A and B exhibit the desired properties in all respects. However, form B offers improved solubility and dissolution profile, as well as flow characteristics suitable for capsule formulation methods.

[0591] To prevent the formation of toluenesulfonates, which are known to have genotoxic effects, the use of methanol, ethanol, or any other alcohol should be carefully avoided during the manufacture of active pharmaceutical ingredients or pharmaceutical products.

[0592] Form C Form C ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H Preparation of p-toluenesulfonate of indole-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid amorphous ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H 5 g of indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid and p-toluenesulfonic acid monohydrate (TSA•H2O) (2.30 g, 1.1 equivalents) were added to a 100 mL EasyMax container. Ethanol (17.5 mL, 3.5 vol.) was then added, and the resulting suspension was heated to 50 °C with stirring (240 rpm) for 15 min, followed by cooling to 25 °C over 15 min. EtOAc (12.5 mL, 2.5 vol.) was added to the resulting clear, dark brown solution, and the mixture was allowed to stand at 25 °C for 30 min. EtOAc (37.5 mL, 7.5 vol.) was then added to the reactor over 2 h using a feed pump. After the antisolvent addition was complete, the purple slurry was aged at 25 °C for 1 h. The final slurry was filtered, washed twice with 2 volumes of EtOH : EtOAc (26 : 74 v / v), and drained until a transferable powder was obtained.

[0593] Figure 23 Here is the X-ray powder diffraction pattern of form C, and the XRPD peak table is shown below.

[0594] Table 8. Form C ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H List of XRPD peaks for p-toluenesulfonate of indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid.

[0595] Thermogravimetric analysis (TGA) spectral plots depicted on Figure 24 The differential scanning calorimetry (DSC) image is displayed in the image. Figure 25 middle.

[0596] Form C ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H Alternative Preparation of p-Toluenesulfonate of Indole-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic Acid 1 g of form B was dissolved in 3 mL of MeOH, and the solution was then added to 15 mL of EA. The suspension was filtered after several hours, and the filter cake was vacuum dried overnight at 40 °C to produce approximately 650 mg of form C (65%).

[0597] X-ray powder diffraction pattern of form C and Figure 23 Consistent.

[0598] Polymorphic stability The competitive balance between form B and form C shows that form B is a stable polymorphic form in all tested solvents or solvent mixtures.

[0599] Form D Form D ( S Preparation of 4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoate Towards amorphous ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 HA solution of -indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid in EtOAc (5.5 vol.) was prepared by adding a portion (0.55 equivalents) of 1 M HCl in EtOAc, followed by the addition of seed slurry to produce a gray suspension. The remaining 1 M HCl in EtOAc (1.65 equivalents) was then added in one go to produce a thick gray slurry. The resulting thick slurry was stirred and aged at 24 °C for 16 h. The resulting slurry was filtered and washed twice with 1.5 volumes of top EtOAc. The filter cake was dried under vacuum to give a grayish-white solid (71% yield). The X-ray powder diffraction pattern of form D is shown in the figure. Figure 26 In the middle. Thermogravimetric analysis pyrograph depicted on Figure 27 The differential scanning calorimetry (DSC) image is displayed in the image. Figure 28 middle.

[0600] Table 9. List of XRPD peaks for form D.

[0601] Solubility Study Form A ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H -indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid, form B ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H -indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid p-toluenesulfonate, form C( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H -indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid p-toluenesulfonate and form D( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H Solubility data of -indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoate in simulated solution at 37 °C Table 10

[0602] Pharmacokinetic studies The assessment was conducted ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 HPharmacokinetic characteristics of (-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid as an amorphous compound in rats, dogs or non-human primates (NHP) as a solution of 20% kleptose in water and as a suspension of form A in water in 0.5% methocel + 0.1% tween 80.

[0603] Preparation of amorphous solution formulations amorphous ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H Weigh indo-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid into a glass vial with a magnetic stir bar to give a dosage concentration of 0.1-1000 mg / kg. Add approximately 1 / 3 of the final volume of 20% kleptose in water (hydroxypropyl β-cyclodextrin, Aldrich, CAS No. 128446-35-5) to the vial (to give a dosage volume of 5 mL / kg or 10 mL / kg depending on the species). Alkalize the mixture to pH 8.5-10 by adding 2-5 M NaOH aqueous solution dropwise, and monitor the pH. Stir, vortex, and sonicate the suspension for 15-20 minutes to obtain a homogeneous mixture. Add a second 1 / 3 of the final volume of 20% kleptose to the vial and stir, vortex, and sonicate further for 15-20 minutes to obtain a homogeneous mixture. Monitor the pH value and, if necessary, further adjust it to pH 8.5 to 10. Add the last 1 / 3 of the final volume of 20% kleptose to the vial and stir, vortex, and sonicate for 15–20 minutes to obtain a homogeneous solution. Adjust the pH of the solution to 7.5 to 8.0 by adding dropwise 1.0 M HCl aqueous solution with gentle stirring. The preparation should remain in solution.

[0604] Table 10 describes the pharmacokinetic characteristics of the amorphous solution formulation after oral administration.

[0605] Table 11. Amorphous ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H -indol-4-yl)methyl)-7- Pharmacokinetic characteristics of azirospiro[3.5]nonane-6-yl)benzoic acid.

[0606] Preparation of Form A Suspension Formulation Crystallize form A ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H-Indo-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid is weighed into a glass vial equipped with a magnetic stir bar to provide a dosage concentration of 0.1-1000 mg / kg. The particle size of the crystalline material should preferably be D. 50 Below 50 µm, and ideally D 50 Below 5 µm. Add the required volume of 0.5% methocel (viscosity 400 cP, Aldrich, CAS No. 9004-67-5) / 0.1% tween-80 (Aldrich, CAS No. 9005-65-6) (to obtain a 5 mL / kg dose volume). Stir the vial contents on a stirring plate at 400–500 rpm. Gentle vortexing or sonication can be applied to break up any large clumps. The vial should be thoroughly mixed to ensure homogeneity before administration to the animal.

[0607] Table 12 describes the pharmacokinetic characteristics of the crystalline suspension formulation after oral administration.

[0608] Table 12. Form A crystals ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H -indol-4-yl)methyl)- Pharmacokinetic characteristics of 7-azaspiro[3.5]nonane-6-yl)benzoic acid.

[0609] 1. Particle size D 50 = 5.1 µm. 2. Particle size D 50 = 101 µm.

[0610] Form A exhibits a higher form of C than amorphous forms. max AUC 0-24h and C 24h This results in a higher overall exposure and smaller particle size. This is because smaller particles have a larger surface area.

[0611] Several embodiments of this disclosure have been described. However, it should be understood that various modifications may be made without departing from the spirit and scope of this disclosure. Accordingly, other embodiments are described in the claims.

Claims

1. A kind of ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H Crystalline form of (-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid.

2. The crystalline form of claim 1, wherein the crystalline form is form A, and wherein the XRPD plot has peaks at 10.7, 20.5, and 18.8 (± 0.2 degrees 2θ).

3. The crystalline form of claim 1, wherein the crystalline form is form A, and wherein the XRPD plot has peaks at 10.7, 20.5, 18.8, and 21.7 (± 0.2 degrees 2θ).

4. The crystalline form of claim 1, wherein the crystalline form is form A, and wherein the XRPD plot has peaks at 10.7, 20.5, 18.8, 21.7, 19.6, 19.8, 12.5, 21.1, 23.3, 22.5, 27.3, and 15.5 (± 0.2 degrees 2θ).

5. The crystalline form according to any one of claims 1-4, wherein the crystalline form is form A having a thermogravimetric analysis (TGA) curve characterized by a weight loss of approximately 0.51% at 150°C when heated from 30°C to 300°C at a rate of 10 K / min.

6. The crystalline form as described in claim 1, wherein ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H -Indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid is in free form, and further wherein the free form is anhydrous.

7. A kind of ( S )-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1 H The crystalline form of p-toluenesulfonate of (-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)benzoic acid.

8. The crystalline form of claim 7, wherein the crystalline form is form B, and wherein the XRPD diagram is at 11.

8. 0 9.3 0 It has a peak at 19.9 (± 0.2 degrees 2θ).

9. The crystalline form of claim 7, wherein the crystalline form is form B, and wherein the XRPD plot has peaks at 11.8, 9.3, 19.9, and 22.9 (± 0.2 degrees 2θ).

10. The crystalline form of claim 7, wherein the crystalline form is form B, and wherein the XRPD plot has peaks at 11.8, 9.3, 19.9, 22.9, 17.2, 10.2, 20.4, 21.3 and 14.2 (±0.2 degrees 2θ).

11. The crystalline form of claim 7, wherein the crystalline form is form B, and wherein form B contains 0% to 2.7% w / w of water.

12. The crystalline form according to any one of claims 7-11, wherein the crystalline form is form B having a TGA curve characterized by a weight loss of about 1.9% to about 2.0% at 100°C when heated from 30°C to 300°C at 10 K / min.

13. The crystalline form according to any one of claims 7-11, wherein the crystalline form is form B having a DSC thermogram, characterized in that when heated from 30°C to 300°C at a rate of 10 K / min, at T 起始 = 29.8℃ and T 峰 = A broad endothermic peak at 65℃.

14. The crystalline form according to any one of claims 7-11, wherein the crystalline form is form B, which absorbs up to 2.7% moisture by dynamic vapor adsorption (DVS) at 25°C and 95% RH.

15. A pharmaceutical composition comprising a crystalline form as described in any one of claims 1-14, and a pharmaceutically acceptable carrier.

16. A method of treating a disease or condition associated with complement factor B (CFB), the method comprising administering to a subject suffering from such a disease or condition a therapeutically effective amount of the crystalline form as described in any one of claims 1-14, or the pharmaceutical composition as described in claim 15.

17. The method of claim 16, wherein the disease or condition associated with complement factor B (CFB) is selected from the group consisting of: age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyanagi-Harada syndrome, intermediate uveitis, shotgun retinal choroiditis, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigoid, non-arteritis-associated ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, glaucoma, multifactorial celluloid retinal dystrophy / familial dominant drusen, Sotheby's retinal dystrophy, late-onset macular dystrophy, North Carolina Macular dystrophy, macular degeneration, corneal inflammation, multiple sclerosis, stroke, Guillain-Barré syndrome, spinal cord injury, traumatic brain injury, Parkinson's disease, Alzheimer's disease, schizophrenia, amyotrophic lateral sclerosis (ALS), Huntington's disease, multifocal motor neuropathy, autism spectrum disorder, schizophrenia, drug-induced neurotoxicity, hemodialysis complications, hyperacute allogeneic graft rejection, xenograft rejection, IL-2-induced toxicity during interleukin-2 therapy, inflammatory conditions, paroxysmal nocturnal hemoglobinuria, C3 glomerulonephritis (including dense deposit disease and C3 glomerulonephritis), immune complex membrane proliferative glomerulonephritis (IC-MPGN), IgA nephropathy, including idiopathic... Membranous nephropathy, diabetic nephropathy, atypical hemolytic uremic syndrome (aHUS), hemolytic uremic syndrome, STEC-HUS (Shiga toxin-producing Escherichia coli hemolytic uremic syndrome), periodontitis, CD55 deficiency with complement hyperactivation, vascular thrombosis, protein-losing enteropathy (CHAPLE syndrome), Crohn's disease, neuromyelitis optica (NMO), IgA vasculitis (formerly known as allergic purpura or HSP), hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA), adult respiratory distress syndrome (ARDS), myocarditis, ischemia-reperfusion condition, myocardial infarction, post-pump syndrome after balloon angioplasty, cardiopulmonary bypass, or renal bypass. Atherosclerosis, hemodialysis, renal ischemia, acute kidney injury, mesenteric artery reperfusion after aortic reconstruction, COVID-19, rheumatoid arthritis, osteoarthritis, spondyloarthritis, psoriatic arthritis, systemic lupus erythematosus (SLE), lupus nephritis, SLE nephritis, proliferative nephritis, myasthenia gravis, liver fibrosis, hemolytic anemia, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, acute respiratory distress syndrome (ARDS), asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and infarction, pneumonia, fibrotic dust disease, pulmonary fibrosis, asthma, allergic reactions, bronchoconstriction, allergic pneumonia, parasitic diseases, pulmonary hemorrhage nephritis syndrome, pulmonary vasculitis, microimmune vasculitis.Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), Berger's vasculitis, cryoglobulinemia, Kawasaki disease, aortitis, cryoglobulinemia, immune complex-related inflammation, antiphospholipid syndrome, glomerulonephritis and obesity, immune thrombocytopenic purpura, cold agglutinin disease, warm antibody-type autoimmune hemolytic anemia (wAIHA), thrombotic thrombocytopenic purpura (TTP), abdominal aortic aneurysm, Graves' disease, and hidradenitis suppurativa.

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