Salts and solid forms of compounds having GLP-1 agonist activity

Abstract

The present disclosure relates to salts and solid forms of compounds that are GLP-1 agonists, and their use as therapeutic agents for the treatment of diseases, disorders or conditions associated with GLP-1, such as type 2 diabetes mellitus (T2DM).

Description

Cross-references to related applications

[0001] This application claims the benefit of International Patent Application No. PCT / CN2022 / 139277, filed on December 15, 2022, the contents of which are hereby incorporated in their entirety. Technical Field

[0002] This disclosure generally relates to salt and solid forms of GLP-1 agonists, pharmaceutical compositions, and methods of use thereof. Background Technology

[0003] This disclosure relates to the salt and solid forms of compounds that are glucagon-like peptide-1 (GLP-1) agonists, and their use as therapeutic agents for the treatment of GLP-1-related diseases, disorders, or conditions such as type 2 diabetes mellitus (T2DM). Summary of the Invention

[0004] This disclosure provides salts and solid forms of compound I (CAS Registry No.: 2685823-26-9), as well as their eutectics and solvates. It also describes methods for preparing salts and solid forms of compound I, pharmaceutical compositions comprising salts or solid forms of compound I, and methods for using said salts and solid forms or said pharmaceutical compositions in the treatment of GLP-1-related diseases. Attached Figure Description

[0005] Figure 1A The X-ray powder diffraction (XRPD) of compound I in L-arginine salt form A is shown.

[0006] Figure 1B The differential scanning calorimetry (DSC) curves of compound I in L-arginine salt form A are shown.

[0007] Figure 1C Thermogravimetric analysis (TGA) plot of compound I in L-arginine salt form A is shown.

[0008] Figure 2A The XRPD of compound I in L-arginine salt form B is shown.

[0009] Figure 2B The DSC curve of compound IL-arginine salt form B is shown.

[0010] Figure 2C The TGA graph of compound I in L-arginine salt form B is shown.

[0011] Figure 3A XRPD of compound I in L-arginine salt form C is shown.

[0012] Figure 3B The DSC curve of compound C in the form of IL-arginine salt is shown.

[0013] Figure 3C The TGA graph of compound I in L-arginine salt form C is shown.

[0014] Figure 4A The XRPD of compound I in its free acid form A is shown.

[0015] Figure 4B The DSC curve of compound I in its free acid form A is shown.

[0016] Figure 4C The TGA graph of compound I in its free acid form A is shown.

[0017] Figure 5A The XRPD of compound I in its free acid form B is shown.

[0018] Figure 5B The DSC curve of compound I in its free acid form B is shown.

[0019] Figure 5C The TGA graph of compound I in its free acid form B is shown.

[0020] Figure 6A The XRPD of compound I in its free acid form C is shown.

[0021] Figure 6B The DSC curve of compound I in its free acid form C is shown.

[0022] Figure 6C The TGA graph of compound I in its free acid form C is shown.

[0023] Figure 7A The XRPD of compound I in its free acid form D is shown.

[0024] Figure 7B The DSC curve of compound I in its free acid form D is shown.

[0025] Figure 7C The TGA graph of compound I in its free acid form D is shown.

[0026] Figure 8A The XRPD of compound I in its free acid form E is shown.

[0027] Figure 8B The DSC curve of compound I in its free acid form E is shown.

[0028] Figure 8C The TGA graph of compound I in its free acid form E is shown.

[0029] Figure 9A XRPD of compound I in its free acid form F is shown.

[0030] Figure 9B The DSC curve of compound I in its free acid form F is shown.

[0031] Figure 9C The TGA graph of compound I in its free acid form F is shown.

[0032] Figure 10A The XRPD of compound I in its free acid form G is shown.

[0033] Figure 10B The DSC curve of compound I in its free acid form G is shown.

[0034] Figure 10C The TGA graph of compound I in its free acid form G is shown.

[0035] Figure 11A XRPD of compound I in its free acid form H is shown.

[0036] Figure 11B The DSC curve of compound I in its free acid form H is shown.

[0037] Figure 11C The TGA graph of compound I in its free acid form H is shown.

[0038] Figure 12A The XRPD of compound I in its free acid form I is shown.

[0039] Figure 12B The DSC curve of compound I in its free acid form I is shown.

[0040] Figure 12C The TGA graph of compound I in its free acid form I is shown.

[0041] Figure 13A The XRPD of compound I in its free acid form J is shown.

[0042] Figure 13B The DSC curve of compound I in its free acid form J is shown.

[0043] Figure 13C The TGA graph of compound I in its free acid form J is shown.

[0044] Figure 14A The XRPD of compound I in its free acid form K is shown.

[0045] Figure 14B The DSC curve of compound I in its free acid form K is shown.

[0046] Figure 14CThe TGA graph of compound I in its free acid form K is shown.

[0047] Figure 15A XRPD of compound I in its free acid form L is shown.

[0048] Figure 15B The DSC curve of compound I in its free acid form L is shown.

[0049] Figure 15C The TGA graph of compound I in its free acid form L is shown.

[0050] Figure 16A The XRPD of compound I in its free acid form M is shown.

[0051] Figure 17A The XRPD of compound I in its free acid form N is shown.

[0052] Figure 17B The DSC curve of compound I in its free acid form N is shown.

[0053] Figure 17C The TGA graph of compound I in its free acid form N is shown.

[0054] Figure 18A XRPD of compound I in sodium salt form A is shown.

[0055] Figure 18B The DSC curve of sodium salt form A of compound I is shown.

[0056] Figure 18C The TGA graph of sodium salt form A of compound I is shown.

[0057] Figure 19A XRPD of compound I in sodium salt form B is shown.

[0058] Figure 20A XRPD of compound I in potassium salt form A is shown.

[0059] Figure 20B The DSC curve of potassium salt form A of compound I is shown.

[0060] Figure 20C The TGA graph of potassium salt form A of compound I is shown. Detailed Implementation

[0061] Compound 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one is referred to herein as Compound I, and has the following formula:

[0062] Compound I is a GLP-1 agonist. Its synthesis and use are described in PCT International Application Publication No. WO 2021 / 155841, which is incorporated herein by reference in its entirety.

[0063] While not wishing to be bound by any particular theory, certain solid forms are characterized by physical properties suitable for pharmaceutical and therapeutic dosage forms, such as stability, solubility, and dissolution rate. However, while not wishing to be bound by any particular theory, certain solid forms are characterized by physical properties (e.g., density, compressibility, hardness, morphology, cleavage, viscosity, solubility, water absorption, electrical properties, thermal behavior, solid-state reactivity, physical stability, and chemical stability) that affect specific processes (e.g., yield, filtration, washing, drying, grinding, mixing, tableting, flowability, dissolution, formulation, and lyophilization), making certain solid forms suitable for manufacturing solid dosage forms. As described herein, such properties can be determined using specific analytical chemistry techniques, including solid-state analysis techniques (e.g., X-ray diffraction, microscopy, spectroscopy, and thermal analysis).

[0064] The identification and selection of solid forms for pharmaceutical compounds is complex because variations in solid form can affect a wide range of physical and chemical properties that can provide benefits or drawbacks in processing, formulation, stability, bioavailability, storage and handling (e.g., transportation), and other important pharmaceutical characteristics. Useful pharmaceutical solids include crystalline and amorphous solids, depending on the product and its administration method. Amorphous solids are characterized by a lack of long-range structural order, while crystalline solids are characterized by periodic structures. The desired category of pharmaceutical solid depends on the specific application; amorphous solids are sometimes selected based on, for example, enhanced dissolution profiles, while crystalline solids may be desirable for properties such as physical or chemical stability.

[0065] Whether crystalline or amorphous, the solid forms of pharmaceutical compounds include single-component and multi-component solids. Single-component solids consist primarily of the pharmaceutical compound or active ingredient, without other compounds present. The diversity of single-component crystalline materials can potentially stem from polymorphism, where a particular pharmaceutical compound can exist in multiple three-dimensional arrangements.

[0066] It is noteworthy that the existence of a crystalline form of a compound cannot be predicted a priori, let alone how it can be successfully prepared (see, for example, Braga and Grepioni, 2005, “Making crystals from crystals: a green route to crystal engineering and polymorphism,” Chem. Commun.: 3635-3645 (in terms of crystal engineering, the results can be unpredictable if the instructions are not very precise and / or if other external factors influence the process); Jones et al., 2006, Pharmaceutical Cocrystals: An Emerging Approach to Physical Property Enhancement,” MRS Bulletin 31: 875-879 (currently, even for the simplest molecules, it is generally impossible to predict the number of observable polymorphs by calculation); Price, 2004, “The computational prediction of pharmaceutical crystal structures and polymorphism,” Advanced Drug Delivery Reviews 56: 301-319 (“Price”); and Bernstein, 2004, “Crystal Structure Prediction and…” Polymorphism, “ACA Transactions 39:14-23” (Before one can have the ability to assert predictions of crystal structures with any degree of confidence, much more learning and work is still needed, not to mention polymorphic forms).

[0067] The variety of possible solid forms creates a potential diversity of physical and chemical properties for a given drug compound. The discovery and selection of solid forms are crucial for developing effective, stable, and marketable drug products. 1. Definition

[0068] As used in this specification, the following words and phrases are generally intended to have the meanings set forth below, unless the context in which they are used indicates otherwise.

[0069] The term “comprise” and its variations, such as “comprises” and “comprising”, should be interpreted in an open, inclusive sense, meaning “including but not limited to”. Unless the context clearly indicates otherwise, the singular forms “a,” “an,” and “the” include plural indicators. Therefore, references to “the compound” include a variety of such compounds, and references to “the assay” include references to one or more assays known to those skilled in the art and their equivalents.

[0070] This document refers to the term "about" for a value or parameter, including (and describing) embodiments relating to that value or parameter itself. In some embodiments, the term "about" includes ±10% of the indicated amount. In other embodiments, the term "about" includes ±5% of the indicated amount. In some other embodiments, the term "about" includes ±2.5% of the indicated amount. In some other embodiments, the term "about" includes ±1% of the indicated amount. Furthermore, the term "about x" includes a description of "x".

[0071] The range of values ​​listed throughout this disclosure is intended to be used as a shorthand for each individual value (including the value that defines the range) falling within that range, and each individual value is incorporated into the specification as if it were individually listed herein.

[0072] This document provides for the form of compound I or its salts, eutectics, solvates, or hydrates. In one embodiment, reference to the form of compound I or its salts, eutectics, solvates, or hydrates means that at least 50% to 99% (e.g., at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of compound I or its salts, eutectics, solvates, or hydrates are present in the composition in the specified form. For example, in one embodiment, reference to the free acid form A of compound I means that at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% of compound I is present in the composition as a free acid in form A.

[0073] The term "solid form" refers to a solid material, including both amorphous and crystalline forms. The term "crystalline form" refers to polymorphs, solvates, hydrates, etc. The term "polymorph" refers to a specific crystal structure possessing particular physical properties such as X-ray diffraction and melting point.

[0074] The term "eutectic" refers to a molecular complex formed by the disclosed compound and one or more non-ionized eutectic forms linked by non-covalent interactions. In some embodiments, the eutectic disclosed herein may comprise a non-ionized form of compound I (e.g., a free form of compound I) and one or more non-ionized eutectic forms, wherein the non-ionized compound I and one or more eutectic forms are linked by non-covalent interactions. In some embodiments, the eutectic disclosed herein may comprise an ionized form of compound I (e.g., a salt of compound I) and one or more non-ionized eutectic forms, wherein the ionized compound I and one or more eutectic forms are linked by non-covalent interactions. The eutectic may additionally exist in anhydrous, solvated, or hydrated forms. In some cases, the eutectic may have improved properties compared to the parent form (i.e., a free molecule, zwitterion, etc.) or a salt of the parent compound. Improved properties may include increased solubility, increased dissolution rate, increased bioavailability, increased dose-response, reduced hygroscopicity, increased stability, crystalline form of compounds that are normally amorphous, crystalline form of compounds that are difficult or impossible to salt, reduced form diversity, and a more desirable morphology. Methods for preparing and characterizing eutectics are known to those skilled in the art.

[0075] The terms “cocrystal former” or “co-forming agent” refer to one or more pharmaceutically acceptable bases or pharmaceutically acceptable acids disclosed herein that associate with Compound I or any other compound disclosed herein.

[0076] The term "solvent" refers to a complex formed by the combination of solvent molecules with molecules or ions of a solute. Solvents can be organic compounds, inorganic compounds, or mixtures of both. As used herein, the term "solvent" includes "hydrate" (i.e., a complex formed by the combination of water molecules with molecules or ions of a solute), hemihydrate, channel hydrate, etc. The term "heterogeneous solvate" refers to a complex comprising a mixture of one or more different organic solvents and / or water. Some examples of solvents include, but are not limited to, methanol, N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, and water.

[0077] The term "desolvated" refers to a form of compound I that is a solvate as described herein, wherein the solvent molecules have been partially or completely removed. Desolvation techniques for producing a desolvated form include, but are not limited to, exposing the compound I form (solvate) to a vacuum, subjecting the solvate to elevated temperatures, exposing the solvate to a gas stream (such as air or nitrogen), or any combination thereof. Thus, the desolvated form of compound I can be anhydrous, i.e., completely devoid of solvent molecules; or partially solvated, wherein solvent molecules are present in stoichiometric or non-stoichiometric amounts.

[0078] The term "amorphous" refers to a state in which a material lacks long-range order at the molecular level and, depending on temperature, exhibits physical properties that are either solid or liquid. Typically, such materials do not display distinctive X-ray powder diffraction patterns and, while exhibiting solid properties, are more formally described as liquids. Upon heating, a change in properties from solid to liquid occurs, characterized as a change of state, typically second-order (glass transition).

[0079] Any formula or structure given herein, including compound I, is also intended to represent the unlabeled form of the compound as well as the isotopically labeled form. It should be understood that for any given atom, isotopes may exist substantially in proportion to their natural occurrence, or one or more specific atoms may be reinforced with one or more isotopes using synthetic methods known to those skilled in the art. Thus, hydrogen includes, for example... 1 H, 2 H, 3 H; carbon includes, for example 11 C 12 C 13 C 14 C; oxygen includes, for example 16 O、 17 O、 18 O; nitrogen includes, for example 13 N、 14 N、 15 N; sulfur includes, for example 32 S, 33 S, 34 S, 35 S, 36 S, 37 S, 38 S; Fluorine includes, for example 17 F, 18 F, 19 F; chlorine includes, for example 35 Cl、 36 Cl、 37 Cl、 38 Cl、 39 Cl; etc.

[0080] As used herein, the terms “treat” or “treating”, “therapy” or “therapies”, etc., refer to an amount of material (e.g., any one or more solid, crystalline or polymorphic forms of Compound I as described herein) applied to effectively prevent, reduce or improve one or more symptoms of a disease or condition (i.e., indications) and / or prolong the survival of the treated subject.

[0081] The term "administration" refers to oral administration to a subject, as a suppository, through local contact, intravenous, intraperitoneal, intramuscular, intralesional, intranasal, or subcutaneous administration, or implantation of a sustained-release device (e.g., a micro-osmotic pump). Administration can be performed via any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intra-arterial, intradermal, subcutaneous, intraperitoneal, intravenous, and intracranial administration. Other delivery methods include, but are not limited to, the use of liposome formulations, intravenous infusion, and transdermal patches.

[0082] As used herein, the term "modulating" or "modulate" refers to the alteration of biological activity, particularly biological activity associated with a specific biomolecule such as GLP-1. For example, agonists or antagonists of a specific biomolecule modulate GLP-1 activity by increasing (e.g., agonists, activators) or decreasing (e.g., antagonists, inhibitors) the activity of the biomolecule. This activity is typically expressed as the inhibitory concentration (IC50) of the inhibitory or activating compound, respectively. 50 ) or activation concentration (EC) 50 )instruct.

[0083] As used herein, the term "composition" refers to a pharmaceutical preparation suitable for administration to an intended subject for therapeutic purposes, containing at least one pharmaceutically active compound, including in any solid form. A composition may comprise at least one pharmaceutically acceptable component (such as a suitable carrier or excipient) to provide a formulation of an improved compound.

[0084] As used herein, the terms “subject” or “patient” refer to a living organism treated with compounds as described herein, including but not limited to any mammal, such as a human, other primates, locomotion animals, commercially valuable animals (such as cattle), farm animals (such as horses), or pets (such as dogs and cats).

[0085] The term "pharmaceutically acceptable" indicates that the material does not possess characteristics that would cause a reasonably prudent medical practitioner to avoid administering the material to a patient, taking into account the disease or condition to be treated and the corresponding route of administration. For example, it is generally required that the material be substantially sterile, e.g., for injectable formulations.

[0086] In the context of this invention, the terms "therapeuticly effective" or "effective amount" indicate that a material or amount of material is effective in preventing, alleviating, or improving one or more symptoms of a disease or medical condition, and / or prolonging the survival of the treated subject. Therapeuticly effective amounts will vary depending on the compound, the impairment or condition and its severity, and the age, weight, etc., of the mammal to be treated. For example, an effective amount is an amount sufficient to achieve a beneficial or desired clinical outcome. An effective amount may be provided all at once in a single administration, or in multiple separate amounts provided over several administrations. What will be considered an effective amount can be precisely determined based on factors individual to each subject, including their size, age, lesion and / or the disease or lesion being treated, and the amount of time since the lesion occurred or the disease began. Those skilled in the art will be able to determine an effective amount for a given subject based on these considerations conventional in the art.

[0087] In some implementations, the phrase "basically as shown" means, when applied to X-ray powder diffraction patterns, to include a variation of ±0.2°2θ or ±0.1°2θ, when applied to DSC thermography, to include a variation of ±3 degrees Celsius, and when applied to thermogravimetric analysis (TGA), to include a variation of ±2% weight loss.

[0088] In some embodiments, "(of a polymorph) substantially pure form" means that at least 99.9% of the material mentioned is the mentioned polymorph. In some embodiments, "(of a polymorph) substantially pure form" means that at least 99.5% of the material mentioned is the mentioned polymorph. In some embodiments, "(of a polymorph) substantially pure form" means that at least 99% of the material mentioned is the mentioned polymorph. In some embodiments, "(of a polymorph) substantially pure form" means that at least 98% of the material mentioned is the mentioned polymorph. In some embodiments, "(of a polymorph) substantially pure form" means that at least 97% of the material mentioned is the mentioned polymorph. In some embodiments, "(of a polymorph) substantially pure form" means that at least 96% of the material mentioned is the mentioned polymorph. In some embodiments, "(of a polymorph) substantially pure form" means that at least 95% of the material mentioned is the mentioned polymorph. In the context of using, testing, or screening compounds as or potentially as modifiers, the term "contact" means bringing one or more compounds into sufficient proximity with a particular molecule, complex, cell, tissue, organism, or other designated material such that potential binding interactions and / or chemical reactions between the compound and the other designated material can occur. 2. Salts and forms of compound I

[0089] As generally described above, this disclosure provides salts and crystalline forms of compound 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (hereinafter “Compound I”), as well as salts, eutectics, solvates or hydrates of said salts and crystalline forms. The crystalline form of compound I and its salts, eutectics, solvates or hydrates, as well as other forms of compound I (e.g., amorphous form) and their salts, eutectics, solvates or hydrates, are collectively referred to herein as “forms of compound I”.

[0090] In some embodiments, compound I is in a free form, such as a free acid. In some embodiments, compound I is a salt. In some embodiments, compound I is a pharmaceutically acceptable salt. In some embodiments, compound I is a solvate. In some embodiments, compound I is a hydrate. In some embodiments, compound I is anhydrous. Salts of compound I

[0091] In one embodiment, a salt or solvation thereof of 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound I) is provided, having the formula IA: Where: X is sodium and n is 1; or X is potassium and n is 1.

[0092] In one embodiment, a 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one L-arginine salt (compound I L-arginine salt) or a solvation thereof is provided, having the formula IB:

[0093] In one embodiment, an L-arginine salt of compound I or a solvation thereof is provided. In another embodiment, a sodium salt of compound I or a solvation thereof is provided. In yet another embodiment, a potassium salt of compound I or a solvation thereof is provided.

[0094] In one embodiment, a crystalline salt form or a solvation thereof of 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one L-arginine salt (compound I L-arginine salt) is provided.

[0095] In one embodiment, a crystalline sodium salt of 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (sodium salt of compound I) or a solvation thereof is provided. In one embodiment, a crystalline potassium salt of 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-ketone (potassium salt of compound I) or a solvation thereof is provided. In the form of compound I Compound I, L-arginine salt form A

[0096] In one embodiment, a crystalline form A (compound I) is provided as a crystalline 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one L-arginine salt. L-arginine salt form A), characterized by an X-ray powder diffraction pattern containing the following peaks, represented by ±0.2 degrees 2θ selected from 5.3, 9.1 and 11.5, as determined on a diffractometer using Cu-Kα radiation.

[0097] In some embodiments, the compound I L-arginine salt form A is further characterized by an X-ray powder diffraction pattern containing one or more additional peaks, which are represented by ±0.2 degrees 2θ selected from 13.8, 15.9, 16.5, 18.9, 20.9 and 22.8, as determined on a diffractometer using Cu-Kα radiation.

[0098] In some embodiments, compound I, L-arginine salt form A, is further characterized by essentially as follows: Figure 1A The X-ray powder diffraction pattern shown is shown.

[0099] In some embodiments, compound IL-arginine salt form A is further characterized by containing endothermic DSC at about 66.0 °C (peak) and about 35.8 °C (onset). In some embodiments, compound IL-arginine salt form A is further characterized by substantially as Figure 1B The DSC shown in the figure.

[0100] In some embodiments, crystalline compound I in L-arginine salt form A is prepared by slurrying compound I in free acid form A and an equimolar amount of L-arginine in THF at room temperature for 4 days.

[0101] In some embodiments, compound I L-arginine salt form A is further characterized by a TGA showing a weight loss of about 3.2% up to about 120°C.

[0102] In some embodiments, the molar ratio of L-arginine to free acid of compound I in L-arginine salt form A is about 1.0. In some embodiments, compound I in L-arginine salt form A is a solvate. In some embodiments, compound I in L-arginine salt form A is a THF solvate. In some embodiments, compound I in L-arginine salt form A is a THF-water heterosolvent. In some embodiments, the molar ratio of THF to compound I in L-arginine salt form A is 0.8 (5.0 wt%). In some embodiments, the molar ratio of water to compound I in L-arginine salt form A is 1.0 (1.9 wt%). Compound I, L-arginine salt form B

[0103] In one embodiment, a crystalline form B (compound I) is provided as a crystalline 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one L-arginine salt. L-arginine salt form B), characterized by an X-ray powder diffraction pattern containing the following peaks, represented by ±0.2 degrees 2θ selected from 6.1, 7.4 and 10.3, as determined on a diffractometer using Cu-Kα radiation.

[0104] In some embodiments, compound I L-arginine salt form B is further characterized by an X-ray powder diffraction pattern containing one or more additional peaks, represented by ±0.2 degrees 2θ selected from 10.8, 15.3, 15.5, 18.0, 20.6 and 22.8, as determined on a diffractometer using Cu-Kα radiation.

[0105] In some embodiments, compound I L-arginine salt form B is further characterized by essentially as follows: Figure 2A The X-ray powder diffraction pattern shown is shown.

[0106] In some embodiments, compound IL-arginine salt form B is further characterized by containing endothermic DSC at about 17.6 °C (peak) and about 243.7 °C (peak). In some embodiments, compound IL-arginine salt form B is further characterized by substantially as Figure 2B The DSC shown in the figure.

[0107] In some embodiments, crystalline compound I L-arginine salt form B is prepared by equilibrating compound I L-arginine salt form A in IPA / water (17:1 v / v) at room temperature for about 2 weeks. In some embodiments, crystalline compound I L-arginine salt form B is prepared by equilibrating compound I L-arginine salt form A in IPA / water (17:1 v / v) at 50°C for 1 week.

[0108] In some embodiments, compound I L-arginine salt form B is further characterized by a two-step weight loss of TGA, showing about 1.6% up to about 100°C and about 6.7% from about 100°C to 250°C.

[0109] In some embodiments, the molar ratio of L-arginine to free acid of compound I in L-arginine salt form B is about 1.0. In some embodiments, compound I in L-arginine salt form B is a solvate. In some embodiments, compound I in L-arginine salt form B is an IPA solvate. In some embodiments, compound I in L-arginine salt form B is an IPA-water heterosolvent. In some embodiments, the molar ratio of IPA to compound I in L-arginine salt form B is 0.8 (6.0 wt%). In some embodiments, the molar ratio of water to compound I in L-arginine salt form B is 1.7 (2.6 wt%).

[0110] In some embodiments, compound IL-arginine salt form B is a hydrate. In some embodiments, compound IL-arginine salt form B is a channel hydrate.

[0111] Compared to other forms, compound I L-arginine salt form B exhibited enhanced pharmacokinetic properties, such as better exposure. Compound I L-arginine salt form C

[0112] In one embodiment, a crystalline form of 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one L-arginine salt, C(compound I), is provided. L-arginine salt form C), characterized by an X-ray powder diffraction pattern containing peaks represented by ±0.2 degrees 2θ selected from 6.1, 7.4, and 10.3, as determined on a diffractometer using Cu-Kα radiation. Form C is a hydrate of form B described above.

[0113] In some embodiments, the compound 1 L-arginine salt form C (e.g., the hydrate of form B) is further characterized by an X-ray powder diffraction pattern containing one or more additional peaks, represented by ±0.2 degrees 2θ selected from 10.8, 15.3, 15.5, 18.0, 20.6, and 22.8, as determined on a diffractometer using Cu-Kα radiation.

[0114] In some embodiments, compound 1 L-arginine salt form C is further characterized by essentially as follows: Figure 3A The X-ray powder diffraction pattern shown is shown.

[0115] In some embodiments, compound IL-arginine salt form C is further characterized by two endothermic DSCs at approximately 52.9 °C (peak) and approximately 232.9 °C (peak). In some embodiments, compound IL-arginine salt form C is further characterized by substantially as Figure 3B The DSC shown in the figure.

[0116] In some embodiments, crystalline compound IL-arginine salt form C is prepared by equilibrating compound IL-arginine salt form A in acetone at room temperature for 2 weeks. In some embodiments, crystalline compound IL-arginine salt form C is prepared by equilibrating compound IL-arginine salt form A in ACN at room temperature for 2 weeks. In some embodiments, crystalline compound IL-arginine salt form C is prepared by equilibrating compound IL-arginine salt form A in ethanol at 50°C for 1 week. In some embodiments, crystalline compound IL-arginine salt form C is prepared by equilibrating compound IL-arginine salt form A in acetone at 50°C for 1 week. In some embodiments, crystalline compound IL-arginine salt form C is prepared by equilibrating compound IL-arginine salt form A in ACN / water (1:1 v / v) at 50°C for 1 week.

[0117] In some embodiments, the compound I L-arginine salt form C is further characterized by a two-step weight loss of TGA, showing about 4.2% up to about 100°C and about 4.5% from about 100°C to 260°C.

[0118] In some embodiments, the molar ratio of L-arginine to free acid of compound I in L-arginine salt form C is about 1.0. In some embodiments, compound I in L-arginine salt form C is a hydrate. In some embodiments, the molar ratio of acetone to compound I in L-arginine salt form C is 0.02 (0.1 wt%). In some embodiments, the molar ratio of water to compound I in L-arginine salt form C is 4.4 (6.8 wt%).

[0119] Initial polymorph screening failed to provide a suitable basic crystalline form for compound I. Subsequent polymorph screening is described below. Compound I in free acid form A

[0120] In one embodiment, a 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl group is provided. The free acid form A of compound I (compound I free acid form A) is characterized by an X-ray powder diffraction pattern containing the following peaks, expressed in ±0.2 degrees 2θ selected from 5.2, 6.1 and 12.4, as determined on a diffractometer using Cu-Kα radiation.

[0121] In some embodiments, the free acid form A of compound I is further characterized by an X-ray powder diffraction pattern containing one or more additional peaks, which are represented by ±0.2 degrees 2θ selected from 15.0, 16.5, 16.9, 18.8, 20.2 and 21.9, as determined on a diffractometer using Cu-Kα radiation.

[0122] In some embodiments, the free acid form A of compound I is further characterized essentially as follows: Figure 4A The X-ray powder diffraction pattern shown is shown.

[0123] In some embodiments, the free acid form A of compound I is further characterized by two endothermic DSCs at approximately 49.7 °C (peak) and approximately 211.3 °C (peak). In some embodiments, the crystalline free acid form A of compound I is further characterized by substantially as follows: Figure 4B The DSC shown in the figure.

[0124] In some embodiments, the free acid form A of compound I is obtained by slurrying the free acid of compound I in EtOAc at room temperature for 2 days.

[0125] In some embodiments, the free acid form A of compound I is further characterized by a TGA showing a weight loss of about 2.3% up to about 200°C.

[0126] In some embodiments, the free acid form A of compound I is a hydrate. In some embodiments, the molar ratio of water to free acid of compound I in free acid form A is 1.7 (3.3 wt%). Compound I in free acid form B

[0127] In one embodiment, a 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl group is provided. The free acid form B of compound I (compound I free acid form B) is characterized by an X-ray powder diffraction pattern containing the following peaks, expressed in ±0.2 degrees 2θ selected from 7.8, 9.2 and 10.0, as determined on a diffractometer using Cu-Kα radiation.

[0128] In some embodiments, the free acid form B of compound I is further characterized by an X-ray powder diffraction pattern containing one or more additional peaks, which are represented by ±0.2 degrees 2θ selected from 10.3, 13.0, 13.7, 16.5, 20.5 and 23.2, as determined on a diffractometer using Cu-Kα radiation.

[0129] In some embodiments, the free acid form B of compound I is further characterized substantially as follows: Figure 5A The X-ray powder diffraction pattern shown is shown.

[0130] In some embodiments, the free acid form B of compound I is further characterized by two endothermic DSCs at approximately 32.4 °C (peak) and approximately 199.0 °C (peak). In some embodiments, the crystalline free acid form B of compound I is further characterized by substantially as follows: Figure 5B The DSC shown in the figure.

[0131] In some embodiments, compound I in its free acid form B is obtained by equilibrating compound I in its free acid form A in ACN for 10 cycles at a heating / cooling rate of 0.1°C / min under temperature cycling between 5°C and 50°C. In some embodiments, compound I in its free acid form B is obtained by crystallizing a saturated solution of compound I in its free acid form A in ACN by slowly cooling it from 50°C to 5°C at a rate of 0.1°C / min.

[0132] In some embodiments, the free acid form B of compound I is further characterized by a TGA showing a weight loss of about 3.3% up to about 180°C.

[0133] In some embodiments, the free acid form B of compound I is a hydrate. In some embodiments, the molar ratio of water to free acid of compound I in the free acid form B is 2.5 (4.6 wt%). Compound I in free acid form C

[0134] In one embodiment, a 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl group is provided. The free acid form C of compound I (compound I free acid form C) is characterized by an X-ray powder diffraction pattern containing the following peaks, expressed in ±0.2 degrees 2θ selected from 4.1, 8.1 and 10.4, as determined on a diffractometer using Cu-Kα radiation.

[0135] In some embodiments, the free acid form C of compound I is further characterized by an X-ray powder diffraction pattern containing one or more additional peaks, which are represented by ±0.2 degrees 2θ selected from 13.5, 14.6, 15.0, 15.5, 15.8 and 20.8, as determined on a diffractometer using Cu-Kα radiation.

[0136] In some embodiments, the free acid form C of compound I is further characterized essentially as follows: Figure 6A The X-ray powder diffraction pattern shown is shown.

[0137] In some embodiments, the free acid form C of compound I is further characterized by three endothermic DSCs at approximately 31.7 °C (peak), approximately 134.9 °C (peak), and approximately 194.7 °C (peak). In some embodiments, the crystalline free acid form C of compound I is further characterized by substantially as follows: Figure 6B The DSC shown in the figure.

[0138] In some embodiments, the free acid form C of compound I is obtained by equilibrating the free acid form A of compound I in MTBE at room temperature for 2 weeks. In some embodiments, the free acid form C of compound I is obtained by equilibrating the free acid form A of compound I in MTBE at 50°C for 1 week. In some embodiments, the free acid form C of compound I is obtained by equilibrating the free acid form A of compound I in MTBE for 10 cycles at a heating / cooling rate of 0.1°C / min under temperature cycling between 5°C and 50°C.

[0139] In some embodiments, the free acid form C of compound I is further characterized by a TGA showing a weight loss of about 5.5% up to about 180°C.

[0140] In some embodiments, compound I free acid C is a solvate. In some embodiments, the molar ratio of MTBE / compound I free acid in compound I free acid form C is 0.02 (0.2 wt%). In some embodiments, the molar ratio of water / compound I free acid in compound I free acid form C is 2.7 (5.1 wt%). Compound I in free acid form D

[0141] In one embodiment, a 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl) is provided. -5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one free acid form D (compound I free acid form D), characterized by an X-ray powder diffraction pattern containing the following peaks, represented by ±0.2 degrees 2θ selected from 6.5, 12.1 and 12.9, as determined on a diffractometer using Cu-Kα radiation.

[0142] In some embodiments, the free acid form D of compound I is further characterized by an X-ray powder diffraction pattern containing one or more additional peaks, which are represented by ±0.2 degrees 2θ selected from 14.0, 16.5, 16.9, 17.5, 18.8 and 21.0, as determined on a diffractometer using Cu-Kα radiation.

[0143] In some embodiments, the free acid form D of compound I is further characterized essentially as follows: Figure 7A The X-ray powder diffraction pattern shown is shown.

[0144] In some embodiments, the free acid form D of compound I is further characterized by three endothermic DSCs at about 36.1 °C (peak), about 198.1 °C (peak), and about 223.9 °C (peak), and a broad exothermic DSC at about 133.7 °C (peak). In some embodiments, the crystalline free acid form D of compound I is further characterized by substantially as follows: Figure 7B The DSC shown in the figure.

[0145] In some embodiments, the free acid form D of compound I is obtained by equilibrating the free acid form A of compound I in ACN / water (9:1 v / v) at room temperature for 2 weeks. In some embodiments, the free acid form D of compound I is obtained by equilibrating the free acid form A of compound I in ACN / water (9:1 v / v) for 10 cycles at a heating / cooling rate of 0.1 °C / min under temperature cycling between 5 °C and 50 °C.

[0146] In some embodiments, the free acid form D of compound I is further characterized by a TGA showing a weight loss of about 1.4% up to about 200°C.

[0147] In some embodiments, the free acid form D of compound I is a hydrate. In some embodiments, the molar ratio of water to free acid of compound I in the free acid form D is 1.1 (2.2 wt%). Compound I in free acid form E

[0148] In one embodiment, a 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl) is provided. -5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one free acid form E (compound I free acid form E), characterized by an X-ray powder diffraction pattern containing the following peaks, represented in ±0.2 degrees 2θ selected from 5.7, 11.1 and 16.1, as determined on a diffractometer using Cu-Kα radiation.

[0149] In some embodiments, the free acid form E of compound I is further characterized by an X-ray powder diffraction pattern containing one or more additional peaks, which are represented by ±0.2 degrees 2θ selected from 17.1, 18.1, 18.7, 21.0, 21.3 and 21.6, as determined on a diffractometer using Cu-Kα radiation.

[0150] In some embodiments, the free acid form E of compound I is further characterized essentially as follows: Figure 8A The X-ray powder diffraction pattern shown is shown.

[0151] In some embodiments, the free acid form E of compound I is further characterized by two endothermic DSCs at approximately 43.6 °C (peak) and approximately 223.9 °C (peak). In some embodiments, the crystalline free acid form E of compound I is further characterized by substantially as follows: Figure 8B The DSC shown in the figure.

[0152] In some embodiments, the free acid form E of compound I is obtained by equilibrating the free acid form A of compound I in THF / water (9:1 v / v) at room temperature for 2 weeks. In some embodiments, the free acid form E of compound I is obtained by equilibrating the free acid form A of compound I in THF / water (9:1 v / v) at 50°C for 1 week. In some embodiments, the free acid form E of compound I is obtained by equilibrating the free acid form A of compound I in THF / water (9:1 v / v) at a heating / cooling rate of 0.1°C / min for 10 cycles at a temperature cycling rate between 5°C and 50°C. In some embodiments, the free acid form E of compound I is obtained by crystallizing the free acid form A of compound I in 1,4-dioxane by adding an antisolvent (water).

[0153] In some embodiments, the free acid form E of compound I is further characterized by a TGA showing a weight loss of about 2.5% up to about 200°C.

[0154] In some embodiments, the free acid form E of compound I is a hydrate. In some embodiments, the molar ratio of water to free acid of compound I in the free acid form E is 5.8 (10.3 wt%). Compound I in free acid form F

[0155] In one embodiment, a 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl) is provided. -5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one free acid form F (compound I free acid form F), characterized by an X-ray powder diffraction pattern containing the following peaks, represented in ±0.2 degrees 2θ selected from 7.2, 12.9 and 14.6, as determined on a diffractometer using Cu-Kα radiation.

[0156] In some embodiments, the free acid form F of compound I is further characterized by an X-ray powder diffraction pattern containing one or more additional peaks, which are represented by ±0.2 degrees 2θ selected from 16.1, 16.6, 17.5, 19.1, 19.9 and 21.8, as determined on a diffractometer using Cu-Kα radiation.

[0157] In some embodiments, the free acid form F of compound I is further characterized essentially as follows: Figure 9A The X-ray powder diffraction pattern shown is shown.

[0158] In some embodiments, the free acid form F of compound I is further characterized by endothermic DSC at approximately 46.2 °C (peak), approximately 121.0 °C (peak), approximately 159.4 °C (peak), and approximately 230.4 °C (peak). In some embodiments, the crystalline free acid form F of compound I is further characterized by substantially as follows: Figure 9B The DSC shown in the figure.

[0159] In some embodiments, the free acid form F of compound I is obtained by equilibrating the free acid form A of compound I in ACN at room temperature for 2 weeks. In some embodiments, the free acid form E of compound I is obtained by equilibrating the free acid form F of compound I in ACN at 50°C for 1 week. In some embodiments, the free acid form F of compound I is obtained by crystallizing by rapidly cooling a saturated solution of the free acid form A of compound I in ACN from 50°C to 5°C.

[0160] In some embodiments, the free acid form F of compound I is further characterized by a TGA showing a weight loss of about 1.2% up to about 200°C.

[0161] In some embodiments, the free acid form F of compound I is a hydrate. In some embodiments, the molar ratio of water to free acid of compound I in the free acid form F is 0.9 (1.7 wt%). Compound I in free acid form G

[0162] In one embodiment, a 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl) is provided. -5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one free acid form G (compound I free acid form G), characterized by an X-ray powder diffraction pattern containing the following peaks, represented in ±0.2 degrees 2θ selected from 6.0, 11.9 and 14.8, as determined on a diffractometer using Cu-Kα radiation.

[0163] In some embodiments, the free acid form G of compound I is further characterized by an X-ray powder diffraction pattern containing one or more additional peaks, which are represented by ±0.2 degrees 2θ selected from 16.3, 16.6, 18.4, 18.8, 21.3 and 23.9, as determined on a diffractometer using Cu-Kα radiation.

[0164] In some embodiments, the free acid form G of compound I is further characterized essentially as follows: Figure 10A The X-ray powder diffraction pattern shown is shown.

[0165] In some embodiments, the free acid form G of compound I is further characterized by two endothermic DSCs at approximately 52.9 °C (peak) and approximately 208.7 °C (peak). In some embodiments, the crystalline free acid form G of compound I is further characterized by substantially as follows: Figure 10B The DSC shown in the figure.

[0166] In some embodiments, the free acid form G of compound I is obtained by equilibrating the free acid form A of compound I in DMSO / water (1:1 v / v) at room temperature for 2 weeks. In some embodiments, the free acid form G of compound I is obtained by equilibrating the free acid form A of compound I in DMSO / water (1:1 v / v) at 50°C for 1 week.

[0167] In some embodiments, the free acid form G of compound I is further characterized by a two-step weight loss of TGA, showing about 8.5% up to about 55°C and about 5.9% from about 55°C to 180°C.

[0168] In some embodiments, the free acid form G of compound I is a hydrate. In some embodiments, the molar ratio of water to free acid of compound I in the free acid form G is 8.4 (14.1 wt%). In some embodiments, the molar ratio of DMSO to free acid of compound I in the free acid form G is 0.1 (0.7 wt%). Compound I in free acid form H

[0169] In one embodiment, a 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl group is provided. The free acid form H of compound I (compound I free acid form H) is characterized by an X-ray powder diffraction pattern containing the following peaks, represented by ±0.2 degrees 2θ selected from 5.3, 5.5 and 7.6, as determined on a diffractometer using Cu-Kα radiation.

[0170] In some embodiments, the free acid form H of compound I is further characterized by an X-ray powder diffraction pattern containing one or more additional peaks, which are represented by ±0.2 degrees 2θ selected from 11.0, 11.3, 11.9, 14.4, 16.5 and 18.1, as determined on a diffractometer using Cu-Kα radiation.

[0171] In some embodiments, the free acid form H of compound I is further characterized by essentially as follows: Figure 11A The X-ray powder diffraction pattern shown is shown.

[0172] In some embodiments, the free acid form H of compound I is further characterized by endothermic DSC at approximately 51.3 °C (peak), approximately 105.5 °C (peak), and approximately 217.2 °C (peak). In some embodiments, the crystalline free acid form H of compound I is further characterized by substantially as follows: Figure 11B The DSC shown in the figure.

[0173] In some embodiments, the free acid form H of compound I is obtained by equilibrating the free acid form A of compound I in acetone / water (1:1 v / v) at room temperature for 2 weeks. In some embodiments, the free acid form H of compound I is obtained by adding an antisolvent (water) to the free acid form A of compound I in 1,4-dioxane, followed by equilibration for 10 days.

[0174] In some embodiments, the free acid form H of compound I is further characterized by a TGA showing a weight loss of about 7.7% up to about 180°C.

[0175] In some embodiments, the free acid form H of compound I is a hydrate. In some embodiments, the molar ratio of water to free acid of compound I in the free acid form H is 5.5 (9.6 wt%). Compound I in free acid form I

[0176] In one embodiment, a 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl) is provided. -5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one free acid form I (compound I free acid form I), characterized by an X-ray powder diffraction pattern containing the following peaks, represented in ±0.2 degrees 2θ selected from 4.0, 12.2 and 14.0, as determined on a diffractometer using Cu-Kα radiation.

[0177] In some embodiments, the free acid form I of compound I is further characterized by an X-ray powder diffraction pattern containing one or more additional peaks, which are represented by ±0.2 degrees 2θ selected from 15.1, 15.8, 16.7, 18.4, 21.0 and 22.0, as determined on a diffractometer using Cu-Kα radiation.

[0178] In some embodiments, compound I in its free acid form I is further characterized by essentially as follows: Figure 12A The X-ray powder diffraction pattern shown is shown.

[0179] In some embodiments, the free acid form I of compound I is further characterized by endothermic DSC at approximately 41.5 °C (peak) and approximately 207.3 °C (peak). In some embodiments, the free acid form I of crystalline compound I is further characterized by substantially as follows: Figure 12B The DSC shown in the figure.

[0180] In some embodiments, compound I free acid form I is obtained by adding compound I free acid form A in 1,4-dioxane to an antisolvent (water) and then equilibrating for 10 days.

[0181] In some embodiments, the free acid form of compound I is further characterized by a TGA showing a weight loss of about 7.4% up to about 200°C. Compound I in free acid form J

[0182] In one embodiment, a 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl) is provided. -5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one free acid form J (compound I free acid form J), characterized by an X-ray powder diffraction pattern containing the following peaks, represented in ±0.2 degrees 2θ selected from 6.8, 11.6 and 13.5, as determined on a diffractometer using Cu-Kα radiation.

[0183] In some embodiments, the free acid form J of compound I is further characterized by an X-ray powder diffraction pattern containing one or more additional peaks, which are represented by ±0.2 degrees 2θ selected from 14.0, 15.0, 17.0, 17.3, 17.9 and 19.7, as determined on a diffractometer using Cu-Kα radiation.

[0184] In some embodiments, the free acid form J of compound I is further characterized by essentially the following: Figure 13A The X-ray powder diffraction pattern shown is shown.

[0185] In some embodiments, the free acid form J of compound I is further characterized by endothermic DSC containing approximately 68.6 °C (peak) and approximately 221.2 °C (peak). In some embodiments, the crystalline free acid form J of compound I is further characterized by substantially as follows: Figure 13B The DSC shown in the figure.

[0186] In some embodiments, compound I in its free acid form D is obtained by storing it under ambient conditions (23°C-27°C, 50%-70% RH) for 2 weeks to obtain compound I in its free acid form J.

[0187] In some embodiments, the free acid form J of compound I is further characterized by a TGA exhibiting a weight loss of about 2.2% up to about 200°C. Compound I in free acid form K

[0188] In one embodiment, a 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl group is provided. The free acid form K of compound I (compound I free acid form K) is characterized by an X-ray powder diffraction pattern containing the following peaks, expressed in ±0.2 degrees 2θ selected from 8.7, 9.9 and 12.5, as determined on a diffractometer using Cu-Kα radiation.

[0189] In some embodiments, the free acid form K of compound I is further characterized by an X-ray powder diffraction pattern containing one or more additional peaks, which are represented by ±0.2 degrees 2θ selected from 14.2, 15.8, 16.4, 19.6, 21.1 and 23.6, as determined on a diffractometer using Cu-Kα radiation.

[0190] In some embodiments, the free acid form K of compound I is further characterized essentially as follows: Figure 14A The X-ray powder diffraction pattern shown is shown.

[0191] In some embodiments, the free acid form K of compound I is further characterized by endothermic DSC at approximately 46.1 °C (peak) and approximately 198.4 °C (peak). In some embodiments, the crystalline free acid form K of compound I is further characterized by substantially as follows: Figure 14B The DSC shown in the figure.

[0192] In some embodiments, compound I in its free acid form B is obtained by storing it under ambient conditions (23°C-27°C, 50%-70% RH) for 2 weeks.

[0193] In some embodiments, the free acid form K of compound I is further characterized by a two-step weight loss of TGA, showing about 2.4% up to about 70°C and about 2.6% from about 70°C to 170°C. Compound I in free acid form L

[0194] In one embodiment, a free acid form L of 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound I free acid form L) is provided, characterized in that it is substantially as Figure 15A The X-ray powder diffraction pattern shown is given. Form L is a DMSO-water heterosolvent.

[0195] In some embodiments, the free acid form L of compound I is further characterized by including an endothermic DSC at about 120°C (peak). In some embodiments, the crystalline free acid form L of compound I is further characterized by substantially as Figure 15B The DSC shown in the figure.

[0196] In some embodiments, the free acid form L of compound I exhibits a weight loss of about 7.9% at about 70°C and about 7.4% from about 70°C to about 200°C. In one embodiment, the form is characterized by substantially as Figure 15C The TGA diagram shown is shown below. Compound I in free acid form M

[0197] In one embodiment, a free acid form M of 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound I free acid form M) is provided, characterized in that it is substantially as Figure 16A The X-ray powder diffraction pattern shown is shown in the image. Compound I in free acid form N

[0198] In one embodiment, a 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl group is provided. The free acid form N of compound I (compound I free acid form N) is characterized by an X-ray powder diffraction pattern containing the following peaks, expressed in ±0.2 degrees 2θ selected from 4.6, 6.3 and 7.2, as determined on a diffractometer using Cu-Kα radiation.

[0199] In some embodiments, the free acid form N of compound I is further characterized by an X-ray powder diffraction pattern containing one or more additional peaks, which are represented in terms of ±0.2 degrees 2θ, such as 9.2, 11.9, 16.1, 18.6, 20.4 and 21.0 determined on a diffractometer using Cu-Kα radiation.

[0200] In some embodiments, the free acid form N of compound I is further characterized essentially as follows: Figure 17A The X-ray powder diffraction pattern shown is shown.

[0201] In some embodiments, the free acid form N of compound I is further characterized by endothermic DSC at approximately 68.6 °C (peak), approximately 81.0 °C (peak), and approximately 207.7 °C (peak). In some embodiments, the free acid form N of crystalline compound I is further characterized by substantially as follows: Figure 17B The DSC shown in the figure.

[0202] In some embodiments, the free acid form A is equilibrated in ACN / water (9:1 v / v) at room temperature for 2 weeks to obtain the free acid form N of compound I.

[0203] In some embodiments, the free acid form N of compound I is further characterized by a TGA showing a weight loss of about 9.0% up to about 200°C.

[0204] In some embodiments, the free acid form N of compound I is a hydrate. In some embodiments, the molar ratio of water to free acid of compound I in the free acid form N is 5.8 (10.3 wt%). Sodium salt form of compound I A

[0205] In one embodiment, a crystalline sodium salt form A of 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one is provided (sodium salt form A of compound I). In some embodiments, sodium salt form A of compound I is characterized by substantially as follows: Figure 18A The X-ray powder diffraction pattern shown is shown.

[0206] In some embodiments, the sodium salt form A of compound I is further characterized by an endothermic DSC at approximately 124.8 °C (peak). In some embodiments, the sodium salt form A of crystalline compound I is further characterized by substantially as Figure 18B The DSC shown in the figure.

[0207] In some embodiments, the sodium salt form A of compound I is obtained by slurrying the free acid form A of compound I and an equimolar amount of NaOH in acetone at room temperature for 4 days.

[0208] In some embodiments, the sodium salt form A of compound I is further characterized by a two-step weight loss of TGA, showing about 4.1% up to about 100°C and about 3.9% from about 100°C to 250°C.

[0209] In some embodiments, sodium salt form A of crystalline compound I is a solvate. In some embodiments, sodium salt form A of crystalline compound I is an acetone solvate. In some embodiments, sodium salt form A of crystalline compound I is an acetone-water heterosolvent. In some embodiments, sodium salt form A of compound I has a molar ratio of acetone to free acid of compound I of 0.6 (3.8 wt%). In some embodiments, sodium salt form A of compound I has a molar ratio of water to free acid of compound I of 2.1 (4.0 wt%). In some embodiments, the molar ratio of sodium to free acid of compound I in sodium salt form A of crystalline compound I is 1:1. Compound I in sodium salt form B

[0210] In one embodiment, a crystalline sodium salt form B of 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one is provided (sodium salt form B of compound I). In some embodiments, sodium salt form B of compound I is characterized by substantially as follows: Figure 19A The X-ray powder diffraction pattern shown is shown.

[0211] In some embodiments, the sodium salt form B of compound I is obtained by slurrying compound I in free acid form A and equimolar amounts of NaOH in THF at room temperature for 4 days, then slowly cooling to 5°C and stirring for 2 days, followed by the addition of an antisolvent (water). Compound I potassium salt form A

[0212] In one embodiment, a crystalline potassium salt form A of 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-ketone is provided (potassium salt form A of compound I). In some embodiments, potassium salt form A of compound I is characterized by substantially as follows: Figure 20A The X-ray powder diffraction pattern shown is shown.

[0213] In some embodiments, the potassium salt form A of compound I is further characterized by endothermic DSC at about 50.9 °C (peak), about 166.2 °C (peak), and about 237.7 °C (peak). In some embodiments, the crystalline potassium salt form A of compound I is further characterized by substantially as follows: Figure 20B The DSC shown in the figure.

[0214] In some embodiments, compound I potassium salt form A is obtained by slurrying compound I free acid form A and equimolar amounts of KOH in acetone at room temperature for 4 days, then slowly cooling to 5°C and stirring for 2 days, followed by the addition of an antisolvent (MTBE).

[0215] In some embodiments, the potassium salt form A of compound I is further characterized by a TGA showing a weight loss of about 1.4% up to about 130°C.

[0216] In some embodiments, the potassium salt form A of crystalline compound I is a solvate. In some embodiments, the potassium salt form A of crystalline compound I is an acetone solvate. In some embodiments, the potassium salt form A of crystalline compound I is an MTBE solvate. In some embodiments, the potassium salt form A of crystalline compound I is an acetone-MTBE heterosolvate. In some embodiments, the molar ratio of acetone to free acid of compound I in the potassium salt form A of compound I is 0.04 (0.3 wt%). In some embodiments, the molar ratio of MTBE to free acid of compound I in the potassium salt form A of compound I is 0.45 (4.1 wt%). In some embodiments, the molar ratio of potassium to free acid of compound I in the sodium salt form A of crystalline compound I is 0.9:1. Composition

[0217] In some embodiments, a composition is provided comprising a salt or crystalline form of 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound I), or a salt or solvation of said salt or crystalline form.

[0218] In one embodiment, a composition is provided comprising 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H- The salt or crystalline form of indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound I), or a salt or solvate of said salt or crystalline form, wherein at least 50% to 99% (e.g., at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of compound I is present in the composition in the specified salt, crystalline form, or crystalline salt form.

[0219] In one embodiment, a composition is provided comprising 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one L-arginine salt (compound I) L-arginine salt or its solvates, wherein at least 50% to 99% (e.g., at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of compound I present in the composition is compound IL-arginine salt.

[0220] In one embodiment, a composition is provided comprising crystalline 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one L-arginine salt form B (compound I). L-arginine salt form B) or its solvates, wherein at least 50% to 99% (e.g., at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of compound I present in the composition is compound IL-arginine salt form B.

[0221] In one embodiment, a composition is provided comprising crystalline 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one L-arginine salt form A (compound I). L-arginine salt form A) or its solvates, wherein at least 50% to 99% (e.g., at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of compound I present in the composition is compound IL-arginine salt form A.

[0222] In one embodiment, a composition is provided comprising crystalline 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one L-arginine salt form C(compound I) L-arginine salt form C) or its solvates, wherein at least 50% to 99% (e.g., at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of compound I present in the composition is compound IL-arginine salt form C.

[0223] In one embodiment, a composition is provided comprising crystalline 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4- The free acid form A of compound I (free acid form A) or a solvate thereof, wherein at least 50% to 99% (e.g., at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of compound I present in the composition is free acid form A of compound I.

[0224] In one embodiment, a composition is provided comprising crystalline 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4- The free acid form B of compound I (free acid form B) or a solvate thereof, wherein at least 50% to 99% (e.g., at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of compound I present in the composition is free acid form B of compound I.

[0225] In one embodiment, a composition is provided comprising crystalline 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4- The free acid form C of compound I (compound I free acid form C) or its solvate thereof, wherein at least 50% to 99% (e.g., at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99%) of compound I present in the composition is compound I free acid form C.

[0226] In one embodiment, a composition is provided comprising crystalline 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4- The free acid form D of compound I (free acid form D of compound I) or a solvate thereof, wherein at least 50% to 99% (e.g., at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99%) of compound I present in the composition is free acid form D of compound I.

[0227] In one embodiment, a composition is provided comprising crystalline 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4- The free acid form E of compound I (free acid form E of compound I) or a solvate thereof, wherein at least 50% to 99% (e.g., at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99%) of compound I present in the composition is free acid form E of compound I.

[0228] In one embodiment, a composition is provided comprising crystalline 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4- The free acid form F of compound I (free acid form F of compound I) or a solvate thereof, wherein at least 50% to 99% (e.g., at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99%) of compound I present in the composition is free acid form F of compound I.

[0229] In one embodiment, a composition is provided comprising crystalline 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4- The free acid form G of compound I (free acid form G) or a solvate thereof, wherein at least 50% to 99% (e.g., at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of compound I present in the composition is free acid form G of compound I.

[0230] In one embodiment, a composition is provided comprising crystalline 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4- The free acid form H of compound I (compound I free acid form H) or a solvate thereof, wherein at least 50% to 99% (e.g., at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99%) of compound I present in the composition is compound I free acid form H.

[0231] In one embodiment, a composition is provided comprising crystalline 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4- The free acid form I of compound I (compound I free acid form I) or a solvate thereof, wherein at least 50% to 99% (e.g., at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99%) of compound I present in the composition is compound I free acid form I.

[0232] In one embodiment, a composition is provided comprising crystalline 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4- The free acid form J of compound I (free acid form J) or a solvate thereof, wherein at least 50% to 99% (e.g., at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99%) of compound I present in the composition is the free acid form J of compound I.

[0233] In one embodiment, a composition is provided comprising crystalline 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4- The free acid form K of compound I (compound I free acid form K) or a solvate thereof, wherein at least 50% to 99% (e.g., at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99%) of compound I present in the composition is compound I free acid form K.

[0234] In one embodiment, a composition is provided comprising crystalline 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4- The free acid form L of compound I (compound I free acid form L) or a solvate thereof, wherein at least 50% to 99% (e.g., at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99%) of compound I present in the composition is compound I free acid form L.

[0235] In one embodiment, a composition is provided comprising crystalline 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4- The free acid form N of compound I (compound I free acid form N) or its solvate thereof, wherein at least 50% to 99% (e.g., at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99%) of compound I present in the composition is compound I free acid form N.

[0236] In one embodiment, a composition is provided comprising crystalline 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4) (-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one sodium salt form A (sodium salt form A of compound I) or a solvate thereof, wherein at least 50% to 99% (e.g., at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99%) of compound I present in the composition is sodium salt form A of compound I.

[0237] In one embodiment, a composition is provided comprising crystalline 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4) (-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one sodium salt form B (sodium salt form B of compound I) or a solvation thereof, wherein at least 50% to 99% (e.g., at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99%) of compound I present in the composition is sodium salt form B of compound I.

[0238] In one embodiment, a composition is provided comprising crystalline 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4) (-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-keto potassium salt form A (potassium salt form A of compound I) or a solvation thereof, wherein at least 50% to 99% (e.g., at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99%) of compound I present in the composition is potassium salt form A of compound I.

[0239] In some embodiments, the composition is a pharmaceutical composition that further comprises a pharmaceutically acceptable excipient.

[0240] In some embodiments, a method is provided for preparing crystalline 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one L-arginine salt (compound I L-arginine salt), said method comprising contacting compound I with L-arginine in a solvent for a sufficient time to provide crystalline compound I L-arginine salt.

[0241] In some embodiments, the solvent is a mixture of IPA and H2O. In some embodiments, the solvent is a mixture of IPA and H2O in a 7:3 v / v ratio.

[0242] In some embodiments, the contact includes adding 1.1 molar equivalents of L-arginine to compound I. In some embodiments, the contact includes adding 1.1 molar equivalents of L-arginine to compound I at a temperature of about 10°C to about 90°C. In some embodiments, the contact includes adding 1.1 molar equivalents of L-arginine to compound I at a temperature of about 30°C to about 70°C. In some embodiments, the contact includes adding 1.1 molar equivalents of L-arginine to compound I at a temperature of about 50°C to about 55°C.

[0243] In some embodiments, the contact further includes adding about 2 wt% of seed crystals to the mixture of compound I and L-arginine.

[0244] In some embodiments, the contact further includes adding additional IPA dropwise to the mixture of compound I and L-arginine. In some embodiments, the contact further includes adding about 10 to about 20 molar equivalents of IPA dropwise to the mixture of compound I and L-arginine.

[0245] In some embodiments, the contact further includes adding 10 to 20 molar equivalents of IPA followed by stirring at a temperature of about -10°C to about 15°C. In some embodiments, the contact further includes adding 10 to 20 molar equivalents of IPA followed by stirring at a temperature of about -0°C to about 5°C. In some embodiments, the contact further includes adding 10 to 20 molar equivalents of IPA followed by stirring at a temperature of about -0°C to about 5°C.

[0246] In some embodiments, the contact further comprises adding additional IPA dropwise to the mixture of compound I and L-arginine and stirring at a temperature of about -10°C to about 15°C. In some embodiments, the contact further comprises adding 10 to 20 molar equivalents of additional IPA dropwise to the mixture of compound I and L-arginine and stirring at a temperature of about -10°C to about 15°C.

[0247] In some embodiments, the method further includes separating the crystalline compound IL-arginine salt after the contact step.

[0248] In some implementations, the separation includes the following steps: filtering, washing, and drying the crystalline compound IL-arginine salt.

[0249] In some embodiments, a method for preparing crystalline compound IL-arginine salt is provided, wherein at least about 95% of the crystalline compound IL-arginine salt is in form B.

[0250] In some embodiments, a method for preparing crystalline compound 1 L-arginine salt is provided, wherein at least about 95% of the crystalline compound 1 L-arginine salt is in form A.

[0251] In some embodiments, a method for preparing crystalline compound IL-arginine salt is provided, wherein at least about 95% of the crystalline compound IL-arginine salt is in form C.

[0252] In some embodiments, a method is provided for preparing crystalline sodium salt of 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (sodium salt of compound I), said method comprising contacting compound I with sodium hydroxide in a solvent for a sufficient time to provide crystalline sodium salt of compound I.

[0253] In some implementations, the solvent is acetone.

[0254] In some embodiments, the contact includes adding an equimolar amount of sodium hydroxide to compound I. In some embodiments, the contact includes adding an equimolar amount of sodium hydroxide to compound I at a temperature of about 0°C to about 50°C. In some embodiments, the contact includes adding an equimolar amount of sodium hydroxide to compound I at a temperature of about 20°C to about 30°C.

[0255] In some embodiments, the method further includes separating the sodium salt of crystalline compound I after the contact step.

[0256] In some implementations, the separation includes the following steps: centrifugation and drying of the crystalline sodium salt of compound I.

[0257] In some embodiments, a method for preparing crystalline compound I L-arginine salt is provided, wherein at least about 95% of the crystalline compound I sodium salt is in form A. Pharmaceutical composition and administration

[0258] In some embodiments, the chemical entity that modulates (e.g., excites) GLP-1 activity (e.g., 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3]) is used. [c]Pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound I) in salt or crystalline form, or a salt or solvate of said salt or crystalline form) is administered as a pharmaceutical composition comprising the chemical entity as described herein and one or more pharmaceutically acceptable excipients and optionally one or more additional therapeutic agents.

[0259] In some implementations, the chemical entity may be administered in combination with one or more conventional pharmaceutical excipients. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers; alumina; aluminum stearate; lecithin; self-emulsifying drug delivery systems (SEDDS), such as d-α-tocopherol polyethylene glycol 1000 succinate; surfactants used in pharmaceutical dosage forms, such as Tween, poloxamer, or other similar polymer delivery matrices; serum proteins, such as human serum albumin; buffering substances, such as phosphates, tris, glycine, sorbic acid, potassium sorbate; mixtures of saturated vegetable fatty acid metaglycerides; water, salts, or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride; zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; cellulose-based substances; polyethylene glycol; sodium carboxymethyl cellulose; polyacrylates; waxes; polyethylene-polyoxypropylene block copolymers; and lanolin. Cyclodextrins (such as α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin) or chemically modified derivatives such as hydroxyalkylcyclodextrins (including 2- and 3-hydroxypropyl-β-cyclodextrin) or other soluble derivatives can also be used to enhance the delivery of the compounds described herein. Dosage forms or compositions containing 0.005% to 100% of the chemical entities described herein, with the remainder supplemented by non-toxic excipients, can be prepared. The compositions considered may contain 0.001% to 100% of the chemical entities provided herein, 0.1% to 95% in one embodiment, 75% to 85% in another embodiment, and 20% to 80% in yet another embodiment. Practical methods for preparing such dosage forms are known to or will be apparent to those skilled in the art; see, for example, Remington: The Science and Practice of Pharmacy, 22nd edition (Pharmaceutical Press, London, UK. 2012). Application route and composition components

[0260] In some implementations, the chemical entities described herein or their pharmaceutical compositions may be administered to the subject in need via any acceptable route of administration. Acceptable routes of administration include, but are not limited to, buccal, skin, intracervical, intrasinusial, tracheal, intestinal, epidural, interstitial, intraperitoneal, intraarterial, intrabronchial, intrabursal, intracerebral, intracisary, intracoronary, intradermal, intracatheter, intraduodenal, intradural, intraepithelial, intraepithelial, intraesophageal, intragastric, intragingival, intraileum, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinusial, spinal, intrasynovial, intratestinal, intrasheath, intraductal, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, percutaneous, epidural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, external, transdermal, transmucosal, tracheal, ureteral, urethral, ​​and vaginal.

[0261] The compositions can be formulated for parenteral administration, for example, for injection via intravenous, intramuscular, subcutaneous, or even intraperitoneal routes. Typically, such compositions can be prepared as injectable preparations, as liquid solutions or suspensions; they can also be prepared in solid forms suitable for preparing solutions or suspensions after the addition of liquid prior to injection; and they can also be emulsified formulations. The preparation of such formulations will be known to those skilled in the art in light of this disclosure.

[0262] Suitable drug forms for injection include sterile aqueous solutions or dispersions; formulations containing sesame oil, peanut oil, or propylene glycol; and sterile powders for the ad hoc preparation of sterile injectable solutions or dispersions. Generally, the form must be sterile and fluid in a manner that facilitates injection. It should also be stable under the conditions of manufacture and storage and must be preserved against contamination by microorganisms such as bacteria and fungi.

[0263] The carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, etc.), suitable mixtures thereof, and vegetable oils. Appropriate flowability can be maintained, for example, by using coatings (e.g., lecithin), by maintaining the desired particle size in the case of dispersions, and by using surfactants. Antimicrobial activity can be achieved using a variety of antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.). In many cases, isotonic agents, such as sugars or sodium chloride, are preferred. The absorption of the injectable composition can be prolonged by using agents that delay absorption (e.g., aluminum monostearate and gelatin) in the composition.

[0264] Sterile injectable solutions can be prepared by incorporating the active compound in the desired amount into a suitable solvent containing, as needed, several other components listed above, followed by filtration and sterilization. Dispersions are typically prepared by incorporating several sterile active ingredients into a sterile medium containing a base dispersion medium and other desired components from those listed above. In the case of sterile powders used to prepare sterile injectable solutions, the preferred preparation method is vacuum drying and freeze-drying techniques, which produce powders of the active ingredient and any other desired components from a previously sterile filtered solution.

[0265] Pharmacologically acceptable excipients that may be used in rectal compositions as gels, creams, enemas, or rectal suppositories include, but are not limited to, any one or more of the following: glyceryl cocoa butter, synthetic polymers (such as polyvinylpyrrolidone), PEG (such as PEG ointment), glycerin, glycerin-treated gelatin, hydrogenated vegetable oils, poloxamer, mixtures of polyethylene glycol and polyethylene glycol fatty acid esters of various molecular weights, petrolatum, anhydrous lanolin, shark liver oil, sodium saccharin, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxidase, etc. SBN, vanilla essential oil, aerosols, parabens in phenoxyethanol, sodium methylparaben, sodium propylparaben, diethylamine, carbomer, carbopol, methylparaben, polyethylene glycol cetearyl ether, cocoylcaprylocaprate, isopropanol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metasulfite, sodium edetate, sodium benzoate, potassium metasulfite, grapefruit seed extract, methanesulfonylmethane (MSM), lactic acid, glycine, vitamins (such as vitamins A and E), and potassium acetate.

[0266] In some embodiments, the suppository can be prepared by mixing a chemical entity as described herein with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or suppository wax, which is solid at ambient temperature but liquid at body temperature, and thus melts in the rectum and releases the active compound. In other embodiments, the composition for rectal administration is in the form of an enema.

[0267] In other embodiments, the compounds or pharmaceutical compositions thereof described herein are suitable for local delivery to the digestive or gastrointestinal (GI) tract by means of oral administration (e.g., solid or liquid dosage forms).

[0268] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, a chemical entity is mixed with one or more pharmaceutically acceptable excipients (such as 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, calcium carbonate, potato or cassava starch, alginate, 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) adsorbents, such as kaolin and bentonite; and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain a buffer. Similar types of solid compositions can also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or toffee and high molecular weight polyethylene glycol.

[0269] In one embodiment, the composition will be in the form of a unit dosage form such as pills or tablets, and therefore the composition may contain a diluent, such as lactose, sucrose, dicalcium phosphate, etc., along with the chemical entities provided herein; a lubricant, such as magnesium stearate, etc.; and a binder, such as starch, gum arabic, polyvinylpyrrolidone, gelatin, cellulose, cellulose derivatives, etc. In another solid dosage form, powders, marumes, solutions, or suspensions (e.g., in propylene carbonate, vegetable oil, PEG, poloxamer 124, or triglycerides) are encapsulated in capsules (gelatin or cellulose matrix capsules). Unit dosage forms in which one or more chemical entities or other active agents provided herein are physically separated are also contemplated; for example, capsules (or tablets in capsules) having particles of each drug; two-layer tablets; two-compartment gel caps, etc. Enteric-coated or delayed-release oral dosage forms are also contemplated.

[0270] Other physiologically acceptable compounds include wetting agents, emulsifiers, dispersants, or preservatives that are particularly useful for preventing the growth or action of microorganisms. Many preservatives are well-known and include, for example, phenol and ascorbic acid.

[0271] In some implementations, the excipients are sterile and generally do not contain unwanted substances. These compositions can be sterilized using conventional, well-known sterilization techniques. For various oral dosage form excipients, such as tablets and capsules, sterilization is not required. USP / NF standards are generally sufficient.

[0272] The ophthalmic composition may contain, but is not limited to, any one or more of the following: viscogen (e.g., carboxymethyl cellulose, glycerin, polyvinylpyrrolidone, polyethylene glycol); stabilizers (e.g., Pluronic (triblock copolymer), cyclodextrin); preservatives (e.g., benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloride complex; Allergan, Inc.)).

[0273] Topical compositions may include ointments and creams. Ointments are typically semi-solid formulations based on petrolatum or other petroleum derivatives. Creams containing selected active agents are typically viscous liquids or semi-solid emulsions, often oil-in-water or water-in-oil emulsions. Cream bases are typically water-washable and contain an oil phase, an emulsifier, and an aqueous phase. The oil phase, sometimes referred to as the "internal" phase, typically includes paraffin esters and fatty alcohols such as cetyl alcohol or stearyl alcohol; although not essential, the aqueous phase usually exceeds the volume of the oil phase and typically contains humectants. Emulsifiers in cream formulations are typically nonionic, anionic, cationic, or amphoteric surfactants. Like other carriers or mediators, ointment bases should be inert, stable, non-irritating, and non-sensitizing.

[0274] In any of the foregoing embodiments, the pharmaceutical composition described herein may comprise one or more of the following: lipids, interlayer cross-linked multilayer vesicles, biodegradable poly(D,L-lactic acid-co-glycolic acid) [PLGA] or polyanhydride nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers. dose

[0275] Dosage can vary depending on the patient's needs, the severity of the condition being treated, and the specific compound used. The appropriate dosage for a particular situation can be determined by a medical professional. In some cases, the total daily dose can be divided into multiple doses and administered throughout the day, or by means of a continuous delivery method.

[0276] In some embodiments, the compounds described herein are administered in doses from about 0.001 mg / kg to about 500 mg / kg (e.g., from about 0.001 mg / kg to about 200 mg / kg; from about 0.01 mg / kg to about 200 mg / kg; from about 0.01 mg / kg to about 150 mg / kg; from about 0.01 mg / kg to about 100 mg / kg; from about 0.01 mg / kg to about 50 mg / kg; from about 0.01 mg / kg to about 10 mg / kg; from about 0.01 mg / kg to about 5 mg / kg; from about 0.01 mg / kg to...). About 1 mg / kg; from about 0.01 mg / kg to about 0.5 mg / kg; from about 0.01 mg / kg to about 0.1 mg / kg; from about 0.1 mg / kg to about 200 mg / kg; from about 0.1 mg / kg to about 150 mg / kg; from about 0.1 mg / kg to about 100 mg / kg; from about 0.1 mg / kg to about 50 mg / kg; from about 0.1 mg / kg to about 10 mg / kg; from about 0.1 mg / kg to about 5 mg / kg; from about 0.1 mg / kg to about 1 mg / kg; from about 0.1 mg / kg to about 0.5 mg / kg. plan

[0277] The aforementioned dosage may be administered daily (e.g., as a single dose or in two or more divided doses) or non-daily (e.g., every other day, every two days, every three days, once a week, twice a week, once every two weeks, once a month).

[0278] In some embodiments, the application period of the compounds described herein is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer. In another embodiment, the period for discontinuing administration is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer. In one embodiment, the therapeutic compound is administered to an individual for a certain period, followed by separate periods. In another embodiment, the therapeutic compound is administered for a first period and a second period following the first period, during which administration is discontinued, followed by a third period initiating administration of the therapeutic compound, and then a fourth period following the third period initiating administration. In one aspect of this embodiment, the periods for administering the therapeutic compound and the subsequent periods for discontinuing administration are repeated, either defined or undefined. In another implementation, the application period is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer. In another implementation, the discontinuation period is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer. Treatment

[0279] This disclosure is characterized by methods for treating a subject (e.g., a person) suffering from a disease, disorder, or condition, wherein modulation of GLP-1R (e.g., inhibited or weakened and / or elevated or undesirable GLP-1R) is beneficial for treating the underlying pathology and / or symptoms and / or progression of the disease, disorder, or condition. In some embodiments, a method is provided for treating a subject suffering from a disease, disorder, or condition at least partially mediated by GLP-1, said method comprising administering to the subject a compound as described herein, such as compound IL-arginine salt form A, B, or C. In some embodiments, the method described herein may include or further include treatment of one or more conditions, comorbidities, or sequelae associated with any one or more of the conditions described herein.

[0280] In some embodiments, the compounds and pharmaceutical compositions and methods for treating the patients described herein induce one or more of the following by administering a solid form of compound I as described herein to a patient in need: a decrease in blood glucose levels (e.g., reduced blood glucose levels), a decrease in blood hemoglobin A1c (HbA1c) levels, promotion of insulin synthesis, stimulation of insulin secretion, increase in β-cell mass, regulation of gastric acid secretion, regulation of gastric emptying, a decrease in body mass index (BMI), and / or a decrease in glucagon production (e.g., levels). In some embodiments, the compounds and pharmaceutical compositions and methods for treating the patients described herein may decrease blood glucose levels, decrease blood hemoglobin A1c (HbA1c) levels, promote insulin synthesis, stimulate insulin secretion, increase β-cell mass, regulate gastric acid secretion, regulate gastric emptying, decrease body mass index (BMI), decrease glucagon production (e.g., levels), or any combination thereof. In some embodiments, the compounds and pharmaceutical compositions and methods for treating the patients described herein stabilize serum glucose and serum insulin levels (e.g., serum glucose and serum insulin concentrations). This article also provides a method for regulating glucose or insulin levels in patients who require such regulation, the method comprising administering to the patient an effective amount of compound I as disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.

[0281] In some embodiments, this document provides a method for reducing the risk of major adverse cardiovascular events (MACE) in patients in need (e.g., a reduction of about 20%, 30%, 40%, 50%, 60%, 70%, or 80%), said method comprising administering to the patient an effective amount of a compound I as disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. In some of these embodiments, the patient is an adult diagnosed with type 2 diabetes (T2D). In some embodiments, the patient is an adult diagnosed with heart disease. In some embodiments, the patient is an adult diagnosed with both type 2 diabetes (T2D) and heart disease. In some embodiments, the patient is an adult with type 2 diabetes (T2D). In some embodiments, the patient is an adult with heart disease. In some embodiments, the patient has both type 2 diabetes (T2D) and heart disease.

[0282] In some implementations, the method described herein further includes the step of identifying a patient (e.g., a subject) who requires such treatment (e.g., by blood tests, body mass index, or other conventional methods known in the art).

[0283] In some implementations, the methods described herein further include the step of identifying a patient (e.g., a patient) suffering from a disease, disorder, or condition as described herein (e.g., a GLP-1 related disease, disorder, or condition).

[0284] In some embodiments, the method described herein further includes the step of identifying a patient with type 2 diabetes (e.g., a patient). In some embodiments, determining whether a patient has type 2 diabetes includes performing measurements to determine the levels of hemoglobin A1c (HbA1c), fasting plasma glucose, non-fasting plasma glucose, or any combination thereof. In some embodiments, the HbA1c level is from about 6.5% to about 24.0%. In some embodiments, the HbA1c level is greater than or about 6.5%. In some embodiments, the HbA1c level is greater than or about 8.0%. In some embodiments, the HbA1c level is greater than or about 10.0%. In some embodiments, the HbA1c level is greater than or about 12.0%. In some embodiments, the HbA1c level is greater than or about 14.0%. In some embodiments, the HbA1c level is greater than or about 16.0%. In some embodiments, the HbA1c level is greater than or about 18.0%. In some embodiments, the HbA1c level is greater than or about 20.0%. In some implementations, the HbA1c level is greater than or about 22.0%. In some implementations, the HbA1c level is greater than or about 24.0%.

[0285] In some embodiments, the fasting plasma glucose level is greater than or about 120 mg / dL to greater than or about 750 mg / dL. In some embodiments, the fasting plasma glucose level is greater than or about 200 mg / dL to greater than or about 500 mg / dL. In some embodiments, the fasting plasma glucose level is greater than or about 300 mg / dL to greater than or about 700 mg / dL.

[0286] In some embodiments, the non-fasting plasma glucose level is greater than or about 190 mg / dL to greater than or about 750 mg / dL. In some embodiments, the non-fasting plasma glucose level is greater than or about 250 mg / dL to greater than or about 450 mg / dL. In some embodiments, the non-fasting plasma glucose level is greater than or about 400 mg / dL to greater than or about 700 mg / dL.

[0287] In some implementations, determining whether a patient has type 2 diabetes further includes determining the patient's BMI. In some implementations, the patient's BMI is greater than or about 22 kg / m². 2 Up to or greater than 100 kg / m 2 In some implementation schemes, the patient's BMI is greater than or approximately 30 kg / m². 2 Up to or greater than 90 kg / m 2 In some implementation schemes, the patient's BMI is greater than or approximately 40 kg / m². 2 Up to or approximately 80 kg / m 2 In some implementation schemes, the patient's BMI is greater than or approximately 50 kg / m². 2 Up to or greater than 70 kg / m 2 .

[0288] In some embodiments, additional factors (e.g., risk factors) used to determine whether a patient has type 2 diabetes further include the patient's age and race. In some embodiments, the patient's age is greater than or approximately 10 years. In some embodiments, the patient's age is greater than or approximately 15 years. In some embodiments, the patient's age is greater than or approximately 20 years. In some embodiments, the patient's age is greater than or approximately 25 years. In some embodiments, the patient's age is greater than or approximately 30 years. In some embodiments, the patient's age is greater than or approximately 35 years. In some embodiments, the patient's age is greater than or approximately 40 years. In some embodiments, the patient's age is greater than or approximately 42 years. In some embodiments, the patient's age is greater than or approximately 44 years. In some embodiments, the patient's age is greater than or approximately 46 years. In some embodiments, the patient's age is greater than or approximately 48 years. In some embodiments, the patient's age is greater than or approximately 50 years. In some embodiments, the patient's age is greater than or approximately 52 years. In some embodiments, the patient's age is greater than or approximately 54 years. In some embodiments, the patient's age is greater than or approximately 56 years. In some embodiments, the patient's age is greater than or approximately 58 years. In some embodiments, the patient's age is greater than or approximately 60 years. In some embodiments, the patient's age is greater than or approximately 62 years. In some embodiments, the patient's age is greater than or approximately 64 years. In some embodiments, the patient's age is greater than or approximately 66 years. In some embodiments, the patient's age is greater than or approximately 68 years. In some embodiments, the patient's age is greater than or approximately 70 years. In some embodiments, the patient's age is greater than or approximately 72 years. In some embodiments, the patient's age is greater than or approximately 74 years. In some embodiments, the patient's age is greater than or approximately 76 years. In some embodiments, the patient's age is greater than or approximately 78 years. In some embodiments, the patient's age is greater than or approximately 80 years. In some embodiments, the patient's age is greater than or approximately 85 years. In some embodiments, the patient's age is greater than or approximately 90 years. In some embodiments, the patient's age is greater than or approximately 95 years. In some implementation schemes, the patient's race can be African American, American Indian or Alaskan Native, Asian American, Hispanic or Latino or Native Hawaiian or Pacific Islander.

[0289] In some implementations, the patient is a pediatric patient. As used herein, the term “pediatric patient” refers to a patient under the age of 21 years at the time of diagnosis or treatment. The term “pediatric” can be further subdivided into different subgroups, including: neonates (from birth to the first month of life); infants (1 month to two years); children (two years to 12 years); and adolescents (12 to 21 years (up to but not including the twenty-second birthday)). (References: Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th edition Philadelphia: WBSaunders Company, 1996; Rudolph AM et al. Rudolph's Pediatrics, 21st edition New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd edition Baltimore: Williams & Wilkins; 1994.) In some implementations, pediatric patients are defined as those born within the first 28 days of life, 29 days old to less than two years old, two years old to less than 12 years old, or 12 years old to 21 years old (up to but not including the twenty-second birthday). In some implementations, pediatric patients are defined as those born within the first 28 days of life, 29 days old to less than one year old, one month old to less than four months old, three months old to less than seven months old, six months old to less than one year old, one year old to less than two years old, two years old to less than three years old, two years old to less than seven years old, three years old to less than five years old, five years old to less than ten years old, six years old to less than 13 years old, ten years old to less than 15 years old, or 15 years old to less than 22 years old. In some implementations, patients are adult patients. Indications obesity

[0290] In some implementations, the condition, disease, or disorder is obesity and conditions, diseases, or disorders related to or associated with obesity. Non-limiting examples of obesity and obesity-related conditions include symptomatic obesity, simple obesity, childhood obesity, morbid obesity, and abdominal obesity (central obesity characterized by excessive abdominal fat). Non-limiting examples of symptomatic obesity include endocrine obesity (e.g., Cushing syndrome, hypothyroidism, insulinoma, type II diabetes mellitus, pseudohypoparathyroidism, hypogonadism), hypothalamic obesity, hereditary obesity (e.g., Prader-Willi syndrome, Laurence-Moon-Biedl syndrome), and drug-induced obesity (e.g., obesity induced by steroids, phenothiazines, insulin, sulfonylureas, or beta-blockers).

[0291] In some implementations, the condition, disease, or disorder is associated with obesity. Examples of such conditions, diseases, or disorders include, but are not limited to, glucose intolerance, diabetes (e.g., type 2 diabetes, obese diabetes), lipid metabolism disorders, hyperlipidemia, hypertension, heart failure, hyperuricemia, gout, fatty liver (including non-alcoholic steatohepatitis (NASH)), coronary artery disease (e.g., myocardial infarction, angina pectoris), cerebral infarction (e.g., cerebral thrombosis, transient ischemic attack), bone or joint disorders (e.g., knee osteoarthritis, hip osteoarthritis, degenerative spondylitis, low back pain), sleep apnea syndrome, obesity-hypopnea syndrome (Pickwickian syndrome), menstrual disorders (e.g., abnormal menstrual cycles, abnormal menstrual flow and cycle, amenorrhea, abnormal menstrual symptoms), visceral obesity syndrome, urinary incontinence, and metabolic syndrome. In some implementations, the chemical compounds and pharmaceutical compositions described herein can be used to treat patients exhibiting both obesity and insulin deficiency. diabetes

[0292] In some implementations, the condition, disease, or disorder is diabetes. Non-limiting examples of diabetes include type 1 diabetes, type 2 diabetes (e.g., type 2 diabetes treated with diet, type 2 diabetes treated with sulfonylureas, very advanced type 2 diabetes, type 2 diabetes treated with long-term insulin therapy), diabetes (e.g., non-insulin-dependent diabetes, insulin-dependent diabetes), gestational diabetes, obese diabetes, autoimmune diabetes, and borderline diabetes. In some implementations, the condition, disease, or disorder is type 2 diabetes (e.g., type 2 diabetes treated with diet, type 2 diabetes treated with sulfonylureas, very advanced type 2 diabetes, type 2 diabetes treated with long-term insulin therapy).

[0293] In some implementations, the condition, disease, or disorder is associated with diabetes (e.g., complications of diabetes). Non-limiting examples of diabetes-related disorders include obesity, obesity-related disorders, metabolic syndrome, neuropathy, nephropathy (e.g., diabetic nephropathy), retinopathy, diabetic cardiomyopathy, cataracts, macrovascular disease, osteoporosis, hyperosmolar diabetic coma, infectious diseases (e.g., respiratory infections, urinary tract infections, gastrointestinal infections, skin and soft tissue infections, lower extremity infections), diabetic gangrene, xerostomia, hearing loss, cerebrovascular disorders, diabetic cachexia, delayed wound healing, diabetic dyslipidemia, peripheral circulatory disorders, cardiovascular risk factors (e.g., coronary artery disease, peripheral artery disease, cerebrovascular disease, hypertension and risk factors associated with unmanaged cholesterol and / or lipid levels, and / or inflammation), NASH, fractures, and cognitive impairment.

[0294] Other non-limiting examples of diabetes-related disorders include prediabetes, hyperlipidemia (e.g., hypertriglyceridemia, hypercholesterolemia, hyperLDL-cholesterolemia, hypoHDL-cholesterolemia, postprandial hyperlipidemia), metabolic syndrome (e.g., metabolic X syndrome, where activation of GLP-1R is a beneficial metabolic disorder), hypertension, impaired glucose tolerance (IGT), insulin resistance, and sarcopenia.

[0295] In some implementations, the condition, disease, or disorder is diabetes and obesity (diabetic obesity). In some implementations, the compounds described herein can be used to improve the therapeutic efficacy of metformin. Metabolic barriers

[0296] In some implementations, the condition, disease, or disorder is a disorder of a metabolically important tissue. Non-limiting examples of metabolically important tissues include the liver, fat, pancreas, kidneys, and intestines.

[0297] In some implementations, the condition, disease, or disorder is fatty liver disease. Fatty liver disease includes, but is not limited to, non-alcoholic fatty liver disease (NAFLD), steatohepatitis, non-alcoholic steatohepatitis (NASH), fatty liver disease caused by hepatitis, fatty liver disease caused by obesity, fatty liver disease caused by diabetes, fatty liver disease caused by insulin resistance, fatty liver disease caused by hypertriglyceridemia, abeta-lipoproteinemia, hyperlipoproteinemia, glycogen storage disease, Weber-Christian disease, Wolman disease, acute fatty liver of pregnancy, and lipodystrophy.

[0298] Nonalcoholic fatty liver disease (NAFLD) refers to a range of diseases that occur in the absence of alcohol abuse and are typically characterized by the presence of steatosis (fat in the liver). NAFLD is believed to be associated with a variety of conditions, such as metabolic syndrome (including obesity, diabetes, and hypertriglyceridemia) and insulin resistance. It can cause liver disease in adults and children and may eventually lead to cirrhosis (Skelly et al., J Hepatol 2001; 35:195-9; Chitturi et al., Hepatology 2002; 35(2):373-9). The severity of NAFLD ranges from relatively benign, isolated, predominantly macrovesicular steatosis (i.e., nonalcoholic fatty liver or NAFL) to nonalcoholic steatohepatitis (NASH) (Angulo et al., J Gastroenterol Hepatol 2002; 17Suppl:S186-90).

[0299] Other non-limiting examples of disorders in metabolically important tissues include joint disorders (e.g., osteoarthritis, secondary osteoarthritis), steatosis (e.g., in the liver); fibrosis (e.g., in the liver); cirrhosis (e.g., in the liver); gallstones; gallbladder disorders; gastroesophageal reflux; sleep apnea; hepatitis; fatty liver; and skeletal disorders characterized by changes in bone metabolism, such as osteoporosis, including postmenopausal osteoporosis, poor bone strength, osteopenia, Paget's disease, and cancer. This treatment is indicated for patients with osteolytic metastases, osteodystrophy in liver disease, and bone metabolic changes caused by renal failure or hemodialysis, fractures, bone surgery, aging, pregnancy, fracture protection, and malnutrition due to polycystic ovary syndrome; kidney diseases (e.g., chronic renal failure, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end-stage renal disease); muscular dystrophy, angina pectoris, acute or chronic diarrhea, testicular dysfunction, respiratory dysfunction, weakness, sexual dysfunction (e.g., erectile dysfunction), and geriatric syndromes. In some embodiments, the compounds and pharmaceutical compositions described herein can be used to treat surgical trauma by improving postoperative recovery and / or by preventing catabolism responses caused by surgical trauma. Cardiovascular and vascular diseases

[0300] In some implementations, the condition, disease, or disorder is a cardiovascular disease. Non-limiting examples of cardiovascular diseases include congestive heart failure, atherosclerosis, arteriosclerosis, coronary artery disease, coronary artery disease, hypertension, heart failure, cerebrovascular disorders (e.g., cerebral infarction), vascular dysfunction, myocardial infarction, elevated blood pressure (e.g., 130 / 85 mm Hg or higher), and prethrombotic states (exemplified by high levels of fibrinogen or plasminogen activator inhibitors in the blood).

[0301] In some implementations, the condition, disease, or disorder is associated with vascular disease. Non-limiting examples of vascular disease include peripheral vascular disease, large vessel complications (e.g., stroke), vascular dysfunction, peripheral artery disease, abdominal aortic aneurysm, carotid artery disease, cerebrovascular disorders (e.g., cerebral infarction), pulmonary embolism, chronic venous insufficiency, severe limb ischemia, retinopathy, nephropathy, and neuropathy. Nervous system diseases

[0302] In some implementations, the condition, disease, or disorder is a neurological disorder (e.g., a neurodegenerative disorder) or a mental disorder. Non-limiting examples of neurological disorders include idiopathic intracranial hypertension (IIH), cerebral insulin resistance, mild cognitive impairment (MCI), Alzheimer's disease (AD), Parkinson's disease (PD), anxiety disorders, dementia (e.g., Alzheimer's disease), traumatic brain injury, Huntington's chores, tardive dyskinesia, hyperkinesia, mania, Morbus Parkinson's disease, Steele-Richard syndrome, Down's syndrome, myasthenia gravis, neurological trauma, brain trauma, angioamylindness, intracerebral hemorrhage with amyloidosis, encephalitis, Friedrich's ataxia, acute confusional disorder, amyotrophic lateral sclerosis (ALS), glaucoma, and apoptosis-mediated central nervous system degenerative diseases (e.g., Creutzfeld-Jakob disease, bovine spongiform encephalopathy (BSE), and chronic wasting syndrome). See, for example, U.S. Publication No. 20060275288A1.

[0303] In some embodiments, the condition, disease, or disorder is idiopathic intracranial hypertension. Idiopathic intracranial hypertension is characterized by elevated intracranial pressure and papilledema. See, for example, Virdee et al., Ophthalmol Ther. 2020; 9(4):767-781. In some embodiments, the compounds and pharmaceutical compositions and methods described herein reduce cerebrospinal fluid secretion in patients with idiopathic intracranial hypertension. In some embodiments, the compounds and pharmaceutical compositions and methods described herein reduce intracranial pressure in patients with idiopathic intracranial hypertension. In some embodiments, the compounds and pharmaceutical compositions and methods described herein reduce one or more symptoms in patients with idiopathic intracranial hypertension. Symptoms of idiopathic intracranial hypertension may include severe headache and visual impairment. In some embodiments, the patient with idiopathic intracranial hypertension is female. In some embodiments, the patient with idiopathic intracranial hypertension is approximately 20 to approximately 30 years old. In some embodiments, the patient with idiopathic intracranial hypertension is obese.

[0304] In some embodiments, the condition, disease, or disorder is Wolfram syndrome. Wolfram syndrome is caused by a biallelic mutation in the Wolframin ER transmembrane glycoprotein (Wfs1) gene. See, for example, Seppa et al., Sci Rep 9, 15742 (2019). Wolfram syndrome can initially present as diabetes, followed by symptoms of optic atrophy, deafness, and neurodegeneration. Patients with Wolfram syndrome may have symptoms of ataxia, sleep apnea, dysphagia, hearing loss, and loss of taste due to brainstem atrophy. In some embodiments, the compounds and pharmaceutical compositions and methods described herein reduce neuroinflammation in patients with Wolfram syndrome. In some embodiments, neuroinflammation in the inferior olivary nucleus of the patient is reduced. In some embodiments, the compounds and pharmaceutical compositions and methods described herein reduce retinal ganglion cell death in patients with Wolfram syndrome. In some embodiments, the compounds and pharmaceutical compositions and methods described herein reduce axonal degeneration in patients with Wolfram syndrome. In some embodiments, the compounds and pharmaceutical compositions and methods described herein reduce one or more symptoms (e.g., any of the symptoms described herein) in patients with Wolfram syndrome.

[0305] Non-limiting examples of mental disorders include substance dependence / addiction (narcotics and amphetamines) and attention deficit / hyperactivity disorder (ADHD). The compounds and pharmaceutical compositions described herein can be used to improve behavioral responses to addictive substances, reduce substance dependence, prevent relapse into substance abuse, and alleviate anxiety caused by the absence of a given addictive substance. See, for example, U.S. Publication No. 20120021979A1.

[0306] In some embodiments, the compounds and pharmaceutical compositions described herein can be used to improve learning and memory by enhancing neuronal plasticity and promoting cell differentiation, and also to protect dopamine neurons and motor function in Parkinson's disease. Insulin-related

[0307] In some implementations, the condition, disease, or disorder is impaired fasting glucose (IFG), impaired fasting glucose parameters (IFG), hyperglycemia, insulin resistance (impaired glucose homeostasis), hyperinsulinemia, elevated blood fatty acid or glycerol levels, hypoglycemia, insulin resistance syndrome, paresthesia caused by hyperinsulinemia, hyperlipidemia, hypercholesterolemia, impaired wound healing, leptin resistance, glucose intolerance, increased fasting glucose, dyslipidemia (e.g., hyperlipidemia, atherogenic dyslipidemia characterized by high triglycerides and low HDL cholesterol), glucagonoma, hyperuricemia, hypoglycemia (e.g., nocturnal hypoglycemia), and insulin-related coma endpoints.

[0308] In some embodiments, the compounds and pharmaceutical compositions described herein can reduce or slow the progression of borderline, impaired fasting glucose, or impaired fasting glucose to diabetes. Autoimmune disorders

[0309] In some implementations, the symptom, disease, or disorder is an autoimmune disorder. Non-limiting examples of autoimmune disorders include multiple sclerosis, experimental autoimmune encephalomyelitis, autoimmune disorders associated with immune rejection, graft-versus-host disease, uveitis, optic neuropathy, optic neuritis, transverse myelitis, inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, myasthenia gravis, and Graves' disease. See, for example, U.S. Publication No. 20120148586A1. Gastrointestinal disorders

[0310] In some implementations, the symptom, disease, or disorder is a gastrointestinal-related disorder. Non-limiting examples of these disorders include ulcers of any etiology (e.g., gastric ulcers, Zollinger-Ellison syndrome, drug-induced ulcers, ulcers associated with infection or other pathogens), digestive disorders, malabsorption, short bowel syndrome, cul-de-sac syndrome, inflammatory bowel disease (Crohn's disease and ulcerative colitis), steatorrhea (celiac sprue), hypogammaglobulinemic sprue, mucositis and diarrhea induced by chemotherapy and / or radiation therapy, gastrointestinal inflammation, short bowel syndrome, ulcerative colitis, gastric mucosal damage (e.g., gastric mucosal damage caused by aspirin), small intestinal mucosal damage, and cachexia (e.g., cancer cachexia, tuberculous cachexia, cachexia associated with blood disorders, cachexia associated with endocrine disorders, cachexia associated with infectious diseases, and cachexia caused by acquired immunodeficiency syndrome). weight

[0311] In some embodiments, the compounds and pharmaceutical compositions described herein can be used to reduce weight (e.g., excess weight) in patients (e.g., patients in need), prevent weight gain, induce weight loss, reduce body fat, or reduce food intake. In some embodiments, a patient's weight gain may be attributed to overeating or an unbalanced diet, or it may be due to weight gain from accompanying medications (e.g., insulin sensitizers with PPARγ agonist-like effects, such as troglitazone, rosiglitazone, empaglitazone, cycloglitazone, pioglitazone, etc.). In some embodiments, the weight gain may be pre-obesity weight gain or weight gain in obese patients. In some embodiments, the weight gain may also be drug-induced weight gain or weight gain following cessation of smoking. In some embodiments, the weight gain is induced by the use of steroids or antipsychotics.

[0312] In some implementations, the symptom, disease, or disorder is an eating disorder, such as overeating, binge eating, bulimia, compulsive eating, or syndromic obesity, such as Prad-Willi syndrome and Bard-Biedl syndrome. Inflammatory diseases

[0313] In some implementations, the symptom, disease, or disorder is an inflammatory disorder. Non-limiting examples of inflammatory disorders include chronic rheumatoid arthritis, degenerative spondylitis, osteoarthritis, low back pain, gout, postoperative or post-traumatic inflammation, abdominal distension, neuralgia, pharyngitis, cystitis, pneumonia, pancreatitis, enteritis, inflammatory bowel disease (including inflammatory colitis), inflammation in metabolically important tissues (including the liver, fat, pancreas, kidneys, and intestines), and pro-inflammatory states (e.g., elevated levels of pro-inflammatory cytokines or markers such as inflammatory-like C-reactive protein in the blood). cancer

[0314] In some implementations, the symptom, disease, or obstacle is cancer. Suitable examples of cancer include breast cancer (e.g., invasive ductal breast cancer, non-invasive ductal breast cancer, inflammatory breast cancer), prostate cancer (e.g., hormone-dependent prostate cancer, non-hormone-dependent prostate cancer), pancreatic cancer (e.g., ductal pancreatic cancer), gastric cancer (e.g., papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous carcinoma), lung cancer (e.g., non-small cell lung cancer, small cell lung cancer, malignant mesothelioma), colon cancer (e.g., gastrointestinal stromal tumor), and colorectal cancer (e.g., stomach cancer). Gastrointestinal stromal tumors (GISTs), colorectal cancers (e.g., familial colorectal cancer, hereditary nonpolyposis colorectal cancer, GISTs), small bowel cancers (e.g., non-Hodgkin's lymphoma, GISTs), esophageal cancer, duodenal cancer, tongue cancer, pharyngeal cancer (e.g., nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer), salivary gland cancer, brain tumors (e.g., pineal astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma), schwannomas, liver cancers (e.g., [missing information]). Primary liver cancer, extrahepatic bile duct cancer, kidney cancer (e.g., renal cell carcinoma, transitional cell carcinoma of the renal pelvis and ureter), bile duct cancer, endometrial cancer, cervical cancer, ovarian cancer (e.g., epithelial ovarian cancer, extragonadal germ cell tumors, ovarian germ cell tumors, low-potency ovarian tumors), bladder cancer, urethral cancer, skin cancer (e.g., intraocular (ocular) melanoma, Merkel cell carcinoma), hemangioma, malignant lymphoma, malignant melanoma, thyroid cancer (e.g., medullary thyroid carcinoma). Cancer, parathyroid carcinoma, nasal cavity carcinoma, sinus carcinoma, bone tumors (e.g., osteosarcoma, Ewing's tumor, uterine sarcoma, soft tissue sarcoma), angiofibroma, retinal sarcoma, penile cancer, testicular tumors, pediatric solid tumors (e.g., nephroblastoma, pediatric kidney tumors), Kaposi's sarcoma, Kaposi's sarcoma caused by AIDS, maxillary sinus tumors, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, and leukemia (e.g., acute myeloid leukemia, acute lymphoblastic leukemia). Hypothalamic-pituitary disorders

[0315] In some implementations, the condition, disease, or disorder is associated with the hypothalamic-pituitary-gonadal axis. For example, the condition, disease, or disorder is associated with the hypothalamic-pituitary-ovarian axis. In another example, the condition, disease, or disorder is associated with the hypothalamic-pituitary-testicular axis. Hypothalamic-pituitary-gonadal axis disorders include, but are not limited to, hypogonadism, polycystic ovary syndrome, hypothyroidism, hypopituitarism, sexual dysfunction, and Cushing's disease.

[0316] In some implementations, conditions, diseases, or disorders associated with diabetes are linked to the hypothalamic-pituitary-gonadal axis. pulmonary disease

[0317] In some implementations, the condition, disease, or disorder is associated with a lung disease. Lung diseases include, but are not limited to, asthma, idiopathic pulmonary fibrosis, pulmonary hypertension, obstructive sleep apnea-hypopnea syndrome, and chronic obstructive pulmonary disease (COPD) (e.g., emphysema, chronic bronchitis, and refractory (irreversible) asthma).

[0318] In some implementations, the condition, disease, or disorder associated with diabetes is lung disease. Combination therapy

[0319] In some implementations, this disclosure considers both monotherapy regimens and combination therapy regimens.

[0320] In some embodiments, the methods described herein may further include administering one or more additional therapies (e.g., one or more additional therapeutic agents and / or one or more treatment regimens) in combination with the compounds described herein.

[0321] In some embodiments, the methods described herein include administering the compounds described herein in combination with one or more of the following: diet therapy (e.g., diet monitoring, diet therapy for diabetes), exercise therapy (e.g., physical activity), blood glucose monitoring, and gastric electrical stimulation (e.g., And dietary changes.

[0322] In some implementations, the compound described herein or its pharmaceutically acceptable salt or solvate may be administered in combination with one or more other therapeutic agents.

[0323] Other representative therapeutic agents include, but are not limited to, anti-obesity agents, diabetes treatment agents, diabetes complication treatment agents, hyperlipidemia treatment agents, antihypertensive agents, diuretics, chemotherapy drugs, immunotherapy drugs, anti-inflammatory drugs, antithrombotic agents, antioxidants, osteoporosis treatment agents, vitamins, anti-dementia drugs, erectile dysfunction drugs, urinary frequency or incontinence treatment agents, NAFLD treatment agents, NASH treatment agents, and dysuria treatment agents.

[0324] In some embodiments, the one or more additional therapeutic agents include those suitable for use as anti-obesity agents. Non-limiting examples include monoamine uptake inhibitors (e.g., tramadol, phentermine, sibutramine, mazindol, fluoxetine, tesofensine), serotonin 2C receptor agonists (e.g., lorcaserin), serotonin 6 receptor antagonists, histamine H3 receptor modulators, GABA modulators (e.g., topiramate) (including GABA receptor agonists (e.g., gabapentin, pregabalin)), neuropeptide Y antagonists (e.g., velneperitone), peptide YY or analogues thereof, and cannabinoid receptor antagonists (e.g., rimonaba). nt), taranabant), orexin antagonists, orexin receptor antagonists, orexin acyltransferase inhibitors, opioid receptor antagonists (e.g., GSK-1521498, naltrexone), orexin receptor antagonists, melanocortin 4 receptor agonists, 11β-hydroxysteroid dehydrogenase inhibitors (e.g., AZD-4017, BVT-3498, INCB-13739), pancreatic lipase inhibitors (e.g., orlistat, cetilistat), β3 agonists (e.g., N-5984), diacylglycerol acyltransferase 1 (DGAT1) inhibitors, acetyl-CoA carboxyltransferase (ACC) inhibitors (e.g., described in WO Compounds from U.S. Patent No. 8,859,577, 2020 / 234726, WO2020 / 044266, and U.S. Patent No. 8,859,577; stearoyl-CoA desaturase inhibitors; microsomal triglyceride transfer protein inhibitors (e.g., R-256918); sodium-glucose cotransporter 2 (SGLT-2) inhibitors (e.g.,JNJ-28431754, Dapagliflozin, AVE2268, TS-033, YM543, TA-7284, ASP1941, Remogliflozin, Empagliflozin, Canagliflozin, Ipragliflozin, Tofogliflozin, Sergliflozin Tabonate, Remogliflozin Tabonate etabonate (or ertugliflozin), SGLT-1 inhibitors, MCR-4 agonists, monoamine reuptake inhibitors, melanocyte-stimulating hormone analogs, 5HT2c agonists, saccharin antagonists, anorexia nervosa (such as bufotin agonists), thyroxine agents, dehydroepiandrosterone or its analogues, human scorpion-associated protein (AGRP) inhibitors, neuropeptide U agonists, NFK inhibitors (e.g., HE-3286), PPAR agonists (e.g., GFT-505, DRF-11605, gemfibrozil, fenofibrate, bagliflozin). (laglitazone), cycloglitazone, daglitazone, empaglitazone, isaglitazone, pioglitazone, rosiglitazone, CLX-0940, GW-1536, GW-1929, GW-2433, KRP-297, L-796449, LR-90, MK-0767 and SB-219994), phosphotyrosine phosphatase inhibitors (e.g., sodium vanadate, trodusquemin), GPR119 agonists (e.g., compounds described in PSN-821, MBX-2982, APD597, WO2010 / 140092, WO 2010 / 128425, WO 2010 / 128414, WO 2010 / 106457), glucoskinase activators (e.g.,Piraglitin, AZD-1656, AZD6370, TTP-355, TTP-399, TTP547, ARRY403, MK-0599, TAK-329, AZD5658 or described in WO 2010 / 103437, WO 2010 / 103438, WO 2010 / 013161, WO 2007 / 122482, WO 2006 / 112549, WO 2007 / 028135, WO 2008 / 047821, WO 2008 / 050821, WO 2008 / 136428 and WO Compound GKM-001 in 2008 / 156757), leptin, leptin derivatives (e.g., metropritine), leptin resistance modifiers, CNTF (ciliary neurotrophic factor), BDNF (brain-derived neurotrophic factor), cholecystokinin agonists, amylin preparations (e.g., pramlinide, AC-2307), neuropeptide Y agonists (e.g., PYY3-36, PYY3-36 derivatives, obineptide, TM-30339, TM-30335), oximin (OXM) preparations, appetite suppressants (e.g., ephedrine), FGF21 preparations (e.g., animal FGF21 preparations extracted from bovine or porcine pancreas; using Escherichia coli). Human FGF21 preparations synthesized from the gene of *C. coli* or yeast; fragments or derivatives of FGF21; appetite suppressants (e.g., P-57); human pro-insulin peptide (HIP); melanocortin receptor 4 agonists (e.g., setmelanotide); melanin-concentrating hormone receptor 1 antagonists; serotonergic agents (e.g., sibutramine, lorcaserin); farnesoid X receptor (FXR) agonists (e.g., obeticholic acid, tropifexor, cilofexor); LY2562175; Met409; TERN-101; EDP305; described in WO 2020 / 234726 and WO Compounds listed in WO 2020 / 044266), phentermine, zonisamide, norepinephrine / dopamine reuptake inhibitors (e.g., bupropion), GDF-15 analogs, methionine aminopeptidase 2 (MetAP2) inhibitors (e.g., beronanib or ZGN-1061), diethylamine acetone, benzotriazine, benzphenamine, fibroblast growth factor receptor (FGFR) modulators, biotin, MAS receptor modulators, glucagon receptor agonists, CCKa agonists (e.g., compounds described in WO 2005 / 116034 and U.S. Publication No. 2005 / 0287100), and AMP-activated protein kinase (AMPK) activators.

[0325] In some embodiments, the one or more additional therapeutic agents include those that can be used as, for example, antidiabetic agents. Non-limiting examples include insulin and insulin preparations (e.g., animal insulin preparations extracted from bovine or porcine pancreas; human insulin preparations synthesized using E. coli or yeast genes; zinc insulin; protamine zinc insulin; insulin fragments or derivatives (e.g., INS-1), oral insulin preparations, synthetic human insulin), insulin sensitizers (e.g., pioglitazone or its salts), biguanides (e.g., metformin, buprofen, or their salts (e.g., hydrochloride, fumarate, succinate)), glucagon analogs (e.g., those described in, for example, WO Any glucagon analogues from 2010 / 011439, agents that antagonize glucagon or reduce glucagon secretion, sulfonylurea agents (e.g., chlorpropamide, tolazamide, glimepiride, tolbutamide, glibenclamide, gliclazide, acetohexamide, glipizide, glybuzole, glibenclamide, glipizide), thiazolidinedione agents (e.g., rosiglitazone, lobeglitazone, troglitazone, pagodalitazone, rivoglitazone, lobeglitazone, or pioglitazone), gleevec. (e.g., alglitazar, chiglitazar, saroglitazar, muraglitazar, tesaglitazar), SGLT2 inhibitors (e.g., JNJ-28431754, dapagliflozin, AVE2268, TS-033, YM543, TA-7284, ASP1941, THR1474, TS-071, ISIS388626, LX4211, repaggliflozin, empagliflozin, canagliflozin, ioggliflozin, togliflozin, seraggliflozin carbonate, repaggliflozin carbonate, eleggliflozin, described in WO Compounds listed in 2010 / 023594), GPR40 agonists (e.g., FFAR1 / FFA1 agonists, such as fasiglifam), α-glucosidase inhibitors (e.g., adiposin, camiglibose, pradimicin-Q, salbostatin, voglibose, acarbose, miglitol, emiglitate), and insulin secretagogues such as dietary glucose regulators (sometimes referred to as "short-acting secretagogues"), such as megglitinide (e.g.,Repaglinide and nateglinide), cholinesterase inhibitors (e.g., donepezil, galantamine, rivastigmine, tacrine), NMDA receptor antagonists, dual GLP-1 / GIP receptor agonists (e.g., LBT-2000, ZPD1-70), GLP-1R agonists (e.g., exenatide, liraglutide, abiglutide, duraglutide, abiglutide, tasglutide, lixinatide, smegglutide, AVE-0010, S4P, and Boc5), and dipeptidyl peptidase IV (DPP-4) inhibitors (e.g., vildagliptin, dutogliptin). Gemigliptin, alogliptin, saxagliptin, sitagliptin, linagliptin, berberine, adogliptin, anagliptin (SK-0403), teneligliptin, omarigliptin, BI1356, GRC8200, MP-513, PF-00734200, PHX1149, ALS2-0426, TA-6666, TS-021, KRP-104, trelagliptin.

[0326] In some embodiments, the one or more additional therapeutic agents include those that can be used, for example, to treat NAFL and NASH. Non-limiting examples include FXR agonists (e.g., obeticholic acid), PF-05221304, PPARα / δ agonists (e.g., elafibranor), synthetic fatty acid-bile conjugates (e.g., aramchol), anti-lysyl oxidase homolog 2 (LOXL2) monoclonal antibodies (e.g., simtuzumab), caspase inhibitors (e.g., emricasan), MAPK5 inhibitors (e.g., GS-4997), galactoglobulin 3 inhibitors (e.g., GR-MD-02), fibroblast growth factor 21 (FGF21) (e.g., BMS-986036), niacin analogs (e.g., ARJ 3037MO), leukotriene D4 (LTD4) receptor antagonists (e.g., tipelukast), and acetyl-CoA carboxylase (ACC) inhibitors (e.g., NDI). 010976 and compounds described in WO 2009 / 144554, WO 2003 / 072197, WO 2009 / 144555 and WO 2008 / 065508), hexokinase (KHK) inhibitors (compounds described in WO 2020 / 234726), apoptosis signal-regulated kinase 1 (ASK1) inhibitors, ileal bile acid transporter (IBAT) inhibitors, dual antagonists of chemokine receptor 2 (CCR2) and CCR5 (e.g., cenicriviroc), diacylglycerol acyltransferase 2 (DGAT2) inhibitors (e.g., those described in WO 2009 / 144554, WO 2003 / 072197, WO 2009 / 144555 and WO 2008 / 065508), acetyl kinase 2 (KHK) inhibitors (compounds described in WO 2020 / 234726 ... Compounds listed in 2020 / 234726 and U.S. Publication No. 20180051012), CB1 receptor antagonists, anti-CB1R antibodies, glycyrrhizin, schisandra extract, ascorbic acid, glutathione, silymarin, lipoic acid and d-α-tocopherol, ascorbic acid, glutathione, vitamin B complex, glitazone / thiazolidinediones (e.g., troglitazone, rosiglitazone, pioglitazone, balazolidinone, linaglitazone, lobeglitazone), metformin, cysteine, sulfonylureas, α-glucosidase inhibitors, megglitinide, vitamin E, tetrahydrolipstatin, milk thistle protein, antiviral agents and antioxidants.

[0327] In some embodiments, the one or more additional therapeutic agents include those that can be used, for example, to treat complications of diabetes. Non-limiting examples include aldose reductase inhibitors (e.g., tolrestat, epalrestat, zopolrestat, fidarestat, CT-112, ranirestat, lidorestat), neurotrophic factors and their enhancers (e.g., NGF, NT-3, BDNF, neurotrophic production / secretion promoters described in WO 01 / 14372 (e.g., 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxy)propyl]oxazole), compounds described in WO 2004 / 039365), and PKC inhibitors (e.g., rubosta mesylate). mesylate), AGE inhibitors (e.g., ALT946, N-benzoylthiazolium bromide (ALT766), EXO-226, pyridorin, pyridoxamine), serotonin and norepinephrine reuptake inhibitors (e.g., duloxetine), sodium channel inhibitors (e.g., lacosamide), reactive oxygen species scavengers (e.g., lipoic acid), cerebral vasodilators (e.g., tiapuride, mexiletine), somatostatin receptor agonists (e.g., BIM23190), and apoptosis signal-regulated kinase-1 (ASK-1) inhibitors.

[0328] In some embodiments, the one or more additional therapeutic agents include those that can be used, for example, to treat hyperlipidemia. Non-limiting examples include HMG-COA reductase inhibitors (e.g., pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin, pitavastatin, or salts thereof (e.g., sodium, calcium salts)) and squalene synthase inhibitors (e.g., WO3). Compounds described in 97 / 10224, such as N-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazon-3-yl]acetyl]piperidin-4-acetic acid), fibrates (e.g., bezafibrate, clofibrate, simfibrate, clinofibrate), anion exchange resins (e.g., colestyramine), nicotinic acid drugs (e.g., nicomol, niceritrol, niaspan), phytosterols (e.g., daidzein, gamma-oryzanol). (oryzanol, γ-oryzanol), cholesterol absorption inhibitors (e.g., zechia), CETP inhibitors (e.g., dalcetrapib, anacetrapib), and ω-3 fatty acid preparations (e.g., ω-3-fatty acid ethyl ester 90).

[0329] In some embodiments, the one or more additional therapeutic agents include those that can be used as, for example, antihypertensive agents. Non-limiting examples include angiotensin-converting enzyme inhibitors (e.g., captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril), and angiotensin II antagonists (e.g., candesartan cilexetil, candesartan, losartan, losartan potassium). Potassium, eprosartan, valsartan, telmisartan, irbesartan, tasosartan, olmesartan, olmesartan medoxomil, azilsartan, azilsartan medoxomil, calcium channel blockers (e.g., manidipine, nifedipine, amlodipine, efonidipine, nicardipine, cilnidipine), and beta-blockers (e.g., metoprolol, atenolol, propranolol, carvedilol, pindolol).Other non-limiting examples of antihypertensive agents include: diuretics (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid). (Acid), trinicafen, chlorthalidone, torsemide, furosemide, musolimine, bumetanide, triamtrenene, amiloride, spironolactone, alpha-adrenergic blockers, beta-adrenergic blockers, calcium channel blockers (e.g., diltiazem), Verapamil, nifedipine, and amlodipine, vasodilators (e.g., hydralazine), renin inhibitors, AT-1 receptor antagonists (e.g., losartan, irbesartan, valsartan), ET receptor antagonists (e.g., sitaxentan, atrsentan, and compounds disclosed in U.S. Patent Nos. 5,612,359 and 6,043,265), dual ET / AII antagonists (e.g., compounds disclosed in WO 2000 / 01389), neutral endopeptidase (NEP) inhibitors, If channel blockers ivabradin, and angiopeptidase inhibitors (dual NEP-ACE inhibitors) (e.g., gemoptrilat and nitrates).

[0330] In some embodiments, the one or more additional therapeutic agents include those that can be used as, for example, diuretics. Non-limiting examples include xanthine derivatives (e.g., sodium theobromine salicylate, calcium theobromine salicylate), thiazide preparations (e.g., ethiothiazide, cyclopenthiazine, trichlorothiazide, hydrochlorothiazide, hydrofluorothiazide, benzyl hydrochlorothiazide, penfluthiazide, polythiazide, methyclothiazide)), antialdosterone preparations (e.g., spironolactone, triamterene)), carbonic anhydrase inhibitors (e.g., acetazolamide) and chlorobenzenesulfonamides (e.g., chlortalidone, mefruside, indapamide)).

[0331] In some embodiments, the one or more additional therapeutic agents include those that can be used as, for example, immunotherapeutic agents. Non-limiting examples include microbial or bacterial compounds (e.g., muramyl dipeptide derivatives, picibanil), polysaccharides with immunomodulatory activity (e.g., lentinan, sizofiran, krestin), cytokines obtained through genetic engineering (e.g., interferons, interleukins (ILs), such as IL-1, IL-2, IL-12), and colony-stimulating factors (e.g., granulocyte colony-stimulating factor, erythropoietin).

[0332] In some embodiments, the one or more additional therapeutic agents include those that can be used as, for example, antithrombin agents. Non-limiting examples include heparin (e.g., heparin sodium, heparin calcium, enoxaparin sodium, dalteparin sodium), warfarin (e.g., warfarin potassium); antithrombin drugs (e.g., aragatroban, dabigatran, boron arginine derivatives, boreptides, heparin, hirudin, and melagatran); FXa inhibitors (e.g., rivaroxaban, apixaban, edoxaban, YM150, described in WO 02 / 06234, WO 2004 / 048363, WO 2005 / 030740, WO 2005 / 058823 and WO Compounds listed in 2005 / 113504), thrombolytics (e.g., anistreplase, streptokinase, tenecteplase (TNK), lanoteplase (nPA), urokinase, tisokinase, alteplase, nateplase, monteplase, pamiteplase, factor VI1a inhibitors, PAI-1 inhibitors, α2-antifibrinolytic enzyme inhibitors, and anisyl plasminogen activator complexes), and platelet aggregation inhibitors (e.g., ticlopidine hydrochloride, clopidogrel, prasugrel, E5555, SHC530348, cilostazol, ethyl eicosapentaenoate, beraprost sodium, and sarpogrelate hydrochloride)).

[0333] In some embodiments, the one or more additional therapeutic agents include those that can be used, for example, to treat osteoporosis. Non-limiting examples include alfacalcidol, calcitriol, elcatonin, calcitonin salmon, estriol, ipriflavone, pamidronate disodium, alendronate sodium hydrate, incadronate disodium, and risedronated sodium. Suitable examples of vitamins include vitamin B1 and vitamin B12. Suitable examples of erectile dysfunction medications include apomorphine and sildenafil citrate. Suitable examples of medications for treating urinary frequency or incontinence include flavorxate hydrochloride, oxybutynin hydrochloride, and propiverine hydrochloride. Suitable examples of medications for treating dysuria include acetylcholinesterase inhibitors (e.g., distigmine). Suitable examples of anti-inflammatory agents include nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, acetaminophen, and indomethacin.

[0334] Other exemplary therapeutic agents include agents that regulate hepatic glucose balance (e.g., fructose-1,6-bisphosphatase inhibitors, glycogen phosphorylase inhibitors, glycogen synthase kinase inhibitors, glucosamine activators), agents designed to treat complications of chronic hyperglycemia such as aldose reductase inhibitors (e.g., epalrestat and ranisitar), agents for treating complications associated with microvascular disease, anti-dyslipidemia agents such as HMG-CoA reductase inhibitors (statins, such as rosuvastatin, pravastatin, pitavastatin, lovastatin, atorvastatin, simvastatin, fluvastatin, irivastatin, ZD-4522), HMG-CoA synthase inhibitors, cholesterol lowering agents, bile acid sequestrants (e.g., cholestyramine, questran, colestipol, and colesevelam), and cholesterol absorption inhibitors (e.g., plant sterols). Species such as phytosterols, cholesterol ester transfer protein (CETP) inhibitors, ileal bile acid transport system inhibitors (IBAT inhibitors), diacylglycerol acyltransferase 1 (DGAT1) inhibitors (e.g., AZD7687, LCQ908, compounds described in WO 2009 / 016462, WO 2010 / 086820), monoacylglycerol O-acyltransferase inhibitors, α-amylase inhibitors (e.g., amylase aprotinin, tustatin, AL-3688), α-glucosidase inhibitors, SIRT-1 activators, c-Jun N-terminal kinase (JNK) inhibitors, VPAC2 receptor agonists, TGR5 receptor modulators (e.g., compounds described in [the original text]), GPBAR1 receptor modulators, GPR120 modulators, high-affinity niacin receptor (HM74A) activators, carnitine palmitoyltransferase inhibitors, mineralocorticoid receptor inhibitors, TORC2 inhibitors, fatty acid synthase inhibitors, serine palmitoyltransferase inhibitors, GPR81 modulators, GPR39 modulators, GPR43 modulators, GPR41 modulators, GPR105 modulators, Kv1.3 modulators, retinol-binding protein 4 modulators, somatostatin receptor modulators, PDHK2 modulators, PDHK4 modulators, MAP4K4 inhibitors, IL1 family modulators (e.g., ILIβ modulators), ACAT inhibitors, MTP inhibitors (e.g., diriotapide, mitratapide, and impritapide), lipoxygenase inhibitors, PCSK9 modulators (e.g., [the original text]).Alizumab and evolocumab), RXRα modulators, cysteine, cystamine, RNA antisense constructs that inhibit protein tyrosine phosphatase PTPRU, vitamin B complex, permein protein, protein tyrosine phosphatase-1B (PTP-1B) inhibitors (e.g., trodusquemine, hyrtiosal extract, and compounds described in Zhang et al. Drug Discovery Today. 2007, 12(9-10):373-381), ezitimbe, betaine, pentoxifylline, αδ-9 desaturase, BCKDK inhibitors, branched-chain alpha-keto acid dehydrogenase kinase (BCBK) inhibitors, PNPLA3 inhibitors, FGF19 analogs, SCD1 inhibitors, bile acid conjugating resins, nicotinic acid Niacin (niacin) and its analogues, antioxidants (e.g., probucol), omega-3 fatty acids, antihypertensive agents (including adrenergic receptor antagonists such as beta blockers (e.g., atenolol), alpha blockers (e.g., doxazosin), and mixed alpha / beta blockers (e.g., labetalol), adrenergic receptor agonists (including alpha-2 agonists (e.g., clonidine), angiotensin-converting enzyme (ACE) inhibitors (e.g., lisinopril), calcium channel blockers (e.g., dihydropyridine (e.g., nifedipine), phenylalkylamines (e.g., verapamil), and benzo[a]thiazide (... For example, diltiazem), angiotensin II receptor antagonists (e.g., candesartan), aldosterone receptor antagonists (e.g., eplerenone, spironolactone), centrally acting adrenergic drugs (e.g., central alpha agonists (e.g., clonidine), diuretics (e.g., furosemide, torasemide, bemetanide, ethacrylic acid), thiazide diuretics (e.g., chlorothiazide, hydrochlorothiazide, benzylthiazide, hydrofluorothiazide, benzylfluorothiazide, methylchlorothiazide, polythiazide, trichlorothiazide, indapamide), benzopyrrolidone diuretics (e.g., chlorthalidone, metoprazone), quinazoline diuretics (e.g., quinetrazol), potassium-sparing diuretics (e.g., triamterene and amiloride), thyroid receptor agonists (e.g., those described in WO Compounds listed in 2020 / 117987), hemostatic modifiers (including antithrombotic agents (e.g., fibrinolytic activators), thrombin antagonists, factor VIIa inhibitors, anticoagulants (e.g., vitamin K antagonists, such as warfarin), heparin and its low molecular weight analogs, factor Xa inhibitors and direct thrombin inhibitors (e.g., argatroban)), antiplatelet agents (e.g., cyclooxygenase inhibitors (e.g., ...Aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), thrombocytidine A2-receptor antagonists (e.g., ifetroban), thrombocytidine A2-synthetase inhibitors, PDE inhibitors (e.g., cilostazol, dipyridamole), purinergic receptor antagonists (e.g., P2Y1 and P2Y12), adenosine diphosphate (ADP) receptor inhibitors (e.g., clopidogrel), phosphodiesterase inhibitors (e.g., cilostazol), glycoprotein IIB / IIA inhibitors (e.g., tirofiban, eptifibatide, and abciximene). Anti-abcixima, adenosine reuptake inhibitors (e.g., dipyridamole), norepinephrine agents (e.g., phenbutazone), serotonergic agents (e.g., sibutramine, lorcaserin), diacylglycerol acyltransferase (DGAT) inhibitors, feeding behavior modulators, pyruvate dehydrogenase kinase (PDK) modulators, serotonin receptor modulators, monoamine transport modulators (such as selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine), norepinephrine reuptake inhibitors (NARIs), norepinephrine-serotonin reuptake inhibitors (SNRIs), and monoamine oxidase inhibitors (MAOIs) (e.g., toloxacin and amivamide), described in WO Compounds described in WO 2007 / 013694, WO 2007 / 018314, WO 2008 / 093639 and WO 2008 / 099794, GPR40 agonists (e.g., fasiglifam or its hydrate, compounds described in WO 2004 / 041266, WO 2004 / 106276, WO 2005 / 063729, WO 2005 / 063725, WO 2005 / 087710, WO 2005 / 095338, WO2007 / 013689 and WO Compounds listed in 2008 / 001931), SGLT1 inhibitors, adiponectin or its agonists, IKK inhibitors (e.g., AS-2868), somatostatin receptor agonists, ACC2 inhibitors, cachexia improvers (e.g., cyclooxygenase inhibitors (e.g., indomethacin)), progesterone derivatives (e.g., megestrol acetate), glucocorticoids (e.g., dexamethasone), metoclopramide preparations, tetrahydrocannabinol preparations, and preparations for improving lipid metabolism (e.g., ...Eicosapentaenoic acid (EPA), growth hormone, IGF-1, antibodies against cachexia-inducing factor TNF-α, LIF, IL-6 and oncogene M, metabolically modified proteins or peptides (such as glucoskinase (GK), glucokinase regulatory protein (GKRP), uncoupling proteins 2 and 3 (UCP2 and UCP3)), peroxisome proliferator-activated receptor α (PPARα), MC4r agonists, insulin receptor agonists, PDEs 5. Inhibitors, glycation inhibitors (e.g., ALT-711), neurotrophic drugs (e.g., Y-128, VX853, neurotrophic peptides), antidepressants (e.g., desipramine, amitriptyline, imipramine), antiepileptic drugs (e.g., lamotrigine, trileptal, keppra, zonegran, pregabalin, harkoseride, carbamazepine), antiarrhythmic drugs (e.g., K, +Channel openers, mexiletine, propafenone, metoprolol, atenolol, carvedilol, propranolol, sotalol, dofetilide, amiodarone, azimilide, ibutilide, diltiazem, and verapamil, acetylcholine receptor ligands (e.g., ABT-594), endothelin receptor antagonists (e.g., ABT-627), narcotic analgesics (e.g., morphine), α2 receptor agonists (e.g.) Examples of drugs that affect T cell migration include clonidine, local analgesics (e.g., capsaicin), anti-anxiety drugs (e.g., benzothiazazepine), phosphodiesterase inhibitors (e.g., sildenafil), dopamine receptor agonists (e.g., apomorphine), cytotoxic antibodies (e.g., T cell receptor and IL-2 receptor specific antibodies), B cell depletion therapy (e.g., anti-CD20 antibodies (e.g., rituxan), i-BLyS antibodies), drugs that affect T cell migration (e.g., anti-integrin α4 / β1 antibodies (e.g., tysabri), and drugs that act on immunoaffinity (e.g., cyclosporine, tacrolimus, sirolimus, rapamici). Interferon (e.g., IFN-β), immunomodulators (e.g., glatiramer), TNF-binding proteins (e.g., circulating receptors), immunosuppressants (e.g., mycophenolate), metaglidasen, AMG-131, balaglitazone, MBX-2044, rivoglitazone, aglitazone, siglitazone, saroglitazar, moglitazone, tesaglitazar, lobeglitazone, PLX-20 4. PN-2034, GFT-505, THR-0921, exenatide, exendin-4, memantine, midazolam, ketoconazole, ethyl eicosapentaenoic acid, clonidine, azosemide, isosorbide, ethacrylic acid, piretanin, bumetanide, etoposide, piroxicam, NO suppliers (e.g., organic nitrates) and NO promoters (e.g., phosphodiesterase inhibitors).

[0335] In some embodiments, the one or more additional therapeutic agents include those that can be used, for example, as antiemetics. As used herein, an "antiemetic" means any agent that counteracts (e.g., reduces or eliminates) nausea or vomiting (vomiting). It should be understood that when referring to a therapeutically effective amount of an antiemetic, the amount administered is the amount required to counteract (e.g., reduce or eliminate) nausea or vomiting (vomiting). Without wishing to be bound by theory, it is believed that administering one or more antiemetics in combination with a compound of formula (I) described herein may allow for the administration of higher doses of the compound of formula (I), for example because the patient may be able to ingest food normally and therefore respond to treatment more quickly.

[0336] Non-limiting examples of antiemetics include 5HT3 receptor antagonists (serotonin receptor antagonists), sedatives / antipsychotics, antihistamines, anticholinergics, sterols (e.g., corticosteroids), NK1-receptor antagonists (neurokine 1P substance receptor antagonists), antidopaminergics / dopamine receptor antagonists, benzodiazepines, and cannabinoids.

[0337] For example, antiemetics can be selected from sedatives, antihistamines, anticholinergics, sterols, 5HT3 receptor antagonists, NK1 receptor antagonists, antidopaminergics / dopamine receptor antagonists, benzodiazepines, and non-psychoactive cannabinoids.

[0338] In some implementations, the antiemetic is a 5HT3 receptor antagonist (serotonin receptor antagonist). Non-limiting examples of 5HT3 receptor antagonists (serotonin receptor antagonists) include: granisetron (Kytril), dolasetron, ondansetron (Zofran), tropisetron, ramosetron, palonosetron, alosetron, azasetron, bemistron, zatisetron, batanopirde, MDL-73147EF, metoclopramide, N-3389 (ne-3,9-dimethyl-3,9-diazabicyclo[3,3,1]one-7-yl-1H-indazole-3-carboxamide dihydrochloride), Y-25130 hydrochloride, MDL72222, tropyl-3,5-dimethylbenzoic acid, 3-(4-allylpiperazin-1-yl)-2-quinoxaloline carboxylic acid, zacopride hydrochloride, and mirtazapine. Other non-limiting examples of 5HT3 receptor antagonists (serotonin receptor antagonists) include: celestron, clozapine, cyproheptadine, dazopride, hydroxyzine, lerisetron, metoclopramide, mianserin, olanzapine, palonosetron (+netostitan), quetiapine, qamosetron, ramosteron, licastron, risperidone, ziprasidone, and zatosetron.

[0339] In some implementations, the 5HT-3 receptor antagonist is granisetron, dolasetron, ondansetron, hydrochloride, tropisetron, ramosetron, palonosetron, alosetron, bemyrosetron, zatisetron, batanopirde, MDL-73147EF, metoclopramide, N-3389, Y-25130 hydrochloride, MDL 72222, tropyl-3,5-dimethylbenzoate, 3-(4-allyl-piperazin-1-yl)-2-quinoxaloline carboxylon maleate, zacopride hydrochloride, and mirtazapine.

[0340] In some embodiments, the 5HT-3 receptor antagonist is granisetron, dolasetron, ondansetron, hydrochloride, tropisetron, ramosetron, palonosetron, alosetron, bemyrosetron, and zartosetron.

[0341] In some embodiments, the 5HT-3 receptor antagonist is granisetron, dolasetron, or ondansetron.

[0342] In some embodiments, the 5HT-3 receptor antagonist is granisetron.

[0343] In some embodiments, the 5HT-3 receptor antagonist is ondansetron.

[0344] In some implementations, the antiemetic is an antihistamine. Non-limiting examples of antihistamines include: piperazine derivatives (e.g., cyclazine, meclozine, and cinnarizine); promirtine; dimenhydrinate (Dramamine, Gravol); diphenhydramine; hydroxyzine; bucrozine; and meclozine hydrochloride (chlorobenzamine (Bonine, Antivert)), doxylamine, and mirtazapine.

[0345] In some embodiments, the antiemetic is an anticholinergic agent (acetylcholine receptor inhibitor). Non-limiting examples of anticholinergic agents include: atropine, scopolamine, glycopyrron, hyoscine, Trihexy-5 (benhexol hydrochloride), benzalkonium chloride, bisperidone hydrochloride, disipal (olphenadrine citrate), diphenhydramine, hydroxyzine, hyoscyamine, and carmatrazine (propiconazole hydrochloride).

[0346] In some implementations, the antiemetic is a steroid (e.g., a corticosteroid). Non-limiting examples of steroids include: betamethasone, dexamethasone, methylprednisolone, etc. And trimethoprim (Tigan).

[0347] In some embodiments, the antiemetic is an NK1 receptor antagonist (e.g., a substance kinin 1P receptor antagonist). Non-limiting examples of NK1 receptor antagonists include aprepitant, cassopindant, elopitant, fosaprepitant, maropitant, netupitant, lorapitant, and vertepitant.

[0348] Other non-limiting examples of NK1 receptor antagonists include: MPC-4505, GW597599, MPC-4505, GR205171, L-759274, SR 140333, CP-96,345, BIIF 1149, NKP 608C, NKP 608A, CGP 60829, SR 140333 (nomipitan ammonium besylate / nomipitan ammonium chloride), LY 303870 (lanepitan), MDL-105172A, MDL-103896, MEN-11149, MEN-11467, DNK 333A, YM-49244, YM-44778, ZM-274773, MEN-10930, S-19752, Neuronorm, YM-35375, DA-5018, MK-869, L-754030, CJ-11974, L-758298, DNK-33A, 6b-l, CJ-11974j. Benserazide and Carbidopa K. TAK-637[(aR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazaarocto[2,1-g][1,7]naphthidine-6,13-dione], PD 154075, ([(2-benzofuran)-CH2OCO]-(R)-α-MeTrp-(S)-NHCH(CH3)Ph), FK888 and (D-Pro4,D-Trp7,9,10,Phe11)SP4-11.

[0349] In some embodiments, the antiemetic is an antidopaminergic agent / dopamine receptor antagonist (e.g., a dopamine receptor antagonist, such as a D2 or D3 antagonist). Non-limiting examples include phenothiazines (e.g., propranolol, chlorpromazine, prochlorazine, perphenazine, hydroxyzine, thiotetracycline, metoprolol); benzamides (e.g., metoclopramide, domperidone); butyrophenones (e.g., haloperidol, droperidol); aripiprazole, bromapride, clopazole, domperidone, itopride, metoclopramide, trimebenzamide, and amisulpride.

[0350] In some embodiments, the antiemetic is a non-psychoactive cannabinoid (e.g., cannabidiol (CBD), cannabidiol dimethylheptyl (CBD-DMH), tetrahydrocannabidiol (THC), cannabinoid agonists such as WIN 55-212 (CB1 and CB2 receptor agonists), dronabinol). And cemesamet).

[0351] Other exemplary antiemetics include: c-9280 (Merck); benzodiazepines (diazepam, midazolam, cloxacillin); and nerve blockers / antipsychotics (e.g., diazepam, haloperidol, and prochloraz). ); cerium oxalate; propofol; sodium citrate; dextrose; fructose (Nauzene); orthophosphate; fructose; glucose (Emetrol); bismuth subsalicylate (Pepto Bismol); ephedrine; vitamin B6; peppermint, lavender and lemon essential oils; and ginger.

[0352] Other exemplary antiemetics include those disclosed in US20120101089 A1; US10,071,088B2; US 6,673,792B1; US ​​6,197,329 B1; US10,828,297B2; US 10,322,106B2; US10,525,033B2; WO2009080351 A1; WO 2019203753A2; WO 2002020001 A2; US 8,119,697 B2; US 5,039,528; US20090305964A1; and WO 2006 / 111169, each of which is incorporated herein by reference in its entirety.

[0353] In some implementations, the antiemetic is a 5HT3 receptor antagonist (serotonin receptor antagonist), a sedative, an antipsychotic, an antihistamine, an anticholinergic, a steroid (e.g., a corticosteroid), an NK1 receptor antagonist (e.g., a neurokinin 1P substance receptor antagonist), an antidopaminer / dopamine receptor antagonist, a benzodiazepine, or a cannabinoid (e.g., a nonpsychoactive cannabinoid).

[0354] In some implementations, the antiemetic is selected from: granisetron, dolasetron, ondansetron, ondansetron hydrochloride, tropisetron, ramosetron, palonosetron, alosetron, azasetron, bemistron, zartosetron, bartasetron, MDL-73147EF; metoclopramide, N-3389, Y-25130 hydrochloride, MDL 72222, tropyl-3,5-dimethylbenzoic acid, 3-(4-allylpiperazin-1-yl)-2-quinoxaloline carboxynitrile maleic acid, zacopride hydrochloride, mirtazapine, celestron, clozapine, cyproheptadine, dazopride, hydroxyzine, lerisetron, mianserin, olanzapine, palonosetron (+ netotipantan), quetiapine, carmustron, ramosetron, licasseroletron, risperidone, zirazine. Ketones, Zartosetron, Cyclazine, Meclozine, Meclozine Hydrochloride, Cinnarizine, Promirtine, Dimenhydrinate, Diphenhydramine, Bucrozine, Doxylamine, Mirtazapine, Atropine, Hyoscyamine, Glycolone, Scopolamine, Antane, Benzatropine Mesylate, Ancolytica Hydrochloride, Ophenadrine Citrate, Diphenhydramine, Hyoscyamine, Procyclophosphamide Hydrochloride, Betamethasone, Dexamethasone, Methylprednisolone Trimetrazine (Tigan), Aprepitant, Cassopithant, Elopipant, Fosaprepitant, Maropipant, Netupitant, Lorapipant and Verticipant, MPC-4505, GW597599, MPC-4505, GR205171, L-759274, SR 140333, CP-96,345, BIIF1149, NKP 608C, NKP 608A, CGP 60829, SR 140333 (Norpitant Besylate / Chloride), LY 303870 (Ranepitant), MDL-105172A, MDL-103896, MEN-11149, MEN-11467, DNK 333A, YM-49244, YM-44778, ZM-274773, MEN-10930, S-19752, Neuronorm, YM-35375, DA-5018, MK-869, L-754030, CJ-11974, L-758298, DNK-33A, 6b-l, CJ-11974, Benserazide, Carbidopa, TAK-637, PD 154075, FK888, (D-Pro4, D-Trp7,9,10, Phe11)SP4-11, Chlorpromazine, Prochlorazine Perphenazine, Thioraprazine, Metoprolol, Domperidone, Haloperidol, Haloperidol, Aripiprazole, Brompride, Clopride, Etopride, Amisulpride, Cannabidiol (CBD), Cannabidiol Dimethyl Heptyl (CBD-DMH), Tetrahydrocannabidiol (THC), WIN55-212 (CB1 and CB2 receptor agonists), Drostanol Cesamet, c-9280, diazepam, midazolam, chlorhexidine, diazepam, cerium oxalate, propofol, sodium citrate, dextrose, fructose (Nauzene), phosphoric acid, glucose (Emetrol), bismuth subsalicylate, ephedrine, vitamin B6, peppermint, lavender, lemon essential oil, and ginger.

[0355] In some embodiments, an additional therapeutic agent or regimen is administered to the patient at approximately the same time as the compound and pharmaceutical composition is contacted or administered. For example, the additional therapeutic agent or regimen is administered to the patient simultaneously with the compound and pharmaceutical composition in the same dosage form.

[0356] In some embodiments, a fixed-dose combination is provided, the fixed-dose combination comprising an antiemetic and a compound as described herein, or a pharmaceutically acceptable salt or solvation thereof, or a compound disclosed herein, or a pharmaceutically acceptable salt or solvation thereof.

[0357] For example, additional therapeutic agents or regimens, as well as compounds and pharmaceutical compositions, may be provided to patients in parallel in separate dosage forms.

[0358] In some embodiments, an additional therapeutic agent or regimen is administered to the patient after contact with or application of the compound and pharmaceutical composition (e.g., about one hour, about six hours, about 12 hours, about 24 hours, or about 48 hours later).

[0359] In some embodiments, the antiemetic is a 5HT3 receptor antagonist (serotonin receptor antagonist). In some embodiments, the antiemetic is ondansetron. In some embodiments, the antiemetic is a dopamine receptor antagonist. In some embodiments, the antiemetic is benzamide. In some embodiments, the antiemetic is metoclopramide. Example Example 1: Synthesis of 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound I)

[0360] KOH (10.00 equivalents) was added to a solution of compound 1-B1 (1 equivalent) in 2-methoxyethanol (4 volumes) and H2O (10.00 equivalents), and the mixture was heated at 100-105°C for 12 h. After the reaction was complete, the reaction mixture was cooled to 10-20°C, and water (4 volumes) was added sequentially. The resulting mixture was poured into HCl (2M aqueous solution, 20 volumes). A solid was formed, and the mixture was then filtered. The filter cake was slurried with ACN (4 volumes) at 80-85°C for 8 h. The mixture was then filtered, the filter cake was collected, and dried under vacuum. Compound 1-B was obtained as a grayish-white solid.

[0361] LC-MS: m / z 384.2 (M+H) + .

[0362] 1 H NMR(400MHz, DMSO-d6)δ:12.85(s,1H),12.01-12.27(m,1H),7.54(d,J=4.8Hz,1H),7.27-7.40(m,2H),7.19(d,J=4.0Hz ,1H),3.95-3.98(m,2H),3.45-3.47(m,2H),2.83-2.86(m,1H),1.89-2.08(m,1H),1.55-1.80(m,6H),1.26-1.41(m,3H).

[0363] 6M HCl (13.5 equivalents) was slowly added to a solution of 1-A1 (1.0 equivalents) in 2-MeTHF (2-3 volumes) at below 25°C for approximately 3 hours. The mixture was stirred at 15-25°C for 10 hours. After the reaction was complete, 5V H2O and 5V ethyl acetate were added to the reaction mixture. Phase separation was observed. The pH of the aqueous phase was adjusted to 7-8 with 18% NaOH. The pH of the aqueous phase was further adjusted to 9-10 with 5% NaOH aqueous solution, and the solid in the aqueous phase was filtered off. After drying, compound 1-A was obtained as a grayish-white solid.

[0364] LC-MS: m / z 551.36 (M+H) + .

[0365] 1H NMR(400MHz,DMSO-d6)δ:7.72(q,J=4.8Hz,1H),7.35(d,J=2.8Hz,1H),7.26(dd,J =8.0,12.8Hz,1H),7.11(d,J=4.8Hz,2H),6.85-6.93(m,3H),3.94-3.97(m,1H),3 .21-3.24(m,1H),2.86-2.91(m,1H),2.73(d,J=4.8Hz,3H),2.65-2.69(m,2H),2. 19(d,J=1.2Hz,6H),1.88-1.97(m,4H),1.11(d,J=6.0Hz,3H),0.95-1.04(m,6H).

[0366] Compound I was prepared from 1-A. A mixture of 1.10 equivalents of 1-B, 1.5 equivalents of EDCI, and 1.6 equivalents of HOBt in 8V DMF was stirred at room temperature for 1 h. A solution of 1-A and TEA (4.0 equivalents) in 7V DMF was added to a solution of 1-B in DMF. After stirring at room temperature for 8 h, the product was obtained. 30V H2O was added to the reaction mixture. The reaction mixture was extracted twice with DCM (10V and 5V). The combined DCM solutions were washed with 15V 7% NaHCO3 solution. The DCM solutions were washed again with 5V H2O. Then, the organic phase was exchanged for 10V EtOH. Approximately 1.5V ethyl acetate was added to the mixture. The precipitated solid was collected by filtration. Finally, the product was washed with EtOH and dried under vacuum at 40-50°C for 16-24 h.

[0367] LC-MS: m / z 916.4 (M+H) + .

[0368] 1HNMR (400MHz, DMSO-d6, 80℃) δ: 11.58 (br.s, 1H), 7.66 (br.s, 1H), 7.52 (s, 1H), 7.42 (d, J=8 .4Hz,1H),7.05-7.30(m,5H),6.70-6.95(m,4H),5.56(br.s,1H),4.45(br.s,1H),3.95-3. 99(m,2H),3.40-3.70(m,3H),2.83-2.90(m,3H),2.60-2.80(m,3H),2.22(d,J=1.6Hz,6H), 1.88-1.96(m,4H),1.58-1.80(m,7H),1.43(br.s,3H),1.17(br.s,3H),0.95-1.10(m,6H). Example 2: Synthesis of compound IL-arginine salt

[0369] Compound I L-arginine salt was prepared by the reaction of compound I (1.0 equivalent) and L-arginine (1.1 equivalent) in IPA / H₂O (7:3 v / v). After stirring at 50-55°C for about 2 h, 2.38 equivalents of IPA and 2 wt% seed crystals were added to the clear solution, causing the mixture to become turbid. After stirring for 2 h, about 15.5 equivalents of IPA were added dropwise to the mixture. After stirring at 50-55°C for 8 h, the mixture was further stirred at 0-5°C for 10 h. The precipitated solid was collected by filtration, washed with IPA, and dried at 65-75°C to obtain compound I L-arginine salt.

[0370] HR-MS: m / z 916.4048 [M+H] +

[0371] 1H NMR(400MHz,DMSO-d6)δ:7.71-7.73(m,1H),7.37-7.65(m,2H),7.24-7.31(m,1H),7.0 0-7.21(m,5H),6.72-6.94(m,2H),6.74(br.s,1H),5.62(br.s,1H),4.70-4.81(m,1H), 3.78-3.98(m,2H),3.28-3.46(m,4H),3.01-3.11(m,2H),2.66-2.90(m,4H),2.16-2.2 0(m,6H),1.88-1.95(m,4H),1.55-1.74(m,10H),1.13-1.35(m,6H),0.94-1.05(m,6H). Example 3: Polymorphs of the free acid of compound I

[0372] Polymorphs of compound I free acid were studied using free acid (compound I free acid form A) as starting material (prepared using the procedure described in Example 1). Approximate solubility at 25°C and 50°C

[0373] Weigh approximately 5 mg of compound I in its free acid form A into a 2 mL glass vial. Add 20 μL of each solvent aliquot to dissolve the drug at 25 °C. Use vortexing and sonication to aid dissolution. The maximum volume of each solvent added is 1 mL. Determine approximate solubility by visual observation.

[0374] Weigh approximately 10 mg of compound I in its free acid form A into a 2 mL glass vial. Add 20 μL of each solvent aliquot to dissolve the drug at 50 °C. Vortexing and sonication are used to aid dissolution. The maximum volume of each solvent added is 1 mL. Approximate solubility is determined by visual observation. The results of the two solubility experiments are summarized in Table 3-1. Table 3-1 Summary of approximate solubility at 25℃ and 50℃ / / : Not tested Screening of polymorphs of compound I in free acid form A Preparation of compound I in its free acid form A

[0375] Compound I in its free acid form A was prepared using the procedure described in Example 1. Approximately 7.5 g of the final product was weighed and dried under vacuum at 60°C for approximately 8 hours. 1 ¹H-NMR showed approximately 0.4% EtOH residue by weight (approximately 0.08 equivalents by molar ratio). In this section, the dried free acid form A was used for subsequent polymorph screening experiments. Equilibrate with solvent at 25°C for 2 weeks.

[0376] Based on approximate solubility results, approximately 50 mg of compound I in its free acid form A was equilibrated for 2 weeks at 25°C using a stirring rod at a rate of 300-400 rpm on a magnetic stirring plate in 0.2-1 mL of solvent. The resulting suspension was centrifuged at 14,000 rpm and filtered through a 0.45 μm nylon membrane filter. The solid fraction (wet filter cake) was studied by XRPD. For samples with different XRPD patterns, the hydrate was further analyzed, including DSC, TGA, etc. 1 H-NMR and KF. The results are summarized in Table 3-2. Table 3-2 Summary of solvent equilibration at 25°C for 2 weeks / / : Not tested Equilibrate with solvent at 50°C for 1 week.

[0377] Based on approximate solubility results, approximately 60 mg of compound I in its free acid form A was equilibrated for 1 week at 50°C using a stirring rod at a rate of 300-400 rpm on a magnetic stirring plate in 0.2-1 mL of solvent. The resulting suspension was centrifuged at 14,000 rpm and filtered through a 0.45 μm nylon membrane filter. The solid fraction (wet filter cake) was studied by XRPD. For samples with different XRPD patterns, additional analyses of the hydrate were performed, including DSC, TGA, etc. 1 H-NMR and KF. The results are summarized in Table 3-3. Table 3-3 Summary of solvent equilibration at 50℃ for 1 week / / : Not tested Equilibrium under temperature cycling

[0378] Based on approximate solubility results, approximately 50 mg of compound I in its free acid form A was equilibrated in 0.2–1 mL of solvent at a heating / cooling rate of 0.1 °C / min for 10 cycles between 5 °C and 50 °C. Equilibration was performed on a magnetic stirring plate using a stirring rod at a rate of 300–400 rpm. The resulting suspension was centrifuged at 14,000 rpm and filtered through a 0.45 μm nylon membrane filter. The solid fraction (wet filter cake) was studied by XRPD. For samples with different XRPD patterns, additional analyses of the hydrate were performed, including DSC, TGA, etc. 1 H-NMR and KF. The results are summarized in Tables 3-4. Table 3-4 Summary of Equilibrium under Temperature Cycling / / : Not tested The amorphous form was equilibrated with solvent at 25°C for one week.

[0379] Approximately 30 mg of the free acid compound I in its amorphous form was equilibrated for 1 week at 25 °C using a stirring rod at a rate of 300–400 rpm on a magnetic stirring plate in 0.2–1 mL of solvent. The resulting suspension was centrifuged at 14,000 rpm and filtered through a 0.45 μm nylon membrane filter. The solid fraction (wet filter cake) was studied by XRPD. The results are summarized in Tables 3–5. Table 3-5 summarizes the process of equilibrating the amorphous form with solvent at 25°C for one week. solvent XRPD Note EtOH Form A - IPA Form A - acetone Almost amorphous form - EA Form A - MTBE Form C - MEK Form A - water Form M Low crystallinity. Crystallization by slow evaporation at room temperature

[0380] Based on approximate solubility results, approximately 20 mg of compound I in its free acid form A was dissolved in approximately 1 mL of solvent. The resulting solution was filtered through a 0.45 μm syringe-type nylon membrane filter. The clarified solution was slowly evaporated under ambient conditions (approximately 20-25 °C, 30%-70% RH). The solid residue was studied by XRPD. The results are summarized in Tables 3-6. Table 3-6 Summary of crystallization by slow evaporation at room temperature solvent XRPD Note acetone / / Adhesive material Acetonitrile amorphous form - Tetrahydrofuran amorphous form - 2-MeTHF amorphous form - IPAc Form A + Form H - dichloromethane amorphous form - Toluene amorphous form - / / : Not tested Crystallization by rapid evaporation at room temperature

[0381] Based on approximate solubility results, approximately 20 mg of compound I in its free acid form A was dissolved in approximately 0.2–1 mL of solvent. The resulting solution was filtered through a 0.45 μm syringe membrane filter. The clarified solution was rapidly evaporated at room temperature (approximately 20–25 °C) under a dry nitrogen stream. The solid residue was studied by XRPD. The results are summarized in Tables 3–7. Table 3-7 Summary of crystallization by rapid evaporation at room temperature solvent XRPD acetone amorphous form Acetonitrile amorphous form Tetrahydrofuran amorphous form 2-MeTHF amorphous form IPAc amorphous form dichloromethane amorphous form Toluene amorphous form Crystallization from a hot saturated solution by slow cooling

[0382] Based on approximate solubility results, approximately 30 mg of compound I in its free acid form A was dissolved in a minimal amount of the selected solvent at 50 °C. The resulting solution was filtered through a 0.45 μm syringe membrane filter. The clarified solution was cooled to 5 °C at 0.1 °C / min. The sample without precipitate was further cooled to -20 °C at 5 °C. The precipitate was collected by centrifugation at 14,000 rpm and filtration through a 0.45 μm nylon membrane filter. The solid fraction (wet filter cake) was studied by XRPD. The results are summarized in Tables 3-8. Table 3-8 Summary of Crystallization from Hot Saturated Solutions by Slow Cooling solvent XRPD Other analyses Note acetone / / Clear solution, at -20℃ – Acetonitrile Form B / / - IPAc Form A / / - Toluene Form A / / - THF / water (v:v = 1:1) / / / / Oil THF / MTBE (v:v = 2:1) / / Clear solution, at -20℃ - 2-MeTHF / heptane (v:v = 2:1) Form A / / - / / : Not tested Crystallization from a hot saturated solution by rapid cooling

[0383] Based on approximate solubility results, approximately 30 mg of compound I in its free acid form A was dissolved in a minimal amount of the selected solvent at 50 °C. The resulting solution was filtered through a 0.45 μm syringe membrane filter. The clarified solution was placed in a stirring plate at 5 °C and stirred. The precipitate was collected by centrifugation at 14,000 rpm and then filtered through a 0.45 μm nylon membrane filter. The solid fraction (wet filter cake) was studied by XRPD. The results are summarized in Tables 3-9. Table 3-9 Summary of crystallization from hot saturated solutions by rapid cooling solvent XRPD Other analyses Note acetone / / Clear solution, at -20°C - Acetonitrile Form F / / - IPAc / / Clear solution, at -20℃ - Toluene Form A / / - THF / water (v:v = 1:1) / / / / Oil THF / MTBE (v:v = 2:1) / / Clear solution, at -20℃ - 2-MeTHF / heptane (v:v = 2:1) Form A / / - / / : Not tested By adding antisolvent crystallization

[0384] Based on approximate solubility results, approximately 40 mg of compound I in its free acid form A was dissolved in a minimal amount of a selected good solvent at ambient temperature (approximately 20°C–25°C). The resulting solution was filtered through a 0.45 μm syringe membrane filter. 4–8 times the amount of antisolvent was slowly added to the clear solution until a large amount of solid precipitated. The precipitate was collected by centrifugation at 14,000 rpm and filtration through a 0.45 μm nylon membrane filter. The solid fraction (wet filter cake) was studied by XRPD. The results are summarized in Tables 3–10. Table 3-10 Summary of Crystallization by Adding Antisolvents / / : Not tested Crystallization by reverse addition of antisolvent

[0385] Based on approximate solubility results, approximately 40 mg of compound I in its free acid form A was dissolved in a minimal amount of a selected good solvent at ambient temperature (approximately 20°C–25°C). The resulting solution was filtered through a 0.45 μm syringe membrane filter. The clarified solution was rapidly added to 4–8 times its volume in an anti-solvent. The precipitate was collected by centrifugation at 14,000 rpm and then filtered through a 0.45 μm nylon membrane filter. The solid fraction (wet filter cake) was studied by XRPD. For samples with different XRPD patterns, additional analyses of the hydrate were performed, including DSC, TGA, etc. 1 H-NMR and KF. The results are summarized in Table 3-11. Table 3-11 Summary of Crystallization by Reverse Addition of Antisolvent / / : Not tested Crystallization by vapor diffusion

[0386] Based on approximate solubility results, approximately 30 mg of compound I in its free acid form A was dissolved in a minimal amount of the selected solvent at ambient temperature (approximately 20°C–25°C). The resulting solution was filtered through a 0.45 μm syringe membrane filter. The clarified solution was transferred to open 4 mL glass vials. These 4 mL vials were then placed into 40 mL glass vials. An antisolvent was added to the 40 mL vials. These 40 mL vials were then capped and incubated at ambient temperature (approximately 20°C–25°C) for up to 14 days. The precipitate was collected by centrifugation at 14,000 rpm and filtration through a 0.45 μm nylon membrane filter. The solid fraction (wet filter cake) was studied by XRPD. The results are summarized in Tables 3–12. Table 3-12 Summary of Crystallization by Vapor Diffusion / / : Not tested Crystallization by hot-cold DSC

[0387] The polymorphic behavior of compound I in its free acid form A was investigated using two different hot-cold DSC cycles. The results are summarized in Table 3-13. Table 3-13 Summary of crystallization by hot-cold DSC The interaction of polymorphs was studied using variable-temperature XRPD.

[0388] The interactions among the polymorphs of the free acid compound I were investigated using variable temperature XRPD (VT-XRPD). The results are summarized in Table 3-14. Table 3-14 Summary of VT-XRPD Experiments Water activity test

[0389] Water activity experiments were performed at 25 °C in a MeOH / water system to determine the critical water activities of free acid forms A, C, E, F, H, I, J, K, M, and N of compound I. Approximately 1.5 mg of each sample was added to 0.2 mL of saturated solution in the MeOH / water system. The resulting suspensions were stirred at 25 °C for 3 days. The solid fraction (wet filter cake) was separated by centrifugation and filtration and studied by XRPD. The results are summarized in Tables 3-15. Table 3-15 Summary of Water Activity Experiments Note: Water activity was calculated using the UNIFAC method. in conclusion

[0390] Using free acid form A as the starting material, a total of 12 stable crystalline polymorphs of compound I free acid were obtained from screening experiments. Free acid form M is a metastable hydrate with low crystallinity, and free acid form L is a DMSO-water heterosolvent isomorphic to free acid form N. Free acid form A

[0391] The free acid form A of compound I was prepared by slurrying the free acid of compound I in EtOAc at room temperature for 2 days using the procedure described in Example 1. The XRPD of the free acid form A is shown in... Figure 4A The DSC curve of the free acid form A is shown in the figure. Figure 4B The figure shows two endothermic peaks at 49.7 °C and 211.3 °C. The TGA curve for free acid form A is shown in [the figure]. Figure 4C In the meantime, it showed a weight loss of 2.3% up to 200°C. Free acid form B

[0392] Compound I free acid form B was prepared by equilibrating free acid form A in acetonitrile under temperature cycling or by crystallization from a saturated solution of compound I free acid form A in ACN by slow cooling. The XRPD of free acid form B is shown in... Figure 5A The DSC curve of the free acid form B is shown in the figure. Figure 5B The figure shows two endothermic peaks at 32.4 °C and 199.0 °C. The TGA curve for the free acid form B is shown in [the figure]. Figure 5C In the meantime, it showed a 3.3% weight loss up to 180°C. Free acid form C

[0393] Compound I in its free acid form C was prepared by equilibrating free acid form A in MTBE. The XRPD of free acid form C is shown in... Figure 6A The DSC curve of the free acid form C is shown in the figure. Figure 6B The figure shows three endothermic peaks at 31.7℃, 134.9℃, and 194.7℃. The TGA curve for the free acid form C is shown in [the figure / image / etc.]. Figure 6C In the meantime, it showed a 5.5% weight loss up to 180°C. Free acid form D

[0394] Compound I in its free acid form D was prepared by equilibrating free acid form A in ACN / water (9:1 v / v). The XRPD of free acid form D is shown in... Figure 7A The DSC curve of the free acid form D is shown in the figure. Figure 7B The figure shows three endothermic peaks at 36.1℃, 198.1℃, and 223.9℃, and an exothermic peak at 133.7℃. The TGA curve for the free acid form D is shown in [the figure / image / data]. Figure 7C In the meantime, it showed a weight loss of 1.4% up to 200°C. Free acid form E

[0395] Compound I was prepared in its free acid form E by equilibrating free acid form A in THF / water (9:1 v / v). The XRPD of free acid form E is shown in... Figure 8A The DSC curve of the free acid form E is shown in the figure. Figure 8B The figure shows two endothermic peaks at 43.6 °C and 223.9 °C. The TGA curve for the free acid form E is shown in [the figure]. Figure 8C In the meantime, it showed a 2.5% weight loss up to 200°C. Free acid form F

[0396] Compound I was prepared in its free acid form F by equilibrating free acid form A in acetonitrile. The XRPD of free acid form F is shown in... Figure 9A The DSC curve of the free acid form F is shown in the figure. Figure 9B The figure shows four endothermic peaks at 46.2℃, 121.0℃, 159.4℃, and 230.4℃. The TGA curve for the free acid form F is shown in [the figure / image / data]. Figure 9C In the meantime, it showed a weight loss of 1.2% up to 200°C. Free acid form G

[0397] Compound I in its free acid form G was prepared by equilibrating free acid form A in DMSO / water (1:1 v / v). The XRPD of free acid form G is shown in... Figure 10A The DSC curve of the free acid form G is shown in the figure. Figure 10B The figure shows two endothermic peaks at 52.9 °C and 208.7 °C. The TGA curve for the free acid form G is shown in [the figure]. Figure 10CIn the range of 55°C, an 8.5% weight loss was observed up to 55°C, and an additional 5.9% weight loss was observed from 55°C to 180°C. Free acid form H

[0398] The free acid form H of compound I was prepared by equilibrating the free acid form A in acetone / water (1:1 v / v) at 25 °C. The XRPD of the free acid form H is shown in... Figure 11A The DSC curve of the free acid form H is shown in the figure. Figure 11B The figure shows three endothermic peaks at 51.3℃, 105.5℃, and 217.2℃. The TGA curve for the free acid form H is shown in [the figure / image / etc.]. Figure 11C In the meantime, it showed a 7.7% weight loss up to 180°C. Free acid form I

[0399] Compound I (free acid form I) was prepared from free acid form A in 1,4-dioxane via reverse addition of an antisolvent (water). The XRPD of free acid form I is shown in... Figure 12A The DSC curve of free acid form I is shown in... Figure 12B The figure shows two endothermic peaks at 41.5 °C and 207.3 °C. The TGA curve for free acid form I is shown in [the figure]. Figure 12C In the meantime, it showed a 7.4% weight loss up to 200°C. Free acid form J

[0400] Compound I free acid form J was obtained by storing the free acid form D under ambient conditions (23℃-27℃, 50%-70% RH) for 2 weeks. The XRPD of free acid form J is shown in... Figure 13A The DSC curve of the free acid form J is shown in the figure. Figure 13B The figure shows two endothermic peaks at 68.6 °C and 221.2 °C. The TGA curve of the free acid form J is shown in [the figure]. Figure 13C In the meantime, it showed a weight loss of 2.2% up to 200°C. Free acid form K

[0401] Compound I in its free acid form K was obtained by storing the free acid form B under ambient conditions (23°C–27°C, 50%–70% RH) for 2 weeks. The XRPD of the free acid form K is shown in [image / image / description]. Figure 14A The DSC curve of the free acid form K is shown in the figure. Figure 14B The figure shows two endothermic peaks at 46.1 °C and 198.4 °C. The TGA curve for the free acid form K is shown in [the figure]. Figure 14C In the range up to 70°C, a weight loss of 2.4% was observed, and an additional weight loss of 2.6% was observed from 70°C to 170°C. Free acid form L

[0402] Compound I, in its free acid form L, is a DMSO-water heterosolvent. This solvate is isomorphous to the hydrate form N. It is obtained from DMSO / water (v:v = 1:1) via equilibrium at 50 °C. DSC shows a dehydration / desolvation peak starting at approximately 6 °C and an endothermic peak starting at approximately 120 °C. Based on the DSC thermogram and observation via a melting apparatus, the endothermic peak starting at approximately 120 °C is due to dehydration / desolvation accompanied by melting. No recrystallization was observed after melting. TGA shows approximately 7.9% weight loss at 70 °C and approximately 7.4% weight loss from 70 °C to 200 °C. KF shows a water content of 9.6% (approximately 6.2 equivalents by molar ratio). 1 H-NMR showed 1.8 equivalent DMSO (approximately 12.0% by weight). Free acid form M

[0403] Compound I in its free acid form M is a metastable hydrate. The metastable hydrate was obtained from water at 25°C through equilibrium using an amorphous form as the starting material. It was then transformed into Figure N by adding a seed from Figure N. Free acid form N

[0404] Compound I in its free acid form N was prepared by equilibrating free acid form A in DMSO / water (1:1 v / v) at 50 °C. XRPD of free acid form N was shown in... Figure 17A The DSC curve of N in its free acid form is shown in the figure. Figure 17B The figure shows three endothermic peaks at 68.6℃, 81.0℃, and 207.7℃. The TGA curve for free acid form N is shown in [the figure / image / data]. Figure 17C In the study, up to 200°C, a weight loss of 9.0% was observed.

[0405] In summary, the free acid form A of compound I is the most stable polymorph over a wide water activity range of 0 to 0.8. This free acid form exhibits good chemical and physical stability and only slight hygroscopicity. It demonstrates reversible dehydration-hydration behavior upon heating, with rapid hydration kinetics. Although it transforms into another hydrated form, N, in water, free acid form A remains stable in bulk at 92.5% RH for up to one week. Therefore, the free acid form A of compound I is recommended as the optimal polymorph for further development. Abbreviations for the solvents used

[0406] Solvent abbreviations are listed in Table 3-16. Table 3-16 List of Solvent Abbreviations abbreviation solvent abbreviation solvent MeOH methanol THF Tetrahydrofuran EtOH ethanol 2-MeTHF 2-Methyltetrahydrofuran IPA Isopropanol DCM dichloromethane MIBK 4-Methyl-2-pentanone ACN Acetonitrile EtOAc Ethyl acetate DMSO dimethyl sulfoxide IPAc Isopropyl acetate DMAc N,N-Dimethylacetamide MTBE Methyl tert-butyl ether NMP 1-Methyl-2-pyrrolidone <![CDATA[CHCl3]]> Chloroform MEK Methyl ethyl ketone PG Propylene glycol Instruments and methods XRPD

[0407] XRPD data were collected using a Bruker D8 Advance X-ray powder diffractometer. Detailed parameters are listed in Table 3-17. Table 3-17 Parameters for XRPD Testing Variable Temperature XRPD XRPD

[0408] For variable temperature XRPD (VT-XRPD) analysis, a Bruker D8 Advance X-ray powder diffractometer was used. The XRPD parameters used are listed in Table 3-18. Table 3-18 Parameters for VT-XRPD Testing DSC and TGA

[0409] DSC data was collected using a TA Discovery 2500 from TA Instruments. DSC was performed using a TA Discovery 5500 from TA Instruments. Detailed parameters used are listed in Table 3-19. Table 3-19 Parameters for DSC and TGA Tests DVS

[0410] DVS is measured via SMS (Surface Measurement Systems) DVS Intrinsic or ProUmid SPSx-1μAdvance. Detailed parameters for DVS testing are listed in Table 3-20. Table 3-20 Parameters for DVS Test KF

[0411] Karl Fischer data were collected from a Mettler Toledo or Metrohm 851 / 885 system using a KF titrator C30 for coulometric titration. Detailed parameters used are listed in Table 3-21. Table 3-21 Parameters of KF Test 1 H NMR

[0412] Data were collected using DMSO-d6 as the solvent on a Bruker Avance-AV 400MHz NMR spectrometer. 1H NMR data. Detailed parameters used are listed in Table 3-22. Table 3-22 1 Parameters measured by H NMR instrument Bruker Avance-AV 400M frequency 400MHz probe 5mm PABBO BB / 19F-1H / DZ-GRD Z108618 / 0406 Number of scans 8 temperature 297.6K Relaxation delay 1 second Example 4: Evaluation of the free acid form A of compound I Physicochemical characteristics of compound I in its free acid form A

[0413] To obtain a representative sample with no residual solvent, compound I in its free acid form A was prepared using the following procedure. This batch was used for evaluation in this section.

[0414] Weigh approximately 500 mg of compound I, free acid form A, into a 20 mL glass vial. Add 4 mL of EtOAc to the vial. Stir the resulting suspension at 200 rpm at 25 °C. Continue stirring the suspension at 25 °C for approximately 2 days. Collect the solid by centrifugation and then place it under ambient conditions (23 °C–27 °C, 50%–70% RH) for approximately 20 hours. Approximately 443 mg of free acid form A was obtained (yield: 89%). Bulk stability

[0415] Compound I, in its free acid form A, was stored for one week in an open container at 25°C / 92.5% RH, in an open container at 40°C / 75% RH, and in a closed container at 60°C. The stored samples were characterized by XRPD and HPLC, and color changes were examined. The results are summarized in Table 4-1. No changes in morphology or purity were observed under all three storage conditions. Table 4-1 Summary of Large-Scale Stability Water adsorption and desorption experiments

[0416] The water adsorption and desorption behavior of compound I in its free acid form A was investigated by DVS at 25 °C using the following cycles: 40%-95%-0%-95%-40% RH, dm / dt 0.002, minimum equilibrium time 60 min, and maximum equilibrium time 360 ​​min. XRPD was measured after the DVS test to determine the form change. The results are summarized in Table 4-2. Table 4-2 Summary of DVS Test Compression simulation experiment

[0417] Approximately 20 mg of compound I in its free acid form A was compressed for 5 minutes at 2.5 MPa, 5 MPa, and 10 MPa using a hydraulic press. Potential changes in form and degree of crystallinity were evaluated by XRPD. The results are summarized in Table 4-3. A decrease in crystallinity was observed under all conditions, but the morphology remained unchanged. Table 4-3 Summary of Compression Simulation Experiments Dry grinding simulation experiment

[0418] Approximately 20 mg of compound I in its free acid form A was manually ground for 3 minutes using a mortar and pestle. XRPD showed no change in form or degree of crystallinity. Wet granulation simulation experiment

[0419] Water or ethanol was added dropwise to approximately 20 mg of the free acid form A of compound I until the sample was fully wetted. The wet sample was gently ground using a mortar and pestle. The granulated sample was then dried under ambient conditions for 10 min. The results are summarized in Table 4-4. For samples wetted with water, no change in form or degree of crystallinity was observed by XRPD. For samples wetted with ethanol, no change in form and a slight decrease in crystallinity were observed by XRPD. Table 4-4 Summary of Wet Granulation Experiments in conclusion

[0420] Compound I in its free acid form A was evaluated through large-scale stability, hygroscopicity, compression simulation, and dry / wet granulation simulation experiments. After one week of pressurization under all three conditions, free acid form A was physically and chemically stable. No form change and significant chemical degradation were observed after the large-scale stability study. Free acid form A is slightly hygroscopic, exhibiting 1.0% water absorption from 40% RH to 95% RH. The samples obtained after DVS testing remained in free acid form A. Free acid form A showed good tolerance to artificial grinding and wet granulation using water as a dispersant, with no form change and no significant decrease in crystallinity. After wet granulation using EtOH as a dispersant and compression tests at 2.5 MPa and 5 MPa, free acid form A showed no form change and a slight decrease in crystallinity. After compression at 10 MPa, free acid form A showed no form change but a significant decrease in crystallinity. Instruments and methods

[0421] The XRPD and DVS instruments and methods used are the same as in Example 3. HPLC

[0422] HPLC data were collected using an Agilent 1260 Infinity II binary pump instrument. Detailed parameters are listed in Tables 4-5. Table 4-5 HPLC parameters Example 5: Additional Salt Screening Experiment

[0423] Further salt screening was performed using five counter-charged ions as salt-forming agents. Approximately 200 mg of the free acid form A of compound 1 was added to an appropriate amount of acetone or ACN to obtain a clear solution. 1.0 equivalent of the selected counter-charged ion was dissolved in water. The solutions were mixed and applied to rotary evaporation to obtain an amorphous solid. The salt form of the obtained solid was confirmed by IR. The amorphous solid was then equilibrated in different solvents to obtain crystalline salts. Acetone, ACN, THF, DCM, and ethanol / water (1:1, v / v) were used as crystallization solvents. The results are summarized in Table 5-1. Two crystalline salt hits (Na salt form A and L-arginine salt form A) were obtained and characterized by XRPD, TGA, DSC, and NMR or HPLC / IC. Table 5-1 Summary of screening for other salts of compound I

[0424] The clarified solution obtained above was further slowly cooled to 5°C. After stirring at 5°C for 2 days, no solid precipitate was observed. The solution was further treated by adding an antisolvent. The resulting suspension was centrifuged to obtain a solid, which was dried under vacuum at 50°C for 2 hours and analyzed by XRPD. The results are summarized in Table 5-2. Two new crystalline salts were obtained (potassium salt form A and sodium salt form B). Table 5-2 Salt screening of compound I by adding antisolvents. / / : Not performed Characterization of Compound I salt form

[0425] Four salt forms were obtained from salt screening and further experiments, and these four salt forms were characterized by XRPD, TGA, and DSC. HPLC / IC or 1 ¹H NMR determined the salt stoichiometry. All characterization results are summarized in Table 5-3. Table 5-3 Summary of characterization of salt of compound I / / : Indicates that Na salt was not tested due to insufficient sample.

[0426] The sodium salt form of compound I (Na salt form A) was obtained by slurrying free acid form A and equimolar amounts of NaOH in acetone at room temperature for 4 days.

[0427] The TGA / DSC curves of the sodium salt form A of compound I show a weight loss of 1.8% up to 120 °C and an endothermic reaction at 66.5 °C (peak). 1 ¹H NMR showed an acetone / API molar ratio of 0.37 (2.3 wt%). HPLC / IC showed a molar ratio of 1.0 (base / FA).

[0428] Compound I sodium salt form B (Na salt form B) was obtained by slurrying free acid form A and equimolar amounts of NaOH in THF at room temperature for 4 days, slowly cooling to 5°C and stirring for 2 days, followed by the addition of an antisolvent (water). XRPD plots are shown in... Figure 19A middle. K salt

[0429] Compound I in potassium salt form A (K salt form A) was obtained by slurrying free acid form A and equimolar amounts of KOH in acetone at room temperature for 4 days, slowly cooling to 5°C and stirring for 2 days, followed by the addition of an antisolvent (MTBE). XRPD plots are shown in... Figure 20A middle.

[0430] The DSC curve of compound I in potassium salt form A (K salt form A) is shown in Figure 20B The figure shows three endothermic temperatures at 50.9℃, 166.2℃, and 237.7℃ (peak). The TGA curves are shown in... Figure 20C In the meantime, it showed a weight loss of 1.4% up to 130°C. 1 ¹H NMR showed that the molar ratio of MTBE / API was 0.45 (4.1 wt%) and the molar ratio of acetone / API was 0.04 (0.3 wt%). HPLC / IC results showed a molar ratio of 0.9 (base / FA). L-arginine salt

[0431] The compound IL-arginine salt form A (L-arginine form A) was obtained by slurrying free acid form A and equimolar amounts of L-arginine in THF at room temperature for 4 days.

[0432] The TGA / DSC curves of L-arginine salt form A showed a 2.4% weight loss up to 120 °C and an endothermic reaction at 57.3 °C (peak). 1 1H NMR showed that the molar ratio of L-arginine / API was 1.0 and the molar ratio of THF / API was 0.2 (1.5 wt%). Re-preparation of the selected salt

[0433] Na salt form A, Na salt form B, and L-arginine salt form A were selected for reprocessing. To prepare Na salt form B, approximately 40 mg of free acid form A and 1.0 equivalent of sodium hydroxide were stirred in 0.6 mL of water. After stirring at 50 °C for 4 days, the suspension was removed and centrifuged. The obtained solid was analyzed by XRPD, which showed that only an amorphous form was obtained.

[0434] The Na salt form A and the L-arginine salt form A were successfully reconstituted at a scale of 600 mg and characterized by XRPD, TGA, DSC, NMR, or HPLC / IC. The results are summarized in Table 5-4. Table 5-4 Summary of the characterization of the re-prepared salts Na salt

[0435] Compound I sodium salt form A (Na salt form A) was prepared by slurrying approximately 600 mg of free acid form A and equimolar amounts of NaOH in 7.5 mL of acetone at room temperature for 4 days. The obtained solid was centrifuged and dried under vacuum at 50 °C for 2 h. XRPD plots are shown in... Figure 18A The DSC curve of Na salt form A is shown in... Figure 18B The TGA curve for Na salt form A is shown in [the figure]. Figure 18C In this study, a 4.1% weight loss was observed up to 100°C. HPLC / IC results showed a molar ratio of 1.0 (alkali / FA). 1 ¹H NMR showed an acetone / API molar ratio of 0.6 (3.8 wt%). Based on the data, the Na salt form A is likely a heterosolvent of acetone and water. L-arginine salt

[0436] The compound IL-arginine salt form A (L-arginine salt form A) was prepared by slurry preparation in 3.4 mL ACN / H₂O (7.5:1, v / v) from approximately 600 mg of free acid form A and an equimolar amount of L-arginine, followed by rotary evaporation and equilibration in THF at room temperature for 5 days. The obtained solid was centrifuged and dried under vacuum at 50 °C for 2 h. XRPD illustration is shown below. Figure 1A The DSC curve of L-arginine salt form A is shown in... Figure 1B The TGA curve for L-arginine salt form A is shown in [the figure]. The endothermic reaction occurs at 66.0 °C (peak). Figure 1C In the meantime, it showed a 3.2% weight loss up to 120°C. 1¹H NMR showed that the molar ratio of base / FA was 1.0 and the molar ratio of THF / API was 0.8 (5.6 wt%). Based on the data, L-arginine salt form A is likely a heterosolvent of THF and water. Salt Evaluation

[0437] The two reconstituted salt samples were used for salt evaluation, including hygroscopicity, kinetic solubility, and solid stability. The free acid form A of starting material compound I was also evaluated for comparison. Solid stability

[0438] The bulk stability of the free acid form A and the two salt candidates was studied for 2 weeks at 25 °C / 92.5% RH in an open container, at 40 °C / 75% RH in an open container, and at 60 °C in a closed container. Under these conditions, the free acid form A and the L-arginine salt form A were physically and chemically stable. The solid stability results are summarized in Tables 5-5. Under these conditions (25 °C / 92.5% RH and 40 °C / 75% RH), the Na salt form A was chemically stable but physically unstable, and form changes were observed under both conditions as seen by XRPD. Table 5-5 Summary of solid stability evaluation of compound I *Possibly isomorphic hydrates kinetic solubility

[0439] The kinetic solubility of compound I in its free acid form A and its reconstituted salt form was measured in water and three biorelevant media. Table 4-11 summarizes the procedures for preparing the biorelevant media. The solubility of the free acid form A and the two salt candidates was tested in four pH buffers (pH 1.2 HCl buffer, pH 4.5 acetate buffer, pH 8.0 alkaline borate buffer, and water) and three biorelevant media (SGF, FaSSIF-V1, and FeSSIF-V1) at 37 °C for 0.5 h and 1 h.

[0440] Weigh approximately 10 mg of the material into 5 mL of water, buffer solution, SGF, FaSSIF, or FeSSIF. 1 The suspension was then rolled at 25 rpm for 0.5 h and 1 h at 37 °C. At each time point, approximately 0.8 mL of the suspension was sampled for centrifugation and filtration. The solids were tested by XRPD. The results are summarized in Tables 5-6. Based on the results, the salt was more soluble in water, alkaline borate buffer, and FeSSIF than in the free acid form A, and the Na salt form A was more soluble than the L-arginine salt form A. The XRPD results show that disproportionation of the Na salt form A was observed after the solubility studies. Table 5-6 Summary of kinetic solubility tests *LOQ = 0.500 μg / mL; / / : Not tested due to insufficient material. FA: Free acid form A; NA: Na salt form A; LA: L-arginine salt form A; AF: Amorphous form 1 NaCl was also detected. 2 Another peak at 2θ: 8.9° 3 Another peak at 2θ: 28.5° 5 Similar to free acid form A hygroscopic

[0441] To evaluate the hygroscopicity of compound I in its free acid form A and its reconstituted salt forms (Na salt form A and L-arginine salt form A), DVS isotherms were collected at 25 °C between 0% and 95% RH. The samples were characterized by XRPD after the DVS tests. The DVS evaluation results are summarized in Tables 5-7. Based on the results, all three forms are hygroscopic, and compound I in its free acid form A was observed to have the lowest water absorption. After the DVS test, compound I in its Na salt form A was converted to a new form. Table 5-7 Summary of DVS Evaluation *XRPD analysis showed that it transformed into a potentially isomorphic hydrate. in conclusion

[0442] Using compound I in its free acid form A as the starting material, salt screening was performed under 33 conditions using 11 bases in 3 solvent systems. No crystalline salts were obtained, but two new free acid forms were identified. Further experiments using 6 bases as solvents in ACN / H₂O (7:3 v / v) also failed to produce any crystalline salts, but identified 4 new free acid forms. Finally, further experiments using 5 anti-charged ions and 5 solvents, followed by slow cooling and / or the addition of an antisolvent, yielded 4 crystalline salts. Compound I sodium salt form A, compound I sodium salt form B, and compound IL-arginine salt form A were selected for reprocessing. Of the three forms, compound I sodium salt form A and compound IL-arginine salt form A were successfully prepared.

[0443] The reconstituted salt was used together with the free acid form A of compound I for salt evaluation. DVS results showed that the free acid form A exhibited the lowest water absorption, and a change in form was observed in the Na salt form A of compound I after DVS. Kinetic solubility results showed that the salt was more soluble in water, alkaline borate buffer, and FeSSIF than the free acid form A, and the Na salt form A was more soluble than the L-arginine salt form A. Solid stability evaluation results showed that both the free acid form A and the L-arginine salt form A were chemically and physically stable under all test conditions, but the Na salt form A was physically stable at 25°C / 92.5% RH and 40°C / 75% RH.

[0444] Based on the salt evaluation and solid-state characterization results, compound I L-arginine salt form A was selected for further polymorph screening. Instruments and Methods XRPD

[0445] For XRPD analysis, a Bruker X-ray powder diffractometer was used. The XRPD parameters used are listed in Table 5-8. Table 5-8 Parameters for XRPD Testing TGA and DSC

[0446] TGA data was collected using a Discovery 5500 or Q5000 TGA from TA Instruments. DSC was performed using a Discovery 2500DSC from TA Instruments. Detailed parameters used are listed in Table 5-9. Table 5-9 Parameters for TGA and DSC tests DVS

[0447] DVS was measured via SMS (Surface Measurement Systems) DVS Intrinsic. The deliquescence points of LiCl, Mg(NO3)2, and KCl were calibrated at 25°C using relative humidity. Parameters for the DVS test are listed in Table 5-10. Table 5-10 Parameters of DVS Test PLM

[0448] PLM images were captured on an Olympus BX53LED using an orthogonal polarizer with added silicone oil. Karl Fischer

[0449] KF analysis was performed using coulometric titration on a Mettler Toledo KF titrator C30. Solution NMR

[0450] Solution NMR was collected on a Bruker Avance-AV 400MHz NMR spectrometer. HPLC / IC

[0451] Waters H-Class UPLC was used, and detailed chromatographic conditions are listed in Table 5-11. IC parameters are listed in Table 5-12. Table 5-11 HPLC methods for purity testing Table 5-12: IC parameters for chemometrics testing instrument Metrohm940professionalIC Sample Center 889IC detector conductivity detector Eluent (anionic) <![CDATA[3.2mmol / L Na2CO3+1.0mmol / L NaHCO3]]> Eluent (cationic) 2.5 mmol / L MSA Inhibition solution <![CDATA[0.5%H2SO4]]> column: Anion A SUPP 5-150 or cation C4-150 column Column temperature: 30℃ Flow rate: 0.7 mL / min (anion) or 0.9 mL / min (cation) Diluent: ACN / Water (1:1, v:v) Injection volume: 20μL Example 6: Screening and evaluation of polymorphs of compound I L-arginine salt

[0452] The aim of this project was to screen and evaluate polymorphs of L-arginine salts to select the dominant form for further research. The starting material was characterized by XRPD, TGA, and DSC. The XRPD plot showed the material was in the free acid form A. TGA / DSC results showed a 3.8% weight loss up to 200 °C and endothermic melting at 232.2 °C (starting temperature). Re-preparation of L-arginine salt

[0453] Approximately 8 g of compound I-arginine salt form B was prepared from the reaction of compound I and L-arginine in IPA / H₂O (7:3 v / v). After stirring at 50-55°C for approximately 2 h, 2.38 equivalents of IPA and 2 wt% seed crystals were added to the clear solution, causing the mixture to become turbid. After stirring for 2 h, approximately 15.5 equivalents of IPA were added dropwise to the mixture. After stirring at 50-55°C for 8 h, the mixture was further stirred at 0-5°C for 10 h. The precipitated solid was collected by filtration, washed with IPA, and dried at 65-75°C. Purity determined by HPLC: 97.7%. Approximate solubility at 25°C and 50°C

[0454] The solubility of the starting material in 21 solvents was determined at two temperatures.

[0455] To determine the solubility at 25°C, weigh approximately 5 mg of L-arginine salt into a 2 mL glass vial. Add 20 μL of each solvent aliquot to dissolve the substance at 25°C. Use vortexing and sonication to aid dissolution. The maximum volume of each solvent added is 1 mL. Determine the approximate solubility by visual observation.

[0456] For solubility at 50°C, approximately 10 mg of L-arginine salt was weighed into a 2 mL glass vial. 20 μL aliquots of each solvent were added to dissolve the substance at 50°C. Vortexing and sonication were used to aid dissolution. The maximum volume of each solvent added was 1 mL. Approximate solubility was determined by visual observation. The results are summarized in Table 6-1. Table 6-1 Summary of solubility experiments at 25℃ and 50℃ / / : Not performed Equilibrate with solvent at 25°C and 50°C.

[0457] Based on approximate solubility results, approximately 40 mg of compound I L-arginine salt was equilibrated in 0.2–1 mL of solvent at 25 °C for 2 weeks or at 50 °C for 1 week, with stirring at 300–400 rpm. The resulting suspension was centrifuged at 14,000 rpm and filtered through a 0.45 μm nylon membrane filter. The solid precipitate (wet filter cake) was studied by XRPD. For samples with different XRPD patterns, the hydrate was further analyzed, including DSC, TGA, etc. 1 H-NMR and KF. The results are summarized in Tables 6-2 and 6-3. Table 6-2 Summary of the equilibrium experiment conducted at 25℃ for 2 weeks Table 6-3 Summary of the equilibrium experiment conducted at 50℃ for one week Equilibrium under temperature cycling

[0458] Based on approximate solubility results, approximately 50 mg of L-arginine salt was equilibrated in 0.2–1 mL of solvent at a heating / cooling rate of 0.1 °C / min for 10 cycles between 5 °C and 50 °C. Equilibration was carried out on a magnetic stirring plate using a stirring rod at a rate of 300–400 rpm.

[0459] The obtained suspension was centrifuged at 14,000 rpm and filtered through a 0.45 μm nylon membrane filter. The solid fraction (wet filter cake) was studied by XRPD. For samples with different XRPD patterns, additional analyses of the hydrates were performed, including DSC, TGA, and [other methods not specified]. 1 H-NMR and KF. The results are summarized in Table 6-4. Table 6-4 Summary of Equilibrium Experiments under Temperature Cycling Crystallization by slow evaporation at room temperature

[0460] Based on approximate solubility results, approximately 20 mg of L-arginine salt was dissolved in 0.1–15 mL of solvent. The resulting solutions were filtered through a 0.45 μm syringe-type nylon membrane filter. The clarified solutions were then slowly evaporated under ambient conditions (approximately 23–27 °C, 60%–80% RH). The solid residues were studied by XRPD. The results are summarized in Tables 6–5. Table 6-5 Summary of crystallization by rapid evaporation at room temperature Crystallization by rapid evaporation at room temperature

[0461] Based on approximate solubility results, approximately 20 mg of L-arginine salt was dissolved in 0.1–15 mL of solvent. The resulting solutions were filtered through a 0.45 μm syringe membrane filter. The clarified solutions were rapidly evaporated under ambient conditions (approximately 23–27 °C, 60%–80% RH) under a dry nitrogen stream. The solid residues were studied by XRPD. The results are summarized in Tables 6–6. Table 6-6 Summary of crystallization by rapid evaporation at room temperature Crystallization from a hot saturated solution by slow cooling

[0462] Based on approximate solubility results, approximately 30 mg of L-arginine salt was dissolved in a minimal amount of the selected solvent at 50 °C. The resulting solution was filtered through a 0.45 μm syringe membrane filter. The clarified solution was cooled to 5 °C at a rate of 0.1 °C / min. The sample without precipitate was further cooled from 5 °C to -20 °C. The results are summarized in Tables 6-7. Table 6-7 Summary of Crystallization from Hot Saturated Solutions by Slow Cooling solvent Note MeOH Clear solution DMSO Clear solution (cooled from 70°C to 25°C) DMF Clear solution NMP Clear solution MeOH / water (v:v = 1:1) Clear solution MeOH / DCM (v:v = 1:1) Clear solution MeOH / THF (v:v = 1:1) Clear solution ACN / Water (v:V = 1:1) Clear solution Acetone / water (v:v = 1:1) The amount of solids is too small to be used for XRPD testing. <![CDATA[CHCl3]]> Clear solution Crystallization from a hot saturated solution by rapid cooling

[0463] Based on approximate solubility results, approximately 30 mg of L-arginine salt was dissolved in a minimal amount of the selected solvent at 50 °C. The resulting solution was filtered through a 0.45 μm syringe membrane filter. The clarified solution was placed at 5 °C and stirred. The clarified solution was further cooled to -20 °C. The results are summarized in Tables 6-8. Table 6-8 Summary of Crystallization from Hot Saturated Solutions by Rapid Cooling By adding antisolvent crystallization

[0464] Based on approximate solubility results, approximately 40 mg of L-arginine salt was dissolved in a minimal amount of a selected good solvent under ambient conditions (approximately 23°C–27°C, 60%–80% RH). The resulting solution was filtered through a 0.45 μm syringe membrane filter. 4–8 times the volume of the antisolvent was slowly added to the clear solution until a significant amount of solid precipitated out.

[0465] The precipitate was collected by centrifugation at 14,000 rpm and filtration through a 0.45 μm nylon membrane filter. The solid fraction (wet filter cake) was studied by XRPD. Further analyses were performed on samples with different XRPD patterns, including… 1 H-NMR. The results are summarized in Tables 6-9. Table 6-9 Summary of Crystallization by Adding Antisolvents Crystallization by reverse addition of antisolvent

[0466] Based on approximate solubility results, approximately 40 mg of L-arginine salt was dissolved in a minimal amount of a selected good solvent under ambient conditions (approximately 23°C–27°C, 60%–80% RH). The resulting solution was filtered through a 0.45 μm syringe membrane filter. The clarified solution was rapidly added to 4–8 times its volume of antisolvent.

[0467] The precipitate was collected by centrifugation at 14,000 rpm and filtered through a 0.45 μm nylon membrane filter. The solid fraction (wet filter cake) was studied by XRPD. For samples with different XRPD patterns, additional analyses, including TGA, DSC, and [other methods], were performed. 1 H-NMR. The results are summarized in Table 6-10. Table 6-10 Summary of Crystallization by Reverse Addition of Antisolvent Crystallization by vapor diffusion

[0468] Based on approximate solubility results, approximately 30 mg of L-arginine salt was dissolved in a minimum amount of the selected solvent at approximately 20-25°C and 60%-80% RH. The resulting solution was filtered through a 0.45 μm syringe membrane filter. The clarified solution was transferred to open 4 mL glass vials. These 4 mL vials were then placed in 40 mL glass vials. An antisolvent was added to the 40 mL vials. These 40 mL vials were then capped and stored at approximately 23-27°C and 60%-80% RH for up to 14 days. The results are summarized in Tables 6-11. Table 6-11 Summary of Crystallization via Vapor Diffusion Solvent (mL) Antisolvent (mL) Note DMSO (0.4) Acetone (1.6) Yellow solution DMSO (0.4) ACN(1.6) Turbid suspension DMF(10) Acetone (18) Clear solution DMF(8.5) ACN(19) The amount of solids is too small to be used for XRPD testing. Crystallization by hot-cold DSC

[0469] The polymorphic behavior of L-arginine salts was investigated using two different hot-cold DSC cycles. The results are summarized in Tables 6-12. Table 6-12 Summary of Crystallization via Hot-Cold DSC Variable Temperature XRPD (VT-XRPD)

[0470] The interactions between polymorphs were studied using variable-temperature XRPD. The results are summarized in Table 6-13. Table 6-13 Summary of Variable Temperature XRPD (VT-XRPD) in conclusion

[0471] A total of three crystalline polymorphs of compound I L-arginine salt were obtained from the screening experiments. L-arginine salt form A

[0472] Compound I, in L-arginine salt form A, was prepared using the procedure given in Example 2, and subsequently equilibrated in THF at room temperature for 5 days. The obtained solid was centrifuged and dried under vacuum at 50°C for 2 hours. XRPD illustrations are shown below. Figure 1A The DSC curve of L-arginine salt form A is shown in... Figure 1B The TGA curve for L-arginine salt form A is shown in [the figure]. The endothermic reaction occurs at 66.0 °C (peak). Figure 1C In the meantime, it showed a 3.2% weight loss up to 120°C. L-arginine form B

[0473] Compound I, L-arginine salt form B, was prepared by equilibrating L-arginine salt starting material in IPA / water (17:1 v / v) at 25 °C. The XRPD of L-arginine salt form B is shown in... Figure 2AThe DSC curve of L-arginine salt form B is shown in [the figure]. Figure 2B The figure shows endothermic reactions at 17.6 °C (peak) and 243.7 °C (peak). The TGA curves for the free acid form B are shown in [the figure / image / data]. Figure 2C In the range of 200°C, a weight loss of 3.9% was observed up to 200°C and an additional 4.5% weight loss was observed from 200°C to 250°C. L-arginine salt form C

[0474] Compound I, in L-arginine salt form C, was prepared by equilibrating the L-arginine salt starting material in acetone at 25 °C. XRPD of the free acid form B is shown in... Figure 3A The DSC curve of the free acid form B is shown in the figure. Figure 3B The figure shows two endothermic peaks at 52.9 °C and 232.9 °C. The TGA curve for free acid form B is shown in [the figure]. Figure 3C In the range up to 200°C, a weight loss of 5.2% was observed, and an additional weight loss of 3.7% was observed from 200°C to 260°C. Instruments and Methods XRPD

[0475] For XRPD analysis, a Bruker D8 Advance X-ray powder diffractometer was used. The XRPD parameters used are listed in Table 6-14. Table 6-14 Parameters for XRPD Testing Variable Temperature XRPD

[0476] For variable temperature XRPD (VT-XRPD) analysis, a Bruker D8 Advance X-ray powder diffractometer was used. The XRPD parameters used are listed in Table 6-15. Table 6-15 Parameters of VT-XRPD Test DSC and TGA

[0477] DSC data was collected using the TA Discovery 2500 from TA Instruments. DSC was performed using the TA Discovery 5500 from TA Instruments. Detailed parameters used are listed in Table 6-16. Table 6-16 Parameters for DSC and TGA Tests DVS

[0478] DVS is measured via SMS (Surface Measurement Systems) DVS Intrinsic or ProUmid SPSx-1μAdvance. Detailed parameters for DVS testing are listed in Table 6-17. Table 6-17 Parameters for DVS Test KF

[0479] Karl Fischer data were collected from Mettler Toledo or Metrohm 851 / 885 systems using a KF titrator C30 for coulometric titration. Detailed parameters used are listed in Table 6-18. Table 6-18 Parameters of KF Test 1 H NMR

[0480] Data were collected using DMSO-d6 as the solvent on a Bruker Avance-AV 400MHz NMR spectrometer. 1 H NMR data. Detailed parameters used are listed in Table 6-19. Table 6-19 1 Parameters measured by H NMR instrument Bruker Avance-AV 400M frequency 400MHz probe 5mm PABBOBB / 19F-1H / DZ-GRD Z108618 / 0406 Number of scans 8 temperature 297.6K Relaxation delay 1 second Example 7: Preparation and Evaluation of Compound I in L-Arginine Salt Form C Preparation of Compound I in L-Arginine Salt Form C

[0481] Compound I, L-arginine salt form C, was prepared using the following procedure: Approximately 1 g of L-arginine salt was weighed into a 20 mL glass vial and equilibrated with 2 mL of acetone at 50 °C. A suspension was obtained. Approximately 5 mg of L-arginine salt form C seed crystals were added to the suspension. After stirring for 1 day, the suspension thickened. 3 mL of acetone was then added. After stirring for another 2 days, the solid was collected by centrifugation at 4000 rpm. The wet filter cake was dried under vacuum at 50 °C under humidity control (approximately 65% ​​RH). Approximately 711 mg of L-arginine salt form C was obtained, with a yield of 71%. Physicochemical characteristics

[0482] XRPD, DSC / TGA, HPLC, 1 The physical and chemical characteristics of compound IL-arginine salt C obtained above were thoroughly investigated by 1H NMR, KF and scanning electron microscopy (SEM). The results are summarized in Table 7-1. Table 7-1 Summary of the physicochemical characteristics of compound C in IL-arginine salt form Large-scale stability

[0483] L-arginine salt form C was stored for one week in open containers at 25°C / 92.5% RH, in open containers at 40°C / 75% RH, and in closed containers at 60°C. The stored samples were characterized by XRPD and HPLC, and color changes were examined. No changes in HPLC purity, color, or XRPD were observed for all storage conditions. The results are summarized in Table 7-2. Table 7-2 Summary of the bulk stability of compound IL-arginine salt form C Water adsorption and desorption experiments

[0484] The water adsorption and desorption behavior of L-arginine salt form C was investigated by DVS, and XRPD was measured after DVS testing to determine the form change. The samples were observed to be slightly hygroscopic from 40% RH to 95% RH, with a water absorption of approximately 4.3%. The results are summarized in Table 7-3. Table 7-3 Summary of water adsorption and desorption experiments Compression simulation experiment

[0485] Approximately 20 mg of L-arginine salt in form C was compressed for 3 minutes at 2.5 MPa, 5 MPa, and 10 MPa using a hydraulic press. Potential form changes and the degree of crystallinity were evaluated by XRPD. No form changes were observed, but a slight decrease in crystallinity was observed. The results are summarized in Table 7-4. Table 7-4 Summary of Compression Simulation Experiments Dry grinding simulation experiment

[0486] Approximately 20 mg of L-arginine salt pattern C was manually ground for 3 min using a mortar and pestle. Potential form changes and the degree of crystallinity were evaluated by XRPD. No form changes were observed, but a slight decrease in crystallinity was observed. Wet granulation simulation experiment

[0487] Water or ethanol was added dropwise to approximately 20 mg of L-arginine salt in mode C until the sample was fully wetted. The wet sample was gently ground with a mortar and pestle for 3 min. The granulated sample was then dried under ambient conditions (approximately 20-25°C, 60-80% RH) for 10 min. The potential for form change and degree of crystallinity was evaluated by XRPD. No form change was observed, but a slight decrease in crystallinity was observed. The results are summarized in Tables 7-5. Table 7-5 Summary of Wet Granulation Simulation Experiment Granulation solvent XRPD water No change in form, but crystallinity decreases. ethanol No change in form, but crystallinity decreases. Instruments and methods

[0488] The TGA, DSC, DVS, KF, and NMR instruments and methods used were the same as in Example 7. XRPD

[0489] XRPD data were collected using a Bruker D8 Advance X-ray powder diffractometer. Detailed parameters are listed in Table 7-6. Table 7-6 Parameters for XRPD Testing SEM

[0490] SEM images were collected using the Phenom Prox SEM-EDS instrument. Detailed parameters are listed in Table 7-7. Table 7-7 SEM Parameters HPLC

[0491] HPLC data were collected using an Agilent 1260 Infinity II binary pump instrument. Detailed parameters are listed in Tables 7-8. Table 7-8 HPLC parameters Example 8: Pharmacokinetic study in dogs of compound IL-arginine salt form B, L-arginine salt form A, free acid form A, and sodium salt form A.

[0492] The aim of this study was to characterize the pharmacokinetics (PK) of compound I in male beagle dogs after oral (PO) or intravenous (IV) administration. Compound I in its free acid form A-PO / IV

[0493] LC-MS / MS was performed using the following instruments / conditions for the study of compound I in its free acid form, APK. Table 8-1. LC-MS / MS used for PK studies of compound I in its free acid form APO / IV

[0494] Compound I, in its free acid form A, was formulated to a concentration of 10%. HS15 + 90% saline solution at 1 mg / mL, administered orally by gavage (PO) at a target dose level of 2 mg / kg, or intravenously (IV) at a target dose level of 1 mg / kg.

[0495] Prepare the preparation on the day of administration and store at room temperature before administration. Administer the dose via cephalic vein injection and oral gavage at a volume of 1 mL / kg of the target dose, respectively. Collect blood samples from the cephalic vein after intravenous and oral administration. For both IV and PO groups, collect blood samples before administration and at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration.

[0496] The plasma concentration of compound I in its free acid form, A, was determined by liquid chromatography-mass spectrometry (LC-MS / MS). The pharmacokinetic (PK) data are summarized in Table 8-2 below. Table 8-2. Summary of average PK parameters for the free acid form APO / IV of compound I For PO / IV administration, AUC last t = 24h. T max Presented as a range. Compound IL-arginine salt form B-PO ​​formulation

[0497] LC-MS / MS was performed using the following instruments / conditions for the BPK study of compound I in the form of L-arginine salt. Table 8-3. LC-MS / MS for PK studies of compound I L-arginine salt formulation BPO

[0498] Compound I, L-arginine salt form B, was formulated into oral HPMC capsules (POA) and an oral solution in 10% TPGS (POB) in water. The target dose for both formulations was 2 mg / kg.

[0499] Prepare the preparation on the day of administration and store at room temperature before administration. Administer the dose orally to the dogs via gavage. After oral administration, collect blood samples from the animals via a peripheral vein at 0.25, 0.5, 1, 2, 4, 8, and 24 hours post-administration.

[0500] The plasma concentration of compound I, L-arginine salt form B, was determined by liquid chromatography-mass spectrometry (LC-MS / MS). The pharmacokinetic (PK) data are summarized in Table 8-4 below. Table 8-4. Summary of average PK parameters for formulations of compound IL-arginine salt BPO AUC last t = 8 or 24h. T max Presented as median and range. Compound I exists in its free acid form A, sodium salt form A, and L-arginine salt form A.

[0501] LC-MS / MS was performed using the instruments and conditions shown in Table 8-3 for PK studies.

[0502] Compound I was formulated into oral HPMC capsules (PO) at a target dose of 2 mg / kg in its free acid form A, sodium salt form A, and L-arginine salt form A.

[0503] The dose was administered orally to the dogs via gavage. Blood samples were collected from the animals via a peripheral vein at 0.25, 0.5, 1, 2, 4, 8, and 24 hours after oral administration.

[0504] The plasma concentration of compound I was determined by liquid chromatography-mass spectrometry (LC-MS / MS). The pharmacokinetic (PK) data are summarized in Table 8-5 below. Table 8-5. Summary of the average PK parameters of compound I For the free acid form A, AUC last t = 6h, t = 8h for sodium salt form A, and t = 24h for L-arginine salt form A. T max Presented as median and range. in conclusion

[0505] Compound I, in its L-arginine salt form B, exhibits excellent pharmacokinetic characteristics. The mean AUC of compound I, in its L-arginine salt form B within the capsules... last and C max The value is higher than the average AUC of compound I in its free acid form A, sodium salt form A, or L-arginine salt form A. last and C max Therefore, compound I, L-arginine salt form B, exhibits better oral bioavailability than the other tested forms.

[0506] Those skilled in the art will readily understand that this disclosure is highly suitable for achieving the mentioned results and advantages, as well as those inherent therein. The methods, variations, and compositions described herein are representative of present embodiments and are exemplary, and are not intended to limit the scope of this disclosure. Changes and other uses will be apparent to those skilled in the art, and are covered within the spirit of this disclosure and defined by the scope of the claims.

Claims

1. A 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one L-arginine salt (compound I L-arginine salt), having the formula IB: Or its solvates.

2. A crystalline form or a solvation thereof of 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one L-arginine salt (compound IL-arginine salt).

3. A crystalline form B (compound I) of 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one L-arginine salt. L-arginine salt form B), characterized by an X-ray powder diffraction pattern containing the following peaks, represented by ±0.2 degrees 2θ selected from 6.1, 7.4 and 10.3, as determined on a diffractometer using Cu-Kα radiation.

4. The crystalline compound IL-arginine salt form B according to claim 3, further characterized by an X-ray powder diffraction pattern containing one or more additional peaks, said additional peaks being represented by ±0.2 degrees 2θ selected from 10.8, 15.3, 15.5, 18.0, 20.6 and 22.8, as determined on a diffractometer using Cu-Kα radiation.

5. The crystalline compound IL-arginine salt form B according to claim 3 or 4, further characterized by an X-ray powder diffraction pattern substantially as shown in FIG2A.

6. The crystalline compound IL-arginine salt form B according to any one of claims 3-5, further characterized by comprising an endothermic DSC at about 17.6°C (peak) and about 243.7°C (peak).

7. The crystalline compound IL-arginine salt form B according to any one of claims 3-5, further characterized by or substantially as shown in FIG2B, the DSC.

8. A crystalline form A (compound I) of 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one L-arginine salt. L-arginine salt form A), characterized by an X-ray powder diffraction pattern containing the following peaks, represented by ±0.2 degrees 2θ selected from 5.3, 9.1 and 11.5, as determined on a diffractometer using Cu-Kα radiation.

9. The crystalline compound IL-arginine salt form A according to claim 8, further characterized by an X-ray powder diffraction pattern comprising one or more additional peaks, said additional peaks being represented by ±0.2 degrees 2θ selected from 13.8, 15.9, 16.5, 18.9, 20.9 and 22.8, as determined on a diffractometer using Cu-Kα radiation; an X-ray powder diffraction pattern substantially as shown in FIG1A; a broad endothermic DSC containing about 66.0 °C (peak) and about 35.8 °C (onset); or a DSC substantially as shown in FIG1B.

10. A crystalline 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one L-arginine salt form C(compound I) L-arginine salt form C), characterized by an X-ray powder diffraction pattern containing the following peaks, represented by ±0.2 degrees 2θ selected from 6.1, 7.4 and 10.3, as determined on a diffractometer using Cu-Kα radiation.

11. The crystalline compound IL-arginine salt form C according to claim 10, further characterized by an X-ray powder diffraction pattern containing one or more additional peaks, said additional peaks being represented by ±0.2 degrees 2θ selected from 10.8, 15.3, 15.5, 18.0, 20.6 and 22.8, as determined on a diffractometer using Cu-Kα radiation; an X-ray powder diffraction pattern substantially as shown in FIG3A; a DSC containing peaks at approximately 52.9 °C (peak) and approximately 232.9 °C (peak); or a DSC substantially as shown in FIG3B.

12. A crystalline 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound I, free acid form A), characterized by an X-ray powder diffraction pattern containing the following peaks, represented in ±0.2 degrees 2θ selected from 5.2, 6.1, and 12.4, as determined on a diffractometer using Cu-Kα radiation.

13. The free acid form A of the crystalline compound I according to claim 12, further characterized by an X-ray powder diffraction pattern containing one or more additional peaks, said additional peaks being represented by ±0.2 degrees 2θ selected from 15.0, 16.5, 16.9, 18.8, 20.2 and 21.9, as determined on a diffractometer using Cu-Kα radiation; an X-ray powder diffraction pattern substantially as shown in FIG4A; a DSC containing peaks at approximately 49.7 °C (peak) and approximately 211.3 °C (peak); or a DSC substantially as shown in FIG4B.

14. A crystalline 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound I in free acid form B), characterized by an X-ray powder diffraction pattern comprising the following peaks, represented in ±0.2 degrees 2θ selected from 7.8, 9.2, and 10.0, as determined on a diffractometer using Cu-Kα radiation.

15. The free acid form B of the crystalline compound I according to claim 14, further characterized by an X-ray powder diffraction pattern containing one or more additional peaks, said additional peaks being represented by ±0.2 degrees 2θ selected from 10.3, 13.0, 13.7, 16.5, 20.5, and 23.2, as determined on a diffractometer using Cu-Kα radiation; an X-ray powder diffraction pattern substantially as shown in FIG5A; a DSC containing peaks at approximately 32.4 °C (peak) and approximately 199.0 °C (peak); or a DSC substantially as shown in FIG5B.

16. A crystalline 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound I in free acid form C), characterized by an X-ray powder diffraction pattern comprising the following peaks, represented in ±0.2 degrees 2θ selected from 4.1, 8.1, and 10.4, as determined on a diffractometer using Cu-Kα radiation.

17. The free acid form C of the crystalline compound I according to claim 16, further characterized by an X-ray powder diffraction pattern containing one or more additional peaks, said additional peaks being represented by ±0.2 degrees 2θ selected from 13.5, 14.6, 15.0, 15.5, 15.8 and 20.8, as determined on a diffractometer using Cu-Kα radiation; essentially the X-ray powder diffraction pattern shown in FIG6A; DSC containing peaks at approximately 31.7 °C (peak), 134.9 °C (peak) and approximately 194.7 °C (peak); or essentially the DSC shown in FIG6B.

18. A crystalline 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound I in free acid form D), characterized by an X-ray powder diffraction pattern comprising the following peaks, represented in ±0.2 degrees 2θ selected from 6.5, 12.1, and 12.9, as determined on a diffractometer using Cu-Kα radiation.

19. The free acid form D of the crystalline compound I according to claim 18, further characterized by an X-ray powder diffraction pattern containing one or more additional peaks, said additional peaks being represented by ±0.2 degrees 2θ selected from 14.0, 16.5, 16.9, 17.5, 18.8 and 21.0, as determined on a diffractometer using Cu-Kα radiation; essentially the X-ray powder diffraction pattern shown in FIG7A; DSC containing peaks at about 36.1 °C (peak), about 133.7 °C (peak), about 198.1 °C (peak) and about 223.9 °C (peak); or essentially the DSC shown in FIG7B.

20. A crystalline 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound I in free acid form E), characterized by an X-ray powder diffraction pattern containing the following peaks, represented in ±0.2 degrees 2θ selected from 5.7, 11.1, and 16.1, as determined on a diffractometer using Cu-Kα radiation.

21. The free acid form E of the crystalline compound I according to claim 20, further characterized by an X-ray powder diffraction pattern containing one or more additional peaks, said additional peaks being represented by ±0.2 degrees 2θ selected from 17.1, 18.1, 18.7, 21.0, 21.3 and 21.6, as determined on a diffractometer using Cu-Kα radiation; an X-ray powder diffraction pattern substantially as shown in FIG8A; a DSC containing peaks at approximately 43.6 °C (peak) and approximately 223.9 °C (peak); or a DSC substantially as shown in FIG8B.

22. A crystalline 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound I in free acid form F), characterized by an X-ray powder diffraction pattern containing the following peaks, represented in ±0.2 degrees 2θ selected from 7.2, 12.9, and 14.6, as determined on a diffractometer using Cu-Kα radiation.

23. The free acid form F of the crystalline compound I according to claim 22, further characterized by an X-ray powder diffraction pattern containing one or more additional peaks, said additional peaks being represented by ±0.2 degrees 2θ selected from 16.1, 16.6, 17.5, 19.1, 19.9, and 21.8, as determined on a diffractometer using Cu-Kα radiation; an X-ray powder diffraction pattern substantially as shown in FIG9A; a DSC containing peaks at approximately 46.2 °C (peak), approximately 121.0 °C (peak), approximately 159.4 °C (peak), and approximately 230.4 °C (peak); or a DSC substantially as shown in FIG9B.

24. A crystalline 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound I in free acid form G), characterized by an X-ray powder diffraction pattern containing the following peaks, represented in ±0.2 degrees 2θ selected from 6.0, 11.9, and 14.8, as determined on a diffractometer using Cu-Kα radiation.

25. The free acid form G of the crystalline compound I according to claim 24, further characterized by an X-ray powder diffraction pattern containing one or more additional peaks, said additional peaks being represented by ±0.2 degrees 2θ selected from 16.3, 16.6, 18.4, 18.8, 21.3 and 23.9, as determined on a diffractometer using Cu-Kα radiation; an X-ray powder diffraction pattern substantially as shown in FIG10A; a DSC containing peaks at approximately 52.9 °C (peak) and approximately 208.7 °C (peak); or a DSC substantially as shown in FIG10B.

26. A crystalline 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound I in free acid form H), characterized by an X-ray powder diffraction pattern containing the following peaks, represented in ±0.2 degrees 2θ selected from 5.3, 5.5 and 7.6, as determined on a diffractometer using Cu-Kα radiation.

27. The free acid form H of the crystalline compound I according to claim 26, further characterized by an X-ray powder diffraction pattern containing one or more additional peaks, said additional peaks being represented by ±0.2 degrees 2θ selected from 11.0, 11.3, 11.9, 14.4, 16.5 and 18.1, as determined on a diffractometer using Cu-Kα radiation; an X-ray powder diffraction pattern substantially as shown in FIG11A; a DSC containing peaks at approximately 51.3 °C (peak), approximately 105.5 °C (peak) and approximately 217.2 °C (peak); or a DSC substantially as shown in FIG11B.

28. A crystalline 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound I in free acid form I), characterized by an X-ray powder diffraction pattern comprising the following peaks, represented in ±0.2 degrees 2θ selected from 4.0, 12.2, and 14.0, as determined on a diffractometer using Cu-Kα radiation.

29. The free acid form I of the crystalline compound I according to claim 28, further characterized by an X-ray powder diffraction pattern containing one or more additional peaks, said additional peaks being represented by ±0.2 degrees 2θ selected from 15.1, 15.8, 16.7, 18.4, 21.0 and 22.0, as determined on a diffractometer using Cu-Kα radiation; an X-ray powder diffraction pattern substantially as shown in FIG12A; a DSC containing peaks at approximately 41.5 °C (peak) and approximately 207.3 °C (peak); or a DSC substantially as shown in FIG12B.

30. A crystalline 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound I in free acid form J), characterized by an X-ray powder diffraction pattern containing the following peaks, represented in ±0.2 degrees 2θ selected from 6.8, 11.6, and 13.5, as determined on a diffractometer using Cu-Kα radiation.

31. The free acid form J of crystalline compound I according to claim 30, further characterized by an X-ray powder diffraction pattern containing one or more additional peaks, said additional peaks being represented by ±0.2 degrees 2θ selected from 14.0, 15.0, 17.0, 17.3, 17.9 and 19.7, as determined on a diffractometer using Cu-Kα radiation; essentially the X-ray powder diffraction pattern shown in Figure 13A; DSC containing peaks at about 68.6 °C (peak) and about 221.2 °C (peak); or essentially the DSC shown in Figure 13B.

32. A crystalline 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound I in free acid form K), characterized by an X-ray powder diffraction pattern containing the following peaks, represented in ±0.2 degrees 2θ selected from 8.7, 9.9, and 12.5, as determined on a diffractometer using Cu-Kα radiation.

33. The free acid form K of the crystalline compound I according to claim 32, further characterized by an X-ray powder diffraction pattern containing one or more additional peaks, said additional peaks being represented by ±0.2 degrees 2θ selected from 14.2, 15.8, 16.4, 19.6, 21.1 and 23.6, as determined on a diffractometer using Cu-Kα radiation; an X-ray powder diffraction pattern substantially as shown in FIG14A; a DSC containing peaks at approximately 46.1 °C (peak) and approximately 198.4 °C (peak); or a DSC substantially as shown in FIG14B.

34. A crystalline 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound I in free acid form N), characterized by an X-ray powder diffraction pattern comprising the following peaks, represented in ±0.2 degrees 2θ selected from 4.6, 6.3 and 7.2, as determined on a diffractometer using Cu-Kα radiation.

35. The free acid form N of the crystalline compound I according to claim 34, further characterized by an X-ray powder diffraction pattern containing one or more additional peaks, said additional peaks being represented by ±0.2 degrees 2θ selected from 9.2, 11.9, 16.1, 18.6, 20.4 and 21.0, as determined on a diffractometer using Cu-Kα radiation; essentially the X-ray powder diffraction pattern shown in Figure 17A; DSC containing peaks at about 68.6 °C (peak), about 81.0 °C (peak) and about 207.7 °C (peak); or essentially the DSC shown in Figure 17B.

36. A crystalline salt of 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound I) or a solvation thereof, having the formula IA: in: X is sodium and n is 1; X is potassium and n is 1; X is calcium and n is 2; or X is magnesium and n is 2.

37. The crystalline salt form according to claim 36, wherein the crystalline salt form is selected from: sodium salt form A of compound I, sodium salt form B of compound I, and potassium salt form A of compound I.

38. A pharmaceutical composition comprising the compound IL-arginine salt or a solvate thereof according to claim 1, the crystalline form of the compound I IL-arginine salt according to any one of claims 2-11, the crystalline compound I according to any one of claims 12-35 or the crystalline salt form according to claim 36 or 37, and a pharmaceutically acceptable excipient.

39. The pharmaceutical composition of claim 38, wherein at least 99% of compound I is the IL-arginine salt of claim 1 or a solvation thereof.

40. The pharmaceutical composition of claim 38, wherein at least 99% of compound I is the crystalline form of compound IL-arginine salt of claim 2 or a solvate thereof.

41. The pharmaceutical composition according to claim 38, wherein at least 99% of compound I is the crystalline form of compound IL-arginine salt B according to any one of claims 3-7.

42. The pharmaceutical composition of claim 38, wherein at least 99% of compound I is the crystalline form of compound IL-arginine salt A as claimed in claim 8 or 9.

43. The pharmaceutical composition of claim 38, wherein at least 99% of compound I is the crystalline form of compound IL-arginine salt C as claimed in claim 10 or 11.

44. The pharmaceutical composition according to claim 38, wherein at least 99% of compound I is crystalline compound I according to any one of claims 12-35.

45. The pharmaceutical composition of claim 38, wherein at least 99% of compound I is in the crystalline salt form of claim 36 or 37.

46. ​​A method for treating a disease, disorder, or condition, wherein modulation of inhibited or weakened and / or elevated or unwanted GLP-1R is beneficial to the treatment of the underlying pathology and / or symptoms and / or progression of said disease, disorder, or condition, said method comprising administering to a subject in need an effective amount of the pharmaceutical composition according to any one of claims 38-45.

47. The method of claim 46, wherein the disease, disorder, or condition is selected from type 1 diabetes, type 2 diabetes, early-onset type 2 diabetes, idiopathic type 1 diabetes (type 1b), juvenile-onset atypical diabetes (YOAD), adolescent-onset adult-onset diabetes (MODY), latent autoimmune diabetes in adults (LADA), obesity, weight gain due to the use of other medications, idiopathic intracranial hypertension, Wolfram syndrome, gout, excessive sugar consumption, hypertriglyceridemia, dyslipidemia, malnutrition-related diabetes, gestational diabetes, kidney disease, adipocyte dysfunction, sleep apnea, visceral fat deposition, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral artery disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, traumatic brain injury, peripheral vascular disease, endothelial cell dysfunction, impaired vascular compliance, restenosis, etc. Thrombosis, hypertension, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, hyperglycemia, postprandial lipemia, metabolic acidosis, ketoacidosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataracts, glomerulosclerosis. Arthritis, osteoporosis, addiction treatment, cocaine dependence, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulcers, psoriasis, essential polydipsia, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn's disease, short bowel syndrome, Parkinson's disease, Alzheimer's disease, cognitive impairment, schizophrenia, polycystic ovary syndrome (PCOS), or any combination thereof.

48. The method of claim 47, wherein the disease, disorder, or condition is type 2 diabetes.

49. A method of treating type 2 diabetes in a patient in need, the method comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition according to any one of claims 38-45.

50. A method for regulating insulin levels in a patient who requires such regulation, the method comprising administering to the patient an effective amount of the pharmaceutical composition according to any one of claims 38-45.

51. The method of claim 50, wherein the regulation results in an increase in insulin levels.

52. A method for regulating glucose levels in a patient who requires such regulation, the method comprising administering to the patient an effective amount of the pharmaceutical composition according to any one of claims 38-45.

53. The method of claim 52, wherein the regulation results in a decrease in glucose levels.

54. A method for preparing crystalline 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one L-arginine salt (compound I L-arginine salt), said method comprising contacting compound I with L-arginine in a solvent for a sufficient time to provide crystalline compound I L-arginine salt.

55. The method of claim 54, wherein the solvent is a mixture of IPA / H2O.

56. The method of claim 54, wherein the contact comprises adding 1.1 molar equivalents of L-arginine to compound I at a temperature of about 10°C to about 90°C.

57. The method of claim 54, wherein the contact further comprises adding about 2 wt% of seed crystals to the mixture of compound I and L-arginine.

58. The method of claim 54, wherein the contact further comprises adding additional IPA dropwise to the mixture of compound I and L-arginine and stirring at a temperature of about -10°C to about 15°C.

59. The method of claim 54, wherein the method further comprises separating the crystalline compound IL-arginine salt after the contact step.

60. The method of claim 59, wherein the separation comprises the following steps: The crystalline compound IL-arginine salt is filtered, washed, and dried.

61. The method according to any one of claims 54-60, wherein at least about 95% of the crystalline compound IL-arginine salt is form B.

Images