Salts and solid forms of compounds with 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 treating GLP-1-related diseases, disorders or conditions, such as type 2 diabetes mellitus (T2DM).

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of International Patent Application No. PCT / CN2022 / 139277, filed December 15, 2022, the contents of which are incorporated herein by reference in their entirety.

[0002] FIELD OF THE INVENTION FIELD OF THE DISCLOSURE This disclosure relates generally to salts and solid forms of GLP-1 agonists, pharmaceutical compositions and methods of use thereof. [Background technology]

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

[0004] The present disclosure provides salts and solid forms of Compound I (CAS Registry Number: 2685823-26-9), as well as co-crystals and solvates thereof. Also described herein are methods for making salts and solid forms of Compound I, pharmaceutical compositions containing salts or solid forms of Compound I, and methods of using same in the treatment of GLP-1-related diseases. [Brief explanation of the drawings]

[0005] [Figure 1A] FIG. 1A shows the X-ray powder diffraction (XRPD) of Form A of Compound I L-arginine salt.

[0006] [Figure 1B] FIG. 1B shows the differential scanning calorimetry (DSC) curve of Form A of Compound I L-arginine salt.

[0007] [Figure 1C]FIG. 1C shows a thermogravimetric analysis (TGA) plot of Form A of Compound I L-arginine salt.

[0008] [Figure 2A] FIG. 2A shows the XRPD of Form B of Compound I L-arginine salt.

[0009] [Figure 2B] FIG. 2B shows the DSC curve of Form B of Compound I L-arginine salt.

[0010] [Figure 2C] FIG. 2C shows the TGA plot of Form B of Compound I L-arginine salt.

[0011] [Figure 3A] FIG. 3A shows the XRPD of Form C of Compound I L-arginine salt.

[0012] [Figure 3B] FIG. 3B shows the DSC curve of Form C of Compound I L-arginine salt.

[0013] [Figure 3C] FIG. 3C shows a TGA plot of Form C of Compound I L-arginine salt.

[0014] [Figure 4A] FIG. 4A shows the XRPD of Form A of Compound I free acid.

[0015] [Figure 4B] FIG. 4B shows the DSC curve of Form A of Compound I free acid.

[0016] [Figure 4C] FIG. 4C shows a TGA plot of Form A of Compound I free acid.

[0017] [Figure 5A]FIG. 5A shows the XRPD of Form B of Compound I free acid.

[0018] [Figure 5B] FIG. 5B shows the DSC curve of Form B of Compound I free acid.

[0019] [Figure 5C] FIG. 5C shows a TGA plot of Form B of Compound I free acid.

[0020] [Figure 6A] FIG. 6A shows the XRPD of Form C of Compound I free acid.

[0021] [Figure 6B] FIG. 6B shows the DSC curve of Form C of Compound I free acid.

[0022] [Figure 6C] FIG. 6C shows a TGA plot of Form C of Compound I free acid.

[0023] [Figure 7A] FIG. 7A shows the XRPD of Form D of Compound I free acid.

[0024] [Figure 7B] FIG. 7B shows the DSC curve of Form D of Compound I free acid.

[0025] [Figure 7C] FIG. 7C shows the TGA plot of Form D of Compound I free acid.

[0026] [Figure 8A] FIG. 8A shows the XRPD of Form E of Compound I free acid.

[0027] [Figure 8B] FIG. 8B shows the DSC curve of Form E of Compound I free acid.

[0028] [Figure 8C] FIG. 8C shows the TGA plot of Form E of Compound I free acid.

[0029] [Figure 9A] FIG. 9A shows the XRPD of Form F of Compound I free acid.

[0030] [Figure 9B] FIG. 9B shows the DSC curve of Form F of Compound I free acid.

[0031] [Figure 9C] FIG. 9C shows the TGA plot of Form F of Compound I free acid.

[0032] [Figure 10A] FIG. 10A shows the XRPD of Form G of Compound I free acid.

[0033] [Figure 10B] FIG. 10B shows the DSC curve of Form G of Compound I free acid.

[0034] [Figure 10C] FIG. 10C shows the TGA plot of Form G of Compound I free acid.

[0035] [Figure 11A] FIG. 11A shows the XRPD of Form H of Compound I free acid.

[0036] [Figure 11B] FIG. 11B shows the DSC curve of Form H of Compound I free acid.

[0037] [Figure 11C] FIG. 11C shows the TGA plot of Form H of Compound I free acid.

[0038] [Figure 12A] FIG. 12A shows the XRPD of Form I of Compound I free acid.

[0039] [Figure 12B] FIG. 12B shows the DSC curve of Form I of Compound I free acid.

[0040] [Figure 12C] FIG. 12C shows the TGA plot of Form I of Compound I free acid.

[0041] [Figure 13A] FIG. 13A shows the XRPD of Form J of Compound I free acid.

[0042] [Figure 13B] FIG. 13B shows the DSC curve of Form J of Compound I free acid.

[0043] [Figure 13C] FIG. 13C shows the TGA plot of Form J of Compound I free acid.

[0044] [Figure 14A] FIG. 14A shows the XRPD of Form K of Compound I free acid.

[0045] [Figure 14B] FIG. 14B shows the DSC curve of Form K of Compound I free acid.

[0046] [Figure 14C] FIG. 14C shows the TGA plot of Form K of Compound I free acid.

[0047] [Figure 15A] FIG. 15A shows the XRPD of Form L of Compound I free acid.

[0048] [Figure 15B] FIG. 15B shows the DSC curve of Form L of Compound I free acid.

[0049] [Figure 15C] FIG. 15C shows the TGA plot of Form L of Compound I free acid.

[0050] [Figure 16A] FIG. 16A shows the XRPD of Form M of Compound I free acid.

[0051] [Figure 17A] FIG. 17A shows the XRPD of Form N of Compound I free acid.

[0052] [Figure 17B] FIG. 17B shows the DSC curve of Form N of Compound I free acid.

[0053] [Figure 17C] FIG. 17C shows the TGA plot of Form N of Compound I free acid.

[0054] [Figure 18A] FIG. 18A shows the XRPD of Form A of Compound I sodium salt.

[0055] [Figure 18B] FIG. 18B shows the DSC curve of Form A of Compound I sodium salt.

[0056] [Figure 18C] FIG. 18C shows the TGA plot of Form A of Compound I sodium salt.

[0057] [Figure 19A] FIG. 19A shows the XRPD of Form B of Compound I sodium salt.

[0058] [Figure 20A] FIG. 20A shows the XRPD of Form A of Compound I potassium salt.

[0059] [Figure 20B] FIG. 20B shows the DSC curve of Form A of Compound I potassium salt.

[0060] [Figure 20C] FIG. 20C shows the TGA plot of Form A of Compound I potassium salt. DETAILED DESCRIPTION OF THE INVENTION

[0061] The 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]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one, referred to herein as Compound I, has the formula: [ka] Compound I It has.

[0062] Compound I is a GLP-1 agonist, the synthesis and methods of use of which are described in PCT International Application Publication No. WO2021 / 155841, which is incorporated herein by reference in its entirety.

[0063] Without intending to be bound by any particular theory, certain solid forms are characterized by physical properties such as stability, solubility, and dissolution rate that make them suitable for pharmaceutical and therapeutic dosage forms. Furthermore, without wishing to be bound by any particular theory, certain solid forms are characterized by physical properties (e.g., density, compressibility, hardness, morphology, shear, adhesiveness, solubility, water absorption, electrical properties, thermal behavior, solid-state reactivity, physical stability, chemical stability) that affect certain processes (e.g., yield, filtration, washing, drying, milling, mixing, tableting, flowability, dissolution, formulation, lyophilization) that make certain solid forms suitable for manufacturing solid dosage forms. Such properties can be determined using certain analytical chemistry techniques, including the solid-state analytical techniques described herein (e.g., X-ray diffraction, microscopy, spectroscopy, and thermal analysis).

[0064] Identifying and selecting solid forms of pharmaceutical compounds is complex, given that changes in solid form can affect various physical and chemical properties, which can offer advantages or disadvantages in processing, formulation, stability, bioavailability, storage, and handling (e.g., transportation), among other important pharmaceutical characteristics. Useful pharmaceutical solids include crystalline and amorphous solids, depending on the product and its mode of administration. Amorphous solids are characterized by a lack of long-range structural order, while crystalline solids are characterized by structural periodicity. The desired class of pharmaceutical solid depends on the specific application; amorphous solids may be selected, for example, based on an improved dissolution profile, while crystalline solids may be desirable for properties such as physical or chemical stability.

[0065] Solid forms of pharmaceutical compounds, whether crystalline or amorphous, include single-component and multi-component solids. Single-component solids consist essentially of the pharmaceutical compound or active ingredient in the absence of other compounds. Variability among single-component crystalline materials can potentially arise from polymorphism, where multiple three-dimensional configurations exist for a particular pharmaceutical compound.

[0066] In particular, it is impossible to predict in advance whether crystalline forms of a compound will exist, much less whether they can be produced (e.g., Braga and Grepioni, 2005, "Making crystals from crystals: a green route to crystal engineering and polymorphism," Chem. Commun.:3635-3645 (with respect to crystal engineering, if the instructions are not very precise and / or if other external factors affect the process, the results can be unpredictable); Jones et al., 2006, "Pharmaceutical Cocrystals: An Emerging Approach to Physical Property Enhancement," MRS Bulletin 31:875-879 (currently, it is generally not possible to computationally predict the number of observable polymorphs, even for the simplest molecules); 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 (see: Much remains to be learned and done before we can demonstrate with any degree of confidence the ability to predict crystal structures, let alone polymorphic forms).

[0067] The various possible solid forms result in variability in the physical and chemical properties of a given pharmaceutical compound, and the discovery and selection of solid forms is crucial in the development of effective, stable, and marketable pharmaceutical products.

[0068] 1.Definition As used herein, the following words and phrases are generally intended to have the meanings set forth below, unless the context of their use dictates otherwise.

[0069] The term "comprise" and variations thereof, such as "comprises" and "comprising," are to be construed in an open and inclusive sense, i.e., "including, but not limited to." Furthermore, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, reference to "the compound" includes a plurality of such compounds, and reference to "the assay" includes reference to one or more assays and equivalents thereof known to those skilled in the art.

[0070] Reference herein to "about" a value or parameter includes (and describes) embodiments that are directed to that value or parameter itself. In certain embodiments, the term "about" includes the indicated amount ±10%. In other embodiments, the term "about" includes the indicated amount ±5%. In other specific embodiments, the term "about" includes the indicated amount ±2.5%. In other specific embodiments, the term "about" includes the indicated amount ±1%. Also, the term "about x" includes the description "x".

[0071] Recitation of numerical ranges of values ​​throughout this disclosure is intended to serve as a shorthand notation for referring individually to each separate value falling within the range, inclusive of the values ​​defining the range, and each separate value is incorporated herein as if individually listed herein.

[0072] Provided herein is a form of Compound I or its salt, cocrystal, solvate or hydrate. In one embodiment, a reference to a form of Compound I or its salt, cocrystal, solvate or hydrate 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 salt, cocrystal, solvate or hydrate present in the composition is in a given form. For example, in one embodiment, a reference to Form A of Compound I free acid 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 as a free acid is present in the composition as Form A.

[0073] The term "solid form" refers to a type of solid substance, including amorphous and crystalline forms. The term "crystalline form" refers to polymorphs as well as solvates, hydrates, etc. The term "polymorph" refers to a particular crystalline structure having particular physical properties such as X-ray diffraction, melting point, etc.

[0074] The term "cocrystal" refers to a molecular complex of a compound disclosed herein and one or more non-ionized co-crystal formers bound via non-covalent interactions. In some embodiments, the co-crystals disclosed herein can include a non-ionized form of compound I (e.g., a free form of compound I) and one or more non-ionized co-crystal formers, where the non-ionized compound I and the co-crystal formers are bound via non-covalent interactions. In some embodiments, the co-crystals disclosed herein can include an ionized form of compound I (e.g., a salt of compound I) and one or more non-ionized co-crystal formers, where the ionized compound I and the co-crystal formers are bound via non-covalent interactions. The co-crystals can also exist in anhydrous, solvated, or hydrated forms. In certain cases, the co-crystals can have improved properties compared to the parent form (i.e., the free molecule, the zwitterion, etc.) or the salt of the parent compound. The improved properties can be increased solubility, increased dissolution, increased bioavailability, increased dose response, decreased hygroscopicity, increased stability, crystalline forms of normally amorphous compounds, crystalline forms of difficult to salt or unsaltable compounds, reduced form diversity, more desirable forms, etc. Methods for making and characterizing cocrystals are known to those skilled in the art.

[0075] The term "co-crystal former" or "coformer" refers to one or more pharmaceutically acceptable bases or pharmaceutically acceptable acids disclosed herein in association with Compound I or any other compound disclosed herein.

[0076] The term "solvate" refers to a complex formed by the combination of solvent molecules with solute molecules or ions. The solvent can be an organic compound, an inorganic compound, or a mixture of both. As used herein, the term "solvate" includes "hydrates" (i.e., complexes formed by the combination of water molecules with solute molecules or ions), hemihydrates, channel hydrates, etc. The term "heterosolvate" refers to a complex containing 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 solvate, as described herein, in which the solvent molecules have been partially or completely removed. Desolvation techniques for producing desolvated forms include, but are not limited to, exposing the compound I form (solvate) to a vacuum, exposing the solvate to high temperatures, exposing the solvate to a gas stream (e.g., air or nitrogen), or any combination thereof. Thus, the desolvated compound I form may be anhydrous, i.e., completely free of solvent molecules, or partially solvated, in which the 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, may exhibit the physical properties of a solid or a liquid. Typically, such materials do not exhibit distinctive X-ray diffraction patterns and exhibit the properties of a solid, but are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs, which is typically characterized by a second-order change of state (glass transition).

[0079] Any formula or structure described herein, including Compound I, is also intended to represent unlabeled and isotopically labeled forms of the compound.It is understood that for any given atom, isotopes may be present essentially in the proportions according to their natural occurrence, or one or more specific atoms may be enriched with one or more isotopes using synthetic methods known to those skilled in the art.Thus, hydrogen may be, for example, 1 H, 2 H, 3 H; carbon, for example, 11 C. 12 C. 13 C. 14 C; oxygen, for example, 16 O. 17 O. 18 O; nitrogen, for example, 13 N, 14 N, 15 Examples of sulfur include: 32 S, 33 S, 34 S, 35 S, 36 S, 37 S, 38 S; fluorine, for example, 17 F, 18 F, 19 F; chlorine, for example, 35 Cl, 36 Cl, 37 Cl, 38 Cl, 39 Examples include Cl.

[0080] As used herein, the terms "treat," "treating," "therapy," "therapies," and similar terms refer to the administration of a substance, e.g., any one or more solid, crystalline, or polymorphic forms of Compound I described herein, in an amount effective to prevent, alleviate, or ameliorate one or more symptoms of a disease or condition, i.e., an indication, and / or prolong the survival of the subject being treated.

[0081] The term "administering" refers to oral administration, administration as a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, or implantation of a sustained-release device, such as a mini-osmotic pump, to a subject. Administration can be by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal or transdermal). Parenteral administration can include, for example, intravenous, intramuscular, intraarteriolar, intradermal, subcutaneous, intraperitoneal, intraventricular and intracranial. Other delivery modes include, but are not limited to, the use of liposome formulations, intravenous infusion, transdermal patches, etc.

[0082] As used herein, the terms "modulating" or "modulate" refer to the effect of changing a biological activity, particularly a biological activity associated with a particular biological molecule, such as GLP-1. For example, an agonist or antagonist of a particular biological molecule modulates the activity of GLP-1 by either increasing (e.g., agonist, activator) or decreasing (e.g., antagonist, inhibitor) the activity of the biological molecule. Such activity is typically measured in terms of the inhibitory concentration (IC) of the compound for an inhibitor or activator, respectively. 50 ) or excitatory concentration (EC 50 ) is shown.

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

[0084] As used herein, the term "subject" or "patient" refers to an organism that is treated with the compounds described herein, including, but not limited to, any mammal, such as humans, other primates, sports animals, animals of commercial interest such as cattle, farm animals such as horses, or pets such as dogs and cats.

[0085] The term "pharmaceutically acceptable" indicates that the indicated substance does not possess properties that would cause a reasonably prudent physician to avoid administering the substance to a patient, taking into account the disease or condition to be treated and the respective route of administration. For example, such substances are generally required to be essentially sterile, e.g., for injectable solutions.

[0086] As used herein, the term "therapeutically effective" or "effective amount" refers to a substance or amount of a substance that is effective to prevent, alleviate, or ameliorate one or more symptoms of a disease or medical condition and / or prolong the survival of the subject being treated. A therapeutically effective amount varies depending on the compound, the disorder or condition and its severity, and the age, weight, etc., of the mammal being treated. For example, an effective amount is an amount sufficient to achieve a beneficial or desired clinical result. An effective amount may be provided all at once in a single administration, or may be provided in divided amounts that provide an effective amount in several administrations. The precise determination of what is considered an effective amount can be based on factors individual to each subject, such as the subject's size, age, injury and / or disease or injury being treated, and the amount of time since the injury occurred or the disease began. One of ordinary skill in the art can determine the effective amount for a given subject based on these considerations, which are routine in the art.

[0087] In some embodiments, the phrase "substantially as shown in the figures" when applied to an X-ray powder diffraction pattern means including a variation of ±0.2°2θ or ±0.1°2θ, when applied to a DSC thermogram means including a variation of ±3°C, and when applied to a thermogravimetric analysis (TGA) means including a variation of ±2% in weight loss.

[0088] In some embodiments, a "substantially pure (polymorphic) form" means that, in the referenced substance, at least 99.9% of the material is the referenced polymorph. In some embodiments, a "substantially pure (polymorphic) form" means that, in the referenced substance, at least 99.5% of the material is the referenced polymorph. In some embodiments, a "substantially pure (polymorphic) form" means that, in the referenced substance, at least 99% of the material is the referenced polymorph. In some embodiments, a "substantially pure (polymorphic) form" means that, in the referenced substance, at least 98% of the material is the referenced polymorph. In some embodiments, a "substantially pure (polymorphic) form" means that, in the referenced substance, at least 97% of the material is the referenced polymorph. In some embodiments, a "substantially pure (polymorphic) form" means that, in the referenced substance, at least 96% of the material is the referenced polymorph. In some embodiments, a "substantially pure (polymorphic) form" means that, in the referenced substance, at least 95% of the material is the referenced polymorph. In the context of using, testing or screening compounds that are or may be modulators, the term "contacting" means bringing the compound into sufficient proximity with a particular molecule, complex, cell, tissue, organism or other particular substance that a potential binding interaction and / or chemical reaction between the compound and the other particular substance can occur.

[0089] 2. Salts and Forms of Compound I As generally described above, the disclosure provides salts and crystalline forms of the 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]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (hereinafter “Compound” or “Compound I”), and salts, co-crystals, solvates, or hydrates thereof. Crystalline forms of Compound I and its salts, co-crystals, solvates, or hydrates, and other forms (e.g., amorphous forms) of Compound I and its salts, co-crystals, solvates, or hydrates are collectively referred to herein as "forms of Compound I."

[0090] In some embodiments, Compound I is in a free form, for example, 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 a non-hydrate.

[0091] Salts of Compound I In one embodiment, a compound of formula IA: [ka] IA wherein X is sodium and n is 1; or X is potassium and n is 1. or a solvate thereof.

[0092] In one embodiment, a compound of formula IB: [ka] IB or a solvate thereof.

[0093] In one embodiment, there is provided an L-arginine salt of Compound I, or a solvate thereof. In one embodiment, there is provided a sodium salt of Compound I, or a solvate thereof. In one embodiment, there is provided a potassium salt of Compound I, or a solvate thereof.

[0094] In one embodiment, there is provided a crystalline salt 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]pyridine-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 solvate thereof.

[0095] In one embodiment, there is provided 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-oxadiazol-5(4H)-one sodium salt (Compound I sodium salt), or a solvate thereof. In one embodiment, there is provided 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-oxadiazol-5(4H)-one potassium salt (Compound I potassium salt), or a solvate thereof.

[0096] Forms of Compound I Compound I L-Arginine Salt Form A In one embodiment, 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-oxadiazol-5(4H)-one L-arginine salt Form A (Compound I), characterized by an X-ray powder diffraction pattern containing peaks expressed in ±0.2 degrees 2θ selected from 5.3, 9.1, and 11.5, as determined on a diffractometer using Cu-Kα radiation. Form A) of L-arginine salt is provided.

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

[0098] In some embodiments, Form A of the Compound I L-arginine salt is further characterized by an X-ray powder diffraction pattern substantially as shown in Figure 1A.

[0099] In some embodiments, Form A of the L-arginine salt of Compound I is further characterized by a DSC comprising an endotherm at about 66.0° C. (peak) and about 35.8° C. (onset). In some embodiments, Form A of the L-arginine salt of Compound I is further characterized by a DSC substantially as shown in FIG. 1B.

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

[0101] In some embodiments, Form A of Compound I L-arginine salt is further characterized by 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 Compound I free acid in Form A of the Compound I L-arginine salt is about 1.0. In some embodiments, Form A of the Compound I L-arginine salt is a solvate. In some embodiments, Form A of the Compound I L-arginine salt is a THF solvate. In some embodiments, Form A of the Compound I L-arginine salt is a THF-water heterosolvate. In some embodiments, the molar ratio of THF to Compound I in Form A of the Compound I L-arginine salt is 0.8 (5.0% by weight). In some embodiments, the molar ratio of water to Compound I in Form A of the Compound I L-arginine salt is 1.0 (1.9% by weight).

[0103] Compound I L-Arginine Salt Form B In one embodiment, 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-oxadiazol-5(4H)-one L-arginine salt Form B (Compound I), 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 B) of L-arginine salt is provided.

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

[0105] In some embodiments, Form B of the Compound I L-arginine salt is further characterized by an X-ray powder diffraction pattern substantially as shown in Figure 2A.

[0106] In some embodiments, Form B of the L-arginine salt of Compound I is further characterized by a DSC comprising an endotherm at about 17.6° C. (peak) and an endotherm at about 243.7° C. (peak). In some embodiments, Form B of the L-arginine salt of Compound I is further characterized by a DSC substantially as shown in FIG. 2B.

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

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

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

[0110] In some embodiments, Form B of the L-arginine salt of Compound I is a hydrate. In some embodiments, Form B of the L-arginine salt of Compound I is a channel hydrate.

[0111] Form B of Compound I L-arginine salt has been found to exhibit improved pharmacokinetic properties, eg, better exposure, than other forms.

[0112] Compound I L-Arginine Salt Form C In one embodiment, 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-oxadiazol-5(4H)-one L-arginine salt Form C (Compound I), 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 of an L-arginine salt is provided. Form C is a hydrate of Form B above.

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

[0114] In some embodiments, Form C of Compound I L-arginine salt is further characterized by an X-ray powder diffraction pattern substantially as shown in Figure 3A.

[0115] In some embodiments, Form C of Compound I L-arginine salt is further characterized by a DSC comprising two endotherms at about 52.9° C. (peak) and about 232.9° C. (peak). In some embodiments, Form C of Compound I L-arginine salt is further characterized by a DSC substantially as shown in FIG. 3B.

[0116] In some embodiments, Form C of the crystalline Compound I L-arginine salt is prepared by equilibrating Form A of the Compound I L-arginine salt in acetone at room temperature for two weeks. In some embodiments, Form C of the crystalline Compound I L-arginine salt is prepared by equilibrating Form A of the Compound I L-arginine salt in ACN at room temperature for two weeks. In some embodiments, Form C of the crystalline Compound I L-arginine salt is prepared by equilibrating Form A of the Compound I L-arginine salt in ethanol at 50°C for one week. In some embodiments, Form C of the crystalline Compound I L-arginine salt is prepared by equilibrating Form A of the Compound I L-arginine salt in acetone at 50°C for one week. In some embodiments, Form C of the crystalline Compound I L-arginine salt is prepared by equilibrating Form A of the Compound I L-arginine salt in ACN at 50°C for one week. In some embodiments, Form C of the crystalline Compound I L-arginine salt is prepared by equilibrating Form A of the Compound I L-arginine salt in ACN / water (1:1 v / v) at 50° C. for 1 week.

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

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

[0119] Initial polymorph screening failed to yield a suitable substantially crystalline form of Compound I. Subsequent polymorph screening is described below.

[0120] Compound I Free Acid Form A In one embodiment, there is provided 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-oxadiazol-5(4H)-one free acid Form A (Form A of Compound I free acid), characterized by an X-ray powder diffraction pattern containing peaks expressed in ±0.2 degrees two-theta selected from 5.2, 6.1, and 12.4, as determined on a diffractometer using Cu-Kα radiation.

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

[0122] In some embodiments, Form A of Compound I free acid is further characterized by an X-ray powder diffraction pattern substantially as shown in Figure 4A.

[0123] In some embodiments, Form A of Compound I free acid is further characterized by a DSC comprising two endotherms at about 49.7° C. (peak) and about 211.3° C. (peak). In some embodiments, Form A of crystalline Compound I free acid is further characterized by a DSC substantially as shown in FIG. 4B.

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

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

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

[0127] Compound I Free Acid Form B In one embodiment, there is provided 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-oxadiazol-5(4H)-one free acid Form B (Form B of Compound I free acid), characterized by an X-ray powder diffraction pattern containing 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, Form B of the free acid of Compound I is further characterized by an X-ray powder diffraction pattern containing one or more additional peaks expressed at ±0.2 degrees 2θ selected from 10.3, 13.0, 13.7, 16.5, 20.5, and 23.2, as determined by a diffractometer using Cu-Kα radiation.

[0129] In some embodiments, Form B of Compound I free acid is further characterized by an X-ray powder diffraction pattern substantially as shown in Figure 5A.

[0130] In some embodiments, Form B of Compound I free acid is further characterized by a DSC comprising two endotherms at about 32.4° C. (peak) and about 199.0° C. (peak). In some embodiments, Form B of crystalline Compound I free acid is further characterized by a DSC substantially as shown in FIG. 5B.

[0131] In some embodiments, Form B of Compound I free acid is obtained by equilibrating Form A of Compound I free acid in ACN at temperatures ranging from 5 to 50° C. for 10 cycles at a heating / cooling rate of 0.1° C. / min. In some embodiments, Form B of Compound I free acid is obtained by crystallization by slowly cooling a saturated solution of Form A of Compound I free acid in ACN, cooled to 50° C., to 5° C. at 0.1° C. / min.

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

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

[0134] Compound I free acid form C In one embodiment, there is provided 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-oxadiazol-5(4H)-one free acid Form C (Form C of Compound I free acid), characterized by an X-ray powder diffraction pattern containing peaks expressed in ±0.2 degrees two-theta selected from 4.1, 8.1, and 10.4, as determined on a diffractometer using Cu-Kα radiation.

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

[0136] In some embodiments, Form C of Compound I free acid is further characterized by an X-ray powder diffraction pattern substantially as shown in Figure 6A.

[0137] In some embodiments, Form C of Compound I free acid is further characterized by a DSC comprising three endotherms at about 31.7° C. (peak), about 134.9° C. (peak), and about 194.7° C. (peak). In some embodiments, Form C of crystalline Compound I free acid is further characterized by a DSC substantially as shown in FIG. 6B.

[0138] In some embodiments, Form C of Compound I free acid is obtained by equilibrating Form A of Compound I free acid in MTBE at room temperature for two weeks. In some embodiments, Form C of Compound I free acid is obtained by equilibrating Form A of Compound I free acid in MTBE at 50° C. for one week. In some embodiments, Form C of Compound I free acid is obtained by equilibrating Form A of Compound I free acid in MTBE at 5° C. for 10 cycles at a heating / cooling rate of 0.1° C. / min.

[0139] In some embodiments, Form C of Compound I free acid is further characterized by 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 Form C of Compound I free acid is 0.02 (0.2% by weight). In some embodiments, the molar ratio of water / Compound I free acid in Form C of Compound I free acid is 2.7 (5.1% by weight).

[0141] Compound I Free Acid Form D In one embodiment, there is provided 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-oxadiazol-5(4H)-one free acid Form D (Form D of Compound I free acid), characterized by an X-ray powder diffraction pattern containing peaks expressed in ±0.2 degrees two-theta selected from 6.5, 12.1, and 12.9, as determined on a diffractometer using Cu—Kα radiation.

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

[0143] In some embodiments, Form D of Compound I free acid is further characterized by an X-ray powder diffraction pattern substantially as shown in Figure 7A.

[0144] In some embodiments, Form D of Compound I free acid is further characterized by a DSC comprising three peaks at about 36.1° C., about 198.1° C., and about 223.9° C., and a broad exotherm at about 133.7° C. (peak). In some embodiments, Form D of crystalline Compound I free acid is further characterized by a DSC substantially as shown in FIG. 7B.

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

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

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

[0148] Compound I Free Acid Form E In one embodiment, there is provided 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-oxadiazol-5(4H)-one free acid Form E (Form E of Compound I free acid), characterized by an X-ray powder diffraction pattern containing peaks expressed in ±0.2 degrees two-theta selected from 5.7, 11.1, and 16.1, as determined on a diffractometer using Cu—Kα radiation.

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

[0150] In some embodiments, Form E of Compound I free acid is further characterized by an X-ray powder diffraction pattern substantially as shown in Figure 8A.

[0151] In some embodiments, Form E of Compound I free acid is further characterized by a DSC comprising two endotherms at about 43.6° C. (peak) and about 223.9° C. (peak). In some embodiments, Form E of crystalline Compound I free acid is further characterized by a DSC substantially as shown in FIG. 8B.

[0152] In some embodiments, Form E of Compound I free acid is obtained by equilibrating Form A of Compound I free acid in THF / water (9:1 v / v) at room temperature for two weeks. In some embodiments, Form E of Compound I free acid is obtained by equilibrating Form A of Compound I free acid in THF / water (9:1 v / v) at 50°C for one week. In some embodiments, Form E of Compound I free acid is obtained by equilibrating Form A of Compound I free acid in THF / water (9:1 v / v) at 5°C for 10 cycles at a heating / cooling rate of 0.1°C / min. In some embodiments, Form E of Compound I free acid is obtained by crystallization of Form A of Compound I free acid in 1,4-dioxane by the addition of an anti-solvent (water).

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

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

[0155] Compound I free acid form F In one embodiment, there is provided 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-oxadiazol-5(4H)-one free acid Form F (Form F of Compound I free acid), characterized by an X-ray powder diffraction pattern containing peaks expressed in ±0.2 degrees two-theta selected from 7.2, 12.9, and 14.6, as determined on a diffractometer using Cu-Kα radiation.

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

[0157] In some embodiments, Form F of Compound I free acid is further characterized by an X-ray powder diffraction pattern substantially as shown in Figure 9A.

[0158] In some embodiments, Form F of Compound I free acid is further characterized by a DSC comprising endotherms at about 46.2° C. (peak), about 121.0° C. (peak), about 159.4° C. (peak), and about 230.4° C. (peak). In some embodiments, crystalline Compound I free acid Form F is further characterized by a DSC substantially as shown in FIG. 9B.

[0159] In some embodiments, Form F of Compound I free acid is obtained by equilibrating Form A of Compound I free acid in ACN at room temperature for two weeks. In some embodiments, Form E of Compound I free acid is obtained by equilibrating Form F of Compound I free acid in ACN at 50° C. for one week. In some embodiments, Form F of Compound I free acid is obtained by crystallization by rapidly cooling a saturated solution of Form A of Compound I free acid in ACN to 5° C. after cooling to 50° C.

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

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

[0162] Compound I Free Acid Form G In one embodiment, there is provided 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-oxadiazol-5(4H)-one free acid Form G (Form G of Compound I free acid), characterized by an X-ray powder diffraction pattern containing peaks expressed in ±0.2 degrees two-theta selected from 6.0, 11.9, and 14.8, as determined on a diffractometer using Cu—Kα radiation.

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

[0164] In some embodiments, Form G of Compound I free acid is further characterized by an X-ray powder diffraction pattern substantially as shown in Figure 10A.

[0165] In some embodiments, Form G of Compound I free acid is further characterized by a DSC comprising two endotherms at about 52.9° C. (peak) and about 208.7° C. (peak). In some embodiments, Form G of crystalline Compound I free acid is further characterized by a DSC substantially as shown in FIG. 10B.

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

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

[0168] In some embodiments, Form G of Compound I free acid is a hydrate. In some embodiments, the molar ratio of water / Compound I free acid in Form G of Compound I free acid is 8.4 (14.1% by weight). In some embodiments, the molar ratio of DMSO / Compound I free acid in Form G of Compound I free acid is 0.1 (0.7% by weight).

[0169] Compound I free acid form H In one embodiment, there is provided 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-oxadiazol-5(4H)-one free acid Form H (Form H of Compound I free acid), characterized by an X-ray powder diffraction pattern containing peaks represented by ±0.2 degrees two-theta selected from 5.3, 5.5, and 7.6, as determined on a diffractometer using Cu-Kα radiation.

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

[0171] In some embodiments, Form H of Compound I free acid is further characterized by an X-ray powder diffraction pattern substantially as shown in Figure 11A.

[0172] In some embodiments, Form H of Compound I free acid is further characterized by a DSC comprising endotherms at about 51.3° C. (peak), about 105.5° C. (peak), and about 217.2° C. (peak). In some embodiments, crystalline Compound I free acid Form H is further characterized by a DSC substantially as shown in FIG. 11B.

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

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

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

[0176] Compound I Free Acid Form I In one embodiment, there is provided 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-oxadiazol-5(4H)-one free acid Form I (Compound I free acid Form I), characterized by an X-ray powder diffraction pattern containing peaks expressed 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, Form I of Compound I free acid is further characterized by an X-ray powder diffraction pattern containing one or more additional peaks expressed at ±0.2° 2θ selected from 15.1, 15.8, 16.7, 18.4, 21.0, and 22.0, as determined by a diffractometer using Cu-Kα radiation.

[0178] In some embodiments, Form I of Compound I free acid is further characterized by an X-ray powder diffraction pattern substantially as shown in Figure 12A.

[0179] In some embodiments, Form I of Compound I free acid is further characterized by a DSC comprising an endotherm at about 41.5° C. (peak) and an endotherm at about 207.3° C. (peak). In some embodiments, Form I of crystalline Compound I free acid is further characterized by a DSC substantially as shown in FIG. 12B.

[0180] In some embodiments, Form I of Compound I free acid is obtained by adding Form A of Compound I free acid to an anti-solvent (water) in 1,4-dioxane, followed by equilibration for 10 days.

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

[0182] Compound I free acid form J In one embodiment, there is provided 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-oxadiazol-5(4H)-one free acid Form J (Form J of Compound I free acid), characterized by an X-ray powder diffraction pattern containing peaks expressed in ±0.2 degrees two-theta selected from 6.8, 11.6, and 13.5, as determined on a diffractometer using Cu-Kα radiation.

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

[0184] In some embodiments, Form J of Compound I free acid is further characterized by an X-ray powder diffraction pattern substantially as shown in Figure 13A.

[0185] In some embodiments, Form J of Compound I free acid is further characterized by a DSC comprising an endotherm at about 68.6° C. (peak) and an endotherm at about 221.2° C. (peak). In some embodiments, crystalline Form J of Compound I free acid is further characterized by a DSC substantially as shown in FIG. 13B.

[0186] In some embodiments, Form J of Compound I free acid is obtained after storing Form D of Compound I free acid at ambient conditions (23-27° C., 50-70% RH) for 2 weeks.

[0187] In some embodiments, Form J of Compound I free acid is further characterized by TGA showing a weight loss of about 2.2% up to about 200°C.

[0188] Compound I free acid form K In one embodiment, there is provided 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-oxadiazol-5(4H)-one free acid Form K (Form K of Compound I free acid), characterized by an X-ray powder diffraction pattern containing peaks expressed in ±0.2 degrees two-theta selected from 8.7, 9.9, and 12.5, as determined on a diffractometer using Cu-Kα radiation.

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

[0190] In some embodiments, Form K of Compound I free acid is further characterized by an X-ray powder diffraction pattern substantially as shown in Figure 14A.

[0191] In some embodiments, Form K of Compound I free acid is further characterized by a DSC comprising an endotherm at about 46.1° C. (peak) and an endotherm at about 198.4° C. (peak). In some embodiments, crystalline Form K of Compound I free acid is further characterized by a DSC substantially as shown in FIG. 14B.

[0192] In some embodiments, Form K of Compound I free acid is obtained after storing Form B of Compound I free acid at ambient conditions (23-27° C., 50-70% RH) for 2 weeks.

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

[0194] Compound I free acid form L In one embodiment, there is provided 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-oxadiazol-5(4H)-one free acid Form L (Form L of Compound I free acid), characterized by an X-ray powder diffraction diagram substantially as shown in Figure 15A. Form L is a DMSO-water heterosolvate.

[0195] In some embodiments, Form L of Compound I free acid is further characterized by a DSC comprising an endotherm at about 120° C. (peak). In some embodiments, Form L of crystalline Compound I free acid is further characterized by a DSC substantially as shown in FIG. 15B.

[0196] In some embodiments, Form L of Compound I free acid exhibits a weight loss of about 7.9% at about 70° C. and a weight loss of about 7.4% from about 70° C. to about 200° C. In one embodiment, the form is substantially as shown in FIG. 15C. TGA plots are characterized.

[0197] Compound I free acid form M In one embodiment, there is provided 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-oxadiazol-5(4H)-one free acid Form M (Form M of Compound I free acid), characterized by an X-ray powder diffraction diagram substantially as shown in Figure 16A.

[0198] Compound I free acid form N In one embodiment, there is provided 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-oxadiazol-5(4H)-one free acid Form N (Form N of Compound I free acid), characterized by an X-ray powder diffraction pattern containing 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, Form N of Compound I free acid is further characterized by an X-ray powder diffraction pattern containing one or more additional peaks expressed at ±0.2 degrees 2θ selected from 9.2, 11.9, 16.1, 18.6, 20.4, and 21.0, as determined by a diffractometer using Cu-Kα radiation.

[0200] In some embodiments, Form N of Compound I free acid is further characterized by an X-ray powder diffraction pattern substantially as shown in Figure 17A.

[0201] In some embodiments, Form N of Compound I free acid is further characterized by a DSC comprising endotherms at about 68.6° C. (peak), about 81.0° C. (peak), and about 207.7° C. (peak). In some embodiments, crystalline Form N of Compound I free acid is further characterized by a DSC substantially as shown in FIG. 17B.

[0202] In some embodiments, Form N of the free acid of Compound I is obtained by equilibrating the free acid Form A in ACN / water (9:1 v / v) at room temperature for two weeks.

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

[0204] In some embodiments, Form N of Compound I free acid is a hydrate. In some embodiments, the molar ratio of water to Compound I free acid in Form N of Compound I free acid is 5.8 (10.3% by weight).

[0205] Compound I sodium salt form A In one embodiment, provided is 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-oxadiazol-5(4H)-one sodium salt Form A (Form A of Compound I sodium salt). In some embodiments, Form A of Compound I sodium salt is characterized by an X-ray powder diffraction diagram substantially as shown in FIG. 18A.

[0206] In some embodiments, Form A of Compound I sodium salt is further characterized by a DSC comprising an endotherm at about 124.8° C. (peak). In some embodiments, Form A of crystalline Compound I sodium salt is further characterized by a DSC substantially as shown in FIG. 18B.

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

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

[0209] In some embodiments, Form A of the crystalline Compound I sodium salt is a solvate. In some embodiments, Form A of the crystalline Compound I sodium salt is an acetone solvate. In some embodiments, Form A of the crystalline Compound I sodium salt is an acetone-water heterosolvate. In some embodiments, Form A of the sodium salt of Compound I has a molar ratio of acetone / Compound I free acid of 0.6 (3.8% by weight). In some embodiments, Form A of the sodium salt of Compound I has a molar ratio of water / Compound I free acid of 2.1 (4.0% by weight). In some embodiments, the molar ratio of sodium / Compound I free acid in Form A of the crystalline Compound I sodium salt is 1:1.

[0210] Compound I sodium salt form B In one embodiment, provided is 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-oxadiazol-5(4H)-one sodium salt Form B (Form B of Compound I sodium salt). In some embodiments, Form B of Compound I sodium salt is characterized by an X-ray powder diffraction diagram substantially as shown in FIG. 19A.

[0211] In some embodiments, Form B of Compound I sodium salt is obtained by slurrying Form A of Compound I free acid and equimolar 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 anti-solvent.

[0212] Compound I potassium salt form A In one embodiment, provided is 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-oxadiazol-5(4H)-one potassium salt Form A (Form A of Compound I potassium salt). In some embodiments, Form A of Compound I potassium salt is characterized by an X-ray powder diffraction diagram substantially as shown in FIG. 20A.

[0213] In some embodiments, Form A of Compound I potassium salt is further characterized by a DSC comprising endotherms at about 50.9° C. (peak), about 166.2° C. (peak), and about 237.7° C. (peak). In some embodiments, Form A of crystalline Compound I potassium salt is further characterized by a DSC substantially as shown in FIG. 20B.

[0214] In some embodiments, Form A of the potassium salt of Compound I is obtained by slurrying Form A of the free acid of Compound I and equimolar 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 anti-solvent (MTBE).

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

[0216] In some embodiments, Form A of the crystalline Compound I potassium salt is a solvate. In some embodiments, Form A of the crystalline Compound I potassium salt is an acetone solvate. In some embodiments, Form A of the crystalline Compound I potassium salt is an MTBE solvate. In some embodiments, Form A of the crystalline Compound I potassium salt is an acetone-MTBE heterosolvate. In some embodiments, Form A of the crystalline Compound I potassium salt has a molar ratio of acetone / Compound I free acid of 0.04 (0.3% by weight). In some embodiments, Form A of the Compound I potassium salt has a molar ratio of acetone / Compound I free acid of 0.45 (4.1% by weight). In some embodiments, the molar ratio of potassium / Compound I free acid in Form A of the crystalline Compound I sodium salt is 0.9:1.

[0217] composition In some embodiments, there is provided a composition 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]pyridine-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 solvate thereof, as described herein.

[0218] In one embodiment, 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, Provided are compositions comprising a salt or crystalline form of 4-oxadiazol-5(4H)-one (Compound I), or a salt or 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 the Compound I present in the composition is a given salt, crystalline form, or crystalline salt form.

[0219] In one embodiment, 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-oxadiazol-5(4H)-one L-arginine salt (Compound I The present invention provides a composition comprising Compound I L-arginine salt), 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 L-arginine salt.

[0220] In one embodiment, 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-oxadiazol-5(4H)-one L-arginine salt Form B (Compound I The present invention provides a composition comprising Compound I L-arginine salt 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 Compound I L-arginine salt Form B.

[0221] In one embodiment, 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-oxadiazol-5(4H)-one L-arginine salt Form A (Compound I The present invention provides a composition comprising Compound I L-arginine salt 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 Compound I L-arginine salt Form A.

[0222] In one embodiment, 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-oxadiazol-5(4H)-one L-arginine salt Form C (Compound I The present invention provides a composition comprising Compound I L-arginine salt Form C), 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 L-arginine salt Form C.

[0223] In one embodiment, 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 ... The present invention provides a composition comprising 2,4-oxadiazol-5(4H)-one free acid Form A (Form A of Compound I free acid), 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 the Compound I present in the composition is Form A of Compound I free acid.

[0224] In one embodiment, 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 ... The present invention provides a composition comprising 2,4-oxadiazol-5(4H)-one free acid Form B (Form B of Compound I free acid), 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 the Compound I present in the composition is Form B of Compound I free acid.

[0225] In one embodiment, 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 ... The present invention provides a composition comprising 2,4-oxadiazol-5(4H)-one free acid Form C (Form C of Compound I free acid), 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 the Compound I present in the composition is Form C of Compound I free acid.

[0226] In one embodiment, 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 ... The present invention provides a composition comprising 2,4-oxadiazol-5(4H)-one free acid Form D (Form D of Compound I free acid), 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 the Compound I present in the composition is Form D of Compound I free acid.

[0227] In one embodiment, 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 ... The present invention provides a composition comprising 2,4-oxadiazol-5(4H)-one free acid Form E (Form E of Compound I free acid), 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 Form E of Compound I free acid.

[0228] In one embodiment, 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 ... The present invention provides a composition comprising 2,4-oxadiazol-5(4H)-one free acid Form F (Form F of Compound I free acid), 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 Form F of Compound I free acid.

[0229] In one embodiment, 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 ... The present invention provides a composition comprising 2,4-oxadiazol-5(4H)-one free acid Form G (Form G of Compound I free acid), 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 the Compound I present in the composition is Form G of Compound I free acid.

[0230] In one embodiment, 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 ... The present invention provides a composition comprising 2,4-oxadiazol-5(4H)-one free acid Form H (Form H of Compound I free acid), 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 Form H of Compound I free acid.

[0231] In one embodiment, 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 ... The present invention provides a composition comprising, for example, 2,4-oxadiazol-5(4H)-one free acid Form 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 the Compound I present in the composition is Compound I free acid Form I.

[0232] In one embodiment, 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 ... The present invention provides a composition comprising 2,4-oxadiazol-5(4H)-one free acid Form J (Form J of Compound I free acid), 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 Form J of Compound I free acid.

[0233] In one embodiment, 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 ... The present invention provides a composition comprising 2,4-oxadiazol-5(4H)-one free acid Form K (Form K of Compound I free acid), 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 Form K of Compound I free acid.

[0234] In one embodiment, 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 ... The present invention provides a composition comprising 2,4-oxadiazol-5(4H)-one free acid Form L (Form L of Compound I free acid), 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 Form L of Compound I free acid.

[0235] In one embodiment, 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 ... The present invention provides a composition comprising 2,4-oxadiazol-5(4H)-one free acid Form N (Form N of Compound I free acid), 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 Form N of Compound I free acid.

[0236] In one embodiment, 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- Provided is a composition comprising oxadiazol-5(4H)-one sodium salt Form A (Form A of Compound I sodium salt), 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 Form A of Compound I sodium salt.

[0237] In one embodiment, 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- Provided is a composition comprising oxadiazol-5(4H)-one sodium salt Form B (Form B of Compound I sodium salt), 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 Form B of Compound I sodium salt.

[0238] In one embodiment, 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, Provided is a composition comprising 4-oxadiazol-5(4H)-one potassium salt Form A (Form A of the potassium salt 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 the Compound I present in the composition is Form A of the potassium salt of Compound I.

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

[0240] In some embodiments, provided is a method for producing 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-oxadiazol-5(4H)-one L-arginine salt (Compound I L-arginine salt), comprising contacting Compound I with L-arginine in a solvent for a sufficient time to obtain crystalline Compound I L-arginine salt.

[0241] In some embodiments, the solvent is a mixture of IPA / H 2 O. In some embodiments, the solvent is a mixture of IPA / H 2 O in a ratio of 7:3 v / v.

[0242] In some embodiments, the contacting comprises adding 1.1 molar equivalents of L-arginine to Compound I. In some embodiments, the contacting comprises 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 contacting comprises 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 contacting comprises 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 contacting further comprises adding about 2% by weight of seed crystals to the mixture of Compound I and L-arginine.

[0244] In some embodiments, the contacting further comprises adding additional IPA dropwise to the mixture of Compound I and L-arginine. In some embodiments, the contacting further comprises 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 contacting further comprises stirring at a temperature of about −10° C. to about 15° C. after the addition of 10 to 20 molar equivalents. In some embodiments, the contacting further comprises stirring at a temperature of about −0° C. to about 5° C. after the addition of 10 to 20 molar equivalents. In some embodiments, the contacting further comprises stirring at a temperature of about −0° C. to about 5° C. after the addition of 10 to 20 molar equivalents.

[0246] In some embodiments, the contacting 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 contacting 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 comprises isolating the crystalline Compound I L-arginine salt after the contacting step.

[0248] In some embodiments, the isolating comprises filtering, washing, and drying the crystalline Compound I L-arginine salt.

[0249] In some embodiments, methods for producing crystalline Compound I L-arginine salt, wherein at least about 95% of the crystalline Compound I L-arginine salt is Form B, are provided.

[0250] In some embodiments, methods for producing crystalline Compound I L-arginine salt are provided, wherein at least about 95% of the crystalline Compound I L-arginine salt is Form A.

[0251] In some embodiments, methods for producing crystalline Compound I L-arginine salt are provided, wherein at least about 95% of the crystalline Compound I L-arginine salt is Form C.

[0252] In some embodiments, 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]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one sodium salt (Compound I sodium salt) is provided, comprising contacting Compound I with sodium hydroxide in a solvent for a sufficient time to obtain crystalline Compound I sodium salt.

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

[0254] In some embodiments, the contacting comprises adding an equimolar amount of sodium hydroxide to Compound I. In some embodiments, the contacting comprises 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 contacting comprises 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 comprises isolating the crystalline Compound I sodium salt after the contacting step.

[0256] In some embodiments, the isolating comprises centrifuging and drying the crystalline Compound I sodium salt.

[0257] In some embodiments, a method for producing crystalline Compound I L-arginine salt is provided, wherein at least about 95% of the crystalline Compound I sodium salt is Form A.

[0258] Pharmaceutical Compositions and Administration In some embodiments, a chemical entity that modulates (e.g., agonizes) GLP-1 activity (e.g., 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]pyridine-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 solvate thereof, as described herein) is administered as a pharmaceutical composition comprising the chemical entity and one or more pharmaceutically acceptable excipients, and optionally one or more additional therapeutic agents as described herein.

[0259] In some embodiments, chemical substance can be administered in combination with one or more conventional pharmaceutical additives.Pharmaceutically acceptable additives include but are not limited to ion exchanger, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery system (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 matrix, serum protein, such as human serum albumin, buffer substances, such as phosphate, Tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixture of saturated vegetable fatty acids, water, salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substance, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene block polymer and wool fat. Cyclodextrins, such as α-, β-, and γ-cyclodextrin, or chemically modified derivatives, such as hydroxyalkylcyclodextrins, e.g., 2- and 3-hydroxypropyl-β-cyclodextrin, or other solubilizing derivatives, may also be used to enhance delivery of the compounds described herein. Forms or compositions may be prepared containing 0.005% to 100% of the chemicals described herein, with the remainder consisting of non-toxic additives. Contemplated compositions may contain 0.001% to 100% of the chemicals provided herein, and in one embodiment, 0.1 to 95%, in another embodiment, 75 to 85%, and in a further embodiment, 20 to 80%. Actual methods for preparing such dosage forms are known or apparent to those skilled in the art. See, for example, Remington: The Science and Practice of Pharmacy, 22 nd Edition (Pharmaceutical Press, London, UK. 2012).

[0260] Route of administration and composition In some embodiments, the chemical entities described herein or pharmaceutical compositions thereof may be administered to a subject in need thereof by any acceptable route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, intracervical, intranasal, intratracheal, enteral, epidural, intrainterstitial, intraperitoneal, intra-arterial, intrabronchial, intrasynovial, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinus, intraspinal, intraspinal, intrasynovial, intratesticular, intrathecal, intraductal, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, transdermal, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral, ​​and vaginal.

[0261] The composition can be formulated for parenteral administration, for example, it can be formulated for injection by intravenous, intramuscular, subcutaneous or intraperitoneal route.Typically, such compositions can be prepared as injections either as liquid solutions or suspensions, and solid forms suitable for preparing solutions or suspensions by adding liquid before injection can also be prepared, and the preparation can also be emulsified.The preparation of such preparations is known to those skilled in the art in light of the present disclosure.

[0262] The pharmaceutical forms suitable for injection include sterile aqueous solution or dispersion; formulations containing sesame oil, peanut oil or aqueous propylene glycol; and sterile powder for the immediate preparation of sterile injectable solution or dispersion.Generally, the form must be sterile and fluid enough to be easily squirted.It should also be stable under the conditions of manufacture and storage, and must be protected against the contaminating action of microorganisms, such as bacteria and fungi.

[0263] The carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, etc.), suitable mixtures thereof, and vegetable oils. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Prevention of microbial action can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it is preferable to include an isotonic agent, for example, sugar or sodium chloride. Prolonged absorption of injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0264] Sterile injectable solution is prepared by incorporating the required amount of active compound into suitable solvent with various other components as listed above as necessary, and then filtration sterilization.Generally, dispersion is prepared by incorporating various sterile active components into a sterile vehicle that contains basic dispersion medium and other components as listed above that are required.For the sterile powder that is used to prepare sterile injectable solution, the preferred preparation method is vacuum drying and freeze-drying technology, which obtains the powder of active component and any other desired component from its previously sterile filtered solution.

[0265] Pharmaceutically acceptable excipients that can be used in rectal compositions as gels, creams, enemas, or rectal suppositories include cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (e.g., PEG ointment), glycerin, glycerinated gelatin, hydrogenated vegetable oils, poloxamer, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol, petrolatum, anhydrous lanolin, shark liver oil, sodium saccharinate, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxide SBN, vanilla essential oil, parabens in aerosols, phenoxyethanol, These include, but are not limited to, one or more of sodium methylparaben, sodium propylparaben, diethylamine, carbomer, carbopol, methylparaben, macrogol cetostearyl ether, cocoyl caprylocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxymetabisulfite, edetate sodium, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methylsulfonylmethane (MSM), lactic acid, glycine, vitamins such as vitamins A and E, and potassium acetate.

[0266] In certain embodiments, suppositories can be prepared by mixing the chemical compounds described herein with suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol, or a suppository wax, which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum to release the active compound. In other embodiments, the composition for rectal administration is in the form of an enema.

[0267] In other embodiments, the compounds described herein or pharmaceutical compositions thereof are suitable for local delivery to the digestive or GI tract by oral administration (eg, in solid or liquid dosage form).

[0268] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the chemical entity is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate, and / or: a) fillers or fillers, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants, such as glycerol; d) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarders, such as paraffin; f) absorption accelerators, such as quaternary ammonium compounds; g) wetting agents, such as cetyl alcohol and glycerol monostearate; h) absorbents, such as kaolin and bentonite clay; and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols.

[0269] In one embodiment, the composition is in the form of a unit dosage form, for example, a pill or tablet. Thus, the composition may contain, together with the chemical compound provided herein, a diluent such as lactose, sucrose, dicalcium phosphate, etc.; a lubricant such as magnesium stearate, etc.; and a binder such as starch, acacia gum, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives, etc. In another solid dosage form, a powder, quince, solution, or suspension (e.g., in propylene carbonate, vegetable oil, PEG, poloxamer 124, or triglycerides) is encapsulated in a capsule (gelatin or cellulose-based capsule). Unit dosage forms in which one or more chemical compounds provided herein or additional active agents are physically separated are also contemplated; for example, a capsule (or tablet in a capsule) containing granules of each drug; a two-layer tablet; a two-compartment gel cap, etc. Enteric-coated or sustained-release oral dosage forms are also contemplated.

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

[0271] In certain embodiments, the additive is sterile and generally does not contain undesirable substances.These compositions can be sterilized by conventional and well-known aseptic techniques.The additives for various oral dosage forms, such as tablets and capsules, do not require sterility.USP / NF standards are usually sufficient.

[0272] Ophthalmic compositions may include, but are not limited to, one or more of the following: viscosity enhancers (e.g., carboxymethylcellulose, glycerin, polyvinylpyrrolidone, polyethylene glycol), stabilizers (e.g., Pluronic (triblock copolymers), cyclodextrin), preservatives (e.g., benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloro complex; Allergan, Inc.).

[0273] Topical compositions can include ointments and creams. Ointments are typically semi-solid formulations based on petrolatum or other petroleum derivatives. Creams containing selected active ingredients are typically viscous liquids or semi-solid emulsions, often either oil-in-water or water-in-oil. Cream bases are typically water-washable and contain an oil phase, an emulsifier, and an aqueous phase. The oil phase, also known as the "internal" phase, is generally composed of petrolatum and a fatty alcohol, such as cetyl or stearyl alcohol; the aqueous phase is usually, but not always, larger in volume than the oil phase and generally contains a humectant. Emulsifiers in cream formulations are generally nonionic, anionic, cationic, or amphoteric surfactants. Like other carriers or vehicles, ointment bases must be inert, stable, non-irritating, and non-sensitizing.

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

[0275] Dosage Dosage can vary depending on the patient's requirements, the severity of the condition being treated, and the specific compound being used.The dosage that is appropriate for a specific situation can be determined by those skilled in the medical field.In some cases, the total daily dosage can be divided and administered in portions throughout the day or by means of providing continuous delivery.

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

[0277] Regimen The dosages may be administered daily (e.g., as a single dose or as two or more divided doses) or non-daily (e.g., every other day, every third day, every third day, weekly, twice weekly, biweekly, monthly).

[0278] In some embodiments, the administration 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 more. In further embodiments, the period of time during which administration is suspended 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 more. In one embodiment, a therapeutic compound is administered to an individual for one period of time followed by another period of time. In another embodiment, a therapeutic compound is administered for a first period of time and a second period of time following the first period, administration is suspended during the second period of time, followed by administration of the therapeutic compound for a third period of time, and then administration is suspended for a fourth period of time following the third period of time. In one aspect of this embodiment, the period of administration of a therapeutic compound followed by a period of time during which administration is suspended is repeated for a fixed or indefinite period of time. In further embodiments, the administration 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 more. In further embodiments, the period of time for which administration is discontinued 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 more.

[0279] Treatment method The present disclosure features a method for treating a subject (e.g., a human) with a disease, disorder, or condition in which modulation of GLP-1R (e.g., suppressed or impaired and / or elevated or undesired GLP-1R) is beneficial for treating the underlying pathology and / or symptoms and / or progression of the disease, disorder, or condition. In certain embodiments, a method for treating a subject with a disease, disorder, or condition mediated at least in part by GLP-1 is provided, comprising administering to the subject a compound described herein, for example, Form A, B, or C of Compound I L-arginine salt. In certain embodiments, the methods described herein may comprise, or may further comprise, treating one or more conditions associated with, coexisting with, or secondary to any one or more of the conditions described herein.

[0280] In some embodiments, the compounds and pharmaceutical compositions and methods for treating patients described herein can be administered to a patient in need thereof by administering the solid form of Compound I described herein to induce one or more of the following: lowering blood glucose levels (e.g., lowering blood glucose levels), lowering blood hemoglobin A1c (HbA1c) levels, promoting insulin synthesis, stimulating insulin secretion, increasing β-cell mass, regulating gastric acid secretion, regulating gastric emptying, reducing body mass index (BMI), and / or reducing glucagon production (e.g., level).In some embodiments, the compounds and pharmaceutical compositions and methods for treating patients described herein can lower blood glucose levels, lower blood hemoglobin A1c (HbA1c) levels, promote insulin synthesis, stimulate insulin secretion, increase β-cell mass, regulate gastric acid secretion, regulate gastric emptying, reduce body mass index (BMI), reduce glucagon production (e.g., level), or any combination thereof. In certain embodiments, the compound and pharmaceutical compositions and methods for treating patients described herein stabilize serum glucose and serum insulin levels (for example, serum glucose and serum insulin concentration).Also provided is a method for adjusting glucose or insulin levels in patients who need adjustment, said method comprising administering to patients an effective amount of compound I disclosed herein, or its pharmaceutically acceptable salt or solvate, or pharmaceutical composition.

[0281] In some embodiments, provided herein is a method for reducing the risk of major adverse cardiovascular events (MACE) in a patient in need thereof (e.g., by about at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80%), the method comprising administering to the patient an effective amount of Compound I or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition described herein. In some of these embodiments, the patient is an adult diagnosed with type 2 diabetes (T2D). In certain embodiments, the patient is an adult diagnosed with heart disease. In certain embodiments, the patient is an adult diagnosed with type 2 diabetes (T2D) and heart disease. In certain embodiments, the patient is an adult with type 2 diabetes (T2D). In certain embodiments, the patient is an adult with heart disease. In certain embodiments, the patient has type 2 diabetes (T2D) and heart disease.

[0282] In some embodiments, the methods described herein further comprise identifying a patient (e.g., a subject) in need of such treatment (e.g., by blood assay, body mass index, or other conventional methods known in the art).

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

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

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

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

[0287] In some embodiments, determining whether the patient has type 2 diabetes further comprises determining the patient's BMI. In some embodiments, the patient's BMI is about 22 kg / m 2 More than ~ about 100kg / m 2 In some embodiments, the patient's BMI is about 30 kg / m or greater. 2 More than ~90kg / m 2 In some embodiments, the patient's BMI is about 40 kg / m 2 More than ~about 80kg / m 2 In some embodiments, the patient's BMI is about 50 kg / m or greater. 2 More than ~ about 70kg / m 2 That's all.

[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 ethnicity. In some embodiments, the patient is about 10 years or older. In some embodiments, the patient is about 15 years or older. In some embodiments, the patient is about 20 years or older. In some embodiments, the patient is about 25 years or older. In some embodiments, the patient is about 30 years or older. In some embodiments, the patient is about 35 years or older. In some embodiments, the patient is about 40 years or older. In some embodiments, the patient is about 42 years or older. In some embodiments, the patient is about 44 years or older. In some embodiments, the patient is about 46 years or older. In some embodiments, the patient is about 48 years or older. In some embodiments, the patient is about 50 years or older. In some embodiments, the patient is about 52 years or older. In some embodiments, the patient is about 54 years or older. In some embodiments, the patient is about 56 years or older. In some embodiments, the patient is about 58 years or older. In some embodiments, the patient is about 60 years of age or older. In some embodiments, the patient is about 62 years of age or older. In some embodiments, the patient is about 64 years of age or older. In some embodiments, the patient is about 66 years of age or older. In some embodiments, the patient is about 68 years of age or older. In some embodiments, the patient is about 70 years of age or older. In some embodiments, the patient is about 72 years of age or older. In some embodiments, the patient is about 74 years of age or older. In some embodiments, the patient is about 76 years of age or older. In some embodiments, the patient is about 78 years of age or older. In some embodiments, the patient is about 80 years of age or older. In some embodiments, the patient is about 85 years of age or older. In some embodiments, the patient is about 90 years of age or older.In some embodiments, the patient's age is about 95 years or older. In some embodiments, the patient's ethnicity can be African American, American Indian or Alaska Native, Asian American, Hispanic or Latino, or Native Hawaiian, or Pacific Islander.

[0289] In some embodiments, the patient is a pediatric patient.As used herein, the term "pediatric patient" refers to patients who are under 21 years old at the time of diagnosis or treatment.The term "child" can be further divided into various subgroups, including neonates (birth to 1 month old); infants (1 month to 2 years old); children (2 to 12 years old); and adolescents (12 to 21 years old (up to but not including their 22nd birthday)).Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: WB Saunders Company, 1996; Rudolph AM, et al. Rudolph's Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994. In some embodiments, the pediatric patient is from birth to 28 days of age, from 29 days to less than 2 years of age, from 2 years to less than 12 years of age, or from 12 years to 21 years of age (up to, but not including, the 22nd birthday). In some embodiments, the pediatric patient is from birth to 28 days of age, from 29 days to less than 1 year of age, from 1 month to less than 4 months of age, from 3 months to less than 7 months of age, from 6 months to less than 1 year of age, from 1 year to less than 2 years of age, from 2 years to less than 3 years of age, from 2 years to less than 7 years of age, from 3 years to less than 5 years of age, from 5 years to less than 10 years of age, from 6 years to less than 13 years of age, from 10 years to less than 15 years of age, or from 15 years to less than 22 years of age. In some embodiments, the patient is an adult patient.

[0290] Indications obesity In some embodiments, the condition, disease or disorder is obesity and the condition, disease or disorder associated with or related to 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 abdominal adiposity).Non-limiting examples of symptomatic obesity include endocrine obesity (e.g., Cushing's syndrome, hypothyroidism, insulinoma, obesity type II diabetes, pseudohypoparathyroidism, hypogonadism), hypothalamic obesity, genetic obesity (e.g., Prader-Willi syndrome, Laurence-Moon-Biedl syndrome), and drug-induced obesity (e.g., steroid-, phenothiazine-, insulin-, sulfonylurea-, or beta-blocker-induced obesity).

[0291] In some embodiments, the condition, disease or disorder is related to obesity.Examples of such condition, disease or disorder include but are not limited to glucose intolerance, diabetes (for example, type 2 diabetes, obesity diabetes), dyslipidemia, hyperlipidemia, hypertension, heart failure, hyperuricemia, gout, fatty liver (including non-alcoholic steatohepatitis (NASH)), coronary heart disease (for example, myocardial infarction, angina pectoris), cerebral infarction (for example, cerebral thrombosis, transient ischemic attack), bone or joint disease (for example, knee osteoarthritis, hip osteoarthritis, spondylosis, lower back pain), sleep apnea syndrome, obesity hypoventilation syndrome (Pickwickian syndrome), menstrual disorders (for example, menstrual cycle abnormality, menstrual volume and cycle abnormality, amenorrhea, menstrual symptom abnormality), visceral obesity syndrome, urinary incontinence and metabolic syndrome.In some embodiments, the compounds and pharmaceutical compositions described herein can be used to treat patients who show both symptoms of obesity and insulin deficiency.

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

[0293] In some embodiments, the condition, disease or disorder is related to diabetes (for example, diabetic complications).Non-limiting examples of the disease related to diabetes include obesity, obesity-related disease, metabolic syndrome, neuropathy, nephropathy (for example, diabetic nephropathy), retinopathy, diabetic cardiomyopathy, cataract, macroangiopathy, osteopenia, hyperosmolar diabetic coma, infectious diseases (for example, respiratory infection, urinary tract infection, gastrointestinal infection, skin and soft tissue infection, lower limb infection), diabetic gangrene, xerostomia, hearing impairment, cerebrovascular disease, diabetic cachexia, delayed wound healing, diabetic dyslipidemia, peripheral blood circulation disorder, cardiovascular risk factors (for example, coronary artery disease, peripheral artery disease, cerebrovascular disease, hypertension and uncontrolled cholesterol and / or lipid level and / or inflammation-related risk factors), NASH, fracture, cognitive dysfunction.

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

[0295] In some embodiments, the condition, disease, or disorder is diabetes and obesity (diabetic obesity). In some embodiments, the compounds described herein are useful for improving the therapeutic effect of metformin.

[0296] Disorders of metabolically important tissues In some embodiments, the condition, disease, or disorder is a disorder of a metabolically important tissue. Non-limiting examples of metabolically important tissues include the liver, adipose tissue, pancreas, kidney, and intestine.

[0297] In some embodiments, the condition, disease or disorder is fatty liver disease.Fatty liver disease includes but is not limited to non-alcoholic fatty acid 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, abetalipoproteinemia, hyperlipoproteinemia, glycogen storage disease, Weber-Christian disease, Wolman disease, acute fatty liver of pregnancy and lipodystrophy.

[0298] Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of disorders occurring in the absence of alcohol abuse and is typically characterized by the presence of steatosis (fat in the liver). NAFLD is thought to be associated with various conditions, including metabolic syndrome (including obesity, diabetes, and hypertriglyceridemia) and insulin resistance. It can lead to liver disease in adults and children, ultimately resulting in cirrhosis (Skelly et al., J Hepatol 2001; 35: 195-9; Chitturi et al., Hepatology 2002; 35(2):373-9). NAFLD ranges in severity from the relatively benign isolated macrovesicular steatosis (also known as nonalcoholic fatty liver or NAFL) to nonalcoholic steatohepatitis (NASH) (Angulo et al., J Gastroenterol Hepatol 2002; 17 Suppl:S186-90).

[0299] Other non-limiting examples of disorders in metabolically important tissues include joint disorders (e.g., osteoarthritis, secondary osteoarthritis), fatty liver (e.g., liver); fibrosis (e.g., liver); cirrhosis (e.g., liver); gallstones; gallbladder disorders; gastroesophageal reflux disease; sleep apnea; hepatitis; fatty liver; bone diseases characterized by altered bone metabolism, such as osteoporosis, e.g., postmenopausal osteoporosis, decreased bone strength, osteopenia, Paget's disease, osteolytic metastases in cancer patients, bone disease in liver disease, and the like. Dystrophies and bone metabolism changes due to renal failure or hemodialysis, fractures, bone surgery, aging, pregnancy, protection against fractures, and nutritional disorders include polycystic ovary syndrome; renal disease (for example, 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, frailty, sexual dysfunction (for example, erectile dysfunction) and geriatric syndrome.In some embodiments, the compounds and pharmaceutical compositions described herein can be used to treat surgical trauma by improving postoperative recovery and / or preventing the catabolic response caused by surgical trauma.

[0300] Cardiovascular and vascular diseases In some embodiments, the condition, disease or disorder is cardiovascular disease.Non-limiting examples of cardiovascular disease include congestive heart failure, atherosclerosis, arteriosclerosis, coronary heart disease, coronary artery disease, congestive heart failure, coronary heart disease, hypertension, heart failure, cerebrovascular disease (for example, cerebral infarction), vascular dysfunction, myocardial infarction, elevated blood pressure (for example, 130 / 85 mmHg or more) and prothrombotic state (exemplified by high fibrinogen or plasminogen activator inhibitor in blood).

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

[0302] Neurological disorders In some embodiments, the condition, disease or disorder is a neurological disorder (e.g., neurodegenerative disease) or psychiatric disorder.Non-limiting examples of neurological disorders include idiopathic intracranial hypertension (IIH), brain insulin resistance, mild cognitive impairment (MCI), Alzheimer's disease (AD), Parkinson's disease (PD), anxiety, dementia (e.g., senile dementia), traumatic brain injury, Huntington's disease, tardive dyskinesia, hyperactivity disorder, mania, Parkinson's disease, Steele-Richard syndrome, Down syndrome, myasthenia gravis, neurotrauma, brain trauma, vascular amyloidosis, cerebral hemorrhage with amyloidosis type I, encephalitis, Friedrich ataxia, acute confusion disorder, amyotrophic lateral sclerosis (ALS), glaucoma, and apoptosis-mediated degenerative diseases of the central nervous system (e.g., Creutzfeldt-Jakob disease, bovine spongiform encephalopathy (mad cow disease) and chronic wasting syndrome). See, for example, US Patent 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, e.g., Virdee et al. Ophthalmol Ther. 2020; 9(4):767-781. In some embodiments, the compounds, pharmaceutical compositions, and methods described herein reduce cerebrospinal fluid secretion in patients with idiopathic intracranial hypertension. In some embodiments, the compounds, pharmaceutical compositions, and methods described herein reduce intracranial pressure in patients with idiopathic intracranial hypertension. In some embodiments, the compounds, pharmaceutical compositions, and methods described herein alleviate one or more symptoms in patients with idiopathic intracranial hypertension. Symptoms of idiopathic intracranial hypertension may include severe headaches and visual impairment. In some embodiments, the patient with idiopathic intracranial hypertension is female. In some embodiments, the patient with idiopathic intracranial hypertension is between about 20 and about 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 biallelic mutations in the Wolframin ER transmembrane glycoprotein (Wfs1) gene. See, for example, Seppa et al. Sci Rep 9, 15742 (2019). Wolfram syndrome initially manifests as diabetes, followed by symptoms of optic atrophy, hearing loss, and neurodegeneration. Patients with Wolfram syndrome may experience symptoms such as ataxia, sleep apnea, dysphagia, hearing loss, and loss of taste due to brainstem atrophy. In some embodiments, the compounds, pharmaceutical compositions, and methods described herein reduce neuroinflammation in patients with Wolfram syndrome. In some embodiments, neuroinflammation is reduced in the inferior olive of patients. In some embodiments, the compounds, pharmaceutical compositions, and methods described herein reduce retinal ganglion cell death in patients with Wolfram syndrome. In some embodiments, the compounds, 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 alleviate one or more symptoms (eg, any of the symptoms described herein) in patients with Wolfram Syndrome.

[0305] Non-limiting examples of psychiatric disorders include drug dependence / addiction (narcotics and amphetamine) and attention deficit / hyperactivity disorder (ADHD).The compounds and pharmaceutical compositions described herein can be useful for improving the behavioral response to addictive drugs, reducing drug dependence, preventing relapse of drug abuse, and reducing the anxiety caused by the absence of certain addictive substances.See, for example, US Patent Publication No. 20120021979A1.

[0306] In some embodiments, the compounds and pharmaceutical compositions described herein are useful for improving learning and memory by increasing neuronal plasticity and promoting cell differentiation, and also for preserving dopamine neuron and motor function in Parkinson's disease.

[0307] Insulin-related In some embodiments, the condition, disease or disorder is impaired fasting glucose (IFG), impaired fasting glucose (IFG), hyperglycemia, insulin resistance (impaired glucose homeostasis), hyperinsulinemia, elevated blood levels of fatty acids or glycerol, hypoglycemic conditions, insulin resistance syndrome, paresthesia caused by hyperinsulinemia, hyperlipidemia, hypercholesterolemia, impaired wound healing, leptin resistance, impaired glucose tolerance, elevated fasting glucose, dyslipidemia (e.g., atherosclerotic dyslipidemia characterized by hyperlipidemia, high triglycerides and low HDL cholesterol), glucagonoma, hyperuricemia, hypoglycemia (e.g., nocturnal hypoglycemia), and insulin-related concurrent coma endpoints.

[0308] In some embodiments, the compounds and pharmaceutical compositions described herein may reduce or delay the progression of borderline, impaired fasting glucose, or impaired fasting glycemia to diabetes.

[0309] autoimmune disease In some embodiments, the condition, disease or disorder is autoimmune disease.Non-limiting examples of autoimmune disease include multiple sclerosis, experimental autoimmune encephalomyelitis, autoimmune disease 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, US Patent Publication No. 20120148586A1.

[0310] Gastrointestinal disorders In some embodiments, the condition, disease or disorder is a stomach or intestinal disorder.Non-limiting examples of these disorders include ulcers of any etiology (e.g., peptic ulcer, Zollinger-Ellison syndrome, drug-induced ulcer, ulcer associated with infection or other pathogen), digestive disorders, malabsorption, short bowel syndrome, appendicitis, inflammatory bowel disease (Crohn's disease and ulcerative colitis), celiac sprue, hypogammaglobulinemia sprue, chemotherapy and / or radiotherapy-induced mucositis and diarrhea, gastroenteritis, 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, tuberculosis cachexia, cachexia associated with blood disorders, cachexia associated with endocrine disorders, cachexia associated with infectious diseases, cachexia caused by acquired immune deficiency syndrome, etc.).

[0311] body weight In some embodiments, the compounds and pharmaceutical compositions described herein can be used to reduce weight (e.g., excess weight), prevent weight gain, induce weight loss, reduce body fat, or reduce food intake in patients (e.g., patients in need thereof). In some embodiments, the patient's weight gain can be due to excessive food intake or an unbalanced diet, or can be due to concomitant medication (e.g., insulin sensitizers with PPARγ agonist-like activity, such as troglitazone, rosiglitazone, englitazone, ciglitazone, pioglitazone, etc.). In some embodiments, the weight gain can be prior to obesity or can be in obese patients. In some embodiments, the weight gain can also be drug-induced weight gain or weight gain after smoking cessation. In some embodiments, the weight gain can be induced by the use of steroids or antipsychotics.

[0312] In some embodiments, the condition, disease or disorder is an eating disorder, such as hyperphagia, binge eating, bulimia, compulsive eating, or syndromic obesity, such as Prader-Willi and Bardet-Biedl syndrome.

[0313] inflammatory diseases In some embodiments, condition, disease or disorder is inflammatory disorder.Non-limiting examples of inflammatory disease include chronic rheumatoid arthritis, spondylitis deformans, osteoarthritis, lower back pain, gout, post-operative or post-traumatic inflammation, abdominal distension, neuralgia, pharyngitis, cystitis, pneumonia, pancreatitis, enteritis, inflammatory bowel disease (including inflammatory bowel disease), the inflammation of metabolically important tissues, including liver, fat, pancreas, kidney, intestine, and pro-inflammatory condition (for example, the level of pro-inflammatory cytokine or inflammatory C-reactive protein marker in blood increases).

[0314] cancer In some embodiments, the condition, disease or disorder is cancer. Suitable examples of cancer include breast cancer (e.g., invasive ductal carcinoma, ductal carcinoma in situ, inflammatory breast cancer), prostate cancer (e.g., hormone-dependent prostate cancer, hormone-independent prostate cancer), pancreatic cancer (e.g., pancreatic ductal carcinoma), gastric cancer (e.g., papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous carcinoma), lung cancer (e.g., non-small cell lung cancer, small cell lung carcinoma, malignant mesothelioma), colon cancer (e.g., gastrointestinal stromal tumor), rectal cancer (e.g., gastrointestinal stromal tumor), tumors), colorectal cancer (e.g., familial colorectal cancer, hereditary nonpolyposis colorectal cancer, gastrointestinal stromal tumors), small intestine cancer (e.g., non-Hodgkin's lymphoma, gastrointestinal stromal tumors), 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), schwannoma, liver cancer (e.g., , 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 tumor, ovarian germ cell tumor, low-grade ovarian tumor), bladder cancer, urethral cancer, skin cancer (e.g., intraocular (eye) melanoma, Merkel cell carcinoma), hemangioma, malignant lymphoma, malignant melanoma, thyroid cancer (e.g., medullary thyroid carcinoma), parathyroid carcinoma , nasal cavity cancer, paranasal sinus cancer, bone tumors (e.g., osteosarcoma, Ewing's tumor, uterine sarcoma, soft tissue sarcoma), angiofibroma, retinal sarcoma, penile cancer, testicular tumor, pediatric solid tumors (e.g., Wilms' tumor, pediatric kidney tumor), Kaposi's sarcoma, AIDS-related Kaposi's sarcoma, maxillary sinus tumor, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, and leukemia (e.g., acute myeloid leukemia, acute lymphoblastic leukemia).

[0315] Hypothalamic-pituitary disorders In some embodiments, the condition, disease or disorder is related to the hypothalamic-pituitary-gonadal axis. For example, the condition, disease or disorder is related to the hypothalamic-pituitary-ovarian axis. In another example, the condition, disease or disorder is related to 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 embodiments, the diabetes-related condition, disease or disorder is associated with the hypothalamic-pituitary-gonadal axis.

[0317] Pulmonary disease In some embodiments, the condition, disease or disorder is associated with a pulmonary disease. Pulmonary 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, refractory (irreversible) asthma).

[0318] In some embodiments, the diabetes-related condition, disease or disorder is a pulmonary disease.

[0319] Combination treatment In some embodiments, the present disclosure contemplates both monotherapy 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 therapeutic regimens) in combination with the administration of the compounds described herein.

[0321] In some embodiments, the methods described herein include administering a compound described herein in combination with one or more of dietary therapy (e.g., dietary monitoring, dietary therapy for diabetes), exercise therapy (e.g., physical activity), blood glucose monitoring, gastric electrical stimulation (e.g., TANTALUS®), and dietary modification.

[0322] In some embodiments, the compounds described herein, or pharmaceutically acceptable salts or solvates thereof, may be administered in combination with one or more additional therapeutic agents.

[0323] Representative additional therapeutic agents include, but are not limited to, anti-obesity agents, therapeutic agents for diabetes, therapeutic agents for diabetic complications, therapeutic agents for hyperlipidemia, antihypertensive agents, diuretics, chemotherapy agents, immunotherapeutic agents, anti-inflammatory agents, antithrombotic agents, antioxidants, therapeutic agents for osteoporosis, vitamins, anti-dementia agents, therapeutic agents for erectile dysfunction, therapeutic agents for frequent urination or urinary incontinence, therapeutic agents for NAFLD, therapeutic agents for NASH, and therapeutic agents for dysuria.

[0324] In some embodiments, the one or more additional therapeutic agents include, for example, those useful 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), GABA receptor agonists (e.g., gabapentin, pregabalin), neuropeptide Y antagonists (e.g., velneperit), peptide YY or its analogs, Cannabinoid receptor antagonists (e.g., rimonabant, taranabant), ghrelin antagonists, ghrelin receptor antagonists, ghrelin acylation enzyme 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 carboxylase (ACC) inhibitors (e.g., compounds described in WO2020 / 234726, WO2020 / 044266, and U.S. Patent No. 8,859,577), stearate-CoA desaturase inhibitors, microsomal triglyceride transfer protein inhibitors (e.g., R-256918), sodium-glucose transporter 2 (SGLT-2) inhibitors (e.g., JNJ-2843 1754, dapagliflozin, AVE2268, TS-033, YM543, TA-7284, ASP1941, remogliflozin, empagliflozin, canagliflozin, ipragliflozin, tofogliflozin, sergliflozin etabonate, remogliflozin etabonate, or ertugliflozin), SGLT-1 inhibitors, MCR-4 agonists, monoamine reuptake inhibitors, melanocyte-stimulating hormone analogs, 5HT2c agonists, galanin antagonists, appetite suppressants (e.g., bombesin agonists),Thyroid hormone mimetics, dehydroepiandrosterone or analogs thereof, human agouti-related protein (AGRP) inhibitors, neuromedin U agonists, NFK inhibitors (e.g., HE-3286), PPAR agonists (e.g., GFT-505, DRF-11605, gemfibrozil, fenofibrate, balaglitazone, ciglitazone, darglitazone, englitazone, isaglitazone, pioglitazone, rosiglitazone, CLX-0940, GW-1536, GW-1929, GW-2433, KRP-297, L-796449, LR-90, MK-0767, and SB-21 9994), phosphotyrosine phosphatase inhibitors (e.g., sodium vanadate, trodasquemine), GPR119 agonists (e.g., PSN-821, MBX-2982, APD597, compounds described in WO2010 / 140092, WO2010 / 128425, WO2010 / 128414, WO2010 / 106457), glucokinase activators (e.g., pyragliatin, AZD-1656, AZD6370, TTP-355, TTP-399, TTP547, ARRY403, MK-0599, TAK-329, AZD5658 or GKM-001, WO2010 / 103437, WO2010 / 103438, WO2010 / 013161, WO2007 / 122482, WO2006 / 112549, WO2007 / 028135, WO2008 / 047821, W compounds described in WO2008 / 050821, WO2008 / 136428 and WO2008 / 156757), leptin, leptin derivatives (e.g., metreleptin), leptin resistance improving agents, CNTF (ciliary neurotrophic factor), BDNF (brain-derived neurotrophic factor), cholecystokinin agonists, amylin preparations (e.g., pramlintide, AC-2307), neuropeptide Y agonists (e.g., PY Y3-36, PYY3-36 derivatives, obinineptide, TM-30339, TM-30335), oxyntomodulin (OXM) preparations, appetite suppressants (e.g., ephedrine), FGF21 preparations (e.g., animal FGF21 preparations extracted from bovine or porcine pancreas; human FGF21 preparations genetically synthesized using E. coli or yeast; fragments or derivatives of FGF21), appetite suppressants (e.g., P-57),Human islet-promoting peptide (HIP), melanocortin receptor 4 agonists (e.g., setomelanotide), 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, compounds described in WO2020 / 234726 and WO2020 / 044266), phentermine, zonisamide, norepinephrine / dopamine reuptake inhibitors agents (e.g., bupropion), GDF-15 analogs, methionine aminopeptidase 2 (MetAP2) inhibitors (e.g., beloranib or ZGN-1061), diethylpropion, phendimetrazine, benzphetamine, fibroblast growth factor receptor (FGFR) modulators, biotin, MAS receptor modulators, glucagon receptor agonists, CCKa agonists (e.g., compounds described in WO2005 / 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 useful, for example, as antidiabetic agents. Non-limiting examples include insulin and insulin preparations (e.g., animal insulin preparations extracted from bovine or porcine pancreas; human insulin preparations genetically synthesized using E. coli or yeast; 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 a salt thereof), biguanides (e.g., metformin, buformin or a salt thereof (e.g., hydrochloride, fumarate, succinate), etc. glucagon salts), glucagon analogues (e.g., any of the glucagon analogues described in WO2010 / 011439), agents that antagonise the action of glucagon or reduce glucagon secretion, sulfonylureas (e.g., chlorpropamide, tolazamide, glimepiride, tolbutamide, glibenclamide, gliclazide, acetohexamide, glyclopyramide, glybuzole, glyburide, glipizide), thiazolidinediones (e.g., rosiglitazone, lobeglitazone, troglitazone, balaglitazone, rivoglitazone, lobeglitazone, glitazones, pioglitazone), glitazars (e.g., aleglitazar, tiglitazar, saroglitazar, muraglitazar, tesaglitazar), SGLT2 inhibitors (e.g., JNJ-28431754, dapagliflozin, AVE2268, TS-033, YM543, TA-7284, ASP1941, THR1474, TS-071, ISIS388626, LX4211, remogliflozin, empagliflozin, canagliflozin, ipragliflozin, tofogliflozin, sergliflozin etabonate, remogliflozin fluozin etabonate, ertugliflozin, compounds described in WO2010 / 023594), GPR40 agonists (e.g. FFAR1 / FFA1 agonists, e.g. fasiglifam), α-glucosidase inhibitors (e.g. adipocin, camiglibose, pradimicin-Q, salbostatin, voglibose, acarbose, miglitol, emiglitate), insulin secretagogues, e.g. prandial glucose regulators (sometimes also referred to as "short-acting secretagogues"), e.g. meglitinides (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, albiglutide, dulaglutide, aviglutide, taspoglutide, lixisenatide, semaglutide, AVE-0010, S4P and Boc5), and dipeptidyl Dipeptidase IV (DPP-4) inhibitors (e.g., vildagliptin, dutogliptin, gemigliptin, alogliptin, saxagliptin, sitagliptin, linagliptin, berberine, aggliptin, anagliptin (SK-0403), teneligliptin, omarigliptin, BI1356, GRC8200, MP-513, PF-00734200, PHX1149, ALS2-0426, TA-6666, TS-021, KRP-104, trelagliptin) are also included.

[0326] In some embodiments, the one or more additional therapeutic agents include, for example, those useful for treating 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 acid conjugates (e.g., aramchol), anti-lysine oxidase homolog 2 (LOXL2) monoclonal antibodies (e.g., simtuzumab), caspase inhibitors (e.g., emricasan), MAPK5 inhibitors (e.g., GS-4997), galectin 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), acetyl-CoA carboxylase (ACC) inhibitors (e.g., NDI 010976 and compounds described in WO2009 / 144554, WO2003 / 072197, WO2009 / 144555 and WO2008 / 065508), ketohexokinase (KHK) inhibitors (e.g., compounds described in WO2020 / 234726), apoptosis signal-regulating kinase 1 (ASK1) inhibitors, ileal bile acid transporter (IBAT) inhibitors, dual antagonists of chemokine receptor 2 (CCR2) and CCR5 (e.g., cenicriviroc), diacylglyceryl acyltransferase 2 (DGAT2) inhibitors (e.g., compounds described in WO2020 / 234726 and U.S. Publication No. 201 No. 80051012), CB1 receptor antagonists, anti-CB1R antibodies, glycyrrhizin, Schisandra berry extract, ascorbic acid, glutathione, silymarin, lipoic acid, and d-α-tocopherol, ascorbic acid, glutathione, vitamin B complex, glitazones / thiazolidinediones (e.g., troglitazone, rosiglitazone, pioglitazone, balaglitazone, rivoglitazone, lobeglitazone), metformin, cysteamine, sulfonylureas, α-glucosidase inhibitors, meglitinides, vitamin E, tetrahydrolipstatin, milk thistle protein, antivirals, and antioxidants.

[0327] In some embodiments, the one or more additional therapeutic agents include, for example, those useful for treating diabetic complications. Non-limiting examples include aldose reductase inhibitors (e.g., tolrestat, epalrestat, zopolrestat, fidarestat, CT-112, ranirestat, lidrestat), neurotrophic factors and their enhancers (e.g., NGF, NT-3, BDNF, neurotrophic factor production / secretion promoters described in WO01 / 14372 (e.g., 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxyl)propyl]oxazole), compounds described in WO2004 / 039365), PKC inhibitors (e.g., ruthenium phosphate phosphate inhibitors), and the like. Examples of anti-inflammatory drugs include benzodiazepines (e.g., benzodiazepine mesylate), AGE inhibitors (e.g., ALT946, N-phenacylthiazolium bromide (ALT766), EXO-226, pyridoline, pyridoxamine), serotonin and noradrenaline reuptake inhibitors (e.g., duloxetine), sodium channel inhibitors (e.g., lacosamide), reactive oxygen scavengers (e.g., thioctic acid), cerebral vasodilators (e.g., tiapride, mexiletine), somatostatin receptor agonists (e.g., BIM23190), and apoptosis signal-regulating kinase-1 (ASK-1) inhibitors.

[0328] In some embodiments, the one or more additional therapeutic agents include, for example, those useful for treating hyperlipidemia. Non-limiting examples include HMG-COA reductase inhibitors (e.g., pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin, pitavastatin or a salt thereof (e.g., sodium salt, calcium salt)), squalene synthase inhibitors (e.g., compounds described in WO97 / 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-benzoxazepin-3-yl] [acetyl]piperidine-4-acetic acid), fibrate compounds (e.g., bezafibrate, clofibrate, simfibrate, clinofibrate), anion exchange resins (e.g., cholestyramine), nicotinic acid drugs (e.g., nicomol, niceritrol, niaspan), phytosterols (e.g., soybean sterol, gamma oryzanol (γ-oryzanol)), cholesterol absorption inhibitors (e.g., Zekia), CETP inhibitors (e.g., dalcetrapib, anacetrapib), and omega-3 fatty acid preparations (e.g., omega-3 fatty acid ethyl ester 90).

[0329] In some embodiments, the one or more additional therapeutic agents include those useful as, for example, antihypertensive agents. Non-limiting examples include angiotensin-converting enzyme inhibitors (e.g., captopril, zofenopril, febusinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril), angiotensin II antagonists (e.g., candesartan cilexetil, candesartan, losartan, losartan potassium, eprosartan, valsartan, telmisartan, irbesartan, tasosartan, olmesartan, olmesartan medoxomil, azilsartan, azilsartan medoxomil), calcium antagonists (e.g., manidipine, nifedipine, amlodipine, efonidipine, nicardipine, cilnidipine), and beta-blockers (e.g., metoprolol, atenolol, propranolol, carvedilol, pindolol). Further non-limiting examples of antihypertensive agents include diuretics (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid, triclinafen, 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., sitaxsentan, atorsentan, compounds disclosed in U.S. Pat. Nos. 5,612,359 and 6,043,265), dual ET / AII antagonists (e.g., compounds disclosed in WO 2000 / 01389), neutral endopeptidase (NEP) inhibitors, the IF channel blocker ivabradinand, and vasopeptidase inhibitors (dual NEP-ACE inhibitors) (e.g., gemopatrilat and nitrates).

[0330] In some embodiments, the one or more additional therapeutic agents include, for example, those useful as diuretics. Non-limiting examples include xanthine derivatives (e.g., theobromine sodium salicylate, theobromine calcium salicylate), thiazide preparations (e.g., ethiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, penfluthiazide, polythiazide, methyclothiazide), antialdosterone preparations (e.g., spironolactone, triamterene), carbonic anhydrase inhibitors (e.g., acetazolamide), chlorobenzenesulfonamides (e.g., chlorthalidone, mefruside, indapamide).

[0331] In some embodiments, the one or more additional therapeutic agents include, for example, those useful as immunotherapeutic agents. Non-limiting examples include microbial or bacterial compounds (e.g., muramyl dipeptide derivatives, picibanil), polysaccharides with immunopotentiating activity (e.g., lentinan, schizofiran, krestin), cytokines obtained by genetic engineering techniques (e.g., interferons, interleukins (IL), 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, for example, those useful as antithrombotic 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, boroarginine derivatives, boropeptides, heparin, hirudin, and melagatran), FXa inhibitors (e.g., rivaroxaban, apixaban, edoxaban, YM150, compounds described in WO02 / 06234, WO2004 / 048363, WO2005 / 030740, WO2005 / 058823, and WO2005 / 113504), thrombus inhibitors, and the like. These include lytic agents (e.g., anistreplase, streptokinase, tenecteplase (TNK), lanoteplase (nPA), urokinase, tisokinase, alteplase, nateplase, monteplase, pamiteplase, factor VIIa inhibitors, PAI-1 inhibitors, α2-antiplasmin inhibitors, and anisoylated plasminogen streptokinase activator complex), and platelet aggregation inhibitors (e.g., ticlopidine hydrochloride, clopidogrel, prasugrel, E5555, SHC530348, cilostazol, ethyl icosapentate, beraprost sodium, and sarpogrelate hydrochloride).

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

[0334] Other exemplary additional therapeutic agents include drugs that regulate hepatic glucose balance (e.g., fructose 1,6-bisphosphatase inhibitors, glycogen phosphorylase inhibitors, glycogen synthase kinase inhibitors, glucokinase activators), drugs designed to treat complications of long-term hyperglycemia, such as aldose reductase inhibitors (e.g., epalrestat and ranirestat), drugs used to treat complications associated with microangiopathy, anti-dyslipidemic drugs, such as HMG-CoA reductase inhibitors (statins, e.g., rosuvastatin, pravastatin, pitavastatin, lovastatin, atorvastatin, simvastatin, fluvastatin, itavastatin, ZD-4522), HMG-CoA synthase inhibitors, cholesterol inhibitors, and the like. cholesterol-lowering agents, bile acid metal sequestering agents (e.g., cholestyramine, questran, colestipol, and colesevelam), cholesterol absorption inhibitors (e.g., plant sterols, such as phytosterols), cholesterol ester transfer protein (CETP) inhibitors, inhibitors of the ileal bile acid transport system (IBAT inhibitors), diacylglyceryl acyltransferase 1 (DGAT1) inhibitors (e.g., AZD7687, LCQ908, compounds described in WO2009 / 016462, WO2010 / 086820), monoacylglycerol O-acyltransferase inhibitors, α-amylase inhibitors (e.g., tendamistat, trestatin, AL-3688), α-glucoside hydrolase inhibitors, SIRT-1 activators, c-Jun N-terminal kinase (JNK) inhibitors, VPAC2 receptor agonists, TGR5 receptor modulators (e.g., compounds described in), GPBAR1 receptor modulators, GPR120 modulators, high affinity nicotinic acid receptor (HM74A) activators, carnitine palmitoyltransferase enzyme 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., diliotapide, mitratapide, and implitapide), lipoxygenase inhibitors, PCSK9 modulators (e.g., alirocumab and evolocumab), RXRα modulators, cysteamine, cystamine, RNA antisense constructs inhibiting protein tyrosine phosphatase PTPRU, vitamin B complex, pentraxin proteins, protein tyrosine phosphatase-1B (PTP-1B) inhibitors (e.g., trodasquemin, hirtiosalu extract, and Zhang et al. Drug Discovery Today. 2007, 12(9-10): 373-381), editinbe, betaine, pentoxifylline, alpha-delta-9 desaturase, BCKDK inhibitors, branched-chain alpha-keto acid dehydrogenase kinase (BCBK) inhibitors, PNPLA3 inhibitors, FGF19 analogs, SCD1 inhibitors, bile acid binding resins, nicotinic acid (niacin) and its analogs, antioxidants (e.g., probucol), omega-3 fatty acids, antihypertensive agents, e.g., adrenoceptor antagonists, e.g., beta-blockers (e.g., atenolol), alpha-blockers (e.g., doxazosin), mixed alpha / beta-blockers (e.g., labetalol), adrenoceptor agonists, e.g., alpha-2 agonists (e.g., clonidine), angiotensin-converting enzyme (ACE) inhibitors (e.g., lisinolol), prill), calcium channel blockers, e.g., dihydropyridines (e.g., nifedipine), phenylalkylamines (e.g., verapamil), benzothiazepines (e.g., 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, torsemide, bemethanide, ethacrynic acid, thiazide diuretics (e.g., chlorothiazide, hydrochlorothiazide, benzthiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, polythiazide, trichlormethiazide, indapamide),Phthalimidine diuretics (e.g., chlorthalidone, metolazone), quinazoline diuretics (e.g., quinethazone), potassium-sparing diuretics (e.g., triamterene and amiloride), thyroid receptor agonists (e.g., compounds described in WO2020 / 117987), hemostatic regulators, such as antithrombotic agents (e.g., fibrinolysis activators), thrombin antagonists, factor VIIa inhibitors, anticoagulants (e.g., vitamin K antagonists, e.g., warfarin), heparin and its low molecular weight analogues, factor Xa inhibitors and direct thrombin inhibitors (e.g., argatroban), antiplatelet agents (e.g., cyclooxygenase inhibitors (e.g., aspirin), nonsteroidal anti-inflammatory drugs (NSAIDs), thromboxane A2 receptor antagonists (e.g., ifetroban), thromboxane A2 synthase inhibitors, PDE inhibitors (e.g., pletal, dipyridamole)), purinergic receptor antagonists (e.g., P2Y1 and P2Y12), adenosine diphosphate (ADP) receptor inhibitors (e.g., clopidogrel), phosphodiesterase inhibitors (e.g., cilostazol), glycoprotein IIB / I IA inhibitors (e.g., tirofiban, eptifibatide, and abscissima), adenosine reuptake inhibitors (e.g., dipyridamole), noradrenergic agents (e.g., phentermine), serotonergic agents (e.g., sibutramine, lorcaserin), diacylglycerol transferase (DGAT) inhibitors, feeding behavior modifiers, pyruvate dehydrogenase kinase (PDK) modulators, serotonin receptor modulators, monoamine transport modulators, such as selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine). , noradrenaline reuptake inhibitors (NARIs), noradrenaline-serotonin reuptake inhibitors (SNRIs), and monoamine oxidase inhibitors (MAOIs) (e.g., toloxatone and amiflamine), compounds described in WO2007 / 013694, WO2007 / 018314, WO2008 / 093639 and WO2008 / 099794, GPR40 agonists (e.g., fasiglifam or its hydrate, WO2004 / 041266, WO2004 / 106276, WO2005 / 063729, WO2005 / 063725,compounds described in WO2005 / 087710, WO2005 / 095338, WO2007 / 013689 and WO2008 / 001931), SGLT1 inhibitors, adiponectin or its agonists, IKK inhibitors (e.g., AS-2868), somatostatin receptor agonists, ACC2 inhibitors, cachexia-improving drugs, for example, cyclooxygenase inhibitors (e.g., indomethacin), progesterone derivatives (e.g., megestrol acetate), glucocorticoids (e.g., dexamethasone), metoclopramide drugs, tetrahydrocannabinol drugs, fat metabolism improving drugs (e.g., eicosapentaenoic acid), growth hormone, IGF-1, cachexia-inducing factors TNF-α, LIF, IL-6 and and antibodies against oncostatin M, metabolism-improving proteins or peptides, such as glucokinase (GK), glucokinase regulatory protein (GKRP), uncoupling proteins 2 and 3 (UCP2 and UCP3), peroxisome proliferator-activated receptor α (PPARα), MC4r agonists, insulin receptor agonists, PDE5 inhibitors, glycation inhibitors (e.g., ALT-711), neuroregeneration promoters (e.g., Y-128, VX853, prosaptide), antidepressants (e.g., desipramine, amitriptyline, imipramine), antiepileptic drugs (e.g., lamotrigine, trileptal, keppra, zonegran, pregabalin, halcoceride, carbamazepine), antiarrhythmic drugs (e.g., K, +channel openers, mexiletine, propafenone, metoprolol, atenolol, carbaziol, propranolol, sotalol, dofetilide, amiodarone, azimilide, ibutilide, ditiazem, and verapamil), acetylcholine receptor ligands (e.g., ABT-594), endothelin receptor antagonists (e.g., ABT-627), narcotic analgesics (e.g., morphine), alpha-2 receptor agonists (e.g., clonidine), topical Analgesics (e.g., capsaicin), anxiolytics (e.g., benzothiazepines), 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 treatments (e.g., anti-CD20 antibodies (e.g., Rituxan), i-BLyS antibodies), drugs affecting T cell migration (e.g., anti-integrin α4 / β1 antibodies (e.g., Tysa)), buri), drugs acting on immunophilins (e.g., cyclosporine, tacrolimus, sirolimus, rapamycin), interferons (e.g., IFN-β), immunomodulatory agents (e.g., glatiramer), TNF-binding proteins (e.g., circulating receptors), immunosuppressants (e.g., mycophenolate), metaglidasen, AMG-131, balaglitazone, MBX-2044, rivoglitazone, aleglitazar, tiglitazar, saroglitazar, muraglitazapine tetracycline, tesaglitazar, lobeglitazone, PLX-204, PN-2034, GFT-505, THR-0921, exenatide, exendin-4, memantine, midazolam, ketoconazole, ethyl icosapentate, clonidine, azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide, etoposide, piroxicam, NO donors (e.g., nitrates), and NO promoters (e.g., phosphodiesterase inhibitors).

[0335] In some embodiments, one or more additional therapeutic agents include, for example, those useful as antiemetics. As used herein, "antiemetic" refers to any agent that counters (e.g., reduces or eliminates) nausea or vomiting (vomiting). When referring to the therapeutically effective amount of an antiemetic, it is understood that the amount administered is the amount necessary to counter (e.g., reduces or eliminates) nausea or vomiting (vomiting). Without wishing to be bound by theory, it is believed that administering one or more antiemetics in combination with the compound of formula (I) described herein can, for example, allow patients to eat normally, thereby speeding up the response to treatment, and therefore allowing the compound of formula (I) to be administered.

[0336] Non-limiting examples of antiemetic agents include 5HT3 receptor antagonists (serotonin receptor antagonists), neuroleptics / antipsychotics, antihistamines, anticholinergics, steroids (e.g., corticosteroids), NK1 receptor antagonists (e.g., neurokinin 1 substance P receptor antagonists), antidopaminergics / dopamine receptor antagonists, benzodiazepines, and cannabinoids.

[0337] For example, the antiemetic agent may be selected from the group consisting of neuroleptics, antihistamines, anticholinergics, steroids, 5HT-3 receptor antagonists, NK1 receptor antagonists, antidopamines / dopamine receptor antagonists, benzodiazepines and non-psychoactive cannabinoids.

[0338] In some embodiments, the antiemetic agent 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, bemesetron, zatisetron, batanopiride, MDL-73147EF, metoclopramide, N-3389 (endo-3,9-dimethyl-3,9-diazabicyclo[3,3,1]non-7-yl-1H-indazole-3-carboxamide dihydrochloride), Y-25130 hydrochloride, MDL 72222, tropanyl-3,5-dimethylbenzoate, 3-(4-allylpiperazin-1-yl)-2-quinoxalinecarbonitrile maleate, zacopride hydrochloride, and mirtazepine. Other non-limiting examples of 5HT3 receptor antagonists (serotonin receptor antagonists) include cilansetron, clozapine, cyproheptadine, dazopride, hydroxyzine, lerisetron, metoclopramide, mianserin, olanzapine, palonosetron (plus netupitant), quetiapine, camosetron, lamosterone, licasetron, risperidone, ziprasidone, and zatosetron.

[0339] In certain embodiments, the 5HT-3 receptor antagonist is granisetron, dolasetron, ondansetron hydrochloride, tropisetron, ramosetron, palonosetron, alosetron, bemesetron, zatisetron, batanopiride, MDL-73147EF, metoclopramide, N-3389, Y-25130 hydrochloride, MDL 72222, tropanyl-3,5-dimethylbenzoate, 3-(4-allyl-piperazin-1-yl)-2-quinoxalinecarbonitrile maleate, zacopride hydrochloride, and mirtazepine.

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

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

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

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

[0344] In some embodiments, the antiemetic agent is an antihistamine.Non-limiting examples of antihistamines include piperazine derivatives (e.g., cyclizine, meclizine, and cinnarizine); promethazine; dimenhydrinate (Dramine, Gravol); diphenhydramine; hydroxyzine; buclizine; and meclizine hydrochloride (Bonine, Antivert), doxylamine, and mirtazapine.

[0345] In some embodiments, the antiemetic agent is an anticholinergic agent (an inhibitor of acetylcholine receptors).Non-limiting examples of anticholinergic agents include atropine, scopolamine, glycopyrone, hyoscine, Artan (trihexy-5 trihexyphenidyl hydrochloride), Cogentin (benztropine mesylate), Akineton (biperiden hydrochloride), Dicypal (Norflex orphenadrine citrate), diphenhydramine, hydroxyzine, hyoscyamine, and Chemadrin (procyclidine hydrochloride).

[0346] In some embodiments, the antiemetic agent is a steroid (e.g., a corticosteroid). Non-limiting examples of steroids include betamethasone, dexamethasone, methylprednisolone, Prednisone®, and trimethobenzamide (Tigan).

[0347] In some embodiments, the antiemetic agent is an NK1 receptor antagonist (e.g., a neurokinin 1 substance P receptor antagonist). Non-limiting examples of NK1 receptor antagonists include aprepitant, casopitant, ezlopitant, fosaprepitant, maropitant, netupitant, rolapitant, and vestipitant.

[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 (norpitantium 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 j. 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]diazocino[2,1-g][1,7]naphthyridine-6,13-dione], PD 154075, ([(2-benzofuran)-CHOCO]-(R)-α-MeTrp-(S)-NHCH(CH)Ph), FK888, and (D-Pro, D-Trp, Phe)SP.

[0349] In some embodiments, the antiemetic agent is an antidopamine / dopamine receptor antagonist (e.g., a dopamine receptor antagonist, e.g., a D2 or D3 antagonist).Non-limiting examples include phenothiazines (e.g., promethazine, chlorpromazine, prochlorperazine, perphenazine, hydroxyzine, thiethylperazine, metopimazine); benzamides (e.g., metoclopramide, domperidone), butyrophenones (e.g., haloperidol, droperidol); alizapride, bromopride, clebopride, domperidone, itopride, metoclopramide, trimethobenzamide, and amisulpride.

[0350] In some embodiments, the antiemetic agent is a non-psychoactive cannabinoid (e.g., cannabidiol (CBD), cannabidiol dimethylheptyl (CBD-DMH), tetrahydrocannabinol (THC), a cannabinoid agonist such as WIN 55-212 (a CB1 and CB2 receptor agonist), dronabinol (Marinol®), and nabilone (Cesamet®)).

[0351] Other exemplary antiemetic agents include c-9280 (Merck); benzodiazepines (diazepam, midazolam, lorazepam); neuroleptic / antipsychotics (e.g., dixyrazine, haloperidol, and prochlorperazine (Compazine®)); cerium oxalate; propofol; sodium citrate; dextrose; fructose (Nausene); orthophosphate; fructose; glucose (Emetrol); bismuth subsalicylate (Pepto-Bismol); ephedrine; vitamin B6; essential oils of peppermint, lavender, and lemon; and ginger.

[0352] Still other exemplary antiemetic agents include those described in US20120101089A1; US10,071,088B2; US6,673,792B1; US6,197,329B1; US10,828,297B2; US10,322,106B2; US10,525,033B2; WO2009080351A1; WO2019203753A2; WO2002020001A2; US8,119,697B2; US5,039,528; US20090305964A1; and WO2006 / 111169, each of which is incorporated herein by reference in its entirety.

[0353] In some embodiments, the antiemetic agent is a 5HT3 receptor antagonist (serotonin receptor antagonist), a neuroleptic, an antipsychotic, an antihistamine, an anticholinergic, a steroid (e.g., a corticosteroid), an NK1 receptor antagonist (e.g., a neurokinin 1 substance P receptor antagonist), an antidopamine / dopamine receptor antagonist, a benzodiazepine, or a cannabinoid (e.g., a non-psychoactive cannabinoid).

[0354] In some embodiments, the antiemetic agent is granisetron, dolasetron, ondansetron, ondansetron hydrochloride, tropisetron, ramosterone, palonosetron, alosetron, azasetron, bemesetron, zatisetron, batanopiride, MDL-73147EF; metoclopramide, N-3389, Y-25130 hydrochloride, MDL 72222, tropanyl-3,5-dimethylbenzoate, 3-(4-allylpiperazin-1-yl)-2-quinoxalinecarbonitrile maleate, zacopride hydrochloride, mirtazepine, cilansetron, clozapine, cyproheptadine, dazopride, hydroxyzine, lerisetron, mianserin, olanzapine, palonosetron (+ netupitant), quetiapine, camosetron, ramosterone, licasetron, risperidone, ziprasidone, zatosetron, cyclizine, meclizine, meclizine hydrochloride, cinnarizine, promethazine, dimenhydrinate, diphenhydramine, buclizine, doxylamine, Mirtazapine, atropine, scopolamine, glycopyrone, hyoscine, artane, benztropine mesylate, biperiden hydrochloride, Norflex Orphenadrink citrate, diphenhydramine, hyoscyamine, procyclidine hydrochloride, betamethasone, dexamethasone, methylprednisolone, prednisone, trimethobenzamide (Tigan), aprepitant, casopitant, ezlopitant, fosaprepitant, maropitant, netupitant, rolapitant, and vestipitant, MPC-4505, GW597599, MPC-4505, GR205171, L-759274, SR 140333, CP-96,345, BIIF 1149, NKP 608C, NKP 608A, CGP 60829, SR 140333 (norpitantium 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, prochlorperazine (Compazine®), perphenazine, thiethylperazine, metopimazine, domperidone, haloperidol, droperidol, alizapride, bromopride, clebopride, itopride, amisulpride, cannabidiol (CBD), cannabidiol dimethylheptyl (CBD-DMH), tetrahydrocannabinol (THC), WIN 55-212 (CB1 and CB2 receptor agonist), dronabinol (Marinol®), nabilone (Cesamet®), c-9280, diazepam, midazolam, lorazepam, dixyrazine, cerium oxalate, propofol, sodium citrate, dextrose, fructose (Nausene), orthophosphate, glucose (Emetrol), bismuth subsalicylate, ephedrine, vitamin B6, essential oils of peppermint, lavender, lemon, and ginger.

[0355] In some embodiments, the additional therapeutic agent or regimen is administered to the patient at about the same time as contacting or administering the compound and pharmaceutical composition. For example, the additional therapeutic agent or regimen and the compound and pharmaceutical composition are provided to the patient simultaneously in the same dosage form.

[0356] In certain embodiments, a fixed-dose combination is provided comprising an antiemetic drug and a compound described herein or a pharmaceutically acceptable salt or solvate thereof, or a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof.

[0357] As another example, the additional therapeutic agent or regimen and the compound and pharmaceutical composition are provided to the patient concurrently in separate dosage forms.

[0358] In some embodiments, the additional therapeutic agent or regimen is administered to the patient subsequent to or after (e.g., about 1 hour, or about 6 hours, or about 12 hours, or about 24 hours, or about 48 hours after) contacting or administering the compound and pharmaceutical composition.

[0359] In certain embodiments, the antiemetic agent is a 5HT3 receptor antagonist (serotonin receptor antagonist). In certain embodiments, the antiemetic agent is ondansetron. In certain embodiments, the antiemetic agent is a dopamine receptor antagonist. In certain embodiments, the antiemetic agent is a benzamide. In certain embodiments, the antiemetic agent is metoclopramide. [Example]

[0360] 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]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound I) [ka] To a solution of compound 1-B1 (1 equiv.) in 2-methoxyethanol (4 vol.) and HO (10.00 equiv.), KOH (10.00 equiv.) was added, and the mixture was heated at 100-105°C for 12 h. After completion of the reaction, the reaction mixture was cooled to 10-20°C, and water (4 vol.) was added portionwise. The resulting mixture was poured into HCl (aq. 2M, 20 vol.). A solid formed, and the mixture was then filtered. The filter cake was slurried with ACN (4 vol.) at 80-85°C for 8 h. The mixture was then filtered, and the filter cake was collected and dried under vacuum. Compound 1-B was obtained as an off-white solid.

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

[0362] 1 H NMR(400 MHz, DMSO-d6)δ: 12.85(s, 1H), 12.01-12.27(m, 1H), 7.54(d, J = 4.8 Hz, 1H), 7.27-7.40(m, 2H), 7.19(d, J = 4.0 Hz, 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] [ka] To a solution of 1-A1 (1.0 equiv.) in 2-MeTHF (2-3 vol.), 6M HCl (13.5 equiv.) was slowly added over approximately 3 hours at below 25°C. After stirring for 10 hours at 15-25°C, 5V of HO and 5V of ethyl acetate were added to the reaction mixture. Separation of two phases 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% aqueous NaOH, and the solid in the aqueous phase was filtered. After drying, compound 1-A was obtained as an off-white solid.

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

[0365] 1 H NMR(400 MHz, DMSO-d6)δ: 7.72(q, J = 4.8 Hz,1H), 7.35(d, J = 2.8 Hz, 1H), 7.26(dd, J = 8.0, 12.8Hz, 1H), 7.11(d, J = 4.8 Hz, 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 = 4.8 Hz, 3H), 2.65-2.69(m, 2H), 2.19(d, J = 1.2 Hz, 6H), 1.88-1.97(m, 4H), 1.11(d, J = 6.0 Hz, 3H), 0.95-1.04(m, 6H).

[0366] [ka] 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 hour. 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 hours, 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 solution was washed with 15V 7% NaHCO3 solution. The DCM solution was washed again with 5V H2O. The organic phase was then switched to 10V EtOH. Approximately 1.5V of 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 hours.

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

[0368] 1HNMR(400 MHz, DMSO-d6, 80℃)δ: 11.58(br. s, 1 H), 7.66(br. s, 1 H), 7.52(s, 1 H), 7.42(d, J=8.4 Hz, 1 H), 7.05-7.30(m, 5 H), 6.70-6.95(m, 4 H), 5.56(br. s, 1 H), 4.45(br. s, 1 H), 3.95-3.99(m, 2 H), 3.40-3.70(m, 3 H), 2.83-2.90(m, 3 H), 2.60-2.80(m,3 H), 2.22(d, J=1.6 Hz, 6 H), 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).

[0369] Example 2: Synthesis of Compound I L-Arginine Salt [ka] Compound I L-arginine salt was prepared from the reaction of Compound I (1.0 equivalent) and L-arginine (1.1 equivalent) in IPA / HO (7:3 v / v). After stirring at 50-55°C for approximately 2 hours, 2.38 volume equivalents of IPA and 2% by weight of crystal seeds were added to the clear solution, causing the mixture to become cloudy. After stirring for 2 hours, approximately 15.5 volume equivalents of IPA were added dropwise to the mixture. After stirring at 50-55°C for 8 hours, the mixture was further stirred at 0-5°C for 10 hours. 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(400 MHz, DMSO-d6) δ: 7.71-7.73(m, 1H), 7.37-7.65(m, 2H), 7.24-7.31(m, 1H), 7.00-7.21(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), 2.16-2.20(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).

[0372] Example 3: Polymorphs of Compound I Free Acid The polymorphism of Compound I free acid was investigated using the free acid starting material (Compound I free acid Form A) prepared using the procedure described in Example 1.

[0373] Approximate solubility at 25°C and 50°C Approximately 5 mg of Compound I free acid Form A was weighed into a 2 mL glass vial. 20 μL aliquots of each solvent were added to dissolve the drug substance at 25° C. Vortexing and sonication were performed to aid dissolution. The maximum volume of each solvent added was 1 mL. Approximate solubility was determined by visual observation.

[0374] Approximately 10 mg of Compound I free acid Form A was weighed into a 2 mL glass vial. 20 μL aliquots of each solvent were added to dissolve the drug substance at 50° C. Vortexing and sonication were performed to aid dissolution. The maximum volume of each solvent added was 1 mL. Approximate solubility was determined by visual observation. The results of both solubility experiments are summarized in Table 3-1. [Table 1]

[0375] Polymorphic Screening of Form A of Compound I Free Acid Preparation of Form A of Compound I Free Acid Form A of Compound I free acid 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 H-NMR showed about 0.4 wt% EtOH residual (about 0.08 molar equivalents). The dried free acid Form A was used in subsequent polymorph screening experiments in this section.

[0376] Equilibrate with solvent for 2 weeks at 25°C Based on the approximate solubility results, approximately 50 mg of Compound I free acid Form A was equilibrated in 0.2-1 mL of solvent at 25 °C for 2 weeks at 300-400 rpm on a magnetic stir plate with a stir bar. The resulting suspension was filtered through a 0.45 μm nylon membrane filter by centrifugation at 14,000 rpm. The solid portion (wet cake) was examined by XRPD. Samples with different XRPD patterns were analyzed by DSC, TGA, and hydrate analysis. 1 Further analyses were performed, including H-NMR and KF, and the results are summarized in Table 3-2. [Table 2]

[0377] Equilibration with solvent at 50°C for 1 week Based on the approximate solubility results, approximately 60 mg of Compound I free acid Form A was equilibrated in 0.2-1 mL of solvent at 50 °C for 1 week at 300-400 rpm on a magnetic stir plate with a stir bar. The resulting suspension was filtered through a 0.45 μm nylon membrane filter by centrifugation at 14,000 rpm. The solid portion (wet cake) was examined by XRPD. Samples with different XRPD patterns were analyzed by DSC, TGA, and hydrate analysis. 1 Further analysis was performed, including H-NMR and KF, and the results are summarized in Table 3-3. [Table 3-1] [Table 3-2]

[0378] Equilibration under temperature cycling Based on the approximate solubility results, approximately 50 mg of Compound I free acid Form A was equilibrated in 0.2-1 mL of solvent at temperatures ranging from 5 to 50°C, with a heating / cooling rate of 0.1°C / min for 10 cycles. Equilibration was performed using a stir bar on a magnetic stir plate at 300-400 rpm. The resulting suspension was filtered through a 0.45 μm nylon membrane filter by centrifugation at 14,000 rpm. The solid portion (wet cake) was examined by XRPD. Samples with different XRPD patterns were analyzed by DSC, TGA, and HCl for the hydrate. 1 Further analysis was carried out including H-NMR and KF. The results are summarized in Table 3-4. [Table 4-1] [Table 4-2]

[0379] Equilibrate with the amorphous form and solvent for 1 week at 25 °C Approximately 30 mg of the amorphous form of Compound I free acid was equilibrated in 0.2–1 mL of solvent at 25°C for 1 week on a magnetic stir plate at 300–400 rpm with a stir bar. The resulting suspension was filtered through a 0.45 μm nylon membrane filter by centrifugation at 14,000 rpm. The solid portion (wet cake) was examined by XRPD, and the results are summarized in Tables 3-5. [Table 5]

[0380] Crystallization by slow evaporation at room temperature Based on the approximate solubility results, approximately 20 mg of Compound I free acid Form A was dissolved in approximately 1 mL of solvent. The resulting solution was filtered through a 0.45 μm nylon membrane filter. The clear solution was allowed to slowly evaporate under ambient conditions (approximately 20-25°C, 30-70% RH). The solid residue was examined by XRPD. The results are summarized in Tables 3-6. [Table 6]

[0381] Crystallization by rapid evaporation at room temperature Based on the approximate solubility results, approximately 20 mg of Compound I free acid Form A was dissolved in 0.2-1 mL of solvent. The resulting solution was filtered through a 0.45 μm syringe membrane filter. The clear solution was rapidly evaporated under a stream of dry nitrogen at room temperature (approximately 20-25°C). The solid residue was examined by XRPD. The results are summarized in Tables 3-7. [Table 7]

[0382] Crystallization from a hot saturated solution by slow cooling Based on the approximate solubility results, approximately 30 mg of Compound I free acid Form A was dissolved in a minimum amount of selected solvent at 50°C. The resulting solution was filtered through a 0.45 μm syringe membrane filter. The clear solution was cooled to 5°C at 0.1°C / min. Precipitate-free samples at 5°C were further cooled to -20°C. The precipitate was collected by centrifugal filtration through a 0.45 μm nylon membrane filter at 14,000 rpm. The solid portion (wet cake) was examined by XRPD. The results are summarized in Tables 3-8. [Table 8]

[0383] Crystallization from hot saturated solutions by rapid cooling Based on the approximate solubility results, approximately 30 mg of Compound I free acid Form A was dissolved in a minimum amount of selected solvent at 50°C. The resulting solution was filtered through a 0.45 μm syringe membrane filter. The clear solution was placed on a stir plate at 5°C and stirred. The precipitate was collected by centrifugal filtration through a 0.45 μm nylon membrane filter at 14,000 rpm. The solid portion (wet cake) was examined by XRPD. The results are summarized in Tables 3-9. [Table 9]

[0384] Crystallization by addition of antisolvent Based on the approximate solubility results, approximately 40 mg of Compound I free acid Form A was dissolved in a minimum amount of a selected good solvent at ambient temperature (approximately 20-25°C). The resulting solution was filtered through a 0.45 μm syringe membrane filter. 4-8 times the amount of poor solvent was slowly added to the clear solution until a large amount of solid precipitated. The precipitate was collected by centrifugal filtration through a 0.45 μm nylon membrane filter at 14,000 rpm. The solid portion (wet cake) was examined by XRPD. The results are summarized in Tables 3-10. [Table 10]

[0385] Crystallization by reverse addition of antisolvent Based on the approximate solubility results, approximately 40 mg of Compound I free acid Form A was dissolved in a minimum amount of a selected good solvent at ambient temperature (approximately 20-25°C). The resulting solution was filtered through a 0.45 μm syringe membrane filter. The clear solution was quickly added to 4-8 times the amount of poor solvent. The precipitate was collected by centrifugal filtration through a 0.45 μm nylon membrane filter at 14,000 rpm. The solid portion (wet cake) was examined by XRPD. Samples with different XRPD patterns were analyzed by DSC, TGA, and HCl for the hydrate. 1 Further analyses were performed, including H-NMR and KF, and the results are summarized in Tables 3-11. [Table 11]

[0386] Crystallization by vapor diffusion Based on the approximate solubility results, approximately 30 mg of Compound I free acid Form A was dissolved in a minimal amount of selected solvent at ambient temperature (approximately 20-25°C). The resulting solution was filtered through a 0.45 μm syringe membrane filter. The clear solution was transferred to an open 4 mL glass vial. These 4 mL open vials were then placed in a 40 mL glass vial. To the 40 mL vial, antisolvent was added. These 40 mL vials were then tightly capped and placed at ambient temperature (approximately 20-25°C) for up to 14 days. The precipitate was collected by centrifugal filtration through a 0.45 μm nylon membrane filter at 14,000 rpm. The solid portion (wet cake) was examined by XRPD. The results are summarized in Table 3-12. [Table 12]

[0387] Crystallization by heating and cooling DSC The polymorphic behavior of Compound I free acid Form A was investigated by two different heating-cooling DSC cycles. The results are summarized in Tables 3-13. [Table 13]

[0388] Investigating polymorphic correlations by variable temperature XRPD The correlation between polymorphs of Compound I free acid was investigated by variable temperature XRPD (VT-XRPD), and the results are summarized in Tables 3-14. [Table 14]

[0389] Water activity experiment Water activity experiments were carried out in MeOH / water system at 25°C to determine the critical water activity between Form A, Form C, Form E, Form F, Form H, Form I, Form J, Form K, Form M, and Form N of Compound I free acid. Approximately 1.5 mg of each sample was added to 0.2 mL of saturated solution in MeOH / water system. The resulting suspensions were each stirred at 25°C for 3 days. The solid portion (wet cake) was isolated by centrifugal filtration and examined by XRPD. The results are summarized in Table 3-15. [Table 15]

[0390] conclusion A total of 12 stable crystalline polymorphs of Compound I free acid were obtained from screening experiments using free acid Form A as the starting material. Free acid Form M is a metastable hydrate with low crystallinity, and free acid Form L is a DMSO-water heterosolvate that is isomorphous with free acid Form N.

[0391] Free Acid Form A Form A of Compound I free acid was prepared by the procedure described in Example 1 by slurrying Compound I free acid in EtOAc at room temperature for 2 days. The XRPD of free acid Form A is shown in Figure 4A. The DSC curve of free acid Form A is shown in Figure 4B and exhibits two endothermic peaks at 49.7°C and 211.3°C. The TGA curve of free acid Form A is shown in Figure 4C and exhibits a 2.3% weight loss up to 200°C.

[0392] Free Acid Form B Compound I free acid Form B was prepared by equilibrating free acid Form A in acetonitrile under temperature cycling or by crystallization by slow cooling from a saturated solution of Compound I free acid Form A in ACN. The XRPD of free acid Form B is shown in Figure 5A. The DSC curve of free acid Form B is shown in Figure 5B and exhibits two endothermic peaks at 32.4°C and 199.0°C. The TGA curve of free acid Form B is shown in Figure 5C and exhibits a 3.3% weight loss up to 180°C.

[0393] Free Acid Form C Form C of Compound I free acid was prepared by equilibration of free acid Form A in MTBE. The XRPD of free acid Form C is shown in Figure 6A. The DSC curve of free acid Form C is shown in Figure 6B and exhibited three endothermic peaks at 31.7°C, 134.9°C, and 194.7°C. The TGA curve of free acid Form C is shown in Figure 6C and exhibited a 5.5% weight loss up to 180°C.

[0394] Free Acid Form D Form D of the free acid of Compound I was prepared by equilibration of 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 free acid Form D is shown in Figure 7B and showed three endothermic peaks at 36.1 °C, 198.1 °C, and 223.9 °C, and an exothermic peak at 133.7 °C. The TGA curve of free acid Form D is shown in Figure 7C and showed a weight loss of 1.4% up to 200 °C.

[0395] Free Acid Form E Form E of the free acid of Compound I was prepared by equilibration of 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 free acid Form E is shown in Figure 8B and exhibited two endothermic peaks at 43.6°C and 223.9°C. The TGA curve of free acid Form E is shown in Figure 8C and exhibited a 2.5% weight loss up to 200°C.

[0396] Free Acid Form F Form F of the free acid of Compound I was prepared by equilibration of free acid Form A in acetonitrile. The XRPD of free acid Form F is shown in Figure 9A. The DSC curve of free acid Form F is shown in Figure 9B and exhibited four endothermic peaks at 46.2°C, 121.0°C, 159.4°C, and 230.4°C. The TGA curve of free acid Form F is shown in Figure 9C and exhibited a weight loss of 1.2% up to 200°C.

[0397] Free Acid Form G Compound I free acid Form G was prepared by equilibration of 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 free acid Form G is shown in Figure 10B and exhibits two endothermic peaks at 52.9 °C and 208.7 °C. The TGA curve of free acid Form G is shown in Figure 10C and exhibits a weight loss of 8.5% up to 55 °C and a further 5.9% from 55 to 180 °C.

[0398] Free Acid Form H Compound I free acid Form H was prepared by equilibration of free acid Form A in acetone / water (1:1 v / v) at 25° C. The XRPD of free acid Form H is shown in Figure 11A. The DSC curve of free acid Form H is shown in Figure 11B and exhibited three endothermic peaks at 51.3° C., 105.5° C., and 217.2° C. The TGA curve of free acid Form H is shown in Figure 11C and exhibited a 7.7% weight loss up to 180° C.

[0399] Free Acid Form I Form I of the free acid of Compound I was prepared from free acid Form A in 1,4-dioxane by inverse addition of an anti-solvent (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 and showed two endothermic peaks at 41.5°C and 207.3°C. The TGA curve of free acid Form I is shown in Figure 12C and showed a 7.4% weight loss up to 200°C.

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

[0401] Free Acid Form K Compound I free acid Form K was obtained by storing free acid Form B at ambient conditions (23-27°C, 50-70% RH) for two weeks. The XRPD of free acid Form K is shown in Figure 14A. The DSC curve of free acid Form K is shown in Figure 14B and exhibits two endothermic peaks at 46.1°C and 198.4°C. The TGA curve of free acid Form K is shown in Figure 14C and exhibits a weight loss of 2.4% up to 70°C and a further 2.6% from 70 to 170°C.

[0402] Free Acid Form L Compound I free acid Form L is a DMSO-water heterosolvate. It is isomorphous with hydrate Form N. It was obtained from DMSO / water (v:v=1:1) by equilibration at 50°C. DSC shows a dehydration / desolvation peak beginning at approximately 6°C and an endothermic peak beginning at approximately 120°C. Based on the DSC thermogram and observations using a melting apparatus, the endothermic peak beginning at approximately 120°C corresponds to dehydration / desolvation accompanied by melting. No recrystallization was observed after melting. TGA shows a weight loss of approximately 7.9% at 70°C and approximately 7.4% from 70°C to 200°C. KF indicates a water content of 9.6% (approximately 6.2 equivalents by molar ratio). 1 H-NMR indicates 1.8 equivalents of DMSO (approximately 12.0% by weight).

[0403] Free Acid Form M Compound I free acid Form M is a metastable hydrate. It was obtained from water by equilibration at 25° C. using the amorphous form as the starting material. It was converted to Form N by the addition of Form N species.

[0404] Free Acid Form N Form N of the free acid of Compound I was prepared by equilibration of free acid Form A in DMSO / water (1:1 v / v) at 50° C. The XRPD of free acid Form N is shown in Figure 17A. The DSC curve of free acid Form N is shown in Figure 17B and showed three endothermic peaks at 68.6° C., 81.0° C., and 207.7° C. The TGA curve of free acid Form N is shown in Figure 17C and showed a 9.0% weight loss up to 200° C.

[0405] In summary, Compound I free acid Form A is the most stable polymorph over a wide water activity range of 0 to 0.8. It exhibits good chemical and physical stability and is slightly hygroscopic. It exhibits reversible dehydration-hydration behavior upon heating, with a rapid hydration rate. While it converts to another hydrate, Form N, in water, free acid Form A is stable in bulk at 92.5% RH for up to one week. Therefore, Compound I free acid Form A is recommended as the optimal polymorph for further development.

[0406] Solvent abbreviations used Solvent abbreviations are listed in Table 3-16. [Table 16]

[0407] Apparatus and method XRPD XRPD data were collected on a Bruker D8 Advance X-ray powder diffractometer, and the detailed parameters are listed in Table 3-17. [Table 17]

[0408] Variable Temperature XRPD XRPD For variable temperature XRPD (VT-XRPD) analysis, a Bruker D8 Advance X-ray powder diffractometer was used. The XRPD parameters used are shown in Table 3-18. [Table 18]

[0409] DSC and TGA DSC data was collected using a TA Instruments TA Discovery 2500. DSC was performed using a TA Instruments TA Discovery 5500. The detailed parameters used are shown in Table 3-19. [Table 19]

[0410] DVS DVS was measured by SMS (Surface Measurement System) DVS Intrinsic or ProUmid SPSx-1μ Advance. The parameters used for DVS testing are listed in Table 3-20. [Table 20]

[0411] KF Karl Fischer data were collected using a Mettler Toledo Coulometric KF Titrator C30 or a Metrohm 851 / 885 system. Detailed parameters used are shown in Table 3-21. [Table 21]

[0412] 1 H NMR 1 H NMR data was collected on a Bruker Avance-AV 400 MHz NMR using DMSO-d as the solvent. Detailed parameters used are listed in Table 3-22. [Table 22]

[0413] Example 4: Evaluation of Compound I Free Acid Form A Physicochemical characteristics of Form A of Compound I free acid To obtain a representative sample free of residual solvent, Form A of Compound I free acid was prepared using the following procedure: This batch was used for the evaluations in this section.

[0414] Approximately 500 mg of Compound I free acid Form A was weighed into a 20 mL glass vial. 4 mL of EtOAc was added to the vial. The resulting suspension was stirred at 200 rpm at 25°C. The suspension was allowed to stir at 25°C for approximately 2 days. The solid was collected by centrifugation and then placed under ambient conditions (23-27°C, 50%-70% RH) for approximately 20 hours. Approximately 443 mg of free acid Form A was obtained (yield: 89%).

[0415] Bulk Stability Form A of Compound I free acid was stored 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 for one week. After storage, samples were characterized by XRPD and HPLC and examined for color change. The results are summarized in Table 4-1. No change in morphology or purity was observed under all three storage conditions. [Table 23]

[0416] Water adsorption and desorption experiments The water adsorption and desorption behavior of Compound I free acid Form A was investigated by DVS at 25°C using cycles of 40-95-0-95-40% RH, dm / dt 0.002, a minimum equilibration time of 60 minutes, and a maximum equilibration time of 360 minutes. XRPD was measured after the DVS test to determine the form change. The results are summarized in Table 4-2. [Table 24]

[0417] Compression simulation experiment Approximately 20 mg of Compound I free acid Form A was compressed for 5 minutes using a hydraulic press under pressures of 2.5 MPa, 5 MPa, and 10 MPa. Potential morphology changes and crystallinity were assessed by XRPD. The results are summarized in Table 4-3. A decrease in crystallinity was observed under all conditions, while morphology remained unchanged. [Table 25]

[0418] Dry grinding simulation experiment Approximately 20 mg of Compound I free acid Form A was manually ground with a mortar and pestle for 3 minutes. No change in morphology or crystallinity was observed by XRPD.

[0419] Wet granulation simulation experiment Water or ethanol was added dropwise to approximately 20 mg of Compound I free acid Form A until the sample was sufficiently wet. The wet sample was gently crushed with a mortar and pestle. The granulated sample was allowed to dry under ambient conditions for 10 minutes. The results are summarized in Table 4-4. For the water-wetted sample, no change in morphology or crystallinity was observed by XRPD. For the ethanol-wetted sample, no change in morphology was observed by XRPD, and a slight decrease in crystallinity was observed. [Table 26]

[0420] conclusion Compound I free acid Form A was evaluated for bulk stability, hygroscopicity, compression simulation, and dry / wet granulation simulation experiments. Free acid Form A was physically and chemically stable after stress under all three conditions for one week. No morphological changes or obvious chemical degradation were observed after the bulk stability test. Free acid Form A was slightly hygroscopic at 40% RH to 95% RH, with a water uptake of 1.0%. After the DVS test, the resulting sample remained free acid Form A. Free acid Form A exhibited good resistance to manual milling and wet granulation using water as a dispersant, without morphological changes or obvious loss of crystallinity. Free acid Form A showed no morphological changes and only a slight decrease in crystallinity after wet granulation using EtOH as a dispersant and compression experiments under 2.5 MPa and 5 MPa. Free acid Form A showed no morphological changes after compression under 10 MPa, but showed an obvious decrease in crystallinity.

[0421] Apparatus and method The XRPD and DVS instruments and methods used were the same as in Example 3.

[0422] HPLC HPLC data were collected on an Agilent 1260 Infinity II Binary Pump instrument, and detailed parameters are shown in Tables 4-5. [Table 27]

[0423] Example 5: Further salt screening experiments Further salt screening was performed using five counterions as salt formers. Approximately 200 mg of Compound 1 free acid Form A was added to an appropriate amount of acetone or ACN to obtain a clear solution. 1.0 equivalent of the selected counterion was dissolved in water. The solution was mixed and subjected to rotary evaporation to obtain an amorphous solid. Salt formation 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 28]

[0424] The clear solution obtained from above was further cooled slowly to 5°C. After stirring at 5°C for 2 days, no solid precipitated. The solution was further treated by adding anti-solvent. 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 salt hits (potassium salt Form A and sodium salt Form B) were obtained. [Table 29]

[0425] Characterization of salt forms of compound I Four salt forms were obtained from the salt screening and further experiments and were characterized by XRPD, TGA and DSC. The stoichiometry of the salts was determined by HPLC / IC or 1 The results of all characterizations were determined using H NMR. Table 5-3 summarizes the results of all characterizations. [Table 30]

[0426] Sodium salt Form A of the sodium salt of Compound I (Na Salt Form A) was obtained by slurrying the free acid Form A and equimolar NaOH in acetone at room temperature for 4 days.

[0427] The TGA / DSC curve for Compound I sodium salt Form A showed a weight loss of 1.8% by 120° C. and an endotherm at 66.5° C. (peak). 1 H NMR showed the acetone / API molar ratio to be 0.37 (2.3 wt%). HPLC / IC showed the molar ratio to be 1.0 (base / FA).

[0428] Form B of the sodium salt of Compound I (Na salt Form B) was obtained by slurrying the free acid Form A and equimolar NaOH in THF at room temperature for 4 days, slowly cooling to 5° C., stirring for 2 days, followed by the addition of an anti-solvent (water). The XRPD pattern is shown in Figure 19A.

[0429] K salt Form A of the potassium salt of Compound I (K Salt Form A) was obtained by slurrying the free acid Form A and equimolar KOH in acetone at room temperature for 4 days, slowly cooling to 5° C., stirring for 2 days, followed by the addition of an anti-solvent (MTBE). The XRPD pattern is shown in Figure 20A.

[0430] The DSC curve for Form A of the potassium salt of Compound I (K Salt Form A) is shown in Figure 20B and exhibited three endotherms at 50.9°C, 166.2°C, and 237.7°C (peaks). The TGA curve is shown in Figure 20C and exhibited a 1.4% weight loss by 130°C. 1 H 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 the molar ratio was 0.9 (base / FA).

[0431] L-Arginine Salt Form A of the Compound I L-arginine salt (L-arginine Form A) was obtained by slurrying the free acid Form A and equimolar L-arginine in THF at room temperature for 4 days.

[0432] The TGA / DSC curve for L-arginine salt Form A showed a weight loss of 2.4% by 120°C and an endotherm at 57.3°C (peak). 1 H 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 %).

[0433] Remanufacturing selected salt Na salt Form A, Na salt Form B, and L-arginine salt Form A were selected for re-preparation. To prepare Na salt Form B, approximately 40 mg of free acid Form A and 1.0 equivalents 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 resulting solid was analyzed by XRPD, which showed that only the amorphous form was obtained.

[0434] Na salt Form A and L-arginine salt Form A could be reproduced on a 600 mg scale and characterized by XRPD, TGA, DSC, NMR, or HPLC / IC. The results are summarized in Table 5-4. [Table 31]

[0435] Sodium salt Form A of the sodium salt of Compound I (Na salt Form A) was reprepared by slurrying approximately 600 mg of free acid Form A and equimolar NaOH in 7.5 mL of acetone at room temperature for 4 days. The resulting solid was centrifuged and dried under vacuum at 50°C for 2 hours. The XRPD pattern is shown in Figure 18A. The DSC curve of Na salt Form A is shown in Figure 18B and exhibited an endotherm at 124.8°C (peak). The TGA curve of Na salt Form A is shown in Figure 18C and exhibited a 4.1% weight loss by 100°C. HPLC / IC results indicated a molar ratio of 1.0 (base / FA). 1 H NMR indicated that the acetone / API molar ratio was 0.6 (3.8 wt%). Based on the data, Na salt Form A is likely a heterosolvate of acetone and water.

[0436] L-Arginine Salt Form A of Compound I L-arginine salt (L-arginine salt Form A) was reconstituted from approximately 600 mg of free acid Form A and equimolar L-arginine by slurrying in 3.4 mL of ACN / HO (7.5:1, v / v), followed by rotary evaporation and equilibration in THF at room temperature for 5 days. The resulting solid was centrifuged and vacuum dried at 50°C for 2 hours. The XRPD pattern is shown in Figure 1A. The DSC curve of L-arginine salt Form A is shown in Figure 1B, which exhibited an endotherm at 66.0°C (peak). The TGA curve of L-arginine salt Form A is shown in Figure 1C, which exhibited a 3.2% weight loss by 120°C. 1 H NMR indicated that the base / FA molar ratio was 1.0 and the THF / API molar ratio was 0.8 (5.6 wt%). Based on the data, L-arginine salt Form A is likely a heterosolvate of THF and water.

[0437] Salt Rating Two remanufactured salt samples were used for salt evaluation, including hygroscopicity, dynamic solubility, and solid state stability. The starting material, Compound I free acid Form A, was also evaluated for comparison.

[0438] solid state stability The bulk stability of the free acid Form A and two salt candidates was examined for two weeks at 25°C / 92.5% RH in open containers, 40°C / 75% RH in open containers, and 60°C in airtight containers. The free acid Form A and L-arginine salt Form A are chemically and physically stable under these conditions. The solid-state stability results are summarized in Table 5-5. The Na salt Form A was chemically stable under these conditions but physically unstable at 25°C / 92.5% RH and 40°C / 75% RH, and exhibited morphological changes at the two conditions as observed by XRPD. [Table 32]

[0439] dynamic solubility Dynamic solubilities were measured for Compound I free acid Form A and remanufactured salt forms in water and three biorelevant media. Tables 4-11 summarize the biorelevant media preparation procedures. The solubility of free acid Form A and 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 and 1 hour.

[0440] Approximately 10 mg of material in 5 mL of water, buffer, SGF, FaSSIF, or FeSSIF 1 The solids were weighed into a 100 ml container and subsequently rotated at 25 rpm at 37°C for 0.5 and 1 hour. Approximately 0.8 mL of the suspension was sampled at each time point for centrifugation and filtration. The solids were tested by XRPD. The results are summarized in Tables 5-6. Based on the results, the solubility of the salts was higher than that of the free acid Form A in water, alkaline borate buffer, and FeSSIF, and the solubility of the Na salt Form A was higher than that of the L-arginine salt Form A. The XRPD results indicated that disproportionation was observed for the Na salt Form A after the solubility test. [Table 33]

[0441] Hygroscopic To evaluate the hygroscopicity of Compound I free acid Form A and the remanufactured salt forms (Na salt Form A and L-arginine salt Form A), DVS isotherm plots were collected at 25°C between 0% RH and 95% RH. XRPD characterization was performed on the samples after DVS testing. The DVS evaluation results are summarized in Tables 5-7. Based on the results, all three forms were hygroscopic, with the lowest water uptake observed for Compound I free acid Form A. Compound I Na salt Form A was converted to a new form after DVS testing. [Table 34]

[0442] conclusion Using Compound I free acid Form A as the starting material, salt screening was performed under 33 conditions with 11 bases in three solvent systems. No crystalline salt hits were obtained, but two new free acid forms were identified. Further experiments using six bases in ACN / HO (7:3 v / v) as the solvent also failed to yield crystalline salt hits, but four new free acid forms were identified. Finally, further experiments using five counterions and five solvents, followed by slow cooling and / or addition of antisolvent, yielded four crystalline salt hits. Compound I sodium salt Form A, Compound I sodium salt Form B, and Compound I L-arginine salt Form A were selected for reproducibility. Of the three, Compound I sodium salt Form A and Compound I L-arginine salt Form A were successfully produced.

[0443] The remanufactured salts were used in salt evaluations along with Compound I free acid Form A. DVS results indicated that free acid Form A exhibited the lowest water uptake, and a morphological change was observed for Compound I Na salt Form A after DVS. Dynamic solubility results indicated that the salts were more soluble than free acid Form A in water, alkaline borate buffer, and FeSSIF, and that the solubility of Na salt Form A was higher than that of L-arginine salt Form A. Solid-state stability evaluation results indicated that free acid Form A and L-arginine salt Form A were chemically and physically stable under all test conditions, but Na salt Form A was physically unstable at 25°C / 92.5% RH and 40°C / 75% RH.

[0444] Based on the results of the salt evaluation and solid-state characterization, Form A of the Compound I L-arginine salt was selected for further polymorph screening.

[0445] Apparatus and method XRPD For XRPD analysis, a Bruker X-ray powder diffractometer was used, and the XRPD parameters used are listed in Tables 5-8. [Table 35]

[0446] TGA and DSC TGA data were collected using a TA Instruments Discovery 5500 or Q5000 TGA. DSC was performed using a TA Instruments Discovery 2500 DSC. Detailed parameters used are listed in Tables 5-9. [Table 36]

[0447] DVS DVS was measured by SMS (Surface Measurement System) DVS Intrinsic. Relative humidity at 25°C was calibrated against the deliquescence points of LiCl, Mg(NO3)2 and KCl. DVS test parameters are shown in Tables 5-10. [Table 37]

[0448] PLM PLM photographs were captured with an Olympus BX53 LED using crossed polarizers and silicone oil was added.

[0449] Karl Fischer KF analysis was performed on a Mettler Toledo Coulometric KF Titrator C30 using coulometry.

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

[0451] HPLC / IC A Waters H-Class UPLC was used, and the detailed chromatographic conditions are shown in Table 5-11. The IC parameters are shown in Table 5-12. [Table 38] [Table 39]

[0452] Example 6: Polymorph Screening and Evaluation of Compound I L-Arginine Salt The objective of this project was to perform polymorph screening and evaluation of L-arginine salts to select a lead form for further study. The starting material was characterized by XRPD, TGA, and DSC. The XRPD pattern indicated the material was free acid Form A. The TGA / DSC results showed a 3.8% weight loss by 200°C and a melting endotherm at 232.2°C (onset).

[0453] Remanufacturing L-arginine salts Approximately 8 g of Compound I L-arginine salt Form B was prepared from the reaction of Compound I and L-arginine in IPA / HO (7:3 v / v). After stirring for approximately 2 hours at 50-55°C, 2.38 volume equivalents of IPA and 2 wt% crystal seeds were added to the clear solution, causing the mixture to become cloudy. After stirring for 2 hours, approximately 15.5 volume equivalents of IPA were added dropwise to the mixture. After stirring for 8 hours at 50-55°C, the mixture was further stirred at 0-°C for 10 hours. The precipitated solid was collected by filtration, washed with IPA, and dried at 65-75°C. Purity by HPLC: 97.7%.

[0454] Approximate solubility at 25°C and 50°C The solubility of the starting material was determined in 21 solvents at two temperatures.

[0455] For solubility at 25°C, approximately 5 mg of L-arginine salt was weighed into a 2 mL glass vial. A 20 μL aliquot of each solvent was added to dissolve the material at 25°C. Vortexing and sonication were performed to aid dissolution. The maximum volume of each solvent added was 1 mL. Approximate solubility was determined by visual observation.

[0456] For solubility at 50°C, approximately 10 mg of L-arginine salt was weighed into a 2 mL glass vial. A 20 μL aliquot of each solvent was added to dissolve the material at 50°C. Vortexing and sonication were performed 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 40]

[0457] Equilibration with solvent at 25°C and 50°C Based on the 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 filtered through a 0.45 μm nylon membrane filter by centrifugation at 14,000 rpm. The solid precipitate (wet cake) was examined by XRPD. Samples with different XRPD patterns were analyzed by DSC, TGA, and HCl for the hydrate. 1 Further analyses were performed, including H-NMR and KF, and the results are summarized in Tables 6-2 and 6-3. [Table 41-1] [Table 41-2] [Table 42-1] [Table 42-2]

[0458] Equilibration under temperature cycling Based on the approximate solubility results, approximately 50 mg of L-arginine salt was equilibrated in 0.2 to 1 mL of solvent at 5 to 50 °C for 10 cycles at a heating / cooling rate of 0.1 °C / min. Equilibration was performed on a magnetic stir plate at 300 to 400 rpm with a stir bar.

[0459] The resulting suspension was filtered through a 0.45 μm nylon membrane filter by centrifugation at 14,000 rpm. The solid portion (wet cake) was examined by XRPD. Samples with different XRPD patterns were analyzed by DSC, TGA, and hydrate analysis.1 Further analysis was performed, including H-NMR and KF, and the results are summarized in Table 6-4. [Table 43-1] [Table 43-2] [Table 43-3]

[0460] Crystallization by slow evaporation at room temperature Based on the approximate solubility results, approximately 20 mg of L-arginine salt was dissolved in 0.1-15 mL of solvent. The resulting solution was filtered through a 0.45 μm nylon membrane filter. The clear solution was allowed to slowly evaporate under ambient conditions (approximately 23-27°C, 60-80% RH). The solid residue was examined by XRPD. The results are summarized in Table 6-5. [Table 44]

[0461] Crystallization by rapid evaporation at room temperature Based on the approximate solubility results, approximately 20 mg of L-arginine salt was dissolved in 0.1-15 mL of solvent. The resulting solution was filtered through a 0.45 μm syringe membrane filter. The clear solution was rapidly evaporated under a stream of dry nitrogen at ambient conditions (approximately 23-27 °C, 60-80% RH). The solid residue was examined by XRPD. The results are summarized in Table 6-6. [Table 45]

[0462] Crystallization from a hot saturated solution by slow cooling Based on the approximate solubility results, approximately 30 mg of L-arginine salt was dissolved in a minimum amount of selected solvent at 50°C. The resulting solution was filtered through a 0.45 μm syringe membrane filter. The clear solution was cooled to 5°C at a rate of 0.1°C / min. Samples without precipitate at 5°C were further cooled to -20°C. The results are summarized in Tables 6-7. [Table 46]

[0463] Crystallization from hot saturated solutions by rapid cooling Based on the approximate solubility results, approximately 30 mg of L-arginine salt was dissolved in a minimal amount of selected solvent at 50°C. The resulting solution was filtered through a 0.45 μm syringe membrane filter. The clear solution was brought to 5°C and stirred. The clear solution was further cooled to -20°C. The results are summarized in Tables 6-8. [Table 47]

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

[0465] The precipitate was collected by centrifugal filtration through a 0.45 μm nylon membrane filter at 14,000 rpm. The solid portion (wet cake) was examined by XRPD. For samples with different XRPD patterns, 1 Further analysis was carried out, including H-NMR, and the results are summarized in Tables 6-9. [Table 48]

[0466] Crystallization by reverse addition of antisolvent Based on the approximate solubility results, approximately 40 mg of L-arginine salt was dissolved in a minimum amount of the selected good solvent at ambient conditions (approximately 23-27°C, 60-80% RH). The resulting solution was filtered through a 0.45 μm syringe membrane filter. The clear solution was quickly added to 4-8 volumes of the poor solvent.

[0467] The precipitate was collected by centrifugal filtration through a 0.45 μm nylon membrane filter at 14,000 rpm. The solid portion (wet cake) was examined by XRPD. Samples with different XRPD patterns were analyzed by TGA, DSC, and 1 Further analysis was carried out, including H-NMR, and the results are summarized in Tables 6-10. [Table 49]

[0468] Crystallization by vapor diffusion Based on the approximate solubility results, approximately 30 mg of L-arginine salt was dissolved in a minimal amount of 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 clear solution was transferred to an open 4 mL glass vial. These 4 mL vials were then placed in a 40 mL glass vial. To the 40 mL vial, antisolvent was added. These 40 mL vials were then tightly capped and placed at approximately 23-27°C and 60-80% RH for up to 14 days. The results are summarized in Tables 6-11. [Table 50]

[0469] Crystallization by heating and cooling DSC The polymorphic behavior of L-arginine salts was investigated by two different heating-cooling DSC cycles, and the results are summarized in Tables 6-12. [Table 51]

[0470] Variable Temperature XRPD (VT-XRPD) The correlation between polymorphs was investigated by variable temperature XRPD, and the results are summarized in Tables 6-13. [Table 52]

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

[0472] L-Arginine Salt Form A Form A of Compound I L-arginine salt was prepared by the procedure described in Example 2, followed by equilibration in THF at room temperature for 5 days. The resulting solid was centrifuged and dried under vacuum at 50°C for 2 hours. The XRPD pattern is shown in Figure 1A. The DSC curve of L-arginine salt Form A is shown in Figure 1B, which exhibited an endotherm at 66.0°C (peak). The TGA curve of L-arginine salt Form A is shown in Figure 1C, which exhibited a weight loss of 3.2% by 120°C.

[0473] L-Arginine Salt Form B Compound I L-arginine salt Form B was prepared by equilibration of the 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 2A. The DSC curve of L-arginine salt Form B is shown in Figure 2B and exhibited endotherms at 17.6°C (peak) and 243.7°C (peak). The TGA curve of the free acid Form B is shown in Figure 2C and exhibited a weight loss of 3.9% up to 200°C and a further 4.5% from 200 to 250°C.

[0474] L-Arginine Salt Form C Form C of Compound I L-arginine salt was prepared by equilibration of the L-arginine salt starting material in acetone at 25°C. The XRPD of free acid Form B is shown in Figure 3A. The DSC curve of free acid Form B is shown in Figure 3B and exhibits two endothermic peaks at 52.9°C and 232.9°C. The TGA curve of free acid Form B is shown in Figure 3C and exhibits a weight loss of 5.2% up to 200°C and a further 3.7% from 200 to 260°C.

[0475] Apparatus and method XRPD For XRPD analysis, a Bruker D8 Advance X-ray powder diffractometer was used, and the XRPD parameters used are listed in Tables 6-14. [Table 53]

[0476] Variable Temperature XRPD XRPD For variable temperature XRPD (VT-XRPD) analysis, a Bruker D8 Advance X-ray powder diffractometer was used. The XRPD parameters used are shown in Table 6-15. [Table 54]

[0477] DSC and TGA DSC data was collected using a TA Instruments TA Discovery 2500. DSC was performed using a TA Instruments TA Discovery 5500. Detailed parameters used are listed in Tables 6-16. [Table 55]

[0478] DVS DVS was measured by SMS (Surface Measurement System) DVS Intrinsic or ProUmid SPSx-1μ Advance. The detailed parameters of DVS test are shown in Table 6-17. [Table 56]

[0479] KF Karl Fischer data were collected using a Mettler Toledo Coulometric KF Titrator C30 or a Metrohm 851 / 885 system. Detailed parameters used are shown in Tables 6-18. [Table 57]

[0480] 1 H NMR 1 H NMR data was collected on a Bruker Avance-AV 400 MHz NMR using DMSO-d as the solvent. Detailed parameters used are listed in Table 6-19. [Table 58]

[0481] Example 7: Preparation and Evaluation of Form C of Compound I L-Arginine Salt Preparation of Form C of Compound I L-Arginine Salt Form C of Compound I L-arginine salt 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. An additional 3 mL of acetone was added. After stirring for an additional 2 days, the solid was collected by centrifugation at 4000 rpm. The wet cake was dried under vacuum at 50°C with humidity control (approximately 65% ​​RH). Approximately 711 mg of L-arginine salt Form C was obtained in 71% yield.

[0482] Physicochemical properties The physical and chemical characteristics of Compound I L-arginine salt Form C obtained above were analyzed by XRPD, DSC / TGA, HPLC, and the like. 1 It was investigated in detail by H NMR, KF and scanning electron microscopy (SEM), and the results are summarized in Table 7-1. [Table 59]

[0483] Bulk Stability L-arginine salt Form C 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. After storage, samples were characterized by XRPD and HPLC and examined for color changes. No changes in HPLC purity, color, or XRPD were observed under any storage condition. The results are summarized in Table 7-2. [Table 60]

[0484] Water adsorption and desorption experiments The water adsorption and desorption behavior of L-arginine salt Form C was investigated by DVS, and XRPD was measured after the DVS test to determine the morphology change. The sample was slightly hygroscopic, with approximately 4.3% water uptake observed from 40% RH to 95% RH. The results are summarized in Table 7-3. [Table 61]

[0485] Compression simulation experiment Approximately 20 mg of L-arginine salt Form C was compressed using a hydraulic press under pressures of 2.5 MPa, 5 MPa, and 10 MPa for 3 minutes. Potential morphological changes and crystallinity were assessed by XRPD. No morphological changes were observed, but a decrease in crystallinity was observed. The results are summarized in Table 7-4. [Table 62]

[0486] Dry grinding simulation experiment Approximately 20 mg of L-arginine salt Pattern C was manually ground with a mortar and pestle for 3 minutes. No morphological change was observed, but a slight decrease in crystallinity was observed.

[0487] Wet granulation simulation experiment Water or ethanol was added dropwise to approximately 20 mg of L-arginine salt Pattern C until the sample was sufficiently wet. The wet sample was gently ground with a mortar and pestle for 3 minutes. The granulated sample was dried under ambient conditions (approximately 20-25°C, 60-80% RH) for 10 minutes. Potential morphological changes and crystallinity were evaluated by XRPD. No morphological changes were observed, but a slight decrease in crystallinity was observed. The results are summarized in Table 7-5. [Table 63]

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

[0489] XRPD XRPD data were collected on a Bruker D8 Advance X-ray powder diffractometer, and the detailed parameters are listed in Table 7-6. [Table 64]

[0490] SEM SEM images were collected on a Phenom Prox SEM-EDS instrument, and the detailed parameters are listed in Table 7-7. [Table 65]

[0491] HPLC HPLC data were collected on an Agilent 1260 Infinity II Binary Pump instrument, and detailed parameters are shown in Tables 7-8. [Table 66]

[0492] Example 8: Pharmacokinetic study of Compound I L-arginine salt Form B, L-arginine salt Form A, free acid Form A, and sodium salt Form A in dogs The objective of this study was to characterize the pharmacokinetics (PK) of Compound I in male beagle dogs after oral (PO) or IV administration.

[0493] Compound I Free Acid Form A - PO / IV LC-MS / MS for PK studies of Compound I free acid Form A was performed using the following equipment / conditions. [Table 67]

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

[0495] The formulations were prepared on the day of administration and stored at room temperature before administration. The doses were administered via cephalic vein injection and oral gavage at target dose volumes of 1 and 2 mL / kg, respectively. After intravenous and oral administration, blood samples were collected from the cephalic vein. For the IV and PO groups, blood samples were collected pre-dose and 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours post-dose.

[0496] Plasma concentrations of Compound I free acid Form A were determined by liquid chromatography with mass spectrometry detection (LC-MS / MS). PK data are summarized in Table 8-2 below. [Table 68]

[0497] Compound I L-Arginine Salt Form B - PO Formulation LC-MS / MS for PK studies of Compound I L-arginine salt Form B was performed using the following equipment / conditions. [Table 69]

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

[0499] The formulation was prepared on the day of administration and stored at room temperature before administration. The dose was administered orally to the dogs by gavage. After oral administration, blood samples were collected from the animals via a peripheral vein at 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration.

[0500] Plasma concentrations of Compound I L-arginine salt Form B were determined by liquid chromatography with mass spectrometry detection (LC-MS / MS). PK data are summarized in Table 8-4 below. [Table 70]

[0501] Compound I free acid Form A, sodium salt Form A, and L-arginine salt Form A LC-MS / MS for PK studies was performed using the equipment and conditions shown in Table 8-3.

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

[0503] The doses were administered orally to the dogs by gavage. After oral administration, blood samples were taken from the animals via a peripheral vein at 0.25, 0.5, 1, 2, 4, 8 and 24 hours after administration.

[0504] Plasma concentrations of Compound I were determined by liquid chromatography with mass spectrometry detection (LC-MS / MS). PK data are summarized in Table 8-5 below. [Table 71]

[0505] conclusion Form B of the Compound I L-arginine salt exhibited a superior pharmacokinetic profile. Mean AUC of Compound I L-Arginine Salt Form B in Capsules last and Cmax The values ​​were higher than those of Compound I free acid Form A, sodium salt Form A, or L-arginine salt Form A. Thus, Compound I L-arginine salt Form B exhibited better oral bioavailability than the other forms tested.

[0506] Those skilled in the art will readily appreciate that the present disclosure is well adapted to obtain the objects and advantages mentioned, as well as those inherent therein. The methods, variations, and compositions described herein as presently representative of the embodiments are exemplary and are not intended as limitations on the scope of the disclosure. Modifications therein and other uses will occur to those skilled in the art which are encompassed within the spirit of the disclosure and defined by the scope of the claims.

Claims

1. Formula IB: 【Chemistry 1】 IB 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-oxadiazol-5(4H)-one L-arginine salt (Compound I L-arginine salt), having the formula:

2. 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]pyridine-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 solvate thereof.

3. 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-oxadiazol-5(4H)-one L-arginine salt Form B (Compound I L-arginine salt Form B), 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.

4. 4. The crystalline Compound I L-arginine salt Form B of claim 3, further characterized by an X-ray powder diffraction pattern containing one or more additional peaks expressed at ±0.2 degrees 2θ selected from 10.8, 15.3, 15.5, 18.0, 20.6, and 22.8, as determined by a diffractometer using Cu-Kα radiation.

5. 5. The crystalline Compound I L-arginine salt Form B of claim 3 or 4, further characterized by an X-ray powder diffraction pattern substantially as shown in Figure 2A.

6. 6. The crystalline Compound I L-arginine salt Form B of any one of claims 3 to 5, further characterized by a DSC comprising an endotherm at about 17.6°C (peak) and about 243.7°C (peak).

7. 6. The crystalline Compound I L-arginine salt Form B of any one of claims 3 to 5, further characterized by a DSC substantially as shown in Figure 2B.

8. 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-oxadiazol-5(4H)-one L-arginine salt Form A (Compound I L-arginine salt Form A), characterized by an X-ray powder diffraction pattern containing peaks expressed at ±0.2 degrees 2θ selected from 5.3, 9.1, and 11.5, as determined on a diffractometer using Cu-Kα radiation.

9. 10. The crystalline Compound I L-arginine salt Form A of claim 8, further characterized by an X-ray powder diffractogram comprising one or more additional peaks expressed at ±0.2 degrees two-theta selected from 13.8, 15.9, 16.5, 18.9, 20.9, and 22.8, as determined with a diffractometer using Cu-Kα radiation; an X-ray powder diffractogram substantially as shown in FIG. 1A; a DSC comprising a broad endotherm at about 66.0°C (peak) and about 35.8°C (onset); or a DSC substantially as shown in FIG. 1B.

10. 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-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 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. 11. The crystalline Compound I L-arginine salt Form C of claim 10, further characterized by an X-ray powder diffraction pattern comprising one or more additional peaks expressed at ±0.2 degrees two-theta selected from 10.8, 15.3, 15.5, 18.0, 20.6, and 22.8, as determined by a diffractometer using Cu-Kα radiation; an X-ray powder diffraction pattern substantially as shown in Figure 3A; a DSC comprising peaks at about 52.9°C (peak) and about 232.9°C (peak); or a DSC substantially as shown in Figure 3B.

12. 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-oxadiazol-5(4H)-one (Form A of Compound I free acid), characterized by an X-ray powder diffraction pattern containing peaks represented at ±0.2 degrees 2θ selected from 5.2, 6.1, and 12.4, as determined on a diffractometer using Cu-Kα radiation.

13. Form A of the crystalline Compound I free acid of claim 12, further characterized by an X-ray powder diffraction pattern comprising one or more additional peaks expressed at ±0.2°2θ selected from 15.0, 16.5, 16.9, 18.8, 20.2 and 21.9 as determined by a diffractometer using Cu-Kα radiation; an X-ray powder diffraction pattern substantially as shown in Figure 4A; a DSC comprising endotherms at about 49.7°C (peak) and about 211.3°C (peak), or a DSC substantially as shown in Figure 4B.

14. 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-oxadiazol-5(4H)-one (Form B of Compound I free acid), characterized by an X-ray powder diffraction pattern containing peaks expressed at ±0.2 degrees 2θ selected from 7.8, 9.2, and 10.0, as determined on a diffractometer using Cu-Kα radiation.

15. Form B of the crystalline Compound I free acid of claim 14, further characterized by an X-ray powder diffraction pattern comprising one or more additional peaks expressed at ±0.2°2θ selected from 10.3, 13.0, 13.7, 16.5, 20.5 and 23.2 as determined by a diffractometer using Cu-Kα radiation; an X-ray powder diffraction pattern substantially as shown in Figure 5A; a DSC comprising endotherms at about 32.4°C (peak) and about 199.0°C (peak), or a DSC substantially as shown in Figure 5B.

16. 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-oxadiazol-5(4H)-one (Form C of Compound I free acid), characterized by an X-ray powder diffraction pattern containing peaks represented by ±0.2 degrees 2θ selected from 4.1, 8.1, and 10.4, as determined on a diffractometer using Cu-Kα radiation.

17. Form C of the crystalline Compound I free acid of claim 16, further characterized by an X-ray powder diffraction pattern comprising one or more additional peaks expressed at ±0.2°2θ selected from 13.5, 14.6, 15.0, 15.5, 15.8 and 20.8 as determined by a diffractometer using Cu-Kα radiation; an X-ray powder diffraction pattern substantially as shown in Figure 6A; a DSC comprising endotherms at about 31.7°C (peak), 134.9°C (peak) and about 194.7°C (peak), or a DSC substantially as shown in Figure 6B.

18. 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-oxadiazol-5(4H)-one (Form D of Compound I free acid), characterized by an X-ray powder diffraction pattern containing peaks expressed at ±0.2 degrees 2θ selected from 6.5, 12.1, and 12.9, as determined on a diffractometer using Cu-Kα radiation.

19. 19. Form D of crystalline Compound I free acid of claim 18, further characterized by: an X-ray powder diffraction pattern including one or more additional peaks expressed at ±0.2°2θ selected from 14.0, 16.5, 16.9, 17.5, 18.8, and 21.0, as determined by a diffractometer using Cu-Kα radiation; an X-ray powder diffraction pattern substantially as shown in Figure 7A; a DSC including endotherms at about 36.1°C (peak), about 133.7°C (peak), about 198.1°C (peak), and about 223.9°C (peak), or a DSC substantially as shown in Figure 7B.

20. 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-oxadiazol-5(4H)-one (Form E of Compound I free acid), characterized by an X-ray powder diffraction pattern containing peaks expressed at ±0.2 degrees 2θ selected from 5.7, 11.1, and 16.1, as determined on a diffractometer using Cu-Kα radiation.

21. Form E of the crystalline Compound I free acid of claim 20, further characterized by an X-ray powder diffraction pattern comprising one or more additional peaks expressed at ±0.2°2θ selected from 17.1, 18.1, 18.7, 21.0, 21.3 and 21.6 as determined by a diffractometer using Cu-Kα radiation; an X-ray powder diffraction pattern substantially as shown in Figure 8A; a DSC comprising endotherms at about 43.6°C (peak) and about 223.9°C (peak), or a DSC substantially as shown in Figure 8B.

22. 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-oxadiazol-5(4H)-one (Form F of Compound I free acid), characterized by an X-ray powder diffraction pattern containing peaks represented by ±0.2 degrees 2θ selected from 7.2, 12.9, and 14.6, as determined on a diffractometer using Cu-Kα radiation.

23. 23. Form F of crystalline Compound I free acid of claim 22, further characterized by: an X-ray powder diffraction pattern including one or more additional peaks expressed at ±0.2°2θ selected from 16.1, 16.6, 17.5, 19.1, 19.9, and 21.8, as determined by a diffractometer using Cu-Kα radiation; an X-ray powder diffraction pattern substantially as shown in Figure 9A; a DSC including endotherms at about 46.2°C (peak), about 121.0°C (peak), about 159.4°C (peak), and about 230.4°C (peak), or a DSC substantially as shown in Figure 9B.

24. 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-oxadiazol-5(4H)-one (Form G of Compound I free acid), characterized by an X-ray powder diffraction pattern containing peaks expressed at ±0.2 degrees 2θ selected from 6.0, 11.9, and 14.8, as determined on a diffractometer using Cu-Kα radiation.

25. Form G of crystalline Compound I free acid of claim 24, further characterized by an X-ray powder diffraction pattern including one or more additional peaks expressed at ±0.2°2θ selected from 16.3, 16.6, 18.4, 18.8, 21.3 and 23.9 as determined by a diffractometer using Cu-Kα radiation; an X-ray powder diffraction pattern substantially as shown in Figure 10A; a DSC including endotherms at about 52.9°C (peak) and about 208.7°C (peak), or a DSC substantially as shown in Figure 10B.

26. 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-oxadiazol-5(4H)-one (Form H of Compound I free acid), characterized by an X-ray powder diffraction pattern containing 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.

27. 27. Form H of crystalline Compound I free acid of claim 26, further characterized by: an X-ray powder diffraction pattern including one or more additional peaks expressed at ±0.2°2θ selected from 11.0, 11.3, 11.9, 14.4, 16.5, and 18.1 as determined by a diffractometer using Cu-Kα radiation; an X-ray powder diffraction pattern substantially as shown in Figure 11A; a DSC including endotherms at about 51.3°C (peak), about 105.5°C (peak), and about 217.2°C (peak), or a DSC substantially as shown in Figure 11B.

28. 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-oxadiazol-5(4H)-one (Compound I free acid Form I), characterized by an X-ray powder diffraction pattern containing peaks expressed at ±0.2 degrees 2θ selected from 4.0, 12.2, and 14.0, as determined on a diffractometer using Cu-Kα radiation.

29. Form I of the crystalline Compound I free acid of claim 28, further characterized by an X-ray powder diffraction pattern comprising one or more additional peaks expressed at ±0.2°2θ selected from 15.1, 15.8, 16.7, 18.4, 21.0 and 22.0 as determined by a diffractometer using Cu-Kα radiation; an X-ray powder diffraction pattern substantially as shown in Figure 12A; a DSC comprising endotherms at about 41.5°C (peak) and about 207.3°C (peak), or a DSC substantially as shown in Figure 12B.

30. 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-oxadiazol-5(4H)-one (Form J of Compound I free acid), characterized by an X-ray powder diffraction pattern containing peaks expressed at ±0.2 degrees 2θ selected from 6.8, 11.6, and 13.5, as determined on a diffractometer using Cu-Kα radiation.

31. Form J of crystalline Compound I free acid of claim 30, further characterized by an X-ray powder diffraction pattern comprising one or more additional peaks expressed at ±0.2°2θ selected from 14.0, 15.0, 17.0, 17.3, 17.9 and 19.7 as determined by a diffractometer using Cu-Kα radiation; an X-ray powder diffraction pattern substantially as shown in Figure 13A; a DSC comprising endotherms at about 68.6°C (peak) and about 221.2°C (peak), or a DSC substantially as shown in Figure 13B.

32. 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-oxadiazol-5(4H)-one (Form K of Compound I free acid), characterized by an X-ray powder diffraction pattern containing peaks expressed at ±0.2 degrees 2θ selected from 8.7, 9.9, and 12.5, as determined on a diffractometer using Cu-Kα radiation.

33. Form K of crystalline Compound I free acid of claim 32, further characterized by an X-ray powder diffraction pattern including one or more additional peaks expressed at ±0.2°2θ selected from 14.2, 15.8, 16.4, 19.6, 21.1 and 23.6 as determined by a diffractometer using Cu-Kα radiation; an X-ray powder diffraction pattern substantially as shown in Figure 14A; a DSC including endotherms at about 46.1°C (peak) and about 198.4°C (peak), or a DSC substantially as shown in Figure 14B.

34. 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-oxadiazol-5(4H)-one (Form N of Compound I free acid), characterized by an X-ray powder diffraction pattern containing peaks expressed at ±0.2 degrees 2θ selected from 4.6, 6.3, and 7.2, as determined on a diffractometer using Cu-Kα radiation.

35. Form N of crystalline Compound I free acid of claim 34, further characterized by: an X-ray powder diffraction pattern including one or more additional peaks expressed at ±0.2°2θ selected from 9.2, 11.9, 16.1, 18.6, 20.4, and 21.0, as determined by a diffractometer using Cu-Kα radiation; an X-ray powder diffraction pattern substantially as shown in Figure 17A; a DSC including endotherms at about 68.6°C (peak), about 81.0°C (peak), and about 207.7°C (peak), or a DSC substantially as shown in Figure 17B.

36. Formula IA: 【Chemistry 2】 IA wherein 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. 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-oxadiazol-5(4H)-one (Compound I), having the formula:

37. 37. The crystalline salt form of claim 36, wherein the crystalline salt form is selected from the group consisting of Form A of the sodium salt of Compound I, Form B of the sodium salt of Compound I, and Form A of the potassium salt of Compound I.

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

39. 39. The pharmaceutical composition of claim 38, wherein at least 99% of compound I is compound I L-arginine salt or a solvate thereof according to claim 1.

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

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

42. 39. The pharmaceutical composition of claim 38, wherein at least 99% of Compound I is in the crystalline form of Form A of Compound I L-arginine salt as defined in claim 8 or 9.

43. 39. The pharmaceutical composition of claim 38, wherein at least 99% of Compound I is in the crystalline form of Form C of the L-arginine salt of Compound I of claim 10 or 11.

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

45. 39. The pharmaceutical composition of claim 38, wherein at least 99% of Compound I is a crystalline salt form of claim 36 or 37.

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

47. If your disease, disorder or condition is type 1 diabetes, type 2 diabetes, early-onset type 2 diabetes, idiopathic type 1 diabetes (type 1b), young-onset atypical diabetes (YOAD), maturity-onset diabetes of the young (MODY), latent autoimmune diabetes of adults (LADA), obesity, weight gain due to use of other medications, idiopathic intracranial hypertension, Wolfram syndrome, gout, excessive sugar cravings, 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 arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, arteriosclerotic cardiovascular disease, traumatic brain injury, peripheral vascular disease, endothelial cell dysfunction, impaired vascular compliance, vascular restenosis, thrombosis, hypertension, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, hyperglycemia, postprandial lipemia, metabolic syndrome 47. The method of claim 46, wherein the condition is selected from the group consisting of: urinary tract infection, urinary tract infection, urinary tract infection (URI) syndrome, urinary tract infection (URS), urinary tract infection (USA ...

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

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

50. 46. ​​A method for regulating insulin levels in a patient in need thereof, comprising administering to the patient an effective amount of the pharmaceutical composition of any one of claims 38 to 45.

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

52. 46. ​​A method for regulating glucose levels in a patient in need thereof, comprising administering to the patient an effective amount of the pharmaceutical composition of any one of claims 38 to 45.

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

54. 1. A process for producing 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-oxadiazol-5(4H)-one L-arginine salt (Compound I L-arginine salt), comprising contacting Compound I with L-arginine in a solvent for a sufficient time to obtain crystalline Compound I L-arginine salt.

55. The solvent is IPA / H 2 55. The method of claim 54, wherein the mixture is O.

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

57. 55. The method of claim 54, wherein the contacting further comprises adding about 2% by weight of seed crystals to the mixture of Compound I and L-arginine.

58. 55. The method of claim 54, wherein the contacting 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. 55. The method of claim 54, wherein the method further comprises isolating the crystalline Compound I L-arginine salt after the contacting step.

60. 60. The method of claim 59, wherein the isolating comprises filtering, washing, and drying the crystalline Compound I L-arginine salt.

61. 61. The method of any one of claims 54-60, wherein at least about 95% of the crystalline Compound I L-arginine salt is Form B.

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