Pharmaceutically acceptable salts of CD47-SIRP alpha pathway inhibitors

Abstract

The present disclosure relates to pharmaceutically acceptable salts of compounds of formula (I), in particular alkali metal or alkaline earth metal salts, crystalline forms thereof, and processes for their preparation. The present disclosure also relates to formulations suitable for pharmaceutical use for the treatment of various diseases or conditions mediated by CD47, in particular cancer or other proliferative diseases. (I).

Description

[0001] This application claims priority and benefits from Indian Patent Application No. IN202341071231, filed on October 19, 2023, the entire contents of which are incorporated herein by reference. Technical Field

[0002] This disclosure relates to pharmaceutically acceptable salts of compounds of formula (I), including their crystalline forms and methods of preparation thereof. This disclosure also relates to pharmaceutical compositions comprising salts of said compounds of formula (I) and their crystalline forms, and methods of using them as therapeutic agents. Background Technology

[0003] CD47, also known as integrin-associated protein (IAP), ovarian cancer antigen (OA3), Rh-associated antigen, and MER6, is a transmembrane protein encoded by the CD47 gene in humans. Belonging to the immunoglobulin superfamily, CD47 pairs with membrane integrins and also binds to ligands platelet-reactive protein-1 (TSP-1) and signal regulatory protein α (SIRPα). CD47 is widely known for its crucial role in preventing the clearance of healthy cells by phagocytes through binding to SIRPα, an expression of phagocytes. SIRPα is an inhibitory protein expressed on macrophages that, once activated, inhibits the phagocytosis of CD47-expressing cells. This CD47 / SIRPα axis is a vital homeostatic mechanism preventing the clearance of normal, healthy cells expressing CD47. Conversely, downregulation of CD47 expression in damaged, senescent, or redundant cells ensures their timely clearance.

[0004] CD47 is expressed on almost all non-malignant cells. Blocking CD47, loss of CD47 expression, or alterations in its membrane distribution can all serve as markers of senescent or damaged cells, particularly erythrocytes (RBCs). Furthermore, blocking SIRPα can induce phagocytosis of targets that are not normally phagocytosed (these cells also exhibit pre-phagocytic signals). CD47 is a widely expressed transmembrane glycoprotein with an immunoglobulin-like domain and five transmembrane regions. It functions as a cellular ligand for SIRPα, and its binding is mediated by the NH2-terminal V-like domain of SIRPα. SIRPα is primarily expressed in myeloid cells, including macrophages, granulocytes, myeloid dendritic cells (DCs), mast cells, and their precursor cells, including hematopoietic stem cells.

[0005] CD47 is also constitutively upregulated in a variety of cancers, such as non-Hodgkin's lymphoma (NHL), acute myeloid leukemia (AML), breast cancer, colon cancer, glioblastoma, glioma, ovarian cancer, bladder cancer, and prostate cancer. Overexpression of CD47 by tumor cells effectively helps them evade immune surveillance and be killed by innate immune cells.

[0006] Previous studies have shown that CD47 can be considered a potential therapeutic target for atherosclerosis. This is because the formation of atherosclerotic plaques on the arterial wall is associated with the upregulation of CD47, which makes malignant cells resistant to programmed cell clearance or “cytotoxicity.” This cytotoxic effect is reversed upon administration of CD47 blocking antibodies, restoring normal clearance function in diseased vascular tissue and improving atherosclerosis in various mouse models (Kojima Y, et al., Nature. 2016 Aug 4; 536 (7614): 86-90). Furthermore, it has been reported that blocking CD47 with the CD47-Fc fusion protein effectively modulates experimental autoimmune encephalomyelitis (EAE) in multiple sclerosis (MS) animal models, thus providing a potential therapeutic target for the prevention and treatment of MS (Gao Q et al., J Autoimmun. 2016 May; 69: 74-85).

[0007] International publications WO2019138367 and WO2020095256 describe inhibitors of the CD47-SIRPα signaling pathway, methods of their preparation, pharmaceutical compositions comprising them, and their use as therapeutic agents in monotherapy and combination therapy for a variety of conditions (particularly cancer and other proliferative diseases), the contents of which are incorporated herein by reference for all purposes.

[0008] CD47 inhibitors are currently being developed for cancer treatment. For drug development, it is generally advantageous to prepare a suitable drug formulation using a drug form that possesses the desired properties in its preparation, purification, reproducibility, stability, bioavailability, and other characteristics. However, the salt or crystalline forms of the CD47 inhibitors reported in the aforementioned literature are difficult to obtain because the compounds are unstable under environmental conditions.

[0009] WO2019138367 discloses a group of 1,2,4-oxadiazole compounds that can be used as inhibitors of the CD47 signaling pathway. One disclosed 1,2,4-oxadiazole compound is (((S)-1-(3-((S)-1-amino-3-carboxypropyl)-1,2,4-oxadiazole-5-yl)-4-guanidinobutyl)carbamoyl)-L-proline.

[0010] There is an urgent need to develop novel CD47 inhibitory compounds that, in addition to possessing the necessary pharmacological properties, can also be formulated into pharmaceutically useful formulations and dosage forms with suitable properties (e.g., allowing for the preparation of safe, effective, and high-quality drug products). Summary of the Invention

[0011] Compound (I) is also known as (((S)-1-(3-(((S)-1-amino-3-carboxypropyl)-1,2,4-oxadiazol-5-yl)-4-guanidinylbutyl)carbamoyl)-L-proline. In its free acid form, (((S)-1-(3-(((S)-1-amino-3-carboxypropyl)-1,2,4-oxadiazol-5-yl)-4-guanidinylbutyl)carbamoyl)-L-proline is inherently hygroscopic and presents stability issues.

[0012] This disclosure provides methods and synthesis of pharmaceutically acceptable salts of the compounds of formula (I) with high yields and high purity. The pharmaceutically acceptable salts of the compounds of formula (I) of this invention (preferably calcium and sodium salts of the compounds of formula (I)) exhibit unexpected physicochemical properties for drug development, such as higher stability, higher purity, and better adaptability.

[0013] This disclosure also covers pharmaceutically acceptable salts of the compounds of formula (I) and their polymorphs, eutectic forms, anhydrous forms and amorphous forms.

[0014] In one aspect, this disclosure provides pharmaceutically acceptable salts of compounds of formula (I):

[0015] (I);

[0016] The pharmaceutically acceptable salts mentioned therein are alkali metal salts or alkaline earth metal salts.

[0017] In one aspect, this disclosure provides pharmaceutically acceptable salts of compounds of formula (I):

[0018] (I);

[0019] The pharmaceutically acceptable salts mentioned therein are calcium or sodium salts.

[0020] In one aspect, this disclosure provides a method for preparing a pharmaceutically acceptable salt of the compound of formula (I).

[0021] In one aspect, this disclosure provides a calcium salt of a crystalline compound of formula (I).

[0022] In one aspect, this disclosure provides a sodium salt of a crystalline compound of formula (I).

[0023] In one aspect, this disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable salt of a compound of formula (I) and one or more pharmaceutically acceptable carriers or excipients.

[0024] In one aspect, this disclosure provides a pharmaceutically acceptable salt of a compound of formula (I) according to this disclosure for use as a medicament, or a pharmaceutical composition comprising a salt of a compound of formula (I) according to this disclosure.

[0025] In one aspect, this disclosure provides a method for treating or delaying the progression of a disease or condition, wherein the method comprises administering to an individual an effective amount of a pharmaceutically acceptable salt of the compound of formula (I).

[0026] In one aspect, this disclosure provides a pharmaceutically acceptable salt of a compound of formula (I) according to this disclosure, or a pharmaceutical composition comprising a salt of a compound of formula (I) according to this disclosure, for use in a method of treating or delaying the progression of a CD47-mediated disease or condition, wherein the CD47-mediated disease or condition is cancer or other proliferative disease.

[0027] Physicochemical data obtained from the crystal structure of the free acid of the compound of formula (I) indicate that the compound of formula (I) exists in zwitterionic form, making it difficult to form salts. In fact, most salts of the compounds of formula (I) have been found to be unsuitable for drug development. However, it has been unexpectedly found that the salts and their forms disclosed in this disclosure have low hygroscopicity, high stability, and are substantially pure, thus making them suitable for drug development. Attached Figure Description

[0028] Figure 1 Shown in 2 XRPD spectrum of the calcium salt of compound (I) collected by C.

[0029] Figure 2 The XRPD spectrum of the free acid of the compound of formula (I) is shown.

[0030] Figure 3A Shown in 2 XRPD spectrum of the disodium salt of compound (I) collected by C.

[0031] Figure 3B Shown in 2 XRPD spectrum of monosodium salt of compound (I) collected by C.

[0032] Figure 4 The differential scanning calorimetry (DSC) thermogram of the calcium salt of the compound of formula (I) is shown.

[0033] Figure 5 Thermogravimetric analysis (TGA) of the calcium salt of the compound of formula (I) is shown.

[0034] Figure 6XRPD overlay plots of the calcium salt of compound (I) exposed to different conditions are shown.

[0035] Figure 7 The adsorption-desorption isotherm of the calcium salt of the compound of formula (I) at 25°C is shown.

[0036] Figure 8 Echo detection of the calcium salt of the compound of formula (I) is shown. 1 HMAS NMR spectrum.

[0037] Figure 9 The calcium salt of the compound of formula (I) is shown. 1 H- 13 C CPMAS-NMR spectra.

[0038] Figure 10A The calcium salt of the compound of formula (I) is shown. 13 C- 1 Two-dimensional correlation NMR spectrum (HetCor).

[0039] Figure 10B The image shows an amplified view of the calcium salt of the compound of formula (I). 13 C- 1 Two-dimensional correlation NMR spectrum (HetCor).

[0040] Figure 11 A rod-shaped model showing the crystal structure of the free acid of the compound of formula (I) is displayed. Detailed Implementation

[0041] As used in this specification, the following words and phrases are generally intended to have the meanings described below, unless the context in which they are used indicates otherwise.

[0042] As used herein, the free acid of the compound (((S)-1-(3-((S)-1-amino-3-carboxypropyl)-1,2,4-oxadiazol-5-yl)-4-guanidinobutyl)carbamoyl)-L-proline or a compound of formula (I) refers to a compound having the following formula:

[0043] (I).

[0044] As used herein, the terms “alkali metal salt of formula (I),” “alkali metal salt of compound of formula (I),” “alkali metal of compound of formula (I),” and “pharmaceutically acceptable salt of compound of formula (I), wherein the salt is an alkali metal” are used interchangeably and all refer to the compound of formula (I) bonded to one or more alkali metal ions by ionic bonds.

[0045] As used herein, the terms “basic metal salt of formula (I),” “basic metal salt of compound (I),” “basic metal of compound (I),” and “pharmaceutically acceptable salt of compound (I), wherein the salt is an basic metal” are used interchangeably and all refer to the compound of formula (I) bonded to one or more basal metal ions by ionic bonds.

[0046] As used herein, the terms “calcium salt of formula (I),” “calcium salt of compound (I),” “compound of formula (I) calcium,” and “pharmaceutically acceptable salt of compound (I), wherein the salt is calcium” are used interchangeably and all refer to the compound of formula (I) bonded to one or more calcium ions by ionic bonds.

[0047] As used herein, the terms “sodium salt of formula (I),” “sodium salt of compound (I),” “compound of formula (I) sodium,” and “pharmaceutically acceptable salt of compound (I), wherein the salt is sodium” are used interchangeably and all refer to the compound of formula (I) bonded to one or more sodium ions by ionic bonds. Sodium salts of formula (I) may comprise monosodium salts and / or disodium salts.

[0048] As used herein, the term "alkali metal salt" refers to a salt of an alkali metal selected from lithium, sodium, and potassium. In one embodiment, the alkali metal salt comprises a sodium salt or a potassium salt. In one embodiment, the alkali metal salt comprises a sodium salt. In one embodiment, the alkali metal salt comprises a potassium salt.

[0049] As used herein, the term "alkaline earth metal salt" refers to a salt of an alkaline earth metal selected from beryllium, magnesium, calcium, strontium, and barium. In one embodiment, the alkaline earth metal salt comprises a magnesium salt or a calcium salt. In one embodiment, the alkaline earth metal salt comprises a calcium salt. In one embodiment, the alkaline earth metal salt comprises a magnesium salt.

[0050] As used herein, the term “pharmaceutically acceptable” means compounds, materials, compositions, and / or dosage forms that, within reasonable medical judgment, are suitable for contact with human and animal tissues without causing excessive toxicity, irritation, allergic reactions, immunogenicity, or other problems or complications, and have a reasonable benefit / risk ratio.

[0051] As used herein, the phrase “pharmaceuticalally acceptable carrier or excipient” refers to a pharmaceutically acceptable material, composition, or carrier, such as a liquid or solid filler, diluent, solvent, or encapsulating material. Excipients or carriers are generally safe, non-toxic, and have no adverse effects on biology or otherwise, and include excipients or carriers acceptable for veterinary and human pharmaceutical use.

[0052] As used herein, "pharmaceutically acceptable salt" refers to a derivative of the disclosed compound, wherein the parent compound is modified by converting an existing acidic or basic moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to: inorganic or organic acid salts of basic residues such as amino groups; basic or organic salts of acidic residues such as carboxylic acids, etc. Pharmaceutically acceptable salts described in this disclosure include conventional, non-toxic salts of the parent compounds formed therefrom. Pharmaceutically acceptable salts described in this disclosure can be synthesized from parent compounds containing basic or acidic moieties by conventional chemical methods. Typically, such salts are prepared by reacting the free acid or free base form of these compounds with a stoichiometric amount of a suitable base or acid in water or an organic solvent, or a mixture of both; generally, non-aqueous media are preferred, such as diethyl ether, ethyl acetate, alcohols, or acetonitrile (ACN). In practical applications, using the salt form is equivalent to using the acid. Suitable pharmaceutically acceptable salts within the scope of this disclosure are those derived from bases such as sodium hydroxide, sodium bicarbonate, potassium hydroxide, lithium hydroxide, calcium hydroxide, calcium carbonate, magnesium sulfate, etc. In some embodiments, the cation is sodium, potassium, magnesium, and calcium. In some embodiments, the cation is sodium and calcium. In some embodiments, the cation is calcium. In some embodiments, the cation is sodium.

[0053] Depending on solubility, the inorganic salts that can be used include halide salts such as CaCl2, CaF2, CaBr2 and CaI2, as well as calcium borate (B4CaO7), calcium tetrafluoroborate (CaBF4), calcium carbonate (CaCO3), calcium dihydrogen phosphate (Ca(H2PO4)2), calcium hydrogen phosphate (CaHPO4) and tricalcium phosphate (Ca(PO4)2), calcium sulfate (CaSO4) and calcium hydroxide (Ca(OH)2), and their hydrates.

[0054] As used herein, "crystalline" or "crystalline form" refers to a specific crystal lattice configuration of a crystalline substance. Different crystalline forms of the same substance typically have different crystal lattices (e.g., unit cells), which results in different physical properties characteristic of each crystalline form. In some cases, different lattice configurations may have different water or solvent contents.

[0055] As used herein, the terms “subject,” “individual,” or “patient” are used interchangeably and refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, and most preferably humans.

[0056] As used herein, "therapeutic effective amount" means an amount sufficient to produce a therapeutic effect when administered to a mammal in need of treatment. The therapeutic effective amount varies depending on factors such as the subject being treated, their weight, age, severity of the disease, and method of administration, which can be readily determined by those skilled in the art.

[0057] As used herein, the term "substantially pure" means a crystalline form (i.e., a polymorph) with a purity greater than 90%, implying that it contains less than 10% of any other compound or other polymorphs of that crystalline form. In some embodiments, the crystalline form (i.e., the polymorph) has a purity greater than 95%, or even greater than 98%. In some embodiments, the crystalline form A, crystalline form B, and / or crystalline form C has a purity greater than 90%, greater than 95%, greater than 98%, greater than 99%, or greater than 99.5%.

[0058] The phrase "basically as shown" refers to a spectrum in which at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the values ​​appear in the illustrated graph. In some embodiments, when referring to an XRPD graph, the phrase "basically as shown" refers to a 2θ value spectrum having at least 3, 4, 5, 6, 7, 8, 9, or more than 9 peaks.

[0059] As used herein, the term “about” when referring to a numerical value or range indicates that the value or range is an approximation within the range of experimental variability (or statistical experimental error), and therefore the value or range may vary, for example, between 1% and 15% of the value or range shown.

[0060] Each embodiment is provided to explain this disclosure and not to limit it. In fact, it will be apparent to those skilled in the art that various modifications and variations can be made to the compounds, compositions, and methods described herein without departing from the scope or spirit of this disclosure. For example, features shown or described as part of the embodiments may be applied to another embodiment to produce yet another embodiment. Therefore, this disclosure is intended to cover such modifications, variations, and equivalents. Other objects, features, and aspects of this disclosure will be disclosed in or will become apparent from the following detailed description. It should be understood by those skilled in the art that this discussion is merely a description of exemplary embodiments and should not be construed as limiting the broader aspects of this disclosure.

[0061] Compounds of formula (I) and their pharmaceutically acceptable salts

[0062] In one embodiment, this disclosure provides a pharmaceutically acceptable salt of the compound of formula (I):

[0063] (I); The pharmaceutically acceptable salts mentioned therein are alkali metal salts or alkaline earth metal salts.

[0064] In some embodiments, the pharmaceutically acceptable salt of the compound of formula (I) comprises about 1% to about 5% by weight of the salt. In some embodiments, the pharmaceutically acceptable salt of the compound of formula (I) comprises about 1.5% to about 4% by weight of the salt. In some embodiments, the pharmaceutically acceptable salt of the compound of formula (I) comprises about 2% to about 3% by weight of the salt.

[0065] In some embodiments, the pharmaceutically acceptable salt of the compound of formula (I) comprises about 1% to about 10% by weight of the salt. In some embodiments, the pharmaceutically acceptable salt of the compound of formula (I) comprises about 5% to about 10% by weight of the salt. In some embodiments, the pharmaceutically acceptable salt of the compound of formula (I) comprises about 8% to about 10% by weight of the salt.

[0066] In one embodiment, this disclosure provides a pharmaceutically acceptable salt of the compound of formula (I), wherein the salt is an alkaline earth metal salt.

[0067] In one embodiment, the alkaline earth metal salt is a calcium salt or a magnesium salt.

[0068] In one embodiment, the alkaline earth metal salt is a calcium salt.

[0069] In one embodiment, this disclosure provides a calcium salt of a compound of formula (I). In some embodiments, the calcium content in the calcium salt of the compound of formula (I) is from about 1% to about 5% by weight of the salt.

[0070] In some embodiments, the calcium content in the calcium salt of the compound of formula (I) is about 1.5% to about 4% by weight of the salt.

[0071] In some embodiments, the calcium content in the calcium salt of the compound of formula (I) is about 2% to about 3% by weight of the salt.

[0072] In one embodiment, the stoichiometric ratio of the compound of formula (I) to calcium ranges from 5:1 to 1:1.

[0073] In one embodiment, the stoichiometric ratio of the compound of formula (I) to calcium is 5:1.

[0074] In one embodiment, the stoichiometric ratio of the compound of formula (I) to calcium is 4:1.

[0075] In one embodiment, the stoichiometric ratio of the compound of formula (I) to calcium is 3:1.

[0076] In one embodiment, the stoichiometric ratio of the compound of formula (I) to calcium is 2:1.

[0077] In one embodiment, the stoichiometric ratio of the compound of formula (I) to calcium is 1:1.

[0078] In one embodiment, the molar ratio of the free acid to calcium in the calcium salt of the compound of formula (I) is 1:<1, 1:0.5-0.9, 1:0.1-0.5, 1:0.1-0.3, or 1:0.25, etc.

[0079] In one embodiment, the molar ratio of the free acid to calcium in the calcium salt of the compound of formula (I) is 1:<1, for example, 1:0.9, 1:0.8, 1:0.7, 1:0.6, 1:0.5, 1:0.4, 1:0.3 or 1:0.25, etc.

[0080] In one embodiment, the molar ratio of the free acid to calcium in the calcium salt of the compound of formula (I) is 1:<1, for example, 1:0.25. In some embodiments, the calcium salt of the compound of formula (I) is in the form of crystal form A. In some embodiments, the molar ratio of the free acid to calcium in crystal form A is 1:<1, for example, 1:0.9, 1:0.8, 1:0.7, 1:0.6, 1:0.5, 1:0.4, 1:0.3, or 1:0.25, etc.

[0081] In some embodiments, the molar ratio of the free acid to calcium in crystal form A is about 1:1 to about 3:1. In some embodiments, the molar ratio of the free acid to calcium in crystal form A is about 2:1. In some embodiments, the molar ratio of the free acid to calcium in crystal form A is about 1:1.

[0082] In one embodiment, this disclosure provides a pharmaceutically acceptable salt of the compound of formula (I), wherein the alkali metal salt is a lithium, sodium, or potassium salt.

[0083] In one embodiment, the alkali metal salt is a sodium salt or a potassium salt.

[0084] In one embodiment, the alkali metal salt is a sodium salt.

[0085] In one embodiment, the alkali metal salt is a monosodium salt or a disodium salt.

[0086] In one embodiment, the sodium salt is a monosodium salt or a disodium salt.

[0087] In one embodiment, the sodium salt is a disodium salt.

[0088] In one embodiment, the sodium salt is a monosodium salt.

[0089] In one embodiment, this disclosure provides a sodium salt of the compound of formula (I).

[0090] In some embodiments, the sodium content in the sodium salt of the compound of formula (I) is about 1% to about 10% by weight of the salt.

[0091] In some embodiments, the sodium content in the sodium salt of the compound of formula (I) is about 5% to about 10% by weight of the salt.

[0092] In some embodiments, the sodium content in the sodium salt of the compound of formula (I) is about 8% to about 10% by weight of the salt.

[0093] In one embodiment, the molar ratio of the free acid to sodium in the sodium salt of the compound of formula (I) is 1:<1, for example, 1:0.9, 1:0.8, 1:0.7, 1:0.6, 1:0.5, 1:0.4, 1:0.3 or 1:0.25, etc.

[0094] In some embodiments, the sodium salt of the compound of formula (I) is in the form of crystal form B. In some embodiments, form B is the crystalline form of the disodium salt of the compound of formula (I). In some embodiments, the molar ratio of the free acid to sodium in crystal form B is 1:<1, for example, 1:0.9, 1:0.8, 1:0.7, 1:0.6, 1:0.5, 1:0.4, 1:0.3, or 1:0.25, etc. In some embodiments, the sodium salt of the compound of formula (I) is in the form of crystal form C. In some embodiments, form C is the crystalline form of the monosodium salt of the compound of formula (I). In some embodiments, the molar ratio of the free acid to sodium in crystal form C is 1:<1, for example, 1:0.9, 1:0.8, 1:0.7, 1:0.6, 1:0.5, 1:0.4, 1:0.3, or 1:0.25, etc.

[0095] Method for preparing pharmaceutically acceptable salts of compounds of formula (I)

[0096] In one embodiment, this disclosure provides a method for preparing a pharmaceutically acceptable salt of the compound of formula (I), the method comprising the steps of: a) Provide a mixture comprising a compound of formula (I) and solvent A;

[0097] (I);

[0098] b) Reacting the mixture with a cation source and precipitating the salt of the compound of formula (I) using solvent B; and

[0099] c) Separate the salts of the compound of formula (I); The solvent A and the solvent B are independently selected from tetrahydrofuran, acetonitrile, methanol, anisole, diethyl ether, ethanol, 1,4-dioxane, acetonitrile, acetone, dichloromethane, isopropanol, methyl tert-butyl ether (MTBE), n-heptane, water, and mixtures thereof.

[0100] In one embodiment, solvent A is water.

[0101] In one embodiment, the compound of formula (I) in step (a) is in the form of a free acid.

[0102] In one embodiment, the compound of formula (I) in step (a) is a sodium salt of the compound of formula (I).

[0103] In one embodiment, solvent B is ethanol. In another embodiment, solvent B is an antisolvent.

[0104] In one embodiment, the cation source is selected from calcium carbonate, calcium hydroxide, calcium methoxide, calcium chloride, magnesium carbonate, magnesium chloride, or a combination thereof.

[0105] In some embodiments, the cation source in step (b) is calcium carbonate.

[0106] In one embodiment of the method for preparing a pharmaceutically acceptable salt of compound (I), compound (I) is provided in the form of a free acid. In one embodiment of the method for preparing a pharmaceutically acceptable salt of compound (I), compound (I) is provided in the form of a salt, wherein the cation is different from the cation source provided when preparing the salt. In one embodiment of the method for preparing a pharmaceutically acceptable salt of compound (I), compound (I) is provided in the form of its sodium salt. In one embodiment of step a) of the method for preparing a pharmaceutically acceptable salt of compound (I), compound (I) is a free acid. In one embodiment of step a) of the method for preparing a pharmaceutically acceptable salt of compound (I), compound (I) is present in the form of a salt, wherein the cation is different from the cation source provided when preparing the salt. In one embodiment of step a) of the method for preparing a pharmaceutically acceptable salt of compound (I), compound (I) in step a) is a free acid. In one embodiment of step a) of the method for preparing a pharmaceutically acceptable salt of the compound of formula (I), the compound of formula (I) is its sodium salt.

[0107] In some embodiments, a method for preparing a pharmaceutically acceptable salt of the compound of formula (I) includes treating the mixture of step (a) with a metal ion exchange resin under aqueous conditions. In some embodiments, in a method for preparing a pharmaceutically acceptable salt of the compound of formula (I), the cation is selected from sodium, potassium, magnesium, and lithium. In some embodiments, the cation is sodium.

[0108] In one embodiment, the method for preparing a pharmaceutically acceptable salt of the compound of formula (I) further includes treating the mixture of step (a) with a metal ion exchange resin under aqueous conditions to remove sodium ions from the mixture.

[0109] In one embodiment, the method for preparing a pharmaceutically acceptable salt of the compound of formula (I) further includes an optional step of treating the mixture of step (a) with a metal ion exchange resin under aqueous conditions.

[0110] In one embodiment, the method for preparing a pharmaceutically acceptable salt of the compound of formula (I) further includes an optional step of treating the mixture of step (a) with a metal ion exchange resin under aqueous conditions to remove sodium ions from the mixture.

[0111] In one embodiment, precipitation in step (b) is achieved by adding solvent B.

[0112] In one embodiment, a method for preparing a calcium salt of compound (I) includes treating a mixture comprising a sodium salt of compound (I) under aqueous conditions with a metal ion exchange resin. In one embodiment, treating the sodium salt of compound (I) with a metal ion exchange resin aims to remove the sodium ions from the mixture, thereby purifying the mixture comprising compound (I).

[0113] In one embodiment, the compound of formula (I) is isolated as a pharmaceutically acceptable salt. In some embodiments, the compound of formula (I) is isolated as a sodium salt, wherein the compound of formula (I) is dissolved in a suitable solvent and passed through a cation exchange resin. In other embodiments, the compound of formula (I) is dissolved in a TFA:TIPS:water mixture, and the mixture is subsequently treated with a sodium ion source, and the compound of formula (I) is isolated as a sodium salt. In some embodiments, the sodium salt of the compound of formula (I) is passed through a column packed with a cation exchange resin (e.g., a sodium ion exchange resin). In some embodiments, the sodium salt of the compound of formula (I) is passed through a column packed with a cation exchange resin selected from, but not limited to, Dowex 50WX8 200 sodium resin, Indion 225 sodium resin, etc. In some embodiments, the sodium salt of the compound of formula (I) is dissolved in a suitable solvent, such as acetone, tetrahydrofuran, ethanol, isopropanol, acetonitrile, etc., and treated with calcium carbonate or any other alkaline earth metal ion source to provide the corresponding calcium salt or other alkaline earth metal salt of the compound of formula (I).

[0114] In one embodiment, a method for preparing a calcium salt of compound (I) includes treating a mixture comprising a sodium salt of compound (I) under aqueous conditions with a metal ion exchange resin. In one embodiment, the sodium salt of compound (I) is treated with a metal ion exchange resin to remove sodium ions from the mixture.

[0115] In one embodiment, the metal ion exchange resin is a cation exchange resin. In one embodiment, the cation exchange resin is based on cations such as hydrogen, ammonium, sodium, potassium, and calcium. In one embodiment, the metal ion exchange resin is a sodium ion exchange resin. In one embodiment, the metal ion exchange resin is an Indion resin. In one embodiment, the metal ion exchange resin is an Indion 225H resin.

[0116] In one embodiment, in step b) of the method for preparing the calcium salt of compound (I), precipitation of the salt is carried out by adding solvent B. In one embodiment, solvent B is an antisolvent.

[0117] In one embodiment of step b) of the method for preparing the calcium salt of the compound of formula (I), the precipitation of the salt is carried out by adding an antisolvent, and the antisolvent is solvent B.

[0118] In one embodiment, solvent B is selected from tetrahydrofuran, acetonitrile, methanol, anisole, diethyl ether, ethanol, 1,4-dioxane, acetonitrile, acetone, dichloromethane, isopropanol, methyl tert-butyl ether (MTBE), n-heptane, water, and mixtures thereof. In one embodiment, solvent B is ethanol.

[0119] In one embodiment, in step b) of the method for preparing a salt of the compound of formula (I), the cation source is selected from calcium carbonate, calcium hydroxide, calcium methoxide, calcium chloride, magnesium carbonate, magnesium chloride, NaOH, Na2CO3, or combinations thereof.

[0120] According to the foregoing embodiments, the salt is a pharmaceutically acceptable salt.

[0121] In one embodiment, the cation source is a calcium ion source.

[0122] In one embodiment, the cation source is a sodium ion source.

[0123] In one embodiment of step b) of the method for preparing the calcium salt of the compound of formula (I), the cation source is selected from calcium carbonate, calcium hydroxide, calcium methoxide and calcium chloride.

[0124] In one embodiment of step b) of the method for preparing the calcium salt of the compound of formula (I), the calcium ion source is selected from calcium carbonate, calcium hydroxide, calcium methoxide and calcium chloride.

[0125] In one embodiment, the cation source in step (b) is calcium carbonate.

[0126] In one embodiment, the calcium source described in (b) is calcium carbonate.

[0127] In one embodiment, in step b) of the method for preparing the sodium salt of compound (I), the cation source is selected from NaOH or Na₂CO₃. 3。

[0128] In one embodiment, in step b) of the method for preparing the sodium salt of compound (I), the sodium ion source is selected from NaOH or Na₂CO₃. 3。

[0129] In one embodiment, the separation in step (c) includes filtering the mixture and the salt of the compound of formula (I) precipitated in step (b), and washing and drying the salt of the precipitated compound of formula (I) obtained by filtration.

[0130] In one embodiment, step c) of separating the calcium salt of compound (I) from the mixture includes filtering the mixture containing the salt and washing and drying the salt obtained by filtration.

[0131] In one embodiment, step (c) of separating the salt of the compound of formula (I) further includes the following sub-steps: i) filtering the mixture and precipitating the salt of the compound of formula (I) from step (b); and ii) washing and drying the precipitated salt of the compound of formula (I) obtained by the filtration.

[0132] In one embodiment, step c) of separating the calcium salt of the compound of formula (I) from the mixture further includes the following sub-steps: i) filtering the mixture containing the salt; and ii) washing and drying the salt obtained by filtration.

[0133] In one embodiment, a method for preparing a calcium salt of compound (I) includes reacting a sodium salt of compound (I) with a calcium ion source, wherein the calcium ion source is calcium carbonate, under aqueous conditions.

[0134] As used herein, the terms "anti-solvent" or "anti-solvent" refer to a solvent in which the compound crystals are insoluble, very slightly soluble, or partially soluble (i.e., solubility less than 1 mg / mL). In practical applications, adding an anti-solvent to a solution in which crystals are dissolved reduces the solubility of the crystals in the solution (i.e., supersaturation), thereby promoting precipitation of the target compound. In one embodiment, the crystals are washed using a combination of an anti-solvent and an organic solvent. In one embodiment, the anti-solvent is water; in other embodiments, it is an alkane solvent, such as hexane or pentane, or an aromatic solvent, such as 1,2-dichloroethane, benzene, toluene, methylcyclohexane, or xylene.

[0135] In one embodiment, the antisolvent is dichloromethane, dichloroethane, ethanol, methanol, propanol, butanol, pentanol, isobutyl acetate, isobutylene vinyl ester, methylcyclohexane, n-hexane, n-heptane, tetrahydrofuran, and mixtures thereof.

[0136] In one embodiment, this disclosure provides a method for preparing a calcium salt of the compound of formula (I), comprising reacting the compound of formula (I) with a cation source in the presence of solvent C:

[0137] (I)

[0138] The solvent C is selected from tetrahydrofuran, acetonitrile, methanol, anisole, diethyl ether, ethanol, 1,4-dioxane, acetonitrile, acetone, dichloromethane, isopropanol, methyl tert-butyl ether (MTBE), n-heptane, water, and mixtures thereof.

[0139] In one embodiment, the cation source includes calcium carbonate, calcium hydroxide, calcium methoxide, calcium chloride, or a combination thereof.

[0140] In one embodiment, the reaction is carried out at about 20°C to about 40°C. In another embodiment, the reaction is carried out at a temperature of about 20°C, about 25°C, about 30°C, about 35°C, or about 40°C. In one embodiment, the resulting salt is a calcium salt of a crystalline compound of formula (I).

[0141] In another embodiment, this disclosure provides a method for preparing a sodium salt of the compound of formula (I), comprising reacting the compound of formula (I) with a cation source in the presence of solvent C:

[0142] (I);

[0143] The solvent C is selected from tetrahydrofuran, acetonitrile, methanol, anisole, diethyl ether, ethanol, 1,4-dioxane, acetonitrile, acetone, dichloromethane, isopropanol, methyl tert-butyl ether (MTBE), n-heptane, water, and mixtures thereof.

[0144] In some embodiments, the cation source is NaOH or Na₂CO₃. In another embodiment, the cation source is NaOH.

[0145] In one embodiment, the reaction is carried out at a temperature of about 20°C, about 25°C, about 30°C, about 35°C, or about 40°C.

[0146] In one embodiment, the salt of the obtained compound of formula (I) is a crystalline calcium salt of the compound of formula (I) or a crystalline sodium salt of the compound of formula (I).

[0147] In one embodiment, the resulting salt is a sodium salt of a crystalline compound of formula (I).

[0148] In some embodiments, the salts of the compounds of formula (I) described herein, such as alkali metal salts and / or basic metal salts, exhibit improved solubility in solvents, for example, improved solubility in aqueous environments (e.g., in vivo). In some embodiments, the salts of the compounds of formula (I) described herein, such as alkali metal salts and / or basic metal salts, exhibit increased dissolution rates in aqueous environments (e.g., in vivo). In some embodiments, the salts of the compounds of formula (I) described herein, such as alkali metal salts and / or basic metal salts, have improved bioavailability. In some embodiments, the salts of the compounds of formula (I) described herein, such as alkali metal salts and / or basic metal salts, have improved physical stability. In some embodiments, the salts of the compounds of formula (I) described herein, such as alkali metal salts and / or basic metal salts, have improved chemical stability, for example, reduced formation of degradation products. In some embodiments, the salts of the compounds of formula (I) described herein, such as alkali metal salts and / or basic metal salts, have reduced oxidizing properties.

[0149] In one embodiment, the salt exists in crystalline form. In another embodiment, the salt exists in a non-crystalline form.

[0150] In one embodiment, these salts may exist in a substantially crystalline form or a partially crystalline form.

[0151] In one embodiment, the salt may be present in a substantially crystalline form. As used herein, the term "substantially crystalline" refers to a salt of the compound of formula (I) wherein 50% to 100% is crystalline. Within this range, the salt of the compound of formula (I) may be at least 55% crystalline, or at least 60% crystalline, or at least 70% crystalline, or at least 80% crystalline, or at least 90% crystalline, or at least 90% crystalline, or at least 95% crystalline, or at least 98% crystalline, or at least 99% crystalline, or at least 99.5% crystalline, or at least 99.9% crystalline, for example, 100% crystalline.

[0152] In one embodiment, as used herein, the term "basically crystalline" refers to a calcium salt of the compound of formula (I) in which 50% to 100% of the crystals are crystalline. Within this range, the calcium salt of the compound of formula (I) may be at least 55% crystalline, or at least 60% crystalline, or at least 70% crystalline, or at least 80% crystalline, or at least 90% crystalline, or at least 95% crystalline, or at least 98% crystalline, or at least 99% crystalline, or at least 99.5% crystalline, or at least 99.9% crystalline, for example, 100% crystalline.

[0153] In one embodiment, as used herein, the term "basically crystalline" refers to a sodium salt of the compound of formula (I) that is 50% to 100% crystalline, with a crystallinity between 50% and 100%. Within this range, the sodium salt of the compound of formula (I) may be at least 55% crystalline, or at least 60% crystalline, or at least 70% crystalline, or at least 80% crystalline, or at least 90% crystalline, or at least 95% crystalline, or at least 98% crystalline, or at least 99% crystalline, or at least 99.5% crystalline, or at least 99.9% crystalline, for example, 100% crystalline.

[0154] In some embodiments, the crystalline forms described herein, such as types A, B, and / or C, exhibit improved solubility in solvents, for example, improved solubility in aqueous solvents. In some embodiments, the crystalline forms described herein, such as types A, B, and / or C, exhibit increased dissolution rates in aqueous environments, for example, improved solubility in aqueous solvents. In some embodiments, the crystalline forms described herein, such as types A, B, and / or C, have improved physical stability, for example, the crystal structure remains stable over long periods. In some embodiments, the crystalline forms described herein, such as types A, B, and / or C, have improved chemical stability, for example, reduced formation of degradation products. In one embodiment, the salt described herein may be present in an amorphous form. In some embodiments, the salt described herein may be present in an amorphous form, for example, containing up to 30% crystalline form. In some embodiments, the salt described herein may be present in an amorphous form, for example, it may also contain up to 25%, 20%, 15%, 10%, 5%, or 2% crystalline solids. In some embodiments, the salts described herein comprise a mixture of crystalline and amorphous solids, and their characterization data (e.g., XRPD) may include indicative features of both crystalline and amorphous forms. In one embodiment, the salts described herein may be present in a substantially amorphous form. As used herein, the term "substantially amorphous" refers to a solid material having little or no long-range order at its molecular positions. For example, a substantially amorphous material has less than 15% crystallinity, such as less than 10%, less than 5%, or less than 2%. In one embodiment, the salt is present in a non-solventized or solvent-free form. In another embodiment, the salt is present in a solvated / hydrated form.

[0155] In one embodiment, a calcium salt of a specific form of formula (I) is provided, which is in a partially crystalline form. In one embodiment, the calcium salt may be present in a partially crystalline, crystalline, or amorphous form. In one embodiment, the partially crystalline form of the calcium salt of formula (I) has a crystalline purity of 10-90%, preferably 10-80%, or at least 10-70%, or at least 10-60%, or at least 10-50%, or at least 10-40%, or 10-30%, or 10-20%, and includes all values ​​within the ranges defined above.

[0156] In one embodiment, this disclosure provides the crystalline form of the calcium salt of the compound of formula (I):

[0157] (I).

[0158] In one embodiment, the crystalline form is characterized by X-ray powder diffraction analysis.

[0159] In some embodiments, the calcium salt of the compound of formula (I) is in the form of type A.

[0160] In some embodiments, the crystalline form is type A, characterized in that the X-ray powder diffraction (XRPD) pattern includes 2θ values ​​selected from 6.5±0.2, 6.8±0.2, 8.1±0.2, 9.5±0.2, 9.9±0.2, 10.6±0.2, 11.8±0.2, 12.9±0.2, 13.2±0.2, 13.8±0.2, 14.1±0.2, 15.1±0.2, 16.3±0.2, 16.5±0.2, 17.7±0.2, 18.0±0.2, 18.7±0.2, 19.2±0.2, 19.5±0.2, 1 At least three peaks of 9.8±0.2, 20.1±0.2, 20.5±0.2, 21.5±0.2, 22.1±0.2, 22.7±0.2, 23.5±0.2, 23.9±0.2, 24.4±0.2, 24.9±0.2, 25.7±0.2, 26.7±0.2, 27.2±0.2, 27.8±0.2, 28.5±0.2, 29.1±0.2, 29.9±0.2, 31.2±0.2, 32.2±0.2, 33.4±0.2, 35.1±0.2, 37.6±0.2, and 38.4±0.2.

[0161] In some embodiments, the crystalline form is type A, characterized in that the X-ray powder diffraction (XRPD) pattern includes 2θ values ​​selected from 6.5±0.2, 6.8±0.2, 8.1±0.2, 9.5±0.2, 9.9±0.2, 10.6±0.2, 11.8±0.2, 12.9±0.2, 13.2±0.2, 13.8±0.2, 14.1±0.2, 15.1±0.2, 16.3±0.2, 16.5±0.2, 17.7±0.2, 18.0±0.2, 18.7±0.2, 19.2±0.2, 19.5±0.2, 1 At least four peaks of 9.8±0.2, 20.1±0.2, 20.5±0.2, 21.5±0.2, 22.1±0.2, 22.7±0.2, 23.5±0.2, 23.9±0.2, 24.4±0.2, 24.9±0.2, 25.7±0.2, 26.7±0.2, 27.2±0.2, 27.8±0.2, 28.5±0.2, 29.1±0.2, 29.9±0.2, 31.2±0.2, 32.2±0.2, 33.4±0.2, 35.1±0.2, 37.6±0.2, and 38.4±0.2.

[0162] In some embodiments, the crystalline form is type A, characterized in that the XRPD spectrum includes 2θ values ​​selected from 6.5±0.2, 6.8±0.2, 8.1±0.2, 9.5±0.2, 9.9±0.2, 10.6±0.2, 11.8±0.2, 12.9±0.2, 13.2±0.2, 13.8±0.2, 14.1±0.2, 15.1±0.2, 16.3±0.2, 16.5±0.2, 17.7±0.2, 18.0±0.2, 18.7±0.2, 19.2±0.2, 19.5±0.2, 19.8±0. At least five peaks of 20.1±0.2, 20.5±0.2, 21.5±0.2, 22.1±0.2, 22.7±0.2, 23.5±0.2, 23.9±0.2, 24.4±0.2, 24.9±0.2, 25.7±0.2, 26.7±0.2, 27.2±0.2, 27.8±0.2, 28.5±0.2, 29.1±0.2, 29.9±0.2, 31.2±0.2, 32.2±0.2, 33.4±0.2, 35.1±0.2, 37.6±0.2, and 38.4±0.2.

[0163] In some embodiments, the crystalline form is type A, characterized in that its XRPD spectrum includes at least 6 peaks, at least 7 peaks, at least 8 peaks, at least 9 peaks, or at least 10 peaks, as described in the foregoing embodiments.

[0164] In one embodiment, the crystal form A is characterized in that its X-ray powder diffraction pattern includes at least one peak with a 2θ value of 9.9 ± 0.2.

[0165] In one embodiment, the crystal form A is characterized in that its X-ray powder diffraction pattern includes at least one peak with a 2θ value of 13.2 ± 0.2.

[0166] In one embodiment, the crystal form A is characterized in that its X-ray powder diffraction pattern includes at least one peak with a 2θ value of 19.8 ± 0.2.

[0167] In one embodiment, the crystal form A is characterized in that its X-ray powder diffraction pattern includes at least one peak with 2θ values ​​of 9.9±0.2, 13.2±0.2, and 19.8±0.2.

[0168] In one embodiment, the crystal form A is characterized in that its X-ray powder diffraction pattern includes peaks with 2θ values ​​of 9.9±0.2, 13.2±0.2, and 19.8±0.2.

[0169] In one embodiment, the crystal form A is characterized in that its X-ray powder diffraction pattern includes at least one peak with 2θ values ​​of 9.9±0.2, 11.8±0.2, 12.9, 13.2±0.2, 19.8±0.2, and 23.9±0.2.

[0170] In one embodiment, the crystal form A is characterized in that its X-ray powder diffraction pattern includes peaks with 2θ values ​​of 9.9±0.2, 11.8±0.2, 12.9, 13.2±0.2 and 19.8±0.2 and 23.9±0.2.

[0171] In one embodiment, the crystal form A is characterized in that its X-ray powder diffraction pattern includes at least one peak with 2θ values ​​of 9.9±0.2, 11.8±0.2, 13.2±0.2, 13.8±0.2, 19.2±0.2, 19.8±0.2 and 23.9±0.2.

[0172] In one embodiment, the crystal form A is characterized in that its X-ray powder diffraction pattern includes peaks with 2θ values ​​of 9.9±0.2, 11.8±0.2, 13.2±0.2, 13.8±0.2, 19.2±0.2, 19.8±0.2 and 23.9±0.2.

[0173] In one embodiment, the crystal form A is characterized in that its X-ray powder diffraction pattern includes at least one peak with 2θ values ​​of 8.1±0.2, 9.9±0.2, 11.8±0.2, 12.9±0.2, 13.2±0.2, 13.8±0.2, 16.3±0.2, 16.5±0.2, 19.2±0.2, 19.8±0.2, 20.1±0.2, and 23.9±0.2.

[0174] In one embodiment, the crystal form A is characterized in that its X-ray powder diffraction pattern includes peaks with 2θ values ​​of 8.1±0.2, 9.9±0.2, 11.8±0.2, 12.9±0.2, 13.2±0.2, 13.8±0.2, 16.3±0.2, 16.5±0.2, 19.2±0.2, 19.8±0.2, 20.1±0.2, and 23.9±0.2.

[0175] In one embodiment, the crystal form A is characterized in that its X-ray powder diffraction pattern includes at least one peak with 2θ values ​​of 8.1±0.2, 9.9±0.2, 10.6±0.2, 11.8±0.2, 12.9±0.2, 13.2±0.2, 13.8±0.2, 16.3±0.2, 16.5±0.2, 17.7±0.2, 19.2±0.2, 19.8±0.2, 20.1±0.2, 21.5±0.2, and 23.9±0.2.

[0176] In one embodiment, the crystal form A is characterized in that its X-ray powder diffraction pattern includes peaks with 2θ values ​​of 8.1±0.2, 9.9±0.2, 10.6±0.2, 11.8±0.2, 12.9±0.2, 13.2±0.2, 13.8±0.2, 16.3±0.2, 16.5±0.2, 17.7±0.2, 19.2±0.2, 19.8±0.2, 20.1±0.2, 21.5±0.2, and 23.9±0.2.

[0177] In one embodiment, crystal form A is characterized in that its X-ray powder diffraction pattern includes 2θ values ​​of 6.5±0.2, 6.8±0.2, 8.1±0.2, 9.5±0.2, 9.9±0.2, 10.6±0.2, 11.8±0.2, 12.9±0.2, 13.2±0.2, 13.8±0.2, 14.1±0.2, 15.1±0.2, 16.3±0.2, 16.5±0.2, 17.7±0.2, 18.0±0.2, 18.7±0.2, 19.2±0.2, 19.5±0.2, and 19.8±0. At least one peak of 20.1±0.2, 20.5±0.2, 21.5±0.2, 22.1±0.2, 22.7±0.2, 23.5±0.2, 23.9±0.2, 24.4±0.2, 24.9±0.2, 25.7±0.2, 26.7±0.2, 27.2±0.2, 27.8±0.2, 28.5±0.2, 29.1±0.2, 29.9±0.2, 31.2±0.2, 32.2±0.2, 33.4±0.2, 35.1±0.2, 37.6±0.2, and 38.4±0.2.

[0178] In one embodiment, crystal form A is characterized in that its X-ray powder diffraction pattern includes 2θ values ​​of 6.5±0.2, 6.8±0.2, 8.1±0.2, 9.5±0.2, 9.9±0.2, 10.6±0.2, 11.8±0.2, 12.9±0.2, 13.2±0.2, 13.8±0.2, 14.1±0.2, 15.1±0.2, 16.3±0.2, 16.5±0.2, 17.7±0.2, 18.0±0.2, 18.7±0.2, 19.2±0.2, 19.5±0.2, and 19.8. Peaks of ±0.2, 20.1±0.2, 20.5±0.2, 21.5±0.2, 22.1±0.2, 22.7±0.2, 23.5±0.2, 23.9±0.2, 24.4±0.2, 24.9±0.2, 25.7±0.2, 26.7±0.2, 27.2±0.2, 27.8±0.2, 28.5±0.2, 29.1±0.2, 29.9±0.2, 31.2±0.2, 32.2±0.2, 33.4±0.2, 35.1±0.2, 37.6±0.2, and 38.4±0.2.

[0179] In one embodiment, crystal form A is characterized in that its X-ray powder diffraction (XRPD) pattern is substantially as follows: Figure 1 As shown.

[0180] Table 1: Exemplary peaks of calcium salts of compounds of formula (I)

[0181] This document provides characterization information for describing any solid form of crystal form A. However, it should be understood that it is not necessary for a person skilled in the art to determine the presence of such a particular form in a given composition all such information is required. Rather, any portion of the characterization information that a person skilled in the art would consider sufficient to confirm the presence of such a particular form can be used to determine the presence of such a particular form. For example, even a single distinctive peak may be sufficient for a person skilled in the art to confirm the presence of such a particular form.

[0182] In one embodiment, the calcium salt of the compound of formula (I) (e.g., type A) exhibits an endothermic peak with a peak temperature selected from about 145°C to about 160°C, as determined by differential scanning calorimetry (DSC), the endothermic peak corresponding to the melting of the compound. In some embodiments, the calcium salt of the compound of formula (I) (e.g., type A) exhibits an endothermic peak with a peak temperature selected from about 145°C to about 155°C, the endothermic peak corresponding to the melting of the compound. In some embodiments, type A has an endothermic peak with a peak temperature selected from about 145°C to about 155°C, as determined by differential scanning calorimetry (DSC). In one embodiment, the calcium salt of the compound of formula (I) (e.g., type A) exhibits an endothermic peak with a peak temperature selected from the ranges of about 145°C to about 155°C, about 150°C to about 155°C, and about 150°C to about 153°C, the endothermic peak corresponding to the melting of the compound. In some embodiments, type A, as determined by DSC, exhibits an endothermic peak with a peak temperature of about 145°C to 155°C, preferably about 150°C to 155°C, and more preferably about 150°C to 153°C. In one embodiment, the calcium salt of the compound of formula (I), as determined by DSC, shows an endothermic peak with a peak temperature of 153°C ± 3°C. In some embodiments, type A, as determined by DSC, exhibits an endothermic peak with a peak temperature of about 153°C ± 3°C. See also Figure 4 .

[0183] In one embodiment, the calcium salt (e.g., type A) of the compound of formula (I) has the following characteristics: Figure 4 The endothermic peak shown is the peak temperature.

[0184] In one embodiment, the calcium salt (e.g., type A) of the compound of formula (I) has essentially the following properties: Figure 5 The thermogravimetric analysis (TGA) spectrum is shown.

[0185] In one embodiment, this disclosure provides a crystalline form of the calcium salt of formula (I) or the calcium salt of (((S)-1-(3-((S)-1-amino-3-carboxypropyl)-1,2,4-oxadiazol-5-yl)-4-guanidinobutyl)carbamoyl)-L-proline, having at least one of the following characteristics: a) The basic XRPD map is as follows Figure 1 As shown; and b) At least one XRPD peak with 2θ values ​​of 9.9±0.2, 13.2±0.2, and 19.8±0.2.

[0186] In one embodiment, this disclosure provides a crystalline form of the calcium salt of formula (I) or the calcium salt of (((S)-1-(3-((S)-1-amino-3-carboxypropyl)-1,2,4-oxadiazol-5-yl)-4-guanidinobutyl)carbamoyl)-L-proline, having at least one of the following characteristics: a) The basic XRPD map is as follows Figure 1 As shown; b) At least one XRPD peak with 2θ values ​​of 9.9±0.2, 13.2±0.2, and 19.8±0.2; and c) The endothermic peak, as determined by DSC, has a peak temperature of 153°C ± 3°C.

[0187] In one embodiment, this disclosure provides a crystalline form of the calcium salt of formula (I) or the calcium salt of (((S)-1-(3-((S)-1-amino-3-carboxypropyl)-1,2,4-oxadiazol-5-yl)-4-guanidinobutyl)carbamoyl)-L-proline, having at least one of the following characteristics: a) The basic XRPD map is as follows Figure 1 As shown; b) At least one XRPD peak with 2θ values ​​of 9.9±0.2, 13.2±0.2, and 19.8±0.2; c) An endothermic peak with a peak temperature of 153°C ± 3°C, as determined by DSC; and d) The basic TGA chart is as follows Figure 5 As shown; In one embodiment, this disclosure provides a sodium salt of a crystalline compound of formula (I).

[0188]

[0189] (I).

[0190] In one embodiment, this disclosure provides a crystalline monosodium salt of the compound of formula (I). In some embodiments, this disclosure provides a crystalline compound of a monosodium salt of (((S)-1-(3-(((S)-1-amino-3-carboxypropyl)-1,2,4-oxadiazol-5-yl)-4-guanidinobutyl)carbamoyl)-L-proline. In one embodiment, this disclosure provides a crystalline disodium salt of the compound of formula (I).

[0191] In one embodiment, this disclosure provides a crystalline form of disodium salt of formula (I) or (((S)-1-(3-((S)-1-amino-3-carboxypropyl)-1,2,4-oxadiazol-5-yl)-4-guanidinobutyl)carbamoyl)-L-proline.

[0192] In one embodiment, the crystalline form of the disodium salt of the compound of formula (I) is characterized by X-ray powder diffraction analysis.

[0193] In some embodiments, the disodium salt of the compound of formula (I) is in the B-type crystalline form.

[0194] In some embodiments, the disodium salt is crystalline in type B, characterized in that the XRPD spectrum includes at least three peaks with 2θ values ​​selected from 18.5±0.2, 18.9±0.2, 22.5±0.2, 23.5±0.2, 25.4±0.2, 27.9±0.2, 28.9±0.2, 31.7±0.2, 33.9±0.2, 37.7±0.2, and 42.4±0.2.

[0195] In some embodiments, the disodium salt is crystalline in type B, characterized in that the XRPD spectrum includes at least four peaks with 2θ values ​​selected from 18.5±0.2, 18.9±0.2, 22.5±0.2, 23.5±0.2, 25.4±0.2, 27.9±0.2, 28.9±0.2, 31.7±0.2, 33.9±0.2, 37.7±0.2, and 42.4±0.2.

[0196] In some embodiments, the disodium salt is crystalline in type B, characterized in that the XRPD spectrum includes at least five peaks with 2θ values ​​selected from 18.5±0.2, 18.9±0.2, 22.5±0.2, 23.5±0.2, 25.4±0.2, 27.9±0.2, 28.9±0.2, 31.7±0.2, 33.9±0.2, 37.7±0.2, and 42.4±0.2.

[0197] In some embodiments, the crystalline form is type B, characterized in that, as described in the foregoing embodiments, its XRPD spectrum includes at least 6 peaks, at least 7 peaks, at least 8 peaks, at least 9 peaks, or at least 10 peaks.

[0198] In one embodiment, the crystal form B is characterized in that its X-ray powder diffraction pattern includes at least one peak with a 2θ value of 31.7 ± 0.2.

[0199] In one embodiment, the crystal form B is characterized in that its X-ray powder diffraction pattern includes at least one peak with a 2θ value of 33.9 ± 0.2.

[0200] In one embodiment, the crystal form B is characterized in that its X-ray powder diffraction pattern includes at least one peak with a 2θ value of 22.5 ± 0.2.

[0201] In one embodiment, the crystal form B is characterized in that its X-ray powder diffraction pattern includes at least one peak with a 2θ value of 23.5 ± 0.2.

[0202] In one embodiment, the crystal form B is characterized in that its X-ray powder diffraction pattern includes at least one peak with a 2θ value of 25.4 ± 0.2.

[0203] In one embodiment, the crystal form B is characterized in that its X-ray powder diffraction pattern includes at least one peak with a 2θ value of 27.9 ± 0.2.

[0204] In one embodiment, the crystal form B is characterized in that its X-ray powder diffraction pattern includes at least one peak with a 2θ value of 28.9 ± 0.2.

[0205] In one embodiment, the crystal form B is characterized in that its X-ray powder diffraction pattern includes at least one peak with a 2θ value of 37.7 ± 0.2.

[0206] In one embodiment, the crystal form B is characterized in that its X-ray powder diffraction pattern includes at least one peak with a 2θ value of 42.4 ± 0.2.

[0207] In one embodiment, the crystal form B is characterized in that its X-ray powder diffraction pattern includes at least one peak with 2θ values ​​of 22.5±0.2, 23.5±0.2, 31.7±0.2, and 33.9±0.2.

[0208] In one embodiment, the crystal form B is characterized in that its X-ray powder diffraction pattern includes at least one peak with 2θ values ​​of 22.5±0.2, 23.5±0.2, 25.4±0.2, 31.7±0.2, 33.9±0.2 and 37.7±0.2.

[0209] In one embodiment, the crystal form B is characterized in that its X-ray powder diffraction pattern includes peaks with 2θ values ​​of 22.5±0.2, 23.5±0.2, 25.4±0.2, 31.7±0.2, 33.9±0.2 and 37.7±0.2.

[0210] In one embodiment, the crystal form B is characterized in that its X-ray powder diffraction pattern includes at least one peak with 2θ values ​​of 18.9±0.2, 22.5±0.2, 23.5±0.2, 25.4±0.2, 27.9±0.2, 28.9±0.2, 31.7±0.2, 33.9±0.2, 37.7±0.2, and 42.4±0.2.

[0211] In one embodiment, the crystal form B is characterized in that its X-ray powder diffraction pattern includes peaks with 2θ values ​​of 18.9±0.2, 22.5±0.2, 23.5±0.2, 25.4±0.2, 27.9±0.2, 28.9±0.2, 31.7±0.2, 33.9±0.2, 37.7±0.2, and 42.4±0.2.

[0212] In one embodiment, the crystal form B is characterized in that its X-ray powder diffraction pattern includes at least one peak with 2θ values ​​of 18.5±0.2, 18.9±0.2, 22.5±0.2, 23.5±0.2, 25.4±0.2, 27.9±0.2, 28.9±0.2, 31.7±0.2, 33.9±0.2, 37.7±0.2, and 42.4±0.2.

[0213] In one embodiment, the crystal form B is characterized in that its X-ray powder diffraction pattern includes peaks with 2θ values ​​of 18.5±0.2, 18.9±0.2, 22.5±0.2, 23.5±0.2, 25.4±0.2, 27.9±0.2, 28.9±0.2, 31.7±0.2, 33.9±0.2, 37.7±0.2, and 42.4±0.2.

[0214] In one embodiment, crystal form B is characterized by having essentially the following properties: Figure 3A The X-ray powder diffraction pattern shown is shown.

[0215] Table 2: Exemplary peaks of disodium salts of compounds of formula (I)

[0216] In one embodiment, this disclosure provides a crystalline form of a monosodium salt of the compound of formula (I) or a monosodium salt of (((S)-1-(3-((S)-1-amino-3-carboxypropyl)-1,2,4-oxadiazol-5-yl)-4-guanidinobutyl)carbamoyl)-L-proline.

[0217] In one embodiment, the crystalline form of the monosodium salt of the compound of formula (I) is characterized by X-ray powder diffraction analysis.

[0218] In one embodiment, the monosodium salt of the compound of formula (I) is crystalline in the form of type C.

[0219] In one embodiment, the monosodium salt of the crystalline compound of formula (I) is of type C, characterized in that its X-ray powder diffraction pattern includes at least one peak with 2θ values ​​of 42.3±0.2, 42.9±0.2, 43.2±0.2 and 43.8±0.2.

[0220] In one embodiment, crystal form C is characterized by having essentially the following properties: Figure 3B The X-ray powder diffraction pattern shown is shown.

[0221] Table 3: Exemplary peaks of monosodium salts of compounds of formula (I)

[0222] In one embodiment, this disclosure provides compounds that are obtainable by methods including: i) Provide an aqueous mixture comprising a compound of formula (I); ii) React the mixture with calcium carbonate; iii) Filter the mixture obtained in (ii) and add the antisolvent to the filtrate; and iv) Separate the resulting compound from the mixture; wherein the antisolvent is ethanol.

[0223] In one embodiment, this disclosure provides a compound obtainable by a method comprising the following steps: i) Provide an aqueous mixture comprising a compound of formula (I); ii) React the mixture with calcium carbonate; iii) Filter the mixture from step (ii) to obtain filtrate; iv) Add solvent B to the filtrate to form a reaction mixture, wherein solvent B is ethanol; and v) Separate the compound from the reaction mixture.

[0224] In some embodiments, this disclosure provides compounds that are obtainable by methods including: i) Provide an aqueous mixture comprising a compound of formula (I); ii) React the mixture with calcium carbonate, and then filter the mixture to obtain a filtrate; iii) Adding an antisolvent to the filtrate to form a reaction mixture, wherein the antisolvent is ethanol; and Iv) Separate the compound from the reaction mixture.

[0225] In some embodiments, this disclosure provides compounds that are obtainable by methods including: i) Provide an aqueous mixture comprising a compound of formula (I); ii) React the mixture with calcium carbonate; iii) Filter the mixture from step (ii) to obtain filtrate; iv) Add solvent B to the filtrate to form a reaction mixture, wherein solvent B is ethanol; and v) Separate the compound from the reaction mixture.

[0226] In one embodiment, solvent B is added to the filtrate to form a reaction mixture, wherein a calcium salt crystallizes out from the reaction mixture.

[0227] In one embodiment, solvent B is added to the filtrate to form a reaction mixture, wherein the calcium salt of the compound of formula (I) crystallizes out from the reaction mixture.

[0228] According to the foregoing embodiments, solvent B is an antisolvent that promotes the crystallization of the calcium salt of compound (I) from the filtrate.

[0229] In one embodiment of a compound obtainable by a method, the separation step of the compound includes: filtering the compound from the reaction mixture and washing and drying the compound obtained from the reaction mixture under vacuum conditions.

[0230] In one embodiment, the compound is obtained by a method wherein step (v) of separating the compound further comprises the following sub-steps: i) filtering the compound from the reaction mixture; and ii) washing and drying the compound obtained from the reaction mixture under vacuum conditions.

[0231] In one embodiment, the calcium salt of the crystalline compound of formula (I) is the crystalline calcium salt of the compound of formula (I) described herein.

[0232] In some embodiments, the calcium salt or sodium salt of the compound of formula (I) is substantially separated.

[0233] "Substantial separation" refers to the separation of a salt, eutectic, or compound from its formation or detection environment at least partially or substantially. Partial separation may include, for example, compositions rich in the salts described herein. Substantial separation may include compositions containing at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, or at least 99% by weight of the salts described herein or their salts. Methods for separating compounds and their salts are conventional techniques in the art.

[0234] In one embodiment, the preparation method further includes induced crystallization. The method may also include drying the crystals, for example, under reduced pressure. In one embodiment, induced precipitation or crystallization includes secondary nucleation, wherein nucleation occurs in the presence of a seed crystal or in interaction with the environment (crystallizer walls, stirring impeller, ultrasonic treatment, etc.).

[0235] In some embodiments, the calcium salt of the compound of formula (I) is represented by formula (IA):

[0236] (IA).

[0237] The calcium salt of the compound of formula (I) according to the foregoing embodiments, wherein the compound is in crystalline form.

[0238] Pharmaceutical Composition

[0239] In one embodiment, this disclosure relates to a pharmaceutical composition comprising a pharmaceutically acceptable salt of a compound of formula (I) and one or more pharmaceutically acceptable carriers or excipients.

[0240] In one embodiment, a pharmaceutically acceptable salt of the compound of formula (I) is a calcium salt of the compound of formula (I). In another embodiment, a pharmaceutically acceptable salt of the compound of formula (I) is a disodium salt of the compound of formula (I).

[0241] In one embodiment, this disclosure relates to a pharmaceutical composition comprising a calcium salt of a compound of formula (I) and one or more pharmaceutically acceptable excipients.

[0242] In one embodiment, this disclosure relates to a pharmaceutical composition comprising a calcium salt of a compound of formula (I) (1:0.25) and one or more pharmaceutically acceptable excipients.

[0243] In one embodiment, this disclosure relates to a pharmaceutical composition comprising a calcium salt of a compound of formula (I), at least one other therapeutic agent, and a pharmaceutically acceptable carrier or excipient.

[0244] In one embodiment, this disclosure provides the use of a pharmaceutical composition comprising a calcium salt or a sodium salt of a compound of formula (I) and at least one pharmaceutically acceptable excipient (e.g., a pharmaceutically acceptable carrier or diluent). In another embodiment, this disclosure provides the use of a pharmaceutical composition comprising a calcium salt of a compound of formula (I) as described herein and at least one pharmaceutically acceptable excipient (e.g., a pharmaceutically acceptable carrier or diluent). The calcium salt or sodium salt of the compound of formula (I) described herein may be combined with, diluted with, or encapsulated within a pharmaceutically acceptable excipient (e.g., a carrier or diluent), said carrier may be in the form of a capsule, sachet, paper, or other container.

[0245] The compounds described in this disclosure are typically administered in the form of pharmaceutical compositions. Such compositions can be prepared using processes known in the pharmaceutical field and include at least one compound described in this disclosure. The pharmaceutical compositions described in this disclosure include one or more of the compounds described herein, and one or more pharmaceutically acceptable excipients. Generally, the pharmaceutically acceptable excipients are approved by regulatory agencies or are generally considered safe for use in humans or animals. The pharmaceutically acceptable excipients include, but are not limited to: carriers, diluents, flow aids and lubricants, preservatives, buffers, chelating agents, polymers, gelling agents, thickeners, solvents, etc.

[0246] The pharmaceutical composition may be administered orally, parenterally, or by inhalation. Examples of parenterally administration include injection, transdermal, transmucosal, nasal, and transpulmonary administration.

[0247] Examples of suitable carriers include, but are not limited to: water, salt solutions, alcohols, polyethylene glycol, lactose, sucrose, dextrin, magnesium carbonate, sugar, amylose, magnesium stearate, talc, stearic acid, lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, fatty acid esters, and polyoxyethylene, etc.

[0248] The pharmaceutical composition may also contain one or more pharmaceutically acceptable adjuvants, wetting agents, suspending agents, preservatives, buffers, sweeteners, flavoring agents, coloring agents, or any combination thereof.

[0249] The pharmaceutical compositions may be in conventional dosage forms, such as tablets, capsules, solutions, suspensions, injections, or products for topical application. Furthermore, the pharmaceutical compositions described in this disclosure may be prepared to provide desired release characteristics.

[0250] The compounds disclosed herein may be administered in pure form or as a suitable pharmaceutical composition via any recognized route of administration. The route of administration may be any route that effectively delivers the compounds of this disclosure to the appropriate or desired site of action. Suitable routes of administration include, but are not limited to: oral, nasal, buccal, skin, intradermal, percutaneous, parenteral, rectal, subcutaneous, intravenous, intraurethral, ​​intramuscular, or local administration.

[0251] Solid oral preparations include, but are not limited to: tablets, capsules (soft capsules or hard gelatin capsules), sugar-coated pills (containing active ingredients in powder or granule form), lozenges, and throat lozenges.

[0252] Liquid formulations include, but are not limited to: syrups, emulsions, and sterile injectable solutions, such as suspensions or solutions.

[0253] Topical dosage forms of the compound include ointments, pastes, creams, lotions, powders, solutions, eye drops or ear drops, and impregnated dressings, and may contain appropriate conventional additives, such as preservatives and solvents that facilitate drug penetration.

[0254] The pharmaceutical compositions disclosed herein can be prepared using conventional techniques known in the literature.

[0255] In another embodiment, this disclosure provides a product comprising a sodium salt of a compound of formula (I) for use as a pharmaceutical.

[0256] In another embodiment, this disclosure provides a product comprising a calcium salt of a compound of formula (I) for use in a method of treating a disease and / or condition mediated by the CD47-SIRPα signaling pathway in a subject, the method comprising administering a therapeutically effective amount of the calcium salt of the compound of formula (I) to a subject in need of it.

[0257] In another embodiment, this disclosure provides a product or pharmaceutical composition comprising a therapeutically effective amount of a calcium salt or a sodium salt of a compound of formula (I) described herein, for use in treating a disease and / or condition mediated by the CD47-SIRPα signaling pathway in a subject, the method comprising administering the mixture to a subject in need of it.

[0258] In another embodiment, this disclosure provides a product or pharmaceutical composition comprising a calcium salt of the compound described herein or a sodium salt of the compound (I) for use in a method of treating a disease and / or condition mediated by the CD47-SIRPα signaling pathway in a subject, the method comprising administering a therapeutically effective amount of the calcium salt of the compound (I) or the sodium salt of the compound (I) to a subject in need.

[0259] In another embodiment, this disclosure provides a product or pharmaceutical composition comprising a therapeutically effective amount of a calcium salt or sodium salt of a compound of formula (I) described herein, for use in a method of treating a disease and / or condition mediated by the CD47-SIRPα signaling pathway in a subject, the method comprising administering the product or pharmaceutical composition to a subject.

[0260] In another embodiment, this disclosure provides a product or pharmaceutical composition comprising a calcium salt of a compound of formula (I) described herein or a sodium salt of a compound of formula (I) for use as a medicament.

[0261] In another embodiment, this disclosure provides a product or pharmaceutical composition comprising a therapeutically effective amount of a calcium salt or a sodium salt of a compound of formula (I) described herein for use as a medicament.

[0262] In another embodiment, this disclosure provides a product comprising a sodium salt of a compound of formula (I) for use in a method of treating a disease and / or condition mediated by the CD47-SIRPα signaling pathway in a subject, the method comprising administering a therapeutically effective amount of the sodium salt of the compound of formula (I) to a subject in need. In another embodiment, this disclosure provides a product for use in a method of treating a disease and / or condition mediated by the CD47-SIRPα signaling pathway, wherein the disease and / or condition is cancer.

[0263] In another embodiment, this disclosure provides a method for treating a disease and / or condition mediated by the CD47-SIRPα pathway in a subject, the method comprising administering to a subject in need a therapeutically effective amount of a calcium salt of the compound of formula (I) described herein or a crystalline form thereof.

[0264] In another embodiment, this disclosure provides a method for treating a disease and / or condition mediated by the CD47-SIRPα pathway in a subject, the method comprising administering to a subject in need a therapeutically effective amount of a sodium salt of the compound of formula (I) described herein or a crystalline form thereof.

[0265] In one embodiment, the disease or condition mediated by the CD47-SIRPα pathway is cancer.

[0266] In one embodiment, the cancer is selected from melanoma, kidney cancer, prostate cancer, breast cancer, colon cancer, lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, malignant melanoma of the skin or eye, uterine cancer, ovarian cancer, rectal cancer, anal region cancer, stomach cancer, testicular cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, chronic or acute leukemia (including acute myeloid leukemia), Chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia), childhood solid tumors, lymphocytic lymphoma, bladder cancer, kidney or ureteral cancer, renal pelvis cancer, central nervous system (CNS) tumors, non-small cell lung cancer (NSCLC), primary central nervous system lymphoma, tumor angiogenesis, spinal axis tumors, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, B-cell lymphoma, environmentally induced cancers (including asbestos-induced cancers such as mesothelioma), and combinations of the aforementioned cancers.

[0267] In one embodiment, the calcium salt of the compound of formula (I) is represented by formula (IA):

[0268] (IA).

[0269] experiment

[0270] This disclosure provides a method for preparing pharmaceutically acceptable salts of compounds of formula (I) using appropriate materials and conditions, according to the procedures of the following examples. Those skilled in the art will understand that known variations of the conditions and processes in the following preparation methods can be used to prepare these compounds of this disclosure. Furthermore, other compounds of this disclosure can be prepared by those skilled in the art using the procedures described in detail.

[0271] abbreviation: The abbreviations used throughout the instruction manual and their definitions are summarized below: IPA: Isopropanol; DMSO: N,N-Dimethyl sulfoxide; DMF: N,N-Dimethylformamide; NaOH: Sodium hydroxide; EtOAc: Ethyl acetate; TFA: Trifluoroacetic acid; MTBE: Methyl tert-butyl ether; TIPS: Triisopropylsilane; XRPD: X-ray powder diffraction; ICP-MS: Inductively coupled plasma mass spectrometry; LCMS: Liquid chromatography-mass spectrometry; HPLC: High performance liquid chromatography; NMR: Nuclear magnetic resonance; RT: Room temperature; C: Degrees Celsius; N: Equivalent concentration; g: Gram; h: Hour; SSNMR: Solid-state nuclear magnetic resonance; NMR: Nuclear magnetic resonance.

[0272] Analysis method: X-ray powder diffraction (XRPD): X-ray powder diffraction patterns were acquired using an X'Pert3 PRO MPD diffractometer with CuKα radiation (45 kV, 40 mA). Detailed data acquisition parameters are shown in Table 4. Table 4: X-ray powder diffraction parameters

[0273] Those skilled in the art will understand that obtained X-ray diffraction patterns may contain measurement errors depending on the measurement conditions employed. It is well known that the intensity in an X-ray diffraction pattern can fluctuate depending on the measurement conditions used. It should also be understood that relative intensity can vary depending on experimental conditions, sample texture, and the wavelength of the X-ray radiation used. For the same crystal form, the 2θ diffraction angle agreement between the sample and the reference is within 0.2°; this level of measurement error should be considered relevant to the diffraction angle disclosed herein. Therefore, it should be understood that the crystal form described in this disclosure is not limited to crystal forms that provide an X-ray diffraction pattern identical to that depicted in the accompanying drawings. Any crystal form that provides an X-ray diffraction pattern substantially identical to that disclosed in the drawings is within the scope of this disclosure. The ability to determine that X-ray diffraction patterns are substantially identical is a matter of ordinary skill for those skilled in the art.

[0274] HPLC method: Analytical HPLC was performed using a ZIC HILIC 200A column (4.6 mm × 250 mm, 5 µm) at a flow rate of 1.0 mL / min. The elution conditions were as follows: Buffer A: 5 mmol ammonium acetate, Buffer B: acetonitrile. The column was equilibrated with 80% Buffer B, followed by gradient elution with 80% to 50% Buffer B over 32 minutes. LC-MS was performed on an AP1 2000 LC / MS / MS triple quadrupole (Applied Biosystems) HPLC system equipped with an Agilent 1100 series HPLC system with G1315 B DAD, using a Mercury MS column; or on an Agilent LC / MSD VL single quadrupole HPLC system equipped with an Agilent 1100 series HPLC system with G1315 B DAD, using a Mercury MS column; or on a Shimadzu LCMS 2020 single quadrupole HPLC system equipped with a Prominence UFLC system with SPD-20 ADAD. Sodium content was analyzed using an ASAgilent Technologies 240 AA, and calcium content was analyzed by ICP-OES using a Perkin Elmer Inc. (Optima 5300 DV) or by ICP-MS using an Agilent Technologies 7800X ICP-MS system.

[0275] Thermogravimetric analysis and differential scanning calorimetry:

[0276] Thermogravimetric analysis (TGA) data were acquired using a TA Instruments Q5000 TGA. Differential scanning calorimetry (DSC) was performed using a TA Instruments TA Q2000 DSC. Method parameters are detailed in Table 5 below.

[0277] Table 5: TGA and DSC parameters

[0278] XRPD studies of the compound of formula (I) obtained using the method described in Example 1 of WO201938367 as a free acid revealed that the compound is amorphous. Such amorphous free acids are unstable under environmental conditions. XRPD, as... Figure 2 As shown.

[0279] In the preparation of any pharmaceutical product, the pharmaceutical compound must exhibit sufficient stability and possess suitable physicochemical properties to be developed into a pharmaceutical product. It has been observed that the compound of formula (I), when present as a free acid, is hygroscopic under environmental conditions; therefore, it is considered unsuitable for further drug development. Thus, the physicochemical properties of the free acid form of the compound of formula (I) must be improved.

[0280] To obtain compounds of formula (I) with improved physicochemical properties for further drug development, the inventors conducted numerous experiments using various reagents, solvent systems, and reaction conditions, including salt screening studies, co-lyophilization, chelate conversion, and prodrug methods; however, none of these methods were successful. Salt screening methods using various salts or amines, such as sodium citrate, sodium phosphate, and ammonium chloride, in different solvent systems, such as ethanol, methanol, IPA, DMSO, and DMF, and at different temperature ranges, only yielded hygroscopic compounds, failing to achieve any yield suitable for further drug development.

[0281] Studies have revealed that the calcium and sodium salts of compound (I) are unexpectedly stable and are inherently crystalline. Furthermore, these salts of compound (I) exhibit unexpected advantages in several desired properties, such as filterability, stability, and solubility, compared to other salts tested on the free acid of compound (I) and products of other methods. Moreover, the calcium and sodium salts of compound (I) described in this disclosure exhibit crystalline properties.

[0282] The compound of formula (I) as a free acid was prepared using the steps described in Example 1 of WO2019138367, the entire contents of which are incorporated herein by reference.

[0283] Example 1: Preparation of the sodium salt of compound (I)

[0284] Synthesis of sodium (((S)-1-(3-((S)-1-amino-3-carboxypropyl)-1,2,4-oxadiazol-5-yl)-4-guanidinobutyl)carbamoyl)-L-proline

[0285] Method A: Dissolve 12 g of (((S)-1-(3-(((S)-1-amino-3-carboxypropyl)-1,2,4-oxadiazol-5-yl)-4-guanidinobutyl)carbamoyl)-L-proline in water, and cool the resulting solution to 5-10°C. Add cold 0.5N NaOH solution to the solution until the pH is greater than 9.3. Stir the resulting solution for 10-20 minutes and extract with ethyl acetate. Concentrate the aqueous layer under high vacuum at 28°C and co-evaporate with acetonitrile. Grind the resulting gelatinous syrup with acetonitrile to obtain a grayish-white solid, which is dried under vacuum to give 12.5 g of the title sodium salt. LCMS: 441.4 (M+H) + 463.2 (M+Na) + 485.4 (M+2Na) + .

[0286] Alternatively, the title compound can be separated by adding an antisolvent (e.g., isopropanol) in a post-processing step. Atomic absorption spectrometry confirmed the presence of the sodium salt, with a sodium content of 9.6%.

[0287] Method B: At 10±5°C, 200 g (0.235 mol) of (((S)-1-(3-((S)-4-(tert-butoxy)-1-((tert-butoxycarbonyl)amino)-4-oxobutyl)-1,2,4-oxadiazol-5-yl)-4-(3-(((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)guanidinyl)butyl)carbamoyl)-L-proline) was slowly added to a stirred solution of TFA (4.5 v / L), TIPS (0.25 v / L), and water (0.25 v / L). The reaction temperature was slowly increased to 30±5°C, and the mixture was stirred for 3.5 h. The reaction was quenched by adding water. The aqueous layer was washed with MTBE. At 30±5°C, the pH of the aqueous layer was adjusted to 4.5 to 6.6 with sodium bicarbonate. The aqueous layer was concentrated and isopropanol (10 volumes) was added. The reaction mixture was stirred for 20 to 24 hours and filtered. The crude solids were washed with a methanol-water mixture (volume ratio 7:0.5), filtered, and dried under vacuum to give sodium (((S)-1-(3-((S)-1-amino-3-carboxypropyl)-1,2,4-oxadiazol-5-yl)-4-guanidinobutyl)carbamoyl)-L-proline (41 g).

[0288] Resin treatment: Sodium (((S)-1-(3-(((S)-1-amino-3-carboxypropyl)-1,2,4-oxadiazol-5-yl)-4-guanidinobutyl)carbamoyl)-L-proline was dissolved in water. The aqueous solution was treated three times (1 w / w each time) with a water-washed sodium ion exchange resin (e.g., Indion 225H resin) and filtered. The filtrate obtained was used for subsequent steps.

[0289] Example 2: Preparation of calcium salts of compound (I)

[0290] In 0 o C to 10 o C. Calcium carbonate (41 g) was added to an aqueous solution of (((S)-1-(3-(((S)-1-amino-3-carboxypropyl)-1,2,4-oxadiazol-5-yl)-4-guanidinylbutyl)carbamoyl)-L-proline (compound of formula (I), 150 g) or resin-treated sodium salt of (((S)-1-(3-(((S)-1-amino-3-carboxypropyl)-1,2,4-oxadiazol-5-yl)-4-guanidinylbutyl)carbamoyl)-L-proline. The reaction mixture was stirred at room temperature for 24 hours, filtered, and washed with water. Using ethanol as an antisolvent, the filtrate containing the calcium salt of formula (I) was precipitated from the solution and filtered at room temperature. The resulting solid was washed with MTBE and dried under vacuum to give 120 g of the title compound (LCMS: 440.46(M+H)). + ; Actual mass 441.2).

[0291] Differential scanning calorimetry

[0292] Differential scanning calorimetry (DSC) analysis of the calcium salt of compound (I) showed an endothermic peak at 152.9 °C (peak temperature) before melting / decomposition, with an initial temperature of 150.92 °C. Figure 4 ).

[0293] Thermogravimetric analysis

[0294] The calcium salt of compound (I) was analyzed by thermogravimetric analysis using a Q5000 TA TGA instrument. 23.6 mg of sample was accurately weighed and placed in a platinum crucible. The sample was heated from 30°C to 300°C at a heating rate of 10°C / min under nitrogen purging at 50 mL / min. The TGA thermogram showed that weight loss began after 26°C, corresponding to the adsorption of water or residual solvent (…). Figure 5 ).

[0295] Determination of the solubility of calcium salts of compound (I)

[0296] The equilibrium solubility of the calcium salt of compound (I) in water was determined at 20°C and 30°C. All samples were equilibrated at the corresponding temperatures for 6 hours and were highly soluble in water, with a solubility of 82.59 ± 3.341 mg / mL measured at 24 hours. The compound exhibited pH-independent solubility in aqueous pH buffer solutions ranging from pH 1.2 to 9.0.

[0297] Stability and forced degradation studies

[0298] To understand the advantages of the calcium salt of compound (I) relative to its free acid form, and the effects of temperature and humidity on the calcium salt of compound (I), stability and forced degradation studies were conducted under various stress conditions for extended periods. Samples prepared according to the above method were placed in polyethylene bags and stored in a stability chamber. Various storage conditions were tested, including 25°C ± 2°C / 60% relative humidity (RH) ± 5% RH and 5°C ± 3°C, for a maximum duration of 3 months. The HPLC purity and water content of the samples were measured at predetermined time intervals. The results showed that the calcium salt of compound (I) was stable against degradation after 3 months of storage at 25°C ± 2°C / 60% relative humidity (RH) and 5°C ± 3°C, maintaining its physical form. In contrast, the free acid of compound (I) was only stable for about 7 days at room temperature. The forced degradation results of the calcium salt of compound (I) are listed in Table 6 below.

[0299] Table 6: Results of Forced Degradation

[0300] Stability in solid form

[0301] The calcium salt of compound (I) was exposed to different stability conditions (5°C, 25°C±2°C / 60%RH, 30°C / 75%RH, and 40°C / 75%RH) in a stability chamber for 3 months. Subsequently, XRPD analysis was performed on samples under different conditions, and the results were compared with those of the solid form of the calcium salt of compound (I). The results showed that the XRPD spectra of the samples under different conditions were in good agreement with those of the calcium salt of compound (I). Figure 6 ).

[0302] Dynamic vapor adsorption study

[0303] To evaluate the physical stability and hygroscopic tendency of the calcium salt of compound (I) under humid conditions, dynamic vapor adsorption analysis was performed. The adsorption-desorption isotherms of the calcium salt of compound (I) were studied at 25°C. An increase in sample weight with increasing humidity was observed, indicating moisture absorption. The sample exhibited a typical hysteresis-free "S"-shaped curve during desorption, indicating that the absorbed moisture adsorbed onto the solid surface under high humidity did not affect its internal structure, as no stepwise changes corresponding to hydrate formation were observed in the adsorption and desorption curves. At 80% RH, the calcium salt of compound (I) increased in weight by approximately 7.81% (w / w). Figure 7 ).

[0304] Mass spectrometry analysis: The molecular weight of the calcium salt of compound (I) was analyzed using mass spectrometry. The experimental conditions used for mass determination involved dissolving the calcium salt of compound (I) in a suitable buffer solution with appropriate solubility. In this example, the calcium salt of compound (I) dissociated into the free acid and calcium ions of compound (I), indicating that the calcium salt of compound (I) does not exist in a chelated form. Only the mass of the free acid (molecular weight 441) was observed in the mass spectrometry analysis, which is typical for any salt form. Therefore, the mass spectrometry data support the presence of calcium in the calcium salt of compound (I) as a salt, rather than a chelated form. Therefore, the molecular weight of the calcium salt of compound (I) could not be determined.

[0305] Determination of the structure, molecular formula, and molecular weight of the calcium salt of compound (I)

[0306] The calcium salt of compound (I) is highly soluble in water but extremely difficult to dissolve in organic solvents. Due to its high solubility in water, the calcium salt of compound (I) dissociates into a free acid and a calcium cation of compound (I). Therefore, single crystals of the calcium salt of compound (I) cannot be obtained.

[0307] Due to the lack of single-crystal data, the molecular structure or formula of the calcium salt of compound (I) cannot be determined. However, to address the issue of drug potency related to molecular weight, a correction factor method was employed. In this method, the molecular formula of the free acid of compound (I) is corrected based on the percentage of calcium content determined by ICP-MS experiments. This method allows for the determination of drug potency even when the molecular formula or molecular weight of the salt is unavailable.

[0308] Solid-state nuclear magnetic resonance (SSNMR)

[0309] All SSNMR experiments were performed on a 400 MHz (9.4 T) solid-state NMR spectrometer. Calcium salt samples of compound (I) in powder form were loaded into a 1.9 mm rotor at room temperature. The samples were rotated at 35 kHz at a magic angle of 54.7° relative to the main magnetic field. 1 H and 13 In the C channel, pulse lengths of 1.35 ms and 2.5 ms are used for 900 rotations. As shown in the structure below, carbon atoms are labeled "A" to "Q" to facilitate the interpretation of SSNMR and single-crystal XRD data.

[0310]

[0311] i) Echo detection 1 HMAS-NMR spectrum

[0312] Echo detection of calcium salts of compound (I) 1 HMAS-NMR spectra as follows Figure 8 As shown. Echo detection is used to overcome... 1 Baseline distortion in the H-map is reduced, and spectral resolution is improved by suppressing irrelevant background signals. Figure 8 The spectrum in the image shows a clear separation between the aliphatic protons and acidic protons of the calcium salt of compound (I). Peaks concentrated around 9-10 ppm correspond to the acidic protons, and the presence or absence of these peaks is directly related to the stoichiometry of calcium in the compound.

[0313] ii) 1 H- 13 C CPMAS-NMR spectrum

[0314] Figure 9 The calcium salt of the compound of formula (I) is shown. 1 H- 13 C10 CPMAS-NMR spectra. This experiment involves... 1 H polarization shifts to 13 C and detection 13 C signal. Peak identification was based on information from chemical structure, electronic environment, stereochemistry, and regional chemistry. Four peaks were observed in the region between 150 and 190 ppm, belonging to acid carbonyl groups (A, Q), imine bonds (E+F+K), and amide carbonyl groups (L). The relative intensity of the peak corresponding to "Q" was less than that of the peak corresponding to "A," indicating that the Q site has fewer adjacent protons, i.e., a weaker bond, compared to the A site. 1 H- 13 C-interactions. The imine and amide peaks also follow the same trend. To obtain more conclusive evidence, two-dimensional heteronuclear correlation (HetCor) spectroscopy was also used.

[0315] iii) Two-dimensional heteronuclear correlation (HetCor) spectroscopy

[0316] Calcium salts of compound (I) 13 C- 1 Two-dimensional correlation NMR spectrum (HetCor) such as Figure 10A and 10B As shown. Figure 10A The full spectrum correlation plot was displayed. Figure 10B Showing 13 Magnified spectra of the C carbonyl / acidic region to clearly highlight the involved 13 The difference in cross-peak intensity between the “A” and “Q” sites of C.

[0317] from Figure 10B The peaks marked within the oval boxes clearly show that the "A" site is strongly correlated with the acidic proton, implying its -COOH form. However, the area marked with rectangular boxes indicates a weak correlation between "Q" and the acidic proton. Therefore, it should be in ionic form [i.e., -COO]. - [Form]. This experiment clearly shows that Ca... 2+ It is bonded between two "Q" carbonyl groups, as shown in formula (IA), and in this case, the stoichiometric ratio is Ca:compound of formula (I) = 1:2.

[0318] Determination of the crystal structure of the free acid of compound (I)

[0319] The crystal structure of the free acid of compound (I) is as follows: Figure 11 As shown, the asymmetric unit of this single-crystal structure consists of two independent free acid molecules (zwitterions) of compound (I), two water molecules, and three acetone molecules. Data indicates that one of the acetone molecules is severely disordered; therefore, it was omitted from the structural model through solvent masking analysis. Figure 11 The presence of only two acetone molecules indicates that the crystal is an acetone-water cosolvent of the free acid of compound (I). These findings also support the observations of the SSNMR experiment that only one carboxylic acid group, namely the Q carbon atom, participates in the salt formation.

[0320] 13 The lower intensity of the Q site relative to the A site in the CCP spectrum indicates that the Q site is a relatively proton-deficient site. This conclusion was verified by two-dimensional HetCor MAS-NMR spectroscopy, which clearly shows that the A- 13 C site and acidity 1 H site 13 C- 1 H cross peak; however, Q 13 C site and acidity 1The cross peaks between H are missing (see the structure diagram below). These observations confirm that Q... 13 C site and acidity 1 Hs is uncorrelated, indicating that these protons have been affected by Ca. 2+ Ion substitution. Based on experimental data, the structure of the calcium salt of compound (I) is shown in formula (IA):

[0321] (IA).

[0322] References merged

[0323] All publications and patents mentioned herein are incorporated herein by reference in their entirety, as if each individual publication or patent were specifically and individually designated to be incorporated by reference. In case of any conflict, this application (including any definitions herein) shall prevail.

[0324] Equivalent scheme

[0325] While specific embodiments of this disclosure have been discussed, the foregoing description is illustrative only and not restrictive. Various modifications of this disclosure will become apparent to those skilled in the art upon review of this specification and the following claims. The full scope of this disclosure should be determined by reference to the claims and all their equivalents, as well as the description and its various modifications.

Claims

1. Pharmaceutically acceptable salts of compounds of formula (I): ； The pharmaceutically acceptable salts mentioned therein are alkali metal salts or alkaline earth metal salts.

2. The pharmaceutically acceptable salt of claim 1, wherein the alkali metal salt is a sodium or potassium salt.

3. The pharmaceutically acceptable salt of claim 1, wherein the alkaline earth metal salt is a calcium salt or a magnesium salt.

4. The pharmaceutically acceptable salt of claim 1, wherein the alkaline earth metal salt is a calcium salt.

5. The pharmaceutically acceptable salt of claim 4, wherein the stoichiometric ratio of the compound of formula (I) to calcium is 2:

1.

6. The pharmaceutically acceptable salt according to claims 3 to 5, wherein the calcium content is from about 1% to about 5% by weight of the salt.

7. The pharmaceutically acceptable salt according to claims 3 to 5, wherein the calcium content is from about 1.5% to about 4% by weight of the salt.

8. The pharmaceutically acceptable salt according to claims 3 to 5, wherein the calcium content is from about 2% to about 3% by weight of the salt.

9. The pharmaceutically acceptable salt of claim 1, wherein the alkali metal salt is a sodium salt.

10. The pharmaceutically acceptable salt of claim 9, wherein the sodium content is from about 1% to about 10% by weight of the salt.

11. The pharmaceutically acceptable salt of claim 9, wherein the sodium content is from about 5% to about 10% by weight of the salt.

12. The pharmaceutically acceptable salt of claim 9, wherein the sodium content is from about 8% to about 10% by weight of the salt.

13. The pharmaceutically acceptable salt of any one of claims 9 to 12, wherein the alkali metal salt is a monosodium salt or a disodium salt.

14. A method for preparing the pharmaceutically acceptable salt of claim 1, the method comprising the following steps: a) Provide a mixture comprising a compound of formula (I) and solvent A; b) React the mixture with a cation source and precipitate the salt of the compound of formula (I) using solvent B; and c) Separate the salts of the compound of formula (I); The solvent A and the solvent B are independently selected from tetrahydrofuran, acetonitrile, methanol, anisole, diethyl ether, ethanol, 1,4-dioxane, acetonitrile, acetone, dichloromethane, isopropanol, methyl tert-butyl ether (MTBE), n-heptane, water, and mixtures thereof.

15. The method of claim 14, wherein the solvent A is water.

16. The method of claim 14, wherein the compound of formula (I) in step (a) is in the form of a free acid.

17. The method of claim 14, wherein the compound of formula (I) in step (a) is a sodium salt of the compound of formula (I).

18. The method of claim 17, further comprising treating the mixture of step (a) with a metal ion exchange resin under aqueous conditions to remove sodium ions from the mixture.

19. The method of any one of claims 14 to 18, wherein the precipitation in step (b) is carried out by adding the solvent B.

20. The method of claim 19, wherein the solvent B is ethanol.

21. The method of claim 14, wherein the cation source is selected from calcium carbonate, calcium hydroxide, calcium methoxide, calcium chloride, magnesium carbonate, magnesium chloride, or a combination thereof.

22. The method of claim 14, wherein the cation source in step (b) is calcium carbonate.

23. The method of any one of claims 14 to 22, wherein step (c) of separating the salt of the compound of formula (I) further comprises the following sub-step: i) Filter the mixture and precipitate the salt of the compound of formula (I) from step (b); and ii) Wash and dry the salt of the precipitate of compound (I) obtained by filtration.

24. A method for preparing the sodium salt of any one of claims 9 to 13, comprising reacting the compound of formula (I) with a cation source in the presence of solvent C: The solvent C is selected from tetrahydrofuran, acetonitrile, methanol, anisole, diethyl ether, ethanol, 1,4-dioxane, acetonitrile, acetone, dichloromethane, isopropanol, methyl tert-butyl ether (MTBE), n-heptane, water, and mixtures thereof.

25. The method of claim 24, wherein the cation source is NaOH or Na2CO3.

26. The method of claim 25, wherein the cation source is NaOH.

27. A method for preparing the calcium salt according to any one of claims 4 to 8, comprising the step of reacting a compound of formula (I) with a cation source in the presence of solvent C: ； The solvent C is selected from tetrahydrofuran, acetonitrile, methanol, anisole, diethyl ether, ethanol, 1,4-dioxane, acetonitrile, acetone, dichloromethane, isopropanol, methyl tert-butyl ether (MTBE), n-heptane, water, and mixtures thereof.

28. The method of claim 27, wherein the cation source comprises calcium carbonate, calcium hydroxide, calcium methoxide, calcium chloride, or a combination thereof.

29. The method of any one of claims 14 to 28, wherein the reaction is carried out at about 20°C to about 40°C.

30. The method of any one of claims 14 to 29, wherein the salt of the obtained compound of formula (I) is a crystalline calcium salt of the compound of formula (I) or a crystalline sodium salt of the compound of formula (I).

31. Crystalline form of the calcium salt of compound (I) 。 32. The crystalline form according to claim 31, wherein the crystalline form is type A, characterized in that, Its X-ray powder diffraction (XRPD) pattern includes 2θ values ​​selected from 6.5±0.2, 6.8±0.2, 8.1±0.2, 9.5±0.2, 9.9±0.2, 10.6±0.2, 11.8±0.2, 12.9±0.2, 13.2±0.2, 13.8±0.2, 14.1±0.2, 15.1±0.2, 16.3±0.2, 16.5±0.2, 17.7±0.2, 18.0±0.2, 18.7±0.2, 19.2±0.2, 19.5±0.2, 19.8±0.2, and 20. At least three peaks of 1±0.2, 20.5±0.2, 21.5±0.2, 22.1±0.2, 22.7±0.2, 23.5±0.2, 23.9±0.2, 24.4±0.2, 24.9±0.2, 25.7±0.2, 26.7±0.2, 27.2±0.2, 27.8±0.2, 28.5±0.2, 29.1±0.2, 29.9±0.2, 31.2±0.2, 32.2±0.2, 33.4±0.2, 35.1±0.2, 37.6±0.2, and 38.4±0.

2.

33. The crystalline form of claim 32, wherein type A is characterized in that its XRPD spectrum includes 2θ values ​​selected from 6.5±0.2, 6.8±0.2, 8.1±0.2, 9.5±0.2, 9.9±0.2, 10.6±0.2, 11.8±0.2, 12.9±0.2, 13.2±0.2, 13.8±0.2, 14.1±0.2, 15.1±0.2, 16.3±0.2, 16.5±0.2, 17.7±0.2, 18.0±0.2, 18.7±0.2, 19.2±0.2, 19.5±0.2, 19. At least five peaks of 8±0.2, 20.1±0.2, 20.5±0.2, 21.5±0.2, 22.1±0.2, 22.7±0.2, 23.5±0.2, 23.9±0.2, 24.4±0.2, 24.9±0.2, 25.7±0.2, 26.7±0.2, 27.2±0.2, 27.8±0.2, 28.5±0.2, 29.1±0.2, 29.9±0.2, 31.2±0.2, 32.2±0.2, 33.4±0.2, 35.1±0.2, 37.6±0.2, and 38.4±0.

2.

34. The crystalline form of claim 32, wherein type A is characterized in that its XRPD spectrum includes peaks with 2θ values ​​of 9.9±0.2, 13.2±0.2 and 19.8±0.

2.

35. The crystalline form of claim 32, wherein type A is characterized in that its XRPD spectrum includes peaks with 2θ values ​​of 9.9±0.2, 11.8±0.2, 12.9±0.2, 13.2±0.2, 19.8±0.2 and 23.9±0.

2.

36. The crystalline form of claim 32, wherein type A is characterized in that its XRPD spectrum includes peaks with 2θ values ​​of 9.9±0.2, 11.8±0.2, 13.2±0.2, 13.8±0.2, 19.2±0.2, 19.8±0.2 and 23.9±0.

2.

37. The crystalline form of claim 32, wherein type A is characterized in that its XRPD spectrum includes peaks with 2θ values ​​of 8.1±0.2, 9.9±0.2, 11.8±0.2, 12.9±0.2, 13.2±0.2, 13.8±0.2, 16.3±0.2, 16.5±0.2, 19.2±0.2, 19.8±0.2, 20.1±0.2, and 23.9±0.

2.

38. The crystalline form of claim 32, wherein type A is characterized in that its XRPD spectrum includes peaks with 2θ values ​​of 8.1±0.2, 9.9±0.2, 10.6±0.2, 11.8±0.2, 12.9±0.2, 13.2±0.2, 13.8±0.2, 16.3±0.2, 16.5±0.2, 17.7±0.2, 19.2±0.2, 19.8±0.2, 20.1±0.2, 21.5±0.2, and 23.9±0.

2.

39. The crystalline form of claim 32, wherein type A is characterized in that its XRPD spectrum includes 2θ values ​​of 6.5±0.2, 6.8±0.2, 8.1±0.2, 9.5±0.2, 9.9±0.2, 10.6±0.2, 11.8±0.2, 12.9±0.2, 13.2±0.2, 13.8±0.2, 14.1±0.2, 15.1±0.2, 16.3±0.2, 16.5±0.2, 17.7±0.2, 18.0±0.2, 18.7±0.2, 19.2±0.2, 19.5±0.2, 1 Peaks at 9.8±0.2, 20.1±0.2, 20.5±0.2, 21.5±0.2, 22.1±0.2, 22.7±0.2, 23.5±0.2, 23.9±0.2, 24.4±0.2, 24.9±0.2, 25.7±0.2, 26.7±0.2, 27.2±0.2, 27.8±0.2, 28.5±0.2, 29.1±0.2, 29.9±0.2, 31.2±0.2, 32.2±0.2, 33.4±0.2, 35.1±0.2, 37.6±0.2, and 38.4±0.

2.

40. The crystalline form of claim 32, wherein type A is characterized in that its XRPD pattern is substantially as shown in Figure 1.

41. The crystalline form of claim 31, having an endothermic peak with a peak temperature of about 145°C to about 155°C as measured by differential scanning calorimetry (DSC).

42. The crystalline form of claim 31, having an endothermic peak with a peak temperature of about 145°C to about 155°C, preferably about 150°C to about 155°C, or more preferably about 150°C to about 153°C as determined by DSC.

43. The crystalline form of claim 31, having an endothermic peak with a peak temperature of about 153°C ± 3°C as determined by DSC.

44. The crystalline form of claim 31, the thermogravimetric analysis (TGA) spectrum of which is basically as shown in Figure 5.

45. The crystalline form according to claim 31, having at least one of the following characteristics: a) The basic XRPD map is shown in Figure 1; b) At least one XRPD peak with 2θ values ​​of 9.9±0.2, 13.2±0.2, and 19.8±0.2; and c) An endothermic peak with a peak temperature of 153°C ± 3°C as determined by DSC.

46. ​​The crystalline form of claim 31, having at least one of the following characteristics: a) The basic XRPD map is shown in Figure 1; b) At least one XRPD peak with 2θ values ​​of 9.9±0.2, 13.2±0.2, and 19.8±0.2; c) An endothermic peak with a peak temperature of 153°C ± 3°C as determined by DSC; and d) The basic TGA chart is shown in Figure 5.

47. Crystalline form of the disodium salt of compound (I) 。 48. The crystalline form of claim 47, wherein the crystalline form is type B, characterized in that, Its XRPD spectrum includes at least three peaks with 2θ values ​​selected from 18.5±0.2, 18.9±0.2, 22.5±0.2, 23.5±0.2, 25.4±0.2, 27.9±0.2, 28.9±0.2, 31.7±0.2, 33.9±0.2, 37.7±0.2 and 42.4±0.

2.

49. The crystalline form of claim 47, wherein the crystalline form is type B, characterized in that, Its XRPD spectrum includes at least five peaks with 2θ values ​​selected from 18.5±0.2, 18.9±0.2, 22.5±0.2, 23.5±0.2, 25.4±0.2, 27.9±0.2, 28.9±0.2, 31.7±0.2, 33.9±0.2, 37.7±0.2 and 42.4±0.

2.

50. The crystalline form of claim 47, wherein the crystalline form is type B, characterized in that, Its XRPD spectrum includes peaks with 2θ values ​​of 22.5±0.2, 23.5±0.2, 25.4±0.2, 31.7±0.2, 33.9±0.2 and 37.7±0.

2.

51. The crystalline form of claim 48, wherein the crystalline form is type B, characterized in that, Its XRPD spectrum includes peaks with 2θ values ​​of 18.9±0.2, 22.5±0.2, 23.5±0.2, 25.4±0.2, 27.9±0.2, 28.9±0.2, 31.7±0.2, 33.9±0.2, 37.7±0.2 and 42.4±0.

2.

52. The crystalline form of claim 48, wherein the crystalline form is type B, characterized in that, Its XRPD spectrum includes peaks with 2θ values ​​of 18.5±0.2, 18.9±0.2, 22.5±0.2, 23.5±0.2, 25.4±0.2, 27.9±0.2, 28.9±0.2, 31.7±0.2, 33.9±0.2, 37.7±0.2 and 42.4±0.

2.

53. The crystalline form according to claims 47 to 52, wherein the crystalline form is type B, characterized in that, Its XRPD pattern is basically shown in Figure 3A.

54. Crystalline form of the monosodium salt of compound (I) 。 55. The crystalline form of claim 54, wherein the crystalline form is type C, characterized in that, Its XRPD spectrum includes peaks with 2θ values ​​of 42.3±0.2, 42.9±0.2, 43.2±0.2 and 43.8±0.

2.

56. The crystalline form according to any one of claims 54 or 55, characterized in that, Its XRPD map is basically shown in Figure 3B.

57. A compound obtainable by a method comprising the following steps: i) Provide an aqueous mixture containing a compound of formula (I) ； ii) React the mixture with calcium carbonate; iii) Filter the mixture from step (ii) to obtain a filtrate; iv) Add solvent B to the filtrate to form a reaction mixture, wherein solvent B is ethanol; and v) Separate the compound from the reaction mixture.

58. The compound of claim 57, wherein step (v) of isolating the compound further comprises the following sub-steps: i) Filtering the compound from the reaction mixture; and ii) Wash and dry the compound obtained from the reaction mixture under vacuum conditions.

59. A pharmaceutical composition comprising: a pharmaceutically acceptable salt of any one of claims 1 to 13 or a crystalline form of any one of claims 31 to 56, and one or more pharmaceutically acceptable carriers or excipients.

60. A product comprising a calcium salt or a sodium salt of a compound of formula (I) for use as a pharmaceutical, wherein the compound of formula (I) is: 。 61. A product comprising a calcium salt of a compound of formula (I) for use in a method of treating a disease and / or condition mediated by the CD47-SIRPα signaling pathway in a subject, the method comprising administering to the subject in need a therapeutically effective amount of the calcium salt of the compound of formula (I) according to any one of claims 4 to 8 or its crystalline form according to any one of claims 31 to 46.

62. A product comprising a sodium salt of a compound of formula (I) for use in a method of treating a disease and / or condition mediated by the CD47-SIRPα signaling pathway in a subject, the method comprising administering to the subject in need a therapeutically effective amount of the sodium salt of the compound of formula (I) according to any one of claims 9 to 13 or its crystalline form according to any one of claims 47 to 56.

63. The product of claim 61 or 62, used in a method of treating a disease and / or condition, wherein the disease and / or condition mediated by the CD47-SIRPα signaling pathway is cancer.

64. The product for the use of claim 63, wherein the cancer is selected from melanoma, kidney cancer, prostate cancer, breast cancer, colon cancer, lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, malignant melanoma of the skin or eye, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small bowel cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, including acute myeloid leukemia, chronic myeloid leukemia, etc. Myeloid leukemia, acute lymphoblastic leukemia, chronic or acute lymphoblastic leukemia, childhood solid tumors, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal pelvis cancer, central nervous system (CNS) tumors, non-small cell lung cancer (NSCLC), primary central nervous system lymphoma, tumor angiogenesis, spinal axis tumors, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, B-cell lymphoma, including environmentally induced cancers such as mesothelioma induced by asbestos, and combinations thereof.

65. Calcium salts of compounds of formula (I) represented by formula (IA): (IA).

66. The compound of claim 65, wherein the compound is in crystalline form.

Images