Solid form of pyrrolidone derivatives as glucokinase activators

Abstract

The present invention relates to the free state of (R)-3-(3-((S)-2-(4-(2-chlorophenoxy)-2-oxo-2,5-dihydro-1H-pyrrole-1-yl)-4-methylpentanoylamino)-1H-pyrazole-1-yl)-2-hydroxypropylnicotinate (compound A) or crystalline forms of its pharmaceutically acceptable salts, pharmaceutical compositions and methods for preparing the same, and the use of the above crystalline form in the preparation of pharmaceuticals for the treatment of diabetes and related conditions. [C1] TIFF2026511448000095.tif36156

Description

[Technical Field]

[0001] This application is,

[0002] We claim priority from CN202310245157.X (filing date: March 13, 2023).

[0003] <Technical field> This disclosure belongs to the field of pharmaceutical technology and, more specifically, to the solid form of pyrrolidone derivatives as glucokinase activators (GKAs), and in particular to the free state of (R)-3-(3-((S)-2-(4-(2-chlorophenoxy)-2-oxo-2,5-dihydro-1H-pyrrole-1-yl)-4-methylpentanamide)-1H-pyrazole-1-yl)-2-hydroxypropylnicotinate (compound A) or the crystalline form of a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof and a method of preparation thereof, and the use of the above crystalline form and pharmaceutical composition in the manufacture of pharmaceuticals for the treatment of diabetes and related conditions. [Background technology]

[0004] Diabetes has become a common disease worldwide. According to data from the 24th National Congress of the Chinese Diabetes Society (CDS), China has the highest number of diabetes patients in the world, with approximately 129.8 million adults. Type II diabetes, or non-insulin-dependent diabetes mellitus (NIDDM), which accounts for over 90% of diabetes cases, is a hyperglycemic chronic metabolic disorder resulting from an imbalance in blood glucose homeostasis in the human body, caused by impaired insulin secretion and insulin resistance.

[0005] Glucokinase (GK) plays a central role in stabilizing blood glucose homeostasis in the human body. Acting as a glucose sensor in glucose homeostasis, GK senses changes in blood glucose and regulates the secretion of messenger glucose-regulating hormones such as insulin, glucagon, and GLP-1, forming a sensing system for regulating blood glucose homeostasis in the human body. GK is mainly distributed in the liver, where it is rapidly converted into hepatic glycogen for glucose storage in response to rising blood glucose levels, while simultaneously lowering blood glucose levels. Glucose storage during glucose intake and glucose supply during fasting, regulated by glucose-regulating hormones, constitute the regulation of blood glucose homeostasis in the human body.

[0006] Abnormalities in the function and expression of glucokinase, as well as sensor dysfunction, lead to impaired initial secretion of glucose-regulating hormones, affecting glucose uptake and release, resulting in postprandial hyperglycemia and preprandial hypoglycemia. Abnormal signaling of glucose-regulating hormones causes abnormalities in the function and expression of key proteins in the glucose uptake and release execution system, forming abnormal operating states and leading to type II diabetes.

[0007] A glucokinase activator has been developed that can improve the secretion function of insulin, glucagon, and GLP-1 for glucose regulation by enhancing the sensitivity of α, β, and L cells to changes in glucose concentration, targeting the characteristics of GK as a target.

[0008] Compound A is a novel glucokinase activator developed by the applicant of this disclosure, with the chemical name (R)-3-(3-((S)-2-(4-(2-chlorophenoxy)-2-oxo-2,5-dihydro-1H-pyrrole-1-yl)-4-methylpentanamide)-1H-pyrazole-1-yl)-2-hydroxypropylnicotinate (Compound A), C 28 H 30 ClN5O6 has the following chemical formula and chemical structure. [ka]

[0009] Compound A is a derivative of HMS5552 and can be efficiently converted to HMS5552 in the body (particularly in the small intestine) (e.g., through enzymatic and / or chemical conversion), thereby being absorbed into the circulatory system to achieve the objective of treating or preventing certain metabolic syndrome diseases. Alternatively, the compounds disclosed herein are characterized by being stable in gastric juice and being efficiently converted to HMS5552 in the intestinal tract and small intestinal cells.

[0010] Therefore, in this field, there is a need to develop the free state of compound A and the solid form (especially the crystalline form) of its salts in order to meet the requirements of drug properties such as activity, drug stability, and bioavailability during the manufacture, storage, and use of pharmaceuticals. [Overview of the Initiative] [Means for solving the problem]

[0011] In one embodiment, the present disclosure provides a free-state crystalline form of compound A.

[0012] In one embodiment, the present disclosure provides a free crystalline form A of compound A.

[0013] In another embodiment, the disclosure provides a crystalline form of a salt of compound A. In one embodiment, the disclosure provides a crystalline form of an inorganic salt of compound A. In another embodiment, the disclosure provides a crystalline form of an organic salt of compound A.

[0014] In one particular embodiment, the Disclosure provides crystalline form A of the hydrochloride salt of compound A. In another particular embodiment, the Disclosure provides crystalline form B of the hydrochloride salt of compound A. In yet another particular embodiment, the Disclosure provides crystalline form C of the hydrochloride salt of compound A.

[0015] In another specific embodiment, the present disclosure provides crystalline form A of the maleate of compound A. In another specific embodiment, the present disclosure provides crystalline form B of the maleate of compound A. In another specific embodiment, the present disclosure provides crystalline form A of the naphthalenedisulfonate of compound A. In another specific embodiment, the present disclosure provides crystalline form A of the oxalate of compound A. In another specific embodiment, the present disclosure provides crystalline form A of the hydrobromide of compound A. In another specific embodiment, the present disclosure provides crystalline form B of the hydrobromide of compound A.

[0016] In another aspect, the present disclosure provides a pharmaceutical composition comprising a crystalline form of the present disclosure and one or more pharmaceutically acceptable excipients.

[0017] In another aspect, the present disclosure provides the use of a crystalline form of the present disclosure in the manufacture of a medicament for treating and / or preventing one or more diseases selected from type I diabetes, type II diabetes, impaired glucose tolerance, impaired fasting glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, and metabolic syndrome.

[0018] In another aspect, the present disclosure provides a crystalline form of the present disclosure for use in the treatment and / or prevention of one or more diseases selected from type I diabetes, type II diabetes, impaired glucose tolerance, impaired fasting glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, and metabolic syndrome.

[0019] In another aspect, the present disclosure provides a method for treating and / or preventing a disease in a subject, comprising administering a crystalline form of the present disclosure to the subject, wherein the disease is selected from one or more of type I diabetes, type II diabetes, impaired glucose tolerance, impaired fasting glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, and metabolic syndrome.

[0020] In another aspect, the Disclosure provides the use of the crystalline form or pharmaceutical composition of the Disclosure in the manufacture of a medicament for curing diabetes, relieving diabetes, and / or regressing diabetes.

[0021] In another embodiment, the Disclosure provides a crystalline form or pharmaceutical composition of the Disclosure for use in curing diabetes, relieving diabetes, and / or regressing diabetes.

[0022] In another aspect, the Disclosure provides a method for curing, relieving, and / or regressing diabetes in a subject, comprising administering the crystalline form or pharmaceutical composition of the Disclosure to the subject. [Brief explanation of the drawing]

[0023] [Figure 1] This is the XRPD pattern of the starting material sample.

[0024] [Figure 2] This is the TGA / mDSC curve of the starting material sample.

[0025] [Figure 3] This graph shows a comparison of the retention / generation rate of compounds A and HMS5552 in artificially simulated gastric juice and the incubation time.

[0026] [Figure 4] This graph shows a comparison of the retention / generation rate of compounds A and HMS5552 in artificially simulated intestinal fluid and the incubation time.

[0027] [Figure 5] This graph shows a comparison of OGTT blood glucose-time curves and AUC0-120min for HMS5552 and compound A in C57BL / 6J mice. In the graph, * indicates P<0.05 and ** indicates P<0.01 compared to the vehicle control group, and # indicates P<0.05 and ## indicates P<0.01 compared to the corresponding HMS5552 dose group.

[0028] [Figure 6] This graph shows a comparison of insulin levels (0 min and 15 min) for HMS5552 and compound A in C57BL / 6J mice. In the graph, * means P<0.05 and ** means P<0.01 compared to the vehicle control group, and # means P<0.05 and ## means P<0.01 compared to the corresponding HMS5552 dose group.

[0029] [Figure 7] This is the XRPD pattern of crystal morphology A in the free state.

[0030] [Figure 8] This is the TGA / DSC curve for free-state crystal morphology A.

[0031] [Figure 9] This is the XRPD pattern of crystalline form A of the hydrochloride salt.

[0032] [Figure 10] This is the TGA / DSC curve for crystalline form A of the hydrochloride salt.

[0033] [Figure 11] This is the XRPD pattern of crystalline form A of maleate.

[0034] [Figure 12] This is the XRPD pattern of maleate crystal morphology B.

[0035] [Figure 13] This is the TGA / DSC curve for crystalline form B of maleate.

[0036] [Figure 14] This is the XRPD pattern of crystalline form A of naphthalenedisulfonate.

[0037] [Figure 15]This is the TGA / DSC curve for crystalline form A of naphthalenedisulfonate.

[0038] [Figure 16] This is the XRPD pattern of crystalline form A of oxalate.

[0039] [Figure 17] This is the TGA / DSC curve for crystalline form A of oxalate.

[0040] [Figure 18] This is the XRPD pattern of crystalline form A of hydrobromide.

[0041] [Figure 19] This is the XRPD pattern of crystalline form B of hydrobromide.

[0042] [Figure 20] This is the TGA / DSC curve for crystalline form B of hydrobromide.

[0043] [Figure 21] This shows the superimposed XRPD patterns of free-state crystal morphology A, prepared by solution crystallization.

[0044] [Figure 22] This is the XRPD pattern of crystalline form B of the hydrochloride salt.

[0045] [Figure 23] This is the TGA / DSC curve for crystalline form B of the hydrochloride salt.

[0046] [Figure 24] This is the XRPD pattern of the hydrochloride salt in crystalline form C.

[0047] [Figure 25] This is the TGA / DSC curve for crystalline form C of the hydrochloride salt.

[0048] [Figure 26] The DVS test results for free crystal form A and hydrochloride crystal form B are shown. [Figure 27] The DVS test results for free crystal form A and hydrochloride crystal form B are shown.

[0049] [Figure 28] This graph shows a comparison of the XRPD patterns of free crystalline form A before and after solubility stability tests in media with different pH levels and biologically relevant media. [Figure 29] This graph shows a comparison of the XRPD patterns of free crystalline form A before and after solubility stability tests in media with different pH levels and biologically relevant media.

[0050] [Figure 30] This graph shows a comparison of the XRPD patterns of free-state crystal morphology A before and after the forced decomposition stability test. [Figure 31] This graph shows a comparison of the XRPD patterns of free-state crystal morphology A before and after the forced decomposition stability test. [Figure 32] This graph shows a comparison of the XRPD patterns of free-state crystal morphology A before and after the forced decomposition stability test. [Figure 33] This graph shows a comparison of the XRPD patterns of free-state crystal morphology A before and after the forced decomposition stability test. [Modes for carrying out the invention]

[0051] definition Unless otherwise specified, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to the extent of this disclosure; however, in the event of any conflict, the definitions herein shall prevail.

[0052] As used herein and in the claims, the singular forms "a," "an," and "the (said)" include the plural form unless explicitly specified otherwise in the context.

[0053] All numbers or expressions used herein and in the claims should be understood to be modified in all cases by “approximately.” When referring to a quantity or numerical range, the term “approximately” means that the quantity or numerical range referred to is an approximation within experimental variation (or within statistical experimental error). Thus, the quantity or numerical range may vary, for example, between ±10% or ±5% of the quantity or numerical range referred to.

[0054] As used herein, the term “substantially” means taking into account the typical variability of a particular method and the standard error of the measured values. For example, with respect to the position of X-ray powder diffraction peaks, the term “substantially” means taking into account the typical variability of the peak position and intensity. Those skilled in the art will recognize that the peak position (2θ) may exhibit some variability, typically up to ±0.2°. Furthermore, those skilled in the art will recognize that the relative peak intensity may exhibit inter-instrumental variability, as well as variability due to crystallinity, preferred orientation, the surface of the sample tested, and other factors known to those skilled in the art. Similarly, tests such as differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) may also exhibit inter-instrumental variability, as well as variability caused by crystallinity, preferred orientation, the surface of the sample tested, and other factors known to those skilled in the art. Typically, the error range for DSC is ±5°C, ±4°C, ±3°C, ±2°C, ±1°C, or ±0.5°C, while the error range for TGA is ±2.5%, ±2%, ±1.5%, ±1%, or ±0.5%.

[0055] As used herein, the terms “crystalline” and “crystalline form” refer to a solid composed of molecules having a regular repeating arrangement. Crystalline forms can differ in thermodynamic stability, physical parameters, X-ray structure, and preparation process.

[0056] The term "amorphous" refers to a solid composed of molecules arranged in an irregular pattern.

[0057] As used herein, the term “solvate” refers to a crystalline form having a stoichiometric or non-stoichiometric amount of solvent (e.g., water, methanol, ethyl acetate, etc., or mixtures thereof) in the crystal lattice by non-covalent intermolecular bonds. The term “hydrate” refers to a solvate in which the solvent is water.

[0058] As used herein, the term “anhydrous” refers to a crystalline form containing less than approximately 1% (w / w) of adsorbed water, as determined by standard methods such as Karl Fischer analysis.

[0059] As used herein and in the claims, “and / or” should be understood to mean “either or both” of the relevant elements, that is, each element may exist together or separately. Multiple elements enumerated by “and / or” should similarly be interpreted as “one or more” of the relevant elements. In addition to the elements specifically identified by the “and / or” clause, other elements may be present at their discretion, whether related to or unrelated to the specifically identified elements. Thus, as a non-restrictive example, a reference to “A and / or B” when used in combination with open-ended language such as “includes” may refer to A only in one embodiment (optionally including elements other than B), B only in another embodiment (optionally including elements other than A), and both A and B in yet another embodiment (optionally including other elements), and so on.

[0060] "Pharmacologically available" or "pharmaceutically acceptable" means a material that is not biologically or otherwise undesirable, i.e., the material can be administered to an individual without causing an undesirable biological effect or adversely interacting with any other components of a composition containing the material.

[0061] The term "pharmaceutically acceptable salt" refers to a salt that does not significantly irritate living organisms and retains the biological activity and properties of the compound.

[0062] The term "pharmaceutically acceptable carrier" refers to an inert component that does not significantly irritate the organism and does not negate the biological activity and properties of the administered compound. As used herein, "carrier" and "excipient" have the same meaning.

[0063] The term “therapeutic dose” refers to the amount of a drug sufficient to produce a desired biological effect. This effect may be a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or other desired changes in the biological system. For example, “therapeutic dose” for therapeutic use refers to the required amount of a composition containing a compound disclosed herein as an active ingredient to provide a clinically significant reduction in a disease. In each individual case, a suitable “therapeutic dose” can be determined by those skilled in the art through routine experimentation. Therefore, the expression “therapeutic dose” generally refers to the amount of an active substance that has a therapeutic effect.

[0064] As used herein, the term “treat” is synonymous with the terms “prevent” and “alleviate” and is intended to mean slowing disease progression, preventing disease progression, and / or reducing the severity of symptoms that have developed or are expected to develop. Accordingly, these terms include improving existing disease symptoms, preventing further symptoms, improving or preventing the underlying metabolic causes of symptoms, inhibiting a disorder or disease, for example, preventing the onset of a disorder or disease, alleviating a disorder or disease, reversing a disorder or disease, alleviating a condition caused by a disease or disorder, or stopping the symptoms of a disease or disorder.

[0065] As used herein, the term “subject” encompasses mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates such as chimpanzees, and other ape and monkey species; domestic animals such as cattle, horses, sheep, goats, and pigs; pet animals such as rabbits, dogs, and cats; and laboratory animals, including rodents such as rats, mice, and guinea pigs. Examples of non-mammals include, but are not limited to, birds and fish. In one embodiment of this disclosure, mammal is human. The term “subject” includes confirmed patients, but “subject” does not need to have any special attributes to a hospital, clinic, or research facility (e.g., as a confirmed patient, research participant, etc.).

[0066] It should be understood that the technical terms used herein are for the purpose of describing specific embodiments and are not intended to limit them. This disclosure can be more readily understood by referring to the following detailed descriptions of embodiments and examples contained herein. Furthermore, any methods, devices, and materials similar or equivalent to those described herein may be used in the implementation or testing of this disclosure, although alternative methods, devices, and materials are described below.

[0067] Compound A and its crystalline form

[0068] The free state of compound A, referred to herein as compound A, is (R)-3-(3-((S)-2-(4-(2-chlorophenoxy)-2-oxo-2,5-dihydro-1H-pyrrole-1-yl)-4-methylpentanamide)-1H-pyrazole-1-yl)-2-hydroxypropylnicotinate, or compound A, has the following formula: [ka]

[0069] This disclosure relates to the crystalline form of compound A, i.e., "crystalline form A of compound A". In some embodiments, the crystalline form of these compounds is anhydrous.

[0070] Crystal form of compound A

[0071] In one embodiment, the present disclosure provides a crystalline form A of compound A, which is an anhydrous compound.

[0072] In another embodiment, the X-ray powder diffraction pattern of crystalline form A obtained using CuKα radiation includes characteristic peaks represented by at least the following °2θ: 8.5±0.2, 17.7±0.2, 18.0±0.2, and 18.6±0.2. In another embodiment, the X-ray powder diffraction pattern further includes characteristic peaks represented by the following °2θ: 10.1±0.2, 14.5±0.2, 20.2±0.2, 20.6±0.2, 25.1±0.2, and 25.7±0.2. In yet another embodiment, the X-ray powder diffraction pattern further includes characteristic peaks represented by the following °2θ: 12.9±0.2, 15.2±0.2, 22.0±0.2, 23.2±0.2, and 23.9±0.2. In another embodiment, the X-ray powder diffraction pattern further includes characteristic peaks represented by the following °2θ: 11.2±0.2, 12.1±0.2, 14.2±0.2, 15.7±0.2, 19.6±0.2, 21.2±0.2, 28.6±0.2, and 30.0±0.2.

[0073] In another embodiment, the X-ray powder diffraction pattern has the following characteristic peaks. [Table 1]

[0074] In another embodiment, the X-ray powder diffraction pattern includes one or more peaks at 2θ in Table 18. In yet another embodiment, the X-ray powder diffraction pattern is substantially as shown in Figure 7.

[0075] In another embodiment, crystal morphology A has an endothermic peak at 135.5±2°C in differential scanning calorimetry.

[0076] In another embodiment, crystalline form A has a weight loss of 1.36 ± 0.5% at 150°C in thermogravimetric analysis.

[0077] Salt of compound A and its crystalline form

[0078] This disclosure relates to several salts of compound A, including hydrochloride, maleate, naphthalenedisulfonate, oxalate, and hydrobromide.

[0079] Furthermore, this disclosure relates to multiple crystalline forms of salts of compound A, such as "crystalline form A of the hydrochloride salt of compound A," "crystalline form B of the hydrochloride salt of compound A," "crystalline form C of the hydrochloride salt of compound A," "crystalline form A of the maleate salt of compound A," "crystalline form B of the maleate salt of compound A," "crystalline form A of the naphthalenedisulfonate salt of compound A," "crystalline form A of the oxalate salt of compound A," "crystalline form A of the hydrobromide salt of compound A," and "crystalline form B of the hydrobromide salt of compound A."

[0080] Crystal form A of the hydrochloride salt of compound A

[0081] In one embodiment, the present disclosure provides crystalline form A of the hydrochloride salt of compound A. In another embodiment, crystalline form A of the hydrochloride salt is anhydrous.

[0082] In another embodiment, the X-ray powder diffraction pattern of crystalline form A of the hydrochloride obtained using CuKα radiation includes characteristic peaks represented by at least the following °2θ: 4.1±0.2, 15.3±0.2, and 18.5±0.2. In another embodiment, the X-ray powder diffraction pattern further includes characteristic peaks represented by the following °2θ: 8.1±0.2, 10.6±0.2, 11.9±0.2, 22.1±0.2, and 22.9±0.2. In yet another embodiment, the X-ray powder diffraction pattern further includes characteristic peaks represented by the following °2θ: 12.2±0.2, 17.9±0.2, 21.5±0.2, and 24.9±0.2.

[0083] In another embodiment, the X-ray powder diffraction pattern has the following characteristic peaks. [Table 2]

[0084] In another embodiment, the X-ray powder diffraction pattern includes one or more peaks at 2θ in Table 21. In yet another embodiment, the X-ray powder diffraction pattern is substantially as shown in Figure 9.

[0085] In another embodiment, crystalline form A of the hydrochloride salt has endothermic peaks at 125.9±2°C and 177.8±2°C in differential scanning calorimetry.

[0086] In another embodiment, crystalline form A of the hydrochloride salt has a weight loss of 4.91 ± 0.5% at 150°C in thermogravimetric analysis.

[0087] Crystal form B of the hydrochloride salt of compound A

[0088] In one embodiment, the present disclosure provides crystalline form B of the hydrochloride salt of compound A. In another embodiment, crystalline form B of the hydrochloride salt is anhydrous.

[0089] In another embodiment, the X-ray powder diffraction pattern of crystalline form B of the hydrochloride obtained using CuKα radiation includes characteristic peaks represented by at least the following °2θ: 4.5±0.2, 18.1±0.2, and 21.4±0.2. In another embodiment, the X-ray powder diffraction pattern further includes characteristic peaks represented by the following °2θ: 11.1±0.2 and 21.7±0.2. In yet another embodiment, the X-ray powder diffraction pattern further includes characteristic peaks represented by the following °2θ: 8.7±0.2, 13.7±0.2, 14.4±0.2, 15.1±0.2, and 23.2±0.2.

[0090] In another embodiment, the X-ray powder diffraction pattern has the following characteristic peaks. [Table 3]

[0091] In another embodiment, the X-ray powder diffraction pattern includes one or more peaks at 2θ in Table 44. In yet another embodiment, the X-ray powder diffraction pattern is substantially as shown in Figure 22.

[0092] In another embodiment, crystalline form B of the hydrochloride salt has endothermic peaks at 123.1±2°C, 135.2±2°C, and 187.5±2°C in differential scanning calorimetry.

[0093] In another embodiment, crystalline form B of the hydrochloride salt exhibits a weight loss of 1.32 ± 0.5% at 70°C and a weight loss of 5.32 ± 0.5% at 70–150°C in thermogravimetric analysis.

[0094] Crystal form C of the hydrochloride salt of compound A

[0095] In one embodiment, the present disclosure provides a crystalline form C of the hydrochloride salt of compound A. In another embodiment, the crystalline form C of the hydrochloride salt is anhydrous.

[0096] In another embodiment, the X-ray powder diffraction pattern of the crystalline form C of the hydrochloride obtained using CuKα radiation includes characteristic peaks represented by at least the following °2θ: 8.2±0.2, 10.6±0.2, 13.4±0.2, and 20.2±0.2. In another embodiment, the X-ray powder diffraction pattern further includes characteristic peaks represented by the following °2θ: 16.8±0.2 and 17.7±0.2. In yet another embodiment, the X-ray powder diffraction pattern further includes characteristic peaks represented by the following °2θ: 4.1±0.2, 8.8±0.2, and 12.2±0.2.

[0097] In another embodiment, the X-ray powder diffraction pattern has the following characteristic peaks. [Table 4]

[0098] In another embodiment, the X-ray powder diffraction pattern includes one or more peaks at 2θ in Table 45. In yet another embodiment, the X-ray powder diffraction pattern is substantially as shown in Figure 24.

[0099] In another embodiment, the crystalline form C of the hydrochloride salt has endothermic peaks at 60.7±2°C, 114.4±2°C, and 182.4±2°C in differential scanning calorimetry.

[0100] In another embodiment, the crystalline form C of the hydrochloride salt has a weight loss of 5.53 ± 0.5% at 80°C and 6.72 ± 0.5% at 80–150°C as determined by thermogravimetric analysis.

[0101] Crystal form A of the maleate salt of compound A

[0102] In one embodiment, the present disclosure provides crystalline form A of the maleate of compound A. In another embodiment, crystalline form A of the maleate is anhydrous.

[0103] In another embodiment, the X-ray powder diffraction pattern of crystalline form A of the maleate obtained using CuKα radiation includes characteristic peaks represented by at least the following °2θ: 6.0±0.2 and 18.4±0.2. In another embodiment, the X-ray powder diffraction pattern further includes characteristic peaks represented by the following °2θ: 10.4±0.2, 15.9±0.2 and 17.4±0.2. In yet another embodiment, the X-ray powder diffraction pattern further includes characteristic peaks represented by the following °2θ: 6.9±0.2, 12.0±0.2, 21.2±0.2 and 21.8±0.2.

[0104] In another embodiment, the X-ray powder diffraction pattern has the following characteristic peaks. [Table 5]

[0105] In another embodiment, the X-ray powder diffraction pattern includes one or more peaks at 2θ in Table 22. In yet another embodiment, the X-ray powder diffraction pattern is substantially as shown in Figure 11.

[0106] Crystal form B of the maleate salt of compound A

[0107] In one embodiment, the present disclosure provides crystalline form B of the maleate of compound A. In another embodiment, crystalline form B of the maleate is anhydrous.

[0108] In another embodiment, the X-ray powder diffraction pattern of crystalline form B of the maleate obtained using CuKα radiation includes characteristic peaks represented by at least the following °2θ: 4.1±0.2, 8.1±0.2, 16.7±0.2, and 20.2±0.2. In another embodiment, the X-ray powder diffraction pattern further includes characteristic peaks represented by the following °2θ: 17.5±0.2 and 21.3±0.2. In yet another embodiment, the X-ray powder diffraction pattern further includes characteristic peaks represented by the following °2θ: 16.2±0.2, 20.4±0.2, 22.4±0.2, 24.1±0.2, 24.6±0.2, and 26.5±0.2.

[0109] In another embodiment, the X-ray powder diffraction pattern has the following characteristic peaks. [Table 6]

[0110] In another embodiment, the X-ray powder diffraction pattern includes one or more peaks at 2θ in Table 23. In yet another embodiment, the X-ray powder diffraction pattern is substantially as shown in Figure 12.

[0111] In another embodiment, crystalline form B of the maleate has an endothermic peak at 85.6±2°C in differential scanning calorimetry.

[0112] In another embodiment, crystalline form B of the maleate has a weight loss of 12.02 ± 0.5% at 120°C in thermogravimetric analysis.

[0113] Crystal form A of naphthalenedisulfonate of compound A

[0114] In one embodiment, the present disclosure provides crystalline form A of the naphthalenedisulfonate of compound A. In another embodiment, crystalline form A of the naphthalenedisulfonate is anhydrous.

[0115] In another embodiment, the X-ray powder diffraction pattern of crystalline form A of the naphthalenedisulfonate obtained using CuKα radiation includes characteristic peaks represented by at least the following °2θ: 4.0±0.2 and 13.7±0.2. In yet another embodiment, the X-ray powder diffraction pattern further includes characteristic peaks represented by the following °2θ: 10.3±0.2, 15.5±0.2, 21.0±0.2 and 22.3±0.2.

[0116] In another embodiment, the X-ray powder diffraction pattern has the following characteristic peaks. [Table 7]

[0117] In another embodiment, the X-ray powder diffraction pattern includes one or more peaks at 2θ in Table 24. In yet another embodiment, the X-ray powder diffraction pattern is substantially as shown in Figure 14.

[0118] In another embodiment, crystalline form A of naphthalenedisulfonate has endothermic peaks at 119.2±2°C and 207.9±2°C in differential scanning calorimetry.

[0119] In another embodiment, crystalline form A of naphthalenedisulfonate has a weight loss of 5.97 ± 0.5% at 150°C as determined by thermogravimetric analysis.

[0120] Crystal form A of the oxalate salt of compound A

[0121] In one embodiment, the disclosure provides crystalline form A of the oxalate of compound A. In another embodiment, crystalline form A of the oxalate is anhydrous.

[0122] In another embodiment, the X-ray powder diffraction pattern of crystalline morphology A of the oxalate obtained using CuKα radiation includes characteristic peaks represented by at least the following °2θ: 5.0±0.2 and 15.0±0.2. In yet another embodiment, the X-ray powder diffraction pattern further includes characteristic peaks represented by the following °2θ: 7.4±0.2, 16.5±0.2, 19.3±0.2, 20.1±0.2, 25.2±0.2, and 26.0±0.2.

[0123] In another embodiment, the X-ray powder diffraction pattern has the following characteristic peaks. [Table 8]

[0124] In another embodiment, the X-ray powder diffraction pattern includes one or more peaks at 2θ in Table 25. In yet another embodiment, the X-ray powder diffraction pattern is substantially as shown in Figure 16.

[0125] In another embodiment, crystalline form A of the oxalate has endothermic peaks at 131.4±2°C and 192.8±2°C in differential scanning calorimetry.

[0126] In another embodiment, crystalline form A of the oxalate has a weight loss of 3.91 ± 0.5% at 150°C in thermogravimetric analysis.

[0127] Crystal morphology A of hydrobromide salt of compound A

[0128] In one embodiment, the present disclosure provides crystalline form A of the hydrobromide salt of compound A. In another embodiment, crystalline form A of the hydrobromide salt is anhydrous.

[0129] In another embodiment, the X-ray powder diffraction pattern of crystalline form A of the hydrobromide obtained using CuKα radiation includes characteristic peaks represented by at least the following °2θ: 4.3±0.2 and 8.3±0.2. In yet another embodiment, the X-ray powder diffraction pattern further includes characteristic peaks represented by the following °2θ: 12.4±0.2, 17.5±0.2, 17.9±0.2, 20.5±0.2, and 21.3±0.2.

[0130] In another embodiment, the X-ray powder diffraction pattern has the following characteristic peaks. [Table 9]

[0131] In another embodiment, the X-ray powder diffraction pattern includes one or more peaks at 2θ in Table 26. In yet another embodiment, the X-ray powder diffraction pattern is substantially as shown in Figure 18.

[0132] Crystalline form B of hydrobromide salt of compound A

[0133] In one embodiment, the present disclosure provides crystalline form B of the hydrobromide salt of compound A. In another embodiment, crystalline form B of the hydrobromide salt is an anhydrous form.

[0134] In another embodiment, the X-ray powder diffraction pattern of crystalline form B of the hydrobromide obtained using CuKα radiation includes characteristic peaks represented by at least the following °2θ: 4.1±0.2, 8.1±0.2, 15.0±0.2, 18.4±0.2, and 24.4±0.2. In yet another embodiment, the X-ray powder diffraction pattern further includes characteristic peaks represented by the following °2θ: 17.8±0.2, 20.3±0.2, 21.3±0.2, 22.0±0.2, and 22.8±0.2.

[0135] In another embodiment, the X-ray powder diffraction pattern has the following characteristic peaks. [Table 10]

[0136] In another embodiment, the X-ray powder diffraction pattern includes one or more peaks at 2θ in Table 27. In yet another embodiment, the X-ray powder diffraction pattern is substantially as shown in Figure 19.

[0137] In another embodiment, crystalline form B of the hydrobromide has endothermic peaks at 101.6±2°C and 113.3±2°C in differential scanning calorimetry.

[0138] In another embodiment, crystalline form B of the hydrobromide has a weight loss of 4.59 ± 0.5% at 90°C as determined by thermogravimetric analysis.

[0139] Drug combinations and / or pharmaceutical compositions The crystalline forms of the present disclosure can be used alone or in combination with other therapeutic agents to treat a variety of conditions or diseases. The crystalline forms of the present disclosure and other therapeutic agents may be administered simultaneously (in the same dosage form or in separate dosage forms) or sequentially.

[0140] In one embodiment, another therapeutic agent to be combined with the crystalline form of the present disclosure is a hypoglycemic agent.

[0141] In another embodiment, pharmaceutical compositions comprising the crystalline form of the present disclosure and optionally one or more pharmaceutically acceptable excipients are provided herein. Use for the treatment and / or prevention of disease Further embodiments of the present disclosure relate to the use of the crystalline form of the present disclosure or a pharmaceutical composition thereof in the manufacture of a pharmaceutical. In particular, specific embodiments of the present disclosure relate to the use of the crystalline form of the present disclosure or a pharmaceutical composition thereof in the manufacture of a pharmaceutical for the treatment and / or prevention of one or more diseases selected from the following diseases and medical conditions, in particular type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance, impaired fasting blood glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, and metabolic syndrome.

[0142] Further specific embodiments of the present disclosure relate to the use of the crystalline form of the present disclosure or a pharmaceutical composition thereof in the manufacture of a medicament for curing, relieving, or regressing diabetes.

[0143] Methods of treating and / or preventing diseases Further embodiments of the present disclosure relate to methods for treating and / or preventing one or more diseases selected from type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance, impaired fasting blood glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, and metabolic syndrome, comprising administering a therapeutically effective amount of the crystalline form of the present disclosure, or administering a combination of drugs or pharmaceutical compositions comprising the crystalline form of the present disclosure.

[0144] The methods disclosed herein for treating and / or preventing diabetes and related diseases are

[0145] To prevent, slow, delay, or treat metabolic disorders selected from the group consisting of type 1 diabetes, type 2 diabetes, impaired glucose tolerance, impaired fasting blood glucose, hyperglycemia, postprandial hyperglycemia, hypertension, overweight, obesity, insulin resistance, and metabolic syndrome, or

[0146] To cure diabetes, to put diabetes into remission, or to regress diabetes,

[0147] To improve blood glucose control and / or reduce fasting plasma glucose, postprandial plasma glucose, and / or glycosylated hemoglobin HbA1c, or

[0148] To prevent, slow, delay, or reverse the progression from impaired glucose tolerance, insulin resistance, and / or metabolic syndrome to type 2 diabetes, or

[0149] To prevent, slow, delay, or treat any condition or impairment selected from the group consisting of complications of diabetes, such as cataracts and microvascular and macrovascular diseases, such as nephropathy, retinopathy, neuropathy, learning and memory impairment, neurodegenerative disorders or cognitive impairment, cardiovascular or cerebrovascular disease, tissue ischemia, diabetic foot or ulcers, arteriosclerosis, hypertension, endothelial dysfunction, myocardial infarction, acute coronary syndrome, unstable angina, stable angina, stroke, peripheral artery occlusive disease, cardiomyopathy, heart failure, arrhythmias, and restenosis, or

[0150] • To reduce weight and / or body fat, or to prevent weight and / or body fat gain, or to promote weight and / or body fat loss,

[0151] To prevent, slow, delay, or treat the degeneration and / or decline in pancreatic beta-cell function, and / or improve and / or restore or protect the function of pancreatic beta-cells, and / or restore the function of pancreatic insulin secretion, or

[0152] To prevent, slow, delay, or treat diseases or conditions caused by abnormal accumulation of liver or ectopic fat, or

[0153] • To maintain and / or improve insulin sensitivity, and / or to treat or prevent hyperinsulinemia and / or insulin resistance,

[0154] • To prevent, slow, delay, or treat new-onset diabetes mellitus (NODAT) and / or post-transplant metabolic syndrome (PTMS), or

[0155] To prevent, delay, or reduce NODAT and / or PTMS-related complications, including microvascular and macrovascular diseases and events, graft rejection, infection, and death, or

[0156] • To treat hyperuricemia and hyperuricemia-related conditions. Includes.

[0157] In alternative embodiments of the present disclosure, the diseases include type 1 diabetes, type 2 diabetes, impaired glucose tolerance, impaired fasting blood glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, and metabolic syndrome.

[0158] According to another embodiment, the Disclosure also provides a method for treating type II diabetes by orally administering a therapeutically effective amount of the crystalline form of the Disclosure or a pharmaceutical composition thereof to a subject in need of treatment. In one embodiment, the subject in need of treatment is a human. In another embodiment, the pharmaceutical composition is in the form of a tablet.

[0159] According to another embodiment, the Disclosure also provides a method for administering one or more other combination drug therapies concurrently with or sequentially with a therapeutically effective amount of the crystalline form of the Disclosure, or a pharmaceutical composition comprising a therapeutically effective amount of the crystalline form.

[0160] The compound or pharmaceutical composition of formula (A) of this disclosure may be administered once daily (QD), twice daily (BID), or three times daily (TID). [Examples]

[0161] The materials or reagents used herein are either commercially available or prepared by synthetic methods commonly known in the art.

[0162] The following embodiments further describe and illustrate embodiments within the scope of this disclosure. However, this disclosure is not limited to these embodiments, and any technically-based modifications and substitutions made to this disclosure are also included within the scope of this disclosure.

[0163] In the following examples, the meanings of the abbreviations shown in Table 1 may be used.

[0164] [Table 11]

[0165] General methods for identifying crystal morphology

[0166] 1. X-ray powder diffraction (XRPD)

[0167] A PANalytacal X-ray powder diffractometer was used. The specific parameters acquired are shown in the table below. [Table 12]

[0168] 2. Thermogravimetric analysis (TGA) and differential scanning calorimetry (DCS)

[0169] TGA was collected using a TA5500 thermogravimetric analyzer, and DCS was collected using a TA2500 differential scanning calorimeter. The specific acquisition parameters are shown in the table below. [Table 13]

[0170] 3. Modulated Differential Scanning Calorimetry (mDSC)

[0171] mDSC was collected using a TA2500 differential scanning calorimeter. The specific acquisition parameters are shown in the table below. [Table 14]

[0172] 4. Solution 1 1H NMR

[0173] solution1 ¹H NMR spectra were collected using a Bruker 400M NMR instrument with DMSO-d6 as the solvent.

[0174] 5. Ultra-high-performance liquid chromatography / ion chromatography (UPLC / IC)

[0175] In the experiment, the concentration was tested using a Waters H-Class ultra-high-performance liquid chromatography system, and the molar ratio of ions to form salts was tested using ion chromatography. The analytical conditions were as follows:

[0176] [Table 15]

[0177] [Table 16]

[0178] Example 1: Preparation of Compound A [ka]

[0179] Synthesis process:

[0180] 1.73 g (14.1 mmol, 1.3 equivalents) of nicotinic acid was dissolved in DMF, and 4.19 g (32.4 mmol, 3.0 equivalents) of diisopropylethylamine and 5.34 g (14.0 mmol, 1.3 equivalents) of HATU were added at 0°C. The reaction mixture was stirred at 0°C for 30 minutes, and then 5.0 g (10.8 mmol, 1.0 equivalent) of compound HMS5552 was added in several portions. The reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was quenched by adding water and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by preparative chromatography to obtain 3.3 g of compound A (yield 53.7%, pinkish-brown solid).

[0181] Compound A was subjected to X-ray powder diffraction and TGA / mDSC analysis (thermogravimetric analysis / modulated differential scanning calorimetry), revealing that it is amorphous (Figure 1). The TGA / mDSC results (Figure 2) show that the sample exhibits a 6.06% weight loss when heated to 150°C and has a glass transition temperature (intermediate temperature) of 32.8°C.

[0182] MS[M+H] + : 568.11; 1 H-NMR (d 6 -DMSO, 400 MHz): δ 10.81(s, 1H), 9.16(s, 1H), 8.82-8.84(d, J=4.52, 1H), 8.32-8.34(d, J=8.00, 1H), 7.62-7.66(t, J=8.78, 2H), 7.57-7.60(dd, J1=7.88, J2=4.68, 1H), 7.52-7.54(d, J=8.04, 1H), 7.45-7.49(t, J=7.72, 1H), 7.35-7.39(t, J=7.62, 1H), 6.45(s, 1H), 5.40-5.60(br, 1H), 4.89-4.92(dd, J1=10.60, J2=4.72, 1H), 4.80(s, 1H), 4.60-4.64(d, J=18.44, 1H), 4.012-4.29(m, 6H), 1.68-1.80(m, 1H), 1.48-1.62(m, 1H), 1.32-1.50(m, 1H), 0.94-0.95(d, J=6.52, 3H), 0.90-0.92(d, J=6.52, 3H)

[0183] Example 2: Stability test of compound A in simulated gastric juice (SGF)

[0184] Preparation of simulated gastric juice (SGF): 0.04 g of NaCl and 0.064 g of pepsin were dissolved in 0.14 mL of HCl, and water was added to make a total volume of 20 mL. The pH of the test solution was approximately 1.20 ± 0.05.

[0185] Preparation of compound A working solution: 5 μL of 30 mM compound A stock solution was added to 745 μL of DMSO to obtain a 200 μM compound A working solution. 1) 2 μL of 200 μM compound A working solution was added to the corresponding wells (n=2) T0, T60, T120, T360, and T1440 of a 96-deep-well plate. 2) 198 μL of SGF solution was transferred to the corresponding wells, except for T0, and allowed to reach a final test compound concentration of 2 μM at each time point (60, 120, 360, and 1440 minutes). The final concentration of DMSO in the incubation mixture was 1%. 3) The sample was incubated at 37°C and 600 rpm for the specified time. 4) At the corresponding incubation time points (60, 120, 360, and 1440 minutes), the samples were removed and immediately mixed thoroughly with 400 μL of cold acetonitrile containing 200 ng / mL tolbutamide (internal standard). 5) 200 μL of supernatant was removed and thoroughly mixed again with 400 μL of cold acetonitrile containing 200 ng / mL tolbutamide (internal standard). 6) Preparation of T0 sample: 198 μL of SGF solution was added to the corresponding well and thoroughly mixed with 400 μL of cold acetonitrile containing 200 ng / mL tolbutamide (internal standard). Then, 200 μL of the supernatant was pipetted and thoroughly mixed again with 400 μL of cold acetonitrile containing 200 ng / mL tolbutamide (internal standard). 7) All samples were centrifuged at 4000 rpm at 4°C for 20 minutes. 8) 60 μL of the supernatant was pipettered and thoroughly mixed with 180 μL of ultrapure water, and the mixture was subjected to LC-MS / MS analysis. The concentrations of the test compound and the converted compound HMS5552 were measured, and the stability of the test compound in simulated gastric juice (SGF) was evaluated by plotting retention rate / production rate against incubation time.

[0186] LC-MS / MS conditions:

[0187] LC: Shimadzu LC-30AD,

[0188] MS:QTRAP 6500+,

[0189] Autosampler: CTC PAL,

[0190] Mobile phase: A: 0.1% formic acid in water, B: 0.1% formic acid in acetonitrile.

[0191] Column: ACQUITY UPLC Protein BEH C4 300Å 2.1*50mm Part No. 186004495

[0192] Total flow rate: 600 μL / min

[0193] Scan type: Multiple response monitoring (MRM).

[0194] The results are shown in Table 2 and Figure 3.

[0195] [Table 17]

[0196] The results in Table 2 and Figure 3 indicate that compound A remained stable in SGF for 24 hours, and that only a small amount of compound A was degraded into the parent drug HMS5552.

[0197] Example 3: Stability test of compound A in simulated intestinal fluid (SIF)

[0198] Preparation of simulated intestinal fluid (SIF): 0.136 g of KH2PO4 and 0.2 g of pancreatin were dissolved in water to a final volume of 20 mL. The pH of the test solution was approximately 6.80 ± 0.05.

[0199] Preparation of compound A working solution: 10 μL of 10 mM compound A stock solution was added to 90 μL of DMSO to obtain a 200 μM compound A working solution. 1) 2 μL of 200 μM working solution was added to the corresponding wells (n=2) of a 96-deep-well plate, T0, T60, T120, T360, and T1440. 2) 198 μL of SIF solution was transferred to the corresponding wells, except for T0, and allowed to reach a final test compound concentration of 2 μM at each time point (60, 120, 360, and 1440 minutes). The final concentration of DMSO in the incubation mixture was 1%. 3) The sample was incubated at 37°C and 600 rpm for the specified time. 4) At the corresponding incubation time points (60, 120, 360, and 1440 minutes), the samples were removed and immediately mixed thoroughly with 400 μL of cold acetonitrile containing 200 ng / mL tolbutamide (internal standard). 5) 200 μL of supernatant was removed and thoroughly mixed again with 400 μL of cold acetonitrile containing 200 ng / mL tolbutamide (internal standard). 6) Preparation of T0 sample: 198 μL of SIF solution was added to the corresponding well and thoroughly mixed with 400 μL of cold acetonitrile containing 200 ng / mL tolbutamide (internal standard). Then, 200 μL of the supernatant was pipetted and thoroughly mixed again with 400 μL of cold acetonitrile containing 200 ng / mL tolbutamide (internal standard). 7) All samples were centrifuged at 4000 rpm at 4°C for 20 minutes. 8) 60 μL of the supernatant was pipettered and thoroughly mixed with 180 μL of ultrapure water, and the mixture was subjected to LC-MS / MS analysis. The concentrations of compound A and the converted compound HMS5552 were measured, and the stability of compound A in simulated intestinal fluid (SIF) was evaluated by plotting retention rate / production rate against incubation time.

[0200] LC-MS / MS conditions:

[0201] LC: Shimadzu LC 30-AD,

[0202] MS:API4000,

[0203] Autosampler: CTC PAL,

[0204] Mobile phase: A: 0.1% formic acid in water, B: 0.1% formic acid in acetonitrile.

[0205] Column: ACQUITY UPLC BEH C18 1.7μm 2.1×50mm Part No.186002350

[0206] Scan type: Multiple response monitoring (MRM).

[0207] The results are shown in Table 3 and Figure 4.

[0208] [Table 18]

[0209] The results in Table 3 and Figure 4 show that compound A was significantly degraded in SIF, and that most of compound A was converted to the parent drug HMS5552.

[0210] Example 4: Simulated metabolic study of compound A in human gut S9

[0211] Preparation of phosphate buffer (PB): 73.21 g of K2HPO4·3H2O (AR grade) and 10.78 g of KH2PO4 (AR grade) were dissolved in ultrapure water to a final volume of 4000 mL and a final concentration of 100 mM. The pH of the final test solution was adjusted to 7.40 ± 0.10 using H3PO4 / KOH.

[0212] Preparation of compound A working solution: 5 μL of compound A stock solution (10 mM in DMSO) was diluted with 995 μL of acetonitrile (ACN) to obtain compound A working solution (50 μM in 99% ACN).

[0213] The main materials used in the test are shown in Table 4, and the parameters of the components used to prepare the human intestinal S9 (HIS9) solution are shown in Table 5.

[0214] [Table 19]

[0215] [Table 20]

[0216] Using an Apricot automated workstation, 50 μL / well of HIS9 solution was added to the corresponding wells of all reaction plates (blank, T0, T5, T15, T30, T45, T60).

[0217] Using an Apricot automated workstation, 2 μL / well of compound A working solution was added to the corresponding wells of all 96-well reaction plates (T0, T5, T15, T30, T45, T60), excluding the blank.

[0218] Using an Apricot automated workstation, the reaction was initiated by adding 48 μL / well of PB to the corresponding wells of each reaction plate (blank, T0, T5, T15, T30, T45, T60).

[0219] The reaction plates were incubated at 37°C and the timer was started. Using an Apricot automated workstation, the reaction was stopped by adding 300 μL / well of stop solution (cold acetonitrile containing 200 ng / mL tolbutamide (internal standard)) to the corresponding wells of each reaction plate at the appropriate termination point.

[0220] Each plate was sealed and shaken for 10 minutes. Each plate was centrifuged at 4000 rpm and 4°C for 20 minutes. After centrifugation, 100 μL of supernatant was transferred from each reaction plate to the corresponding analysis plate and thoroughly mixed with 300 μL of ultrapure water.

[0221] Each analysis plate was sealed and LC-MS / MS analysis was performed to obtain the concentrations of compound A and its conversion compound HMS5552, and the metabolic transformation of compound A in human intestinal S9 was evaluated.

[0222] LC-MS / MS conditions:

[0223] LC: Shimadzu LC30-AD,

[0224] MS: API4000,

[0225] Autosampler: CTC PAL,

[0226] Mobile phase: A: 0.1% formic acid in water, B: 0.1% formic acid in acetonitrile,

[0227] Column: ACQUITY UPLC BEH C18 1.7μm 2.1×50mm Part No.186002350.

[0228] The results are shown in Table 6.

[0229]

Table 21

[0230] The results of the simulated experiment of human intestinal S9 in Table 6 indicate that compound A was sufficiently metabolized in human intestinal S9 and was completely metabolized to the parent drug HMS5552 within 5 minutes.

[0231] Example 5: Test using Caco-2 cells for bidirectional evaluation of the permeability of compound A

[0232] Caco-2 cell culture: Caco-2 cells (purchased from American Type Culture Collection (ATCC)) were seeded on a polyethylene film (PET) of a 96-well culture plate at a concentration of 1×10 5 cells / cm 2 . The culture medium was changed every 4 days until the cells became confluent, and a cell monolayer was formed on the 21st or 28th day.

[0233] Transport Test: The transport buffer used in the test was Hanks equilibrium salt solution (HBSS) containing 10 mM 2-[4-(2-hydroxyethyl)-1-piperazinyl]ethanesulfonic acid (HEPES) at pH 7.40 ± 0.05. In vitro permeability studies were performed using nadolol, metoprolol, and digoxin as model permeators. Test compound A was evaluated bidirectionally at test concentrations of 2.00, 10.0, and 30.0 μM (n=2). Digoxin was evaluated bidirectionally at a test concentration of 10.0 μM (n=2). Nadolol and metoprolol were both evaluated unidirectionally at a test concentration of 2.00 μM (n=2). The final concentration of DMSO in the incubation system was adjusted to <1%.

[0234] Specific steps: 1) The plates were placed in an incubator at 37±1°C with 5% CO2 and saturated humidity and incubated for 2 hours without shaking. 2) At the end of incubation, all samples were mixed with acetonitrile containing an internal standard and centrifuged at 3200 g for 10 minutes. 3) For compound A in the 10.0 μM and 30.0 μM groups, the T0 sample and donor sample were diluted 10-fold with the supernatant of the blank sample. 4) For nadolol and metoprolol, 200 μL of supernatant was diluted with 600 μL of ultrapure water and analyzed by LC-MS / MS. 5) For digoxin and the test compound, LC-MS / MS analysis was performed by diluting 200 μL of the supernatant with 200 μL of ultrapure water. 6) Using LC-MS / MS, the concentrations of compound A, parent drug HMS5552, and the control compound in the initial solution, donor solution, and receiver solution were quantitatively measured by the peak area ratio between the test substance and the internal standard.

[0235] The results of the permeability test of the compound are shown in Table 7.

[0236] [Table 22]

[0237] From the results in Table 7, it was found that the permeability of Compound A from side A to side B was low, but the permeability from side B to side A was high, suggesting that Compound A is likely a substrate of the efflux transporter.

[0238] Example 6: Pharmacokinetic Study

[0239] Two groups of SD male rats (HMS5552 group and Compound A group, 6 rats in each group) were divided into two subgroups in each group (intravenous bolus group (IV) and enteral nutrition group (PO)). In the intravenous bolus group (IV), 10 mg / kg of HMS5552 or 10 mg / kg of Compound A was administered by single intravenous bolus injection. In the enteral nutrition group (PO), 30 mg / kg of HMS5552 or 30 mg / kg of Compound A was administered by single enteral nutrition.

[0240] Whole blood samples (about 0.2 mL per time point) were collected before dosing (0), 0.083, 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours after dosing by jugular vein puncture. All blood samples were immediately transferred to labeled pre-cooled commercial microcentrifuge tubes containing 4 μL of 0.5 M K2-EDTA and 10 μL of cocktail stabilizer. Samples were placed on wet ice until centrifugation (within 30 minutes). Plasma samples were then prepared by centrifuging the blood samples at about 4°C and 3200×g for 10 minutes. The supernatant plasma was pipetted out and then rapidly frozen with dry ice and kept at a temperature of -60°C or lower until LC-MS / MS analysis. The cocktail stabilizer was prepared according to Table 8 below.

[0241]

Table 23

[0242] Plasma concentrations were subjected to non-compartmental pharmacokinetic analysis using the WinNonlin (trademark) software program (version 6.3). The PK parameters were calculated by applying the linear / logarithmic trapezoidal rule, and the results are shown in Table 9.

[0243] [Table 24]

[0244] *:T max is the median [minimum, maximum]; **: converted based on moles (the MWs of HMS5552 and compound A are 462.93 and 568.03, respectively).

[0245] The results in Table 9 show that compound A was metabolized very rapidly in rats by intravenous injection. When administered orally, the exposure (Cmax, Cmax ratio, AUC, AUC ratio) to compound A was comparable to that of compound HMS5552. The above findings indicate that in rats, compound A is converted to compound HMS5552 in the gastrointestinal tract and intestinal cells, which is then absorbed and enters the circulatory system.

[0246] Example 7: Pharmacodynamic study

[0247] The hypoglycemic effects of compounds HMS5552 and A were evaluated in C57BL / 6J mice.

[0248] method

[0249] There were seven groups of mice, with eight mice in each group. Group #1 mice were orally administered a control vehicle, while the mice in the other groups were orally administered compound A at a corresponding concentration at a dose of 5 mL / kg. The low, medium, and high dose levels of compound A in the compound A-administered groups were equivalent (equimolar) to the doses of HMS5552 at 5, 15, and 40 mg / kg, respectively. An oral glucose tolerance test (OGTT) was performed one hour after administration. The mice's blood glucose levels were tested before administration (-60 minutes), before glucose loading (0 minutes), and at 15, 30, 60, and 120 minutes after glucose loading. Additionally, 40 μl of blood was collected from the tail end before glucose loading (0 minutes) and 15 minutes after glucose loading to collect plasma for insulin level testing.

[0250] Data processing and statistical analysis

[0251] All data was transferred to an Excel document. Blood glucose results were expressed in mg / dL and presented as MEAN±SEM. For comparison, differences between multiple groups were analyzed using Dunnett's method in one-way or two-way ANOVA using Graphpad Prism 8 software, and differences were considered statistically significant if the P-value was less than 0.05.

[0252] result

[0253] Body weight: During the experiment, the body weight of the mice in each group was similar, and there were no significant differences between the groups.

[0254] The OGTT results are shown in detail in Figure 5. Blood glucose levels in each group of mice at 60 minutes (before administration) were similar, with no significant differences between groups. After administering compounds HMS5552 and A to mice, blood glucose levels in each administration group at 0 minutes (before glucose loading) were generally lower than those in the vehicle control group, indicating a dose-response relationship. After glucose loading, blood glucose levels in each group of mice increased significantly. Blood glucose levels in the HMS5552-40 mg / kg group were significantly lower than those in the vehicle control group at 30, 60, and 120 minutes. Blood glucose levels in the compound A-49.1 mg / kg group were significantly lower than those in the vehicle control group at 15, 30, 60, and 120 minutes, and significantly lower than those in the HMS5552-40 mg / kg group at 30, 60, and 120 minutes. AUC of mice in each administration group. 0-120min The AUC was significantly lower than that of the vehicle control group, indicating a dose-response relationship. Furthermore, the AUC of mice in the medium and high dose groups of compound A was also lower. 0-120min This was significantly lower than that of the corresponding dose group for HMS5552. The data indicate that compound A has a good hypoglycemic effect in mice.

[0255] Insulin levels in mice are shown in detail in Figure 6. Insulin levels in the vehicle control group at 0 and 15 minutes were 0.13±0.02 (μg / L) and 0.50±0.05 (μg / L), respectively. Insulin levels in each dose group of HMS5552 at 0 and 15 minutes were slightly higher than those in the vehicle control group, but the difference was not significant. At 0 minutes, insulin levels in the high-dose compound A group were significantly higher than those in the vehicle control group and the high-dose HMS5552 group. At 15 minutes, insulin levels in the compound A-18.4 mg / kg group and compound A-49.1 mg / kg group were significantly higher than those in the vehicle control group, and the insulin level in the compound A-18.4 mg / kg group was significantly higher than that of the corresponding dose group of HMS5552.

[0256] This study demonstrates that compound A of the present disclosure exhibits favorable hypoglycemic activity in C57BL / 6J mice. Compared to HMS5552, compound A results in increased insulin secretion and a greater hypoglycemic effect.

[0257] Example 8: Solubility test of compound A starting material

[0258] Preliminary solubility tests of amorphous compound A starting material were performed at room temperature (RT, 25±3℃) using 21 single solvents and 5 mixed solvents, and included the following steps: Approximately 2 mg of compound A starting material was weighed into a 3 mL vial, and the corresponding solvent was gradually added until the solid was clearly dissolved. If the sample was not clearly dissolved after adding 2 mL of solvent, no further solvent was added. As shown in Table 10 below, the solubility range of compound A in the corresponding solvent was calculated based on the mass of the sample and the volume of solvent added.

[0259] [Table 25]

[0260] Example 9: Screening of the free crystalline form of compound A

[0261] Based on preliminary solubility results, amorphous compound A was used as the starting material, and a total of 50 polymorphism screening tests were set up using a screening method that included suspension and stirring at room temperature, temperature cycling, slow cooling, slow evaporation, gas-liquid permeation, and poor solvent addition. The specific screening methods and results are summarized in Table 11. According to the XRPD results of the obtained solid, one free-state crystalline form (crystalline form A) was found, which was determined to be an anhydrous crystalline form based on the physical characterization results.

[0262] [Table 26]

[0263] Example 9.1: Suspension and stirring at room temperature

[0264] Approximately 15 mg of amorphous starting material was weighed into HPLC vials, and 0.5 mL of each solvent listed in Table 12 was added. The resulting turbid liquid was magnetically stirred (1000 rpm) at room temperature for approximately 3 days, and then the solid was collected by centrifugation. The solid was subjected to XRPD analysis. The test results are shown in Table 12. Amorphous and gel-forming samples were obtained.

[0265] [Table 27]

[0266] *: The sample formed a gel when suspended and stirred at room temperature, and retained the gel even after being treated with temperature cycling.

[0267] Example 9.2: Temperature Cycle

[0268] A total of eight temperature cycling tests were set up using various solvent systems. Approximately 15 mg of amorphous starting material was weighed into HPLC vials, and 0.5 mL of each solvent listed in Table 13 was added. The resulting suspensions were magnetically stirred (1000 rpm) under temperature cycling (the sample was heated to 50°C, then cooled to 5°C at a rate of 0.1°C / min. This cycle was then repeated, and finally the sample was held at 5°C), and the solids were collected by centrifugation. The solids were subjected to XRPD analysis. The test results are shown in Table 13. Amorphous, gel-forming, and oily material-forming samples were obtained.

[0269] [Table 28]

[0270] *: The sample was clear at 5°C, and the final sample was obtained by stirring at -20°C.

[0271] Example 9.3: Slow Cooling

[0272] A total of six slow-cooling tests were set up using various solvent systems. Approximately 15 mg of amorphous starting material was weighed into 3 mL vials, and 1.5 to 3.0 mL of each solvent listed in Table 14 was added. The mixtures were stirred at 50°C for approximately 2 hours to equilibrate, and then filtered to obtain the supernatant. The obtained supernatant was placed in a biochemical incubator and cooled from 50°C to 5°C at a rate of 0.1°C / min, and then maintained at a constant temperature of 5°C. The precipitated solid was collected and subjected to XRPD analysis. The test results are shown in Table 14. In the slow-cooling tests, free crystalline form A and gel-forming samples were obtained.

[0273] [Table 29]

[0274] *: The sample contained a small amount of oil droplets at 5°C. After being placed at -20°C, the liquid became cloudy and gelatinous. The sample was then moved to room temperature and exposed to slow evaporation.

[0275] #: The sample was transparent at 5°C. Next, the sample was moved to room temperature and exposed to slow evaporation.

[0276] **: The sample was clear at 5°C and remained clear after being placed at -20°C. The sample was then transferred to room temperature and subjected to slow evaporation using a perforated sealing film.

[0277] Example 9.4: Slow evaporation

[0278] A total of six slow evaporation tests were set up using various solvent systems. Approximately 15 mg of amorphous starting material was weighed into 3 mL vials, and 0.2 to 3.0 mL of the solvents listed in Table 15 was added to dissolve the samples. The vials were sealed with a sealing film, and four pinholes were made in the sealing film. The samples were left at room temperature and slow evaporation was performed. The resulting solids were collected and subjected to XRPD analysis. The test results are shown in Table 15. Samples that formed gels and oily substances were obtained.

[0279] [Table 30]

[0280] Example 9.5: Gas-liquid permeability

[0281] A total of seven gas-liquid permeability tests were set up using various solvents. Approximately 15 mg of amorphous starting material was weighed into 3 mL vials, and 0.4–0.5 mL of solvent was added to dissolve the sample. Another 20 mL vial was taken, and approximately 3 mL of poor solvent was added to it. An unsealed 3 mL vial containing a clear liquid was placed into the 20 mL vial, and then the 20 mL vial was sealed and left at room temperature. The resulting solids were collected and subjected to XRPD analysis. The test results are shown in Table 16. Gel-forming and oil-forming samples were obtained.

[0282] [Table 31]

[0283] *: The sample remained gel-forming even after being subjected to temperature cycling.

[0284] #: The sample was transparent and the product was obtained by slow evaporation at room temperature without sealing.

[0285] Example 9.6: Poor solvent addition

[0286] A total of 11 poor solvent addition tests were set up using various solvents. Approximately 15 mg of amorphous starting material was weighed into 20 mL vials, and the solid was completely dissolved in 0.2 mL of solvent (Table 17). The poor solvents from Table 17 were added dropwise to the clear solution with stirring (1000 rpm) until the solid precipitated. Alternatively, if the solid did not precipitate even after the total amount of added poor solvent reached 10 mL, the sample was suspended and stirred at 5°C. The clear sample was transferred to -20°C, suspended, and stirred. The still clear sample was transferred to room temperature and evaporated. The precipitated solid was separated and subjected to XRPD analysis. The results are shown in Table 17. Amorphous and gel-forming samples were obtained in the poor solvent addition tests.

[0287] [Table 32]

[0288] *: The sample remained gel-forming even after being subjected to temperature cycling.

[0289] In summary, Examples 9.1 to 9.6 demonstrate that, in 50 polymorph screening tests, free crystalline form A can only be obtained in a 2-MeTHF / n-heptane (1:1, v / v) system after slow cooling and evaporation at room temperature.

[0290] Example 9.7: Characterization of free-state crystalline form A

[0291] XRPD analysis

[0292] Figure 7 shows the XRPD pattern of the free crystalline form A of compound A, and the diffraction angle 2θ°, d-interval, and relative intensity of the main peak are listed in Table 18.

[0293] [Table 33]

[0294] DSC and TGA

[0295] The TGA / DSC results (Figure 8) show that the sample exhibits a 1.36% weight loss when heated to 150°C and has an endothermic peak at 135.5°C (peak temperature). Crystal morphology A in the free state shows little weight loss in TGA and only a single endothermic signal is observed in the DSC curve, thus it is identified as an anhydrous crystalline morphology.

[0296] Example 10: Screening of salt form / cocrystal of compound A

[0297] Using amorphous compound A as the starting material, a total of 100 salt morphology / cocrystal screening tests were set up using 25 acids in 4 solvent systems. The screening tests yielded a total of 7 salt crystalline morphologies and 1 free-state crystalline morphology (i.e., free-state crystalline morphology A). All salt morphologies were characterized by X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC). Furthermore, solution analysis was performed. 1 H NMR spectroscopy ( 1 The molar ratio for salt formation was determined by 1H NMR or ultra-high-performance liquid chromatography (UPLC / IC) combined with ion chromatography.

[0298] Approximately 15 mg of amorphous starting material was stirred in 0.5 mL of solvent with equimolar proportions of the corresponding acid for 3 days at room temperature. If a solid was obtained, the sample was centrifuged to separate the solid, and the solid was characterized by XRPD. The results are summarized in Table 19.

[0299] [Table 34-1] [Table 34-2]

[0300] *: The sample was stirred for 3 days, after which a slight gel formed. After stirring and a 10-day temperature cycle treatment, the product was obtained.

[0301] #: The sample was stirred for 3 days, after which a slight gel formed. After stirring and temperature cycling for 15 days, the product was obtained.

[0302] **: The sample was stirred for 3 days, after which a slight gel formed. After stirring and temperature cycling for 19 days, the product was obtained.

[0303] As shown in Table 19, the salt morphology screening test yielded a total of 7 salt crystal morphologies and 1 free-state crystal morphology. The obtained salt crystal morphologies and free-state crystal morphology A were classified as XRPD, TGA, DSC, 1 The samples were characterized by 1H NMR or UPLC / IC.

[0304] Example 10.1: Hydrochloride crystal form A

[0305] Approximately 15 mg of the starting material and an equimolar amount of hydrochloric acid were stirred in MTBE at room temperature for 3 days, then separated by centrifugation, and subsequently vacuum-dried at room temperature for 18 hours to obtain crystalline form A of the hydrochloride salt.

[0306] XRPD analysis

[0307] Figure 9 shows the XRPD pattern of crystalline form A of the hydrochloride salt of compound A, with the diffraction angle 2θ°, d-interval, and relative intensity of the main peak listed in Table 20.

[0308] [Table 35]

[0309] 1 H NMR analysis

[0310] Crystal form A of hydrochloride 1 The 1H NMR data is as follows:

[0311] 1 1H NMR (400 MHz, d 6 -DMSO) δ 10.78(s, 1H), 9.20(d, J=2.08 Hz, 1H), 8.87-8.89(dd, J1=5.00 Hz, J2=1.68 Hz, 1H), 8.44-8.47(dt, J1=8.00 Hz, J2=2.00 Hz, 1H), 7.68-7.71(dd, J1=7.96 Hz, J2=5.04 Hz, 1H), 7.64-7.67(dd, J1=8.00 Hz, J2=1.40 Hz, 1H), 7.62-7.63(d, J=2.28 Hz, 1H), 7.51-7.54(dd, J1=8.12 Hz, J2=1.56 Hz, 1H), 7.45-7.49(td, J1=7.68 Hz, J2=1.39 Hz, 1H), 7.35-7.39(td, J1=7.64 Hz, J2=1.93 Hz, 1H), 6.44(d, J=2.28 Hz, 1H), 4.88-4.92(dd, J1=10.76 Hz, J2=4.96 Hz, 1H), 4.80(s, 1H), 4.59-4.63(d, J=18.44 Hz, 1H), 4.12-4.30(m, ov, 7H), 1.73-1.82(m, 1H), 1.56-1.60(m, 1H), 1.41-1.48(m, 1H), 0.93-0.95(d, J=6.56 Hz, 3H), 0.90-0.91(d, J=6.56 Hz, 3H).

[0312] DSC and TGA

[0313] The TGA / DSC results (Figure 10) show that the sample exhibits a 4.91% weight loss when heated to 150°C and has two endothermic peaks at 125.9°C and 177.8°C (peak temperature). Crystal morphology A of the hydrochloride salt does not change even when heated to 100°C, and because crystal morphology A of the hydrochloride salt exhibits little weight loss in TGA from room temperature to 80°C, crystal morphology A of the hydrochloride salt is identified as an anhydrous crystalline form.

[0314] UPLC / IC

[0315] The UPLC / IC results indicate that the molar ratio of crystalline form A of the hydrochloride salt is 1.0 (acid / free state). The IC results show that the chloride ion content in the sample after heating to 150°C is 1.88 wt%, and the corresponding acid-base molar ratio is calculated to be 0.3. Therefore, the weight loss in TGA from 80°C to 150°C is presumed to correspond to a deoxidation signal.

[0316] Example 10.2: Maleate crystal form A

[0317] Approximately 15 mg of the starting material and an equimolar amount of maleic acid were stirred in toluene at room temperature for 3 days to obtain crystalline form A of maleic acid.

[0318] XRPD analysis

[0319] Figure 11 shows the XRPD pattern of crystalline form A of the maleate of compound A, and the diffraction angle 2θ°, d interval, and relative intensity of the main peak are listed in Table 21.

[0320] [Table 36]

[0321] Example 10.3: Maleate crystal form B

[0322] The above maleate crystal form A was vacuum-dried at room temperature for 18 hours to transform it into a new crystal form, which was named maleate crystal form B.

[0323] XRPD analysis

[0324] Figure 12 shows the XRPD pattern of crystalline form B of the maleate of compound A, with the diffraction angle 2θ°, d-interval, and relative intensity of the main peak listed in Table 22.

[0325] [Table 37]

[0326] 1 The 1H NMR spectrum shows that the molar ratio of the acid to the free state in crystalline form B of the maleate is 1.2, and the molar ratio of toluene to the API is 0.2 (approximately 2.2 wt%).

[0327] DSC and TGA

[0328] The TGA / DSC results (Figure 13) show that the sample exhibits a 12.0% weight loss when heated to 120°C and has an endothermic peak at 85.6°C (peak temperature).

[0329] Example 10.4: Naphthalenedisulfonate crystal form A

[0330] Approximately 15 mg of the starting material and an equimolar ratio of naphthalenedisulfonate were stirred in toluene at room temperature for 3 days, followed by temperature cycling. After separation by centrifugation, the naphthalenedisulfonate was obtained by vacuum drying at room temperature for 2 hours to obtain crystalline form A of naphthalenedisulfonate.

[0331] XRPD analysis

[0332] Figure 14 shows the XRPD pattern of crystalline form A of compound A's naphthalenedisulfonate, with the diffraction angle 2θ°, d-interval, and relative intensity of the main peak listed in Table 23.

[0333] [Table 38]

[0334] 1 The 1H NMR spectrum shows that the molar ratio of acid to base in crystalline form A of naphthalenedisulfonate is 1.0, and the molar ratio of residual toluene to API is 0.02 (0.3 wt%).

[0335] DSC and TGA

[0336] The TGA / DSC results (Figure 15) show that the sample exhibits a 6.0% weight loss when heated to 150°C and has two endothermic peaks at 119.2°C and 207.9°C (peak temperature).

[0337] Example 10.5: Oxalate crystal form A

[0338] Approximately 15 mg of the starting material and an equimolar amount of oxalic acid were stirred in toluene at room temperature for 3 days, followed by a temperature cycling treatment with stirring for 10 days. After separation by centrifugation, the oxalate was vacuum-dried at room temperature for 3 hours to obtain crystalline form A.

[0339] XRPD analysis

[0340] Figure 16 shows the XRPD pattern of crystalline form A of the oxalate of compound A, and the diffraction angle 2θ°, d interval, and relative intensity of the main peak are listed in Table 24.

[0341] [Table 39]

[0342] DSC and TGA

[0343] The TGA / DSC results (Figure 17) show that the sample exhibits a 3.9% weight loss when heated to 150°C and has two endothermic peaks at 125.4°C (start temperature) and 192.8°C (peak temperature).

[0344] UPLC / IC

[0345] The UPLC / IC results indicate that the molar ratio of crystalline form A of the oxalate is 1.1 (ligand / free state).

[0346] Example 10.6: Hydrobromide crystal form A

[0347] Approximately 15 mg of the starting material and an equimolar ratio of hydrobromic acid were stirred in MTBE at room temperature for 3 days to obtain hydrobromide crystalline form A. After vacuum drying at room temperature for 18 hours, hydrobromide crystalline form A became the free state crystalline form A.

[0348] XRPD analysis

[0349] Figure 18 shows the XRPD pattern of crystalline form A of the hydrobromide salt of compound A, with the diffraction angle 2θ°, d-interval, and relative intensity of the main peak listed in Table 25.

[0350] [Table 40]

[0351] Example 10.7: Hydrobromide crystal form B

[0352] Approximately 15 mg of the starting material and an equimolar amount of hydrobromic acid were stirred in toluene at room temperature for 3 days, then separated by centrifugation, and finally vacuum-dried at room temperature for 18 hours to obtain crystalline form B of the hydrobromide salt.

[0353] XRPD analysis

[0354] Figure 19 shows the XRPD pattern of crystalline form B of the hydrobromide salt of compound A, with the diffraction angle 2θ°, d-interval, and relative intensity of the main peak listed in Table 26.

[0355] [Table 41]

[0356] DSC and TGA

[0357] The TGA / DSC results (Figure 20) show that the sample exhibits a 4.6% weight loss when heated to 90°C and has two endothermic peaks at 101.6°C and 113.3°C (peak temperature).

[0358] UPLC / IC

[0359] The UPLC / IC results indicate that the molar ratio of hydrobromide crystal form B is 1.0 (acid / free state).

[0360] Example 11: Repeated preparation of free-state crystal form A

[0361] As described in Example 10, in the salt form (cocrystal) screening test, free crystalline form A was also obtained by stirring succinic acid in an equimolar ratio with the starting material of compound A in MTBE at room temperature for 3 days, separating by centrifugation, and then vacuum drying at room temperature for 18 hours. Therefore, free crystalline form A was repeatedly prepared using this method.

[0362] Specifically, approximately 105 mg of the starting material and succinic acid in an equimolar ratio were stirred in MTBE at room temperature for 3 days, separated by centrifugation, and then vacuum-dried at room temperature for 3 hours to obtain the product.

[0363] 1 The 1H NMR spectrum shows that no succinic acid signal was detected in the free crystal morphology A, indicating a molar ratio of residual MTBE to API of 0.08 (1.2 wt%).

[0364] Furthermore, in order to study the feasibility of developing a process for free-state crystal morphology A, we attempted to prepare free-state crystal morphology A by solution crystallization.

[0365] Specifically, approximately 50 mg of amorphous compound A starting material was weighed into a 20 mL vial, and the corresponding solvent from Table 27 was added. The solid was dissolved by sonication. A total of approximately 5.0 mg of seed crystals of free crystalline form A was added to this vial, and a poor solvent was added dropwise until the solid precipitated. The sample was suspended and stirred at room temperature for a further 3 hours, and the wet sample was subjected to XRPD analysis. After stirring the sample overnight, it was separated by centrifugation and dried at room temperature without sealing. The dried sample was subjected to XRPD analysis. The results are summarized in Table 27, and the superimposed XRPD patterns are shown in Figure 21. The results indicate that free crystalline form A was obtained in both the acetone / H2O system and the IPAc / n-heptane system.

[0366] [Table 42]

[0367] *: After stirring at room temperature for 3 hours, the sample became a suspension.

[0368] Example 12: Screening of other free-state crystal forms

[0369] Using free-state crystalline form A as the starting material, further polymorphic screening of compound A was performed to investigate whether other potential crystalline forms could be obtained and to determine the interconversion relationships.

[0370] Specifically, a total of 52 polymorphism screening tests were set up using screening methods that included gas-solid permeation, suspension and stirring at room temperature and 50°C, temperature cycling with stirring, and grinding. Based on the X-ray powder diffraction (XRPD) results of the isolated solids, no new crystalline morphologies were identified.

[0371] Example 12.1: Solubility test of free-state crystalline form A

[0372] Preliminary solubility tests were performed on free-state crystalline starting material samples using 20 different single solvents at room temperature (RT, 25±3℃), and included the following steps: Approximately 2 mg of the starting material sample was weighed into a 3 mL vial, and the corresponding solvent was gradually added until the solid was clearly dissolved. If the sample was not clearly dissolved after adding 2 mL of solvent, no further solvent was added. As shown in Table 28, the solubility range in the corresponding solvent was calculated based on the mass of the sample and the volume of solvent added. This data was used to guide the selection of solvents in the screening tests.

[0373] [Table 43]

[0374] Example 12.2: Polymorphic Screening

[0375] Using free-state crystalline form A as the starting material, a total of 52 polymorphism screening tests were established using a screening method that included gas-solid permeation, suspension and stirring at room temperature and 50°C, temperature cycling with stirring, and grinding. The specific test methods and results are summarized in Table 29.

[0376] [Table 44]

[0377] Example 12.2.1: Gas-solid permeability

[0378] A total of eight gas-solid permeation tests were set up using various solvents. Approximately 20 mg of free crystalline form A was weighed into a 3 mL vial, and approximately 3.0 mL of the solvents listed in Table 30 was added to a 20 mL vial. The unsealed 3 mL vial was placed into the 20 mL vial, and the 20 mL vial was sealed. After standing at room temperature for 6 days, the solid was collected and subjected to XRPD analysis. The test results are shown in Table 30. Gels and free crystalline form A were obtained.

[0379] [Table 45]

[0380] *: The sample was left at room temperature for 3 days, after which it clearly dissolved. Subsequently, it was evaporated slowly at room temperature to obtain a gel-forming sample.

[0381] Example 12.2.2: Suspension and stirring at room temperature

[0382] Seventeen suspension and stirring tests were conducted at room temperature using various solvent systems. Approximately 20 mg of free crystalline form A was weighed into an HPLC glass vial, and 0.5 mL of each solvent listed in Table 31 was added. The resulting turbid liquid was magnetically stirred (1000 rpm) at room temperature for approximately 3 days, and then the solid was collected by centrifugation. The solid was subjected to XRPD analysis. The test results are shown in Table 31. Gels and free crystalline form A were obtained.

[0383] [Table 46]

[0384] *: The sample was stirred at room temperature for 2 days to form an oily substance, and then stirred at 5°C for 1 day to form another oily substance. Next, the sample was evaporated slowly at room temperature to obtain a gel-forming sample.

[0385] #: The sample was clear after being stirred at room temperature for 2 days, and also clear after being stirred at 5°C for 1 day. The sample was then slowly evaporated at room temperature to obtain a gel-forming sample.

[0386] Example 12.2.3: Suspension and stirring at 50°C

[0387] A total of 13 suspension and stirring tests were set up at 50°C using various solvent systems. Approximately 20 mg of free crystalline form A was weighed into an HPLC glass vial, and 0.5 mL of each solvent listed in Table 32 was added. The resulting suspension was magnetically stirred (1000 rpm) at 50°C for approximately 3 days, and then the solid was collected by centrifugation. The solid was subjected to XRPD analysis. The test results are shown in Table 32. Free crystalline form A was obtained.

[0388] [Table 47]

[0389] *: The sample was stirred at 50°C for 3 days, after which it was clear. Then it was transferred to 5°C and stirred for 1 day to precipitate the solid.

[0390] Example 12.2.4: Temperature cycle for stirring

[0391] A total of 12 temperature cycling tests involving stirring were set up using various solvent systems. Approximately 20 mg of free crystalline form A was weighed into an HPLC glass vial, and 0.5 mL of each solvent listed in Table 33 was added. The resulting suspension was magnetically stirred (1000 rpm) under temperature cycling (the sample was heated to 50°C, then cooled to 5°C at a rate of 0.1°C / min. This cycle was then repeated, and finally the sample was held at 5°C), and the solid was collected by centrifugation. The solid was subjected to XRPD analysis. The test results are shown in Table 33. Free crystalline form A was obtained.

[0392] [Table 48]

[0393] Example 12.2.5: Grinding

[0394] Two grinding tests were conducted under various conditions. Approximately 20 mg of free crystalline form A was weighed into a mortar, and 20 μL of each of the solvents listed in Table 34 was added. The sample was ground by hand for 3 to 5 minutes. The resulting solid was collected and subjected to XRPD analysis. The test results are shown in Table 34. Free crystalline form A was obtained.

[0395] [Table 49]

[0396] In summary, a total of 52 polymorphism screening tests were set up using free-state crystalline form A as the starting material. XRPD results of the isolated solids did not reveal any new crystalline forms.

[0397] Example 13: Preparation of hydrochloride crystal form B

[0398] 5 g of compound A was dissolved in 100 mL of tetrahydrofuran, and 2 mL of 6N hydrochloric acid was slowly added dropwise at room temperature. The mixture was stirred overnight at room temperature, filtered, washed with tetrahydrofuran, and dried to obtain crystalline form B of the hydrochloride salt of compound A in 98% yield.

[0399] Example 14: Further screening of hydrochloride crystal morphology

[0400] Using crystalline form B of the hydrochloride salt of compound A as the starting material, a total of 50 polymorphism screening tests were established using a screening method that included slow evaporation, temperature cycling with stirring, grinding, suspension and stirring at room temperature and 50°C, and addition of a poor solvent. X-ray powder diffraction (XRPD) results of the isolated solids confirmed three hydrochloride crystalline forms (hydrochloride crystalline forms A / B / C) and free state crystalline form A, which were characterized by thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). Molar ratios were determined by ion chromatography (IC).

[0401] Example 14.1: Solubility test of hydrochloride crystal form B

[0402] Preliminary solubility tests were performed on hydrochloride crystalline form B starting material samples using 20 single solvents and 6 mixed solvents at room temperature (RT, 25±3℃), and included the following steps: Approximately 2 mg of the starting material sample was weighed into a 3 mL vial, and the corresponding solvent was gradually added until the solid was clearly dissolved. If the sample was not clearly dissolved after adding 2 mL of solvent, no further solvent was added. As shown in Table 35, the solubility range in the corresponding solvent was calculated based on the mass of the sample and the volume of solvent added. This data was used to guide the selection of solvents in the screening tests.

[0403] [Table 50]

[0404] Example 14.2: Polymorphic Screening

[0405] Using crystalline form B of the hydrochloride salt of compound A as the starting material, a total of 50 polymorphism screening tests were set up using a screening method that included slow evaporation, temperature cycling with stirring, grinding, suspension and stirring at room temperature and 50°C, and addition of a poor solvent. A total of three hydrochloride crystalline forms (hydrochloride crystalline forms A / B / C) and free state crystalline form A were confirmed. The specific test methods and results are summarized in Table 36.

[0406] [Table 51]

[0407] Example 14.2.1: Slow evaporation

[0408] Three slow evaporation tests were conducted using various solvent systems. Approximately 20 mg of the starting material was weighed into a 3 mL vial, and 1.0–2.0 mL of the solvents listed in Table 37 was added to dissolve the sample (undissolved sample was filtered using a 0.45 μm PTFE filter). The vial was sealed with a sealing film, and four pinholes were made in the sealing film. The sample was left at room temperature and evaporated slowly. The resulting solid was collected and subjected to XRPD analysis. The test results are shown in Table 37. Hydrochloride crystalline form A and amorphous products were obtained.

[0409] [Table 52]

[0410] Example 14.2.2: Temperature cycle for stirring

[0411] A total of nine temperature cycling tests were set up using various solvent systems and stirring. Approximately 20 mg of hydrochloride crystalline form B was weighed into an HPLC glass vial, and 0.5 mL of each solvent listed in Table 38 was added. The resulting suspension was magnetically stirred (1000 rpm) under temperature cycling (the sample was heated to 50°C, then cooled to 5°C at a rate of 0.1°C / min. This cycle was then repeated, and finally the sample was held at 5°C), and the solid was collected by centrifugation. The solid was subjected to XRPD analysis. The test results are shown in Table 38. Hydrochloride crystalline forms A / B and free state crystalline form A were obtained.

[0412] [Table 53]

[0413] Example 14.2.3: Grinding

[0414] Two grinding tests were conducted under various conditions. Approximately 20 mg of hydrochloride crystalline form B was weighed into a mortar, and 20 μL of each of the solvents listed in Table 39 was added. The sample was ground by hand for 3 to 5 minutes. The resulting solid was collected and subjected to XRPD analysis. The test results are shown in Table 39. Hydrochloride crystalline form B and hydrochloride crystalline form A+B were obtained.

[0415] [Table 54]

[0416] Example 14.2.4: Suspension and stirring at room temperature

[0417] A total of 14 suspension and stirring tests were set up at room temperature using various solvent systems. Approximately 20 mg of hydrochloride in crystalline form B was weighed into an HPLC glass vial, and 0.5 mL of each solvent listed in Table 40 was added. The resulting turbid liquid was magnetically stirred (1000 rpm) at room temperature for approximately 3 days, and then the solid was collected by centrifugation. The solid was subjected to XRPD analysis. The test results are shown in Table 40. Samples of hydrochloride in crystalline forms A / B and free-state crystalline form A were obtained.

[0418] [Table 55]

[0419] *: The sample was clear at room temperature and remained clear after stirring at 5°C for 3 days. The sample was then transferred to room temperature without sealing and evaporated slowly to obtain a solid.

[0420] Example 14.2.5: Suspension and stirring at 50°C

[0421] A total of eight suspension and stirring tests were conducted at 50°C using various solvent systems. Approximately 20 mg of hydrochloride crystalline form B was weighed into an HPLC glass vial, and 0.5 mL of each solvent listed in Table 41 was added. The resulting suspensions were magnetically stirred (1000 rpm) at 50°C for approximately 3 days, and then the solid was collected by centrifugation. The solid was subjected to XRPD analysis. The test results are shown in Table 41. Hydrochloride crystalline forms A / B and free state crystalline form A were obtained.

[0422] [Table 56]

[0423] Example 14.2.6: Poor solvent addition

[0424] A total of 14 poor solvent addition tests were set up using various solvents. Approximately 20 mg of the starting material was weighed into a 20 mL vial, and the solid was completely dissolved in 0.8–1.4 mL of solvent (see Table 42) (undissolved samples were filtered through a 0.45 μm PTFE filter to obtain a clear solution). The poor solvents from Table 42 were added dropwise to the clear solution with stirring (1000 rpm) until the solid precipitated. Alternatively, if the solid did not precipitate even after the total amount of added poor solvent reached 10 mL, the sample was suspended and stirred at 5°C. The clear sample was then transferred to -20°C and suspended and stirred. If it remained clear, the sample was transferred to room temperature and evaporated. The precipitated solid was separated and subjected to XRPD analysis. The results are shown in Table 42. The poor solvent addition tests yielded hydrochloride crystalline form A / C, free state crystalline form A, and amorphous samples.

[0425] [Table 57]

[0426] *: The sample formed a gel at room temperature and was subjected to temperature cycling (50°C to 5°C, 0.1°C / min) before forming another gel. The sample was then transferred to room temperature and allowed to evaporate slowly without sealing to obtain a solid.

[0427] #: The sample was clear at room temperature and remained clear after stirring at 5°C for 3 days. The sample was transferred to room temperature and evaporated slowly without sealing to obtain a solid.

[0428] **: The sample was clear at room temperature and remained clear after stirring at 5°C for 3 days. The sample remained clear after stirring at -20°C for 1 day, and was transferred to room temperature and evaporated slowly without sealing to obtain a solid.

[0429] Example 14.3: Hydrochloride crystal form B

[0430] XRPD analysis

[0431] Figure 22 shows the XRPD pattern of crystalline form B of the hydrochloride salt of compound A, with the diffraction angle 2θ°, d-interval, and relative intensity of the main peak listed in Table 43.

[0432] [Table 58]

[0433] DSC and TGA

[0434] The TGA / DSC results (Figure 23) show that the sample exhibits a 1.32% weight loss when heated to 70°C, a 5.32% weight loss between 70°C and 150°C, and three endothermic peaks at 123.1°C, 135.2°C, and 187.5°C (peak temperature). Crystal morphology B of the hydrochloride salt does not change even when heated to 90°C, and because crystal morphology B of the hydrochloride salt exhibits a small weight loss in TGA from room temperature to 70°C, crystal morphology B of the hydrochloride salt is identified as an anhydrous crystalline form.

[0435] I C

[0436] The IC results indicate that the chloride ion content in the sample after heating to 150°C was 3.52 wt%, and the corresponding acid-base molar ratio was calculated to be 0.6. Therefore, the weight loss in TGA is presumed to correspond to a deoxidation signal.

[0437] Example 14.4: Hydrochloride crystal form C

[0438] XRPD analysis

[0439] Figure 24 shows the XRPD pattern of crystalline form C of the hydrochloride salt of compound A, with the diffraction angle 2θ°, d-interval, and relative intensity of the main peak listed in Table 44.

[0440] [Table 59]

[0441] DSC and TGA

[0442] The TGA / DSC results (Figure 25) show that the sample exhibits a 5.53% weight loss when heated to 80°C, a 6.72% weight loss when further heated to 150°C, and three endothermic peaks at 60.7°C, 114.4°C, and 182.4°C (peak temperature).

[0443] I C

[0444] The IC result indicates that the acid-base molar ratio of the sample is 1.1.

[0445] To study the weight loss of hydrochloride crystalline form C in TGA, a heating test was performed. XRPD results show that hydrochloride crystalline form C changes when heated to 80°C and cooled to room temperature, and diffraction peaks of hydrochloride crystalline form A appear. The hydrochloride crystalline form C sample melts when heated to 150°C. IC results show that the chloride ion content in the sample after heating to 150°C is 2.69 wt%, and the corresponding acid-base molar ratio is calculated to be 0.4. Therefore, the weight loss in TGA is presumed to correspond to a deoxidation signal.

[0446] Example 15: Dynamic water vapor sorption test

[0447] Dynamic vapor sorption (DVS) tests were performed on free crystal morphology A and hydrochloride crystal morphology B.

[0448] A certain amount of powder was collected and placed in a sample pan, and the hygroscopicity of the sample was evaluated using DVS according to the following instrumental method. [Table 60]

[0449] The DVS trial results are shown in Table 45.

[0450] [Table 61]

[0451] From Table 45, Figure 26, and Figure 27, it can be seen that the free crystal form A shows a weight increase due to moisture absorption of less than 0.5% at relative humidity below 90% and less than 0.7% at relative humidity below 95%, while the hydrochloride crystal form B also shows a weight increase due to moisture absorption of less than 0.7% at relative humidity below 90%.

[0452] Therefore, both the free crystalline form A and the hydrochloride crystalline form B have advantages in hygroscopicity, are suitable for drug development, and can meet pharmaceutical requirements for production, transportation, and storage.

[0453] Example 16: Dissolution stability of free crystalline form A in various pH levels and biologically relevant media.

[0454] The solubility of free crystalline form A was tested under pH 1.0, 1.2, 3.0, 4.5, 5.0, 6.8, 7.0, 7.4, and 9.0, as well as under FaSSGF (pH 1.6), FaSSIF (pH 6.5), and FeSSIF (pH 5.0). XRPD was also performed before and after the tests, as shown in Figures 28 and 29. The results show that free crystalline form A remained unchanged under all of the above test conditions, indicating that free crystalline form A is stable.

[0455] Example 17: Forced decomposition stability test of free-state crystalline form A (under heat, humidity, and light conditions)

[0456] Crystal morphology A in its free state was subjected to the following conditions for forced decomposition stability testing.

[0457] Approximately 10 mg of the sample powder was weighed into a vial and placed under conditions of 50°C, 80°C, and 40°C / 75%RH (unsealed) for 1 day, 2 weeks, and 4 weeks, respectively. Thermal stability was then evaluated.

[0458] Approximately 10 mg of the sample powder was weighed and placed into a clear vial, an amber vial, and a clear vial sealed with aluminum foil. These vials were then divided into 1.2 × 10⁻⁶ containers. 6 Lux, total illuminance per hour, and 200 watts per hour / m² 2 The photostability was evaluated by placing the samples in a lightbox with near-UV energy for 10 days.

[0459] Samples were collected at each point in time and their chemical and physical stability was evaluated by HPLC and XRPD analysis.

[0460] Graphs comparing the XRPD patterns before and after stability testing are shown in Figures 30-33. [Table 62]

[0461] From the table above, it can be seen that under the above test conditions, the crystal morphology of free-state crystal morphology A does not change and is of high purity, indicating that free-state crystal morphology A has excellent high-temperature and moist-heat stability. At the same time, light does not affect the stability of free-state crystal morphology A. Therefore, free-state crystal morphology A has excellent forced-decomposition stability.

[0462] Example 18: High-temperature, high-humidity, and photostability tests of free-state crystalline form A

[0463] [Table 63] [Table 64]

[0464] (1) High-temperature stability of free-state crystal form A

[0465] Approximately 300 mg of free crystalline raw material A was weighed into a Petri dish and placed in a 60°C oven without a lid to perform a high-temperature stability test. The resulting sample was sampled on days 6, 14, and 34 and analyzed by HPLC. The results are shown in the table below. [Table 65]

[0466] Conclusion: The sample remained stable even after being left at 60°C for 14 days.

[0467] (2) High humidity stability of free-state crystalline form A

[0468] Approximately 300 mg of free crystalline raw material A was weighed into a Petri dish and subjected to a high-humidity stability test under 90% RH (saturated KNO3 solution dryer) conditions without a lid. The resulting samples were sampled on days 6, 14, and 34 and analyzed by HPLC. The results are shown in the table below. [Table 66]

[0469] Conclusion: The sample remained stable even after being left for 14 days under conditions of 90% relative humidity.

[0470] (3) Photostability of free-state crystalline form A

[0471] Approximately 300 mg of the free crystalline form A raw material was weighed into a Petri dish and a photostability test was performed under direct sunlight. The resulting samples were sampled on day 4 and day 15 and analyzed by HPLC. The results are shown in the table below. [Table 67]

[0472] Conclusion: The sample remained stable even after being exposed to sunlight for 15 days.

[0473] Example 19: High-temperature and high-humidity stability test of hydrochloride crystal form B

[0474] Approximately 10 mg of hydrochloride crystalline form B raw material was weighed into a Petri dish and subjected to a high-temperature, high-humidity stability test under the conditions shown in the table below. [Table 68] [Table 69]

[0475] Conclusion: Crystal morphology B of the hydrochloride salt was not as stable as the free crystal morphology A under high temperature and high humidity conditions.

[0476] The foregoing is a further detailed description of the Disclosure relating to specific alternative embodiments, and specific embodiments of the Disclosure are not limited to this description. Those skilled in the art can make some simple inferences or substitutions without departing from the concepts of the Disclosure, which should be considered to fall within the scope of the Disclosure.

Claims

1. Characterized by an X-ray powder diffraction pattern obtained using CuKα rays, which includes characteristic peaks represented by at least the following °2θ: 8.5±0.2, 17.7±0.2, 18.0±0.2, and 18.6±0.2, Equation (A): 【Chemistry 1】 Crystal form A of the compound.

2. Crystalline form A of the compound of formula (A) according to claim 1, characterized by an X-ray powder diffraction pattern obtained using CuKα rays, further including characteristic peaks represented by the following °2θ: 10.1±0.2, 14.5±0.2, 20.2±0.2, 20.6±0.2, 25.1±0.2, and 25.7±0.

2.

3. Crystalline form A of the compound of formula (A) according to claim 1 or 2, characterized by an X-ray powder diffraction pattern obtained using CuKα rays, further including characteristic peaks represented by the following °2θ: 12.9±0.2, 15.2±0.2, 22.0±0.2, 23.2±0.2, and 23.9±0.

2.

4. Crystalline form A of the compound of formula (A) according to any one of claims 1 to 3, characterized by an X-ray powder diffraction pattern obtained using CuKα rays, further including characteristic peaks represented by the following °2θ: 11.2±0.2, 12.1±0.2, 14.2±0.2, 15.7±0.2, 19.6±0.2, 21.2±0.2, 28.6±0.2, and 30.0±0.

2.

5. The following characteristic peaks: Table 1 A crystalline form A of the compound of formula (A) according to claim 1, characterized by an X-ray powder diffraction pattern obtained using CuKα rays, which includes the above.

6. Crystal morphology A of the compound of formula (A) according to claim 1, characterized by having an X-ray powder diffraction pattern substantially as shown in Figure 7.

7. Crystal morphology A of the compound of formula (A) according to any one of claims 1 to 6, characterized in that it has an endothermic peak at 135.5 ± 2°C in differential scanning calorimetry.

8. Crystal morphology A of the compound of formula (A) according to any one of claims 1 to 7, characterized in that it has a weight loss of 1.36 ± 0.5% at 150°C in thermogravimetric analysis.

9. Characterized by an X-ray powder diffraction pattern obtained using CuKα rays, which includes characteristic peaks represented by at least the following °2θ: 4.1±0.2, 15.3±0.2, and 18.5±0.2, Equation (A): 【Chemistry 2】 Crystal form A of the hydrochloride salt of the compound.

10. Crystalline form A of the hydrochloride salt of the compound of formula (A) according to claim 9, characterized by an X-ray powder diffraction pattern obtained using CuKα rays, further including characteristic peaks represented by the following °2θ: 8.1±0.2, 10.6±0.2, 11.9±0.2, 22.1±0.2, and 22.9±0.

2.

11. Crystalline form A of the hydrochloride salt of the compound of formula (A) according to claim 9 or 10, characterized by an X-ray powder diffraction pattern obtained using CuKα rays, further including characteristic peaks represented by the following °2θ: 12.2±0.2, 17.9±0.2, 21.5±0.2, and 24.9±0.

2.

12. The following characteristic peaks: Table 2 Crystalline form A of the hydrochloride salt of the compound of formula (A) according to claim 9, characterized by an X-ray powder diffraction pattern obtained using CuKα rays, including the above.

13. Crystal morphology A of the hydrochloride salt of the compound of formula (A) according to claim 9, characterized by having an X-ray powder diffraction pattern substantially as shown in Figure 9.

14. Crystal morphology A of the hydrochloride salt of the compound of formula (A) according to any one of claims 9 to 13, characterized in that it has endothermic peaks at 125.9 ± 2°C and 177.8 ± 2°C in differential scanning calorimetry.

15. Crystal morphology A of the hydrochloride salt of the compound of formula (A) according to any one of claims 9 to 14, characterized by having a weight loss of 4.91 ± 0.5% at 150°C in thermogravimetric analysis.

16. Characterized by an X-ray powder diffraction pattern obtained using CuKα rays, which includes characteristic peaks represented by at least the following °2θ: 4.5±0.2, 18.1±0.2, and 21.4±0.2, Equation (A): 【Transformation 3】 Crystal form B of the hydrochloride salt of the compound.

17. Crystalline form B of the hydrochloride salt of the compound of formula (A) according to claim 16, characterized by an X-ray powder diffraction pattern obtained using CuKα rays, further including characteristic peaks represented by the following °2θ: 11.1±0.2 and 21.7±0.

2.

18. Crystalline form B of the hydrochloride salt of the compound of formula (A) according to claim 16 or 17, characterized by an X-ray powder diffraction pattern obtained using CuKα rays, further including characteristic peaks represented by the following °2θ: 8.7±0.2, 13.7±0.2, 14.4±0.2, 15.1±0.2, and 23.2±0.

2.

19. The following characteristic peaks: Table 3 Crystalline form B of the hydrochloride salt of the compound of formula (A) according to claim 16, characterized by an X-ray powder diffraction pattern obtained using CuKα rays, including the presence of CuKα rays.

20. Crystalline form B of the hydrochloride salt of the compound of formula (A) according to claim 16, characterized by having an X-ray powder diffraction pattern substantially as shown in Figure 22.

21. Crystalline form B of the hydrochloride salt of the compound of formula (A) according to any one of claims 16 to 20, characterized in that it has endothermic peaks at 123.1±2°C, 135.2±2°C, and 187.5±2°C in differential scanning calorimetry.

22. Crystalline form B of the hydrochloride salt of the compound of formula (A) according to any one of claims 16 to 21, characterized in that it has a weight loss of 1.32 ± 0.5% at 70°C and a weight loss of 5.32 ± 0.5% at 70 to 150°C in thermogravimetric analysis.

23. Characterized by an X-ray powder diffraction pattern obtained using CuKα rays, which includes characteristic peaks represented by at least the following °2θ: 8.2±0.2, 10.6±0.2, 13.4±0.2, and 20.2±0.2, Equation (A): 【Chemistry 4】 The crystalline form of the hydrochloride salt of the compound C.

24. Crystalline form C of the hydrochloride salt of the compound of formula (A) according to claim 23, characterized by an X-ray powder diffraction pattern obtained using CuKα rays, further including characteristic peaks represented by the following °2θ: 16.8±0.2 and 17.7±0.

2.

25. Crystalline form C of the hydrochloride salt of the compound of formula (A) according to claim 23 or 24, characterized by an X-ray powder diffraction pattern obtained using CuKα rays, further including characteristic peaks represented by the following °2θ: 4.1±0.2, 8.8±0.2, and 12.2±0.

2.

26. The following characteristic peaks: Table 4 Crystalline form C of the hydrochloride salt of the compound of formula (A) according to claim 23, characterized by an X-ray powder diffraction pattern obtained using CuKα rays, including the above.

27. Crystal morphology C of the hydrochloride salt of the compound of formula (A) according to claim 23, characterized by having an X-ray powder diffraction pattern substantially as shown in Figure 24.

28. Crystalline form C of the hydrochloride salt of the compound of formula (A) according to any one of claims 23 to 27, characterized in that it has endothermic peaks at 60.7±2°C, 114.4±2°C, and 182.4±2°C in differential scanning calorimetry.

29. Crystal morphology C of the hydrochloride salt of the compound of formula (A) according to any one of claims 23 to 28, characterized in that it exhibits a weight loss of 5.53 ± 0.5% at 80°C and a weight loss of 6.72 ± 0.5% at 80 to 150°C in thermogravimetric analysis.

30. Characterized by an X-ray powder diffraction pattern obtained using CuKα rays, which includes characteristic peaks represented by at least the following °2θ: 6.0 ± 0.2 and 18.4 ± 0.2, Equation (A): 【Transformation 5】 Crystal form A of the compound maleate.

31. Crystalline form A of the maleate of the compound of formula (A) according to claim 30, characterized by an X-ray powder diffraction pattern obtained using CuKα rays, further including characteristic peaks represented by the following °2θ: 10.4±0.2, 15.9±0.2, and 17.4±0.

2.

32. Crystalline form A of the maleate of the compound of formula (A) according to claim 30 or 31, characterized by an X-ray powder diffraction pattern obtained using CuKα rays, further including characteristic peaks represented by the following °2θ: 6.9±0.2, 12.0±0.2, 21.2±0.2, and 21.8±0.

2.

33. The following characteristic peaks: Table 5 Crystalline form A of the maleate of the compound of formula (A) according to claim 30, characterized by an X-ray powder diffraction pattern obtained using CuKα rays, including the above.

34. Crystal morphology A of the maleate of the compound of formula (A) according to claim 30, characterized by having an X-ray powder diffraction pattern substantially as shown in Figure 11.

35. Characterized by an X-ray powder diffraction pattern obtained using CuKα rays, which includes characteristic peaks represented by at least the following °2θ: 4.1±0.2, 8.1±0.2, 16.7±0.2, and 20.2±0.2, Equation (A): 【Transformation 6】 The crystalline form B of the compound maleate.

36. Crystalline form B of the maleate of the compound of formula (A) according to claim 35, characterized by an X-ray powder diffraction pattern obtained using CuKα rays, further including characteristic peaks represented by the following °2θ: 17.5±0.2 and 21.3±0.

2.

37. Crystalline form B of the maleate of the compound of formula (A) according to claim 35 or 36, characterized by an X-ray powder diffraction pattern obtained using CuKα rays, further including characteristic peaks represented by the following °2θ: 16.2±0.2, 20.4±0.2, 22.4±0.2, 24.1±0.2, 24.6±0.2, and 26.5±0.

2.

38. The following characteristic peaks: Table 6 Crystalline form B of the maleate of the compound of formula (A) according to claim 35, characterized by an X-ray powder diffraction pattern obtained using CuKα rays, including the above.

39. Crystal morphology B of the maleate of the compound of formula (A) according to claim 35, characterized by having an X-ray powder diffraction pattern substantially as shown in Figure 12.

40. Crystalline form B of the maleate of the compound of formula (A) according to any one of claims 35 to 39, characterized in that it has an endothermic peak at 85.6 ± 2°C in differential scanning calorimetry.

41. Crystalline form B of the maleate of the compound of formula (A) according to any one of claims 35 to 40, characterized by having a weight loss of 12.02 ± 0.5% at 120°C in thermogravimetric analysis.

42. Characterized by an X-ray powder diffraction pattern obtained using CuKα rays, which includes at least the following characteristic peaks represented by °2θ: 4.0 ± 0.2 and 13.7 ± 0.2, Equation (A): 【Transformation 7】 Crystal form A of the compound naphthalenedisulfonate.

43. Crystalline form A of the naphthalenedisulfonate of the compound of formula (A) according to claim 42, characterized by an X-ray powder diffraction pattern obtained using CuKα rays, further including characteristic peaks represented by the following °2θ: 10.3±0.2, 15.5±0.2, 21.0±0.2, and 22.3±0.

2.

44. The following characteristic peaks: Table 7 Crystalline form A of the naphthalenedisulfonate of the compound of formula (A) according to claim 42, characterized by an X-ray powder diffraction pattern obtained using CuKα rays, including the presence of CuKα rays.

45. Crystal morphology A of the naphthalenedisulfonate of the compound of formula (A) according to claim 42, characterized by having an X-ray powder diffraction pattern substantially as shown in Figure 14.

46. Crystal morphology A of a naphthalenedisulfonate of the compound of formula (A) according to any one of claims 42 to 45, characterized in that it has endothermic peaks at 119.2 ± 2°C and 207.9 ± 2°C in differential scanning calorimetry.

47. Crystal morphology A of a naphthalenedisulfonate of the compound of formula (A) according to any one of claims 42 to 46, characterized by having a weight loss of 5.97 ± 0.5% at 150°C in thermogravimetric analysis.

48. Characterized by an X-ray powder diffraction pattern obtained using CuKα rays, which includes characteristic peaks represented by at least the following °2θ: 5.0 ± 0.2 and 15.0 ± 0.2, Equation (A): 【Transformation 8】 Crystal form A of the oxalate salt of the compound.

49. Crystalline form A of the oxalate of the compound of formula (A) according to claim 48, characterized by an X-ray powder diffraction pattern obtained using CuKα rays, further including characteristic peaks represented by the following °2θ: 7.4±0.2, 16.5±0.2, 19.3±0.2, 20.1±0.2, 25.2±0.2, and 26.0±0.

2.

50. The following characteristic peaks: Table 8 Crystalline form A of the oxalate of the compound of formula (A) according to claim 48, characterized by an X-ray powder diffraction pattern obtained using CuKα rays, including the above.

51. Crystal morphology A of the oxalate of the compound of formula (A) according to claim 48, characterized by having an X-ray powder diffraction pattern substantially as shown in Figure 16.

52. Crystal morphology A of the oxalate of the compound of formula (A) according to any one of claims 48 to 51, characterized in that it has endothermic peaks at 131.4 ± 2°C and 192.8 ± 2°C in differential scanning calorimetry.

53. Crystal morphology A of the oxalate salt of the compound of formula (A) according to any one of claims 48 to 52, characterized by having a weight loss of 3.91 ± 0.5% at 150°C in thermogravimetric analysis.

54. Characterized by an X-ray powder diffraction pattern obtained using CuKα rays, which includes characteristic peaks represented by at least the following °2θ: 4.3±0.2 and 8.3±0.2, Equation (A): 【Chemistry 9】 Crystal form A of the compound hydrobromide.

55. Crystalline form A of the hydrobromide salt of the compound of formula (A) according to claim 54, characterized by an X-ray powder diffraction pattern obtained using CuKα rays, further including characteristic peaks represented by the following °2θ: 12.4±0.2, 17.5±0.2, 17.9±0.2, 20.5±0.2, and 21.3±0.

2.

56. The following characteristic peaks: Table 9 Crystalline form A of the hydrobromide salt of the compound of formula (A) according to claim 54, characterized by an X-ray powder diffraction pattern obtained using CuKα rays, including the above.

57. Crystal morphology A of the hydrobromide salt of the compound of formula (A) according to claim 54, characterized by having an X-ray powder diffraction pattern substantially as shown in Figure 18.

58. Characterized by an X-ray powder diffraction pattern obtained using CuKα rays, which includes characteristic peaks represented by at least the following °2θ: 4.1±0.2, 8.1±0.2, 15.0±0.2, 18.4±0.2, and 24.4±0.2, Equation (A): 【Chemistry 10】 The crystalline form B of the compound hydrobromide salt.

59. Crystalline form B of the hydrobromide salt of the compound of formula (A) according to claim 58, characterized by an X-ray powder diffraction pattern obtained using CuKα rays, further including characteristic peaks represented by the following °2θ: 17.8±0.2, 20.3±0.2, 21.3±0.2, 22.0±0.2, and 22.8±0.

2.

60. The following characteristic peaks: Table 10 Crystalline form B of the hydrobromide salt of the compound of formula (A) according to claim 58, characterized by an X-ray powder diffraction pattern obtained using CuKα rays, including the presence of CuKα rays.

61. Crystalline form B of the hydrobromide salt of the compound of formula (A) according to claim 58, characterized by having an X-ray powder diffraction pattern substantially as shown in Figure 19.

62. Crystalline form B of the hydrobromide salt of the compound of formula (A) according to any one of claims 58 to 61, characterized in that it has endothermic peaks at 101.6 ± 2°C and 113.3 ± 2°C in differential scanning calorimetry.

63. Crystalline form B of the hydrobromide salt of the compound of formula (A) according to any one of claims 58 to 62, characterized by having a weight loss of 4.59 ± 0.5% at 90°C in thermogravimetric analysis.

64. A pharmaceutical composition comprising a crystalline form according to any one of claims 1 to 63 and one or more pharmaceutically acceptable excipients.

65. Use of the crystalline form according to any one of claims 1 to 63 or the pharmaceutical composition according to claim 64 in the manufacture of a pharmaceutical for treating and / or preventing one or more diseases selected from type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance, impaired fasting blood glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, and metabolic syndrome.

66. A crystalline form according to any one of claims 1 to 63 or a pharmaceutical composition according to claim 64 for use in the treatment and / or prevention of one or more diseases selected from type 1 diabetes, type 2 diabetes, impaired glucose tolerance, impaired fasting blood glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, and metabolic syndrome.

67. A method for treating and / or preventing a target disease, comprising administering to the target a crystalline form described in any one of claims 1 to 63 or a pharmaceutical composition described in claim 64, wherein the disease is selected from one or more of the following: type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance, impaired fasting blood glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, and metabolic syndrome.

68. Use of the crystalline form according to any one of claims 1 to 63 or the pharmaceutical composition according to claim 64 in the manufacture of a pharmaceutical for curing diabetes, relieving diabetes, and / or regressing diabetes.

69. A crystalline form according to any one of claims 1 to 63 or a pharmaceutical composition according to claim 64, for use in curing diabetes, relieving diabetes, and / or regressing diabetes.

70. A method for curing diabetes, relieving diabetes, and / or regressing diabetes in a subject, comprising administering to the subject a crystalline form described in any one of claims 1 to 63 or a pharmaceutical composition described in claim 64.

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