Crystal of compound containing polyfused ring structure and preparation method therefor

Abstract

The present disclosure belongs to the field of pharmaceutical chemistry, relates to a crystal of a compound containing a polyfused ring structure and a preparation method therefor, and specifically relates to a crystal of a compound of formula (A) and a preparation method therefor.

Description

Crystallization and preparation methods of compounds containing polyfused ring structures

[0001] Cross-reference to related applications

[0002] This application claims priority and benefit to Chinese patent application No. 202411997884.2 filed with the China National Intellectual Property Administration on December 31, 2024, and Chinese patent application No. 202511958926.6 filed with the China National Intellectual Property Administration on December 23, 2025, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] This disclosure pertains to the field of medicinal chemistry and relates to the crystallization of compounds containing polycyclic ring structures and methods for their preparation, specifically to the crystallization of compound (A) and methods for its preparation. Background Technology

[0004] Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease characterized by elevated blood glucose levels, with high morbidity and mortality. Obesity is considered a significant risk factor for T2DM, with approximately 85% of T2DM patients being overweight or obese. Glucagon-like peptide-1 (GLP-1) is an intestinal hypoglycemic agent secreted by L cells in the small intestine as nutrients pass through the digestive tract. GLP-1 is known to exhibit various physiological effects through its receptor, such as promoting glucose-dependent insulin secretion, inhibiting glucagon secretion, delaying gastric emptying, and suppressing appetite. Although GLP-1 analogs have been commercialized as diabetes treatments and are considered among the most effective due to their efficacy in lowering HbA1c and reducing weight, they must be administered subcutaneously, leading to poor patient compliance. Therefore, the development of non-peptide GLP-1 receptor small molecule agonists to improve patient compliance is of great importance and has become a hot research topic in the field of diabetes.

[0005] Therefore, it is necessary to study the crystal form of non-peptide GLP-1 receptor small molecule agonists and improve their physicochemical or pharmacokinetic properties while preserving their biological activity. Summary of the Invention

[0006] On the one hand, this disclosure provides crystallization of compounds of formula (I) or pharmaceutically acceptable salts thereof:

[0007] in,

[0008] X 1 X 2 Each is independently selected from C or N;

[0009] Y 1 Y2 Y 3 Or Y 4 Each is independently selected from CH, C, or N;

[0010] R 1 Selected from C 11-15 cycloalkyl, C 11-15 Aryl, 11-15 membered heteroaryl, 11-15 membered heterocyclic, said C 11-15 cycloalkyl, C 11-15 The aryl, 11-15 membered heteroaryl, and 11-15 membered heterocyclic group are tricyclic rings, and the C 11-15 cycloalkyl, C 11-15 Aryl, 11-15 membered heteroaryl, and 11-15 membered heterocyclic groups can be optionally and independently bonded by one or more R groups. a replace;

[0011] Or, R 1 Selected from C 3-7 Cycloalkyl, phenyl, 5-6 membered heteroaryl or 3-7 membered heterocyclic, wherein R 1 By a C 2-4 Alkyne substitution, R 1 Further, it can be optionally and independently controlled by one or more R a Instead, the C 2-4 The alkynyl group may optionally be replaced by one or more R groups. b replace;

[0012] Each R a Each is independently selected from deuterium, halogens, =O, and deuterated C. 1-6 Alkyl, -OH, -CN, NH2, -COOH, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-3 Alkylene, C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, or 3-6 membered heterocyclic, wherein the deuterated C 1-6 Alkyl, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy or C 1-6 Alkoxy C 1-3 Alkylenes are optionally and independently controlled by one or more R c1 Replace; the C 3-6Cycloalkyl, phenyl, 5-6-membered heteroaryl, or 3-6-membered heterocyclic groups may be independently bound by one or more R groups. d1 replace;

[0013] Each R 2 Each is independently selected from halogens, -OH, -CN, NH2, -COOH, and C. 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-3 Alkylene, C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, or 3-6 membered heterocyclic group, wherein C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy or C 1-6 Alkoxy C 1-3 Alkylenes are optionally and independently controlled by one or more R c2 Replace; the C 3-6 Cycloalkyl, phenyl, 5-6-membered heteroaryl, or 3-6-membered heterocyclic groups may be independently bound by one or more R groups. d2 replace;

[0014] Or, R on two adjacent carbon atoms 2 Together with the carbon atom it is attached to, they form C 4-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-6 membered heterocyclic group, wherein C 4-6 Cycloalkyl, phenyl, 5-6-membered heteroaryl, or 4-6-membered heterocyclic groups are optionally and independently bound by one or more R groups. d3 replace;

[0015] Each R 3 Each is independently selected from deuterium, halogens, -OH, -CN, NH2, -COOH, and C. 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-3 Alkylene, C 3-6Cycloalkyl, phenyl, 5-6 membered heteroaryl, or 3-6 membered heterocyclic group, wherein C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy or C 1-6 Alkoxy C 1-3 Alkylenes are optionally and independently controlled by one or more R c3 Replace; the C 3-6 Cycloalkyl, phenyl, 5-6-membered heteroaryl, or 3-6-membered heterocyclic groups may be independently bound by one or more R groups. d4 replace;

[0016] R 4 Selected from H, deuterium, halogens, -CN, NH2, -COOH, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkoxy C 1-3 Alkylene, the C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkoxy C 1-3 Alkylenes are optionally and independently controlled by one or more R c4 replace;

[0017] Each R 5 Each is independently selected from halogens, -CN, -OH, -SH, -NH2, and C. 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-3 Alkylene, C 1-6 Alkylthio, -CONH2, -CONHC 1-3 Alkyl, -NHCOC 1-3 Alkyl group, -SO2NH2, -SO2NHC 1-3 Alkyl or -NHSO2C 1-3 Alkyl, the C 1-6 Alkyl NH-, (C 1-6Alkyl)2N-, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-3 Alkylene, C 1-6 Alkylthio, -CONH2, -CONHC 1-3 Alkyl, -NHCOC 1-3 Alkyl group, -SO2NH2, -SO2NHC 1-3 Alkyl or -NHSO2C 1-3 Alkyl groups are optionally and independently bound by one or more R groups. c5 replace;

[0018] R' and R" are independently selected from H, halogens, -CN, -OH, -SH, -NH2, and C, respectively. 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-3 Alkylene, C 1-6 Alkylthio, -CONH2, -CONHC 1-3 Alkyl, -NHCOC 1-3 Alkyl group, -SO2NH2, -SO2NHC 1-3 Alkyl or -NHSO2C 1-3 Alkyl, the C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-3 Alkylene, C 1-6 Alkylthio, -CONH2, -CONHC 1-3 Alkyl, -NHCOC 1-3 Alkyl group, -SO2NH2, -SO2NHC 1-3 Alkyl or -NHSO2C 1-3 Alkyl groups are optionally and independently bound by one or more R groups. c6 replace;

[0019] Alternatively, R' and R" together with their attached carbon atoms form C. 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl groups are optionally and independently constituting one or more R groups. d5 replace;

[0020] Each Each is independently selected from either a single bond or a double bond;

[0021] Each R b Each element is independently selected from deuterium, halogens, -CN, -OH, -NH2, and C. 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl or C 1-3 The alkoxy group may be independently substituted by one or more substituents selected from deuterium, halogen, OH, CN or NH2;

[0022] Each R c1 R c2 R c3 R c4 R c5 and R c6 Each is independently selected from deuterium, halogens, -CN, -OH, or -NH2;

[0023] Each R d1 R d2 R d3 R d4 and R d5 Each element is independently selected from deuterium, halogens, -CN, -OH, =O, -NH2, and C. 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl or C 1-3 The alkoxy group may be independently substituted by one or more substituents selected from deuterium, halogen, OH, CN or NH2;

[0024] q is selected from 0, 1, 2, 3, or 4;

[0025] n is selected from 0, 1, 2, 3 or 4;

[0026] m is selected from 0, 1, 2, 3 or 4.

[0027] On the other hand, this disclosure provides crystallization of compounds of formula (II-B) or pharmaceutically acceptable salts thereof.

[0028] Among them, R 2 R 3 R 4 R 5 、R′、R”、R a The definitions of , q, n, or m are as described in the compound of formula (I);

[0029] r can be selected from 0, 1, 2, 3 or 4.

[0030] On the other hand, this disclosure provides crystals of the following compounds or pharmaceutically acceptable salts thereof.

[0031] On the other hand, this disclosure provides crystallization of the compound of formula (A):

[0032] In some embodiments of this disclosure, the crystallization of the compound of formula (A) shows diffraction peaks at 9.52±0.20°, 12.68±0.20°, and 15.85±0.20° in the X-ray powder diffraction pattern using Cu Kα radiation, indicated by 2θ values.

[0033] In some embodiments of this disclosure, the crystallization of the compound of formula (A) shows diffraction peaks at 6.36±0.20°, 9.52±0.20°, 12.68±0.20° and 15.85±0.20° in the X-ray powder diffraction pattern using Cu Kα radiation, expressed as 2θ values.

[0034] In some embodiments of this disclosure, the crystallization of the compound of formula (A) shows diffraction peaks at 6.36±0.20°, 9.52±0.20°, 12.68±0.20°, 15.85±0.20°, 19.05±0.20°, and 19.70±0.20°, expressed as 2θ values, in X-ray powder diffraction patterns using Cu Kα radiation.

[0035] In some embodiments of this disclosure, the crystallization of the compound of formula (A) exhibits diffraction peaks, expressed as 2θ values, at 6.36±0.20°, 9.52±0.20°, 12.68±0.20°, 15.85±0.20°, 19.05±0.20°, 19.70±0.20°, 20.73±0.20°, and 22.25±0.20° in X-ray powder diffraction patterns using Cu Kα radiation.

[0036] In some embodiments of this disclosure, the crystallization of the compound of formula (A) exhibits diffraction peaks, expressed as 2θ values, at 6.36±0.20°, 9.52±0.20°, 12.68±0.20°, 13.82±0.20°, 15.85±0.20°, 16.74±0.20°, 19.05±0.20°, 19.70±0.20°, 20.73±0.20°, and 22.25±0.20° in X-ray powder diffraction patterns using Cu Kα radiation.

[0037] In some embodiments of this disclosure, the crystallization of the compound of formula (A) exhibits diffraction peaks, expressed as 2θ values, in X-ray powder diffraction patterns using Cu Kα radiation at 6.36±0.20°, 9.52±0.20°, 12.68±0.20°, 13.82±0.20°, 15.85±0.20°, 16.31±0.20°, 16.74±0.20°, 19.05±0.20°, 19.70±0.20°, 20.73±0.20°, 22.25±0.20°, and 22.75±0.20°.

[0038] In some embodiments of this disclosure, the crystallization of the compound of formula (A) exhibits diffraction peaks, expressed as 2θ values, at 6.36±0.20°, 7.24±0.20°, 8.89±0.20°, 9.52±0.20°, 12.68±0.20°, 13.82±0.20°, 15.85±0.20°, 16.31±0.20°, 16.74±0.20°, 17.74±0.20°, 19.05±0.20°, 19.70±0.20°, 20.73±0.20°, 22.25±0.20°, and 22.75±0.20° in an X-ray powder diffraction pattern using Cu Kα radiation.

[0039] In some embodiments of this disclosure, the crystallization of the compound of formula (A), in X-ray powder diffraction patterns using Cu Kα radiation, is expressed by 2θ values ​​at 6.36±0.20°, 6.79±0.20°, 7.24±0.20°, 7.70±0.20°, 8.89±0.20°, 9.52±0.20°, 11.22±0.20°, 12.68±0.20°, 13.53±0.20°, 13.82±0.20°, 14.83±0.20°, and 15.57. Diffraction peaks are observed at ±0.20°, 15.85±0.20°, 16.31±0.20°, 16.74±0.20°, 17.20±0.20°, 17.74±0.20°, 18.39±0.20°, 19.05±0.20°, 19.70±0.20°, 20.73±0.20°, 22.25±0.20°, 22.75±0.20°, and 23.80±0.20°.

[0040] In some embodiments of this disclosure, the crystallization of the compound of formula (A), in X-ray powder diffraction patterns using Cu Kα radiation, is represented by 2θ values ​​at 6.36±0.20°, 6.79±0.20°, 7.24±0.20°, 7.70±0.20°, 8.89±0.20°, 9.52±0.20°, 11.22±0.20°, 12.68±0.20°, 13.53±0.20°, 13.82±0.20°, 14.83±0.20°, 15.57±0.20°, 15.85±0.20°, and 16.31. Diffraction peaks are observed at ±0.20°, 16.74±0.20°, 17.20±0.20°, 17.74±0.20°, 18.39±0.20°, 19.05±0.20°, 19.70±0.20°, 20.73±0.20°, 22.25±0.20°, 22.75±0.20°, 23.80±0.20°, 24.37±0.20°, 25.48±0.20°, 26.93±0.20°, and 28.98±0.20°.

[0041] In some embodiments of this disclosure, the crystallization of the compound of formula (A), in an X-ray powder diffraction pattern using Cu Kα radiation, expressed as 2θ values, contains 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more diffraction peaks selected from the following: 6.36±0.20°, 6.79±0.20°, 7.24±0.20°, 7.70±0.20°, 8.89±0.20°, 9.52±0.20°, 11.22±0.20°, 12.68±0.20°, 13.53±0.20°, 13.82±0.20°. 0.20°, 14.83±0.20°, 15.57±0.20°, 15.85±0.20°, 16.31±0.20°, 16.74±0.20°, 17.20±0.20°, 17.74±0.20°, 18.39±0.20°, 19.05±0.20°, 19.70±0.20°, 20.73±0.20°, 22.25±0.20°, 22.75±0.20° and 23.80±0.20°.

[0042] In some embodiments of this disclosure, the crystallization of the compound of formula (A), in an X-ray powder diffraction pattern using Cu Kα radiation, represented by 2θ values, contains 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 diffraction peaks selected from the following: 6.36±0.20°, 9.52±0.20°, 12.68±0.20°, 13.82±0.20°, 15.85±0.20°, 16.31±0.20°, 16.74±0.20°, 19.05±0.20°, 19.70±0.20°, 20.73±0.20°, 22.25±0.20°, and 22.75±0.20°.

[0043] In some embodiments of this disclosure, the crystallization of the compound of formula (A), in an X-ray powder diffraction pattern using Cu Kα radiation, represented by 2θ values, contains 3, 4, 5, 6, 7, or 8 diffraction peaks selected from the following: 6.36±0.20°, 9.52±0.20°, 12.68±0.20°, 15.85±0.20°, 19.05±0.20°, 19.70±0.20°, 20.73±0.20°, and 22.25±0.20°.

[0044] In some embodiments of this disclosure, the crystallization of the compound of formula (A), in an X-ray powder diffraction pattern using Cu Kα radiation, exhibits diffraction peaks at approximately 6.36, 6.79, 7.24, 7.70, 8.89, 9.52, 11.22, 12.68, 13.53, 13.82, 14.83, 15.57, 15.85, 16.31, 16.74, 17.20, 17.74, 18.39, 19.05, 19.70, 20.73, 22.25, 22.75, and 23.80.

[0045] In some embodiments of this disclosure, the crystallization of the compound of formula (A) exhibits diffraction peaks, expressed as 2θ values, at approximately 6.36°, 7.24°, 8.89°, 9.52°, 12.68°, 13.82°, 15.85°, 16.31°, 16.74°, 17.74°, 19.05°, 19.70°, 20.73°, 22.25°, and 22.75° in an X-ray powder diffraction pattern using Cu Kα radiation.

[0046] In some embodiments of this disclosure, the crystallization of the compound of formula (A), in an X-ray powder diffraction pattern using Cu Kα radiation, exhibits diffraction peaks at approximately 6.36°, 9.52°, 12.68°, 13.82°, 15.85°, 16.31°, 16.74°, 19.05°, 19.70°, 20.73°, 22.25°, and 22.75°, expressed as 2θ values.

[0047] In some embodiments of this disclosure, the crystallization of the compound of formula (A) shows diffraction peaks at approximately 6.36°, 9.52°, 12.68°, 15.85°, 19.05°, 19.70°, 20.73°, and 22.25° in X-ray powder diffraction patterns using Cu Kα radiation, expressed as 2θ values.

[0048] In some embodiments of this disclosure, the peak positions and relative intensities of the diffraction peaks in the X-ray powder diffraction pattern of the crystallized compound of formula (A) using Cu Kα radiation are shown in Table 1 below:

[0049] Table 1 shows the peak positions and relative intensities of the X-ray powder diffraction patterns of the crystallized compound (A).

[0050] In some embodiments of this disclosure, the crystallization of the compound of formula (A) and the X-ray powder diffraction (XRPD) pattern using Cu Kα radiation are shown in Figure 1.

[0051] On the other hand, this application provides crystallization of the compound of formula (A), characterized by the Cu Kα radiation X-ray powder diffraction (XRPD) pattern shown in Figure 1.

[0052] In some embodiments of this disclosure, the crystals of the compound of formula (A) have an endothermic peak at 252 ± 5 °C in their differential scanning calorimetry (DSC) plots.

[0053] In some embodiments of this disclosure, the crystallization of the compound of formula (A) has a DSC spectrum as shown in Figure 2.

[0054] On the other hand, this application provides crystallization of the compound of formula (A), which is characterized by differential scanning calorimetry (DSC) curves shown in Figure 2.

[0055] In some embodiments of this disclosure, the crystallization of the compound of formula (A) shows a weight loss of 0.44% at 150.0 ± 5.0 °C according to thermogravimetric analysis.

[0056] In some embodiments of this disclosure, the crystallization of the compound of formula (A) has a TGA spectrum as shown in Figure 3.

[0057] On the other hand, this application provides crystals of compound (A), characterized by TGA as shown in Figure 3.

[0058] On the other hand, this application provides crystals of compound (A), characterized by the ultraviolet absorption spectrum shown in Figure 4.

[0059] On the other hand, this application provides crystals of the compound of formula (A), characterized by the infrared absorption spectrum shown in Figure 5.

[0060] In some embodiments of this disclosure, the compound of formula (A) is amorphous.

[0061] In some embodiments of this disclosure, the amorphous form of the compound of formula (A) is shown in Figure 6 using Cu Kα radiation X-ray powder diffraction (XRPD) patterns.

[0062] In some embodiments of this disclosure, the amorphous form of the compound of formula (A) has an endothermic peak at 48 ± 5 °C in its differential scanning calorimetry (DSC) plot.

[0063] In some embodiments of this disclosure, the amorphous form of the compound of formula (A) has an endothermic peak at 190 ± 5 °C in its differential scanning calorimetry (DSC) plot.

[0064] In some embodiments of this disclosure, the amorphous form of the compound of formula (A) has a DSC spectrum as shown in Figure 7.

[0065] In some embodiments of this disclosure, the amorphous form of the compound of formula (A) exhibits a weight loss of 1.44% at 150.0 ± 5.0 °C according to thermogravimetric analysis.

[0066] In some embodiments of this disclosure, the amorphous form of the compound of formula (A) is shown in Figure 8.

[0067] On the other hand, this disclosure provides a method for preparing crystals of the compound of formula (A), comprising crystallizing the compound of formula (A) in a solvent to obtain crystals of the compound of formula (A).

[0068] In some embodiments of this disclosure, the method for preparing the crystallization of the compound of formula (A) is selected from: place crystallization, evaporation crystallization, suspension crystallization, antisolvent crystallization, rotary evaporation crystallization, or freeze drying; preferably place crystallization or evaporation crystallization.

[0069] In some embodiments of this disclosure, the method for preparing the crystallization of the compound of formula (A) is selected from the method of placement crystallization.

[0070] In some embodiments of this disclosure, a method for preparing the crystallization of the compound of formula (A) is provided, wherein the solvent is selected from one or more mixed solvents of water, methanol, ethanol, isopropanol, n-propanol, cyclohexane, n-heptane, acetone, acetonitrile, ethyl acetate, dichloromethane, tetrahydrofuran, DMSO, and chloroform.

[0071] In some embodiments of this disclosure, a method for preparing the crystallization of the compound of formula (A) is provided, wherein the solvent is selected from one or more mixed solvents of ethanol, water, methanol, n-heptane, isopropanol, acetone, acetonitrile, ethyl acetate, and dichloromethane.

[0072] In some embodiments of this disclosure, a method for preparing the crystallization of the compound of formula (A) is provided, wherein the solvent is selected from methanol.

[0073] In some embodiments of this disclosure, a method for preparing the crystallization of the compound of formula (A) includes the following steps:

[0074] (1) Add solvent to compound (A) and heat and stir until the solution is clear;

[0075] (2) Cool down and let it crystallize.

[0076] In another aspect, this disclosure provides a crystalline composition comprising crystals of a compound of formula (A), wherein the crystals of said compound (A) constitute 50% or more by weight of the crystalline composition, preferably 80% or more, more preferably 90% or more, and most preferably 95% or more. The crystalline composition may also contain small amounts of other crystalline or amorphous forms of the compound of formula (A).

[0077] In another aspect, this disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of crystals of a compound of formula (A) as described in this disclosure, or a crystalline composition thereof. The pharmaceutical compositions of this disclosure may or may not contain pharmaceutically acceptable excipients. Furthermore, the pharmaceutical compositions of this disclosure may further comprise one or more other therapeutic agents.

[0078] In another aspect, this disclosure provides an amorphous pharmaceutical composition comprising a compound of formula (A), the pharmaceutical composition comprising a therapeutically effective amount of the amorphous form of compound (A). The pharmaceutical composition may or may not contain pharmaceutically acceptable excipients. The pharmaceutical composition may further comprise one or more other therapeutic agents.

[0079] In some embodiments of this disclosure, pharmaceutically acceptable excipients in the above-described pharmaceutical compositions include, but are not limited to, flow aids, sweeteners, diluents, preservatives, dyes / coloring agents, flavor enhancers, surfactants, wetting agents, dispersants, disintegrants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers.

[0080] In another aspect, this disclosure provides a method for treating GLP-1R-related conditions, the method comprising administering to an individual in need a therapeutically effective amount of a crystal of the compound of formula (A), or the crystalline composition thereof, or the pharmaceutical composition thereof.

[0081] In another aspect, this disclosure provides the use of crystallization of the compound of formula (A), or the crystallized composition thereof, or the pharmaceutical composition thereof in the preparation of a medicament for treating GLP-1R-related conditions.

[0082] In another aspect, this disclosure provides the use of crystallized compounds of formula (A), or the crystallized compositions thereof, or the pharmaceutical compositions thereof in the treatment of GLP-1R-related conditions.

[0083] In another aspect, this disclosure provides crystals of the compound of formula (A) for treating GLP-1R-related conditions, or the crystallized composition thereof, or the pharmaceutical composition thereof.

[0084] In another aspect, this disclosure provides a method for treating GLP-1R-related conditions, the method comprising administering to an individual in need a therapeutically effective amount of an amorphous form of the compound of formula (A), or the pharmaceutical composition thereof.

[0085] In another aspect, this disclosure provides the use of the amorphous form of the compound of formula (A), or the pharmaceutical composition thereof, in the preparation of a medicament for treating GLP-1R-related conditions.

[0086] In another aspect, this disclosure provides the use of the amorphous form of the compound of formula (A), or the pharmaceutical composition thereof, in the treatment of GLP-1R-related conditions.

[0087] In another aspect, this disclosure provides an amorphous form of the compound of formula (A) for treating GLP-1R-related conditions, or the pharmaceutical composition thereof.

[0088] In some embodiments of this disclosure, the GLP-1R-related condition is diabetes or obesity.

[0089] The crystals of the compound of formula (A) described in this disclosure can be in the form of a nonsolvent or a solvate, such as a hydrate.

[0090] The amorphous form of the compound of formula (A) described in this disclosure can be either a nonsolvent or a solvate, such as a hydrate.

[0091] In this disclosure, the X-ray powder diffraction spectra of the samples were determined under the following conditions:

[0092] Instrument Information: Bruker D8 X-ray diffractometer, manufacturer: Bruker, model: D8;

[0093] Test parameters: Target tube - Cu. Tube voltage 40KV, tube current 40mA, scan 2θ range 4-40°, increment 0.02°, time 0.2s, Twin Primary 0.681mm, Twin Secondary 5.5mm.

[0094] In this disclosure, the DSC spectra are measured under the following conditions:

[0095] Instrument information: Differential scanning calorimeter manufacturer: METTLER TOLEDO; Model: DSC3;

[0096] Test parameters: temperature range 0-270℃, heating rate 10K / min, N2 50ml / min.

[0097] In this disclosure, TGA thermogravimetric analysis is performed under the following conditions:

[0098] Instrument Information: Thermogravimetric analyzer manufacturer: NETZSCH; Model: TG 209F3;

[0099] Test parameters: Temperature range 30-300℃; Heating rate: 10℃ / min.

[0100] Technical effect

[0101] The crystalline and amorphous forms of the compound of this disclosure (A) possess favorable properties in at least one or more aspects such as pharmacokinetics, bioavailability, hygroscopicity, flowability, physical stability, chemical stability, solubility, purity, or mass homogeneity (e.g., as can be demonstrated by the experimental methods of this disclosure), and are suitable for use as a medicine.

[0102] Definitions and Explanations

[0103] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular phrase or term should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When trade names appear herein, they are intended to refer to the corresponding product or its active ingredient.

[0104] For any given crystal form, the relative intensity of diffraction peaks can vary due to preferred orientations caused by factors such as crystal morphology, as is well known in the field of crystallography. Furthermore, for any given crystal form, the peak positions may be subject to slight measurement errors, which is also well known in the field of crystallography. For example, peak positions can shift due to temperature variations during sample analysis, sample movement, or instrument calibration, with measurement errors sometimes around ±0.2 degrees of measurement. Therefore, it is understood by those skilled in the art that this error should be taken into account when determining each crystal structure.

[0105] DSC determines the transition temperature when crystals absorb or release heat due to changes in their crystalline structure or melting. For the same crystal form of the same compound, the error in thermal transition temperature and melting point is typically within ±5°C in continuous analysis. When we say a compound has a given DSC peak or melting point, this means that the DSC peak or melting point is ±5°C, for example, an absorption peak at 252 ±5°C, including absorption peaks at 247°C, 248°C, 249°C, 250°C, 251°C, 252°C, 253°C, 254°C, 255°C, 256°C, and 257°C. DSC provides an auxiliary method for distinguishing different crystal forms. Different crystalline forms can be identified based on their different transition temperature characteristics. It should be noted that for mixtures, their DSC peaks or melting points may vary over a wider range. Furthermore, since decomposition occurs during the melting process, the melting temperature is related to the heating rate.

[0106] The term "pharmaceuticalally acceptable excipients" refers to inert substances that are administered together with the active ingredient and that facilitate the administration of the active ingredient, including but not limited to any flow aids, sweeteners, diluents, preservatives, dyes / coloring agents, flavor enhancers, surfactants, wetting agents, dispersants, disintegrants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that are permitted by the State Food and Drug Administration for use in humans or animals (e.g., livestock).

[0107] The term "crystalline composition" refers to a mixture of one or more crystals of the compound of formula (A) of this disclosure with other crystal forms or amorphous forms of the compound. For example, a crystalline composition of the compound of formula (A) refers to a mixture containing, in addition to crystals of the compound of formula (A) of this disclosure, other crystal forms or amorphous forms of the compound of formula (A).

[0108] The term "pharmaceutical composition" refers to a mixture of one or more compounds of this disclosure, their salts, their crystalline or amorphous forms, and optional pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the compounds of this disclosure to an organism.

[0109] The therapeutic dose of the disclosed compound may be determined based on factors such as the specific therapeutic purpose, the manner of administration of the compound, the patient's health and condition, and the prescribing physician's judgment. The proportion or concentration of the disclosed compound in the pharmaceutical composition may not be fixed and may depend on a variety of factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration.

[0110] The term "treatment" means administering the compounds or preparations described in this disclosure to improve or eliminate a disease or one or more symptoms related to said disease, and includes:

[0111] (i) Suppress the disease or disease state, that is, curb its development;

[0112] (ii) To alleviate the disease or disease state, that is, to make the disease or disease state disappear.

[0113] The therapeutically effective doses of the crystalline and amorphous forms described in this disclosure range from about 0.0001 to 200 mg / kg body weight / day.

[0114] The term "therapeutic effective amount" means (i) the amount of the disclosed compound used to treat a particular disease, condition, or disorder, and (ii) to reduce, improve, or eliminate the occurrence of one or more symptoms of a particular disease, condition, or disorder. The amount of the disclosed compound constituting a "therapeutic effective amount" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by a person skilled in the art based on their own knowledge and the content of this disclosure.

[0115] Unless otherwise required in this disclosure, throughout the specification and the subsequent claims, the word “comprise” and its English variations such as “comprises” and “comprising” and their equivalents shall be interpreted in an open-ended, non-exclusive sense, meaning “including but not limited to”.

[0116] Throughout this specification, the terms "an embodiment," "an embodiment," "in another embodiment," or "in some embodiments" refer to including, in at least one embodiment, a specific reference element, structure, or feature related to that embodiment. Therefore, the phrases "in an embodiment," "in another embodiment," or "in some embodiments" appearing in different places throughout the specification do not necessarily all refer to the same embodiment. Furthermore, specific elements, structures, or features may be combined in one or more embodiments in any suitable manner.

[0117] Unless otherwise stated, in this document, parameter values ​​representing the amount of an ingredient, its physicochemical properties, or reaction conditions, etc., should be understood to be modified by the term "about" in all cases. When the term "about" is used to describe this disclosure, the term "about" indicates an existing error value.

[0118] The intermediate compounds disclosed herein can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments disclosed herein.

[0119] The chemical reactions in the specific embodiments of this disclosure are carried out in a suitable solvent, which must be suitable for the chemical changes of this disclosure and the reagents and materials required therefor. To obtain the compounds of this disclosure, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction flow based on existing embodiments.

[0120] The present disclosure will be described in detail below through embodiments, which are not intended to limit the present disclosure in any way.

[0121] All solvents used in this disclosure are commercially available and can be used without further purification.

[0122] For purposes of description and disclosure, the contents of international patent application PCT / CN2024 / 102306, filed on June 28, 2024, are incorporated herein by reference in their entirety. Attached Figure Description

[0123] Figure 1 shows the XRPD spectrum of the crystallized compound of formula (A).

[0124] Figure 2 shows the DSC spectrum of the crystallization of compound (A).

[0125] Figure 3 shows the TGA spectrum of the crystallization of compound (A).

[0126] Figure 4 shows the ultraviolet absorption spectrum of the crystal of compound (A).

[0127] Figure 5 shows the infrared absorption spectrum of the crystallized compound of formula (A).

[0128] Figure 6 shows the amorphous XRPD spectrum of compound (A).

[0129] Figure 7 shows the amorphous DSC spectrum of compound (A).

[0130] Figure 8 shows the amorphous TGA spectrum of compound (A). Detailed Implementation

[0131] The present disclosure is described in detail below with reference to examples, but this does not imply any adverse limitation thereof. The compounds of the present disclosure can be prepared by various synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present disclosure. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present disclosure without departing from the spirit and scope of the present disclosure, and such changes and modifications do not depart from the protection scope of the present disclosure. The reactants used in the embodiments of the present disclosure can be prepared by commercially available or prior art methods.

[0132] Example 1: Preparation of compound (A)

[0133] Step 1: Synthesis of Intermediate 5-2

[0134] 0.5 g of 6'-bromospiro[cyclopropane-1,3'-dihydroindole]-2'-one was dissolved in 10 mL of N,N-dimethylformamide, followed by the addition of 1.38 g of cesium carbonate and 0.17 mL of iodomethane. The mixture was heated to 80 °C and stirred for 1 h. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to give 0.51 g of intermediate 5-2.

[0135] MS(ESI, [M+H+2]) + )m / z:254.02.

[0136] 1 H-NMR (500MHz, CDCl3): δ7.15 (dd, J=7.9, 1.7Hz, 1H), 7.04 (d, J=1.8Hz, 1H), 6. 69(d,J=7.9Hz,1H),3.27(s,3H),1.75(q,J=4.1Hz,2H),1.51(q,J=4.2Hz,2H).

[0137] Step 2: Synthesis of intermediate 5-3

[0138] Intermediate 5-2 (0.14 g), intermediate A-1 (0.2 g), cuprous iodide (17.25 mg), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (25.8 mg), potassium carbonate (125 mg), and N-methylpyrrolidone (5 mL) were mixed. Under nitrogen protection, the mixture was heated to 130 °C and stirred for 6 h. The mixture was diluted with water and ethyl acetate, extracted with ethyl acetate, and the organic layer was washed successively with water, saturated NaCl aqueous solution, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain 0.18 g of intermediate 5-3.

[0139] MS(ESI, [M+H]) + )m / z:613.38.

[0140] 1 H-NMR (500MHz, CDCl3): δ7.26 (s, 1H), 7.09 (d, J = 6.2Hz, 2H), 7.05 (d, J = 7.4Hz, 1H), 6.87(d,J=7.9Hz,1H),6.68(d,J=3.2Hz,1H),6.29(s,1H),5.43-5.16(m,1H),4.59- 4.21(m,1H),3.31(s,3H),3.23-3.06(m,1H),2.82-2.75(m,2H),2.22(d,J=2.2Hz,6 H),1.77(q,J=4.2Hz,2H),1.54(q,J=4.1Hz,2H),1.50(s,9H),1.32(d,J=6.7Hz,3H).

[0141] Step 3: Synthesis of intermediate 5-4

[0142] Intermediate 5-3 (0.17 g) was mixed with 1 mL of 6N dioxane hydrochloride solution and stirred at room temperature for 1 h. After concentrating and removing the solvent, a saturated sodium bicarbonate aqueous solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to obtain 0.11 g of intermediate 5-4.

[0143] MS(ESI, [M+H]) + )m / z:513.36.

[0144] Step 4: Synthesis of intermediate 5-5 and compound of formula (A)

[0145] Intermediate B-1 (0.08 g) and N,N-dimethylformamide (2 mL) were mixed, followed by the addition of triethylamine (44 mg) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (110 mg). After stirring for 10 min, intermediate 5-4 (0.082 g) was added, and the mixture was stirred at 40 °C for 2 h. The mixture was diluted with water and ethyl acetate, extracted with ethyl acetate, and the organic layer was washed successively with water, saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The filtrate was concentrated and purified by column chromatography (dichloromethane:methanol = 98:2) to obtain 60 mg of intermediate 5-5. Intermediate 5-5 was prepared and separated by chiral HPLC (column: CHIRALART Cellulose-SB, 30×250mm, 10μm; mobile phase: n-hexane: dichloromethane: ethanol = 72:21:7; flow rate: 40mL / min) to obtain 17mg of compound (A).

[0146] Compound (A): Rt = 2.08 min (UPCC conditions: column: CHIRALPAK IB-3 (4.6 × 100 mm, 3 μm); mobile phase: carbon dioxide: methanol (containing 0.1% ammonia) = 30:70; flow rate: 2.0 mL / min; column temperature: 40℃)

[0147] HRMS:(ESI, [M+H]) + )m / z:906.4103.

[0148] 1 H-NMR (500MHz, DMSO-d6): δ11.73(s,1H),7.53(s,1H),7.41-7.32(m,3H),7.31-7.24(m,2H),7.17-7.11( m,3H),7.00-6.95(m,2H),5.57(d,J=6.8Hz,1H),4.38(d,J=13.9Hz,1H),3.71(d,J=8.9Hz,2H),3.24(s,3 H),3.09-3.03(m,1H),2.89(d,J=16.7Hz,1H),2.22-2.18(m,7H),1.64-1.62(m,2H),1.55-1.53(m,2H),1 .40(d,J=6.4Hz,2H),1.36-1.33(m,4H),1.30(s,2H),1.27(s,3H),1.24(s,4H),1.18(s,3H),1.15(s,2H).

[0149] Example 2: Preparation of crystallization of compound (A)

[0150] Weigh out 0.2 g of compound (A), add 15 mL of methanol, heat at 60 °C to dissolve, and crystallize at room temperature to obtain crystals of compound (A).

[0151] The crystallization characterization of compound (A) is shown in Figure 1-5.

[0152] Example 3: Preparation of the amorphous form of compound (A)

[0153] Weigh 20 mg of compound (A), add 1 ml of acetonitrile, heat and shake at 60 °C to dissolve, then add 1 ml of water, and let it stand at room temperature to crystallize, thus obtaining the amorphous compound (A).

[0154] The amorphous characterization of compound (A) is shown in Figure 6-8.

[0155] Experimental Example 1: Investigation of the physical stability of the crystallization of compound (A)

[0156] Crystals of compound (A) were prepared according to the method in Example 2.

[0157] 1. High temperature stability

[0158] The prepared crystals were placed in an 80°C oven for 2 hours and XRD was immediately measured. The results showed that the crystals of compound (A) did not change and it has high temperature stability.

[0159] 2. High humidity stability

[0160] The prepared crystals were placed in a saturated ammonium sulfate solution at room temperature (25℃, 80% ± 2%) for 24 hours to induce moisture, and XRD was measured. The results showed that the crystals of compound (A) did not change and it has high moisture stability.

[0161] Experimental Example 2: Study on the chemical stability of the crystallization of compound (A)

[0162] According to the "Guidelines for Stability Testing of Drug Substances and Preparations" (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 9001), the stability of the compound under the influence of high temperature and high humidity was investigated. An appropriate amount of crystals of compound (A) prepared according to the method in Example 2 was weighed and placed at the bottom of a glass sample vial, spreading it into a thin layer. The sample was then placed under the following conditions: high temperature test 1 (40℃±2℃), high temperature test 2 (60℃±2℃), high humidity test (RH 92.5%), and accelerated test (40℃±2℃, RH 75%) for 5 days, 14 days, and 30 days, respectively. The samples were then characterized by XRD after placement, and the results were compared with the initial results from day 0.

[0163] The results are shown in Table 2:

[0164] Table 2: Comparison of crystal forms and total impurities of compound (A) under high temperature, high humidity, and accelerated testing conditions.

[0165] Experimental results show that the crystal form of compound (A) remains unchanged under high temperature, high humidity and accelerated experimental conditions, and its chemical properties are stable.

[0166] Experimental Example 3: Study on the hygroscopicity of crystallization of compound (A)

[0167] 1. Operation process:

[0168] 1) Take two dry, stoppered glass weighing bottles (outer diameter 50 mm, height 30 mm), place them in a desiccator containing a saturated ammonium sulfate solution (set temperature 25℃, relative humidity 80%) to balance, and accurately weigh the weighing bottles m1 after balancing.

[0169] 2) Take an appropriate amount of crystals of compound (A) prepared according to the method of Example 2, spread them evenly in the two weighing bottles mentioned above, the thickness of the sample is generally about 1 mm, and accurately weigh the total weight m2.

[0170] 3) Leave the weighing bottle open and place it, along with its cap, under the aforementioned constant temperature and humidity conditions for 24 hours. Then, close the weighing bottle cap and accurately weigh the total weight (m³).

[0171] 2. Calculation and Judgment Basis

[0172] Calculate: Percentage weight gain = (m3 - m2) / (m2 - m1) × 100%

[0173] Table 3: Criteria for Judging Hygroscopicity

[0174] 3. Experimental Results

[0175] Table 4: Results of Hygroscopicity Test

[0176] Experimental results show that the crystals of compound (A) are slightly hygroscopic.

[0177] Experimental Example 4: Assay of cAMP Expression Activity at the In Vitro Cellular Level

[0178] HEK293 / CRE-Luc / GLP1R cells (manufacturer: GenScript Biotech Inc.) in good growth condition were washed with PBS, digested with trypsin, and the culture was terminated with complete medium. The cells were collected into centrifuge tubes and the cell density was adjusted to 4 × 10⁶ cells / mL using DMEM + 2% FBS medium. 5Cells were seeded at a concentration of 100 μL / well in 96-well plates and incubated at 37°C for 1 h. After 1 h, the compound was added using a nanoparticle pipette to achieve a final concentration of 10 nM - 0.0006 nM, with two replicates and a control. After culturing for another 6 hours in a cell culture incubator, Luciferase (manufacturer: Novizan Biosciences, 50 μL / well) was added, and the cells were incubated at room temperature for 3 min to allow for complete cell lysis. Luminescence was measured using a PerkinElmer Envision microplate reader, and four-parameter analysis was performed to fit a dose-response curve and calculate EC50. 50 The results are shown in Table 5.

[0179] Table 5. In vitro cell cAMP expression activity

[0180] Experimental Example 5: In vitro liver microsomal stability assay

[0181] Liver microsomal incubation samples were prepared by incubating with mixed PBS buffer (pH 7.4), liver microsomal solution (0.5 mg / ml), compound (A), and NADPH + MgCl2 solution at 37°C and 300 rpm for 1 hour. Samples prepared at 0 hours were prepared with mixed PBS buffer (pH 7.4), liver microsomal solution (0.5 mg / ml), and the test compound. The samples were precipitated with acetonitrile solution containing an internal standard to prepare the supernatant, which was then diluted for LC / MS / MS analysis. The results are shown in Table 6.

[0182] Table 6. In vitro liver microsomal stability

[0183] Experimental Example 6: Pharmacokinetic Evaluation in Mice

[0184] ICR mice, weighing 18-22g, were randomly divided into 4 groups of 9 mice each after acclimatization for 3-5 days. The test compound was administered by gavage (IG) at a dose of 10mg / kg and by intravenous injection (IV) at a dose of 1mg / kg.

[0185] The test animals (ICR mice) were fasted for 12 hours before administration and given food 4 hours after administration. They had free access to water before, during, and after the experiment.

[0186] Following oral administration, approximately 0.1 mL of blood was collected from the orbital sinus at 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h, and 24 h. Following intravenous administration, approximately 0.1 mL of blood was collected from the orbital sinus at 5 min, 10 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, and 24 h. Blood was collected from each mouse at 3-4 time points, with 3 mice at each time point. Whole blood was collected and placed in centrifuge tubes containing EDTA-K2, stored at 4°C, and centrifuged at 4°C and 4000 rpm for 10 min within 1 hour to separate plasma. All collected plasma was immediately stored at -20°C for analysis.

[0187] Take 30 μL of the plasma sample to be tested and the standard sample, add 300 μL of acetonitrile solution containing internal standard (diazepam 20 ng / mL), shake to mix for 5 min, centrifuge at 13000 rpm for 10 min, take 80 μL of supernatant, add 80 μL of ultrapure water to dilute, mix well, take 2 μL for liquid chromatography-mass spectrometry determination, and record the chromatogram.

[0188] The results are shown in Table 7.

[0189] Table 7 Pharmacokinetic properties in mice

[0190] Example 6: Evaluation of the hypoglycemic effect in mice

[0191] The experiment used GLP-1R humanized C57BL / 6J mice, weighing 20-22g. After 3 days of acclimatization, the experiment was conducted. All animals were fasted but allowed free access to water until the end of the experiment. Blood was collected from the tip of the mouse tail.

[0192] Animals were fasted the night before the experiment but allowed free access to water. Blood was collected from all animals the following day for blood glucose testing. Animals were randomly divided into a normal control group, a positive drug control group, and a test drug group, with six animals in each group, based on blood glucose and body weight. The drugs were then administered via gavage according to their group classification. Five hours after administration, a glucose solution (2 g / kg) was injected intraperitoneally. Blood glucose concentrations were measured at 0.25 h, 0.5 h, 1 h, 2 h, and 3 h after glucose administration. Blood glucose levels were recorded throughout the experiment, and the area under the blood glucose-time curve (AUC0-180min Glu) was calculated.

[0193] The results are shown in Table 8.

[0194] Table 8 Evaluation of hypoglycemic efficacy in mice

Claims

1. Crystallization of a compound of formula (A):

2. The crystallization of the compound of formula (A) as described in claim 2, wherein the X-ray powder diffraction pattern using Cu Kα radiation shows diffraction peaks at 9.52±0.20°, 12.68±0.20° and 15.85±0.20°, indicated by 2θ values; Alternatively, the crystallization of the compound of formula (A) shows diffraction peaks at 6.36±0.20°, 9.52±0.20°, 12.68±0.20° and 15.85±0.20° in the X-ray powder diffraction pattern using Cu Kα radiation, expressed as 2θ values. Alternatively, the crystallization of the compound of formula (A), in the X-ray powder diffraction pattern using Cu Kα radiation, shows diffraction peaks at 6.36±0.20°, 9.52±0.20°, 12.68±0.20°, 15.85±0.20°, 19.05±0.20° and 19.70±0.20°, expressed as 2θ values. Alternatively, the crystallization of the compound of formula (A), in the X-ray powder diffraction pattern using Cu Kα radiation, shows diffraction peaks at 6.36±0.20°, 9.52±0.20°, 12.68±0.20°, 15.85±0.20°, 19.05±0.20°, 19.70±0.20°, 20.73±0.20°, and 22.25±0.20°, expressed as 2θ values. Alternatively, the crystallization of the compound of formula (A), in an X-ray powder diffraction pattern using Cu Kα radiation, is expressed with 2θ values ​​at 6.36±0.20°, 6.79±0.20°, 7.24±0.20°, 7.70±0.20°, 8.89±0.20°, 9.52±0.20°, 11.22±0.20°, 12.68±0.20°, 13.53±0.20°, 13.82±0.20°, 14.83±0.20°, 15.57±0.20°, 15.85±0.20°, and 16.

31. Diffraction peaks are observed at ±0.20°, 16.74±0.20°, 17.20±0.20°, 17.74±0.20°, 18.39±0.20°, 19.05±0.20°, 19.70±0.20°, 20.73±0.20°, 22.25±0.20°, 22.75±0.20°, 23.80±0.20°, 24.37±0.20°, 25.48±0.20°, 26.93±0.20°, and 28.98±0.20°. Alternatively, the crystallization of the compound of formula (A), in an X-ray powder diffraction pattern using Cu Kα radiation, expressed as 2θ values, contains 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more diffraction peaks selected from the following: 6.36±0.20°, 6.79±0.20°, 7.24±0.20°, 7.70±0.20°, 8.89±0.20°, 9.52±0.20°, 11.22±0.20°, 12.68±0.20°, 13.53±0.20°, 13.82±0.20°. 0.20°, 14.83±0.20°, 15.57±0.20°, 15.85±0.20°, 16.31±0.20°, 16.74±0.20°, 17.20±0.20°, 17.74±0.20°, 18.39±0.20°, 19.05±0.20°, 19.70±0.20°, 20.73±0.20°, 22.25±0.20°, 22.75±0.20° and 23.80±0.20°; Alternatively, the crystallization of the compound of formula (A), in the X-ray powder diffraction pattern using Cu Kα radiation, expressed as 2θ values, contains 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 diffraction peaks selected from the following: 6.36±0.20°, 9.52±0.20°, 12.68±0.20°, 13.82±0.20°, 15.85±0.20°, 16.31±0.20°, 16.74±0.20°, 19.05±0.20°, 19.70±0.20°, 20.73±0.20°, 22.25±0.20° and 22.75±0.20°; Alternatively, the crystallization of the compound of formula (A), in the X-ray powder diffraction pattern using Cu Kα radiation, expressed as 2θ values, contains 3, 4, 5, 6, 7, or 8 diffraction peaks selected from the following: 6.36±0.20°, 9.52±0.20°, 12.68±0.20°, 15.85±0.20°, 19.05±0.20°, 19.70±0.20°, 20.73±0.20°, and 22.25±0.20°; Alternatively, the crystallization of the compound of formula (A), in the X-ray powder diffraction pattern using Cu Kα radiation, shows diffraction peaks at approximately 6.36, 6.79, 7.24, 7.70, 8.89, 9.52, 11.22, 12.68, 13.53, 13.82, 14.83, 15.57, 15.85, 16.31, 16.74, 17.20, 17.74, 18.39, 19.05, 19.70, 20.73, 22.25, 22.75, and 23.

80. Alternatively, the crystallization of the compound of formula (A), in the X-ray powder diffraction pattern using Cu Kα radiation, shows diffraction peaks at approximately 6.36°, 7.24°, 8.89°, 9.52°, 12.68°, 13.82°, 15.85°, 16.31°, 16.74°, 17.74°, 19.05°, 19.70°, 20.73°, 22.25°, and 22.75°, expressed as 2θ values. Alternatively, the crystallization of the compound of formula (A), in the X-ray powder diffraction pattern using Cu Kα radiation, shows diffraction peaks at approximately 6.36°, 9.52°, 12.68°, 13.82°, 15.85°, 16.31°, 16.74°, 19.05°, 19.70°, 20.73°, 22.25°, and 22.75°, expressed as 2θ values. Alternatively, the crystallization of the compound of formula (A) shows diffraction peaks at approximately 6.36°, 9.52°, 12.68°, 15.85°, 19.05°, 19.70°, 20.73° and 22.25° in the X-ray powder diffraction pattern using Cu Kα radiation, expressed as 2θ values. Alternatively, the crystallization of the compound of formula (A), and the X-ray powder diffraction (XRPD) pattern using Cu Kα radiation, are shown in Figure 1.

3. The crystallization of the compound of formula (A) as described in claim 1 or 2, wherein the differential scanning calorimetry (DSC) curve has an endothermic peak at 252±5℃; Alternatively, the DSC spectrum of the crystallized compound of formula (A) is shown in Figure 2.

4. The crystallization of the compound of formula (A) according to any one of claims 1-3, wherein the thermogravimetric analysis curve shows a weight loss of 0.44% at 150.0±5.0℃; Alternatively, the TGA spectrum of the crystallized compound of formula (A) is shown in Figure 3.

5. An amorphous form of a compound of formula (A):

6. The amorphous form of the compound of formula (A) as described in claim 5, and the X-ray powder diffraction (XRPD) pattern using Cu Kα radiation are shown in Figure 6; Alternatively, the crystals of the compound of formula (A) are amorphous, and its differential scanning calorimetry (DSC) curve has an endothermic peak at 48±5℃; or its differential scanning calorimetry (DSC) curve has an endothermic peak at 190±5℃; or its DSC spectrum is shown in Figure 7. Alternatively, the crystals of the compound of formula (A) are amorphous, and its thermogravimetric analysis curve shows a weight loss of 1.44% at 150.0±5.0℃; or, its TGA spectrum is shown in Figure 8.

7. A method for preparing crystals of a compound of formula (A), comprising crystallizing the compound of formula (A) in a solvent to obtain crystals of the compound of formula (A); Alternatively, the crystallization can be selected from: place crystallization, evaporation crystallization, suspension crystallization, antisolvent crystallization, rotary evaporation crystallization, or freeze drying; place crystallization or evaporation crystallization is preferred. Alternatively, the solvent is selected from one or more mixed solvents of water, methanol, ethanol, isopropanol, n-propanol, cyclohexane, n-heptane, acetone, acetonitrile, ethyl acetate, dichloromethane, tetrahydrofuran, DMSO, and chloroform.

8. A crystalline composition comprising the crystallization of the compound of formula (A) according to any one of claims 1-4, wherein, The crystals of the compound of formula (A) account for more than 50% by weight of the crystalline composition, preferably more than 80%, more preferably more than 90%, and most preferably more than 95%.

9. A pharmaceutical composition comprising a therapeutically effective amount of crystals of the compound of formula (A) according to any one of claims 1-4, or the crystalline composition according to claim 8, or the amorphous form of the compound of formula (A) according to claim 5 or 6.

10. Use of the crystallized compound of formula (A) according to any one of claims 1-4, or the crystalline composition according to claim 8, or the amorphous compound of formula (A) according to claim 5 or 6, or the pharmaceutical composition according to claim 9 in the preparation of a medicament for treating GLP-1R-related conditions, wherein the GLP-1R-related conditions are diabetes or obesity.

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