Crystal form of thieno-imidazole compound and preparation method thereof

Abstract

The invention relates to a crystal form of a thieno-imidazole compound and a preparation method thereof, and also relates to an application of the crystal form in preparation of drugs for treating related diseases. # imgabs0 # imgabs1 #

Description

[0001] This is a divisional application of the case with an application date of December 2, 2022, an invention title of "Crystal Forms of Thienobenzimidazole Compounds and Their Preparation Methods", and an application number of CN202211537195.4. Technical Field

[0002] The present invention relates to crystal forms of thienobenzimidazole compounds and their preparation methods, and also includes the use of the crystal forms in the preparation of drugs for treating related diseases. Background Art

[0003] Diabetes is a common metabolic disease characterized by hyperglycemia. Several major types of diabetes are caused by complex interactions between genetic and environmental factors. Factors leading to hyperglycemia include reduced insulin secretion capacity, decreased glucose utilization ability, and increased glucose output, and these factors vary depending on the cause of diabetes. The metabolic abnormalities associated with diabetes lead to secondary pathophysiological changes in multiple systems throughout the body. Abnormal blood glucose levels over a long period can lead to serious complications, including cardiovascular diseases, chronic renal failure, retinal damage, nerve damage, microvascular damage, and obesity. The classification of diabetes is based on different pathological processes leading to hyperglycemia and can be divided into two main types: type 1 diabetes and type 2 diabetes. During the development of the disease, both type 1 and type 2 diabetes have a stage of abnormal glucose homeostasis before the onset. Type 1 diabetes is the result of complete or almost complete insulin deficiency. Type 2 diabetes is a heterogeneous group of diseases characterized by varying degrees of insulin resistance, decreased insulin secretion function, and increased glucose production. In the early stage of diabetes treatment, diet control and exercise therapy are the preferred blood glucose control regimens. When these methods are difficult to achieve blood glucose control, insulin or oral hypoglycemic drugs need to be used for treatment. Currently, drugs used for diabetes treatment include insulin, insulin secretagogues, metformin, insulin sensitizers, α-glucosidase inhibitors, dipeptidyl peptidase-IV inhibitors (gliptins), sodium-glucose cotransporter 2 (SGLT2) inhibitors, and glucagon-like peptide-1 (GLP-1) receptor agonists, etc. These drugs have good therapeutic effects, but there are still safety problems in long-term treatment. For example, biguanides are prone to cause lactic acidosis; sulfonylureas can lead to hypoglycemic symptoms; insulin sensitizers can cause edema, heart failure, and weight gain; α-glucosidase inhibitors can cause symptoms such as abdominal pain, abdominal distension, and diarrhea; sodium-glucose cotransporter 2 (SGLT2) inhibitors increase the risk of urinary and reproductive system infections, etc. Therefore, there is an urgent need to develop a new, safer, and more effective hypoglycemic drug to meet the treatment needs of diabetes.

[0004] Glucagon-like peptide-1 receptor (GLP-1R) is one of the most important therapeutic targets for type 2 diabetes. GLP-1R belongs to the class B subfamily of G protein-coupled receptors and is widely expressed in tissues such as the stomach, small intestine, heart, kidney, lung, and brain in the body. In pancreatic islet cells, GLP-1R mainly promotes insulin release, increases the regeneration of pancreatic islet β-cells, inhibits β-cell apoptosis, and reduces glucagon release. In tissues such as the gastrointestinal tract, GLP-1R can inhibit gastrointestinal motility and gastric juice secretion, delay gastric emptying, and increase satiety by binding to its agonists. In neural tissues, small molecule GLP-1R agonists can penetrate the brain to activate subsets of neurons expressing GLP-1R, protect against neuronal apoptosis, and enhance learning and memory abilities. Moreover, GLP-1R can also control food intake to reduce body weight. GLP-1 receptor agonists or enhancers of endogenous GLP-1 activity have been approved for the treatment of type 2 diabetes. These drugs do not cause hypoglycemia because insulin secretion stimulated by incretin is glucose-dependent. Exenatide is a synthetic peptide that was initially discovered in the saliva of venomous lizards and is a GLP-1 analogue. Compared with natural GLP-1, exenatide has a different amino acid sequence, which enables exenatide to resist the enzyme [dipeptidyl peptidase IV (DPP-IV)] that degrades GLP-1. Therefore, exenatide has extended GLP-1-like activity and can bind to GLP-1 receptors in the pancreas, gastrointestinal tract, and brain. Liraglutide, another GLP-1 receptor agonist, is almost identical to natural GLP-1 except that one of its amino acids is replaced and a fatty acyl group is added, which can promote its binding to albumin and plasma proteins and extend its half-life. GLP-1 receptor agonists increase glucose-stimulated insulin secretion, inhibit glucagon, and delay gastric emptying. These drugs do not increase body weight. In fact, most patients will experience a certain degree of weight loss and reduced appetite. DPP-IV inhibitors inhibit the degradation of natural GLP-1, thereby enhancing the effect of incretin. DPP-IV, which is abundantly expressed on the cell surface of endothelial cells and some lymphocytes, can degrade a variety of polypeptides (not only GLP-1). DPP-IV inhibitors promote insulin secretion without lowering blood glucose, do not increase body weight, and have an advantage in reducing postprandial blood glucose. Patients using GLP-1 receptor agonists have a higher level of GLP-1 action in their bodies than those using DPP-IV inhibitors.

[0005] Developing small molecule GLP-1 receptor agonists with oral activity can effectively avoid long-term self-injection by patients and has good compliance. Small molecule GLP-1 receptor agonists control blood glucose through multiple pathways of glucose metabolism and excretion, and are expected to develop safer and more effective new hypoglycemic drugs to meet the treatment needs of diabetes. Summary of the Invention

[0006] 1. Compounds of formula (O) or formula (I) and their pharmaceutically acceptable salts,

[0007]

[0008] wherein s is selected from 0 to 3,

[0009] wherein the pharmaceutically acceptable salts are selected from tromethamine salts, phosphate salts, citrate salts, oxalate salts, maleate salts, L-tartrate salts, p-toluenesulfonate N salts, sodium salts, potassium salts, L-arginine salts, choline hydroxide salts, meglumine salts, preferably tromethamine salts, phosphate salts, oxalate salts, maleate salts, p-toluenesulfonate N salts, L-arginine salts, meglumine salts, more preferably tromethamine salts, meglumine salts.

[0010] 2. The pharmaceutically acceptable salt according to item 1, wherein the chemical molar ratio of the compound to the acid or base molecule is 1:2 to 2:1, preferably 1:2 to 1:1 or 1:1 to 2:1, preferably 1:2, 1:1, 2:1.

[0011] 3. The method for preparing item 1 or 2, comprising: the step of salifying the compound of formula (I) with an acid or a base;

[0012] Preferably, the solvent used in the salification reaction is selected from at least one of methyl ethyl ketone, methanol, ethanol, tetrahydrofuran, ethyl acetate, isopropanol, acetonitrile, methyl tert-butyl ether.

[0013] 4. A pharmaceutical composition comprising the pharmaceutically acceptable salt according to item 1 and a pharmaceutically acceptable excipient selected at will.

[0014] 5. Use of the pharmaceutically acceptable salt according to item 1 in the preparation for preventing and / or treating metabolic diseases, preferably diabetes, obesity, non-alcoholic fatty liver disease.

[0015] 6. Compounds of formula (II),

[0016]

[0017] wherein n is selected from 0 to 12, preferably selected from 0 to 8, preferably selected from 0 to 5, preferably selected from 0 to 3, preferably n is selected from 0, 1 / 2, 2 / 3, 1, 2, 2.7 and 3.

[0018] 7. The compound according to item 6, the compound of formula (II) has the following structure:

[0019]

[0020]

[0021] 8. The A crystal form of the compound of formula (II-1), characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 11.1426 ± 0.2000°, 14.4804 ± 0.2000°, 21.4921 ± 0.2000°;

[0022] Preferably, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 11.1426 ± 0.2000°, 14.4804 ± 0.2000°, 17.7642 ± 0.2000°, 19.6235 ± 0.2000°, 21.4921 ± 0.2000°;

[0023] Preferably, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 11.1426 ± 0.2000°, 14.4804 ± 0.2000°, 17.0921 ± 0.2000°, 17.7642 ± 0.2000°, 19.6235 ± 0.2000°, 20.4359 ± 0.2000°, 21.4921 ± 0.2000°, 22.8874 ± 0.2000°; Preferably, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 5.6759°, 10.2572°, 11.1426°, 14.4804°, 16.2701°, 17.0921°, 17.7642°, 19.6235°, 20.4359°, 20.9310°, 21.4921°, 22.8874°, 25.1971°, 26.5995°, 27.9955°, 28.6836°, 29.4212°, 30.9896°.

[0024] 9. The A crystal form according to item 8, the XRPD pattern of which is substantially as Figure 1 shown; or

[0025] its differential scanning calorimetry curve has a peak value of an endothermic peak at 76.0 ± 3.0 °C and 130.3 ± 3.0 °C respectively; or

[0026] its DSC pattern is substantially as Figure 2 shown; or

[0027] its thermogravimetric analysis curve shows a weight loss of 2.43% at 150.0 ± 3.0 °C; or

[0028] its TGA pattern is substantially as Figure 3 shown.

[0029] 10. The E crystal form of the compound of formula (II), characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 18.8216 ± 0.2000°, 20.0568 ± 0.2000°, 25.1936 ± 0.2000°;

[0030] Preferably, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 10.8415 ± 0.2000°, 13.3963 ± 0.2000°, 18.8216 ± 0.2000°, 20.0568 ± 0.2000°, 25.1936 ± 0.2000°;

[0031] Preferably, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 10.3742 ± 0.2000°, 10.8415 ± 0.2000°, 13.3963 ± 0.2000°, 16.1259 ± 0.2000°, 18.8216 ± 0.2000°, 20.0568 ± 0.2000°, 20.7958 ± 0.2000°, 25.1936 ± 0.2000°; Preferably, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 5.3759°, 10.3742°, 10.8415°, 11.5008°, 13.3963°, 15.7418°, 16.1259°, 16.6392°, 17.2881°, 18.8216°, 19.2577°, 20.0568°, 20.7958°, 21.4850°, 22.1639°, 23.0777°, 24.1467°, 24.6828°, 25.1936°, 25.5960°, 26.2392°, 26.7365°, 27.1146°, 27.8176°, 28.5679°, 29.6443°, 30.8753°, 33.0123°, 33.8173°, 36.5754°.

[0032] 11. The E crystal form according to item 10, the XRPD pattern of which is substantially as Figure 7 shown; or

[0033] its differential scanning calorimetry curve has peak values of an endothermic peak at 91.0 ± 3.0 °C and 149.9 ± 3.0 °C respectively; or

[0034] its DSC pattern is substantially as Figure 8 shown; or

[0035] its thermogravimetric analysis curve shows a weight loss of 6.37% at 150.0 ± 3.0 °C; or

[0036] its TGA pattern is substantially asFigure 9 as shown

[0037] 12. The J crystal form of the compound of formula (III), characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 6.763 ± 0.200°, 13.619 ± 0.200°, 18.128 ± 0.200°,

[0038]

[0039] wherein i is selected from 0 to 2.

[0040] 13. The J crystal form according to item 12, wherein its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 6.763 ± 0.200°, 13.619 ± 0.200°, 15.848 ± 0.200°, 18.128 ± 0.200°, 24.643 ± 0.200°;

[0041] Preferably, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 6.763 ± 0.200°, 13.619 ± 0.200°, 15.848 ± 0.200°, 18.128 ± 0.200°, 19.438 ± 0.200°, 21.422 ± 0.200°, 22.621 ± 0.200°, 24.643 ± 0.200°;

[0042] Preferably, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 6.763°, 9.065°, 9.535°, 11.902°, 12.066°, 12.874°, 13.619°, 14.169°, 14.918°, 15.848°, 16.105°, 16.573°, 17.620°, 18.128°, 18.510°, 18.826°, 19.107°, 19.438°, 20.538°, 21.191°, 21.422°, 21.794°, 22.416°, 22.621°, 22.806°, 23.376°, 23.609°, 24.643°, 25.149°, 25.650°, 27.329°, 28.990°, 29.368°, 29.916°, 30.162°, 31.416°, 33.040°, 33.684°, 35.327°, 37.570°.

[0043] 14. The J crystal form according to item 12, wherein its XRPD pattern is substantially as Figure 14 shown

[0044] 15. The compound of formula (IV),

[0045]

[0046] Among them, m is selected from 0 to 2.

[0047] 16. The K crystal form of the compound of formula (IV-1), characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 16.860 ± 0.200°, 18.189 ± 0.200°, 20.709 ± 0.200°,

[0048]

[0049] 17. The K crystal form according to item 16, whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 9.972 ± 0.200°, 16.860 ± 0.200°, 18.189 ± 0.200°, 20.709 ± 0.200°, 23.950 ± 0.200°;

[0050] Preferably, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 4.581 ± 0.200°, 9.972 ± 0.200°, 10.392 ± 0.200°, 16.860 ± 0.200°, 18.189 ± 0.200°, 20.709 ± 0.200°, 23.950 ± 0.200°, 26.841 ± 0.200°;

[0051] Preferably, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 4.581°, 6.439°, 9.972°, 10.232°, 10.392°, 13.328°, 14.053°, 14.696°, 16.860°, 18.189°, 20.709°, 22.766°, 23.950°, 25.785°, 26.841°.

[0052] 18. The K crystal form according to item 16, whose XRPD pattern is substantially as Figure 15 shown.

[0053] 19. The L crystal form of the compound of formula (IV), characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 18.726 ± 0.200°, 21.044 ± 0.200°, 24.648 ± 0.200°;

[0054] Preferably, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 6.494 ± 0.200°, 18.726 ± 0.200°, 19.547 ± 0.200°, 21.044 ± 0.200°, 24.648 ± 0.200°;

[0055] Preferably, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 6.494 ± 0.200°, 15.366 ± 0.200°, 17.885 ± 0.200°, 18.726 ± 0.200°, 19.547 ± 0.200°, 21.044 ± 0.200°, 24.648 ± 0.200°, 27.453 ± 0.200°;

[0056] Preferably, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 5.797°, 6.494°, 7.655°, 10.474°, 13.036°, 13.388°, 15.366°, 16.235°, 17.885°, 18.726°, 19.547°, 21.044°, 24.368°, 24.648°, 27.453°.

[0057] 20. The L crystal form according to claim 19, whose XRPD pattern is substantially as Figure 16 shown.

[0058] 21. The compound of formula (V),

[0059]

[0060] wherein o is selected from 0 to 2.

[0061] 22. The M crystal form of the compound of formula (V), characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 5.682 ± 0.200°, 11.389 ± 0.200°, 17.202 ± 0.200°;

[0062] Preferably, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 5.682 ± 0.200°, 11.389 ± 0.200°, 16.009 ± 0.200°, 17.202 ± 0.200°, 29.418 ± 0.200°;

[0063] Preferably, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 5.682 ± 0.200°, 11.389 ± 0.200°, 16.009 ± 0.200°, 17.202 ± 0.200°, 17.854 ± 0.200°, 24.147 ± 0.200°, 25.302 ± 0.200°, 29.418 ± 0.200°;

[0064] Preferably, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 5.682°, 10.619°, 11.389°, 12.280°, 12.637°, 14.434°, 15.764°, 16.009°, 17.202°, 17.854°, 18.783°, 19.352°, 20.673°, 21.044°, 21.729°, 22.632°, 23.341°, 24.147°, 25.302°, 26.982°, 28.950°, 29.418°, 30.123°, 33.086°.

[0065] 23. The M crystal form according to item 22, whose XRPD pattern is substantially as Figure 17 shown.

[0066] 24. The compound of formula (VI),

[0067]

[0068] 25. The N crystal form of the compound of formula (VI), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 11.439 ± 0.200°, 18.363 ± 0.200°, 28.859 ± 0.200°;

[0069] Preferably, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 11.439 ± 0.200°, 18.363 ± 0.200°, 20.062 ± 0.200°, 22.657 ± 0.200°, 28.859 ± 0.200°;

[0070] Preferably, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 8.581 ± 0.200°, 11.439 ± 0.200°, 18.363 ± 0.200°, 20.062 ± 0.200°, 22.657 ± 0.200°, 23.664 ± 0.200°, 25.356 ± 0.200°, 28.859 ± 0.200°;

[0071] Preferably, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 5.697°, 8.581°, 8.801°, 11.439°, 12.051°, 12.568°, 13.226°, 14.357°, 14.846°, 15.655°, 16.120°, 17.223°, 17.880°, 18.363°, 18.914°, 19.236°, 20.062°, 20.397°, 21.454°, 22.657°, 22.991°, 23.664°, 24.391°, 24.844°, 25.356°, 26.003°, 26.573°, 26.956°, 27.309°, 28.283°, 28.859°, 29.089°, 29.935°, 31.553°, 31.847°, 32.174°, 32.715°, 34.782°, 38.569°.

[0072] 26. The N crystal form according to item 25, whose XRPD pattern is substantially as Figure 18 shown.

[0073] 27. The compound of formula (VII),

[0074]

[0075] wherein p is selected from 0 to 3.

[0076] 28. The O crystal form of the compound of formula (VII), characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 9.485 ± 0.200°, 11.273 ± 0.200°, 17.536 ± 0.200°;

[0077] Preferably, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 9.485 ± 0.200°, 11.273 ± 0.200°, 12.495 ± 0.200°, 17.536 ± 0.200°, 18.874 ± 0.200°;

[0078] Preferably, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 9.485 ± 0.200°, 11.273 ± 0.200°, 12.495 ± 0.200°, 15.005 ± 0.200°, 17.536 ± 0.200°, 18.874 ± 0.200°, 19.568 ± 0.200°, 20.291 ± 0.200°;

[0079] Preferably, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 4.859°, 7.487°, 9.485°, 10.000°, 11.273°, 12.495°, 12.842°, 14.649°, 15.005°, 16.766°, 17.536°, 18.874°, 19.568°, 20.082°, 20.291°, 21.189°, 22.679°, 23.508°, 25.140°, 25.788°, 28.081°, 29.067°, 29.739°, 31.639°, 35.581°.

[0080] 29. The O crystal form according to item 28, whose XRPD pattern is substantially as Figure 19 shown.

[0081] 30. The P crystal form of the compound of formula (VII), characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 12.481 ± 0.200°, 14.965 ± 0.200°, 17.480 ± 0.200°;

[0082] Preferably, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 9.998 ± 0.200°, 12.481 ± 0.200°, 14.965 ± 0.200°, 17.480 ± 0.200°, 19.969 ± 0.200°;

[0083] Preferably, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 5.007°, 7.512°, 9.604°, 9.998°, 12.481°, 14.965°, 17.480°, 18.908°, 19.969°, 20.933°, 25.629°, 27.587°, 35.375°.

[0084] 31. The P crystal form according to item 30, whose XRPD pattern is substantially as Figure 20 shown.

[0085] 32. The compound of formula (VIII),

[0086]

[0087] 33. The Q crystal form of the compound of formula (VIII), characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 6.123 ± 0.200°, 9.130 ± 0.200°, 12.123 ± 0.200°;

[0088] Preferably, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 6.123 ± 0.200°, 9.130 ± 0.200°, 12.123 ± 0.200°, 20.095 ± 0.200°, 22.942 ± 0.200°;

[0089] Preferably, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 6.123 ± 0.200°, 9.130 ± 0.200°, 12.123 ± 0.200°, 15.071 ± 0.200°, 18.151 ± 0.200°, 20.095 ± 0.200°, 22.045 ± 0.200°, 22.942 ± 0.200°;

[0090] Preferably, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 6.123°, 7.677°, 9.130°, 10.013°, 11.598°, 12.123°, 14.770°, 15.071°, 15.986°, 16.493°, 16.692°, 17.365°, 18.151°, 18.915°, 20.095°, 20.569°, 21.147°, 22.045°, 22.942°, 24.106°, 24.617°, 26.108°, 27.014°, 27.822°, 28.433°, 29.464°, 30.256°, 30.863°, 31.820°, 33.446°, 34.822°, 36.389°, 37.646°, 37.803°.

[0091] 34. The Q crystal form according to item 33, its XRPD pattern is substantially as Figure 21 shown.

[0092] 35. Use of the compound according to any one of items 6, 7, 15, 21, 24, 27 or 32 or the A crystal form according to item 8 or 9 or the E crystal form according to item 10 or 11 or the J crystal form according to any one of items 12 to 14 or the K crystal form according to any one of items 16 to 18 or the L crystal form according to item 19 or 20 or the M crystal form according to item 22 or 23 or the N crystal form according to item 25 or 26 or the O crystal form according to item 28 or 29 or the P crystal form according to item 30 or 31 or the Q crystal form according to item 33 or 34 in the preparation of a medicament for treating metabolic diseases.

[0093] 36. The compound of formula (III),

[0094] wherein, i is selected from 0 to 2.

[0095] The present invention provides pharmaceutically acceptable salts of the compound of formula (O). Wherein, the pharmaceutically acceptable salts are selected from tromethamine salts, phosphate salts, citrate salts, oxalate salts, maleate salts, L-tartrate salts, p-toluenesulfonate N salts, sodium salts, potassium salts, L-arginine salts, choline hydroxide salts, meglumine salts, preferably tromethamine salts, phosphate salts, oxalate salts, maleate salts, p-toluenesulfonate N salts, L-arginine salts, meglumine salts, more preferably tromethamine salts, meglumine salts.

[0096] In some embodiments of the present invention, the chemical molar ratio of the compound to an acid or a base molecule is 1:2 to 2:1, for example, it can be 2:3, 3:4, 4:5, 1:1, 5:4, 4:3, 3:2. In some embodiments, the chemical molar ratio is preferably 1:2 to 1:1. In some embodiments, the chemical molar ratio is preferably 1:1 to 2:1. In some embodiments, the chemical molar ratio is preferably 1:2, 1:1, 2:1.

[0097] The present invention provides a method for preparing the above-mentioned pharmaceutically acceptable salts, including: the step of forming a salt of the compound of formula (I) with an acid or a base.

[0098] In some embodiments of the present invention, the solvent used in the salt-forming reaction is selected from at least one of methyl ethyl ketone, methanol, ethanol, tetrahydrofuran, ethyl acetate, isopropyl alcohol, acetonitrile, methyl tert-butyl ether.

[0099] The present invention provides a pharmaceutical composition containing the above-mentioned pharmaceutically acceptable salts and any pharmaceutically acceptable carrier, excipient selected therefrom.

[0100] In some embodiments of the present invention, the above-mentioned pharmaceutically acceptable salts are used in the preparation for preventing and / or treating metabolic diseases, and the metabolic diseases are preferably diabetes, obesity, non-alcoholic fatty liver.

[0101] The present invention provides a compound of formula (II)

[0102]

[0103] Wherein, n is selected from 0 to 12, for example, it can be 0, 1 / 2, 2 / 3, 1, 2, 2.7, 3, 4, 5, 6, 7, 8. In some embodiments of the present invention, n is selected from 0 to 8. In some embodiments of the present invention, n is selected from 0 to 5. In some embodiments of the present invention, n is selected from 0 to 3.

[0104] In some embodiments of the present invention, the n is selected from 0, 1 / 2, 2 / 3, 1, 2, 2.7 and 3.

[0105] In some embodiments of the present invention, the compound of formula (II) has the following structure

[0106]

[0107] The present invention provides an A crystal form of the compound of formula (II-1), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 11.1426 ± 0.2000°, 14.4804 ± 0.2000°, 21.4921 ± 0.2000°.

[0108]

[0109] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above A crystal form has characteristic diffraction peaks at the following 2θ angles: 11.1426 ± 0.2000°, 14.4804 ± 0.2000°, 17.7642 ± 0.2000°, 19.6235 ± 0.2000°, 21.4921 ± 0.2000°.

[0110] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above A crystal form has characteristic diffraction peaks at the following 2θ angles: 11.1426 ± 0.2000°, 14.4804 ± 0.2000°, 17.0921 ± 0.2000°, 17.7642 ± 0.2000°, 19.6235 ± 0.2000°, 20.4359 ± 0.2000°, 21.4921 ± 0.2000°, 22.8874 ± 0.2000°.

[0111] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above A crystal form has characteristic diffraction peaks at the following 2θ angles: 5.6759°, 10.2572°, 11.1426°, 14.4804°, 16.2701°, 17.0921°, 17.7642°, 19.6235°, 20.4359°, 20.9310°, 21.4921°, 22.8874°, 25.1971°, 26.5995°, 27.9955°, 28.6836°, 29.4212°, 30.9896°.

[0112] In some embodiments of the present invention, the above A crystal form, its XRPD pattern is substantially as Figure 1 shown.

[0113] In some embodiments of the present invention, the XRPD pattern analysis data of the above A crystal form is shown in Table 1:

[0114] Table 1 XRPD pattern analysis data of the A crystal form of the compound of formula (II-1)

[0115]

[0116] In some embodiments of the present invention, the differential scanning calorimetry curve of the above A crystal form has peak values of endothermic peaks at 76.0 ± 3.0 °C and 130.3 ± 3.0 °C respectively.

[0117] In some embodiments of the present invention, the DSC pattern of the above A crystal form is substantially as Figure 2 shown.

[0118] In some embodiments of the present invention, the thermogravimetric analysis curve of the above A crystal form shows a weight loss of 2.43% at 150.0 ± 3.0 °C.

[0119] In some embodiments of the present invention, the TGA pattern of the above A crystal form is substantially as Figure 3 shown.

[0120] The present invention provides a B crystal form of the compound of formula (II), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 13.3946 ± 0.2000 °, 16.0867 ± 0.2000 °, 18.7923 ± 0.2000 °.

[0121] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above B crystal form has characteristic diffraction peaks at the following 2θ angles: 5.3578 ± 0.2000 °, 10.7076 ± 0.2000 °, 13.3946 ± 0.2000 °, 16.0867 ± 0.2000 °, 18.7923 ± 0.2000 °.

[0122] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above B crystal form has characteristic diffraction peaks at the following 2θ angles: 5.3578 ± 0.2000 °, 10.7076 ± 0.2000 °, 13.3946 ± 0.2000 °, 16.0867 ± 0.2000 °, 18.7923 ± 0.2000 °, 26.9882 ± 0.2000 °.

[0123] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above B crystal form has characteristic diffraction peaks at the following 2θ angles: 5.3578 °, 10.7076 °, 13.3946 °, 16.0867 °, 17.2158 °, 18.7923 °, 20.0218 °, 20.7079 °, 21.5030 °, 23.0606 °, 24.3029 °, 25.5466 °, 26.9882 °, 28.4762 °, 29.7465 °, 30.8461 °, 32.5003 °, 35.2977 °, 37.0829 °, 38.1654 °.

[0124] In some embodiments of the present invention, the above B crystal form, its XRPD pattern is substantially asFigure 4 as shown

[0125] In some embodiments of the present invention, the XRPD pattern analysis data of the above B crystal form are shown in Table 2:

[0126] Table 2 XRPD pattern analysis data of the B crystal form of the compound of formula (II)

[0127]

[0128] The present invention provides a C crystal form of the compound of formula (II), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 5.2235±0.2000°, 13.0633±0.2000°, 18.3202±0.2000°.

[0129] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above C crystal form has characteristic diffraction peaks at the following 2θ angles: 5.2235±0.2000°, 13.0633±0.2000°, 18.3202±0.2000°, 19.0603±0.2000°, 20.9687±0.2000°.

[0130] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above C crystal form has characteristic diffraction peaks at the following 2θ angles: 5.2235±0.2000°, 10.6330±0.2000°, 13.0633±0.2000°, 18.3202±0.2000°, 19.0603±0.2000°, 20.9687±0.2000°, 23.0438±0.2000°, 23.6332±0.2000°.

[0131] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above C crystal form has characteristic diffraction peaks at the following 2θ angles: 5.2235°, 10.2060°, 10.4366°, 10.6330°, 11.6394°, 13.0633°, 16.3161°, 16.8840°, 17.9453°, 18.3202°, 19.0603°, 19.6631°, 20.5231°, 20.9687°, 21.3445°, 21.9752°, 22.4037°, 23.0438°, 23.3931°, 23.6332°, 23.9781°, 24.7774°, 25.4626°, 26.2681°, 26.7514°, 28.0533°, 28.9221°, 29.4437°, 30.4397°, 30.9179°, 32.6038°, 34.3656°, 36.3357°, 37.4691°.

[0132] In some embodiments of the present invention, the above-mentioned Form C has an XRPD pattern substantially as Figure 5 shown.

[0133] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned Form C are shown in Table 3:

[0134] Table 3 XRPD Pattern Analysis Data of Form C of the Compound of Formula (II)

[0135]

[0136] The present invention provides Form D of the compound of formula (II), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 5.4120±0.2000°, 13.5502±0.2000°, 24.5140±0.2000°.

[0137] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned Form D has characteristic diffraction peaks at the following 2θ angles: 5.4120±0.2000°, 8.1209±0.2000°, 13.5502±0.2000°, 16.2767±0.2000°, 24.5140±0.2000°.

[0138] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned Form D has characteristic diffraction peaks at the following 2θ angles: 5.4120±0.2000°, 8.1209±0.2000°, 13.5502±0.2000°, 16.2767±0.2000°, 18.9363±0.2000°, 20.4857±0.2000°, 21.7578±0.2000°, 24.5140±0.2000°.

[0139] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above D crystal form has characteristic diffraction peaks at the following 2θ angles: 5.4120°, 8.1209°, 10.4811°, 10.8250°, 11.4035°, 12.8266°, 13.5502°, 14.6390°, 16.2767°, 17.3099°, 17.6879°, 18.9363°, 20.4857°, 20.9317°, 21.4104°, 21.7578°, 21.9895°, 22.3592°, 22.9155°, 23.6785°, 24.5140°, 25.0791°, 25.8055°, 26.2813°, 27.7237°, 29.5078°, 30.9747°, 36.0140°, 36.8748°.

[0140] In some embodiments of the present invention, the above D crystal form, its XRPD pattern is substantially as Figure 6 shown.

[0141] In some embodiments of the present invention, the XRPD pattern analysis data of the above D crystal form is shown in Table 4:

[0142] Table 4 XRPD Pattern Analysis Data of the D Crystal Form of the Compound of Formula (II)

[0143]

[0144] The present invention provides an E crystal form of the compound of formula (II), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 18.8216 ± 0.2000°, 20.0568 ± 0.2000°, 25.1936 ± 0.2000°.

[0145] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above E crystal form has characteristic diffraction peaks at the following 2θ angles: 10.8415 ± 0.2000°, 13.3963 ± 0.2000°, 18.8216 ± 0.2000°, 20.0568 ± 0.2000°, 25.1936 ± 0.2000°.

[0146] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above E crystal form has characteristic diffraction peaks at the following 2θ angles: 10.3742 ± 0.2000°, 10.8415 ± 0.2000°, 13.3963 ± 0.2000°, 16.1259 ± 0.2000°, 18.8216 ± 0.2000°, 20.0568 ± 0.2000°, 20.7958 ± 0.2000°, 25.1936 ± 0.2000°.

[0147] The present invention provides the E crystal form of the compound of formula (II), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 18.8216±0.2000°, 20.0568±0.2000°, and / or 25.1936±0.2000°, and / or 10.8415±0.2000°, and / or 13.3963±0.2000°, and / or 10.3742±0.2000°, and / or 16.1259±0.2000°, and / or 20.7958±0.2000°, and / or 5.3759±0.2000°, and / or 11.5008±0.2000°, and / or 15.7418±0.2000°, and / or 16.6392±0.2000°, and / or 17.2881±0.2000°, and / or 19.2577±0.2000°, and / or 21.4850±0.2000°, and / or 22.1639±0.2000°, and / or 23.0777±0.2000°, and / or 24.1467±0.2000°, and / or 24.6828±0.2000°, and / or 25.5960±0.2000°, and / or 26.2392±0.2000°, and / or 26.7365±0.2000°, and / or 27.1146±0.2000°, and / or 27.8176±0.2000°, and / or 28.5679±0.2000°, and / or 29.6443±0.2000°, and / or 30.8753±0.2000°, and / or 33.0123±0.2000°, and / or 33.8173±0.2000°, and / or 36.5754±0.2000°.

[0148] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above E crystal form has characteristic diffraction peaks at the following 2θ angles: 5.3759°, 10.3742°, 10.8415°, 11.5008°, 13.3963°, 15.7418°, 16.1259°, 16.6392°, 17.2881°, 18.8216°, 19.2577°, 20.0568°, 20.7958°, 21.4850°, 22.1639°, 23.0777°, 24.1467°, 24.6828°, 25.1936°, 25.5960°, 26.2392°, 26.7365°, 27.1146°, 27.8176°, 28.5679°, 29.6443°, 30.8753°, 33.0123°, 33.8173°, 36.5754°.

[0149] In some embodiments of the present invention, the above E crystal form has an XRPD pattern substantially as shown in Figure 7 .

[0150] In some embodiments of the present invention, the XRPD pattern analysis data of the above E crystal form are shown in Table 5:

[0151] Table 5 XRPD pattern analysis data of the E crystal form of the compound of formula (II)

[0152]

[0153]

[0154] In some embodiments of the present invention, the differential scanning calorimetry curve of the above E crystal form has a peak of an endothermic peak at 91.0 ± 3.0 °C and 149.9 ± 3.0 °C, respectively.

[0155] In some embodiments of the present invention, the DSC pattern of the above E crystal form is substantially as shown in Figure 8 .

[0156] In some embodiments of the present invention, the thermogravimetric analysis curve of the above E crystal form shows a weight loss of 6.37% at 150.0 ± 3.0 °C.

[0157] In some embodiments of the present invention, the TGA pattern of the above E crystal form is substantially as shown in Figure 9 . The present invention provides an F crystal form of the compound of formula (II), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 5.4518 ± 0.2000 °, 19.3372 ± 0.2000 °, 20.6984 ± 0.2000 °.

[0158] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above F crystal form has characteristic diffraction peaks at the following 2θ angles: 5.4518 ± 0.2000 °, 10.5789 ± 0.2000 °, 16.4789 ± 0.2000 °, 19.3372 ± 0.2000 °, 20.6984 ± 0.2000 °.

[0159] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above F crystal form has characteristic diffraction peaks at the following 2θ angles: 5.4518 ± 0.2000 °, 10.5789 ± 0.2000 °, 16.4789 ± 0.2000 °, 17.7935 ± 0.2000 °, 19.3372 ± 0.2000 °, 20.6984 ± 0.2000 °, 22.3282 ± 0.2000 °, 26.3477 ± 0.2000 °.

[0160] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above F crystal form has characteristic diffraction peaks at the following 2θ angles: 5.4518°, 10.5789°, 11.5837°, 13.0825°, 13.6602°, 14.9423°, 16.4789°, 17.7935°, 19.3372°, 20.6984°, 21.2538°, 22.3282°, 24.7246°, 26.3477°, 27.4475°, 28.7110°.

[0161] In some embodiments of the present invention, the above F crystal form, its XRPD pattern is substantially as Figure 10 shown.

[0162] In some embodiments of the present invention, the XRPD pattern analysis data of the above F crystal form is shown in Table 6:

[0163] Table 6 XRPD pattern analysis data of the F crystal form of the compound of formula (II)

[0164]

[0165]

[0166] The present invention provides the G crystal form of the compound of formula (II), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 13.2453 ± 0.2000°, 18.1001 ± 0.2000°, 20.5915 ± 0.2000°.

[0167] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above G crystal form has characteristic diffraction peaks at the following 2θ angles: 5.3356 ± 0.2000°, 13.2453 ± 0.2000°, 18.1001 ± 0.2000°, 19.3293 ± 0.2000°, 20.5915 ± 0.2000°.

[0168] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above G crystal form has characteristic diffraction peaks at the following 2θ angles: 5.3356 ± 0.2000°, 13.2453 ± 0.2000°, 18.1001 ± 0.2000°, 18.5528 ± 0.2000°, 19.3293 ± 0.2000°, 19.7622 ± 0.2000°, 20.5915 ± 0.2000°, 23.5540 ± 0.2000°.

[0169] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned G crystal form has characteristic diffraction peaks at the following 2θ angles: 5.3356°, 10.7072°, 13.2453°, 14.9037°, 16.6883°, 18.1001°, 18.5528°, 19.3293°, 19.7622°, 20.5915°, 21.3864°, 22.0249°, 22.5324°, 23.1856°, 23.5540°, 24.9841°, 25.5102°, 26.9502°, 28.1389°, 29.0651°, 30.3926°.

[0170] In some embodiments of the present invention, the above-mentioned G crystal form, its XRPD pattern is substantially Figure 11 as shown.

[0171] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned G crystal form are shown in Table 7:

[0172] Table 7 XRPD pattern analysis data of the G crystal form of the compound of formula (II)

[0173]

[0174]

[0175] The present invention provides the H crystal form of the compound of formula (II), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 5.2142 ± 0.2000°, 9.2475 ± 0.2000°, 17.8933 ± 0.2000°.

[0176] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned H crystal form has characteristic diffraction peaks at the following 2θ angles: 5.2142 ± 0.2000°, 9.2475 ± 0.2000°, 17.8933 ± 0.2000°, 22.0544 ± 0.2000°, 23.0224 ± 0.2000°.

[0177] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned H crystal form has characteristic diffraction peaks at the following 2θ angles: 5.2142 ± 0.2000°, 9.2475 ± 0.2000°, 17.8933 ± 0.2000°, 19.3686 ± 0.2000°, 20.2031 ± 0.2000°, 21.2391 ± 0.2000°, 22.0544 ± 0.2000°, 23.0224 ± 0.2000°.

[0178] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned H crystal form has characteristic diffraction peaks at the following 2θ angles: 5.2142°, 9.2475°, 10.2712°, 13.6133°, 15.5872°, 16.1306°, 17.8933°, 18.7847°, 19.3686°, 20.2031°, 20.7049°, 21.2391°, 22.0544°, 23.0224°, 24.1930°, 26.9749°.

[0179] In some embodiments of the present invention, the above-mentioned H crystal form, its XRPD pattern is substantially as Figure 12 shown.

[0180] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned H crystal form are shown in Table 8:

[0181] Table 8 XRPD Pattern Analysis Data of the H Crystal Form of the Compound of Formula (II)

[0182]

[0183] The present invention provides the I crystal form of the compound of formula (II), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 5.1906 ± 0.2000°, 12.9022 ± 0.2000°, 15.4944 ± 0.2000°.

[0184] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned I crystal form has characteristic diffraction peaks at the following 2θ angles: 5.1906 ± 0.2000°, 10.3443 ± 0.2000°, 12.9022 ± 0.2000°, 15.4944 ± 0.2000°, 18.0816 ± 0.2000°.

[0185] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned I crystal form has characteristic diffraction peaks at the following 2θ angles: 5.1906 ± 0.2000°, 10.3443 ± 0.2000°, 12.9022 ± 0.2000°, 13.4027 ± 0.2000°, 15.4944 ± 0.2000°, 16.1068 ± 0.2000°, 18.0816 ± 0.2000°, 18.8121 ± 0.2000°.

[0186] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned Form I has characteristic diffraction peaks at the following 2θ angles: 5.1906°, 7.7331°, 10.3443°, 10.7143°, 12.9022°, 13.4027°, 15.4944°, 16.1068°, 18.0816°, 18.8121°, 23.3219°, 26.9651°, 28.5725°.

[0187] In some embodiments of the present invention, the above-mentioned Form I, its XRPD pattern is substantially as Figure 13 shown.

[0188] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned Form I are shown in Table 9:

[0189] Table 9 XRPD Pattern Analysis Data of Compound Form I of Formula (II)

[0190]

[0191] The present invention also provides a compound of formula (III),

[0192]

[0193] wherein, i is selected from 0 to 2, for example, it can be 0, 1 / 2, 2 / 3, 1, 1.5, 2.

[0194] The present invention provides Form J of the compound of formula (III), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 6.763±0.200°, 13.619±0.200°, 18.128±0.200°.

[0195] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned Form J has characteristic diffraction peaks at the following 2θ angles: 6.763±0.200°, 13.619±0.200°, 15.848±0.200°, 18.128±0.200°, 24.643±0.200°.

[0196] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned Form J has characteristic diffraction peaks at the following 2θ angles: 6.763±0.200°, 13.619±0.200°, 15.848±0.200°, 18.128±0.200°, 19.438±0.200°, 21.422±0.200°, 22.621±0.200°, 24.643±0.200°.

[0197] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned J crystal form has characteristic diffraction peaks at the following 2θ angles: 6.763°, 9.065°, 9.535°, 11.902°, 12.066°, 12.874°, 13.619°, 14.169°, 14.918°, 15.848°, 16.105°, 16.573°, 17.620°, 18.128°, 18.510°, 18.826°, 19.107°, 19.438°, 20.538°, 21.191°, 21.422°, 21.794°, 22.416°, 22.621°, 22.806°, 23.376°, 23.609°, 24.643°, 25.149°, 25.650°, 27.329°, 28.990°, 29.368°, 29.916°, 30.162°, 31.416°, 33.040°, 33.684°, 35.327°, 37.570°.

[0198] In some embodiments of the present invention, the above-mentioned J crystal form, its XRPD pattern is substantially as Figure 14 shown.

[0199] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned J crystal form are shown in Table 10:

[0200] Table 10 XRPD Pattern Analysis Data of Compound J Crystal Form of Formula (III)

[0201]

[0202]

[0203] The present invention also provides a compound of formula (IV),

[0204]

[0205] wherein, m is selected from 0 to 2, for example, it can be 0, 1 / 2, 2 / 3, 1, 1.5, 2.

[0206] In some embodiments of the present invention, the compound of formula (IV) has the following structure,

[0207]

[0208] The present invention provides a K crystal form of a compound of formula (IV-1), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 16.860 ± 0.200°, 18.189 ± 0.200°, 20.709 ± 0.200°.

[0209] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned K crystal form has characteristic diffraction peaks at the following 2θ angles: 9.972±0.200°, 16.860±0.200°, 18.189±0.200°, 20.709±0.200°, 23.950±0.200°.

[0210] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned K crystal form has characteristic diffraction peaks at the following 2θ angles: 4.581±0.200°, 9.972±0.200°, 10.392±0.200°, 16.860±0.200°, 18.189±0.200°, 20.709±0.200°, 23.950±0.200°, 26.841±0.200°.

[0211] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned K crystal form has characteristic diffraction peaks at the following 2θ angles: 4.581°, 6.439°, 9.972°, 10.232°, 10.392°, 13.328°, 14.053°, 14.696°, 16.860°, 18.189°, 20.709°, 22.766°, 23.950°, 25.785°, 26.841°.

[0212] In some embodiments of the present invention, the above-mentioned K crystal form, its XRPD pattern is substantially as Figure 15 shown.

[0213] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned K crystal form is shown in Table 11:

[0214] Table 11 XRPD pattern analysis data of the K crystal form of the compound of formula (IV-1)

[0215]

[0216]

[0217] The present invention provides the L crystal form of the compound of formula (IV), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 18.726±0.200°, 21.044±0.200°, 24.648±0.200°.

[0218] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned L crystal form has characteristic diffraction peaks at the following 2θ angles: 6.494±0.200°, 18.726±0.200°, 19.547±0.200°, 21.044±0.200°, 24.648±0.200°.

[0219] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned L crystal form has characteristic diffraction peaks at the following 2θ angles: 6.494 ± 0.200°, 15.366 ± 0.200°, 17.885 ± 0.200°, 18.726 ± 0.200°, 19.547 ± 0.200°, 21.044 ± 0.200°, 24.648 ± 0.200°, 27.453 ± 0.200°.

[0220] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned L crystal form has characteristic diffraction peaks at the following 2θ angles: 5.797°, 6.494°, 7.655°, 10.474°, 13.036°, 13.388°, 15.366°, 16.235°, 17.885°, 18.726°, 19.547°, 21.044°, 24.368°, 24.648°, 27.453°.

[0221] In some embodiments of the present invention, the above-mentioned L crystal form, its XRPD pattern is substantially as Figure 16 shown.

[0222] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned L crystal form is shown in Table 12:

[0223] Table 12 XRPD Pattern Analysis Data of Compound L Crystal Form of Formula (IV)

[0224]

[0225]

[0226] The present invention also provides a compound of formula (V),

[0227]

[0228] wherein, o is selected from 0 to 2, for example, it can be 0, 1 / 2, 2 / 3, 1, 1.5, 2.

[0229] The present invention provides an M crystal form of the compound of formula (V), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 5.682 ± 0.200°, 11.389 ± 0.200°, 17.202 ± 0.200°.

[0230] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned M crystal form has characteristic diffraction peaks at the following 2θ angles: 5.682 ± 0.200°, 11.389 ± 0.200°, 16.009 ± 0.200°, 17.202 ± 0.200°, 29.418 ± 0.200°.

[0231] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned M crystal form has characteristic diffraction peaks at the following 2θ angles: 5.682 ± 0.200°, 11.389 ± 0.200°, 16.009 ± 0.200°, 17.202 ± 0.200°, 17.854 ± 0.200°, 24.147 ± 0.200°, 25.302 ± 0.200°, 29.418 ± 0.200°.

[0232] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned M crystal form has characteristic diffraction peaks at the following 2θ angles: 5.682°, 10.619°, 11.389°, 12.280°, 12.637°, 14.434°, 15.764°, 16.009°, 17.202°, 17.854°, 18.783°, 19.352°, 20.673°, 21.044°, 21.729°, 22.632°, 23.341°, 24.147°, 25.302°, 26.982°, 28.950°, 29.418°, 30.123°, 33.086°.

[0233] In some embodiments of the present invention, the above-mentioned M crystal form, its XRPD pattern is substantially as Figure 17 shown.

[0234] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned M crystal form is shown in Table 13:

[0235] Table 13 XRPD Pattern Analysis Data of Compound M Crystal Form of Formula (V)

[0236]

[0237] The present invention also provides a compound of formula (VI),

[0238]

[0239] The present invention provides an N crystal form of a compound of formula (VI), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 11.439 ± 0.200°, 18.363 ± 0.200°, 28.859 ± 0.200°.

[0240] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned N crystal form has characteristic diffraction peaks at the following 2θ angles: 11.439 ± 0.200°, 18.363 ± 0.200°, 20.062 ± 0.200°, 22.657 ± 0.200°, 28.859 ± 0.200°.

[0241] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above N crystal form has characteristic diffraction peaks at the following 2θ angles: 8.581±0.200°, 11.439±0.200°, 18.363±0.200°, 20.062±0.200°, 22.657±0.200°, 23.664±0.200°, 25.356±0.200°, 28.859±0.200°.

[0242] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above N crystal form has characteristic diffraction peaks at the following 2θ angles: 5.697°, 8.581°, 8.801°, 11.439°, 12.051°, 12.568°, 13.226°, 14.357°, 14.846°, 15.655°, 16.120°, 17.223°, 17.880°, 18.363°, 18.914°, 19.236°, 20.062°, 20.397°, 21.454°, 22.657°, 22.991°, 23.664°, 24.391°, 24.844°, 25.356°, 26.003°, 26.573°, 26.956°, 27.309°, 28.283°, 28.859°, 29.089°, 29.935°, 31.553°, 31.847°, 32.174°, 32.715°, 34.782°, 38.569°.

[0243] In some embodiments of the present invention, the above N crystal form, its XRPD pattern is substantially as Figure 18 shown.

[0244] In some embodiments of the present invention, the XRPD pattern analysis data of the above N crystal form are shown in Table 14:

[0245] Table 14 XRPD pattern analysis data of the N crystal form of the compound of formula (VI)

[0246]

[0247]

[0248]

[0249] The present invention also provides a compound of formula (VII),

[0250]

[0251] wherein p is selected from 0 to 3, and for example can be 0, 1 / 2, 2 / 3, 1, 1.5, 2, 2.5, 2.7, 3.

[0252] The present invention provides an O crystal form of a compound of formula (VII), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 9.485 ± 0.200°, 11.273 ± 0.200°, 17.536 ± 0.200°.

[0253] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above O crystal form has characteristic diffraction peaks at the following 2θ angles: 9.485 ± 0.200°, 11.273 ± 0.200°, 12.495 ± 0.200°, 17.536 ± 0.200°, 18.874 ± 0.200°.

[0254] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above O crystal form has characteristic diffraction peaks at the following 2θ angles: 9.485 ± 0.200°, 11.273 ± 0.200°, 12.495 ± 0.200°, 15.005 ± 0.200°, 17.536 ± 0.200°, 18.874 ± 0.200°, 19.568 ± 0.200°, 20.291 ± 0.200°.

[0255] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above O crystal form has characteristic diffraction peaks at the following 2θ angles: 4.859°, 7.487°, 9.485°, 10.000°, 11.273°, 12.495°, 12.842°, 14.649°, 15.005°, 16.766°, 17.536°, 18.874°, 19.568°, 20.082°, 20.291°, 21.189°, 22.679°, 23.508°, 25.140°, 25.788°, 28.081°, 29.067°, 29.739°, 31.639°, 35.581°.

[0256] In some embodiments of the present invention, the above O crystal form, its XRPD pattern is substantially as Figure 19 shown.

[0257] In some embodiments of the present invention, the XRPD pattern analysis data of the above O crystal form is shown in Table 15:

[0258] Table 15 XRPD Pattern Analysis Data of O Crystal Form of Compound of Formula (VII)

[0259]

[0260]

[0261] The present invention provides the P crystal form of the compound of formula (VII), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 12.481 ± 0.200°, 14.965 ± 0.200°, 17.480 ± 0.200°.

[0262] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned P crystal form has characteristic diffraction peaks at the following 2θ angles: 9.998 ± 0.200°, 12.481 ± 0.200°, 14.965 ± 0.200°, 17.480 ± 0.200°, 19.969 ± 0.200°.

[0263] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned P crystal form has characteristic diffraction peaks at the following 2θ angles: 5.007°, 7.512°, 9.604°, 9.998°, 12.481°, 14.965°, 17.480°, 18.908°, 19.969°, 20.933°, 25.629°, 27.587°, 35.375°.

[0264] In some embodiments of the present invention, the above-mentioned P crystal form, its XRPD pattern is substantially as Figure 20 shown.

[0265] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned P crystal form is shown in Table 16:

[0266] Table 16 XRPD Pattern Analysis Data of the P Crystal Form of the Compound of Formula (VII)

[0267]

[0268] The present invention also provides a compound of formula (VIII),

[0269]

[0270] The present invention provides the Q crystal form of the compound of formula (VIII), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 6.123 ± 0.200°, 9.130 ± 0.200°, 12.123 ± 0.200°.

[0271] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned Q crystal form has characteristic diffraction peaks at the following 2θ angles: 6.123 ± 0.200°, 9.130 ± 0.200°, 12.123 ± 0.200°, 20.095 ± 0.200°, 22.942 ± 0.200°.

[0272] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned Q crystal form has characteristic diffraction peaks at the following 2θ angles: 6.123 ± 0.200°, 9.130 ± 0.200°, 12.123 ± 0.200°, 15.071 ± 0.200°, 18.151 ± 0.200°, 20.095 ± 0.200°, 22.045 ± 0.200°, 22.942 ± 0.200°.

[0273] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned Q crystal form has characteristic diffraction peaks at the following 2θ angles: 6.123°, 7.677°, 9.130°, 10.013°, 11.598°, 12.123°, 14.770°, 15.071°, 15.986°, 16.493°, 16.692°, 17.365°, 18.151°, 18.915°, 20.095°, 20.569°, 21.147°, 22.045°, 22.942°, 24.106°, 24.617°, 26.108°, 27.014°, 27.822°, 28.433°, 29.464°, 30.256°, 30.863°, 31.820°, 33.446°, 34.822°, 36.389°, 37.646°, 37.803°.

[0274] In some embodiments of the present invention, the above-mentioned Q crystal form, its XRPD pattern is substantially as Figure 21 shown.

[0275] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned Q crystal form is shown in Table 17:

[0276] Table 17 XRPD Pattern Analysis Data of Compound Q Crystal Form of Formula (VIII)

[0277]

[0278]

[0279] The present invention also provides a compound of formula (I),

[0280]

[0281] wherein, s is selected from 0 to 3, for example, it can be 0, 1 / 2, 2 / 3, 1, 1.5, 2, 2.5, 2.7, 3.

[0282] In some embodiments of the present invention, the s is selected from 0, 1, 2, and 3.

[0283] In some embodiments of the present invention, the compound of formula (I) has the following structure,

[0284]

[0285] The present invention provides the R crystal form of the compound of formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 7.933 ± 0.200°, 15.900 ± 0.200°, 23.970 ± 0.200°.

[0286] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned R crystal form has characteristic diffraction peaks at the following 2θ angles: 7.933 ± 0.200°, 11.906 ± 0.200°, 15.900 ± 0.200°, 19.923 ± 0.200°, 23.970 ± 0.200°.

[0287] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned R crystal form has characteristic diffraction peaks at the following 2θ angles: 3.935 ± 0.200°, 7.933 ± 0.200°, 11.906 ± 0.200°, 15.900 ± 0.200°, 19.923 ± 0.200°, 23.970 ± 0.200°.

[0288] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned R crystal form has characteristic diffraction peaks at the following 2θ angles: 3.935°, 7.933°, 11.906°, 15.900°, 17.731°, 19.923°, 21.294°, 23.503°, 23.970°, 25.040°, 26.811°, 28.041°, 28.913°, 31.180°, 32.172°, 34.091°, 38.072°.

[0289] In some embodiments of the present invention, the above-mentioned R crystal form, its XRPD pattern is substantially as Figure 22 shown.

[0290] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned R crystal form is shown in Table 18:

[0291] Table 18 XRPD Pattern Analysis Data of the R Crystal Form of the Compound of Formula (I)

[0292]

[0293] The present invention provides the S crystal form of the compound of formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 20.032 ± 0.200°, 21.239 ± 0.200°, 23.474 ± 0.200°.

[0294] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above S crystal form has characteristic diffraction peaks at the following 2θ angles: 15.569±0.200°, 17.781±0.200°, 20.032±0.200°, 21.239±0.200°, 23.474±0.200°.

[0295] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above S crystal form has characteristic diffraction peaks at the following 2θ angles: 14.527±0.200°, 15.569±0.200°, 17.781±0.200°, 20.032±0.200°, 21.239±0.200°, 23.474±0.200°, 24.275±0.200°, 26.863±0.200°.

[0296] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above S crystal form has characteristic diffraction peaks at the following 2θ angles: 3.871°, 7.901°, 9.387°, 9.859°, 11.461°, 14.527°, 15.569°, 15.906°, 16.743°, 17.781°, 18.461°, 20.032°, 20.378°, 21.239°, 23.474°, 24.275°, 25.367°, 26.863°, 27.063°, 28.954°, 31.135°, 34.181°.

[0297] In some embodiments of the present invention, the above S crystal form, its XRPD pattern is substantially as Figure 23 shown.

[0298] In some embodiments of the present invention, the XRPD pattern analysis data of the above S crystal form is shown in Table 19:

[0299] Table 19 XRPD pattern analysis data of the S crystal form of the compound of formula (I)

[0300]

[0301]

[0302] The present invention provides the T crystal form of the compound of formula (I-1), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 6.347±0.200°, 11.735±0.200°, 18.221±0.200°.

[0303] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above T crystal form has characteristic diffraction peaks at the following 2θ angles: 6.347 ± 0.200°, 11.012 ± 0.200°, 11.735 ± 0.200°, 18.221 ± 0.200°, 20.525 ± 0.200°.

[0304] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above T crystal form has characteristic diffraction peaks at the following 2θ angles: 6.347 ± 0.200°, 11.012 ± 0.200°, 11.735 ± 0.200°, 15.525 ± 0.200°, 17.028 ± 0.200°, 18.221 ± 0.200°, 20.525 ± 0.200°, 25.872 ± 0.200°.

[0305] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above T crystal form has characteristic diffraction peaks at the following 2θ angles: 6.347°, 9.315°, 10.351°, 11.012°, 11.735°, 12.780°, 14.017°, 15.525°, 16.475°, 17.028°, 18.221°, 19.285°, 20.213°, 20.525°, 22.738°, 23.383°, 23.924°, 25.039°, 25.872°, 26.855°, 31.419°.

[0306] In some embodiments of the present invention, the above T crystal form, its XRPD pattern is substantially as Figure 24 shown.

[0307] In some embodiments of the present invention, the XRPD pattern analysis data of the above T crystal form is shown in Table 20:

[0308] Table 20 XRPD Pattern Analysis Data of the T Crystal Form of the Compound of Formula (I-1)

[0309]

[0310]

[0311] The present invention provides the U crystal form of the compound of formula (I-1), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 4.486 ± 0.200°, 9.021 ± 0.200°, 27.215 ± 0.200°.

[0312] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above U crystal form has characteristic diffraction peaks at the following 2θ angles: 4.486 ± 0.200°, 9.021 ± 0.200°, 14.894 ± 0.200°, 23.876 ± 0.200°, 27.215 ± 0.200°.

[0313] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above U crystal form has characteristic diffraction peaks at the following 2θ angles: 4.486 ± 0.200°, 9.021 ± 0.200°, 14.894 ± 0.200°, 18.620 ± 0.200°, 19.150 ± 0.200°, 22.042 ± 0.200°, 23.876 ± 0.200°, 27.215 ± 0.200°.

[0314] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above U crystal form has characteristic diffraction peaks at the following 2θ angles: 4.486°, 9.021°, 10.970°, 13.600°, 14.894°, 15.853°, 18.076°, 18.620°, 19.150°, 22.042°, 23.876°, 26.295°, 27.215°, 28.304°, 30.674°, 31.304°.

[0315] In some embodiments of the present invention, the above U crystal form, its XRPD pattern is substantially as Figure 25 shown.

[0316] In some embodiments of the present invention, the XRPD pattern analysis data of the above U crystal form is shown in Table 21:

[0317] Table 21 XRPD pattern analysis data of the U crystal form of the compound of formula (I-1)

[0318]

[0319]

[0320] The present invention provides a V crystal form of the compound of formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 3.729 ± 0.200°, 11.208 ± 0.200°, 23.480 ± 0.200°.

[0321] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above V crystal form has characteristic diffraction peaks at the following 2θ angles: 3.729 ± 0.200°, 11.208 ± 0.200°, 15.943 ± 0.200°, 21.259 ± 0.200°, 23.480 ± 0.200°.

[0322] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned Form V has characteristic diffraction peaks at the following 2θ angles: 3.729 ± 0.200°, 11.208 ± 0.200°, 15.943 ± 0.200°, 18.814 ± 0.200°, 19.613 ± 0.200°, 20.013 ± 0.200°, 21.259 ± 0.200°, 23.480 ± 0.200°.

[0323] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned Form V has characteristic diffraction peaks at the following 2θ angles: 3.729°, 7.556°, 7.930°, 11.208°, 14.132°, 14.587°, 15.943°, 17.855°, 18.814°, 19.613°, 20.013°, 21.259°, 21.476°, 21.966°, 23.271°, 23.480°, 24.340°, 25.142°, 25.409°, 26.267°, 26.849°, 27.469°.

[0324] In some embodiments of the present invention, the above-mentioned Form V, its XRPD pattern is substantially as Figure 26 shown.

[0325] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned Form V is shown in Table 22:

[0326] Table 22 XRPD Pattern Analysis Data of Form V of the Compound of Formula (I)

[0327]

[0328]

[0329] The present invention also provides the use of the above compound or Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form L, Form M, Form N, Form O, Form P, Form Q, Form R, Form S, Form T, Form U, Form V in the preparation of drugs for treating diabetes, weight loss and NASH.

[0330] Definitions and Explanations

[0331] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular phrase or term should not be considered indeterminate or unclear without a special definition, but should be understood in its ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding product or its active ingredient.

[0332] The intermediate compounds of the present invention can be prepared by various synthetic methods well-known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by their combination with other chemical synthesis methods, and the equivalent replacement methods well-known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present invention.

[0333] The chemical reactions of the specific embodiments of the present invention are completed in a suitable solvent, and the solvent must be suitable for the chemical changes of the present invention and the reagents and materials required therefor. In order to obtain the compounds of the present invention, sometimes those skilled in the art need to modify or select the synthesis steps or reaction processes on the basis of the existing embodiments.

[0334] The structures of the compounds of the present invention can be confirmed by conventional methods well-known to those skilled in the art. If the present invention relates to the absolute configuration of a compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction method (SXRD), the diffraction intensity data of the cultivated single crystal is collected with a Bruker D8 venture diffractometer, the light source is CuKα radiation, and the scanning mode: Scanning, after collecting the relevant data, the crystal structure is further analyzed by the direct method (Shelxs97), and the absolute configuration can be confirmed.

[0335] The present invention will be specifically described below by way of examples, and these examples do not mean any limitation to the present invention.

[0336] All solvents used in the present invention are commercially available and can be used without further purification.

[0337] The solvents used in the present invention are commercially available.

[0338] The present invention uses the following abbreviations: aq represents water; eq represents equivalent; DCM represents dichloromethane; PE represents petroleum ether; DMF represents N,N-dimethylformamide; DMSO represents dimethyl sulfoxide; MEK represents methyl ethyl ketone; EtOH represents ethanol; MeOH represents methanol; IPA represents isopropanol; MTBE represents methyl tert-butyl ether; THF represents tetrahydrofuran; Pd(dppf)Cl2 represents dichlorobis(1,1'-bis(diphenylphosphino)ferrocene)palladium(II); Pd(OH)2 represents palladium hydroxide; LiAlH4 represents lithium aluminum hydride; Tris represents tris(hydroxymethyl)aminomethane.

[0339] Compounds are named according to the conventional naming principles in the art or using software, and commercially available compounds use the supplier catalog names.

[0340] Technical effects

[0341] The compounds of the present invention have stable crystal forms, are less affected by heat and humidity, and have good in vivo administration efficacy, showing broad prospects for drug development; the compounds of formula (I) exhibit excellent agonistic ability towards the GLP-1 receptor.

[0342] The X-ray powder diffraction (XRPD) method of the present invention

[0343] 1. Instrument model: X'Pert3 X-ray diffractometer from PANalytical

[0344] Testing method: Approximately 20 mg of the sample is used for XRPD detection.

[0345] The detailed parameters are as follows:

[0346]

[0347]

[0348] 2. The X-ray diffraction pattern is obtained by collecting with a D2 Phaser type of Bruker instrument, and the instrument parameters are as follows.

[0349]

[0350] The differential scanning calorimetry (DSC) method of the present invention

[0351] Instrument model: TA 2500 differential scanning calorimeter

[0352] The parameters and testing methods are as follows:

[0353] Parameter Set Value Method Linear Temperature Rise Sample Pan Aluminum Pan, With / Without Capping Temperature Range 25 to Set End Temperature Scanning Rate (°C / minute) 10 Protective Gas Nitrogen

[0354] The thermogravimetric analysis (TGA) method of the present invention

[0355] Instrument model: TA 5500 thermogravimetric analyzer

[0356] The parameters and testing methods are as follows:

[0357]

[0358]

[0359] The dynamic vapor sorption (DVS) method of the present invention

[0360] Dynamic vapor sorption (DVS) curves were collected on a DVS Intrinsic plus from Surface Measurement Systems (SMS). The relative humidity at 25 °C was calibrated using the deliquescence points of lithium chloride (LiCl), magnesium nitrate [Mg(NO3)2], and potassium chloride (KCl).

[0361] The test parameters are as follows:

[0362]

[0363] The classification of hygroscopicity evaluation is as follows:

[0364] Hygroscopic Classification ΔW% Deliquescence Absorb Sufficient Moisture to Form Liquid Highly Hygroscopic ΔW%≥15% Hygroscopic 15%>ΔW%≥2% Slightly Hygroscopic 2%>ΔW%≥0.2% No or Almost No Hygroscopicity ΔW% < 0.2%

[0365] Note: ΔW% represents the weight gain of the test article under 25 ± 1 °C and 80 ± 2% RH. Description of the Drawings

[0366] Figure 1 XRPD pattern of crystalline form of Compound A of formula (II-1) with Cu-Kα radiation;

[0367] Figure 2 DSC pattern of crystalline form of Compound A of formula (II-1);

[0368] Figure 3 TGA pattern of crystalline form of Compound A of formula (II-1);

[0369] Figure 4 XRPD pattern of crystalline form of Compound B of formula (II) with Cu-Kα radiation;

[0370] Figure 5 XRPD pattern of crystalline form of Compound C of formula (II) with Cu-Kα radiation;

[0371] Figure 6 XRPD pattern of crystalline form of Compound D of formula (II) with Cu-Kα radiation;

[0372] Figure 7 XRPD pattern of crystalline form of Compound E of formula (II) with Cu-Kα radiation;

[0373] Figure 8 DSC pattern of crystalline form of Compound E of formula (II);

[0374] Figure 9 TGA pattern of crystalline form of Compound E of formula (II);

[0375] Figure 10 XRPD pattern of crystalline form of Compound F of formula (II) with Cu-Kα radiation;

[0376] Figure 11 XRPD pattern of the G crystal form of the compound of formula (II) with Cu-Kα radiation;

[0377] Figure 12 XRPD pattern of the H crystal form of the compound of formula (II) with Cu-Kα radiation;

[0378] Figure 13 XRPD pattern of the I crystal form of the compound of formula (II) with Cu-Kα radiation;

[0379] Figure 14 XRPD pattern of the J crystal form of the compound of formula (III) with Cu-Kα radiation;

[0380] Figure 15 XRPD pattern of the K crystal form of the compound of formula (IV-1) with Cu-Kα radiation;

[0381] Figure 16 XRPD pattern of the L crystal form of the compound of formula (IV) with Cu-Kα radiation;

[0382] Figure 17 XRPD pattern of the M crystal form of the compound of formula (V) with Cu-Kα radiation;

[0383] Figure 18 XRPD pattern of the N crystal form of the compound of formula (VI) with Cu-Kα radiation;

[0384] Figure 19 XRPD pattern of the O crystal form of the compound of formula (VII) with Cu-Kα radiation;

[0385] Figure 20 XRPD pattern of the P crystal form of the compound of formula (VII) with Cu-Kα radiation;

[0386] Figure 21 XRPD pattern of the Q crystal form of the compound of formula (VII) with Cu-Kα radiation;

[0387] Figure 22 XRPD pattern of the R crystal form of the compound of formula (I) with Cu-Kα radiation;

[0388] Figure 23 XRPD pattern of the S crystal form of the compound of formula (I) with Cu-Kα radiation;

[0389] Figure 24 XRPD pattern of the T crystal form of the compound of formula (I-1) with Cu-Kα radiation;

[0390] Figure 25 XRPD pattern of the U crystal form of the compound of formula (I-1) with Cu-Kα radiation;

[0391] Figure 26 XRPD pattern of the U crystal form of the compound of formula (I) for Cu-Kα radiation;

[0392] Figure 27 DVS spectrum of the A crystal form of the compound of formula (II-1);

[0393] Figure 28 DVS spectrum of the E crystal form of the compound of formula (II);

[0394] Figure 29 DVS spectrum of the Q crystal form of the compound of formula (VIII). Detailed implementation manners

[0395] For a better understanding of the content of the present invention, the following is further described in conjunction with specific embodiments, but the specific implementation manners do not limit the content of the present invention.

[0396] Example 1: Synthesis of the compound of formula (I)

[0397]

[0398] Step 1: Synthesis of compound B-1-3

[0399] Add B-1-1 (1.00 g, 6.23 mmol, 1 eq) to a reaction flask containing THF (40 mL). Under nitrogen protection, add NaH (375 mg, 9.38 mmol, 60% content, 1.51 eq) at 0 °C, warm up to 22 °C and stir for 1 hour, then add B-1-2 (1.5 g, 6.33 mmol, 1.02 eq) and warm up to 60 °C and stir for 16 hours. Add 20 mL of water to quench the reaction mixture, extract with DCM (20 mL * 3), collect the organic phase, dry over anhydrous sodium sulfate, and concentrate to obtain the crude product. The crude product is separated and purified by column chromatography (petroleum ether:ethyl acetate = 1:0) to obtain B-1-3. LCMS: m / z = 317.8 [M+H] + .

[0400] Step 2: Synthesis of compound B-1-5

[0401] B-1-3 (1.50 g, 4.74 mmol, 1 eq), B-1-4 (1.50 g, 4.85 mmol, 1.02 eq), sodium carbonate (1.50 g, 14.15 mmol, 2.99 eq), dioxane (30 mL), and water (6 mL) were added to a reaction flask. Under a nitrogen atmosphere, Pd(dppf)Cl2 (0.17 g, 232.33 μmol, 0.05 eq) was added, and the reaction system was stirred at 100 °C for 3 hours. The reaction solution was concentrated to obtain a crude product, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 1:0 - 20:1) to obtain B-1-5. LCMS: m / z = 419.2 [M+H] + 。

[0402] Step 3: Synthesis of Compound B-1

[0403] B-1-5 (1.80 g, 4.30 mmol, 1 eq) and anhydrous DCM (30 mL) were added to a reaction flask. Trifluoroacetic acid (7.70 g, 67.53 mmol, 5.0 mL, 15.72 eq) was added, and the reaction system was stirred at 20 °C for 12 hours. Sodium carbonate solution (30 mL) was added to the reaction solution, and sodium carbonate solid was added to adjust the pH of the solution to about 9 - 10. The mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was separated and purified by column chromatography (DCM:MeOH = 1:0 - 10:1) to obtain B-1. LCMS: m / z = 319.1 [M+H] + 。

[0404]

[0405] Step 4: Synthesis of Compound B-2-2

[0406] Compound B-2-1 (12 g, 67.33 mmol, 1 eq) was dissolved in THF (120 mL), the argon was displaced, Pd(OH)2 (6.00 g, 4.27 mmol, 10% content, 6.35e-2 eq) was added, hydrogen was introduced, and the pressure was 50 psi. The mixture was stirred at 45 °C for 24 hours. The reaction solution was filtered through diatomaceous earth and rinsed with anhydrous THF. The THF solution of B-2-2 was obtained and directly used for the next step without further treatment. 11H NMR (400 MHz, CDCl3) δ ppm 7.10 - 7.16 (m, 2H), 7.03 - 7.07 (m, 2H), 4.75 - 4.83 (m, 1H), 4.52 - 4.61 (m, 1H), 4.39 - 4.46 (m, 1H).

[0407] Step 5: Synthesis of Compound B-2

[0408] Add Compound B-2-2 (2 g, 22.70 mmol, 1 eq), TEA (13.78 g, 136.20 mmol, 18.96 mL, 6 eq) to the reaction flask. After evacuation and replacement with nitrogen, add methanesulfonic anhydride (11.86 g, 68.10 mmol, 2.64 mL, 3 eq) portionwise at 0 °C. Then warm the reaction mixture to 25 °C and react for 24 h. Pour the reaction solution into water (125 mL) to quench the reaction. Separate the organic phase, extract the aqueous phase with ethyl acetate (50 mL), combine the organic phases, wash with saturated brine (100 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure using a water pump at 45 °C to obtain the crude product. Purify by column chromatography (PE:EA = 1:0 to 1:1, gradient elution). Obtain B-2. 1 1H NMR (400 MHz, CDCl3) δ ppm 4.99 - 5.05 (m, 1H), 4.64 - 4.71 (m, 1H), 4.57 (dt, J = 9.10, 6.08 Hz, 1H), 4.36 (d, J = 3.88 Hz, 2H), 3.10 (s, 3H), 2.70 - 2.81 (m, 1H), 2.58 - 2.68 (m, 1H).

[0409]

[0410]

[0411] Step 6: Synthesis of Compound 1-2

[0412] Compound 1-1 (23 g, 164.12 mmol, 1 eq) and DMF (115 mL) were added to a reaction flask. The nitrogen was displaced, and the temperature was lowered to 0 °C. Then, NaH (9.85 g, 246.18 mmol, 60% content, 1.5 eq) was added. The nitrogen was displaced again, and 2-(trimethylsilyl)ethoxymethyl chloride (41.04 g, 246.18 mmol, 43.57 mL, 1.5 eq) was added dropwise. After the addition was complete, the temperature was raised to 25 °C and the reaction was carried out for 12 hours. The reaction mixture was quenched with ice water (500 mL), extracted with ethyl acetate (200 mL × 3), and the organic phases were combined, washed with saturated brine (200 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 45 °C using a water pump to obtain the crude product. The crude product was separated and purified by column chromatography (PE:EA = 1:0 to 1:1, gradient elution) to obtain 1-2. 1 H NMR (400 MHz, CDCl3) δ ppm 7.24 (d, J = 0.63 Hz, 1H), 7.17 (s, 1H), 5.76 (s, 2H), 4.39 (q, J = 7.13 Hz, 2H), 3.49 - 3.56 (m, 2H), 1.40 (t, J = 7.13 Hz, 3H), 0.86 - 0.93 (m, 2H), -0.07 - -0.04 (m, 9H).

[0413] Step 7: Synthesis of Compound 1-3

[0414] THF (1000 mL) was added to a reaction flask, and LiAlH4 (6.04 g, 159.21 mmol, 1.5 eq) was added in batches. The nitrogen was displaced, and the temperature was lowered to 0 °C. After stirring for 15 minutes, Compound 1-2 (28.7 g, 106.14 mmol, 1 eq) was added at 0 °C, and then the temperature was raised to 25 °C and the reaction was carried out for 0.5 hour. The reaction mixture was cooled to 0 °C, and then 6 mL of water, 6 mL of 15% sodium hydroxide, and 18 mL of water were added in sequence. The temperature was raised to 25 °C and stirred for 15 minutes, then anhydrous magnesium sulfate was added and stirred for 15 minutes, and then filtered. The filtrate was collected, washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 45 °C using a water pump to obtain Compound 1-3. 1 H NMR (400 MHz, CDCl3) δ ppm 6.98 (d, J = 1.13 Hz, 1H), 6.93 (d, J = 1.13 Hz, 1H), 5.37 (s, 2H), 4.72 (s, 2H), 3.52 (dd, J = 8.76, 7.75 Hz, 2H), 0.89 - 0.95 (m, 2H), -0.02 - -0.01 (m, 9H).

[0415] Step 8: Synthesis of Compound 1-4

[0416] Compound 1-3 (18.81 g, 82.37 mmol, 1 eq), tert-butyldiphenylchlorosilane (27.17 g, 98.84 mmol, 25.39 mL, 1.2 eq), imidazole (14.02 g, 205.92 mmol, 2.5 eq), and DMF (188 mL) were added to a reaction flask. The nitrogen was displaced, and the reaction was carried out at 25 °C for 16 h. The reaction solution was poured into water (1000 mL) for quenching, extracted with ethyl acetate (200 mL × 3), the organic phases were combined, washed with saturated brine (200 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 45 °C with a water pump to obtain the crude product. The crude product was separated and purified by column chromatography (PE:EA = 1:0 to 1:1, gradient elution) to obtain 1-4. 1 H NMR (400 MHz, CDCl3) δ ppm 7.66 - 7.72 (m, 4H), 7.37 - 7.46 (m, 6H), 6.96 - 7.02 (m, 2H), 5.41 (s, 2H), 4.84 (s, 2H), 3.41 - 3.48 (m, 2H), 1.06 (s, 9H), 0.85 - 0.91 (m, 2H), -0.03 (s, 9H).

[0417] Step 9: Synthesis of Compound 1-5

[0418] Compound 1-4 (22 g, 47.13 mmol, 1 eq) and THF (440 mL) were added to a reaction flask. After purging and replacing with nitrogen, N-bromosuccinimide (25.17 g, 141.40 mmol, 44.18 μL, 3 eq) was added portionwise at 0 °C, and then the temperature was raised to 25 °C and the reaction was carried out for 12 h. The reaction solution was quenched with water (440 mL), extracted with ethyl acetate (2200 mL × 2), the organic phases were combined, washed with saturated brine (2200 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 30 °C with a water pump to obtain the crude product. The crude product was separated and purified by column chromatography (PE:EA = 1:1 to 2:1, gradient elution) to obtain 1-5. 1 H NMR (400 MHz, CDCl3) δ ppm 7.64 - 7.67 (m, 4H), 7.37 - 7.48 (m, 6H), 5.44 (s, 2H), 4.80 (s, 2H), 3.45 - 3.51 (m, 2H), 1.07 (s, 9H), 0.85 - 0.90 (m, 2H), -0.02 (s, 9H).

[0419] Step 10: Synthesis of Compound 1-6

[0420] Compound 1-5 (6 g, 9.61 mmol, 1 eq) and THF (60 mL) were added to a reaction flask. The nitrogen was displaced, and the temperature was lowered to -40 °C. Then, i-PrMgCl-LiCl (1.3 M, 8.13 mL, 1.1 eq) was added dropwise, and the mixture was stirred for 1.5 hours. Then, DMF (61.62 g, 843.09 mmol, 64.86 mL, 87.76 eq) was added dropwise, and the temperature was raised to 25 °C and stirred for another 30 minutes. The reaction mixture was quenched with water (120 mL), extracted with ethyl acetate (50 mL × 2), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 45 °C using a water pump to obtain the crude product. The crude product was separated and purified by column chromatography (PE:EA = 1:0 to 10:1, gradient elution) to obtain 1-6. 1 H NMR (400 MHz, CDCl3) δ ppm 9.76 (s, 1H), 7.64 - 7.68 (m, 5H), 7.38 - 7.42 (m, 5H), 5.85 (s, 2H), 4.86 (s, 2H), 3.49 - 3.54 (m, 2H), 1.07 (s, 9H), 0.84 - 0.88 (m, 2H), -0.03 (s, 9H).

[0421] Step 11: Synthesis of Compound 1-8

[0422] Compound 1-6 (1.23 g, 2.14 mmol, 1 eq) was dissolved in EtOH (61.5 mL), sodium ethoxide (2.19 g, 6.43 mmol, 20% content, 3 eq), 1-7 (273.10 mg, 2.57 mmol, 233.42 μL, 1.2 eq) were added, and the mixture was stirred at 20 °C for 2 hours. Then, the temperature was raised to 80 °C and stirred for 12 hours. The reaction mixture was quenched with water (50 mL), extracted twice with ethyl acetate (25 mL), the organic phases were combined, washed with saturated brine (50 mL), filtered, and the filtrate was concentrated under reduced pressure at 45 °C using a water pump and dried to obtain the crude product. The crude product was separated and purified by column chromatography (PE:EA = 1:0 to 10:1, gradient elution) to obtain Compound 1-8. 1 H NMR (400 MHz, CDCl3) δ ppm 7.72 (s, 1H), 5.54 (s, 2H), 4.91 (s, 2H), 4.39 (q, J = 7.13 Hz, 2H), 3.55 - 3.61 (m, 2H), 2.30 - 2.64 (m, 1H), 1.40 (t, J = 7.13 Hz, 3H), 0.91 - 0.96 (m, 2H), -0.02 (s, 9H).

[0423] Step 12: Synthesis of Compound 1-9

[0424] Compound 1-8 (120 mg, 336.59 μmol, 1 eq), triethylamine (102.18 mg, 1.01 mmol, 140.55 μL, 3 eq) and DCM (2 mL) were added to a reaction flask. After purging with nitrogen, methanesulfonyl chloride (57.84 mg, 504.89 μmol, 39.08 μL, 1.5 eq) was added portionwise at 0 °C, and then the temperature was raised to 25 °C and the reaction was carried out for 12 hours. The reaction solution was directly concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by thin-layer chromatography silica gel plate (DCM:MeOH = 20:1) to obtain compound 1-9. 1 H NMR (400 MHz, CDCl3) δ ppm 7.72 (s, 1H), 5.57 (s, 2H), 4.85 (s, 2H), 4.39 (q, J = 7.13 Hz, 2H), 3.56 - 3.61 (m, 2H), 1.40 (t, J = 7.13 Hz, 3H), 0.92 - 0.97 (m, 2H), -0.02 (s, 9H).

[0425] Step 13: Synthesis of Compound 1-10

[0426] 1-9 (0.16 g, 426.72 μmol, 1 eq), B-1 (0.30 g, 941.11 μmol, 2.21 eq), potassium carbonate (0.10 g, 723.56 μmol, 1.70 eq) and acetonitrile (10 mL) were successively added to a reaction flask. The reaction system was stirred at 60 °C for 10 hours. The reaction solution was concentrated to obtain the crude product, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL * 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 1:0 - 5:1) to obtain 1-10. LCMS: m / z = 657.3 [M + H] + ; 11H NMR (400 MHz, CDCl3) δ ppm 7.74 (s, 1H), 7.55 (t, J = 7.91 Hz, 1H), 7.43 (t, J = 8.03 Hz, 1H), 7.08 - 7.17 (m, 2H), 6.94 (d, J = 7.28 Hz, 1H), 6.72 (br s, 1H), 6.66 (d, J = 8.28 Hz, 1H), 5.66 (s, 2H), 5.43 (s, 2H), 4.38 (q, J = 7.03 Hz, 2H), 3.95 (s, 2H), 3.52 - 3.57 (m, 2H), 3.29 (br s, 2H), 2.79 - 2.85 (m, 2H), 2.61 (br s, 2H), 1.40 (t, J = 7.03 Hz, 3H), 0.89 - 0.94 (m, 2H), -0.10 - -0.03 (m, 9H).

[0427] Step 14: Synthesis of Compound 1-11

[0428] To the reaction flask, add 1-10 (0.30 g, 456.43 μmol, 1 eq), anhydrous DCM (5.0 mL) in sequence, then add trifluoroacetic acid (1.54 g, 13.51 mmol, 1.0 mL, 29.59 eq). The reaction system is stirred at 40 °C for 5 hours. Add sodium carbonate solution (10 mL) to the reaction solution, add solid sodium carbonate to adjust the pH of the solution to about 9 - 10, extract with ethyl acetate (10 mL * 3), combine the organic phases, wash the organic phases with saturated sodium chloride aqueous solution (10 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain the crude product. The crude product is separated and purified by column chromatography (petroleum ether:ethyl acetate = 10:1 - 1:1) to obtain 1-11. LCMS: m / z = 527.2 [M+H] + ; 1 1H NMR (400 MHz, CDCl3) δ ppm 10.08 (br s, 1H), 7.68 (br s, 1H), 7.57 (t, J = 7.78 Hz, 1H), 7.43 (t, J = 8.16 Hz, 1H), 7.09 - 7.17 (m, 2H), 6.96 (d, J = 7.53 Hz, 1H), 6.73 (br s, 1H), 6.69 (d, J = 8.28 Hz, 1H), 5.44 (s, 2H), 4.37 (q, J = 7.11 Hz, 2H), 3.96 (s, 2H), 3.35 (br d, J = 3.01 Hz, 2H), 2.83 - 2.91 (m, 2H), 2.68 (br s, 2H), 1.39 (t, J = 7.15 Hz, 3H).

[0429] Step 15: Synthesis of Compounds 1-12 and 1-13

[0430] 1-11 (0.20 g, 379.50 μmol, 1 eq), B-2 (0.35 g, 2.11 mmol, 5.55 eq), potassium carbonate (0.40 g, 1.23 mmol, 3.23 eq) and acetonitrile (5 mL) were successively added to a reaction flask, and the reaction system was stirred at 80 °C for 10 h. The reaction solution was concentrated to obtain a crude product, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 1:0 - 1:1) to obtain a mixture of 1-12 and 1-13. LCMS (retention time: 3.508): m / z = 597.1 [M+H] + ; LCMS (retention time: 3.566): m / z = 597.3 [M+H] + . Step 16: Synthesis of the compound of formula (I)

[0431] A mixture of 1-12 and 1-13 (90 mg, 150.73 μmol, 1 eq), water (0.4 mL) and acetonitrile (2 mL) were successively added to a reaction flask, and 1,5,7-triazabicyclo[4.4.0]dec-5-ene (50 mg, 359.20 μmol, 2.38 eq) was added. The reaction system was stirred at 20 °C for 10 h. The reaction solution was concentrated to obtain a crude product. The crude product was separated and purified by preparative TLC (DCM:MeOH = 10:1) to obtain a mixture. The mixture was separated by supercritical fluid chromatography (chromatographic column: DAICEL CHIRALPAK IG (250 mm×30 mm, 10 μm); mobile phase: [0.1% NH₃·H₂O MeOH]; CO₂: 55% - 55%, min) to obtain the compound of formula (I) (retention time: 6.815 min).

[0432] Detection method (chromatographic column: Chiralpak IG-3 50 0.6 mm I.D., 3 μm, mobile phase: A: CO₂ B: methanol (0.05% diethylamine), isocratic elution: methanol (0.05% diethylamine) 40%, flow rate: 4 mL / min, column temperature: 35 °C, back pressure: 1500 psi). LCMS: m / z = 569.2 [M+H] + ; 11H NMR (400 MHz, DMSO-d6) δ ppm 7.68 (t, J = 7.91 Hz, 1H), 7.55 (t, J = 8.16 Hz, 1H), 7.40 - 7.50 (m, 2H), 7.30 (dd, J = 8.28, 1.76 Hz, 1H), 7.08 (d, J = 7.53 Hz, 1H), 6.68 - 6.77 (m, 2H), 5.39 (s, 2H), 4.97 - 5.08 (m, 1H), 4.52 - 4.60 (m, 1H), 4.40 - 4.50 (m, 2H), 4.28 - 4.38 (m, 1H), 3.74 - 3.92 (m, 2H), 3.18 (br s, 2H), 2.68 (br d, J = 5.52 Hz, 2H), 2.58 - 2.66 (m, 1H), 2.32 - 2.38 (m, 1H); 1 1H NMR (400 MHz, CD3OD) δ ppm 7.64 (s, 1H), 7.62 (t, J = 7.91 Hz, 1H), 7.48 (t, J = 8.03 Hz, 1H), 7.16 - 7.24 (m, 2H), 7.05 (d, J = 7.53 Hz, 1H), 6.71 (br s, 1H), 6.68 (d, J = 8.03 Hz, 1H), 5.42 (s, 2H), 5.19 (br d, J = 4.27 Hz, 2H), 4.36 - 4.45 (m, 1H), 3.93 - 4.05 (m, 2H), 2.82 - 2.90 (m, 2H), 2.68 - 2.76 (m, 1H), 2.63 (br s, 2H), 2.48 (br d, J = 8.78 Hz, 1H).

[0433] The C8-H and C 10 -H correlations were identified by two-dimensional nuclear magnetic NOE, and the product structure was correct.

[0434]

[0435] Example 2: Preparation of Crystal Forms

[0436] Preparation of Form A:

[0437] To the reaction flask, add tris(hydroxymethyl)aminomethane (1.31 g, 10.8 mmol, 1.02 eq) and 30 mL of methanol in sequence, and place the system in a 50 °C water bath with stirring until it is completely dissolved. Cool to 25 °C, add the compound of formula (I) (6 g, 10.54 mmol, 1 eq), and the system is completely dissolved. Add 90 mL of methyl tert-butyl ether, and stir at 25 °C for 16 hours. Filter, and wash the filter cake three times with 12 mL of a mixed solvent of methanol:methyl tert-butyl ether = 1:3. Transfer the filter cake to a 50 °C vacuum dryer for 16 hours. The crystal form A of the compound of formula (II-1) is obtained. 11H NMR (400 MHz, CD3OD) δ ppm 7.57 - 7.68 (m, 2H) 7.50 (t, J = 7.91 Hz, 1H) 7.16 - 7.28 (m, 2H) 7.06 (d, J = 7.53 Hz, 1H) 6.63 - 6.79 (m, 2H) 5.44 (s, 2H) 5.15 - 5.28 (m, 1H) 4.55 - 4.80 (m, 3H) 4.44 (dt, J = 9.29, 6.02 Hz, 1H) 3.89 - 4.04 (m, 2H) 3.68 (s, 6H) 3.26 (br s, 2H) 2.68 - 2.86 (m, 3H) 2.63 (br s, 2H) 2.43 - 2.55 (m, 1H).

[0438] Preparation of Form B:

[0439] Weigh approximately 15 mg of Form A of Compound (II-1) into an HPLC glass vial, add 0.5 mL of H2O respectively. The obtained turbid solution is placed under magnetic stirring (1000 rpm) at room temperature for about 4 days, then the solid is collected by centrifugation to obtain Form B of Compound (II). After drying the sample in the open air at room temperature overnight, it is converted to Form E.

[0440] Preparation of Form C:

[0441] Weigh approximately 15 mg of Compound (I) and an equimolar ratio of Tris (3 mg) into an HPLC glass vial, add 0.5 mL of EtOH respectively. The obtained turbid solution is placed under magnetic stirring (1000 rpm) at room temperature for about 4 days, then the solid is collected by centrifugation to obtain Form C of Compound (II). After air-drying the sample at room temperature, it is converted to Form E.

[0442] Preparation of Form D:

[0443] Weigh approximately 15 mg of Form A of Compound (II-1) into a 3 mL vial, add 1.0 mL of MeOH / MTBE (1:1, v / v). After stirring and equilibration at 50 °C for about 1 hour, filter to obtain the supernatant. The obtained supernatant is placed in a biochemical incubator and cooled from 50 °C to 5 °C at a rate of 0.1 °C per minute and kept at a constant temperature of 5 °C. The precipitated solid is collected to obtain Form D of Compound (II). After air-drying the sample at room temperature, it is converted to Form E.

[0444] Preparation of Form E:

[0445] Weigh approximately 15 mg of Form A of Compound (II-1) into an HPLC glass vial, add 0.5 mL of IPA respectively. The obtained suspension is magnetically stirred (1000 rpm) under temperature cycling conditions (40 °C to 5 °C, 0.1 °C per minute, 2 cycles), then the solid is collected by centrifugation to obtain Form E of Compound (II).1 1H NMR (400 MHz, CD3OD) δ ppm 7.59 - 7.64 (m, 2H) 7.50 (t, J = 8.03 Hz, 1H) 7.21 (t, J = 10.16 Hz, 2H) 7.06 (d, J = 7.28 Hz, 1H) 6.72 - 6.75 (m, 1H) 6.68 (d, J = 8.29 Hz, 1H) 5.44 (s, 2H) 5.21 (qd, J = 7.03, 3.01 Hz, 1H) 4.55 - 4.73 (m, 3H) 4.44 (dt, J = 9.03, 6.02 Hz, 1H) 3.91 - 4.01 (m, 2H) 3.68 (s, 6H) 3.26 (br s, 2H) 2.70 - 2.84 (m, 3H) 2.63 (br s, 2H) 2.40 - 2.54 (m, 1H)

[0446] Preparation of Form F:

[0447] Weigh about 15 mg of Form A of Compound (II-1) and add it to a 20 mL vial. Completely dissolve the solid with 0.2 - 1.0 mL of MeOH (for samples that are not completely dissolved, filter through a 0.45 μm PTFE filter head to obtain a clear solution). While stirring (1000 rpm), add MTBE dropwise to this clear solution until a solid precipitates to obtain Form F of Compound (II). After drying the sample in the open air at room temperature, it is converted to Form E.

[0448] Preparation of Form G:

[0449] Weigh about 15 mg of Form A of Compound (II-1) into a 3 mL vial. In another 20 mL vial, add about 3 mL of EtOH. After placing the 3 mL vial open in the 20 mL vial, seal the 20 mL vial. After standing at room temperature for 7 days, collect the solid to obtain Form G of Compound (II). After drying the sample in the open air at room temperature, it is converted to Form E.

[0450] Preparation of Form H:

[0451] Weigh about 15 mg of Form A of Compound (II-1) into a 3 mL vial. In another 20 mL vial, add about 3 mL of THF. After placing the 3 mL vial open in the 20 mL vial, seal the 20 mL vial. After standing at room temperature for 7 days, collect the solid to obtain Form H of Compound (II). After drying the sample in the open air at room temperature, it is converted to Form E.

[0452] Preparation of Form I:

[0453] Weigh approximately 15 mg of Compound A in Crystal Form (II-1) into an HPLC glass vial, add 0.5 mL of H2O respectively. After the resulting suspension is magnetically stirred (1000 rpm) under temperature cycling conditions (40 °C to 5 °C, 0.1 °C per minute, 2 cycles), the solid is collected by centrifugation to obtain Compound I in Crystal Form (II). After the sample is dried in the open air at room temperature, it is converted to Crystal Form E.

[0454] Preparation of Crystal Form J:

[0455] Weigh approximately 50 mg of Compound (I) and dissolve it in 0.8 mL of methyl ethyl ketone. After adding 0.9 mL of 0.1 mol / L phosphoric acid MEK solution at 50 °C, the solid first dissolves and then precipitates out at 50 °C. After stirring at 50 °C for 1 h, it is slowly cooled to 18 °C (about 0.5 K / min); after stirring at 18 °C for about 18 h, it is filtered and dried at 50 °C for 3 - 4 h to obtain Compound (III) in Crystal Form J.

[0456] Preparation of Crystal Form K:

[0457] Weigh approximately 50 mg of Compound (I) and dissolve it in 0.4 mL of methyl ethyl ketone. After adding 0.9 mL of 0.1 mol / L oxalic acid methanol solution at 50 °C, it dissolves clearly at 50 °C and no precipitation occurs when cooled to 18 °C; add 3.0 mL of n - heptane, and it forms layers; after stirring at 18 °C for about 18 h, a solid precipitates out, it is filtered and dried at 50 °C for 3 - 4 h to obtain Compound (IV) in Crystal Form K.

[0458] Preparation of Crystal Form L:

[0459] Weigh approximately 50 mg of Compound (I) and dissolve it in 1.0 mL of ethyl acetate. After adding 8.43 mg of oxalic acid solid at 50 °C, a white solid precipitates out at 50 °C. After stirring at 50 °C for 1 h, it becomes an oily substance; it is slowly cooled to 18 °C; after stirring at 18 °C for about 18 h, it turns into a solid, it is filtered and dried at 50 °C for 3 - 4 h to obtain Compound (IV) in Crystal Form L.

[0460] Preparation of Crystal Form M:

[0461] Weigh approximately 50 mg of Compound (I) and dissolve it in 1.2 mL of methyl ethyl ketone. Add 10.18 mg of maleic acid at 18 °C to precipitate a white solid and continue stirring for about 18 h; filter and dry at 50 °C for 3 - 4 h to obtain Compound (V) in Crystal Form M.

[0462] Preparation of Crystal Form N:

[0463] Weigh about 50 mg of the compound of formula (I) and dissolve it in 0.4 mL of methyl ethyl ketone. Add 0.9 mL of p-toluenesulfonic acid solution (0.1 mol / L methanol solution) at 18 °C and continue stirring for about 18 h. If no solid precipitates, add 1.0 mL of n-heptane to precipitate the solid. Filter and dry at 50 °C for 3 - 4 h to obtain the N crystal form of the compound of formula (VI).

[0464] Preparation of O crystal form:

[0465] Weigh about 50 mg of the compound of formula (I) and dissolve it in 0.8 mL of methyl ethyl ketone. Add 0.9 mL of L-arginine solution (0.1 mol / L methanol solution) at 18 °C. First, it dissolves clearly, and then white solid precipitates rapidly. Continue stirring for about 18 h. Filter and dry the solid at 50 °C for 3 - 4 h to obtain the O crystal form of the compound of formula (VII). 1 H NMR (400 MHz, CD3OD) δ ppm 7.60 (t, J = 7.78 Hz, 1H) 7.57 (s, 1H) 7.48 (t, J = 8.11 Hz, 1H) 7.15 - 7.23 (m, 2H) 7.04 (d, J = 7.45 Hz, 1H) 6.71 (br s, 1H) 6.66 (d, J = 8.33 Hz, 1H) 5.42 (s, 2H) 5.13 - 5.24 (m, 1H) 4.51 - 4.71 (m, 3H) 4.41 (dt, J = 9.15, 5.95 Hz, 1H) 3.87 - 4.06 (m, 3H) 3.82 (dd, J = 4.82, 1.75 Hz, 1H) 3.73 - 3.80 (m, 1H) 3.60 - 3.71 (m, 3H) 3.24 (br s, 2H) 3.15 (d, J = 6.14 Hz, 2H) 2.76 - 2.84 (m, 2H) 2.66 - 2.75 (m, 4H) 2.61 (br s, 2H) 2.40 - 2.52 (m, 1H).

[0466] Preparation of P crystal form:

[0467] Weigh about 50 mg of the compound of formula (I) and dissolve it in 1.4 mL of acetonitrile. Add 0.9 mL of L-arginine solution (0.1 mol / L methanol solution) at 18 °C. First, it dissolves clearly, and then white solid precipitates rapidly. Continue stirring for about 18 h. Filter and dry the solid at 50 °C for 3 - 4 h to obtain the P crystal form of the compound of formula (VII).

[0468] Preparation of Q crystal form:

[0469] Weigh about 50 mg of the compound of formula (I) and dissolve it in 1.0 mL of acetonitrile. At 18 °C, add 0.9 mL of meglumine solution (0.1 mol / L methanol solution). After dissolving it clearly, add 2.0 mL of methyl tert-butyl ether. Stir for about 10 min and then a solid will precipitate. Continue to stir for about 18 h; filter, and dry the solid at 50 °C for 3 - 4 h to obtain the Q crystal form of the compound of formula (VIII).

[0470] Preparation of R crystal form:

[0471] Weigh about 50 mg of the compound of formula (I) and dissolve it in 0.6 mL of tetrahydrofuran. Slowly add 0.8 mL of acetonitrile to the solution at 17 °C. A solid will precipitate. Filter to obtain the R crystal form of the compound of formula (I).

[0472] Preparation of S crystal form:

[0473] Weigh about 50 mg of the compound of formula (I) and dissolve it in 0.2 mL of tetrahydrofuran at 50 °C. After stirring for a period of time at 50 °C, cool it to 20 °C at a certain cooling rate. A solid will precipitate. Filter to obtain the S crystal form of the compound of formula (I).

[0474] Preparation of T crystal form:

[0475] Weigh about 50 mg of the compound of formula (I), add 0.8 mL of methanol, and keep the system in a suspended stirring state at 20 °C. After a period of time, filter the solid to obtain the T crystal form of the compound of formula (I-1).

[0476] Preparation of U crystal form:

[0477] Weigh about 50 mg of the compound of formula (I), add 0.8 mL of ethyl acetate, and keep the system in a suspended stirring state at 20 °C. After a period of time, filter the solid to obtain the U crystal form of the compound of formula (I-1).

[0478] Preparation of V crystal form:

[0479] Weigh about 50 mg of the compound of formula (I), add 0.6 mL of acetonitrile, and keep the system in a suspended stirring state at 50 °C. After a period of time, filter the solid to obtain the V crystal form of the compound of formula (I).

[0480] Example 3: Hygroscopicity study of crystal forms

[0481] Using an SMS Intrinsic dynamic vapor sorption instrument, take 10 mg each of the A crystal form of the compound of formula (II-1), the E crystal form of the compound of formula (II), and the Q crystal form of the compound of formula (VIII) and place them in the DVS sample pan for testing. The specific results are shown in the DVS spectrum Figures 27 - 29 as shown

[0482] As can be seen from the above, the weight gain due to moisture absorption of polymorph A of compound (II-1) is 2.20% at 25°C and 80% RH, indicating hygroscopicity. The crystal form changes before and after adsorption and desorption. The weight gain due to moisture absorption of polymorph E of compound (II) is 2.20% at 25°C and 80% RH, indicating hygroscopicity. The crystal form changes before and after adsorption and desorption. The weight gain due to moisture absorption of polymorph Q of compound (VIII) is 1.08% at 25°C and 80% RH, showing slight hygroscopicity. The crystal form remains unchanged before and after adsorption and desorption.

[0483] Example 4: Solid Stability Study of Polymorph E of Compound (II)

[0484] Weigh 500 mg of polymorph E of compound (II) and place it at the bottom of a glass sample bottle, spreading it into a thin layer. Place it under accelerated conditions (40°C / 75% RH and 60°C / 75% RH), and the sample is a completely exposed sample. Samples are taken on the 5th day, 15th day, 1 month, and 2 months after placement for XRPD testing, and the test results are compared with the initial test results on day 0. The test results are shown in Table 23 below:

[0485] Table 23 Results of Solid Stability Study of Polymorph E

[0486]

[0487] Conclusion: Polymorph E of compound (II) has good stability.

[0488] Example 5: Solid Stability Study of Polymorph Q of Compound (VIII)

[0489] Weigh 500 mg of polymorph Q of compound (VIII) and place it at the bottom of a glass sample bottle, spreading it into a thin layer. Place it under accelerated conditions (40°C / 75% RH and 60°C / 75% RH), and the sample is a completely exposed sample. Samples are taken on the 5th day, 15th day, and 1 month after placement for XRPD testing, and the test results are compared with the initial test results on day 0. The test results are shown in Table 24 below:

[0490] Table 24 Results of Solid Stability Study of Polymorph Q

[0491]

[0492] Conclusion: Polymorph Q of compound (VIII) has good stability.

[0493] Experimental Example 1: In Vitro Cell Activity Test

[0494] 1. Materials

[0495] 1) Cell line This cell line was constructed by Shanghai WuXi AppTec Co., Ltd. The detailed information is shown in the following table.

[0496] Target Host Cell GLP-1 HEK293

[0497] 2) Reagents

[0498] cAMP Detection Kit, Cisbio (Cat#62AM4PEJ) 1M HEPES, Invitrogen (Cat#15630-106) 1X HBSS, Invitrogen (Cat#14025) BSA, Sigma (Cat#B2064) IBMX, Sigma (Cat#I5879) Exenatide, Hao Yuan (HY-13443A)

[0499] 3) Instruments

[0500] OptiPlate-384, White, PerkinElmer (Cat#6007290); 384-well plate for Echo, Labcyte (Cat#P-05525); EnVision, PerkinElmer; Vi-cell counter, Beckman (Cat#Vi-CELL TM XR Cell Viability Analyzer)

[0501] 4) Compound information: The compound was formulated into a working concentration of 30 μM with DMSO. In this experiment, the usage amount of each sample was 5 μL.

[0502] 2. Methods

[0503] 1) Experimental materials

[0504] Experimental Buffer

[0505]

[0506] Detection Reagent Preparation Prepare the cAMP detection reagent: Add 250 μL of cAMP-D2 and 250 μL of anti-cAMP cryptate reagent to 4 mL of lysis buffer and mix gently.

[0507] 2) Experimental methods

[0508] a) Prepare the compound plate:

[0509] The compound to be tested was serially diluted 3-fold at 10 points, with an initial concentration of 30 μM, and the dilution was completed by Bravo.

[0510] The reference compound exenatide was serially diluted 3-fold at 10 points, with an initial concentration of 500 nM, and the dilution was completed by Bravo.

[0511] b) Transfer the compound:

[0512] 1) Use Echo to transfer 100 nL of the compound to the OptiPlate-384 plate.

[0513] 2) Centrifuge the OptiPlate-384 plate at 1000 rpm for 5 seconds.

[0514] c) Preparation of cell suspension

[0515] 1) Quickly place a cryotube of GLP-1 cells in warm water at 37 °C to thaw.

[0516] 2) Transfer the cell suspension to a 15 mL centrifuge tube and gently rinse with 10 mL of HBSS.

[0517] 3) Centrifuge the centrifuge tube at 1000 rpm at room temperature for 1 minute.

[0518] 4) Discard the supernatant.

[0519] 5) Gently disperse the cells at the bottom and gently rinse again with 10 mL of HBSS, centrifuge to sediment the cells, and finally resuspend the cells with the experimental buffer.

[0520] 6) Measure the cell density and viability using Vi-cell.

[0521] 7) Dilute the GLP-1 cell concentration to 2.0*10 5 / mL with the experimental buffer.

[0522] 8) Transfer 100 nL of the diluted cell suspension into the OptiPlate-384 plate.

[0523] 9) Incubate at room temperature for 30 minutes.

[0524] d) Add detection reagents:

[0525] 1) Add 10 μL of the 800 nM gradient-diluted cAMP standard to the empty wells of the OptiPlate-384 plate.

[0526] 2) Add 10 μL of the cAMP detection reagent.

[0527] 3) Cover the OptiPlate-384 plate with a TopSeal-A film and incubate at room temperature for 60 minutes.

[0528] Remove the TopSeal-A and read on the EnVision.

[0529] The experimental results are shown in Table 25:

[0530] Table 25 Results of in vitro cell activity test

[0531] Compound <![CDATA[Human-GLP1,EC 50 (nM)]]> Compound of Formula (O) 0.37

[0532] Conclusion: The compounds of the present invention exhibit excellent agonistic ability towards the GLP-1 receptor.

[0533] Experimental Example 2: DMPK Study in Rats

[0534] Experimental Purpose

[0535] Using male SD rats as test animals, the blood drug concentration of the compound was measured after single-dose administration, and the pharmacokinetic behavior was evaluated.

[0536] Experimental Operation

[0537] Two healthy adult male SD rats were selected for the oral group. The vehicle for the oral group was 20% PEG400 / 10% solutol / 70% water. After mixing the test compound with the vehicle, it was vortexed and sonicated to prepare a clear solution of 0.5 mg / mL. After oral administration of the rats at 5 mg / kg, whole blood was collected at a certain time, and plasma was prepared. The drug concentration was analyzed by LC-MS / MS method, and the pharmacokinetic parameters were calculated using Phoenix WinNonlin software (Pharsight Corporation, USA). The experimental results are shown in Table 26:

[0538] Table 26 PK Test Results of the Compounds of the Present Invention

[0539] Compound Number <![CDATA[C max (nM)]]> <![CDATA[AUC 0-last (h*nmol / L)]]> F％ Compound of Formula (O) 85.5 234 6.6％ Form A of Compound of Formula (II-1) 174 476 11.5％ Form Q of Compound of Formula (VIII) 185 530 13.6％

[0540] Note: PEG represents polyethylene glycol; solutol represents polyethylene glycol-15 hydroxystearate; C max is the maximum concentration; AUC 0-last is the oral exposure for 24 hours, Dose is the drug dose; F% is the oral bioavailability.

[0541] Conclusion: The crystal forms of the compounds of the present invention exhibit relatively high oral exposure and good oral bioavailability, demonstrating good pharmacokinetic properties of oral drugs.

[0542] Experimental Example 3: DMPK Study in Cynomolgus Monkeys

[0543] Experimental Purpose

[0544] Using male cynomolgus monkeys as test animals, the blood drug concentration of the compound was measured after single-dose administration, and the pharmacokinetic behavior was evaluated.

[0545] Experimental Operation

[0546] Two healthy male cynomolgus monkeys were selected as a group. The vehicle for the oral group was an aqueous solution of 20% HP-β-CD. After mixing the test compound with the vehicle, it was vortexed and sonicated to prepare an approximately clear solution of 4 mg / mL. The oral administration dose for cynomolgus monkeys was 20 mg / kg. After oral administration, whole blood was collected at certain time points, and plasma was prepared. The drug concentration was analyzed by LC-MS / MS method, and the pharmacokinetic parameters were calculated using Phoenix WinNonlin software (Pharsight Corporation, USA). The experimental results are shown in Table 27:

[0547] Table 27 PK test results of the compounds of the present invention

[0548]

[0549]

[0550] Note: HP-β-CD represents hydroxypropyl-β-cyclodextrin; C max is the maximum concentration; AUC 0-last is the oral exposure amount in 24 hours; F% is the oral bioavailability.

[0551] Conclusion: The crystalline form of the compound of the present invention exhibits a relatively high oral exposure amount and good oral bioavailability. The in vivo exposure of the crystalline form is significantly higher than that of the free form, demonstrating good pharmacokinetic properties of oral drugs.

Claims

1. A pharmaceutically acceptable salt of formula (O), wherein, The pharmaceutically acceptable salts are selected from tromethamine salts, phosphate salts, citrate salts, oxalate salts, maleate salts, L-tartrate salts, p-toluenesulfonate N salts, sodium salts, potassium salts, L-arginine salts, choline hydroxide salts or meglumine salts.

2. The pharmaceutically acceptable salt according to claim 1, wherein, The pharmaceutically acceptable salts are selected from tromethamine salts, phosphate salts, oxalate salts, maleate salts, p-toluenesulfonate N salts, L-arginine salts or meglumine salts.

3. The pharmaceutically acceptable salt according to claim 1, wherein, The pharmaceutically acceptable salt is a tromethamine salt or a meglumine salt.

4. The pharmaceutically acceptable salt according to claim 1, wherein, The chemical molar ratio of the compound to the acid or base molecule is 1:2 to 2:

1.

5. The pharmaceutically acceptable salt according to claim 1, wherein, The chemical molar ratio of the compound to the acid or base molecule is preferably 1:2 to 1:1 or 1:1 to 2:

1.

6. The pharmaceutically acceptable salt according to claim 1, wherein, The chemical molar ratio of the compound to the acid or base molecule is preferably 1:2, 1:1, 2:

1.

7. A method for preparing the pharmaceutically acceptable salt according to any one of claims 1 - 6, comprising: The step of salifying the compound of formula (O) with an acid or a base; The solvent used in the salification reaction is selected from at least one of methyl ethyl ketone, methanol, ethanol, tetrahydrofuran, ethyl acetate, isopropanol, acetonitrile, methyl tert-butyl ether.

8. The method according to claim 7, wherein, The solvent used in the salification reaction is methanol or isopropanol.

9. A pharmaceutical composition comprising the pharmaceutically acceptable salt according to any one of claims 1 - 6 or the pharmaceutically acceptable salt prepared by the method according to claim 7 or 8 and a pharmaceutically acceptable excipient selected at will.

10. Use of the pharmaceutically acceptable salt according to any one of claims 1 - 6 or the pharmaceutically acceptable salt prepared by the method according to claim 7 or 8 in the preparation for preventing and / or treating metabolic diseases, preferably, the metabolic diseases are preferably diabetes, obesity, non - alcoholic fatty liver.

11. The A crystal form of the compound of formula (II - 1), characterized in that Its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 11.1426±0.2000°，14.4804±0.2000°，17.0921±0.2000°，17.7642±0.2000°，19.6235±0.2000°，21.4921±0.2000°。 12. The A crystal form according to claim 11, characterized in that Its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 11.1426±0.2000°，14.4804±0.2000°，17.0921±0.2000°，17.7642±0.2000°，19.6235±0.2000°，21.4921±0.2000°，22.8874±0.2000°。 13. The A crystal form according to claim 11, characterized in that Its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 11.1426±0.2000°，14.4804±0.2000°，17.0921±0.2000°，17.7642±0.2000°，19.6235±0.2000°，20.4359±0.2000°，21.4921±0.2000°，22.8874±0.2000°。 14. The E crystal form of the tromethamine salt of the compound of formula (O), characterized in that Its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 10.8415±0.2000°，13.3963±0.2000°，18.8216±0.2000°，20.0568±0.2000°，25.1936±0.2000°，25.5960±0.2000°。 15. The E crystal form according to claim 14, characterized in that Its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 10.3742±0.2000°，10.8415±0.2000°，13.3963±0.2000°，18.8216±0.2000°，20.0568±0.2000°，25.1936±0.2000°，25.5960±0.2000°。 16. The E crystal form according to claim 14, characterized in that Its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 10.3742±0.2000°，10.8415±0.2000°，13.3963±0.2000°，18.8216±0.2000°，20.0568±0.2000°，20.7958±0.2000°，25.1936±0.2000°，25.5960±0.2000°。 17. The A crystal form of the compound of formula (II), n is selected from 0 to 4, characterized in that Its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 11.1426±0.2000°，14.4804±0.2000°，17.0921±0.2000°，17.7642±0.2000°，19.6235±0.2000°，21.4921±0.2000°。 18. The A crystal form according to claim 17, characterized in that Its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 11.1426±0.2000°，14.4804±0.2000°，17.0921±0.2000°，17.7642±0.2000°，19.6235±0.2000°，21.4921±0.2000°，22.8874±0.2000°。 19. The A crystal form according to claim 17, characterized in that Its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 11.1426±0.2000°，14.4804±0.2000°，17.0921±0.2000°，17.7642±0.2000°，19.6235±0.2000°，20.4359±0.2000°，21.4921±0.2000°，22.8874±0.2000°。 20. The E crystal form of the compound of formula (II), n is selected from 0 to 4, characterized in that Its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 10.8415±0.2000°，13.3963±0.2000°，18.8216±0.2000°，20.0568±0.2000°，25.1936±0.2000°，25.5960±0.2000°。 21. The E crystal form according to claim 20, characterized in that Its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 10.3742±0.2000°，10.8415±0.2000°，13.3963±0.2000°，18.8216±0.2000°，20.0568±0.2000°，25.1936±0.2000°，25.5960±0.2000°。 22. The E crystal form according to claim 20, characterized in that Its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 10.3742±0.2000°，10.8415±0.2000°，13.3963±0.2000°，18.8216±0.2000°，20.0568±0.2000°，20.7958±0.2000°，25.1936±0.2000°，25.5960±0.2000°。 23. Use of the A crystal form as described in any one of claims 11-13, 17-19 or the E crystal form as described in any one of claims 14-16, 20-22 in the preparation of a medicament for treating metabolic diseases.

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