A crystal form of thienoimidazole compound and preparation method thereof

Abstract

A crystal form of a thienoimidazole compound and a preparation method thereof, and also includes the use of the crystal form in preparing drugs for treating related diseases.

Description

Technical Field

[0001] The present invention relates to a crystal form of a thienoimidazole compound and a preparation method thereof, and also comprises application of the crystal form in preparing medicines for treating related diseases. Background Art

[0002] Diabetes is a common metabolic disease characterized by high blood sugar. Several major types of diabetes are caused by a complex interaction between genetic and environmental factors. Factors that lead to high blood sugar include reduced insulin secretion, decreased glucose utilization, and increased glucose output, and the dominance of these factors varies depending on the cause of diabetes. Metabolic abnormalities associated with diabetes lead to secondary pathophysiological changes in multiple systems throughout the body. Long-term abnormal blood sugar levels can lead to serious complications, including cardiovascular disease, chronic renal failure, retinal damage, nerve damage, microvascular damage, and obesity. The classification of diabetes is based on different pathological processes that lead to high blood sugar, and can be divided into two main types: type 1 diabetes and type 2 diabetes. In the development of the disease, there is a stage of abnormal glucose homeostasis before the onset of type 1 and type 2 diabetes. Type 1 diabetes is the result of complete or almost complete insulin deficiency. Type 2 diabetes is a group of heterogeneous diseases, manifested by varying degrees of insulin resistance, decreased insulin secretion, and increased glucose production. In the treatment of diabetes, in the early stages, diet control and exercise therapy are the preferred blood sugar control options. When these methods are difficult to achieve blood sugar control, insulin or oral hypoglycemic drugs are needed for treatment. At present, drugs used for the treatment of diabetes include insulin, insulin secretagogues, metformin, insulin sensitizers, α-glucosidase inhibitors, dipeptidyl peptidase-IV inhibitors (glitins), sodium-glucose co-transporter (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists. These drugs have good therapeutic effects, but long-term treatment still has safety issues. For example, biguanides are prone to cause lactic acidosis; sulfonylureas can cause hypoglycemia symptoms; insulin sensitizers can cause edema, heart failure and weight gain; α-glucosidase inhibitors can cause abdominal pain, bloating, diarrhea and other symptoms; sodium-glucose co-transporter (SGLT2) inhibitors increase the risk of urinary and reproductive system infections. Therefore, there is an urgent need to develop a safer and more effective new hypoglycemic drug to meet the treatment needs of diabetes.

[0003] Glucagon-like peptide-1 receptor (GLP-1R) is one of the most important therapeutic targets for type 2 diabetes. GLP-1R belongs to the B cluster subfamily of G protein-coupled receptors and is widely expressed in the stomach, small intestine, heart, kidney, lung and brain. In pancreatic islet cells, GLP-1R mainly promotes the release of insulin, increases the regeneration of pancreatic B cells, inhibits the apoptosis of B cells, and reduces the release of glucagon. In tissues such as the gastrointestinal tract, GLP-1R can inhibit gastrointestinal motility and gastric juice secretion by binding to its agonist, delay gastric emptying, and increase satiety. In neural tissue, small molecule GLP-1R agonists can penetrate the brain to activate a subset of neurons expressing GLP-1R, protect nerve cells from apoptosis and enhance learning and memory ability. Not only that, GLP-1R can also control food intake to reduce weight. GLP-1 receptor agonists or endogenous GLP-1 activity enhancers are both approved for the treatment of type 2 diabetes. These drugs do not cause hypoglycemia because secretin-stimulated insulin secretion is glucose-dependent. Exenatide is a synthetic peptide originally discovered in the saliva of poisonous lizards and is a GLP-1 analog. Compared with natural GLP-1, exenatide has a different amino acid sequence that makes it resistant to the enzyme that degrades GLP-1 [dipeptidyl peptidase IV (DPP-IV)]. As a result, exenatide has prolonged 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 the amino acids has been replaced and a fatty acyl group has been added, which promotes its binding to albumin and plasma proteins and prolongs its half-life. GLP-1 receptor agonists increase glucose-stimulated insulin secretion, inhibit glucagon, and delay gastric emptying. These drugs do not cause weight gain; in fact, most patients experience some weight loss and decreased appetite. DPP-IV inhibitors inhibit the degradation of native GLP-1, thereby enhancing the effects of secretin. DPP-IV, which is abundantly expressed on the cell surface of endothelial cells and some lymphocytes, can degrade a wide variety of peptides (not just GLP-1). DPP-IV inhibitors promote insulin secretion without lowering blood sugar, without increasing body weight, and are more effective at lowering postprandial blood sugar. Patients taking GLP-1 receptor agonists have higher levels of GLP-1 activity than those taking DPP-IV inhibitors.

[0004] The development of 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 sugar through multiple pathways of glucose metabolism and excretion, and are expected to develop safer and more effective new glucose-lowering drugs to meet the treatment needs of diabetes. Summary of the invention

[0005] The present invention provides a pharmaceutically acceptable salt of a compound of formula (O), Wherein, the pharmaceutically acceptable salt is selected from tromethamine salts, phosphates, citrates, oxalates, maleates, L-tartrates, p-toluenesulfonate N, sodium salts, potassium salts, L-arginine salts, hydroxycholine salts, and meglumine salts, preferably tromethamine salts, phosphates, oxalates, maleates, p-toluenesulfonate N, L-arginine salts, and meglumine salts, and more preferably tromethamine salts and meglumine salts.

[0006] In some embodiments of the present invention, the chemical molar ratio of the compound to the acid or 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.

[0007] The present invention provides a method for preparing the above-mentioned pharmaceutically acceptable salt, comprising: a step of forming a salt with an acid or a base.

[0008] In some embodiments of the present invention, the solvent used in the salt-forming reaction is selected from at least one of butanone, methanol, ethanol, tetrahydrofuran, ethyl acetate, isopropanol, acetonitrile and methyl tert-butyl ether.

[0009] The present invention provides a pharmaceutical composition comprising the above-mentioned pharmaceutically acceptable salt and any pharmaceutically acceptable carrier and excipient.

[0010] In some embodiments of the present invention, the above-mentioned pharmaceutically acceptable salt is used in the preparation of a compound for preventing and / or treating metabolic diseases, wherein the metabolic diseases are preferably diabetes, obesity, and non-alcoholic fatty liver disease.

[0011] The present invention provides a compound of formula (II)

[0012]

[0013] 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, and in some embodiments of the present invention, n is selected from 0 to 3.

[0014] In some embodiments of the present invention, n is selected from 0, 1 / 2, 2 / 3, 1, 2, 2.7 and 3.

[0015] In some embodiments of the present invention, the compound of formula (II) has the following structure,

[0016]

[0017] The present invention provides a crystal form A of a compound of formula (II-1), characterized in that its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2θ angles: 11.1426±0.2000°, 14.4804±0.2000°, 21.4921±0.2000°.

[0018]

[0019] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form A 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°.

[0020] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form A 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°.

[0021] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form A 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°, and 30.9896°.

[0022] In some embodiments of the present invention, the above-mentioned Form A has an XRPD pattern substantially as follows Figure 1 shown.

[0023] In some embodiments of the present invention, the XRPD spectrum analysis data of the above-mentioned Form A is shown in Table 1:

[0024] Table 1 XRPD spectrum analysis data of the crystal form of compound A of formula (II-1)

[0025]

[0026] In some embodiments of the present invention, the differential scanning calorimetry curve of the above-mentioned Form A has an endothermic peak at 76.0±3.0°C and 130.3±3.0°C, respectively.

[0027] In some embodiments of the present invention, the DSC spectrum of the above-mentioned Form A is substantially as follows Figure 2 shown.

[0028] In some embodiments of the present invention, the thermogravimetric analysis curve of the above-mentioned crystal form A shows a weight loss of 2.43% at 150.0±3.0°C.

[0029] In some embodiments of the present invention, the TGA spectrum of the above-mentioned A crystal form is substantially as follows Figure 3 shown.

[0030] The present invention provides a B crystal form of a compound of formula (II), characterized in that its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2θ angles: 13.3946±0.2000°, 16.0867±0.2000°, and 18.7923±0.2000°.

[0031] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned 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°.

[0032] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned 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°.

[0033] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned 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°, and 38.1654°.

[0034] In some embodiments of the present invention, the above-mentioned Form B has an XRPD pattern substantially as follows: Figure 4 shown.

[0035] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned Form B is shown in Table 2:

[0036] Table 2 XRPD spectrum analysis data of the crystal form of compound B of formula (II)

[0037]

[0038] The present invention provides a crystal form C of a compound of formula (II), characterized in that its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2θ angles: 5.2235±0.2000°, 13.0633±0.2000°, and 18.3202±0.2000°.

[0039] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned 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°.

[0040] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned 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°.

[0041] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form C 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°.

[0042] In some embodiments of the present invention, the above-mentioned C crystal form has an XRPD pattern substantially as follows Figure 5 shown.

[0043] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned Form C are shown in Table 3:

[0044] Table 3 XRPD spectrum analysis data of the crystal form of compound C of formula (II)

[0045]

[0046] The present invention provides a D crystal form of a compound of formula (II), characterized in that its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2θ angles: 5.4120±0.2000°, 13.5502±0.2000°, 24.5140±0.2000°.

[0047] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned D crystal form 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°.

[0048] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned D crystal form 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°.

[0049] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned 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°.

[0050] In some embodiments of the present invention, the XRPD pattern of the above-mentioned D crystal form is substantially as follows Figure 6 shown.

[0051] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned D crystal form are shown in Table 4:

[0052] Table 4 XRPD spectrum analysis data of the crystal form of compound D of formula (II)

[0053]

[0054]

[0055] The present invention provides an E crystal form of a compound of formula (II), characterized in that its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2θ angles: 18.8216±0.2000°, 20.0568±0.2000°, and 25.1936±0.2000°.

[0056] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned 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°.

[0057] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned 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°.

[0058] The present invention provides a crystalline form E of a 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°, and / or 25.1936±0.2000°, and / or 10.8415±0.2000°, and / or 13.3963±0.2000°, and / or 10.3742±0.20 00°, 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°.

[0059] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned 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°.

[0060] In some embodiments of the present invention, the above-mentioned E crystal form has an XRPD pattern substantially as follows Figure 7 shown.

[0061] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned E crystal form is shown in Table 5:

[0062] Table 5 XRPD spectrum analysis data of the crystal form E of compound of formula (II)

[0063]

[0064]

[0065] In some embodiments of the present invention, the differential scanning calorimetry curve of the above-mentioned E crystal form has a peak value of an endothermic peak at 91.0±3.0°C and 149.9±3.0°C, respectively.

[0066] In some embodiments of the present invention, the DSC spectrum of the above-mentioned E crystal form is substantially as follows Figure 8 shown.

[0067] In some embodiments of the present invention, the thermogravimetric analysis curve of the above-mentioned E crystal form shows a weight loss of 6.37% at 150.0±3.0°C.

[0068] In some embodiments of the present invention, the TGA spectrum of the above-mentioned E crystal form is substantially as follows Fig. 9 The present invention provides a crystal form F of a compound of formula (II), characterized in that its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2θ angles: 5.4518±0.2000°, 19.3372±0.2000°, 20.6984±0.2000°.

[0069] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned 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°.

[0070] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned 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°.

[0071] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned 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°, and 28.7110°.

[0072] In some embodiments of the present invention, the above-mentioned F crystal form has an XRPD pattern substantially as follows Fig.10 shown.

[0073] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned F crystal form are shown in Table 6:

[0074] Table 6 XRPD spectrum analysis data of the crystal form of compound F of formula (II)

[0075]

[0076]

[0077] The present invention provides a G crystal form of a compound of formula (II), characterized in that its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2θ angles: 13.2453±0.2000°, 18.1001±0.2000°, 20.5915±0.2000°.

[0078] 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±0.2000°, 13.2453±0.2000°, 18.1001±0.2000°, 19.3293±0.2000°, 20.5915±0.2000°.

[0079] 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±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°.

[0080] 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°, and 30.3926°.

[0081] In some embodiments of the present invention, the above-mentioned G crystal form has an XRPD pattern as substantially Fig.11 shown.

[0082] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned G crystal form are shown in Table 7:

[0083] Table 7 XRPD spectrum analysis data of the crystal form of compound G of formula (II)

[0084]

[0085]

[0086] The present invention provides an H crystal form of a compound of formula (II), characterized in that its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2θ angles: 5.2142±0.2000°, 9.2475±0.2000°, and 17.8933±0.2000°.

[0087] 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°.

[0088] 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°.

[0089] 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°, and 26.9749°.

[0090] In some embodiments of the present invention, the above-mentioned H crystal form has an XRPD pattern substantially as follows Fig.12 shown.

[0091] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned H crystal form is shown in Table 8:

[0092] Table 8 XRPD spectrum analysis data of compound H of formula (II)

[0093]

[0094] The present invention provides a crystal form I of a compound of formula (II), characterized in that its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2θ angles: 5.1906±0.2000°, 12.9022±0.2000°, and 15.4944±0.2000°.

[0095] 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±0.2000°, 10.3443±0.2000°, 12.9022±0.2000°, 15.4944±0.2000°, 18.08160.2000°.

[0096] 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±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°.

[0097] 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°, and 28.5725°.

[0098] In some embodiments of the present invention, the above-mentioned Form I has an XRPD pattern substantially as follows Fig.13 shown.

[0099] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned Form I are shown in Table 9:

[0100] Table 9 XRPD spectrum analysis data of the crystal form of compound I of formula (II)

[0101]

[0102] The present invention also provides a compound of formula (III),

[0103]

[0104] Here, i is selected from 0 to 2, for example, 0, 1 / 2, 2 / 3, 1, 1.5, or 2.

[0105] The present invention provides a J crystal form of a compound of formula (III), characterized in that its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2θ angles: 6.763±0.200°, 13.619±0.200°, and 18.128±0.200°.

[0106] 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±0.200°, 13.619±0.200°, 15.848±0.200°, 18.128±0.200°, 24.643±0.200°.

[0107] 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±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°.

[0108] 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°, 19.43 8°, 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°.

[0109] In some embodiments of the present invention, the XRPD pattern of the above-mentioned J crystal form is substantially as follows Fig.14 shown.

[0110] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned J crystal form are shown in Table 10:

[0111] Table 10 XRPD spectrum analysis data of the crystal form J of compound of formula (III)

[0112]

[0113]

[0114] The present invention also provides a compound of formula (IV),

[0115]

[0116] Herein, m is selected from 0 to 2, for example, 0, 1 / 2, 2 / 3, 1, 1.5, or 2.

[0117] In some embodiments of the present invention, the compound of formula (IV) has the following structure,

[0118]

[0119] The present invention provides a K crystal form of a 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°.

[0120] 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°.

[0121] 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°.

[0122] 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°, and 26.841°.

[0123] In some embodiments of the present invention, the above-mentioned K crystal form has an XRPD pattern substantially as follows Fig.15 shown.

[0124] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned K crystal form are shown in Table 11:

[0125] Table 11 XRPD spectrum analysis data of compound K of formula (IV-1)

[0126]

[0127]

[0128] The present invention provides an L crystal form of a compound of formula (IV), characterized in that its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2θ angles: 18.726±0.200°, 21.044±0.200°, and 24.648±0.200°.

[0129] 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°.

[0130] 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°.

[0131] 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°, and 27.453°.

[0132] In some embodiments of the present invention, the above-mentioned L crystal form has an XRPD pattern substantially as follows Fig.16 shown.

[0133] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned L crystal form are shown in Table 12:

[0134] Table 12 XRPD spectrum analysis data of the crystal form L of the compound of formula (IV)

[0135]

[0136]

[0137] The present invention also provides a compound of formula (V),

[0138]

[0139] Here, o is selected from 0 to 2, for example, 0, 1 / 2, 2 / 3, 1, 1.5, or 2.

[0140] The present invention provides an M crystal form of a compound of formula (V), characterized in that its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2θ angles: 5.682±0.200°, 11.389±0.200°, and 17.202±0.200°.

[0141] 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°.

[0142] 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°.

[0143] 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°, and 33.086°.

[0144] In some embodiments of the present invention, the above-mentioned M crystal form has an XRPD pattern substantially as follows Fig.17 shown.

[0145] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned M crystal form is shown in Table 13:

[0146] Table 13 XRPD spectrum analysis data of the crystal form M of the compound of formula (V)

[0147]

[0148] The present invention also provides a compound of formula (VI),

[0149]

[0150] The present invention provides an N crystal form of a compound of formula (VI), characterized in that its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2θ angles: 11.439±0.200°, 18.363±0.200°, and 28.859±0.200°.

[0151] 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°.

[0152] 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: 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°.

[0153] 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: 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°, 2 0.397°, 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°.

[0154] In some embodiments of the present invention, the above-mentioned N crystal form has an XRPD pattern substantially as follows Fig.18 shown.

[0155] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned N crystal form are shown in Table 14:

[0156] Table 14 XRPD spectrum analysis data of the crystal form N of the compound of formula (VI)

[0157]

[0158]

[0159]

[0160] The present invention also provides a compound of formula (VII),

[0161]

[0162] Here, p is selected from 0 to 3, for example, 0, 1 / 2, 2 / 3, 1, 1.5, 2, 2.5, 2.7, or 3.

[0163] The present invention provides an O crystal form of a compound of formula (VII), characterized in that its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2θ angles: 9.485±0.200°, 11.273±0.200°, and 17.536±0.200°.

[0164] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned 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°.

[0165] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned 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°.

[0166] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned 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°.

[0167] In some embodiments of the present invention, the above-mentioned O crystal form has an XRPD pattern substantially as follows Fig.19 shown.

[0168] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned O crystal form are shown in Table 15:

[0169] Table 15 XRPD spectrum analysis data of the compound of formula (VII) O crystal form

[0170]

[0171]

[0172] The present invention provides a P crystal form of a compound of formula (VII), characterized in that its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2θ angles: 12.481±0.200°, 14.965±0.200°, and 17.480±0.200°.

[0173] 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°.

[0174] 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°, and 35.375°.

[0175] In some embodiments of the present invention, the above-mentioned P crystal form has an XRPD pattern substantially as follows Fig. 20 shown.

[0176] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned P crystal form are shown in Table 16:

[0177] Table 16 XRPD spectrum analysis data of the crystal form P of the compound of formula (VII)

[0178]

[0179] The present invention also provides a compound of formula (VIII),

[0180]

[0181] The present invention provides a Q crystal form of a compound of formula (VIII), characterized in that its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2θ angles: 6.123±0.200°, 9.130±0.200°, and 12.123±0.200°.

[0182] 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°.

[0183] 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°.

[0184] 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°, 20.09 5°, 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°.

[0185] In some embodiments of the present invention, the XRPD pattern of the above-mentioned Q crystal form is substantially as follows Fig.21 shown.

[0186] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned Q crystal form is shown in Table 17:

[0187] Table 17 XRPD spectrum analysis data of the Q crystal form of the compound of formula (VIII)

[0188]

[0189]

[0190] The present invention also provides a compound of formula (I),

[0191]

[0192] Here, s is selected from 0 to 3, for example, 0, 1 / 2, 2 / 3, 1, 1.5, 2, 2.5, 2.7, or 3.

[0193] In some embodiments of the present invention, s is selected from 0, 1, 2 and 3.

[0194] In some embodiments of the present invention, the compound of formula (I) has the following structure,

[0195]

[0196] The present invention provides an R crystal form of a compound of formula (I), characterized in that its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2θ angles: 7.933±0.200°, 15.900±0.200°, and 23.970±0.200°.

[0197] 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°.

[0198] 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°.

[0199] 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°, and 38.072°.

[0200] In some embodiments of the present invention, the above-mentioned R crystal form has an XRPD pattern substantially as follows Fig. 22 shown.

[0201] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned R crystal form are shown in Table 18:

[0202] Table 18 XRPD spectrum analysis data of the R crystal form of the compound of formula (I)

[0203]

[0204] The present invention provides an S crystal form of a compound of formula (I), characterized in that its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2θ angles: 20.032±0.200°, 21.239±0.200°, and 23.474±0.200°.

[0205] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned 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°.

[0206] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned 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°.

[0207] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned 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°, and 34.181°.

[0208] In some embodiments of the present invention, the above-mentioned S crystal form has an XRPD pattern substantially as follows Fig.23 shown.

[0209] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned S crystal form are shown in Table 19:

[0210] Table 19 XRPD spectrum analysis data of the S crystal form of the compound of formula (I)

[0211]

[0212]

[0213] The present invention provides a T crystal form of a compound of formula (I-1), characterized in that its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2θ angles: 6.347±0.200°, 11.735±0.200°, 18.221±0.200°.

[0214] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned 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°.

[0215] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned 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°.

[0216] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned 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°.

[0217] In some embodiments of the present invention, the above-mentioned T crystal form has an XRPD pattern substantially as follows Fig.24 shown.

[0218] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned T crystal form are shown in Table 20:

[0219] Table 20 XRPD spectrum analysis data of the crystal form T of the compound of formula (I-1)

[0220]

[0221]

[0222] The present invention provides a U-crystalline form of a compound of formula (I-1), characterized in that its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2θ angles: 4.486±0.200°, 9.021±0.200°, and 27.215±0.200°.

[0223] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned 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°.

[0224] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned 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°.

[0225] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned 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°, and 31.304°.

[0226] In some embodiments of the present invention, the above-mentioned U crystal form has an XRPD pattern substantially as follows Fig.25 shown.

[0227] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned U crystal form is shown in Table 21:

[0228] Table 21 XRPD spectrum analysis data of the U crystal form of the compound of formula (I-1)

[0229]

[0230]

[0231] The present invention provides a V crystal form of a compound of formula (I), characterized in that its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2θ angles: 3.729±0.200°, 11.208±0.200°, and 23.480±0.200°.

[0232] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned 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°.

[0233] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned V crystal form 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°.

[0234] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned V crystal form 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°.

[0235] In some embodiments of the present invention, the above-mentioned Form V has an XRPD pattern substantially as follows Fig.26 shown.

[0236] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned Form V is shown in Table 22:

[0237] Table 22 XRPD spectrum analysis data of the crystal form V of the compound of formula (I)

[0238]

[0239]

[0240] The present invention also provides use of the above-mentioned compound or crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, crystal form F, crystal form G, crystal form H, crystal form I, crystal form J, crystal form K, crystal form L, crystal form M, crystal form N, crystal form O, crystal form P, crystal form Q, crystal form R, crystal form S, crystal form T, crystal form U, and crystal form V in the preparation of drugs for treating diabetes, weight loss and NASH.

[0241] Definition and Description

[0242] 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 to be uncertain or unclear in the absence of a special definition, but should be understood according to its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding commercial product or its active ingredient.

[0243] The intermediate compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the embodiments of the present invention.

[0244] The chemical reactions of the specific embodiments of the present invention are carried out in a suitable solvent, which must be suitable for the chemical changes of the present invention and the reagents and materials required. In order to obtain the compounds of the present invention, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction processes based on the existing embodiments.

[0245] The structure of the compound of the present invention can be confirmed by conventional methods known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction (SXRD) is used to collect diffraction intensity data of the cultured single crystal using a Bruker D8 venture diffractometer, the light source is CuKα radiation, and the scanning mode is: After scanning and collecting relevant data, the crystal structure is further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.

[0246] The present invention will be described in detail below by way of examples, which are not intended to limit the present invention in any way.

[0247] All solvents used in the present invention were commercially available and used without further purification.

[0248] The solvent used in the present invention is commercially available.

[0249] The present invention adopts 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 butanone; EtOH represents ethanol; MeOH represents methanol; IPA represents isopropanol; MTBE represents methyl tert-butyl ether; THF represents tetrahydrofuran; Pd(dppf)Cl2 represents [1,1-bis(diphenylphosphino)ferrocene] dichloropalladium; Pd(OH)2 represents palladium hydroxide, LiAlH4 represents lithium aluminum tetrahydride; Tris represents tromethamine.

[0250] Compounds are named according to the conventional nomenclature in the art or using The software names were used, and commercially available compounds were named using the supplier's catalog names.

[0251] Technical Effects

[0252] The compound of the present invention has stable crystal form, is less affected by heat and humidity, has good in vivo drug efficacy, and has broad prospects for drug development; the compound of formula (I) exhibits relatively good agonist ability to the GLP-1 receptor.

[0253] X-ray powder diffractometer (XRPD) method of the present invention

[0254] 1. Instrument model: X'Pert3 X-ray diffractometer from PANalytical

[0255] Test method: Approximately 20 mg of sample was used for XRPD testing.

[0256] The detailed parameters are as follows:

[0257]

[0258]

[0259] 2. The X-ray diffraction pattern was acquired by a Bruker Instruments D2 Phaser, and the instrument parameters were as follows.

[0260]

[0261] Differential Scanning Calorimeter (DSC) method of the present invention

[0262] Instrument model: TA 2500 differential scanning calorimeter

[0263] The parameters and test methods are as follows:

[0264] parameter Settings method Linear temperature rise Sample tray Aluminum tray, with cover or without cover Temperature range 25~Set the end temperature Scan rate (℃ / min) 10 Protective gas Nitrogen

[0265] Thermogravimetric analysis (TGA) method of the present invention

[0266] Instrument model: TA 5500 Thermogravimetric Analyzer

[0267] The parameters and test methods are as follows:

[0268]

[0269]

[0270] Dynamic Vapor Sorption (DVS) method of the present invention

[0271] Dynamic moisture sorption (DVS) curves were collected on SMS (Surface Measurement Systems) on DVS Intrinsic plus. The relative humidity at 25 °C was calibrated using the deliquescent point of lithium chloride (LiCl), magnesium nitrate [Mg(NO3)2] and potassium chloride (KCl).

[0272] The test parameters are as follows:

[0273]

[0274] The moisture absorption evaluation is classified as follows:

[0275] Hygroscopicity classification ΔW% deliquescence Absorb enough water to form a liquid Highly hygroscopic ΔW%≥15% Hygroscopic 15%>ΔW%≥2% Slightly hygroscopic 2%>ΔW%≥0.2% No or almost no hygroscopicity ΔW%<0.2%

[0276] Note: ΔW% indicates the weight gain of the test sample at 25±1℃ and 80±2%RH. BRIEF DESCRIPTION OF THE DRAWINGS

[0277] Figure 1 The XRPD spectrum of the crystal form A of the compound of formula (II-1) under Cu-Kα radiation;

[0278] Figure 2 is the DSC spectrum of the crystalline form A of the compound of formula (II-1);

[0279] Figure 3 is the TGA spectrum of the crystalline form A of the compound of formula (II-1);

[0280] Figure 4 is the XRPD spectrum of the crystal form B of the compound of formula (II) under Cu-Kα radiation;

[0281] Figure 5 is the XRPD spectrum of the crystal form C of the compound of formula (II) under Cu-Kα radiation;

[0282] Figure 6 is the XRPD spectrum of the crystal form D of the compound of formula (II) using Cu-Kα radiation;

[0283] Figure 7 is the XRPD spectrum of the crystal form E of the compound of formula (II) under Cu-Kα radiation;

[0284] Figure 8 is the DSC spectrum of the crystalline form E of the compound of formula (II);

[0285] Fig. 9 is the TGA spectrum of the crystal form E of the compound of formula (II);

[0286] Fig.10 is the XRPD spectrum of the crystal form F of the compound of formula (II) under Cu-Kα radiation;

[0287] Fig.11 is the XRPD spectrum of the crystal form G of the compound of formula (II) under Cu-Kα radiation;

[0288] Fig.12 is the XRPD spectrum of the H-form of the compound of formula (II) using Cu-Kα radiation;

[0289] Fig.13is the XRPD spectrum of the crystal form I of the compound of formula (II) under Cu-Kα radiation;

[0290] Fig.14 is the XRPD spectrum of the crystal form J of the compound of formula (III) using Cu-Kα radiation;

[0291] Fig.15 The XRPD spectrum of the K crystal form of the compound of formula (IV-1) under Cu-Kα radiation;

[0292] Fig.16 is the XRPD spectrum of the L crystal form of the compound of formula (IV) using Cu-Kα radiation;

[0293] Fig.17 is the XRPD spectrum of the crystal form M of the compound of formula (V) under Cu-Kα radiation;

[0294] Fig.18 is the XRPD spectrum of the crystal form N of the compound of formula (VI) using Cu-Kα radiation;

[0295] Fig.19 is the XRPD spectrum of the crystal form O of the compound of formula (VII) using Cu-Kα radiation;

[0296] Fig. 20 is the XRPD spectrum of the crystal form P of the compound of formula (VII) using Cu-Kα radiation;

[0297] Fig.21 is the XRPD spectrum of the Q crystal form of the compound of formula (VII) using Cu-Kα radiation;

[0298] Fig. 22 is the XRPD spectrum of the R crystal form of the compound of formula (I) using Cu-Kα radiation;

[0299] Fig.23 is the XRPD spectrum of the S crystalline form of the compound of formula (I) using Cu-Kα radiation;

[0300] Fig.24 The XRPD spectrum of the T-form of the compound of formula (I-1) with Cu-Kα radiation;

[0301] Fig.25 The XRPD spectrum of the U crystal form of the compound of formula (I-1) using Cu-Kα radiation;

[0302] Fig.26 is the XRPD spectrum of the U crystal form of the compound of formula (I) using Cu-Kα radiation;

[0303] Fig. 27 It is the DVS spectrum of the crystal form A of the compound of formula (II-1);

[0304] Fig.28is the DVS spectrum of the crystal form E of the compound of formula (II);

[0305] Fig.29 This is the DVS spectrum of the Q crystal form of the compound of formula (VIII). DETAILED DESCRIPTION

[0306] In order to better understand the content of the present invention, further description is given below in conjunction with specific embodiments, but the specific implementation methods are not intended to limit the content of the present invention.

[0307] Example 1: Synthesis of compound of formula (I)

[0308]

[0309] Step 1: Synthesis of compound B-1-3

[0310] B-1-1 (1.00 g, 6.23 mmol, 1 eq) was added to a reaction bottle containing THF (40 mL). Under nitrogen protection, NaH (375 mg, 9.38 mmol, 60% content, 1.51 eq) was added at 0 ° C, the temperature was raised to 22 ° C and stirred for 1 hour, and B-1-2 (1.5 g, 6.33 mmol, 1.02 eq) was added and the temperature was raised to 60 ° C and stirred for 16 hours. 20 mL of water was added to the reaction solution to quench, and DCM (20 mL * 3) was added to extract, the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 1:0) to obtain B-1-3. LCMS: m / z = 317.8 [M + H] + .

[0311] Step 2: Synthesis of compound B-1-5

[0312] 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, and Pd (dppf) Cl2 (0.17 g, 232.33 μmol, 0.05 eq) was added under a nitrogen atmosphere. 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 it was extracted with ethyl acetate (50 mL*3). The organic phases were combined, washed with a saturated sodium chloride aqueous 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] + .

[0313] Step 3: Synthesis of Compound B-1

[0314] B-1-5 (1.80 g, 4.30 mmol, 1 eq) and anhydrous DCM (30 mL) were added to the 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 solution pH to about 9-10, extracted with ethyl acetate (30 mL*3), combined organic phases, washed with saturated sodium chloride aqueous 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] + .

[0315]

[0316] Step 4: Synthesis of compound B-2-2

[0317] Compound B-2-1 (12 g, 67.33 mmol, 1 eq) was dissolved in THF (120 mL), argon was replaced, Pd(OH)2 (6.00 g, 4.27 mmol, 10% content, 6.35e-2 eq) was added, and hydrogen was introduced at a pressure of 50 psi and stirred at 45 ° C for 24 hours. The reaction solution was filtered with diatomaceous earth and rinsed with anhydrous THF. The THF solution of B-2-2 was obtained and directly subjected to the next step of reaction without post-treatment. 1 H NMR (400MHz, CDCl3) δppm 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).

[0318] Step 5: Synthesis of compound B-2

[0319] Compound B-2-2 (2g, 22.70mmol, 1eq) and TEA (13.78g, 136.20mmol, 18.96mL, 6eq) were added to the reaction flask. After nitrogen was replaced, methanesulfonic anhydride (11.86g, 68.10mmol, 2.64mL, 3eq) was added in batches at 0°C, and then the temperature was raised to 25°C for reaction for 24 hours. The reaction solution was poured into water (125mL) for quenching, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (50mL), the organic phases were combined, washed with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 45°C by a water pump to obtain a crude product. Separate and purify by column chromatography (PE:EA=1:0 to 1:1, gradient elution). B-2 was obtained. 1 HNMR(400MHz,CDCl3)δppm 4.99-5.05(m,1H),4.64-4.71(m,1H),4.57(dt,J=9.10,6.08Hz,1H),4. 36(d,J=3.88Hz,2H),3.10(s,3H),2.70-2.81(m,1H),2.58-2.68(m,1H).

[0320]

[0321]

[0322] Step 6: Synthesis of compound 1-2

[0323] Compound 1-1 (23 g, 164.12 mmol, 1 eq) and DMF (115 mL) were added to the reaction flask, nitrogen was replaced, the temperature was lowered to 0 ° C, and then NaH (9.85 g, 246.18 mmol, 60% content, 1.5 eq) was added, nitrogen was replaced again, 2-(trimethylsilyl)ethoxymethyl chloride (41.04 g, 246.18 mmol, 43.57 mL, 1.5 eq) was added dropwise, and the temperature was raised to 25 ° C for 12 hours after the addition was completed. The reaction solution was quenched with ice water (500 mL), extracted with ethyl acetate (200 mL*3), 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 by water pump to obtain a 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. 1H NMR (400MHz, CDCl3) δppm 7.24(d,J=0.63Hz,1H),7.17(s,1H),5.76(s,2H),4.39(q,J=7.13Hz,2H),3.49 -3.56(m,2H),1.40(t,J=7.13Hz,3H),0.86-0.93(m,2H),-0.07--0.04(m,9H).

[0324] Step 7: Synthesis of compound 1-3

[0325] THF (1000mL) was added to the reaction flask, and LiAlH4 (6.04g, 159.21mmol, 1.5eq) was added in batches, nitrogen was replaced, the temperature was lowered to 0°C, and the mixture was stirred for 15 minutes. Then, compound 1-2 (28.7g, 106.14mmol, 1eq) was added at 0°C, and the mixture was heated to 25°C and reacted for 0.5 hours. The reaction solution was cooled to 0°C, and then 6mL of water, 6mL of 15% sodium hydroxide, and 18mL of water were added in sequence, the mixture was heated to 25°C and stirred for 15 minutes, and then anhydrous magnesium sulfate was added and stirred for 15 minutes, and the mixture was filtered. The filtrate was collected, washed with saturated brine (500mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 45°C by a water pump to obtain compound 1-3. 1 H NMR (400MHz, CDCl3) δppm 6.98(d,J=1.13Hz,1H),6.93(d,J=1.13Hz,1H),5.37(s,2H),4.72(s,2H) ,3.52(dd,J=8.76,7.75Hz,2H),0.89-0.95(m,2H),-0.02--0.01(m,9H).

[0326] Step 8: Synthesis of Compound 1-4

[0327] Compound 1-3 (18.81 g, 82.37 mmol, 1 eq), tert-butyldiphenylsilyl chloride (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, nitrogen was replaced, and the reaction was carried out at 25°C for 16 hours. The reaction solution was poured into water (1000 mL) for quenching, and ethyl acetate (200 mL*3) was added for extraction. 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 to obtain a 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. 1H NMR (400MHz, CDCl3) δppm 7.66-7.72(m,4H),7.37-7.46(m,6H),6.96-7.02(m,2H),5.41(s,2H),4.8 4(s,2H),3.41-3.48(m,2H),1.06(s,9H),0.85-0.91(m,2H),-0.03(s,9H).

[0328] Step 9: Synthesis of Compound 1-5

[0329] Compound 1-4 (22 g, 47.13 mmol, 1 eq) and THF (440 mL) were added to the reaction flask, and N-bromosuccinimide (25.17 g, 141.40 mmol, 44.18 μL, 3 eq) was added in batches at 0 ° C after nitrogen was replaced, and then the temperature was raised to 25 ° C for 12 hours. The reaction solution was quenched with water (440 mL), extracted with ethyl acetate (2200 mL*2), and 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 by water pump to obtain a 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 (400MHz, CDCl3) δppm 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).

[0330] Step 10: Synthesis of Compound 1-6

[0331] Compound 1-5 (6 g, 9.61 mmol, 1 eq) and THF (60 mL) were added to the reaction flask, nitrogen was replaced, the temperature was lowered to -40 ° C, and then i-PrMgCl-LiCl (1.3 M, 8.13 mL, 1.1 eq) was added dropwise, stirred for 1.5 hours, and 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 continued to stir for 30 minutes. The reaction solution 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 by water pump to obtain a 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. 1H NMR (400MHz, CDCl3) δppm9.76(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).

[0332] Step 11: Synthesis of Compound 1-8

[0333] 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) and 1-7 (273.10 mg, 2.57 mmol, 233.42 μL, 1.2 eq) were added, stirred at 20 ° C for 2 hours, and then heated to 80 ° C for 12 hours. The reaction solution 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 by water pump to obtain a 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 (400MHz, CDCl3) δppm7.72 (s, 1H), 5.54 (s, 2H), 4.91 (s, 2H), 4.39 (q, J = 7.13Hz, 2H), 3.5 5-3.61(m,2H),2.30-2.64(m,1H),1.40(t,J=7.13Hz,3H),0.91-0.96(m,2H),-0.02(s,9H).

[0334] Step 12: Synthesis of Compound 1-9

[0335] 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 the reaction flask. Methanesulfonyl chloride (57.84 mg, 504.89 μmol, 39.08 μL, 1.5 eq) was added in batches at 0 ° C after nitrogen was replaced, and then the temperature was raised to 25 ° C for 12 hours. The reaction solution was directly concentrated under reduced pressure to obtain a crude product. Compound 1-9 was obtained by separation and purification by thin layer chromatography on silica gel plate (DCM: MeOH = 20: 1). 1H NMR (400MHz, CDCl3) δppm 7.72(s,1H),5.57(s,2H),4.85(s,2H),4.39(q,J=7.13Hz,2H),3.56-3.61(m,2H),1.40(t,J=7.13Hz,3H),0.92-0.97(m,2H),-0.02(s,9H).

[0336] Step 13: Synthesis of Compound 1-10

[0337] 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), acetonitrile (10 mL) were added to the reaction flask in sequence, and the reaction system was stirred at 60 ° C for 10 hours. The reaction solution was concentrated to obtain a crude product, water (10 mL) was added, and it was extracted with ethyl acetate (10 mL*3), the organic phases were combined, the organic phases were washed with saturated sodium chloride aqueous 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 = 1:0-5:1) to obtain 1-10. LCMS: m / z = 657.3 [M+H] + ; 1 H NMR (400MHz, CDCl3) δppm 7.74 (s, 1H), 7.55 (t, J = 7.91Hz, 1H), 7.43 (t, J = 8.03Hz, 1H), 7.08-7.17 (m, 2H), 6.94 (d, J = 7.28Hz, 1H), 6.72 (br s,1H),6.66(d,J=8.28Hz,1H),5.66(s,2H),5.43(s,2H),4.38(q,J=7.03Hz,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=7.03Hz,3H),0.89-0.94(m,2H),-0.10--0.03(m,9H).

[0338] Step 14: Synthesis of Compound 1-11

[0339] 1-10 (0.30 g, 456.43 μmol, 1 eq), anhydrous DCM (5.0 mL), and trifluoroacetic acid (1.54 g, 13.51 mmol, 1.0 mL, 29.59 eq) were added to the reaction flask in sequence, and the reaction system was stirred at 40 ° C for 5 hours. Sodium carbonate solution (10 mL) was added to the reaction solution, and sodium carbonate solid was added to adjust the solution pH to about 9-10, and extracted with ethyl acetate (10 mL*3), and 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 a crude product. The crude product was 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 H NMR(400MHz,CDCl3)δppm 10.08(br s,1H),7.68(br s,1H),7.57(t,J=7.78Hz,1H),7.43(t,J=8.16Hz,1H),7.09-7.17(m,2H),6.96(d,J=7.53Hz,1H),6.73(br s,1H),6.69(d,J=8.28Hz,1H),5.44(s,2H),4.37(q,J=7.11Hz,2H),3.96(s,2H),3.35(br d,J=3.01Hz,2H),2.83-2.91(m,2H),2.68(br s, 2H), 1.39 (t, J = 7.15Hz, 3H).

[0340] Step 15: Synthesis of compounds 1-12 and 1-13

[0341] 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), acetonitrile (5 mL) were added to the reaction flask in sequence, and the reaction system was stirred at 80 ° C for 10 hours. The reaction solution was concentrated to obtain a crude product, water (10 mL) was added, and it was extracted with ethyl acetate (10 mL*3), the organic phases were combined, the organic phases were washed with saturated sodium chloride aqueous 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)

[0342] A mixture of 1-12 and 1-13 (90 mg, 150.73 μmol, 1 eq), water (0.4 mL), acetonitrile (2 mL) were added to the reaction flask in sequence, and 1,5,7-triazidobicyclo (4.4.0) dec-5-ene (50 mg, 359.20 μmol, 2.38 eq) was added, and the reaction system was stirred at 20°C for 10 hours. 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% NH3H2O ​​MeOH]; CO2: 55%-55%, min) to obtain the compound of formula (I) (retention time: 6.815 min).

[0343] Detection method (chromatographic column: Chiralpak IG-3 4.6mm ID, 3μm, mobile phase: A: CO2B: methanol (0.05% diethylamine), isocratic elution: methanol (0.05% diethylamine) 40%, flow rate: 4mL / min, column temperature: 35°C, back pressure: 1500psi). LCMS: m / z=569.2[M+H] + ; 1 H NMR(400MHz,DMSO-d6)δppm 7.68(t,J=7.91Hz,1H),7.55(t,J=8.16Hz,1H),7.40-7.50(m,2H),7.30(dd,J=8.28,1.76Hz,1H),7.08(d,J=7.53Hz,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=5.52Hz,2H),2.58-2.66(m,1H),2.32-2.38(m,1H); 1H NMR (400MHz, CD3OD) δppm7.64(s,1H),7.62(t,J=7.91Hz,1H),7.48(t,J=8.03Hz,1H),7.16-7.24(m,2H),7.05(d,J=7.53Hz,1H),6.71(br s,1H),6.68(d,J=8.03Hz,1H),5.42(s,2H),5.19(br d,J=4.27Hz,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(brd,J=8.78Hz,1H).

[0344] The two-dimensional NMR NOE was used to identify C8-H and C 10 -H related, the product structure is correct.

[0345]

[0346] Example 2: Preparation of Crystalline Form

[0347] Preparation of Form A:

[0348] Add tromethamine (1.31 g, 10.8 mmol 1.02 eq) and 30 mL of methanol to the reaction flask, stir and dissolve at 50 °C. Cool to 25 °C, add compound (I) (6 g, 10.54 mmol, 1 eq), dissolve the system. Add 90 mL of methyl tert-butyl ether and stir at 25 °C for 16 hours. Filter, rinse the filter cake with 12 mL of a 1:3 mixed solvent of methanol: methyl tert-butyl ether for 3 times, transfer the filter cake to 50 °C and vacuum dry for 16 hours. Obtain the crystal form A of compound (II-1). 1 H NMR(400MHz,CD3OD)δppm 7.57-7.68(m,2H)7.50(t,J=7.91Hz,1H)7.16-7.28(m,2H)7.06(d,J=7.53Hz,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=9.29,6.02Hz,1H)3.89-4.04(m,2H)3.68(s,6H)3.26(br s,2H)2.68-2.86(m,3H)2.63(brs,2H)2.43-2.55(m,1H).

[0349] Preparation of Form B:

[0350] About 15 mg of the compound of formula (II-1) Form A was weighed into a HPLC glass vial, and 0.5 mL of H2O was added. The resulting turbid solution was magnetically stirred (1000 rpm) at room temperature for about 4 days, and then the solid was collected by centrifugation to obtain the compound of formula (II) Form B. The sample was dried overnight in an open container at room temperature and then converted to Form E.

[0351] Preparation of Form C:

[0352] About 15 mg of the compound of formula (I) and 3 mg of Tris in an equal molar ratio were weighed into a HPLC glass vial, and 0.5 mL of EtOH was added to each of them. The resulting turbid solution was placed under magnetic stirring (1000 rpm) at room temperature for about 4 days, and then the solid was collected by centrifugation to obtain the compound of formula (II) in Form C. The sample was dried in the open at room temperature and then converted to Form E.

[0353] Preparation of Form D:

[0354] Weigh about 15 mg of the compound of formula (II-1) A crystal form into a 3 mL vial, add 1.0 mL of MeOH / MTBE (1:1, v / v), stir and balance at 50°C for about 1 hour, and then filter the supernatant. The obtained supernatant was placed in a biochemical incubator, cooled from 50°C to 5°C at 0.1°C / min and kept at a constant temperature of 5°C, and the precipitated solid was collected to obtain the compound of formula (II) D crystal form. The sample was exposed to air at room temperature and then converted to E crystal form.

[0355] Preparation of E crystal form:

[0356] About 15 mg of the crystalline form A of the compound of formula (II-1) was weighed into a HPLC glass vial, and 0.5 mL of IPA was added respectively. The resulting suspension was magnetically stirred (1000 rpm) under temperature cycling conditions (40°C to 5°C, 0.1°C / min, 2 cycles), and the solid was collected by centrifugation to obtain the crystalline form E of the compound of formula (II). 1 H NMR(400MHz,CD3OD)δppm 7.59-7.64(m,2H)7.50(t,J=8.03Hz,1H)7.21(t,J=10.16Hz,2H)7.06(d,J=7.28Hz,1H)6.72-6. 75(m,1H)6.68(d,J=8.29Hz,1H)5.44(s,2H)5.21(qd,J=7.03,3.01Hz,1H)4.55-4.73(m,3H)4.4 4(dt,J=9.03,6.02Hz,1H)3.91-4.01(m,2H)3.68(s,6H)3.26(br s,2H)2.70-2.84(m,3H)2.63(brs,2H)2.40-2.54(m,1H)

[0357] Preparation of Form F:

[0358] Weigh about 15 mg of the compound of formula (II-1) Form A into a 20 mL vial, and use 0.2-1.0 mL of MeOH to completely dissolve the solid (the undissolved sample is filtered using a 0.45 μm PTFE filter to obtain a clear solution). Add MTBE dropwise to the clear solution while stirring (1000 rpm) until solid precipitates to obtain the compound of formula (II) Form F. The sample is exposed to air at room temperature and then converted to Form E.

[0359] Preparation of Form G:

[0360] Weigh about 15 mg of the compound of formula (II-1) A crystal form into a 3 mL vial, add about 3 mL EtOH into a 20 mL vial, place the 3 mL vial open into the 20 mL vial, and seal the 20 mL vial. After standing at room temperature for 7 days, collect the solid to obtain the compound of formula (II) G crystal form. After the sample is dried open at room temperature, it is converted into E crystal form.

[0361] Preparation of H crystal form:

[0362] Weigh about 15 mg of the compound of formula (II-1) A crystal form into a 3 mL vial, add about 3 mL of THF into a 20 mL vial, place the 3 mL vial open into the 20 mL vial, and then seal the 20 mL vial. After standing at room temperature for 7 days, collect the solid to obtain the compound of formula (II) H crystal form. After the sample is dried open at room temperature, it is converted into E crystal form.

[0363] Preparation of Form I:

[0364] About 15 mg of the crystal form A of the compound of formula (II-1) was weighed into a HPLC glass vial, and 0.5 mL of H2O was added respectively. The resulting suspension was magnetically stirred (1000 rpm) under temperature cycling conditions (40°C to 5°C, 0.1°C / min, 2 cycles), and the solid was collected by centrifugation to obtain the crystal form I of the compound of formula (II). The sample was dried in the open at room temperature and then converted to the crystal form E.

[0365] Preparation of Form J:

[0366] About 50 mg of the compound of formula (I) was weighed and dissolved in 0.8 mL of butanone. After 0.9 mL of 0.1 mol / L phosphoric acid MEK solution was added at 50°C, the solid first dissolved and then precipitated at 50°C. After stirring at 50°C for 1 hour, the temperature was slowly lowered to 18°C ​​(about 0.5K / min); after stirring at 18°C ​​for about 18 hours, it was filtered and dried at 50°C for 3-4 hours to obtain the compound of formula (III) J crystal form.

[0367] Preparation of K crystal form:

[0368] About 50 mg of the compound of formula (I) was weighed and dissolved in 0.4 mL of butanone. After adding 0.9 mL of 0.1 mol / L oxalic acid methanol solution at 50°C, the solution was dissolved at 50°C and no precipitation occurred when the temperature was lowered to 18°C. 3.0 mL of n-heptane was added and the layers were separated. After stirring at 18°C ​​for about 18 hours, a solid was precipitated, which was filtered and dried at 50°C for 3-4 hours to obtain a crystalline form K of the compound of formula (IV).

[0369] Preparation of L crystal form:

[0370] About 50 mg of the compound of formula (I) was weighed and dissolved in 1.0 mL of ethyl acetate. After 8.43 mg of solid oxalic acid was added at 50°C, a white solid precipitated at 50°C and became an oil after stirring at 50°C for 1 hour. The temperature was slowly lowered to 18°C. After stirring at 18°C ​​for about 18 hours, it turned into a solid, filtered, and dried at 50°C for 3-4 hours to obtain the L-form of the compound of formula (IV).

[0371] Preparation of M crystal form:

[0372] About 50 mg of the compound of formula (I) was weighed and dissolved in 1.2 mL of butanone. 10.18 mg of maleic acid was added at 18°C ​​to precipitate a white solid and continued to stir for about 18 hours; filtered, and dried at 50°C for 3-4 hours to obtain a crystalline form M of the compound of formula (V).

[0373] Preparation of N crystal form:

[0374] About 50 mg of the compound of formula (I) was weighed and dissolved in 0.4 mL of butanone. 0.9 mL of p-toluenesulfonic acid solution (0.1 mol / L methanol solution) was added at 18°C ​​and stirring was continued for about 18 h. If no solid was precipitated, 1.0 mL of n-heptane was added to precipitate the solid, which was filtered and dried at 50°C for 3-4 h to obtain the N-form of the compound of formula (VI).

[0375] Preparation of O crystal form:

[0376] About 50 mg of the compound of formula (I) was weighed and dissolved in 0.8 mL of butanone. 0.9 mL of L-arginine solution (0.1 mol / L methanol solution) was added at 18°C. The solution was first dissolved and then a white solid was quickly precipitated. Stirring was continued for about 18 hours. The solid was filtered and dried at 50°C for 3-4 hours to obtain the compound of formula (VII) in form O. 1H NMR (400MHz, CD3OD) δppm 7.60 (t, J = 7.78Hz, 1H) 7.57 (s, 1H) 7.48 (t, J = 8.11Hz, 1H) 7.15-7.23 (m, 2H) 7.04 (d, J = 7.45Hz, 1H) 6.71 (br s,1H)6.66(d,J=8.33Hz,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=4.82,1.75Hz,1H)3.73-3.80(m,1H)3.60-3.71(m,3H)3.24(br s,2H)3.15(d,J=6.14Hz,2H)2.76-2.84(m,2H)2.66-2.75(m,4H)2.61(br s,2H)2.40-2.52(m,1H).

[0377] Preparation of P crystal form:

[0378] About 50 mg of the compound of formula (I) was weighed and dissolved in 1.4 mL of acetonitrile. 0.9 mL of L-arginine solution (0.1 mol / L methanol solution) was added at 18°C. The solution was first dissolved and then a white solid was quickly precipitated. Stirring was continued for about 18 hours. The solid was filtered and dried at 50°C for 3-4 hours to obtain the compound of formula (VII) in form P.

[0379] Preparation of Q crystal form:

[0380] About 50 mg of the compound of formula (I) was weighed and dissolved in 1.0 mL of acetonitrile. 0.9 mL of meglumine solution (0.1 mol / L methanol solution) was added at 18°C ​​to dissolve the solution first. 2.0 mL of methyl tert-butyl ether was added and stirred for about 10 min to precipitate a solid. The mixture was stirred for about 18 h. The solid was filtered and dried at 50°C for 3-4 h to obtain a crystalline form Q of the compound of formula (VIII).

[0381] Preparation of R crystal form:

[0382] About 50 mg of the compound of formula (I) was weighed and dissolved in 0.6 mL of tetrahydrofuran. 0.8 mL of acetonitrile was slowly added to the solution at 17° C. Solid precipitated and was filtered to obtain the R crystal form of the compound of formula (I).

[0383] Preparation of S crystal form:

[0384] About 50 mg of the compound of formula (I) was weighed and dissolved in 0.2 mL of tetrahydrofuran at 50°C. After stirring at 50°C for a period of time, the mixture was cooled to 20°C at a certain cooling rate. Solid precipitated and was filtered to obtain the S crystal form of the compound of formula (I).

[0385] Preparation of T crystal form:

[0386] About 50 mg of the compound of formula (I) was weighed, 0.8 mL of methanol was added, and the system was maintained in a suspended stirring state at 20° C. After a period of time, the solid was filtered to obtain the T crystal form of the compound of formula (I-1).

[0387] Preparation of U crystal form:

[0388] About 50 mg of the compound of formula (I) was weighed, 0.8 mL of ethyl acetate was added, and the system was maintained in a suspended stirring state at 20° C. After a period of time, the solid was filtered to obtain the U crystal form of the compound of formula (I-1).

[0389] Preparation of Form V:

[0390] About 50 mg of the compound of formula (I) was weighed, 0.6 mL of acetonitrile was added, and the system was maintained in a suspended stirring state at 50° C. After a period of time, the solid was filtered to obtain the crystal form V of the compound of formula (I).

[0391] Example 3: Hygroscopicity study of crystal forms

[0392] SMS Intrinsic dynamic vapor sorption instrument was used to test 10 mg of each of the crystal form A of the compound of formula (II-1), the crystal form E of the compound of formula (II), and the crystal form Q of the compound of formula (VIII) in the DVS sample tray. See the DVS spectrum for specific results. Figures 27 to 29 shown.

[0393] From the above, it can be seen that the moisture absorption weight gain of the crystal form A of the compound of formula (II-1) at 25°C and 80% RH is 2.20%, which is hygroscopic. Before and after adsorption and desorption, the crystal form changes. The moisture absorption weight gain of the crystal form E of the compound of formula (II) at 25°C and 80% RH is 2.20%, which is hygroscopic. Before and after adsorption and desorption, the crystal form changes. The moisture absorption weight gain of the crystal form Q of the compound of formula (VIII) at 25°C and 80% RH is 1.08%, which is slightly hygroscopic. Before and after adsorption and desorption, the crystal form remains unchanged.

[0394] Example 4: Solid Stability Study of Crystalline Form E of Compound (II)

[0395] Weigh 500 mg of the crystal form E of the compound of formula (II), place it at the bottom of a glass sample bottle, and spread it into a thin layer. Place it under accelerated conditions (40°C / 75% RH and 60°C / 75% RH), and the sample is a fully exposed sample. The sample was sampled and tested by XRPD on the 5th day, 15th day, 1 month, and 2 months after placement. The test results were compared with the initial test results on day 0. The test results are shown in Table 23 below:

[0396] Table 23E Solid Stability Study Results

[0397]

[0398] Conclusion: The crystalline form E of compound of formula (II) has good stability.

[0399] Example 5: Solid Stability Study of Crystalline Form Q of Compound (VIII)

[0400] Weigh 500 mg of the Q crystal form of the compound of formula (VIII), place it at the bottom of a glass sample bottle, and spread it into a thin layer. Place it under accelerated conditions (40°C / 75% RH and 60°C / 75% RH), and the sample is a fully exposed sample. The sample was sampled and tested by XRPD on the 5th day, 15th day, and 1 month after being placed. The test results were compared with the initial test results on day 0. The test results are shown in Table 24 below:

[0401] Table 24Q solid stability study results

[0402]

[0403] Conclusion: The Q crystal form of compound (VIII) has good stability.

[0404] Experimental Example 1: In vitro cell activity test

[0405] 1. Materials

[0406] 1) Cell line This cell line was constructed by Shanghai WuXi AppTec Pharmaceutical Development Co., Ltd. The detailed information is shown in the following table.

[0407] Target Host cells GLP-1 HEK293

[0408] 2) Reagents

[0409] 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)

[0410] 3) Instruments

[0411] 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

[0412] 4) Compound information

[0413] The compounds were prepared with DMSO to a working concentration of 30 μM. In this test, 5 μL of each sample was used.

[0414] 2. Methods

[0415] 1) Experimental Materials

[0416] Assay buffer

[0417]

[0418] Adjust pH to 7.4 and make up to 25 mL with HBSS 1x.

[0419] Preparation of detection reagents

[0420] Prepare cAMP detection reagent: add 250 μL cAMP-D2, 250 μL anti-cAMP cryptate reagent to 4 mL lysis buffer and mix gently.

[0421] 2) Experimental methods

[0422] a) Preparation of compound plates:

[0423] The test compound was diluted 3-fold at 10 points, with a starting concentration of 30 μM, and Bravo completed the dilution.

[0424] The reference compound exenatide was diluted 3-fold at 10 points with a starting concentration of 500 nM and Bravo completed the dilution.

[0425] b) Transfer compounds:

[0426] 1) Use Echo to transfer 100 nL of compound to OptiPlate-384 plate.

[0427] 2) Centrifuge the OptiPlate-384 plate at 1000 rpm for 5 seconds.

[0428] c) Preparation of cell suspension

[0429] 1) Thaw a GLP-1 cell cryopreservation tube rapidly in 37°C warm water.

[0430] 2) Transfer the cell suspension to a 15 mL centrifuge tube and gently rinse with 10 mL HBSS.

[0431] 3) Centrifuge the tube at 1000 rpm at room temperature for 1 minute.

[0432] 4) Discard the supernatant.

[0433] 5) Gently break up the cells at the bottom and gently rinse with 10 mL HBSS, centrifuge to sediment the cells, and finally resuspend the cells with experimental buffer.

[0434] 6) Use Vi-cell to measure cell density and activity.

[0435] 7) Dilute the GLP-1 cell concentration to 2.0*10 with assay buffer 5 / mL.

[0436] 8) Transfer 100 nL of the diluted cell suspension into the OptiPlate-384 plate.

[0437] 9) Incubate at room temperature for 30 minutes.

[0438] d) Add detection reagent:

[0439] 1) Add 10 μL of 800 nM serially diluted cAMP standard to the empty wells of the OptiPlate-384 plate.

[0440] 2) Add 10 μL cAMP detection reagent.

[0441] 3) Cover the OptiPlate-384 plate with TopSeal-A film and incubate at room temperature for 60 minutes.

[0442] Remove TopSeal-A and read on EnVision.

[0443] The experimental results are shown in Table 25:

[0444] Table 25 In vitro cell activity test results

[0445] Compound <![CDATA[Human-GLP1,EC 50 (nM)]]> Compound of formula (O) 0.37

[0446] Conclusion: The compounds of the present invention exhibit superior agonist ability on GLP-1 receptor.

[0447] Experimental Example 2: DMPK study in rats:

[0448] Purpose:

[0449] Male SD rats were used as test animals. The blood concentrations of the compounds were measured after a single administration and the pharmacokinetic behavior was evaluated.

[0450] Experimental operation:

[0451] Two healthy adult male SD rats were selected as the oral group. The oral solvent was 20% PEG400 / 10% solutol / 70% water. After the test compound was mixed with the solvent, it was vortexed and sonicated to prepare a 0.5 mg / mL clear solution. After 5 mg / kg of oral administration to rats, whole blood was collected for a certain period of time to prepare plasma. The drug concentration was analyzed by LC-MS / MS method, and the pharmacokinetic parameters were calculated using Phoenix WinNonlin software (Pharsight, USA). The experimental results are shown in Table 26:

[0452] Table 26 PK test results of the compounds of the present invention

[0453] Compound No. <![CDATA[C max (nM)]]> <![CDATA[AUC 0-last (h*nmol / L)]]> F％ Compound of formula (O) 85.5 234 6.6％ Compound A of formula (II-1) 174 476 11.5％ Formula (VIII) Compound Q Crystal Form 185 530 13.6％

[0454] Note: PEG means polyethylene glycol; solutol means polyethylene glycol-15 hydroxystearate; C max is the maximum concentration; AUC 0-last is the 24-hour oral exposure, Dose is the drug dose, and F% is the oral bioavailability.

[0455] Conclusion: The crystalline form of the compound of the present invention exhibits higher oral exposure and better oral bioavailability, demonstrating the good pharmacokinetic properties of oral drugs.

[0456] Experimental Example 3: DMPK study in cynomolgus monkeys:

[0457] Purpose:

[0458] Male cynomolgus monkeys were used as test animals. The blood concentration of the compound was measured after a single dose and the pharmacokinetic behavior was evaluated.

[0459] Experimental operation:

[0460] Two healthy male cynomolgus monkeys were selected as a group. The oral solvent was a 20% HP-β-CD aqueous solution. After the test compound was mixed with the solvent, it was vortexed and sonicated to prepare a 4 mg / mL approximately clear solution. The oral dosage of cynomolgus monkeys was 20 mg / kg. After oral administration, whole blood was collected for a certain period of time to prepare plasma. The drug concentration was analyzed by LC-MS / MS method, and the pharmacokinetic parameters were calculated using Phoenix WinNonlin software (Pharsight, USA). The experimental results are shown in Table 27:

[0461] Table 27 PK test results of the compounds of the present invention

[0462]

[0463]

[0464] Note: HP-β-CD stands for hydroxypropyl-β-cyclodextrin; C max is the maximum concentration; AUC 0-last is the 24-hour oral exposure; F% is the oral bioavailability.

[0465] Conclusion: The crystalline form of the compound of the present invention exhibits higher oral exposure and better oral bioavailability. The in vivo exposure of the crystalline form is significantly higher than that of the free state, demonstrating the good pharmacokinetic properties of oral drugs.

Claims

1. A pharmaceutically acceptable salt of a compound represented by formula (I), in, The pharmaceutically acceptable salt is selected from tromethamine salt, phosphate salt, citrate salt, oxalate salt, maleate salt, L-tartrate salt, p-toluenesulfonate salt, sodium salt, potassium salt, L-arginine salt, hydroxycholine salt or meglumine salt; When the pharmaceutically acceptable salt is selected from tromethamine salt, s is selected from 0 to 4; Alternatively, when the pharmaceutically acceptable salt is selected from phosphate, citrate, oxalate, maleate, L-tartrate, p-toluenesulfonate, sodium salt, potassium salt, L-arginine salt, hydroxycholine salt or meglumine salt, s is selected from 0.

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

3. The pharmaceutically acceptable salt according to claim 2, 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, and the acid or base is selected from tromethamine, phosphoric acid, citric acid, oxalic acid, maleic acid, L-tartaric acid, p-toluenesulfonic acid, sodium, potassium, L-arginine, hydroxycholine or meglumine.

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

1.

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

1.

7. A method for preparing the pharmaceutically acceptable salt of claim 1, comprising: The step of forming a salt with an acid or a base, wherein the acid or the base is selected from tromethamine, phosphoric acid, citric acid, oxalic acid, maleic acid, L-tartaric acid, p-toluenesulfonic acid, sodium, potassium, L-arginine, hydroxycholine or meglumine.

8. The method according to claim 7, wherein: The solvent used in the salt-forming reaction is selected from at least one of butanone, methanol, ethanol, tetrahydrofuran, ethyl acetate, isopropanol, acetonitrile and methyl tert-butyl ether.

9. A pharmaceutical composition comprising the pharmaceutically acceptable salt according to any one of claims 1 to 6 and optionally a pharmaceutically acceptable excipient.

10. Use of the pharmaceutically acceptable salt according to any one of claims 1 to 6 in the preparation of a medicament for preventing and / or treating metabolic diseases.

11. The use according to claim 10, wherein: The metabolic disease is diabetes, obesity or non-alcoholic fatty liver.

12. A compound of formula (II), in, n is selected from 0 to 4. The compound according to claim 12 , wherein n is selected from 0 to 3.

14. The compound of claim 12, wherein n is selected from 0, 1 / 2, 2 / 3, 1, 2, 2.7 or 3.

15. The compound according to claim 12, wherein the compound of formula (II) has the following structure:

16. Crystal form A of the compound of formula (II), characterized in that Its X-ray powder diffraction spectrum 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°, Wherein, n is selected from 0 to 4.

17. The crystal form A according to claim 16, characterized in that: 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°, and 30.9896°.

18. The crystal form A according to claim 16 or 17, whose XRPD pattern is substantially as shown in Figure 1; or 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; or Its DSC spectrum is substantially as shown in Figure 2; or Its thermogravimetric analysis curve shows a weight loss of 2.43% at 150.0±3.0°C; or Its TGA spectrum is basically shown in Figure 3.

19. Crystal form E of the compound of formula (II), characterized in that Its X-ray powder diffraction spectrum 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°, Wherein, n is selected from 0 to 4.

20. The crystal form E according to claim 19, characterized in that: Its X-ray powder diffraction spectrum 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°, 21.485 0°, 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°.

21. The crystal form E according to claim 19 or 20, whose XRPD pattern is substantially as shown in Figure 7; or Its differential scanning calorimetry curve has a peak value of an endothermic peak at 91.0±3.0°C and 149.9±3.0°C; or Its DSC spectrum is substantially as shown in Figure 8; or Its thermogravimetric analysis curve shows a weight loss of 6.37% at 150.0±3.0°C; or Its TGA spectrum is basically shown in Figure 9.

22. Crystal form J of the compound of formula (III), characterized in that Its X-ray powder diffraction spectrum 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°, Wherein, i is selected from 0.

23. The J crystal form according to claim 22, characterized in that: Its X-ray powder diffraction spectrum 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°, 20.53 8°, 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°.

24. The J crystalline form according to claim 22 or 23, whose XRPD pattern is substantially as shown in Figure 14.

25. Compounds of formula (IV), in, m is selected from 0.

26. Crystal form K of the compound of formula (IV-1), characterized in that Its X-ray powder diffraction spectrum 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°, 27. The K crystal form according to claim 26, characterized in that 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°, and 26.841°.

28. The K crystal form according to claim 26 or 27, whose XRPD pattern is substantially as shown in Figure 15.

29. The L crystal form of the compound of formula (IV), characterized in that Its X-ray powder diffraction spectrum 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°, Wherein, m is selected from 0.

30. The L crystal form according to claim 29, characterized in that 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°.

31. The L crystalline form according to claim 29 or 30, which has an XRPD pattern substantially as shown in Figure 16.

32. A compound of formula (V), in, o is selected from 0.

33. Crystalline form M of the compound of formula (V), characterized in that: Its X-ray powder diffraction spectrum 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°, Among them, o is selected from 0.

34. The M crystal form according to claim 33, characterized in that 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°, and 33.086°.

35. The M crystalline form according to claim 33 or 34, whose XRPD pattern is substantially as shown in Figure 17.

36. A compound of formula (VI), 37. The N-crystalline form of the compound of formula (VI), characterized in that Its X-ray powder diffraction spectrum 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°, 38. The N crystal form according to claim 37, characterized in that: Its X-ray powder diffraction spectrum 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°, 2 1.454°, 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°.

39. The N crystalline form according to claim 37 or 38, whose XRPD pattern is substantially as shown in Figure 18.

40. A compound of formula (VII), in, p is selected from 0.

41. Crystalline Form O of the compound of formula (VII), characterized in that Its X-ray powder diffraction spectrum 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°, Wherein, p is selected from 0.

42. The O crystal form according to claim 41, characterized in that 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°, and 35.581°.

43. The O crystal form according to claim 41 or 42, whose XRPD pattern is substantially as shown in Figure 19.

44. Crystalline Form P of the compound of formula (VII), characterized in that Its X-ray powder diffraction spectrum 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°, Wherein, p is selected from 0.

45. The P crystal form according to claim 44, whose XRPD pattern is substantially as shown in Figure 20.

46. ​​A compound of formula (VIII), 47. The Q crystal form of the compound of formula (VIII), characterized in that Its X-ray powder diffraction spectrum 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°, 48. The Q crystal form according to claim 47, characterized in that Its X-ray powder diffraction spectrum 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°, 20.56 9°, 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°.

49. The Q crystal form according to claim 47 or 48, which has an XRPD pattern substantially as shown in Figure 21.

50. A compound of formula (III), in, i is selected from 0.

51. Use of a compound according to any one of claims 12-15, 25, 32, 36, 40, 46 or 50, or the A crystal form according to any one of claims 16-18, or the E crystal form according to any one of claims 19-21, or the J crystal form according to any one of claims 22-24, or the K crystal form according to any one of claims 26-28, or the L crystal form according to any one of claims 29-31, or the M crystal form according to any one of claims 33-35, or the N crystal form according to any one of claims 37-39, or the O crystal form according to any one of claims 41-43, or the P crystal form according to claims 44 or 45, or the Q crystal form according to any one of claims 47-49 in the preparation of a medicament for treating metabolic diseases.

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