Crystals of pyridinopyrimidinone compounds, acid salts thereof, crystals of acid salts thereof and use thereof

Abstract

Disclosed are crystals of pyridopyrimidinone compounds of formula I, pharmaceutically acceptable salts thereof, and crystals of pharmaceutically acceptable salts thereof, which exhibit significant inhibitory effects on RAS and SOS1 binding and have ideal physical and chemical properties, such as higher stability, solubility and bioavailability, and lower hygroscopicity, making them suitable for the production of desirable pharmaceutical formulations. [Formula 1] TIFF2025526715000104.tif46170

Description

Detailed Description of the Invention

[0001] This application claims priority from Chinese Patent Application No. 2022109460522, filed on August 8, 2022. This application cites the above Chinese patent application in its entirety. [Technical field] The present invention relates to a crystal of a pyridinopyrimidinone compound, an acid salt thereof, a crystal of the acid salt, and use thereof.

[0002] [Background technology] RAS proteins are membrane-bound proteins with intrinsic GTPase activity that are activated by numerous extracellular stimuli and cycle between GDP-bound (off) and GTP-bound (on) states. In the GTP-bound (on) state, they activate downstream pathways and promote a series of processes, including cell proliferation, differentiation, migration, and immunity.

[0003] The RAS protein family includes three highly homologous isoforms: KRAS (Kirsten rat sarcoma virus oncogene), HRAS (Harvey rat sarcoma virus oncogene), and NRAS (Neuroblastoma ras oncogene). KRAS includes two alternative splicing variants, KRAS4A and KRAS4B. RAS family proteins have weak intrinsic GTPase activity and slow nucleotide exchange rates.

[0004] Activating mutations in the RAS gene are an important cause of tumorigenesis, and RAS mutations occur in 27% of all tumor patients. Among them, KRAS mutations are the most common, accounting for 86% of all tumors. KRAS-4B mutations are present in approximately 90% of pancreatic cancers, 30%-40% of colon cancers, and 15%-20% of lung cancers. These mutations are also present in bile duct malignancies, endometrial cancer, cervical cancer, bladder cancer, liver cancer, myeloid leukemia, and breast cancer. The most common type of KRAS gene mutation is point mutation, with the most common mutations being KRAS-G12D (41%), KRAS-G12V (28%), and KRAS-G12C (14%). Mutant KRAS activates GTPase-activating proteins (GTPases). It affects the ability of GTPase to bind to GAP (glutamic acid protein, or GAP), thereby inhibiting GAP-induced GTP hydrolysis. As the GTPase hydrolysis ability decreases, GTP gradually accumulates, making it easier for KRAS to bind to GTP, leading to the activation of most KRAS enzymes and the development of malignant tumors.

[0005] The transition from an inactive to an active state of RAS proteins involves the release of GDP and the binding of GTP. GDP release requires the involvement of guanine nucleotide exchange factors (GMP exchange factors, GEFs) such as the SOS (Son of Sevenless) protein. SOS proteins, first discovered in Drosophila in 1992, are GEFs for RAS and Rac proteins and play an important role in the RAS and Rac signaling pathways. Humans have two SOS homologs, SOS1 and SOS2, which share 70% homology in structure and sequence, but differ in their biological functions. The SOS1 protein consists of 1,300 amino acid residues and contains a proline-rich domain at its C-terminus that interacts with growth factor receptor-bound protein 2 (Grb2) in the RAS pathway. After Grb2 and SOS1 bind to form a complex, they transport SOS1 to the plasma membrane near the RAS proteins. The interaction between SOS1 and RAS involves two domains of SOS1: the CDC25 domain, which contains the active site for nucleotide exchange, and the REM domain, which contains the active site for nucleotide exchange. It contains a site that can bind RAS-GTP, triggering allosteric activation of the CDC25 domain. SOS1 can convert GDP to GTP through catalytic exchange, which is then hydrolyzed by RAS, activating downstream signals and triggering a corresponding series of biological effects.

[0006] Specific SOS1 inhibitors can block the interaction between SOS1 and KRAS-GDP, thereby reducing the formation of activated KRAS-GTP. Reduced KRAS-GTP levels lead to a decrease in downstream MAPK signaling, which plays a role in both wild-type and multiple KRAS mutants. The SOS1 small molecule inhibitor BAY-293 effectively reduces the activity of mutant and wild-type KRAS in tumor cells. Boehringer Ingelheim's SOS1 inhibitors BI-3406 and BI-1701963 bind to the catalytic domain of SOS1, blocking its interaction with KRAS and reducing KRAS-GTP formation, thereby inhibiting the proliferation of various KRAS-driven cancer cells. The combined use of SOS1 and MEK inhibitors significantly reduces KRAS signaling and enhances antitumor activity through complementary mechanisms of action. According to Boehringer Ingelheim, BI-3406 inhibits cytochrome P450 3A4 (CYP3A4) in a time-dependent manner, posing a potential risk of drug-drug interactions (DDIs). Therefore, the development of inhibitors that do not inhibit cytochrome P450 has the advantage that SOS1 inhibitors that do not inhibit CYP3A4 have greater clinical value, and combination therapy with BI-1701963 and the MEK inhibitor trametinib is currently undergoing clinical research.

[0007] In addition to cancer, mutations and abnormal expression of the SOS1 gene are closely associated with the development of several genetic disorders. Noonan syndrome (NS) is an autosomal dominant disorder. Approximately 20% of NS patients have SOS1 mutations, which are distributed across six domains of SOS1. Patients with SOS1 mutations exhibit phenotypic characteristics such as curly hair and ectodermal abnormalities. Mutations in the CDC25 domain directly increase the GEF activity of SOS1, which can induce overactivation of the RAS / ERK pathway. Cardio-facio-cutaneous syndrome, a member of the renin-angiotensin-dependent cardiomyopathies, has been reported to be associated with SOS1 mutations. Hereditary gingival fibromatosis type 1 is an autosomal dominant disorder whose etiology is associated with mutations in the proline-rich domain of SOS1.

[0008] A compound of Formula I, having the structure represented by Formula I:

[0009] [ka]

[0010] This compound is described in Patent CN202210117751.6 and is used as an inhibitor of the interaction between the catalytic site of SOS1 and RAS family proteins, which are involved in the control of cell proliferation, and can be used to treat diseases involving excessive or abnormal cell proliferation.

[0011] The phenomenon in which a substance can exist in two or more different crystalline structures is called polymorphism. In the case of drugs, this crystalline polymorphism can affect drug absorption and further affect drug bioavailability, which may result in different clinical effects and toxic side effects. In light of this, it is very important to develop advantageous crystalline forms of the compound of formula I and its salts that have advantageous properties.

[0012] [Summary of the Invention] The present invention provides a crystal of the compound of formula I and its acid salt, as well as a crystal of the acid salt. The preparation method of the above crystal is simple, suitable for industrial production, does not absorb water easily, and has good stability and solubility, which is of great value for drug optimization and development.

[0013] The present invention provides a crystalline form A of the compound of formula I, which has a powder X-ray diffraction spectrum expressed as 2θ angles, with diffraction peaks at 12.06±0.2°, 14.68±0.2°, 18.13±0.2°, 19.12±0.2°, 20.25±0.2°, 22.09±0.2°, and 24.75±0.2°.

[0014] [ka]

[0015] Furthermore, the A-type crystal of the compound of formula I has a powder X-ray diffraction spectrum represented by 2θ angles, which has diffraction peaks at 10.30±0.2°, 12.06±0.2°, 12.42±0.2°, 14.68±0.2°, 15.10±0.2°, 17.78±0.2°, 18.13±0.2°, 19.12±0.2°, 20.25±0.2°, 21.76±0.2°, 22.09±0.2° and 24.75±0.2°; Furthermore, the A-type crystal of the compound of formula I has a powder X-ray diffraction spectrum represented by 2θ angles, which has diffraction peaks at 6.02±0.2°, 7.78±0.2°, 10.30±0.2°, 11.42±0.2°, 12.06±0.2°, 12.42±0.2°, 14.68±0.2°, 15.10±0.2°, 16.61±0.2°, 17.78±0.2°, 18.13±0.2°, 18.48±0.2°, 19.12±0.2°, 19.98±0.2°, 20.25±0.2°, 21.76±0.2°, 22.09±0.2° and 24.75±0.2°; Furthermore, the A-type crystal of the compound of formula I may have a powder X-ray diffraction pattern represented by 2θ angles, whose diffraction peaks and relative intensities are further as shown in Table 8, The Form A crystal of the compound of formula I may further have a powder X-ray diffraction pattern expressed in 2θ angles essentially as shown in FIG.

[0016] In a preferred embodiment, the thermogravimetric analysis spectrum (TGA) of the A-type crystal of the compound of formula I shows a weight loss upon heating from the start to 120±5°C, preferably a weight loss of 2% to 4% (e.g., 3.24%) (the weight loss percentage is the percentage of the weight loss of the sample to the weight of the sample before the weight loss).

[0017] In one preferred embodiment, the differential scanning calorimetry (DSC) of the A-type crystal of the compound of formula I is The DSC spectrum may have a major endothermic peak at 73.3°C ± 3°C and / or 178.0°C ± 3°C.

[0018] In a preferred embodiment, the DSC spectrum of the crystalline form A of the compound of formula I may further be essentially as shown in FIG. In a preferred embodiment, the TGA spectrum of the Form A crystal of the compound of formula I may further be essentially as shown in FIG.

[0019] In a preferred embodiment, the Type A crystal of the compound of formula I is a hydrate of the compound of formula I, wherein the molar ratio of the compound of formula I to water is 1:(0.5 to 1.5), preferably 1:(1 to 1.5), for example, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1.0, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4 or 1:1.5, and most preferably 1:1 or 1:1.5.

[0020] The present invention provides a type B crystal of the compound of formula I, which has a powder X-ray diffraction spectrum expressed as 2θ angles and has diffraction peaks at 12.30±0.2°, 12.89±0.2°, 14.49±0.2°, 18.10±0.2°, 18.70±0.2°, 20.33±0.2°, and 21.66±0.2°.

[0021] Furthermore, the type B crystal of the compound of formula I has diffraction peaks at 2θ angles of 12.30±0.2°, 12.89±0.2°, 14.49±0.2°, 15.32±0.2°, 17.45±0.2°, 18.10±0.2°, 18.70±0.2°, 20.33±0.2°, 21.66±0.2°, 22.01±0.2°, 22.52±0.2°, 23.23±0.2°, 24.35±0.2° and 24.69±0.2° in a powder X-ray diffraction spectrum; Furthermore, in the powder X-ray diffraction spectrum, the type B crystals of the compound of formula I have 2θ angles: 10.08±0.2°, 10.30±0.2°, 11.58±0.2°, 12.30±0.2°, 12.89±0.2°, 14.49±0.2°, 15.32±0.2°, 16.39±0.2°, 16.89±0.2°, 17.45±0.2°. 2°, 18.10±0.2°, 18.21±0.2°, 18.70±0.2°, 19.84±0.2°, 20.33±0.2°, 21.05±0.2°, 21.66±0.2°, 22.01±0.2°, 22.52±0.2°, 23.23±0.2°, 24.35±0.2° and 24.69±0.2°, Furthermore, the B-type crystal of the compound of formula I may have a powder X-ray diffraction pattern represented by 2θ angles, whose diffraction peaks and relative intensities are as shown in Table 10: The B-type crystal of the compound of formula I may further have a powder X-ray diffraction pattern expressed in 2θ angles essentially as shown in FIG.

[0022] The present invention also provides pharmaceutically acceptable salts of compounds of Formula I, which are salts formed by compounds of Formula I with an acid, wherein the acid is hydrochloric acid, sulfuric acid, maleic acid, aspartic acid, phosphoric acid, fumaric acid, tartaric acid, citric acid, glucuronic acid, glycolic acid, malic acid, hippuric acid, gluconic acid, lactic acid, succinic acid, ascorbic acid, adipic acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, oxalic acid, 2-hydroxyethanesulfonic acid, ethanesulfonic acid, gentisic acid, or benzoic acid.

[0023] In one preferred embodiment, the pharmaceutically acceptable salt of the compound of formula I is in crystalline form. In one preferred embodiment, the acid is fumaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, maleic acid, L-tartaric acid, glycolic acid, L-malic acid, hippuric acid, succinic acid, ascorbic acid, adipic acid, p-toluenesulfonic acid, benzenesulfonic acid, acid, oxalic acid or 2-hydroxyethanesulfonic acid.

[0024] In a preferred embodiment, the molar ratio of the compound of formula I to the acid is 1:(0.5 to 1.2), for example, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1, or 1:1.2.

[0025] In one preferred embodiment, the pharmaceutically acceptable salt of the compound of formula I is any of the pharmaceutically acceptable salts below. (1) a fumarate salt of the compound of formula I, wherein the molar ratio of the compound of formula I to fumaric acid is 1:1; (2) a citrate salt of the compound of formula I, wherein the molar ratio of the compound of formula I to citric acid is 1:(1-1.2), for example, 1:1, 1:1.1, or 1:1.2; (3) a methanesulfonate salt of the compound of formula I, wherein the molar ratio of the compound of formula I to methanesulfonic acid is 1:(0.8-1), for example, 1:1, 1:0.9, or 1:0.8; (4) an ethanesulfonic acid salt of the compound of formula I, wherein the molar ratio of the compound of formula I to ethanesulfonic acid is 1:1; (5) a maleate salt of the compound of formula I, wherein the molar ratio of the compound of formula I to maleic acid is 1:1; (6) L-tartrate salt of the compound of formula I, wherein the molar ratio of the compound of formula I to L-tartaric acid is 1:(0.5-1.1), for example, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, or 1:1.1; (7) A glycolate salt of the compound of formula I, wherein the molar ratio of the compound of formula I to glycolic acid is 1:(1-1.1), for example, 1:1 or 1:1.1; (8) L-malate salt of the compound of formula I, wherein the molar ratio of the compound of formula I to L-malic acid is 1:(1 to 1.1), for example, 1:1 or 1:1.1; (9) The hippuric acid salt of the compound of formula I, wherein the molar ratio of the compound of formula I to hippuric acid is 1:1; (10) A succinate salt of the compound of formula I, wherein the molar ratio of the compound of formula I to succinic acid is 1:(0.8-1.2), for example, 1:0.8, 1:0.9, 1:1, or 1:1.2; (11) Ascorbate salt of the compound of formula I, wherein the molar ratio of the compound of formula I to ascorbic acid is 1:(0.5-1.2), for example, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, or 1:1.2; (12) Adipic acid salt of the compound of formula I, wherein the molar ratio of the compound of formula I to adipic acid is 1:1; (13) p-toluenesulfonic acid salt of the compound of formula I, wherein the molar ratio of the compound of formula I to p-toluenesulfonic acid is 1:1; (14) benzenesulfonic acid salt of the compound of formula I, wherein the molar ratio of the compound of formula I to benzenesulfonic acid is 1:1; (15) The oxalate salt of the compound of formula I, wherein the molar ratio of the compound of formula I to oxalic acid is 1:1; (16) 2-hydroxyethanesulfonic acid salt of the compound of formula I, wherein the molar ratio of the compound of formula I to 2-hydroxyethanesulfonic acid is 1:(1 to 1.1), for example, 1:1 or 1:1.1.

[0026] The present invention provides a method for preparing a pharmaceutically acceptable salt of a compound of formula I, comprising the step of reacting a compound of formula I with an acid in a solvent to form a salt, to obtain a pharmaceutically acceptable salt of the compound of formula I, wherein the acid is selected from the group consisting of hydrochloric acid, sulfuric acid, maleic acid, aspartic acid, phosphoric acid, fumaric acid, tartaric acid, citric acid, glucuronic acid, glycolic acid, malic acid, hippuric acid, gluconic acid, and the like. The acid may be, for example, lactic acid, succinic acid, ascorbic acid, adipic acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, oxalic acid, 2-hydroxyethanesulfonic acid, ethanesulfonic acid, gentisic acid or benzoic acid.

[0027] In one preferred embodiment, the solvent comprises one or more of water, ethyl acetate, methyl tert-butyl ether, acetone, n-heptane, and isopropanol, preferably one or more of water, ethyl acetate, methyl tert-butyl ether, acetone, and n-heptane.

[0028] In one preferred embodiment, the molar ratio of the compound of formula I to the acid is 1:(1±0.5), preferably 1:(1±0.2), 1:(1±0.1), for example 1:1.

[0029] In one preferred embodiment, the acid is fumaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, maleic acid, L-tartaric acid, glycolic acid, L-malic acid, hippuric acid, succinic acid, ascorbic acid, adipic acid, p-toluenesulfonic acid, benzenesulfonic acid, oxalic acid, or 2-hydroxyethanesulfonic acid.

[0030] The present invention provides a crystalline form A of the fumarate salt of the compound of formula I, which has a powder X-ray diffraction spectrum expressed as 2θ angles, with diffraction peaks at 6.86±0.2°, 7.72±0.2°, 16.47±0.2°, 19.20±0.2°, 19.63±0.2°, 22.47±0.2°, and 23.26±0.2°.

[0031] Furthermore, in a powder X-ray diffraction spectrum, the A-type crystal of the fumarate salt has diffraction peaks at 2θ angles of 6.86±0.2°, 7.72±0.2°, 9.57±0.2°, 16.47±0.2°, 19.20±0.2°, 19.63±0.2°, 22.47±0.2°, 23.26±0.2°, and 23.95±0.2°; Furthermore, the type A crystal of the fumarate salt may have diffraction peaks at 2θ angles of 6.86±0.2°, 7.72±0.2°, 9.57±0.2°, 13.72±0.2°, 15.45±0.2°, 15.87±0.2°, 16.47±0.2°, 17.13±0.2°, 17.47±0.2°, 18.19±0.2°, 18.72±0.2°, 19.20±0.2°, 19.63±0.2°, 19.97±0.2°, 22.47±0.2°, 23.26±0.2°, 23.95±0.2°, 25.93±0.2°, and 31.16±0.2° in a powder X-ray diffraction pattern; Furthermore, in the powder X-ray diffraction pattern, the A-type crystal of the fumarate salt further exhibits 2θ angles of 6.86±0.2°, 7.72±0.2°, 9.57±0.2°, 12.90±0.2°, 13.17±0.2°, 13.72±0.2°, 15.45±0.2°, 15.87±0.2°, 16.47±0.2°, 17.13±0.2°, 17.47±0.2°, 18.19±0.2°, and may have diffraction peaks at 18.72±0.2°, 19.20±0.2°, 19.63±0.2°, 19.97±0.2°, 20.89±0.2°, 22.47±0.2°, 23.26±0.2°, 23.95±0.2°, 25.93±0.2°, 26.28±0.2°, 27.23±0.2°, 29.54±0.2°, 29.82±0.2° and 31.16±0.2°; Furthermore, the A-type crystals of the fumarate salt may have a powder X-ray diffraction pattern represented by 2θ angles, with diffraction peaks and relative intensities as shown in Table 11, The Form A crystal of the fumarate salt of the compound of Formula I may further have a powder X-ray diffraction pattern, expressed in 2θ angles, essentially as shown in FIG.

[0032] In one preferred embodiment, the molar ratio of the compound of formula I to fumaric acid is 1:1. In one preferred embodiment, the thermogravimetric analysis spectrum of the A-type crystals of the fumarate salt shows a weight loss of 0% to 5% (e.g., 3.35%) when heated to 150±5°C from the start (the weight loss percentage is the percentage of the weight loss of the sample to the weight of the sample before this weight loss).

[0033] In one preferred embodiment, the differential scanning calorimetry spectrum of the Form A crystals of the fumarate salt may have a major endothermic peak at 214.7°C ± 3°C. In a preferred embodiment, the DSC spectrum of the crystalline form A of the fumarate salt may further be essentially as shown in FIG.

[0034] In a preferred embodiment, the TGA spectrum of crystalline Form A of the fumarate salt may further be essentially as shown in FIG. In a preferred embodiment, the Type A crystals of fumarate are hydrates of the fumarate of the compound of Formula I, wherein the molar ratio of the compound of Formula I to water is 1:(0.5 to 1.5), preferably 1:(1 to 1.5), for example, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1.0, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4 or 1:1.5, and most preferably 1:1 or 1:1.5.

[0035] The present invention provides a B-type crystalline form of a fumarate salt of the compound of formula I, which has diffraction peaks at 4.78±0.2°, 8.02±0.2°, 9.68±0.2°, 16.57±0.2°, 17.93±0.2°, 18.57±0.2°, and 28.81±0.2° in a powder X-ray diffraction spectrum expressed as 2θ angles, Furthermore, in a powder X-ray diffraction spectrum, the type B crystals of the fumarate salt have diffraction peaks at 2θ angles of 4.78±0.2°, 8.02±0.2°, 9.68±0.2°, 11.93±0.2°, 16.57±0.2°, 17.93±0.2°, 18.57±0.2°, 19.41±0.2°, 19.95±0.2°, 21.10±0.2°, and 28.81±0.2°.

[0036] Furthermore, in the powder X-ray diffraction spectrum, the B-type crystals of the fumarate salt exhibited 2θ angles of 4.78±0.2°, 5.98±0.2°, 8.02±0.2°, 9.68±0.2°, 11.93±0.2°, 12.44±0.2°, 12.78±0.2°, 14.01±0.2°, 15.38±0.2°, 15.80±0.2°, 16.57 ±0.2°, 17.36±0.2°, 17.93±0.2°, 18.57±0.2°, 19.41±0.2°, 19.95±0.2°, 21.10±0.2°, 23.97±0.2°, 24.76±0.2°, 25.74±0.2°, 26.56±0.2°, 28.81±0.2° and 29.48±0.2°, Furthermore, in the powder X-ray diffraction spectrum, the B-type crystals of the fumarate salt exhibited 2θ angles of 4.78±0.2°, 5.98±0.2°, 8.02±0.2°, 9.68±0.2°, 11.55±0.2°, 11.93±0.2°, 12.44±0.2°, 12.78±0.2°, 14.01±0.2°, 15.24±0.2°, 15.38±0.2°, 15.80±0.2°, 16.57±0.2°, 17.36 ±0.2°, 17.93±0.2°, 18.57±0.2°, 19.41±0.2°, 19.95±0.2°, 21.10±0.2°, 22.15±0.2°, 22.53±0.2°, 22.89±0.2°, 23.97±0.2°, 24.76±0.2°, 25.18±0.2°, 25.74±0.2°, 26.56±0.2°, 28.81±0.2° and 29.48±0.2°, Furthermore, the B-type crystals of the fumarate salt may have a powder X-ray diffraction pattern represented by 2θ angles, whose diffraction peaks and relative intensities are as shown in Table 12, The B-type crystal of the fumarate salt of the compound of formula I has a powder X-ray diffraction pattern represented by 2θ angles: may also be essentially as shown in FIG.

[0037] In one preferred embodiment, the molar ratio of the compound of formula I to fumaric acid is 1:1. In one preferred embodiment, the thermogravimetric analysis spectrum of the B-type crystals of the fumarate salt shows a weight loss of 4% to 6% (e.g., 5.64%) when heated from the start to 150±5°C, and a weight loss of 5% to 7% (e.g., 6.76%) when heated from 150±5°C to 250±5°C (the weight loss percentage is the percentage of the weight loss of the sample to the weight of the sample before this weight loss).

[0038] In one preferred embodiment, the differential scanning calorimetry spectrum of the B-type crystals of the fumarate salt has a main endothermic peak at 154.4°C±3°C and an exothermic peak at 191.9°C±3°C.

[0039] In a preferred embodiment, the DSC spectrum of the crystalline form B of the fumarate salt may further be essentially as shown in FIG. In a preferred embodiment, the TGA spectrum of the crystalline form B of the fumarate salt may further be essentially as shown in FIG.

[0040] The present invention provides a C-type crystalline form of a fumarate salt of the compound of formula I, which has a powder X-ray diffraction spectrum expressed as 2θ angles and has diffraction peaks at 6.85±0.2°, 8.72±0.2°, 13.13±0.2°, 14.09±0.2°, and 17.27±0.2°, Furthermore, in a powder X-ray diffraction spectrum, the C-type crystals of the fumarate salt have diffraction peaks at 2θ angles of 6.85±0.2°, 8.72±0.2°, 13.13±0.2°, 14.09±0.2°, 17.27±0.2°, 17.90±0.2°, 20.60±0.2°, 21.42±0.2°, 23.16±0.2°, and 24.04±0.2°.

[0041] Furthermore, the C-type crystals of the fumarate salt have a powder X-ray diffraction spectrum expressed in 2θ angles, which has diffraction peaks at 6.85±0.2°, 8.72±0.2°, 9.90±0.2°, 12.17±0.2°, 13.13±0.2°, 14.09±0.2°, 14.29±0.2°, 16.33±0.2°, 17.27±0.2°, 17.90±0.2°, 20.60±0.2°, 21.42±0.2°, 23.16±0.2° and 24.04±0.2°; The C-type crystals of the fumarate salt may have a powder X-ray diffraction pattern represented by 2θ angles, whose diffraction peaks and relative intensities are further as shown in Table 13; The C-form crystal of the fumarate salt of the compound of formula I may further have a powder X-ray diffraction pattern, expressed in 2θ angles, essentially as shown in FIG.

[0042] In one preferred embodiment, the molar ratio of the compound of formula I to fumaric acid is 1:1. In one preferred embodiment, the thermogravimetric analysis spectrum of the C-type crystals of the fumarate salt shows a weight loss of 1% to 3% (e.g., 1.69%) when heated from the start to 150±5°C, and a weight loss of 5% to 7% (e.g., 6.21%) when heated from 150±5°C to 250±5°C (the weight loss percentage is the percentage of the weight loss of the sample to the weight of the sample before this weight loss).

[0043] In one preferred embodiment, the differential scanning calorimetry spectrum of the C-type crystals of the fumarate salt has main endothermic peaks at 94.4°C±3°C, 145.0°C±3°C, and 161.2°C±3°C, and an exothermic peak at 190.4°C±3°C.

[0044] In one preferred embodiment, a DSC spectrum of the C-type crystal of the fumarate salt is may also be essentially as shown in FIG. In a preferred embodiment, the TGA spectrum of crystalline Form C of the fumarate salt may further be essentially as shown in FIG.

[0045] The present invention provides a crystalline form A of the citrate salt of the compound of formula I, which has a powder X-ray diffraction spectrum expressed in 2θ angles, with diffraction peaks at 6.27±0.2°, 10.79±0.2°, 12.21±0.2°, 12.58±0.2°, 16.38±0.2°, and 25.33±0.2°.

[0046] Furthermore, the A-type crystal of the citrate salt has diffraction peaks at 2θ angles of 6.27±0.2°, 10.79±0.2°, 12.21±0.2°, 12.58±0.2°, 16.38±0.2°, 18.33±0.2°, and 25.33±0.2° in a powder X-ray diffraction spectrum; Furthermore, the A-type crystals of the citrate salt of the compound of formula I may have a powder X-ray diffraction pattern represented by 2θ angles, whose diffraction peaks and relative intensities are further as shown in Table 14, The Form A crystals of the citrate salt of the compound of Formula I may further have a powder X-ray diffraction pattern, expressed in 2θ angles, essentially as shown in FIG.

[0047] In one preferred embodiment, the molar ratio of the compound of formula I to citric acid is 1:1. In one preferred embodiment, the thermogravimetric analysis spectrum of the A-type crystals of the citrate salt shows a weight loss of 5% to 7% (e.g., 5.72%) when heated from the start to 150±5°C (the weight loss percentage is the ratio of the weight loss of the sample to the weight of the sample before this weight loss), and a weight loss of 18% to 20% (e.g., 19.25%) when heated from 150±5°C to 230±5°C.

[0048] In one preferred embodiment, the differential scanning calorimetry spectrum of the Type A crystals of the Citrate Salt may have major endothermic peaks at 99.1°C±3°C and 137.9°C±3°C.

[0049] In a preferred embodiment, the DSC spectrum of the Form A crystals of the Citrate Salt may further be essentially as shown in FIG. In a preferred embodiment, the TGA spectrum of the Form A crystals of the Citrate Salt may further be essentially as shown in FIG.

[0050] The present invention provides a B-type crystalline form of the citrate salt of the compound of formula I, which has, in a powder X-ray diffraction spectrum expressed as 2θ angles, diffraction peaks at 11.93±0.2°, 15.45±0.2°, 16.45±0.2°, 17.60±0.2°, 19.86±0.2° and 21.18±0.2°, or diffraction peaks at 9.91±0.2°, 12.79±0.2°, 16.45±0.2°, 17.60±0.2° and 20.88±0.2°, In addition, the type B crystals of the citrate salt have diffraction peaks at 2θ angles of 11.93±0.2°, 12.79±0.2°, 15.45±0.2°, 16.45±0.2°, 17.60±0.2°, 19.86±0.2°, 20.88±0.2°, 21.18±0.2°, 23.55±0.2°, and 25.19±0.2° in a powder X-ray diffraction spectrum, or at 9.91±0.2°, 12.79±0.2°, 16.45±0.2°, 17.60±0.2°, 20.88±0.2°, 24.34±0.2°, and 24.70±0.2°.

[0051] Furthermore, the B-type crystals of the citrate salt further exhibit one or more of the following 2θ° angles ±0.2° in the powder X-ray diffraction pattern: 9.90±0.2°, 11.93±0.2°, 12.7 9±0.2°, 15.45±0.2°, 16.45±0.2°, 17.60±0.2°, 18.25±0.2°, 19.34±0.2°, 19.86±0.2°, 20.88±0.2°, 21.18±0.2°, 23.55±0.2°, 25.19±0.2°, 27.72±0.2°, 28.47±0.2°, 29.97±0.2°, 30.65±0.2° and 31.19±0.2°.

[0052] Furthermore, the B-type crystals of the citrate salt further exhibit one or more of the following 2θ° angles ±0.2° in the powder X-ray diffraction pattern: 9.90±0.2°, 11.93±0.2°, 12.79±0.2°, 15.45±0.2°, 16.45±0.2°, 16.72±0.2°, 17.60±0.2°, 18.25±0.2°, 19.34±0.2°, 19.70±0.2°, 20.70±0.2°, 21.70±0.2°, 22.70±0.2°, 23.70±0.2°, 24.70±0.2°, 25.70±0.2°, 26.70±0.2°, 27.70±0.2°, 28.70±0.2°, 29.70±0.2°, 30.70±0.2°, 31.70±0.2°, 32.70±0.2°, 33.70±0.2°, 34.70±0.2°, 35.70±0.2°, 36.70±0.2°, 37.70±0.2°, 38.70±0.2°, 39.70±0.2°, 40.70±0.2°, 41.70±0.2°, 42.70±0.2°, 43.70±0.2°, 44.70±0.2°, 45.70±0.2°, 46.70±0.2°, 47.70±0.2°, 48.70±0.2°, 49 It may have diffraction peaks at 0.86±0.2°, 20.88±0.2°, 21.18±0.2°, 23.22±0.2°, 23.55±0.2°, 24.35±0.2°, 24.68±0.2°, 25.19±0.2°, 27.72±0.2°, 28.47±0.2°, 29.97±0.2°, 30.65±0.2° and 31.19±0.2°.

[0053] Furthermore, the B-type crystals of the citrate salt further exhibit one or more of the following 2θ° angles in the powder X-ray diffraction pattern: 9.90±0.2°, 10.38±0.2°, 11.78±0.2°, 11.93±0.2°, 12.79±0.2°, 15.19±0.2°, 15.45±0.2°, 16.45±0.2°, 16.72±0.2°, 17.60±0.2°, 18.25±0.2°, 19.34±0.2°, 20.34±0.2°, 21.34±0.2°, 22.34±0.2°, 23.34±0.2°, 24.34±0.2°, 25.34±0.2°, 26.34±0.2°, 27.34±0.2°, 28.34±0.2°, 29.34±0.2°, 30.34±0.2°, 31.34±0.2°, 32.34±0.2°, 33.34±0.2°, 34.34±0.2°, 35.34±0.2°, 36.34±0.2°, 37.34±0.2°, 38.34±0.2°, 39.34±0.2°, 40.34±0.2°, 41.34±0.2°, 42.34±0.2°, 43.34±0.2°, 44.34±0.2°, 45.34±0.2°, 46.34±0.2°, 47.34±0 The compound may have diffraction peaks at 19.86±0.2°, 20.88±0.2°, 21.18±0.2°, 23.22±0.2°, 23.55±0.2°, 24.35±0.2°, 24.68±0.2°, 25.19±0.2°, 25.75±0.2°, 27.72±0.2°, 28.47±0.2°, 29.97±0.2°, 30.65±0.2° and 31.19±0.2°.

[0054] The B-type crystals of the citrate salt of the compound of formula I may have a powder X-ray diffraction pattern represented by 2θ angles, whose diffraction peaks and relative intensities are further as shown in Table 15; The B-type crystals of the citrate salt may further have a powder X-ray diffraction pattern, expressed in 2θ angles, essentially as shown in FIG.

[0055] In one preferred embodiment, the molar ratio of the compound of formula I to citric acid is 1:1. In one preferred embodiment, the thermogravimetric analysis spectrum of the B-type crystals of the citrate salt shows a weight loss of 0% to 2% (e.g., 1.26%) when heated to 150±5°C from the start (the weight loss percentage is the percentage of the weight loss of the sample to the weight of the sample before this weight loss).

[0056] In one preferred embodiment, the differential scanning calorimetry spectrum of the B-type crystals of the citrate salt may have a main endothermic peak at 195.0°C ± 3°C. In a preferred embodiment, the DSC spectrum of the B-type crystals of the Citrate Salt may further be essentially as shown in FIG.

[0057] In a preferred embodiment, the TGA spectrum of the Type B crystals of the Citrate Salt may further be essentially as shown in FIG. The present invention provides a crystalline form A of the methanesulfonate salt of the compound of formula I, which has a powder X-ray diffraction spectrum expressed as 2θ angles, with diffraction peaks at 7.28±0.2°, 10.86±0.2°, 12.71±0.2°, 14.20±0.2°, 14.58±0.2°, 16.67±0.2°, 18.70±0.2°, and 19.96±0.2°.

[0058] Furthermore, the type A crystal of the methanesulfonate salt has diffraction peaks at 2θ angles of 7.28±0.2°, 10.86±0.2°, 12.71±0.2°, 14.20±0.2°, 14.58±0.2°, 16.67±0.2°, 18.70±0.2°, 19.96±0.2°, 21.57±0.2°, and 21.93±0.2° in a powder X-ray diffraction spectrum; Furthermore, the A-type crystals of the methanesulfonate salt further have diffraction peaks at 2θ angles of 7.28±0.2°, 10.86±0.2°, 12.71±0.2°, 14.20±0.2°, 14.58±0.2°, 16.67±0.2°, 18.70±0.2°, 19.96±0.2°, 21.57±0.2°, 21.93±0.2°, 22.86±0.2°, 23.39±0.2°, 23.77±0.2°, 24.50±0.2°, 24.84±0.2°, and 25.59±0.2° in a powder X-ray diffraction pattern; Furthermore, in the powder X-ray diffraction pattern, the A-type crystal of the methanesulfonate further exhibits the following 2θ angles: 7.28±0.2°, 9.84±0.2°, 10.86±0.2°, 12.71±0.2°, 14.20±0.2°, 14.58±0.2°, 16.67±0.2°, 18.70±0.2°, 18.92±0.2°. 0.2°, 19.96±0.2°, 20.38±0.2°, 21.31±0.2°, 21.57±0.2°, 21.93±0.2°, 22.86±0.2°, 23.39±0.2°, 23.77±0.2°, 24.50±0.2°, 24.84±0.2° and 25.59±0.2°, The A-type crystals of the methanesulfonate salt may have a powder X-ray diffraction pattern represented by 2θ angles, and the diffraction peaks and relative intensities may be as shown in Table 16. The A-type crystals of the methanesulfonate salt may further have a powder X-ray diffraction pattern, expressed as 2θ angles, essentially as shown in FIG.

[0059] In one preferred embodiment, the molar ratio of the compound of formula I to methanesulfonic acid is 1:1. In a preferred embodiment, the thermogravimetric analysis spectrum of the A-type crystals of the methanesulfonate salt shows a weight loss of 0% to 5% (e.g., 2.14%) when heated to 150±5°C from the start (the weight loss percentage is the percentage of the weight loss of the sample to the weight of the sample before this weight loss).

[0060] In one preferred embodiment, the differential scanning calorimetry spectrum of the A-type crystals of the methanesulfonate salt has a main endothermic peak at 206.0°C ± 3°C. In a preferred embodiment, the DSC spectrum of the Type A crystals of the methanesulfonate salt may further be essentially as shown in FIG.

[0061] In a preferred embodiment, the TGA spectrum of the Type A crystals of the methanesulfonate salt may further be essentially as shown in FIG. The present invention provides a crystalline form A of the ethanesulfonate salt of the compound of formula I, which has a powder X-ray diffraction spectrum expressed as 2θ angles, with diffraction peaks at 7.13±0.2°, 10.80±0.2°, 12.60±0.2°, 14.26±0.2°, 16.43±0.2°, 18.28±0.2°, 19.95±0.2°, 21.45±0.2°, and 23.26±0.2°.

[0062] The type A crystal of the ethanesulfonate salt has diffraction peaks at 2θ angles of 7.13±0.2°, 9.63±0.2°, 10.80±0.2°, 12.60±0.2°, 14.03±0.2°, 14.26±0.2°, 16.43±0.2°, 18.28±0.2°, 18.73±0.2°, 18.95±0.2°, 19.96±0.2°, 20.98±0.2°, 21.45±0.2°, 22.46±0.2°, 22.95±0.2°, 23.26±0.2°, 24.40±0.2°, 24.69±0.2°, and 25.36±0.2° in a powder X-ray diffraction spectrum; The A-type crystals of the ethanesulfonate salt may have a powder X-ray diffraction pattern represented by 2θ angles, and the diffraction peaks and relative intensities may be as shown in Table 17. The Form A crystal of the ethanesulfonate salt of the compound of Formula I may further have a powder X-ray diffraction pattern, expressed in 2θ angles, essentially as shown in FIG.

[0063] In one preferred embodiment, the molar ratio of the compound of formula I to ethanesulfonic acid is 1:1. In a preferred embodiment, the thermogravimetric analysis spectrum of the A-type crystals of the ethanesulfonate salt of the compound of Formula I shows a weight loss of 0% to 5% (e.g., 0.87%) when heated from the start to 150±5°C (the weight loss percentage is the ratio of the weight loss of the sample to the weight of the sample before the weight loss).

[0064] In a preferred embodiment, the differential scanning calorimetry spectrum of Form A crystals of the ethanesulfonate salt of the compound of Formula I may have a major endothermic peak at 218.7°C ± 3°C.

[0065] In a preferred embodiment, the DSC spectrum of crystalline Form A of the ethanesulfonate salt of the compound of Formula I may further be essentially as shown in FIG. In a preferred embodiment, the TGA spectrum of crystalline Form A of the ethanesulfonate salt of the compound of Formula I may further be essentially as shown in FIG.

[0066] The present invention provides a type B crystal of the ethanesulfonate salt of the compound of formula I, which has a powder X-ray diffraction spectrum expressed as 2θ angles, with diffraction peaks at 6.92±0.2°, 9.86±0.2°, 19.20±0.2°, 20.10±0.2°, 21.38±0.2°, 25.27±0.2°, and 29.85±0.2°.

[0067] Furthermore, the type B crystals of the ethanesulfonate salt have diffraction peaks at 2θ angles of 6.92±0.2°, 8.71±0.2°, 9.86±0.2°, 12.73±0.2°, 15.01±0.2°, 16.84±0.2°, 19.20±0.2°, 20.10±0.2°, 21.38±0.2°, 23.30±0.2°, 25.27±0.2°, and 29.85±0.2° in a powder X-ray diffraction spectrum; The B-type crystals of the ethanesulfonate salt may have a powder X-ray diffraction pattern represented by 2θ angles, and the diffraction peaks and relative intensities may be as shown in Table 18. The B-type crystals of the ethanesulfonate salt may further have a powder X-ray diffraction pattern, expressed as 2θ angles, essentially as shown in FIG.

[0068] In one preferred embodiment, the molar ratio of the compound of formula I to ethanesulfonic acid is 1:1. In a preferred embodiment, the thermogravimetric analysis spectrum of the B-type crystals of the ethanesulfonate salt shows a weight loss of 1% to 3% (e.g., 2.17%) when heated to 150±5°C from the start (the weight loss percentage is the ratio of the weight loss of the sample to the weight of the sample before the weight loss).

[0069] In a preferred embodiment, the differential scanning calorimetry spectrum of the B-type crystalline form of the ethanesulfonate salt may have main endothermic peaks at 156.8°C±3°C and 211.9°C±3°C.

[0070] In a preferred embodiment, the DSC spectrum of the B-type crystals of the ethanesulfonate salt may further be essentially as shown in FIG. In a preferred embodiment, the TGA spectrum of the ethanesulfonate salt crystalline form B may further be essentially as shown in FIG.

[0071] The present invention provides a crystalline form A of the maleate salt of the compound of formula I, which has a powder X-ray diffraction spectrum expressed as 2θ angles, with diffraction peaks at 4.46±0.2°, 5.61±0.2°, 11.23±0.2°, 16.86±0.2°, 18.30±0.2°, 19.20±0.2°, and 19.91±0.2°.

[0072] Furthermore, in a powder X-ray diffraction spectrum, the A-type crystals of the maleate salt have diffraction peaks at 2θ angles of 4.46±0.2°, 5.61±0.2°, 11.23±0.2°, 15.38±0.2°, 16.86±0.2°, 18.30±0.2°, 19.20±0.2°, 19.91±0.2°, 20.42±0.2°, and 23.00±0.2°.

[0073] Furthermore, the A-type crystal of the maleate salt has diffraction peaks at 2θ angles of 4.46±0.2°, 5.61±0.2°, 11.23±0.2°, 11.86±0.2°, 15.38±0.2°, 16.86±0.2°, 18.30±0.2°, 19.20±0.2°, 19.91±0.2°, 20.42±0.2°, 23.00±0.2°, and 24.26±0.2° in a powder X-ray diffraction spectrum; Furthermore, the A-type crystal of the maleate salt may have a powder X-ray diffraction pattern represented by 2θ angles, whose diffraction peaks and relative intensities are as shown in Table 19, The A-type crystal of the maleate salt may further have a powder X-ray diffraction pattern, expressed in 2θ angles, essentially as shown in FIG.

[0074] In one preferred embodiment, the molar ratio of the compound of formula I to maleic acid is 1:1. In one preferred embodiment, the thermogravimetric analysis spectrum of the A-type crystal of the maleate salt shows a weight loss of 2% to 4% (e.g., 3.14%) when heated from the start to 100±5°C (the weight loss percentage is the percentage of the weight loss of the sample to the weight of the sample before this weight loss), and a weight loss of 14% to 16% (e.g., 14.49%) when heated from 100±5°C to 225±5°C.

[0075] In one preferred embodiment, the differential scanning calorimetry spectrum of the A-type crystals of the maleate salt may have main endothermic peaks at 160.4°C±3°C and 219.1°C±3°C.

[0076] In a preferred embodiment, the DSC spectrum of the maleate salt crystalline form A may further be essentially as shown in FIG. In a preferred embodiment, the TGA spectrum of the maleate salt crystalline form A may further be essentially as shown in FIG.

[0077] The present invention provides a B-type crystalline form of the maleate salt of the compound of formula I, which has a powder X-ray diffraction spectrum expressed as 2θ angles, with diffraction peaks at 4.99±0.2°, 10.46±0.2°, 11.21±0.2°, 16.82±0.2°, 18.30±0.2°, 18.92±0.2°, and 19.50±0.2°.

[0078] Furthermore, the B-type crystals of the maleate salt have diffraction peaks in a powder X-ray diffraction spectrum at 2θ angles of 4.99±0.2°, 6.99±0.2°, 10.46±0.2°, 11.21±0.2°, 15.02±0.2°, 15.60±0.2°, 16.82±0.2°, 18.30±0.2°, 18.92±0.2°, and 19.50±0.2°.

[0079] The B-type crystals of the maleate salt may have a powder X-ray diffraction pattern represented by 2θ angles, and the diffraction peaks and relative intensities may be as shown in Table 20. The B-type crystal of the maleate salt may further have a powder X-ray diffraction pattern, expressed in 2θ angles, essentially as shown in FIG.

[0080] In one preferred embodiment, the molar ratio of the compound of formula I to maleic acid is 1:1. In one preferred embodiment, the thermogravimetric analysis spectrum of the B-type crystals of the maleate salt shows a weight loss of 2% to 4% (e.g., 2.84%) when heated from the start to 100±5°C (the weight loss percentage is the percentage of the weight loss of the sample to the weight of the sample before this weight loss), and a weight loss of 11% to 13% (e.g., 12.43%) when heated from 100±5°C to 225±5°C.

[0081] In one preferred embodiment, the differential scanning calorimetry spectrum of the B-type crystalline maleate salt may have main endothermic peaks at 152.9°C±3°C and 220.7°C±3°C.

[0082] In a preferred embodiment, the DSC spectrum of the B-type crystals of the maleate salt may further be essentially as shown in FIG. In a preferred embodiment, the TGA spectrum of the B-type crystals of the maleate salt may further be essentially as shown in FIG.

[0083] The present invention provides a crystalline form A of the L-tartrate salt of the compound of formula I, which has a powder X-ray diffraction spectrum expressed as 2θ angles, with diffraction peaks at 9.28±0.2°, 11.38±0.2°, 15.62±0.2°, 19.54±0.2°, 19.89±0.2°, and 25.21±0.2°.

[0084] Furthermore, the type A crystal of the L-tartrate salt has diffraction peaks at 2θ angles of 9.28±0.2°, 11.38±0.2°, 12.97±0.2°, 15.62±0.2°, 16.95±0.2°, 18.07±0.2°, 19.54±0.2°, 19.89±0.2°, 22.94±0.2°, 23.51±0.2°, 25.21±0.2°, 26.92±0.2°, and 28.46±0.2° in a powder X-ray diffraction spectrum; The powder X-ray diffraction pattern of the A-type crystal of the L-tartrate salt, expressed in terms of 2θ angles, may further have diffraction peaks and relative intensities as shown in Table 21, The Form A crystal of the L-tartrate salt may further have a powder X-ray diffraction pattern, expressed in 2θ angles, essentially as shown in FIG.

[0085] In one preferred embodiment, the molar ratio of the compound of formula I to L-tartaric acid is 1:1. In one preferred embodiment, the thermogravimetric analysis spectrum of the A-type crystals of the L-tartrate salt shows a weight loss of 2% to 4% (e.g., 3.18%) when heated to 150±5°C from the start (the weight loss percentage is the ratio of the weight loss of the sample to the weight of the sample before the weight loss).

[0086] In one preferred embodiment, the differential scanning calorimetry spectrum of the crystalline form A of the L-tartrate salt may have major endothermic peaks at 82.2°C±3°C and 213.2°C±3°C.

[0087] In a preferred embodiment, the DSC spectrum of the crystalline form A of the L-tartrate salt may further be essentially as shown in FIG. In a preferred embodiment, the TGA spectrum of the crystalline form A of the L-tartrate salt may further be essentially as shown in FIG.

[0088] The present invention provides a B-type crystal of the L-tartrate salt of the compound of formula I, which has a powder X-ray diffraction spectrum expressed as 2θ angles, with diffraction peaks at 4.22±0.2°, 5.17±0.2°, 5.77±0.2°, 8.65±0.2°, 11.51±0.2°, 14.08±0.2°, 16.59±0.2°, 17.29±0.2°, and 23.11±0.2°.

[0089] Furthermore, the B-type crystals of the L-tartrate salt have diffraction peaks at 2θ angles of 4.22±0.2°, 5.17±0.2°, 5.77±0.2°, 8.65±0.2°, 10.09±0.2°, 11.51±0.2°, 14.08±0.2°, 16.59±0.2°, 17.29±0.2°, 18.20±0.2°, 18.64±0.2°, 19.75±0.2°, 20.22±0.2°, 20.74±0.2°, 21.95±0.2°, and 23.11±0.2° in a powder X-ray diffraction spectrum; Furthermore, the B-type crystal of the L-tartrate salt exhibited the following 2θ angles in the powder X-ray diffraction spectrum: 4.22±0.2°, 5.17±0.2°, 5.77±0.2°, 8.65±0.2°, 10.09±0.2°, 11.51±0.2°, 12.58±0.2°, 14.08±0.2°, 14.91±0.2°, 15.59±0.2°, 16.4 1±0.2°, 16.59±0.2°, 17.29±0.2°, 18.20±0.2°, 18.64±0.2°, 19.75±0.2°, 20.22±0.2°, 20.74±0.2°, 21.95±0.2°, 23.11±0.2°, 24.84±0.2°, 25.27±0.2° and 25.56±0.2°, Furthermore, the B-type crystals of the L-tartrate salt may have a powder X-ray diffraction pattern represented by 2θ angles, with diffraction peaks and relative intensities as shown in Table 22, The B-type crystals of the L-tartrate salt may further have a powder X-ray diffraction pattern, expressed in 2θ angles, essentially as shown in FIG.

[0090] In one preferred embodiment, the molar ratio of the compound of formula I to L-tartaric acid is 1:1. In one preferred embodiment, the thermogravimetric analysis spectrum of the B-type crystals of the L-tartrate salt shows a weight loss of 5% to 7% (e.g., 5.57%) when heated to 180±5°C from the start (the weight loss percentage is the ratio of the weight loss of the sample to the weight of the sample before this weight loss).

[0091] In a preferred embodiment, the differential scanning calorimetry spectrum of the B-type crystals of the L-tartrate salt may have major endothermic peaks at 114.5°C±3°C, 160.5°C±3°C, 193.2°C±3°C, and 219.5°C±3°C.

[0092] In a preferred embodiment, the DSC spectrum of the crystalline form B of the L-tartrate salt may further be essentially as shown in FIG. In a preferred embodiment, the TGA spectrum of the crystalline form B of the L-tartrate salt may further be essentially as shown in FIG.

[0093] The present invention provides a C-type crystalline form of the L-tartrate salt of the compound of formula I, which has a powder X-ray diffraction spectrum expressed as 2θ angles and has diffraction peaks at 5.77±0.2°, 11.54±0.2°, 16.50±0.2°, 17.33±0.2°, 18.46±0.2°, 19.80±0.2°, and 24.85±0.2°, Furthermore, the C-type crystals of the L-tartrate salt have diffraction peaks at 2θ angles of 4.60±0.2°, 5.77±0.2°, 11.54±0.2°, 14.06±0.2°, 16.50±0.2°, 17.33±0.2°, 18.46±0.2°, 19.80±0.2°, 21.91±0.2°, 23.16±0.2°, 24.85±0.2°, and 25.27±0.2° in a powder X-ray diffraction spectrum; In addition, the C-type crystal of the L-tartrate salt has a powder X-ray diffraction spectrum of 2θ angle: 4 and diffraction peaks at 0.60±0.2°, 5.77±0.2°, 9.20±0.2°, 11.54±0.2°, 12.07±0.2°, 12.56±0.2°, 14.06±0.2°, 14.68±0.2°, 16.50±0.2°, 17.33±0.2°, 18.46±0.2°, 19.10±0.2°, 19.80±0.2°, 20.56±0.2°, 21.91±0.2°, 23.16±0.2°, 24.16±0.2°, 24.85±0.2° and 25.27±0.2°. Furthermore, the C-type crystals of the L-tartrate salt may have a powder X-ray diffraction pattern represented by 2θ angles, with diffraction peaks and relative intensities as shown in Table 23, The C-type crystal of the L-tartrate salt may further have a powder X-ray diffraction pattern, expressed in 2θ angles, essentially as shown in FIG.

[0094] In one preferred embodiment, the molar ratio of the compound of formula I to L-tartaric acid is 1:0.5. In one preferred embodiment, the thermogravimetric analysis spectrum of the C-type crystals of the L-tartrate salt shows a weight loss of 2% to 4% (e.g., 3.16%) when heated to 150±5°C from the start (the weight loss percentage is the ratio of the weight loss of the sample to the weight of the sample before this weight loss).

[0095] In one preferred embodiment, the differential scanning calorimetry spectrum of the C-type crystals of the L-tartrate salt may have main endothermic peaks at 128.5°C±3°C, 157.1°C±3°C, and 220.5°C±3°C.

[0096] In a preferred embodiment, the DSC of the Form C crystals of the L-tartrate salt may further be essentially as shown in FIG. In a preferred embodiment, the TGA of the Form C crystals of the L-tartrate salt may further be essentially as shown in FIG.

[0097] The present invention provides a D-type crystalline form of the L-tartrate salt of compound of formula I, which has a powder X-ray diffraction spectrum expressed as 2θ angles and has diffraction peaks at 5.80±0.2°, 11.56±0.2°, 15.74±0.2°, 16.50±0.2°, 17.38±0.2°, 19.63±0.2°, 23.23±0.2°, 23.64±0.2°, 24.86±0.2°, and 25.28±0.2°, Furthermore, the D-type crystal of the L-tartrate salt has diffraction peaks at 2θ angles of 5.80±0.2°, 11.56±0.2°, 15.74±0.2°, 16.50±0.2°, 17.38±0.2°, 18.24±0.2°, 19.35±0.2°, 19.63±0.2°, 20.02±0.2°, 23.23±0.2°, 23.64±0.2°, 24.86±0.2°, and 25.28±0.2° in a powder X-ray diffraction spectrum; In addition, the D-type crystals of the L-tartrate salt have diffraction peaks at 2θ angles of 4.24±0.2°, 5.80±0.2°, 9.45±0.2°, 11.56±0.2°, 13.07±0.2°, 15.74±0.2°, 16.50±0.2°, 17.38±0.2°, 18.24±0.2°, 19.35±0.2°, 19.63±0.2°, 20.02±0.2°, 20.48±0.2°, 20.70±0.2°, 21.93±0.2°, 23.23±0.2°, 23.64±0.2°, 24.86±0.2°, and 25.28±0.2° in a powder X-ray diffraction spectrum.

[0098] Furthermore, the D-type crystals of the L-tartrate salt may have a powder X-ray diffraction pattern represented by 2θ angles, with diffraction peaks and relative intensities as shown in Table 24, The D-form crystal of the L-tartrate salt may further have a powder X-ray diffraction pattern, expressed in 2θ angles, essentially as shown in FIG.

[0099] In one preferred embodiment, the molar ratio of the compound of formula I to L-tartaric acid is 1:1. In one preferred embodiment, the thermogravimetric analysis spectrum of the D-type crystals of the L-tartrate salt shows a weight loss of 2% to 4% (e.g., 2.72%) when heated to 150±5°C from the start (the weight loss percentage is the ratio of the weight loss of the sample to the weight of the sample before this weight loss).

[0100] In a preferred embodiment, the differential scanning calorimetry spectrum of the D-form crystals of the L-tartrate salt may have major endothermic peaks at 75.0°C±3°C, 111.6°C±3°C, 161.9°C±3°C, 200.9°C±3°C, and 218.8°C±3°C.

[0101] In a preferred embodiment, the DSC spectrum of the crystalline form D of the L-tartrate salt may further be essentially as shown in FIG. In a preferred embodiment, the TGA spectrum of the crystalline form D of the L-tartrate salt may further be essentially as shown in FIG.

[0102] The present invention provides a crystalline form A of glycolate salt of compound of formula I, which has a powder X-ray diffraction spectrum expressed as 2θ angles and has diffraction peaks at 5.90±0.2°, 7.21±0.2°, 7.80±0.2°, 11.42±0.2°, 11.79±0.2°, 17.72±0.2°, 19.80±0.2°, 23.10±0.2°, and 23.71±0.2°, Furthermore, in a powder X-ray diffraction spectrum, the type A crystals of the glycolate have diffraction peaks at 2θ angles of 5.90±0.2°, 7.21±0.2°, 7.80±0.2°, 11.42±0.2°, 11.79±0.2°, 13.24±0.2°, 14.74±0.2°, 16.45±0.2°, 17.72±0.2°, 18.65±0.2°, 19.80±0.2°, 20.54±0.2°, 21.96±0.2°, 23.10±0.2°, and 23.71±0.2°.

[0103] Furthermore, in the powder X-ray diffraction spectrum, the A-type crystal of the glycolate has 2θ angles of 5.90±0.2°, 7.21±0.2°, 7.80±0.2°, 8.83±0.2°, 9.34±0.2°, 11.03±0.2°, 11.42±0.2°, 11.79±0.2°, 12.18±0.2°, 13.24±0.2°, 13.49±0.2°, 14.4 3±0.2°, 14.74±0.2°, 15.60±0.2°, 15.86±0.2°, 16.16±0.2°, 16.45±0.2°, 16.98±0.2°, 17.72±0.2°, 18.65±0.2°, 19.80±0.2°, 20.54±0.2°, 21.96±0.2°, 23.10±0.2° and 23.71±0.2°, Furthermore, the powder X-ray diffraction pattern of the glycolate A-type crystals, expressed in terms of 2θ angles, may further have diffraction peaks and relative intensities as shown in Table 25, The type A crystal of the glycolate salt may further have a powder X-ray diffraction pattern, expressed in 2θ angles, essentially as shown in FIG.

[0104] In one preferred embodiment, the molar ratio of the compound of formula I to glycolic acid is 1:1. In one preferred embodiment, the thermogravimetric analysis spectrum of the A-type crystals of the glycolate salt shows a weight loss of 2% to 4% (e.g., 3.40%) when heated from the start to 150±5°C (the weight loss percentage is the percentage of the weight loss of the sample to the weight of the sample before this weight loss).

[0105] In one preferred embodiment, the differential scanning calorimetry spectrum of the glycolate salt type A crystals may have a main endothermic peak at 110.1°C ± 3°C. In one preferred embodiment, the DSC spectrum of the A-type crystals of the glycolate salt is The torque may also be essentially as shown in FIG.

[0106] In a preferred embodiment, the TGA spectrum of the glycolate salt crystalline form A may further be essentially as shown in FIG. The present invention provides a crystalline form A of the L-malate salt of the compound of formula I, which has a powder X-ray diffraction spectrum expressed as 2θ angles, with diffraction peaks at 5.92±0.2°, 11.82±0.2°, 16.56±0.2°, 17.68±0.2°, 21.97±0.2°, and 23.75±0.2°, Furthermore, the A-type crystals of the L-malate have diffraction peaks at 2θ angles of 5.92±0.2°, 7.54±0.2°, 8.32±0.2°, 8.76±0.2°, 11.82±0.2°, 16.56±0.2°, 17.68±0.2°, 18.71±0.2°, 19.69±0.2°, 21.97±0.2°, and 23.75±0.2° in a powder X-ray diffraction spectrum; Furthermore, the A-type crystals of the L-malate have diffraction peaks at 2θ angles of 5.92±0.2°, 7.54±0.2°, 8.32±0.2°, 8.76±0.2°, 10.35±0.2°, 11.82±0.2°, 12.40±0.2°, 14.10±0.2°, 16.56±0.2°, 17.68±0.2°, 18.71±0.2°, 19.69±0.2°, 20.81±0.2°, 21.97±0.2°, and 23.75±0.2° in a powder X-ray diffraction spectrum; Furthermore, the powder X-ray diffraction pattern of the A-type crystals of the L-malate, expressed in terms of 2θ angles, may further have diffraction peaks and relative intensities as shown in Table 26, The A-type crystal of the L-malate salt may further have a powder X-ray diffraction pattern, expressed in 2θ angles, essentially as shown in FIG.

[0107] In one preferred embodiment, the molar ratio of the compound of formula I to L-malic acid is 1:1. In one preferred embodiment, the thermogravimetric analysis spectrum of the A-type crystals of L-malic acid shows a weight loss of 2% to 4% (e.g., 2.88%) when heated from the start to 50±5°C (the weight loss percentage is the percentage of the weight loss of the sample to the weight of the sample before this weight loss), a weight loss of 1% to 3% (e.g., 2.46%) when heated from 50±5°C to 100±5°C, and a weight loss of 0% to 2% (e.g., 1.31%) when heated from 100±5°C to 150±5°C.

[0108] In one preferred embodiment, the differential scanning calorimetry spectrum of the L-malate salt Form A crystals has major endothermic peaks at 72.9°C±3°C, 122.2°C±3°C, 142.1°C±3°C, and 222.4°C±3°C, and an exothermic peak at 195.9°C±3°C.

[0109] In a preferred embodiment, the DSC spectrum of the Form A crystals of the L-malate salt may further be essentially as shown in FIG. In a preferred embodiment, the TGA spectrum of the Form A crystals of the L-malate salt may further be essentially as shown in FIG.

[0110] The present invention provides a B-type crystalline form of the L-malate salt of the compound of formula I, which has a powder X-ray diffraction spectrum expressed as 2θ angles, with diffraction peaks at 6.69±0.2°, 8.99±0.2°, 9.30±0.2°, 13.38±0.2°, 17.00±0.2°, 18.71±0.2°, 21.18±0.2°, and 26.89±0.2°.

[0111] Furthermore, the B-type crystals of the L-malate have the following 2θ angles in the powder X-ray diffraction spectrum: 6.69±0.2°, 8.99±0.2°, 9.30±0.2°, 10.69±0.2°, 10.97±0.2°, 11.29±0.2°, 12.77±0.2°, 13.02± 0.2°, 13.38±0.2°, 14.64±0.2°, 14.89±0.2°, 15.89±0.2°, 17.00±0.2°, 17.55±0.2°, 18.27±0.2°, 18.71±0.2°, 20.70±0.2°, 21.18±0.2°, 21.71±0.2° and 26.89±0.2°, Furthermore, the B-type crystals of the L-malate may have a powder X-ray diffraction pattern represented by 2θ angles, whose diffraction peaks and relative intensities are as shown in Table 27, The B-type crystals of the L-malate salt may further have a powder X-ray diffraction pattern, expressed in 2θ angles, essentially as shown in FIG.

[0112] In one preferred embodiment, the molar ratio of the compound of formula I to L-malic acid is 1:1. In one preferred embodiment, the thermogravimetric analysis spectrum of the B-type crystals of the L-malate salt shows a weight loss of 2% to 4% (e.g., 3.40%) when heated to 150±5°C from the start (the weight loss percentage is the ratio of the weight loss of the sample to the weight of the sample before the weight loss).

[0113] In one preferred embodiment, the differential scanning calorimetry spectrum of the B-type crystals of the L-malate may have a main endothermic peak at 134.8°C ± 3°C. In a preferred embodiment, the DSC spectrum of the B-form crystals of the L-malate salt may further be essentially as shown in FIG.

[0114] In a preferred embodiment, the TGA spectrum of the L-malate salt crystalline form B may further be essentially as shown in FIG. The present invention provides a crystalline form A of the hippurate salt of compound of formula I, which has a powder X-ray diffraction spectrum expressed as 2θ angles and has diffraction peaks at 9.10±0.2°, 10.41±0.2°, 12.69±0.2°, 15.00±0.2°, 15.22±0.2°, 16.93±0.2°, 18.00±0.2°, 18.71±0.2°, 24.53±0.2° and 26.00±0.2°, Furthermore, in a powder X-ray diffraction spectrum, the type A crystal of hippurate has diffraction peaks at 2θ angles of 9.10±0.2°, 10.41±0.2°, 12.69±0.2°, 12.91±0.2°, 15.00±0.2°, 15.22±0.2°, 16.02±0.2°, 16.57±0.2°, 16.93±0.2°, 17.69±0.2°, 18.00±0.2°, 18.71±0.2°, 20.65±0.2°, 21.27±0.2°, 22.33±0.2°, 24.53±0.2°, and 26.00±0.2°.

[0115] Furthermore, in the powder X-ray diffraction spectrum, the A-type crystal of the hippurate has 2θ angles of 8.78±0.2°, 9.10±0.2°, 10.41±0.2°, 12.69±0.2°, 12.91±0.2°, 15.00±0.2°, 15.22±0.2°, 16.02±0.2°, 16.57±0.2°, 16.93±0.2°, 17.69±0.2°, 18.00±0.2°, 18.71±0.2°, 20.40 ±0.2°, 20.65±0.2°, 20.89±0.2°, 21.27±0.2°, 22.33±0.2°, 24.53±0.2°, 24.87±0.2°, 25.50±0.2°, 26.00±0.2°, 26.14±0.2°, 27.64±0.2°, 28.43±0.2°, 29.31±0.2°, 29.89±0.2°, 31.11±0.2° and 32.36±0.2°.

[0116] Furthermore, the A-type crystal of the hippurate may have a powder X-ray diffraction pattern represented by 2θ angles, whose diffraction peaks and relative intensities are as shown in Table 28, The A-type crystal of the hippurate salt may further have a powder X-ray diffraction pattern expressed in 2θ angles essentially as shown in FIG.

[0117] In one preferred embodiment, the molar ratio of the compound of formula I to hippuric acid is 1:1. In one preferred embodiment, the thermogravimetric analysis spectrum of the A-type crystal of the hippuric acid salt shows a weight loss of 2% to 4% (e.g., 3.04%) when heated to 150±5°C from the start (the weight loss percentage is the percentage of the weight loss of the sample to the weight of the sample before this weight loss).

[0118] In one preferred embodiment, the differential scanning calorimetry spectrum of the A-type crystals of the hippurate salt may have main endothermic peaks at 62.4°C±3°C, 120.1°C±3°C, and 207.0°C±3°C.

[0119] In a preferred embodiment, the DSC spectrum of the crystalline form A of the hippurate salt may further be essentially as shown in FIG. In a preferred embodiment, the TGA spectrum of the crystalline form A of the hippuric acid salt may further be essentially as shown in FIG.

[0120] The present invention provides a crystalline form A of the succinate salt of the compound of formula I, which has a powder X-ray diffraction spectrum expressed as 2θ angles, with diffraction peaks at 4.72±0.2°, 5.83±0.2°, 7.87±0.2°, 9.34±0.2°, 11.71±0.2°, 12.39±0.2°, 16.67±0.2°, 17.58±0.2°, 19.99±0.2°, 21.89±0.2°, 23.57±0.2°, and 25.40±0.2°.

[0121] Furthermore, the A-type crystal of the succinate may further have a powder X-ray diffraction pattern represented by 2θ angles, whose diffraction peaks and relative intensities are as shown in Table 29, The A-type crystal of the succinate salt may further have a powder X-ray diffraction pattern expressed in 2θ angles essentially as shown in FIG.

[0122] In one preferred embodiment, the molar ratio of the compound of formula I to succinic acid is 1:1. In one preferred embodiment, the thermogravimetric analysis spectrum of the A-type crystal of the succinate salt shows a weight loss of 3% to 5% (e.g., 3.94%) when heated to 150±5°C from the start (the weight loss percentage is the percentage of the weight loss of the sample to the weight of the sample before this weight loss).

[0123] In one preferred embodiment, the differential scanning calorimetry spectrum of the A-type crystals of the succinate salt may have main endothermic peaks at 70.0°C±3°C, 124.1°C±3°C, and 221.0°C±3°C.

[0124] In a preferred embodiment, the DSC spectrum of the crystalline form A of the succinate salt may further be essentially as shown in FIG. In a preferred embodiment, the TGA spectrum of the crystalline form A of the succinate salt may further be essentially as shown in FIG.

[0125] The present invention provides a B-type crystalline form of succinate salt of the compound of formula I, which has diffraction peaks at 5.70±0.2°, 9.24±0.2°, 11.42±0.2°, 13.55±0.2°, 17.17±0.2°, and 22.95±0.2° in a powder X-ray diffraction spectrum expressed as 2θ angles, Furthermore, the B-type crystal of the succinate has, in a powder X-ray diffraction spectrum, 2θ angles of 5.70±0.2°, 9.24±0.2°, 11.42±0.2°, and 13.55±0.2°. having diffraction peaks at 15.10±0.2°, 17.17±0.2°, 18.67±0.2°, 19.13±0.2°, 19.99±0.2°, 20.59±0.2°, 22.95±0.2°, 23.25±0.2°, 24.10±0.2°, 25.13±0.2°, 25.48±0.2° and 26.12±0.2°; Furthermore, in the powder X-ray diffraction spectrum, the B-type crystal of the succinate has 2θ angles of 5.70±0.2°, 6.75±0.2°, 9.24±0.2°, 11.42±0.2°, 12.31±0.2°, 13.13±0.2°, 13.55±0.2°, 15.10±0.2°, 15.80±0.2°, 16.35±0.2°, 17.17±0.2°, 18.67±0.2°, and 19.13±0.2°. , 19.50±0.2°, 19.99±0.2°, 20.59±0.2°, 21.60±0.2°, 21.93±0.2°, 22.58±0.2°, 22.95±0.2°, 23.25±0.2°, 24.10±0.2°, 25.13±0.2°, 25.48±0.2°, 25.79±0.2°, 26.12±0.2°, 28.98±0.2° and 31.50±0.2°.

[0126] Furthermore, the B-type crystals of the succinate may further have a powder X-ray diffraction pattern represented by 2θ angles, whose diffraction peaks and relative intensities are as shown in Table 30, The B-type crystals of the succinate salt may further have a powder X-ray diffraction pattern expressed in 2θ angles essentially as shown in FIG.

[0127] In one preferred embodiment, the molar ratio of the compound of formula I to succinic acid is 1:1. In one preferred embodiment, the thermogravimetric analysis spectrum of the B-type crystals of the succinate salt shows a weight loss of 3% to 5% (e.g., 4.44%) when heated to 150±5°C from the start (the weight loss percentage is the percentage of the weight loss of the sample to the weight of the sample before this weight loss).

[0128] In one preferred embodiment, the differential scanning calorimetry spectrum of the B-type crystals of the succinate salt may have main endothermic peaks at 105.1°C±3°C and 223.3°C±3°C.

[0129] In a preferred embodiment, the DSC spectrum of the B-form crystals of the succinate salt may further be essentially as shown in FIG. In a preferred embodiment, the TGA spectrum of the B-form crystals of the succinate salt may further be essentially as shown in FIG.

[0130] The present invention provides a crystalline form A of the ascorbate salt of the compound of formula I, which has a powder X-ray diffraction spectrum expressed as 2θ angles, with diffraction peaks at 5.72±0.2°, 9.20±0.2°, 11.30±0.2°, 15.55±0.2°, 16.71±0.2°, 17.58±0.2°, 18.83±0.2° and 25.94±0.2°, Furthermore, the type A crystals of ascorbate have diffraction peaks in a powder X-ray diffraction spectrum at 2θ angles of 5.72±0.2°, 9.20±0.2°, 11.30±0.2°, 14.38±0.2°, 15.55±0.2°, 16.71±0.2°, 17.58±0.2°, 18.83±0.2°, 20.30±0.2°, 22.33±0.2°, and 25.94±0.2°.

[0131] Furthermore, the type A crystals of the ascorbate may further have a powder X-ray diffraction pattern represented by 2θ angles, with diffraction peaks and relative intensities as shown in Table 31, The ascorbate type A crystal may further have a powder X-ray diffraction pattern (2θ angles) as shown in FIG.

[0132] In one preferred embodiment, the molar ratio of the compound of formula I to ascorbic acid is 1 :0.5. In a preferred embodiment, the thermogravimetric analysis spectrum of the ascorbate type A crystals shows a weight loss of 3% to 5% (e.g., 4.36%) when heated to 150±5°C from the start (the weight loss percentage is the ratio of the weight loss of the sample to the weight of the sample before the weight loss).

[0133] In one preferred embodiment, the differential scanning calorimetry spectrum of the ascorbate type A crystals has a main endothermic peak at 185.7°C±3°C and an exothermic peak at 195.8°C±3°C.

[0134] In a preferred embodiment, the DSC spectrum of the ascorbate crystalline form A may further be essentially as shown in FIG. In a preferred embodiment, the TGA spectrum of the Form A crystals of ascorbate may further be essentially as shown in FIG.

[0135] The present invention provides a type B crystal of ascorbate salt of compound of formula I, which has a powder X-ray diffraction spectrum expressed as 2θ angles and has diffraction peaks at 5.50±0.2°, 11.00±0.2°, 16.63±0.2°, 17.47±0.2°, 19.82±0.2°, 28.08±0.2°, and 30.05±0.2°, Furthermore, the type B crystals of ascorbate have diffraction peaks in a powder X-ray diffraction spectrum at 2θ angles of 4.47±0.2°, 5.50±0.2°, 9.11±0.2°, 11.00±0.2°, 15.27±0.2°, 16.09±0.2°, 16.63±0.2°, 17.47±0.2°, 19.82±0.2°, 25.30±0.2°, 28.08±0.2°, and 30.05±0.2°.

[0136] Furthermore, the type B crystals of ascorbate have diffraction peaks at 2θ angles of 4.47±0.2°, 5.50±0.2°, 9.11±0.2°, 11.00±0.2°, 13.23±0.2°, 15.27±0.2°, 16.09±0.2°, 16.63±0.2°, 17.47±0.2°, 19.82±0.2°, 21.09±0.2°, 21.53±0.2°, 25.30±0.2°, 25.92±0.2°, 26.81±0.2°, 28.08±0.2°, and 30.05±0.2° in a powder X-ray diffraction spectrum; Furthermore, the type B crystals of the ascorbate may have a powder X-ray diffraction pattern represented by 2θ angles, whose diffraction peaks and relative intensities are as shown in Table 32, The type B crystal of the ascorbate may further have a powder X-ray diffraction pattern, expressed in 2θ angles, essentially as shown in FIG.

[0137] In one preferred embodiment, the molar ratio of the compound of formula I to ascorbic acid is 1:1. In one preferred embodiment, the thermogravimetric analysis spectrum of the ascorbate type B crystals shows a weight loss of 0% to 2% (e.g., 1.33%) when heated to 150±5°C from the start (the weight loss percentage is the percentage of the weight loss of the sample to the weight of the sample before this weight loss).

[0138] In one preferred embodiment, the differential scanning calorimetry spectrum of the ascorbate B-type crystals has a main endothermic peak at 153.6°C±3°C and one exothermic peak at 190.3±3°C.

[0139] In a preferred embodiment, the DSC spectrum of the ascorbate crystalline form B may further be essentially as shown in FIG. In one preferred embodiment, the TGA spectrum of the B-type crystals of the ascorbate salt is The vector may also be essentially as shown in FIG.

[0140] The present invention provides a crystalline form A of the adipate salt of the compound of formula I, which has a powder X-ray diffraction spectrum expressed as 2θ angles and has diffraction peaks at 8.47±0.2°, 11.41±0.2°, 15.57±0.2°, 16.29±0.2°, 17.52±0.2°, 18.23±0.2°, and 19.84±0.2°, Furthermore, in a powder X-ray diffraction spectrum, the A-type crystals of the adipate salt have diffraction peaks at 2θ angles of 8.47±0.2°, 8.99±0.2°, 11.41±0.2°, 12.40±0.2°, 13.60±0.2°, 15.57±0.2°, 16.29±0.2°, 17.52±0.2°, 18.23±0.2°, 19.84±0.2°, 21.29±0.2°, 23.81±0.2°, 24.62±0.2°, 26.55±0.2°, 27.79±0.2°, and 29.82±0.2°.

[0141] Furthermore, the A-type crystals of the adipate may have a powder X-ray diffraction pattern expressed in terms of 2θ angles, whose diffraction peaks and relative intensities are as shown in Table 33, The powder X-ray diffraction pattern (2θ angles) of the A-type crystals of the adipate salt may further be as shown in FIG.

[0142] In one preferred embodiment, the molar ratio of the compound of formula I to adipic acid is 1:1. In one preferred embodiment, the thermogravimetric analysis spectrum of the A-type crystals of the adipate salt shows a weight loss of 6% to 8% (e.g., 6.60%) when heated to 150±5°C from the start (the weight loss percentage is the ratio of the weight loss of the sample to the weight of the sample before the weight loss).

[0143] In one preferred embodiment, the differential scanning calorimetry spectrum of the A-type crystals of the adipate salt may have a main endothermic peak at 88.3°C ± 3°C. In a preferred embodiment, the DSC spectrum of the crystalline form A of the adipate salt may further be essentially as shown in FIG.

[0144] In a preferred embodiment, the TGA spectrum of the crystalline form A of the adipate salt may further be essentially as shown in FIG. The present invention provides a type A crystal of p-toluenesulfonate salt of compound of formula I, which has diffraction peaks at 8.91±0.2°, 9.43±0.2°, 12.31±0.2°, 15.93±0.2°, 16.43±0.2°, 20.69±0.2°, 20.95±0.2°, 24.76±0.2°, and 26.36±0.2° in a powder X-ray diffraction spectrum expressed as 2θ angles, Furthermore, in a powder X-ray diffraction spectrum, the type A crystal of the p-toluenesulfonate salt has diffraction peaks at 2θ angles of 8.91±0.2°, 9.43±0.2°, 12.31±0.2°, 15.93±0.2°, 16.43±0.2°, 17.26±0.2°, 17.91±0.2°, 18.31±0.2°, 20.69±0.2°, 20.95±0.2°, 23.11±0.2°, 23.29±0.2°, 24.76±0.2°, and 26.36±0.2°.

[0145] Furthermore, in the powder X-ray diffraction spectrum, the A-type crystal of the p-toluenesulfonate has 2θ angles of 8.91±0.2°, 9.43±0.2°, 11.51±0.2°, 12.31±0.2°, 13.70±0.2°, 15.93±0.2°, 16.43±0.2°, 17.26±0.2°, 17.91±0.2°, 18.31±0.2°, 19.49±0.2°, 20.69±0.2°, 20.95±0.2°, 21.19±0.2°, 22.77±0.2°, 23.11±0.2°, 23.29±0.2°, and 24.34±0.2°. , 24.76±0.2°, 25.55±0.2°, 26.36±0.2°, 26.83±0.2°, 27.69±0.2° and 29.25±0.2°, Furthermore, the A-type crystals of the p-toluenesulfonate may have a powder X-ray diffraction pattern represented by 2θ angles, whose diffraction peaks and relative intensities are as shown in Table 34, The A-type crystal of the p-toluenesulfonate salt may further have a powder X-ray diffraction pattern, expressed as 2θ angles, essentially as shown in FIG.

[0146] In one preferred embodiment, the molar ratio of the compound of formula I to p-toluenesulfonic acid is 1:1. In one preferred embodiment, the thermogravimetric analysis spectrum of the A-type crystal of the p-toluenesulfonate salt shows a weight loss of 0% to 2% (e.g., 0.76%) when heated from the start to 100±5°C (the weight loss percentage is the percentage of the weight loss of the sample to the weight of the sample before this weight loss), and a weight loss of 2% to 4% (e.g., 3.07%) when heated from 100°C to 170°C.

[0147] In a preferred embodiment, the differential scanning calorimetry spectrum of the A-type crystals of the p-toluenesulfonate salt may have a main endothermic peak at 150.9°C ± 3°C. In a preferred embodiment, the DSC spectrum of the A-type crystals of the p-toluenesulfonate salt may further be essentially as shown in FIG.

[0148] In a preferred embodiment, the TGA spectrum of the Type A crystals of the p-toluenesulfonate salt may further be essentially as shown in FIG. The present invention provides a type A crystal of benzenesulfonate salt of compound of formula I, which has diffraction peaks at 10.81±0.2°, 11.38±0.2°, 16.25±0.2°, 17.41±0.2°, 18.35±0.2°, 19.90±0.2°, and 21.31±0.2° in a powder X-ray diffraction spectrum expressed as 2θ angles, In addition, the type A crystal of the benzenesulfonate salt has diffraction peaks at 2θ angles of 6.54±0.2°, 8.76±0.2°, 10.81±0.2°, 11.38±0.2°, 11.91±0.2°, 13.32±0.2°, 14.01±0.2°, 15.40±0.2°, 16.25±0.2°, 17.41±0.2°, 18.35±0.2°, 19.38±0.2°, 19.90±0.2°, 20.67±0.2°, 21.31±0.2°, 22.89±0.2°, 25.86±0.2°, 27.75±0.2°, and 32.21±0.2° in a powder X-ray diffraction spectrum; Furthermore, in the powder X-ray diffraction pattern of the A-type crystals of the benzenesulfonate salt, expressed in terms of 2θ angles, the diffraction peaks and relative intensities may be as shown in Table 35.

[0149] The powder X-ray diffraction pattern (2θ angles) of the A-type crystal of the benzenesulfonate may further be as shown in FIG. In one preferred embodiment, the molar ratio of the compound of formula I to benzenesulfonic acid is 1:1.

[0150] In one preferred embodiment, the thermogravimetric analysis spectrum of the A-type crystal of the benzenesulfonate salt shows a weight loss of 2% to 4% (e.g., 2.55%) when heated from the start to 80±5°C (the weight loss percentage is the percentage of the weight loss of the sample to the weight of the sample before this weight loss), and a weight loss of 5% to 7% (e.g., 6.23%) when heated from 80°C to 150°C.

[0151] In one preferred embodiment, the differential scanning calorimeter of the A-type crystal of the benzenesulfonate salt is The calorimetric spectrum may have a major endothermic peak at 111.7°C ± 3°C. In a preferred embodiment, the DSC spectrum of the crystalline form A of the benzenesulfonate salt may further be essentially as shown in FIG.

[0152] In a preferred embodiment, the TGA spectrum of the crystalline form A of the benzenesulfonate salt may further be essentially as shown in FIG. The present invention provides a crystalline form A of the oxalate salt of the compound of formula I, which has a powder X-ray diffraction spectrum expressed as 2θ angles and has diffraction peaks at 6.15±0.2°, 10.44±0.2°, 13.94±0.2°, 16.74±0.2°, 17.49±0.2°, and 24.50±0.2°, Furthermore, the A-type crystal of the oxalate salt has diffraction peaks at 2θ angles of 6.15±0.2°, 7.02±0.2°, 10.44±0.2°, 13.94±0.2°, 16.74±0.2°, 17.49±0.2°, 20.07±0.2°, 24.50±0.2°, 25.79±0.2°, and 26.53±0.2° in a powder X-ray diffraction spectrum; Furthermore, in a powder X-ray diffraction spectrum, the type A crystal of the oxalate salt has diffraction peaks at 2θ angles of 6.15±0.2°, 7.02±0.2°, 9.18±0.2°, 10.44±0.2°, 13.94±0.2°, 15.12±0.2°, 15.54±0.2°, 16.74±0.2°, 17.49±0.2°, 18.16±0.2°, 19.51±0.2°, 20.07±0.2°, 22.64±0.2°, 23.59±0.2°, 24.50±0.2°, 25.22±0.2°, 25.79±0.2°, 26.53±0.2°, 27.90±0.2°, and 28.47±0.2°.

[0153] Furthermore, the A-type crystal of the oxalate may have a powder X-ray diffraction pattern represented by 2θ angles, whose diffraction peaks and relative intensities are as shown in Table 36, The Form A crystal of the oxalate salt of the compound of Formula I may further have a powder X-ray diffraction pattern, expressed in 2θ angles, essentially as shown in FIG.

[0154] In one preferred embodiment, the molar ratio of the compound of formula I to oxalic acid is 1:1. In one preferred embodiment, the thermogravimetric analysis spectrum of the A-type crystal of the oxalate salt shows a weight loss of 2% to 7% (e.g., 5.88%) when heated to 100±5°C from the start (the weight loss percentage is the ratio of the weight loss of the sample to the weight of the sample before this weight loss).

[0155] In one preferred embodiment, the differential scanning calorimetry spectrum of the A-type crystals of the oxalate salt may have main endothermic peaks at 103.4°C±3°C and 141.6°C±3°C.

[0156] In a preferred embodiment, the DSC spectrum of the crystalline form A of the oxalate salt may further be essentially as shown in FIG. In a preferred embodiment, the TGA spectrum of the crystalline form A of the oxalate salt may further be essentially as shown in FIG.

[0157] The present invention provides a type A crystal of 2-hydroxyethanesulfonate salt of compound of formula I, which has a powder X-ray diffraction spectrum expressed as 2θ angles and has diffraction peaks at 6.46±0.2°, 9.89±0.2°, 10.95±0.2°, 13.14±0.2°, 18.38±0.2°, 18.81±0.2°, and 21.70±0.2°, In addition, the A-type crystal of the 2-hydroxyethanesulfonate salt of the compound of formula I has the following 2θ angles in the powder X-ray diffraction spectrum: 6.46±0.2°, 9.89±0.2°, 10.95±0.2°, 13.14±0.2°, 13.60±0.2°, 15.69±0.2°, 18.38±0.2°, 18.81±0.2°, 20.44±0.2° and 21.70±0.2°. It has a diffraction peak at 0.2°, Furthermore, the type A crystal of 2-hydroxyethanesulfonate salt of the compound of formula I has diffraction peaks at 2θ angles of 6.46±0.2°, 9.89±0.2°, 10.95±0.2°, 13.14±0.2°, 13.60±0.2°, 15.69±0.2°, 18.38±0.2°, 18.81±0.2°, 20.44±0.2°, 21.70±0.2°, 23.25±0.2°, 24.04±0.2°, 24.82±0.2°, 26.03±0.2°, 26.35±0.2° and 26.70±0.2° in a powder X-ray diffraction spectrum; Furthermore, the powder X-ray diffraction pattern of the A-type crystal of 2-hydroxyethanesulfonate expressed in terms of 2θ angles may further have diffraction peaks and relative intensities as shown in Table 37, The Form A crystal of the 2-hydroxyethanesulfonic acid salt of the compound of Formula I may further have a powder X-ray diffraction pattern, expressed in 2θ angles, essentially as shown in FIG.

[0158] In one preferred embodiment, the molar ratio of the compound of formula I to 2-hydroxyethanesulfonic acid is 1:1. In a preferred embodiment, the thermogravimetric analysis spectrum of the A-type crystal of 2-hydroxyethanesulfonate shows a weight loss of 0% to 3% (e.g., 1.61%) when heated to 150±5°C from the start (the weight loss percentage is the ratio of the weight loss of the sample to the weight of the sample before the weight loss).

[0159] In a preferred embodiment, the differential scanning calorimetry spectrum of the A-type crystals of 2-hydroxyethanesulfonate may have a main endothermic peak at 203.5°C ± 3°C.

[0160] In a preferred embodiment, the DSC spectrum of the crystalline form A of the 2-hydroxyethanesulfonate salt may further be essentially as shown in FIG. In a preferred embodiment, the TGA spectrum of the crystalline form A of the 2-hydroxyethanesulfonate salt may further be essentially as shown in FIG.

[0161] The present invention also provides a method for preparing crystalline Form A of the compound of formula I, comprising the steps of crystallizing the compound of formula I in a solvent M and isolating the solid. The solvent M is an alkane solvent.

[0162] The alkane solvent is preferably n-hexane. The crystallization temperature is room temperature, preferably 40 to 60°C, for example 50°C.

[0163] The mass / volume ratio of the solvent M to the compound of formula I is preferably 30 to 50 mg / mL, for example, 40 mg / mL. The present invention also provides type A crystals of the compound of formula I, prepared according to the above-mentioned method for preparing type A crystals of the compound of formula I.

[0164] The present invention also provides a method for preparing a crystalline pharmaceutically acceptable salt of a compound of formula I, comprising the steps of reacting a compound of formula I with an acid in a solvent N and isolating the solid; The crystals of the pharmaceutically acceptable salts of the compound of formula I include crystalline forms of a fumarate salt of the compound of formula I, crystalline forms of a fumarate salt of the compound of formula I, crystalline forms of a citrate salt of the compound of formula I, crystalline forms of a citrate salt of the compound of formula I, crystalline forms of a methanesulfonate salt of the compound of formula I, crystalline forms of an ethanesulfonate salt of the compound of formula I, crystalline forms of a maleate salt of the compound of formula I, crystalline forms of a maleate salt of the compound of formula I, crystalline forms of an L-tartrate salt of the compound of formula I, crystalline forms of a L-tartrate salt of the compound of formula I, crystalline forms of a L-tartrate salt of the compound of formula I, crystalline forms of a L-tartrate salt of the compound of formula I, crystalline forms of a methanesulfonate salt of the compound of formula I, crystalline forms of an ethanesulfonate salt of the compound of formula I, crystalline forms of a maleate salt of the compound of formula I, crystalline forms of a maleate salt of the compound of formula I, crystalline forms of a L-tartrate salt of the compound of formula I, crystalline forms of a L-tartrate salt of the compound of formula I, crystalline forms of a L-tartrate salt of the compound of formula I, crystalline forms of a methanesulfonate ... Form D crystals of the L-tartrate salt of the compound of formula I, Form A crystals of the glycolate salt of the compound of formula I, Form A crystals of the L-malate salt of the compound of formula I, Form B crystals of the L-malate salt of the compound of formula I, Form A crystals of the hippurate salt of the compound of formula I, Form A crystals of the succinate salt of the compound of formula I, Form B crystals of the succinate salt of the compound of formula I, Form A crystals of the ascorbate salt of the compound of formula I, Form A crystals of the adipate salt of the compound of formula I, Form A crystals of the p-toluenesulfonate salt of the compound of formula I, Form A crystals of the benzenesulfonate salt of the compound of formula I, and Form A crystals of the oxalate salt of the compound of formula I or Form A crystals of the 2-hydroxyethanesulfonate salt of the compound of formula I; the solvent N is one or more of an alcohol-based solvent, an alkane-based solvent, an ester-based solvent, and water; The acid is fumaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, maleic acid, L-tartaric acid, glycolic acid, L-malic acid, hippuric acid, succinic acid, ascorbic acid, adipic acid, p-toluenesulfonic acid, benzenesulfonic acid, 2-hydroxyethanesulfonic acid, oxalic acid, or 2-hydroxyethanesulfonic acid.

[0165] The solvent N is preferably a mixture of isopropanol and water, n-hexane, or ethyl acetate, and more preferably, the volume ratio of isopropanol to water is 19:1±5.

[0166] The mass / volume ratio of the solvent N to the compound of formula I is preferably 30 to 50 mg / mL, for example, 40 mg / mL. The molar ratio of the compound of formula I to the acid is 1:(1±0.5), for example 1:1.

[0167] The reaction method may be crystallization under stirring. The crystallization temperature is room temperature, preferably 10 to 30°C. The present invention also provides a method for preparing crystalline form A of the fumarate salt of the compound of formula I, comprising the steps of reacting a pyridinopyrimidinone compound of formula I with fumaric acid in a solvent A, and isolating the resulting solid; The solvent A is a mixture of an alcoholic solvent and water.

[0168] The solvent A is preferably a mixture of isopropanol and water, more preferably a mixture of isopropanol and water in a volume ratio of 19:1±5. The reaction temperature is preferably 10 to 30°C.

[0169] The mass / volume ratio of the solvent A to the pyridinopyrimidinone compound represented by the formula I is preferably 30 to 50 mg / mL, for example, 40 mg / mL. The reaction method may be crystallization under stirring.

[0170] The present invention also provides Form A crystals of fumarate of the compound of formula I, prepared according to the method for preparing Form A crystals of fumarate of the compound of formula I described above. The present invention also provides a pharmaceutical composition I comprising substance A and a pharmaceutically acceptable carrier, wherein substance A is selected from the group consisting of type A crystals of the compound of formula I, type B crystals of the compound of formula I, type A crystals of a fumarate salt of the compound of formula I, type B crystals of a fumarate salt of the compound of formula I, type C crystals of a fumarate salt of the compound of formula I, type A crystals of a citrate salt of the compound of formula I, type B crystals of a citrate salt of the compound of formula I, type A crystals of a methanesulfonate salt of the compound of formula I, and type C crystals of a methanesulfonate salt of the compound of formula I. Form A crystals of the compound of formula I, Form B crystals of the ethanesulfonate salt of the compound of formula I, Form A crystals of the maleate salt of the compound of formula I, Form B crystals of the maleate salt of the compound of formula I, Form A crystals of the L-tartrate salt of the compound of formula I, Form B crystals of the L-tartrate salt of the compound of formula I, Form C crystals of the L-tartrate salt of the compound of formula I, Form D crystals of the L-tartrate salt of the compound of formula I, Form A crystals of the glycolate salt of the compound of formula I, Form A crystals of the L-malate salt of the compound of formula I, Form B crystals of the L-malate salt of the compound of formula I Form A crystal of the hippurate salt of the compound of formula I, Form A crystal of the succinate salt of the compound of formula I, Form B crystal of the succinate salt of the compound of formula I, Form A crystal of the ascorbate salt of the compound of formula I, Form B crystal of the ascorbate salt of the compound of formula I, Form A crystal of the adipate salt of the compound of formula I, Form A crystal of the p-toluenesulfonate salt of the compound of formula I, Form A crystal of the benzenesulfonate salt of the compound of formula I, Form A crystal of the oxalate salt of the compound of formula I, Form A crystal of the 2-hydroxyethanesulfonate salt of the compound of formula I, and one or more of the above pharmaceutically acceptable salts of the compound of formula I.

[0171] The present invention also provides a pharmaceutical composition II comprising substance A and at least one other pharmacologically active inhibitor, said substance A being as defined above. Preferably, said other pharmacologically active inhibitor is a MEK inhibitor, an EGFR inhibitor or a KRAS inhibitor; More preferably, the MEK inhibitor is trametinib; More preferably, the EGFR inhibitor is osimertinib or gefitinib, preferably osimertinib; More preferably, the KRAS inhibitor is MRTX-849, AMG-510 or JDQ443.

[0172] The chemical structure of MRTX849 is

[0173] [ka] is.

[0174] The chemical structure of AMG-510 is

[0175] [ka] is.

[0176] The chemical structure of JDQ443 is

[0177] [ka] is.

[0178] Preferably, said other pharmacologically active inhibitor is an inhibitor of MEK and / or a mutant thereof. More preferably, said other pharmacologically active inhibitor is trametinib.

[0179] Preferably, said other pharmacologically active inhibitor is an inhibitor of EGFR and / or its mutants, more preferably said other pharmacologically active inhibitor is osimertinib or gefitinib, preferably osimertinib.

[0180] The present invention also provides (1) Use in inhibiting the interaction between SOS1 and RAS family proteins, (2) Use in the prevention and / or treatment of diseases associated with SOS1 and RAS family proteins, (3) Use in the manufacture of a medicine that inhibits the interaction between SOS1 and RAS family proteins; (4) Use in the manufacture of a medicament for preventing and / or treating a disease associated with (or mediated by) SOS1 and RAS family proteins; The present invention provides the use of a substance A, the pharmaceutical composition I or the pharmaceutical composition II selected from the group consisting of: wherein substance A is as defined above.

[0181] The diseases associated with (or mediated by) SOS1 and RAS family proteins include, but are not limited to, cancer and RAS diseases. The RAS diseases are preferably Noonan syndrome, CFC syndrome (cardio-facial-cutaneous syndrome), hereditary gingival fibromatosis type 1, neurofibromatosis type 1 (NF1), capillary malformation-arteriovenous malformation syndrome, Costello syndrome, or Regius syndrome, and more preferably neurofibromatosis type 1. The cancer is preferably selected from melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, gastric cancer, esophageal cancer, colorectal cancer, gallbladder cancer, bile duct cancer, choriocarcinoma, pancreatic cancer, polycythemia vera, childhood cancer, cervical cancer, ovarian cancer, breast cancer, bladder cancer, urothelial cancer, ureteral cancer, prostate cancer, seminoma, testicular tumor, leukemia, head and neck tumor, endometrial cancer, thyroid cancer, lymphoma, sarcoma, osteoma, neuroblastoma, brain tumor, myeloma, astrocytoma, glioblastoma and glioma, more preferably selected from colorectal cancer, lung cancer and pancreatic cancer.

[0182] The lung cancer is preferably non-small cell lung cancer, more preferably metastatic non-small cell lung cancer, the leukemia is preferably chronic lymphocytic leukemia or acute myeloid leukemia, the lymphoma is preferably diffuse large B-cell lymphoma, the myeloma is preferably multiple myeloma, the osteoma is preferably osteochondroma, the liver cancer is preferably hepatocellular carcinoma, the head and neck tumor is preferably head and neck squamous cell carcinoma, the sarcoma is preferably osteosarcoma, and the colorectal cancer is preferably colon cancer or rectal cancer.

[0183] Preferably, the use comprises combining substance A with a MEK inhibitor (e.g., trametinib). Includes: Preferably, the medicament comprises substance A and a MEK inhibitor (eg, trametinib).

[0184] Preferably, said use comprises combining substance A with an EGFR inhibitor (e.g. osimertinib, gefitinib). Preferably, the medicament comprises substance A and an EGFR inhibitor (eg, osimertinib, gefitinib).

[0185] Preferably, said use comprises using substance A in combination with a KRAS inhibitor (eg MRTX-849, AMG-510, JDQ443). Preferably, the medicament comprises substance A and a KRAS inhibitor (eg, MRTX-849, AMG-510, JDQ443).

[0186] Preferably, said use comprises combining substance A with trametinib or osimertinib. Preferably, the medicament comprises substance A and trametinib or osimertinib.

[0187] The RAS family protein may be KRAS, for example, KRAS G12C, KRAS G12D, and KRAS G12V. The present invention also provides a method for inhibiting SOS1 and RAS family proteins or preventing and / or treating a disease associated with (or mediated by) SOS1 and RAS family proteins, comprising the step of administering to a subject in need thereof a therapeutically effective amount of substance A. Preferably, the method comprises using substance A in combination with a MEK inhibitor, an EGFR inhibitor or a KRAS inhibitor, more preferably, the method comprises using substance A in combination with trametinib or osimertinib.

[0188] The present invention also provides a method for detecting the quality of substance B, comprising the step of eluting the substance to be tested on a silica gel chromatography column using high performance liquid chromatography.

[0189] The test substances include substance B, and substance B is selected from the group consisting of a compound of formula I, a type A crystal of the compound of formula I, a type B crystal of the compound of formula I, a type A crystal of a fumarate salt of the compound of formula I, a type B crystal of a fumarate salt of the compound of formula I, a type A crystal of a citrate salt of the compound of formula I, a type B crystal of a citrate salt of the compound of formula I, a type A crystal of a methanesulfonate salt of the compound of formula I, a type A crystal of an ethanesulfonate salt of the compound of formula I, a type B crystal of an ethanesulfonate salt of the compound of formula I, a type A crystal of a maleate salt of the compound of formula I, a type B crystal of a maleate salt of the compound of formula I, a type A crystal of an L-tartrate salt of the compound of formula I, a type B crystal of an L-tartrate salt of the compound of formula I, a type C crystal of an L-tartrate salt of the compound of formula I, and a compound of formula I. Form D crystals of the L-tartrate salt of the compound of formula I, Form A crystals of the glycolate salt of the compound of formula I, Form A crystals of the L-malate salt of the compound of formula I, Form B crystals of the L-malate salt of the compound of formula I, Form A crystals of the hippurate salt of the compound of formula I, Form A crystals of the succinate salt of the compound of formula I, Form B crystals of the succinate salt of the compound of formula I, Form A crystals of the ascorbate salt of the compound of formula I, Form A crystals of the adipate salt of the compound of formula I, Form A crystals of the p-toluenesulfonate salt of the compound of formula I, Form A crystals of the benzenesulfonate salt of the compound of formula I, Form A crystals of the oxalate salt of the compound of formula I, Form A crystals of the 2-hydroxyethanesulfonate salt of the compound of formula I, and pharmaceutically acceptable salts of the compound of formula I, The mobile phases used for the elution are mobile phase A and mobile phase B, The mobile phase A is an aqueous solution of 0.1±0.05% ammonia water, said mobile phase B is acetonitrile; In the elution program, the volume ratio of the mobile phase A to the mobile phase B is 1:1.5 to 9; Preferably, the elution program used for said elution is as follows:

[0190] [Table 1]

[0191] Preferably, the quality detection refers to purity testing, dynamic solubility and stability testing; Preferably, the detection method comprises: (1) The injection volume of the elution is 5±1 μL; (2) The flow rate of the elution is 1.0±0.2 mL / min; (3) The wavelength of the UV detector for the elution is 228±5 nm; (4) The model of the chromatography column is Waters XBridge C18, 4.6 mm / 150 mm / 3 μm; (5) The column temperature of the chromatography column is room temperature, preferably 30°C; (6) The dilution of the test substance is ACN / H2O (1:1 ± 0.5). Satisfy one or more of the following.

[0192] Unless contrary to common knowledge in the art, the above-mentioned preferable conditions can be arbitrarily combined to obtain each preferable embodiment of the present invention. The reagents and raw materials used in the present invention are commercially available.

[0193] In the present invention, the powder X-ray diffraction patterns are all measured using Kα spectral lines of a Cu target. When referring to XRPD peak positions, the 2θ angles can be retained to two or four significant decimal places, regardless of rounding. For example, if the 2θ angle is 4.8473, after retaining two significant decimal places, the 2θ angle can be 4.84 or 4.85, but it should be understood that such retention of significant digits has the same meaning.

[0194] Positive advances of the present invention: Through extensive and thorough research, the inventors have unexpectedly developed crystals, salts, and crystalline salts (e.g., Substance A) of the compound of Formula I described herein, as well as methods for preparing and using the compound. The compound of Formula I (including its crystals, salts, and crystalline salts) exhibits significant inhibitory effects on KRAS G12C::SOS1 binding, KRAS G12C-SOS1 binding, ERK phosphorylation levels in DLD-1 cells, and 3D proliferation of H358 cells. It also exhibits better hepatic metabolic stability, slower metabolism in the human body, higher exposure, no inhibitory effects on CYP3A4 enzymes, a low risk of potential drug-drug interactions, excellent pharmacokinetic properties, high safety and drug formation properties, and is more suitable for combined administration. Experiments have shown that the compounds described in the present invention, when administered alone or in combination with trametinib, exhibit significant inhibitory effects on Mia Paca-2 cancer cell growth, with the combined use being superior to the administration of the compounds alone.

[0195] The crystals, salts, and crystalline salts of the compounds of Formula I described herein (e.g., Substance A) have ideal physical and chemical properties, such as higher stability, solubility, bioavailability, and lower hygroscopicity, making them suitable for the preparation of desirable pharmaceutical formulations.

[0196] The present invention also provides a method for producing a crystal, a salt, or a crystalline salt of a compound of formula I (e.g., substance A), which is simple to operate, has high yields, is highly pure, and can be used in the industrial production of pharmaceuticals. [Brief explanation of the drawings]

[0197] [Figure 1] 1 is an XRPD pattern of the compound of formula I in Example 1. [Figure 2] 1 is a DSC pattern of the compound of formula I in Example 1. [Figure 3] 1 is a TGA pattern of the compound of formula I in Example 1. [Figure 4] 1 is an XRPD pattern of the A-type crystal of the compound of formula I in Example 2. [Figure 5] 1 is a DSC pattern of type A crystals of the compound of formula I in Example 2. [Figure 6] 1 is a TGA pattern of type A crystals of the compound of formula I in Example 2. [Figure 7] 1 shows a PLM pattern of type A crystals of the compound of formula I in Example 2. [Figure 8] 1 is an XRPD overlay of a sample of crystalline Form A of the compound of Formula I in Example 2 before and after drying. [Figure 9] 1 is a VT-XRPD pattern of the A-type crystal of the compound of formula I in Example 2. [Figure 10] 1 is an XRPD pattern of type B crystals of the compound of formula I in Example 3. [Figure 11] 1 is an XRPD pattern of crystalline form A of the fumarate salt of the compound of formula I in Example 4. [Figure 12] 1 is a DSC pattern of type A crystals of the fumarate salt of the compound of formula I in Example 4. [Figure 13] 1 is a TGA pattern of type A crystals of the fumarate salt of the compound of formula I in Example 4. [Figure 14] 1 shows the PLM pattern of type A crystals of the fumarate salt of the compound of formula I in Example 4. [Figure 15] 1 is a VT-XRPD pattern of crystalline form A of the fumarate salt of the compound of formula I in Example 4. [Figure 16] 1 is an XRPD pattern of type B crystals of the fumarate salt of the compound of formula I in Example 5. [Figure 17] 1 is a DSC pattern of type B crystals of the fumarate salt of the compound of formula I in Example 5. [Figure 18] 1 is a TGA pattern of type B crystals of the fumarate salt of the compound of formula I in Example 5. [Figure 19] 1 is an XRPD pattern of crystalline form C of the fumarate salt of the compound of formula I in Example 6. [Figure 20] 1 is a DSC pattern of C-type crystals of the fumarate salt of the compound of formula I in Example 6. [Figure 21] 1 is a TGA pattern of type C crystals of the fumarate salt of the compound of formula I in Example 6. [Figure 22] 1 is an XRPD pattern of crystalline form A of the citrate salt of the compound of formula I in Example 7. [Figure 23] 1 is a DSC pattern of type A crystals of the citrate salt of the compound of formula I in Example 7. [Figure 24] 1 is a TGA pattern of type A crystals of the citrate salt of the compound of formula I in Example 7. [Figure 25] 1 is an XRPD pattern of type B crystals of the citrate salt of the compound of formula I in Example 8. [Figure 26] 1 is a VT-XRPD pattern of type B crystals of the citrate salt of the compound of formula I in Example 8. [Figure 27] 1 is a DSC pattern of type B crystals of the citrate salt of the compound of formula I in Example 8. [Figure 28] 1 is a TGA pattern of type B crystals of the citrate salt of the compound of formula I in Example 8. [Figure 29] 1 is a PLM pattern of type B crystals of the citrate salt of the compound of formula I in Example 8. [Figure 30] 1 is an XRPD pattern of type A crystals of the methanesulfonate salt of the compound of formula I in Example 9. [Figure 31] 1 is a DSC pattern of type A crystals of the methanesulfonate salt of the compound of formula I in Example 9. [Figure 32] 1 shows a TGA pattern of type A crystals of the methanesulfonate salt of the compound of formula I in Example 9. [Figure 33] 1 shows a PLM pattern of type A crystals of the methanesulfonate salt of the compound of formula I in Example 9. [Figure 34] 1 is a VT-XRPD pattern of type A crystals of the methanesulfonate salt of the compound of formula I in Example 9. [Figure 35] 1 is an XRPD pattern of type A crystals of the ethanesulfonic acid salt of the compound of formula I in Example 10. [Figure 36] 1 is a VT-XRPD pattern of type A crystals of the ethanesulfonic acid salt of the compound of formula I in Example 10. [Figure 37] 1 is a DSC pattern of type A crystals of the ethanesulfonic acid salt of the compound of formula I in Example 10. [Figure 38] 1 shows a TGA pattern of type A crystals of the ethanesulfonic acid salt of the compound of formula I in Example 10. [Figure 39] 1 shows a PLM pattern of type A crystals of the ethanesulfonic acid salt of the compound of formula I in Example 10. [Figure 40] 1 is an XRPD pattern of type B crystals of the ethanesulfonic acid salt of the compound of formula I in Example 11. [Figure 41] 1 shows a DSC pattern of type B crystals of the ethanesulfonic acid salt of the compound of formula I in Example 11. [Figure 42] 1 shows a TGA pattern of type B crystals of the ethanesulfonic acid salt of the compound of formula I in Example 11. [Figure 43] 1 is an XRPD pattern of type A crystals of the maleate salt of the compound of formula I in Example 12. [Figure 44] 1 is a DSC pattern of type A crystals of the maleate salt of the compound of formula I in Example 12. [Figure 45] 1 shows a TGA pattern of type A crystals of the maleate salt of the compound of formula I in Example 12. [Figure 46] 1 is an XRPD pattern of type B crystals of the maleate salt of the compound of formula I in Example 13. [Figure 47] 1 is a DSC pattern of type B crystals of the maleate salt of the compound of formula I in Example 13. [Figure 48] 1 is a TGA pattern of type B crystals of the maleate salt of the compound of formula I in Example 13. [Figure 49] 1 is an XRPD pattern of crystalline form A of the L-tartrate salt of the compound of formula I in Example 14. [Figure 50] 1 is a DSC pattern of type A crystals of the L-tartrate salt of the compound of formula I in Example 14. [Figure 51] 1 is a TGA pattern of type A crystals of the L-tartrate salt of the compound of formula I in Example 14. [Figure 52] 1 is an XRPD pattern of type B crystals of the L-tartrate salt of the compound of formula I in Example 15. [Figure 53] 1 is a DSC pattern of type B crystals of the L-tartrate salt of the compound of formula I in Example 15. [Figure 54] 1 is a TGA pattern of type B crystals of the L-tartrate salt of the compound of formula I in Example 15. [Figure 55] 1 is an XRPD pattern of crystalline form C of the L-tartrate salt of the compound of formula I in Example 16. [Figure 56] 1 is a DSC pattern of C-type crystals of the L-tartrate salt of the compound of formula I in Example 16. [Figure 57] 1 shows a TGA pattern of type C crystals of the L-tartrate salt of the compound of formula I in Example 16. [Figure 58] 1 is an XRPD pattern of crystalline form D of the L-tartrate salt of the compound of formula I in Example 17. [Figure 59] 1 is a DSC pattern of D-form crystals of the L-tartrate salt of the compound of formula I in Example 17. [Figure 60] 1 shows a TGA pattern of D-form crystals of the L-tartrate salt of the compound of formula I in Example 17. [Figure 61] 1 is an XRPD pattern of type A crystals of the glycolic acid salt of the compound of formula I in Example 18. [Figure 62] 1 is a DSC pattern of type A crystals of glycolate salt of the compound of formula I in Example 18. [Figure 63] 1 shows a TGA pattern of type A crystals of glycolate salt of the compound of formula I in Example 18. [Figure 64] 1 is an XRPD pattern of crystalline form A of the L-malate salt of the compound of formula I in Example 19. [Figure 65] 1 is a DSC pattern of type A crystals of the L-malate salt of the compound of formula I in Example 19. [Figure 66]1 is a TGA pattern of type A crystals of the L-malate salt of the compound of formula I in Example 19. [Figure 67] 1 is an XRPD pattern of type B crystals of the L-malate salt of the compound of formula I in Example 20. [Figure 68] 1 is a DSC pattern of type B crystals of the L-malate salt of the compound of formula I in Example 20. [Figure 69] 1 is a TGA pattern of type B crystals of the L-malate salt of the compound of formula I in Example 20. [Figure 70] 1 is an XRPD pattern of crystalline form A of the hippurate salt of the compound of formula I in Example 21. [Figure 71] 2 is a DSC pattern of type A crystals of the hippurate salt of the compound of formula I in Example 21. [Figure 72] 2 is a TGA pattern of type A crystals of the hippurate salt of the compound of formula I in Example 21. [Figure 73] 2 is a DSC pattern of crystals of type A of the succinate salt of the compound of formula I in Example 22. [Figure 74] 2 is a TGA pattern of crystals of type A of the succinate salt of the compound of formula I in Example 22. [Figure 75] 1 is an XRPD pattern of B-type crystals of the succinate salt of the compound of formula I in Example 23. [Figure 76] 2 is a DSC pattern of B-type crystals of the succinate salt of the compound of formula I in Example 23. [Figure 77] 2 is a TGA pattern of type B crystals of the succinate salt of the compound of formula I in Example 23. [Figure 78] 1 is a DSC pattern of type A crystals of the ascorbate salt of the compound of formula I in Example 24. [Figure 79] 1 is a TGA pattern of type A crystals of the ascorbate salt of the compound of formula I in Example 24. [Figure 80] 1 is an XRPD pattern of type B crystals of the ascorbate salt of the compound of formula I in Example 25. [Figure 81]2 is a DSC pattern of type B crystals of the ascorbate salt of the compound of formula I in Example 25. [Figure 82] 2 is a TGA pattern of type B crystals of the ascorbate salt of the compound of formula I in Example 25. [Figure 83] 2 is a DSC pattern of type A crystals of the adipate salt of the compound of formula I in Example 26. [Figure 84] 2 is a TGA pattern of type A crystals of the adipate salt of the compound of formula I in Example 26. [Figure 85] 1 is an XRPD pattern of type A crystals of p-toluenesulfonic acid salt of the compound of formula I in Example 27. [Figure 86] 2 is a DSC pattern of type A crystals of p-toluenesulfonic acid salt of the compound of formula I in Example 27. [Figure 87] 2 is a TGA pattern of type A crystals of p-toluenesulfonic acid salt of the compound of formula I in Example 27. [Figure 88] 2 is a DSC pattern of type A crystals of the benzenesulfonate salt of the compound of formula I in Example 28. [Figure 89] 2 is a TGA pattern of type A crystals of the benzenesulfonate salt of the compound of formula I in Example 28. [Figure 90] 1 is an XRPD pattern of crystalline form A of the oxalate salt of the compound of formula I in Example 29. [Figure 91] 1 is a DSC pattern of type A crystals of the oxalate salt of the compound of formula I in Example 29. [Figure 92] 1 is a TGA pattern of type A crystals of the oxalate salt of the compound of formula I in Example 29. [Figure 93] 1 is an XRPD pattern of type A crystals of 2-hydroxyethanesulfonic acid salt of the compound of formula I in Example 30. [Figure 94] 1 is a DSC pattern of type A crystals of 2-hydroxyethanesulfonic acid salt of the compound of formula I in Example 30. [Figure 95]1 shows a TGA pattern of type A crystals of 2-hydroxyethanesulfonic acid salt of the compound of formula I in Example 30. [Figure 96] 1 is an XRPD overlay of a solubility sample in H2O of crystalline Form A of the compound of Formula I in Example 2. [Figure 97] 1 is an XRPD overlay of a solubility sample of crystalline Form A of the compound of Formula I in SGF in Example 2. [Figure 98] 1 is an XRPD overlay of a solubility sample in FaSSIF of crystalline Form A of the compound of Formula I in Example 2. [Figure 99] 1 is an XRPD overlay of a solubility sample in FeSSIF of crystalline Form A of the compound of Formula I in Example 2. [Figure 100] 1 is an XRPD overlay of a solubility sample in H2O of crystalline Form A of the fumarate salt of the compound of Formula I in Example 4. [Figure 101] 1 is an XRPD overlay of a solubility sample in SGF of crystalline Form A of the fumarate salt of the compound of Formula I in Example 4. [Figure 102] 1 is an XRPD overlay of a solubility sample in FaSSIF of crystalline Form A of the fumarate salt of the compound of Formula I in Example 4. [Figure 103] 1 is an XRPD overlay of a solubility sample in FeSSIF of crystalline Form A of the fumarate salt of the compound of Formula I in Example 4. [Figure 104] 1 is an XRPD overlay of a solubility sample in HO of crystalline Form B of the citrate salt of the compound of Formula I in Example 8. [Figure 105] 1 is an XRPD overlay of a solubility sample in SGF of crystalline Form B of the citrate salt of the compound of Formula I in Example 8. [Figure 106] 1 is an XRPD overlay of a solubility sample in FaSSIF of crystalline Form B of the citrate salt of the compound of Formula I in Example 8. [Figure 107] 1 is an XRPD overlay of a solubility sample in FeSSIF of crystalline Form B of the citrate salt of the compound of Formula I in Example 8. [Figure 108] 1 is an XRPD overlay of a solubility sample in FaSSIF of crystalline Form A of the methanesulfonate salt of the compound of Formula I in Example 9. [Figure 109] 1 is an XRPD overlay of a solubility sample in FeSSIF of crystalline Form A of the methanesulfonate salt of the compound of Formula I in Example 9. [Figure 110] 1 is an XRPD overlay of a solubility sample in H2O of crystalline Form A of the ethanesulfonic acid salt of the compound of Formula I in Example 10. [Figure 111] 1 is an XRPD overlay of a solubility sample in FaSSIF of crystalline Form A of the ethanesulfonate salt of the compound of Formula I in Example 10. [Figure 112] 1 is an XRPD overlay of a solubility sample in FeSSIF of crystalline Form A of the ethanesulfonate salt of the compound of Formula I in Example 10. [Figure 113] 1 shows the DVS pattern of type A crystals of the compound of formula I in Example 2. [Figure 114] 1 is an XRPD overlay of crystalline form A of the compound of formula I in Example 2 before and after DVS testing. [Figure 115] 1 is a DVS pattern of type A crystals of the fumarate salt of the compound of formula I in Example 4. [Figure 116] 1 is an XRPD overlay of crystalline Form A of the fumarate salt of the compound of Formula I in Example 4 before and after DVS testing. [Figure 117] 1 is a DVS pattern of type B crystals of the citrate salt of the compound of formula I in Example 8. [Figure 118] 1 is an XRPD overlay of type B crystals of the citrate salt of the compound of Formula I in Example 8 before and after DVS testing. [Figure 119] 1 shows the DVS pattern of type A crystals of the methanesulfonate salt of the compound of formula I in Example 9. [Figure 120] 1 is an XRPD overlay of crystalline form A of the methanesulfonate salt of the compound of Formula I in Example 9 before and after DVS testing. [Figure 121]1 shows a DVS pattern of type A crystals of the ethanesulfonic acid salt of the compound of formula I in Example 10. [Figure 122] 1 is an XRPD overlay of crystalline form A of the ethanesulfonic acid salt of the compound of Formula I in Example 10 before and after DVS testing. [Figure 123] 1 is an XRPD overlay of a stability evaluation sample of crystalline form A of the compound of formula I in Example 2. [Figure 124] 1 is an XRPD overlay of a stability evaluation sample of crystalline form A of the fumarate salt of the compound of Formula I in Example 4. [Figure 125] 1 is an XRPD overlay of a stability evaluation sample of type B crystals of the citrate salt of the compound of Formula I in Example 8. [Figure 126] 1 is an XRPD overlay of a stability evaluation sample of crystalline form A of the methanesulfonate salt of the compound of Formula I in Example 9. [Figure 127] 1 is an XRPD overlay of a stability evaluation sample of crystalline form A of the ethanesulfonic acid salt of the compound of Formula I in Example 10. [Figure 128] 1 is an XRPD pattern of crystal form A of the succinate salt of the compound of formula I in Example 22. [Figure 129] 1 is an XRPD pattern of crystalline form A of the ascorbate salt of the compound of formula I in Example 24. [Figure 130] 1 is an XRPD pattern of type A crystals of the adipate salt of the compound of formula I in Example 26. [Figure 131] 1 is an XRPD pattern of type A crystals of the benzenesulfonate salt of the compound of formula I in Example 28. DETAILED DESCRIPTION OF THE INVENTION

[0198] The present invention will be further described below by way of examples, but the present invention is not limited to the scope of the examples. In the following examples, experimental methods for which specific conditions are not described are selected according to conventional methods and conditions or product instructions.

[0199] The equipment used in the following examples is as shown in Table 1.

[0200] [Table 2]

[0201] X-ray powder diffraction analysis (XRPD) The XRPD patterns were collected on a PANalytacal X-ray powder diffraction analyzer, and the scan parameters were as shown in Table 2.

[0202] [Table 3]

[0203] Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) TGA and DSC patterns were collected on a TA 5500 thermogravimetric analyzer and a TA 2500 differential scanning calorimeter, respectively, and Table 3 shows the test parameters.

[0204] [Table 4]

[0205] Dynamic Water Sorption (DVS) Dynamic moisture sorption (DVS) curves were collected using a DVS IntrInsic from SMS (Surface Measurement Systems). Relative humidity at 25 °C was corrected using the deliquescence points of LiCl, Mg(NO3)2, and KCl. DVS test parameters are listed in Table 4.

[0206] [Table 5]

[0207] Polarized Light Microscope (PLM) Polarized light micrographs were taken at room temperature using a Zeiss Axio Scope.A1 microscope.

[0208] Liquid NMR ( 1 H NMR) Liquid NMR spectra were collected on a Bruker 400M nuclear magnetic resonance instrument using DMSO-d6, CDCl3, or CD3OD as solvents.

[0209] High-Performance Liquid Chromatography and Ion Chromatography (HPLC / IC) In the test, purity test, dynamic solubility test and stability test were performed by Agilent 1260 high performance liquid chromatography, and ion salt formation molar ratio test was performed by ion chromatography. The analysis conditions are as shown in Table 5 and Table 6.

[0210] [Table 6]

[0211] [Table 7]

[0212] Comparison table of solvents in Japanese and English The solvent abbreviations and corresponding Japanese names are shown in Table 7.

[0213] [Table 8]

[0214] Example 1 Preparation of Compounds of Formula I The synthesis route (see patent CN202210117751.6) is as follows:

[0215] [ka]

[0216] Step 1: Synthesis of 1-(3-(pentafluorosulfanyl)phenyl)ethan-1-one (B3-2)

[0217] [ka]

[0218] The compound 3-bromo-(pentafluorosulfanyl)benzene (3.00 g, 10.6 mmol) was added to dioxane (100 mL) at room temperature, and bis(triphenylphosphine)palladium(II) chloride (744 mg, 1.06 mmol) and tributyl(1-ethoxyvinyl)tin (4.20 g, 11.7 mmol) were added, and the mixture was heated to 90° C. under N2 protection and stirred for 14 hours. After cooling to room temperature, 2N hydrochloric acid (100 mL) was added and stirred for 4 hours. The mixture was extracted with ethyl acetate (200 mL × 3), separated, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 8:1) to give 1-(3-(pentafluorosulfanyl)phenyl)ethan-1-one (B3-2, yellow liquid, 2.4 g, yield: 89%).

[0219] LC-MS, M / Z (ESI): 247.0 [M+H] + . Step 2: Synthesis of (S,E)-2-methyl-N-(1-(3-(pentafluorosulfanyl)phenyl)ethylidene)propane-2-sulfinamide (B3-3)

[0220] [ka]

[0221] At room temperature, 3'-fluoro-5'-(pentafluorosulfur)acetophenone (1.0 g, 4.06 mmol) was added to THF (150 mL), and (S)-methyl-2-propanesulfinamide (492 mg, 4.06 mmol) and titanium ethoxide (1.14 g, 5.0 mmol) were added, heated to 70°C, and stirred for 16 hours. The mixture was cooled to room temperature, diluted with water (100 mL), extracted with ethyl acetate (100 mL × 3), and the organic phases were combined. The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 8:1) to give (S,E)-2-methyl-N-(1-(3-(pentafluorosulfanyl)phenyl)ethylidene)propane-2-sulfinamide (B3-3, white solid, 1.42 g, yield: 100%).

[0222] LC-MS, M / Z (ESI): 350.2 [M+H] + . Step 3: Synthesis of (S)-2-methyl-N-((R)-1-(3-(pentafluorosulfanyl)phenyl)ethyl)propane-2-sulfinamide (B3-4)

[0223] [ka]

[0224] The starting material (S,E)-2-methyl-N-(1-(3-(pentafluorosulfanyl)phenyl)ethylidene)propane-2-sulfinamide (1.5 g, 4.3 mmol) was added to methanol (30 mL) at room temperature and cooled to 0 °C. NaBH (744 mg, 20.1 mmol) was added to the methanol in batches, and the mixture was warmed to room temperature and stirred for 3 hours. The reaction solution was concentrated and purified by thin-layer preparative plate to give (S)-2-methyl-N-((R)-1-(3-(pentafluorosulfanyl)phenyl)ethyl)propane-2-sulfinamide (B3-4, white solid, 600 mg, yield: 40.0%).

[0225] LC-MS, M / Z (ESI): 352.1 [M+H] + . Step 4: Synthesis of (R)-1-(3-(pentafluorosulfanyl)phenyl)ethan-1-amine hydrochloride (B3-5)

[0226] [ka]

[0227] At room temperature, the starting material (R)-2-methyl-N-((R)-1-(3-(pentafluorosulfanyl)phenyl)ethyl)propane-2-sulfinamide (600 mg, 1.70 mmol) was added to a 4 mol / L hydrochloric acid-dioxane solution (10 mL) and stirred for 4 hours. The reaction solution was concentrated, methyl tert-butyl ether (20 mL) was added, stirred for 1 hour, and filtered to obtain (R)-1-(3-(pentafluorosulfanyl)phenyl)ethan-1-amine hydrochloride (B3-5, white solid, 350 mg, yield: 72.7%).

[0228] LC-MS, M / Z (ESI): 248.2 [M+H] + . Step 5: Synthesis of (R)-6-(1-(fluoromethyl)cyclopropyl)-2-methyl-4-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one

[0229] [ka]

[0230] At room temperature, the raw material 6-(1-(fluoromethyl)cyclopropyl)-4-hydroxy-2-methylpyridine[4,3-d]pyrimidin-7(6H)-one (A1) (200 mg, 0.80 mmol) was added to acetonitrile (20 mL), potassium phosphate (678 mg, 3.20 mmol), phosphonitrile chloride trimer (416 mg, 1.20 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The raw material (R)-1-(3-(pentafluorosulfanyl)phenyl)ethan-1-amine hydrochloride (160 mg, 0.56 mmol) was added to DCM (10 mL), DIPEA (2 mL) was added, and the mixture was stirred for 0.5 hours. The solution was added to the above reaction system and stirred at room temperature for 6 hours. The reaction solution was concentrated and purified under acidic preparation conditions B (Welch, Ultimate C18 column, 10 μm, 21.2 mm × 250 mm. Mobile phase A: 1‰ formic acid in pure water, mobile phase B: acetonitrile. Gradient conditions: Mobile phase A was maintained at 90% for 0-3 min, then gradient elution from 90% to 5% for 3-18 min, and maintained at 5% for 18-22 min.) to give (R)-6-(1-(fluoromethyl)cyclopropyl)-2-methyl-4-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one (i.e., compound of Formula I, white solid, 44 mg, yield: 16.4%).

[0231] The XRPD is shown in Figure 1 and indicates that the obtained sample of the compound of formula I is essentially amorphous. In Figure 2, the DSC spectrum shows that the compound of formula I has major endothermic signals at 75.7°C, 95.2°C, 142.2°C and 180.4°C.

[0232] In Figure 3, the TGA spectrum shows that the compound of formula I loses 6.26% weight when heated to 180°C from the onset. of the compound of formula I 1 H NMR spectral data: 1 H NMR (400m Hz, DMSO-d6) δ9.18 (s,1H), 8.87(d, 1H),7.96(s, 1H),7.78(d, 1H), 7.71 (d, 1H),7.60 (t, 1H),6.08 (s, 1H), 5.60(q, 1H), 4.68-4.56 (m, 2H), 2.21(s, 3H), 1.61 (d, 3H), 1.32-1.28(m, 4H).

[0233] LC-MS, M / Z (ESI): 479.4 [M+H] + . Example 2 Preparation of Form A Crystals of the Compound of Formula I Preparation method: 300.3 mg of the compound of formula I was weighed into a 20 mL glass vial, and 7.5 mL of n-heptane was added to form a suspension, which was then placed under magnetic stirring at 50°C for 5 days. The solid was separated and dried under vacuum at room temperature overnight to obtain a solid sample.

[0234] The obtained sample was determined to be a type A crystal of the compound of formula I by measuring the powder X-ray diffraction pattern. The diffraction peaks and relative intensities in the powder X-ray diffraction pattern, expressed as 2θ angles, may be further shown in Table 8.

[0235] [Table 9]

[0236] The XRPD of a sample of crystalline Form A of the compound of Formula I is shown in FIG. In Figure 5, the DSC spectrum shows that Form A crystals of the compound of Formula I have major endothermic signals at 73.3°C and 178.0°C.

[0237] In Figure 6, the TGA spectrum shows that Form A crystals of the compound of Formula I lose 3.24% weight when heated to 120±5°C from the onset. Form A crystals of the compound of formula I 1 H NMR spectral data: 1H NMR (400m Hz, DMSO-d6) δ9.12 (1H, s), 8.89(1H, d), 7.91(1H, t), 7.83-7.76(1H, m), 7.72(1H, d), 7.60(1H, t), 6.09(1H, s), 5.60(1H, m), 4.62(2H, d), 2.21(3H, s), 1.61(3H, d), 1.37-1.24(4H, m).

[0238] In Figure 7, PLM shows that the A-type crystals appear as small aggregated granules. In order to evaluate the effect of drying conditions on the A-type crystals of the compound of formula I, the A-type crystals of the compound of formula I were vacuum dried at 60 ° C. / 80 ° C. for 4 hours, and the changes in the samples were evaluated. The XRPD of the sample after drying was 1 H NMR and HPLC purity were tested. After drying, the sample was exposed to room temperature and humidity conditions (19°C / 27%RH) for 10-15 minutes, and then XRPD analysis was performed (Figure 8), which showed that it was still Form A crystals of the compound of Formula I. 1 From the H NMR results, no n-heptane solvent residue was observed in the dried sample, and from the HPLC results (Table 9), no significant change in the purity of the sample before and after drying was observed.

[0239] [Table 10]

[0240] Example 3 Preparation of Crystalline Form B of the Compound of Formula I Variable temperature XRPD (VT-XRPD) was used to identify the type A crystals of the compound of formula I in Example 2. The VT-XRPD results (FIG. 9) showed that when the type A crystals of the compound of formula I were purged under N2 for 20 minutes, the sample was observed to crystallize, and the new crystals were type B crystals of the compound of formula I. No change in the crystals was observed when the sample was heated to 100°C under the protection of N2 and then cooled to 30°C. When the sample was exposed to air, the sample was observed to revert to type A crystals of the compound of formula I. TGA, DSC and1 Combined with the H NMR results, it was speculated that the type A crystals were hydrates, possibly containing 0.5–1.5 molecules, such as monohydrates or sesquihydrates. The type A crystals could be dehydrated under N2 purging or heating conditions to transform into anhydrous type B crystals, and upon exposure to air, the sample absorbed water and reverted to type A crystals.

[0241] The obtained sample was determined by powder X-ray diffraction pattern to be a B-type crystal of the compound of formula I, whose diffraction peaks and relative intensities in the powder X-ray diffraction pattern expressed in terms of 2θ angles may be further as shown in Table 10.

[0242] [Table 11]

[0243] The powder X-ray diffraction pattern of the B-type crystals of the compound of formula I is shown in FIG. Example 4 Preparation of Form A Crystals of the Fumarate Salt of the Compound of Formula I 300.1 mg of the compound of formula I and 72.5 mg of fumaric acid (1:1 molar ratio) were weighed into a 20 mL glass vial, 7.5 mL of IPA / HO (19:1, v / v) was added, and the mixture was stirred at room temperature for 4 days. The solid was separated and dried under vacuum at room temperature overnight, and a total of 280 mg of sample was collected.

[0244] The obtained sample was determined by powder X-ray diffraction pattern to be a Form A crystal of the fumarate salt of the compound of formula I, whose diffraction peaks and relative intensities in the powder X-ray diffraction pattern expressed in terms of 2θ angles may be as shown in Table 11.

[0245] [Table 12]

[0246] The powder X-ray diffraction pattern of crystalline form A of the fumarate salt is shown in FIG. In Figure 12, the DSC spectrum showed that the sample had one endothermic peak at 214.7°C.

[0247] In Figure 13, the TGA spectrum showed that the sample had a weight loss of 3.35% when heated to 150°C. Form A crystals of the fumarate salt of the compound of formula I 1 H NMR spectral data: 1 H NMR (400m Hz, DMSO-d6) δ9.12(1H, s), 8.89(1H, s), 7.96(1H, t), 7.79(1H, dd), 7.71(1H, d), 7.60(1H, t), 6.62(2H, s), 6.09(1H, s), 5.60(1H, m), 4.62(2H, d), 2.21(3H, s), 1.61 (3H, d), 1.37-1.23 (4H, m); in the sample of crystalline Form A of the fumarate salt, the molar ratio of fumaric acid to the compound of Formula I was 1.0:1.

[0248] In FIG. 14, PLM shows that the fumarate salt type A crystals are small needle-like granules, and aggregation of the sample was observed. VT-XRPD was used to identify the fumarate type A crystals, and the results (see Figure 15) showed that when the fumarate type A crystals were purged under N2 for 20 minutes, a peak shift was observed, and when heated to 150°C under N2 protection and then cooled to 30°C, no change in the crystals was observed, and when the sample was exposed to air, it was observed that the sample reverted to the fumarate type A crystals. TGA, DSC and 1 Combining the H NMR results, we speculate that the fumarate form A crystal is a hydrate, which may be a monohydrate or sesquihydrate containing 0.5 to 1.5 water molecules.

[0249] Example 5 Preparation of Crystalline Form B of the Fumarate Salt of the Compound of Formula I The compound of formula I and an equimolar amount of fumaric acid were suspended and stirred in EtOAc at room temperature for 3 days, and the solid was centrifuged and dried under vacuum at room temperature overnight to give a solid.

[0250] The obtained sample was determined by powder X-ray diffraction pattern to be Type B crystals of the fumarate salt of the compound of Formula I, whose diffraction peaks and relative intensities in the powder X-ray diffraction pattern expressed in terms of 2θ angles may further be as shown in Table 12.

[0251] [Table 13]

[0252] The powder X-ray diffraction pattern of the B-form crystals of the fumarate salt is shown in FIG. In FIG. 17, the DSC spectrum showed that the sample had one endothermic peak at 154.4°C and one exothermic peak at 191.9°C.

[0253] In Figure 18, the TGA spectrum showed that the sample lost 5.64% weight when heated to 150°C, and 6.76% weight when heated from 150°C to 250°C.

[0254] Form B crystals of the fumarate salt of the compound of formula I 1 H NMR spectral data: 1 H NMR (400m Hz, DMSO-d6) δ9.12(1H, s), 8.90(1H, d), 7.96(1H, t), 7.80(1H, dd), 7.72(1H, d), 7.60(1H, t), 6.62(2H, s), 6.09(1H, s), 5.60(1H, m), 4.61(2H, d), 2.22(3H, s), 1.61(3H, d), 1.35-1.26(4H, m); 1 1 H NMR results showed that the molar ratio of fumaric acid to the compound of formula I was 1:1 in the sample of crystalline Form B of the fumarate salt.

[0255] Example 6 Preparation of Form C Crystals of the Fumarate Salt of the Compound of Formula I The compound of formula I and an equimolar amount of fumaric acid were suspended and stirred in MTBE at room temperature for 3 days, and the solid was centrifuged and vacuum dried overnight at room temperature to obtain a solid.

[0256] The obtained sample was determined by powder X-ray diffraction pattern to be Form C crystals of the fumarate salt of the compound of formula I, whose diffraction peaks and relative intensities in the powder X-ray diffraction pattern expressed in terms of 2θ angles may further be as shown in Table 13.

[0257] [Table 14]

[0258] The powder X-ray diffraction pattern of crystalline form C of the fumarate salt is shown in FIG. In Figure 20, the DSC spectrum showed that the sample had three endothermic peaks at 94.4°C, 145.0°C and 161.2°C, and one exothermic peak at 190.4°C.

[0259] In FIG. 21, the TGA spectrum showed that the sample lost 1.69% weight when heated to 150°C, and 6.21% weight when heated from 150°C to 250°C.

[0260] C-type crystals of fumarate 1 H NMR spectral data: 1H NMR (400 m Hz, DMSO-d₆) 9.12 (1H, s), 8.90 (1H, d), 7.96 (1H, t), 7.79 (1H, dd), 7.72 (1H, d), 7.60 (1H, t), 6.63 (2H, s), 6.09 (1H, s), 5.60 (1H, m), 4.59 (2H, d), 2.22 (3H, s), 1.61 (3H, d), 1.35–1.24 (4H, m); in a sample of crystalline Form C of the fumarate salt, the molar ratio of fumaric acid to the compound of Formula I was 1:1.

[0261] Example 7 Preparation of Form A Crystals of the Citrate Salt of the Compound of Formula I The compound of formula I and an equimolar amount of anhydrous citric acid were suspended and stirred in acetone / n-heptane (1:3, v / v) at room temperature for 3 days, and the solid was centrifuged and vacuum dried overnight at room temperature to obtain the solid.

[0262] The obtained sample was determined by powder X-ray diffraction pattern to be Form A crystals of the citrate salt of the compound of Formula I, whose diffraction peaks and relative intensities in the powder X-ray diffraction pattern expressed in terms of 2θ angles may further be as shown in Table 14.

[0263] [Table 15]

[0264] The powder X-ray diffraction pattern of the crystalline form A of the citrate salt is shown in FIG. In Figure 23, the DSC spectrum showed that the sample had two endothermic peaks at 99.1°C and 137.9°C.

[0265] In Figure 24, the TGA spectrum showed that the sample lost 5.72% weight when heated to 150°C, and 19.25% weight when heated from 150°C to 230°C.

[0266] Citrate A crystals 1 H NMR spectral data:1 H NMR (400m Hz, DMSO-d6) 9.15(1H, s), 7.97(1H, t), 7.80(1H, dd), 7.72(1H, d), 7.61(1H, t), 6.09(1H, s), 5.63(1H, m), 4.59(2H, d), 2.74(2H, d), 2.63(2H, d), 2.24(3H, s), 1.62(3H, d), 1.35 -1.26(4H, m); 1 1 H NMR results showed that the molar ratio of citric acid to the compound of Formula I was 1:1 in the sample of crystalline Form A of the citrate salt.

[0267] Example 8 Preparation of Form B Crystals of the Citrate Salt of the Compound of Formula I 300.0 mg of the compound of formula I and 120.7 mg of anhydrous citric acid (1:1 molar ratio) were weighed into a 60 mL glass vial, 7.5 mL of IPA / HO (19:1, v / v) was added, and the mixture was stirred at room temperature. After 10 minutes, the sample was observed to be almost dissolved. Next, 15 mL of n-heptane was added to the vial, and the temperature cycle was switched on. After stirring for 3 days, the solid was separated and dried under vacuum at room temperature overnight. A total of 303 mg of sample was collected.

[0268] The obtained sample was determined by powder X-ray diffraction pattern to be a B-type crystal of the citrate salt of the compound of formula I, whose diffraction peaks and relative intensities in the powder X-ray diffraction pattern expressed in terms of 2θ angles may further be as shown in Table 15.

[0269] [Table 16]

[0270] The powder X-ray diffraction pattern of the B-type crystals of the citrate salt is shown in FIG. VT-XRPD was used to identify the Form B crystals of the citrate salt, and the results (Figure 26) showed that no change in the crystals was observed when the sample was purged under N2 for 20 minutes, heated to 150°C, and then cooled to room temperature.

[0271] In Figure 27, the DSC spectrum shows that the sample has one endothermic peak at 195.0°C. It was shown that it has. In Figure 28, the TGA spectrum showed that the sample had a weight loss of 1.26% when heated to 150°C.

[0272] Citrate B-type crystals 1 H NMR spectral data: 1 H NMR (400 m Hz, DMSO-d₆) 9.15 (1H, s), 7.96 (1H, t), 7.80 (1H, dd), 7.72 (1H, d), 7.60 (1H, t), 6.09 (1H, s), 5.62 (1H, m), 4.61 (2H, d), 2.73 (2H, d), 2.63 (2H, d), 2.24 (3H, s), 1.61 (3H, d), 1.37–1.20 (4H, m); in the sample of crystalline Form B of the citrate salt, the molar ratio of citric acid to compound of Formula I was 1:1.

[0273] In Figure 29, PLM shows that the Citrate B crystals are small irregular granules, and aggregation of the sample was observed. Example 9 Preparation of Form A Crystals of the Methanesulfonate Salt of the Compound of Formula I 60.6 mg of methanesulfonic acid (1:1 molar addition ratio) was weighed into a 20 mL glass vial and diluted with 7.5 mL of EtOAc. 300.2 mg of the compound of formula I was weighed into the diluted reaction system. After 10 minutes, the sample was observed to be almost dissolved. 3 mL of n-heptane was then added to the vial, and the temperature cycle was switched on. After stirring for 3 days, the solid was separated and dried under vacuum at room temperature overnight. A total of 270 mg of sample was collected.

[0274] The obtained sample was determined by powder X-ray diffraction pattern to be a Form A crystal of the methanesulfonate salt of the compound of Formula I, whose diffraction peaks and relative intensities in the powder X-ray diffraction pattern expressed in terms of 2θ angles may be further as shown in Table 16.

[0275] [Table 17]

[0276] The powder X-ray diffraction pattern of the A-type crystals of the methanesulfonate salt is shown in FIG. In Figure 31, the DSC spectrum showed that the sample had one endothermic peak at 206.0°C.

[0277] In Figure 32, the TGA spectrum showed that the sample had a weight loss of 2.14% when heated to 150°C. Methanesulfonate A-type crystals 1 H NMR spectral data: 1 H NMR (400m Hz, CDCl3) δ13.27(1H, s), 10.69(1H, d), 9.32(1H, s), 7.90(1H, t), 7.79(1H, d), 7.63(1H, dd), 7.43(1H, s), 6.40(1H, s), 5.64(1H, m), 4.44(2H, t), 2.86(3H, s), 2.49(3H, s), 1.86(3H, d), 1.55(2H, s), 1.27(2H, s); 1 1 H NMR results indicated that the molar ratio of methanesulfonic acid to the compound of Formula I was 1:1 in the sample of crystalline Form A of the methanesulfonate salt.

[0278] In Figure 33, PLM shows that the methanesulfonate salt form A crystals are small irregular granules, and aggregation of the sample was observed. VT-XRPD was used to identify the Form A crystals of the methanesulfonate salt, and the results (Figure 34) showed that no crystalline changes were observed when the sample was purged under N2 for 20 minutes, heated to 150°C, and then cooled to room temperature.

[0279] Example 10 Preparation of Form A Crystals of the Ethanesulfonic Acid Salt of the Compound of Formula I 69.3 mg of ethanesulfonic acid (1:1 molar addition ratio) was weighed into a 20 mL glass vial and diluted with 7.5 mL of EtOAc. 300.0 mg of the compound of formula I was weighed into the diluted reaction system and stirred at room temperature for 3 days. The solid was separated and dried under vacuum at room temperature overnight. A total of 304 mg of sample was collected.

[0280] The obtained sample was determined by powder X-ray diffraction pattern to be a Form A crystal of the ethanesulfonate salt of the compound of Formula I, whose diffraction peaks and relative intensities in the powder X-ray diffraction pattern expressed in terms of 2θ angles may be further as shown in Table 17.

[0281] [Table 18]

[0282] The powder X-ray diffraction pattern of the A-type crystals of the ethanesulfonate salt is shown in FIG. VT-XRPD was used to identify the Form A crystals of the ethanesulfonate salt, and the results (Figure 36) showed that no change in the crystals was observed when the sample was purged under N2 for 20 minutes, heated to 150°C, and then cooled to room temperature.

[0283] In Figure 37, the DSC spectrum showed that the sample had one endothermic peak at 218.7°C. In Figure 38, the TGA spectrum showed that the sample had a weight loss of 0.87% when heated to 150°C.

[0284] PLM (Figure 39) showed that Form A crystals of the ethanesulfonate salt were irregular granules. Ethanesulfonic acid salt A-type crystals 1 H NMR spectral data: 1H NMR (400 m Hz, DMSO-d₆) δ 9.38 (1H, s), 8.00 (1H, t), 7.86 (1H, dd), 7.77 (1H, d), 7.65 (1H, t), 6.16 (1H, s), 5.81 (1H, m), 4.59 (2H, d), 2.44 (3H, s), 2.36 (2H, dd), 1.68 (3H, d), 1.43-1.27 (4H, m), 1.05 (3H, t); in a sample of crystalline Form A of the ethanesulfonate salt, the molar ratio of ethanesulfonic acid to the compound of Formula I was 1:1.

[0285] Example 11 Preparation of Crystalline Form B of the Ethanesulfonic Acid Salt of the Compound of Formula I The compound of formula I and an equimolar amount of ethanesulfonic acid were suspended and stirred in MTBE at room temperature for 3 days, and the solid was centrifuged and vacuum dried overnight at room temperature to obtain the solid.

[0286] The obtained sample was determined by powder X-ray diffraction pattern to be Type B crystals of the ethanesulfonate salt of the compound of Formula I, whose diffraction peaks and relative intensities in the powder X-ray diffraction pattern expressed in terms of 2θ angles may be further as shown in Table 18.

[0287] [Table 19]

[0288] The powder X-ray diffraction pattern of the B-type crystals of the ethanesulfonate salt is shown in Figure 40. . In Figure 41, the DSC spectrum showed that the sample had two endothermic peaks at 156.8°C and 211.9°C, and one exothermic peak at 193.0°C.

[0289] In Figure 42, the TGA spectrum showed that the sample had a weight loss of 2.17% when heated to 150°C. Ethanesulfonate B-type crystals 1 H NMR spectral data: 1H NMR (400 m Hz, DMSO-d₆) δ 9.40 (1H, s), 8.01 (1H, t), 7.87 (1H, dd), 7.77 (1H, d), 7.66 (1H, t), 6.16 (1H, s), 5.82 (1H, m), 4.64 (2H, d), 2.44 (3H, s), 2.36 (3H, dd), 1.68 (3H, d), 1.43–1.27 (4H, m), 1.05 (3H, s); in a sample of crystalline Form B of the ethanesulfonate salt, the molar ratio of ethanesulfonic acid to the compound of Formula I was 1:1.

[0290] Example 12 Preparation of Form A Crystals of the Maleate Salt of the Compound of Formula I The compound of formula I and an equimolar amount of maleic acid were suspended and stirred in IPA / HO (19:1, v / v) at room temperature for 3 days. The resulting clear liquid was transferred to 5°C and stirred for 1 day. The solid was then centrifuged and vacuum dried overnight at room temperature to obtain the solid.

[0291] The obtained sample was determined by powder X-ray diffraction pattern to be Form A crystal of the maleate salt of the compound of formula I, whose diffraction peaks and relative intensities in the powder X-ray diffraction pattern expressed in terms of 2θ angles may further be as shown in Table 19.

[0292] [Table 20]

[0293] The powder X-ray diffraction pattern of the A-type crystals of the maleate salt is shown in FIG. In Figure 44, the DSC spectrum showed that the sample had two endothermic peaks at 160.4°C and 219.1°C.

[0294] In Figure 45, the TGA spectrum shows that the sample is heated to 100°C and the % weight loss, indicating that the sample had a weight loss of 14.49% when heated from 100°C to 225°C.

[0295] Maleate A-type crystals 1 H NMR spectral data: 1 H NMR (400m Hz, DMSO-d6) δ9.31(1H, s), 7.99(1H, t), 7.84(1H, dd), 7.75(1H, d), 7.66(1H, t), 6.13 (1H, s), 6.09 (2H, s), 5.75 (1H, m), 4.61 (2H, d), 2.44 (3H, s), 1.68 (3H, d), 1.41-1.27 (4H, m); in a sample of crystalline Form A of the maleate salt, the maleic acid peak overlapped with the compound of Formula I, and the molar ratio of maleic acid to the compound of Formula I was 1:1.

[0296] Example 13 Preparation of B-type crystals of the maleate salt of the compound of formula I A sample of the maleate salt crystals of type B was obtained by suspending and stirring the compound of formula I and equimolar maleic acid in MTBE for 3 days, centrifuging the solid, and drying it under vacuum overnight at room temperature.

[0297] The obtained sample was determined by powder X-ray diffraction pattern to be a B-type crystal of the maleate salt of the compound of formula I, whose diffraction peaks and relative intensities in the powder X-ray diffraction pattern expressed in terms of 2θ angles may further be as shown in Table 20.

[0298] [Table 21]

[0299] The powder X-ray diffraction pattern of the B-type crystals of the maleate salt is shown in FIG. In Figure 47, the DSC spectrum showed that the sample had two endothermic peaks at 152.9°C and 220.7°C.

[0300] In Figure 48, the TGA spectrum showed that the sample had a weight loss of 2.84% when heated to 100°C, and a weight loss of 12.43% when heated from 100°C to 225°C.

[0301] Maleate B-type crystals 1 H NMR spectral data: 1 H NMR (400m Hz, DMSO-d6) δ9.33(1H, s), 7.99(1H, t), 7.85(1H, dd), 7.76(1H, d), 7.66(1H, t), 6.14 (1H, s), 6.11 (2H, s), 5.75 (1H, m), 4.61 (2H, d), 2.39 (3H, s), 1.66 (3H, d), 1.40-1.27 (4H, m); in a sample of maleate B crystals, The peak of overlapped with that of the compound of formula I, and the molar ratio of maleic acid to the compound of formula I was 1:1.

[0302] Example 14 Preparation of Form A Crystals of the L-Tartrate Salt of the Compound of Formula I The compound of formula I and an equimolar amount of L-tartaric acid were suspended and stirred in IPA / HO (19:1, v / v) at room temperature for 3 days, and the solid was centrifuged and vacuum dried overnight at room temperature to obtain a solid.

[0303] The obtained sample was determined by powder X-ray diffraction pattern to be Form A crystals of the L-tartrate salt of the compound of formula I, whose diffraction peaks and relative intensities in the powder X-ray diffraction pattern expressed in 2θ angles may be further as shown in Table 21.

[0304] [Table 22]

[0305] The powder X-ray diffraction pattern of the A-form crystals of the L-tartrate salt is shown in FIG. In Figure 50, the DSC spectrum showed that the sample had two endothermic peaks at 82.2°C and 213.2°C.

[0306] In Figure 51, the TGA spectrum showed that the sample had a weight loss of 3.18% when heated to 150°C. L-tartrate salt A-type crystals 1 H NMR spectral data: 1 H NMR (400m Hz, DMSO-d6) δ9.13(1H, s), 7.96(1H, t), 7.85(1H, dd), 7.76(1H, d), 7.66(1H, t), 6.09 (1H, s), 5.61 (1H, t), 4.61 (2H, d), 4.28 (2H, s), 2.22 (3H, s), 1.61 (3H, d), 1.34-1.27 (4H, m); for a sample of crystalline form A of the L-tartrate salt. 1 1 H NMR results showed that the molar ratio of L-tartaric acid to the compound of formula I was 1:1.

[0307] Example 15 Preparation of Form B Crystals of the L-Tartrate Salt of the Compound of Formula I The compound of formula I and an equimolar amount of L-tartaric acid were suspended and stirred in EtOAc at room temperature for 3 days, and the solid was centrifuged and dried under vacuum overnight at room temperature to obtain the solid.

[0308] The sample obtained by measuring the powder X-ray diffraction pattern is the powder X-ray diffraction pattern expressed as 2θ angles. The diffraction peaks and relative intensities in the pattern were Form B crystals of the L-tartrate salt of the compound of Formula I, which may be further shown in Table 22.

[0309] [Table 23]

[0310] The powder X-ray diffraction pattern of the B-form crystals of the L-tartrate salt is shown in FIG. In Figure 53, the DSC spectrum showed that the sample had four endothermic peaks at 114.5°C, 160.5°C, 193.2°C and 219.5°C.

[0311] In Figure 54, the TGA spectrum showed that the sample had a weight loss of 5.57% when heated to 180°C. B-type crystals of L-tartrate 1 H NMR spectral data: 1 H NMR (400m Hz, DMSO-d6) δ9.13(1H, s), 8.92(1H, s), 7.96(1H, t), 7.80(1H, dd), 7.72(1H, d), 7.66(1H, t), 6.09(1H, s), 5.61(1H, t), 4.63(2H, d), 4.28 (2H, s), 2.22(3H, s), 1.61(3H, d), 1.37-1.25(4H, m); 1 1 H NMR results showed that the molar ratio of L-tartaric acid to the compound of formula I was 1:1 in the sample of crystalline Form B of the L-tartrate salt.

[0312] Example 16 Preparation of Form C Crystals of the L-Tartrate Salt of the Compound of Formula I The compound of formula I and an equimolar amount of L-tartaric acid were suspended and stirred in MTBE at room temperature for 3 days, and the solid was centrifuged and vacuum dried overnight at room temperature to obtain a solid.

[0313] The obtained sample was determined by powder X-ray diffraction pattern to be Form C crystals of the L-tartrate salt of the compound of formula I, whose diffraction peaks and relative intensities in the powder X-ray diffraction pattern expressed in terms of 2θ angles may be further as shown in Table 23.

[0314] [Table 24]

[0315] The powder X-ray diffraction pattern of the C-form crystals of the L-tartrate salt is shown in FIG. In Figure 56, the DSC spectrum showed that the sample had three endothermic peaks at 128.5°C, 157.1°C, and 220.5°C.

[0316] In Figure 57, the TGA spectrum showed that the sample had a weight loss of 3.16% when heated to 150°C. C-type crystals of L-tartrate 1 H NMR data: 1 H NMR (400 m Hz, DMSO-d₆) δ 9.13 (1H, s), 8.93 (1H, d), 7.96 (1H, t), 7.80 (1H, dd), 7.72 (1H, d), 7.60 (1H, t), 6.09 (1H, s), 5.61 (1H, t), 4.63 (2H, d), 4.28 (1H, s), 2.22 (3H, s), 1.61 (3H, d), 1.39–1.20 (4H, m); in a sample of crystalline Form C of the L-tartrate salt, the molar ratio of L-tartaric acid to the compound of Formula I was 0.5:1.

[0317] Example 17 Preparation of Form D Crystals of the L-Tartrate Salt of the Compound of Formula I The compound of formula I and an equimolar amount of L-tartaric acid were suspended and stirred in acetone / n-heptane (1:3, v / v) at room temperature for 3 days, and the solid was centrifuged and vacuum dried overnight at room temperature to obtain the solid.

[0318] The obtained sample was determined by powder X-ray diffraction pattern to be Form D crystals of the L-tartrate salt of the compound of formula I, whose diffraction peaks and relative intensities in the powder X-ray diffraction pattern expressed in terms of 2θ angles may be further as shown in Table 24.

[0319] [Table 25]

[0320] The powder X-ray diffraction pattern of the D-form crystals of the L-tartrate salt is shown in FIG. In Figure 59, the DSC spectrum showed that the sample had five endothermic peaks at 75.0°C, 111.6°C, 161.9°C, 200.9°C, and 218.5°C.

[0321] In Figure 60, the TGA spectrum showed that the sample had a weight loss of 2.72% when heated to 150°C. D-type crystals of L-tartrate 1 H NMR spectral data: 1 H NMR (400m Hz, DMSO-d6) δ9.13(1H, s), 8.93(1H, s), 7.96(1H, t), 7.80(1H, d), 7.72(1H, d), 7.60(1H, t), 6.09(1H, s), 5.61(1H, t), 4.58(2H, d), 4.29(2H, s), 2.22(3H, s), 1.61(3H, d), 1.35-1.24(4H, m); 1 1 H NMR results showed that the molar ratio of L-tartaric acid to the compound of formula I was 1:1 in the sample of crystalline Form D of the L-tartrate salt.

[0322] Example 18 Preparation of Form A Crystals of the Glycolic Acid Salt of the Compound of Formula I The compound of formula I and an equimolar amount of glycolic acid were suspended and stirred in acetone / n-heptane (1:3, v / v) at room temperature for 3 days, and the solid was centrifuged and vacuum dried overnight at room temperature to obtain a solid.

[0323] The obtained sample was determined by powder X-ray diffraction pattern to be a Form A crystal of the glycolate salt of the compound of Formula I, whose diffraction peaks and relative intensities in the powder X-ray diffraction pattern expressed in terms of 2θ angles may further be as shown in Table 25.

[0324] [Table 26]

[0325] The powder X-ray diffraction pattern of the crystalline form A of the glycolate salt is shown in FIG. In Figure 62, the DSC spectrum showed that the sample had one endothermic peak at 110.1°C.

[0326] In Figure 63, the TGA spectrum showed that the sample had a weight loss of 3.40% when heated to 150°C. Glycolate salt type A crystals 1 H NMR spectral data: 1 H NMR (400m Hz, DMSO-d6) δ9.12(1H, s), 8.90(1H, d), 7.96(1H, t), 7.79(1H, dd), 7.72(1H, d), 7.60(1H, t), 6.09(1H, s), 5.60(1H, t), 4.59(2H, d), 3.91(2H, s), 2.21(3H, s), 1.61(3H, d), 1.35-1.23(4H, m).

[0327] Example 19 Preparation of Form A Crystals of the L-Malate Salt of the Compound of Formula I The compound of formula I and an equimolar amount of L-malic acid were suspended and stirred in IPA / HO (19:1, v / v) at room temperature for 3 days, and the solid was centrifuged and vacuum dried overnight at room temperature to obtain a solid.

[0328] The sample obtained by measuring the powder X-ray diffraction pattern is the powder X-ray diffraction pattern expressed as 2θ angles. The diffraction peaks and relative intensities in the pattern were Form A crystals of the L-malate salt of the compound of Formula I, which may be further as shown in Table 26.

[0329] [Table 27]

[0330] The powder X-ray diffraction pattern of the A-form crystals of the L-malate salt is shown in Figure 64. In Figure 65, the DSC spectrum showed that the sample had four endothermic peaks at 72.9°C, 122.2°C, 142.1°C and 222.4°C, and one exothermic peak at 195.9°C.

[0331] In Figure 66, the TGA spectra showed that when the sample was heated to 50°C, the sample lost 2.88% weight, when heated from 50°C to 100°C, the sample lost 2.46% weight, and when heated from 100°C to 150°C, the sample lost 1.31% weight.

[0332] L-malate A-type crystals 1 H NMR spectral data: 1 H NMR (400m Hz, DMSO-d6) δ9.13(1H, s), 8.94(1H, s), 7.96(1H, t), 7.79(1H, dd), 7.72(1H, d), 7.60(1H, t), 6.09(1H, s), 5.61(1H, t), 4.58(2H, d), 4.22(1H, m), 2.63-2.57(2H, m), 2.22 (3H, s), 1.61 (3H, d), 1.35-1.25 (4H, m); in the sample of crystalline Form A of the L-malate salt, the molar ratio of L-malic acid to the compound of formula I was 1:1.

[0333] Example 20 Preparation of Form B Crystals of the L-Malate Salt of the Compound of Formula I The compound of formula I and an equimolar amount of L-apple were suspended and stirred in acetone / n-heptane (1:3, v / v) at room temperature for 3 days, and the solid was centrifuged and vacuum dried overnight at room temperature to obtain the compound of formula I.

[0334] The obtained sample was determined by powder X-ray diffraction pattern to be a B-type crystal of the L-malate salt of the compound of formula I, whose diffraction peaks and relative intensities in the powder X-ray diffraction pattern expressed in terms of 2θ angles may further be as shown in Table 27.

[0335] [Table 28]

[0336] The powder X-ray diffraction pattern of the B-form crystals of the L-malate salt is shown in FIG. In Figure 68, the DSC spectrum showed that the sample had one endothermic peak at 134.8°C.

[0337] In Figure 69, the TGA spectrum showed that the sample had a weight loss of 3.40% when heated to 150°C. L-malate B-type crystals 1 H NMR spectral data: 1 H NMR (400m Hz, DMSO-d6) δ9.14(1H, s), 8.96(1H, s), 7.96(1H, t), 7.79(1H, dd), 7.72(1H, d), 7.60(1H, t), 6.09(1H, s), 5.61(1H, t), 4.63(2H, d), 4.23(1H, m), 2.64-2.57(2H, m), 2.23(3H, s), 1.61(3H, d), 1.35-1.26(4H, m); 1 1 H NMR results showed that the molar ratio of L-malic acid to the compound of formula I was 1:1 in the sample of crystalline Form B of the L-malate salt.

[0338] Example 21 Preparation of Crystalline Form A of the Hippurate Salt of the Compound of Formula I The compound of formula I and an equimolar amount of hippuric acid were suspended and stirred in acetone / n-heptane (1:3, v / v) at room temperature for 3 days, and the solid was centrifuged and vacuum dried overnight at room temperature to obtain the compound.

[0339] The obtained sample was determined by powder X-ray diffraction pattern to be Form A crystal of the hippuric acid salt of compound of formula I, whose diffraction peaks and relative intensities in the powder X-ray diffraction pattern expressed in 2θ angles may further be as shown in Table 28.

[0340] [Table 29]

[0341] The powder X-ray diffraction pattern of the A-type crystals of hippurate salt is shown in FIG. In Figure 71, the DSC spectrum showed that the sample had three endothermic peaks at 62.4°C, 120.1°C and 207.0°C.

[0342] In Figure 72, the TGA spectrum showed that the sample had a weight loss of 3.04% when heated to 150°C. Hippurate A-type crystals 1 H NMR spectral data: 1 H NMR (400m Hz, DMSO-d6) δ9.12(1H, s), 8.93-8.80(2H, m), 7.96(1H, t), 7.90-7.85(2H, m), 7.79(1H, dd), 7.72(1H, d), 7.60(1H, t), 7.57-7.53(1H, m), 7.52-7.46(2H, m), 6.09(1H, s), 5.61(1H, t), 4.63(2H, d). 3.92(2H, d), 2.21(3H, s), 1.61(3H, d), 1.37-1.22(4H, m); In the sample of crystalline form A of the hippurate salt, the molar ratio of hippuric acid to the compound of formula I was 1:1.

[0343] Example 22 Preparation of Crystalline Form A of the Succinate of the Compound of Formula I The compound of formula I and an equimolar amount of succinic acid were suspended and stirred in MTBE at room temperature for 3 days, and the solid was centrifuged and vacuum dried overnight at room temperature to obtain the solid.

[0344] The obtained sample was determined by powder X-ray diffraction pattern to be Form A crystals of the succinate salt of the compound of Formula I, whose diffraction peaks and relative intensities in the powder X-ray diffraction pattern expressed in terms of 2θ angles may further be as shown in Table 29.

[0345] [Table 30]

[0346] In Figure 73, the DSC spectrum showed that the sample had three endothermic peaks at 70.0°C, 124.1°C and 221.0°C, and one exothermic peak at 189.8°C.

[0347] In Figure 74, the TGA spectrum showed that the sample had a weight loss of 3.94% when heated to 150°C. FIG. 128 is an XRPD pattern for crystalline Form A of the succinate salt of the compound of Formula I.

[0348] Succinate A-type crystals 1 H NMR spectral data: 1 H NMR (400m Hz, DMSO-d6) δ9.12(1H, s), 8.90(1H, d), 7.96(1H, t), 7.80(1H, dd), 7.72(1H, d), 7.60(1H, t), 6.09(1H, s), 5.60(1H, m), 4.62(2H, d), 2.42(3H, s), 2.21(3H, s), 1.61(3H, d), 1.39-1.21(4H, m); 1 1 H NMR results showed that the molar ratio of succinic acid to the compound of formula I was 1:1 in the sample of crystalline Form A of the succinate salt.

[0349] Example 23 Preparation of Crystalline Form B of the Succinate of the Compound of Formula I The compound of formula I and an equimolar amount of succinic acid were suspended and stirred in acetone / n-heptane (1:3, v / v) at room temperature for 3 days, and the solid was centrifuged and vacuum dried overnight at room temperature to obtain the compound.

[0350] The obtained sample was determined by powder X-ray diffraction pattern to be a B-type crystal of the succinate salt of the compound of formula I, whose diffraction peaks and relative intensities in the powder X-ray diffraction pattern expressed in terms of 2θ angles may further be as shown in Table 30.

[0351] [Table 31]

[0352] The powder X-ray diffraction pattern of the B-form crystals of the succinate salt is shown in FIG. In Figure 76, the DSC spectrum showed that the sample had two endothermic peaks at 105.1°C and 223.3°C.

[0353] In Figure 77, the TGA spectrum showed that the sample had a weight loss of 4.44% when heated to 150°C. B-type crystals of succinate 1 H NMR spectral data: 1 H NMR (400m Hz, DMSO-d6) δ9.12(1H, s), 8.90(1H, d), 7.96(1H, t), 7.80(1H, dd), 7.72(1H, d), 7.60(1H, t), 6.09(1H, s), 5.60(1H, m), 4.61(2H, d), 2.42(5H, s), 2.22(3H, s), 1.61(3H, d), 1.35-1.24(4H, m); 1 1 H NMR results showed that the molar ratio of succinic acid to the compound of formula I was 1:1 in the sample of crystalline Form B of the succinate salt.

[0354] Example 24 Preparation of Form A Crystals of the Ascorbate Salt of the Compound of Formula I The compound of formula I and an equimolar amount of L-ascorbic acid were suspended and stirred in IPA / HO (19:1, v / v) at room temperature for 3 days, and the solid was centrifuged and vacuum dried overnight at room temperature to obtain a solid.

[0355] The obtained sample was determined by powder X-ray diffraction pattern to be a Form A crystal of the ascorbate salt of the compound of Formula I, whose diffraction peaks and relative intensities in the powder X-ray diffraction pattern expressed in terms of 2θ angles may be further as shown in Table 31.

[0356] [Table 32]

[0357] In Figure 78, the DSC spectrum showed that the sample had one endothermic peak at 185.7°C and one exothermic peak at 195.8°C. In Figure 79, the TGA spectrum showed that the sample had a weight loss of 4.36% when heated to 150°C.

[0358] FIG. 129 is an XRPD pattern for crystalline Form A of the ascorbate salt of the compound of Formula I. Ascorbate type A crystals 1 H NMR spectral data: 1 H NMR (400m Hz, CD3OD) δ9.18(1H, s), 7.92(1H, t), 7.74-7.65(2H, m), 7.54(1H, t), 6.35(1H, s), 5.67(1H, m), 4.72(0.5H, d), 3.89(0.5H, d), 3.67(1H, d), 2.34(3H, s), 1.68(3H, d), 1.41-1.35(4H, m); 1 1 H NMR results indicated that the molar ratio of ascorbate to the compound of formula I was 0.5:1 in the sample of crystalline Form A of ascorbate.

[0359] Example 25 Preparation of Crystalline Form B of the Ascorbate Salt of the Compound of Formula I The compound of formula I and an equimolar amount of L-ascorbic acid were suspended and stirred in EtOAc at room temperature for 3 days, and the solid was centrifuged and dried under vacuum at room temperature overnight to obtain a solid.

[0360] The obtained sample was determined by powder X-ray diffraction pattern to be Type B crystals of the ascorbate salt of the compound of Formula I, whose diffraction peaks and relative intensities in the powder X-ray diffraction pattern expressed in 2θ angles may be further as shown in Table 32.

[0361] [Table 33]

[0362] The powder X-ray diffraction pattern of the ascorbate crystalline form B is shown in FIG. In Figure 81, the DSC spectrum showed that the sample had one endothermic peak at 153.6°C and one exothermic peak at 190.3°C.

[0363] In Figure 82, the TGA spectrum showed that the sample had a weight loss of 1.33% when heated to 150°C. Ascorbate B-type crystals 1 H NMR spectral data: 1 H NMR (400m Hz, CD3OD) δ9.19(1H, s), 7.92(1H, t), 7.73-7.65(2H, m), 7.53(1H, t), 6.35(1H, s), 5.67(1H, m), 4.74(1H, d), 3.89(1H, m), 3.67(2H, d), 2.34(3H, s), 1.69(3H, d), 1.42-1.35(4H, m); 1 1 H NMR results indicated that the molar ratio of L-ascorbic acid to the compound of formula I was 1:1 in the sample of crystalline Form B of the ascorbate salt.

[0364] Example 26 Preparation of Form A Crystals of the Adipic Acid Salt of the Compound of Formula I The compound of formula I and an equimolar amount of adipic acid were suspended and stirred in MTBE at room temperature for 3 days, and the solid was centrifuged and vacuum dried overnight at room temperature to obtain a solid.

[0365] The obtained sample was determined by powder X-ray diffraction pattern to be Form A crystals of the adipate salt of the compound of Formula I, whose diffraction peaks and relative intensities in the powder X-ray diffraction pattern expressed in terms of 2θ angles may further be as shown in Table 33.

[0366] [Table 34]

[0367] In Figure 83, the DSC spectrum showed that the sample had one endothermic peak at 88.3°C. In Figure 84, the TGA spectrum showed that the sample had a weight loss of 6.60% when heated to 150°C.

[0368] FIG. 130 is an XRPD pattern for crystalline Form A of the adipate salt of the compound of Formula I. Adipic acid salt type A crystals 1 H NMR spectral data: 1 H NMR (400m Hz, DMSO-d6) δ9.12(1H, s), 8.89(1H, d), 7.96 (1H, t), 7.80 (1H, m), 7.72 (1H, d), 7.60 (1H, t), 6.09 (1H, s), 5.60 (1H, m), 4.61 (2H, d), 2.21 (7H, m), 1.61 (3H, d), 1.50 (4H, m), 1.35-1.25 (4H, m); in the sample of crystalline form A of the adipate salt, the molar ratio of adipic acid to the compound of formula I was 1:1.

[0369] Example 27 Preparation of Form A Crystals of p-Toluenesulfonate of Compound of Formula I The compound of formula I and an equimolar amount of p-toluenesulfonic acid monohydrate were suspended and stirred in IPA / HO (19:1, v / v) at room temperature for 3 days, and the solid was centrifuged and dried under vacuum overnight at room temperature to obtain a solid.

[0370] The obtained sample was determined by powder X-ray diffraction pattern to be a Form A crystal of p-toluenesulfonate salt of the compound of Formula I, whose diffraction peaks and relative intensities in the powder X-ray diffraction pattern expressed in terms of 2θ angles may be further as shown in Table 34.

[0371] [Table 35]

[0372] The powder X-ray diffraction pattern of the A-type crystals of p-toluenesulfonic acid salt is shown in FIG. In Figure 86, the DSC spectrum showed that the sample had one endothermic peak at 150.9°C.

[0373] In Figure 87, the TGA spectrum showed that the sample lost 0.76% weight when heated to 100°C, and 3.07% weight when heated from 100°C to 170°C.

[0374] p-Toluenesulfonate A-type crystals 1 H NMR spectral data: 1 H NMR (400m Hz, DMSO-d6) δ9.38(1H, s), 8.00(1H, t), 7.87(1H, dd), 7.77(1H, d), 7.67(1H, t), 7.47(2H, dd), 7.11(2H, d), 6.15(1H, s), 5.81(1H, t), 4.63(2H, d), 2.44(3H, s), 2.29(3H, s), 1.68(3H, d), 1.41-1.2 In the sample of Form A crystals of 7(4H, m);p-toluenesulfonic acid salt, the molar ratio of p-toluenesulfonic acid to the compound of formula I was 1:1.

[0375] Example 28 Preparation of Form A Crystals of the Benzenesulfonate of the Compound of Formula I The compound of formula I and an equimolar amount of benzenesulfonic acid were suspended and stirred in MTBE at room temperature for 3 days, and the solid was centrifuged and vacuum dried overnight at room temperature to obtain the solid.

[0376] The obtained sample was determined by powder X-ray diffraction pattern to be a Form A crystal of the benzenesulfonate salt of the compound of Formula I, whose diffraction peaks and relative intensities in the powder X-ray diffraction pattern expressed in terms of 2θ angles may be further as shown in Table 35.

[0377] [Table 36]

[0378] In Figure 88, the DSC spectrum showed that the sample had one endothermic peak at 111.7°C. In Figure 89, the TGA spectrum showed that the sample lost 2.55% weight when heated to 80°C, and 6.23% weight when heated from 80°C to 150°C.

[0379] FIG. 131 is an XRPD pattern of crystalline form A of the benzenesulfonate salt of the compound of Formula I in Example 28. A-type crystals of benzenesulfonate 1 H NMR spectral data: 1 H NMR (400m Hz, DMSO-d6) δ9.40(1H, s), 8.01(1H, t), 7.87(1H, dd), 7.77(1H, d), 7.67(1H, t), 7.62-7.56(2H, m), 7.35-7.28(3H, m), 6.16 (1H, s), 5.82 (1H, m), 4.64 (2H, d), 2.45 (3H, s), 1.68 (3H, d), 1.42-1.28 (4H, m); in the sample of crystalline Form A of the benzenesulfonate salt, the molar ratio of benzenesulfonic acid to the compound of Formula I was 1:1.

[0380] Example 29 Preparation of Form A Crystals of the Oxalate Salt of the Compound of Formula I The compound of formula I and an equimolar amount of oxalic acid were suspended and stirred in acetone / n-heptane (1:3, v / v) at room temperature for 3 days, and the solid was centrifuged and vacuum dried overnight at room temperature to obtain the solid.

[0381] The obtained sample was determined by powder X-ray diffraction pattern to be Form A crystal of the oxalate salt of the compound of Formula I, whose diffraction peaks and relative intensities in the powder X-ray diffraction pattern expressed in terms of 2θ angles may further be as shown in Table 36.

[0382] [Table 37]

[0383] The powder X-ray diffraction pattern of the crystalline form A of the oxalate salt is shown in FIG. In Figure 91, the DSC spectrum showed that the sample had two endothermic peaks at 103.4°C and 141.6°C.

[0384] In Figure 92, the TGA spectrum showed that the sample had a weight loss of 5.88% when heated to 100°C. A-type crystals of oxalate 1 H NMR spectral data: 1 H NMR (400 m Hz, DMSO-d₆) δ 9.21 (1H, s), 7.98 (1H, t), 7.82 (1H, dd), 7.73 (1H, d), 7.62 (1H, t), 6.11 (1H, s), 5.67 (1H, m), 4.60 (2H, d), 2.28 (3H, s), 1.68 (3H, d), 1.37-1.22 (4H, m); in a sample of crystalline Form A of the oxalate salt, the molar ratio of the solvent EtOAc to the compound of Formula I was 0.15:1 (approximately 2.3 wt%). HPLC / IC results indicated that in a sample of crystalline Form A of the oxalate salt, the molar ratio of oxalic acid to the compound of Formula I was 1:1.

[0385] Example 30 Preparation of Form A Crystals of 2-hydroxyethanesulfonate of the Compound of Formula I The compound of formula I and an equimolar amount of 2-hydroxyethanesulfonic acid were suspended and stirred in EtOAc at room temperature for 3 days, and the solid was centrifuged and dried under vacuum overnight at room temperature to obtain the solid.

[0386] The obtained sample was determined by powder X-ray diffraction pattern to be a Form A crystal of 2-hydroxyethanesulfonate salt of the compound of Formula I, whose diffraction peaks and relative intensities in the powder X-ray diffraction pattern expressed in terms of 2θ angles may be further as shown in Table 37.

[0387] [Table 38]

[0388] The powder X-ray diffraction pattern of the A-type crystals of 2-hydroxyethanesulfonate is shown in FIG. In Figure 94, the DSC spectrum showed that the sample had an endothermic peak at 203.5°C.

[0389] In Figure 95, the TGA spectrum showed that the sample had a weight loss of 1.61% when heated to 150°C. Form A crystals of 2-hydroxyethanesulfonate 1 H NMR spectral data: 1 H NMR (400 m Hz, DMSO-d6) δ 9.39 (1H, s), 8.00 (1H, t), 7.86 (1H, dd), 7.77 (1H, d), 7.66 (1H, t), 6.15 (1H, s), 5.81 (1H, m), 4.65 (2H, d), 2.44 (3H, s), 2.36 (3H, dd), 1.68 (3H, d), 1.42-1.27 (4H, m), 1.05 (3H, s); The molar ratio of sulfonic acid to the compound of formula I was 1:1.

[0390] Example 31 Screening test for crystal polymorphism 1. Gas-solid permeation Gas-solid permeability tests were carried out using various solvents. Approximately 20 mg of each sample of the compound of formula I was weighed into a 3 mL vial, and approximately 3 mL of solvent was added to another 20 mL vial. The 3 mL vial was placed in an open 20 mL vial, and then the 20 mL vial was sealed. After standing at room temperature for 10 days, the solid was collected and subjected to XRPD testing. The test results are shown in Table 38. Form A crystals of the compound of formula I were obtained by the gas-solid permeability test.

[0391] [Table 39]

[0392] 2. Gas-liquid permeation Gas-liquid permeability tests were performed using various solvents. Approximately 20 mg of each sample of the compound of Formula I was weighed into a 3 mL vial and dissolved in 0.1-0.2 mL of solvent to obtain a clear solution. Approximately 3 mL of antisolvent was then added to the 20 mL vial. The 3 mL vial containing the clear liquid was then placed into a 20 mL vial with the opening closed. The 20 mL vial was then sealed and left at room temperature. The resulting solid was collected and subjected to XRPD testing. The test results are shown in Table 39. Form A crystals of the compound of Formula I were obtained by the gas-liquid permeability test.

[0393] [Table 40]

[0394] 3. Polymer Derivatization Approximately 20 mg of each sample of the compound of formula I was weighed into a 3 mL vial, and 1.0 mL of ACN was added to dissolve the sample. After dissolution, the sample was filtered, and 2 mg of mixed polymer A: polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, hydroxypropylmethylcellulose, and methylcellulose (mixed in equal masses) was added. The vial was sealed with parafilm, several small holes were made in it, and the vial was allowed to stand at room temperature to slowly evaporate, thereby obtaining type A crystals of the compound of formula I.

[0395] 4. Suspension and stirring at room temperature Suspension and stirring tests were carried out at room temperature using various solvents. Approximately 20 mg of each sample of the compound of formula I was weighed into an HPLC glass vial, and 0.5 mL of each of the solvents listed in Table 40 was added. The resulting cloudy solution was left at room temperature and magnetically stirred for approximately 7 days. The solid sample was then centrifuged and subjected to XRPD testing. The test results are shown in Table 40. Form A crystals of the compound of formula I were obtained by the suspension and stirring test at room temperature.

[0396] [Table 41]

[0397] 5. Suspension and stirring at 50°C Suspension and stirring tests were carried out at 50°C using various solvents. Approximately 20 mg of each sample of the compound of formula I was weighed into an HPLC glass vial, and 0.5 mL of each of the solvents listed in Table 41 was added. The resulting suspension was placed at 50°C and magnetically stirred for approximately 3 days. The solid sample was then centrifuged and subjected to XRPD testing. The test results are shown in Table 41, and Form A crystals of the compound of formula I were obtained by the suspension and stirring test at 50°C.

[0398] [Table 42]

[0399] 6. Temperature increase and decrease cycle A total of 12 temperature-rise and -fall cycle tests were conducted using various solvents. Approximately 20 mg of each sample of the compound of Formula I was weighed into an HPLC glass vial, and 0.5 mL of each solvent listed in Table 42 was added. The resulting suspension was subjected to magnetic stirring under temperature cycling (50°C to 5°C, 0.1°C / min, two cycles). The solid sample was centrifuged and subjected to XRPD testing. The test results are shown in Table 42. Form A crystals of the compound of Formula I were obtained by the temperature-rise and -fall cycle test.

[0400] [Table 43]

[0401] 7. Slow cooling Slow-cooling experiments were performed using various solvent systems. Approximately 20 mg of each sample of the compound of Formula I was weighed into an HPLC vial, and 0.5 mL of the solvent listed in Table 43 was added. The mixture was stirred and equilibrated at 50°C for approximately 2 hours, after which the supernatant was filtered (through a 0.45 μm PTFE filter). The resulting supernatant was placed in a biological incubator and cooled from 50°C to 5°C at a rate of 0.05°C / min. The temperature was maintained at 5°C, and the clear solution was then transferred to a constant temperature of -20°C. The precipitated solid was collected and subjected to XRPD analysis. Samples that did not precipitate solids were transferred to room temperature and volatilized. The test results are shown in Table 43. Form A crystals of the compound of Formula I were obtained by the slow-cooling experiment.

[0402] [Table 44]

[0403] 8. Addition of antisolvent Anti-solvent addition tests were performed using various solvents. Approximately 20 mg of each sample of the compound of Formula I was weighed into a 20 mL vial, and 0.1 to 0.5 mL of solvent (see Table 44) was used to completely dissolve the solid. The anti-solvent in Table 44 was added dropwise with stirring to the clear solution until a solid precipitated, or when the total volume of the anti-solvent reached 5 mL, samples without precipitated solids were transferred to room temperature and evaporated. The precipitated solids were isolated and subjected to XRPD testing. The results are shown in Table 44. Form A crystals of the compound of Formula I were obtained by the anti-solvent addition test.

[0404] [Table 45]

[0405] In the effect examples of the present invention, the control compounds 1 and 2 were prepared with reference to patent WO2019122129A1, and their structures are as follows:

[0406] [ka]

[0407] Effect Example 1 Binding Inhibition Test of Compound of Formula I to KRAS G12C::SOS1 Test compounds were prepared at 10 mM stock solutions in DMSO and gradient diluted using 1X test buffer. 0.1 μL of the compound solutions at different concentrations was transferred to a 384-well plate. 5 μL of GST-KRAS G12C was added to the 384-well plate and centrifuged at 1000 rpm for 1 minute. 5 μL of His-SOS1 was added to the 384-well plate and centrifuged at 1000 rpm for 1 minute. The plate was then incubated at room temperature for 15 minutes.

[0408] After incubation, 10 μL of a mixture of anti-6his-Tb monoclonal antibody (Cisbio, Cat. No. 61HI2TLA) and anti-GST-XL665 monoclonal antibody (Cisbio, Cat. No. 61GSTXLA) was added to the test wells, centrifuged at 1000 rpm for 1 minute, and incubated at room temperature for 1 hour.

[0409] After incubation, the fluorescence signal ratio at 665 nm and 615 nm wavelengths was read using a multi-function microplate reader (Perkin Elmer, Envision 2104), and the IC was calculated using Graphpad 5 software. 50 values were calculated.

[0410] The binding inhibition results of the compound of formula I to KRAS G12C::SOS1 are shown in Table 45.

[0411] [Table 46]

[0412] Effect Example 2 Inhibitory test of the compound of formula I on the ERK phosphorylation level of DLD-1 cells Intracellular Western blot quantitative analysis was used to detect the inhibitory level of compounds on ERK phosphorylation in DLD-1 cells.

[0413] DLD-1 cells (ATCC, CCL-221) were cultured at 2.5 × 10 6 Cells were seeded into T75 culture bottles according to the number of cells per bottle and cultured in RPMI 1640 medium containing 10% FBS for two days. On day three, cells were seeded into 384-well plates and cultured overnight at 37°C, 5% CO2. After overnight incubation, gradient-diluted compounds (final DMSO content: 0.5%) were added. DMSO was added to the negative group and cultured in an incubator at 37°C, 5% CO2.

[0414] The cells were fixed, washed once with PBS, disrupted, and blocked at room temperature for 1 hour. The blocking solution was removed, and primary antibody (CST, Cat. No. #4370S) was added and incubated overnight at 4°C. The cells were washed three times with PBST (PBS solution with 0.05% Twain 20), with a 2-minute soak each time. Secondary antibody (LI-COR, Cat. No. 926-32211) was added and incubated in the dark at room temperature. The cells were washed three times with PBST, with a 2-minute soak each time. The culture plate was centrifuged at 1000 rpm for 1 minute and scanned with a dual laser imaging system (Odyssey® CLX) to read the signal.

[0415] Relative signal = 800 channel signal values / 700 channel signal values. Relative expression level of ERK phosphorylation = (test compound - control compound I) / (DMSO group - control compound I) IC using Graphpad 5 software 50 values were calculated.

[0416] The inhibitory results of the compound of formula I on the ERK phosphorylation level of DLD-1 cells are shown in Table 46.

[0417] [Table 47]

[0418] Effect Example 3: Inhibition test of 3D cell proliferation by compounds of formula I For subsequent culture or seeding into 384-well plates to perform experiments, H358 cells were seeded into T75 culture bottles and cultured in RPMI 1640 medium containing 10% FBS for 2 days.

[0419] On day 1, cells were seeded into a 384-well plate, and 40 μL of medium was added to each well. Gradient-diluted compounds or DMSO were added to each well. Other wells without cells but with medium served as blank controls. The plates were cultured at 37°C and 5% CO2 for 7 days. On day 8, 3D CellTiter-Glo reagent (Promega, Cat. No. G9683) was added, the plates were shaken at 320 rpm for 20 minutes, and then left at room temperature for 2 hours. Luminescence signals were read using a multi-function microplate reader. The cell viability inhibition rate was calculated as follows: Cell viability inhibition rate = (DMSO group - test compound) / (DMSO group - blank control group) x 100% IC using Graphpad 5 software 50 values were calculated.

[0420] The 3D growth inhibition results of H358 cells by compounds of formula I are shown in Table 47.

[0421] [Table 48]

[0422] Effect Example 4 Human liver microsome stability test of the compound of formula I Human liver microsome stability testing was performed by in vitro co-incubation of compounds with human liver microsomes. Test compounds were prepared in DMSO to a 10 mM stock solution and then diluted to 0.5 mM with acetonitrile. Human liver microsomes (Corning) were diluted with PBS in microsome / buffer solution, and this solution was used to prepare a 0.5 mM working solution. The compound concentration in the working solution was 1.5 μM, and the concentration of human liver microsomes was 0.75 mg / mL. A deep-well plate was prepared, and 30 μL of working solution was added to each well. Then, 15 μL of pre-warmed 6 mM NADPH solution was added to initiate the reaction, and the mixture was incubated at 37°C. At 0, 5, 15, 30, and 45 minutes after incubation, 135 μL of acetonitrile was added to the corresponding wells to terminate the reaction. After the reaction was stopped with acetonitrile at the final 45-minute point, the deep-well plate was vortexed and shaken (600 rpm / min) for 10 minutes, followed by centrifugation for 15 minutes. After centrifugation, the supernatant was removed and purified water was added at a 1:1 ratio. LC-MS / MS detection was performed to obtain the ratio of the compound peak area to the internal standard peak area at each time point. The peak area ratio of the compound at 5, 15, 30, and 45 minutes was compared with the peak area ratio at 0 minutes to calculate the remaining compound percentage at each time point. The T value was calculated using Graphpad 5 software. 1 / 2 was calculated.

[0423] The results of the human liver microsome stability test of the compound of formula I are shown in Table 48.

[0424] [Table 49]

[0425] Effect Example 5 Inhibition test of the compound of formula I against cytochrome P450 The inhibitory potential of compounds against the cytochrome P450 (CYP450) isoform CYP3A4 (two substrates: midazolam and testosterone) was determined. Test compounds were prepared in DMSO as 10 mM stock solutions, and the CYP3A4 inhibitor ketoconazole was prepared in DMSO as 10, 2.5, and 2.5 mM stock solutions. The test compounds and ketoconazole were diluted with acetonitrile to a final concentration of 400:1 (compound: 10 μM, ketoconazole: 2.5 μM).

[0426] Potassium phosphate buffer (0.1 M, pH 7.4) was used to prepare the NADPH cofactor (66.7 mg of NADPH in 10 mL of potassium phosphate buffer) and substrate at four times the final concentration, resulting in a final concentration of 320 μM for the CYP3A4 substrate midazolam and 20 μM for the CYP3A4 substrate testosterone.

[0427] Human liver microsome solution was prepared on ice in potassium phosphate buffer at a concentration of 0.2 mg / mL. Using the human liver microsome solution, test compound and control inhibitor (control compound) solutions were prepared on ice at double the final concentration. 30 mL of test compound and control inhibitor solution was added to each test well, followed by 15 mL of substrate, in duplicate. The 96-well test plate and NADPH solution were incubated at 37°C for 5 minutes, and 15 μL of prewarmed 8 mM NADPH solution was added to the test plate to initiate the reaction. The CYP3A4 test plate was preincubated at 37°C for 5 minutes. The reaction was terminated and quenched by adding 120 μL of acetonitrile. The plate was then shaken (600 rpm / min) on a shaker (IKA, MTS2 / 4) for 10 minutes, followed by centrifugation for 15 minutes. The supernatant was collected by centrifugation, and purified water was added in a 1:1 ratio to perform LC-MS / MS detection. The ratio of the compound's peak area to that of the internal standard was obtained, and the peak area ratio of the compound was compared with that of the control inhibitor to calculate the inhibition rate.

[0428] The results of the CYP450 enzyme inhibition test of the compound of formula I are shown in Table 49.

[0429] [Table 50]

[0430] Effect Example 6 Plasma protein binding rate of the compound of formula I Plasma protein binding of compounds was determined by equilibrium dialysis (HTD 96b ) was detected. Compounds were prepared into 0.5 nM stock solutions using DMSO, and then diluted 25-fold with 0.05 M sodium phosphate buffer as the working solution. A blank 96-well plate was taken, and 380 μL of plasma was pre-loaded into each well. Then, 20 μL / well of the working solution was added to the plasma and mixed evenly. The final compound concentration was 1 μM, and each well contained 0.2% DMSO.

[0431] To each dialysis chamber (HTD 96b), 100 μL of 0.05 M sodium phosphate buffer was added, followed by 100 μL of compound-containing plasma in the donor chamber. After covering with a plastic cover, the chamber was placed at 37°C and incubated with shaking for 5 hours.

[0432] After incubation, 25 μL samples were taken from the donor and receiver sides of the dialysis chamber and placed in a blank 96-well plate. The donor samples were mixed with the same volume of plasma, and the receiver samples were mixed with the same volume of 0.05 M sodium phosphate buffer. 200 μL of acetonitrile solution containing the internal standard was added to each well, and the 96-well plate was vortexed and shaken at 600 rpm for 10 minutes. Then, the plate was centrifuged at 5594 g for 15 minutes (Thermo Multifuge ×3R). 50 μL of the supernatant was transferred to a new 96-well plate, mixed with 50 μL of ultrapure water, and analyzed by LC-MS / MS.

[0433] Plasma protein binding and free fraction were calculated using the following formula: % binding = 100 × ([donor concentration] 5h -[receptor concentration] 5h ) / [supply side concentration] 5h % Free Fraction = 100 - % Bound Fraction The free fraction of the compound of formula I in plasma is shown in Table 50.

[0434] [Table 51]

[0435] Effect Example 7 Pharmacokinetics test of the compound of formula I in mice Male ICR mice weighing 20-25 g were fasted overnight. Three mice were selected and administered 10 mg / kg orally intragastrically. Blood samples were collected before administration and at 15 and 30 minutes and 1, 2, 4, 8, and 24 hours after administration. Blood samples were centrifuged at 6800 g for 6 minutes at 2-8°C, and plasma was collected and stored at -80°C. Plasma samples were collected at each time point, mixed with 3-5 volumes of acetonitrile solution containing an internal standard, vortexed for 1 minute, and centrifuged at 13,000 rpm for 10 minutes at 4°C. The supernatant was removed, mixed with 3 volumes of water, and an appropriate volume of the mixture was collected for LC-MS / MS analysis. Key pharmacokinetic parameters were analyzed using a noncompartmental model in WinNonlin 7.0 software.

[0436] The pharmacokinetic test results of the compound of formula I in mice are shown in Table 51.

[0437] [Table 52]

[0438] Effect Example 8 In vivo efficacy test of the compound of formula I on Mia Paca-2 pancreatic cancer After the mice were adaptively reared for 1 week, log-phase Mia Paca-2 cells were resuspended in serum-free DMEM and mixed 1:1 with Matrigel. Then, 1 × 10 cells were added to 100 μL / mouse. 7 Mia Paca-2 cells were subcutaneously inoculated into the right hypochondrium of mice, and tumor growth was monitored periodically until tumors reached an average volume of 150–200 mm. 3When the tumors grew to 100 mg / kg, they were randomly divided into a model group and an administration group (single agent, combined with trametinib) according to tumor size and mouse weight. The tumor size and animal weight were measured and recorded before and during administration. After treatment was completed, the difference in tumor size between the model group and the administration group was compared to determine the efficacy of the drug.

[0439] The tumor-inhibiting potency of compounds of formula I at tumor weight levels is shown in Table 52.

[0440] [Table 53]

[0441] The experimental results showed that the compound of formula I, either administered alone or in combination with trametinib, had a significant inhibitory effect on the growth of Mia Paca-2 cancer, and the combination was superior to the compound administered alone.

[0442] Effect Example 9: NCI-H1975 non-small cell lung cancer in vivo efficacy experiment NCI-H1975 tumor cells were cultured in a 37°C, 5% CO2 incubator using inactivated RPMI1640 + 10% FBS medium. When the cell confluence reached 80-90%, the cells were divided into bottles and passaged. After the mice were adapted for 1 week, 5 × 10 NCI-H1975 cells in log phase were cultured. 6 The mice were inoculated subcutaneously into the right hypochondrium at an inoculation concentration of 100 μg / 100 μL. Tumor growth was monitored periodically until the tumor reached an average volume of 100–150 mm. 3 When the tumors grew to 1000mcg, they were randomly divided into a model group and an administration group (combined with osimertinib) according to tumor size and mouse weight. The tumor size and animal weight were measured before and during administration. The difference in tumor size between the model group and the treatment group was compared to determine the efficacy of the drug. The Mann Whitney detection method was used in Graph Pad 8.0 to compare the significance of the difference between the combination treatment group and the osimertinib single-agent group. The results are shown in Table 53.

[0443] [Table 54]

[0444] The results showed that, compared with the osimertinib monotherapy group, the combination of compound I-1 (7.5 mg / kg, bid or 25 mg / kg, bid) with osimertinib (1 mg / kg, QD) significantly reduced the mean tumor volume of the animals at the end of treatment, and the difference was statistically significant. The antitumor effect of compound I-1 in combination with osimertinib was significantly superior to that of either monotherapy, and the combination of compound I-1 (25 mg / kg, bid) with osimertinib (1 mg / kg, QD) had a synergistic effect.

[0445] Efficacy Example 10: In vivo efficacy test of the compound of formula I against LOVO colorectal cancer After the mice were adapted for 1 week, log-phase LOVO cells were resuspended in serum-free F12K at 100 μL / mouse, at a concentration of 5 × 10 6 LOVO cells were subcutaneously inoculated into the right hypochondrium of mice, and tumor growth was monitored periodically until the tumor reached an average volume of 150–200 mm. 3 When the tumors grew to 100 mm Hg, they were randomly divided into a model group and an administration group according to tumor size and mouse weight. The tumor size and animal weight were measured and recorded before and during administration. After treatment was completed, the difference in tumor size between the model group and the administration group was compared to determine the efficacy of the drug.

[0446] The tumor-inhibiting potency of the compound of formula I at tumor weight levels is shown in Table 54.

[0447] [Table 55]

[0448] The experimental results showed that the compound of the present invention had significant effect on inhibiting LOVO tumor tissue growth, and was more effective than the control compound II. Effect example 11 Dynamic solubility Preparation of simulated gastric fluid (SGF) Weigh 100 mg of NaCl and 50 mg of Triton X-100 into a 50 mL volumetric flask. The solution was weighed out and dissolved in purified water. 816 μL of 1 M hydrochloric acid was added, and the pH was adjusted to 1.8 with 1 M hydrochloric acid or 1 M NaOH solution. The solution was then adjusted to the required volume with purified water.

[0449] Production of simulated fasting state intestinal fluid (FaSSIF) 340 mg of anhydrous NaH2PO4, 42 mg of NaOH, and 620 mg of NaCl were weighed into a 100 mL volumetric flask. Purified water was added to dissolve the mixture, and the pH was adjusted to 6.5 with 1 M hydrochloric acid or 1 M NaOH solution. Purified water was added to the volumetric solution. 110 mg of SIF powder was then weighed into a 50 mL volumetric flask and dissolved in the above solution to the volumetric solution.

[0450] Production of simulated fed-state intestinal fluid (FaSSIF) 0.82 mL of glacial acetic acid, 400 mg of NaOH, and 1.18 g of NaCl were weighed into a 100 mL volumetric flask. Approximately 90 mL of purified water was added to dissolve the mixture, and the pH was adjusted to 5.0 with 1 M hydrochloric acid or 1 M NaOH solution. Purified water was added to the final volume. 560 mg of SIF powder was then weighed into a 50 mL volumetric flask and dissolved in the above solution to the final volume.

[0451] The solubility of crystalline Form A of the compound of Formula I, crystalline Form A of the fumarate salt, crystalline Form B of the citrate salt, crystalline Form A of the methanesulfonate salt, and crystalline Form A of the ethanesulfonate salt was measured in four reaction systems: water, SGF, FaSSIF, and FeSSIF, using a solid feed concentration of 10 mg / mL (based on the compound of Formula I) at 37°C with rotational mixing for different time periods (1, 4, and 24 hours). After sampling at each time point, the samples were centrifuged (10,000 rpm) and filtered (0.45 μm PTFE filter). The HPLC concentration and pH of the filtrate were measured, and the solid samples were subjected to XRPD analysis after centrifugation. The solubility test results are summarized in Table 55, and the solubility curves are shown in Figure 1. The XRPD results of the samples after solubility testing are shown in Figures 96 to 112. The results showed that the type A crystals of the compound of formula I, the type A crystals of the fumarate salt, the type B crystals of the citrate salt, the type A crystals of the methanesulfonate salt, and the type A crystals of the ethanesulfonate salt all had high solubility in the four solvents, and no crystal changes were observed after the test for the type A crystals of the compound of formula I, the type A crystals of the fumarate salt, and the type B crystals of the citrate salt.

[0452] [Table 56]

[0453] Effect Example 12 Hygroscopicity Using a dynamic moisture sorption spectrometer (DVS), hygroscopicity evaluations were performed on the fumarate type A crystals, the citrate type B crystals, the methanesulfonate type A crystals, the ethanesulfonate type A crystals, and the compound of Formula I type A crystals. Starting from 0% RH or room humidity, the mass change rate of the samples was measured as the humidity changed (from 0% RH to 95% RH) at a constant temperature of 25°C. The DVS test results and XRPD results of the samples before and after the DVS test are shown in Figures 113 to 122. Below 10% RH, the compound of Formula I type A crystals and the fumarate type A crystals rapidly dehydrated. Above 10% RH, the samples absorbed more water and increased in weight as the humidity increased. The citrate type B crystals, the methanesulfonate type A crystals, and the ethanesulfonate type A crystals were slightly hygroscopic. No crystal changes were observed in any of the samples after the DVS test.

[0454] Effect example 13 Solid state stability Fumarate type A crystals, citrate type B crystals, methanesulfonate type A crystals, ethanol The Type A crystals of the methanesulfonate salt and the Type A crystals of the compound of Formula I were left open for one week at 25°C / 60% RH and 40°C / 75% RH, respectively, and the physical and chemical stability of the samples was examined by XRPD and HPLC. The XRPD results are shown in Figures 123 to 127. The results in Table 56 indicate that no significant decrease was observed in any of the samples after the solid-state stability test, and the crystals of the samples before and after the test were consistent. The Type A crystals of the fumarate salt, Type B crystals of the citrate salt, Type A crystals of the methanesulfonate salt, Type A crystals of the ethanesulfonate salt, and Type A crystals of the compound of Formula I were shown to have good stability.

[0455] [Table 57]

Claims

1. Form A crystals of the compound of formula I, Form B crystals of the compound of formula I, Form A crystals of the fumarate salt of the compound of formula I, Form B crystals of the fumarate salt of the compound of formula I, Form C crystals of the fumarate salt of the compound of formula I, Form A crystals of the citrate salt of the compound of formula I, Form B crystals of the citrate salt of the compound of formula I, Form A crystals of the methanesulfonate salt of the compound of formula I, Form A crystals of the ethanesulfonate salt of the compound of formula I, Form B crystals of the ethanesulfonate salt of the compound of formula I, Form A crystals of the maleate salt of the compound of formula I, Form B crystals of the maleate salt of the compound of formula I, Form A crystals of the L-tartrate salt of the compound of formula I, Form B crystals of the L-tartrate salt of the compound of formula I, Form C crystals of the L-tartrate salt of the compound of formula I, Crystals characterized by being Type D crystals, Type A crystals of the glycolate salt of the compound of formula I, Type A crystals of the L-malate salt of the compound of formula I, Type B crystals of the L-malate salt of the compound of formula I, Type A crystals of the hippurate salt of the compound of formula I, Type A crystals of the succinate salt of the compound of formula I, Type B crystals of the succinate salt of the compound of formula I, Type A crystals of the ascorbate salt of the compound of formula I, Type B crystals of the ascorbate salt of the compound of formula I, Type A crystals of the adipate salt of the compound of formula I, Type A crystals of the p-toluenesulfonate salt of the compound of formula I, Type A crystals of the benzenesulfonate salt of the compound of formula I, Type A crystals of the oxalate salt of the compound of formula I, and Type A crystals of the 2-hydroxyethanesulfonate salt of the compound of formula I. 【Chemical 1】 (wherein the A-type crystal of the compound of formula I has diffraction peaks at 2θ angles of 12.06±0.2°, 14.68±0.2°, 18.13±0.2°, 19.12±0.2°, 20.25±0.2°, 22.09±0.2° and 24.75±0.2° in a powder X-ray diffraction spectrum; The B-type crystals of the compound of formula I have diffraction peaks at 2θ angles of 12.30±0.2°, 12.89±0.2°, 14.49±0.2°, 18.10±0.2°, 18.70±0.2°, 20.33±0.2°, and 21.66±0.2° in a powder X-ray diffraction spectrum; The A-type crystals of the fumarate salt of the compound of formula I have diffraction peaks at 2θ angles of 6.86±0.2°, 7.72±0.2°, 16.47±0.2°, 19.20±0.2°, 19.63±0.2°, 22.47±0.2°, and 23.26±0.2° in a powder X-ray diffraction spectrum; The B-type crystals of the fumarate salt of the compound of formula I have diffraction peaks at 2θ angles of 4.78±0.2°, 8.02±0.2°, 9.68±0.2°, 16.57±0.2°, 17.93±0.2°, 18.57±0.2° and 28.81±0.2° in a powder X-ray diffraction spectrum; The C-type crystals of the fumarate salt of the compound of formula I have diffraction peaks at 2θ angles of 6.85±0.2°, 8.72±0.2°, 13.13±0.2°, 14.09±0.2°, and 17.27±0.2° in a powder X-ray diffraction spectrum; The type A crystal of the citrate salt of the compound of formula I has diffraction peaks at 2θ angles of 6.27±0.2°, 10.79±0.2°, 12.21±0.2°, 12.58±0.2°, 16.38±0.2°, and 25.33±0.2° in a powder X-ray diffraction spectrum; The B-type crystals of the citrate salt of the compound of formula I have a powder X-ray diffraction spectrum with 2θ angles of 11.93±0.2°, 15.45±0.2°, 16.45±0.2°, and 17.60 having diffraction peaks at 9.91±0.2°, 12.79±0.2°, 16.45±0.2°, 17.60±0.2°, and 20.88±0.2°; The type A crystal of the methanesulfonate salt of the compound of formula I has diffraction peaks at 2θ angles of 7.28±0.2°, 10.86±0.2°, 12.71±0.2°, 14.20±0.2°, 14.58±0.2°, 16.67±0.2°, 18.70±0.2°, and 19.96±0.2° in a powder X-ray diffraction spectrum; The type A crystal of the ethanesulfonate salt of the compound of formula I has diffraction peaks at 2θ angles of 7.13±0.2°, 10.80±0.2°, 12.60±0.2°, 14.26±0.2°, 16.43±0.2°, 18.28±0.2°, 19.95±0.2°, 21.45±0.2° and 23.26±0.2° in a powder X-ray diffraction spectrum; The B-type crystals of the ethanesulfonate salt of the compound of formula I have diffraction peaks at 2θ angles of 6.92±0.2°, 9.86±0.2°, 19.20±0.2°, 20.10±0.2°, 21.38±0.2°, 25.27±0.2°, and 29.85±0.2° in a powder X-ray diffraction spectrum; The A-type crystal of the maleate salt of the compound of formula I has diffraction peaks at 2θ angles of 4.46±0.2°, 5.61±0.2°, 11.23±0.2°, 16.86±0.2°, 18.30±0.2°, 19.20±0.2°, and 19.91±0.2° in a powder X-ray diffraction spectrum; The B-type crystals of the maleate salt of the compound of formula I have diffraction peaks at 2θ angles of 4.99±0.2°, 10.46±0.2°, 11.21±0.2°, 16.82±0.2°, 18.30±0.2°, 18.92±0.2°, and 19.50±0.2° in a powder X-ray diffraction spectrum; The A-type crystals of the L-tartrate salt of the compound of formula I have diffraction peaks at 2θ angles of 9.28±0.2°, 11.38±0.2°, 15.62±0.2°, 19.54±0.2°, 19.89±0.2°, and 25.21±0.2° in a powder X-ray diffraction spectrum; The B-type crystals of the L-tartrate salt of the compound of formula I have diffraction peaks at 2θ angles of 4.22±0.2°, 5.17±0.2°, 5.77±0.2°, 8.65±0.2°, 11.51±0.2°, 14.08±0.2°, 16.59±0.2°, 17.29±0.2° and 23.11±0.2° in a powder X-ray diffraction spectrum; The C-type crystals of the L-tartrate salt of the compound of formula I have diffraction peaks at 2θ angles of 5.77±0.2°, 11.54±0.2°, 16.50±0.2°, 17.33±0.2°, 18.46±0.2°, 19.80±0.2°, and 24.85±0.2° in a powder X-ray diffraction spectrum; The D-type crystals of the L-tartrate salt of the compound of formula I have diffraction peaks at 2θ angles of 5.80±0.2°, 11.56±0.2°, 15.74±0.2°, 16.50±0.2°, 17.38±0.2°, 19.63±0.2°, 23.23±0.2°, 23.64±0.2°, 24.86±0.2° and 25.28±0.2° in a powder X-ray diffraction spectrum; The type A crystals of the glycolate salt of the compound of formula I have diffraction peaks at 2θ angles of 5.90±0.2°, 7.21±0.2°, 7.80±0.2°, 11.42±0.2°, 11.79±0.2°, 17.72±0.2°, 19.80±0.2°, 23.10±0.2° and 23.71±0.2° in a powder X-ray diffraction spectrum; The A-type crystals of the L-malate salt of the compound of formula I have diffraction peaks at 2θ angles of 5.92±0.2°, 11.82±0.2°, 16.56±0.2°, 17.68±0.2°, 21.97±0.2°, and 23.75±0.2° in a powder X-ray diffraction spectrum; The B-type crystals of the L-malate salt of the compound of formula I have diffraction peaks at 2θ angles of 6.69±0.2°, 8.99±0.2°, 9.30±0.2°, 13.38±0.2°, 17.00±0.2°, 18.71±0.2°, 21.18±0.2° and 26.89±0.2° in a powder X-ray diffraction spectrum; The A-type crystals of the hippurate salt of the compound of formula I have diffraction peaks at 2θ angles of 9.10±0.2°, 10.41±0.2°, 12.69±0.2°, 15.00±0.2°, 15.22±0.2°, 16.93±0.2°, 18.00±0.2°, 18.71±0.2°, 24.53±0.2° and 26.00±0.2° in a powder X-ray diffraction spectrum; The A-type crystal of the succinate salt of the compound of formula I has diffraction peaks at 2θ angles of 4.72±0.2°, 5.83±0.2°, 7.87±0.2°, 9.34±0.2°, 11.71±0.2°, 12.39±0.2°, 16.67±0.2°, 17.58±0.2°, 19.99±0.2°, 21.89±0.2°, 23.57±0.2° and 25.40±0.2° in a powder X-ray diffraction spectrum; The B-type crystals of the succinate salt of the compound of formula I have diffraction peaks at 2θ angles of 5.70±0.2°, 9.24±0.2°, 11.42±0.2°, 13.55±0.2°, 17.17±0.2°, and 22.95±0.2° in a powder X-ray diffraction spectrum; The type A crystal of the ascorbate salt of the compound of formula I has diffraction peaks at 2θ angles of 5.72±0.2°, 9.20±0.2°, 11.30±0.2°, 15.55±0.2°, 16.71±0.2°, 17.58±0.2°, 18.83±0.2° and 25.94±0.2° in a powder X-ray diffraction spectrum; The B-type crystals of the ascorbate salt of the compound of formula I have diffraction peaks at 2θ angles of 5.50±0.2°, 11.00±0.2°, 16.63±0.2°, 17.47±0.2°, 19.82±0.2°, 28.08±0.2°, and 30.05±0.2° in a powder X-ray diffraction spectrum; The A-type crystals of the adipate salt of the compound of formula I have diffraction peaks at 2θ angles of 8.47±0.2°, 11.41±0.2°, 15.57±0.2°, 16.29±0.2°, 17.52±0.2°, 18.23±0.2°, and 19.84±0.2° in a powder X-ray diffraction spectrum; The type A crystal of the p-toluenesulfonate salt of the compound of formula I has diffraction peaks at 2θ angles of 8.91±0.2°, 9.43±0.2°, 12.31±0.2°, 15.93±0.2°, 16.43±0.2°, 20.69±0.2°, 20.95±0.2°, 24.76±0.2° and 26.36±0.2° in a powder X-ray diffraction spectrum; The type A crystal of the benzenesulfonate salt of the compound of formula I has diffraction peaks at 2θ angles of 10.81±0.2°, 11.38±0.2°, 16.25±0.2°, 17.41±0.2°, 18.35±0.2°, 19.90±0.2° and 21.31±0.2° in a powder X-ray diffraction spectrum; The A-type crystal of the oxalate salt of the compound of formula I has diffraction peaks at 2θ angles of 6.15±0.2°, 10.44±0.2°, 13.94±0.2°, 16.74±0.2°, 17.49±0.2°, and 24.50±0.2° in a powder X-ray diffraction spectrum; The type A crystal of the 2-hydroxyethanesulfonate salt of the compound of formula I has diffraction peaks at 2θ angles of 6.46±0.2°, 9.89±0.2°, 10.95±0.2°, 13.14±0.2°, 18.38±0.2°, 18.81±0.2°, and 21.70±0.2° in a powder X-ray diffraction spectrum.

2. The type A crystal of the compound of formula I has diffraction peaks at 2θ angles of 10.30±0.2°, 12.06±0.2°, 12.42±0.2°, 14.68±0.2°, 15.10±0.2°, 17.78±0.2°, 18.13±0.2°, 19.12±0.2°, 20.25±0.2°, 21.76±0.2°, 22.09±0.2° and 24.75±0.2° in a powder X-ray diffraction spectrum; and / or the Type A crystal of the compound of formula I is a hydrate, wherein the molar ratio of the compound of formula I to water is 1:(0.5-1.5), preferably 1:(1-1.5); and / or the thermogravimetric analysis spectrum of the A-type crystal of the compound of formula I shows a weight loss when heated to 120±5°C from the start, preferably a weight loss of 2% to 4%; and / or the differential scanning calorimetry spectrum of the A-type crystal of the compound of formula I is 73.3°C ± 3°C and / or 178.0°C ± 3°C, and / or the B-type crystals of the compound of formula I have diffraction peaks at 2θ angles of 12.30±0.2°, 12.89±0.2°, 14.49±0.2°, 15.32±0.2°, 17.45±0.2°, 18.10±0.2°, 18.70±0.2°, 20.33±0.2°, 21.66±0.2°, 22.01±0.2°, 22.52±0.2°, 23.23±0.2°, 24.35±0.2°, and 24.69±0.2° in a powder X-ray diffraction spectrum; and / or the A-type crystal of the fumarate salt has, in a powder X-ray diffraction pattern, diffraction peaks at 2θ angles of 6.86±0.2°, 7.72±0.2°, 9.57±0.2°, 16.47±0.2°, 19.20±0.2°, 19.63±0.2°, 22.47±0.2°, 23.26±0.2° and 23.95±0.2°, preferably 6.86±0.2°, 7.72±0.2°, 9.57±0.2°, 16.47±0.2°, 19.20±0.2°, 19.63±0.2°, 22.47±0.2°, 23.26±0.2° and 23.95±0.2°. Diffraction peaks at 17.72±0.2°, 15.45±0.2°, 15.87±0.2°, 16.47±0.2°, 17.13±0.2°, 17.47±0.2°, 18.19±0.2°, 18.72±0.2°, 19.20±0.2°, 19.63±0.2°, 19.97±0.2°, 22.47±0.2°, 23.26±0.2°, 23.95±0.2°, 25.93±0.2° and 31.16±0.2°, and / or wherein the crystalline Form A of the fumarate salt has a molar ratio of the compound of Formula I to fumaric acid of 1:1; and / or the thermogravimetric analysis spectrum of the A-type crystals of the fumarate salt shows a weight loss upon heating from the start to 150±5°C, preferably a weight loss of 0% to 5%; and / or the differential scanning calorimetry spectrum of the Type A crystals of the fumarate salt has a main endothermic peak at 214.7°C ± 3°C; and / or the Form A crystals of fumarate are hydrates of the fumarate of the compound of formula I, wherein the molar ratio of the compound of formula I to water is 1:(0.5-1.5), preferably 1:(1-1.5); and / or the B-type crystals of the fumarate salt have diffraction peaks at 2θ angles of 4.78±0.2°, 8.02±0.2°, 9.68±0.2°, 11.93±0.2°, 16.57±0.2°, 17.93±0.2°, 18.57±0.2°, 19.41±0.2°, 19.95±0.2°, 21.10±0.2° and 28.81±0.2° in a powder X-ray diffraction spectrum, and preferably have diffraction peaks at 4.78±0.2°, 5.98±0.2°, 8.02±0.2°, 9.68±0.2°, 11.93±0.2°, 16.57±0.2°, 17.93±0.2°, 18.57±0.2°, 19.41±0.2°, 19.95±0.2°, 21.10±0.2° and 28.81±0.2°. Diffraction peaks at 19.93±0.2°, 12.44±0.2°, 12.78±0.2°, 14.01±0.2°, 15.38±0.2°, 15.80±0.2°, 16.57±0.2°, 17.36±0.2°, 17.93±0.2°, 18.57±0.2°, 19.41±0.2°, 19.95±0.2°, 21.10±0.2°, 23.97±0.2°, 24.76±0.2°, 25.74±0.2°, 26.56±0.2°, 28.81±0.2° and 29.48±0.2°, and / or the thermogravimetric analysis spectrum of the B-type crystals of the fumarate salt shows a weight loss, preferably a weight loss of 4% to 6%, when heated from the start to 150±5°C, and a weight loss, preferably a weight loss of 5% to 7% when heated from 150±5°C to 250±5°C; and / or, in the crystalline form B of the fumarate salt, the molar ratio of the compound of Formula I to fumaric acid is 1:1; and / or the differential scanning calorimetry spectrum of the B-type crystals of the fumarate salt has a main endothermic peak at 154.4°C ± 3°C and an exothermic peak at 191.9°C ± 3°C; and / or the C-type crystals of the fumarate salt have diffraction peaks at 2θ angles of 6.85±0.2°, 8.72±0.2°, 13.13±0.2°, 14.09±0.2°, 17.27±0.2°, 17.90±0.2°, 20.60±0.2°, 21.42±0.2°, 23.16±0.2° and 24.04±0.2° in a powder X-ray diffraction spectrum, and preferably have diffraction peaks at 6.85±0.2°, 8.72±0.2°, 13.13±0.2°, 14.09±0.2°, 17.27±0.2°, 17.90±0.2°, 20.60±0.2°, 21.42±0.2°, 23.16±0.2° and 24.04±0.2°. ±0.2°, 13.13±0.2°, 14.09±0.2°, 14.29±0.2°, 16.33±0.2°, 17.27±0.2°, 17.90±0.2°, 20.60±0.2°, 21.42±0.2°, 23.16±0.2° and 24.04±0.2°, and / or the thermogravimetric analysis spectrum of the C-type crystals of the fumarate salt shows a weight loss, preferably a weight loss of 1% to 3%, when heated from the start to 150±5°C, and a weight loss, preferably a weight loss of 5% to 7% when heated from 150±5°C to 250±5°C; and / or wherein the crystalline form C of the fumarate salt comprises a molar ratio of the compound of Formula I to fumaric acid of 1:1; and / or the differential scanning calorimetry spectrum of the C-type crystals of the fumarate salt has main endothermic peaks at 94.4°C±3°C, 145.0°C±3°C, and 161.2°C±3°C, and an exothermic peak at 190.4°C±3°C; and / or the A-type crystals of the citrate salt have diffraction peaks at 2θ angles of 6.27±0.2°, 10.79±0.2°, 12.21±0.2°, 12.58±0.2°, 16.38±0.2°, 18.33±0.2°, and 25.33±0.2° in a powder X-ray diffraction spectrum; and / or wherein the molar ratio of the compound of Formula I to citric acid in the Form A crystals of the Citrate Salt is 1:1; and / or the thermogravimetric analysis spectrum of the A-type crystals of the citrate salt shows a weight loss, preferably a weight loss of 5% to 7%, when heated from the start to 150±5°C, and a weight loss, preferably a weight loss of 18% to 20% when heated from 150±5°C to 230±5°C; and / or the differential scanning calorimetry spectrum of the Type A crystals of the citrate salt has main endothermic peaks at 99.1°C ± 3°C and 137.9°C ± 3°C; and / or the B-type crystals of the citrate salt have diffraction peaks at 2θ angles of 11.93±0.2°, 12.79±0.2°, 15.45±0.2°, 16.45±0.2°, 17.60±0.2°, 19.86±0.2°, 20.88±0.2°, 21.18±0.2°, 23.55±0.2°, and 25.19±0.2° in a powder X-ray diffraction pattern, or have diffraction peaks at 2θ angles of 9.91±0.2°, 12.79±0.2°, 16.45±0.2°, 17.60±0.2°, 20.88±0.2°, 24.34±0.2°, and 24.70±0.2°. and preferably has diffraction peaks at one or more of the following 2θ° angles: 9.90±0.2°, 11.93±0.2°, 12.79±0.2°, 15.45±0.2°, 16.45±0.2°, 17.60±0.2°, 18.25±0.2°, 19.34±0.2°, 19.86±0.2°, 20.88±0.2°, 21.18±0.2°, 23.55±0.2°, 25.19±0.2°, 27.72±0.2°, 28.47±0.2°, 29.97±0.2°, 30.65±0.2°, and 31.19±0.2°; and / or the B-type crystals of the citrate salt, wherein the molar ratio of the compound of formula I to citric acid is 1:1; and / or the thermogravimetric analysis spectrum of the B-type crystals of the citrate salt shows a weight loss when heated to 150±5°C from the start, preferably a weight loss of 0% to 2%; and / or the differential scanning calorimetry spectrum of the B-type crystals of the citrate salt has a main endothermic peak at 195.0°C ± 3°C; and / or the A-type crystal of the methanesulfonate salt has a powder X-ray diffraction pattern with 2θ angles of 7.28±0.2°, 10.86±0.2°, 12.71±0.2°, 14.20±0.2°, 14.58±0.2°, 16.67±0.2°, 18.70±0.2°, 19.96±0.2°, 21.57±0.2°. and 21.93±0.2°, and preferably has diffraction peaks at 7.28±0.2°, 10.86±0.2°, 12.71±0.2°, 14.20±0.2°, 14.58±0.2°, 16.67±0.2°, 18.70±0.2°, 19.96±0.2°, 21.57±0.2°, 21.93±0.2°, 22 Diffraction peaks at 23.86±0.2°, 23.39±0.2°, 23.77±0.2°, 24.50±0.2°, 24.84±0.2° and 25.59±0.2°, and / or, in the Type A crystals of the methanesulfonate salt, the molar ratio of the compound of Formula I to methanesulfonic acid is 1:1; and / or the thermogravimetric analysis spectrum of the A-type crystal of the methanesulfonate salt shows a weight loss when heated to 150±5°C from the start, preferably a weight loss of 0% to 5%; and / or the differential scanning calorimetry spectrum of the A-type crystals of the methanesulfonate salt has a main endothermic peak at 206.0°C ± 3°C; and / or the type A crystal of the ethanesulfonate salt has diffraction peaks at 2θ angles of 7.13±0.2°, 9.63±0.2°, 10.80±0.2°, 12.60±0.2°, 14.03±0.2°, 14.26±0.2°, 16.43±0.2°, 18.28±0.2°, 18.73±0.2°, 18.95±0.2°, 19.96±0.2°, 20.98±0.2°, 21.45±0.2°, 22.46±0.2°, 22.95±0.2°, 23.26±0.2°, 24.40±0.2°, 24.69±0.2°, and 25.36±0.2° in a powder X-ray diffraction spectrum; and / or, in the Form A crystals of the ethanesulfonate salt, the molar ratio of the compound of Formula I to ethanesulfonic acid is 1:1; and / or the thermogravimetric analysis spectrum of the A-type crystals of the ethanesulfonate salt shows a weight loss, preferably a weight loss of 0% to 5%, when heated to 150±5°C from the start of heating; and / or the differential scanning calorimetry spectrum of the A-type crystals of the ethanesulfonate salt has a main endothermic peak at 218.7°C ± 3°C; and / or the B-type crystals of the ethanesulfonate salt have diffraction peaks at 2θ angles of 6.92±0.2°, 8.71±0.2°, 9.86±0.2°, 12.73±0.2°, 15.01±0.2°, 16.84±0.2°, 19.20±0.2°, 20.10±0.2°, 21.38±0.2°, 23.30±0.2°, 25.27±0.2°, and 29.85±0.2° in a powder X-ray diffraction spectrum; and / or, in the B-type crystals of the ethanesulfonate salt, the molar ratio of the compound of formula I to ethanesulfonic acid is 1:1; and / or the thermogravimetric analysis spectrum of the B-type crystals of the ethanesulfonate salt shows a weight loss, preferably a weight loss of 1% to 3%, when heated to 150±5°C from the start of heating; and / or the differential scanning calorimetry spectrum of the B-type crystals of the ethanesulfonate salt has main endothermic peaks at 156.8°C ± 3°C and 211.9°C ± 3°C; and / or the A-type crystal of the maleate salt exhibits diffraction at 2θ angles of 4.46±0.2°, 5.61±0.2°, 11.23±0.2°, 15.38±0.2°, 16.86±0.2°, 18.30±0.2°, 19.20±0.2°, 19.91±0.2°, 20.42±0.2°, and 23.00±0.2° in a powder X-ray diffraction spectrum. and preferably has diffraction peaks at 4.46±0.2°, 5.61±0.2°, 11.23±0.2°, 11.86±0.2°, 15.38±0.2°, 16.86±0.2°, 18.30±0.2°, 19.20±0.2°, 19.91±0.2°, 20.42±0.2°, 23.00±0.2° and 24.26±0.2°; and / or, in the Form A crystals of the maleate salt, the molar ratio of the compound of formula I to maleic acid is 1:1; and / or the thermogravimetric analysis spectrum of the A-type crystal of the maleate salt shows a weight loss, preferably a weight loss of 2% to 4%, when heated from the start to 100±5°C, and a weight loss, preferably a weight loss of 14% to 16% when heated from 100±5°C to 225±5°C; and / or the differential scanning calorimetry spectrum of the A-type crystals of the maleate salt has main endothermic peaks at 160.4°C ± 3°C and 219.1°C ± 3°C; and / or the B-type crystals of the maleate salt of the compound of formula I have, in a powder X-ray diffraction spectrum, 2θ angles of 4.99±0.2°, 6.99±0.2°, and 10.46±0.2°; having diffraction peaks at 11.21±0.2°, 15.02±0.2°, 15.60±0.2°, 16.82±0.2°, 18.30±0.2°, 18.92±0.2° and 19.50±0.2°; and / or, in the B-type crystals of the maleate salt, the molar ratio of the compound of formula I to maleic acid is 1:1; and / or the thermogravimetric analysis spectrum of the B-type crystals of the maleate salt shows a weight loss, preferably a weight loss of 2% to 4%, when heated from the start to 100±5°C, and a weight loss, preferably a weight loss of 11% to 13% when heated from 100±5°C to 225±5°C; and / or the differential scanning calorimetry spectrum of the B-type crystals of the maleate salt has main endothermic peaks at 152.9°C ± 3°C and 220.7°C ± 3°C; and / or the type A crystals of the L-tartrate salt have diffraction peaks at 2θ angles of 9.28±0.2°, 11.38±0.2°, 12.97±0.2°, 15.62±0.2°, 16.95±0.2°, 18.07±0.2°, 19.54±0.2°, 19.89±0.2°, 22.94±0.2°, 23.51±0.2°, 25.21±0.2°, 26.92±0.2°, and 28.46±0.2° in a powder X-ray diffraction spectrum; and / or, in the Form A crystals of the L-tartrate salt, the molar ratio of the compound of formula I to L-tartaric acid is 1:1; and / or the thermogravimetric analysis spectrum of the A-type crystals of the L-tartrate salt shows a weight loss when heated to 150±5°C from the start, preferably a weight loss of 2% to 4%; and / or the differential scanning calorimetry spectrum of the A-type crystals of the L-tartrate salt has main endothermic peaks at 82.2°C ± 3°C and 213.2°C ± 3°C; and / or the B-type crystals of the L-tartrate salt have diffraction peaks at 2θ angles of 4.22±0.2°, 5.17±0.2°, 5.77±0.2°, 8.65±0.2°, 10.09±0.2°, 11.51±0.2°, 14.08±0.2°, 16.59±0.2°, 17.29±0.2°, 18.20±0.2°, 18.64±0.2°, 19.75±0.2°, 20.22±0.2°, 20.74±0.2°, 21.95±0.2°, and 23.11±0.2° in a powder X-ray diffraction spectrum; and / or, in the B-type crystals of the L-tartrate salt, the molar ratio of the compound of formula I to L-tartaric acid is 1:1; and / or the thermogravimetric analysis spectrum of the B-type crystals of the L-tartrate salt shows a weight loss when heated to 180±5°C from the start, preferably a weight loss of 5% to 7%; and / or the differential scanning calorimetry spectrum of the B-type crystals of the L-tartrate salt has main endothermic peaks at 114.5°C±3°C, 160.5°C±3°C, 193.2°C±3°C, and 219.5°C±3°C; And / or, the C-type crystals of the L-tartrate salt have diffraction peaks at 2θ angles of 4.60±0.2°, 5.77±0.2°, 11.54±0.2°, 14.06±0.2°, 16.50±0.2°, 17.33±0.2°, 18.46±0.2°, 19.80±0.2°, 21.91±0.2°, 23.16±0.2°, 24.85 and 25.27±0.2° in a powder X-ray diffraction spectrum, preferably 4.60±0.2°, 5.77±0.2°, 11.54±0.2°, 14.06±0.2°, 16.50±0.2°, 17.33±0.2°, 18.46±0.2°, 19.80±0.2°, 21.91±0.2°, 23.16±0.2°, 24.85 and 25.27±0.2°. and having diffraction peaks at 9.20±0.2°, 11.54±0.2°, 12.07±0.2°, 12.56±0.2°, 14.06±0.2°, 14.68±0.2°, 16.50±0.2°, 17.33±0.2°, 18.46±0.2°, 19.10±0.2°, 19.80±0.2°, 20.56±0.2°, 21.91±0.2°, 23.16±0.2°, 24.16±0.2°, 24.85±0.2° and 25.27±0.2°, and / or, in the C-type crystals of the L-tartrate salt, the molar ratio of the compound of formula I to L-tartaric acid is 1:0.5; and / or the thermogravimetric analysis spectrum of the C-type crystals of the L-tartrate salt shows a weight loss upon heating from the start to 150±5°C, preferably a weight loss of 2% to 4%; and / or the differential scanning calorimetry spectrum of the C-type crystals of the L-tartrate salt is 128.5°C 157.1°C ± 3°C, 157.1°C ± 3°C, and 220.5°C ± 3°C, and / or the D-type crystals of the L-tartrate salt have diffraction peaks at 2θ angles of 5.80±0.2°, 11.56±0.2°, 15.74±0.2°, 16.50±0.2°, 17.38±0.2°, 18.24±0.2°, 19.35±0.2°, 19.63±0.2°, 20.02±0.2°, 23.23±0.2°, 23.64±0.2°, 24.86±0.2°, and 25.28±0.2° in a powder X-ray diffraction spectrum, and preferably have diffraction peaks at 2θ angles of 4.24±0.2°, 11.56±0.2°, 15.74±0.2°, 16.50±0.2°, 17.38±0.2°, 18.24±0.2°, 19.35±0.2°, 19.63±0.2°, 20.02±0.2°, 23.23±0.2°, 23.64±0.2°, 24.86±0.2°, and 25.28±0.2°. and having diffraction peaks at 5.80±0.2°, 9.45±0.2°, 11.56±0.2°, 13.07±0.2°, 15.74±0.2°, 16.50±0.2°, 17.38±0.2°, 18.24±0.2°, 19.35±0.2°, 19.63±0.2°, 20.02±0.2°, 20.48±0.2°, 20.70±0.2°, 21.93±0.2°, 23.23±0.2°, 23.64±0.2°, 24.86±0.2° and 25.28±0.2°. and / or, in the D-type crystals of the L-tartrate salt, the molar ratio of the compound of formula I to L-tartaric acid is 1:1; and / or the thermogravimetric analysis spectrum of the D-type crystals of the L-tartrate salt shows a weight loss when heated to 150±5°C from the start, preferably a weight loss of 2% to 4%; and / or the differential scanning calorimetry spectrum of the D-type crystals of the L-tartrate salt has main endothermic peaks at 75.0°C±3°C, 111.6°C±3°C, 161.9°C±3°C, 200.9°C±3°C, and 218.8°C±3°C; and / or the type A crystals of the glycolate have diffraction peaks at 2θ angles of 5.90±0.2°, 7.21±0.2°, 7.80±0.2°, 11.42±0.2°, 11.79±0.2°, 13.24±0.2°, 14.74±0.2°, 16.45±0.2°, 17.72±0.2°, 18.65±0.2°, 19.80±0.2°, 20.54±0.2°, 21.96±0.2°, 23.10±0.2°, and 23.71±0.2° in a powder X-ray diffraction spectrum, preferably 5.90±0.2°, 7.21±0.2°, 7.80±0.2°, having diffraction peaks at 8.83±0.2°, 9.34±0.2°, 11.03±0.2°, 11.42±0.2°, 11.79±0.2°, 12.18±0.2°, 13.24±0.2°, 13.49±0.2°, 14.43±0.2°, 14.74±0.2°, 15.60±0.2°, 15.86±0.2°, 16.16±0.2°, 16.45±0.2°, 16.98±0.2°, 17.72±0.2°, 18.65±0.2°, 19.80±0.2°, 20.54±0.2°, 21.96±0.2°, 23.10±0.2° and 23.71±0.2°; and / or the Type A crystals of the glycolate salt have a molar ratio of the compound of formula I to glycolic acid of 1:1; and / or the thermogravimetric analysis spectrum of the A-type crystals of the glycolate salt shows a weight loss when heated to 150±5°C from the start, preferably a weight loss of 2% to 4%; and / or the differential scanning calorimetry spectrum of the A-type crystals of the glycolate salt has a main endothermic peak at 110.1°C ± 3°C; and / or the A-type crystal of the L-malate has diffraction peaks at 2θ angles of 5.92±0.2°, 7.54±0.2°, 8.32±0.2°, 8.76±0.2°, 11.82±0.2°, 16.56±0.2°, 17.68±0.2°, 18.71±0.2°, 19.69±0.2°, 21.97±0.2° and 23.75±0.2° in a powder X-ray diffraction spectrum, preferably has diffraction peaks at 5.92±0.2°, 7.54±0.2°, 8.32±0.2°, 8.76±0.2°, 10.35±0.2°, 11.82±0.2°, 12.40±0.2°, 14.10±0.2°, 16.56±0.2°, 17.68±0.2°, 18.71±0.2°, 19.69±0.2°, 20.81±0.2°, 21.97±0.2° and 23.75±0.2°, and / or the molar ratio of the compound of formula I to L-malic acid in the Form A crystals of the L-malate salt is 1:1; And / or, the thermogravimetric analysis spectrum of the A-type crystal of the L-malate salt is a weight loss when heated to 50±5°C, preferably a weight loss of 2% to 4%, a weight loss when heated from 50±5°C to 100±5°C, preferably a weight loss of 1% to 3%, and a weight loss when heated from 100±5°C to 150±5°C, preferably a weight loss of 0% to 2%; and / or the differential scanning calorimetry spectrum of the A-type crystals of the L-malate salt has main endothermic peaks at 72.9°C±3°C, 122.2°C±3°C, 142.1°C±3°C, and 222.4°C±3°C, and an exothermic peak at 195.9°C±3°C; and / or the B-type crystals of the L-malate have, in a powder X-ray diffraction spectrum, 2θ angles of 6.69±0.2°, 8.99±0.2°, 9.30±0.2°, 10.69±0.2°, 10.97±0.2°, 11.29±0.2°, 12.77±0.2°, 13.02±0.2°, 13.38±0.2°, 2°, 14.64±0.2°, 14.89±0.2°, 15.89±0.2°, 17.00±0.2°, 17.55±0.2°, 18.27±0.2°, 18.71±0.2°, 20.70±0.2°, 21.18±0.2°, 21.71±0.2° and 26.89±0.2°, and / or, in the B-type crystals of the L-malate salt, the molar ratio of the compound of formula I to L-malic acid is 1:1; and / or the thermogravimetric analysis spectrum of the B-type crystals of the L-malate salt shows a weight loss when heated to 150±5°C from the start, preferably a weight loss of 2% to 4%; and / or the differential scanning calorimetry spectrum of the B-type crystals of the L-malate salt has a main endothermic peak at 134.8°C ± 3°C; And / or, the A-type crystal of the hippurate salt has, in a powder X-ray diffraction spectrum, 2θ angles: 8.78±0.2°, 9.10±0.2°, 10.41±0.2°, 12.69±0.2°, 12.91±0.2°, 15.00±0.2°, 15.22±0.2°, 16.02±0.2°, 16.57±0.2°, 16.93±0. and 26.00±0.2°, and preferably has diffraction peaks at 8.78±0.2°, 9.10±0.2°, 10.41±0.2°, 12.69±0.2°, 17.69±0.2°, 18.00±0.2°, 18.71±0.2°, 20.65±0.2°, 21.27±0.2°, 22.33±0.2°, 24.53±0.2°, and 26.00±0.2°. .2°, 12.91±0.2°, 15.00±0.2°, 15.22±0.2°, 16.02±0.2°, 16.57±0.2°, 16.93±0.2°, 17.69±0.2°, 18.00±0.2°, 18.71±0.2°, 20.40±0.2°, 20.65±0.2°, 20.89±0.2°, 21.27±0.2° and having diffraction peaks at 22.33±0.2°, 24.53±0.2°, 24.87±0.2°, 25.50±0.2°, 26.00±0.2°, 26.14±0.2°, 27.64±0.2°, 28.43±0.2°, 29.31±0.2°, 29.89±0.2°, 31.11±0.2° and 32.36±0.2°, and / or, in the A-type crystals of the hippurate salt, the molar ratio of the compound of formula I to hippuric acid is 1:1; and / or the thermogravimetric analysis spectrum of the A-type crystal of the hippurate salt shows a weight loss when heated to 150±5°C from the start, preferably a weight loss of 2% to 4%; and / or the differential scanning calorimetry spectrum of the A-type crystals of the hippurate salt has main endothermic peaks at 62.4°C ± 3°C, 120.1°C ± 3°C, and 207.0°C ± 3°C; and / or, in the crystalline form A of the succinate salt, the molar ratio of the compound of formula I to succinic acid is 1:1; and / or the thermogravimetric analysis spectrum of the A-type crystal of the succinate salt shows a weight loss when heated to 150±5°C from the start, preferably a weight loss of 3% to 5%; and / or the differential scanning calorimetry spectrum of the A-type crystals of the succinate salt has main endothermic peaks at 70.0°C ± 3°C, 124.1°C ± 3°C, and 221.0°C ± 3°C; and / or the B-type crystal of the succinate has, in a powder X-ray diffraction spectrum, 2θ angles of 5.70±0.2°, 9.24±0.2°, 11.42±0.2°, 13.55±0.2°, 15.10±0.2°, 17.17±0.2°, 18.67±0.2°, 19.1 and 26.12±0.2°, and preferably has diffraction peaks at 5.70±0.2°, 6.75±0.2°, 9.24±0.2°, 11.42±0.2°, 12.31±0.2°, 13.13±0.2°, 13.55±0.2°, 15.10±0.2°, 15.80±0.2°, 16.35±0.2°, 17.3±0.2°, 19.99±0.2°, 20.59±0.2°, 22.95±0.2°, 23.25±0.2°, 24.10±0.2°, 25.13±0.2°, 25.48±0.2° and 26.12±0.2°. 0.2°, 17.17±0.2°, 18.67±0.2°, 19.13±0.2°, 19.50±0.2°, 19.99±0.2°, 20.59±0.2°, 21.60±0.2°, 21.93±0.2°, 22.58±0.2°, 22.95±0.2°, 23.25±0.2°, 24.10±0.2°, 25.13±0.2°, 25.48±0.2°, 25.79±0.2°, 26.12±0.2°, 28.98±0.2° and 31.50±0.2°, and / or, in the B-type crystals of the succinate salt, the molar ratio of the compound of formula I to succinic acid is 1:1; and / or the thermogravimetric analysis spectrum of the B-type crystals of the succinate salt shows a weight loss when heated to 150±5°C from the start, preferably a weight loss of 3% to 5%; and / or the differential scanning calorimetry spectrum of the B-type crystals of the succinate salt has main endothermic peaks at 105.1°C ± 3°C and 222.3°C ± 3°C; and / or the type A crystal of the ascorbate has diffraction peaks at 2θ angles of 5.72±0.2°, 9.20±0.2°, 11.30±0.2°, 14.38±0.2°, 15.55±0.2°, 16.71±0.2°, 17.58±0.2°, 18.83±0.2°, 20.30±0.2°, 22.33±0.2°, and 25.94±0.2° in a powder X-ray diffraction spectrum; and / or the ascorbate type A crystals have a molar ratio of the compound of formula I to ascorbic acid of 1:0.5; and / or the thermogravimetric analysis spectrum of the ascorbate type A crystals shows a weight loss, preferably a weight loss of 3% to 5%, when heated to 150±5°C from the start of heating; and / or the differential scanning calorimetry spectrum of the Type A crystals of the ascorbate salt has a main endothermic peak at 185.7°C ± 3°C and one exothermic peak at 195.8°C ± 3°C; and / or the type B crystals of ascorbate have diffraction peaks at 2θ angles of 4.47±0.2°, 5.50±0.2°, 9.11±0.2°, 11.00±0.2°, 15.27±0.2°, 16.09±0.2°, 16.63±0.2°, 17.47±0.2°, 19.82±0.2°, 25.30±0.2°, 28.08±0.2° and 30.05±0.2° in a powder X-ray diffraction spectrum, and preferably have diffraction peaks at 2θ angles of 4.47±0.2°, 5.50±0.2°, 9.11±0.2°, 11.00±0.2°, 15.27±0.2°, 16.09±0.2°, 16.63±0.2°, 17.47±0.2°, 19.82±0.2°, 25.30±0.2°, 28.08±0.2° and 30.05±0.2°. 7±0.2°, 5.50±0.2°, 9.11±0.2°, 11.00±0.2°, 13.23±0.2°, 15.27±0.2°, 16.09±0.2°, 16.63±0.2°, 17.47±0.2°, 19.82±0.2°, 21.09±0.2°, 21.53±0.2°, 25.30±0.2°, 25.92±0.2°, 26.81±0.2°, 28.08±0.2° and 30.05±0.2°, and / or the ascorbate type B crystals have a molar ratio of the compound of formula I to ascorbic acid of 1:1; and / or the thermogravimetric analysis spectrum of the ascorbate type B crystals shows a weight loss when heated to 150±5°C from the start, preferably a weight loss of 0% to 2%; and / or the differential scanning calorimetry spectrum of the type B crystals of the ascorbate has a main endothermic peak at 153.6°C ± 3°C; and / or the A-type crystals of the adipate salt have diffraction peaks at 2θ angles of 8.47±0.2°, 8.99±0.2°, 11.41±0.2°, 12.40±0.2°, 13.60±0.2°, 15.57±0.2°, 16.29±0.2°, 17.52±0.2°, 18.23±0.2°, 19.84±0.2°, 21.29±0.2°, 23.81±0.2°, 24.62±0.2°, 26.55±0.2°, 27.79±0.2°, and 29.82±0.2° in a powder X-ray diffraction spectrum; and / or, in the A-type crystals of the adipate salt, the molar ratio of the compound of formula I to adipic acid is 1:1; and / or the thermogravimetric analysis spectrum of the A-type crystal of the adipate salt shows a weight loss when heated to 150±5°C from the start, preferably a weight loss of 6% to 8%; and / or the differential scanning calorimetry spectrum of the A-type crystals of the adipate salt has a main endothermic peak at 88.3°C ± 3°C; And / or, the A-type crystal of the p-toluenesulfonate salt has diffraction peaks at 2θ angles of 8.91±0.2°, 9.43±0.2°, 12.31±0.2°, 15.93±0.2°, 16.43±0.2°, 17.26±0.2°, 17.91±0.2°, 18.31±0.2°, 20.69±0.2°, 20.95±0.2°, 23.11±0.2°, 23.29±0.2°, 24.76±0.2° and 26.36±0.2° in a powder X-ray diffraction spectrum, preferably 8.91±0.2°, 9.43±0.2°, 11.51±0.2°, 12.31±0.2°, 15.93±0.2°, 16.43±0.2°, 17.26±0.2°, 17.91±0.2°, 18.31±0.2°, 20.69±0.2°, 20.95±0.2°, 23.11±0.2°, 23.29±0.2°, 24.76±0.2° and 26.36±0.2°. and having diffraction peaks at 12.31±0.2°, 13.70±0.2°, 15.93±0.2°, 16.43±0.2°, 17.26±0.2°, 17.91±0.2°, 18.31±0.2°, 19.49±0.2°, 20.69±0.2°, 20.95±0.2°, 21.19±0.2°, 22.77±0.2°, 23.11±0.2°, 23.29±0.2°, 24.34±0.2°, 24.76±0.2°, 25.55±0.2°, 26.36±0.2°, 26.83±0.2°, 27.69±0.2° and 29.25±0.2°, and / or, in the Type A crystals of the p-toluenesulfonate salt, the molar ratio of the compound of formula I to p-toluenesulfonic acid is 1:1; and / or the thermogravimetric analysis spectrum of the A-type crystal of the p-toluenesulfonate salt shows a weight loss when heated from the start to 100±5°C, preferably a weight loss of 0% to 2%, and a weight loss of 2% to 4% when heated from 100°C to 170°C; and / or the differential scanning calorimetry spectrum of the A-type crystals of the p-toluenesulfonate salt has a main endothermic peak at 150.9°C ± 3°C; and / or the type A crystal of the p-toluenesulfonate salt has diffraction peaks at 2θ angles of 6.54±0.2°, 8.76±0.2°, 10.81±0.2°, 11.38±0.2°, 11.91±0.2°, 13.32±0.2°, 14.01±0.2°, 15.40±0.2°, 16.25±0.2°, 17.41±0.2°, 18.35±0.2°, 19.38±0.2°, 19.90±0.2°, 20.67±0.2°, 21.31±0.2°, 22.89±0.2°, 25.86±0.2°, 27.75±0.2°, and 32.21±0.2° in a powder X-ray diffraction spectrum; and / or, in the Type A crystal of the benzenesulfonate salt, the molar ratio of the compound of formula I to benzenesulfonic acid is 1:1; and / or the thermogravimetric analysis spectrum of the A-type crystal of the benzenesulfonate salt shows a weight loss, preferably a weight loss of 2% to 4%, when heated from the start to 80±5°C, and a weight loss, preferably a weight loss of 5% to 7% when heated from 80°C to 150°C; and / or the differential scanning calorimetry spectrum of the A-type crystals of the benzenesulfonate salt has main endothermic peaks at 111.7°C ± 3°C and 122.6°C ± 3°C; and / or the A-type crystal of the oxalate has diffraction peaks at 2θ angles of 6.15±0.2°, 7.02±0.2°, 10.44±0.2°, 13.94±0.2°, 16.74±0.2°, 17.49±0.2°, 20.07±0.2°, 24.50±0.2°, 25.79±0.2° and 26.53±0.2° in a powder X-ray diffraction spectrum, and preferably at 6.15±0.2°, 7.02±0.2°, 10.44±0.2°, 13.94±0.2°, 16.74±0.2°, 17.49±0.2°, 20.07±0.2°, 24.50±0.2°, 25.79±0.2° and 26.53±0.2°. 0.2°, 9.18±0.2°, 10.44±0.2°, 13.94±0.2°, 15.12±0.2°, 15.54±0.2°, 16.74±0.2°, 17.49±0.2°, 18.16±0.2°, 19.51±0.2°, 20.07±0.2°, 22.64±0.2°, 23.59±0.2°, 24.50±0.2°, 25.22±0.2°, 25.79±0.2°, 26.53±0.2°, Diffraction peaks at 27.90±0.2° and 28.47±0.2°, and / or wherein the molar ratio of the compound of Formula I to oxalic acid in the crystalline form A of the oxalate salt is 1:1; and / or the thermogravimetric analysis spectrum of the A-type crystal of the oxalate salt shows a weight loss when heated to 100±5°C from the start, preferably a weight loss of 2% to 7%; and / or the differential scanning calorimetry spectrum of the A-type crystals of the oxalate salt has main endothermic peaks at 103.4°C ± 3°C and 141.6°C ± 3°C; and / or the type A crystal of the 2-hydroxyethanesulfonate has, in a powder X-ray diffraction spectrum, diffraction peaks at 2θ angles of 6.46±0.2°, 9.89±0.2°, 10.95±0.2°, 13.14±0.2°, 13.60±0.2°, 15.69±0.2°, 18.38±0.2°, 18.81±0.2°, 20.44±0.2°, and 21.70±0.2°; and / or, in the Type A crystal of 2-hydroxyethanesulfonate, the molar ratio of the compound of formula I to 2-hydroxyethanesulfonic acid is 1:1; and / or the thermogravimetric analysis spectrum of the A-type crystal of the 2-hydroxyethanesulfonate salt shows a weight loss, preferably a weight loss of 0% to 3%, when heated to 150±5°C from the start of heating; And / or the crystal according to claim 1, characterized in that the differential scanning calorimetry spectrum of the A-type crystal of 2-hydroxyethanesulfonate has a main endothermic peak at 203.5°C ± 3°C.

3. The type A crystal of the compound of formula I has diffraction peaks at 2θ angles of 6.02±0.2°, 7.78±0.2°, 10.30±0.2°, 11.42±0.2°, 12.06±0.2°, 12.42±0.2°, 14.68±0.2°, 15.10±0.2°, 16.61±0.2°, 17.78±0.2°, 18.13±0.2°, 18.48±0.2°, 19.12±0.2°, 19.98±0.2°, 20.25±0.2°, 21.76±0.2°, 22.09±0.2° and 24.75±0.2° in a powder X-ray diffraction spectrum; and / or the thermogravimetric analysis spectrum of the A-type crystal of the compound of formula I shows a weight loss when heated from the start to 120±5°C, the weight loss being 3.24%; and / or the Form A crystal of the compound of formula I is a hydrate of the compound of formula I, wherein the molar ratio of the compound of formula I to water is 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4 or 1:1.5, most preferably 1:1 or 1:1.5; and / or the B-type crystal of the compound of formula I has, in a powder X-ray diffraction spectrum, 2θ angles of 10.08±0.2°, 10.30±0.2°, 11.58±0.2°, 12.30±0.2°, 12.89±0.2°, 14.49±0.2°, 15.32±0.2°, 16.39±0.2°, 16.89±0.2°, 17.45±0.2°, 18.50±0.2°, 19.50±0.2°, 20.50±0.2°, 21.50±0.2°, 22.50±0.2°, 23.50±0.2°, 24.50±0.2°, 25.50±0.2°, 26.50±0.2°, 27.50±0.2°, 28.50±0.2°, 29.50±0.2°, 30.50±0.2°, 31.50±0.2°, 32.50±0.2°, 33.50±0.2°, 34.50±0.2°, 35.50±0.2°, 36.50±0.2°, 37.50±0.2°, 38.50±0.2°, 39.50±0.2°, 40.50±0.2°, 41.50±0.2°, 42.50±0.2°, 43.50±0.2°, 44.50±0.2°, 45.50±0.2°, 46.50±0.2°, 47.50±0.2°, 0.2°, 18.10±0.2°, 18.21±0.2°, 18.70±0.2°, 19.84±0.2°, 20.33±0.2°, 21.05±0.2°, 21.66±0.2°, 22.01±0.2°, 22.52±0.2°, 23.23±0.2°, 24.35±0.2° and 24.69±0.2°, And / or, the A-type crystal of the fumarate salt further has, in a powder X-ray diffraction pattern, 2θ angles: 6.86±0.2°, 7.72±0.2°, 9.57±0.2°, 12.90±0.2°, 13.17±0.2°, 13.72±0.2°, 15.45±0.2°, 15.87±0.2°, 16.47±0.2°, 17.13±0.2°, 17.47±0.2°, 18.19±0.2°. and having diffraction peaks at 18.72±0.2°, 19.20±0.2°, 19.63±0.2°, 19.97±0.2°, 20.89±0.2°, 22.47±0.2°, 23.26±0.2°, 23.95±0.2°, 25.93±0.2°, 26.28±0.2°, 27.23±0.2°, 29.54±0.2°, 29.82±0.2° and 31.16±0.2°, and / or the thermogravimetric analysis spectrum of the crystalline form A of the fumarate salt shows a weight loss of 3.35% when heated from the start to 150±5°C; and / or the Form A crystalline form of the fumarate salt is a hydrate of the fumarate salt of the compound of Formula I, wherein the molar ratio of the compound of Formula I to water is 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4 or 1:1.5, most preferably 1:1 or 1:1.5; And / or, the B-type crystals of the fumarate salt have, in a powder X-ray diffraction spectrum, 2θ angles: 4.78±0.2°, 5.98±0.2°, 8.02±0.2°, 9.68±0.2°, 11.55±0.2°, 11.93±0.2°, 12.44±0.2°, 12.78±0.2°, 14.01±0.2°, 15.24±0.2°, 15.38±0.2°, 15.80±0.2°, 16.57±0.2°, 17. having diffraction peaks at 36±0.2°, 17.93±0.2°, 18.57±0.2°, 19.41±0.2°, 19.95±0.2°, 21.10±0.2°, 22.15±0.2°, 22.53±0.2°, 22.89±0.2°, 23.97±0.2°, 24.76±0.2°, 25.18±0.2°, 25.74±0.2°, 26.56±0.2°, 28.81±0.2° and 29.48±0.2°, and / or the thermogravimetric analysis spectrum of the B-type crystals of the fumarate salt shows a weight loss of 5.64% when heated from the start to 150±5°C, and a weight loss of 6.76% when heated from 150±5°C to 250±5°C; and / or the thermogravimetric analysis spectrum of the C-type crystals of the fumarate salt shows a weight loss of 1.69% when heated from the start to 150±5°C, and a weight loss of 6.21% when heated from 150±5°C to 250±5°C; and / or the thermogravimetric analysis spectrum of the A-type crystals of the citrate salt shows a weight loss of 5.72% when heated from the start to 150±5°C, and a weight loss of 19.25% when heated from 150±5°C to 230±5°C; and / or the B-type crystals of the citrate salt further exhibit one or more of the following 2θ° angles ±0.2° in the powder X-ray diffraction pattern: 9.90±0.2°, 11.93±0.2°, 12.79±0.2°, 15.45±0.2°, 16.45±0.2°, 16.72±0.2°, 17.60±0.2°, 18.25±0.2°, 19.34±0.2° , 19.86±0.2°, 20.88±0.2°, 21.18±0.2°, 23.22±0.2°, 23.55±0.2°, 24.35±0.2°, 24.68±0.2°, 25.19±0.2°, 27.72±0.2°, 28.47±0.2°, 29.97±0.2°, 30.65±0.2° and 31.19, preferably One or more of the following 2θ° angles ±0.2°: 9.90±0.2°, 10.38±0.2°, 11.78±0.2°, 11.93±0.2°, 12.79±0.2°, 15.19±0.2°, 15.45±0.2°, 16.45±0.2°, 16.72±0.2°, 17.60±0.2°, 18.25±0.2°, 19.34±0.2°, 19.8 and having diffraction peaks at 20.6±0.2°, 20.88±0.2°, 21.18±0.2°, 23.22±0.2°, 23.55±0.2°, 24.35±0.2°, 24.68±0.2°, 25.19±0.2°, 25.75±0.2°, 27.72±0.2°, 28.47±0.2°, 29.97±0.2°, 30.65±0.2° and 31.19, and / or the thermogravimetric analysis spectrum of the B-type crystals of the citrate salt shows a weight loss of 1.26% when heated from the start to 150±5°C; and / or the A-type crystal of the methanesulfonate salt further exhibits, in a powder X-ray diffraction pattern, 2θ angles of 7.28±0.2°, 9.84±0.2°, 10.86±0.2°, 12.71±0.2°, 14.20±0.2°, 14.58±0.2°, 16.67±0.2°, 18.70±0.2°, 18.92±0.2°, 19.92±0.2°, 20.92±0.2°, 21.92±0.2°, 22.92±0.2°, 23.92±0.2°, 24.92±0.2°, 25.92±0.2°, 26.92±0.2°, 27.92±0.2°, 28.92±0.2°, 29.92±0.2°, 30.92±0.2°, 31.92±0.2°, 32.92±0.2°, 33.92±0.2°, 34.92±0.2°, 35.92±0.2°, 36.92±0.2°, 37.92±0.2°, 38.92±0.2°, 39.92±0.2°, 40.92±0.2°, 41.92±0.2°, 42.92±0.2°, 43.92±0.2°, 44.92±0.2°, 45.92±0.2°, 46.92±0.2°, 47.92±0.2°, 48.92±0.2°, 49.92±0.2 ±0.2°, 19.96±0.2°, 20.38±0.2°, 21.31±0.2°, 21.57±0.2°, 21.93±0.2°, 22.86±0.2°, 23.39±0.2°, 23.77±0.2°, 24.50±0.2°, 24.84±0.2° and 25.59±0.2°, And / or, the thermogravimetric analysis spectrum of the A-type crystal of the methanesulfonate salt is When heated from 0°C to 150°C, the weight decreased by 2.14%. and / or the thermogravimetric analysis spectrum of the A-type crystal of the ethanesulfonate salt shows a weight loss of 0.87% when heated from the start to 150±5°C; and / or the thermogravimetric analysis spectrum of the B-type crystals of the ethanesulfonate salt shows a weight loss of 2.17% when heated from the start to 150±5°C; and / or the thermogravimetric analysis spectrum of the A-type crystal of the maleate salt shows a weight loss of 3.14% when heated from the start to 100±5°C, and a weight loss of 14.49% when heated from 100±5°C to 225±5°C; and / or the thermogravimetric analysis spectrum of the B-type crystals of the maleate salt shows a weight loss of 2.84% when heated from the start to 100±5°C, and a weight loss of 12.43% when heated from 100±5°C to 225±5°C; and / or the thermogravimetric analysis spectrum of the A-type crystals of the L-tartrate salt shows a weight loss of 3.18% when heated from the start to 150±5°C; And / or, the B-type crystals of the L-tartrate salt have, in a powder X-ray diffraction spectrum, 2θ angles: 4.22±0.2°, 5.17±0.2°, 5.77±0.2°, 8.65±0.2°, 10.09±0.2°, 11.51±0.2°, 12.58±0.2°, 14.08±0.2°, 14.91±0.2°, 15.59±0.2°, 16. 41±0.2°, 16.59±0.2°, 17.29±0.2°, 18.20±0.2°, 18.64±0.2°, 19.75±0.2°, 20.22±0.2°, 20.74±0.2°, 21.95±0.2°, 23.11±0.2°, 24.84±0.2°, 25.27±0.2° and 25.56±0.2°, and / or the thermogravimetric analysis spectrum of the B-type crystals of the L-tartrate salt shows a weight loss of 5.57% when heated from the start to 180±5°C; and / or the thermogravimetric analysis spectrum of the C-type crystals of the L-tartrate salt shows a weight loss of 3.16% when heated from the start to 150±5°C; and / or the thermogravimetric analysis spectrum of the D-type crystals of the L-tartrate salt shows a weight loss of 2.72% when heated from the start to 150±5°C; and / or the thermogravimetric analysis spectrum of the A-type crystals of the glycolate salt shows a weight loss of 3.40% when heated from the start to 150±5°C; and / or the thermogravimetric analysis spectrum of the A-type crystal of the L-malate salt shows a weight loss of 2.88% when heated from the start to 50±5°C, a weight loss of 2.46% when heated from 50±5°C to 100±5°C, and a weight loss of 1.31% when heated from 100±5°C to 150±5°C; and / or the thermogravimetric analysis spectrum of the B-type crystals of the L-malate salt shows a weight loss of 3.40% when heated from the start to 150±5°C; and / or the thermogravimetric analysis spectrum of the A-type crystal of the hippuric acid salt shows a weight loss of 3.04% when heated from the start to 150±5°C; and / or the thermogravimetric analysis spectrum of the A-type crystal of the succinate salt shows a weight loss of 3.94% when heated from the start to 150±5°C; and / or the thermogravimetric analysis spectrum of the B-type crystals of the succinate salt shows a weight loss of 4.44% when heated from the start to 150±5°C; and / or the thermogravimetric analysis spectrum of the ascorbate type A crystals shows a weight loss of 4.36% when heated from the start to 150±5°C; and / or the thermogravimetric analysis spectrum of the ascorbate type B crystals shows a weight loss of 1.33% when heated from the start to 150±5°C; and / or the thermogravimetric analysis spectrum of the A-type crystal of the adipate salt shows a weight loss of 6.60% when heated from the start to 150±5°C; and / or, the thermogravimetric analysis spectrum of the A-type crystal of the p-toluenesulfonate salt shows a weight loss of 0.76% when heated from the start to 100±5°C, and a weight loss of 3.07% when heated from 100°C to 170°C; and / or, the thermogravimetric analysis spectrum of the A-type crystal of the benzenesulfonate salt shows a weight loss of 2.55% when heated from the start to 80±5°C, and a weight loss of 6.23% when heated from 80°C to 150°C; and / or the thermogravimetric analysis spectrum of the A-type crystal of the oxalate salt shows a weight loss of 5.88% when heated from the start to 100±5°C; and / or the type A crystal of 2-hydroxyethanesulfonate has diffraction peaks at 2θ angles of 6.46±0.2°, 9.89±0.2°, 10.95±0.2°, 13.14±0.2°, 13.60±0.2°, 15.69±0.2°, 18.38±0.2°, 18.81±0.2°, 20.44±0.2°, 21.70±0.2°, 23.25±0.2°, 24.04±0.2°, 24.82±0.2°, 26.03±0.2°, 26.35±0.2°, and 26.70±0.2° in a powder X-ray diffraction spectrum; And / or the thermogravimetric analysis spectrum of the A-type crystal of 2-hydroxyethanesulfonate is characterized by a weight loss of 1.61% when heated from the start to 150±5°C.

4. The A-type crystal of the compound of formula I has a powder X-ray diffraction pattern represented by 2θ angles, whose diffraction peaks and relative intensities are as shown in Table 8. 【Table 1】 and / or the B-type crystals of the compound of formula I have a powder X-ray diffraction pattern represented by 2θ angles, whose diffraction peaks and relative intensities are as shown in Table 10; 【Table 2】 and / or the type A crystal of the fumarate salt has a powder X-ray diffraction pattern expressed in terms of 2θ angles, the diffraction peaks and relative intensities of which are as shown in Table 11; 【Table 3】 and / or the type B crystals of the fumarate salt have a powder X-ray diffraction pattern expressed in terms of 2θ angles, the diffraction peaks and relative intensities of which are as shown in Table 12; 【Table 4】 and / or the C-type crystals of the fumarate salt have a powder X-ray diffraction pattern expressed in terms of 2θ angles, whose diffraction peaks and relative intensities are as shown in Table 13; 【Table 5】 and / or, the A-type crystals of the citrate salt have a powder X-ray diffraction pattern expressed in terms of 2θ angles, in which the diffraction peaks and relative intensities are as shown in Table 14; 【Table 6】 and / or, the B-type crystals of the citrate salt have a powder X-ray diffraction pattern expressed in terms of 2θ angles, in which the diffraction peaks and relative intensities are as shown in Table 15; 【Table 7】 and / or the type A crystal of the methanesulfonate salt has a powder X-ray diffraction pattern represented by 2θ angles, whose diffraction peaks and relative intensities are as shown in Table 16; 【Table 8】 and / or the type A crystals of the ethanesulfonate have a powder X-ray diffraction pattern represented by 2θ angles, whose diffraction peaks and relative intensities are as shown in Table 17; 【Table 9】 and / or the type B crystals of the ethanesulfonate salt have a powder X-ray diffraction pattern represented by 2θ angles, whose diffraction peaks and relative intensities are as shown in Table 18; 【Table 10】 and / or the A-type crystal of the maleate salt has a powder X-ray diffraction pattern expressed in terms of 2θ angles, the diffraction peaks and relative intensities of which are as shown in Table 19; 【Table 11】 and / or the B-type crystals of the maleate salt have a powder X-ray diffraction pattern expressed in terms of 2θ angles, in which the diffraction peaks and relative intensities are as shown in Table 20; 【Table 12】 and / or the type A crystal of the L-tartrate salt has a powder X-ray diffraction pattern expressed in 2θ angles, whose diffraction peaks and relative intensities are as shown in Table 21; 【Table 13】 and / or the B-type crystals of the L-tartrate salt have a powder X-ray diffraction pattern expressed in terms of 2θ angles, whose diffraction peaks and relative intensities are as shown in Table 22; 【Table 14】 and / or, the C-type crystals of the L-tartrate salt have a powder X-ray diffraction pattern expressed in terms of 2θ angles, whose diffraction peaks and relative intensities are as shown in Table 23; 【Table 15】 and / or, the D-type crystals of the L-tartrate salt have a powder X-ray diffraction pattern expressed in terms of 2θ angles, whose diffraction peaks and relative intensities are as shown in Table 24; Table 16 and / or the type A crystals of the glycolate have a powder X-ray diffraction pattern represented by 2θ angles, whose diffraction peaks and relative intensities are as shown in Table 25; Table 17 and / or the A-type crystals of the L-malate have a powder X-ray diffraction pattern expressed in terms of 2θ angles, whose diffraction peaks and relative intensities are as shown in Table 26; Table 18 and / or the B-type crystals of the L-malate have a powder X-ray diffraction pattern expressed in terms of 2θ angles, whose diffraction peaks and relative intensities are as shown in Table 27; 【Table 19】 and / or the A-type crystal of the hippurate salt has a powder X-ray diffraction pattern represented by 2θ angles, the diffraction peaks and relative intensities of which are as shown in Table 28; Table 20 and / or, the type A crystal of the succinate salt has a powder X-ray diffraction pattern represented by 2θ angles, in which the diffraction peaks and relative intensities are as shown in Table 29; Table 21 and / or, the B-type crystals of the succinate have a powder X-ray diffraction pattern expressed in terms of 2θ angles, whose diffraction peaks and relative intensities are as shown in Table 30; Table 22 and / or the type A crystal of the ascorbate has a powder X-ray diffraction pattern expressed in terms of 2θ angles, the diffraction peaks and relative intensities of which are as shown in Table 31; Table 23 and / or the type B crystals of the ascorbate have a powder X-ray diffraction pattern expressed in terms of 2θ angles, in which the diffraction peaks and relative intensities are as shown in Table 32; Table 24 and / or the A-type crystals of the adipate salt have a powder X-ray diffraction pattern expressed in terms of 2θ angles, in which the diffraction peaks and relative intensities are as shown in Table 33; Table 25 and / or the type A crystal of the p-toluenesulfonate has a powder X-ray diffraction pattern represented by 2θ angles, whose diffraction peaks and relative intensities are as shown in Table 34; Table 26 and / or the A-type crystal of the benzenesulfonate has a powder X-ray diffraction pattern represented by 2θ angles, whose diffraction peaks and relative intensities are as shown in Table 35; Table 27 and / or, the A-type crystal of the oxalate has a powder X-ray diffraction pattern represented by 2θ angles, whose diffraction peaks and relative intensities are as shown in Table 36; Table 28 And / or, the A-type crystal of the 2-hydroxyethanesulfonate has a powder X-ray diffraction pattern represented by 2θ angles in which the diffraction peaks and relative intensities are as shown in Table 37. The crystal according to claim 1, characterized in that it is Table 29

5. The A-type crystal of the compound of formula I has a powder X-ray diffraction pattern expressed in 2θ angles essentially as shown in FIG. and / or the DSC spectrum of the Form A crystal of the compound of formula I is essentially as shown in Figure 5; and / or the TGA spectrum of the Form A crystal of the compound of Formula I is essentially as shown in Figure 6; and / or the B-type crystal of the compound of formula I has a powder X-ray diffraction pattern expressed in 2θ angles essentially as shown in FIG. 10; and / or the A-type crystal of the fumarate salt of the compound of formula I has a powder X-ray diffraction pattern, expressed in 2θ angles, essentially as shown in FIG. 11; and / or the DSC spectrum of Form A crystals of the fumarate salt is essentially as shown in FIG. 12; and / or the TGA spectrum of the Form A crystals of the fumarate salt is essentially as shown in FIG. 13; and / or the B-type crystals of the fumarate salt of the compound of formula I have a powder X-ray diffraction pattern, expressed in 2θ angles, essentially as shown in FIG. 16; and / or the DSC spectrum of the Type B crystals of the fumarate salt is essentially as shown in FIG. 17; and / or the TGA spectrum of the Type B crystals of the fumarate salt is essentially as shown in FIG. 18; and / or the C-type crystal of the fumarate salt of the compound of formula I has a powder X-ray diffraction pattern, expressed in 2θ angles, essentially as shown in FIG. 19; and / or the DSC spectrum of Form C crystals of the fumarate salt is essentially as shown in Figure 20; and / or the TGA spectrum of Form C crystals of the fumarate salt is essentially as shown in Figure 21; and / or the A-type crystal of the citrate salt of the compound of formula I has a powder X-ray diffraction pattern, expressed in 2θ angles, essentially as shown in FIG. 22; and / or the DSC spectrum of the Form A crystals of the Citrate Salt is essentially as shown in FIG. 23; and / or the TGA spectrum of the Form A crystals of the Citrate Salt is essentially as shown in FIG. 24; and / or the B-type crystal of the citrate salt has a powder X-ray diffraction pattern expressed in 2θ angles essentially as shown in FIG. 25; and / or the DSC spectrum of Type B crystals of the Citrate Salt is essentially as shown in FIG. 27; and / or the TGA spectrum of the Type B crystals of the Citrate Salt is essentially as shown in FIG. 28; and / or the A-type crystal of the methanesulfonate salt has a powder X-ray diffraction pattern, expressed in 2θ angles, essentially as shown in FIG. 30; and / or the DSC spectrum of the Type A crystals of the methanesulfonate salt is essentially as shown in FIG. 31 ; and / or the TGA spectrum of the Type A crystals of the methanesulfonate salt is essentially as shown in FIG. 32 ; and / or the A-type crystals of the ethanesulfonate salt of the compound of formula I have a powder X-ray diffraction pattern, expressed in 2θ angles, essentially as shown in Figure 35; and / or the DSC spectrum of Form A crystals of the ethanesulfonate salt of the compound of Formula I is essentially as shown in Figure 37; and / or the TGA spectrum of crystalline Form A of the ethanesulfonate salt of the compound of Formula I is essentially as shown in Figure 38; and / or the B-type crystals of the ethanesulfonate have a powder X-ray diffraction pattern, expressed in 2θ angles, essentially as shown in FIG. 40; and / or the DSC spectrum of the B-type crystals of the ethanesulfonate salt is essentially as shown in FIG. 41 ; and / or the TGA spectrum of the B-type crystals of the ethanesulfonate salt is essentially as shown in FIG. 42 ; and / or the A-type crystal of the maleate salt has a powder X-ray diffraction pattern expressed in 2θ angles essentially as shown in FIG. 43; and / or the DSC spectrum of the A-type crystals of the maleate salt is essentially as shown in Figure 44; and / or the TGA spectrum of the A-type crystals of the maleate salt is essentially as shown in Figure 45; and / or the B-type crystal of the maleate salt has a powder X-ray diffraction pattern expressed in 2θ angles essentially as shown in FIG. 46; and / or the DSC spectrum of the B-type crystals of the maleate salt is essentially as shown in Figure 47; and / or the TGA spectrum of the B-type crystals of the maleate salt is essentially as shown in Figure 48; and / or the A-type crystal of the L-tartrate salt has a powder X-ray diffraction pattern expressed in 2θ angles essentially as shown in FIG. 49; and / or the DSC spectrum of the Form A crystals of the L-tartrate salt is essentially as shown in Figure 50; and / or the TGA spectrum of the Form A crystals of the L-tartrate salt is essentially as shown in FIG. 51; and / or the B-type crystals of the L-tartrate salt have a powder X-ray diffraction pattern expressed in 2θ angles essentially as shown in FIG. 52; and / or the DSC spectrum of the B-type crystals of the L-tartrate salt is essentially as shown in FIG. 53; and / or the TGA spectrum of the B-type crystals of the L-tartrate salt is essentially as shown in FIG. 54; and / or the C-type crystal of the L-tartrate salt has a powder X-ray diffraction pattern expressed in 2θ angles essentially as shown in FIG. 55; and / or the DSC of the C-type crystals of the L-tartrate salt is essentially as shown in FIG. 56; and / or the TGA of the Form C crystals of the L-tartrate salt is essentially as shown in Figure 57; and / or the D-type crystal of the L-tartrate salt has a powder X-ray diffraction pattern expressed in 2θ angles essentially as shown in FIG. 58; and / or the DSC spectrum of the D-type crystals of the L-tartrate salt is essentially as shown in FIG. 59; and / or the TGA spectrum of the D-type crystals of the L-tartrate salt is essentially as shown in Figure 60; and / or the A-type crystal of the glycolate salt has a powder X-ray diffraction pattern expressed in 2θ angles essentially as shown in FIG. 61; and / or the DSC spectrum of the Type A crystals of the glycolate salt is essentially as shown in Figure 62; and / or the TGA diagram of the Type A crystals of the glycolate salt is essentially as shown in Figure 63; and / or the A-type crystal of the L-malate has a powder X-ray diffraction pattern, expressed in 2θ angles, essentially as shown in FIG. 64; and / or the DSC spectrum of the A-type crystals of the L-malate salt is essentially as shown in Figure 65; and / or the TGA spectrum of the A-type crystals of the L-malate salt is essentially as shown in Figure 66; and / or the B-type crystal of the L-malate has a powder X-ray diffraction pattern expressed in 2θ angles essentially as shown in FIG. 67; and / or the DSC spectrum of the B-type crystals of the L-malate salt is essentially as shown in Figure 68; and / or the TGA spectrum of the B-type crystals of the L-malate salt is essentially as shown in Figure 69; and / or the A-type crystal of the hippurate salt has a powder X-ray diffraction pattern expressed in 2θ angles essentially as shown in FIG. 70; and / or the DSC spectrum of the hippurate salt type A crystals is essentially as shown in Figure 71; and / or the TGA spectrum of the hippurate salt type A crystals is essentially as shown in Figure 72; and / or the A-type crystal of the succinate has a powder X-ray diffraction pattern expressed in 2θ angles essentially as shown in FIG. 128; and / or the DSC spectrum of the A-type crystal of the succinate salt is essentially as shown in Figure 73; and / or the TGA spectrum of the A-type crystal of the succinate salt is essentially as shown in Figure 74; and / or the B-type crystal of the succinate has a powder X-ray diffraction pattern expressed in 2θ angles essentially as shown in FIG. 75; and / or the DSC spectrum of the B-type crystals of the succinate salt is essentially as shown in Figure 76; and / or the TGA spectrum of the B-type crystals of the succinate salt is essentially as shown in Figure 77; and / or the type A crystal of the ascorbate has a powder X-ray diffraction pattern expressed in 2θ angles essentially as shown in Figure 129; and / or the DSC spectrum of the Form A crystals of the ascorbate salt is essentially as shown in Figure 78; and / or the TGA spectrum of the Form A crystals of the ascorbate salt is essentially as shown in Figure 79; and / or the ascorbate B-type crystals have a powder X-ray diffraction pattern expressed in 2θ angles essentially as shown in Figure 80; and / or the DSC spectrum of the Type B crystals of the ascorbate salt is essentially as shown in Figure 81; and / or the TGA spectrum of the Type B crystals of the ascorbate salt is essentially as shown in Figure 82; and / or the A-type crystal of the adipate salt has a powder X-ray diffraction pattern expressed in 2θ angles essentially as shown in Figure 130; and / or the DSC spectrum of the A-type crystals of the adipate salt is essentially as shown in Figure 83; and / or the TGA spectrum of the A-type crystals of the adipate salt is essentially as shown in Figure 84; and / or the A-type crystal of the p-toluenesulfonate has a powder X-ray diffraction pattern, expressed in 2θ angles, essentially as shown in FIG. 85; and / or the DSC spectrum of the A-type crystals of the p-toluenesulfonate salt is essentially as shown in FIG. 86; and / or the TGA spectrum of the A-type crystals of the p-toluenesulfonate salt is essentially as shown in FIG. 87; and / or the A-type crystal of the benzenesulfonate has a powder X-ray diffraction pattern expressed in 2θ angles essentially as shown in FIG. 131; and / or the DSC spectrum of the A-type crystals of the benzenesulfonate salt is essentially as shown in Figure 88; and / or the TGA spectrum of the A-type crystal of the benzenesulfonate salt is essentially as shown in Figure 89; and / or the A-type crystal of the oxalate has a powder X-ray diffraction pattern expressed in 2θ angles essentially as shown in FIG. 90; and / or the DSC spectrum of Form A crystals of the oxalate salt is essentially as shown in Figure 91; and / or the TGA spectrum of the Form A crystals of the Oxalate Salt is essentially as shown in Figure 92; and / or the A-type crystal of the 2-hydroxyethanesulfonate has a powder X-ray diffraction pattern, expressed in 2θ angles, essentially as shown in FIG. 93; and / or the DSC spectrum of the Type A crystals of the 2-hydroxyethanesulfonate salt is essentially as shown in Figure 94; And / or the crystal according to any one of claims 1 to 4, characterized in that the TGA spectrum of the A-type crystal of the 2-hydroxyethanesulfonate salt is essentially as shown in Figure 95.

6. A pharmaceutically acceptable salt of a compound of formula I, characterized in that it is a salt formed by a compound of formula I with an acid, wherein the acid is hydrochloric acid, sulfuric acid, maleic acid, aspartic acid, phosphoric acid, fumaric acid, tartaric acid, citric acid, glucuronic acid, glycolic acid, malic acid, hippuric acid, gluconic acid, lactic acid, succinic acid, ascorbic acid, adipic acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, oxalic acid, 2-hydroxyethanesulfonic acid, ethanesulfonic acid, gentisic acid, or benzoic acid. 【Chemistry 2】

7. the acid is fumaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, maleic acid, L-tartaric acid, glycolic acid, L-malic acid, hippuric acid, succinic acid, ascorbic acid, adipic acid, p-toluenesulfonic acid, benzenesulfonic acid, oxalic acid, or 2-hydroxyethanesulfonic acid; and / or the molar ratio of the compound of formula I to the acid is 1:(0.5-1.2), such as 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1 or 1:1.

2.

8. Pharmaceutically acceptable salts of the compounds of formula I include (1) a fumarate salt of the compound of formula I, wherein the molar ratio of the compound of formula I to fumaric acid is 1:1; (2) a citrate salt of the compound of formula I, wherein the molar ratio of the compound of formula I to citric acid is 1:(1-1.2), for example, 1:1, 1:1.1, or 1:1.2; (3) a methanesulfonate salt of the compound of formula I, wherein the molar ratio of the compound of formula I to methanesulfonic acid is 1:(0.8-1), for example, 1:1, 1:0.9, or 1:0.8; (4) an ethanesulfonic acid salt of the compound of formula I, wherein the molar ratio of the compound of formula I to ethanesulfonic acid is 1:1; (5) a maleate salt of the compound of formula I, wherein the molar ratio of the compound of formula I to maleic acid is 1:1; (6) L-tartrate salt of the compound of formula I, wherein the molar ratio of the compound of formula I to L-tartaric acid is 1:(0.5-1.1), for example, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, or 1:1.1; (7) A glycolic acid salt of the compound of formula I, wherein the molar ratio of the compound of formula I to glycolic acid is (1 to 1.1), for example, 1:1 or 1:1.1; (8) L-malate salt of the compound of formula I, wherein the molar ratio of the compound of formula I to L-malic acid is 1:(1-1.1), for example, 1:1 or 1:1.1; (9) The hippurate salt of the compound of formula I, wherein the molar ratio of the compound of formula I to hippuric acid is 1:1; (10) A succinate salt of the compound of formula I, wherein the molar ratio of the compound of formula I to succinic acid is 1:(0.8-1.2), for example, 1:0.8, 1:0.9, 1:1, or 1:1.2; (11) Ascorbate salts of compounds of formula I, wherein the compounds of formula I and ascorbic acid the molar ratio of the carboxylic acid to the carboxylic acid is 1:(0.5 to 1.2), for example, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, or 1:1.2; (12) Adipic acid salt of the compound of formula I, wherein the molar ratio of the compound of formula I to adipic acid is 1:1; (13) p-toluenesulfonic acid salt of the compound of formula I, wherein the molar ratio of the compound of formula I to p-toluenesulfonic acid is 1:1; (14) benzenesulfonic acid salt of the compound of formula I, wherein the molar ratio of the compound of formula I to benzenesulfonic acid is 1:1; (15) The oxalate salt of the compound of formula I, wherein the molar ratio of the compound of formula I to oxalic acid is 1:1; (16) 2-hydroxyethanesulfonic acid salt of the compound of formula I, wherein the molar ratio of the compound of formula I to 2-hydroxyethanesulfonic acid is 1:(1-1.1), for example, 1:1 or 1:1.

1.

8. A pharmaceutically acceptable salt of a compound of formula I according to claim 7, characterized in that it is a pharmaceutically acceptable salt of any one of:

9. 9. A method for preparing a pharmaceutically acceptable salt of a compound of formula I according to any one of claims 6 to 8, characterized in that it comprises a step of reacting a compound of formula I with an acid in a solvent to form a salt to obtain a pharmaceutically acceptable salt of the compound of formula I, wherein the acid is hydrochloric acid, sulfuric acid, maleic acid, aspartic acid, phosphoric acid, fumaric acid, tartaric acid, citric acid, glucuronic acid, glycolic acid, malic acid, hippuric acid, gluconic acid, lactic acid, succinic acid, ascorbic acid, adipic acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, oxalic acid, 2-hydroxyethanesulfonic acid, ethanesulfonic acid, gentisic acid or benzoic acid; 【Chemistry 3】 Preferably, the manufacturing method comprises: (1) The solvent is one or more of water, ethyl acetate, methyl tert-butyl ether, acetone, n-heptane, and isopropanol, preferably one or more of water, ethyl acetate, methyl tert-butyl ether, acetone, and n-heptane; (2) the molar ratio of the compound of formula I to the acid is 1:(1±0.5), preferably 1:(1±0.2), 1:(1±0.1), for example, 1:1; (3) The acid is fumaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, maleic acid, L-tartaric acid, glycolic acid, L-malic acid, hippuric acid, succinic acid, ascorbic acid, adipic acid, p-toluenesulfonic acid, benzenesulfonic acid, oxalic acid, or 2-hydroxyethanesulfonic acid. and satisfy one or more of the following conditions: Preferably, when the crystals are type A crystals of the compound of formula I, the production method thereof comprises the steps of crystallizing the compound of formula I in a solvent M and separating the solid, wherein the solvent M is an alkane solvent, and the alkane solvent is preferably n-hexane, and the crystallization temperature is room temperature, preferably 40 to 60°C, for example 50°C; The crystals are type A crystals of the fumarate salt of the compound of formula I, type B crystals of the fumarate salt of the compound of formula I, type C crystals of the fumarate salt of the compound of formula I, type A crystals of the citrate salt of the compound of formula I, Form B crystals of the citrate salt of the compound of formula I, Form A crystals of the methanesulfonate salt of the compound of formula I, Form A crystals of the ethanesulfonate salt of the compound of formula I, Form B crystals of the ethanesulfonate salt of the compound of formula I, Form A crystals of the maleate salt of the compound of formula I, Form B crystals of the maleate salt of the compound of formula I, Form A crystals of the L-tartrate salt of the compound of formula I, Form B crystals of the L-tartrate salt of the compound of formula I, Form C crystals of the L-tartrate salt of the compound of formula I, Form D crystals of the L-tartrate salt of the compound of formula I, Form A crystals of the glycolate salt of the compound of formula I, Form A crystals of the L-malate salt of the compound of formula I, Form B crystals of the L-malate salt of the compound of formula I, In the case of Type A crystals of a hippurate salt of a compound of Formula I, Type A crystals of a succinate salt of a compound of Formula I, Type B crystals of a succinate salt of a compound of Formula I, Type A crystals of an ascorbate salt of a compound of Formula I, Type B crystals of an ascorbate salt of a compound of Formula I, Type A crystals of an adipate salt of a compound of Formula I, Type A crystals of a p-toluenesulfonate salt of a compound of Formula I, Type A crystals of a benzenesulfonate salt of a compound of Formula I, and Type A crystals of an oxalate salt of a compound of Formula I or Type A crystals of a 2-hydroxyethanesulfonate salt of a compound of Formula I, the preparation method thereof comprises the steps of reacting a compound of Formula I with an acid in a solvent N and separating the solid; The solvent N is one or more of an alcohol solvent, an alkane solvent, an ester solvent, and water, and the solvent N is preferably a mixture of isopropanol and water, n-hexane, or ethyl acetate, and more preferably, the volume ratio of isopropanol to water is 19:1±5. The reaction temperature is room temperature, preferably 10 to 30° C.; The acid is fumaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, maleic acid, L-tartaric acid, glycolic acid, L-malic acid, hippuric acid, succinic acid, ascorbic acid, adipic acid, p-toluenesulfonic acid, benzenesulfonic acid, 2-hydroxyethanesulfonic acid, oxalic acid, or 2-hydroxyethanesulfonic acid.

10. The substance A comprises a substance A and a pharmaceutically acceptable carrier, wherein the substance A is selected from the group consisting of type A crystals of the compound of formula I according to any one of claims 1 to 5, type B crystals of the compound of formula I, type A crystals of a fumarate salt of the compound of formula I, type B crystals of a fumarate salt of the compound of formula I, type A crystals of a citrate salt of the compound of formula I, type B crystals of a citrate salt of the compound of formula I, type A crystals of a methanesulfonate salt of the compound of formula I, type A crystals of an ethanesulfonate salt of the compound of formula I, type B crystals of an ethanesulfonate salt of the compound of formula I, type A crystals of a maleate salt of the compound of formula I, type B crystals of a maleate salt of the compound of formula I, type A crystals of an L-tartrate salt of the compound of formula I, type B crystals of an L-tartrate salt of the compound of formula I, type C crystals of an L-tartrate salt of the compound of formula I, and type D crystals of an L-tartrate salt of the compound of formula I.

10. Pharmaceutical composition I, characterized in that it is one or more of the following crystals: Type A crystals of the glycolate salt of the compound of formula I; Type A crystals of the L-malate salt of the compound of formula I; Type B crystals of the L-malate salt of the compound of formula I; Type A crystals of the hippurate salt of the compound of formula I; Type A crystals of the succinate salt of the compound of formula I; Type B crystals of the succinate salt of the compound of formula I; Type A crystals of the ascorbate salt of the compound of formula I; Type A crystals of the adipate salt of the compound of formula I; Type A crystals of the p-toluenesulfonate salt of the compound of formula I; Type A crystals of the benzenesulfonate salt of the compound of formula I; Type A crystals of the oxalate salt of the compound of formula I; Type A crystals of the 2-hydroxyethanesulfonate salt of the compound of formula I; and a pharmaceutically acceptable salt of the compound of formula I according to any one of claims 6 to 8.

11. comprising substance A and at least one other pharmacologically active inhibitor, The substance A is as defined in claim 10, Preferably, said other pharmacologically active inhibitor is a MEK inhibitor, an EGFR inhibitor or a KRAS inhibitor; Preferably, the MEK inhibitor is trametinib; Preferably, the EGFR inhibitor is osimertinib or gefitinib, preferably osimertinib; More preferably, the KRAS inhibitor is MRTX-849, AMG-510 or JDQ443.

12. (1) Use in the manufacture of a medicament for inhibiting the interaction between SOS1 and a RAS family protein; (2) Manufacturing of a medicine for preventing and / or treating a disease associated with or mediated by SOS1 and RAS family proteins 12. Use of substance A according to claim 10, pharmaceutical composition I according to claim 10 or pharmaceutical composition II according to claim 11, characterized in that it is selected from:

13. (1) The diseases associated with or mediated by SOS1 and RAS family proteins include, but are not limited to, cancer and RAS diseases. The RAS disease is preferably Noonan syndrome, CFC syndrome, hereditary gingival fibromatosis type 1, neurofibromatosis type 1 (NF1), capillary malformation-arteriovenous malformation syndrome, Costello syndrome, or Regius syndrome, and more preferably neurofibromatosis type 1; The cancer is preferably a condition selected from melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, gastric cancer, esophageal cancer, colorectal cancer, gallbladder cancer, bile duct cancer, chorioepithelioma, pancreatic cancer, polycythemia vera, childhood cancer, cervical cancer, ovarian cancer, breast cancer, bladder cancer, urothelial cancer, ureteral cancer, prostate cancer, seminoma, testicular tumor, leukemia, head and neck tumor, endometrial cancer, thyroid cancer, lymphoma, sarcoma, osteoma, neuroblastoma, brain tumor, myeloma, astrocytoma, glioblastoma and glioma; (2) The medicine contains the substance A and trametinib or osimertinib; (3) The RAS family protein may be KRAS, for example, KRAS Conditions where KRAS G12C, KRAS G12D and KRAS G12V 13. The use according to claim 12, characterized in that one or more of the following is satisfied:

14. 14. The use according to claim 13, characterized in that the cancer is selected from colorectal cancer, lung cancer and pancreatic cancer, the lung cancer being preferably non-small cell lung cancer.

15. (1) The use includes the combined use of substance A and a MEK inhibitor; (2) The use includes the combined use of substance A and an EGFR inhibitor; (3) The use includes the combined use of substance A and a KRAS inhibitor; and satisfy one or more of the following conditions:

13. Use according to claim 12, characterized in that said use preferably comprises the combination of substance A with trametinib or osimertinib.

16. (1) Use of inhibiting the interaction between SOS1 and RAS family proteins; (2) Use for preventing and / or treating diseases associated with SOS1 and RAS family proteins characterized in that it is selected from Use of substance A according to claim 10, pharmaceutical composition I according to claim 10 or pharmaceutical composition II according to claim 11.

17. 1. A method for inhibiting SOS1 and RAS family proteins or preventing and / or treating a disease associated with or mediated by SOS1 and RAS family proteins, comprising administering to a subject in need thereof a therapeutically effective amount of substance A, The substance A is as defined in claim 10, Preferably, the method comprises combining substance A with a MEK inhibitor, an EGFR inhibitor or a KRAS inhibitor; More preferably, the method comprises combining substance A with trametinib or osimertinib.

18. A method for detecting the quality of substance B, comprising the step of eluting a test substance through a silica gel chromatography column using high performance liquid chromatography, The test substance includes substance B, and substance B is selected from the group consisting of a compound of formula I, a crystalline form A of the compound of formula I according to any one of claims 1 to 5, a crystalline form B of the compound of formula I, a crystalline form A of a fumarate salt of the compound of formula I, a crystalline form B of a fumarate salt of the compound of formula I, a crystalline form A of a citrate salt of the compound of formula I, a crystalline form B of a citrate salt of the compound of formula I, a crystalline form A of a methanesulfonate salt of the compound of formula I, a crystalline form A of an ethanesulfonate salt of the compound of formula I, a crystalline form B of an ethanesulfonate salt of the compound of formula I, a crystalline form A of a maleate salt of the compound of formula I, a crystalline form B of a maleate salt of the compound of formula I, a crystalline form A of an L-tartrate salt of the compound of formula I, a crystalline form B of an L-tartrate salt of the compound of formula I, a crystalline form C of an L-tartrate salt of the compound of formula I, a Form D crystalline form of the L-tartrate salt of the compound of formula I, Form A crystalline form of the glycolate salt of the compound of formula I, Form A crystalline form of the L-malate salt of the compound of formula I, Form B crystalline form of the L-malate salt of the compound of formula I, Form A crystalline form of the hippurate salt of the compound of formula I, Form A crystalline form of the succinate salt of the compound of formula I, Form B crystalline form of the succinate salt of the compound of formula I, Form A crystalline form of the ascorbate salt of the compound of formula I, Form B crystalline form of the ascorbate salt of the compound of formula I, Form A crystalline form of the adipate salt of the compound of formula I, Form A crystalline form of the p-toluenesulfonate salt of the compound of formula I, Form A crystalline form of the benzenesulfonate salt of the compound of formula I, Form A crystalline form of the oxalate salt of the compound of formula I, Form A crystalline form of the 2-hydroxyethanesulfonate salt of the compound of formula I and a pharmaceutically acceptable salt of the compound of formula I according to claim 6 or 7, The mobile phases used for the elution are mobile phase A and mobile phase B, The mobile phase A is an aqueous solution of 0.1±0.05% ammonia water, said mobile phase B is acetonitrile; In the elution program, the volume ratio of the mobile phase A to the mobile phase B is 1:1.5 to 9; Preferably, the elution program used for said elution is: 【Table 30】 and Preferably, the quality detection refers to purity testing, dynamic solubility and stability testing; Preferably, the detection method comprises: (1) The injection volume of the elution is 5±1 μL; (2) The elution flow rate is 1.0±0.2 mL / min; (3) The wavelength of the UV detector for the elution is 228±5 nm; (4) The model of the chromatography column is Waters XBridge C18, 4.6 mm / 150 mm / 3 μm; (5) The column temperature of the chromatography column is room temperature, preferably 30°C; (6) The diluent for the test substance is ACN / H ２ O (1:1±0.5) A method for detecting the quality of substance B, which satisfies one or more of the following conditions.

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