Salt of class of nitrogen-containing heterocyclic derivatives and crystal form thereof, preparation method therefor, and use thereof

Abstract

Provide are an acid salt of a class of nitrogen-containing heterocyclic derivatives and a crystal form thereof, a preparation method therefor, and a use thereof. Specifically, provided are an acid salt of a compound represented by general formula (I) and a crystal form thereof, a preparation method therefor, and a pharmaceutical composition containing a therapeutically effective amount of the crystal form, as well as a use thereof as an inhibitor in the treatment of cardiovascular diseases, cerebrovascular diseases, and other diseases.

Description

Salts of a class of nitrogen-containing heterocyclic derivatives, their crystal forms, preparation methods, and applications

[0001] This application claims priority to Chinese Patent Application No. 2025100175466, filed on January 3, 2025, and Chinese Patent Application No. 2025114629638, filed on October 13, 2025. The full text of the aforementioned Chinese patent applications is incorporated herein by reference. Technical Field

[0002] This invention belongs to the field of drug synthesis, specifically relating to salts of a class of nitrogen-containing heterocyclic derivative inhibitors, their crystal forms, preparation methods, and applications. Background Technology

[0003] Cardiovascular disease (CVD) is a leading cause of death worldwide, and high levels of low-density lipoprotein cholesterol (LDL-C) are a major risk factor. The accumulation of LDL-C on the arterial walls leads to atherosclerosis and can trigger inflammatory responses, resulting in cardiovascular events such as heart attacks and strokes. Although statins can lower serum LDL-C and are currently the main lipid-lowering drugs in clinical practice, patients who are intolerant to statins or who fail to reach their treatment goals when receiving tolerated doses still face risks, such as patients with familial hypercholesterolemia. The discovery of PCSK9 inhibitors provides a more aggressive treatment option for homozygous and heterozygous familial hypercholesterolemia. The non-statin ezetimibe, when used in combination with statins, can lower LDL-C by 15%-20%, while PCSK9 inhibitors combined with statins can significantly lower LDL-C by 54%-74%. PCSK9 inhibitors can also overcome the intolerable side effects of statins, such as muscle pain.

[0004] PCSK9 (Proprotein convertase subtilisin kexin type 9) is a serine protease highly expressed in the liver. Loss-of-function mutations in the PCSK9 gene are associated with low LDL-C levels and reduced cardiovascular risk (Cohen, JC, 2006), and it has been clinically validated as a therapeutic target for hyperlipidemia. PCSK9 is synthesized as an enzyme precursor, and after synthesis, it undergoes autocatalytic cleavage within the cell. The propeptide binds to mature PCSK9 and is secreted extracellularly, thus blocking the catalytic activity of PCSK9.

[0005] PCSK9 is a major regulator of low-density lipoprotein receptor (LDLR) levels on the surface of hepatocytes and can inhibit the LDLR circulation pathway. LDLR function is crucial for maintaining cholesterol homeostasis, responsible for the uptake and degradation of low-density lipoprotein. Circulating LDL binds to the N-terminal ligand-binding domain of LDLR via apolipoprotein B100. The LDL / LDLR complex is internalized through receptor-mediated endocytosis. The low intracellular pH environment causes LDLR to release LDL, which then circulates back to the cell membrane. Intracellular free LDL is transported to lysosomes and degraded. Secreted PCSK9 interferes with LDLR circulation by binding to LDLR on the hepatocyte surface. After the PCSK9 / LDLR complex migrates through clathrin-encapsulated pits into the acidic endosomal chamber, a conformational change in LDLR leads to the formation of additional binding sites with PCSK9. Therefore, PCSK9 accompanies LDLR to lysosomes for degradation, preventing LDLR circulation and thus upregulating LDL-C levels.

[0006] Familial hypercholesterolemia (FH) is a hereditary disorder of low-density lipoprotein cholesterol metabolism, affecting approximately 1 in 250 people, characterized by significantly elevated LDL-c levels. Heterozygous FH patients have a 3-4 times higher risk of developing coronary artery disease (CAD) and often develop CAD an average of 10 years earlier than the general population. Statins lower LDL-C in heterozygous FH patients; studies by Besselin have shown that high-intensity statin therapy can reduce the risk of CAD and mortality by 44%. However, in many cases, the reduction in LDL-C is considered insufficient. The complementarity mechanism of statins involves upregulating sterol regulatory element-binding protein 2 (SREBP-2), thereby activating LDL receptors and PCSK9, increasing PCSK9 expression and secretion to bind LDLR, leading to elevated LDL-C levels in the blood. Therefore, while statins lower LDL by inhibiting HMGCoA, they counteract the effects of SREBP; adding a PCSK9 inhibitor to statin therapy can help overcome this mechanism. Considering that patients with familial hypercholesterolemia may not fully benefit from statin therapy, alternative treatments such as PCSK9 inhibitors are needed.

[0007] PCSK9 macromolecule inhibitors, such as the monoclonal antibody-based drugs Alirocumab and Evolocumab, selectively bind to extracellular PCSK9 and prevent its interaction with LDLR. They have been approved by the FDA for lowering LDL-C levels with a good safety profile. Studies have shown that in heterozygous FH patients who have not reached their LDL-C target after statin monotherapy, once-every-two-week injections of Alirocumab maximally reduce cardiovascular risk. Alirocumab has also shown a moderate increase in "good" cholesterol (HDL-C). Additionally, a PCSK9 siRNA drug, Inclisiran, is currently marketed. It lowers PCSK9 protein expression levels for long-term lipid reduction with a good safety profile. However, both of these drugs require injection and are expensive to produce. Currently, there are no marketed PCSK9 small molecule inhibitors, therefore there is a high demand for oral PCSK9 small molecule inhibitors.

[0008] There are already patent reports on PCSK9 small molecule inhibitors, such as WO2014170786 (Pfizer), WO2014150326 (Shifa), WO2020150473 (AZ), and WO2022133529 (Nyrada). Currently, AZD-0780 is the most advanced in Phase I clinical trials, while the others are in preclinical development. Several peptides have also been reported, with the most advanced being in Phase II clinical trials. This invention aims to develop an orally administered PCSK9 small molecule inhibitor.

[0009] PCT / CN2024 / 103568 discloses the structures of a series of nitrogen-containing heterocyclic compounds. In subsequent research and development, in order to facilitate the handling, filtration and drying of the products, and to seek suitable crystals that are easy to store and have long-term product stability, this invention has conducted a comprehensive study on the crystal forms of the above-mentioned compounds. Summary of the Invention

[0010] All contents relating to patent PCT / CN2024 / 103568 are incorporated herein by reference.

[0011] The object of this invention is to provide an acid salt of a compound of general formula (I) or its stereoisomers.

[0012] in:

[0013] Ring A is selected from 5-membered nitrogen-containing heterocyclic group, 6-membered nitrogen-containing heterocyclic group, 5-membered nitrogen-containing heteroaryl group, 6-membered nitrogen-containing heteroaryl group, 5-membered 6-membered bicyclic nitrogen-containing heterocyclic group, 6-membered 5-membered bicyclic nitrogen-containing heterocyclic group, 5-membered 6-membered bicyclic nitrogen-containing heteroaryl group, 6-membered 5-membered bicyclic nitrogen-containing heteroaryl group or 6-membered 6-membered bicyclic nitrogen-containing heteroaryl group;

[0014] R a Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or C 1-6 Hydroxyalkyl;

[0015] R b Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or C 1-6 hydroxyalkyl; and

[0016] x is 0, 1, 2, 3 or 4.

[0017] The acid in the acid salt is selected from inorganic or organic acids, wherein the inorganic acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, or phosphoric acid; and the organic acid is selected from 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphtholic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetoxyxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetaminobenzoic acid, 4-aminobenzoic acid, decanoic acid, hexanoic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfonic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, and pyroglutamic acid. Tartaric acid, dodecyl sulfuric acid, dibenzoyl tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactobionic acid, gentian acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, hydroxyethyl sulfonic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, dihydroxynaphthalic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanate, undecanoic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, or L-malic acid;

[0018] Preferably, the acid is selected from hydrochloric acid, methanesulfonate, p-toluenesulfonate, benzenesulfonate, or hydrobromic acid.

[0019] In a further technical solution of the present invention, ring A is selected from...

[0020] And / or,

[0021] Ra Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy or C 1-3 Hydroxyalkyl;

[0022] Preferably, R a Selected from -H, -F, -OCHF2, -OCF3, -CHF2, -CF3, -CH2CHF2, -OCH3, -CH3, or -CH2CF3;

[0023] And / or,

[0024] R b Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy or C 1-3 Hydroxyalkyl;

[0025] Preferably, R b Selected from -H, -D, -F, -Cl, -CN, -CH3, -CF3, -CH(CH3)2, -C(CH3)3, -C(CH3)2OH, -C(CH3)2CH2OH, -OCH3, -CH2NH2, -CH2OH or -OH.

[0026] The acid salts or crystal forms of the compounds or stereoisomers shown in this invention contain 0.2-3 acids; the number of acids in the acid salts is 0.2-3; preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3; more preferably 0.5, 1, 2 or 3, and even more preferably 1.

[0027] The acid salts or crystal forms of the compounds or their stereoisomers shown in this invention are hydrates or anhydrous salts; when the acid salt is a hydrate, the number of water molecules is 0.2-3; preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3.

[0028] The crystal form is a solvate, hydrate, or anhydrous; when the crystal form is a hydrate, the number of water molecules is 0.2-3; preferably 0.2, 0.5, 1, 1.5, 2, 2.5, or 3.

[0029] The purpose of this invention is to provide a crystal form that is an acid salt of the aforementioned compound or its stereoisomer.

[0030] A further technical solution of the present invention is the crystal form of compound 1, which is 5'-fluoro-6'-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one salt, specifically, the hydrochloride crystal form A, whose X-ray powder diffraction pattern has a diffraction peak at 2θ of 22.1±0.2°; or at 23.6±0.2°; or at 17.3±0.2°; or at 24.0±0.2°; or The diffraction peak is present at 26.0±0.2°; or at 14.0±0.2°; or at 24.9±0.2°; or at 32.2±0.2°; or at 17.9±0.2°; or at 12.4±0.2°; preferably, any 2-3, 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 diffraction peaks are included; more preferably, any 2, 3, 4, 5, 6, 7, 8, 9, or 10 of the above diffraction peaks are included.

[0031] Methanesulfonate crystal form A has an X-ray powder diffraction pattern showing a diffraction peak at 2θ = 24.1 ± 0.2°; or at 11.6 ± 0.2°; or at 6.4 ± 0.2°; or at 22.7 ± 0.2°; or at 24.4 ± 0.2°; or at 21.0 ± 0.2°; or at 27.3 ± 0.2°; or The diffraction peak is present at 19.0±0.2°; or at 15.7±0.2°; or at 26.0±0.2°; preferably, any 2-3, 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 diffraction peaks are included; more preferably, any 2, 3, 4, 5, 6, 7, 8, 9, or 10 of the above diffraction peaks are included.

[0032] Benzenesulfonate crystal form A has an X-ray powder diffraction pattern showing a diffraction peak at 2θ of 22.1 ± 0.2°; or at 23.7 ± 0.2°; or at 20.0 ± 0.2°; or at 12.3 ± 0.2°; or at 17.8 ± 0.2°; or at 24.1 ± 0.2°; or at 20.2 ± 0.2°. Alternatively, it may have a diffraction peak at 9.2±0.2°; or a diffraction peak at 28.4±0.2°; or a diffraction peak at 19.0±0.2°; preferably, it may include any 2-3, 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 of the above diffraction peaks, more preferably, it may include any 2, 3, 4, 5, 6, 7, 8, 9, or 10 of the above diffraction peaks;

[0033] Hydrobromide crystal form A has an X-ray powder diffraction pattern showing a diffraction peak at 2θ of 9.1 ± 0.2°; or at 20.0 ± 0.2°; or at 23.5 ± 0.2°; or at 23.9 ± 0.2°; or at 25.9 ± 0.2°; or at 17.3 ± 0.2°; or at 27.4 ± 0.2°. Alternatively, it may have a diffraction peak at 24.8±0.2°; or a diffraction peak at 9.4±0.2°; or a diffraction peak at 28.1±0.2°; preferably, it may include any 2-3, 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 of the above diffraction peaks, more preferably, it may include any 2, 3, 4, 5, 6, 7, 8, 9, or 10 of the above diffraction peaks.

[0034] The present invention further illustrates a crystal form in which the X-ray powder diffraction pattern of the hydrochloride crystal form A includes at least one or more diffraction peaks located at 2θ of 22.1±0.2°, 23.6±0.2°, and 17.3±0.2°, preferably two, more preferably three; optionally, it may further include at least one peak located at 2θ of 24.0±0.2°, 26.0±0.2°, 14.0±0.2°, 24.9±0.2°, and 32.2±0.2°, preferably two, three, four, or five.

[0035] The X-ray powder diffraction pattern of methanesulfonate crystal form A contains at least one or more diffraction peaks located at 2θ of 24.1±0.2°, 11.6±0.2°, and 6.4±0.2°, preferably two, more preferably three; optionally, it may further contain at least one of the following: 22.7±0.2°, 24.4±0.2°, 21.0±0.2°, 27.3±0.2°, and 19.0±0.2°, preferably two, three, four, or five.

[0036] The X-ray powder diffraction pattern of benzenesulfonate crystal form A contains at least one or more diffraction peaks located at 2θ of 22.1±0.2°, 23.7±0.2°, and 20.0±0.2°, preferably two, more preferably three; optionally, it may further contain at least one diffraction peak located at 2θ of 12.3±0.2°, 17.8±0.2°, 24.1±0.2°, 20.2±0.2°, and 9.2±0.2°, preferably two, three, four, or five.

[0037] The X-ray powder diffraction pattern of hydrobromide crystal form A contains at least one or more diffraction peaks located at 2θ of 9.1±0.2°, 20.0±0.2°, and 23.5±0.2°, preferably two, more preferably three; optionally, it may further contain at least one of 2θ of 23.9±0.2°, 25.9±0.2°, 17.3±0.2°, 27.4±0.2°, and 24.8±0.2°, preferably two, three, four, or five.

[0038] The present invention further describes an acid salt or crystal form of the compound or its stereoisomer thereof, characterized in that the X-ray powder diffraction pattern of the hydrochloride crystal form A optionally includes one or more diffraction peaks located at 2θ of 17.9±0.2°, 12.4±0.2°, 28.4±0.2°, 20.1±0.2°, 20.7±0.2°, 18.3±0.2°, and 30.8±0.2°; preferably, it includes at least any 2-3 peaks, or 4-5 peaks, or 6-7 peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks.

[0039] The X-ray powder diffraction pattern of methanesulfonate crystal form A optionally includes one or more diffraction peaks located at 2θ of 15.7±0.2°, 26.0±0.2°, 20.5±0.2°, 20.0±0.2°, 28.6±0.2°, 23.3±0.2°, and 17.5±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 of these peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks.

[0040] The X-ray powder diffraction pattern of benzenesulfonate crystal form A optionally includes one or more diffraction peaks located at 2θ of 28.4±0.2°, 19.0±0.2°, 32.3±0.2°, 17.3±0.2°, 14.1±0.2°, 26.1±0.2°, and 25.1±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 of these peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks.

[0041] The X-ray powder diffraction pattern of hydrobromide crystal form A optionally includes one or more diffraction peaks located at 2θ of 9.4±0.2°, 28.1±0.2°, 20.6±0.2°, 32.0±0.2°, 17.8±0.2°, 18.3±0.2°, and 25.1±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 of these peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks.

[0042] The present invention further illustrates an acid salt or crystal form of the compound or its stereoisomer thereof, wherein the X-ray powder diffraction pattern of the hydrochloride crystal form A includes one or more diffraction peaks located at 2θ of 22.1±0.2°, 23.6±0.2°, 17.3±0.2°, 24.0±0.2°, 26.0±0.2°, 14.0±0.2°, 24.9±0.2°, 32.2±0.2°, 17.9±0.2°, 12.4±0.2°, 28.4±0.2°, and 20.1±0.2°; preferably, it includes any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 peaks.

[0043] The X-ray powder diffraction pattern of methanesulfonate crystal form A includes one or more diffraction peaks located at 2θ of 24.1±0.2°, 11.6±0.2°, 6.4±0.2°, 22.7±0.2°, 24.4±0.2°, 21.0±0.2°, 27.3±0.2°, 19.0±0.2°, 15.7±0.2°, 26.0±0.2°, 20.5±0.2°, and 20.0±0.2°; preferably, it includes any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 of these peaks.

[0044] The X-ray powder diffraction pattern of benzenesulfonate crystal form A includes one or more diffraction peaks located at 2θ of 22.1±0.2°, 23.7±0.2°, 20.0±0.2°, 12.3±0.2°, 17.8±0.2°, 24.1±0.2°, 20.2±0.2°, 9.2±0.2°, 28.4±0.2°, 19.0±0.2°, 32.3±0.2°, and 17.3±0.2°; preferably, it includes any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 of these peaks.

[0045] The X-ray powder diffraction pattern of hydrobromide crystal form A includes one or more diffraction peaks located at 2θ of 9.1±0.2°, 20.0±0.2°, 23.5±0.2°, 23.9±0.2°, 25.9±0.2°, 17.3±0.2°, 27.4±0.2°, 24.8±0.2°, 9.4±0.2°, 28.1±0.2°, 20.6±0.2°, and 32.0±0.2°; preferably, it includes any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 of these peaks.

[0046] A further technical solution of the present invention is the crystal form of compound 2, which is 6-(5-fluoro-6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)aminopyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, specifically,

[0047] Hydrochloride crystal form A has an X-ray powder diffraction pattern showing a diffraction peak at 2θ = 24.4 ± 0.2°; or at 15.2 ± 0.2°; or at 5.6 ± 0.2°; or at 27.7 ± 0.2°; or at 26.4 ± 0.2°; or at 16.8 ± 0.2°; or at 32.7 ± 0.2°; or The diffraction peak is present at 19.1±0.2°; or at 12.9±0.2°; or at 14.7±0.2°; preferably, any 2-3, 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 diffraction peaks are included; more preferably, any 2, 3, 4, 5, 6, 7, 8, 9, or 10 of the above diffraction peaks are included.

[0048] Hydrochloride crystal form B has an X-ray powder diffraction pattern showing a diffraction peak at 2θ = 24.4 ± 0.2°; or at 26.0 ± 0.2°; or at 28.6 ± 0.2°; or at 8.7 ± 0.2°; or at 21.4 ± 0.2°; or at 29.6 ± 0.2°; or at 15.5 ± 0.2°; or The diffraction peak is present at 11.4±0.2°; or at 13.1±0.2°; or at 14.9±0.2°; preferably, any 2-3, 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 diffraction peaks are included; more preferably, any 2, 3, 4, 5, 6, 7, 8, 9, or 10 of the above diffraction peaks are included.

[0049] Sulfate crystal form A has an X-ray powder diffraction pattern showing a diffraction peak at 2θ = 20.7 ± 0.2°; or at 21.8 ± 0.2°; or at 25.1 ± 0.2°; or at 12.4 ± 0.2°; or at 12.0 ± 0.2°; or at 23.2 ± 0.2°; or at 10.6 ± 0.2°; or The diffraction peak is present at 23.7±0.2°; or at 19.6±0.2°; or at 16.3±0.2°; preferably, any 2-3, 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 diffraction peaks are included; more preferably, any 2, 3, 4, 5, 6, 7, 8, 9, or 10 of the above diffraction peaks are included.

[0050] Sulfate crystal form B has an X-ray powder diffraction pattern showing a diffraction peak at 2θ of 11.4 ± 0.2°; or at 10.6 ± 0.2°; or at 20.5 ± 0.2°; or at 21.0 ± 0.2°; or at 13.5 ± 0.2°; or at 17.0 ± 0.2°; or at 26.2 ± 0.2°. Alternatively, it may have a diffraction peak at 14.1±0.2°; or a diffraction peak at 28.5±0.2°; or a diffraction peak at 7.4±0.2°; preferably, it may include any 2-3, 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 of the above diffraction peaks, more preferably, it may include any 2, 3, 4, 5, 6, 7, 8, 9, or 10 of the above diffraction peaks;

[0051] The sulfate crystal form C exhibits the following X-ray powder diffraction patterns: a diffraction peak at 2θ = 26.5 ± 0.2°; or at 10.6 ± 0.2°; or at 27.9 ± 0.2°; or at 12.5 ± 0.2°; or at 13.5 ± 0.2°; or at 15.3 ± 0.2°; or at 21.3 ± 0.2°. Or it has a diffraction peak at 20.6±0.2°; or it has a diffraction peak at 7.0±0.2°; or it has a diffraction peak at 29.2±0.2°; preferably it includes any 2-3, 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 of the above diffraction peaks, more preferably it includes any 2, 3, 4, 5, 6, 7, 8, 9 or 10 of them;

[0052] Phosphate crystal form A has an X-ray powder diffraction pattern showing a diffraction peak at 2θ = 24.4 ± 0.2°; or at 26.0 ± 0.2°; or at 22.5 ± 0.2°; or at 21.4 ± 0.2°; or at 7.9 ± 0.2°; or at 13.2 ± 0.2°; or at 18.4 ± 0.2°; or The diffraction peak is present at 19.5±0.2°; or at 14.3±0.2°; or at 23.4±0.2°; preferably, any 2-3, 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 diffraction peaks are included; more preferably, any 2, 3, 4, 5, 6, 7, 8, 9, or 10 of the above diffraction peaks are included.

[0053] Hydrobromide crystal form A has an X-ray powder diffraction pattern showing a diffraction peak at 2θ = 24.6 ± 0.2°; or at 5.8 ± 0.2°; or at 12.4 ± 0.2°; or at 18.6 ± 0.2°; or at 17.0 ± 0.2°; or at 14.7 ± 0.2°; or at 22.5 ± 0.2°; or The diffraction peak is present at 28.7±0.2°; or at 26.7±0.2°; or at 29.6±0.2°; preferably, any 2-3, 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 diffraction peaks are included; more preferably, any 2, 3, 4, 5, 6, 7, 8, 9, or 10 of the above diffraction peaks are included.

[0054] Hydrobromide crystal form B has an X-ray powder diffraction pattern showing a diffraction peak at 2θ = 25.3 ± 0.2°; or at 25.9 ± 0.2°; or at 6.7 ± 0.2°; or at 19.2 ± 0.2°; or at 12.7 ± 0.2°; or at 13.5 ± 0.2°; or at 14.6 ± 0.2°; or The diffraction peak is present at 21.1±0.2°; or at 27.6±0.2°; or at 24.6±0.2°; preferably, any 2-3, 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 diffraction peaks are included; more preferably, any 2, 3, 4, 5, 6, 7, 8, 9, or 10 of the above diffraction peaks are included.

[0055] Hydrobromide crystal form C has an X-ray powder diffraction pattern showing a diffraction peak at 2θ = 24.2 ± 0.2°; or at 28.6 ± 0.2°; or at 26.0 ± 0.2°; or at 21.4 ± 0.2°; or at 29.6 ± 0.2°; or at 11.4 ± 0.2°; or at 24.9 ± 0.2°. Alternatively, it may have a diffraction peak at 12.6±0.2°; or a diffraction peak at 13.5±0.2°; or a diffraction peak at 12.9±0.2°; preferably, it may include any 2-3, 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 of the above diffraction peaks, more preferably, it may include any 2, 3, 4, 5, 6, 7, 8, 9, or 10 of the above diffraction peaks;

[0056] Hydrobromide crystal form D has an X-ray powder diffraction pattern showing a diffraction peak at 2θ = 26.5 ± 0.2°; or at 12.9 ± 0.2°; or at 23.9 ± 0.2°; or at 24.4 ± 0.2°; or at 21.4 ± 0.2°; or at 11.2 ± 0.2°; or at 28.4 ± 0.2°. Alternatively, it may have a diffraction peak at 22.5±0.2°; or a diffraction peak at 13.7±0.2°; or a diffraction peak at 22.9±0.2°; preferably, it may include any 2-3, 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 of the above diffraction peaks, more preferably, it may include any 2, 3, 4, 5, 6, 7, 8, 9, or 10 of the above diffraction peaks;

[0057] Methanesulfonate crystal form A has the following X-ray powder diffraction patterns: a diffraction peak at 2θ = 24.5 ± 0.2°; or at 26.1 ± 0.2°; or at 14.3 ± 0.2°; or at 21.5 ± 0.2°; or at 20.8 ± 0.2°; or at 10.7 ± 0.2°; or at 6.7 ± 0.2°. Or it has a diffraction peak at 27.6±0.2°; or it has a diffraction peak at 26.5±0.2°; or it has a diffraction peak at 28.2±0.2°; preferably it includes any 2-3, 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 of the above diffraction peaks, more preferably it includes any 2, 3, 4, 5, 6, 7, 8, 9 or 10 of them;

[0058] Fumarate crystal form A has an X-ray powder diffraction pattern showing a diffraction peak at 2θ = 26.1 ± 0.2°; or at 15.1 ± 0.2°; or at 28.2 ± 0.2°; or at 9.0 ± 0.2°; or at 12.9 ± 0.2°; or at 27.2 ± 0.2°; or at 21.0 ± 0.2°; or The diffraction peak is present at 12.1±0.2°; or at 20.2±0.2°; or at 16.9±0.2°; preferably, any 2-3, 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 diffraction peaks are included; more preferably, any 2, 3, 4, 5, 6, 7, 8, 9, or 10 of the above diffraction peaks are included.

[0059] Fumarate crystal form B has an X-ray powder diffraction pattern showing a diffraction peak at 2θ of 9.1 ± 0.2°; or at 26.9 ± 0.2°; or at 22.2 ± 0.2°; or at 22.0 ± 0.2°; or at 15.5 ± 0.2°; or at 16.8 ± 0.2°; or at 13.1 ± 0.2°; or The diffraction peak is present at 27.4±0.2°; or at 13.9±0.2°; or at 10.2±0.2°; preferably, any 2-3, 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 diffraction peaks are included; more preferably, any 2, 3, 4, 5, 6, 7, 8, 9, or 10 of the above diffraction peaks are included.

[0060] The X-ray powder diffraction pattern of hydrochloride crystal form C contains at least one or more diffraction peaks located at 2θ of 25.1±0.2°, 4.6±0.2°, and 8.2±0.2°, preferably two, more preferably three; optionally, it may further contain at least one diffraction peak located at 2θ of 15.3±0.2°, 21.4±0.2°, 28.2±0.2°, 17.1±0.2°, and 12.0±0.2°, preferably two, three, four, or five.

[0061] The X-ray powder diffraction pattern of phosphate crystal form B contains at least one or more diffraction peaks located at 2θ of 17.6±0.2°, 13.1±0.2°, and 4.4±0.2°, preferably two, more preferably three; optionally, it may further contain at least one of the following: 2θ of 12.8±0.2°, 24.3±0.2°, 8.8±0.2°, 21.0±0.2°, and 9.4±0.2°, preferably two, three, four, or five.

[0062] The X-ray powder diffraction pattern of hydrobromide crystal form E contains at least one or more diffraction peaks located at 2θ of 9.3±0.2°, 15.5±0.2°, and 6.2±0.2°, preferably two, more preferably three; optionally, it may further contain at least one diffraction peak located at 2θ of 18.6±0.2°, 12.4±0.2°, 31.2±0.2°, 27.5±0.2°, and 21.7±0.2°, preferably two, three, four, or five.

[0063] The X-ray powder diffraction pattern of hydrobromide crystal form F contains at least one or more diffraction peaks located at 2θ of 25.4±0.2°, 24.7±0.2°, and 26.2±0.2°, preferably two, more preferably three; optionally, it may further contain at least one of 2θ of 12.4±0.2°, 17.4±0.2°, 18.5±0.2°, 32.0±0.2°, and 20.2±0.2°, preferably two, three, four, or five.

[0064] A further technical solution of the present invention is that the X-ray powder diffraction pattern of hydrochloride crystal form A includes at least one or more diffraction peaks located at 2θ of 24.4±0.2°, 15.2±0.2°, and 5.6±0.2°, preferably two, more preferably three; optionally, it may further include at least one of 2θ of 27.7±0.2°, 26.4±0.2°, 16.8±0.2°, 32.7±0.2°, and 19.1±0.2°, preferably two, three, four, or five.

[0065] The X-ray powder diffraction pattern of hydrochloride crystal form B includes at least one or more diffraction peaks located at 2θ of 24.4±0.2°, 26.0±0.2°, and 28.6±0.2°, preferably two, more preferably three; optionally, it may further include at least one of the following: 2θ of 8.7±0.2°, 21.4±0.2°, 29.6±0.2°, 15.5±0.2°, and 11.4±0.2°, preferably two, three, four, or five.

[0066] The X-ray powder diffraction pattern of sulfate crystal form A contains at least one or more diffraction peaks located at 2θ of 20.7±0.2°, 21.8±0.2°, and 25.1±0.2°, preferably two, more preferably three; optionally, it may further contain at least one of the following: 2θ of 12.4±0.2°, 12.0±0.2°, 23.2±0.2°, 10.6±0.2°, and 23.7±0.2°, preferably two, three, four, or five.

[0067] The X-ray powder diffraction pattern of sulfate crystal form B contains at least one or more diffraction peaks located at 2θ of 11.4±0.2°, 10.6±0.2°, and 20.5±0.2°, preferably two, more preferably three; optionally, it may further contain at least one diffraction peak located at 2θ of 21.0±0.2°, 13.5±0.2°, 17.0±0.2°, 26.2±0.2°, and 14.1±0.2°, preferably two, three, four, or five.

[0068] The X-ray powder diffraction pattern of sulfate crystal form C includes at least one or more diffraction peaks located at 2θ of 26.5±0.2°, 10.6±0.2°, and 27.9±0.2°, preferably two, more preferably three; optionally, it may further include at least one of the following: 2θ of 12.5±0.2°, 13.5±0.2°, 15.3±0.2°, 21.3±0.2°, and 20.6±0.2°, preferably two, three, four, or five.

[0069] The X-ray powder diffraction pattern of phosphate crystal form A contains at least one or more diffraction peaks located at 2θ of 24.4±0.2°, 26.0±0.2°, and 22.5±0.2°, preferably two, more preferably three; optionally, it may further contain at least one of the following: 2θ of 21.4±0.2°, 7.9±0.2°, 13.2±0.2°, 18.4±0.2°, and 19.5±0.2°, preferably two, three, four, or five.

[0070] The X-ray powder diffraction pattern of hydrobromide crystal form A contains at least one or more diffraction peaks located at 2θ of 24.6±0.2°, 5.8±0.2°, and 12.4±0.2°, preferably two, more preferably three; optionally, it may further contain at least one diffraction peak located at 2θ of 18.6±0.2°, 17.0±0.2°, 14.7±0.2°, 22.5±0.2°, and 28.7±0.2°, preferably two, three, four, or five.

[0071] The X-ray powder diffraction pattern of hydrobromide crystal form B contains at least one or more diffraction peaks located at 2θ of 25.3±0.2°, 25.9±0.2°, and 6.7±0.2°, preferably two, more preferably three; optionally, it may further contain at least one diffraction peak located at 2θ of 19.2±0.2°, 12.7±0.2°, 13.5±0.2°, 14.6±0.2°, and 21.1±0.2°, preferably two, three, four, or five.

[0072] The X-ray powder diffraction pattern of hydrobromide crystal form C contains at least one or more diffraction peaks located at 2θ of 24.2±0.2°, 28.6±0.2°, and 26.0±0.2°, preferably two, more preferably three; optionally, it may further contain at least one diffraction peak located at 2θ of 21.4±0.2°, 29.6±0.2°, 11.4±0.2°, 24.9±0.2°, and 12.6±0.2°, preferably two, three, four, or five.

[0073] The X-ray powder diffraction pattern of hydrobromide crystal form D contains at least one or more diffraction peaks located at 2θ of 26.5±0.2°, 12.9±0.2°, and 23.9±0.2°, preferably two, more preferably three; optionally, it may further contain at least one diffraction peak located at 2θ of 24.4±0.2°, 21.4±0.2°, 11.2±0.2°, 28.4±0.2°, and 22.5±0.2°, preferably two, three, four, or five.

[0074] The X-ray powder diffraction pattern of methanesulfonate crystal form A contains at least one or more diffraction peaks located at 2θ of 24.5±0.2°, 26.1±0.2°, and 14.3±0.2°, preferably two, more preferably three; optionally, it may further contain at least one of the following: 21.5±0.2°, 20.8±0.2°, 10.7±0.2°, 6.7±0.2°, and 27.6±0.2°, preferably two, three, four, or five.

[0075] The X-ray powder diffraction pattern of fumarate crystal form A contains at least one or more diffraction peaks located at 2θ of 26.1±0.2°, 15.1±0.2°, and 28.2±0.2°, preferably two, more preferably three; optionally, it may further contain at least one of the following: 2θ of 9.0±0.2°, 12.9±0.2°, 27.2±0.2°, 21.0±0.2°, and 12.1±0.2°, preferably two, three, four, or five.

[0076] The X-ray powder diffraction pattern of fumarate crystal form B contains at least one or more diffraction peaks located at 2θ of 9.1±0.2°, 26.9±0.2°, and 22.2±0.2°, preferably two, more preferably three; optionally, it may further contain at least one of the following: 2θ of 22.0±0.2°, 15.5±0.2°, 16.8±0.2°, 13.1±0.2°, and 27.4±0.2°, preferably two, three, four, or five.

[0077] The X-ray powder diffraction pattern of hydrochloride crystal form C optionally includes one or more diffraction peaks located at 2θ of 14.3±0.2°, 19.0±0.2°, 27.7±0.2°, 9.1±0.2°, 12.8±0.2°, 7.1±0.2°, and 11.1±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 of these peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks.

[0078] The X-ray powder diffraction pattern of phosphate crystal form B optionally includes one or more diffraction peaks located at 2θ of 16.8±0.2°, 18.4±0.2°, 20.5±0.2°, 22.0±0.2°, 14.3±0.2°, 25.2±0.2°, and 26.5±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 of these peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks.

[0079] The X-ray powder diffraction pattern of hydrobromide crystal form E optionally includes one or more diffraction peaks located at 2θ of 24.8±0.2°, 19.1±0.2°, 21.0±0.2°, 34.4±0.2°, 17.7±0.2°, 22.9±0.2°, and 21.4±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 of these peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks.

[0080] The X-ray powder diffraction pattern of hydrobromide crystal form F optionally includes one or more diffraction peaks located at 2θ of 21.5±0.2°, 28.3±0.2°, 18.7±0.2°, 21.9±0.2°, 28.7±0.2°, 29.8±0.2°, and 14.5±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 of these peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks.

[0081] A further technical solution of the present invention is that the X-ray powder diffraction pattern of hydrochloride crystal form A optionally includes one or more diffraction peaks located at 2θ of 12.9±0.2°, 14.7±0.2°, 23.5±0.2°, 29.0±0.2°, 8.5±0.2°, 20.4±0.2°, and 12.0±0.2°; preferably, it includes at least any 2-3 peaks, or 4-5 peaks, or 6-7 peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks.

[0082] The X-ray powder diffraction pattern of hydrochloride crystal form B optionally includes one or more diffraction peaks located at 2θ of 13.1±0.2°, 14.9±0.2°, 18.9±0.2°, 23.0±0.2°, 14.3±0.2°, 30.2±0.2°, and 28.0±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 of these peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks.

[0083] The X-ray powder diffraction pattern of sulfate crystal form A optionally includes one or more diffraction peaks located at 2θ of 19.6±0.2°, 16.3±0.2°, 27.1±0.2°, 28.1±0.2°, 39.4±0.2°, 41.5±0.2°, and 35.7±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 of these peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks.

[0084] The X-ray powder diffraction pattern of sulfate crystal form B optionally includes one or more diffraction peaks located at 2θ of 28.5±0.2°, 7.4±0.2°, 22.3±0.2°, 27.8±0.2°, 33.1±0.2°, 9.6±0.2°, and 6.5±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 of these peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks.

[0085] The X-ray powder diffraction pattern of sulfate crystal form C optionally includes one or more diffraction peaks located at 2θ of 7.0±0.2°, 29.2±0.2°, 17.8±0.2°, 16.4±0.2°, 17.2±0.2°, 25.3±0.2°, and 22.1±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 of these peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks.

[0086] The X-ray powder diffraction pattern of phosphate crystal form A optionally includes one or more diffraction peaks located at 2θ of 14.3±0.2°, 23.4±0.2°, 14.8±0.2°, 21.9±0.2°, 28.7±0.2°, 26.5±0.2°, and 20.3±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 of these peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks.

[0087] The X-ray powder diffraction pattern of hydrobromide crystal form A optionally includes one or more diffraction peaks located at 2θ of 26.7±0.2°, 29.6±0.2°, 17.5±0.2°, 22.0±0.2°, 16.5±0.2°, 23.4±0.2°, and 28.1±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 of these peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks.

[0088] The X-ray powder diffraction pattern of hydrobromide crystal form B optionally includes one or more diffraction peaks located at 2θ of 27.6±0.2°, 24.6±0.2°, 11.5±0.2°, 15.4±0.2°, 31.1±0.2°, 34.4±0.2°, and 16.3±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 of these peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks.

[0089] The X-ray powder diffraction pattern of hydrobromide crystal form C optionally includes one or more diffraction peaks located at 2θ of 13.5±0.2°, 12.9±0.2°, 20.4±0.2°, 18.2±0.2°, 8.7±0.2°, 5.5±0.2°, and 27.9±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks.

[0090] The X-ray powder diffraction pattern of hydrobromide crystal form D optionally includes one or more diffraction peaks located at 2θ of 13.7±0.2°, 22.9±0.2°, 28.5±0.2°, 33.1±0.2°, 27.9±0.2°, 12.1±0.2°, and 29.5±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 of these peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks.

[0091] The X-ray powder diffraction pattern of methanesulfonate crystal form A optionally includes one or more diffraction peaks located at 2θ of 26.5±0.2°, 28.2±0.2°, 24.8±0.2°, 19.3±0.2°, 27.1±0.2°, 19.6±0.2°, and 15.5±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 of these peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks.

[0092] The X-ray powder diffraction pattern of fumarate crystal form A optionally includes one or more diffraction peaks located at 2θ of 20.2±0.2°, 16.9±0.2°, 16.4±0.2°, 18.6±0.2°, 21.8±0.2°, 13.9±0.2°, and 29.0±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 of these peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks.

[0093] The X-ray powder diffraction pattern of fumarate crystal form B optionally includes one or more diffraction peaks located at 2θ of 13.9±0.2°, 10.2±0.2°, 18.4±0.2°, 23.4±0.2°, 7.7±0.2°, 21.1±0.2°, and 14.5±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 of these peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks.

[0094] The X-ray powder diffraction pattern of hydrochloride crystal form A includes one or more diffraction peaks located at 2θ of 24.4±0.2°, 15.2±0.2°, 5.6±0.2°, 27.7±0.2°, 26.4±0.2°, 16.8±0.2°, 32.7±0.2°, 19.1±0.2°, 12.9±0.2°, 14.7±0.2°, 23.5±0.2°, 29.0±0.2°, 8.5±0.2°, 20.4±0.2°, and 12.0±0.2°; preferably, it includes any 2, 3, 4, 5, 6, 8, 10, or 12 of these peaks.

[0095] The X-ray powder diffraction pattern of hydrochloride crystal form B includes one or more diffraction peaks located at 2θ of 24.4±0.2°, 26.0±0.2°, 28.6±0.2°, 8.7±0.2°, 21.4±0.2°, 29.6±0.2°, 15.5±0.2°, 11.4±0.2°, 13.1±0.2°, 14.9±0.2°, 18.9±0.2°, 23.0±0.2°, 14.3±0.2°, 30.2±0.2°, and 28.0±0.2°; preferably, it includes any 2, 3, 4, 5, 6, 8, 10, or 12 of these peaks.

[0096] The X-ray powder diffraction pattern of sulfate crystal form A includes one or more diffraction peaks located at 2θ of 20.7±0.2°, 21.8±0.2°, 25.1±0.2°, 12.4±0.2°, 12.0±0.2°, 23.2±0.2°, 10.6±0.2°, 23.7±0.2°, 19.6±0.2°, 16.3±0.2°, 27.1±0.2°, 28.1±0.2°, 39.4±0.2°, 41.5±0.2°, and 35.7±0.2°; preferably, it includes any 2, 3, 4, 5, 6, 8, 10, or 12 of these peaks.

[0097] The X-ray powder diffraction pattern of sulfate crystal form B includes one or more diffraction peaks located at 2θ of 11.4±0.2°, 10.6±0.2°, 20.5±0.2°, 21.0±0.2°, 13.5±0.2°, 17.0±0.2°, 26.2±0.2°, 14.1±0.2°, 28.5±0.2°, 7.4±0.2°, 22.3±0.2°, 27.8±0.2°, 33.1±0.2°, 9.6±0.2°, and 6.5±0.2°; preferably, it includes any 4, 5, 6, 8, 10, or 12 of these peaks.

[0098] The X-ray powder diffraction pattern of sulfate crystal form C includes one or more diffraction peaks located at 2θ of 26.5±0.2°, 10.6±0.2°, 27.9±0.2°, 12.5±0.2°, 13.5±0.2°, 15.3±0.2°, 21.3±0.2°, 20.6±0.2°, 7.0±0.2°, 29.2±0.2°, 17.8±0.2°, 16.4±0.2°, 17.2±0.2°, 25.3±0.2°, and 22.1±0.2°; preferably, it includes any 2, 3, 4, 5, 6, 8, 10, or 12 of these peaks.

[0099] The X-ray powder diffraction pattern of phosphate crystal form A includes one or more diffraction peaks located at 2θ of 24.4±0.2°, 26.0±0.2°, 22.5±0.2°, 21.4±0.2°, 7.9±0.2°, 13.2±0.2°, 18.4±0.2°, 19.5±0.2°, 14.3±0.2°, 23.4±0.2°, 14.8±0.2°, 21.9±0.2°, 28.7±0.2°, 26.5±0.2°, and 20.3±0.2°; preferably, it includes any 2, 3, 4, 5, 6, 8, 10, or 12 of these peaks.

[0100] The X-ray powder diffraction pattern of hydrobromide crystal form A includes one or more diffraction peaks located at 2θ of 24.6±0.2°, 5.8±0.2°, 12.4±0.2°, 18.6±0.2°, 17.0±0.2°, 14.7±0.2°, 22.5±0.2°, 28.7±0.2°, 26.7±0.2°, 29.6±0.2°, 17.5±0.2°, 22.0±0.2°, 16.5±0.2°, 23.4±0.2°, and 28.1±0.2°; preferably, it includes any 2, 3, 4, 5, 6, 8, 10, or 12 of these peaks.

[0101] The X-ray powder diffraction pattern of hydrobromide crystal form B includes one or more diffraction peaks located at 2θ of 25.3±0.2°, 25.9±0.2°, 6.7±0.2°, 19.2±0.2°, 12.7±0.2°, 13.5±0.2°, 14.6±0.2°, 21.1±0.2°, 27.6±0.2°, 24.6±0.2°, 11.5±0.2°, 15.4±0.2°, 31.1±0.2°, 34.4±0.2°, and 16.3±0.2°; preferably, it includes any 2, 3, 4, 5, 6, 8, 10, or 12 of these peaks.

[0102] The X-ray powder diffraction pattern of hydrobromide crystal form C includes one or more diffraction peaks located at 2θ of 24.2±0.2°, 28.6±0.2°, 26.0±0.2°, 21.4±0.2°, 29.6±0.2°, 11.4±0.2°, 24.9±0.2°, 12.6±0.2°, 13.5±0.2°, 12.9±0.2°, 20.4±0.2°, 18.2±0.2°, 8.7±0.2°, 5.5±0.2°, and 27.9±0.2°; preferably, it includes any 2, 3, 4, 5, 6, 8, 10, or 12 of these peaks.

[0103] The X-ray powder diffraction pattern of hydrobromide crystal form D includes one or more diffraction peaks located at 2θ of 26.5±0.2°, 12.9±0.2°, 23.9±0.2°, 24.4±0.2°, 21.4±0.2°, 11.2±0.2°, 28.4±0.2°, 22.5±0.2°, 13.7±0.2°, 22.9±0.2°, 28.5±0.2°, 33.1±0.2°, 27.9±0.2°, 12.1±0.2°, and 29.5±0.2°; preferably, it includes any 2, 3, 4, 5, 6, 8, 10, or 12 of these peaks.

[0104] The X-ray powder diffraction pattern of methanesulfonate crystal form A includes one or more diffraction peaks located at 2θ of 24.5±0.2°, 26.1±0.2°, 14.3±0.2°, 21.5±0.2°, 20.8±0.2°, 10.7±0.2°, 6.7±0.2°, 27.6±0.2°, 26.5±0.2°, 28.2±0.2°, 24.8±0.2°, 19.3±0.2°, 27.1±0.2°, 19.6±0.2°, and 15.5±0.2°; preferably, it includes any 2, 3, 4, 5, 6, 8, 10, or 12 of these peaks.

[0105] The X-ray powder diffraction pattern of fumarate crystal form A includes one or more diffraction peaks located at 2θ of 26.1±0.2°, 15.1±0.2°, 28.2±0.2°, 9.0±0.2°, 12.9±0.2°, 27.2±0.2°, 21.0±0.2°, 12.1±0.2°, 20.2±0.2°, 16.9±0.2°, 16.4±0.2°, 18.6±0.2°, 21.8±0.2°, 13.9±0.2°, and 29.0±0.2°; preferably, it includes any 2, 3, 4, 5, 6, 8, 10, or 12 of these peaks.

[0106] The X-ray powder diffraction pattern of fumarate crystal form B includes one or more diffraction peaks located at 2θ of 9.1±0.2°, 26.9±0.2°, 22.2±0.2°, 22.0±0.2°, 15.5±0.2°, 16.8±0.2°, 13.1±0.2°, 27.4±0.2°, 13.9±0.2°, 10.2±0.2°, 18.4±0.2°, 23.4±0.2°, 7.7±0.2°, 21.1±0.2°, and 14.5±0.2°; preferably, it includes any 2, 3, 4, 5, 6, 8, 10, or 12 of these peaks.

[0107] The X-ray powder diffraction pattern of hydrochloride crystal form C includes one or more diffraction peaks located at 2θ of 25.1±0.2°, 4.6±0.2°, 8.2±0.2°, 15.3±0.2°, 21.4±0.2°, 28.2±0.2°, 17.1±0.2°, 12.0±0.2°, 14.3±0.2°, 19.0±0.2°, 27.7±0.2°, 9.1±0.2°, 12.8±0.2°, 7.1±0.2°, and 11.1±0.2°; preferably, it includes any 2, 3, 4, 5, 6, 8, 10, or 12 of these peaks.

[0108] The X-ray powder diffraction pattern of phosphate crystal form B includes one or more diffraction peaks located at 2θ of 17.6±0.2°, 13.1±0.2°, 4.4±0.2°, 12.8±0.2°, 24.3±0.2°, 8.8±0.2°, 21.0±0.2°, 9.4±0.2°, 16.8±0.2°, 18.4±0.2°, 20.5±0.2°, 22.0±0.2°, 14.3±0.2°, 25.2±0.2°, and 26.5±0.2°; preferably, it includes any 2, 3, 4, 5, 6, 8, 10, or 12 of these peaks.

[0109] The X-ray powder diffraction pattern of hydrobromide crystal form E includes one or more diffraction peaks located at 2θ of 9.3±0.2°, 15.5±0.2°, 6.2±0.2°, 18.6±0.2°, 12.4±0.2°, 31.2±0.2°, 27.5±0.2°, 21.7±0.2°, 24.8±0.2°, 19.1±0.2°, 21.0±0.2°, 34.4±0.2°, 17.7±0.2°, 22.9±0.2°, and 21.4±0.2°; preferably, it includes any 2, 3, 4, 5, 6, 8, 10, or 12 of these peaks.

[0110] The X-ray powder diffraction pattern of hydrobromide crystal form F includes one or more diffraction peaks located at 2θ of 25.4±0.2°, 24.7±0.2°, 26.2±0.2°, 12.4±0.2°, 17.4±0.2°, 18.5±0.2°, 32.0±0.2°, 20.2±0.2°, 21.5±0.2°, 28.3±0.2°, 18.7±0.2°, 21.9±0.2°, 28.7±0.2°, 29.8±0.2°, and 14.5±0.2°; preferably, it includes any 2, 3, 4, 5, 6, 8, 10, or 12 of these peaks.

[0111] The present invention further describes the acid salt of the compound or its stereoisomer or its crystal form. The X-ray powder diffraction pattern of the hydrochloride crystal form A of the compound 1 is basically shown in Figure 1; the DSC pattern is basically shown in Figure 2; and the TGA pattern is basically shown in Figure 3.

[0112] The X-ray powder diffraction pattern of the methanesulfonate crystal form A of compound 1 is shown in Figure 4; the DSC pattern is shown in Figure 5; and the TGA pattern is shown in Figure 6.

[0113] The X-ray powder diffraction pattern of benzenesulfonate crystal form A of compound 1 is shown in Figure 7; the DSC pattern is shown in Figure 8; and the TGA pattern is shown in Figure 9.

[0114] The X-ray powder diffraction pattern of the hydrobromide crystal form A of compound 1 is shown in Figure 10; the DSC pattern is shown in Figure 11; and the TGA pattern is shown in Figure 12.

[0115] The X-ray powder diffraction pattern of the hydrochloride crystal form A of compound 2 is shown in Figure 13; the DSC pattern is shown in Figure 14; and the TGA pattern is shown in Figure 15.

[0116] The X-ray powder diffraction pattern of the hydrochloride crystal form B of compound 2 is shown in Figure 16; the DSC pattern is shown in Figure 17; and the TGA pattern is shown in Figure 18.

[0117] The X-ray powder diffraction pattern of sulfate crystal form A of compound 2 is shown in Figure 19; the DSC pattern is shown in Figure 20; and the TGA pattern is shown in Figure 21.

[0118] The X-ray powder diffraction pattern of the sulfate crystal form B of compound 2 is shown in Figure 22; the DSC pattern is shown in Figure 23; and the TGA pattern is shown in Figure 24.

[0119] The X-ray powder diffraction pattern of the sulfate crystal form C of compound 2 is shown in Figure 25; the DSC pattern is shown in Figure 26; and the TGA pattern is shown in Figure 27.

[0120] The X-ray powder diffraction pattern of phosphate crystal form A of compound 2 is shown in Figure 28; the DSC pattern is shown in Figure 29; and the TGA pattern is shown in Figure 30.

[0121] The X-ray powder diffraction pattern of the hydrobromide crystal form A of compound 2 is shown in Figure 31; the DSC pattern is shown in Figure 32; and the TGA pattern is shown in Figure 33.

[0122] The X-ray powder diffraction pattern of the hydrobromide crystal form B of compound 2 is shown in Figure 34; the DSC pattern is shown in Figure 35; and the TGA pattern is shown in Figure 36.

[0123] The X-ray powder diffraction pattern of the hydrobromide crystal form C of compound 2 is shown in Figure 37; the DSC pattern is shown in Figure 38; and the TGA pattern is shown in Figure 39.

[0124] The X-ray powder diffraction pattern of the hydrobromide crystal form D of compound 2 is shown in Figure 40; the DSC pattern is shown in Figure 41; and the TGA pattern is shown in Figure 42.

[0125] The X-ray powder diffraction pattern of the methanesulfonate crystal form A of compound 2 is shown in Figure 43; the DSC pattern is shown in Figure 44; and the TGA pattern is shown in Figure 45.

[0126] The X-ray powder diffraction pattern of fumarate crystal form A of compound 2 is shown in Figure 46; the DSC pattern is shown in Figure 47; and the TGA pattern is shown in Figure 48.

[0127] The X-ray powder diffraction pattern of the fumarate crystal form B of compound 2 is shown in Figure 49; the DSC pattern is shown in Figure 50; and the TGA pattern is shown in Figure 51.

[0128] The X-ray powder diffraction pattern of the hydrochloride crystal form C of compound 2 is shown in Figure 52; the DSC pattern is shown in Figure 53; and the TGA pattern is shown in Figure 54.

[0129] The X-ray powder diffraction pattern of phosphate crystal form B of compound 2 is shown in Figure 55; the DSC pattern is shown in Figure 56; and the TGA pattern is shown in Figure 57.

[0130] The X-ray powder diffraction pattern of the hydrobromide crystal form E of compound 2 is shown in Figure 58; the DSC pattern is shown in Figure 59; and the TGA pattern is shown in Figure 60.

[0131] The X-ray powder diffraction pattern of the hydrobromide crystal form F of compound 2 is shown in Figure 61; the DSC pattern is shown in Figure 62; and the TGA pattern is shown in Figure 63.

[0132] The 2θ error between the positions of the top ten diffraction peaks with the highest relative peak intensities in the X-ray powder diffraction pattern and the corresponding positions in the attached figure is ±0.2°~±0.5°; preferably ±0.2°~±0.3°; most preferably ±0.2°.

[0133] This invention further relates to a method for preparing an acid salt of the compound or its stereoisomer, or its crystal form, comprising the following steps:

[0134] 1) Weigh an appropriate amount of free alkali or free alkali crystal form and dissolve it in a good solvent;

[0135] 2) Weigh an appropriate amount of the counterion acid and dissolve it in an organic solvent; the amount of counterion acid is preferably 1 to 1.2 equivalents.

[0136] 3) Combine the two solutions and stir until a solid precipitates out;

[0137] 4) Drying yields the target product;

[0138] in:

[0139] The beneficial solvent is selected from one or more of methanol, acetone, ethyl acetate, acetonitrile, ethanol, 88% acetone, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropanol, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, tert-butanol, 2-butanone, 3-pentanone, or N-methylpyrrolidone; preferably one or more of methanol, 88% acetone, dichloromethane, or anhydrous ethanol.

[0140] The organic solvent is selected from methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, dichloroethane, tetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, tert-butanol, or N,N-dimethylformamide; preferably methanol, ethanol, or acetonitrile; the above-mentioned benign solvents and organic solutions must be miscible when used.

[0141] The aforementioned counterionic acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid or phosphoric acid, 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphtholic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetoxyxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetaminobenzoic acid, 4-aminobenzoic acid, decanoic acid, hexanoic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfonic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, and dodecyl sulfonate. Acids, benzoyl tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactobionic acid, gentian acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, hydroxyethyl sulfonic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, dihydroxynaphthalic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanate, undecanoic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, or L-malic acid;

[0142] Preferably, the counterionic acid is selected from hydrochloric acid, methanesulfonate, p-toluenesulfonate, benzenesulfonate, phosphoric acid, or hydrobromic acid; more preferably, it is hydrochloric acid, methanesulfonate, p-toluenesulfonate, benzenesulfonate, or hydrobromic acid.

[0143] Preferably, the temperature is 25℃~50℃, and the pulping time is 1-7 days;

[0144] And / or,

[0145] Method 2:

[0146] 1) Weigh an appropriate amount of free alkali or free alkali crystal form and dissolve it in a good solvent;

[0147] 2) Weigh an appropriate amount of the counterion acid and dissolve it in an organic solvent; the amount of counterion acid is preferably 1 to 1.2 equivalents.

[0148] 3) Combine the two solutions and filter.

[0149] 4) Curing occurs at room temperature;

[0150] 5) A solid product is obtained;

[0151] Drying yields the target product;

[0152] in:

[0153] The beneficial solvent is selected from one or more of methanol, acetone, ethyl acetate, acetonitrile, ethanol, 88% acetone, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropanol, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, tert-butanol, 2-butanone, 3-pentanone, or N-methylpyrrolidone; preferably one or more of methanol, 88% acetone, dichloromethane, or anhydrous ethanol.

[0154] The organic solvent is selected from methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, dichloroethane, tetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, tert-butanol, or N,N-dimethylformamide; preferably methanol, ethanol, or acetonitrile; the above-mentioned benign solvents and organic solutions must be miscible when used.

[0155] The aforementioned counterionic acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid or phosphoric acid, 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphtholic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetoxyxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetaminobenzoic acid, 4-aminobenzoic acid, decanoic acid, hexanoic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfonic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, and dodecyl sulfonate. Acids, benzoyl tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactobionic acid, gentian acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, hydroxyethyl sulfonic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, dihydroxynaphthalic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanate, undecanoic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, or L-malic acid;

[0156] Preferably, the counterionic acid is selected from hydrochloric acid, methanesulfonate, p-toluenesulfonate, benzenesulfonate, phosphoric acid, or hydrobromic acid;

[0157] Preferably, the temperature is 25℃~50℃; the volatilization time is 1-14 days;

[0158] And / or,

[0159] Method 3:

[0160] In both of the above methods, seed crystals can be added after step one, followed by stirring to induce crystallization.

[0161] The present invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of any of the compounds or their stereoisomers, an acid salt or a crystal form thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0162] Further, the compound, its stereoisomer, acid salt, or crystal form thereof, constitute 0.1% to 95% by weight in the composition, preferably 0.5% to 85%, more preferably 1% to 60%, more preferably 2% to 50%, more preferably 2% to 40%, even more preferably 2-30%, even more preferably 2-20%, even more preferably 4% to 30%, even more preferably 5% to 30%, even more preferably 5% to 20%, specifically preferably 1%, 2%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60% (based on the total weight of the pharmaceutical composition).

[0163] The present invention further relates to the use of the acid salt of the compound or its stereoisomer or its crystal form, or a pharmaceutical composition thereof, in the preparation of a PCSK9 inhibitor drug.

[0164] The present invention further relates to the use of any of the said compounds or their stereoisomers, acid salts or crystal forms thereof, or pharmaceutical compositions thereof, in the preparation of drugs for lowering LDL.

[0165] The present invention further relates to the use of the acid salts of the said compound or its stereoisomers or their crystal forms, or pharmaceutical compositions thereof, in the treatment and / or prevention of cardiovascular diseases, cerebrovascular diseases, atherosclerosis and / or their related diseases or symptoms; preferably, in the treatment and / or prevention of stroke, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome and / or coronary artery disease.

[0166] The present invention also relates to a method for treating, preventing and / or treating stroke, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome and / or coronary artery disease, comprising administering to a patient a therapeutically effective dose of an acidic salt of the compound of the present invention or a stereoisomer thereof or a crystal form thereof, or a pharmaceutical composition thereof.

[0167] The present invention also provides a method for treating disease conditions using acid salts of the compounds described herein or their stereoisomers or their crystal forms, or pharmaceutical compositions thereof, including but not limited to conditions related to PCSK9. Attached Figure Description

[0168] Figure 1 shows the XRPD diagram of the hydrochloride crystal form A of compound 1.

[0169] Figure 2 shows the DSC diagram of crystal form A of the hydrochloride salt of compound 1.

[0170] Figure 3 is a TGA illustration of the hydrochloride crystal form A of compound 1.

[0171] Figure 4 shows the XRPD diagram of the methanesulfonate crystal form A of compound 1.

[0172] Figure 5 shows the DSC diagram of the methanesulfonate crystal form A of compound 1.

[0173] Figure 6 is a TGA illustration of the methanesulfonate crystal form A of compound 1.

[0174] Figure 7 shows the XRPD diagram of benzenesulfonate crystal form A of compound 1.

[0175] Figure 8 shows the DSC diagram of benzenesulfonate crystal form A of compound 1.

[0176] Figure 9 is a TGA illustration of the benzenesulfonate crystal form A of compound 1.

[0177] Figure 10 shows the XRPD diagram of the hydrobromide crystal form A of compound 1.

[0178] Figure 11 shows the DSC diagram of the hydrobromide crystal form A of compound 1.

[0179] Figure 12 is a TGA illustration of the hydrobromide crystal form A of compound 1.

[0180] Figure 13 shows the XRPD diagram of the hydrochloride crystal form A of compound 2.

[0181] Figure 14 shows the DSC diagram of crystal form A of the hydrochloride salt of compound 2.

[0182] Figure 15 is a TGA illustration of the hydrochloride crystal form A of compound 2.

[0183] Figure 16 shows the XRPD diagram of the hydrochloride crystal form B of compound 2.

[0184] Figure 17 shows the DSC diagram of the hydrochloride crystal form B of compound 2.

[0185] Figure 18 is a TGA illustration of the hydrochloride crystal form B of compound 2.

[0186] Figure 19 shows the XRPD diagram of sulfate crystal form A of compound 2.

[0187] Figure 20 shows the DSC diagram of sulfate crystal form A of compound 2.

[0188] Figure 21 is a TGA illustration of the sulfate crystal form A of compound 2.

[0189] Figure 22 shows the XRPD diagram of sulfate crystal form B of compound 2.

[0190] Figure 23 shows the DSC diagram of the sulfate crystal form B of compound 2.

[0191] Figure 24 is a TGA illustration of the sulfate crystal form B of compound 2.

[0192] Figure 25 shows the XRPD diagram of the sulfate crystal form C of compound 2.

[0193] Figure 26 shows the DSC diagram of the sulfate crystal form C of compound 2.

[0194] Figure 27 is a TGA illustration of the sulfate crystal form C of compound 2.

[0195] Figure 28 shows the XRPD diagram of phosphate crystal form A of compound 2.

[0196] Figure 29 shows the DSC diagram of phosphate crystal form A of compound 2.

[0197] Figure 30 is a TGA illustration of phosphate crystal form A of compound 2.

[0198] Figure 31 shows the XRPD diagram of the hydrobromide crystal form A of compound 2.

[0199] Figure 32 is a DSC diagram of the hydrobromide crystal form A of compound 2.

[0200] Figure 33 is a TGA illustration of the hydrobromide crystal form A of compound 2.

[0201] Figure 34 shows the XRPD diagram of the hydrobromide crystal form B of compound 2.

[0202] Figure 35 shows the DSC diagram of the hydrobromide crystal form B of compound 2.

[0203] Figure 36 is a TGA illustration of the hydrobromide crystal form B of compound 2.

[0204] Figure 37 shows the XRPD diagram of the hydrobromide crystal form C of compound 2.

[0205] Figure 38 shows the DSC diagram of the hydrobromide crystal form C of compound 2.

[0206] Figure 39 is a TGA illustration of the hydrobromide crystal form C of compound 2.

[0207] Figure 40 shows the XRPD diagram of the hydrobromide crystal form D of compound 2.

[0208] Figure 41 shows the DSC diagram of the hydrobromide crystal form D of compound 2.

[0209] Figure 42 is a TGA illustration of the hydrobromide crystal form D of compound 2.

[0210] Figure 43 shows the XRPD diagram of the methanesulfonate crystal form A of compound 2.

[0211] Figure 44 shows the DSC diagram of the methanesulfonate crystal form A of compound 2.

[0212] Figure 45 is a TGA illustration of the methanesulfonate crystal form A of compound 2.

[0213] Figure 46 shows the XRPD diagram of fumarate crystal form A of compound 2.

[0214] Figure 47 shows the DSC diagram of fumarate crystal form A of compound 2.

[0215] Figure 48 is a TGA illustration of the fumarate crystal form A of compound 2.

[0216] Figure 49 shows the XRPD diagram of the fumarate crystal form B of compound 2.

[0217] Figure 50 shows the DSC diagram of the fumarate crystal form B of compound 2.

[0218] Figure 51 is a TGA illustration of the fumarate crystal form B of compound 2.

[0219] Figure 52 shows the XRPD diagram of the hydrochloride crystal form C of compound 2.

[0220] Figure 53 shows the DSC diagram of the hydrochloride crystal form C of compound 2.

[0221] Figure 54 is a TGA illustration of the hydrochloride crystal form C of compound 2.

[0222] Figure 55 shows the XRPD diagram of phosphate crystal form B of compound 2.

[0223] Figure 56 shows the DSC diagram of phosphate crystal form B of compound 2.

[0224] Figure 57 is a TGA illustration of phosphate crystal form B of compound 2.

[0225] Figure 58 shows the XRPD diagram of the hydrobromide crystal form E of compound 2.

[0226] Figure 59 shows the DSC diagram of the hydrobromide crystal form E of compound 2.

[0227] Figure 60 is a TGA illustration of the hydrobromide crystal form E of compound 2.

[0228] Figure 61 shows the XRPD diagram of the hydrobromide crystal form F of compound 2.

[0229] Figure 62 shows the DSC diagram of the hydrobromide crystal form F of compound 2.

[0230] Figure 63 shows the XRPD diagram of the hydrobromide crystal form F of compound 2.

[0231] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0232] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. More preferably, lower alkyl groups containing 1 to 6 carbon atoms are used. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. Alkyl groups can be substituted or unsubstituted. When substituted, the substituent can be substituted at any usable connection point. The substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester groups. The present invention preferably uses methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuteralkyl, alkoxy-substituted alkyl, and hydroxy-substituted alkyl.

[0233] The term "alkylene" refers to an alkyl group in which one hydrogen atom is further substituted, for example: "methylene" refers to -CH2-, "ethylene" refers to -(CH2)2-, "propylene" refers to -(CH2)3-, "butylene" refers to -(CH2)4-, etc. The term "alkenyl" refers to an alkyl group as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, etc. Alkenyl groups can be substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

[0234] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentenyl, cyclohexyl, cyclohexenediyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl.

[0235] The term "fused-ring alkyl" refers to a 5- to 20-membered polycyclic carbon group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a fully conjugated π-electron system. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused-ring alkyl, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl. Non-limiting examples of fused-ring alkyl include:

[0236] wait.

[0237] The cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, and non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc. The cycloalkyl group may be optionally substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester group.

[0238] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, or S(O). m (where m is an integer from 0 to 2) heteroatoms, but excluding the ring portions of -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 10 ring atoms; most preferably, it contains 3 to 8 ring atoms; further preferably, it contains 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclic groups containing 1 to 3 nitrogen atoms, optionally substituted with 1 to 2 oxygen atoms, sulfur atoms, or oxo groups, including nitrogen-containing monocyclic heterocyclic groups, nitrogen-containing spirocyclic groups, or nitrogen-containing fused heterocyclic groups; or, preferably, it contains 5 to 12 ring atoms, of which 1 to 4 are heteroatoms, further preferably, it contains 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered heterocyclic groups containing 1 to 3 nitrogen and / or oxygen atoms.

[0239] Non-limiting examples of monocyclic heterocyclic groups include pyrrolyl, imidazoyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazoyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, acrylonitrile, 1,4-diazaheptanyl, pyranyl, etc., preferably pyrrolyl, morpholinyl, piperidinyl, acrylonitrile, 1,4-diazaheptanyl, and piperazinyl. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups; wherein the spirocyclic, fused-ring, and bridged-ring heterocyclic groups involved are optionally connected to other groups by single bonds, or further cyclically linked to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups by any two or more atoms on the ring.

[0240] The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system. One or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. One or more ring atoms are selected from nitrogen, oxygen, or S(O). m (where m is an integer from 0 to 2) heteroatoms, with the remaining ring atoms being carbon. Preferably, they are 6 to 14 members, more preferably 7 to 10 members. Depending on the number of rings, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered and 5-membered or 5-membered and 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

[0241] The heterocyclic ring may be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples include:

[0242] wait.

[0243] The heterocyclic group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester group.

[0244] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 12-membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, including benzo5- to 10-membered heteroaryl, benzo3- to 8-membered cycloalkyl, and benzo3- to 8-membered heteroalkyl, preferably benzo5- to 6-membered heteroaryl, benzo3- to 6-membered cycloalkyl, and benzo3- to 6-membered heteroalkyl, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen, oxygen, and sulfur atoms; or may further include a ternary nitrogen-containing fused ring containing a benzene ring.

[0245] The ring connected to the parent structure is an aryl ring, and non-limiting examples include:

[0246] wait.

[0247] The aryl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, oxo, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0248] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 12-membered, more preferably 5- or 6-membered monocyclic heteroaryl or 8-12-membered bicyclic heteroaryl, such as imidazolyl, furanyl, thiophene, thiazolyl, pyrazolyl, oxazolyl, oxadiazolyl, pyrroleyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazinyl, triazinyl, pyridazinyl, etc., preferably triazolyl, thiophene, imidazolyl, pyrazolyl, oxazolyl, pyrimidinyl, or thiazolyl; more preferably pyrazolyl, pyrroleyl, and oxazolyl.

[0249] The bicyclic heteroaryl group is preferably a 5-membered 5-membered bicyclic heteroaryl group, a 5-membered 6-membered bicyclic heteroaryl group, a 6-membered 5-membered bicyclic heteroaryl group, or a 6-membered 6-membered bicyclic heteroaryl group. Non-limiting examples include:

[0250] The heteroaryl ring may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include:

[0251] wait.

[0252] The heteroaryl group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, oxo, or carboxylic acid ester group.

[0253] The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester group.

[0254] "Halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0255] "Haloalkoxy" refers to an alkoxy group that has been substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0256] "Hydroxyalkyl" refers to an alkyl group that has been replaced by a hydroxyl group, where the alkyl group is as defined above.

[0257] The different terms such as "X is selected from A, B, or C", "X is selected from A, B, and C", "X is A, B, or C", and "X is A, B, and C" all express the same meaning, that is, X can be any one or more of A, B, and C.

[0258] All hydrogen atoms described in this invention can be replaced by their isotope deuterium, and any hydrogen atom in the compounds of the embodiments of this invention can also be replaced by a deuterium atom.

[0259] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or absence of such event or environment. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may but does not have to be present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0260] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, and more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0261] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0262] X-ray powder diffraction (XRPD) refers to the experimentally observed diffraction pattern or parameters derived from it, characterized by peak positions (x-axis) and peak intensities (y-axis). Those skilled in the art will understand that experimental errors depend on instrument conditions, sample preparation, and sample purity. In particular, it is known to those skilled in the art that X-ray diffraction patterns typically change with instrument conditions, and appropriate error tolerances for XRPD can be: 2θ ± 0.5°; 2θ ± 0.4°; 2θ ± 0.3°; 2θ ± 0.2°. It is particularly important to note that the relative intensities of the X-ray diffraction pattern can also vary with experimental conditions, so the order of peak intensities cannot be considered the sole or decisive factor. Furthermore, the influence of experimental factors such as sample height can cause an overall shift in peak angles, which is generally permissible. Therefore, those skilled in the art will understand that any crystal form with characteristic peaks identical or similar to those of the patterns of this invention falls within the scope of this invention.

[0263] "TGA" refers to thermogravimetric analysis (TGA) experiments.

[0264] "DSC" refers to the Differential Scanning Calorimetry (DSC) experiment. Detailed Implementation

[0265] The present invention is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the present invention.

[0266] Example

[0267] The structures of the compounds of this invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer in the following solvents: deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), deuterated chloroform (CDCl3), or deuterated water (D2O), with tetramethylsilane (TMS) as the internal standard (if applicable).

[0268] LC-MS analysis was performed using an Agilent 1200 Infinity Series mass spectrometer. HPLC analysis was performed using an Agilent 1200DAD high-performance liquid chromatograph (Sunfire C18 150×4.6 mm column) and a Waters 2695-2996 high-performance liquid chromatograph (Gimini C). 18 (150×4.6mm chromatographic column).

[0269] Thin-layer chromatography (TLC) uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The standard size for TLC is 0.15mm to 0.20mm, while the standard size for separating and purifying products using TLC is 0.4mm to 0.5mm. Column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0270] The starting materials used in the embodiments of the present invention are known and commercially available, or can be synthesized using or in accordance with methods known in the art.

[0271] Unless otherwise specified, all reactions in this invention are carried out under continuous magnetic stirring, in a dry nitrogen or argon atmosphere, using a dry solvent, and the reaction temperature is expressed in degrees Celsius.

[0272] The eluent system for silica gel column chromatography and the developing solvent system for thin-layer chromatography used in the intermediates and the purification compounds in the examples include: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: dichloromethane and acetone system. The volume ratio of the solvent is adjusted according to the polarity of the compound, and small amounts of basic or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

[0273] Unless otherwise specified, in the embodiments of the present invention, the ratio of the mobile phase in the HPLC chiral separation condition and the HPLC chiral analysis condition is a volume ratio.

[0274] Synthesis of Intermediate 1

[0275] (1S,3S)-N1-(7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopentane-1,3-diamine

[0276] Step 1: Under nitrogen protection, 2-bromo-7-fluoro-[1,2,4]triazolo[1,5-a]pyridine (500 mg, 2.31 mmol), N-[(1S,3S)-3-aminocyclopentyl]carbamate tert-butyl ester (510 mg, 2.55 mmol), cesium carbonate (1.51 g, 4.63 mmol), tris(dibenzylacetone)dipalladium (424 mg, 0.46 mmol), and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (536 mg, 0.92 mmol) were dissolved in 1,4-dioxane (15 mL). The mixture was microwaved to 130 °C and stirred for 2 hours. The reaction solution was filtered, and the filtrate was concentrated. The residue was analyzed by silica gel column chromatography (elution system B) and preparative HPLC (formic acid system) to give N-[(1S,3S)-3-[(7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino]cyclopentyl]carbamate tert-butyl ester (240 mg), yield: 30.9%. MS m / z (ESI): 336.0 [M+H] + .

[0277] Step 2: The product from the previous step (202 mg, 0.60 mmol) was dissolved in methanol (2 mL) at room temperature and stirred. A solution of 1,4-dioxane hydrochloric acid (4 M, 5 mL) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the residue was purified by preparative HPLC (ammonia system) to obtain (1S,3S)-N1-(7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopentane-1,3-diamine intermediate 1 (140 mg), yield: 98.6%. MS m / z (ESI): 236.2 [M+H] + .

[0278] Synthesis of intermediate 2

[0279] (1S,3S)-N1-(7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopentane-1,3-diamine

[0280] Step 1: 4-(trifluoromethyl)pyridin-2-amine (5 g, 30.84 mmol) and ethyl N-(thiomethylene)carbamate (4.85 g, 37.01 mmol) were dissolved in 1,2-dichloroethane (50 mL) at room temperature and stirred for 16 hours. The reaction solution was concentrated to obtain N-[[4-(trifluoromethyl)-2-pyridyl]aminomethylthiazolyl]carbamate ethyl ester (9.05 g). The product did not require purification and was used directly in the next reaction. MS m / z (ESI): 294.1 [M+H] + .

[0281] Step 2: The product from the previous step (9 g, 30.69 mmol), hydroxylamine hydrochloride (10.66 g, 153.44 mmol), and N,N-diisopropylethylamine (11.90 g, 92.07 mmol) were dissolved in methanol (100 mL) at room temperature and stirred for 20 minutes. The mixture was then heated to 65 °C and stirred for 3 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (elution system A) to give 7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine (5.0 g), yield: 80.60%. MS m / z (ESI): 203.1 [M+H] + .

[0282] Step 3: The product from the previous step (5 g, 24.74 mmol) and copper bromide (5.52 g, 24.74 mmol) were dissolved in acetonitrile (50 mL), and tert-butyl nitrite (12.75 g, 123.68 mmol) was added. The reaction was stirred at room temperature for 0.5 hours, then heated to 70 °C and stirred for 2 hours. The reaction solution was concentrated, the residue was diluted with ethyl acetate (150 mL), filtered, the organic phase was washed with water (100 mL), concentrated, and the residue was purified by silica gel column chromatography (elution system A) to give 2-bromo-7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine (5 g), yield 75.99%. MS m / z (ESI): 266.0, 268.0 [M+H] + .

[0283] Step 4: Under nitrogen protection, the product from the previous step (4.5 g, 16.92 mmol), N-[(1S,3S)-3-aminocyclopentyl]carbamate tert-butyl ester (3.39 g, 16.92 mmol), cesium carbonate (11.02 g, 33.83 mmol), tris(dibenzylacetone)dipalladium (2.32 g, 2.54 mmol), and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (2.94 g, 5.07 mmol) were dissolved in 1,4-dioxane (120 mL). The reaction mixture was heated to 130 °C and stirred for 16 hours. The reaction solution was filtered and concentrated. The residue was purified by silica gel column chromatography (elution system A) to give N-[(1S,3S)-3-[[7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]cyclopentyl]tert-butyl carbamate (3.7 g), yield: 56.76%. MS m / z (ESI): 386.2 [M+H] + .

[0284] Step 5: The product from the previous step (3.7 g, 9.60 mmol) and hydrochloric acid (4 M in dioxane, 36.00 mL) were dissolved in methanol (10 mL) at room temperature and stirred for one hour. The reaction solution was concentrated, and the residue was diluted with methanol and the pH was adjusted to 8-10 with saturated sodium bicarbonate solution. After concentration, the residue was purified by silica gel column chromatography (elution system A) to obtain (1S,3S)-N1-(7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopentane-1,3-diamine (2.74 g), yield: 100%. MS m / z (ESI): 286.2 [M+H] + .

[0285] Example 1

[0286] 5'-Fluoro-6'-(((1S,3S)-3-((7-Fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one

[0287] Step 1: Intermediate 1 (60 mg, 0.26 mmol), 5-bromo-2,3-difluoropyridine (99 mg, 0.51 mmol), and N,N-diisopropylethylamine (132 mg, 1.02 mmol) were dissolved in dimethyl sulfoxide (2 mL). The reaction mixture was heated to 100 °C and stirred for 16 hours. Saturated sodium chloride solution was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried, concentrated, and the residue was separated by silica gel column chromatography to obtain (1S,3S)-N 1 -(5-bromo-3-fluoropyridin-2-yl)-N3 -(7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopentane-1,3-diamine 1a (75 mg), yield: 71.86%. MS m / z (ESI): 409.1 [M+H] + .

[0288] Step 2: Under nitrogen protection, 1a (75 mg, 0.18 mmol), 2-pyridone (52 mg, 0.55 mmol), cuprous iodide (35 mg, 0.18 mmol), trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (26 mg, 0.18 mmol) and cesium carbonate (119 mg, 0.37 mmol) were dissolved in 1,4-dioxane (1.5 mL), and the reaction was heated to 120 °C and stirred for 16 hours. A saturated ammonium chloride solution was added to the reaction mixture. The aqueous phase was extracted with ethyl acetate (25 mL × 2). The organic phases were combined, dried, and concentrated. The residue was subjected to reversed-phase HPLC (formic acid system) to prepare 5'-fluoro-6'-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one 1 (27.9 mg), yield: 35.95%. MS m / z (ESI): 424.2 [M+H] + .

[0289] 1 H NMR(400MHz,DMSO-d6)δ8.71-8.61(m,1H),7.84(d,1H),7.68-7.62(m,1H),7 .58-7.53(m,1H),7.52-7.46(m,1H),7.30-7.24(m,1H),6.94(d,1H),6.90-6 .82(m,1H),6.75(d,1H),6.46(d,1H),6.32-6.25(m,1H),4.62-4.42(m,1H), 4.24-4.09(m,1H),2.22-2.07(m,2H),2.05-1.88(m,2H),1.69-1.48(m,2H).

[0290] Example 2

[0291] 6-(5-fluoro-6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[0292] Step 1: Intermediate 2 (150 mg, 0.53 mmol), 2,3-difluoro-5-nitro-pyridine (93 mg, 0.58 mmol), and cesium carbonate (428 mg, 1.31 mmol) were dissolved in N,N-dimethylformamide (3 mL), and the mixture was heated to 80 °C and stirred for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (elution system B) to give (1S,3S)-N1-(3-fluoro-5-nitro-2-pyridyl)-N3-[7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopentane-1,3-diamine 2a (180 mg), yield: 80.5%. MS m / z (ESI): 426.1 [M+H] + .

[0293] Step 2: Under a hydrogen atmosphere, 2a (158 mg, 0.37 mmol) and palladium / carbon (40 mg, 0.037 mmol, purity: 10%) were dissolved in methanol (10 mL), and the reaction was stirred at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was concentrated to give 3-fluoro-N2-[(1S,3S)-3-[[7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]cyclopentyl]pyridin-2,5-diamine 2b (131 mg), yield: 88.5%. MS m / z (ESI): 396.1 [M+H] + .

[0294] Step 3: 2b (131 mg, 0.33 mmol), methyl 3-(bromomethyl)pyridine-2-carboxylic acid (85 mg, 0.28 mmol), and N,N-diisopropylethylamine (107 mg, 0.83 mmol) were dissolved in a mixed solvent of n-butanol (6 mL) and N,N-dimethylformamide (0.5 mL). The mixture was heated to 40 °C and stirred for 11 hours, then heated to 110 °C and stirred for 5 hours. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by preparative HPLC (formic acid system) to give 2 (100.4 mg), yield: 70.7%. MS m / z (ESI): 513.2 [M+H] + .

[0295] 1H NMR(400MHz,DMSO-d6)δ8.82(d,1H),8.76(dd,1H),8.24(d,1H),8.12(dd,1H),8.03(dd,1H),7.85(s,1H),7.63(dd,1H),7.14 (dd,1H),7.01(d,1H),6.66(d,1H),4.96(s,2H),4.59–4.15(m,2H),2.24–2.10(m,2H),2.04–1.93(m,2H),1.68–1.51(m,2H).

[0296] Example 3

[0297] 6-(5-Fluoro-6-(((1S,3S)-3-((7-Fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)aminopyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[0298] Step 1: Under nitrogen protection, intermediate 1 (150 mg, 0.6 mmol), 2,3-difluoro-5-nitropyridine (123 mg, 0.7 mmol), and N,N-diisopropylethylamine (233 mg, 1.8 mmol) were dissolved in N,N-dimethylformamide (5 mL), and the reaction was stirred at 25 °C for 16 hours. The reaction mixture was filtered, the filtrate was concentrated, and the residue was separated by silica gel column chromatography (elution system A) to obtain (1S,3S)-N 1 -(3-Fluoro-5-nitropyridin-2-yl)-N 3 -(7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopentane-1,3-diamine 3a (200 mg), yield: 87%. MS m / z (ESI): 376.2 [M+H] + .

[0299] Step 2: Under a hydrogen atmosphere, 3a (200 mg, 0.5 mmol) and palladium on carbon (70 mg, 10%) were dissolved in methanol (5 mL), and the reaction was heated to 50°C and stirred for 2 hours. The reaction was filtered, and the filtrate was concentrated to obtain 3-fluoro-N. 2 -((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)pyridin-2,5-diamine 3b (170 mg), yield: 97%. MS m / z (ESI): 346.2 [M+H] + .

[0300] Step 3: Under nitrogen protection, 3b (90 mg, 0.25 mmol) and N,N-diisopropylethylamine (130 mg, 1 mmol) were dissolved in a mixture of N,N-dimethylformamide (2 mL) and tert-butanol (5 mL). Methyl 3-(bromomethyl)pyridinecarboxylate (50 mg, 0.23 mmol) was added with stirring. The reaction was stirred at 25 °C for 16 hours, and then heated to 85 °C and stirred for 16 hours. The reaction was filtered, the filtrate was concentrated, and the residue was separated by preparative HPLC (formic acid system) to obtain 6-(5-fluoro-6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)aminopyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 3 (20 mg), yield: 17%. MS m / z (ESI): 463.2 [M+H] + .

[0301] 1 H NMR(400MHz,DMSO-d6)δ8.76(dd,1H),8.65(dd,1H),8.24(d,1H),8.12(dd,1H),8.03(dd,1H),7.63(dd,1H),7.27(dd,1H),6.86 (td,1H),6.74(d,1H),6.67(d,1H),4.96(s,2H),4.49(q,1H),4.16(q,1H),2.20–2.10(m,2H),1.98(dt,2H),1.63–1.52(m,2H).

[0302] The synthesis method of the embodiments can be referred to the above embodiments.

[0303] The NMR characterization data of the relevant embodiments are shown in the table below:

[0304] Biological testing evaluation

[0305] The present invention will be further described and explained below with reference to test examples, but these embodiments are not intended to limit the scope of the present invention.

[0306] I. Combining experiments

[0307] Test Example 1: Determination of the binding ability of the compounds of the present invention to PCSK9 protein.

[0308] 1. Experimental objective: To detect the effect of compounds on the binding of PCSK9 protein using the HTRF method.

[0309] 2. Experimental Methods:

[0310] 1) Prepare a 1x experimental buffer solution with the following components: 20mM HEPES, 150mM NaCl, 1mM CaCl2, 0.01% Tween 20, and 0.01% BSA;

[0311] 2) Prepare a 2.5x final concentration PCSK9-His working solution (30nM) using 1x experimental buffer. Add 8uL of protein solution to each well of the 384-well plate except for the low control wells, and add 8uL of 1x experimental buffer to the low control wells.

[0312] 3) Preparation of compound working solution: First, the compound in the storage solution is uniformly serially diluted with DMSO (300 uM top, 3-fold, 10 doses). Then, 3.33 uL of each serially diluted compound is pipetted into 96.7 uL of 1x experimental buffer and mixed thoroughly to obtain the prepared compound working solution (10x).

[0313] 4) Pipette 2 μL of the compound into the corresponding well and incubate at 25°C for 10 minutes;

[0314] 5) Prepare a working solution of the probe compound at a final concentration of 4x using 1x experimental buffer (90 nM), mix thoroughly, add 5 μL to each well, and incubate at 25°C for 10 minutes;

[0315] 6) Prepare a 4x final concentration Anti-His Tb working solution (4x) using 1x experimental buffer, add 5 μL to each well, and incubate at 25°C for 2 hours;

[0316] 7) Envision reading HTRF665 / 615 program.

[0317] 3. Experimental data processing methods: XLfit four-parameter log(inhibitor) vs. response-variable slope (four parameters) was used to fit the compound concentration, corresponding inhibition rate, and nonlinearity, and IC was calculated. 50 .

[0318] 4. Experimental Results:

[0319] 5. Experimental conclusions: As can be seen from the data in the table, the compounds in the embodiments of this invention have a significant binding effect on the PCSK-9 protein.

[0320] II. Cell Function Experiments

[0321] Test Example 1: Determination of the effect of the compound of the present invention on the concentration of PCSK9 secreted by HepG2 cells.

[0322] 1. Experimental objective: To detect the inhibitory effect of the compound on PCSK9.

[0323] 2. Experimental Methods:

[0324] 1) HepG2 cell line was cultured in complete medium at 37°C with 5% CO2 until 70%–90% confluence.

[0325] 2) Digest and resuspend the cells in experimental culture medium, and seed 25,000 cells / well / 200μL into a 96-well cell culture plate and incubate at 37°C and 5% CO2 for 20-24 hours.

[0326] 3) Remove the culture medium from the cell culture plate and wash each well with 200 μL of experimental culture medium.

[0327] 4) Prepare positive control compound and test compound: Dilute positive control compound and test compound on compound plate.

[0328] 5) Add the diluted compound to the cell culture plate at 250 μL per well and incubate at 37°C with 5% CO2 for 48 hours.

[0329] 6) Collect 200 μL of cell culture medium per well and freeze at -80℃ for later use.

[0330] 7) Take the cell culture medium sample out of -80℃ to dissolve, vortex, centrifuge, and set aside.

[0331] 8) Prepare standard curves: Add the corresponding volume of dilution buffer to each standard tube in sequence. Take the corresponding volume of standard from the original tube or the previous concentration tube in the order of concentration 10, 5, 2.5, 1.25, 0.625, 0.313, 0.16, 0 ng / mL and dilute it in sequence.

[0332] 9) Prepare washing solution: Dilute 10x Wash buffer with Milli-Q to 1x and set aside.

[0333] 10) According to the plate map settings for standard curve wells and sample wells, add 100 μL of the corresponding standard and culture medium sample to each well, with 2 replicates. Seal with adhesive tape, place on a shaker at room temperature, gently shake to mix, and incubate for 1 hour.

[0334] 11) Place the plate on the plate washer, set the washing solution to 350 μL per well, repeat 4 times to wash the plate.

[0335] 12) Add 100 μL of HRP-conjugated detection antibody to each well, seal with adhesive tape, mix thoroughly on a shaker, and incubate for 1 hour.

[0336] 13) Place the plate on the plate washer, set the washing solution to 350 μL per well, repeat 4 times to wash the plate.

[0337] 14) Add 100 μL of Substrate reagent to each well, protect from light, seal with adhesive tape, mix thoroughly on a shaker, and incubate for 10-20 minutes.

[0338] 15) Add 100 μL of stop solution (1N H2SO4) to each well and mix well.

[0339] 16) Measure the optical density (OD) value of each well sequentially at a wavelength of 450 nm using an ELISA reader. Perform the detection within 30 minutes after the reaction is terminated.

[0340] 3. Experimental Data Processing Method: The OD values ​​read by the microplate reader were subtracted from the OD values ​​of the standard group (0 concentration) from those of the standard, control group, and sample to obtain the actual values ​​for each well. A standard curve was then plotted using GraphPad to calculate the sample concentration. If the sample was over-diluted, the final calculation needed to multiply by the corresponding dilution factor to obtain the actual sample concentration. Inhibition rate = (actual control concentration - actual sample concentration) / actual control concentration * 100. Based on the inhibition rates corresponding to different concentrations, the IC50 was plotted using GraphPad. 50 .

[0341] 4. Experimental Results:

[0342] 5. Experimental Conclusion: As can be seen from the data in the table, the compounds in the embodiments of this invention showed a strong inhibitory effect on the concentration of PCSK9 secreted by HepG2 cells in the experiment.

[0343] III. Pharmacokinetic Experiments

[0344] Test Example 1: Pharmacokinetic Determination in Mice

[0345] 1. Experimental objective: Using C57BL / 6J mice as test animals, to study the pharmacokinetic behavior of the compound of the present invention in mice (plasma) after oral and intravenous administration.

[0346] 2. Test Plan

[0347] 2.1 Test reagents: The compounds of this invention, prepared in-house;

[0348] 2.2 Test animals: C57 mice, male, purchased from Shanghai Bikai Laboratory Animal Co., Ltd., with animal production license number (SCXK(Shanghai)2013-0006N0.311620400001794).

[0349] 2.3 Drug preparation: Oral administration drug preparation: 10% Solutol HS15

[0350] Weigh 10 g of Solutol HS15 solid, dissolve it in 90 mL of pure water, mix evenly, stir and sonicate to form a clear solution. Weigh the compound of the present invention and dissolve it in this solution, shake well, and sonicate for 15 minutes to obtain a colorless clear solution with a concentration of 0.5 mg / mL. Intravenous administration drug preparation: 5% DMSO + 10% Solutol HS15 + 85% PBS. Weigh the compound of the present invention, first add 5% DMSO according to the total administration volume ratio, vortex and sonicate for 2 min to completely dissolve it; then add 10% Solutol HS15, vortex and sonicate for 2 min to completely dissolve it; finally add 85% PBS, vortex and sonicate for 5 min, and filter through a 0.22 um filter membrane to obtain a colorless transparent clear solution with a concentration of 0.2 mg / mL.

[0351] 2.4 Administration: 3 male C57 mice; after fasting overnight, they were administered orally respectively, with a dose of 5 mg / kg and an administration volume of 10 mL / kg. 3 male C57 mice; after fasting overnight, they were administered intravenously respectively, with a dose of 1 mg / kg and an administration volume of 5 mL / kg.

[0352] 2.5 Sample collection: Before and 0.083 (iv), 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration to the mice, 0.04 mL of blood was collected from the orbital cavity, placed in an EDTA-K2 test tube, centrifuged at 6000 rpm for 6 min at 4°C to separate plasma, and stored at -80°C; the mice were allowed to eat 4 hours after administration.

[0353] 2.6 Measurement results: The final measurement results were obtained using the LCMS / MS method.

[0354] 3. Experimental results: The main pharmacokinetic parameters were calculated using WinNonlin 6.1.

[0355] 4. Experimental conclusion: The pharmacokinetic measurement results of C57BL / 6J mice showed that the compound of the present invention exhibited good PK advantages.

[0356] Test Example 2, Pharmacokinetic Determination of Cynomolgus Monkeys

[0357] 1. Research objective: To investigate the pharmacokinetic behavior of the compound of the present invention in cynomolgus monkeys (plasma) after oral administration at a dose of 5 mg / kg.

[0358] 2. Experimental Design:

[0359] 2.1 Experimental reagents: The compounds in the embodiments of this invention were prepared in-house.

[0360] 2.2 Experimental animals: 3 male cynomolgus monkeys per group, from Guangxi Xiongsen, Animal Production License No.: SCXK(Gui)2021-0004).

[0361] 2.3 Formulation: Oral administration drug preparation: 10% Solutol HS15 in water

[0362] Weigh 10g of solid Solutol HS15 and add it to 90ml of ddH2O in a 100ml volumetric flask. Vortex, mix, and sonicate to obtain a clear solution. Weigh the compound and add it to a 100mL glass bottle. Add the solution, vortex, and sonicate for 10 minutes to obtain a white suspension with a concentration of 1mg / mL.

[0363] 2.4 Administration: Three male cynomolgus monkeys were fasted overnight and then administered orally; the dose was 5 mg / kg, and the administration volume was 5 mL / kg.

[0364] 2.5 Sample collection: Blood collection: 0.3 mL of blood was collected from the forelimb veins of cynomolgus monkeys before and 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after drug administration. The blood was placed in EDTA-K2 anticoagulant tubes and centrifuged at 6000 rpm for 6 min at 4℃ to separate plasma. The plasma was stored at -80℃. The monkeys were fed 4 hours after drug administration.

[0365] 2.6 Sample preparation:

[0366] 1) Add 40 μL of plasma sample to 160 μL of acetonitrile to precipitate, mix, and centrifuge at 3500×g for 5–20 minutes.

[0367] 2) Take the supernatant solution after treatment and perform LC / MS / MS analysis to determine the concentration of the analyte. LC / MS / MS instrument: AB Sciex API 4000Qtrap.

[0368] Liquid phase analysis: Liquid phase conditions: Shimadzu LC-20AD pump

[0369] Chromatographic column: Agilent ZORBAX XDB-C18 (50×2.1mm, 3.5μm); Mobile phase: Solution A was 0.1% formic acid aqueous solution, Solution B was acetonitrile; Flow rate: 0.4mL / min

[0370] Elution time: 0-4.0 minutes, eluent as follows:

[0371] 3. Experimental results: The main pharmacokinetic parameters were calculated using WinNonlin 6.1.

[0372] 4. Experimental Conclusions: Pharmacokinetic analysis results in cynomolgus monkeys showed that the compounds of this invention exhibited good pharmacokinetic advantages, with the compound AUC being [missing information]. 0- ∞ (ng / mL×h) ranges from 20,000 to 50,000, with the AUC of the dominant compound being... 0-∞ (ng / mL×h) is 30,000 to 50,000.

[0373] Test Example 3: In vitro metabolic stability study of the compounds of the present invention in mouse, rat and human liver microsomes

[0374] 1. Experimental objective: The objective of this experiment is to evaluate the metabolic stability of the compound in phase I and part of phase II in mouse, rat and human liver microsomes.

[0375] 2. Experimental Design

[0376] 2.1 Drug Preparation: The compounds of this invention were prepared into 10 mM stock solutions using DMSO (or other suitable solutions) and stored at -20°C for later use. The compounds of this invention were prepared in-house.

[0377] 2.2 Experimental Procedure

[0378] 1) Prepare buffer solution: Take 4.01 mL of 1M K2HPO4·3H2O (AR grade) and 0.99 mL of 1M KH2PO4 (AR grade), dissolve them in ultrapure water and bring the volume to 50 mL to prepare a phosphate buffer solution with a final concentration of 100 mM.

[0379] 2) Preparation of working solution: Add 2 μL of the compound stock solution to 998 μL of phosphate buffer to achieve a final concentration of 20 μM. The ratio and final concentration can be adjusted according to the properties of the compound.

[0380] 3) Prepare liver microsome working solution: 156.3 μL of 20 mg / mL microsomes, diluted to 5 mL with 100 mM phosphate buffer, mixed well, with a final concentration of 0.625 mg / mL.

[0381] 4) Prepare NADPH and UDPGA: Weigh 33.3 mg of NADPH and 25.8 mg of UDPGA, add 2 mL of 100 mM phosphate buffer, and the final concentration of both is 20 mM.

[0382] 5) Prepare the pore-drilling agent (Alamethicin): Weigh 1 mg of Alamethicin and add it to 200 μL of methanol to prepare a solution of 5 mg / mL. Then take 10 μL of this solution and add it to 990 μL of phosphate buffer (pH 7.4) to obtain a final concentration of 50 μg / mL.

[0383] 6) Prepare the reaction termination solution: Dilute the internal standard with acetonitrile (or other suitable solution) to prepare the termination solution and store it in a refrigerator at 2-8℃.

[0384] 7) Incubation Procedure: Add 400 μL of prepared liver microsomes, 25 μL of the compound working solution (20 μM), and 25 μL of Alamethicin (50 μg / mL) sequentially to a 96-well plate, and pre-incubate at 37°C for 10 min. Then add 50 μL of prepared NADPH / UDPGA to initiate the reaction and incubate at 37°C. The total reaction volume is 500 μL. The final concentrations of each component are as follows:

[0385] At time points of 0, 5, 15, 30, 60 and 120 min, 50 μL of each sample was taken and 200 μL of cold stop solution containing internal standard was added to terminate the reaction. The sample was centrifuged at 3500 rpm for 10 min and the supernatant was taken for LC-MS / MS analysis.

[0386] 2.4 Chromatographic Analysis

[0387] 1) Chromatographic conditions:

[0388] Instrument: Shimadzu LC-20AD; Column: Phenomenex C18 (50*4.6mm, 5μm particle size); Mobile phase: A: 0.1% formic acid aqueous solution, B: acetonitrile; Wash gradient: 0.2–1.6 min 5% A to 95% A, 3.0–3.1 min 95% A to 5% A; Flow rate: 1.0 ml / min; Run time: 4.0 min; Injection volume: 5 μL.

[0389] 2) Mass spectrometry conditions

[0390] Instrument: API4000 liquid chromatography-mass spectrometry system, AB Sciex; Ion source: electrospray ionization source (ESI); Dry gas: N2, temperature 500℃; Electrospray voltage: 5000V; Detection mode: positive ion detection; Scan mode: reaction monitoring (MRM); Scan time: 0.8401s.

[0391] 3. Data Processing: Calculate the raw data using the following formula:

[0392] Residual percentage % = (Peak area ratio of compound to internal standard at any time point) / (Peak area ratio of compound to internal standard at 0 minutes) × 100

[0393] T 1 / 2 =0.693 / Ke, where Ke represents the elimination rate constant.

[0394] In vitro intrinsic clearance rate of liver microsomes (CL) was calculated using Ke. int ) and hepatic intrinsic clearance (CL) int,liver )

[0395] CL int =0.693 / T 1 / 2 / Microsomal protein content (microsomal concentration during incubation, mg / mL)

[0396] CL int,liver =CL int × Liver microsomal protein content (mg / g) × Liver weight to body weight ratio

[0397] Based on the well-stirred model, the in vivo liver clearance rate (CL) was estimated. int,liver )

[0398] CL = (CL) int,liver ×fu×Qh) / (CL int,liver ×fu+Qh), where fu represents the free fraction in the blood, which is 1 by default. The parameters in the formula are shown in the table below.

[0399] 4. Experimental Results:

[0400] 5. Experimental conclusions: The results show that the compounds of the advantageous embodiments of the present invention exhibit stable metabolic effects in various liver microsomes, especially in human liver microsomes.

[0401] IV. Drug Efficacy Experiment

[0402] Test Example 1: In vivo pharmacodynamic study of the compound of the present invention in a B6-hPCSK9 transgenic mouse model of hyperlipidemia.

[0403] 1. Experimental objective: To evaluate the in vivo efficacy of the compound in a B6-hPCSK9 transgenic mouse model of hyperlipidemia.

[0404] 2 Experimental Operation and Data Processing

[0405] 2.1 Animals: B6-hPCSK9 transgenic C57 mice, 6-8 weeks old, male, purchased from Jiangsu Jicui Pharmaceutical Biotechnology Co., Ltd.

[0406] 2.2 Animal Model: After animals arrived at the barrier system, they were allowed to adapt for one week before being fed a high-fat diet. Animal weight and feed intake were recorded weekly.

[0407] 2.3 Grouping and Administration

[0408] a. Grouping is done using a random grouping method.

[0409] c. Based on the grouping results, begin administering the test drug (administration route: oral; administration volume: 10 mL / kg; administration frequency: once daily or single dose; administration period: 21 days; solvent: 10% Solutol HS15 / 90% Saline). Test drug: the compound of this invention, prepared in-house.

[0410] d. After starting the test drug, weigh and feed twice a week, and collect blood once a week.

[0411] e. Process data using software such as Excel. Body weight change rate (BWC) (%) = (Weight at the end of treatment - Weight at the beginning of treatment) / Weight at the beginning of treatment × 100%; Feed intake (g / mice / day) = (Previous feed addition + Previous feed residue - Current feed residue) / Number of animals / Number of feeding days; Calculation of blood biochemical inhibition rate: Using the blood biochemical results of the Vehicle group tested in the same batch as a baseline, normalize the data of each treatment group, and then calculate the percentage of TC and LDL-C according to the formulas: TC change percentage (%) = (TC value after administration - TC value before administration) / TC value before administration * 100%; LDL-C change percentage (%) = (LDL-C value after administration - LDL-C value before administration) / LDL-C value before administration * 100%. Detect PCSK9 in plasma using ELISA.

[0412] 3. Experimental Results:

[0413] 4. Experimental conclusion: The compounds in the embodiments of this invention can effectively reduce LDL-C in the B6-hPCSK9 transgenic mouse model of hyperlipidemia.

[0414] Crystal form study of the examples

[0415] As is well known to those skilled in the art, the compounds in the above embodiments have been shown to effectively bind to the PCSK9 protein and exhibit good inhibitory effects on PCSK9 secreted by HepG2 cells. Their crystal forms often possess the same pharmacological and efficacy activities. Based on this, the inventors further investigated the physicochemical properties of the corresponding crystal forms. However, the preparation and characterization of the specific crystal forms described below do not constitute a limitation on the scope of protection of this invention. Those skilled in the art can use this invention as a basis to obtain more crystals of the compounds of this invention through conventional crystallization methods. These crystals are all schemes protected by this invention. Specifically, as follows:

[0416] 1.1 Experimental Apparatus

[0417] 1.1.1 Some parameters of physicochemical detection instruments

[0418] 1.2 Instruments and Liquid Chromatography Analysis Conditions

[0419] 1.2.1 Instruments and Equipment

[0420] 1.2.2 Chromatographic conditions

[0421] Chromatographic column: Waters Xbridge C18 (4.6mm*150mm, 3.5μm)

[0422] Flow rate: 1.0 mL / min; Column temperature: 37℃; Detection wavelength: 230 nm

[0423] Injection volume: 5 μL; Run time: 15 min; Diluent: Methanol

[0424] Mobile phase: A: 0.1% aqueous solution of phosphoric acid; B: acetonitrile

[0425] Salts and crystal forms of compounds

[0426] 1. Preparation of different salts and crystal forms of 5'-fluoro-6'-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one

[0427] 1.1 Preparation of free alkali crystal form A

[0428] Take 6.5g of crude product, add 20mL of methanol, and slurry at 60℃ for 40min. After slow cooling, cool with ice water and then pump dry to obtain the product solid. The obtained solid was tested and found to be free alkali crystal form A by XRPD.

[0429] The characteristic X-ray diffraction peaks of crystal form A, expressed in terms of 2θ angle and interplanar spacing d, are shown in the table below:

[0430] 1.2. Preparation of Salt Crystal Forms

[0431] 1.2.1 Preparation of hydrochloride crystal form A

[0432] Weigh 20 mg of free base, add 0.2 mL of 88% acetone aqueous solution, stir and dissolve at 50 °C, add 0.06 mL of 1 M hydrochloric acid methanol solution to the system, dissolve and precipitate, react for 6 h, then cool to room temperature and stir for 12 h, centrifuge and dry the solid to finally obtain hydrochloride crystal form A.

[0433] The characteristic X-ray diffraction peaks of the hydrochloride crystal form A, expressed in terms of 2θ angle and interplanar spacing d, are shown in the table below:

[0434] After testing and analysis, it has the XRPD diagram shown in Figure 1, the DSC diagram shown in Figure 2, and the TGA diagram shown in Figure 3.

[0435] 1.2.2 Preparation of Methanesulfonate Crystal Form A

[0436] Weigh 20 mg of free alkali crystal form A, add 0.2 mL of acetone, stir and suspend at 50 °C, add 0.06 mL of 1 M methanesulfonic acid methanol solution to the system, react for 6 h, then cool to room temperature and stir for 12 h, centrifuge and dry the solid to finally obtain methanesulfonate crystal form A.

[0437] The characteristic X-ray diffraction peaks of the methanesulfonate crystal form A, expressed as 2θ angle and interplanar spacing d, are shown in the table below:

[0438] After testing and analysis, it has the XRPD diagram shown in Figure 4, the DSC diagram shown in Figure 5, and the TGA diagram shown in Figure 6.

[0439] 1.2.3 Preparation of benzenesulfonate crystal form A

[0440] Weigh 20 mg of free alkali crystal form A, add 0.2 mL of ethanol, stir and suspend at 50 °C, add 0.06 mL of 1 M benzenesulfonic acid methanol solution to the system, react for 6 h, then cool to room temperature and stir for 12 h, centrifuge and dry the solid to finally obtain benzenesulfonate crystal form A.

[0441] The characteristic X-ray diffraction peaks of the benzenesulfonate crystal form A, expressed in terms of 2θ angle and interplanar spacing d, are shown in the table below:

[0442] After testing and analysis, it has the XRPD diagram shown in Figure 7, the DSC diagram shown in Figure 8, and the TGA diagram shown in Figure 9.

[0443] 1.2.4 Preparation of hydrobromide crystal form A

[0444] Weigh 150 mg of free alkali crystal form A, add 3 mL of ethanol, stir and suspend at 50 °C, add 0.32 mL of 1 M hydrobromic acid methanol solution to the system, react for 24 h, centrifuge and dry the solid to finally obtain hydrobromide crystal form A.

[0445] The characteristic X-ray diffraction peaks of the hydrobromide crystal form A, expressed as 2θ angle and interplanar spacing d, are shown in the table below:

[0446] After testing and analysis, it has the XRPD diagram shown in Figure 10, the DSC diagram shown in Figure 11, and the TGA diagram shown in Figure 12.

[0447] 2. Salt-type crystal form screening

[0448] 2.1 Salt type screening

[0449] 2.1.1 Experimental objective: To select different counterionic acids and, through appropriate crystallization methods, to detect which counterionic acids can form compound salts.

[0450] 2.1.2 Experimental Procedure:

[0451] 1) Instruments and equipment

[0452] 2) Procedure: Weigh approximately 20 mg of free alkali crystal form A, add 200 μL of acetone, suspend and stir at 45°C or room temperature, then add the corresponding volume of counterion acid solution (base:acid molar ratio = 1:1.2) to react. After stirring for 12 hours, centrifuge or evaporate, remove the supernatant, dry the solid at 50°C, and characterize it. The results are as follows:

[0453] 2.2 Polymorph screening of different salts

[0454] 2.2.1 Solid-liquid reaction crystallization using 88% acetone-water as solvent.

[0455] Approximately 200 mg of free alkali crystal form A was weighed and divided into 9 portions. Each portion was then dissolved in 200 μL of 88% acetone aqueous solution by stirring at 50 °C. After dissolving, 40 μL of a counter-ionic acid solution (base:acid molar ratio of 1:1.2) was added, and the mixture was allowed to crystallize at room temperature. The results are as follows:

[0456] 2.2.2 Screening of hydrochloride polymorphs

[0457] Approximately 20 mg of hydrochloride crystal form A was weighed into a small glass vial, and 200 μL of organic solvent was added. The mixture was stirred at 50°C for 7 days. The results are as follows:

[0458] Results and Discussion: No polymorphism was found in hydrochloride crystal form A when it was pulped in an organic solvent.

[0459] 2.2.3 Screening of polymorphs of methanesulfonate

[0460] Approximately 20 mg of polycrystalline methanesulfonate A was weighed into a glass vial, and 200 μL of organic solvent was added. The mixture was stirred at 50°C for 7 days. The results are as follows:

[0461] 2.2.4 Experimental Results

[0462] After screening the above salt crystal forms, we obtained crystal forms A for hydrochloride, hydrobromide, methanesulfonate, p-benzene methanesulfonate, and benzenesulfonate.

[0463] 3. Preparation of different salts and crystal forms of 6-(5-fluoro-6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)aminopyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[0464] 3.1 Preparation of hydrochloride crystal form A

[0465] 15 mg of compound 2 was added to 0.2 mL of the solvent listed in the table below and 17.04 μL of 2M HCl ethanol solution. The mixture was stirred for 3 days under varying temperatures (40-5℃), centrifuged, and the solid was dried under vacuum at 40℃ to obtain the solid product. X-ray powder diffraction analysis showed that the product was crystalline and named hydrochloride crystal form A.

[0466] The characteristic X-ray diffraction peaks of the hydrochloride crystal form A, expressed in terms of 2θ angle and interplanar spacing d, are shown in the table below:

[0467] 3.2 Preparation of hydrochloride crystal form B

[0468] 15 mg of compound 2 was added to 0.2 mL of MTBE and 17.04 μL of 2 M HCl ethanol solution, and the mixture was stirred for 3 days under varying temperatures (40-5℃). After centrifugation, the solid was dried under vacuum at 40℃ to obtain the solid product. X-ray powder diffraction analysis showed that the product was crystalline and named hydrochloride crystal form B.

[0469] The characteristic X-ray diffraction peaks of the hydrochloride crystal form B, expressed as 2θ angle and interplanar spacing d, using Cu-Kα radiation are shown in the table below:

[0470] 3.3 Preparation of Sulfate Crystal Form A

[0471] 15 mg of compound 2 was added to 0.2 mL of EtOH and 17.04 μL of 2M sulfuric acid ethanol solution. The mixture was stirred for 3 days under varying temperatures (40-5℃), centrifuged, and the solid was dried under vacuum at 40℃ to obtain the solid product. X-ray powder diffraction analysis showed that the product was crystalline and named sulfate crystal form A.

[0472] The characteristic X-ray diffraction peaks of the sulfate crystal form A, expressed as 2θ angle and interplanar spacing d, are shown in the table below using Cu-Kα radiation:

[0473] 3.4 Preparation of sulfate crystal form B

[0474] 15 mg of compound 2 was added to 0.2 mL of acetone and 17.04 μL of 2M sulfuric acid ethanol solution. The mixture was stirred for 3 days under varying temperatures (40-5℃), centrifuged, and the solid was dried under vacuum at 40℃ to obtain the solid product. X-ray powder diffraction analysis showed that the product was crystalline and named sulfate crystal form B.

[0475] The characteristic X-ray diffraction peaks of the sulfate crystal form B, expressed as 2θ angle and interplanar spacing d, using Cu-Kα radiation are shown in the table below:

[0476] 3.5 Preparation of sulfate crystal form C

[0477] 15 mg of compound 2 was added to 0.2 mL of EA or MTBE and 17.04 μL of 2M sulfuric acid ethanol solution. The mixture was stirred for 3 days under varying temperatures (40-5℃), centrifuged, and the solid was dried under vacuum at 40℃ to obtain the solid product. X-ray powder diffraction analysis showed that the product was crystalline and named sulfate crystal form C.

[0478] The characteristic X-ray diffraction peaks of the sulfate crystal form C, expressed as 2θ angle and interplanar spacing d, using Cu-Kα radiation are shown in the table below:

[0479] 3.6 Preparation of Phosphate Crystal Form A

[0480] 15 mg of compound 2 was added to 0.2 mL of acetone and 17.04 μL of 2M phosphate ethanol solution. The mixture was stirred for 3 days under varying temperatures (40-5℃), centrifuged, and the solid was dried under vacuum at 40℃ to obtain the solid product. X-ray powder diffraction analysis showed that the product was crystalline and named phosphate crystal form A.

[0481] The characteristic X-ray diffraction peaks of the phosphate crystal form A, expressed as 2θ angle and interplanar spacing d, are shown in the table below:

[0482] 3.7 Preparation of hydrobromide crystal form A

[0483] 15 mg of compound 2 was added to 0.2 mL of LEtOH and 17.04 μL of 2 M hydrobromic acid ethanol solution, and the mixture was stirred for 3 days under varying temperatures (40-5℃). After centrifugation, the solid was dried under vacuum at 40℃ to obtain the solid product. X-ray powder diffraction analysis showed that the product was crystalline and named hydrobromide crystal form A.

[0484] The characteristic X-ray diffraction peaks of the hydrobromide crystal form A, expressed as 2θ angle and interplanar spacing d, are shown in the table below:

[0485] 3.8 Preparation of hydrobromide crystal form B

[0486] 15 mg of compound 2 was added to 0.2 mL of acetone and 17.04 μL of 2M hydrobromic acid ethanol solution. The mixture was stirred for 3 days under varying temperatures (40-5℃), centrifuged, and the solid was dried under vacuum at 40℃ to obtain the solid product. X-ray powder diffraction analysis showed that the product was crystalline and named hydrobromide crystal form B.

[0487] The characteristic X-ray diffraction peaks of the hydrobromide crystal form B, expressed as 2θ angle and interplanar spacing d, are shown in the table below:

[0488] 3.9 Preparation of hydrobromide crystal form C

[0489] 15 mg of compound 2 was added to 0.2 mL of EA and 17.04 μL of 2M hydrobromic acid ethanol solution, and the mixture was stirred for 3 days under varying temperatures (40-5℃). After centrifugation, the solid was dried under vacuum at 40℃ to obtain the solid product. X-ray powder diffraction analysis showed that the product was crystalline and named hydrobromide crystal form C.

[0490] The characteristic X-ray diffraction peaks of the hydrobromide crystal form C, expressed as 2θ angle and interplanar spacing d, using Cu-Kα radiation are shown in the table below:

[0491] 3.10 Preparation of hydrobromide crystal form D

[0492] 15 mg of compound 2 was added to 0.2 mL of MTBE and 17.04 μL of 2 M hydrobromic acid ethanol solution, and the mixture was stirred for 3 days under varying temperatures (40-5℃). After centrifugation, the solid was dried under vacuum at 40℃ to obtain the solid product. X-ray powder diffraction analysis showed that the product was crystalline and named hydrobromide crystal form D.

[0493] The characteristic X-ray diffraction peaks of the hydrobromide crystal form D, expressed in terms of 2θ angle and interplanar spacing d, are shown in the table below:

[0494] 3.11 Preparation of Methanesulfonate Crystal Form A

[0495] 15 mg of compound 2 was added to 0.2 mL of acetone and 17.04 μL of 2M methanesulfonic acid ethanol solution. The mixture was stirred for 3 days under varying temperatures (40-5℃), centrifuged, and the solid was dried under vacuum at 40℃ to obtain the solid product. X-ray powder diffraction analysis showed that the product was crystalline and named it methanesulfonate crystal form A.

[0496] The characteristic X-ray diffraction peaks of the methanesulfonate crystal form A, expressed as 2θ angle and interplanar spacing d, are shown in the table below:

[0497] 3.12 Preparation of fumarate crystal form A

[0498] 15 mg of compound 2 was added to 0.2 mL of LEtOH and 3.96 mg of fumaric acid. The mixture was stirred for 3 days under varying temperatures (40-5℃), centrifuged, and the solid was dried under vacuum at 40℃ to obtain a solid product. X-ray powder diffraction analysis showed that the product was crystalline and named fumarate crystal form A.

[0499] The fumarate crystal form A, when subjected to Cu-Kα radiation, exhibits characteristic X-ray diffraction peaks expressed in terms of 2θ angle and interplanar spacing d, as shown in the table below:

[0500] 3.13 Preparation of fumarate crystal form B

[0501] 15 mg of compound 2 was added to 0.2 mL of acetone and 3.96 mg of fumaric acid, and the mixture was stirred for 3 days under varying temperatures (40-5℃). After centrifugation, the solid was dried under vacuum at 40℃ to obtain the solid product. X-ray powder diffraction analysis showed that the product was crystalline and named fumarate crystal form B.

[0502] The fumarate crystal form B, when subjected to Cu-Kα radiation, exhibits characteristic X-ray diffraction peaks expressed in terms of 2θ angle and interplanar spacing d, as shown in the table below:

[0503] 3.14 Preparation of hydrochloride crystal form C

[0504] 15 mg of compound 2 was added to 0.6 mL of DCM:MeOH = 3:1 and 40 μL of 1 M HCl methanol solution, filtered, and allowed to evaporate and solidify at room temperature to obtain a solid product. The solid was then dried under vacuum at 40 °C to obtain a solid product. X-ray powder diffraction analysis showed that the product was crystalline and named hydrochloride crystal form C.

[0505] The characteristic X-ray diffraction peaks of the hydrochloride crystal form C, expressed as 2θ angle and interplanar spacing d, using Cu-Kα radiation are shown in the table below:

[0506] After testing and analysis, it has the XRPD diagram shown in Figure 52, the DSC diagram shown in Figure 53, and the TGA diagram shown in Figure 54.

[0507] 3.15 Preparation of Phosphate Crystal Form B

[0508] 15 mg of compound 2 was added to 0.6 mL of DCM:MeOH = 3:1 and 40 μL of 1 M H3PO4 methanol solution, filtered, and allowed to evaporate and solidify at room temperature to obtain a solid product. The solid was then dried under vacuum at 40 °C to obtain a solid product. X-ray powder diffraction analysis showed that the product was crystalline and named phosphate crystal form B.

[0509] The characteristic X-ray diffraction peaks of the phosphate crystal form B, expressed as 2θ angle and interplanar spacing d, using Cu-Kα radiation are shown in the table below:

[0510] After testing and analysis, it has the XRPD diagram shown in Figure 55, the DSC diagram shown in Figure 56, and the TGA diagram shown in Figure 57.

[0511] 3.16 Preparation of hydrobromide crystal form E

[0512] 15 mg of compound 2 was added to 0.6 mL of DCM:MeOH = 3:1 and 40 μL of 1 M HBr methanol solution, filtered, and allowed to evaporate and solidify at room temperature to obtain a solid product. The solid was then dried under vacuum at 40 °C to obtain a solid product. X-ray powder diffraction analysis showed that the product was crystalline and named hydrobromide crystal form E.

[0513] The characteristic X-ray diffraction peaks of the hydrobromide crystal form E, expressed as 2θ angle and interplanar spacing d, are shown in the table below:

[0514] After testing and analysis, it has the XRPD diagram shown in Figure 58, the DSC diagram shown in Figure 59, and the TGA diagram shown in Figure 60.

[0515] 3.17 Preparation of hydrobromide crystal form F

[0516] 100 mg of compound 2 was added to 1.5 mL of ethanol and 266 μL of 1 M HBr methanol solution. The mixture was stirred at 50 °C for 1 h, then cooled to room temperature and stirred for another 3 days. After centrifugation, the solid was dried under vacuum at 40 °C to obtain the solid product. X-ray powder diffraction analysis showed that the product was crystalline and named hydrobromide crystal form F.

[0517] The characteristic X-ray diffraction peaks of the hydrobromide crystal form F, expressed as 2θ angle and interplanar spacing d, using Cu-Kα radiation are shown in the table below:

[0518] After testing and analysis, it has the XRPD diagram shown in Figure 61, the DSC diagram shown in Figure 62, and the TGA diagram shown in Figure 63.

[0519] 4. Preparation of pharmaceutical compositions

[0520] 4.1 Raw Material Formula

[0521] 4.2 Preparation method

[0522] 4.2.1 Pretreatment of raw and auxiliary materials

[0523] The raw materials were pulverized using an air jet mill, with an inlet pressure range of 0.30–0.35 MPa and a pulverizing pressure range of 0.25–0.30 MPa. Colloidal silica and sodium bicarbonate were passed through a 40-mesh sieve.

[0524] 4.2.2 Premix

[0525] The mixture is mixed using a hopper mixer and granulated using a vacuum pelletizer.

[0526] Premix I: Add microcrystalline cellulose, HS-10510, anhydrous lactose, low-substituted hydroxypropyl cellulose, and sodium bicarbonate to a hopper mixer and mix at a speed of 10 pm for 10 min.

[0527] Granulation: The premixed material I is granulated through a vacuum granulator with a screen aperture of 0.8mm and a rotation speed of 300-900rpm.

[0528] Premix II: Transfer the granulated material back to the hopper mixer, add the internally added magnesium stearate and mix at 10 rpm for 15 minutes.

[0529] 4.2.3 Dry Granulation

[0530] The dry granulation process is adopted, and the parameters of the dry granulator are set as follows: roller speed 2.0~4.0rpm, roller pressure 2.0~5.0MPa, and feeding speed 2.0~10.0rpm.

[0531] 4.2.4 Total Mixing

[0532] The mixture was mixed using a mixer at a speed of 10 rpm for 10 minutes.

[0533] 4.2.5 Tableting

[0534] Select the mold according to the specifications (5mg specification: Φ6.0mm shallow concave, 10mg specification: Φ7.0mm shallow concave; 50mg specification: Φ10.0mm shallow concave).

[0535] 4.2.6 Coating

[0536] The coating is performed using a high-efficiency coating machine.

[0537] ① Preparation of coating solution

[0538] Add the prescribed amount of purified water to a beaker, and while stirring, add the prescribed amount of film coating premix (gastric-soluble type). Stir for ≥60 minutes, and then pass the prepared coating solution through an 80-mesh sieve for later use.

[0539] ② Coating

[0540] Add the uncoated flakes to the coating pan. During the coating process, check the appearance of the flakes and record the weight gain of the coated flakes. When the weight gain reaches 2.0%–4.0%, stop coating and continue drying for 5 minutes.

[0541] 5. Determination of chloride ion content in hydrochloride

[0542] Using sodium chloride aqueous solution as a reference, the chloride ion content in the hydrochloride salt of the compound was determined by HPLC external standard method. The results are as follows:

[0543] Experimental conclusion: Based on the chloride ion content measurement data, the ratio of free base to chloride ions in hydrochloride was finally determined to be 1:1.

[0544] 6. Determination of chemical stability of different salt forms

[0545] 6.1 Experimental objective: To investigate the stability of the acid salt of the compound under different temperature, humidity and light conditions.

[0546] 6.2 Experimental Procedure: Different salt forms of compounds 1 and 2 were accurately weighed to investigate their stability for 7 and 14 days under conditions of 60℃ (GW), 92.5% RH (room temperature, GS), 50℃ / 75% RH (JS), and light irradiation (5000±500 lux, GZ). Changes in related substances of the salts were calculated using the chromatographic peak area normalization method.

[0547] 6.3 Experimental Data

[0548] 6.4 Experimental Conclusions

[0549] The salt forms of compounds 1 and 2 were relatively stable under high temperature, high humidity, light, and high temperature and high humidity conditions for 14 days, with little change in purity.

[0550] 7. Hygroscopicity test

[0551] 7.1 Experimental objective: To investigate the hygroscopicity of the acid salts of the compound and their crystal forms under different relative humidity conditions.

[0552] 7.2 Experimental Procedure: The compound salt was placed in saturated water vapor at different relative humidities to allow the compound to reach dynamic equilibrium with the water vapor, and the percentage of the compound's weight gain due to moisture absorption after equilibrium was calculated.

[0553] 7.3 Hygroscopicity of Compound Salts

[0554] The hydrochloride crystal form A of compound 1 showed a moisture absorption weight gain of 0.376% under RH 80% conditions, indicating that it is essentially non-hygroscopic. After one cycle of moisture absorption and desorption under 0-95% relative humidity, the XRPD spectrum of the hydrochloride crystal form A of compound 1 did not change, meaning that the crystal form did not change.

[0555] The acid salts of compound 1 and compound 2 are essentially non-hygroscopic under RH 80% conditions.

[0556] Other acid salt crystal forms of compound 1 and the acid salt crystal form of compound 2 have virtually no hygroscopicity under RH 80% conditions. After one cycle of moisture absorption and desorption under 0-95% relative humidity, the acid salt crystal forms did not change.

[0557] 8. Solid stability test

[0558] 8.1 Experimental objective: To investigate the physicochemical stability of compounds with different salt crystal forms under high temperature (60℃) and high temperature and high humidity (50℃, 75% RH) conditions for 7 days.

[0559] 8.2 Experimental Procedure: Approximately 0.5 mg of different salts were tested for 14 days under various conditions, including high temperature (60℃), high humidity (25℃ / 92.5%RH), light intensity (5000 lux), and high temperature and high humidity (50℃ / 75%RH). The changes in salt-related substances were calculated using the chromatographic peak area normalization method.

[0560] 8.3 Experimental Results:

[0561] 8.4 Experimental Conclusions

[0562] Based on stability data, hydrochloride, methanesulfonate, and hydrobromide were all relatively stable under high temperature, high humidity, light, and high temperature and high humidity conditions for 14 days, with the maximum increase in single impurities being less than 0.1%. Other acid salts also showed stability under high temperature, high humidity, light, and high temperature and high humidity conditions for 14 days, with relatively small maximum increases in single impurities.

[0563] 9. Solubility Experiments in Different Solvents

[0564] 9.1 Experimental Objective

[0565] The solubility of different acid salt crystal forms of Compound 1 and Compound 2 in water, artificial gastric juice (FaSSGF), fasting artificial intestinal juice (FaSSIF), and non-fasting artificial intestinal juice (FeSSIF) was compared.

[0566] 9.2 Experimental Procedure:

[0567] Approximately 1 mg of the compound was suspended in different media for 2 hours, and its solubility at 37°C was determined by HPLC external standard method. 9.3 Experimental Results:

[0568] 9.4 Experimental Conclusions

[0569] The solubility of the hydrochloride crystal form A of compound 1 is comparable to that of the free base crystal form A, both meeting the drug development requirements. Other acid salt crystal forms of compound 1 and the acid salt crystal form of compound 2 also exhibit good solubility, meeting the drug development requirements.

[0570] 10. PK Study of Rats with Different Salt Types

[0571] 10.1 Experimental Objective

[0572] Using SD rats as the test animals, the pharmacokinetic behavior of different acid salt crystal forms after a single oral administration in rats (plasma) was studied. 10.2 Experimental Protocol:

[0573] Both the hydrochloride crystal form A and the free base crystal form A of compound 1 were suspended in an aqueous solution containing 0.5% HPMC K4M and then administered to rats by gavage. Three parallel rats were administered the drug at a dose of 30 mpk.

[0574] Other acid salt crystal forms of compound 1 and the acid salt crystal forms of compound 2 were tested using the same experimental protocol.

[0575] 10.3 Experimental Results:

[0576] 10.4 Experimental Conclusions:

[0577] The data above show that the acid salt crystal forms of compounds 1 and 2 of this invention can meet the requirements for high exposure at low doses and have good pharmacokinetic properties.

Claims

1. A compound of the general formula (I) ###0001### or an acid salt of a stereoisomer thereof, in: Ring A is selected from 5-membered nitrogen-containing heterocyclic group, 6-membered nitrogen-containing heterocyclic group, 5-membered nitrogen-containing heteroaryl group, 6-membered nitrogen-containing heteroaryl group, 5-membered 6-membered bicyclic nitrogen-containing heterocyclic group, 6-membered 5-membered bicyclic nitrogen-containing heterocyclic group, 5-membered 6-membered bicyclic nitrogen-containing heteroaryl group, 6-membered 5-membered bicyclic nitrogen-containing heteroaryl group or 6-membered 6-membered bicyclic nitrogen-containing heteroaryl group; R a selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or C 1-6 hydroxyalkyl; R b selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or C 1-6 hydroxyalkyl; and x is 0, 1, 2, 3 or 4. The acid in the acid salt is selected from inorganic or organic acids, wherein the inorganic acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, or phosphoric acid; and the organic acid is selected from 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphtholic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetoxyxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetaminobenzoic acid, 4-aminobenzoic acid, decanoic acid, hexanoic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfonic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, and pyroglutamic acid. Tartaric acid, dodecyl sulfuric acid, dibenzoyl tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactobionic acid, gentian acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, hydroxyethyl sulfonic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, dihydroxynaphthalic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanate, undecanoic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, or L-malic acid; Preferably, the acid is selected from hydrochloric acid, methanesulfonate, p-toluenesulfonate, benzenesulfonate, or hydrobromic acid.

2. The compound according to claim 1, or a stereoisomeric, acid salt thereof, characterized in that, Ring A is selected from And / or, R a selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, or C 1-3 hydroxyalkyl; Preferably, R a is selected from -H, -F, -OCHF2, -OCF3, -CHF2, -CF3, -CH2CHF2, -OCH3, -CH3, or -CH2CF3; And / or, R b selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, or C 1-3 hydroxyalkyl; Preferably, R b Selected from -H, -D, -F, -Cl, -CN, -CH3, -CF3, -CH(CH3)2, -C(CH3)3, -C(CH3)2OH, -C(CH3)2CH2OH, -OCH3, -CH2NH2, -CH2OH or -OH.

3. The compound according to any one of claims 1 to 2, or an acid salt of a stereoisomer thereof, characterized in that, The compounds are shown below:

4. The compound according to any one of claims 1 to 3, or an acid salt of a stereoisomer thereof, characterized in that, The number of acids is 0.2-3; the number of acids in the acid salt is 0.2-3; preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3; more preferably 0.5, 1, 2 or 3, and even more preferably 1.

5. The compound according to any one of claims 1 to 4, or an acid salt of a stereoisomer thereof, wherein, The acid salt is a hydrate or anhydrous form; when the acid salt is a hydrate, the number of water molecules is 0.2-3; preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3.

6. A crystalline form characterized by, It is the crystal form of the acid salt of the compound or its stereoisomer as shown in any one of claims 1-5, preferably the crystal form is a solvate, hydrate or anhydrous; when the crystal form is a hydrate, the number of water molecules is 0.2-3; preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3.

7. The crystal form according to claim 6, characterized in that, It is the crystal form of compound 1, which is 5'-fluoro-6'-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one salt, specifically, Hydrochloride crystal form A has the following X-ray powder diffraction patterns: a diffraction peak at 2θ = 22.1 ± 0.2°; or at 23.6 ± 0.2°; or at 17.3 ± 0.2°; or at 24.0 ± 0.2°; or at 26.0 ± 0.2°; or at 14.0 ± 0.2°; or at 24.9 ± 0.2°. The diffraction peak is present at 32.2±0.2°; or at 17.9±0.2°; or at 12.4±0.2°; preferably, any 2-3, 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 diffraction peaks are included; more preferably, any 2, 3, 4, 5, 6, 7, or 8 of the above diffraction peaks are included. Methanesulfonate crystal form A exhibits the following diffraction peaks in its X-ray powder diffraction pattern: at 2θ = 24.1 ± 0.2°; or at 11.6 ± 0.2°; or at 6.4 ± 0.2°; or at 22.7 ± 0.2°; or at 24.4 ± 0.2°; or at 21.0 ± 0.2°; or at 27.3 ± 0.2°. The diffraction peak is present at 19.0±0.2°; or at 15.7±0.2°; or at 26.0±0.2°; preferably, any 2-3, 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 diffraction peaks are included; more preferably, any 2, 3, 4, 5, 6, 7, or 8 of the above diffraction peaks are included. Benzenesulfonate crystal form A has an X-ray powder diffraction pattern showing a diffraction peak at 2θ = 22.1 ± 0.2°; or at 23.7 ± 0.2°; or at 20.0 ± 0.2°; or at 12.3 ± 0.2°; or at 17.8 ± 0.2°; or at 24.1 ± 0.2°; or at 20.2 ± 0.2°. Diffraction peak; or a diffraction peak at 9.2±0.2°; or a diffraction peak at 28.4±0.2°; or a diffraction peak at 19.0±0.2°; preferably including any 2-3, 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 of the above diffraction peaks, more preferably including any 2, 3, 4, 5, 6, 7 or 8 of them; Hydrobromide crystal form A exhibits the following diffraction peaks in its X-ray powder diffraction pattern: at 2θ = 9.1 ± 0.2°; or at 20.0 ± 0.2°; or at 23.5 ± 0.2°; or at 23.9 ± 0.2°; or at 25.9 ± 0.2°; or at 17.3 ± 0.2°; or at 27.4 ± 0.2°. The diffraction peak is present at 24.8±0.2°; or at 9.4±0.2°; or at 28.1±0.2°; preferably, any 2-3, 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 diffraction peaks are included; more preferably, any 2, 3, 4, 5, 6, 7, or 8 of the above diffraction peaks are included.

8. The crystal form according to claim 7, characterized in that, The X-ray powder diffraction pattern of the hydrochloride crystal form A includes at least one or more diffraction peaks located at 2θ of 22.1±0.2°, 23.6±0.2°, and 17.3±0.2°, preferably two, more preferably three; optionally, it may further include at least one of the following: 2θ of 24.0±0.2°, 26.0±0.2°, 14.0±0.2°, 24.9±0.2°, and 32.2±0.2°, preferably two, three, four, or five. The X-ray powder diffraction pattern of methanesulfonate crystal form A contains at least one or more diffraction peaks located at 2θ of 24.1±0.2°, 11.6±0.2°, and 6.4±0.2°, preferably two, more preferably three; optionally, it may further contain at least one of the following: 22.7±0.2°, 24.4±0.2°, 21.0±0.2°, 27.3±0.2°, and 19.0±0.2°, preferably two, three, four, or five. The X-ray powder diffraction pattern of benzenesulfonate crystal form A contains at least one or more diffraction peaks located at 2θ of 22.1±0.2°, 23.7±0.2°, and 20.0±0.2°, preferably two, more preferably three; optionally, it may further contain at least one diffraction peak located at 2θ of 12.3±0.2°, 17.8±0.2°, 24.1±0.2°, 20.2±0.2°, and 9.2±0.2°, preferably two, three, four, or five. The X-ray powder diffraction pattern of hydrobromide crystal form A contains at least one or more diffraction peaks located at 2θ of 9.1±0.2°, 20.0±0.2°, and 23.5±0.2°, preferably two, more preferably three; optionally, it may further contain at least one of the following diffraction peaks located at 2θ of 23.9±0.2°, 25.9±0.2°, 17.3±0.2°, 27.4±0.2°, and 24.8±0.2°, preferably two, three, four, or five.

9. The crystal form according to claim 8, characterized in that, The X-ray powder diffraction pattern of the hydrochloride crystal form A may optionally include one or more diffraction peaks located at 2θ of 17.9±0.2°, 12.4±0.2°, 28.4±0.2°, 20.1±0.2°, 20.7±0.2°, 18.3±0.2°, and 30.8±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks. The X-ray powder diffraction pattern of methanesulfonate crystal form A optionally includes one or more diffraction peaks located at 2θ of 15.7±0.2°, 26.0±0.2°, 20.5±0.2°, 20.0±0.2°, 28.6±0.2°, 23.3±0.2°, and 17.5±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 of these peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks. The X-ray powder diffraction pattern of benzenesulfonate crystal form A optionally includes one or more diffraction peaks located at 2θ of 28.4±0.2°, 19.0±0.2°, 32.3±0.2°, 17.3±0.2°, 14.1±0.2°, 26.1±0.2°, and 25.1±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 of these peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks. The X-ray powder diffraction pattern of hydrobromide crystal form A optionally includes one or more diffraction peaks located at 2θ of 9.4±0.2°, 28.1±0.2°, 20.6±0.2°, 32.0±0.2°, 17.8±0.2°, 18.3±0.2°, and 25.1±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 of these peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks.

10. The crystalline form of any one of claims 5-9 characterized by, The X-ray powder diffraction pattern of the hydrochloride crystal form A includes one or more diffraction peaks located at 2θ of 22.1±0.2°, 23.6±0.2°, 17.3±0.2°, 24.0±0.2°, 26.0±0.2°, 14.0±0.2°, 24.9±0.2°, 32.2±0.2°, 17.9±0.2°, 12.4±0.2°, 28.4±0.2°, and 20.1±0.2°; preferably, it includes any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 of these peaks. The X-ray powder diffraction pattern of methanesulfonate crystal form A includes one or more diffraction peaks located at 2θ of 24.1±0.2°, 11.6±0.2°, 6.4±0.2°, 22.7±0.2°, 24.4±0.2°, 21.0±0.2°, 27.3±0.2°, 19.0±0.2°, 15.7±0.2°, 26.0±0.2°, 20.5±0.2°, and 20.0±0.2°; preferably, it includes any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 of these peaks. The X-ray powder diffraction pattern of benzenesulfonate crystal form A includes one or more diffraction peaks located at 2θ of 22.1±0.2°, 23.7±0.2°, 20.0±0.2°, 12.3±0.2°, 17.8±0.2°, 24.1±0.2°, 20.2±0.2°, 9.2±0.2°, 28.4±0.2°, 19.0±0.2°, 32.3±0.2°, and 17.3±0.2°; preferably, it includes any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 of these peaks. The X-ray powder diffraction pattern of hydrobromide crystal form A includes one or more diffraction peaks located at 2θ of 9.1±0.2°, 20.0±0.2°, 23.5±0.2°, 23.9±0.2°, 25.9±0.2°, 17.3±0.2°, 27.4±0.2°, 24.8±0.2°, 9.4±0.2°, 28.1±0.2°, 20.6±0.2°, and 32.0±0.2°; preferably, it includes any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 of these peaks.

11. The crystal form according to claim 6, characterized in that, It is the crystal form of compound 2, which is 6-(5-fluoro-6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)aminopyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, specifically, Hydrochloride crystal form A has an X-ray powder diffraction pattern showing diffraction peaks at 2θ = 24.4 ± 0.2°; or at 15.2 ± 0.2°; or at 5.6 ± 0.2°; or at 27.7 ± 0.2°; or at 26.4 ± 0.2°; or at 16.8 ± 0.2°; or at 32.7 ± 0.2°. The peak; or has a diffraction peak at 19.1±0.2°; or has a diffraction peak at 12.9±0.2°; or has a diffraction peak at 14.7±0.2°; preferably includes any 2-3, 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 of the above diffraction peaks, more preferably includes any 2, 3, 4, 5, 6, 7 or 8 of them; Hydrochloride crystal form B exhibits the following diffraction peaks in its X-ray powder diffraction pattern: 2θ = 24.4 ± 0.2°; or 26.0 ± 0.2°; or 28.6 ± 0.2°; or 8.7 ± 0.2°; or 21.4 ± 0.2°; or 29.6 ± 0.2°; or 15.5 ± 0.2°. The peak; or has a diffraction peak at 11.4±0.2°; or has a diffraction peak at 13.1±0.2°; or has a diffraction peak at 14.9±0.2°; preferably includes any 2-3, 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 of the above diffraction peaks, more preferably includes any 2, 3, 4, 5, 6, 7 or 8 of them; Sulfate crystal form A exhibits the following diffraction peaks in its X-ray powder diffraction pattern: 2θ = 20.7 ± 0.2°; or 21.8 ± 0.2°; or 25.1 ± 0.2°; or 12.4 ± 0.2°; or 12.0 ± 0.2°; or 23.2 ± 0.2°; or 10.6 ± 0.2°. The diffraction peak is present at 23.7±0.2°; or at 19.6±0.2°; or at 16.3±0.2°; preferably, any 2-3, 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 diffraction peaks are included; more preferably, any 2, 3, 4, 5, 6, 7, or 8 of the above diffraction peaks are included. Sulfate crystal form B exhibits the following X-ray powder diffraction peaks in its 2θ pattern: at 11.4 ± 0.2°; or at 10.6 ± 0.2°; or at 20.5 ± 0.2°; or at 21.0 ± 0.2°; or at 13.5 ± 0.2°; or at 17.0 ± 0.2°; or at 26.2 ± 0.2°. The diffraction peak is present at 14.1±0.2°; or at 28.5±0.2°; or at 7.4±0.2°; preferably, any 2-3, 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 diffraction peaks are included; more preferably, any 2, 3, 4, 5, 6, 7, or 8 of the above diffraction peaks are included. The sulfate crystal form C exhibits the following diffraction peaks in its X-ray powder diffraction pattern: at 2θ = 26.5 ± 0.2°; or at 10.6 ± 0.2°; or at 27.9 ± 0.2°; or at 12.5 ± 0.2°; or at 13.5 ± 0.2°; or at 15.3 ± 0.2°; or at 21.3 ± 0.2°. The diffraction peak is present at 20.6±0.2°; or at 7.0±0.2°; or at 29.2±0.2°; preferably, any 2-3, 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 diffraction peaks are included; more preferably, any 2, 3, 4, 5, 6, 7, or 8 of the above diffraction peaks are included. Phosphate crystal form A exhibits the following diffraction peaks in its X-ray powder diffraction pattern: 2θ = 24.4 ± 0.2°; or 26.0 ± 0.2°; or 22.5 ± 0.2°; or 21.4 ± 0.2°; or 7.9 ± 0.2°; or 13.2 ± 0.2°; or 18.4 ± 0.2°. The peak; or has a diffraction peak at 19.5±0.2°; or has a diffraction peak at 14.3±0.2°; or has a diffraction peak at 23.4±0.2°; preferably includes any 2-3, 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 of the above diffraction peaks, more preferably includes any 2, 3, 4, 5, 6, 7 or 8 of them; Hydrobromide crystal form A exhibits the following diffraction peaks in its X-ray powder diffraction pattern: at 2θ = 24.6 ± 0.2°; or at 5.8 ± 0.2°; or at 12.4 ± 0.2°; or at 18.6 ± 0.2°; or at 17.0 ± 0.2°; or at 14.7 ± 0.2°; or at 22.5 ± 0.2°. The diffraction peak is present at 28.7±0.2°; or at 26.7±0.2°; or at 29.6±0.2°; preferably, any 2-3, 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 of the above diffraction peaks are included; more preferably, any 2, 3, 4, 5, 6, 7, or 8 of the above diffraction peaks are included. Hydrobromide crystal form B exhibits the following diffraction peaks in its X-ray powder diffraction pattern: 2θ = 25.3 ± 0.2°; or 25.9 ± 0.2°; or 6.7 ± 0.2°; or 19.2 ± 0.2°; or 12.7 ± 0.2°; or 13.5 ± 0.2°; or 14.6 ± 0.2°. The diffraction peak is present at 21.1±0.2°; or at 27.6±0.2°; or at 24.6±0.2°; preferably, any 2-3, 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 diffraction peaks are included; more preferably, any 2, 3, 4, 5, 6, 7, or 8 of the above diffraction peaks are included. Hydrobromide crystal form C exhibits the following diffraction peaks in its X-ray powder diffraction pattern: 2θ = 24.2 ± 0.2°; or 28.6 ± 0.2°; or 26.0 ± 0.2°; or 21.4 ± 0.2°; or 29.6 ± 0.2°; or 11.4 ± 0.2°; or 24.9 ± 0.2°. The diffraction peak is present at 12.6±0.2°; or at 13.5±0.2°; or at 12.9±0.2°; preferably, any 2-3, 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 diffraction peaks are included; more preferably, any 2, 3, 4, 5, 6, 7, or 8 of the above diffraction peaks are included. Hydrobromide crystal form D exhibits the following diffraction peaks in its X-ray powder diffraction pattern: 2θ = 26.5 ± 0.2°; or 12.9 ± 0.2°; or 23.9 ± 0.2°; or 24.4 ± 0.2°; or 21.4 ± 0.2°; or 11.2 ± 0.2°; or 28.4 ± 0.2°. The diffraction peak is present at 22.5±0.2°; or at 13.7±0.2°; or at 22.9±0.2°; preferably, any 2-3, 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 diffraction peaks are included; more preferably, any 2, 3, 4, 5, 6, 7, or 8 of the above diffraction peaks are included. Methanesulfonate crystal form A has the following X-ray powder diffraction pattern: a diffraction peak at 2θ = 24.5 ± 0.2°; or at 26.1 ± 0.2°; or at 14.3 ± 0.2°; or at 21.5 ± 0.2°; or at 20.8 ± 0.2°; or at 10.7 ± 0.2°; or at 6.7 ± 0.2°. Diffraction peak; or a diffraction peak at 27.6±0.2°; or a diffraction peak at 26.5±0.2°; or a diffraction peak at 28.2±0.2°; preferably including any 2-3, 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 of the above diffraction peaks, more preferably including any 2, 3, 4, 5, 6, 7, or 8 of them; Fumarate crystal form A exhibits the following X-ray powder diffraction peaks in its 2θ pattern: at 2θ = 26.1 ± 0.2°; or at 15.1 ± 0.2°; or at 28.2 ± 0.2°; or at 9.0 ± 0.2°; or at 12.9 ± 0.2°; or at 27.2 ± 0.2°; or at 21.0 ± 0.2°. The diffraction peak is present at 12.1±0.2°; or at 20.2±0.2°; or at 16.9±0.2°; preferably, any 2-3, 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 of the above diffraction peaks are included; more preferably, any 2, 3, 4, 5, 6, 7, or 8 of the above diffraction peaks are included. Fumarate crystal form B exhibits the following X-ray powder diffraction peaks: at 2θ = 9.1 ± 0.2°; or at 26.9 ± 0.2°; or at 22.2 ± 0.2°; or at 22.0 ± 0.2°; or at 15.5 ± 0.2°; or at 16.8 ± 0.2°; or at 13.1 ± 0.2°. The diffraction peak is present at 27.4±0.2°; or at 13.9±0.2°; or at 10.2±0.2°; preferably, any 2-3, 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 diffraction peaks are included; more preferably, any 2, 3, 4, 5, 6, 7, or 8 of the above diffraction peaks are included. The hydrochloride crystal form C exhibits the following diffraction peaks in its X-ray powder diffraction pattern: at 2θ = 25.1 ± 0.2°; or at 4.6 ± 0.2°; or at 8.2 ± 0.2°; or at 15.3 ± 0.2°; or at 21.4 ± 0.2°; or at 28.2 ± 0.2°; or at 17.1 ± 0.2°. The peak; or has a diffraction peak at 12.0±0.2°; or has a diffraction peak at 14.3±0.2°; or has a diffraction peak at 19.0±0.2°; preferably includes any 2-3, 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 of the above diffraction peaks, more preferably includes any 2, 3, 4, 5, 6, 7 or 8 of them; Phosphate crystal form B exhibits the following diffraction peaks in its X-ray powder diffraction pattern: at 2θ = 17.6 ± 0.2°; or at 13.1 ± 0.2°; or at 4.4 ± 0.2°; or at 12.8 ± 0.2°; or at 24.3 ± 0.2°; or at 8.8 ± 0.2°; or at 21.0 ± 0.2°. The peak; or has a diffraction peak at 9.4±0.2°; or has a diffraction peak at 16.8±0.2°; or has a diffraction peak at 18.4±0.2°; preferably includes any 2-3, 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 of the above diffraction peaks, more preferably includes any 2, 3, 4, 5, 6, 7 or 8 of them; Hydrobromide crystal form E has an X-ray powder diffraction pattern showing diffraction peaks at 2θ of 9.3 ± 0.2°; or at 15.5 ± 0.2°; or at 6.2 ± 0.2°; or at 18.6 ± 0.2°; or at 12.4 ± 0.2°; or at 31.2 ± 0.2°; or at 27.5 ± 0.2°. The peak; or has a diffraction peak at 21.7±0.2°; or has a diffraction peak at 24.8±0.2°; or has a diffraction peak at 19.1±0.2°; preferably includes any 2-3, 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 of the above diffraction peaks, more preferably includes any 2, 3, 4, 5, 6, 7 or 8 of them; Hydrobromide crystal form F exhibits the following X-ray powder diffraction peaks in its 2θ pattern: at 25.4 ± 0.2°; or at 24.7 ± 0.2°; or at 26.2 ± 0.2°; or at 12.4 ± 0.2°; or at 17.4 ± 0.2°; or at 18.5 ± 0.2°; or at 32.0 ± 0.2°. The diffraction peak is present at 20.2±0.2°; or at 21.5±0.2°; or at 28.3±0.2°; preferably, any 2-3, 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 diffraction peaks are included; more preferably, any 2, 3, 4, 5, 6, 7, or 8 of the above diffraction peaks are included.

12. The crystal form of the compound according to claim 11, characterized in that, The X-ray powder diffraction pattern of hydrochloride crystal form A contains at least one or more diffraction peaks located at 2θ of 24.4±0.2°, 15.2±0.2°, and 5.6±0.2°, preferably two, more preferably three; optionally, it may further contain at least one diffraction peak located at 2θ of 27.7±0.2°, 26.4±0.2°, 16.8±0.2°, 32.7±0.2°, and 19.1±0.2°, preferably two, three, four, or five. The X-ray powder diffraction pattern of hydrochloride crystal form B includes at least one or more diffraction peaks located at 2θ of 24.4±0.2°, 26.0±0.2°, and 28.6±0.2°, preferably two, more preferably three; optionally, it may further include at least one of the following: 2θ of 8.7±0.2°, 21.4±0.2°, 29.6±0.2°, 15.5±0.2°, and 11.4±0.2°, preferably two, three, four, or five. The X-ray powder diffraction pattern of sulfate crystal form A contains at least one or more diffraction peaks located at 2θ of 20.7±0.2°, 21.8±0.2°, and 25.1±0.2°, preferably two, more preferably three; optionally, it may further contain at least one of the following: 2θ of 12.4±0.2°, 12.0±0.2°, 23.2±0.2°, 10.6±0.2°, and 23.7±0.2°, preferably two, three, four, or five. The X-ray powder diffraction pattern of sulfate crystal form B contains at least one or more diffraction peaks located at 2θ of 11.4±0.2°, 10.6±0.2°, and 20.5±0.2°, preferably two, more preferably three; optionally, it may further contain at least one diffraction peak located at 2θ of 21.0±0.2°, 13.5±0.2°, 17.0±0.2°, 26.2±0.2°, and 14.1±0.2°, preferably two, three, four, or five. The X-ray powder diffraction pattern of sulfate crystal form C includes at least one or more diffraction peaks located at 2θ of 26.5±0.2°, 10.6±0.2°, and 27.9±0.2°, preferably two, more preferably three; optionally, it may further include at least one of the following: 2θ of 12.5±0.2°, 13.5±0.2°, 15.3±0.2°, 21.3±0.2°, and 20.6±0.2°, preferably two, three, four, or five. The X-ray powder diffraction pattern of phosphate crystal form A contains at least one or more diffraction peaks located at 2θ of 24.4±0.2°, 26.0±0.2°, and 22.5±0.2°, preferably two, more preferably three; optionally, it may further contain at least one of the following: 2θ of 21.4±0.2°, 7.9±0.2°, 13.2±0.2°, 18.4±0.2°, and 19.5±0.2°, preferably two, three, four, or five. The X-ray powder diffraction pattern of hydrobromide crystal form A contains at least one or more diffraction peaks located at 2θ of 24.6±0.2°, 5.8±0.2°, and 12.4±0.2°, preferably two, more preferably three; optionally, it may further contain at least one diffraction peak located at 2θ of 18.6±0.2°, 17.0±0.2°, 14.7±0.2°, 22.5±0.2°, and 28.7±0.2°, preferably two, three, four, or five. The X-ray powder diffraction pattern of hydrobromide crystal form B contains at least one or more diffraction peaks located at 2θ of 25.3±0.2°, 25.9±0.2°, and 6.7±0.2°, preferably two, more preferably three; optionally, it may further contain at least one diffraction peak located at 2θ of 19.2±0.2°, 12.7±0.2°, 13.5±0.2°, 14.6±0.2°, and 21.1±0.2°, preferably two, three, four, or five. The X-ray powder diffraction pattern of hydrobromide crystal form C contains at least one or more diffraction peaks located at 2θ of 24.2±0.2°, 28.6±0.2°, and 26.0±0.2°, preferably two, more preferably three; optionally, it may further contain at least one diffraction peak located at 2θ of 21.4±0.2°, 29.6±0.2°, 11.4±0.2°, 24.9±0.2°, and 12.6±0.2°, preferably two, three, four, or five. The X-ray powder diffraction pattern of hydrobromide crystal form D contains at least one or more diffraction peaks located at 2θ of 26.5±0.2°, 12.9±0.2°, and 23.9±0.2°, preferably two, more preferably three; optionally, it may further contain at least one diffraction peak located at 2θ of 24.4±0.2°, 21.4±0.2°, 11.2±0.2°, 28.4±0.2°, and 22.5±0.2°, preferably two, three, four, or five. The X-ray powder diffraction pattern of methanesulfonate crystal form A contains at least one or more diffraction peaks located at 2θ of 24.5±0.2°, 26.1±0.2°, and 14.3±0.2°, preferably two, more preferably three; optionally, it may further contain at least one of the following: 21.5±0.2°, 20.8±0.2°, 10.7±0.2°, 6.7±0.2°, and 27.6±0.2°, preferably two, three, four, or five. The X-ray powder diffraction pattern of fumarate crystal form A contains at least one or more diffraction peaks located at 2θ of 26.1±0.2°, 15.1±0.2°, and 28.2±0.2°, preferably two, more preferably three; optionally, it may further contain at least one of the following: 2θ of 9.0±0.2°, 12.9±0.2°, 27.2±0.2°, 21.0±0.2°, and 12.1±0.2°, preferably two, three, four, or five. The X-ray powder diffraction pattern of fumarate crystal form B contains at least one or more diffraction peaks located at 2θ of 9.1±0.2°, 26.9±0.2°, and 22.2±0.2°, preferably two, more preferably three; optionally, it may further contain at least one of the following: 2θ of 22.0±0.2°, 15.5±0.2°, 16.8±0.2°, 13.1±0.2°, and 27.4±0.2°, preferably two, three, four, or five. The X-ray powder diffraction pattern of hydrochloride crystal form C contains at least one or more diffraction peaks located at 2θ of 25.1±0.2°, 4.6±0.2°, and 8.2±0.2°, preferably two, more preferably three; optionally, it may further contain at least one diffraction peak located at 2θ of 15.3±0.2°, 21.4±0.2°, 28.2±0.2°, 17.1±0.2°, and 12.0±0.2°, preferably two, three, four, or five. The X-ray powder diffraction pattern of phosphate crystal form B contains at least one or more diffraction peaks located at 2θ of 17.6±0.2°, 13.1±0.2°, and 4.4±0.2°, preferably two, more preferably three; optionally, it may further contain at least one of the following: 2θ of 12.8±0.2°, 24.3±0.2°, 8.8±0.2°, 21.0±0.2°, and 9.4±0.2°, preferably two, three, four, or five. The X-ray powder diffraction pattern of hydrobromide crystal form E contains at least one or more diffraction peaks located at 2θ of 9.3±0.2°, 15.5±0.2°, and 6.2±0.2°, preferably two, more preferably three; optionally, it may further contain at least one diffraction peak located at 2θ of 18.6±0.2°, 12.4±0.2°, 31.2±0.2°, 27.5±0.2°, and 21.7±0.2°, preferably two, three, four, or five. The X-ray powder diffraction pattern of hydrobromide crystal form F contains at least one or more diffraction peaks located at 2θ of 25.4±0.2°, 24.7±0.2°, and 26.2±0.2°, preferably two, more preferably three; optionally, it may further contain at least one of 2θ of 12.4±0.2°, 17.4±0.2°, 18.5±0.2°, 32.0±0.2°, and 20.2±0.2°, preferably two, three, four, or five.

13. The crystal form of the compound according to claim 12, characterized in that, The X-ray powder diffraction pattern of hydrochloride crystal form A optionally includes one or more diffraction peaks located at 2θ of 12.9±0.2°, 14.7±0.2°, 23.5±0.2°, 29.0±0.2°, 8.5±0.2°, 20.4±0.2°, and 12.0±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 of these peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks. The X-ray powder diffraction pattern of hydrochloride crystal form B optionally includes one or more diffraction peaks located at 2θ of 13.1±0.2°, 14.9±0.2°, 18.9±0.2°, 23.0±0.2°, 14.3±0.2°, 30.2±0.2°, and 28.0±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 of these peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks. The X-ray powder diffraction pattern of sulfate crystal form A optionally includes one or more diffraction peaks located at 2θ of 19.6±0.2°, 16.3±0.2°, 27.1±0.2°, 28.1±0.2°, 39.4±0.2°, 41.5±0.2°, and 35.7±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 of these peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks. The X-ray powder diffraction pattern of sulfate crystal form B optionally includes one or more diffraction peaks located at 2θ of 28.5±0.2°, 7.4±0.2°, 22.3±0.2°, 27.8±0.2°, 33.1±0.2°, 9.6±0.2°, and 6.5±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 of these peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks. The X-ray powder diffraction pattern of sulfate crystal form C optionally includes one or more diffraction peaks located at 2θ of 7.0±0.2°, 29.2±0.2°, 17.8±0.2°, 16.4±0.2°, 17.2±0.2°, 25.3±0.2°, and 22.1±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 of these peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks. The X-ray powder diffraction pattern of phosphate crystal form A optionally includes one or more diffraction peaks located at 2θ of 14.3±0.2°, 23.4±0.2°, 14.8±0.2°, 21.9±0.2°, 28.7±0.2°, 26.5±0.2°, and 20.3±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 of these peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks. The X-ray powder diffraction pattern of hydrobromide crystal form A optionally includes one or more diffraction peaks located at 2θ of 26.7±0.2°, 29.6±0.2°, 17.5±0.2°, 22.0±0.2°, 16.5±0.2°, 23.4±0.2°, and 28.1±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 of these peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks. The X-ray powder diffraction pattern of hydrobromide crystal form B optionally includes one or more diffraction peaks located at 2θ of 27.6±0.2°, 24.6±0.2°, 11.5±0.2°, 15.4±0.2°, 31.1±0.2°, 34.4±0.2°, and 16.3±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 of these peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks. The X-ray powder diffraction pattern of hydrobromide crystal form C optionally includes one or more diffraction peaks located at 2θ of 13.5±0.2°, 12.9±0.2°, 20.4±0.2°, 18.2±0.2°, 8.7±0.2°, 5.5±0.2°, and 27.9±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks. The X-ray powder diffraction pattern of hydrobromide crystal form D optionally includes one or more diffraction peaks located at 2θ of 13.7±0.2°, 22.9±0.2°, 28.5±0.2°, 33.1±0.2°, 27.9±0.2°, 12.1±0.2°, and 29.5±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 of these peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks. The X-ray powder diffraction pattern of methanesulfonate crystal form A optionally includes one or more diffraction peaks located at 2θ of 26.5±0.2°, 28.2±0.2°, 24.8±0.2°, 19.3±0.2°, 27.1±0.2°, 19.6±0.2°, and 15.5±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 of these peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks. The X-ray powder diffraction pattern of fumarate crystal form A optionally includes one or more diffraction peaks located at 2θ of 20.2±0.2°, 16.9±0.2°, 16.4±0.2°, 18.6±0.2°, 21.8±0.2°, 13.9±0.2°, and 29.0±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 of these peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks. The X-ray powder diffraction pattern of fumarate crystal form B optionally includes one or more diffraction peaks located at 2θ of 13.9±0.2°, 10.2±0.2°, 18.4±0.2°, 23.4±0.2°, 7.7±0.2°, 21.1±0.2°, and 14.5±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 of these peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks. The X-ray powder diffraction pattern of hydrochloride crystal form C optionally includes one or more diffraction peaks located at 2θ of 14.3±0.2°, 19.0±0.2°, 27.7±0.2°, 9.1±0.2°, 12.8±0.2°, 7.1±0.2°, and 11.1±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 of these peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks. The X-ray powder diffraction pattern of phosphate crystal form B optionally includes one or more diffraction peaks located at 2θ of 16.8±0.2°, 18.4±0.2°, 20.5±0.2°, 22.0±0.2°, 14.3±0.2°, 25.2±0.2°, and 26.5±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 of these peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks. The X-ray powder diffraction pattern of hydrobromide crystal form E optionally includes one or more diffraction peaks located at 2θ of 24.8±0.2°, 19.1±0.2°, 21.0±0.2°, 34.4±0.2°, 17.7±0.2°, 22.9±0.2°, and 21.4±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 of these peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks. The X-ray powder diffraction pattern of hydrobromide crystal form F optionally includes one or more diffraction peaks located at 2θ of 21.5±0.2°, 28.3±0.2°, 18.7±0.2°, 21.9±0.2°, 28.7±0.2°, 29.8±0.2°, and 14.5±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 of these peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks.

14. The crystal form of the compound according to any one of claims 11-13, characterized in that, The X-ray powder diffraction pattern of hydrochloride crystal form A includes one or more diffraction peaks located at 2θ of 24.4±0.2°, 15.2±0.2°, 5.6±0.2°, 27.7±0.2°, 26.4±0.2°, 16.8±0.2°, 32.7±0.2°, 19.1±0.2°, 12.9±0.2°, 14.7±0.2°, 23.5±0.2°, 29.0±0.2°, 8.5±0.2°, 20.4±0.2°, and 12.0±0.2°; preferably, it includes any 2, 3, 4, 5, 6, 8, 10, or 12 of these peaks. The X-ray powder diffraction pattern of hydrochloride crystal form B includes one or more diffraction peaks located at 2θ of 24.4±0.2°, 26.0±0.2°, 28.6±0.2°, 8.7±0.2°, 21.4±0.2°, 29.6±0.2°, 15.5±0.2°, 11.4±0.2°, 13.1±0.2°, 14.9±0.2°, 18.9±0.2°, 23.0±0.2°, 14.3±0.2°, 30.2±0.2°, and 28.0±0.2°; preferably, it includes any 2, 3, 4, 5, 6, 8, 10, or 12 of these peaks. The X-ray powder diffraction pattern of sulfate crystal form A includes one or more diffraction peaks located at 2θ of 20.7±0.2°, 21.8±0.2°, 25.1±0.2°, 12.4±0.2°, 12.0±0.2°, 23.2±0.2°, 10.6±0.2°, 23.7±0.2°, 19.6±0.2°, 16.3±0.2°, 27.1±0.2°, 28.1±0.2°, 39.4±0.2°, 41.5±0.2°, and 35.7±0.2°; preferably, it includes any 2, 3, 4, 5, 6, 8, 10, or 12 of these peaks. The X-ray powder diffraction pattern of sulfate crystal form B includes one or more diffraction peaks located at 2θ of 11.4±0.2°, 10.6±0.2°, 20.5±0.2°, 21.0±0.2°, 13.5±0.2°, 17.0±0.2°, 26.2±0.2°, 14.1±0.2°, 28.5±0.2°, 7.4±0.2°, 22.3±0.2°, 27.8±0.2°, 33.1±0.2°, 9.6±0.2°, and 6.5±0.2°; preferably, it includes any 2, 3, 4, 5, 6, 8, 10, or 12 of these peaks. The X-ray powder diffraction pattern of sulfate crystal form C includes one or more diffraction peaks located at 2θ of 26.5±0.2°, 10.6±0.2°, 27.9±0.2°, 12.5±0.2°, 13.5±0.2°, 15.3±0.2°, 21.3±0.2°, 20.6±0.2°, 7.0±0.2°, 29.2±0.2°, 17.8±0.2°, 16.4±0.2°, 17.2±0.2°, 25.3±0.2°, and 22.1±0.2°; preferably, it includes any 2, 3, 4, 5, 6, 8, 10, or 12 of these peaks. The X-ray powder diffraction pattern of phosphate crystal form A includes one or more diffraction peaks located at 2θ of 24.4±0.2°, 26.0±0.2°, 22.5±0.2°, 21.4±0.2°, 7.9±0.2°, 13.2±0.2°, 18.4±0.2°, 19.5±0.2°, 14.3±0.2°, 23.4±0.2°, 14.8±0.2°, 21.9±0.2°, 28.7±0.2°, 26.5±0.2°, and 20.3±0.2°; preferably, it includes any 2, 3, 4, 5, 6, 8, 10, or 12 of these peaks. The X-ray powder diffraction pattern of hydrobromide crystal form A includes one or more diffraction peaks located at 2θ of 24.6±0.2°, 5.8±0.2°, 12.4±0.2°, 18.6±0.2°, 17.0±0.2°, 14.7±0.2°, 22.5±0.2°, 28.7±0.2°, 26.7±0.2°, 29.6±0.2°, 17.5±0.2°, 22.0±0.2°, 16.5±0.2°, 23.4±0.2°, and 28.1±0.2°; preferably, it includes any 2, 3, 4, 5, 6, 8, 10, or 12 of these peaks. The X-ray powder diffraction pattern of hydrobromide crystal form B includes one or more diffraction peaks located at 2θ of 25.3±0.2°, 25.9±0.2°, 6.7±0.2°, 19.2±0.2°, 12.7±0.2°, 13.5±0.2°, 14.6±0.2°, 21.1±0.2°, 27.6±0.2°, 24.6±0.2°, 11.5±0.2°, 15.4±0.2°, 31.1±0.2°, 34.4±0.2°, and 16.3±0.2°; preferably, it includes any 2, 3, 4, 5, 6, 8, 10, or 12 of these peaks. The X-ray powder diffraction pattern of hydrobromide crystal form C includes one or more diffraction peaks located at 2θ of 24.2±0.2°, 28.6±0.2°, 26.0±0.2°, 21.4±0.2°, 29.6±0.2°, 11.4±0.2°, 24.9±0.2°, 12.6±0.2°, 13.5±0.2°, 12.9±0.2°, 20.4±0.2°, 18.2±0.2°, 8.7±0.2°, 5.5±0.2°, and 27.9±0.2°; preferably, it includes any 2, 3, 4, 5, 6, 8, 10, or 12 of these peaks. The X-ray powder diffraction pattern of hydrobromide crystal form D includes one or more diffraction peaks located at 2θ of 26.5±0.2°, 12.9±0.2°, 23.9±0.2°, 24.4±0.2°, 21.4±0.2°, 11.2±0.2°, 28.4±0.2°, 22.5±0.2°, 13.7±0.2°, 22.9±0.2°, 28.5±0.2°, 33.1±0.2°, 27.9±0.2°, 12.1±0.2°, and 29.5±0.2°; preferably, it includes any 2, 3, 4, 5, 6, 8, 10, or 12 of these peaks. The X-ray powder diffraction pattern of methanesulfonate crystal form A includes one or more diffraction peaks located at 2θ of 24.5±0.2°, 26.1±0.2°, 14.3±0.2°, 21.5±0.2°, 20.8±0.2°, 10.7±0.2°, 6.7±0.2°, 27.6±0.2°, 26.5±0.2°, 28.2±0.2°, 24.8±0.2°, 19.3±0.2°, 27.1±0.2°, 19.6±0.2°, and 15.5±0.2°; preferably, it includes any 2, 3, 4, 5, 6, 8, 10, or 12 of these peaks. The X-ray powder diffraction pattern of fumarate crystal form A includes one or more diffraction peaks located at 2θ of 26.1±0.2°, 15.1±0.2°, 28.2±0.2°, 9.0±0.2°, 12.9±0.2°, 27.2±0.2°, 21.0±0.2°, 12.1±0.2°, 20.2±0.2°, 16.9±0.2°, 16.4±0.2°, 18.6±0.2°, 21.8±0.2°, 13.9±0.2°, and 29.0±0.2°; preferably, it includes any 2, 3, 4, 5, 6, 8, 10, or 12 of these peaks. The X-ray powder diffraction pattern of fumarate crystal form B includes one or more diffraction peaks located at 2θ of 9.1±0.2°, 26.9±0.2°, 22.2±0.2°, 22.0±0.2°, 15.5±0.2°, 16.8±0.2°, 13.1±0.2°, 27.4±0.2°, 13.9±0.2°, 10.2±0.2°, 18.4±0.2°, 23.4±0.2°, 7.7±0.2°, 21.1±0.2°, and 14.5±0.2°; preferably, it includes any 2, 3, 4, 5, 6, 8, 10, or 12 of these peaks. The X-ray powder diffraction pattern of hydrochloride crystal form C includes one or more diffraction peaks located at 2θ of 25.1±0.2°, 4.6±0.2°, 8.2±0.2°, 15.3±0.2°, 21.4±0.2°, 28.2±0.2°, 17.1±0.2°, 12.0±0.2°, 14.3±0.2°, 19.0±0.2°, 27.7±0.2°, 9.1±0.2°, 12.8±0.2°, 7.1±0.2°, and 11.1±0.2°; preferably, it includes any 2, 3, 4, 5, 6, 8, 10, or 12 of these peaks. The X-ray powder diffraction pattern of phosphate crystal form B includes one or more diffraction peaks located at 2θ of 17.6±0.2°, 13.1±0.2°, 4.4±0.2°, 12.8±0.2°, 24.3±0.2°, 8.8±0.2°, 21.0±0.2°, 9.4±0.2°, 16.8±0.2°, 18.4±0.2°, 20.5±0.2°, 22.0±0.2°, 14.3±0.2°, 25.2±0.2°, and 26.5±0.2°; preferably, it includes any 2, 3, 4, 5, 6, 8, 10, or 12 of these peaks. The X-ray powder diffraction pattern of hydrobromide crystal form E includes one or more diffraction peaks located at 2θ of 9.3±0.2°, 15.5±0.2°, 6.2±0.2°, 18.6±0.2°, 12.4±0.2°, 31.2±0.2°, 27.5±0.2°, 21.7±0.2°, 24.8±0.2°, 19.1±0.2°, 21.0±0.2°, 34.4±0.2°, 17.7±0.2°, 22.9±0.2°, and 21.4±0.2°; preferably, it includes any 2, 3, 4, 5, 6, 8, 10, or 12 of these peaks. The X-ray powder diffraction pattern of hydrobromide crystal form F includes one or more diffraction peaks located at 2θ of 25.4±0.2°, 24.7±0.2°, 26.2±0.2°, 12.4±0.2°, 17.4±0.2°, 18.5±0.2°, 32.0±0.2°, 20.2±0.2°, 21.5±0.2°, 28.3±0.2°, 18.7±0.2°, 21.9±0.2°, 28.7±0.2°, 29.8±0.2°, and 14.5±0.2°; preferably, it includes any 2, 3, 4, 5, 6, 8, 10, or 12 of these peaks.

15. The crystalline form of any one of claims 7-14 characterized by, The X-ray powder diffraction pattern of the hydrochloride crystal form A of compound 1 is basically shown in Figure 1; the DSC pattern is basically shown in Figure 2; and the TGA pattern is basically shown in Figure 3. The X-ray powder diffraction pattern of the methanesulfonate crystal form A of compound 1 is shown in Figure 4; the DSC pattern is shown in Figure 5; and the TGA pattern is shown in Figure 6. The X-ray powder diffraction pattern of benzenesulfonate crystal form A of compound 1 is shown in Figure 7; the DSC pattern is shown in Figure 8; and the TGA pattern is shown in Figure 9. The X-ray powder diffraction pattern of the hydrobromide crystal form A of compound 1 is shown in Figure 10; the DSC pattern is shown in Figure 11; and the TGA pattern is shown in Figure 12. The X-ray powder diffraction pattern of the hydrochloride crystal form A of compound 2 is shown in Figure 13; the DSC pattern is shown in Figure 14; and the TGA pattern is shown in Figure 15. The X-ray powder diffraction pattern of the hydrochloride crystal form B of compound 2 is basically shown in Figure 16; the DSC pattern is basically shown in Figure 17; and the TGA pattern is basically shown in Figure 18. The X-ray powder diffraction pattern of the sulfate crystal form A of compound 2 is basically shown in Figure 19; the DSC pattern is basically shown in Figure 20; and the TGA pattern is basically shown in Figure 21. The X-ray powder diffraction pattern of the sulfate crystal form B of compound 2 is shown in Figure 22; the DSC pattern is shown in Figure 23; and the TGA pattern is shown in Figure 24. The X-ray powder diffraction pattern of the sulfate crystal form C of compound 2 is shown in Figure 25; the DSC pattern is shown in Figure 26; and the TGA pattern is shown in Figure 27. The X-ray powder diffraction pattern of phosphate crystal form A of compound 2 is shown in Figure 28; the DSC pattern is shown in Figure 29; and the TGA pattern is shown in Figure 30. The X-ray powder diffraction pattern of the hydrobromide crystal form A of compound 2 is shown in Figure 31; the DSC pattern is shown in Figure 32; and the TGA pattern is shown in Figure 33. The X-ray powder diffraction pattern of the hydrobromide crystal form B of compound 2 is shown in Figure 34; the DSC pattern is shown in Figure 35; and the TGA pattern is shown in Figure 36. The X-ray powder diffraction pattern of the hydrobromide crystal form C of compound 2 is shown in Figure 37; the DSC pattern is shown in Figure 38; and the TGA pattern is shown in Figure 39. The X-ray powder diffraction pattern of the hydrobromide crystal form D of compound 2 is shown in Figure 40; the DSC pattern is shown in Figure 41; and the TGA pattern is shown in Figure 42. The X-ray powder diffraction pattern of the methanesulfonate crystal form A of compound 2 is shown in Figure 43; the DSC pattern is shown in Figure 44; and the TGA pattern is shown in Figure 45. The X-ray powder diffraction pattern of fumarate crystal form A of compound 2 is shown in Figure 46; the DSC pattern is shown in Figure 47; and the TGA pattern is shown in Figure 48. The X-ray powder diffraction pattern of the fumarate crystal form B of compound 2 is shown in Figure 49; the DSC pattern is shown in Figure 50; and the TGA pattern is shown in Figure 51. The X-ray powder diffraction pattern of the hydrochloride crystal form C of compound 2 is shown in Figure 52; the DSC pattern is shown in Figure 53; and the TGA pattern is shown in Figure 54. The X-ray powder diffraction pattern of phosphate crystal form B of compound 2 is shown in Figure 55; the DSC pattern is shown in Figure 56; and the TGA pattern is shown in Figure 57. The X-ray powder diffraction pattern of the hydrobromide crystal form E of compound 2 is shown in Figure 58; the DSC pattern is shown in Figure 59; and the TGA pattern is shown in Figure 60. The X-ray powder diffraction pattern of the hydrobromide crystal form F of compound 2 is basically shown in Figure 61; the DSC pattern is basically shown in Figure 62. The basic TGA chart is shown in Figure 63. The 2θ error between the positions of the top ten diffraction peaks with the highest relative peak intensities in the X-ray powder diffraction pattern and the corresponding positions in the attached figure is ±0.2°~±0.5°; preferably ±0.2°~±0.3°; most preferably ±0.2°.

16. A method for preparing an acid salt of the compound or its stereoisomer as described in any one of claims 1-15, or its crystal form, specifically comprising the following steps: 1) Weigh an appropriate amount of free alkali or free alkali crystal form and dissolve it in a good solvent; 2) Weigh an appropriate amount of the counterion acid and dissolve it in an organic solvent; the amount of counterion acid is preferably 1 to 1.2 equivalents. 3) Combine the two solutions and stir until a solid precipitates out; 4) Drying yields the target product; in: The beneficial solvent is selected from one or more of methanol, acetone, ethyl acetate, acetonitrile, ethanol, 88% acetone, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropanol, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, tert-butanol, 2-butanone, 3-pentanone, or N-methylpyrrolidone; preferably one or more of methanol, 88% acetone, dichloromethane, or anhydrous ethanol. The organic solvent is selected from methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, dichloroethane, tetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, tert-butanol, or N,N-dimethylformamide; preferably methanol, ethanol, or acetonitrile; the above-mentioned benign solvents and organic solutions must be miscible when used. The aforementioned counterionic acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid or phosphoric acid, 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphtholic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetoxyxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetaminobenzoic acid, 4-aminobenzoic acid, decanoic acid, hexanoic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfonic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, and dodecyl sulfonate. Acids, benzoyl tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactobionic acid, gentian acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, hydroxyethyl sulfonic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, dihydroxynaphthalic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanate, undecanoic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, or L-malic acid; Preferably, the counterionic acid is selected from hydrochloric acid, methanesulfonate, p-toluenesulfonate, benzenesulfonate, phosphoric acid, or hydrobromic acid; more preferably, it is hydrochloric acid, methanesulfonate, p-toluenesulfonate, benzenesulfonate, or hydrobromic acid. Preferably, the temperature is 25℃~50℃, and the pulping time is 1-7 days; And / or, Method 2: 1) Weigh an appropriate amount of free alkali or free alkali crystal form and dissolve it in a good solvent; 2) Weigh an appropriate amount of the counterion acid and dissolve it in an organic solvent; the amount of counterion acid is preferably 1 to 1.2 equivalents. 3) Combine the two solutions and filter. 4) Curing occurs at room temperature; 5) A solid product is obtained; Drying yields the target product; in: The beneficial solvent is selected from one or more of methanol, acetone, ethyl acetate, acetonitrile, ethanol, 88% acetone, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropanol, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, tert-butanol, 2-butanone, 3-pentanone, or N-methylpyrrolidone; preferably one or more of methanol, 88% acetone, dichloromethane, or anhydrous ethanol. The organic solvent is selected from methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, dichloroethane, tetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, tert-butanol, or N,N-dimethylformamide; preferably methanol, ethanol, or acetonitrile; the above-mentioned benign solvents and organic solutions must be miscible when used. The aforementioned counterionic acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid or phosphoric acid, 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphtholic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetoxyxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetaminobenzoic acid, 4-aminobenzoic acid, decanoic acid, hexanoic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfonic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, and dodecyl sulfonate. Acids, benzoyl tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactobionic acid, gentian acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, hydroxyethyl sulfonic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, dihydroxynaphthalic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanate, undecanoic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, or L-malic acid; Preferably, the counterionic acid is selected from hydrochloric acid, methanesulfonate, p-toluenesulfonate, benzenesulfonate, phosphoric acid, or hydrobromic acid; Preferably, the temperature is 25℃~50℃; the volatilization time is 1-14 days; And / or, Method 3: In both of the above methods, seed crystals can be added after step one, followed by stirring to induce crystallization.

17. A pharmaceutical composition comprising a therapeutically effective dose of an acid salt of any one of the compounds of claims 1-15 or a stereoisomer thereof or a crystal form thereof, and one or more pharmaceutically acceptable carriers or excipients.

18. The pharmaceutical composition of claim 17, wherein, The effective dose of the compound or its stereoisomer acid salt or its crystal form is 0.1% to 95% by weight, preferably 1% to 60%, more preferably 2% to 50%, more preferably 2% to 40%, even more preferably 2-30%, even more preferably 2-20%, even more preferably 4% to 30%, even more preferably 5% to 30%, even more preferably 5% to 20%, and specifically preferably 1%, 2%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60%.

19. Use of the compound or its stereoisomer, an acid salt or crystal form thereof, according to any one of claims 1-15, or the pharmaceutical composition of claim 17, in a medicament for treating and / or preventing PCSK9-related diseases.

20. The use of the compound or its stereoisomer, an acid salt or crystal form thereof, according to any one of claims 1-15, or the pharmaceutical composition according to claim 17, in the preparation of an LDL-lowering drug.

21. The use of the compound or its stereoisomer, an acid salt or crystal form thereof, according to any one of claims 1-15, or the pharmaceutical composition of claim 17, in the treatment and / or prevention of cardiovascular disease, cerebrovascular disease, atherosclerosis, and / or related diseases or symptoms thereof; preferably, in the treatment and / or prevention of stroke, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome, and / or coronary artery disease.

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