Free base crystal form of nitrogen-containing heterocyclic derivative, acid salt and crystal form thereof, preparation method therefor, and use thereof

Abstract

The present invention relates to a free base crystal form of a nitrogen-containing heterocyclic derivative, an acid salt and a crystal form thereof, a preparation method therefor, and a use thereof. In particular, the present invention relates to a free base crystal form of a compound represented by a general formula, an acid salt and a crystal form thereof, a preparation method therefor, a pharmaceutical composition containing a therapeutically effective amount of the salt or crystal form, and a use thereof as an inhibitor in the treatment of diseases such as cardiovascular disease and cerebrovascular disease.

Description

Free base crystal form and acid salt of nitrogen-containing heterocyclic derivative and crystal form thereof, preparation method and application thereof TECHNICAL FIELD

[0001] The present application belongs to the field of drug synthesis, and particularly relates to a free base crystal form and acid salt of a nitrogen-containing heterocyclic derivative inhibitor and crystal form thereof, a preparation method and application thereof. BACKGROUND

[0002] Cardiovascular disease (CVD) is a major cause of death worldwide, and high levels of low-density lipoprotein cholesterol (LDL-C) are a major risk factor. The accumulation of LDL-C in the inner wall of the artery can cause atherosclerosis and may trigger an inflammatory response, leading to cardiovascular events such as heart attack and stroke. Although statins can reduce serum LDL-C and are currently the main lipid-lowering drugs in clinical use, patients who are intolerant of statins or who fail to achieve therapeutic targets despite receiving a tolerated dose of treatment are still at risk, such as patients with familial hypercholesterolemia. The discovery of PCSK9 inhibitors provides a more aggressive treatment method for homozygous and heterozygous patients with familial hypercholesterolemia. Non-statin ezetimibe combined with statins can reduce LDL-C by 15%-20%, while PCSK9 inhibitors combined with statins can significantly reduce LDL-C by 54%-74%. PCSK9 inhibitors can also overcome the intolerable side effects of statins, such as muscle pain.

[0003] PCSK9 (Proprotein convertase subtilisin kexin type 9) is a serine protease that is highly expressed in the liver. Loss-of-function mutations in the PCSK9 gene are associated with low levels of LDL-C and reduced cardiovascular risk (Cohen, J.C., 2006), and it has been clinically verified as a target for the treatment of hyperlipidemia. PCSK9 is synthesized as a proenzyme, and after synthesis, it undergoes autocatalytic cleavage in the cell. The propeptide binds to the mature PCSK9 and is secreted into the extracellular space, and the propeptide binding blocks the catalytic activity of PCSK9.

[0004] PCSK9 is the major regulator of the level of low-density lipoprotein receptor (LDLR) on the surface of hepatocytes, which can inhibit the LDLR cycle pathway. LDLR function is critical to maintain cholesterol homeostasis, responsible for the uptake and degradation of low-density lipoprotein. Circulating LDL binds to the N-terminal ligand binding domain of LDLR through apolipoprotein B100, and the LDL / LDLR complex is internalized by receptor-mediated endocytosis, and the intracellular low pH environment releases LDL from LDLR, and LDLR circulates back to the cell membrane, and intracellular free LDL is sent to lysosomes and degraded. Secreted PCSK9 interferes with the cycling ability of LDLR by binding to LDLR on the surface of hepatocytes, and after the PCSK9 / LDLR complex migrates to the acidic endosome chamber through clathrin-coated pits, the conformational change of LDLR leads to the formation of additional binding sites with PCSK9. Therefore, PCSK9 accompanies LDLR to lysosomes for degradation, preventing LDLR from circulating, thereby up-regulating the level of LDL-C.

[0005] Familial hypercholesterolemia (FH) is a genetic disease of low-density lipoprotein cholesterol metabolism, with a prevalence of 1 in 250 people, characterized by significantly elevated levels of LDL-c. The risk of coronary heart disease (CAD) in heterozygous FH patients is 3-4 times that of normal people, and CAD often occurs 10 years earlier than normal. Statins reduce low-density lipoprotein cholesterol in heterozygous FH patients, and high-intensity statin therapy is considered to reduce the risk of coronary heart disease and mortality by 44% in the Beselins study. However, in many cases, the reduction of LDL-C is considered to be insufficient. The countermechanism of statins is to up-regulate sterol regulatory element binding protein 2 (SREBP-2), thereby activating LDL receptors and PCSK9, increasing PCSK9 expression and secretion binding to LDLR, resulting in elevated LDL-C levels in the blood. Therefore, although statins lower LDL by inhibiting HMGCoA, their effect on SREPB acts as a counterbalancing effect, and the addition of a PCSK9 inhibitor to statin therapy can help overcome this mechanism. Given that patients with familial hypercholesterolemia may not fully benefit from statin therapy, alternative treatment approaches such as PCSK9 inhibitors are needed.

[0006] PCSK9 macromolecular inhibitors, monoclonal antibody-based drugs Alirocumab and Evolocumab, can selectively bind to extracellular PCSK9 and prevent its interaction with LDLR, and have been approved by FDA for reducing LDL-C levels with good safety. Studies have shown that in heterozygous FH patients who did not achieve LCL-C target after statin therapy, Alirocumab injected every 2 weeks can maximally reduce cardiovascular risk. Alirocumab also shows a moderate increase in "good" cholesterol (HDL-C). In addition, there is a PCSK9 siRNA drug Inclisiran on the market, which can reduce cholesterol by reducing PCSK9 protein expression levels, and has good safety. However, both of the above drugs need to be injected, and the production cost is high and the price is expensive. So far, there is no PCSK9 small molecule inhibitor on the market, so there is a high demand for oral PCSK9 small molecule inhibitor drugs.

[0007] PCSK9 small molecule inhibitors have been reported in patents, such as: WO2014170786 (Pfizer), WO2014150326 (Shifa), WO2020150473 (AZ) and WO2022133529 (Nyrada). The most advanced AZD-0780 is in clinical phase I, and the others are in preclinical development stage. There are also some polypeptides reported, and the most advanced one is in clinical phase II. The present invention needs to develop oral PCSK9 small molecule inhibitors.

[0008] A series of nitrogen-containing heterocyclic compounds are disclosed in PCT / CN2023 / 124530. In subsequent research and development, in order to facilitate the handling, filtration and drying of products, suitable crystals that are easy to store and stable for a long period of time are sought. The present invention comprehensively studies the crystal forms of the above-mentioned compounds. SUMMARY

[0009] All contents related to the patent PCT / CN2023 / 124530 are added to the present invention by reference.

[0010] The purpose of the present invention is to provide a free base crystal form of a compound as shown in general formula (I), an acid salt and a crystal form thereof:

[0011] wherein: ring A is selected from 3-8 membered heterocyclyl, 7-10 membered bicyclic heterocyclyl, 5 membered heteroaryl, 6 membered heteroaryl, 5 membered and 5 membered bicyclic heteroaryl, 5 membered and 6 membered bicyclic heteroaryl, 5 membered and 6 membered bicyclic heterocyclyl, 6 membered and 5 membered bicyclic heteroaryl or 6 membered and 6 membered bicyclic heteroaryl;

[0012] Preferably, ring A is selected from More preferably, ring A is selected from

[0013] M1is selected from N or CH; M2is selected from N or CH; M3is selected from N or CH; M4is selected from N or CH;

[0014] R a selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, haloC 1-6 alkoxy or C 3-8 cycloalkyl;

[0015] R b selected from hydrogen, halogen or C 1-6 alkyl; R c selected from hydrogen, halogen or C 1-6 alkyl;

[0016] R d selected from hydrogen, halogen, C 1-6 alkyl, oxo, C 1-6 haloalkyl, C 1-6 alkoxy, haloC 1-6 alkoxy or C 3-8 cycloalkyl;

[0017] x is 0, 1 or 2; y is 0, 1 or 2; z is 0, 1 or 2; e is 0, 1 or 2; and

[0018] the acid of the acid salt is selected from an inorganic acid or an organic acid, wherein the inorganic acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid or phosphoric acid; the organic acid is selected from 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetyloxyhydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetylamino benzoic acid, 4-aminobenzoic acid, capric acid, hexanoic acid, octanoic acid, cinnamic acid, citric acid, cyclohexanesulfamic 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, dodecylsulfuric acid, dibenzoyl tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galacturonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalene disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, undecylenic acid, trifluoroacetic acid, benzene sulfonic acid, p-toluene sulfonic acid or L-malic acid;

[0019] Preferably, the acid is selected from hydrochloric acid, ethanesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, isethionic acid or salicylic acid; further preferably, the acid is selected from hydrochloric acid.

[0020] Another object of the present application is to provide a free base crystal form of a compound as shown in general formula (II), an acid salt thereof and a crystal form thereof:

[0021] wherein: ring B is selected from a 6-membered mono-heteroaryl, a 5-membered and 5-membered bicyclic heteroaryl, a 5-membered and 6-membered bicyclic heteroaryl, a 6-membered and 5-membered bicyclic heteroaryl or a 6-membered and 6-membered bicyclic heteroaryl;

[0022] Preferably, ring B is selected from

[0023] M1, M2, M3, M4, acid, R a , R b , R c , R d , x, y, z and e are as defined above.

[0024] In a preferred embodiment of the present application, the free base crystal form of a compound, an acid salt thereof and a crystal form thereof are further shown in general formula (IV):

[0025] In a preferred embodiment of the present application, R a is selected from hydrogen, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, haloC 1-3 alkoxy or cyclopropyl;

[0026] R b is selected from hydrogen, halogen or C 1-3 alkyl; R c is selected from hydrogen, halogen or C 1-3 alkyl;

[0027] R d is selected from hydrogen, halogen, C 1-6 alkyl, oxo, C 1-3 haloalkyl, C 1-3 alkoxy, haloC 1-3 alkoxy or cyclopropyl.

[0028] In a preferred embodiment of the present application, the number of acids in the acid salt of the compound is 0.2-3; preferably 1, 2 or 3; more preferably 1 or 2, further preferably 1.

[0029] In preferred embodiments of the present application, the acid salt of the compound is a hydrate or an anhydrate; when the acid salt is a hydrate, the number of waters is from 0.2 to 3; preferably 1 or 2; preferably, the acid salt is an anhydrate.

[0030] In preferred embodiments of the present application, the acid salt and the free base of the compound 1 are in a crystalline form.

[0031] In preferred embodiments of the present application, the hydrochloride salt Form A, the hydrochloride salt Form B, the mesylate salt Form A, the mesylate salt Form B, the besylate salt Form A, the besylate salt Form B, the p-toluenesulfonate salt Form A, the hydroxyethylsulfonate salt Form A, the ethanesulfonate salt Form A, the salicylate salt Form A, the free base Form A, the free base Form B or the free base Form C of the compound 1.

[0032] In preferred embodiments of the present application, the hydrochloride salt Form A has an X-ray powder diffraction pattern comprising a diffraction peak at 2-theta of 10.9±0.2°; or at 14.9±0.2°; or at 15.5±0.2°; or at 16.3±0.2°; or at 17.3±0.2°; or at 17.9±0.2°; or at 22.0±0.2°; or at 23.4±0.2°; or at 25.8±0.2°; or at 26.3±0.2°; preferably comprising any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, more preferably comprising any 6, 7 or 8 of them;

[0033] In preferred embodiments of the present application, the hydrochloride salt Form A has an X-ray powder diffraction pattern comprising at least one diffraction peak at 2-theta of 17.3±0.2°, 22.0±0.2°, 25.8±0.2°, preferably comprising two of them, more preferably comprising three of them; optionally, further comprising at least one diffraction peak at 2-theta of 10.9±0.2°, 14.9±0.2°, 15.5±0.2°, 17.9±0.2°, 26.3±0.2°, preferably comprising 2, 3, 4 or 5 of them; for example, 10.9±0.2°, 17.3±0.2°; 14.9±0.2°, 22.0±0.2°;

[0034] 10.9±0.2°, 17.3±0.2°, 22.0±0.2°; 14.9±0.2°, 22.0±0.2°, 25.8±0.2°;

[0035] 10.9 ± 0.2°, 17.3 ± 0.2°, 22.0 ± 0.2°, 25.8 ± 0.2°;

[0036] 14.9 ± 0.2°, 15.5 ± 0.2°, 17.3 ± 0.2°, 25.8 ± 0.2°;

[0037] 10.9 ± 0.2°, 14.9 ± 0.2°, 17.3 ± 0.2°, 22.0 ± 0.2°, 25.8 ± 0.2°;

[0038] 14.9 ± 0.2°, 15.5 ± 0.2°, 17.3 ± 0.2°, 22.0 ± 0.2°, 25.8 ± 0.2°;

[0039] In preferred embodiments of the application, the X-ray powder diffraction pattern of said hydrochloride salt Form A optionally further comprises one or more of the diffraction peaks at 2Θ of 8.8 ± 0.2°, 12.6 ± 0.2°, 15.2 ± 0.2°, 16.3 ± 0.2°, 22.7 ± 0.2°, 23.4 ± 0.2°, 27.4 ± 0.2°; preferably at least any 2-3 thereof, or 4-5 thereof, or 6-7 thereof; further preferably, any 2, 3, 4, 5, 6, 7 thereof; for example, 8.8 ± 0.2°, 12.6 ± 0.2°; 12.6 ± 0.2°, 15.2 ± 0.2°;

[0040] 12.6 ± 0.2°, 15.2 ± 0.2°, 16.3 ± 0.2°;

[0041] 15.2 ± 0.2°, 16.3 ± 0.2°, 22.7 ± 0.2°;

[0042] 8.8 ± 0.2°, 12.6 ± 0.2°, 16.3 ± 0.2°, 22.7 ± 0.2°;

[0043] 12.6 ± 0.2°, 16.3 ± 0.2°, 22.7 ± 0.2°, 23.4 ± 0.2°, 27.4 ± 0.2°;

[0044] In preferred embodiments of the application, the hydrochloride salt Form A has an X-ray powder diffraction pattern comprising one or more of the following peaks expressed in degrees 2-theta: 10.9 ± 0.2°, 12.6 ± 0.2°, 14.9 ± 0.2°, 15.5 ± 0.2°, 16.3 ± 0.2°, 17.3 ± 0.2°, 17.9 ± 0.2°, 22.0 ± 0.2°, 23.4 ± 0.2°, 25.8 ± 0.2°, 26.3 ± 0.2°, 27.4 ± 0.2°; preferably, any 4, 5, 6, 8, 10 or 12 thereof; for example, 10.9 ± 0.2°, 12.6 ± 0.2°, 14.9 ± 0.2°, 15.5 ± 0.2°;

[0045] 12.6 ± 0.2°, 14.9 ± 0.2°, 16.3 ± 0.2°, 17.3 ± 0.2°;

[0046] 10.9 ± 0.2°, 17.9 ± 0.2°, 22.0 ± 0.2°, 23.4 ± 0.2°, 25.8 ± 0.2°;

[0047] 17.9 ± 0.2°, 22.0 ± 0.2°, 23.4 ± 0.2°, 25.8 ± 0.2°, 26.3 ± 0.2°, 27.4 ± 0.2°;

[0048] 14.9 ± 0.2°, 15.5 ± 0.2°, 16.3 ± 0.2°, 17.3 ± 0.2°, 23.4 ± 0.2°, 25.8 ± 0.2°, 26.3 ± 0.2°, 27.4 ± 0.2°;

[0049] 10.9 ± 0.2°, 12.6 ± 0.2°, 14.9 ± 0.2°, 15.5 ± 0.2°, 16.3 ± 0.2°, 17.3 ± 0.2°, 17.9 ± 0.2°, 22.0 ± 0.2°, 23.4 ± 0.2°, 27.4 ± 0.2°;

[0050] In preferred embodiments of the application, the hydrochloride salt Form A has an X-ray powder diffraction pattern comprising one or more of the following peaks expressed in degrees 2-theta: 10.9 ± 0.2°, 12.6 ± 0.2°, 14.9 ± 0.2°, 15.5 ± 0.2°, 16.3 ± 0.2°, 17.3 ± 0.2°, 17.9 ± 0.2°, 22.0 ± 0.2°, 23.4 ± 0.2°, 25.8 ± 0.2°, 26.3 ± 0.2°, 27.4 ± 0.2°; preferably, any 4, 5, 6, 8, 10 or 12 thereof; for example, 10.9 ± 0.2°, 12.6 ± 0.2°, 14.9 ± 0.2°, 15.5 ± 0.2°;

[0051] Table 1

[0052] In preferred embodiments of the application, the hydrochloride salt Form A has an X-ray powder diffraction pattern substantially as shown in Figure 1; a DSC pattern substantially as shown in Figure 2; and a TGA pattern substantially as shown in Figure 3.

[0053] In preferred embodiments of the present application, the hydrochloride salt Form B has an X-ray powder diffraction pattern comprising at least one diffraction peak at 2-theta 5.8±0.2°; or at 8.0±0.2°; or at 13.2±0.2°; or at 15.6±0.2°; or at 16.1±0.2°; or at 19.6±0.2°; or at 23.5±0.2°; or at 24.1±0.2°; or at 24.8±0.2°; or at 33.7±0.2°; preferably comprising any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, more preferably comprising any 6, 7 or 8 of the above diffraction peaks;

[0054] In preferred embodiments of the present application, the hydrochloride salt Form B has an X-ray powder diffraction pattern comprising at least one diffraction peak at 2-theta 5.8±0.2°; or at 8.0±0.2°; or at 13.2±0.2°; or at 15.6±0.2°; or at 16.1±0.2°; or at 19.6±0.2°; or at 23.5±0.2°; or at 24.1±0.2°; or at 24.8±0.2°; or at 33.7±0.2°; preferably comprising any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, more preferably comprising any 6, 7 or 8 of the above diffraction peaks;

[0055] 13.2±0.2°, 15.6±0.2°; 16.1±0.2°, 24.1±0.2°; 19.6±0.2°, 24.8±0.2°;

[0056] 15.6±0.2°, 23.5±0.2°, 24.1±0.2°; 24.1±0.2°, 24.8±0.2°, 33.7±0.2°;

[0057] 13.2±0.2°, 15.6±0.2°, 24.1±0.2°, 24.8±0.2°;

[0058] 15.6±0.2°, 23.5±0.2°, 24.1±0.2°, 33.7±0.2°;

[0059] 13.2±0.2°, 15.6±0.2°, 24.1±0.2°, 19.6±0.2°, 23.5±0.2°;

[0060] 15.6±0.2°, 16.1±0.2°, 19.6±0.2°, 24.8±0.2°, 33.7±0.2°;

[0061] In preferred embodiments of the application, the hydrochloride salt Form B has an X-ray powder diffraction pattern comprising one or more of the following peaks, in terms of 2-theta: 5.8 ± 0.2°, 8.0 ± 0.2°, 20.1 ± 0.2°, 20.9 ± 0.2°, 22.2 ± 0.2°, 26.3 ± 0.2°, 27.4 ± 0.2°; preferably, at least any 2-3, or 4-5, or 6-7 thereof; more preferably, at least any 2, 3, 4, 5, 6, 7 thereof; for example, 5.8 ± 0.2°, 8.0 ± 0.2°; 8.0 ± 0.2° 20.1 ± 0.2°;

[0062] 5.8 ± 0.2°, 20.9 ± 0.2°, 22.2 ± 0.2°; 20.1 ± 0.2°, 20.9 ± 0.2°, 22.2 ± 0.2°;

[0063] 5.8 ± 0.2°, 20.1 ± 0.2°, 26.3 ± 0.2°, 27.4 ± 0.2°;

[0064] 8.0 ± 0.2°, 20.1 ± 0.2°, 20.9 ± 0.2°, 26.3 ± 0.2°, 27.4 ± 0.2°;

[0065] In preferred embodiments of the application, the hydrochloride salt Form B has an X-ray powder diffraction pattern comprising one or more of the following peaks, in terms of 2-theta: 5.8 ± 0.2°, 8.0 ± 0.2°, 13.2 ± 0.2°, 15.6 ± 0.2°, 16.1 ± 0.2°, 19.6 ± 0.2°, 20.9 ± 0.2°, 23.5 ± 0.2°, 24.1 ± 0.2°, 24.8 ± 0.2°, 27.4 ± 0.2°, 33.7 ± 0.2°; preferably, at least any 4, 5, 6, 8, 10, or 12 thereof; for example, 5.8 ± 0.2°, 8.0 ± 0.2°, 13.2 ± 0.2°, 15.6 ± 0.2°;

[0066] 13.2 ± 0.2°, 15.6 ± 0.2°, 16.1 ± 0.2°, 19.6 ± 0.2°;

[0067] 8.0 ± 0.2°, 16.1 ± 0.2°, 20.9 ± 0.2°, 23.5 ± 0.2°, 24.1 ± 0.2°;

[0068] 5.8 ± 0.2°, 16.1 ± 0.2°, 19.6 ± 0.2°, 24.8 ± 0.2°, 27.4 ± 0.2°, 33.7 ± 0.2°;

[0069] 8.0 ± 0.2°, 13.2 ± 0.2°, 19.6 ± 0.2°, 20.9 ± 0.2°, 23.5 ± 0.2°, 24.1 ± 0.2°, 24.8 ± 0.2°, 27.4 ± 0.2°;

[0070] 5.8 ± 0.2°, 13.2 ± 0.2°, 15.6 ± 0.2°, 16.1 ± 0.2°, 20.9 ± 0.2°, 23.5 ± 0.2°, 24.1 ± 0.2°, 24.8 ± 0.2°, 27.4 ± 0.2°, 33.7 ± 0.2°;

[0071] In a preferred embodiment of the present application, the hydrochloride salt Form B has X-ray characteristic diffraction peaks expressed in terms of 2 theta angle and interplanar spacing d value as shown in Table 2 using Cu-Ka radiation.

[0072] Table 2

[0073] In a preferred embodiment of the present application, the hydrochloride salt Form B has an X-ray powder diffraction pattern substantially as shown in Figure 4; and a DSC pattern substantially as shown in Figure 5.

[0074] In a preferred embodiment of the present application, the methanesulfonate salt Form A has an X-ray powder diffraction pattern having a diffraction peak at 2 theta of 12.4 ± 0.2°; or at 17.3 ± 0.2°; or at 18.2 ± 0.2°; or at 20.3 ± 0.2°; or at 20.9 ± 0.2°; or at 21.2 ± 0.2°; or at 22.5 ± 0.2°; or at 22.8 ± 0.2°; or at 24.4 ± 0.2°; or at 26.8 ± 0.2°; preferably comprising any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, more preferably comprising any 6, 7 or 8 of them;

[0075] In a preferred embodiment of the present application, the methanesulfonate salt Form A has an X-ray powder diffraction pattern comprising at least one or more of the diffraction peaks at 2 theta of 17.3 ± 0.2°, 20.9 ± 0.2°, 22.8 ± 0.2°, preferably comprising two of them, more preferably comprising three of them; optionally, further comprising at least one of the diffraction peaks at 2 theta of 12.4 ± 0.2°, 21.2 ± 0.2°, 22.5 ± 0.2°, 24.4 ± 0.2°, 26.8 ± 0.2°, preferably comprising 2, 3, 4 or 5 of them; for example,

[0076] 12.4 ± 0.2°, 17.3 ± 0.2°; 20.9 ± 0.2°, 21.2 ± 0.2°; 22.5 ± 0.2°, 22.8 ± 0.2°;

[0077] 17.3 ± 0.2°, 20.9 ± 0.2°, 22.8 ± 0.2°; 12.4 ± 0.2°, 20.9 ± 0.2°, 21.2 ± 0.2°;

[0078] 12.4 ± 0.2°, 17.3 ± 0.2°, 20.9 ± 0.2°, 22.5 ± 0.2°;

[0079] 17.3 ± 0.2°, 21.2 ± 0.2°, 22.8 ± 0.2°, 26.8 ± 0.2°;

[0080] 20.9 ± 0.2°, 22.5 ± 0.2°, 22.8 ± 0.2°, 24.4 ± 0.2°, 26.8 ± 0.2°;

[0081] 17.3 ± 0.2°, 12.4 ± 0.2°, 21.2 ± 0.2°, 24.4 ± 0.2°, 26.8 ± 0.2°;

[0082] In preferred embodiments of the application, the X-ray powder diffraction pattern of said methanesulfonic acid salt Form A optionally further comprises one or more of the diffraction peaks at 2Θ of 18.2 ± 0.2°, 18.5 ± 0.2°, 19.4 ± 0.2°, 20.0 ± 0.2°, 20.3 ± 0.2°, 26.6 ± 0.2°, 38.7 ± 0.2°; preferably at least any 2-3 thereof, or 4-5 thereof, or 6-7 thereof; further preferably, at least any 2 thereof, 3 thereof, 4 thereof, 5 thereof, 6 thereof, 7 thereof; for example, 18.2 ± 0.2°, 19.4 ± 0.2°; 20.0 ± 0.2°, 20.3 ± 0.2°;

[0083] 18.5 ± 0.2°, 26.6 ± 0.2°, 38.7 ± 0.2°;

[0084] 18.2 ± 0.2°, 19.4 ± 0.2°, 20.0 ± 0.2°, 20.3 ± 0.2°;

[0085] 18.5 ± 0.2°, 20.0 ± 0.2°, 20.3 ± 0.2°, 26.6 ± 0.2°, 38.7 ± 0.2°;

[0086] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the mesylate salt form A comprises one or more diffraction peaks located at 2θ of 12.4±0.2°, 17.3±0.2°, 18.2±0.2°, 19.4±0.2°, 20.3±0.2°, 20.9±0.2°, 21.2±0.2°, 22.5±0.2°, 22.8±0.2°, 24.4±0.2°, 26.6±0.2°, and 26.8±0.2°; preferably, comprising 4, 5, 6, 8, 10 or 12 of the diffraction peaks selected therefrom; for example, 12.4±0.2°, 18.2±0.2°, 20.3±0.2°, and 21.2±0.2°;

[0087] 17.3±0.2°, 19.4±0.2°, 20.9±0.2°, 22.5±0.2°;

[0088] 12.4±0.2°, 22.8±0.2°, 24.4±0.2°, 26.6±0.2°, 26.8±0.2°;

[0089] 18.2±0.2°, 19.4±0.2°, 21.2±0.2°, 22.5±0.2°, 24.4±0.2°, 26.6±0.2°;

[0090] 19.4±0.2°, 20.9±0.2°, 21.2±0.2°, 22.5±0.2°, 22.8±0.2°, 24.4±0.2°, 26.6±0.2°, 26.8±0.2°;

[0091] 12.4±0.2°, 18.2±0.2°, 19.4±0.2°, 20.3±0.2°, 20.9±0.2°, 21.2±0.2°, 22.5±0.2°, 22.8±0.2°, 24.4±0.2°, 26.8±0.2°;

[0092] In a preferred embodiment of the present invention, the mesylate salt crystalline form A uses Cu-Kα radiation, and the X-ray characteristic diffraction peaks represented by 2θ angles and interplanar spacing d values ​​are shown in Table 3.

[0093] Table 3

[0094] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the mesylate salt form A is substantially as shown in FIG6 ; and the DSC pattern is substantially as shown in FIG7 .

[0095] In preferred embodiments of the present application, the methanesulfonic acid salt Form B has an X-ray powder diffraction pattern comprising at least one of the following peaks: 6.9±0.2°, 12.5±0.2°, 18.9±0.2°, 21.8±0.2°, 27.2±0.2°; preferably, it comprises at least two of them, more preferably at least three of them; optionally, it can further comprise at least one of the following peaks: 6.9±0.2°, 17.3±0.2°, 20.7±0.2°, 22.8±0.2°; preferably, it comprises at least two of them, more preferably at least three of them; for example,

[0096] In preferred embodiments of the present application, the methanesulfonic acid salt Form B has an X-ray powder diffraction pattern comprising at least one of the following peaks: 6.9±0.2°, 12.5±0.2°, 18.9±0.2°, 21.8±0.2°, 27.2±0.2°; preferably, it comprises at least two of them, more preferably at least three of them; optionally, it can further comprise at least one of the following peaks: 6.9±0.2°, 17.3±0.2°, 20.7±0.2°, 22.8±0.2°; preferably, it comprises at least two of them, more preferably at least three of them; for example,

[0097] 6.9±0.2°, 17.3±0.2°; 12.5±0.2°, 20.7±0.2°; 18.9±0.2°, 22.8±0.2°;

[0098] 17.3±0.2°, 20.7±0.2°, 22.8±0.2°; 18.9±0.2°, 20.7±0.2°, 27.2±0.2°;

[0099] 17.3±0.2°, 21.8±0.2°, 22.8±0.2°, 27.2±0.2°;

[0100] 6.9±0.2°, 18.9±0.2°, 20.7±0.2°, 21.8±0.2°;

[0101] 12.5±0.2°, 18.9±0.2°, 20.7±0.2°, 21.8±0.2°, 27.2±0.2°;

[0102] 17.3±0.2°, 18.9±0.2°, 20.7±0.2°, 21.8±0.2°, 22.8±0.2°;

[0103] In preferred embodiments of the application, the X-ray powder diffraction pattern of the mesylate salt Form B optionally further comprises one or more of the diffraction peaks at 2Θ of 21.4±0.2°, 22.5±0.2°, 23.0±0.2°, 23.2±0.2°, 25.1±0.2°, 30.7±0.2°, 39.0±0.2°; preferably at least any 2-3, or 4-5, or 6-7 thereof; more preferably, any 2, 3, 4, 5, 6, 7 thereof; for example, 21.4±0.2°, 22.5±0.2°; 23.0±0.2°, 25.1±0.2°;

[0104] 22.5±0.2°, 23.2±0.2°, 30.7±0.2°;

[0105] 21.4±0.2°, 23.2±0.2°, 25.1±0.2°, 39.0±0.2°;

[0106] 21.4±0.2°, 22.5±0.2°, 23.0±0.2°, 25.1±0.2°, 30.7±0.2°;

[0107] In preferred embodiments of the application, the X-ray powder diffraction pattern of the mesylate salt Form B comprises one or more of the diffraction peaks at 2Θ of 6.9±0.2°, 12.5±0.2°, 17.3±0.2°, 18.9±0.2°, 20.7±0.2°, 21.4±0.2°, 21.8±0.2°, 22.5±0.2°, 22.8±0.2°, 23.0±0.2°, 25.1±0.2°, 27.2±0.2°; preferably, 4, 5, 6, 8, 10, or 12 thereof; for example, 6.9±0.2°, 17.3±0.2°, 20.7±0.2°, 21.4±0.2°;

[0108] 12.5±0.2°, 18.9±0.2°, 21.8±0.2°, 22.5±0.2°;

[0109] 6.9±0.2°, 21.8±0.2°, 22.8±0.2°, 23.0±0.2°, 27.2±0.2°;

[0110] 12.5±0.2°, 18.9±0.2°, 22.5±0.2°, 23.0±0.2°, 25.1±0.2°, 27.2±0.2°;

[0111] 17.3 ± 0.2°, 20.7 ± 0.2°, 21.4 ± 0.2°, 22.5 ± 0.2°, 22.8 ± 0.2°, 23.0 ± 0.2°, 25.1 ± 0.2°, 27.2 ± 0.2°;

[0112] 12.5 ± 0.2°, 18.9 ± 0.2°, 20.7 ± 0.2°, 21.4 ± 0.2°, 21.8 ± 0.2°, 22.5 ± 0.2°, 22.8 ± 0.2°, 23.0 ± 0.2°, 25.1 ± 0.2°, 27.2 ± 0.2°;

[0113] In preferred embodiments of the application, the mesylate salt Form B has X-ray characteristic diffraction peaks expressed in terms of 2 theta angle and interplanar spacing d value as shown in Table 4 using Cu-Ka radiation.

[0114] Table 4

[0115] In preferred embodiments of the application, the mesylate salt Form B has an X-ray powder diffraction pattern substantially as shown in Figure 8; and a DSC pattern substantially as shown in Figure 9.

[0116] In preferred embodiments of the application, the besylate salt Form A has an X-ray powder diffraction pattern having a diffraction peak at 2 theta of 12.5 ± 0.2°; or at 16.0 ± 0.2°; or at 18.5 ± 0.2°; or at 18.8 ± 0.2°; or at 19.0 ± 0.2°; or at 19.3 ± 0.2°; or at 20.1 ± 0.2°; or at 21.1 ± 0.2°; or at 22.6 ± 0.2°; or at 25.2 ± 0.2°; preferably comprising any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above-mentioned diffraction peaks, more preferably comprising any 6, 7 or 8 thereof;

[0117] In preferred embodiments of the application, the besylate salt Form A has an X-ray powder diffraction pattern comprising at least one, preferably two, more preferably three, of the diffraction peaks at 2 theta of 19.0 ± 0.2°, 19.3 ± 0.2°, 20.1 ± 0.2°; and optionally further comprising at least one, preferably two, three, four or five, of the diffraction peaks at 2 theta of 12.5 ± 0.2°, 16.0 ± 0.2°, 21.1 ± 0.2°, 22.6 ± 0.2°, 25.2 ± 0.2°; for example,

[0118] 12.5 ± 0.2°, 19.0 ± 0.2°; 16.0 ± 0.2°, 19.3 ± 0.2°; 20.1 ± 0.2°, 21.1 ± 0.2°;

[0119] 19.0 ± 0.2°, 19.3 ± 0.2°, 20.1 ± 0.2°; 19.0 ± 0.2°, 20.1 ± 0.2°, 21.1 ± 0.2°;

[0120] 16.0 ± 0.2°, 19.3 ± 0.2°, 20.1 ± 0.2°, 25.2 ± 0.2°;

[0121] 12.5 ± 0.2°, 19.0 ± 0.2°, 20.1 ± 0.2°, 22.6 ± 0.2°;

[0122] 12.5 ± 0.2°, 19.3 ± 0.2°, 21.1 ± 0.2°, 22.6 ± 0.2°, 25.2 ± 0.2°;

[0123] 16.0 ± 0.2°, 19.0 ± 0.2°, 21.1 ± 0.2°, 22.6 ± 0.2°, 25.2 ± 0.2°;

[0124] In preferred embodiments of the application, the X-ray powder diffraction pattern of said benzenesulfonic acid salt Form A optionally further comprises one or more of the diffraction peaks at 2Θ of 12.7 ± 0.2°, 17.7 ± 0.2°, 18.5 ± 0.2°, 18.8 ± 0.2°, 20.3 ± 0.2°, 22.3 ± 0.2°, 22.9 ± 0.2°; preferably at least any 2-3 thereof, or 4-5 thereof, or 6-7 thereof; further preferably, at least any 2, 3, 4, 5, 6, 7 thereof; for example, 12.7 ± 0.2°, 18.5 ± 0.2°; 17.7 ± 0.2°, 18.8 ± 0.2°;

[0125] 20.3 ± 0.2°, 22.3 ± 0.2°, 22.9 ± 0.2°;

[0126] 12.7 ± 0.2°, 18.8 ± 0.2°, 20.3 ± 0.2°, 22.9 ± 0.2°;

[0127] 17.7 ± 0.2°, 18.5 ± 0.2°, 20.3 ± 0.2°, 22.3 ± 0.2°, 22.9 ± 0.2°;

[0128] In a preferred embodiment of the application, the X-ray powder diffraction pattern of the besylate Form A comprises one or more of the diffraction peaks at 2-theta = 12.5±0.2°, 16.0±0.2°, 17.7±0.2°, 18.5±0.2°, 18.8±0.2°, 19.0±0.2°, 19.3±0.2°, 20.1±0.2°, 21.1±0.2°, 22.3±0.2°, 22.6±0.2°, 25.2±0.2°; preferably, any 4, 5, 6, 8, 10 or 12 thereof; for example, 12.5±0.2°, 17.7±0.2°, 18.8±0.2°, 19.0±0.2°;

[0129] 16.0±0.2°, 18.5±0.2°, 20.1±0.2°, 21.1±0.2°;

[0130] 17.7±0.2°, 19.0±0.2°, 19.3±0.2°, 22.6±0.2°, 25.2±0.2°;

[0131] 16.0±0.2°, 18.5±0.2°, 19.3±0.2°, 20.1±0.2°, 22.3±0.2°, 25.2±0.2°;

[0132] 12.5±0.2°, 18.5±0.2°, 18.8±0.2°, 20.1±0.2°, 21.1±0.2°, 22.3±0.2°, 22.6±0.2°, 25.2±0.2°;

[0133] 16.0±0.2°, 17.7±0.2°, 18.8±0.2°, 19.0±0.2°, 19.3±0.2°, 20.1±0.2°, 21.1±0.2°, 22.3±0.2°, 22.6±0.2°, 25.2±0.2°;

[0134] In a preferred embodiment of the application, the X-ray powder diffraction pattern of the besylate Form A is substantially as shown in Figure 10; the DSC pattern is substantially as shown in Figure 11.

[0135] Table 5

[0136] In a preferred embodiment of the application, the X-ray powder diffraction pattern of the besylate Form A is substantially as shown in Figure 10; the DSC pattern is substantially as shown in Figure 11.

[0137] In preferred embodiments of the present application, the benzenesulfonate salt Form B has an X-ray powder diffraction pattern comprising at least one diffraction peak at 2-theta = 6.2 ± 0.2°; or at 9.3 ± 0.2°; or at 12.4 ± 0.2°; or at 15.5 ± 0.2°; or at 18.7 ± 0.2°; or at 21.8 ± 0.2°; or at 25.0 ± 0.2°; or at 28.2 ± 0.2°; or at 31.4 ± 0.2°; or at 37.9 ± 0.2°; preferably comprising any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, more preferably comprising any 6, 7 or 8 of the above diffraction peaks;

[0138] In preferred embodiments of the present application, the benzenesulfonate salt Form B has an X-ray powder diffraction pattern comprising at least one diffraction peak at 2-theta = 6.2 ± 0.2°; or at 9.3 ± 0.2°; or at 12.4 ± 0.2°; or at 15.5 ± 0.2°; or at 18.7 ± 0.2°; or at 21.8 ± 0.2°; or at 25.0 ± 0.2°; or at 28.2 ± 0.2°; or at 31.4 ± 0.2°; or at 37.9 ± 0.2°; preferably comprising any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, more preferably comprising any 6, 7 or 8 of the above diffraction peaks;

[0139] 12.4 ± 0.2°, 25.0 ± 0.2°; 6.2 ± 0.2°, 9.3 ± 0.2°, 12.4 ± 0.2°;

[0140] 6.2 ± 0.2°, 12.4 ± 0.2°, 37.9 ± 0.2°;

[0141] 9.3 ± 0.2°, 15.5 ± 0.2°, 25.0 ± 0.2°, 37.9 ± 0.2°;

[0142] 6.2 ± 0.2°, 12.4 ± 0.2°, 18.7 ± 0.2°, 31.4 ± 0.2°;

[0143] 9.3 ± 0.2°, 15.5 ± 0.2°, 25.0 ± 0.2°, 31.4 ± 0.2°, 37.9 ± 0.2°;

[0144] 12.4 ± 0.2°, 15.5 ± 0.2°, 18.7 ± 0.2°, 31.4 ± 0.2°, 37.9 ± 0.2°;

[0145] In preferred embodiments of the application, the X-ray powder diffraction pattern of the besylate Form B optionally further comprises one or more of the diffraction peaks at 2-theta = 16.1 ± 0.2°, 17.4 ± 0.2°, 20.3 ± 0.2°, 21.8 ± 0.2°, 27.8 ± 0.2°, 28.2 ± 0.2°, 30.9 ± 0.2°; preferably at least any 2-3, or 4-5, or 6-7 thereof; more preferably, any 2, 3, 4, 5, 6, 7 thereof; for example, 16.1 ± 0.2°, 20.3 ± 0.2°; 17.4 ± 0.2°, 21.8 ± 0.2°;

[0146] 16.1 ± 0.2°, 27.8 ± 0.2°, 30.9 ± 0.2°;

[0147] 17.4 ± 0.2°, 20.3 ± 0.2°, 21.8 ± 0.2°, 28.2 ± 0.2°;

[0148] 16.1 ± 0.2°, 20.3 ± 0.2°, 27.8 ± 0.2°, 28.2 ± 0.2°, 30.9 ± 0.2°;

[0149] In preferred embodiments of the application, the X-ray powder diffraction pattern of the besylate Form B comprises one or more of the diffraction peaks at 2-theta = 6.2 ± 0.2°, 9.3 ± 0.2°, 12.4 ± 0.2°, 15.5 ± 0.2°, 16.1 ± 0.2°, 18.7 ± 0.2°, 21.8 ± 0.2°, 25.0 ± 0.2°, 28.2 ± 0.2°, 30.9 ± 0.2°, 31.4 ± 0.2°, 37.9 ± 0.2°; preferably, 4, 5, 6, 8, 10, or 12 thereof; for example, 6.2 ± 0.2°, 12.4 ± 0.2°, 16.1 ± 0.2°, 21.8 ± 0.2°;

[0150] 9.3 ± 0.2°, 15.5 ± 0.2°, 18.7 ± 0.2°, 25.0 ± 0.2°;

[0151] 6.2 ± 0.2°, 15.5 ± 0.2°, 25.0 ± 0.2°, 28.2 ± 0.2°, 30.9 ± 0.2°;

[0152] 12.4 ± 0.2°, 15.5 ± 0.2°, 25.0 ± 0.2°, 30.9 ± 0.2°, 31.4 ± 0.2°, 37.9 ± 0.2°;

[0153] 6.2 ± 0.2°, 16.1 ± 0.2°, 18.7 ± 0.2°, 21.8 ± 0.2°, 28.2 ± 0.2°, 30.9 ± 0.2°, 31.4 ± 0.2°, 37.9 ± 0.2°;

[0154] 9.3 ± 0.2°, 12.4 ± 0.2°, 16.1 ± 0.2°, 18.7 ± 0.2°, 21.8 ± 0.2°, 25.0 ± 0.2°, 28.2 ± 0.2°, 30.9 ± 0.2°, 31.4 ± 0.2°, 37.9 ± 0.2°;

[0155] In preferred embodiments of the application, the benzenesulfonate salt Form B has X-ray characteristic diffraction peaks expressed in terms of 2 theta angle and interplanar spacing d value as shown in Table 6 using Cu-Ka radiation.

[0156] Table 6

[0157] In preferred embodiments of the application, the benzenesulfonate salt Form B has an X-ray powder diffraction pattern substantially as shown in Figure 12; and a DSC pattern substantially as shown in Figure 13.

[0158] In preferred embodiments of the application, the p-toluenesulfonate salt Form A has an X-ray powder diffraction pattern having a diffraction peak at 2 theta of 8.7 ± 0.2°; or at 11.8 ± 0.2°; or at 12.8 ± 0.2°; or at 18.9 ± 0.2°; or at 19.3 ± 0.2°; or at 19.8 ± 0.2°; or at 20.2 ± 0.2°; or at 20.8 ± 0.2°; or at 21.0 ± 0.2°; or at 22.4 ± 0.2°; preferably comprising any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, more preferably comprising any 6, 7 or 8 of the above diffraction peaks.

[0159] In preferred embodiments of the application, the p-toluenesulfonate salt Form A has an X-ray powder diffraction pattern comprising at least one, preferably two, more preferably three of the diffraction peaks at 2 theta of 19.3 ± 0.2°, 19.8 ± 0.2°, 20.2 ± 0.2°; and optionally further comprising at least one, preferably two, three, four or five of the diffraction peaks at 2 theta of 11.8 ± 0.2°, 12.8 ± 0.2°, 18.9 ± 0.2°, 20.8 ± 0.2°, 21.0 ± 0.2°; for example,

[0160] 11.8 ± 0.2°, 19.3 ± 0.2°; 12.8 ± 0.2°, 19.8 ± 0.2°; 18.9 ± 0.2°, 20.2 ± 0.2°;

[0161] 19.3 ± 0.2°, 19.8 ± 0.2°, 20.2 ± 0.2°; 19.8 ± 0.2°, 20.2 ± 0.2°, 20.8 ± 0.2°;

[0162] 11.8 ± 0.2°, 18.9 ± 0.2°, 19.3 ± 0.2°, 20.8 ± 0.2°;

[0163] 12.8 ± 0.2°, 19.3 ± 0.2°, 19.8 ± 0.2°, 21.0 ± 0.2°;

[0164] 11.8 ± 0.2°, 12.8 ± 0.2°, 18.9 ± 0.2°, 20.2 ± 0.2°, 20.8 ± 0.2°;

[0165] 12.8 ± 0.2°, 18.9 ± 0.2°, 19.8 ± 0.2°, 20.8 ± 0.2°, 21.0 ± 0.2°;

[0166] In preferred embodiments of the application, the X-ray powder diffraction pattern of said p-toluenesulfonic acid salt Form A optionally further comprises one or more of the diffraction peaks at 2Θ of 8.7 ± 0.2°, 8.8 ± 0.2°, 17.9 ± 0.2°, 21.8 ± 0.2°, 22.4 ± 0.2°, 23.0 ± 0.2°, 23.7 ± 0.2°; preferably at least any 2-3 thereof, or 4-5 thereof, or 6-7 thereof; further preferably, at least any 2, 3, 4, 5, 6, 7 thereof; for example,

[0167] 8.7 ± 0.2°, 17.9 ± 0.2°; 21.8 ± 0.2°, 23.0 ± 0.2°;

[0168] 8.8 ± 0.2°, 17.9 ± 0.2°, 23.0 ± 0.2°;

[0169] 17.9 ± 0.2°, 21.8 ± 0.2°, 22.4 ± 0.2°, 23.7 ± 0.2°;

[0170] 8.8 ± 0.2°, 21.8 ± 0.2°, 22.4 ± 0.2°, 23.0 ± 0.2°, 23.7 ± 0.2°;

[0171] In preferred embodiments of the application, the p-toluenesulfonic acid salt Form A has an X-ray powder diffraction pattern comprising one or more of the following peaks expressed in degrees 2-theta: 8.7 ± 0.2°, 11.8 ± 0.2°, 12.8 ± 0.2°, 18.9 ± 0.2°, 19.3 ± 0.2°, 19.8 ± 0.2°, 20.2 ± 0.2°, 20.8 ± 0.2°, 21.0 ± 0.2°, 21.8 ± 0.2°, 22.4 ± 0.2°, 23.7 ± 0.2°; preferably, any 4, 5, 6, 8, 10 or 12 thereof; for example,

[0172] 8.7 ± 0.2°, 12.8 ± 0.2°, 19.3 ± 0.2°, 20.2 ± 0.2°;

[0173] 11.8 ± 0.2°, 18.9 ± 0.2°, 19.8 ± 0.2°, 20.8 ± 0.2°;

[0174] 8.7 ± 0.2°, 11.8 ± 0.2°, 21.0 ± 0.2°, 21.8 ± 0.2°, 23.7 ± 0.2°;

[0175] 8.7 ± 0.2°, 18.9 ± 0.2°, 20.8 ± 0.2°, 21.0 ± 0.2°, 22.4 ± 0.2°, 23.7 ± 0.2°;

[0176] 11.8 ± 0.2°, 19.3 ± 0.2°, 19.8 ± 0.2°, 20.8 ± 0.2°, 21.0 ± 0.2°, 21.8 ± 0.2°, 22.4 ± 0.2°, 23.7 ± 0.2°;

[0177] 8.7 ± 0.2°, 18.9 ± 0.2°, 19.3 ± 0.2°, 19.8 ± 0.2°, 20.2 ± 0.2°, 20.8 ± 0.2°, 21.0 ± 0.2°, 21.8 ± 0.2°, 22.4 ± 0.2°, 23.7 ± 0.2°;

[0178] In preferred embodiments of the application, the p-toluenesulfonic acid salt Form A has an X-ray powder diffraction pattern comprising one or more of the following peaks expressed in degrees 2-theta: 8.7 ± 0.2°, 11.8 ± 0.2°, 12.8 ± 0.2°, 18.9 ± 0.2°, 19.3 ± 0.2°, 19.8 ± 0.2°, 20.2 ± 0.2°, 20.8 ± 0.2°, 21.0 ± 0.2°, 21.8 ± 0.2°, 22.4 ± 0.2°, 23.7 ± 0.2°; preferably, any 4, 5, 6, 8, 10 or 12 thereof; for example,

[0179] Table 7

[0180] In preferred embodiments of the application, the p-toluenesulfonic acid salt Form A has an X-ray powder diffraction pattern substantially as shown in Figure 14; and a DSC pattern substantially as shown in Figure 15.

[0181] In a preferred embodiment of the present invention, the isethionate salt crystalline form A has an X-ray powder diffraction pattern with a diffraction peak at 2θ of 6.7±0.2°; or a diffraction peak at 12.9±0.2°; or a diffraction peak at 13.4±0.2°; or a diffraction peak at 16.8±0.2°; or a diffraction peak at 17.2±0.2°; or a diffraction peak at 19.8±0.2°. ; or having a diffraction peak at 20.1±0.2°; or having a diffraction peak at 20.9±0.2°; or having a diffraction peak at 22.3±0.2°; or having a diffraction peak at 23.2±0.2°; preferably comprising any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, more preferably comprising any 6, 7 or 8 thereof;

[0182] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the isethionate salt crystalline form A comprises at least one or more diffraction peaks located at 2θ of 13.4±0.2°, 19.8±0.2°, and 20.9±0.2°, preferably two of them, and more preferably three of them; optionally, it may further comprise at least one diffraction peak located at 2θ of 6.7±0.2°, 16.8±0.2°, 17.2±0.2°, 20.1±0.2°, and 22.3±0.2°, preferably two, three, four, or five of them; for example,

[0183] 6.7±0.2°, 13.4±0.2°; 16.8±0.2°, 19.8±0.2°; 17.2±0.2°, 20.9±0.2;

[0184] 13.4±0.2°, 19.8±0.2°, 20.9±0.2; 6.7±0.2°, 16.8±0.2°, 17.2±0.2°;

[0185] 13.4±0.2°, 16.8±0.2°, 20.1±0.2°, 22.3±0.2°;

[0186] 16.8±0.2°, 19.8±0.2°, 20.9±0.2, 22.3±0.2°;

[0187] 6.7±0.2°, 17.2±0.2°, 20.1±0.2°, 20.9±0.2, 22.3±0.2°;

[0188] 13.4±0.2°, 17.2±0.2°, 19.8±0.2°, 20.1±0.2°, 22.3±0.2°;

[0189] In preferred embodiments of the application, the isethionate Form A has an X-ray powder diffraction pattern comprising one or more peaks at 2-theta = 10.0 ± 0.2°, 12.9 ± 0.2°, 16.0 ± 0.2°, 21.4 ± 0.2°, 23.2 ± 0.2°, 26.7 ± 0.2°, 28.5 ± 0.2°; preferably, at least any 2-3, or 4-5, or 6-7 thereof; more preferably, at least any 2, 3, 4, 5, 6, 7 thereof; for example,

[0190] 10.0 ± 0.2°, 16.0 ± 0.2°; 12.9 ± 0.2°, 21.4 ± 0.2°;

[0191] 10.0 ± 0.2°, 23.2 ± 0.2°, 28.5 ± 0.2°;

[0192] 12.9 ± 0.2°, 16.0 ± 0.2°, 26.7 ± 0.2°, 28.5 ± 0.2°;

[0193] 10.0 ± 0.2°, 16.0 ± 0.2°, 21.4 ± 0.2°, 26.7 ± 0.2°, 28.5 ± 0.2°;

[0194] In preferred embodiments of the application, the isethionate Form A has an X-ray powder diffraction pattern comprising one or more peaks at 2-theta = 6.7 ± 0.2°, 10.0 ± 0.2°, 12.9 ± 0.2°, 13.4 ± 0.2°, 16.8 ± 0.2°, 17.2 ± 0.2°, 19.8 ± 0.2°, 20.1 ± 0.2°, 20.9 ± 0.2°, 21.4 ± 0.2°, 22.3 ± 0.2°, 23.2 ± 0.2°; preferably, at least any 4, 5, 6, 8, 10, or 12 thereof; for example, 6.7 ± 0.2°, 12.9 ± 0.2°, 16.8 ± 0.2°, 19.8 ± 0.2°;

[0195] 10.0 ± 0.2°, 13.4 ± 0.2°, 17.2 ± 0.2°, 20.1 ± 0.2°;

[0196] 6.7 ± 0.2°, 10.0 ± 0.2°, 17.2 ± 0.2°, 20.9 ± 0.2°, 23.2 ± 0.2°;

[0197] 12.9 ± 0.2°, 13.4 ± 0.2°, 20.1 ± 0.2°, 21.4 ± 0.2°, 22.3 ± 0.2°, 23.2 ± 0.2°;

[0198] 6.7±0.2°, 13.4±0.2°, 19.8±0.2°, 20.1±0.2°, 20.9±0.2°, 21.4±0.2°, 22.3±0.2°, 23.2±0.2°;

[0199] 10.0±0.2°, 12.9±0.2°, 13.4±0.2°, 16.8±0.2°, 17.2±0.2°, 19.8±0.2°, 20.1±0.2°, 20.9±0.2°, 22.3±0.2°, 23.2±0.2°;

[0200] In preferred embodiments of the application, the hydroxyethyl sulfonate Form A has X-ray characteristic diffraction peaks expressed in terms of 2 theta angle and interplanar spacing d value as shown in Table 8 using Cu-Ka radiation.

[0201] Table 8

[0202] In preferred embodiments of the application, the hydroxyethyl sulfonate Form A has an X-ray powder diffraction pattern substantially as shown in Figure 16; and a DSC pattern substantially as shown in Figure 17.

[0203] In preferred embodiments of the application, the ethanesulfonate Form A has an X-ray powder diffraction pattern with a diffraction peak at 2 theta of 17.1±0.2°; or at 18.2±0.2°; or at 18.7±0.2°; or at 19.3±0.2°; or at 19.8±0.2°; or at 20.4±0.2°; or at 20.8±0.2°; or at 22.9±0.2°; or at 23.5±0.2°; or at 25.9±0.2°; preferably comprising any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, more preferably comprising any 6, 7 or 8 of them;

[0204] In preferred embodiments of the application, the ethanesulfonate Form A has an X-ray powder diffraction pattern comprising at least one or more of the diffraction peaks at 2 theta of 18.7±0.2°, 19.3±0.2°, 19.8±0.2°, preferably comprising two of them, more preferably comprising three of them; optionally, further comprising at least one of the diffraction peaks at 2 theta of 17.1±0.2°, 20.4±0.2°, 22.9±0.2°, 23.5±0.2°, 25.9±0.2°, preferably comprising 2, 3, 4 or 5 of them; for example,

[0205] 17.1 ± 0.2°, 18.7 ± 0.2°; 19.3 ± 0.2°, 20.4 ± 0.2°; 19.8 ± 0.2°, 22.9 ± 0.2°;

[0206] 18.7 ± 0.2°, 19.3 ± 0.2°, 19.8 ± 0.2°; 17.1 ± 0.2°, 19.3 ± 0.2°, 22.9 ± 0.2°;

[0207] 18.7 ± 0.2°, 19.8 ± 0.2°, 22.9 ± 0.2°, 25.9 ± 0.2°;

[0208] 17.1 ± 0.2°, 19.8 ± 0.2°, 23.5 ± 0.2°, 25.9 ± 0.2°;

[0209] 18.7 ± 0.2°, 20.4 ± 0.2°, 22.9 ± 0.2°, 23.5 ± 0.2°, 25.9 ± 0.2°;

[0210] 17.1 ± 0.2°, 19.3 ± 0.2°, 20.4 ± 0.2°, 23.5 ± 0.2°, 25.9 ± 0.2°;

[0211] In preferred embodiments of the application, the X-ray powder diffraction pattern of said ethanesulfonic acid salt Form A optionally further comprises one or more of the diffraction peaks at 2-theta = 12.8 ± 0.2°, 13.1 ± 0.2°, 18.2 ± 0.2°, 20.8 ± 0.2°, 21.3 ± 0.2°, 22.1 ± 0.2°, 23.8 ± 0.2°; preferably at least any 2-3 thereof, or 4-5 thereof, or 6-7 thereof; further preferably, at least any 2, 3, 4, 5, 6, 7 thereof; for example, 12.8 ± 0.2°, 18.2 ± 0.2°; 13.1 ± 0.2°, 20.8 ± 0.2°;

[0212] 18.2 ± 0.2°, 21.3 ± 0.2°, 22.1 ± 0.2°;

[0213] 13.1 ± 0.2°, 20.8 ± 0.2°, 22.1 ± 0.2°, 23.8 ± 0.2°;

[0214] 12.8 ± 0.2°, 18.2 ± 0.2°, 21.3 ± 0.2°, 22.1 ± 0.2°, 23.8 ± 0.2°;

[0215] In preferred embodiments of the application, the ethanesulfonic acid salt Form A has an X-ray powder diffraction pattern comprising one or more of the following peaks expressed in degrees 2-theta: 13.1 ± 0.2°, 17.1 ± 0.2°, 18.2 ± 0.2°, 18.7 ± 0.2°, 19.3 ± 0.2°, 19.8 ± 0.2°, 20.4 ± 0.2°, 20.8 ± 0.2°, 22.1 ± 0.2°, 22.9 ± 0.2°, 23.5 ± 0.2°, 25.9 ± 0.2°; preferably, any 4, 5, 6, 8, 10 or 12 thereof; for example, 13.1 ± 0.2°, 18.2 ± 0.2°, 19.3 ± 0.2°, 20.4 ± 0.2°;

[0216] 17.1 ± 0.2°, 8.7 ± 0.2°, 19.8 ± 0.2°, 20.8 ± 0.2°;

[0217] 13.1 ± 0.2°, 18.7 ± 0.2°, 19.8 ± 0.2°, 22.1 ± 0.2°, 22.9 ± 0.2°, 25.9 ± 0.2°;

[0218] 17.1 ± 0.2°, 18.2 ± 0.2°, 19.8 ± 0.2°, 20.4 ± 0.2°, 22.1 ± 0.2°, 22.9 ± 0.2°, 23.5 ± 0.2°, 25.9 ± 0.2°;

[0219] 13.1 ± 0.2°, 19.3 ± 0.2°, 19.8 ± 0.2°, 20.8 ± 0.2°, 22.1 ± 0.2°, 22.9 ± 0.2°, 23.5 ± 0.2°, 25.9 ± 0.2°;

[0220] 17.1 ± 0.2°, 18.2 ± 0.2°, 19.3 ± 0.2°, 19.8 ± 0.2°, 20.4 ± 0.2°, 20.8 ± 0.2°, 22.1 ± 0.2°, 22.9 ± 0.2°, 23.5 ± 0.2°, 25.9 ± 0.2°;

[0221] In preferred embodiments of the application, the ethanesulfonic acid salt Form A has an X-ray powder diffraction pattern comprising one or more of the following peaks expressed in degrees 2-theta: 13.1 ± 0.2°, 17.1 ± 0.2°, 18.2 ± 0.2°, 18.7 ± 0.2°, 19.3 ± 0.2°, 19.8 ± 0.2°, 20.4 ± 0.2°, 20.8 ± 0.2°, 22.1 ± 0.2°, 22.9 ± 0.2°, 23.5 ± 0.2°, 25.9 ± 0.2°; preferably, any 4, 5, 6, 8, 10 or 12 thereof; for example, 13.1 ± 0.2°, 18.2 ± 0.2°, 19.3 ± 0.2°, 20.4 ± 0.2°;

[0222] Table 9

[0223] In preferred embodiments of the application, the ethanesulfonic acid salt Form A has an X-ray powder diffraction pattern substantially as shown in Figure 18; and a DSC pattern substantially as shown in Figure 19.

[0224] In preferred embodiments of the present application, the salicylate Form A has an X-ray powder diffraction pattern comprising at least one of the following peaks: 7.9 ± 0.2°, 8.6 ± 0.2°, 9.5 ± 0.2°, 14.5 ± 0.2°, 17.2 ± 0.2°, 18.6 ± 0.2°, 20.3 ± 0.2°, 21.6 ± 0.2°, 24.9 ± 0.2°, 26.3 ± 0.2°, and / or 27.3 ± 0.2°, preferably two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, or twenty of the above peaks, more preferably twenty-one of the above peaks.

[0225] In preferred embodiments of the present application, the salicylate Form A has an X-ray powder diffraction pattern comprising at least one of the following peaks: 7.9 ± 0.2°, 8.6 ± 0.2°, 9.5 ± 0.2°, 14.5 ± 0.2°, 17.2 ± 0.2°, 18.6 ± 0.2°, 20.3 ± 0.2°, 21.6 ± 0.2°, 24.9 ± 0.2°, 26.3 ± 0.2°, and / or 27.3 ± 0.2°, preferably two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, or twenty of the above peaks, more preferably twenty-one of the above peaks.

[0226] 7.9 ± 0.2°, 8.6 ± 0.2°; 14.5 ± 0.2°, 18.6 ± 0.2°; 17.2 ± 0.2°, 20.3 ± 0.2°;

[0227] 8.6 ± 0.2°, 14.5 ± 0.2°, 17.2 ± 0.2°; 7.9 ± 0.2°, 14.5 ± 0.2°, 20.3 ± 0.2°;

[0228] 14.5 ± 0.2°, 17.2 ± 0.2°, 20.3 ± 0.2°, 24.9 ± 0.2°

[0229] 8.6 ± 0.2°, 18.6 ± 0.2°, 21.6 ± 0.2°, 24.9 ± 0.2°

[0230] 7.9 ± 0.2°, 17.2 ± 0.2°, 18.6 ± 0.2°, 21.6 ± 0.2°, 24.9 ± 0.2°;

[0231] 8.6 ± 0.2°, 14.5 ± 0.2°, 20.3 ± 0.2°, 21.6 ± 0.2°, 24.9 ± 0.2°;

[0232] In preferred embodiments of the application, the X-ray powder diffraction pattern of the salicylate Form A optionally further comprises one or more of the following peaks: at 9.5 ± 0.2°, 15.9 ± 0.2°, 18.1 ± 0.2°, 22.4 ± 0.2°, 23.5 ± 0.2°, 23.9 ± 0.2°, 26.3 ± 0.2° in terms of 2-theta; preferably at least any 2 to 3, or 4 to 5, or 6 to 7 thereof; more preferably, any 2, 3, 4, 5, 6, 7 thereof; for example, 9.5 ± 0.2°, 18.1 ± 0.2°; 15.9 ± 0.2°, 22.4 ± 0.2°;

[0233] 18.1 ± 0.2°, 23.5 ± 0.2°, 26.3 ± 0.2°;

[0234] 9.5 ± 0.2°, 18.1 ± 0.2°, 23.9 ± 0.2°, 26.3 ± 0.2°;

[0235] 15.9 ± 0.2°, 18.1 ± 0.2°, 23.5 ± 0.2°, 23.9 ± 0.2°, 26.3 ± 0.2°;

[0236] In preferred embodiments of the application, the X-ray powder diffraction pattern of the salicylate Form A comprises one or more of the following peaks: at 7.9 ± 0.2°, 8.6 ± 0.2°, 9.5 ± 0.2°, 14.5 ± 0.2°, 17.2 ± 0.2°, 18.1 ± 0.2°, 18.6 ± 0.2°, 20.3 ± 0.2°, 21.6 ± 0.2°, 23.9 ± 0.2°, 24.9 ± 0.2°, 26.3 ± 0.2° in terms of 2-theta; preferably, 4, 5, 6, 8, 10, or 12 thereof; for example, 7.9 ± 0.2°, 9.5 ± 0.2°, 17.2 ± 0.2°, 18.6 ± 0.2°;

[0237] 8.6 ± 0.2°, 14.5 ± 0.2°, 18.1 ± 0.2°, 20.3 ± 0.2°;

[0238] 8.6 ± 0.2°, 9.5 ± 0.2°, 18.1 ± 0.2°, 21.6 ± 0.2°, 26.3 ± 0.2°;

[0239] 7.9 ± 0.2°, 9.5 ± 0.2°, 14.5 ± 0.2°, 18.6 ± 0.2°, 20.3 ± 0.2°, 23.9 ± 0.2°;

[0240] 8.6 ± 0.2°, 17.2 ± 0.2°, 18.6 ± 0.2°, 20.3 ± 0.2°, 21.6 ± 0.2°, 23.9 ± 0.2°, 24.9 ± 0.2°, 26.3 ± 0.2°;

[0241] 7.9 ± 0.2°, 9.5 ± 0.2°, 17.2 ± 0.2°, 18.1 ± 0.2°, 18.6 ± 0.2°, 20.3 ± 0.2°, 21.6 ± 0.2°, 23.9 ± 0.2°, 24.9 ± 0.2°, 26.3 ± 0.2°;

[0242] In preferred embodiments of the present application, the salicylate Form A has X-ray characteristic diffraction peaks expressed in terms of 2 theta angle and interplanar spacing d value as shown in Table 10 using Cu-Ka radiation.

[0243] Table 10

[0244] In preferred embodiments of the present application, the salicylate Form A has an X-ray powder diffraction pattern substantially as shown in Figure 20; and a DSC pattern substantially as shown in Figure 21.

[0245] In preferred embodiments of the present application, the hydrochloride Form A, the hydrochloride Form B, the mesylate Form A, the mesylate Form B, the besylate Form A, the besylate Form B, the p-toluenesulfonate Form A, the isethionate Form A, the ethanesulfonate Form A, and the salicylate Form A have X-ray powder diffraction patterns in which the relative peak intensities of the top ten peaks are within ± 0.2° to ± 0.5°, preferably ± 0.2° to ± 0.3°, most preferably ± 0.2° of the 2 theta values of the peaks at the corresponding positions in Figures 1, 4, 6, 8, 10, 12, 14, 16, 18, and 20.

[0246] In preferred embodiments of the present application, the free base Form A has an X-ray powder diffraction pattern with a diffraction peak at 7.3 ± 0.2°; or with a diffraction peak at 9.7 ± 0.2°; or with a diffraction peak at 14.6 ± 0.2°; or with a diffraction peak at 18.0 ± 0.2°; or with a diffraction peak at 19.4 ± 0.2°; or with a diffraction peak at 21.3 ± 0.2°; or with a diffraction peak at 21.8 ± 0.2°; or with a diffraction peak at 22.0 ± 0.2°; or with a diffraction peak at 24.3 ± 0.2°; or with a diffraction peak at 25.6 ± 0.2°; preferably comprising any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above-mentioned diffraction peaks.

[0247] In preferred embodiments of the application, the free base Form A has an X-ray powder diffraction pattern comprising at least one, preferably two, more preferably three, of the peaks at 9.7 ± 0.2°, 14.6 ± 0.2°, 18.0 ± 0.2°; optionally, further comprising at least one, preferably two, three, four or five, of the peaks at 21.3 ± 0.2°, 21.8 ± 0.2°, 22.0 ± 0.2°, 24.3 ± 0.2°, 25.6 ± 0.2°; for example, 9.7 ± 0.2°, 21.3 ± 0.2°; 14.6 ± 0.2°, 21.8 ± 0.2°;

[0248] 9.7 ± 0.2°, 14.6 ± 0.2°; 9.7 ± 0.2°, 14.6 ± 0.2°, 18.0 ± 0.2°;

[0249] 18.0 ± 0.2°, 22.0 ± 0.2°, 24.3 ± 0.2°; 9.7 ± 0.2°, 18.0 ± 0.2°, 21.3 ± 0.2°, 24.3 ± 0.2°;

[0250] 14.6 ± 0.2°, 18.0 ± 0.2°, 21.8 ± 0.2°, 25.6 ± 0.2°;

[0251] 9.7 ± 0.2°, 14.6 ± 0.2°, 21.8 ± 0.2°, 24.3 ± 0.2°, 25.6 ± 0.2°;

[0252] 14.6 ± 0.2°, 18.0 ± 0.2°, 21.3 ± 0.2°, 22.0 ± 0.2°, 25.6 ± 0.2°.

[0253] In preferred embodiments of the application, the free base Form A has an X-ray powder diffraction pattern comprising at least one, preferably two, more preferably three, of the peaks at 9.7 ± 0.2°, 14.6 ± 0.2°, 18.0 ± 0.2°; optionally, further comprising at least one, preferably two, three, four or five, of the peaks at 21.3 ± 0.2°, 21.8 ± 0.2°, 22.0 ± 0.2°, 24.3 ± 0.2°, 25.6 ± 0.2°; for example, 9.7 ± 0.2°, 21.3 ± 0.2°; 14.6 ± 0.2°, 21.8 ± 0.2°;

[0254] 19.4 ± 0.2°, 27.9 ± 0.2°, 28.7 ± 0.2°;

[0255] 19.0 ± 0.2°, 23.3 ± 0.2°, 27.6 ± 0.2°, 27.9 ± 0.2°;

[0256] 7.3 ± 0.2°, 9.7 ± 0.2°, 14.6 ± 0.2°, 18.0 ± 0.2°, 19.4 ± 0.2°, 21.3 ± 0.2°, 21.8 ± 0.2°, 22.0 ± 0.2°, 23.3 ± 0.2°, 24.3 ± 0.2°, 25.6 ± 0.2°, 28.7 ± 0.2°.

[0257] In preferred embodiments of the application, the free base Form A has an X-ray powder diffraction pattern comprising one or more of the following peaks expressed in degrees two-theta (2Θ) and interplanar spacing (d) values: 7.3 ± 0.2°, 9.7 ± 0.2°, 14.6 ± 0.2°, 18.0 ± 0.2°, 19.4 ± 0.2°, 21.3 ± 0.2°, 21.8 ± 0.2°, 22.0 ± 0.2°, 23.3 ± 0.2°, 24.3 ± 0.2°, 25.6 ± 0.2°, 28.7 ± 0.2°; preferably, any 4, 5, 6, 8, 10 or 12 thereof; for example, 7.3 ± 0.2°, 14.6 ± 0.2°, 19.4 ± 0.2°, 21.8 ± 0.2°;

[0258] 9.7 ± 0.2°, 18.0 ± 0.2°, 21.3 ± 0.2°, 22.0 ± 0.2°;

[0259] 7.3 ± 0.2°, 9.7 ± 0.2°, 23.3 ± 0.2°, 24.3 ± 0.2°, 25.6 ± 0.2°, 28.7 ± 0.2°;

[0260] 9.7 ± 0.2°, 14.6 ± 0.2°, 19.4 ± 0.2°, 22.0 ± 0.2°, 23.3 ± 0.2°, 24.3 ± 0.2°, 25.6 ± 0.2°, 28.7 ± 0.2°;

[0261] 7.3 ± 0.2°, 9.7 ± 0.2°, 14.6 ± 0.2°, 19.4 ± 0.2°, 21.3 ± 0.2°, 21.8 ± 0.2°, 22.0 ± 0.2°, 23.3 ± 0.2°, 25.6 ± 0.2°, 28.7 ± 0.2°.

[0262] In preferred embodiments of the application, the free base Form A has an X-ray powder diffraction pattern comprising one or more of the following peaks expressed in degrees two-theta (2Θ) and interplanar spacing (d) values: 7.3 ± 0.2°, 9.7 ± 0.2°, 14.6 ± 0.2°, 18.0 ± 0.2°, 19.4 ± 0.2°, 21.3 ± 0.2°, 21.8 ± 0.2°, 22.0 ± 0.2°, 23.3 ± 0.2°, 24.3 ± 0.2°, 25.6 ± 0.2°, 28.7 ± 0.2°; preferably, any 4, 5, 6, 8, 10 or 12 thereof; for example, 7.3 ± 0.2°, 14.6 ± 0.2°, 19.4 ± 0.2°, 21.8 ± 0.2°;

[0263] Table 11

[0264] In preferred embodiments of the application, the free base Form A has an X-ray powder diffraction pattern substantially as shown in Figure 22; a DSC pattern substantially as shown in Figure 23; and a TGA pattern substantially as shown in Figure 24.

[0265] In preferred embodiments of the application, the free base Form A is a sesqui-hydrate.

[0266] In preferred embodiments of the present application, the free base Form B has an X-ray powder diffraction pattern comprising at least one diffraction peak at 2-theta = 8.0 ± 0.2°; or at 14.9 ± 0.2°; or at 15.1 ± 0.2°; or at 17.3 ± 0.2°; or at 18.5 ± 0.2°; or at 19.7 ± 0.2°; or at 23.5 ± 0.2°; or at 23.9 ± 0.2°; or at 24.3 ± 0.2°; or at 25.0 ± 0.2°; preferably comprising any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, more preferably comprising any 6, 7 or 8 of the above diffraction peaks.

[0267] In preferred embodiments of the present application, the free base Form B has an X-ray powder diffraction pattern comprising at least one diffraction peak at 2-theta = 8.0 ± 0.2°; or at 14.9 ± 0.2°; or at 15.1 ± 0.2°; or at 17.3 ± 0.2°; or at 18.5 ± 0.2°; or at 19.7 ± 0.2°; or at 23.5 ± 0.2°; or at 23.9 ± 0.2°; or at 24.3 ± 0.2°; or at 25.0 ± 0.2°; preferably comprising any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, more preferably comprising any 6, 7 or 8 of the above diffraction peaks.

[0268] 8.0 ± 0.2°, 15.1 ± 0.2°, 25.0 ± 0.2°; 15.1 ± 0.2°, 19.7 ± 0.2°, 23.9 ± 0.2°;

[0269] 8.0 ± 0.2°, 14.9 ± 0.2°, 17.3 ± 0.2°, 25.0 ± 0.2°;

[0270] 15.1 ± 0.2°, 23.9 ± 0.2°, 24.3 ± 0.2°, 25.0 ± 0.2°;

[0271] 14.9 ± 0.2°, 17.3 ± 0.2°, 19.7 ± 0.2°, 23.9 ± 0.2°, 24.3 ± 0.2°;

[0272] 8.0 ± 0.2°, 19.7 ± 0.2°, 23.9 ± 0.2°, 24.3 ± 0.2°, 25.0 ± 0.2°.

[0273] In preferred embodiments of the application, the X-ray powder diffraction pattern of the free base Form B optionally further comprises one or more of the following peaks: at 2-theta 12.0 ± 0.2°, 18.5 ± 0.2°, 22.3 ± 0.2°, 23.0 ± 0.2°, 23.5 ± 0.2°, 28.3 ± 0.2°, 28.6 ± 0.2°; preferably at least any 2-3, or 4-5, or 6-7 thereof; more preferably, any 2, 3, 4, 5, 6, 7 thereof; for example, 12.0 ± 0.2°, 22.3 ± 0.2°; 18.5 ± 0.2°, 23.0 ± 0.2°;

[0274] 12.0 ± 0.2°, 23.5 ± 0.2°, 28.6 ± 0.2°;

[0275] 18.5 ± 0.2°, 22.3 ± 0.2°, 23.5 ± 0.2°, 28.6 ± 0.2°;

[0276] 22.3 ± 0.2°, 23.0 ± 0.2°, 23.5 ± 0.2°, 28.3 ± 0.2°, 28.6 ± 0.2°.

[0277] In preferred embodiments of the application, the X-ray powder diffraction pattern of the free base Form B comprises one or more of the following peaks: at 2-theta 8.0 ± 0.2°, 12.0 ± 0.2°, 14.9 ± 0.2°, 15.1 ± 0.2°, 17.3 ± 0.2°, 18.5 ± 0.2°, 19.7 ± 0.2°, 23.5 ± 0.2°, 23.9 ± 0.2°, 24.3 ± 0.2°, 25.0 ± 0.2°, 28.3 ± 0.2°; preferably, any 4, 5, 6, 8, 10, or 12 thereof; for example, 8.0 ± 0.2°, 14.9 ± 0.2°, 17.3 ± 0.2°, 19.7 ± 0.2°;

[0278] 12.0 ± 0.2°, 15.1 ± 0.2°, 18.5 ± 0.2°, 23.5 ± 0.2°, 24.3 ± 0.2°;

[0279] 8.0 ± 0.2°, 15.1 ± 0.2°, 17.3 ± 0.2°, 19.7 ± 0.2°, 23.9 ± 0.2°, 25.0 ± 0.2°;

[0280] 12.0 ± 0.2°, 14.9 ± 0.2°, 17.3 ± 0.2°, 23.5 ± 0.2°, 23.9 ± 0.2°, 24.3 ± 0.2°, 25.0 ± 0.2°, 28.3 ± 0.2°;

[0281] 8.0 ± 0.2°, 12.0 ± 0.2°, 14.9 ± 0.2°, 15.1 ± 0.2°, 17.3 ± 0.2°, 18.5 ± 0.2°, 19.7 ± 0.2°, 23.5 ± 0.2°, 24.3 ± 0.2°, 25.0 ± 0.2°.

[0282] In preferred embodiments of the application, the free base Form B has X-ray characteristic diffraction peaks, expressed in terms of 2 theta angle and interplanar spacing d-value, as shown in Table 12 using Cu-Ka radiation.

[0283] Table 12

[0284] In preferred embodiments of the application, the free base Form B has an X-ray powder diffraction pattern substantially as shown in Figure 25; a DSC pattern substantially as shown in Figure 26; and a TGA pattern substantially as shown in Figure 27.

[0285] In preferred embodiments of the application, the free base Form B is an anhydrate.

[0286] In preferred embodiments of the application, the free base Form C has an X-ray powder diffraction pattern comprising at least one diffraction peak at 2-theta 5.5 ± 0.2°; or at 10.8 ± 0.2°; or at 13.5 ± 0.2°; or at 17.4 ± 0.2°; or at 18.9 ± 0.2°; or at 19.7 ± 0.2°; or at 21.6 ± 0.2°; or at 22.0 ± 0.2°; or at 23.9 ± 0.2°; or at 27.0 ± 0.2°; preferably comprising any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, more preferably comprising any 6, 7 or 8 of them.

[0287] In preferred embodiments of the application, the free base Form C has an X-ray powder diffraction pattern comprising at least one diffraction peak at 2-theta 17.4 ± 0.2°, 22.0 ± 0.2°, 27.0 ± 0.2°, preferably comprising two of them, more preferably comprising three of them; optionally, further comprising at least one of 2-theta 10.8 ± 0.2°, 13.5 ± 0.2°, 18.9 ± 0.2°, 21.6 ± 0.2°, 23.9 ± 0.2°, preferably comprising 2, 3, 4 or 5 of them; for example, 10.8 ± 0.2°, 17.4 ± 0.2°; 13.5 ± 0.2°, 27.0 ± 0.2°;

[0288] 22.0 ± 0.2°, 27.0 ± 0.2°; 17.4 ± 0.2°, 22.0 ± 0.2°, 27.0 ± 0.2°;

[0289] 17.4 ± 0.2°, 22.0 ± 0.2°, 23.9 ± 0.2°; 18.9 ± 0.2°, 21.6 ± 0.2°, 22.0 ± 0.2°, 27.0 ± 0.2°;

[0290] 10.8 ± 0.2°, 13.5 ± 0.2°, 17.4 ± 0.2°, 23.9 ± 0.2°;

[0291] 13.5 ± 0.2°, 18.9 ± 0.2°, 22.0 ± 0.2°, 23.9 ± 0.2°, 27.0 ± 0.2°;

[0292] 10.8 ± 0.2°, 18.9 ± 0.2°, 21.6 ± 0.2°, 23.9 ± 0.2°, 27.0 ± 0.2°.

[0293] In preferred embodiments of the application, the X-ray powder diffraction pattern of said free base Form C optionally further comprises one or more of the diffraction peaks at 2-theta = 5.5 ± 0.2°, 19.7 ± 0.2°, 20.6 ± 0.2°, 24.7 ± 0.2°, 25.3 ± 0.2°, 29.3 ± 0.2°, 32.8 ± 0.2°; preferably at least 2-3, or 4-5, or 6-7 of any of these; further preferably, 2, 3, 4, 5, 6, 7 of any of these; for example, 5.5 ± 0.2°, 24.7 ± 0.2°; 19.7 ± 0.2°, 20.6 ± 0.2°;

[0294] 24.7 ± 0.2°, 29.3 ± 0.2°, 32.8 ± 0.2°;

[0295] 5.5 ± 0.2°, 19.7 ± 0.2°, 25.3 ± 0.2°, 29.3 ± 0.2°;

[0296] 19.7 ± 0.2°, 24.7 ± 0.2°, 25.3 ± 0.2°, 29.3 ± 0.2°, 32.8 ± 0.2°.

[0297] In preferred embodiments of the application, the free base Form C has an X-ray powder diffraction pattern comprising one or more of the following peaks expressed in degrees two-theta (2Θ) ± 0.2°: 5.5 ± 0.2°, 10.8 ± 0.2°, 13.5 ± 0.2°, 17.4 ± 0.2°, 18.9 ± 0.2°, 19.7 ± 0.2°, 21.6 ± 0.2°, 22.0 ± 0.2°, 23.9 ± 0.2°, 24.7 ± 0.2°, 27.0 ± 0.2°, 29.3 ± 0.2°; preferably, any 4, 5, 6, 8, 10 or 12 thereof; for example, 5.5 ± 0.2°, 13.5 ± 0.2°, 18.9 ± 0.2°, 21.6 ± 0.2°;

[0298] 10.8 ± 0.2°, 17.4 ± 0.2°, 19.7 ± 0.2°, 22.0 ± 0.2°, 24.7 ± 0.2°;

[0299] 5.5 ± 0.2°, 10.8 ± 0.2°, 18.9 ± 0.2°, 24.7 ± 0.2°, 27.0 ± 0.2°, 29.3 ± 0.2°;

[0300] 13.5 ± 0.2°, 17.4 ± 0.2°, 19.7 ± 0.2°, 21.6 ± 0.2°, 22.0 ± 0.2°, 23.9 ± 0.2°, 27.0 ± 0.2°, 29.3 ± 0.2°;

[0301] 10.8 ± 0.2°, 13.5 ± 0.2°, 17.4 ± 0.2°, 18.9 ± 0.2°, 19.7 ± 0.2°, 21.6 ± 0.2°, 22.0 ± 0.2°, 23.9 ± 0.2°, 24.7 ± 0.2°, 29.3 ± 0.2°.

[0302] In preferred embodiments of the application, the free base Form C has an X-ray powder diffraction pattern comprising one or more of the following peaks expressed in degrees two-theta (2Θ) ± 0.2°: 5.5 ± 0.2°, 10.8 ± 0.2°, 13.5 ± 0.2°, 17.4 ± 0.2°, 18.9 ± 0.2°, 19.7 ± 0.2°, 21.6 ± 0.2°, 22.0 ± 0.2°, 23.9 ± 0.2°, 24.7 ± 0.2°, 27.0 ± 0.2°, 29.3 ± 0.2°; preferably, any 4, 5, 6, 8, 10 or 12 thereof; for example, 5.5 ± 0.2°, 13.5 ± 0.2°, 18.9 ± 0.2°, 21.6 ± 0.2°;

[0303] Table 13

[0304] In preferred embodiments of the application, the free base Form C has an X-ray powder diffraction pattern substantially as shown in Figure 28; a DSC pattern substantially as shown in Figure 29; and a TGA pattern substantially as shown in Figure 30.

[0305] In preferred embodiments of the application, the free base Form C is an anhydrate.

[0306] The relative peak intensity of the X-ray powder diffraction pattern of the free base crystal form A, the free base crystal form B or the free base crystal form C is ±0.2° to ±0.5°, preferably ±0.2° to ±0.3°, most preferably ±0.2° from the 2θ error of the diffraction peak at the corresponding position of Figure 22, Figure 25 or Figure 28.

[0307] In a preferred embodiment of the present application, the compound free base crystal form is a hydrate or an anhydrate; preferably, the hydrate is a 1.5 hydrate.

[0308] The present application also provides a method for preparing the free base crystal form or the acid salt of the compound as described above, which specifically comprises the following steps:

[0309] 1) weigh an appropriate amount of free base and dissolve it in a benign solvent;

[0310] 2) weigh an appropriate amount of counterion acid and dissolve it in an organic solvent; the amount of counterion acid is preferably 1 to 1.2 equivalents;

[0311] 3) combine the above two solutions and stir until solids precipitate;

[0312] 4) centrifuge quickly or stand to blow dry to obtain the target product;

[0313] The benign 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, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, t-butyl alcohol, 2-butanone, 3-pentanone or N-methylpyrrolidone; preferably one or more of methanol, 88% acetone, dichloromethane or anhydrous ethanol;

[0314] 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, t-butyl alcohol or N,N-dimethylformamide; preferably methanol, ethanol or acetonitrile; the above benign solvent and organic solvent are used to be mutually soluble;

[0315] The counterion acid is selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphoric acid, 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetoxyhydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, capric acid, hexanoic acid, octanoic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, erythorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecylsulfuric acid, dibenzoyl tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galacturonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalene disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, undecylenic acid, trifluoroacetic acid, benzene sulfonic acid, p-toluenesulfonic acid, or L-malic acid; preferably hydrochloric acid.

[0316] The present application also provides a method for preparing the acid salt crystal form of the compound as described above, which specifically comprises the following steps:

[0317] 1) weigh an appropriate amount of free base, suspend in a poor solvent;

[0318] 2) weigh an appropriate amount of counterion acid, dissolve in an organic solvent; the amount of counterion acid is preferably 1.2 equivalents;

[0319] 3) combine the above two solutions and stir to dissolve, continue stirring to precipitate;

[0320] 4) centrifuge quickly or stand to blow dry to obtain the target product;

[0321] The poor solvent is selected from one or more of the group consisting of methanol, ethanol, acetone, ethyl acetate, isopropyl acetate, acetonitrile, ethanol, 88% acetone, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropyl alcohol, n-butanol, isobutyl alcohol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, t-butyl alcohol, 2-butanone or 3-pentanone, methyl t-butyl ether or water; preferably one or more of acetone, ethyl acetate or 2-methyltetrahydrofuran.

[0322] 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-butyl alcohol or N,N-dimethylformamide; preferably methanol, ethanol or acetonitrile; the above benign solvent and organic solution are mutually soluble when used;

[0323] The counter ion acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphoric acid, 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetoxyhydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, decanoic acid, hexanoic acid, octanoic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, erythorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecylsulfuric acid, dibenzoyltartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galacturonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic 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, pamoic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, undecylenic acid, trifluoroacetic acid, benzene sulfonic acid, p-toluenesulfonic acid or L-malic acid; preferably hydrochloric acid, methanesulfonic acid, benzene sulfonic acid, p-toluenesulfonic acid, isethionic acid, ethanesulfonic acid or salicylic acid.

[0324] The application also provides a preparation method of the free base crystal form of the compound described above: comprising the following steps:

[0325] 1) A certain amount of free base is weighed and dissolved in a benign solvent at a certain temperature, preferably 0-50℃;

[0326] 2) Optionally, a poor solvent is added to the above obtained solution and stirred until the solid precipitates;

[0327] 3) Optionally, stirring and cooling crystallization are carried out to obtain the target product;

[0328] wherein: the good 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, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propyl alcohol, t-butyl alcohol, 2-butanone, 3-pentanone, or N-methylpyrrolidone; preferably one or more of N-methylpyrrolidone, methanol, dichloromethane, or anhydrous ethanol;

[0329] the poor solvent is selected from one or more of heptane, cyclohexane, n-hexane, n-pentane, water, ethyl acetate, methyl tert-butyl ether, toluene, or isopropyl ether; preferably one or more of water, heptane, methyl tert-butyl ether, or isopropyl ether;

[0330] The present application also provides a method for preparing the free base crystalline form of the compound described above, comprising the following steps:

[0331] 1) an appropriate amount of the free base or its crystalline form is weighed, and is slurried with a poor solvent at a temperature, preferably 0-60°C;

[0332] wherein: the poor solvent is selected from one or more of acetone, ethyl acetate, isopropyl acetate, acetonitrile, ethanol, 88% acetone, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propyl alcohol, t-butyl alcohol, 2-butanone, or 3-pentanone, methyl tert-butyl ether, or water; preferably one or more of water, ethanol, or tetrahydrofuran.

[0333] The present application also provides a pharmaceutical composition comprising a therapeutically effective amount of the free base crystalline form or acid salt of the compound described above, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0334] The present application further relates to a pharmaceutical composition, the amount of the acid salt or free base crystalline form of the compound being about 0.1% to 95% by weight of the free base; preferably 0.5% to 85%; more preferably 1% to 60%; further preferably 10% to 50%; more further preferably 15-40%; again further preferably 20-30%; most preferably 20-25%.

[0335] The present application further relates to a pharmaceutical composition comprising an amount of the compound, acid salt, or free base crystalline form thereof, from about 1 mg to about 1000 mg; preferably from about 1 mg to about 500 mg; more preferably from about 3 mg to about 300 mg; further preferably from about 5 mg to about 200 mg; more preferably 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 20 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, 200 mg, 300 mg, 400 mg, or 500 mg of the free base, by weight of the free base.

[0336] The present application further relates to the use of any of the compounds, acid salts, or free base crystalline forms thereof, or the pharmaceutical composition described for the preparation of a PCSK9 inhibitor medicament.

[0337] The present application further relates to the use of any of the compounds, acid salts, or free base crystalline forms thereof, or the pharmaceutical composition described for the preparation of a LDL lowering medicament.

[0338] The present application further relates to the use of any of the compounds, acid salts, or free base crystalline forms thereof, or the pharmaceutical composition described for the preparation of a medicament for the treatment of cardiovascular diseases, cerebrovascular diseases, atherosclerosis, and / or their related diseases or their symptoms; preferably for the preparation of a medicament for the treatment of stroke, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome, and / or coronary artery disease.

[0339] The present application further relates to the use of any of the compounds, acid salts, or free base crystalline forms thereof, or the pharmaceutical composition described for the preparation of a method for the treatment of cardiovascular diseases, cerebrovascular diseases, atherosclerosis, and / or their related diseases or their symptoms; preferably for the preparation of a method for the treatment of stroke, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome, and / or coronary artery disease.

[0340] The present application further relates to a method for the prophylaxis and / or treatment of 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 amount of a compound, acid salt, or free base crystalline form thereof, or a pharmaceutical composition thereof.

[0341] The present application further provides a method of treating a disease condition using a compound, acid salt, or free base crystalline form thereof, or a pharmaceutical composition thereof, the disease condition including, but not limited to, a condition associated with PCSK9. BRIEF DESCRIPTION OF DRAWINGS

[0342] Figure 1 is an XRPD pattern of the hydrochloride salt Form A.

[0343] Figure 2 is a DSC pattern of the hydrochloride salt Form A.

[0344] Figure 3 is a TGA pattern of the hydrochloride salt Form A.

[0345] Figure 4 is an XRPD pattern of the hydrochloride salt Form B.

[0346] Figure 5 is a DSC pattern of the hydrochloride salt Form B.

[0347] Figure 6 is an XRPD pattern of the mesylate salt Form A.

[0348] Figure 7 is a DSC pattern of the mesylate salt Form A.

[0349] Figure 8 is an XRPD pattern of the mesylate salt Form B.

[0350] Figure 9 is a DSC pattern of the mesylate salt Form B.

[0351] Figure 10 is an XRPD pattern of the besylate salt Form A.

[0352] Figure 11 is a DSC pattern of the besylate salt Form A.

[0353] Figure 12 is an XRPD pattern of the besylate salt Form B.

[0354] Figure 13 is a DSC pattern of the besylate salt Form B.

[0355] Figure 14 is an XRPD pattern of the p-toluenesulfonate salt Form A.

[0356] Figure 15 is a DSC pattern of the p-toluenesulfonate salt Form A.

[0357] Figure 16 is an XRPD pattern of the isethionate salt Form A.

[0358] Figure 17 is a DSC pattern of the isethionate salt Form A.

[0359] Figure 18 is an XRPD pattern of the ethanesulfonate salt Form A.

[0360] Figure 19 is a DSC pattern of the ethanesulfonate salt Form A.

[0361] Figure 20 is an XRPD pattern of the salicylate salt Form A.

[0362] Figure 21 is a DSC pattern of the salicylate salt Form A.

[0363] Figure 22 is an XRPD pattern of the free base Form A.

[0364] Figure 23 is a DSC pattern of the free base Form A.

[0365] Figure 24 is a TGA plot of the free base Form A.

[0366] Figure 25 is an XRPD plot of the free base Form B.

[0367] Figure 26 is a DSC plot of the free base Form B.

[0368] Figure 27 is a TGA plot of the free base Form B.

[0369] Figure 28 is an XRPD plot of the free base Form C.

[0370] Figure 29 is a DSC plot of the free base Form C.

[0371] Figure 30 is a TGA plot of the free base Form C. DETAILED DESCRIPTION

[0372] DETAILED DESCRIPTION

[0373] Unless otherwise indicated, the terms used in the specification and claims have the following meanings.

[0374] The term "alkyl" refers to saturated aliphatic hydrocarbon groups which are straight-chain or branched-chain groups containing 1 to 20 carbon atoms, preferably alkyl groups containing 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, most preferably 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-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 various branched isomers thereof, and the like. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-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, and the like. The alkyl group can be substituted or unsubstituted, and when substituted, the substituents can be substituted at any available point of attachment, and are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halo, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate, with methyl, ethyl, i-propyl, t-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl, and hydroxyl-substituted alkyl being preferred.

[0375] The term "cycloalkyl" refers to saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituents, the cycloalkyl ring comprising 3 to 20 carbon atoms, preferably comprising 3 to 12 carbon atoms, more preferably comprising 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spirocyclic, fused, and bridged cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl.

[0376] The cycloalkyl ring can be fused to an aryl, heteroaryl, or heterocycloalkyl ring, where the ring that is attached to the parent structure together is cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, and the like. The cycloalkyl group can be optionally substituted or unsubstituted, when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate.

[0377] The term "heterocyclyl" refers to saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituents comprising 3 to 20 ring atoms, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen, or S(O) m (wherein m is an integer from 0 to 2) but excluding -O-O-, -O-S-, or -S-S- ring moieties, the remaining ring atoms being carbon. Preferably comprising 3 to 12 ring atoms, wherein 1 to 4 are heteroatoms; more preferably comprising 3 to 10 ring atoms; most preferably comprising 3 to 8 ring atoms; further preferably 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclyl groups comprising 1 to 3 nitrogen atoms, optionally substituted with 1 to 2 oxygen atoms, sulfur atoms, oxo, including nitrogen-containing monocyclic heterocyclyl groups, nitrogen-containing spiroheterocyclyl groups, or nitrogen-containing fused heterocyclyl groups; or, preferably comprising 5 to 12 ring atoms, wherein 1 to 4 are heteroatoms, further preferably 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered heterocyclyl groups comprising 1 to 3 nitrogen and / or oxygen atoms.

[0378] Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, azepinyl, 1,4-diazepinyl, pyranyl, and the like, preferably pyrrolidinyl, morpholinyl, piperidinyl, azepinyl, 1,4-diazepinyl, and piperazinyl. Polycyclic heterocyclyl groups include spiro, fused, and bridged heterocyclyl groups; wherein the spiro, fused, and bridged heterocyclyl groups are optionally connected to other groups by a single bond, or further annelated to other cycloalkyl, heterocyclyl, aryl, and heteroaryl groups through any two or more atoms of the ring.

[0379] The heterocyclyl ring can be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring that is connected to the parent structure is a heterocyclyl ring, non-limiting examples of which include:

[0380] and the like.

[0381] The heterocyclyl group can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate.

[0382] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (that is, rings which share adjacent pairs of carbon atoms) ring having a conjugated pi-electron system, preferably 6- to 12-membered, such as phenyl and naphthyl. More preferably, phenyl. The aryl ring can be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, including benzo 5- to 10-membered heteroaryl, benzo 3- to 8-membered cycloalkyl, and benzo 3- to 8-membered heteroalkyl, preferably benzo 5- to 6-membered heteroaryl, benzo 3- to 6-membered cycloalkyl, and benzo 3- to 6-membered heteroalkyl, wherein the heterocyclyl is a 1- to 3- nitrogen, oxygen, or sulfur atom containing heterocyclyl; or further comprising a three-membered nitrogen-containing fused ring containing a benzene ring.

[0383] The aryl ring can be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, non-limiting examples of which include:

[0384] and the like.

[0385] Aryl can be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, oxo, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate.

[0386] The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 12 membered, more preferably 5 membered or 6 membered monocyclic heteroaryl or 8 to 12 membered bicyclic heteroaryl, such as imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, oxadiazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazolyl, pyrazinyl, triazinyl, pyridazinyl and the like, preferably triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, pyrimidinyl or thiazolyl; more preferably pyrazolyl, pyrrolyl and oxazolyl.

[0387] The bicyclic heteroaryl is preferably 5 membered and 5 membered bicyclic heteroaryl, 5 membered and 6 membered bicyclic heteroaryl, 6 membered and 5 membered bicyclic heteroaryl, 6 membered and 6 membered bicyclic heteroaryl, non-limiting examples include:

[0388] The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring that is attached to the parent structure together with the heteroaryl ring is an aryl, heterocyclyl or cycloalkyl ring, non-limiting examples include:

[0389] and the like.

[0390] Heteroaryl can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, oxo or carboxylate.

[0391] The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy. Alkoxy can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0392] "Haloalkyl" means an alkyl group, as defined above, substituted by one or more halogens.

[0393] "Haloalkoxy" means an alkoxy group, as defined above, substituted by one or more halogens.

[0394] "Heteroalkyl" means an alkyl group in which one or more carbon atoms, preferably 1, 2, 3, 4 or 5 carbon atoms, more preferably 1 or 2 carbon atoms, have been independently replaced by -O-, -S-, -NR'- with R' being independently of each other hydrogen or alkyl, or by -SiRR' with R and R' being independently of each other alkyl.

[0395] "Alkenyl" means an alkenyl group, also known as an olefinic group, wherein said alkenyl group can be further substituted by other relevant groups, such as alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0396] "Alkynyl" means (CH≡C-), wherein said alkynyl group can be further substituted by other relevant groups, such as alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0397] "X is selected from A, B, or C", "X is selected from A, B and C", "X is A, B or C", "X is A, B and C", and the like, all express the same meaning, i.e. X can be any one or several of A, B, C.

[0398] The hydrogen atoms in the present application can be replaced by their isotope deuterium, and any of the hydrogen atoms in the compounds of the embodiments involved in the present application can also be replaced by deuterium.

[0399] "Optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and thus such description includes instances in which the event or circumstance occurs and instances in which it does not. For example, "heterocyclyl optionally substituted with alkyl" means that alkyl can or can not be present, and such description includes instances in which the heterocyclyl group is substituted with alkyl and instances in which the heterocyclyl group is not substituted with alkyl.

[0400] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3, of a group are independently of each other replaced by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, which can or cannot be possible (experimentally or theoretically) by the person skilled in the art without undue effort. For example, an amino or hydroxyl group with a free hydrogen can not be stable when bound to a carbon atom with an unsaturated (e.g. olefinic) bond.

[0401] "Pharmaceutical composition" means a mixture of one or more of the compounds described herein, or physiologically / pharmaceutically acceptable salts or prodrugs thereof, with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The goal of a pharmaceutical composition is to facilitate administration of the active ingredient to a subject, to enhance delivery of the active ingredient into or through the subject, and to facilitate or enable the active ingredient to exert its biological activity.

[0402] "Pharmaceutically acceptable salt" refers to those salts of the compounds of the present application which are safe and effective for use in a mammal and possess the desirable biological activity.

[0403] X-ray powder diffraction pattern (XRPD) refers to the experimentally observed diffraction pattern or parameters derived therefrom, characterized by peak position (abscissa) and peak intensity (ordinate). Those skilled in the art will appreciate that experimental error is dependent on the conditions of the instrument, the preparation of the sample, and the purity of the sample. In particular, it is well known in the art that X-ray diffraction patterns can vary somewhat depending on the conditions of the instrument, and those skilled in the art will appreciate that a suitable error tolerance 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, and therefore the order of peak intensities cannot be used as an absolute or determinative factor. In addition, some overall shift in peak angles can be expected due to sample height and other experimental factors, and some shift is generally allowed. Thus, those skilled in the art will appreciate that any crystalline form having the same or similar peaks as those of the patterns of the present application are within the scope of the present application.

[0404] "TGA" refers to a thermal gravimetric analysis (TGA) experiment.

[0405] "DSC" refers to a differential scanning calorimetry (DSC) experiment.

[0406] DETAILED DESCRIPTION

[0407] The present application is further described in connection with the following examples, which are not intended to limit the scope of the application.

[0408] EXAMPLES

[0409] The structures of the compounds of the present application were determined by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were made on a Bruker AVANCE-400 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), deuterated chloroform (CDCl3), or deuterated water (D2O) as the solvent, and tetramethylsilane (TMS) as the internal standard (if any).

[0410] LC-MS determination was performed using Agilent 1200 Infinity Series Mass Spectrometer. HPLC determination was performed using Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150x4.6mm column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C 18 150x4.6mm column).

[0411] Thin layer chromatography silica gel plates were used Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates, TLC used specifications were 0.15mm-0.20mm, thin layer chromatography separation and purification products used specifications were 0.4mm-0.5mm. Column chromatography generally used Yantai Huanghai silica gel 200-300 mesh silica gel as a carrier.

[0412] The starting materials in the embodiments of the present application are known and commercially available, or can be synthesized using or according to methods known in the art.

[0413] Unless otherwise specified, all reactions of the present application were carried out under continuous magnetic stirring, under a dry nitrogen or argon atmosphere, with dry solvents, and the reaction temperature was in degrees Celsius.

[0414] The eluent system of the silica gel column chromatography and the developing agent system of the thin layer chromatography used for purifying compounds in the intermediates and examples included: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: dichloromethane and acetone system, the volume ratio of the solvents was adjusted according to the different polarity of the compounds, and a small amount of triethylamine and basic or acidic reagents such as acetic acid could also be added for adjustment.

[0415] Unless otherwise specified, the ratio in the mobile phase in the HPLC chiral resolution conditions and the HPLC chiral analysis conditions in the embodiments of the present application was a volume ratio.

[0416] Intermediate 1

[0417] 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridinyl]-2-one

[0418] First Step: Dissolve 2-fluoro-5-iodopyridine 1A (5 g, 22.4 mmol), 2-hydroxypyridine (2.35 g, 24.7 mmol), cuprous iodide (427 mg, 2.24 mmol), trans-(1R,2R)-N,N'-dimethyl 1,2-cyclohexanediamine (159 mg, 1.12 mmol) and cesium carbonate (9.5 g, 29.2 mmol) in 1,4-dioxane (75 mL), heat the reaction to 100 °C and stir for 16 hours. Cool the reaction to room temperature, pour into 100 mL of water, extract the aqueous phase with ethyl acetate (100 mL x 2). Combine the organic phases, wash sequentially with water (100 mL), saturated sodium chloride solution (100 mL), dry, concentrate and purify the residue by silica gel chromatography (eluent system B) to give 6'-fluoro-2H-[1,3'-bipyridinyl]-2-one 1B (3.1 g), yield: 72.7%. MS m / z (ESI): 191.1 [M+H] + .

[0419] Second Step: Dissolve tert-butyl (1S,3S)-3-aminocyclopentylcarbamate (2.0 g, 9.99 mmol), 6'-fluoro-2H-[1,3'-bipyridinyl]-2-one 1B (2.85 g, 14.9 mmol) and N,N-diisopropylethylamine (3.87 g, 30.0 mmol) in dimethyl sulfoxide (30 mL), heat the reaction to 130 °C and stir for 16 hours. Cool the reaction to room temperature, pour into 100 mL of water, extract the aqueous phase with ethyl acetate (100 mL x 2). Combine the organic phases, wash sequentially with water (100 mL), saturated sodium chloride solution (100 mL), dry, concentrate and purify the residue by silica gel chromatography (eluent system B) to give tert-butyl ((1S,3S)-3-((2-oxo-2H-[1,3'-bipyridinyl]-6'-yl)amino)cyclopentyl)carbamate 1C (2.9 g), yield: 78.4%. MS m / z (ESI): 371.2 [M+H] + .

[0420] Third Step: Dissolve tert-butyl ((1S,3S)-3-((2-oxo-2H-[1,3'-bipyridinyl]-6'-yl)amino)cyclopentyl)carbamate 1C (2.9 g, 7.83 mmol) in 4 M hydrochloric acid in dioxane (30 mL), stir the reaction at room temperature for 3 hours. Concentrate the reaction, purify the residue by reverse phase chromatography (eluent system C) to give 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridinyl]-2-one intermediate 1 (1.5 g), yield: 70.9%. MS m / z (ESI): 271.2 [M+H] + .

[0421] Reference Example 1

[0422] 6'-(((1S,3S)-3-(pyrrolo[2,1-f][1,2,4]triazin-2-ylamino)cyclopentyl)amino)- 2H-[1,3'-bipyridinyl]-2-one

[0423] First Step: 2-chloropyrrolo[2,1-f][1,2,4]triazine r-1a (50 mg, 0.326 mmol), Intermediate 1 (88 mg, 0.326 mmol) and diisopropylethylamine (84 mg, 0.651 mmol) were dissolved in dimethyl sulfoxide (3 mL), the reaction was heated to 110 °C and stirred for 16 hours. The reaction was cooled to room temperature, saturated sodium chloride solution (10 mL) was added to the reaction, the aqueous phase was extracted with ethyl acetate (10 mL x 3), the organic phase was combined, dried, concentrated, and the residue was separated by silica gel column chromatography (eluent system A) to obtain 6'-(((1S,3S)-3-(pyrrolo[2,1-f][1,2,4]triazin-2-ylamino)cyclopentyl)amino)-2H-[1,3'-bipyridinyl]-2-one Reference Example 1 (85 mg), yield: 67.4%. MS m / z (ESI): 388.2 [M+H] + .

[0424] 1 H NMR (400 MHz, CD3OD) δ 8.67 (s, 1H), 7.98 (s, 1H), 7.63-7.57 (m, 2H), 7.51 (dd, 1H), 7.45 (d, 1H), 6.71 (m, 2H), 6.61 (dt, 2H), 6.46 (td, 1H), 4.39-4.26 (m, 2H), 2.34-2.17 (m, 2H), 2.13-1.98 (m, 2H), 1.71-1.57 (m, 2H).

[0425] Example 1

[0426] First Step: 4-(trifluoromethyl)pyridin-2-amine (5 g, 30.84 mmol) and ethyl N-(thioacyl)carbamate (4.85 g, 37.01 mmol) were dissolved in 1,2-dichloroethane (50 mL) and stirred at room temperature for 16 hours. The reaction was concentrated to obtain ethyl N-[[4-(trifluoromethyl)-2-pyridyl]aminothioacyl]carbamate 1a (9.05 g), the product was used directly in the next step without purification. MS m / z (ESI): 294.1 [M+H] + .

[0427] Second step: 1a (9 g, 30.69 mmol), hydroxylamine hydrochloride (10.66 g, 153.44 mmol) and N, N-diisopropyl ethylamine (11.90 g, 92.07 mmol) were dissolved in methanol (100 mL) and stirred at room temperature for 20 minutes, then heated to 65 °C and stirred for 3 hours. The reaction was concentrated, and the residue was purified by silica gel column chromatography (eluent system A) to obtain 7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine 1b (5.0 g), yield: 80.60%. MS m / z (ESI): 203.1 [M+H] + .

[0428] Third step: 1b (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 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 (eluent system A) to obtain 2-bromo-7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine 1c (5 g), yield 75.99%. MS m / z (ESI): 266.0, 268.0 [M+H] + .

[0429] Fourth step: 1c (4.5 g, 16.92 mmol), tert-butyl N-[(1S,3S)-3-aminocyclopentyl]carbamate (3.39 g, 16.92 mmol), cesium carbonate (11.02 g, 33.83 mmol), tris(dibenzylideneacetone)dipalladium (2.32 g, 2.54 mmol) and 4,5-bisdiphenylphosphin-9,9-dimethylxanthene (2.94 g, 5.07 mmol) were dissolved in 1'4-dioxane (120 mL) under nitrogen protection. The reaction was heated to 130 °C and stirred for 16 hours. The reaction was filtered and concentrated. The residue was purified by silica gel column chromatography (eluent system A) to obtain tert-butyl N-[(1S,3S)-3-[[7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]cyclopentyl]carbamate 1d (3.7 g), yield: 56.76%. MS m / z (ESI): 386.2 [M+H] + .

[0430] Step 5: 1d (3.7 g, 9.60 mmol) and hydrochloric acid (4 M in dioxane, 36.00 mL) were dissolved in methanol (10 mL) and stirred at room temperature for one hour. The reaction was concentrated, 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 1e (2.74 g), yield: 100%. MS m / z (ESI): 286.2 [M+H] + .

[0431] Step 6: 1e (2.74 g, 9.61 mmol), 2-fluoro-5-nitro-pyridine (1.50 g, 10.57 mmol) and cesium carbonate (7.82 g, 24.01 mmol) were dissolved in N,N-dimethylformamide (40 mL) and heated to 80 °C and stirred for 16 hours. The reaction was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (elution system B) to obtain (1S,3S)-N1-(5-nitropyridin-2-yl)-N3-(7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopentane-1,3-diamine 1f (3.8 g), yield: 97.12%. MS m / z (ESI): 408.1 [M+H] + .

[0432] Step 7: 1f (3.8 g, 9.33 mmol) and palladium on carbon (993 mg, 0.93 mmol, purity: 10%) were dissolved in methanol (60 mL) and stirred at room temperature for 2 hours under a hydrogen atmosphere. The reaction was filtered and concentrated to obtain N2-((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)pyridine-2,5-diamine 1g (3.2 g), which was used directly in the next reaction without purification. MS m / z (ESI): 378.1 [M+H] +

[0433] Eighth step: 1 g (2.0 g, 5.30 mmol), 3-(bromomethyl)pyridine-2-carboxylate (1.30 g, 4.24 mmol) and N, N-diisopropylethylamine (2.05 g, 15.90 mmol) were dissolved in a mixed solvent of tert-butyl alcohol (20 mL) and N, N-dimethylformamide (4 mL), stirred at room temperature for 1 hour, then heated to 40 °C for 16 hours, and then heated to 80 °C for 1 hour. The reaction solution was filtered, and the filtrate was purified by preparative HPLC (ammonium bicarbonate system) to obtain 6-(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 1 (1.2 g), yield: 45.79%. MS m / z (ESI): 495.2 [M+H] +

[0434] 1 H NMR (400 MHz, DMSO-d6) δ 8.82 (d, 1H), 8.75 (dd, 1H), 8.35 (d, 1H), 8.10 (d, 1H), 7.92 - 7.82 (m, 2H), 7.61 (dd, 1H), 7.15 (dd, 1H), 7.02 (d, 1H), 6.69 (d, 1H), 6.56 (d, 1H), 4.92 (s, 2H), 4.32 4.13 (m, 2H), 2.23 - 2.10 (m, 2H), 2.04 - 1.85 (m, 2H), 1.67 - 1.43 (m, 2H).

[0435] Example 2

[0436] First step: 7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-amine 2a (100 mg, 0.657 mmol) was dissolved in acetonitrile and stirred in an ice bath, sodium nitrite (91 mg, 1.31 mmol) was added to the reaction solution and stirred for 1 minute. Hydrochloric acid (4M, 0.41 mL) was added dropwise to the reaction solution, the reaction was warmed to room temperature and continued to stir, and thin layer chromatography plate was used to detect the completion of the reaction. Saturated sodium bicarbonate solution was added dropwise to the reaction solution to pH = 7. The reaction solution was extracted with dichloromethane (10 mL x 3), the organic phase was dried and concentrated, and the residue was separated by silica gel column chromatography (eluent system A) to obtain 2-chloro-7-fluoro-[1,2,4]triazolo[1,5-a]pyridine 2b (65 mg), yield: 77.5%. MS m / z (ESI): 172.1 [M+H] + .

[0437] Second Step: The target product 6'-((3-(((1S,3S)-7-fluoro-[1,2,4]triazolo[1,5- a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridinyl]-2-one 2 was synthesized according to the synthetic method of the first step of Reference Example 1. MS m / z (ESI): 406.2 [M+H] + .

[0438] 1 H NMR (400 MHz, DMSO-d6) δ 8.69 - 6.59 (m, 1H), 7.92 (d, 1H), 7.60 (dd, 1H), 7.51 - 7.35 (m, 2H), 7.27 (dd, 1H), 6.97 - 6.82 (m, 2H), 6.74 (d, 1H), 6.52 (d, 1H), 6.44 (d, 1H), 6.26 (t, 1H), 4.35 - 4.28 (m, 1H), 4.20 - 4.10 (m, 1H), 2.20 - 2.07 (m, 2H), 2.00 - 1.82 (m, 2H), 1.60 - 1.42 (m, 2H).

[0439] The synthetic method of the examples can refer to the above examples.

[0440] Evaluation of Example Test

[0441] The following further describes and explains the present application in conjunction with test examples, but these examples are not meant to limit the scope of the present application.

[0442] 1.1 Experimental Instruments

[0443] Envision (PE-Cisbio: 2105-0020), centrifuge (Eppendorf: 5810R), pure water instrument (THERMO: Pacific T II + Micropure), plate washer (Thermo: WELLWASH VERSA), microporous plate oscillator (Thermo: 88882006)

[0444] 1.2 Experimental Reagents

[0445] CircuLex Human PCSK9 ELISA Kit (MBL: CY-8079)

[0446] Human LDL R Quantikine ELISA Kit (R&D: DLDLR0)

[0447] DMEM (Gibco: 31966-021) FBS (Sigma: S5394)

[0448] Compound plate (Thermo: 1353506) Complete medium: DMEM + 10% FBS + 1X P / S

[0449] Experimental medium: DMEM + 10% FBS Cell line: HepG2 (ATCC: HB-8065)

[0450] Cell lysis solution (Thermo: 78503) Protease inhibitor (Pierce: 78430)

[0451] I. Binding experiment

[0452] 1. Purpose of the experiment: The effect of the compound on the binding of PCSK9 protein was detected by using the conventional surface plasmon resonance (SPR) method.

[0453] 2. Experimental results: Note: E-04 is x10 -4

[0454] 3. Experimental conclusion: The compound of the embodiment shown in the present application has good binding effect on PCSK-9 protein, and the compound has slow dissociation rate of PCSK9 protein.

[0455] II. Cell function experiment

[0456] Test example 1, determination of the effect of the compound of the present application on the concentration of PCSK9 secreted by HepG2 cells

[0457] 1. Purpose of the experiment: To detect the inhibitory effect of the compound on PCSK9.

[0458] 2. Experimental method:

[0459] 1) The HepG2 cell line was cultured in complete medium at 37°C, 5% CO2 to 70%-90% confluence.

[0460] 2) The cells were digested and resuspended in experimental medium, 25,000 cells / well / 200ul were inoculated into a 96-well cell culture plate, and incubated at 37°C, 5% CO2 for 20-24 hours.

[0461] 3) Remove the culture medium of the cell culture plate, add 200ul experimental medium per well and wash once.

[0462] 4) Prepare positive control compound and test compound: dilute the positive control compound and test compound on the compound plate.

[0463] 5) Add diluted compound to cell culture plate at 250 μL per well, incubate at 37°C, 5% CO2for 48 hours.

[0464] 6) Collect cell culture medium at 200 μL per well, store at -80°C for later use.

[0465] 7) Thaw cell culture medium sample from -80°C, vortex, centrifuge, and store for later use.

[0466] 8) Prepare standard curve: In each standard tube, add corresponding volume of Dilution buffer, and dilute the standard from the original tube or the previous concentration tube according to the order of 10, 5, 2.5, 1.25, 0.625, 0.313, 0.16, 0 ng / mL.

[0467] 9) Prepare wash buffer: Dilute 10x Wash buffer with Milli-Q to 1x, and store for later use.

[0468] 10) Add 100 μL of corresponding standard and cell culture medium sample to each well according to the plate map, 2 replicates. Seal with adhesive seal, and incubate at room temperature for 1 hour with gentle shaking.

[0469] 11) Place the plate in a plate washer, set wash buffer at 350 μL per well, repeat 4 times, and wash the plate.

[0470] 12) Add 100 μL of HRP-conjugated detection antibody to each well, seal with adhesive seal, and incubate at room temperature for 1 hour with gentle shaking.

[0471] 13) Place the plate in a plate washer, set wash buffer at 350 μL per well, repeat 4 times, and wash the plate.

[0472] 14) Add 100 μL of Substrate reagent to each well, avoid light, seal with adhesive seal, and incubate at room temperature for 10-20 minutes with gentle shaking.

[0473] 15) Add 100 μL of Stop solution (1 N H2SO4) to each well, and mix well.

[0474] 16) Measure the optical density (OD) value of each well with a microplate reader at 450 nm wavelength. The detection should be performed within 30 minutes after the reaction is terminated.

[0475] 3. Experimental data processing method: the OD value read by the enzyme label instrument is used to subtract the OD value of the 0 concentration of the standard sample from the OD values of the standard sample, control group and sample, to obtain the actual value of each well, and a standard curve is drawn by using Graphpad to calculate the concentration of the sample. If the sample detection is diluted, the corresponding dilution multiple needs to be multiplied in the final calculation, that is, the actual concentration of the sample. Inhibition rate = (control actual concentration-sample actual concentration) / control actual concentration * 100. According to the inhibition rate corresponding to different concentrations, an IC 50 .

[0476] 4. Experimental results:

[0477] 5. Experimental conclusion: the experiment of the compound of the embodiment shown in the application on the influence of the concentration of PCSK9 secreted by HepG2 cells shows good inhibitory effect.

[0478] Test example 2, determination of the influence of the compound of the application on the LDLR level of HepG2 cells

[0479] 1. Experimental purpose: to detect the effect of the compound on the level of LDLR protein.

[0480] 2. Experimental method:

[0481] 1) HepG2 cell strain is cultured in complete culture medium at 37℃, 5% CO2 to 70%-90% confluence.

[0482] 2) The cells are digested and resuspended in experimental culture medium, 25,000 cells / well / 200ul are inoculated into a 96-well cell culture plate, and incubated at 37℃, 5% CO2 for 20-24 hours.

[0483] 3) Remove the culture medium of the cell culture plate, and add 200ul of experimental culture medium to each well for washing once.

[0484] 4) Prepare the positive control compound and the test compound: dilute the positive control compound and the test compound on the compound plate.

[0485] 5) Add the diluted compound to the cell culture plate at 250ul per well, and incubate at 37℃, 5% CO2 for 48 hours.

[0486] 6) Remove the cell culture medium, wash the cells with PBS, and add 50pL of cell lysis solution and protein inhibitor.

[0487] 7) Centrifuge, remove the lysate, and store the sample for later use.

[0488] 8) Preparation of standard curve: In each standard tube, add corresponding volume of Dilution buffer, take corresponding volume of standard from the original tube or the previous concentration tube, and dilute in sequence.

[0489] 9) Preparation of washing solution: Dilute 10x Wash buffer with Milli-Q to 1x, and reserve.

[0490] 10) According to the plate map, add 80 μL of corresponding standard and sample to each well, and repeat twice. Do not add standard to the well as background value. Paste the non-dry adhesive sealing sheet, place in the shaking plate instrument at room temperature, mix gently, and incubate for 2 hours.

[0491] 11) Place the plate in the plate washing instrument, set the washing solution to 350 μL per well, repeat 4 times, and perform plate washing.

[0492] 12) Add 200 μL of Human LDLR conjugate to each well, paste the non-dry adhesive sealing sheet, place in the shaking plate instrument, mix thoroughly, and incubate for 2 hours.

[0493] 13) Place the plate in the plate washing instrument, set the washing solution to 350 μL per well, repeat 4 times, and perform plate washing.

[0494] 14) Add 200 μL of Substrate solution to each well, avoid light, paste the non-dry adhesive sealing sheet, place in the shaking plate instrument, mix thoroughly, and incubate for 20 minutes.

[0495] 15) Add 50 μL of Stop solution to each well, mix, and incubate for 20 minutes.

[0496] 16) Use the enzyme label instrument to sequentially measure the optical density OD value of each well at 450 nm wavelength.

[0497] 3. Experimental data processing method: The OD value read by the enzyme label instrument is used to subtract the OD value of the 0 concentration of the standard group from the OD values of the standard, control group and sample, to obtain the actual value of each well. The standard curve is drawn by using Graphpad, and the concentration of the sample is calculated. If the sample detection is diluted, the corresponding dilution multiple needs to be multiplied in the final calculation, that is, the actual concentration of the sample. Concentration increase percentage % = (control actual concentration - sample actual concentration) / control actual concentration * 100.

[0498] 4. Experimental results:

[0499] 5. Experimental conclusion: The compound of the embodiment shown in the present application shows an effect of improving the concentration of LDLR in the HepG2 cell LDLR concentration influence experiment.

[0500] III. Pharmacokinetic experiment

[0501] Test example 1, mouse pharmacokinetic determination

[0502] 1. Purpose of the experiment: C57BL / 6J mice as test animals, to study the pharmacokinetic behavior of the compound of the present application in mice (plasma) after oral and intravenous administration.

[0503] 2. Test plan

[0504] 2.1 Test drug: The compound of the present application, self-made;

[0505] 2.2 Test animals: C57 mice, male, purchased from Shanghai Bk Experimental Animal Co., Ltd., Animal Production License No. (SCXK (Shanghai) 2013-0006N0.311620400001794).

[0506] 2.3 Drug preparation: Oral administration drug preparation: 10% Solutol HS15

[0507] Weigh 10g of Solutol HS15 solid, dissolve in 90mL of pure water, mix well and stir ultrasonically to form a clear solution.

[0508] Weigh the compound of the present application and dissolve it in the solution, shake well, and ultrasonically for 15 minutes to obtain a colorless clear solution with a concentration of 0.5mg / mL.

[0509] Intravenous drug preparation: 5% DMSO + 10% Solutol HS15 + 85% PBS

[0510] Weigh the compound of the present application, add 5% DMSO according to the total volume ratio, vortex, ultrasonic for 2min, make it completely dissolved; then add 10% Solutol HS15, vortex, ultrasonic for 2min, make it completely dissolved; finally add 85% PBS, vortex, ultrasonic for 5min, pass through 0.22um filter membrane, obtain a colorless transparent clear solution, concentration is 0.2mg / mL.

[0511] 2.4 Administration: C57 mice 3, male; after overnight fasting, PO administration, dose 5mg / kg, administration volume 10mL / kg. C57 mice 3, male; after overnight fasting, IV administration, dose 1mg / kg, administration volume 5mL / kg.

[0512] 2.5 Sample collection: Before and after administration of mice 0.083(iv), 0.25, 0.5, 1, 2, 4, 8 and 24 hours, 0.04mL of orbital blood was collected and placed in EDTA-K2 test tube, centrifuged at 6000rpm for 6min at 4℃ to separate plasma, stored at-80℃; food after administration for 4h.

[0513] 2.6 Determination results: The final determination results were obtained by using LCMS / MS method.

[0514] 3. Experimental results: The main pharmacokinetic parameters were calculated by WinNonlin 6.1.

[0515] 4. Experimental conclusion: The pharmacokinetic determination results of C57BL / 6J mice showed that the compound of the present application exhibited significant PK advantage.

[0516] Four, pharmacodynamic experiment

[0517] Test example 1, in vivo pharmacodynamic study of the compound of the present application in B6-hPCSK9 transgenic mouse hyperlipidemia animal model

[0518] 1. Experimental purpose: To evaluate the in vivo efficacy of the compound in B6-hPCSK9 transgenic mouse hyperlipidemia animal model.

[0519] 2 Experimental instruments and reagents

[0520] 2.1 Instruments: Refrigerator (BCD-268TN, Haier)

[0521] Biological safety cabinet (BSC-1300II A2, Shanghai Boxin Industrial Co., Ltd. Medical Equipment Factory)

[0522] Clean bench (CJ-2F, Suzhou Fengshi Experimental Animal Equipment Co., Ltd.)

[0523] 1 mL / 5 mL pipette (Research Plus, Eppendorf)

[0524] Constant temperature water bath (HWS-12, Shanghai Yiheng Science)

[0525] Centrifuge (Centrifuge 5720R, Eppendorf) Electronic balance (CPA2202S, Sartorius)

[0526] Electronic balance (BSA2202S-CW, Sartorius) Ultrasonic cleaner (115F0032, Shanghai Kedo)

[0527] Pure water instrument (Pacific TII, Thermo) Magnetic stirrer (08-2G, Chi Jiu)

[0528] Fully automatic blood biochemical analyzer (HITACHI 7180 type, HITACHI)

[0529] 2.2 Reagents: High-fat feed (Western Diet, D12079B)

[0530] Saline (MA0083-D, meilunbio) Solutol HS 15 (102483882, Sigma)

[0531] 2.3 Test drug: Compound of the present application, self-made

[0532] 3 Experimental operation and data processing

[0533] 3.1 Animals: B6-hPCSK9 transgenic C57 mice, 6-8 weeks, male, purchased from Jiangsu Jizhu Pharmaceutical Biotechnology Co., Ltd.

[0534] 3.2 Animal model: After the animals arrived at the barrier system, they were adapted for 1 week, and then fed with high-fat feed. The animals were weighed and fed once a week, and the body weight and food intake were recorded.

[0535] 3.3 Grouping, drug administration

[0536] a. Randomized grouping method was used for grouping.

[0537] c. According to the grouping results, the test drug was administered (administration method: oral administration; administration volume: 10 mL / kg; administration frequency: once / day or single administration; administration period: 21 days; solvent: 10% Solutol HS 15 / 90% Saline).

[0538] d. After the start of test drug administration, the animals were weighed and fed twice a week, and blood samples were taken once a week.

[0539] e. Data were processed using Excel and other software. Body weight change rate BWC (%) = (body weight at the end of treatment - body weight at the start of treatment) / body weight at the start of treatment x 100%; food intake (g / mice / day) = (previous feed addition + previous feed remaining - this time feed remaining) / number of animals / feeding days; blood biochemical inhibition rate calculation: using the blood biochemical results of the Vehicle group in the same batch as the baseline, the data of each administration group were normalized, and then the percentage of TC and LDL-C was calculated according to the formula, 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%. ELISA was used to detect PCSK9 in plasma.

[0540] 4 Experimental results:

[0541] 5. Experimental Conclusion: The compound of the embodiment shown in the present application can effectively reduce LDL-C in B6-hPCSK9 transgenic mouse hyperlipidemia animal models.

[0542] Salt and crystal form research of the embodiment

[0543] It is well known to those skilled in the art that the above-mentioned compound of the embodiment is proved to be effective in binding PCSK9 protein and has good inhibitory effect on HepG2 cell secretion of PCSK9, and the pharmaceutically acceptable salt thereof often has the same pharmacological and pharmacodynamic activity. On this basis, the inventors further studied the salt type and crystal form of the corresponding compound. However, the preparation and characterization of the following specific salt type or crystal form do not represent the limitation of the protection scope of the present application. Those skilled in the art can obtain more salt types and crystals of the compounds of the present application based on the present application by conventional salification or crystallization means, and these salt types and crystals are all the protected schemes of the present application. The specific embodiments are as follows:

[0544] 1.1 Experimental instrument

[0545] 1.1.1 Some parameters of physical and chemical detection instruments

[0546] 1.2 Instrument and liquid phase analysis conditions

[0547] 1.2.1 Instruments and equipment

[0548] 1.2.2 Chromatographic conditions

[0549] Chromatographic column: Waters Xbridge C18 (4.6mm*150mm, 3.5μm)

[0550] Flow rate: 1.0 mL / min Column temperature: 37℃

[0551] Detection wavelength: 230nm Injection volume: 5μL

[0552] Run time: 15min Diluent: methanol

[0553] Mobile phase: A: 0.1% phosphoric acid in water; B: acetonitrile

[0554] Compound salt and crystal form

[0555] 1. Preparation of different crystal forms of compound 1

[0556] 1.1 Preparation of free base Form A: Take crude product 6.5 g, add 20 mL water, 60 °C for 40 min, slow cooling, ice water cooling, oil pump dry to get the product solid. The obtained solid was detected by XRPD as free base Form A. The analysis showed that it had the XRPD pattern as shown in Figure 22, the DSC pattern as shown in Figure 23 and the TGA pattern as shown in Figure 24.

[0557] 1.2 Preparation of free base Form B: Take free base Form A 6.8 g, add 20 mL ethanol, 50 °C for 2 days. Filtration, to obtain a white solid. The obtained solid was detected by XRPD as free base Form B. The analysis showed that it had the XRPD pattern as shown in Figure 25, the DSC pattern as shown in Figure 26 and the TGA pattern as shown in Figure 27.

[0558] 1.3 Preparation of free base Form C: Take free base Form A 7.1 g, add 20 mL tetrahydrofuran, 50 °C for 2 days. Filtration, to obtain a white solid. The obtained solid was detected by XRPD as free base Form C. The analysis showed that it had the XRPD pattern as shown in Figure 28, the DSC pattern as shown in Figure 29 and the TGA pattern as shown in Figure 30.

[0559] 1.4 Preparation of hydrochloride Form A: Take free base 20 mg, add 0.2 mL 88% aqueous acetone solution, 50 °C for stirring and dissolution, add 0.06 mL 1M hydrochloric acid in methanol to the system, after the solution is clear, precipitation, after 6h reaction, reduce to room temperature and stir for 12h, centrifugal drying of the solid, finally obtain hydrochloride Form A. The analysis showed that it had the XRPD pattern as shown in Figure 1, the DSC pattern as shown in Figure 2 and the TGA pattern as shown in Figure 3.

[0560] 1.5 Preparation of hydrochloride Form B: Take hydrochloride Form A 10 mg, add 0.2 mL dichloromethane solution, 50 °C for stirring and slurry for 12h, centrifugal drying of the solid, finally obtain hydrochloride Form B. The analysis showed that it had the XRPD pattern as shown in Figure 4 and the DSC pattern as shown in Figure 5.

[0561] 1.6 Preparation of methanesulfonate Form A: Take free base Form A 20 mg, add 0.2 mL ethyl acetate, 50 °C for stirring and suspension, add 0.06 mL 1M methanesulfonic acid in methanol to the system, the solution color changes, after 6h reaction, reduce to room temperature and stir for 12h, centrifugal drying of the solid, finally obtain methanesulfonate Form A. The analysis showed that it had the XRPD pattern as shown in Figure 6 and the DSC pattern as shown in Figure 7.

[0562] 1.7 Preparation of mesylate salt Form B: Take 50 mg of free base Form A, add 1 mL of acetone, stir the suspension at 50 °C, add 0.11 mL of 1 M methanesulfonic acid in methanol to the system, react for 24 h, centrifuge the solid and dry, finally obtain mesylate salt Form B. The analysis shows that it has the XRPD pattern as shown in Figure 8 and the DSC pattern as shown in Figure 9.

[0563] 1.8 Preparation of besylate salt Form A: Take 20 mg of free base Form A, add 0.2 mL of ethyl acetate, stir the suspension at 50 °C, add 0.06 mL of 1 M benzenesulfonic acid in methanol to the system, react for 6 h, then cool to room temperature and stir for 12 h, centrifuge the solid and dry, finally obtain besylate salt Form A. The analysis shows that it has the XRPD pattern as shown in Figure 10 and the DSC pattern as shown in Figure 11.

[0564] 1.9 Preparation of besylate salt Form B: Take 150 mg of free base Form A, add 3 mL of acetone, stir the suspension at 50 °C, add 0.32 mL of 1 M benzenesulfonic acid in methanol to the system, react for 24 h, centrifuge the solid and dry, finally obtain besylate salt Form B. The analysis shows that it has the XRPD pattern as shown in Figure 12 and the DSC pattern as shown in Figure 13.

[0565] 1.10 Preparation of p-toluenesulfonate salt Form A: Take 10 mg of free base Form A, add 0.2 mL of acetone, stir the suspension at 50 °C, add 0.023 mL of 1 M p-toluenesulfonic acid in methanol to the system, react for 24 h, centrifuge the solid and dry, finally obtain p-toluenesulfonate salt Form A. The analysis shows that it has the XRPD pattern as shown in Figure 14 and the DSC pattern as shown in Figure 15.

[0566] 1.11 Preparation of isethionate salt Form A: Take 10 mg of free base Form A, add 0.2 mL of acetone, stir the suspension at 50 °C, add 0.023 mL of 1 M isethionic acid in methanol to the system, react for 24 h, centrifuge the solid and dry, finally obtain isethionate salt Form A. The analysis shows that it has the XRPD pattern as shown in Figure 16 and the DSC pattern as shown in Figure 17.

[0567] 1.12 Preparation of ethanesulfonate salt Form A: Take 10 mg of free base Form A, add 0.2 mL of acetone, stir the suspension at 50 °C, add 0.023 mL of 1 M ethanesulfonic acid in methanol to the system, react for 24 h, centrifuge the solid and dry, finally obtain ethanesulfonate salt Form A. The analysis shows that it has the XRPD pattern as shown in Figure 18 and the DSC pattern as shown in Figure 19.

[0568] 1.13 Preparation of Salicylate Form A: Take 12 mg of free base Form A, add 0.2 mL of acetone, stir the suspension at 50 °C, add 0.026 mL of 1 M salicylic acid in methanol to the system, react for 24 h, centrifuge the solid to dry, and finally obtain salicylate Form A. The analysis shows that it has an XRPD pattern as shown in Figure 20 and a DSC pattern as shown in Figure 21.

[0569] 2. Screening of Compound 1 salt forms

[0570] 2.1 Screening of Compound salts

[0571] 2.1.1 Purpose of the experiment: select different counterion acids, and through suitable crystallization methods, detect which counterion acids can form Compound salts.

[0572] 2.1.2 Experimental steps:

[0573] 1) Instruments and equipment

[0574] 2) Operation procedure: take about 20 mg of free base Form A, divide it into 15 parts, and add 200 μL of ethyl acetate to each part to stir and mix the suspension at 45 °C or room temperature, add a corresponding volume of counterion acid solution (molar reaction ratio of base: acid = 1: 1.2) to react, stir for 12 hours, centrifuge, remove the supernatant, and dry the solid at 50 °C for characterization. The results are as follows:

[0575] 2.2 Polymorph screening of different salts

[0576] 2.2.1 Solid-liquid reaction crystallization using 88% acetone water as solvent

[0577] Take about 20 mg of free base Form A, divide it into 9 parts, and add 200 μL of 88% acetone water to each part to stir and dissolve at 50 °C. After adding 60 μL of counterion acid solution (molar reaction ratio of base: acid = 1: 1.2), react and crystallize at room temperature. The results are as follows:

[0578] 2.2.2 Polymorph screening of hydrochloride: take about 20 mg of hydrochloride Form A in a glass vial, add 200 μL of organic solvent, and slurry at 50 °C for 7 days. The results are as follows:

[0579] Results and discussion: hydrochloride Form A was slurred in dichloromethane to obtain hydrochloride Form B, and no polymorphs were found in other organic solvents.

[0580] 2.2.3 Polymorph screening of benzenesulfonate

[0581] A. Slurry conversion test

[0582] About 20 mg of benzenesulfonate polymorph A was weighed into a glass vial, 200 μL of organic solvent was added, and the slurry was prepared at 50 °C for 7 days. The results are as follows:

[0583] B. Dissolution crystallization test

[0584] About 150 mg of free base polymorph A was weighed into a glass vial, 3 mL of acetone was added, and the slurry was stirred at 50 °C. 0.32 mL of 1 M benzenesulfonic acid in methanol was added to the system, and the reaction was allowed to proceed for 24 h. The solid was centrifuged and dried, and XRD analysis was performed to characterize the product. Finally, benzenesulfonate polymorph B was obtained.

[0585] Results and discussion: Benzenesulfonate polymorph B was obtained through the above experiments.

[0586] 2.2.4 p-toluenesulfonate polymorph screening

[0587] About 10 mg of p-toluenesulfonate polymorph A was weighed into a glass vial, 200 μL of organic solvent was added, and the slurry was prepared at 40 °C for 7 days. The results are as follows:

[0588] Results and discussion: No new polymorph was obtained through the above experiments.

[0589] 2.2.5 mesylate polymorph screening

[0590] Dissolution crystallization test: 50 mg of free base polymorph A was weighed into a glass vial, 1 mL of acetone was added, and the slurry was stirred at 50 °C. 0.11 mL of 1 M methanesulfonic acid in methanol was added to the system, and the reaction was allowed to proceed for 24 h. The solid was centrifuged and dried, and XRD analysis was performed to characterize the product. Finally, mesylate polymorph B was obtained.

[0591] 2.2.6 Experimental results

[0592] Through the above salt polymorph screening, hydrochloride polymorph A, hydrochloride polymorph B, mesylate polymorph A, mesylate polymorph B, p-toluenesulfonate polymorph A, benzenesulfonate polymorph A, benzenesulfonate polymorph B, hydroxyethylsulfonate polymorph A, ethanesulfonate polymorph A, and salicylate polymorph A were obtained.

[0593] 3. Determination of chloride ion content in hydrochloride

[0594] Using sodium chloride aqueous solution as a control, the content of chloride ions in the compound hydrochloride was determined by HPLC external standard method. The results are as follows:

[0595] According to the chloride ion content determination data, the final ratio of free base to chloride ions in the hydrochloride was determined to be 1:1.

[0596] 4. Hygroscopicity determination

[0597] 4.1 Purpose of the experiment: To investigate the hygroscopicity of the compound hydrochloride salt and free base crystal form under different relative humidity conditions.

[0598] 4.2 Experimental scheme: The compound salt and free base crystal form are placed in saturated water vapor of different relative humidity, allowing the compound and water vapor to reach dynamic equilibrium, and the percentage of the weight gain of the compound after equilibrium is calculated.

[0599] 4.3 Hygroscopicity of the compound salt: The hydrochloride salt crystal form A gained 1.247% in weight under RH 80% conditions, showing no obvious hygroscopicity. After one cycle of hygroscopicity and desorption under 0-95% relative humidity conditions, the XRPD spectrum of the hydrochloride salt crystal form A did not change, i.e. the crystal form did not change.

[0600] The free base crystal form A was cycled once for hygroscopicity and desorption under 0-95% relative humidity conditions, and the XRPD spectrum of the free base crystal form A did not change, i.e. the crystal form did not change.

[0601] The free base crystal form B gained about 0.1304% in weight under RH 80% conditions, showing almost no hygroscopicity. After one cycle of hygroscopicity and desorption under 0-95% relative humidity conditions, the XRPD spectrum of the free base crystal form B did not change, i.e. the crystal form did not change.

[0602] 5. Solid stability experiment

[0603] 5.1 Purpose of the experiment: To investigate the physical and chemical stability of the compound under different salt crystal forms at high temperature 60°C and high temperature and high humidity 50°C 75% RH for 7 days.

[0604] 5.2 Experimental scheme: About 1 mg of different salt or free base crystal form was taken and investigated at high temperature 60°C and high temperature and high humidity 50°C 75% RH for 7 days. The change in salt related substances was calculated using the chromatographic peak area normalization method.

[0605] 5.3 Experimental results: Stability results of different salt forms:

[0606] 5.4 Experimental conclusion: From the stability data, the hydrochloride salt, p-toluenesulfonic acid salt, benzenesulfonic acid salt, hydroxyethylsulfonic acid salt, ethanesulfonic acid salt and salicylic acid salt are relatively stable under high temperature and high temperature and high humidity conditions for 7 days. The free base crystal form is stable under high temperature and high temperature and high humidity conditions, and the impurity increases little.

[0607] 6. Solubility experiment in different solvents

[0608] 6.1 Experimental purpose: compare the solubility of hydrochloride salt form A, free base form A, free base form B in water, artificial simulated gastric fluid (FaSSGF), fasted artificial simulated intestinal fluid (FaSSIF) and non-fasted artificial simulated intestinal fluid (FeSSIF) and the like.

[0609] 6.2 Experimental scheme: about 1 mg of hydrochloride salt form A, free base form A and free base form B are respectively suspended in different media for 2 hours, and the solubility of the compound at 37°C is determined by HPLC external standard method.

[0610] 6.3 Experimental results:

[0611] 6.4 Experimental conclusion: the solubility of hydrochloride salt form A is good.

[0612] 7. Rat PK study of different salts

[0613] 7.1 Experimental purpose: SD rats are used as test animals to study the pharmacokinetic behavior of hydrochloride salt form A and benzenesulfonate salt form A in rats (plasma) after single oral administration.

[0614] 7.2 Experimental scheme: hydrochloride salt form A and benzenesulfonate salt form A are both suspended in 0.5% HPMC K4M aqueous solution, then gavaged, and three rats are used in parallel for administration, and the administration dose is hydrochloride salt form A (30 mg / kg as a suspension) and benzenesulfonate salt form A (30 mg / kg as a suspension).

[0615] 7.3 Experimental results:

[0616] 7.4 Experimental conclusion: from the above data, it can be seen that the PK data of the crystal form of the application is good, and the oral bioavailability is high.

Claims

1. A free base crystalline form, an acid salt and a crystalline form thereof of a compound represented by general formula (I): in: Ring A is selected from 3-8 membered heterocyclyl, 7-10 membered bicyclic heterocyclyl, 5 membered heteroaryl, 6 membered heteroaryl, 5-membered and 5-membered bicyclic heteroaryl, 5-membered and 6-membered bicyclic heteroaryl, 5-membered and 6-membered bicyclic heterocyclyl, 6-membered and 5-membered bicyclic heteroaryl or 6-membered and 6-membered bicyclic heteroaryl; Preferably, ring A is selected from More preferably, ring A is selected from M1 is selected from N or CH; M2 is selected from N or CH; M3 is selected from N or CH; M4 is selected from N or CH; R a Selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy or C 3-8 Cycloalkyl; R b Selected from hydrogen, halogen or C 1-6 Alkyl; R c Selected from hydrogen, halogen or C 1-6 alkyl; R d Selected from hydrogen, halogen, C 1-6 Alkyl, oxo, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy or C 3-8 Cycloalkyl; x is 0, 1, or 2; y is 0, 1, or 2; z is 0, 1, or 2; e is 0, 1, or 2; and The acid of the acid salt is selected from an inorganic acid or an organic acid, wherein the inorganic acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid or phosphoric acid; the organic acid is selected from 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, capric acid, hexanoic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfamic 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, dodecyl sulfuric acid, dibenzoyltartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactosonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalene disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, or L-malic acid; Preferably, the acid is selected from hydrochloric acid, ethanesulfonate, methanesulfonate, p-toluenesulfonate, benzenesulfonate, isethionate or salicylic acid; further preferably, the acid is hydrochloric acid; The general formula (I) is further preferably the free base crystal form, acid salt and crystal form of the compound represented by the general formula (III): in: R a Selected from hydrogen, halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy or cyclopropyl; R b Selected from hydrogen, halogen or C 1-3 Alkyl; R c Selected from hydrogen, halogen or C 1-3 alkyl; R d Selected from hydrogen, halogen, C 1-3 Alkyl, oxo, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy or cyclopropyl.

2. The free base crystalline form, acid salt and crystalline acid salt of the compound represented by general formula (II): in: Ring B is selected from a 6-membered monoheteroaryl, a 5-membered and 5-membered bicyclic heteroaryl, a 5-membered and 6-membered bicyclic heteroaryl, a 6-membered and 5-membered bicyclic heteroaryl, or a 6-membered and 6-membered bicyclic heteroaryl; Preferably, ring B is selected from Other groups are as described in claim 1.

3. The free base crystal form, acid salt and crystal form of the compound according to any one of claims 1-2, characterized in that: The compound is selected from:

4. The free base crystal form, acid salt and crystal form of the compound according to any one of claims 1 to 3, characterized in that: The number of acids is 0.2-3; preferably 1, 2 or 3; more preferably 1 or 2, further preferably 1.

5. The free base crystal form, acid salt and crystal form of the compound according to any one of claims 1 to 4, characterized in that: The acid salt and the free base are hydrates or anhydrates; when the acid salt is a hydrate, the number of water is 0.2-3; preferably 1 or 2; preferably, the acid salt is anhydrate; when the free base is a hydrate, preferably 1.5 hydrate.

6. The free base crystal form, acid salt and crystal form of the compound according to any one of claims 1 to 5, characterized in that: The acid salt and free base are crystalline; Preferably, the crystalline form is hydrochloride form A, hydrochloride form B, methanesulfonate form A, methanesulfonate form B, benzenesulfonate form A, benzenesulfonate form B, p-toluenesulfonate form A, isethionate form A, ethanesulfonate form A, salicylate form A, free base form A, free base form B or free base form C of compound 1.

7. The free base crystal form, acid salt and crystal form of the compound according to claim 6, characterized in that: Hydrochloride salt form A, whose X-ray powder diffraction pattern has a diffraction peak at 2θ of 10.9±0.2°; or a diffraction peak at 14.9±0.2°; or a diffraction peak at 15.5±0.2°; or a diffraction peak at 16.3±0.2°; or a diffraction peak at 17.3±0.2°; or a diffraction peak at 17.9±0.2°; or a diffraction peak at 22.0±0.2°; or a diffraction peak at 23.4±0.2°; or a diffraction peak at 25.8±0.2°; or a diffraction peak at 26.3±0.2°; preferably includes any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, more preferably includes any 6, 7 or 8 thereof; Hydrochloride Form B, whose X-ray powder diffraction pattern has a diffraction peak at 2θ of 5.8±0.2°; or a diffraction peak at 8.0±0.2°; or a diffraction peak at 13.2±0.2°; or a diffraction peak at 15.6±0.2°; or a diffraction peak at 16.1±0.2°; or a diffraction peak at 19.6±0.2°; or a diffraction peak at 23.5±0.2°; or a diffraction peak at 24.1±0.2°; or a diffraction peak at 24.8±0.2°; or a diffraction peak at 33.7±0.2°; preferably includes any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, more preferably includes any 6, 7 or 8 thereof; The mesylate salt form A has an X-ray powder diffraction pattern with a diffraction peak at 2θ of 12.4±0.2°; or a diffraction peak at 17.3±0.2°; or a diffraction peak at 18.2±0.2°; or a diffraction peak at 20.3±0.2°; or a diffraction peak at 20.9±0.2°; or a diffraction peak at 21.2±0.2°; or a diffraction peak at 22.5 ±0.2°; or a diffraction peak at 22.8±0.2°; or a diffraction peak at 24.4±0.2°; or a diffraction peak at 26.8±0.2°; preferably including any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, more preferably including any 6, 7 or 8 thereof; Methanesulfonate crystalline form B, whose X-ray powder diffraction pattern has a diffraction peak at 6.9±0.2° 2θ; or a diffraction peak at 12.5±0.2°; or a diffraction peak at 17.3±0.2°; or a diffraction peak at 18.9±0.2°; or a diffraction peak at 20.7±0.2°; or a diffraction peak at 21.4±0.2°; or a diffraction peak at 21.8±0.2°; or a diffraction peak at 22.8±0.2°; or a diffraction peak at 23.0±0.2°; or a diffraction peak at 27.2±0.2°; preferably comprising any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, more preferably comprising any 6, 7 or 8 thereof; The benzenesulfonate salt form A has an X-ray powder diffraction pattern with a diffraction peak at 2θ of 12.5±0.2°; or a diffraction peak at 16.0±0.2°; or a diffraction peak at 18.5±0.2°; or a diffraction peak at 18.8±0.2°; or a diffraction peak at 19.0±0.2°; or a diffraction peak at 19.3±0.2°; or a diffraction peak at 20.1 ±0.2°; or a diffraction peak at 21.1±0.2°; or a diffraction peak at 22.6±0.2°; or a diffraction peak at 25.2±0.2°; preferably including any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, more preferably including any 6, 7 or 8 thereof; Benzenesulfonate salt form B, whose X-ray powder diffraction pattern has a diffraction peak at 6.2±0.2°; or a diffraction peak at 9.3±0.2°; or a diffraction peak at 12.4±0.2°; or a diffraction peak at 15.5±0.2°; or a diffraction peak at 18.7±0.2°; or a diffraction peak at 21.8±0.2°; or a diffraction peak at 25.0±0.2°; or a diffraction peak at 28.2±0.2°; or a diffraction peak at 31.4±0.2°; or a diffraction peak at 37.9±0.2°; preferably comprising any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, more preferably comprising any 6, 7 or 8 thereof; The p-toluenesulfonate crystalline form A has an X-ray powder diffraction pattern with a diffraction peak at 2θ of 8.7±0.2°; or a diffraction peak at 11.8±0.2°; or a diffraction peak at 12.8±0.2°; or a diffraction peak at 18.9±0.2°; or a diffraction peak at 19.3±0.2°; or a diffraction peak at 19.8±0.2°; or a diffraction peak at 20.2 ±0.2°; or a diffraction peak at 20.8±0.2°; or a diffraction peak at 21.0±0.2°; or a diffraction peak at 22.4±0.2°; preferably including any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, more preferably including any 6, 7 or 8 thereof; The isethionate salt crystalline form A has an X-ray powder diffraction pattern with a diffraction peak at 2θ of 6.7±0.2°; or a diffraction peak at 12.9±0.2°; or a diffraction peak at 13.4±0.2°; or a diffraction peak at 16.8±0.2°; or a diffraction peak at 17.2±0.2°; or a diffraction peak at 19.8±0.2°; or a diffraction peak at 20.1 ±0.2°; or a diffraction peak at 20.9±0.2°; or a diffraction peak at 22.3±0.2°; or a diffraction peak at 23.2±0.2°; preferably including any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, more preferably including any 6, 7 or 8 thereof; The ethanesulfonate salt form A has an X-ray powder diffraction pattern with a diffraction peak at 2θ of 17.1±0.2°; or a diffraction peak at 18.2±0.2°; or a diffraction peak at 18.7±0.2°; or a diffraction peak at 19.3±0.2°; or a diffraction peak at 19.8±0.2°; or a diffraction peak at 20.4±0.2°; or a diffraction peak at 20.8 ±0.2°; or a diffraction peak at 22.9±0.2°; or a diffraction peak at 23.5±0.2°; or a diffraction peak at 25.9±0.2°; preferably including any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, more preferably including any 6, 7 or 8 thereof; Salicylate crystalline form A, whose X-ray powder diffraction pattern has a diffraction peak at 7.9±0.2°; or a diffraction peak at 8.6±0.2°; or a diffraction peak at 9.5±0.2°; or a diffraction peak at 14.5±0.2°; or a diffraction peak at 17.2±0.2°; or a diffraction peak at 18.6±0.2°; or a diffraction peak at 20.3±0.2°; or a diffraction peak at 21.6±0.2°; or a diffraction peak at 24.9±0.2°; or a diffraction peak at 26.3±0.2°; preferably includes any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, more preferably includes any 6, 7 or 8 thereof; The free base crystalline form A has an X-ray powder diffraction pattern having a diffraction peak at 7.3±0.2° 2θ; or a diffraction peak at 9.7±0.2°; or a diffraction peak at 14.6±0.2°; or a diffraction peak at 18.0±0.2°; or a diffraction peak at 19.4±0.2°; or a diffraction peak at 21.3±0.2°; or a diffraction peak at 21.8±0.2°; or a diffraction peak at 22.0±0.2°; or a diffraction peak at 24.3±0.2°; or a diffraction peak at 25.6±0.2°; preferably comprising any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, more preferably comprising any 6, 7 or 8 thereof; The free base form B has an X-ray powder diffraction pattern having a diffraction peak at 8.0±0.2° 2θ; or a diffraction peak at 14.9±0.2°; or a diffraction peak at 15.1±0.2°; or a diffraction peak at 17.3±0.2°; or a diffraction peak at 18.5±0.2°; or a diffraction peak at 19.7±0.2°; or a diffraction peak at 23.5±0.2°; or a diffraction peak at 23.9±0.2°; or a diffraction peak at 24.3±0.2°; or a diffraction peak at 25.0±0.2°; preferably comprising any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, more preferably comprising any 6, 7 or 8 thereof; The free base form C has an X-ray powder diffraction pattern having a diffraction peak at 2θ of 5.5±0.2°; or a diffraction peak at 10.8±0.2°; or a diffraction peak at 13.5±0.2°; or a diffraction peak at 17.4±0.2°; or a diffraction peak at 18.9±0.2°; or a diffraction peak at 19.7±0.2°; or a diffraction peak at 21.6±0.2°; or a diffraction peak at 22.0±0.2°; or a diffraction peak at 23.9±0.2°; or a diffraction peak at 27.0±0.2°; preferably includes any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above-mentioned diffraction peaks, and more preferably includes any 6, 7 or 8 thereof.

8. The free base crystal form, acid salt and crystal form of the compound according to any one of claims 6-7, characterized in that: The X-ray powder diffraction pattern of the hydrochloride salt form A comprises at least one or more diffraction peaks located at 2θ of 17.3±0.2°, 22.0±0.2°, and 25.8±0.2°, preferably two of them, and more preferably three of them; optionally, it may further comprise at least one of 2θ of 10.9±0.2°, 14.9±0.2°, 15.5±0.2°, 17.9±0.2°, and 26.3±0.2°, preferably two, three, four or five of them; The X-ray powder diffraction pattern of the hydrochloride salt form B comprises at least one or more diffraction peaks located at 2θ of 15.6±0.2°, 24.1±0.2°, and 24.8±0.2°, preferably two of them, and more preferably three of them; optionally, it may further comprise at least one of 2θ of 13.2±0.2°, 16.1±0.2°, 19.6±0.2°, 23.5±0.2°, and 33.7±0.2°, preferably two, three, four or five of them; The X-ray powder diffraction pattern of the mesylate salt form A comprises at least one or more diffraction peaks located at 2θ of 17.3±0.2°, 20.9±0.2°, and 22.8±0.2°, preferably two of them, more preferably three; optionally, it may further comprise at least one of 2θ of 12.4±0.2°, 21.2±0.2°, 22.5±0.2°, 24.4±0.2°, and 26.8±0.2°, preferably two, three, four or five of them; The X-ray powder diffraction pattern of the mesylate salt form B comprises at least one or more diffraction peaks located at 2θ of 17.3±0.2°, 20.7±0.2°, and 22.8±0.2°, preferably two of them, and more preferably three of them; optionally, it may further comprise at least one of 2θ of 6.9±0.2°, 12.5±0.2°, 18.9±0.2°, 21.8±0.2°, and 27.2±0.2°, preferably two, three, four or five of them; The X-ray powder diffraction pattern of the benzenesulfonate salt form A comprises at least one or more diffraction peaks located at 2θ of 19.0±0.2°, 19.3±0.2°, and 20.1±0.2°, preferably two of them, and more preferably three of them; optionally, it may further comprise at least one of 2θ of 12.5±0.2°, 16.0±0.2°, 21.1±0.2°, 22.6±0.2°, and 25.2±0.2°, preferably 2, 3, 4 or 5 of them; The X-ray powder diffraction pattern of the benzenesulfonate salt form B comprises at least one or more diffraction peaks located at 2θ of 6.2±0.2°, 9.3±0.2°, and 12.4±0.2°, preferably two of them, and more preferably three of them; optionally, it may further comprise at least one of 2θ of 15.5±0.2°, 18.7±0.2°, 25.0±0.2°, 31.4±0.2°, and 37.9±0.2°, preferably 2, 3, 4 or 5 of them; The X-ray powder diffraction pattern of the p-toluenesulfonate salt form A comprises at least one or more diffraction peaks located at 2θ of 19.3±0.2°, 19.8±0.2°, and 20.2±0.2°, preferably two of them, and more preferably three of them; optionally, it may further comprise at least one of 2θ of 11.8±0.2°, 12.8±0.2°, 18.9±0.2°, 20.8±0.2°, and 21.0±0.2°, preferably two, three, four or five of them; The X-ray powder diffraction pattern of the isethionate salt form A comprises at least one or more diffraction peaks located at 2θ of 13.4±0.2°, 19.8±0.2°, and 20.9±0.2°, preferably two of them, and more preferably three of them; optionally, it may further comprise at least one diffraction peak located at 2θ of 6.7±0.2°, 16.8±0.2°, 17.2±0.2°, 20.1±0.2°, and 22.3±0.2°, preferably two, three, four, or five of them; The X-ray powder diffraction pattern of the ethanesulfonate salt form A comprises at least one or more diffraction peaks located at 2θ of 18.7±0.2°, 19.3±0.2°, and 19.8±0.2°, preferably two of them, and more preferably three of them; optionally, it may further comprise at least one of 2θ of 17.1±0.2°, 20.4±0.2°, 22.9±0.2°, 23.5±0.2°, and 25.9±0.2°, preferably two, three, four or five of them; The X-ray powder diffraction pattern of the salicylate salt form A comprises at least one or more diffraction peaks located at 2θ of 8.6±0.2°, 14.5±0.2°, and 17.2±0.2°, preferably two of them, and more preferably three of them; optionally, it may further comprise at least one of 2θ of 7.9±0.2°, 18.6±0.2°, 20.3±0.2°, 21.6±0.2°, and 24.9±0.2°, preferably two, three, four or five of them; The X-ray powder diffraction pattern of the free base crystalline form A comprises at least one or more diffraction peaks located at 2θ of 9.7±0.2°, 14.6±0.2°, and 18.0±0.2°, preferably two of them, and more preferably three of them; optionally, it may further comprise at least one of 2θ of 21.3±0.2°, 21.8±0.2°, 22.0±0.2°, 24.3±0.2°, and 25.6±0.2°, preferably two, three, four or five of them; The X-ray powder diffraction pattern of the free base crystalline form B comprises at least one or more diffraction peaks located at 2θ of 8.0±0.2°, 15.1±0.2°, and 25.0±0.2°, preferably two of them, and more preferably three of them; optionally, it may further comprise at least one of 2θ of 14.9±0.2°, 17.3±0.2°, 19.7±0.2°, 23.9±0.2°, and 24.3±0.2°, preferably two, three, four or five of them; The X-ray powder diffraction pattern of the free base crystalline form C comprises at least one or more diffraction peaks located at 2θ of 17.4±0.2°, 22.0±0.2°, and 27.0±0.2°, preferably two of them, and more preferably three; optionally, it may further comprise at least one of 2θ of 10.8±0.2°, 13.5±0.2°, 18.9±0.2°, 21.6±0.2°, and 23.9±0.2°, preferably 2, 3, 4 or 5 of them.

9. The free base crystal form, acid salt and crystal form of the compound according to claim 8, characterized in that: The X-ray powder diffraction pattern of the hydrochloride salt form A optionally further comprises one or more diffraction peaks located at 2θ of 8.8±0.2°, 12.6±0.2°, 15.2±0.2°, 16.3±0.2°, 22.7±0.2°, 23.4±0.2°, and 27.4±0.2°; preferably, at least any 2-3, or 4-5, or 6-7 thereof; further preferably, any 2, 3, 4, 5, 6, or 7 thereof; The X-ray powder diffraction pattern of the hydrochloride salt form B optionally further includes one or more diffraction peaks located at 2θ of 5.8±0.2°, 8.0±0.2°, 20.1±0.2°, 20.9±0.2°, 22.2±0.2°, 26.3±0.2°, and 27.4±0.2°; preferably, at least any 2-3, or 4-5, or 6-7 thereof; further preferably, any 2, 3, 4, 5, 6, or 7 thereof; The X-ray powder diffraction pattern of the mesylate salt form A optionally further comprises one or more diffraction peaks located at 2θ of 18.2±0.2°, 18.5±0.2°, 19.4±0.2°, 20.0±0.2°, 20.3±0.2°, 26.6±0.2°, and 38.7±0.2°; preferably, at least any 2-3, or 4-5, or 6-7 thereof; further preferably, any 2, 3, 4, 5, 6, or 7 thereof; The X-ray powder diffraction pattern of the mesylate salt form B optionally further comprises one or more diffraction peaks located at 2θ of 21.4±0.2°, 22.5±0.2°, 23.0±0.2°, 23.2±0.2°, 25.1±0.2°, 30.7±0.2°, and 39.0±0.2°; preferably, at least any 2-3, or 4-5, or 6-7 thereof; further preferably, any 2, 3, 4, 5, 6, or 7 thereof; The X-ray powder diffraction pattern of the benzenesulfonate salt form A optionally further comprises one or more diffraction peaks located at 2θ of 12.7±0.2°, 17.7±0.2°, 18.5±0.2°, 18.8±0.2°, 20.3±0.2°, 22.3±0.2°, and 22.9±0.2°; preferably, at least any 2-3, or 4-5, or 6-7 thereof; further preferably, any 2, 3, 4, 5, 6, or 7 thereof; The X-ray powder diffraction pattern of the benzenesulfonate salt form B optionally further includes one or more diffraction peaks located at 2θ of 16.1±0.2°, 17.4±0.2°, 20.3±0.2°, 21.8±0.2°, 27.8±0.2°, 28.2±0.2°, and 30.9±0.2°; preferably, at least any 2-3, or 4-5, or 6-7 thereof; further preferably, any 2, 3, 4, 5, 6, or 7 thereof; The X-ray powder diffraction pattern of the p-toluenesulfonate salt form A optionally further comprises one or more diffraction peaks located at 2θ of 8.7±0.2°, 8.8±0.2°, 17.9±0.2°, 21.8±0.2°, 22.4±0.2°, 23.0±0.2°, and 23.7±0.2°; preferably, at least any 2-3, or 4-5, or 6-7 thereof; further preferably, any 2, 3, 4, 5, 6, or 7 thereof; The X-ray powder diffraction pattern of the isethionate salt form A optionally further comprises one or more diffraction peaks located at 2θ of 10.0±0.2°, 12.9±0.2°, 16.0±0.2°, 21.4±0.2°, 23.2±0.2°, 26.7±0.2°, and 28.5±0.2°; preferably, at least any 2-3, or 4-5, or 6-7 of these peaks are included; further preferably, any 2, 3, 4, 5, 6, or 7 of these peaks are included; The X-ray powder diffraction pattern of the ethanesulfonate salt form A optionally further comprises one or more diffraction peaks located at 2θ of 12.8±0.2°, 13.1±0.2°, 18.2±0.2°, 20.8±0.2°, 21.3±0.2°, 22.1±0.2°, and 23.8±0.2°; preferably, at least any 2-3, or 4-5, or 6-7 thereof; further preferably, any 2, 3, 4, 5, 6, or 7 thereof; The X-ray powder diffraction pattern of the salicylate salt form A optionally further comprises one or more diffraction peaks located at 2θ of 9.5±0.2°, 15.9±0.2°, 18.1±0.2°, 22.4±0.2°, 23.5±0.2°, 23.9±0.2°, and 26.3±0.2°; preferably, at least any 2-3, or 4-5, or 6-7 thereof; further preferably, any 2, 3, 4, 5, 6, or 7 thereof; The X-ray powder diffraction pattern of the free base crystalline form A optionally further comprises one or more diffraction peaks located at 2θ of 7.3±0.2°, 19.0±0.2°, 19.4±0.2°, 23.3±0.2°, 27.6±0.2°, 27.9±0.2°, and 28.7±0.2°; preferably, at least any 2-3, or 4-5, or 6-7 thereof; further preferably, any 2, 3, 4, 5, 6, or 7 thereof; The X-ray powder diffraction pattern of the free base crystalline form B optionally further comprises one or more diffraction peaks located at 2θ of 12.0±0.2°, 18.5±0.2°, 22.3±0.2°, 23.0±0.2°, 23.5±0.2°, 28.3±0.2°, and 28.6±0.2°; preferably, at least any 2-3, or 4-5, or 6-7 thereof; further preferably, any 2, 3, 4, 5, 6, or 7 thereof; The X-ray powder diffraction pattern of the free base crystalline form C optionally further includes one or more diffraction peaks located at 2θ of 5.5±0.2°, 19.7±0.2°, 20.6±0.2°, 24.7±0.2°, 25.3±0.2°, 29.3±0.2°, and 32.8±0.2°; preferably, at least any 2-3, or 4-5, or 6-7 thereof; further preferably, any 2, 3, 4, 5, 6, or 7 thereof are included.

10. The free base crystal form, acid salt and crystal form of the compound according to any one of claims 6 to 9, characterized in that: The X-ray powder diffraction pattern of the hydrochloride salt form A comprises one or more diffraction peaks located at 2θ of 10.9±0.2°, 12.6±0.2°, 14.9±0.2°, 15.5±0.2°, 16.3±0.2°, 17.3±0.2°, 17.9±0.2°, 22.0±0.2°, 23.4±0.2°, 25.8±0.2°, 26.3±0.2°, and 27.4±0.2°; preferably, comprising 4, 5, 6, 8, 10, or 12 of the diffraction peaks selected therefrom; The X-ray powder diffraction pattern of the hydrochloride salt form B comprises one or more diffraction peaks located at 2θ of 5.8±0.2°, 8.0±0.2°, 13.2±0.2°, 15.6±0.2°, 16.1±0.2°, 19.6±0.2°, 20.9±0.2°, 23.5±0.2°, 24.1±0.2°, 24.8±0.2°, 27.4±0.2°, and 33.7±0.2°; preferably, comprising 4, 5, 6, 8, 10, or 12 of the diffraction peaks selected therefrom; The X-ray powder diffraction pattern of the mesylate salt form A comprises one or more diffraction peaks located at 2θ of 12.4±0.2°, 17.3±0.2°, 18.2±0.2°, 19.4±0.2°, 20.3±0.2°, 20.9±0.2°, 21.2±0.2°, 22.5±0.2°, 22.8±0.2°, 24.4±0.2°, 26.6±0.2°, and 26.8±0.2°; preferably, comprising 4, 5, 6, 8, 10 or 12 of the diffraction peaks selected therefrom; The X-ray powder diffraction pattern of the mesylate salt form B comprises one or more diffraction peaks located at 2θ of 6.9±0.2°, 12.5±0.2°, 17.3±0.2°, 18.9±0.2°, 20.7±0.2°, 21.4±0.2°, 21.8±0.2°, 22.5±0.2°, 22.8±0.2°, 23.0±0.2°, 25.1±0.2°, and 27.2±0.2°; preferably, comprising 4, 5, 6, 8, 10, or 12 of the diffraction peaks selected therefrom; The X-ray powder diffraction pattern of the benzenesulfonate salt form A comprises one or more diffraction peaks located at 2θ of 12.5±0.2°, 16.0±0.2°, 17.7±0.2°, 18.5±0.2°, 18.8±0.2°, 19.0±0.2°, 19.3±0.2°, 20.1±0.2°, 21.1±0.2°, 22.3±0.2°, 22.6±0.2°, and 25.2±0.2°; preferably, comprising 4, 5, 6, 8, 10, or 12 of the diffraction peaks selected therefrom; The X-ray powder diffraction pattern of the benzenesulfonate salt form B comprises one or more diffraction peaks located at 2θ of 6.2±0.2°, 9.3±0.2°, 12.4±0.2°, 15.5±0.2°, 16.1±0.2°, 18.7±0.2°, 21.8±0.2°, 25.0±0.2°, 28.2±0.2°, 30.9±0.2°, 31.4±0.2°, and 37.9±0.2°; preferably, comprising 4, 5, 6, 8, 10, or 12 of the diffraction peaks selected therefrom; The X-ray powder diffraction pattern of the p-toluenesulfonate salt form A comprises one or more diffraction peaks located at 2θ of 8.7±0.2°, 11.8±0.2°, 12.8±0.2°, 18.9±0.2°, 19.3±0.2°, 19.8±0.2°, 20.2±0.2°, 20.8±0.2°, 21.0±0.2°, 21.8±0.2°, 22.4±0.2°, and 23.7±0.2°; preferably, comprising 4, 5, 6, 8, 10, or 12 of the diffraction peaks selected therefrom; The X-ray powder diffraction pattern of the isethionate salt form A comprises one or more diffraction peaks located at 2θ of 6.7±0.2°, 10.0±0.2°, 12.9±0.2°, 13.4±0.2°, 16.8±0.2°, 17.2±0.2°, 19.8±0.2°, 20.1±0.2°, 20.9±0.2°, 21.4±0.2°, 22.3±0.2°, and 23.2±0.2°; preferably, the X-ray powder diffraction pattern comprises one or more diffraction peaks selected from 4, 5, 6, 8, 10, or 12 of the following: The X-ray powder diffraction pattern of the ethanesulfonate salt form A comprises one or more diffraction peaks located at 2θ of 13.1±0.2°, 17.1±0.2°, 18.2±0.2°, 18.7±0.2°, 19.3±0.2°, 19.8±0.2°, 20.4±0.2°, 20.8±0.2°, 22.1±0.2°, 22.9±0.2°, 23.5±0.2°, and 25.9±0.2°; preferably, comprising 4, 5, 6, 8, 10, or 12 of the diffraction peaks selected therefrom; The X-ray powder diffraction pattern of the salicylate salt form A comprises one or more diffraction peaks located at 2θ of 7.9±0.2°, 8.6±0.2°, 9.5±0.2°, 14.5±0.2°, 17.2±0.2°, 18.1±0.2°, 18.6±0.2°, 20.3±0.2°, 21.6±0.2°, 23.9±0.2°, 24.9±0.2°, and 26.3±0.2°; preferably, comprising 4, 5, 6, 8, 10, or 12 of the diffraction peaks selected therefrom; The X-ray powder diffraction pattern of the free base crystalline form A comprises one or more diffraction peaks located at 2θ of 7.3±0.2°, 9.7±0.2°, 14.6±0.2°, 18.0±0.2°, 19.4±0.2°, 21.3±0.2°, 21.8±0.2°, 22.0±0.2°, 23.3±0.2°, 24.3±0.2°, 25.6±0.2°, and 28.7±0.2°; preferably, comprising 4, 5, 6, 8, 10, or 12 of the diffraction peaks selected therefrom; The X-ray powder diffraction pattern of the free base crystalline form B comprises one or more diffraction peaks located at 2θ of 8.0±0.2°, 12.0±0.2°, 14.9±0.2°, 15.1±0.2°, 17.3±0.2°, 18.5±0.2°, 19.7±0.2°, 23.5±0.2°, 23.9±0.2°, 24.3±0.2°, 25.0±0.2°, and 28.3±0.2°; preferably, comprising 4, 5, 6, 8, 10, or 12 of the diffraction peaks selected therefrom; The X-ray powder diffraction pattern of the free base form C comprises one or more diffraction peaks located at 2θ of 5.5±0.2°, 10.8±0.2°, 13.5±0.2°, 17.4±0.2°, 18.9±0.2°, 19.7±0.2°, 21.6±0.2°, 22.0±0.2°, 23.9±0.2°, 24.7±0.2°, 27.0±0.2°, and 29.3±0.2°; preferably, it comprises 4, 5, 6, 8, 10 or 12 of the diffraction peaks selected therefrom.

11. The free base crystal form, acid salt and crystal form of the compound according to any one of claims 6 to 10, characterized in that: Its X-ray powder diffraction pattern: the hydrochloride crystal form A is shown in Figure 1; the hydrochloride crystal form B is shown in Figure 4; the methanesulfonate crystal form A is shown in Figure 6; the methanesulfonate crystal form B is shown in Figure 8; the benzenesulfonate crystal form A is shown in Figure 10; the benzenesulfonate crystal form B is shown in Figure 12; the p-toluenesulfonate crystal form A is shown in Figure 14; the isethionate crystal form A is shown in Figure 16; the ethanesulfonate crystal form A is shown in Figure 18; the salicylate crystal form A is shown in Figure 20; the free base crystal form A is shown in Figure 22; the free base crystal form B is shown in Figure 25; and the free base crystal form C is shown in Figure 28. Its DSC spectrum: the hydrochloride crystal form A is shown in Figure 2; the hydrochloride crystal form B is shown in Figure 5; the methanesulfonate crystal form A is shown in Figure 7; the methanesulfonate crystal form B is shown in Figure 9; the benzenesulfonate crystal form A is shown in Figure 11; the benzenesulfonate crystal form B is shown in Figure 13; the p-toluenesulfonate crystal form A is shown in Figure 15; the isethionate crystal form A is shown in Figure 17; the ethanesulfonate crystal form A is shown in Figure 19; the salicylate crystal form A is shown in Figure 21; the free base crystal form A is shown in Figure 23; the free base crystal form B is shown in Figure 26; and the free base crystal form C is shown in Figure 29. Its TGA spectrum: the hydrochloride crystal form A is shown in Figure 3; the free base crystal form A is shown in Figure 24; the free base crystal form B is shown in Figure 27; and the free base crystal form C is shown in Figure 30.

12. The free base crystal form, acid salt and crystal form of the compound according to any one of claims 6 to 11, characterized in that: The 2θ error of the diffraction peak positions with the top ten relative peak intensities in the X-ray powder diffraction patterns of the hydrochloride form A, hydrochloride form B, methanesulfonate form A, methanesulfonate form B, benzenesulfonate form A, benzenesulfonate form B, p-toluenesulfonate form A, isethionate form A, ethanesulfonate form A, salicylate form A, free base form A, free base form B, and free base form C and the diffraction peaks at the corresponding positions in Figures 1, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 25, or 28 is ±0.2° to ±0.5°, preferably ±0.2° to ±0.3°, and most preferably ±0.2°.

13. A method for preparing a free base crystal form, an acid salt, and a crystal form thereof of the compound according to any one of claims 1 to 5, comprising the following steps: Method 1 includes the following steps: 1) Weigh an appropriate amount of free base and dissolve it in a benign solvent; 2) Weigh an appropriate amount of counterion acid and dissolve it in an organic solvent; the amount of counterion acid is preferably 1 to 1.2 equivalents; 3) Combine the above two solutions and stir until solid precipitates; 4) Rapidly centrifuge or allow to dry to obtain the target product; in: The benign 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, isopropyl alcohol, n-butanol, isobutyl alcohol, 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 solvent and organic solution need to be miscible when used; The counterion acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphoric acid, 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, capric acid, hexanoic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfamic 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, dodecyl sulfuric acid, di Benzoyltartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic 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, pamoic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, or L-malic acid; preferably hydrochloric acid; Method 2 includes the following steps: 1) Weigh an appropriate amount of free base and suspend it in a poor solvent; 2) Weigh an appropriate amount of counterion acid and dissolve it in an organic solvent; the amount of counterion acid is preferably 1.2 equivalents; 3) Combine the above two solutions and stir to dissolve, and continue stirring to precipitate; 4) Rapidly centrifuge or allow to dry to obtain the target product; Wherein: the poor solvent is selected from one or more of methanol, ethanol, acetone, ethyl acetate, isopropyl 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 or 3-pentanone, methyl tert-butyl ether or water; preferably one or more of acetone, ethyl acetate or 2-methyltetrahydrofuran; 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 counterion acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphoric acid, 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, capric acid, hexanoic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfamic 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, dodecyl sulfuric acid, dibenzoyltartaric acid, ethane-1,2- disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic 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, pamoic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid or L-malic acid; preferably hydrochloric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, isethionic acid, ethanesulfonic acid or salicylic acid; Method 3 includes the following steps: 1) Weigh an appropriate amount of free base and dissolve it in a good solvent at a certain temperature, preferably 0-50°C; 2) adding a poor solvent to the above obtained solution and stirring until a solid precipitates; 3) stirring, cooling and crystallizing to obtain the target product; Wherein: the benign 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, isopropyl alcohol, n-butanol, isobutyl alcohol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, tert-butanol, 2-butanone, 3-pentanone or N-methylpyrrolidone; preferably one or more of N-methylpyrrolidone, methanol, dichloromethane or anhydrous ethanol; The poor solvent is selected from one or more of heptane, cyclohexane, n-hexane, n-pentane, water, ethyl acetate, methyl tert-butyl ether, toluene or isopropyl ether; preferably one or more of water, heptane, methyl tert-butyl ether or isopropyl ether; Method 4 includes the following steps: 1) Weigh an appropriate amount of free base or its crystal form, and beat with a poor solvent at a certain temperature, preferably 0-60°C; Wherein: the poor solvent is selected from one or more of acetone, ethyl acetate, isopropyl 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 or 3-pentanone, methyl tert-butyl ether or water; preferably one or more of water, ethanol or tetrahydrofuran.

14. A pharmaceutical composition comprising a therapeutically effective dose of a free base crystalline form, an acid salt and a crystalline form thereof of the compound according to any one of claims 1 to 12, and one or more pharmaceutically acceptable carriers, diluents or excipients.

15. The pharmaceutical composition according to claim 14, wherein The amount of the free base crystalline form or acid salt of the compound is about 0.1% to 95% by weight of the free base; preferably 0.5% to 85%; more preferably 1% to 60%; further preferably 10% to 50%; further preferably 15-40%; further preferably 20-30%, and most preferably 20-25%; Alternatively, the amount of the free base crystalline form or acid salt of the compound is about 1-1000 mg, preferably about 1-500 mg, more preferably about 3-300 mg, further preferably about 5-200 mg, and more preferably 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 20 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, 200 mg, 300 mg, 400 mg or 500 mg, based on the weight of the free base.

16. Use of the free base crystal form, acid salt and crystal form thereof of the compound according to any one of claims 1 to 12, or the pharmaceutical composition according to any one of claims 14 to 15 in the preparation of a PCSK9 inhibitor drug.

17. Use of the free base crystal form, acid salt and crystal form thereof of the compound according to any one of claims 1 to 12, or the pharmaceutical composition according to any one of claims 14 to 15 in the preparation of an LDL-lowering drug.

18. Use of the free base crystalline form, acid salt, and crystalline form thereof of the compound according to any one of claims 1 to 12, or the pharmaceutical composition according to any one of claims 14 to 15, in the preparation of a medicament for treating cardiovascular disease, cerebrovascular disease, atherosclerosis, and / or related diseases or symptoms thereof; preferably, in the preparation of a medicament for treating stroke, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome, and / or coronary artery disease.

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