Heterocyclic derivative inhibitor salts, crystalline forms, and methods for preparing and using the same

Abstract

The present invention relates to salts and crystalline forms of heterocyclic derivative inhibitors, and their preparation methods and uses. In particular, the present invention relates to salts, crystalline forms, preparation methods, and pharmaceutical compositions containing therapeutically effective amounts of the salts and / or crystalline forms of the compound represented by general formula (I), and their use as inhibitors in the treatment of cancer, wherein each substituent in general formula (I) is as defined in the specification. [Case 1] TIFF2025535427000054.tif41170

Description

[Technical Field]

[0001] The present invention relates to the field of biopharmaceuticals, specifically to salts and crystalline forms of heterocyclic derivative inhibitors, as well as their preparation and use. [Background technology]

[0002] Poly(ADP-ribose) polymerases (PARPs) are a protein superfamily that catalyzes the ADP-ribosylation of proteins in eukaryotic cells and comprise at least 17 protein subtypes. PARPs catalyze the cleavage of the substrate nicotinamide adenine dinucleotide (NAD) into nicotinamide and ADP-ribose, which then polyADP-ribosylate their target proteins. PARPs are localized in the cell nucleus and are important enzymes for cellular DNA damage repair.

[0003] PARP1, the earliest discovered and most widely studied PARP subtype, contains three main domains: an N-terminal DNA-binding domain (DBD), an automodification domain (AMD), and a C-terminal catalytic domain. PARP1 is a key functional protein in the DNA damage repair process. It functions as a sensor of DNA single-strand breaks. DNA damage activates PARP1, which then performs poly (ADP-ribosyl) modification on its target proteins, such as histones, and recruits related repair proteins to promote DNA damage repair. PARP1 is crucial for stabilizing the genome of normal cells. However, in tumor therapy, PARP1-mediated DNA repair in tumor cells destroyed by radiochemotherapy antagonizes the tumor-killing effects of radiochemotherapy. Therefore, PARP1 inhibitors could be developed as tumor radiochemotherapy-sensitizing agents.

[0004] The breast cancer susceptibility gene (BRCA) is an important tumor suppressor gene, mainly consisting of two subtypes: BRCA1 and BRCA2. BRCA plays a key role in the double-strand break DNA repair process through DNA homologous recombination. BRCA deficiency in tumor cells frequently results in the loss of double-strand break DNA damage repair function. Concomitant loss or inhibition of PARP1 function also leads to the loss of single-strand DNA damage repair, ultimately resulting in tumor cell death and a "synthetic lethal" effect. Therefore, blocking single-strand break DNA damage repair function using PARP1 inhibitors has a selective killing effect on BRCA-deficient tumors.

[0005] PARP inhibitors have achieved great success in precision medicine in the field of oncology, with particularly notable therapeutic effects on tumors with BRCA mutations or deficiencies. Currently available PARP inhibitors include AstraZeneca's Olaparib (AZD2281), Clovis's Rucaparib (CO-338), Tesaro's Niraparib (MK-4827), and Pfizer's Talazoparib (BMN-673), primarily for BRCA-mutated ovarian and breast cancers. There are also numerous PARP inhibitors currently under clinical study. Because PARP2 and PARP1 share the highest homology within the PARP family, most of the PARP inhibitors currently on the market or in clinical trials are nonselective PARP inhibitors, exhibiting potent inhibitory effects against both the PARP1 and PARP2 subtypes. Research has shown that PARP2 plays an important role in regulating red blood cell production, and inhibition of PARP2 is closely associated with clinical side effects, such as hematologic toxicity, including anemia. Summary of the Invention [Problem to be solved by the invention]

[0006] The patent application of Jiangsu Haosen Pharmaceutical Group Co., Ltd. (International Patent Application No.: PCT / CN2022 / 088466) discloses the structure of a series of heterocyclic derivative inhibitors. In subsequent research, in order to facilitate the handling, filtration, drying and storage of the products, and to achieve long-term stability and high bioavailability of the products, the present invention has conducted comprehensive research on the salts and crystalline forms of the above substances and is committed to obtaining the optimal crystalline form.

[0007] The entire contents of International Patent Application No. PCT / CN2022 / 088466 are incorporated herein by reference. [Means for solving the problem]

[0008] An object of the present invention is to provide a compound represented by general formula (I) or an acid salt of a stereoisomer thereof, [ka] where: R1 is hydrogen, deuterium, halogen, nitro group, hydroxy group, mercapto group, cyano group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-8 is selected from a cycloalkyl group or a 3- to 8-membered heterocyclyl group, preferably C 1-3 Alkyl group, C 1-3 Haloalkyl group, C 2-4 Alkynyl group or C 3-6 is a cycloalkyl group, R a are independently hydrogen, deuterium, halogen, nitro group, hydroxy group, mercapto group, cyano group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6Alkoxy group, C 2-6 Alkenyl group or C 2-6 alkynyl groups, R b are independently hydrogen, deuterium, halogen, nitro group, hydroxy group, mercapto group, cyano group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 2-6 Alkenyl group or C 2-6 Alkynyl groups, preferably hydrogen, deuterium, halogen, C 1-3 Alkyl group, C 1-3 Deuterated alkyl group or C 1-3 is a haloalkyl group, R c are independently hydrogen, deuterium, halogen, nitro group, hydroxy group, mercapto group, cyano group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-8 A cycloalkyl group or a 3- to 8-membered heterocyclyl group is preferably selected from hydrogen, deuterium, halogen, cyano group, C 1-3 Alkyl group, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, C 2-4 Alkynyl group or C 3-6 cycloalkyl groups, R d represents hydrogen, deuterium, halogen, nitro group, hydroxy group, mercapto group, cyano group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C3-8 a cycloalkyl group or a 3- to 8-membered heterocyclyl group, 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-8 The cycloalkyl group or the 3- to 8-membered heterocyclyl group may optionally be substituted with hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 2-4 Alkenyl group, C 2-4 may be further substituted with one or more alkynyl groups, R d is preferably a cyano group, C 1-3 Alkyl group, C 1-3 Haloalkyl group, C 1-3 C substituted with alkoxy or cyano groups 1-3 C substituted with alkyl or cyano groups 3-6 Cycloalkyl groups, C 3-6 selected from a cycloalkyl group or a 3- to 6-membered heterocyclyl group; x is 1, 2 or 3; y is 1, 2, 3 or 4; z is 1, 2, 3 or 4; The acid in the acid salt is an inorganic acid or an organic acid, and optionally the inorganic acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, or phosphoric acid, and the organic acid is selected from 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, ethanesulfonic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic 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, 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.

[0009] In some embodiments of the invention, the compound is as shown below: [ka] The acid in the acid salt is selected from isethionic acid, hydrochloric acid, sulfuric acid, 1,5-naphthalenedisulfonic acid, methanesulfonic acid, hydrobromic acid, ethanesulfonic acid, phosphoric acid, benzenesulfonic acid, oxalic acid, maleic acid, adipic acid, hydrochloric acid, citric acid, malonic acid, L-malic acid, pamoic acid, p-toluenesulfonic acid, and fumaric acid, and is preferably hydrochloric acid, sulfuric acid, methanesulfonic acid, hydrobromic acid, or p-toluenesulfonic acid.

[0010] In some embodiments of the present invention, the number of acids in the acid salt is 0.2 to 3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3, more preferably 0.5, 1, 2 or 3, and even more preferably 1.

[0011] In some embodiments of the present invention, the acid salt is a hydrate or anhydrous. When the acid salt is a hydrate, the water is preferably water of crystallization or tap water, and the number of water molecules is 0.2 to 3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5, or 3, and more preferably 2.

[0012] The present invention further provides a crystalline form of an acid salt of the compound described above or a stereoisomer thereof, Optionally, it is 1'-((7-ethyl-6-carbonyl-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide [ka] Acid salt crystalline form of N-cyclopropyl-1'-((7-ethyl-6-carbonyl-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide [ka] Acid salt crystalline form of 1'-((7-ethyl-6-carbonyl-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-2-methoxy-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide [ka] crystalline form of the acid salt of 1'-((7-ethyl-6-carbonyl-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide, crystalline form of the acid salt monohydrate of N-cyclopropyl-1'-((7-ethyl-6-carbonyl-5,6-dihydro-1,5-naphthyridin-3-yl) 1'-((7-ethyl-6-carbonyl-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-2-methoxy-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide acid salt monohydrate crystalline form, 1'-((7-ethyl-6-carbonyl-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-2-methoxy-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide acid salt monohydrate crystalline form Crystalline form, acid salt dihydrate of 1'-((7-ethyl-6-carbonyl-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide Crystalline form, N-cyclopropyl-1'-((7-ethyl-6-carbonyl-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)- a dihydrate crystalline form of an acid salt of 1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide, and a dihydrate crystalline form of an acid salt of 1'-((7-ethyl-6-carbonyl-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-2-methoxy-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide; More optionally, the acid salt in the acid salt crystalline form, acid salt monohydrate crystalline form, or acid salt dihydrate crystalline form is an isethionate, sulfate, hydrochloride, 1,5-naphthalenedisulfonate, methanesulfonate, ethanesulfonate, hydrobromide, phosphate, benzenesulfonate, oxalate, maleate, adipate, hydrochloride, citrate, malonate, L-malate, pamoate, p-toluenesulfonate, or fumarate salt crystalline form.

[0013] In some embodiments of the present invention, the crystalline form of an acid salt of 1′-((7-ethyl-6-carbonyl-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1′,2′,3′,6′-tetrahydro-[3,4′-bipyridine]-6-carboxamide is hydrochloride crystalline form A, sulfate crystalline form A, methanesulfonate crystalline form A, p-toluenesulfonate crystalline form A, p-toluenesulfonate crystalline form B, p-toluenesulfonate crystalline form C, p-toluenesulfonate dihydrate crystalline form A, or benzenesulfonate crystalline form A.

[0014] In some embodiments of the present invention, the X-ray powder diffraction pattern of the hydrochloride salt crystalline form A has a diffraction peak at 4.6±0.2 degrees 2θ, or a diffraction peak at 7.0±0.2 degrees 2θ, or a diffraction peak at 9.2±0.2 degrees 2θ, or a diffraction peak at 13.8±0.2 degrees 2θ, or a diffraction peak at 15.0±0.2 degrees 2θ, or a diffraction peak at 16.1±0.2 degrees 2θ, or a diffraction peak at 18.2±0.2 degrees 2θ, or a diffraction peak at 20.8±0.2 degrees 2θ. The diffraction peak may be at 22.4±0.2°, or at 25.2±0.2°, or at 28.1±0.2°, and preferably includes any 2 to 5, or 3 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8, or 6 to 9, or 8 to 10, or 8 to 11 of the above diffraction peaks, and more preferably includes any 6, 7, 8, 9, 10, or 11 of them.

[0015] In some embodiments of the present invention, the X-ray powder diffraction pattern of the hydrochloride salt crystalline form A comprises at least one or more of the following diffraction peaks at angles 2θ: 9.2±0.2°, 13.8±0.2°, and 15.0±0.2°; preferably two of them, more preferably three of them; and optionally, at least one of the following angles 2θ: 4.6±0.2°, 7.0±0.2°, and 20.8±0.2°; preferably two or three of them.

[0016] In some embodiments of the present invention, the X-ray powder diffraction pattern of the hydrochloride salt crystalline form A optionally further comprises diffraction peaks at one or more of the positions where 2θ is 16.1±0.2°, 18.2±0.2°, 22.4±0.2°, 25.2±0.2°, or 28.1±0.2°, preferably at least any 2-3, or 4-5, of these positions, more preferably any 2, 3, 4, or 5 of these positions.

[0017] In some embodiments of the present invention, the X-ray powder diffraction pattern of the hydrochloride salt crystalline Form A comprises diffraction peaks at one or more of the following positions in degrees 2θ: 4.6±0.2°, 7.0±0.2°, 9.2±0.2°, 13.8±0.2°, 15.0±0.2°, 16.1±0.2°, 18.2±0.2°, 20.8±0.2°, 22.4±0.2°, 25.2±0.2°, 28.1±0.2°, and optionally any 4, 5, 6, 8, or 10 positions therein.

[0018] In some embodiments of the present invention, the hydrochloride salt crystalline form A has characteristic X-ray diffraction peaks, expressed as 2θ angles and d-spacings, as shown in the table below using Cu-Kα radiation.

[0019] [Table 1]

[0020] In some embodiments of the present invention, the X-ray powder diffraction pattern of the hydrochloride salt crystalline form A is substantially as shown in FIG.

[0021] In some embodiments of the present invention, the DSC pattern of the hydrochloride salt crystalline form A is substantially as shown in FIG.

[0022] In some embodiments of the present invention, the X-ray powder diffraction pattern of the Sulfate Salt crystalline Form A has a diffraction peak at 6.5±0.2 degrees 2θ, or a diffraction peak at 9.7±0.2 degrees, or a diffraction peak at 14.3±0.2 degrees, or a diffraction peak at 16.1±0.2 degrees, or a diffraction peak at 18.6±0.2 degrees, or a diffraction peak at 19.3±0.2 degrees, or a diffraction peak at 19.7±0.2 degrees, or a diffraction peak at 22.0±0.2 degrees, or a diffraction peak at 22.5±0.2 degrees, or a diffraction peak at 23.6±0.2 degrees. It has a diffraction peak at 25.5±0.2°, or at 25.9±0.2°, or at 29.2±0.2°, and preferably includes any 2 to 5, or 3 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8, or 7 to 9, or 8 to 10, or 9 to 10, or 10 to 12, or 11 to 13 of the above diffraction peaks, and more preferably includes any 6, 7, 8, 9, 10, 11, 12, or 13 of them.

[0023] In some embodiments of the present invention, the X-ray powder diffraction pattern of the Sulfate Salt Crystalline Form A comprises at least one or more of the following diffraction peaks at angles 2θ: 6.5±0.2°, 9.7±0.2°, 16.1±0.2°, and 23.6±0.2°; preferably two of these, more preferably three of these, and optionally at least one of the following angles 2θ: 18.6±0.2°, 19.3±0.2°, 25.5±0.2°, and 25.9±0.2°; preferably two or three of these.

[0024] In some embodiments of the present invention, the X-ray powder diffraction pattern of the Sulfate Salt Crystalline Form A optionally further includes diffraction peaks at one or more of the following positions where 2θ is 11.6±0.2°, 12.9±0.2°, 13.7±0.2°, 20.4±0.2°, and 20.9±0.2°, preferably including any 2-3 or 4-5 of these positions, more preferably including any 2, 3, 4, or 5 of these positions.

[0025] In some embodiments of the present invention, the X-ray powder diffraction pattern of the Sulfate Salt crystalline Form A comprises diffraction peaks at one or more of the following positions in degrees 2θ: 6.5±0.2°, 9.7±0.2°, 11.6±0.2°, 12.9±0.2°, 13.7±0.2°, 14.3±0.2°, 16.1±0.2°, 18.6±0.2°, 19.3±0.2°, 19.7±0.2°, 20.4±0.2°, 20.9±0.2°, 22.0±0.2°, 22.5±0.2°, 23.6±0.2°, 25.5±0.2°, 25.9±0.2°, 29.2±0.2°, and optionally any 4, 5, 6, 8, or 10 positions therein.

[0026] In some embodiments of the present invention, the Sulfate Salt Crystalline Form A has characteristic X-ray diffraction peaks, expressed as 2θ angles and d-spacings, as shown in the following table using Cu-Kα radiation.

[0027] [Table 2]

[0028] In some embodiments of the present invention, the X-ray powder diffraction pattern of the Sulfate Salt Crystalline Form A is substantially as shown in FIG.

[0029] In some embodiments of the present invention, the DSC pattern of the Sulfate Salt crystalline form A is substantially as shown in FIG.

[0030] In some embodiments of the present invention, the X-ray powder diffraction pattern of the methanesulfonate salt crystalline form A has a diffraction peak at 5.2±0.2 degrees 2θ, or at 7.5±0.2 degrees 2θ, or at 7.9±0.2 degrees 2θ, or at 8.6±0.2 degrees 2θ, or at 12.3±0.2 degrees 2θ, or at 15.8±0.2 degrees 2θ, or at 17.1±0.2 degrees 2θ, or at 17.6±0.2 degrees 2θ, or at 19.8±0.2 degrees 2θ, or at 20.1±0.2 degrees 2θ, or at 21.8±0.2 degrees 2θ. or has a diffraction peak at 22.6±0.2°, or has a diffraction peak at 25.9±0.2°, or has a diffraction peak at 26.6±0.2°, or has a diffraction peak at 27.4±0.2°, and preferably includes any 2 to 5, or 3 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8, or 7 to 9, or 8 to 10, or 9 to 10, or 10 to 12, or 11 to 13, or 12 to 14, or 14 to 15 of the above diffraction peaks, and more preferably includes any 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 of them.

[0031] In some embodiments of the present invention, the X-ray powder diffraction pattern of the methanesulfonate salt crystalline Form A comprises at least one or more of the following diffraction peaks with 2θ angles of 5.2±0.2°, 7.5±0.2°, 15.8±0.2°, 20.1±0.2°, and 22.6±0.2°, preferably two of them, more preferably three of them, and optionally further comprises at least one of the following peaks with 2θ angles of 7.9±0.2°, 8.6±0.2°, 12.3±0.2°, 17.1±0.2°, 17.6±0.2°, 19.8±0.2°, 25.9±0.2°, 26.6±0.2°, and 27.4±0.2°, preferably two or three of them.

[0032] In some embodiments of the present invention, the X-ray powder diffraction pattern of the methanesulfonate salt crystalline Form A optionally further includes diffraction peaks at one or more of the following positions where 2θ is 4.6±0.2°, 9.1±0.2°, 10.8±0.2°, 14.6±0.2°, 15.1±0.2°, 16.7±0.2°, 20.6±0.2°, 24.4±0.2°, or 28.2±0.2°, preferably including any 2 to 3, or 4 to 5, and more preferably including any 2, 3, 4, or 5, of these positions.

[0033] In some embodiments of the present invention, the X-ray powder diffraction pattern of the methanesulfonate salt crystalline Form A comprises diffraction peaks at one or more of the following positions in degrees 2θ: 5.2±0.2°, 7.5±0.2°, 7.9±0.2°, 8.6±0.2°, 10.8±0.2°, 12.3±0.2°, 15.8±0.2°, 17.1±0.2°, 17.6±0.2°, 19.8±0.2°, 20.1±0.2°, 20.6±0.2°, 22.6±0.2°, 24.4±0.2°, 25.9±0.2°, 26.6±0.2°, 27.4±0.2°, 28.2±0.2°, and optionally any 4, 5, 6, 8, or 10 positions therein.

[0034] In some embodiments of the present invention, the methanesulfonate salt crystalline form A has characteristic X-ray diffraction peaks, expressed as 2θ angles and d-spacings, as shown in the following table using Cu-Kα radiation.

[0035] [Table 3]

[0036] In some embodiments of the present invention, the X-ray powder diffraction pattern of the methanesulfonate salt crystalline form A is substantially as shown in FIG.

[0037] In some embodiments of the present invention, the DSC pattern of the methanesulfonate salt crystalline form A is substantially as shown in FIG.

[0038] In some embodiments of the present invention, the X-ray powder diffraction pattern of the p-toluenesulfonate salt crystalline form A has a diffraction peak at 2θ of 5.3±0.2°, or a diffraction peak at 13.8±0.2°, or a diffraction peak at 15.7±0.2°, or a diffraction peak at 15.9±0.2°, or a diffraction peak at 18.2±0.2°, or a diffraction peak at 19.7±0.2°, or a diffraction peak at 23.2±0.2°, or a diffraction peak at 24.1±0.2°, preferably including any 2 to 5, or 3 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8 of the above diffraction peaks, more preferably including any 6, 7, or 8 of the above diffraction peaks.

[0039] In some embodiments of the present invention, the X-ray powder diffraction pattern of the p-toluenesulfonate salt crystalline form A comprises at least one or more diffraction peaks at 2θ of 5.3±0.2°, 15.9±0.2°, and 18.2±0.2°, preferably two of these, more preferably three of these, and optionally further comprises at least one of 13.8±0.2°, 15.7±0.2°, 19.7±0.2°, 23.2±0.2°, and 24.1±0.2°, preferably two or three of these.

[0040] In some embodiments of the present invention, the X-ray powder diffraction pattern of the p-toluenesulfonate salt crystalline form A optionally further includes diffraction peaks at one or more of the positions where 2θ is 11.3±0.2°, 19.1±0.2°, 21.6±0.2°, 25.3±0.2°, or 26.1±0.2°, preferably including any 2 to 3, or 4 to 5 of these positions, more preferably including any 2, 3, 4, or 5 of these positions.

[0041] In some embodiments of the present invention, the X-ray powder diffraction pattern of the p-toluenesulfonate salt crystalline Form A comprises diffraction peaks at one or more of the following positions in degrees 2θ: 5.3±0.2°, 11.3±0.2°, 13.8±0.2°, 15.7±0.2°, 15.9±0.2°, 18.2±0.2°, 19.1±0.2°, 19.7±0.2°, 21.6±0.2°, 23.2±0.2°, 25.3±0.2°, 26.1±0.2°, and optionally any 4, 5, 6, 8, or 10 positions therein.

[0042] In some embodiments of the present invention, the p-toluenesulfonate crystalline form A has characteristic X-ray diffraction peaks, expressed as 2θ angles and d-spacings, as shown in the following table using Cu-Kα radiation.

[0043] [Table 4]

[0044] In some embodiments of the present invention, the X-ray powder diffraction pattern of the p-toluenesulfonate salt crystalline form A is substantially as shown in FIG.

[0045] In some embodiments of the present invention, the p-toluenesulfonate salt crystalline form A has a DSC pattern substantially as shown in FIG.

[0046] In some embodiments of the present invention, the X-ray powder diffraction pattern of the p-toluenesulfonate salt crystalline form B has a diffraction peak at 2θ of 4.7±0.2°, or a diffraction peak at 5.2±0.2°, or a diffraction peak at 13.8±0.2°, or a diffraction peak at 14.3±0.2°, or a diffraction peak at 18.1±0.2°, or a diffraction peak at 18.7±0.2°, or a diffraction peak at 23.1±0.2°, or a diffraction peak at 25.3±0.2°, preferably including any 2 to 5, or 3 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8 of the above diffraction peaks, more preferably including any 6, 7, or 8 of the above diffraction peaks.

[0047] In some embodiments of the present invention, the X-ray powder diffraction pattern of the p-toluenesulfonate salt crystalline form B comprises at least one or more of the following diffraction peaks at 2θ: 4.7±0.2°, 14.3±0.2°, 23.1±0.2°, and 25.3±0.2°; preferably two of them, more preferably three of them; and optionally, at least one of the following peaks at 2θ: 5.2±0.2°, 13.8±0.2°, 18.1±0.2°, and 18.7±0.2°; preferably two or three of them.

[0048] In some embodiments of the present invention, the X-ray powder diffraction pattern of the p-toluenesulfonate salt crystalline form B optionally further includes diffraction peaks at one or more of the following positions where 2θ is 9.2±0.2°, 16.4±0.2°, 21.7±0.2°, 23.5±0.2°, 25.7±0.2°, or 28.1±0.2°, preferably including any 2 to 3, or 4 to 5 of these positions, more preferably including any 2, 3, 4, or 5 of these positions.

[0049] In some embodiments of the present invention, the X-ray powder diffraction pattern of the p-toluenesulfonate salt crystalline form B comprises diffraction peaks at one or more of the following positions in degrees 2θ: 4.7±0.2°, 5.2±0.2°, 9.2±0.2°, 13.8±0.2°, 14.3±0.2°, 16.4±0.2°, 18.1±0.2°, 18.7±0.2°, 21.7±0.2°, 23.1±0.2°, 23.5±0.2°, 25.3±0.2°, 25.7±0.2°, 28.1±0.2°, and optionally at any 4, 5, 6, 8, or 10 positions therein.

[0050] In some embodiments of the present invention, the p-toluenesulfonate crystalline form B has characteristic X-ray diffraction peaks, expressed as 2θ angles and d-spacings, as shown in the following table using Cu-Kα radiation.

[0051] [Table 5]

[0052] In some embodiments of the present invention, the X-ray powder diffraction pattern of the p-toluenesulfonate salt crystalline form B is substantially as shown in FIG.

[0053] In some embodiments of the present invention, the p-toluenesulfonate salt crystalline form B has a DSC pattern substantially as shown in FIG.

[0054] In some embodiments of the present invention, the X-ray powder diffraction pattern of the p-toluenesulfonate salt crystalline form C has a diffraction peak at 2θ of 4.6±0.2°, or 13.6±0.2°, or 14.3±0.2°, or 18.6±0.2°, or 19.4±0.2°, or 23.1±0.2°, or 25.2±0.2°, preferably any 2 to 5, or 3 to 5, or 3 to 6, or 3 to 7, or 5 to 7, or 6 to 7 of the above diffraction peaks, more preferably any 6 or 7 of the above diffraction peaks.

[0055] In some embodiments of the present invention, the X-ray powder diffraction pattern of the p-toluenesulfonate salt crystalline Form C comprises at least one or more of the following diffraction peaks with 2θ angles of 4.6±0.2°, 14.3±0.2°, 18.6±0.2°, and 25.2±0.2°, preferably two of them, more preferably three of them, and optionally further comprises at least one of the following peaks with 2θ angles of 9.1±0.2°, 13.6±0.2°, 16.3±0.2°, 19.4±0.2°, and 23.1±0.2°, preferably two or three of them.

[0056] In some embodiments of the present invention, the X-ray powder diffraction pattern of the p-toluenesulfonate salt crystalline Form C optionally further includes diffraction peaks at one or more of the following positions where 2θ is 17.7±0.2°, 21.7±0.2°, 23.5±0.2°, 25.5±0.2°, 26.7±0.2°, or 28.1±0.2°, preferably including any 2 to 3, or 4 to 5 of these positions, more preferably including any 2, 3, 4, or 5 of these positions.

[0057] In some embodiments of the present invention, the p-toluenesulfonate salt crystalline Form C has an X-ray powder diffraction pattern comprising diffraction peaks at one or more of the following positions in degrees 2θ: 4.6±0.2°, 9.1±0.2°, 13.6±0.2°, 14.3±0.2°, 16.3±0.2°, 17.7±0.2°, 18.6±0.2°, 19.4±0.2°, 21.7±0.2°, 23.1±0.2°, 23.5±0.2°, 25.2±0.2°, 25.5±0.2°, 26.7±0.2°, 28.1±0.2°, and optionally any 4, 5, 6, 8, or 10 positions therein.

[0058] In some embodiments of the present invention, the p-toluenesulfonate salt crystalline form C has characteristic X-ray diffraction peaks, expressed as 2θ angles and d-spacings, as shown in the following table using Cu-Kα radiation.

[0059] [Table 6]

[0060] In some embodiments of the present invention, the X-ray powder diffraction pattern of the p-toluenesulfonate salt crystalline form C is substantially as shown in FIG.

[0061] In some embodiments of the present invention, the DSC pattern of the p-toluenesulfonate salt crystalline form C is substantially as shown in FIG.

[0062] In some embodiments of the present invention, the X-ray powder diffraction pattern of the p-toluenesulfonate dihydrate crystalline form A has a diffraction peak at 2θ of 3.3±0.2°, or at 6.6±0.2°, or at 9.9±0.2°, or at 13.3±0.2°, or at 13.7±0.2°, or at 14.2±0.2°, or at 16.9±0.2°, or at 23.3±0.2°, or at 24.9±0.2°, preferably including any 2 to 5, or 3 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8, or 6 to 9, or 7 to 9 of the above diffraction peaks, more preferably including any 6, 7, 8, or 9 of the above diffraction peaks.

[0063] In some embodiments of the present invention, the X-ray powder diffraction pattern of the p-toluenesulfonate dihydrate crystalline form A comprises at least one or more diffraction peaks at angles 2θ of 3.3±0.2°, 6.6±0.2°, 9.9±0.2°, and 13.3±0.2°, preferably two of these, more preferably three of these, and optionally further comprises at least one of 13.7±0.2°, 14.2±0.2°, 16.9±0.2°, 23.3±0.2°, and 24.9±0.2°, preferably two, three, or four of these, such as 3.3±0.2°, 6.6±0.2°, 3.3±0.2°, 9.9±0.2°, 9.9±0.2°, 13.3±0.2°, 6.6±0.2°, 9.9±0.2°, 3.3±0.2°, 13.3±0.2°, 6.6±0.2°, 13.3±0.2°, 3.3±0.2°, 6.6±0.2°, 9.9±0.2°, 3.3±0.2°, 6.6±0.2°, 13.3±0.2°, 3.3±0.2°、9.9±0.2°、13.3±0.2°、 6.6±0.2°、9.9±0.2°、13.3±0.2°、 3.3±0.2°、6.6±0.2°、13.7±0.2°、 3.3±0.2°、9.9±0.2°、13.7±0.2°、 9.9±0.2°、13.3±0.2°、13.7±0.2°、 6.6±0.2°、9.9±0.2°、13.7±0.2°、 3.3±0.2°、13.3±0.2°、13.7±0.2°、 6.6±0.2°、13.3±0.2°、13.7±0.2°、 3.3±0.2°、6.6±0.2°、14.2±0.2°、 3.3±0.2°、9.9±0.2°、14.2±0.2°、 9.9±0.2°、13.3±0.2°、14.2±0.2°、 6.6±0.2°、9.9±0.2°、14.2±0.2°、 3.3±0.2°、13.3±0.2°、14.2±0.2°、 6.6±0.2°、13.3±0.2°、14.2±0.2°、 3.3±0.2°、6.6±0.2°、16.9±0.2°、 3.3±0.2°、9.9±0.2°、16.9±0.2°、 9.9±0.2°、13.3±0.2°、16.9±0.2°、 6.6±0.2°、9.9±0.2°、16.9±0.2°、 3.3±0.2°、13.3±0.2°、16.9±0.2°、 6.6±0.2°、13.3±0.2°、16.9±0.2°、 3.3±0.2°、6.6±0.2°、23.3±0.2°、 3.3±0.2°、9.9±0.2°、23.3±0.2°、 9.9±0.2°、13.3±0.2°、23.3±0.2°、 6.6±0.2°、9.9±0.2°、23.3±0.2°、 3.3±0.2°、13.3±0.2°、23.3±0.2°、 6.6±0.2°、13.3±0.2°、23.3±0.2°、 3.3±0.2°、6.6±0.2°、24.9±0.2°、 3.3±0.2°、9.9±0.2°、24.9±0.2°、 9.9±0.2°、13.3±0.2°、24.9±0.2°、 6.6±0.2°、9.9±0.2°、24.9±0.2°、 3.3±0.2°、13.3±0.2°、24.9±0.2°、 6.6±0.2°、13.3±0.2°、24.9±0.2°、 3.3±0.2°、6.6±0.2°、9.9±0.2°、 3.3±0.2°、6.6±0.2°、13.3±0.2°、 3.3±0.2°、9.9±0.2°、13.3±0.2°、 6.6±0.2°、9.9±0.2°、13.3±0.2°、 3.3±0.2°、6.6±0.2°、9.9±0.2°、13.3±0.2°、 3.3±0.2°、6.6±0.2°、9.9±0.2°、13.7±0.2°、 3.3±0.2°、6.6±0.2°、13.3±0.2°、13.7±0.2°、 3.3±0.2°、9.9±0.2°、13.3±0.2°、13.7±0.2°、 6.6±0.2°、9.9±0.2°、13.3±0.2°、13.7±0.2°、 3.3±0.2°、6.6±0.2°、9.9±0.2°、14.2±0.2°、 3.3±0.2°、6.6±0.2°、13.3±0.2°、14.2±0.2°、 3.3±0.2°、9.9±0.2°、13.3±0.2°、14.2±0.2°、 6.6±0.2°、9.9±0.2°、13.3±0.2°、14.2±0.2°、 3.3±0.2°、6.6±0.2°、9.9±0.2°、16.9±0.2°、 3.3±0.2°、6.6±0.2°、13.3±0.2°、16.9±0.2°、 3.3±0.2°、9.9±0.2°、13.3±0.2°、16.9±0.2°、 6.6±0.2°、9.9±0.2°、13.3±0.2°、16.9±0.2°、 3.3±0.2°、6.6±0.2°、9.9±0.2°、23.3±0.2°、 3.3±0.2°、6.6±0.2°、13.3±0.2°、23.3±0.2°、 3.3±0.2°、9.9±0.2°、13.3±0.2°、23.3±0.2°、 6.6±0.2°、9.9±0.2°、13.3±0.2°、23.3±0.2°、 3.3±0.2°、6.6±0.2°、9.9±0.2°、24.9±0.2°、 3.3±0.2°、6.6±0.2°、13.3±0.2°、24.9±0.2°、 3.3±0.2°、9.9±0.2°、13.3±0.2°、24.9±0.2°、 6.6±0.2°、9.9±0.2°、13.3±0.2°、24.9±0.2°、 3.3±0.2°、6.6±0.2°、9.9±0.2°、13.3±0.2°、13.7±0.2°、 3.3±0.2°、6.6±0.2°、9.9±0.2°、13.3±0.2°、14.2±0.2°、 3.3±0.2°、6.6±0.2°、9.9±0.2°、13.3±0.2°、16.9±0.2°、 3.3±0.2°、6.6±0.2°、9.9±0.2°、13.3±0.2°、23.3±0.2°、 3.3±0.2°、6.6±0.2°、9.9±0.2°、13.3±0.2°、24.9±0.2°、 3.3±0.2°、6.6±0.2°、9.9±0.2°、13.7±0.2°、14.2±0.2°、 3.3±0.2°、6.6±0.2°、13.3±0.2°、13.7±0.2°、24.9±0.2°、 3.3±0.2°、9.9±0.2°、13.3±0.2°、16.9±0.2°、23.3±0.2°、 6.6±0.2°、9.9±0.2°、13.3±0.2°、14.2±0.2°、23.3±0.2°、 3.3±0.2°、6.6±0.2°、9.9±0.2°、13.3±0.2°、13.7±0.2°、14.2±0.2°、 3.3±0.2°、6.6±0.2°、9.9±0.2°、13.3±0.2°、23.3±0.2°、24.9±0.2°、 3.3±0.2°、6.6±0.2°、9.9±0.2°、13.3±0.2°、13.7±0.2°、24.9±0.2°、 3.3±0.2°、6.6±0.2°、9.9±0.2°、13.3±0.2°、14.2±0.2°、16.9±0.2°、 3.3±0.2°、6.6±0.2°、9.9±0.2°、13.3±0.2°、14.2±0.2°、23.3±0.2°、 3.3±0.2°、6.6±0.2°、9.9±0.2°、13.3±0.2°、16.9±0.2°、24.9±0.2°、 3.3±0.2°、6.6±0.2°、9.9±0.2°、13.7±0.2°、14.2±0.2°、16.9±0.2°、 3.3±0.2°、6.6±0.2°、13.3±0.2°、16.9±0.2°、23.3±0.2°、24.9±0.2°、 3.3±0.2°、9.9±0.2°、13.3±0.2°、13.7±0.2°、23.3±0.2°、24.9±0.2°、 6.6±0.2°、9.9±0.2°、13.3±0.2°、14.2±0.2°、16.9±0.2°、23.3±0.2°、 3.3±0.2°、6.6±0.2°、9.9±0.2°、13.3±0.2°、14.2±0.2°、16.9±0.2°、23.3±0.2°、24.9±0.2°、 3.3±0.2°、6.6±0.2°、9.9±0.2°、13.3±0.2°、13.7±0.2°、16.9±0.2°、23.3±0.2°、24.9±0.2°、 3.3±0.2°, 6.6±0.2°, 9.9±0.2°, 13.3±0.2°, 13.7±0.2°, 14.2±0.2°, 23.3±0.2°, 24.9±0.2°, 3.3±0.2°, 6.6±0.2°, 9.9±0.2°, 13.3±0.2°, 13.7±0.2°, 14.2±0.2°, 16.9±0.2°, 24.9±0.2°, 3.3±0.2°, 6.6±0.2°, 9.9±0.2°, 13.3±0.2°, 13.7±0.2°, 14.2±0.2°, 16.9±0.2°, 23.3±0.2°, 3.3±0.2°, 6.6±0.2°, 9.9±0.2°, 13.7±0.2°, 14.2±0.2°, 16.9±0.2°, 23.3±0.2°, 24.9±0.2°, 3.3±0.2°, 6.6±0.2°, 13.3±0.2°, 13.7±0.2°, 14.2±0.2°, 16.9±0.2°, 23.3±0.2°, 24.9±0.2°, 3.3±0.2°, 9.9±0.2°, 13.3±0.2°, 13.7±0.2°, 14.2±0.2°, 16.9±0.2°, 23.3±0.2°, 24.9±0.2°, 6.6±0.2°, 9.9±0.2°, 13.3±0.2°, 13.7±0.2°, 14.2±0.2°, 16.9±0.2°, 23.3±0.2°, and 24.9±0.2°.

[0064] In some embodiments of the present invention, the X-ray powder diffraction pattern of the p-toluenesulfonate dihydrate crystalline Form A optionally further comprises diffraction peaks at one or more of the following positions where 2θ is 11.4±0.2°, 14.4±0.2°, 19.2±0.2°, 20.0±0.2°, 22.7±0.2°, 22.9±0.2°, or 26.9±0.2°, preferably at least any 2 to 3 or 4 to 5 of these positions, more preferably any 2, 3, 4, or 5 of these positions, for example: 11.4±0.2°, 14.4±0.2°, 11.4±0.2°, 26.9±0.2°, 19.2±0.2°、20.0±0.2°、 14.4±0.2°、19.2±0.2°、 14.4±0.2°、22.7±0.2°、 22.9±0.2°、26.9±0.2°、 11.4±0.2°、14.4±0.2°、19.2±0.2°、 22.7±0.2°、22.9±0.2°、26.9±0.2°、 19.2±0.2°、20.0±0.2°、22.7±0.2°、 14.4±0.2°、19.2±0.2°、20.0±0.2°、 20.0±0.2°、22.7±0.2°、22.9±0.2°、 22.7±0.2°、22.9±0.2°、26.9±0.2°、 14.4±0.2°、20.0±0.2°、22.7±0.2°、 11.4±0.2°、14.4±0.2°、19.2±0.2°、20.0±0.2°、 20.0±0.2°、22.7±0.2°、22.9±0.2°、26.9±0.2°、 11.4±0.2°、22.7±0.2°、22.9±0.2°、26.9±0.2°、 11.4±0.2°、14.4±0.2°、22.9±0.2°、26.9±0.2°、 11.4±0.2°、14.4±0.2°、19.2±0.2°、26.9±0.2°、 14.4±0.2°、19.2±0.2°、20.0±0.2°、22.7±0.2°、 19.2±0.2°、20.0±0.2°、22.7±0.2°、22.9±0.2°、 20.0±0.2°、22.7±0.2°、22.9±0.2°、26.9±0.2°、 11.4±0.2°、14.4±0.2°、19.2±0.2°、20.0±0.2°、22.7±0.2°、 11.4±0.2°、14.4±0.2°、19.2±0.2°、20.0±0.2°、26.9±0.2°、 11.4±0.2°, 14.4±0.2°, 19.2±0.2°, 22.9±0.2°, 26.9±0.2°, 11.4±0.2°, 14.4±0.2°, 22.7±0.2°, 22.9±0.2°, 26.9±0.2°, 11.4±0.2°, 20.0±0.2°, 22.7±0.2°, 22.9±0.2°, 26.9±0.2°, 19.2±0.2°, 20.0±0.2°, 22.7±0.2°, 22.9±0.2°, 26.9±0.2°, 14.4±0.2°, 19.2±0.2°, 20.0±0.2°, 22.7±0.2°, 22.9±0.2°, 11.4±0.2°, 19.2±0.2°, 20.0±0.2°, 22.7±0.2°, 26.9±0.2°, 11.4±0.2°, 19.2±0.2°, 20.0±0.2°, 22.7±0.2°, 22.9±0.2°, 11.4±0.2°, 14.4±0.2°, 20.0±0.2°, 22.7±0.2°, 26.9±0.2°, 14.4±0.2°, 19.2±0.2°, 22.7±0.2°, 22.9±0.2°, 26.9±0.2°, 14.4±0.2°, 19.2±0.2°, 20.0±0.2°, 22.7±0.2°, and 26.9±0.2°.

[0065] In some embodiments of the present invention, the X-ray powder diffraction pattern of the p-toluenesulfonate dihydrate crystalline form A has the following refractive indices 2θ: 3.3±0.2°, 6.6±0.2°, 9.9±0.2°, 11.4±0.2°, 13.3±0.2°, 13.7±0.2°, 14.2±0.2°, 14.4±0.2°, 16.9±0.2°, 19.2±0.2°, 20.0±0.2°, 22.7±0.2°, 22.9±0.2° and optionally at any of 4, 5, 6, 8, or 10 positions within the X-ray powder diffraction pattern of the p-toluenesulfonate dihydrate crystalline Form A, including diffraction peaks at angles 2θ of 23.3±0.2°, 23.3±0.2°, 24.9±0.2°, 26.9±0.2°, and optionally at any of 4, 5, 6, 8, or 10 positions within the X-ray powder diffraction pattern of the p-toluenesulfonate dihydrate crystalline Form A, including diffraction peaks at angles 2θ of 23.3±0.2°, 24.9±0.2°, 26.9±0.2°, 26.9±0.2°, and optionally at any of 4, 5, 6, 8, or 10 positions within the X-ray powder diffraction pattern of the p-toluenesulfonate dihydrate crystalline Form A, for example, the X-ray powder diffraction pattern of the p-toluenesulfonate dihydrate crystalline Form A has diffraction peaks at angles 2θ of

[0066] 3.3±0.2°, 6.6±0.2°, 9.9±0.2°, 11.4±0.2°, 3.3±0.2°, 6.6±0.2°, 13.3±0.2°, 14.4±0.2°, 3.3±0.2°, 9.9±0.2°, 13.3±0.2°, 19.2±0.2°, 6.6±0.2°, 9.9±0.2°, 13.3±0.2°, 20.0±0.2°, 3.3±0.2°, 6.6±0.2°, 13.7±0.2°, 22.7±0.2°, 3.3±0.2°, 9.9±0.2°, 13.7±0.2°, 22.9±0.2°, 9.9±0.2°, 13.3±0.2°, 13.7±0.2°, 26.9±0.2°, 6.6±0.2°, 9.9±0.2°, 11.4±0.2°, 13.7±0.2°, 3.3±0.2°, 13.3±0.2°, 13.7±0.2°, 14.4±0.2°, 6.6±0.2°, 13.3±0.2°, 13.7±0.2°, 19.2±0.2°, 3.3±0.2°, 6.6±0.2°, 14.2±0.2°, 20.0±0.2°, 3.3±0.2°, 9.9±0.2°, 14.2±0.2°, 22.7±0.2°, 9.9±0.2°、13.3±0.2°、14.2±0.2°、22.9±0.2°、 6.6±0.2°、9.9±0.2°、14.2±0.2°、26.9±0.2°、 3.3±0.2°、11.4±0.2°、13.3±0.2°、14.2±0.2°、 6.6±0.2°、13.3±0.2°、14.2±0.2°、14.4±0.2°、 3.3±0.2°、6.6±0.2°、16.9±0.2°、19.2±0.2°、 3.3±0.2°、9.9±0.2°、16.9±0.2°、20.0±0.2°、 9.9±0.2°、13.3±0.2°、16.9±0.2°、22.7±0.2°、 6.6±0.2°、9.9±0.2°、16.9±0.2°、22.9±0.2°、 3.3±0.2°、13.3±0.2°、16.9±0.2°、26.9±0.2°、 3.3±0.2°、6.6±0.2°、9.9±0.2°、11.4±0.2°、13.3±0.2°、 3.3±0.2°、6.6±0.2°、9.9±0.2°、13.7±0.2°、14.4±0.2°、 3.3±0.2°、6.6±0.2°、13.3±0.2°、13.7±0.2°、19.2±0.2°、 3.3±0.2°、9.9±0.2°、13.3±0.2°、13.7±0.2°、20.0±0.2°、 6.6±0.2°、9.9±0.2°、13.3±0.2°、13.7±0.2°、22.7±0.2°、 3.3±0.2°、6.6±0.2°、9.9±0.2°、14.2±0.2°、22.9±0.2°、 3.3±0.2°、6.6±0.2°、13.3±0.2°、14.2±0.2°、26.9±0.2°、 3.3±0.2°、9.9±0.2°、11.4±0.2°、13.3±0.2°、14.2±0.2°、 6.6±0.2°、9.9±0.2°、13.3±0.2°、14.2±0.2°、14.4±0.2°、 3.3±0.2°、6.6±0.2°、9.9±0.2°、16.9±0.2°、19.2±0.2°、 3.3±0.2°、6.6±0.2°、13.3±0.2°、16.9±0.2°、20.0±0.2°、 3.3±0.2°、9.9±0.2°、13.3±0.2°、16.9±0.2°、22.7±0.2°、 6.6±0.2°、9.9±0.2°、13.3±0.2°、16.9±0.2°、22.9±0.2°、 3.3±0.2°、6.6±0.2°、9.9±0.2°、23.3±0.2°、26.9±0.2°、 3.3±0.2°、6.6±0.2°、11.4±0.2°、13.3±0.2°、23.3±0.2°、 3.3±0.2°、9.9±0.2°、13.3±0.2°、14.4±0.2°、23.3±0.2°、 6.6±0.2°、9.9±0.2°、13.3±0.2°、19.2±0.2°、23.3±0.2°、 3.3±0.2°、6.6±0.2°、9.9±0.2°、20.0±0.2°、24.9±0.2°、 3.3±0.2°、6.6±0.2°、13.3±0.2°、22.7±0.2°、24.9±0.2°、 3.3±0.2°、9.9±0.2°、13.3±0.2°、22.9±0.2°、24.9±0.2°、 6.6±0.2°、9.9±0.2°、13.3±0.2°、26.9±0.2°、24.9±0.2°、 3.3±0.2°、6.6±0.2°、9.9±0.2°、11.4±0.2°、13.3±0.2°、13.7±0.2°、 3.3±0.2°、6.6±0.2°、9.9±0.2°、13.3±0.2°、14.2±0.2°、14.4±0.2°、 3.3±0.2°、6.6±0.2°、9.9±0.2°、13.3±0.2°、16.9±0.2°、19.2±0.2°、 3.3±0.2°、6.6±0.2°、9.9±0.2°、13.3±0.2°、20.0±0.2°、23.3±0.2°、 3.3±0.2°、6.6±0.2°、9.9±0.2°、13.3±0.2°、22.7±0.2°、24.9±0.2°、 3.3±0.2°、6.6±0.2°、9.9±0.2°、13.7±0.2°、14.2±0.2°、22.9±0.2°、 3.3±0.2°、6.6±0.2°、13.3±0.2°、13.7±0.2°、24.9±0.2°、26.9±0.2°、 3.3±0.2°、9.9±0.2°、13.3±0.2°、14.4±0.2°、16.9±0.2°、23.3±0.2°、 6.6±0.2°、9.9±0.2°、13.3±0.2°、14.2±0.2°、19.2±0.2°、23.3±0.2°、 3.3±0.2°、6.6±0.2°、9.9±0.2°、11.4±0.2°、13.3±0.2°、13.7±0.2°、14.2±0.2°、14.4±0.2°、 3.3±0.2°、6.6±0.2°、9.9±0.2°、13.3±0.2°、14.4±0.2°、19.2±0.2°、23.3±0.2°、24.9±0.2°、 3.3±0.2°、6.6±0.2°、9.9±0.2°、13.3±0.2°、13.7±0.2°、19.2±0.2°、20.0±0.2°、24.9±0.2°、 3.3±0.2°、6.6±0.2°、9.9±0.2°、13.3±0.2°、14.2±0.2°、16.9±0.2°、20.0±0.2°、22.7±0.2°、 3.3±0.2°、6.6±0.2°、9.9±0.2°、13.3±0.2°、14.2±0.2°、22.7±0.2°、22.9±0.2°、23.3±0.2°、 3.3±0.2°、6.6±0.2°、9.9±0.2°、13.3±0.2°、16.9±0.2°、22.9±0.2°、24.9±0.2°、26.9±0.2°、 3.3±0.2°、6.6±0.2°、9.9±0.2°、11.4±0.2°、13.7±0.2°、14.2±0.2°、16.9±0.2°、19.2±0.2°、 3.3±0.2°、6.6±0.2°、13.3±0.2°、14.4±0.2°、16.9±0.2°、20.0±0.2°、23.3±0.2°、24.9±0.2°、 3.3±0.2°、9.9±0.2°、13.3±0.2°、13.7±0.2°、19.2±0.2°、22.7±0.2°、23.3±0.2°、24.9±0.2°、 6.6±0.2°、9.9±0.2°、13.3±0.2°、14.2±0.2°、16.9±0.2°、20.0±0.2°、22.9±0.2°、23.3±0.2°、 3.3±0.2°、6.6±0.2°、9.9±0.2°、11.4±0.2°、13.3±0.2°、14.2±0.2°、14.4±0.2°、16.9±0.2°、23.3±0.2°、24.9±0.2°、 3.3±0.2°、6.6±0.2°、9.9±0.2°、13.3±0.2°、13.7±0.2°、14.4±0.2°、16.9±0.2°、19.2±0.2°、23.3±0.2°、24.9±0.2°、 3.3±0.2°、6.6±0.2°、9.9±0.2°、13.3±0.2°、13.7±0.2°、14.2±0.2°、19.2±0.2°、20.0±0.2°、23.3±0.2°、24.9±0.2°、 3.3±0.2°、6.6±0.2°、9.9±0.2°、13.3±0.2°、13.7±0.2°、14.2±0.2°、16.9±0.2°、20.0±0.2°、22.7±0.2°、24.9±0.2°、 3.3±0.2°、6.6±0.2°、9.9±0.2°、13.3±0.2°、13.7±0.2°、14.2±0.2°、16.9±0.2°、22.7±0.2°、22.9±0.2°、23.3±0.2°、 3.3±0.2°, 6.6±0.2°, 9.9±0.2°, 13.7±0.2°, 14.2±0.2°, 16.9±0.2°, 22.9±0.2°, 23.3±0.2°, 24.9±0.2°, 26.9±0.2°, 3.3±0.2°, 6.6±0.2°, 13.3±0.2°, 13.7±0.2°, 14.2±0.2°, 14.4±0.2°, 16.9±0.2°, 20.0±0.2°, 23.3±0.2°, 24.9±0.2°, 3.3±0.2°, 9.9±0.2°, 13.3±0.2°, 13.7±0.2°, 14.2±0.2°, 16.9±0.2°, 19.2±0.2°, 22.7±0.2°, 23.3±0.2°, 24.9±0.2°, 6.6±0.2°, 9.9±0.2°, 13.3±0.2°, 13.7±0.2°, 14.2±0.2°, 16.9±0.2°, 20.0±0.2°, 23.3±0.2°, 24.9±0.2°, 26.9±0.2°.

[0067] In some embodiments of the present invention, the p-toluenesulfonate dihydrate crystalline form A has characteristic X-ray diffraction peaks, expressed as 2θ angles and d-spacings, as shown in the following table using Cu-Kα radiation.

[0068] [Table 7-1] [Table 7-2]

[0069] In some embodiments of the present invention, the X-ray powder diffraction pattern of the p-toluenesulfonate dihydrate crystalline form A is substantially as shown in FIG.

[0070] In some embodiments of the present invention, the p-toluenesulfonate dihydrate crystalline form A has a DSC pattern substantially as shown in FIG.

[0071] In some embodiments of the present invention, the TGA pattern of the p-toluenesulfonate dihydrate crystalline form A is substantially as shown in FIG.

[0072] In some embodiments of the present invention, the X-ray powder diffraction pattern of the benzenesulfonate salt crystalline form A has a diffraction peak at 2θ of 5.3±0.2°, or a diffraction peak at 9.1±0.2°, or a diffraction peak at 13.9±0.2°, or a diffraction peak at 15.7±0.2°, or a diffraction peak at 18.9±0.2°, or a diffraction peak at 23.3±0.2°, or a diffraction peak at 23.9±0.2°, or a diffraction peak at 26.1±0.2°, preferably including any 2 to 5, or 3 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8 of the above diffraction peaks, more preferably including any 6, 7, or 8 of the above diffraction peaks.

[0073] In some embodiments of the present invention, the X-ray powder diffraction pattern of the benzenesulfonate salt crystalline form A comprises at least one or more of the following diffraction peaks with 2θ of 5.3±0.2°, 9.1±0.2°, 13.9±0.2°, 15.7±0.2°, and 26.1±0.2°, preferably two of them, more preferably three of them, and optionally further comprises at least one of the following peaks with 2θ of 18.9±0.2°, 23.3±0.2°, and 23.9±0.2°, preferably two or three of them.

[0074] In some embodiments of the present invention, the X-ray powder diffraction pattern of the benzenesulfonate salt crystalline form A optionally further includes diffraction peaks at one or more of the following positions where 2θ is 10.5±0.2°, 11.3±0.2°, 18.2±0.2°, 22.8±0.2°, 25.0±0.2°, 28.2±0.2°, or 32.2±0.2°, preferably including any 2 to 3, or 4 to 5 of these positions, more preferably including any 2, 3, 4, or 5 of these positions.

[0075] In some embodiments of the present invention, the X-ray powder diffraction pattern of the benzenesulfonate salt crystalline Form A comprises diffraction peaks at one or more of the following positions in degrees 2θ: 5.3±0.2°, 9.1±0.2°, 10.5±0.2°, 11.3±0.2°, 13.9±0.2°, 15.7±0.2°, 18.2±0.2°, 18.9±0.2°, 22.8±0.2°, 23.3±0.2°, 23.9±0.2°, 25.0±0.2°, 26.1±0.2°, 28.2±0.2°, 32.2±0.2°, and optionally at any 4, 5, 6, 8, or 10 positions therein.

[0076] In some embodiments of the present invention, the benzenesulfonate salt crystalline form A has characteristic X-ray diffraction peaks, expressed as 2θ angles and d-spacings, as shown in the following table using Cu-Kα radiation.

[0077] [Table 8]

[0078] In some embodiments of the present invention, the X-ray powder diffraction pattern of the benzenesulfonate salt crystalline form A is substantially as shown in FIG.

[0079] In some embodiments of the present invention, the DSC pattern of the benzenesulfonate salt crystalline form A is substantially as shown in FIG.

[0080] In some embodiments of the present invention, the hydrochloride crystalline form A, sulfate crystalline form A, methanesulfonate crystalline form A, p-toluenesulfonate crystalline form A, p-toluenesulfonate crystalline form B, p-toluenesulfonate crystalline form C, p-toluenesulfonate dihydrate crystalline form A, and benzenesulfonate crystalline form A have a 2θ error between the positions of the top 10 diffraction peaks in terms of relative peak intensity in an X-ray powder diffraction pattern and the corresponding diffraction peaks in an X-ray powder diffraction pattern of ±0.2° to ±0.5°, preferably ±0.2° to ±0.3°, and most preferably ±0.2°.

[0081] The present invention further provides a method for preparing an acid salt of the compound described above or a stereoisomer thereof, which comprises: 1) Weighing an appropriate amount of free base and dissolving it in a good solvent; 2) Weighing an appropriate amount of counter ion acid and dissolving it in an organic solvent, the amount of the counter ion acid is preferably 1.2 equivalents; 3) combining the two solutions and stirring to cause precipitation, or adding a poor solvent dropwise and then stirring to cause precipitation; 4) rapidly centrifuging or allowing to stand and blow dry to obtain the acid salt; where: 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, isopropanol, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, tert-butanol, 2-butanone, 3-pentanone, and N-methylpyrrolidone, and preferably one or more of N-methylpyrrolidone, methanol, dichloromethane, and absolute 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, and N,N-dimethylformamide, and is preferably methanol, ethanol, or acetonitrile. The good solvent and the organic solution must be compatible with each other when used. the anti-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; The counter ion acid may be 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, caproic acid, caprylic 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, or the like. The acid salt is selected from 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 a fumarate, p-toluenesulfonate or succinate salt, most preferably a p-toluenesulfonate salt.

[0082] The present invention further provides a method for preparing the crystalline form of the acid salt of the compound or its stereoisomer described above, characterized in that it is Method 1, Method 2 or Method 3, Method 1 is, 1) suspending the compound in an antisolvent; 2) adding a counter ion acid, the amount of which is preferably 1.2 equivalents, said counter ion acid being soluble in an organic solvent; 3) stirring to dissolve the solution, and continuing to stir to precipitate, or adding a poor solvent dropwise and then stirring to precipitate the solution; 4) isolating to obtain the anhydrous crystalline form; Method 2 is subjecting the anhydrous crystalline form of Method 1 to a crystalline transformation; Method 3 is suspending the anhydrous crystalline form of Method 1 in water and separating to obtain a hydrate crystalline form; where: The anti-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 acetone, ethanol, tetrahydrofuran, acetonitrile or toluene.

[0083] 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 counter ion acid may be 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, caproic acid, caprylic 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, or the like. The acid salt is selected from 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 a fumarate, p-toluenesulfonate or succinate salt, most preferably a p-toluenesulfonate salt.

[0084] In some embodiments of the present invention, the compound is suspended in ethanol, then suspended in a methanolic solution of hydrochloric acid, and separated to obtain crystalline Form A of the hydrochloride salt of the compound.

[0085] In some embodiments of the present invention, the compound is suspended in ethanol, then suspended in a methanolic solution of sulfuric acid, and separated to obtain crystalline Form A of the sulfate salt of the compound.

[0086] In some embodiments of the present invention, the compound is suspended in ethanol, then suspended in a solution of methanesulfonic acid in methanol, and separated to obtain crystalline Form A of the methanesulfonate salt of the compound.

[0087] In some embodiments of the present invention, the compound is suspended in ethanol, then suspended in a methanolic solution of p-toluenesulfonic acid, and separated to obtain p-toluenesulfonic acid crystalline Form A of the compound.

[0088] In some embodiments of the present invention, the p-toluenesulfonic acid crystalline form A of the compound is subjected to crystal transformation in tetrahydrofuran or 2-methyltetrahydrofuran to obtain the p-toluenesulfonic acid crystalline form B of the compound.

[0089] In some embodiments of the present invention, the p-toluenesulfonic acid crystalline form A of the compound is subjected to crystal transformation in 1,4-dioxane to obtain the p-toluenesulfonic acid crystalline form C of the compound.

[0090] In some embodiments of the present invention, the p-toluenesulfonic acid crystalline Form A of the Compound is suspended in water and separated to obtain the p-toluenesulfonic acid salt dihydrate crystalline Form A of the Compound.

[0091] In some embodiments of the present invention, the compound is suspended in ethanol, then suspended in a methanolic solution of benzenesulfonic acid, and separated to obtain crystalline Form A of the benzenesulfonate salt of the compound.

[0092] The present invention further provides pharmaceutical compositions, which contain a therapeutically effective amount of an acid salt of a compound described above or a stereoisomer thereof and / or a crystalline form of a compound described above or an acid salt of a stereoisomer thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0093] The present invention further provides the use of the acid salt of the compound or a stereoisomer thereof, a crystalline form of the compound or a stereoisomer thereof described above, or a pharmaceutical composition described above in the manufacture of a PARP inhibitor drug, wherein the PARP is preferably PARP1.

[0094] The present invention further provides an acid salt of the compound or a stereoisomer thereof, a crystalline form of the compound or a stereoisomer thereof described above, or a pharmaceutical composition described above, which is a PARP inhibitor drug, wherein the PARP is preferably PARP1.

[0095] The present invention further provides a use of an acid salt of the compound or a stereoisomer thereof as described above, a crystalline form of an acid salt of the compound or a stereoisomer thereof as described above, or a pharmaceutical composition as described above, in the manufacture of a medicament for treating cancer, an ischemic disease or a neurodegenerative disease, optionally wherein the cancer is selected from breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastric cancer, colorectal cancer, gastrointestinal cancer and lung cancer.

[0096] The present invention further provides an acid salt of the compound or a stereoisomer thereof as described above, a crystalline form of the compound or a stereoisomer thereof as described above, or a pharmaceutical composition as described above, for treating cancer, an ischemic disease or a neurodegenerative disease, optionally wherein the cancer is selected from breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastric cancer, colorectal cancer, gastrointestinal cancer and lung cancer.

[0097] The present invention further relates to a method for the treatment, prevention and / or treatment of cancer, ischemic disease or neurodegenerative disease, comprising administering to a patient a therapeutically effective amount of a compound as described above or an acid salt of a stereoisomer thereof, a crystalline form of a compound as described above or an acid salt of a stereoisomer thereof, or a pharmaceutical composition as described above, optionally wherein said cancer is selected from breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, hematological cancer, gastric cancer, colorectal cancer, gastrointestinal cancer and lung cancer. [Brief explanation of the drawings]

[0098] [Figure 1] FIG. 1 shows the inhibition of PAR by Example 1 within 24 hours after a single administration in the MDA-MB-436 model. [Figure 2] FIG. 1 shows the inhibition of PAR by Example 1 within 24 to 72 hours after a single administration in the MDA-MB-436 model. [Figure 3] 1 is an XRPD pattern of the hydrochloride salt crystalline form A. [Figure 4] 1 is a DSC pattern of the hydrochloride salt crystalline form A. [Figure 5] 1 is an XRPD pattern of crystalline form A of the sulfate salt. [Figure 6] 1 is a DSC pattern of sulfate salt crystalline form A. [Figure 7] 1 is an XRPD pattern of methanesulfonate salt crystalline form A. [Figure 8] 1 is a DSC pattern of crystalline form A of the methanesulfonate salt. [Figure 9] 1 is an XRPD pattern of p-toluenesulfonic acid salt crystalline form A. [Figure 10] 1 is a DSC pattern of p-toluenesulfonate crystalline form A. [Figure 11] 1 is an XRPD pattern of p-toluenesulfonate crystalline form B. [Figure 12] 1 is a DSC pattern of p-toluenesulfonate crystalline form B. [Figure 13] 1 is an XRPD pattern of p-toluenesulfonate crystalline form C. [Figure 14] 1 is a DSC pattern of p-toluenesulfonate crystalline form C. [Figure 15] 1 is an XRPD pattern of p-toluenesulfonate dihydrate crystalline form A. [Figure 16] 1 is a DSC pattern of p-toluenesulfonate dihydrate crystalline form A. [Figure 17] 1 is a TGA pattern of p-toluenesulfonate dihydrate crystalline form A. [Figure 18] 1 is an XRPD pattern of crystalline form A of the benzenesulfonate salt. [Figure 19] 1 is a DSC pattern of crystalline form A of the benzenesulfonate salt. [Figure 20] FIG. 1 is a single crystal structure of p-toluenesulfonate dihydrate crystalline form A (no hydrogen atoms included). DETAILED DESCRIPTION OF THE INVENTION

[0099] Unless stated to the contrary, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art, and specifically, the terms used in the specification and claims have the following meanings:

[0100] The term "alkyl group" refers to a straight or branched chain saturated aliphatic hydrocarbon group, which may be optionally substituted with one or more substituents. In specific embodiments, the alkyl group is a group having 1 to 20 carbon atoms (C 1-20 ), 1~15(C 1-15 ), 1-12(C 1-12 ), 1 to 10 (C 1-10 ), 1~8(C 1-8 ), 1~6(C 1-6 ) or 1 to 3 (C 1-3 ) carbon atoms, or a linear saturated hydrocarbon group having 3 to 20 (C 3-20 ), 3~15(C 3-15 ), 3~12(C 3-12 ), 3~10(C 3-10 ), 3~8(C 3-8 ) or 3 to 6 (C 3-6 ) carbon atoms. 1-6 Alkyl group and branched C 3-6 Alkyl groups are also called "lower alkyl groups." For example, C 1-6 An alkyl group refers to a linear saturated monovalent hydrocarbon group having 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon group having 3 to 6 carbon atoms. 1-6An alkyl group contains 1 to 6 (eg, 1, 2, 3, 4, 5, 6) carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, and 5-methylhexyl groups. , 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 chain isomers thereof. In one embodiment, the alkyl group is an optionally substituted alkyl group, as described elsewhere herein.

[0101] "Alkynyl group" refers to a straight-chain or branched-chain unsaturated aliphatic hydrocarbon group that contains at least one carbon-carbon triple bond, and the carbon-carbon triple bond may be located at any position within the alkynyl group, and the alkynyl group may be optionally substituted with one or more substituents. In specific embodiments, the alkynyl group is an alkyl group having 2 to 20 carbon atoms.2-20 ), 2~15(C 2-15 ), 2~12(C 2-12 ), 2~10(C 2-10 ), 2~8(C 2-8 ), 2~6(C 2-6 ) or 2 to 4 (C 2-4 ) carbon atoms, or a straight-chain unsaturated hydrocarbon group having 3 to 20 (C 3-20 ), 3~15(C 3-15 ), 3~12(C 3-12 ), 3~10(C 3-10 ), 3~8(C 3-8 ) or 3 to 6 (C 3-6 ) carbon atoms. Unless otherwise specified, the term "alkynyl group" as used herein includes both straight-chain and branched alkynyl groups. For example, C 2-6 The alkynyl group refers to a linear unsaturated hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated hydrocarbon group having 3 to 6 carbon atoms. 2-6 Alkynyl groups contain 2 to 6 (e.g., 2, 3, 4, 5, 6) carbon atoms. Non-limiting examples of alkynyl groups include: [ka] In one embodiment, the alkynyl group is an optionally substituted alkynyl group, as described elsewhere herein.

[0102] The term "cycloalkyl group" refers to a saturated or partially unsaturated aliphatic hydrocarbon monocyclic or polycyclic (two or more) ring group, which may be optionally substituted with one or more substituents. In specific embodiments, the ring of a cycloalkyl group may be 3 to 20 (C 3-20 ), 3~12(C 3-12 ), 3~8(C 3-8 ) or 3 to 6 (C 3-6 ) carbon atoms, and in one embodiment, the ring of the cycloalkyl group contains 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10) carbon atoms, which may contain one or more double bonds but do not have a completely conjugated π-electron system. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, or cyclooctyl groups, and the like; in one embodiment, polycyclic cycloalkyl groups include spirocycloalkyl groups, fused cycloalkyl groups, and bridged cycloalkyl groups. In one embodiment, the cycloalkyl group is an optionally substituted cycloalkyl group or a cycloalkyl group optionally fused with a heterocyclyl, aryl, or heteroaryl group, as described elsewhere herein; non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, and the like.

[0103] The term "heterocyclyl group" refers to a saturated or partially unsaturated mono- or polycyclic cyclic hydrocarbon group, in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus, or sulfur, wherein the nitrogen, phosphorus, or sulfur atoms can optionally be oxidized, the nitrogen atoms can optionally be quaternized, and ring carbon atoms are optionally replaced with oxygen, but does not include -OO-, -OS- ring moieties, and the remaining ring atoms are carbon, which may contain one or more double bonds, but do not have a completely conjugated pi-electron system. In specific embodiments, the heterocyclyl group contains 3 to 20, 3 to 12, 3 to 8, or 3 to 6 ring atoms, wherein 1 to 4 are heteroatoms; in one embodiment, the heterocyclyl group contains 3 to 6, 4 to 6, 3 to 8, 3 to 10, 6 to 10, or 7 to 11 ring atoms; in one embodiment, the heterocyclyl group contains 3 to 8 (e.g., 3, 4, 5, 6, 7, 8) ring atoms. Non-limiting examples of monocyclic heterocyclyl groups include tetrahydropyrrolyl, oxetanyl, oxanyl, imidazolidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, and the like. Polycyclic heterocyclyl groups include spiroheterocyclyl, fused heterocyclyl, and bridged heterocyclyl groups. In one embodiment, the heterocyclyl group is an optionally substituted heterocyclyl group, as described elsewhere herein, or further linked to form a fused ring with other cycloalkyl, heterocyclyl, aryl, and heteroaryl groups through any two or more atoms in the ring.

[0104] The term "alkoxy group" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), where alkyl or cycloalkyl are as defined above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, or cyclohexyloxy. In one embodiment, the alkoxy group is an optionally substituted alkoxy group, as described elsewhere herein.

[0105] The term "haloalkyl group" refers to an alkyl group substituted with one or more halogens, where alkyl is as defined above. Non-limiting examples of haloalkyl groups include trifluoromethyl, -CH2CF3, [ka] Examples include:

[0106] The term "hydrogen" refers to a proton ( 1 H), deuterium ( 2 H), tritium ( 3 H) and / or mixtures thereof. In specific embodiments, one or more hydrogen-occupied positions in the compound can be enriched with deuterium and / or tritium. Such isotopically enriched analogs can be prepared with appropriate isotopically labeled starting materials obtained from commercial sources or can be prepared by known literature procedures.

[0107] Various terms such as "X is selected from A, B, or C," "X is selected from A, B, and C," "X is A, B, or C," and "X is A, B, and C" all mean the same thing, i.e., X can be any one or more of A, B, and C.

[0108] "Optionally" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and the description includes cases where the event or circumstance has occurred or not occurred. For example, "a heterocyclyl group optionally substituted with an alkyl group" means that the alkyl group may, but need not, be present, and the description includes cases where the heterocyclyl group is substituted with an alkyl group and cases where the heterocyclyl group is not substituted with an alkyl group.

[0109] In each section of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood to be the linking group. For example, when the structure requires a linking group and the Markush group definition for that variable lists an "alkyl group" or an "aryl group," it should be understood that the "alkyl group" or "aryl group" represents the linking alkylene group or arylene group, respectively.

[0110] In one embodiment, "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom with a substituent, provided that the valence of the particular atom is normal and the resulting compound is stable. When the substituent is oxo (i.e., =O), this means that two hydrogen atoms are replaced. The term "optionally substituted" refers to a group that may or may not be substituted, and unless otherwise specified, the type and number of substituents are chemically feasible. Needless to say, substituents are present only in their possible chemical positions, and those skilled in the art can determine (experimentally or theoretically) possible or impossible substitutions without much effort. For example, an amino group or hydroxy group having a free hydrogen atom may be unstable if it is attached to a carbon atom that has an unsaturated (e.g., olefinic) bond.

[0111] Unless stated to the contrary, in this specification and claims, the indefinite articles "a," "an," and "one," and the definite article "the" include the plural and the singular.

[0112] A "pharmaceutical composition" is meant to contain a mixture of one or more compounds described herein, or physiologically / pharmaceutically acceptable salts or prodrugs thereof, with other chemical components, as well as other components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism and promote absorption of the active ingredients, thereby exerting their biological activity.

[0113] "Pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, which is safe and effective when used in a mammalian body and possesses the desired biological activity.

[0114] "Stereoisomers" includes all enantiomerically / non-enantiomerically / stereoisomerically pure compounds of the invention and enantiomerically / non-enantiomerically / stereoisomerically enriched compounds of the invention.

[0115] "Stereoisomerically pure" refers to a composition that contains one stereoisomer of a compound but is substantially free of other stereoisomers of the compound. For example, a stereoisomeric composition of a compound having one chiral center will be substantially free of the corresponding enantiomer of the compound. A stereoisomeric composition of a compound having two chiral centers will be substantially free of the other non-enantiomer of the compound. Exemplary stereoisomerically pure compounds include one stereoisomer of the compound at a mass prevalence of greater than about 80% and another stereoisomer of the compound at a mass prevalence of less than about 20%, one stereoisomer of the compound at a mass prevalence of greater than about 90% and another stereoisomer of the compound at a mass prevalence of less than about 10%, one stereoisomer of the compound at a mass prevalence of greater than about 95% and another stereoisomer of the compound at a mass prevalence of less than about 5%, one stereoisomer of the compound at a mass prevalence of greater than about 97% and another stereoisomer of the compound at a mass prevalence of less than about 3%, or one stereoisomer of the compound at a mass prevalence of greater than about 99% and another stereoisomer of the compound at a mass prevalence of less than about 1%.

[0116] "Stereoisomerically enriched" refers to a composition comprising greater than about 55% by mass, greater than about 60% by mass, greater than about 70% by mass, or greater than about 80% by mass of one stereoisomer of a compound.

[0117] "Enantiomerically pure" refers to a stereomerically pure composition of a compound having one chiral center. Similarly, the term "enantiomerically enriched" refers to a stereomerically enriched composition of a compound having one chiral center.

[0118] "Optically active" and "enantiomerically active" refer to a combination of molecules having an enantiomeric or non-enantiomeric excess of about 50% or more, about 70% or more, about 80% or more, about 90% or more, about 91% or more, about 92% or more, about 93% or more, about 94% or more, about 95% or more, about 96% or more, about 97% or more, about 98% or more, about 99% or more, about 99.5% or about 99.8% or more. In specific embodiments, the compound comprises a desired enantiomer or non-enantiomer that accounts for about 95% or more of the total racemic weight, and a preferred enantiomer or non-enantiomer that accounts for about 5% or less.

[0119] When describing an optically active compound, the prefixes R and S are used to denote the absolute configuration of the molecule with respect to its chiral center. (+) and (-) are used to denote the optical rotation of the compound, i.e., the direction of plane of polarized light rotated by the optically active compound. The prefix (-) means that the compound is levorotatory, i.e., the compound rotates the plane of polarized light to the left or counterclockwise. The prefix (+) means that the compound is dextrorotatory, i.e., the compound rotates the plane of polarized light to the right or clockwise. However, the signs of optical rotation (+) and (-) are independent of the absolute configuration R and S of the molecule. [Example]

[0120] The present invention will be further described below in conjunction with examples, but these examples are not intended to limit the scope of the present invention.

[0121] Example The structures of the compounds of the present invention are confirmed by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 nuclear magnetometer in deuterated dimethyl sulfoxide (DMSO-d), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3). The internal standard was tetramethylsilane (TMS).

[0122] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 1200 Infinity Series mass spectrometer. HPLC was performed using an Agilent 1200DAD high-pressure liquid chromatograph (Sunfire C18 150 × 4.6 mm chromatography column) and a Waters 2695-2996 high-pressure liquid chromatograph (Gimini C). 18 A 150 x 4.6 mm chromatography column is used.

[0123] Thin-layer chromatography silica gel plates are Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plates, with TLC using 0.15mm to 0.20mm specifications, and thin-layer chromatography product separation and purification using 0.4mm to 0.5mm specifications. Column chromatography generally uses Yantai Yellow Sea silica gel 200-300 mesh silica gel as the carrier.

[0124] The starting materials in the embodiments of the present invention are either known and commercially available, or can be synthesized using or according to methods known in the art.

[0125] Unless otherwise specified, all reactions of the present invention are carried out under a dry nitrogen or argon atmosphere with continuous magnetic stirring, the solvents are dry solvents, and the reaction temperatures are in degrees Celsius.

[0126] [Example 1] 1'-((7-ethyl-6-carbonyl-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide [ka]

[0127] Step 1: Preparation of ethyl 6-formyl-5-nitronicotinate [ka] Selenium dioxide (3.96 g, 35.68 mmol) was added to a solution (25 mL) of ethyl 6-methyl-5-nitronicotinate (5.0 g, 23.8 mmol) in 1,4-dioxane, heated to 110°C, and stirred for 20 hours. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure using diatomaceous earth. After filtration, the organic solvent was concentrated under reduced pressure and separated by column chromatography to obtain the compound ethyl 6-formyl-5-nitronicotinate (4.8 g, 90%) as a brown oil. MS m / z (ES + ): 224.1[M] + .

[0128] Step 2: Preparation of ethyl (E)-6-(2-(ethoxycarbonyl)but-1-en-1-yl)-5-nitronicotinate [ka] Triethyl 2-phosphocarboxybutyrate (12.8 g, 50.6 mmol) was slowly added dropwise to a solution of NaH (60 wt%, 2.0 g, 50.6 mmol) in tetrahydrofuran (30 mL) in an ice bath and stirred for 0.5 h, then warmed to room temperature and stirred for 0.5 h, then heated to 40° C. and stirred for 10 min. The reaction was cooled to −78° C., and a solution of ethyl 6-formyl-5-nitronicotinate (4.8 g, 21 mmol) in tetrahydrofuran (20 mL) was slowly added dropwise, and the mixture was stirred at −78° C. for 1 h. The reaction was quenched with saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate. The organic phases were combined and washed with saturated brine. The organic phase was separated, dried over anhydrous sodium sulfate, and filtered. The organic solvent was concentrated under reduced pressure and separated by column chromatography to obtain the title compound, ethyl (E)-6-(2-(ethoxycarbonyl)but-1-en-1-yl)-5-nitronicotinate (5.1 g, 75%). MS m / z (ES + ): 322.2[M] + .

[0129] Step 3: Preparation of ethyl 7-ethyl-6-carbonyl-5,6,7,8-tetrahydro-1,5-naphthyridine-3-carboxylate [ka] To a solution of ethyl (E)-6-(2-(ethoxycarbonyl)but-1-en-1-yl)-5-nitronicotinate (3.76 g, 11.6 mmol) in ethanol (50 mL) was added palladium on carbon (1.86 g, 1.76 mmol), deoxygenated with nitrogen for 5 minutes, the reaction was placed under an atmosphere of hydrogen gas, stirred at room temperature overnight, concentrated under reduced pressure through diatomaceous earth, and after filtration, the filtrate was concentrated under reduced pressure to give crude ethyl 7-ethyl-6-carbonyl-5,6,7,8-tetrahydro-1,5-naphthyridine-3-carboxylate (2.8 g), which was used directly in the next step. MS m / z (ESI): 249.2[M+H] + .

[0130] Step 4: Preparation of ethyl 7-ethyl-6-carbonyl-5,6-dihydro-1,5-naphthyridine-3-carboxylate [ka] To a solution (50 mL) of ethyl 7-ethyl-6-carbonyl-5,6,7,8-tetrahydro-1,5-naphthyridine-3-carboxylate (2.8 g, 11.3 mmol) in 1,4-dioxane, DDQ (2.85 g, 12.5 mmol) was added, and the mixture was heated to 110° C. and stirred for 4 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure using diatomaceous earth. The filtrate was concentrated under reduced pressure and then separated by column chromatography to obtain the compound ethyl 7-ethyl-6-carbonyl-5,6-dihydro-1,5-naphthyridine-3-carboxylate (2.1 g, 76%). MS m / z (ESI): 247.2[M+H] + .

[0131] Step 5: Preparation of 3-ethyl-7-(hydroxymethyl)-1,5-naphthyridin-2(1H)-one [ka] To a solution of 7-ethyl-6-carbonyl-5,6-dihydro-1,5-naphthyridine-3-carboxylate (2.1 g, 8.5 mmol) in THF (30 mL), a solution of lithium aluminum hydride in THF (2 M, 8.5 mL, 17.0 mmol) was slowly added in an ice bath, and the mixture was stirred for 2 hours. The reaction was quenched with sodium sulfate decahydrate, concentrated under reduced pressure with diatomaceous earth, and the filtrate was concentrated under reduced pressure and then separated by column chromatography to give 3-ethyl-7-(hydroxymethyl)-1,5-naphthyridin-2(1H)-one (1.5 g, 86%). MS m / z (ESI): 205.2[M+H] + .

[0132] Step 6: Preparation of 7-(chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one [ka] To a solution of 3-ethyl-7-(hydroxymethyl)-1,5-naphthyridin-2(1H)-one (1.5 g, 7.4 mmol) in dichloromethane (30 mL) was added thionyl chloride (3.2 mL, 44.1 mmol) followed by DMF (0.06 mL, 0.77 mmol) under ice bath, and the mixture was stirred at room temperature for 6 hours. The organic solvent was concentrated under reduced pressure to give crude 7-(chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (1.61 g), which was used directly in the next step. MS m / z (ESI): 223.1[M+H] + .

[0133] Step 7: Preparation of 1″-(tert-butyl) 6-methyl 3″,6″-dihydro-[3,4″-bipyridine]-1″,6(2″H)-dicarboxylate [ka] Methyl 5-bromopicolinate (1.0 g, 4.6 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.6 g, 5.1 mmol), 1,1'-bisdiphenylphosphineferrocene palladium dichloride (146 mg, 0.2 mmol), and potassium carbonate (1.6 g, 11.6 mmol) were dissolved in N,N-dimethylformamide (10 mL) at room temperature. The mixture was purged with nitrogen gas for 1 minute, heated to 140 °C, and reacted in a microwave oven for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was separated and washed with saturated brine. The filtrate was dried over anhydrous sodium sulfate and filtered. The organic solvent was concentrated under reduced pressure, and the product was separated by column chromatography to give the compound 1'-(tert-butyl ) 6-Methyl 3',6'-dihydro-[3,4'-bipyridine]-1',6(2'H)-dicarboxylate (620 mg, 42%) was obtained. MS m / z (ES+): 319.1[M+H] + .

[0134] Step 8: Preparation of tert-butyl 6-(methylcarbamoyl)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate [ka] To a solution of 1'-(tert-butyl) 6-methyl 3',6'-dihydro-[3,4'-bipyridine]-1',6(2'H)-dicarboxylate (620 mg, 1.9 mmol) in methanol (8 mL) was added methylamine solution (30 wt%, 2.0 g, 19.5 mmol) at room temperature and stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous ammonium chloride solution was added, and the mixture was extracted three times with DCM. The organic phases were combined, the filtrate was dried over anhydrous sodium sulfate, and after filtration, the organic solvent was concentrated under reduced pressure to give crude tert-butyl 6-(methylcarbamoyl)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate (600 mg), which was used directly in the next step without further purification. MS m / z (ESI): 318.2[M+H] + .

[0135] Step 9: Preparation of N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide [ka] To a solution of tert-butyl 6-(methylcarbamoyl)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate (200 mg, 0.6 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL) under ice bath, the reaction was stirred at room temperature for 4 hours, and the organic solvent was concentrated under reduced pressure to give crude N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide (155 mg), which was used directly in the next step without further purification. MS m / z (ESI): 218.2[M+H] + .

[0136] Step 10: Preparation of 1'-((7-ethyl-6-carbonyl-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide [ka] To a solution of 7-(chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (20 mg, 0.09 mmol) and N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide (52 mg, 0.24 mmol) in acetonitrile (3 mL), DIPEA (58 mg, 0.45 mmol) and potassium iodide (3 mg, 0.02 mmol) were added, heated to 80°C, and stirred for 2 hours. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure. The filtrate was concentrated under reduced pressure and then separated by column chromatography to give the compound 1'-((7-ethyl-6-carbonyl-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide (6.2 mg, 17%). 1 H NMR (400 MHz,DMSO-d6) δ 11.76-11.91(m,1H),8.68-8.73(m,2H),8.40-8.44(m,1H),8.02-7.95(m,2H),7.76(s,1H),7.65(s,1H),6.41-6.44(m,1 H),3.69-3.76(m,2H),3.19-3.13(m,2H),2.77-2.85(m,3H),2.66-2.74(m,2H),2.51-2.59(m,4H),1.18(t,J=7.4Hz,3H); MS m / z (ESI): 404.2[M+H] + .

[0137] The following examples are prepared with reference to Example 1

[0138] [Table 9]

[0139] [Table 10]

[0140] [Biological test evaluation] The present invention will be further explained below in conjunction with test examples, but these examples are not intended to limit the scope of the present invention.

[0141] Test Example 1 Measurement of the inhibitory activity of the compound of the present invention against PARP1 enzyme 1. Experimental Objective: The objective of this experiment is to measure the inhibitory activity of compounds against the PARP1 enzyme.

[0142] 2. Experimental Instruments: Centrifuge (Eppendorf 5810R) Pipette (Eppendorf or Rainin) Microplate reader (BioTek Synergy H1 or PerkinElmer Envision)

[0143] 3. Experimental Reagents: PARP1 Chemiluminescent Assay Kit, purchased from BPS bioscience, catalog number 80569; 20x PBST, purchased from Thermo, catalog number 28352 PBS, purchased from Gibco, catalog number 10010023

[0144] 4. Experimental Method: This experiment was performed using a chemiluminescence method to detect the inhibitory activity of compounds against the PARP1 enzyme. This experiment was performed in a 384-well plate. First, histones were coated onto the plate. A 5x histone solution was diluted 5-fold with PBS, and 25 μL of the solution was added to a 384-well ELISA plate at 25 μL per well. The plate was then incubated overnight at 4°C. After washing the plate with 1x PBST buffer, it was blocked with blocking buffer 3 (included in the kit) at 100 μL per well for 30–120 minutes and washed 3–6 times with 1x PBST buffer. For the PARP reaction, a mixture of biotin-labeled substrate, activated DNA, 10x PARP buffer, and water was added at 12.5 μL per well. Compound solutions were formulated in experimental buffer (10% DMSO containing 1.25 mM DTT) at different concentrations, starting at a final detection concentration of 100 nM. Dilutions were made threefold, resulting in eight concentrations. 2.5 μL of the compound solution was added per well to the reaction wells of a 384-well plate. 2.5 μL of 10% DMSO containing 1.25 mM DTT was added per well to the positive control and blank wells. 10 μL of PARP1 enzyme solution formulated in 1x PARP buffer was then added to initiate the reaction. The reaction was centrifuged at 1000 rpm for 1 minute and incubated at room temperature for 60 minutes. After the reaction was complete, the reaction solution was discarded and the wells were washed with 1x PBST buffer. 25 μL of 50x Streptavidin-HRP solution, diluted 3x with blocking buffer, was added per well and incubated for 30 minutes at room temperature. The reaction solution was then discarded and washed three to six times with 1x PBST buffer. A 50 μL luminescence reaction mixture, a 1:1 mixture of ECL substrate A and ELISA ECL substrate B, was added per well and reacted. Chemiluminescence readings were immediately taken using a BioTek Synergy H1 or Envision instrument.

[0145] 5. Experimental data processing method: Readings were taken on a BioTek Synergy H1 or Envision instrument, chemiluminescence readings were recorded, and percent inhibition was calculated using Graphpad Prism software by performing nonlinear regression curve fitting for concentration and percent inhibition to determine the IC. 50 The values ​​were obtained and the inhibitory activity of some example compounds of the present invention against PARP1 enzyme is shown in the table below.

[0146] [Table 11]

[0147] 6. Experimental conclusion: The compounds disclosed in the present invention exhibited excellent biological activity in PARP1 enzyme inhibition experiments.

[0148] Test Example 2 Measurement of the inhibitory activity of the compound of the present invention against PARP2 enzyme 1. Experimental Objective: The objective of this experiment is to measure the inhibitory activity of compounds against the PARP2 enzyme.

[0149] 2. Experimental Instruments: Centrifuge (Eppendorf 5810R) Pipette (Eppendorf or Rainin) Microplate reader (BioTek Synergy H1 or PerkinElmer Envision)

[0150] 3. Experimental Reagents: PARP2 Chemiluminescent Assay Kit, purchased from BPS bioscience, catalog number 80552; 20x PBST purchased from Thermo Scientific, catalog number 28352; PBS purchased from Gibco, catalog number 10010023

[0151] 4. Experimental Method: This experiment used a chemiluminescence method to detect the inhibitory activity of compounds against the PARP2 enzyme. This experiment was performed in a 96-well plate. First, histones were coated on the 96-well plate. A 5x histone solution was diluted 5-fold with PBS, and 50 μL of this solution was added to a 96-well ELISA plate at 50 μL per well and incubated overnight at 4°C. The coated ELISA plate was then washed with 1x PBST buffer, blocked with blocking buffer 3 (included in the kit) at 200 μL per well for 30–120 minutes, and washed 3–6 times with 1x PBST buffer. For the PARP reaction, a mixture of biotin-labeled substrate, activated DNA, 10x PARP buffer, and water was added at 25 μL per well. Compound solutions were formulated in experimental buffer (10% DMSO containing 1.25 mM DTT) at different concentrations, starting at a final detection concentration of 10 μM. Dilutions were made threefold, resulting in eight concentrations. 5 μL of this solution was added per well to the reaction wells of a 96-well plate. 5 μL of 10% DMSO containing 1.25 mM DTT was added per well to the positive control and blank wells. 20 μL of PARP2 enzyme solution formulated in 1× PARP buffer was then added to initiate the reaction. The reaction was centrifuged at 1000 rpm for 1 minute and incubated at room temperature for 60 minutes. After the reaction was complete, the reaction mixture was discarded and washed with 1× PBST buffer. 50 μL of 50x Streptavidin-HRP solution, diluted 3x with blocking buffer, was added per well and incubated at room temperature for 30 minutes. The reaction mixture was then discarded and washed three to six times with 1× PBST buffer. A 1:1 mixture of ECL substrate A and ELISA ECL substrate B was added to each well at 100 μL per well, and the chemiluminescence was immediately read using a BioTek Synergy H1 or Envision instrument.

[0152] 5. Experimental Data Processing Method: Read on a BioTek Synergy H1 or Envision instrument, record the chemiluminescence readings, calculate the percentage of inhibition, and obtain the IC by performing nonlinear regression curve fitting for concentration and percentage of inhibition using Graphpad Prism software. 50 got the value.

[0153] 6. Experimental Conclusion: The compounds shown in the present invention showed high selectivity for PARP2 in the PARP2 enzyme inhibitory activity experiment.

[0154] Test Example 3 Measurement of the inhibitory effect of the compound of the present invention on the proliferation activity of BRCA2 Knockout DLD-1 cells 1. Experimental Objective: The objective of this test example is to measure the inhibitory effect of compounds on the proliferation activity of BRCA2 Knockout DLD-1 cells.

[0155] 2. Experimental Instruments: Centrifuge (Eppendorf 5810R) Pipette (Eppendorf or Rainin) Microplate reader (BioTek Synergy H1 or PerkinElmer Envision), 3. Experimental Reagents: BRCA2 Knockout DLD-1 cells purchased from Creative Biogene Cell Titer-Glo was purchased from Promega and has the catalog number G7573. RPMI 1640, purchased from Gibco, catalog number 22400089; FBS purchased from Gibco, catalog number 10091148; PBS purchased from Gibco, catalog number 10010023; Pancreatin purchased from Gibco, catalog number 25200056; cell culture plates purchased from Corning, catalog number 3610 4. Experimental method: BRCA2 Knockout DLD-1 cells were cultured in RPMI1640 medium containing 10% FBS to an appropriate cell density. The cells were harvested and adjusted to the appropriate cell concentration using complete medium. The cell suspension was seeded into a 96-well plate at 90 μL per well and placed in a 37°C, 5% CO2 incubator to allow adhesion overnight. DMSO and medium were used to formulate compound solutions at different concentrations. A vehicle control was then added. The compound solutions were added to the 96-well plate at 10 μL per well and placed in a 37°C, 5% CO2 incubator for approximately 144 hours. After this, CellTiter-Glo solution was added and the cells were shaken to mix evenly. The cells were then incubated in the dark for 10-30 minutes and counted using a Synergy H1 or Envision microplate reader.

[0156] 5. Experimental data processing method: Calculate the inhibition rate using the luminescence signal value, and perform nonlinear regression curve fitting for the concentration and inhibition rate using Graphpad Prism software to obtain the IC 50 The values ​​were obtained, and the inhibitory effects of some examples of the compounds of the present invention on the proliferation activity of BRCA2 Knockout DLD-1 cells are shown in the table below.

[0157] [Table 12]

[0158] 6. Experimental conclusion: The compounds disclosed in the present invention showed excellent biological activity in the BRCA2 knockout DLD-1 cell proliferation inhibition test.

[0159] Test Example 4: Two-way permeability test of compounds through Caco-2 cell model 1. Purpose of the experiment: The purpose of this study was to examine the two-way permeability of compounds across the Caco-2 cell model.

[0160] 2. Experimental equipment and materials: Liquid-phase mass spectrometer, centrifuge, vortexometer, pipettor, 24-well test plate, acetonitrile solution with added internal standard, Caco-2 cells (ATCC), Hank's balanced salt solution (HBSS), dimethyl sulfoxide (DMSO)

[0161] 3. Experimental steps: 1) Cultivation of Caco-2 monolayer cells: Caco-2 cells in good condition were selected and spread on the surface. The medium was changed every 2-3 days and the cells were cultured for 21-28 days to form a dense cell monolayer, which was then used for the permeability test.

[0162] 2) Evaluation of the permeability of test compounds: a. 100 μL of transport buffer (HBSS containing 10 μM test compound, 0.5% BSA and 0.5% DMSO) was added to the administration end from A to B.

[0163] b. 300 μL of transport buffer (HBSS containing 0.5% BSA) was added to the dosing end from A to B.

[0164] c. 300 μL of transport buffer (HBSS containing 10 μM test compound, 0.5% BSA and 0.5% DMSO) was added to the administration end from B to A.

[0165] 100 μL of transport buffer (HBSS containing 0.5% BSA) was added to the dosing end of dB to A.

[0166] e. Incubated for 2 hours.

[0167] d. Samples were collected, processed, and detected by mass spectrometry.

[0168] 4. Chromatography conditions: Instrument: Liquid chromatography, Chromatography column: Waters XSelect HSS T3 C18 (2.1*50mm, 2.5um), Mobile phase: Phase A: aqueous solution containing 0.1% formic acid, Phase B: acetonitrile solution containing 0.1% formic acid.

[0169] 5. Mass spectrometry conditions: Instrument: API4000 liquid chromatography mass spectrometer, The ion source is electrospray ionization (ESI), The detection method is positive ion detection. The scanning method is a selected reaction monitoring (MRM) method.

[0170] 6. Experimental Results: The two-way permeability of the compounds of the examples of the present invention through the Caco-2 cell model is shown in the table below.

[0171] [Table 13]

[0172] 7. Experimental conclusion: As can be seen from the experimental structure in the above table, the compounds of the examples of the present invention have high permeability.

[0173] Test Example 5 Pharmacokinetics measurement in Balb / C mice 1. Experimental Objective: Balb / C mice were used as test animals to study the pharmacokinetic behavior in mouse plasma of the following compound examples when orally administered at a dose of 1 mg / kg.

[0174] 2. Experimental plan: 2.1 Test drugs: Examples of the present invention, self-made.

[0175] 2.2 Test animals: 6 Balb / C mice per example, male, Shanghai Jieshijie Laboratory Animal Co., Ltd., Animal Production Permit Number (SCXK (Shanghai) 2013-0006 No. 0.311620400001794).

[0176] 2.3 Drug formulation: 5 g of hydroxyethyl cellulose (HEC, CMC-Na, viscosity: 800-1200 Cps) was weighed and dissolved in 1000 mL of purified water, and 10 g of Tween 80 was added. The mixture was mixed uniformly to form a clear solution.

[0177] 2.05 mg of the cell suspension was weighed out and dissolved in the solution, and the solution was homogenized by shaking well, disrupted in a cell disrupter for 1 minute, and then subjected to ultrasonic treatment for 15 minutes to obtain a suspension with a concentration of 0.1 mg / mL.

[0178] 2.4 Administration: Male Balb / C mice were administered po after overnight fasting, with a dose of 1 mg / kg and a volume of 10 mL / kg.

[0179] 2.5 Sampling: After administration to the mice, 0.04 mL of blood was collected from the orbit at 0, 0.5, 1, 2, 4, 6, 8 and 24 hours. The blood was placed in an EDTA-K2 tube and the plasma was separated at 6000 rpm at 4°C for 6 minutes, stored at -80°C, and fed 4 hours after administration.

[0180] 2.6 Sample Processing: 1) 40 μL of plasma sample was added to 160 μL of acetonitrile, mixed, and then centrifuged at 3500 × g for 5 to 20 minutes. 2) 100 μL of the treated supernatant solution was taken and analyzed for the concentration of the test compound by LC / MS / MS.

[0181] 2.7 Liquid phase analysis ● Liquid phase conditions: Shimadzu LC-20AD pump ● Mass spectrometry conditions: AB Sciex API 4000 mass spectrometer ● Chromatography column: phenomenex Gemiu 5um C18 50×4.6mm ● Mobile phase: Solution A was 0.1% formic acid in water, and solution B was acetonitrile. ● Flow rate: 0.8mL / min Elution time: 0 to 4.0 minutes, elution solution was as follows:

[0182] [Table 14]

[0183] 3. Experimental results and analysis: The main pharmacokinetic parameters were calculated using WinNonlin 8.2, and the mouse pharmacokinetic experimental results are shown in the table below.

[0184] [Table 15]

[0185] 4. Experimental Conclusion: From the pharmacokinetic experiment results in mice in the table, the compounds of the examples of the present invention exhibit good absorption and metabolic properties, and the exposure amount AUC and maximum blood concentration C max Both were shown to be good.

[0186] Test Example 6 PK / PD study of the compound in a nude mouse subcutaneously implanted human breast cancer cell line MDA-MB-436 tumor model 1. Experimental objective: To evaluate the distribution of the compound in plasma and tumor after a single oral administration in a nude mouse subcutaneously implanted human breast cancer cell line MDA-MB-436 tumor model, and to evaluate the inhibitory effect of PAR in tumor tissue.

[0187] 2. Laboratory equipment and reagents 2.1 Instrumentation Refrigerator (BCD-268TN, Haier) Electronic pipette helper (Easypet 3, Eppendorf) Biological safety cabinet (BSC-1300II A2, Shanghai Boken Industrial Co., Ltd. Medical Equipment Factory) Clean bench (CJ-2F, Suzhou Feng Experimental Animal Equipment Co., Ltd.) Constant temperature water bath (HWS-12, Shanghai Yiheng Science) CO2 incubator (Thermo-311, Thermo) Centrifuge (Centrifuge 5720R, Eppendorf) Fully automated cytometer (Countess II, Life Technologies) Vernier (CD-6''AX, Mitoyo, Japan) Cell culture flasks (T25 / T75 / T225, Corning) Electronic balance (CPA2202S, Sartorius) Electronic balance (BSA2202S-CW, Sartorius) Ultrasonic cleaner (115F0032, Shanghai KODAO) Pure water equipment (Pacific TII, Thermo) Magnetic stirrer (08-2G, Hashiku) Centrifuge (Centrifuge 5418R, Eppendorf) Miniature protein vertical electrophoresis and transfer system (PowerPac Universal Power Supply, Bio-Rad) Microplate reader (H1MFD, Biotek) Molecular imaging system (ChemiDoc™ MP, Bio-Rad) Semi-dry transfer device (690BR027087, Bio-Rad) Pipette (METTLER TOLEDO / Eppendorf) Tissue grinder (TISS-48, Shanghai Jingxin Experimental Equipment Science and Technology Department) Dry thermostat (MK200-2, Hangzhou Okangsheng Instrument Co., Ltd.)

[0188] 2.2 Reagents DMEM medium (31600-034, Gibco) Fetal bovine serum (FBS) (10099-141C, Gibco) Insulin-transferrin-selenium (ITS-G) (41400-045, Gibco) Phosphate buffer solution (PBS) (10010-023, Gibco) Tween 80 (30189828, National Pharmaceutical Reagents) Sodium carboxymethylcellulose (30036365, National Pharmaceutical Reagents) Matrigel Matrix (356234, Corning) Trans-Blot Turbo Transfer Pack (1704157, Bio-Rad) 4-15% Criterion(TM) TGX(TM) Gel (5671085, Bio-Rad) GAPDH (D4C6R) Mouse(97166S, CST) IRDye(R) 800CW Goat anti-Mouse IgG (H+L) (P / N 926-32210, LI-COR) IRDye(R) 680RD Goat anti-Rabbit IgG (H+L)(P / N 926-68071, LI-COR) Poly / Mono-ADP Ribose (E6F6A)Rabbit mAb(83732S, CST) Pierce BCA Protein Assay Kit (23227, Thermo Fisher) QuickBlock Western Mounting Fluid (P0252-500ml, Beyotime) NuPAGE® Sample Reducing Agent (10x) (NP0009, Thermo Fisher Scientific) NuPAGE™ LDS Sample Buffer (4x) (NP0007, Thermo Fisher) Pierce 20×TBS with Tween-20 (28360, Thermo Fisher)

[0189] 3. Experimental Method 3.1 Animals BALB / c nude mice, 6-8 weeks old, female, purchased from the Laboratory Animal Management Department of the Shanghai Institute of Life Planning.

[0190] 3.2 Cell culture and cell suspension production a. One MDA-MB-436 cell line was extracted from the cell bank and resuscitated in DMEM medium (DMEM + 10% FBS + 1% ITS-G). The resuscitated cells were placed in a cell culture flask (the flask wall was marked with the cell type, date, name of the culturer, etc.) and cultured in a CO2 incubator (incubator temperature 37°C, CO2 concentration 5%).

[0191] b, The cells were passaged every 3 days, and after passage, they were placed in a CO2 incubator and continued to be cultured. The process was repeated until the cell number met the pharmacodynamic requirements in vivo.

[0192] c) Cultured cells were collected and counted using an automated cytometer. Based on the counting results, the cells were resuspended in PBS and mixed with Matrigel Matrix at a 1:1 ratio to a final concentration of 5 × 10 cells. 7 / mL and kept in an ice box.

[0193] 3.3 Cell inoculation a) Before inoculation, nude mice were marked with disposable rat / mouse ear tags. b. At the time of inoculation, mix the cell suspension evenly, aspirate 0.1-1 mL of cell suspension with a 1 mL syringe, remove air bubbles, and place the syringe on an ice pack. c) Fix the nude mouse with your left hand, disinfect the area on the right back of the nude mouse near the right shoulder (the inoculation site) with a 75% alcohol cotton ball, and start the inoculation after 30 seconds. d, Test nude mice were inoculated sequentially (each mouse was inoculated with 0.1 mL of cell suspension).

[0194] 3.4 PK / PD experiments a, Grouping: According to tumor growth, tumors with a volume of 300-500 mm 3 Once the tumor-bearing mice reached maturity, they were selected according to the experimental design and randomly divided into groups (3 mice per time point) to initiate the PK / PD experiments.

[0195] b, Fasting: All tumor-bearing mice were fasted overnight (fasting >8 hours) without water restriction before dosing.

[0196] c. Administration: Except for the blank control group, a single oral administration was performed according to the experimental design time, and the administration volume was 10 mL / kg.

[0197] d. Sample collection: Experimental mice were euthanized by CO2 asphyxiation according to the designated time, and samples were collected. One plasma sample and three tumor tissue samples were collected per animal.

[0198] Mice were euthanized by CO2 asphyxiation at the designated time and samples were collected.

[0199] Plasma collection: After euthanasia, mice were bled via the heart. The collected blood was placed in a centrifuge tube containing EDTA-K2, manually inverted 3-4 times, placed on ice, and centrifuged at 8000 rpm at 4°C for 5 minutes. 100 μL of the plasma was transferred to a newly marked centrifuge tube, and one portion was quickly frozen on dry ice and stored in a refrigerator at -80±10°C for PK detection.

[0200] Tumor tissue collection: After blood collection, the tumor tissue was peeled off, divided into three portions (~0.1 g / portion), placed in marked 2 mL centrifuge tubes, and stored in a refrigerator at -80 ± 10 °C for PK or PD detection. The remaining tumor-bearing mice were used to collect blank plasma and blank tumor tissue.

[0201] 3.5 PK detection a, Sample processing: 1) A 4-fold weight ratio of 20% methanol water was added to the tumor tissue sample, and the mixture was homogenized at 40 Hz for 400 seconds. 20 μL of the homogenate was taken, and 100 μL of acetonitrile was added to precipitate the mixture. After uniform mixing, the mixture was centrifuged at 3500 × g for 5 to 20 minutes.

[0202] 2) 100 μL of the treated supernatant solution was taken and analyzed for the concentration of the test compound by LC / MS / MS.

[0203] b, Liquid phase analysis ● Liquid phase conditions: Shimadzu LC-20AD pump ● Mass spectrometry conditions: AB Sciex API 4000 mass spectrometer ● Chromatography column: phenomenex Gemiu 5um C18 50×4.6mm ● Mobile phase: Solution A was 0.1% formic acid in water, and solution B was acetonitrile. ● Flow rate: 0.8mL / min Elution time: 0 to 4.0 minutes, elution solution was as follows:

[0204] [Table 16]

[0205] 3.6 PD detection a. Lysis of tissue samples One mL of tumor lysis solution was added to each tube of tumor tissue sample, and the tissue was homogenized in a tissue grinder with steel beads, lysed on ice for 20 minutes, centrifuged at 10,000 g for 5 minutes at 4°C in a freezing centrifuge, and the protein supernatant was collected.

[0206] b. Protein sample preparation Protein was quantified using a BCA protein quantification kit, and protein supernatant samples were mixed with 10x Sample Reducing Agent, 4x LDS Sample Buffer, and lysis solution to prepare a protein loading solution of matching concentrations. The protein loading solution was placed in a preheated dry thermostat and incubated at 100°C for 10 minutes to denature the proteins.

[0207] c. Western blot experiment using protein samples

[0208] 1) Electrophoresis: A 4-15% Criterion™ TGX™ Gel protein gel was taken, samples were added, and 15 μL of each protein sample was placed in an electrophoresis tank containing electrophoresis solution for protein gel electrophoresis. The gel was run at 150 V for 60 minutes.

[0209] 2) Transfer: Using the Trans-Blot Turbo Transfer Pack Kit, the multilayer filter paper, PVDF membrane, protein gel, and thick filter paper were sequentially arranged and placed in the transfer device. The program MIXED MW (2.5A-25V-7min) was selected and the transfer was performed.

[0210] 3) Antibody blocking and incubation: The PVDF membrane was removed from the transfer device, placed in QuickBlock Western mounting solution, and shaken at room temperature for at least 1 hour to perform protein blocking. The PVDF membrane was then placed in a solution of PAR (1:500) or GAPDH (1:5000) primary antibody diluted in QuickBlock Western mounting solution and incubated overnight at 4°C. The primary antibody solution was then removed and the membrane was washed six times with 1x TBST. A solution of sheep anti-rabbit (1:3000) and mouse fluorescent secondary antibody (1:5000) diluted in QuickBlock Western mounting solution was then added and incubated at room temperature in the dark for 1 hour. The antibody solution was then removed and the membrane was washed six times with 1x TBST.

[0211] 4) Imaging: The washed PVDF membrane was placed in a Biorad ChemiDoc™ MP imaging device and imaged for PAR and fluorescence imaging, using the IRDye 800 CW channel against the Gapdh internal standard. 4. Experimental Results

[0212] [Table 17]

[0213] [Table 18]

[0214] 5. Experimental conclusions: In the MDA-MB-436 (breast cancer, BRCA1 mutation) model, Example 1 achieved a higher tumor blood concentration than AZD5305 within 24 hours after a single administration, and the level of inhibition of intratumoral PAR was comparable. Example 1's inhibition of intratumoral PAR after a single administration was sustained for 72 hours, demonstrating superiority over AZD5305.

[0215] Test Example 7: Effect of the compound on human colorectal cancer cell line DLD-1 BRCA2 - / - In vivo pharmacodynamic study in a nude mouse subcutaneous tumor model 1. Experimental Objective: To evaluate the efficacy of the compound on human colorectal cancer cell line DLD-1 BRCA2 - / - To evaluate the in vivo efficacy in a nude mouse subcutaneous tumor model.

[0216] 2. Laboratory equipment and reagents 2.1 Instrumentation Refrigerator (BCD-268TN, Haier) Electronic pipette helper (Easypet 3, Eppendorf) Biological safety cabinet (BSC-1300II A2, Shanghai Boken Industrial Co., Ltd. Medical Equipment Factory) Clean bench (CJ-2F, Suzhou Feng Experimental Animal Equipment Co., Ltd.) Constant temperature water bath (HWS-12, Shanghai Yiheng Science) CO2 incubator (Thermo-311, Thermo) Centrifuge (Centrifuge 5720R, Eppendorf) Magnetic stirrer (08-2G, Hashikyu) Fully automated cytometer (Countess II, Life Technologies) Vernier (CD-6''AX, Mitoyo, Japan) Cell culture flasks (T25 / T75 / T225, Corning) Electronic balance (CPA2202S, Sartorius) Electronic balance (BSA2202S-CW, Sartorius) Ultrasonic cleaner (115F0032, Shanghai KODAO) Pure water equipment (Pacific TII, Thermo) 2.2 Reagents RPMI-1640 medium (22400-089, Gibco) and fetal bovine serum (FBS) (10099-141C, Gibco) Phosphate buffer solution (PBS) (10010-023, Gibco) Tween 80 (30189828, National Pharmaceutical Reagents) Sodium carboxymethylcellulose (30036365, National Pharmaceutical Reagents)

[0217] 3. Experimental Procedures and Data Processing 3.1 Animals: BALB / c nude mice, 6-8 weeks old, female, purchased from the Laboratory Animal Management Department of the Shanghai Institute of Family Planning.

[0218] 3.2 Cell culture and cell suspension production a, DLD-1 BRCA2 from the cell bank - / - One cell line was removed and resuscitated in RPMI-1640 medium (RPMI-1640 + 10% FBS). The resuscitated cells were placed in a cell culture flask (the flask wall was marked with the cell type, date, name of the culturer, etc.) and cultured in a CO2 incubator (incubator temperature 37°C, CO2 concentration 5%).

[0219] b, The cells were passaged every 3 days, and after passage, they were placed in a CO2 incubator and continued to be cultured. The process was repeated until the cell number met the pharmacodynamic requirements in vivo.

[0220] c) The cultured cells were collected and counted using an automated cytometer. Based on the counting results, the cells were resuspended in PBS and the cell suspension (density 5 × 10 7 / mL) was prepared and kept in an ice box.

[0221] 3.3 Cell inoculation a) Before inoculation, nude mice were marked with disposable rat / mouse ear tags. b. At the time of inoculation, mix the cell suspension evenly, aspirate 0.1-1 mL of cell suspension with a 1 mL syringe, remove air bubbles, and place the syringe on an ice pack. c) Fix the nude mouse with your left hand, disinfect the area on the right back of the nude mouse near the right shoulder (the inoculation site) with a 75% alcohol cotton ball, and start the inoculation after 30 seconds. d, Test nude mice were inoculated sequentially (each mouse was inoculated with 0.1 mL of cell suspension).

[0222] 3.4 Tumor Measurement, Grouping, and Dosing of Tumor-Bearing Mice a) Based on the tumor growth status, tumor measurements were performed 10 to 18 days after inoculation, and the tumor size was calculated. Tumor volume calculation: Tumor volume (mm 3 ) = length (mm) x width (mm) x width (mm) / 2 b, Tumor-bearing mice were grouped using a random grouping method based on their body weight and tumor size; c) Based on the results of grouping, administration of the test drug was initiated (administration method: oral administration, administration volume: 10 mL / kg, administration frequency: once / day, administration cycle: 28 days, vehicle: 0.5% CMC-Na / 1% Tween 80).

[0223] d) After the start of test drug administration, tumor masses were measured and weighed twice a week.

[0224] e, After the experiment was completed, the animals were euthanized.

[0225] f, Data was processed using software such as Excel. Calculation of the compound's tumor growth inhibition rate TGI (%): If tumors did not regress, TGI (%) = [1 - (mean tumor volume at the end of treatment in a treatment group - mean tumor volume at the start of treatment in the treatment group) / (mean tumor volume at the end of treatment in the solvent control group - mean tumor volume at the start of treatment in the solvent control group)] × 100%. If tumors regressed, TGI (%) = [1 - (mean tumor volume at the end of treatment in a treatment group - mean tumor volume at the start of treatment in the treatment group) / mean tumor volume at the start of treatment in the treatment group] × 100%.

[0226] 1.4 Experimental results and conclusions: The example compounds 1, 2 and 7 of the present invention showed excellent tumor-inhibiting effects in this model experiment, with tumor inhibition rates of TGI (%) > 90%, and the tumor-bearing tumor inhibition rates of the preferred compounds were TGI (%) > 150%, with no significant decrease in animal body weight.

[0227] III. Study on salts and crystalline forms of the compound of Example 1 1.1 Experimental instruments 1.1.1 Some parameters of physicochemical detection instruments

[0228] [Table 19]

[0229] 1.2 Instruments and liquid phase analysis conditions 1.2.1 Instruments and Equipment

[0230] [Table 20]

[0231] 1.2.2 Chromatography conditions Chromatography column: Waters Xbridge C18 (4.6 mm * 150 mm, 3.5 μm) Flow rate: 1.0 mL / min Column temperature: 40°C Detection wavelength: 260 nm Sample volume: 5 μL Run time: 15 min Diluent: Methanol Mobile phase: A: Water (0.05% trifluoroacetic acid), B: Acetonitrile (0.05% trifluoroacetic acid)

[0232] [Table 21]

[0233] 1.3 Preparation of different crystalline forms of the compound of Example 1 1.3.1 Preparation of Hydrochloride Crystalline Form A 20 mg of the compound of Example 1 was weighed out, added with 0.2 mL of ethanol, and stirred at 50°C to form a suspension. 0.06 mL of a 1 M solution of hydrochloric acid in methanol was added to the system, which became clear and precipitated. After reacting for 1 hour, the temperature was lowered to room temperature and the mixture was stirred for 2 hours. The solid was centrifuged and dried to finally obtain hydrochloride crystalline form A. After detection and analysis, it has the XRPD pattern shown in Figure 3 and the DSC pattern shown in Figure 4.

[0234] 1.3.2 Preparation of Sulfate Crystalline Form A 20 mg of the compound of Example 1 was weighed out, and 0.2 mL of ethanol was added, followed by stirring at 50°C to form a suspension. 0.06 mL of a 1 M methanol solution of sulfuric acid was added to the system, which became clear and precipitated. After reacting for 1 hour, the temperature was lowered to room temperature and the system was stirred for 2 hours. The solid was centrifuged and dried to finally obtain sulfate crystalline form A. Upon detection and analysis, it has the XRPD pattern shown in Figure 5 and the DSC pattern shown in Figure 6.

[0235] 1.3.3 Preparation of Methanesulfonate Crystalline Form A 20 mg of the compound of Example 1 was weighed out, and 0.2 mL of ethanol was added, followed by stirring at 50°C to form a suspension. 0.06 mL of a 1 M solution of methanesulfonic acid in methanol was added to the system, which became clear and cooled to room temperature, causing a solid to precipitate. The system was stirred at room temperature for 2 hours, and the solid was centrifuged and dried to finally obtain methanesulfonate crystalline form A. Upon detection and analysis, it has the XRPD pattern shown in Figure 7 and the DSC pattern shown in Figure 8.

[0236] 1.3.4 Preparation of p-Toluenesulfonate Crystalline Form A 20 mg of the compound of Example 1 was weighed out, and 0.2 mL of ethanol was added, followed by stirring and suspending at 50°C. 0.06 mL of a 1 M solution of p-toluenesulfonic acid in methanol was added to the system, which became clear and precipitated. After reacting for 1 hour, the temperature was lowered to room temperature and the system was stirred for 2 hours. The solid was centrifuged and dried, finally obtaining p-toluenesulfonate crystalline form A. After detection and analysis, it has the XRPD pattern shown in Figure 9 and the DSC pattern shown in Figure 10.

[0237] 1.3.5 Preparation of p-Toluenesulfonate Crystalline Form B 20 mg of p-toluenesulfonate crystalline form A was weighed, added with 0.2 mL of tetrahydrofuran, suspended at 50° C., and beaten for 7 days, and the solid was centrifuged and dried to finally obtain p-toluenesulfonate crystalline form B. Upon detection and analysis, it has the XRPD pattern shown in FIG. 11 and the DSC pattern shown in FIG. 12.

[0238] 1.3.6 Preparation of p-Toluenesulfonate Crystalline Form C 20 mg of p-toluenesulfonate crystalline form A was weighed, added with 0.2 mL of 1,4-dioxane, suspended at 50° C., and beaten for 7 days, and the solid was centrifuged and dried to finally obtain p-toluenesulfonate crystalline form C. Upon detection and analysis, it has the XRPD pattern shown in FIG. 13 and the DSC pattern shown in FIG. 14.

[0239] 1.3.7 Preparation of p-toluenesulfonate dihydrate crystalline form A 20 mg of p-toluenesulfonate crystalline form A was weighed, added with 0.2 mL of water, and suspended at room temperature. After beating for 12 hours, the solid was centrifuged and dried to finally obtain p-toluenesulfonate hydrate crystalline form A. Upon detection and analysis, it has the XRPD pattern shown in Figure 15, the DSC pattern shown in Figure 16, and the TGA pattern shown in Figure 17.

[0240] Here, the components of p-toluenesulfonate hydrate crystalline form A are determined by the following method.

[0241] 1) Determination of water content in p-toluenesulfonate hydrate crystalline form A The water content of p-toluenesulfonate hydrate crystalline form A is determined primarily by TGA weight loss in conjunction with the water content measured by Karl Fischer moisture analyzer.

[0242] As can be seen from Figure 17, the TGA weight loss is about 6.02%.

[0243] The moisture content was measured three times using a Karl Fischer moisture meter, and the results are as follows:

[0244] [Table 22]

[0245] Three moisture determinations were comparable, with an average moisture content of 5.945%, consistent with the TGA weight loss.

[0246] 2) Liquid phase free base content analysis Using the compound of Example 1 as a control, the content of free base in compound p-toluenesulfonate hydrate crystalline form A was measured using the HPLC external standard method. The results are as follows:

[0247] [Table 23]

[0248] Based on the above water content measurement results and free base content measurement data, it was finally determined that the ratio of free base:p-toluenesulfonic acid:water in p-toluenesulfonate hydrate crystalline form A was 1:1:2.

[0249] As described above, p-toluenesulfonate hydrate crystalline form A is p-toluenesulfonate dihydrate crystalline form A.

[0250] 1.3.8 Preparation of benzenesulfonate salt crystalline form A 20 mg of the compound of Example 1 was weighed out, and 0.2 mL of ethanol was added, followed by stirring at 50°C to form a suspension. 0.06 mL of a 1 M benzenesulfonic acid solution in methanol was added to the system, and the system became clear and cooled to room temperature, causing a solid to precipitate. The system was stirred at room temperature for 2 hours, and the solid was centrifuged and dried to finally obtain benzenesulfonate crystalline form A. Upon detection and analysis, it had the XRPD pattern shown in Figure 18 and the DSC pattern shown in Figure 19.

[0251] 1.4 Example 1 Polymorphism Study of Salt Forms 1.4.1 Hydrochloride Polymorphism Study: Approximately 20 mg of hydrochloride form A was weighed into a glass vial, and 200 μL of organic solvent was added and the mixture was beaten at 50° C. for 7 days. The results are as follows:

[0252] [Table 24]

[0253] Results and Discussion: Hydrochloride crystalline form A does not undergo crystal transformation in the above solvents and is stable in the above solvents.

[0254] 1.4.2 Polymorphism study of sulfate salts Approximately 20 mg of crystalline form A of the sulfate salt was weighed and placed in a glass vial, and 200 μL of an organic solvent was added and the mixture was beaten at 50° C. for 7 days. The results are as follows:

[0255] [Table 25]

[0256] Results and Discussion: The sulfate salt crystalline form A is stable in the above solvents and is advantageous for subsequent drug development.

[0257] 1.4.3 Polymorphism study of methanesulfonate salt Approximately 20 mg of methanesulfonate crystalline form A was weighed and placed in a glass vial, and 200 μL of an organic solvent was added and the mixture was beaten at 50° C. for 7 days. The results are as follows:

[0258] [Table 26]

[0259] Results and Discussion: Methanesulfonate crystalline form A is stable, the manufacturing process is easy, and a stable single crystalline form can be obtained.

[0260] 1.4.4 Polymorphism study of p-toluenesulfonate Approximately 20 mg of p-toluenesulfonate crystalline polymorph A was weighed and placed in a glass vial, and 200 μL of an organic solvent was added and the mixture was beaten at 50° C. for 7 days. The results are as follows:

[0261] [Table 27]

[0262] Results and Discussion: Through the above experiments, polymorphs B, C and hydrate A of p-toluenesulfonate were selected.

[0263] 1.4.5 Polymorphic study of p-toluenesulfonate hydrate 1.4.5.1 Slurry conversion test: Approximately 10 mg of p-toluenesulfonate dihydrate crystalline form A was weighed and placed in a glass vial, and 200 μL of an organic solvent was added and the mixture was beaten at 40° C. for 7 days. The results were as follows:

[0264] [Table 28]

[0265] 1.4.5.2 Results and Discussion: p-Toluenesulfonate dihydrate crystalline form A was shown to be stable and advantageous for further drug development.

[0266] 1.5 Hygroscopicity measurement 1.5.1 Experimental objective: To investigate the hygroscopicity of different salt crystal forms of the compound under different humidity conditions.

[0267] 1.5.2 Experimental method: The salt crystal form of the compound was placed in saturated water vapor with different relative humidities to dynamically equilibrate the salt crystal form of the compound with the water vapor, and the percentage of weight increase due to moisture absorption after equilibration was calculated.

[0268] 1.5.3 Experimental Results: 1) Form A of the sulfate salt absorbed moisture at 80% RH, increasing its weight by 1.785%, indicating that it was slightly hygroscopic. Repeating a cycle of moisture absorption and desorption under 0-95% relative humidity conditions once did not change the XRPD pattern of Form A of the sulfate salt, indicating that the crystal form was unchanged.

[0269] 2) p-Toluenesulfonate crystalline form A absorbed moisture at 80% RH, increasing its weight by 9.00%, demonstrating its hygroscopicity. Repeating a cycle of moisture absorption and desorption under 0-95% relative humidity conditions once did not change the XRPD pattern of p-toluenesulfonate crystalline form A, i.e., the crystalline form remained unchanged.

[0270] 3) Form A of p-toluenesulfonate dihydrate absorbed moisture at 80% RH, increasing its weight by 1.906% and showing slight hygroscopicity. After a single cycle of moisture absorption and dehumidification under 0-95% relative humidity, the XRPD pattern of Form A of p-toluenesulfonate dihydrate did not change, meaning that the crystal form was unchanged.

[0271] 1.5.4 Experimental conclusion: The above crystal forms did not undergo crystal transformation under different relative humidity conditions.

[0272] 1.6. Solid-state stability experiments 1.6.1 Experimental objective: To investigate the physicochemical stability of different salt crystal forms of the compound when they are placed at high temperature 60℃, high humidity RH=92.5% and high temperature and humidity 50℃, 75% RH.

[0273] 1.6.2 Experimental method: Approximately 1 mg of different salt crystal forms was taken and examined under high temperature 60°C, high humidity RH=92.5% and high temperature and humidity 50°C, 75% RH for 7 days and 14 days, respectively. The changes in related substances in the salt crystal forms were calculated using the chromatographic peak area normalization method. 1.6.3 Experimental Results:

[0274] [Table 29]

[0275] 1.6.4 Experimental Conclusions: Comparing the stability results, after salt formation, p-toluenesulfonate dihydrate crystalline form A significantly improved its solid-state stability and remained stable under high temperature, high humidity, and high temperature and humidity conditions without significant impurity increase, meeting the requirements for subsequent drug development. Benzenesulfonate crystalline form A remained stable under high temperature and humidity conditions without significant impurity increase, indicating that benzenesulfonate crystalline form A is not sensitive to temperature and humidity changes and can meet the requirements for subsequent drug storage. p-toluenesulfonate crystalline form A and sulfate crystalline form A remained stable under each condition for a certain period of time without significant impurity increase, indicating that p-toluenesulfonate crystalline form A and sulfate crystalline form A can effectively expand the operational space for subsequent drug formulation development. Crystalline form A of the methanesulfonate salt is stable under high humidity and high temperature and humidity conditions, and no significant increase in impurities is observed. This indicates that crystalline form A of the methanesulfonate salt is very insensitive to humidity; even when the temperature is raised to 50°C under 75% humidity, no significant increase in impurities is observed, and subsequent storage conditions for the drug can be made less stringent.

[0276] 1.7. Solubility experiments in different vehicles 1.7.1 Experimental Objective: To compare the solubilities of p-toluenesulfonate dihydrate crystalline form A and sulfate crystalline form A in media such as water, simulated gastric fluid (FaSSGF), fasted simulated intestinal fluid (FaSSIF), and non-fasted simulated intestinal fluid (FeSSIF).

[0277] 1.7.2 Experimental method: Approximately 1 mg of the salt crystal form was suspended in different media for 2 hours, and the solubility of the compound at 37°C was measured by HPLC external standard method. 1.7.3 Experimental Results:

[0278] [Table 30]

[0279] 1.7.4 Experimental Conclusion: The solubility of the two salt crystal forms described above in the gastrointestinal simulant fluid and aqueous medium was essentially the same, with no significant difference.

[0280] 1.8. PK studies of different salt crystalline forms in rats 1.8.1 Experimental objective: To investigate the pharmacokinetic behavior in rats (plasma) following a single oral administration of sulfate crystalline form A and p-toluenesulfonate dihydrate crystalline form A using SD rats as test animals, and to compare the changes in exposure and the bioavailability of sulfate crystalline form A and p-toluenesulfonate dihydrate crystalline form A following oral administration.

[0281] 1.8.2 Experimental method: Both sulfate form A and p-toluenesulfonate dihydrate form A were homogeneously suspended in an aqueous solution containing 0.5% HPMC K4M, and then administered orally to rats. Three rats were used in parallel experiments, with the dosages of sulfate form A (5 mg / kg clear solution) and p-toluenesulfonate dihydrate form A (5 mg / kg and 20 mg / kg suspensions, respectively). 1.8.3 Experimental Results:

[0282] [Table 31]

[0283] 1.8.4 Experimental Conclusions: The above data show that the PK oral bioavailability of both sulfate form A and p-toluenesulfonate dihydrate form A is high, and the exposure of p-toluenesulfonate dihydrate is linearly related to the dose (5mpk and 20mpk).

[0284] 1.9 Single crystal experiments of the p-toluenesulfonate dihydrate crystal form 1.9.1 Experimental objective: To confirm the structure of the toluenesulfonate dihydrate crystalline form.

[0285] 1.9.2 Experimental method: At room temperature, weigh 50 mg of p-toluenesulfonate, add 20 ml of methanol, 10 ml of methyl tert-butyl ether, and 5 ml of n-heptane, mix and stir for 0.5 hours, filter through a 0.22 filter membrane, add 2 ml of methanol to the filtrate to dilute it, place the diluted solution in a beaker, seal it with tin foil, poke a small hole in it, and place it in a well-ventilated place without vibration to allow the solvent to evaporate slowly and naturally, obtaining granular crystals.

[0286] 1.9.3 Data Representation and Results 1.9.3.1 Instrument Parameters Single crystal measurement instruments and parameters: a Rigaku Saturn70 CCD diffractometer, Mo-Kα radiation. Wavelength: γ=0.71073 Angstroms Temperature: 113K Scanning range (theta range for data collection) 2.3-32.3° Single crystal structure data: Empirical formula: C7H7O3S·C 23 H 26 N5O2·2(H2O) Molecular weight: 611.70 Crystal system and space group: Triclinic, P -1 Unit cell dimensions: a=7.0829 (3) Angstroms alpha=95.646 (3)° b=8.2802 (4) Angstroms beta=91.317 (3)° c=26.7236 (9) Angstroms gamma=109.519 (4)° Volume of unit cell: 1467.43 (11) Angstroms 3 Calculated density: Z=2,D c=1.384 Mg m -3 Absorption coefficient: μ(MoKα)=0.167mm -1 , F(000)=648 R(int)=0.056 (Reflections collected / unique)for 6640 / 9435 Final R indices[I>2σ(I)] R1=0.0597,wR2=0.1447 R indices (all data) R1=0.0868,wR2=0.1676 1.9.3.2 Experimental results: The single crystal structure shown in Figure 20 was obtained.

Claims

1. An acid salt of a compound represented by general formula (I) or a stereoisomer thereof, 【Chemical 1】 R １ represents hydrogen, deuterium, halogen, nitro group, hydroxy group, mercapto group, cyano group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－８ is selected from a cycloalkyl group or a 3- to 8-membered heterocyclyl group, preferably １－３ Alkyl group, C １－３ Haloalkyl group, C ２－４ Alkynyl group or C ３－６ is a cycloalkyl group, R ａ are independently hydrogen, deuterium, halogen, a nitro group, a hydroxy group, a mercapto group, a cyano group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C ２－６ Alkenyl group or C ２－６ alkynyl groups, R ｂ are independently hydrogen, deuterium, halogen, a nitro group, a hydroxy group, a mercapto group, a cyano group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C ２－６ Alkenyl group or C ２－６ alkynyl groups, preferably hydrogen, deuterium, halogen, C １－３ Alkyl group, C １－３ Deuterated alkyl group or C １－３ is a haloalkyl group, R ｃ are independently hydrogen, deuterium, halogen, a nitro group, a hydroxy group, a mercapto group, a cyano group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－８ cycloalkyl groups or 3- to 8-membered heterocyclyl groups, preferably hydrogen, deuterium, halogen, cyano group, C １－３ Alkyl group, C １－３ Haloalkyl group, C １－３ Alkoxy group, C ２－４ Alkynyl group or C ３－６ cycloalkyl groups, R ｄ represents hydrogen, deuterium, halogen, nitro group, hydroxy group, mercapto group, cyano group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－８ a cycloalkyl group or a 3- to 8-membered heterocyclyl group, １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Haloalkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－８ The cycloalkyl group or the 3- to 8-membered heterocyclyl group may optionally be selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, C １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C ２－４ Alkenyl group, C ２－４ may be further substituted with one or more alkynyl groups, R ｄ is preferably a cyano group, C １－３ Alkyl group, C １－３ Haloalkyl group, C １－３ C substituted with an alkoxy group or a cyano group １－３ C substituted with alkyl group or cyano group ３－６ Cycloalkyl group, C ３－６ selected from a cycloalkyl group or a 3- to 6-membered heterocyclyl group; x is 1, 2 or 3; y is 1, 2, 3 or 4; z is 1, 2, 3 or 4; The acid in the acid salt is an inorganic acid or an organic acid, and optionally the inorganic acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, or phosphoric acid, and the organic acid is selected from 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, ethanesulfonic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic 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, dodecyl benzoate, benzoic acid ... benzoic acid, benzoic acid, benzoic acid, 4-aminobenzoic acid, benzoic acid, benzoic acid, 4-aminobenzoic acid, benzoic acid, benzoic acid, 4-aminobenzoic acid, benzoic acid, benzo and an acid salt of a compound or a stereoisomer thereof selected from the group consisting of methylsulfuric 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, and L-malic acid.

2. The compound is as follows: 【Chemistry 2】 2. The acid salt of the compound or its stereoisomer according to claim 1, wherein the acid in the acid salt is selected from isethionic acid, hydrochloric acid, sulfuric acid, 1,5-naphthalenedisulfonic acid, methanesulfonic acid, hydrobromic acid, ethanesulfonic acid, phosphoric acid, benzenesulfonic acid, oxalic acid, maleic acid, adipic acid, hydrochloric acid, citric acid, malonic acid, L-malic acid, pamoic acid, p-toluenesulfonic acid, and fumaric acid, and preferably hydrochloric acid, sulfuric acid, methanesulfonic acid, hydrobromic acid, or p-toluenesulfonic acid.

3. The acid salt of the compound or stereoisomer thereof according to claim 1 or 2, wherein the number of acids in the acid salt is 0.2 to 3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3, more preferably 0.5, 1, 2 or 3, and even more preferably 1.

4. The acid salt of the compound or stereoisomer thereof according to any one of claims 1 to 3, wherein the acid salt is a hydrate or anhydrous. When the acid salt is a hydrate, the water is preferably water of crystallization or tap water, and the number of water atoms is 0.2 to 3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3, and more preferably 2.

5. A crystalline form of an acid salt of the compound of claim 4 or a stereoisomer thereof, Optionally, it is an acid salt crystalline form of 1′-((7-ethyl-6-carbonyl-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1′,2′,3′,6′-tetrahydro-[3,4′-bipyridine]-6-carboxamide; an acid salt crystalline form of N-cyclopropyl-1'-((7-ethyl-6-carbonyl-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide; an acid salt crystalline form of 1'-((7-ethyl-6-carbonyl-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-2-methoxy-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide; an acid salt monohydrate crystalline form of 1'-((7-ethyl-6-carbonyl-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide; A crystalline form of the acid salt monohydrate of N-cyclopropyl-1'-((7-ethyl-6-carbonyl-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide, The acid salt monohydrate crystalline form of 1'-((7-ethyl-6-carbonyl-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-2-methoxy-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide, a dihydrate crystalline form of the acid salt of 1'-((7-ethyl-6-carbonyl-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide; the acid salt dihydrate crystalline form of N-cyclopropyl-1'-((7-ethyl-6-carbonyl-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide; a dihydrate crystalline form of the acid salt of 1'-((7-ethyl-6-carbonyl-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-2-methoxy-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide; More optionally, the acid salt in the acid salt crystalline form, acid salt monohydrate crystalline form, or acid salt dihydrate crystalline form is an isethionate, sulfate, hydrochloride, 1,5-naphthalenedisulfonate, methanesulfonate, ethanesulfonate, hydrobromide, phosphate, benzenesulfonate, oxalate, maleate, adipate, hydrochloride, citrate, malonate, L-malate, pamoate, p-toluenesulfonate, or fumarate salt.

6. The crystalline forms of acid salts of 1'-((7-ethyl-6-carbonyl-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide are hydrochloride crystalline form A, sulfate crystalline form A, methanesulfonate crystalline form A, p-toluenesulfonate crystalline form A, p-toluenesulfonate crystalline form B, p-toluenesulfonate crystalline form C, p-toluenesulfonate dihydrate crystalline form A, and benzenesulfonate crystalline form A; Optionally, where: The X-ray powder diffraction pattern of the hydrochloride salt crystalline form A has a diffraction peak at 2θ of 4.6±0.2°, or a diffraction peak at 7.0±0.2°, or a diffraction peak at 9.2±0.2°, or a diffraction peak at 13.8±0.2°, or a diffraction peak at 15.0±0.2°, or a diffraction peak at 16.1±0.2°, or a diffraction peak at 18.2±0.2°, or a diffraction peak at 20.8±0.2°; has a diffraction peak at 22.4±0.2°, or has a diffraction peak at 25.2±0.2°, or has a diffraction peak at 28.1±0.2°, preferably including any 2 to 5, or 3 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8, or 6 to 9, or 8 to 10, or 8 to 11 of the diffraction peaks, more preferably including any 6, 7, 8, 9, 10, or 11 of the diffraction peaks, The X-ray powder diffraction pattern of the sulfate salt crystalline form A has a diffraction peak at 2θ of 6.5±0.2°, or a diffraction peak at 9.7±0.2°, or a diffraction peak at 14.3±0.2°, or a diffraction peak at 16.1±0.2°, or a diffraction peak at 18.6±0.2°, or a diffraction peak at 19.3±0.2°, or a diffraction peak at 19.7±0.2°, or a diffraction peak at 22.0±0.2°, or a diffraction peak at 22.5±0.2°, or a diffraction peak at 23.6±0.2°. or a diffraction peak at 25.5±0.2°, or a diffraction peak at 25.9±0.2°, or a diffraction peak at 29.2±0.2°, and preferably any 2 to 5, or 3 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8, or 7 to 9, or 8 to 10, or 9 to 10, or 10 to 12, or 11 to 13 of the diffraction peaks, more preferably any 6, 7, 8, 9, 10, 11, 12, or 13 of the diffraction peaks, The X-ray powder diffraction pattern of the methanesulfonate salt crystalline form A has a diffraction peak at 2θ of 5.2±0.2°, or at 7.5±0.2°, or at 7.9±0.2°, or at 8.6±0.2°, or at 12.3±0.2°, or at 15.8±0.2°, or at 17.1±0.2°, or at 17.6±0.2°, or at 19.8±0.2°, or at 20.1±0.2°, or at 21.8±0.2°, or at 22. The diffraction peak may be at 6±0.2°, or at 25.9±0.2°, or at 26.6±0.2°, or at 27.4±0.2°, and preferably at any 2 to 5, or 3 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8, or 7 to 9, or 8 to 10, or 9 to 10, or 10 to 12, or 11 to 13, or 12 to 14, or 14 to 15 of the diffraction peaks, and more preferably at any 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 of the diffraction peaks, The X-ray powder diffraction pattern of the p-toluenesulfonate salt crystalline form A has a diffraction peak at 2θ of 5.3±0.2°, or a diffraction peak at 13.8±0.2°, or a diffraction peak at 15.7±0.2°, or a diffraction peak at 15.9±0.2°, or a diffraction peak at 18.2±0.2°, or a diffraction peak at 19.7±0.2°, or a diffraction peak at 23.2±0.2°, or a diffraction peak at 24.1±0.2°, and preferably includes any 2 to 5, or 3 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8 of the diffraction peaks, more preferably any 6, 7, or 8 of the diffraction peaks. The X-ray powder diffraction pattern of the p-toluenesulfonate salt crystalline form B has a diffraction peak at 2θ of 4.7±0.2°, or a diffraction peak at 5.2±0.2°, or a diffraction peak at 13.8±0.2°, or a diffraction peak at 14.3±0.2°, or a diffraction peak at 18.1±0.2°, or a diffraction peak at 18.7±0.2°, or a diffraction peak at 23.1±0.2°, or a diffraction peak at 25.3±0.2°, and preferably includes any 2 to 5, or 3 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8 of the diffraction peaks, more preferably any 6, 7, or 8 of the diffraction peaks. The X-ray powder diffraction pattern of the p-toluenesulfonate salt crystalline form C has a diffraction peak at 2θ of 4.6±0.2°, or a diffraction peak at 13.6±0.2°, or a diffraction peak at 14.3±0.2°, or a diffraction peak at 18.6±0.2°, or a diffraction peak at 19.4±0.2°, or a diffraction peak at 23.1±0.2°, or a diffraction peak at 25.2±0.2°, and preferably includes any 2 to 5, or 3 to 5, or 3 to 6, or 3 to 7, or 5 to 7, or 6 to 7 of the diffraction peaks, more preferably any 6 or 7 of the diffraction peaks; The X-ray powder diffraction pattern of the p-toluenesulfonate dihydrate crystalline form A has a diffraction peak at 2θ of 3.3±0.2°, or a diffraction peak at 6.6±0.2°, or a diffraction peak at 9.9±0.2°, or a diffraction peak at 13.3±0.2°, or a diffraction peak at 13.7±0.2°, or a diffraction peak at 14.2±0.2°, or a diffraction peak at 16.9±0.2°, or a diffraction peak at 23.3±0.2°, or a diffraction peak at 24.9±0.2°, and preferably includes any 2 to 5, or 3 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8, or 6 to 9, or 7 to 9 of the diffraction peaks, more preferably any 6, 7, 8, or 9 of the diffraction peaks. The crystalline form of claim 5, wherein the X-ray powder diffraction pattern of the benzenesulfonate salt crystalline form A has a diffraction peak at a 2θ of 5.3±0.2°, or a diffraction peak at 9.1±0.2°, or a diffraction peak at 13.9±0.2°, or a diffraction peak at 15.7±0.2°, or a diffraction peak at 18.9±0.2°, or a diffraction peak at 23.3±0.2°, or a diffraction peak at 23.9±0.2°, or a diffraction peak at 26.1±0.2°, and preferably includes any 2 to 5, or 3 to 5, or 3 to 6, or 3 to 8, or 5 to 8, or 6 to 8 of the diffraction peaks, more preferably any 6, 7, or 8 of the diffraction peaks.

7. The X-ray powder diffraction pattern of the hydrochloride salt crystalline form A contains at least diffraction peaks located at one or more of the positions where 2θ is 9.2±0.2°, 13.8±0.2°, and 15.0±0.2°, preferably two of them, more preferably three of them, and optionally further contains at least one of 4.6±0.2°, 7.0±0.2°, and 20.8±0.2°, preferably two or three of them; The X-ray powder diffraction pattern of the Sulfate Crystalline Form A contains at least diffraction peaks located at one or more of the positions where 2θ is 6.5±0.2°, 9.7±0.2°, 16.1±0.2°, and 23.6±0.2°, preferably two of these, more preferably three of these, and optionally further contains at least one of 18.6±0.2°, 19.3±0.2°, 25.5±0.2°, and 25.9±0.2°, preferably two or three of these; The X-ray powder diffraction pattern of the methanesulfonate salt crystalline form A comprises at least diffraction peaks located at one or more of the positions where 2θ is 5.2±0.2°, 7.5±0.2°, 15.8±0.2°, 20.1±0.2°, and 22.6±0.2°, preferably two of these, more preferably three of these, and optionally may further comprise at least one of 7.9±0.2°, 8.6±0.2°, 12.3±0.2°, 17.1±0.2°, 17.6±0.2°, 19.8±0.2°, 25.9±0.2°, 26.6±0.2°, and 27.4±0.2°, preferably two or three of these. The X-ray powder diffraction pattern of the p-toluenesulfonate salt crystalline form A contains at least diffraction peaks located at one or more of the positions where 2θ is 5.3±0.2°, 15.9±0.2°, and 18.2±0.2°, preferably two of these, more preferably three of these, and optionally further contains at least one of the positions where 2θ is 13.8±0.2°, 15.7±0.2°, 19.7±0.2°, 23.2±0.2°, and 24.1±0.2°, preferably two or three of these, The X-ray powder diffraction pattern of the p-toluenesulfonate salt crystalline form B contains at least diffraction peaks at one or more of the positions where 2θ is 4.7±0.2°, 14.3±0.2°, 23.1±0.2°, and 25.3±0.2°, preferably two of them, more preferably three of them, and optionally further contains at least one of the positions where 2θ is 5.2±0.2°, 13.8±0.2°, 18.1±0.2°, and 18.7±0.2°, preferably two or three of them; The X-ray powder diffraction pattern of the p-toluenesulfonate salt crystalline form C contains at least diffraction peaks at one or more of the positions where 2θ is 4.6±0.2°, 14.3±0.2°, 18.6±0.2°, and 25.2±0.2°, preferably two of these, more preferably three of these, and optionally further contains at least one of the positions where 2θ is 9.1±0.2°, 13.6±0.2°, 16.3±0.2°, 19.4±0.2°, and 23.1±0.2°, preferably two or three of these; The X-ray powder diffraction pattern of the p-toluenesulfonate dihydrate crystalline form A contains at least diffraction peaks at one or more of the positions where 2θ is 3.3±0.2°, 6.6±0.2°, 9.9±0.2°, and 13.3±0.2°, preferably two of these, more preferably three of these, and optionally further contains at least one of 13.7±0.2°, 14.2±0.2°, 16.9±0.2°, 23.3±0.2°, and 24.9±0.2°, preferably two, three, or four of these.

7. The crystalline form of claim 6, wherein the X-ray powder diffraction pattern of the benzenesulfonate salt crystalline form A comprises at least one or more diffraction peaks at 2θ of 5.3±0.2°, 9.1±0.2°, 13.9±0.2°, 15.7±0.2°, and 26.1±0.2°, preferably two of these, more preferably three of these, and optionally further comprises at least one of 18.9±0.2°, 23.3±0.2°, and 23.9±0.2°, preferably two or three of these.

8. The X-ray powder diffraction pattern of the hydrochloride salt crystalline form A optionally further comprises diffraction peaks at one or more of the positions where 2θ is 16.1±0.2°, 18.2±0.2°, 22.4±0.2°, 25.2±0.2°, and 28.1±0.2°, preferably at least any 2-3 or 4-5 of these positions, more preferably any 2, 3, 4, or 5 of these positions; The X-ray powder diffraction pattern of the Sulfate Salt Crystalline Form A optionally further comprises diffraction peaks at one or more of the positions where 2θ is 11.6±0.2°, 12.9±0.2°, 13.7±0.2°, 20.4±0.2°, and 20.9±0.2°, preferably at least any 2-3 or 4-5 of these positions, more preferably any 2, 3, 4, or 5 of these positions; The X-ray powder diffraction pattern of the methanesulfonate salt crystalline form A optionally further comprises diffraction peaks located at one or more of the following positions where 2θ is 4.6±0.2°, 9.1±0.2°, 10.8±0.2°, 14.6±0.2°, 15.1±0.2°, 16.7±0.2°, 20.6±0.2°, 24.4±0.2°, or 28.2±0.2°, preferably at least any 2-3 or 4-5 of these positions, more preferably any 2, 3, 4, or 5 of these positions; The X-ray powder diffraction pattern of the p-toluenesulfonate salt crystalline form A optionally further comprises diffraction peaks at one or more of the positions where 2θ is 11.3±0.2°, 19.1±0.2°, 21.6±0.2°, 25.3±0.2°, and 26.1±0.2°, preferably at least any 2 to 3, or 4 to 5, of these positions, more preferably any 2, 3, 4, or 5 of these positions; The X-ray powder diffraction pattern of the p-toluenesulfonate salt crystalline form B optionally further comprises diffraction peaks located at one or more of the following positions where 2θ is 9.2±0.2°, 16.4±0.2°, 21.7±0.2°, 23.5±0.2°, 25.7±0.2°, and 28.1±0.2°, preferably including any 2-3 or 4-5 of these positions, more preferably including any 2, 3, 4, or 5 of these positions; The X-ray powder diffraction pattern of the p-toluenesulfonate salt crystalline form C optionally further comprises diffraction peaks at one or more of the following positions where 2θ is 17.7±0.2°, 21.7±0.2°, 23.5±0.2°, 25.5±0.2°, 26.7±0.2°, and 28.1±0.2°, preferably at least any 2-3 or 4-5 of these positions, more preferably any 2, 3, 4, or 5 of these positions; The X-ray powder diffraction pattern of the p-toluenesulfonate dihydrate crystalline form A optionally further comprises diffraction peaks at one or more of the following positions where 2θ is 11.4±0.2°, 14.4±0.2°, 19.2±0.2°, 20.0±0.2°, 22.7±0.2°, 22.9±0.2°, and 26.9±0.2°, preferably at least any 2-3 or 4-5 of these positions, more preferably any 2, 3, 4, or 5 of these positions; The crystalline form of claim 6 or 7, wherein the X-ray powder diffraction pattern of the benzenesulfonate salt crystalline form A optionally further comprises diffraction peaks at one or more of the following positions where 2θ is 10.5±0.2°, 11.3±0.2°, 18.2±0.2°, 22.8±0.2°, 25.0±0.2°, 28.2±0.2°, or 32.2±0.2°, preferably at least any two to three, or at least any four to five, and more preferably any two, three, four, or five of these positions.

9. the X-ray powder diffraction pattern of the hydrochloride salt crystalline form A comprises diffraction peaks at one or more of the following positions in degrees 2θ: 4.6±0.2°, 7.0±0.2°, 9.2±0.2°, 13.8±0.2°, 15.0±0.2°, 16.1±0.2°, 18.2±0.2°, 20.8±0.2°, 22.4±0.2°, 25.2±0.2°, 28.1±0.2°, and optionally at any 4, 5, 6, 8, or 10 positions therein; the X-ray powder diffraction pattern of the Sulfate Salt Crystalline Form A comprises diffraction peaks at one or more of the following positions in degrees 2θ: 6.5±0.2°, 9.7±0.2°, 11.6±0.2°, 12.9±0.2°, 13.7±0.2°, 14.3±0.2°, 16.1±0.2°, 18.6±0.2°, 19.3±0.2°, 19.7±0.2°, 20.4±0.2°, 20.9±0.2°, 22.0±0.2°, 22.5±0.2°, 23.6±0.2°, 25.5±0.2°, 25.9±0.2°, 29.2±0.2°, and optionally at any 4, 5, 6, 8, or 10 positions therein; the X-ray powder diffraction pattern of the methanesulfonate salt crystalline form A comprises diffraction peaks at one or more of the following positions in degrees 2θ: 5.2±0.2°, 7.5±0.2°, 7.9±0.2°, 8.6±0.2°, 10.8±0.2°, 12.3±0.2°, 15.8±0.2°, 17.1±0.2°, 17.6±0.2°, 19.8±0.2°, 20.1±0.2°, 20.6±0.2°, 22.6±0.2°, 24.4±0.2°, 25.9±0.2°, 26.6±0.2°, 27.4±0.2°, 28.2±0.2°, and optionally at any 4, 5, 6, 8, or 10 positions therein; the X-ray powder diffraction pattern of the p-toluenesulfonate salt crystalline form A comprises diffraction peaks at one or more of the following positions in degrees 2θ: 5.3±0.2°, 11.3±0.2°, 13.8±0.2°, 15.7±0.2°, 15.9±0.2°, 18.2±0.2°, 19.1±0.2°, 19.7±0.2°, 21.6±0.2°, 23.2±0.2°, 25.3±0.2°, 26.1±0.2°, and optionally at any 4, 5, 6, 8, or 10 positions therein; the X-ray powder diffraction pattern of the p-toluenesulfonate salt crystalline form B comprises diffraction peaks at one or more of the following positions 2θ: 4.7±0.2°, 5.2±0.2°, 9.2±0.2°, 13.8±0.2°, 14.3±0.2°, 16.4±0.2°, 18.1±0.2°, 18.7±0.2°, 21.7±0.2°, 23.1±0.2°, 23.5±0.2°, 25.3±0.2°, 25.7±0.2°, 28.1±0.2°, and optionally at any 4, 5, 6, 8, or 10 positions therein; the X-ray powder diffraction pattern of the p-toluenesulfonate salt crystalline form C comprises diffraction peaks at one or more of the following positions 2θ: 4.6±0.2°, 9.1±0.2°, 13.6±0.2°, 14.3±0.2°, 16.3±0.2°, 17.7±0.2°, 18.6±0.2°, 19.4±0.2°, 21.7±0.2°, 23.1±0.2°, 23.5±0.2°, 25.2±0.2°, 25.5±0.2°, 26.7±0.2°, 28.1±0.2°, and optionally at any 4, 5, 6, 8, or 10 positions therein; the X-ray powder diffraction pattern of the p-toluenesulfonate dihydrate crystalline form A comprises diffraction peaks at one or more of the following positions in degrees 2θ: 3.3±0.2°, 6.6±0.2°, 9.9±0.2°, 11.4±0.2°, 13.3±0.2°, 13.7±0.2°, 14.2±0.2°, 14.4±0.2°, 16.9±0.2°, 19.2±0.2°, 20.0±0.2°, 22.7±0.2°, 22.9±0.2°, 23.3±0.2°, 24.9±0.2°, 26.9±0.2°, and optionally at any 4, 5, 6, 8, or 10 positions therein; 7. The crystalline form of claim 6, wherein the X-ray powder diffraction pattern of the benzenesulfonate salt crystalline form A comprises diffraction peaks at one or more of the following positions in degrees 2θ: 5.3±0.2°, 9.1±0.2°, 10.5±0.2°, 11.3±0.2°, 13.9±0.2°, 15.7±0.2°, 18.2±0.2°, 18.9±0.2°, 22.8±0.2°, 23.3±0.2°, 23.9±0.2°, 25.0±0.2°, 26.1±0.2°, 28.2±0.2°, 32.2±0.2°, and optionally at any 4, 5, 6, 8, or 10 positions therein.

10. 7. The crystalline form of claim 6, wherein 2θ in the X-ray powder diffraction pattern of the hydrochloride crystalline form A is as shown in Table 1; or 2θ in the X-ray powder diffraction pattern of the sulfate crystalline form A is as shown in Table 2; or 2θ in the X-ray powder diffraction pattern of the methanesulfonate crystalline form A is as shown in Table 3; or 2θ in the X-ray powder diffraction pattern of the p-toluenesulfonate crystalline form A is as shown in Table 4; or 2θ in the X-ray powder diffraction pattern of the p-toluenesulfonate crystalline form B is as shown in Table 5; or 2θ in the X-ray powder diffraction pattern of the p-toluenesulfonate crystalline form C is as shown in Table 6; or 2θ in the X-ray powder diffraction pattern of the p-toluenesulfonate dihydrate crystalline form A is as shown in Table 7; or 2θ in the X-ray powder diffraction pattern of the benzenesulfonate crystalline form A is as shown in Table 8.

11. the X-ray powder diffraction pattern of the hydrochloride salt crystalline form A is substantially as shown in FIG. 3, or the X-ray powder diffraction pattern of the sulfate salt crystalline form A is substantially as shown in FIG. 5, or the X-ray powder diffraction pattern of the methanesulfonate salt crystalline form A is substantially as shown in FIG. 7, or the X-ray powder diffraction pattern of the p-toluenesulfonate salt crystalline form A is substantially as shown in FIG. 9, or the X-ray powder diffraction pattern of the p-toluenesulfonate salt crystalline form B is substantially as shown in FIG. 11, or the X-ray powder diffraction pattern of the p-toluenesulfonate salt crystalline form C is substantially as shown in FIG. 13, or the X-ray powder diffraction pattern of the p-toluenesulfonate salt dihydrate crystalline form A is substantially as shown in FIG. 15, or the X-ray powder diffraction pattern of the benzenesulfonate salt crystalline form A is substantially as shown in FIG. 18; or the DSC pattern of the hydrochloride salt crystalline form A is substantially as shown in FIG. 4, or the DSC pattern of the sulfate salt crystalline form A is substantially as shown in FIG. 6, or the DSC pattern of the methanesulfonate salt crystalline form A is substantially as shown in FIG. 8, or the DSC pattern of the p-toluenesulfonate salt crystalline form A is substantially as shown in FIG. 10, or the DSC pattern of the p-toluenesulfonate salt crystalline form B is substantially as shown in FIG. 12, or the DSC pattern of the p-toluenesulfonate salt crystalline form C is substantially as shown in FIG. 14, or the DSC pattern of the p-toluenesulfonate salt dihydrate crystalline form A is substantially as shown in FIG. 16, or the DSC pattern of the benzenesulfonate salt crystalline form A is substantially as shown in FIG. 19; 17. The crystalline form of claim 6, wherein the TGA pattern of the p-toluenesulfonate dihydrate crystalline form A is substantially as shown in FIG.

17.

12. 12. The crystalline form of claim 11, wherein the hydrochloride crystalline form A, sulfate crystalline form A, methanesulfonate crystalline form A, p-toluenesulfonate crystalline form A, p-toluenesulfonate crystalline form B, p-toluenesulfonate crystalline form C, p-toluenesulfonate dihydrate crystalline form A, and benzenesulfonate crystalline form A have a 2θ error between the positions of the top 10 diffraction peaks in terms of relative peak intensity in an X-ray powder diffraction pattern and the corresponding diffraction peaks in an X-ray powder diffraction pattern of ±0.2° to ±0.5°, preferably ±0.2° to ±0.3°, and most preferably ±0.2°.

13. A method for producing an acid salt of the compound according to any one of claims 1 to 4 or a stereoisomer thereof, comprising: 1) Weighing out an appropriate amount of free base and dissolving it in a good solvent; 2) Weighing out an appropriate amount of counter ion acid and dissolving it in an organic solvent, where the amount of the counter ion acid is preferably 1.2 equivalents; 3) combining the two solutions and stirring to cause precipitation, or adding an anti-solvent dropwise and then stirring to cause precipitation; 4) rapidly centrifuging or allowing to stand and blow dry to obtain the acid salt; where: 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, isopropanol, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, tert-butanol, 2-butanone, 3-pentanone, and N-methylpyrrolidone, and preferably one or more of N-methylpyrrolidone, methanol, dichloromethane, and absolute 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, and N,N-dimethylformamide, and is preferably methanol, ethanol, or acetonitrile. The good solvent and the organic solution must be compatible with each other when used. the anti-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; Examples of the counter ion acid include 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, caproic acid, caprylic 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, galactosamine, methylparaben ... and wherein the acid is selected from the group consisting of carboxylic 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, and L-malic acid, and is preferably a fumarate, p-toluenesulfonate, or succinate, and most preferably a p-toluenesulfonate.

14. A method for producing a crystalline form of the acid salt of the compound or stereoisomer thereof according to any one of claims 5 to 12, comprising the steps of: Method 1 is 1) suspending the compound in an antisolvent; 2) adding a counter ion acid, the amount of the counter ion acid being preferably 1.2 equivalents, said counter ion acid being soluble in an organic solvent; 3) stirring to dissolve the solution and continuing to stir to precipitate, or adding a poor solvent dropwise and then stirring to precipitate the solution; 4) isolating to obtain the anhydrous crystalline form; Method 2 comprises a step of converting the anhydrous crystalline form of Method 1 into a crystalline form; Method 3 comprises suspending the anhydrous crystalline form of Method 1 in water and separating to obtain a hydrate crystalline form; where: the anti-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 acetone, ethanol, tetrahydrofuran, acetonitrile or toluene; 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, and is preferably methanol, ethanol, or acetonitrile; Examples of the counter ion acid include 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, caproic acid, caprylic 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, galactosamine, methylparaben ... and wherein the acid is selected from the group consisting of carboxylic 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, and L-malic acid, and is preferably a fumarate, p-toluenesulfonate, or succinate, and most preferably a p-toluenesulfonate.

15. 13. A pharmaceutical composition comprising a therapeutically effective amount of a crystalline form of the compound of any one of claims 1 to 4 or an acid salt of a stereoisomer thereof and / or a crystalline form of the compound of any one of claims 5 to 12 or an acid salt of a stereoisomer thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

16. Use of the compound according to any one of claims 1 to 4 or an acid salt of a stereoisomer thereof, a crystalline form of the compound according to any one of claims 5 to 12 or an acid salt of a stereoisomer thereof, or the pharmaceutical composition according to claim 15 in the manufacture of a PARP inhibitor drug, wherein the PARP is preferably PARP1.

17. Use of the compound according to any one of claims 1 to 4 or an acid salt of a stereoisomer thereof, a crystalline form of the compound according to any one of claims 5 to 12 or an acid salt of a stereoisomer thereof, or the pharmaceutical composition according to claim 15 in the manufacture of a medicament for treating cancer, an ischemic disease or a neurodegenerative disease, optionally wherein the cancer is selected from breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastric cancer, colorectal cancer, gastrointestinal cancer and lung cancer.

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