Salt and crystal form of heterocyclic derivative inhibitor, and preparation method and application of salt and crystal form

Abstract

The invention relates to a salt and a crystal form of a heterocyclic derivative inhibitor as well as a preparation method and application of the salt and the crystal form. In particular, the present invention relates to a salt, a crystal form and a preparation method of a compound represented by general formula (I), a pharmaceutical composition containing a therapeutically effective amount of the salt and / or the crystal form, and a use of the pharmaceutical composition as an inhibitor in cancer treatment, each substituent in the general formula (I) being as defined in the specification. # imgabs0 #

Description

Salt, crystal form, preparation method and application of heterocyclic derivative inhibitor Technical Field

[0001] The present invention belongs to the field of biomedicine, and specifically relates to a salt, a crystal form, a preparation method and an application of a heterocyclic derivative inhibitor. Background Art

[0002] Poly(ADP-ribose) polymerases (PARPs) are a superfamily of proteins that catalyze the ADP-ribosylation of proteins in eukaryotic cells and include at least 17 isoforms. PARPs catalyze the cleavage of their substrate, nicotinamide adenine dinucleotide (NAD+), into nicotinamide and ADP-ribose, and subsequently poly(ADP-ribosyl)ate their target proteins. Localized in the cell nucleus, PARPs are key enzymes in cellular DNA repair.

[0003] PARP1 is the earliest discovered and most studied PARP isoform, consisting of three major domains: the N-terminal DNA binding domain (DBD), the self-modification domain (AMD), and the C-terminal catalytic domain. PARP1 is an important functional protein in the DNA damage repair process. As a sensor of single-strand DNA damage, PARP1 can activate DNA damage, and then poly ADP-ribosylate its target proteins, such as histones, and recruit related repair proteins to promote DNA damage repair. PARP1 is very important for the stability of the genome of normal cells. However, in tumor treatment, PARP1 repairs the DNA of tumor cells damaged by radiotherapy and chemotherapy, which antagonizes the tumor-killing effect of radiotherapy and chemotherapy. Therefore, PARP1 inhibitors can be developed as sensitizers for tumor radiotherapy and chemotherapy.

[0004] The breast cancer susceptibility gene (BRCA) is an important tumor suppressor gene, primarily consisting of two subtypes: BRCA1 and BRCA2. BRCA plays a crucial role in repairing double-strand breaks (DSBs) during homologous recombination. BRCA deficiency often occurs in tumor cells, leading to a loss of DSB repair. Simultaneously, PARP1 function is lost or inhibited, leading to a loss of SSB repair, ultimately causing tumor cell death and resulting in a "synthetic lethality" effect. Therefore, PARP1 inhibitors, designed to block SSB repair, have a selective killing effect on BRCA-deficient tumors.

[0005] PARP inhibitors have achieved significant success in precision medicine oncology, particularly against tumors harboring BRCA mutations or deficiencies. Currently marketed 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 ovarian and breast cancers harboring BRCA mutations. Numerous PARP inhibitors are currently under clinical development. Within the PARP family, PARP2 shares the highest homology with PARP1. Therefore, most PARP inhibitors currently marketed or in clinical trials are non-selective, potent inhibitors of both PARP1 and PARP2. Studies have shown that PARP2 plays a crucial role in regulating erythropoiesis, and PARP2 inhibition is closely linked to the clinically observed hematologic side effects of PARP inhibitors, such as anemia.

[0006] Summary of the Invention

[0007] Jiangsu Hausen Pharmaceuticals Group Co., Ltd.'s patent application (Application Number: PCT / CN2022 / 088466) discloses the structures of a series of heterocyclic derivative inhibitors. In subsequent research and development, to ensure ease of handling, filtration, drying, storage, long-term product stability, and high bioavailability, the present inventors conducted a comprehensive study of the salts and crystal forms of the aforementioned substances, aiming to identify the most suitable crystal form.

[0008] All contents involved in patent application PCT / CN2022 / 088466 are added to the present invention by reference.

[0009] The object of the present invention is to provide a compound represented by general formula (I) or an acid salt of its stereoisomers.

[0010] in,

[0011] R1 is selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group; preferably C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 2-4 Alkynyl or C3-6 Cycloalkyl;

[0012] R a independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0013] R b independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl or C 2-6 Alkynyl; preferably hydrogen, deuterium, halogen, C 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 alkyl halide;

[0014] R c independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group; preferably selected from hydrogen, deuterium, halogen, cyano, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 2-4 Alkynyl or C 3-6 Cycloalkyl;

[0015] R d Selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, the C1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, optionally further substituted by hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 One or more substitutions in the alkynyl group; R d Preferably selected from cyano, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, cyano substituted C 1-3 Alkyl, cyano substituted C 3- 6 cycloalkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group;

[0016] x is 1, 2, or 3;

[0017] y is 1, 2, 3, or 4;

[0018] z is 1, 2, 3, or 4;

[0019] The acid in the acid salt is an inorganic acid or an organic acid; preferably, the inorganic acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid or phosphoric acid; the organic acid is selected from 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, 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, hexanoic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid aminoacid, tartaric acid, dodecylsulfuric acid, dibenzoyltartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactosonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalene disulfonic acid, naphthalene-2-sulfonic acid, niacin, 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.

[0020] In certain embodiments of the present invention, the compound is as follows:

[0021] 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 or fumaric acid; preferably hydrochloric acid, sulfuric acid, methanesulfonic acid, hydrobromic acid or p-toluenesulfonic acid.

[0022] In certain embodiments of the present invention, the number of acids in the acid salt is 0.2-3; preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3; more preferably 0.5, 1, 2 or 3, and even more preferably 1.

[0023] In certain embodiments of the present invention, the acid salt is a hydrate or an anhydrate; when the acid salt is a hydrate, the water is preferably crystal water or pipeline water; the number of water is 0.2-3; preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3; more preferably 2.

[0024] The present invention also provides a crystalline form of the acid salt of the above compound or its stereoisomer;

[0025] Preferably, 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 Acid salt crystalline form, 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 Acid salt 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 crystalline form, 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, N-cyclopropyl-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, 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, acid salt dihydrate 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, 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 acid salt dihydrate 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 dihydrate crystalline form;

[0026] More preferably, the acid salt in the acid salt crystalline form, the acid salt monohydrate crystalline form or the acid salt dihydrate crystalline form is isethionate, sulfate, hydrochloride, 1,5-naphthalene disulfonate, methanesulfonate, ethanesulfonate, hydrobromide, phosphate, benzenesulfonate, oxalate, maleate, adipate, hydrochloride, citrate, malonate, L-malate, pamoate, p-toluenesulfonate or fumarate.

[0027] In certain embodiments of the present invention, the 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 is hydrochloride form A, sulfate form A, methanesulfonate form A, p-toluenesulfonate form A, p-toluenesulfonate form B, p-toluenesulfonate form C, p-toluenesulfonate dihydrate form A, or benzenesulfonic acid form A.

[0028] In certain embodiments of the present invention, the X-ray powder diffraction pattern of the hydrochloride 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; or 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 includes any 2-5 of the above diffraction peaks, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8, or 6-9, or 8-10, or 8-11, more preferably includes any 6, 7, 8, 9, 10 or 11 of them.

[0029] In certain embodiments of the present invention, the X-ray powder diffraction pattern of the hydrochloride salt form A comprises at least one or more diffraction peaks located at 2θ of 9.2±0.2°, 13.8±0.2°, and 15.0±0.2°, preferably two of them, more preferably three; optionally, it may further comprise at least one of 4.6±0.2°, 7.0±0.2°, and 20.8±0.2°, preferably two or three of them.

[0030] In certain embodiments of the present invention, the X-ray powder diffraction pattern of the hydrochloride salt form A optionally further comprises one or more diffraction peaks located at 2θ of 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 them; further preferably, any 2, 3, 4, or 5 of them are included.

[0031] In certain embodiments of the present invention, the X-ray powder diffraction pattern of the hydrochloride salt form A comprises one or more diffraction peaks located at 2θ of 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°, and 28.1±0.2°; preferably, it comprises diffraction peaks at any of 4, 5, 6, 8 or 10 locations.

[0032] In certain embodiments of the present invention, the hydrochloride salt form A, using Cu-Kα radiation, has X-ray characteristic diffraction peaks expressed in 2θ angles and interplanar spacing d values ​​as shown in the following table:

[0033] Table 1

[0034] In certain embodiments of the present invention, the X-ray powder diffraction pattern of hydrochloride Form A is substantially as shown in FIG3 XRPD.

[0035] In certain embodiments of the present invention, the DSC spectrum of hydrochloride salt form A is substantially as shown in FIG4 .

[0036] In certain embodiments of the present invention, the X-ray powder diffraction pattern of the sulfate 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 It has a diffraction peak at 23.6±0.2°; or it has a diffraction peak at 25.5±0.2°; or it has a diffraction peak at 25.9±0.2°; or it has a diffraction peak at 29.2±0.2°; it preferably contains any 2-5 of the above diffraction peaks, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8, or 7-9, or 8-10, or 9-10, or 10-12, or 11-13, and more preferably contains any 6, 7, 8, 9, 10, 11, 12 or 13 of them.

[0037] In certain embodiments of the present invention, the X-ray powder diffraction pattern of the sulfate salt crystalline form A comprises at least one or more diffraction peaks located at 2θ of 6.5±0.2°, 9.7±0.2°, 16.1±0.2°, and 23.6±0.2°, preferably two of them, more preferably three; optionally, it may further comprise 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 them.

[0038] In certain embodiments of the present invention, the X-ray powder diffraction pattern of the sulfate salt crystalline form A optionally further comprises one or more diffraction peaks located at 2θ of 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 them; further preferably, any 2, 3, 4, or 5 of them are included.

[0039] In certain embodiments of the present invention, the X-ray powder diffraction pattern of the sulfate salt crystalline form A comprises one or more diffraction peaks located at 2θ of 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°, and 29.2±0.2°; preferably, the diffraction peaks are selected from 4, 5, 6, 8, or 10 of them.

[0040] In certain embodiments of the present invention, the sulfate crystalline form A, using Cu-Kα radiation, has X-ray characteristic diffraction peaks expressed in 2θ angles and interplanar spacing d values ​​as shown in the following table:

[0041] Table 2

[0042] In certain embodiments of the present invention, the X-ray powder diffraction pattern of sulfate salt form A is substantially as shown in FIG5 .

[0043] In certain embodiments of the present invention, the DSC spectrum of sulfate salt form A is substantially as shown in FIG6 .

[0044] In certain embodiments of the present invention, the X-ray powder diffraction pattern of the mesylate salt form A has a diffraction peak at 2θ of 5.2±0.2°; or a diffraction peak at 7.5±0.2°; or a diffraction peak at 7.9±0.2°; or a diffraction peak at 8.6±0.2°; or a diffraction peak at 12.3±0.2°; or a diffraction peak at 15.8±0.2°; or a diffraction peak at 17.1±0.2°; or a diffraction peak at 17.6±0.2°; or a diffraction peak at 19.8±0.2°; or a diffraction peak at 20.1±0.2°; or a diffraction peak at 21.8±0.2°. Peak; 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°; preferably includes any 2-5 of the above diffraction peaks, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8, or 7-9, or 8-10, or 9-10, or 10-12, or 11-13, or 12-14, or 14-15, more preferably includes any 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 thereof.

[0045] In certain embodiments of the present invention, the X-ray powder diffraction pattern of the mesylate salt form A comprises at least one or more diffraction peaks located at 2θ 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, and more preferably three; optionally, it 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 them.

[0046] In certain embodiments of the present invention, the X-ray powder diffraction pattern of the mesylate salt form A optionally further comprises one or more diffraction peaks located at 2θ of 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°, and 28.2±0.2°; preferably, at least any 2-3 or 4-5 of them; further preferably, any 2, 3, 4, or 5 of them are included.

[0047] In certain embodiments of the present invention, the X-ray powder diffraction pattern of the mesylate salt form A comprises one or more diffraction peaks located at 2θ of 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°, and 28.2±0.2°; preferably, the diffraction peaks are selected from 4, 5, 6, 8, or 10 of them.

[0048] In certain embodiments of the present invention, the mesylate salt crystalline form A, using Cu-Kα radiation, has X-ray characteristic diffraction peaks expressed in 2θ angles and interplanar spacing d values ​​as shown in the following table:

[0049] Table 3

[0050] In certain embodiments of the present invention, the X-ray powder diffraction pattern of the mesylate salt Form A is substantially as shown in FIG. 7 .

[0051] In certain embodiments of the present invention, the DSC spectrum of mesylate salt Form A is substantially as shown in FIG8 .

[0052] In certain embodiments of the present invention, the X-ray powder diffraction pattern of the p-toluenesulfonate salt 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 includes any 2-5 of the above diffraction peaks, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8, and more preferably includes any 6, 7 or 8 of them.

[0053] In certain embodiments of the present invention, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form A comprises at least one or more diffraction peaks located at 2θ of 5.3±0.2°, 15.9±0.2°, and 18.2±0.2°, preferably two of them, and more preferably three; optionally, it may further comprise 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 them.

[0054] In certain embodiments of the present invention, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form A optionally further comprises one or more diffraction peaks located at 2θ of 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 2-3 or 4-5 of them; further preferably, any 2, 3, 4, or 5 of them are included.

[0055] In certain embodiments of the present invention, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form A comprises one or more diffraction peaks located at 2θ of 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°, and 26.1±0.2°; preferably, the diffraction peaks are selected from 4, 5, 6, 8, or 10 of them.

[0056] In certain embodiments of the present invention, the p-toluenesulfonate crystalline form A, using Cu-Kα radiation, has X-ray characteristic diffraction peaks expressed in 2θ angles and interplanar spacing d values ​​as shown in the following table:

[0057] Table 4

[0058] In certain embodiments of the present invention, the X-ray powder diffraction pattern of the p-toluenesulfonate crystalline form A is substantially as shown in FIG9 .

[0059] In certain embodiments of the present invention, the DSC spectrum of the p-toluenesulfonate crystalline form A is substantially as shown in FIG10 .

[0060] In certain embodiments of the present invention, the X-ray powder diffraction pattern of the p-toluenesulfonate salt 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 includes any 2-5 of the above diffraction peaks, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8, and more preferably includes any 6, 7 or 8 of them.

[0061] In certain embodiments of the present invention, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form B comprises at least one or more diffraction peaks located at 2θ of 4.7±0.2°, 14.3±0.2°, 23.1±0.2°, and 25.3±0.2°, preferably two of them, and more preferably three; optionally, it may further comprise at least one of 5.2±0.2°, 13.8±0.2°, 18.1±0.2°, and 18.7±0.2°, preferably two or three of them.

[0062] In certain embodiments of the present invention, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form B optionally further comprises one or more diffraction peaks located at 2θ of 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, at least any 2-3 or 4-5 of them; further preferably, any 2, 3, 4, or 5 of them are included.

[0063] In certain embodiments of the present invention, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form B comprises one or more diffraction peaks located at 2θ of 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°, and 28.1±0.2°; preferably, the diffraction peaks are selected from 4, 5, 6, 8, or 10 of them.

[0064] In certain embodiments of the present invention, the p-toluenesulfonate crystalline form B, using Cu-Kα radiation, has characteristic X-ray diffraction peaks expressed in 2θ angles and interplanar spacing d values ​​as shown in the following table:

[0065] Table 5

[0066] In certain embodiments of the present invention, the X-ray powder diffraction pattern of the p-toluenesulfonate crystalline Form B is substantially as shown in FIG11 .

[0067] In certain embodiments of the present invention, the DSC spectrum of the p-toluenesulfonate crystalline Form B is substantially as shown in FIG12 .

[0068] In certain embodiments of the present invention, the X-ray powder diffraction pattern of the p-toluenesulfonate 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°; preferably includes any 2-5 of the above diffraction peaks, or 3-5, or 3-6, or 3-7, or 5-7, or 6-7, and more preferably includes any 6 or 7 of them.

[0069] In certain embodiments of the present invention, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form C comprises at least one or more diffraction peaks located at 2θ of 4.6±0.2°, 14.3±0.2°, 18.6±0.2°, and 25.2±0.2°, preferably two of them, and more preferably three; optionally, it may further comprise at least one 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.

[0070] In certain embodiments of the present invention, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form C optionally further comprises one or more diffraction peaks located at 2θ of 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 them; further preferably, any 2, 3, 4, or 5 of them are included.

[0071] In certain embodiments of the present invention, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form C comprises one or more diffraction peaks located at 2θ of 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°, and 28.1±0.2°; preferably, the diffraction peaks are selected from 4, 5, 6, 8, or 10 of them.

[0072] In certain embodiments of the present invention, the p-toluenesulfonate crystalline form C, using Cu-Kα radiation, has X-ray characteristic diffraction peaks expressed in 2θ angles and interplanar spacing d values ​​as shown in the following table:

[0073] Table 6

[0074] In certain embodiments of the present invention, the X-ray powder diffraction pattern of p-toluenesulfonate Form C is substantially as shown in FIG. 13 .

[0075] In certain embodiments of the present invention, the DSC spectrum of p-toluenesulfonate Form C is substantially as shown in FIG14 .

[0076] In certain 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 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°. Peak; or has a diffraction peak at 16.9±0.2°; or has a diffraction peak at 23.3±0.2°; or has a diffraction peak at 24.9±0.2°; preferably includes any 2-5 of the above diffraction peaks, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8, or 6-9, or 7-9, more preferably includes any 6, 7, 8 or 9 thereof.

[0077] In certain 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 located at 2θ of 3.3±0.2°, 6.6±0.2°, 9.9±0.2°, and 13.3±0.2°, preferably two of them, more preferably three; optionally, it may further comprise 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 them; for example,

[0078] 3.3±0.2°, 6.6±0.2°;

[0079] 3.3±0.2°, 9.9±0.2°;

[0080] 9.9±0.2°, 13.3±0.2°;

[0081] 6.6±0.2°, 9.9±0.2°;

[0082] 3.3±0.2°, 13.3±0.2°;

[0083] 6.6±0.2°, 13.3±0.2°;

[0084] 3.3±0.2°, 6.6±0.2°, 9.9±0.2°;

[0085] 3.3±0.2°, 6.6±0.2°, 13.3±0.2°;

[0086] 3.3±0.2°, 9.9±0.2°, 13.3±0.2°;

[0087] 6.6±0.2°, 9.9±0.2°, 13.3±0.2°;

[0088] 3.3±0.2°, 6.6±0.2°, 13.7±0.2°;

[0089] 3.3±0.2°, 9.9±0.2°, 13.7±0.2°;

[0090] 9.9±0.2°, 13.3±0.2°, 13.7±0.2°;

[0091] 6.6±0.2°, 9.9±0.2°, 13.7±0.2°;

[0092] 3.3±0.2°, 13.3±0.2°, 13.7±0.2°;

[0093] 6.6±0.2°、13.3±0.2°、13.7±0.2°；

[0094] 3.3±0.2°、6.6±0.2°、14.2±0.2°；

[0095] 3.3±0.2°、9.9±0.2°、14.2±0.2°；

[0096] 9.9±0.2°、13.3±0.2°、14.2±0.2°；

[0097] 6.6±0.2°、9.9±0.2°、14.2±0.2°；

[0098] 3.3±0.2°、13.3±0.2°、14.2±0.2°；

[0099] 6.6±0.2°、13.3±0.2°、14.2±0.2°；

[0100] 3.3±0.2°、6.6±0.2°、16.9±0.2°；

[0101] 3.3±0.2°、9.9±0.2°、16.9±0.2°；

[0102] 9.9±0.2°、13.3±0.2°、16.9±0.2°；

[0103] 6.6±0.2°、9.9±0.2°、16.9±0.2°；

[0104] 3.3±0.2°、13.3±0.2°、16.9±0.2°；

[0105] 6.6±0.2°、13.3±0.2°、16.9±0.2°；

[0106] 3.3±0.2°、6.6±0.2°、23.3±0.2°；

[0107] 3.3±0.2°、9.9±0.2°、23.3±0.2°；

[0108] 9.9±0.2°、13.3±0.2°、23.3±0.2°；

[0109] 6.6±0.2°、9.9±0.2°、23.3±0.2°；

[0110] 3.3±0.2°、13.3±0.2°、23.3±0.2°；

[0111] 6.6±0.2°、13.3±0.2°、23.3±0.2°；

[0112] 3.3±0.2°、6.6±0.2°、24.9±0.2°；

[0113] 3.3±0.2°、9.9±0.2°、24.9±0.2°；

[0114] 9.9±0.2°、13.3±0.2°、24.9±0.2°；

[0115] 6.6±0.2°、9.9±0.2°、24.9±0.2°；

[0116] 3.3±0.2°、13.3±0.2°、24.9±0.2°；

[0117] 6.6±0.2°、13.3±0.2°、24.9±0.2°；

[0118] 3.3±0.2°、6.6±0.2°、9.9±0.2°；

[0119] 3.3±0.2°、6.6±0.2°、13.3±0.2°；

[0120] 3.3±0.2°、9.9±0.2°、13.3±0.2°；

[0121] 6.6±0.2°、9.9±0.2°、13.3±0.2°；

[0122] 3.3±0.2°、6.6±0.2°、9.9±0.2°、13.3±0.2°；

[0123] 3.3±0.2°、6.6±0.2°、9.9±0.2°、13.7±0.2°；

[0124] 3.3±0.2°、6.6±0.2°、13.3±0.2°、13.7±0.2°；

[0125] 3.3±0.2°、9.9±0.2°、13.3±0.2°、13.7±0.2°；

[0126] 6.6±0.2°、9.9±0.2°、13.3±0.2°、13.7±0.2°；

[0127] 3.3±0.2°、6.6±0.2°、9.9±0.2°、14.2±0.2°；

[0128] 3.3±0.2°、6.6±0.2°、13.3±0.2°、14.2±0.2°；

[0129] 3.3±0.2°、9.9±0.2°、13.3±0.2°、14.2±0.2°；

[0130] 6.6±0.2°、9.9±0.2°、13.3±0.2°、14.2±0.2°；

[0131] 3.3±0.2°、6.6±0.2°、9.9±0.2°、16.9±0.2°；

[0132] 3.3±0.2°、6.6±0.2°、13.3±0.2°、16.9±0.2°；

[0133] 3.3±0.2°、9.9±0.2°、13.3±0.2°、16.9±0.2°；

[0134] 6.6±0.2°、9.9±0.2°、13.3±0.2°、16.9±0.2°；

[0135] 3.3±0.2°、6.6±0.2°、9.9±0.2°、23.3±0.2°；

[0136] 3.3±0.2°、6.6±0.2°、13.3±0.2°、23.3±0.2°；

[0137] 3.3±0.2°、9.9±0.2°、13.3±0.2°、23.3±0.2°；

[0138] 6.6±0.2°、9.9±0.2°、13.3±0.2°、23.3±0.2°；

[0139] 3.3±0.2°、6.6±0.2°、9.9±0.2°、24.9±0.2°；

[0140] 3.3±0.2°、6.6±0.2°、13.3±0.2°、24.9±0.2°；

[0141] 3.3±0.2°、9.9±0.2°、13.3±0.2°、24.9±0.2°；

[0142] 6.6±0.2°、9.9±0.2°、13.3±0.2°、24.9±0.2°；

[0143] 3.3±0.2°、6.6±0.2°、9.9±0.2°、13.3±0.2°、13.7±0.2°；

[0144] 3.3±0.2°、6.6±0.2°、9.9±0.2°、13.3±0.2°、14.2±0.2°；

[0145] 3.3±0.2°、6.6±0.2°、9.9±0.2°、13.3±0.2°、16.9±0.2°；

[0146] 3.3±0.2°、6.6±0.2°、9.9±0.2°、13.3±0.2°、23.3±0.2°；

[0147] 3.3±0.2°、6.6±0.2°、9.9±0.2°、13.3±0.2°、24.9±0.2°；

[0148] 3.3±0.2°、6.6±0.2°、9.9±0.2°、13.7±0.2°、14.2±0.2°；

[0149] 3.3±0.2°、6.6±0.2°、13.3±0.2°、13.7±0.2°、24.9±0.2°；

[0150] 3.3±0.2°、9.9±0.2°、13.3±0.2°、16.9±0.2°、23.3±0.2°；

[0151] 6.6±0.2°、9.9±0.2°、13.3±0.2°、14.2±0.2°、23.3±0.2°；

[0152] 3.3±0.2°、6.6±0.2°、9.9±0.2°、13.3±0.2°、13.7±0.2°、14.2±0.2°；

[0153] 3.3±0.2°、6.6±0.2°、9.9±0.2°、13.3±0.2°、23.3±0.2°、24.9±0.2°；

[0154] 3.3±0.2°、6.6±0.2°、9.9±0.2°、13.3±0.2°、13.7±0.2°、24.9±0.2°；

[0155] 3.3±0.2°、6.6±0.2°、9.9±0.2°、13.3±0.2°、14.2±0.2°、16.9±0.2°；

[0156] 3.3±0.2°、6.6±0.2°、9.9±0.2°、13.3±0.2°、14.2±0.2°、23.3±0.2°；

[0157] 3.3±0.2°、6.6±0.2°、9.9±0.2°、13.3±0.2°、16.9±0.2°、24.9±0.2°；

[0158] 3.3±0.2°、6.6±0.2°、9.9±0.2°、13.7±0.2°、14.2±0.2°、16.9±0.2°；

[0159] 3.3±0.2°、6.6±0.2°、13.3±0.2°、16.9±0.2°、23.3±0.2°、24.9±0.2°；

[0160] 3.3±0.2°、9.9±0.2°、13.3±0.2°、13.7±0.2°、23.3±0.2°、24.9±0.2°；

[0161] 6.6±0.2°、9.9±0.2°、13.3±0.2°、14.2±0.2°、16.9±0.2°、23.3±0.2°；

[0162] 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°；

[0163] 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°；

[0164] 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°；

[0165] 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°；

[0166] 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°；

[0167] 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°;

[0168] 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°;

[0169] 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°;

[0170] 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°, 24.9±0.2°.

[0171] In certain embodiments of the present invention, the X-ray powder diffraction pattern of the p-toluenesulfonate dihydrate crystalline form A optionally further comprises one or more diffraction peaks located at 2θ of 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 them; further preferably, any 2, 3, 4, or 5 of them; for example,

[0172] 11.4±0.2°, 14.4±0.2°;

[0173] 11.4±0.2°, 26.9±0.2°;

[0174] 19.2±0.2°, 20.0±0.2°;

[0175] 14.4±0.2°, 19.2±0.2°;

[0176] 14.4±0.2°, 22.7±0.2°;

[0177] 22.9±0.2°, 26.9±0.2°;

[0178] 11.4±0.2°, 14.4±0.2°, 19.2±0.2°;

[0179] 22.7±0.2°、22.9±0.2°、26.9±0.2°；

[0180] 19.2±0.2°、20.0±0.2°、22.7±0.2°；

[0181] 14.4±0.2°、19.2±0.2°、20.0±0.2°；

[0182] 20.0±0.2°、22.7±0.2°、22.9±0.2°；

[0183] 22.7±0.2°、22.9±0.2°、26.9±0.2°；

[0184] 14.4±0.2°、20.0±0.2°、22.7±0.2°；

[0185] 11.4±0.2°、14.4±0.2°、19.2±0.2°、20.0±0.2°；

[0186] 20.0±0.2°、22.7±0.2°、22.9±0.2°、26.9±0.2°；

[0187] 11.4±0.2°、22.7±0.2°、22.9±0.2°、26.9±0.2°；

[0188] 11.4±0.2°、14.4±0.2°、22.9±0.2°、26.9±0.2°；

[0189] 11.4±0.2°、14.4±0.2°、19.2±0.2°、26.9±0.2°；

[0190] 14.4±0.2°、19.2±0.2°、20.0±0.2°、22.7±0.2°；

[0191] 19.2±0.2°、20.0±0.2°、22.7±0.2°、22.9±0.2°；

[0192] 20.0±0.2°、22.7±0.2°、22.9±0.2°、26.9±0.2°；

[0193] 11.4±0.2°、14.4±0.2°、19.2±0.2°、20.0±0.2°、22.7±0.2°；

[0194] 11.4±0.2°、14.4±0.2°、19.2±0.2°、20.0±0.2°、26.9±0.2°；

[0195] 11.4±0.2°、14.4±0.2°、19.2±0.2°、22.9±0.2°、26.9±0.2°；

[0196] 11.4±0.2°、14.4±0.2°、22.7±0.2°、22.9±0.2°、26.9±0.2°；

[0197] 11.4±0.2°、20.0±0.2°、22.7±0.2°、22.9±0.2°、26.9±0.2°；

[0198] 19.2±0.2°、20.0±0.2°、22.7±0.2°、22.9±0.2°、26.9±0.2°；

[0199] 14.4±0.2°、19.2±0.2°、20.0±0.2°、22.7±0.2°、22.9±0.2°；

[0200] 11.4±0.2°、19.2±0.2°、20.0±0.2°、22.7±0.2°、26.9±0.2°；

[0201] 11.4±0.2°、19.2±0.2°、20.0±0.2°、22.7±0.2°、22.9±0.2°；

[0202] 11.4±0.2°、14.4±0.2°、20.0±0.2°、22.7±0.2°、26.9±0.2°；

[0203] 14.4±0.2°、19.2±0.2°、22.7±0.2°、22.9±0.2°、26.9±0.2°；

[0204] 14.4±0.2°、19.2±0.2°、20.0±0.2°、22.7±0.2°、26.9±0.2°。

[0205] In certain embodiments of the present invention, the X-ray powder diffraction pattern of the p-toluenesulfonate dihydrate crystalline form A comprises 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°, One or more diffraction peaks selected from 20.0±0.2°, 22.7±0.2°, 22.9±0.2°, 23.3±0.2°, 24.9±0.2°, and 26.9±0.2°; preferably, diffraction peaks are selected from 4, 5, 6, 8, or 10 of the diffraction peaks; for example, the X-ray powder diffraction pattern of the p-toluenesulfonate dihydrate crystalline form A has diffraction peaks at the following positions in 2θ:

[0206] 3.3±0.2°, 6.6±0.2°, 9.9±0.2°, 11.4±0.2°;

[0207] 3.3±0.2°, 6.6±0.2°, 13.3±0.2°, 14.4±0.2°;

[0208] 3.3±0.2°, 9.9±0.2°, 13.3±0.2°, 19.2±0.2°;

[0209] 6.6±0.2°, 9.9±0.2°, 13.3±0.2°, 20.0±0.2°;

[0210] 3.3±0.2°, 6.6±0.2°, 13.7±0.2°, 22.7±0.2°;

[0211] 3.3±0.2°, 9.9±0.2°, 13.7±0.2°, 22.9±0.2°;

[0212] 9.9±0.2°, 13.3±0.2°, 13.7±0.2°, 26.9±0.2°;

[0213] 6.6±0.2°, 9.9±0.2°, 11.4±0.2°, 13.7±0.2°;

[0214] 3.3±0.2°, 13.3±0.2°, 13.7±0.2°, 14.4±0.2°;

[0215] 6.6±0.2°, 13.3±0.2°, 13.7±0.2°, 19.2±0.2°;

[0216] 3.3±0.2°, 6.6±0.2°, 14.2±0.2°, 20.0±0.2°;

[0217] 3.3±0.2°、9.9±0.2°、14.2±0.2°、22.7±0.2°；

[0218] 9.9±0.2°、13.3±0.2°、14.2±0.2°、22.9±0.2°；

[0219] 6.6±0.2°、9.9±0.2°、14.2±0.2°、26.9±0.2°；

[0220] 3.3±0.2°、11.4±0.2°、13.3±0.2°、14.2±0.2°；

[0221] 6.6±0.2°、13.3±0.2°、14.2±0.2°、14.4±0.2°；

[0222] 3.3±0.2°、6.6±0.2°、16.9±0.2°、19.2±0.2°；

[0223] 3.3±0.2°、9.9±0.2°、16.9±0.2°、20.0±0.2°；

[0224] 9.9±0.2°、13.3±0.2°、16.9±0.2°、22.7±0.2°；

[0225] 6.6±0.2°、9.9±0.2°、16.9±0.2°、22.9±0.2°；

[0226] 3.3±0.2°、13.3±0.2°、16.9±0.2°、26.9±0.2°；

[0227] 3.3±0.2°、6.6±0.2°、9.9±0.2°、11.4±0.2°、13.3±0.2°；

[0228] 3.3±0.2°、6.6±0.2°、9.9±0.2°、13.7±0.2°、14.4±0.2°；

[0229] 3.3±0.2°、6.6±0.2°、13.3±0.2°、13.7±0.2°、19.2±0.2°；

[0230] 3.3±0.2°、9.9±0.2°、13.3±0.2°、13.7±0.2°、20.0±0.2°；

[0231] 6.6±0.2°、9.9±0.2°、13.3±0.2°、13.7±0.2°、22.7±0.2°；

[0232] 3.3±0.2°、6.6±0.2°、9.9±0.2°、14.2±0.2°、22.9±0.2°；

[0233] 3.3±0.2°、6.6±0.2°、13.3±0.2°、14.2±0.2°、26.9±0.2°；

[0234] 3.3±0.2°、9.9±0.2°、11.4±0.2°、13.3±0.2°、14.2±0.2°；

[0235] 6.6±0.2°、9.9±0.2°、13.3±0.2°、14.2±0.2°、14.4±0.2°；

[0236] 3.3±0.2°、6.6±0.2°、9.9±0.2°、16.9±0.2°、19.2±0.2°；

[0237] 3.3±0.2°、6.6±0.2°、13.3±0.2°、16.9±0.2°、20.0±0.2°；

[0238] 3.3±0.2°、9.9±0.2°、13.3±0.2°、16.9±0.2°、22.7±0.2°；

[0239] 6.6±0.2°、9.9±0.2°、13.3±0.2°、16.9±0.2°、22.9±0.2°；

[0240] 3.3±0.2°、6.6±0.2°、9.9±0.2°、23.3±0.2°、26.9±0.2°；

[0241] 3.3±0.2°、6.6±0.2°、11.4±0.2°、13.3±0.2°、23.3±0.2°；

[0242] 3.3±0.2°、9.9±0.2°、13.3±0.2°、14.4±0.2°、23.3±0.2°；

[0243] 6.6±0.2°、9.9±0.2°、13.3±0.2°、19.2±0.2°、23.3±0.2°；

[0244] 3.3±0.2°、6.6±0.2°、9.9±0.2°、20.0±0.2°、24.9±0.2°；

[0245] 3.3±0.2°、6.6±0.2°、13.3±0.2°、22.7±0.2°、24.9±0.2°；

[0246] 3.3±0.2°、9.9±0.2°、13.3±0.2°、22.9±0.2°、24.9±0.2°；

[0247] 6.6±0.2°、9.9±0.2°、13.3±0.2°、26.9±0.2°、24.9±0.2°；

[0248] 3.3±0.2°、6.6±0.2°、9.9±0.2°、11.4±0.2°、13.3±0.2°、13.7±0.2°；

[0249] 3.3±0.2°、6.6±0.2°、9.9±0.2°、13.3±0.2°、14.2±0.2°、14.4±0.2°；

[0250] 3.3±0.2°、6.6±0.2°、9.9±0.2°、13.3±0.2°、16.9±0.2°、19.2±0.2°；

[0251] 3.3±0.2°、6.6±0.2°、9.9±0.2°、13.3±0.2°、20.0±0.2°、23.3±0.2°；

[0252] 3.3±0.2°、6.6±0.2°、9.9±0.2°、13.3±0.2°、22.7±0.2°、24.9±0.2°；

[0253] 3.3±0.2°、6.6±0.2°、9.9±0.2°、13.7±0.2°、14.2±0.2°、22.9±0.2°；

[0254] 3.3±0.2°、6.6±0.2°、13.3±0.2°、13.7±0.2°、24.9±0.2°、26.9±0.2°；

[0255] 3.3±0.2°、9.9±0.2°、13.3±0.2°、14.4±0.2°、16.9±0.2°、23.3±0.2°；

[0256] 6.6±0.2°、9.9±0.2°、13.3±0.2°、14.2±0.2°、19.2±0.2°、23.3±0.2°；

[0257] 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°；

[0258] 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°；

[0259] 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°；

[0260] 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°；

[0261] 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°；

[0262] 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°；

[0263] 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°；

[0264] 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°；

[0265] 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°；

[0266] 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°；

[0267] 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°；

[0268] 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°；

[0269] 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°；

[0270] 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°；

[0271] 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°；

[0272] 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°；

[0273] 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°；

[0274] 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°;

[0275] 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°.

[0276] In certain embodiments of the present invention, the p-toluenesulfonate dihydrate crystalline form A, using Cu-Kα radiation, has X-ray characteristic diffraction peaks expressed in 2θ angles and interplanar spacing d values ​​as shown in the following table:

[0277] Table 7

[0278] In certain embodiments of the present invention, the X-ray powder diffraction pattern of the p-toluenesulfonate dihydrate crystalline form A is substantially as shown in FIG15 .

[0279] In certain embodiments of the present invention, the DSC spectrum of the p-toluenesulfonate dihydrate crystalline form A is substantially as shown in FIG16 .

[0280] In certain embodiments of the present invention, the TGA spectrum of the p-toluenesulfonate dihydrate crystalline form A is substantially as shown in FIG17 .

[0281] In certain embodiments of the present invention, the X-ray powder diffraction pattern of the benzenesulfonic acid 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 includes any 2-5 of the above diffraction peaks, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8, and more preferably includes any 6, 7 or 8 thereof.

[0282] In certain embodiments of the present invention, the X-ray powder diffraction pattern of the benzenesulfonic acid crystalline form A comprises at least one or more diffraction peaks located 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 them, more preferably three; optionally, it may further comprise at least one of 18.9±0.2°, 23.3±0.2°, and 23.9±0.2°, preferably two or three of them.

[0283] In certain embodiments of the present invention, the X-ray powder diffraction pattern of the benzenesulfonate salt form A optionally further comprises one or more diffraction peaks located at 2θ of 10.5±0.2°, 11.3±0.2°, 18.2±0.2°, 22.8±0.2°, 25.0±0.2°, 28.2±0.2°, and 32.2±0.2°; preferably, at least any 2-3 or 4-5 of them; further preferably, any 2, 3, 4, or 5 of them are included.

[0284] In certain embodiments of the present invention, the X-ray powder diffraction pattern of the benzenesulfonate salt form A comprises one or more diffraction peaks located at 2θ of 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°, and 32.2±0.2°; preferably, there are diffraction peaks at any of 4, 5, 6, 8 or 10 locations.

[0285] In certain embodiments of the present invention, the benzenesulfonic acid crystalline form A, using Cu-Kα radiation, has X-ray characteristic diffraction peaks expressed in 2θ angles and interplanar spacing d values ​​as shown in the following table:

[0286] Table 8

[0287] In certain embodiments of the present invention, the X-ray powder diffraction pattern of benzenesulfonate salt Form A is substantially as shown in FIG18 .

[0288] In certain embodiments of the present invention, the DSC spectrum of benzenesulfonate Form A is substantially as shown in Figure 19.

[0289] In certain embodiments of the present invention, the 2θ error of the diffraction peak positions with the top ten relative peak intensities in the X-ray powder diffraction pattern of the hydrochloride form A, the sulfate form A, the methanesulfonate form A, the p-toluenesulfonate form A, the p-toluenesulfonate form B, the p-toluenesulfonate form C, the p-toluenesulfonate dihydrate form A, and the benzenesulfonate form A and the corresponding X-ray powder diffraction figure position diffraction peak is ±0.2° to ±0.5°, preferably ±0.2° to ±0.3°, and most preferably ±0.2°.

[0290] The present invention also provides a method for preparing the above-mentioned compound or an acid salt of its stereoisomer, which comprises the following steps:

[0291] 1) Weigh an appropriate amount of free base and dissolve it in a benign solvent;

[0292] 2) Weigh an appropriate amount of counterion acid and dissolve it in an organic solvent; the amount of counterion acid is preferably 1.2 equivalents;

[0293] 3) Combine the above two solutions and stir to precipitate or add a poor solvent dropwise and stir to precipitate;

[0294] 4) rapidly centrifuging or standing to dry to obtain the acid salt;

[0295] in:

[0296] The benign solvent is selected from one or more of methanol, acetone, ethyl acetate, acetonitrile, ethanol, 88% acetone, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropyl alcohol, n-butanol, isobutyl alcohol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, tert-butanol, 2-butanone, 3-pentanone or N-methylpyrrolidone; preferably one or more of N-methylpyrrolidone, methanol, dichloromethane or anhydrous ethanol;

[0297] The organic solvent is selected from methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, dichloroethane, tetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, tert-butanol or N,N-dimethylformamide; preferably methanol, ethanol or acetonitrile; the above-mentioned benign solvent and organic solution need to be miscible when used;

[0298] The poor solvent is selected from one or more of heptane, cyclohexane, n-hexane, n-pentane, water, ethyl acetate, methyl tert-butyl ether, toluene or isopropyl ether; preferably one or more of water, heptane, methyl tert-butyl ether or isopropyl ether;

[0299] The counterion acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphoric acid, 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, capric acid, hexanoic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecyl sulfuric acid, dibenzoyltartaric acid, ethane-1, Preferably, the present invention comprises the following: 1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactosonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-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, fumarate, p-toluenesulfonate or succinate; most preferably, p-toluenesulfonate.

[0300] The present invention also provides a method for preparing a crystalline form of the compound or an acid salt of a stereoisomer thereof, characterized in that it is method one, method two or method three;

[0301] Method 1 includes the following steps:

[0302] 1) suspending the compound with a poor solvent;

[0303] 2) Adding a counterion acid; the amount of the counterion acid is preferably 1.2 equivalents; the counterion acid can be dissolved in an organic solvent

[0304] 3) stirring to dissolve, continuing to stir to precipitate or adding a poor solvent dropwise and stirring to precipitate;

[0305] 4) isolating and obtaining an anhydrate crystalline form;

[0306] Method 2 includes the following steps:

[0307] Transform the anhydrate crystal form of method 1;

[0308] Method 3 includes the following steps:

[0309] The anhydrate crystal form prepared in method 1 is suspended in water to separate the hydrate crystal form;

[0310] in:

[0311] The poor solvent is selected from one or more of acetone, ethyl acetate, isopropyl acetate, acetonitrile, ethanol, 88% acetone, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropanol, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, tert-butanol, 2-butanone or 3-pentanone, methyl tert-butyl ether or water; preferably one or more of acetone, ethanol, tetrahydrofuran, acetonitrile or toluene.

[0312] 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;

[0313] The counterion acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphoric acid, 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, capric acid, hexanoic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecyl sulfuric acid, dibenzoyltartaric acid, ethane-1, Preferably, the present invention comprises the following: 1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactosonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-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, fumarate, p-toluenesulfonate or succinate; most preferably, p-toluenesulfonate.

[0314] In certain embodiments of the present invention, the compound is suspended with ethanol, and then mixed with a methanolic hydrochloric acid solution to separate and obtain the hydrochloride salt form A of the compound.

[0315] In certain embodiments of the present invention, the compound is suspended with ethanol, and then mixed with a methanolic sulfuric acid solution to separate and obtain the sulfate salt form A of the compound.

[0316] In certain embodiments of the present invention, the compound is suspended with ethanol, and then mixed with a methanol solution of methanesulfonic acid to separate and obtain the mesylate salt form A of the compound.

[0317] In certain embodiments of the present invention, the compound is suspended in ethanol and then mixed with a methanol solution of p-toluenesulfonic acid to obtain the p-toluenesulfonic acid crystalline form A of the compound.

[0318] In certain embodiments of the present invention, the p-toluenesulfonic acid crystalline form A of the compound is crystallized in tetrahydrofuran or 2-methyltetrahydrofuran to obtain the p-toluenesulfonic acid crystalline form B of the compound.

[0319] In certain embodiments of the present invention, the p-toluenesulfonic acid crystalline form A of the compound is crystallized in 1,4-dioxane to obtain the p-toluenesulfonic acid crystalline form C of the compound.

[0320] In certain embodiments of the present invention, the p-toluenesulfonic acid crystalline Form A of the compound is suspended in water, and the p-toluenesulfonic acid salt dihydrate crystalline Form A of the compound is separated.

[0321] In certain embodiments of the present invention, the compound is suspended in ethanol and then mixed with a benzenesulfonic acid methanol solution to separate and obtain the benzenesulfonic acid crystalline form A of the compound.

[0322] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the above-mentioned compound or an acid salt of its stereoisomer and / or a crystalline form of the above-mentioned compound or an acid salt of its stereoisomer, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0323] The present invention also provides use of the compound or an acid salt of its stereoisomer, a crystalline form of the compound or an acid salt of its stereoisomer, or the pharmaceutical composition described above in the preparation of PARP inhibitor drugs; wherein the PARP is preferably PARP1.

[0324] The present invention also provides the compound or an acid salt of its stereoisomer, a crystalline form of the compound or an acid salt of its stereoisomer, or the pharmaceutical composition as described above, which is a PARP inhibitor drug; wherein the PARP is preferably PARP1.

[0325] The present invention also provides the use of the above-mentioned compound or an acid salt of its stereoisomer, a crystalline form of the above-mentioned compound or an acid salt of its stereoisomer, or the above-mentioned pharmaceutical composition in the preparation of a medicament for treating cancer, ischemic disease or neurodegenerative disease; preferably, the cancer is selected from breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastric cancer, colorectal cancer, gastrointestinal cancer and lung cancer.

[0326] The present invention also provides the above-mentioned compound or an acid salt of its stereoisomer, a crystalline form of the above-mentioned compound or an acid salt of its stereoisomer, or a pharmaceutical composition as described above, for use in treating cancer, ischemic diseases or neurodegenerative diseases; preferably, the cancer is selected from breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastric cancer, colorectal cancer, gastrointestinal cancer and lung cancer.

[0327] The present invention also relates to a method for treating, preventing and / or treating cancer, ischemic diseases or neurodegenerative diseases, which comprises administering to a patient a therapeutically effective dose of the compound as described above or an acid salt of its stereoisomer, a crystalline form of the compound as described above or an acid salt of its stereoisomer, or a pharmaceutical composition as described above; preferably, the cancer is selected from breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastric cancer, colorectal cancer, gastrointestinal cancer and lung cancer.

[0328] Detailed Description of the Invention

[0329] Unless otherwise stated, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art. Specifically, the terms used in the specification and claims have the following meanings.

[0330] The term "alkyl" refers to a straight or branched saturated aliphatic hydrocarbon group, which may be optionally substituted with one or more substituents. In a specific embodiment, an alkyl group refers to a saturated aliphatic hydrocarbon group having 1 to 20 (C 1-20 ), 1 to 15 (C 1- 15 ), 1 to 12 (C 1-12 ), 1 to 10 (C 1-10 ), 1 to 8 (C 1-8 ), 1 to 6 (C 1-6 ) or 1 to 3 (C 1-3 ) carbon atoms, or a straight-chain saturated hydrocarbon group having 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 12 (C 3-12 ), 3 to 10 (C 3-10 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 ) carbon atoms. The straight chain C 1-6 Alkyl and branched C 3-6 Alkyl groups are also called "lower alkyl". For example, C 1-6 Alkyl 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. 1-6Alkyl groups contain 1 to 6 (e.g., 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, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl and various branched chain isomers thereof, etc. In one embodiment, the alkyl group is an optionally substituted alkyl group as described elsewhere herein.

[0331] The term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon triple bond, which may be located at any position within the alkynyl group, and which may be optionally substituted with one or more substituents. In a particular embodiment, the alkynyl group is a 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 12 (C 2-12 ), 2 to 10 (C 2-10 ), 2 to 8 (C 2-8 ), 2 to 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 to 15 (C 3-15 ), 3 to 12 (C 3-12 ), 3 to 10 (C 3- 10 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 Unless otherwise indicated, the term "alkynyl" as used herein includes both straight-chain and branched alkynyl groups. For example, C 2-6Alkynyl refers to a straight chain 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: In one embodiment, the alkynyl group is an optionally substituted alkynyl group described elsewhere herein.

[0332] The term "cycloalkyl" refers to a saturated or partially unsaturated aliphatic hydrocarbon monocyclic, polycyclic (two or more) cyclic group, which may be optionally substituted with one or more substituents. In a particular embodiment, the cycloalkyl ring contains 3 to 20 (C 3-20 ), 3 to 12 (C 3-12 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 ) carbon atoms; in one embodiment, the cycloalkyl ring contains 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10 ) carbon atoms; it may contain one or more double bonds, but does not have a completely conjugated π electron system. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl or cyclooctyl, etc.; polycyclic cycloalkyls include spirocycloalkyl, fused cycloalkyl and bridged cycloalkyl in one embodiment. In one embodiment, the cycloalkyl is an optionally substituted cycloalkyl described elsewhere herein or a cycloalkyl optionally fused to a heterocyclyl, aryl or heteroaryl group, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc.

[0333] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus or sulfur, wherein the nitrogen, phosphorus or sulfur atom may be optionally oxidized, the nitrogen atom may be optionally quaternized, the ring carbon atoms may be optionally substituted with oxygen, but does not include the ring portion of -OO- or -OS-, and the remaining ring atoms are carbon, which may contain one or more double bonds but does not have a completely conjugated π electron system. In certain embodiments, the heterocyclyl group contains 3 to 20, 3 to 12, 3 to 8, or 3 to 6 ring atoms, of which 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. The limiting examples of monocyclic heterocyclic radical include tetrahydropyrrolyl, azetidinyl, oxetanyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and pyranyl etc..Polycyclic heterocyclic radical includes spiro heterocyclic radical, condensed heterocyclic radical and bridged heterocyclic radical.In one embodiment, described heterocyclic radical is the optionally substituted described elsewhere herein, or the heterocyclic radical further and ring-connected with other cycloalkyl, heterocyclic radical, aryl and heteroaryl by any two or more atoms on the ring.

[0334] The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl or cycloalkyl are as defined above. Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, or cyclohexyloxy. In one embodiment, the alkoxy is an optionally substituted alkoxy described elsewhere herein.

[0335] The term "haloalkyl" refers to an alkyl group substituted by one or more halogens, wherein the definition of alkyl is the same as above. Non-limiting examples of the haloalkyl group include: trifluoromethyl, -CH2CF3,

[0336] The term "hydrogen" includes protons ( 1 H), deuterium ( 2 H), tritium ( 3 H) and / or mixtures thereof. In a particular embodiment, one or more positions occupied by hydrogen in the compound may be enriched with deuterium and / or tritium. Such isotopically enriched analogs may be prepared by appropriately isotopically labeled starting materials obtained from commercial sources or by known literature procedures.

[0337] Different expressions such as “X is selected from A, B, or C”, “X is selected from A, B and C”, “X is A, B or C”, and “X is A, B and C” all express the same meaning, that is, X can be any one or more of A, B, and C.

[0338] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and that the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0339] In various parts 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 a linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" represents a linking alkylene group or arylene group, respectively.

[0340] " substituted " refers to that any one or more hydrogen atoms on a particular atom are replaced by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable in one embodiment in one embodiment. When a substituent is an oxo (i.e., =O), it means that two hydrogen atoms are replaced. The term "optionally substituted" refers to that it may be substituted or not, and unless otherwise specified, the type and number of the substituent may be arbitrary on the basis of chemical achievable. It goes without saying that the substituent is only in its possible chemical position, and those skilled in the art can determine (by experiment or theory) possible or impossible substitution without paying too much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (such as olefinic) bond.

[0341] In this specification and the claims, the indefinite articles "a" and "an" and the definite article "the" include plural as well as singular, unless stated to the contrary.

[0342] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, together 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, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0343] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention that are safe and effective when used in mammals and have the desired biological activity.

[0344] "Stereoisomers" encompass all enantiomerically / diastereomerically / stereomerically pure and enantiomerically / diastereomerically / stereomerically enriched forms of the compounds of the invention.

[0345] "Stereomerically pure" refers to a composition comprising one stereoisomer of a compound and being substantially free of another stereoisomer of the compound. For example, a stereomerically pure composition of a compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A stereomerically pure composition of a compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical stereoisomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of another stereoisomer of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of another stereoisomer of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of another stereoisomer of the compound, greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of another stereoisomer of the compound, or greater than about 99% by weight of one stereoisomer of the compound and less than about 1% by weight of another stereoisomer of the compound.

[0346] "Stereoisomerically enriched" refers to a composition comprising greater than about 55% by weight, greater than about 60% by weight, greater than about 70% by weight, or greater than about 80% by weight of one stereoisomer of a compound.

[0347] "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.

[0348] "Optically active" and "enantiomeric active" refer to a combination of molecules having an enantiomeric or diastereomeric excess of not less than about 50%, not less than about 70%, not less than about 80%, not less than about 90%, not less than about 91%, not less than about 92%, not less than about 93%, not less than about 94%, not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.8%. In certain embodiments, the compound comprises about 95% or more of the desired enantiomer or diastereomer and about 5% or less of the less preferred enantiomer or diastereomer, based on the total weight of the racemate.

[0349] When describing an optically active compound, the prefixes R and S are used to denote the absolute configuration of the molecule about its chiral center. (+) and (-) are used to denote the optical rotation of the compound, i.e., the direction of the plane of polarized light rotated by the optically active compound. The prefix (-) indicates that the compound is levorotatory, i.e., the compound rotates the plane of polarized light to the left, or counterclockwise. The prefix (+) indicates that the compound is dextrorotatory, i.e., the compound rotates the plane of polarized light to the right, or clockwise. However, the signs of the optical rotations (+) and (-) have nothing to do with the absolute configuration, R or S, of the molecule. BRIEF DESCRIPTION OF THE DRAWINGS

[0350] FIG1 shows the inhibition of PAR in the MDA-MB-436 model after a single administration of Example 1 within 24 hours;

[0351] FIG2 shows the inhibition of PAR in the MDA-MB-436 model after a single administration of Example 1 within 24-72 hours;

[0352] FIG3 is an XRPD diagram of hydrochloride Form A;

[0353] FIG4 is a DSC diagram of hydrochloride salt form A;

[0354] FIG5 is an XRPD diagram of sulfate salt form A;

[0355] FIG6 is a DSC diagram of sulfate salt form A;

[0356] FIG7 is an XRPD diagram of mesylate salt Form A;

[0357] FIG8 is a DSC diagram of mesylate salt Form A;

[0358] FIG9 is an XRPD diagram of p-toluenesulfonate Form A;

[0359] Figure 10 is a DSC diagram of p-toluenesulfonate Form A;

[0360] FIG11 is an XRPD diagram of p-toluenesulfonate Form B;

[0361] FIG12 is a DSC diagram of p-toluenesulfonate Form B;

[0362] FIG13 is an XRPD diagram of p-toluenesulfonate Form C;

[0363] FIG14 is a DSC diagram of p-toluenesulfonate Form C;

[0364] FIG15 is an XRPD diagram of p-toluenesulfonate dihydrate Form A;

[0365] FIG16 is a DSC diagram of p-toluenesulfonate dihydrate Form A;

[0366] FIG17 is a TGA diagram of p-toluenesulfonate dihydrate Form A;

[0367] FIG18 is an XRPD diagram of benzenesulfonate salt Form A;

[0368] Figure 19 is a DSC diagram of benzenesulfonate Form A;

[0369] FIG20 is a diagram showing the single crystal structure of p-toluenesulfonate dihydrate Form A (excluding hydrogen atoms). DETAILED DESCRIPTION

[0370] The present invention is further described below with reference to the following examples, but these examples are not intended to limit the scope of the present invention.

[0371] Example

[0372] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer, using deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as the solvents, with tetramethylsilane (TMS) as the internal standard.

[0373] Liquid chromatography-mass spectrometry (LC-MS) was performed on an Agilent 1200 Infinity Series mass spectrometer. HPLC was performed on an Agilent 1200DAD high-pressure liquid chromatograph (Sunfire C18 150 × 4.6 mm column) and a Waters 2695-2996 high-pressure liquid chromatograph (Gimini C 18 150×4.6mm chromatographic column).

[0374] Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications used for TLC are 0.15mm-0.20mm, and the specifications used for thin layer chromatography separation and purification products are 0.4mm-0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0375] The starting materials in the examples of the present invention are known and can be purchased commercially, or can be synthesized using or according to methods known in the art.

[0376] Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, with dry solvents and reaction temperatures in degrees Celsius.

[0377] Example 1

[0378] 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

[0379] Step 1: Preparation of ethyl 6-formyl-5-nitronicotinate

[0380] To a solution of ethyl 6-methyl-5-nitronicotinate (5.0 g, 23.8 mmol) in 1,4-dioxane (25 mL) was added selenium dioxide (3.96 g, 35.68 mmol), and the mixture was heated to 110°C and stirred for 20 hours. After the reaction was cooled to room temperature, it was filtered through celite under reduced pressure. After filtration, the organic solvent was concentrated under reduced pressure and separated by column chromatography to obtain ethyl 6-formyl-5-nitronicotinate (4.8 g, 90%) as a brown oil.

[0381] MS m / z(ES + ):224.1[M] + .

[0382] Step 2: Preparation of ethyl (E)-6-(2-(carboethoxy)but-1-en-1-yl)-5-nitronicotinate

[0383] To a solution of NaH (60wt%, 2.0g, 50.6mmol) in tetrahydrofuran (30mL) was slowly added dropwise triethyl 2-phosphocarboxybutyrate (12.8g, 50.6mmol) under ice-cooling. The mixture was then stirred under ice-cooling for 0.5 hour, then warmed to room temperature and stirred for 0.5 hour. The mixture was then heated to 40°C and stirred for 10 minutes. The reaction mixture was cooled to -78°C, and a solution of ethyl 6-formyl-5-nitronicotinate (4.8g, 21mmol) in tetrahydrofuran (20mL) was slowly added dropwise. The mixture was then stirred at -78°C for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride solution, extracted three times with ethyl acetate, and the organic phases were combined and washed with saturated brine. The organic phase was separated and dried over anhydrous sodium sulfate. After filtration, the organic solvent was concentrated under reduced pressure and separated by column chromatography to obtain the title compound, ethyl (E)-6-(2-(carboethoxy)but-1-en-1-yl)-5-nitronicotinate (5.1 g, 75%).

[0384] MS m / z(ES + ):322.2[M] + .

[0385] Step 3: Preparation of ethyl 7-ethyl-6-carbonyl-5,6,7,8-tetrahydro-1,5-naphthyridine-3-carboxylate

[0386] To a solution of ethyl (E)-6-(2-(carboethoxy)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). The mixture was deoxygenated with nitrogen for five minutes. The reaction was placed under a hydrogen atmosphere and stirred at room temperature overnight. The mixture was filtered under reduced pressure through celite, and 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.

[0387] MS m / z(ESI):249.2[M+H] + .

[0388] Step 4: Preparation of ethyl 7-ethyl-6-carbonyl-5,6-dihydro-1,5-naphthyridine-3-carboxylate

[0389] To a solution 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 (50 mL) was added DDQ (2.85 g, 12.5 mmol), and the mixture was heated to 110°C and stirred for 4 hours. After cooling to room temperature, the reaction mixture was filtered through celite under reduced pressure. The filtrate was concentrated under reduced pressure and separated by column chromatography to afford ethyl 7-ethyl-6-carbonyl-5,6-dihydro-1,5-naphthyridine-3-carboxylate (2.1 g, 76%).

[0390] MS m / z(ESI):247.2[M+H] + .

[0391] Step 5: Preparation of 3-ethyl-7-(hydroxymethyl)-1,5-naphthyridin-2(1H)-one

[0392] 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) was slowly added a 2M solution of lithium aluminum hydride in THF (8.5 mL, 17.0 mmol) under ice-cooling. The mixture was then stirred under ice-cooling for 2 hours. The reaction was quenched with sodium sulfate decahydrate and filtered through celite under reduced pressure. The filtrate was concentrated under reduced pressure and separated by column chromatography to afford 3-ethyl-7-(hydroxymethyl)-1,5-naphthyridine-2(1H)-one (1.5 g, 86%).

[0393] MS m / z(ESI):205.2[M+H] + .

[0394] Step 6: Preparation of 7-(chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one

[0395] 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) and then DMF (0.06 mL, 0.77 mmol) under ice cooling. The mixture was then stirred at room temperature for 6 hours. The organic solvent was concentrated under reduced pressure to afford crude 7-(chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (1.61 g), which was used directly in the next step.

[0396] MS m / z(ESI):223.1[M+H] + .

[0397] Step 7: Preparation of 1'-(tert-butyl)6-methyl 3',6'-dihydro-[3,4'-bipyridine]-1',6(2'H)-dicarboxylate

[0398] At room temperature, methyl 5-bromomethyl pyridinate (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'-bis(diphenylphosphino)ferrocenedichloridopalladium (146 mg, 0.2 mmol), and potassium carbonate (1.6 g, 11.6 mmol) were dissolved in dimethylformamide ( 10mL), the air was replaced by nitrogen for 1 minute, the temperature was raised to 140°C and microwaved for 30 minutes, water was added to the reaction system, extracted with ethyl acetate, the organic phase was separated and washed with saturated brine, the filtrate was dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. Column chromatography separation gave a brown oily compound 1'-(tert-butyl) 6-methyl 3',6'-dihydro-[3,4'-bipyridine]-1',6(2'H)-dicarboxylate (620 mg, 42%).

[0399] MS m / z(ES+):319.1[M+H] + .

[0400] Step 8: Preparation of tert-butyl 6-(methylcarbamoyl)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate

[0401] 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 alcohol solution (30 wt%, 2.0 g, 19.5 mmol) at room temperature, followed by stirring at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and saturated aqueous ammonium chloride was added. The mixture was extracted three times with DCM. The organic phases were combined, and the filtrate was dried over anhydrous sodium sulfate. 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.

[0402] MS m / z(ESI):318.2[M+H] + .

[0403] Step 9: Preparation of N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0404] Under ice bath, trifluoroacetic acid (1 mL) was added 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). The reaction was stirred at room temperature for 4 hours. 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.

[0405] MS m / z(ESI):218.2[M+H] + .

[0406] 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

[0407] 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) were added DIPEA (58 mg, 0.45 mmol) and potassium iodide (3 mg, 0.02 mmol). The mixture was heated to 80°C and stirred for 2 hours. After cooling to room temperature, the reaction mixture was filtered under reduced pressure. The filtrate was concentrated under reduced pressure and separated by column chromatography to afford 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%).

[0408] 1 H NMR(400MHz,DMSO-d6)δ11.76-11.91(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),6.4 1-6.44(m,1H),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);

[0409] MS m / z(ESI):404.2[M+H] + .

[0410] The following examples were prepared with reference to Example 1

[0411] Biological test evaluation

[0412] The present invention is further described and explained below in conjunction with test examples, but these examples are not intended to limit the scope of the present invention.

[0413] Test Example 1: Determination of the inhibitory activity of the compounds of the present invention on PARP1 enzyme

[0414] 1. Experimental purpose: The purpose of this test case is to measure the inhibitory activity of the compound on the PARP1 enzyme.

[0415] 2. Experimental instruments:

[0416] Centrifuge (Eppendorf 5810R) and pipettes (Eppendorf or Rainin)

[0417] Microplate reader (BioTek Synergy H1 or PerkinElmer Envision)

[0418] 3. Experimental reagents:

[0419] PARP1 Chemiluminescent Assay Kit was purchased from BPS bioscience, catalog number 80569

[0420] 20×PBST was purchased from Thermo, catalog number 28352. PBS was purchased from Gibco, catalog number 10010023.

[0421] 4. Experimental methods:

[0422] This experiment uses a chemiluminescence method to detect the inhibitory activity of compounds on the PARP1 enzyme. This experiment was carried out in a 384-well plate. First, histones were coated in the 384-well plate: 5× histone solution was diluted 5 times with PBS and added to the 384-well ELISA plate, 25 μL per well, and incubated overnight at 4 degrees Celsius. The coated ELISA plate was washed with 1× PBST buffer and then blocked with blocking solution (blocking buffer 3 in the kit) for 30 to 120 minutes, 100 μL per well, and washed 3 to 6 times with 1× PBST buffer. A mixture of PARP reaction biotin-labeled substrate, activated DNA, 10× PARP buffer, and water was added to each well, 12.5 μL. Compound solutions of varying concentrations were prepared in assay buffer (10% DMSO containing 1.25 mM DTT) starting at a final concentration of 100 nM. Eight concentrations were diluted three-fold and added to the reaction wells of a 384-well plate, 2.5 μL per well. Positive controls and blank wells were treated with 2.5 μL of 10% DMSO containing 1.25 mM DTT. The reaction was initiated with 10 μL of PARP1 enzyme solution prepared in 1× PARP buffer. The cells were centrifuged at 1000 rpm for 1 minute and allowed to incubate at room temperature for 60 minutes. After the reaction was complete, the reaction mixture was discarded, washed with 1× PBST, and then 25 μL of Streptavidin-HRP solution diluted 50-fold in Blocking Buffer 3 was added to each well. The cells were incubated at room temperature for 30 minutes. The reaction mixture was discarded and washed three to six times with 1× PBST. A luminescence reaction solution (a 1:1 mixture of ECL substrate A and ELISA ECL substrate B) was added to each well, 50 μL per well. Chemiluminescence readings were performed immediately using a BioTek Synergy H1 or Envision instrument.

[0423] 5. Experimental data processing method:

[0424] The inhibition rate was calculated by reading with a BioTek Synergy H1 or Envision instrument, recording the chemiluminescence readings, and fitting the concentration and inhibition rate with a nonlinear regression curve using Graphpad Prism software to obtain the IC 50 The inhibitory activities of some of the compounds of the present invention on PARP1 enzyme are shown in the following table:

[0425] Table 3

[0426] 6. Experimental conclusion: The compounds shown in the present invention showed excellent biological activity in the PARP1 enzyme inhibition experiment.

[0427] Test Example 2: Determination of the inhibitory activity of the compounds of the present invention on PARP2 enzyme

[0428] 1. Experimental purpose: The purpose of this test case is to measure the inhibitory activity of the compound on the PARP2 enzyme.

[0429] 2. Experimental instruments:

[0430] Centrifuge (Eppendorf 5810R) and pipettes (Eppendorf or Rainin)

[0431] Microplate reader (BioTek Synergy H1 or PerkinElmer Envision)

[0432] 3. Experimental reagents:

[0433] PARP2 Chemiluminescent Assay Kit was purchased from BPS bioscience, catalog number 80552

[0434] 20× PBST was purchased from Thermo Fisher Scientific, catalog number 28352. PBS was purchased from Gibco, catalog number 100100234. Experimental Methods: This experiment used chemiluminescence to detect the inhibitory activity of compounds against the PARP2 enzyme. This experiment was conducted in a 96-well plate. First, the 96-well plate was coated with histones: 5× histone solution was diluted 5-fold with PBS and added to a 96-well ELISA plate at 50 μL per well. The plate was incubated overnight at 4°C. The coated ELISA plate was washed with 1× PBST buffer and then blocked with blocking buffer (blocking buffer 3 in the kit) for 30 to 120 minutes, 200 μL per well. The plate was then washed three to six times with 1× PBST buffer. A mixture of PARP reaction biotin-labeled substrate, activated DNA, 10× PARP buffer, and water was added at 25 μL per well. Compound solutions of varying concentrations were prepared in assay buffer (10% DMSO containing 1.25 mM DTT) starting at a final concentration of 10 μM. Eight concentrations were diluted three-fold and added to 5 μL of each well in a 96-well plate. For the positive control and blank wells, 5 μL of 10% DMSO containing 1.25 mM DTT was added to each well. The reaction was initiated by adding 20 μL of PARP2 enzyme solution prepared in 1× PARP buffer. The cells were centrifuged at 1000 rpm for 1 minute and allowed to incubate at room temperature for 60 minutes. After the reaction was complete, the cells were decanted, washed with 1× PBST, and then 50 μL of Streptavidin-HRP solution diluted 50-fold in Blocking Buffer 3 was added to each well. The cells were incubated at room temperature for 30 minutes. The reaction was then decanted and washed three to six times with 1× PBST. A luminescence reaction solution (a 1:1 mixture of ECL substrate A and ELISA ECL substrate B) was added to each well, with 100 μL of each well. Chemiluminescence readings were performed immediately using a BioTek Synergy H1 or Envision instrument.

[0435] 5. Experimental data processing method: Read the chemiluminescence readings using a BioTek Synergy H1 or Envision instrument, calculate the inhibition rate, and use Graphpad Prism software to perform nonlinear regression curve fitting on the concentration and inhibition rate to obtain the IC 50 value.

[0436] 6. Experimental conclusion: The compounds of the present invention showed high selectivity for PARP2 in the PARP2 enzyme inhibitory activity experiment.

[0437] Test Example 3: Determination of the inhibitory effect of the compounds of the present invention on the proliferation activity of BRCA2 Knockout DLD-1 cells

[0438] 1. Experimental purpose: The purpose of this test case is to measure the inhibitory effect of the compound on the proliferation activity of BRCA2 Knockout DLD-1 cells.

[0439] 2. Experimental instruments:

[0440] Centrifuge (Eppendorf 5810R) and pipettes (Eppendorf or Rainin)

[0441] Microplate reader (BioTek Synergy H1 or PerkinElmer Envision),

[0442] 3. Experimental reagents:

[0443] BRCA2 Knockout DLD-1 cells were purchased from Creative Biogene.

[0444] Cell Titer-Glo was purchased from Promega, catalog number G7573

[0445] RPMI 1640 was purchased from Gibco, catalog number 22400089;

[0446] FBS was purchased from Gibco, catalog number 10091148; PBS was purchased from Gibco, catalog number 10010023;

[0447] Trypsin was purchased from Gibco with the catalog number 25200056; cell culture plates were purchased from Corning with the catalog number 36104. Experimental method: When BRCA2 Knockout DLD-1 cells were cultured to an appropriate cell density in RPMI1640 medium containing 10% FBS, the cells were collected and adjusted to an appropriate cell concentration using complete culture medium. The cell suspension was plated on a 96-well plate at 90 μL per well and placed in a 37°C, 5% CO2 incubator to adhere overnight. Compound solutions of different concentrations were prepared using DMSO and culture medium, and a solvent control was set up. The compound solution was added to a 96-well plate at 10 μL per well and continued to be cultured in a 37°C, 5% CO2 incubator for approximately 144 hours. Then, CellTiter-Glo solution was added, the plates were shaken to mix evenly, and the plates were incubated in the dark for 10 to 30 minutes. The plates were read using a Synergy H1 or Envision microplate reader.

[0448] 5. Experimental data processing method: The inhibition rate was calculated using the luminescence signal value, and the concentration and inhibition rate were fitted with a nonlinear regression curve using Graphpad Prism software to obtain the IC 50The inhibitory effects of some of the compounds of the present invention on the proliferation activity of BRCA2 Knockout DLD-1 cells are shown in the following table:

[0449] Table 4

[0450] 6. Experimental conclusion: The compounds of the present invention showed excellent biological activity in the inhibition test of BRCA2 Knockout DLD-1 cell proliferation activity.

[0451] Test Example 4: Bidirectional Permeability Test of Compounds Through Caco-2 Cell Model

[0452] 1. Experimental purpose:

[0453] The purpose of this study was to test the bidirectional permeability of compounds across the Caco-2 cell model.

[0454] 2. Experimental instruments and materials:

[0455] Liquid chromatography-mass spectrometry instrument, centrifuge, vortexer, pipette, 24-well test plate, acetonitrile solution with internal standard, Caco-2 cells (ATCC), Hanks' balanced solution (HBSS), dimethyl sulfoxide (DMSO) 3. Experimental steps:

[0456] 1) Cultivation of Caco-2 cell monolayers: Select Caco-2 cells in good condition for plating, replace the culture medium every 2-3 days, and culture for 21-28 days to form a dense cell monolayer for permeability testing.

[0457] 2) Evaluation of the permeability of test compounds:

[0458] Add 100 μL of transport buffer (HBSS containing 10 μM test compound, 0.5% BSA and 0.5% DMSO) to the dosing end of aA to B.

[0459] Add 300 μL of transport buffer (HBSS containing 0.5% BSA) to the receiving end of bA to B.

[0460] Add 300 μL of transport buffer (HBSS containing 10 μM test compound, 0.5% BSA and 0.5% DMSO) to the dosing end of cB A.

[0461] Add 100 μL of transport buffer (HBSS containing 0.5% BSA) to the receiving end of dBA.

[0462] e. Incubate for 2 hours.

[0463] d. Take samples for processing and detect by mass spectrometry.

[0464] 4. Chromatographic conditions:

[0465] Instrument: Liquid chromatography;

[0466] Chromatographic column: Waters XSelect HSS T3 C18 (2.1*50mm, 2.5um);

[0467] Mobile phase: Phase A: aqueous solution containing 0.1% formic acid; Phase B: acetonitrile solution containing 0.1% formic acid.

[0468] 5. Mass spectrometry conditions:

[0469] Instrument: API4000 liquid chromatography-mass spectrometer;

[0470] The ion source was electrospray ionization (ESI);

[0471] The detection method is positive ion detection;

[0472] The scanning mode was selected reaction monitoring (MRM).

[0473] 6. Experimental results: The bidirectional permeability of the compounds of the present invention through the Caco-2 cell model is shown in the following table:

[0474] Table 5

[0475] 7. Experimental conclusion: It can be seen from the experimental results in the above table that the example compounds of the present invention have high permeability.

[0476] Test Example 5: Pharmacokinetic Determination in Balb / C Mice

[0477] 1. Experimental purpose: Balb / C mice were used as test animals to study the pharmacokinetic behavior of the following compound examples in mouse plasma after oral administration at a dose of 1 mg / kg.

[0478] 2. Experimental plan

[0479] 2.1 Test drug: Example of the present invention, homemade.

[0480] 2.2 Experimental animals: 6 Balb / C mice / example, male, Shanghai Jiesijie Experimental Animal Co., Ltd., animal production license number (SCXK (Shanghai) 2013-0006 No. 311620400001794).

[0481] 2.3 Drug preparation: Weigh 5g of hydroxyethyl cellulose (HEC, CMC-Na, viscosity: 800-1200 cps), dissolve in 1000mL of purified water, add 10g of Tween 80, and mix well to form a clear solution.

[0482] Weigh 2.05 mg, dissolve in the solution, shake well, break with a cell disrupter for 1 min, and sonicate for 15 minutes to obtain a suspension solution with a concentration of 0.1 mg / mL.

[0483] 2.4 Administration: Male Balb / C mice were fasted overnight and administered orally at a dose of 1 mg / kg in a volume of 10 mL / kg.

[0484] 2.5 Sample collection: After administration, mice were collected from the eye socket at 0, 0.5, 1, 2, 4, 6, 8, and 24 hours. Blood (0.04 mL) was placed in an EDTA-K2 tube and centrifuged at 6000 rpm for 6 min at 4°C to separate plasma. The plasma was stored at -80°C and fed 4 hours after administration.

[0485] 2.6 Sample processing:

[0486] 1) 40 μL of plasma sample was added to 160 μL of acetonitrile for precipitation, mixed, and centrifuged at 3500×g for 5-20 minutes.

[0487] 2) Take 100 μL of the supernatant solution after treatment and perform LC / MS / MS analysis to determine the concentration of the test compound.

[0488] 2.7 Liquid phase analysis

[0489] Liquid phase conditions: Shimadzu LC-20AD pump

[0490] ●Mass spectrometry conditions: AB Sciex API 4000 mass spectrometer

[0491] ●Chromatographic column: phenomenex Gemiu 5um C18 50×4.6mm

[0492] ●Mobile phase: Liquid A is 0.1% formic acid aqueous solution, Liquid B is acetonitrile

[0493] Flow rate: 0.8 mL / min

[0494] Elution time: 0-4.0 minutes, eluent is as follows:

[0495] 3. Experimental results and analysis: The main pharmacokinetic parameters were calculated using WinNonlin 8.2. The results of the mouse pharmacokinetic experiment are shown in the table below:

[0496] Table 6

[0497] Note: 0.5% CMC-Na (1% Tween 80)

[0498] 4. Experimental conclusion: From the results of the mouse pharmacokinetic experiment in the table, it can be seen that the compounds of the present invention exhibit good absorption and metabolism properties, and the exposure amount AUC and the maximum blood concentration C max All performed well.

[0499] Test Example 6: PK / PD study of the compound in a nude mouse subcutaneous transplant tumor model of human breast cancer cell line MDA-MB-436

[0500] 1. Experimental purpose: To evaluate the distribution of the compound in plasma and tumor after a single oral administration in a nude mouse subcutaneous xenograft tumor model of human breast cancer cell line MDA-MB-436, and its inhibitory effect on PAR in tumor tissue.

[0501] 2. Experimental instruments and reagents

[0502] 2.1 Instruments

[0503] Refrigerator (BCD-268TN, Haier) Electronic pipette (Easypet 3, Eppendorf)

[0504] Biological safety cabinet (BSC-1300II A2, Shanghai Boxun Industrial Co., Ltd. Medical Equipment Factory)

[0505] Clean bench (CJ-2F, Suzhou Fengshi Experimental Animal Equipment Co., Ltd. )

[0506] Constant temperature water bath (HWS-12, Shanghai Yiheng Science) CO2 incubator (Thermo-311, Thermo) centrifuge (Centrifuge 5720R, Eppendorf)

[0507] Automated cell counter (Countess II, Life Technologies)

[0508] Vernier caliper (CD-6" AX, Mitutoyo, Japan) Cell culture flask (T25 / T75 / T225, Corning)

[0509] Electronic balance (CPA2202S, Sartorius) Electronic balance (BSA2202S-CW, Sartorius)

[0510] Ultrasonic cleaner (115F0032, Shanghai Kedao) and water purifier (Pacific TII, Thermo)

[0511] Magnetic stirrer (08-2G, Chijiu) Centrifuge (Centrifuge 5418R, Eppendorf)

[0512] Small protein vertical electrophoresis and transfer system (PowerPac Universal Power Supply, Bio-Rad)

[0513] Microplate reader (H1MFD, Biotek) and molecular imaging system (ChemiDoc TM MP, Bio-Rad)

[0514] Semi-dry transfer apparatus (690BR027087, Bio-Rad) and pipette (METTLER TOLEDO / Eppendorf)

[0515] Tissue grinder (TISS-48, Shanghai Jingxin Laboratory Equipment Technology Department)

[0516] Dry-type thermostat (MK200-2, Hangzhou Aokangsheng Instrument Co., Ltd.)

[0517] 2.2 Reagents

[0518] DMEM medium (31600-034, Gibco) Fetal bovine serum (FBS) (10099-141C, Gibco)

[0519] Insulin-transferrin-selenium (ITS-G) (41400-045, Gibco)

[0520] Phosphate buffered saline (PBS) (10010-023, Gibco) Tween 80 (30189828, Sinopharm Reagent)

[0521] Sodium carboxymethyl cellulose (30036365, Sinopharm Reagent) Matrigel Matrix (356234, Corning)

[0522] Trans-Blot Turbo Transfer Pack (1704157, Bio-Rad)

[0523] 4-15% Criterion TM TGX TM Gel (5671085, Bio-Rad)

[0524] GAPDH(D4C6R)Mouse(97166S, CST)

[0525] 800CW Goat anti-Mouse IgG(H+L)(P / N 926-32210, LI-COR)

[0526] 680RD Goat anti-Rabbit IgG(H+L)(P / N 926-68071, LI-COR)

[0527] Poly / Mono-ADP Ribose(E6F6A)Rabbit mAb(83732S, CST)

[0528] Pierce BCA Protein Assay Kit (23227, Thermo Fisher)

[0529] QuickBlock Western blocking solution (P0252-500ml, Beyotime)

[0530] Sample Reducing Agent(10×)(NP0009, Thermo Fisher)

[0531] NuPAGE TM LDS Sample Buffer(4×)(NP0007, Thermo Fisher)

[0532] Pierce 20×TBS with Tween-20 (28360, Thermo Fisher)

[0533] 3. Experimental methods

[0534] 3.1 Animals

[0535] BALB / c nude mice, 6-8 weeks old, were purchased from the Experimental Animal Management Department of Shanghai Institute of Family Planning Science.

[0536] 3.2 Cell culture and cell suspension preparation

[0537] a. Remove a strain of MDA-MB-436 cells from the cell bank and resuscitate the cells in DMEM medium (DMEM + 10% FBS + 1% ITS-G). Place the revived cells in a cell culture flask (label the flask wall with the cell type, date, and culturer's name) and culture in a CO2 incubator (37°C, 5% CO2 concentration).

[0538] b. Subculture the cells every three days and continue to culture them in a CO2 incubator. Repeat this process until the cell count meets the in vivo efficacy requirement.

[0539] c. Collect the cultured cells and count them using an automatic cell counter. Resuspend the cells in PBS according to the counting results and mix with Matrigel Matrix at a ratio of 1:1 to a final concentration of 5×10 7 / mL, and place in an ice box until use.

[0540] 3.3 Cell seeding

[0541] a, Nude mice were marked with disposable ear tags for both mice and rats before inoculation.

[0542] b. Mix the cell suspension thoroughly during inoculation, draw out 0.1-1 mL of cell suspension with a 1 mL syringe, remove any bubbles, and place the syringe on an ice pack until ready to use.

[0543] c. Secure the nude mouse with your left hand and disinfect the right side of the nude mouse's back near the right shoulder (inoculation site) with a 75% alcohol cotton ball. Start inoculation 30 seconds later.

[0544] d. The experimental nude mice were inoculated sequentially (0.1 mL of cell suspension per mouse).

[0545] 3.4 PK / PD studies

[0546] a. Grouping: According to the growth of the tumor, the tumor will be divided into two groups when it grows to a volume of 300-500mm 3 According to the experimental design, tumor-bearing mice were selected and randomly divided into groups (3 mice at each time point) to start the PK / PD experiment.

[0547] b. Fasting: All tumor-bearing mice were fasted overnight (>8 hours) before administration.

[0548] c. Administration: Except for the blank control group, a single oral administration was performed according to the experimental design time, with an administration volume of 10 mL / kg.

[0549] d. Sample collection: Experimental mice were euthanized by CO2 asphyxiation according to the designed time and samples were collected. One plasma sample and three tumor tissue samples were collected from each animal.

[0550] According to the designed time, mice were euthanized by CO2 asphyxiation and samples were taken.

[0551] Plasma Collection: After euthanasia, blood was collected from the heart and placed into a centrifuge tube containing EDTA-K2. The collected blood was manually inverted 3-4 times and then centrifuged on ice at 8000 rpm for 5 minutes at 4°C. 100 μL of the centrifuged plasma was transferred to a new, labeled centrifuge tube. An aliquot was quickly frozen on dry ice and stored at -80 ± 10°C for PK analysis.

[0552] Tumor Tissue Collection: After blood collection, remove tumor tissue. Divide the removed tumor tissue into three portions (~0.1 g each) and place them into labeled 2 mL centrifuge tubes. Store in a -80 ± 10°C freezer for PK or PD testing. Collect blank plasma and blank tumor tissue from the remaining tumor-bearing mice.

[0553] PK testing

[0554] a. Sample processing:

[0555] 1) Tumor tissue samples were added to 20% methanol water at a 4-fold weight ratio and homogenized at 40 Hz for 400 s. 20 μL of the homogenate was taken and precipitated by adding 100 μL of acetonitrile. After mixing, the mixture was centrifuged at 3500×g for 5-20 minutes.

[0556] 2) Take 100 μL of the supernatant solution after treatment and perform LC / MS / MS analysis to determine the concentration of the test compound.

[0557] b. Liquid phase analysis

[0558] Liquid phase conditions: Shimadzu LC-20AD pump

[0559] ●Mass spectrometry conditions: AB Sciex API 4000 mass spectrometer

[0560] ●Chromatographic column: phenomenex Gemiu 5um C18 50×4.6mm

[0561] ●Mobile phase: Liquid A is 0.1% formic acid aqueous solution, Liquid B is acetonitrile

[0562] Flow rate: 0.8 mL / min

[0563] Elution time: 0-4.0 minutes, eluent is as follows:

[0564] 3.6 PD Detection

[0565] a, Lysis of tumor tissue samples

[0566] Add 1 mL of tumor lysis buffer to each tube of tumor tissue sample, add steel balls and place it in a tissue grinder for tissue homogenization. Lyse on ice for 20 minutes, centrifuge in a refrigerated centrifuge at 4°C, 10,000 g for 5 minutes, and collect the protein supernatant.

[0567] b. Protein sample preparation

[0568] Protein was quantified using a BCA protein quantification kit. Protein supernatant, 10× Sample Reducing Agent, 4× LDS Sample Buffer, and lysate were combined to create a protein loading solution of consistent concentration. The loading solution was placed in a preheated dry block incubator at 100°C for 10 minutes to denature the protein.

[0569] c, Western blot experiment of protein samples.

[0570] 1) Electrophoresis: Take 4-15% Criterion TM TGX TM 15 μL of each protein sample was loaded into the gel and placed in an electrophoresis tank containing electrophoresis buffer for protein gel electrophoresis at 150 V for 60 minutes.

[0571] 2) Transfer: Using the Trans-Blot Turbo Transfer Pack Kit, place the multi-layer filter paper, PVDF membrane, protein gel, and thick filter paper in order, place them in a transfer apparatus, and select the MIXED MW program (2.5A-25V-7min) to transfer the membrane.

[0572] 3) Blocking and Incubation with Antibodies: Remove the PVDF membrane from the transfer apparatus and place it in QuickBlock Western blocking buffer. Place the membrane on a shaker and shake at room temperature for at least 1 hour for protein blocking. Add PAR (1:500) or GAPDH (1:5000) primary antibody diluent diluted in QuickBlock Western blocking buffer to the PVDF membrane and incubate overnight at 4°C. Remove the primary antibody diluent and wash the membrane six times with 1× TBST. Add goat anti-rabbit (1:3000) and mouse fluorescent secondary antibody solution (1:5000) diluted in QuickBlock Western blocking buffer and incubate at room temperature in the dark for 1 hour. Remove the antibody diluent and wash the membrane six times with 1× TBST.

[0573] 4) Imaging: Place the cleaned PVDF membrane into the Biorad ChemiDoc TM Imaging was performed using an MP imager, fluorescence imaging of PAR and Gapdh was performed using the IRDye 800 CW channel for internal reference fluorescence imaging.

[0574] 4. Experimental results

[0575] Table 7

[0576] 5. Experimental conclusion: In the MDA-MB-436 (breast cancer, BRCA1 mutation) model, the tumor blood concentration of Example 1 within 24 hours of a single administration was higher than that of AZD5305, and the degree of inhibition of intratumoral PAR was comparable. A single administration of Example 1 could sustain the inhibition of intratumoral PAR for 72 hours, which was superior to AZD5305.

[0577] Test Example 7: Compounds in human colorectal cancer cell line DLD-1 BRCA2 - / - In vivo pharmacodynamic study of subcutaneous transplanted tumor model in nude mice

[0578] 1. Experimental purpose: To evaluate the effect of the compound on the human colorectal cancer cell line DLD-1 BRCA2 - / - In vivo efficacy in a nude mouse subcutaneous xenograft tumor model.

[0579] 2. Experimental instruments and reagents

[0580] 2.1 Instruments

[0581] Refrigerator (BCD-268TN, Haier) Electronic pipette (Easypet 3, Eppendorf)

[0582] Biological safety cabinet (BSC-1300II A2, Shanghai Boxun Industrial Co., Ltd. Medical Equipment Factory)

[0583] Clean bench (CJ-2F, Suzhou Fengshi Experimental Animal Equipment Co., Ltd. )

[0584] Constant temperature water bath (HWS-12, Shanghai Yiheng Science) CO2 incubator (Thermo-311, Thermo) centrifuge (Centrifuge 5720R, Eppendorf) magnetic stirrer (08-2G, Chijiu)

[0585] Automated cell counter (Countess II, Life Technologies)

[0586] Vernier caliper (CD-6" AX, Mitutoyo, Japan) Cell culture flask (T25 / T75 / T225, Corning)

[0587] Electronic balance (CPA2202S, Sartorius) Electronic balance (BSA2202S-CW, Sartorius)

[0588] Ultrasonic cleaner (115F0032, Shanghai Kedao) and water purifier (Pacific TII, Thermo)

[0589] 2.2 Reagents

[0590] RPMI-1640 medium (22400-089, Gibco) Fetal bovine serum (FBS) (10099-141C, Gibco)

[0591] Phosphate buffered saline (PBS) (10010-023, Gibco) Tween 80 (30189828, Sinopharm Reagent)

[0592] Sodium carboxymethyl cellulose (30036365, Sinopharm Reagent)

[0593] 3. Experimental operation and data processing

[0594] 3.1 Animals: BALB / c nude mice, 6-8 weeks old, purchased from the Experimental Animal Management Department of Shanghai Institute of Family Planning Science.

[0595] 3.2 Cell culture and cell suspension preparation

[0596] a. Take out a DLD-1BRCA2 cell line from the cell bank - / - Cells were revived with RPMI-1640 medium (RPMI-1640 + 10% FBS). The revived cells were placed in cell culture flasks (labeled with cell type, date, culturer's name, etc. on the flask wall) and cultured in a CO2 incubator (incubator temperature: 37°C, CO2 concentration: 5%).

[0597] b. Subculture the cells every three days and continue to culture them in a CO2 incubator. Repeat this process until the cell count meets the in vivo efficacy requirement.

[0598] c. Collect the cultured cells, count them using an automatic cell counter, and resuspend the cells in PBS according to the counting results to prepare a cell suspension (density 5×10 7 / mL) and placed in an ice box for use.

[0599] 3.3 Cell seeding

[0600] a, Nude mice were marked with disposable ear tags for both mice and rats before inoculation.

[0601] b. Mix the cell suspension thoroughly during inoculation, draw out 0.1-1 mL of cell suspension with a 1 mL syringe, remove any bubbles, and place the syringe on an ice pack until ready to use.

[0602] c. Secure the nude mouse with your left hand and disinfect the right side of the nude mouse's back near the right shoulder (inoculation site) with a 75% alcohol cotton ball. Start inoculation 30 seconds later.

[0603] d. The experimental nude mice were inoculated sequentially (0.1 mL of cell suspension per mouse).

[0604] 3.4 Tumor measurement, grouping, and drug administration in tumor-bearing mice

[0605] a, Tumors were measured and their size was calculated on days 10-18 after inoculation, depending on tumor growth.

[0606] Tumor volume calculation: Tumor volume (mm 3 ) = length (mm) × width (mm) × width (mm) / 2

[0607] b, Tumor-bearing mice were randomly divided into groups according to their weight and tumor size;

[0608] c. According to the grouping results, the test drug was started to be administered (administration method: oral administration; administration volume: 10 mL / kg; administration frequency: once / day; administration cycle: 28 days; solvent: 0.5% CMC-Na / 1% Tween 80).

[0609] d, Tumors were measured and weighed twice a week after the start of the test drug administration.

[0610] e, Animals were euthanized after the experiment.

[0611] f. Data were processed using Excel or other software. Calculation of compound tumor inhibition rate (TGI) (%): If tumors did not regress, TGI (%) = [1 - (average tumor volume at the end of dosing in a given treatment group - average tumor volume at the start of dosing in that treatment group) / (average tumor volume at the end of treatment in the solvent control group - average tumor volume at the start of treatment in the solvent control group)] × 100%. If tumors regressed, TGI (%) = [1 - (average tumor volume at the end of dosing in a given treatment group - average tumor volume at the start of dosing in that treatment group) / average tumor volume at the start of dosing in that treatment group] × 100%.

[0612] 1.4 Experimental results and conclusions:

[0613] The example compounds 1, 2 and 7 of the present invention showed excellent tumor inhibition effects in this model experiment, with tumor inhibition rates TGI (%) > 90%, and the tumor inhibition rates TGI (%) of the preferred compounds > 150%, without significant reduction in animal body weight.

[0614] III. Study on the Salt and Crystalline Form of the Compound of Example 1

[0615] 1.1 Experimental Instruments

[0616] 1.1.1 Some parameters of physical and chemical testing instruments

[0617] 1.2 Instruments and liquid analysis conditions

[0618] 1.2.1 Instruments and Equipment

[0619] 1.2.2 Chromatographic conditions

[0620] Chromatographic column: Waters Xbridge C18 (4.6mm*150mm, 3.5μm)

[0621] Flow rate: 1.0 mL / min Column temperature: 40°C Detection wavelength: 260 nm

[0622] Injection volume: 5 μL Run time: 15 min Diluent: Methanol

[0623] Mobile phase: A: water (0.05% trifluoroacetic acid); B: acetonitrile (0.05% trifluoroacetic acid)

[0624] 1.3 Preparation of different crystalline forms of the compound of Example 1

[0625] 1.3.1 Preparation of Hydrochloride Form A

[0626] 20 mg of the compound from Example 1 was weighed, 0.2 mL of ethanol was added, and the mixture was suspended with stirring at 50°C. 0.06 mL of a 1 M hydrochloric acid solution in methanol was added to the mixture to dissolve and precipitate. After reacting for 1 hour, the mixture was cooled to room temperature and stirred for 2 hours. The solid was centrifuged and dried to obtain hydrochloride Form A. Analysis showed the XRPD pattern shown in Figure 3 and the DSC pattern shown in Figure 4.

[0627] 1.3.2 Preparation of Sulfate Form A

[0628] 20 mg of the compound from Example 1 was weighed, 0.2 mL of ethanol was added, and the mixture was suspended with stirring at 50°C. 0.06 mL of a 1 M solution of sulfuric acid in methanol was added to the mixture, and the mixture was dissolved and precipitated. After reacting for 1 hour, the mixture was cooled to room temperature and stirred for 2 hours. The solid was centrifuged and dried to obtain sulfate salt Form A. Analysis showed the XRPD pattern shown in Figure 5 and the DSC pattern shown in Figure 6.

[0629] 1.3.3 Preparation of Methanesulfonate Form A

[0630] 20 mg of the compound from Example 1 was weighed and suspended in 0.2 mL of ethanol at 50°C with stirring. 0.06 mL of a 1 M methanesulfonic acid solution in methanol was added to the mixture, and the solution was cooled to room temperature to precipitate a solid. The mixture was stirred at room temperature for 2 hours, and the solid was centrifuged and dried to obtain the mesylate salt Form A. Analysis showed the XRPD pattern shown in Figure 7 and the DSC pattern shown in Figure 8.

[0631] 1.3.4 Preparation of p-toluenesulfonate Form A

[0632] 20 mg of the compound from Example 1 was weighed, 0.2 mL of ethanol was added, and the mixture was suspended with stirring at 50°C. 0.06 mL of a 1 M solution of p-toluenesulfonic acid in methanol was added to the mixture, and the mixture was allowed to dissolve and precipitate. After reacting for 1 hour, the mixture was cooled to room temperature and stirred for 2 hours. The solid was then centrifuged and dried to obtain p-toluenesulfonate salt Form A. Analysis showed the XRPD pattern shown in Figure 9 and the DSC pattern shown in Figure 10.

[0633] 1.3.5 Preparation of p-toluenesulfonate Form B

[0634] 20 mg of p-toluenesulfonate Form A was weighed, 0.2 mL of tetrahydrofuran was added, and the mixture was suspended and slurried at 50°C for 7 days. The solid was centrifuged and dried to obtain p-toluenesulfonate Form B. After testing and analysis, the p-toluenesulfonate Form B had the XRPD pattern shown in Figure 11 and the DSC pattern shown in Figure 12.

[0635] 1.3.6 Preparation of p-toluenesulfonate Form C

[0636] 20 mg of p-toluenesulfonate Form A was weighed, 0.2 mL of 1,4-dioxane was added, and the mixture was suspended and slurried at 50°C for 7 days. The solid was centrifuged and dried to obtain p-toluenesulfonate Form C. After testing and analysis, it has the XRPD pattern shown in Figure 13 and the DSC pattern shown in Figure 14.

[0637] 1.3.7 Preparation of p-Toluenesulfonate Dihydrate Form A

[0638] 20 mg of p-toluenesulfonate crystalline Form A was weighed, added to 0.2 mL of water, and suspended and slurried at room temperature for 12 h. The solid was then centrifuged and dried to obtain p-toluenesulfonate hydrate crystalline Form A. After testing and analysis, the XRPD pattern is shown in Figure 15 , the DSC pattern is shown in Figure 16 , and the TGA pattern is shown in Figure 17 .

[0639] The components of the p-toluenesulfonate hydrate crystal form A are determined by the following method:

[0640] 1) Moisture Quantification of Form A of p-Toluenesulfonate Hydrate

[0641] The water content of p-toluenesulfonate hydrate form A is mainly determined by TGA weight loss combined with the water content measured by Karl Fischer moisture analyzer:

[0642] According to FIG17 , it can be concluded that the TGA weight loss is about 6.02%.

[0643] The moisture content was measured three times using a Karl Fischer titrator, and the results are as follows:

[0644] The results of three moisture determinations were comparable, with an average moisture content of 5.945%, which was consistent with the TGA weight loss.

[0645] 2) Analysis of free base content in liquid phase

[0646] The free base content in the p-toluenesulfonate hydrate crystalline form A of the compound was determined using the HPLC external standard method, using the compound of Example 1 as a reference. The results are as follows:

[0647] Table 8

[0648] Based on the above moisture determination results and free base content determination data, it was finally determined that the ratio of free base: p-toluenesulfonic acid: water in p-toluenesulfonate hydrate form A was 1:1:2.

[0649] In summary, p-toluenesulfonate hydrate crystal form A is p-toluenesulfonate dihydrate crystal form A. 1.3.8 Preparation of benzenesulfonate crystal form A

[0650] 20 mg of the compound from Example 1 was weighed and suspended in 0.2 mL of ethanol at 50°C with stirring. 0.06 mL of a 1 M benzenesulfonic acid solution in methanol was added to the mixture, and the solution was cooled to room temperature to precipitate a solid. The mixture was stirred at room temperature for 2 hours, and the solid was centrifuged and dried to obtain benzenesulfonate salt Form A. Analysis showed the XRPD pattern shown in Figure 18 and the DSC pattern shown in Figure 19.

[0651] 1.4 Study on polymorphism of salt forms in Example 1

[0652] 1.4.1 Hydrochloride Polymorph Study: Approximately 20 mg of hydrochloride Form A was weighed into a glass vial, 200 μL of organic solvent was added, and the mixture was blended at 50°C for 7 days. The results are as follows:

[0653] Table 9

[0654] Results and discussion: The hydrochloride crystal form A did not undergo crystal transformation in the above solvents and was stable in the above solvents.

[0655] 1.4.2 Study on sulfate polymorphs

[0656] Weigh approximately 20 mg of sulfate Form A into a glass vial, add 200 μL of organic solvent, and blend at 50°C for 7 days. The results are as follows:

[0657] Table 10

[0658] Results and discussion: The sulfate salt form A is stable in the above solvents, which is beneficial for later drug development.

[0659] 1.4.3 Methanesulfonate Polymorph Studies

[0660] About 20 mg of mesylate Form A was weighed into a glass vial, 200 μL of organic solvent was added, and the mixture was blended at 50°C for 7 days. The results are as follows:

[0661] Table 11

[0662] Results and discussion: The mesylate salt crystal form A is stable, the preparation process is highly operable, and a stable single crystal form can be obtained.

[0663] 1.4.4 Study on polymorphic forms of p-toluenesulfonate

[0664] Weigh approximately 20 mg of p-toluenesulfonate polymorph A into a glass vial, add 200 μL of organic solvent, and blend at 50°C for 7 days. The results are as follows:

[0665] Table 12

[0666] Results and discussion: The above experiments screened out p-toluenesulfonate polymorph B, polymorph C and hydrate form A.

[0667] 1.4.5 Study on polymorphs of p-toluenesulfonate hydrate

[0668] 1.4.5.1 Slurry conversion test: Weigh approximately 10 mg of p-toluenesulfonate dihydrate Form A into a glass vial, add 200 μL of organic solvent, and slurry at 40°C for 7 days. The results are as follows:

[0669] Table 13

[0670] 1.4.5.2 Results and discussion: This shows that the p-toluenesulfonate dihydrate crystal form A is relatively stable, which is beneficial for later drug development.

[0671] 1.5 Hygroscopicity determination

[0672] 1.5.1 Experimental purpose: To investigate the hygroscopicity of different salt crystal forms of the compound under different relative humidity conditions.

[0673] 1.5.2 Experimental plan: Place the compound salt crystal form in saturated water vapor at different relative humidity levels to allow the compound salt crystal form to reach dynamic equilibrium with the water vapor, and calculate the percentage of weight gain due to moisture absorption after equilibrium.

[0674] 1.5.3 Experimental results:

[0675] 1) The sulfate salt Form A absorbed moisture at 80% relative humidity and gained 1.785% weight, indicating slight hygroscopicity. After one cycle of moisture absorption and desorption at 0-95% relative humidity, the XRPD pattern of the sulfate salt Form A remained unchanged, indicating no crystal form transformation.

[0676] 2) The p-toluenesulfonate salt Form A absorbed moisture at 80% relative humidity and gained 9.00% weight, indicating hygroscopicity. After one cycle of moisture absorption and desorption at 0-95% relative humidity, the XRPD pattern of the p-toluenesulfonate salt Form A did not change, indicating that the crystal form did not change.

[0677] 3) Form A of p-toluenesulfonate dihydrate absorbed moisture at 80% relative humidity and gained 1.906% weight, indicating slight hygroscopicity. After one cycle of moisture absorption and desorption at 0-95% relative humidity, the XRPD pattern of Form A of p-toluenesulfonate dihydrate remained unchanged, indicating no crystalline form change.

[0678] 1.5.4 Experimental conclusion: The above-mentioned crystal forms did not undergo crystal transformation under different relative humidity conditions.

[0679] 1.6. Solid stability test

[0680] 1.6.1 Experimental purpose: To investigate the physicochemical stability of different salt crystal forms at high temperature (60°C, high humidity (RH) = 92.5%) and high temperature (50°C, high humidity) (75%).

[0681] 1.6.2 Experimental plan: Approximately 1 mg of different salt crystal forms were tested at high temperature (60°C, high humidity (RH) = 92.5%) and high temperature (50°C, high humidity (75%)) for 7 and 14 days, respectively. The changes in the related substances of the salt crystal forms were calculated using the chromatographic peak area normalization method.

[0682] 1.6.3 Experimental results:

[0683] Table 14

[0684] 1.6.4 Experimental Conclusions: Comparing the stability results, after salt formation, Form A of the p-toluenesulfonate dihydrate significantly improved its solid stability. It was relatively stable under high temperature, high humidity, and high temperature and high humidity conditions, with no significant increase in impurities, meeting the requirements of later-stage drug development. Form A of the benzenesulfonate was relatively stable under high temperature and high humidity conditions, with no significant increase in impurities. This indicates that Form A of the benzenesulfonate is insensitive to changes in temperature and humidity, and can meet the requirements of later-stage drug storage. Form A of the p-toluenesulfonate and sulfate salts remained stable after storage for a period of time under various conditions, with no significant increase in impurities. This indicates that Form A of the p-toluenesulfonate and sulfate salts can effectively improve the operating margin for later-stage drug formulation development. Form A of the methanesulfonate was relatively stable under high humidity and high temperature and high humidity conditions, with no significant increase in impurities. This indicates that Form A of the methanesulfonate is extremely insensitive to humidity. Even when the temperature was increased to 50°C at 75% humidity, no significant increase in impurities was observed, reducing the harshness of later-stage drug storage conditions.

[0685] 1.7. Solubility experiments in different solvents

[0686] 1.7.1 Experimental purpose: To compare the solubility of p-toluenesulfonate dihydrate crystalline form A and sulfate crystalline form A in media such as water, artificial simulated gastric fluid (FaSSGF), fasting artificial simulated intestinal fluid (FaSSIF) and non-fasting artificial simulated intestinal fluid (FeSSIF).

[0687] 1.7.2 Experimental plan: About 1 mg of salt crystals were suspended in different media for 2 hours, and the solubility of the compound at 37°C was determined by HPLC external standard method.

[0688] 1.7.3 Experimental results:

[0689] Table 15

[0690] 1.7.4 Experimental Conclusion: The solubility of the two salt crystal forms described above in gastrointestinal simulated fluid and aqueous medium is basically the same, with no significant difference.

[0691] 1.8. PK studies in rats with different salt crystal forms

[0692] 1.8.1 Experimental Objective: To study the pharmacokinetic behavior of sulfate Form A and p-toluenesulfonate dihydrate Form A in rats (plasma) after a single oral administration using SD rats as test animals, and to compare the changes in exposure; and to investigate the bioavailability of sulfate Form A and p-toluenesulfonate dihydrate Form A after oral administration.

[0693] 1.8.2 Experimental Protocol: Both sulfate Form A and p-toluenesulfonate dihydrate Form A were uniformly suspended in an aqueous solution containing 0.5% HPMC K4M. The mixture was then gavage-administered to rats. Three rats were administered the following doses: sulfate Form A (5 mg / kg as a clear solution) and p-toluenesulfonate dihydrate Form A (5 mg / kg and 20 mg / kg as suspensions).

[0694] 1.8.3 Experimental results:

[0695] Table 16

[0696] 1.8.4 Experimental Conclusion: From the above data, it can be seen that the PK oral bioavailability of sulfate salt form A and p-toluenesulfonate dihydrate form A is high, and the exposure of p-toluenesulfonate dihydrate form is linearly related to the administered dose (5 mpk and 20 mpk).

[0697] 1.9 Single crystal experiment of p-toluenesulfonate dihydrate

[0698] 1.9.1 Experimental Purpose: Confirm the structure of the dihydrate crystalline form of tosylate

[0699] 1.9.2 Experimental Plan: Weigh 50 mg of p-toluenesulfonate at room temperature, add 20 ml of methanol, 10 ml of methyl tert-butyl ether, and 5 ml of n-heptane, and stir for 0.5 hour. Filter through a 0.22 filter membrane. Dilute the filtrate with 2 ml of methanol. Place the dilution in a beaker, seal with tin foil, poke a small hole, and place in a ventilated place without vibration to allow the solvent to evaporate naturally and slowly to dry, to obtain granular crystals.

[0700] 1.9.3 Data Characterization and Results

[0701] 1.9.3.1 Instrument Parameters

[0702] Single crystal measurement instrument and parameters: a Rigaku Saturn70 CCD diffractometer Mo-Kα radiation.

[0703] wavelength: Temperature: 113K

[0704] Scan range (theta range for data collection) 2.3-32.3°

[0705] Single crystal structure related data: Empirical formula: C7H7O3S·C 23 H 26 N5O2·2(H2O) molecular weight (Formula weight): 611.70

[0706] Crystal system and space group (Crystal system, space group): Triclinic, P -1

[0707] Unit cell dimensions:

[0708] alpha=95.646(3)°

[0709] beta=91.317(3)°

[0710] gamma=109.519(4)°

[0711] Unit cell volume (Volumn):

[0712] Calculated density: Z = 2, D c =1.384Mg m-3

[0713] Absorption coefficient: μ(MoKα) = 0.167 mm -1 , F(000)=648

[0714] R(int)=0.056(Reflections collected / unique)for 6640 / 9435

[0715] Final R indices[I>2σ(I)] R1=0.0597, wR2=0.1447

[0716] R indices (all data) R1=0.0868, wR2=0.1676

[0717] 1.9.3.2 Experimental Results: A single crystal structure was obtained as shown in FIG20 .

Claims

1. A compound represented by general formula (I) or an acid salt of a stereoisomer thereof, in, R1 is selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group; preferably C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 2-4 Alkynyl or C 3-6 Cycloalkyl; R a independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl or C 2-6 Alkynyl; R b independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl or C 2-6 Alkynyl; preferably hydrogen, deuterium, halogen, C 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 alkyl halide; R c independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group; preferably selected from hydrogen, deuterium, halogen, cyano, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 2-4 Alkynyl or C 3-6 Cycloalkyl; R d Selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, the C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, optionally further substituted by hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 One or more substitutions in the alkynyl group; R d Preferably selected from cyano, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, cyano substituted C 1-3 Alkyl, cyano substituted C 3- 6 cycloalkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic 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; preferably, the inorganic acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid or phosphoric acid; the organic acid is selected from 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, ethanesulfonic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, decanoic acid, hexanoic acid, octanoic acid, meat Cinnamic acid, citric acid, cyclohexanesulfamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, lauryl sulfate, 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-naphthalene disulfonic acid, naphthalene-2-sulfonic acid, niacin, 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.

2. The compound according to claim 1 or an acid salt of its stereoisomer, characterized in that The compound is shown below: The acid in the acid salt is selected from isethionic acid, hydrochloric acid, sulfuric acid, 1,5-naphthalene disulfonic acid, methanesulfonic acid, hydrobromic acid 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 or fumaric acid; preferably hydrochloric acid, sulfuric acid, methanesulfonic acid, hydrobromic acid or p-toluenesulfonic acid.

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

4. The compound according to any one of claims 1 to 3 or an acid salt of its stereoisomer, characterized in that The acid salt is a hydrate or an anhydrate; when the acid salt is a hydrate, the water is preferably crystal water or pipeline water; the number of water is 0.2-3; preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3; more preferably 2.

5. A crystalline form of an acid salt of the compound according to claim 4 or a stereoisomer thereof; Preferably, 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, Acid salt 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, 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, 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, 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, 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, Acid salt dihydrate 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, Acid salt dihydrate 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 crystalline dihydrate 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 preferably, the acid salt in the acid salt crystalline form, the acid salt monohydrate crystalline form or the acid salt dihydrate crystalline form is isethionate, sulfate, hydrochloride, 1,5-naphthalene disulfonate, methanesulfonate, ethanesulfonate, hydrobromide, phosphate, benzenesulfonate, oxalate, maleate, adipate, hydrochloride, citrate, malonate, L-malate, pamoate, p-toluenesulfonate or fumarate.

6. The crystal form according to claim 5, characterized in that The crystalline forms 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 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 benzenesulfonic acid crystalline form A; Preferably, wherein: The X-ray powder diffraction pattern of the hydrochloride salt 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°. diffraction peak; or a diffraction peak at 22.4±0.2°; or a diffraction peak at 25.2±0.2°; or a diffraction peak at 28.1±0.2°; preferably comprising any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8, or 6-9, or 8-10, or 8-11 of the above diffraction peaks, more preferably comprising any 6, 7, 8, 9, 10 or 11 thereof; The X-ray powder diffraction pattern of the sulfate 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 ° has a diffraction peak; or has a diffraction peak at 25.5 ± 0.2 °; or has a diffraction peak at 25.9 ± 0.2 °; or has a diffraction peak at 29.2 ± 0.2 °; preferably includes any 2-5 of the above diffraction peaks, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8, or 7-9, or 8-10, or 9-10, or 10-12, or 11-13, more preferably includes any 6, 7, 8, 9, 10, 11, 12 or 13 thereof; The X-ray powder diffraction pattern of the mesylate salt crystalline form A has a diffraction peak at 2θ of 5.2±0.2°; or a diffraction peak at 7.5±0.2°; or a diffraction peak at 7.9±0.2°; or a diffraction peak at 8.6±0.2°; or a diffraction peak at 12.3±0.2°; or a diffraction peak at 15.8±0.2°; or a diffraction peak at 17.1±0.2°; or a diffraction peak at 17.6±0.2°; or a diffraction peak at 19.8±0.2°; or a diffraction peak at 20.1±0.2°; or a diffraction peak at 21.8±0.2°; or a diffraction peak at 2 2.6±0.2° has a diffraction peak; 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°; preferably includes any 2-5 of the above diffraction peaks, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8, or 7-9, or 8-10, or 9-10, or 10-12, or 11-13, or 12-14, or 14-15, more preferably includes any 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 thereof; The X-ray powder diffraction pattern of the p-toluenesulfonate 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 includes any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, more preferably includes any 6, 7 or 8 thereof; The X-ray powder diffraction pattern of the p-toluenesulfonate salt 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 includes any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, more preferably includes any 6, 7 or 8 thereof; The X-ray powder diffraction pattern of the p-toluenesulfonate 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°; preferably includes any 2-5, or 3-5, or 3-6, or 3-7, or 5-7, or 6-7 of the above diffraction peaks, more preferably includes any 6 or 7 thereof; 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°; preferably, it includes any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8, or 6-9, or 7-9 of the above diffraction peaks, and more preferably includes any 6, 7, 8 or 9 thereof; The X-ray powder diffraction pattern of the benzenesulfonic acid 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 includes any 2-5 of the above diffraction peaks, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8, and more preferably includes any 6, 7 or 8 of them.

7. The crystal form according to claim 6, characterized in that: The X-ray powder diffraction spectrum of the hydrochloride crystal form A at least includes a 2θ of 9.2±0.2°, One or more diffraction peaks among 13.8±0.2°, 15.0±0.2°, preferably two of them, more preferably three of them; optionally, at least one of 4.6±0.2°, 7.0±0.2°, 20.8±0.2°, preferably two or three of them The X-ray powder diffraction pattern of the sulfate crystalline form A comprises at least one or more diffraction peaks located at 2θ of 6.5±0.2°, 9.7±0.2°, 16.1±0.2°, and 23.6±0.2°, preferably two of them, more preferably three; optionally, it may further comprise 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 them; The X-ray powder diffraction pattern of the mesylate salt crystalline form A comprises at least one or more diffraction peaks located at 2θ 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, and more preferably three of them; optionally, it 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 them; The X-ray powder diffraction pattern of the p-toluenesulfonate crystalline form A comprises at least one or more diffraction peaks located at 2θ of 5.3±0.2°, 15.9±0.2°, and 18.2±0.2°, preferably two of them, and more preferably three of them; optionally, it may further comprise 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 them; The X-ray powder diffraction pattern of the p-toluenesulfonate salt form B comprises at least one or more diffraction peaks located at 2θ of 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; optionally, further comprises at least one of 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 crystalline form C comprises at least one or more diffraction peaks located at 2θ 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; optionally, further comprises at least one 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; The X-ray powder diffraction pattern of the p-toluenesulfonate dihydrate crystalline form A comprises at least one or more diffraction peaks located at 2θ of 3.3±0.2°, 6.6±0.2°, 9.9±0.2°, and 13.3±0.2°, preferably two of them, more preferably three; optionally, it may further comprise 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 them; The X-ray powder diffraction pattern of the benzenesulfonic acid crystalline form A includes at least one or more diffraction peaks located 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 them, more preferably three; optionally, it may further include at least one of 18.9±0.2°, 23.3±0.2°, and 23.9±0.2°, preferably 2 or 3 of them.

8. The crystal form according to claim 6 or 7, characterized in that: The X-ray powder diffraction pattern of the hydrochloride salt form A optionally further comprises one or more diffraction peaks located at 2θ of 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 them; further preferably, any 2, 3, 4, or 5 of them; The X-ray powder diffraction pattern of the sulfate salt crystalline form A optionally further comprises one or more diffraction peaks located at 2θ of 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 them; further preferably, any 2, 3, 4, or 5 of them; The X-ray powder diffraction pattern of the mesylate salt form A optionally further comprises one or more diffraction peaks located at 2θ of 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°, and 28.2±0.2°; preferably, at least any 2-3 or 4-5 of them; further preferably, any 2, 3, 4, or 5 of them are included; The X-ray powder diffraction pattern of the p-toluenesulfonate salt form A optionally further comprises one or more diffraction peaks located at 2θ of 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 2-3, or 4-5 of these peaks are included; further preferably, any 2, 3, 4, or 5 of these peaks are included; The X-ray powder diffraction pattern of the p-toluenesulfonate salt form B optionally further comprises one or more diffraction peaks located at 2θ of 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, at least any 2-3 or 4-5 of these peaks are included; more preferably, any 2, 3, 4, or 5 of these peaks are included; The X-ray powder diffraction pattern of the p-toluenesulfonate salt form C optionally further comprises one or more diffraction peaks located at 2θ of 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; further preferably, any 2, 3, 4, or 5 of these are included; The X-ray powder diffraction pattern of the p-toluenesulfonate dihydrate crystalline form A optionally further comprises one or more diffraction peaks located at 2θ of 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 peaks are included; more preferably, any 2, 3, 4, or 5 of these peaks are included; The X-ray powder diffraction pattern of the benzenesulfonate salt form A optionally further includes one or more diffraction peaks located at 2θ of 10.5±0.2°, 11.3±0.2°, 18.2±0.2°, 22.8±0.2°, 25.0±0.2°, 28.2±0.2°, and 32.2±0.2°; preferably, at least any 2-3 or 4-5 of them are included; further preferably, any 2, 3, 4, or 5 of them are included.

9. The crystal form according to claim 6, characterized in that: The X-ray powder diffraction pattern of the hydrochloride crystal form A includes the following positions: 4.6±0.2°, 7.0± One or more diffraction peaks selected from 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°, and 28.1±0.2°; preferably, one or more diffraction peaks selected from 4, 5, 6, 8, or 10 of the diffraction peaks; The X-ray powder diffraction pattern of the sulfate crystalline form A comprises one or more diffraction peaks located at 2θ of 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°, and 29.2±0.2°; preferably, the X-ray powder diffraction pattern comprises one or more diffraction peaks selected from 4, 5, 6, 8, or 10 of the diffraction peaks. The X-ray powder diffraction pattern of the mesylate salt form A comprises one or more diffraction peaks located at 2θ of 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°, and 28.2±0.2°; preferably, the diffraction peaks are selected from 4, 5, 6, 8, or 10 of the diffraction peaks. The X-ray powder diffraction pattern of the p-toluenesulfonate crystalline form A comprises one or more diffraction peaks located at 2θ of 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°, and 26.1±0.2°; preferably, the diffraction peaks are selected from 4, 5, 6, 8, or 10 of the diffraction peaks. The X-ray powder diffraction pattern of the p-toluenesulfonate crystalline form B comprises one or more diffraction peaks located at 2θ of 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°, and 28.1±0.2°; preferably, the diffraction peaks are selected from 4, 5, 6, 8, or 10 of the diffraction peaks. The X-ray powder diffraction pattern of the p-toluenesulfonate crystalline form C comprises one or more diffraction peaks located at 2θ of 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°, and 28.1±0.2°; preferably, the diffraction peaks are selected from 4, 5, 6, 8, or 10 of the diffraction peaks. The X-ray powder diffraction pattern of the p-toluenesulfonate dihydrate crystalline form A comprises one or more diffraction peaks located at 2θ of 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°, and 26.9±0.2°; preferably, the X-ray powder diffraction pattern comprises one or more diffraction peaks selected from 4, 5, 6, 8, or 10 of the diffraction peaks. The X-ray powder diffraction pattern of the benzenesulfonate salt form A includes 2θ of 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 One or more diffraction peaks among 22.8±0.2°, 23.3±0.2°, 23.9±0.2°, 25.0±0.2°, 26.1±0.2°, 28.2±0.2°, and 32.2±0.2°; preferably, comprising any 4, 5, 6, 8 or 10 diffraction peaks.

10. The crystal form according to claim 6, characterized in that: The 2θ in the X-ray powder diffraction pattern of the hydrochloride crystal form A is shown in Table 1; or the 2θ in the X-ray powder diffraction pattern of the sulfate crystal form A is shown in Table 2; Or the 2θ in the X-ray powder diffraction pattern of the mesylate salt form A is shown in Table 3; or the 2θ in the X-ray powder diffraction pattern of the p-toluenesulfonate salt form A is shown in Table 4; Or the 2θ in the X-ray powder diffraction pattern of the p-toluenesulfonate salt form B is shown in Table 5; or the 2θ in the X-ray powder diffraction pattern of the p-toluenesulfonate salt form C is shown in Table 6; or the 2θ in the X-ray powder diffraction pattern of the p-toluenesulfonate salt dihydrate form A is shown in Table 7; or the 2θ in the X-ray powder diffraction pattern of the benzenesulfonate salt form A is shown in Table 8.

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

12. The crystal form according to claim 11, characterized in that: The hydrochloride crystal form A, sulfate crystal form A, methanesulfonate crystal form A, p-toluenesulfonate crystal form A, p-toluenesulfonate crystal form B, p-toluenesulfonate crystal form C, p-toluenesulfonate dihydrate crystal form The 2θ error of the diffraction peak position with the top ten relative peak intensities in the X-ray powder diffraction pattern of form A and benzenesulfonate salt form A and the diffraction peak position corresponding to the X-ray powder diffraction figure is ±0.2° to ±0.5°, preferably ±0.2° to ±0.3°, and most preferably ±0.2°.

13. A method for preparing the compound according to any one of claims 1 to 4 or an acid salt thereof, characterized in that: It includes the following steps: 1) Weigh an appropriate amount of free base and dissolve it in a benign solvent; 2) Weigh an appropriate amount of counterion acid and dissolve it in an organic solvent; the amount of counterion acid is preferably 1.2 equivalents; 3) Combine the above two solutions and stir to precipitate or add a poor solvent dropwise and stir to precipitate; 4) rapidly centrifuging or standing to dry to obtain the acid salt; in: The benign solvent is selected from one or more of methanol, acetone, ethyl acetate, acetonitrile, ethanol, 88% acetone, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropyl alcohol, n-butanol, isobutyl alcohol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, tert-butanol, 2-butanone, 3-pentanone or N-methylpyrrolidone; preferably one or more of N-methylpyrrolidone, methanol, dichloromethane or anhydrous ethanol; The organic solvent is selected from methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, dichloroethane, tetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, tert-butanol or N,N-dimethylformamide; preferably methanol, ethanol or acetonitrile; the above-mentioned benign solvent and organic solution need to be miscible when used; The poor solvent is selected from one or more of heptane, cyclohexane, n-hexane, n-pentane, water, ethyl acetate, methyl tert-butyl ether, toluene or isopropyl ether; preferably one or more of water, heptane, methyl tert-butyl ether or isopropyl ether; The counterion acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphoric acid, 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, capric acid, hexanoic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecyl sulfuric acid, dibenzoyltartaric acid, ethane-1, Preferably, the present invention comprises the following: 1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactosonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-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, fumarate, p-toluenesulfonate or succinate; most preferably, p-toluenesulfonate.

14. A method for preparing a crystalline form of the compound according to any one of claims 5 to 12 or an acid salt of its stereoisomer, characterized in that: whether it is Method 1, Method 2, or Method 3; Method 1 includes the following steps: 1) suspending the compound with a poor solvent; 2) Adding a counterion acid; the amount of the counterion acid is preferably 1.2 equivalents; the counterion acid can be dissolved in an organic solvent 3) stirring to dissolve, continuing to stir to precipitate or adding a poor solvent dropwise and stirring to precipitate; 4) isolating the anhydrate crystal form; Method 2 includes the following steps: Transform the anhydrate crystal form of method 1; Method 3 includes the following steps: The anhydrate crystal form prepared in method 1 is suspended in water to separate the hydrate crystal form; in: The poor solvent is selected from one or more of acetone, ethyl acetate, isopropyl acetate, acetonitrile, ethanol, 88% acetone, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropyl alcohol, n-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; preferably methanol, ethanol or acetonitrile; The counterion acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphoric acid, 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, capric acid, hexanoic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecyl sulfuric acid, dibenzoyltartaric acid, ethane-1, Preferably, the present invention comprises the following: 1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactosonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-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, fumarate, p-toluenesulfonate or succinate; most preferably, p-toluenesulfonate.

15. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 4 or an acid salt of its stereoisomer and / or a crystalline form of the compound according to any one of claims 5 to 12 or an acid salt of its stereoisomer, 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 its stereoisomer, the crystalline form of the compound according to any one of claims 5 to 12 or an acid salt of its stereoisomer, or the pharmaceutical composition according to claim 15 in the preparation of a PARP inhibitor; 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 its stereoisomer, the compound according to any one of claims 5 to 12 or a crystalline form of its acid salt, or the pharmaceutical composition according to claim 15 in the preparation of a medicament for treating cancer, ischemic disease or neurodegenerative disease; preferably, 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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