Medicinal salt of nitrogen-containing heterocyclic compound, crystal form and preparation method

Abstract

The invention relates to a pharmaceutically acceptable salt of a nitrogen-containing heterocyclic compound, a crystal form and a preparation method of the pharmaceutically acceptable salt. Specifically, the invention provides a pharmaceutically acceptable salt, a crystal form and a preparation method of a compound (R)-3-((7-ethyl-6-oxo-5, 6-dihydro-1, 5-naphthyridine-3-yl) methyl)-N-methyl-1, 2, 3, 4, 4a, 5-hexahydro-7H-pyrazino [2, 1-c] pyridino [3, 2-e] [1, 4] oxazepin-9-formamide as shown in a formula 1, and the corresponding salt has good stability and can be better used for clinical treatment.

Description

A pharmaceutically acceptable salt, crystal form and preparation method of a nitrogen-containing heterocyclic compound Technical Field

[0001] The present invention relates to the pharmaceutical field and relates to a pharmaceutically acceptable salt, a crystal form and a preparation method of a nitrogen-containing heterocyclic compound. Background Art

[0002] Poly(ADP-ribose) polymerase 1 (PARP1) was first described over 50 years ago and has since been found to play a crucial role in DNA repair, maintaining genomic integrity, and regulating various metabolic and signal transduction processes. PARP1 catalyzes the transfer of an ADP-ribose residue from NAD+ to its target substrate, forming a poly(ADP-ribose) (PAR) chain. PAR chain formation and clearance occurs in nearly all eukaryotic cells.

[0003] ADP-ribosylation is a post-translational modification of proteins that is widely present in various physiological and pathological processes. It refers to the incorporation of one or more ADP-ribose units into specific sites on proteins under the catalysis of enzymes. PARP1 is the first member of the PARP superfamily, which consists of proteins with homology to PARP1. There are currently 17 members, of which 4 (PARP1, PARP2, PARP5A and PARP5B) can synthesize PAR chains. Most other enzymes in the family can only build a single ADP-ribose unit and are therefore classified as mono(ADP-ribosyl)ases (MARs), i.e.

[0004] PARP1 and PARP2 have been extensively studied for their roles in DNA damage repair. PARP1 is activated by DNA damage and acts to catalyze the attachment of poly(ADP-ribose) (PAR) chains to target proteins. This post-translational modification, called poly-ADP-ribosylation (PARylation), mediates the recruitment of other DNA repair factors to DNA damage. Once this recruitment mission is completed, PARP autoPARylation triggers the release of bound PARP from DNA, allowing access to other DNA repair proteins to complete the repair. Therefore, the binding of PARP to damaged sites, its catalytic activity, and ultimately its release from DNA are all important steps in the response of cancer cells to DNA damage caused by chemotherapeutic agents and radiation therapy.

[0005] Inhibition of the PARP family of enzymes has been used as a strategy to selectively kill cancer cells by inactivating complementary DNA repair pathways. Numerous preclinical and clinical studies have shown that tumor cells harboring deleterious alterations in BRCA1 or BRCA2, key tumor suppressor proteins involved in the repair of double-stranded DNA breaks (DSBs) through deleterious recombination (HR), are selectively sensitive to small molecule inhibitors of the PARP family of DNA repair enzymes. These tumors have deficient homologous recombination repair (HRR) pathways and rely on the PARP enzymes for their survival function. Although PARP inhibitor therapy is primarily targeted at BRCA-mutated cancers, PARP inhibitors have been clinically tested in non-BRCA-mutated tumors that exhibit homologous recombination deficiency (HRD).

[0006] PARP inhibitors with enhanced selectivity for PARP1 may have improved efficacy and reduced toxicity compared to other PARP1 / 2 inhibitors. We believe that selective and potent inhibition of PARP1 will lead to PARP1 trapping on DNA, causing DNA double-strand breaks (DSBs) by collapsing replication forks during S phase. PARP1-DNA trapping is an effective mechanism for selectively killing tumor cells with HRD.

[0007] Therefore, effective and safe PARP inhibitors are urgently needed clinically, especially PARP inhibitors that are selective for PARP1.

[0008] The relevant patent applications that have been published include WO2021013735A1, WO2021260092A1, WO2009053373A1, WO2008107478A1, etc.

[0009] PCT / CN2022 / 094612 discloses a novel class of tetralin derivatives, including one represented by Formula 1, named (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide, demonstrating its application as a PARP inhibitor. The present disclosure incorporates the entire text of PCT / CN2022 / 094612.

[0010] The crystalline structure of a pharmaceutically active ingredient often affects the chemical and physical stability of the drug. Different crystallization and storage conditions can lead to changes in the compound's crystal structure, sometimes accompanied by the formation of other crystalline forms. Generally speaking, amorphous drug products lack a regular crystal structure and often have other defects, such as poor product stability, difficulty in filtration, easy agglomeration, and poor flowability. Therefore, studying the pharmaceutically acceptable salts and crystalline forms of the compound of Formula 1 (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide is of great significance for the development of drugs suitable for industrial production and with good biological activity.

[0011] Summary of the Invention

[0012] On the one hand, the present disclosure provides a crystalline form A of compound Formula 1, compound (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide.

[0013] In some embodiments, the Form A has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 7.877, 11.871, and 17.876.

[0014] In other embodiments, the Form A has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 7.877, 9.115, 11.871 and 17.876.

[0015] In other embodiments, the Form A has an X-ray powder diffraction pattern represented by a diffraction angle of 2θ, with characteristic peaks at 7.877, 9.115, 11.871, 15.851, 17.876 and 18.900.

[0016] In other embodiments, the X-ray powder diffraction pattern of the crystal form A expressed in terms of a diffraction angle 2θ is shown in FIG2 .

[0017] On the other hand, the present disclosure provides a method for preparing a crystalline form A of the compound of formula 1 (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide, comprising: dissolving the compound of formula 1 (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide in a solvent (1), adding a solvent (2), and stirring to crystallize.

[0018] In some embodiments, the solvent (1) is selected from at least one solvent selected from dichloromethane, methanol, water, isopropanol, tetrahydrofuran, ethanol, dimethyl sulfoxide, and N,N-dimethylformamide.

[0019] In some embodiments, the solvent (2) is selected from acetone, water, acetonitrile, methyl tert-butyl ether, n-heptane, and isopropyl acetate.

[0020] On the other hand, the present disclosure provides a method for preparing a crystalline form A of the compound of formula 1 (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide, comprising: mixing the compound of formula 1 (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide with a solvent (3), stirring and crystallizing.

[0021] In some embodiments, the solvent (3) is selected from water, methanol, ethanol, isopropanol, n-propanol, acetone, ethyl acetate, acetonitrile, isopropyl acetate, methyl tert-butyl ether, 2-butanone, tetrahydrofuran, n-heptane, 1,4-dioxane, isopentanol, methanol / water (1:1), ethyl acetate / ethanol (1:1), ethyl acetate / n-heptane (1:1), cyclohexane, isopropyl ether, propylene glycol methyl ether, 10% water / methanol, 7% water / ethanol, 10% water / isopropanol, 10% water / acetone, acetonitrile / methanol (v / v=1:1), tetrahydrofuran / ethanol (v / v=2:1)).

[0022] On the other hand, the present disclosure provides a method for preparing a crystalline form A of the compound of formula 1 (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazepane-9-carboxamide, comprising: dissolving the compound of formula 1 (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazepane-9-carboxamide in (4), and volatilizing and crystallizing.

[0023] In some embodiments, the solvent (4) is selected from DMSO, dichloromethane, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide, and DMSO / tetrahydrofuran (v / v=1:5).

[0024] On the other hand, the present disclosure provides a crystalline form B of compound Formula 1, compound (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide.

[0025] In some embodiments, the Form B has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 8.002, 9.248, 11.985, 13.412, and 17.526.

[0026] In other embodiments, the B crystalline form has an X-ray powder diffraction pattern represented by a diffraction angle of 2θ, with characteristic peaks at 8.002, 9.248, 11.985, 13.412, 17.526 and 17.929.

[0027] In other embodiments, the B crystalline form has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 8.002, 8.978, 9.248, 11.985, 13.412, 17.526 and 17.929.

[0028] In other embodiments, the X-ray powder diffraction pattern of the B crystal form expressed in terms of a diffraction angle 2θ is shown in FIG3 .

[0029] On the other hand, the present disclosure provides a pharmaceutically acceptable salt of compound Formula 1 (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide, wherein the pharmaceutically acceptable salt is selected from hydrochloride, sulfate, phosphate, methanesulfonate, succinate, fumarate, maleate, p-toluenesulfonate, L-tartrate, D-malate, L-malate and citrate.

[0030] In an optional embodiment, the chemical ratio of compound Formula 1 (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide to the acid is 3:1-1:3, including but not limited to 3:1, 2:1, 1:1, 1:2, and 1:3.

[0031] In another embodiment, the chemical ratio of the compound of Formula 1 (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide to the acid is 2:1-1:2.

[0032] In an optional embodiment, the chemical ratio of the compound of formula 1, compound (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide and hydrochloric acid is 1:1 or 1:2.

[0033] In an optional embodiment, the chemical ratio of the compound of formula 1, compound (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide and sulfuric acid is 1:1 or 2:1.

[0034] In an optional embodiment, the chemical ratio of the compound of formula 1, compound (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide and phosphoric acid is 1:1.

[0035] In an optional embodiment, the chemical ratio of the compound of formula 1, compound (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide and methanesulfonic acid is 1:1.

[0036] In an optional embodiment, the chemical ratio of the compound of formula 1 (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide to succinic acid is 2:1 or 1:1.

[0037] In an optional embodiment, the chemical ratio of the compound of formula 1, compound (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide and fumaric acid is 2:1 or 1:1.

[0038] In an optional embodiment, the chemical ratio of the compound of formula 1, compound (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide and maleic acid is 2:1 or 1:1.

[0039] In an optional embodiment, the chemical ratio of the compound of formula 1, compound (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide and p-toluenesulfonic acid is 1:1.

[0040] In an optional embodiment, the chemical ratio of the compound of formula 1, compound (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide and L-tartaric acid is 1:1-1:2.

[0041] The present disclosure also provides a method for preparing a pharmaceutically acceptable salt of (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazepane-9-carboxamide, comprising: The step of reacting the hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, succinic acid, fumaric acid, maleic acid, p-toluenesulfonic acid, L-tartaric acid, D-malic acid, L-malic acid and citric acid.

[0042] The solvent used for salt formation in the present invention is selected from but not limited to acetonitrile, acetone, tetrahydrofuran, ethanol, methanol, 1,4-dioxane, dichloromethane / methanol, water / isopropanol, and tetrahydrofuran / ethanol.

[0043] Furthermore, in an optional embodiment, the method for preparing the aforementioned pharmaceutically acceptable salt further comprises the steps of crystallization, filtration, washing or drying.

[0044] On the other hand, the present disclosure also provides a crystalline form a of the hydrochloride salt of compound formula 1 (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide, which has an X-ray powder diffraction pattern expressed in terms of a diffraction angle of 2θ, and has characteristic peaks at 8.164, 10.795, 11.375, 12.281, 13.481, 14.813, 17.195 and 17.606.

[0045] In other embodiments, the hydrochloride salt form a has an X-ray powder diffraction pattern expressed as a diffraction angle of 2θ, with characteristic peaks at 8.164, 10.795, 11.375, 12.281, 13.481, 14.813, 17.195, 17.606, 21.523, 22.982, 23.845, 24.814 and 25.962.

[0046] In other embodiments, the hydrochloride salt form a has an X-ray powder diffraction pattern expressed as a diffraction angle of 2θ, with characteristic peaks at 8.164, 10.795, 11.375, 12.281, 13.481, 14.813, 17.195, 17.606, 18.208, 20.026, 21.523, 22.982, 23.845, 24.814, 25.363, 25.962, 27.149 and 29.207.

[0047] In other embodiments, the X-ray powder diffraction pattern of the hydrochloride salt form a expressed in terms of a diffraction angle 2θ is shown in FIG4 .

[0048] The present disclosure also provides a method for preparing a crystalline form of the hydrochloride salt of compound (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide of formula 1, comprising: dissolving compound (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide of formula 1 in tetrahydrofuran / ethanol (v / v=2:1), adding hydrochloric acid, and stirring.

[0049] The present disclosure also provides a crystalline form b of the hydrochloride salt of compound Formula 1 (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide, which has an X-ray powder diffraction pattern expressed in terms of a diffraction angle of 2θ, and has characteristic peaks at 5.166, 7.759, 10.741, 14.887, 15.685, 16.604, 17.641, 21.855, and 26.448.

[0050] In some embodiments, the hydrochloride salt form b has an X-ray powder diffraction pattern expressed as a diffraction angle of 2θ, with characteristic peaks at 5.166, 7.759, 10.741, 14.201, 14.887, 15.685, 16.604, 17.641, 18.963, 21.855, 22.337, 22.949 and 26.448.

[0051] In some embodiments, the hydrochloride salt form b has an X-ray powder diffraction pattern expressed as a diffraction angle of 2θ, with characteristic peaks at 5.166, 7.759, 10.741, 14.201, 14.887, 15.685, 16.604, 17.641, 18.963, 21.855, 22.337, 22.949, 24.269, 26.448, 27.540, 28.187, 28.606 and 29.149.

[0052] In some embodiments, the hydrochloride salt form b has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 5.166, 7.759, 10.741, 14.201, 14.887, 15.685, 16.604, 17.641, 18.963, 21.059, 21.855, 22.337, 22.949, 24.269, 25.838, 26.448, 27.540, 28.187, 28.606, 29.149, 30.188, 32.330, 33.121, 33.450, 33.780 and 34.670.

[0053] In other embodiments, the X-ray powder diffraction pattern of the hydrochloride salt form b expressed in terms of a diffraction angle 2θ is shown in FIG5 .

[0054] The present disclosure also provides a method for preparing a crystalline form b of the hydrochloride salt of compound (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide of compound formula 1, comprising: dissolving compound (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide of compound formula 1 in dichloromethane / methanol (v / v=2:1), adding hydrochloric acid, and stirring.

[0055] The present disclosure also provides a hydrochloride form c of compound formula 1 (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide, which has an X-ray powder diffraction pattern expressed in terms of a diffraction angle 2θ, having characteristic peaks at 5.095, 8.779, 10.203, and 25.834.

[0056] In other embodiments, the X-ray powder diffraction pattern of hydrochloride form c expressed in diffraction angle 2θ is shown in FIG6 .

[0057] The present disclosure also provides a method for preparing a hydrochloride crystal form C of compound (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide of compound formula 1, comprising: dissolving compound (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide of compound formula 1 in 10% water / isopropanol, adding hydrochloric acid, adding isopropyl acetate, and stirring.

[0058] The present disclosure also provides a sulfate salt α-crystalline form of the compound of formula 1 (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide, having an X-ray powder diffraction pattern expressed in terms of a diffraction angle 2θ, and having characteristic peaks at 5.180, 8.955, 10.380, 13.767, and 15.578.

[0059] In some embodiments, the sulfate salt α-crystalline form has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 5.180, 8.955, 10.380, 13.767, 15.578 and 25.809.

[0060] In some embodiments, the sulfate salt α-crystalline form has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 5.180, 8.955, 10.380, 13.767, 15.578, 18.063, 18.781 and 25.809.

[0061] In other embodiments, the X-ray powder diffraction pattern of the sulfate α-crystalline form expressed in terms of a diffraction angle 2θ is shown in FIG7 .

[0062] The present disclosure also provides a method for preparing a sulfate salt α-crystalline form of compound (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazepane-9-carboxamide of compound formula 1, comprising: dissolving compound (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazepane-9-carboxamide of compound formula 1 in a solvent (5), adding sulfuric acid, and stirring.

[0063] The solvent (5) disclosed herein is selected from 10% water / isopropanol, tetrahydrofuran / ethanol (v / v=2:1), and dichloromethane / methanol (v / v=2:1).

[0064] The present disclosure also provides a phosphate α-crystalline form of the compound of formula 1 (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide, having an X-ray powder diffraction pattern expressed in terms of a diffraction angle 2θ, and having characteristic peaks at 5.175, 9.006, 10.437, 13.863, 15.707, and 18.979.

[0065] In some embodiments, the α-crystalline form of the phosphate has an X-ray powder diffraction pattern represented by a diffraction angle of 2θ, with characteristic peaks at 5.175, 9.006, 10.437, 10.999, 13.863, 15.707, 18.225, and 18.979.

[0066] In some embodiments, the α-crystalline form of the phosphate has an X-ray powder diffraction pattern represented by a diffraction angle of 2θ, with characteristic peaks at 5.175, 9.006, 10.437, 10.999, 13.863, 15.707, 18.225, 18.979, 20.767, and 25.682.

[0067] In other embodiments, the X-ray powder diffraction pattern of the α-crystalline form of the phosphate expressed in terms of a diffraction angle 2θ is shown in FIG8 .

[0068] The present disclosure also provides a method for preparing a phosphate α-crystalline form of a compound of formula 1 (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazepane-9-carboxamide, comprising: (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide was dissolved in 10% water / isopropanol or tetrahydrofuran / ethanol (v / v=2:1), phosphoric acid was added and stirred.

[0069] The present disclosure also provides a succinate salt form I of the compound of formula 1 (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide, which has an X-ray powder diffraction pattern expressed in terms of a diffraction angle of 2θ, and has characteristic peaks at 6.106, 8.589, 12.276, 14.812, 17.517, and 20.400.

[0070] In some embodiments, the succinate salt crystal form I has an X-ray powder diffraction pattern expressed in terms of a diffraction angle 2θ, with characteristic peaks at 6.106, 8.589, 9.156, 10.134, 12.276, 14.812, 17.517, 20.400, and 24.213.

[0071] In some embodiments, the succinate salt form I has an X-ray powder diffraction pattern expressed as a diffraction angle of 2θ, with characteristic peaks at 6.106, 7.931, 8.589, 9.156, 10.134, 12.276, 14.812, 15.357, 17.517, 20.400, 24.213, 29.362, and 38.514.

[0072] In some embodiments, the X-ray powder diffraction pattern of the succinate salt crystal form I is represented by a diffraction angle of 2θ, and the X-ray powder diffraction pattern is represented by a diffraction angle of 2θ as shown in FIG11 .

[0073] The present disclosure also provides a method for preparing a crystalline form I of a succinate salt of compound Formula 1 (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide, comprising: dissolving compound Formula 1 (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide in dichloromethane / methanol (v / v=2:1), adding succinic acid, and stirring.

[0074] The present disclosure also provides a crystalline form I of a fumarate salt of compound Formula 1 (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide, which has an X-ray powder diffraction pattern expressed in terms of a diffraction angle of 2θ, and has characteristic peaks at 6.163, 8.552, 12.317, 17.407, and 24.336.

[0075] In some embodiments, the fumarate salt crystalline form I has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 6.163, 8.552, 10.102, 12.317, 17.407, 20.302, 23.331, 24.336, 27.279 and 28.148.

[0076] In some embodiments, the fumarate salt crystalline form I has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 6.163, 7.982, 8.552, 10.102, 12.317, 14.750, 17.407, 20.302, 21.069, 22.678, 23.331, 24.336, 26.692, 27.279 and 28.148.

[0077] In some embodiments, the fumarate salt crystalline form I has an X-ray powder diffraction pattern represented by a diffraction angle of 2θ, and the X-ray powder diffraction pattern represented by a diffraction angle of 2θ is shown in FIG12 .

[0078] The present disclosure also provides a method for preparing a crystalline form I of a fumarate salt of compound (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazepane-9-carboxamide of compound formula 1, comprising: dissolving compound (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazepane-9-carboxamide of compound formula 1 in a solvent (6), adding fumaric acid, and stirring.

[0079] The solvent (6) is selected from tetrahydrofuran / ethanol (v / v=2:1), 10% water / isopropanol, and dichloromethane / methanol (v / v=2:1).

[0080] The present disclosure also provides a hemi-fumarate crystalline form i of the compound of formula 1 (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide, having an X-ray powder diffraction pattern expressed in terms of a diffraction angle 2θ, and having characteristic peaks at 3.95, 7.89, 8.43, 10.97, 11.85, and 14.17.

[0081] In some embodiments, the hemi-fumarate crystalline form i has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 3.95, 6.83, 7.30, 7.89, 8.43, 10.58, 10.97, 11.85 and 14.17.

[0082] In some embodiments, the hemi-fumarate salt form i has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 3.95, 6.83, 7.30, 7.89, 8.43, 9.95, 10.58, 10.97, 11.85 and 14.17.

[0083] In some embodiments, the X-ray powder diffraction pattern of the hemi-fumarate salt form i, represented by a diffraction angle of 2θ, is shown in FIG16 .

[0084] The present disclosure also provides a hemi-fumarate ii crystalline form of compound formula 1 (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide, having an X-ray powder diffraction pattern expressed in terms of a diffraction angle of 2θ, with characteristic peaks at 8.581, 9.892, 17.287, and 20.078.

[0085] In some embodiments, the hemi-fumarate salt form II has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 8.581, 9.892, 12.605, 14.336, 15.293, 17.287, 18.293, 19.342, 20.078 and 22.996.

[0086] In some embodiments, the X-ray powder diffraction pattern of the hemi-fumarate salt form II is represented by a diffraction angle of 2θ, and the X-ray powder diffraction pattern is represented by a diffraction angle of 2θ as shown in FIG17 .

[0087] The present disclosure also provides a hemi-fumarate iii crystalline form of compound formula 1 (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide, having an X-ray powder diffraction pattern expressed in terms of a diffraction angle of 2θ, and having characteristic peaks at 8.363, 11.005, 12.498, 14.267, and 28.341.

[0088] In some embodiments, the X-ray powder diffraction pattern of the hemi-fumarate salt form III is represented by a diffraction angle of 2θ, and the X-ray powder diffraction pattern is represented by a diffraction angle of 2θ as shown in FIG18 .

[0089] The present disclosure also provides a maleate salt form a of compound formula 1 (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide, which has an X-ray powder diffraction pattern expressed in terms of a diffraction angle 2θ, and has characteristic peaks at 7.902, 9.389, 11.879, 15.683, and 21.632.

[0090] In some embodiments, the maleate salt crystalline form a has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 7.902, 8.629, 9.109, 9.389, 11.879, 15.683, 17.043, 17.871, 20.015, 21.632, and 25.672.

[0091] In some embodiments, the maleate salt crystalline form a has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 7.902, 8.629, 9.109, 9.389, 11.879, 13.509, 14.285, 15.683, 17.043, 17.453, 17.871, 19.572, 20.015, 21.632, 24.489, and 25.672.

[0092] In some embodiments, the maleate salt crystalline form a has an X-ray powder diffraction pattern represented by a diffraction angle of 2θ, and the X-ray powder diffraction pattern represented by a diffraction angle of 2θ is shown in FIG13 .

[0093] The present disclosure also provides a method for preparing a maleate crystalline form a of a compound of formula 1 (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyridino[3,2-e][1,4]oxazepane-9-carboxamide, comprising: (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide was dissolved in dichloromethane / methanol (v / v=2:1), maleic acid was added, and then methyl tert-butyl ether was added and stirred for crystallization.

[0094] Furthermore, the present invention discloses a crystalline form of compound Formula 1 (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide, wherein the error range of the 2θ angle is ±0.2.

[0095] In certain embodiments, the method for preparing the crystalline form described in the present disclosure further comprises the steps of crystallization, filtration, washing or drying.

[0096] On the other hand, the present disclosure also provides a pharmaceutical composition comprising the aforementioned compound Formula 1 compound (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide crystalline form A, or the compound Formula 1 compound (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide pharmaceutically acceptable salt or a crystalline form thereof, and optionally a pharmaceutically acceptable excipient.

[0097] The present disclosure also provides a method for preparing a pharmaceutical composition, comprising the step of mixing the aforementioned crystalline form A of compound (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide of compound formula 1, or a pharmaceutically acceptable salt thereof of compound (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide or a crystalline form thereof with a pharmaceutically acceptable excipient.

[0098] The present disclosure also provides the aforementioned compound of formula 1, compound (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide, in crystalline form A or crystalline form B, or the compound of formula 1, compound (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide, a pharmaceutically acceptable salt thereof or a crystalline form thereof, or the use of the aforementioned pharmaceutical composition as a PARP1 inhibitor.

[0099] The present disclosure also provides the use of the aforementioned compound of Formula 1, compound (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide, in crystalline form A or crystalline form B, or a pharmaceutically acceptable salt or crystalline form thereof of the compound of Formula 1, compound (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide, or the aforementioned pharmaceutical composition in the preparation of a medicament for a PARP1 inhibitor.

[0100] The present disclosure also provides the aforementioned compound of formula 1, compound (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide, crystalline form A or crystalline form B, or the compound of formula 1, compound (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide, a pharmaceutically acceptable salt thereof or a crystalline form thereof, or the use of the aforementioned pharmaceutical composition for treating and / or preventing cancer.

[0101] The present disclosure also provides the aforementioned compound of formula 1, compound (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide, crystalline form A and crystalline form B, or the compound of formula 1, compound (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide, a pharmaceutically acceptable salt thereof or a crystalline form thereof, or the use of the aforementioned pharmaceutical composition in the preparation of a medicament for treating and / or preventing cancer.

[0102] The use disclosed herein, wherein the cancer is selected from breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, colorectal cancer, lung cancer, kidney cancer, liver cancer, cervical cancer, endometrial cancer, myeloma, leukemia, lymphoma, acoustic neuroma, basal cell carcinoma, bile duct cancer, bladder cancer, brain cancer, bronchial cancer, sarcoma, chordoma, choriocarcinoma, craniopharyngioma, cystadenocarcinoma, embryonal carcinoma, hemangioendothelioma, ependymoma, epithelial cancer, esophageal cancer, essential thrombocythemia, Ewing's tumor, testicular cancer, glioma, heavy chain disease, Hemangioblastoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, neuroblastoma, NUT midline carcinoma, glioma, bone cancer, nasopharyngeal cancer, oral cancer, thyroid cancer, pinealoma, polycythemia vera, retinoblastoma, sebaceous gland carcinoma, seminoma, skin cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, Waldenstrom's macroglobulinemia and Wilms' tumor; preferably, the cancer is selected from breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, colorectal cancer and lung cancer.

[0103] The "2θ or 2θ angle" mentioned in the present disclosure refers to the diffraction angle, θ is the Bragg angle, and the unit is ° or degree; the error range of each characteristic peak 2θ is ±0.20 (including the case where the number exceeding 1 decimal place is rounded off), specifically -0.20, -0.19, -0.18, -0.17, -0.16, -0.15, -0.14, -0.13, -0.12, -0.11, -0.10, -0.09, -0.08, -0.07, -0.06, -0.05, -0.04, -0.03, -0.02, -0.01, 0.00, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20.

[0104] The chemical ratios of the compounds and the acid molecules described herein are subject to a certain degree of error. Generally, a range of plus or minus 10% is considered within a reasonable error range. The term "about" is used in a context where the error may vary, but this error may not exceed plus or minus 10%. The error may be plus or minus 9%, plus or minus 8%, plus or minus 7%, plus or minus 6%, plus or minus 5%, plus or minus 4%, plus or minus 3%, plus or minus 2%, or plus or minus 1%, preferably plus or minus 5%. Numerical values ​​expressed as "about" in this disclosure are within the aforementioned reasonable error range.

[0105] The "crystallization" or "crystallization" described in the present disclosure includes but is not limited to stirring crystallization, slurry crystallization, cooling crystallization and volatile crystallization.

[0106] The "differential scanning calorimetry or DSC" described in this disclosure refers to measuring the temperature difference and heat flow difference between a sample and a reference object during the process of heating or maintaining the sample at a constant temperature to characterize all physical and chemical changes related to thermal effects and obtain phase change information of the sample.

[0107] The drying temperature in the present disclosure is generally 25° C. to 100° C., preferably 40° C. to 70° C., and the drying can be performed under normal pressure or reduced pressure.

[0108] The "pharmaceutically acceptable excipients" described in this disclosure include, but are not limited to, any adjuvant, carrier, glidant, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent or emulsifier approved by the U.S. Food and Drug Administration for use by humans or livestock animals. BRIEF DESCRIPTION OF THE DRAWINGS

[0109] Figure 1 is the XRPD spectrum of the amorphous form of compound 1.

[0110] Figure 2 is the XRPD spectrum of Form A of Compound 1.

[0111] Figure 3 is the XRPD spectrum of Form B of Compound 1.

[0112] Figure 4 is the XRPD spectrum of Compound 1 hydrochloride salt form a.

[0113] Figure 5 is the XRPD spectrum of Compound 1 hydrochloride b crystal form.

[0114] Figure 6 is the XRPD spectrum of Compound 1 hydrochloride Form C.

[0115] Figure 7 is the XRPD spectrum of compound 1 sulfate α-crystalline form.

[0116] Figure 8 is the XRPD spectrum of the α-crystalline form of the phosphate salt of Compound 1.

[0117] Figure 9 is the XRPD spectrum of the amorphous phosphate salt of Compound 1.

[0118] Figure 10 is the XRPD spectrum of the amorphous form of the methanesulfonate salt of Compound 1.

[0119] Figure 11 is the XRPD spectrum of the succinate salt Form I of Compound 1.

[0120] Figure 12 is the XRPD spectrum of Compound 1 fumarate salt Form I.

[0121] Figure 13 is the XRPD spectrum of the maleate salt form a of Compound 1.

[0122] FIG14 is an XRPD spectrum of the amorphous p-toluenesulfonate salt of Compound 1.

[0123] FIG15 is an XRPD spectrum of the amorphous L-tartrate salt of compound 1.

[0124] Figure 16 is the XRPD spectrum of the hemi-fumarate crystal form i of Compound 1.

[0125] Figure 17 is the XRPD spectrum of the hemi-fumarate crystalline form ii of Compound 1.

[0126] Figure 18 is the XRPD spectrum of the hemi-fumarate iii crystal form of Compound 1. DETAILED DESCRIPTION

[0127] The present disclosure is further described in detail by the following examples and experimental examples. These examples and experimental examples are for illustrative purposes only and are not intended to limit the scope of the present disclosure.

[0128] Test conditions of the instruments used in the experiment:

[0129] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The unit of ppm is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and tetramethylsilane (TMS) was used as the internal standard.

[0130] MS measurements were performed using an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid chromatography-mass spectrometer (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), a Waters ACQuity UPLC-QD / SQD (manufacturer: Waters, MS model: Waters ACQuity Qda Detector / Waters SQ Detector), and a THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q 15 Exactive).

[0131] HPLC analysis was performed using an Agilent 1260DAD high pressure liquid chromatograph (Sunfire C18 150×4.6 mm column) and a Thermo U3000 high pressure liquid chromatograph (Gimini C18 150×4.6 mm column).

[0132] XRPD is X-ray powder diffraction detection: the measurement is carried out using a BRUKER D8 X-ray diffractometer, specific collection information: Cu anode (40kV, 40mA), radiation: monochromatic Cu-Ka radiation Scanning mode: θ / 2θ, scanning range: 3-48°.

[0133] XRPD is X-ray powder diffraction detection: the measurement is carried out using a BRUKER D8FOCUS X-ray diffractometer, and the specific collection information is: Radiation: monochromatic Cu-Ka radiation Scanning mode: θ / 2θ, scanning range: 2-40°.

[0134] DSC is differential scanning calorimetry: the measurement was performed using a METTLER TOLEDO DSC 3+ differential scanning calorimeter with a heating rate of 10°C / min, from 25 to 350°C, and a nitrogen purge rate of 50 mL / min.

[0135] TGA is thermogravimetric analysis: the test was performed using a METTLER TOLEDO TGA 2 thermogravimetric analyzer with a heating rate of 10°C / min. The specific temperature range was referred to the corresponding spectrum, and the nitrogen purge rate was 50 mL / min.

[0136] DVS stands for dynamic moisture sorption: using the Surface Measurement Systems instrument, humidity starts at 50% and the humidity range is 0%-95% with a step of 10%. The judgment standard is that the mass change of each gradient dM / dT is ≤ 0.002%, TMAX is 360min, and there are two cycles.

[0137] The known starting materials disclosed herein can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co.KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals, etc.

[0138] The reaction progress in the examples was monitored by thin layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compound, and the developing solvent system for thin layer chromatography included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system. The volume ratio of the solvent was adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0139] Example 1. Preparation of Compound 1 (Refer to the preparation method of Example 8 in application number PCT / CN2022 / 094612)

[0140] first step

[0141] (R)-tert-Butyl 3-(((6-bromo-3-fluoropyridin-2-yl)methoxy)methyl)piperazine-1-carboxylate 1b

[0142] The compound 6-bromo-2-(bromomethyl)-3-fluoropyridine 1g (2.5g, 9.29mmol, prepared by the method disclosed in Preparation Example 6 on page 12 of the specification of the patent application "WO2016077161A1") and the compound (R)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester 1a (2.25g, 10.40mmol, Shanghai Hanhong) were dissolved in tetrahydrofuran (30mL), and sodium hydride (812.5mg, 21.20mmol, 60% purity) was added under ice bath. The reaction was stirred for 2 hours, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 1b (3g, yield: 79.8%).

[0143] MS m / z(ESI):404.1[M+1].

[0144] Step 2

[0145] (R)-tert-Butyl 3-(((6-(ethoxycarbonyl)-3-fluoropyridin-2-yl)methoxy)methyl)piperazine-1-carboxylate 1c

[0146] Compound 1b (2 g, 4.94 mmol) was dissolved in a mixed solvent of N,N-dimethylformamide (20 mL) and ethanol (10 mL), and bis(triphenylphosphine)palladium dichloride (0.52 g, 740.8 μmol) and N,N-diisopropylethylamine (1.52 g, 15 mmol) were added. The reaction was stirred at 100°C under a carbon monoxide atmosphere for 14 hours. After cooling, ethyl acetate (100 mL) was added to dilute the mixture, and the mixture was washed with water and saturated sodium chloride solution in sequence. The organic phase was collected and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System B to give the title compound 1c (1.5 g, yield: 76.2%).

[0147] MS m / z(ESI):398.2[M+1].

[0148] Step 3

[0149] 3-(tert-Butyl)9-methyl(R)-1,2,4a,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-3,9(4H)-dicarboxylate 1d

[0150] Compound 1c (4 g, 10.06 mmol) was dissolved in N,N-dimethylacetamide (20 mL), and N,N-diisopropylethylamine (4 g, 30.9 mmol) was added. The mixture was reacted in a microwave oven at 140°C for 6 hours. The reaction solution was cooled and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System A to give the title compound 1d (2.3 g, yield: 60%).

[0151] MS m / z(ESI):364.2[M+1].

[0152] Step 4

[0153] tert-Butyl (R)-9-(methylaminocarbonyl)-1,2,4a,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-3(4H)-carboxylate 1e

[0154] Compound 1d (600 mg, 1.58 mmol) was dissolved in 5 mL of 1 M methylamine ethanol solution and stirred for 14 hours. The reaction solution was concentrated under reduced pressure to give the crude title compound 1e (570 mg, yield: 98%), which was used directly in the next step without purification.

[0155] MS m / z(ESI):363.2[M+1].

[0156] Step 5

[0157] (R)-N-Methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide hydrochloride 1f

[0158] The crude compound 1e (140 mg, 386.2 μmol) was dissolved in dichloromethane (3 mL), and 1 mL of 4 M hydrochloric acid dioxane solution was added. The mixture was stirred for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 1f (110 mg, yield: 95%), which was used directly in the next step without purification.

[0159] MS m / z(ESI):263.2[M+1].

[0160] Step 6

[0161] (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide 1

[0162] The crude compound 1f (570 mg, 1.9 mol), compound 7-(chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one 1h (430 mg, 1.93 mol, prepared by the method disclosed in Example 4 on page 15 of the specification of patent application "WO2021013735A1"), and N,N-diisopropylethylamine (1.5 g, 11.6 mmol) were dissolved in acetonitrile (30 mL), and sodium iodide (30 mg, 200 μmol) was added. The mixture was reacted at 80°C for 5 hours. After the reaction solution was concentrated under reduced pressure, the crude product was purified by high performance liquid chromatography (Waters-2545, chromatographic column: SharpSil-T C18, 30*150mm, 5μm; mobile phase: water (10mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30mL / min) to obtain the title compound 1 (5.4mg, yield: 8%).

[0163] MS m / z(ESI):449.2[M+1].

[0164] 1 H NMR (500MHz, CD3OD): δ8.51(d,1H),7.93(d,1H),7.86(s,1H),7.79(d,1H),7.50(d,1H),4.99(t,2H),4.85(d,1H),4.08(dd,2H) ,3.87(dd,1H),3.81-3.71(m,2H),3.46(ddd,2H),2.95(s,3H),2.86-2.78(m,1H),2.75-2.61(m,3H),2.57(dd,1H),1.31(t,3H).

[0165] The X-ray powder diffraction spectrum of the amorphous form is shown in FIG1 .

[0166] Example 2: Cell proliferation experiment

[0167] The following method detects the intracellular ATP content according to IC 50 Evaluation of the effect of compound 1 on DLD1 cells and DLD1 BRCA2- / - The experimental method is briefly described as follows:

[0168] 1. Experimental Materials and Instruments

[0169] 1.DLD1, human colon cancer cells (Nanjing Kebai, CBP60037), DLD1 BRCA2- / - Human BRCA2 gene knockout colon cancer tumor cells (Creative biogene, CSC-RT0015)

[0170] 2. MDA-MB-436, human breast cancer cells (ATCC, HTB-130)

[0171] 3. Fetal bovine serum (GIBCO, 10091-148)

[0172] 4.CellTite-Glo reagent (Promega, G7573)

[0173] 5. 96-well cell culture plate (Corning, 3903)

[0174] 6. Pancreatin (Invitrogen, 25200-072)

[0175] 7. Microplate reader (BMG, PHERAsta)

[0176] 8. Cell counter (Shanghai Ruiyu Biotechnology Co., Ltd., IC1000)

[0177] 2. Experimental steps

[0178] DLD1 cells were cultured in RPMI-1640 medium containing 10% FBS and passaged 2-3 times a week at a passage ratio of 1:6 or 1:8. During passage, cells were trypsinized and transferred to a centrifuge tube. Centrifuged at 1200 rpm for 3 minutes, the supernatant was discarded, and fresh medium was added to resuspend the cells. 180 μL of cell suspension was added to a 96-well cell culture plate at a density of 2.78 × 10 3 cells / mL, and only 180 μL of complete culture medium was added to the periphery of the 96-well plate.

[0179] DLD1 BRCA2- / - Cells were cultured in RPMI-1640 medium supplemented with 10% FBS and passaged 2-3 times a week at a subculture ratio of 1:6 or 1:8. During subculture, cells were trypsinized and transferred to a centrifuge tube. Centrifuged at 1200 rpm for 3 minutes, the supernatant was discarded, and fresh medium was added to resuspend the cells. 180 μL of the cell suspension was added to a 96-well cell culture plate at a density of 8.34 × 10 3 cells / mL, and only 180 μL of complete culture medium was added to the periphery of the 96-well plate.

[0180] MDA-MB-436 cells were cultured in Leibovitz's L-15 medium supplemented with 10% FBS, 10 μg / mL insulin, and 16 μg / mL glutathione. The cells were passaged 2-3 times per week at a subculture ratio of 1:3 or 1:5. During subculture, the cells were trypsinized and transferred to a centrifuge tube. The cells were centrifuged at 1200 rpm for 3 minutes, the supernatant was discarded, and fresh medium was added to resuspend the cells. 180 μL of the cell suspension was added to a 96-well cell culture plate at a density of 8.34 × 10 3 cells / mL, and only 180 μL of complete culture medium was added to the periphery of the 96-well plate.

[0181] The culture plate was incubated in an incubator (37° C., 5% CO 2 ) for 24 hours.

[0182] The test sample was diluted to 2 mM with DMSO, and diluted 3 times in sequence to 10 concentrations, and blank and control wells were set. 5 μL of the test compound solution prepared into a gradient concentration was added to 95 μL of fresh culture medium. 20 μL of the above-mentioned drug-containing culture medium solution was then added to the culture plate. The culture plate was incubated in an incubator for 6 days (37°C, 5% CO2). In a 96-well cell culture plate, 90 μL of CellTiter-Glo reagent was added to each well, and the plate was placed in the dark at room temperature for 5-10 minutes. The chemiluminescence signal value was read in PHERAstar, and the data was processed using GraphPad software. The results are shown in Table 1.

[0183] Table 1 Effects of the compounds disclosed herein on DLD1, DLD1 BRCA2- / - and the inhibitory effect on MDA-MB-436 cell proliferation

[0184] Conclusion: Compound 1 of the present disclosure has an effect on DLD1 BRCA2- / - It has a good inhibitory effect on the proliferation of MDA-MB-436 cells.

[0185] Example 3: Determination of the Binding Activity of Compound 1 of the Present Disclosure to PARP1 and PARP2

[0186] The in vitro PARP1 and PARP2 binding activities were tested by the following method.

[0187] 1. Experimental Materials and Instruments

[0188] 1.PARP1 recombinant protein (Sino Biological, Cat. No. 11040-H08B);

[0189] 2.PARP2 recombinant protein (BPS, Cat. No. 80502)

[0190] 3. Fluorescent probe (made using compound CAS No. 1380359-84-1, Shanghai Hengrui); 384-well plate (Corning, 3575)

[0191] 4. Microplate reader PHERAstar FS (BMG Labtech)

[0192] 2. Experimental steps

[0193] 8 μL of binding buffer was added to each well of a 384-well plate. The fluorescent probe was dissolved in dimethyl sulfoxide and diluted to the desired concentration. The fluorescent probe prepared in dimethyl sulfoxide was then diluted 20-fold in binding buffer (50 mM Tris-HCl pH 8.0, 50 mM NaCl, 1 mM MgCl2, 0.1 mM EDTA, 0.01% IGEPAL) and 2 μL was added to each well. The test compound was dissolved in dimethyl sulfoxide and diluted to the desired concentration range according to the experimental requirements. The compound prepared in dimethyl sulfoxide was then diluted 20-fold in binding buffer and 2 μL was added to each well. PARP1 or PARP2 protein was diluted to the desired concentration in binding buffer and 8 μL / well was added to a black 384-well plate. After mixing, the plate was incubated at 25°C for 40 minutes. Signals were read using the FP program in a PHERAstar FS microplate reader. Data were processed using GraphPad software.

[0194] The PARP1 and PARP2 binding inhibitory activity of compound 1 of the present disclosure was determined by the above test, and the measured IC 50 See Table 2 for values.

[0195] Table 2 Inhibitory activity of the disclosed compounds on PARP1 and PARP2 binding

[0196] Conclusion: The disclosed compounds have selective inhibitory effects on PARP1.

[0197] Example 4: Preparation of Crystalline Form A of Compound 1

[0198] 120 mg of the compound represented by Formula 1 was dissolved in 2 mL of dichloromethane / methanol (v / v=1:1), 2.1 mL of acetone was added, and the mixture was stirred for crystallization. The mixture was filtered and the solid was vacuum dried to obtain an off-white solid.

[0199] X-ray powder diffraction analysis identified the product as Form A. The XRPD spectrum is shown in Figure 2, and the positions of its characteristic peaks are shown in Table 3. The DSC spectrum showed an endothermic peak at 259.82°C. The TGA spectrum showed a weight loss of 0.53% from 30°C to 185°C.

[0200] DVS testing revealed that under normal storage conditions (i.e., 25°C, 60% RH), the sample experienced a moisture gain of approximately 0.31%. Under accelerated storage conditions (i.e., 70% RH), the moisture gain was approximately 0.40%. Under extreme conditions (90% RH), the moisture gain was approximately 0.76%. Over a humidity range of 0% to 95% RH, the sample's desorption and adsorption processes largely overlapped, and subsequent DVS testing revealed no change in crystal form.

[0201] Table 3

[0202] Example 5: Preparation of Crystalline Form A of Compound 1

[0203] 8 mg of the compound of formula 1 was added to 0.4 mL of 10% water / isopropanol and dissolved with stirring at 60°C. The mixture was cooled to room temperature, 1.2 mL of water was added, stirred to precipitate, centrifuged, and the solid was vacuum dried. X-ray powder diffraction analysis revealed that the solid was Form A.

[0204] The solid obtained by the above preparation method using the solvents listed in Table 4 was found to be Form A by X-ray powder diffraction.

[0205] Table 4 Preparation of Compound A Crystalline Form

[0206] Example 6: Preparation of Crystalline Form A of Compound 1

[0207] 8 mg of the compound represented by Formula 1 was dissolved in 0.1 mL of dichloromethane / methanol (v / v=2:1), 1 mL of acetone was added, and the mixture was stirred for crystallization. The mixture was centrifuged and the solid was vacuum dried. X-ray powder diffraction analysis revealed that the solid was Form A.

[0208] The solid obtained by the above preparation method using the solvents listed in Table 5 was found to be Form A by X-ray powder diffraction.

[0209] Table 5 Preparation of Compound A Crystalline Form

[0210] Example 7 Preparation of Crystalline Form A of Compound 1

[0211] 8 mg of the compound represented by Formula 1 was dissolved in 0.3 mL of DMSO, evaporated and crystallized, and X-ray powder diffraction analysis showed that it was crystal form A.

[0212] The solid obtained by the above preparation method using the solvents listed in Table 6 was found to be Form A by X-ray powder diffraction.

[0213] Table 6 Preparation of Compound A Crystalline Form

[0214] Example 8: Preparation of Crystalline Form A of Compound 1

[0215] The compound of formula 1, form A (12.30 g, 27.42 mmol), was dispersed in 120 mL of anhydrous ethanol, heated to 75°C with stirring for 1 hour, cooled to room temperature with stirring for 12 hours, filtered, and the filter cake was collected. The resulting solid was ground and dispersed in 100 mL of anhydrous ethanol, stirred and slurried for 1 hour, filtered, and the filter cake was collected, washed with ethanol (20 mL × 2), and dried under vacuum at 25°C for 2 hours to obtain the compound of formula 1 (8.96 g, yield 72.8%). X-ray powder diffraction analysis confirmed the compound to be form A.

[0216] Example 9: Preparation of Crystalline Form B of Compound 1

[0217] The crude product of the compound of Formula 1 (0.856 g, 1.91 mmol) was purified by high performance liquid chromatography (HPLC column: SharpSil-T Prep C18 150*30 mm, 5 μm; mobile phase A: water (containing 10 mmol / L ammonium bicarbonate); mobile phase B: acetonitrile; 10-minute gradient: 32% acetonitrile, flow rate: 30 mL / min). The prepared solution was lyophilized to obtain the compound of Formula 1 (0.09 g, yield 10.9%).

[0218] The product was defined as Form B by X-ray powder diffraction analysis. The X-ray powder diffraction data are shown in Table 7, and the X-ray powder diffraction spectrum is shown in FIG3.

[0219] The DSC spectrum showed an endothermic peak at 258.01°C, and the TGA spectrum showed that the compound lost 0.69% of its weight from 40°C to 160°C.

[0220] Table 7

[0221] Example 10 Preparation of Crystalline Form A of the Hydrochloride Salt of Compound of Formula 1

[0222] 120 mg of the compound represented by Formula 1 was added to 9 mL of tetrahydrofuran / ethanol (v / v=2:1), stirred and dissolved at 60°C, cooled to room temperature, and 145 μL of 2M hydrochloric acid ethanol solution was added. The mixture was stirred for crystallization, filtered, and the solid was vacuum dried to obtain an off-white solid.

[0223] X-ray powder diffraction analysis identified the product as hydrochloride Form a. The XRPD spectrum is shown in Figure 4, and the locations of its characteristic peaks are shown in Table 8. The DSC spectrum revealed an endothermic peak at 283.01°C. The TGA spectrum showed a weight loss of 1.53% between 30°C and 170°C, and a weight loss of 6.49% between 170°C and 258°C. Ion chromatography revealed a chloride ion content of 7.08%.

[0224] Table 8

[0225] Example 11: Preparation of Form B of the Hydrochloride Salt of the Compound of Formula 1

[0226] 120 mg of the compound represented by Formula 1 was dissolved in 1 mL of dichloromethane / methanol (v / v=2:1), and 290 μL of 2M hydrochloric acid ethanol solution was added. The mixture was stirred to precipitate, filtered, and the solid was vacuum dried to obtain an off-white solid.

[0227] X-ray powder diffraction analysis identified the product as hydrochloride Form b. The XRPD spectrum is shown in Figure 5, and the locations of its characteristic peaks are shown in Table 9. The DSC spectrum revealed endothermic peaks at 49.81°C, 258.00°C, and 284.29°C. The TGA spectrum showed a weight loss of 1.88% from 30°C to 150°C and 8.12% from 150°C to 235°C. Ion chromatography revealed a chloride ion content of 13.19%.

[0228] DVS testing revealed that under normal storage conditions (i.e., 25°C, 60% RH), the sample experienced a moisture gain of approximately 3.26%; under accelerated storage conditions (i.e., 70% RH), the moisture gain was approximately 3.65%; and under extreme conditions (90% RH), the moisture gain was approximately 4.60%. Over a humidity range of 0% to 95% RH, the sample's desorption and adsorption processes largely overlapped, and subsequent DVS testing revealed no change in crystal form.

[0229] Table 9

[0230] Example 12: Preparation of Form C of Hydrochloride Salt of Compound of Formula 1

[0231] 7 mg of the compound represented by Formula 1 was added to 0.4 mL of 10% water / isopropanol, stirred and dissolved at 60°C, cooled to room temperature, and 8.5 μL of 2M hydrochloric acid ethanol solution was added, followed by 0.8 mL of isopropyl acetate. The mixture was stirred for crystallization, filtered, and the solid was vacuum dried to obtain an off-white solid.

[0232] X-ray powder diffraction analysis identified the product as hydrochloride Form C. The XRPD spectrum is shown in Figure 6, and the positions of its characteristic peaks are shown in Table 10. The DSC spectrum showed endothermic peaks at 71.69°C and 190.85°C. The TGA spectrum showed a weight loss of 16.01% from 30°C to 180°C.

[0233] Table 10

[0234] Example 13: Preparation of the α-crystalline sulfate salt of the compound of formula 1

[0235] 7 mg of the compound represented by Formula 1 was added to 0.4 mL of 10% water / isopropanol, stirred and dissolved at 60°C, cooled to room temperature, and 8.5 μL of 2M ethanolic sulfuric acid solution was added. The mixture was stirred for crystallization, centrifuged, and the solid was vacuum dried to obtain an off-white solid.

[0236] X-ray powder diffraction analysis identified the product as the sulfate α-crystalline form. The XRPD spectrum is shown in Figure 7, and the positions of its characteristic peaks are shown in Table 11. The DSC spectrum showed endothermic peaks at 62.16°C, 196.17°C, 249.16°C, and 252.16°C. The TGA spectrum showed a weight loss of 9.75% from 30°C to 165°C.

[0237] Table 11

[0238] Example 14: Preparation of the α-crystalline sulfate salt of the compound of formula 1

[0239] 7 mg of the compound represented by Formula 1 was added to 0.6 mL of tetrahydrofuran / ethanol (v / v = 2:1) and dissolved with stirring at 60°C. The mixture was cooled to room temperature, and 8.5 μL of 2M ethanolic sulfuric acid solution was added. The mixture was stirred to crystallize, centrifuged, and vacuum dried to obtain an off-white solid. X-ray powder diffraction analysis confirmed the product to be the sulfate salt α-crystalline form.

[0240] Example 15: Preparation of α-crystalline sulfate of the compound of formula 1

[0241] 7 mg of the compound represented by Formula 1 was added to 0.1 mL of dichloromethane / methanol (v / v = 2:1) and dissolved with stirring at 60°C. The mixture was cooled to room temperature, and 8.5 μL of 2M ethanolic sulfuric acid solution was added. The mixture was stirred to crystallize, centrifuged, and vacuum dried to obtain an off-white solid. X-ray powder diffraction analysis confirmed the product to be the sulfate salt α-crystalline form.

[0242] Example 16: Preparation of α-crystalline phosphate of the compound of formula 1

[0243] 120 mg of the compound represented by Formula 1 was added to 7 mL of 10% water / isopropanol and dissolved with stirring at 60° C. 145 μL of 2 M ethanolic phosphoric acid solution was added and stirred at room temperature for crystallization. The mixture was filtered and the solid was vacuum dried to obtain an off-white solid.

[0244] X-ray powder diffraction analysis identified the product as an α-crystalline phosphate. The XRPD spectrum is shown in Figure 8, and the locations of its characteristic peaks are shown in Table 12. The DSC spectrum revealed endothermic peaks at 60.98°C and 180.14°C. The TGA spectrum showed a 4.67% weight loss from 30°C to 170°C. Ion chromatography revealed a phosphate ion content of 18.47%.

[0245] DVS testing revealed that under normal storage conditions (i.e., 25°C, 60% RH), the sample experienced a moisture absorption weight gain of approximately 11.72%. Under accelerated test conditions (i.e., 70% RH), the moisture absorption weight gain was approximately 13.94%. Under extreme conditions (i.e., 90% RH), the moisture absorption weight gain was approximately 23.17%. During the humidity fluctuations from 0% to 95% RH, the sample's desorption process essentially overlapped with the adsorption process. Furthermore, subsequent DVS testing revealed no change in crystal form.

[0246] Table 12

[0247] Example 17: Preparation of α-crystalline phosphate of the compound of formula 1

[0248] 7 mg of the compound represented by Formula 1 was added to 0.6 mL of tetrahydrofuran / ethanol (v / v = 2:1), stirred and dissolved at 60°C, 8.5 μL of 2M ethanolic phosphoric acid solution was added, stirred at room temperature for crystallization, centrifuged, and the solid was vacuum dried. X-ray powder diffraction analysis revealed that the solid was an α-crystalline form of the phosphate.

[0249] Example 18: Preparation of amorphous phosphate of compound of formula 1

[0250] 7 mg of the compound represented by Formula 1 was dissolved in 0.1 mL of dichloromethane / methanol (v / v = 2:1), and 8.5 μL of 2M ethanolic phosphoric acid solution was added. The mixture was stirred overnight, and 0.6 mL of MTBE was added. The mixture was stirred to crystallize, centrifuged, and vacuum dried to obtain an off-white solid. X-ray powder diffraction analysis revealed that the product was amorphous, as shown in the XRPD spectrum in Figure 9. Ion chromatography revealed a phosphate ion content of 20.82%.

[0251] Example 19: Preparation of amorphous methanesulfonate of the compound of formula 1

[0252] 7 mg of the compound represented by Formula 1 was added to 0.1 mL of dichloromethane / methanol (v / v = 2:1) and dissolved by stirring at room temperature. 8.5 μL of a 2M methanesulfonic acid ethanol solution was added, stirred to crystallize, centrifuged, and the solid dried under vacuum to obtain an off-white solid. X-ray powder diffraction analysis revealed that the product was amorphous, as shown in the XRPD spectrum in Figure 10. Ion chromatography revealed a methanesulfonate ion content of 16.66%.

[0253] Example 20: Preparation of Crystalline Form I of the Succinate Salt of the Compound of Formula 1

[0254] 120 mg of the compound represented by Formula 1 was dissolved in 0.6 mL of dichloromethane / methanol (v / v=2:1), 34 mg of succinic acid solid was added, and the mixture was stirred for crystallization. The mixture was filtered and the solid was vacuum dried to obtain an off-white solid.

[0255] X-ray powder diffraction analysis identified the product as succinate salt Form I. The XRPD spectrum is shown in Figure 11, and the locations of its characteristic peaks are shown in Table 13. The DSC spectrum revealed endothermic peaks at 196.14°C and 259.26°C. The TGA spectrum showed a weight loss of 1.35% between 30°C and 150°C, and a weight loss of 20.52% between 150°C and 230°C. Ion chromatography revealed a succinate ion content of 20.85%.

[0256] DVS testing showed that under normal storage conditions (i.e., 25°C, 60% RH), the sample gained approximately 0.29% in moisture absorption; under accelerated test conditions (i.e., 70% RH), the gain was approximately 0.38%; and under extreme conditions (90% RH), the gain was approximately 0.64%. During the humidity fluctuations from 0% to 95% RH, the desorption process of the sample essentially overlapped with the adsorption process, and subsequent DVS testing revealed no change in the crystal form.

[0257] Table 13

[0258] Example 21: Preparation of Crystalline Form I of Fumarate Salt of Compound of Formula 1

[0259] 120 mg of the compound represented by Formula 1 was added to 9 mL of tetrahydrofuran / ethanol (v / v=2:1), stirred and dissolved at 60° C. 34 mg of fumaric acid was added, stirred at room temperature for crystallization, filtered, and the solid was vacuum dried to obtain an off-white solid.

[0260] X-ray powder diffraction analysis identified the product as fumarate salt Form I. The XRPD spectrum is shown in Figure 12, and the positions of its characteristic peaks are shown in Table 14. The DSC spectrum revealed an endothermic peak at 245.22°C. The TGA spectrum showed a weight loss of 0.19% between 30°C and 165°C, and a weight loss of 20.27% between 165°C and 270°C. Ion chromatography revealed a fumarate ion content of 20.76%.

[0261] DVS testing revealed that under normal storage conditions (i.e., 25°C, 60% RH), the sample experienced a moisture gain of approximately 0.21%; under accelerated storage conditions (i.e., 70% RH), the moisture gain was approximately 0.24%; and under extreme conditions (90% RH), the moisture gain was approximately 0.38%. Over a humidity range of 0% to 95% RH, the sample's desorption and adsorption processes largely overlapped, and subsequent DVS testing revealed no change in crystal form.

[0262] Table 14

[0263] Example 22: Preparation of Crystalline Form I of Fumarate Salt of Compound of Formula 1

[0264] 7 mg of the compound of formula 1 was added to 0.4 mL of 10% water / isopropanol and dissolved with stirring at 60° C. 2 mg of fumaric acid was added and stirred at room temperature for crystallization. The mixture was filtered and the solid was vacuum dried. X-ray powder diffraction analysis revealed that the solid was Form I.

[0265] Example 23: Preparation of Crystalline Form I of Fumarate Salt of Compound of Formula 1

[0266] 7 mg of the compound represented by Formula 1 was added to 0.6 mL of tetrahydrofuran / ethanol (v / v=2:1), stirred and dissolved at 60°C, 2 mg of fumaric acid was added, stirred at room temperature for crystallization, filtered, and the solid was vacuum dried. X-ray powder diffraction analysis showed that it was Form I.

[0267] Example 24: Preparation of Crystalline Form I of Fumarate Salt of Compound of Formula 1

[0268] 7 mg of the compound represented by Formula 1 was added to 0.1 mL of dichloromethane / methanol (v / v=2:1), stirred and dissolved at 60°C, 2 mg of fumaric acid was added, stirred at room temperature for crystallization, filtered, and the solid was vacuum dried. X-ray powder diffraction analysis showed that it was Form I.

[0269] Example 25: Preparation of Crystalline Form A of the Maleate Salt of Formula 1

[0270] 7 mg of the compound represented by Formula 1 was dissolved in 0.1 mL of dichloromethane / methanol (v / v = 2:1), and 8.5 μL of a 2M maleic acid ethanol solution was added. The mixture was stirred at room temperature overnight. 0.6 mL of methyl tert-butyl ether was added, and the mixture was stirred to separate crystals. The mixture was centrifuged and the solid was dried under vacuum to obtain an off-white solid. X-ray powder diffraction analysis identified the product as maleate salt form a. The XRPD spectrum is shown in Figure 13, and the positions of its characteristic peaks are shown in Table 15. The DSC spectrum showed endothermic peaks at 215.91°C and 258.32°C. The TGA spectrum showed a weight loss of 2.49% between 30°C and 130°C, and a weight loss of 9.95% between 130°C and 260°C. Ion chromatography results showed a maleate ion content of 9.37%.

[0271] Table 15

[0272] Example 26: Preparation of amorphous p-toluenesulfonate salt of the compound of formula 1

[0273] 7 mg of the compound represented by Formula 1 was dissolved in 0.1 mL of dichloromethane / methanol (v / v = 2:1), and 8.5 μL of a 2M p-toluenesulfonic acid ethanol solution was added. The mixture was stirred overnight, and 0.6 mL of MTBE was added. The mixture was stirred to crystallize, centrifuged, and vacuum dried to obtain an off-white solid. X-ray powder diffraction analysis revealed that the product was amorphous, as shown in the XRPD spectrum in Figure 14. Ion chromatography revealed a p-toluenesulfonate ion content of 26.91%.

[0274] Example 27: Preparation of amorphous L-tartrate salt of compound of formula 1

[0275] 7 mg of the compound represented by Formula 1 was added to 0.4 mL of 10% water / isopropanol and dissolved with stirring at 60°C. 8.5 μL of a 2M tartaric acid ethanol solution was added and stirred overnight. 0.8 mL of isopropyl acetate was added and crystallized with stirring. The mixture was centrifuged and vacuum dried to obtain an off-white solid. X-ray powder diffraction analysis revealed that the product was amorphous, as shown in the XRPD spectrum in Figure 15. Ion chromatography revealed an L-tartrate ion content of 31.43%.

[0276] Example 28: Preparation of Crystalline Form I of the Compound of Formula 1 Hemifumarate

[0277] Take 10.0g of the compound of formula 1 and 1.294g of fumaric acid, add 800ml of anhydrous methanol. Heat to reflux, dissolve the solid, and then cool naturally to crystallize to obtain the hemifumarate of the compound of formula 1. Take 0.5g of the hemifumarate of the compound of formula 1 in a reaction flask, add 15ml of anhydrous methanol, and reflux to dissolve the solid. Stop heating, cool and crystallize. Filter with suction, and dry the filter cake at 45°C with air to obtain a white solid. X-ray powder diffraction analysis shows that the product is defined as hemifumarate i crystal form. The XRPD spectrum is shown in Figure 16, and the positions of its characteristic peaks are shown in Table 16. HPLC results show that the fumarate ion content is 11.3% (based on anhydrous matter).

[0278] Table 16

[0279] Example 29: Preparation of Crystalline Form II of the Compound of Formula 1 Hemifumarate

[0280] 5 mg of the hemifumaric acid form I of the compound shown in Example 28 was heated to 170° C. to obtain the product.

[0281] X-ray powder diffraction analysis identified the product as hemi-fumarate crystalline form II. The XRPD spectrum is shown in Figure 17, and the positions of its characteristic peaks are shown in Table 17. The DSC spectrum revealed an endothermic peak at 235.42°C. The TGA spectrum showed a weight loss of 0.77% between 30°C and 120°C, and a weight loss of 11.04% between 120°C and 250°C. Ion chromatography revealed a fumarate ion content of 11.5%.

[0282] Table 17

[0283] Example 30: Preparation of Crystalline Form III of Hemifumarate of Compound of Formula 1

[0284] 500 mg of the free compound of Formula 1 was added to 10 mL of methanol and 1.2 mL of a 0.5 M fumaric acid methanol solution. The mixture was stirred for crystallization and centrifuged. The solid was collected and dried in vacuo at 60° C. to obtain the product.

[0285] X-ray powder diffraction analysis identified the product as hemi-fumarate crystalline form III. The XRPD spectrum is shown in Figure 18, and the positions of its characteristic peaks are shown in Table 18. The DSC spectrum revealed an endothermic peak at 235.45°C. The TGA spectrum showed a weight loss of 0.55% between 30°C and 100°C, and a weight loss of 10.25% between 100°C and 250°C. Ion chromatography revealed a fumarate ion content of 11.8%.

[0286] Table 18

[0287] Experimental Example 1: Crystal Stability Study

[0288] The free form A, hydrochloride form a, phosphate form α, succinate form I and fumarate form I were laid out in the open, and the stability of the samples was investigated under light (4500 Lux), high temperature (40°C, 60°C), and high humidity (RH 75%, RH 92.5%) conditions, respectively. The sampling period was 30 days.

[0289] Table 19

[0290] Table 18

[0291] Conclusion: The influencing factors experiment showed that:

[0292] The free crystalline form A has good physical and chemical stability under high temperature 40°C and high humidity 75% and 92.5% conditions for 30 days.

[0293] The hydrochloride salt form a has good physical and chemical stability under high temperature 40°C, 60°C and high humidity 75% for 30 days.

[0294] The α-crystalline form of phosphate showed good physical and chemical stability under high humidity conditions of 75% and 92.5% for 30 days.

[0295] The succinate salt form I exhibited good physical and chemical stability under high temperature conditions of 40°C and 60°C and high humidity conditions of 75% and 92.5% for 30 days.

[0296] The fumarate salt form I exhibited good physical and chemical stability under high temperature conditions of 40°C and 60°C and high humidity conditions of 75% and 92.5% for 30 days.

[0297] Experimental Example 2: Long-term / accelerated stability

[0298] The free form A, hydrochloride form a, hydrochloride form b, phosphate form α, succinate form I and fumarate form I were placed under 25°C / 60% RH and 40°C / 75% RH conditions, respectively, to investigate their stability.

[0299] Table 20

[0300] Table 21

[0301] Conclusion: Long-term accelerated experiments show that Form A, hydrochloride Form a, hydrochloride Form b, phosphate Form α, fumarate Form I and succinate Form I have good physical and chemical stability at 25°C / 60RH and 40°C / 75RH for 6 months.

Claims

1. A crystalline form A of (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide, having an X-ray powder diffraction pattern expressed at a diffraction angle of 2θ degrees, with characteristic peaks at 7.877, 11.871 and 17.876, preferably having characteristic peaks at 7.877, 9.115, 11.871 and 17.876, and most preferably having an X-ray powder diffraction pattern expressed at a diffraction angle of 2θ degrees as shown in Figure 2.

2. A pharmaceutically acceptable salt of (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, sulfate, phosphate, methanesulfonate, succinate, fumarate, maleate, p-toluenesulfonate, L-tartrate, D-malate, L-malate and citrate.

3. The pharmaceutically acceptable salt according to claim 2, characterized in that The chemical ratio of the (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide and the acid is 3:1-1:3, preferably 2:1-1:2, and more preferably 2:1, 1:1 or 1:

2.

4. A method for preparing a pharmaceutically acceptable salt of (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide, comprising: a step of reacting N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide with an acid, wherein the acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, succinic acid, fumaric acid, maleic acid, p-toluenesulfonic acid, L-tartaric acid, D-malic acid, L-malic acid and citric acid.

5. A fumarate salt of (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide, wherein the chemical ratio of (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide to fumaric acid is 1:

1.

6. A crystalline form I of a fumarate salt of (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide, having an X-ray powder diffraction pattern expressed in terms of a diffraction angle 2θ, with characteristic peaks at 6.163, 8.552, 12.317, 17.407, and 24.336, preferably at 6.163, 8.552, 10.102, 12.317, 17.407, and 24.

336. 148, more preferably, there are characteristic peaks at 6.163, 7.982, 8.552, 10.102, 12.317, 14.750, 17.407, 20.302, 21.069, 22.678, 23.331, 24.336, 26.692, 27.279 and 28.148, and most preferably, the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is shown in Figure 12.

7. A succinate salt of (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide, wherein the chemical ratio of (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide to succinic acid is 1:

1.

8. A crystalline form I of the succinate salt of (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide, having an X-ray powder diffraction pattern expressed in terms of a diffraction angle 2θ, with characteristic peaks at 6.106, 8.589, 12.276, 14.812, 17.517, and 20.400, preferably at 6.1 06, 8.589, 9.156, 10.134, 12.276, 14.812, 17.517, 20.400, and 24.213, more preferably at 6.106, 7.931, 8.589, 9.156, 10.134, 12.276, 14.812, 15.357, 17.517, 20.400, 24.213, 29.362, and 38.514, and most preferably the X-ray powder diffraction pattern expressed in terms of a diffraction angle 2θ is shown in Figure 11.

9. A crystalline form of (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide, wherein: The error range of the 2θ angle is ±0.

2.

10. A pharmaceutical composition comprising the following components: i) the crystalline form A of (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide according to claim 1, or the pharmaceutically acceptable salt of (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide according to any one of claims 2, 3, 5, and 7, or the crystalline form according to claims 6 or 8; and ii) one or more pharmaceutically acceptable excipients.

11. A method for preparing a pharmaceutical composition, comprising the steps of: treating the (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide of claim 1 in Form A, or treating the (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide of any one of claims 2, 3, 5, and 7 in Form A. A step of mixing a pharmaceutically acceptable salt of methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide, or the crystalline form according to claim 6 or 8 with a pharmaceutically acceptable excipient.

12. Use of the crystalline form A of (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide according to claim 1, or the pharmaceutically acceptable salt of (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide according to any one of claims 2, 3, 5, and 7, or the crystalline form according to claims 6 or 8, or the composition according to claim 10 in the preparation of a PARP1 inhibitor.

13. The crystal form A of (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide according to claim 1, or the crystal form A of (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide according to any one of claims 2, 3, 5, and 7. Use of a pharmaceutically acceptable salt of 1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide, or the crystalline form according to claims 6 or 8, or the composition according to claim 10 in the preparation of a medicament for treating and / or preventing cancer.

14. The method of claim 13, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, colorectal cancer, lung cancer, kidney cancer, liver cancer, cervical cancer, endometrial cancer, myeloma, leukemia, lymphoma, acoustic neuroma, basal cell carcinoma, bile duct cancer, bladder cancer, brain cancer, bronchial cancer, sarcoma, chordoma, choriocarcinoma, craniopharyngioma, cystadenocarcinoma, embryonal carcinoma, hemangioendothelioma, ependymoma, epithelial cancer, esophageal cancer, essential thrombocythemia, Ewing's tumor, testicular cancer, glioma, Heavy chain disease, hemangioblastoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, neuroblastoma, NUT midline carcinoma, glioma, bone cancer, nasopharyngeal cancer, oral cancer, thyroid cancer, pinealoma, polycythemia vera, retinoblastoma, sebaceous gland carcinoma, seminoma, skin cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, Waldenstrom's macroglobulinemia and Wilms' tumor; preferably, the cancer is selected from breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, colorectal cancer and lung cancer.

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