Medicinal salts of nitrogen-containing heterocyclic compounds, crystalline forms and preparation methods

Abstract

The present disclosure relates to medicinal salts, crystalline forms and preparation methods thereof of nitrogen-containing heterocyclic compounds. Specifically, the present disclosure provides medicinal salts, crystalline forms and preparation methods thereof 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, a compound of Formula 1, wherein the corresponding salts have good stability and can be more easily used in clinical treatment.

Description

[Technical Field]

[0001] The present disclosure belongs to the pharmaceutical field and relates to medicinal salts, crystalline forms of nitrogen-containing heterocyclic compounds and methods for preparing the same. [Background technology]

[0002] Since its first description over 50 years ago, poly(ADP-ribose) polymerase 1 (PARP1) has gradually been discovered to play important roles in DNA repair, maintaining genome integrity, and regulating various metabolic and signaling processes. PARP1 catalyzes the transfer of ADP-ribose residues from NAD+ to target substrates, allowing the construction of poly(ADP-ribose) (PAR) chains. The formation and removal of PAR chains 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 involves the attachment of one or more ADP-ribose units to specific sites on proteins under enzyme catalysis. PARP1 is the first member of the PARP superfamily, which consists of proteins with homology to PARP1 and currently has 17 members, four of which (PARP1, PARP2, PARP5A, and PARP5B) can synthesize PAR chains. Many of the other enzymes in the family can only assemble a single ADP-ribose unit and are therefore classified as mono(ADP-ribosyl)ases (MARs).

[0004] PARP1 and PARP2 have been extensively studied due to their role in DNA damage repair. PARP1 is activated by DNA breaks and functions as a catalyst for the attachment of poly(ADP-ribose) (PAR) chains to target proteins. This post-translational modification, called polyadenosine diphosphate ribosylation (PARylation), can mediate the recruitment of other DNA repair factors to DNA lesions. After completing this recruitment task, PARP automatically undergoes PARylation, triggering the release of bound PARP from DNA, allowing access to other DNA repair proteins to complete the repair. Therefore, PARP binding to damage sites, its catalytic activity, and eventual release from DNA are all critical steps in cancer cell response to DNA damage induced by chemotherapy and radiation therapy.

[0005] Inhibition of PARP family enzymes has been used to selectively kill cancer cells by inactivating complementary DNA repair pathways. Extensive preclinical and clinical studies have demonstrated that tumor cells with deleterious alterations in BRCA1 or BRCA2, key tumor suppressor proteins involved in double-strand DNA break (DSB) repair via deleterious recombination (HR), are selectively sensitive to small molecules, inhibitors of the PARP family of DNA repair enzymes. These tumors lack the homologous recombination repair (HRR) pathway and rely on the survival function of PARP enzymes. While PARP inhibitor therapy has primarily been targeted at BRCA-mutated cancers, PARP inhibitors have already been tested in clinical trials in non-BRCA-mutated tumors, where these tumors exhibit homologous recombination deficiency (HRD).

[0006] Compared with other PARP1 / 2 inhibitors, PARP inhibitors with improved selectivity for PARP1 may have improved efficacy and reduced toxicity. It is believed that selective and strong inhibition of PARP1 leads to the trapping of PARP1 on DNA, which causes DNA double-strand breaks (DSBs) due to the collapse of replication forks during S phase. PARP1-DNA trapping is an effective mechanism for selectively killing tumor cells with HRD.

[0007] Therefore, there is an urgent clinical need for effective and safe PARP inhibitors, especially PARP inhibitors selective for PARP1.

[0008] Currently, related patent applications that have already been published include WO2021013735A1, WO2021260092A1, WO2009053373A1, and WO2008107478A1.

[0009] PCT / CN2022 / 094612 discloses a novel tetralin derivative having the chemical name (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, represented by Formula 1, and indicates its use as a PARP inhibitor. This disclosure incorporates PCT / CN2022 / 094612 in its entirety.

[0010] [ka] The crystalline structure of a pharmaceutical active ingredient often affects the chemical and physical stability of the drug, and crystallization and storage conditions can change the crystalline structure of the compound, sometimes resulting in the formation of other crystalline forms. Generally, amorphous drug products lack a regular crystalline structure and often suffer from other defects, such as poor product stability, difficulty in filtration, tendency to solidify, and poor flowability. Therefore, studying the crystalline form of medicinal salts 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 pharmaceuticals suitable for industrial production and with good biological activity. Summary of the Invention

[0011] One aspect of the present disclosure provides 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, a compound of Formula 1.

[0012] In some embodiments, the A-type crystal has a powder X-ray diffraction pattern expressed in 2θ angles having characteristic peaks at 7.877, 11.871, and 17.876.

[0013] In some other embodiments, the A-type crystal has a powder X-ray diffraction pattern expressed in terms of diffraction angle 2θ angles, which has characteristic peaks at 7.877, 9.115, 11.871, and 17.876.

[0014] In some other embodiments, the A-type crystal has a powder X-ray diffraction pattern expressed in 2θ angles, which has characteristic peaks at 7.877, 9.115, 11.871, 15.851, 17.876, and 18.900.

[0015] In some other embodiments, the powder X-ray diffraction pattern of the A-type crystals, expressed at 2θ angles, is as shown in FIG.

[0016] In another aspect, the disclosure provides a method for preparing 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, a compound of Formula 1, The present invention provides a preparation method comprising dissolving (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 cause crystallization.

[0017] In some embodiments, the solvent (1) is at least one solvent selected from dichloromethane, methanol, water, isopropanol, tetrahydrofuran, ethanol, dimethyl sulfoxide, and N,N-dimethylformamide.

[0018] In some embodiments, the solvent (2) is selected from acetone, water, acetonitrile, methyl tert-butyl ether, n-heptane, and isopropyl acetate.

[0019] In another aspect, the present disclosure provides a method for preparing 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, a compound of Formula 1, comprising mixing (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 compound of Formula 1, with a solvent (3) and stirring to cause crystallization.

[0020] 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, isoamyl alcohol, 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), and tetrahydrofuran / ethanol (v / v=2:1).

[0021] In another aspect, the disclosure provides a method for preparing 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, a compound of Formula 1, comprising dissolving (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 (4) and allowing to crystallize.

[0022] 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).

[0023] Another aspect of the present disclosure provides crystalline Form B 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, a compound of Formula 1.

[0024] In some embodiments, the B-type crystal has a powder X-ray diffraction pattern expressed in 2θ angles having characteristic peaks at 8.002, 9.248, 11.985, 13.412, and 17.526.

[0025] In some other embodiments, the B-type crystal has a powder X-ray diffraction pattern expressed in 2θ angles having characteristic peaks at 8.002, 9.248, 11.985, 13.412, 17.526, and 17.929.

[0026] In some other embodiments, the type B crystal has a powder X-ray diffraction pattern expressed in terms of diffraction angle 2θ angles, which has characteristic peaks at 8.002, 8.978, 9.248, 11.985, 13.412, 17.526, and 17.929.

[0027] In some other embodiments, the type B crystal has a powder X-ray diffraction pattern shown at diffraction angles 2θ as shown in FIG.

[0028] Another aspect of the present disclosure provides 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, a compound of Formula 1, selected from hydrochloride, sulfate, phosphate, mesylate, succinate, fumarate, maleate, p-toluenesulfonate, L-tartrate, D-malate, L-malate, and citrate.

[0029] In an alternative embodiment, 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, has a chemical ratio with the acid of 3:1 to 1:3, including, but not limited to, 3:1, 2:1, 1:1, 1:2, and 1:3.

[0030] In another embodiment, 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, has a chemical ratio with the acid of 2:1 to 1:2.

[0031] In an alternative embodiment, 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 in a chemical ratio of 1:1 or 1:2 with hydrochloric acid.

[0032] In an alternative embodiment, 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 in a 1:1 or 2:1 chemical ratio with sulfuric acid.

[0033] In an alternative embodiment, 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, has a 1:1 chemical ratio with phosphoric acid.

[0034] In an alternative embodiment, 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, has a 1:1 chemical ratio with methanesulfonic acid.

[0035] In an alternative embodiment, 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, has a chemical ratio of 2:1 or 1:1 with succinic acid.

[0036] In an alternative embodiment, 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, has a chemical ratio of 2:1 or 1:1 with fumaric acid.

[0037] In an alternative embodiment, 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, has a chemical ratio of 2:1 or 1:1 with maleic acid.

[0038] In an alternative embodiment, 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, has a chemical ratio of 1:1 with p-toluenesulfonic acid.

[0039] In an alternative embodiment, 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, has a chemical ratio of 1:1 to 1:2 with L-tartaric acid.

[0040] The present disclosure relates to 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)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 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.

[0041] The solvents used in the salt formation of the present disclosure are selected from, but not limited to, acetonitrile, acetone, tetrahydrofuran, ethanol, methanol, 1,4-dioxane, dichloromethane / methanol, water / isopropanol, tetrahydrofuran / ethanol.

[0042] Furthermore, in an optional embodiment, the method for preparing the pharmaceutically acceptable salt further comprises steps such as crystallization, filtering, washing, or drying.

[0043] In another embodiment of the present disclosure, there is further provided a hydrochloride salt form 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, which is a compound of Formula 1, wherein the powder X-ray diffraction pattern, measured at diffraction angles 2θ, has characteristic peaks at 8.164, 10.795, 11.375, 12.281, 13.481, 14.813, 17.195, and 17.606.

[0044] In some other embodiments, the hydrochloride salt type a crystals have a powder X-ray diffraction pattern, expressed as diffraction angles 2θ, having 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.

[0045] In some other embodiments, the hydrochloride salt type a crystals have a powder X-ray diffraction pattern, expressed in diffraction angles 2θ, having 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.

[0046] In some other embodiments, the hydrochloride salt a-type crystals have a powder X-ray diffraction pattern shown at 2θ angles as shown in FIG.

[0047] The present disclosure relates to a method for preparing crystalline form a of the hydrochloride 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, a compound of formula 1, comprising: and (c) dissolving 1,2-dimethyl-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 tetrahydrofuran / ethanol (v / v=2:1), adding hydrochloric acid, and stirring.

[0048] The present disclosure further provides hydrochloride salt type b crystals 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, a compound of Formula 1, wherein the powder X-ray diffraction pattern, measured at diffraction angles 2θ, has characteristic peaks at 5.166, 7.759, 10.741, 14.887, 15.685, 16.604, 17.641, 21.855, and 26.448.

[0049] In some embodiments, the hydrochloride salt type b crystals have a powder X-ray diffraction pattern expressed in 2θ angles having 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.

[0050] In some embodiments, the hydrochloride salt type b crystals have a powder X-ray diffraction pattern, expressed in diffraction angles 2θ, having 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.

[0051] In some embodiments, the hydrochloride salt type b crystals have a powder X-ray diffraction pattern, expressed in diffraction angles 2θ, having 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.

[0052] In some other embodiments, the hydrochloride salt type b crystals have a powder X-ray diffraction pattern shown at 2θ angles as shown in FIG.

[0053] The present disclosure relates to a method for preparing crystalline form b of the hydrochloride 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, a compound of compound formula 1, wherein the crystalline form b of the hydrochloride 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 in dichloromethane / methanol (v / v=2:1), adding hydrochloric acid, and stirring.

[0054] The present disclosure further provides hydrochloride salt type c crystals 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, a compound of Formula 1, wherein the hydrochloride salt type c crystals have characteristic peaks at 5.095, 8.779, 10.203, and 25.834 in a powder X-ray diffraction pattern measured at diffraction angles 2θ.

[0055] In some other embodiments, the hydrochloride salt crystals of type c have a powder X-ray diffraction pattern shown at 2θ angles as shown in FIG.

[0056] The present disclosure relates to a method for preparing crystalline form c of the hydrochloride 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, a compound of formula 1, comprising: Further provided is a method comprising dissolving 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 10% water / isopropanol, adding hydrochloric acid, adding isopropyl acetate, and stirring.

[0057] The present disclosure further provides an α-form crystal of sulfate 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, a compound represented by Formula 1, wherein the powder X-ray diffraction pattern, measured at diffraction angles 2θ, has characteristic peaks at 5.180, 8.955, 10.380, 13.767, and 15.578.

[0058] In some embodiments, the α-form crystals of the sulfate salt have a powder X-ray diffraction pattern expressed in 2θ angles, which has characteristic peaks at 5.180, 8.955, 10.380, 13.767, 15.578, and 25.809.

[0059] In some embodiments, the α-form crystals of the sulfate salt have a powder X-ray diffraction pattern expressed in 2θ angles, which has characteristic peaks at 5.180, 8.955, 10.380, 13.767, 15.578, 18.063, 18.781, and 25.809.

[0060] In some other embodiments, the α-form sulfate crystals have a powder X-ray diffraction pattern shown at 2θ angles as shown in FIG.

[0061] The present disclosure further provides a method for preparing α-form crystals of the sulfate 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, a compound of compound formula 1, comprising dissolving (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 compound of compound formula 1, in a solvent (5), adding sulfuric acid, and stirring.

[0062] The solvent (5) described in the present disclosure is selected from 10% water / isopropanol, tetrahydrofuran / ethanol (v / v=2:1), dichloromethane / methanol (v / v=2:1).

[0063] The present disclosure further provides an α-form crystal of phosphate 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, a compound represented by Formula 1, wherein the powder X-ray diffraction pattern, measured at diffraction angles 2θ, has characteristic peaks at 5.175, 9.006, 10.437, 13.863, 15.707, and 18.979.

[0064] In some embodiments, the α-form crystals of phosphate have a powder X-ray diffraction pattern expressed in terms of diffraction angle 2θ angles, which has characteristic peaks at 5.175, 9.006, 10.437, 10.999, 13.863, 15.707, 18.225, and 18.979.

[0065] In some embodiments, the α-form crystals of phosphate have a powder X-ray diffraction pattern expressed in 2θ angles, which has characteristic peaks at 5.175, 9.006, 10.437, 10.999, 13.863, 15.707, 18.225, 18.979, 20.767, and 25.682.

[0066] In some other embodiments, the α-form phosphate crystals have a powder X-ray diffraction pattern shown at 2θ angles as shown in FIG.

[0067] The present disclosure relates to a method for preparing α-form crystals of the phosphate 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, a compound of compound formula 1, comprising: The present invention further provides a method for the preparation of a methyl-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 methyl-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 10% water / isopropanol or tetrahydrofuran / ethanol (v / v=2:1), adding phosphoric acid, and stirring.

[0068] The present disclosure further provides succinate Form I crystals 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, a compound represented by Formula 1, wherein the powder X-ray diffraction pattern, measured at diffraction angles 2θ, has characteristic peaks at 6.106, 8.589, 12.276, 14.812, 17.517, and 20.400.

[0069] In some embodiments, the succinate salt Form I crystals have a powder X-ray diffraction pattern expressed in 2θ angles, which has characteristic peaks at 6.106, 8.589, 9.156, 10.134, 12.276, 14.812, 17.517, 20.400, and 24.213.

[0070] In some embodiments, the succinate salt Form I crystals have a powder X-ray diffraction pattern, expressed in 2θ angles, having 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.

[0071] In some embodiments, the succinate salt Form I crystals have a powder X-ray diffraction pattern shown at 2θ angles, the powder X-ray diffraction pattern shown at 2θ angles is as shown in FIG.

[0072] The present disclosure provides a method for preparing Form I crystalline 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, a compound of compound formula 1, comprising: )-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.

[0073] The present disclosure further provides a fumarate Form I 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, a compound represented by Formula 1, wherein the powder X-ray diffraction pattern, measured at diffraction angles 2θ, has characteristic peaks at 6.163, 8.552, 12.317, 17.407, and 24.336.

[0074] In some embodiments, the fumarate salt Form I crystals have a powder X-ray diffraction pattern, expressed in 2θ angles, having characteristic peaks at 6.163, 8.552, 10.102, 12.317, 17.407, 20.302, 23.331, 24.336, 27.279, and 28.148.

[0075] In some embodiments, the fumarate salt Form I crystals have a powder X-ray diffraction pattern, expressed in 2θ angles, having 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.

[0076] In some embodiments, the fumarate Form I crystals have a powder X-ray diffraction pattern shown at 2θ angles, the powder X-ray diffraction pattern shown at 2θ angles is as shown in FIG.

[0077] The present disclosure further provides a method for preparing Form I crystalline 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, a compound of compound Formula 1, comprising dissolving (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 compound of compound Formula 1, in a solvent (6), adding fumaric acid, and stirring.

[0078] Here, the solvent (6) is selected from tetrahydrofuran / ethanol (v / v=2:1), 10% water / isopropanol, and dichloromethane / methanol (v / v=2:1).

[0079] The present disclosure further provides a hemi-fumaric acid salt form i crystal 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, which is a compound of Formula 1, wherein the powder X-ray diffraction pattern, measured at diffraction angles 2θ, has characteristic peaks at 3.95, 7.89, 8.43, 10.97, 11.85, and 14.17.

[0080] In some embodiments, the hemi-fumarate Form i crystals have a powder X-ray diffraction pattern expressed in 2θ angles having characteristic peaks at 3.95, 6.83, 7.30, 7.89, 8.43, 10.58, 10.97, 11.85, and 14.17.

[0081] In some embodiments, the hemi-fumarate Form i crystals have a powder X-ray diffraction pattern expressed in 2θ angles having characteristic peaks at 3.95, 6.83, 7.30, 7.89, 8.43, 9.95, 10.58, 10.97, 11.85, and 14.17.

[0082] In some embodiments, the hemi-fumarate Form i crystals have a powder X-ray diffraction pattern shown at 2θ angles, the powder X-ray diffraction pattern shown at 2θ angles is as shown in FIG.

[0083] The present disclosure further provides a hemi-fumarate type II crystal 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, which is a compound of Formula 1, wherein the powder X-ray diffraction pattern, measured at diffraction angles 2θ, has characteristic peaks at 8.581, 9.892, 17.287, and 20.078.

[0084] In some embodiments, the hemi-fumarate Form II crystals have a powder X-ray diffraction pattern, expressed in 2θ angles, having characteristic peaks at 8.581, 9.892, 12.605, 14.336, 15.293, 17.287, 18.293, 19.342, 20.078, and 22.996.

[0085] In some embodiments, the hemi-fumarate Form II crystals have a powder X-ray diffraction pattern at 2θ angles, the powder X-ray diffraction pattern at 2θ angles is as shown in FIG.

[0086] The present disclosure further provides a hemi-fumarate type III crystal 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, a compound of Formula 1, wherein the powder X-ray diffraction pattern, measured at diffraction angles 2θ, has characteristic peaks at 8.363, 11.005, 12.498, 14.267, and 28.341.

[0087] In some embodiments, the hemi-fumarate Form III crystals have a powder X-ray diffraction pattern shown at 2θ angles, the powder X-ray diffraction pattern shown at 2θ angles is as shown in FIG.

[0088] The present disclosure further provides a maleate a-type crystal 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, a compound represented by Formula 1, wherein the powder X-ray diffraction pattern, measured at diffraction angles 2θ, has characteristic peaks at 7.902, 9.389, 11.879, 15.683, and 21.632.

[0089] In some embodiments, the maleate salt a-type crystals have a powder X-ray diffraction pattern expressed in 2θ angles having 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.

[0090] In some embodiments, the maleate salt a-type crystals have a powder X-ray diffraction pattern, expressed in 2θ angles, having 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.

[0091] In some embodiments, the maleate a-type crystals have a powder X-ray diffraction pattern shown at 2θ angles, the powder X-ray diffraction pattern shown at 2θ angles is as shown in FIG.

[0092] The present disclosure relates to a method for preparing a type a crystal of maleate 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, a compound of formula 1, comprising:

[0013] The present invention further provides a method for crystallizing N-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 by dissolving the compound (I) in dichloromethane / methanol (v / v=2:1), adding maleic acid, and then adding methyl tert-butyl ether and stirring to cause crystallization.

[0093] Furthermore, the present disclosure provides 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]pyrido[3,2-e][1,4]oxazepane-9-carboxamide crystalline form, in which the error range of the 2θ angle is ±0.2.

[0094] In certain embodiments, the method for preparing the crystalline forms described herein further comprises a crystallization, filtration, washing, or drying step.

[0095] In another aspect, the present disclosure provides a Form A crystal 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, which is a compound of Formula 1 above; Further provided is a pharmaceutical composition comprising a medicinal salt or a crystalline form thereof comprising 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 optionally a pharmaceutically acceptable excipient.

[0096] The present disclosure relates to a method for preparing a pharmaceutical composition, comprising the steps of: obtaining 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, which is a compound of Formula 1; Further provided is a method of preparation, comprising the step of mixing 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 or a crystalline form thereof with a pharmaceutically acceptable excipient.

[0097] The present disclosure relates to a type A crystal or type B crystal 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, which is a compound of the above-mentioned compound formula 1, or a compound of the above-mentioned compound formula 1, (R) The present invention further provides the use of a medicinal salt of -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, or the pharmaceutical composition as a PARP1 inhibitor.

[0098] The present disclosure relates to a type A crystal or type B crystal 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, which is a compound of the above-mentioned compound formula 1, or a compound of the above-mentioned compound formula 1, (R)-3-( Further provided is the use of a medicament salt of (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, or the pharmaceutical composition, in the preparation of a medicament that is a PARP1 inhibitor.

[0099] The present disclosure relates to a type A crystal or type B crystal 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, which is a compound of the above-mentioned compound formula 1, or a compound of the above-mentioned compound formula 1, (R)-3 Further provided is the use of a medicinal salt of -((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, or the pharmaceutical composition described above, for treating and / or preventing cancer.

[0100] The present disclosure relates to a type A crystal or type B crystal 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, which is a compound of the above-mentioned compound formula 1, or a compound of the above-mentioned compound formula 1, (R)-3-((7

[0013] Further provided is the use of a medicinal salt of N-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, or said pharmaceutical composition, in the preparation of a medicament for treating and / or preventing cancer.

[0101] The use according to the present disclosure, wherein the cancer is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, colorectal cancer, lung cancer, renal cancer, liver cancer, cervical cancer, endometrial cancer, myeloma, leukemia, lymphoma, acoustic neuroma, basal cell carcinoma, bile duct cancer, bladder cancer, brain cancer, bronchial carcinoma, sarcoma, chordoma, choriocarcinoma, craniopharyngioma, cystadenocarcinoma, embryonal carcinoma, hemangioendothelioma, ependymoma, epithelial carcinoma, esophageal cancer, primary thrombocytosis, Ewing's sarcoma, testicular cancer, glioma, heavy chain disease, hematopoietic carcinoma, thyroid cancer ... The cancer is selected from tuboblastoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, neuroblastoma, NUT midline carcinoma, glioma, bone cancer, nasopharyngeal carcinoma, oral cancer, thyroid cancer, pinealoma, polycythemia vera, retinoblastoma, sebaceous gland carcinoma, seminoma, skin cancer, squamous cell carcinoma, synovium, 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.

[0102] The term "2θ or 2θ angle" used in the present disclosure refers to the diffraction angle, where θ is the Bragg angle and is expressed in ° or degrees. The error range of 2θ for each characteristic peak is ±0.20 (including rounding to the nearest decimal place), and specifically includes -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.

[0103] In the present disclosure, there is a certain degree of error in the measurement of the chemical ratio of the compound and the acid molecule, and generally, ±10% is within a reasonable error range. Depending on the context of use, there is a certain degree of error variation, and the variation of the error does not exceed ±10%, and may be ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1%, and preferably ±5%. In the present disclosure, numerical values ​​indicated by "about" are within the above reasonable error range.

[0104] "Crystallization" or "crystallization" as referred to in this disclosure includes, but is not limited to, stirred crystallization, slurry crystallization, cooling crystallization, and volatile crystallization.

[0105] "Differential scanning calorimetry or DSC" as used herein refers to the measurement of temperature and heat flow differences between a sample and a reference during a heating or isothermal process of the sample to characterize all physical and chemical changes associated with thermal effects and obtain information on the phase transitions of the sample.

[0106] The drying temperature described in the present disclosure is generally 25°C to 100°C, preferably 40°C to 70°C, and drying may be performed under normal pressure or reduced pressure.

[0107] "Pharmaceutically acceptable excipients" as referred to in this disclosure include, but are not limited to, any auxiliary agent, carrier, glidant, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, or emulsifier that has already been approved by the U.S. Food and Drug Administration and is acceptable for use in humans or domestic animals. [Brief explanation of the drawings]

[0108] [Figure 1] 1 is an XRPD spectrum of amorphous Compound 1. [Figure 2] 1 is an XRPD spectrum of the A-type crystal of Compound 1. [Figure 3] 1 is an XRPD spectrum of type B crystal of Compound 1. [Figure 4] 1 is an XRPD spectrum of a-type crystals of the hydrochloride salt of Compound 1. [Figure 5] 1 is an XRPD spectrum of the hydrochloride b-type crystal of Compound 1. [Figure 6] 1 is an XRPD spectrum of the hydrochloride c-type crystal of Compound 1. [Figure 7] 1 is an XRPD spectrum of α-form crystals of Compound 1 sulfate. [Figure 8]1 is an XRPD spectrum of an α-form crystal of Compound 1 phosphate. [Figure 9] 1 is an XRPD spectrum of an amorphous phosphate salt of Compound 1. [Figure 10] 1 is an XRPD spectrum of an amorphous mesylate salt of Compound 1. [Figure 11] 1 is an XRPD spectrum of succinate type I crystals of Compound 1. [Figure 12] 1 is an XRPD spectrum of the fumarate salt form I crystal of Compound 1. [Figure 13] 1 is an XRPD spectrum of a-type crystals of the maleate salt of Compound 1. [Figure 14] 1 is an XRPD spectrum of an amorphous p-toluenesulfonate salt of Compound 1. [Figure 15] 1 is an XRPD spectrum of an amorphous L-tartrate salt of Compound 1. [Figure 16] 1 is an XRPD spectrum of the crystalline form i of the hemi-fumaric acid salt of Compound 1. [Figure 17] 1 is an XRPD spectrum of the hemi-fumaric acid salt type II crystal of Compound 1. [Figure 18] 1 is an XRPD spectrum of a crystalline form iii of the hemi-fumaric acid salt of Compound 1. DETAILED DESCRIPTION OF THE INVENTION

[0109] The present disclosure is further illustrated by the following examples and experimental examples, which are for illustrative purposes only and are not intended to limit the scope of the disclosure.

[0110] Test conditions for the equipment used in the experiment: The structure of the compound is determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR shift (δ) is 10 -6The NMR data are shown in ppm. A Bruker AVANCE-400 nuclear magnetic resonance spectrometer was used for the NMR measurements. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0111] For MS measurements, a liquid chromatograph mass spectrometer, Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS (manufacturer: Agilent, MS model number: 6110 / 6120 Quadrupole MS), a waters ACQuity UPLC-QD / SQD (manufacturer: waters, MS model number: waters ACQuity Qda Detector / waters SQ Detector), and a THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model number: THERMO Q 15 Exactive) were used.

[0112] For the HPLC measurements, a high performance liquid chromatograph Agilent 1260DAD (Sunfire C18 150 x 4.6 mm column) and a high performance liquid chromatograph Thermo U3000 (Gimini C18 150 x 4.6 mm column) were used.

[0113] XRPD is a method of detecting powder X-ray diffraction. A BRUKER D8 X-ray diffractometer is used for the measurement. The specific collected information is a Cu anode (40 kV, 40 mA), radiation: monochromatic Cu-Ka radiation (l = 1.5418 Å), scanning method: θ / 2θ, scanning range: 3 to 48 o is.

[0114] XRPD is a method of detecting powder X-ray diffraction. A BRUKER D8 FOCUS type X-ray diffractometer is used for the measurement. The specific collected information is radiation: monochromatic Cu-Ka radiation (l = 1.5418 Å). Scanning method: θ / 2θ, scanning range: 2 to 40 o is.

[0115] DSC stands for differential scanning calorimetry. A METTLER TOLEDO DSC 3+ differential scanning calorimeter was used for the measurements, with a heating rate of 10°C / min, from 25 to 350°C, and a nitrogen gas purge rate of 50 mL / min.

[0116] TGA is thermogravimetric analysis. A METTLER TOLEDO TGA 2 type thermogravimetric analyzer is used for detection. The heating rate is 10°C / min. The specific temperature range is based on the corresponding pattern. The nitrogen gas purge rate is 50mL / min.

[0117] DVS stands for dynamic moisture sorption. Instru- mental Surface Measurement Systems were used. The humidity range was considered from 0% to 95% in 10% increments, starting from 50%. The criterion was a mass change per gradient dM / dT ≤ 0.002%, with a TMAX of 360 min, and two cycles were repeated.

[0118] Known starting materials of the present disclosure may be synthesized by or according to methods known in the art, or may be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical 30 Technology (Accela ChemBio Inc.), and Darui Chemical.

[0119] In the examples, thin layer chromatography (TLC) was used to monitor the reaction process. The developing solvents used in the reactions, the column chromatographic eluent system used to purify the compounds, and the developing solvent system for thin layer chromatography included A: dichloromethane / methanol system and B: n-hexane / ethyl acetate system. The volume ratio of the solvents may be adjusted according to the polarity of the compounds, and may be adjusted by adding small amounts of basic or acidic reagents such as triethylamine and acetic acid.

[0120] Example 1. Preparation of Compound 1 (see the preparation method of Example 8 in the application with application number PCT / CN2022 / 094612) [ka]

[0121] Step 1 (R)-tert-butyl 3-(((6-bromo-3-fluoropyridin-2-yl)methoxy)methyl)piperazine-1-carboxylate 1b 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 patent application "WO2016077161A1") and the compound (R)-3-(hydroxymethyl)piperazine-1-carboxylate tert-butyl 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, and the reaction was carried out with stirring for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to obtain the title compound 1b (3g, yield: 79.8%). MS m / z (ESI): 404.1[M+1].

[0122] Step 2 (R)-tert-butyl 3-(((6-(ethoxycarbonyl)-3-fluoropyridin-2-yl)methoxy)methyl)piperazine-1-carboxylate 1c Compound 1b (2 g, 4.94 mmol) was dissolved in a mixed solvent of N,N-dimethylformamide (20 mL) and ethanol (10 mL). Bis(triphenylphosphino)palladium dichloride (0.52 g, 740.8 μmol) and N,N-diisopropylethylamine (1.52 g, 15 mmol) were added, and the mixture was stirred under a carbon monoxide atmosphere at 100°C for 14 hours. After cooling, the mixture was diluted with ethyl acetate (100 mL) and washed with water and saturated sodium chloride solution, successively. The organic phase was collected, dried over anhydrous sodium sulfate, and filtered to remove the desiccant. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 1c (1.5 g, yield: 76.2%). MS m / z (ESI): 398.2[M+1].

[0123] Step 3 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)-dicarboxylic acid ester 1d Compound 1c (4 g, 10.06 mmol) was dissolved in N,N-dimethylacetamide (20 mL), N,N-diisopropylethylamine (4 g, 30.9 mmol) was added, and the mixture was reacted in a microwave oven at 140°C for 6 hours. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to obtain the title compound 1d (2.3 g, yield: 60%). MS m / z (ESI): 364.2[M+1].

[0124] Step 4 (R)-9-(Methylaminocarbonyl)-1,2,4a,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-3(4H)-carboxylate tert-butyl ester 1e Compound 1d (600 mg, 1.58 mmol) was dissolved in 5 mL of a 1 M ethanol solution of methylamine and reacted with stirring for 14 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product, title compound 1e (570 mg, yield: 98%), which was used directly in the next reaction without purification. MS m / z (ESI): 363.2[M+1].

[0125] Step 5 (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 The crude product, Compound 1e (140 mg, 386.2 μmol), was dissolved in dichloromethane (3 mL), and 1 mL of a 4 M solution of hydrochloric acid in dioxane was added. The mixture was stirred for 2 hours, and the reaction mixture was concentrated under reduced pressure to give the crude product, title Compound 1f (110 mg, yield: 95%). The product was used in the next reaction without further purification. MS m / z (ESI): 263.2[M+1].

[0126] Step 6 (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 The crude product, Compound 1f (570 mg, 1.9 mol), Compound 7-(chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one 1h (430 mg, 1.93 mol, obtained 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), sodium iodide (30 mg, 200 μmol) was added, and the reaction was carried out at 80°C for 5 hours. The reaction solution was concentrated under reduced pressure, and the crude product was then purified by high-performance liquid chromatography (Waters-2545, column: SharpSil-T The mixture was purified using a C18 column, 30 × 150 mm, 5 μm, mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30% to 45%, flow rate: 30 mL / min, to obtain the title compound 1 (5.4 mg, yield: 8%). MS m / z (ESI): 449.2[M+1]. 1 H NMR (500 MHz, CD3OD): δ 8.51 (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). The powder X-ray diffraction spectrum of the amorphous material is shown in FIG.

[0127] Example 2: Cell proliferation experiment The following method measures IC by detecting intracellular ATP content. 50 DLD1 cells, DLD1 BRCA2- / - The inhibitory effect on the proliferation of MDA-MB-436 cells was evaluated. The experimental method is briefly explained as follows.

[0128] 1. Experimental materials and equipment 1. DLD1, human colon cancer tumor cells (Nanjing Kebai, CBP60037), DLD1 BRCA2- / - , human BRCA2 gene knockout colon cancer tumor cells (Creative Biogene, CSC-RT0015) 2. MDA-MB-436, human breast cancer cells (ATCC, HTB-130) 3. Fetal bovine serum (GIBCO, 10091-148) 4. CellTite-Glo Reagent (Promega, G7573) 5. 96-well cell culture plate (Corning, 3903) 6. Pancreatin (Invitrogen, 25200-072) 7. Plate reader (BMG, PHERAsta) JPEG2025538371000003.jpg10119

[0129] 2. Experimental Procedure 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, the cells were digested with pancreatin, transferred to a centrifuge tube, and centrifuged at 1200 rpm for 3 minutes. The remaining supernatant medium 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, and the cells were cultured at a density of 2.78 × 10 3 cells / mL, and 180 μL of complete medium alone was added to the periphery of a 96-well plate.

[0130] DLD1 BRCA2- / - The 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, the cells were digested with pancreatin, transferred to a centrifuge tube, and centrifuged at 1200 rpm for 3 minutes. The remaining supernatant medium 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, and the cells were cultured at a density of 8.34 × 10 3cells / mL, and 180 μL of complete medium alone was added to the periphery of a 96-well plate.

[0131] MDA-MB-436 cells were cultured in Leibovitz's L-15 medium containing 10% FBS, 10 μg / mL insulin, and 16 μg / mL glutathione and passaged 2-3 times a week at a passage ratio of 1:3 or 1:5. During passage, cells were digested with pancreatin, transferred to a centrifuge tube, and centrifuged at 1200 rpm for 3 minutes. The remaining supernatant medium 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, and the cells were cultured at a density of 8.34 × 10 3 cells / mL, and 180 μL of complete medium alone was added to the periphery of a 96-well plate.

[0132] The culture plate was incubated in an incubator (37°C, 5% CO2) for 24 hours.

[0133] The test samples were diluted to 2 mM with DMSO and then serially diluted three-fold to 10 concentrations to set up blank and control wells. Five microliters of the test compound solution was added to 95 μL of fresh medium. Then, 20 μL of the drug-containing medium solution was added to the culture plate. The culture plate was incubated in an incubator (37°C, 5% CO2) for 6 days. Ninety microliters of CellTiter-Glo reagent was added to each well of a 96-well cell culture plate and left in the dark at room temperature for 5-10 minutes. The chemiluminescence signal was read using a PHERAstar, and the data was processed using GraphPad software. The results are shown in Table 1.

[0134] [Table 1] Conclusion: Compound 1 of the present disclosure is BRCA2- / - It also has a relatively good inhibitory effect on the proliferation of MDA-MB-436 cells.

[0135] Example 3: Measurement of PARP1 and PARP2 binding activity of Compound 1 according to the present disclosure In vitro PARP1 and PARP2 binding activity was tested by the following method.

[0136] 1. Experimental materials and equipment 1. PARP1 recombinant protein (Yiqiao Shenzhou, product number 11040-H08B), 2. PARP2 Recombinant Protein (BPS, Product No. 80502) 3. Fluorescent probe (self-made using the compound with CAS number 1380359-84-1, Shanghai Hengrui Co., Ltd.), 384-well plate (Corning, 3575) 4. Plate Reader PHERAstar FS (BMG Labtech)

[0137] 2. Experimental Procedure Eight microliters 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 corresponding concentration. The fluorescent probe prepared in dimethyl sulfoxide was 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. Test compounds were dissolved in dimethyl sulfoxide and diluted to various concentrations as needed for the experiment. Compounds prepared in dimethyl sulfoxide were further diluted 20-fold in binding buffer and 2 μL was added to each well. PARP1 or PARP2 protein was diluted to the corresponding concentration in binding buffer and added to a black 384-well plate at 8 μL per well. After uniform mixing, the mixture was incubated at 25°C for 40 minutes. Signal values ​​were read using the FP program on a PHERAstar FS plate reader. Data were processed using GraphPad software.

[0138] The PARP1 and PARP2 binding inhibitory activity of Compound 1 according to the present disclosure was measured by the above test. 50 The values ​​are shown in Table 2.

[0139] [Table 2] Conclusion: The compounds disclosed herein have selective inhibitory activity against PARP1.

[0140] Example 4: Preparation of Form A Crystals of the Compound of Formula 1 120 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 to cause crystallization. The mixture was filtered, and the solid was dried under vacuum to obtain an off-white solid.

[0141] Powder X-ray diffraction analysis confirmed that the product was crystalline type A. Its XRPD spectrum is shown in Figure 2, and its characteristic peak positions 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% between 30°C and 185°C.

[0142] DVS detection showed that the sample's weight gain due to moisture absorption was approximately 0.31% under normal storage conditions (i.e., 25°C, 60% RH), approximately 0.40% under accelerated storage conditions (i.e., 70% RH), and approximately 0.76% under extreme storage conditions (i.e., 90% RH). During the 0% to 95% RH humidity change process, the desorption and adsorption processes of the sample essentially overlapped, and re-measurement of the crystal form after DVS detection revealed no change in crystal form.

[0143] [Table 3]

[0144] Example 5. Preparation of Form A Crystals of the Compound of Formula 1 8 mg of the compound represented by formula 1 was added to 0.4 mL of 10% water / isopropanol and dissolved by stirring at 60°C. The mixture was cooled to room temperature, 1.2 mL of water was added, and the mixture was stirred to precipitate. The mixture was centrifuged, and the solid was dried under vacuum and detected to be type A crystals by powder X-ray diffraction.

[0145] The solid obtained using the solvents in Table 4 and following the preparation method above was detected to be a type A crystal by powder X-ray diffraction.

[0146] [Table 4]

[0147] Example 6: Preparation of Form A Crystals of the Compound of Formula 1 8 mg of the compound of 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 to cause crystallization. The mixture was centrifuged, and the solid was dried under vacuum. The resulting crystal was identified as type A crystal by powder X-ray diffraction.

[0148] The solid obtained using the solvents in Table 5 and referring to the above preparation method was detected to be a type A crystal by powder X-ray diffraction.

[0149] [Table 5-1] [Table 5-2]

[0150] Example 7 Preparation of Form A Crystals of the Compound of Formula 1 8 mg of the compound represented by formula 1 was dissolved in 0.3 mL of DMSO and subjected to crystallization, which was detected to be type A crystals by powder X-ray diffraction.

[0151] The solid obtained using the solvents in Table 6 and following the preparation method above was detected to be a type A crystal by powder X-ray diffraction.

[0152] [Table 6]

[0153] Example 8: Preparation of Form A Crystals of the Compound of Formula 1 Form A crystals of the compound of Formula 1 (12.30 g, 27.42 mmol) were dispersed in 120 mL of absolute ethanol, heated to 75°C, slurried and stirred for 1 hour, cooled to room temperature, stirred for 12 hours, and filtered to collect the filter cake. The resulting solid was polished, dispersed in 100 mL of absolute ethanol, slurried and stirred for 1 hour, filtered to collect the filter cake, washed with ethanol (20 mL x 2), and dried under vacuum at 25°C for 2 hours to obtain the compound of Formula 1 (8.96 g, 72.8% yield). Powder X-ray diffraction confirmed that the solid was Form A crystals.

[0154] Example 9: Preparation of B-type crystals of the compound of formula 1 The crude product of the compound of formula 1 (0.856 g, 1.91 mmol) was purified by high-performance liquid chromatography (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), and the preparation was lyophilized to obtain the compound of formula 1 (0.09 g, yield 10.9%).

[0155] When detected by powder X-ray diffraction, the product was defined as B-type crystals, and the powder X-ray diffraction data is shown in Table 7, and the powder X-ray diffraction spectrum is shown in FIG.

[0156] According to the DSC spectrum, the peak value of the endothermic peak is 258.01°C. According to the TGA spectrum, the weight of the compound decreased by 0.69% between 40°C and 160°C.

[0157] [Table 7-1] [Table 7-2]

[0158] Example 10 Preparation of a-type crystals of the hydrochloride salt of the compound of formula 1 120 mg of the compound represented by formula 1 was added to 9 mL of tetrahydrofuran / ethanol (v / v=2:1), and the mixture was stirred at 60°C to dissolve. The mixture was then cooled to room temperature, and 145 μL of a 2 M hydrochloric acid ethanol solution was added, and the mixture was stirred to cause crystallization. The mixture was filtered, and the solid was dried under vacuum to obtain an off-white solid.

[0159] Powder X-ray diffraction analysis confirmed that the product was a-type hydrochloride crystals. The XRPD spectrum is shown in Figure 4, and its characteristic peak positions are shown in Table 8. The DSC spectrum showed 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%.

[0160] [Table 8-1] [Table 8-2]

[0161] Example 11: Preparation of hydrochloride type b crystals of the compound of formula 1 120 mg of the compound represented by formula 1 was dissolved in 1 mL of dichloromethane / methanol (v / v=2:1), 290 μL of a 2 M hydrochloric acid ethanol solution was added, and the mixture was stirred to precipitate. The precipitate was filtered, and the solid was dried under vacuum to obtain an off-white solid.

[0162] Powder X-ray diffraction analysis confirmed that the product was hydrochloride type b crystals. The XRPD spectrum is shown in Figure 5, and its characteristic peak positions are shown in Table 9. The DSC spectrum showed endothermic peaks at 49.81°C, 258.00°C, and 284.29°C. The TGA spectrum showed a weight loss of 1.88% between 30°C and 150°C, and a weight loss of 8.12% between 150°C and 235°C. Ion chromatography revealed that the chloride ion content was 13.19%.

[0163] According to DVS detection, the weight gain due to moisture absorption of this sample under normal storage conditions (i.e., 25°C, 60% RH) was approximately 3.26%, under accelerated storage conditions (i.e., 70% RH) the weight gain due to moisture absorption was approximately 3.65%, and under extreme conditions (i.e., 90% RH) the weight gain due to moisture absorption was approximately 4.60%. During the RH change process from 0% to 95%, the desorption and adsorption processes of this sample essentially overlapped, and re-measurement of the crystal form after DVS detection showed no change in crystal form.

[0164] [Table 9-1] [Table 9-2]

[0165] Example 12: Preparation of hydrochloride c-type crystals of the compound of formula 1 7 mg of the compound represented by formula 1 was added to 0.4 mL of 10% water / isopropanol and dissolved by stirring at 60°C. The mixture was cooled to room temperature, and 8.5 μL of a 2 M hydrochloric acid ethanol solution and 0.8 mL of isopropyl acetate were added. The mixture was stirred to cause crystallization, filtered, and the solid was dried under vacuum to obtain an off-white solid.

[0166] Powder X-ray diffraction analysis confirmed that the product was hydrochloride c-type crystals. The XRPD spectrum is shown in Figure 6, and its characteristic peak positions 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% between 30°C and 180°C.

[0167] [Table 10]

[0168] Example 13: Preparation of α-form crystals of the sulfate salt of the compound of formula 1 7 mg of the compound represented by formula 1 was added to 0.4 mL of 10% water / isopropanol and dissolved by stirring at 60°C. The mixture was cooled to room temperature, and 8.5 μL of a 2 M sulfuric acid ethanol solution was added, followed by stirring to crystallize the mixture. The mixture was centrifuged, and the solid was dried under vacuum to obtain an off-white solid.

[0169] Powder X-ray diffraction analysis confirmed that the product was sulfate α-crystalline. The XRPD spectrum is shown in Figure 7, and its characteristic peak positions 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% between 30°C and 165°C.

[0170] [Table 11]

[0171] Example 14: Preparation of α-form crystals of the sulfate salt of the compound of formula 1 7 mg of the compound of formula 1 was added to 0.6 mL of tetrahydrofuran / ethanol (v / v = 2:1), stirred at 60 °C to dissolve, cooled to room temperature, added 8.5 μL of 2 M sulfuric acid ethanol solution, stirred to crystallize, centrifuged, and dried under vacuum to obtain an off-white solid. When detected by powder X-ray diffraction, the product was sulfate α-form crystals.

[0172] Example 15: Preparation of α-form crystals of the sulfate salt of the compound of formula 1 7 mg of the compound of formula 1 was added to 0.1 mL of dichloromethane / methanol (v / v = 2:1), stirred at 60 °C to dissolve, cooled to room temperature, added 8.5 μL of 2 M sulfuric acid ethanol solution, stirred to crystallize, centrifuged, and dried under vacuum to obtain an off-white solid. Powder X-ray diffraction revealed that the product was sulfate α-form crystals.

[0173] Example 16: Preparation of α-form crystals of the phosphate salt of the compound of formula 1 120 mg of the compound represented by formula 1 was added to 7 mL of 10% water / isopropanol and dissolved by stirring at 60°C. 145 μL of a 2 M ethanolic solution of phosphoric acid was added, and the mixture was stirred at room temperature to cause crystallization. The mixture was filtered, and the solid was dried under vacuum to obtain an off-white solid.

[0174] Powder X-ray diffraction analysis confirmed that the product was α-crystalline phosphate. The XRPD spectrum is shown in Figure 8, and its characteristic peak positions are shown in Table 12. The DSC spectrum showed endothermic peaks at 60.98°C and 180.14°C. The TGA spectrum showed a weight loss of 4.67% between 30°C and 170°C. Ion chromatography revealed that the phosphate ion content was 18.47%.

[0175] DVS detection showed that the sample's weight gain due to moisture absorption was approximately 11.72% under normal storage conditions (i.e., 25°C, 60% RH), approximately 13.94% under accelerated storage conditions (i.e., 70% RH), and approximately 23.17% under extreme storage conditions (i.e., 90% RH). During the 0% to 95% RH humidity change process, the desorption and adsorption processes of the sample essentially overlapped, and re-measurement of the crystal form after DVS detection revealed no change in crystal form.

[0176] [Table 12]

[0177] Example 17: Preparation of α-form crystals of the phosphate salt of the compound of formula 1 7 mg of the compound represented by formula 1 was added to 0.6 mL of tetrahydrofuran / ethanol (v / v=2:1) ​​and dissolved by stirring at 60°C. 8.5 μL of a 2 M ethanolic solution of phosphoric acid was added, and the mixture was stirred at room temperature to cause crystallization. The mixture was centrifuged, and the solid was dried under vacuum. The solid was detected to be α-type crystalline phosphate by powder X-ray diffraction.

[0178] Example 18. Preparation of amorphous phosphate salt of compound of formula 1 7 mg of the compound of Formula 1 was dissolved in 0.1 mL of dichloromethane / methanol (v / v = 2:1), 8.5 μL of a 2 M ethanol solution of phosphoric acid was added, and the mixture was stirred overnight. 0.6 mL of MTBE was added, and the mixture was stirred to crystallize. The mixture was centrifuged and the solid was dried under vacuum to obtain an off-white solid. Powder X-ray diffraction revealed that the product was amorphous, and the XRPD spectrum is shown in Figure 9. Ion chromatography revealed that the phosphate ion content was 20.82%.

[0179] Example 19. Preparation of amorphous mesylate salt of compound of formula 1 7 mg of the compound of Formula 1 was added to 0.1 mL of dichloromethane / methanol (v / v = 2:1) and stirred at room temperature to dissolve. 8.5 μL of a 2 M methanesulfonic acid ethanol solution was added and stirred to crystallize. The mixture was centrifuged and the solid was dried under vacuum to obtain an off-white solid. Powder X-ray diffraction revealed that the product was amorphous, and the XRPD spectrum is shown in Figure 10. Ion chromatography revealed that the methanesulfonate ion content was 16.66%.

[0180] Example 20: Preparation of Form I Crystals of Succinate of the Compound of Formula 1 120 mg of the compound represented by formula 1 was dissolved in 0.6 mL of dichloromethane / methanol (v / v=2:1), 34 mg of solid succinic acid was added, and the mixture was stirred to crystallize. The crystal was filtered, and the solid was dried under vacuum to obtain an off-white solid.

[0181] Powder X-ray diffraction analysis confirmed that the product was succinate type I crystals. The XRPD spectrum is shown in Figure 11, and its characteristic peak positions are shown in Table 13. The DSC spectrum showed 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%.

[0182] DVS detection showed that the sample's weight gain due to moisture absorption was approximately 0.29% under normal storage conditions (i.e., 25°C, 60% RH), approximately 0.38% under accelerated storage conditions (i.e., 70% RH), and approximately 0.64% under extreme storage conditions (i.e., 90% RH). During the 0% to 95% RH humidity change process, the desorption and adsorption processes of the sample essentially overlapped, and re-measurement of the crystal form after DVS detection revealed no change in crystal form.

[0183] [Table 13-1] [Table 13-2]

[0184] Example 21: Preparation of Form I Crystals of Fumarate of the Compound of Formula 1 120 mg of the compound represented by formula 1 was added to 9 mL of tetrahydrofuran / ethanol (v / v=2:1) ​​and dissolved by stirring at 60°C. 34 mg of fumaric acid was added, and the mixture was stirred at room temperature to cause crystallization. The mixture was filtered, and the solid was dried under vacuum to obtain an off-white solid.

[0185] Powder X-ray diffraction analysis confirmed that the product was fumarate type I crystals. The XRPD spectrum is shown in Figure 12, and its characteristic peak positions are shown in Table 14. The DSC spectrum showed 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%.

[0186] DVS detection showed that the sample's weight gain due to moisture absorption was approximately 0.21% under normal storage conditions (i.e., 25°C, 60% RH), approximately 0.24% under accelerated storage conditions (i.e., 70% RH), and approximately 0.38% under extreme storage conditions (i.e., 90% RH). During the 0% to 95% RH humidity change process, the desorption and adsorption processes of the sample essentially overlapped, and re-measurement of the crystal form after DVS detection revealed no change in crystal form.

[0187] [Table 14-1] [Table 14-2]

[0188] Example 22: Preparation of Form I Crystals of Fumarate of the Compound of Formula 1 7 mg of the compound represented by formula 1 was added to 0.4 mL of 10% water / isopropanol and dissolved by stirring at 60°C. 2 mg of fumaric acid was added, and the mixture was stirred at room temperature to cause crystallization. The mixture was filtered, and the solid was dried under vacuum. It was detected to be Form I crystals by powder X-ray diffraction.

[0189] Example 23: Preparation of Form I Crystals of Fumarate of Compound of Formula 1 7 mg of the compound represented by formula 1 was added to 0.6 mL of tetrahydrofuran / ethanol (v / v=2:1), and the mixture was stirred at 60°C to dissolve it. 2 mg of fumaric acid was added, and the mixture was stirred at room temperature to crystallize it. The mixture was filtered, and the solid was dried under vacuum. It was detected to be a type I crystal by powder X-ray diffraction.

[0190] Example 24: Preparation of Form I Crystals of Fumarate of the Compound of Formula 1 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 60°C. 2 mg of fumaric acid was added, and the mixture was stirred at room temperature to cause crystallization. The mixture was filtered, and the solid was dried under vacuum. It was detected to be a type I crystal by powder X-ray diffraction.

[0191] Example 25: Preparation of maleate a-type crystals of the compound of formula 1 7 mg of the compound of Formula 1 was dissolved in 0.1 mL of dichloromethane / methanol (v / v = 2:1), 8.5 μL of a 2 M maleic acid ethanol solution was added, and the mixture was stirred overnight at room temperature. 0.6 mL of methyl tert-butyl ether was added, and the mixture was stirred to crystallize. The mixture was centrifuged and the solid was dried under vacuum to obtain an off-white solid. Powder X-ray diffraction analysis confirmed the product to be maleate type a crystal. The XRPD spectrum is shown in Figure 13, and its characteristic peak positions are shown in Table 15. The DSC spectrum showed endothermic peaks at 215.91 °C and 258.32 °C. The TGA spectrum showed a 2.49% weight loss between 30 °C and 130 °C, and a 9.95% weight loss between 130 °C and 260 °C. Ion chromatography revealed a maleate ion content of 9.37%.

[0192] [Table 15-1] [Table 15-2]

[0193] Example 26 Preparation of amorphous p-toluenesulfonate salt of compound of formula 1 7 mg of the compound of Formula 1 was dissolved in 0.1 mL of dichloromethane / methanol (v / v = 2:1), 8.5 μL of a 2 M p-toluenesulfonic acid ethanol solution was added, and the mixture was stirred overnight. 0.6 mL of MTBE was added, and the mixture was stirred to crystallize. The mixture was centrifuged and the solid was dried under vacuum to obtain an off-white solid. Powder X-ray diffraction revealed that the product was amorphous, and the XRPD spectrum is shown in Figure 14. Ion chromatography revealed that the p-toluenesulfonic acid ion content was 26.91%.

[0194] Example 27 Preparation of Amorphous L-Tartrate Salt of Compound of Formula 1 7 mg of the compound of formula 1 was added to 0.4 mL of 10% water / isopropanol and stirred at 60°C to dissolve. 8.5 μL of a 2 M ethanolic tartaric acid solution was added and stirred overnight. 0.8 mL of isopropyl acetate was added and stirred to crystallize. The mixture was centrifuged and the solid was dried under vacuum to obtain an off-white solid. Powder X-ray diffraction revealed that the product was amorphous, and the XRPD spectrum is shown in Figure 15. Ion chromatography revealed that the L-tartrate ion content was 31.43%.

[0195] Example 28: Preparation of Form i Crystals of Hemi-Fumarate of the Compound of Formula 1 10.0 g of the compound of Formula 1 and 1.294 g of fumaric acid were added to 800 mL of anhydrous methanol. The mixture was heated to reflux to dissolve the solid, then cooled and crystallized to obtain the hemi-fumaric acid salt of the compound of Formula 1. 0.5 g of the hemi-fumaric acid salt of the compound of Formula 1 was placed in a reaction flask, and 15 mL of anhydrous methanol was added. The mixture was refluxed to dissolve the solid. Heating was stopped, and the mixture was cooled to allow crystallization. The mixture was suction filtered, and the filter cake was blown dry at 45°C to obtain a white solid. Powder X-ray diffraction analysis identified the product as type i crystals of the hemi-fumaric acid salt. The XRPD spectrum is shown in Figure 16, and its characteristic peak positions are shown in Table 16. HPLC analysis revealed a fumarate ion content of 11.3% (calculated based on the anhydrous base).

[0196] [Table 16-1] [Table 16-2]

[0197] Example 29: Preparation of Form II Crystals of Hemi-Fumarate of the Compound of Formula 1 5 mg of the hemi-fumaric acid salt type i crystals of the compound shown in Example 28 was heated to 170° C. to obtain the product.

[0198] Powder X-ray diffraction analysis confirmed that the product was hemi-fumarate type II crystals. The XRPD spectrum is shown in Figure 17, and its characteristic peak positions are shown in Table 17. The DSC spectrum showed 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%.

[0199] [Table 17]

[0200] Example 30: Preparation of Crystalline Form III of Hemi-Fumarate of the Compound of Formula 1 500 mg of the compound of formula 1 in free form was added to 10 mL of methanol, and 1.2 mL of a 0.5 M fumaric acid methanol solution was added, followed by stirring to crystallize. The mixture was centrifuged, and the solid was collected and dried under vacuum at 60°C to obtain the product.

[0201] Powder X-ray diffraction analysis confirmed that the product was hemi-fumarate type III crystals. The XRPD spectrum is shown in Figure 18, and its characteristic peak positions are shown in Table 18. The DSC spectrum showed 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%.

[0202] [Table 18-1] [Table 18-2]

[0203] Experimental Example 1: Study of Crystalline Form Stability Free state crystalline form A, hydrochloride a-type crystals, phosphate α-type crystals, succinate I-type crystals, and fumarate I-type crystals were placed flat in an open state, and the stability of the samples was examined under the conditions of light exposure (4500 Lux), high temperature (40°C, 60°C), and high humidity (RH 75%, RH 92.5%). The sampling examination period was 30 days.

[0204] [Table 19] [Table 20-1] [Table 20-2] [Table 20-3]

[0205] Conclusion: As is evident from the influencing factors experiment, The free crystalline form A exhibits good physical and chemical stability when stored at a high temperature of 40°C and high humidity of 75% and 92.5% for 30 days.

[0206] The hydrochloride salt type a crystals have good physical and chemical stability when stored at high temperatures of 40°C and 60°C and high humidity of 75% for 30 days.

[0207] The α-type phosphate crystals exhibit good physical and chemical stability when stored under high humidity conditions of 75% and 92.5% for 30 days.

[0208] The succinate type I crystals have good physical and chemical stability when stored at high temperatures of 40℃ and 60℃ and high humidity of 75% and 92.5% for 30 days.

[0209] The fumarate type I crystals exhibit good physical and chemical stability when stored at high temperatures of 40°C and 60°C and high humidity of 75% and 92.5% for 30 days.

[0210] Experimental Example 2: Long-term / accelerated stability The stability of free crystalline form A, hydrochloride type a crystal, hydrochloride type b crystal, phosphate type α crystal, succinate type I crystal, and fumarate type I crystal was examined under the conditions of 25°C / 60%RH and 40°C / 75%RH, respectively.

[0211] [Table 21] [Table 22-1] [Table 22-2]

[0212] Conclusion: As is evident from the long-term accelerated experiments, crystalline form A, hydrochloride type a crystal, hydrochloride type b crystal, phosphate type α crystal, fumarate type I crystal, and succinate type I crystal have good physical and chemical stability when stored for 6 months under conditions of 25°C / 60RH and 40°C / 75RH.

Claims

1. A type A crystal 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 powder X-ray diffraction pattern measured at 2θ angles has characteristic peaks at 7.877, 11.871 and 17.876, preferably has characteristic peaks at 7.877, 9.115, 11.871 and 17.876, and most preferably has a powder X-ray diffraction pattern measured at 2θ angles as shown in FIG.

2. A type crystal.

2. Medicinal salts 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, selected from the group consisting of hydrochloride, sulfate, phosphate, mesylate, succinate, fumarate, maleate, p-toluenesulfonate, L-tartrate, D-malate, L-malate and citrate. Medicinal salt.

3. 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 has a chemical compounding ratio with an acid of 3:1 to 1:3, preferably 2:1 to 1:2, and more preferably 2:1, 1:1, or 1:

2.

3. The medicinal salt of claim 2.

4. 1. A process 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 the steps 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; Preparation method.

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 (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 in a 1:1 chemical ratio with fumaric acid; Fumarate.

6. The 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, in a form I crystal, has characteristic peaks at 6.163, 8.552, 12.317, 17.407, and 24.336 in a powder X-ray diffraction pattern shown at diffraction angles 2θ, and preferably has characteristic peaks at 6.163, 8.552, 12.317, 17.407, and 24.336 in a powder X-ray diffraction pattern shown at diffraction angles 2θ. and more preferably 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 ... Fumarate Form I crystals.

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, in which 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; Succinate salt.

8. The succinate type I crystal 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 has characteristic peaks at 6.106, 8.589, 12.276, 14.812, 17.517, and 20.400 in a powder X-ray diffraction pattern shown at diffraction angles 2θ, and preferably has characteristic peaks at 6.106, 8.589, 12.276, 14.812, 17.517, and 20.400 in a powder X-ray diffraction pattern shown at diffraction angles 2θ. and more preferably, it has 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, and most preferably, it has a powder X-ray diffraction pattern shown in terms of diffraction angle 2θ angles as shown in FIG.

11. Succinate type I crystals.

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. Crystalline form.

10. A pharmaceutical composition comprising the following components: i) A type crystal 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 a medicinal 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 crystal form according to claims 6 and 8; ii) one or more pharmaceutically acceptable excipients; and A pharmaceutical composition comprising:

11. A method for preparing a pharmaceutical composition, comprising the steps of: preparing 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 according to claim 1; or preparing 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 according to any one of claims 2, 3, 5, and 7. The method of the present invention comprises the step of mixing a pharmaceutical 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 described above, or the crystalline form described in claims 6 or 8, with a pharmaceutically acceptable excipient. method.

12. The A-type crystal 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 A-type crystal 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 (methyl-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 crystalline form of claim 6 or 8, or the composition of claim 10, in the preparation of a PARP1 inhibitor.

13. The A-type crystal 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 A-type crystal 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 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 crystalline form of claim 6 or 8, or the composition of claim 10, in the preparation of a medicament for treating and / or preventing cancer.

14. The cancers include breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, colorectal cancer, lung cancer, renal cancer, liver cancer, cervical cancer, endometrial cancer, myeloma, leukemia, lymphoma, acoustic neuroma, basal cell carcinoma, bile duct cancer, bladder cancer, brain cancer, bronchial carcinoma, sarcoma, chordoma, choriocarcinoma, craniopharyngioma, cystadenocarcinoma, embryonal carcinoma, hemangioendothelioma, ependymoma, epithelial carcinoma, esophageal carcinoma, primary thrombocytosis, Ewing's sarcoma, testicular cancer, glioma, heavy chain disease, hemangioblastoma, medullary carcinoma, and thyroid carcinoma. blastoma, melanoma, meningioma, mesothelioma, neuroblastoma, NUT midline carcinoma, glioma, bone cancer, nasopharyngeal carcinoma, oral cancer, thyroid cancer, pinealoma, polycythemia vera, retinoblastoma, sebaceous gland carcinoma, seminoma, skin cancer, squamous cell carcinoma, synovium, sweat gland carcinoma, Waldenstrom's macroglobulinemia and Wilms' tumor, preferably said cancer is selected from breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, colorectal cancer and lung cancer, 14. The use according to claim 13.

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