Crystalline forms and uses of PARP7 inhibitors and their salts

Abstract

Crystalline forms of the compound of formula (I) as PARP7 inhibitors, crystalline forms of pharmaceutically acceptable salts of the compound of formula (I), and their use in the preparation of medicaments for treating related diseases. [Case 1] JPEG2026503626000034.jpg32170

Description

[Technical Field]

[0001] This invention claims priority to the Chinese patent application filed on January 28, 2023, with application number 202310072130.5, entitled "Crystalline form of PARP7 inhibitor and preparation method thereof," and the Chinese patent application filed on January 28, 2023, with application number CN202310072098.0, entitled "Salt, crystalline form of PARP7 inhibitor and preparation method thereof," the entire contents of which are incorporated herein by reference.

[0002] The present invention belongs to the field of medicinal chemistry, and specifically relates to crystalline forms and uses of PARP7 inhibitors and their salts. [Background technology]

[0003] The poly(ADP-ribose) polymerase (PARP) family consists of 17 members and regulates fundamental cellular processes, including gene expression, protein degradation, and multicellular stress responses (CoHen, ​​P. Chang, Insights into the biogenesis, function, and regulation of ADP-ribosylation. NaT Them Biol 14, 236-243 (2018)). The ability of cancer cells to survive under stressful conditions is a fundamental mechanism of cancer and a novel avenue for novel therapeutic agents.

[0004] Seventeen members of the PARP family have been identified in the human genome based on homology within the catalytic domain. However, based on differences in activity, they are classified into three subfamilies: polyPARPs, monoPARPs, and inactive (S. Vyas et al., Family-Wide analysis of poly(ADP-ribose) polymerase activity. NaTCommun 5, 4426 (2014)). Most PARP family members catalyze the transfer of mono(ADP-ribose) units onto substrates (monoPARPs), while others (PARP1, PARP2, TNKS, and TNKS2) catalyze the transfer of poly(ADP-ribose) units onto substrates (polyPARPs). Meanwhile, PARP13 is the only PARP that has not yet demonstrated catalytic activity in vitro or in vivo. These monoPARPs regulate signaling pathways by modifying targets via a single ADP-ribose unit, a process similar to kinase phosphorylation. The PolyPARPs described above modify their protein targets with large, branched polymers called poly(ADP-ribose); these large, highly charged attachments form a scaffold for the protein that guides it to function at specific sites within the cell.

[0005] PARP1, a member of the PARP family, has proven to be a valid cancer target associated with cellular stress induced by DNA damage induced by genetic mutations or cytotoxic chemotherapy. Four clinically approved drugs are available, with several others in late-stage development (A. Ohmoto, S. Yachida, Current status of poly(ADP-ribose) polymerase inhibitors and future directions. Onco Targets Ther 10, 5195-5208 (2017)).

[0006] The PARP7 gene is located on chromosome 3 (3q25), a region frequently amplified in squamous cell carcinoma. Genome-wide association studies have identified susceptibility loci for ovarian cancer, demonstrating the role of PARP7 in this type of cancer (EL Goode et al., A genome-wide association study identifies susceptibility loci for ovarian cancer atT2q31and8q24. NaTGeneT42, 874-879 (2010)). PARP7 has multiple cellular functions. Under AHR signaling, PARP7 regulates the expression of P4501A1 and P4501B1 as a negative feedback mechanism. PARP7 has also been reported to regulate ADP-ribosylation and liver X receptor transcription by regulating its transcriptional activity (C. Bigetsboll et al., TCDD-Inducible Poly-ADP-ribose (TIPARP / PARP7) Mono-ADP-ribosylates and Co-activates Liver X Receptors. Biochem J 473, 899-910 (2016)). During viral infection, PARP7 can bind to Sindbis virus and promote viral RNA degradation. Furthermore, in the context of viral infection, AHR-induced PARP7 interacts with TBK1. TBK1 is a key kinase during the onset of the pathogen-associated molecular pattern pathway, leading to the activation of type I interferon responses and antiviral immunity. PARP7 has been shown to inhibit type I interferon responses by ADP-ribosylating TBK1 and preventing its activation.

[0007] Research has shown that many cancer cells depend on PARP7 for intrinsic cell survival and that PARP7 allows them to "hide" from the immune system. Therefore, inhibiting PARP7 can effectively inhibit cancer cell proliferation, restore interferon signaling, and inhibit cancer. PARP7 inhibitors have demonstrated sustained tumor growth inhibition, effective antiproliferative activity, and restoration of interferon signaling in several cancer models. In vivo models have also shown the induction of tumor-specific adaptive immune memory. This effect is achieved by activating IFN-β signaling in immune cells, strengthening immune system signals, and achieving immune memory, thereby inhibiting tumors. Research has shown that the use of PARP7 alone has excellent in vivo efficacy. Compounds targeting this compound have been found to effectively inhibit PARP7 enzymatic activity. Therefore, further development of crystalline forms and preparation methods of these compounds, as well as pharmaceutical compositions of these crystalline forms, may provide more effective treatments for cancer patients. Summary of the Invention

[0008] The present invention provides crystalline forms of the compound of formula (I), salts of the compound of formula (I) and crystalline forms thereof, and uses thereof. [ka]

[0009] A first aspect of the present invention provides crystalline Form IV of compound of formula (I), which has an X-ray powder diffraction pattern using Cu-Kα radiation having characteristic peaks at one, two, three, four or five of the following 2θ values: 14.13°, 15.56°, 17.33°, 18.07°, and 22.30°, with an error in 2θ of ±0.2°.

[0010] In some embodiments of the present invention, the crystalline form IV has an X-ray powder diffraction pattern using Cu-Kα radiation, with characteristic peaks at 2θ values ​​of 14.13°, 15.56°, 17.33°, 18.07°, and 22.30°, with an error range of 2θ of ±0.2°.

[0011] In some embodiments of the present invention, Form IV has an X-ray powder diffraction pattern using Cu-Kα radiation having characteristic peaks at one, two, three, four, five, six, seven, or eight of the following 2θ values: 14.13°, 14.46°, 15.56°, 17.02°, 17.33°, 18.07°, 19.17°, and 22.30°, with an error range of ±0.2° 2θ.

[0012] In some embodiments of the present invention, the crystalline form IV has an X-ray powder diffraction pattern using Cu-Kα radiation, with characteristic peaks at 2θ values ​​of 14.13°, 14.46°, 15.56°, 17.02°, 17.33°, 18.07°, 19.17°, and 22.30°, with an error range of 2θ of ±0.2°.

[0013] In some embodiments of the present invention, Form IV has an X-ray powder diffraction pattern using Cu-Kα radiation with characteristic peaks at one, two, three, four, five, six, seven, eight, nine, or ten of the following 2θ values: 7.25°, 10.00°, 14.13°, 14.46°, 15.56°, 17.02°, 17.33°, 18.07°, 19.17°, and 22.30°, with an error range of ±0.2° 2θ.

[0014] In some embodiments of the present invention, Form IV has an X-ray powder diffraction pattern using Cu-Kα radiation, with characteristic peaks at 2θ values ​​of 7.25°, 10.00°, 14.13°, 14.46°, 15.56°, 17.02°, 17.33°, 18.07°, 19.17°, and 22.30°, with an error in 2θ of ±0.2°.

[0015] In some embodiments of the present invention, the crystalline form IV has an X-ray powder diffraction pattern substantially as shown in FIG.

[0016] In some embodiments of the present invention, the crystalline form IV has X-ray powder diffraction peak analysis data as shown in Table 1.

[0017] [Table 1]

[0018] In some embodiments of the present invention, the crystalline form IV has an endothermic peak at 175±2° C. in a TGA-DSC pattern.

[0019] In some embodiments of the present invention, the crystalline form IV is characterized by a TGA-DSC pattern substantially as shown in FIG.

[0020] The present invention further provides a process for preparing crystalline Form IV of compound of formula (I), said process comprising: (a) adding a compound of formula (I) to a solvent and stirring with heating; and (b) filtering to obtain a solid. The solvent is selected from organic solvents, preferably n-heptane, and the temperature of the heating and stirring is 40°C-60°C, preferably 50°C.

[0021] The present invention further provides another method for preparing crystalline form IV of compound of formula (I), said method comprising: (a) adding and dissolving a compound of formula (I) in a solvent; and (b) After filtration, n-heptane is slowly added dropwise to precipitate a solid. The solvent is selected from organic solvents, preferably 2-methyltetrahydrofuran.

[0022] A second aspect of the present invention provides crystalline Form VI of compound of formula (I), which has an X-ray powder diffraction pattern using Cu-Kα radiation having characteristic peaks at one, two, three, four, five, six, seven or eight of the following 2θ values: 5.20°, 7.49°, 10.70°, 13.42°, 14.30°, 14.85°, 16.01°, and 18.66°, with an error in 2θ of ±0.2°.

[0023] In some embodiments of the present invention, Form VI has an X-ray powder diffraction pattern using Cu-Kα radiation, with characteristic peaks at 2θ values ​​of 5.20°, 7.49°, 10.70°, 13.42°, 14.30°, 14.85°, 16.01°, and 18.66°, with an error in 2θ of ±0.2°.

[0024] In some embodiments of the present invention, Form VI has an X-ray powder diffraction pattern using Cu-Kα radiation having characteristic peaks at one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, or fourteen of the following 2θ values: 5.20°, 7.49°, 7.95°, 9.70°, 10.70°, 11.53°, 13.05°, 13.42°, 14.30°, 14.85°, 16.01°, 16.38°, 17.11°, and 18.66°, with an error range of ±0.2° 2θ. In some embodiments of the present invention, Form VI has an X-ray powder diffraction pattern using Cu-Kα radiation, with characteristic peaks at 2θ values ​​of 5.20°, 7.49°, 7.95°, 9.70°, 10.70°, 11.53°, 13.05°, 13.42°, 14.30°, 14.85°, 16.01°, 16.38°, 17.11°, and 18.66°, with an error in 2θ of ±0.2°.

[0025] In some embodiments of the present invention, the crystalline form VI has an X-ray powder diffraction pattern using Cu-Kα radiation at 2θ values ​​of 5.20°, 6.68°, 7.49°, 7.95°, 9.70°, 10.70°, 11.53°, 13.05°, 13.42°, 13.67°, 14.30°, 14.85°, 16.01°, 16.38°, 17.11°, 18.21°, 19.22°, 20.23°, 21.24°, 22.25°, 23.26°, 24.27°, 25.28°, 26.29°, 27.29°, 28.29°, 29.26°, 30.28°, 31.29°, 32.29°, 33.29°, 34.29°, 35.29°, 36.29°, 37.29°, 38.29°, 39.29°, 40.29°, 41.29°, 42.29°, 43.29°, 44.29°, 45.29°, 46.29°, 47.29°, 48.29°, 49.29°, 50.29°, 51.29°, 52.29°, 53.29°, 54.29°, 55.29°, 56.29°, 57.29°, 58.29°, 59.29°, 60.29°, 61.29°, 62.29°, 6 The sample has characteristic peaks at one, two, three, four, five, six, seven, eight, nine, ten, eleven, 12, 13, 14, 15, 16, 17, 18, or 19 of the following angles: 18.66°, 19.37°, 23.44°, and 24.36°, and the error range of 2θ is ±0.2°.

[0026] In some embodiments of the present invention, Form VI has an X-ray powder diffraction pattern using Cu-Kα radiation, with characteristic peaks at 2θ values ​​of 5.20°, 6.68°, 7.49°, 7.95°, 9.70°, 10.70°, 11.53°, 13.05°, 13.42°, 13.67°, 14.30°, 14.85°, 16.01°, 16.38°, 17.11°, 18.66°, 19.37°, 23.44°, and 24.36°, with an error in 2θ of ±0.2°.

[0027] In some embodiments of the present invention, the crystalline form VI has an X-ray powder diffraction pattern substantially as shown in FIG.

[0028] In some embodiments of the present invention, the crystalline form VI has X-ray powder diffraction peak analysis data as shown in Table 2.

[0029] [Table 2]

[0030] In some embodiments of the present invention, the crystalline form VI has a TGA-DSC pattern with an exothermic peak at 105±2°C and an endothermic peak at 177±2°C.

[0031] In some embodiments of the present invention, the crystalline form VI has a TGA-DSC pattern substantially as shown in FIG.

[0032] The present invention further provides a process for preparing crystalline form VI of compound of formula (I), said process comprising: (a) dissolving a compound of formula (I) in a solvent at elevated temperature; and (b) Filtration followed by gradual cooling to precipitate a solid. The solvent is any one selected from methanol, acetonitrile, acetone, and water, or a combination thereof, and the temperature at which the solution is heated is selected from 40°C to 60°C, preferably 50°C.

[0033] The present invention further provides another method for preparing crystalline form VI of compound of formula (I), said method comprising: (a) stirring a compound of formula (I) in a solvent at room temperature; and (b) Including obtaining a solid after filtration. The solvent is any one or a combination of methanol, acetonitrile, acetone, and water.

[0034] The present invention further provides another method for preparing crystalline form VI of compound of formula (I), said method comprising: (a) dissolving a compound of formula (I) in a solvent; (b) After filtration, the mixture is gradually cooled and stirred while keeping the temperature constant; and (c) Filtration followed by vacuum drying. The solvent is any one or a combination of methanol, acetonitrile, acetone, and water.

[0035] The present invention further provides crystalline Form VIII of compound of formula (I), wherein the crystalline Form VIII of compound of formula (I) has an X-ray powder diffraction pattern using Cu-Kα radiation having characteristic peaks at one, two, three, four, five, six or seven of the following 2θ values: 8.97°, 13.51°, 16.20°, 18.05°, 18.56°, 20.94°, and 21.25°, with an error in 2θ of ±0.2°.

[0036] In some embodiments of the present invention, crystalline Form VIII has an X-ray powder diffraction pattern using Cu-Kα radiation, with characteristic peaks at 2θ values ​​of 8.97°, 13.51°, 16.20°, 18.05°, 18.56°, 20.94°, and 21.25°, with an error range of 2θ of ±0.2°.

[0037] In some embodiments of the present invention, crystalline Form VIII has an X-ray powder diffraction pattern using Cu-Kα radiation with characteristic peaks at one, two, three, four, five, six, seven, eight, nine, or ten of the following 2θ values: 8.97°, 13.51°, 15.51°, 16.20°, 18.05°, 18.56°, 19.94°, 20.94°, 21.25°, and 27.13°, with an error range of ±0.2° 2θ.

[0038] In some embodiments of the present invention, crystalline Form VIII has an X-ray powder diffraction pattern using Cu-Kα radiation, with characteristic peaks at 2θ values ​​of 8.97°, 13.51°, 15.51°, 16.20°, 18.05°, 18.56°, 19.94°, 20.94°, 21.25°, and 27.13°, with an error in 2θ of ±0.2°.

[0039] In some embodiments of the present invention, crystalline Form VIII has an X-ray powder diffraction pattern using Cu-Kα radiation with characteristic peaks at one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, or fourteen of the following 2θ values: 8.97°, 10.75°, 13.51°, 15.51°, 16.20°, 17.88°, 18.05°, 18.56°, 19.94°, 20.94°, 21.25°, 22.67°, 25.07°, and 27.13°, with an error range of ±0.2° 2θ.

[0040] In some embodiments of the present invention, crystalline Form VIII has an X-ray powder diffraction pattern using Cu-Kα radiation, with characteristic peaks at 2θ values ​​of 8.97°, 10.75°, 13.51°, 15.51°, 16.20°, 17.88°, 18.05°, 18.56°, 19.94°, 20.94°, 21.25°, 22.67°, 25.07°, and 27.13°, with an error in 2θ of ±0.2°.

[0041] In some embodiments of the present invention, the crystalline form VIII has an X-ray powder diffraction pattern substantially as shown in FIG.

[0042] In some embodiments of the present invention, the crystalline form VIII has X-ray powder diffraction peak analysis data as shown in Table 3.

[0043] [Table 3]

[0044] In some embodiments of the present invention, the crystalline form VIII has a TGA-DSC pattern with endothermic peaks at 124±2°C, 179±2°C, and an exothermic peak at 128±2°C.

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

[0046] The present invention further provides crystalline form X of compound of formula (I), which has an X-ray powder diffraction pattern using Cu-Kα radiation having characteristic peaks at one, two, three, four, five, six, seven or eight of the following 2θ values: 11.61°, 15.66°, 17.49°, 18.36°, 19.51°, 21.28°, 23.60°, and 25.43°, with an error in 2θ of ±0.2°.

[0047] In some embodiments of the present invention, crystalline form X has an X-ray powder diffraction pattern using Cu-Kα radiation, with characteristic peaks at 2θ values ​​of 11.61°, 15.66°, 17.49°, 18.36°, 19.51°, 21.28°, 23.60°, and 25.43°, with an error range of 2θ of ±0.2°.

[0048] In some embodiments of the present invention, crystalline form X has an X-ray powder diffraction pattern using Cu-Kα radiation with characteristic peaks at one, two, three, four, five, six, seven, eight, nine, ten, or eleven of the following 2θ values: 11.61°, 14.07°, 14.70°, 15.66°, 17.49°, 18.36°, 18.54°, 19.51°, 21.28°, 23.60°, and 25.43°, with an error range of ±0.2° 2θ.

[0049] In some embodiments of the present invention, crystalline form X has an X-ray powder diffraction pattern using Cu-Kα radiation, with characteristic peaks at 2θ values ​​of 11.61°, 14.07°, 14.70°, 15.66°, 17.49°, 18.36°, 18.54°, 19.51°, 21.28°, 23.60°, and 25.43°, with an error in 2θ of ±0.2°.

[0050] In some embodiments of the present invention, crystalline form X has an X-ray powder diffraction pattern using Cu-Kα radiation with characteristic peaks at one, two, three, four, five, six, seven, eight, nine, ten, eleven, 12, 13, 14, 15, or 16 of the following 2θ values: 11.24°, 11.61°, 14.07°, 14.70°, 14.88°, 15.66°, 15.84°, 17.49°, 18.36°, 18.54°, 19.51°, 19.90°, 21.28°, 23.60°, 25.43°, and 27.67°, with an error range of ±0.2° 2θ.

[0051] In some embodiments of the present invention, crystalline form X has an X-ray powder diffraction pattern using Cu-Kα radiation, with characteristic peaks at 2θ values ​​of 11.24°, 11.61°, 14.07°, 14.70°, 14.88°, 15.66°, 15.84°, 17.49°, 18.36°, 18.54°, 19.51°, 19.90°, 21.28°, 23.60°, 25.43°, and 27.67°, with an error in 2θ of ±0.2°.

[0052] In some embodiments of the present invention, the crystalline form X has an X-ray powder diffraction pattern substantially as shown in FIG.

[0053] In some embodiments of the present invention, the crystalline form X has X-ray powder diffraction peak analysis data as shown in Table 4.

[0054] [Table 4]

[0055] In some embodiments of the present invention, the crystalline form X has an endothermic peak at 179±2° C. in a TGA-DSC pattern.

[0056] In some embodiments of the present invention, the crystalline form X has a TGA-DSC pattern substantially as shown in FIG.

[0057] The present invention further provides pharmaceutically acceptable salts of the compound of formula (I), 2-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxylate. [ka]

[0058] In some embodiments of the present invention, the pharmaceutically acceptable salt of the compound of Formula (I) is a sodium salt.

[0059] In some embodiments of the present invention, the pharmaceutically acceptable salt of the compound of Formula (I) is a sodium salt, having the following structure: [ka]

[0060] The present invention further provides a crystalline form of a pharmaceutically acceptable sodium salt of formula (I-1).

[0061] In some embodiments of the present invention, the crystalline form of the pharmaceutically acceptable sodium salt of Formula (I-1) is Form I, which has an X-ray powder diffraction pattern using Cu-Kα radiation having characteristic peaks at one, two, three, four, or five of the following 2θ values: 15.99°, 17.16°, 17.29°, 17.70°, and 23.24°, with an error range of 2θ of ±0.2°.

[0062] In some embodiments of the present invention, crystalline Form I has an X-ray powder diffraction pattern using Cu-Kα radiation, with characteristic peaks at 2θ values ​​of 15.99°, 17.16°, 17.29°, 17.70°, and 23.24°, with an error range of 2θ of ±0.2°.

[0063] In some embodiments of the present invention, crystalline Form I has an X-ray powder diffraction pattern using Cu-Kα radiation with characteristic peaks at one, two, three, four, five, six, seven, or eight of the following 2θ values: 8.99°, 15.99°, 17.16°, 17.29°, 17.70°, 21.39°, 22.92°, and 23.24°, with an error range of ±0.2° 2θ.

[0064] In some embodiments of the present invention, crystalline Form I has an X-ray powder diffraction pattern using Cu-Kα radiation, with characteristic peaks at 2θ values ​​of 8.99°, 15.99°, 17.16°, 17.29°, 17.70°, 21.39°, 22.92°, and 23.24°, with an error range of 2θ of ±0.2°.

[0065] In some embodiments of the present invention, crystalline Form I has an X-ray powder diffraction pattern using Cu-Kα radiation with characteristic peaks at one, two, three, four, five, six, seven, eight, nine, or ten of the following 2θ values: 8.99°, 12.92°, 15.99°, 17.16°, 17.29°, 17.70°, 20.98°, 21.39°, 22.92°, and 23.24°, with an error range of ±0.2° 2θ.

[0066] In some embodiments of the present invention, crystalline Form I has an X-ray powder diffraction pattern using Cu-Kα radiation, with characteristic peaks at 2θ values ​​of 8.99°, 12.92°, 15.99°, 17.16°, 17.29°, 17.70°, 20.98°, 21.39°, 22.92°, and 23.24°, with an error range of 2θ of ±0.2°.

[0067] In some embodiments of the present invention, the crystalline form I has an X-ray powder diffraction pattern substantially as shown in FIG.

[0068] In some embodiments of the present invention, the crystalline form I has X-ray powder diffraction peak analysis data as shown in Table 5.

[0069] [Table 5]

[0070] In some embodiments of the present invention, the crystalline form I has an exothermic peak at 241±2° C. in the TGA-DSC pattern.

[0071] In some embodiments of the present invention, the crystalline form I is characterized by a TGA-DSC pattern substantially as shown in FIG.

[0072] The present invention further provides a method for preparing the sodium salt compound of formula (I-1), the method comprising adding the compound of formula (I) to a solvent to dissolve it, filtering, and adding a solution of sodium ethoxide dropwise to form the salt.

[0073] In some embodiments of the present invention, the solvent used in the above salt-forming reaction is selected from organic solvents, preferably ethanol.

[0074] The present invention further provides a method for preparing crystalline Form I of the pharmaceutically acceptable sodium salt of formula (I-1), said method comprising: (a) adding and dissolving the compound of formula (I-1) in solvent 1; and (b) After filtration, the mixture is stirred at room temperature, and solvent 2 is gradually added dropwise to precipitate a solid.

[0075] In some embodiments of the present invention, Solvent 1 is selected from organic solvents, preferably tetrahydrofuran, and Solvent 2 is selected from organic solvents, preferably n-heptane or methyl isobutyl ketone.

[0076] The present invention further provides a pharmaceutical composition, which contains a pharmaceutically acceptable salt of the compound of formula (I) or any one of the above crystalline forms and one or more pharmaceutically acceptable carriers. Preferably, the pharmaceutically acceptable salt of the compound of formula (I) or any one of the above crystalline forms is in a therapeutically effective amount. The pharmaceutically acceptable salt of the compound of formula (I) or any one of the above crystalline forms according to the present invention may contain the pharmaceutically acceptable salt of the compound of formula (I) alone, or may contain two or more of the pharmaceutically acceptable salt of the compound of formula (I), or crystalline form IV, crystalline form VI, crystalline form VIII, crystalline form X, or crystalline form I.

[0077] The present invention further provides use of a pharmaceutically acceptable salt of the compound of formula (I), any one of the above crystalline forms, or a pharmaceutical composition containing any one of the above crystalline forms of the compound of formula (I), in the preparation of a medicament for treating and / or preventing a tumor. Any one of the above crystalline forms according to the present invention means the above crystalline form IV, crystalline form VI, crystalline form VIII, crystalline form X, or crystalline form I.

[0078] The present invention further provides a method for treating and / or preventing tumors, said method comprising administering to a patient a therapeutically and / or prophylactically effective amount of a pharmaceutically acceptable salt of the compound of formula (I), any one of the crystalline forms above.

[0079] In some embodiments of the present invention, in the above drug compositions, pharmaceutical uses and methods of treatment, said pharmaceutically acceptable salt is a sodium salt.

[0080] In some embodiments of the present invention, in the above drug compositions, pharmaceutical uses and methods of treatment, the pharmaceutically acceptable salt is a sodium salt and has the following structure: [ka]

[0081] In some embodiments of the present invention, the pharmaceutically acceptable sodium salt of formula (I-1) above is in a crystalline form.

[0082] In some embodiments of the present invention, the crystalline form of the pharmaceutically acceptable sodium salt of formula (I-1) above is crystalline form I.

[0083] In some embodiments of the present invention, the tumor formation is associated with PARP, preferably, the PARP is PARP7.

[0084] The crystalline form provided by the present invention has good chemical stability, physical stability and low hygroscopicity, and is therefore less affected by temperature, humidity and light irradiation, making it convenient for storage and formulation development. [Brief explanation of the drawings]

[0085] The drawings described herein are intended to provide a further understanding of the present invention and constitute a part of the present invention, and the illustrative embodiments of the present invention and the description thereof are intended to interpret the present invention and do not constitute an undue limitation of the present invention. [Figure 1] FIG. 1 is an XRPD pattern of crystalline Form IV of compound of formula (I). [Figure 2] FIG. 2 is a TGA-DSC pattern of crystalline Form IV of the compound of formula (I). [Figure 3] FIG. 3 is a DVS pattern of crystalline Form IV of the compound of formula (I). [Figure 4] FIG. 4 shows a comparison of the crystal form patterns of crystalline Form IV of the compound of formula (I) before and after DVS measurement. [Figure 5] FIG. 5 is an XRPD pattern of crystalline Form VI of compound of formula (I). [Figure 6] FIG. 6 is a TGA-DSC pattern of crystalline Form VI of the compound of formula (I). [Figure 7] FIG. 7 is an XRPD pattern of crystalline Form VIII of the compound of formula (I). [Figure 8]FIG. 8 is a TGA-DSC pattern of crystalline Form VIII of compound of formula (I). [Figure 9] FIG. 9 is an XRPD pattern of crystalline form X of compound of formula (I). [Figure 10] FIG. 10 is a TGA-DSC pattern of crystalline form X of compound of formula (I). [Figure 11] FIG. 11 is a DVS pattern of crystalline form X of compound of formula (I). [Figure 12] FIG. 12 shows the comparison patterns of crystalline form X of compound of formula (I) before and after DVS measurement. [Figure 13] FIG. 13 is an XRPD pattern of crystalline Form I of a pharmaceutically acceptable salt of the compound of formula (I). [Figure 14] FIG. 14 is a TGA-DSC pattern of crystalline Form I of a pharmaceutically acceptable salt of the compound of formula (I). [Figure 15] FIG. 15 is a DVS pattern of crystalline Form I of a pharmaceutically acceptable salt of the compound of formula (I). DETAILED DESCRIPTION OF THE INVENTION

[0086] The present invention will be described in detail below through examples, which are not intended to limit the present invention in any way. The compounds of the present invention include the specific embodiments described below, embodiments combined with other chemical synthesis methods, and equivalent alternative forms familiar to those skilled in the art, and preferred embodiments can be prepared by various synthesis methods familiar to those skilled in the art, including, but not limited to, the examples of the present invention. It will be apparent to those skilled in the art that various modifications and improvements can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention.

[0087] Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring under a dry nitrogen or argon atmosphere, the solvents are dry solvents, and the reaction temperatures are in degrees Celsius or °C. Unless otherwise specified, room temperature means 25±5°C.

[0088] Description and Definition Unless otherwise specified, the following terms and phrases used herein have the following meanings: A particular term or phrase, unless specifically defined, should not be considered indefinite or unclear, but should be understood according to its general meaning.

[0089] The term "composition" refers to a product containing predetermined amounts of ingredients and to a product produced directly or indirectly from a combination of predetermined amounts of each of the predetermined ingredients.

[0090] The term "pharmaceutically acceptable carrier" refers to a medium generally accepted in the art for delivering a bioactive agent to an animal, particularly a mammal, and includes, depending on the method of administration and the nature of the dosage form, for example, adjuvants, excipients or vehicles, such as diluents, preservatives, fillers, flow regulators, disintegrating agents, wetting agents, emulsifiers, suspending agents, sweeteners, flavorings, fragrances, antibacterial agents, antifungal agents, lubricants and dispersing agents. Pharmaceutically acceptable carriers are determined by many factors within the knowledge of those skilled in the art.

[0091] The term "therapeutically effective amount" means a sufficient amount of the compound of the present invention or its pharmaceutically acceptable salt to treat a disorder at a reasonable benefit / risk ratio appropriate for any medical treatment and / or prophylaxis. However, it should be understood that the total daily usage of the compound of formula (I) or its pharmaceutically acceptable salt and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. For any particular patient, the specific therapeutically effective dose level will depend on a variety of factors. Such factors include the disorder being treated and the severity of the disorder, the activity of the specific compound used, the specific composition used, the patient's age, weight, general health, sex, and diet, the administration time, route of administration, and excretion rate of the specific compound used, the duration of treatment, any medications used in combination with or simultaneously with the specific compound used, and similar factors well known in the medical field.

[0092] It is known in the art that X-ray powder diffraction patterns have one or more measurement errors depending on minute changes in measurement conditions. The structures of the crystals, crystals, or crystalline forms disclosed or claimed in the present invention may exhibit similar but not identical analytical properties within a reasonable error range, depending on the test conditions, purity, equipment, and other common variables known to those skilled in the art. For example, since the diffraction angle (2θ) in powder X-ray powder diffraction typically has an error within ±0.20°, the present invention includes not only crystals whose diffraction angles in powder X-ray powder diffraction are perfectly consistent, but also crystals whose diffraction angles are consistent within an error range of ±0.20°. The crystalline form of the compound of formula (I) of the present invention is not limited to crystals having the same X-ray powder diffraction pattern as the X-ray powder diffraction pattern shown in the drawings, but any crystals having substantially the same X-ray powder diffraction pattern as the X-ray powder diffraction pattern shown in the drawings are within the scope of the present invention.

[0093] In the present invention, the organic solvent includes an ester solvent or ester, an alcohol solvent or alcohol, an aliphatic hydrocarbon solvent or aliphatic hydrocarbon, a ketone solvent or ketone, and an ether solvent or ether.

[0094] In the present invention, examples of ester solvents or esters include, but are not limited to, dichloromethane, methyl acetate, ethyl acetate, n-propyl acetate, and isopropyl acetate.

[0095] In the present invention, examples of alcoholic solvents or alcohols include, but are not limited to, methanol, ethanol, propanol, isopropanol, and n-butanol.

[0096] In the present invention, aliphatic hydrocarbon solvents or aliphatic hydrocarbons include, but are not limited to, n-pentane, isopentane, n-hexane, n-heptane, and n-octane.

[0097] In the present invention, the ketone solvent or ketone includes, but is not limited to, acetone, methyl ethyl ketone, methyl butyl ketone, and methyl isobutyl ketone.

[0098] In the present invention, ethereal solvents or ethers include, but are not limited to, ethyl ether, isopropyl ether, ethylene oxide, and methyl t-butyl ether.

[0099] In the present invention, alcohol / aliphatic hydrocarbon means a mixed solvent of an alcohol solvent and an aliphatic hydrocarbon solvent.

[0100] In the present invention, the X-ray powder diffraction pattern of crystalline form IV has characteristic peaks at one, two, three, four or five of the 2θ values ​​14.12, 15.56, 17.32, 18.06 and 22.29, with a 2θ error range of ±0.2°, where one, two, three, four or five means that any one, two, three, four or five characteristic peaks are the same as those of crystalline form I.

[0101] With regard to "an X-ray powder diffraction pattern that is substantially the same as the X-ray powder diffraction pattern shown in the drawings" in the present invention, it should also be understood that the term "substantially the same" used in this context means that the 2θ angle values ​​in the X-ray powder diffraction pattern may vary slightly due to inherent experimental variations in these measurements, and that both are of the same crystalline form.

[0102] It should be understood that DSC patterns and endothermic transition temperature readings may vary slightly depending on the type of equipment or measurement conditions. DSC data can reflect changes in the morphology of a substance; a strong endothermic peak can indicate dehydration or desolvation, a change in crystalline form, or melting. When reflecting a molten state, the corresponding temperature is usually considered to be the melting point of the substance. This value is affected by the purity of the compound, sample weight, heating rate, particle size, and the calibration and maintenance of the measuring device. The temperature at which a substance transforms from a solid state to a liquid state is usually not a fixed point value but a temperature range. Therefore, those skilled in the art will understand that the onset value, peak value, or other reasonable value can all characterize the temperature corresponding to the endothermic peak or the melting point of a substance. The maximum endothermic transition temperature of a crystalline form may be within a range of ±5.0°C, preferably ±2.0°C, of ​​the specific value disclosed above.

[0103] The present invention further analyzes the relationship between the temperature and the degree of decomposition, sublimation, or evaporation (weight loss) of the crystalline form using thermogravimetric analysis (TGA). It should be understood that even for the same crystalline form, the obtained values ​​will have a certain error depending on the purity of the sample, particle size, different types of equipment, different measurement methods, etc. The temperature at which the crystalline form decomposes, sublimes, or evaporates may be within a range of ±3.0°C of the specific value disclosed above, for example, within a range of ±2.0°C.

[0104] The "stability" of a crystalline form includes "chemical stability" and / or "physical stability." "Chemical stability" refers to the degree to which this crystalline form undergoes a decomposition reaction under certain conditions of temperature, humidity, and light exposure, while "chemical stability" reflects the stability of this crystalline form under storage conditions. "Physical stability" refers to the degree to which this crystalline form undergoes a change in solid form under certain conditions, such as conversion to another crystalline form under conditions of high temperature, high humidity, grinding, tableting, desolvation, and solvent adsorption. "Physical stability" can, to some extent, reflect the stability of the crystalline form during use, such as in formulations.

[0105] Characteristics of hygroscopicity and definition of hygroscopic weight gain (Chinese Pharmacopoeia 2020 General Principle 9103 Guideline for Drug Hygroscopicity Testing): Deliquescent: Absorbs sufficient water to form a liquid. Extremely hygroscopic: Weight increase due to moisture absorption is 15.0% or more. Hygroscopic: Weight increase due to moisture absorption is less than 15.0% and more than 2.0%. Slightly hygroscopic: Weight increase due to moisture absorption is less than 2.0% and more than 0.2%. Not hygroscopic or only slightly hygroscopic: Weight increase due to moisture absorption is less than 0.2%.

[0106] Hygroscopicity directly affects the physical and chemical stability of drugs. High hygroscopicity is prone to chemical decomposition and changes in crystalline form. Furthermore, high hygroscopicity reduces the fluidity of drugs, thereby affecting the processing of drugs. Furthermore, drugs with high hygroscopicity require a low-humidity environment during production and storage, which increases production requirements and costs. More importantly, high hygroscopicity can easily change the content of active ingredients in drugs, affecting their quality.

[0107] During storage, transportation, and manufacturing, drug substances and drug products are exposed to high temperature and humidity conditions due to seasonal variations, regional climate differences, and weather factors. The good stability of crystalline forms is advantageous in avoiding adverse effects on drug quality when storage conditions deviate from those specified on the label.

[0108] Changes in crystalline form can alter drug absorption and affect bioavailability. Good chemical stability ensures that impurities are not substantially generated during storage. Good physical and chemical stability of the crystalline form ensures that the quality of the drug substance and drug product can be constantly controlled, and minimizes changes in drug quality, bioavailability, and toxic side effects caused by changes in crystalline form or the generation of impurities.

[0109] In the present invention, the "stirring" is carried out by a method conventional in the art, for example, using magnetic stirring or mechanical stirring, with a stirring speed of 50-1800 rpm, preferably 300-900 rpm for magnetic stirring, and preferably 100-300 rpm for mechanical stirring.

[0110] The "drying" is carried out at a temperature above room temperature. The drying temperature is from room temperature to about 60°C, or up to 50°C, or up to 40°C. The drying time may be 2-48 hours, or overnight. Drying is carried out in a fume hood, a blast oven, or a vacuum oven.

[0111] The crystalline structures of the present invention can be prepared by a variety of methods including crystallization or recrystallization from an appropriate solvent, sublimation, growth from the melt, solid state conversion from another phase, crystallization from supercritical fluids, jet spray, etc. Techniques for crystallization or recrystallization of the crystalline structure from a solvent mixture include evaporation of the solvent, lowering the temperature of the solvent mixture, seeding a supersaturated solvent mixture with the molecule and / or salt, freeze drying the solvent mixture, adding an anti-solvent to the solvent mixture, etc.

[0112] Reaction temperatures are in degrees Celsius or °C. Unless otherwise specified, room temperature means 25±5°C.

[0113] Unless otherwise specified, all references to formula (I), the compound of formula (I), or the free acid of the present invention refer to 2-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxylate. [ka]

[0114] Unless otherwise specified, the crystalline forms of the present invention all refer to crystalline forms of the sodium salt of the compound of formula (I), i.e., crystalline forms of formula (I-1). [ka]

[0115] The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments in combination with other chemical synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present invention.

[0116] In the examples of the present invention, the names of compounds have been converted from the compound structures by Chemdraw. If the compound names and compound structures are inconsistent, they can be confirmed by combining related information and reaction pathways, and if they cannot be confirmed by other methods, the structural formulas of the compounds shown will be used as the basis.

[0117] The preparation methods of some compounds in the present invention refer to the preparation methods of similar compounds mentioned above. Those skilled in the art should understand that when using or referring to the preparation methods mentioned above, the reactant loading ratio, reaction solvent, reaction temperature, etc. can be appropriately adjusted according to the reactants.

[0118] Equipment and analytical methods: 1. X-ray powder diffraction (XRPD) The solid sample was analyzed using a powder X-ray diffractometer (X'PerTPRO). An appropriate amount of fine powder of the sample was taken, placed in the groove of the sample holder, and pressed with a glass sheet to form a flat, dense surface. The XRPD measurement parameters were as shown in Table 6.

[0119] [Table 6] 2.Thermogravimetric analysis (TGA)

[0120] Thermogravimetric analysis was performed on the solids using a TA Instruments Thermogravimetric Analyzer. Approximately 1-5 mg of sample was placed in a tared aluminum sample pan, the sample was heated according to the parameters listed in Table 7, and the data was analyzed using TRIOS.

[0121] [Table 7] 3. Differential scanning calorimetry (DSC)

[0122] DSC analysis was performed on the solids using a TA Instrument Differential Scanning Calorimeter. Approximately 1-3 mg of sample was accurately weighed and placed in a perforated aluminum sample pan. The sample was heated according to the parameters listed in Table 8, and the data was analyzed using TA Universal Analysis.

[0123] [Table 8]

[0124] Alternatively, combined thermogravimetric and differential scanning calorimetry was performed on solids using a Mettler-Toledo simultaneous thermal analyzer. A spoon was used to place an appropriate amount of sample into a crucible, spread it evenly, weigh it, and heat the sample according to the parameters listed in Table 9. The data was analyzed using STARe.

[0125] [Table 9]

[0126] 4. Dynamic moisture sorption / desorption analysis (DVS) The moisture absorption of the samples was measured using a DVS Intrinsic Dynamic Moisture Sorption Apparatus. The sample was placed in a tared sample basket, and the instrument automatically weighed and analyzed the sample according to the parameters in Table 10.

[0127] [Table 10]

[0128] 5. Nuclear magnetic resonance hydrogen spectrum ( 1 H-NMR) NMR measurements were carried out using a Bruker AVANCE NEO 400 nuclear magnetic device, with deuterated dimethyl sulfoxide (DMSO-d6) as the measurement solvent.

[0129] 6. High-Performance Liquid Chromatography (HPLC) For HPLC measurements, high performance liquid chromatography analysis was performed on the samples using a Waters e2695 high performance liquid chromatograph.

[0130] 7. Karl Fischer titration (KF) measurement method: (1) Equipment Analytical balance (Sartorius, MSE125P), Karl Fischer moisture analyzer (Beijing Pioneer Weifeng Technology Co., Ltd., ZDJ400).

[0131] (2) Reagents and test solutions Water, Fisher's reagent, methanol.

[0132] (3) Operation steps Measurement was performed according to the moisture determination method (Chinese Pharmacopoeia, 2020 edition, Part 4, General Provisions 0832, Method 1, 1). Standardization: Take an appropriate amount of water, weigh it accurately, and perform standardization three times to determine the titer of the titrant used, and then perform back-standardization to check the recovery rate. The recovery rate should be within the range of 97.5%-102.5%. Detection: 0.1-0.2g of sample was weighed and added to a titration cup containing methanol, and the sample was measured after it was completely dissolved.

[0133] (4) Calculation formula: Water content (%) in sample = (A × F) / (W × 1000) × 100%. Where: A: Volume (mL) of Fisher's RT consumed by the sample. F: Weight (mg) of water equivalent per mL of Fisher's test solution. W: weight of sample (g).

[0134] 8. Gas Chromatography (GC) For GC measurements, samples were analyzed by gas chromatography using an Agilent gas chromatography system, Agilent 7890A / B-7697A.

[0135] The present invention will now be further described with reference to specific examples.

[0136] Example 1 Preparation of Compounds of Formula (I) 2-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxylate (compound of formula I) [ka]

[0137] Step A: Under nitrogen gas protection, activated zinc powder (0.8 g, 12 mmol) was added to dry tetrahydrofuran (20 mL) and t-butyl bromoacetate (1.5 g, 7.6 mmol) was added dropwise at reflux for 1 hour. 5-Bromo-2-methoxy-3-(trifluoromethyl)pyridine (300 mg, 1.2 mmol) was added to the reaction mixture, followed by catalytic amounts of tris(dibenzylideneacetone)dipalladium (Pd2(dba)3) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-Phos). The reaction mixture was then stirred at reflux overnight. After cooling to room temperature, the reaction mixture was quenched with water, the aqueous phase was extracted with ethyl acetate (100 ml x 3), and the combined organic phases were washed with saturated brine (30 ml x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 350 mg of t-butyl 2-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)acetate (3-2). MS(ESI)M / Z:292.1[M+H] + . 1H NMR (400MHz, CDCl3) δ8.18(d,J=2.2Hz,1H),7.82(d,J=2.4Hz,1H),4.03(s,3H),3.50(s,2H),1.45(s,9H).

[0138] Step B: t-Butyl 2-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)acetate (200 mg, 0.7 mmol) was dissolved in tetrahydrofuran (10 mL), lithium aluminum hydride (60 mg, 1.5 mmol) was added, and the reaction mixture was heated to reflux and stirred for 5 hours. After cooling to room temperature, the reaction mixture was quenched with saturated ammonium chloride solution, and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 104 mg of 2-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)ethan-1-ol (3-3). MS(ESI)M / Z:221.9[M+H] + .

[0139] Step C: 2-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)ethan-1-ol (75 mg, 0.34 mmol) was dissolved in N,N-dimethylformamide (2 mL). Bis(4-nitrophenyl)carbonate (206 mg, 0.68 mmol) and N,N-diisopropylethylamine (90 mg, 0.68 mmol) were added, and the reaction mixture was heated to 80 °C and stirred for 2 h. After cooling to room temperature, the reaction mixture was quenched with water and extracted with ethyl acetate (20 mL x 3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 130 mg of 2-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)ethyl(4-nitrophenyl)carbonate (3-4), which was used directly in the next reaction. MS(ESI)M / Z:386.9[M+H] + .

[0140] Step D: At room temperature, 2-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)ethyl(4-nitrophenyl)carbonate (130 mg, 0.34 mmol) was dissolved in N,N-dimethylformamide (2 mL), and 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine (80 mg, 0.34 mmol) and N,N-diisopropylethylamine (90 mg, 0.68 mmol) were added. The reaction mixture was heated to 80° C. and stirred for 2 hours. After cooling to room temperature, the reaction mixture was quenched by adding saturated ammonium chloride solution, the aqueous phase was extracted with dichloromethane (50 ml x 2), the organic phase was washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain 205 mg of 2-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)ethyl 4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxylate (3-5), which was used directly in the next reaction. MS(ESI)M / Z:480.2[M+H] + .

[0141] Step E: At room temperature, 2-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)ethyl 4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxylate (200 mg, 0.2 mmol) was dissolved in dichloromethane (5 mL). Then, iodotrimethylsilane (400 mg, 2 mmol) was added to the above solution under ice-water bath. The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with ice water under ice bath cooling, adjusted to pH 7-8 with saturated sodium bicarbonate solution, and then extracted with dichloromethane (20 ml x 3). The organic phase was washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to give 5.6 mg of 2-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxylate (compound of formula I). MS(ESI)M / Z:466.4[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ12.21(s,1H),8.73(s,2H),7.90(d,J=2.0Hz,1H),7.59(d,J=1.9H) z,1H),4.16(t,J=6.3Hz,2H),3.86-3.76(m,4H),3.48-3.41(m,4H),2.73(t,J=6.2Hz,2H).

[0142] Example 2 Preparation of Crystalline Form IV 700.2 mg of the compound of formula (I) was weighed into a reaction flask, 50 mL of n-heptane was added, and the mixture was stirred for 24 hours at 50° C. After filtration, the obtained solid was characterized by XRPD, TGA-DSC, and DVS, and the solid was found to be crystalline form IV, with an XRPD pattern substantially as shown in FIG.

[0143] The TGA-DSC pattern is shown in Figure 2. There was no obvious weight loss in the TGA, indicating that Form IV was anhydrous. The DSC results showed that Form IV had one endothermic peak at 175±2°C.

[0144] The DVS pattern is shown in Figure 3. Form IV showed a slight hygroscopicity, with a weight gain of 1.07% at 80% RH. Comparison of the XRPD patterns before and after DVS measurement showed no change in the crystalline form before and after DVS measurement, as shown in Figure 4.

[0145] Example 3 Preparation of Crystalline Form IV 50.0 mg of the compound of formula (I) was weighed into a vial, and 0.2 mL of 2-methyltetrahydrofuran was added thereto to dissolve the compound. The solution was then filtered into a new vial, and 2 mL of n-heptane was slowly added dropwise thereto to precipitate a solid, which was then filtered. The resulting solid was characterized by XRPD and TGA-DSC. The solid was found to be crystalline form IV, and its XRPD pattern was substantially as shown in FIG. 1.

[0146] Example 4 Preparation of Crystalline Form VI 10.6 mg of the compound of formula (I) was weighed into a vial, and 1.5 mL of acetone and 2.0 mL of water were added thereto. The mixture was heated to 50°C to dissolve the compound. After filtering into a new vial, the mixture was gradually cooled to 0°C to precipitate a solid. The obtained solid was characterized by XRPD and TGA-DSC. The solid was found to be crystalline form VI, and its XRPD pattern was substantially as shown in Figure 5.

[0147] The TGA-DSC pattern is shown in Figure 6. The TGA showed no obvious weight loss and one exothermic peak at 105±2°C, and upon continued heating to 175±2°C, one endothermic peak appeared, indicating that Form VI was anhydrous.

[0148] Example 5 Preparation of Crystalline Form VI 9.5 mg of the compound of formula (I) was weighed into a reaction flask, and 0.5 mL of acetonitrile and 1.0 mL of water were added thereto and stirred at room temperature for 5 days. After filtration, the resulting solid was characterized by XRPD, and the solid was found to be crystalline form VI, with an XRPD pattern substantially as shown in Figure 5.

[0149] Example 6 Preparation of Crystalline Form VI 10.3 mg of compound of formula (I) was weighed into a vial, dissolved in 1.5 mL of acetone and 2.0 mL of water at 35°C, filtered, and then gradually cooled to 5°C and stirred for 1 hour. The solid was filtered and dried under vacuum at 50°C for 4 hours. The resulting solid was characterized by XRPD and TGA-DSC. The XRPD results indicated that it was crystalline form VI. The XRPD pattern was substantially as shown in Figure 5.

[0150] The TGA-DSC pattern is shown in Figure 6. In TGA, there was a 1.56% weight loss between 35°C and 117°C, but no corresponding endothermic peak, indicating that this process was due to the desorption of surface solvent and that Form VI was an anhydrous product. DSC results showed that the TGA-DSC pattern of the crystalline form had an exothermic peak at 105±2°C and an endothermic peak at 177±2°C.

[0151] Example 7 Preparation of Crystalline Form VIII 10.7 mg of the compound of formula (I) was weighed, dissolved in 1.0 mL of dichloromethane, and filtered into a vial. 4.0 mL of n-heptane was slowly added dropwise thereto to precipitate a solid. After filtration, the solid was characterized by XRPD and TGA-DSC. The XRPD pattern was substantially as shown in Figure 7, and the resulting solid was identified as crystalline form VIII. The TGA-DSC pattern is shown in Figure 8. There is no obvious weight loss in the TGA, and the DSC pattern has endothermic peaks at 124±2°C and 179±2°C, and an exothermic peak at 128±2°C.

[0152] Example 8 Preparation of Crystalline Form X 10.2 mg of crystalline form I of compound of formula (I) was weighed, added with 1.0 mL of ethanol, triturated at room temperature for 5 days, filtered, and the resulting solid was characterized by XRPD, TGA-DSC and DVS, and was found to be crystalline form X, with an XRPD pattern substantially as shown in Figure 9. The TGA-DSC pattern is substantially as shown in Figure 10. There was no obvious weight loss in the TGA, indicating that Form X was anhydrous. The DSC results showed that Form X had an endothermic peak at 179±2°C. The DVS pattern is shown in Figure 11. The weight gain at 80% RH was 1.4%, indicating slight hygroscopicity. A comparison of the XRPD before and after DVS measurement is shown in Figure 12. No change in the crystal form occurred before and after DVS measurement.

[0153] Example 9 Preparation of the sodium salt compound of formula (I-1) 1.0 g of compound of formula (I) was weighed out, dissolved in 1.8 mL of absolute ethanol at 70°C, filtered, and 1.05 eq of sodium ethoxide solution was added dropwise to form a salt. The reaction was allowed to proceed for 30 minutes, followed by suction filtration and drying at 50°C for 2 hours to obtain the sodium salt compound of formula (I-1).

[0154] Example 10 Preparation of Crystalline Form I 10.5 mg of the compound of formula (I-1) was weighed into a reaction flask, 0.1 mL of tetrahydrofuran was added, and the mixture was stirred at room temperature to dissolve. After filtration, 0.4 mL of n-heptane was slowly added dropwise to the solution to precipitate a solid, which was then centrifuged and dried. The obtained solid was characterized by XRPD, TGA-DSC, and DVS. The solid was found to be crystalline form I, and its XRPD pattern was substantially as shown in Figure 13. The TGA-DSC pattern is shown in Figure 14. There was no obvious weight loss in the TGA, indicating that Form I was anhydrous, and the DSC results showed that Form I had one exothermic peak at 241±2°C. The DVS pattern is shown in Figure 15. Form I is hygroscopic, with a weight gain of 13.29% at 80% RH.

[0155] Example 11 Preparation of Crystalline Form I 10.3 mg of compound of formula (I) was weighed into a vial, dissolved in 0.1 mL of tetrahydrofuran, and filtered into a new vial. 0.4 mL of methyl isobutyl ketone was slowly added dropwise thereto, and a solid precipitated, which was then filtered. The resulting solid was characterized by XRPD and TGA-DSC. The solid was found to be crystalline form I, and its XRPD pattern was substantially as shown in Figure 13.

[0156] Example 12 Influence factor experiment The stability of crystalline Form IV of compound of formula (I) under different temperatures and humidity conditions was investigated in accordance with the "Guidelines for Stability Testing of Drug Substances and Preparations" in the 2020 edition of the Chinese Pharmacopoeia. On days 0, 2, and 7, the purity was measured by HPLC and the crystalline form was measured by XRPD. The experimental results are shown in Table 11.

[0157] [Table 11]

[0158] Conclusion: Crystalline Form IV is stable in both physical and chemical properties under high temperature and humidity conditions.

[0159] The stability of the sodium salt crystalline Form I of compound of formula (I) under different temperatures and humidity conditions was examined in accordance with the "Guidelines for Stability Testing of Drug Substances and Formulations" in the 2020 edition of the Chinese Pharmacopoeia. On days 0, 5, and 10, the purity was measured by HPLC and the crystalline form was measured by XRPD. The experimental results are shown in Table 12.

[0160] [Table 12]

[0161] Conclusion: Form I has stable physical and chemical properties at high temperature, but the form changes under high humidity conditions.

[0162] Example 13 Hygroscopicity Experiment The moisture adsorption / desorption data for Form IV of compound of formula (I) was measured according to the "Guidelines for Drug Hygroscopicity Testing" in the 2020 edition of the Chinese Pharmacopoeia. The DVS curve for Form IV is shown in Figure 3, and its hygroscopicity data is shown in Table 13. After the DVS experiment, the residual solid was analyzed by XRPD, and Form IV remained unchanged, as shown in Figure 4.

[0163] [Table 13]

[0164] Conclusion: Hygroscopicity experiments showed that crystalline Form IV is slightly hygroscopic.

[0165] The moisture adsorption / desorption data of crystalline Form I of the sodium salt of compound of formula (I) was measured in accordance with the "Guidelines for Drug Hygroscopicity Testing" in the 2020 edition of the Chinese Pharmacopoeia. The DVS curve of crystalline Form I is shown in Figure 1, and its hygroscopicity data is shown in Table 14.

[0166] [Table 14] Conclusion: The hygroscopicity experiment showed that crystalline form I is slightly hygroscopic.

[0167] Biological Test Evaluation: 1. PARP7 in vitro enzymatic experiment This experiment detects the inhibitory effect of compounds of formula (I) on PARP7 enzyme activity. Test compounds were diluted in a gradient and detected in duplicate.

[0168] 1. A histone-coated 384-well plate was prepared, and 25 μL of histone solution was added to each well and incubated at 4°C overnight.

[0169] 2. PBST buffer, blocking buffer and detection buffer were prepared.

[0170] 3. The histone-coated 384-well plate was washed three times with PBST buffer. 50 μL of blocking buffer was added for 1 hour at room temperature. The plate was then washed three times with PBST buffer.

[0171] 4. Compound Preparation: A 96-well source plate was prepared with 2000x compounds. 50 nL of compound was transferred from the source plate to a 96-well intermediate plate, and each well was supplemented with 39.95 μL of detection buffer. The plate was shaken until homogenous and centrifuged at 1000 rpm for 1 minute. 5 μL of compound in DMSO was transferred to each well.

[0172] 5. Enzyme reaction: The enzyme mixture was incubated at 25°C for 10 minutes. 10 μL of the enzyme mixture was added and incubated with the compounds for 10 minutes at room temperature. 10 μL of detection buffer was added to the negative control wells of the detection plate. 10 μL of 2.5×Biotin-NAD+ was added to each well, and the mixture was incubated at 25° C. for 60 minutes. The plate was washed three times with PBST buffer.

[0173] 6. Detection: 25 μL of Stre-HRP was added. After incubation at room temperature for 1 hour, the plate was washed three times with PBS buffer. 25 μL of QuantaRedEnhancermix was added and incubated for 10 minutes. 2.5 μL of QuantaRedStopSolution was added to stop the peroxidase reaction, and the plate was shaken for 10-30 seconds.

[0174] 7. The plate was read immediately using a Paradigm to detect the Ex550 / Em620 readings.

[0175] 8. Data Processing The data was fitted in Excel using equation (1) to obtain inhibition values. Formula (1): Inhibition rate % = (maximum signal value - target signal value) / (maximum signal value - minimum signal value) × 100%. Equation (2) was used to fit the data in XL-Fit and calculate the IC 50 got the value. Equation (2): Y=Bottom+(Top-Bottom) / (1+(IC 50 / X)×HillSlope). Y is the percentage inhibition and X is the concentration of the compound.

[0176] Experimental results [Table 15] Conclusion: The compound of formula (I) can effectively inhibit PARP7 enzyme activity.

[0177] II. In vivo pharmacokinetics in mice and rats 1. Purpose of the experiment: Male C57BL / 6 mice or SD male rats were used as test animals to study the pharmacokinetic behavior of the compounds of the present invention in plasma in vivo after a single intravenous bolus injection and oral administration.

[0178] 2. Test Plan 2.1 Test animals Healthy adult C57BL / 6 mice or SD rats (3 per group), male, were used. They were supplied by Shanghai Jihui Laboratory Animal Husbandry Co., Ltd. and Weitong Lihua Laboratory Animal Technology Co., Ltd.

[0179] 2.2 Administration The intravenous bolus injection and oral administration groups consisted of three mice or rats each. The intravenous bolus dose was 1 mg / kg in a volume of 5 mL / kg, and the oral dose was 5 mg / kg in a volume of 10 mL / kg. The administration vehicle was 5% DMSO, 5% Kolliphor HS15, and 90% saline. The structure of the comparative compound RBN-2397 is as follows: [ka]

[0180] 2.3 Experimental equipment The centrifuge was purchased from Eppendorf, and the pipettes were purchased from Eppendorf.

[0181] 2.4 Sample collection After administration to the animals, 0.0833 (IV), 0.25, 0.5, 1, 2, 4, 8, and 24 hours later, 0.02 mL of venous blood was collected, placed in EDTA-K2 tubes, centrifuged at 4°C, 4600 rpm for 5 minutes to separate plasma, and stored at -80°C.

[0182] 2.5 Sample processing 1) 10 μL of plasma sample was precipitated by adding 200 μL of acetonitrile, mixed by vortexing, and then centrifuged for 15 minutes. 2) After treatment, the supernatant was collected and diluted with water, and then the concentration of the test compound was analyzed by LC / MS / MS.

[0183] 2.6 Biological analysis Liquid phase conditions: Shimadzu LC-30AD Mass spectrometry conditions: AB Sciex API 5500 Column: Phenomenex Kinetex 2.6 μm C18 Mobile phase: A: 5 mM ammonium acetate aqueous solution (containing 0.05 vol% formic acid), B: acetonitrile (containing 0.1 vol% formic acid). Flow rate: 0.5 mL / min. The elution gradient is shown in Table 16.

[0184] [Table 16]

[0185] Experimental Results and Analysis Pharmacokinetic parameters were calculated using WinNonlin 8.0, and the pharmacokinetic parameters for intravenous injection and oral administration to mice or rats are shown in Tables 17 and 18. Dose is the dose, CL is the plasma clearance, Vss is the drug distribution volume, and T 1 / 2 is the half-life of the drug, AUC is the area under the drug blood concentration-time curve, C max represents the peak drug concentration, and F represents the bioavailability.

[0186] [Table 17]

[0187] [Table 18]

[0188] Conclusion: At the same dose, the exposure of the compound of formula (I) of the present invention in the plasma of mice and rats after intravenous bolus injection and oral administration was significantly higher than that of the comparative compound RBN-2397.

[0189] The above are only preferred embodiments of the present invention, and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included in the scope of protection of the present invention.

Claims

1. Crystalline Form IV of the compound of formula (I), 【Chemistry 1】 Crystalline Form IV, characterized in that the X-ray powder diffraction pattern of said crystalline Form IV using Cu-Kα radiation has characteristic peaks at 2θ values ​​of 14.13°, 15.56°, 17.33°, 18.07°, and 22.30°, with an error range of 2θ of ±0.2°.

2. 2. The crystalline form IV of claim 1, characterized in that the X-ray powder diffraction pattern of the crystalline form IV using Cu-Kα radiation has characteristic peaks at 2θ values ​​of 14.13°, 14.46°, 15.56°, 17.02°, 17.33°, 18.07°, 19.17°, and 22.30°, with an error range of 2θ of ±0.2°.

3. 3. The crystalline form IV of claim 2, characterized in that the X-ray powder diffraction pattern of the crystalline form IV using Cu-Kα radiation has characteristic peaks at 2θ values ​​of 7.25°, 10.00°, 14.13°, 14.46°, 15.56°, 17.02°, 17.33°, 18.07°, 19.17°, and 22.30° with an error range of 2θ of ±0.2°.

4. 4. The crystalline form IV of claim 3, characterized in that the X-ray powder diffraction pattern of said crystalline form IV is substantially as shown in Figure 1.

5. The crystalline form IV according to any one of claims 1 to 4, characterized in that the TGA-DSC pattern of the crystalline form IV has an endothermic peak at 175±2°C.

6. 6. The crystalline form IV according to any one of claims 1 to 5, characterized in that the TGA-DSC pattern of said crystalline form IV is substantially as shown in Figure 2.

7. Crystalline Form VI of the compound of formula (I), 【Chemistry 2】 Crystalline Form VI, characterized in that the X-ray powder diffraction pattern of said crystalline Form VI using Cu-Kα radiation has characteristic peaks at 2θ values ​​of 5.20°, 7.49°, 10.70°, 13.42°, 14.30°, 14.85°, 16.01°, and 18.66°, with an error range of 2θ of ±0.2°.

8. 8. Crystalline Form VI according to claim 7, characterized in that the X-ray powder diffraction pattern of said crystalline Form VI using Cu-Kα radiation has characteristic peaks at 2θ values ​​of 5.20°, 7.49°, 7.95°, 9.70°, 10.70°, 11.53°, 13.05°, 13.42°, 14.30°, 14.85°, 16.01°, 16.38°, 17.11°, and 18.66°, with an error range of 2θ of ±0.2°.

9. 9. Crystalline Form VI according to claim 8, characterized in that the X-ray powder diffraction pattern of said crystalline Form VI using Cu-Kα radiation has characteristic peaks at 2θ values ​​of 5.20°, 6.68°, 7.49°, 7.95°, 9.70°, 10.70°, 11.53°, 13.05°, 13.42°, 13.67°, 14.30°, 14.85°, 16.01°, 16.38°, 17.11°, 18.66°, 19.37°, 23.44°, and 24.36°, with an error range of 2θ of ±0.2°.

10. 10. The crystalline form VI of claim 9, wherein the X-ray powder diffraction pattern of said crystalline form VI is substantially as shown in Figure 5.

11. 11. The crystalline form VI according to any one of claims 7 to 10, wherein the TGA-DSC pattern of the crystalline form VI has an exothermic peak at 105±2°C and an endothermic peak at 177±2°C.

12. 12. Crystalline form VI according to any one of claims 7 to 11, characterized in that the TGA-DSC pattern of said crystalline form VI is substantially as shown in Figure 6.

13. Crystalline Form VIII of the compound of formula (I), 【Transformation 3】 Crystalline Form VIII, wherein the X-ray powder diffraction pattern of said crystalline Form VIII using Cu-Kα radiation has characteristic peaks at 2θ values ​​of 8.97°, 13.51°, 16.20°, 18.05°, 18.56°, 20.94°, and 21.25°, with an error range of 2θ of ±0.2°.

14. 14. Crystalline Form VIII according to claim 13, characterized in that the X-ray powder diffraction pattern of said crystalline Form VIII using Cu-Kα radiation has characteristic peaks at 2θ values ​​of 8.97°, 13.51°, 15.51°, 16.20°, 18.05°, 18.56°, 19.94°, 20.94°, 21.25°, and 27.13°, with an error range of 2θ of ±0.2°.

15. 15. Crystalline Form VIII according to claim 14, characterized in that the X-ray powder diffraction pattern of said crystalline Form VIII using Cu-Kα radiation has characteristic peaks at 2θ values ​​of 8.97°, 10.75°, 13.51°, 15.51°, 16.20°, 17.88°, 18.05°, 18.56°, 19.94°, 20.94°, 21.25°, 22.67°, 25.07°, and 27.13°, with an error range of 2θ of ±0.2°.

16. 16. The crystalline form VIII of claim 15, wherein the X-ray powder diffraction pattern of said crystalline form VIII is substantially as shown in Figure 7.

17. 17. The crystalline form VIII of any one of claims 13 to 16, wherein the TGA-DSC pattern of the crystalline form VIII has endothermic peaks at 124±2°C and 179±2°C, and an exothermic peak at 128±2°C.

18. 18. Crystalline Form VIII according to any one of claims 13 to 17, characterized in that the TGA-DSC pattern of said crystalline Form VIII is substantially as shown in Figure 8.

19. Crystalline form X of compound of formula (I), 【Chemistry 4】 The X-ray powder diffraction pattern of the crystalline form X using Cu-Kα radiation has characteristic peaks at 2θ values ​​of 11.61°, 15.66°, 17.49°, 18.36°, 19.51°, 21.28°, 23.60°, and 25.43°, with an error range of 2θ of ±0.2°.

20. 20. The crystalline form X of claim 19, wherein the X-ray powder diffraction pattern of the crystalline form X using Cu-Kα radiation has characteristic peaks at 2θ values ​​of 11.61°, 14.07°, 14.70°, 15.66°, 17.49°, 18.36°, 18.54°, 19.51°, 21.28°, 23.60°, and 25.43°, with an error range of 2θ of ±0.2°.

21. 21. The crystalline form X of claim 20, wherein the X-ray powder diffraction pattern of the crystalline form X using Cu-Kα radiation has characteristic peaks at 2θ values ​​of 11.24°, 11.61°, 14.07°, 14.70°, 14.88°, 15.66°, 15.84°, 17.49°, 18.36°, 18.54°, 19.51°, 19.90°, 21.28°, 23.60°, 25.43°, and 27.67°, with an error range of 2θ of ±0.2°.

22. 22. The crystalline form X of claim 21, wherein the X-ray powder diffraction pattern of the crystalline form X is substantially as shown in Figure 9.

23. The crystalline form X according to any one of claims 19 to 22, characterized in that the TGA-DSC pattern of the crystalline form X has an endothermic peak at 179±2°C.

24. 24. The crystalline form X of any one of claims 19 to 23, wherein the TGA-DSC pattern of the crystalline form X is substantially as shown in Figure 10. 【Request Item 25】 【Chemistry 5】 A pharmaceutically acceptable salt of a compound of formula (I). 【Request Item 26】 【Chemistry 6】 26. A pharmaceutically acceptable salt of a compound of formula (I) according to claim 25, characterized in that it has the structure:

27. 27. Crystalline Form I of the pharmaceutically acceptable salt of compound of formula (I) according to claim 25 or 26, characterized in that the X-ray powder diffraction pattern of said crystalline Form I using Cu-Kα radiation has characteristic peaks at 2θ values ​​of 15.99°, 17.16°, 17.29°, 17.70° and 23.24°, with an error range of 2θ of ±0.2°.

28. 28. Crystalline Form I according to claim 27, characterized in that the X-ray powder diffraction pattern of said crystalline Form I using Cu-Kα radiation has characteristic peaks at 2θ values ​​of 8.99°, 15.99°, 17.16°, 17.29°, 17.70°, 21.39°, 22.92°, and 23.24°, with an error range of 2θ of ±0.2°.

29. 29. Crystalline Form I according to claim 28, characterized in that the X-ray powder diffraction pattern of said crystalline Form I using Cu-Kα radiation has characteristic peaks at 2θ values ​​of 8.99°, 12.92°, 15.99°, 17.16°, 17.29°, 17.70°, 20.98°, 21.39°, 22.92°, and 23.24°, with an error range of 2θ of ±0.2°.

30. 30. Crystalline Form I according to claim 29, characterized in that the X-ray powder diffraction pattern of said crystalline Form I using Cu-Kα radiation is substantially as shown in Figure 13.

31. 31. The crystalline form I of any one of claims 27-30, wherein the TGA-DSC pattern of the crystalline form I has an exothermic peak at 241±2°C.

32. 32. Crystalline Form I according to any one of claims 27-31, characterized in that the TGA-DSC pattern of said crystalline form I is substantially as shown in Figure 14.

33. 32. A pharmaceutical composition comprising crystalline form IV according to any one of claims 1-6, crystalline form VI according to any one of claims 7-12, crystalline form VIII according to any one of claims 13-18, crystalline form X according to any one of claims 19-24, a pharmaceutically acceptable salt of the compound of formula (I) according to claim 25 or 26, or crystalline form I according to any one of claims 27-32, and one or more pharmaceutically acceptable carriers.

34. Use of crystalline form IV according to any one of claims 1-6, crystalline form VI according to any one of claims 7-12, crystalline form VIII according to any one of claims 13-18, crystalline form X according to any one of claims 19-24, a pharmaceutically acceptable salt of the compound of formula (I) according to claim 25 or 26, crystalline form I according to any one of claims 27-32, or a pharmaceutical composition according to claim 33 in the preparation of a medicament for the treatment and / or prevention of tumors.

35. 35. The use according to claim 34, characterized in that the formation of the tumor is associated with PARP, preferably the PARP is PARP7.

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