Crystal forms and uses of PARP7 inhibitor and salt thereof

Abstract

The present invention relates to a crystalline form of a compound of formula (I) as a PARP7 inhibitor, a crystalline form of a pharmaceutically acceptable salt of the compound of formula (I), and use thereof in the preparation of medicaments for the treatment of related diseases. # imgabs0 #

Description

PARP7 inhibitors and their crystal forms and applications

[0001] This application claims priority to the Chinese patent application filed with the Patent Office of China on January 28, 2023, with application number 202310072130.5 and invention name “Crystal form of PARP7 inhibitor and preparation method thereof”, and the Chinese patent application filed with the Patent Office of China on January 28, 2023, with application number CN202310072098.0 and invention name “Salt, crystal form and preparation method of PARP7 inhibitor”, the entire contents of which are incorporated into this application by reference. Technical Field

[0002] The present application belongs to the field of medicinal chemistry, and specifically relates to a PARP7 inhibitor and a crystal form and application of its salt. Background Art

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

[0004] The 17 members of the PARP family were identified in the human genome based on homology within the catalytic domain. However, based on differences in activity, they are divided into three subfamilies: polyPARPs, monoPARPs, and inactive ones (S. Vyas et al., Family-wide analysis of poly(ADP-ribose) polymerase activity. Nat Commun 5, 4426 (2014)). Most PARP family members catalyze the transfer of a single (ADP-ribose) unit on their substrate (MonoPARPs), while other members (PARP1, PARP2, TNKS, TNKS2) catalyze the transfer of poly(ADP-ribose) units on their substrate (PolyPARPs). PARP13 is the only PARP to date that has not shown catalytic activity in vitro or in vivo. The above-mentioned MonoPARPs modify their targets through a single ADP-ribose unit to regulate signal transduction pathways, a process similar to kinase phosphorylation. These polyPARPs modify their protein targets with large, branched polymers called poly(ADP-ribose). These bulky, highly charged attachments form a protein scaffold that directs proteins to perform their functions at specific sites within cells.

[0005] PARP1, a member of the PARP family, has been shown to be a potent cancer target, linked to DNA damage-induced cellular stress, triggered by genetic mutations or cytotoxic chemotherapy. Four drugs have been approved for this target, 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 histological cancers. Genome-wide association studies have identified ovarian cancer susceptibility genes, suggesting a role for PARP7 in this cancer type (EL Goode et al., A genome-wide association study identifies susceptibility loci for ovarian cancer at 2q31 and 8q24. Nat Genet 42, 874-879 (2010)). PARP7 has multiple cellular functions. Under AHR signaling, PARP7 acts as a negative feedback mechanism to regulate the expression of P4501A1 and P4501B1. PARP7 has also been described to ADP-ribosylate liver X receptors, leading to regulation of their 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 to promote viral RNA degradation. In addition, in the context of viral infection, AHR-induced PARP7 can interact with TBK1, a major 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 ADP-ribosylate TBK1, preventing TBK1 activation and thereby inhibiting the type I interferon response.

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

[0008] Summary of the Invention

[0009] The present application provides a crystalline form of the compound of formula (I), a salt of the compound of formula (I) and a crystalline form thereof, and uses thereof.

[0010] The first aspect of the present application provides a crystalline form IV of a compound of formula (I), using Cu-K α Radiation, its X-ray powder diffraction pattern has characteristic peaks at 1, 2, 3, 4 or 5 of the 2θ values ​​of 14.13°, 15.56°, 17.33°, 18.07°, 22.30°, and the 2θ error range is ±0.2°.

[0011] In some embodiments of the present application, the crystal form IV is formed using Cu-K α Radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 14.13°, 15.56°, 17.33°, 18.07°, and 22.30°, and the 2θ error range is ±0.2°.

[0012] In some embodiments of the present application, the crystal form IV is formed using Cu-K α Radiation, its X-ray powder diffraction pattern has characteristic peaks at 1, 2, 3, 4, 5, 6, 7 and 8 among the 2θ values ​​of 14.13°, 14.46°, 15.56°, 17.02°, 17.33°, 18.07°, 19.17° and 22.30°, and the 2θ error range is ±0.2°.

[0013] In some embodiments of the present application, the crystal form IV is formed using Cu-K α Radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 14.13°, 14.46°, 15.56°, 17.02°, 17.33°, 18.07°, 19.17°, and 22.30°, and the 2θ error range is ±0.2°.

[0014] In some embodiments of the present application, the crystal form IV is formed using Cu-K α Radiation, its X-ray powder diffraction pattern has characteristic peaks at 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 of the 2θ values ​​of 7.25°, 10.00°, 14.13°, 14.46°, 15.56°, 17.02°, 17.33°, 18.07°, 19.17°, 22.30°, and the 2θ error range is ±0.2°.

[0015] In some embodiments of the present application, the crystal form IV is formed using Cu-K αRadiation, its X-ray powder diffraction pattern 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°, and the 2θ error range is ±0.2°.

[0016] In some embodiments of the present application, the X-ray powder diffraction pattern of the crystalline form IV is substantially as shown in FIG1 .

[0017] In some embodiments of the present application, the X-ray powder diffraction peak analysis data of the crystalline form IV are shown in Table 1.

[0018] Table 1 XRPD diffraction peak analysis data of Form IV of the compound of formula (I)

[0019] In some embodiments of the present application, the crystal form IV has a TGA-DSC spectrum with an endothermic peak at 175±2°C.

[0020] In some embodiments of the present application, the crystalline form IV is characterized by having a TGA-DSC spectrum substantially as shown in FIG2 .

[0021] The present application also provides a method for preparing the crystalline form IV of the compound of formula (I), comprising:

[0022] (a) adding the compound of formula (I) to a solvent and heating and stirring;

[0023] (b) Filtration to obtain a solid.

[0024] Wherein, the solvent is selected from an organic solvent, preferably n-heptane; the temperature of the heating and stirring is 40°C-60°C, preferably 50°C.

[0025] The present application also provides another method for preparing the crystalline form IV of the compound of formula (I), comprising:

[0026] (a) adding the compound of formula (I) into a solvent and dissolving it;

[0027] (b) After filtration, n-heptane was slowly added dropwise to precipitate a solid.

[0028] Wherein, the solvent is selected from organic solvents, preferably 2-methyltetrahydrofuran.

[0029] The second aspect of the present application provides a crystalline form VI of a compound of formula (I), using Cu-K αRadiation, its X-ray powder diffraction pattern has characteristic peaks at 1, 2, 3, 4, 5, 6, 7 or 8 of the 2θ values ​​of 5.20°, 7.49°, 10.70°, 13.42°, 14.30°, 14.85°, 16.01°, 18.66°, and the 2θ error range is ±0.2°.

[0030] In some embodiments of the present application, the crystal form VI is formed using Cu-K α Radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 5.20°, 7.49°, 10.70°, 13.42°, 14.30°, 14.85°, 16.01°, and 18.66°, and the 2θ error range is ±0.2°.

[0031] In some embodiments of the present application, the crystal form VI is formed using Cu-K α Radiation, its X-ray powder diffraction pattern has characteristic peaks at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 of 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°, 18.66°, and the 2θ error range is ±0.2°. In some embodiments of the present application, the crystal form VI, using Cu-K α Radiation, its X-ray powder diffraction pattern 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°, and the 2θ error range is ±0.2°.

[0032] In some embodiments of the present application, the crystal form VI is prepared using Cu-K α Radiation, its X-ray powder diffraction pattern has characteristic peaks at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19 of 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°, and the 2θ error range is ±0.2°.

[0033] In some embodiments of the present application, the crystal form VI is prepared using Cu-K α Radiation, its X-ray powder diffraction pattern 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°, and the 2θ error range is ±0.2°.

[0034] In some embodiments of the present application, the X-ray powder diffraction pattern of the crystalline form VI is substantially as shown in FIG5 .

[0035] In some embodiments of the present application, the X-ray powder diffraction peak analysis data of the crystalline form VI are shown in Table 2.

[0036] Table 2 XRPD diffraction peak analysis data of Form VI of Formula (I)

[0037] In some embodiments of the present application, the crystal form VI has a TGA-DSC spectrum with an exothermic peak at 105±2°C and an endothermic peak at 177±2°C.

[0038] In some embodiments of the present application, the TGA-DSC spectrum of the crystalline form VI is substantially as shown in FIG6 .

[0039] The present application also provides a method for preparing the crystalline form VI of the compound of formula (I), comprising:

[0040] (a) dissolving the compound of formula (I) in a solvent at elevated temperature;

[0041] (b) After filtration, the temperature was slowly lowered to precipitate a solid.

[0042] The solvent is selected from any one of methanol, acetonitrile, acetone, and water, or a combination thereof; and the temperature for heating and dissolving is selected from 40° C. to 60° C., preferably 50° C.

[0043] The present application also provides another method for preparing the crystalline form VI of the compound of formula (I), comprising:

[0044] (a) stirring the compound of formula (I) in a solvent at room temperature;

[0045] (b) A solid was obtained after filtration.

[0046] Wherein, the solvent is selected from any one of methanol, acetonitrile, acetone, water or a combination thereof.

[0047] The present application also provides another method for preparing the crystalline form VI of the compound of formula (I), comprising:

[0048] (a) dissolving the compound of formula (I) in a solvent;

[0049] (b) slowly cooling after filtration and keeping warm with stirring;

[0050] (c) Filter and dry in vacuum.

[0051] Wherein, the solvent is selected from any one of methanol, acetonitrile, acetone, water or a combination thereof.

[0052] The present application also provides a crystalline form VIII of the compound of formula (I), using Cu-K α Radiation, its X-ray powder diffraction pattern has characteristic peaks at 1, 2, 3, 4, 5, 6 or 7 of the 2θ values ​​of 8.97°, 13.51°, 16.20°, 18.05°, 18.56°, 20.94°, 21.25°, and the 2θ error range is ±0.2°.

[0053] In some embodiments of the present application, the crystal form VIII is prepared using Cu-K α Radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 8.97°, 13.51°, 16.20°, 18.05°, 18.56°, 20.94°, and 21.25°, and the 2θ error range is ±0.2°.

[0054] In some embodiments of the present application, the crystal form VIII is prepared using Cu-K α Radiation, its X-ray powder diffraction pattern has characteristic peaks at 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 of the 2θ values ​​of 8.97°, 13.51°, 15.51°, 16.20°, 18.05°, 18.56°, 19.94°, 20.94°, 21.25°, 27.13°, and the 2θ error range is ±0.2°.

[0055] In some embodiments of the present application, the crystal form VIII is prepared using Cu-K α Radiation, its X-ray powder diffraction pattern 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°, and the 2θ error range is ±0.2°.

[0056] In some embodiments of the present application, the crystal form VIII is prepared using Cu-K αRadiation, its X-ray powder diffraction pattern has characteristic peaks at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 of the 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°, 27.13°, and the 2θ error range is ±0.2°.

[0057] In some embodiments of the present application, the crystal form VIII is prepared using Cu-K α Radiation, its X-ray powder diffraction pattern 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°, and the 2θ error range is ±0.2°.

[0058] In some embodiments of the present application, the X-ray powder diffraction pattern of the crystalline form VIII is substantially as shown in FIG7 .

[0059] In some embodiments of the present application, the X-ray powder diffraction peak analysis data of the crystalline form VIII are shown in Table 3.

[0060] Table 3 XRPD diffraction peak analysis data of Form VIII of Formula (I)

[0061] In some embodiments of the present application, the crystalline form VIII has a TGA-DSC spectrum with endothermic peaks at 124±2°C and 179±2°C, and an exothermic peak at 128±2°C.

[0062] In some embodiments of the present application, the TGA-DSC spectrum of the crystalline form VIII is substantially as shown in FIG8 .

[0063] The present application also provides a crystalline form X of the compound of formula (I), using Cu-K α Radiation, its X-ray powder diffraction pattern has characteristic peaks at 1, 2, 3, 4, 5, 6, 7 or 8 of the 2θ values ​​of 11.61°, 15.66°, 17.49°, 18.36°, 19.51°, 21.28°, 23.60°, 25.43°, and the 2θ error range is ±0.2°.

[0064] In some embodiments of the present application, the crystal form X is formed using Cu-K αRadiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 11.61°, 15.66°, 17.49°, 18.36°, 19.51°, 21.28°, 23.60°, and 25.43°, and the 2θ error range is ±0.2°.

[0065] In some embodiments of the present application, the crystal form X is formed using Cu-K α Radiation, its X-ray powder diffraction pattern has characteristic peaks at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 of the 2θ values ​​of 11.61°, 14.07°, 14.70°, 15.66°, 17.49°, 18.36°, 18.54°, 19.51°, 21.28°, 23.60°, 25.43°, and the 2θ error range is ±0.2°.

[0066] In some embodiments of the present application, the crystal form X is formed using Cu-K α Radiation, its X-ray powder diffraction pattern 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°, and the 2θ error range is ±0.2°.

[0067] In some embodiments of the present application, the crystal form X is formed using Cu-K α Radiation, its X-ray powder diffraction pattern has characteristic peaks at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 of the 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°, 27.67°, and the 2θ error range is ±0.2°.

[0068] In some embodiments of the present application, the crystal form X is formed using Cu-K α Radiation, its X-ray powder diffraction pattern 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°, and the 2θ error range is ±0.2°.

[0069] In some embodiments of the present application, the X-ray powder diffraction pattern of the crystal form X is basically as shown in Figure 9.

[0070] In some embodiments of the present application, the X-ray powder diffraction peak analysis data of the crystal form X are shown in Table 4.

[0071] Table 4 XRPD diffraction peak analysis data of Form X of Formula (I)

[0072] In some embodiments of the present application, the crystal form X has an endothermic peak at 179±2°C in its TGA-DSC spectrum.

[0073] In some embodiments of the present application, the TGA-DSC spectrum of the crystal form X is basically as shown in Figure 10.

[0074] The present application also provides a pharmaceutically acceptable salt of a compound of formula (I) 2-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxylate,

[0075] In some embodiments of the present application, the pharmaceutically acceptable salt of the compound of formula (I) is a sodium salt.

[0076] In some embodiments of the present application, the pharmaceutically acceptable salt of the compound of formula (I) is a sodium salt having the following structure:

[0077] The present application also provides a crystalline form of the pharmaceutically acceptable sodium salt of formula (I-1).

[0078] In some embodiments of the present application, the crystalline form of the pharmaceutically acceptable sodium salt of formula (I-1) is Form I, using Cu-K α Radiation, its X-ray powder diffraction pattern has characteristic peaks at 1, 2, 3, 4 or 5 of the 2θ values ​​of 15.99°, 17.16°, 17.29°, 17.70°, 23.24°, and the 2θ error range is ±0.2°.

[0079] In some embodiments of the present application, the crystal form I is formed using Cu-K α Radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 15.99°, 17.16°, 17.29°, 17.70°, and 23.24°, and the 2θ error range is ±0.2°.

[0080] In some embodiments of the present application, the crystal form I is formed using Cu-K αRadiation, its X-ray powder diffraction pattern has characteristic peaks at 1, 2, 3, 4, 5, 6, 7 or 8 of the 2θ values ​​of 8.99°, 15.99°, 17.16°, 17.29°, 17.70°, 21.39°, 22.92°, 23.24°, and the 2θ error range is ±0.2°.

[0081] In some embodiments of the present application, the crystal form I is formed using Cu-K α Radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 8.99°, 15.99°, 17.16°, 17.29°, 17.70°, 21.39°, 22.92°, and 23.24°, and the 2θ error range is ±0.2°.

[0082] In some embodiments of the present application, the crystal form I is formed using Cu-K α Radiation, its X-ray powder diffraction pattern has characteristic peaks at 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 of the 2θ values ​​of 8.99°, 12.92°, 15.99°, 17.16°, 17.29°, 17.70°, 20.98°, 21.39°, 22.92°, 23.24°, and the 2θ error range is ±0.2°.

[0083] In some embodiments of the present application, the crystal form I is formed using Cu-K α Radiation, its X-ray powder diffraction pattern 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°, and the 2θ error range is ±0.2°.

[0084] In some embodiments of the present application, the X-ray powder diffraction pattern of the crystalline form I is substantially as shown in FIG13 .

[0085] In some embodiments of the present application, the X-ray powder diffraction peak analysis data of the crystalline form I are shown in Table 5.

[0086] Table 5 XRPD diffraction peak analysis data of Form I

[0087] In some embodiments of the present application, the crystal form I has an exothermic peak at 241±2°C in its TGA-DSC spectrum.

[0088] In some embodiments of the present application, the crystalline form I is characterized by having a TGA-DSC spectrum substantially as shown in FIG14 .

[0089] The present application also provides a method for preparing a sodium salt compound of formula (I-1), comprising: adding the compound of formula (I) into a solvent to dissolve it, filtering it, and adding dropwise a sodium ethanol solution to form a salt.

[0090] In some embodiments of the present application, the solvent used in the above-mentioned salt-forming reaction is selected from organic solvents, preferably ethanol.

[0091] The present application also provides a method for preparing the crystalline form I of the pharmaceutically acceptable sodium salt of formula (I-1), comprising:

[0092] (a) adding the compound of formula (I-1) into solvent 1 and dissolving it;

[0093] (b) After filtration, the mixture was stirred at room temperature and solvent 2 was slowly added dropwise to precipitate a solid.

[0094] In some embodiments of the present application, the solvent 1 is selected from an organic solvent, preferably tetrahydrofuran; the solvent 2 is selected from an organic solvent, preferably n-heptane or methyl isobutyl ketone.

[0095] The present application also provides a pharmaceutical composition comprising a pharmaceutically acceptable salt of a compound of formula (I) or any one of the above-mentioned crystalline forms, and one or more pharmaceutically acceptable carriers. Preferably, the pharmaceutically acceptable salt of a compound of formula (I) or any one of the above-mentioned crystalline forms is an effective therapeutic amount. The pharmaceutically acceptable salt or any one of the above-mentioned crystalline forms of a compound of formula (I) described herein may contain a pharmaceutically acceptable salt, crystalline form IV, crystalline form VI, crystalline form VIII, crystalline form X or crystalline form I of the above-mentioned compound of formula (I) alone, or may contain two or more of a pharmaceutically acceptable salt, crystalline form IV, crystalline form VI, crystalline form VIII, crystalline form X and crystalline form I of the above-mentioned compound of formula (I).

[0096] The present application also provides the use of a pharmaceutically acceptable salt of a compound of formula (I), any of the aforementioned crystalline forms, or a pharmaceutical composition containing any of the aforementioned crystalline forms of a compound of formula (I) in the preparation of a medicament for treating and / or preventing tumors. Any of the aforementioned crystalline forms described herein refers to the aforementioned crystalline form IV, crystalline form VI, crystalline form VIII, crystalline form X, or crystalline form I.

[0097] The present application also provides a method for treating and / or preventing tumors, comprising administering to a patient a therapeutically and / or preventively effective amount of a pharmaceutically acceptable salt of compound (I) or any one of the above-mentioned crystal forms.

[0098] In some embodiments of the present application, in the above-mentioned pharmaceutical composition, pharmaceutical application and treatment method, the pharmaceutically acceptable salt is a sodium salt.

[0099] In some embodiments of the present application, in the above-mentioned pharmaceutical compositions, pharmaceutical applications and treatment methods, the pharmaceutically acceptable salt is a sodium salt having the following structure:

[0100] In some embodiments of the present application, the pharmaceutically acceptable sodium salt of the above formula (I-1) is in crystalline form.

[0101] In some embodiments of the present application, the crystalline form of the pharmaceutically acceptable sodium salt of the above formula (I-1) is Form I.

[0102] In some embodiments of the present application, the formation of the tumor is associated with PARP; preferably, the PARP is PARP7.

[0103] The crystal form provided in this application has good chemical stability, physical stability and low hygroscopicity, is less affected by temperature, humidity and light, and is convenient for storage and formulation development. BRIEF DESCRIPTION OF THE DRAWINGS

[0104] The drawings described herein are used to provide further understanding of the present application and constitute a part of the present application. The illustrative embodiments of the present application and their descriptions are used to explain the present application and do not constitute improper limitations on the present application.

[0105] FIG1 is an XRPD spectrum of Form IV of the compound of formula (I);

[0106] FIG2 is a TGA-DSC spectrum of Form IV of the compound of formula (I);

[0107] FIG3 is a DVS spectrum of Form IV of the compound of formula (I);

[0108] FIG4 is a comparison spectrum of the crystal form IV of the compound of formula (I) before and after DVS testing;

[0109] FIG5 is an XRPD spectrum of Form VI of the compound of formula (I);

[0110] FIG6 is a TGA-DSC spectrum of Form VI of the compound of formula (I);

[0111] FIG7 is an XRPD spectrum of Form VIII of the compound of formula (I);

[0112] FIG8 is a TGA-DSC spectrum of Form VIII of the compound of formula (I);

[0113] FIG9 is an XRPD spectrum of Form X of the compound of formula (I);

[0114] FIG10 is a TGA-DSC spectrum of Form X of the compound of formula (I);

[0115] FIG11 is a DVS spectrum of Form X of the compound of formula (I);

[0116] FIG12 is a comparison spectrum of the crystal form X of the compound of formula (I) before and after DVS testing;

[0117] FIG13 is an XRPD spectrum of Form I of a pharmaceutically acceptable salt of the compound of formula (I);

[0118] FIG14 is a TGA-DSC spectrum of Form I of a pharmaceutically acceptable salt of the compound of formula (I);

[0119] FIG15 is a DVS spectrum of Form I of a pharmaceutically acceptable salt of the compound of formula (I). DETAILED DESCRIPTION

[0120] The present invention is described in detail below by way of examples, but is not intended to limit the present invention in any adverse way. The compound 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, the embodiments formed by combining the specific embodiments with other chemical synthesis methods, and equivalent replacement modes well known to those skilled in the art, and preferred embodiments include but are not limited to the examples of the present invention. It will be apparent to those skilled in the art that various changes and improvements will be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention.

[0121] Unless otherwise specified, all reactions in this application were carried out under a dry nitrogen or argon atmosphere with continuous magnetic stirring, with dry solvents, and the reaction temperature was expressed in degrees Celsius or ° C. Unless otherwise specified, room temperature refers to 25 ± 5 ° C.

[0122] Description and Definition

[0123] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered ambiguous or unclear without a specific definition, but should be understood according to its ordinary meaning.

[0124] The term "composition" refers to a product comprising ingredients in the specified amounts, as well as a product that results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0125] The term "pharmaceutically acceptable carrier" refers to a medium generally accepted in the art for delivering biologically active agents to animals, particularly mammals, and includes, for example, adjuvants, excipients, or vehicles, such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, aromatics, antibacterial agents, antifungal agents, lubricants, and dispersants, depending on the mode of administration and the nature of the dosage form. Pharmaceutically acceptable carriers are formulated within the scope of ordinary skill in the art based on a variety of factors.

[0126] The term "effective therapeutic amount" refers to a compound of the present invention or a pharmaceutically acceptable salt thereof, which is a sufficient amount of the compound to treat the disorder at a reasonable effect / risk ratio applicable to any medical treatment and / or prevention. However, it should be recognized that the total daily dosage of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof and the composition of the present invention must be determined by the attending physician within the scope of sound medical judgment. For any particular patient, the specific therapeutically effective dose level must be determined based on a variety of factors, including 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; drugs used in combination with or concurrently with the specific compound used; and similar factors well known in the medical field.

[0127] It is well known in the art that X-ray powder diffraction patterns have one or more measurement errors depending on slight changes in measurement conditions. The structures of the crystals, crystals or crystal forms disclosed or claimed in this application may exhibit similar but not identical analytical characteristics within a reasonable error range depending on the experimental conditions, purity, equipment and other constant variables known to those skilled in the art. For example, the diffraction angle (2θ) in powder X-ray powder diffraction generally produces an error within the range of ±0.20°. Therefore, this application not only includes crystals with completely consistent diffraction angles in powder X-ray powder diffraction, but also includes crystals with consistent diffraction angles within the error range of ±0.20°. The crystalline form of the compound of formula (I) of the present application is not limited to crystals having an X-ray powder diffraction pattern identical to the X-ray powder diffraction pattern shown in the accompanying drawings, and any crystals having an X-ray powder diffraction pattern substantially identical to that shown in the accompanying drawings are within the scope of this application.

[0128] In the present application, the organic solvent includes ester solvents or esters, alcohol solvents or alcohols, aliphatic hydrocarbon solvents or aliphatic hydrocarbons, ketone solvents or ketones, and ether solvents or ethers.

[0129] In the present application, examples of ester solvents or esters include, but are not limited to, dichloromethane, methyl acetate, ethyl acetate, n-propyl acetate, and isopropyl acetate.

[0130] In the present application, examples of alcohol solvents or alcohols include, but are not limited to, methanol, ethanol, propanol, isopropanol and n-butanol.

[0131] In the present application, aliphatic hydrocarbon solvents or aliphatic hydrocarbons include but are not limited to n-pentane, isopentane, n-hexane, n-heptane and n-octane.

[0132] In the present application, ketone solvents or ketones include but are not limited to acetone, methyl ethyl ketone, methyl butyl ketone and methyl isobutyl ketone.

[0133] In the present application, ether solvents or ethers include but are not limited to diethyl ether, isopropyl ether, ethylene oxide and methyl tert-butyl ether.

[0134] In the present application, alcohol / aliphatic hydrocarbon refers to a mixed solvent of an alcohol solvent and an aliphatic hydrocarbon solvent.

[0135] In the present application, the X-ray powder diffraction pattern of the crystalline form IV has characteristic peaks at 1, 2, 3, 4 or 5 positions with 2θ values ​​of 14.12, 15.56, 17.32, 18.06, or 22.29, and the 2θ error range is ±0.2°, wherein 1, 2, 3, 4 or 5 positions means that any 1, 2, 3, 4 or 5 characteristic peaks are the same as those of the crystalline form I and are included in the scope of this application.

[0136] The X-ray powder diffraction patterns appearing in this application are “substantially identical to the X-ray powder diffraction patterns shown in the accompanying drawings. It should be understood that the term “substantially identical” as used in this context is also intended to indicate that the 2θ angle values ​​of the X-ray powder diffraction patterns may have slight variations due to the inherent experimental variations associated with such measurements, and both are of the same crystalline form.

[0137] It should be understood that using different types of equipment or different test conditions may give slightly different DSC spectra and endothermic transition temperature readings. DSC data can reflect changes in the form of a substance. A strong endothermic peak can indicate that the substance has undergone dehydration or desolvation, or has undergone crystallization, or has melted, etc. When reflecting a molten state, the corresponding temperature is usually understood to be the melting point of the substance. This value will be affected by the purity of the compound, sample weight, heating rate, particle size, and calibration and maintenance of the test equipment. Those skilled in the art will understand that the temperature when a substance transforms from a solid state to a liquid state is usually a temperature range, not a fixed point value. Therefore, whether it is an onset value or a peak value or other reasonable values, it can characterize the temperature corresponding to the endothermic peak or the melting point of the substance. The maximum endothermic transition temperature of the crystal form can be within the range of ±5.0°C of the specific value disclosed above, preferably within the range of ±2.0°C.

[0138] This application also uses thermogravimetric analysis (TGA) to analyze the relationship between the degree of decomposition, sublimation, and evaporation (weight loss) of the crystal form and temperature. It should be understood that the values ​​obtained for the same crystal form are affected by sample purity, particle size, different types of equipment, different testing methods, etc., and there will be certain errors in the values ​​obtained. The temperature at which the crystal form decomposes, sublimates, or evaporates can be within the range of ±3.0°C of the specific values ​​disclosed above, for example, within the range of ±2.0°C.

[0139] The "stability" of a crystal form includes "chemical stability" and / or "physical stability." "Chemical stability" refers to the degree to which a crystal form degrades under certain conditions of temperature, humidity, and light. "Chemical stability" reflects the stability of a crystal form under storage conditions. "Physical stability" refers to the degree to which a crystal form undergoes solid-state transformation under certain conditions, such as conversion to another crystal form under conditions of high temperature, high humidity, grinding, tableting, desolvation, or solvent adsorption. Therefore, "physical stability" can, to a certain extent, reflect the stability of a crystal form during use, such as during formulation.

[0140] Regarding the description of hygroscopic characteristics and the definition of hygroscopic weight gain (Chinese Pharmacopoeia 2020 Edition General Chapter 9103 Guiding Principles for Drug Hygroscopicity Testing):

[0141] Deliquescent: Absorbs sufficient water to form a liquid;

[0142] Highly hygroscopic: weight gain due to moisture absorption is not less than 15.0%;

[0143] Hygroscopic: weight gain due to moisture absorption is less than 15.0% but not less than 2.0%;

[0144] Slightly hygroscopic: weight gain due to moisture absorption is less than 2.0% but not less than 0.2%;

[0145] No or almost no hygroscopicity: weight gain due to moisture is less than 0.2%.

[0146] Hygroscopicity directly impacts a drug's physicochemical stability. High hygroscopicity can easily lead to chemical degradation and crystal transformation. Furthermore, high hygroscopicity can reduce drug flowability, thereby impacting drug processing. Furthermore, highly hygroscopic drugs require low humidity during production and storage, placing higher demands on production and incurring high costs. More importantly, high hygroscopicity can easily cause variations in the active ingredient content, impacting drug quality.

[0147] During storage, transportation, and production, APIs and drug products are subject to high temperatures and humidity due to seasonal variations, regional climate differences, and weather factors. Crystal forms with excellent stability can help prevent the effects of deviations from labeled storage conditions on drug quality.

[0148] Crystalline changes can alter drug absorption and bioavailability. Good chemical stability ensures virtually no impurities are generated during storage. Crystalline forms exhibit excellent physical and chemical stability, ensuring consistent quality control of both APIs and drug products. This minimizes changes in drug quality, bioavailability, and even toxic side effects caused by changes in crystal form or impurities.

[0149] In this application, the "stirring" is accomplished by conventional methods in the art, such as magnetic stirring or mechanical stirring, with a stirring speed of 50-1800 rpm, wherein the magnetic stirring is preferably 300-900 rpm and the mechanical stirring is preferably 100-300 rpm.

[0150] The drying process can be carried out at room temperature or above. The drying temperature ranges from room temperature to about 60°C, or to 50°C, or to 40°C. The drying time can be 2-48 hours, or overnight. Drying is carried out in a fume hood, forced air oven, or vacuum oven.

[0151] The crystalline structures of the present application can be prepared by various methods, including crystallization or recrystallization from a suitable solvent, sublimation, growth from a melt, solid-state transformation from another phase, crystallization from a supercritical fluid, and jet spraying. Techniques for crystallizing or recrystallizing the crystalline structure from a solvent mixture include evaporation of the solvent, lowering the temperature of the solvent mixture, seeding of a supersaturated solvent mixture of the molecule and / or salt, freeze-drying the solvent mixture, adding an antisolvent to the solvent mixture, and the like.

[0152] Reaction temperatures are expressed in degrees Celsius or °C. Unless otherwise specified, room temperature refers to 25±5°C.

[0153] Unless otherwise specified, the formula (I), compound of formula (I) or free acid herein refers to 2-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxylate:

[0154] Unless otherwise specified, the crystal form in this application refers to the crystal form of the sodium salt of the compound of formula (I), that is, the crystal form of formula (I-1).

[0155] The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent replacement methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.

[0156] In the examples of this application, the compound names were converted from the compound structures using ChemDraw. If there is a discrepancy between the compound name and the compound structure, the correct identification can be made by combining relevant information and reaction routes. If other methods are unavailable for confirmation, the given compound structure will prevail.

[0157] The preparation methods of some compounds in this application refer to the preparation methods of the aforementioned similar compounds. Those skilled in the art should be aware that when using or referring to the preparation methods cited, the feed ratio of reactants, reaction solvent, reaction temperature, etc. can be appropriately adjusted according to the different reactants.

[0158] Instruments and analytical methods:

[0159] 1. X-ray powder diffraction (XRPD)

[0160] Solid samples were analyzed using an X-ray powder diffractometer (X'Pert PRO). An appropriate amount of sample powder was placed in the groove of the sample holder and pressed into a flat and dense surface using a glass sheet. The XRPD measurement parameters are shown in Table 6.

[0161] Table 6 XRPD test parameters

[0162] 2. Thermogravimetric analysis (TGA)

[0163] Thermogravimetric analysis of the solids was performed using a TA Instrument thermogravimetric analyzer. Approximately 1-5 mg of sample was placed in a tared aluminum sample pan and heated according to the parameters listed in Table 7. The data was analyzed using TRIOS.

[0164] Table 7 TGA analysis method parameters

[0165] 3. Differential Scanning Calorimetry (DSC)

[0166] Solid DSC analysis was performed 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 a TA Universal Analysis.

[0167] Table 8 DSC analysis method parameters

[0168] Alternatively, use a Mettler Toledo simultaneous thermal analyzer for thermogravimetric and differential scanning calorimetry analysis of solids. Use a small spoon to place an appropriate amount of the sample into a crucible, ensuring it is evenly spread. Weigh the crucible, heat the sample according to the parameters listed in Table 9, and analyze the data using STARe.

[0169] Table 9 TGA-DSC analysis method parameters

[0170] 4. Dynamic moisture sorption and desorption analysis (DVS)

[0171] The hygroscopicity of the samples was measured using a DVS Intrinsic dynamic moisture sorption instrument. The samples were placed in a tared sample basket and automatically weighed. The samples were analyzed according to the parameters in Table 10.

[0172] Table 10 DVS analysis method parameters

[0173] 5. H NMR spectroscopy ( 1 H-NMR)

[0174] NMR measurements were performed using a Bruker AVANCE NEO 400 nuclear magnetic resonance instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d6).

[0175] 6. High Performance Liquid Chromatography (HPLC)

[0176] HPLC determination: Waters e2695 high performance liquid chromatograph was used to perform high performance liquid chromatography analysis on the samples.

[0177] 7. Karl Fischer titration (KF) test method:

[0178] (1) Instruments and equipment

[0179] Analytical balance (Sartorius, MSE125P) and Karl Fischer moisture analyzer (Beijing Pioneer Weifeng Technology Co., Ltd., ZDJ400).

[0180] (2) Reagents and test solutions

[0181] Water, Fischer's test solution, methanol.

[0182] (3) Operation process

[0183] Test according to the moisture determination method (Chinese Pharmacopoeia 2020 Edition Part IV General Chapter 0832 Method 1).

[0184] Calibration: Take an appropriate amount of water, weigh accurately, and perform calibration three times to determine the titration solution used; then perform back calibration to confirm the recovery rate, which should be within the range of 97.5%-102.5%.

[0185] Detection: Weigh 0.1-0.2g of this product, add it into a titration cup filled with methanol, and measure it after the sample is completely dissolved.

[0186] (4) Calculation formula: Water content in the test sample (%) = (A × F) / (W × 1000) × 100%;

[0187] Where: A: volume of Fischer's test solution consumed by the test sample (mL);

[0188] F: weight of water per 1 mL of Fischer's test solution (mg);

[0189] W: weight of the test sample (g).

[0190] 8. Gas chromatography (GC)

[0191] GC determination Agilent 7890A / B-7697A gas chromatograph was used to perform chromatographic analysis on the samples.

[0192] The present application will be further described below through specific examples.

[0193] Example 1 Preparation method of compound of formula (I)

[0194] 2-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)ethyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxylate (compound of formula I)

[0195] Step A: Under nitrogen, activated zinc powder (0.8 g, 12 mmol) was added to dry tetrahydrofuran (20 mL). Tert-butyl bromoacetate (1.5 g, 7.6 mmol) was added dropwise at reflux. After initiation, reflux was continued for 1 hour. 5-Bromo-2-methoxy-3-(trifluoromethyl)pyridine (300 mg, 1.2 mmol) was added to the reaction solution, followed by catalytic amounts of trisdibenzylideneacetone dipalladium (Pd2(dba)3) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-Phos). The reaction solution was then stirred at reflux overnight. After cooling to room temperature, the reaction solution was quenched with water. The aqueous phase was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, 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 tert-butyl 2-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)acetate (3-2).

[0196] MS (ESI) M / Z: 292.1 [M+H] + .

[0197] 1 H 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).

[0198] Step B: Dissolve tert-butyl 2-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)acetate (200 mg, 0.7 mmol) in tetrahydrofuran (10 mL). Add lithium aluminum hydride (60 mg, 1.5 mmol). The reaction mixture is heated under reflux with stirring for 5 hours. After cooling to room temperature, the reaction mixture is quenched with saturated ammonium chloride solution. The aqueous phase is extracted with ethyl acetate (50 mL x 3). The organic phases are combined, washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography to provide 104 mg of 2-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)ethan-1-ol (3-3).

[0199] MS (ESI) M / Z: 221.9 [M+H] + .

[0200] 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), and di(p-nitrobenzene) carbonate (206 mg, 0.68 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 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 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 step.

[0201] MS (ESI) M / Z: 386.9 [M+H] + .

[0202] Step D: 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) at room temperature. 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 solution was quenched by adding saturated ammonium chloride solution, the aqueous phase was extracted with dichloromethane (50 ml × 2 times), the organic phase was washed with saturated brine (20 ml), then 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 step.

[0203] MS (ESI) M / Z: 480.2 [M+H] + .

[0204] Step E: 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) at room temperature. Iodotrimethylsilane (400 mg, 2 mmol) was then added to the solution in an ice-water bath. The reaction was stirred at room temperature for 2 hours. Under ice cooling, the reaction was quenched with ice water, the pH was adjusted to 7-8 with saturated sodium bicarbonate solution, and then extracted with dichloromethane (20 ml × 3 times), the organic phase was washed with saturated brine (20 ml), then 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).

[0205] MS (ESI) M / Z: 466.4 [M+H] + .

[0206] 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).

[0207] Example 2 Preparation method of Form IV

[0208] 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 at 50°C for 24 hours. The mixture was filtered, and the resulting solid was characterized by XRPD, TGA-DSC, and DVS. The solid was Form IV, and its XRPD spectrum is substantially as shown in Figure 1.

[0209] The TGA-DSC spectrum is shown in Figure 2. TGA shows no obvious weight loss, indicating that Form IV is anhydrous. The DSC results show that Form IV has an endothermic peak at 175±2°C.

[0210] The DVS spectrum is shown in Figure 3. Form IV gained 1.07% weight at 80% RH, indicating slight hygroscopicity. A comparison of XRPD patterns before and after the DVS test is shown in Figure 4. The results indicate no crystal transformation before and after the DVS test.

[0211] Example 3 Preparation method of Form IV

[0212] 50.0 mg of the compound of formula (I) was weighed into a vial, 0.2 mL of 2-methyltetrahydrofuran was added to dissolve the mixture, and the mixture was filtered into a new vial. 2 mL of n-heptane was slowly added dropwise thereto. After solid precipitation, the mixture was filtered. The resulting solid was characterized by XRPD and TGA-DSC. The solid was Form IV, and its XRPD spectrum is substantially as shown in Figure 1.

[0213] Example 4 Preparation Method of Form VI

[0214] Weigh 10.6 mg of the compound of formula (I) into a vial, add 1.5 mL of acetone and 2.0 mL of water, and heat to 50°C to dissolve. Filter into a new vial, then slowly cool to 0°C to precipitate a solid. The resulting solid was characterized by XRPD and TGA-DSC, revealing Form VI. Its XRPD spectrum is generally shown in Figure 5.

[0215] The TGA-DSC spectrum is shown in Figure 6. There is no obvious weight loss in TGA, an exothermic peak at 105±2°C, and an endothermic peak appears when heated to 175±2°C, indicating that Form VI is anhydrous.

[0216] Example 5 Preparation method of crystal form VI

[0217] 9.5 mg of the compound of formula (I) was weighed into a reaction flask, 0.5 mL of acetonitrile and 1.0 mL of water were added, and stirred at room temperature for 5 days. The mixture was filtered, and the resulting solid was characterized by XRPD. The solid was Form VI, and its XRPD spectrum is substantially as shown in Figure 5.

[0218] Example 6 Preparation Method of Form VI

[0219] Weigh 10.3 mg of the compound of formula (I) into a vial, add 1.5 mL of acetone and 2.0 mL of water, and dissolve at 35°C. After filtering, slowly cool to 5°C and stir for 1 hour. Filter and dry under vacuum at 50°C for 4 hours. The resulting solid was characterized by XRPD and TGA-DSC. XRPD results indicated Form VI. The XRPD spectrum is generally shown in Figure 5.

[0220] The TGA-DSC spectrum is shown in Figure 6. TGA has a 1.56% weight loss between 35°C and 117°C, but no corresponding endothermic peak. This process is a surface solvent desorption process, indicating that Form VI is anhydrous. The DSC results show that the TGA-DSC spectrum of the crystal form has an exothermic peak at 105±2°C and an endothermic peak at 177±2°C.

[0221] Example 7 Preparation Method of Form VIII

[0222] 10.7 mg of the compound of formula (I) was weighed and dissolved in 1.0 mL of dichloromethane. The mixture was then filtered into a vial, and 4.0 mL of n-heptane was slowly added dropwise to the solution. Solid precipitated. After filtration, XRPD and TGA-DSC characterization revealed that the solid was Form VIII. Its XRPD spectrum is generally shown in Figure 7.

[0223] The TGA-DSC spectrum is shown in Figure 8. There is no obvious weight loss in the TGA, and the DSC spectrum has endothermic peaks at 124±2℃ and 179±2℃, and an exothermic peak at 128±2℃.

[0224] Example 8 Preparation Method of Crystal Form X

[0225] 10.2 mg of Form I of the compound of formula (I) was weighed, 1.0 mL of ethanol was added, and the mixture was slurried at room temperature for 5 days. The resulting solid was filtered and characterized by XRPD, TGA-DSC, and DVS. The solid was Form X, and its XRPD spectrum is substantially as shown in FIG9 .

[0226] The TGA-DSC spectrum is basically as shown in Figure 10. There is no obvious weight loss in TGA, indicating that Form X is anhydrous. The DSC results show that Form X has an endothermic peak at 179±2°C.

[0227] The DVS spectrum is shown in Figure 11. At 80% RH, the weight gain was 1.4%, indicating slight hygroscopicity. A comparison of the XRPD patterns before and after the DVS test is shown in Figure 12. No crystal transformation was observed before and after the DVS test.

[0228] Example 9 Preparation Method of Sodium Salt Compound of Formula (I-1)

[0229] Weigh 1.0 g of the compound of formula (I), add 1.8 mL of anhydrous ethanol to dissolve at 70°C, and filter; add 1.05 eq of sodium ethanol solution dropwise to form a salt, react for 30 minutes; filter with suction, and dry at 50°C for 2 hours to obtain the sodium salt compound of formula (I-1).

[0230] Example 10 Preparation method of crystal form I

[0231] 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 and dissolved at room temperature. Filtered, 0.4 mL of n-heptane was then slowly added dropwise to the solution. The precipitated solid was then centrifuged and dried. The resulting solid was characterized by XRPD, TGA-DSC, and DVS. The solid was Form I, and its XRPD spectrum is substantially as shown in Figure 13.

[0232] The TGA-DSC spectrum is shown in Figure 14. TGA shows no obvious weight loss, indicating that Form I is anhydrous. The DSC results show that Form I has an exothermic peak at 241±2°C.

[0233] The DVS spectrum is shown in FIG15 . Form I has a weight gain of 13.29% at 80% RH, indicating that it is hygroscopic.

[0234] Example 11 Preparation method of crystal form I

[0235] 10.3 mg of the compound of formula (I) was weighed into a vial, 0.1 mL of tetrahydrofuran was added to dissolve the mixture, and the mixture was filtered into a new vial. 0.4 mL of methyl isobutyl ketone was slowly added dropwise thereto. After solid precipitation, the mixture was filtered. The resulting solid was characterized by XRPD and TGA-DSC. The solid was Form I, and its XRPD spectrum was substantially as shown in Figure 13.

[0236] Example 12 Influencing Factors Experiment

[0237] With reference to the "Guidelines for Stability Testing of Raw Materials and Preparations" in the 2020 edition of the Chinese Pharmacopoeia, the stability of Form IV of the compound of formula (I) at different temperatures and humidities was investigated. Purity was tested by HPLC on day 0, day 2, and day 7, and the crystal form was tested by XRPD. The experimental results are shown in Table 11.

[0238] Table 11 Experimental test on factors affecting Form IV

[0239] Conclusion: The physical and chemical properties of Form IV are relatively stable under high temperature and high humidity conditions.

[0240] With reference to the "Guidelines for Stability Testing of Raw Materials and Preparations" in the 2020 edition of the Chinese Pharmacopoeia, the stability of the sodium salt form I of the compound of formula (I) at different temperatures and humidities was investigated. Purity was tested by HPLC on day 0, day 5, and day 10, and the crystal form was tested by XRPD. The experimental results are shown in Table 12.

[0241] Table 12 Experimental test on factors affecting Form I

[0242] Conclusion: The physical and chemical properties of Form I are stable at high temperature, and there is a crystal transformation phenomenon under high humidity conditions.

[0243] Example 13: Hygroscopicity Test

[0244] Referring to the "Guidelines for Hygroscopicity Testing of Drugs" in the 2020 edition of the Chinese Pharmacopoeia, the moisture adsorption / desorption data of Form IV of the compound of Formula (I) were tested. The DVS curve of Form IV is shown in Figure 3, and its hygroscopicity data are shown in Table 13. The XRPD of the solid remaining after the DVS experiment showed that Form IV did not change, as shown in Figure 4.

[0245] Table 13 Hygroscopicity of Form IV

[0246] Conclusion: From the hygroscopicity experiment, it can be seen that Form IV is slightly hygroscopic.

[0247] Referring to the "Guidelines for Hygroscopicity Testing of Drugs" in the 2020 edition of the Chinese Pharmacopoeia, moisture adsorption / desorption data of Form I, the sodium salt of the compound of Formula (I), was tested. The DVS curve of Form I is shown in the figure, and its hygroscopicity data is shown in Table 14.

[0248] Table 14 Hygroscopicity of Form I

[0249] Conclusion: From the hygroscopicity experiment, it can be seen that Form I is slightly hygroscopic.

[0250] Biological test evaluation:

[0251] 1. PARP7 in vitro enzymatic assay

[0252] This experiment detects the inhibitory effect of the compound of formula (I) on PARP7 enzyme activity. The test compound is diluted in series and tested in duplicate.

[0253] 1. Prepare histone-coated 384-well plates. Add 25 μL of histone solution to each well and incubate overnight at 4°C.

[0254] 2. Prepare PBST buffer, blocking buffer, and detection buffer.

[0255] 3. Wash the histone-coated 384-well plate three times with PBST buffer. Block with 50 μL of blocking buffer for 1 hour at room temperature. Wash the plate three times with PBST buffer.

[0256] 4. Compound Preparation:

[0257] Prepare 2000× of compound in a 96-well source plate. Transfer 50 nL of compound from the source plate to a 96-well center plate and add 39.95 μL of assay buffer to each well. Shake well and centrifuge at 1000 rpm for 1 minute.

[0258] Transfer 5 μL of compound DMSO solution to each well.

[0259] 5. Enzymatic reaction:

[0260] The enzyme mixture was incubated at 25°C for 10 minutes.

[0261] Add 10 μL of enzyme mix and incubate with compound for 10 minutes at room temperature

[0262] And add 10 μL of assay buffer to the negative control wells of the assay plate.

[0263] Add 10 μL of 2.5× Biotin-NAD+ to each well and incubate at 25°C for 60 minutes.

[0264] Wash the plate three times with PBST buffer.

[0265] 6. Detection:

[0266] Add 25 μL of Stre-HRP.

[0267] Incubate at room temperature for 1 hour, and wash the plate three times with PBS buffer.

[0268] Add 25 μL of QuantaRed Enhancer Mix and incubate for 10 minutes.

[0269] Add 2.5 μL Quanta Red Stop Solution to stop the peroxidase reaction and shake the plate for 10-30 seconds.

[0270] 7. Use Paradigm to read the plate immediately and detect the Ex550 / Em620 readings.

[0271] 8. Data Processing

[0272] The data were fitted in Excel using equation (1) to obtain inhibition values;

[0273] Equation (1): Inhibition rate % = (maximum signal value - target signal value) / (maximum signal value - minimum signal value) × 100%;

[0274] Fit the data in XL-Fit using equation (2) to obtain IC 50 value;

[0275] Equation (2): Y = Bottom + (Top - Bottom) / (1 + (IC 50 / X)×HillSlope);

[0276] Y is the percentage of inhibition and X is the compound concentration.

[0277] Experimental results

[0278] Table 15: PARP7 enzyme inhibition results

[0279] Conclusion: The compound of formula (I) can effectively inhibit PARP7 enzyme activity.

[0280] Pharmacokinetics in Mice and Rats

[0281] 1. Experimental purpose:

[0282] Male C57BL / 6 mice or SD male rats were used as test animals to study the pharmacokinetic behavior of the present compound in plasma after single intravenous injection and oral administration.

[0283] 2. Experimental Plan

[0284] 2.1 Experimental animals

[0285] Healthy adult C57BL / 6 mice or SD rats (3 / group), male, were supplied by Shanghai Jihui Laboratory Animal Breeding Co., Ltd. and Weitong Lihua Laboratory Animal Technology Co., Ltd.

[0286] 2.2 Administration

[0287] Three mice or rats were administered in each intravenous bolus and oral groups. The intravenous bolus dose was 1 mg / kg in a 5 mL / kg volume, while the oral dose was 5 mg / kg in a 10 mL / kg volume. The dosing vehicle was 5% DMSO / 5% Kolliphor HS15 / 90% Saline.

[0288] The structure of the reference compound RBN-2397 is as follows:

[0289] 2.3 Experimental equipment

[0290] The centrifuge and pipette were purchased from Eppendorf.

[0291] 2.4 Sample collection

[0292] After the animals were administered, 0.02 mL of venous blood was collected at 0.0833 (IV), 0.25, 0.5, 1, 2, 4, 8 and 24 hours, placed in EDTA-K2 test tubes, centrifuged at 4°C, 4600 rpm for 5 minutes to separate plasma, and stored at -80°C.

[0293] 2.5 Sample processing

[0294] 1) 10 μL of plasma sample was added to 200 μL of acetonitrile for precipitation, vortexed and centrifuged for 15 minutes.

[0295] 2) The supernatant after treatment was diluted with water and analyzed by LC / MS / MS for the concentration of the test compound.

[0296] 2.6 Biological analysis

[0297] Liquid phase conditions: Shimadzu LC-30AD;

[0298] Mass spectrometry conditions: AB Sciex API 5500;

[0299] Column: Phenomenex Kinetex 2.6 μm C18;

[0300] 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;

[0301] The elution gradient is shown in Table 16:

[0302] Table 16

[0303] Experimental results and analysis

[0304] The pharmacokinetic parameters were calculated using WinNonlin 8.0. The pharmacokinetic parameters of intravenous injection and oral administration of drugs in mice or rats are shown in Tables 17 and 18 below. Wherein, Dose represents the dose, CL represents the plasma clearance, Vss represents the volume of drug distribution, T 1 / 2 represents the half-life of the drug, AUC represents the area under the drug-time curve, C max represents the peak concentration of the drug, and F represents the bioavailability.

[0305] Table 17 Pharmacokinetic parameters of the compounds of the present application after intravenous injection in mice or rats

[0306] Table 18. Pharmacokinetic parameters of the compounds of the present invention after oral administration to mice or rats

[0307] Conclusion: At the same dose, the exposure of the compound of formula (I) of the present application in the plasma of mice and rats after intravenous injection and oral administration is significantly higher than that of the control compound RBN-2397.

[0308] The above description is only a preferred embodiment of the present application and is not intended to limit the present application. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present application shall be included in the scope of protection of the present application.

Claims

1. Form IV of the compound of formula (I), It is characterized in that Using Cu-K α Radiation, the X-ray powder diffraction pattern of the crystalline form IV has characteristic peaks at 2θ values ​​of 14.13°, 15.56°, 17.33°, 18.07°, and 22.30°, and the 2θ error range is ±0.2°.

2. The crystalline form IV according to claim 1, characterized in that Using Cu-K α Radiation, the X-ray powder diffraction pattern of the crystalline form IV has characteristic peaks at 2θ values ​​of 14.13°, 14.46°, 15.56°, 17.02°, 17.33°, 18.07°, 19.17°, and 22.30°, and the 2θ error range is ±0.2°.

3. The crystalline form IV according to claim 2, characterized in that Using Cu-K α Radiation, the X-ray powder diffraction pattern of the crystalline form IV 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°, and the 2θ error range is ±0.2°.

4. The crystalline form IV according to claim 3, characterized in that The X-ray powder diffraction pattern of the crystalline form IV is substantially as shown in FIG1 .

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

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

7. Crystalline form VI of the compound of formula (I), It is characterized in that Using Cu-K α Radiation, the X-ray powder diffraction pattern of the crystalline form VI has characteristic peaks at 2θ values ​​of 5.20°, 7.49°, 10.70°, 13.42°, 14.30°, 14.85°, 16.01°, and 18.66°, and the 2θ error range is ±0.2°.

8. The crystal form VI according to claim 7, characterized in that Using Cu-K α Radiation, the X-ray powder diffraction pattern of the crystalline form VI 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°, and the 2θ error range is ±0.2°.

9. The crystal form VI according to claim 8, characterized in that Using Cu-K α Radiation, the X-ray powder diffraction pattern of the crystalline form VI 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°, and the 2θ error range is ±0.2°.

10. The crystal form VI according to claim 9, characterized in that The X-ray powder diffraction pattern of the crystalline form VI is substantially as shown in FIG5 .

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

12. The crystalline form VI according to any one of claims 7 to 11, characterized in that The TGA-DSC spectrum of the Form VI is substantially as shown in FIG6 .

13. Crystalline form VIII of the compound of formula (I), It is characterized in that Using Cu-K α Radiation, the X-ray powder diffraction pattern of the crystalline form VIII has characteristic peaks at 2θ values ​​of 8.97°, 13.51°, 16.20°, 18.05°, 18.56°, 20.94°, and 21.25°, and the 2θ error range is ±0.2°.

14. The crystalline form VIII according to claim 13, characterized in that: Using Cu-K α Radiation, the X-ray powder diffraction pattern of the crystalline form VIII 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°, and the 2θ error range is ±0.2°.

15. The crystalline form VIII according to claim 14, characterized in that Using Cu-K α Radiation, the X-ray powder diffraction pattern of the crystalline form VIII 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°, and the 2θ error range is ±0.2°.

16. The crystalline form VIII according to claim 15, characterized in that The X-ray powder diffraction pattern of the crystalline form VIII is substantially as shown in FIG7 .

17. The crystalline form VIII according to any one of claims 13 to 16, characterized in that The TGA-DSC spectrum 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. The crystalline form VIII according to any one of claims 13 to 17, characterized in that The TGA-DSC spectrum of the Form VIII is substantially as shown in FIG8 .

19. Crystalline form X of the compound of formula (I), It is characterized in that Using Cu-K α Radiation, the X-ray powder diffraction pattern of the crystal form X has characteristic peaks at 2θ values ​​of 11.61°, 15.66°, 17.49°, 18.36°, 19.51°, 21.28°, 23.60°, and 25.43°, and the 2θ error range is ±0.2°.

20. The crystal form X according to claim 19, characterized in that: Using Cu-K α Radiation, the X-ray powder diffraction pattern of the crystal form X 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°, and the 2θ error range is ±0.2°.

21. The crystal form X according to claim 20, characterized in that: Using Cu-K α Radiation, the X-ray powder diffraction pattern of the crystal form X 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°, and the 2θ error range is ±0.2°.

22. The crystal form X according to claim 21, characterized in that The X-ray powder diffraction pattern of the crystal form X is basically shown in Figure 9.

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

24. The crystal form X according to any one of claims 19 to 23, characterized in that The TGA-DSC spectrum of the crystal form X is basically shown in Figure 10.

25. A pharmaceutically acceptable salt of a compound of formula (I), 26. A pharmaceutically acceptable salt of a compound of formula (I) according to claim 25, characterized in that It has the following structure:

27. Crystalline Form I of a pharmaceutically acceptable salt of a compound of formula (I) according to claim 25 or 26, characterized in that: Using Cu-K α Radiation, the X-ray powder diffraction pattern of the crystalline form I has characteristic peaks at 2θ values ​​of 15.99°, 17.16°, 17.29°, 17.70°, and 23.24°, and the 2θ error range is ±0.2°.

28. The crystalline form I according to claim 27, characterized in that Using Cu-K α Radiation, the X-ray powder diffraction pattern of the crystalline form I has characteristic peaks at 2θ values ​​of 8.99°, 15.99°, 17.16°, 17.29°, 17.70°, 21.39°, 22.92°, and 23.24°, and the 2θ error range is ±0.2°.

29. The crystalline form I according to claim 28, characterized in that Using Cu-K α Radiation, the X-ray powder diffraction pattern of the crystalline form I 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°, and the 2θ error range is ±0.2°.

30. The crystalline form I according to claim 29, characterized in that Using Cu-K α After irradiation, the X-ray powder diffraction pattern of the crystalline form I is substantially as shown in FIG13 .

31. The crystalline form I according to any one of claims 27 to 30, characterized in that The TGA-DSC spectrum of the crystalline form I has an exothermic peak at 241±2°C.

32. The crystalline form I according to any one of claims 27 to 31, characterized in that The TGA-DSC spectrum of the crystalline form I is basically shown in Figure 14.

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

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

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

Images