Solid forms of compound i or salt thereof

Abstract

The present invention relates to novel forms of Compound I wherein said compounds are (S)-5-((1-(3-(5-methyl-3-(trifluoromethyl)-8, 9-dihydropyrido [3 ', 2': 4, 5] pyrrolo [1, 2, 4] triazolo [1, 2, 4] triazolo [1, 2, 4] triazolo [1, 2, 4] triazolo [1, 2, 4] triazolo [1, 2, 4] triazolo [1, 2, 4] triazolo [1, 2, 4] triazolo [1, 2, 4] triazolo [1, 2, 4] triazolo [ The compound is (2R, 3R)-1, 2-a] pyrazine-7 (6H)-yl)-3-oxopropoxy) propan-2-yl) amino)-4-(trifluoromethyl) pyridazine-3 (2H)-one.

Description

[0001] This application claims the benefit of priority of PCT / CN2022 / 112917, filed on August 17, 2022, which is hereby incorporated by reference in its entirety into the present invention. Technical Field

[0002] The present invention relates to a solid form of (S)-5-((1-(3-(5-methyl-3-(trifluoromethyl)-8,9-dihydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-7(6H)-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one or a salt thereof, and a pharmaceutical composition comprising the solid form of the compound or the salt thereof and use thereof. Background Art

[0003] Members of the poly(ADP-ribose) polymerase (PARP) enzyme family use β-NAD + The post-translational modification of substrate-catalyzed proteins to continuously add ADP-ribose moieties to target proteins is known as the PARsylation process. In the 1960s, this post-translational modification was initially characterized by the identification of PARP1 and its role in DNA repair. Subsequently, 16 additional PARP family members were identified, each with a structurally similar PARP catalytic domain. In addition, in addition to its well-studied role in DNA repair, PARsylation has now been shown to regulate a variety of processes such as cell proliferation, apoptosis, DNA methylation, transcriptional regulation, and WNT signaling. The PARP family can be divided into three categories based on catalytic activity: monoPARPS (catalyzing the transfer of a mono-ADP-ribose unit to its substrate), including most PARP family members; polyPARPS (catalyzing the transfer of a poly-ADP-ribose unit to its substrate), including PARP1, PARP2, PARP5A, and PARP5b; and PARP13, which is the only PARP family member whose catalytic activity cannot be demonstrated in vitro or in vivo.

[0004] The single-PARP family of proteins plays an important role in a variety of stress responses associated with the development of cancer, inflammatory diseases, and neurodegenerative diseases. PARP7, as a member of the single-PARP family, has been shown to be overactive in tumors and plays a key role in cancer cell survival. Studies have found that many cancer cells rely on PARP7 for internal cell survival, and PARP7 allows cancer cells to "hide from the immune system." Inhibiting PARP7 can effectively inhibit cancer cell growth and restore interferon signaling, effectively preventing cancer cells from escaping from the immune system, and inhibiting the brakes of innate and adaptive immune mechanisms. In multiple cancer models, PARP7 inhibitors showed sustained inhibition of tumor growth, potent anti-proliferative activity, and restoration of interferon signaling. There are currently few reports on research on PARP7 inhibitors. Therefore, there is still a need for compounds and methods for treating cancer related to PARP7.

[0005] In addition, the solid form of the compound is crucial for drugs. Therefore, it is necessary to improve the properties of the compound, such as higher physical and chemical stability under high temperature, high humidity and / or light exposure to maintain the quality of the drug containing Compound I as an active ingredient, and / or higher absorption to obtain good therapeutic use when oral administration of Compound I. Therefore, it is desirable to develop a new crystalline form of Compound I to meet these needs. Summary of the invention

[0006] The compound called (S)-5-((1-(3-(5-methyl-3-(trifluoromethyl)-8,9-dihydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-7(6H)-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one has the following structure, referred to herein as Compound I, and is a potent PARP7 inhibitor with excellent activity against PARP7-related cancers.

[0007]

[0008] In one aspect, provided herein is a form of Compound 1 selected from: a crystal of Compound 1; a salt of Compound 1 and an acid; and a crystal of a salt of Compound 1 and an acid.

[0009] In one aspect, provided herein is a method for preparing crystalline Form 1 of Compound 1.

[0010] In one aspect, provided herein is a method for preparing crystalline Form A of a salt of Compound I with an acid.

[0011] In one aspect, provided herein is a pharmaceutical composition comprising a form of Compound 1.

[0012] In another aspect, provided herein is the use of a form of Compound I for the preparation of a medicament for treating PARP7-related cancers.

[0013] In another aspect, provided herein is a method of treating a subject having a cancer associated with PARP7, comprising administering to the subject an effective amount of a form of Compound I. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 : XRPD pattern of crystalline Form 1 of Compound 1 prepared in Example 2.

[0015] Figure 2 : TGA chart of crystalline form 1 of compound 1 prepared in Example 2.

[0016] Figure 3 : DSC thermogram of crystalline form 1 of compound 1 prepared in Example 2.

[0017] Figure 4 : DVS diagram of crystalline form 1 of compound 1 prepared in Example 2.

[0018] Figure 5 : Isothermal adsorption curve of crystalline form 1 of compound 1 prepared in Example 2.

[0019] Figure 6 : XRPD comparison chart of solid equilibrium solubility test of crystalline form 1 of compound 1 prepared in Example 2.

[0020] Figure 7 : Another solid equilibrium solubility test XRPD comparison diagram of the crystalline form 1 of compound 1 prepared in Example 2.

[0021] Figure 8 : DSC comparison chart of stability study of crystalline form 1 of compound 1 prepared in Example 2.

[0022] Fig. 9 : Another stability study DSC comparison chart of the crystalline form 1 of compound 1 prepared in Example 2.

[0023] Fig.10 : XRPD pattern of amorphous Compound I prepared in Example 5.

[0024] Fig.11 : XRPD pattern of crystalline Form A of the p-toluenesulfonate salt of Compound 1 prepared in Example 6.

[0025] Fig.12 : TGA chart of crystalline Form A of the p-toluenesulfonate salt of Compound 1 prepared in Example 6.

[0026] Fig.13 : DSC thermogram of crystalline Form A of the p-toluenesulfonate salt of Compound 1 prepared in Example 6.

[0027] Fig.14 : PLM image of crystalline Form A of the p-toluenesulfonate salt of Compound 1 prepared in Example 6.

[0028] Fig.15 : Crystalline Form A of the p-toluenesulfonate of Compound I prepared in Example 6 1 H-NMR spectrum.

[0029] Fig.16 : Hygroscopic XRPD pattern of crystalline Form A of the p-toluenesulfonate salt of Compound 1 prepared in Example 6. DETAILED DESCRIPTION

[0030] In the following description, certain specific details are set forth in order to provide a comprehensive understanding of various embodiments of the present invention. However, those skilled in the art will appreciate that the present invention can be practiced without these details. The following description of several embodiments is carried out with the understanding that the present invention is disclosed as an example of the subject matter of the claims, rather than being intended to limit the appended claims to the specific embodiments described. The titles used in this disclosure are provided only for convenience and should not be interpreted as limiting the claims in any way. The embodiments described under any title may be combined with the embodiments described under any other title.

[0031] definition

[0032] The names of the compounds of the present invention are named according to IUPAC rules or using ChemBioDraw Ultra, and those skilled in the art understand that the compound structure can be named or identified using other recognized naming systems and symbols. For example, the compound can be named or identified using common names, systematic or non-systematic names. The naming systems and symbols generally recognized in the chemical field include, but are not limited to, the Chemical Abstracts Service (CAS) and the International Union of Pure and Applied Chemistry (IUPAC). Accordingly, Compound I having the above structure can be named or identified as (S)-5-((1-(3-(5-methyl-3-(trifluoromethyl)-8,9-dihydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-7(6H)-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one.

[0033] Unless otherwise indicated, the word "comprise" and variations thereof, e.g., "comprises" and "comprising," as used herein, should be interpreted as meaning "including, but not limited to" in an open, inclusive sense. In other words, additional elements not specifically disclosed or listed may be included. The term "comprising" includes "consisting essentially of." The term "consisting essentially of" includes "consisting of."

[0034] As used herein, the singular forms "a," "an," and "the" include plural forms unless otherwise stated.

[0035] As used herein, unless otherwise indicated, the term "about" refers to a numerical value that has an acceptable standard of error within the particular value as considered by one of ordinary skill in the art.

[0036] References in this specification to "one embodiment", "an embodiment", or "embodiments" mean that the specific features, structures, or characteristics described in connection with the embodiment are included in at least one embodiment of the present invention. Therefore, the phrases "in one embodiment" or "in an embodiment" appearing in various places throughout this specification do not necessarily refer to the same embodiment. In addition, specific features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0037] Unless otherwise specified, the term "room temperature" used herein refers to the temperature of the external environment in the range of 10°C to 30°C.

[0038] Unless otherwise indicated, when referring to the term "substantially", e.g. 1H-NMR spectra, XRPD patterns, DSC thermograms or TGA patterns, including patterns, thermograms or plots, are not necessarily the same as those described herein, but fall within the range of experimental error or deviation when considered by one of ordinary skill in the art. For example, the term "essentially the same" means that the usual variability of a particular method is taken into account. For example, with respect to X-ray diffraction peak positions, the term "essentially the same" means that the usual variations in peak position and intensity are taken into account. One skilled in the art will understand that peak position (2θ) will show some variability, typically up to ±0.2°. Further, one skilled in the art will understand that relative peak intensity will show inter-instrument variability as well as variability due to crystallinity, preferred orientation, surface of the prepared sample, and other factors known to one skilled in the art, and should be considered only as a qualitative measurement.

[0039] Unless otherwise indicated, the term "X-ray powder diffraction (XRPD)" ("X-ray powder diffraction (XRPD) pattern") used herein refers to a diffraction pattern observed experimentally or a parameter derived therefrom. X-ray powder diffraction is characterized by peak position and / or peak intensity. The characteristic peaks of a given XRPD can be selected based on the peak position and its relative intensity to facilitate the distinction between the crystal structure and other crystal structures. The XRPD pattern of the present invention is obtained using a Bruker D8Advance Diffractometer. Those skilled in the art will recognize that for a given crystalline form of the same compound, the measured values ​​of the XRPD peak position and / or intensity will vary within an error range. In the present invention, the value of the 2θ angle allows an appropriate error range. Typically, the error range is expressed as "±". For example, a 2θ angle of about "8.88±0.2" represents a range from about "8.88+0.2", i.e., about 9.08, to about "8.88-0.2", i.e., about 8.68.

[0040] Unless otherwise specified, the term "Differential Scanning Calorimeter (DSC) thermogram" as used herein refers to a thermogram obtained by a differential scanning calorimeter.

[0041] Unless otherwise specified, the term "Thermogravimetric Analysis (TGA) thermogram" as used herein refers to a thermogram obtained by a thermogravimetric analysis instrument.

[0042] Unless otherwise specified, the term "dynamic vapor sorption (DVS) graph" or "isotherm sorption graph" as used herein refers to a graph produced by a dynamic vapor sorption instrument.

[0043] Unless otherwise specified, the term "polarizing light microscopy (PLM) image" used herein refers to an image obtained by a polarizing light microscope instrument.

[0044] Unless otherwise specified, the term "Fourier transform infrared (FT-IR) graph" used herein refers to a graph obtained by a Fourier transform infrared spectrometer.

[0045] As used herein, and unless otherwise indicated, the term "anhydrous" means that the crystalline form contains less than about 1% (w / w) absorbed water as determined by standard methods, such as Karl Fischer analysis.

[0046] Unless otherwise indicated, the term "effective amount" as used herein refers to the amount of a therapeutic compound that is necessary or sufficient to exert its intended function in a mammal. The effective amount of a therapeutic compound may vary depending on factors such as the amount of pathogenic factors already present in the mammal, the age, sex and weight of the mammal, and the like.

[0047] Unless otherwise indicated, the terms "treat", "treating", or "treatment" as used herein in connection with a disease or condition refer to ameliorating the disease or condition (i.e., slowing down, inhibiting, or alleviating the development of the disease in at least one of its clinical symptoms) in some embodiments. In another embodiment, "treat", "treating", or "treatment" refers to alleviating or improving at least one physical parameter, including one that may not be perceptible to the patient. In another embodiment, "treat", "treating", or "treatment" refers to regulating the disease or condition physically (e.g., stabilizing identifiable symptoms), physiologically (e.g., stabilizing physical parameters), or in both. In another embodiment, "treat", "treating", or "treatment" refers to preventing or delaying the onset or development or progression of a disease or condition or its symptoms.

[0048] Unless otherwise indicated, the terms "subject" or "patient" as used herein refer to human and non-human mammals, including but not limited to primates, rabbits, pigs, horses, dogs, cats, sheep and cattle. In some specific embodiments, the subject or patient refers to a human. In some embodiments, the term "subject" or "patient" refers to a person who suffers from a condition (i.e., a disease or condition) described herein and who will benefit from treatment. As used herein, a subject (patient) is "in need of" treatment if the subject (patient) will benefit biologically, medically, or in quality of life from such treatment.

[0049] Unless otherwise indicated, the term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic response, or other problems or complications, and commensurate with a reasonable benefit / risk ratio.

[0050] Unless otherwise indicated, all ingredient concentrations are expressed as weight / volume percentages (% w / v). As is commonly understood, % w / v values ​​refer to the amount of a particular ingredient or excipient in a formulation. It is commonly understood that equivalent concentrations can be expressed in different units. For example, a concentration of 0.1% w / v can also be expressed as a 1 mg / ml solution.

[0051] Unless otherwise specified, the weight or dosage of the crystalline form of the salt of Compound I referred to herein refers to the weight or dosage of Compound I itself, not the weight or dosage of its salt. The weight or dosage of the corresponding salt of the compound suitable for use in the methods, compositions, or combinations disclosed herein can be calculated based on the ratio of the molecular weight of the salt to the molecular weight of the compound itself.

[0052] In one aspect, provided herein is a form of Compound 1 selected from:

[0053] Crystallization of Compound I;

[0054] A salt of compound I with an acid; and

[0055] Crystallization of the salt of compound I with an acid;

[0056] Wherein, compound I is:

[0057]

[0058] The acid is selected from hydrochloric acid, sulfuric acid, hydrobromic acid, methanesulfonic acid, p-toluenesulfonic acid, oxalic acid, maleic acid, phosphoric acid, L-tartaric acid, fumaric acid, citric acid, lactobionic acid, mandelic acid, L-malic acid, hippuric acid, L-lactic acid, succinic acid, benzoic acid, adipic acid, and acetic acid.

[0059] In some embodiments, the crystal of Compound 1 is crystalline Form 1 of Compound 1, and the crystalline Form I of Compound 1 is characterized in that an X-ray powder diffraction pattern comprises characteristic peaks at the following 2θ values: 8.12±0.2°, 11.96±0.2°, 13.48±0.2°, and 15.27±0.2°.

[0060] In some embodiments, the crystalline Form 1 of Compound 1 is characterized in that the X-ray powder diffraction pattern further comprises one or more characteristic peaks selected from the following 2θ values: 16.11±0.2°, 16.49±0.2°, 19.79±0.2° and 20.30±0.2°.

[0061] In some embodiments, the crystalline Form 1 of Compound 1 is characterized in that the X-ray powder diffraction pattern further comprises:

[0062] The 2θ value is selected from one or two characteristic peaks of 19.79±0.2° and 20.30±0.2°, and

[0063] The 2θ value is selected from one or two characteristic peaks of 16.11±0.2° and 16.49±0.2°.

[0064] In some embodiments, the crystalline Form 1 of Compound 1 is characterized in that the X-ray powder diffraction pattern further comprises characteristic peaks selected from the following 2θ values:

[0065] 16.11 ± 0.2° and 16.49 ± 0.2°;

[0066] 16.11±0.2°, 16.49±0.2°, and 20.30±0.2°;

[0067] 16.11 ± 0.2°, 16.49 ± 0.2°, and 19.79 ± 0.2°;

[0068] 19.79 ± 0.2° and 20.30 ± 0.2°;

[0069] 16.11±0.2°, 19.79±0.2° and 20.30±0.2°; or

[0070] 16.49±0.2°, 19.79±0.2° and 20.30±0.2°.

[0071] In some embodiments, the crystalline Form 1 of Compound 1 is characterized in that the X-ray powder diffraction pattern comprises characteristic peaks at the following 2θ values: 8.12±0.2°, 11.96±0.2°, 13.48±0.2°, 15.27±0.2°, 16.11±0.2°, 16.49±0.2°, 19.79±0.2° and 20.30±0.2°.

[0072] In some embodiments, the crystalline Form 1 of Compound 1 is characterized in that an X-ray powder diffraction pattern comprises one or two characteristic peaks selected from the following 2θ values: 12.49±0.2° and 21.45±0.2°.

[0073] In some embodiments, the crystalline Form 1 of Compound 1 is characterized in that the X-ray powder diffraction pattern comprises characteristic peaks at the following 2θ values: 8.12±0.2°, 11.96±0.2°, 12.49±0.2°, 13.48±0.2°, 15.27±0.2°, 16.11±0.2°, 16.49±0.2°, 19.79±0.2°, 20.30±0.2° and 21.45±0.2°.

[0074] In some embodiments, the crystalline Form 1 of Compound 1 is characterized in that an X-ray powder diffraction pattern comprises one or two characteristic peaks selected from the following 2θ values: 22.59±0.2° and 24.06±0.2°.

[0075] In some embodiments, the crystalline Form 1 of Compound 1 is characterized in that the X-ray powder diffraction pattern comprises characteristic peaks at the following 2θ values: 8.12±0.2°, 11.96±0.2°, 12.49±0.2°, 13.48±0.2°, 15.27±0.2°, 16.11±0.2°, 16.49±0.2°, 19.79±0.2° and 20.30±0.2°, 21.45±0.2°, 22.59±0.2° and 24.06±0.2°.

[0076] In some embodiments, the crystalline Form 1 of Compound 1 is characterized in that an X-ray powder diffraction pattern comprises characteristic peaks with 2θ values ​​in Table 1 below:

[0077] Table 1

[0078]

[0079]

[0080] In some embodiments, the crystalline Form 1 of Compound 1 is characterized in that the X-ray powder diffraction pattern is Figure 1 same.

[0081] In some embodiments, the acid is p-toluenesulfonic acid.

[0082] In some embodiments, the crystalline Form A of the salt of Compound I with an acid is characterized in that an X-ray powder diffraction pattern comprises characteristic peaks at the following 2θ values: 6.74±0.2°, 9.12±0.2°, 14.75±0.2°, and 15.93±0.2°.

[0083] In some embodiments, the crystalline Form A of the salt of Compound I with an acid is characterized in that the X-ray powder diffraction pattern further comprises one or more characteristic peaks selected from the following 2θ values: 11.94±0.2°, 12.73±0.2°, 15.26±0.2° and 16.55±0.2°.

[0084] In some embodiments, the crystalline Form A of the salt of Compound 1 with an acid is characterized in that the X-ray powder diffraction pattern further comprises:

[0085] The 2θ value is selected from one or two characteristic peaks of 11.94±0.2° and 12.73±0.2°, and

[0086] The 2θ value is selected from one or two characteristic peaks of 15.26±0.2° and 16.55±0.2°.

[0087] In some embodiments, the crystalline Form A of the salt of Compound 1 with an acid is characterized in that an X-ray powder diffraction pattern comprises characteristic peaks at the following 2θ values: 6.74±0.2°, 9.12±0.2°, 11.94±0.2°, 12.73±0.2°, 14.75±0.2°, 15.26±0.2°, 15.93±0.2°, and 16.55±0.2°.

[0088] In some embodiments, the crystalline Form A of the salt of Compound I with an acid is characterized in that the X-ray powder diffraction pattern further comprises one or two characteristic peaks selected from the following 2θ values: 18.24±0.2°, 21.09±0.2°, and 22.25±0.2°.

[0089] In some embodiments, the crystalline Form A of the salt of Compound 1 with an acid is characterized in that an X-ray powder diffraction pattern comprises characteristic peaks at the following 2θ values: 6.74±0.2°, 9.12±0.2°, 11.94±0.2°, 12.73±0.2°, 14.75±0.2°, 15.26±0.2°, 15.93±0.2°, 16.55±0.2°, 18.24±0.2°, 21.09±0.2°, and 22.25±0.2°.

[0090] In some embodiments, the crystalline Form 1 of Compound 1 is characterized in that the X-ray powder diffraction pattern is Fig.11 same.

[0091] In one aspect, the present invention provides a method for preparing crystalline form 1 of compound 1, comprising: dissolving compound 1 in ethanol; adding water to precipitate a solid; and filtering.

[0092] On the one hand, the present invention provides a method for preparing a crystalline form A of a salt of compound I and an acid, comprising: dissolving compound I in ethyl acetate to obtain solution 1; dissolving p-toluenesulfonic acid in ethanol to obtain solution 2; adding solution 2 to solution 1 to obtain solution 3; adding n-heptane and stirring until a precipitate is produced, and then continuing to stir and the precipitate does not disappear; centrifuging the precipitate and drying to obtain a crystalline form A of a salt of compound I and an acid.

[0093] In one aspect, the present invention provides a pharmaceutical composition comprising: a therapeutically effective amount of a form of Compound I, and a pharmaceutically acceptable excipient.

[0094] In one aspect, the invention provides use of a form or pharmaceutical composition of Compound I for the preparation of a medicament for treating a cancer associated with PARP7.

[0095] In one aspect, the invention provides a method of treating a subject suffering from a PARP7-related cancer, the method comprising administering to the subject a therapeutically effective amount of a form or pharmaceutical composition of Compound I.

[0096] In one aspect, the invention provides a form or pharmaceutical composition of Compound I for use in treating cancer associated with PARP7.

[0097] In some embodiments, the PARP7-associated cancer is a cancer associated with PARP7 overexpression.

[0098] In some embodiments, the cancer is selected from: the cancer is selected from breast cancer, central nervous system cancer, endometrial cancer, kidney cancer, colorectal cancer, lung cancer, esophageal cancer, tongue cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, mesothelioma, melanoma, fibrosarcoma, bladder cancer, rectal cancer, lymphoma, cervical cancer, head and neck cancer, upper aerodigestive tract cancer, colorectal cancer, urinary tract cancer or colon cancer; more preferably, each cancer is independently selected from adenocarcinoma, squamous cell carcinoma, mixed adenosquamous carcinoma, undifferentiated carcinoma; more preferably, the ovarian cancer includes high-grade ovarian severe adenocarcinoma, ovarian mucinous cystadenocarcinoma or malignant ovarian Brenner tumor; renal cancer includes clear cell renal cell carcinoma, ovarian mucinous cystadenocarcinoma or malignant ovarian Brenner tumor; renal cancer includes clear cell renal cell carcinoma, ovarian mucinous cystadenocarcinoma or malignant ovarian Brenner tumor; The following types of cancer include non-small cell lung cancer, ...

[0099] Example

[0100] The following examples are provided to better illustrate the present invention. Unless otherwise expressly stated, all parts and percentages are by weight, and all temperatures are in degrees Celsius. The abbreviations in Table 2 below are used in the examples:

[0101] Table 2

[0102]

[0103]

[0104] Example 1. Synthesis and pharmacological experiments of compound I

[0105] Synthesis of (S)-5-((1-(3-(5-methyl-3-(trifluoromethyl)-8,9-dihydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-7(6H)-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound I)

[0106]

[0107] Step 1: Synthesis of Intermediate A1 (INT A1)

[0108]

[0109] (S)-2-(Benzyloxy)propan-1-ol (21.33 g, 128.33 mmol, 1.0 eq.), tert-butyl acrylate (70.84 g, 552.71 mmol, 4.31 eq.) and Cs2CO3 (125.61 g, 385.52 mmol, 3.00 eq.) were dispersed in DMSO (210 mL). The reaction mixture was stirred at room temperature for 3 hours, poured into water (200 mL), and extracted with EA (200 mL×3). The organic phases were combined, dried over anhydrous Na2SO4 and then concentrated under pressure to give a residue, which was purified by Prep-HPLC (C18 column, H2O / CH3CN elution) to give INT A1-1 (26.52 g), LCMS: m / z=295 [M+1] + .

[0110] A mixture of INT A1-1 (10.71 g, 36.38 mmol, 1.0 eq.), Pd / C (1.02 g, 9.58 mmol, 0.26 eq.) and methanol (10 ml) was purged and maintained under a hydrogen atmosphere, stirred at room temperature for 48 hours, and then filtered. The filtrate was concentrated under reduced pressure to obtain a crude product (9.15 g) containing INT A1-2, which was used directly in the next step without further purification. LCMS: m / z=205[M+1] + .

[0111] Under nitrogen atmosphere, INT A1-2 (9.15 g, 44.80 mmol, 1.09 eq.), 5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazine-3(2H)-one (13.11 g, 41.14 mmol, 1.0 eq.) and t-BuONa (5.52 g, 57.44 mmol, 1.40 eq.) were dispersed in DCM (50 mL). The reaction mixture was stirred at room temperature for 2 hours, washed with NH4Cl(aq.), and then extracted with DCM (50 mL×3). The organic phases were combined, dried over anhydrous Na2SO4, and then concentrated under reduced pressure to give a residue, which was purified by Prep-HPLC (C18 column, H2O / CH3CN elution) to give INT A1-3 (12.81 g). LCMS: m / z=487[M+1] + .

[0112] TFA (10 mL) was added dropwise to a solution of INT A1-3 (12.81 g, 26.33 mmol, 1.0 eq.) dissolved in DCM (40 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours, quenched with saturated NaHCO3 aqueous solution (50 mL), and extracted with EA (100 mL×3). The organic phases were combined, dried over anhydrous Na2SO4, and then concentrated under reduced pressure to give the crude product (11.33 g) of INT A1-4, which was used directly in the next step without further purification. LCMS: m / z=431[M+1] + .

[0113] TfOH (30 mL) was added dropwise to a solution of INT A1-4 (12.81 g, crude product) dissolved in TFA (200 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours, quenched with saturated NaHCO3 aqueous solution (850 mL), and then extracted with EA (500 mL×3). The organic phases were combined, dried over anhydrous Na2SO4, and then concentrated under reduced pressure to give a residue, which was purified by Prep-HPLC (C18 column, H2O / CH3CN elution) to give INT A1 (5.23 g, yield 64%). LCMS: m / z=311[M+1] + .

[0114] Step 2: Synthesis of Intermediate B1 (INT B1)

[0115]

[0116] 4-(tert-Butyloxycarbonyl)piperazine-2-carboxylic acid (21.59 g, 93.76 mmol, 1.0 eq.), N,O-dimethylhydroxylamine hydrochloride (21.55 g, 220.93 mmol, 2.36 eq.), DIPEA (42.43 g, 328.30 mmol, 3.50 eq.) and HATU (43.87 g, 115.38 mmol, 1.23 eq.) were dispersed in CH3CN (200 mL). The reaction mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure to obtain a residue, which was purified by Prep-HPLC (C18 column, eluted with H2O / CH3CN) to obtain INT B1-1 (12.68 g, yield 49%). LCMS: m / z=274[M+1] + .

[0117] 3-Bromo-2-fluoro-5-(trifluoromethyl)pyridine (19.09 g, 78.24 mmol, 1.25 eq.), INT B1-1 (17.10 g, 62.56 mmol, 1.0 eq.) and DIPEA (9.22 g, 71.34 mmol, 1.14 eq.) were dispersed in DMF (100 mL). The reaction mixture was stirred at 80 ° C for 16 hours, poured into water (100 mL), and extracted with DCM (100 mL×3). The organic phases were combined and concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (Hex / EA elution) to obtain INT B1-2 (15.59 g, yield 50%). LCMS: m / z=497, 499 [M+1] + .

[0118] Under nitrogen atmosphere, MeMgBr (14 mL, 42 mmol, 1.54 eq.) was added dropwise to a solution of INT B1-2 (13.59 g, 27.33 mmol, 1.0 eq.) dissolved in THF (140 mL) at -20 ° C. The reaction mixture was stirred at -20 ° C for 3 hours, quenched with saturated NH4Cl aqueous solution (200 mL), and extracted with EA (200 mL×3). The organic phases were combined and then concentrated under reduced pressure to give a residue, which was purified by Prep-HPLC (C18 column, H2O / CH3CN elution) to give INT B1-3 (10.9 g, yield 88%). LCMS: m / z=452,454[M+1] + .

[0119] Under nitrogen atmosphere, n-BuLi (14 mL, 42.0 mmol, 1.74 eq.) was added dropwise to a solution of INT B1-3 (10.9 g, 24.10 mmol, 1.0 eq.) dissolved in THF (100 mL) at -78 ° C. The reaction mixture was stirred at -78 ° C for 1 hour, quenched with saturated NH4Cl aqueous solution (200 mL), and then extracted with EA (200 mL×3). The organic phases were combined and then concentrated under reduced pressure to give a residue, which was purified by Prep-HPLC (C18 column, H2O / CH3CN elution) to give INT B1-4 (2.76 g, yield 30%). LCMS: m / z=374[M+1] + .

[0120] A mixture of INT B1-4 (6.19 g, 16.58 mmol, 1.0 eq.), Et3N (3.69 g, 36.47 mmol, 2.20 eq.), DMAP (122 mg, 0.99 mmol, 0.06 eq.) and DCM (100 mL) was cooled to 0°C, and then MsCl (2.94 g, 25.67 mmol, 1.55 eq.) was added dropwise. The reaction mixture was stirred at 0°C for 1 hour, poured into a saturated aqueous NaHCO3 solution (100 mL), and then extracted with DCM (100 mL×3). The organic phases were combined and then concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (Hex / EA elution) to give INT B1-5 (5.40 g, yield 91%). LCMS: m / z=356[M+1] + .

[0121] A mixture of INT B1-5 (5.05 g, 14.21 mmol, 1.0 eq.) and HCl / 1,4-dioxane (100 mL, 1 N) was stirred at room temperature for 3 hours, and then concentrated under reduced pressure to obtain a crude product of INT B1 hydrochloride (6.72 g), which was used directly in the next step without further purification. LCMS: m / z=256[M+1] + .

[0122] Step 3: Synthesis of Compound I

[0123]

[0124] INT A1 (99 mg, 0.32 mmol, 1.0 eq.), INT B1 (104 mg, 0.36 mmol, 1.13 eq.) and TEA (194 mg, 1.92 mmol, 6.00 eq.) were dissolved in THF (1 mL) to form a solution, and then T3P (312 mg, 0.98 mmol, 3.06 eq.) (50% content in EA) was added to the solution. The reaction mixture was stirred at room temperature for 1 hour. The resulting solution was diluted with water (2 mL), extracted with EA (2×3 mL) and the organic phases were combined, washed with saturated brine (3 mL) and concentrated under vacuum. The resulting residue was purified by Prep-HPLC (C18 column, H2O / CH3CN elution) to give compound I (149.5 mg, yield 85%) as a white foam. LCMS: m / z=548[M+1] + .

[0125] 1H NMR (400MHz, CD3OD) δ8.43(s,1H),8.18(s,1H),8.14(d,J=19.8Hz,1H),5.12-4.98(m,1H),4.89-4.96(m,2H),4.23-4.30(m,2H) ),4.11-3.98(m,2H),3.90-3.81(m,1H),3.77(m,1H),3.72-3.54(m,2H),2.76(t,2H),2.27(d,J=6.2Hz,3H),1.27-1.32(m,3H).

[0126] Pharmacological experiments

[0127] 1. PARP7 enzyme assay

[0128] The PARP7 enzyme inhibitory activity of each compound was tested using HTRF (homogeneous time-resolved fluorescence) assay to obtain its half inhibitory concentration IC 50 .

[0129] (1) Each test compound was prepared by gradient dilution using DMSO and water to obtain solutions with concentrations of 50 nM, 10 nM, 2 nM, 0.4 nM, and 0.08 nM. The concentration of DMSO in each test compound solution was 2%.

[0130] (2) PARP7 enzyme (Cell Chemistry and Biology 27, 877-887, July 16, 2020; its fusion tag is

[0131] N-His6-TEV-AviMHHHHHHSSGVDLGTENLYFQSNAGLNDIFEAQKIEWHE) was dissolved in a buffer solution (the pH value of the buffer solution was 7.4, and the buffer solution contained 25 mM HEPES (N-(2-hydroxyethyl)piperazine-N'-2-sulfonic acid), 120 mM NaCl, 5 mM MgCl2, 2 mM DTT (dithiothreitol), 0.002% (ml / ml) Tween-20, 0.1% (ml / ml) BSA (bovine serum albumin) and water) to obtain a PARP7 enzyme solution with a concentration of 6 nM.

[0132] (3) RBN011147 (Cell Chem Biol 27, 877-887, July 16, 2020), MAb Anti His-Tbcryptate Gold (Cisbio, Cat. No 61GSTTLF, Lot. No 09A) and Streptavidin-d2 (Cisbio, Cat. No610SADLF, Lot. No19G) were diluted with a buffer solution (the pH value of the buffer solution was 7.4, and the buffer solution contained 25 mM HEPES (N-(2-hydroxyethyl)piperazine-N'-2-sulfonic acid), 120 mM NaCl, 5 mM MgCl2, 2 mM DTT (dithiothreitol), 0.002% (ml / ml) Tween-20, 0.1% (ml / ml) BSA (bovine serum albumin) and water) to obtain solutions containing fluorescent groups with concentrations of 10 nM, 0.7 nM and 2.5 nM, respectively.

[0133] (4) 2.5 μl of the test compound solution was transferred to a 384-well plate, and 2.5 μl of PARP7 enzyme solution was added. The resulting solution was incubated for 15 minutes, and then 5 μl of a solution containing a fluorescent group was added. The resulting mixture was incubated at 25° C. for 3 hours to obtain the final test solution.

[0134] (5) Read the fluorescence signal on a SPARK microplate reader (Tecan). The excitation spectrum wavelength of the SPARK microplate reader is 320 nm, and the emission spectrum wavelength of the SPARK microplate reader is 620 nm and 665 nm. Calculate the ratio of the absorbance of each well solution at 620 nm to the absorbance at 665 nm. The ratio is calculated according to the following formula: ratio = absorbance at 665 nm / absorbance at 620 nm × 10 4 .

[0135] (6) The activity of the test compound was calculated according to the following formula: Activity (%) = 100 × (ratio 化合物 -ratio 阴性对照组 ) / (ratio 阳性对照组 -ratio 阴性对照组 ). The positive control group is a whole reaction system containing PARP7 enzyme, RBN011147, MAb AntiHis-Tb cryptate Gold and streptavidin-d2, but DMSO is used instead of the compound. The negative control group is a whole reaction system containing RBN011147, MAb Anti His-Tb cryptate Gold, streptavidin-d2, DMSO is used instead of the compound and does not contain PARP7 enzyme.

[0136] IC was obtained by fitting the four-parameter Logistic (4PL 1 / y2) model 50Value, and the test results are shown in Table 3:

[0137] Table 3

[0138] Compound <![CDATA[PARP7 enzyme (IC 50 μM)]]> Compound I 0.001582

[0139] As can be seen from Table 3, the representative compounds of the present invention have a good inhibitory effect on the PARP7 enzyme.

[0140] 2. Lung cancer cell proliferation inhibition experiment

[0141] In this experiment, the CTG method was used to detect the inhibitory effect of the compound on the proliferation of lung cancer cell line H1373 (highly expressing PARP7), and the half-maximal inhibitory concentration IC of the compound on H1373 was obtained. 50 H1373 cell line was purchased from ATCC, and the complete culture medium was ATCC modified RPMI 1640 medium + 10% FBS (fetal bovine serum) + 1% PS (penicillin-streptomycin liquid). RPMI1640 medium, fetal bovine serum, trypsin were purchased from Gibco, cell culture flasks were purchased from Greiner, disposable cell counting chambers, and trypan blue solution were purchased from Bio-Rad.

[0142] (1) 100 μl of H1373 cell suspension was inoculated into a 96-well cell culture plate, with a density of 1.5×10 4 The culture plate was incubated in an incubator for 16 to 24 hours (37°C, 5% CO2);

[0143] (2) A gradient dilution method was used to obtain solutions of the test compounds of different concentrations. 2 μl of the solution of each test compound was mixed with 198 μl of RPMI 1640 containing 1% PS to obtain a final solution. The final solution was transferred to a culture plate (25 μl / well, 2 parallel wells for each concentration), and the culture plate was cultured in an incubator (37° C., 5% CO2) for 144 hours. Cell Titer Glo reagent was added to each well of the culture plate, and the culture plate was then shaken for 2 minutes and incubated at room temperature for another 10 minutes.

[0144] (3) Measure the luminescence signal of each well on a SPARK microplate reader.

[0145] (4) Calculate the inhibition rate based on the luminescence signal value.

[0146] (5) The inhibition rate curves of different concentrations were fitted, and then the IC of the compound was calculated. 50 .

[0147] The test results are shown in Table 4:

[0148] Table 4

[0149] Compound <![CDATA[H1373(IC 50 μM)]]> Compound I 0.013012

[0150] As can be seen from Table 4, the representative compounds of the present invention have a good inhibitory effect on the proliferation of H1373 cells.

[0151] Example 2. Preparation and Characterization of Crystalline Form 1 of Compound 1

[0152] The compound I (30.98g, 0.057mol) synthesized in Example 1 as a white foam is added to ethanol (300mL) and stirred until the solid is completely dissolved at room temperature. The resulting solution is added dropwise to water (300mL). The mixture is stirred for 1.5 hours and filtered. The filter cake is dried under vacuum at 40 ° C for 20h to obtain a crystalline form 1 of compound I (26.67g, 86% yield) as a white solid. The crystalline form 1 of compound I is analyzed by XRPD, DSC, TGA and DVS by the following general method.

[0153] General Method 1: X-ray Powder Diffraction (XRPD)

[0154] The XRPD patterns and data in the present invention were collected according to the following general protocols.

[0155] Instruments, parameters and methods:

[0156] XRPD was performed on each sample using a Bruker D8 Advance diffractometer. The X-ray tube voltage and current were set to 40 kV and 40 mA, respectively. The collection software (Diffrac Plus XRD Commander) was used to collect the X-rays at a wavelength of Data were collected from 3.0 to 40 degrees (2θ) / 3.0 to 30 degrees (2θ) under Cu Kα radiation using an increment of 0.02 o (2θ) degrees and a scan rate of 0.2 seconds. Typical errors associated with the measurements may be caused by a variety of factors. Therefore, the peaks are considered to have a typical associated error of ±0.2° 2θ.

[0157] The zero background sample holder was 24.6 mm diameter x 1.0 mm thick and manufactured by MTI. Unless otherwise specified, the samples were not ground prior to testing and the sample weight was >2 mg.

[0158] Peak selection method:

[0159] The collected XRPD pattern is imported into MDI Jade. The measured XRPD pattern is aligned with the internal reference sample pattern to determine the absolute peak positions of the sample. The calibration material is corundum and the absolute peak positions of corundum are calculated based on the corundum unit cell parameters. All peaks of the sample are extracted into a table with accurate peak positions and relative peak intensities. A typical error of ±0.2° 2θ for peak position is applicable to this data. Small errors associated with this measurement can be caused by a variety of factors, including:

[0160] (a) Sample preparation (e.g. sample height);

[0161] (b) Instruments;

[0162] (c) calibration;

[0163] (d) operator (including those errors that occur in determining peak positions), and

[0164] (e) Properties of the material (e.g. errors in preferred orientation and transparency).

[0165] Therefore, the peaks are considered to have a typical associated error of ±0.2° 2θ. When the higher intensity peak has a shoulder, whether the 2θ difference between the higher intensity peak and the shoulder is less than or greater than 0.2° 2θ, the higher intensity peak is preferably selected as the characteristic peak and the lower intensity shoulder is not selected as the characteristic peak.

[0166] General Method 2: Differential Scanning Calorimetry (DSC)

[0167] DSC analysis was performed using a TA Instruments Q200 DSC. The sample pan was aluminum with holes on it. The sample weight was 0.5 mg to 5 mg. The sample was analyzed at a heating rate of 10 °C / min from a starting temperature of 0 °C to a maximum end temperature of 300 °C or 350 °C under a nitrogen flow of 50 mL / min.

[0168] General Method 3: Thermogravimetric Analysis (TGA)

[0169] TGA measurements were performed using a TAInstruments Q500 TGA with nitrogen purge gas at a flow rate of 40 ml / min (high resolution sensitivity 3.0; ramp 10.00°C / min, resolution 5.0 to 150.00°C; ramp 10.00°C / min to 350°C). The sample pan was a platinum pan. The sample weight was 1 mg to 10 mg.

[0170] General Method 4: Dynamic Vapor Sorption Analysis (DVS)

[0171] DVS analysis was performed using Intrinsic PLUS. The sample pan was a stainless steel pan. The sample weight was 58.24 mg. The sample was analyzed at an equilibrium temperature of 25°C and a humidity of 0%; isothermal for 90 minutes; if the weight (%) < 0.0100 for 15.00 minutes, the next step was aborted; the humidity was increased from 10% to 80% every 90 minutes; if the weight (%) < 0.0100 for 15.00 minutes, the next step was aborted; the humidity was gradually reduced from 10% to 0% every 90 minutes at a nitrogen flow rate of 200 sccm.

[0172] The results are as follows Figure 1-Figure 5 Some characteristic peaks in the XRPD pattern are listed in Table 5.

[0173] Table 5

[0174] 2θ d-spacing strength% 8.12 10.88 5.4 11.96 7.40 100 12.49 7.08 13.8 13.48 6.56 30.7 15.27 5.80 58.7 16.11 5.50 12.5 16.49 5.37 12.1 19.79 4.48 25.4 20.30 4.37 35 21.45 4.14 65.2 22.59 3.93 83 24.06 3.70 58.4

[0175] Example 3. Stability Evaluation of Compound 1 Crystalline Form 1

[0176] The stability of crystalline form 1 of Compound 1 was tested as shown in Table 6 below.

[0177] Table 6 Solid-state stability information of crystalline form 1 of compound 1

[0178]

[0179]

[0180] The solid-state stability of the crystalline form 1 of compound I was studied under high humidity (25°C ± 2°C, 90% RH ± 5% RH), high temperature (50°C ± 5°C, <30% RH), long-term (25°C ± 5°C, 60% RH ± 5%), and accelerated (40°C ± 2°C, 75% RH ± 5%) conditions, and was placed in an open and dark environment for 10 days. The results showed that the crystal form did not change under the four conditions, the melting point was within the range of ± 1°C, and the purity decreased by no more than 0.1%.

[0181] Example 4. Equilibrium Solubility of Crystalline Form 1 of Compound 1

[0182] The equilibrium solubility of crystalline Form 1 of Compound 1 was tested according to Table 7 below.

[0183] Table 7 Equilibrium solubility experimental information of crystalline form 1 of compound 1

[0184] project content Crystal form Crystalline Form 1 medium Water, gastric simulation fluid, full stomach simulation fluid, fasting stomach simulation fluid temperature 25℃、37℃ Detection time 4h、24h Test items Concentration (HPLC); Crystal form (detection if sufficient solids remain after 24 hours, XRPD)

[0185] The equilibrium solubility of the crystalline form 1 of compound I was determined, and the results showed that:

[0186] (1) The solubility of crystalline form 1 of compound I in the satiety intestinal simulated fluid was slightly higher, 0.1 mg / mL;

[0187] (2) The crystalline form 1 of compound I has basically reached saturation in water (25°C), gastric simulated fluid (37°C), fasting intestinal simulated fluid (37°C), and full intestinal simulated fluid (37°C) within 4 h;

[0188] (3) The crystalline form 1 of compound I remained unchanged after being in water (25°C), gastric simulated fluid (37°C), fasting intestinal simulated fluid (37°C), and full intestinal simulated fluid (37°C) for 24 hours.

[0189] Example 5. Preparation and characterization of amorphous compound I

[0190] About 1.5 g of compound I was ultrasonically dissolved in 10 mL of acetone and concentrated under reduced pressure at 50° C. to obtain amorphous compound I. The amorphous compound I was analyzed by XRPD spectrum using the general method 1 above. The results are as follows: Fig.12 shown.

[0191] Example 6. Preparation and characterization of crystalline form A of tosylate salt of compound I

[0192] Step 1: About 200 mg of compound I in the form of white foam was dissolved in 5.0 mL of ethyl acetate to obtain solution 1.

[0193] Step 2: About 69 mg of p-toluenesulfonic acid was dissolved in 0.2 mL of ethanol to obtain Solution 2.

[0194] Step 3: Add solution 2 to solution 1 under stirring at room temperature to obtain solution 3.

[0195] Step 4: Stir at room temperature for 0.5 h, no precipitation occurs, then stir at 4°C overnight, no precipitation occurs, add 15.0 mL of n-heptane, precipitation occurs, then stir at 4°C overnight, the precipitate does not disappear.

[0196] Step 5: The precipitate was centrifuged and dried under vacuum at room temperature overnight to obtain crystalline Form A of the tosylate salt.

[0197] Step 6: Perform XRPD, DSC, TGA, PLM and 1 H-NMR analysis, the results are as follows Figure 11-16 shown.

[0198] Example 7. Evaluation of the Hygroscopicity of the Crystalline Form A of the Tosylate Salt of Compound I

[0199] The hygroscopicity of the crystalline form A of the tosylate salt of Compound I was tested, and the results were as follows: Fig.16 shown.

[0200] Each reference, including all patents, patent applications and publications cited in this application, is incorporated herein by reference in its entirety, just as each of them is incorporated individually. Further, it should be understood that in the above teachings of the present invention, those skilled in the art may make certain changes or modifications to the present invention, and these equivalents still fall within the scope of the present invention as defined by the appended claims of the present application.

Claims

1. A form of Compound I selected from: Crystallization of Compound I; A salt of compound I with an acid; and Crystallization of the salt of compound I with an acid; in, The compound I is: The acid is selected from hydrochloric acid, sulfuric acid, hydrobromic acid, methanesulfonic acid, p-toluenesulfonic acid, oxalic acid, maleic acid, phosphoric acid, L-tartaric acid, fumaric acid, citric acid, lactobionic acid, mandelic acid, L-malic acid, hippuric acid, L-lactic acid, succinic acid, benzoic acid, adipic acid, and acetic acid.

2. The form of Compound 1 according to claim 1, wherein the crystal of Compound 1 is Crystalline Form 1 of Compound 1, and the Crystalline Form 1 of Compound 1 is characterized in that the X-ray powder diffraction pattern comprises characteristic peaks at the following 2θ values: 8.12±0.2°, 11.96±0.2°, 13.48±0.2° and 15.27±0.2°.

3. The form of Compound 1 according to claim 2, wherein the X-ray powder diffraction pattern further comprises one or more characteristic peaks selected from the following 2θ values: 16.11±0.2°, 16.49±0.2°, 19.79±0.2° and 20.30±0.2°.

4. The form of Compound 1 according to claim 2 or 3, wherein the X-ray powder diffraction pattern further comprises: The 2θ value is selected from one or two characteristic peaks of 19.79±0.2° and 20.30±0.2°, and The 2θ value is selected from one or two characteristic peaks of 16.11±0.2° and 16.49±0.2°.

5. The form of Compound 1 according to any one of claims 2 to 4, wherein the X-ray powder diffraction pattern further comprises characteristic peaks selected from the following 2θ values: 16.11 ± 0.2° and 16.49 ± 0.2°; 16.11±0.2°, 16.49±0.2°, and 20.30±0.2°; 16.11 ± 0.2°, 16.49 ± 0.2°, and 19.79 ± 0.2°; 19.79 ± 0.2° and 20.30 ± 0.2°; 16.11±0.2°, 19.79±0.2° and 20.30±0.2°; or 16.49±0.2°, 19.79±0.2° and 20.30±0.2°.

6. The form of Compound 1 according to any one of claims 2 to 5, wherein the X-ray powder diffraction pattern comprises characteristic peaks at the following 2θ values: 8.12±0.2°, 11.96±0.2°, 13.48±0.2°, 15.27±0.2°, 16.11±0.2°, 16.49±0.2°, 19.79±0.2°, and 20.30±0.2°.

7. The form of Compound 1 according to any one of claims 2 to 6, wherein the X-ray powder diffraction pattern comprises one or two characteristic peaks selected from the following 2θ values: 12.49±0.2° and 21.45±0.2°.

8. The form of Compound 1 according to any one of claims 2 to 7, wherein the X-ray powder diffraction pattern comprises characteristic peaks at the following 2θ values: 8.12±0.2°, 11.96±0.2°, 12.49±0.2°, 13.48±0.2°, 15.27±0.2°, 16.11±0.2°, 16.49±0.2°, 19.79±0.2°, 20.30±0.2°, and 21.45±0.2°.

9. The form of Compound 1 according to any one of claims 2 to 8, wherein the X-ray powder diffraction pattern comprises one or two characteristic peaks selected from the following 2θ values: 22.59±0.2° and 24.06±0.2°.

10. The form of Compound 1 according to any one of claims 2 to 9, wherein the X-ray powder diffraction pattern comprises characteristic peaks at the following 2θ values: 8.12±0.2°, 11.96±0.2°, 12.49±0.2°, 13.48±0.2°, 15.27±0.2°, 16.11±0.2°, 16.49±0.2°, 19.79±0.2° and 20.30±0.2°, 21.45±0.2°, 22.59±0.2° and 24.06±0.2°; In some embodiments, the crystalline Form 1 of Compound 1 is characterized in that an X-ray powder diffraction pattern comprises characteristic peaks with 2θ values ​​in Table 1 in the specification.

11. The form of Compound 1 according to any one of claims 2 to 10, wherein the X-ray powder diffraction pattern is the same as Figure 1.

12. The form of Compound 1 according to claim 1, wherein the acid is p-toluenesulfonic acid.

13. The form of Compound 1 according to claim 12, wherein the crystalline Form A of the salt of Compound 1 with an acid is characterized in that the X-ray powder diffraction pattern comprises characteristic peaks at the following 2θ values: 6.74±0.2°, 9.12±0.2°, 14.75±0.2° and 15.93±0.2°.

14. The form of Compound 1 according to claim 12 or 13, wherein the X-ray powder diffraction pattern further comprises one or more characteristic peaks selected from the following 2θ values: 11.94±0.2°, 12.73±0.2°, 15.26±0.2°, and 16.55±0.2°.

15. The form of Compound 1 according to any one of claims 12 to 14, wherein the X-ray powder diffraction pattern further comprises: The 2θ value is selected from one or two characteristic peaks of 11.94±0.2° and 12.73±0.2°, and The 2θ value is selected from one or two characteristic peaks of 15.26±0.2° and 16.55±0.2°.

16. The form of Compound 1 according to any one of claims 12 to 15, wherein the X-ray powder diffraction pattern comprises characteristic peaks at the following 2θ values: 6.74±0.2°, 9.12±0.2°, 11.94±0.2°, 12.73±0.2°, 14.75±0.2°, 15.26±0.2°, 15.93±0.2°, and 16.55±0.2°.

17. The form of Compound 1 according to any one of claims 12 to 16, wherein the X-ray powder diffraction pattern further comprises one or two characteristic peaks selected from the following 2θ values: 18.24±0.2°, 21.09±0.2°, and 22.25±0.2°.

18. The form of Compound 1 according to any one of claims 12 to 17, wherein the X-ray powder diffraction pattern comprises characteristic peaks at the following 2θ values: 6.74±0.2°, 9.12±0.2°, 11.94±0.2°, 12.73±0.2°, 14.75±0.2°, 15.26±0.2°, 15.93±0.2°, 16.55±0.2°, 18.24±0.2°, 21.09±0.2°, and 22.25±0.2°.

19. The form of Compound 1 according to any one of claims 12 to 18, wherein the X-ray powder diffraction pattern is the same as Figure 11.

20. A method for preparing the crystalline Form 1 of Compound 1 according to any one of claims 2 to 11, comprising: Dissolving compound I in ethanol; Add water to precipitate the solid; And filter.

21. A method for preparing a crystalline form A of a salt of compound I with an acid according to any one of claims 12 to 19, comprising: Dissolve compound I in ethyl acetate to obtain solution 1; Dissolve p-toluenesulfonic acid in ethanol to obtain solution 2; Solution 2 is added to solution 1 to obtain solution 3; n-heptane is added and stirred until a precipitate is produced, and then stirring is continued and the precipitate does not disappear; The precipitate is centrifuged and dried to obtain the crystalline form A of the salt of compound I with an acid.

22. A pharmaceutical composition comprising: a therapeutically effective amount of a form of Compound I according to any one of claims 1 to 19, and a pharmaceutically acceptable excipient.

23. Use of a form of Compound 1 according to any one of Claims 1 to 19 or a pharmaceutical composition according to Claim 22 for the preparation of a medicament for treating cancer associated with PARP7.

24. The use according to claim 23, wherein the cancer associated with PARP7 is a cancer associated with overexpression of PARP7.

25. The use according to claim 23 or 24, wherein the cancer is selected from: the cancer is selected from breast cancer, central nervous system cancer, endometrial cancer, kidney cancer, colorectal cancer, lung cancer, esophageal cancer, tongue cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, mesothelioma, melanoma, fibrosarcoma, bladder cancer, rectal cancer, lymphoma, cervical cancer, head and neck cancer, upper aerodigestive tract cancer, colorectal cancer, urinary tract cancer or colon cancer; more preferably, each cancer is independently selected from adenocarcinoma, squamous cell carcinoma, mixed adenosquamous carcinoma, undifferentiated carcinoma; more preferably, the ovarian cancer includes high-grade ovarian severe adenocarcinoma, ovarian mucinous cystadenocarcinoma or malignant ovarian Brenner tumor; kidney cancer includes percutaneous cystic fibrosis; The following types of cancer include: clear cell renal cell carcinoma; tongue cancer includes tongue squamous cell carcinoma; lung cancer includes lung adenocarcinoma, lung adenosquamous carcinoma, squamous cell lung cancer, large cell lung cancer, small cell lung cancer, lung papillary adenocarcinoma or non-small cell lung cancer; pancreatic cancer includes pancreatic adenocarcinoma or pancreatic ductal adenocarcinoma; esophageal cancer includes esophageal squamous cell carcinoma; mesothelioma includes biphasic mesothelioma; central nervous system cancer includes glioma, glioblastoma or glioblastoma multiforme; gastric cancer includes gastric adenocarcinoma; breast cancer includes ductal breast cancer, breast cancer or HR+ breast cancer; bladder cancer includes bladder squamous cell carcinoma; melanoma includes malignant melanoma; colon cancer includes colon adenocarcinoma; head and neck cancer includes head and neck small squamous cell carcinoma.

26. A method of treating a subject having a cancer associated with PARP7, the method comprising: Administering to a subject a therapeutically effective amount of Compound 1 according to any one of claims 1 to 19 in the form of a pharmaceutical composition according to claim 22.

27. The method of claim 26, wherein the PARP7-associated cancer is a cancer associated with PARP7 overexpression.

28. The method according to claim 26 or 27, wherein the cancer is selected from: the cancer is selected from breast cancer, central nervous system cancer, endometrial cancer, kidney cancer, colorectal cancer, lung cancer, esophageal cancer, tongue cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, mesothelioma, melanoma, fibrosarcoma, bladder cancer, rectal cancer, lymphoma, cervical cancer, head and neck cancer, upper aerodigestive tract cancer, colorectal cancer, urinary tract cancer or colon cancer; more preferably, each cancer is independently selected from adenocarcinoma, squamous cell carcinoma, mixed adenosquamous carcinoma, undifferentiated carcinoma; more preferably, the ovarian cancer includes high-grade ovarian severe adenocarcinoma, ovarian mucinous cystadenocarcinoma or malignant ovarian Brenner tumor; kidney cancer includes clear cell renal cell carcinoma; tongue cancer includes tongue squamous cell carcinoma; lung cancer includes lung adenocarcinoma, lung adenosquamous carcinoma, squamous cell lung cancer, large cell lung cancer, small cell lung cancer, lung papillary adenocarcinoma, or non-small cell lung cancer; pancreatic cancer includes pancreatic adenocarcinoma or pancreatic ductal adenocarcinoma; esophageal cancer includes esophageal squamous cell carcinoma; mesothelioma includes biphasic mesothelioma; central nervous system cancer includes glioma, glioblastoma, or glioblastoma multiforme; gastric cancer includes gastric adenocarcinoma; breast cancer includes ductal breast cancer, breast cancer, or HR+ breast cancer; bladder cancer includes bladder squamous cell carcinoma; melanoma includes malignant melanoma; colon cancer includes colon adenocarcinoma; head and neck cancer includes head and neck small squamous cell carcinoma.

29. A form of Compound 1 according to claims 1-19 or a pharmaceutical composition according to claim 22 for use in treating cancer associated with PARP7.

30. A form or pharmaceutical composition of Compound 1 for use in treating a PARP7-associated cancer according to claim 29, wherein the PARP7-associated cancer is a cancer associated with PARP7 overexpression.

31. A form or pharmaceutical composition of Compound 1 for use in treating a cancer associated with PARP7 according to claim 29 or 30, wherein the cancer is selected from breast cancer, central nervous system cancer, endometrial cancer, kidney cancer, colorectal cancer, lung cancer, esophageal cancer, tongue cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, mesothelioma, melanoma, fibrosarcoma, bladder cancer, rectal cancer, lymphoma, cervical cancer, head and neck cancer, upper aerodigestive tract cancer, colorectal cancer, urinary tract cancer or colon cancer; more preferably, each cancer is independently selected from adenocarcinoma, squamous cell carcinoma, mixed adenosquamous carcinoma, undifferentiated carcinoma; more preferably, the ovarian cancer comprises high-grade ovarian severe adenocarcinoma, ovarian mucinous cystadenocarcinoma or malignant ovarian cancer. ovarian Brenner tumor; renal cancer includes clear cell renal cell carcinoma; tongue cancer includes tongue squamous cell carcinoma; lung cancer includes lung adenocarcinoma, lung adenosquamous carcinoma, squamous cell lung cancer, large cell lung cancer, small cell lung cancer, lung papillary adenocarcinoma or non-small cell lung cancer; pancreatic cancer includes pancreatic adenocarcinoma or pancreatic ductal adenocarcinoma; esophageal cancer includes esophageal squamous cell carcinoma; mesothelioma includes biphasic mesothelioma; central nervous system cancer includes glioma, glioblastoma or glioblastoma multiforme; gastric cancer includes gastric adenocarcinoma; breast cancer includes ductal breast cancer, breast cancer or HR+ breast cancer; bladder cancer includes bladder squamous cell carcinoma; melanoma includes malignant melanoma; colon cancer includes colon adenocarcinoma; head and neck cancer includes head and neck small squamous cell carcinoma.

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