Heterocyclic deuterated compound and application thereof

Abstract

The invention discloses a heterocyclic-fused deuterated compound and application thereof, and belongs to the technical field of chemical medicines. The heterocycle deuterated compound as shown in the formula (I) provided by the invention can be used as a PARP1 inhibitor, has the advantages of high activity and high selectivity, and also has excellent pharmacokinetic properties and excellent safety. # imgabs0 #

Description

Heterocyclic deuterated compounds and uses thereof Technical Field

[0001] The present invention belongs to the field of chemical medicine and relates to a class of heterocyclic deuterated compounds and uses thereof. Background Art

[0002] As cells grow, their DNA is constantly damaged by various internal and external factors. The most severe types of DNA damage are single-strand breaks and double-strand breaks, with single-strand breaks being more common. If these breaks are not repaired promptly and accurately, they can lead to genomic instability, cancer, and even direct cell death. The repair of single-strand breaks in DNA primarily relies on the enzyme PARP. Double-strand breaks can be repaired through two methods: non-homologous end joining repair and homologous recombination repair. Homologous recombination repair is a high-fidelity, error-free repair method and the primary pathway for double-stranded DNA repair. Numerous proteins are involved in homologous recombination repair, the most well-known of which are the BRCA proteins. Two studies in 2005 (Farmer H, McCabe N, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy [J]. Nature, 2005, 434(7035): 917-921. Bryant, H., Schultz, N., Thomas, H. et al. Specific killing of BRCA2-deficient tumors with inhibitors of poly(ADP-ribose)polymerase. Nature 434, 913–917 (2005)) showed that tumor cells lacking BRCA1 or BRCA2 are selectively inhibited by PARP inhibitors. Based on this research result, scholars proposed the concept of synthetic lethality: the loss of either BRCA or PARP gene is not lethal in itself, but the simultaneous inactivation of both will lead to cell death. Based on the theory of synthetic lethality, PARP inhibitors (PARPi) have been developed to selectively target cancer cells with BRCA1 / 2 mutations.

[0003] PARP inhibitors have shown excellent clinical efficacy in patients with homologous recombination-deficient cancers. However, whether used as a single agent or in combination therapy, hematological toxicity (anemia, neutropenia, and thrombocytopenia) and other toxicities limit the application of this type of drug. Related studies have shown (Harris PA, Boloor A, Cheung M, et al. Discovery of 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methyl-benzenesulfonamide (Pazopanib), a novel and potent vascular endothelial growth factor receptor inhibitor. [J]. Journal of Medicinal Chemistry, 2008, 51(15): 4632.) These adverse reactions may be due to the inhibition of PARP2 by marketed PARP inhibitors, which is not essential for efficacy. Highly selective PARP1 inhibitors can reduce hematological toxicity, increase the therapeutic safety window, and increase the potential for combination with other chemotherapy or targeted drugs.

[0004] Therefore, there is an unmet clinical need for effective and safe PARP inhibitors, particularly PARP inhibitors that are selective for PARP1. The novel PARP1 inhibitors described in the present invention are unexpectedly selective for PARP1 over other PARP family members (such as PARP2, PARP3, PARP5a, and PARP6) and can be used to treat diseases related to PARP function.

[0005] Summary of the Invention

[0006] The purpose of the present invention is to provide a class of heterocyclic deuterated compounds and their uses to achieve highly selective and efficient prevention or treatment of diseases related to PARP function.

[0007] In a first aspect, the present invention provides a compound represented by Formula I or a pharmaceutically acceptable form thereof, wherein the structure of Formula I is as follows:

[0008] in:

[0009] R1 is selected from halogen, C 1-4 Alkyl, C 1-4 Fluorinated alkyl, C 1-4 Alkoxy, C 1-4 Fluorinated alkoxy, 3- to 6-membered cycloalkyl, or 3- to 6-membered fluorinated cycloalkyl;

[0010] X1 is selected from N or CR 5a , X2 is selected from N or CR 5b , X3 is selected from N or CR 5c ;

[0011] R6 is selected from hydrogen or halogen;

[0012] R4 is -CONHR7, R7 is selected from C 1-4 Alkyl, C 1-4 Fluorinated alkyl, C 1-4 Deuterated alkyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered fluorinated cycloalkyl;

[0013] R 9a Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Fluorinated alkyl, C 1-4 Alkoxy, C 1-4 Fluorinated alkoxy, 3- to 6-membered cycloalkyl, 3- to 6-membered fluorinated cycloalkyl or cyano;

[0014] R 9c is selected from hydrogen or halogen;

[0015] R2 is selected from hydrogen or C 1-4 alkyl;

[0016] R 5a Selected from hydrogen, halogen or C 1-4 Alkyl, R 5b is selected from hydrogen or halogen, R 5c is selected from hydrogen or halogen;

[0017] Ring A is selected from (Ring A's right end is connected to the main ring pyridine)

[0018] The pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled substances, metabolites, or prodrugs.

[0019] In some preferred embodiments of the present invention, in the compound represented by the above formula I or a pharmaceutically acceptable form thereof, R1 is selected from chloro, methyl, ethyl, fluoromethyl, fluoroethyl, cyclopropyl or fluorocyclopropyl.

[0020] In some preferred embodiments of the present invention, in the compound represented by the above formula I or a pharmaceutically acceptable form thereof, R6 is selected from hydrogen or fluorine.

[0021] In some preferred embodiments of the present invention, in the compound represented by the above formula I or a pharmaceutically acceptable form thereof, R7 is selected from methyl, ethyl, deuterated methyl, deuterated ethyl, fluoromethyl, fluoroethyl, cyclopropyl or fluorocyclopropyl.

[0022] In some preferred embodiments of the present invention, in the compound represented by the above formula I or a pharmaceutically acceptable form thereof, R 9a is selected from hydrogen, fluorine, chlorine, methyl, ethyl, fluoromethyl, fluoroethyl, cyclopropyl or fluorocyclopropyl.

[0023] In some preferred embodiments of the present invention, in the compound represented by the above formula I or a pharmaceutically acceptable form thereof, R 9c is selected from hydrogen or fluorine.

[0024] In some preferred embodiments of the present invention, in the compound represented by the above formula I or a pharmaceutically acceptable form thereof, R2 is selected from hydrogen or methyl.

[0025] In some preferred embodiments of the present invention, in the compound represented by the above formula I or a pharmaceutically acceptable form thereof, R 5a is selected from hydrogen, fluorine or methyl, R 5b is selected from hydrogen or fluorine, R 5c is selected from hydrogen or fluorine.

[0026] In some preferred embodiments of the present invention, in the compound represented by the above formula I or a pharmaceutically acceptable form thereof, the structural unit Selected from the following structures:

[0027] In some preferred embodiments of the present invention, in the compound represented by the above formula I or a pharmaceutically acceptable form thereof, the structural unit Selected from the following structures:

[0028] The present invention also provides some specific compounds, which are selected from:

[0029] The present invention also provides some specific compounds, which are selected from:

[0030] In a second aspect, the present invention provides a pharmaceutical composition comprising the aforementioned compound of formula I or its pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, nitrogen oxides, isotope-labeled substances, metabolites or prodrugs as an active ingredient, supplemented with a pharmaceutically acceptable carrier.

[0031] A further object of the present invention is to provide a method for preparing the pharmaceutical composition of the present invention, which comprises combining any compound of Formula I or a pharmaceutically acceptable form thereof, or a mixture thereof, with one or more pharmaceutically acceptable carriers.

[0032] The pharmaceutically acceptable carrier that can be used in the pharmaceutical composition of the present invention is a pharmaceutically acceptable carrier. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (2005).

[0033] The pharmaceutical composition can be administered in any form, as long as it prevents, alleviates, prevents or cures the symptoms of a human or animal patient. For example, it can be prepared into various suitable dosage forms according to the route of administration.

[0034] In other embodiments, the administration of the compound or pharmaceutical composition of the present invention can be combined with another treatment method. The other treatment method can be selected from, but not limited to: radiation therapy, chemotherapy, immunotherapy, or a combination thereof.

[0035] The present invention also relates to a pharmaceutical preparation comprising any compound of Formula I or a pharmaceutically acceptable form thereof, or a mixture thereof as an active ingredient, or a pharmaceutical composition of the present invention. In some embodiments, the preparation is in the form of a solid preparation, a semi-solid preparation, a liquid preparation, or a gaseous preparation.

[0036] A further object of the present invention is to provide an article of manufacture, for example, in the form of a kit. As used herein, an article of manufacture is intended to include, but is not limited to, a kit and packaging. The article of manufacture of the present invention comprises: (a) a first container; (b) a pharmaceutical composition in the first container, wherein the composition comprises: a first therapeutic agent, wherein the first therapeutic agent comprises: any compound comprising Formula I or a pharmaceutically acceptable form thereof, or a mixture thereof; (c) an optional package insert indicating that the pharmaceutical composition can be used to treat a neoplastic condition (as defined below); and (d) a second container.

[0037] The first container is a container for holding a pharmaceutical composition. This container can be used for preparation, storage, transportation and / or individual / bulk sales. The first container is intended to encompass bottles, jars, vials, flasks, syringes, tubes (e.g., for cream products), or any other container for preparing, holding, storing, or dispensing pharmaceutical products.

[0038] The second container is a container for accommodating the first container and optional package insert. Examples of the second container include, but are not limited to, boxes (e.g., paper or plastic boxes), boxes, cartons, bags (e.g., paper or plastic bags), pouches, and sacks. The package insert can be physically adhered to the outside of the first container via a cable tie, glue, staples, or other adhesion methods, or it can be placed inside the second container without any physical tool for adhering to the first container. Alternatively, the package insert is located outside the second container. When located outside the second container, it is preferred that the package insert is physically adhered via a cable tie, glue, staples, or other adhesion methods. Alternatively, it can abut or contact the outside of the second container without physical adhesion.

[0039] The package insert is a trademark, label, or indicia that lists information about the pharmaceutical composition within the first container. The information listed is typically determined by the regulatory agency (e.g., the U.S. Food and Drug Administration) that governs the region in which the product is to be sold. Preferably, the package insert specifically lists the indications for which the pharmaceutical composition is approved. The package insert can be made of any material from which the information contained therein or thereon can be read. Preferably, the package insert is a printable material (e.g., paper, plastic, cardboard, foil, adhesive paper, or plastic, etc.) onto which the desired information can be formed (e.g., printed or applied).

[0040] In a third aspect, the present invention provides the use of the aforementioned compound of formula I, and related specific compounds or pharmaceutically acceptable forms thereof, or the pharmaceutical composition of the present invention in the preparation of a medicament for preventing or treating PARP1 enzyme-related diseases.

[0041] The present invention provides a method for preventing or treating PARP1 enzyme-related diseases, comprising administering a compound of formula I or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the present invention to a subject in need thereof.

[0042] The present invention provides a compound of formula I or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the present invention, for use in preventing or treating PARP1 enzyme-related diseases.

[0043] The present invention provides a method for preventing or treating PARP1 enzyme-related diseases in combination with a compound of Formula I or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the present invention, wherein the additional treatment method includes but is not limited to: radiotherapy, chemotherapy, immunotherapy, or a combination thereof.

[0044] In some embodiments, the PARP1 enzyme-related disease is a disease that is sensitive or responsive to PARP1 enzyme inhibition.

[0045] In some embodiments, the PARP1 enzyme-related disease is a tumor-related disorder.

[0046] In some preferred embodiments, the oncological disorder is deficient in a HR-dependent DNA DSB repair pathway.

[0047] In some preferred embodiments, the neoplastic disorder comprises one or more cancer cells that have a reduced or absent ability to repair DNA DSBs by HR relative to normal cells.

[0048] In some preferred embodiments, the cancer cells have a BRCA1 or BRCA2 deficient phenotype.

[0049] In some embodiments, the PARP1 enzyme-related disease is a tumor-related disorder, including but not limited to solid and hematological malignancies. In further embodiments, the tumor-related disorder includes but is not limited to breast cancer, colorectal cancer, colon cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer and bronchioloalveolar cancer) and prostate cancer, as well as bile duct cancer, bone cancer, bladder cancer, head and neck cancer, kidney cancer, liver cancer, gastrointestinal tissue cancer, esophageal cancer, ovarian cancer, pancreatic cancer, skin cancer, testicular cancer, thyroid cancer, uterine cancer, cervical cancer and vulvar cancer, as well as leukemia (including chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL) and chronic myeloid leukemia (CML)), multiple myeloma or lymphoma.

[0050] In some preferred embodiments, the tumor-like disorder is breast cancer, ovarian cancer, primary peritoneal cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer, glioblastoma or lung cancer.

[0051] In a further preferred embodiment, the compounds of the present invention can be used in combination with chemoradiotherapy or immunotherapy to prevent or treat cancer.

[0052] Beneficial effects of the present invention:

[0053] The present invention provides a novel class of highly active and highly selective PARP1 inhibitors capable of achieving at least one of the following technical effects: (1) high inhibitory activity against PARP1 enzyme; (2) selective inhibition of PARP1 enzyme, with high selectivity for other PARP family enzymes such as PARP2, PARP5a, and PARP5b; (3) strong inhibitory activity against homologous recombination-deficient tumor cells and weak inhibitory effect on non-homologous recombination-deficient cells; (4) excellent pharmacokinetic properties (e.g., good bioavailability, suitable half-life and duration of action); (5) excellent safety (lower toxicity and / or fewer side effects, wider therapeutic window), etc.

[0054] Definition of terms:

[0055] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by those skilled in the art. The terms "include," "comprising," "having," "containing," or "involving," and their variations herein, are inclusive or open-ended and do not exclude other unrecited elements or method steps. It should be understood by those skilled in the art that the above terms, such as "comprising," encompass the meaning of "consisting of."

[0056] In the present invention, "a", "an", "the", "at least one" and "one or more" are used interchangeably. Thus, for example, a composition comprising "a" pharmaceutically acceptable excipient can be interpreted to mean that the composition includes "one or more" pharmaceutically acceptable excipients.

[0057] When the lower and upper limits of a numerical range are disclosed, any value and any included range falling within the range are specifically disclosed. In particular, each range of values ​​disclosed herein (in the form "about a to b," or equivalently, "approximately a to b," or equivalently, "about a b") should be understood to represent each value and range encompassed within the broader range.

[0058] For example, the statement "C 1-4 " should be understood to include any sub-ranges therein and each point value, such as C 2-4 、C 3-4 、C 1-2 、C 1-3 、C 1-4 etc., as well as C1, C2, C3, C4, etc.

[0059] In the present invention, unless otherwise specified, halogen means fluorine, chlorine, bromine or iodine.

[0060] In the present invention, unless otherwise specified, "alkyl" includes a linear or branched monovalent saturated hydrocarbon group. For example, alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, etc. Similarly, "C 1-4 C in "alkyl" 1-4 It refers to a group containing 1, 2, 3 or 4 carbon atoms in a straight or branched chain.

[0061] In the present invention, unless otherwise specified, "cycloalkyl", "carbocycle" or "cycloalkylene" refers to a saturated or partially saturated, monocyclic or polycyclic (such as bicyclic) non-aromatic hydrocarbon group. Common cycloalkyl groups include (but are not limited to) monocyclic cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclobutene, cyclopentene, cyclohexene, etc.; or bicyclic cycloalkyl groups, including fused rings, bridged rings or spiro rings, such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[5.2.0]nonyl, decalinyl, etc. For example, "C 3-12 cycloalkyl" refers to a cycloalkyl group having 3-12 ring carbon atoms (such as 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12). The cycloalkyl or cycloalkylene group in the present invention is optionally substituted with one or more substituents described herein.

[0062] In the present invention, unless otherwise specified, "fluoroalkyl" refers to the alkyl group described above, wherein one or more hydrogen atoms are replaced by fluorine atoms. For example, the term "C 1-4 "Fluoroalkyl" refers to a C group optionally substituted by one or more (e.g. 1-3) fluorine atoms. 1-4 Alkyl. It will be understood by those skilled in the art that when there are more than one fluorine atom substituent, the fluorine atoms may be the same or different and may be located on the same or different C atoms. Examples of haloalkyl groups include -CH2F, -CHF2, -CF3, -C2F5, -CH2CF3, -CH2CH2CF3, etc. The fluoroalkyl groups of the present invention are optionally substituted with one or more substituents described herein.

[0063] The present invention also includes all pharmaceutically acceptable isotopically labeled compounds, which are identical to the compounds of the present invention except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevalent in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium ( 2 H), tritium ( 3 H)); carbon isotopes (e.g. 13 C and 14 C); isotopes of chlorine (such as 37Cl); isotopes of iodine (such as 125 I); isotopes of nitrogen (e.g. 13 N and 15 N); oxygen isotopes (e.g. 17 O and 18 O); isotopes of phosphorus (such as 32 P); and sulfur isotopes (e.g. 34 S).

[0064] As used herein, "polymorph" refers to different solid crystalline phases of certain compounds of the present invention resulting from the presence of two or more different molecular arrangements in the solid state. Certain compounds of the present invention may exist in more than one crystalline form, and the present invention is intended to encompass various crystalline forms and mixtures thereof. Typically, crystallization produces solvates of the compounds of the present invention. The term "solvate," as used herein, refers to an aggregate comprising one or more molecules of the compound of the present invention and one or more solvent molecules. The solvent may be water, in which case the solvate is a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compounds of the present invention may exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, and the like, as well as corresponding solvated forms. The compounds of the present invention may form true solvates, but in some cases, they may only retain adventitious water or a mixture of water and a portion of adventitious solvent. The compounds of the present invention may react in a solvent or precipitate or crystallize from a solvent. Solvates of the compounds of the present invention are also encompassed by the present invention. The present invention also encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be single polymorphs or mixtures of more than one polymorph in any ratio.

[0065] In the present invention, "stereoisomer" means an isomer formed due to at least one asymmetric center. In compounds with one or more (e.g., one, two, three, or four) asymmetric centers, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers can be produced. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of the present invention can exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, and imine-enamine tautomers. It is to be understood that the scope of the present invention encompasses all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0066] In the present invention, pharmaceutically acceptable salts include acid addition salts and base addition salts thereof. Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Suitable base addition salts are formed from bases that form pharmaceutically acceptable salts. For a review of suitable salts, see, for example, "Remington's Pharmaceutical Sciences," Mack Publishing Company, Easton, Pa., (2005); and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use," Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art. "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the biological effectiveness of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobromides, sulfates, nitrates, and phosphates; organic acid salts include, but are not limited to, formate, acetate, 2,2-dichloroacetate, trifluoroacetate, propionate, caproate, octanoate, decanoate, undecylenate, glycolate, gluconate, lactate, sebacate, adipate, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate, cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, alginate, ascorbate, salicylate, 4-aminosalicylate, and naphthalene disulfonate. These salts can be prepared by methods known in the art. "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic or organic bases that retain the biological effectiveness of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like. Preferred inorganic salts are ammonium salts, sodium salts, calcium salts, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines, including natural substituted amines, cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like.Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline hexyl caffeine. These salts can be prepared by methods known in the art.

[0067] In the present invention, unless otherwise indicated, "ester" refers to an ester derived from a compound described herein, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the compound of the present invention in the form of a free acid or alcohol). The compound of the present invention itself may also be an ester.

[0068] The compounds of the present invention may exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent as a structural element of the crystal lattice of the compound, in particular water, methanol or ethanol. The amount of polar solvent, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.

[0069] Those skilled in the art will appreciate that, since nitrogen requires an available lone pair of electrons to be oxidized to oxides, not all nitrogen-containing heterocycles are capable of forming nitrogen oxides. Those skilled in the art will recognize nitrogen-containing heterocycles that are capable of forming nitrogen oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming nitrogen oxides. Synthetic methods for preparing nitrogen oxides of heterocycles and tertiary amines are well known to those skilled in the art and include oxidizing heterocycles and tertiary amines with peroxyacids such as Peracetic Acid and Metachloroperbenzoic Acid (mCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and dioxirane such as dimethyldioxirane. These methods for preparing nitrogen oxides have been extensively described and reviewed in the literature, see for example: TL Gilchrist, Comprehensive Organic Synthesis, vol. 7, pp 748-750 (AR Katritzky and AJ Boulton, Eds., Academic Press); and GWH Cheeseman and ESGWerstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp 390-392 (AR Katritzky and AJ Boulton, Eds., Academic Press).

[0070] As used herein, "metabolite" refers to a substance formed in vivo upon administration of a compound of the present invention. Metabolites of a compound can be identified using techniques known in the art, and their activity can be characterized using assays. Such products can be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, and the like of the administered compound. Therefore, the present invention includes metabolites of the compounds of the present invention, including compounds produced by contacting a compound of the present invention with a mammal for a period of time sufficient to produce a metabolic product thereof.

[0071] In the present invention, "prodrug" refers to certain derivatives of the compounds of the present invention that can be converted into compounds of the present invention having the desired activity by, for example, hydrolytic cleavage when administered to the body or thereon. Typically, such prodrugs will be functional group derivatives of the compound that are easily converted into the desired therapeutically active compound in vivo. Further information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Volume 14, ACS Symposium Series (T. Higuchi and V. Stella). Prodrugs of the present invention can be prepared, for example, by replacing appropriate functional groups present in the compounds of the present invention with certain moieties known to those skilled in the art as "pro-moieties" (e.g., as described in "Design of Prodrugs", H. Bundgaard (Elsevier, 1985)).

[0072] As used herein, a "pharmaceutical composition" refers to a formulation of a compound of the present invention and a medium generally accepted in the art for delivering a biologically active compound to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient, and thereby exert its biological activity.

[0073] In this application, "pharmaceutically acceptable carrier" includes but is not limited to any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavoring, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved or accepted by relevant governmental regulatory authorities for use in humans or livestock.

[0074] As used herein, the terms "drug combination," "drug combination," "combination therapy," "administration of an additional therapy," "administration of an additional therapeutic agent," and the like refer to a drug therapy obtained by mixing or combining more than one active ingredient, and include both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient as a single entity or single dosage form. The term "non-fixed combination" refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient as separate entities, either in combination or sequentially at variable intervals. This also applies to cocktail therapies, e.g., administration of three or more active ingredients.

[0075] In the present invention, unless otherwise specified, "tumor" includes but is not limited to leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, squamous cell lung cancer, lung adenocarcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, cervical cancer, ovarian cancer, intestinal cancer, rhinitis cancer, brain cancer, bone cancer, esophageal cancer, melanoma, kidney cancer, oral cancer and other diseases.

[0076] As used herein, unless otherwise indicated, "treating" or "treating" means reversing, alleviating, inhibiting the progression of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.

[0077] On the basis of not violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention. DETAILED DESCRIPTION

[0078] The scheme of the present invention will be explained below with reference to the examples. Those skilled in the art will understand that the following examples are only used to illustrate the present invention and should not be construed as limiting the scope of the present invention. Where specific techniques or conditions are not specified in the examples, the techniques or conditions described in the literature in this area or the product specifications shall be followed.

[0079] The reagents and raw materials used in the examples of the present invention are all commercially available.

[0080] Table 1 Abbreviations and their meanings in the present invention

[0081] The structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). NMR measurements were performed using a Bruker AVANCE-400 nuclear magnetic spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS). Chemical shifts were measured at 10 -6The units are given in ppm.

[0082] MS was measured using an Agilent SQD (ESI) mass spectrometer (manufacturer: Agilent, signal: 6110).

[0083] HPLC analysis was performed using an Agilent 1200DAD high pressure liquid chromatograph (Sunfirc C18, 150×4.6 mm, 5 μm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18, 150×4.5 mm, 5 μm column).

[0084] The thin layer chromatography silica gel plate used was Qingdao Ocean GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) had a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products was 0.4mm-0.5mm silica gel plate.

[0085] Column chromatography generally uses Qingdao Ocean 100-200, 200-300 mesh silica gel as the carrier.

[0086] Unless otherwise specified, all reactions in the following examples were conducted under an argon or nitrogen atmosphere. Argon or nitrogen atmosphere refers to the reaction flask being connected to an approximately 1 L argon or nitrogen balloon. Hydrogen atmosphere refers to the reaction flask being connected to an approximately 1 L hydrogen balloon. The hydrogenation reaction was typically performed by evacuating the flask and then filling it with hydrogen, repeating this process three times.

[0087] Intermediate preparation

[0088] Intermediate INT1: 7-(chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one

[0089] Step 1: Add compound INT1a (20 g, 95.1 mmol) and selenium dioxide (16 g, 144 mmol) to a 250 ml reaction flask, add 120 ml of 1,4-dioxane, and heat to 110°C with stirring overnight. After the reaction is complete as monitored by TLC, the reaction solution is filtered, the residue is rinsed with ethyl acetate, and the filtrates are combined and concentrated by rotary evaporation. The resulting crude product is purified by column chromatography to obtain compound INT1b (16 g, yellow solid). LC-MS: ESI [M+H] + =225.2.

[0090] Step 2: Add sodium hydride (6.86 g, 171.4 mmol) and 60 ml of 1,4-dioxane to a 250 ml reaction flask, then replace the nitrogen atmosphere three times. Cool to 0°C and slowly add triethyl 2-phosphonobutyrate (43.2 g, 171.4 mmol) dropwise under nitrogen. Stir and react at 0°C for 10 minutes. Warm to room temperature, stir and react for 10 minutes, then heat to 40°C, stir and react for 5 minutes. Cool the reaction to -78°C. Slowly add INT1b (16 g, 71.4 mmol) dissolved in 60 ml of 1,4-dioxane solution dropwise and stir and react at -78°C for 1 minute. After TLC monitoring, quench the reaction by slowly adding ice-cold saturated ammonium chloride aqueous solution. Extract three times with 150 ml of ethyl acetate. Combine the organic phases, dry over anhydrous sodium sulfate, filter, and spin dry. The crude product was purified by column chromatography to obtain compound INT1c (13.26 g, brown liquid). LC-MS: ESI [M+H] + =323.3.

[0091] Step 3: Add compound INT1c (13.26 g, 41.1 mmol) to 100 ml of anhydrous ethanol, then add Pd / C (1.33 g, 10%), and stir at room temperature overnight. After the reaction is complete as monitored by LC-MS, the reaction solution is filtered, the residue is rinsed with a large amount of ethanol, the filtrates are combined and concentrated by rotary evaporation. Add a 4 mol / L hydrochloric acid solution in 1,4-dioxane (50 ml), stir at room temperature for 30 minutes, add diethyl ether to precipitate a large amount of solid, filter, and dry to obtain compound INT1d (7.32 g, white solid). LC-MS: ESI [M+H] + =249.3; 1 H NMR (400MHz, DMSO-d6) δ10.44(s,1H),8.62(d,J=1.9Hz,1H),7.75(d,J=1.9Hz,1H),4.34(q,J=7.1Hz,2H),3.87(s,0H),3.24(dd,J= 16.8, 6.3Hz, 1H), 2.97 (dd, J = 16.8, 10.1Hz, 1H), 1.81–1.65 (m, 1H), 1.52–1.36 (m, 1H), 1.32 (t, J = 7.1Hz, 3H), 0.93 (t, J = 7.4Hz, 3H).

[0092] Step 4: Compound INT1d (7.32 g, 29.5 mmol) and 120 ml of 1,4-dioxane were added to a 250 ml reaction flask, followed by DDQ (7.38 g, 32.5 mmol). The mixture was refluxed overnight. After completion of the reaction as monitored by LC-MS, the reaction solution was concentrated by rotary evaporation, saturated sodium bicarbonate solution was added, and the mixture was stirred for 1 hour. The mixture was filtered, and the residue was rinsed with water and then washed with a small amount of ether. After drying, compound INT1e (2.31 g, yellow solid) was obtained. LC-MS: ESI [M+H] + =247.3.

[0093] Step 5: Add compound INT1e (2.0 g, 8.1 mmol) and 60 ml of tetrahydrofuran to a 150 ml reaction flask, cool to 0°C, then add 2.5 mol / L lithium aluminum hydride in tetrahydrofuran (6.48 ml, 16.2 mmol) and react at 0°C for 2 hours. After TLC monitoring, quench the reaction by adding 5 ml of water, dry with a large amount of anhydrous sodium sulfate, filter, and rinse the filter residue with a large amount of dichloromethane. The filtrates are combined and concentrated by rotary evaporation. After drying, compound INT1f (1.2 g, white solid) is obtained. LC-MS: ESI [M+H] + =205.3; 1 H NMR (400MHz, DMSO-d6) δ11.87(s,1H),8.03(d,J=2.0Hz,1H),7.36(d,J=1.0Hz,1H),7 .34(dd,J=2.0,0.9Hz,1H),4.51(s,2H),2.52(d,J=1.8Hz,1H),1.15(t,J=7.4Hz,3H).

[0094] Step 6: Add compound INT1f (0.82 g, 4.0 mmol) to a 50 ml reaction flask, add 20 ml of dichloromethane and 1 ml of N,N-dimethylformamide, cool to 0°C, add thionyl chloride (0.87 ml, 12 mmol) dropwise, and react at 0°C for 1 hour. After completion of the reaction as monitored by TLC, concentrate the reaction solution by rotary evaporation, and purify the crude product by column chromatography to obtain compound INT1 (0.66 g, gray solid). LC-MS: ESI [M+H] + =223.7. 1 H NMR (400MHz, DMSO) δ12.16 (s, 1H), 8.55 (s, 1H), 7.97–7.73 (m, 2H), 4.95 (s, 2H), 2.56 (d, J = 7.4Hz, 2H), 1.19 (t, J = 7.4Hz, 3H).

[0095] Intermediate INT2: 7-(chloromethyl)-3-cyclopropyl-1,5-naphthyridin-2(1H)-one

[0096] Step 1: Compound INT2a (15 g, 72.4 mmol) and triethyl phosphite (24.1 g, 144.9 mmol) were weighed into a reaction flask and stirred at 130°C under nitrogen for 24 h. After the reaction, column chromatography was performed to obtain a colorless liquid INT2b (10 g, 52%). LC-MS: ESI [M+H] + =265.1.

[0097] Step 2: INT2b (10 g, 37.8 mmol) was dissolved in 100 mL of THF. Solid NaH (60%, 2.3 g, 56.8 mmol) was slowly added at 0°C under nitrogen protection. The mixture was stirred for 0.5 h after addition and then at room temperature for 10 min. Finally, a THF solution of INT1b (10.2 g, 45.4 mmol) was slowly added at -78°C. The mixture was stirred at -78°C for 1 h after addition. After confirmation by LC-MS, a saturated aqueous solution of NH4Cl was added to quench the reaction. The mixture was extracted with EA (150 mL × 3). The organic phases were combined and dried over anhydrous Na2SO4, filtered and dried, and purified by column chromatography to obtain a yellow oil INT2c (10 g, 79%). LC-MS: ESI [M+H] + =335.1.

[0098] Step 3: Compound INT2c (10 g, 29.9 mmol) was weighed into a reaction flask and dissolved in 150 mL of glacial acetic acid. Then, Fe (5.0 g, 89.7 mmol) powder was slowly added. After the addition, the temperature was raised to 70°C and stirred for 2 h. After cooling to room temperature, the mixture was filtered and the filter cake was washed with a small amount of DCM and MeOH. The filtrate was concentrated in vacuo and then purified by column chromatography to obtain a light yellow solid INT2d (1.85 g, 24%). LC-MS: ESI [M+H] + =259.1.

[0099] Step 4: Compound INT2d (1.85 g, 7.2 mmol) was weighed into a reaction flask, 20 mL of THF was added and stirred at -20 °C, DIBAL-H (1.5 M in toluene, 16 mL, 25.1 mmol) was slowly added dropwise under nitrogen protection, and the mixture was returned to room temperature and stirred for 0.5 h. Saturated aqueous potassium sodium tartrate was added dropwise at 0 °C to quench the reaction, and stirred at room temperature overnight. The mixture was extracted three times with a mixed solution of DCM and MeOH (3:1). The organic phases were combined and dried over anhydrous Na2SO4, filtered and dried to give a pale yellow solid crude product INT2e (1.46 g, 94%). LC-MS: ESI [M+H] +=217.1.

[0100] Step 5: Compound INT2e (1.46 g, 6.8 mmol) and DMF (98.7 mg, 1.4 mmol) were weighed into a reaction flask and dissolved in 50 mL of toluene. SOCl2 (1.1 g, 9.5 mmol) was slowly added dropwise at 0°C. After the addition was complete, the temperature was slowly raised to room temperature and stirred overnight. After the reaction, the solvent was concentrated in vacuo and the product was purified by column chromatography using DCM and MeOH (0-7%) to obtain a pale yellow solid compound INT2 (1.24 g, 78%). LC-MS: ESI [M+H] + =235.1.

[0101] Example 1: 1'-(7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0102] Step 1: Compound 1a (1 g, 4.6 mmol), 1b (1.7 g, 5.5 mmol), Pd(dppf)Cl2 (0.3 g, 0.46 mmol), and potassium carbonate (1.6 g, 11.5 mmol) were added to a mixed solvent of 7 ml of dioxane, 3 ml of anhydrous ethanol, and 4 ml of water. The nitrogen atmosphere was then replaced three times and the mixture was reacted at 90°C under nitrogen for 2 h. After TLC analysis of the reaction, the reaction mixture was cooled to room temperature, 30 ml of dichloromethane and 20 ml of water were added, and the layers were separated in a separatory funnel. The aqueous phase was extracted twice with dichloromethane, and the combined organic phases were washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried. The resulting crude product was purified by column chromatography to yield compound 1c (1 g, white solid).

[0103] Step 2: Add 1c (1 g, 3 mmol), aqueous methylamine (5 g, 161.3 mmol), and anhydrous methanol (20 ml) to a 100 ml reaction flask and stir overnight at room temperature. After completion of the reaction as monitored by TLC, the reaction solution was concentrated under reduced pressure to dryness to yield compound 1d (0.8 g, white solid).

[0104] Step 3: Compound 1d (0.5 g, 1.5 mmol) was added to 10 ml of anhydrous methanol, followed by 10 ml of 4 mol / L hydrochloric acid-dioxane solution. The mixture was stirred at room temperature for 0.5-1 h. After the reaction was completed as monitored by TLC, the reaction solution was concentrated under reduced pressure to dryness to obtain compound 1e (0.5 g, white solid).

[0105] Step 4: Compound 1e (0.05 g, 0.23 mmol), INT1 (0.06 g, 0.28 mmol), N,N-diisopropylethylamine (0.15 g, 1.15 mmol) and potassium iodide (0.19 g, 1.15 mmol) were added to 10 ml of anhydrous acetonitrile and stirred at 80°C for 2 h. After the reaction was completed as monitored by TLC, the reaction solution was concentrated under reduced pressure. The crude product was purified by column chromatography to obtain compound 1 (0.02 g, white solid); LC-MS: ESI [M+H] + =404.5; 1 H NMR (400MHz, DMSO): 11.85(s,1H),8.71(d,J=5.0Hz,1H),8.69(s,1H),8.41(d,J=1.3Hz,1H),8.06–7.91(m,2H),7.75(s,1H),7.6 4(s,1H),6.42(s,1H),3.72(s,2H),3.16(s,2H),2.81(d,J=4.8Hz,3H),2.70(s,2H),2.54(d,J=7.4Hz,4H),1.18(t,J=7.4Hz,3H).

[0106] Example 2: 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-2',2',6',6'-d4-6-carboxamide

[0107] Step 1: Compound 2a (6.0 g, 49.2 mmol) was added to 50 ml of tetrahydrofuran, cooled to -78°C, and LDA (2M, 29.5 ml, 59.0 mmol) was added dropwise at a temperature of -60 to -78°C. After the addition, the mixture was stirred for 15 min. 40 ml of a tetrahydrofuran solution of 2b (19.3 g, 54.1 mmol) was added dropwise. After the addition, the mixture was naturally warmed to room temperature, stirred for 2 h, and sampled. After TLC detection, the reaction was complete, and 60 ml of a saturated aqueous ammonium chloride solution was added and stirred. The layers were separated, and 100 ml of ethyl acetate was added to the aqueous layer for extraction. The layers were separated, and the combined organic layers were washed with 100 ml of saturated brine. The layers were separated, and the organic phase was concentrated under reduced pressure to remove the solvent to obtain compound 2c (20.0 g, oil).

[0108] Step 2: To 100 ml of a 1,4-dioxane / water solution (10:1) were added 2c (19.3 g, 28.7 mmol), potassium carbonate (7.93 g, 57.4 mmol), and 2d (8.32 g, 31.6 mmol) (100 ml). The mixture was replaced with nitrogen three times, heated to 80° C. and stirred for 2 h. After the reaction was complete as detected by LC-MS, the mixture was cooled to room temperature, 100 ml of water and 100 ml of ethyl acetate were added, the layers were separated, and the aqueous layer was extracted three times with 100 ml of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was purified by column chromatography to obtain compound 2e (4.2 g, yellow solid).

[0109] Step 3: 2e (4.2 g, 13.0 mmol) and 40% methylamine aqueous solution (5.1 g, 65.2 mmol) were added to 21 ml of anhydrous methanol, and stirred at room temperature for 1 h. After the reaction was completed by LC-MS, the reaction solution was concentrated to dryness, 40 ml of 1,4-dioxane was added, and 4M / dioxane hydrochloride solution (16.3 ml, 65.2 mmol) was added dropwise. The mixture was stirred at room temperature for 2 h. After the reaction was completed by LC-MS, the mixture was filtered and dried to obtain compound 2f (3.4 g, off-white solid).

[0110] Step 4: 2f (3.4 g, 11.5 mmol), DIEA (5.6 g, 46.0 mmol), INT1 (2.4 g, 10.5 mmol), and KI (340 mg, 2.1 mmol) were added to 48 ml of acetonitrile, and the mixture was heated to 80 ° C and stirred for 2 h. After the reaction was complete by LC-MS, 200 ml of saturated sodium bicarbonate solution was added, stirred, filtered, and dried by column chromatography to obtain compound 2 (2.4 g, white solid); LC-MS: ESI [M+H] + =408.2; 1 H NMR (400MHz, DMSO-d6) δ11.90(s,1H),8.82-8.72(m,2H),8.48(d,J=1.9Hz,1H),8.10-7.99(m,2H),7.82(q,J=1.0Hz,1H) ,7.75-7.66(m,1H),6.48(d,J=1.5Hz,1H),3.78(s,2H),2.88(d,J=4.9Hz,3H),2.64-2.58(m,4H),1.25(t,J=7.4Hz,3H).

[0111] Example 3: 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-2-fluoro-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-2',2',6',6'-d4-6-carboxamide

[0112] Step 1: Compound 2c (20 g, 60 mmol), pinacol diboronate (15.2 g, 72 mmol), potassium acetate (11.8 g, 120 mmol), and PdCl2(dppf) (2.1 g, 3 mmol) were added sequentially to a reaction flask under N2 protection and reacted at 80°C overnight. After completion of the reaction, the mixture was filtered, washed with EA, and the filtrate was concentrated. The residue was purified by column chromatography to obtain compound 3a (15 g, oil).

[0113] Step 2: To 100 ml of a 1,4-dioxane / water solution (10:1) were added 3a (15 g, 22.3 mmol), potassium carbonate (7.93 g, 57.4 mmol), and 3b (8.32 g, 31.6 mmol) (100 ml). The mixture was replaced with nitrogen three times, heated to 80°C and stirred for 2 h. After the reaction was complete as detected by LC-MS, the mixture was cooled to room temperature, 100 ml of water and 100 ml of ethyl acetate were added, the layers were separated, and the aqueous layer was extracted three times with 100 ml of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was purified by column chromatography to obtain compound 3c (12 g, yellow solid).

[0114] Step 3: 3c (4.2 g, 13.0 mmol) and 40% methylamine aqueous solution (5.1 g, 65.2 mmol) were added to 21 ml of anhydrous methanol, and the mixture was stirred at room temperature for 1 h. After the reaction was completed by LC-MS, the reaction solution was concentrated to dryness, 40 ml of 1,4-dioxane was added, and 4 M / dioxane hydrochloride solution (16.3 ml, 65.2 mmol) was added dropwise. The mixture was stirred at room temperature for 2 h. After the reaction was completed by LC-MS, it was filtered and the filtrate was dried to give compound 3d (3.4 g, off-white solid).

[0115] Step 4: 3d (3.4 g, 11.5 mmol), DIEA (5.6 g, 46.0 mmol), INT1 (2.4 g, 10.5 mmol), and KI (340 mg, 2.1 mmol) were added to 48 ml of acetonitrile, and the mixture was heated to 80 ° C and stirred for 2 h. After the reaction was complete by LC-MS, 200 ml of saturated sodium bicarbonate solution was added, stirred, filtered, and dried by column chromatography to obtain compound 3 (2.4 g, white solid); LC-MS: ESI [M+H] + =426.5; 1H NMR (400MHz, DMSO) δ11.84(s,1H),8.63(d,J=4.8Hz,1H),8.42(t,J=4.4Hz,1H),8.16–8.03(m,1H),7.92(dd,J=7.7,1.5Hz,1H),7.75( s,1H),7.65(s,1H),6.24(s,1H),3.72(s,2H),2.88(t,J=8.1Hz,1H),2.80(d,J=4.8Hz,3H),2.60–2.52(m,3H),1.18(t,J=7.4Hz,3H).

[0116] Example 4: 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N,2-dimethyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-2',2',6',6'-d4-6-carboxamide

[0117] Step 1: To 100 ml of a 1,4-dioxane / water solution (10:1) were added 3a (13 g, 21.2 mmol), potassium carbonate (7.8 g, 55 mmol), and 4a (8.1 g, 28.6 mmol) (100 ml). The mixture was replaced with nitrogen three times, heated to 80° C. and stirred for 2 h. After the reaction was complete as detected by LC-MS, the mixture was cooled to room temperature, 100 ml of water and 100 ml of ethyl acetate were added, the layers were separated, and the aqueous layer was extracted three times with 100 ml of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and spin-dried. The resulting crude product was purified by column chromatography to obtain compound 4b (10.6 g, yellow solid).

[0118] Step 2: 4b (3.8 g, 11.3 mmol) and 40% aqueous methylamine solution (4.5 g, 60.5 mmol) were added to 21 ml of anhydrous methanol, and the mixture was stirred at room temperature for 1 h. After the reaction was completed by LC-MS, the reaction solution was concentrated to dryness, 40 ml of 1,4-dioxane was added, and a 4M hydrochloric acid solution of dioxane (15 ml, 64 mmol) was added dropwise. The mixture was stirred at room temperature for 2 h. After the reaction was completed by LC-MS, the mixture was filtered, and the filtrate was dried to give compound 4c (3.2 g, off-white solid).

[0119] Step 3: 4c (3.2 g, 11.2 mmol), DIEA (5.4 g, 45.2 mmol), INT1 (2.1 g, 10.5 mmol), and KI (320 mg, 1.9 mmol) were added to 48 ml of acetonitrile, and the mixture was heated to 80°C and stirred for 2 h. After the reaction was complete as determined by LC-MS, 200 ml of saturated sodium bicarbonate solution was added, the mixture was stirred and filtered, and the mixture was purified by spin column chromatography to obtain compound 4 (1.8 g, white solid); LC-MS: ESI [M+H] + =426.5; 1 H NMR (400MHz, DMSO) δ11.84(s,1H),8.63(d,J=4.8Hz,1H),8.42(t,J=4.4Hz,1H),8.16–8.03(m,1H),7.92(dd,J=7.7,1.5Hz,1H),7.75( s,1H),7.65(s,1H),6.24(s,1H),3.72(s,2H),2.88(t,J=8.1Hz,1H),2.80(d,J=4.8Hz,3H),2.60–2.52(m,3H),1.18(t,J=7.4Hz,3H).

[0120] Example 5: 1'-((7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-2',2',6',6'-d4-6-carboxamide

[0121] Step 1: Add 5a (500 g, 1.99 mol) and 2.5 L of methanol under nitrogen protection and cool to 0-5°C. Add a solution of sodium methoxide (118 g) in methanol (1.0 L) dropwise at 0-5°C. After complete addition, warm to room temperature and stir for 1 hour. Add water (2.0 L) to the reaction system, stir for 30 minutes, and then concentrate under reduced pressure at 40°C until no liquid is discharged. Then add ethyl acetate (4.0 L), stir and separate the layers, extract the aqueous layer with ethyl acetate, and separate the layers. Combine the organic layers, add saturated brine, wash, separate the layers, and concentrate the organic layer under reduced pressure at 40°C to obtain 5b (480 g) as a white solid.

[0122] Step 2: Compound 5b (475 g, 1.93 mol) was weighed and added to DMF (2.85 L). DMF-DMA (2.85 L) was then added dropwise. After addition, the temperature was raised to 100°C and stirred for 2 h. After the reaction was complete, the temperature was lowered to 70-80°C and concentrated under reduced pressure until no liquid was released. The mixture was then added to water and stirred to precipitate. The temperature was lowered to 20-30°C, stirred for 1 h, and filtered. The filter cake was dried in a vacuum oven at 70°C to constant weight to obtain 5c (612 g, 95.3% yield), a red solid.

[0123] Step 3: Compound 5c (500 g, 1.91 mol) was added to THF (2.56 L) and stirred to dissolve. A solution of sodium periodate (805 g, 3.72 mol) in water (2.56 L) was added dropwise to the reaction system. Stir at room temperature for 2-4 h. After the reaction, ethyl acetate (4.0 L) and water (4.0 L) were added to the reaction system, stirred and separated, and the aqueous layer was extracted twice with ethyl acetate (2.0 L). The organic layers were combined and washed with saturated sodium thiosulfate solution and saturated brine. The organic layer was concentrated under reduced pressure at 40-45°C until no fractions were left, yielding 500 g of oily product 5d, which was used directly in the next step.

[0124] Step 4: Compounds 5d (512 g, 1.69 mol) and 5e (1457.0 g, 7.61 mol) were added to anhydrous ethanol (7.5 L) and stirred to dissolve. SnCl2 (1815.0 g, 9.57 mol) was added to the reaction system in batches at room temperature. After the addition, the temperature was raised to reflux and stirred for 1-2 h. The reaction system was cooled to 45-50°C and concentrated under reduced pressure until no fractions were obtained. Ethyl acetate was added to the system and stirred to dissolve. The pH was then adjusted to 7-8 with saturated sodium bicarbonate. During this process, there was vigorous gas evolution, resulting in the precipitation of a large amount of solid. The reaction solution was centrifuged, and the filtrate was collected and allowed to stand for separation. The organic layer was concentrated under reduced pressure at 40-45°C until no fractions were obtained. Purification by column chromatography afforded 5f (230 g, 36.5% yield) as a flocculent solid.

[0125] Step 5: Compound 5f (1.20 g, 3.85 mmol) and CuCl (0.57 g, 5.78 mmol) were added to DMF (10 mL). The resulting mixture was stirred at 120°C overnight. After the reaction was completed, the reaction solution was cooled to room temperature. The resulting mixture was diluted with ethyl acetate (20 mL). Washed with 10% ammonia solution. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 5g (800 mg, 77.78%) as a white solid. LC-MS: ESI [M+H] + =267.0.

[0126] Step 6: Under nitrogen protection, compound 5g (800 mg, 3.00 mmol) and TMSI (1.80 g, 9.00 mmol) were added to acetonitrile (8 mL). The reaction solution was heated to 50 ° C and stirred for 2 hours. After the reaction was detected by LCMS, the reaction solution was cooled to room temperature. The resulting mixture was diluted with ethyl acetate (50 mL). The aqueous layer was washed with 3x50 mL of water (10% triethylamine). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 5h (740 mg, 97.64%) as a white solid. LC-MS: ESI [M + H] + =252.9.

[0127] Step 7: Compound 5h (0.74 g, 2.92 mmol) was added to anhydrous THF (300 mL), the reaction solution was cooled to -20 ° C, DIBAL-H (4.9 mL, 7.3 mmol, 1.5 M toluene solution) was added under a -20 ° C N2 atmosphere, and the reaction mixture was further stirred between -15-0 ° C for 3 hours. TLC showed that the reaction was complete. The reaction was slowly quenched with 3N NaOH aqueous solution between -15-0 ° C, and the internal temperature was kept below 0 ° C. The volatile substances were removed under reduced pressure at 25 ° C, and the resultant was extracted with ethyl acetate (30 mL * 3). The combined organic phase was washed with water (30 mL) and brine (30 ml), dried over anhydrous Na2SO4 and evaporated to dryness. The crude product was purified by silica gel column chromatography (pure DCM, then DCM / acetone = 30:1 to 10:1). The product 5i (0.42 g) was obtained as a yellow solid. LC-MS: ESI [M+H] + =211.2.

[0128] Step 8: Under a nitrogen atmosphere at 0-5°C, SOCl2 (357 mg, 3.0 mmol) was slowly added to a solution of compound 5i (0.42 g, 2.0 mmol) in DMF (100 mL). The mixture was stirred at 25°C for 3 h until the starting material was completely consumed. The reaction mixture was cooled to 0-5°C with an ice-water bath and quenched with 1N NaOH to pH = 9, and then water (10 mL) was added with stirring. The reaction mixture was stirred at room temperature for 1 hour, and the formed off-white precipitate was collected by filtration, washed with water (10 mL*3), and dried in vacuo to obtain compound 5j (250 mg). LC-MS: ESI [M+H] + =229.0.

[0129] Step 9: Compound 5j (229 mg, 1.0 mmol), 2f (331.5 mg, 1.5 mmol), N,N-diisopropylethylamine (0.55 g, 5 mmol) and potassium iodide (332 mg, 2 mmol) were added to 10 ml of anhydrous acetonitrile and stirred at 85°C for 2 hours. After the reaction was complete as monitored by TLC, the reaction solution was concentrated under reduced pressure. The crude product was purified by column chromatography to obtain compound 5 (142 mg, white solid); LC-MS: ESI [M+H] + =414.2.

[0130] Example 6: 1'-((7-chloro-8-methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-2',2',6',6'-d4-6-carboxamide

[0131] Step 1: Compound 6a (50 g, 0.23 mol), isopropenylboronic acid pinacol ester (77.6 g, 0.46 mol), potassium carbonate (150.4 g, 0.46 mol), and Pd(dppf)Cl2 (8.4 g, 0.012 mmol) were weighed into a reaction flask. The nitrogen atmosphere was purged three times, and 550 mL of dioxane / H2O (10:1) was added. The nitrogen atmosphere was purged three more times, and the mixture was reacted at 110°C under nitrogen for 5 h. After completion of the reaction, the reaction mixture was cooled to room temperature and filtered through a pad of Celite. The filter cake was washed with EA (100 mL x 3), and the mother liquor was concentrated. EA (200 mL x 5) and HO were then added for extraction. The organic phases were combined, dried over anhydrous Na2SO4, filtered, and purified by column chromatography to obtain 6b (44.5 g, 87%) as a yellow oil. LC-MS: ESI [M+H] + =223.1.

[0132] Step 2: 6b (44.5 g, 0.20 mol) was weighed into a reaction flask, and 400 mL of glacial acetic acid was added. Iron powder (35.4 g, 0.60 mol) was slowly added. The reaction was allowed to react at 70°C for 4 h. After the reaction, the reaction mixture was cooled to room temperature, and the excess iron powder was removed by filtration. The mother liquor was then dried by spin-drying. EA (150 mL x 4) and saturated aqueous NaHCO₃ were then added for extraction. The organic phases were combined, dried over anhydrous Na₂SO₄, filtered, and then purified by column chromatography to obtain a light yellow solid 6c (32.3 g, 84%). LC-MS: ESI [M+H] + =193.1.

[0133] Step 3: 6c (10 g, 52.0 mmol) and TEA (15.8 g, 156.1 mmol) were weighed into a reaction flask and dissolved in 70 mL of toluene. A toluene solution of triphosgene (7.7 g, 26.0 mmol) (30 mL) was added dropwise at 0°C. After the addition, the mixture was stirred at 60°C for 5 h. After the reaction was complete, a small amount of methanol was added to quench the reaction. The solvent was then concentrated in vacuo, and some impurities were removed by slurrying with ether. The solid residue was purified by column chromatography to obtain 6d (3.2 g, 28%) as a white solid. LC-MS: ESI [M+H] + =219.1.

[0134] Step 4: 6d (3.2 g, 14.7 mmol) and NCS (3.1 g, 23.5 mmol) were weighed into a reaction flask and dissolved in 35 mL of glacial acetic acid. Dichloroacetic acid (0.38 g, 2.9 mmol) was added under nitrogen and stirred at 90°C overnight. After completion of the reaction, the solvent was removed by vacuum concentration, and the mixture was washed with saturated aqueous NaHCO₃ and extracted three times with DCM. The organic phases were combined and dried over anhydrous Na₂SO₄, filtered and dried, and purified by column chromatography to obtain a light yellow solid 6e (3.1 g, 84%). LC-MS: ESI [M+H] + =253.0.

[0135] Step 5: 6e (3.1 g, 12.3 mmol) was weighed into a reaction flask, 30 mL of THF was added, and the mixture was stirred at -20°C. DIBAL-H (1.5 M in toluene, 65.4 mL) was slowly added dropwise under nitrogen. After the addition was complete, the mixture was returned to room temperature and stirred for 0.5 h. Saturated aqueous potassium sodium tartrate was added dropwise at 0°C to quench the reaction. The mixture was stirred at room temperature overnight and extracted five times with a mixture of DCM and MeOH (3:1). The organic phases were combined, dried over anhydrous Na2SO4, filtered, and spun down to give 6f (810 mg, 29%) as a light yellow solid. LC-MS: ESI [M+H] + =225.0.

[0136] Step 6: 6f (810 mg, 3.6 mmol) and DMF (26.4 mg, 0.36 mmol) were weighed into a reaction flask and dissolved in DCM. SOCl2 (2.1 g, 21.6 mmol) was slowly added dropwise at 0°C. After the addition was complete, the temperature was slowly raised to room temperature and stirred overnight. After the reaction was completed, the solvent was concentrated in vacuo and purified by column chromatography to obtain 6 g (172 mg, 20%) of a light yellow solid. LC-MS: ESI [M+H] + =243.0.

[0137] Step 7: Compound 6g (40.0 mg, 0.16 mmol), 2f (53.3 mg, 0.18 mmol), DIEPA (106.3 mg, 0.82 mmol), and KI (2.7 mg, 0.016 mmol) were weighed into a reaction tube, 5 mL of acetonitrile was added, and the mixture was reacted at 80°C for 3 h. The reaction was cooled to room temperature, the solvent was concentrated, and the mixture was extracted with DCM (20 mL x 3). The organic phases were combined, dried over anhydrous Na2SO4, filtered, and purified by column chromatography with MeOH (0-10%) and DCM to obtain 6 (45 mg, 64% yield) as a pale yellow solid. LC-MS: ESI [M+H] + =428.2; 1 H NMR (400MHz, DMSO) δ12.28(s,1H),8.71(d,J=5.2Hz,2H),8.53(d,J=1.8Hz,1H),8.02–7.95(m,2H) ,7.71(d,J=1.8Hz,1H),6.42(s,1H),3.76(s,2H),2.82(d,J=4.9Hz,3H),2.65(s,3H),2.54(s,2H).

[0138] Example 7: 1-(3-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)methyl)-N-methyl-1,2,3,6-tetrahydrobipyridine-2,2,6,6-d4-6-carboxamide

[0139] Step 1: Compound 7a (3.85 g, 24.6 mmol), DIEA (16.0 g, 123.3 mmol), and DMAP (0.6 g, 4.81 mmol) were added to 100 ml of dichloromethane and cooled to 0°C. Butyryl chloride (8.10 g, 76.3 mmol) was added dropwise. After the addition, the mixture was allowed to warm to room temperature and react for 24 h. After the reaction was complete as determined by LC-MS, 100 ml of ethyl acetate and 100 ml of water were added. The layers were separated in a separatory funnel, and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were spin-dried, and 40 ml of dichloromethane was added to precipitate the solid. The solid was filtered, and the filter cake was spin-dried to obtain compound 7b (0.8 g, pink solid).

[0140] Step 2: Compound 7b (0.2 g, 0.96 mmol), potassium vinyl trifluoroborate (141.6 mg, 1.04 mmol), Pd(dppf)Cl2 (17.4 mg, 0.024 mmol), and potassium carbonate (199 mg, 1.44 mmol) were added to 4 ml of dioxane / water = 9:1, and the atmosphere was replaced with nitrogen three times. The temperature was raised to 90°C and stirred for 4 h. After the reaction was complete as monitored by TLC, the reaction solution was concentrated under reduced pressure and the crude product was purified by column chromatography to obtain compound 7c (0.1 g, yellow solid).

[0141] Step 3: Compound 7c (0.1 g, 0.5 mmol) was added to 10 ml of dioxane and 2.5 ml of water, followed by sodium periodate (425 g, 2.0 mmol) and potassium osmate (75 mg, 0.15 mmol). The mixture was stirred at room temperature for 2 h. After the reaction was complete as detected by LC-MS, 50 ml of ethyl acetate and 50 ml of water were added. The layers were separated in a separatory funnel, and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated sodium sulfite, and the separated organic layer was dried over anhydrous sodium sulfate, filtered, and the filter cake was spin-dried to obtain compound 7d (80 mg, yellow solid).

[0142] Step 4: 7d (167 mg, 0.54 mmol) and triethylamine (198 mg, 1.96 mmol) were added to 10 ml of dichloromethane and stirred to dissolve; a DCM solution of 2f (100 mg, 0.49 mmol) (10 ml) was added to the reaction solution and stirred at room temperature for 1 h. Sodium triacetoxyborohydride (623 mg, 2.94 mmol) was added and stirred at room temperature for 2 h. After the reaction was complete as detected by LC-MS, 20 ml of saturated ammonium chloride was added, stirred and separated, and the organic layer was washed with saturated sodium bicarbonate and saturated sodium chloride in sequence, dried over anhydrous sodium sulfate, filtered, and purified by spin column chromatography to give compound 7 (60 mg, white solid); LC-MS: ESI [M+H] + =408.5;1H NMR (400MHz, DMSO-d6) δ11.90(s,1H),8.79-8.62(m,3H),8.06-7.93(m,2H),7.81(d,J=1.8Hz,1H),7.35(s, 1H), 6.45 (d, J = 1.6Hz, 1H), 3.77 (s, 2H), 2.82 (d, J = 4.9Hz, 3H), 2.57 (d, J = 1.6Hz, 2H), 1.17 (t, J = 7.4Hz, 3H).

[0143] Example 8: 1'-((7-ethyl-4-fluoro-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-2',2',6',6'-d4-6-carboxamide

[0144] Step 1: To a solution of MeONa (618.0 g, 11.4 mol, 15.0 eq) in methanol (2 L) was slowly added compound 8a (180 g, 0.763 mol) at 0°C. The reaction mixture was stirred at 20°C for 1 hour and then quenched with saturated aqueous NH4Cl (2 L) under stirring. The formed white precipitate was filtered, and the filter cake was washed with water (500 mL*3) and dried under vacuum. The product 8b (150 g, 84.5% yield) was obtained as a white solid. 1 HNMR (400MHz, DMSO-d6) δ (ppm) 9.06 (d, J = 2.4Hz, 1H), 8.78 (d, J = 2.4Hz, 1H), 4.07 (s, 3H).

[0145] Step 2: To a solution of compound 8b (150 g, 0.647 mol) in a mixed solvent of 1,4-dioxane (2.4 L) and water (600 mL) were added KCO (178.8 g, 1.29 mol, 2 eq.), potassium vinyl trifluoroborate (104.0 g, 0.776 mmol, 1.2 eq.), and Pd(dppf)Cl (14.2 g, 19.4 mmol, 0.03 eq.). The mixture was degassed and backfilled with N three times, then stirred at 80° C. for 8 hours. Volatile substances were removed under reduced pressure, and the resulting mixture was extracted with ethyl acetate (1 L*3), dried over anhydrous NaSO, and the combined organic layers were concentrated and purified by silica gel column chromatography (0-10% ethyl acetate / petroleum ether). 8c (81.5 g, 70% yield) was obtained as a yellow solid. 1 HNMR (400MHz, DMSO-d6) δ (ppm) 8.96 (d, J = 2.7Hz, 1H), 8.57 (d, J = 2.8Hz, 1H), 6.82 (dd, J = 1 7.8,11.3Hz,1H),6.15(dd,J=17.7,1.0Hz,1H),5.56(dd,J=11.3,1.0Hz,1H),4.05(s,3H).

[0146] Step 3: Pd / C (10% wt, 5.0 g) was added to a solution of 8c (50.0 g, 0.28 mol) in methanol (500 mL) under N2. The mixture was degassed and backfilled with hydrogen three times, then stirred at room temperature under a hydrogen atmosphere for 12 h. After completion of the reaction, the mixture was filtered through celite and washed with ethyl acetate (50 mL x 3). The combined filtrate was concentrated under vacuum to afford 8d as a dark purple solid (38.8 g, 92% yield). 1 H NMR (400MHz, DMSO-d6) δ7.33 (d, J=2.8Hz, 1H), 6.85 (dt, J=2.8, 0.7Hz, 1H), 4.65 (br s, 2H), 3.73 (s, 3H), 2.42 (q, J=7.5Hz, 2H), 1.08 (t, J=7.5Hz, 3H).

[0147] The fourth step: to 8d (16g, 0.105mol) in a solution of EtOH (300mL) was added 2-(ethoxymethylene) diethyl malonate (27.3g, 0.126mol, 25.5mL, 1.2eq), and the reaction mixture was refluxed for 2 hours under agitation. TLC showed that the reaction was complete. After cooling to room temperature, the mixture was concentrated under vacuum to obtain a dark purple residue. The product was further purified to give compound 8e (32.0g, 94% yield, white solid) by silica gel column chromatography (0-10% ethyl acetate / petroleum ether). 1 HNMR (400MHz, DMSO-d6) δ10.65(s,1H),8.28(s,1H),8.05(d,J=2.8Hz,1H),7.66(d,J=2.8Hz,1H),4.15( dd,J=32.3,6.9Hz,4H),3.86(s,3H),2.54(q,J=7.5Hz,2H),1.24(q,J=6.4Hz,6H),1.14(t,J=7.5Hz,3H).

[0148] Step 5: Compound 8e (32.0 g, 0.099 mol) was added to a three-necked round-bottom flask (1.0 L) equipped with a reflux condenser and a mechanical stirrer, followed by the addition of phenyl ether-biphenyl cocrystal (CAS: 8004-13-5, 300 mL). The system was degassed and filled with N2 three times, then placed in an oil bath preheated to 240°C. The reaction mixture was stirred at 250-260°C for 1 hour and then cooled to room temperature. TLC showed that the reaction was complete. 1.2 L of diisopropyl ether was added with stirring, and the mixture was stirred at room temperature for 1 hour. The off-white precipitate formed was collected by filtration, washed with diisopropyl ethyl ether (100 mL*3), and dried in vacuo. The product 8f (21.3 g, 77% yield) was obtained as an off-white solid. LC-MS: ESI[M+H] + =277.1.

[0149] Step 6: DAST (37.3 g, 0.23 mol, 30.5 mL, 3.0 eq) was slowly added to a suspension of compound 8f (21.3 g, 0.077 mol) in DCM (400 mL) at 0-5°C. The ice-water bath was removed and the reaction mixture was stirred at room temperature for 8 hours until a clear orange solution formed. TLC showed that only a trace of starting material remained (DCM / MeOH = 20:1, Rf = 0.3) and a major product (PE / EA = 5:1, Rf = 0.35) was produced. The reaction was quenched with saturated NaHCO3 aqueous solution (1.0 L) at 0-5°C until pH = 8. The organic layer was separated and the remaining aqueous phase was extracted with DCM (200 mL * 2). The combined DCM layers were washed with saturated NaHCO3 solution (200 mL), then washed with water (200 ml), dried over anhydrous Na2SO4, and spin-dried. The product was purified by silica gel column chromatography (PE / EA=20:1 to 10:1) to obtain 8 g (18.0 g, 84% yield, white needle-like solid). 1 H NMR (400MHz, CDCl3) δ9.15(d,J=8.5Hz,1H),8.02(d,J=1.5Hz,1H),4.48(q,J=7 .1Hz, 2H), 2.79 (q, J = 7.4Hz, 2H), 1.45 (t, J = 7.1Hz, 3H), 1.33 (t, J = 7.4Hz, 3H).

[0150] Step 7: Compound 8g (13.0 g, 0.047 mol) was added to anhydrous THF (300 mL). The reaction mixture was cooled to -20°C and DIBAL-H (78.0 mL, 0.117 mol, 1.5 M solution in toluene, 2.5 eq.) was added under a -20°C N atmosphere. The reaction mixture was further stirred between -15°C and 0°C for 3 hours. TLC indicated the reaction was complete. The reaction was slowly quenched with 3N aqueous NaOH at -15°C and 0°C, maintaining the internal temperature above 0°C. Volatile substances were removed under reduced pressure at 25°C, and the resulting product was extracted with ethyl acetate (300 mL x 3). The combined organic phases were washed with water (300 mL) and brine (300 mL), dried over anhydrous NaSO, and evaporated to dryness. The crude product was purified by silica gel column chromatography (pure DCM, then DCM / acetone = 30:1 to 10:1). The product 8h was obtained as a yellow solid (8.0 g, 72% yield). 1 H NMR(400MHz,DMSO-d6)δ8.79(d,J=8.8Hz,1H),8.10(d,J=1.2Hz,1H),5.52(s,1 H), 4.75 (s, 2H), 4.07 (s, 3H), 2.74 (q, J = 7.9, 7.4Hz, 2H), 1.26 (t, J = 7.4Hz, 3H).

[0151] Step 8: A suspension of compound 8h (8.0 g, 0.034 mol) in acetonitrile (100 mL) was cooled to -15-0°C with an ice-salt bath, and TMSI (3.0 eq) was slowly added with stirring under N2. Afterwards, the ice-salt bath was removed, and the reaction mixture was slowly warmed to 30°C and stirred at the same temperature for 24 hours until the starting material was completely consumed. The volatile substances were removed under reduced pressure, and ethyl acetate (250 mL) and 1N NaOH aqueous solution (100 mL) were added to the solid residue, and the resulting mixture was stirred at room temperature for 1 hour, during which a large amount of white precipitate was formed. The white solid was collected by filtration, washed with water (10 mL*3), then washed with ethyl acetate (10 mL*2) and dried in vacuo to obtain compound 8i. Yield: 5.3 g (70%). 1 H NMR (400MHz, DMSO-d6) δ12.09(s,1H),8.46(d,J=8.7Hz,1H),7.77(d,J=1.5Hz,1H),5 .50 (s, 1H), 4.66 (d, J = 3.9Hz, 2H), 2.56 (qd, J = 7.4, 1.1Hz, 2H), 1.19 (t, J = 7.5Hz, 3H).

[0152] Step 9: Under a nitrogen atmosphere at 0-5°C, SOCl2 (4.3 g, 0.036 mol, 2.6 mL, 1.5 eq) was slowly added to a solution of compound 8i (5.3 g, 0.024 mol) in DMF (100 mL). The mixture was stirred at 25°C for 3 h until the starting material was completely consumed. The reaction mixture was cooled to 0-5°C with an ice-water bath and quenched with 1N NaOH (70 mL) to pH = 9, followed by the addition of water (180 mL) with stirring. The reaction mixture was stirred at room temperature for 1 hour, and the formed off-white precipitate was collected by filtration, washed with water (10 mL*3), and dried in vacuo to give compound 8j (4.01 g, 70% yield). 1 H NMR (400MHz, DMSO-d6) δ12.25 (s, 1H), 8.55 (d, J = 8.7Hz, 1H), 7.79 (q, J = 1.4Hz, 1H), 4.95 (s, 2H), 2.57 (qd, J = 7.4, 1.3Hz, 2H), 1.19 (t, J = 7.4Hz, 3H); 13 C NMR(101MHz,DMSO-d6)δ161.2,152.2(d,J=266.6Hz),145.8(d,J=3.0Hz),141.67,140.1(d,J=4.0H z), 135.0 (d, J = 3.0Hz), 123.0 (d, J = 10.1Hz), 119.9 (d, J = 8.1Hz), 39.9 (d, J = 4.0Hz), 23.14, 12.25; 19 F NMR(376MHz,DMSO-d6)δ-125.12. MS(ESI):241.0(M+1) + .

[0153] Step 10: Compound 8j (40 mg, 0.17 mmol), 2f (51 mg, 0.17 mmol), N,N-diisopropylethylamine (72 mg, 0.56 mmol), and potassium iodide (3 mg, 0.02 mmol) were added to 10 ml of anhydrous acetonitrile and stirred at 85°C for 2 hours. After the reaction was complete as monitored by TLC, the reaction solution was concentrated under reduced pressure. The crude product was purified by column chromatography to obtain compound 8 (42 mg, white solid). LC-MS: ESI [M+H] + =426.2. 1H NMR(400MHz,Chloroform-d)δ9.64(s,1H),8.48(dd,J=5.5,3.2Hz,2H),8.07(d,J=8.1Hz,1H),7.88(d,J=5.3Hz,1H),7.83-7.64(m,2H ), 6.14(d,J=1.6Hz,1H),3.79(s,2H),2.96(d,J=5.1Hz,3H),2.66(qd,J=7.4,1.4Hz,2H),2.51(d,J=1.6Hz,2H),1.24(t,J=7.4Hz,3H).

[0154] Example 9: 1'-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-2',2',6',6'-d4-6-carboxamide

[0155] Preparation of 1'-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-2',2',6',6'-d4-6-carboxamide Reference Example 2. LC-MS: ESI [M+H] + =420.2. 1 H NMR(400MHz,Chloroform-d)δ11.85(s,1H),8.47(dd,J=11.1,2.0Hz,2H),8.07( d,J=8.1Hz,1H),7.90(d,J=5.3Hz,1H),7.72(dd,J=8.2,2.3Hz,1H),7.66(d,J=1. 9Hz,1H),7.44(s,1H),6.15(d,J=1.6Hz,1H),3.71(s,2H),2.97(d,J=5.1Hz,3H) ,2.51(d,J=1.6Hz,2H),2.36–2.18(m,1H),1.06–0.96(m,2H),0.84–0.70(m,2H).

[0156] Example 10: 1'-(7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-(methyl-d3)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-2',2',6',6'-d4-6-carboxamide

[0157] Step 1: 2e (1.4 g, 4.5 mmol) was weighed and dissolved in 20 mL of MeOH. 5 mL of water was added, followed by lithium hydroxide (570 mg, 13.5 mmol). The reaction was allowed to react at room temperature for 12 h. The reaction was monitored by TLC. After completion, 2 M HCl was added to adjust the pH to 6. EA (3 x 25 mL) was added for extraction. The combined organic phases were dried over anhydrous sodium sulfate, and then evaporated in vacuo to afford product 10a (730 mg, light yellow solid).

[0158] Step 2: Weigh 10a (230 mg, 0.7 mmol), EDCI (191 mg, 1 mmol), HOBT (100 mg, 1 mmol) 2 mL DMF, N-methylmorpholine (250 mg, 2.8 mmol), d3-methylamine hydrochloride (49 mg, 0.7 mmol), and react at room temperature for 12 h. Monitor by TLC. After the starting materials are completely consumed, dilute with water, extract with EA, and wash the organic phase with water 5 times, dry over anhydrous sodium sulfate, and spin dry to give the crude product 10b (220 mg, light yellow oily liquid).

[0159] Step 3: The crude product of 10b (220 mg, 0.7 mmol) was dissolved in 4 mL of MeOH, followed by the addition of 1.1 mL of 4 M HCl in dioxane solution. The reaction was allowed to react at room temperature for 12 h. The reaction was monitored by TLC. After the reaction was complete, potassium carbonate was added and stirred for 30 minutes. The potassium carbonate was removed by filtration to obtain a crude product of compound 10c (270 mg).

[0160] Step 4: Compound 10c (40 mg, 0.17 mmol), INT2 (51 mg, 0.17 mmol), N,N-diisopropylethylamine (72 mg, 0.56 mmol), and potassium iodide (3 mg, 0.02 mmol) were added to 10 ml of anhydrous acetonitrile and stirred at 85°C for 2 hours. After the reaction was complete as monitored by TLC, the reaction solution was concentrated under reduced pressure. The crude product was purified by column chromatography to obtain compound 10 (42 mg, white solid). LC-MS: ESI [M+H] + =423.2. 1H NMR(400MHz,Chloroform-d)δ11.85(s,1H),8.47(dd,J=11.1,2.0Hz,2H),8.07(d,J=8.1Hz,1H),7.90(d,J=5.3Hz,1H),7.72(dd,J=8.2,2.3Hz,1H),7 .66(d,J=1.9Hz,1H),7.44(s,1H),6.15(d,J=1.6Hz,1H),3.71(s,2H),2.51 (d,J=1.6Hz,2H),2.36–2.18(m,1H),1.06–0.96(m,2H),0.84–0.70(m,2H).

[0161] Example 11: N-cyclopropyl-1'-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-2',2',6',6'-d4-6-carboxamide

[0162] Preparation of N-cyclopropyl-1'-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-2',2',6',6'-d4-6-carboxamide Reference Example 10. LC-MS: ESI [M+H] + =446.2.

[0163] Biological activity test:

[0164] 1. PARP-1 enzyme assay

[0165] Experimental materials: PARP1 protein (BPS, Cat. No. 80501), PARP2 protein (BPS, Cat. No. 80502), PARP5A protein (BPS, Cat. No. 80504), Biotin-NAD+ (R&D, Cat. No. 6573), Strep-HRP (Thermo Pierce, Cat. No. 21127), NAD+ (TCI, Cat. No. D0919-5G), quantitative enhanced chemiluminescence HRP substrate kit (Thermo Pierce, Cat. No. 15159), histone (Active Motif, Cat. No. 81167), activated DNA (Genscript, Cat. No. L05182-01&02&03), anti-rabbit IgG, HRP-linked Antibody (CST, Cat. No. 7074P2), anti-Poly / Mono-ADP Ribose (E6F6A) Rabbit mAb (CST, Cat. No. 83732S), SuperSignal ELISA Femto Substrate (THERMO PIERCE, Cat. No. 37074), and reference compound AZD5305 were purchased from MedChemExpress (MCE).

[0166] 1.1 PARP1 enzyme assay

[0167] 1.1.1 Buffer preparation: PBST: 1X PBS, 0.05% Tween-20, blocking solution: 1X PBS, 0.05% Tween-20, 5% BSA, reaction buffer: 50 mM Tris-HCl (pH 7.5), 0.005% Tween-20, 0.01% BSA.

[0168] 1.1.2 Coating: Prepare 50 ng / mL Histone coating solution in 1xPBS, transfer 25 μL of the coating solution to a 384-well reaction plate, and coat overnight at 4°C.

[0169] 1.1.3 Washing: After coating, discard the coating solution and wash with PBST solution. Transfer 50uL PBST to a 384-well reaction plate, let it stand for 5 minutes, discard the wash solution, refill the plate, and repeat the washing process three times. Finally, pat the reaction plate dry and wait for the next step of blocking.

[0170] 1.1.4 Blocking: Transfer 50 μL of blocking solution to a 384-well reaction plate and let it stand for 1 hour.

[0171] Washing: After blocking, discard the blocking solution and wash the plate three times with PBST solution according to step 2. Finally, pat the reaction plate dry.

[0172] 1.1.5 Prepare a 1000-fold dilution of the compound, transfer 1 μL of the compound to 199 μL of reaction buffer in a 96-well plate, mix thoroughly, and transfer 5 μL of the mixed compound to a 384-well reaction plate.

[0173] 1.1.6 Prepare a 25 / 10x PARP1-DNA solution using reaction buffer. Transfer 10 μL of PARP1-DNA solution to a 384-well reaction plate. For the negative control wells, transfer 10 μL of DNA solution. The final concentration of PARP1 is 0.02 nM, and the final concentration of DNA is 0.8 nM.

[0174] 1.1.7 Prepare a 25 / 10x NAD+ solution in reaction buffer. Transfer 10 μL of NAD+ solution to a 384-well reaction plate. The final NAD+ concentration is 3.5 μM. Incubate at room temperature for 60 minutes.

[0175] 1.1.8 Prepare a 25 / 10x NAD+ solution in reaction buffer. Transfer 10 μL of NAD+ solution to a 384-well reaction plate. The final NAD+ concentration is 3.5 μM. Incubate at room temperature for 60 minutes.

[0176] 1.1.9 Washing: After the reaction is completed, discard the reaction solution and wash the plate three times with PBST solution according to the method in step 2. Finally, pat the reaction plate dry.

[0177] 1.1.10 Dilute the primary antibody (anti-Poly / Mono-ADP Ribose Rabbit mAb) 2000-fold with blocking buffer, add 20 μL of primary antibody, and incubate at room temperature for 1.5 hours.

[0178] 1.1.11 Washing: Discard the primary antibody and wash the plate three times with PBST solution according to the method in step 2. Finally, pat the reaction plate dry.

[0179] 1.1.12 Dilute the secondary antibody (anti-rabbit IgG, HRP-linked Antibody) 2000-fold with blocking solution, add 20 μL of secondary antibody, and incubate at room temperature for 1 hour.

[0180] 1.1.13 Washing: Discard the secondary antibody and wash the plate three times with PBST solution according to step 2. Finally, pat the reaction plate dry.

[0181] 1.1.14 Color development: Mix Femto-ECL Substrate A and Femto-ECL Substrate B in a 1:1 ratio and transfer 25 μL to a 384-well reaction plate.

[0182] 1.1.15 Reading: Use Envision to read the chemiluminescence value RLU.

[0183] The test results are shown in Table 2 below:

[0184] Table 2 PARP-1 enzyme test results

[0185] Conclusion: The compounds of the present invention have a significant inhibitory effect on PARP1.

[0186] 2. Cell anti-proliferation activity test:

[0187] BRCA-mutant MDA-MB-436 cells were cultured in DMEM medium supplemented with 10% fetal bovine serum, 100 U / mL penicillin, and 100 μg / mL streptomycin at 37°C in a 5% saturated CO2 incubator. When cells reached 80% confluency, they were harvested, centrifuged at 300 g for 10 minutes, and plated at 1200 cells / well in a 96-well plate. After 24 hours, PARPi was added at various final concentrations (0, 0.01, 0.1, 1, 10, 100, and 1000 nM) and cultured for an additional 72 hours. The medium was then replaced (with the same final concentration of PARPi added) and cultured for an additional 96 hours. The 96-well plate was removed and the OD values ​​at a wavelength of 450 nM were measured using the CCK8 assay. The cell inhibition rate was calculated as follows: % inhibition = 1 - (mean OD value of the treatment group - mean OD value of the blank group) / (mean OD value of the control group - mean OD value of the blank group) * 100%.

[0188] BRCA wild-type cells DLD-1 cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum, 100U / mL penicillin, and 100μg / mL streptomycin, and cultured in a 5% saturated CO2 incubator at 37°C. When the cells grew to 80% confluence, the cells were collected, centrifuged at 300g for 10 minutes, and plated on a 96-well plate at 1000 cells / well. After 24 hours, different final concentrations of PARPi (0, 1, 10μM) were added and cultured for 72 hours. The cells were treated with a new medium (PARPi was re-added with the same final concentration) and cultured for 96 hours. The 96-well plate was removed, and the OD value at a wavelength of 450nM was detected by CCK8, and the cell inhibition rate was calculated:

[0189] Inhibition rate %=1-(average OD value of the drug administration group-average OD value of the Blank group) / (average OD value of the Control group-average OD value of the Blank group)*100%.

[0190] The test results are shown in Table 3 below:

[0191] Table 3 Cell antiproliferative activity test results

[0192] Conclusion: The compounds of the present invention have a significant inhibitory effect on BRCA mutant MDA-MB-436 cells, but have no significant inhibitory effect on BRCA wild-type DLD-1 cells, indicating that the compounds of the present invention specifically inhibit homologous recombination-deficient tumor cells.

[0193] 3. Pharmacokinetic evaluation of the compound in Balb / c mice

[0194] Experimental purpose: To understand the pharmacokinetics of the compound.

[0195] Experimental basis: Technical Guidelines for Nonclinical Pharmacokinetic Studies of Chemical Drugs, 2014.

[0196] Experimental plan: The pharmacokinetics of the compound were investigated by intravenous administration (1 mg·kg-1) and oral administration (1 mg·kg-1) to Balb / c mice.

[0197] Sample preparation: weigh about 0.2 mg of the compound, add 10 μL of DMSO to dissolve it, and then add sodium chloride solution for injection to make a 0.1 mg·mL-1 compound solution for administration.

[0198] Sample collection: 6 male Balb / c mice (Chengdu Dashuo Experimental Animal Co., Ltd., license number: SCXK (Chuan) 2020-030), 3 were intravenously administered (IV) at 1 mg·kg-1, and 3 were gavage administered (PO) at 1 mg·kg-1. Approximately 0.05 mL of blood was collected 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 24 h, and 48 h after administration. The collected blood was centrifuged at 3500 rpm for 15 min, the supernatant plasma was collected, and frozen at -40 ° C for testing. The plasma concentration was quantitatively analyzed by LC-MS / MS analysis, and pharmacokinetic parameters such as peak time (Cmax), area under the concentration-time curve (AUC(0-t)), and half-life (T) were calculated. 1 / 2 ), clearance (CL), tissue distribution (Vdss), bioavailability (F), etc.

[0199] The results of the pharmacokinetic evaluation are shown in Table 4 below:

[0200] Table 4 Pharmacokinetic test results of the compounds in Balb / c mice

[0201] Conclusion: The compounds of the present invention have good pharmacokinetic properties in Balb / c mice, including good oral bioavailability, exposure, half-life and clearance. maxOutperformed the reference compound AZD5305.

[0202] 4. Pharmacokinetic evaluation of the compound in SD rats

[0203] Experimental purpose: To understand the pharmacokinetics of the compound.

[0204] Experimental basis: Technical Guidelines for Nonclinical Pharmacokinetic Studies of Chemical Drugs, 2014.

[0205] Experimental plan: The pharmacokinetics of the compound were investigated by oral and intravenous administration in SD rats.

[0206] Experimental Procedure: Weigh the compound, add a small amount of DMSO, and then add sodium chloride solution for injection to prepare a solution for administration. Six male SD rats were administered intravenously and orally. Approximately 0.1 mL of blood was collected 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, and 24 hours after administration. The blood was centrifuged at 3500 rpm for 15 minutes, and the supernatant plasma was collected. 5 μL of plasma was transferred to an EP tube and protein was precipitated by adding 100 μL of acetonitrile containing 20 ng·ml⁻¹ of internal standard SAHA. The solution was vortexed for 30 seconds and centrifuged at 13000 rpm for 15 minutes. The supernatant was transferred to a vial for analysis. The standard curve range is 10 to 10,000 ng·ml⁻¹.

[0207] The results of the pharmacokinetic evaluation are shown in Table 5 below:

[0208] Table 5 Pharmacokinetic test results of the compounds in SD rats

[0209] Conclusion: The compound of the present invention has good pharmacokinetic properties in SD rats, including good oral bioavailability, exposure, half-life and clearance. max and AUC(0-t) were better than those of the reference compound AZD5305.

[0210] 5. Evaluation of PARP enzymatic selectivity

[0211] Table 6 Reagents

[0212] Experimental process:

[0213] (1) Coating histone substrate: 5x histone was diluted to 1x with PARP buffer solution, 25uL per well was coated at 4℃ overnight.

[0214] (2) Add 100uL of PBST to the 384 reaction plate and wash the plate three times, 5 minutes each time.

[0215] (3) Add 25 μL of blocking buffer solution to the 384-well plate and incubate at room temperature for 90 minutes. Add 100 μL of PBST to the 384-well plate and wash three times for 5 minutes each.

[0216] (4) Compound preparation: Add 100 nL of compound to a 384-well reaction plate and centrifuge for 1 minute.

[0217] (5) Add 5uL PARP protein to the 384 reaction plate and centrifuge at 1000rpm for 1 minute.

[0218] (6) Add 5 μL of PARP substrate mixture to a 384-well plate and centrifuge at 1000 rpm for 1 minute. Incubate at room temperature for 1 hour.

[0219] (7) Detection: Add 100 μL of PBST to a 384-well plate and wash the plate three times for 5 minutes each. Dilute Stre-HRP 2000-fold in blocking buffer and add 25 μL to each well. Incubate at room temperature for 30 minutes.

[0220] (8) Add 100uL of PBST to the 384 reaction plate and wash the plate three times for 5 minutes each time. Mix ELISA ECL substrate A and substrate B in a 1:1 ratio and add 25uL to each well of the 384 reaction plate.

[0221] (9) Read the luminescence signal of the compound using a BMG microplate reader.

[0222] The results of the enzyme selectivity experiment are shown in Table 7 below:

[0223] Table 7 Results of the test on the selectivity of compounds for PARP family enzymes

[0224] Conclusion: The compounds of this invention have high inhibitory activity against the PARP-1 enzyme, but weaker inhibitory activity against the same family members PARP-2, PARP-5A, and PARP-11. Compound 2 has superior selectivity for PARP-2 and PARP-5A to that of the reference compound AZD5305, while compound 9 has superior selectivity for PARP-2, PARP-5A, and PARP1 to that of the reference compound AZD5305.

Claims

1. A compound of formula I or a pharmaceutically acceptable form thereof, characterized in that: The structure of Formula I is as follows: in: R1 is selected from halogen, C 1-4 Alkyl, C 1-4 Fluorinated alkyl, C 1-4 Alkoxy, C 1-4 Fluorinated alkoxy, 3- to 6-membered cycloalkyl, or 3- to 6-membered fluorinated cycloalkyl; X1 is selected from N or CR 5a , X2 is selected from N or CR 5b , X3 is selected from N or CR 5c ; R6 is selected from hydrogen or halogen; R4 is -CONHR7, R7 is selected from C 1-4 Alkyl, C 1-4 Fluorinated alkyl, C 1-4 Deuterated alkyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered fluorinated cycloalkyl; R 9a Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Fluorinated alkyl, C 1-4 Alkoxy, C 1-4 Fluorinated alkoxy, 3- to 6-membered cycloalkyl, 3- to 6-membered fluorinated cycloalkyl or cyano; R 9c is selected from hydrogen or halogen; R2 is selected from hydrogen or C 1-4 alkyl; R 5a Selected from hydrogen, halogen or C 1-4 Alkyl, R 5b is selected from hydrogen or halogen, R 5c is selected from hydrogen or halogen; Ring A is selected from The pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled substances, metabolites, or prodrugs.

2. The compound according to claim 1, characterized in that: R1 is selected from chloro, methyl, ethyl, fluoromethyl, fluoroethyl, cyclopropyl or fluorocyclopropyl.

3. The compound according to claim 1, characterized in that: R6 is selected from hydrogen or fluorine.

4. The compound according to claim 1, characterized in that: R7 is selected from methyl, ethyl, deuterated methyl, deuterated ethyl, fluoromethyl, fluoroethyl, cyclopropyl or fluorocyclopropyl.

5. The compound according to claim 1, characterized in that: R 9a is selected from hydrogen, fluorine, chlorine, methyl, ethyl, fluoromethyl, fluoroethyl or cyclopropyl.

6. The compound according to claim 1, characterized in that: R 9c is selected from hydrogen or fluorine.

7. The compound according to claim 1, characterized in that: R2 is selected from hydrogen or methyl.

8. The compound according to claim 1, characterized in that: R 5a is selected from hydrogen, fluorine or methyl, R 5b is selected from hydrogen or fluorine, R 5c is selected from hydrogen or fluorine.

9. The compound according to any one of claims 1 to 8, characterized in that: Structural unit Selected from the following structures:

10. The compound according to any one of claims 1 to 9, characterized in that: Structural unit Selected from the following structures:

11. The compound according to any one of claims 1 to 10, characterized in that: The compound is selected from:

12. The compound according to any one of claims 1 to 10, characterized in that: The compound is selected from:

13. A pharmaceutical composition, characterized in that: The active ingredient is a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite or prodrug thereof, supplemented with a pharmaceutically acceptable carrier.

14. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotope-labeled substance, metabolite or prodrug thereof, and the pharmaceutical composition according to claim 13, are used in the preparation of a medicament for preventing and / or treating PARP1 enzyme-related diseases.

15. The use according to claim 14, characterized in that: The PARP1 enzyme-related disease is a tumor-related disease.

16. The use according to claim 15, characterized in that: The tumor-like disorders are deficient in the HR-dependent DNA DSB repair pathway.

17. The use according to claim 15 or 16, characterized in that: The neoplastic disorder comprises one or more cancer cells that have a reduced or absent ability to repair DNA DSBs by HR relative to normal cells.

18. The use according to claim 17, characterized in that: The cancer cells have a BRCA1 or BRCA2 deficient phenotype.

19. The use according to any one of claims 15 to 18, characterized in that: The tumor-related disease is breast cancer, ovarian cancer, primary peritoneal cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer, glioblastoma or lung cancer.

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